International journal of molecular medicine最新文献

Glioblastoma (GBM) is the most aggressive primary malignant brain tumor type in adults, and is characterized by high invasiveness, therapeutic resistance and recurrence. Current treatments, primarily surgery combined with radiotherapy and chemotherapy, offer limited efficacy, thus necessitating more effective interventions. Matrix metalloproteinases (MMPs) crucially contribute to GBM progression through extracellular matrix degradation, epithelial‑mesenchymal transition and angiogenesis. MMP expression is intricately regulated by signaling pathways, non‑coding RNAs and the tumor microenvironment. Recently, strategies targeting MMPs have gained attention, including natural active substances and small‑molecule compounds with promising therapeutic potential. Nano‑delivery systems have notably improved drug delivery efficiency to the brain by overcoming the blood‑brain barrier, and combination therapies have demonstrated enhanced efficacy. However, chemotherapy resistance and functional heterogeneity remain critical challenges. The present review summarizes recent advances in understanding MMP regulatory mechanisms in GBM, highlighting the roles of signaling pathways and non‑coding RNAs. Additionally, the therapeutic potential of natural products, small‑molecule inhibitors, smart nanocarriers and combination treatments are discussed. Future research should focus on identifying novel inhibitors, and leveraging interdisciplinary approaches to facilitate precision‑targeted drug development, thereby addressing current treatment bottlenecks in GBM.

Ferroptosis, an iron‑catalyzed form of regulated cell death driven by lipid peroxidation‑induced membrane rupture, has emerged as a critical determinant of cellular fate across diverse physiological and pathological contexts. Simultaneously, lactate has undergone a notable conceptual transformation, evolving from being regarded as merely a glycolytic waste product to being recognized as a key signaling metabolite that modulates iron homeostasis, lipid dynamics, cellular redox balance and the immune response. This metabolic renaissance has revealed an intricate lactate‑ferroptosis regulatory network with implications for human disease. Notably, lactate exhibits diametrically contrasting effects on ferroptosis susceptibility: Promoting cell death in certain contexts while conferring protection in others. This apparent paradox, particularly evident when contrasting tumor and normal cell responses, suggests sophisticated context‑dependent regulatory mechanisms that are yet to be fully elucidated. The present review explores the molecular basis of both ferroptosis execution and lactate signaling, synthesizing recent advances that illuminate their dynamic interplay. Crucially, the present review discusses putative key contextual determinants, including the metabolic state, pH tolerance and antioxidant capacity, which may govern divergent roles of lactate in ferroptosis regulation. Furthermore, understanding these context‑specific mechanisms promises to unlock new therapeutic strategies for diseases ranging from cancer to neurodegeneration, where the lactate‑ferroptosis axis represents both a vulnerability and an opportunity.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the 'Normal ctrl' and 'mimic ctrl' data panels shown for the flow cytometry experiments in Fig. 3B on p. 1743 were strikingly similar to data panels that had already been published in an article in the journal Molecular and Cellular Biochemistry which had been written by different authors at different research institutes. Owing to the fact that the contentious data in the above article were found to be strikingly similar to data that had already been published elsewhere, the Editor of International Journal of Molecular Medicine has decided that this paper 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 41: 1740‑1748, 2018; DOI: 10.3892/ijmm.2018.3358].

Macrophages, an essential component of the innate immune system, exhibit remarkable plasticity and functional heterogeneity governed by the intricate transcriptional regulatory networks. Activating transcription factors (ATFs) have recently been recognized to modulate multiple signaling pathways, including the MAPK cascades, endoplasmic reticulum stress response and NF‑κB signaling, thereby regulating macrophage biological processes such as inflammatory response, glucose‑lipid metabolism, cellular stress adaptation, autophagy‑apoptosis balance and senescence. By integrating stress signals and metabolic cues, ATF family members construct a sophisticated regulatory network implicated in the pathogenesis of infectious and inflammatory diseases, metabolic disorders, malignancies and neurodegenerative diseases. Therefore, targeted modulations of ATFs or their associated pathways are considered to be capable of precisely regulating macrophage anti‑inflammatory function, metabolic activity and tissue repair capacity in disease settings. Recent technological advances, such as specific targeted delivery systems and gene‑editing strategies, offer promising avenues for the spatiotemporal ATF‑targeting interventions in macrophages, which is critical for improving therapeutic efficacy and safety. The present review systematically summarized recent advances in the understanding of ATF‑mediated regulation of macrophage development, survival, migration, phagocytosis, activation/cytokine secretion, along with polarization and metabolic reprogramming. It also elucidated the pathophysiological implications of these regulatory mechanisms and critically evaluated the clinical feasibility of ATF‑targeted therapeutic interventions.

Emerging evidence from our prior investigations has elucidated the dose-dependent regulatory effects of low-dose ionizing radiation on cellular behaviors including proliferation, migration and differentiation in HLE-B3 lens epithelial cells, with concomitant activation of the canonical Wnt/β-catenin signaling cascade. To extend these findings to alternative cellular models, the present study systematically evaluated the biological responses of the well-characterized human lens epithelial cell line SRA01/04 to low-dose ionizing radiation exposure (0.05-0.2 Gy) versus high-dose radiation (0.5-2 Gy), with particular emphasis on temporal dynamics during acute (0-72 h) and chronic (7 days) phases. Mechanistically, lentivirus-mediated RNA interference was employed to establish stable High mobility group box protein 1 (HMGB1)-knockdown cell models, enabling rigorous interrogation of β-catenin subcellular localization and functional readouts under 0, 0.1 and 0.2 Gy γ-ray exposures. Key findings revealed the following: i) low-dose ionizing radiation within the 0.05-0.2 Gy range significantly potentiated SRA01/04 cell proliferation and migration capacity (P<0.05), concomitant with nuclear accumulation of β-catenin; ii) genetic ablation of HMGB1 abolished radiation-induced β-catenin nuclear translocation, resulting in 77% reduction in proliferation rate and 82% suppression of migratory activity compared with wild-type counterparts under equivalent radiation. The experimental evidence identifies HMGB1-mediated signaling as the critical molecular nexus connecting low-dose ionizing radiation exposure to dysregulated Wnt/β-catenin activity in lens epithelium, offering a new therapeutic target for preventing radiation-related cataracts.

Following the publication of this paper, a concerned reader drew to the Editor's attention that a pair of the fluorescence microscopic images shown in Fig. 2A on p. 1518 were strikingly similar to data which had already been accepted for publication in the journal The Anatolian Journal of Cardiology written by different authors, although the same department and research institute were held in common. Upon performing an independent analysis of the data in this paper in the Editorial Office, it also came to light that flow cytometric data in Fig. 2B had already been submitted for publication in another paper to the journal Drug Design, Development and Therapy that featured some of the same authors, although the experimental conditions in the two papers were reported to be different. Owing to the fact that the contentious flow cytometric and fluorescence microscopic data in the above article had apparently already been submitted for publication elsewhere, the Editor of International Journal of Molecular Medicine has decided that this paper 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 satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine  45: 1514‑1524, 2020; DOI: 10.3892/ijmm.2020.4513].

Skeletal muscle satellite cells (MuSCs) play a central role in muscle regeneration; however, their capacity declines with age, contributing to sarcopenia. A disintegrin and metalloproteinase with thrombospondin motifs‑1 (ADAMTS‑1) regulates MuSC activation and differentiation. The present study aimed to investigate the potential of recombinant ADAMTS‑1 (rADAMTS‑1) as a therapeutic strategy to enhance MuSC proliferation and improve regeneration. After barium chloride injection, mice received daily intraperitoneal injections of rADAMTS‑1 at 5 or 10 mg/kg for 1, 3, 7, or 14 days to monitor recovery. Primary skeletal muscle and C2C12 cells were also treated with rADAMTS‑1 to evaluate its effects on gene and protein expression during proliferation and differentiation in vitro. The number of MuSCs and the expression of myogenic markers increased in all injured groups by day 3 post‑injury in vivo. These levels were particularly elevated in the high‑dose rADAMTS‑1 group and remained sustained until day 14. Grip strength recovered to normal levels by day 7 in the high‑dose rADAMTS‑1 group, suggesting improved functional recovery compared with the untreated controls. In vitro, rADAMTS‑1 treatment induced a dose‑dependent increase in muscle fiber length and upregulation of regeneration‑related factors in primary skeletal muscle cells. Furthermore, C2C12 cells treated with rADAMTS‑1 exhibited enhanced expression of myocyte developmental genes during differentiation. The findings highlighted the therapeutic potential of rADAMTS‑1 for sarcopenia, potentially addressing limitations associated with conventional MuSC‑based treatments.

Long‑term hyperglycemia can damage the capillaries and neural regulation of the lungs, leading to pulmonary microvascular disease and neural regulation disorders, causing abnormalities in lung structure and function. The present study explored the effect of fibroblast growth factor (FGF)4 as a potential therapeutic growth factor on the effect of hyperglycemia on the lungs in vitro and in vivo models. The effect of FGF4 on the damage of lung cells caused by high glucose was evaluated in vitro and in vivo by a series of biochemical experiments (indirect immunofluorescence, western blotting, immunohistochemistry and siRNA). The results showed that FGF4 could effectively alleviate the inhibition of lung cell proliferation caused by high glucose. Further experiments found that high glucose caused inflammation, oxidative stress and fibrosis of lung cells, while the above pathological reactions were alleviated after treatment with FGF4. Further mechanism research showed that FGF4 treatment could markedly improve the survival rate of lung cells, reduce cell death and inflammatory responses and enhance the antioxidant stress resistance of cells. These effects are achieved by activating the adenosine monophosphate (AMP)‑activated protein kinase (AMPK)‑peroxisome proliferator‑activated receptor coactivator 1 (PGC‑1) signaling axis, which plays an important role in regulating cellular metabolism, antioxidant stress and anti‑inflammatory responses. In vivo experiments further confirmed the mitigating effect of FGF4 on lung tissue damage caused by high glucose. FGF4 treatment to diabetic model animals, lung function can be markedly improved and the degree of lung inflammation and fibrosis can be reduced. In summary, FGF4 exhibits a significant mitigating effect on high‑glucose‑induced lung cell damage through the AMPK‑PGC‑1 signaling axis, providing a new strategy for the treatment of diabetes and its pulmonary complications.

Lysine lactylation (Kla), an emerging post‑translational modification, bidirectionally regulates cell fate decisions through epigenetic reprogramming and the direct modification of key ferroptosis proteins. It drives disease progression or mediates therapeutic resistance in inflammation, neurodegenerative diseases, cancer and ischemia‑reperfusion injury, with its regulatory direction being disease‑type‑dependent. The present review discusses the functions of the Kla‑ferroptosis regulatory network, unraveling the role of Kla‑ferroptosis in diseases and its therapeutic implications. The present review aimed to provide novel perspectives for the treatment of human diseases.

Macrophages play a key role in hepatocellular carcinoma (HCC) progression, but the mechanisms underlying this involvement remain unclear. In the present study, mice with HCC were used for in vivo experiments, and 97H and THP‑1 cells were used for in vitro experiments. Metabolomic analysis was performed to detect changes of metabolites in the supernatant of 97H cells. Flow cytometry and immunohistochemical staining were performed to assess macrophage polarization. Western blotting was performed to examine the levels of phosphorylated (p‑) PI3K, p‑AKT and NRF2. Reverse transcription‑quantitative polymerase chain reaction was performed to examine FBXO22, IMPA1 and PTEN mRNA expression levels. FBXO22 significantly promoted the release of myo‑inositol in the cell supernatant of 97H cells, markedly decreased the number of CD86‑positive cells (M1 macrophages), and increased the number of CD206‑positive cells (M2 macrophages) in both THP‑1 cells and mouse HCC tumor tissues. The promoting effect of myo‑inositol on M2 macrophages was reversed by transfection with small interfering (si)‑SLC5A3 in vitro. In addition, FBXO22 overexpression reduced PTEN protein levels and then elevated NRF2 protein levels upregulating IMPA1 and inducing myo‑inositol release in 97H cells. Co‑culturing of 97H and THP‑1 cells revealed that the stimulatory effect of 97H cells transfected with an overexpression (oe)‑FBXO22 construct on M2 macrophages was reversed by co‑transfection with the si‑IMPA1. Co‑immunoprecipitation revealed a promoting effect of FBXO22 on PTEN ubiquitination via direct interaction in 97H cells. Furthermore, luciferase activity and chromatin immunoprecipitation assays indicated direct transcriptional regulation of IMPA1 expression by NRF2 in 97H cells. The in vivo experiments further revealed that transfection with the si‑IMPA1 reversed the promoting effect of oe‑FBXO22 on tumor growth and M2 polarization by reducing myo‑inositol levels in tumor tissues. In conclusion, FBXO22 degrades PTEN by inducing its ubiquitination to elevate NRF2 protein levels. As a result, IMPA1 expression is increased, which causes myo‑inositol release by HCC cells and further induces M2‑type macrophages via SLC5A3 to promote HCC tumor growth. The present study identified a novel molecular mechanism by which FBXO22 promotes HCC progression.