International journal of molecular medicine最新文献

Ischemia‑reperfusion injury (IRI) is a complex pathophysiological process characterized by oxidative stress, inflammatory response and cell death during tissue reperfusion, leading to organ dysfunction. In liver transplantation, hepatic ischemia‑reperfusion injury (HIRI) can result in irreversible liver failure and subsequently trigger rejection. Neutrophils, as the first recruited innate immune cells, play a central role in the initiation, progression and resolution stages of HIRI. However, current research predominantly focuses on their pro‑inflammatory and damaging mechanisms, lacking a theoretical framework that systematically integrates their dual functions. Based on a systematic review of key processes involving neutrophils in HIRI, including recruitment, adhesion, migration, neutrophil extracellular trap (NET) formation and phenotypic polarization, the present review proposed the 'injury‑repair balance' theory. It emphasized that neutrophils are dynamically regulated by the hepatic microenvironment and can undergo functional conversion between pro‑inflammatory N1 and anti‑inflammatory/repair N2 phenotypes. Their polarization state is a critical factor determining the progression and recovery of HIRI. The present review further explores multi‑dimensional intervention strategies targeting neutrophils, including inhibiting excessive recruitment and activation, regulating migration to reduce local accumulation, suppressing NET formation and promoting their clearance, as well as combining antioxidant and anti‑inflammatory therapies to reestablish immune homeostasis. Additionally, extracellular vesicles, due to their excellent targeting delivery and immunomodulatory capabilities, have emerged as potential tools for precise regulation of neutrophil function. Notably, current research on neutrophil polarization mechanisms remains incomplete. Future studies should delve into the temporal regulatory mechanisms of polarization and explore the possibility of driving neutrophils toward an N2‑like reparative phenotype through pharmacological or biological interventions. This strategy is expected to shift the treatment paradigm for HIRI from traditional 'cell suppression' to a more precise 'functional reprogramming,' transforming the approach from merely mitigating injury to actively promoting tissue regeneration.

Adipose tissue hypertrophy, the local infiltration of immune cells, the increased production of proinflammatory cytokines, the whitening of brown adipose tissue, local hypoxia and angiogenesis disorders occur in obese individuals, which in turn lead to adipose tissue inflammation and promote the occurrence and development of metabolic diseases such as type 2 diabetes (T2DM), atherosclerosis and metabolic dysfunction‑associated steatotic liver disease (MASLD). In recent years, N6‑methyladenine (m⁶A), the most representative epigenetic modification, has been shown to be significantly altered in individuals with obesity and to participate in the regulation of various metabolic diseases. In the present review, the links between m6A modification and obesity‑related metabolic diseases, such as MASLD and T2DM, from the perspective of adipose tissue inflammation are examined. Additionally, the challenges and prospects associated with targeting m6A in adipose tissue inflammation and metabolic diseases are discussed to provide new ideas for the treatment of these conditions.

Abnormal activation and pyroptosis of microglia caused by cerebral ischemia‑reperfusion injury (CIRI) are key mechanisms underlying neuronal damage. The NF‑κB/NLRP3 pathway is a core mediator of microglial pyroptosis and neuroinflammatory cascades in CIRI. Milk fat globule‑EGF factor 8 (MFG‑E8) is a critical anti‑inflammatory and neuroprotective factor. Propofol (PPF) exhibits antioxidant activity and ameliorates neuronal injury, but its effects on CIRI and underlying mechanisms remain unclear. The present study aimed to investigate whether PPF alleviates neuronal injury by modulating NF‑κB/NLRP3 pathway via regulating MFG‑E8 expression. An oxygen‑glucose deprivation/reoxygenation (OGD/R) model was established using mouse microglial BV‑2 and hippocampal neuronal HT22 cells and cell survival was assessed via Cell Counting Kit‑8 assay. Polarity in BV‑2 cells was evaluated using flow cytometry, while cell death was assessed by Calcein AM/PI and TUNEL staining. A transient middle cerebral artery occlusion (tMCAO) mouse model was established and neurological deficit scores were assessed. The impacts of PPF on cortical damage, neuroinflammation, apoptosis and pyroptosis in tMCAO mice were observed by histopathological staining. Inflammatory factor levels were assessed using ELISA kits. Western blotting was performed to assess MFG‑E8, pyroptosis and NF‑κB/NLRP3 pathway‑related proteins. OGD/R decreased viability, increased apoptosis and pyroptosis rates in BV‑2 and HT22 cells and promoted M1 polarization in BV‑2 cells; PPF treatment reversed these effects. MFG‑E8 was downregulated in OGD/R‑treated BV2 cells, while PPF upregulated MFG‑E8 expression. Additionally, PPF decreased cerebral infarction volume in tMCAO mice, improved neurological deficit score, mitigated pathological brain tissue damage and decreased the number of degenerating neurons. PPF also inhibited pro‑inflammatory microglia activation and decreased pro‑inflammatory factor levels. Mechanistically, PPF suppressed NF‑κB pathway activation and downregulated NLRP3 by upregulating MFG‑E8; silencing MFG‑E8 reduced the protective effects of PPF in tMCAO mice and OGD/R cell models. PPF improved neuronal injury in CIRI by upregulating MFG‑E8 to inhibit pyroptosis induced by the NF‑κB/NLRP3 pathway.

The prevalence of diabetes and its complications has become a major global health challenge, with its pathological process closely linked to the phenomenon of 'metabolic memory' induced by persistent hyperglycemia. Epigenetic regulation is recognized as the core molecular mechanism underpinning this process. The present review systematically elucidated how the hyperglycemic microenvironment profoundly regulates cellular functions and drives the onset and progression of diabetes and its vascular complications by reprogramming three major epigenetic pathways: DNA methylation, histone modifications and non‑coding RNA expression. The present review elaborated in detail how high glucose induces alterations in the DNA methylation status of specific genes (such as PDX1 and CXCR4) within key target cells including pancreatic β‑cells, hepatocytes, muscle cells and adipocytes; how it modulates multiple histone modifications, including emerging histone lactylation (such as H3K18la), thereby directly activating pathogenic gene transcription; and how it disrupts non‑coding) RNA networks (such as long non‑coding RNA MALAT1 and microRNA 21) to mediate inflammation, oxidative stress and fibrosis by interfering with signaling pathways such as PI3K/Akt and TGF‑β. Furthermore, the present review specifically emphasized the cellular and tissue specificity of high‑glucose‑induced epigenetic regulation, thereby elucidating its unique mode of action in specific complications such as diabetic nephropathy and cardiovascular disease. Finally, the present review considered the substantial potential of targeting key epigenetic enzymes (such as DNA methyltransferases, histone deacetylases) or using epigenetic markers as biomarkers and novel therapeutic strategies. This provides a conceptual framework and directions for ultimately 'eradicating' metabolic memory and achieving precise prevention and treatment of diabetes and its complications.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the TRAP‑stained images shown in Fig. 1 for the 'Diabetes' and 'IGF‑I' panels contained an overlapping section, such that data which were intended to have shown the results of differently performed experiments were apparently derived from the same original source. The authors have been contacted by the Editorial Office to offer an explanation for the apparent anomaly in the presentation of the data in their paper, and we are awaiting their response. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [International Journal of Molecular Medicine 28: 455-462, 2011; DOI: 10.3892/ijmm.2011.697].

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that, regarding the histopathological images shown in Fig. 3 on p. 90, Fig. 3E and F showed an overlapping section, suggesting that these data panels were derived from the same original source where different treatment groups were reported. The authors have been contacted by the Editorial Office to offer an explanation for this apparent anomaly in the presentation of the data in this paper, and we are awaiting their response. Due to the fact that we have been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of these potential problems while the Editorial Office continues to investigate this matter further. [International Journal of Molecular Medicine 27: 87‑94, 2011; DOI: 10.3892/ijmm.2010.552].

Cardiovascular and cerebrovascular diseases (CCVDs) have become prominent global health threats, presenting substantial challenges due to their intricate pathological mechanisms and diverse clinical manifestations. Tanshinone IIA (TSA), an active compound derived from the traditional Chinese medicinal herb Salvia miltiorrhiza, exhibits notable therapeutic potential in these diseases due to its multifaceted mechanism of action. TSA protects the cardiovascular and cerebrovascular systems by inhibiting inflammation, reducing oxidative stress, preventing apoptosis and fibrosis, and modulating key signaling pathways, including toll‑like receptor 4/NF‑κB, PI3K/AKT and nuclear factor erythroid 2‑related factor 2/heme oxygenase‑1. Notably, considerable progress has been made in applying TSA to conditions such as atherosclerosis, myocardial infarction, heart failure and hypertension. The present review synthesizes current research on the molecular mechanisms of TSA in treating CCVDs and highlights innovations in nanodelivery systems (for example, rHDL, TPP‑TPGS/LPNs and CBSA‑PEG‑TSA‑NPs) that enhance its therapeutic efficacy by improving solubility, prolonging its half‑life and enhancing targeting capabilities. These advancements not only establish a foundation for the broader clinical application of TSA in CCVDs but also offer valuable insights for the development of new therapeutic agents.

Mechanotransduction, the process by which cells convert mechanical stimuli into biochemical signals, serves as a fundamental biological mechanism driving tissue adaptation and repair in orthopedic rehabilitation. The present review explores how mechanical forces regulate cellular behavior in bone, cartilage, tendon and ligament healing, emphasizing their critical role in optimizing regenerative outcomes. Specialized mechanosensors, including integrins, ion channels and primary cilia, detect physical cues such as compression, tension and shear stress, activating downstream pathways that direct stem cell differentiation, matrix synthesis and tissue remodeling. The extracellular matrix functions not only as a structural scaffold but also as a dynamic mediator of mechanical signaling, influencing cellular responses to therapeutic loading. Clinically, mechanotherapy strategies, including controlled weight‑bearing, eccentric exercises and devices providing dynamic compression, are designed to exploit these principles, promoting anabolic activity while preventing catabolic damage. Advances in biomechanically optimized scaffolds, bioreactor systems and technologies (such as low‑intensity pulsed ultrasound) further demonstrate how targeted mechanical conditioning enhances tissue‑engineered constructs and accelerates functional recovery. However, challenges remain in defining optimal loading parameters across diverse tissues and individual patients. Future directions should prioritize personalized rehabilitation protocols informed by real‑time biomechanical monitoring and genetic profiling, alongside biomaterials that can adapt to in vivo mechanical cues. The integration of mechanobiology with regenerative medicine is paving the way for a new era in orthopedic rehabilitation. This evolution promises more precise, effective and biologically driven interventions that harness the innate mechanoresponsive capacity of the body to restore function.

Ubiquitin‑specific peptidase 22 (USP22), a key member of the deubiquitinase family, serves pivotal roles in tumorigenesis by driving tumor proliferation, metastasis and drug resistance. In addition to its role in oncology, its versatile functions in diverse physiological and pathological contexts have been revealed. These include ensuring embryonic viability through developmental signaling regulation, promoting tissue repair and contributing to ischemia‑reperfusion injury, inflammatory responses and immune activation via cytokine and immune cell regulation. USP22 is also involved in fibrosis, metabolic homeostasis and tissue remodeling in patients with conditions such as asthma and pneumoconiosis. These multifaceted actions are mediated primarily through the deubiquitination of target proteins such as silent mating‑type information regulation 2 homologue 1 and through epigenetic mechanisms, including histone modification. The present review summarized recent advances in USP22‑mediated cell fate regulation and evaluates its therapeutic potential across diseases, underscoring promising prospects for clinical translation.

Accumulating evidence indicates that environmental exposures, particularly to nitrites, play a critical role in the initiation and progression of gastric cancer (GC). During carcinogenesis, exosomes act as key mediators of intercellular communication. Exosomes derived from N‑methyl-N'‑nitro‑N‑nitrosoguanidine (MNNG)‑induced malignantly transformed GES‑1 cells (TGES‑1), as well as serum exosomes from gastric cancer patients with a history of high nitrite exposure, were found to influence normal cells and promote GC initiation. The present study established a malignant transformation model and applied bioinformatics analyses to screen and validate candidate circRNAs. A series of functional and mechanistic experiments were performed to elucidate the regulatory role of exosomes in GC progression. Circ0000549 was markedly upregulated in MNNG‑exposed GES‑1 cells, their derived exosomes and serum exosomes from patients with GC. Further investigations revealed that circ0000549 overexpression enhanced GES‑1 cell malignant features, while also modulating epithelial‑mesenchymal transition and stemness‑related properties. Nude mouse experiments demonstrated that circ0000549, carried by malignantly transformed exosomes, plays a crucial role in MNNG‑induced gastric carcinogenesis. Mechanistically, miR‑15b‑5p was identified as a potential target of circ0000549. Circ0000549 functioned as a sponge for miR‑15b‑5p, leading to increased KIF1B expression and subsequent activation of the PI3K/AKT signaling pathway. Collectively, these findings reveal that exosomal circ0000549 promotes malignant transformation of GES‑1 cells through the miR‑15b‑5p/KIF1B/PI3K/AKT axis. Exosomal circ0000549 may serve as a promising biomarker for GC diagnosis and prognosis, highlighting its potential as a target for future therapeutic investigation.