Browsing by Author "Zhang, Mei"

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Open Access
Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites.
(Acta neuropathologica, 2021-05) Tokarew, Jacqueline M; El-Kodsi, Daniel N; Lengacher, Nathalie A; Fehr, Travis K; Nguyen, Angela P; Shutinoski, Bojan; O'Nuallain, Brian; Jin, Ming; Khan, Jasmine M; Ng, Andy CH; Li, Juan; Jiang, Qiubo; Zhang, Mei; Wang, Liqun; Sengupta, Rajib; Barber, Kathryn R; Tran, An; Im, Doo Soon; Callaghan, Steve; Park, David S; Zandee, Stephanie; Dong, Xiajun; Scherzer, Clemens R; Prat, Alexandre; Tsai, Eve C; Takanashi, Masashi; Hattori, Nobutaka; Chan, Jennifer A; Zecca, Luigi; West, Andrew B; Holmgren, Arne; Puente, Lawrence; Shaw, Gary S; Toth, Gergely; Woulfe, John M; Taylor, Peggy; Tomlinson, Julianna J; Schlossmacher, Michael G
The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (H₂O₂) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of H₂O₂. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, H₂O₂ levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; H₂O₂ levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering H₂O₂. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63⁺ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H₂O₂, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson's-linked neurodegeneration.
Open Access
Dietary Patterns Associated with Cognitive Function among the Older People in Underdeveloped Regions: Finding from the NCDFaC Study.
(Nutrients, 2018-04-09) Yin, Zhaoxue; Chen, Jing; Zhang, Jian; Ren, Zeping; Dong, Kui; Kraus, Virginia B; Wang, Zhuoqun; Zhang, Mei; Zhai, Yi; Song, Pengkun; Zhao, Yanfang; Pang, Shaojie; Mi, Shengquan; Zhao, Wenhua
Although dietary patterns are crucial to cognitive function, associations of dietary patterns with cognitive function have not yet been fully understood. This cross-sectional study explored dietary patterns associated with cognitive function among the older adults in underdeveloped regions, using 1504 community-dwelling older adults aged 60 and over. Diet was assessed using a food frequency questionnaire and 24-h dietary recall. Factor analysis was used to extract dietary patterns. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE). Two dietary patterns, a "mushroom, vegetable, and fruits" (MVF) pattern and a "meat and soybean products" (MS) pattern, were identified. The MVF pattern, characterized by high consumption of mushrooms, vegetables, and fruits was significantly positively associated with cognitive function (p < 0.05), with an odds ratio of (95% CIs) 0.60 (0.38, 0.94) for cognitive impairment and β (95% CIs) 0.15 (0.02, 0.29) for -log (31-MMSE score). The MS pattern, characterized by high consumption of soybean products and meat, was also associated with better cognitive function, with an odds ratio of 0.47 (95% CIs 0.30, 0.74) for cognitive impairment and β (95% CIs) 0.34 (0.21, 0.47) for -log (31-MMSE score). Our results suggested that both the MVF and MS patterns were positively associated with better cognitive function among older adults in underdeveloped regions.
Open Access
Fiber type-specific nitric oxide protects oxidative myofibers against cachectic stimuli.
(PLoS One, 2008-05-07) Yu, Zengli; Li, Ping; Zhang, Mei; Hannink, Mark; Stamler, Jonathan S; Yan, Zhen
Oxidative skeletal muscles are more resistant than glycolytic muscles to cachexia caused by chronic heart failure and other chronic diseases. The molecular mechanism for the protection associated with oxidative phenotype remains elusive. We hypothesized that differences in reactive oxygen species (ROS) and nitric oxide (NO) determine the fiber type susceptibility. Here, we show that intraperitoneal injection of endotoxin (lipopolysaccharide, LPS) in mice resulted in higher level of ROS and greater expression of muscle-specific E3 ubiqitin ligases, muscle atrophy F-box (MAFbx)/atrogin-1 and muscle RING finger-1 (MuRF1), in glycolytic white vastus lateralis muscle than in oxidative soleus muscle. By contrast, NO production, inducible NO synthase (iNos) and antioxidant gene expression were greatly enhanced in oxidative, but not in glycolytic muscles, suggesting that NO mediates protection against muscle wasting. NO donors enhanced iNos and antioxidant gene expression and blocked cytokine/endotoxin-induced MAFbx/atrogin-1 expression in cultured myoblasts and in skeletal muscle in vivo. Our studies reveal a novel protective mechanism in oxidative myofibers mediated by enhanced iNos and antioxidant gene expression and suggest a significant value of enhanced NO signaling as a new therapeutic strategy for cachexia.