Search Results (851)

Particulate matter (PM) is a significant contributor to air pollution-associated negative health effects, and cardiovascular disease patients are more susceptible to air pollution-mediated damage of the heart and vessels. The present study investigated the protective effects against PM-induced cardiovascular damage by classic cardiovascular drugs, as used for the standard therapy of cardiovascular disease patients. Male C57BL/6J mice were exposed to ambient PM_2.5 (<2.5 µm) for 3 days with or without treatment with the cholesterol-lowering drug atorvastatin (20 mg/kg/d) or the angiotensin-converting enzyme (ACE) inhibitor captopril (50 mg/kg/d). Both drugs mitigated PM_2.5-induced systolic blood pressure increases and partially prevented endothelial dysfunction, as reflected by a mixed effect on endothelial nitric oxide synthase phosphorylation. Both drugs ameliorated reactive oxygen species (ROS) formation and phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX-2) expression in the vasculature of PM_2.5-exposed mice. Pulmonary ROS levels showed a minor improvement by the treatments, whereas Nox2 mRNA expression was not diminished. Only captopril showed some anti-inflammatory effects in the heart and lung of PM_2.5-exposed mice, whereas both drugs failed to reduce systemic inflammation measured in plasma. These findings offer new insights into potential mitigation strategies for PM_2.5-induced cardiovascular complications, particularly for patients at higher cardiovascular risk, like those with coronary artery or ischemic heart disease or hypertension. Full article

Oxidative stress is a key driver of chronic inflammatory diseases. Anodendron affine is a native Formosan plant species in Taiwan that remains largely underexplored phytochemically and bioactivity. To reveal the bioactive constituents and assess its potential as a source of anti-inflammatory antioxidants, we performed bioactivity-guided fractionation and evaluated the inhibition of superoxide anion (O₂^•−) generation in formyl-L-methionyl-L-leucyl-L-phenylalanine-stimulated human neutrophils. Molecular docking simulations were employed to model interactions with Formyl peptide receptor 1 (FPR1) and the Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, including neutrophil cytosol factor 1 (p47phox) and NADPH oxidase 2 (NOX2), to propose a theoretical mechanism of action. Phytochemical investigation led to the isolation of two new compounds, methyl 4,5-O-diferuloyl-3-methoxyquinate (1) and 16-pregnen-3,12,20-trione (2), together with four known compounds. Notably, 4-hydroxy-3-prenylbenzoic acid (5) exhibited potent inhibitory activity (IC₅₀ = 17.65 ± 0.97 μM), surpassing the activity of the positive control, ibuprofen (IC₅₀ = 27.85 ± 3.56 μM). Docking studies suggested that anodendrosin H (4) and 4-hydroxy-3-prenylbenzoic acid (5) exhibit high predicted binding affinity to p47phox and NOX2. Based on these results, compounds 1, 4, and 5 from A. affine were identified as potential lead candidates for the development of novel anti-inflammatory therapeutics. Full article

Hepatic ischemia–reperfusion injury (IRI) is a critical clinical condition associated with liver transplantation and acute liver injury. This study investigated the role of sulfide quinone oxidoreductase (SQOR) and its downstream product, supersulfides, in hepatic IRI. C57BL/6NJ mice were subjected to 45 min of partial hepatic ischemia, followed by reperfusion lasting 4 h. Control of shRNA mediated knockdown of SQOR expressing adeno-associated viral vectors were administered 3 weeks prior to liver ischemia. In the shRNA-mediated knockdown of SQOR group, the hydro-trisulfide donor sodium trisulfide was administered daily for 1 week prior to the induction of liver ischemia. SQOR played a crucial protective role during hepatic IRI by facilitating electron transport to the mitochondrial respiratory chain and maintaining the oxidized and reduced nicotinamide adenine dinucleotide ratio. Administration of sodium trisulfide, exhibited protective effects against hepatic IRI. Sodium trisulfide restored the oxidized and reduced nicotinamide adenine dinucleotide ratio, reduced oxidative stress, and preserved the expression of key enzymes involved in the sulfide oxidation pathway. SQOR and supersulfides contribute to hepatic protection against IRI, likely through their potent antioxidative and redox-regulating functions, and highlight sodium trisulfide as a potential therapeutic agent. Full article

Mitochondrial dysfunction represents a central hallmark of aging and a broad spectrum of chronic diseases, ranging from metabolic to neurodegenerative and ocular disorders. Nicotinamide riboside (NR), a vitamin B₃ derivative and efficient precursor of NAD⁺ (nicotinamide adenine dinucleotide), and berberine (BBR), an isoquinoline alkaloid widely investigated in metabolic regulation, have independently emerged as promising mitochondrial modulators. NR enhances cellular NAD⁺ pools, thereby activating sirtuin-dependent pathways, stimulating PGC-1α–mediated mitochondrial biogenesis, and triggering the mitochondrial unfolded protein response (UPR^mt). BBR, by contrast, primarily activates AMPK (AMP-activated protein kinase) and interacts with respiratory complex I, improving bioenergetics, reducing mitochondrial reactive oxygen species, and promoting mitophagy and organelle quality control. Importantly, despite distinct upstream mechanisms, NR and BBR converge on shared signaling pathways that support mitochondrial health, including redox balance, metabolic flexibility, and immunometabolic regulation. Unlike previous reviews addressing these compounds separately, this article integrates current preclinical and clinical findings to provide a unified perspective on their converging actions. We critically discuss translational opportunities as well as limitations, including heterogeneous clinical outcomes and the need for robust biomarkers of mitochondrial function. By outlining overlapping and complementary mechanisms, we highlight NR and BBR as rational combinatorial strategies to restore mitochondrial resilience. This integrative perspective may guide the design of next-generation clinical trials and advance precision approaches in mitochondrial medicine. Full article

Chronic liver disease (CLD) encompasses a spectrum of progressive disorders, including metabolic dysfunction steatotic-associated liver disease (MASLD) and primary biliary cholangitis (PBC), which together represent a significant global health burden with few effective therapeutic options. The fibrogenic process, common to most forms of CLD, is driven by a complex interplay of cellular stress, inflammation, and wound-healing responses. Nicotinamide adenine dinucleotide phosphate oxidase isoforms 1 and 4 (NOX1 and NOX4) have emerged as key enzymatic sources of reactive oxygen species (ROS), serving as central mediators of hepatic oxidative stress, fibrogenesis, and inflammation. Setanaxib is a first-in-class, orally bioavailable, selective dual inhibitor of NOX1 and NOX4 that has progressed to clinical evaluation. This review synthesizes current knowledge on the molecular pharmacology of the NOX1/4 axis, preclinical evidence from translational models, and clinical trial outcomes to critically assess the therapeutic potential of targeted NOX inhibition in hepatic fibrosis. By attenuating hepatic stellate cell activation, modulating TGF-β signaling, reducing extracellular matrix (ECM) deposition, and regulating hepatic macrophage polarization, setanaxib exhibits pleiotropic antifibrotic effects. The compound also demonstrates favorable pharmacokinetic properties and a good safety profile in patients with PBC, with emerging evidence suggesting meaningful improvements in fatigue and quality of life. Finally, we examine the complex, and sometimes paradoxical, roles of NOX4 in liver pathophysiology, compare the evolving therapeutic landscape with other approaches such as farnesoid X receptor (FXR) agonists, and propose future paradigms integrating artificial intelligence–driven predictive modeling to optimize patient stratification and therapeutic response in this new era of redox-targeted hepatoprotective therapy. Full article

This review elucidates the foundational principles of nicotinamide adenine dinucleotide (NAD⁺) homeostasis in humans, emphasizing its depletion during aging and in age-associated disorders. Subsequently, the discussion extends to NAD⁺ precursors and their potential therapeutic applications, with insights from research using zebrafish as a disease model. This information sheds light on the growing interest in NAD and its metabolism in the medical field and sparks curiosity among researchers focused on fish studies. The review further explores the role of nicotinamide in fish, encompassing core NAD⁺ metabolism, its participation in oxidative stress, environmental challenges, and the mitigation of pollutant-induced toxicity. Additionally, the implications of NAD⁺ in fish neurobiology, immune regulation, host–pathogen interactions, skin, eggs, and post mortem muscle were considered. Dietary modulation of NAD⁺ pathways to enhance growth, immunity, and product quality in aquaculture has also been highlighted. This review highlights the significance of NAD⁺ metabolism in fish biology, covering cellular energy production, physiological processes, and environmental adaptation, and proposes targeting NAD⁺-related pathways as a strategy for aquaculture and fish health management. Full article

Background/Objectives: Chlorella pyrenoidosa polysaccharides (CPPs) exhibit digestion-resistant properties, with their bioactivity largely driven by gut microbiota metabolism. However, the fermentation characteristics of CPPs within the intestinal tract remain to be fully elucidated. Elucidating the utilization and metabolic processes of CPPs with respect to the gut microbiota aids in understanding the potential mechanisms underlying the biological activity of these polysaccharides. Methods: This work fractionated CPPs into a neutral polysaccharide fraction (CPP-1) and an acidic polysaccharide fraction (CPP-2), followed by the characterization of their structure, physicochemical properties, and in vitro fermentation characteristics. Results: The results demonstrated that both CPP-1 and CPP-2 were non-starch heteropolysaccharides linked primarily by α-glycosidic bonds and lacking a triple helix structure. Both samples exhibited exceptional thermal stability, high water solubility, and low viscosity properties. CPP-2 selectively promoted Enterocloster, whereas CPP-1 significantly enriched Bacteroides and Bifidobacterium in gut microbiota. This differential regulation may be attributable to structural variations between the polysaccharides. Functional predictions indicated that CPP-1 enhances intestinal barrier integrity and immune homeostasis, whereas CPP-2 has anti-inflammatory activity. CPP-1 and CPP-2 interventions significantly upregulated the levels of health-promoting metabolites, including nicotinamide adenine dinucleotide, putrescine, and 3′-adenosine monophosphate. CPP-1 predominantly modulated amino acid metabolic pathways, while CPP-2 could effectively regulate purine, pyrimidine, amino acid, and butanoate metabolic pathways. Conclusions: This work identifies CPPs (CPP-1 and CPP-2) as novel modulators of gut homeostasis and host metabolism through microbiota–metabolite axis remodeling, supporting their prebiotic potential for functional food innovation. Full article

Raspberry ketone (RK) is the primary aromatic compound in raspberry fruit, which is widely utilized in perfume, cosmetics, and food additive industries. Currently, RK is predominantly produced chemically. RK biosynthesis through enzyme or whole cell has garnered significant attention due to the mild reaction conditions and the process being regarded as ‘natural’. This study proposed a ‘dual-microorganism, two-phase’ stepwise cascade strategy to produce RK from an economical precursor, 4-hydroxybenzaldehyde (4-HBD). An acetone-tolerant deoxyribose-phosphate aldolase DERA_Ec (S238D) mutant was obtained through a site-specific rigidification strategy for converting 4-HBD to 4-hydroxybenzylaceton (4-HBA). Then, an engineered E. coli co-expressing isocitrate dehydrogenase and raspberry ketone synthase RiRZS1 with a citrate-sodium citrate buffer to recycle nicotinamide adenine dinucleotide phosphate (NADPH) was constructed for the conversion of 4-HBA to RK. The final concentration of RK was 50.00 ± 1.92 mmol·L⁻¹ with a yield of 86.96%. This strategy provides a scalable coenzyme self-recycling and two-phase catalysis platform for high-value phenolic compounds. Full article

Nicotinamide adenine dinucleotide (NAD⁺) serves as a critical cofactor in redox reactions and metabolic transformations catalyzed by NAD-dependent enzymes and is essential for bacterial survival and virulence. The biosynthesis of NAD⁺ in the cariogenic pathogen Streptococcus Sobrinus (S. sobrinus), a pivotal participant in oral cavities of children and adolescents with a history of caries, has yet to be explored. Bioinformatics, genetics, and biochemical techniques were used to identify NAD⁺ biosynthesis pathways and corresponding regulator in S. Sobrinus. S. sobrinus lacks de novo NAD⁺ synthesis pathway but comprises NA and Nam salvage pathway I (PncA-PncB-NadD-NadE) and PnuC-NadR salvage pathway III. NiaY and PnuC were involved in the salvage pathways. N-terminal domain of SsNrtR regulator was identified as DNA-binding domain binding to the pnuC and pncB probe, and addition of ADP-ribose reversed the binding of SsNrtR to the target promoters to regulate NAD⁺ salvage pathways. C-terminal domain of SsNrtR was non-catalytic, consistent with loss of Nudix motif conservation. Furthermore, the abrogation of niaR compromised multiple pathogenic traits, including cellular proliferation, acidogenesis, and the architecture/mechanical integrity of biofilms. Consequently, this mutant exhibited attenuated virulence in a rat caries model. Our findings conclusively demonstrate that SsNrtR-mediated regulation of NAD⁺ homeostasis is a critical determinant of the cariogenic potential of S. sobrinus. This study identifies SsNrtR as a previously uncharacterized NAD⁺-responsive regulator that integrates metabolic homeostasis with the control of virulence in Streptococcus sobrinus. These findings elucidate a novel metabolic–virulence regulatory axis in this species and position SsNrtR as a promising target for the development of anti-caries interventions. Full article

Various non-pharmacological practices have been reported to enhance overall health. The molecular effects of exercise have been shown to involve the upregulation of enzymes and transcription factors that enhance antioxidative and anti-inflammatory activity, boost mitochondrial function and growth, and promote a parasympathetic tone. These beneficial changes occur as an adaptive/hormetic response to an initial increase in oxygen radical and nitric oxide production in working muscles. The redox-sensitive nuclear factor erythroid 2-related factor 2 (Nrf2) was identified as the key mediator of the cellular defense response. A similar adaptive response appears to occur in response to exposure to heat or cold, hyperbaric or hypobaric oxygen, cupping therapy, acupuncture, caloric restriction, and the consumption of polyphenol-rich plant-based foods or spices, and there is direct or indirect evidence for the involvement of Nrf2. In many cases, additional stress signaling pathways have been observed to be upregulated, including the nicotinamide adenine dinucleotide (NAD+)-sirtuin and the adenosine monophosphate (AMP)-activated protein kinase pathways. We conclude that while several traditional health practices may share a hormetic mechanism—mild radical-induced damage triggers a defense response through upregulation of antioxidative, anti-inflammatory, and repair activities, which may impact body-wide tissue function. Full article

Ultraviolet B (UV-B) radiation significantly contributes to skin photoaging, which is characterized by epidermal thickening, collagen degradation, wrinkle formation, barrier dysfunction, and oxidative stress. Nicotinamide mononucleotide (NMN), a key precursor of nicotinamide adenine dinucleotide, regulates cellular energy metabolism and antioxidant defense and demonstrates anti-aging effects in animal models. Here, we investigated the protective effects of oral NMN supplementation against UV-B-induced photoaging in SKH-1 hairless mice. Over a 10-week experimental period, oral NMN administration significantly alleviated epidermal hypertrophy, reduced wrinkle formation and skin surface roughness, improved hydration and elasticity, and restored transepidermal water loss to near-normal levels. Histological analyses revealed marked preservation of collagen fiber density and attenuation of dermal matrix degradation. Furthermore, NMN supplementation inhibited the phosphorylation of MAPK signaling components (ERK, JNK, and p38), suppressed pro-inflammatory cytokine (TNF-α and IL-6) and matrix-degrading enzyme (MMP-1) expression, and restored hyaluronan synthase (HAS-1 and HAS-2) expression. Additionally, NMN enhanced the systemic antioxidant defense, as indicated by the restored superoxide dismutase activity. Thus, NMN has multi-layered protective effects against UV-B–induced skin aging by modulating oxidative stress, inflammatory signaling, extracellular matrix remodeling, and hyaluronic acid metabolism. Full article

Sirtuin 6 (SIRT6), a (Nicotinamide adenine dinucleotide) NAD⁺-dependent deacylase and mono- (adenosine diphosphate) ADP-ribosyltransferase, is increasingly recognized as a pivotal regulator of genomic stability, metabolic reprogramming, and epigenetic remodeling. This review synthesizes current evidence on the dual roles of SIRT6 in cancer, highlighting its context-dependent functions as both a tumor suppressor and promoter across various malignancies. We detail its involvement in DNA damage sensing, repair coordination, glycolytic regulation, and chromatin modification, and discuss how these mechanisms contribute to tumor initiation, progression, and therapy resistance. Emerging therapeutic strategies targeting SIRT6, including small-molecule modulators, genetic interventions, and combination therapies, are critically evaluated. Our analysis underscores the necessity for context-specific therapeutic targeting, and pharmacological modulation of SIRT6 represents a promising avenue for precision oncology. Full article

Background and Objectives: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, yet its molecular basis remains unclear. Nicotinamide adenine dinucleotide (NAD⁺) metabolism is crucial for energy regulation, redox balance, and inflammation. This study investigated the dysregulation of key NAD⁺ salvage enzymes (CD38, NAMPT, and SIRT1) across albuminuria stages in type 2 diabetes (T2D). Materials and Methods: A cross-sectional study was conducted on 225 participants: healthy controls (n = 45), T2D with normoalbuminuria (n = 60), microalbuminuria (n = 60), and macroalbuminuria (n = 60). Serum CD38, NAMPT, and SIRT1 were measured by ELISA, while CD38 and SIRT1 gene expression in peripheral blood mononuclear cells was analyzed by qPCR. Results: CD38 and NAMPT levels increased progressively with albuminuria, whereas SIRT1 levels declined significantly. CD38 and NAMPT correlated positively with HbA1c, creatinine, and urinary albumin-to-creatinine ratio (UACR), while SIRT1 showed inverse correlations and a positive association with eGFR. Regression analysis identified CD38 and NAMPT as independent positive predictors of albuminuria, and SIRT1 as a negative predictor. ROC analysis revealed strong diagnostic performance for CD38 (AUC = 0.89) and SIRT1 (AUC = 0.88). Conclusions: These findings highlight disrupted NAD⁺ salvage pathways in DN and suggest that restoring NAD⁺ balance, through CD38 inhibition, SIRT1 activation, or NAD⁺ precursor supplementation, may offer promising renoprotective strategies. Full article

Nicotinamide mononucleotide (NMN), a key precursor of nicotinamide adenine dinucleotide (NAD⁺), plays a central role in cellular energy metabolism. This study investigated the effect of NMN supplementation on boar sperm quality during liquid storage. Semen samples diluted with Modena extender containing 0 to 80 μM NMN were stored at 17 °C for 7 days. Results demonstrate that supplementation with 20 μM NMN significantly improved sperm motility, acrosome integrity, and mitochondrial activity compared with the control group, accompanied by markedly elevated intracellular NAD⁺ and ATP level (p < 0.05). Also, Western blot analysis confirmed the presence of nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3) in boar sperm. Furthermore, sperm treated with 20 μM NMN exhibited a higher level of protein tyrosine phosphorylation and an increased capacitation rate following storage. Tissue explant assays further revealed a significant increase in the number of sperm attached to oviductal epithelial fragments, indicating enhanced sperm–oviduct interactions. The present findings demonstrate that 20 μM NMN supplementation effectively preserves the metabolic activity and functional competence of boar sperm during liquid storage. It provides a promising strategy for improving boar semen preservation. Full article

Background: Although luteolin (Lut) is well recognized for its anti-inflammatory and antioxidant effects, its potential role in preventing vascular senescence remains underexplored in primary vascular aging. This study aimed to investigate the anti-vascular-aging effects of Lut in both cellular and murine aging models and to elucidate its conserved molecular mechanisms across species. Methods: Canine and feline vascular endothelial cells (cVECs and fVECs) were subjected to doxorubicin-induced senescence, while senescence-accelerated mice prone 8 (SAMP8) received an 8-week dietary supplementation with Lut. Senescence markers, inflammatory cytokines, antioxidant activities, vascular biomechanics, and histological changes were assessed. Transcriptomic and metabolomic analyses were combined to identify molecular pathways. Statistical significance was determined by one-way analysis of variance with Tukey’s or Games–Howell post hoc tests (p < 0.05). Results: Lut markedly reduced senescence-associated β-galactosidase activity, suppressed interleukin-6 and matrix metalloproteinase expression (p < 0.05), and enhanced superoxide dismutase activity and nicotinamide adenine dinucleotide levels (p < 0.05) in cVECs, fVECs, and SAMP8 sera. In aged mice, Lut alleviated arterial wall thickening and vascular inflammation, improved vascular biomechanics and systemic oxygenation (p < 0.05), and attenuated cardiac and hepatic inflammatory infiltration. Multi-omics analyses in cVECs revealed that Lut targets aldehyde dehydrogenase 1 to increase 9-cis retinoic acid, thereby activating the retinol X receptor–peroxisome proliferator-activated receptor (PPAR) network, which accelerates lipid clearance and oxidation. Consistent activation of this pathway was validated in murine vascular transcriptomes. Conclusions: These findings demonstrate that Lut delays vascular aging by activating the retinoic acid–PPAR axis and reprogramming lipid metabolism. This conserved mechanism was consistently observed in doxorubicin-induced cVEC senescence and the SAMP8 model, underscoring the robustness of Lut’s action across distinct contexts of vascular aging. Full article