International journal of molecular medicine最新文献

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.

B‑lymphocytes (B‑cells) develop from hematopoietic stem cells in the bone marrow or fetal liver and differentiate into antibody‑secreting cells and memory B‑cells upon encountering antigens in peripheral lymphoid organs. Throughout this process, the expression of lineage‑associated genes is upregulated, whereas that of lineage‑inappropriate genes is repressed, thereby directing commitment to a specific B‑cell fate. Epigenetic regulatory mechanisms, including DNA methylation, post‑translational histone modifications and non‑coding RNAs, regulate gene transcription and play crucial roles in B‑cell development and differentiation. The dysregulation of these epigenetic processes may contribute to the pathogenesis of autoimmune diseases and B‑cell malignancies. Recent advances in high‑throughput techniques, including single‑cell RNA sequencing, chromatin immunoprecipitation‑sequencing and whole‑genome bisulfite sequencing, have significantly enhanced the understanding of epigenetic dysregulation in these disorders. The present review summarizes recent advances in the understanding of dysregulated epigenetic mechanisms underlying B‑cell‑mediated autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, primary Sjögren's syndrome, multiple sclerosis and type 1 diabetes mellitus) and lymphomas (such as diffuse large B‑cell lymphoma, follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma and marginal zone lymphoma), and highlights emerging diagnostic biomarkers and therapeutic strategies.

Air pollution, an emerging global environmental issue, alongside extreme meteorological conditions exacerbated by climate change, threaten the sustainability of modern society and contribute to the onset and progression of various ear and nose diseases. Nonetheless, the impact of these environmental factors on ear and nose diseases and related dysfunctions remain inadequately explored. The present review involved a comprehensive search of PubMed, Web of Science, the Cochrane Library and Embase for relevant epidemiological and experimental data. How environmental factors contribute to olfactory and auditory system dysfunctions as well as the potential underlying mechanisms from the perspectives of immunity and inflammation were examined in the present review. It was found that air pollution and meteorological factors significantly influence the prevalence of major ear and nose diseases, including allergic rhinitis, otitis media and sudden sensorineural hearing loss. Of note, the present review also provides an examination of the interaction between severe acute respiratory syndrome coronavirus 2 and environmental factors in ear and nose diseases, highlighting how environmental stressors may worsen disease progression. In conclusion, the present review underscores the burden of multimorbidity caused by air pollution and extreme weather and emphasizes the need for more targeted prevention and management strategies for ear and nose diseases.

Lung cancer is a highly aggressive malignancy associated with a high global mortality rate. Immunotherapy, particularly anti‑programmed cell death protein 1 (PD‑1) therapy, has offered new hope for patients; however, therapeutic resistance remains a major obstacle to clinical success. In the present study, single‑cell RNA sequencing was utilized to investigate the molecular characteristics of lung cancer and to elucidate the mechanisms underlying resistance to anti‑PD‑1 immunotherapy. Cancer‑associated fibroblasts (CAFs) were identified as key contributors to immune resistance. Functional assays, including CCK‑8, EdU, TUNEL and Transwell experiments, demonstrated that CAFs regulated the expression of lipocalin 2 (LCN2) in lung cancer cells, and elevated LCN2 levels were found to promote resistance to immunotherapy, as well as to enhance cellular proliferation and invasion. The effects of LCN2 on tumor growth, invasion, immune infiltration and ferroptosis were further validated by molecular and histological analyses. The results showed that silencing LCN2 induced ferroptosis in lung cancer cells, resulting in increased sensitivity to anti‑PD‑1 therapy, suppressed tumor growth and reduced invasiveness. These findings highlight the critical role of the CAF‑LCN2 axis in mediating resistance to anti‑PD‑1 immunotherapy and suggest that targeting this pathway may represent a promising strategy to enhance treatment efficacy in lung cancer.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by marked genetic heterogeneity and diverse environmental influences. Current treatment approaches focus on symptom management, with only a limited number of effective interventions targeting the underlying causes. Recently, mesenchymal stem cells (MSCs) and their derived exosomes (MSC‑Exos) have emerged as promising candidates for ASD therapy owing to their potent immunomodulatory, neuroprotective and targeted delivery properties. The present review discusses the functions of MSC‑Exos and their potential use in ASD. MSC‑Exos improve neuroinflammation, enhance synaptic plasticity and restore neural network function by delivering bioactive molecules. Moreover, MSC‑Exos exhibit a low immunogenicity, a favorable safety profile and scalability for clinical production. Despite promising results however, clinical trials continue to face challenges, particularly in standardizing the isolation, characterization, dosing and administration routes of exosomes. In addition, significant challenges persist in production processes, quality control and the elucidation of the mechanisms of action. In conclusion, MSC‑Exos represent a groundbreaking, cell‑free therapeutic strategy with substantial potential to target the core pathophysiology of ASD. In the future, multicenter randomized controlled trials and interdisciplinary collaborations will be crucial for translating preclinical findings into the development of effective and transformative therapies for ASD. 

In cells, copper levels are tightly regulated because copper deficiency leads to Menkes disease, anemia and neurodegeneration, whereas copper overload is associated with Wilson disease, liver injury, neurodegeneration and several cancers. Cuproptosis, a form of regulated cell death, depends on the intracellular accumulation of excessive copper. This process induces mitochondrial dysfunction and cell death by disrupting the stability of mitochondrial lipoylated proteins and iron‑sulfur cluster proteins. The present review aimed to summarize the mechanisms underlying cuproptosis in gastrointestinal cancer, with a focus on the relationship between copper metabolism imbalance and tumor initiation and progression, as well as the potential therapeutic applications of cuproptosis‑associated agents in oncology. The application prospects of cuproptosis in gastrointestinal tumor therapy are broad, offering novel therapeutic options that may improve prognosis in patients and survival outcomes.

Pancreatic cancer has nearly doubled in incidence over the past two decades, becoming one of the deadliest types of malignancy in humans, with poor prognosis. With advances in modern medicine, the 5‑year survival rate for pancreatic cancer has increased from <5% in 1990 to ~10% in 2021. Most patients are diagnosed at an advanced stage, and ~20% of patients diagnosed at an early stage are eligible for surgical resection, with a 5‑year survival rate after surgery of up to 25%. With the aging population, the incidence of pancreatic cancer is expected to continue rising. The gut microbiota, a crucial ecosystem, comprises >1x10¹⁴ microorganisms that influence the development of pancreatic cancer through immune modulation and metabolites. Circadian rhythms, as a conserved molecular feedback loop, regulate cell metabolism and immune function, and their dysregulation is associated with metabolic disorders and tumor progression. Circadian rhythm disruption not only affects the gut microbiota and its metabolites but also accelerates pancreatic cancer progression through mechanisms such as promoting inflammation, immune suppression and drug resistance. The present review summarizes the impact of circadian rhythm dysregulation on the gut microbiota and its metabolites, specific microbiota associated with pancreatic cancer and their mechanisms in tumor progression and aims to deepen the understanding of the role of gut microbiota in pancreatic cancer treatment, providing a theoretical basis for future therapeutic strategies.

Sepsis, an infection‑triggered systemic inflammatory response syndrome, ranks as the third leading cause of death worldwide due to its high incidence and mortality. Sepsis‑induced myocardial dysfunction (SIMD) is a frequent and serious complication that notably increases patient morbidity and mortality. The underlying pathophysiology of SIMD involves a complex interplay of inflammation, oxidative stress, mitochondrial impairment and apoptosis, yet no effective therapies have been established. Thus, uncovering the molecular mechanisms of SIMD, identifying novel therapeutic targets and developing efficacious agents are key. For centuries, natural products have been used in traditional medical systems across China and Asia to manage cardiovascular disease. These compounds can confer cardioprotection by modulating inflammatory pathways, decreasing oxidative stress, inhibiting apoptotic cell death and improving mitochondrial function. The present review aimed to summarize the clinical manifestations and pathophysiology of SIMD and how natural products exert their protective effects. The present study aimed to explore structure‑activity relationships and highlight key molecular targets and representative natural product binding affinities for SIMD‑related proteins. In summary, the present study presents a comprehensive overview of the multi‑targeted strategies employed by natural products against SIMD and provides guidance for the discovery of SIMD‑focused dietary supplements and lead compounds, laying the groundwork for future translational research.

Radiation‑induced lung injury (RILI) remains a dose‑limiting and life‑threatening complication of thoracic radiotherapy. The present study aimed to evaluate the therapeutic efficacy and mechanism of the naturally extracted flavonoid, 5,7,8‑trimethoxyflavone (HY‑N7656), in inhibiting RILI. Lung injury in mice was evaluated using micro‑computed tomography, histopathological analysis, enzyme‑linked immunosorbent assay and western blotting. Network pharmacology was conducted to predict the potential therapeutic targets and signaling pathways of HY‑N7656 in RILI. Cell Counting Kit‑8, wound healing, immunofluorescence, reverse transcription‑quantitative (RT‑q) PCR and protein expression analyses were carried out in vitro using TGF‑β‑stimulated A549 cells to evaluate epithelial‑mesenchymal transition (EMT) and signaling activity. Results of the present study revealed that HY‑N7656 markedly alleviated pulmonary inflammation and fibrosis in irradiated mice, leading to a reduction in α‑smooth muscle actin expression. In addition, EMT was effectively reversed following treatment with HY‑N7656 in A549 alveolar epithelial cells treated with TGF‑β, accompanied by restoration of E‑cadherin expression and downregulation of mesenchymal markers, such as N‑cadherin and vimentin. Network pharmacology analysis and molecular docking validation identified the PI3K/Akt pathway as a central target, which was subsequently confirmed via western blot analysis. Moreover, results of the present study demonstrated that HY‑N7656 inhibited radiation‑induced activation of PI3K and Akt. To the best of the authors' knowledge, the present study was the first to demonstrate that HY‑N7656 modulates the PI3K/Akt signaling pathway to suppress the progression of EMT in RILI, establishing HY‑N7656 as a multi‑target inhibitor of RILI. These findings present a potential strategy to enhance the safety of radiotherapy, warranting further preclinical and clinical evaluation.

Following the publication of this article, a concerned reader drew to the Editor's attention that the image showing silica nanoparticles in Fig. 1 on p. 906 had also been used to show the same data in another paper published by the same research group in International Journal of Molecular Medicine. Upon performing a separate investigation of the data in this paper in the Editorial Office, it also came to light that flow cytometric plots featured in Fig. 3 on p. 908 had originally been included in a paper featuring some of the same authors that had already been published in International Journal of Nanomedicine, and western blot data featured in Fig. 7 on p. 910 were originally included in another paper featuring some of the same authors in the journal Stem Cell Research & Therapy. Given the apparent re‑use of the abovementioned data in this article from previously published papers, the Editor of International Journal of Molecular Medicine has decided that this article should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 44: 903‑912, 2019; DOI: 10.3892/ijmm.2019.4265]