Search Results (661)

Excessive accumulation of reactive oxygen species from exogenous and endogenous stressors can cause cellular damage. Chlorella contains diverse bioactive compounds, and violaxanthin, a major carotenoid pigment found in Chlorella sp. HS-V, has been reported to possess anti-inflammatory, anticancer, and antioxidant properties. We investigated the effect of violaxanthin on hydrogen peroxide (H₂O₂)-induced oxidative stress in human keratinocytes. Chlorella sp. HS-V extract significantly restored the H₂O₂-induced decrease in cell viability. Similarly, violaxanthin reduced H₂O₂-induced cytotoxicity and intracellular reactive oxygen species levels, which was associated with the upregulation of antioxidant enzyme expression. Under H₂O₂-induced oxidative stress conditions, violaxanthin may enhance cellular antioxidant defense by promoting nuclear factor erythroid 2-related factor 2 (NRF2) translocation through the phosphoinositide 3-kinase/protein kinase B/glycogen synthase kinase 3β (PI3K/AKT/GSK3β) signaling pathway. Additionally, violaxanthin improved H₂O₂-impaired wound healing in HaCaT human keratinocyte cells and reduced senescence-associated beta-galactosidase-positive normal human epidermal keratinocytes. Overall, these findings suggest that violaxanthin may serve as a potential therapeutic agent for mitigating oxidative stress-induced cellular dysfunction. Full article

Adenosine has emerged as a central metabolic signal linking cellular stress to systemic physiological adaptation. Under conditions such as hypoxia, ischemia, inflammation, and tissue injury, extracellular adenosine triphosphate (eATP) released from stressed cells is sequentially metabolized by the ectonucleotidases CD39 and CD73, generating adenosine that accumulates in the extracellular microenvironment. This stress-responsive nucleoside activates four G-protein-coupled receptors (A1, A2A, A2B, and A3), triggering intracellular signaling networks including the cyclic adenosine monophosphate–protein kinase A (cAMP–PKA), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase–protein kinase B (PI3K–Akt), and hypoxia-inducible factor-1 alpha (HIF-1α) pathways. Through these integrated mechanisms, adenosine orchestrates diverse physiological processes such as vascular regulation, metabolic adaptation, immune modulation, and cellular survival. In the cardiovascular system, adenosine promotes coronary vasodilation and ischemic preconditioning, limiting reperfusion injury. In pulmonary tissues, it mediates acute anti-inflammatory responses but may also drive chronic fibrotic remodeling. Within the central nervous system, adenosine functions as a neuromodulator regulating neuronal excitability, sleep–wake homeostasis, and neuroprotection. In the tumor microenvironment, hypoxia-driven adenosine accumulation suppresses cytotoxic T cell and natural killer activity, facilitating immune evasion and tumor progression. Collectively, adenosine signaling represents a central integrative network that links metabolic stress sensing to coordinated cellular adaptation while simultaneously emerging as a clinically actionable therapeutic target across cardiovascular, inflammatory, neurological, and oncological diseases. Full article

Background: Intestinal acute radiation syndrome (IARS) represents a life-threatening component of acute radiation syndrome with limited effective countermeasures. Understanding molecular determinants governing intestinal epithelial resilience to ionizing radiation is critical for developing radiation toxicity mitigation strategies. Objectives: This study investigates the role of PIKfyve, a phosphoinositide kinase essential for endolysosomal homeostasis, in modulating radiation-induced intestinal toxicity. Methods: We utilized an inducible intestinal epithelial-specific PIKfyve-knockout mouse model (PIKfyve cKO) subjected to 10 Gy abdominal irradiation. Intestinal toxicity was assessed through histopathology, barrier permeability (FD4 assay), apoptosis markers, and transcriptomic profiling. Small intestinal organoids were employed for mechanistic validation. Results: PIKfyve deletion alone did not perturb normal gut architecture but precipitated severe post-irradiation toxicity, including villous atrophy, crypt hypoplasia, and massive crypt-cell apoptosis. Barrier dysfunction was evidenced by elevated serum FD4 and heightened systemic pro-inflammatory cytokines, culminating in markedly increased mortality. Transcriptomic analysis revealed potentiated DNA-damage signaling and amplified inflammatory cascades in PIKfyve-deficient intestines. Conclusions: These findings identify PIKfyve as a critical guardian of intestinal epithelial integrity against radiation toxicity. Given emerging PIKfyve inhibitors in cancer therapy, our results raise important safety considerations for clinical radiotherapy and position PIKfyve as a potential target for radiation toxicity mitigation. Full article

Phospholipids function as dynamic regulators of plant growth and environmental adaptation, extending well beyond their structural roles in biological membranes. This review synthesizes the phospholipid metabolic network and its regulatory functions in plant physiology. We first describe enzymatic reactions and acyl-chain remodeling in phospholipid biosynthesis, and then examine the interaction between phospholipid metabolism and auxin signaling, focusing on phosphatidic acid (PA) and phosphoinositide phosphate (PIP). These lipid molecules regulate the polarization and vesicular trafficking of PIN-FORMED proteins via endocytosis and phosphorylation-dependent mechanisms, thereby controlling auxin distribution during development and stress adaptation. Particular emphasis is placed on PA, a multifunctional signaling lipid that serves as a central molecular hub. PA coordinates hormonal, stress, and circadian signals by engaging and modulating a broad spectrum of protein targets, including kinases, phosphatases, and transcription factors. We also discuss the emerging and evolutionarily conserved functions of phospholipid signaling in cell fate determination, drawing parallels from mammalian cell reprogramming to the regulation of plant cell totipotency and root patterning. Collectively, these findings underscore the critical role of phospholipid-mediated signaling in converting metabolic and environmental cues into developmental reprogramming, providing novel theoretical and functional frameworks for future research in plant lipid biology. Full article

Background: Treatment options for recurrent ovarian cancer (OC) are limited, leading to poor prognosis. Targeting tumor-promoting signaling transduction pathways (STPs), such as Hedgehog (HH) and Phosphoinositide-3-kinase (PI3K) STPs, might be an option for treatment. This study evaluates the efficacy of itraconazole as a targeted treatment in HH and/or PI3K active recurrent OC. Methods: We assessed HH and PI3K STP activity in recurrent OC patients. If activity was aberrantly high in either STP, patients received itraconazole treatment, which has been shown to inhibit both HH and PI3K pathways. The primary objective is to compare progression-free survival (PFS) on itraconazole therapy (PFS2) to the PFS on therapy prior to enrolment (PFS1). A PFS2/PFS1 ≥ 1.0 was considered successful. Secondary objectives included side effects, best overall response, one-year survival, and CA125 levels, though this was not a secondary endpoint. Results: Of sixteen patients with successful STP analysis, 93% were eligible for itraconazole therapy. Nine patients started treatment, with a mean duration of 55 days. None achieved a PFS2/PFS1 ratio ≥ 1.0 (mean 0.26, range 0.1–0.7). One patient had radiologically stable disease, while the others experienced disease progression. Side effects were mostly limited to grade 1–2, including fatigue, nausea, dysgeusia, dyspnea, cough, vertigo, and edema. No grade ≥ 3 adverse effects were linked to treatment. One-year survival was 22%. CA125 levels did not correlate with the treatment outcome, but increased rapidly after ceasing treatment. Conclusions: Itraconazole monotherapy for recurrent HH and/or PI3K aberrantly active OC is an ineffective treatment. While CA125 did not correlate with treatment outcome, the rapid increase in CA125 after therapy cessation suggests tumor inhibitory effects. Full article

Mastitis is a common disease in dairy cows, mainly caused by Staphylococcus aureus and Escherichia coli. Berberine (BBR) has antibacterial and anti-inflammatory potential, but its application is limited due to poor oral absorption and difficulty in reaching mammary tissue. To address this, this study developed a BBR-loaded composite ethosome hydrogel (BBR-CEH) to achieve targeted mammary delivery through local transdermal administration. The experimental results showed that BBR-CEH has good chemical stability and biosafety. Subsequently, a mouse mastitis model was established by intraductal injection of 50 µL of bacterial mixture (E. coli:S. aureus = 1:1, each at 1 × 10⁷ CFU/mL). The results showed that after BBR-CEH treatment, the mRNA expression of TNF-α (tumor necrosis factor-alpha), IL-6 (interleukin-6), and IL-1β (interleukin-1 beta) was significantly decreased, the mRNA expression of ZO-1 (zonula occludens-1), Occludin, and Claudin-4 was significantly increased, and Bax/Bcl-2 (Bcl-2-associated X protein/B-cell lymphoma 2) was significantly reduced (p < 0.01), indicating alleviation of mastitis by reducing inflammation, improving tight junctions, and inhibiting apoptosis. Finally, network pharmacology and in vivo experiments confirmed that its mechanism involves the NF-κB (nuclear factor kappa-B) and PI3K/Akt (phosphoinositide 3-kinase/protein kinase B) pathways. Thus, topical BBR-CEH may represent a promising new strategy for mastitis treatment. Full article

Thyroid cancer is the most common malignancy of the endocrine system and represents a biologically heterogeneous disease driven by the interplay between endocrine regulation, oncogenic signaling pathways, and tumor microenvironment dynamics. Although most follicular cell-derived thyroid cancers follow an indolent clinical course, a subset progresses toward aggressive, therapy-refractory phenotypes, underscoring the need for refined molecular understanding and improved biomarkers. This review comprehensively examines the molecular determinants of thyroid cancer progression, with particular emphasis on Thyroid Hormone (TH) signaling, the Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K)/AKT pathways, and the emerging role of microRNAs (miRNAs). We discuss how oncogenic alterations, most notably the ^V600EBRAF mutation, act as central drivers of tumor initiation and aggressiveness by sustaining MAPK/ERK signaling, promoting dedifferentiation, metabolic reprogramming, immune evasion, and resistance to targeted therapies. The cooperative role of PI3K/AKT signaling in reinforcing survival, invasion, and treatment resistance is highlighted, emphasizing the network-level integration of oncogenic pathways rather than linear dependency on single drivers. In parallel, thyroid hormones exert context-dependent effects on tumor biology through both genomic actions mediated by nuclear thyroid hormone receptors and non-genomic mechanisms initiated at the integrin αvβ3 receptor, linking endocrine status to cancer progression and therapeutic response. Finally, we review the expanding evidence supporting miRNAs as critical regulators of thyroid carcinogenesis and as promising diagnostic, prognostic, and predictive biomarkers. The clinical validation of miRNA-based panels and circulating miRNAs offers new opportunities to improve preoperative risk stratification, reduce overtreatment, and guide personalized therapeutic strategies. Collectively, these insights support a multidimensional framework for understanding thyroid cancer progression and highlight future directions for precision oncology. Full article

Milk-derived exosomes (MDEs) are bioactive nanocarriers rich in microRNAs (miRNAs) that play critical roles in post-transcriptional regulation during neonatal development and immune adaptation. However, the dynamic changes in miRNA expression across lactation stages and their biological functions remain insufficiently explored. We hypothesized that the miRNA cargo of buffalo MDEs exhibits temporal specificity, thereby dynamically matching the immune requirements of the neonatal calves. Therefore, the present study aimed to systematically characterize the miRNA expression profiles of MDEs derived from colostrum, transitional milk, and mature milk. MDEs were isolated, purified using differential ultracentrifugation, and characterized via transmission electron microscopy, Western blotting, and nanoparticle-tracking analysis. A total of 370 miRNAs were identified in the MDEs, with 220 (59.5%) co-expressed across colostrum, transitional milk, and mature milk. Comparative analysis revealed that colostrum MDEs exhibited the greatest miRNA diversity. Expression patterns of miRNAs showed distinct stage-specific clustering as lactation progressed. Compared to mature milk, 100 differentially expressed miRNAs (DE-miRNAs) were identified in colostrum MDEs, including 39 upregulated and 61 downregulated miRNAs. Bioinformatics analyses indicated that predicted target genes were associated with transmembrane transport, immune response, cell development, and apoptosis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis identified pathways involved in immune regulation, inflammation, and apoptosis. Moreover, macrophages incubated with buffalo colostrum MDEs showed upregulation of proliferation-related genes and downregulation of pro-inflammatory factors, suggesting an anti-inflammatory effect through activation of the phosphoinositide 3-kinase-protein kinase B (PI3K-Akt) signaling pathway. These findings offer new insights into miRNA profiles of buffalo MDEs across the early postpartum transition and provide a preliminary basis for exploring immunomodulatory potential of buffalo MDEs. Full article

Plant foods have been the cornerstone of human diets since ancient times, fueling civilization and shaping cultures. Plants became central to sustainable food systems, offering diverse and nutritious options for the future. Sea buckthorn (Hippophae rhamnoides L.) has attracted growing scientific interest due to the presence of bioactive compounds, polyphenols, fatty acids, phytosterols, carotenoids, vitamins, and minerals in its fruit, seeds, and leaves. Moreover, sea buckthorn exhibit antioxidant, anti-inflammatory, antimicrobial, antidiabetic, antihyperlipidemic, anticancer, hepatoprotective, neuroprotective, and metabolic regulatory properties supported by in vitro and in vivo models. The biological activity of these phytochemical compounds plays a crucial role in regulating the AMP-activated protein kinase (AMPK) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathways, as well as pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), cell proliferation, and apoptosis. Furthermore, its potential against microbial growth, including S. aureus, S. epidermidis, S. intermedius, and S. pyogenes, among others, not only expands its applications in the pharmaceutical industry but also attracts researchers to incorporate it into food products. This could lead to the discovery of plant-based therapeutic products without significant adverse effects. However, further exploration of each component’s potential side effects is necessary to support the commercialization of formulated products in either the pharmaceutical or food industries, ensuring the highest safety standards for consumers. Including studies on bioavailability and pharmacodynamics could further strengthen the scientific evidence supporting the specific phytochemicals in sea buckthorn and their mechanistic interactions. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer accounting for the majority of cases and exhibiting persistent challenges related to therapy resistance and metastatic progression. Increasing evidence indicates that dysregulated G protein-coupled receptor signaling and ion channel activity function cooperatively as master regulators of tumor cell proliferation, migration, survival, and therapeutic response. Cannabinoids, including phytocannabinoids such as delta-9-tetrahydrocannabinol and cannabidiol, as well as endogenous endocannabinoids, are uniquely positioned to modulate both G protein-coupled receptors and ion channels, thereby influencing key oncogenic signaling networks. This review synthesizes current knowledge on the role of major ion channel families, including transient receptor potential channels, potassium channels, and sodium channels, and principal G protein-coupled receptor pathways involved in lung cancer progression. We further discuss how cannabinoids reprogram these interconnected signaling systems through canonical cannabinoid receptors, non-classical targets such as G protein-coupled receptor 55 and adenosine receptors, and direct modulation of ion channel activity. Special attention is given to G protein-coupled receptor–ion channel coupling within membrane microdomains and to the capacity of cannabinoids to act as biased ligands, redirecting downstream pathways, such as the phosphoinositide 3-kinase–protein kinase B–mechanistic target of rapamycin and epidermal growth factor receptor signaling, toward apoptosis and reduced metastatic potential. Emerging strategies, including cannabinoid-based combination therapies, selective receptor biasing, and targeted delivery systems, are also highlighted. Altogether, cannabinoid-driven rewiring of G protein-coupled receptor and ion channel signaling represents a promising mechanistic framework for developing innovative therapeutic approaches against lung cancer. Full article

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) possesses dual enzymatic functions, i.e., kinase and E3 ubiquitin ligase activities, orchestrating proliferation, survival, apoptosis, DNA damage response, and immune modulation. Recent genomic and mechanistic studies have revealed MAP3K1’s paradoxical, context-dependent roles as both an oncogene and a tumor suppressor. We discuss MAP3K1’s multidomain architecture, featuring an N-terminal RING and PHD domain (E3 ligase activity), a TOG domain (microtubule dynamics), and a C-terminal kinase domain, enabling the integration of c-jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and nuclear factor kappa B (NF-κB) signaling pathways. MAP3K1 functions as a molecular switch balancing survival and apoptosis, with caspase-3 cleavage at Asp878 activating pro-apoptotic JNK/p38 signaling. Genomic analyses across >35 cancer types reveal MAP3K1 alterations at frequencies of <1–14%, highest in breast and endometrial cancers. These alterations show tissue specificity: loss-of-function mutations predominate in hormone receptor-positive breast cancer with a favorable prognosis, whereas gain-of-function mutations in melanoma activate oncogenic ERK signaling. MAP3K1 mutations predict response to mitogen-activated protein kinase kinase (MEK) and phosphoinositide 3-kinase (PI3K) inhibitors, with mutant cancers showing higher MEK inhibitor response than wild-type tumors. Despite substantial progress, critical gaps remain regarding MAP3K1’s E3 ligase substrates, context-dependent activity determinants, and therapeutic strategies. Addressing these through inhibitor development, biomarker validation, and mechanistic studies will accelerate potential clinical translation of MAP3K1 biology. Full article

Ginkgetin (GK) is a naturally occurring biflavonoid predominantly isolated from Ginkgo biloba and has attracted increasing attention because of its broad pharmacological activities. Structurally, GK belongs to the 3′-8″-linked biflavone subclass, which distinguishes it from other biflavonoids like amentoflavone (the parent compound of this subclass) and its monomeric counterparts such as apigenin. This unique C-C linked dimeric architecture confers distinct molecular planarity and lipophilicity, contributing to its enhanced membrane permeability and multitarget engagement capabilities. GK has been shown to exert pleiotropic biological effects in preclinical studies, including anti-inflammatory, antioxidant, antifibrotic, anticancer, neuroprotective, cardioprotective, metabolic regulatory and antibacterial activities. Mechanistically, preclinical evidence indicates that GK functions as a multitarget modulator of key signaling pathways involved in oxidative stress, inflammation, cell death and tissue remodeling, such as nuclear factor erythroid 2–related factor 2/heme oxygenase-1 (Nrf2/HO-1), nuclear factor kappa-B(NF-κB), Janus kinase/signal transducer and activator of transcription(JAK/STAT), mitogen-activated protein kinases(MAPKs), AMP-activated protein kinase/mechanistic target of rapamycin(AMPK/mTOR), phosphoinositide 3-kinase/protein kinase B(PI3K/Akt) and cyclic GMP-AMP synthase–stimulator of interferon genes(cGAS–STING). Notably, GK has been observed to display context-dependent regulation of cell fate decisions, including apoptosis, autophagy and ferroptosis, thereby enabling the selective elimination of pathological cells while preserving normal tissue function. Preclinical studies further demonstrate that GK exhibits therapeutic potential across diverse disease systems, including cancer, metabolic disorders, cardiovascular diseases, neurological disorders and musculoskeletal diseases. In addition, emerging evidence highlights its antibacterial and antivirulence properties through the inhibition of biofilm formation and quorum sensing. It is crucial to note, however, that this promising profile is predominantly derived from preclinical studies, and clinical evidence in humans remains to be established. Despite these promising findings, the clinical translation of GK remains limited by challenges related to pharmacokinetics, bioavailability and druggability. This review systematically summarizes the chemical characteristics, pharmacological activities and molecular mechanisms of GK, with an emphasis on its multitarget actions and therapeutic potential across disease systems, and discusses current limitations and future perspectives to facilitate the rational development of GK-based interventions. Full article

There is no approved drug therapy for schwannomas associated with NF2-related schwannomatosis (NF2-SWN). Neither life-saving surgical resection or radiation are curative and can compound the debilitating neurological effects of the schwannomas. We previously identified fimepinostat, a dual histone deacetylase (HDAC)/phosphoinositide-3 kinase (PI3K) inhibitor, as a promising drug candidate with pro-apoptotic effects on NF2-related schwannomas. This preclinical study used the pharmaceutical formulation of fimepinostat to confirm its efficacy in schwannomas and identify pro-apoptotic signaling pathways. Fimepinostat was tested in human schwannoma model cells, patient-derived primary vestibular and non-vestibular schwannoma cells, and in a sciatic nerve allograft model. The signaling pathways leading to caspase-3-dependent apoptosis were elucidated using immune assays, flow cytometry, imaging, proteome, and acetylome analysis. Acute exposure to fimepinostat led to p21-dependent cell cycle inhibition, upregulation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL R2), and downregulation of tumor necrosis factor receptor 1 (TNFR1), Yes-associated protein (YAP), and inhibitors of apoptosis. Moreover, fimepinostat downregulated cytokine and chemokine secretion increased by merlin loss in schwannoma cells. Fimepinostat is a promising new drug intervention for NF2-SWN patients with the potential to promote tumor regression. Full article

Alzheimer’s disease (AD) is a prevalent chronic neurodegenerative disorder; the progression of this disease is driven by cellular determinants such as oxidative stress and dysregulated neurotrophic signaling. Lavender essential oil is traditionally used in aromatherapy for neuronal regulation and neuroprotection, suggesting its potential neuroprotective effects for chronic neurodegenerative disorders like AD. However, the key active constituents responsible for its benefits and the specific molecular pharmacological mechanisms remain unclear. In this study, we isolated myrtenol from lavender essential oil under the guidance of activity evaluation. Its neuroprotective effects were evaluated in PC12 cells via neurite outgrowth, anti-Aβ/H₂O₂ cytotoxicity, and antioxidant assays. Targets and pathways were explored using inhibitor experiments, cell thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and Western blot. Myrtenol significantly induced neurite outgrowth in PC12 cells and effectively mitigated cytotoxicity and oxidative stress damage induced by Aβ_25–35 and H₂O₂. Mechanistic studies revealed that myrtenol’s effects are associated with the modulation of tyrosine kinase receptor A (TrkA) and insulin-like growth factor-1 receptor (IGF-1R), activating phospholipase C (PLC)/protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways to jointly mediate neuroprotection effects against the pathology of AD. This study demonstrates that myrtenol as a highly active component of lavender essential oil possesses NGF-like neuritogenic activity and neuroprotective effects. It provides a foundation for understanding the cellular mechanisms of myrtenol as a small-molecule lead for further investigation in neurodegeneration-related research. Full article

Heat stress (HS) occurs when animals are unable to effectively dissipate excess body heat, leading to increased core temperature and physiological imbalance. In mammals, HS negatively affects female reproduction. Infertility associated with HS is well documented in swine and is increasingly recognized in other mammals, including humans. HS disrupts several systemic processes that are essential for normal reproductive function, including endocrine regulation, nutrient metabolism, immune activity, and intestinal barrier integrity. Reduced feed intake and changes in metabolic hormones such as insulin and prolactin can impair ovarian function. Increased intestinal permeability during HS may allow bacterial endotoxins to enter the bloodstream, triggering inflammation that further compromises reproductive physiology. At the ovarian level, HS alters key cellular pathways involved in cell survival and metabolism, including Janus Kinase/Signal Transducer and Activator of Transcription (JAK–STAT), Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/AKT), oxidative stress responses, autophagy, apoptosis, and heat shock protein expression. These changes disrupt follicular development, hormone production, oocyte quality, and corpus luteum function, resulting in reduced conception rates and increased embryonic loss. This review summarizes current knowledge of systemic and ovarian mechanisms by which HS impairs female reproduction in pigs and identifies areas requiring further investigation to improve fertility under increasing environmental temperatures. Full article