International journal of molecular medicine最新文献

Despite advances in HER2‑targeted therapy for HER2‑positive breast cancer, resistance to trastuzumab and tumor recurrence remain major barriers to durable outcomes. The present study evaluated the therapeutic potential of ebastine, a second‑generation H1‑antihistamine, as a repurposing candidate to overcome trastuzumab resistance by targeting HER2 signaling and cancer stem cell (CSC)‑associated phenotypes in HER2‑positive breast cancer cells. Molecular docking studies revealed that ebastine bound to the ATP‑binding site of the HER2 tyrosine kinase domain, thereby suppressing the phosphorylation of HER2, p95HER2 and HER3, as assessed by immunoblotting. Immunoprecipitation assay further demonstrated that this binding disrupted HER2/HER3 and HER2/EGFR heterodimerization, leading to reduced downstream AKT activation. Ebastine significantly decreased aldehyde dehydrogenase (ALDH)1 activity, decreased the CD44^high/CD24^low CSC‑like population, as assessed by flow cytometry, and inhibited mammosphere formation. In a trastuzumab‑resistant xenograft model, ebastine markedly suppressed tumor growth, decreased the Ki‑67 proliferation index and angiogenesis and induced apoptosis. These effects were accompanied by decreased expression of HER2, HER3, ALDH1, CD44, and vimentin in tumor tissues, as determined by immunohistochemistry. Furthermore, serum biochemical analyses revealed no significant hepatotoxicity or nephrotoxicity, indicating a favorable in vivo safety profile. These findings demonstrated that ebastine effectively disrupts key pathways involved in CSC‑like traits and HER2 activity, even under trastuzumab‑resistant conditions. Its multifaceted inhibitory effects support the repositioning of ebastine as a promising therapeutic strategy for treating refractory HER2‑positive breast cancer.

Following the publication of this paper, it was drawn to the Editor's attention by an interested reader that, for the Transwell migration and invasion assay experiments shown in Fig. 3A and 3C respectively on p. 772, one and two pairs of data panels respectively were overlapping, such that data which were intended to show the results of differently performed experiments had apparently been derived from the same original sources. In addition, in Fig. 1 on p. 771, the same data panel had apparently been included to show the results of (C) strong cytoplasmic Rac1 expression and (E) weak cytoplasmic Rac1 expression in lung squamous cell carcinoma tissues. Upon contacting the authors about these issues, they realized that certain of the data had inadvertently been included in Figs. 1 and 3 incorrectly. The revised versions of Figs. 1 and 3, now featuring the correct data for weak cytoplasmic expression in Fig. 1E and the correct data panels for the 801D‑shRNA control and 801D‑NSC23766 experiments in Fig. 3A and C respectively, are shown opposite and on the next page. The authors wish to emphasize that the errors made in assembling the data in this pair of 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 28: 769‑776, 2011; DOI: 10.3892/ijmm.2011.775].

Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by impaired neuromuscular junction transmission, leading to fluctuating muscle weakness and fatigue. This condition is driven primarily by autoantibodies targeting the acetylcholine receptor at the neuromuscular junction. These antibodies are predominantly generated through a T‑cell‑dependent pathway, initiating immunomodulatory responses via complement activation. Cytokines and inflammatory mediators also play pivotal roles in the pathogenesis of MG. Recently, increasing attention has been given to the involvement of cytokines in autoimmune diseases. Interleukin‑35 (IL‑35), an immunoregulatory cytokine, is critical in various inflammatory and autoimmune conditions. It modulates immune responses by promoting Treg proliferation, enhancing their immunosuppressive functions, inhibiting Th17 cell differentiation, and reducing proinflammatory cytokine levels. IL‑35 is thus pivotal in the onset and progression of MG. The present review outlines the key functions of IL‑35 in MG pathogenesis and the impact of IL‑35 on the treatment and prognosis of myasthenia gravis, explores its therapeutic potential, and assesses its prognostic value, offering insights into its mechanisms and implications for treatment.

Metabolic reprogramming is a hallmark feature of malignant tumors. These metabolic pathways are regulated in a cell‑autonomous manner by oncogenic signaling and transcriptional networks, and tracking their metabolic reprogramming is frequently used in the diagnosis, detection and treatment of cancer. There are currently promising therapeutic prospects for a variety of types targeting fixed core metabolic pathways in tumor metabolic reprogramming. Among these, inosine monophosphate (IMP) is an essential intermediate in purine nucleotide synthesis that demonstrates significant target potential. Nevertheless, further research is needed to elucidate the regulatory networks that control IMP metabolism in tumor cells. This review combines the latest insights into IMP metabolism into an interesting conceptual framework. This includes the supply of IMP precursor substrates (reprogramming of glucose metabolism, serine/one‑carbon metabolism, glutamine and mitochondrial metabolism), the dynamic regulation of important enzymes [phosphoribosyl pyrophosphate synthetase, phosphoribosyl pyrophosphate amidotransferase, IMP dehydrogenase (IMPDH)], purinosomes and signaling pathways (RAS‑ERK, PI3K/AKT‑mTORC1 and Hippo‑YAP) that ultimately regulate IMP synthesis in tumor cells. Additionally, it focused on downstream associations between IMPDH and the immune microenvironment, offering a fresh perspective for current research on tumor therapy targeting IMP metabolism.

Helicobacter pylori (H. pylori) is a Gram‑negative bacterial pathogen, and infection with this pathogen is a primary risk factor for gastric cancer (GC), often inducing chronic gastritis, which further increases the risk of cancer. Glycolysis carries out a key role in GC metabolism, serving as the primary energy pathway for cancer cells, particularly under hypoxic conditions. Enhanced glycolysis allows GC cells to sustain high proliferation rates and produce lactic acid, creating an acidic tumor microenvironment that promotes tumor progression. Understanding the mechanisms of H. pylori‑driven glycolysis may provide new insights into GC pathogenesis and reveal novel therapeutic targets. The present review addresses advances in glycolysis research in GC, summarizing its characteristics, identifying key mediators involved in metabolic reprogramming and exploring potential molecular mechanisms to recommend new targets for therapy.

Food additive acesulfame‑K (AK), a non‑nutritive sweetener, is widely used as a low‑calorie sugar substitute to reduce energy intake. However, its potential impact on nonalcoholic fatty liver disease (NAFLD) and the involvement of peroxisome proliferator‑activated receptor α (PPARα) remain unclear. In the present study, male wild‑type (WT) and PPARα‑null (KO) mice fed a 60% high‑fat diet were treated with AK (2 mg/ml) in drinking water for 12 weeks to evaluate the effects of chronic AK exposure on NAFLD progression and the role of PPARα. PPARα inhibition and activation strategies were further applied in in vivo and in vitro models to validate the key findings. AK supplementation markedly increased hepatic lipid accumulation and impaired glucose tolerance through activation of phospholipase C beta (PLCβ) in hepatic sweet taste receptor (STR) signaling in the WT mice, but not in the KO mice. Consistently, PLCβ activation was observed in AK‑induced lipid accumulation in Hepa1‑6 and Huh‑7 cells and was abolished by PPARα knockdown or inhibition. Pharmacological activation of PPARα mitigated AK‑induced NAFLD progression by suppressing PLCβ activation in STR signaling. These findings demonstrated that chronic AK intake exacerbates NAFLD progression via PLCβ activation in hepatic STR signaling and that PLCβ activation depends on physiological PPARα activity. Pharmacological PPARα activation exerts a protective effect, highlighting the dual roles of PPARα in regulating AK‑associated NAFLD risk.

Following the publication of the above article, an interested reader drew to the authors' attention that the control β‑actin western blots shown in Figs. 2C and 5A were strikingly similar, even though the experimental conditions reported in these figures were different. After having re‑examined the original data, the authors have realized that these western blots were inadvertently included in Fig. 2C erroneously. The revised version of Fig. 2, now incorporating the correct data for the β‑actin bands in Fig. 2C, is shown below. The authors confirm that the error associated with this figure did not have a significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this Corrigendum; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 43: 1778‑1788, 2019; DOI: 10.3892/ijmm.2019.4085].

Donation after circulatory death (DCD) is a key source of liver grafts but it is associated with more severe ischemia‑reperfusion injury (IRI) and poorer transplant outcomes compared with donation after brain death. Hypothermic machine perfusion (HMP) effectively decreases DCD graft injury, but its protective molecular mechanisms remain unclear. Kruppel‑like factor 2 (KLF2) is an endothelial protective transcription factor induced by hemodynamic mechanical stimulation. However, the role of KLF2 in IRI during HMP in DCD livers is unclear. Rat livers undergoing DCD modeling followed by static cold storage (CS) or HMP were used to assess KLF2 expression and macrophage efferocytosis. Injury was assessed by serum alanine transferase/aspartate transferase levels, histology, TUNEL apoptosis assay and immunofluorescence (IF) for in situ efferocytosis. Protein markers were analyzed via western blotting, immunohistochemistry and IF. In vitro, HUVECs and macrophages were subjected to simulated CS/reperfusion. Macrophages efferocytosis was quantified using fluorescently labeled apoptotic Jurkat cells. Mechanisms were explored by RNA sequencing and co‑immunoprecipitation. Compared with the CS group, HMP decreased pathological injury, apoptosis and inflammation in DCD liver injury. KLF2 expression was upregulated. However, knockdown of KLF2 abrogated these endothelial protective effects in vitro. Furthermore, overexpression of KLF2 enhanced macrophage efferocytosis, whereas suppression of KLF2 impaired this. Moreover, enhanced efferocytosis contributed to inflammation resolution, ultimately improving overall graft injury and decreasing apoptosis. Mechanistically, KLF2 inhibited the NOD‑like receptor protein 3 (NLRP3) inflammasome to suppress pyroptosis, thereby indirectly enhancing efferocytosis. HMP alleviated IRI in DCD liver grafts by upregulating endothelial KLF2, which inhibited NLRP3 inflammasome‑mediated pyroptosis, thereby improving the inflammatory microenvironment and promoting macrophage efferocytosis.

Ovarian granulosa cells (GCs), as key components of follicles, orchestrate follicular development and ovarian maturation through bidirectional communication with oocytes and through hormone synthesis. Their dysfunction substantially contributes to female infertility. Post‑translational modifications (PTMs) carry out pivotal roles in the regulation of ovarian physiology and pathology by modulating GC proliferation, differentiation, apoptosis and steroid hormone secretion. The present review seeks to summarize the current advances in canonical PTMs such as phosphorylation, methylation, acetylation and ubiquitination, as well as novel protein modifications such as SUMOylation and lactylation, particularly focusing on their roles in the proliferation, differentiation and apoptosis of GCs at the molecular level. Moreover, the present review explores how aberrant PTMs impair GC function, leading to follicular developmental disorders, and proposes that targeting PTM‑regulated signaling in GCs may provide novel therapeutic strategies for ovarian dysfunction. Collectively, the present review aims to provide insights into elucidating the etiology of infertility, and establishing a theoretical foundation for the development of PTM‑targeted reproductive interventions.

Lipid droplets (LDs) are dynamic organelles that extend beyond lipid storage to regulate diverse aspects of reproductive physiology. In both mammals and Caenorhabditis elegans, LDs support gamete maturation, fertilization, embryogenesis and steroidogenesis by modulating lipid mobilization, signaling pathways, protein quality control and hormone production. The present review highlights the roles of LDs in oocytes, sperm, Sertoli and granulosa cells, embryonic stem cells and early embryos. Key regulatory molecules, including perilipins, adipose triglyceride lipase, Hormone‑Sensitive Lipase (HSL), Diacylglycerol O‑acyltransferases and seipin, as well as lipophagy, are discussed in the context of reproductive cell function. C. elegans demonstrates conserved genetic pathways linking LD metabolism with gamete quality and embryonic viability. The present review aimed to discuss emerging technologies such as lipidomics, high‑resolution imaging, Clustered Regularly Interspaced Short Palindromic Repeats screening and single‑cell sequencing that enable deeper investigation into LD dynamics. Finally, the present review aimed to examine how LD dysfunction contributes to reproductive disorders including infertility, polycystic ovary syndrome and metabolic syndrome. Understanding LD biology offers promising avenues for improving reproductive health and gamete and embryonic developmental potential.