International journal of molecular medicine最新文献

Liver fibrosis is a pathophysiologic manifestation of chronic liver disease and a precursor to cirrhosis and hepatocellular carcinoma. Glycolysis provides intermediate metabolites as well as energy support for cell proliferation and phenotypic transformation in liver fibers. 6‑Phosphofructo‑2‑kinase/fructose‑2,6‑bisphosphatase 3 (PFKFB3) is a key activator of glycolysis and plays an important role in the process of glycolysis. The role of PFKFB3‑mediated glycolysis in myocardial fibrosis, renal fibrosis and pulmonary fibrosis has been demonstrated, and the role of PFKFB3 in the activation of hepatic stellate cells by aerobic glycolysis has been proven by relevant experiments. The present study reviews the research progress on the role and mechanism of action of PFKFB3‑mediated glycolysis in the progression of hepatic fibrosis to discuss the role of PFKFB3‑mediated glycolysis in hepatic fibrosis and to provide new ideas for research on PFKFB3 as a target for the treatment of hepatic fibrosis.

Uveal melanoma (UM) is the most prevalent type of primary intraocular malignancy and is prone to metastasize, particularly to the liver. However, due to the poor understanding of the pathogenesis of UM, effective therapeutic approaches are lacking. As a phenolic compound extracted from grapes, piceatannol (PIC) exhibits anti‑cancer properties. To the best of our knowledge, however, the effects of PIC on UM have not been well investigated. Therefore, in the present study, considering the impact of pyroptosis on modulating cell viability, the mechanism underlying the effects of PIC on UM cell proliferation was explored. The inhibitory effect of PIC on proliferation of UM cells was detected by cell counting kit‑8 assay. Wound healing was used to investigate the effects of PIC on the migration of UM cells. Activity detecting assays were performed to test the apoptosis and oxidant level in UM cells. Western blotting and RT‑qPCR were used to detect the inflammatory and pyroptotic levels of UM cell after PIC treatment. PIC‑treated UM cells were screened by high‑throughput sequencing to detect the differential expression of RNA and differential genes. Si‑TREM2 transfection was used to verify the important role of TREM2 in the effects of PIC. Immunohistochemical staining was used to observe the expressions of TREM2 and GSDMR of tumor in nude mice after PIC administration. PIC effectively inhibited proliferation ability of C918 and Mum‑2b UM cell lines via enhancing apoptosis, as evidenced by enhanced activities of caspase 3 and caspase 9. In addition, treatment of UM cells with PIC attenuated cell migration in a dose‑dependent manner. PIC increased reactive oxygen species levels and suppressed the activity of the antioxidant enzymes superoxide dismutase, glutathione‑S‑transferase, glutathione peroxidase and catalase. PIC inhibited inflammatory responses in C918 cells. PIC treatment upregulated IL‑1β, IL‑18 and Nod‑like receptor protein 3 and downregulated gasdermin D (GSDMD). RNA sequencing results revealed the activation of an unconventional pyroptosis‑associated signaling pathway, namely caspase 3/GSDME signaling, following PIC treatment, which was mediated by triggering receptor expressed on myeloid cells 2 (TREM2) upregulation. As an agonist of TREM2, COG1410‑mediated TREM2 upregulation inhibited proliferation of C918 cells, displaying similar effects to PIC. Furthermore, PIC inhibited tumor growth via regulating the TREM2/caspase 3/GSDME pathway in a mouse model. Collectively, the present study revealed a novel mechanism underlying the inhibitory effects of PIC on UM, providing a potential treatment approach for UM in clinic.

Anaemia is a common health problem worldwide that disproportionately affects vulnerable groups, such as children and expectant mothers. It has a variety of underlying causes, some of which are genetic. A comprehensive strategy combining physical examination, laboratory testing (for example, a complete blood count), and molecular tools for accurate identification is required for diagnosis. With nearly 400 varieties of anaemia, accurate diagnosis remains a challenging task. Red blood cell abnormalities are largely caused by genetic factors, which means that a thorough understanding requires interpretation at the molecular level. As a result, precision medicine has become a key paradigm, utilising artificial intelligence (AI) techniques, such as deep learning and machine learning, to improve prognostic evaluation, treatment prediction, and diagnostic accuracy. Furthermore, exploring the immunomodulatory role of vitamin D along with biomarker‑based molecular techniques offers promising avenues for insight into anaemia's pathophysiology. The intricacy of aplastic anaemia makes it particularly noteworthy as a topic deserving of concentrated molecular research. Given the complexity of anaemia, an integrated strategy integrating clinical, laboratory, molecular, and AI techniques shows a great deal of promise. Such an approach holds promise for enhancing global anaemia management options in addition to advancing our understanding of the illness.

The 24 claudin (CLDN) genes in the human genome encode 26 representative CLDN family proteins. CLDNs are tetraspan‑transmembrane proteins at tight junctions. Because several CLDN isoforms, such as CLDN6 and CLDN18.2, are specifically upregulated in human cancer, CLDN‑targeting monoclonal antibodies (mAbs), antibody‑drug conjugates (ADCs), bispecific antibodies (bsAbs) and chimeric antigen receptor (CAR) T cells have been developed. In the present review, CLDN1‑, 4‑, 6‑ and 18.2‑targeting investigational drugs in clinical trials are discussed. CLDN18.2‑directed therapy for patients with gastric and other types of cancer is the most advanced area in this field. The mouse/human chimeric anti‑CLDN18.2 mAb zolbetuximab has a single‑agent objective response rate (ORR) of 9%, and increases progression‑free and overall survival in combination with chemotherapy. The human/humanized anti‑CLDN18.2 mAb osemitamab, and ADCs AZD0901, IBI343 and LM‑302, with single‑agent ORRs of 28‑60%, have been tested in phase III clinical trials. In addition, bsAbs, CAR T cells and their derivatives targeting CLDN4, 6 or 18.2 are in phase I and/or II clinical trials. AZD0901, IBI343, zolbetuximab and the anti‑CLDN1 mAb ALE.C04 have been granted fast track designation or priority review designation by the US Food and Drug Administration.

Tissue regeneration is a complex process that involves the recruitment of various types of cells for healing after injury; it is mediated by numerous precise interactions. However, the identification of effective targets for improving tissue regeneration remains a challenge. As an extracellular matrix protein, Agrin plays a critical role in neuromuscular junction formation. Furthermore, recent studies have revealed the role of Agrin in regulating tissue proliferation and regeneration, which contributes to the repair process of injured tissues. An in‑depth understanding of the role of Agrin will therefore be of value. Given that repair and regeneration processes occur in various parts of the human body, the present systematic review focuses on the role of Agrin in typical tissue and highlights the potential signaling pathways that are involved in Agrin‑induced repair and regeneration. This review offers important insight into novel strategies for the future clinical applications of Agrin‑based therapies, which may represent a feasible treatment option for patients who require organ replacement or repair.

Psoriasis is a chronic inflammatory skin condition with numerous causes, including genetic, immunological and infectious factors. The course of psoriasis is long and recurrence is common; pathogenesis is not completely understood. However, there is an association between advancement of psoriasis and aberrant microRNA (miR or miRNA)‑155 expression. Through bioinformatics, the present study aimed to analyze the differentially expressed genes and miRNAs in psoriasis and its biological mechanism and function psoriatic inflammation. First of all, differentially expressed genes (DEGs) and miRNAs (DEMs) in patients with psoriasis were identified using GEO2R interactive web application. A psoriasis inflammatory model was established using lipopolysaccharide (LPS)‑treated HaCaT keratinocytes, which were transfected with miR‑155 mimic or inhibitor. Cell Counting Kit‑8 was used for the assessment of cell viability and proliferation, and changes in the cell cycle were examined using flow cytometry. ELISA and reverse transcription‑quantitative PCR (RT‑qPCR) were used to detect the expression levels of the inflammatory factors IL‑1β and IL‑6. The dual‑luciferase reporter assay was used to verify the targeting association between miR‑155‑5p and IFN regulatory factor 2 binding protein 2 (IRF2BP2). To verify the targeting association of miR‑155 and the IRF2BP2/kruppel‑like factor 2 (KLF2)/NF‑κB signaling pathway, expression levels of IRF2BP2, KLF2 and p65 were identified by RT‑qPCR and western blotting. IRF2BP2 levels were also confirmed by immunofluorescence, in conjunction with bioinformatics database analysis. Overexpression of miR‑155 inhibited proliferation of HaCaT cells and increased the number of cells in S phase and decreasing number of cells in G1 and G2 phase. In the LPS‑induced inflammatory state, miR‑155 overexpression heightened the inflammatory response of HaCaT cells while inhibition of miR‑155 lessened it. Suppression of inflammatory cytokine expression by miR‑155‑5p inhibitor was reversed by knockdown of IRF2BP2. miR‑155 was shown to interact with IRF2BP2 to negatively regulate its expression, leading to decreased KLF2 expression and increased p65 expression and secretion of inflammatory factors, intensifying the inflammatory response of HaCaT cells. Therefore, miR‑155 may contribute to development of psoriasis by inducing tissue and cell damage by increasing the inflammatory response of HaCaT cells via the IRF2BP2/KLF2/NF‑κB pathway. In conclusion, the results of the present study offer novel perspectives on the role of miR‑155 in the onset and progression of psoriasis.

Diabetic foot ulcer (DFU) is a destructive complication of diabetes. Negative pressure wound therapy (NPWT) promotes DFU wound healing through an undetermined mechanism. In the present study, RNA sequencing was performed on wound granulation tissue from 3 patients with DFU before and after 1 week of NPWT. The fused in sarcoma (FUS) and interleukin enhancer binding factor 2 (ILF2) encoding RNA‑binding proteins (RBPs) were screened from the sequencing data, and wound tissue samples from 24 patients with DFU were validated and analyzed before and after receiving NPWT by reverse transcription‑quantitative PCR, western blotting and immunohistochemistry. In addition, in vitro and in vivo experiments were conducted to determine the effect of the expression of FUS and ILF2 on the function of human epidermal keratinocyte cells (HaCaT cells) and the healing of diabetic skin wounds. The results indicated that NPWT induced the upregulation of 101 genes and the downregulation of 98 genes in DFU wound granulation tissue. After NPWT, the expression of FUS and ILF2 was significantly upregulated (P<0.05). Pearson's correlation coefficient showed that the changes in FUS and ILF2 before and after NPWT were negatively correlated with changes in white blood cells, the neutrophil percentage, C‑reactive protein, tumor necrosis factor‑α, reactive oxygen species, lipid peroxides, matrix metalloproteinase (MMP) 2 and MMP9 (P<0.05), but positively correlated with the anti‑inflammatory factor, IL‑4 (P<0.01). There was also a positive correlation (P<0.05) with the 4‑week ulcer healing rate. Additionally, the knockdown of FUS and ILF2 expression inhibited the proliferation and migration of HaCaT cells, while increasing cell apoptosis. In vivo, the knockdown of FUS and ILF2 significantly reduced the rate of skin wound healing in diabetic mice. The results of the present study therefore provide new insights into the mechanism by which NPWT promotes DFU wound healing. In conclusion, the RBPs, FUS and ILF2, promoted DFU wound healing by regulating the function of keratinocytes and reducing the inflammatory response and oxidative stress.

Sepsis‑induced myopathy (SIM) is one of the leading causes of death in critically ill patients. SIM mainly involves the respiratory and skeletal muscles of patients, resulting in an increased risk of lung infection, aggravated respiratory failure, and prolonged mechanical ventilation and hospital stay. SIM is also an independent risk factor associated with increased mortality in critically ill patients. At present, no effective treatment for SIM has yet been established. However, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach and have been utilized in the treatment of various clinical conditions. A significant body of basic and clinical research supports the efficacy of MSCs in managing sepsis and muscle‑related diseases. This literature review aims to explore the relationship between MSCs and sepsis, as well as their impact on skeletal muscle‑associated diseases. Additionally, the present review discusses the potential mechanisms and therapeutic benefits of MSCs in the context of SIM.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the colony formation assay data shown in Fig. 4D on p. 807 and western blot assay data shown in Fig. 7A on p. 809 were strikingly similar to data appearing in different form other articles written by different authors at different research institutes that had already been published elsewhere prior to the submission of this paper to International Journal of Molecular Medicine.  In view of the fact that the abovementioned data had already apparently been published previously, 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 38: 803‑811, 2016; DOI: 10.3892/ijmm.2016.2685].

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end‑stage renal disease, and is characterized by persistent proteinuria and decreased glomerular filtration rate. Despite extensive efforts, the increasing incidence highlights the urgent need for more effective treatments. Histone methylation is a crucial epigenetic modification, and its alteration can destabilize chromatin structure, thereby regulating the transcriptional activity of specific genes. Histone methylation serves a substantial role in the onset and progression of various diseases. In patients with DKD, changes in histone methylation are pivotal in mediating the interactions between genetic and environmental factors. Targeting these modifications shows promise in ameliorating renal histological manifestations, tissue fibrosis and proteinuria, and represents a novel therapeutic frontier with the potential to halt DKD progression. The present review focuses on the alterations in histone methylation during the development of DKD, systematically summarizes its impact on various renal parenchymal cells and underscores the potential of targeted histone methylation modifications in improving DKD outcomes.