Estrogen deficiency exacerbates learning and memory deficits associated with glucose metabolism disorder in APP/PS1 double transgenic female mice

Alterations in glucose metabolism occur in the brain in the early stage of Alzheimer's disease(AD),and menopausal women have more severe metabolic dysfunction and are more prone to dementia than men.Although estrogen deficiency-induced changes in glucose metabolism have been previously studied in animal models,their molecular mechanisms in AD remain elusive.To investigate this issue,double transgenic(APP/PS1)female mice were subjected to bilateral ovariectomy at 3 months of age and were sacrificed 1 week,1 month and 3 months after surgery to simulate early,middle and late postmenopause,respectively.Our analysis demonstrated that estrogen deficiency exacerbates learning and memory deficits in this mouse model of postmenopause.Estrogen deficiency impairs the function of mitochondria in glucose metabolism.It is possible that the occurrence of AD is associated with the aberrant mitochondrial ERβ-mediated IGF-1/IGF-1R/GSK-3βsignaling pathway.In this study,we established a potential mechanism for the increased risk of AD in postmenopausal women and proposed a therapeutic target for AD due to postmenopause.

Comparative Efficacy of Lifestyle Modifications versus Pharmacotherapy on Weight Loss and Metabolic Health Outcomes: A Comprehensive Review

Background: Obesity has become a serious global public health challenge, given that it leads to various adverse health outcomes that include cardiovascular illnesses, diabetes, and certain types of cancer. The World Health Organization (WHO) has estimated that, at the end of 2022, 1 out of every 8 individuals were obese, and that the global adult obesity rates have over doubled since 1990, even as the adolescent obesity rates have quadrupled. Thus, as of 2022, nearly 2.5 billion adults, aged 18 years and above, were overweight, with 890 million being obese. Obesity and overweight incidence rate has been gradually increasing over the years, presenting significant challenges to the healthcare systems throughout the globe. In this regard, the objective of this systematic review was to evaluate the effectiveness and safety of lifestyle modifications (diet and physical activity) and pharmacotherapy in promoting weight loss and improving metabolic health in overweight adults. Methodology: To attain the above stated study objective, a systematic evaluation of previous studies was carried out, particularly studies that assessed the effectiveness and safety of lifestyle modifications (diet and physical activity) and pharmacotherapy in promoting weight loss and improving metabolic health in overweight adults. The authors have used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) in the selection of eligible studies for inclusion in the study. Results: The findings indicate that lifestyle interventions resulted in 5% - 10% weight reduction and significant improvements in metabolic indicators, while pharmacotherapy (GLP-1 receptor agonists) achieved up to 15% weight reduction and considerable metabolic health benefits. Further, comparative studies show lifestyle modifications provide overall health benefits, while medication is necessary for non-responders. Conclusion: Individualized treatment strategies are crucial, and further research is needed on long-term consequences and combination therapies.

Subclinical abnormal glucose tolerance is a predictor of death in liver cirrhosis

AIM: To determine if subclinical abnormal glucose tolerance (SAGT) has influence on survival of non-diabetic patients with liver cirrhosis.

Gentiopicroside targets PAQR3 to activate the PI3K/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism

The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes.Progestin and adipoQ receptor 3(PAQR3),a key regulator of inflammation and metabolism,can negatively regulate the PI3 K/AKT signaling pathway.Here,we report that gentiopicroside(GPS),the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa,decreased lipid synthesis and increased glucose utilization in palmitic acid(PA) treated HepG2 cells.Additionally,GPS improved glycolipid metabolism in streptozotocin(STZ) treated high-fat diet(HFD)-induced diabetic mice.Our findings revealed that GPS promoted the activation of the PI3 K/AKT axis by facilitating DNA-binding protein 2(DDB2)-mediated PAQR3 ubiquitinated degradation.Moreover,results of surface plasmon resonance(SPR),microscale thermophoresis(MST) and thermal shift assay(TSA) indicated that GPS directly binds to PAQR3.Results of molecular docking and cellular thermal shift assay(CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH2-terminus including Leu40,Asp42,Glu69,Tyr125 and Ser129,and spatially inhibited the interaction between PAQR3 and the PI3 K catalytic subunit(P110α) to restore the PI3 K/AKT signaling pathway.In summary,our study identified GPS,which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway,as a potential drug candidate for the treatment of diabetes.

Xiaoyao San,a Chinese herbal formula,ameliorates depression-like behavior in mice through the AdipoR1/AMPK/ACC pathway in hypothalamus

Objective Depression and metabolic disorders have overlapping psychosocial and pathophysiological causes.Current research is focused on the possible role of adiponectin in regulating common biological mechanisms.Xiaoyao San(XYS),a classic Chinese medicine compound,has been widely used in the treatment of depression and can alleviate metabolic disorders such as lipid or glucose metabolism disorders.However,the ability of XYS to ameliorate depression-like behavior as well as metabolic dysfunction in mice and the underlying mechanisms are unclear.Methods An in vivo animal model of depression was established by chronic social defeat stress(CSDS).XYS and fluoxetine were administered by gavage to the drug intervention group.Depression-like behaviors were analyzed by the social interaction test,open field test,forced swim test,and elevated plus maze test.Glucose levels were measured using the oral glucose tolerance test.The involvement of certain molecules was validated by immunofluorescence,histopathology,and Western blotting.In vitro,hypothalamic primary neurons were exposed to high glucose to induce neuronal damage,and the neuroprotective effect of XYS was evaluated by cell counting kit-8 assay.Immunofluorescence and Western blotting were used to evaluate the influences of XYS on adiponectin receptor 1(AdipoR1),adenosine 5’-monophosphate-activated protein kinase(AMPK),acetyl-coenzyme A carboxylase(ACC)and other related proteins.Results XYS ameliorated CSDS-induced depression-like behaviors and glucose tolerance impairment in mice and increased the level of serum adiponectin.XYS also restored Nissl bodies in hypothalamic neurons in mice that exhibited depression-like behaviors and decreased the degree of neuronal morphological damage.In vivo and in vitro studies indicated that XYS increased the expression of AdipoR1 in hypothalamic neurons.Conclusion Adiponectin may be a key regulator linking depression and metabolic disorders;regulation of the hypothalamic AdipoR1/AMPK/ACC pathway plays an important role in treatment of depression by XYS.