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Redox status plays a multifaceted role in the intricate physiology and pathology of pancreatic β-cells, the pivotal regulators of glucose homeostasis through insulin secretion. They are highly responsive to changes in metabolic cues where reactive oxygen species are part of it, all arising from nutritional intake. These molecules not only serve as crucial signaling intermediates for insulin secretion but also participate in the nuanced heterogeneity observed within the β-cell population. A central aspect of β-cell redox biology revolves around the localized production of hydrogen peroxide and the activity of NADPH oxidases which are tightly regulated and serve diverse physiological functions. Pancreatic β-cells possess a remarkable array of antioxidant defense mechanisms although considered relatively modest compared to other cell types, are efficient in preserving redox balance within the cellular milieu. This intrinsic antioxidant machinery operates in concert with redox-sensitive signaling pathways, forming an elaborate redox relay system essential for β-cell function and adaptation to changing metabolic demands. Perturbations in redox homeostasis can lead to oxidative stress exacerbating insulin secretion defect being a hallmark of type 2 diabetes. Understanding the interplay between redox signaling, oxidative stress, and β-cell dysfunction is paramount for developing effective therapeutic strategies aimed at preserving β-cell health and function in individuals with type 2 diabetes. Thus, unraveling the intricate complexities of β-cell redox biology presents exciting avenues for advancing our understanding and treatment of metabolic disorders. [ABSTRACT FROM AUTHOR]

Importance: Endochondral ossification plays an important role in skeletal development. Recent studies have suggested a link between increased intracellular reactive oxygen species (ROS) and skeletal disorders. Moreover, previous studies have revealed that increasing the levels of myeloperoxidase (MPO) and osteopontin (OPN) while inhibiting NADPH oxidase 4 (NOX4) can enhance bone growth. This investigation provides further evidence by showing a direct link between NOX4 and MPO, OPN in bone function. Objective: This study investigates NOX4, an enzyme producing hydrogen peroxide, in endochondral ossification and bone remodeling. NOX4's role in osteoblast formation and osteogenic signaling pathways is explored. Methods: Using NOX4-deficient (NOX4+) and ovariectomized (OVX) mice, we identify NOX4's potential mediators in bone maturation. Results: NOX4+ mice displayed significant differences in bone mass and structure. Compared to the normal Control and OVX groups. Hematoxylin and eosin staining showed NOX4+ mice had the highest trabecular bone volume, while OVX had the lowest. Proteomic analysis revealed significantly elevated MPO and OPN levels in bone marrow-derived cells in NOX4+ mice. Immunohistochemistry confirmed increased MPO, OPN, and collagen II (COLII) near the epiphyseal plate. Collagen and chondrogenesis analysis supported enhanced bone development in NOX4+ mice. Conclusions and Relevance: Our results emphasize NOX4's significance in bone morphology, mesenchymal stem cell proteomics, immunohistochemistry, collagen levels, and chondrogenesis. NOX4 deficiency enhances bone development and endochondral ossification, potentially through increased MPO, OPN, and COLII expression. These findings suggest therapeutic implications for skeletal disorders. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of wedelolactone, a major flavonoid from Vietnamese Eclipta prostrata (L) L., on inflammation and insulin resistance. Methods: Wedelolactone was extracted from the leaves of Vietnamese Eclipta prostrata (L.) L. with methanol by Soxhlet. The effects of wedelolactone on lipopolysaccharide (LPS)-induced cytokine production, reactive oxygen species (ROS) generation, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activities in Raw 264.7 cells were measured by enzyme-linked immunosorbent assay (ELISA), specific immunofluorescent dyes and luminometric analysis, respectively. In addition, its effects on glucose uptake and the protein expression of insulin receptor substrate 1 (IRS1) and glucose transporter 4 (GLUT4) were examined in 3T3-L1 cells by immunofluorescent dyes and Western blot. Results: Wedelolactone at 30 µg/mL significantly inhibited LPSinduced production of tumor necrosis factor-α, interleukin (IL)-6, and IL-8 (P<0.01) with no noticeable effects on IL-10 level. It also reduced ROS generation and NADPH oxidase activities in LPSstimulated Raw 264.7 cells (P<0.01). Furthermore, wedelolactone showed anti-insulin resistance activity, as evidenced by improved glucose uptake and the upregulated expression of IRS1 and GLUT4 in 3T3-L1 cells (P<0.01). Conclusions: Wedelolactone exhibits anti-inflammation and antiinsulin resistance effects, which may be used for the treatment of diabetes and inflammation-associated diseases. [ABSTRACT FROM AUTHOR]

Neuroinflammation, mediated by the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing-3 (NLRP3) inflammasome, is a significant contributor to the pathogenesis of neurodegenerative diseases (NDDs). Reynosin, a natural sesquiterpene lactone (SL), exhibits a broad spectrum of pharmacological effects, suggesting its potential therapeutic value. However, the effects and mechanism of reynosin on neuroinflammation remain elusive. The current study explores the effects and mechanisms of reynosin on neuroinflammation using mice and BV-2 microglial cells treated with lipopolysaccharide (LPS). Our findings reveal that reynosin effectively reduces microglial inflammation in vitro , as demonstrated by decreased CD11b expression and lowered interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) mRNA and protein levels. Correspondingly, in vivo , results showed a reduction in the number of Iba-1 positive cells and alleviation of morphological alterations, alongside decreased expressions of IL-1β and IL-18. Further analysis indicates that reynosin inhibits NLRP3 inflammasome activation, evidenced by reduced transcription of NLRP3 and caspase-1, diminished NLRP3 protein expression, inhibited apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization, and decreased caspase-1 self-cleavage. Additionally, reynosin curtailed the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, demonstrated by reduced NADP+ and NADPH levels, downregulation of gp91phox mRNA, protein expression, suppression of p47phox expression and translocation to the membrane. Moreover, reynosin exhibited a neuroprotective effect against microglial inflammation in vivo and in vitro. These collective findings underscore reynosin's capacity to mitigate microglial inflammation by inhibiting the NLRP3 inflammasome, thus highlighting its potential as a therapeutic agent for managing neuroinflammation. [ABSTRACT FROM AUTHOR]

Objective: To provide surgeons with an understanding of the latest research on NETosis, including the pathophysiology and treatment of conditions involving neutrophil extracellular traps (NETs) in the care of surgical patients. Background: A novel function of neutrophils, the formation of NETs, was described in 2004. Neutrophils form mesh-like structures of extruded decondensed chromatin, comprising DNA and histones decorated with bactericidal proteins. These NETs exert antimicrobial action by trapping microorganisms and preventing their wider dissemination through the body. Results: A narrative review of the existing literature describing NETosis was conducted, including NET pathophysiology, conditions related to NET formation, and treatments relevant to surgeons. Conclusions: In addition to its canonical antimicrobial function, NETosis can exacerbate inflammation, resulting in tissue damage and contributing to numerous diseases. NETs promote gallstone formation and acute pancreatitis, impair wound healing in the early postoperative period and in chronic wounds, and facilitate intravascular coagulation, cancer growth, and metastasis. Agents that target NET formation or removal have shown promising efficacy in treating these conditions, although large clinical trials are required to confirm these benefits. [ABSTRACT FROM AUTHOR]

Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases (CVDs), the world's primary cause of death. Ginkgo biloba , a well-known traditional Chinese medicine with notable cardiovascular actions, has been used as a cardio- and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries. Preclinical studies have shown that ginkgolide B, a bioactive component in Ginkgo biloba , can ameliorate atherosclerosis in cultured vascular cells and disease models. Of clinical relevance, several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases, such as ischemia stroke. Here, we present a comprehensive review of the pharmacological activities, pharmacokinetic characteristics, and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy. We highlight new molecular targets of ginkgolide B, including nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidase), lectin-like oxidized LDL receptor-1 (LOX-1), sirtuin 1 (SIRT1), platelet-activating factor (PAF), proprotein convertase subtilisin/kexin type 9 (PCSK9) and others. Finally, we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis. Ginkgolide B possesses the antiatherosclerotic advantage of "multitarget and multipathway", which is closely linked to its regulating endothelial dysfunction, thrombosis, leukocyte action, and risk factors. [Display omitted] [ABSTRACT FROM AUTHOR]

Entamoeba histolytica is an enteric tissue-invasive protozoan parasite causing amoebic colitis and liver abscesses in humans. Amoebic contact with host cells activates intracellular signaling pathways that lead to host cell death via generation of caspase-3, calpain, Ca2+ elevation, and reactive oxygen species (ROS). We previously reported that various NADPH oxidases (NOXs) are responsible for ROS-dependent death of various host cells induced by amoeba. In the present study, we investigated the specific NOX isoform involved in ROS-dependent death of hepatocytes induced by amoebas. Co-incubation of hepatoma HepG2 cells with live amoebic trophozoites resulted in remarkably increased DNA fragmentation compared to cells incubated with medium alone. HepG2 cells that adhered to amoebic trophozoites showed strong dichlorodihydrofluorescein diacetate (DCF-DA) fluorescence, suggesting intracellular ROS accumulation within host cells stimulated by amoebic trophozoites. Pretreatment of HepG2 cells with the general NOX inhibitor DPI or NOX2-specific inhibitor GSK 2795039 reduced Entamoeba-induced ROS generation. Similarly, Entamoeba-induced LDH release from HepG2 cells was effectively inhibited by pretreatment with DPI or GSK 2795039. In NOX2-silenced HepG2 cells, Entamoeba-induced LDH release was also significantly inhibited compared with controls. Taken together, the results support an important role of NOX2-derived ROS in hepatocyte death induced by E. histolytica. [ABSTRACT FROM AUTHOR]

Inorganic toxicants like arsenic, copper, lead, nickel and fluoride are notorious agro-pollutants, impeding plant-productivity due to high bioaccumulation. Consumption of such contaminated plant-parts causes irreversible health hazards. We identified a G-protein coupled receptor, serving as melatonin receptor (MelR) in Nicotiana tabacum (NtMelR), that relayed downstream-signaling after binding melatonin, a potent growth regulator and antioxidant. Using inhibitors against G-protein-α and NADPH oxidase (NOX), and by supplementing epidermal strips with exogenous melatonin and H 2 O 2 , we established that NtMelR acted upstream of reactive oxygen species (ROS) production in guard cells. Transgenic lines of N. benthamiana overexpressing NtMelR maintained constitutive melatonin-signaling via MelR, leading to efficient stomatal closure for preventing desiccation during oxidative stress. Melatonin biosynthesis was stimulated in the transgenic lines, exposed to different agro-pollutant stress, providing a steady-abundance of ligand for NtMelR binding and activating the defence machinery, comprising of enzymatic-antioxidants like superoxide dismutase, catalase, peroxidases and glyoxalases. Due to increased antioxidant capacity, the transgenics exhibited less molecular injuries (electrolyte leakage, methylglyoxal accumulation and NOX activity), generated less ROS and bioaccumulated significantly lower levels of toxicants. Unlike the wild-type counterparts, the transgenics maintained high relative water content, photosynthetic efficiency, could flower abundantly and even produce seeds. Overall, we established that overexpression of NtMelR is a single-window strategy to generate multiple-stress tolerant genotypes. [Display omitted] • Mel-bound NtMelR activated NOX signaling in guard cells. • Stomatal closure prevented desiccation during stress. • Overexpression of NtMelR promoted tolerance against inorganic pollutants. • Mel biosynthesis and activity of enzymatic antioxidants were stimulated. • Transgenics exhibited less molecular injuries and reproduced normally. [ABSTRACT FROM AUTHOR]

Inorganic toxicants like arsenic, copper, lead, nickel and fluoride are notorious agro-pollutants, impeding plant-productivity due to high bioaccumulation. Consumption of such contaminated plant-parts causes irreversible health hazards. We identified a G-protein coupled receptor, serving as melatonin receptor (MelR) in Nicotiana tabacum (NtMelR), that relayed downstream-signaling after binding melatonin, a potent growth regulator and antioxidant. Using inhibitors against G-protein-α and NADPH oxidase (NOX), and by supplementing epidermal strips with exogenous melatonin and H 2 O 2 , we established that NtMelR acted upstream of reactive oxygen species (ROS) production in guard cells. Transgenic lines of N. benthamiana overexpressing NtMelR maintained constitutive melatonin-signaling via MelR, leading to efficient stomatal closure for preventing desiccation during oxidative stress. Melatonin biosynthesis was stimulated in the transgenic lines, exposed to different agro-pollutant stress, providing a steady-abundance of ligand for NtMelR binding and activating the defence machinery, comprising of enzymatic-antioxidants like superoxide dismutase, catalase, peroxidases and glyoxalases. Due to increased antioxidant capacity, the transgenics exhibited less molecular injuries (electrolyte leakage, methylglyoxal accumulation and NOX activity), generated less ROS and bioaccumulated significantly lower levels of toxicants. Unlike the wild-type counterparts, the transgenics maintained high relative water content, photosynthetic efficiency, could flower abundantly and even produce seeds. Overall, we established that overexpression of NtMelR is a single-window strategy to generate multiple-stress tolerant genotypes. [Display omitted] • Mel-bound NtMelR activated NOX signaling in guard cells. • Stomatal closure prevented desiccation during stress. • Overexpression of NtMelR promoted tolerance against inorganic pollutants. • Mel biosynthesis and activity of enzymatic antioxidants were stimulated. • Transgenics exhibited less molecular injuries and reproduced normally. [ABSTRACT FROM AUTHOR]

Algae respond rapidly with a respiratory oxidative burst during and after exposure to numerous environmental stresses. However, NADPH oxidase (Nox) homologs related to the generation of reactive oxygen species by algae are still poorly understood. In the present study, we identified 46 Nox homologs in eight red algae species; these Noxs possessed key functional domains similar to plant respiratory burst oxidase homologs but most of them were clustered into an independent clade in evolution. Furthermore, the cis-acting regulatory elements, transcription profiles, transcription factors co-expression correlation and differential expression of Pyropia haitanensis nox genes (Phnoxs) were detected. Results revealed that abundant elements involved in phytohormone responsiveness, abiotic stress induction, light regulation and transcription factor binding were harbored at the promoter region of Phnoxs. And they possessed differential transcript profiles during alternating heteromorphic generations. Phnox5C and 2C were the main genes expressed in free-living conchocelis and gametophyte, respectively, and their expression might be regulated by different transcription factors; an implication of their importance in nori growth and carpospore development. In addition, Phnox2C , 4 and 5A were significantly up-regulated after flg22 or oligoagar exposure, indicating they may provide resistance to pathogens. Conversely, Phnox2A , 2C , 4 and 5A responded positively to mechanical damage or drought stress. The findings presented in this study could be valuable for further elucidating the functions and regulatory mechanisms of NADPH oxidases during the development and adaptation of red algae to diverse stresses. • Noxs in P. haitanensis possessed key functional domains similar to plant Rbohs. • Phnox5C and 2C were key to the P. haitanensis growth and carpospore development. • Phnox2C , 4 and 5A may play an important role in resistance to pathogens. • Phnox2A , 2C , 4 and 5A responded positively to mechanical damage or drought stress. [ABSTRACT FROM AUTHOR]

The overproduction of reactive oxygen species (ROS) and burst of inflammation following cardiac ischemia–reperfusion (I/R) are the leading causes of cardiomyocyte injury. Monotherapeutic strategies designed to enhance anti-inflammatory or anti-ROS activity explicitly for treating I/R injury have demonstrated limited success because of the complex mechanisms of ROS production and induction of inflammation. Intense oxidative stress leads to sustained injury, necrosis, and apoptosis of cardiomyocytes. The damaged and necrotic cells can release danger-associated molecular patterns (DAMPs) that can cause the aggregation of immune cells by activating Toll-like receptor 4 (TLR4). These immune cells also promote ROS production by expressing NADPH oxidase. Finally, ROS production and inflammation form a vicious cycle, and ROS and TLR4 are critical nodes of this cycle. In the present study, we designed and prepared an injectable hydrogel system of EGCG@Rh-gel by co-assembling epigallocatechin-3-gallate (EGCG) and the rhein-peptide hydrogel (Rh-gel). The co-assembled hydrogel efficiently blocked the ROS–inflammation cycle by ROS scavenging and TLR4 inhibition. Benefited by the abundant noncovalent interactions of π–π stacking and hydrogen bonding between EGCG and Rh-gel, the co-assembled hydrogel had good mechanical strength and injectable property. Following the injection EGCG@Rh-gel into the damaged region of the mice's heart after I/R, the hydrogel enabled to achieve long-term sustained release and treatment, improve cardiac function, and significantly reduce the formation of scarring. Further studies demonstrated that these beneficial outcomes arise from the reduction of ROS production, inhibition of inflammation, and induction of anti-apoptosis in cardiomyocytes. Therefore, EGCG@Rh-gel is a promising drug delivery system to block the ROS-inflammation cycle for resisting myocardial I/R injury. 1. Monotherapeutic strategies designed to enhance anti-inflammatory or anti-ROS effects for treating I/R injury have demonstrated limited success because of the complex mechanisms of ROS and inflammation. 2. ROS production and inflammation form a vicious cycle, and ROS and TLR4 are critical nodes of this cycle. 3. Here, we designed an injectable hydrogel system of EGCG@Rh-gel by co-assembling epigallocatechin-3-gallate (EGCG) and a rhein-peptide hydrogel (Rh-gel). EGCG@Rh-gel efficiently blocked the ROS–inflammation cycle by ROS scavenging and TLR4 inhibition. 4. EGCG@Rh-gel achieved long-term sustained release and treatment, improved cardiac function, and significantly reduced the formation of scarring after I/R. 5. The beneficial outcomes arise from reducing ROS production, inhibiting inflammation, and inducing anti-apoptosis in cardiomyocytes. [Display omitted] [ABSTRACT FROM AUTHOR]

Gefitinib is a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR), used for the treatment of advanced or metastatic non-small cell lung cancer. Recently, studies proved that Gefitinib-induced cardiotoxicity through induction of oxidative stress leads to cardiac hypertrophy. The current study was conducted to understand the mechanisms underlying gefitinib-induced cardiac hypertrophy through studying the roles of angiotensin II (AngII), oxidative stress, and mitogen-activated protein kinase (MAPK) pathway. Male Wistar albino rats were treated with valsartan, gefitinib, or both for four weeks. Blood samples were collected for AngII and cardiac markers measurement, and hearts were harvested for histological study and biochemical analysis. Gefitinib caused histological changes in the cardiac tissues and increased levels of cardiac hypertrophy markers, AngII and its receptors. Blocking of AngII type 1 receptor (AT1R) via valsartan protected hearts and normalized cardiac markers, AngII levels, and the expression of its receptors during gefitinib treatment. valsartan attenuated gefitinib-induced NADPH oxidase and oxidative stress leading to down-regulation of JNK/p38-MAPK pathway. Collectively, AT1R blockade adjusted AngII-induced NADPH oxidase and JNK/p38-MAPK leading to attenuation of gefitinib-induced cardiac hypertrophy. This study found a pivotal role of AngII/AT1R signaling in gefitinib-induced cardiac hypertrophy, which may provide novel approaches in the management of EGFRIs-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

[Figure: see text]. [ABSTRACT FROM AUTHOR]

Stimulation of human keratinocytes with particulate matter 2.5 (PM 2.5) elicits complex signaling events, including a rise in the generation of reactive oxygen species (ROS). However, the mechanisms underlying PM 2.5 -induced ROS production remain unknown. Here, we show that PM 2.5 -induced ROS production in human keratinocytes is mediated via the NADPH oxidase (NOXs) system and the Ca2+ signaling pathway. PM 2.5 treatment increased the expression of NOX1, NOX4, and a calcium-sensitive NOX, dual oxidase 1 (DUOX1), in human epidermal keratinocyte cell line. PM 2.5 bound to aryl hydrocarbon receptor (AhR), and this complex bound to promoter regions of NOX1 and DUOX1 , suggesting that AhR acted as a transcription factor of NOX1 and DUOX1. PM 2.5 increased the transcription of DUOX1 via epigenetic modification. Moreover, a link between DNA demethylase and histone methyltransferase with the promoter regions of DUOX1 led to an elevation in the expression of DUOX1 mRNA. Interestingly, PM 2.5 increased NOX4 expression and promoted the interaction of NOX4 and Ca2+ channels within the cytoplasmic membrane or endoplasmic reticulum, leading to Ca2+ release. The increase in intracellular Ca2+ concentration activated DUOX1, responsible for ROS production. Our findings provide evidence for a PM 2.5 -mediated ROS-generating system network, in which increased NOX1, NOX4, and DUOX1 expression serves as a ROS signal through AhR and Ca2+ activation. [Display omitted] • PM 2.5 mediates AhR-DUOX1 expression by epigenetically modifying DNA and histones. • PM 2.5 stimulates interaction of NOX4 and Ca2+ channels and leads to release of Ca2+. • Increased levels serve as an oxidative stress induced by PM 2.5. [ABSTRACT FROM AUTHOR]

The release of cerium oxide nanoparticles (CeO 2 -NPs) into the aquatic environment has raised concerns, however there are limited comprehensive studies on their ecotoxicological effects and environmental implications. Herein, we investigated the effects of CeO 2 -NPs accumulation on the growth, physiological, molecular, and enzymatic antioxidant responses of two freshwater cyanobacteria, Anabaena laxa and Nostoc muscorum. Over a week, the two species were exposed to mild (4 mg/L) and high (8 mg/L) levels of CeO 2 -NPs. Compared to Nostoc, Anabaena experienced higher accumulation of CeO 2 -NPs (62.26 and 184.19 µg/g FW) and removal efficiency (92% and 91.5%) at mild and high level, respectively. Consequentially, CeO 2 -NPs accumulation diminished growth and evoked dose dependent decreases in photosynthesis rate, RuBisCo enzyme activity and chlorophyll a. Additionally, it triggered oxidative damage, as evidenced by elevated levels of H 2 O 2 and increased NADPH oxidase activity, along with protein and lipid peroxidation, particularly at high level of CeO 2 -NPs in Nostoc. Anabaena and Nostoc under CeO 2 -NPs stress exhibited distinct molecular and enzymatic detoxification pathways, with significant increased antioxidant enzymes (peroxidase (POX), catalase (CAT), glutathione peroxidase (GPX)) activity and antioxidant metabolites (glutathione (GSH), polyphenols, flavonoids, and tocopherols) levels in Anabaena. Conversely, ascorbate (ASC) level and POX, dehydroascorbate reductase (DHAR), and monodehydroascorbate reductase (MDHAR) activities were significantly increased in Nostoc. For CeO 2 -NPs detoxification, glutathione-S-transferases (GST) activity and metal chelator metabolites (phytochelatins (PYC) and metallothionine (MTs)) were increased in the two species, but to more extent in Anabaena. Collectively, the high removal efficiency and the robust stress tolerance mechanism of Anabaena to CeO 2 -NPs toxicity suggest its use as bioremediator to combat the ecological risk of CeO 2 -NPs. [Display omitted] • Anabaena exhibited a higher capacity for the uptake and removal of CeO 2 NPs. • CeO 2 NPs inhibited growth and photosynthesis and provoked oxidative stress. • Compared to Anabaena, Nostoc was more sanative to CeO 2 NPs toxicity. • Anabaena showed more increase in antioxidant and detoxification system. • Anabaena is recommended as an effective phytoremediator for CeO 2 NPs. [ABSTRACT FROM AUTHOR]

NADPH oxidase (NOX) is a membrane‐bound enzyme complex that generates reactive oxygen species (ROS). Mutations in NOX subunit genes have been implicated in the pathogenesis of inflammatory bowel disease (IBD), indicating a crucial role for ROS in regulating host immune responses. In this study, we utilize genetically deficient mice to investigate whether defects in p40phox, one subunit of NOX, impair host immune response in the intestine and aggravate disease in an infection‐based (Citrobacter rodentium) model of colitis. We show that p40phox deficiency does not increase susceptibility of mice to C. rodentium infection, as no differences in body weight loss, bacterial clearance, colonic pathology, cytokine production, or immune cell recruitment were observed between p40phox−/− and wild‐type mice. Interestingly, higher IL‐10 levels were observed in the supernatants of MLN cells and splenocytes isolated from infected p40phox‐deficient mice. Further, a higher expression level of inducible nitric oxide synthase (iNOS) was also noted in mice lacking p40phox. In contrast to wild‐type mice, p40phox−/− mice exhibited greater NO production after LPS or bacterial antigen re‐stimulation. These results suggest that p40phox−/− mice do not develop worsened colitis. While the precise mechanisms are unclear, it may involve the observed alteration in cytokine responses and enhancement in levels of iNOS and NO. [ABSTRACT FROM AUTHOR]

Molecular oxygen (O2), reactive oxygen species (ROS), and associated redox networks are cornerstones of aerobic life. These molecules and networks have gained recognition as fundamental players in mechanisms that regulate the development of multicellular organisms. First, we present a brief review in which we provide a historical description of some relevant discoveries that led to this recognition. We also discuss the fact that, despite its abundance in nature, oxygen is a limiting factor, and its high availability variation impacted the evolution of adaptive mechanisms to guarantee the proper development of diverse species under such extreme environments. Finally, some examples of when oxygen and ROS were identified as relevant for the control of developmental processes are discussed. We take into account not only the current knowledge on animal redox developmental biology, but also briefly discuss potential scenarios on the origin and evolution of redox developmental mechanisms and the importance of the ever-changing environment. [ABSTRACT FROM AUTHOR]

Y‐box‐binding protein 1 (Ybx1, YB‐1), also known as Y‐box transcription factor, is involved in a variety of biological processes (BPs) and pathways, including embryogenesis, reproduction and development in vertebrates. Several noncoding RNAs regulate Ybx1 signaling. However, the role of long noncoding RNAs (lncRNAs) in embryogenesis remains incompletely understood. Here, we investigated the possible involvement of lncRNAs in Ybx1‐mediated regulation of vertebrate development by performing systematic transcriptome analysis of RNA sequencing data derived from ybx1 homozygous mutant zebrafish on day 5 (day5_ybx1−/−) and wild‐type zebrafish on days 5 and 6 (day5_ybx1+/+ and day6_ybx1+/+). We identified several lncRNAs affected by ybx1 disruption that may target reduction–oxidation‐related genes, such as duox (NADPH oxidase) and noxo1a (NADPH oxidase organizer). Knockdown of three selected lncRNAs led to morphological deformation of larvae, implying an involvement of these lncRNAs in zebrafish embryo development. In summary, our study provides new insights into the lncRNA‐mediated mechanisms underlying development in Ybx1‐deficient zebrafish larvae. [ABSTRACT FROM AUTHOR]

L-arginine is a substrate for nitric oxide synthase (NOS) responsible for the production of NO. This investigation studied the effect of apocynin, an NADPH oxidase inhibitor and catalase, an H2O2 scavenger on L-arginine-induced oxidative stress and hypotension. Forty Wistar-Kyoto rats were treated for 14 days with vehicle, L-arginine (12.5 mg/ml p.o.), L-arginine + apocynin (2.5 mmol/l p.o.), L-arginine + catalase (10000 U/kg/day i.p.) and L-arginine plus apocynin + catalase respectively. Weekly renal functional and hemodynamic parameters were measured and kidneys harvested at the end of the study for histopathological and renal NADPH oxidase 4 (Nox4) assessments. L-arginine administration in normotensive rats decreased systolic blood pressure (120±2 vs. 91±2 mmHg) and heart rate (298±21 vs. 254±15 bpm), enhanced urinary output (21.5±4.2 vs. 32±1.9 ml/24 h, increased creatinine clearance (1.72±0.56 vs. 2.62±0.40 ml/min/kg), and fractional sodium excretion (0.88±0.16 vs. 1.18±0.16 %), caused proteinuria (28.10±1.93 vs. 35.26±1.69 mg/kg/day) and a significant decrease in renal cortical blood perfusion (292±3 vs. 258±5 bpu) and pulse wave velocity (3.72±0.20 vs 2.84±0.13 m/s) (all P<0.05). L-arginine increased plasma malondialdehyde (by ~206 % P<0.05) and NO (by ~51 %, P<0.05) but decreased superoxide dismutase (by ~31 %, P<0.05) and total antioxidant capacity (by ---35 %, P<0.05) compared to control. Renal Nox4 mRNA activity was approximately 2.1 fold higher (P<0.05) in the L-arginine-treated rats but was normalized by apocynin and apocynin plus catalase treatment. Administration of apocynin and catalase, but not catalase alone to rats fed L-arginine, restored the deranged renal function and structure, prevented hypotension and enhanced the antioxidant capacity and suppressed Nox4 expression. These findings suggest that apocynin and catalase might be used prophylactically in the states of oxidative stress. [ABSTRACT FROM AUTHOR]

NOX5 (NADPH oxidase 5) is a homolog of the gp91phox subunit of the phagocyte NOX, which generates reactive oxygen species. NOX5 is involved in sperm motility and vascular contraction and has been implicated in diabetic nephropathy, atherosclerosis, and stroke. The function of NOX5 in the cardiac hypertrophy is unknown. Because NOX5 is a Ca2+-sensitive, procontractile NOX isoform, we questioned whether it plays a role in cardiac hypertrophy. Studies were performed in (1) cardiac tissue from patients undergoing heart transplant for cardiomyopathy and heart failure, (2) NOX5-expressing rat cardiomyocytes, and (3) mice expressing human NOX5 in a cardiomyocyte-specific manner. Cardiac hypertrophy was induced in mice by transverse aorta coarctation and Ang II (angiotensin II) infusion. NOX5 expression was increased in human failing hearts. Rat cardiomyocytes infected with adenoviral vector encoding human NOX5 cDNA exhibited elevated reactive oxygen species levels with significant enlargement and associated increased expression of ANP (atrial natriuretic peptides) and β-MHC (β-myosin heavy chain) and prohypertrophic genes (Nppa, Nppb, and Myh7) under Ang II stimulation. These effects were reduced by N-acetylcysteine and diltiazem. Pressure overload and Ang II infusion induced left ventricular hypertrophy, interstitial fibrosis, and contractile dysfunction, responses that were exaggerated in cardiac-specific NOX5 trangenic mice. These phenomena were associated with increased reactive oxygen species levels and activation of redox-sensitive MAPK (mitogen-activated protein kinase). N-acetylcysteine treatment reduced cardiac oxidative stress and attenuated cardiac hypertrophy in NOX5 trangenic. Our study defines Ca2+-regulated NOX5 as an important NOX isoform involved in oxidative stress- and MAPK-mediated cardiac hypertrophy and contractile dysfunction. [ABSTRACT FROM AUTHOR]

Testicular torsion and detorsion (TTD) is a serious urological condition affecting young males that is underlined by an ischemia reperfusion injury (tIRI) to the testis as the pathophysiological mechanism. During tIRI, uncontrolled production of oxygen reactive species (ROS) causes DNA damage leading to germ cell apoptosis (GCA). The aim of the study is to explore whether inhibition of NADPH oxidase (NOX), a major source of intracellular ROS, will prevent tIRI-induced GCA and its association with endoplasmic reticulum (ER) stress. Sprague-Dawley rats (n = 36) were divided into three groups: sham, tIRI only and tIRI treated with apocynin (a NOX inhibitor). Rats undergoing tIRI endured an ischemic injury for 1 h followed by 4 h of reperfusion. Spermatogenic damage was evaluated histologically, while cellular damages were assessed using real time PCR, immunofluorescence staining, Western blot and biochemical assays. Disrupted spermatogenesis was associated with increased lipid and protein peroxidation and decreased antioxidant activity of the enzyme superoxide dismutase (SOD) as a result of tIRI. In addition, increased DNA double strand breaks and formation of 8-OHdG adducts associated with increased phosphorylation of the DNA damage response (DDR) protein H2AX. The ASK1/JNK apoptosis signaling pathway was also activated in response to tIRI. Finally, increased immuno-expression of the unfolded protein response (UPR) downstream targets: GRP78, eIF2-α1, CHOP and caspase 12 supported the presence of ER stress. Inhibition of NOX by apocynin protected against tIRI-induced GCA and ER stress. In conclusion, NOX inhibition minimized tIRI-induced intracellular oxidative damages leading to GCA and ER stress. [ABSTRACT FROM AUTHOR]

Hypersensitive pain response is observed in patients with Parkinson's disease (PD). However, the signal pathways leading to hyperalgesia still need to be clarified. Chronic oxidative stress is one of the hallmarks of PD pathophysiology. Since the midbrain periaqueductal gray (PAG) is an important component of the descending inhibitory pathway controlling on central pain transmission, we examined the role NADPH oxidase (NOX) of the PAG in regulating exaggerated pain evoked by PD. PD was induced by central microinjection of 6-hydroxydopamine to lesion the left medial forebrain bundle of rats. Then, Western Blot analysis and ELISA were used to determine NOXs and products of oxidative stress (i.e., 8-isoprostaglandin F2a and 8-hydroxy-2'- deoxyguanosine). Pain responses to mechanical and thermal stimulation were further examined in control rats and PD rats. In results, among the NOXs, protein expression of NOX4 in the PAG of PD rats was significantly upregulated, thereby the products of oxidative stress were increased. Blocking NOX4 pathway in the PAG attenuated mechanical and thermal pain responses in PD rats and this was accompanied with decreasing production of oxidative stress. In addition, inhibition of NOX4 largely restored the impaired GABA within the PAG. Stimulation of GABA receptors in the PAG of PD rats also blunted pain responses. In conclusions, NOX4 activation of oxidative stress in the PAG of PD rats is likely to impair the descending inhibitory GABAergic pathways in regulating pain transmission and thereby plays a role in the development of pain hypersensitivity in PD. Inhibition of NOX4 has beneficial effects on the exaggerated pain evoked by PD. [ABSTRACT FROM AUTHOR]

Dendritic cell is one of the first innate immune cell to encounter T. gondii after the parasite crosses the host intestinal epithelium. T. gondii requires intact DC as a carrier to infiltrate into host central nervous system (CNS) without being detected or eliminated by host defense system. The mechanism by which T. gondii avoids innate immune defense of host cell, especially in the dendritic cell is unknown. Therefore, we examined the role of host PI3K/AKT signaling pathway activation by T. gondii in dendritic cell. T. gondii infection or T. gondii excretory/secretory antigen (TgESA) treatment to the murine dendritic cell line DC2.4 induced AKT phosphorylation, and treatment of PI3K inhibitors effectively suppressed the T. gondii proliferation but had no effect on infection rate or invasion rate. Furthermore, it is found that T. gondii or TgESA can reduce H2O2-induced intracellular reactive oxygen species (ROS) as well as host endogenous ROS via PI3K/AKT pathway activation. While searching for the main source of the ROS, we found that NADPH oxidase 4 (NOX4) expression was controlled by T. gondii infection or TgESA treatment, which is in correlation with previous observation of the ROS reduction by identical treatments. These findings suggest that the manipulation of the host PI3K/AKT signaling pathway and NOX4 expression is an essential mechanism for the down-regulation of ROS, and therefore, for the survival and the proliferation of T. gondii. [ABSTRACT FROM AUTHOR]

Hypertension is a risk factor for the vascular permeability and neovascularization that threatens vision in diabetic retinopathy. Excess reactive oxygen species derived from the Nox (NADPH oxidase) isoforms, Nox1 and Nox4, contributes to vasculopathy in diabetic retinopathy; however, if Nox1/4 inhibition is beneficial in hypertensive diabetic retinopathy is unknown. Here, we determined that diabetic spontaneously hypertensive rats had exacerbated retinal vascular permeability and expression of angiogenic and inflammatory factors, compared with normotensive diabetic Wistar Kyoto rats. GKT136901, a specific dual inhibitor of Nox1 and Nox4, prevented these events in diabetic Wistar Kyoto rats and spontaneously hypertensive rats. Retinal neovascularization does not develop in diabetic rodents, and therefore, the oxygen-induced retinopathy model is used to evaluate this pathology. We previously demonstrated that Nox1/4 inhibition reduced retinal neovascularization in oxygen-induced retinopathy. However, although Nox5 is expressed in human retina, its contribution to retinopathy has not been studied in vivo, largely due to its absence from the rodent genome. We generated transgenic mice with inducible human Nox5 expressed in endothelial cells (vascular endothelial-cadherin+Nox5+ mice). In vascular endothelial-cadherin+Nox5+ mice with oxygen-induced retinopathy, retinal vascular permeability and neovascularization, as well as the expression of angiogenic and inflammatory factors, were increased compared with wild-type littermates. In bovine retinal endothelial cells, which express Nox1, Nox4, and Nox5, Nox1/4 inhibition, as well as Nox5 silencing RNA, reduced the high glucose-induced upregulation of oxidative stress, angiogenic, and inflammatory factors. Collectively, these data indicate the potential of Nox1, Nox4, and Nox5 inhibition to reduce vision-threatening damage to the retinal vasculature. [ABSTRACT FROM AUTHOR]