International journal of molecular medicine最新文献

Alzheimer's disease (AD) is a neurodegenerative disorder marked by progressive cognitive decline and whose pathology is closely linked to cellular autophagy dysfunction. Autophagy is a key process involved in cell clearance. Impaired autophagy can drive neuronal damage and death related to AD pathology. Therefore, targeting autophagy dysfunction has emerged as a promising therapeutic strategy. Exercise, as a non‑pharmaceutical and low‑cost intervention method, can enhance autophagy activity and alleviate AD symptoms. However, the mechanism by which it regulates autophagy in AD remains unclear. The present review summarizes evidence that exercise acts as an effective early intervention. Exercise activates key cellular signaling pathways (mammalian target of rapamycin, sirtuin 1 and adiponectin receptor 1) and regulates microRNAs (small non‑coding RNAs) and irisin (a muscle hormone) to restore normal autophagy. The present review also explores the use of exercise combined with natural products for potential synergistic therapeutic effects. This review provides insights into developing new AD prevention and management strategies by detailing how exercise corrects AD‑related autophagy dysfunction.

Sepsis is a life‑threatening clinical syndrome characterized by a dysregulated host immune response to infection, with its pathogenesis closely linked to the aberrant activation and dysfunction of various immune cells. The kidney is among the most vulnerable organs in sepsis. The development of acute kidney injury (AKI) in sepsis, referred to as sepsis‑associated AKI (SA‑AKI), is often associated with significantly increased mortality. Despite its clinical impact, specific and effective therapies for SA‑AKI remain scarce. Increasing evidence highlights that complex intrarenal inflammatory processes, primarily driven by diverse immune cell populations, are central to the onset and progression of SA‑AKI. The present review provides a comprehensive analysis of the roles of both innate and adaptive immune cells, such as macrophages, neutrophils, dendritic cells, natural killer cells, natural killer T (NKT) cells, B cells and T cells, in SA‑AKI and explores potential therapeutic strategies, offering a theoretical foundation and insights for the development of more effective prevention and treatment approaches.

Diabetic kidney disease (DKD) is a microvascular complication of diabetes, characterized by region‑specific metabolic reprogramming that disrupts kidney function and markedly impairs patient prognosis. By enabling in situ visualization and analysis of metabolite distribution within kidney tissue, spatial metabolomics offers a unique advantage in detecting spatial heterogeneity in metabolic alterations, which is inaccessible through conventional metabolomics. This approach not only enhances the understanding of DKD pathophysiology but also provides a solid foundation for the development of precision nephrology strategies informed by spatial metabolite data. The present review discusses the fundamental workflows and spatial resolution capabilities of spatial metabolomics, summarizing the key metabolites involved in regional metabolic disruptions in multiple DKD animal models. Moreover, it highlights notable metabolites, including glucose, succinate, phosphatidylserine, lysophosphatidylglycerol, phosphatidylglycerol, sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, taurine, glutamate, L‑carnitine, choline, adenosine monophosphate and guanosine monophosphate. The continued advancement of imaging technologies and data analysis methodologies is expected to further refine the spatial resolution and precision of spatial metabolomics, thereby facilitating its broader application in clinical practice.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder that can progress from asymptomatic glandular involvement to systemic manifestations affecting multiple organs, thereby imposing a notable economic burden on both patients and society. The pathogenesis of pSS is complex and involves multifactorial interactions between genetic, environmental and immune components. Although pSS is a common rheumatic disease, current therapeutic approaches primarily focus on symptom management and no curative treatment is available. Therefore, it is key to identify novel and effective therapeutic strategies for affected individuals. The mTOR signaling pathway is a key regulatory pathway in numerous types of cell, playing a crucial role in immune regulation, inflammation and autophagy. Activation of this pathway can promote inflammation by inducing immune dysregulation, thereby contributing to the pathogenesis of pSS. Conversely, inhibition of the mTOR signaling pathway mitigates these pathological processes and may help alleviate disease severity. Thus, the mTOR signaling pathway represents a promising therapeutic target for pSS. The present review aimed to elucidate the role and underlying mechanisms of the mTOR signaling pathway in pSS and provide a theoretical foundation for developing targeted therapeutic interventions.

The tumor microenvironment (TME) in oral squamous cell carcinoma (OSCC) represents a dynamic and heterogeneous ecosystem in which non-immune stromal cells play important roles in tumor progression, invasion and therapeutic resistance. Among these, cancer-associated fibroblasts (CAFs), derived mainly from normal oral fibroblasts under the influence of tumor-derived cytokines such as transforming growth factor β (TGF-β), angiopoietin-like 3 and platelet-derived growth factor-BB, are the most abundant. CAFs exhibit a myofibroblastic phenotype characterized by α-smooth muscle actin, fibroblast activation protein and integrin α6 expression and their presence correlates with aggressive tumor behavior and poor prognosis. Functionally, CAFs contribute to the 'reverse Warburg effect', remodeling of the extracellular matrix via matrix metalloproteinases and lysyl oxidase, promotion of angiogenesis and immunosuppression through cytokines such as TGF-β, interleukin (IL) 6 and IL-10. Programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule, suppresses T-cell activation by binding programmed death-1 (PD-1) on lymphocytes while also exerting intrinsic oncogenic functions, including enhancement of epithelial-mesenchymal transition, proliferation and resistance to radiotherapy and chemotherapy. PD-L1-enriched extracellular vesicles released by CAFs and tumor cells further propagate immune evasion and metastasis. Although PD-1/PD-L1 blockade with pembrolizumab or nivolumab has improved outcomes in advanced OSCC, variability in PD-L1 expression and intratumoral heterogeneity challenge predictive accuracy. The present review integrated stromal and immune perspectives, emphasizing the dual oncogenic and immunomodulatory roles of CAFs and PD-L1 in shaping the OSCC TME and identifying future therapeutic opportunities targeting both compartments.

Intracerebral hemorrhage (ICH), a life‑threatening subtype of stroke accounting for 10‑15% of global stroke cases, is characterized by high disability and mortality rates, imposing a heavy socioeconomic burden worldwide. Despite its clinical importance, no effective therapeutic interventions exist for this condition. As the resident immune cells of the central nervous system, microglia play a pivotal role in the pathophysiology of ICH. These cells can be activated to adopt either anti‑inflammatory or pro‑inflammatory phenotypes. Following ICH, pro‑inflammatory mediators derived from microglia act as key drivers of neuroinflammation, thereby exacerbating secondary brain injury. By contrast, promoting the phenotypic shift of microglia toward an anti‑inflammatory state has been shown to mitigate an inflammatory response and facilitate neurological recovery. In the present study, existing evidence was reviewed to propose that post‑ICH brain injury and repair are orchestrated not by isolated cells, but by a highly dynamic neuroimmune network centered on microglia. Elucidating the spatiotemporal dynamics and key communicative nodes within this network represents a critical frontier. Moving beyond the classical M1/M2 dichotomy to target this network contextually offers a promising and precise therapeutic aim for future investigations.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disorder characterized by unexplained fibrosis and limited therapeutic options, highlighting the urgent need for innovative treatments. Hyaluronic acid (HA), which is upregulated in IPF and correlates with disease severity, plays an undefined role in its pathogenesis. Hyaluronic acid synthase 2 (HAS2), a key enzyme in HA production, has an unclear function in IPF progression, particularly regarding its involvement in macrophage polarization. Understanding this mechanism is essential for identifying novel therapeutic targets and developing effective drugs for IPF. The present study investigated the roles of HAS2 and HA in IPF and identified potential therapeutic agents. Transcriptomic analysis revealed HAS2 as a critical IPF‑associated gene in patient samples, bleomycin (BLM)‑induced mouse models, and transforming growth factor β1 (TGF‑β1)‑induced myofibroblasts. Single‑cell RNA sequencing further confirmed the fibroblast‑specific upregulation of HAS2 in fibrotic lungs. Experimental validation showed elevated HAS2 expression and HA accumulation in fibrosis models. HA facilitated macrophage M2 polarization and TGF‑β1 secretion through CD44‑dependent STAT6 activation, with CD44 inhibition blocking this effect. Knockdown of HAS2 in fibroblasts decreased HA release and impaired their ability to promote M2 polarization, suggesting that fibroblast‑derived HA drives this process. High‑throughput virtual screening, coupled with absorption, distribution, metabolism and excretion (ADME) profiling, identified orcinol glucoside (OG) as a potential HAS2 inhibitor, which was validated through surface plasmon resonance, cellular thermal shift assays, and molecular dynamics simulations. OG suppressed HA synthesis in TGF‑β1‑induced and HAS2‑overexpressing myofibroblasts in a dose‑dependent manner, inhibiting M2 polarization induction. In vivo, OG reduced collagen deposition, HA, and TGF‑β1 levels in BLM‑induced fibrotic mice. These findings established HAS2 as a central pathogenic factor in IPF and suggested OG as a promising therapeutic candidate, providing a novel approach for IPF treatment by targeting HA synthesis and macrophage polarization.

Diabetic retinopathy (DR) is a common microvascular complication that leads to vision loss in patients with diabetes. The SLC12A2/SLC12A4 inhibitor, bumetanide, has been reported to alleviate hypoxia‑induced retinopathy. It was hypothesized that it may exert the same effect in DR. DR cell types and SLC12A2/SLC12A4 expression at the cell level were analyzed using single cell RNA‑sequencing (scRNA‑seq) data. Next, cell [high glucose (HG) stimulation] and animal (mice injected with streptozotocin) DR models were constructed. The protective effects and possible mechanisms of bumetanide and SLC12A2 were investigated through a series of experiments, including Cell Counting Kit‑8, TUNEL, Transwell, tube formation, ELISA, immunofluorescence staining, western blot and reverse transcription‑quantitative PCR assays. Bumetanide reduced HG‑induced cell apoptosis by suppressing the expression of SLC12A2 and SLC12A4. Second, scRNA‑seq analysis revealed that SLC12A2 was predominantly expressed in endothelial cells, which are the main targets of hyperglycemic damage. Endothelial cell‑related markers were involved in angiogenesis and adhesion molecule‑related pathways. Third, in HG‑stimulated cells, SLC12A2 knockdown efficiently reduced the inflammatory response and angiogenesis, while maintaining endothelial barrier integrity. This protective process involved reduced release of inflammatory factors (IL‑1β and IL‑6) and growth factors (vascular endothelial growth factor), suppression of adhesion molecule expression (VCAM1, ICAM1, E‑Selectin and P‑Selectin), activation of tight junction protein (ZO‑1), and decreased matrix metalloproteinases (MMP2 and MMP9). Furthermore, SLC12A2 deficiency ameliorated DR progression in streptozotocin‑induced diabetic mice by improving retinal thickness and pathological changes. The present study elucidates the crucial role of bumetanide in DR treatment and suggests that targeting SLC12A2 may represent a novel therapeutic strategy for the prevention of DR.

Secondary osteoarthritis, a degenerative joint disease, is often precipitated by well‑characterized etiological factors, with developmental dysplasia of the hip (DDH) emerging as a leading contributor. Despite its clinical importance, the intricate molecular and cellular cascades triggered by the biomechanical perturbations associated with DDH remain poorly understood. In the present study, a swaddling‑induced rat model of DDH was successfully developed, which recapitulated key pathological features including acetabular labral tears and cartilage degeneration. Through comprehensive mRNA‑sequencing analysis of acetabular cartilage samples from rats with DDH, a notable upregulation of dual‑specificity phosphatase 26 (DUSP26) was identified, a protein with previously unreported roles in joint homeostasis. Subsequently, in an in vitro inflammatory microenvironment induced by interleukin (IL)‑1β, adenovirus‑mediated overexpression of DUSP26 demonstrated marked chondroprotective effects. Specifically, this intervention led to a significant increase in the expression of type II collagen, a hallmark of healthy chondrocytes, while concurrently reducing the levels of catabolic markers such as type I collagen, TNF‑α and IL‑6. Reciprocally, adenovirus‑delivered short hairpin RNA‑mediated DUSP26 silencing exacerbated cartilage degradation, validating its protective function. Employing mass spectrometry‑based proteomics combined with genetic and pharmacological approaches, the underlying mechanism was elucidated: DUSP26 overexpression exerted its chondroprotective effects by dephosphorylating and inactivating histone deacetylase (HDAC)1, HDAC2 and HDAC8, thereby maintaining chondrocyte integrity. Collectively, the findings of the present study underscore DUSP26 as a promising therapeutic target for DDH‑associated osteoarthritis, offering novel mechanistic insights and laying the groundwork for the development of targeted interventions to mitigate secondary joint degeneration.

The one‑carbon metabolism pathway, regulated by the methylenetetrahydrofolate reductase (MTHFR) enzyme, represents a key nexus where genetic predisposition and nutrient status converge to shape the epigenetic landscape of autoimmune diseases. The objective of the present review is to synthesize evidence of how the MTHFR‑folate axis drives epigenomic patterns in these conditions. One of the main diseases involved is rheumatoid arthritis, where drug‑naïve patients show T‑cell and synovial hypomethylation with cytokine‑driven DNMT suppression, a process aggravated by reduced folate availability and MTHFR polymorphisms that constrain S‑adenosylmethionine supply. Similarly, in systemic lupus erythematosus, CD4⁺ T cells exhibit global hypomethylation with an interferon‑skewed signature (such as IFI44L), associated with impaired MTHFR activity and a folate‑dependent SAM:SAH imbalance that further diminishes DNMT function. Finally, in celiac disease, intestinal differential methylation, including LINE‑1 hypomethylation, is observed, driven by gluten‑induced villous atrophy and folate malabsorption. Overall, impaired one‑carbon metabolism and MTHFR‑dependent methylation capacity may be key determinants of epigenomic dysfunction underlying autoimmune disease and its clinical severity.17.