Rejuvenation research最新文献

Elevated levels of Bicaudal-D Family Like Cargo Adaptor 1 (BICDL1) are associated with poor prognosis in various cancers. However, the role of BICDL1 in breast cancer (BC) has not been reported. We analyzed BICDL1 expression in BC using bioinformatics and molecular experiments. Gene Set Enrichment Analysis was conducted to identify significantly enriched signaling pathways related to BICDL1. The effects of BICDL1 on BC cell proliferation, migration, invasion, and expression of epithelial-mesenchymal transition (EMT)-related proteins were assessed using colony formation assays, Transwell assays, and Western blot. The influence of BICDL1 on pyroptosis in BC cells was determined by measuring the expression of key pyroptosis proteins (NLRP3, GSDMD-N, procaspase-1, cleaved caspase-1, ASC), lactate dehydrogenase release, and cytokines (IL-1β and IL-18). We also investigated whether BICDL1 promotes BC proliferation and metastasis by regulating pyroptosis using Nigericin, an agent that induces NLRP3 inflammasome activation. The results showed that BICDL1 was significantly overexpressed in BC tissues and cells. Knockdown of BICDL1 inhibited BC cell proliferation, migration, invasion, and the EMT process, while overexpression of BICDL1 had the opposite effects. BICDL1 was enriched in the pyroptosis pathway; overexpression of BICDL1 suppressed pyroptosis, thus promoting BC cell proliferation, inhibition, and migration. Notably, the addition of Nigericin reversed the effects of BICDL1 overexpression on BC cells. These results suggested that BICDL1 promoted BC cell proliferation, inhibition, and migration by hindering pyroptosis. These findings indicate that BICDL1 is a potential biomarker for BC treatment.

This study investigates the correlation between polypharmacy and gut microbiota compositional changes in older people who were treated with multidrug therapy, aiming to provide insights into the complex interplay between medication use, gut microbiota, and aging. High-throughput sequencing of the 16S rRNA gene was employed to analyze microbial diversity in older patients with multiple chronic diseases and polypharmacy, and the results were compared with a control group of older people without multiple chronic diseases and not undergoing polypharmacy. The study revealed distinct differences in gut microbiota composition between the two groups, with lower alpha-diversity observed in multidrug therapy group. Furthermore, the analysis identified several significant differences in microbiome composition at the genus and family levels between the multidrug therapy and the control group. The findings underscore the importance of understanding the impact of polypharmacy on the gut microbiota and its relationship to overall health in older people. Additionally, the study provides insights into the potential effects of specific medications, such as antihypertensive drugs, proton pump inhibitors, and antibiotics, on the gut microbiota, highlighting the need for continued research in this critical area to optimize therapeutic strategies for the older population.

Emerging evidence suggests that bioactive peptides from various foods have therapeutic potentials in improving cognitive function in Alzheimer's disease (AD) and mild cognitive impairment (MCI). We aimed to explore the characteristics of these peptides and their mechanisms on AD/MCI using a network pharmacology approach. We compiled a dataset of cognition-enhancing peptides from literatures and identified shared targets between these peptides and AD/MCI using Swiss Target Predication, PharmMapper, OMIM, GeneCards, TTD, and Drugbank databases. We then performed functional enrichment analysis and constructed a gene-gene interaction network to identify key hub targets. Additionally, we investigated the transcription factors (TFs) and microRNAs (miRNAs) regulating these hub genes. Molecular docking and dynamic simulations were performed using AutoDock Vina and GROMACS. We identified 59 cognition-enhancing oligopeptides, typically short and rich in arginine. These peptides were predicted to interact with 222 potential targets relevant to AD/MCI, with functional pathways mainly involving neuroactive ligand-receptor interactions and inflammation. We identified 15 hub targets, regulated by 144 TFs and 95 miRNAs. Notably, peptides containing the "Trp-Tyr" sequence demonstrated strong binding affinities to many hub targets, especially matrix metalloproteinase-9. The findings provided valuable insights into the molecular mechanisms through which bioactive peptides may act against AD/MCI and highlight the potential of network pharmacology for future exploration of bioactive peptides from natural foods.

To study the mechanism through which moxibustion alleviates inflammatory injury of synovial tissue in rheumatoid arthritis (RA) rats model by determining moxibustion's effect on ferroptosis regulation by the tumor suppressor protein p53 and solute carrier family 7 member 11 (SLC7A11). Rats were developed as RA models by the administration of Freund's complete adjuvant. In the corresponding groups, moxibustion treatment was carried out using cigarette-like moxa strips that were suspended near "Shenshu" (BL23) and "Zusanli" (ST36) once daily for 15 days, and the p53 agonist NSC59984 was administered intraperitoneally. After 15 days of treatment, histomorphological changes were noted by transmission electron microscopy; p53, glutathione peroxidase 4 (GPX4), and SLC7A11 expression were detected by Western blot; serum levels of reactive oxygen species (ROS), glutathione (GSH), and Fe²⁺ were estimated with the colorimetric and fluorescent probe methods; and serum levels of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) were quantified by enzyme linked immunosorbent assay. Compared with the model group and agonist group, the mitochondrial damage in the moxibustion and moxibustion + agonist groups were showed varying degrees of reduction. The levels of p53, ROS, Fe²⁺, TNF-α, and IL-1β in the model group were significantly higher than those in the normal group, the agonist group was significantly higher than the model group, and the moxibustion and moxibustion + agonists groups were lower than the model and agonist groups. The levels of SLC7A11, GPX4, and GSH were the opposite. Moxibustion can improve RA synovial inflammatory injury by regulating ferroptosis through inhibition of p53 protein expression.

Background: Although previous observational studies suggest a potential association between gut microbiota (GM) and knee osteoarthritis (KOA), the causal relationships remain unclear, particularly concerning the role of blood metabolites (BMs) as potential mediators. Elucidating these interactions is crucial for understanding the mechanisms underlying KOA progression and may inform the development of novel therapeutic strategies. Objective: This study aimed to determine the causal relationship between GM and KOA and to quantify the potential mediating role of BMs. Methods: Instrumental variables (IVs) for GM and BMs were retrieved from the MiBioGen consortium and metabolomics genome-wide association studies (GWAS) databases. KOA-associated single-nucleotide polymorphisms were sourced from the FinnGen consortium. Inverse-variance weighted approach was utilized as the main analytical method for Mendelian randomization (MR) analysis, complemented by MR-Egger, simple mode, weighted mode, and weighted median methods. The causal relationships between GM, BMs, and KOA were sequentially analyzed by multivariate MR. False discovery rate correction was applied to account for multiple comparisons in the MR results. Sensitivity analyses and reverse MR analysis were also conducted to verify the reliability of the findings. Finally, a two-step approach was employed to determine the proportion of BMs mediating the effects of GM on KOA. Results: MR analysis identified seven gut microbial species that are causally associated with KOA. Additionally, MR analysis of 1091 BMs and 309 metabolite ratios revealed 13 metabolites that influence the risk of KOA. Through two-step analysis, three BMs were identified as mediators of the effects of two GMs on KOA. Among them, 6-hydroxyindole sulfate exhibited the highest mediation percentage (10.26%), followed by N-formylanthranilic acid (6.55%). Sensitivity and reverse causality analyses further supported the robustness of these findings. Conclusion: This research identified specific GMs and BMs that have a causal association with KOA. These findings provide critical insights into how GM may influence KOA risk by modulating specific metabolites, which could be valuable for the targeted treatment and prevention of KOA.

Breast cancer (BC) is a prevalent malignancy among women. Evidence has indicated that F-box/WD repeat-containing protein 5 (FBXW5) is crucial in oncogenesis and progression. However, the function of FBXW5 in BC remains elusive. This work aims to explore the regulatory mechanisms of FBXW5 in the development of BC. The expression of FBXW5 in pan-cancer and breast invasive carcinoma (BRCA) was analyzed using The Cancer Genome Atlas (TCGA) database. FBXW5 level was enhanced in BC tissues. Besides, FBXW5 inhibition significantly decreased cell viability by 49.05% in MDA-MB-231 cells and 62.30% in MCF-7 cells. FBXW5 inhibition significantly inhibited cell proliferation by 66% in MDA-MB-231 cells and 74% in MCF-7 cells. FBXW5 inhibition significantly suppressed cell migration by 77.2% in MDA-MB-231 cells and 82.15% in MCF-7 cells. FBXW5 inhibition significantly inhibited cell invasion by 64.14% in MDA-MB-231 cells and 71.33% in MCF-7 cells. In vivo, FBXW5 depletion reduced tumor weight by 63.39% and tumor volume by 65.17%. Moreover, FBXW5 silencing restrained lung metastases in vivo. Besides, the impact of FBXW5 on the malignant behavior of BC cells was mediated through the regulation of ferroptosis. Mechanically, FBXW5 facilitated Kruppel-like factor 13 (KLF13) degradation by enhancing its ubiquitination. The addition of FBXW5 facilitated cell proliferation, migration, and invasion and inhibited ferroptosis in MDA-MB-231 and MCF-7 cells, which were neutralized by KLF13 overexpression. Besides, the knockdown of KLF13 led to the activation of the PI3K/AKT pathway. KLF13 silencing counteracted the inhibitory effects of FBXW5 depletion on cell proliferation, migration, and invasion, as well as its promotion of ferroptosis, effects that were reversed by LY294002. In conclusion, targeting FBXW5 may serve as a potential therapeutic strategy for BC by modulating the KLF13/PI3K/AKT axis.

The use of external therapies for knee osteoarthritis (KOA) in traditional Chinese medicine (TCM) is supported by several guidelines and systematic reviews. However, the relative advantages and disadvantages of TCM external therapies and their mechanisms of action have not yet been confirmed in evidence-based medicine. We used network meta-analysis to rank the effectiveness and safety of TCM external therapies, screen the optimal TCM external therapies. TCM external therapies for KOA published before October 2024 were comprehensively retrieved from eight electronic databases. Using the Cochrane Reviewers' Handbook, two independent reviewers performed study selection, data extraction, and bias assessment of the included randomized controlled trials (RCTs). Data analysis was conducted using Stata 16.0 and RevMan 5.4 software. A total of 68 RCTs were identified, including 6571 participants, involving 11 interventions, 4.41% of which showed a high risk of bias. The results of the network meta-analysis revealed that in terms of improving Visual Analog Scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function scores, each external therapy was better than conventional medicine. Electroacupuncture may be the most effective intervention in improving the VAS score and TNF-α level. Moxibustion resulted in the greatest improvement in WOMAC function and IL-6 levels. The most effective interventions for reducing WOMAC pain scores were the manual needle knife, followed by electroacupuncture and Tuina therapy (SUCRA = 82.9%, 79.0%, and 71.4%, respectively). Warming acupuncture dominantly increased Lysholm scores. The safety results showed that the three safest interventions were the sham intervention, Tuina therapy, and moxibustion (SUCRA = 90.6%, 83.1%, and 68.8%, respectively). Silver needle had the best comprehensive effect. Electroacupuncture has the best effect on improving pain symptoms, and moxibustion can be prioritized when functional limitations are the main symptoms. To some extent, the changes in inflammatory factors correlated with an improvement in KOA symptoms.

Aging is an unavoidable process associated with a progressive decline of muscle mass, strength, and regenerative ability. Satellite cells are a muscle stem cell (MuSC) population that plays a key role in mammalian muscle regeneration, by awakening from quiescence and then migrating to sites of damage, expanding in number to generate progenitor cells, and then either differentiating to rebuild the muscle tissue or self-renewing to repopulate the stem cell pool. Emerging evidence suggests that the aging process impairs the activation potential and the regenerative capacity of MuSCs. This review explores some of the recent discoveries of how mis-regulation of intrinsic and extrinsic mechanisms drive the decline of MuSC function in aging muscles, and we discuss new strategies to rejuvenate aged MuSC function for regenerative medicine. Understanding these processes will speed up the development of novel therapeutics for counteracting muscle loss and improve muscle healing in the elderly.

Age-associated neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are marked by progressive degeneration of the nervous system. Current diagnostic approaches, such as neuroimaging and cerebrospinal fluid biomarkers, are invasive, costly, and lack early diagnostic reliability. Recent studies highlight the potential of extracellular vesicles, particularly exosomes, derived from erythrocytes or red blood cells (RBCs), as emerging indicators of aging and age-associated diseases. Exosomes carry noncoding RNA, lipid, and protein molecules, and modulate cellular pathways at distant sites, providing neuroprotective and anti-inflammatory effects. In this study, we isolated RBC-derived exosomes of young and old mice. MicroRNA sequencing analysis revealed differential expression of several miRNA species between young and old mice. We report an upregulation of miR-125a-5p and a downregulation of miR-302a-5p in old mice that are potentially linked to neurodegenerative pathways. This study underscores the potential of RBC-derived exosomes as noninvasive biomarkers for NDDs.

Aging is associated with a gradual decline in cellular function, largely driven by oxidative stress, which leads to cellular senescence. These processes contribute to tissue degeneration and age-related dysfunction. Human dermal fibroblasts (HDFs), critical for maintaining skin structure, are highly vulnerable to oxidative damage, making them key contributors to skin aging. Umbilical cord blood plasma (UCBP), rich in growth factors and regenerative molecules, has shown potential in preventing cellular senescence and addressing key mechanisms of tissue aging. Based on findings from heterochronic parabiosis experiments that demonstrated the rejuvenating effect of young blood, we investigated the effects of UCBP on hydrogen peroxide (H₂O₂) induced oxidative stress in HDFs and compared its efficacy with adult blood plasma (ABP). Our results indicate that although both UCBP and ABP reduce reactive oxygen species (ROS), UCBP is more effective in suppressing cellular senescence and maintaining fibroblast proliferation. These findings suggest that UCBP's protective effects extend beyond ROS reduction, potentially by modulating the senescence-associated secretory phenotype and the enhancement of tissue repair mechanisms.