Molecular medicine reports最新文献

Glomerular basement membrane (GBM) thickening, the earliest morphological change of diabetic nephropathy (DN), is related to glomerular endothelial cells (GECs) dysfunction which increase extracellular matrix (ECM) synthesizing. Apelin, the endogenous ligand for apelin/apelin receptor (APJ), is reported to alleviate endothelial cell dysfunction in DN. Therefore, it was hypothesized that apelin/APJ reduced GBM thickening by decreasing the synthesis of ECM in GECs. The results showed that apelin reduced glomerular fibrosis and GBM thickening by decreasing the expression of laminin and collagen IV in diabetic mice, which were cancelled following APJ knockout in GECs. Furthermore, apelin/APJ inhibited the synthesis of laminin and collagen IV in GECs by increasing the expression and activity of SIRT3, which promoted KLF15 deacetylation and translocation into nucleus. In conclusion, apelin/APJ reduced GBM thickening in diabetes mellitus by preventing laminin and collagen IV synthesizing via SIRT3‑KLF15 pathway in GECs.

Following the publication of this paper, and subsequently to the publication of a corrigendum (DOI: 10.3892/mmr.2022.12738) that was intended to address the issue of a pair of duplicated data panels in Fig. 2C, it was drawn to the Editor's attention by a concerned reader that there regrettably remained issues with overlapping data panels in the revised version of Fig. 2 that was provided by the authors; furthermore, the revised data that were included in the corrected version of this figure were found to have appeared previously in a paper published in the journal OncoTargets and Therapy featuring different authors at different research institutes, which has subsequently been retracted. In view of the fact that the abovementioned data had already apparently been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should now 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. [Molecular Medicine Reports 18: 105-122, 2018; DOI: 10.3892/mmr.2018.8941].

Hepatocellular carcinoma (HCC) is a severe disease associated with a poor prognosis. The role of aberrant lipid metabolism in the development and progression of HCC necessitates detailed characterization. Sterol regulatory element‑binding proteins (SREBPs), pivotal transcription factors governing lipogenesis, are central to this process. The present study aimed to assess the regulation of HCC by the SREBP signaling pathway, examining the expression levels of genes in this pathway, the clinical implications and its prognostic value using the Kaplan‑Meier method. Pearson's correlation coefficient was used to identify the co‑expression of SREBP pathway genes in HCC. Genomic analysis examined the frequency of TP53 mutations in groups with and without SREBP pathway alterations. In addition, small interfering RNAs targeting genes of the SREBP pathway were transfected into Huh‑7 and HCC‑LM3 cell lines. Subsequently, Cell Counting Kit‑8 and Transwell assays were carried out to evaluate the viability and invasion of these cells. Reverse transcription‑quantitative PCR and western blotting were performed to investigate the expression of TP53 in response to silencing of SREBP pathway genes. Dysregulation of SREBP pathway genes was detected in HCC tissues compared with in normal liver tissues, and predicted a poor prognosis. Silencing these genes reduced the viability and invasion of HCC cells. Furthermore, abnormal SREBP pathway gene expression was associated with poor survival rates, vascular invasion, advanced tumor stage and an increased incidence of TP53 mutations. By contrast, knockdown of SREBP pathway genes decreased mutant TP53 expression at both the mRNA and protein levels in HCC cells. The findings of the present study suggested that SREBP pathway genes could serve as promising prognostic biomarkers for HCC. The combined analysis of individual gene expression levels offers offer novel insights into the pathogenesis and progression of HCC.

Axon regenerative capacity diminishes with aging and differences in the condition of peripheral nerves between young and elderly individuals have been reported. However, the underlying pathology remains unclear. The expression of repressor element‑1 silencing transcription factor (REST) increases with age and is reported to suppress axon regeneration. The present study investigated the pathology and potential treatment of reduced axon regenerative capacity using REST‑regulated cells and a mouse model. This study examined the molecular expression of the janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3) pathway, which is involved in growth‑associated protein 43 (GAP43) expression. In REST‑overexpressed (REST‑OE), glycoprotein 130 (GP130), JAK1 and phosphorylated STAT3 (p‑STAT3) expression was decreased compared with the control (GP130, P=0.004; JAK1, P=0.038; pSTAT3, P=0.015). On the other hand, in REST‑low expressed (siREST), GP130, JAK1 and pSTAT3 expression was increased compared with the control (GP130, P=0.004; JAK1, P=0.003; pSTAT3, P=0.033). It suggested that GP130 plays an important role. Therefore, GP130 agonist was administered to REST‑OE and aged mice and resulted in a significant increase in GAP43 expression (REST‑OE: Protein P=0.018, mRNA P=0.040; aged mice: Protein P=0.016, mRNA P=0.013). The results of this study suggest that the pathology of reduction in peripheral nerve axon regenerative capacity is inhibited by age‑related increase in REST expression, which leads to decreased GP130 expression and inhibition of JAK1/STAT3 pathway activity. These findings suggest that regulating GP130 expression may improve axon regenerative capacity by aging.

Muscle atrophy frequently occurs in patients with anterior cruciate ligament (ACL) injury, despite active participation in muscle strengthening programs. Without appropriate countermeasures such as exercise and pharmacological interventions, the atrophy may worsen. At the cellular and molecular levels, various protein synthesis‑related pathways and redox‑dependent molecules regulate processes associated with atrophy by activating or deactivating key signaling pathways. Muscle atrophy and the associated dysfunction can be reversed by physical exercise, which increases protein synthesis, thereby improving muscle strength and function around the ACL. However, the influence of different features of exercise protocols, including exercise type, intensity and duration, as well as the individual capacity of the patient, on the activity of the aforementioned pathways requires further investigation. Additionally, the mechanism by which redox‑sensitive molecules attenuate atrophy in ACL injury remains to be fully understood. The present review discusses exercise, signaling pathways and muscle atrophy in ACL injury, and highlights potential therapeutic strategies. These findings may also have implications for other joint diseases associated with ACL‑related injury.

Schizophrenia (SCZ) represents a considerable health concern, not only due to its impact on cognitive and psychiatric domains, but also because of its association with metabolic abnormalities. Individuals with SCZ face an increased risk of developing metabolic syndrome (MS), which contributes to the increased cardiovascular burden and reduced life expectancy observed in this population. Metabolic alterations are associated with both the SCZ condition itself and extrinsic factors, particularly the use of antipsychotic medications. Additionally, the link between SCZ and MS seems to be guided by distinct genetic parameters. The present narrative review summarizes the relationship between SCZ and MS and emphasizes the various therapeutic approaches for managing its components in patients with these conditions. Recommended therapeutic approaches include lifestyle modifications as the primary strategy, with a focus on behavioral lifestyle programs, addressing dietary patterns and physical activity. Pharmacological interventions include administering common antidiabetic medications and the selection of less metabolically harmful antipsychotics. Alternative interventions with limited clinical application are also discussed. Ultimately, a personalized therapeutic approach encompassing both the psychological and metabolic aspects is essential for the effective management of MS in patients with SCZ.

LncPrep + 96kb is a long non‑coding RNA expressed in murine granulosa cells. The 2.2-kb fragment of lncPrep + 96kb inhibits aromatase expression and estrogen secretion in ovarian granulosa cells. In the present study, lncPrep + 96kb‑knockout (KO) mice were generated, and significant ovarian fibrosis and reduced female fertility through fertility monitoring and superovulation. The augmentation of ovarian fibrosis was observed by Sirius red staining and western blot and RT‑qPCR. Notably, lncPrep + 96kb was identified in conserved non‑coding sequences adjacent to the prolyl oligopeptidase (POP) gene. Furthermore, POP expression was shown to be reduced in lncPrep + 96kb‑KO mice, whereas overexpression of lncPrep + 96kb increased POP expression. Further studies revealed that POP regulated the expression levels of factors related to fibrosis, including matrix metalloproteinase 2 (MMP2), transforming growth factor β1 (TGF‑β1) and peroxisome proliferator activated receptor γ (PPAR‑γ). In conclusion, ovarian fibrosis was elevated in lncPrep + 96kb‑KO mice, and POP may act as a target of lncPrep + 96kb, which mediates ovarian fibrosis through the regulation of PPAR‑γ, MMP2 and TGF‑β1 expression.

Purslane is a traditional Chinese medicine with a long‑standing history of efficacy in the management of dermatological conditions such as vitiligo. However, the molecular mechanisms underlying its therapeutic effects on vitiligo remain unclear. Therefore, the present study explored these mechanisms using network pharmacology, molecular docking and in vitro experiments. Following the screening process, seven principal active components were identified, namely kaempferol, hesperetin, luteolin, quercetin, arachidonic acid, cycloartenol and β‑sitosterol. In addition, six key targets, namely AKT1, tumor protein p53, peroxisome proliferator‑activated receptor γ (PPARG), estrogen receptor 1, prostaglandin‑endoperoxidase synthase 2 and mitogen‑activated protein kinase 1, and eight pathways in purslane‑based vitiligo treatment were identified. Network pharmacology and molecular docking demonstrated that flavonoids are the key components of purslane likely to mitigate oxidative stress damage in vitiligo. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that the phosphatidylinositol 3‑kinase (PI3K)/AKT, p53 and PPARG signaling pathways are associated with purslane components and vitiligo. In vitro experiments revealed that purslane total flavones (PTF) increased cell viability, decreased ROS levels and increased antioxidant enzyme activities in H₂O₂‑induced B16F10 cells. In addition, PTF activated the PI3K/AKT signaling pathway in H₂O₂‑induced B16F10 cells, and the antioxidant effect of PTF was attenuated by a PI3K/AKT inhibitor. In conclusion, the findings of the present study suggest that the flavonoids of purslane contribute, at least in part, to its therapeutic effectiveness in vitiligo by mitigating oxidative stress in melanocytes through the PI3K/AKT signaling pathway.

The present study aimed to explore the effects of key N6‑methyladenosine (m6A)‑related long non‑coding RNAs (lncRNAs) on the malignant behavior and macrophage polarization of gastric cancer cells, and their preliminary mechanisms. Gastric cancer‑related lncRNA datasets were downloaded from The Cancer Genome Atlas database, and m6A‑related differentially expressed lncRNAs (DElncRNAs) were analyzed. Subsequently, Cox regression and lasso regression analyses were used to screen the m6A‑related DElncRNAs associated with the prognosis of patients with gastric cancer. Additionally, reverse transcription‑quantitative polymerase chain reaction (qPCR) was employed to detect the expression levels of m6A‑related lncRNAs in normal gastric epithelial cells (GES‑1) and human gastric cancer cells (AGS and MKN‑45). In addition, the methylation levels of lncRNAs were measured using a methylated RNA immunoprecipitation qPCR assay kit, and the interaction between m6A‑related lncRNAs and m6A‑related proteins was observed by RNA pull‑down assay. Subsequently, m6A‑related lncRNAs and proteins were knocked down separately or simultaneously in gastric cancer cell lines. Bioinformatics analysis revealed that m6A‑related AC026691.1 was significantly associated with the prognosis of patients with gastric cancer and had a potential binding site for YT521‑B homology domain family member 2 (YTHDF2). The RNA pull‑down assay indicated that YTHDF2 not only had binding sites with AC026691.1 but could also markedly promote the degradation of m6A‑related AC026691.1. Furthermore, AC026691.1 was lowly expressed in gastric cancer cells, whereas YTHDF2 was highly expressed. Knockdown of YTHDF2 inhibited the proliferation, migration and epithelial‑mesenchymal transition of gastric cancer cells, and reduced M2 macrophage polarization. By contrast, knocking down AC026691.1 showed the opposite trend. Knockdown of YTHDF2 and AC026691.1 further confirmed the stable impact of YTHDF2 on AC026691.1. In conclusion, the degradation of AC026691.1 modified by YTHDF2‑mediated m6A may promote gastric cancer cell proliferation, migration, epithelial‑mesenchymal transition and M2 macrophage polarization.

Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) and heme oxygenase 1 (HO‑1) attenuate intervertebral disc degeneration (IVDD). However, whether BMSC‑derived exosomes attenuate IVDD by delivering HO‑1 to nucleus pulposus (NP) cells remains to be elucidated. Mouse BMSCs were characterized by multilineage differentiation and surface marker molecule detection. Exosomes Exo and Exo‑HO‑1 were isolated from BMSCs and HO‑1‑overexpressing BMSCs by ultracentrifugation and characterized by observing their morphology, detecting the exosome marker proteins, tumor susceptibility gene 101 (TSG101) and CD63 and analyzing their particle size. Interleukin‑1 β (IL‑1β)‑stimulated NP cells were used as the IVDD cell model. The influence of Exo or Exo‑HO‑1 on IL‑1β‑urged apoptosis and senescence in NP cells was determined by flow cytometry, western blotting and senescence‑associated β‑galactosidase (SA‑β‑gal) staining. Exo and Exo‑HO‑1 did not vary in size or morphology. Exo‑HO‑1 markedly repressed IL‑1β‑prompted apoptosis in NP cells, accompanied with a prominent increase in Cleaved caspase 3 and Bax protein levels and a marked decrease in Bcl‑2 protein levels. Exo and Exo‑HO‑1 both decreased the number of SA‑β‑gal‑positive NP cells and arrested NP cells in the G₁ phase. Exo‑HO‑1 had stronger effects than Exo, suggesting that Exo‑HO‑1 can weaken IL‑1β‑induced NP cell senescence. In addition, Exo and Exo‑HO‑1 repressed IL‑1β mediating the phosphorylation of p65 and nuclear translocation of p65. In conclusion, HO‑1‑overexpressing BMSC‑derived exosomes blocked the nuclear factor‑kappa B signaling in IL‑1β‑stimulated NP cells, thus impairing cell apoptosis and senescence.