Molecular medicine reports最新文献

The present study investigated the role of connexin 43 (Cx43) in mediating prenatal inflammation‑induced cardiac fibrosis in offspring, specifically exploring its dynamic regulation with autophagy and DNA methylation pathways. Pregnant Sprague‑Dawley rats received intraperitoneal injections of saline (control) or lipopolysaccharide (LPS, 0.79 mg/kg) on gestational days 8, 10 and 12. Offspring were sacrificed at 8 and 16 weeks postpartum. Myocardial tissues were subjected to histopathological examination and molecular analysis. Prenatal LPS exposure consistently induced significant cardiac fibrosis in the offspring. Reverse transcription‑quantitative PCR revealed that mRNA levels of Cx43, LC3 and DNA methyltransferase 1 (DNMT1) were markedly reduced at 8 weeks; however, they were elevated above control levels at 16 weeks. Western blotting revealed persistent suppression of Cx43 protein expression at both ages, whereas the LC3‑II/I ratio and DNMT1 protein levels paralleled the biphasic mRNA trends. In vitro experiments using neonatal rat cardiac fibroblasts treated with LPS (10 µg/ml, 24 h) confirmed Cx43 and LC3 downregulation and DNMT1 upregulation. Targeted pharmacological interventions were used to clarify these regulatory relationships. Cotreatment with the Cx43 gap junction inhibitor carbenoxolone (400 µM) and LPS further suppressed Cx43, LC3 and DNMT1 expression. However, cotreatment with the Cx43 agonist all‑trans retinoic acid (10 µM) attenuated LPS‑induced DNMT1 upregulation and LC3‑II/I ratio suppression. These findings demonstrate that the functional state of Cx43 critically links fetal inflammatory insults to postnatal cardiac fibrogenesis by dynamically regulating interconnected autophagy and DNA methylation, establishing Cx43 as an upstream regulatory node in this pathogenic network.

Urethral injury is a common type of traumatic damage to the urinary system, often leading to urethral stricture, fibrosis and dysfunction, which significantly impair physiological function and quality of life. The present study aimed to investigate the therapeutic efficacy of the novel immune‑regulatory molecule tetrahedral DNA nanostructure (TDN) in a rat model of urethral injury and explore the underlying mechanisms of action. A rat model of urethral injury was established through mechanical injury. Animals were divided into four groups: Control, model, model + rapamycin and model + TDN. Therapeutic effects and associated mechanisms were assessed via retrograde urethrography, Masson's trichrome staining, immunohistochemistry, western blotting, reverse transcription‑quantitative PCR (RT‑qPCR) and transcriptomic analysis. The results revealed that TDN markedly alleviated the immune response after urethral injury, reduced immune cell infiltration, downregulated the expression of inflammatory cytokines, including IL‑6, IL‑1β and TNF‑α, and effectively inhibited the progression of fibrosis. Masson's trichrome staining and western blotting provided evidence of reduced collagen deposition and decreased expression of fibrosis markers, including α‑smooth muscle actin, TGF‑β1, collagen I, collagen III and Smad3, after treatment with TDN. Transcriptomic analysis revealed that TDN modulated multiple immune‑related pathways, including the NF‑κB signaling pathway, NOD‑like receptor signaling pathway and cytokine‑cytokine receptor interaction, accompanied by a decrease in immune‑inflammatory responses, such as reduced inflammatory cytokine production and immune cell infiltration. Additionally, the results suggested that TDN may improve cellular metabolism and inhibit cell proliferation by downregulating the expression of cell cycle‑associated genes, as demonstrated by transcriptomic analysis and RT‑qPCR validation of cyclin B1, ribonucleotide reductase regulatory subunit M2, polo‑like kinase 1 and cyclin‑dependent kinase 1. In conclusion, TDN notably promoted tissue repair after urethral injury in rats by regulating the immune response, inhibiting fibrosis and enhancing cellular metabolism. These findings highlight TDN as a promising therapeutic candidate for urethral injury and offer novel insights into immune-regulatory strategies for the treatment of other fibrotic diseases.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that certain of the flow cytometric data shown in Fig. 5A on p. 4978 were strikingly similar to data that had either appeared previously in other papers written by different authors at different research institutes, or which had already been submitted for publication. 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 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. [Molecular Medicine Reports 20: 4973‑4983, 2019; DOI: 10.3892/mmr.2019.10737].

The present review focuses on the molecular functions of prostate‑specific membrane antigen (PSMA) as a biologically active protein. Its clinical use as a positron emission tomography imaging marker or radioligand therapy target is beyond the scope of the current review. The role of PSMA (also known as folate hydrolase 1/glutamate carboxypeptidase II/N‑acetylated‑α‑linked acidic dipeptidase) has progressed from that of a prostate cancer biomarker to a functional driver of tumor biology. Structurally, PSMA is a type II transmembrane glycoprotein with glutamate carboxypeptidase and folate hydrolase activities, linking glutamate and one‑carbon metabolism to proliferation, redox balance and epigenetic regulation. PSMA undergoes clathrin‑dependent endocytosis and interacts with various scaffolding proteins, such as filamin A and receptor for activated C kinase 1, which are properties that underlie its functional role as a molecular signaling hub, in addition to being a therapeutic entry point. Its expression is dynamically regulated by androgen receptor signaling, NF‑κB activation and epigenetic modifiers, contributing to intra‑patient heterogeneity and treatment resistance. PSMA expression is not restricted to prostate epithelium but is also expressed in tumor‑associated endothelium across multiple malignancies, where it can promote angiogenesis through integrin/PI3K‑AKT‑mTOR signaling and paracrine induction by extracellular vesicles. These molecular functions can result in immune exclusion, stromal activation and neuronal interactions, positioning PSMA as a key regulator of the tumor microenvironment. Although PSMA‑targeted imaging and therapies have demonstrated substantial clinical utility, understanding the biological basis of the function of PSMA is essential for interpreting the heterogeneous clinical responses and for designing next‑generation therapeutic strategies in association with this protein. By integrating enzymatic activity, non‑enzymatic scaffold signaling and tumor microenvironmental regulatory information, the present review provides a functional framework in the PSMA biology field and discusses how these molecular properties can be leveraged to develop novel rational and effective PSMA‑targeted interventions.

Intervertebral disc degeneration (IDD) is a major pathological basis for spinal degenerative diseases, involving mechanisms such as abnormal mechanical loading, inflammatory responses, and genetic and environmental factors. The role of epigenetic regulation in IDD has gained attention as a potential therapeutic target. The present review systematically explores the contributions of DNA methylation, histone modifications, non‑coding RNAs (ncRNAs) and metabolic regulation to IDD progression, and elucidates their molecular mechanisms. Specific examples include: DNA methyltransferase 3β‑mediated DNA methylation promoting ferroptosis and oxidative stress in nucleus pulposus cells; enhancer of zeste homolog 2 (EZH2)‑mediated trimethylation of histone H3 lysine 27 modification inhibiting SOX9 expression, leading to cellular senescence and extracellular matrix degradation; and ncRNAs (such as microRNA‑143 and LINC01121) regulating gene transcription to affect inflammation and apoptosis. Additionally, metabolic products (such as NAD+, α‑ketoglutarate and lactate) interact with epigenetic pathways to influence IDD. Specifically, NAD+ acts as a cofactor for sirtuin deacetylases, thereby regulating histone and non‑histone protein acetylation; α‑ketoglutarate serves as a cofactor for TET DNA demethylases and Jumonji‑C histone demethylases, influencing DNA and histone demethylation; and lactate induces histone lactylation, which modulates gene transcription related to inflammation and extracellular matrix metabolism in IDD. Based on these mechanisms, novel therapies targeting epigenetics (such as DNA methylation inhibitors, EZH2 inhibitors and RNA interference) show therapeutic potential. Future research should further explore the crosstalk between epigenetic and metabolic regulation to advance the development of personalized and precision medicine strategies for IDD intervention.

Tubulointerstitial injury is a key driver of lupus nephritis (LN) progression, and dysregulation of the immune microenvironment is a central feature of this process. The molecular mediators of this dysregulation remain incompletely defined. In the present study an integrated bioinformatics and experimental analysis was performed of the Activator Protein 1 (AP‑1) family transcription factor Fos‑related antigen 1 (FRA1) in LN tubulointerstitium. Analysis of gene expression omnibus datasets (GSE113342, GSE200306 and GSE127797) showed that FRA1 was markedly upregulated in the tubulointerstitium of LN samples and that its expression positively correlated with CD8⁺ T cells, regulatory T cells, monocytes, M1 macrophages and activated mast cells, but negatively correlated with plasma cells, resting CD4⁺ memory T cells, M0/M2 macrophages, resting dendritic cells and resting mast cells. In vivo experiments revealed that, FRA1 expression was also increased in kidneys from MRL/lpr mice. Furthermore, in vitro, lentiviral overexpression of FRA1 in HK‑2 cells induced robust upregulation of IL‑6, IL‑1β, IL‑8, MCP‑1 and RANTES, whereas FRA1 knockdown selectively decreased IL‑6 and RANTES levels. Together, these results indicate that FRA1 is significantly elevated in the LN tubulointerstitium and may foster a proinflammatory microenvironment by regulating key cytokines. The FRA1/AP‑1 axis therefore represents a potential regulator of renal inflammation in LN and a candidate therapeutic target.

Infantile hemangioma (IH) is a type of benign vascular tumor observed in younger patients. Previously, 216 differentially expressed microRNAs (miRs/miRNAs) associated with IH have been identified. In addition, common hub genes and miRNAs related to proteoglycan signaling pathways in angiogenesis and cancer have been identified, including c‑Myc, integrin β1 (ITGB1), Bcl2 and miR‑29a. Therefore, the present study aimed to explore the pathogenesis of IH from the perspective of previously identified miRNA gene network and protein‑protein interactions. Gene and protein levels in human umbilical vein endothelial cells (HUVECs) were analyzed using reverse transcription‑quantitative PCR and western blot (WB) analysis. Cell viability was assessed using a Cell Counting Kit‑8 assay, and the potential association between miR‑29a with ITGB1 was validated using a dual‑luciferase reporter assay. The inhibition of ITGB1 suppressed the β‑catenin/c‑Myc pathway in HUVECs. In addition, transfection with small interfering RNAs (siRNAs) targeting ITGB1 decreased the viability of HUVECs. Furthermore, siRNAs targeting mucin 1 and β‑N‑acetylglucosaminidase significantly inhibited the c‑Myc pathway in HUVECs. The results of WB and dual‑luciferase reporter assays demonstrated that miR‑29a regulated the β‑catenin/c‑Myc pathway and the viability of HUVECs in HUVECs by directly binding to ITGB1. Therefore, miR‑29a may serve as a potential therapeutic target for IH.

Following the publication of the above paper, the authors contacted the Editor to explain that they had made a couple of inadvertent errors in assembling the data in Figs. 1B and 2B. Specifically, the following issues were identified: first, the immunohistochemical staining images representing CD31 in Fig. 1B on p. 3434 were chosen from the wrong dataset; secondly, the immunohistochemical staining images representing HIF‑1α in Fig. 2B on p. 3435 were similarly included in this figure incorrectly. After having performed an  independent analysis of these data in the Editorial Office, it came to light that certain of the data featured in Fig. 2B had been submitted for publication at around the same time in an article featuring some of the same authors to the journal PLoS One. However, the authors were able to consult their original data, and the revised versions of Figs. 1 and 2, now featuring all the correct data for Figs. 1B and 2B, are shown on the next two pages. Note that these errors did not adversely affect either the results or the overall conclusions reported in this study. All the authors agree with the publication of this corrigendum, and are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this. They also wish to apologize to the readership of the Journal for any inconvenience caused. [Molecular Medicine Reports 12: 3432‑3438, 2015; DOI: 10.3892/mmr.2015.3815]

Neuroinflammation is a central component of the pathophysiology of ischemic stroke (IS). Suppressing excessive inflammatory responses after stroke can markedly improve patient outcomes. Interleukin‑6 (IL‑6), a key mediator of the inflammatory cascade, serves a notable role in the pathological process of acute IS through multiple mechanisms. Elevated serum IL‑6 levels serve as an important biomarker for predicting the onset and recurrence of IS and are closely associated with disease severity and prognosis. Anti‑inflammatory interventions are notably important during the acute phase and secondary prevention of stroke. Currently, therapeutic strategies targeting the IL‑6/IL‑6R signaling axis are under investigation and have shown promising clinical potential. The present review summarizes the important role of IL‑6 in neuroinflammation associated with IS, its association with disease severity and prognosis and previous advances in anti‑inflammatory therapeutic strategies targeting the IL‑6/IL‑6R pathway during both the acute phase and secondary prevention of IS.

Asthenozoospermia (AZS) is one of the most common causes of male infertility, and the decreased expression and function of cation channel of sperm (CatSper) in the sperm contributes to the pathology of AZS. Phenylethanoid glycosides, such as echinacoside (ECH), a compound derived from Cistanche tubulosa, exhibit therapeutic potential for AZS. However, the underlying mechanisms of ECH treatment on AZS remain to be fully elucidated. The ornidazole‑induced AZS model rats (AZS rats) were treated with ECH in vivo and human sperm were exposed to ECH in vitro. Computer‑assisted semen analysis was used to assess sperm motility. The functional characteristics of epididymal sperm were evaluated by analyzing hyperactivation and acrosome reaction. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), western blotting and calcium imaging analyses were used to analyze the expression and function of CatSper channels. In addition, RT‑qPCR, western blotting and chromatin immunoprecipitation‑qPCR were used to investigate the Sex‑determining region Y‑related high‑mobility‑group box family, member 5 (Sox5)‑mediated transcriptional activation of the CatSper gene. It was found that ECH treatment enhanced sperm motility, hyperactivation and acrosome reaction in AZS rats. In addition, ECH upregulated the expression and function of the four α subunits of CatSper channel, CatSper1 to CatSper4, in model rats. Furthermore, ECH treatment increased the protein expression of Sox5 and its binding to the CatSper1 gene promoter region in the testes of AZS rats. In vitro results further suggested that ECH treatment improved sperm motility and CatSper function in the sperm samples from both healthy subjects and patients with idiopathic AZS (iAZS). The present findings suggest that ECH treatment exerts certain therapeutic effects on iAZS through the functional upregulation of CatSper channels in the sperm. These findings position ECH as a promising complementary and alternative medicine therapeutic for enhancing sperm function and managing iAZS in clinical practice.