Search Results (2,684)

MicroRNAs are important regulators of skeletal muscle development and regeneration; however, the molecular basis by which exercise-induced miRNAs preserve middle-aged muscle function remains to be elucidated. This study aimed to investigate how aerobic exercise delays skeletal muscle attenuation by reversing age-related miRNAs dysregulation in male mice. Twelve-month-old male C57BL/6J mice (MC) (n = 8/group) were randomly assigned to a sedentary control group (OC) or an aerobic exercise group (OE) (12 m/min, 40 min/session, three sessions/week, for 12 weeks). miRNA sequencing identified differentially expressed miRNAs (DEmiRNAs), followed by miRNA–mRNA network construction. The results demonstrated that aerobic exercise improved muscle strength and mass while attenuating early atrophy and fibrosis. Four atrophy-associated DEmiRNAs (miR-150-5p, miR-199a-5p, miR-3535, and miR-329-5p) were reversed after aerobic exercise intervention. GO and KEGG profiling demonstrated that target genes were predominantly involved in protein binding and the Wnt signaling pathway. miR-199a-5p and miR-150-5p, with the most predicted targets, were selected as candidate mechanistic contributors, and FZD4 was confirmed as a common downstream target. Further analysis confirmed that miR-199a-5p and miR-150-5p inhibition attenuated D-galactose-induced C2C12 myotube atrophy, reducing Atrogin-1 and increasing MyoD1, FZD4, and β-catenin expression. These findings suggest that the exercise-induced miR-150-5p/miR-199a-5p axis may alleviate muscle aging in middle age via the restoration of key proteins in Wnt signaling and contribute preliminary observational evidence relevant to the understanding of aerobic exercise intervention in sarcopenia. Full article

Secreted frizzled-related protein 4 (sFRP4) has traditionally been regarded as a Wnt antagonist with tumor-suppressive properties. However, growing evidence indicates that its role in cancer is far more complex and highly context-dependent. Depending on tumor type, molecular subtype, epigenetic state, and microenvironmental conditions, sFRP4 may exert either inhibitory or tumor-promoting effects. This functional heterogeneity has important implications for understanding cancer biology and for evaluating the clinical relevance of sFRP4. In this review, we summarize current knowledge of the structural features, regulatory mechanisms, and signaling functions of sFRP4, and discuss how these factors shape its diverse roles across malignancies. We further examine its potential significance in diagnosis, prognosis, therapeutic stratification, and systemic metabolic regulation. A clearer understanding of the context-specific behavior of sFRP4 may help refine its value as a biomarker and support the development of more precise and mechanism-informed therapeutic strategies. Full article

Pancreatic ductal adenocarcinoma (PDAC) is molecularly characterized by near-universal KRAS mutations and recurrent alterations in TP53, CDKN2A, and SMAD4. Gene fusions are exceptionally rare and have not been established as canonical drivers of PDAC. We report a case of metastatic PDAC harboring an EIF3E::RSPO2 gene fusion in the absence of detectable KRAS or other common driver mutations. A 48-year-old female was diagnosed with stage IV PDAC via endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). Comprehensive molecular profiling using the Oncomine Precision Assay GX5 revealed no pathogenic single-nucleotide variants, indels, or copy number variations. However, an EIF3E::RSPO2 fusion, predicted to be a gain-of-function alteration, was identified as the sole genomic alteration. Immunohistochemistry showed retained mismatch repair protein expression and preserved SMAD4. Although RSPO2 fusions have been described in preclinical colorectal cancer models and are well-established activators of the Wnt signaling pathway in this setting, their clinical occurrence in PDAC remains poorly documented. This finding indicates a KRAS wild-type tumor with a potential KRAS-independent oncogenic mechanism that may involve aberrant Wnt/β-catenin signaling and raises the possibility of a rare, biologically distinct PDAC subset. Comprehensive genomic profiling in advanced PDAC may uncover actionable non-canonical drivers with therapeutic implications. Full article

Prostate cancer (PCa) is among the highest incidence malignancies in men, with high rates of inevitable resistance development, relapse, and mortality. Castration-resistant prostate cancer (CRPC) continued to pose substantial therapeutic challenges, highlighting the urgent need for effective treatment options. This study assessed the marine cembranoid sarcophine activity against the progression and recurrence of the metastatic CRPC (mCRPC) in mouse xenograft models. Protein and phosphorylation levels were assessed by immunoblotting and mRNA expression by qPCR and RNA sequencing. The in vivo efficacy was evaluated through tumor progression over 3 weeks followed by primary tumor excision and recurrence monitoring over an 8-week course. Sarcophine significantly reduced the mCRPC CWR-R1ca tumor volume by 74.1% and suppressed the epigenetic regulators EZH2 and SMYD2; lineage plasticity factors ASCL1 and BRN2; Wnt/stemness signaling markers β-catenin and LGR6; AKT total expression and activation; and invasion-associated proteins TRPC4 and MMP2 in primary tumors. Sarcophine effectively prevented the mCRPC locoregional recurrence, as well as lung and spleen distant recurrences, and effectively reduced recurrence in other organs. Transcriptomics-RNA-Seq analysis of primary tumors identified 2697 downregulated and 3534 upregulated genes, indicating broad transcriptional reprogramming following sarcophine treatments. These findings demonstrate coordinated suppression of multi-oncogenic pathways and validate the therapeutic potential of sarcophine to control mCRPC. Full article

Buds are continuously renewed sensory organs in which development, adult maintenance, and repair share overlapping molecular circuitry. During embryogenesis, WNT/β-catenin signaling promotes taste placode formation and placodal Shh expression, while SHH refines papilla spacing and restricts neighboring papilla formation. SOX2 functions as a taste-competence and progenitor maintenance factor. In adults, LGR5/LGR6–RSPO–WNT signaling sustains progenitor activity, and gustatory neurons are an important source of RSPO2; available genetic evidence is consistent with a neuron-derived contribution to the LGR5/LGR6 niche, and AAV-Cre-mediated neuron-specific ablation of Rspo2 in the petrosal ganglion led to near-complete loss of circumvallate taste buds. HH signaling from epithelial and neuronal sources further supports SOX2-dependent progenitor homeostasis. Lineage allocation is governed by transcriptional programs that include POU2F3/SKN-1a for sweet, umami, and bitter type II taste receptor cells, and ASCL1 with posterior-field NKX2-2 for type III presynaptic/sour cells. After denervation or irradiation, regeneration depends primarily on LGR5⁺/KRT14⁺ progenitors and may be supplemented, in specific injury contexts, by plasticity of a subset of K8-lineage taste receptor cells that acquire KRT14/SOX2/PCNA progenitor-like features. Key unresolved questions include the direct chromatin targets of taste lineage regulators (which remain to be defined by ChIP-seq in native taste progenitors), the identity of the type I cell selector, the contribution of dedifferentiation across injury models, and the degree to which mouse-derived networks are conserved in human taste biology. Full article

Arrhythmogenic cardiomyopathy (ACM/ARVC) is an inherited myocardial disease characterized by progressive fibro-fatty replacement, ventricular arrhythmias, and an increased risk of sudden cardiac death. In addition to mutations in desmosomal genes, growing evidence suggests that microRNAs (miRNAs) actively contribute to disease pathogenesis by regulating key processes such as fibrosis, cell adhesion, and cardiac remodeling. This systematic review analyzed the main miRNAs identified in studies of human cardiac tissue and animal models of ARVC. Materials and Methods: Studies based on human myocardial tissue analysis (including autopsy and biopsy samples) and animal models of arrhythmogenic cardiomyopathy were included, using RNA sequencing, small RNA sequencing, miRNA arrays, and RT-qPCR. Studies on circulating miRNAs and narrative reviews were excluded. miRNAs were analyzed in relation to their functional pathways and their role in disease pathogenesis. Results: The synthesis of studies on human and animal cardiac tissue reveals a consistent miRNA signature associated with arrhythmogenic cardiomyopathy. MiR-21-5p and miR-29b-3p are associated with fibrosis and extracellular matrix remodeling, whereas miR-133a-b and miR-130a are linked to cardiomyocyte integrity loss and desmosomal dysfunction. A second group of miRNAs, including miR-217-5p, miR-708-5p, and miR-135b, regulates key pathways such as Wnt/β-catenin and Hippo signaling, contributing to structural remodeling and loss of cellular identity. Furthermore, downregulation of miR-499-5p is associated with mitochondrial dysfunction and cellular vulnerability, while the miR-142-3p, miR-182-5p, and miR-183-5p clusters contribute to differential molecular signatures compared with other cardiomyopathies. Overall, miRNAs converge on three main pathogenic axes: myocardial fibrosis, desmosomal impairment, and remodeling of cellular signaling pathways. Conclusions: The available evidence indicates that arrhythmogenic cardiomyopathy is regulated by a coordinated network of miRNAs that actively drives myocardial damage progression. These miRNAs represent not only biomarkers but also functional mediators of disease, suggesting potential diagnostic and therapeutic applications based on tissue-specific molecular signatures, including in post-mortem settings. Full article

Background/Objectives: Cancer, a multifactorial disease with uncontrolled cell growth, oxidative stress, inflammation, genomic instability, and molecular signaling pathways, is a global health concern, leading to the ~20 million newly diagnosed cases annually. Although conventional therapy has been shown to enhance the survival rates of cancer patients, its clinical efficacy is limited by certain side effects that occur as a result of treatment, thus necessitating the exploration of plant-derived bioactive compounds for their potential as safer and alternative supportive therapeutic agents. Aloe vera, known as the plant of immortality, comprises phytochemicals, such as anthraquinones (aloe-emodin, emodin, and aloin), polysaccharides (acemannan), flavonoids, and phenolic acids, which contribute to the pharmacological effect of the compound. Methods: This review summarizes the anticancer potential of Aloe vera, and the data were retrieved from databases, such as PubMed, Google Scholar, ScienceDirect, Web of Science, and Wiley Online Library, during the time period of 2015 to 2025. Results: The literature revealed that Aloe vera and its bioactive compounds have dose-dependent cytotoxic and anti-proliferative properties against hepatocellular, cervical, colorectal, lung, breast, prostate, and hematological cancers, which are significantly mediated by apoptosis and pyroptosis induction, reactive oxygen species (ROS) production, mitochondrial dysfunction, inhibition of angiogenesis and metastasis, and the modulation of key signaling pathways, particularly PI3K/Akt, MAPK, NF-кB, p53, and Wnt/β-catenin. Furthermore, anthraquinones, including Aloe-emodin, demonstrate potent anticancer effects at micro-molar doses, and polysaccharides increase immune reactions and provide tumor immunity. Conclusions: Conclusively, Aloe vera is a promising multi-target natural compound, particularly efficient in the treatment of cancer. However, despite significant therapeutic potential, more research on pharmacokinetics, standard dose, and controlled clinical trials of Aloe vera is required to validate clinical applicability. Full article

This study elucidates the multi-targeted antineoplastic mechanisms of Parkia speciosa empty pod extract (PSET) against HCT-116 and HT-29 colorectal cancer (CRC) cells through integrated transcriptomic and proteomic analyses. Phytochemical profiling indicates that PSET is rich in bioactive metabolites, notably quercetin, rutin, and pyrogallol, which orchestrate its profound ability to inhibit tumor proliferation, migration, and invasion. Transcriptomic data revealed that PSET profoundly suppresses the oncogenic Wnt/β-catenin signaling axis while simultaneously activating p53-mediated cell cycle arrest. Complementary proteomic profiling uncovered critical metabolic vulnerabilities, demonstrating that PSET abrogates the Warburg effect by disrupting key glycolytic enzymes (e.g., ENO1, GAPDH, LDHA), thereby inducing metabolic starvation. Furthermore, the extract precipitated a catastrophic collapse of the cytoskeletal architecture and downregulated epithelial–mesenchymal transition (EMT) markers, effectively paralyzing the cells’ metastatic machinery. The integrated transcriptomic and proteomic signatures also highlighted an irrecoverable state of cellular stress, characterized by an overwhelming unfolded protein response and dysregulated RNA splicing, ultimately driving the cells toward apoptosis. In conclusion, this integrated omics approach provides robust molecular validation that PSET systemically dismantles colorectal cancer survival networks, highlighting its strong potential as a natural, multi-targeted therapeutic agent. Full article

Objectives: The current study examined whether exercise training alleviates cigarette smoke (CS)-induced diaphragm dysfunction by modulating inflammation through the Wnt and Chemerin signaling pathways. Methods: Mechanical stretching was applied for 3 consecutive days to explore the effects on cell proliferation and chemerin/chemokine-like receptor 1 (CMKLR1) expression in C2C12 cells pretreated with lipopolysaccharide. Male wild-type (WT) and CMKLR1 knockout (KO) mice (6–8 weeks old) were exposed to CS for 6 months (1–2 h a day, 6 days a week) to determine the role of chemerin/CMKLR1 in the progression of diaphragm dysfunction. Given that Wnt/β-catenin is a potential modulator of chemerin/CMKLR1, its expression was detected in CS-exposed mice and mice subjected to treadmill exercise training after CS exposure. Wnt/β-catenin agonist lithium chloride (LiCl) and antagonist XAV939 were then intraperitoneally injected into the CS-exposed mice during exercise training to further investigate their potential synergistic effects with exercise training on improving CS-induced diaphragm dysfunction. Isolated diaphragm contraction strength and fiber cross-sectional area were measured to determine the diaphragm dysfunction. Results: Mechanical stretching improved the proliferation level of myoblasts and decreased inflammation and CMKLR1 protein expression (p < 0.05). The KO mice showed diminished diaphragm dysfunction compared with the WT mice after long-term CS exposure. Combined LiCl and exercise training further enhanced the improvement of diaphragmatic isolated strength in mice exposed to CS (p < 0.01), activated the protein degradation and synthesis pathways, and decreased IL-1β level (p < 0.05). Combined XAV939 and exercise training significantly decreased chemerin protein level (p < 0.01). Conclusions: Exercise training can downregulate inflammation levels and improve diaphragm dysfunction in CS-exposed mice, partially by enhancing Wnt expression and reducing abnormally activated chemerin. Full article

The A3 adenosine receptor (A3AR) is a stress-inducible G-protein-coupled receptor that is selectively upregulated in inflamed, hypoxic, and fibrotic tissues as well as in many malignancies, while remaining weakly expressed in most normal organs. This distinctive expression pattern provides a strong biological basis for pathology-selective pharmacology. Activation of A3AR by highly selective agonists, including piclidenoson (IB-MECA) and namodenoson (Cl-IB-MECA), initiates signaling through Gi proteins and phospholipase C (PLC), which in turn regulate a coordinated network of downstream intracellular pathways, including PI3K/Akt, NF-κB, MAPKs, and Wnt/β-catenin, resulting in suppression of inflammation, inhibition of pathological cell survival, and protection of metabolically stressed tissues. Over the three decades, extensive preclinical studies have demonstrated that A3AR agonism exerts anti-cancer, anti-fibrotic, immunomodulatory, neuroprotective, and organ-protective effects across diverse disease models, including hepatocellular carcinoma, pancreatic cancer, psoriasis, osteoarthritis, metabolic dysfunction-associated steatohepatitis, ischemic stroke, neurodegeneration, ophthalmic disorders, and inherited metabolic syndromes. Importantly, these mechanistic insights have been translated into clinical programs, with piclidenoson and namodenoson demonstrating favorable safety profiles and disease-modifying activity in inflammatory, fibrotic, and oncologic indications. This review integrates molecular, cellular, and translational evidence to highlight A3AR activation as a unifying therapeutic principle for diseases driven by inflammation, oxidative stress, hypoxia, and dysregulated cell survival, positioning selective A3AR agonists as first-in-class agents targeting the A3AR, with broad clinical applicability across multiple disease domains. Full article

Background/Objectives: Cardiac allograft fibrosis is an important limiting factor for long-term graft survival. However, the fibrotic process operating in patients with acute cellular rejection (ACR) remains unclear. We aimed to identify altered serum mRNAs related to cardiac fibrosis in patients with ACR and to evaluate their diagnostic accuracy in detecting rejection episodes. Methods: We included 40 serum samples from recipients of transplants undergoing routine endomyocardial biopsies. Results: Several altered mRNAs associated with fibrosis were detected in patients with ACR. Specifically, the activators of fibroblasts and myofibroblasts (TNS1, FAP and ACTA2), TGF-β signaling (TGFBR1 and JAK1) and WNT signaling (WNT7A and WLS) pathways were significantly different when we compared grade ≥ 2R ACR and/or grade 1R ACR groups with the nonrejection group. Furthermore, TNS1 and WLS presented an area under the curve value > 0.90 for identifying patients with moderate and severe grades of cardiac rejection. Conclusions: In conclusion, we found alterations in the relative abundance of circulating activators of fibroblasts and myofibroblasts, such as FAP or ACTA2, as well as in major profibrotic pathways, including TGF-β and WNT signaling, especially in clinically relevant cardiac rejection. These findings may contribute to improving the surveillance of patients with cardiac transplant and provide new therapeutic strategies for targeting fibrosis process activation. Full article

Background: The oral squamous cell carcinoma (OSCC) is a very aggressive cancer that is the product of tumor cell interactions with the microenvironment. The tumor microenvironment (TME) has a severe impact on OSCC progression, metastasis, and resistance to treatment by altering gene expression via various cellular and molecular signal transductions. Aim: This review systematizes the information on gene regulation in the OSCC TME (cellular components, signaling pathways that regulate tumor progression and resistance). Methods: We used PRISMA guidelines to search PubMed, Scopus, Web of Science, and Google Scholar (up to April 2025) with OSCC studies addressing the subject of gene regulation and tumor microenvironment. The quality of human or experimental models was evaluated using the Newcastle–Ottawa Scale and the qualitative synthesis was performed because of heterogeneity. Results: The significant regulatory functions of tumor-associated macrophages, cancer-associated fibroblasts, immune cells, and non-coding RNAs were found, especially in the pathways like JAK/STAT, EGFR, Wnt/ -β catenin, and PI3K/AKT/mTOR. Conclusions: The conceptualization of gene regulatory networks in the OSCC TME identifies the emerging biomarkers and targets of therapy. Merging multimodal omics and single-cell studies can further contribute to the precision strategies to enhance the outcomes of OSCC. Full article

The Chinese bahaba (Bahaba taipingensis), an endangered marine fish, is highly vulnerable to infectious spleen and kidney necrosis virus (ISKNV). In this work, we developed a gill filament-derived cell line, designated BTG, to investigate how these cells respond to ISKNV over time, specifically from 3 to 24 h post-infection (hpi). BTG cells grew steadily, displayed a diploid chromosome number of 2n = 48, demonstrated high transfection efficiency, and were highly susceptible to viral infection. Characteristic cytopathic effects (CPEs) became noticeable as early as 6 hpi at 27 °C. RNA-seq profiling showed that the number of differentially expressed genes (DEGs) steadily increased with time. Standard enrichment analysis at individual time points (3, 6, 12, and 24 hpi) highlighted pathways mainly involved in DNA replication, cell cycle control, ribosome assembly, transcription and translation, mismatch repair, and cell adhesion. Temporal clustering analysis, however, revealed hidden patterns in immune gene expression. Genes that were consistently downregulated were enriched in immune-related pathways, including ECM–receptor interaction, cytokine–receptor signaling, PI3K–AKT, and Wnt signaling, indicating prolonged suppression of host defense mechanisms. In contrast, clusters of genes transiently upregulated during the first 6 h post-infection were associated with antiviral and innate immune pathways, such as NF-κB, JNK, IRF3, IRF7, caspases, JAK, MHC I, and lysosome-related functions, suggesting a rapid but short-lived antiviral response. Genes that were continuously upregulated were primarily involved in nucleic acid replication and protein synthesis, reflecting a gradual host cell reprogramming to support viral replication. Taken together, these findings reveal a temporal shift in BTG cells from an initial burst of immune activity to immune suppression, accompanied by enhanced viral replication. The BTG cell line thus represents a valuable in vitro model for dissecting ISKNV–host interactions and offers new perspectives on the molecular strategies employed by megalocytiviruses in B. taipingensis. Full article

The prevalent endocrine disruptor bisphenol A (BPA) is associated with aging-related conditions, including metabolic disorders. It has been shown that BPA promotes bone fragility through oxidative stress-induced apoptosis and impaired osteoblast differentiation. The identification of sustainable bioactive substances that alleviate BPA-induced bone toxicity is thus of biomedical and environmental significance. Wolffia globosa (WG), the world’s smallest flowering aquatic plant, has recently gained attention as a high-protein, antioxidant-rich nutraceutical, yet its impact on BPA-induced osteoblast dysfunction has not been systematically investigated. This study presents a comprehensive assessment of WG ethanolic extract (WGE) in MC3T3-E1 pre-osteoblasts, incorporating thorough phytochemical characterization, acute high-dose and chronic low-dose BPA exposure models, and multi-faceted mechanistic analysis. LC-MS/MS profiling identified luteolin (116.17 ± 0.69 µg/g), rosmarinic acid (54.80 ± 2.12 µg/g), and apigenin (48.77 ± 0.61 µg/g) as the predominant bioactive compounds. WGE exhibited potent antioxidant capacity across DPPH and ABTS radical scavenging assays, complemented by high ORAC and FRAP values, reflecting broad-spectrum antioxidant mechanisms. Treatment with WGE (25 and 50 µg/mL) resulted in significant alleviation of BPA-induced cytotoxicity, decreased intracellular ROS levels, and inhibited apoptosis. WGE (12.5 µg/mL) also modulated autophagy-related markers (LC3-II, Beclin-1, and p62), suggesting potential autophagic participation, although flux verification was not conducted. Treatment with WGE (12.5 µg/mL) also restored BPA-suppressed osteogenesis under chronic exposure, as evidenced by enhanced alkaline phosphatase activity, and increased both mineralization and upregulation of osteogenic genes including runt-related transcription factor2 (Runx2), collagen type I alpha 1 (Colla1), alkaline phosphatase (ALP), and osteocalcin (OCN). These effects were accompanied by partial reactivation of Wnt/β-catenin signaling. This study is the first to demonstrate that WGE protects osteoblasts from BPA toxicity by concurrently strengthening antioxidant defenses, limiting apoptosis, modulating autophagy-related markers, and supporting β-catenin-mediated osteogenesis, highlighting WG as a promising sustainable nutraceutical candidate for the prevention of environmental toxin-related bone fragility. Full article

Background/Objectives: Tumors are induced by overactivation of oncogenes and loss of tumor suppressor genes. Recently, a family of proteins containing CID (C-terminal domain (CTD)-interacting domain) domains, named CREPT/RPRD1B and p15RS/RPRD1A, has been identified to be involved in tumorigenesis through the regulation of the cell cycle. Interestingly, while p15RS was shown to inhibit cell proliferation, CREPT was demonstrated to promote tumorigenesis by accelerating tumor cell cycle progression. Methods: To decipher why these two proteins function oppositely, we aimed to reveal the disparities in their clinical outcomes and protein properties. Results: We observed that CREPT and p15RS are both highly expressed in tumors, but with opposite prognostic implications. We confirmed that CREPT promotes, but p15RS inhibits cell proliferation via regulation of Wnt/β-catenin signaling activation. The CID domain of CREPT differs from that of p15RS in conformation and charge distribution. CREPT exhibits a significantly stronger oligomerization capacity than p15RS, which is mediated by the CCT (coiled-coil terminus) domain. We demonstrated that the differences in both CID and CCT domains between CREPT and p15RS contribute to their opposite physiological functions. Conclusions: In conclusion, our results demonstrate that despite high primary sequence similarity, CREPT and p15RS exhibit distinctive biochemical properties. These differences ultimately explain their functional divergence in tumorigenesis and offer novel insights into CREPT-targeted drug design. Full article