This article references 69 other publications.

1. 1

   Ahern, T. P.; Broe, A.; Lash, T. L.; Cronin-Fenton, D. P.; Ulrichsen, S. P.; Christiansen, P. M.; Cole, B. F.; Tamimi, R. M.; Sorensen, H. T.; Damkier, P. Phthalate Exposure and Breast Cancer Incidence: A Danish Nationwide Cohort Study. J. Clin. Oncol. 2019, 37 (21), 1800– 1809,  DOI: 10.1200/JCO.18.02202IF: 42.1 Q1 B1

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   1

   Phthalate exposure and breast cancer incidence: a danish nationwide cohort study

   Ahern, Thomas P.; Broe, Anne; Lash, Timothy L.; Cronin-Fenton, Deirdre P.; Ulrichsen, Sinna Pilgaard; Christiansen, Peer M.; Cole, Bernard F.; Tamimi, Rulla M.; Soerensen, Henrik Toft; Damkier, Per

   Journal of Clinical Oncology (2019), 37 (21), 1800-1816CODEN: JCONDN; ISSN:1527-7755. (American Society of Clinical Oncology)

   Phthalate exposure is ubiquitous and esp. high among users of drug products formulated with phthalates. Some phthalates mimic estradiol and may promote breast cancer. Existing epidemiol. studies on this topic are small, mostly not prospective, and have given inconsistent results. We estd. assocns. between longitudinal phthalate exposures and breast cancer risk in a Danish nationwide cohort, using redeemed prescriptions for phthalate-contg. drug products to measure exposure. We ascertained the phthalate content of drugs marketed in Denmark using an internal Danish Medicines Agency ingredient database. We enrolled a Danish nationwide cohort of 1.12 million women at risk for a first cancer diagnosis on Jan. 1, 2005. By combining drug ingredient data with the Danish National Prescription registry, we characterized annual, cumulative phthalate exposure through redeemed prescriptions. We then fit multivariable Cox regression models to est. assocns. between phthalate exposures and incident invasive breast carcinoma according to tumor estrogen receptor status. Over 9.99 million woman-years of follow-up, most phthalate exposures were not assocd. with breast cancer incidence. High-level di-Bu phthalate exposure ($ 10,000 cumulative mg) was assocd. with an approx. two-fold increase in the rate of estrogen receptor-pos. breast cancer (hazard ratio, 1.9; 95% CI, 1.1 to 3.5), consistent with in vitro evidence for an estrogenic effect of this compd. Lower levels of di-Bu phthalate exposure were not assocd. with breast cancer incidence. Our results suggest that women should avoid high-level exposure to di-Bu phthalate, such as through long-term treatment with pharmaceuticals formulated with di-Bu phthalate.

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2. 2

   Xu, R.; Bao, Y.; Li, M.; Zhang, Y.; Xi, L.; Guo, J. Computational Insights into the Allosteric Modulation of a Phthalate-Degrading Hydrolase by Distal Mutations. Biomolecules 2023, 13 (3), 443,  DOI: 10.3390/biom13030443IF: 4.8 Q1 B2

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   2

   Computational Insights into the Allosteric Modulation of a Phthalate-Degrading Hydrolase by Distal Mutations

   Xu, Ran; Bao, Yiqiong; Li, Mengrong; Zhang, Yan; Xi, Lili; Guo, Jingjing

   Biomolecules (2023), 13 (3), 443CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)

   Phthalate esters (PAEs) are a ubiquitous kind of environmental endocrine that disrupt chems., causing environmental and health issues. EstJ6 is an effective phthalate-degrading hydrolase, and its mutant with a combination of three non-conservative distal mutations has an improved activity against PAEs with unknown mol. mechanisms. Herein, we attempt to fill the significant gap between distal mutations and the activity of this enzyme using computational approaches. We found that mutations resulted in a redistribution of the enzyme's preexisting conformational states and dynamic changes of key functional regions, esp. the lid over the active site. The outward motion of the lid upon the mutations made it easier for substrates or products to enter or exit. Addnl., a stronger substrate binding affinity and conformational rearrangements of catalytic reaction-assocd. residues in the mutant, accompanied by the strengthened communication within the protein, could synergistically contribute to the elevated catalytic efficiency. Finally, an attempt was made to improve the thermostability of EstJ6 upon introducing a distal disulfide bond between residues A23 and A29, and the simulation results were as expected. Together, our work explored the allosteric effects caused by distal mutations, which could provide insights into the rational design of esterases for industrial applications in the future.

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3. 3

   Viljoen, S. J.; Brailsford, F. L.; Murphy, D. V.; Hoyle, F. C.; Chadwick, D. R.; Jones, D. L. Leaching of phthalate acid esters from plastic mulch films and their degradation in response to UV irradiation and contrasting soil conditions. J. Hazard. Mater. 2023, 443 (Pt B), 130256,  DOI: 10.1016/j.jhazmat.2022.130256IF: 12.2 Q1 B1

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   3

   Leaching of phthalate acid esters from plastic mulch films and their degradation in response to UV irradiation and contrasting soil conditions

   Viljoen, Samantha J.; Brailsford, Francesca L.; Murphy, Daniel V.; Hoyle, Frances C.; Chadwick, David R.; Jones, Davey L.

   Journal of Hazardous Materials (2023), 443 (Part_B), 130256CODEN: JHMAD9; ISSN:0304-3894. (Elsevier B.V.)

   Phthalate acid esters (PAEs) are commonly used plastic additives, not chem. bound to the plastic that migrate into surrounding environments, posing a threat to environmental and human health. Di-Bu phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) are two common PAEs found in agricultural soils, where degrdn. is attributed to microbial decompn. Yet the impact of the plastic matrix on PAE degrdn. rates is poorly understood. Using 14C-labeled DBP and DEHP we show that migration from the plastic matrix into soil represents a key rate limiting step in their bioavailability and subsequent degrdn. Incorporating PAEs into plastic film decreased their degrdn. in soil, DBP (DEHP) from 79% to 21% (9% to <1%), over four months when compared to direct application of PAEs. Mimicking surface soil conditions, we demonstrated that exposure to UV radiation accelerated PAE mineralization twofold. Turnover of PAE was promoted by the addn. of biosolids, while the presence of plants and other org. residues failed to promote degrdn. We conclude that PAEs persist in soil for longer than previously thought due to phys. trapping within the plastic matrix, suggesting PAEs released from plastics over very long time periods lead to increasing levels of contamination.

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4. 4

   Henkel, C.; Lamprecht, J.; Huffer, T.; Hofmann, T. Environmental factors strongly influence the leaching of di(2-ethylhexyl) phthalate from polyvinyl chloride microplastics. Water Res. 2023, 242, 120235,  DOI: 10.1016/j.watres.2023.120235IF: 11.4 Q1 B1

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   Environmental factors strongly influence the leaching of di(2-ethylhexyl) phthalate from polyvinyl chloride microplastics

   Henkel, Charlotte; Lamprecht, Jonas; Hueffer, Thorsten; Hofmann, Thilo

   Water Research (2023), 242 (), 120235CODEN: WATRAG; ISSN:0043-1354. (Elsevier Ltd.)

   Phthalic acid esters (phthalates) are an important group of additives (plasticizers) to ensure the flexibility and stability esp. of polyvinyl chloride (PVC) and to enable its processing. However, phthalates like di(2-ethylhexyl) phthalate (DEHP) are harmful for aquatic organisms due to their endocrine disrupting effects and toxicity. For the assessment of exposure concns., thorough understanding of leaching kinetics of phthalates from PVC (micro-) plastics into aq. environments is necessary. This study investigates how environmental factors influence the leaching of phthalates from PVC microplastics into aquatic systems. The leaching of phthalates from PVC microplastics into aq. media is limited by aq. boundary layer diffusion (ABLD) and thus, process-specific parameters can be affected by environmental factors such as salinity and the flow conditions. We conducted batch leaching expts. to assess the influence of salinity and flow conditions (turbulence) on the leaching of DEHP from PVC microplastics into aq. media. DEHP is salted out with increasing salinity of the soln. and a salting-out coeff. for DEHP of 0.46 was detd. The partitioning coeff. of DEHP between PVC and water KPVC/W increased with increasing salinity from 108.52 L kg-1 in a 1 mM KCl soln. to 108.75 L kg-1 in artificial seawater thereby slowing down leaching. Increasing flow velocities led to higher leaching rates because the ABL thickness decreased from 1315μm at 0 rpm shaking speed (no-flow conditions) to 38.4μm at 125 rpm (turbulent conditions). Compared to salinity, turbulence had a more pronounced effect on leaching. Increasing the flow velocity led to a 35-fold decrease in the leaching rate, while increasing salinity led to a 2-fold increase. By calcg. specific leaching times, i.e., leaching half-lives (t1/2), time frames for leaching in different aquatic systems such as rivers and the ocean were detd. Given ABLD-limited leaching, DEHP is leached faster from PVC microplastics in rivers (t1/2 > 49 years) than in the ocean (t1/2 > 398 years). In both systems, PVC microplastics are a long-term source of phthalates.

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5. 5

   Yuan, L.; Cheng, J.; Wang, Y.; Liu, Y.; Wang, W.; Gao, R.; Yu, X. Uptake and toxicity of di-(2-ethylhexyl) phthalate in Brassica chinensis L. Chemosphere 2020, 252, 126640,  DOI: 10.1016/j.chemosphere.2020.126640IF: 8.1 Q1 B2

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   5

   Uptake and toxicity of di-(2-ethylhexyl) phthalate in Brassica chinensis L

   Yuan, Li; Cheng, Jinjin; Wang, Ya; Liu, Yan-ai; Wang, Wenfeng; Gao, Ruichang; Yu, Xiangyang

   Chemosphere (2020), 252 (), 126640CODEN: CMSHAF; ISSN:0045-6535. (Elsevier Ltd.)

   This work focuses on the bioaccumulation and toxic effects of di-(2-ethylhexyl) phthalate (DEHP) in the leafy vegetable Shanghaiqing (SHQ) (Brassica chinensis L.). The accumulated DEHP amt. in the edible part and roots of SHQ increased as the DEHP concn. in the soil increased. DEHP accumulation was higher in the roots than in the edible part of the plant. The root concn. factors and bioaccumulation factors for DEHP in SHQ were 0.13-2.49 and 0.03-2.00, resp. The DEHP translocation factors were below 1.0, indicating that DEHP preferentially accumulated in plant roots. The DEHP risk index in the edible part of SHQ in relation to the human body and in terms of dietary exposure risk assessment was also below 1.0, indicating a low health risk. High DEHP concns. caused (1) inhibition of SHQ growth, (2) an increase in SHQ chlorophyll and malondialdehyde contents and (3) a decrease in sol. sugar and vitamin contents. Low DEHP concns. stimulated total superoxide dismutase, peroxidase and catalase activities, while high DEHP levels showed an inhibitory effect. DEHP presence in soil affected not only SHQ growth but also quality. Our results provide the data needed for the proper assessment of food safety and the ecol. impact of DEHP contamination in agricultural soils.

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6. 6

   Fu, X.; Du, Q. Uptake of di-(2-ethylhexyl) phthalate of vegetables from plastic film greenhouses. J. Agric. Food Chem. 2011, 59 (21), 11585– 11588,  DOI: 10.1021/jf203502eIF: 5.7 Q1 B1

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   Uptake of di-(2-ethylhexyl) phthalate of vegetables from plastic film greenhouses

   Fu, Xiao-Wei; Du, Qi-Zhen

   Journal of Agricultural and Food Chemistry (2011), 59 (21), 11585-11588CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)

   Uptake of di-(2-ethylhexyl) phthalate (DEHP) of nine vegetables including potherb mustard, bok choy, celery, spinach, cabbage, leaf of tube, lettuce, garlic, and edible amaranth in plastic film greenhouses with different plastic films, film thickness, greenhouse age, and greenhouse height was studied. The results showed that the higher the DEHP content of film, the thicker the film, the lower the height of the greenhouse, and the younger the age of the greenhouse were, the higher the DEHP concn. of vegetables was. The results afford significant information for prodn. of safe vegetables with low level DEHP contamination.

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7. 7

   Zeng, F.; Cui, K.; Xie, Z.; Wu, L.; Liu, M.; Sun, G.; Lin, Y.; Luo, D.; Zeng, Z. Phthalate esters (PAEs): emerging organic contaminants in agricultural soils in peri-urban areas around Guangzhou, China. Environ. Pollut. 2008, 156 (2), 425– 434,  DOI: 10.1016/j.envpol.2008.01.045IF: 7.6 Q1 B2

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   Phthalate esters (PAEs): Emerging organic contaminants in agricultural soils in peri-urban areas around Guangzhou, China

   Zeng, Feng; Cui, Kunyan; Xie, Zhiyong; Wu, Lina; Liu, Min; Sun, Guoquan; Lin, Yujun; Luo, Danling; Zeng, Zunxiang

   Environmental Pollution (Oxford, United Kingdom) (2008), 156 (2), 425-434CODEN: ENPOEK; ISSN:0269-7491. (Elsevier Ltd.)

   This study reports the first data on the concns. and distribution of phthalate esters (PAEs) in the agricultural soils from the peri-urban areas of Guangzhou city. Σ16PAEs concns. ranged from 0.195 to 33.6 μg g-1-dry wt. (dw). Elevated levels of PAEs were recorded in the vegetable fields located next to the urban districts, and a decreasing trend exists following the distance away from the urban center. Diisobutyl phthalate (DiBP), Di-Bu phthalate (DnBP), and Di(2-ethylhexyl) phthalate (DEHP) dominated the PAEs in the agricultural soils. Significant relationship (correlation coeff. R 2 = 0.85, p <0.01, n = 40) was present between the accumulation of PAEs and total org. carbons in agricultural soils. In addn., both pH and texture of soils are found to be important factors affecting the level of PAEs. This study shows that the agricultural soils in the peri-urban area of Guangzhou city were moderately polluted by PAEs. PAEs are detd. in agricultural soils at high concn. levels, which imply a potential risk for the food chain.

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8. 8

   IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Some chemicals present in industrial and consumer products, food and drinking-water. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans , 2013; Vol. 101, pp 9– 549.

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9. 9

   Zhao, Y.; Zhang, H.; Cui, J. G.; Wang, J. X.; Chen, M. S.; Wang, H. R.; Li, X. N.; Li, J. L. Ferroptosis is critical for phthalates driving the blood-testis barrier dysfunction via targeting transferrin receptor. Redox Biol. 2023, 59, 102584,  DOI: 10.1016/j.redox.2022.102584IF: 10.7 Q1 B1

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   Ferroptosis is critical for phthalates driving the blood-testis barrier dysfunction via targeting transferrin receptor

   Zhao, Yi; Zhang, Hao; Cui, Jia-Gen; Wang, Jia-Xin; Chen, Ming-Shan; Wang, Hao-Ran; Li, Xue-Nan; Li, Jin-Long

   Redox Biology (2023), 59 (), 102584CODEN: RBEIB3; ISSN:2213-2317. (Elsevier B.V.)

   The global rate of human male infertility is rising at an alarming rate owing to environmental and lifestyle changes. Phthalates are the most hazardous chem. additives in plastics and have an apparently neg. impact on the function of male reproductive system. Ferroptosis is a recently described form of iron-dependent cell death and has been linked to several diseases. Transferrin receptor (TfRC), a specific ferroptosis marker, is a universal iron importer for all cells using extracellular transferrin. We aim to investigate the potential involvement of ferroptosis during male reproductive toxicity, and provide means for drawing conclusions on the effect of ferroptosis in phthalates-induced male reproductive disease. In this study, we found that di (2-ethylhexyl) phthalate (DEHP) triggered blood-testis barrier (BTB) dysfunction in the mouse testicular tissues. DEHP also induced mitochondrial morphol. changes and lipid peroxidn., which are manifestations of ferroptosis. As the primary metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP) induced ferroptosis by inhibiting glutathione defense network and increasing lipid peroxidn. TfRC knockdown blocked MEHP-induced ferroptosis by decreasing mitochondrial and intracellular levels of Fe2+. Our findings indicate that TfRC can regulate Sertoli cell ferroptosis and therefore is a novel therapeutic mol. for reproductive disorders in male patients with infertility.

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10. 10

    Zhao, Y.; Cui, J. G.; Zhang, H.; Li, X. N.; Li, M. Z.; Talukder, M.; Li, J. L. Role of mitochondria-endoplasmic reticulum coupling in lycopene preventing DEHP-induced hepatotoxicity. Food Funct. 2021, 12 (21), 10741– 10749,  DOI: 10.1039/D1FO00478FIF: 5.1 Q1 B1

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    10

    Role of mitochondria-endoplasmic reticulum coupling in lycopene preventing DEHP-induced hepatotoxicity

    Zhao, Yi; Cui, Jia-Gen; Zhang, Hao; Li, Xue-Nan; Li, Mu-Zi; Talukder, Milton; Li, Jin-Long

    Food & Function (2021), 12 (21), 10741-10749CODEN: FFOUAI; ISSN:2042-6496. (Royal Society of Chemistry)

    Di (2-ethylhexyl) phthalate (DEHP) is a hazardous compd. used as a plasticizer in plastic products. As a natural carotenoid, lycopene (LYC) is considered an effective protective agent against various types of organ damage. The present study aimed to investigate the role of mitochondria-endoplasmic reticulum (ER) coupling in LYC preventing DEHP-induced hepatotoxicity. The mice were treated with LYC (5 mg kg-1) and/or DEHP (500 or 1000 mg kg-1). In the present study, LYC prevented DEHP-induced histopathol. changes including fibrosis and glycogen storage in the liver. Addnl., LYC alleviated DEHP-induced ultrastructural injury of mitochondria and ER. LYC had the underlying preventability against DEHP-induced mitochondrial dynamics imbalance including an increase in fission and a decrease in fusion. Furthermore, DEHP induced mitochondria-assocd. endoplasmic reticulum membrane (MAM) disorder-induced ER stress through the ER unfolded protein response (UPRER), but LYC alleviated these alterations. Therefore, LYC prevented DEHP-induced hepatic mitochondrial dynamics and MAM disorder, leading to ER stress. The present study provides novel evidence of mitochondria-ER coupling as a target for LYC that prevents DEHP-induced hepatotoxicity.

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11. 11

    Zhao, Y.; Cui, L. G.; Talukder, M.; Cui, J. G.; Zhang, H.; Li, J. L. Lycopene prevents DEHP-induced testicular endoplasmic reticulum stress via regulating nuclear xenobiotic receptors and unfolded protein response in mice. Food Funct. 2021, 12 (24), 12256– 12264,  DOI: 10.1039/D1FO02729HIF: 5.1 Q1 B1

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    11

    Lycopene prevents DEHP-induced testicular endoplasmic reticulum stress via regulating nuclear xenobiotic receptors and unfolded protein response in mice

    Zhao, Yi; Cui, Ling-Ge; Talukder, Milton; Cui, Jia-Gen; Zhang, Hao; Li, Jin-Long

    Food & Function (2021), 12 (24), 12256-12264CODEN: FFOUAI; ISSN:2042-6496. (Royal Society of Chemistry)

    Lycopene (LYC) is a potent antioxidant synthesized by red vegetables or plants. Di-2-ethylhexyl phthalate (DEHP) is frequently detected in diverse agricultural environments and considered as a reproductive toxicant. The present research was designed to assess the potential mechanisms of DEHP-induced testicular toxicity and the treatment efficacy of LYC. In this study, after the oral administration of LYC at the dose of 5 mg per kg b.w. per day, mice were given 500 or 1000 mg per kg b.w. per day of DEHP. This research suggested that LYC prevented the DEHP-induced disorder at the levels of activity and content of CYP450 enzymes. LYC attenuated DEHP-caused enhancement in nuclear xenobiotic receptors (NXRs) and the phase I metabolizing enzymes (CYP1, CYP2, CYP3, etc.) levels. Furthermore, endoplasmic reticulum (ER) stress was induced by DEHP and triggered unfolded protein response (UPR). Interestingly, LYC could effectively ameliorate these "hit". The present study suggested that LYC prevents DEHP-induced ER stress in testis via regulating NXRs and UPRER.

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12. 12

    Wu, H.; Chen, W.; Chen, Z.; Li, X.; Wang, M. Novel tumor therapy strategies targeting endoplasmic reticulum-mitochondria signal pathways. Ageing Res. Rev. 2023, 88, 101951,  DOI: 10.1016/j.arr.2023.101951IF: 12.5 Q1 B1

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    12

    Novel tumor therapy strategies targeting endoplasmic reticulum-mitochondria signal pathways

    Wu, Hongzheng; Chen, Wanxin; Chen, Zhenni; Li, Xianping; Wang, Min

    Ageing Research Reviews (2023), 88 (), 101951CODEN: ARRGAK; ISSN:1568-1637. (Elsevier B.V.)

    A Review. Organelles form tight connections through membrane contact sites, thereby cooperating to regulate homeostasis and cell function. Among them, the contact between endoplasmic reticulum (ER), the main intracellular calcium storage organelles, and mitochondria has been recognized for decades, and its main roles in the ion and lipid transport, ROS signaling, membrane dynamic changes and cellular metab. are basically detd. At present, many tumor chemotherapeutic drugs rely on ER-mitochondrial calcium signal to function, but the mechanism of targeting resident mols. at the mitochondria-assocd. endoplasmic reticulum membranes (MAM) to sensitize traditional chemotherapy and the new tumor therapeutic targets identified based on the signal pathways on the MAM have not been thoroughly discussed. In this review, we highlight the key roles of various signaling pathways at the ER-mitochondria contact site in tumorigenesis and focus on novel anticancer therapy strategies targeting potential targets at this contact site.

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13. 13

    Cho, E.; Woo, Y.; Suh, Y.; Suh, B. K.; Kim, S. J.; Nhung, T. T. M.; Yoo, J. Y.; Nghi, T. D.; Lee, S. B.; Mun, D. J.; Park, S. K. Ratiometric measurement of MAM Ca(2+) dynamics using a modified CalfluxVTN. Nat. Commun. 2023, 14 (1), 3586,  DOI: 10.1038/s41467-023-39343-2IF: 14.7 Q1 B1

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    13

    Ratiometric measurement of MAM Ca2+ dynamics using a modified CalfluxVTN

    Cho, Eunbyul; Woo, Youngsik; Suh, Yeongjun; Suh, Bo Kyoung; Kim, Soo Jeong; Nhung, Truong Thi My; Yoo, Jin Yeong; Nghi, Tran Diem; Lee, Su Been; Mun, Dong Jin; Park, Sang Ki

    Nature Communications (2023), 14 (1), 3586CODEN: NCAOBW; ISSN:2041-1723. (Nature Portfolio)

    Mitochondria-assocd. ER membrane (MAM) is a structure where these calcium-regulating organelles form close phys. contact sites for efficient Ca2+ crosstalk. Despite the central importance of MAM Ca2+ dynamics in diverse biol. processes, directly and specifically measuring Ca2+ concns. inside MAM is tech. challenging. Here, we develop MAM-Calflux, a MAM-specific BRET-based Ca2+ indicator. The successful application of the bimol. fluorescence complementation (BiFC) concept highlights Ca2+-responsive BRET signals in MAM. The BiFC strategy imparts dual functionality as a Ca2+ indicator and quant. structural marker specific for MAM. As a ratiometric Ca2+ indicator, MAM-Calflux ests. steady-state MAM Ca2+ levels. Finally, it enables the visualization of uneven intracellular distribution of MAM Ca2+ and the elucidation of abnormally accumulated MAM Ca2+ from the neurons of Parkinson's disease mouse model in both steady-state and stimulated conditions. Therefore, we propose that MAM-Calflux can be a versatile tool for ratiometrically measuring dynamic inter-organellar Ca2+ communication.

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14. 14

    Lee, H. J.; Jung, Y. H.; Choi, G. E.; Kim, J. S.; Chae, C. W.; Lim, J. R.; Kim, S. Y.; Yoon, J. H.; Cho, J. H.; Lee, S. J.; Han, H. J. Urolithin A suppresses high glucose-induced neuronal amyloidogenesis by modulating TGM2-dependent ER-mitochondria contacts and calcium homeostasis. Cell Death Differ. 2021, 28 (1), 184– 202,  DOI: 10.1038/s41418-020-0593-1IF: 13.7 Q1 B1

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    14

    Urolithin A suppresses high glucose-induced neuronal amyloidogenesis by modulating TGM2-dependent ER-mitochondria contacts and calcium homeostasis

    Lee, Hyun Jik; Jung, Young Hyun; Choi, Gee Euhn; Kim, Jun Sung; Chae, Chang Woo; Lim, Jae Ryong; Kim, Seo Yihl; Yoon, Jee Hyeon; Cho, Ji Hyeon; Lee, Sei-Jung; Han, Ho Jae

    Cell Death & Differentiation (2021), 28 (1), 184-202CODEN: CDDIEK; ISSN:1350-9047. (Nature Research)

    Abstr.:Here, we investigated the effect of urolithin A on high glucose-induced amyloidogenesis caused by mitochondrial calcium dysregulation and mtROS accumulation resulting in neuronal degeneration. We also identified the mechanism related to mitochondria-assocd. ER membrane (MAM) formation. We found that urolithin A-lowered mitochondrial calcium influx significantly alleviated high glucose-induced mtROS accumulation and expression of amyloid beta (Aβ)-producing enzymes, such as amyloid precursor protein (APP) and β-secretase-1 (BACE1), as well as Aβ prodn. Urolithin A injections in a streptozotocin (STZ)-induced diabetic mouse model alleviated APP and BACE1 expressions, Tau phosphorylation, Aβ deposition, and cognitive impairment. In addn., high glucose stimulated MAM formation and transglutaminase type 2 (TGM2) expression. In addn., disruption of the AIP-AhR complex was involved in urolithin A-mediated suppression of high glucose-induced TGM2 expression. Markedly, TGM2 silencing inhibited inositol 1, 4, 5-trisphosphate receptor type 1 (IP3R1)-voltage-dependent anion-selective channel protein 1 (VDAC1) interactions and prevented high glucose-induced mitochondrial calcium influx and mtROS accumulation. In conclusion, we suggest that urolithin A is a promising candidate for the development of therapies to prevent DM-assocd. AD pathogenesis by reducing TGM2-dependent MAM formation and maintaining mitochondrial calcium and ROS homeostasis.

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15. 15

    Eysert, F.; Kinoshita, P. F.; Mary, A.; Vaillant-Beuchot, L.; Checler, F.; Chami, M. Molecular Dysfunctions of Mitochondria-Associated Membranes (MAMs) in Alzheimer’s Disease. Int. J. Mol. Sci. 2020, 21 (24), 9521,  DOI: 10.3390/ijms21249521IF: 4.9 Q1 B2

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    15

    Molecular dysfunctions of mitochondria-associated membranes (MAMs) in Alzheimer's disease

    Eysert, Fanny; Kinoshita, Paula Fernanda; Mary, Arnaud; Vaillant-Beuchot, Loan; Checler, Frederic; Chami, Mounia

    International Journal of Molecular Sciences (2020), 21 (24), 9521CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)

    A review. Alzheimer's disease (AD) is a multifactorial neurodegenerative pathol. characterized by a progressive decline of cognitive functions. Alteration of various signaling cascades affecting distinct subcellular compartment functions and their communication likely contribute to AD progression. Among others, the alteration of the phys. assocn. between the endoplasmic reticulum (ER) and mitochondria, also reffered as mitochondria-assocd. membranes (MAMs), impacts various cellular housekeeping functions such as phospholipids-, glucose-, cholesterol-, and fatty-acid-metab., as well as calcium signaling, which are all altered in AD. Our review describes the phys. and functional proteome crosstalk between the ER and mitochondria and highlights the contribution of distinct mol. components of MAMs to mitochondrial and ER dysfunctions in AD progression. We also discuss potential strategies targeting MAMs to improve mitochondria and ER functions in AD.

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16. 16

    Paillusson, S.; Stoica, R.; Gomez-Suaga, P.; Lau, D. H. W.; Mueller, S.; Miller, T.; Miller, C. C. J. There’s Something Wrong with my MAM; the ER-Mitochondria Axis and Neurodegenerative Diseases. Trends Neurosci. 2016, 39 (3), 146– 157,  DOI: 10.1016/j.tins.2016.01.008IF: 14.6 Q1 B1

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    16

    There's Something Wrong with my MAM; the ER-Mitochondria Axis and Neurodegenerative Diseases

    Paillusson, Sebastien; Stoica, Radu; Gomez-Suaga, Patricia; Lau, Dawn H. W.; Mueller, Sarah; Miller, Tanya; Miller, Christopher C. J.

    Trends in Neurosciences (2016), 39 (3), 146-157CODEN: TNSCDR; ISSN:0166-2236. (Elsevier Ltd.)

    Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis with assocd. frontotemporal dementia (ALS/FTD) are major neurodegenerative diseases for which there are no cures. All are characterised by damage to several seemingly disparate cellular processes. The broad nature of this damage makes understanding pathogenic mechanisms and devising new treatments difficult. Can the different damaged functions be linked together in a common disease pathway and which damaged function should be targeted for therapy. Many functions damaged in neurodegenerative diseases are regulated by communications that mitochondria make with a specialised region of the endoplasmic reticulum (ER; mitochondria-assocd. ER membranes or 'MAM'). Moreover, several recent studies have shown that disturbances to ER-mitochondria contacts occur in neurodegenerative diseases. Here, we review these findings.

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17. 17

    Chen, X.; Cubillos-Ruiz, J. R. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat. Rev. Cancer 2021, 21 (2), 71– 88,  DOI: 10.1038/s41568-020-00312-2IF: 72.5 Q1 B1

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    17

    Endoplasmic reticulum stress signals in the tumour and its microenvironment

    Chen, Xi; Cubillos-Ruiz, Juan R.

    Nature Reviews Cancer (2021), 21 (2), 71-88CODEN: NRCAC4; ISSN:1474-175X. (Nature Research)

    Abstr.: Protein handling, modification and folding in the endoplasmic reticulum (ER) are tightly regulated processes that det. cell function, fate and survival. In several tumor types, diverse oncogenic, transcriptional and metabolic abnormalities cooperate to generate hostile microenvironments that disrupt ER homeostasis in malignant and stromal cells, as well as infiltrating leukocytes. These changes provoke a state of persistent ER stress that has been demonstrated to govern multiple pro-tumoral attributes in the cancer cell while dynamically reprogramming the function of innate and adaptive immune cells. Aberrant activation of ER stress sensors and their downstream signalling pathways have therefore emerged as key regulators of tumor growth and metastasis as well as response to chemotherapy, targeted therapies and immunotherapy. In this Review, we discuss the physiol. inducers of ER stress in the tumor milieu, the interplay between oncogenic signalling and ER stress response pathways in the cancer cell and the profound immunomodulatory effects of sustained ER stress responses in tumors.

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18. 18

    Roussel, B. D.; Kruppa, A. J.; Miranda, E.; Crowther, D. C.; Lomas, D. A.; Marciniak, S. J. Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol. 2013, 12 (1), 105– 118,  DOI: 10.1016/S1474-4422(12)70238-7IF: 46.5 Q1 B1

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    18

    Endoplasmic reticulum dysfunction in neurological disease

    Roussel, Benoit D.; Kruppa, Antonina J.; Miranda, Elena; Crowther, Damian C.; Lomas, David A.; Marciniak, Stefan J.

    Lancet Neurology (2013), 12 (1), 105-118CODEN: LNAEAM; ISSN:1474-4422. (Elsevier Ltd.)

    A review. Summary: Endoplasmic reticulum (ER) dysfunction might have an important part to play in a range of neurol. disorders, including cerebral ischemia, sleep apnoea, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, the prion diseases, and familial encephalopathy with neuroserpin inclusion bodies. Protein misfolding in the ER initiates the well studied unfolded protein response in energy-starved neurons during stroke, which is relevant to the toxic effects of reperfusion. The toxic peptide amyloid β induces ER stress in Alzheimer's disease, which leads to activation of similar pathways, whereas the accumulation of polymeric neuroserpin in the neuronal ER triggers a poorly understood ER-overload response. In other neurol. disorders, such as Parkinson's and Huntington's diseases, ER dysfunction is well recognized but the mechanisms by which it contributes to pathogenesis remain unclear. By targeting components of these signalling responses, amelioration of their toxic effects and so the treatment of a range of neurodegenerative disorders might become possible.

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19. 19

    Burillo, J.; Marques, P.; Jimenez, B.; Gonzalez-Blanco, C.; Benito, M.; Guillen, C. Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease. Cells 2021, 10 (5), 1236,  DOI: 10.3390/cells10051236IF: 5.1 Q2 B2

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    19

    Insulin resistance and diabetes mellitus in Alzheimer's disease

    Burillo, Jesus; Marques, Patricia; Jimenez, Beatriz; Gonzalez-Blanco, Carlos; Benito, Manuel; Guillen, Carlos

    Cells (2021), 10 (5), 1236CODEN: CELLC6; ISSN:2073-4409. (MDPI AG)

    Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main mol. mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer's disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction.

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20. 20

    Kraus, F.; Roy, K.; Pucadyil, T. J.; Ryan, M. T. Function and regulation of the divisome for mitochondrial fission. Nature 2021, 590 (7844), 57– 66,  DOI: 10.1038/s41586-021-03214-xIF: 50.5 Q1 B1

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    20

    Function and regulation of the divisome for mitochondrial fission

    Kraus, Felix; Roy, Krishnendu; Pucadyil, Thomas J.; Ryan, Michael T.

    Nature (London, United Kingdom) (2021), 590 (7844), 57-66CODEN: NATUAS; ISSN:0028-0836. (Nature Research)

    Abstr.: Mitochondria form dynamic networks in the cell that are balanced by the flux of iterative fusion and fission events of the organelles. It is now appreciated that mitochondrial fission also represents an end-point event in a signalling axis that allows cells to sense and respond to external cues. The fission process is orchestrated by membrane-assocd. adaptors, influenced by organellar and cytoskeletal interactions and ultimately executed by the dynamin-like GTPase DRP1. Here we invoke the framework of the 'mitochondrial divisome', which is conceptually and operationally similar to the bacterial cell-division machinery. We review the functional and regulatory aspects of the mitochondrial divisome and, within this framework, parse the core from the accessory machinery. In so doing, we transition from a phenomenol. to a mechanistic understanding of the fission process.

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21. 21

    Shim, M. S.; Takihara, Y.; Kim, K. Y.; Iwata, T.; Yue, B. Y.; Inatani, M.; Weinreb, R. N.; Perkins, G. A.; Ju, W. K. Mitochondrial pathogenic mechanism and degradation in optineurin E50K mutation-mediated retinal ganglion cell degeneration. Sci. Rep. 2016, 6, 33830,  DOI: 10.1038/srep33830IF: 3.8 Q1 B2

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    21

    Mitochondrial pathogenic mechanism and degradation in optineurin E50K mutation-mediated retinal ganglion cell degeneration

    Shim, Myoung Sup; Takihara, Yuji; Kim, Keun-Young; Iwata, Takeshi; Yue, Beatrice Y. J. T.; Inatani, Masaru; Weinreb, Robert N.; Perkins, Guy A.; Ju, Won-Kyu

    Scientific Reports (2016), 6 (), 33830CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)

    Mutations in optineurin (OPTN) are linked to the pathol. of primary open angle glaucoma (POAG) and amyotrophic lateral sclerosis. Emerging evidence indicates that OPTN mutation is involved in accumulation of damaged mitochondria and defective mitophagy. Nevertheless, the role played by an OPTN E50K mutation in the pathogenic mitochondrial mechanism that underlies retinal ganglion cell (RGC) degeneration in POAG remains unknown. We show here that E50K expression induces mitochondrial fission-mediated mitochondrial degrdn. and mitophagy in the axons of the glial lamina of aged E50K-tg mice in vivo. While E50K activates the Bax pathway and oxidative stress, and triggers dynamics alteration-mediated mitochondrial degrdn. and mitophagy in RGC somas in vitro, it does not affect transport dynamics and fission of mitochondria in RGC axons in vitro. These results strongly suggest that E50K is assocd. with mitochondrial dysfunction in RGC degeneration in synergy with environmental factors such as aging and/or oxidative stress.

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22. 22

    Hu, Y.; Chen, H.; Zhang, L.; Lin, X.; Li, X.; Zhuang, H.; Fan, H.; Meng, T.; He, Z.; Huang, H.; Gong, Q.; Zhu, D.; Xu, Y.; He, P.; Li, L.; Feng, D. The AMPK-MFN2 axis regulates MAM dynamics and autophagy induced by energy stresses. Autophagy 2021, 17 (5), 1142– 1156,  DOI: 10.1080/15548627.2020.1749490IF: 14.6 Q1 B1

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    22

    The AMPK-MFN2 axis regulates MAM dynamics and autophagy induced by energy stresses

    Hu, Yongquan; Chen, Hao; Zhang, Luying; Lin, Xiaoying; Li, Xia; Zhuang, Haixia; Fan, Hualin; Meng, Tian; He, Zhengjie; Huang, Haofeng; Gong, Qing; Zhu, Dongxing; Xu, Yiming; He, Pengcheng; Li, Longxuan; Feng, Du

    Autophagy (2021), 17 (5), 1142-1156CODEN: AUTOC9; ISSN:1554-8635. (Taylor & Francis Ltd.)

    Energy deprivation activates the cellular energy sensor AMP-activated protein kinase (AMPK), which in turn induces macroautophagy/autophagy. The mitochondrial-assocd. ER membrane (MAM) plays a key role in mitochondrial division and autophagy, and the mitochondrial fusion protein MFN2 (mitofusin 2) tethers the MAM, but the mechanism by which AMPK and MFN2 regulate autophagy in response to energy stress remains unclear. Here, we found that energy stress not only triggers mitochondrial fission and autophagy, but more importantly increases the no. of MAMs, a process that requires AMPK. Interestingly, under energy stress, considerable amts. of AMPK translocate from cytosol to the MAM and the mitochondrion as mitochondrial fission occurs. Unexpectedly, AMPK interacts directly with MFN2. The autophagic ability of mouse embryonic fibroblasts (MEFs) lacking MFN2 (mfn2-/-) is significantly attenuated in response to energy stress as compared to wild-type MEFs (WT MEFs), while re-expression of MFN2 in mfn2-/- cells rescues the autophagy defects of these cells. The abundance of MAMs is also greatly reduced in MFN2-deficient cells. Functional expts. show that the oxygen consumption rate and the glycolytic function of cells lacking MFN2 but not MFN1 are obviously attenuated, and MFN2 is important for cell survival under energy stress. In conclusion, our study establishes the mol. link between the energy sensor AMPK and the MAM tether MFN2, and reveals the important role of AMPK and MFN2 in energy stress-induced autophagy and MAM dynamics. ACTB, actin beta; AMPK, AMP-activated protein kinase; BECN1, beclin 1; CANX, calnexin; ER, endoplasmic reticulum; HRP, horseradish peroxidase; EM, electron microscopy; FL, full-length; KD, kinase dead, KO, knockout; MAb, monoclonal antibody; MAMs, mitochondria-assocd. membranes; MAP1LC3/LC3B, microtubule assocd. protein 1 light chain 3; MFN2, mitofusin 2; OPA1, OPA1 mitochondrial dynamin like GTPase; PAb, polyclonal antibody; PtdIns3K, class III phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol 3-phosphate; SD, std. deviation; TEM, transmission electron microscopy; TOMM20, translocase of outer mitochondrial membrane 20; ULK1, unc-51 like autophagy activating kinase 1; MEF, mouse embryonic fibroblast; WT, wildtype.

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23. 23

    Cao, Y.; Chen, Z.; Hu, J.; Feng, J.; Zhu, Z.; Fan, Y.; Lin, Q.; Ding, G. Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway. Front. Cell Dev. Biol. 2021, 9, 769213,  DOI: 10.3389/fcell.2021.769213IF: 4.6 Q1 B2

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    23

    Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway

    Cao Yun; Chen Zhaowei; Hu Jijia; Feng Jun; Zhu Zijing; Fan Yanqin; Lin Qiaoxuan; Ding Guohua; Cao Yun; Chen Zhaowei; Hu Jijia; Feng Jun; Zhu Zijing; Fan Yanqin; Lin Qiaoxuan; Ding Guohua

    Frontiers in cell and developmental biology (2021), 9 (), 769213 ISSN:2296-634X.

    The endoplasmic reticulum (ER) stress and mitochondrial dysfunction in high glucose (HG)-induced podocyte injury have been demonstrated to the progression of diabetic kidney disease (DKD). However, the pathological mechanisms remain equivocal. Mitofusin2 (Mfn2) was initially identified as a dynamin-like protein involved in fusing the outer mitochondrial membrane (OMM). More recently, Mfn2 has been reported to be located at the ER membranes that contact OMM. Mitochondria-associated ER membranes (MAMs) is the intercellular membrane subdomain, which connects the mitochondria and ER through a proteinaceous tether. Here, we observed the suppression of Mfn2 expression in the glomeruli and glomerular podocytes of patients with DKD. Streptozotocin (STZ)-induced diabetic rats exhibited abnormal mitochondrial morphology and MAMs reduction in podocytes, accompanied by decreased expression of Mfn2 and activation of all three unfolded protein response (UPR) pathways (IRE1, ATF6, and PERK). The HG-induced mitochondrial dysfunction, MAMs reduction, and increased apoptosis in vitro were accompanied by the downregulation of Mfn2 and activation of the PERK pathway. Mfn2 physically interacts with PERK, and HG promotes a decrease in Mfn2-PERK interaction. In addition, Mfn2-silenced podocytes showed mitochondrial dysfunction, MAMs reduction, activation of PERK pathway, and increased apoptosis. Conversely, all these effects of HG stimulation were alleviated significantly by Mfn2 overexpression. Furthermore, the inhibition of PERK phosphorylation protected mitochondrial functions but did not affect the expression of Mfn2 in HG-treated podocytes. Therefore, this study confirmed that Mfn2 regulates the morphology and functions of MAMs and mitochondria, and exerts anti-apoptotic effects on podocytes by inhibiting the PERK pathway. Hence, the Mfn2-PERK signaling pathway may be a new therapeutic target for preventing podocyte injury in DKD.

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24. 24

    Verfaillie, T.; Rubio, N.; Garg, A. D.; Bultynck, G.; Rizzuto, R.; Decuypere, J. P.; Piette, J.; Linehan, C.; Gupta, S.; Samali, A.; Agostinis, P. PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ. 2012, 19 (11), 1880– 1891,  DOI: 10.1038/cdd.2012.74IF: 13.7 Q1 B1

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    24

    PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress

    Verfaillie, T.; Rubio, N.; Garg, A. D.; Bultynck, G.; Rizzuto, R.; Decuypere, J.-P.; Piette, J.; Linehan, C.; Gupta, S.; Samali, A.; Agostinis, P.

    Cell Death & Differentiation (2012), 19 (11), 1880-1891CODEN: CDDIEK; ISSN:1350-9047. (Nature Publishing Group)

    Endoplasmic reticulum stress is emerging as an important modulator of different pathologies and as a mechanism contributing to cancer cell death in response to therapeutic agents. In several instances, oxidative stress and the onset of endoplasmic reticulum (ER) stress occur together; yet, the mol. events linking reactive oxygen species (ROS) to ER stress-mediated apoptosis are currently unknown. Here, we show that PERK (RNA-dependent protein kinase (PKR)-like ER kinase), a key ER stress sensor of the unfolded protein response, is uniquely enriched at the mitochondria-assocd. ER membranes (MAMs). PERK-/- cells display disturbed ER morphol. and Ca2+ signaling as well as significantly weaker ER-mitochondria contact sites. Re-expression of a kinase-dead PERK mutant but not the cytoplasmic deletion mutant of PERK in PERK-/- cells re-establishes ER-mitochondria juxtapositions and mitochondrial sensitization to ROS-mediated stress. In contrast to the canonical ER stressor thapsigargin, during ROS-mediated ER stress, PERK contributes to apoptosis twofold by sustaining the levels of pro-apoptotic C/EBP homologous protein (CHOP) and by facilitating the propagation of ROS signals between the ER and mitochondria through its tethering function. Hence, this study reveals an unprecedented role of PERK as a MAMs component required to maintain the ER-mitochondria juxtapositions and propel ROS-mediated mitochondrial apoptosis. Furthermore, it suggests that loss of PERK may cause defects in cell death sensitivity in pathol. conditions linked to ROS-mediated ER stress.

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    Sweeney, M. D.; Sagare, A. P.; Zlokovic, B. V. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 2018, 14 (3), 133– 150,  DOI: 10.1038/nrneurol.2017.188IF: 28.2 Q1 B1

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    25

    Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

    Sweeney, Melanie D.; Sagare, Abhay P.; Zlokovic, Berislav V.

    Nature Reviews Neurology (2018), 14 (3), 133-150CODEN: NRNACP; ISSN:1759-4758. (Nature Research)

    A review. The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet. The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning. BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is assocd. with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration. This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-assocd. dementia and chronic traumatic encephalopathy. The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described. The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, pathol. BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed. Finally, future directions, gaps in the field and opportunities to control the course of neurol. diseases by targeting the BBB are presented.

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26. 26

    Heudorf, U.; Mersch-Sundermann, V.; Angerer, J. Phthalates: toxicology and exposure. Int. J. Hyg. Environ. Health 2007, 210 (5), 623– 634,  DOI: 10.1016/j.ijheh.2007.07.011IF: 4.5 Q1 B2

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    26

    Phthalates: toxicology and exposure

    Heudorf, Ursel; Mersch-Sundermann, Volker; Angerer, Juergen

    International Journal of Hygiene and Environmental Health (2007), 210 (5), 623-634CODEN: IJEHFT; ISSN:1438-4639. (Elsevier GmbH)

    A review on current risk assessments on phthalates done by expert panels as well as on exposure assessment data, based on ambient and on current human biomonitoring results. Phthalates are used as plasticizers in PVC plastics. As the phthalate plasticizers are not chem. bound to PVC, they can leach, migrate, or evap. into indoor air and atm., foodstuff, other materials, etc. Consumer products contg. phthalates can result in human exposure through direct contact and use, indirectly through leaching into other products, or general environmental contamination. Humans are exposed through ingestion, inhalation, and dermal exposure during their whole lifetime, including intrauterine development. Some phthalates are reproductive and developmental toxicants in animals and suspected endocrine disruptors in humans. Exposure assessment via modeling ambient data give hints that the exposure of children to phthalates exceeds that in adults. Current human biomonitoring data prove that the tolerable intake of children is exceeded to a considerable degree, in some instances ≤20-fold. Very high exposures to phthalates can occur via medical treatment, i.e. via use of medical devices contg. DEHP or medicaments contg. DBP phthalate in their coating. Because of their chem. properties exposure to phthalates does not result in bioaccumulation. However, health concern is raised regarding the developmental and/or reproductive toxicity of phthalates, even in environmental concns.

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27. 27

    Du, Z. H.; Xia, J.; Sun, X. C.; Li, X. N.; Zhang, C.; Zhao, H. S.; Zhu, S. Y.; Li, J. L. A novel nuclear xenobiotic receptors (AhR/PXR/CAR)-mediated mechanism of DEHP-induced cerebellar toxicity in quails (Coturnix japonica) via disrupting CYP enzyme system homeostasis. Environ. Pollut. 2017, 226, 435– 443,  DOI: 10.1016/j.envpol.2017.04.015IF: 7.6 Q1 B2

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    27

    A novel nuclear xenobiotic receptors (AhR/PXR/CAR)-mediated mechanism of DEHP-induced cerebellar toxicity in quails (Coturnix japonica) via disrupting CYP enzyme system homeostasis

    Du, Zheng-Hai; Xia, Jun; Sun, Xiao-Chen; Li, Xue-Nan; Zhang, Cong; Zhao, Hua-Shan; Zhu, Shi-Yong; Li, Jin-Long

    Environmental Pollution (Oxford, United Kingdom) (2017), 226 (), 435-443CODEN: ENPOEK; ISSN:0269-7491. (Elsevier Ltd.)

    Di-(2-ethylhexyl)-phthalate (DEHP) is causing serious health hazard in wildlife animal and human through environment and food chain, including the effect of brain development and impacted neurobehavioral outcomes. However, DEHP exposure caused cerebellar toxicity in bird remains unclear. To evaluate DEHP-exerted potential neurotoxicity in cerebellum, male quails were exposed with 0, 250, 500 and 750 mg/kg BW/day DEHP by gavage treatment for 45 days. Neurobehavioral abnormality and cerebellar histopathol. alternation were obsd. in DEHP-induced quails. DEHP exposure increased the contents of total Cytochrome P450s (CYPs) and Cytochrome b5 (Cyt b5) and the activities of NADPH-cytochrome c reductase (NCR) and aniline-4-hydeoxylase (AH) in quail cerebellum. The expression of nuclear xenobiotic receptors (NXRs) and the transcriptions of CYP enzyme isoforms were also influenced in cerebellum by DEHP exposure. These results suggested that DEHP exposure caused the toxic effects of quail cerebellum. DEHP exposure disrupted the cerebellar CYP enzyme system homeostasis via affecting the transcription of CYP enzyme isoforms. The cerebellar P450arom and CYP3A4 might be biomarkers in evaluating the neurotoxicity of DEHP in bird. Finally, this study provided new evidence that DEHP-induced toxic effect of quail cerebellum was assocd. with activating the NXRs responses and disrupting the CYP enzyme system homeostasis.

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28. 28

    Zolfaghari, M.; Drogui, P.; Seyhi, B.; Brar, S. K.; Buelna, G.; Dube, R. Occurrence, fate and effects of Di (2-ethylhexyl) Phthalate in wastewater treatment plants: a review. Environ. Pollut. 2014, 194, 281– 293,  DOI: 10.1016/j.envpol.2014.07.014IF: 7.6 Q1 B2

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    28

    Occurrence, fate and effects of Di (2-ethylhexyl) phthalate in wastewater treatment plants: A review

    Zolfaghari, M.; Drogui, P.; Seyhi, B.; Brar, S. K.; Buelna, G.; Dube, R.

    Environmental Pollution (Oxford, United Kingdom) (2014), 194 (), 281-293CODEN: ENPOEK; ISSN:0269-7491. (Elsevier Ltd.)

    A review. Phthalates, such as Di (2-ethylhexyl) Phthalate (DEHP) are compds. extensively used as plasticizer for long time around the world. Due to the extensive usage, DEHP is found in many surface waters (0.013-18.5 μg/L), wastewaters (0.716-122 μg/L), landfill leachate (88-460 μg/L), sludge (12-1250 mg/kg), soil (2-10 mg/kg). DEHP is persistent in the environment and the toxicity of the byproducts resulting from the degrdn. of DEHP sometime exacerbates the parent compd. toxicity. Water/Wastewater treatment processes might play a key role in delivering safe, reliable supplies of water to households, industry and in safeguarding the quality of water in rivers, lakes and aquifers. This review addresses state of knowledge concerning the worldwide prodn., occurrence, fate and effects of DEHP in the environment. Moreover, the fate and behavior of DEHP in various treatment processes, including biol., physicochem. and advanced processes are reviewed and comparison (qual. and quant.) has been done between the processes. The trends and perspectives for treatment of wastewaters contaminated by DEHP are also analyzed in this review.

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    Xie, Y.; Wang, Y.; Zhang, T.; Ren, G.; Yang, Z. Effects of nanoparticle zinc oxide on spatial cognition and synaptic plasticity in mice with depressive-like behaviors. J. Biomed. Sci. 2012, 19 (1), 14,  DOI: 10.1186/1423-0127-19-14IF: 9.0 Q1 B2

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    Effects of nanoparticle zinc oxide on spatial cognition and synaptic plasticity in mice with depressive-like behaviors

    Xie, Yongling; Wang, Yiyi; Zhang, Tao; Ren, Guogang; Yang, Zhuo

    Journal of Biomedical Science (London, United Kingdom) (2012), 19 (), 14CODEN: JBCIEA; ISSN:1423-0127. (BioMed Central Ltd.)

    Background: Nanomaterials, as a new kind of materials, have been greatly applied in different fields due to their special properties. With the industrialization of nanostructured materials and increasing public exposure, the biosafety and potential influences on central nervous system (CNS) have received more attention. Nanosized zinc oxide (nanoZnO) was suggested to up-regulate neuronal excitability and to induce glutamate release in vitro. Therefore, we hypothesized nanoparticles of nanoZnO may lead to changes in balance of neurotransmitter or neuronal excitability of CNS. This study was to investigate if there were effects of nanoZnO on animal model of depression. Methods: Male Swiss mice were given lipopolysaccharides (LPS, 100 μg/kg, 100 μg/mL, every other day, 8 times, i.p.) from weaning to induce depressive-like behaviors. NanoZnO (5.6 mg/kg, 5.6 mg/mL, every other day, 8 times, i.p.) was given as the interaction. The mouse model was characterized using the methods of open field test, tail suspension test and forced swim test. Furthermore, the spatial memory was evaluated using Morris water maze (MWM) and the synaptic plasticity was assessed by measuring the long-term potentiation (LTP) in the perforant pathway (PP) to dentate gyrus (DG) in vivo. Results: Results indicated that model mice showed disrupted spatial memory and LTP after LPS injections and the behavioral and electrophysiol. improvements after nanoZnO treatment. Conclusion: Data suggested that nanoZnO may play some roles in CNS of mental disorders, which could provide some useful direction on the new drug exploring and clin. researches.

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30. 30

    Beretta, S.; Gritti, L.; Ponzoni, L.; Scalmani, P.; Mantegazza, M.; Sala, M.; Verpelli, C.; Sala, C. Rescuing epileptic and behavioral alterations in a Dravet syndrome mouse model by inhibiting eukaryotic elongation factor 2 kinase (eEF2K). Mol. Autism. 2022, 13 (1), 1,  DOI: 10.1186/s13229-021-00484-0IF: 6.3 Q1 B1

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    Rescuing epileptic and behavioral alterations in a Dravet syndrome mouse model by inhibiting eukaryotic elongation factor 2 kinase (eEF2K)

    Beretta, Stefania; Gritti, Laura; Ponzoni, Luisa; Scalmani, Paolo; Mantegazza, Massimo; Sala, Mariaelvina; Verpelli, Chiara; Sala, Carlo

    Molecular Autism (2022), 13 (1), 1CODEN: MAOUBR; ISSN:2040-2392. (BioMed Central Ltd.)

    Dravet Syndrome is a severe childhood pharmaco-resistant epileptic disorder mainly caused by mutations in the SCN1A gene, which encodes for the a1 subunit of the type I voltage-gated sodium channel (NaV1.1), that causes imbalance between excitation and inhibition in the brain. We recently found that eEF2K knock out mice displayed enhanced GABAergic transmission and tonic inhibition and were less susceptible to epileptic seizures. Thus, we investigated the effect of inhibition of eEF2K on the epileptic and behavioral phenotype of Scn1a ± mice, a murine model of Dravet Syndrome. To elucidate the role of eEF2K pathway in the etiopathol. of Dravet syndrome we generated a new mouse model deleting the eEF2K gene in Scn1a ± mice. By crossing Scn1a ± mice with eEF2K-/- mice we obtained the three main genotypes needed for our studies, Scn1a+/+ eEF2K+/+ (WT mice), Scn1a ± eEF2K+/+ mice (Scn1a ± mice) and Scn1a ± eEF2K-/- mice, that were fully characterized for EEG and behavioral phenotype. Furthermore, we tested the ability of a pharmacol. inhibitor of eEF2K in rescuing EEG alterations of the Scn1a ± mice. We showed that the activity of eEF2K/eEF2 pathway was enhanced in Scn1a ± mice. Then, we demonstrated that both genetic deletion and pharmacol. inhibition of eEF2K were sufficient to ameliorate the epileptic phenotype of Scn1a ± mice. Interestingly we also found that motor coordination defect, memory impairments, and stereotyped behavior of the Scn1a ± mice were reverted by eEF2K deletion. The anal. of spontaneous inhibitory postsynaptic currents (sIPSCs) suggested that the rescue of the pathol. phenotype was driven by the potentiation of GABAergic synapses. Even if we found that eEF2K deletion was able to increase inhibitory synapses function, the mol. mechanism underlining the inhibition of eEF2K/eEF2 pathway in rescuing epileptic and behavioral alterations in the Scn1a ± needs further investigations. Our data indicate that pharmacol. inhibition of eEF2K could represent a novel therapeutic intervention for treating epilepsy and related comorbidities in the Dravet syndrome.

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31. 31

    Lei, S.; Li, J.; Yu, J.; Li, F.; Pan, Y.; Chen, X.; Ma, C.; Zhao, W.; Tang, X. Porphyromonas gingivalis bacteremia increases the permeability of the blood-brain barrier via the Mfsd2a/Caveolin-1 mediated transcytosis pathway. Int. J. Oral Sci. 2023, 15 (1), 3,  DOI: 10.1038/s41368-022-00215-yIF: 10.8 Q1 B1

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    31

    Porphyromonas gingivalis bacteremia increases the permeability of the blood-brain barrier via the Mfsd2a/Caveolin-1 mediated transcytosis pathway

    Lei, Shuang; Li, Jian; Yu, Jingjun; Li, Fulong; Pan, Yaping; Chen, Xu; Ma, Chunliang; Zhao, Weidong; Tang, Xiaolin

    International Journal of Oral Science (2023), 15 (1), 3CODEN: IJOSFA; ISSN:2049-3169. (Nature Portfolio)

    Bacteremia induced by periodontal infection is an important factor for periodontitis to threaten general health. P. gingivalis DNA/virulence factors have been found in the brain tissues from patients with Alzheimer disease (AD). The blood-brain barrier (BBB) is essential for keeping toxic substances from entering brain tissues. However, the effect of P. gingivalis bacteremia on BBB permeability and its underlying mechanism remains unclear. In the present study, rats were injected by tail vein with P. gingivalis three times a week for eight weeks to induce bacteremia. An in vitro BBB model infected with P. gingivalis was also established. We found that the infiltration of Evans blue dye and Albumin protein deposition in the rat brain tissues were increased in the rat brain tissues with P. gingivalis bacteremia and P. gingivalis could pass through the in vitro BBB model. Caveolae were detected after P. gingivalis infection in BMECs both in vivo and in vitro. Caveolin-1 (Cav-1) expression was enhanced after P. gingivalis infection. Downregulation of Cav-1 rescued P. gingivalis-enhanced BMECs permeability. We further found P. gingivalis-gingipain could be colocalized with Cav-1 and the strong hydrogen bonding between Cav-1 and arg-specific-gingipain (RgpA) were detected. Moreover, P. gingivalis significantly inhibited the major facilitator superfamily domain contg. 2a (Mfsd2a) expression. Mfsd2a overexpression reversed P. gingivalis-increased BMECs permeability and Cav-1 expression. These results revealed that Mfsd2a/Cav-1 mediated transcytosis is a key pathway governing BBB BMECs permeability induced by P. gingivalis, which may contribute to P. gingivalis/virulence factors entrance and the subsequent neurol. impairments.

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32. 32

    Zhao, Y.; Li, H. X.; Luo, Y.; Cui, J. G.; Talukder, M.; Li, J. L. Lycopene mitigates DEHP-induced hepatic mitochondrial quality control disorder via regulating SIRT1/PINK1/mitophagy axis and mitochondrial unfolded protein response. Environ. Pollut. 2022, 292 (Pt B), 118390,  DOI: 10.1016/j.envpol.2021.118390IF: 7.6 Q1 B2

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    32

    Lycopene mitigates DEHP-induced hepatic mitochondrial quality control disorder via regulating SIRT1/PINK1/mitophagy axis and mitochondrial unfolded protein response

    Zhao, Yi; Li, Hui-Xin; Luo, Yu; Cui, Jia-Gen; Talukder, Milton; Li, Jin-Long

    Environmental Pollution (Oxford, United Kingdom) (2022), 292 (Part_B), 118390CODEN: ENPOEK; ISSN:0269-7491. (Elsevier Ltd.)

    Di (2-ethylhexyl) phthalate (DEHP) is a hazardous chem. which is used as a plasticizer in the plastic products. Lycopene (LYC) is a carotenoid that has protective roles against cellular damage in different organs. The present study sought to explore the role of the interaction between mitophagy and mitochondrial unfolded protein response (UPRmt) in the LYC mitigating DEHP-induced hepatic mitochondrial quality control disorder. The mice were treated with LYC (5 mg/kg) and/or DEHP (500 or 1000 mg/kg). In our findings, LYC prevented DEHP-induced histopathol. alterations including steatosis and fibrosis, and ultrastructural injuries including decreased mitochondrial membrane potential (ΔΨm) and mitochondria vol. d. Furthermore, LYC alleviated DEHP-induced mitochondrial biogenesis disorder by suppressing SIRT1-PGC-1α axis, PINK1-mediated mitophagy and the activation of mitochondrial unfolded protein response (UPRmt). This research suggested that LYC could prevent DEHP-induced hepatic mitochondrial quality control disorder via regulating SIRT1/PINK1/mitophagy axis and UPRmt. The present study provided a current understanding about the potential implication of the SIRT1/PINK1/mitophagy axis and UPRmt in LYC preventing DEHP-induced hepatic mitochondrial quality control disorder.

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33. 33

    Zhao, Y. X.; Li, X. N.; Tang, Y. X.; Talukder, M.; Zhao, Y.; Li, J. L. Cadmium Transforms Astrocytes into the A1 Subtype via Inducing Gap Junction Protein Connexin 43 into the Nucleus. J. Agric. Food Chem. 2023, 71 (31), 12043– 12051,  DOI: 10.1021/acs.jafc.3c02963IF: 5.7 Q1 B1

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    33

    Cadmium Transforms Astrocytes into the A1 Subtype via Inducing Gap Junction Protein Connexin 43 into the Nucleus

    Zhao, Ying-Xin; Li, Xue-Nan; Tang, Yi-Xi; Talukder, Milton; Zhao, Yi; Li, Jin-Long

    Journal of Agricultural and Food Chemistry (2023), 71 (31), 12043-12051CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)

    Cadmium is highly toxic and present in the environment and can be accumulated among various levels of the food chain. Both humans and animals are at risk from toxicity assocd. with cadmium. However, the neurol. endpoint caused by cadmium has not been revealed. The aim of our research is to explore the potential target of cadmium attack when causing neurotoxicity. 80 male chickens (one day old, weighing 36.49 ± 2.88 g) were randomly divided into four groups and independently treated with 0, 35, 70, or 140 mg/kg CdCl2 in diet for 90 days. The result showed that the striatum was damaged due to a high dose of cadmium in the brain, which was characterized by degeneration of neurons and astrocyte dysfunction. Transcriptome anal. demonstrated that striatal astrocytes were transformed into the A1 state under cadmium exposure. Deeper investigation revealed that the internalization of gap junction protein connexin 43 was responsible for this transformation. Eventually, we can conclude that the internalized gap junction protein connexin 43 of astrocytes is the target of cadmium anchoring, and this process was accompanied by the transformation of astrocytes into the A1 subtype. This study provides a new direction for exploring the effects of cadmium on the nervous system and the treatment of subsequent nervous system diseases.

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34. 34

    Chen, J.; Xu, X. W.; Kang, J. X.; Zhao, B. C.; Xu, Y. R.; Li, J. L. Metasilicate-based alkaline mineral water confers diarrhea resistance in maternally separated piglets via the microbiota-gut interaction. Pharmacol. Res. 2023, 187, 106580,  DOI: 10.1016/j.phrs.2022.106580IF: 9.1 Q1 B2

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    34

    Metasilicate-based alkaline mineral water confers diarrhea resistance in maternally separated piglets via the microbiota-gut interaction

    Chen, Jian; Xu, Xiang-Wen; Kang, Jian-Xun; Zhao, Bi-Chen; Xu, Ya-Ru; Li, Jin-Long

    Pharmacological Research (2023), 187 (), 106580CODEN: PHMREP; ISSN:1043-6618. (Elsevier Ltd.)

    Stress or stress-induced intestinal disturbances, esp. diarrhea, are the main triggers for inflammatory bowel disease and irritable bowel syndrome. Diarrhea and intestinal inflammatory disease afflict patients around the world, and it has become a huge burden on the global health care system. Drinking sodium metasilicate-based alk. mineral water (SM-based AMW) exerts a potential therapeutic effect in gastrointestinal disorders, including gut inflammation, and diarrhea, but the supportive evidence on animal studies and mechanism involved remain unreported. The maternally sepd. (MS) piglet (Newly weaned piglet) is an excellent model to investigate the treatment of diarrhea in infant. This study aims to det. whether drinking SM-based AMW confers diarrhea resistance in maternally sepd. (MS) piglets under weaning stress and what the underlying mechanisms are involved. 240 newly weaned piglets were randomly divided into the Control group and the sodium metasilicate pentahydrate (SMP) group. A decreased diarrhea incidence was obsd. in SMP treatment piglets. The intestine injury and activated stress hormones (COR and ACTH) induced by weaning was alleviated by SM-based AMW. This may be related to the improvement of intestinal microflora structure and function by SMP, esp. the increase of s_copri abundance. Meanwhile, SMP maintained the integrity of the duodenal mucus barrier in MS piglets. Importantly, by targeting NF-κB inhibition via the microbiota-gut interaction, SM-based AMW alleviated intestinal inflammation, maintained fluid homeostasis by modulating aquaporins and fluid transporter expression, and enhanced barrier integrity by suppressing MLCK/p-MLC signaling. Therefore, drinking metasilicate-based alk. mineral water confers diarrhea resistance in MS piglets via the microbiota-gut interaction.

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35. 35

    Fan, K. Q.; Li, Y. Y.; Wang, H. L.; Mao, X. T.; Guo, J. X.; Wang, F.; Huang, L. J.; Li, Y. N.; Ma, X. Y.; Gao, Z. J.; Chen, W.; Qian, D. D.; Xue, W. J.; Cao, Q.; Zhang, L.; Shen, L.; Zhang, L.; Tong, C.; Zhong, J. Y.; Lu, W.; Lu, L.; Ren, K. M.; Zhong, G.; Wang, Y.; Tang, M.; Feng, X. H.; Chai, R. J.; Jin, J. Stress-Induced Metabolic Disorder in Peripheral CD4(+) T Cells Leads to Anxiety-like Behavior. Cell 2019, 179 (4), 864– 879.e19,  DOI: 10.1016/j.cell.2019.10.001IF: 45.5 Q1 B1

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    35

    Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior

    Fan, Ke-qi; Li, Yi-yuan; Wang, Hao-li; Mao, Xin-tao; Guo, Jin-xin; Wang, Fei; Huang, Ling-jie; Li, Yi-ning; Ma, Xiang-yu; Gao, Zheng-jun; Chen, Wei; Qian, Dan-dan; Xue, Wen-jin; Cao, Qian; Zhang, Lei; Shen, Li; Zhang, Long; Tong, Chao; Zhong, Jiang-yan; Lu, Wei; Lu, Ling; Ren, Ke-ming; Zhong, Guisheng; Wang, Yuan; Tang, Mingliang; Feng, Xin-Hua; Chai, Ren-jie; Jin, Jin

    Cell (Cambridge, MA, United States) (2019), 179 (4), 864-879.e19CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

    Phys. or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathol. role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Phys. stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a crit. link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.

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36. 36

    Li, X. W.; Yi, B. J.; Wang, Z. Y.; Guo, K.; Saleem, M. A. U.; Ma, X. Y.; Li, X. N.; Li, J. L. The ROS/SIRT1/STAR axis as a target for melatonin ameliorating atrazine-induced mitochondrial dysfunction and steroid disorders in granulosa cells. Ecotoxicol. Environ. Saf. 2024, 269, 115780,  DOI: 10.1016/j.ecoenv.2023.115780IF: 6.2 Q1 B2

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    36

    The ROS/SIRT1/STAR axis as a target for melatonin ameliorating atrazine-induced mitochondrial dysfunction and steroid disorders in granulosa cells

    Li, Xiao-Wei; Yi, Bao-Jin; Wang, Zhao-Yi; Guo, Kai; Saleem, Muhammad Asmat Ullah; Ma, Xiang-Yu; Li, Xue-Nan; Li, Jin-Long

    Ecotoxicology and Environmental Safety (2024), 269 (), 115780CODEN: EESADV; ISSN:0147-6513. (Elsevier B.V.)

    The granulosa cells (GCs) of birds are essential for the reprodn. and maintenance of populations in nature. Atrazine (ATR) is a potent endocrine disruptor that can interfere with reproductive function in females and Diaminochlorotriazine (DACT) is the primary metabolite of ATR in the organism. Melatonin (MT) is an endogenous hormone with antioxidant properties that plays a crucial role in development of animal germ cells. However, how ATR causes mitochondrial dysfunction, abnormal secretion of steroid hormones, and whether MT prevents ATR-induced female reproductive toxicity remains unclear. Thus, the purpose of this study is to investigate the protective effect of MT against ATR-induced female reprodn. In the present study, the GCs of quail were divided into 6 groups, as follows: C (Serum-free medium), MT (10μM MT), A250 (250μM ATR), MA250 (10μM MT+250μM ATR), D200 (200μM DACT) and MD200 (10μM MT+200μM DACT), and were cultured for 24 h. The results revealed that ATR prevented GCs proliferation and decreased cell differentiation. ATR caused oxidative damage and mitochondrial dysfunction, leading to disruption of steroid synthesis, which posed a severe risk to GCs function. However, MT supplements reversed these changes. Mechanistically, our study exhibited that the ROS/SIRT1/STAR axis as a target for MT to ameliorate ATR-induced mitochondrial dysfunction and steroid disorders in GCs, which provides new insights into the role of MT in ATR-induced reproductive capacity and species conservation in birds.

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37. 37

    Zhao, Y.; Bao, R. K.; Zhu, S. Y.; Talukder, M.; Cui, J. G.; Zhang, H.; Li, X. N.; Li, J. L. Lycopene prevents DEHP-induced hepatic oxidative stress damage by crosstalk between AHR-Nrf2 pathway. Environ. Pollut. 2021, 285, 117080,  DOI: 10.1016/j.envpol.2021.117080

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    37

    Lycopene prevents DEHP-induced hepatic oxidative stress damage by crosstalk between AHR-Nrf2 pathway

    Zhao, Yi; Bao, Rong-Kun; Zhu, Shi-Yong; Talukder, Milton; Cui, Jia-Gen; Zhang, Hao; Li, Xue-Nan; Li, Jin-Long

    Environmental Pollution (Oxford, United Kingdom) (2021), 285 (), 117080CODEN: ENPOEK; ISSN:0269-7491. (Elsevier Ltd.)

    Di (2-ethylhexyl) phthalate (DEHP) is a widespread plasticizer that persists in the environment and can significantly contribute to serious health hazards of liver esp. oxidative stress injury. Lycopene (LYC) as a carotenoid has recently gained widespread attention because of antioxidant activity. However, the potential mechanism of DEHP-induced hepatotoxicity and antagonism effect of LYC on it are still unclear. To explore the underlying mechanisms of this hypothesis, the mice were given by gavage with LYC (5 mg/kg) and DEHP (500 or 1000 mg/kg). The data suggested that DEHP caused liver enlargement, redn. of antioxidant activity markers, increase of oxidative stress indicators and disorder of cytochrome P 450 enzymes system (CYP450s) homeostasis. DEHP-induced reactive oxygen species (ROS) activated the NF-E2-relatedfactor2 (Nrf2) and nuclear xenobiotic receptors (NXRs) system including Aryl hydrocarbon receptor (AHR), Pregnane X receptor (PXR) and Constitutive androstane receptor (CAR). Interestingly, these disorders and injuries were prevented after LYC treatment. Taken together, DEHP administration resulted in hepatotoxicity including oxidative stress injury and disordered CYP450 system, but these alterations might be ameliorated by LYC via crosstalk between AHR-Nrf2 pathway.

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38. 38

    Wang, J. X.; Zhao, Y.; Chen, M. S.; Zhang, H.; Cui, J. G.; Li, J. L. Heme-oxygenase-1 as a target for phthalate-induced cardiomyocytes ferroptosis. Environ. Pollut. 2023, 317, 120717,  DOI: 10.1016/j.envpol.2022.120717

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    38

    Heme-oxygenase-1 as a target for phthalate-induced cardiomyocytes ferroptosis

    Wang, Jia-Xin; Zhao, Yi; Chen, Ming-Shan; Zhang, Hao; Cui, Jia-Gen; Li, Jin-Long

    Environmental Pollution (Oxford, United Kingdom) (2023), 317 (), 120717CODEN: ENPOEK; ISSN:0269-7491. (Elsevier Ltd.)

    Phthalates as a large group of environmental pollutants are used primarily as plasticizers and solvents, which have become a growing problem worldwide. Epidemiol. results show that severity of heart disease is related to degree of environmental contamination. As the most usually used phthalate, di(2-ethylhexyl) phthalate (DEHP) has toxic effects on organism health and is also a major cause of heart damage. Ingestion of food, liq., or dust contaminated with DEHP are major routes of exposure. The purpose of the present research was to det. the mechanism of cardiotoxicity in mice after exposure to DEHP. Here, male mice were treated by gavage with three different doses of (50, 200 and 500 mg/kg b.w.) DEHP for 28 days. Our research showed that DEHP brought about histopathol. changes involving cardiomyocyte lysis and rupture, and ultrastructural damage such as dissoln. and loss of mitochondrial cristae. Furthermore, DEHP induced oxidative stress and a significant decline in the antioxidant function, which activates nuclear factor E2-related factor 2 (Nrf2)/heme-oxygense-1 (HO-1) signaling pathways. Interestingly, DEHP resulted in lipid peroxidn. and increased ferrous ion content, suggesting that ferroptosis occurred in mouse hearts. Therefore, our findings demonstrated that DEHP could induce cardiac ferroptosis via upregulation of HO-1. The present study provides novel evidence of HO-1 as a target for DEHP-induced cardiotoxicity.

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39. 39

    Chen, M. S.; Wang, J. X.; Zhang, H.; Cui, J. G.; Zhao, Y.; Li, J. L. Novel Role of Hemeoxygenase-1 in Phthalate-Induced Renal Proximal Tubule Cell Ferroptosis. J. Agric. Food Chem. 2023, 71 (5), 2579– 2589,  DOI: 10.1021/acs.jafc.2c07762

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    39

    Novel Role of Hemeoxygenase-1 in Phthalate-Induced Renal Proximal Tubule Cell Ferroptosis

    Chen, Ming-Shan; Wang, Jia-Xin; Zhang, Hao; Cui, Jia-Gen; Zhao, Yi; Li, Jin-Long

    Journal of Agricultural and Food Chemistry (2023), 71 (5), 2579-2589CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)

    Phthalates are widely used to improve the flexibility of poly(vinyl chloride) (PVC) polymer agriculture products. Di(2-ethylhexyl) phthalate (DEHP) is a type of addn. to plastic and can lead to many health problems. Hemeoxygenase-1 (HO-1) is an extremely important mol. that releases enzymic products to promote ferroptosis. This research aimed to explore the function of HO-1 in DEHP-induced renal proximal tubule cell ferroptosis. In the expt., ICR male mice are exposed to (0, 50, 200, and 500 mg/kg BW/day) DEHP for 28 days. Here, we obsd. that DEHP induced glomeruli atrophy and the tubules swell. Furthermore, DEHP exposure could increase ferrous iron content and decrease antioxidant activity. We also found that DEHP exposure increased the expression of nuclear factor-erythroid 2 p45-related factor 2 (NFE2L2) in the nucleus. In particular, the expression of (HO-1) is significantly increased both in protein and mRNA levels. Glutathione peroxidase 4 (GPX4) as an endogenous control of ferroptosis was downregulated, which proved the occurrence of ferroptosis. In the study, exposure to DEHP activated the NFE2L2/HO-1 signaling pathway and resulted in ferroptosis of the proximal tubule. This research connects ferroptosis with HO-1, providing new insights into the potential roles of phthalates in nephrotoxicity.

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40. 40

    Zhao, Y.; Li, X. N.; Zhang, H.; Cui, J. G.; Wang, J. X.; Chen, M. S.; Li, J. L. Phthalate-induced testosterone/androgen receptor pathway disorder on spermatogenesis and antagonism of lycopene. J. Hazard. Mater. 2022, 439, 129689,  DOI: 10.1016/j.jhazmat.2022.129689

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    40

    Phthalate-induced testosterone/androgen receptor pathway disorder on spermatogenesis and antagonism of lycopene

    Zhao, Yi; Li, Xue-Nan; Zhang, Hao; Cui, Jia-Gen; Wang, Jia-Xin; Chen, Ming-Shan; Li, Jin-Long

    Journal of Hazardous Materials (2022), 439 (), 129689CODEN: JHMAD9; ISSN:0304-3894. (Elsevier B.V.)

    Male infertility is an attracting growing concern owing to decline in sperm quality of men worldwide. Phthalates, in particular to di (2-ethylhexyl) phthalate (DEHP) or its main metabolite mono-2-ethylhexyl phthalate (MEHP), affect male reproductive development and function, which mainly accounts for redn. in male fertility. Lycopene (LYC) is a natural antioxidant agent that has been recognized as a possible therapeutic option for treating male infertility. Testosterone (T)/androgen receptor (AR) signaling pathway is involved in maintaining spermatogenesis and male fertility. How DEHP causes spermatogenesis disturbance and whether LYC could prevent DEHP-induced male reproductive toxicity have remained unclear. Using in vivo and vitro approaches, we demonstrated that DEHP caused T biosynthesis redn. in Leydig cell and secretory function disorder in Sertoli cell, and thereby resulted in spermatogenic impairment. Results also showed that MEHP caused mitochondrial damage and oxidative damage, which imposes a serious threat to the progress of spermatogenesis. However, LYC supplement reversed these changes. Mechanistically, DEHP contributed to male infertility via perturbing T/AR signaling pathway during spermatogenesis. Overall, our study reveals crit. role for T/AR signal transduction in male fertility and provides promising insights into the protective role of LYC in phthalate-induced male reproductive disorders.

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    Chen, J.; Zhao, B. C.; Dai, X. Y.; Xu, Y. R.; Kang, J. X.; Li, J. L. Drinking alkaline mineral water confers diarrhea resistance in maternally separated piglets by maintaining intestinal epithelial regeneration via the brain-microbe-gut axis. J. Adv. Res. 2023, 52, 29– 43,  DOI: 10.1016/j.jare.2022.12.008IF: 11.4 Q1 B1

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    Drinking alkaline mineral water confers diarrhea resistance in maternally separated piglets by maintaining intestinal epithelial regeneration via the brain-microbe-gut axis

    Chen, Jian; Zhao, Bi-Chen; Dai, Xue-Yan; Xu, Ya-Ru; Kang, Jian-Xun; Li, Jin-Long

    Journal of Advanced Research (2023), 52 (), 29-43CODEN: JAROES; ISSN:2090-1224. (Elsevier B.V.)

    Diarrhea has the fourth-highest mortality rate of all diseases and causes a large no. of infant deaths each year. The maternally sepd. (MS) piglet (newly weaned piglet) is an excellent model to investigate the treatment of diarrhea in infants. Drinking alk. mineral water has the potential to be therapeutic in gastrointestinal disorders, particularly diarrhea, but the supporting evidence from system studies and the mechanisms involved have yet to be reported. This study aims to det. whether drinking alk. mineral water confers diarrhea resistance in MS piglets under weaning stress and what the fundamental mechanisms involved are. MS piglets were used to create a stress-induced intestinal disorder-diarrhea susceptibility model. A total of 240 MS piglets were randomly divided into two groups (6 pens/group and 20 piglets/pen). IPEC-J2 cell line was used for in vitro evaluation. An alk. mineral complex (AMC) water was employed, and its effect on the hypothalamus-pituitary-adrenocortical (HPA) axis, gut microbes, gut morphol., and intestinal epithelial cell (IEC) proliferation and differentiation were investigated using a variety of exptl. methodol. AMC water reduced diarrhea rate in MS piglets by inhibiting the HPA axis, ameliorating gut microbiota structure, and stimulating IEC proliferation and differentiation. Apparently, the brain-microbe-gut axis is linked with AMC water conferring diarrhea resistance in piglets. Mechanistically, AMC water decreased stress hormones (COR and Hpt) secretion by suppressing HPA axis, which then increased the abundance of beneficial gut microbes; accordingly, maintained the proliferation of IEC and promoted the differentiation of intestinal stem cells (ISC) into goblet cell and Paneth cell by activating the Wnt/β-catenin signaling pathway. In the absence of gut microbiota (in vitro), AMC activated the LPS-induced Wnt/β-catenin signaling inhibition in IPEC-J2 cells and significantly increased the no. of Lgr5 + cells, whereas had no effect on IPEC-J2 differentiation. Drinking alk. mineral water confers diarrhea resistance in MS piglets by maintaining intestinal epithelial regeneration via the brain-microbe-gut axis; thus, this study provides a potential prevention strategy for young mammals at risk of diarrhea.

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    Boyman, L.; Karbowski, M.; Lederer, W. J. Regulation of Mitochondrial ATP Production: Ca(2+) Signaling and Quality Control. Trends Mol. Med. 2020, 26 (1), 21– 39,  DOI: 10.1016/j.molmed.2019.10.007IF: 12.8 Q1 B1

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    42

    Regulation of Mitochondrial ATP Production: Ca2+ Signaling and Quality Control

    Boyman, Liron; Karbowski, Mariusz; Lederer, W. Jonathan

    Trends in Molecular Medicine (2020), 26 (1), 21-39CODEN: TMMRCY; ISSN:1471-4914. (Elsevier Ltd.)

    Cardiac ATP prodn. primarily depends on oxidative phosphorylation in mitochondria and is dynamically regulated by Ca2+ levels in the mitochondrial matrix as well as by cytosolic ADP. We discuss mitochondrial Ca2+ signaling and its dysfunction which has recently been linked to cardiac pathologies including arrhythmia and heart failure. Similar dysfunction in other excitable and long-lived cells including neurons is assocd. with neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Central to this new understanding is crucial Ca2+ regulation of both mitochondrial quality control and ATP prodn. Mitochondria-assocd. membrane (MAM) signaling from the sarcoplasmic reticulum (SR) and the endoplasmic reticulum (ER) to mitochondria is discussed. We propose future research directions that emphasize a need to define quant. the physiol. roles of MAMs, as well as mitochondrial quality control and ATP prodn.

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43. 43

    Yang, M.; Zhao, L.; Gao, P.; Zhu, X.; Han, Y.; Chen, X.; Li, L.; Xiao, Y.; Wei, L.; Li, C.; Xiao, L.; Yuan, S.; Liu, F.; Dong, L. Q.; Kanwar, Y. S.; Sun, L. DsbA-L ameliorates high glucose induced tubular damage through maintaining MAM integrity. EBioMedicine 2019, 43, 607– 619,  DOI: 10.1016/j.ebiom.2019.04.044IF: 9.7 Q1 B1

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    43

    DsbA-L ameliorates high glucose induced tubular damage through maintaining MAM integrity

    Yang Ming; Gao Peng; Zhu Xuejing; Han Yachun; Chen Xianghui; Li Li; Xiao Ying; Wei Ling; Li Chenrui; Xiao Li; Yuan Shuguang; Liu Fuyou; Zhao Li; Dong Lily Q; Kanwar Yashpal S; Sun Lin

    EBioMedicine (2019), 43 (), 607-619 ISSN:.

    BACKGROUND: The mitochondrial associated endoplasmic reticulum (ER) membrane (MAM) provides a platform for communication between the mitochondria and ER, and it plays a vital role in many biological functions. Disulphide-bond A oxidoreductase-like protein (DsbA-L), expressed in the MAM, serves as an antioxidant and reduces ER stress. However, the role of DsbA-L and MAM in kidney pathobiology remains unclear. METHODS: Molecular biology techniques, transmission electron microscopy (TEM), in situ proximity ligation assays (PLAs), confocal microscopy, TUNEL staining and flow cytometry were utilized to analyse apoptosis and status of MAM in DsbA-L mutant mice. FINDINGS: We showed that MAM was significantly reduced in the kidneys of streptozotocin-induced diabetic mice, which correlated with the extent of renal injury. We also observed a correlation between the loss of MAM integrity and increased apoptosis and renal injury in diabetic nephropathy (DN). These alterations were further exacerbated in diabetic DsbA-L gene-deficient mice (DsbA-L(-/-)). In vitro, overexpression of DsbA-L in HK-2 cells restored MAM integrity and reduced apoptosis induced by high-glucose ambience. These beneficial effects were partially blocked by overexpression of FATE-1, a MAM uncoupling protein. Finally, the expression of DsbA-L was positively correlated with MAM integrity in the kidneys of DN patients but negatively correlated with apoptosis and renal injury. INTERPRETATION: Our results indicate that DsbA-L exerts an antiapoptotic effect by maintaining MAM integrity, which is apparently disrupted in DN. FUND: This work was supported by the National Natural Science Foundation of China (81730018), the National Key R&D Program of China (2016YFC1305501) and NIH (DK60635).

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    Zhang, Y.; Wu, Y.; Zhang, M.; Li, Z.; Liu, B.; Liu, H.; Hao, J.; Li, X. Synergistic mechanism between the endoplasmic reticulum and mitochondria and their crosstalk with other organelles. Cell Death Discovery 2023, 9 (1), 51,  DOI: 10.1038/s41420-023-01353-wIF: 6.1 Q1 B2

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    44

    Synergistic mechanism between the endoplasmic reticulum and mitochondria and their crosstalk with other organelles

    Zhang Yaozhi; Wu Yang; Zhang Minjie; Liu Bin; Hao Junfeng; Li Xiaoyu; Zhang Yaozhi; Wu Yang; Zhang Minjie; Li Zixian; Liu Bin; Liu Huafeng; Hao Junfeng; Li Xiaoyu

    Cell death discovery (2023), 9 (1), 51 ISSN:2058-7716.

    Organelles are functional areas where eukaryotic cells perform processes necessary for life. Each organelle performs specific functions; however, highly coordinated crosstalk occurs between them. Disorder of organelle networks often occur in various diseases. The endoplasmic reticulum (ER) and mitochondria are crucial organelles in eukaryotic cells as they are the material synthesis and oxidative metabolism centers, respectively. Homeostasis and orchestrated interactions are essential for maintaining the normal activities of cells. However, the mode and mechanism of organelle crosstalk is still a research challenge. Furthermore, the intricate association between organelle dyshomeostasis and the progression of many human diseases remains unclear. This paper systematically summarized the latest research advances in the synergistic mechanism between the endoplasmic reticulum and mitochondria and their crosstalk with other organelles based on recent literature. It also highlights the application potential of organelle homeostasis maintenance as a preventative and treatment strategy for diseases.

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    Chang, X.; Wang, W. X. Phthalate acid esters contribute to the cytotoxicity of mask leachate: Cell-based assay for toxicity assessment. J. Hazard. Mater. 2023, 459, 132093,  DOI: 10.1016/j.jhazmat.2023.132093IF: 12.2 Q1 B1

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    45

    Phthalate acid esters contribute to the cytotoxicity of mask leachate: Cell-based assay for toxicity assessment

    Chang, Xinyi; Wang, Wen-Xiong

    Journal of Hazardous Materials (2023), 459 (), 132093CODEN: JHMAD9; ISSN:0304-3894. (Elsevier B.V.)

    After the COVID-19 outbreak, masks have become an essential part of people lives. Although several studies have been conducted to det. the release of hazardous substances from masks, how their co-presence poses a potential exposure risk to human health remains unexplored. In this study, we quant. compared the leaching of substances from six different common types of masks, including phthalate acid esters (PAEs), metals, and microplastics (MPs), and comprehensively evaluated the potential cytotoxicity of different leachates. MPs smaller than 3μm were quantified by Py-GC-MS, and reusable masks showed greater releasing potentials up to 1504μg/g. We also detected the prevalence of PAEs in masks, with the highest release reaching 42μg/g, with di-Bu phthalate (DBP), diisobutyl phthalate (DiBP) and bis (2-ethylhexyl) phthalate (DEHP) being the predominant types. Moreover, the antimicrobial cloth masks released 173.0μg of Cu or 4.5μg of Ag, representing 2.7% and 0.04% of the original masks, resp. Our cell-based assay results demonstrated for the first time that mask leachate induced nuclear condensation with DNA damage, and simultaneously triggered high levels of glutathione and reactive oxidative stress prodn., which exacerbated mitochondrial fragmentation, eventually leading to cell death. Combined with substance identification and correlation anal., PAEs were found to be the contributors to cytotoxicity. Masks contg. Cu or Ag led to acidification of lysosomes and alkalinization of cells. These results strongly suggested that the levels of PAEs in the prodn. of regulatory masks should be strictly controlled.

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    Concetta Scuto, M.; Mancuso, C.; Tomasello, B.; Laura Ontario, M.; Cavallaro, A.; Frasca, F.; Maiolino, L.; Trovato Salinaro, A.; Calabrese, E. J.; Calabrese, V. Curcumin, Hormesis and the Nervous System. Nutrients 2019, 11 (10), 2417,  DOI: 10.3390/nu11102417IF: 4.8 Q1 B2

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    There is no corresponding record for this reference.
47. 47

    Calabrese, V.; Giordano, J.; Signorile, A.; Laura Ontario, M.; Castorina, S.; De Pasquale, C.; Eckert, G.; Calabrese, E. J. Major pathogenic mechanisms in vascular dementia: Roles of cellular stress response and hormesis in neuroprotection. J. Neurosci. Res. 2016, 94 (12), 1588– 1603,  DOI: 10.1002/jnr.23925IF: 2.9 Q2 B3

    Google Scholar

    47

    Major pathogenic mechanisms in vascular dementia: Roles of cellular stress response and hormesis in neuroprotection

    Calabrese, Vittorio; Giordano, James; Signorile, Anna; Ontario, Maria Laura; Castorina, Sergio; De Pasquale, Concetta; Eckert, Gunter; Calabrese, Edward J.

    Journal of Neuroscience Research (2016), 94 (12), 1588-1603CODEN: JNREDK; ISSN:0360-4012. (Wiley-Blackwell)

    Vascular dementia (VaD), considered the second most common cause of cognitive impairment after Alzheimer disease in the elderly, involves the impairment of memory and cognitive function as a consequence of cerebrovascular disease. Chronic cerebral hypoperfusion is a common pathophysiol. condition frequently occurring in VaD. It is generally assocd. with neurovascular degeneration, in which neuronal damage and blood-brain barrier alterations coexist and evoke beta-amyloid-induced oxidative and nitrosative stress, mitochondrial dysfunction, and inflammasome- promoted neuroinflammation, which contribute to and exacerbate the course of disease. Vascular cognitive impairment comprises a heterogeneous group of cognitive disorders of various severity and types that share a presumed vascular etiol. The present study reviews major pathogenic factors involved in VaD, highlighting the relevance of cerebrocellular stress and hormetic responses to neurovascular insult, and addresses these mechanisms as potentially viable and valuable as foci of novel neuroprotective methods to mitigate or prevent VaD. © 2016 Wiley Periodicals, Inc.

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    Calabrese, V.; Mancuso, C.; Calvani, M.; Rizzarelli, E.; Butterfield, D. A.; Giuffrida Stella, A. M. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat. Rev. Neurosci. 2007, 8 (10), 766– 775,  DOI: 10.1038/nrn2214IF: 28.7 Q1 B1

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    48

    Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity

    Calabrese, Vittorio; Mancuso, Cesare; Calvani, Menotti; Rizzarelli, Enrico; Butterfield, D. Allan; Giuffrida Stella, Anna Maria

    Nature Reviews Neuroscience (2007), 8 (10), 766-775CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)

    A review. At the end of the 1980s, it was clearly demonstrated that cells produce nitric oxide and that this gaseous mol. is involved in the regulation of the cardiovascular, immune and nervous systems, rather than simply being a toxic pollutant. In the CNS, nitric oxide has an array of functions, such as the regulation of synaptic plasticity, the sleep-wake cycle and hormone secretion. Particularly interesting is the role of nitric oxide as a Janus mol. in the cell death or survival mechanisms in brain cells. In fact, physiol. amts. of this gas are neuroprotective, whereas higher concns. are clearly neurotoxic.

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    Calabrese, V.; Cornelius, C.; Dinkova-Kostova, A. T.; Calabrese, E. J.; Mattson, M. P. Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid. Redox Signaling 2010, 13 (11), 1763– 1811,  DOI: 10.1089/ars.2009.3074IF: 5.9 Q1 B2

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    49

    Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders

    Calabrese, Vittorio; Cornelius, Carolin; Dinkova-Kostova, Albena T.; Calabrese, Edward J.; Mattson, Mark P.

    Antioxidants & Redox Signaling (2010), 13 (11), 1763-1811CODEN: ARSIF2; ISSN:1523-0864. (Mary Ann Liebert, Inc.)

    A review. Despite the capacity of chaperones and other homeostatic components to restore folding equil., cells appear poorly adapted for chronic oxidative stress that increases in cancer and in metabolic and neurodegenerative diseases. Modulation of endogenous cellular defense mechanisms represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. This article introduces the concept of hormesis and its applications to the field of neuroprotection. It is argued that the hormetic dose response provides the central underpinning of neuroprotective responses, providing a framework for explaining the common quant. features of their dose-response relationships, their mechanistic foundations, and their relationship to the concept of biol. plasticity, as well as providing a key insight for improving the accuracy of the therapeutic dose of pharmaceutical agents within the highly heterogeneous human population. This article describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including sirtuin and Nrf2 and related pathways that integrate adaptive stress responses in the prevention of neurodegenerative diseases. Particular attention is given to the emerging role of nitric oxide, carbon monoxide, and hydrogen sulfide gases in hormetic-based neuroprotection and their relationship to membrane radical dynamics and mitochondrial redox signaling. Antioxid. Redox Signal. 13, 1763-1811.

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    Anacker, C.; Hen, R. Adult hippocampal neurogenesis and cognitive flexibility - linking memory and mood. Nat. Rev. Neurosci. 2017, 18 (6), 335– 346,  DOI: 10.1038/nrn.2017.45IF: 28.7 Q1 B1

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    50

    Adult hippocampal neurogenesis and cognitive flexibility - linking memory and mood

    Anacker, Christoph; Hen, Rene

    Nature Reviews Neuroscience (2017), 18 (6), 335-346CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)

    Adult hippocampal neurogenesis has been implicated in cognitive processes, such as pattern sepn., and in the behavioral effects of stress and antidepressants. Young adult-born neurons have been shown to inhibit the overall activity of the dentate gyrus by recruiting local interneurons, which may result in sparse contextual representations and improved pattern sepn. We propose that neurogenesis-mediated inhibition also reduces memory interference and enables reversal learning both in neutral situations and in emotionally charged ones. Such improved cognitive flexibility may in turn help to decrease anxiety-like and depressive-like behavior.

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    Engel, S. M.; Patisaul, H. B.; Brody, C.; Hauser, R.; Zota, A. R.; Bennet, D. H.; Swanson, M.; Whyatt, R. M. Neurotoxicity of Ortho-Phthalates: Recommendations for Critical Policy Reforms to Protect Brain Development in Children. Am. J. Public Health 2021, 111 (4), 687– 695,  DOI: 10.2105/AJPH.2020.306014

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    51

    Neurotoxicity of Ortho-Phthalates: Recommendations for Critical Policy Reforms to Protect Brain Development in Children

    Engel Stephanie M; Patisaul Heather B; Brody Charlotte; Hauser Russ; Zota Ami R; Bennet Deborah H; Swanson Maureen; Whyatt Robin M

    American journal of public health (2021), 111 (4), 687-695 ISSN:.

    Robust data from longitudinal birth cohort studies and experimental studies of perinatally exposed animals indicate that exposure to ortho-phthalates can impair brain development and increase risks for learning, attention, and behavioral disorders in childhood. This growing body of evidence, along with known adverse effects on male reproductive tract development, calls for immediate action.Exposures are ubiquitous; the majority of people are exposed to multiple ortho-phthalates simultaneously. We thus recommend that a class approach be used in assessing health impacts as has been done with other chemical classes. We propose critically needed policy reforms to eliminate ortho-phthalates from products that lead to exposure of pregnant women, women of reproductive age, infants, and children. Specific attention should be focused on reducing exposures among socially vulnerable populations such as communities of color, who frequently experience higher exposures.Ortho-phthalates are used in a vast array of products and elimination will thus necessitate a multipronged regulatory approach at federal and state levels. The fact that manufacturers and retailers have already voluntarily removed ortho-phthalates from a wide range of products indicates that this goal is feasible.

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    Ducroq, S.; Duplus, E.; Grange-Messent, V.; Trivelloni, F.; Penalva-Mousset, L.; Petropoulos, I.; Mhaouty-Kodja, S. Cognitive and hippocampal effects of adult male mice exposure to environmentally relevant doses of phthalates. Environ. Pollut. 2023, 323, 121341,  DOI: 10.1016/j.envpol.2023.121341

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    52

    Cognitive and hippocampal effects of adult male mice exposure to environmentally relevant doses of phthalates

    Ducroq Suzanne; Grange-Messent Valerie; Francesca Trivelloni; Duplus Eric; Penalva-Mousset Lucille; Petropoulos Isabelle; Mhaouty-Kodja Sakina

    Environmental pollution (Barking, Essex : 1987) (2023), 323 (), 121341 ISSN:.

    We recently showed that chronic exposure of adult male mice to environmental doses of DEHP alone or in a phthalate mixture altered blood brain barrier integrity and induced an inflammatory profile in the hippocampus. Here, we investigate whether such exposure alters hippocampus-dependent behavior and underlying cellular mechanisms. Adult C57BL/6 J male mice were continuously exposed orally to the vehicle or DEHP alone (5 or 50 μg/kg/d) or to DEHP (5 μg/kg/d) in a phthalate mixture. In the Morris water maze, males showed reduced latencies across days to find the platform in the cue and spatial reference memory tasks, regardless of their treatment group. In the probe test, DEHP-50 exposed males displayed a higher latency to find the platform quadrant. In the temporal order memory test, males exposed to DEHP alone or in a phthalate mixture were unable to discriminate between the most recently and previously seen objects. They also displayed reduced ability to show a preference for the new object in the novel object recognition test. These behavioral alterations were associated with a lowered dendritic spine density and protein levels of glutamate receptors and postsynaptic markers, and increased protein levels of the presynaptic synaptophysin in the hippocampus. Metabolomic analysis of the hippocampus indicated changes in amino acid levels including reduced tryptophan and L-kynurenine and elevated NAD + levels, respectively, a precursor, intermediate and endproduct of the kynurenine pathway of tryptophan metabolism. Interestingly, the protein amounts of the xenobiotic aryl hydrocarbon receptor, a target of this metabolic pathway, were elevated in the CA1 area. These data indicate that chronic exposure of adult male mice to environmental doses of DEHP alone or in a phthalate mixture impacted hippocampal function and structure, associated with modifications in amino acid metabolites with a potential involvement of the kynurenine pathway of tryptophan metabolism.

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    Ahmadpour, D.; Mhaouty-Kodja, S.; Grange-Messent, V. Effects and underlying cellular pathway involved in the impairment of the neurovascular unit following exposure of adult male mice to low doses of di(2-ethylhexyl) phthalate alone or in an environmental phthalate mixture. Environ. Res. 2022, 207, 112235,  DOI: 10.1016/j.envres.2021.112235

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    53

    Effects and underlying cellular pathway involved in the impairment of the neurovascular unit following exposure of adult male mice to low doses of di(2-ethylhexyl) phthalate alone or in an environmental phthalate mixture

    Ahmadpour, Delnia; Mhaouty-Kodja, Sakina; Grange-Messent, Valerie

    Environmental Research (2022), 207 (), 112235CODEN: ENVRAL; ISSN:0013-9351. (Elsevier Inc.)

    We have previously shown that adult male mice exposure to low doses of di (2-ethylhexyl)phthalate (DEHP) impacts the blood-brain barrier (BBB) integrity and surrounding parenchyma in the medial preoptic area (mPOA), a key hypothalamic area involved in the male sexual behavior. BBB leakage was assocd. with a decrease in the endothelial tight junction accessory protein, zona occludens-1, and caveolae protein Cav-1, added to an inflammatory profile including glial activation accompanied by enhanced expression of inducible nitric oxide synthase. As this failure of BBB functionality in the mPOA could participate, at least in part, in reported alteration of sexual behavior following DEHP exposure, we explored the cellular pathway connecting cerebral capillaries and neurons. Two-month-old C57BL/6J male mice were orally exposed for 6 wk to DEHP alone (5 and 50μg/kg/day) or to DEHP (5μg/kg/day) in an environmental phthalate mixt. The presence of androgen receptor (AR) and estrogen receptor-α (ERα) were first evidenced in brain capillaries. Protein levels of AR but not of ERα were reduced in cerebral capillaries after phthalate exposure. The amts. of basement membrane and cell-matrix interaction components were decreased, while matrix metalloprotease MMP-2 and MMP-9 activities were increased. Fluorojade labeling suggested that exposure to phthalates also lead to a neurodegenerative process in the mPOA. Altogether, the data suggest that environmental exposure to endocrine disruptors such as phthalates, could alter AR/Cav-1 interaction, impacting a Cav-1/nitric oxide/MMP pathway. This would lead to disruption of the glio-neurovascular coupling which is essential to neuronal functioning.

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    Ren, W. Q.; Liu, N.; Shen, Y.; Wang, X. Y.; Zhou, Q.; Rui, C.; Yang, X. H.; Cao, S. L.; Li, L. Y.; Wang, Y.; Wang, Q. N. Subchronic exposure to di-(2-ethylhexyl) phthalate (DEHP) elicits blood-brain barrier dysfunction and neuroinflammation in male C57BL/6J mice. Toxicology 2023, 499, 153650,  DOI: 10.1016/j.tox.2023.153650

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    Subchronic exposure to di-(2-ethylhexyl) phthalate (DEHP) elicits blood-brain barrier dysfunction and neuroinflammation in male C57BL/6J mice

    Ren, Wen-qiang; Liu, Nuo; Shen, Yan; Wang, Xian-yan; Zhou, Qiong; Rui, Chen; Yang, Xiao-han; Cao, Sheng-long; Li, Ling-yu; Wang, Yan; Wang, Qu-nan

    Toxicology (2023), 499 (), 153650CODEN: TXCYAC; ISSN:0300-483X. (Elsevier Ltd.)

    Exposure to di-(2-ethylhexyl) phthalate (DEHP) can cause neurotoxicity but the mechanism is not clear. Blood brain barrier (BBB) is one of the most important tissues to protect the brain. However, whether DEHP can disrupt the BBB or not remains unclear. The objective of this study is to investigate the potential effects of subchronic DEHP exposure on BBB integrity and discuss the role of BBB in DEHP inducible neurotoxicity with an emphasis on neuroinflammatory responses. Male adult C57BL/6J mice were orally administered with vehicle or 200 or 750 mg/kg/day DEHP for 90 days. Subchronic exposure to high-dose DEHP increased water intake but decreased body wt. and brain wt. The concns. of DEHP metabolites increased in serum from all DEHP-exposed groups while increased in brain only from the high-dose group. DEHP induced neurobehavioural alterations and damaged hippocampal neurons. DEHP increased BBB permeability by Evans blue (EB) extravasation and decreased tight junction proteins (ZO-1, occludin, and claudin-5) while presenting a neuroinflammatory feature characterized by the upregulated inflammatory mediators TNF-α and the NLRP3/caspase-1/IL-1β inflammasome pathway. Our data provide new insights into neurotoxicity caused by subchronic DEHP exposure, which is probably involved in BBB dysfunction and neuroinflammatory responses.

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55. 55

    Sun, D.; Chen, X.; Gu, G.; Wang, J.; Zhang, J. Potential Roles of Mitochondria-Associated ER Membranes (MAMs) in Traumatic Brain Injury. Cell. Mol. Neurobiol. 2017, 37 (8), 1349– 1357,  DOI: 10.1007/s10571-017-0484-2

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    55

    Potential Roles of Mitochondria-Associated ER Membranes (MAMs) in Traumatic Brain Injury

    Sun, Dongdong; Chen, Xin; Gu, Gang; Wang, Jianhao; Zhang, Jianning

    Cellular and Molecular Neurobiology (2017), 37 (8), 1349-1357CODEN: CMNEDI; ISSN:0272-4340. (Springer)

    The endoplasmic reticulum (ER) and mitochondria have both been shown to be crit. in cellular homeostasis. The functions of the ER and mitochondria are independent but interrelated. These two organelles could form phys. interactions, known as MAMs, to regulate physiol. functions between ER and mitochondria to maintain Ca2+, lipid, and metabolite exchange. Several proteins are located in MAMs, including RNA-dependent protein kinase (PKR)-like ER kinase, inositol 1,4,5-trisphosphate receptors, phosphofurin acidic cluster sorting protein-2 and sigma-1 receptor to ensure regulation. Recent studies indicated that MAMs participate in inflammation and apoptosis in various conditions. All of these functions are crucial in detg. cell fate following traumatic brain injury (TBI). We hypothesized that MAMs may assoc. with TBI and could contribute to mitochondrial dysfunction, ER stress, autophagy dysregulation, dysregulation of Ca2+ homeostasis, and oxidative stress. In this review, we summarize the latest understanding of MAM formation and their potential regulatory role in TBI pathophysiol.

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56. 56

    Markovinovic, A.; Greig, J.; Martin-Guerrero, S. M.; Salam, S.; Paillusson, S. Endoplasmic reticulum-mitochondria signaling in neurons and neurodegenerative diseases. J. Cell Sci. 2022, 135 (3), 248534,  DOI: 10.1242/jcs.248534

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    56

    Endoplasmic reticulum-mitochondria signaling in neurons and neurodegenerative diseases

    Markovinovic, Andrea; Greig, Jenny; Martin-Guerrero, Sandra Maria; Salam, Shaakir; Paillusson, Sebastien

    Journal of Cell Science (2022), 135 (3), jcs248534CODEN: JNCSAI; ISSN:1477-9137. (Company of Biologists Ltd.)

    A review. Recent advances have revealed common pathol. changes in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis with related frontotemporal dementia (ALS/FTD). Many of these changes can be linked to alterations in endoplasmic reticulum (ER)-mitochondria signaling, including dysregulation of Ca2+ signaling, autophagy, lipid metab., ATP prodn., axonal transport, ER stress responses and synaptic dysfunction. ER-mitochondria signaling involves specialized regions of ER, called mitochondria-assocd. membranes (MAMs). Owing to their role in neurodegenerative processes, MAMs have gained attention as they appear to be assocd. with all the major neurodegenerative diseases. Furthermore, their specific role within neuronal maintenance is being revealed as mutant genes linked to major neurodegenerative diseases have been assocd. with damage to these specialized contacts. Several studies have now demonstrated that these specialized contacts regulate neuronal health and synaptic transmission, and that MAMs are damaged in patients with neurodegenerative diseases. This Review will focus on the role of MAMs and ER-mitochondria signaling within neurons and how damage of the ER-mitochondria axis leads to a disruption of vital processes causing eventual neurodegeneration.

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57. 57

    Bertholet, A. M.; Delerue, T.; Millet, A. M.; Moulis, M. F.; David, C.; Daloyau, M.; Arnaune-Pelloquin, L.; Davezac, N.; Mils, V.; Miquel, M. C.; Rojo, M.; Belenguer, P. Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity. Neurobiol. Dis. 2016, 90, 3– 19,  DOI: 10.1016/j.nbd.2015.10.011

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    57

    Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity

    Bertholet, A. M.; Delerue, T.; Millet, A. M.; Moulis, M. F.; David, C.; Daloyau, M.; Arnaune-Pelloquin, L.; Davezac, N.; Mils, V.; Miquel, M. C.; Rojo, M.; Belenguer, P.

    Neurobiology of Disease (2016), 90 (), 3-19CODEN: NUDIEM; ISSN:0969-9961. (Elsevier Inc.)

    Mitochondria are dynamic organelles that continually move, fuse and divide. The dynamic balance of fusion and fission of mitochondria dets. their morphol. and allows their immediate adaptation to energetic needs, keeps mitochondria in good health by restoring or removing damaged organelles or ppts. cells in apoptosis in cases of severe defects. Mitochondrial fusion and fission are essential in mammals and their disturbances are assocd. with several diseases. However, while mitochondrial fusion/fission dynamics, and the proteins that control these processes, are ubiquitous, assocd. diseases are primarily neurol. disorders. Accordingly, inactivation of the main actors of mitochondrial fusion/fission dynamics is assocd. with defects in neuronal development, plasticity and functioning, both ex vivo and in vivo. Here, we present the central actors of mitochondrial fusion and fission and review the role of mitochondrial dynamics in neuronal physiol. and pathophysiol. Particular emphasis is placed on the three main actors of these processes i.e. DRP1, MFN1-2, and OPA1 as well as on GDAP1, a protein of the mitochondrial outer membrane preferentially expressed in neurons. This article is part of a Special Issue entitled: Mitochondria & Brain.

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58. 58

    Khacho, M.; Slack, R. S. Mitochondrial dynamics in the regulation of neurogenesis: From development to the adult brain. Dev. Dynam. 2018, 247 (1), 47– 53,  DOI: 10.1002/dvdy.24538

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    There is no corresponding record for this reference.
59. 59

    Hu, L.; Ding, M.; Tang, D.; Gao, E.; Li, C.; Wang, K.; Qi, B.; Qiu, J.; Zhao, H.; Chang, P.; Fu, F.; Li, Y. Targeting mitochondrial dynamics by regulating Mfn2 for therapeutic intervention in diabetic cardiomyopathy. Theranostics 2019, 9 (13), 3687– 3706,  DOI: 10.7150/thno.33684

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    59

    Targeting mitochondrial dynamics by regulating Mfn2 for therapeutic intervention in diabetic cardiomyopathy

    Hu, Lang; Ding, Mingge; Tang, Daishi; Gao, Erhe; Li, Congye; Wang, Kaiyan; Qi, Bingchao; Qiu, Jihuan; Zhao, Huishou; Chang, Pan; Fu, Feng; Li, Yan

    Theranostics (2019), 9 (13), 3687-3706CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)

    Increasing evidence has implicated the important role of mitochondrial pathol. in diabetic cardiomyopathy (DCM), while the underlying mechanism remains largely unclear. The aim of this study was to investigate the role of mitochondrial dynamics in the pathogenesis of DCM and its underlying mechanisms. Obese diabetic (db/db) and lean control (db/+) mice were used in this study. Mitochondrial dynamics were analyzed by transmission electron microscopy in vivo and by confocal microscopy in vitro. Diabetic hearts from 12-wk-old db/db mice showed excessive mitochondrial fission and significant reduced expression of Mfn2, while there was no significant alteration or slight change in the expression of other dynamic-related proteins. Reconstitution of Mfn2 in diabetic hearts inhibited mitochondrial fission and prevented the progression of DCM. In an in-vitro study, cardiomyocytes cultured in high-glucose and high-fat (HG/HF) medium showed excessive mitochondrial fission and decreased Mfn2 expression. Reconstitution of Mfn2 restored mitochondrial membrane potential, suppressed mitochondrial oxidative stress and improved mitochondrial function in HG/HF-treated cardiomyocytes through promoting mitochondrial fusion. In addn., the down-regulation of Mfn2 expression in HG/HF-treated cardiomyocytes was induced by reduced expression of PPARα, which pos. regulated the expression of Mfn2 by directly binding to its promoter. Our study provides the first evidence that imbalanced mitochondrial dynamics induced by down-regulated Mfn2 contributes to the development of DCM. Targeting mitochondrial dynamics by regulating Mfn2 might be a potential therapeutic strategy for DCM.

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60. 60

    Gebara, E.; Zanoletti, O.; Ghosal, S.; Grosse, J.; Schneider, B. L.; Knott, G.; Astori, S.; Sandi, C. Mitofusin-2 in the Nucleus Accumbens Regulates Anxiety and Depression-like Behaviors Through Mitochondrial and Neuronal Actions. Biol. Psychiatr. 2021, 89 (11), 1033– 1044,  DOI: 10.1016/j.biopsych.2020.12.003

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    60

    Mitofusin-2 in the Nucleus Accumbens Regulates Anxiety and Depression-like Behaviors Through Mitochondrial and Neuronal Actions

    Gebara, Elias; Zanoletti, Olivia; Ghosal, Sriparna; Grosse, Jocelyn; Schneider, Bernard L.; Knott, Graham; Astori, Simone; Sandi, Carmen

    Biological Psychiatry (2021), 89 (11), 1033-1044CODEN: BIPCBF; ISSN:0006-3223. (Elsevier Inc.)

    Emerging evidence points to a central role of mitochondria in psychiatric disorders. However, little is known about the mol. players that regulate mitochondria in neural circuits regulating anxiety and depression and about how they impact neuronal structure and function. Here, we investigated the role of mols. involved in mitochondrial dynamics in medium spiny neurons (MSNs) from the nucleus accumbens (NAc), a hub of the brains motivation system. We assessed how individual differences in anxiety-like (measured via the elevated plus maze and open field tests) and depression-like (measured via the forced swim and saccharin preference tests) behaviors in outbred rats relate to mitochondrial morphol. (electron microscopy and 3-dimensional reconstructions) and function (mitochondrial respirometry). Mitochondrial mols. were measured for protein (Western blot) and mRNA (quant. reverse transcriptase polymerase chain reaction, RNAscope) content. Dendritic arborization (Golgi Sholl analyses), spine morphol., and MSN excitatory inputs (patch-clamp electrophysiol.) were characterized. MFN2 overexpression in the NAc was induced through an AAV9-syn1-MFN2. Highly anxious animals showed increased depression-like behaviors, as well as reduced expression of the mitochondrial GTPase MFN2 in the NAc. They also showed alterations in mitochondria (i.e., respiration, vol., and interactions with the endoplasmic reticulum) and MSNs (i.e., dendritic complexity, spine d. and typol., and excitatory inputs). Viral MFN2 overexpression in the NAc reversed all of these behavioral, mitochondrial, and neuronal phenotypes. Our results implicate a causal role for accumbal MFN2 on the regulation of anxiety and depression-like behaviors through actions on mitochondrial and MSN structure and function. MFN2 is posited as a promising therapeutic target to treat anxiety and assocd. behavioral disturbances.

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61. 61

    Rocha, A. G.; Franco, A.; Krezel, A. M.; Rumsey, J. M.; Alberti, J. M.; Knight, W. C.; Biris, N.; Zacharioudakis, E.; Janetka, J. W.; Baloh, R. H.; Kitsis, R. N.; Mochly-Rosen, D.; Townsend, R. R.; Gavathiotis, E.; Dorn, G. W. MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A. Science 2018, 360 (6386), 336– 341,  DOI: 10.1126/science.aao1785IF: 44.7 Q1 B1

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    61

    MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A

    Rocha, Agostinho G.; Franco, Antonietta; Krezel, Andrzej M.; Rumsey, Jeanne M.; Alberti, Justin M.; Knight, William C.; Biris, Nikolaos; Zacharioudakis, Emmanouil; Janetka, James W.; Baloh, Robert H.; Kitsis, Richard N.; Mochly-Rosen, Daria; Townsend, R. Reid; Gavathiotis, Evripidis; Dorn, Gerald W., II

    Science (Washington, DC, United States) (2018), 360 (6386), 336-341CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

    Mitofusins (MFNs) promote fusion-mediated mitochondrial content exchange and subcellular trafficking. Mutations in Mfn2 cause neurodegenerative Charcot-Marie-Tooth disease type 2A (CMT2A). We showed that MFN2 activity can be detd. by Met376 and His380 interactions with Asp725 and Leu727 and controlled by PINK1 kinase-mediated phosphorylation of adjacent MFN2 Ser378. Small-mol. mimics of the peptide-peptide interface of MFN2 disrupted this interaction, allosterically activating MFN2 and promoting mitochondrial fusion. These first-in-class mitofusin agonists overcame dominant mitochondrial defects provoked in cultured neurons by CMT2A mutants MFN2 Arg94→Gln94 and MFN2 Thr105→Met105, as demonstrated by amelioration of mitochondrial dysmotility, fragmentation, depolarization, and clumping. A mitofusin agonist normalized axonal mitochondrial trafficking within sciatic nerves of MFN2 Thr105→Met105 mice, promising a therapeutic approach for CMT2A and other untreatable diseases of impaired neuronal mitochondrial dynamism and/or trafficking.

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62. 62

    Chanaday, N. L.; Nosyreva, E.; Shin, O. H.; Zhang, H.; Aklan, I.; Atasoy, D.; Bezprozvanny, I.; Kavalali, E. T. Presynaptic store-operated Ca(2+) entry drives excitatory spontaneous neurotransmission and augments endoplasmic reticulum stress. Neuron 2021, 109 (8), 1314– 1332.e5,  DOI: 10.1016/j.neuron.2021.02.023IF: 14.7 Q1 B1

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    62

    Presynaptic store-operated Ca2+ entry drives excitatory spontaneous neurotransmission and augments endoplasmic reticulum stress

    Chanaday, Natali L.; Nosyreva, Elena; Shin, Ok-Ho; Zhang, Hua; Aklan, Iltan; Atasoy, Deniz; Bezprozvanny, Ilya; Kavalali, Ege T.

    Neuron (2021), 109 (8), 1314-1332.e5CODEN: NERNET; ISSN:0896-6273. (Cell Press)

    Store-operated calcium entry (SOCE) is activated by depletion of Ca2+ from the endoplasmic reticulum (ER) and mediated by stromal interaction mol. (STIM) proteins. Here, we show that in rat and mouse hippocampal neurons, acute ER Ca2+ depletion increases presynaptic Ca2+ levels and glutamate release through a pathway dependent on STIM2 and the synaptic Ca2+ sensor synaptotagmin-7 (syt7). In contrast, synaptotagmin-1 (syt1) can suppress SOCE-mediated spontaneous release, and STIM2 is required for the increase in spontaneous release seen during syt1 loss of function. We also demonstrate that chronic ER stress activates the same pathway leading to syt7-dependent potentiation of spontaneous glutamate release. During ER stress, inhibition of SOCE or syt7-driven fusion partially restored basal neurotransmission and decreased expression of pro-apoptotic markers, indicating that these processes participate in the amplification of ER-stress-related damage. Taken together, we propose that presynaptic SOCE links ER stress and augmented spontaneous neurotransmission, which may, in turn, facilitate neurodegeneration.

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63. 63

    Yang, Z.; Zhou, C.; Shi, H.; Zhang, N.; Tang, B.; Ji, N. Heme Induces BECN1/ATG5-Mediated Autophagic Cell Death via ER Stress in Neurons. Neurotox. Res. 2020, 38 (4), 1037– 1048,  DOI: 10.1007/s12640-020-00275-0IF: 2.9 Q2 B3

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    63

    Heme Induces BECN1/ATG5-Mediated Autophagic Cell Death via ER Stress in Neurons

    Yang, Zhao; Zhou, Changlong; Shi, Hui; Zhang, Nan; Tang, Bin; Ji, Na

    Neurotoxicity Research (2020), 38 (4), 1037-1048CODEN: NURRFI; ISSN:1029-8428. (Springer)

    Intracerebral hemorrhage (ICH) is a serious medical problem, and effective treatment is limited. Hemorrhaged blood is highly toxic to the brain, and heme, which is mainly released from Hb, plays a vital role in neurotoxicity. However, the specific mechanism involved in heme-mediated neurotoxicity has not been well studied. In this study, we investigated the neurotoxicity of heme in neurons. Neurons were treated with heme, and cell death, autophagy, and endoplasmic reticulum (ER) stress were analyzed. In addn., the relationship between autophagy and apoptosis in heme-induced cell death and the downstream effects were also assessed. We showed that heme induced cell death and autophagy in neurons. The suppression of autophagy using either pharmacol. inhibitors (3-methyladenine) or RNA interference of essential autophagy genes (BECN1 and ATG5) decreased heme-induced cell death in neurons. Moreover, the ER stress activator thapsigargin increased cell autophagy and the cell death ratio following heme treatment. Autophagy promoted heme-induced cell apoptosis and cell death through the BECN1/ATG5 pathway. Our findings suggest that heme potentiates neuronal autophagy via ER stress, which in turn induces cell death via the BECN1/ATG5 pathway. Targeting ER stress-mediated autophagy might be a promising therapeutic strategy for ICH.

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64. 64

    Zhang, S.; Cao, X.; Stablow, A. M.; Shenoy, V. B.; Winkelstein, B. A. Tissue Strain Reorganizes Collagen With a Switchlike Response That Regulates Neuronal Extracellular Signal-Regulated Kinase Phosphorylation In Vitro: Implications for Ligamentous Injury and Mechanotransduction. J. Biomech. Eng. 2016, 138 (2), 021013,  DOI: 10.1115/1.4031975IF: 1.7 Q3 B4

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    64

    Tissue Strain Reorganizes Collagen With a Switchlike Response That Regulates Neuronal Extracellular Signal-Regulated Kinase Phosphorylation In Vitro: Implications for Ligamentous Injury and Mechanotransduction

    Zhang Sijia; Cao Xuan; Stablow Alec M; Shenoy Vivek B; Winkelstein Beth A

    Journal of biomechanical engineering (2016), 138 (2), 021013 ISSN:.

    Excessive loading of ligaments can activate the neural afferents that innervate the collagenous tissue, leading to a host of pathologies including pain. An integrated experimental and modeling approach was used to define the responses of neurons and the surrounding collagen fibers to the ligamentous matrix loading and to begin to understand how macroscopic deformation is translated to neuronal loading and signaling. A neuron-collagen construct (NCC) developed to mimic innervation of collagenous tissue underwent tension to strains simulating nonpainful (8%) or painful ligament loading (16%). Both neuronal phosphorylation of extracellular signal-regulated kinase (ERK), which is related to neuroplasticity (R2 ≥ 0.041; p ≤ 0.0171) and neuronal aspect ratio (AR) (R2 ≥ 0.250; p < 0.0001), were significantly correlated with tissue-level strains. As NCC strains increased during a slowly applied loading (1%/s), a "switchlike" fiber realignment response was detected with collagen reorganization occurring only above a transition point of 11.3% strain. A finite-element based discrete fiber network (DFN) model predicted that at bulk strains above the transition point, heterogeneous fiber strains were both tensile and compressive and increased, with strains in some fibers along the loading direction exceeding the applied bulk strain. The transition point identified for changes in collagen fiber realignment was consistent with the measured strain threshold (11.7% with a 95% confidence interval of 10.2-13.4%) for elevating ERK phosphorylation after loading. As with collagen fiber realignment, the greatest degree of neuronal reorientation toward the loading direction was observed at the NCC distraction corresponding to painful loading. Because activation of neuronal ERK occurred only at strains that produced evident collagen fiber realignment, findings suggest that tissue strain-induced changes in the micromechanical environment, especially altered local collagen fiber kinematics, may be associated with mechanotransduction signaling in neurons.

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65. 65

    Musner, N.; Sidoli, M.; Zambroni, D.; Del Carro, U.; Ungaro, D.; D’Antonio, M.; Feltri, M. L.; Wrabetz, L. Perk Ablation Ameliorates Myelination in S63del-Charcot-Marie-Tooth 1B Neuropathy. ASN Neuro 2016, 8 (2), 175909141664235,  DOI: 10.1177/1759091416642351

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    There is no corresponding record for this reference.
66. 66

    Amara, I.; Ontario, M. L.; Scuto, M.; Lo Dico, G. M.; Sciuto, S.; Greco, V.; Abid-Essefi, S.; Signorile, A.; Salinaro, A. T.; Calabrese, V. Moringa oleifera Protects SH-SY5YCells from DEHP-Induced Endoplasmic Reticulum Stress and Apoptosis. Antioxidants 2021, 10 (4), 532,  DOI: 10.3390/antiox10040532

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    66

    Moringa oleifera protects SH-SY5YCells from DEHP-induced endoplasmic reticulum stress and apoptosis

    Amara, Ines; Ontario, Maria Laura; Scuto, Maria; Dico, Gianluigi Maria Lo; Sciuto, Sebastiano; Greco, Valentina; Abid-Essefi, Salwa; Signorile, Anna; Salinaro, Angela Trovato; Calabrese, Vittorio

    Antioxidants (2021), 10 (4), 532CODEN: ANTIGE; ISSN:2076-3921. (MDPI AG)

    Moringa oleifera (MO) is a medicinal plant that has been shown to possess antioxidant, anticarcinogenic and antibiotic activities. In a rat model, MO ext. (MOe) has been shown to have a protective effect against brain damage and memory decline. As an extending study, here, we have examd. the protective effect of MOe against oxidative stress and apoptosis caused in human neuroblastome (SH-SY5Y) cells by di-(2-ethylhexyl) phthalate (DEHP), a plasticizer known to induce neurotoxicity. Our data show that MOe prevents oxidative damage by lowering reactive oxygen species (ROS) formation, restoring mitochondrial respiratory chain complex activities, and, in addn., by modulating the expression of vitagenes, i.e., antioxidant proteins Nrf2 and HO-1. Moreover, MOe prevented neuronal damage by partly inhibiting endoplasmic reticulum (ER) stress response, as indicated by decreased expression of CCAAT-enhancer-binding protein homologous protein (CHOP) and Glucose-regulated protein 78 (GRP78) proteins. MOe also protected SH-SY5Y cells from DEHP-induced apoptosis, preserving mitochondrial membrane permeability and caspase-3 activation. Our findings provide insight into understanding of mol. mechanisms involved in neuroprotective effects by MOe against DEHP damage.

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67. 67

    Han, S.; Zhao, F.; Hsia, J.; Ma, X.; Liu, Y.; Torres, S.; Fujioka, H.; Zhu, X. The role of Mfn2 in the structure and function of endoplasmic reticulum-mitochondrial tethering in vivo. J. Cell Sci. 2021, 134 (13), 253443,  DOI: 10.1242/jcs.253443

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    67

    The role of Mfn2 in the structure and function of endoplasmic reticulum-mitochondrial tethering in vivo

    Han, Song; Zhao, Fanpeng; Hsia, Jeffrey; Ma, Xiaopin; Liu, Yi; Torres, Sandy; Fujioka, Hisashi; Zhu, Xiongwei

    Journal of Cell Science (2021), 134 (13), jcs253443CODEN: JNCSAI; ISSN:1477-9137. (Company of Biologists Ltd.)

    Mitochondria-endoplasmic reticulum contacts (MERCs) play an essential role in multiple cell physiol. processes. Although Mfn2 was the first protein implicated in the formation of MERCs, there is debate as to whether it acts as a tether or antagonizer, largely based on in vitro studies. To understand the role of Mfn2 in MERCs in vivo, we characterized ultrastructural and biochem. changes of MERCs in pyramidal neurons of hippocampus in Mfn2 conditional knockout mice and in Mfn2 overexpressing mice, and found that Mfn2 ablation caused reduced close contacts, whereas Mfn2 overexpression caused increased close contacts between the endoplasmic reticulum (ER) and mitochondria in vivo. Functional studies on SH-SY5Y cells with Mfn2 knockout or overexpression demonstrating similar biochem. changes found that mitochondrial calcium uptake along with IP3R3-Grp75 interaction was decreased in Mfn2 knockout cells but increased in Mfn2 overexpressing cells. Lastly, we found Mfn2 knockout decreased and Mfn2 overexpression increased the interaction between the ER-mitochondria tethering pair of VAPB-PTPIP51. In conclusion, our study supports the notion that Mfn2 plays a crit. role in ER-mitochondrial tethering and the formation of close contacts in neuronal cells in vivo.

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68. 68

    Che, L.; Yang, C. L.; Chen, Y.; Wu, Z. L.; Du, Z. B.; Wu, J. S.; Gan, C. L.; Yan, S. P.; Huang, J.; Guo, N. J.; Lin, Y. C.; Lin, Z. N. Mitochondrial redox-driven mitofusin 2 S-glutathionylation promotes neuronal necroptosis via disrupting ER-mitochondria crosstalk in cadmium-induced neurotoxicity. Chemosphere 2021, 262, 127878,  DOI: 10.1016/j.chemosphere.2020.127878

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    68

    Mitochondrial redox-driven mitofusin 2 S-glutathionylation promotes neuronal necroptosis via disrupting ER-mitochondria crosstalk in cadmium-induced neurotoxicity

    Che, Lin; Yang, Chuan-Li; Chen, Yu; Wu, Zi-Li; Du, Ze-Bang; Wu, Jia-Shen; Gan, Cong-Ling; Yan, Si-Ping; Huang, Jing; Guo, Ni-Jun; Lin, Yu-Chun; Lin, Zhong-Ning

    Chemosphere (2021), 262 (), 127878CODEN: CMSHAF; ISSN:0045-6535. (Elsevier Ltd.)

    Reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and mitochondrial dysfunction are known to affect the structural and functional damage in the neural system. Cadmium (Cd) is an environmental contaminant that is widely found in numerous environmental matrixes and exhibits potential neurotoxic risk. However, it remains unclear how mitochondrial redox status induces, and whether Cd destabilizes, the ER-mitochondria crosstalk to have a toxic effect on the nervous system. Herein, in our present study, bioinformatics anal. revealed an important role of protein interaction and mitochondrial machinery in brain samples from Alzheimer's disease (AD) patients. Furthermore, we established a neurotoxicity model in vivo and in vitro induced by cadmium chloride (CdCl2). We demonstrated that CdCl2 exposure disrupts the balance in mitochondrial redox represented by enhanced mitochondrial ROS (mitoROS) levels, which enhance mitofusin 2 (Mfn2) S-glutathionylation and interrupt the mitochondria-assocd. ER membranes (MAMs) for crosstalk between the ER and mitochondria to induce neuronal necroptosis. Mechanistically, it was shown that CdCl2 exposure significantly enhances the mitochondria-assocd. degrdn. (MAD) of Mfn2 via S-glutathionylation, which inhibits Mfn2 localization to the MAMs and subsequently leads to the formation of the RIPK1-RIPK3-p-MLKL complex (a key component of the necrosome) at MAMs, to promote neuronal necroptosis. Furthermore, the glutaredoxin 1 (Grx1) catalyzed and Mfn2 overexpression restored S-glu-Mfn2, MAMs perturbation, necrosome formation, and necroptosis in neurons induced by CdCl2 exposure in vitro. Moreover, the intervention with antioxidants to reduce mitochondrial redox, such as N-acetyl-L-cysteine (NAC) and mitochondria-targeted antioxidant Mito-TEMPO, reduced the S-glutathionylation of Mfn2 involved in the antagonism of CdCl2-induced necroptosis and neurotoxicity in vivo and in vitro. Taken together, our results are the first time to demonstrate that S-glutathionylation of Mfn2 promotes neuronal necroptosis via disruption of ER-mitochondria crosstalk in CdCl2-induced neurotoxicity, providing the novel mechanistic insight into how hazardous chem.-induced adverse effects in various organs and tissues could be interpreted by intraorganellar pathways under the control of MAMs components in neurons.

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    Chen, X.; Mi, L.; Gu, G.; Gao, X.; Gao, X.; Shi, M.; Chai, Y.; Chen, F.; Yang, W.; Zhang, J. Dysfunctional Endoplasmic Reticulum-Mitochondrion Coupling Is Associated with Endoplasmic Reticulum Stress-Induced Apoptosis and Neurological Deficits in a Rodent Model of Severe Head Injury. J. Neurotrauma 2022, 39 (7–8), 560– 576,  DOI: 10.1089/neu.2021.0347

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    69

    Dysfunctional Endoplasmic Reticulum-Mitochondrion Coupling Is Associated with Endoplasmic Reticulum Stress-Induced Apoptosis and Neurological Deficits in a Rodent Model of Severe Head Injury

    Chen Xin; Mi Liang; Gu Gang; Gao Xiangliang; Gao Xiangliang; Shi Mingming; Yang Weidong; Zhang Jianning; Chen Xin; Mi Liang; Gu Gang; Gao Xiangliang; Gao Xiangliang; Shi Mingming; Chai Yan; Chen Fanglian; Yang Weidong; Zhang Jianning

    Journal of neurotrauma (2022), 39 (7-8), 560-576 ISSN:.

    Cellular homeostasis requires critical communications between the endoplasmic reticulum (ER) and mitochondria to maintain the viability of cells. This communication is mediated and maintained by the mitochondria-associated membranes and may be disrupted during acute traumatic brain injury (TBI), leading to structural and functional damage of neurons and supporting cells. To test this hypothesis, we subjected male C57BL/6 mice to severe TBI (sTBI) using a controlled cortical impact device. We analyzed the physical ER-mitochondrion contacts in the perilesional cortex using transmission electron microscopy, Western blot, and immunofluorescence. We specifically measured changes in the production of reactive oxygen species (ROS) in mitochondria, the unfolded protein response (UPR), the neuroinflammatory response, and ER stress-mediated apoptosis in the traumatic injured cerebral tissue. A modified neurological severity score was used to evaluate neurological function in the sTBI mice. We found that sTBI induced significant reorganizations of mitochondria-associated ER membranes (MAMs) in the cerebral cortex within the first 24 h post-injury. This ER-mitochondrion coupling was enhanced, reaching its peak level at 6 h post-sTBI. This enhanced coupling correlated closely with increases in the expression of the Ca(2+) regulatory proteins (inositol 1,4,5-trisphosphate receptor type 1 [IP3R1], voltage-dependent anion channel 1 [VDAC1], glucose-regulated protein 75 [GRP75], Sigma 1 receptor [Sigma-1R]), production of ROS, degree of ER stress, levels of UPR, and release of proinflammatory cytokines. Further, the neurological function of sTBI mice was significantly improved by silencing the gene for the ER-mitochondrion tethering factor PACS2, restoring the IP3R1-GRP75-VDAC1 axis of Ca(2+) regulation, alleviating mitochondria-derived oxidative stress, suppressing inflammatory response through the PERK/eIF2α/ATF4/CHOP pathway, and inhibiting ER stress and associated apoptosis. These results indicate that dysfunctional ER-mitochondrion coupling might be primarily involved in the neuronal apoptosis and neurological deficits, and modulating the ER-mitochondrion crosstalk might be a novel therapeutic strategy for sTBI.

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