Search Results (7,291)

Fungi are a prolific source of diverse bioactive metabolites, yet many remain unexplored. Among these, depsidones are a rare class of compounds with significant biological potential, but they are seldom reported in mushrooms. This study investigated the medicinal fungus Ganoderma lucidum, known for its extensive therapeutic use in traditional medicine. Fruiting bodies were extracted using petroleum ether, ethyl acetate, n-butanol, and methanol. Extracts were screened phytochemically and assessed for total phenolic content and antioxidant activity using the DPPH assay. Ethyl acetate extract exhibited the highest phenolic yield and antioxidant potential and was subsequently evaluated for cytotoxicity against HepG2, HCT116, MCF7, and A549 cancer cell lines. It showed notable anticancer activity with minimal toxicity to normal Vero cells. UHPLC/Q-TOF-MS/MS analysis of G. lucidum ethyl acetate extract tentatively identified nine minor depsidones including mollicellin G, simplicildone I, mollicellin B, talaromyone B, simplicildone A, purpactin C, emeguisin B, mollicellin E, and simplicildone D on the basis of high-resolution negative-mode detection and characteristic MS/MS fragmentation patterns. Molecular docking revealed strong binding affinities between these compounds and cancer-related targets (AKT1, CDK2, ERK1, TNFα), with simplicildone D and mollicellin G demonstrating particularly high interactions. These findings provide mechanistic insights into the observed bioactivity and highlight G. lucidum as a promising source of therapeutic depsidones for future anticancer drug development. Full article

To investigate the genetic regulatory mechanism of supplementary feeding on muscle development in Oula sheep, we employed transcriptomic analysis to explore the differentially expressed genes (DEGs) in the longissimus dorsi muscle of Oula sheep at different ages under conditions of supplementary feeding and non-supplementary feeding, as well as the significantly enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways of DEGs. Moreover, by combining with the method of weighted gene co-expression network analysis, we screened for the potential hub genes that might play crucial roles. The results demonstrated that the CD4 and ICAM1 genes and the PI3K-Akt signaling pathway might exert important functions during the lamb stage. At the growth stage, the AGL, PGM2L1, PRKAA2, NEDD4, and GBE1 genes might serve as core genes to regulate the growth of skeletal muscle in Oula sheep after supplementary feeding through signaling pathways such as starch and sucrose metabolism and insulin signaling pathway. This outcome provides a molecular-level interpretation of the regulatory mechanism of supplementary feeding on muscle growth and development in Oula sheep at different ages, offering a theoretical basis for the further improvement of the meat quality of Oula sheep and the enhancement of the quality of livestock products in the Qinghai–Tibet Plateau region. Full article

Background/Objectives: Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with a poor prognosis and limited therapeutic options. This study aimed to repurpose methylstat, a selective histone demethylase inhibitor, as a novel anti-glioma agent. We characterized its anti-proliferative efficacy, elucidated mechanisms of cell cycle regulation, and evaluated its blood–brain barrier (BBB) permeability potential. Methods: Compounds with transcriptional profiles enriched for cell cycle arrest and tumor-suppressive pathways were identified via Connectivity Map (CMAP) analysis. Methylstat was selected based on its high connectivity score and favorable physicochemical properties. In vitro assays were performed to evaluate its effects on cell viability, proliferation, cell cycle progression, and expression of related molecular markers in U251 and HOG glioma cell lines. Molecular docking and 200 ns molecular dynamics (MD) simulations were performed to evaluate the binding mode and stability of the Methylstat–JMJD2A complex. An in vitro BBB model was established to assess the ability of Methylstat to cross the BBB. Results: Methylstat significantly inhibited glioma cell proliferation in a dose-dependent manner without inducing apoptosis. It caused G1-phase arrest in U251 cells and G2-phase arrest in HOG cells. Mechanistically, methylstat downregulated cyclins and cyclin-dependent kinases via the p53/p21 pathway. Additionally, methylstat reduced the expression of JMJD2A and its downstream targets, including PDK1, AKT, and mTOR. Molecular docking studies and 200 ns MD simulations confirmed the stable binding of methylstat to the catalytic pocket of JMJD2A, effectively inhibiting its enzymatic activity. HPLC analysis confirmed that methylstat could penetrate the in vitro BBB model to varying extents. Conclusions: Methylstat is a promising small-molecule agent that effectively suppresses glioma cell growth by modulating key cell cycle regulators. Its ability to cross the BBB highlights its potential as a novel therapeutic strategy for GBM and other brain tumors. Full article

Background: Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide, with its advanced stages presenting significant challenges for the clinical oncologist. Axl is a member of the TAM family of receptor tyrosine kinases that is becoming increasingly important in the pathophysiology of (advanced) GC. This receptor, activated by its ligand Gas6 (growth arrest-specific gene 6), is implicated in various oncogenic processes, including cell survival, proliferation, migration, and immune evasion. Overexpression or aberrant activation of Axl has been associated with poor prognosis, tumor aggressiveness, and resistance to conventional therapies in gastric cancer. Objectives: This review aims to consolidate current knowledge on Axl’s role in gastric cancer pathophysiology and explore its therapeutic implications. Materials and Methods: A thorough search was conducted in the most relevant online databases, using different combinations of the following terms: Axl, GC, pathophysiology, and therapeutic target. Results: In the first part, the molecular mechanisms of Axl in tumors, which involve, among others, the activation of downstream signaling pathways, including PI3K/AKT, MAPK/ERK, and NF-κB, are discussed. Subsequently, potential treatments targeting Axl and potential combination therapies are highlighted, based on the encouraging results from preclinical and clinical studies. Finally, as the Axl–tumor microenvironment interplay is discussed, with therapeutic implications, it thus opens new pathways for research on effective treatments in advanced gastric cancer. Conclusions: Understanding Axl’s role in the pathophysiology of GC is essential to develop efficient targeted therapies with improved clinical effects. Full article

Excessive osteoclast activity in bone remodeling can lead to an imbalance between bone resorption and formation, a common occurrence in abnormal bone metabolic diseases. This research investigates the effect of Coptidis rhizoma water extract (CRW) on osteoclastogenesis provoked by RANKL in vitro and bone destruction mediated by ovariectomy (OVX) in vivo. CRW, prepared from dried Coptidis rhizoma (CR), was analyzed for its active compounds—coptisine and berberine—using HPLC analysis. CRW markedly decreased the size and number of TRAP-positive multinucleated cells (TRAP⁺ MNCs), suppressed F-actin ring formation, and diminished bone resorption in RANKL-treated cultures. In the early phase of differentiation, CRW suppressed the phosphorylation of MAPKs p38, JNK, and ERK, as well as NF-κB p65, Iκ-Bα, and Akt. CRW also down-regulated RANKL-mediated induction of c-Fos and NFATc1 and attenuated the activation of NFATc1- dependent genes, such as OSCAR, ATP6V0D2, ACP5 (TRAP), OC-STAMP, DC-STAMP, CTSK (cathepsin K), CALCR (calcitonin receptor), and MMP-9. In ovariectomized rats, micro-CT and histological analyses showed that CRW alleviated femoral bone destruction. These findings indicate that CRW restrains osteoclast differentiation and function and may have therapeutic potential for disorders driven by excessive osteoclast activity. Full article

The ERK1/2 and PI3K signaling pathways play important roles in cellular proliferation, survival, differentiation, and metabolism. In cancer, these pathways are frequently dysregulated and overactivated, resulting in poor patient prognosis and resistance to treatment. These pathways are activated by receptor tyrosine kinases and send downstream signals to effectors such as RAS, RAF, MEK, AKT, and mTOR. In this review, we highlight the key components of the ERK1/2 and PI3K pathways, the roles they play in tumor progression, and the development of inhibitors and combination therapies designed to enhance therapeutic outcomes and address treatment resistance. Our review demonstrates the need and promise for future research and clinical trials for inhibitors and combination therapies for the ERK1/2 and PI3K pathways in cancer. Full article

Background: Osteosarcoma is an aggressive bone tumor with a high risk of lung metastasis, which severely affects patient survival. EMT plays a major role in tumor spread, therapy resistance, and cancer stemness. This review explores how EMT contributes to osteosarcoma metastasis and the underlying molecular mechanisms. Methods: We reviewed recent studies on EMT-related signaling pathways, transcription factors, and regulatory RNAs in osteosarcoma. We also examined the role of the tumor microenvironment. Results: EMT promotes cell detachment, migration, and lung colonization. Key pathways such as TGF-β, MAPK, PI3K/Akt, STAT3, Notch, and Wnt/β-catenin are involved. Non-coding RNAs further regulate EMT by interacting with these pathways. The tumor microenvironment, including hypoxia and immune cells, also supports EMT and metastasis. Conclusions: EMT is a key driver of metastasis and poor outcomes in osteosarcoma. Targeting EMT and its regulators may help prevent lung spread and improve treatment. Future strategies combining EMT inhibition with existing therapies could be promising for clinical application. Full article

Background: In high-altitude regions, sporadic two-year-old immature Chinese mitten crabs (Eriocheir sinensis) would overwinter and mature in their third year, developing into three-year-old crabs (THCs) with a cold-adaptive strategy. Compared to two-year-old crabs (TWCs) from low-altitude Jiangsu, THCs from Karst landform and high-altitude Guizhou exhibit significantly larger final size but lower gonadosomatic index (GSI) (p < 0.01). Methods: To elucidate the molecular mechanisms underlying this delayed ovarian development, integrated transcriptomic and proteomic analyses were conducted. Results: Results showed downregulation of PI3K-Akt and FoxO signaling pathways, as well as upregulation of protein digestion and absorption pathways. Differentially expressed proteins indicated alterations in mitochondrial energy transduction and nutrient assimilation. Integrated omics analysis revealed significant changes in nucleic acid metabolism, proteostasis, and stress response, indicating systemic reorganization in energy-nutrient coordination and developmental plasticity. Conclusions: The observed growth-reproductive inverse relationship reflects an adaptive life-history trade-off under chronic cold stress, whereby energy repartitioning prioritizes somatic growth over gonadal investment. Our transcriptomic and proteomic data further suggest a pivotal regulatory role for FOXO3 dephosphorylation in potentially coupling altered energy sensing to reproductive suppression. This inferred mechanism reveals a potential conserved pathway for environmental adaptation in crustaceans, warranting further functional validation. Full article

Tanshinone IIA (T-IIA), a fat-soluble diterpene quinone extracted from Salvia miltiorrhiza, is widely recognized for its multiple pharmacological properties, including anti-inflammatory, antioxidant, anti-fibrotic, and anti-tumor effects. Recent studies have highlighted its great potential in treating bone metabolic disorders, especially osteoporosis and bone damage repair. Bone health depends on the dynamic balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Disruption of this balance can lead to diseases such as osteoporosis, which is often diagnosed after a fracture, seriously affecting the quality of life and increasing the medical burden. Early identification of high-risk groups and appropriate treatment are essential for preventing fracture recurrence. Studies have shown that T-IIA can promote osteoblast differentiation and inhibit osteoclast activity, targeting key signaling pathways such as NF-κB, PI3K/Akt, and Wnt/β-catenin, all of which are closely related to bone metabolism. T-IIA has a dual role in regulating bone formation and bone resorption, making it a potential drug for the treatment of osteoporosis. In addition, T-IIA has neuroprotective, hepatic, renal, cardiac, and cerebral effects, which enhance its therapeutic effect. Despite the remarkable efficacy of T-IIA, its clinical application is limited due to poor solubility and low bioavailability. Recent advances in drug delivery systems, such as liposome formulations and nanocarriers, have improved their pharmacokinetics, increased absorption rate, and bioavailability. Combination therapy with growth factors or stem cells can further enhance its efficacy. Future studies should focus on optimizing the delivery system of T-IIA and exploring its combined application with other therapeutic strategies to expand its clinical application range. Full article

Osteoblastogenesis plays a critical role in bone repair. Insulin and insulin-mimetic compounds, such as vanadium (IV) oxide acetylacetonate (VAC), have been reported to enhance bone healing in various models. This study aimed to evaluate the effects of vanadium compounds, VAC and vanadium (IV) oxide sulfate (VOSO₄), on osteoblast proliferation and function. MC3T3-E1 pre-osteoblast cells were treated with insulin, ascorbic acid, and varying concentrations of VAC or VOSO₄, and samples were collected at multiple time points over 21 days. We assessed cell proliferation, functional markers, and gene and protein expression. Our findings demonstrate that both VAC and VOSO₄ stimulate MC3T3-E1 proliferation, increase calcium and proteoglycan deposition, and enhance phosphorylation of Protein Kinase B (Akt) over time. Gene expression analysis revealed that VAC treatment upregulated RUNX2, BGLAP, and TWIST2 at Day 7 compared to controls, with sustained expression patterns observed at Day 10. These results align with existing literature, supporting that VAC and VOSO₄ promote osteoblastogenesis and may serve as effective adjuvants to accelerate bone regeneration during fracture healing. Full article

Low-density lipoprotein receptor-related protein 5 (LRP5) is a multifunctional transmembrane coreceptor that plays a pivotal role in development and disease. Wnt/β-catenin signaling is the primary downstream signaling pathway activated by LRP5. Furthermore, some LRP5 functions are mediated by noncanonical pathways, such as AKT/P21 and TGF-β/Smad signaling. Pathologically, both loss-of-function and gain-of-function mutations in LRP5 produce distinct phenotypes, ranging from osteoporosis-pseudoglioma syndrome to high bone mass disorders. Beyond the skeletal system, LRP5 has emerged as a key regulator of retinal angiogenesis, vascular integrity, renal tubular function, neurodevelopment, and lipid metabolism. Its physiological functions are highlighted by its ability to influence adipocyte differentiation, insulin sensitivity, and neuronal synaptic plasticity. Moreover, LRP5 displays a dual role in development and disease progression. Although it plays a protective role in acute injuries such as myocardial infarction and acute kidney injury, LRP5 also contributes to chronic pathologies such as tubulointerstitial fibrosis, polycystic kidney disease, and atherosclerosis through fibrotic and inflammatory pathways. Recent therapeutic interest has focused on modulating LRP5 activity using agents such as anti-Dickkopf-related protein 1 antibody, sclerostin inhibitors, polyclonal antibodies, CRISPR/Cas9 knockout, and some natural products. This review discusses the current understanding of LRP5's physiological and pathological roles across organ systems and highlights its therapeutic potential, emphasizing the need for targeted approaches considering its context-dependent effects. Full article

Background: Colorectal cancer (CRC) is the third most common cancer worldwide, with liver metastasis being the leading cause of mortality. De novo fatty acid synthesis plays a critical role in CRC progression and metastasis. Bufalin, a cardiotonic steroid isolated from toad skin, has demonstrated anticancer activity in multiple preclinical models. However, the mechanisms underlying its suppression of CRC metastasis and modulation of fatty acid synthesis remain to be elucidated. Methods: The effects of bufalin on CRC cell proliferation, migration, and apoptosis were assessed via colony formation, wound healing, and flow cytometry assays. Transcriptome analysis identified bufalin-affected pathways, with changes in gene and protein expression. FASN protein levels were quantified using ELISA. Results: Bufalin inhibited proliferation and migration of CRC cells and induced the apoptosis of LoVo and HCT8 cells. Transcriptome analysis highlighted lipid metabolism pathways as potential mediators of bufalin’s anti-metastatic activity. Notably, bufalin reduced the expression of fatty acid synthase (FASN) and suppressed CRC metastasis. In vivo experiments demonstrated that bufalin attenuated CRC progression and liver metastasis by inhibiting de novo fatty acid synthesis through the PI3K/AKT-mediated SREBP1/FASN pathway. Conclusions: Bufalin inhibits de novo fatty acid synthesis via the PI3K/AKT-mediated SREBP1/FASN pathway, suppressing CRC progression and liver metastasis. Full article

Background: Ischemic stroke (IS) is a significant cause of global mortality and disability. Yiqi Huoxue Jieyu granules (YHJGs) show therapeutic potential for IS, but their mechanisms remain unclear. This study investigated YHJGs’ effects through network pharmacology, molecular docking, and experimental validation. Methods: Active YHJG components and IS targets were identified from TCMSP, GeneCards, and DisGeNET databases. Network analysis and molecular docking (AutoDock Vina) were performed. In vivo studies used 72 male Sprague-Dawley rats (MCAO model) divided into sham, model, nimodipine (10.8 mg/kg), and three YHJG dose groups (0.72, 1.44, 2.88 g/kg). Assessments included neurological scores, TTC staining, histopathology, and molecular analyses (qPCR/Western blot). Results: Network analysis identified 256 shared targets between YHJG and IS, with PI3K-AKT and MAPK as key pathways. Molecular docking showed strong binding between YHJG compounds (e.g., quercetin) and core targets (AKT1, ERK1/2). YHJG treatment significantly improved neurological function (p < 0.01), reduced infarct volume (p < 0.01), and attenuated neuronal damage. The expression of IL-1β, TNF-α, IL-6, AKT1, and pERK1/2/ERK1/2 significantly increased in the MCAO group (p < 0.01), while YHJG treatment significantly reduced their expression (p < 0.01). PPAR-γ expression significantly increased in the YHJG-H group (p < 0.01). Conclusions: The expression of IL-1β, TNF-α, IL-6, AKT1, and pERK1/2/ERK1/2 significantly increased in the MCAO group, while YHJG treatment significantly reduced their expression. PPAR-γ expression significantly increased in the YHJG-H group. YHJGs could treat IS through diverse ingredients, targets, and pathways by inhibiting inflammatory indices and AKT1 expression, and reducing ERK1/2 phosphorylation. Full article

Obesity-induced insulin resistance and type 2 diabetes mellitus (T2DM) represent complex systemic disorders marked by chronic inflammation, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. These pathophysiological processes disrupt insulin signaling and β-cell function, leading to impaired glucose homeostasis across multiple organs. Conventional therapies often target isolated pathways, overlooking the intricate molecular crosstalk and organelle-level disturbances driving disease progression. Citrus-derived polyphenols—including hesperidin, naringenin, nobiletin, and tangeretin—have emerged as promising agents capable of orchestrating a multi-targeted “metabolic reprogramming.” These compounds modulate key signaling pathways, including AMPK, PI3K/Akt, NF-κB, and Nrf2, thereby enhancing insulin sensitivity, reducing pro-inflammatory cytokine expression, and restoring redox balance. Furthermore, they improve mitochondrial biogenesis, stabilize membrane potential, and alleviate ER stress by modulating the unfolded protein response (UPR), thus supporting cellular energy homeostasis and protein folding capacity. Evidence from preclinical studies and select clinical trials suggests that citrus polyphenols can significantly improve glycemic control, reduce oxidative and inflammatory markers, and preserve β-cell function. Their pleiotropic actions across molecular and organ-level targets position them as integrative metabolic modulators. This review presents a systems-level synthesis of how citrus polyphenols rewire metabolic signaling networks and organelle resilience, offering a holistic therapeutic strategy to mitigate the root causes of obesity-induced insulin resistance. Full article

Swiprosin-1 (SWS1/EFhd2) is a calcium-binding adaptor protein involved in cytoskeletal regulation, but its physiological role in bone homeostasis remains largely undefined. To elucidate its function in osteoclast biology, we examined SWS1 expression and activity during osteoclastogenesis using primary murine bone marrow-derived macrophages, siRNA-mediated knockdown, and SWS1 knockout (KO) mice. SWS1 was predominantly localized to the nucleus in precursor cells and redistributed to the F-actin ring in mature osteoclasts. Receptor activator of nuclear factor-kappa B ligand stimulation significantly downregulated SWS1 mRNA expression. Loss of SWS1 enhanced osteoclast formation, F-actin ring integrity, and bone resorption, accompanied by elevated expression of osteoclastogenic markers. In vivo, male SWS1 KO mice exhibited deteriorated trabecular bone microarchitecture with increased osteoclast numbers. Mechanistically, SWS1 deficiency intensified αvβ3 integrin-associated cytoskeletal signaling and upregulated Akt, MAPK, NF-κB, and PLCγ2 pathways. These results indicate that SWS1 negatively regulates osteoclast differentiation and function by restraining cytoskeletal reorganization and downstream signaling. Collectively, our findings establish SWS1 as a novel modulator of osteoclast activity and a potential therapeutic target for osteolytic bone disorders. Full article