Search Results (745)

Background: Ovarian granulosa cells (GCs) play a pivotal role in folliculogenesis, and their dysfunction is central to disorders such as polycystic ovary syndrome (PCOS) and premature ovarian failure (POF). MicroRNAs (miRNAs) have emerged as crucial post-transcriptional regulators of GC homeostasis. Method: This review synthesizes current evidence by systematically analyzing relevant studies, integrating data from in vitro GC models, animal experiments, human cell lines, and clinical samples to elucidate the specific mechanisms by which miRNAs regulate GCs. Results: miRNAs precisely modulate GC proliferation, apoptosis, steroidogenesis, and oxidative stress responses by targeting key signaling pathways (e.g., PI3K/AKT/mTOR, TGF-β/SMAD) and functional genes (e.g., TP53, CYP19A1). Exosomal miRNAs serve as vital mediators of communication within the follicular microenvironment. To date, nearly 200 miRNAs have been associated with PCOS. Conclusions: miRNAs constitute a decisive regulatory network governing GC fate, offering promising therapeutic targets for PCOS and POF. However, significant challenges remain, primarily miRNA pleiotropy and the lack of follicle-specific delivery systems. Future clinical translation requires rigorous validation in human-relevant models. Full article

Avobenzone (AVO) and ethylhexyl salicylate (EHS) are widely used organic UV filters with distinct photochemical properties and reported biological effects. Experimental and predictive evidence suggests that some lipophilic UV filters may reach systemic circulation and potentially cross the blood–brain barrier (BBB), raising concerns about possible central nervous system effects, although direct evidence for AVO and EHS remains limited. This study evaluated the effects of subcytotoxic concentrations (0.01–1 µM) of AVO and EHS on differentiated SH-SY5Y human neuroblastoma cells, focusing on early stress-related molecular responses. Cell viability and reactive oxygen species production were not significantly affected at any tested concentration. Integrated analyses of microRNA, gene, and protein expression revealed modest and variable modulation of miR-200a-3p and miR-29b-3p. Western blot analysis showed increased phosphorylation of AKT and ERK, no significant changes in mTOR activation, and an increased Bax/Bcl-2 ratio. Overall, these findings indicate that AVO and EHS trigger an early stress-adaptive response involving PI3K/AKT and MAPK/ERK signaling and modulation of apoptosis-related pathways. Such responses reflect a dynamic balance between cellular adaptation and pro-apoptotic signaling, which may become relevant under prolonged or higher-intensity exposure conditions. Full article

Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide. Although cisplatin is widely used in chemotherapy, its clinical efficacy is often limited by adverse effects and resistance. Thus, natural bioactive compounds are gaining attention as complementary therapeutic agents. This study aimed to evaluate the anti-tumor effects of Annona muricata leaf extract on murine breast cancer 4T1 cells, used alone or in combination with cisplatin. Cisplatin induced intrinsic apoptosis through mitochondrial membrane disruption, up-regulation of the Bax gene and inhibition of the PI3K/AKT/mTOR signaling pathway. Cisplatin also promoted hypoxia by HIF1α gene expression, inflammation by TNFα and IL-6 gene expression, and induced cell cycle arrest at the sub-G1 phase by down-regulation of cyclin D1 and cyclin E1 genes. Annona muricata leaf extract triggered autophagy-mediated 4T1 cell death through mainly mTOR down-regulation and increased expression of Beclin1 and LC3 genes. It also induced cell cycle arrest at sub-G1 and S phases in a concentration- and time-dependent manner. When, combined with cisplatin, Annona muricata extract shifts the cell death pathway from intrinsic apoptosis toward autophagy by reduced caspase-3 gene expression and activity and enhanced LC3-I to LC3-II conversion. Moreover, Annona muricata extract attenuated cisplatin-induced inflammation by inhibiting TNFα and IL-6 gene expression and reinforced cell cycle arrest through suppression of the cyclin D1 gene. In conclusion, our results suggest that Annona muricata leaf extract exerts significant anti-tumor activity in breast cancer cells and may enhance cisplatin efficacy by shifting the signaling pathway from intrinsic apoptosis toward autophagy, and attenuating inflammation-related effects, supporting its potential use as a complementary therapeutic strategy. Full article

Melanoma is the deadliest form of skin cancer, characterized by high metastatic potential and intrinsic heterogeneity. In addition to genetic mutations such as BRAF^V600E^ and NRAS, lipid metabolic reprogramming has emerged as a critical factor in tumor progression and therapy resistance. Lipid metabolism supports melanoma cell survival, phenotypic switching, immune evasion, and resistance to targeted therapies and immunotherapy, while also modulating susceptibility to ferroptosis. This review summarizes current knowledge on lipid dysregulation in melanoma, highlighting alterations in fatty acid synthesis, desaturation, uptake, storage, and oxidation, as well as changes in phospholipids, sphingolipids, cholesterol, and bioactive lipid mediators. These lipid pathways are tightly regulated by oncogenic signaling networks, including MAPK and PI3K–AKT–mTOR pathways, and are influenced by tumor microenvironmental stressors such as hypoxia and nutrient limitation. Advances in lipidomics technologies, particularly mass spectrometry-based approaches, have enabled comprehensive profiling of lipid alterations at bulk, spatial, and single-cell levels, offering new opportunities for biomarker discovery and therapeutic stratification. Targeting lipid metabolic vulnerabilities represents a promising strategy to improve melanoma diagnosis, prognosis, and treatment efficacy. Full article

Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease—the major protagonists of NDs—while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials. Full article

Sex-specific factors can influence the onset and progression of osteoarthritis (OA), yet the molecular mechanisms underlying their impact remain poorly defined. This study investigated whether plasma microRNAs (miRNAs) correlate to sex-dependent OA progression, based on evidence of enhanced spontaneous osteoclastogenesis in peripheral blood mononuclear cells (PBMCs) derived from OA patients. miRNAs were evaluated on OA-plasma (n = 20 men, 20 women with knee OA; KL grade I–II) and their role on OA signaling was investigated through bioinformatic analysis. Seven miRNAs were identified as significantly upregulated in men’ vs. women’ samples: hsa-miR-107, hsa-miR-23a-3p, hsa-miR-103a-3p, hsa-let-7g-5p, hsa-miR-22-3p, hsa-miR-106a-5p, hsa-miR-142-3p, and were associated with OA-related tissues and pathways. Notably, two common targets were identified: Adenosine Triphosphate Citrate Lyase (ACLY), a key enzyme linking citrate metabolism to epigenetic regulation, and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), a component of the phosphatidylinositol-3-kinase PI3K/AKT/mTOR pathway. In men, increased miRNA expression may repress ACLY and PIK3R1, affecting catabolic gene expression, inflammation, and OA progression. Conversely, their lower expression in women may mitigate these effects by counterbalancing the OA-promoting influences driven by sex hormones. A functional validation is needed to confirm miRNA–ACLY/PIK3R1 interactions and their sex-specific roles in early OA pathophysiology. Full article

Background/Objectives: Resveratrol is a multi-target polyphenolic stilbene widely studied for its antioxidant, anti-inflammatory, cardioprotective, hepatoprotective, neuroprotective, immunomodulatory and anticancer properties. This review summarizes current evidence on its molecular mechanisms, therapeutic potential, metabolic interactions and biological implications, with particular emphasis on bioavailability, signaling pathways and organ-specific actions. Methods: A comprehensive literature review was conducted focusing on recent in vitro, in vivo and clinical studies evaluating resveratrol’s biochemical activity, molecular targets and physiological effects. Special attention was given to oxidative stress regulation, inflammatory signaling, mitochondrial function, metabolic pathways, gut microbiota interactions, and its influence on chronic diseases. Results: Resveratrol modulates several key signaling pathways including NF-κB, SIRT1, AMPK, MAPK, Nrf2 and PI3K/AKT/mTOR. It reduces oxidative stress, inhibits inflammatory cytokines, regulates apoptosis, improves mitochondrial performance, and activates endogenous antioxidant systems. The compound demonstrates protective effects in cardiovascular diseases, hepatic steatosis, neurodegenerative disorders, metabolic dysfunction, and various cancers through anti-inflammatory, anti-proliferative and anti-fibrotic mechanisms. Additionally, resveratrol beneficially alters gut microbiota composition and microbial metabolites, contributing to improved metabolic homeostasis. Despite high intestinal absorption, systemic bioavailability remains low; however, novel nanoformulations significantly enhance its stability and plasma concentrations. Conclusions: Resveratrol exhibits broad therapeutic potential driven by its capacity to regulate oxidative, inflammatory, metabolic and apoptotic pathways at multiple levels. Its pleiotropic activity makes it a promising candidate for prevention and complementary treatment of chronic diseases. Advances in delivery systems and microbiota-derived metabolites may further enhance its clinical applicability. Full article

Ovarian cancer remains a top mortality contributor within gynecological cancers because patients receive diagnoses late in the disease course and conventional treatment resistance along with high recurrence rates cause poor outcomes. Aberrant regulation of autophagy and apoptosis has a critical role in the development, progression, chemoresistance, and immune escape from ovarian cancer. Recent evidence has demonstrated a complicated and dynamic crosstalk between autophagy and apoptosis, during which autophagy can act as a cytoprotective or cell death-promoting process depending on tumor stage and therapeutic context. In parallel, apoptosis functions as a tightly regulated form of programmed cell death that is essential for eliminating damaged or malignant cells and serves as a major tumor-suppressive mechanism in ovarian cancer. The PI3K/AKT/mTOR signaling pathway is the most active and clinically relevant pathway in the management of ovarian cancer as a master regulator of both autophagy and apoptosis, suppressing apoptotic cell death while promoting cytoprotective autophagy under chemotherapeutic stress. Bioactive natural products derived from plants, marine sources, and dietary intake have emerged as potential modulators of the autophagy-apoptosis crosstalk. Curcumin, resveratrol, quercetin, berberine, and epigallocatechin gallate are known to have the ability to restore apoptotic signaling, block pro-survival autophagy, and sensitize ovarian cancer cells to chemotherapy through the regulation of key pathways including PI3K/AKT/mTOR, AMPK, MAPK, p53, and Bcl-2 family proteins. In this review, we provide an updated understanding of the molecular mechanisms through which bioactive natural products modulate autophagy–apoptosis crosstalk in ovarian cancer. We also highlight the translational challenges, therapeutic potential, and future directions for the integration of natural product-based strategies in precision medicine for ovarian cancer. Full article

Slow-growing and locally invasive, chordoma is a rare malignant bone tumor, with a reported annual worldwide incidence of 0.08 per 100,000 cases. It accounts for about 3 percent of all bone tumors and about 20 percent of primary spinal tumors. The incidence rates vary between countries and races, with white/Caucasian males in the 5th or 6th decade of life having a higher prevalence. Chordoma poses significant challenges because of its high recurrence rate and resistance to several standard treatment techniques. All cancers, including chordomas, have altered energy metabolism processes that contribute to their unchecked growth and survival. The significance of non-coding RNAs, particularly circular RNAs (circRNAs), as key regulators at the intersection of cellular metabolism and immune function has been highlighted by recent discoveries. By focusing on important glycolytic enzymes in tumor cells and altering metabolic reprogramming pathways, CircRNAs can influence cancer metabolic adaptability. Furthermore, via influencing immune cell functions as immunological checkpoint signaling and macrophage polarization, circRNAs influence immune evasion in the tumor microenvironment. These frequently happen via regulating important pathway signals, like PI3K/AKT/mTOR and NRF2, or by processes like miRNA sponging, creating a tumor microenvironment that is immunosuppressive and metabolically friendly. The translational pathway of circRNA-targeted therapeutics is promoted as a developing pharmacological entity in this review, which also highlights recent information on the control of circRNA-mediated immunometabolism in chordoma and examines numerous important molecular axes. There are promising opportunities to develop novel precision treatments for chordoma by considering circRNAs as dual regulators of immunological and metabolic networks. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. It usually arises in cirrhotic liver, where chronic inflammation and fibrosis create a tumor-permissive microenvironment. Dysregulation of microRNAs (miRNAs), particularly upregulation of the oncomiR miR-221 and loss of the tumor suppressor miR-199a-3p represent key drivers of liver carcinogenesis. The TG221 transgenic mouse, designed to overexpress miR-221 in hepatocytes, provides a relevant in vivo platform for mechanistic studies and for testing preventive and therapeutic approaches. The TG221 model recapitulates miR-221-driven tumorigenesis, including suppression of p27, p57 and Bmf. It is characterized by steatohepatitic injury and accelerated tumor formation after genotoxic challenge. In the cirrhotic CCl₄-induced background, TG221 mice develop fibrosis and cirrhosis followed by dysplastic and malignant lesions, mirroring the natural history of human HCC. Metformin administered during early fibrosis prevented macroscopic tumor formation and suppressed PI3K/AKT/mTOR signaling. Anti-miR-221 and miR-199a-3p mimics reduced tumor burden, restored tumor-suppressive pathways and improved liver integrity, thus indicating feasible chemopreventive strategies. From a therapeutic point of view, miR-199a-3p replacement synergized with palbociclib and overcame sorafenib resistance. A miR-199a-3p-responsive oncolytic adenovirus achieved tumor-selective replication with minimal toxicity. This review highlights the importance of the TG221 transgenic mouse as a powerful model for studying miRNA-driven hepatocarcinogenesis and enables preclinical evaluation of RNA-based chemopreventive and therapeutic approaches. Metformin, miRNA inhibition, miRNA replacement and miRNA-guided viral therapies emerge as promising approaches for advancing precision prevention and treatment strategies in HCC. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss and abnormal α-synuclein aggregation. Circulating microRNAs (miRNAs) have emerged as promising biomarkers and potential modulators of PD-related molecular pathways. In this study, we investigated the expression levels of four candidate miRNAs—miR-15a-5p, miR-16-5p, miR-139-5p, and miR-34a-3p—in patients with PD compared with healthy controls. A total of 47 PD patients and 45 age- and sex-matched controls were enrolled. Plasma miRNA levels were quantified using standardized RNA extraction, cDNA synthesis, and qPCR protocols. We observed marked upregulation of miR-15a-5p and robust downregulation of both miR-139-5p and miR-34a-3p in PD patients, whereas miR-16-5p showed no significant difference between groups. Target gene prediction and functional enrichment analysis identified 432 unique genes, with enrichment in biological processes related to protein ubiquitination and catabolic pathways, and signaling cascades such as mTOR, PI3K-Akt, MAPK, and Hippo pathways, all of which are implicated in neurodegeneration. Elevated miR-15a-5p may contribute to pro-apoptotic mechanisms, while reduced miR-139-5p and miR-34a-3p expression may reflect impaired mitochondrial function, diminished neuroprotection, or compensatory regulatory responses. Together, these dysregulated circulating miRNAs provide novel insight into PD pathophysiology and highlight their potential as accessible, non-invasive biomarkers. Further longitudinal studies in larger and more diverse cohorts are warranted to validate their diagnostic and prognostic value and to explore their utility as therapeutic targets. Full article

Background: H3K27-altered diffuse midline glioma (DMG) is a highly aggressive central nervous system malignancy with limited therapeutic options and poor prognosis. Precision medicine strategies that integrate molecular profiling with individualized treatment selection represent a critical avenue for improving outcomes. Case presentation: We describe a 31-year-old woman with H3K27-altered DMG who, after standard chemoradiotherapy, was treated with a personalized, mechanism-guided combination regimen based on her tumor’s molecular profile. Next-generation sequencing identified pathogenic alterations in ATRX, H3F3A, and NF1, with a high NF1 mutation allelic fraction indicating RAS/MAPK pathway activation. Immunohistochemistry demonstrated elevated phosphorylated mTOR consistent with PI3K/AKT/mTOR pathway upregulation. The individualized regimen comprised trametinib and everolimus for dual pathway inhibition, the tissue-agnostic agent dordaviprone (ONC201), metabolic modulation with 2-deoxy-D-glucose, and electric field-based therapy. At seven months, MRI showed approximately a 60% volumetric reduction in the enhancing tumor component, accompanied by marked T2-weighted signal regression. Clinically, the patient remained neurologically intact with a Karnofsky Performance Score of 100%. Conclusions: This case illustrates the potential clinical value of a genomics-guided, multimodal treatment strategy in H3K27-altered DMG. The systematic integration of comprehensive molecular profiling with mechanistically rational treatment selection may contribute to meaningful radiological and clinical benefit in this otherwise uniformly fatal disease. These observations support further investigation of individualized, pathway-targeted approaches in prospective studies and N-of-1 trial frameworks. Full article

Type 2 diabetes mellitus (T2DM) can be traditionally treated by edible and medicinal species rich in flavonoids and triterpenoids known for their metabolic benefits. Cucumis prophetarum L. has shown antioxidant and antidiabetic properties in decoction extracts. Since solvent polarity strongly influences the extraction of secondary metabolites, this study investigated the hydroalcoholic extracts of C. prophetarum L. to explore their chemical composition and insulin-sensitizing potential. Hydroalcoholic extracts from the leaf, stem, and root of C. prophetarum L. were analyzed by UV-Vis spectroscopy, ATR-FTIR, and UHPLC-ESI-QqTOF–MS/MS to profile their secondary metabolites. The insulin-sensitizing potential of each extract was assessed using an in vitro model of palmitic-acid-induced insulin resistance in L6 skeletal muscle cells, followed by Western blot analysis of key insulin-signaling proteins. Flavonoid glycosides such as apigenin-C,O-dihexoside, apigenin-malonylhexoside, and luteolin-C,O-dihexoside were abundant in leaf and stem extracts, while cucurbitacins predominated in the root. MTT assay confirmed that hydroalcoholic stem and root extracts of C. prophetarum L. were non-cytotoxic to L6 myotubes, whereas the leaf extract reduced viability only at higher concentrations. Oil Red O staining revealed a pronounced decrease in lipid accumulation following stem and root extract treatment. Consistently, the stem extract enhanced insulin signaling through the activation of the IRS-1/PI3K/Akt pathway, while the root extract primarily modulated the AMPK–mTOR pathway. Importantly, both extracts promoted GLUT4 translocation to the plasma membrane, highlighting their complementary mechanisms in restoring insulin sensitivity. Hydroalcoholic extracts of C. prophetarum L. alleviate insulin resistance through multiple molecular mechanisms, with bioactivity and composition differing markedly from previously reported in the decoctions, which highlight a promising source of insulin-sensitizing phytochemicals and underscore the importance of solvent selection in maximizing therapeutic potential. Full article

Abdominal fat deposition in chickens significantly impacts production efficiency and is influenced by complex genetic and molecular mechanisms. This review summarizes current genomic and transcriptomic research on the regulation of adipogenesis and fat accumulation in chickens, highlighting key genes and loci identified through genome-wide association studies as well as other candidates involved in lipogenesis, lipolysis, and transcriptional regulation. Major metabolic pathways, including MAPK, AMPK, PI3K/AKT/mTOR, TGFβ1/Smad3, FoxO, JAK–STAT, Wnt/β-catenin, and Sonic Hedgehog signaling, are examined for their roles in fat deposition. The regulatory functions of non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, are discussed, focusing on their interactions with target mRNAs and signaling networks that control lipid metabolism, adipocyte differentiation, and energy balance. Integrating insights from both avian and human studies, this review emphasizes the molecular mechanisms underlying adipogenesis and highlights potential strategies for genetic selection aimed at reducing excessive abdominal fat and improving poultry productivity. Full article

Background: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors demonstrated amyloid-lowering efficacy but failed in phase II/III clinical trials due to adverse effects and limited disease-modifying outcomes. This study employed an integrated network pharmacology and molecular docking approach to quantitatively elucidate the multitarget mechanisms of 4 (phase II/III) discontinued BACE1 inhibitors (Verubecestat, Lanabecestat, Elenbecestat, and Umibecestat) and the preclinical compound AM-6494 in Alzheimer’s disease (AD). Methods: Drug-associated targets were intersected with AD-related genes to construct a protein–protein interaction (PPI) network, followed by topological analysis to identify hub proteins. Gene Ontology (GO) and KEGG pathway enrichment analyses were performed using statistically significant thresholds (p < 0.05, FDR-adjusted). Molecular docking was conducted using AutoDock Vina to quantify binding affinities and interaction modes between the selected compounds and the identified hub proteins. Results: Network analysis identified 10 hub proteins (CASP3, STAT3, BCL2, AKT1, MTOR, BCL2L1, HSP90AA1, HSP90AB1, TNF, and MDM2). GO enrichment highlighted key biological processes, including the negative regulation of autophagy, regulation of apoptotic signalling, protein folding, and inflammatory responses. KEGG pathway analysis revealed significant enrichment in the PI3K–AKT–MTOR signalling, apoptosis, and TNF signalling pathways. Molecular docking demonstrated strong multitarget binding, with binding affinities ranging from approximately −6.6 to −11.4 kcal/mol across the hub proteins. Umibecestat exhibited the strongest binding toward AKT1 (−11.4 kcal/mol), HSP90AB1 (−9.5 kcal/mol), STAT3 (−8.9 kcal/mol), HSP90AA1 (−8.5 kcal/mol), and MTOR (−8.3 kcal/mol), while Lanabecestat showed high affinity for AKT1 (−10.6 kcal/mol), HSP90AA1 (−9.9 kcal/mol), BCL2L1 (−9.2 kcal/mol), and CASP3 (−8.5 kcal/mol), respectively. These interactions were stabilized by conserved hydrogen bonding, hydrophobic contacts, and π–alkyl interactions within key regulatory domains of the target proteins, supporting their multitarget engagement beyond BACE1 inhibition. Conclusions: This study demonstrates that clinically failed BACE1 inhibitors engage multiple non-structural regulatory proteins that are central to AD pathogenesis, particularly those governing autophagy, apoptosis, proteostasis, and neuroinflammation. The identified ligand–hub protein complexes provide a mechanistic rationale for repurposing and optimization strategies targeting network-level dysregulation in Alzheimer’s disease, warranting further in silico refinement and experimental validation. Full article