Protective effects and mechanisms of omega-3 polyunsaturated fatty acid on intestinal injury and macrophage polarization in peritoneal dialysis rats.

AIM: This study was conducted to investigate the chronic injury of peritoneal glucose injection on the peritoneum and intestine and the protective effects of omega-3 polyunsaturated fatty acid (ω-3PUFA) during peritoneal dialysis (PD). METHODS: Peritoneal dialysis animal models were established by intraperitoneal injection of 4.25% glucose for 28 days. Protein expression in ileum and peritoneum was measured by immunofloresence and immunohistochemistry. Protein expression in macrophages was measured by Western blot. Fibrosis was analyzed by Masson staining. RESULTS: Peritoneal dialysis significantly increased the structural injury and decreased junction-related protein ZO-1 and occludin expression in ileum, the expression of proteins relating to the activation of M2 (Erg2, IRF4), but not M1 (CD38, IRF5) macrophages. PD significantly increased the expression of TGF-ß1, VEGF and ALK5 protein in peritoneal tissues. PD significantly increased fibrosis (Masson staining) and the expression of fibroblast marker α-SMA in peritoneal tissues. Injection of macrophage clean reagent and ω-3PUFA significantly inhibited M2 activation, and decreased Masson staining, α-SMA, TGF-ß1, VEGF and ALK5 protein expression in peritoneal tissues in PD treated rats. ω-3PUFA injection significantly decreased PD-induced injury in ileum and normalized the expression of ZO-1 and occludin in the ileum of PD rats. CONCLUSION: Omega-3 fatty acids can provide a protective role on PD-induced peritoneal fibrosis and injury of the intestine.

Icariin targets p53 to protect against ceramide-induced neuronal senescence: Implication in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a leading cause of dementia. The aging brain is particularly vulnerable to various stressors, including increased levels of ceramide. However, the role of ceramide in neuronal cell senescence and AD progression and whether icariin, a natural flavonoid glucoside, could reverse neuronal senescence remain inadequately understood. AIM: In this study, we explore the role of ceramide in neuronal senescence and AD, and whether icariin can counteract these effects. METHODS: We pretreated HT-22 cells with icariin and then induced senescence with ceramide. Various assays were employed to assess cell senescence, such as reactive oxygen species (ROS) production, cell cycle progression, ß-galactosidase staining, and expression of senescence-associated proteins. In vivo studies utilized APP/PS1 mice and C57BL/6J mice injected with ceramide to evaluate behavioral changes, histopathological alterations, and senescence-associated protein expression. Transcriptomics, molecular docking, molecular dynamics simulations, and cellular thermal shift assays were employed to verify the interaction between icariin and P53. The specificity of icariin targeting of P53 was further confirmed through rescue experiments utilizing the P53 activator Navtemadlin. RESULTS: Our data demonstrated that ceramide could induce neuronal senescence and AD-related pathologies, which were reversed by icariin. Moreover, molecular studies revealed that icariin directly targeted P53, and its neuroprotective effects were attenuated by P53 activation, providing evidence for the role of P53 in icariin-mediated neuroprotection. CONCLUSION: Icariin demonstrates a protective effect against ceramide-induced neuronal senescence by inhibiting the P53 pathway. This identifies a novel mechanism of action for icariin, offering a novel therapeutic approach for AD and other age-related neurodegenerative diseases.

The inverse associations between composite-dietary-antioxidant-index and sarcopenia risk in US adults.

Background: It remains unknown whether composite-dietary-antioxidant-index (CDAI) is associated with the risk of sarcopenia. This study investigated the association of CDAI with sarcopenia risk among general US adults. Methods: A total of 10,093 participants were enrolled in the National Health and Nutrition Examination Surveys (NHANES) from 6 survey cycles (2003-2004, 2005-2006, 2011-2012, 2013-2014, 2015-2016 and 2017-2018). Multivariate logistic regression was carried out to examine the relationship between CDAI and the risk of sarcopenia. Restricted cubic spline (RCS) curves were employed to analyze nonlinear relationships. Results: In a multi-variable logistic regression model adjusting for demographics, lifestyle, economic status and other dietary factors, higher CDAI score was related to a lower risk of sarcopenia among US adults. Compared the highest quartile of CDAI score with the lowest, the OR and 95%CI were 0.49 (0.31-0.75). Furthermore, the RCS demonstrated a linear dose-response relationship between CDAI and sarcopenia (P non-linearity=0.92). These results remained consistent across subgroups stratified by age, sex, physical activity, drinking status, body mass index (BMI), smoking habits, energy intake, and Healthy Eating Index (HEI) score. In addition, the favorable associations of CDAI were primarily attributed to Vitamin E intake. Conclusion: A higher CDAI score was associated with a lower risk of sarcopenia. According to these results, a greater adherence to CDAI may benefit sarcopenia prevention in adults.

Melatonin alleviates renal injury by activating mitophagy in diabetic nephropathy.

Diabetic nephropathy (DN) causes serious renal tubule and interstitial damage, but effective prevention and treatment measures are lacking. Abnormal mitophagy may be involved in the progression of DN, but its upstream and downstream regulatory mechanisms remain unclear. Melatonin, a pineal hormone associated with circadian rhythms, is involved in regulating mitochondrial homeostasis. Here, we demonstrated abnormal mitophagy in the kidneys of DN mice or high glucose (HG)-treated HK-2 cells, which was accompanied by increased oxidative stress and inflammation. At the same time, the melatonin treatment alleviated kidney damage. After mitochondrial isolation, we found that melatonin promoted AMPK phosphorylation and accelerated the translocation of PINK1 and Parkin to the mitochondria, thereby activating mitophagy, reducing oxidative stress, and inhibiting inflammation. Interestingly, the renal protective effect of melatonin can be partially blocked by downregulation of PINK1 and inhibition of AMPK. Our studies demonstrated for the first time that melatonin plays a protective role in DN through the AMPK-PINK1-mitophagy pathway.

The CXCL1-CXCR2 Axis Mediates Tubular Injury in Diabetic Nephropathy Through the Regulation of the Inflammatory Response.

Diabetic nephropathy (DN) is one of the most severe complications of diabetes. Inflammation mediated by inflammatory factors is thought to accelerate the progression of renal damage in DN. However, which inflammatory factors mediate the inflammatory response in DN remains unclear. In this study, we determined that the CXCL1-mediated inflammatory response may play an essential role in DN progression through bioassays. Subsequently, we observed that the expression of CXCL1 and its receptor (CXCR2) was significantly increased in the kidneys of mice with HFD + STZ induced diabetes and DN patients. In addition, inhibition of the CXCL1/CXCR2 axis by repertaxin alleviates renal inflammation and pathological damage in the kidneys of db/db mice. Finally, we noted that the CXCL1/CXCR2 axis might lead to inflammatory damage through phosphorylated NF-κB and further activate the NLRP3 inflammasome. Our results revealed the role of the CXCL1/CXCR2 axis in DN progression for the first time, which may be a novel therapeutic target for DN.