International journal of molecular medicine最新文献

Ischemic heart disease remains the leading cause of global disease burden among cardiovascular disorders. In addition to cardiomyocyte injury, ischemia-reperfusion (I/R)-induced microvascular damage plays a crucial role in determining tissue dysfunction and overall prognosis. Mitochondria-associated endoplasmic reticulum membranes (MAMs), specialized contact sites between the ER and mitochondria, are now recognized as key regulators of cardiovascular pathophysiology. The present review summarized current knowledge of the structure of MAMs and their effects on endothelial cells under hypoxia/reoxygenation conditions. Particular attention was given to their role in regulating mitochondrial quality control processes, including fission, fusion, oxidative stress, mitophagy and Ca2+ homeostasis, within the context of cardiac microvascular I/R injury. Targeting MAMs may represent a promising strategy for microvascular protection in ischemic heart disease.

Branched‑chain amino acids (BCAAs) are biologically active amino acids with branched carbon chains, recognized for their diverse biological functions and therapeutic potential. BCAAs have demonstrated promising effects in the prevention and treatment of various conditions, including muscle growth disorders, cardiovascular diseases and cancer. Despite extensive research confirming their targeted therapeutic effects in multiple domains, the mechanisms of action and therapeutic range of BCAAs remain incompletely understood. Osteoporosis, a metabolic bone disease, is a global public health issue characterized by an imbalance between osteoblast‑mediated bone formation and osteoclast‑induced bone resorption, resulting in fragile bones and an elevated risk of fractures. Given the well‑documented therapeutic roles of BCAAs, their potential link to osteoporosis has been explored, emphasizing the influence of BCAA metabolism on bone metabolism. The present review aims to summarize findings on the relationship between BCAA metabolism and osteoporosis, and to investigate the mechanisms by which BCAA metabolism may exert anti‑osteoporotic effects. The review first outlines the fundamental processes and key factors influencing bone metabolism, BCAA metabolism and osteoporosis. It then examines the interactions between these processes and the effects of BCAA metabolism on bone health. Finally, it explores the potential of targeting BCAA metabolic pathways as a future therapeutic strategy for osteoporosis, highlighting BCAAs as a promising target for treating this condition.

Hepatocellular carcinoma (HCC) treatment remains challenging due to the prevalence of metastasis and chemotherapy resistance. Mitochondrial stomatin‑like protein 2 (STOML2), which is upregulated in various solid tumors, is associated with a poor prognosis; however, its biological function and molecular mechanism in HCC remain unclear. The present study aimed to elucidate the oncogenic mechanism of STOML2 in HCC and to explore its potential as a therapeutic target. Firstly, STOML2 expression in HCC and matched normal liver tissues was analyzed. In addition, STOML2‑knockdown (HCCLM3‑short hairpin RNA‑STOML2) and ‑overexpression (Huh7‑STOML2) cell models were established. Wound healing, Cell Counting Kit‑8 and Transwell assays, and flow cytometry were performed to assess cell proliferation, invasion, migration and apoptosis in vitro. Furthermore, the biological function of STOML2 was confirmed in vivo. Co‑immunoprecipitation (co‑IP) and immunofluorescence staining were conducted to validate the interaction of STOML2 with prohibitin (PHB) following the prediction of binding partners. Downstream pathways regulated by STOML2 were identified using western blotting and were further investigated using the RAF1 inhibitor sorafenib. The present study revealed that STOML2 expression was significantly upregulated in HCC tissues and metastatic lesions, and was associated with poor patient prognosis. The in vitro experiments showed that STOML2 overexpression promoted proliferation, invasion, migration and autophagy, while inhibiting apoptosis in Huh7 cells. Conversely, STOML2 knockdown reversed these phenotypic changes. Furthermore, co‑IP confirmed the direct interaction between STOML2 and PHB, which activated the RAF/MEK/ERK signaling pathway. The in vivo experiments further confirmed that STOML2 overexpression significantly accelerated tumor growth, whereas STOML2 or PHB knockdown inhibited tumor progression. In addition, sorafenib treatment suppressed STOML2‑mediated cell migration and the expression of autophagy‑related proteins by blocking the MAPK pathway. These findings elucidated the molecular mechanism by which STOML2 promotes the malignant progression of HCC and demonstrated that targeted inhibition of the PHB‑MAPK pathway may reverse the pro‑tumorigenic effects of STOML2. STOML2 may serve as both a prognostic biomarker and a therapeutic target in HCC. The current study provides a theoretical foundation for individualized treatment in patients with HCC and high STOML2 expression.

Following the publication of the above article, a concerned reader drew to the Editor's attention that, in Fig. 1D, the 'SW1990' and 'Bxpc‑3' data panels were overlapping, suggesting that these data were derived from the same original source where experiments showing different experimental conditions were intended to have been portrayed. In addition, further pairings of overlapping data panels were identified with the Ki67 assay data shown in Figs. 7E and the immunohistochemical data shown in Fig. 10C, suggesting that these figures had similarly been assembled incorrectly. Furthermore, four of the centrally placed flow cytometric plots featured in Fig. 5A appeared to be too similar in terms of the distribution of the data to be confident that these were all derived from independently performed experiments, and finally, some of the western blot data shown in Fig. 4B were strikingly similar to data which had already appeared in another paper, also published in International Journal of Molecular Medicine, that featured the same first author (Guanen Qiao). In view of the number of different problems and potential anomalies identified with various of the figures in this paper, the Editor of International Journal of Molecular Medicine has decided that this paper should be retracted from the journal on account of an overall lack of confidence in the presented data. 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 of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 44: 593‑607, 2019; DOI: 10.3892/ijmm.2019.4206].

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.

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.

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.

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.

Endometriosis is a complex, chronic inflammatory gynecological disorder with estrogen‑dependent characteristics that severely impairs the quality of life of women and potentially leads to infertility. However, its pathogenesis remains poorly understood. Exosomes, small, discoid vesicles released by nearly all cell types, serve essential functions in multiple biological processes, including immune evasion, cellular migration, and differentiation. These vesicles can transport a broad repertoire of bioactive molecules, cross cell membranes readily, and remain stable within cells and body fluids. The present review summarizes global research from the last two decades on the mechanistic associations between exosomes and endometriosis, emphasizing their potential as vehicles for therapeutic delivery. Notably, the biological hallmarks of endometriosis such as fibrosis, immune dysregulation, angiogenesis, and aberrant cellular proliferation and migration, align with exosomal functions, suggesting that exosomes may contribute to disease progression. Furthermore, the use of exosomes as natural carriers for endometriosis treatment has been proposed, suggesting novel therapeutic avenues.

Following the publication of this paper, it was drawn to the Editor's attention by an interested reader that, for the western blot experiments shown in Fig. 7A on p. 405, the Bcl‑2 and PCNA blots for the SO‑Rb50 cell line appeared to be identical, albeit it with possibly slightly different exposure time of the gel and different vertical dimensions. Similarly, the BAX and PCNA blots for the Y79 cell line also appeared to be identical, although the blots were rotated by 180° relative to each other, again with possibly slightly different exposure time of the gel and different vertical dimensions. In addition, for the experiments showing transfection efficiency in Fig. 1 on p. 402, the 'SO‑Rb50/x100/PAX6‑RNAi GFP' and 'Y79/x200/Ctrl GFP' data panels contained overlapping data, and the 'SO‑Rb50/x200/PAX6‑RNAi GFP' and 'Y79/x100/Ctrl GFP' data panels similarly contained overlapping data, suggesting that these pairings of panels had been placed in this figure the wrong way around. Upon contacting the authors about these issues, they realized that Figs. 1 and 7 in this paper had inadvertently been assembled incorrectly. The revised versions of Fig. 1, now featuring the correct data for the PCNA blots for both the SO‑Rb50 and the Y79 cell lines, and Fig. 7, now showing the correctly positioned data panels for the 'SO‑Rb50/x100/PAX6‑RNAi GFP' and 'Y79/x200/Ctrl GFP' experiments, are presented on the next page. The authors wish to emphasize that the errors made in assembling the data in these Figures did not affect the overall conclusions reported in the paper. The authors are grateful to the Editor of International Journal of Molecular Medicine for granting them this opportunity to publish a Corrigendum, and apologize to both the Editor and the readership for any inconvenience caused. [International Journal of Molecular Medicine 34:  399‑408, 2014; DOI: 10.3892/ijmm.2014.1812].