Search Results (134)

Reactive oxygen species (ROS) are often seen solely as harmful byproducts of oxidative metabolism, yet evidence reveals their paradoxical roles in both promoting and inhibiting cancer progression. Despite advances, precise context-dependent mechanisms by which ROS modulate oncogenic signaling, therapeutic response, and tumor microenvironment dynamics remain unclear. Specifically, the spatial and temporal aspects of ROS regulation (i.e., the distinct effects of mitochondrial versus cytosolic ROS on the PI3K/Akt and NF-κB pathways, and the differential cellular outcomes driven by acute versus chronic ROS exposure) have been underexplored. Additionally, the specific contributions of ROS-generating enzymes, like NOX isoforms and xanthine oxidase, to tumor microenvironment remodeling and immune modulation remain poorly understood. This review synthesizes current findings with a focus on these critical gaps, offering novel mechanistic insights into the dualistic nature of ROS in cancer biology. By systematically integrating data on ROS source-specific functions and redox-sensitive signaling pathways, the complex interplay between ROS concentration, localization, and persistence is elucidated, revealing how these factors dictate the paradoxical support of tumor progression or induction of cancer cell death. Particular attention is given to antioxidant mechanisms, including NRF2-mediated responses, that may undermine the efficacy of ROS-targeted therapies. Recent breakthroughs in redox biosensors (i.e., redox-sensitive fluorescent proteins, HyPer variants, and peroxiredoxin–FRET constructs) enable precise, real-time ROS imaging across subcellular compartments. Translational advances, including redox-modulating drugs and synthetic lethality strategies targeting glutathione or NADPH dependencies, further highlight actionable vulnerabilities. This refined understanding advances the field by highlighting context-specific vulnerabilities in tumor redox biology and guiding more precise therapeutic strategies. Continued research on redox-regulated signaling and its interplay with inflammation and therapy resistance is essential to unravel ROS dynamics in tumors and develop targeted, context-specific interventions harnessing their dual roles. Full article

Reactive oxygen species (ROS) play a dual role as both essential signaling molecules and harmful mediators of damage. Imbalances in the redox state of the liver can overwhelm antioxidant defenses and promote mitochondrial dysfunction, oxidative damage, and inflammation. Complex feedback loops between ROS and immune signaling pathways are a hallmark of pathological liver conditions, such as hepatic ischemia–reperfusion injury (IRI). This is a major cause of liver transplant failure and is of increasing significance due to the increased use of marginally discarded livers for transplantation. This review outlines the major enzymatic and metabolic sources of ROS in hepatic IRI, including mitochondrial reverse electron transport, NADPH oxidases, cytochrome P450 enzymes, and endoplasmic reticulum stress. Hepatocyte injury activates redox feedback loops that initiate immune cascades through DAMP release, toll-like receptor signaling, and cytokine production. Emerging regulatory mechanisms, such as succinate accumulation and cytosolic calcium–CAMKII signaling, further shape oxidative dynamics. Pharmacological therapies and the use of antioxidant and immunomodulatory approaches, including nanoparticles and redox-sensitive therapeutics, are discussed as protective strategies. A deeper understanding of how redox and immune feedback loops interact is an exciting and active area of research that warrants further clinical investigation. Full article

Inflammatory Bowel Disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), results from dysregulated immune responses that drive chronic intestinal inflammation. Neutrophils, as key effectors of the innate immune system, contribute to IBD through multiple mechanisms, including the release of reactive oxygen species (ROS), pro-inflammatory cytokines, and neutrophil extracellular traps (NETs). NETs are web-like structures composed of DNA, histones, and associated proteins including proteolytic enzymes and antimicrobial peptides. NET formation is increased in IBD and has a context-dependent role; under controlled conditions, NETs support antimicrobial defense and tissue repair, whereas excessive or dysregulated NETosis contributes to epithelial injury, barrier disruption, microbial imbalance, and thrombotic risk. This review examines the roles of neutrophils and NETs in IBD. We summarize recent single-cell and spatial-omics studies that reveal extensive neutrophil heterogeneity in the inflamed gut. We then address the dual role of neutrophils in promoting tissue damage—through cytokine release, immune cell recruitment, ROS production, and NET formation—and in supporting microbial clearance and mucosal healing. We also analyze the molecular mechanisms regulating NETosis, as well as the pathways involved in NET degradation and clearance. Focus is given to the ways in which NETs disrupt the epithelial barrier, remodel the extracellular matrix, contribute to thrombosis, and influence the gut microbiota. Finally, we discuss emerging therapeutic strategies aimed at restoring NET homeostasis—such as PAD4 inhibitors, NADPH oxidase and ROS pathway modulators, and DNase I—while emphasizing the need to preserve antimicrobial host defenses. Understanding neutrophil heterogeneity and NET-related functions may facilitate the development of new therapies and biomarkers for IBD, requiring improved detection tools and integrated multi-omics and clinical data. Full article

The germin-like protein (GLP) family plays vital roles for plant growth, stress adaptation, and defense; however, its evolutionary dynamics and functional diversity in halophytes remain poorly characterized. Here, we present the genome-wide analysis of the GLP family in the halophytic forage alkaligrass (Puccinellia tenuiflora), which identified 54 PutGLPs with a significant expansion compared to other plant species. Phylogenetic analysis revealed monocot-specific clustering, with 41.5% of PutGLPs densely localized to chromosome 7, suggesting tandem duplication as a key driver of family expansion. Collinearity analysis confirmed evolutionary conservation with monocot GLPs. Integrated gene structure and motif analysis revealed conserved cupin domains (BoxB and BoxC). Promoter cis-acting elements analysis revealed stress-responsive architectures dominated by ABRE, STRE, and G-box motifs. Tissue-/organ-specific expression profiling identified root- and flower-enriched PutGLPs, implying specialized roles in stress adaptation. Dynamic expression patterns under salt-dominated stresses revealed distinct regulatory pathways governing ionic and alkaline stress responses. Functional characterization of PutGLP37 demonstrated its cell wall localization, dual superoxide dismutase (SOD) and oxalate oxidase (OXO) enzymatic activities, and salt stress tolerance in Escherichia coli, yeast (Saccharomyces cerevisiae INVSc1), and transgenic Arabidopsis. This study provides critical insights into the evolutionary innovation and stress adaptive roles of GLPs in halophytes. Full article

Soybean is a dual-purpose crop for food and oil, playing a crucial role in China’s grain production. Seed size and weight are key agronomic traits directly influencing the yield. Cytokinin oxidases/dehydrogenases (CKXs) specifically degrade certain isoforms of endogenous cytokinins (CKs), thereby modulating plant growth and seed development. However, their role in soybeans remains largely uncharacterized. In a previous genome-wide association study of 250 soybean core germplasms, we identified GmCKX3 as a yield-related gene. To elucidate its function, we developed GmCKX3-deficient mutants using CRISPR/Cas9 gene editing in soybean Williams82 and conducted a three-year phenotypic analysis. Loss of GmCKX3 function significantly enhanced the seed size and weight, which was attributed to an increased cell size and fat accumulation in the endosperm. This enhancement was driven by elevated endogenous CK levels resulting from suppressed GmCKX3 expression. Subcellular localization revealed that GmCKX3 resides in the endoplasmic reticulum and predominantly degrades the isopentenyladenine (iP)-type CK. Integrated transcriptomic and metabolomic analyses uncovered key genes and pathways involved in CK regulation, supporting GmCKX3’s central role in seed-trait modulation. These findings advance our understanding of cytokinin-mediated seed development and offer promising targets for molecular breeding aimed at improving the soybean yield. Full article

Nitric oxide (NO) has a dual effect on mitochondria. Incubating liver mitochondria with NO improves oxidative phosphorylation (OXPHOS) efficiency by decreasing state 4 respiration more than ATP synthesis and preventing mitochondrial permeability transition pore (mPTP) opening. We evaluated the effect of L-arginine (L-arg), an NO donor, on isolated liver mitochondrial respiration and mPTP in sepsis. Male mice were subjected to cecal ligation and perforation (CLP) with saline resuscitation or sham. After 8, 24, and 48 h, with and without L-arg, we measured isolated liver mitochondrial respiration and cytochrome c oxidase (COX) activity using polarographic methods and calcium retention capacity (CRC) to assess the mPTP and NO metabolites via the Griess reaction. Mitochondrial NO synthase (mtNOS) was identified by Western blot. CLP decreased state 3 respiration at 24 and 48 h, decreased COX activity at 8, 24, and 48 h, and increased state 4 respiration and decreased the respiratory control ratio (RCR) and CRC at 48 h. L-arg increased NO levels at 8 h, decreased state 4 respiration more than state 3 respiration (−39% versus −12%) at 48 h, decreased the CRC in the CLP groups at 24 and 48 h, but did not improve RCR. Our data suggests that L-arg does not restore liver mitochondrial OXPHOS efficiency or prevent mPTP opening in the late or recovery phases of sepsis. Full article

Alzheimer’s disease (AD) is a multi-factorial neurodegenerative disease with a complex pathomechanism that can be best treated with multi-target medications. Among the possible molecular targets involved in AD, acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) are well recognized because they control the neurotransmitters responsible for memory processes. This review discusses the current understanding of AD pathology, recent advances in AD treatment, and recent reports in the field of dual AChE/MAO-B inhibitors for treating AD. We provide a classification of dual inhibitors based on their chemical structure and describe active compounds belonging to, i.a., chalcones, coumarins, chromones, imines, and hydrazones. Special emphasis is given to the computer-aided strategies of dual inhibitors design, their structure–activity relationships, and their interactions with the molecular targets at the molecular level. Full article

The hyperglycemic microenvironment in diabetic wounds predisposes them to bacterial infections, sustains chronic inflammation, and hinders therapeutic efficacy. In this study, antibiotic-loaded fast-crosslinked hybrid nanogel wound dressings (florfenicol nanogels) based on Schiff’s base bond were obtained through N, O-carboxymethyl chitosan (N, O-CMCS) and oxidized hyaluronic acid (OHA). The successfully prepared florfenicol N, O-CMCS/OHA nanogels exhibited obvious pH- and HAase-responsiveness release, which allowed it to quickly release florfenicol at infected wounds to exert on-demand antibacterial activity, as well as accelerate diabetic bacterial-infected wound healing. The nanogel dressings showed excellent antibacterial activity by destroying the bacterial cell membrane and wall. More specifically, the glucose oxidase in the dressings can catalyze the breakdown of high-concentration glucose, generating abundant ROS that directly cause cellular damage. According to the results of wound healing, the dressings showed satisfactory anti-inflammatory and therapeutic effects for the full-thickness mouse skin defect wounds. The nanogel dressings are anticipated to be excellent wound dressings to synergistically overcome the theraputic difficulty of diabetic bacterial wounds. Full article

Background/Objectives: Gouty arthritis (GA) is a chronic inflammatory condition characterized by hyperuricemia and NLRP3 inflammasome activation, leading to joint damage and systemic inflammation. Although allopurinol (ALP), a xanthine oxidase inhibitor, effectively lowers serum urate levels, it has limited anti-inflammatory effects. This study investigated whether combining disulfiram (DSF), a known NLRP3 inflammasome inhibitor, with ALP enhances therapeutic outcomes in a rat model of gout. Methods: Thirty male Albino Wistar rats (150–200 g) were randomly assigned to five groups (n = 6): control, disease control, ALP-treated, DSF-treated, and ALP + DSF combination. Hyperuricemia was induced using potassium oxonate, followed by MSU crystal injection to trigger acute gout. Treatment lasted 30 days. Efficacy was assessed through clinical scoring, paw swelling, serum uric acid levels, ELISA-based cytokine profiling (IL-1β, TNF-α, IL-6), renal function tests, radiography, and histopathology. Results: Combination therapy with ALP + DSF significantly reduced paw swelling (p < 0.05), inflammation index (p < 0.001), serum uric acid (p < 0.001), and pro-inflammatory cytokines compared to monotherapy. Histopathology revealed preserved synovial architecture and reduced inflammatory infiltration. Radiographic imaging showed attenuated soft tissue swelling and joint erosion. Renal function markers were also improved in the combination group. Conclusions: The combination of ALP and DSF provided superior anti-inflammatory and urate-lowering effects compared to individual treatments. These findings support the potential of disulfiram as an adjunct to conventional ULTs in gout management through dual modulation of urate metabolism and inflammasome-driven inflammation. Full article

Postoperative peritoneal adhesion and high recurrence rates are critical challenges in the clinical treatment of colorectal cancer. In this study, based on amyloid-like protein self-assembly technology, a novel Janus protein film was developed. The protein film encapsulates glucose oxidase (GOx) and catalase (CAT), which is named PTL@GC. Through a one-step method involving cysteine-reduced lysozyme-induced amyloid-like self-assembly, the film was co-loaded with GOx and CAT to achieve synergistic anti-adhesion and anti-tumor recurrence effects. The Janus film features a hydrophobic side that stably adheres to the intestinal surface without exogenous chemical modification and a hydrophilic side that prevents adhesion. The loaded GOx selectively induces disulfidptosis in SLC7A11-overexpressing tumor cells, while CAT degrades H₂O₂ to alleviate hypoxia and inhibit oxidative stress, significantly reducing adhesion-related fibrosis. The experimental results demonstrate that PTL@GC exhibited excellent mechanical properties, high enzyme activity retention (>90%), and controllable degradability (complete metabolism within 50 days). In animal models, PTL@GC reduced postoperative adhesion area by 22.77%, decreased local tumor burden to 28.42% of the control group, and achieved an inhibition rate of 58.49%, without inducing systemic toxicity. This study presents a biologically safe and functionally synergistic approach to addressing dual complications following colorectal cancer surgery, offering potential insights for future research on multifunctional Janus materials. Full article

Reactive oxygen species (ROS) play a dual role in cancer progression, acting as both signaling molecules and drivers of oxidative damage. Emerging evidence highlights the intricate interplay between ROS, microRNAs (miRNAs), and exosomes within the tumor microenvironment (TME), forming a regulatory axis that modulates immune responses, angiogenesis, and therapeutic resistance. In particular, oxidative stress not only stimulates exosome biogenesis but also influences the selective packaging of redox-sensitive miRNAs (miR-21, miR-155, and miR-210) via RNA-binding proteins such as hnRNPA2B1 and SYNCRIP. These miRNAs, delivered through exosomes, alter gene expression in recipient cells and promote tumor-supportive phenotypes such as M2 macrophage polarization, CD8⁺ T-cell suppression, and endothelial remodeling. This review systematically explores how this ROS–miRNA–exosome axis orchestrates communication across immune and stromal cell populations under hypoxic and inflammatory conditions. Particular emphasis is placed on the role of NADPH oxidases, hypoxia-inducible factors, and autophagy-related mechanisms in regulating exosomal output. In addition, we analyze the therapeutic relevance of natural products and herbal compounds—such as curcumin, resveratrol, and ginsenosides—which have demonstrated promising capabilities to modulate ROS levels, miRNA expression, and exosome dynamics. We further discuss the clinical potential of leveraging this axis for cancer therapy, including strategies involving mesenchymal stem cell-derived exosomes, ferroptosis regulation, and miRNA-based immune modulation. Incorporating insights from spatial transcriptomics and single-cell analysis, this review provides a mechanistic foundation for the development of exosome-centered, redox-modulating therapeutics. Ultimately, this work aims to guide future research and drug discovery efforts toward integrating herbal medicine and redox biology in the fight against cancer. Full article

In this study, the structure and functional and in vitro digestion properties of whey protein isolate (WPI) modified by ultrasonic pretreatment combined with a double oxidase system containing horseradish peroxidase (HRP), glucose oxidase and D-glucose were assessed. SDS-PAGE results confirmed the occurrence of crosslinking reactions. Ultrasonic treatment significantly increased HRP-mediated WPI crosslinking, as demonstrated by reductions in free amino and sulfhydryl groups. CD and FTIR spectroscopies indicated that the structure of the crosslinked WPI was more stable. The particle size of the modified WPI was significantly reduced, resulting in better colloidal stability. Compared with the untreated WPI, the crosslinked WPI possessed enhanced surface hydrophobicity, gelation properties, emulsion stability, and thermal stability but reduced digestibility. These findings provide new insights into ultrasonication combined with a double oxidase system to further improve the structure and functional properties of proteins and broaden their application range in the food industry. Full article

Novel herbicide development is a challenge for weed control. Protoporphyrinogen oxidase (PPO) and p-hydroxyphenylpyruvate dioxygenase (HPPD) are two key enzymes involved in plant photosynthesis. The multi virtual screening protocol was adopted to design a common skeleton based on the two target enzymes, and fragment growth of the skeleton was performed. The constructed compounds were searched for structural similarity, and the accuracy of the selected compounds was further verified using the Bayesian model. Finally, eight compounds were obtained, and the binding mode with the target was studied deeply. The obtained compounds interact with the key residues of HPPD and PPO proteins similarly to commercial herbicides, and the stability of binding with proteins is also good. The activity of the screening results was determined by an enzyme activity test in vitro. The herbicidal effect of the compound was studied by phenotypic experiment. The final results showed that Z-4 and Z-7 have the potential to become new dual-target herbicides. Full article

Dual specificity tyrosine-phosphorylation regulated kinase 1A (DYRK1A), a phosphorylation kinase, is localized within the central nervous system and is linked to hyperphosphorylation of Tau. Imaging of DYRK1A may provide an earlier biomarker for Tauopathies, including Alzheimer’s disease (AD). We have used Chimera-Autodock to evaluate potential molecules for binding to the binding site of DYRK1A. Five molecules, 10-bromo-2-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acid (4E3), 10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acid (KuFal184), harmine, 6-(fluoro-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine (MK-6240), and 6-iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)isoquinoline (IPPI), were found to have binding energies of −10.4, −10.1, −9.0, −9.1, and −9.4 kcal/mole, respectively. Two molecules, 4E3 and KuFal184, were selective for DYRK1A, while harmine also had a monoamine oxidase A affinity, and MK-6240 and IPPI had affinity for Tau. Tau present in the brain slices of AD subject were labeled with [¹²⁵I]IPPI. KuFal184 had no effect on the binding of [¹²⁵I]IPPI, suggesting the absence of binding overlap of the two molecules. MK-6240, a known Tau agent was, however, able to compete with [¹²⁵I]IPPI. The binding energies of harmine, MK-6240, and IPPI for the DYRK1A site suggest affinities of approximately 80–100 nM, which is insufficient to serve as an imaging agent. The higher affinity of KuFal184 (6 nM for DYRK1A) suggested that [¹²⁵I]KuFal184 may be a potential imaging agent. Electrophilic radioiodination was used to synthesize [¹²⁵I]KuFal184 in modest yields (25%) and high radiochemical purity (>95%). Preliminary binding studies with [¹²⁵I]KuFal184 in AD brain slices showed some selectivity for cortical grey matter regions containing Tau. Full article

Background/Objectives: Parkinson’s disease (PD) is a progressive neuro-degenerative disorder characterized by α-synuclein aggregation, which promotes neuronal death and accelerates neurodegeneration. Small interfering RNA (siRNA) can reduce α-synuclein levels, but its therapeutic potential is limited by poor stability and delivery challenges. Similarly, Selegiline (Sel), a monoamine oxidase-B (MAO-B) inhibitor, has low bioavailability, restricting its effectiveness. This study aims to develop an intranasal (IN) albumin-coated liposomal system (C-Lip_Sel-siSNCA2) for the co-delivery of Sel and α-synuclein-targeting siRNA (siSNCA2) to enhance brain targeting and therapeutic efficacy. Methods: Liposomes were prepared using the ethanol injection method and optimized via D-optimal design for size, charge, and encapsulation efficiency (EE%). The optimized formulation was coated with human serum albumin (HSA) and characterized for stability, cellular uptake, and gene silencing. In vivo pharmacokinetics and pharmacodynamics were assessed in a rotenone-induced PD rat model to evaluate the motor function, biochemical markers, and brain-targeting efficiency. Results: Optimized liposomes had a particle size of 113.5 ± 6.8 nm, zeta potential of 6.2 ± 0.8 mV, and high EE% (Sel: 92.35%; siRNA: 78.66%). Albumin coating increased size to 136.5 ± 10.3 nm and shifted zeta potential to −13.5 ± 1.4 mV, enhancing stability and targeting. IN administration achieved a 3-fold increase in brain area under the concentration-time curve (AUC) versus intravenous delivery. In PD rats, C-Lip_Sel-siSNCA2 improved motor and non-motor functions, restored dopamine levels, enhanced catalase activity, and reduced MAO-B levels, mitigating dopamine degradation and α-synuclein aggregation. Conclusions: This non-invasive, dual-action nanoplatform offers a targeted therapy for PD, combining siRNA gene silencing and MAO-B inhibition, with the potential for clinical translation in neurodegenerative diseases. Full article