Rejuvenation research最新文献

Taurine and tauroursodeoxycholic acid are used for treating cerebral ischemia. In this study, we used the combination of taurine and tauroursodeoxycholic acid to establish a model of ischemia-reperfusion injury and evaluate the effect and target of the drug combination using the neurovascular unit (NVU) model of hypoxia and reoxygenation in vitro. Results showed that the combined application of these two drugs improved the survival of neurons, astrocytes, and endothelial cells; reduced inflammatory damage, levels of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1β, oxidative stress response, and the release of malondialdehyde and nitric oxide; and enhanced the activity of superoxide dismutase. Simultaneously, they acted on the blood-brain barrier (BBB) and improved the transendothelial electrical resistance value, reduced lactate dehydrogenase levels, improved the activity of γ-glutamyl transferase, and protected the integrity of the BBB against damage caused by oxygen-glucose deprivation/reoxygenation. At the same time, they prevented neuronal apoptosis, reduced the expression of Bax and caspase-3, and increased the expression of Bcl-2. These two drugs regulated the expression of connexin 43 (CX43) and aquaporin 4 (AQP4) in astrocytes, reducing the level of AQP4, and improving the activity of CX43. In addition, the drug combination increased the expression of tight junction proteins in endothelial cells, such as zona occludens-1, occluding, and claudin-5, and decreased the expression of matrix metalloproteinase (MMP)2 and MMP9. Furthermore, they acted together on the p38 mitogen-activated protein kinase (MAPK) signaling pathway, and the addition of the p38 inhibitor SB203580 partially inhibited the expression of p38MAPK. Thus, the combined action of these drugs protected the NVU.

Pancreatic cancer (PC) is a highly lethal malignancy with significant drug resistance and recurrence. This study explores the molecular mechanisms by which resveratrol (RES) inhibits PC proliferation, invasion, and migration, aiming to provide new insights for future therapeutic strategies. Network pharmacology was used to construct a component-pathway-target network diagram for the effect of RES on PC. Transwell assays were used to analyze cell invasion. In addition, scratch assays were conducted to evaluate cell migration ability, and qPCR was utilized to monitor the mRNA expression levels of genes. Immunofluorescence and Western blotting were applied to detect protein expression. The results demonstrate that RES exhibits a significant inhibitory effect on PC cells at different concentrations, with 50 μmol/L RES showing the most pronounced inhibition. This observation was further confirmed by Transwell and scratch assays, which showed that RES significantly inhibits PC cell proliferation, invasion, and migration. Network pharmacology analysis suggests that RES may act on the Rap1 pathway to suppress the progression of PC. In vitro experiments confirmed that RES downregulates the expression of CDC42, MMP2, and MMP9. Notably, immunoprecipitation experiments revealed that RES induces the succinylation of CDC42, which, in turn, inhibits the CDC42 signaling pathway. This disruption leads to the destabilization of the extracellular matrix (ECM), thereby impeding tumor progression. This study demonstrates that RES significantly inhibits the proliferation, invasion, and migration of PC cells by mediating the succinylation of CDC42, which in turn inhibits the CDC42 signaling pathway and disrupts the dynamics of the ECM. This mechanism highlights the potential of RES as an anticancer agent and provides new insights for the development of therapeutic strategies for PC.

Oxidative stress, caused by an imbalance between reactive oxygen species (ROS) and antioxidants, is a fundamental challenge affecting both invertebrate and vertebrate organisms. Environmental triggers such as pollutants, heavy metals, pesticides, and seasonal fluctuations, alongside endogenous factors like heme metabolism and disease, contribute to elevated ROS production across animal taxa. These molecular species can damage proteins, membranes, and nucleic acids, compromising cellular integrity and function. The aim of this study is to comprehensively observe and compare the impact of oxidative stress on invertebrates (including protozoa, annelids, arthropods, and mollusks) and vertebrates (fish, amphibians, birds, and mammals), elucidating common and distinct stress pathways. Using integrative evidence from schematic representations and biological pathways, this work highlights conserved mechanisms such as lipid peroxidation, Fenton chemistry, and the upregulation of defense enzymes. Despite evolutionary divergence, the findings demonstrate that oxidative stress responses are universally pivotal in regulating cellular homeostasis, inflammation, and survival. The study underscores the importance of redox balance in animal adaptation and health, offering insight into stress physiology and potential targets for mitigating oxidative damage in diverse species.

Growth Differentiation Factor 15 (GDF-15) is closely associated with the occurrence and progression of sarcopenia, but the causal relationship between GDF-15 and sarcopenia remains unclear, and it is also uncertain whether immune cells mediate the pathway between GDF-15 and sarcopenia. We employed Mendelian randomization analysis to explore the causal relationship between GDF-15 and sarcopenia, using the inverse variance-weighted (IVW) method as the primary analytical approach, and validated the results through sensitivity analyses. In addition, we explored whether 731 immune cell phenotypes mediate these causal relationships. GDF-15 was negatively correlated with all four traits of sarcopenia, specifically with whole body fat-free mass (odds ratio [OR] = 0.989, 95% confidence interval [CI] = 0.979-0.998, p_IVW = 2.149E-02), left arm fat-free mass (OR = 0.988, 95% CI = 0.979-0.998, p_IVW = 1.345E-02), right arm fat-free mass (OR = 0.987, 95% CI = 0.979-0.995, p_IVW = 1.091E-03), and appendicular lean mass (OR = 0.984, 95% CI = 0.974-0.993, p_IVW = 7.658E-04). Mediation analysis indicated that CD127 on CD28⁺ CD45RA⁺ CD8^br mediated the causal relationship between GDF-15 and sarcopenia, with a mediation proportion of 21.58% (p = 0.023). In conclusion, our study proposed that CD127 on CD28⁺ CD45RA⁺ CD8^br mediates the causal relationship between GDF-15 and sarcopenia, providing potential theoretical support and practical guidance for the innovation of treatment strategies and personalized therapies for sarcopenia.

The Geriatric Nutritional Risk Index (GNRI) is widely used to assess nutritional status. However, its association with postoperative cognitive dysfunction (POCD) and postoperative complications in elderly patients receiving total hip arthroplasty remains inadequately explored. GNRI was calculated based on serum albumin and body weight. POCD was diagnosed using the Z-score method based on cognitive test performance on the seventh postoperative day. Glial fibrillary acidic protein (GFAP) and S100β levels were determined using an enzyme-linked immunosorbent assay. A Receiver Operating Characteristic curve was performed to evaluate the predictive value of GNRI. Multivariate logistic regression was conducted to identify risk factors for POCD in elderly patients undergoing total hip arthroplasty. The POCD group was significantly older, had lower educational attainment, longer surgery duration, greater intraoperative blood loss, and lower preoperative GNRI scores compared to the non-POCD group. Preoperative GNRI demonstrated moderate predictive value for POCD, with an area under curve (AUC) of 0.78. Multivariate logistic regression analysis identified age (odds ratio [OR]: 1.214, 95% confidence interval [CI]: 1.047-1.449), blood loss (OR: 1.198, 95% CI: 1.055-1.493), and anesthesia duration (OR: 1.376, 95% CI: 1.112-1.795) as significant risk factors for POCD, while preoperative GNRI (OR: 0.885, 95% CI: 0.768-0.973) was identified as a protective factor. POCD patients exhibited significantly lower Montreal Cognitive Assessment (MoCA) scores and higher serum S100β and GFAP levels than the non-POCD group. Preoperative GNRI was positively correlated with MoCA scores (r = 0.46, p < 0.001) and negatively correlated with serum S100β (r = -0.43, p < 0.001) and GFAP (r = -0.37, p < 0.001) levels. Higher preoperative GNRI scores were associated with a reduced incidence of postoperative complications, including pulmonary infections and liver dysfunction. Preoperative GNRI serves as an effective predictor of POCD and postoperative complications in elderly patients receiving hip arthroplasty.

The aim of this study was to find potential drug targets of knee osteoarthritis (KOA) through druggable genome and Mendelian randomization (MR) analysis. Through integrating data from expression quantitative trait loci at different tissue and cellular levels, we identified potential therapeutic targets for KOA using drug target MR and single-cell MR analyses. Based on peripheral protein quantitative trait locus (pQTL) data, we validated the identified targets at the proteomic level using summary data-based MR and Heterogeneity in Dependent Instrument tests. Meanwhile, we used mediation MR analysis to explore possible mechanisms of action of the identified targets in KOA. To capture tissue specificity, we further applied the genetically informed spatial mapping (gsMap) framework, integrating KOA genome-wide association studies with spatial transcriptomics of E16.5 mouse embryonic tissues. We identified 12 and 5 potential therapeutic targets for KOA from peripheral and central tissues, respectively. Mitogen-activated protein kinase (MAPK3) and MARK3 were validated at the proteomic level, with MAPK3 showing a genetic association with reduced risk against KOA in both peripheral and central tissues. Single-cell MR analysis revealed that Lymphocyte antigen 6 D (LY6D) was associated with an increased risk of KOA in exogenous cells, MAPK3 showed a protective association in inhibitory neuron cells, and transforming growth factor alpha (TGFA) was associated with a reduced risk of KOA in oligodendrocyte precursor cells. Mediation MR analysis showed that body mass index (BMI) played a 16.6% mediating role in the causal association between MAPK3 and KOA. GsMap analysis revealed significant enrichment of KOA signals in cartilage primordium, cartilage, lung, and brain tissues. Finally, we proposed 16 potential therapeutic targets for KOA from both central and peripheral perspectives. Meanwhile, we found that BMI served as a mediator to mediate the causal effect between MAPK3 and KOA. Further experiments are needed in the future to verify the mechanism of action of the targets identified in this study in KOA.

Ischemic stroke (IS) is the worldwide leading cause of death and disability, so finding new approaches to prevent and treat IS has become urgent. Naomaili granules (NML), a proprietary Chinese medicine modified from Buyang Huanwu Decoction, has significant beneficial effects in treating IS. The present study demonstrated that NML significantly narrowed the volume of cerebral infarction in rats after middle cerebral artery occlusion (MCAO)/reperfusion (R), and in addition, improved their neurological function and reduced neuronal cell damage. Moreover, NML suppressed endoplasmic reticulum (ER) stress in MCAO/R rats and attenuated cellular pyroptosis by inhibiting the Ras Homolog Family Member A (RhoA)/pyrin pathway. In conclusion, the present study demonstrated that cerebral ischemia/reperfusion-induced ER stress in rat cortical neurons and may mediate pyroptosis of the cortical neurons through RhoA/pyrin. Meanwhile, NML reduced neuronal death and improved neurological function in rats by inhibiting ER stress and the RhoA/pyrin cellular pathway.

Findings on the association of both nicotinamide mononucleotide (NMN) and iron metabolism with antiaging or aging led us to speculate that some pharmacological functions of NMN may be achieved partially by affecting iron metabolism. Here, we investigated the effects of NMN on cell viability, iron contents, oxidative stress, and the expression of ferritins, transferrin receptor 1 (TfR1), ferroportin1 (Fpn1), hepcidin, interleukin 6 (IL-6), interleukin-1β (IL-1β), and signal transducer and activator of transcription 3 (STAT3) in BV2 microglia (BV-2) cells treated with 150 μM of ferric ammonium citrate. We found that NMN induced a significant reduction in iron concentration, ferritin expression, and reactive oxygen species level, and an increase in cell viability in iron-overloaded BV-2 cells. Also, NMN significantly up-regulated TfR1 and down-regulated Fpn1 and hepcidin expression as well as IL-6, IL-1β, and pSTAT3 contents in iron-overloaded BV-2 cells. We concluded that NMN is able to regulate the expression of iron transport proteins TfR1 and Fpn1, via IL6/STAT3/hepcidin and IL-1β/hepcidin pathways, and then down-regulate iron contents and the expression of ferritin and inhibit oxidative stress in iron-overloaded BV-2 microglia cells, supporting that some pharmacological functions of NMN may be partly associated with the effects of NMN on iron metabolism. Our results suggest that NMN may have beneficial therapeutic effects on iron-related diseases such as neurodegenerative diseases.

Background: Chronic kidney disease (CKD) is getting more common in elderly people with metabolic syndrome, but early detection and risk prediction are still hard. So we created and validated a CKD risk prediction model tailored for these patients to get past the limits of existing clinical screening tools. Methods: We used data from the National Health and Nutrition Examination Survey and the China Health and Retirement Longitudinal Study to develop and validate the CKD prediction model. We defined CKD based on an estimated glomerular filtration rate < 60 mL/min/1.73 m², calculated with the chronic kidney disease epidemiology collaboration (CKD-EPI) formula. We did feature selection with a mix of strict methods and evaluated model performance across both internal and external validation cohorts. We used 10 machine learning algorithms and four data balancing strategies. The final CKD prediction model had strong predictive power and clinical interpretability for early detection of prevalent CKD. Results: The final model, which uses four key variables (uric acid to high-density lipoprotein cholesterol ratio (UHR), age, uric acid, blood urea nitrogen (BUN)), had predictive accuracies of 0.864 (internal) and 0.831 (external) when using logistic regression. This shows it is robust and can be applied widely. Shapley Additive exPlanations analysis and restricted cubic spline analysis found significant links between the key features and CKD risk. Conclusion: This study developed a reliable, interpretable CKD risk prediction model using routine clinical indicators. It gives an effective tool for large-scale early CKD screening and stratified management in primary care and has high clinical applicability.

Diabetes mellitus and its consequent pathological complications continue to pose serious and growing health care challenges across the world. One promising mechanism for linking hyperglycemia and diabetic complications is the process of spontaneous, nonenzymatic reactions between glucose and its catabolites with amino groups in macromolecules (a.k.a. Maillard reactions). The most reactive sugars in this process are two low-molecular-weight α-dicarbonyls: methylglyoxal and glyoxal (GO). While the origins of methylglyoxal are well documented, little is known about the origins of the equally important GO. This article postulates that GO is produced as an unavoidable byproduct of the transketolase reaction in the pentose-phosphate pathway.