Aim: Skeletal muscle unloading leads to the upregulation of proteolytic gene expression, downregulation of protein synthesis markers, and the development of muscle atrophy. These changes are accompanied by alterations in calcium signaling. We investigated the role of Inositol 1,4,5-triphosphate (IP3) receptors (IP3Rs) in regulating calcium signaling and controlling gene expression in skeletal muscles during unloading.
Methods: Male Wistar rats were randomly assigned to 4 groups (n = 8 per group). C - vivarium control; C+2APB - vivarium control with daily intraperitoneal injections of the IP3 receptor inhibitor 2-aminoethoxydiphenyl borate
Results: Three days of unloading resulted in a significant increase in nuclear phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMK II) content and calcineurin (CaN) expression compared to the C group (P < 0.05); this effect was prevented in the HU+2APB group. In HU+2APB rats, the decline in soleus muscle weight-to-body weight ratio was partially prevented, and the downregulation of protein synthesis markers (as seen in the HU group) was also prevented. However, proteolytic signaling markers were equally upregulated in the HU+2APB and HU groups compared to C.
Conclusion: IP3 receptor inhibition during 3-day hind limb suspension in rats partially prevented the decline in
The study by Li et al., “Single-cell transcriptome analysis reveals the association between histone lactylation and cisplatin resistance in bladder cancer”, investigated how histone lactylation contributes to cisplatin resistance in bladder cancer (BCa). Using high-resolution single-cell lineage tracing, the authors identified a distinct subpopulation of BCa cells with enhanced glycolytic metabolism that exhibited significant cisplatin resistance. Further analyses showed significant enrichment of histone H3 lysine 18 lactylation (H3K18la) at the promoter regions of the transcription factors YY1 and YBX1, which promoted their expression and facilitated the development of a drug-resistant phenotype. This study was the first to combine single-cell omics with lactylation modification mechanisms, providing new insights into strategies for overcoming cisplatin resistance in BCa. Nonetheless, potential limitations of the study should be carefully considered.
This study, “Alveolar fibroblast lineage orchestrates lung inflammation and fibrosis”, provides important new insights into the varied functions of alveolar fibroblasts. It highlights their key involvement in maintaining the stability of pulmonary alveoli and in regulating the prolonged tissue response to injury. Using a Scube2-creER system, the investigators achieved precise labeling of alveolar fibroblasts, thereby overcoming the limitations of previous methodologies that lacked the specificity to distinguish fibroblast subpopulations in different anatomical niches. By integrating lineage tracing, single-cell RNA sequencing, and targeted functional ablation assays, the study delineated the transition of inflammatory fibroblasts into a pro-fibrotic phenotype. These approaches further revealed the pivotal role of TGFβ in driving this fibrogenic conversion. This commentary will critically analyze these findings, discuss their significance, and explore future prospects.
Spinal muscular atrophy (SMA) is a progressive neuromuscular degenerative disorder caused by mutations in the survival motor neuron 1 (SMN1) gene, leading to insufficient production of the survival motor neuron (SMN) protein. The nearly identical SMN2 gene modifies disease severity but generates only limited amounts of functional SMN protein due to a C-to-T transition in exon 7 that disrupts proper splicing. This review summarizes advances in understanding SMN2 splicing regulation and post-transcriptional modification in SMA pathogenesis. It discusses the roles of cis- and trans-acting elements in exon 7 inclusion, as well as the impact of epigenetic mechanisms such as histone acetylation and DNA methylation on SMN2 expression. This review also examines available therapeutic strategies, including antisense oligonucleotides (Nusinersen), small-molecule splicing modulators (Risdiplam and Branaplam), and gene therapy (Onasemnogene abeparvovec). Emerging approaches such as CRISPR/Cas9 genome editing and nanotechnology-based delivery systems are also highlighted. In addition, this review explores translational research using animal models, iPSC-derived neurons, and multi-omics approaches. Finally, it emphasizes the need for integrated therapeutic strategies that address both SMN-dependent and -independent pathways to improve treatment outcomes.
The SLC6A4 gene, which encodes the serotonin (5-hydroxytryptamine; 5-HT) transporter, plays an important role in the pathogenesis of mental disorders by regulating serotonin reuptake in the synaptic cleft. This review summarizes current evidence on the associations of SLC6A4 polymorphisms, epigenetic modifications, and neuroimaging findings with schizophrenia (SCZ), major depressive disorder (MDD), bipolar disorder (BD), and other psychiatric conditions. Studies have shown that the impact of SLC6A4 polymorphisms varies across ethnic groups and populations. Epigenetic studies indicate that DNA methylation in the promoter and exon regions of SLC6A4 can inhibit gene expression and exacerbate imbalances in the 5-HT signaling pathway, which are closely related to negative symptoms in SCZ, childhood trauma, and gender-specific risks for MDD. Neuroimaging evidence further suggests that SLC6A4 polymorphisms and methylation status are significantly associated with brain structural and functional abnormalities, pointing to a multidimensional mechanism involving ontogeny, epigenetics, and neural networks. Moreover, alterations in SLC6A4 have also been implicated in BD and attention-deficit/hyperactivity disorder. Despite significant progress, challenges remain, including ethnic biases in study populations, discrepancies between epigenetic patterns in peripheral and central nervous systems, and unclear mechanisms underlying gene-environment interactions. Future research should integrate multi-omics approaches, large cross-ethnic cohorts, and gender-stratified analyses to elucidate the precise regulatory network of SLC6A4 in mental disorders.
Background: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by joint destruction and functional impairment. Tumor Necrosis Factor inhibitors (TNFi) are widely used biologic therapies for RA; however, patient outcomes show significant individual variation. Genetic factors, including polymorphisms in the PTPRC gene, have been investigated as potential predictors of TNFi efficacy, but results remain inconsistent.
Methods: We conducted a systematic review and meta-analysis following PRISMA guidelines to evaluate the association between PTPRC polymorphisms and TNFi treatment response in RA patients. A comprehensive search was performed in PubMed and Scopus databases up to April 2025. Studies were screened and quality assessed using the Q-Genie tool. Meta-analyses employed Mantel-Haenszel methods with fixed and random effects models.
Results: Five studies met eligibility criteria, including data from 12 European cohorts totaling 1,543 RA patients. The main polymorphism assessed was rs10919563. Meta-analysis revealed the rs10919563 A allele was significantly associated with increased odds of non-response to TNFi (allelic model OR: 1.94; 95%CI: 1.31-2.88). The recessive models supported these findings, and no publication bias was detected.
Conclusions: Our results consolidate evidence supporting the PTPRC rs10919563 polymorphism as a potential predictive genetic biomarker for TNFi efficacy in RA, which could be integrated into personalized treatment strategies. Further studies are required to validate clinical utility across diverse populations.
Duchenne muscular dystrophy (DMD) is an X-linked, progressive muscle disorder caused by pathogenic variants in the DMD gene and resulting in a complete loss of dystrophin protein expression. As of now, there is no cure for DMD, and despite improvements in standard of care, there are significant unmet needs for disease modifying treatments. This article provides an overview of emerging therapies aimed at dystrophin restoration, emphasizing exon skipping and gene therapy, within the rapidly evolving landscape for Duchenne muscular dystrophy.
Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have transformed the therapeutic landscape of non-small cell lung cancer (NSCLC), producing durable responses in a subset of patients. Yet for most, clinical benefit is undermined by the development of acquired resistance (AR), a phenomenon that continues to limit the long-term success of immunotherapy. Recent analyses have drawn attention to persistent interferon-γ (IFN-γ) signaling as a paradoxical hallmark of AR: a cytokine typically associated with effective antitumor immunity that, when chronically engaged, sustains immune dysfunction. In this commentary, we synthesize existing literature to expand upon this model. We review molecular and cellular mechanisms by which chronic IFN-γ drives resistance through the signal transducer and activator of transcription 1 (STAT1)/interferon regulatory factor 1 (IRF1) axis, epigenetic stabilization of exhaustion, antigen-presentation loss, and metabolic suppression. We extend the discussion to innate immunity, bystander T-cell responses, and stromal regulation, emphasizing spatial heterogeneity as a critical mediator of IFN-γ biology. Finally, we explore translational strategies - including rational checkpoint combinations, radiotherapy-immunotherapy sequencing, epigenetic modulation, and innate immune engagement - that may reprogram IFN-γ-permissive resistance states. We argue that IFN-γ persistence should not be viewed as an isolated mechanism but as a central hub in a broader resistance network, and we propose a phenotype-guided framework for therapeutic intervention in AR NSCLC.