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Ageing is a crucial risk factor for Alzheimer’s disease (AD) and is characterised by systemic changes in both intracellular and extracellular microenvironments that affect the entire body instead of a single organ. Understanding the specific mechanisms underlying the role of ageing in disease development can facilitate the treatment of ageing-related diseases, such as AD. Signs of brain ageing have been observed in both AD patients and animal models. Alleviating the pathological changes caused by brain ageing can dramatically ameliorate the amyloid beta- and tau-induced neuropathological and memory impairments, indicating that ageing plays a crucial role in the pathophysiological process of AD. In this review, we summarize the impact of several age-related factors on AD and propose that preventing pathological changes caused by brain ageing is a promising strategy for improving cognitive health.

Obesity, a metabolic disease caused by excessive fat accumulation in the body, has attracted worldwide attention. Microcystin-LR (MC-LR) is a hepatotoxic cyanotoxin which has been reportedly to cause lipid metabolism disorder. In this study, C57BL/6J mice were fed a high-fat diet (HFD) for eight weeks to build obese an animal model, and subsequently, the obese mice were fed MC-LR for another eight weeks, and we aimed to determine how MC-LR exposure affects the liver lipid metabolism in high-fat-diet-induced obese mice. The results show that MC-LR increased the obese mice serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), indicating damaged liver function. The lipid parameters include serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and liver TG, which were all increased, whilst the high-density lipoprotein cholesterol (HDL-c) was decreased. Furthermore, after MC-LR treatment, histopathological observation revealed that the number of red lipid droplets increased, and that steatosis was more severe in the obese mice. In addition, the lipid synthesis-related genes were increased and the fatty acid β-oxidation-related genes were decreased in the obese mice after MC-LR exposure. Meanwhile, the protein expression levels of phosphorylation phosphatidylinositol 3-kinase (p-PI3K), phosphorylation protein kinase B (p-AKT), phosphorylation mammalian target of rapamycin (p-mTOR), and sterol regulatory element binding protein 1c (SREBP1-c) were increased; similarly, the p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, and SREBP1/β-actin were significantly up-regulated in obese mice after being exposed to MC-LR, and the activated PI3K/AKT/mTOR/SREBP1 signaling pathway. In addition, MC-LR exposure reduced the activity of superoxide dismutase (SOD) and increased the level of malondialdehyde (MDA) in the obese mice’s serum. In summary, the MC-LR could aggravate the HFD-induced obese mice liver lipid metabolism disorder by activating the PI3K/AKT/mTOR/SREBP1 signaling pathway to hepatocytes, increasing the SREBP1-c-regulated key enzymes for lipid synthesis, and blocking fatty acid β-oxidation.

Cervical cancer is the second leading cause of morbidity and mortality in women worldwide. Traditional treatment methods have become limited. Naringenin, a flavonoid abundant in various fruits and herbal medicines, has demonstrated anti-tumor properties among other effects. This research undertook to elucidate the mechanism of naringenin in the context of cervical cancer treatment by leveraging network pharmacology and performing experimental validation. Initial steps involved predicting potential naringenin targets and subsequently screening for overlaps between these targets and those related to cervical cancer, followed by analysis of their interrelationships. Molecular docking was subsequently utilized to verify the binding effect of the central target. Within the framework of network pharmacology, it was discovered that naringenin might possess anti-cancer properties specific to cervical cancer. Following this, the anti-tumor effects of naringenin on Hela cell viability, migration, and invasion were assessed employing CCK-8, transwell, wound healing assays, and western blotting. Experimental data indicated that naringenin attenuates the migration and invasion of Hela cells via downregulation EGFR/PI3K/AKT signaling pathway. Thus, our findings suggest that naringenin has therapeutic impacts on cervical cancer via multiple mechanisms, primarily by inhibiting the migration and invasion through the EGFR/PI3K/AKT/mTOR pathway. This study offers fresh insights for future clinical studies.

Background Icariin (ICA), an active ingredient extracted from Epimedium species, has shown promising results in the treatment of Alzheimer's disease (AD), although its potential therapeutic mechanism remains largely unknown. This study aimed to investigate the therapeutic effects and the underlying mechanisms of ICA on AD by an integrated analysis of gut microbiota, metabolomics, and network pharmacology (NP). Methods The cognitive impairment of mice was measured using the Morris Water Maze test and the pathological changes were assessed using hematoxylin and eosin staining. 16S rRNA sequencing and multi-metabolomics were performed to analyze the alterations in the gut microbiota and fecal/serum metabolism. Meanwhile, NP was used to determine the putative molecular regulation mechanism of ICA in AD treatment. Results Our results revealed that ICA intervention significantly improved cognitive dysfunction in APP/PS1 mice and typical AD pathologies in the hippocampus of the APP/PS1 mice. Moreover, the gut microbiota analysis showed that ICA administration reversed AD-induced gut microbiota dysbiosis in APP/PS1 mice by elevating the abundance of Akkermansia and reducing the abundance of Alistipe . Furthermore, the metabolomic analysis revealed that ICA reversed the AD-induced metabolic disorder via regulating the glycerophospholipid and sphingolipid metabolism, and correlation analysis revealed that glycerophospholipid and sphingolipid were closely related to Alistipe and Akkermansia . Moreover, NP indicated that ICA might regulate the sphingolipid signaling pathway via the PRKCA/TNF/TP53/AKT1/RELA/NFKB1 axis for the treatment of AD. Conclusion These findings indicated that ICA may serve as a promising therapeutic approach for AD and that the ICA-mediated protective effects were associated with the amelioration of microbiota disturbance and metabolic disorder. Graphical Abstract

Microcystin-LR (MC-LR), frequently generated by cyanobacteria, has been demonstrated to raise the likelihood of liver disease. Few previous studies have explored the potential antagonist against MC-LR. Astaxanthin (ASX) has been shown to possess various beneficial effects in regulating lipid metabolism in the liver. However, whether ASX could alleviate MC-LR-induced hepatic lipid metabolic dysregulation is as yet unclear. In this work, the important roles and mechanisms of ASX in countering MC-LR-induced liver damage and lipid metabolic dysregulation were explored for the first time. The findings revealed that ASX not only prevented weight loss but also enhanced liver health after MC-LR exposure. Moreover, ASX effectively decreased triglyceride, total cholesterol, aspartate transaminase, and alanine aminotransferase contents in mice that were elevated by MC-LR. Histological observation showed that ASX significantly alleviated lipid accumulation and inflammation induced by MC-LR. Mechanically, ASX could significantly diminish the expression of genes responsible for lipid generation (Srebp-1c, Fasn, Cd36, Scd1, Dgat1, and Pparg), which probably reduced lipid accumulation induced by MC-LR. Analogously, MC-LR increased intracellular lipid deposition in THLE-3 cells, while ASX decreased these symptoms by down-regulating the expression of key genes in the lipid synthesis pathway. Our results implied that ASX played a crucial part in lipid synthesis and effectively alleviated MC-LR-induced lipid metabolism dysregulation. ASX might be developed as a novel protectant against hepatic impairment and lipid metabolic dysregulation associated with MC-LR. This study offers new insights for further management of MC-LR-related metabolic diseases.

Background: Bushen Tiansui Formula (BSTSF) is a traditional formulation of Chinese medicine that has been used to treat Alzheimer’s disease (AD) for decades; however, the underlying mechanisms by which this formula achieves such therapeutic effects have yet to be elucidated. Prupose: To investigate the neuroprotective mechanisms of BSTSF against AD by analyzing metabolite profiles in the hippocampus and cortex of AD rats. Methods: The rat models of AD were established by the injection of Aβ 25–35 . The Morris water maze (MWM) test was performed to evaluate the effect of BSTSF treatment on cognitive dysfunction. Hematoxylin and eosin (HE) staining was used to assess the effect of BSTSF on typical AD pathologies. Underlying mechanisms were investigated using LC-MS/MS-based untargeted metabolomics analysis of the cerebral cortex and hippocampus. Results: BSTSF significantly improved memory deficits and the typical histopathological changes of AD rats. Untargeted metabolomics analysis showed that 145 and 184 endogenous metabolites in the cerebral cortex and hippocampus, respectively, were significantly different in the BSTSF group when compared with the AD group. The differential metabolites in the cerebral cortex were primarily involved in cysteine and methionine metabolism, while those in the hippocampus were mainly involved in d -Glutamine and d -glutamate metabolism. Conclusion: In the present study, we confirmed the neuroprotective effects of BSTSF treatment against AD using a rat model. Our findings indicate that the BSTSF-mediated protective effects were associated with amelioration of metabolic disorders in the hippocampus and cerebral cortex.

Background Patients undergoing non-major orthopedic surgery often face an increased risk of venous thromboembolism due to the necessity of immobilization postoperatively. Current guidelines commonly recommend the use of low-molecular-weight heparin (LMWH) for prophylaxis, but it is associated with low patient compliance and certain side effects. We conducted a meta-analysis of randomized controlled trials (RCTs) to assess the effectiveness and safety of rivaroxaban or LMWH for thromboprophylaxis following non-major orthopedic surgery. Method Relevant literature was systematically searched in PubMed, Web of Science, Cochrane Library, and Embase from their inception to October 1, 2023, to evaluate the effectiveness and safety of rivaroxaban or LMWH in RCTs for thromboprophylaxis following non-major orthopedic surgery. Results A total of 5 randomized controlled trials involving 5,101 patients were included. There was no statistically significant difference in the preventive effect against venous thromboembolism (VTE) when using rivaroxaban or LMWH following non-major orthopedic surgery (RR 0.80; 95%CI 0.31 to 2.07). In terms of safety, there was also no statistically significant difference in the incidence of bleeding events in patients undergoing non-major orthopedic surgery when using rivaroxaban or LMWH (RR 1.15; 95% CI 0.75 to 1.76). Conclusion In non-major orthopedic surgery, the risk of venous thromboembolism and bleeding complications is similar when using rivaroxaban or LMWH.

To address the impact of the dynamic evolution of flood disaster chains and decision-makers’ (DMs’) risk preference heterogeneity on group decision-making, this study proposes a social network group decision-making method that integrates the evolutionary trend of the flood disaster chain with DMs’ risk preferences. First, a Bayesian network is constructed to quantify the disaster chain’s evolution, dynamically adjusting DMs’ evaluation values. Second, DMs’ risk preference types are identified based on the evaluation values, and a bounded confidence (BC) model, incorporating risk preferences, self-confidence and trust networks, is developed to promote consensus formation. Then, the optimal alternative is selected through weighted aggregation and used to update the Bayesian network dynamically during implementation. Finally, the effectiveness and superiority of the proposed method are verified using the flood disaster chain from the “7∙20” extreme rainfall disaster in Zhengzhou, Henan Province, China. The results show that risk-seeking DMs reduce BC values and resist consensus, whereas risk-averse DMs enlarge BC values and accelerate convergence. Moreover, worsening flood disaster chain trends drive DMs to update the optimal alternative. These findings show that the method captures both dynamic disaster evolution and behavioral heterogeneity, providing realistic and adaptive decision support in flood emergency scenarios.

ObjectivesVitamin D deficiency is prevalent among the population. Previous studies have shown that vitamin D supplementation might be useful for treating COVID-19 infection. Therefore, we performed a meta-analysis to explore vitamin D supplementation efficacy in treating COVID-19 patients with vitamin D deficiency.DesignSystematic review and meta-analysisData sourcesPubMed, Cochrane Library, Embase and Web of Science.Eligibility criteriaRandomised controlled trials exploring vitamin D supplementation for patients with COVID-19 and vitamin D deficiency.Data extraction and synthesisTwo independent reviewers employed standardised methods to search, screen and code the included studies. The primary outcomes included mortality during follow-up, 28-day mortality, need for mechanical ventilation and intensive care unit (ICU). The secondary outcome included length of stay in hospital and ICU. The risk of bias was assessed using the Risk of Bias 2 tool. Depending on the level of heterogeneity, either a random-effects model or a fixed-effects model was applied. The findings were summarised using Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence profiles and synthesised qualitatively.ResultsA total of nine studies, comprising 870 participants, were included in the analysis. The pooled results indicated that vitamin D supplementation was associated with a lower risk of mortality (risk ratio 0.76; 95% CI 0.60 to 0.97). However, this apparent benefit was not robust when examined through the leave-one-out method and trial sequential analysis. Regarding other outcomes, there was no statistically significant difference between vitamin D supplementation and no supplementation in terms of 28-day mortality, the need for mechanical ventilation and ICU admission. Vitamin D supplementation was associated with a 0.41 day shorter length of stay in the ICU (mean difference −0.41; 95% CI −1.09 to 0.28) and a 0.07 day shorter length of stay in the hospital (mean difference −0.07; 95% CI −0.61 to 0.46) compared with no supplementation; however, neither difference was statistically significant.ConclusionBased on evidence of low to moderate quality, vitamin D supplementation reduced the mortality rate during follow-up in COVID-19 patients with vitamin D deficiency. However, it did not improve 28-day mortality, nor did it reduce the need for mechanical ventilation and ICU admission, or the length of stay in the ICU and hospital.PROSPERO registration numberCRD42024573791.

Increasing evidence from experimental research suggests that exposure to microcystins (MCs) may induce lipid metabolism disorder. However, population-based epidemiological studies of the association between MCs exposure and the risk of dyslipidemia are lacking. Therefore, we conducted a population-based cross-sectional study involving 720 participants in Hunan Province, China, and evaluated the effects of MCs on blood lipids. After adjusting the lipid related metals, we used binary logistic regression and multiple linear regression models to examine the associations among serum MCs concentration, the risk of dyslipidemia and blood lipids (triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)). Moreover, the additive model was used to explore the interaction effects on dyslipidemia between MCs and metals. Compared to the lowest quartile of MCs exposure, the risk of dyslipidemia [odds ratios (OR) = 2.27, 95% confidence interval (CI): 1.46, 3.53] and hyperTG (OR = 3.01, 95% CI: 1.79, 5.05) in the highest quartile was significantly increased, and showed dose–response relationships. MCs were positively associated with TG level (percent change, 9.43%; 95% CI: 3.53%, 15.67%) and negatively associated with HDL-C level (percent change, −3.53%; 95% CI: −5.70%, −2.10%). In addition, an additive antagonistic effect of MCs and Zn on dyslipidemia was also reported [relative excess risk due to interaction (RERI) = −1.81 (95% CI: −3.56, −0.05)], and the attributable proportion of the reduced risk of dyslipidemia due to the antagonism of these two exposures was 83% (95% CI: −1.66, −0.005). Our study first indicated that MCs exposure is an independent risk factor for dyslipidemia in a dose–response manner.