High-fat diets (HFD) are implicated in metabolic disorders through mechanisms involving hyperuricemia, gut dysbiosis, and intestinal barrier dysfunction. This study investigated the effects of pharmacological uric acid reduction on gut homeostasis in HFD-fed mice. We assessed serum uric acid, gut microbial composition, pro- and anti-inflammatory cytokine expression, intestinal barrier dysfunction markers, and tryptophan metabolism in mice subjected to HFD with or without allopurinol treatment. AhR antagonist CH-223191 was used to provide functional evidence for the role of AhR activation in mediating the observed effects. HFD induced hyperuricemia, microbial dysbiosis characterized by increased Proteobacteria and altered Firmicutes/Bacteroidetes ratios, and elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). These changes correlated with decreased IL-10 and IL-22, increased serum LPS, and systemic inflammation (IL-6, CRP). Allopurinol treatment normalized uric acid levels, restored microbial balance, reduced gut and systemic inflammation, improved intestinal barrier function, and modulated tryptophan metabolism by decreasing IDO1 activity and restoring indole production. Pharmacological blockade of AhR with CH-223191 reversed the anti-inflammatory and barrier-protective effects of allopurinol treatment, providing functional evidence for the role of AhR/IL22 axis in mediating gut protection. Targeting hyperuricemia effectively reverses HFD-induced gut dysbiosis, inflammation, and barrier dysfunction through metabolite-mediated immunoregulatory mechanisms involving the AhR–IL-22 axis. These findings propose uric acid modulation as a promising therapeutic strategy for metabolic and inflammatory gut diseases. HFD causes hyperuricemia, gut dysbiosis, and increased gut inflammation. Allopurinol lowers uric acid and restores gut microbial balance in HFD mice. Allopurinol reduces inflammation and ameliorates intestinal barrier dysfunction. Uric acid reduction shifts tryptophan metabolism to protective indole production. AhR activation is required for allopurinol's gut protection.
Neutrophil extracellular traps (NETs), web-like DNA structures released by neutrophils, were initially recognized as key components of the anti-infective immune response but are now implicated in tumor progression. Tumor cells orchestrate the reprogramming of tumor-associated neutrophils (TANs) and trigger NET formation through paracrine signaling, thereby establishing a "tumor cell-TAN-NETs" positive feedback loop. This axis serves not only as a key hub for awakening dormant tumor foci and mediating immune evasion, but also as a core mechanism driving distant metastasis and dictating poor clinical prognosis. Notably, targeted disruption of this axis effectively reverses tumor therapy resistance and significantly sensitizes tumors to radiotherapy, chemotherapy, and immune checkpoint blockade, establishing NETs as novel therapeutic targets poised to overcome the current bottlenecks in cancer treatment. Nevertheless, limitations in detection technologies, prognostic modeling challenges, tumor heterogeneity, and inconsistent research findings constrain clinical translation. Future studies should prioritize optimizing detection methods, conducting rigorous clinical validation, and identifying specific therapeutic targets to accelerate the translational progress of NETs from basic research to clinical practice. This review synthesizes current knowledge on the biological mechanisms, regulatory pathways, and detection approaches of NETs, providing a theoretical basis for their clinical application in precision oncology.
Ankylosing spondylitis (AS) is an inflammatory disease marked by aberrant new bone formation and spinal ankylosis. Transforming growth factor-β1 (TGFβ1) is implicated in osteogenesis, yet its downstream effectors in AS remain unclear. Osteonectin, a glycoprotein secreted by osteoblasts, plays a critical role in bone formation with TGFβ1, but has not been studied in AS. This study aimed to investigate the TGFβ1-osteonectin mediated regulation of osteogenic activity in AS. Serum levels of TGFβ1, osteonectin, and osteocalcin were measured in AS patients and healthy controls. Measured these serum levels were compared with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Enthesis cells isolated from AS spinal tissues were stimulated with recombinant TGFβ1 in vitro. Proliferation, matrix production, migration, and clonogenicity were evaluated. Immunohistochemical staining of spinal tissues was performed to assess osteonectin expression. AS patients showed significantly elevated serum levels of TGFβ1 and osteonectin compared to healthy controls. Osteonectin expression, but not osteocalcin, was significantly correlated with serum level of TGFβ1. TGFβ1 stimulation enhanced proliferation, collagen deposition, migratory capacity, and colony formation in enthesis cells derived from AS patients. Immunohistochemistry revealed increase of osteonectin expression in periosteal regions of AS tissues. These findings suggest that osteonectin is a TGFβ1-responsive effector involved in early osteoprogenitor activation and may contribute to pathological bone formation in AS. Osteonectin represents a potential biomarker and therapeutic target for early structural progression in AS.
Cardiometabolic diseases remain a major global health burden, and current therapies only partially address the persistent residual risk driven by chronic inflammation, hypoxia, metabolic overload, and mechanical stress. A critical need is to understand how these diverse stress signals are integrated at the cellular and molecular levels to determine whether tissues adapt or undergo pathological remodeling. This review presents a comprehensive framework of kinase-microRNA (miRNA) crosstalk as an emerging regulatory axis in cardiometabolic disease. We discuss how stress-activated kinase pathways, including ERK, p38/JNK, PI3K-Akt-mTOR/S6K2, AMPK, GSK-3, and EGFR, reprogram miRNA output through phosphorylation of key components of the miRNA machinery, including DROSHA/DGCR8, DICER-TRBP, and AGO2. These phosphorylation-dependent mechanisms influence miRNA processing, substrate selection, RISC assembly, and target repression in a context-dependent manner. We further highlight the reciprocal regulation whereby miRNAs modulate kinase signaling pathways, establishing feedback networks that regulate inflammation, apoptosis, fibrosis, angiogenesis, and metabolic adaptation across cardiac, vascular, and immune cells. Emerging technologies, including AGO2 eCLIP, phosphoproteomics, CRISPR-based perturbations, and single-cell/spatial profiling, allow causal mapping of kinase-miRNA networks. Collectively, these advances establish kinase-miRNA crosstalk as a promising mechanistic framework and therapeutic target for precision intervention in heart failure, atherosclerosis, diabetic cardiomyopathy, and related cardiometabolic diseases.
Mechanosensitive Piezo2 channels play a critical role in bladder pressure perception and may contribute to bladder fibrosis in patients with neurogenic bladder (NB), a condition that significantly affects quality of life. This study aimed to investigate the expression of Piezo2 and its role in bladder fibrosis using both human and animal models. Bladder tissue samples were obtained from children with NB undergoing ileocystoplasty, along with normal tissues from control subjects. An NB model was established in juvenile Sprague-Dawley rats through spinal nerve transection. Transcriptome analysis revealed the activation of pathways associated with mechanical stimulation, nuclear factor kappa-B (NF-κB) signaling, and epithelial-mesenchymal transition (EMT) in the context of NB. The results indicated that elevated Piezo2 levels were correlated with increased bladder pressure and fibrosis. Cystometry tests demonstrated significant increases in bladder pressure at week 2, followed by slight decreases, although pressure levels remained elevated compared to controls. Stretching experiments conducted on SV-HUC-1 cells showed that Piezo2 activation exacerbated fibrosis through the Ca²⁺/NF-κB/EMT axis, while the use of Piezo2 siRNA mitigated this effect. These findings suggest that Piezo2 channels, activated by increased pressure, accelerate bladder fibrosis via the Ca²⁺/NF-κB/EMT pathway, indicating that Piezo2 inhibition may serve as a potential therapeutic strategy to prevent fibrosis in NB. Piezo2 expression is significantly increased in bladder tissues of patients and animal models with neurogenic bladder (NB). Elevated Piezo2 levels are positively correlated with increased bladder pressure and the severity of fibrosis. Inhibition of Piezo2 using siRNA reduces fibrosis in bladder epithelial cells subjected to mechanical stretching. Piezo2 channels may promote bladder fibrosis progression via the Ca2+/NF-κB/EMT signaling pathways. Targeting Piezo2 could represent a potential therapeutic approach to prevent fibrosis in neurogenic bladder.
Cytomegalovirus (CMV) reactivation is a frequent complication after allogeneic hematopoietic stem cell transplantation (aHSCT) and critically shapes immune reconstitution. However, the clonal and functional dynamics of T cell responses to CMV remain insufficiently defined. In this study, we combined longitudinal single-cell RNA sequencing with paired T cell receptor sequencing to track γδ and αβ T cell clones at clonal resolution across five post-transplant time points in patients with and without CMV reactivation. This integrative approach revealed marked, patient-specific expansion of non-Vγ9Vδ2 γδ T cell clones, particularly within Vδ1⁺ and Vδ3⁺ subsets, which was associated with differentiation toward cytotoxic and antiviral effector states characterized by IFN-γ and TNF-α expression. Conventional CD8⁺ αβ T cells showed comparatively modest clonal dynamics during CMV reactivation in this cohort. Longitudinal tracking of individual clonotypes demonstrated heterogeneous but recurrent trajectories, with expanding γδ T cell clones frequently acquiring antiviral and cytotoxic phenotypes following CMV reactivation. These findings highlight the adaptive-like behavior and functional plasticity of non-Vγ9Vδ2 γδ T cells and provide a high-resolution framework for studying antiviral immune responses during immune reconstitution.
Glioblastoma (GBM) remains resistant to therapy due to cellular heterogeneity and adaptive stress responses, yet the role of tumor-intrinsic Toll-like receptor 4 (TLR4) signaling in this process remains unresolved. This review addresses a central inconsistency in the field by defining tumor-intrinsic TLR4 as a context-dependent signaling rheostat that generates distinct biological outcomes rather than a uniform tumor-promoting pathway. Across experimental systems, TLR4 signaling produces divergent effects that range from mesenchymal transition, invasion, and adaptive survival under chronic or therapy-associated conditions, to differentiation, apoptosis, and increased treatment sensitivity under specific cellular and temporal contexts. These opposing outputs are not contradictory but arise from defined determinants, including ligand environment, signaling dynamics, tumor cell state, and metabolic conditions. This framework explains previously discordant findings and establishes that the functional role of tumor-intrinsic TLR4 cannot be inferred from receptor activation alone. Instead, its impact is conditional and state-dependent. This perspective defines a clear experimental and translational priority: to identify the contexts in which tumor-intrinsic TLR4 signaling sustains tumor persistence versus exposes therapeutic vulnerability, thereby enabling rational and stratified intervention strategies in GBM.
Under conditions of iron overload, increased non-transferrin-bound iron (NTBI) can gain access to cardiomyocytes, cause cardiac iron accumulation and generate reactive oxygen species which can result in iron-overload cardiomyopathy. Currently, it is not fully understood how cardiomyocytes take up NTBI under iron-overload conditions. However, the large number of studies conducted over the past few decades have greatly improved our understanding of this critical issue in the field of heart disease, but so far there has been no effort to synthesize these studies and isolated ideas into a systematic and coherent summary. Herein, we focus on up-to-date advances in studies on the routes for cardiomyocytes to uptake NTBI, including L-type Ca2 + channels (LTCC), T-type Ca2 + channels (TTCC), divalent metal transporter 1 (DMT1), the Lipocalin-2 (LCN-2) / Lipocalin-2 receptor (LCN-2R) system and ZIP14 (SLC39A14). We also offer suggestions for addressing some critical gaps still extant in our understanding of this important topic.
Wnt signaling inhibitors are under investigation as potential therapies for conditions characterized by upregulated Wnt signaling, such as cancers, hematological disorders, and organ fibrosis. However, because the Wnt pathway is essential for bone homeostasis, its inhibition can adversely affect skeletal health. This review focuses on the bone-related off-target effects of Wnt inhibitors currently in clinical development, specifically those evaluated in Phase I and II trials with available published data. We found that inhibitors targeting upstream components of the pathway—such as Wnt ligands or receptors (e.g., porcupine inhibitors, Ipafricept, or Vantictumab)—frequently lead to bone-related adverse effects, including fractures and early trial termination. Co-administration of bisphosphonates may help mitigate these effects. In contrast, downstream inhibitors (e.g., PRI-724, niclosamide) have not been linked to bone toxicity, although this may reflect either underreporting or a genuinely lower skeletal impact. Further preclinical studies are warranted to better understand these differential effects. A thorough understanding of bone-specific risks is critical as Wnt signaling inhibitors continue to advance in clinical development.
Guillain-Barré syndrome (GBS) is an acute immune-mediated neuropathy triggered by infections, with poorly understood pathophysiological diversity. COVID-19-associated GBS (COVID-GBS) is a rare but severe post-infectious condition, and its immune mechanisms remain unclear. We profiled immune mediators in cerebrospinal fluid (CSF) and serum from COVID-GBS patients, comparing them to non-COVID GBS (Control-GBS), COVID-19 patients without neurological complications (COVID-no-GBS) and non-inflammatory neuropathy controls (Neuropathy-no-GBS). To gain mechanistic insights, we integrated publicly available single-nucleus transcriptomic data from sural nerve biopsies of neuropathy patients. IL-8 was confirmed as a key cytokine in GBS. Analysis of publicly available single-nucleus transcriptomic data from non-GBS sural nerve biopsies suggested myeloid cells as potential sources of IL-8, with evidence of autocrine signaling capacity. LIF and CD8A emerged as novel biomarkers, with this transcriptomic analysis indicating that LIF receptor components are expressed on endothelial and stromal cells, suggesting these as potential cellular targets. COVID-GBS patients exhibited unique CSF alterations and distinct serum profiles marked by altered NK cell activity, cytotoxic T-cell responses, and myeloid differentiation. Moreover, associations between inflammatory, extracellular matrix, and regulatory markers with clinical disability differed between COVID-GBS and Control-GBS, pointing to divergent immune mechanisms. Our findings suggest that GBS involves myeloid-driven cytokine responses and local LIF signaling. Analysis of publicly available transcriptomic data from non-GBS sural nerve biopsies suggests potential cellular sources and targets, though validation in GBS-affected tissue is needed. COVID-GBS features a distinct immune signature involving localized and systemic inflammation. These insights deepen our understanding of GBS pathogenesis and nominate candidate biomarkers for further validation and potential therapeutic targeting. CSF proteomics confirm elevated IL-8 and newly identify increased leukemia inhibitory factor (LIF) in Guillain-Barré Syndrome (GBS). Integration of public transcriptomic nerve biopsy data sets suggests myeloid cells as source of IL-8 and maps LIF receptor (LIFR) to nerve endothelial cells. COVID-associated GBS has a distinct immune profile compared to pre-pandemic GBS. Serum proteins OPG and MMP-10 correlate with clinical disability in COVID-associated GBS.
Autosomal dominant hearing loss (ADHL) is a highly heterogeneous Mendelian disorder with numerous causative genes, yet large well-characterized European cohorts remain limited. We investigated 108 families of Polish origin with confirmed dominant inheritance using a tiered strategy integrating targeted sequencing of 237 hearing loss genes, genome-wide linkage analysis, genome sequencing, segregation studies in 437 individuals, and functional validation by minigene splicing assays. This approach established a molecular diagnosis in 52
Heart failure (HF) affects over 64 million people worldwide causally linked to fibrotic scarring. None of the available cardiac drugs target fibrosis directly, underlining unmet clinical need for novel therapies. This study aimed to explore the therapeutic potential of the cysteine protease inhibitor aloxistatin as a repurposed drug candidate to combat fibrotic progression in predictive HF models. Aloxistatin reduced migratory and proliferative capacities of human cardiac fibroblasts (HCFs) derived from various HF backgrounds. Mechanistically, aloxistatin attenuated TGFβ1-induced pro-fibrotic signaling in cardiomyopathy-derived HCFs by inhibiting extracellular matrix organization-related gene expression and secretion of MMP2 und FN1, partially mediated through CAPN2 inhibition. Transcriptomic analysis of rat ex vivo myocardial slices revealed a pronounced suppression of inflammatory pathways. Anti-inflammatory effects of aloxistatin were further confirmed by reduced NFκB activity in reporter cells and inhibited HLA-DR expression in human iPSC-derived macrophages. Application of diverse preclinical cardiac HF models arguably underlined aloxistatin as a potential drug repurposing strategy by simultaneously counteracting myocardial inflammatory signaling and pro-fibrotic mechanisms. This preclinical study suggests aloxistatin therapy for translational use to attenuate cardiac remodeling and progression of heart failure.
Aortic dissection (AD) is a life-threatening vascular emergency characterized by medial degeneration and vascular smooth muscle cell (VSMC) loss. Although disruption of zinc homeostasis has been reported in patients with AD, how zinc ions and their regulatory proteins influence VSMC survival and disease progression remains unknown. In this study, single-cell analyses revealed that ferroptosis and zinc-related pathways were significantly enriched in VSMCs from patients with AD, showing a strong correlation between the two processes, and zinc levels were markedly elevated in dissected aortas. Furthermore, zinc exposure promoted ferroptosis in cultured primary human aortic smooth muscle cells (HASMCs). By integrating transcriptomic data from AD tissues and VSMC ferroptosis models, metallothionein-3 (MT3), a zinc-binding protein, was identified as a candidate regulator. Functional studies demonstrated that MT3 overexpression markedly attenuated lipid peroxidation, reduced reactive oxygen species accumulation, and protected VSMCs from ferroptotic cell death, whereas MT3 knockdown increased oxidative stress and exacerbated ferroptotic injury. Mechanistically, MT3 directly interacted with glutathione peroxidase 4 (GPX4), enhanced its protein stability, without altering its transcriptional expression, and promoted glutathione synthesis, thereby activating the glutathione-GPX4 antioxidant defense pathway and mitigating oxidative injury. Notably, restoration of GPX4 effectively rescued the pro-ferroptotic effects of MT3 deficiency on HASMCs. These findings establish a previously unrecognized zinc-MT3-GPX4 axis as a critical determinant of VSMC ferroptosis in AD, linking zinc dysregulation to medial degeneration, and highlighting MT3 as a potential mechanistic candidate target to preserve vascular integrity and limit disease progression.Key MessagesImpaired zinc homeostasis is implicated in the development of aortic dissection (AD).Zinc-binding protein metallothionein 3 (MT3) mitigates lipid peroxidation and protects vascular smooth muscle cells from ferroptosis.MT3 directly interacts with glutathione peroxidase 4 (GPX4) to prevent its lysosomal degradation, thereby enhancing the glutathione-GPX4 antioxidant defense pathway.MT3 is a potential mechanistic candidate target for preserving vascular integrity and limiting AD progression.
Accurate diagnosis of central nervous system lymphoma (CNSL) remains challenging, and cerebrospinal fluid (CSF) interleukin-10 (IL-10) has emerged as a promising minimally invasive biomarker. We conducted a PRISMA-DTA systematic review and diagnostic meta-analysis to evaluate the diagnostic performance of CSF IL-10 for CNSL and to examine its clinical utility and robustness using a reproducible Python-based workflow. Eleven studies comprising 1,462 participants (510 CNSL cases and 952 controls) met the inclusion criteria. Using a bivariate random-effects model, the pooled sensitivity and specificity were 79.8
Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is a master transcriptional coactivator responsible for regulating cellular energy metabolism and mitochondrial biogenesis across high-energy tissues such as the heart, skeletal muscle, and brown adipose tissue. To orchestrate its regulatory functions, PGC-1α interacts with a diverse array of transcription factors such as peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and nuclear respiratory factors (NRFs), which is facilitated by its dynamic three-dimensional structure, the presence of distinct functional domains, and the ability to be modulated via post-translational modifications. This review examines the protein’s interactions with key nuclear receptors and the biological consequences of these complexes, including the regulation of thermogenesis, gluconeogenesis, and fatty acid oxidation. Furthermore, we discuss the extensive post-translational modifications—including phosphorylation, acetylation, methylation, O-GlcNAcylation, and ubiquitination—that tightly regulate PGC-1α stability and coactivation efficiency. Finally, this review highlights recent progress in the identification of small molecule modulators, such as the activator ZLN005 and the inhibitor SR18292, evaluating their physiological outcomes and potential as therapeutic agents for metabolic disorders and cancer, while addressing the challenges posed by the protein’s structural disorder in drug discovery.
Inflammatory bowel disease (IBD) is consistently associated with an increased risk of venous thromboembolism, particularly during active disease and hospitalization, yet thrombosis in this context extends beyond a transient inflammatory complication. Emerging evidence supports a unifying thromboinflammatory framework in which chronic intestinal inflammation promotes systemic vascular activation. Endothelial dysfunction represents a central interface in this process and is characterized by reduced nitric oxide bioavailability, increased expression of adhesion molecules, angiogenic remodeling, and glycocalyx disruption, collectively shifting the vascular surface toward a proadhesive and procoagulant phenotype. In parallel, dysregulation of coagulation pathways sustains thrombin generation through enhanced tissue factor signaling, elevated procoagulant factors, most consistently factor VIII, impaired endogenous anticoagulant mechanisms including the protein C and antithrombin systems, and features of hypofibrinolysis. Platelet activation further amplifies these disturbances via CD40 ligand (CD40L)-mediated endothelial crosstalk, platelet leukocyte aggregate formation, and imbalance of the von Willebrand factor (VWF)-ADAMTS13 axis, reinforcing a self perpetuating loop between inflammation and coagulation. Although mechanistic plausibility is strong and multiple biomarkers of endothelial and hemostatic activation have been described, much of the current evidence derives from cross sectional or associative studies, with limited prospective validation linking individual pathways to incident thrombotic outcomes in IBD specific cohorts. Taken together, thrombosis in IBD reflects sustained systemic thromboinflammatory dysregulation rather than an isolated complication of flares. Future longitudinal studies integrating vascular biomarkers with adjudicated thrombotic events are essential to refine risk stratification and inform individualized thromboprophylaxis strategies.
Despite understanding the pathophysiology of Alzheimer's disease (AD), the mechanisms of neuronal regeneration mediated by oleanolic acid (OA) through m6A RNA methylation remain unexplored, forming the crux of this study. In a streptozotocin (STZ)-induced AD rat model, we administered OA and conducted behavioral tests to evaluate cognitive functions. We employed BrdU incorporation assays and immunofluorescence to investigate NSC proliferation, and Western blotting, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), and MeRIP-qPCR assays to analyze protein expression and RNA stability. Bioinformatic predictions focused on the interaction between KLF5, YTHDF2, and FGF13. OA significantly reversed cognitive impairment and enhanced NSC differentiation in the AD model. The modulation of OA on KLF5 expression led to the repression of YTHDF2, which was pivotal in the m6A-dependent RNA decay of FGF13, promoting axonal regeneration. Furthermore, FGF13 harbors multiple m6A modification sites, which contribute to its mRNA stability and translation, thereby influencing neuronal polarization and migration. In addition, the neuroprotective mechanism of OA also involved the upregulation of NSCs, while impaired neurogenesis and reduced NSC function are known to be associated with AD pathology. This research reveals that OA's therapeutic potential in AD is mediated through a previously unidentified mechanism involving modulation of m6A-dependent RNA regulation, highlighting the significance of m6A RNA methylation in neuronal regeneration. The findings pave the way for new therapeutic strategies targeting RNA modifications in neurodegenerative diseases.
Pancreatic β-cell differentiation and regenerative capacity differ markedly between developmental stages, with the neonatal pancreas exhibiting high plasticity that enables ongoing progenitor- and ductal-derived β-cell formation, whereas the adult pancreas demonstrates limited neogenic potential. Glucagon-like peptide-1 (GLP-1) promotes β-cell survival, proliferation, and differentiation; however, its developmental stage-specific effects on β-cell regeneration are not fully understood. To investigate this, we generated a third-generation HIV-based lentiviral vector encoding native GLP-1 (LentiGLP-1) under the control of cytomegalovirus (CMV) promoter using the Multisite Gateway® recombination cloning system. The vector’s ability to modulate β-cell differentiation and proliferation was subsequently assessed in neonatal and adult diabetic rat models. Type 2 Diabetes (T2DM) was induced in neonatal rats by administering low-dose streptozotocin (STZ), exploiting the intrinsic plasticity of the developing pancreas, whereas in adult rats, a high-fat diet combined with low-dose STZ was used. LentiGLP-1 administration markedly promoted differentiation of ductal and progenitor cells into insulin-producing β-cells in neonatal rats, accompanied by enhanced β-cell proliferation, demonstrating effective engagement of developmental plasticity. In adults, LentiGLP-1 partially restored β-cell populations through activation of residual progenitors and stimulation of replication in existing β-cells, improving glycemic control and insulin sensitivity. Notably, acinar cells did not contribute to β-cell generation in either neonatal or adult models. These results indicate that GLP-1 exerts developmentally regulated effects on β-cell differentiation, facilitating neogenesis in neonates and partially restoring regenerative capacity in adults. Long term GLP-1 expression, thus represents a promising strategy to restore β-cell mass by proliferation and differentiation, providing insight into its therapeutic potential for diabetes.
Systemic Sclerosis (SSc) is an idiopathic systemic autoimmune disease characterized by progressive cutaneous and systemic fibrosis, severe vasculopathy, and multiple humoral and cellular immunological alterations. The pathogenesis of SSc is highly complex and remains incompletely elucidated. The fibrotic process is a crucial component of SSc and is responsible for organ failure and high mortality. Although an increasing understanding of the fibrotic process has enabled the clinical development of antifibrotic therapeutic agents, these agents have limited clinical efficacy. Recently, the potential role of a group of transcription factors containing a High Mobility Group (HMG) motif, in the development and pathological manifestations of SSc has been postulated. HMG proteins (notably HMGB1 and SOX9) act as profibrotic and proinflammatory transcription factors; however, HMG proteins can also function as damage-associated molecular patterns, amplifying Toll-like receptors and RAGE signaling, promoting endothelial activation, leukocyte recruitment, and stimulating the production of profibrotic cytokines. This convergent role of HMG proteins across various aspects of SSc pathogenesis, including immune dysregulation, vasculopathy, and fibrosis, makes them among the most attractive novel regulators and a desirable therapeutic target for SSc. Here, we review the recent evidence on the role of HMG proteins in SSc pathogenesis and explore the potential role of inhibiting their function.
The present study investigates how Sirtuin 1 (SIRT1) regulates the worsening of calcium oxalate (CaOx) crystal-induced mitochondrial dysfunction and fibrosis in the kidneys with age. To establish a CaOx crystal deposition model, glyoxylic acid (Gly) was injected intraperitoneally into both young and aged mice. Additionally, an in vitro model was created by stimulating human renal tubular epithelial (HK2) cells with D-galactose (D-gal) and calcium oxalate monohydrate (COM). Lipid deposition, mitochondrial function, and fibrosis levels were assessed using various techniques, including western blotting (WB), polymerase chain reaction (PCR), immunohistochemistry, immunofluorescence, and specific staining methods. The effects on lipid deposition, mitochondrial function, and fibrosis were further analyzed by manipulating the expression of SIRT1 and peroxisome proliferator-activated receptor (PPAR-α), both in vitro and in vivo. Aging exacerbates the kidney mitochondrial dysfunction and fibrosis induced by CaOx crystals, with SIRT1 playing a crucial regulatory role in this process. SIRT1 regulates lipid metabolism via PPARα, intensifying the aging-related kidney mitochondrial damage and fibrosis induced by CaOx crystals.
