JOURNAL OF CELLULAR AND MOLECULAR MEDICINE最新文献

Osteoarthritis (OA) is a prevalent cause of joint pain in elderly individuals, and chondrocyte senescence plays a crucial role in its pathogenesis. FOXO4 has been identified as a crucial molecule in cellular senescence. However, little is known regarding its role in OA and the regulation of its expression. 17-β-Estradiol (E2) has been demonstrated to exert a protective effect in OA, yet the underlying mechanism remains largely unexplained. In this study, we reported a protective effect of E2 against multiple types of chondrocyte senescence, and this effect was mediated by oestrogen receptor α (ERα). Mechanically, E2 activated AKT and facilitated the nuclear export and the degradation of FOXO4, which played a crucial role in resisting senescence. Moreover, knockdown of FOXO4 in osteoarthritic chondrocytes alleviated cellular senescence. Furthermore, we demonstrated that intra-articular injection of E2 was effective in ameliorating surgery-induced OA in a rat model. Collectively, E2 contributed to the alleviation of chondrocyte senescence through the ERα-AKT-FOXO4 signalling pathway and ameliorated OA progression in the rat model. Our study offers a novel therapeutic approach for controlling chondrocyte senescence and provides insights into the role of E2 in treating OA.

Percutaneous coronary intervention (PCI) enables coronary revascularisation and restores haemodynamic stability but also carries risks of delayed complications including in-stent restenosis (ISR), a chronic progressive disease with endovascular damage after PCI, which compromises the long-term efficacy of PCI. Currently, the main treatment strategies for ISR include interventional and drug therapies. From the era of using aspirin as a single antiplatelet agent to the ‘gold standard’ era of dual antiplatelet therapy, the risk of ISR after PCI has been reduced. However, long-term use of antiplatelet drugs inevitably causes a series of side effects such as gastrointestinal mucosal damage and bleeding, which have become key limiting factors in clinical treatment. Saponin natural products have been used to mitigate ISR progression by targeting platelet dysfunction. Specifically, these compounds directly bind to platelet membrane receptors, block ligand–receptor interactions, inhibit the secretion of α-granule and dense-granule contents, regulate intracellular signalling pathways and platelet metabolism, inhibit release of inflammatory mediators, and suppress platelet aggregation. This article reviews the progresses on the application of the active components in saponin natural products to inhibit platelet activation in the development of ISR after PCI, aiming to provide a superior approach for the comprehensive treatment of ISR after PCI.

RETRACTION: A. Mirzaei, S. Rashedi, M. R. Akbari, F. Khatami, and S. M. K. Aghamir, “ Combined Anticancer Effects of Simvastatin and Arsenic Trioxide on Prostate Cancer Cell Lines via Downregulation of the VEGF and OPN Isoforms Genes,” Journal of Cellular and Molecular Medicine 26, no. 9 (2022): 2728-2740, https://doi.org/10.1111/jcmm.17286.

The above article, published online on 02 April 2022 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Stefan N. Constantinescu; the Foundation for Cellular and Molecular Medicine, and John Wiley & Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party. The investigation identified duplication of elements between Figures 3 and 4 in this article. Additional duplications were found between Figures 1, 3, and 4 of this article and figures in other articles published by some of the same authors. Not all authors of the article were involved in the later publications where the additional duplicated elements were found. Although those other articles were published later, some of the duplicated elements were used to represent different scientific contexts. The authors cooperated with the investigation and explained that these duplications were inadvertent errors resulting from figure mismanagement. However, they were unable to provide their original raw data. Due to the extent and nature of the concerns, the editors consider the results and conclusions to be unreliable.

Shorter leukocyte telomere length (LTL) is an aging biomarker and risk factor for aging-related diseases, including abdominal aortic aneurysm (AAA). This study aimed to identify plasma proteins causally associated with LTL and investigate their roles in linking LTL to AAA. A proteomics analysis was conducted for LTL and a polygenic risk score (PRS) for LTL using 4955 plasma proteins by SomaScan in self-identified White participants (N = 7587–8055) from the Atherosclerosis Risk in Communities (ARIC) study. Replications were evaluated in self-identified Black participants (N = 1668–2094) from ARIC and White participants (N = 2333–2431) from the Cardiovascular Health Study (CHS). Mendelian randomization (MR) analysis assessed causality between LTL and proteins. Survival and mediation analyses explored protein-mediated associations between LTL and AAA risk. In ARIC White participants, 15 unique proteins were identified for LTL or LTL PRS. Three LTL-associated proteins (MZB1, PLOD3, COL28A1) replicated in ARIC Black participants, and six (TNFRSF17, MZB1, CHL1, GDF15, THPO and PLOD3) in CHS White participants. Three proteins associated with LTL PRS (THPO, GP1Bα, PEAR1) replicated in CHS White participants. MR analysis supported causal associations between LTL and five proteins (KDR, TNFRSF17, GDF15, ST3GAL6, CHL1) with all except GDF15 being novel to LTL. LTL was associated with AAA risk (HR = 0.873, 95% CI: 0.803–0.950), with GDF15 mediating 12.4% of this association (p = 0.028). We identified five proteins causally influenced by LTL and highlighted GDF15 as a mediator linking LTL to AAA risk, offering novel insights into aging biology and AAA pathogenesis.

Castleman disease (CD) is a rare and heterogeneous group of lymphoproliferative disorders characterised by abnormal proliferation of lymphoid tissue. First described in the 1950s, it has since been classified into two major clinical forms: unicentric CD (UCD), involving a single lymph node region and multicentric CD (MCD), which affects multiple regions and is often systemic. Further subclassification of MCD includes HHV8-associated MCD, POEMS-associated MCD and idiopathic MCD (iMCD), each with distinct pathophysiologic mechanisms and clinical implications. This review summarises current understanding of the epidemiology, clinical presentation, histopathology, pathogenesis and diagnostic challenges of CD. It also explores recent advances in molecular biology, including the role of interleukin-6 (IL-6), human herpesvirus-8 (HHV8) and aberrant immune signalling in disease progression. Therapeutic strategies vary significantly depending on the subtype and range from surgical resection in UCD to immunotherapy, siltuximab and cytotoxic chemotherapy in MCD. Despite progress, CD remains underdiagnosed and poorly understood, especially in its idiopathic forms. Continued research into its molecular underpinnings and targeted treatments is critical to improving patient outcomes and establishing evidence- based guidelines.

Kruppel-like factors (KLFs) constitute a crucial family of transcription factors that are engaged in a variety of biological processes, such as erythropoiesis as well as liver development. A growing body of research underscores the increasing importance of the KLF family in the context of hepatocellular carcinoma (HCC). Despite this, the exact function of KLF1 within HCC remains unclear. Our study demonstrates a significant upregulation of KLF1 expression in tumour samples from HCC patients compared to normal liver tissue, with higher expression levels strongly correlating with poorer survival outcomes. Notably, in vitro experiments have shown that KLF1 enhances liver cancer cell proliferation by inhibiting ferroptosis, and this inhibition is negatively correlated with the transcription levels of fatty acid synthase 4 (ACSL4). These findings suggest that KLF1 may exert its oncogenic potential by repressing ferroptosis through the inhibition of ACSL4 transcription. Further mechanistic investigations reveal that KLF1 inhibits ACSL4 expression via transcriptional repression and suppresses ferroptosis through the ACSL4/LPCAT3 axis, ultimately promoting HCC tumour growth as well as its advancement. In conclusion, KLF1 is essential for onset as well as development in HCC through inhibiting ACSL4 transcription along with ferroptosis, thereby presenting novel therapeutic targets for HCC treatment.

Lipid metabolism reprogramming is one of the most prominent characteristics of cancer, but it is still unclear which regulatory pathways underlie this process in cancer cells. Circular RNAs (circRNAs) represent a novel category of non-coding RNAs with multifaceted regulatory functions. While the biological roles of circRNAs in cancer have been elucidated, there remains a dearth of knowledge regarding their involvement and regulatory mechanisms in lipid metabolism within the context of cancer. This article provides an overview of the regulatory roles and specific mechanisms of circRNAs in cancer lipid metabolism reprogramming. By elucidating these mechanisms, it enhances our comprehension of the metabolic rewiring driving tumour development and uncovers new avenues for targeted therapy.

High mobility group box 1 (HMGB1), a prototypical alarmin and chromatin-binding protein, has emerged as a critical mediator of tumour-associated inflammation and immune regulation. Although its soluble form has been implicated in various malignancies, the functional contribution of HMGB1 encapsulated within exosomes remains incompletely understood, particularly in the context of non-small–cell lung cancer (NSCLC). We profiled exosomal HMGB1 levels in the peripheral blood of 80 clinically annotated NSCLC patients and correlated its abundance with metastatic burden and survival outcomes. Functional experiments using HMGB1-overexpressing NSCLC cell lines were conducted to assess proliferative, migratory and stemness-associated phenotypes in vitro, alongside tumorigenicity and drug responsiveness in vivo. Mechanistic interrogation of the TLR4/NF-κB/IL-6/STAT3 signalling axis was performed via western blotting, ELISA, immunofluorescence and targeted pharmacologic inhibition. The impact of exosomal HMGB1 on macrophage plasticity was evaluated using THP-1-derived macrophage models, and therapeutic relevance was validated in murine tumour models under immunotherapy and chemotherapy regimens. Circulating exosomal HMGB1 levels were significantly elevated in patients with metastatic NSCLC and strongly correlated with poor prognosis. Exosomal HMGB1 markedly enhanced tumour cell proliferation, motility and self-renewal capacity, while promoting chemoresistance and immune evasion. Mechanistically, HMGB1-enriched exosomes activated the TLR4/NF-κB axis, elevating IL-6 secretion and subsequent STAT3 phosphorylation. These effects were further linked to the polarisation of macrophages towards an immunosuppressive M2 phenotype. Therapeutically, cotargeting STAT3 signalling overcame exosomal HMGB1–mediated resistance to paclitaxel in vivo. Our findings delineate a previously unrecognised exosome-mediated mechanism by which HMGB1 drives NSCLC progression and modulates the tumour immune microenvironment. Exosomal HMGB1 not only serves as a potential prognostic biomarker but also represents a tractable target for enhancing the efficacy of immuno- and chemotherapeutic strategies in NSCLC.

Hepatocellular carcinoma (HCC), accounting for over 90% of primary liver cancers, remains a major global challenge for healthcare professionals. While immunotherapy has transformed the landscape of cancer treatment, its success is often limited by immune resistance, particularly through T cell exhaustion which remains a major barrier to effective immune responses in solid tumours, including HCC. As tumours progress, T cells undergo a gradual loss of functionality due to continuous antigen exposure and fail to exert effective anti-tumour responses. During this process, alterations in the epigenome, transcriptome, signalling pathways, and tumour metabolome, in addition to interactions with other cells in the tumour microenvironment, efficiently contribute to T cell exhaustion. Restoring T cell function brings hope for improving therapy outcomes and providing new treatment modalities for HCC patients. In this review, we explore the key cellular and molecular mechanisms driving T cell exhaustion, including the roles of immunosuppressive cells, metabolic stress, and epigenetic alterations focusing on HCC. We also discuss current and emerging strategies aimed at preventing or reversing T cell exhaustion, such as epigenetic modulation, immune checkpoint blockade, metabolic reprogramming, and combination therapies. Understanding these interconnected pathways is critical for designing more effective immunotherapy-based approaches for liver cancer.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, posing a global health challenge. It affects millions of people, causing cognitive decline and a heavy burden on healthcare systems. Neuroinflammation is a key pathological feature of AD, often associated with the dysregulation of microRNAs such as hsa-miR-146a-5p. WGX50 (N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-phenyl-acrylamide), a small molecule derived from Zanthoxylum bungeanum Maxim, has antioxidant and anti-inflammatory activities. While WGX50 demonstrates potent inhibition of neuroinflammation, its poor blood–brain barrier permeability may be improved using targeted delivery strategies. The current study aimed to design a novel nanoconjugate of WGX50 and curcumin with gold nanoparticles (AuNPs) to observe its therapeutic effects in a rat model. All nanoconjugates were synthesised as targeted (Cys-capped AuNPs with WGX50-insulin and curcumin-insulin) and non-targeted (without insulin). Immunohistochemical analysis revealed that both non-targeted (WGX50-NT) and targeted (WGX50-T) therapies have a significant effect in the rat model, with WGX50-T showing a more pronounced effect. The histopathology results of WGX50 and WGX50-T showed an approximate 80%–90% reduction in Aβ plaque deposition. The treatment with both curcumins targeted (C-T) and non-targeted (C-NT) formulations led to a significant reduction in Aβ levels in AD rats. Fluorescence microscopy confirmed that targeted delivery was more effective, potentially leading to better therapeutic outcomes. The expression levels of hsa-miR-146a-5p showed differential expression levels with targeted treatments correlating with lower expression levels, suggesting a role in modulating neuroinflammation and immune responses. Overall, these findings highlight the potential of targeted drug delivery systems in enhancing the efficacy of AD treatments.