Kaiwu He

Aim: The rising global prevalence of obesity has accelerated the incidence of metabolic dysfunction‐associated steatotic liver disease (MASLD), with nonalcoholic steatohepatitis (NASH) representing its progressive and life‐threatening phenotype. Despite its clinical urgency, no pharmacotherapy is currently approved for NASH. AdipoRon, an orally active adiponectin receptor agonist, exhibits dual regulatory effects on glucose/lipid homeostasis alongside anti‐inflammatory and antioxidant properties. However, its therapeutic potential in metabolic stress‐driven NASH remains underexplored. This study elucidates the efficacy and molecular mechanisms of AdipoRon in mitigating metabolic stress‐induced NASH. Materials and Methods: We employed a multi‐modal approach combining in vitro and in vivo models: palmitic acid (PA)‐challenged alpha mouse liver 12 (AML12) hepatocytes and mice fed a Western diet (WD) or a methionine‐choline‐deficient (MCD) diet. Proteomic profiling integrated with bioinformatics analysis was utilized to dissect AdipoRon's mechanism. Pharmacological validation via endoplasmic reticulum (ER) stress modulation (e.g., cinchonine) further clarified pathway specificity. Results: In vitro, AdipoRon attenuated PA‐induced lipid accumulation and inflammatory cytokine release in hepatocytes. In vivo, AdipoRon administration markedly reduced hepatic injury, steatosis, lobular inflammation and collagen deposition in diet‐induced NASH mice. Mechanistically, proteomic analysis identified ER stress suppression as a central pathway, with rescue experiments confirming that cinchonine (an ER stress activator) abrogated AdipoRon's hepatoprotection. Conclusions: Our findings establish AdipoRon as a potent inhibitor of ER stress, effectively counteracting metabolic stress‐induced NASH pathogenesis. These results highlight its translational promise as a targeted therapy for NASH, addressing critical unmet clinical needs.

Effective treatment to prevent or arrest the advance of Alzheimer disease (AD) has yet to be discovered. We investigated whether Oligonol^R, an FDA-approved flavanol-rich extract prepared from lychee fruit and green tea, exerted beneficial effects relevant to AD in a triple transgenic male mouse model of AD (3×Tg-AD). At 9 months of age, untreated 3×Tg-AD mice vs. wild-type (WT) controls displayed cognitive deficits in behavioral assays and, at 12 months, elevated levels of hippocampal amyloid beta-protein (Aβ), amyloid precursor protein (APP), tau phosphorylation, and pro-inflammatory cytokines. 3×Tg-AD mice given Oligonol showed fewer cognitive deficits and attenuated pathological indices at 12 months. Oligonol treatment of 3×Tg-AD mice modulated expression of some critical brain proteins that involve multiple pathways relevant to mitochondrial dysfunction, proteasomal failure, endoplasmic reticulum (ER) stress and synaptic impairment. Together, these results demonstrate that continuous Oligonol treatment attenuates AD-like pathology and cognitive impairment of 3×Tg-AD mice and set the stage for clinical trials of this flavanol-rich plant extract in patients with early AD.

Alzheimer’s disease (AD) is one of the most common progressive neurodegenerative diseases. Apolipoprotein E4 (ApoE4) carriers account for 40% of all AD cases, emphasizing the importance of ApoE4 in the pathogenesis of AD. In the present study, we explored the changes of hippocampal proteins expression profile at the early stage (3 month-old) of APP/PS1 and ApoE4 knockin mice with aim to find potential key pathways involved in AD progression. Proteomic analysis showed a lot of 247 (137 increased and 110 decreased) and 1125 (642 increased and 484 decreased) differentially expressed proteins (DEPs) in the hippocampus of APP/PS1 mice and ApoE4 mice respectively, compared with the wild-type (WT) mice, using a cutoff of 1.2-fold change. Functional classification of DEPs revealed that these proteins mainly comprise proteins involved in acetylation, methylation, endocytosis/exocytosis, chaperone, oxidoreductase, mitochondrial, cytoskeletal and synaptic proteins in APP/PS1 mice compared with the WT mice. Likewise in ApoE4 mice compared with the WT mice the DEPs are mostly involved in the functions of synapses, ribosomes, mitochondria, spliceosomes, endocytosis/exocytosis, oxidative phosphorylation and proteasomes. STRING analysis suggested that some DEPs were involved in insulin signaling and mitochondrial electron transport chain in the two mouse models. The abnormal changes of insulin signaling and mitochondrial electron transport chain were further verified by western blot. Taken together, our study exposed the changes of hippocampal proteins expression profile at the early stage of APP/PS1 and ApoE4 knockin mice, and the change of insulin signaling and mitochondrial electron transport chain may be the key molecular processes involved in AD progression.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Kaiwu He1,2,*, Fei Qi3,*, Chunni Guo4, Shuqin Zhan5, Hua Xu1, Jianjun Liu2 and Xifei Yang2 1 College of Pharmacy, Jinan University, Guangzhou, China 2 Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China 3 Department of Respiratory Medicine, Chinese People’s Liberation Army General Hospital, Beijing, China 4 Department of Neurology, ShanghaiFirst People’s HospitalAffiliated toShanghai Jiaotong University, Shanghai, China 5 Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China * These authors have contributed equally to this work Correspondence to: Xifei Yang, email: // <![CDATA[ mail("xifeiyang","gmail",0,"") // ]]> Hua Xu, email: // <![CDATA[ mail("huax_mail","126",0,"") // ]]> Keywords: TRPC1; basal ganglia; movement disorder; neuronal loss Received: June 29, 2016 Accepted: October 03, 2016 Published: October 11, 2016