Search Results (2,520)

Carbon monoxide (CO) is a poisonous gas because it disrupts functional oxygen transport of red blood cell (RBC) by binding heme of hemoglobin with high affinity. Contrarily, endogenous CO, which is constantly generated in the process of heme degradation by heme oxygenase, functions as a gaseous mediator necessary for maintaining physiological homeostasis. This toxicological (Yin) and physiological (Yang) duality presents a distinctive problem in medical and pharmaceutical applications, prompting the central question of this review: How can strict control over CO’s exposure dynamics, magnitude, kinetics, and tissue context be achieved to enable its safe therapeutic use? Here, we integrate the Yin and Yang of CO through an innovative exposure-engineering framework, leveraging the inherent RBC characteristics to offer a novel conceptualization for therapeutic development. We highlight the role of native RBCs as a biologically grounded platform that can convert hemoglobin binding—classically viewed as the basis of CO toxicity—into a measurable and controllable buffering mechanism. Then, reconciling the Yin and Yang of CO based on RBCs enables medical and pharmaceutical modulation that is attractive for clinical situations, therapeutics and diagnostics. Finally, we discuss key translational challenges—local concentration control, patient-specific risk stratification, manufacturability and critical quality attributes, and regulatory positioning—and outline how quantifiable exposure control can enable the safe clinical development of RBC-based CO therapy. Full article

Vaccinium bracteatum Thunb. leaves (VBTL), a traditional medicinal plant historically consumed as food in certain regions of China, have been documented to possess potent in vitro antioxidant activity. However, its in vivo anti-aging effects and underlying mechanisms remain to be fully elucidated. Therefore, this study aimed to evaluate its anti-aging efficacy to support its potential value as a functional food constituent for healthy aging. Anti-aging efficacy was systematically assessed using D-galactose-induced aging mice, a Caenorhabditis elegans model, and an H₂O₂-induced cellular senescence model. Key active constituents were identified via untargeted metabolomics. In D-galactose-induced aging mice, VBTL extracts effectively ameliorated oxidative stress, significantly increasing the activities of endogenous antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), while reducing malondialdehyde (MDA) levels. In Caenorhabditis elegans, VBTL extended lifespan, reduced lipofuscin accumulation, and demonstrated no reproductive toxicity. Untargeted metabolomics identified xanthotoxol as a key active constituent, which was then selected for mechanistic investigation. In a cellular senescence model, xanthotoxol alleviated H₂O₂-induced oxidative stress, significantly enhanced SOD activity, reduced reactive oxygen species (ROS) and MDA levels, inhibited senescence-associated β-galactosidase (SA-β-gal) activity and the expression of senescence-associated secretory phenotype (SASP) factors (IL-6, MMP1, MMP3), and downregulated the expression of genes in the P53/P21/P16 signaling pathway. Mechanistically, xanthotoxol activated the Nrf2 signaling pathway, promoting the expression of its downstream targets heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). This study demonstrates that VBTL and its active compound xanthotoxol exert anti-aging effects across multiple models by modulating the Nrf2 pathway, providing both theoretical and experimental foundations for developing VBTL as a novel, safe, and effective natural ingredient in anti-aging functional foods. Full article

Liver diseases, including fatty liver, hepatitis, and cirrhosis, remain major global health challenges due to their disruption of metabolic homeostasis and detoxification processes. Redox imbalance plays a central role in liver disease progression by promoting inflammation, hepatic stellate cell activation, mitochondrial dysfunction, and fibrogenesis. Although flavonoids have historically been considered direct reactive oxygen species (ROS) scavengers, emerging evidence indicates that their biological effect at physiological concentrations are primarily mediated through modulation of intracellular redox signalling rather than simple radical neutralisation. This review highlights flavonoids as redox-modulating agents capable of restoring hepatic redox homeostasis through coordinated regulation of molecular pathways. Mechanistically, flavonoids activate the Nrf2-Keap1 axis to enhance endogenous antioxidant defences, including heme oxygenase-1 and glutathione biosynthesis enzyme, while suppressing NF-κB-mediated pro-inflammatory signalling and modulating MAPK and PI3K/Akt pathways. They also regulate mitochondrial redox balance, supporting mitophagy, metabolic adaptation, and cellular resilience to oxidative stress. In addition, flavonoid biotransformation by the gut microbiome improves intestinal barrier integrity, reduces endotoxin-driven hepatic inflammation, and contributes to gut–liver crosstalk. Collectively, these mechanisms position dietary flavonoids as multi-target redox modulators with promising therapeutic potential in chronic liver disease, although further studies are needed to improve their bioavailability and clinical translation. Full article

Chronic liver diseases, including fibrosis and hepatocellular carcinoma (HCC), are primarily driven by oxidative stress, yet traditional antioxidant therapies often lack the specificity and efficacy required for clinical success. This review evaluates the emerging therapeutic potential of two atypical globins, cytoglobin (CYGB) and neuroglobin (NGB), exploring their unique hexacoordinated heme structures that enable potent reactive oxygen and nitrogen species (ROS/RNS) scavenging and redox-regulated signaling. We summarize a broad range of in vitro and in vivo evidence demonstrating that these globins deactivate hepatic stellate cells, reduce extracellular matrix accumulation, and function as tumor suppressors by modulating pathways such as Raf/MEK/ERK and NRF2. In human cohorts, CYGB expression levels inversely correlate with the progression of Metabolic Dysfunction-Associated Steatohepatitis (MASH) and HCC, highlighting its potential as a clinical biomarker. Furthermore, recombinant protein therapies involving CYGB and NGB show promise in promoting collagen degradation and inhibiting malignant transformation. We conclude that CYGB and NGB represent sophisticated catalytic redox regulators that offer a novel therapeutic paradigm for restoring redox homeostasis. While delivery and pharmacokinetic barriers remain, these globins are highly promising candidates for first-in-class biologics in hepatology. Full article

As the key enzyme catalyzing the final step in heme and chlorophyll biosynthesis, protoporphyrinogen oxidase (PPO) is a crucial target for herbicide development. To date, over 40 PPO inhibitors have been commercialized. They offer high efficacy, environmental safety, low application rates, and broad-spectrum weed control. Recently, significant progress has been made in PPO structural biology, with several crystal structures resolved. Despite decades of use, the emergence of resistant weeds necessitates the continuous innovation of novel PPO inhibitors. This review systematically summarizes PPO three-dimensional structures, enzyme-inhibitor interaction mechanisms, and quantitative structure–activity relationships (QSARs). Finally, we outline rational molecular design strategies for the next generation of PPO inhibitors. Full article

Biliverdin (BV) and bilirubin (BR) are established endogenous antioxidants and immune modulators in other organ systems; however, their roles in the male genital tract remain undefined. The aim of this study was to quantify both bile pigments in human seminal plasma using a fluorescent protein biosensor and to examine their associations with basic semen parameters. We analyzed forty-two semen samples from men undergoing infertility evaluation. Biliverdin predominated over bilirubin in 88.1% of samples. Biliverdin concentration ranged from 51.8 to 611.2 nM, whereas bilirubin ranged from 19.7 to 240.7 nM. The mean total amounts per ejaculate were 1054 pmol for biliverdin and 280 pmol for bilirubin. The total amount of bilirubin in the ejaculate was positively correlated with total sperm count (Rs = 0.47; p = 0.028), whereas biliverdin showed no significant association (Rs = 0.21; p = 0.723). Oligozoospermic samples had significantly lower bilirubin concentrations (p < 0.001) and lower total bilirubin amounts (p < 0.005). Teratozoospermic samples exhibited significantly higher biliverdin concentrations (p < 0.05). This study provides the first simultaneous quantification of biliverdin and unconjugated bilirubin in human seminal plasma and identifies distinct associations with sperm quality. These findings suggest that bile pigments may reflect localized redox-related processes in the male genital tract and may influence male fertility potential. Full article

Gamma-tocotrienol (GT3) is one of the constituents of vitamin E that demonstrated significant radioprotective efficacy in murine and nonhuman primate (NHP) models. Considering the antioxidant activity of GT3 and its role in terminating lipid peroxidation, we hypothesize that mechanism of radioprotective effect of GT3 may involve the inhibition of irradiation-induced ferroptosis—a form of regulated cell death characterized by excessive, iron-dependent, peroxidation of lipids in cellular membranes. To test this hypothesis, the metabolomic and proteomic data from serum samples of GT3- or vehicle-treated NHPs exposed to 12 Gy (partial- or total-body) radiation was analyzed with focus on lipid peroxidation markers and proteins involved in iron metabolism. Four secondary lipid peroxidation products were identified including 4-oxo-2-nonenal (4-ONE), 4-hydroperoxy-2-nonenal (4-HPNE), 3,4-epoxynonanal (3,4-ENA), and trans-4,5-epoxy-(2E)-decenal (4,5-EDE). In vehicle-treated animals, their concentrations increased significantly as soon as 4 h after irradiation and then gradually declined. GT3 treatment mitigated this radiation-induced increase. In addition to lipid peroxidation products, similar patterns of change were observed for several polyunsaturated, monounsaturated, and saturated fatty acids as well as amino acids such as lysine and its derivatives. Taken together, these metabolomic changes suggest that irradiation induces cellular membrane damage through enhanced lipid peroxidation, while GT3 exerts a protective effect against this process. In addition, GT3 increased serum levels of haptoglobin and hemopexin—two plasma scavenger proteins that play complementary protective roles in iron and heme homeostasis. Although the present study does not conclusively demonstrate that GT3 mediates radioprotection via inhibition of ferroptosis, the data suggest that GT3 limits membrane damage and reduces susceptibility to ferroptosis by enhancing iron and heme scavenging. Further investigation into the interaction between GT3 and key components of ferroptosis following exposure to ionizing radiation is therefore warranted. Full article

Alcohol-induced liver damage (AILD), characterized by oxidative stress and inflammation, is a major health concern. While black ginseng extract (BGE) exhibits diverse pharmacological activities, its protective effects against AILD and underlying molecular mechanisms remain unclear. This study evaluated the protective effects of BGE against AILD using in vivo, in vitro, and in silico models. In mice, daily oral administration of 25% ethanol (5 g/kg) for 2 weeks induced liver injury. BGE (100–500 mg/kg) significantly reduced serum alanine aminotransferase (AST) and aspartate aminotransferase (ALT)levels while increasing catalase (CAT) and superoxide dismutase (SOD) activities. In ethanol-treated HepG2 cells, BGE inhibited nitric oxide (NO) production and suppressed cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) expression while increasing heme oxygenase-1 (HO-1)expression. Ginsenoside Rh1, quantified at 4.7 mg/g via quadrupole linear ion trap tandem mass spectrometry coupled with UPLC (UPLC-Q-TRAP-MS/MS), was identified as a key bioactive compound. Network pharmacology and molecular docking analyses revealed key inflammatory signaling pathways and core hub genes associated with ginsenoside Rh1. Integrated analyses suggest that ginsenoside Rh1 contributes to the multi-target effects of BGE by modulating inflammatory signaling pathways. Collectively, BGE is a potential therapeutic candidate for the prevention and treatment of AILD, with ginsenoside Rh1 serving as a key bioactive constituent and quality control marker. Full article

Chronic d-galactose (d-gal) treatment is a model to induce accelerated aging-like phenotypes in rodents. However, the sex differences in behavioral and musculoskeletal manifestations of this model are not well understood. Heme oxygenase-1 (HO-1) is a cytoprotective protein that may have anti-aging properties. The goal of this study was to better understand the sex differences in the behavioral and musculoskeletal effects of chronic d-gal treatment in C57BL/6J mice, as well as the role of HO-1 induction or inhibition. Eight-week-old male and female mice received daily saline or d-gal injections (500 mg/kg, s.c.) for 12 weeks. After this time, mice in the d-gal group were randomized into three groups (n = 6/group/sex): d-gal, d-gal + cobalt protoporphyrin (CoPP) (5 mg/kg, s.c. weekly), and d-gal + zinc deutroporphyrin bisglycol (ZnBG) (42 mg/kg, i.p. triweekly) for a period of 4 weeks. Open-field, novel-object recognition, Barnes maze, grip strength, micro-computed tomography (µ-CT), histology, and protein analysis were performed. Chronic d-gal treatment resulted in a sexual dimorphic response, with female mice being more prone to develop deficits in both short- and long-term spatial memory as well as in non-spatial memory. Male mice exhibited deficits only in long-term spatial memory when treated chronically with d-gal. Inhibition of HO-1 was protective in both females and males. Chronic d-gal treatment did not accelerate the development of osteoporosis or sarcopenia in either males or females. Our results demonstrate a sexual dimorphic response to the chronic effects of d-gal treatment on aging, with greater effects in females than in males, which is dependent on HO-1. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most prevalent chronic liver disease worldwide with complex pathogenesis and no approved specific therapy. Siraitia grosvenorii is a widely used medicinal and edible herb, yet its efficacy and underlying mechanisms against MAFLD remain poorly defined. This study explored the protective effects and potential mechanisms of aqueous extract of Siraitia grosvenorii (AESG) on MAFLD. Based on ultra-high-performance liquid chromatography-linear trap quadrupole orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap-MS) analysis, 38 components in AESG were tentatively assigned, with tetracyclic triterpene saponins being the most abundant. In high-fat diet (HFD)-induced MAFLD mice, AESG significantly attenuated body weight gain, reduced plasma total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) levels, and dramatically decreased hepatic triglyceride (TG) accumulation from 0.0141 mmol/g in the model group to 0.0063 mmol/g in the low-dose AESG group, corresponding to a reduction of 55.00%. AESG also alleviated plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and improved hepatocyte steatosis. Furthermore, AESG restored HFD-induced gut dysbiosis by enriching beneficial bacteria including Akkermansia and suppressing harmful bacteria such as Ruminococcus. In free fatty acids (FFA) stimulated HepG2 cells, AESG suppressed de novo lipogenesis via downregulating Fatty Acid Synthase (FASN), Acetyl-CoA Carboxylase (ACC) and Sterol Regulatory Element-Binding Protein 1c (SREBP1c), and enhanced antioxidant capacity via activating the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)/Heme Oxygenase 1 (HO-1)/Sirtuin 1 (SIRT1) pathway, thereby attenuating lipid accumulation and oxidative stress. In conclusion, AESG ameliorates MAFLD by inhibiting lipogenesis, improving oxidative stress, and regulating gut microbiota. These findings support Siraitia grosvenorii as a promising natural dietary intervention for MAFLD prevention and adjuvant therapy. Full article

Normal steps in uptake of non-heme iron by the gastrointestinal tract include ferrireduction and import across the apical enterocyte membrane by divalent metal transporter 1 (DMT1), responsible for the uptake of non-transferrin bound iron (NTBI). This metal import by the intestinal epithelium requires an acidic milieu generated by the proton pump H(+)/K(+) ATPase (ATP4). Gastrointestinal uptake of metal can be affected by altering the acid milieu (e.g., proton pump inhibitors). After metal uptake by enterocytes, ferroxidation and export of the metal by ferroportin (FPN) at the basolateral membrane leads to the export of iron bound to transferrin (Tf). In peripheral tissues, cellular uptake of circulating iron is mediated by receptor-mediated endocytosis of Tf-bound iron, with DMT1 transporting the metal out of the endosomal compartment under acidic conditions generated by the vacuolar H⁺-ATPase. Acidosis is frequently associated with inflammation. The two derangements have relevant consequences like improved solubilization of iron, increased expression of Dmt1, elevated Fe²⁺ uptake due to DMT1’s ability to cotransport H⁺, dissociation of Fe-Tf and hepcidin decreasing Fe export via FPN. These changes result in intracellular iron sequestration that frequently becomes noxious. Pharmacological strategies to inhibit NTBI transport are proposed to protect against iron overload associated with acidosis and inflammation. Full article

Background/Objectives: Oral diseases remain among the most prevalent noncommunicable conditions worldwide, with biofilm-driven dysbiosis playing a central role in dental caries, gingivitis, periodontitis, and oral candidiasis. Curcumin has attracted considerable interest because of its anti-inflammatory, antioxidant, antimicrobial, and regenerative properties. However, its clinical use remains limited by poor water solubility, chemical instability, rapid metabolism, and low bioavailability. This review aimed to provide a comprehensive analysis of curcumin-based nanoformulations for oral health applications, with emphasis on their mechanistic actions, antibiofilm activity, and translational relevance. Methods: This review examined representative nanocarrier systems developed for curcumin delivery in oral health. These included polymeric nanoparticles, nanomicelles and nanoemulsions, solid lipid nanoparticles and nanostructured lipid carriers, nanogels, hydrogels, mucoadhesive films, and metallic or hybrid nanosystems. The analysis focused on molecular mechanisms of action, antimicrobial and antibiofilm effects against major oral pathogens, and key translational challenges. Results/Findings: Across the reviewed studies, nanoformulations consistently improved curcumin solubility, stability, tissue penetration, mucosal retention, and controlled release. Mechanistically, they enhanced anti-inflammatory activity through inhibition of nuclear factor kappa B (NF-κB), strengthened antioxidant defenses via the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) axis, supported tissue repair and osteogenic responses, disrupted oral biofilms, and modulated local immune responses. Antimicrobial activity was reported against Streptococcus mutans, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Candida albicans, with reduced exopolysaccharide production, impaired adhesion, and improved biofilm penetration. Conclusions: Curcumin-based nanoformulations represent promising adjunctive platforms for oral healthcare. However, their clinical translation still requires improved stability in the oral-environment standardized manufacturing and characterization, rigorous safety evaluation, and well-designed controlled clinical studies. Full article

Background/Objectives: Many chronic diseases, including cancer, can be developed in conjunction with excessive intracellular oxidative stress and persistent inflammation. The importance of preventive strategies is highlighted by the potential of phytochemical interventions to mitigate these diseases. The purpose of this study was to investigate how Citrus depressa leaf (CDL) extracts can prevent 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced carcinogenesis in JB6 P+ mouse skin epidermal cells. Methods: CDL extracts were prepared and characterized for their phenolic and flavonoid contents. Effects of the potent extract on cell viability, TPA-induced colony formation, intracellular reactive oxygen species (ROS) levels, and nuclear factor erythroid 2–related factor 2 (Nrf2)-related protein and mRNA expression, mediated by epigenetic modifications, were evaluated in JB6 P+ cells. Results: Both the water extract (CDL-WE) and the 95% ethanol extract (CDL-95EE) contain abundant flavonoids that inhibit TPA-induced cell transformation and colony formation without minimal cytotoxicity. Mechanistic studies indicated that CDL-95EE increased the gene expression of Nrf2-related detoxification and antioxidant enzymes, such as UDP-glucuronosyltransferase 1A (UGT1A) and heme oxygenase-1 (HO-1), and decreased intracellular ROS accumulation. Furthermore, CDL-95EE reduced the expression of epigenetic modifiers, including DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), suggesting involvement in epigenetic regulation. Conclusions: These findings indicate that CDL, an agricultural by-product, may be useful in cancer prevention through antioxidant and epigenetic mechanisms. Full article

While natural muds are widely used in traditional balneotherapy and dermatological applications, the cellular basis of their redox-related effects remains insufficiently defined. In this study, we evaluated the effects of a mineral-rich mud extract on L929 fibroblasts and RAW 264.7 macrophages. This study was designed as an initial in vitro exploratory investigation to evaluate the cellular responses induced by a complex mud-derived material containing multiple inorganic components under standardized extract conditions. The mud extract showed no overt cytotoxicity up to 1000 μg/mL under the tested conditions. Intracellular reactive oxygen species (ROS) levels remained near baseline across the measured time points, with limited cell type-dependent variation. In parallel, antioxidant-related responses were observed primarily in RAW 264.7 cells, including a transient early increase in superoxide dismutase (SOD)-associated activity and subsequent increases in catalase (CAT) and glutathione peroxidase (GPx) activities. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis further showed dose-dependent upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) transcripts, particularly in RAW 264.7 cells. Collectively, these findings suggest that the mud extract is associated with coordinated antioxidant-related responses under non-cytotoxic conditions. However, because the present study was conducted in two murine cell lines and relied partly on assay systems potentially susceptible to matrix effects, the results should be interpreted as supportive of redox-associated modulation rather than definitive proof of a therapeutic mechanism. Furthermore, these findings should be interpreted as preliminary evidence obtained from a standardized aqueous extract system and not as definitive proof of component-specific mechanisms or direct applicability. Full article

Bioelectromethanogenesis, the microbial conversion of carbon dioxide (CO₂) into methane (CH₄) using a cathode, offers a promising route for biogas upgrading and renewable energy storage. The flow field is an essential factor influencing the performance of bioelectromethanogenesis, and the stability and efficiency of the biocathode play important roles in this process. This study systematically investigated the effect of different internal-circulation flow rates on the biocathode initiated without the electric field and the reactor effluent. It was found that the methane production of the biocathode initiated without the electric field was increased by around 30% at an internal-circulation flow rate of 18 mL/min, which was stronger than that of the biocathode initiated by the reactor effluent. The relative content of the extracellular polymeric substance (EPS) heme was increased by 4%, while the EPS electron accepting capacity was much higher than that initiated by reactor effluent. Furthermore, the microbial community analysis showed that the functional methanogen on the biocathode initiated without an electric field was Methanosaeta (17%) and Methanobacterium (8%). This study could provide support for the dynamic operation of biogas upgrading in microbial electrolysis cells. Full article