International journal of molecular medicine最新文献

Centromere protein U (CENPU), a critical component of the kinetochore complex, structurally integrates with spindle microtubules to mediate chromosome segregation during mitosis. However, the association between CENPU expression levels and tumors is largely unknown. Immunohistochemistry and western blotting were used to analyze CENPU expression and prognostic value in breast cancer tissues. CENPU overexpressing/knockdown cell lines were constructed for 4D‑data‑independent acquisition quantitative proteomics and enrichment analyses. Functional assays, including flow cytometry, mammosphere formation, wound healing and Transwell assay, were used to assess the effects of CENPU on breast cancer stemness, migration and invasion. The associations among CENPU, nerve growth factor (NGF), proNGF and furin were also explored through western blotting, co‑immunoprecipitation and ELISA experiments. Finally, xenograft mouse models were established to verify the in vivo effects of CENPU on tumorigenesis and the inhibitory effect of furin inhibitor on CENPU‑promoted tumor growth. In the present study, immunohistochemistry and western blotting assessment of human breast cancer tissue specimens revealed a positive association between CENPU expression and the degree of invasiveness. The aforementioned functional analyses demonstrated that CENPU promoted stem cell‑like behavior and tumorigenicity, and induced malignancy in BC cells. Mechanistically, western blotting analysis demonstrated that CENPU promoted furin activity by inhibiting its lysosomal degradation. Furin, which is a precursor‑processing enzyme of (NGF), promoted the conversion of NGF precursor to NGF, which could promote BC stem cell properties in triple‑negative BC (TNBC). A tumorigenesis assay conducted in xenograft mouse models showed that CENPU promoted tumorigenesis, and treatment with a furin inhibitor suppressed this effect. The findings of the present study revealed that CENPU serves a critical role in furin‑mediated signaling responsible for tumorigenesis. Therefore, CENPU may be a novel molecular target in TNBC.

Sepsis is a life‑threatening disease characterized by a dysregulated immune response, and neutrophils serve an important role in pathogen clearance, multiple organ failure and immune regulation. With the discovery of multiple phenotypical and functional variants of neutrophils in sepsis, the heterogeneity of neutrophils is crucial, as it impacts the effectiveness of the immune response and the overall outcome of sepsis. Various genome, transcriptome, proteome and metabolome properties may contribute to this heterogeneity. Multi‑omics approaches unveil complex details of neutrophil behavior in the context of sepsis, highlighting how neutrophil phenotypes are differentially recruited and activated in response to various stimuli. The present review aimed to provide an overview of the differences in neutrophil phenotypes and functions during sepsis, focusing on neutrophil heterogeneity identified via multi‑omics methods. Comprehensive understanding of multi‑omics data regarding neutrophil heterogeneity enhances the diagnostic accuracy of sepsis and provides a scientific basis for individualized treatment strategies, potentially improving patient outcomes by targeting specific neutrophil functions and states.

Sepsis‑induced liver injury increases mortality through inflammatory dysregulation. Although Radioprotective 105 (RP105) modulates inflammation, its role in septic liver injury remains unclear. The present study investigates the mechanism of RP105 in sepsis‑driven hepatic damage. Sepsis was induced in RP105 knockout (KO) and wild‑type (WT) mice via cecal ligation and puncture (CLP). Liver injury was assessed by serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST), histology (H&E), inflammatory markers (anti‑myeloperoxidase, F4/80, IL‑1β, IL‑6 and TNF‑α) and apoptosis markers (Caspase‑3, BAX/BCL‑2 ratio, GADD45A and PUMA). RNA sequencing identified key differentially expressed genes. RP105‑suppressor of cytokine signaling (SOCS) 2 interaction was validated by co‑immunoprecipitation (Co‑IP) and JAK2/STAT3 pathway activity was measured by western blotting. Lipopolysaccharide‑stimulated RP105‑KO macrophages were used in vitro. RP105‑KO mice exhibited exacerbated liver injury post‑CLP, evidenced by significantly elevated ALT/AST (P<0.001), expanded hepatic necrosis (P<0.001), increased inflammatory infiltration (P<0.001), upregulated pro‑inflammatory cytokines (IL‑1β, IL‑6 and TNF‑α; P<0.001) and enhanced Caspase‑3 expression (P<0.001). RNA‑seq identified SOCS2 as a key RP105‑regulated DEG (fold change >2.0; FDR <0.05). Co‑IP confirmed RP105‑SOCS2 binding in WT liver which was absent in KO mice. SOCS2 protein remained decreased in KO + CLP vs. WT (P<0.001). RP105 deletion activated JAK2/STAT3 signaling in vivo and in vitro (P<0.001). RP105 protects against septic liver injury by binding SOCS2 to inhibit JAK2/STAT3 signaling, thereby attenuating inflammation and apoptosis. The present study is the first to demonstrate the RP105‑SOCS2 interaction in septic liver injury, revealing the RP105/SOCS2 axis as a potential therapeutic target.

Obesity, a global health concern defined by excessive adiposity and persistent metabolic imbalance, has far‑reaching implications that extend beyond standard metabolic and cardiovascular comorbidities. While the association between obesity and reproductive dysfunction is well‑established, the precise molecular mechanisms underlying these associations remain incompletely understood, particularly as regards the distinction between obesity‑specific effects and those mediated by dietary components or metabolic syndrome. The present review integrates currently available knowledge on the mechanisms through which obesity impairs reproductive function in both sexes, from gametogenesis to postnatal development. In males, obesity drives testicular inflammation, disrupts spermatogenesis, impairs sperm motility and DNA integrity, and alters key signaling pathways, with oxidative stress and metabolic endotoxemia as central mediators. In females, obesity induces ovarian dysfunction, alters steroidogenesis, compromises oocyte quality and disrupts follicular environments, leading to reduced fertility and adverse pregnancy outcomes. However, the relative contribution of obesity‑induced inflammation vs. direct lipotoxic effects remains poorly characterized in both sexes. The present review further examines the impact of parental obesity on fertilization capacity, placental function and in utero development, highlighting sex‑specific and intergenerational effects mediated by mitochondrial dysfunction and epigenetic modifications. Notably, maternal obesity impairs placental and fetal organ development, increases the risk of metabolic and reproductive disorders in offspring, and alters key developmental signaling pathways. While some studies suggest that lifestyle interventions and antioxidant therapies may partially reverse obesity‑induced reproductive impairments, significant gaps remain in understanding the precise molecular mechanisms and potential for therapeutic rescue. By synthesizing findings from animal models and human studies, the present review highlights the pivotal role of oxidative stress as a mechanistic link between obesity and reproductive dysfunction. It emphasizes the need for further research to inform clinical strategies aimed at mitigating these adverse outcomes.

Heart failure (HF) is a key public health concern worldwide due to its high morbidity and mortality rates. Calycosin (CA) is a flavonoid natural product that effectively treats HF with cardioprotective effects; however, its mechanism of action remains unclear. The present study aimed to investigate the therapeutic effect of CA on HF and its mechanism through in vivo and in vitro experiments, and to reveal the roles of pyroptosis and mitochondrial dysfunction in the pathophysiology of HF. The HF model was constructed 4 weeks after ligation of the left anterior descending artery in rats. Myocardial ischemia‑reperfusion injury was simulated using a hypoxia‑reoxygenation model and nuclear factor erythroid 2‑related factor (Nrf2) was silenced by transfection using small interfering RNA to further explore the therapeutic mechanism of CA. The results revealed that CA treatment improved cardiac function and myocardial injury, suppressed oxidative stress levels and improved mitochondrial ultrastructure in HF‑induced rats. CA downregulated the expression of relevant pyroptosis proteins via the Nrf2/reactive oxygen species (ROS)/thioredoxin‑interacting protein (TXNIP) pathway. In vitro experiments demonstrated consistent results confirming that CA ameliorated mitochondrial damage by reducing levels of ROS and inhibiting mitochondrial gasdermin D N‑terminal fragments activation. Silencing Nrf2 partially reversed the cardioprotective effects of CA, confirming the key therapeutic role of CA in Nrf2‑mediated anti‑pyroptosis. In conclusion, CA inhibits pyroptosis and improves mitochondrial damage in HF through the Nrf2/ROS/TXNIP pathway, which may disrupt the crosstalk between mitochondrial damage and pyroptosis, thereby exerting cardioprotective effects.

Intermittent fasting (IF) has shown particularly promising short‑term effects in improving metabolic dysfunction‑associated steatotic liver disease (MASLD), although its long‑term efficacy remains unclear. Heterophyllin B (HP‑B), a cyclopeptide compound derived from Pseudostellaria heterophylla, is known for its potent anti‑inflammatory and hypoglycemic properties. However, studies investigating the potential role of HP‑B in the management of MASLD are lacking. In vitro, an OA/PA‑induced lipid accumulation model was established using HepG2/Huh‑7 cells. The therapeutic effects of HP‑B and fasting‑mimicking conditions were evaluated through Cell Counting Kit‑8 assay, Oil Red O staining, reverse transcription‑quantitative PCR, and western blot analysis. For in vivo studies, C57BL/6J mice were fed a high‑fat diet and treated with HP‑B, IF, or their combination. Mechanistic validation was performed via adenovirus‑mediated GLP‑1R knockdown. The present study aimed to explore whether HP‑B can serve as an adjunctive supplement to enhance the benefits of IF in the treatment of MASLD. HepG2 and Huh‑7 liver cancer cells treated with oleic acid/palmitic acid (OA/PA) presented significant lipid accumulation, which was attenuated by HP‑B treatment and fasting. The combination treatment markedly reduced lipid levels and oxidative stress, as well as restored the mitochondrial membrane potential, with a synergistic effect over treatment alone. In addition, the combination of HP‑B and fasting upregulated glucagon‑like peptide‑1 receptor (GLP‑1R) and peroxisome proliferator‑activated receptor gamma coactivator 1‑alpha expression, reversing the OA/PA‑induced decline. In high‑fat diet‑fed mice, the combination treatment reduced hepatic lipid accumulation, decreased liver weight, decreased mouse body weight, and improved biochemical indices of liver function. The beneficial effects of HP‑B and fasting were reversed after silencing GLP‑1R with small interfering RNA or Ad‑GLP‑1R, emphasizing the critical role of GLP‑1R in mediating these protective effects. In conclusion, the synergistic effects of HP‑B and fasting on improving lipid metabolism and mitochondrial function are mediated primarily through the regulation of GLP‑1R, making it a promising therapeutic target for the treatment of MASLD and other lipid metabolism‑related disorders.

Emerging evidence indicates a significant association between the composition and functionality of the gut microbiome and various skin disorders, including psoriasis, atopic dermatitis, acne and several dermatological conditions. The gut‑skin axis theory describes a complex bidirectional communication network between the gut and the skin, providing mechanistic insights into the pathogenesis of certain cutaneous diseases. Specifically, the gut microbiome influences skin health through the regulation of systemic immunity, inflammatory responses and metabolic pathways. Advances in high‑throughput sequencing and bioinformatics technologies have substantially enhanced the understanding of the role of the gut microbiome in skin pathology. Clinical and preclinical studies have demonstrated that restoring gut microbial homeostasis via interventions such as faecal microbiota transplantation, probiotics and prebiotics can ameliorate symptoms of skin diseases. Furthermore, personalized microbiome‑based therapies, next‑generation probiotics and dietary modifications hold promise for refining gut‑skin interactions and advancing precision medicine in dermatology. Therapeutic strategies targeting the gut‑skin axis offer novel avenues for innovative dermatological treatments, with future breakthroughs potentially involving microbial community engineering, postbiotics and artificial intelligence in microbiome‑related diagnostics. This narrative review summarizes recent advances in gut‑skin axis research, explores its potential in the prevention and management of selected dermatoses and discusses future trends and scientific developments in the field.

PTEN‑induced putative kinase 1 (PINK1), a master regulator of mitophagy, is implicated in mitochondrial homeostasis, yet its role in knee osteoarthritis (OA) pathogenesis remains unclear. The present study investigated the mechanisms by which PINK1 modulates chondrocyte senescence during OA progression. Utilizing a destabilization of the medial meniscus‑induced OA murine model, decreased PINK1 expression, impaired mitochondrial function and suppressed mitophagy were observed in OA cartilage. In vitro, lipopolysaccharide‑induced chondrocyte senescence was exacerbated by PINK1 knockdown but mitigated by PINK1 overexpression, which restored mitophagy and reduced senescence‑associated β‑galactosidase activity, reactive oxygen species accumulation and mitochondrial membrane potential collapse. RNA sequencing and mechanistic studies identified the p38 MAPK/NF‑κB pathway as a downstream target; PINK1 knockdown amplified the phosphorylation of p38 MAPK/NF‑κB, promoting mitochondrial dysfunction and senescence. By contrast, pharmacological inhibition of p38 MAPK/NF‑κB rescued these effects in PINK1‑deficient chondrocytes. Collectively, PINK1 attenuated OA progression by suppressing chondrocyte senescence via inhibition of the p38 MAPK/NF‑κB pathway, highlighting its potential as a therapeutic target for OA management.

Diabetic retinopathy (DR), a leading cause of blindness in diabetic microvascular complications, is pathologically associated with the dynamic regulation of retinal microglia. The present review systematically elucidated the dual roles of microglia in DR pathogenesis. Under physiological conditions, microglia maintain blood‑retinal barrier (BRB) integrity by phagocytosing metabolic debris and secreting neurotrophic factors. However, hyperglycaemic stress induces pathological M1 polarization, triggering a cytokine storm (TNF‑α and IL‑1β) via the Toll‑like receptor 4/myeloid differentiation primary response 88/NF‑κB signalling axis, which synergizes with proangiogenic factors (such as VEGF and insulin‑like growth factor 1) to exacerbate BRB breakdown and pathological neovascularization. Notably, activated microglia amplify inflammatory cascades through astrocyte‑Müller cell interaction networks, accelerating neurovascular unit dysfunction. Emerging therapeutic strategies targeting microglial polarization homeostasis (such as promoting M2 anti‑inflammatory phenotypic shifts) and blocking critical inflammatory signalling pathways present novel opportunities for developing multitarget therapeutic agents with combined neuroprotective and anti‑vasopermeability properties. By elucidating microglial heterogeneity and intercellular regulatory networks, the present review highlighted the importance of precise modulation of immune homeostasis in DR management, providing a theoretical foundation for overcoming the limitations of single‑target therapies.

Perimenopause represents a key transition from a reproductive to non‑reproductive state in women, characterized by physiological and psychological changes. Mood disturbances during this period, such as depression, anxiety and cognitive decline, are increasingly understood as complex neuroendocrine and metabolic disorders. Mitochondrial homeostasis carries out a key role in the pathophysiology of these affective symptoms. Disruptions in mitochondrial biogenesis, mitophagy and calcium regulation contribute to synaptic dysfunction and neuroimmune changes. These mitochondrial alterations interact with inflammatory pathways and hormonal signals, exacerbating neuropsychiatric symptoms. A more comprehensive understanding of the molecular mechanisms of mitochondrial dysfunction in menopausal mood disorders unveils potential therapeutic strategies, including mitochondria‑targeted antioxidants, hormone replacement therapy, and lifestyle interventions designed to restore mitochondrial integrity and cerebral bioenergetic function.