Advanced glycation end-products (AGEs) arise from non-enzymatic reactions between reducing sugars and proteins, contributing to oxidative stress and metabolic dysfunction. Excessive AGE accumulation is implicated in chronic diabetic complications and may also be relevant to acute metabolic disturbances encountered in emergency medicine. N-acetylcysteine (NAC), a naturally occurring antioxidant found in Allium species, has demonstrated potential to attenuate oxidative and glycation-mediated damage. The effect of NAC on d-ribose-induced glycation of bovine serum albumin (BSA) was investigated using multiple physicochemical and spectroscopic techniques. AGE formation was assessed by measuring hyperchromicity, early glycation products (ketoamines), carbonyl content, hydroxymethylfurfural (HMF) levels, and fluorescent AGEs. The protective effect of NAC was further evaluated by determining free lysine and arginine contents. Protein aggregation and conformational changes were analyzed using Congo Red binding and fluorescence assays including thioflavin-T and 1-anilinonaphthalene-8-sulfonic acid. NAC significantly inhibited d-ribose-mediated glycation of BSA in a concentration-dependent manner. Treatment with NAC resulted in reduced hyperchromicity, decreased ketoamine formation, and lower carbonyl, HMF, and fluorescent AGE levels. NAC preserved protein integrity by maintaining higher free lysine and arginine contents. In addition, NAC markedly attenuated glycation-induced protein aggregation, as evidenced by reduced Congo Red binding and diminished thioflavin-T and ANS fluorescence, with maximal protection observed at 300 μM. NAC exhibits pronounced anti-glycation and anti-aggregation effects by limiting oxidative stress and glycation-mediated protein modification. These findings demonstrate that NAC effectively attenuates d-ribose-induced glycation and protein aggregation in vitro and provide mechanistic insights into its anti-glycation properties through multiple complementary biochemical mechanisms. Further studies are warranted to evaluate its biological relevance in more complex experimental models.
FOXO6 is a member of the FOXO transcription factor family that differs from FOXO1, FOXO3, and FOXO4 in its nucleocytoplasmic regulation, remaining predominantly within the nucleus because it lacks a functional nuclear export sequence. FOXO6 activity can nevertheless be inhibited by insulin/AKT signaling, whereas impaired insulin signaling increases its transcriptional activity in hepatocytes under insulin-resistant and nutrient-rich conditions. Recent studies indicate that FOXO6 regulates hepatic metabolic pathways associated with oxidative injury, inflammatory signaling, and lipid accumulation. In hepatocellular carcinoma, increased FOXO6 expression is associated with glycolytic activity, proliferation, and invasion. We recently reported that FOXO6-dependent transcriptional regulation contributes to reactive oxygen species (ROS) production and inflammasome-associated inflammatory signaling through induction of thioredoxin-interacting protein (TXNIP). Furthermore, FOXO6 regulates lipid metabolic pathways through transcriptional activation of apolipoprotein C3 (ApoC3) and peroxisome proliferator-activated receptor (PPAR) γ together with suppression of PPARα, thereby promoting triglyceride accumulation, mitochondrial dysfunction, and lipotoxic injury in hepatocytes. These metabolic and inflammatory alterations contribute to hepatic steatosis, mitochondrial injury, and inflammatory hepatocellular damage. In hepatocellular carcinoma, increased FOXO6 expression is associated with glycolytic metabolism, angiogenic signaling, proliferative activity, immune suppression, and invasive phenotypes. FOXO6-dependent signaling interacts with STAT3, NF-κB, and β-catenin pathways involved in metabolic adaptation and tumor progression. Recent studies demonstrate relationships between increased FOXO6 expression, vascular invasion, aggressive tumor phenotypes, and reduced survival in hepatocellular carcinoma. This review examines FOXO6-associated transcriptional mechanisms involved in hepatic metabolic inflammation and hepatocarcinogenesis.
Aging is increasingly recognized as a systems-level process marked by progressive deterioration of mitochondrial performance in tissues with high energetic demand, placing skeletal muscle at the center of systemic metabolic and functional decline. Beyond its mechanical role, skeletal muscle acts as a regulatory hub for energy homeostasis, redox balance, and inter-organ signaling, functions that depend critically on effective mitochondrial quality control. Emerging evidence indicates that age-related mitochondrial dysfunction arises not only from impaired biogenesis but also from dysregulated mitophagy, the selective autophagic removal of damaged mitochondria. Mitophagy is now understood as a dynamic, context-sensitive process integrating metabolic state, mechanical loading, and cellular stress, rather than a binary response to severe mitochondrial damage. Exercise represents a uniquely potent, non-pharmacological modulator of this process. By transiently perturbing cellular energy balance, calcium flux, and redox signaling, physical activity activates coordinated mitophagic and biogenic programs that promote mitochondrial renewal without precipitating energetic collapse. In contrast to chronic pathological stressors, exercise induces pulsatile, recoverable mitochondrial challenges that recalibrate quality-control thresholds. Importantly, mitophagic responses to exercise are heterogeneous and nonlinear. Exercise modality, intensity, frequency, and temporal organization generate distinct mitochondrial signals, producing fiber-type-specific and age-dependent adaptations. In aging muscle, elevated activation thresholds, delayed clearance kinetics, and lysosomal constraints frequently blunt adaptive mitophagy, indicating remodeling rather than a simple suppression of quality-control logic. This review integrates molecular, physiological, and translational evidence to redefine exercise as a precision regulator of mitophagy in aging skeletal muscle. This review proposes that tailored exercise strategies targeting mitophagy may provide a scalable, non-pharmacological approach to preserve mitochondrial quality and functional resilience during aging.
Long non-coding RNAs (lncRNAs) are known to play a vital role in regulating tumorigenesis. Previous studies have shown that long non-coding RNA modulated by transforming growth factor-beta (lncRNA-ATB) is overexpressed in non-small-cell lung cancer (NSCLC); however, the underlying mechanism of lncRNA-ATB as an oncogenic regulator remains elusive. This study elucidates the effect of lncRNA-ATB on cell proliferation, migration, and invasion of NSCLC cell lines (A549 and H522) and triggers cellular immune responses. The tumor microenvironment was simulated in BALB/c mice, and the in vivo pro-tumor effect of lncRNA-ATB was discovered. This study further explores the molecular mechanisms of lncRNA-ATB-mediated effects. The interaction of lncRNA-ATB with insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) has been found, and IGF2BP2 can play a role in tumor immune cell infiltration and tumor cell proliferation by stabilizing lncRNA-ATB. In conclusion, lncRNA-ATB plays a complex regulatory role in the progression of NSCLC and may serve as a potential target for future treatment. This study provides valuable insights into the complex interactions of lncRNAs in the pathogenesis of NSCLC, and the robust methodology and comprehensive analysis presented in this study contribute to advancing our understanding of the molecular mechanisms underlying NSCLC progression.
RAP1 (TERF2IP) is a component of the shelterin complex that protects telomeric DNA and preserves chromosome stability. In addition to its telomeric function, accumulating evidence indicates that mammalian RAP1 also exerts multiple extra-telomeric functions. Notably, RAP1 has been reported to regulate the NF-κB signaling pathway and to function as a transcriptional regulator, suggesting potential roles in tumorigenesis. In this study, we found that RAP1 expression was significantly upregulated in hepatocellular carcinoma (HCC) cells. Functional analyses demonstrated that RAP1 promoted malignant phenotypes in HCC through a non-telomeric mechanism. In cellular models, RAP1 overexpression enhanced cell proliferation while suppressing senescence and apoptosis, whereas RAP1 knockdown produced the opposite effects. Mechanistically, RAP1 functioned as an upstream activator of the NF-κB signaling cascade, resulting in increased phosphorylation of the p65 subunit and upregulation of downstream targets, including IL-1β and BCL-2. Importantly, the oncogenic activity of RAP1 was shown to be dependent on NF-κB signaling in vivo, as pharmacological inhibition of NF-κB significantly suppressed RAP1-driven tumor growth in a xenograft model. Collectively, these findings reveal a previously unrecognized role for RAP1 in promoting HCC progression through activation of NF-κB signaling and identify the RAP1/NF-κB axis as a potential therapeutic target for HCC.
DNA N6-methyladenine (6 mA) has recently been recognized as a novel epigenetic modification, with ALKBH4 identified as a specific demethylase. However, the role of ALKBH4 and DNA 6 mA in the pathogenesis of ossification of the posterior longitudinal ligament (OPLL) remains unclear. Tissue samples from OPLL patients and normal posterior longitudinal ligaments were collected, and ligament fibroblastic cells (LFCs) were isolated from OPLL tissues using primary culture. The expression and functional relevance of ALKBH4 in OPLL were investigated through reverse transcription quantitative polymerase chain reaction and western blot analyses. Osteogenic potential was further assessed using alizarin red S staining and alkaline phosphatase activity assays. Methylation status was evaluated by enzyme-linked immunosorbent assay and chromatin immunoprecipitation. Furthermore, the regulatory role of ALKBH4 in LFC ossification was investigated through the bone morphogenetic protein 2 (BMP2) and Wnt/β-catenin pathways. ALKBH4 expression was significantly elevated in both OPLL tissues and LFCs, whereas global 6 mA levels and BMP2-associated 6 mA were reduced. Overexpression of ALKBH4 promoted the ossification of LFCs, while its knockdown suppressed osteogenesis. ALKBH4-mediated DNA demethylation at the 6 mA site facilitated Yin Yang 1 (YY1) binding to the BMP2 promoter, enhancing BMP2 transcription and driving ossification. Silencing of BMP2, Wnt/β-catenin, or YY1 attenuated the pro-ossification effects of ALKBH4. Furthermore, the mutation that affects the action of ALKBH4 at the 6 mA site fails to induce the osteogenic effect of LFC. These findings demonstrate that ALKBH4 regulates OPLL progression by modulating BMP2 and Wnt/β-catenin signaling and by promoting BMP2 transcription through site-specific demethylation in human OPLL tissues and primary LFCs. ALKBH4 may therefore represent a promising therapeutic target for the management of OPLL.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) acts as a pleiotropic modulator of inflammation. This study aimed to investigate the role and underlying mechanism of PCSK9 in Kawasaki disease (KD)-associated vasculitis. A Candida albicans water-soluble fraction (CAWS)-induced murine vasculitis model (n = 5-8 mice per group) and CAWS-stimulated RAW 264.7 macrophages (n = 3-8 independent experiments) were used. PCSK9 was pharmacologically inhibited in vivo with SBC-115076 and in vitro with PF-06446846. Vascular pathology, inflammatory markers, macrophage polarization, and signaling pathways were evaluated using hematoxylin-eosin (H&E) staining, immunofluorescence (IF), Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), and RNA sequencing (RNA-seq). CAP1 overexpression was performed via lentiviral infection in RAW 264.7 cells to further validate its functional role. PCSK9 expression was significantly upregulated (two-fold) in the coronary arteries of CAWS-treated mice, and PCSK9 was predominantly co-localized with macrophages. Pharmacological inhibition of PCSK9 attenuated coronary arteritis, reduced the inflammatory infiltrate fraction by 54%, attenuated systemic inflammation, and decreased cardiac macrophage infiltration by 89%. In vitro, PCSK9 blockade suppressed CAWS-induced M1 macrophage polarization, as shown by reduced expression of the markers CD86 (by 96%) and iNOS (by 60%), and decreased secretion of the pro-inflammatory cytokines TNF-α (by 80%), IL-1β (by 86%), and IL-6 (by 89%). Transcriptomic analysis identified the NF-κB pathway as a key downstream signaling pathway. Mechanistically, PCSK9 inhibition downregulated CAP1 (adenylyl cyclase-associated protein 1) expression by 64% and suppressed NF-κB p65 nuclear translocation by 91% in macrophages. Importantly, CAP1 overexpression reversed the inhibitory effects of PCSK9 blockade on p65 nuclear translocation, M1 polarization, and inflammatory cytokine production. PCSK9 promotes KD-like vasculitis by activating the CAP1-mediated NF-κB pathway in macrophages, thereby driving pro-inflammatory responses. Pharmacological inhibition of PCSK9 attenuates vascular immunopathology, highlighting PCSK9 as a potential therapeutic target for KD.
Hormesis represents a universal feature of biological plasticity across species and environmental contaminants. Here I propose that the maximum stimulatory peak converges upon the golden ratio (φ = 1.618), representing a 61.8% increase above baseline, a value embedded within the empirically observed 30%-60% range but offering mathematical precision for a unifying quantitative reference. I further hypothesize that the internal architecture of the hormetic zone may follow the complementary proportion of φ (0.382), with the rising phase occupying the smaller fraction (steep ascent) and the falling phase the larger fraction (gradual decline), reflecting natural selection for rapid threat response followed by sustained benefit. This framework positions the golden ratio as a potential evolutionary optimum, a Pareto-efficient allocation where further investment yields diminishing returns. While the dose-width to toxicity remains variable and context-dependent, the peak magnitude may reveal a fundamental constraint on the adaptive capacity of life. Testing this hypothesis requires systematic meta-analysis of existing databases and targeted experiments manipulating resource availability, genetic background, and evolutionary history.
High-risk human papillomavirus (HPV) infection is a key etiological factor in cervical cancer (CC) and oropharyngeal squamous cell carcinoma (OPSCC). Increasing evidence indicates that host microRNAs (miRNAs) are central regulators in HPV-induced carcinogenesis and represent promising molecular biomarkers for diagnosis and prognosis. In cervical cancer, deregulated expressions of miRNAs such as miR-21, miR-27a, miR-34a, miR-155, and miR-218 have been consistently reported. These miRNAs influence critical pathways controlling apoptosis, cell proliferation, and immune evasion. The oncoproteins E6 and E7 from HPV can disrupt normal miRNA biogenesis, leading to the suppression of tumor-suppressor genes such as PTEN and PDCD4 and the activation of oncogenic signaling networks. Circulating miRNAs detected in serum and plasma, including miR-205 and miR-196a, show potential as non-invasive biomarkers for early detection and disease monitoring in cervical cancer (CC). In oropharyngeal cancer (OPC), particularly HPV-positive OPSCC, altered miRNAs such as miR-21, miR-31, miR-375, and miR-9 have been implicated in tumor initiation and progression. Distinct miRNA profiles have been observed between HPV-positive and HPV-negative tumors, suggesting a role for these molecules in differentiating subtypes with different clinical outcomes. Salivary and serum miRNA assays have shown potential for early detection, reflecting tumor-specific molecular changes in a minimally invasive manner. Overall, miRNA profiling offers a promising approach for stratifying HPV-associated cervical and OPCs. Integrating miRNA panels with HPV genotyping and epigenetic data may enhance precision in risk assessment and therapeutic targeting. Future longitudinal studies with standardized methodologies are needed to validate these miRNAs as reliable clinical biomarkers.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by uncontrolled cell cycle progression, profound metabolic reprogramming, and immune evasion, yet effective therapeutic targets remain limited. In this study, we integrated bulk and single-cell transcriptomic analyses to identify phosphoglycerate mutase 1 (PGAM1) as a central regulator of TNBC progression. Functional assays revealed that PGAM1 is significantly upregulated in TNBC tissues and cell lines, particularly associated with enhanced G2/M phase activity. Silencing PGAM1 suppressed TNBC cell proliferation and migration and induced cell cycle arrest at the G2/M phase. Mechanistically, PGAM1 knockdown impaired glycolytic flux by reducing the activity of rate-limiting enzymes, attenuating pyruvate entry into the TCA cycle, and consequently diminishing lactate production. Notably, this metabolic disruption extended beyond tumor-intrinsic effects: reduced lactate secretion inhibited M2-type tumor-associated macrophage polarization in co-culture systems, thereby alleviating immunosuppressive signaling in the tumor microenvironment. These findings highlight PGAM1 as a critical node linking three cancer hallmarks-cell cycle dysregulation, metabolic reprogramming, and immune evasion. By bridging intracellular metabolic control with immune modulation via lactate signaling, PGAM1 emerges as a promising therapeutic target that could simultaneously inhibit TNBC cell proliferation and remodel the tumor immune landscape.
Sideroflexin 1 (SFXN1), predominantly localized in the inner mitochondrial membrane, exhibits differential expression across various tumor types. However, its specific role in colon adenocarcinoma (COAD) remains unclear. This study aimed to investigate the diagnostic and prognostic significance of SFXN1 in COAD. The expression and prognostic value of SFXN1 in COAD were evaluated using the Cancer Genome Atlas (TCGA) database. Bioinformatics analyses were conducted to assess the relationships between SFXN1 expression and clinical stage, prognosis, and immune infiltration in COAD. The biological role of SFXN1 in COAD was further validated through in vivo and in vitro experiments. SFXN1 was found to be expressed at low levels in COAD. Reduced SFXN1 expression was significantly associated with poor clinical outcomes in COAD patients. Furthermore, SFXN1 expression correlated with immune infiltration and immune checkpoint regulation in COAD. Functional experiments demonstrated that SFXN1 inhibition enhanced the proliferation, migration, and invasion of COAD cells, whereas SFXN1 overexpression suppressed tumor growth in vivo. Low SFXN1 expression is associated with an unfavorable clinical prognosis in COAD. Targeting SFXN1 may offer a promising avenue for developing personalized and more effective therapeutic strategies for patients with COAD.
Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy with poor prognosis and limited predictive biomarkers for therapy response. Characterizing malignant cell heterogeneity may improve prognostic and therapeutic stratification. We integrated single-cell RNA sequencing (scRNA-seq) data from 58 HNSCC patients (181,003 cells) to define malignant cell subpopulations, their differentiation states, developmental trajectories, cell-cell interactions, and spatial localization. Coexpression gene modules and meta-programs were identified using hdWGCNA and NMF. These programs were projected onto bulk RNA-seq datasets to classify HNSCC subtypes and examine associations with clinical outcomes, tumor microenvironment (TME), genomic instability, and predicted response to immune checkpoint inhibitors (ICIs). Twelve malignant clusters were identified with distinct clinical and molecular features. MC-5 exhibited a stem-like phenotype associated with poor prognosis, while MC-7 and MC-11 showed high TME communication and immune engagement. Coexpression analysis revealed 16 modules and eight meta-programs encompassing proliferation, differentiation, stress response, and immune activity. Translation to bulk RNA-seq defined three HNSCC subtypes (MS-1, MS-2, MS-3) with divergent survival, immune infiltration, stromal composition, and genomic features. MS-2, an immune-enriched subtype, demonstrated superior survival, high HPV positivity, and predicted ICI responsiveness. A 25-gene malignant cell score (MCScore) robustly predicted both prognosis and immunotherapy response. This study provides a comprehensive map of malignant cell heterogeneity in HNSCC, identifies key functional expression programs, and defines molecular subtypes with clinical and therapeutic relevance. Malignant cell-specific signatures, such as MCScore, offer promising tools for patient stratification and precision immunotherapy.
The core pathogenesis of carotid atherosclerosis (CAS) lies in the rupture of vulnerable plaques, with macrophages (MC) playing a critical role in plaque progression and destabilization. However, the functional characteristics of MC subpopulations in CAS remain poorly understood. This study systematically investigates the cellular composition of CAS and the regulatory mechanisms of MC by integrating single-cell RNA sequencing (scRNA-seq), in vitro models, and spatial transcriptomics. Differentially expressed genes upregulated in MC were significantly enriched in multiple signaling pathways, including Lipid and Atherosclerosis, Lysosome, and Antigen Processing and Presentation. Gene Set Variation Analysis (GSVA) revealed higher MC scores for Angiogenesis and Lipid Metabolism in the atherosclerotic core (AC). A total of seven distinct MC subtypes were identified. Pseudotime analysis indicated that IGSF21+ MC constitute the initial cell population, while FABP4+ MC represent the terminal cells along the trajectory. An in vitro atherosclerosis model was established to validate the diagnostic value of SPP1, FTH1, and FTL. Spatial transcriptomics further revealed the spatial connection patterns of the SPP1 signaling pathway network across different cell types. This study provides novel molecular insights into the pathogenesis of CAS and lays the groundwork for developing diagnostic biomarkers and therapeutic targets.
Hypoxia is associated with increased tumour aggressiveness and relapses in hepatocellular carcinoma (HCC) through HIF signalling. Tumour suppressor p53, its deacetylase SIRT1 and liver-specific miRNAs are deregulated in hypoxia, further driving HCC tumorigenesis. The role of HIFs-p53-SIRT1-miRNAs in tumorigenesis of HepG2 tumourspheres under hypoxic conditions remains unexplored, hence is the focus of this study. HepG2 tumourspheres cultured under hypoxic and serum-free conditions for 19 days showed reduced proliferation and apoptosis, and increased pro-survival autophagy, CSC features and resistance. HIF-1α and HIF-2α proteins were stabilised in HepG2 tumourspheres cultured in hypoxia for up to 15 days compared to only up to 24 h in monolayer cells. p53 was activated in hypoxia, evidenced by significant increase in Ace-p53 expression and Ace-p53/total-p53 ratio, which were negatively correlated with HIF-1α/HIF-2α throughout hypoxia. Concurrently, nuclear p53 localisation was reduced in hypoxia, suggesting HIFs-suppression of p53 transcriptional activity. SIRT1 however, showed no correlation with p53 acetylation and HIF-1α/HIF-2α, with no notable changes in its nuclear-cytoplasmic localisation. Among the six selected miRNAs, miR-145-5p, -26a-5p and -375-3p were upregulated, miR-22-3p was downregulated, while miR-29c-3p and miR-34a-5p remained unchanged. miR-145-5p showed a negative correlation with p53 expression in hypoxia. Pharmacological inhibition of HIFs resulted in significant upregulation of p53 and miR-375-3p, while SIRT1, miR-145-5p and miR-26a-5p were downregulated. miR-145-5p was negatively correlated with p53 protein when HIFs were stabilised but positively correlated when HIFs were inhibited. This study highlights the role of HIFs/p53/miR-145-5p-associated regulation under hypoxic conditions in HepG2 tumourspheres, providing insights for future therapeutic exploration in HCC.
Influenza viruses present an ongoing global health risk because they are always changing, which in turn results in the ineffectiveness of current strain-specific vaccines and leaves the world vulnerable to potential pandemics. The need for a universal influenza vaccine, designed to develop lasting broadly protective immunity against volatile influenza virus strains has led to advances in immunogen design. Nanotechnology, specifically self-assembled nanovaccines, offers a truly revolutionary "bottom-up" strategy to address this issue. Nanovaccines that spontaneously self-assemble into easily discernable pathogen-like nanoparticles, including protein cages (e.g., ferritin) and virus-like particles, provide densely displayed conserved influenza epitopes-such as hemagglutinin (HA) stalk, neuraminidase (NA), and M2 ectodomain (M2e)-in a multivalent array, greatly enhancing B-cell activation, initiated by extensive receptor crosslinking, and generating immune responses to a magnitude and breadth that is unattainable with soluble antigens. Moreover, self-assembled nanovaccines, often in adjuvant-free or self-adjuvanting formulations, not only induce durable and broad cross-protective humoral and cellular immunity but also offer protection from numerous heterosubtypic viral challenges. While significant hurdles remain in scaling the process to a manufacturing level and subsequently translating it into the clinic, self-assembling nanovaccines represent a paradigm shift in influenza prevention, providing a rational and promising pathway toward the development of a universal vaccine and a rapid response platform for future pandemics.
Phosphomannomutase-2 (PMM2) deficiency leads to the prominent Congenital Disorder of Glycosylation (CDG), a rare disease currently lacking effective treatment options. The complete absence of PMM2 activity is incompatible with life, and all patients carry at least one missense destabilising variant that allows residual enzymatic function. This makes PMM2-CDG amenable to pharmacological chaperone treatment. Glucose-1,6-bisphosphate (Glc-1,6-P2) is PMM2's natural activator and stabiliser, but its clinical application is severely limited due to its unfavourable physicochemical profile. Here, we applied the bioprecursor prodrug strategy to design and synthesise Lipo-Glc-1,6-P2, a novel prodrug with good stability and oral bioavailability. Its advantageous physicochemical profile was confirmed through metabolomics-based studies in fibroblasts derived from PMM2-CDG patient.
Angiogenesis, which is the formation of new blood vessels from existing vasculature, exhibits a pivotal role in breast cancer progression and promotes metastasis. This complex biological process is influenced by the dynamic balance of pro- and anti-angiogenic factors within the tumor microenvironment, such as vascular endothelial growth factor, fibroblast growth factors, and angiopoietins. Targeted therapeutic strategies have been developed to interfere with angiogenic signaling, aiming to normalize or inhibit the tumor vasculature. In recent years, miRNAs have arisen as crucial post-transcriptional regulators of gene expression implicated in angiogenic homeostasis. These microRNAs can function as either promoters or suppressors of angiogenesis by targeting mRNAs that encode angiogenic factors or other signaling molecules. Deregulated expressions of these miRNAs in BC are associated with perturbed angiogenesis, tumor progression, and therapeutic resistance. This review presents a thorough overview of the molecular processes controlling angiogenesis in BC and highlights the emerging roles of angioregulatory miRNAs. The article also discusses the therapeutic potential of targeting miRNAs to modulate tumor angiogenesis, providing novel insights for the development of miRNA-based diagnostics and therapeutics in BC management.
The CYP17A1 gene encodes the P450 17α-hydroxylase/17,20-lyase protein, a key enzyme in steroidogenesis. In the past, it was associated with disorders such as congenital adrenal hyperplasia, disorders of sex development, and castration resistant prostate cancer. Recently, genome-wide association studies have revealed that the locus harboring the CYP17A1 gene is strongly associated with multiple other traits, including cardiovascular and metabolic characteristics. This review summarizes the current knowledge about the regulatory mechanisms and monogenic disease implications of the CYP17A1 gene, then attempts to link the locus to cardiovascular and metabolic diseases, using experimental evidence supporting these relationships. Additionally, the review also speculates that the research focus may have been placed solely on one gene of the locus, which could have obscured the effects of other neighboring ones. In summary, our review aimed to highlight this locus as a complex regulatory region with implications that extend beyond a single gene.
Viral myocarditis (VMC) is a common inflammatory myocardial disease in children and is associated with heart failure and sudden cardiac death. Coxsackievirus B3 (CVB3) is the most common pathogen, and inflammation and ferroptosis are the key pathological events of CVB3-induced myocarditis. Studies indicate that the deubiquitinase OTUD1 is involved in cardiac inflammation and ferroptosis, but its role in CVB3-induced myocardial inflammation and ferroptosis remains unclear. Therefore, this study aimed to investigate the function and mechanism of OTUD1 in inflammation and ferroptosis in myocardial cells in the context of CVB3 infection. Mice and H9c2 cells infected with the CVB3 strain were used to construct in vivo and in vitro CVB3 myocarditis models. The inflammatory cytokines IL-1β, IL-6, and TNF-α; Fe2+; MDA; SOD; and the myocardial injury markers CK-MB and cTnI were detected using assay kits. Cell viability was measured by a CCK-8 assay, myocardial injury was evaluated by HE staining, and the expression of key proteins was detected by western blotting, immunohistochemistry, and immunofluorescence. After CVB3 infection, heart tissue was damaged; the levels of CK-MB and cTnI increased; the viability of H9c2 cells decreased; the levels of IL-1β, IL-6, TNF-α, Fe2+, MDA, and ROS increased; the level of SOD decreased; and the expression of the ferroptosis-related proteins GPX4 and SLC7A11 decreased. Second, CVB3 infection also repressed OTUD1 expression in mouse heart tissues and H9c2 cells. Importantly, the above effects of CVB3 were partially attenuated by overexpression of OTUD1, indicating that OTUD1 can inhibit CVB3-induced myocardial ferroptosis and inflammation. In addition, CVB3 infection also repressed the expression of NRF2 in vivo and in vitro and promoted the activation of NF-κB signaling. A mechanistic study revealed that OTUD1 could relieve CVB3-induced inflammation and ferroptosis by stabilizing NRF2 expression and inhibiting NF-κB signaling activation. Our study revealed the potential of OTUD1 to ameliorate inflammation and ferroptosis in myocardial cells induced by CVB3 infection, providing a potential intervention target for the treatment of VMC.
Sjögren's Disease (SjD) is an autoimmune disorder characterized by lymphocyte infiltration into exocrine glands, leading to dry eyes and mouth. Its pathogenesis involves B cell hyperactivity and type I interferon activation. CXCL13 promotes B cell migration and ectopic germinal center formation in target tissues. This study investigated whether paeoniflorin-6'-O-benzene sulfonate (POBS) alleviates Experimental Sjögren's Disease (ESjD) by modulating B cell subsets via the CXCL13/CXCR5 pathway. Altered B cell subsets were observed in SjD patient blood and labial glands, suggesting memory B cell migration. In SG-protein immunised ESjD mice, POBS reduced lymphocyte infiltration in submandibular glands, suppressed splenic B cell activation, and modulated peripheral B cell subpopulations. POBS also downregulated CXCL13 and CXCR5 expression. These results demonstrate that POBS attenuates gland damage and immune infiltration by regulating B cells via CXCL13/CXCR5, indicating its therapeutic potential for SjD.
