Search Results (616)

Sinensetin, a polymethoxylated flavone abundant in citrus fruits, has been recognized for its broad biological activities and wide use in traditional medicine around the world. Emerging clinical evidence from flavonoid-enriched orange juice interventions indicates antioxidant and anti-inflammatory effects, aligning with extensive preclinical data. In this review, we explored in vitro and in vivo findings on the anti-inflammatory and anticancer actions of sinensetin and delineated the underlying cellular pathways, especially in terms of proposed targets for sinensetin. In inflammatory settings, sinensetin attenuates NF-κB activation, lowers pro-inflammatory cytokines (e.g., TNF-α, IL-6), and enhances antioxidant defenses, supporting its reported antioxidant, anti-bacterial, anti-viral, and anti-obesity properties. Across multiple tumor models, sinensetin suppresses oncogenic signaling—including β-catenin, PI3K/AKT, VEGF, NRF2, P53, and MKK6—concomitant with reduced proliferation, migration, and survival signaling. We further discuss emerging immunological effects, including modulation of innate immune cell activation and cytokine production, which may contribute to tumor microenvironment reprogramming and inflammation resolution. Together, these mechanistic insights position sinensetin as a promising lead for chemopreventive and adjunct therapeutic strategies. Our efforts aim to provide insights into the future translational development and clinical evaluation of sinensetin and its derivatives. Full article

Colorectal cancer (CRC) is a life-threatening malignancy, but our understanding of its pathogenic mechanisms remains incomplete—posing a major constraint on the development of effective therapeutic strategies. The transcription-translation feedback loop of clock genes (e.g., BMAL1, CLOCK, PER1/2/3, and CRY1/2) provides a promising novel avenue for deciphering the initiation and progression of CRC. Mounting evidence indicates that core circadian clock genes play pivotal roles in CRC oncogenesis by orchestrating the regulation of the cell cycle, epithelial–mesenchymal transition (EMT), metabolic reprogramming, and the tumor microenvironment. This review systematically summarizes the expression patterns and mechanistic roles of core clock genes in CRC, while elucidating their molecular underpinnings in tumor progression via key signaling cascades (e.g., Wnt/β-catenin and c-Myc/p21 pathways). We emphasize the associations between circadian disruption and CRC—including diagnostic markers, prognostic assessment, and chemosensitivity—and provide an in-depth discussion of chronotherapeutic strategies and their translational potential. Finally, we identify unaddressed scientific questions and propose future research directions to facilitate the development of novel targeted therapies for CRC. Full article

Phosphate is emerging as an active mediator of oxidative stress and vascular injury in chronic kidney disease (CKD). This emerging pathophysiological framework, referred to as “Phosphatopathy”, describes the systemic syndrome driven by chronic phosphate overload and characterized by oxidative stress, inflammation, endothelial dysfunction, vascular calcification, cellular senescence, and metabolic imbalance. Beyond being a biochemical marker, phosphate overload triggers NOX-derived reactive oxygen species (ROS), activates Wnt/β-catenin and TGF-β signaling, and disrupts the FGF23–Klotho axis, promoting endothelial dysfunction, vascular calcification, and left ventricular hypertrophy (LVH). These pathways converge with systemic inflammation and energy imbalance, contributing to the malnutrition–inflammation–atherosclerosis (MIA) syndrome. Experimental and clinical data reveal that the phosphate/urinary urea nitrogen (P/UUN) ratio is a sensitive biomarker of inorganic phosphate load, while emerging regulators such as microRNA-125b and calciprotein particles integrate phosphate-driven oxidative and inflammatory responses. Therapeutic strategies targeting phosphate burden—rather than serum phosphate alone—include dietary restriction of inorganic phosphate, non-calcium binders, magnesium and zinc supplementation, and activation of important pathways related to the activation of antioxidant defense such as AMP-activated protein kinase (AMPK) and SIRT1. This integrative framework redefines phosphate as a modifiable upstream trigger of oxidative and metabolic stress in CKD. Controlling phosphate load and redox imbalance emerges as a convergent strategy to prevent vascular calcification, improve arterial stiffness, and reduce cardiovascular risk through personalized, mechanism-based interventions. Full article

Aflatoxins (AFs) are potent hepatotropic mycotoxins—AFB₁ being the best-characterized—yet their ability to induce intrahepatic cholangiocarcinoma (iCCA) remains underexplored. Male Wistar rats received vehicle (controls; n = 5) or an AFB₁-dominant AF mixture (AFB₁ 39.46 μg/mL; AFB₂ 1.13 μg/mL; AFG₁ 17.44 μg/mL; AFG₂ 0.59 μg/mL— n = 10) by daily gavage for 90 days, at a dose equivalent to 400 μg AFB₁ per kg of diet. After 12 months, twelve iCCA tumors were resected and analyzed by histology (H&E) and tissue-microarray-based immunohistochemistry (Cytokeratin-19, Hep Par-1, p53, Cyclin D1, Rb, β-catenin, and PCNA). Lesions predominantly showed glandular/tubular architecture consistent with iCCA and were cytokeratin-19-positive and Hep Par-1-negative. Cell proliferation was high (PCNA ≈ 69%). p53 displayed nuclear accumulation in 83% of tumors. G1/S control was perturbed, with cyclin D1 overexpression (67%), and Rb was positive in 58% of iCCA. Aberrant Wnt activation was rare (nuclear β-catenin in 8%). Subchronic exposure to an AFB₁-dominant AF mixture in rats was associated with iCCA characterized by high proliferative activity, p53 accumulation, and disruption of G1/S checkpoint components. These findings broaden the oncogenic spectrum of AFs and warrant genomic confirmation of AF mutational signatures. Full article

Alopecia areata (AA) is an autoimmune-mediated nonscarring alopecia with limited therapeutic options and frequent relapses. Exosomes, nanosized extracellular vesicles secreted by various cell types, have recently emerged as potential regenerative and immunomodulatory therapies. The aim of the study is to review the clinical and preclinical evidence regarding the efficacy and safety of EV-based therapies for alopecia areata. a systematic search of PubMed, Embase, Web of Science, and Cochrane Library was performed from 2020 to 2 October 2025. Inclusion criteria were original studies (clinical, preclinical, in vivo, in vitro) investigating exosome-derived interventions for AA. Outcomes of interest were hair regrowth, immune modulation, follicular regeneration, and safety. A total of 499 records were retrieved from electronic database searches. After deduplication and application of the inclusion/exclusion criteria, 40 studies met the eligibility criteria for the review. Of these, two were clinical studies (one retrospective cohort, one case report), while the remainder comprised five animal (in vivo) studies, six in vitro studies, and sixteen mixed translational studies (in vitro/in vivo ± clinical). Experimental studies reported hair coverage improvements of 50–99% and, in one instance, 30% regrowth in totalis and 16% in partialis, with nearly complete regrowth in incipient alopecia. Clinical reports noted density increases of 9–31 hairs per cm² (e.g., from 121.7 to 146.6 hairs/cm², p < 0.001) and improvements in hair count, length, and thickness. Several studies detailed activation of the Wnt/β-catenin pathway along with enhanced dermal papilla and hair follicle stem cell function, as well as anti-inflammatory effects. Reported safety profiles were favorable; when adverse events occurred, they were limited to mild, transient local reactions with no severe systemic issues. EV-based therapy is a novel and biologically plausible approach for AA, but robust randomized controlled trials (RCTs) are lacking. Standardization of small EV sources, doses, and delivery methods is essential before clinical translation. Full article

This study investigated the potential of scale-up mango leaf extract (MLE) as a treatment for diabetes, a global public health concern. MLE was prepared by boiling in water, yielding 12.07% (w/w), with a bioactive mangiferin content of 165.67 ± 10.88 μg/g in the crude powder. Mechanistically, MLE demonstrated a hypoglycemic effect by stimulating glucagon-like peptide-1 (GLP-1) secretion in NCI-H716 L-cells. This occurred through activation of the MAPK signaling pathway, evidenced by increased p-ERK1/2, p-p38, and p-c-Jun expression, and the Wnt signaling pathway, shown by increased β-catenin and decreased GSK-3β and Axin1 expression, consistent with molecular docking. In a type 2 diabetic rat model, MLE administration (40 mg/kg) significantly reduced metabolic parameters, including fasting blood glucose (FBG), body weight, cholesterol (CHOL), triglycerides (TGs), and HbA1c. Notably, MLE lowered serum insulin and the HOMA-IR index, and reduced serum dipeptidyl peptidase-IV (DPP-IV) levels, resulting in increased serum GLP-1, comparable to the drug sitagliptin. These findings suggest that MLE has great potential to lower blood glucose by inducing GLP-1 secretion via MAPKs and Wnt signaling pathways, positioning it as a promising candidate for alternative diabetes treatment or development as a dietary supplement. Full article

Prostate adenocarcinoma is mainly diagnosed based on serum PSA levels, but elevated PSA levels can also be caused by BPH, which weakens its specificity. Recent scientific studies have demonstrated that specific microRNAs regulate cancer cell proliferation by modulating the Wnt/β-catenin pathway. To date, no published literature has provided a comprehensive assessment of the interactions between miR-106a-5p and miR-375-3p and components of the Wnt/β-catenin pathway in prostate cancer. Therefore, the aim of the present study was to perform a pilot evaluation of the expression of miRNAs 106a-5p and 375-3p, as well as β-catenin, Fzd8, Wnt5a, and cyclin D1 in prostate adenocarcinoma compared with BPH. The study material consisted of samples collected from 30 patients with prostate cancer and 30 with BPH. Protein expression was analyzed using IHC and qRT-PCR methods, while miRNA levels were quantified by dPCR. Our study results revealed lower immunoreactivity and expression of genes encoding β-catenin, Fzd8, Wnt5a, and cyclin D1 and significantly higher fluorescence intensity of miRNA 106a-5p and 375-3p with prostate adenocarcinoma compared to BPH. These parallel alterations in miRNA expression and Wnt/β-catenin-related components reflect disease-specific expression patterns and warrant further investigation in larger cohorts to determine their potential utility as diagnostic biomarkers in prostate diseases. Full article

Meester–Loeys syndrome (MLS) is an X-linked connective tissue disorder caused by pathogenic BGN variants. We describe a family carrying a novel missense variant. The index male, initially diagnosed with Ehlers–Danlos syndrome, had joint hypermobility, multiple visceral artery aneurysms, and recurrent musculoskeletal problems. A brother of the proband had an aortic root aneurysm. Female carriers had no or only minor manifestations. Studies of the aortic wall were consistent with a dysregulation of the TGF-β/SMAD pathway and assays with reporter vectors revealed reduced canonical Wnt and TGF-β activity in cell lines expressing mutant biglycan. However, patients’ dermal fibroblasts did not show consistent differences in the nuclear abundance of β-catenin or p-SMAD2/3 compared to cells from controls. This 3-generation family expands the genetic and phenotypic spectrum of MLS and underscores the importance of considering BGN testing in hypermobility syndromes to enable early surveillance and targeted management. Full article

This study investigated the role of SCD5 in bovine preadipocyte proliferation and adipogenic differentiation. SCD5 overexpression suppressed proliferation, reducing the percentage of EdU-positive cells and overall cell viability (p < 0.05). It also downregulated proliferative factors CDK1 and CDK2 (p < 0.05), and reduced lipid accumulation (p < 0.001) along with key adipogenic markers PPARγ, C/EBPα, and FABP4 (p < 0.01). Conversely, SCD5 knockdown promoted these processes. Mechanistically, SCD5 overexpression downregulated WNT5B (p < 0.05), while knockdown had the opposite effect. Silencing WNT5B significantly decreased β-catenin transcription (p < 0.05), total protein (p < 0.05), and phosphorylation (p < 0.001). In conclusion, our findings identify SCD5 as a novel negative regulator of bovine preadipocyte proliferation and differentiation, which exerts its function through the WNT5B/β-catenin signaling axis. This discovery elucidates previously uncharacterized regulatory mechanisms underlying adipogenesis in livestock species. Full article

MicroRNA-221 (miR-221), a conserved small non-coding RNA, acts as a pivotal modulator of biological processes across multiple organ systems, the dysregulation of which is closely linked to the pathogenesis of various human diseases. This review systematically summarizes its multifaceted roles in cancer, cardiovascular diseases (CVDs), neurological disorders, digestive system diseases, respiratory conditions, and adipose-endocrine dysfunction. In cancer, miR-221 exerts context-dependent oncogenic/tumor-suppressive effects by targeting phosphatase and tensin homolog (PTEN), cyclin-dependent kinase inhibitor 1c (CDKN1C/p57), and BCL2 modifying factor (Bmf), thereby regulating cell proliferation, invasion, stemness, and resistance to cancer therapy; it also serves as a non-invasive biomarker for glioma, papillary thyroid carcinoma, and colorectal cancer. In the cardiovascular system, it balances antiviral defense in viral myocarditis, modulates ventricular fibrotic remodeling in heart failure, and regulates endothelial function in atherosclerosis, with cell-type/ventricle-specific effects. In neurological disorders, it protects dopaminergic neurons in Parkinson’s disease and modulates microglial activation in epilepsy. It also regulates hepatic pathogen defense and intestinal mucosal immunity. Mechanistically, miR-221 alters cellular phenotypes by targeting tumor suppressors or signaling components (e.g., PI3K/AKT, TGF-β/suppressor of mothers against decapentaplegic homolog(SMAD), Wnt/β-catenin). Therapeutically, miR-221-targeting strategies show preclinical promise in cancer and CVDs. Despite this progress, further studies are needed to resolve context-dependent functional discrepancies, validate biomarker utility, and develop cell-specific delivery systems. This review provides a framework to understand its pathophysiologcial roles and potential application as a biomarker and therapeutic target. Full article

Cancer involves uncontrolled cell growth, leading to tumor formation, and remains a major cause of mortality worldwide. Colorectal cancer (CRC) arises from abnormal proliferation of colon glandular epithelial cells. We assessed the cytotoxic and molecular effects of lithium carbonate (Li₂CO₃) and lithium chloride (LiCl) in two CRC cell lines (HCT-116 and SW-620) and a non-tumorigenic line (CRL-1790). Viability assays revealed dose-dependent cytotoxicity, with HCT-116 being the most sensitive cell line (IC₅₀: 8.14 mM for Li₂CO₃). Notably, long-term lithium exposure reduced proliferation, lowering colony-forming efficiency (CFE) and a phenotypic shift from holoclones to meroclones and paraclones, indicating diminished self-renewal capacity. Minimal membrane damage was observed (LDH assay), suggesting non-lytic mechanisms consistent with apoptosis. TUNEL and Annexin-V/IP assays confirmed apoptosis in >40% of cells, without caspase-3 cleavage, suggesting a caspase-independent pathway. PARP-1 cleavage occurred only in SW-620 cells. Western blotting exposed cell-specific modulation of GSK-3β: increased inactive form (p-Ser9) in CRC cells and decreased in CRL-1790 cells, implying differential disruption of Wnt/β-catenin signaling. c-Myc levels remained unchanged, suggesting possible post-translational regulatory effects. Overall, these findings indicate that lithium salts selectively reduce CRC cell viability, impair stem-like characteristics, and induced caspase-independent apoptosis. Therefore, we expand the proof of concept of the potential of lithium-based compounds as low-toxicity adjuvant agents in colorectal cancer therapy. Full article

Pancreatic cancer poses a major clinical challenge due to its aggressiveness, frequent recurrence, and limited response to current chemotherapeutic approaches. Cancer stem cells (CSCs), particularly pancreatic CSCs (PCSCs), are key drivers of tumor initiation, therapeutic resistance, and disease relapse. MicroRNAs (miRNAs) have emerged as critical regulators of CSC biology and influence self-renewal, pluripotency, and drug resistance through key signaling pathways. To identify PCSC-specific miRNAs, we enriched these cells using the pancreosphere culture method and isolated PCSC+ and PCSC− populations using FACS based on their expression of CD44, CD24, and CD133 surface markers. MicroRNA microarray analysis revealed 31 differentially expressed miRNAs (DEmiRNAs), of which 10 downregulated miRNAs were involved in pathways regulating pluripotency, including the Wnt/β-catenin, TGF-β, MAPK, and PI3K/AKT pathways. Then, 2 of these 10 DEmiRNAs, let-7b-5p and miR-24-3p, were selected for experimental validation. Their overexpression in PCSC+ cells inhibited these pathways, downregulated pluripotency factors, and induced differentiation into endocrine and exocrine phenotypes, as confirmed by RT-qPCR, Western blot, and RNA-seq. Functionally, each miRNA reduced sphere formation, increased gemcitabine sensitivity, and suppressed tumorigenicity in vivo, highlighting their potential as therapeutic candidates. Restoring tumor-suppressive miRNA expression may offer a novel strategy to overcome chemoresistance and improve outcomes in pancreatic cancer. Full article

Intracellular signalling pathways provide a mechanism to connect events at a cell surface to the nucleus and are of fundamental importance to normal cell functioning. Intracellular signalling pathways control many aspects of cell metabolism, including mitochondrial function, oxidative stress, inflammation, and apoptosis/ferroptosis. Randomised controlled clinical trials supplementing coenzyme Q10 (CoQ10) have reported significant clinical improvements in a number of disorders, in turn associated with the action of CoQ10 to promote normal mitochondrial function, reduce oxidative stress and inflammation, and mediate apoptosis and ferroptosis. However, the precise mechanisms by which CoQ10 facilitates beneficial changes in the above factors is not completely understood. In the present article, the evidence we have reviewed provides a supporting rationale that the beneficial role of CoQ10 in the above disorders occurs via mediation of major intracellular signalling pathways, including the Nrf2/NQO1, NF-κB, P13/AKT/mTOR, MAPK, JAK/STAT, WNT/B-catenin, AMPK-YAP-OPA1, and hedgehog (Hh) pathways; the clinical consequences of such mediation are also reviewed. Full article

Objective: Previous reports showed that periodontopathic bacteria induce epithelial–mesenchymal transition (EMT) in oral squamous cell carcinoma (OSCC). Fisetin, a foodborne flavonoid, is reportedly associated with anticancer potential in various carcinogenic processes. This study aimed to elucidate the effects of fisetin on Fusobacterium nucleatum- and Porphyromonas gingivalis-induced EMT in OSCC cells. Methods: OSCC cells were co-cultured with live and heat-killed forms of F. nucleatum and P. gingivalis. The concentration of fisetin was set at 10 μM. Morphological changes in the OSCC cells were observed under a light microscope. Cell viability was measured using the Cell Counting Kit-8 assay, whereas migration was examined via wound healing. The mRNA expression of EMT-related markers was quantified using quantitative real-time polymerase chain reaction (PCR), and the expression of EMT-related markers and Wnt pathway-associated proteins was examined via Western blotting. Results: At a multiplicity of infection (MOI) of 300:1 for F. nucleatum and 100:1 for P. gingivalis, OSCC cell viability remained unchanged; however, wound closure rates increased significantly relative to the control. Likewise, treatment with fisetin (10 µM) did not materially alter viability; nevertheless, it attenuated promigratory effects induced by heat-killed periodontal pathogens at 3 h and 6 h. The OSCC cells exhibited EMT-like morphological changes after 6 h of co-culture with heat-killed pathogens. Consistently, reverse-transcriptase quantitative PCR and Western blot analyses showed increased expression of TWIST, ZEB1, and N-cadherin, accompanied by decreased E-cadherin expression, which was more pronounced in F. nucleatum than in P. gingivalis. However, fisetin reversed these trends. Moreover, co-culture with heat-killed pathogens markedly elevated β-catenin protein levels. In line with modulation of canonical Wnt/β-catenin signaling, fisetin and a Wnt inhibitor reduced β-catenin expression, whereas co-treatment with a Wnt agonist restored β-catenin levels in the presence of fisetin. Conclusions: Heat-killed F. nucleatum and P. gingivalis induced EMT in OSCC cells, with F. nucleatum exerting the strongest effect. Fisetin suppressed pathogen-driven EMT, at least partly via canonical Wnt/β-catenin signaling, highlighting its potential therapeutic value and warranting further investigation. Full article

Colon cancer (CC) is a common malignancy characterized by poor prognostic outcomes and considerable mortality. Oxaliplatin (OXP) is commonly used in the treatment of CC; however, its efficacy may be limited by side effects and the development of resistance. β-sitosterol (β-Sit), a phytosterol derived from plants, has been documented to be effective in the treatment of tumors. This study aimed to investigate the potential of β-Sit to enhance the antitumor efficacy of OXP in COLO-205 cells, focusing on apoptosis induction and suppression of the vascular endothelial growth factor A (VEGF-A)/survival pathway. Molecular docking studies were performed to assess the binding affinity of β-Sit with the target proteins B-cell lymphoma 2 (Bcl-2), phosphoinositide 3-kinase (PI3K), and VEGF receptor-2 (VEGFR-2). COLO-205 cells were treated with OXP, β-Sit, or a combination of OXP + β-Sit for 48 h. The combination treatment substantially lowered the IC₅₀ achieved with 3.24 µM of OXP and 36.01 µM of β-Sit, compared to 25.64 µM for OXP alone and 275.9 µM for β-Sit alone, demonstrating a pronounced synergistic impact. The combined therapy altered the cell cycle distribution by decreasing the number of cells in the G0/G, S, and G2/M phases, coupled with an increase in the Sub-G1 population. Furthermore, apoptosis was augmented by a shift in cell death from necrosis to late apoptosis, as indicated by an increased BAX/BCL2 ratio relative to each treatment alone. Moreover, the inhibitory effect on angiogenesis was enhanced via the reduction of VEGF-A, and β-catenin and nuclear factor κB (NF-κB-p65) were suppressed, thereby preventing the growth and survival of resistant cancer cells. Additionally, molecular docking supported high binding affinities of β-Sit to Bcl-2, PI3K, and VEGFR-2. This study highlights the potential of β-Sit to enhance the anti-cancer efficacy of OXP in CC. Full article