Search Results (4,351)

Cervical cancer (CC) is an alarming global health problem, with predominantly higher incidence, lethal progression, and mortality among women of African ancestry (AA) than women of European ancestry (EA). Although persistent high-risk human papillomavirus (HPV) integration and infection are the key etiological factors, currently available evidence implicates epigenetic reprogramming as a prime contributor to ancestry-associated differences in CC pathogenesis. To address these disparities, we performed genome-wide DNA methylation profiling of HPV-positive cervical intraepithelial neoplasia (CIN) lesions from AA (n = 15) and EA (n = 15) women. Differential methylation analysis identified a distinct epigenomic landscape in AA-CIN lesions, with widespread hypermethylation and hypomethylation at promoter-associated and regulatory CpG sites. Pathway enrichment analyses highlighted dysregulation of ECM-receptor interaction, focal adhesion, PI3K-Akt, MAPK, Ras, Rap1, and RUNX-dependent transcriptional networks. Comparative analysis across CIN grades (CIN1–CIN3) revealed progressive epigenetic reprogramming affecting cell cycles, cytoskeletal dynamics, signaling, and metabolic pathways. Among hypermethylated tumor suppressor genes, SH3GL2 and ARHGAP25 showed significantly higher methylation in AA lesions, accompanied by concomitant loss of their protein expression. MBD1, a methylation-binding regulator, was upregulated in AA-CIN lesions, coinciding with global loss of 5-hydroxymethylcytosine (5hmC), suggesting enhanced transcriptional repression. In contrast, EA lesions retained protein expression and 5hmC levels. Collectively, these findings indicate that early, ancestry-specific epigenetic modifications target tumor suppressor pathways and converge on oncogenic signaling, cytoskeletal remodeling, and cell–cell adhesion. Our study provides mechanistic insight into CC health disparities, identifying SH3GL2 and ARHGAP25 hypermethylation as potential biomarkers, and highlighting epigenetic regulation as a contributor to disparate CC progression in AA women. Full article

The increasing global burden of cancer, together with the need for more sustainable resource management, has stimulated growing interest in the valorization of agro-industrial plant residues as sources of bioactive compounds with therapeutic potential. This review highlights the potential of plant by-products—including citrus peels, olive leaves, date palm residues, and tea and coffee processing wastes—as sustainable reservoirs of polyphenols and other phytochemicals with significant anticancer activity. Key compounds such as hesperidin and naringenin from citrus peels, oleuropein and hydroxytyrosol from olive leaves, quercetin and syringic acid from date palm residues, and chlorogenic acid and epigallocatechin gallate from tea and coffee by-products have demonstrated promising antitumor effects in both in vitro and in vivo studies. These molecules exert their activity through multiple mechanisms, including the inhibition of cancer cell proliferation, induction of apoptosis, regulation of the cell cycle, and modulation of major oncogenic signaling pathways such as PI3K/AKT, MAPK, NF-κB, and EGFR. For instance, hydroxytyrosol induces apoptosis and cell cycle arrest while inhibiting the PI3K/AKT and MAPK pathways. Quercetin limits metastasis and glycolysis and suppresses VEGF, PKM2, and AKT signaling. Ferulic acid suppresses tumor growth by inhibiting the PI3K/AKT and JAK2/STAT6 pathways, thereby promoting apoptosis (in vitro and in vivo). In addition to their pharmacological potential, the recovery of these compounds from plant waste supports circular economy strategies by reducing environmental impact and promoting the development of value-added products. Future research should focus on optimizing extraction methods, improving bioavailability and stability, and validating safety and efficacy through well-designed preclinical and clinical studies. Full article

Triple-negative breast cancer (TNBC) is one of the most aggressive and clinically challenging subtypes of breast cancer, defined by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. The lack of actionable molecular targets contributes to limited therapeutic options, frequent recurrence, and a high propensity for distant metastasis. Metastatic dissemination remains the principal cause of mortality in patients with TNBC and is driven by complex molecular mechanisms involving multiple interconnected signaling networks. This review summarizes current knowledge of the molecular mechanisms underlying metastatic progression in TNBC, with particular emphasis on signaling pathways that regulate tumor invasion, migration, and colonization of distant organs. We discuss the roles of key pathways, including PI3K/Akt, TGF-β, Wnt/β-catenin, NF-κB, and Rho/ROCK signaling, in the regulation of epithelial–mesenchymal transition, cytoskeletal remodeling, cancer stem cell phenotypes, and tumor–microenvironment interactions. A deeper understanding of these signaling networks may facilitate the identification of novel therapeutic targets and support the development of more effective strategies to limit metastatic disease in TNBC. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial disorder driven by tightly interconnected metabolic, inflammatory, and lipid dysregulation pathways. Glycyrrhetinic acid, a pentacyclic triterpenoid derived from Glycyrrhiza species, has demonstrated anti-inflammatory and hepatoprotective activities in previous experimental studies. Objectives: This study aimed to systematically investigate the potential molecular targets and signaling pathways of glycyrrhetinic acid in MASLD using an integrated network pharmacology and molecular docking strategy. Methods: Predicted protein targets of glycyrrhetinic acid and MASLD-associated genes were collected from public databases. A protein–protein interaction (PPI) network was constructed, and hub genes were identified using the maximal clique centrality algorithm in Cytoscape. Functional annotation was performed through Gene Ontology and KEGG pathway enrichment analyses. Molecular docking simulations were subsequently conducted to assess the binding affinity of glycyrrhetinic acid with biologically prioritized targets derived from the network analysis. Results: Intersection analysis identified 26 shared targets between glycyrrhetinic acid and MASLD. PPI network analysis highlighted IL6, TNFα, AKT1, and PPARγ as central hub genes. Functional enrichment indicated that these targets were mainly involved in NF-κB, TNFα, and PI3K–Akt signaling pathways. Molecular docking results revealed favorable predicted binding affinities, with glycyrrhetinic acid exhibiting the strongest binding toward PPARγ among the evaluated targets. Conclusions: This integrative in silico analysis suggests that glycyrrhetinic acid may interact with multiple MASLD-related targets involved in inflammatory and metabolic regulation. These findings provide a computational framework for target prioritization and support further experimental investigations to elucidate the pharmacological relevance of glycyrrhetinic acid in MASLD. Full article

Melia azedarach L. is a plant known for its traditional medicinal uses. Limonoids (triterpenes), which have a wide range of pharmacological effects, are the most critical active ingredients; however, their potential effects on liver cancer remain to be further explored. In this study, seven limonoids were isolated from the bark of Melia azedarach, including two new compounds, 11α-hydroxy-12-Oxo-Meliarachin I (1) and 29-Oxo-12-dehydroneoazedarachin D (3), along with five known compounds (2, 4–7), to evaluate their effect on liver cancer in vitro. The results showed that compounds 1–7 exhibited varying degrees of inhibitory effects on Hep3B cells. Among these, compound 6, Isotoosendanin (ITSN), displayed the most potent activity, with an IC₅₀ value of 15.06 μg/mL. Mechanism studies have shown that ITSN inhibits cell proliferation and promotes apoptosis in Hep3B cells. It induces reactive oxygen species (ROS) accumulation to trigger oxidative stress injury, suppresses the activation of the MAPK and PI3K/AKT signaling pathways, further activates the p53 pathway to induce cell cycle arrest, and ultimately initiates the apoptotic cascade. ITSN can also inhibit tumor growth in immunodeficient mice receiving allogeneic transplantation. In summary, we systematically studied the limonoids in the bark of Melia azedarach and elucidated the anti-hepatocarcinoma activity of ITSN in vitro and in vivo, providing promising evidence for its potential use as a natural active ingredient in the prevention and treatment of cancer. Full article

Neurodegenerative disorders, including Parkinson’s disease (PD), are largely treated with symptomatic therapies, underscoring the need for strategies that target underlying disease mechanisms. Glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R), a class B G protein-coupled receptor best known for metabolic regulation, have attracted interest due to the increasing evidence of central nervous system (CNS) actions. This review synthesises mechanistic, preclinical, and clinical evidence examining GLP-1R signalling in PD and related neurodegenerative contexts. We integrate findings from cellular and animal models with early-phase clinical studies of GLP-1 receptor agonists (GLP-1RAs). Across experimental systems, GLP-1R activation engages conserved intracellular pathways—cAMP/PKA, PI3K/Akt, and ERK—that regulate mitochondrial function, oxidative stress, autophagy-lysosomal dynamics, and inflammatory signalling. In PD-relevant models, these pathways intersect with key pathogenic features, including α-synuclein accumulation, dopaminergic neuron vulnerability, and glial reactivity. Clinical studies to date demonstrate acceptable safety and tolerability, alongside biomarker evidence of central pathway engagement and variable effects on motor and non-motor outcomes. However, uncertainties remain regarding CNS target engagement, peripheral versus CNS mechanisms, and disease-stage dependence. Overall, the current evidence positions GLP-1R signalling as a biologically plausible therapeutic pathway in PD that warrants further mechanistic clarification and rigorous evaluation in ongoing and future clinical trials. Full article

Background/Objectives: Snow Chrysanthemum (Coreopsis tinctoria Nutt.), a traditional medicinal and edible plant rich in flavonoids (TFSC) with antihypertensive and neuroprotective activities, has unclear effects and mechanisms on vascular dementia (VaD) comorbid with hypertension, a key risk factor accelerating VaD. This study aimed to investigate TFSC’s ameliorative effects on cognitive impairment in hypertensive VaD rats and elucidate its holistic therapeutic mechanisms. Methods: Spontaneously hypertensive rats (SHRs) with unilateral common carotid artery ligation were used to establish the hypertensive VaD model. TFSC was intragastrically administered for 11 weeks. Systolic blood pressure (BP) and cerebral blood flow (CBF) were monitored; cognitive function was assessed via open field, novel object recognition and Morris water maze tests. Histopathological changes were evaluated by H&E and Nissl staining, serum oxidative stress and inflammatory markers were measured, and hippocampal transcriptome sequencing plus RT-qPCR was performed to identify key pathways and genes. Results: The chemical profile of TFSC was characterized, showing a total flavonoid content of 84.96%; 49 compounds were identified, 39 of which were flavonoids. TFSC reduced BP, improved CBF, alleviated cognitive dysfunction and neuronal damage, enhanced antioxidant capacity (increased SOD, CAT, GSH; decreased ROS), and exerted anti-inflammatory effects (reduced TNF-α, IL-1β, IL-6, Ang-II). It modulated multiple pathways, with the PI3K-Akt and MAPK pathways enriched, and validated key differentially expressed genes. Conclusions: This study provides preliminary evidence for the holistic therapeutic potential of TFSC against hypertensive VaD. With integrated vascular regulatory and neuroprotective effects, TFSC serves as a promising candidate for VaD by targeting both vascular risk factors and neuropathological damage. Full article

Depression is a common mental disorder that substantially impairs patients’ daily life and work. To identify natural and safe preventive options, we investigated the preventive effect and underlying mechanism of the Ganoderma lucidum and Rosa roxburghii Tratt formula (GLRRTF) on depression. A total of 72 chemical components in GLRRTF were identified by UHPLC-ESI-Q-Exactive Plus Orbitrap-MS Analysis. GLRRTF (containing 400 mg/kg of G. lucidum extract and 800 mg/kg of R. roxburghii extract per day), administered as a 1-week preventive intervention followed by 4 weeks of co-administration with chronic unpredictable mild stress, prevented the development of depression-like behaviors in male C57BL/6J mice and reduced neuronal damage in the hippocampus. Airflow-assisted desorption electrospray ionization mass spectrometry imaging and enzyme-linked immunosorbent assays showed that GLRRTF corrected abnormalities in neurotransmitter levels. The 16S rRNA sequencing indicated that GLRRTF restored dysbiosis of the gut microbiota. Metabolomic profiling revealed that GLRRTF increased the level of tryptophan and promoted tryptophan metabolism towards the 5-HT and indole pathways in feces and the brain. Western blot demonstrated that GLRRTF increased 5-HT production from tryptophan in the brain by regulating tryptophan hydroxylase 2 and DOPA decarboxylase. GLRRTF activated the PI3K/AKT pathway by regulating brain-derived neurotrophic factor and its receptor tropomyosin receptor kinase B. This research provides a comprehensive mechanistic understanding of GLRRTF’s preventive effect against depression, highlighting its potential as a novel, safe, and preventive functional food formulation. Full article

Background/Objectives: Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1), also known as protein tyrosine phosphatase non-receptor type 6, functions as a tumor suppressor in breast, hepatocellular, and prostate cancers and an oncogene in glioblastoma and cervical cancer. A previous analysis of The Cancer Genome Atlas (TCGA) dataset revealed that lower SHP-1 transcript levels in bladder tumors were associated with poorer overall survival. Methods: This study aimed to evaluate the role of SHP-1 in bladder cancer and to assess the functional impact of its forced expression and knockdown in bladder carcinoma cell lines. SHP-1 expression was assessed in 19 bladder cancer cell lines and 26 bladder tissues. Lentiviral transduction was used to knock down or overexpress SHP-1 in four cell lines, followed by Western blot analysis of SHP-1 and pAkt/Akt protein expression. Results: SHP-1 protein levels were significantly lower in highly invasive cell lines (p < 0.001) and muscle-invasive tumors (p < 0.05). Functional studies demonstrated that SHP-1 modulation influenced the epithelial–mesenchymal transition (EMT) phenotype. SHP-1 expression was positively correlated with E-cadherin expression (p < 0.001) and negatively correlated with N-cadherin (p < 0.01) and Vimentin (p < 0.05) expression. Alteration of SHP-1 expression in bladder cancer cell lines affected proliferation, invasion, and migration (p < 0.05). RNA-seq analysis of the transduced cell lines revealed enrichment of gene sets related to EMT and signaling pathways involving MYC, PI3K, Akt, and mTOR. Furthermore, SHP-1 alteration impacted pAkt/Akt ratios (p < 0.05). Conclusions: Collectively, lower SHP-1 protein expression correlated with more aggressive phenotypes in bladder cancer cell lines and bladder tumors. In our limited dataset, reduced SHP-1 expression correlated with muscle-invasive disease, suggesting a potential link to more advanced tumor biology, consistent with TCGA associating reduced SHP-1 transcript expression to poorer survival rates. Our data provide preliminary functional evidence that SHP-1 may modulate Akt signaling in bladder cancer. Together, these results support further investigation of SHP-1 as a possible tumor suppressor, candidate prognostic biomarker, and potential therapeutic target in bladder cancer. Full article

Adipogenesis is a critical factor in causing obesity, which is a global health problem associated with metabolic disorders, such as insulin resistance and cardiovascular diseases. Natural compounds with anti-adipogenic activity may represent potential approaches for modulating adipocyte function. However, despite increasing interest in natural products, the anti-adipogenic potential of acridone alkaloids, particularly prenylated derivatives, remains largely unexplored. This study examined the effects of N-methylatalaphylline (NMA), a prenylated acridone alkaloid, on adipocyte differentiation, lipid accumulation, and glucose uptake. NMA exhibited anti-adipogenesis, particularly toward preadipocytes, and significantly reduced lipid accumulation in murine 3T3-L1 and human PCS-210-010 adipocytes at nontoxic doses (1.5–6 µM). At 3–6 µM, NMA downregulated adipogenic regulators, including PPARγ, C/EBPα, and SREBP1, along with adipogenic effectors, such as FABP4, adiponectin, LPL, PLIN1, and FAS. Mechanistic studies indicated that NMA treatment was associated with reduced phosphorylation of AKT, ERK, and p38, accompanied by cell-cycle arrest and inhibition of mitotic clonal expansion. Meanwhile, activation of AMPK-ACC signaling, which may contribute to suppression of adipogenesis and reduced glucose uptake, was observed in differentiated 3T3-L1 cells after treatment with 6 µM NMA for 48 h. Additionally, molecular docking and molecular dynamics simulations suggested potential interaction between NMA and ERK1, supported by hydrogen bonding and hydrophobic contacts. Overall, these findings suggest that NMA exerts anti-adipogenic effects in vitro by modulating adipocyte proliferation, differentiation, and lipid metabolism. These findings highlight NMA as a promising acridone alkaloid scaffold for anti-adiposity applications, warranting further in vivo validation. Full article

Dysregulation of the immune system, gut microbiota alteration, and epithelial dynamics in the colon contribute to the pathogenesis of inflammatory bowel disease (IBD). However, the role of epithelial dynamics, particularly epithelial regeneration, remains incompletely understood. CADM1 encodes an immunoglobulin-superfamily cell adhesion molecule involved in epithelial adhesion, immune cell interactions, and tumor suppression in colon and various cancers. Here, we investigated the role of CADM1 in IBD using a murine model of colitis induced by dextran sulfate sodium in both wild-type and conventional Cadm1-deficient (Cadm1^−/−) mice. Cadm1^−/− mice exhibited more severe colitis than wild-type mice with increased mortality (64% vs. 10%) and delayed recovery. Cadm1^−/− mice showed reduced numbers of Ki-67-positive cells in colonic crypts and delayed epithelial regeneration, whereas no significant differences were observed in epithelial apoptosis, intestinal permeability, or immune responses. Immunohistochemistry revealed that CADM1 expression was restricted to regenerative crypt cells in wild-type mice with nuclear accumulation of β-catenin and phospho-Akt. Furthermore, CADM1 overexpression in colon epithelial cells enhanced Tcf-transcriptional activity in a β-catenin-dependent manner. Immunohistochemistry of human IBD materials revealed that CADM1 expression also correlated with nuclear β-catenin accumulation in crypt epithelial cells. Collectively, CADM1 appears to promote colonic epithelial regeneration through the PI3K/Akt/β-catenin axis to protect against severe epithelial injury in IBD. Full article

Objectives: This study aimed to investigate the biological role and molecular mechanism of the RNA m⁵C methyltransferase NSUN4 in cervical cancer progression, with a focus on its involvement in ferroptosis regulation. Methods: Differential expression and survival analyses were performed using TCGA and GEPIA datasets. Functional enrichment and GSEA identified pathways associated with NSUN4 dysregulation. NSUN4 expression was validated in clinical tissues by qRT-PCR, Western blot, and immunohistochemistry. Gain- and loss-of-function assays, including CCK-8, colony formation, and Transwell assays, were conducted to assess cell proliferation and invasion. Furthermore, a nude mouse subcutaneous xenograft model was established to validate the oncogenic role of NSUN4 in vivo. Ferroptosis was evaluated using specific inhibitors and measurement of GSH and ferroptosis-related proteins. RIP, m⁵C-RIP, RNA stability, and dual-luciferase assays were performed to explore the underlying mechanism. Results: NSUN4 was markedly upregulated in cervical cancer tissues and correlated with poor prognosis. Functionally, NSUN4 enhanced tumor cell growth, migration, and invasion while inhibiting ferroptosis. Mechanistically, NSUN4 bound to and stabilized C-MYC mRNA via m⁵C methylation, activating the PI3K/Akt signaling pathway and promoting ferroptosis resistance. Conclusions: NSUN4 promotes cervical cancer progression by stabilizing C-MYC mRNA through m⁵C modification, leading to PI3K/Akt activation and suppression of ferroptosis. These findings identify NSUN4 as a novel oncogenic regulator and potential therapeutic target in cervical cancer. Full article

Background: Cytokine-like receptor family 1 (CRLF1) has been implicated in tumor progression, yet its prognostic function and mechanistic actions in prostate cancer (PCa) remain elusive. Objective: This investigation sought to clarify the functional role, molecular mechanisms, and clinical relevance of CRLF1 in the progression of PCa. Methods: We conducted extensive bioinformatics analyses utilizing the protein interaction networks and the TCGA-PRAD dataset. CRLF1 and cartilage oligomeric matrix protein (COMP) expression were validated in clinical samples by qRT-PCR and Western blot (WB). Functional assessments, including Transwell invasion, flow cytometry, CCK-8, and wound healing, were conducted in vitro. An in vivo xenograft tumor model was used for further validation. Mechanistic investigations involved genetic perturbation (overexpression and inhibition) of CRLF1 and COMP. Results: Compared to benign tissues, the levels of CRLF1 and COMP were markedly elevated in PCa tissues. Bioinformatics assessments illustrated a robust positive relationship between CRLF1 and COMP, suggesting COMP may function as a downstream mediator. In vitro and in vivo investigations illustrated that silencing CRLF1 significantly suppressed PCa cell growth, invasion, and tumor progression, while enhancing apoptosis. Importantly, suppressing COMP counteracted the cancer-promoting effects triggered by CRLF1 overexpression. At the mechanistic level, CRLF1 facilitates tumor progression by modulating COMP to activate the FAK/PI3K/AKT signaling cascade. Conclusions: Our outcomes demonstrate that CRLF1 promotes PCa progression by targeting COMP to stimulate the FAK/PI3K/AKT signaling axis. This newly identified CRLF1/COMP/FAK/PI3K/AKT pathway underscores CRLF1 as a potential biomarker and therapeutic target for PCa. Full article

Diarrhea is a common gastrointestinal disorder in animals, often worsened by antibiotic use. Pulsatilla chinensis (PC) is traditionally used for gastrointestinal issues, but its bioactive constituents and mechanisms remain unclear. This study investigated the preventive effects of PC in a canine model of antibiotic-associated diarrhea using an integrated multi-omics approach. LC–MS identified key constituents of PC, including anemoside B4, berberine, stigmasterol, and quercetin. In silico analyses predicted that stigmasterol and quercetin target EGFR and AKT1, modulating inflammation and epithelial repair via PI3K–Akt and IL-17 signaling pathways. In vivo, treatment with PC significantly reduced serum pro-inflammatory cytokines such as TNF-α and IL-6 and elevated immune markers including IgG and IgA compared to the control group. Furthermore, 16S rRNA analysis revealed that PC restored gut microbial diversity, reflected by increased Sobs and Chao1 indices, enriched beneficial Lactobacillus, and decreased the abundance of inflammation-associated taxa such as Proteobacteria, Desulfobacterota, and Escherichia-Shigella. These findings suggest that PC suppresses inflammation and remodels the gut microbiome, providing a mechanistic basis for its use as an herbal alternative to antibiotics. Future studies should include fecal microbiota transplantation and targeted metabolomics to establish causality and optimize therapeutic strategies. Full article

Background: Supplementing aquafeeds with emulsifiers can enhance lipid utilization, yet the physiological effects of lysolecithin, derived from enzymatic lecithin conversion, remain under-explored. Objectives: This study examined the effects of lysolecithin supplementation on hepatopancreatic transcriptome and gut microbiota in largemouth bass (Micropterus salmoides) fed stearin-based high-lipid diets. Methods: Two diets were formulated: a control containing 130 g kg⁻¹ stearin fish oil (SO), and in the experimental diet (SL), 3.1 g kg⁻¹ rapeseed oil was replaced with 3.1 g kg⁻¹ lysolecithin oil. Each diet was fed to three replicate groups for 56 days. Hepatopancreas and distal intestine were sampled for transcriptome profiling, and gut microbiota were characterized at 28 and 56 days. Results: Lysolecithin supplementation resulted in 424 differentially expressed genes compared with the control (322 up- and 102 downregulated). KEGG enrichment indicated major effects on lipid metabolic processes, notably activation of the PI3K-AKT signaling pathway, enhanced adipocyte lipolysis, and modulation of adipocytokine signaling, suggesting improved insulin sensitivity and lipid mobilization. Histological analysis showed mild distal intestinal inflammation in the SO group. Gut microbiota composition shifted over time; lysolecithin increased the relative abundance of Cetobacterium and reduced potential opportunistic taxa compared with the control. Conclusions: Overall, dietary inclusion of lysolecithin improved lipid utilization in largemouth bass, likely by enhancing lipid metabolism and promoting beneficial gut microbial profiles. These findings support lysolecithin as a promising feed additive for optimizing high-lipid aquafeeds. Full article