Search Results (32,784)

Basal-like breast cancer (BLBC) is associated with poor prognosis, high recurrence rates, and limited therapeutic options, largely due to its molecular heterogeneity and complexity, which include epigenetic alterations. This study investigated epigenetic regulatory networks in BLBC by analyzing DNA methylation in distal cis-regulatory regions and its impact on genes, transcription factors (TFs), and microRNAs (miRNAs) expression. Data from TCGA were processed using the ELMER and DESeq2 tools to identify differentially methylated regions and differentially expressed genes, TFs, and miRNAs. The FANMOD algorithm was used to identify the regulatory interactions uncovering the feed-forward loops (FFLs). The analysis identified 110 TF-mediated FFLs, 43 miRNA-mediated FFLs, and five composite FFLs, involving 18 hypermethylated and 32 hypomethylated genes, eight upregulated and nine downregulated TFs, and 21 upregulated and seven downregulated miRNAs. The TF-mediated FFLs major regulators involved the AR, EBF1, FOS, FOXM1, and TEAD4 TFs, while key miRNAs were miR-3662, miR-429, and miR-4434. Enriched pathways involved cAMP, ErbB, FoxO, p53, TGF-beta, Rap1, and Ras signaling. Differences in hallmark gene set categories reflected distinct methylation and miRNA expression profiles. Overall, this integrative analysis mapped the intricate epigenetic landscape of BLBC, emphasizing the role of FFLs as regulatory motifs that integrate DNA methylation, TFs, and miRNAs in orchestrating disease’s development and progression and offering potential targets for future diagnostic and therapeutic strategies.Overall, this integrative analysis mapped the intricate epigenetic landscape of BLBC, emphasizing the role of FFLs as regulatory motifs that integrate DNA methylation, TFs, and miRNAs in orchestrating the disease’s development and progression, and offering potential targets for future diagnostic and therapeutic strategies. Full article

Epsilon-poly-l-lysine (ε-PL) is a potent antimicrobial agent, but strategies to enhance its biosynthesis remain limited due to insufficient understanding of its physiological regulation. This study explores the interaction between Streptomyces albulus and heterogeneous microbial extracts, with a focus on actinomycete-derived signals. The S. gilvosporeus extract induces the highest ε-PL production (3.4 g/L), exceeding the control by 2.6-fold and outperforming B. cinerea by 1.8-fold. Multi-omics analyses combined with morphological and biochemical profiling reveal that the induced state is characterized by intensified central carbon flux, enhanced lipid turnover, elevated respiratory activity, and cofactor regeneration, alongside suppression of competing secondary pathways. Morphological alterations, including denser mycelial aggregation and compact colony structures, accompany these metabolic shifts. Compared to B. cinerea, S. gilvosporeus elicits more pronounced stress adaptation and metabolic reprogramming in S. albulus. These findings suggest that interspecies interactions can activate intrinsic aggression resistance mechanisms, thereby driving ε-PL biosynthesis through a previously unrecognized physiological route. Full article

Passiflora edulis propagation relies extensively on grafting, yet the optimization of pruning strategies for scion quality remains empirically guided. This study elucidates the physiological and molecular mechanisms underlying scion quality across five leaf retention treatments (0%, 25%, 50%, 75%, and unpruned control). The 50% partial leaf retention (50% PLR) treatment optimally promoted axillary bud development in passion fruit through coordinated physiological and molecular adaptations. This treatment significantly outperformed other treatments in terms of both bud sprouting rate and growth parameters (including length and diameter). Physiological analyses demonstrated transient auxin accumulation coupled with synchronized antioxidant system activation, maintaining redox homeostasis. Transcriptomic profiling identified upregulation of genes in the auxin signaling pathway and cytokinin activators, while dormancy-related genes were suppressed. These findings establish 50% PLR as an optimal threshold that balances photosynthetic capacity with hormonal regulation, providing a science-based strategy to standardize grafted seedling production, while enhancing scion quality for grafting efficiency. Full article

Photophores are light-producing organs found in many fish species living in the mesopelagic, bathypelagic, and abyssal layers of the ocean. They function to attract prey, confuse predators, and communicate with other individuals of the same species. Understanding the structure and function of photophores is crucial to exploring bioluminescence and the ecological adaptations of marine life in deep-sea environments. The present study is the first to investigate the photophore anatomy of the mesopelagic fish Ichthyococcus ovatus (Cocco, 1838), using specimens naturally stranded along the coast of the Strait of Messina. The morphology of the ventral photophores of I. ovatus includes four functional parts: a tank containing photogenic cells, a lens filter, a reflector surrounding the entire organ, and a pigmented layer. An immunohistochemical assay was conducted using anti-nNOS and anti-S100p antibodies. The presence of nNOS/NOS type I immunolabeling the pigmented layer surrounding the photophores and the nerve fibers reaching the lens suggests a potential role of neuronal nitric oxide signaling in modulating light shielding by the pigment sheath, controlling light exposure, and adjusting light focusing though the lens-associated nerves. S100p immunostaining was observed in the nerve fibers reaching the photophores, highlighting its potential involvement in regulating neuronal calcium levels and, consequently, influencing signal transmission to control bioluminescence output. A sensory feedback pathway from the photophore to the CNS is suggested. Within the lens and in the irregularly shaped cells located in the photophore’s lens, S100p immunolabeling could indicate active signaling and differentiation processes. These findings expand our understanding of light-emitting systems in mesopelagic fishes and offer a valuable foundation for future studies on the functional and evolutionary significance of photophores. Full article

Fibro-adipogenic progenitor cells (FAPs) support muscle tissue homeostasis, regulate muscle growth, injury repair, and fibrosis, and activate muscle progenitor cell differentiation to promote regeneration. We aimed to investigate the effects of co-culturing FAPs with muscle satellite cells (MuSCs) on myogenic differentiation. Proteomic profiling of co-culture supernatants identified significant DCX, IMP2A, NUDT16L1, SLC38A2, and IL-6 upregulation. Comparative transcriptomics of mono-cultured versus co-cultured MuSCs revealed differential expression of oxidative stress-related genes (HMOX1, ALOX5, GSTM3, TRPM2, PADI1, and CTSL). Pathway enrichment analyses highlighted cell cycle regulation, TNF signaling, and ferroptosis. Gene ontology analysis of MuSCs indicated significant gene enrichment in myosin-related components. Combined transcriptomic and proteomic analyses demonstrated HO-1 downregulation at the transcriptional and translational levels, with altered pathways being predominantly related to myosin filament, muscle system process, and muscle contraction cellular components. HO-1 knockdown reduced intracellular iron accumulation in MuSCs, suppressing iron-dependent autophagy. This alleviated oxidative stress and promoted myogenic differentiation. Exogenous IL-6 (0.1 ng/mL) downregulated HO-1 expression, initiating an identical regulatory cascade, while HO-1 overexpression reversed the IL-6-mediated reduction in the expression of the autophagy markers LC3 and ATG5, suppressing myogenic enhancement. This establishes the co-culture-induced IL-6/HO-1 axis as a core regulator of iron-dependent oxidative stress and autophagy during myogenic differentiation. Full article

Background/Objectives: Metrnl (Meteorin-like), a secreted protein identified in our lab, has been shown to promote wound healing in mice. However, current therapeutic strategies and the underlying mechanisms remain incompletely understood. This study aimed to (1) develop a recombinant human Metrnl (hMetrnl) hydrogel formulation for topical delivery, and (2) elucidate its molecular mechanism in wound repair. Methods: hMetrnl was dispersed in a thermosensitive PLGA-PEG-PLGA hydrogel (hMet-PPP) and applied topically to full-thickness skin wounds in male C57BL/6 mice. A large initial dose was administered on the day of injury, followed by a lower maintenance dose regimen. Mechanistic studies were performed using molecular/cellular assays to assess the effects of hMetrnl. Results: Administration of hMet-PPP significantly accelerated wound healing, reducing the initial wound area and shortening the overall recovery time. hMetrnl transmits signals to endothelial cells via the KIT receptor tyrosine kinase (C-Kit), a membrane receptor, thereby initiating a dual regulatory mechanism involving eNOS to promote angiogenesis: (1) rapid activation of eNOS activity within 30 min through the PI3K/AKT signaling pathway; and (2) suppression of proteasomal and lysosomal eNOS degradation, resulting in enhanced eNOS expression and prolonged functional activity under sustained treatment. Conclusions: Topical hMet-PPP administration represents a promising therapeutic strategy for enhancing early-stage wound healing. hMetrnl exerts its biological effects through C-Kit, which mediates dual regulation of eNOS, both activation and stabilization, providing a mechanistic basis for its potent angiogenic properties. These findings uncover a novel Metrnl mechanism with potential implications for the development of therapies targeting vascular dysfunction and tissue repair. Full article

Melanin overproduction contributes to hyperpigmentation disorders such as melasma and solar lentigines, leading to increasing demand for safe and effective skin-lightening agents. D-cycloserine (DCS), a known antimicrobial agent, has not been previously evaluated for dermatological applications. This study aimed to explore the potential of DCS as a novel anti-melanogenic compound and to elucidate its underlying molecular mechanisms in melanogenesis inhibition. The cytotoxicity and anti-melanogenic effects of DCS were assessed in B16F10 melanoma cells stimulated with α-MSH. Cell viability was determined via MTT assays, while melanin content, tyrosinase activity, and the expression levels of MITF, TYR, TRP-1, TRP-2, and major signaling proteins (e.g., CREB, MAPKs, GSK-3β/β-catenin) were evaluated using colorimetric assays and Western blotting. A 3D human skin model was also used to confirm in vitro findings, and a primary skin irritation test was conducted to assess dermal safety. DCS significantly reduced α-MSH-induced melanin content and tyrosinase activity without cytotoxicity at concentrations ≤100 µM. It downregulated MITF and melanogenic enzyme expression and modulated signaling pathways by enhancing ERK activation while inhibiting CREB, JNK, and p38 phosphorylation. Additionally, DCS suppressed β-catenin stabilization via GSK-3β activation. These effects were confirmed in a 3D human skin model, and a clinical skin irritation study revealed no adverse reactions in human volunteers. DCS exerts its anti-melanogenic effect by targeting multiple pathways, including CREB/MITF, MAPK, and GSK-3β/β-catenin signaling. Its efficacy and safety profiles support its potential as a novel cosmeceutical agent for the treatment of hyperpigmentation. Further clinical studies are warranted to confirm its therapeutic utility in human skin pigmentation disorders. Full article

Background/Objectives: The synergistic effects of epigallocatechin gallate (EGCG) and taurine in modulating lipid metabolism abnormalities in rats were investigated, and along with their potential mechanisms. Methods/Result: Compared to intervention with EGCG/taurine alone, EGCG combined with taurine (1:3) not only reduced triglyceride (TG) generation in HepG2 cells (46.2%, 75.2%, respectively), but also significantly decreased the total cholesterol (TC) (33.3%, 41.8%), low-density lipoprotein cholesterol (LDL-C) (32.3%, 29.2%) in rats, while the high-density lipoprotein cholesterol (HDL-C) increased by 12.7% and 33.5%. In addition, the combination of EGCG and taurine not only inhibited lipogenic enzyme activity, but also enhanced the levels of lipid catabolic enzymes and antioxidant enzymes, and alleviated hepatic injury. Furthermore, it significantly modulated gut microbiota composition by altering the abundances of Bacteroidetes, Firmicutes, and Proteobacteria, improving intestinal flora balance. Metabolomic profiling showed that reducing N-linoleoyl proline, cortisol, and 3-isocholanolic acid, and increasing phospholipid metabolites are the main ways methods for normalizing lipid metabolism in rats. The combination also elevated short-chain fatty acid (SCFA) synthesis, preserving intestinal barrier integrity; it also promoted lipid catabolism and energy expenditure via activating Peroxisome proliferator- activated receptor alpha (PPARα) and suppressing hepatic fatty acid synthase (FAS)- mediated lipogenesis. Conclusion: These findings indicated that EGCG and taurine can synergistically regulate lipid metabolism abnormalities, which may offer a strategy for regulating lipid metabolism anomalies. Full article

Follicle health determines the number and quality of sows’ ovulation, thereby influencing the litter size and the piglets’ viability. Granulosa cells (GCs) play a crucial role in follicular formation and development, and oxidative stress-induced GC death is a major cause of follicular dysplasia. Previous studies have confirmed that oxidative stress triggers apoptosis in granulosa cells. In this study, we explored how oxidative stress influences apoptosis in porcine ovarian granulosa cells. We find that porcine atretic follicles exhibit significant oxidative stress, accompanied by the activation of the mitogen-activated protein kinase (MAPK) signaling pathway, including the upregulation of key factors such as apoptosis signal-regulating kinase 1 (ASK1). Healthy follicles of 3–5 mm were randomly assigned to the control group, H₂O₂ treatment group, and selonsertib pretreatment group. The porcine ovarian GCs were placed in cell culture medium supplemented with H₂O₂ to assess ROS production, cell proliferation, apoptosis, the expression levels of oxidative stress-related genes, and expression levels of apoptosis-related proteins. In vitro experiments in mouse GCs further confirmed that H₂O₂-induced oxidative stress triggers the upregulation of the MAPK pathway and promotes granulosa cell apoptosis. The results showed that H₂O₂ treatment induced ROS production and apoptosis in porcine GCs and inhibited GC viability. Additionally, selonsertib pretreatment attenuated apoptosis in GCs by inhibiting H₂O₂-induced oxidative stress. In summary, our findings reveal that oxidative stress induced granulosa cell apoptosis via the MAPK signaling pathway, impairing proper follicular development in pigs. Full article

Gastric cancer remains a significant global health challenge, with regional and demographic disparities in incidence, mortality, and treatment outcomes. Despite advances in screening and early detection, prognosis remains poor for many patients, particularly those with advanced disease. Recent insights into DNA damage response pathways have uncovered critical molecular vulnerabilities in gastric tumors, including frequent TP53 mutations, ARID1A loss, ATM deficiency, and oncogene-driven replication stress, which render these cancers highly dependent on the ATR–CHK1 axis for survival. This review synthesizes current clinical and preclinical evidence on ATR and CHK1 inhibitors as therapeutic strategies in gastric cancer. Emphasis is placed on synthetic lethality, immune modulation, and the potential for combination regimens with chemotherapy, radiotherapy, or immune checkpoint blockade. Mechanisms of resistance, including transcription-associated replication stress modulation and bypass signaling networks, are discussed, alongside strategies to predict and overcome therapeutic failure. The review also highlights the importance of biomarker-guided patient selection, adaptive dosing to reduce toxicity, and refined pharmacodynamic monitoring to enhance therapeutic precision. Collectively, these insights support the rational integration of ATR–CHK1 inhibitors into clinical protocols for biomarker-defined gastric cancer subsets and underscore their promise Full article

Chronic itch is a debilitating condition characterized by persistent pruritus lasting more than six weeks, significantly impairing quality of life. While the role of the immune system and neural circuits in itch is increasingly understood, the contribution of the skin microbiome, especially in non-atopic itch disorders, remains underexplored. This review synthesizes emerging evidence on how microbial dysbiosis contributes to chronic pruritus through multiple molecular pathways: disruption of skin barrier integrity, modulation of neuroimmune signaling axes, and direct activation of pruriceptors. We highlight recent studies identifying microbiome shifts in prurigo nodularis (PN) and lichen simplex chronicus (LSC), independent of atopic dermatitis (AD). We also evaluate advances in biologics and small-molecule therapeutics, exploring how targeted immune modulation may restore microbial balance and alleviate neuroinflammation. A systems biology approach integrating microbial genomics, neurobiology, and host immunity is critical to unraveling the complex interplay between host and microbes in chronic itch, particularly in understudied non-atopic conditions that disproportionately affect vulnerable populations. Full article

Uterine leiomyomas (ULM) and uterine leiomyosarcomas (ULMS) represent smooth muscle tumors with similar initial presentations but drastically different outcomes. This literature review analyzes the similarities and differences in their epigenetic profiles to identify diagnostic biomarkers and potential therapeutic targets that could improve clinical management. Both tumor types exhibit mostly distinct epigenetic signatures while sharing key pathway dysregulations. ULMS demonstrates global DNA hypomethylation, increased histone acetyltransferase activity, elevated Histone Deacetylase (HDAC) class I expression, and characteristic microRNA profiles. ULM displays focal methylation patterns and specific microRNA alterations that promote extracellular matrix accumulation. Despite these differences in epigenetic mechanisms, both tumors converge on dysregulation of signaling pathways including PI3K/AKT/mTOR, Wnt/β-catenin, and Transforming Growth Factor beta (TGF-β) signaling, suggesting common downstream effects from distinct epigenetic origins. Understanding the shared and distinct epigenetic landscape between ULM and ULMS will enhance our insights into tumor pathogenesis and may offer promising biomarkers and therapeutic targets. Full article

Hidradenitis suppurativa (HS) is a chronic, relapsing inflammatory dermatosis of the pilosebaceous unit characterized by nodules, abscesses, and dermal tunnels. Recent transcriptomic studies have implicated dysregulation of innate and adaptive immune responses, epidermal barrier dysfunction, and systemic metabolic alterations. This review synthesizes findings from 16 studies investigating the HS transcriptome using bulk and single-cell RNA sequencing. Differential gene expression analyses revealed extensive upregulation of inflammatory cytokines and chemokines, particularly in lesional and perilesional skin. These changes were also mirrored in non-lesional skin, suggesting diffuse immune dysregulation beyond visibly affected areas. Downregulated pathways include those involved in lipid metabolism, muscle contraction, and neuronal signaling, potentially linking HS to obesity, metabolic syndrome, and neuropsychiatric comorbidities. Single-cell transcriptomics confirmed the enrichment of keratinocytes and immune cells (B cells, plasma cells, M1 macrophages, and T cells) with proinflammatory profiles in HS lesions. Keratinocyte dysfunction further implicated a compromised epidermal barrier in disease pathogenesis. While transcriptomic studies have advanced mechanistic understanding and highlighted therapeutic targets—such as the IL-1β–TH17 axis and B cell signaling pathways—methodological heterogeneity limits cross-study comparisons. Integration of multi-omics data and standardized phenotyping will be essential to identify robust biomarkers, stratify HS subtypes, and guide personalized therapeutic approaches. Full article

Amomum villosum, a medicinal and edible plant, has shown promise in improving digestive health; however, the mechanisms underlying its antioxidant and hypoglycemic effects remain unclear. This study aimed to optimize the extraction of A. villosum essential oil (AVEO) and elucidate its bioactive potential. Ultrasound-assisted extraction yielded 3.84% AVEO under optimal conditions. Gas chromatography–mass spectrometry combined with SwissADME analysis identified nine active components, including bornyl acetate, (−)-Spathulenol, and (−)-Pogostol. In vitro assays demonstrated potent α-glucosidase inhibition (IC₅₀: 0.99 mg/mL) and strong free radical scavenging activities against 1,1-diphenyl-2-picrylhydrazyl (IC₅₀: 0.87 mg/mL), hydroxyl (IC₅₀: 0.18 mg/mL), and superoxide anion radicals (IC₅₀: 0.01 mg/mL). A significant positive correlation was observed between its antioxidant and hypoglycemic activities. Network pharmacology identified 11 core targets involved in oxidative stress and glucose metabolism, with functional enrichment pointing to the PPAR and steroid hormone signaling pathways. Molecular docking confirmed stable binding affinities of bornyl acetate, (−)-spathulenol, and (−)-pogostol to JAK2, NCOA2, and PPARA via hydrogen bonding and hydrophobic interactions. These findings provide a mechanistic basis for the dual antioxidant–hypoglycemic effects of AVEO and support its potential application in the development of functional foods and natural therapeutics targeting metabolic disorders. Full article

As the demand for context-aware services in smart environments continues to rise, Indoor Positioning Systems (IPSs) have evolved from auxiliary technologies into indispensable components of mission-critical infrastructure. This paper presents a comprehensive, multidimensional evaluation of IPSs through the lens of critical infrastructure, addressing both their technical capabilities and operational limitations across dynamic indoor environments. A structured taxonomy of IPS technologies is developed based on sensing modalities, signal processing techniques, and system architectures. Through an in-depth trade-off analysis, the study highlights the inherent tensions between accuracy, energy efficiency, scalability, and deployment cost—revealing that no single technology meets all performance criteria across application domains. A novel evaluation framework is introduced that integrates traditional performance metrics with emerging requirements such as system resilience, interoperability, and ethical considerations. Empirical results from long-term Wi-Fi fingerprinting experiments demonstrate the impact of temporal signal fluctuations, heterogeneity features, and environmental dynamics on localization accuracy. The proposed adaptive algorithm consistently outperforms baseline models in terms of Mean Absolute Error (MAE) and Root Mean Square Error (RMSE), confirming its robustness under evolving conditions. Furthermore, the paper explores the role of collaborative and infrastructure-free positioning systems as a pathway to achieving scalable and resilient localization in healthcare, logistics, and emergency services. Key challenges including privacy, standardization, and real-world adaptability are identified, and future research directions are proposed to guide the development of context-aware, interoperable, and secure IPS architectures. By reframing IPSs as foundational infrastructure, this work provides a critical roadmap for designing next-generation indoor localization systems that are technically robust, operationally viable, and ethically grounded. Full article