JOURNAL OF CELLULAR AND MOLECULAR MEDICINE最新文献

Asthma is a chronic inflammatory respiratory disorder triggered by allergens or environmental pollutants, characterised by airway obstruction, increased airway resistance and breathing difficulties. Although substantial progress has been made in elucidating its pathophysiology, the molecular mechanisms underlying asthma progression remain incompletely understood, and no curative therapies are currently available. The present study explored the role of KIF1B (kinesin family member 1B) in asthma pathogenesis using integrated approaches involving human cohort datasets, in vitro airway epithelial cell models and an in vivo ovalbumin (OVA)-induced asthma mouse model. KIF1B knockdown and NLRP3 (NLR family pyrin domain-containing 3) overexpression assays were performed to delineate the molecular mechanisms by which KIF1B modulates pyroptosis. Results showed that KIF1B expression was markedly elevated in bronchial biopsies from asthma patients, OVA-challenged mouse lungs and IL-13–stimulated BEAS-2B cells. Silencing KIF1B significantly attenuated OVA- and IL-13–induced oxidative stress, proinflammatory cytokine release and pulmonary injury. Specifically, KIF1B knockdown reduced the expression of pyroptosis-associated proteins—NLRP3, cleaved caspase-1 and cleaved gasdermin D (GSDMD)—while decreasing TNF-α, IL-1β and IL-18 levels and restoring the anti-inflammatory cytokine IL-10. Mechanistically, NLRP3 overexpression abolished the anti-inflammatory and cytoprotective effects of KIF1B silencing, confirming that KIF1B promotes asthmatic inflammation through activation of the NLRP3 inflammasome. In conclusion, these findings identify KIF1B as a key regulator of airway inflammation and pyroptosis in asthma via NLRP3-dependent signalling. Targeting KIF1B may therefore represent a promising therapeutic strategy for controlling asthma progression.

Myocardial infarction (MI) is a sudden necrosis of cardiomyocytes, often caused by atherosclerosis, with obesity being a significant risk factor. This study aimed to evaluate the effects of a high-fat diet (HFD) on post-MI myocardial remodelling, focusing on inflammatory signalling, nitric oxide synthase (NOS) dysregulation and oxidative stress. Nine-week-old Wistar Kyoto rats fed a control diet or a HFD for 4 weeks, followed by 20 min of left descending coronary artery occlusion and 7 days of reperfusion. Plasma levels of the proinflammatory cytokines TNF-α and IL-6 were measured using a Bioplex kit. NOS activity was assessed via [³H]-l-citrulline production, while the expression of eNOS, iNOS, NFκB and TLR4 in cardiac tissue was analysed by Western blot. Lipid peroxidation was assessed by measuring conjugated diene concentrations in cardiac tissue. MI and HFD both increased proinflammatory cytokine levels, reduced NOS activity and eNOS expression and increased iNOS expression. NFκB was more highly expressed after MI in control-fed animals. Notably, TLR4 expression was reduced by HFD and remained unchanged post-MI. Conjugated dienes were elevated post-MI and further increased by HFD. These findings demonstrate that HFD exacerbates post-MI inflammation and oxidative stress, impairing nitric oxide signalling and promoting adverse cardiac remodelling.

Subtalar arthrodesis (SA) is a widely used salvage procedure for posttraumatic subtalar arthritis (PSA), but its underlying healing mechanisms remain poorly understood. The immune system plays a critical role in the union process after arthrodesis; however, the systemic osteoimmunological response has not been clearly defined. In this study, we investigated immune cell dynamics in patients who underwent SA using single-cell RNA sequencing (scRNA-seq). Peripheral blood mononuclear cells (PBMCs) were collected before surgery and 3 months after the operation. The degree of bone fusion was assessed using computed tomography (CT) scans at 3 months, and patients were categorised into early union (EU) and delayed union (DU) groups. scRNA-seq analysis was performed to examine immune cell composition, gene expression and functional pathways. Monocytes in the EU group showed enhanced antigen processing and presentation, whereas those in the DU group demonstrated increased phagocytic activity. NK cells in the DU group exhibited stronger cytotoxicity through Fc-gamma receptor signalling and antibody-dependent cellular cytotoxicity (ADCC) pathways, while NK cells in the EU group showed higher chemokine and cytokine activity. These immune differences persisted postoperatively, suggesting that variations in the systemic immune environment may influence bone healing outcomes. Our findings emphasise the important roles of monocytes and NK cells in bone union and suggest that immunomodulatory approaches could help improve bone repair.

Myocardial ischaemia continues to be a predominant global cause of mortality, leaving survivors with compromised quality of life and significant loss of functional cardiomyocytes. The main therapeutic approach, which attempts to restore heart function, generally involves myocardial reperfusion. However, this intervention is frequently complicated by the occurrence of myocardial reperfusion injury, which undermines its therapeutic benefits. Consequently, there is an increasing focus on alternative regenerative approaches, such as stem and progenitor cell therapies. Since their initial and successful use in oncology, stem cells have emerged as promising tools for mitigating various pathological conditions. Nonetheless, their efficacy in post-ischaemic myocardial environments is questioned due to their rapid degradation following delivery. Interestingly, small extracellular vesicles, particularly exosomes secreted by stem cells, demonstrate reparative properties akin to those of the stem cells themselves. Indeed, evidence strongly shows that exosomes derived from mesenchymal stem cells, cardiac progenitor cells, and induced pluripotent stem cells exert anti-apoptotic and pro-angiogenic effects in post-ischaemic cardiomyocytes while concomitantly offering protection against myocardial reperfusion injury. In this review, we critically appraise the pivotal findings supporting the potential clinical application of stem cell-derived exosomes, and underscore key considerations necessary to optimise their therapeutic efficacy.

Telomeres are repetitive DNA sequences located at the ends of eukaryotic chromosomes, forming protective caps that prevent chromosomal degradation and inappropriate repair during cell division. Telomere shortening has been linked to ageing and various age-related diseases. In this study, we validated the reference range for telomere length established through the analysis of 1011 Korean individuals to confirm its robustness. Telomere length showed a declining trend with increasing age, with no statistically significant differences observed between sexes. Diabetic and dyslipidaemic groups had shorter telomeres than the control group. These findings suggest that telomere length may be a biomarker of biological ageing and could be linked to metabolic conditions. Future research could build upon these observations to explore telomere dynamics in broader populations and investigate their clinical relevance across diverse health outcomes. Furthermore, longitudinal studies are needed to determine whether telomere shortening is a cause or consequence of these metabolic conditions. Additionally, incorporating advanced methodologies, such as next-generation sequencing, could enhance our understanding of telomere biology and improve the accuracy of telomere-based measurements in both research and clinical settings.

Liver disease is a leading cause of death worldwide. Nucleated red blood cells (NRBCs) are associated with high mortality and poor outcomes in patients with severe illnesses. However, the relationship between NRBCs and severe liver disease remains unclear. Potential confounding effects were managed using propensity score matching. The association between NRBCs and clinical outcomes in patients with liver disease was clarified using Cox proportional hazards regression analysis and smoothing splines. Differences in NRBCs between 30-day survivors and non-survivors within the pre-matched cohort during the first 30 days after ICU admission were assessed using generalised additive mixed models. Compared to the 30-day survivors, the 30-day non-survivors had significantly higher NRBC counts. Higher NRBC counts were significantly correlated with an augmented risk of 30-day, 90-day and in-hospital mortality, with concurrently decreased hospitalisation durations. Inpatients with liver disease, progressive increases in the 30-day mortality risk were associated with increased NRBC counts. The association between NRBCs and enhanced 30-day mortality rates was consistent across stages and etiologies. Moreover, 30-day non-survivors experienced average daily increases in NRBC counts of 0.31% compared with 30-day survivors. Elevated NRBC counts correlated with increased 30-, 90-day and in-hospital mortality in patients with liver disease.

Astragalus polysaccharides (APS) are a crucial bioactive component known for their various pharmacological properties. Abnormal O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is noted in cases of intervertebral disc degeneration (IVDD). Nonetheless, it remains uncertain whether APS regulates the process of O-GlcNAcylation associated with IVDD. We employed molecular docking, cycloheximide chase assay, immunohistochemistry, and immunoprecipitation to investigate APS-mediated OGT/O-GlcNAcylation regulation of Nrf2. The effects of APS and its role in promoting the O-GlcNAcylation of Nrf2 in IVDD through both in vivo and in vitro studies are discussed. In vitro investigations demonstrated an increase in the levels of OGT and O-GlcNAcylation in nucleus pulposus cells (NPCs) following exposure to tert-butyl hydroperoxide (TBHP). APS further facilitated improvements in OGT expression and O-GlcNAcylation processes, restoring the viability of NPCs inhibited by TBHP and promoting the synthesis of collagen II and aggrecan, while reducing apoptosis. Mechanistically, APS promotes the expression of OGT by targeting it. Furthermore, O-GlcNAcylation mediated by OGT stabilizes the expression of Nrf2 via the ubiquitin-proteasome pathway. Rescue experiments indicated that the disruption of either OGT or Nrf2 expression negated the protective role of APS on NPCs. Ultimately, both in vitro and in vivo studies indicated that APS significantly enhanced OGT expression and O-GlcNAcylation, which subsequently improved Nrf2 expression and contributed to the alleviation of IVDD in rats. APS promotes O-GlcNAcylation through OGT, thereby stabilizing the expression of Nrf2, which in turn contributes to the improvement of IVDD.

RETRACTION: I. Crespo, P. Fernández-Palanca, B. San-Miguel, M. Álvarez, J. González-Gallego, and M.J. Tuñón, “ Melatonin Modulates Mitophagy, Innate Immunity and Circadian Clocks in a Model of Viral-Induced Fulminant Hepatic Failure,” Journal of Cellular and Molecular Medicine 24, no. 13 (2020): 7625–7636, https://doi.org/10.1111/jcmm.15398.

The above article, published online on 29 May 2020 in Wiley Online Library (http://onlinelibrary.wiley.com/), has been retracted by agreement between the journal Editor-in-Chief, Stefan N. Constantinescu; the Foundation for Cellular and Molecular Medicine; and John Wiley & Sons Ltd. Following publication, concerns were raised by third parties regarding duplications in panels C and F in Figure 1B. Additional concerns of duplication and splicing were also raised for Figures 2C and 3B, which were investigated and confirmed by the publisher; additionally, portions of Figure 4 were duplicated from Figure 3 of an earlier article by some of the same authors (González-Fernández et al. 2018 [https://doi.org/10.3389/fphar.2018.00556]). The authors provided their raw data, but this was not sufficient to resolve the concerns, and the authors were unable to provide a satisfactory explanation. The retraction has been agreed upon because of concerns that portions of the figures were duplicated, affecting the interpretation of the data and results presented.

Endoplasmic reticulum stress (ERS) emerges as a critical pathophysiological nexus in hypertension and related cardiovascular diseases. Chronic ERS activation via the IRE1α-XBP1, ATF6, and PERK pathways drives vascular endothelial dysfunction (reduced NO bioavailability, increased ET-1), renin-angiotensin system (RAS) hyperactivation, sympathetic overactivation, and vascular smooth muscle cell (VSMC) maladaptive proliferation/apoptosis, collectively promoting hypertension progression and end-organ damage. Pharmacological targeting of ERS demonstrates therapeutic promise: chemical chaperones 4-phenylbutyric acid (4-PBA) and tauroursodeoxycholic acid (TUDCA) stabilise proteostasis, reduce oxidative stress, and inhibit apoptosis; antioxidants N-acetylcysteine (NAC) and melatonin attenuate ERS-oxidative stress crosstalk. Notably, conventional antihypertensives—ACE inhibitors and angiotensin receptor blockers (ARBs)—exert ancillary benefits by suppressing ERS beyond their primary RAS blockade. Preclinical evidence supports the efficacy of these strategies in reversing hypertensive pathophysiology. Future research must prioritise isoform-selective ERS modulator development, validation in human trials, biomarker discovery, and elucidating ERS roles in therapy-induced hypertension. Targeting ERS represents a transformative mechanotherapeutic paradigm for precision hypertension management.

By integrating gene expression data, clinical features and multimodal data, we constructed a machine learning model capable of accurately predicting the prognosis of endometrial cancer patients. The study found that key genes related to lysosome-dependent cell death exhibit significant expression pattern heterogeneity in endometrial cancer and are closely associated with immune cell infiltration and metabolic characteristics within the tumour microenvironment. Patients in the high-risk group tend to have lower immune scores and a higher prevalence of immunosuppressive cell types, such as regulatory T cells and M2 macrophages, which may be linked to poorer prognosis and resistance to immunotherapy. Additionally, we discovered that the expression of lysosome-dependent cell death-related genes correlates with patients' sensitivity to chemotherapeutic drugs, providing new perspectives for personalised treatment of endometrial cancer. Through this study, we characterised the prognostic relevance of lysosome-dependent cell death–related genes in endometrial cancer, and identified biomarkers with potential utility for risk assessment and therapeutic stratification.