Search Results (2,394)

Animal venoms represent an extraordinary, yet largely untapped, biochemical reservoir for oncological drug discovery. This review provides a comprehensive analysis of venom-derived enzyme inhibitors as emerging anticancer agents, emphasizing their chemical diversity, structure–activity relationships (SAR), molecular targets, and mechanistic pathways. Venom-derived peptides and proteins exhibit exceptional binding affinity and structural rigidity, characteristics frequently enforced by conserved disulfide networks. This specific architecture allows them to selectively modulate critical cancer-associated enzymes, including matrix metalloproteinases, phospholipases A₂, serine proteases, and kinases. Inhibiting these highly specific targets successfully disrupts tumour angiogenesis, extracellular matrix remodelling, and metastatic dissemination, while simultaneously inducing apoptosis through unique pathways such as reactive oxygen species generation. Modern computational approaches, encompassing deep learning algorithms, molecular docking, and molecular dynamics simulations, are substantially accelerating and transforming the discovery pipeline by rapidly mapping intricate peptide–receptor interactions and guiding rational drug design. Translating these potent molecules into clinical therapeutics remains heavily challenged by pharmacokinetic instability, rapid proteolytic degradation, and systemic toxicity. The integration of computationally optimized scaffolds with advanced targeted delivery platforms, such as nanocarriers and liposomal encapsulation, offers a highly viable strategy to overcome these barriers, ultimately paving the way for next-generation, venom-inspired cancer therapies. Full article

Background/Objective: An obesogenic diet triggers intestinal inflammation and oxidative stress, leading to epithelial barrier dysfunction and increased risk of metabolic disorders. This study investigated the mechanisms by which quercetin protects intestinal integrity in high-fat diet (HFD)–fed mice. Methods: Mice were fed an HFD or a low-fat diet (LFD) with or without 1% quercetin, intestinal gene and protein expression, microRNA levels, permeability, and circulating intestinal biomarkers were assessed. Results: Mice fed an HFD with quercetin (HFDQ) showed a 17% improvement in intestinal barrier integrity with increased expression of tight junction and mucin genes and proteins. The nuclear translocation of the nuclear factor-κB (NF-κB) p65 subunit in the ileum decreased by 34%, whereas its acetylation was reduced by 50–57% throughout the intestine, with downregulation of NF-κB-regulated pro-inflammatory genes and proteins. Quercetin increased the nuclear factor erythroid 2-related factor 2 (NRF2) by ~ 25% across intestinal segments and upregulated antioxidant enzyme genes. It suppressed toll-like receptor 4 (TLR4) by 50% and restored AMP-activated protein kinase (AMPK) and sirtuin 1 to levels comparable to those in LFD mice. Altered microRNAs (miRNA-16, 200b, 122, 34a, and 21) supported these molecular changes. Quercetin also restored short-chain fatty acid receptors and serotonin transporters that were affected by HFD. Plasma lipopolysaccharide (LPS), cluster of differentiation 14, LPS-binding protein, and myeloperoxidase activity decreased by 36, 31, 42, and 37%, while glucagon-like peptide-1 increased by 23%. Conclusions: Quercetin protects epithelial barrier integrity against HFD-induced intestinal inflammation and oxidative stress via the AMPK-mediated NF-κB and NRF2 signaling pathways. Full article

Asthma is a heterogeneous chronic airway disease in which oxidative stress (OS) plays a central mechanistic role beyond classical immune-mediated inflammation. Reactive oxygen and nitrogen species (ROS/RNS), generated by recruited inflammatory cells and activated airway structural cells, drive epithelial injury, mucus hypersecretion, airway remodeling, and modulate key transcription factors including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. This review synthesizes current evidence on the multilevel redox-based determinants of asthma severity, spanning from genetic polymorphisms to circulating biomarkers. We examine serum antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), peroxiredoxins (PRDXs), and the thioredoxin (Trx) system as dynamic indicators of systemic redox status and disease severity, alongside oxidative enzymes including NADPH oxidases and dual oxidases (NOX/DUOX), xanthine oxidase (XO), and myeloperoxidase (MPO) that serve as upstream sources of airway oxidant burden. Functional genetic polymorphisms in antioxidant genes (SOD2, CAT, glutathione S-transferase mu 1/glutathione S-transferase theta 1 (GSTM1/GSTT1), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/KEAP1)) and oxidative enzyme genes including nitric oxide synthase 1/2/3 (NOS1/2/3), MPO, cytochrome b-245 alpha chain (CYBA), and xanthine dehydrogenase (XDH) are reviewed as modulators of individual redox capacity and asthma susceptibility, with particular attention to gene–environment interactions. We further discuss oxidative damage biomarkers, including malondialdehyde (MDA), 8-isoprostanes, 4-hydroxynonenal, 8-oxo-7, 8-dihydro-2′-deoxyguanosine, protein carbonyls, 3-nitrotyrosine, and advanced oxidation protein products as indicators of lipid, DNA, and protein oxidation that correlate with disease activity and control. The roles of micronutrient cofactors in modulating antioxidant enzyme function and their potential as contextual biomarkers are also addressed. Additionally, emerging evidence on microRNAs (miRNAs) linked to OS biology in asthma is presented. Finally, we critically evaluate the challenges limiting clinical translation, including biomarker non-specificity, analytical variability, gene–environment complexity, and the absence of standardized reference ranges. This integrated framework supports the development of multilevel redox prognostic panels combining genetic, enzymatic, and oxidative damage readouts for improved asthma phenotyping, severity stratification, and personalized therapeutic approaches. Full article

Tumor microenvironment influences the process of tumorigenesis, with hypoxia being a characteristic of many solid tumors and an adverse prognostic factor. Carbonic anhydrases (CAs) are highly efficient zinc-containing enzymes that are overexpressed in many cancers, particularly under acidic and hypoxic conditions. CA IX expression promotes cancer cell proliferation, migration, and invasion. Vascular endothelial growth factor receptor-2 (VEGFR-2) is a tyrosine transmembrane (ΤΜ) protein regulating embryonic development, angiogenesis, tissue homeostasis and cancer. Blocking VEGFR-2 signaling is one of the most promising approaches to hindering angiogenesis and growth of cancer cells. The epidermal growth factor receptor (EGFR) is a member of the ERBB family of receptor tyrosine kinases and plays a key role in cancer progression. EGFR is uniquely found in some brain, lung and other cancers. Development of novel strategies to regulate these factors is important for the treatment of tumors. Multifunctional drugs that act on multiple pathways offer a promising approach, improving therapeutic effectiveness while reducing side effects. The present review focuses on novel compounds that inhibit CA IX and target VEGFR-2 or EGFR. Full article

Epichloë endophytes enhance plant defense and biotic stress resistance through mutualistic interactions in natural hosts. However, whether these protective effects are retained in annual non-native hosts such as barley (Hordeum vulgare L.) remains unclear. An integrated multi-omics approach was used to characterize defense responses in Epichloë bromicola-infected barley (LD1) and endophyte-free barley (CK) following pathogen challenge. The results show that LD1 had 20.0% lower disease incidence and 24.1% lower disease index than CK. LD1 also exhibited 21.1% lower malondialdehyde (MDA) content and higher antioxidant enzyme activities, indicating more effective control of oxidative damage and improved redox homeostasis. Integrated transcriptomic and metabolomic analyses revealed distinct defense responses between LD1 and CK. LD1 showed stronger activation of glutathione metabolism and antioxidant pathways than CK after 6 h of endophyte inoculation. This was consistent with more efficient control of early reactive oxygen species (ROS) dynamics. By 48 h, LD1 preferentially enriched phenylpropanoid biosynthesis and mitogen-activated protein kinase (MAPK) signaling, accompanied by increased accumulation of defense-related metabolites and enhanced structural and chemical defenses. Collectively, the study demonstrates that Epichloë bromicola enhances disease resistance in barley by reprogramming host defense dynamics from early redox regulation to late structural and chemical reinforcement. Full article

Ultraviolet B (UVB) radiation-induced corneal injury poses a significant public health challenge. However, its underlying molecular mechanisms remain incompletely understood, hindering the development of effective interventions. This study identified a key molecular pathway in UVB-induced corneal damage, revealing that UVB exposure triggers a rapid intracellular burst of reactive oxygen species (ROS), which in turn upregulates and aberrantly activates the receptor tyrosine kinase Ephrin type-A receptor 2 (EphA2), thereby collectively accelerating DNA damage and photoaging in corneal epithelial cells. Based on this mechanism, we developed the natural compound Penicophenone F (PP-F), which was screened and identified from the Arctic fungus Penicillium sp. MYA5, as a novel therapeutic strategy against UVB-induced corneal damage. In vitro and in vivo experiments suggest that PP-F may mediate its therapeutic effects via a dual mechanism. On one hand, it may counteract UVB damage by modulating ROS levels through regulation of endogenous antioxidant enzymes, inhibiting aberrant EphA2 activation, and promoting cellular proliferation and DNA repair. On the other hand, it may upregulate IRF6 to activate the cGAS pathway, which could enhance antioxidant defenses and significantly contribute to the restoration of epithelial barrier integrity and overall corneal physiology. These results underscore the safety and potential of PP-F in treating UVB-induced corneal damage and other oxidative stress-related ocular surface diseases. Full article

Sea cucumber Apostichopus japonicus is one of the few animals capable of synthesizing saponins, which are critical components of its nutritional quality and health-beneficial properties. However, the specific mechanism underlying saponin biosynthesis in sea cucumbers remains unclear despite previous investigations. This study aimed to characterize the molecular pathway and regulatory mechanism of saponin biosynthesis in A. japonicus. Thirteen candidate genes involved in de novo saponin skeleton synthesis were identified from the A. japonicus genome, and their full-length cDNAs were obtained via PCR-RACE. Sequence analysis predicted the intracellular localization of these genes. Combined in situ hybridization and quantitative real-time PCR analyses revealed their high expression in coelomocytes, indicating coelomocytes as the primary saponin synthesis sites. Knockdown of mevalonate kinase (AjMVK) and two oxidosqualene cyclases (AjPS and AjLS) caused a more obvious decrease in saponin levels, identifying them as key biosynthetic enzymes. Yeast two-hybrid assays revealed that AjPS and AjLS interact with ficolins, complement component 3-2, O-linked β-N-acetylglucosamine transferase, and α-L-fucosidase, whose regulatory effects were further validated by RNA interference and saponin content measurements. These results suggest that saponin biosynthesis in A. japonicus is regulated by the complement lectin pathway and modulated by glycosylation enzymes, providing a molecular foundation for enhancing bioactive saponin production for pharmaceutical and nutraceutical applications. Full article

Osteoarthritis (OA) is a chronic, debilitating degenerative joint disease whose prevalence is rising markedly with the rapid aging of the global population. In this study, we investigated the chondroprotective efficacy of NP-2007, an enzymatically hydrolyzed low-molecular-weight collagen from Cervi cornu, using IL-1β-stimulated SW1353 human chondrocyte cells and a medial meniscal transection (MMT)-induced OA rat model. In SW1353 cells, NP-2007 considerably suppressed the expression of inflammatory mediators (iNOS, COX-2) and cytokines (TNF-α, IL-6) without cytotoxicity. Crucially, it restored matrix homeostasis by downregulating catabolic enzymes (MMP-3, MMP-13, and ADAMTS-5) and upregulating anabolic markers (COL2A1, aggrecan), a process associated with the modulation of the Wnt/β-catenin and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathways and the recovery of the master chondrogenic factor SOX9. These in vitro findings were consistent with the in vivo results from the MMT model, where oral administration of NP-2007 (50 and 200 mg/kg) for 8 weeks effectively preserved articular cartilage structure and proteoglycan content while markedly reducing serum levels of catabolic biomarkers, including MMP-13 and COMP. Collectively, our findings demonstrate that NP-2007 exerts potent chondroprotective effects by modulating the balance between cartilage degradation and synthesis, suggesting its potential as a therapeutic candidate for the management of OA. Full article

Cancer is a genetic disease driven by the accumulation of mutations that disrupt normal cellular growth. Among the most frequently mutated families are protein kinases, inositol polyphosphate kinases, and GTPases, which together function as central molecular switches controlling proliferation, survival, and metabolism. In cancer, activating mutations in protein kinases, such as EGFR and BRAF, lead to uncontrolled downstream signaling by locking these enzymes in a constitutively active state. Similarly, mutations affecting inositol kinases, notably PI3KCA, hyperactivate the PI3K/AKT pathway, promoting relentless cell survival and resistance to apoptosis. GTPases, particularly Ras family members (KRAS, NRAS, HRAS), are classical oncogenes where single amino acid substitutions impair their intrinsic GTP hydrolysis activity, trapping them in a persistently GTP-bound “on” state. This unleashes continuous mitogenic signaling independently of external growth factors. Collectively, these mutations are not random but converge on a limited set of core pathways, making them key drivers of tumor initiation and progression. Understanding the specific molecular consequences of kinase and GTPase mutations has directly informed the development of targeted therapies, including small molecule inhibitors and monoclonal antibodies, now used in routine clinical practice. Full article

Age-related hyperphosphatemia is increasingly recognized as a contributing factor in sarcopenia. This work studies the metabolic effects of elevated phosphate on muscle. C2C12 cells were differentiated in the absence or presence of 10 mM β-glycerophosphate (BGP), an exogenous phosphate donor. In addition, quadriceps muscles from four experimental groups of male C57BL/6J mice were analyzed: young (5 months) and old (24 months) fed with standard diet; old mice fed with hypophosphatemic diet or supplemented with the phosphate binder Velphoro^®, for the last three months of life. Mice were stratified according to sarcopenia degree based on muscle mass, strength and physical performance. Protein levels were determined by immunoblotting and mRNA expression by RT-qPCR. ATP levels were measured by luminescence and L-lactate production, citrate synthase and cytochrome c oxidase activities by colorimetric assays. Mitochondrial content, membrane potential and reactive oxygen species (ROS) were determined by fluorescence assay. BGP-treated cells showed increased glucose transporter 1 (GLUT1) and decreased NADH Dehydrogenase (CI-NDUFB8) protein expression, elevated hexokinase II (HK2), phosphoglycerate kinase 1 (PGK1) and lactate dehydrogenase A (LDHA) mRNA levels, reduced ATP levels, increased lactate production, and decreased mitochondrial enzyme activities. Moreover, BGP increased ROS, diminished mitochondrial membrane potential, and altered fusion–fission dynamics and mitophagy. In aged quadriceps, oxidative phosphorylation (OXPHOS) subunits and superoxide dismutase 2 (SOD2) expression were reduced. The hypophosphatemic diet improved all parameters, whereas Velphoro^® selectively increased Mitochondrial cytochrome C oxidase subunit 1 (CIV-MTCO1) expression. Several altered mitochondrial markers are associated with sarcopenia degree. Altogether, hyperphosphatemia induces metabolic changes that scale with the sarcopenic degree. Our findings show a relevant association between hyperphosphatemia and mitochondrial dysfunction, and they support the potential benefit of phosphate reduction as a strategy to prevent or mitigate sarcopenia. Full article

Background: Adipose tissue is increasingly recognized as a highly dynamic endocrine and immunometabolic organ with marked functional heterogeneity. It serves as a reservoir for the active form of vitamin D₃, 1α,25-dihydroxyvitamin D₃ or calcitriol (1α,25-D₃), since it expresses enzymes responsible for its activation and inactivation and contains the vitamin D receptor (VDR). Through both classical and non-classical mechanisms, calcitriol modulates adipocyte proliferation and differentiation, protein expression and energy metabolism. This review aims to explore the signal transduction mechanisms of calcitriol in adipocytes, detailing the classical pathways mediated by the nuclear VDR (VDRn), as well as non-classical pathways involving membrane-associated VDR (VDRm), microRNAs, AMP-activated protein kinase (AMPK), and sirtuin 1 (SIRT1). Methods: A literature search was conducted using PubMed, ScienceDirect, and MDPI-indexed journals, prioritizing studies published within the last 10 years to ensure the inclusion of up-to-date evidence. Results: This review summarizes current knowledge on both classical and non-classical signaling pathways that are activated by calcitriol and highlights key molecular targets with potential relevance for drug development and therapeutic intervention. Through VDRn, calcitriol regulates the expression of proteins involved in inflammation and energy metabolism. Additionally, it modulates cellular processes such as energy production and secretion via the AMPK/SIRT1 axis and microRNA-mediated pathways, contributing to mitochondrial function and metabolic homeostasis. Conclusions: Calcitriol plays a central role in adipocyte biology by integrating multiple signaling pathways that regulate metabolic and inflammatory responses. These mechanisms highlight its potential as a therapeutic target and biomarker in metabolic diseases. Moreover, microRNAs emerge as critical posttranscriptional regulators in these processes, reinforcing their relevance as both biomarkers and targets for future interventions. Full article

Grapevine downy mildew, caused by the oomycete pathogen Plasmopara viticola (P. viticola), is one of the most devastating diseases threatening the global grape industry. The pathogen invades host plants through stomata, triggering a series of highly coordinated physiological disorders and biochemical defense events. This review systematically summarizes the dynamic changes in morphological structures (stomatal characteristics), physiological functions (photosynthesis, membrane system integrity, and carbon metabolism), and multi-level biochemical defense systems (reactive oxygen species (ROS) scavenging enzyme system, phenylpropanoid metabolic pathway, pathogenesis-related proteins, and phenolic compounds) in grapevines following infection. It focuses on analyzing the differences in the timing, intensity, and metabolic reprogramming of defense responses between resistant and susceptible cultivars, pointing out that the essence of disease resistance lies in early pathogen recognition and rapid defense induction. The conflicting conclusions regarding indicators such as soluble sugars, peroxidase (POD), and superoxide dismutase (SOD) are discussed from the perspectives of experimental systems, cultivar genetic backgrounds, and pathogen physiological race differences. Furthermore, the known physiological and biochemical alterations are linked to upstream signaling pathways, including salicylic acid and jasmonic acid (SA/JA), calcium signaling, and mitogen-activated protein kinase (MAPK) cascades. Recent advances in revealing resistance mechanisms in the omics era are also introduced. Finally, future research directions are proposed, including constructing multi-indicator dynamic evaluation models, verifying key gene functions using gene editing, exploring the potential of epigenetic regulation, and developing integrated control strategies combined with microbiome research. This review aims to provide theoretical support for grapevine downy mildew resistance breeding and sustainable disease management. Full article

Patients with myeloproliferative neoplasms (MPN) are at increased risk of herpes zoster, particularly during Janus kinase inhibitor (JAKi) therapy, yet the immunogenicity of recombinant zoster vaccine (RZV) in this setting remains incompletely characterized. We performed a prospective pilot translational study including 18 patients with MPN and a small age-matched healthy donor group (n = 4, descriptive reference only). Samples were collected at baseline, 21 days after the first dose, and 21 days after the second dose. Humoral response was assessed by anti-varicella-zoster virus (VZV) immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA), whereas antigen-specific cellular responses were evaluated after ex vivo stimulation with recombinant VZV glycoprotein E followed by flow cytometry and cytokine quantification. IgG levels increased over time in MPN patients, while cellular responses remained limited, heterogeneous, and not consistently enhanced. Cytokine production was low and variable across time points. Overall, RZV in MPN under JAKi was associated with detectable humoral responses but limited cellular activation, supporting an apparent discordance between humoral and cellular immune readouts under the experimental conditions used. Full article

Background/Objectives: Betanin (Bet), a natural compound, exhibits potent antioxidant and metabolic regulatory properties, yet its effect on cellular glucose utilization remains unclear. This study investigated, for the first time, the impact of Bet on glucose consumption and the activation of key carbohydrate–catabolic pathways in human erythrocytes. Methods: In vitro assays were performed to evaluate enzyme inhibition and activation. Human erythrocytes were incubated with Bet to assess glucose consumption. Enzyme activities were measured spectrophotometrically, and molecular docking was used to analyze binding interactions. Results: Our results demonstrate that Bet inhibits digestive enzymes in a dose-dependent manner, with maximal inhibition at 90 µg/mL for pancreatic lipase and 70 µg/mL for α-amylase, showing IC₅₀ values of 48.8 and 31.9 µg/mL, respectively, supported by strong binding affinities of −9.3 and −8.9 Kcal/mol. These interactions are stronger than those of orlistat (−6.9 Kcal/mol) and acarbose (−7.7 Kcal/mol). Bet also induced the activity of AMPK with an IC₅₀ of 1.83 µg/mL and a BE of −7.90 Kcal/mol, compared to the specific AMPK activator A-769662, which had an IC₅₀ of 1.29 µg/mL and a binding energy of −10.0 Kcal/mol. Consequently, Bet stimulated key glycolytic enzymes, reaching maximal activation (~62%) at 1.4 µg/mL for hexokinase (HK) and glucose-6-phosphate dehydrogenase (G6PD), and at 1.6 µg/mL for pyruvate kinase (PK), supported by binding energies of −7.2, −7.5, and −9.0 Kcal/mol and AC₅₀ values of 0.87, 0.98, and 0.91 µg/mL, respectively. Moreover, Bet enhanced key Krebs cycle enzymes (IDH, SDH, MDH, LDH) in a dose-dependent manner, with AC₅₀ values of 0.76, 0.80, 0.72, and 0.52 µg/mL and strong binding energies (−7.8, −7.8, and −8.4 Kcal/mol), reaching maximal activation near 1.4 µg/mL. Bet also increased glucose consumption by human erythrocytes. Conclusions: Bet enhances glucose utilization by inhibiting digestive enzymes and activating intracellular metabolic pathways, suggest potential metabolic regulatory effects. Full article

The purpose of this study was to investigate the adverse effects of 1.5 μg·L⁻¹ environmentally relevant chlorantraniliprole (CAP) on oxidase biomarkers (juvenile, 2.5 g) for 2, 4, and 8 h and transcriptomic response (adult, 254.8 g) for 96 and 192 h in American shad Alosa sapidissima (Wilson, 1981). American shad is sensitive to pollutants and has become an important economic fish in China, especially for recirculating the aquaculture system and photovoltaic farming. For juvenile shad under short-time CAP exposure, acid phosphatase (ACP) and aryl hydrocarbon receptase (AHR) at the protein level significantly increased at 2 h, and for longer-time exposure, alkaline phosphatase (AKP), polyphenol oxidase enzyme (PPO), and tumor necrosis factor alpha (TNFα) at the protein level significantly decreased; ryanodine receptase (RYR) at the protein level was significantly increased at 8 h. Interestingly, malondialdehyde (MDA) contents, biomarkers of oxidative stress, were significantly decreased for depletion at 2 h and 4 h, while they increased for eliminating free radicals at 8 h via longer-time CAP exposure duration. With the same CAP exposure for adult shad, the number of congested and dilated sinuses of the liver changed, with fine granular brown pigmentation and vacuolization of hepatocytes at 96 h, while the sinuses and central veins were dilated and edematous degeneration occurred at 192 h for longer-time exposure. The detected enzymatic activities, except for adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), significantly decreased, and MDA contents significantly increased in adult shad at 96 and 192 h. Ribosome, proteasome, spliceosome, protein processing in endoplasmic reticulum, oxidative phosphorylation, glycerophospholipid metabolism, biosynthesis of amino acids, ferroptosis, peroxisome, apoptosis, necroptosis, and mTOR signaling pathways were the most significantly enriched pathways. For qPCR verification, the genes ppa2, pla1a, psmb13a, pkz and stat1b were significantly upregulated, while hspa8b, capn2, tram2, asns, bcl2l1, diablo, and prkcb were downregulated in adult shad. The results reveal elevated oxidative stress causing time-dependent hepatic damage via 1.5 μg·L⁻¹ CAP exposure both in juvenile and adult shad. Full article