JOURNAL OF CELLULAR AND MOLECULAR MEDICINE最新文献

Tripartite motif 52 (TRIM52) has been identified as a key regulator of inflammatory responses. However, its involvement in doxorubicin (DOX)-induced cardiotoxicity (DIC) and the underlying molecular mechanisms remain poorly understood. To investigate the functional role of TRIM52, we employed an adeno-associated virus serotype 9 (AAV9) delivery system to achieve cardiac-specific Trim52 knockout via tail-vein injection. C57BL/6 mice received intraperitoneal DOX (5 mg/kg, administered once a week, with a total cumulative dose of 15 mg/kg). Myocardial injury was evaluated by histopathological assessment and molecular profiling of cardiac tissues, complemented by in vitro mechanistic studies using neonatal mouse cardiomyocytes. In vivo and in vitro studies revealed that DOX treatment significantly upregulated TRIM52 expression. Trim52 deficiency effectively mitigated DOX-induced cardiac injury and dysfunction, concomitantly attenuating oxidative stress and inflammatory responses. Mechanistically, Trim52 deletion markedly enhanced PI3K and AKT phosphorylation, indicating that PI3K/AKT pathway activation underlies the cardioprotective effects of TRIM52 deficiency. Our findings demonstrate that TRIM52 deletion activates PI3K/AKT signalling and attenuates DOX-induced oxidative and inflammatory myocardial damage. These data identify TRIM52 as a potential therapeutic target for mitigating DIC.

Bone marrow-derived mesenchymal stem cells (BMSCs) are extensively utilised in tissue engineering and regenerative medicine due to their multipotent differentiation capabilities. However, the therapeutic efficacy of BMSCs is highly dependent on the transplantation route. This study aimed to compare the efficacy of commonly used BMSCs transplantation methods and identify the optimal delivery approach for cartilage repair. Our results demonstrated that all transplantation methods could significantly suppress pro-inflammatory factors, including IL-1β, iNOS, and MMP-9, while enhancing the activity of the key antioxidant enzyme superoxide dismutase (SOD). The intra-articular injection group exhibited the most substantial anti-inflammatory and antioxidant improvements. In vivo tracking experiments revealed that BMSCs from all groups were capable of homing to the cartilage defect site at 4 weeks post-modelling. Notably, the intra-articular injection group recruited the highest number of BMSCs to the defect area. Further histological analysis indicated that the joints treated with intra-articular injection displayed superior cartilage regeneration, characterised by a smooth tissue surface and coloration closely resembling adjacent native cartilage. In conclusion, while all tested BMSCs transplantation approaches contributed to cartilage repair, intra-articular injection demonstrated the most favourable therapeutic outcomes.

Glanzmann thrombasthenia (GT) is an inherited hemorrhagic disorder characterised by impaired platelet functions, manifested clinically as spontaneous bleeding. It is usually inherited in an autosomal recessive manner. Platelet dysfunction in patients with GT is caused by quantitative and/or qualitative deficiencies in αIIbβ3, which result from mutations in the genes encoding αIIbβ3. These genetic alterations lead to platelet dysfunction characterised by impaired fibrinogen binding capacity upon agonist stimulation, defective aggregation and spreading. While classical GT typically exhibits normal platelet counts and morphology, very rare mutations in ITGA2B (encoding αIIb) and/or ITGB3 (encoding β3) cause macrothrombocytopenia or increased platelet anisotropy (heterogeneity of platelet size and morphology). This type of mutation mainly localises in the membrane-proximal region of αIIbβ3 and is inherited in an autosomal dominant manner. This particular type of disorder is called ITGA2B/ITGB3-related macrothrombocytopenia and has been considered a subset of congenital macrothrombocytopenia. Current research suggests that gain-of-function mutations in ITGA2B or ITGB3 underlie the pathogenesis of most ITGA2B/ITGB3-related macrothrombocytopenia and mechanistically distinguish it from classical GT. However, recent reports have documented non-activating ITGB3 mutations that also cause macrothrombocytopenia, presenting a profound challenge to the mechanistic understanding of ITGA2B/ITGB3-related macrothrombocytopenia. This review summarises the reported cases of gain-of-function mutations in ITGA2B and ITGB3 associated with ITGA2B/ITGB3-related macrothrombocytopenia hitherto and discusses the potential molecular pathways contributing to the unique phenotypes in ITGA2B/ITGB3-related macrothrombocytopenia.

Hepatitis B and C viruses (HBV and HCV) remain among the leading causes of liver disease worldwide. Current antiviral drugs, such as nucleotide analogues (NAs), can reduce the replication of new HBV and HCV infections but cannot completely eliminate chronic infections. This is primarily because a stable form of viral DNA, known as covalently closed circular DNA (cccDNA), persists in liver cells and continues to sustain the infection. In recent years, the CRISPR/Cas9 gene-editing system has emerged as a powerful tool for precisely cutting and inactivating specific DNA sequences. Due to its efficiency and ease of use, researchers have applied CRISPR/Cas9 in numerous studies to directly target and disrupt the HBV genome, demonstrating promising antiviral effects in both cell cultures and animal models. Targeting multiple sites within the HBV genome has been shown to further enhance its effectiveness, paving the way for potential combination therapies aimed at disabling both cccDNA and HBV and HCV DNA integrated into the host genome. Despite its potential, CRISPR/Cas9 still faces significant challenges before clinical application, most notably the risk of off-target effects—unintended cleavage of non-target DNA sequences—and the difficulty of delivering the system efficiently into liver cells in vivo. Future progress will depend on improving the tool's precision, efficiency, flexibility and delivery methods. In this review, we explore recent advances in designing guide RNAs (gRNAs) for targeting HBV and HCV, as well as the delivery systems used to transport CRISPR/Cas9 into cells. We also discuss the remaining challenges and potential strategies for advancing CRISPR/Cas9 from the laboratory toward a viable clinical cure for HBV and HCV.

This study investigated the potential causal relationship between gut microbiota (GM) and sleep apnoea using Mendelian randomisation (MR) analysis. Summary-level genome-wide association (GWAS) data for 473 GM and sleep apnoea were obtained from the IEU Open GWAS database. A two-sample MR framework was applied to assess the potential causal effects of GM on sleep apnoea. The primary analysis was conducted using the inverse variance–weighted (IVW) method, complemented by MR-Egger regression, weighted median, weighted mode and simple mode approaches to ensure robustness. To further account for horizontal pleiotropy and weak instrument bias, Bayesian Weighted Mendelian Randomisation (BWMR) analysis was performed as a key sensitivity model. Sensitivity analyses, including heterogeneity tests and pleiotropy assessments, were conducted to evaluate the stability and reliability of the results. IVW identified 33 GM associated with sleep apnoea (p < 0.05); BWMR confirmed 24 with significant causal effects, including 10 showing negative (protective) and 14 showing positive (risk) associations. Sensitivity analyses supported robustness: MR-PRESSO indicated outlier signals in 3 GM, Cochran's Q detected heterogeneity in 5 GM, and MR-Egger intercept suggested directional pleiotropy in 3 GM; all remaining GM showed non-significant sensitivity metrics. Leave-one-out analyses showed no single SNP disproportionately influenced the estimates, reinforcing the stability of the findings. This MR study provides genetic evidence supporting a potential causal association between GM and sleep apnoea. These findings provide new insights that may inform future research and prevention strategies.

Between 50% and 80% of children diagnosed with Autism Spectrum Disorder (ASD) are estimated to experience sleep disturbances, highlighting the importance of exploring the role of the circadian clock in ASD development. Previous studies have identified a potential link between Bmal1 deficiency and ASD in mouse models. In this study, we first characterise the expression patterns of circadian proteins. Subsequent behavioural tests and western blot analyses revealed that mice exposed to valproic acid (VPA) displayed autistic-like behaviours, along with altered circadian protein expression and disruption in Wnt signalling protein levels. Further studies showed that Bmal1 knockout exacerbates these behavioural changes and further impaired Wnt signalling and downstream protein expression in VPA-exposed mice. Notably, treatment with the circadian biomarker melatonin reversed Wnt downregulation and improved the behaviour deficit in VPA-exposed mice. The therapeutic effect of melatonin appears to be mediated by its regulation of the Wnt/β-catenin signalling pathway, which is linked to Bmal1-mediated circadian dysfunction. Together, our findings provide experimental evidence supporting the role of circadian dysregulation in ASD pathogenesis, highlight the therapeutic potential of melatonin in VPA-exposed mice, and suggest that Bmal1 may act as a co-activator in the Wnt-β-catenin signalling pathway.

Acute myeloid leukaemia (AML) is a genetically heterogeneous malignancy associated with poor prognosis and limited treatment options. To identify molecular programs conserved across AML subtypes and perturbations, we analysed three RNA sequencing datasets that captured venetoclax treatment under metabolic stress and the knockdown of chromatin regulators (PSPC1, JMJD1C, and RUNX1). Differential expression analysis was performed using DESeq2, followed by functional enrichment and network analyses. An independent AML cell line dataset was used to validate results. We identified a conserved 73-gene transcriptional signature that is consistently dysregulated across perturbations, characterised by the overexpression of CDKN1A, PHGDH, and ALDH1L2, and the downregulation of MYC and E2F targets. Functional analyses implicated cell cycle arrest, metabolic reprogramming, oxidative stress responses, and suppression of proliferative and biosynthetic pathways. PSPC1 emerged as a central hub linking chromatin remodelling to metabolic adaptation. Translational validation in the TCGA-LAML cohort revealed that higher 73-gene enrichment scores were associated with inferior overall survival, and stratification by hub gene expression recapitulated adverse prognostic trends. Collectively, these findings define a stress-adaptive transcriptional program conserved across diverse AML perturbations, providing mechanistic insights into the coupling of metabolism and the cell cycle, and potential therapeutic vulnerabilities. Incorporation of this 73-gene program into patient stratification frameworks may guide biomarker-driven therapies and combination strategies targeting metabolic and apoptotic stress responses.

Familial hypercholesterolemia (FH) is a genetic disorder characterised by elevated plasma LDL-cholesterol, predisposing to premature atherosclerotic cardiovascular disease. Most cases follow an autosomal dominant pattern (ADH) caused by pathogenic variants in LDLR, APOB or PCSK9. In contrast, the rare autosomal recessive form (ARH) results from biallelic mutations in LDLRAP1, leading to defective LDL receptor-mediated endocytosis. Despite the high rate of consanguinity in Tunisia, LDLRAP1 variants have not yet been reported in this population. In this study, Whole Exome Sequencing of two consanguineous Tunisian families, identified distinct pathogenic variants. In the first family (FH-A), a recurrent LDLR splice-site variant (c.1845+1G>A) was detected in both heterozygous and homozygous states, consistent with an autosomal dominant inheritance pattern. In the second family (FH-B), a novel homozygous LDLRAP1 missense variant (c.161G>A; p.Gly54Asp) was identified, confirming autosomal recessive inheritance. In silico analyses using MutationTaster, DynaMut2, MUpro, DDGun, NetSurfP-2.0, ConSurf and PyMOL predicted that the p.Gly54Asp substitution destabilises the PTB domain of LDLRAP1 by disrupting key hydrogen bonds and hydrophobic interactions, thereby likely impairing LDLR internalisation. According to ACMG guidelines, this variant is classified as likely pathogenic. Clinically, ARH patients exhibited early-onset xanthomas and an unusual quadricuspid aortic valve (QAV). Targeted analysis of valvulogenesis genes (NOTCH1, GATA4, NKX2-5, TBX5, AGTR1, BMP2) revealed no co-segregating pathogenic variants, suggesting that QAV may result from embryonic LDL accumulation disrupting Notch1 signalling rather than a monogenic defect. Comparison with other ADH Tunisian families carrying the same LDLR mutation showed phenotypic variability, likely influenced by genetic modifiers, treatment response and environmental factors. These findings provide the first evidence of LDLRAP1-associated ARH in Tunisia and highlight the genetic heterogeneity of FH, emphasising the importance of integrating molecular, structural and functional analyses for accurate diagnosis, personalised management and early prevention.