Search Results (1,121)

Objective: Accumulating evidence demonstrates that melatonin is involved in modulating granulosa cell function and follicular development. lncRNAs (long non-coding RNAs) and circRNAs (circular RNAs) have been reported to participate in multiple biological processes. This study aimed to explore the candidate circRNAs and lncRNAs related to molecular mechanisms when exploring the role of melatonin in regulating ovarian function. Methods: Bovine ovary granulosa cells were collected 48 h after treatment with melatonin at 10⁻⁷ M. The lncRNA and circRNA profiles of bovine granulosa cells were further explored using high-throughput sequencing in the absence/presence of melatonin. The differentially expressed lncRNAs and circRNAs were analyzed through the annotation information of source transcripts for GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes). Results: We identified 99 differentially expressed lncRNAs and 28 differentially expressed circRNAs. Enrichment analysis of differentially expressed lncRNAs and circRNAs showed they were enriched in multiple pathways involved in development, apoptosis, and reproductive function, such as the mTOR (mammalian Target of Rapamycin) signaling pathway, FoxO (Forkhead box O) signaling pathway, MAPK (Mitogen-Activated Protein Kinase) signaling pathway, Hippo signaling pathway, TGF-beta (Transforming Growth Factor-β) signaling pathway, PI3K-Akt (Phosphatidylinositol 3-Kinase-Akt) signaling pathway, apoptosis, and Rap1 (Ras-related protein 1), most of which were mainly related to granulosa cell function and the crosstalk between granulosa cells and oocytes. The present analysis indicated the potential role of melatonin in granulosa cell function by regulating lncRNA and circRNA expression and, thus, mediating follicular development. An lncRNA/circRNA and miRNA regulatory network was also constructed to take their interactions into account. Conclusions: Our study offers details of lncRNA and circRNA expression in bovine granulosa cells and further provides insight into the potential role of melatonin in regulating reproduction by modulating lncRNA and circRNA expression. Full article

Heterosis or hybrid vigor is a well-recognized biological phenomenon, where crossbred progeny exhibit superior growth performance, stress tolerance, and productivity compared to their purebred parents. However, the molecular mechanisms underlying heterosis for meat quality traits in pigs remain poorly understood. In this study, we compared the longissimus dorsi muscle transcriptomes of Songliao Black Pig (SBP), Large White × Landrace pig (LWLDP), and their crossbred progeny (BXW) to uncover genetic mechanisms contributing to hybrid vigor in meat quality. Results identified 4290 differentially expressed genes (DEGs) in SBP vs. BXW and 3820 in LWLDP vs. BXW. Among these, 1358 genes displayed overdominant expression in BXW, indicating potential heterotic activation. Functional enrichment analysis identified key pathways involved in lipid metabolism, energy homeostasis, and muscle growth, including mTOR, AMPK, insulin, PI3K-Akt, MAPK, and calcium signaling. Over dominantly expressed genes such as FASN, CPT1A, PPARG, ACACA, PPARA, SREBF1, FABP4, DGAT1, PPARGC1A, LIPC, ACSL5, PLCG2, and members of the COX family were closely associated with intramuscular fat deposition, oxidative metabolism, and tenderness. Phenotypically, BXW exhibited improved meat color, moderate fat deposition, and lower shear force compared with parental breeds, clearly aligning with transcriptomic findings. These transcriptomic findings offer valuable insights into precision breeding strategies targeting superior meat quality through genomic selection and crossbreeding programs. Full article

Canine mammary tumors (CMTs) are among the most frequent neoplasms in female dogs, with current therapeutic options being limited and non-standardized, prompting the search for alternative treatments such as fungal secondary metabolites. In this study, the fungal pigment Epipyrone A (Epy A) was first isolated from Epicoccum nigrum and then tested in vitro on two CMT cell lines, P114 and CF33. The compound significantly reduced cell viability in both lines in a concentration- and time-dependent manner (p < 0.05), with the strongest effect observed at 175 µg/mL after 48 h (p < 0.0001), while showing no cytotoxicity in MDCK non-tumor cells. Epy A also inhibited cell migration and increased total antioxidant capacity in P114 cells, accompanied by a significant reduction in ROS levels. Western blot analysis revealed modulation of the PI3K/Akt/mTOR pathway, crucial in CMT biology. Specifically, P114 cells showed downregulation of mTOR and p-Akt, indicating inhibition of proliferative signaling, whereas CF33 cells exhibited increased Akt and p-Akt alongside reduced mTOR, consistent with a compensatory feedback mechanism, probably linked to the changing in oxidative balance after treatment. Overall, these results identified Epy A as a promising natural molecule with potential applications in innovative therapeutic approaches for veterinary and comparative oncology. Full article

Hericium erinaceus (H. erinaceus), a medicinal mushroom, is a source of bioactive compounds with demonstrated neuroprotective potential. This activity is primarily attributed to two distinct classes of compounds: erinacines from the mycelium, which potently induce the synthesis of neurotrophins, protein growth factors essential for neuronal survival and health, and hericenones from the fruiting body, which subsequently appear to enhance or potentiate neurotrophin-activated signaling pathways. Preclinical evidence substantiates their ability to enhance neurotrophin levels, particularly Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), and activate their cognate Trk receptors. Activation of these pathways, including PI3K/AKT/mTOR and MAPK/ERK, converges on transcription factors such as CREB, promoting neuronal survival, neurite outgrowth, and synaptic plasticity. However, the precise molecular mechanisms linking these small molecules to the complex orchestration of neurotrophic gene expression remain incompletely defined. This review synthesizes current knowledge of the neurotrophic pharmacology of H. erinaceus bioactives and proposes a novel framework suggesting that non-coding RNAs (ncRNAs) play a key regulatory role. We hypothesize that hericenones and erinacines modulate key transcriptional hubs, such as CREB, Nrf2, and NF-κB, which in turn regulate the expression of specific ncRNAs (e.g., miR-132, miR-146a) known to control neurogenesis, synaptogenesis, oxidative stress, and neuroinflammation. This ncRNA-mediated mechanism may represent an un-explored axis that explains the pleiotropic neuroprotective effects of these compounds. We critically appraise the existing preclinical evidence, identify significant methodological limitations and translational gaps, and propose a structured research roadmap to test these ncRNA-centric hypotheses, aiming to accelerate the rational development of H. erinaceus-derived compounds for neurodegenerative diseases. Full article

Hair loss is a prevalent condition with various causes, and effective treatments are in high demand. Cacumen Platycladi (Platycladus orientalis leaves), a traditional Chinese medicine, has been historically used to prevent hair loss. This study aimed to evaluate the efficacy and mechanisms of Cacumen Platycladi extract (CPE) in preventing hair loss. Using a gradient extraction method with 1,3-butanediol, ethanol, and water, bioactive compounds like quercitrin, myricetin, and myricitrin were enriched and identified via Liquid Chromatography–Mass Spectrometry (LC-MS). The results showed that CPE inhibited 5α-reductase activity, enhanced the antioxidant capacity of human dermal papilla cells (HDPCs), and upregulated the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway to promote vascular endothelial growth factor (VEGF) and collagen type XVII (COL17) expression. A 12-week clinical trial demonstrated that CPE significantly reduced hair loss and increased local hair density compared to placebo, with no adverse effects. These findings support the potential of CPE as a safe and effective natural alternative for hair loss prevention. Full article

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

The past decade has witnessed an unprecedented transformation in breast cancer management, driven by parallel advances in targeted therapies, immunomodulation, drug-delivery technologies, and molecular diagnostic tools. This review summarizes the key achievements of 2015–2025, encompassing all major biological subtypes of breast cancer as well as technological innovations with substantial clinical relevance. In hormone receptor-positive (HR+)/HER2− disease, the integration of CDK4/6 inhibitors, modulators of the PI3K/AKT/mTOR pathway, oral Selective Estrogen Receptor Degraders (SERDs), and real-time monitoring of Estrogen Receptor 1 (ESR1) mutations has enabled clinicians to overcome endocrine resistance and dynamically tailor treatment based on evolving molecular alterations detected in circulating biomarkers. In HER2-positive breast cancer, treatment paradigms have been revolutionized by next-generation antibody–drug conjugates, advanced antibody formats, and technologies facilitating drug penetration across the blood–brain barrier, collectively improving systemic and central nervous system disease control. The most rapid progress has occurred in triple-negative breast cancer (TNBC), where synergistic strategies combining selective cytotoxicity via Antibody-Drug Conjugates (ADCs), DNA damage response inhibitors, immunotherapy, epigenetic modulation, and therapies targeting immunometabolic pathways have markedly expanded therapeutic opportunities for this historically challenging subtype. In parallel, photodynamic therapy has emerged as an investigational and predominantly local phototheranostic approach, incorporating nanocarriers, next-generation photosensitizers, and photoimmunotherapy capable of inducing immunogenic cell death and modulating antitumor immune responses. A defining feature of the past decade has been the surge in patent-driven innovation, encompassing multispecific antibodies, optimized ADC architectures, novel linker–payload designs, and advanced nanotechnological and photoactive delivery systems. By integrating data from clinical trials, molecular analyses, and patent landscapes, this review illustrates how multimechanistic, biomarker-guided therapies supported by advanced drug-delivery technologies are redefining contemporary precision oncology in breast cancer. The emerging therapeutic paradigm underscores the convergence of targeted therapy, immunomodulation, synthetic lethality, and localized immune-activating approaches, charting a path toward further personalization of treatment in the years ahead. Full article

Background/Objectives: Imatinib, the first tyrosine kinase inhibitor, marks the beginning of a revolution in clinical oncology. Disrupting oncogenic kinase-dependent signaling pathways represents a key strategy for advancing targeted cancer therapies. Terpene analogues of imatinib were developed to probe the influence of terminal ring modifications on BCR-ABL inhibition and downstream oncogenic signaling. Methods: Nine novel imatinib analogues bearing bulky aliphatic moieties were designed, synthesised, and structurally characterized by ¹H/¹³C NMR spectroscopy and high-resolution mass spectrometry (HRMS). Molecular docking calculations were performed to assess the binding modes and intermolecular interactions. The cytotoxicity of the newly synthesized imatinib derivatives was evaluated across a panel of BCR-ABL+ leukemia cell lines. Results: Molecular docking analyses demonstrated conserved interactions within the ATP-binding site of BCR-ABL for all derivatives, with calculated docking scores ranging between 123 and 128, while modifications at the terminal ring introduced subtle changes in electrostatic and steric profiles. Biological evaluation using MTT-based cytotoxicity assays in BCR-ABL+ leukemic cell lines revealed enhanced antiproliferative activity compared with imatinib, with compounds 6a (flexible cyclohexyl) and 6d (rigid camphane-type (+)-isopinocampheyl) exhibiting the lowest micromolar activity in the AR-230 model (IC₅₀ values of 1.1 and 1.2 μM, respectively). Proteome-wide phosphokinase profiling demonstrated shared suppression of STAT5/3/6, RSK1/2, S6K1/p70, and Pyk2, confirming effective disruption of canonical BCR-ABL pathways. Critically, the terpene moiety dictated downstream pathway bias: 6a preferentially attenuated CREB activation, whereas 6d more effectively suppressed the PI3K/Akt oncogenic axis and strongly activated proapoptotic p53-mediated stress responses. Conclusions: Our findings establish terpene-engineered imatinib analogues as tunable modulators and promising candidates for targeting downstream BCR-ABL signaling pathways in leukemia treatment. Full article

Endometrial cancer (EC) is the most common gynecological cancer in developed countries, with approximately 417,000 new cases reported worldwide in 2020. Its incidence has been rising for the past 30 years, primarily due to population aging, obesity, and type 2 diabetes; obesity accounts for almost half of cases due to excessive estrogen production. The classic division into types I and II was replaced in 2013 by the molecular TCGA classification, which distinguishes four subtypes: POLE-ultramutated (best prognosis), MSI-hypermutated, copy-number low, and copy-number high (worst prognosis). This classification (refined in ProMisE and TransPORTEC) enables precise treatment: immunotherapy (pembrolizumab, dostarlimab) works excellently in dMMR/MSI-H tumors, PI3K/AKT/mTOR inhibitors and trastuzumab deruxtecan in selected molecular subtypes, and hormone therapy in ER-positive tumors. ctDNA monitoring supports therapeutic decisions. Integrating the molecular profile with FIGO allows for truly personalized treatment, although MMRp/MSS tumors remain a challenge. The future lies in multi-omics, new biomarkers, and combination therapies. 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

Cancer stem cells (CSCs) represent a small but highly resilient tumor subpopulation responsible for sustained growth, metastasis, therapeutic resistance, and recurrence. Their survival is supported by aberrant activation of developmental and inflammatory pathways, including Wnt/β-catenin, Notch, Hedgehog, PI3K/Akt/mTOR, STAT3, and NF-κB, as well as epithelial–mesenchymal transition (EMT) programs and niche-driven cues. Increasing evidence shows that phytochemicals, naturally occurring bioactive compounds from medicinal plants, can disrupt these networks through multi-targeted mechanisms. This review synthesizes current findings on prominent phytochemicals such as curcumin, sulforaphane, resveratrol, EGCG, genistein, quercetin, parthenolide, berberine, and withaferin A. Collectively, these compounds suppress CSC self-renewal, reduce sphere-forming capacity, diminish ALDH⁺ and CD44⁺/CD24⁻ fractions, reverse EMT features, and interfere with key transcriptional regulators that maintain stemness. Many phytochemicals also sensitize CSCs to chemotherapeutic agents by downregulating drug-efflux transporters (e.g., ABCB1, ABCG2) and lowering survival thresholds, resulting in enhanced apoptosis and reduced tumor-initiating potential. This review further highlights the translational challenges associated with poor solubility, rapid metabolism, and limited bioavailability of free phytochemicals. Emerging nanotechnology-based delivery systems, including polymeric nanoparticles, lipid carriers, hybrid nanocapsules, and ligand-targeted formulations, show promise in improving stability, tumor accumulation, and CSC-specific targeting. These nanoformulations consistently enhance intracellular uptake and amplify anti-CSC effects in preclinical models. Overall, the consolidated evidence supports phytochemicals as potent modulators of CSC biology and underscores the need for optimized delivery strategies and evidence-based combination regimens to achieve meaningful clinical benefit. Full article