Dependent Reactive Oxygen Species Research Articles

Inhibiting NOXO1 and CYBA binding to reduce NADPH oxidase I dependent ROS damage in skin explants

NADPH oxidases (NOXs) are newly identified enzymes that generate intracellular reactive oxygen species (ROS) in skin cells. Recent studies demonstrated that NOX1 holoenzyme is expressed in human keratinocytes and melanocytes, which are implicated in skin photo-carcinogenesis due to the high amounts of ROS produced. Holoenzyme activation requires a ternary complex comprised of NOX1, cytochrome B alpha chain (CYBA), and cytoplasmic NADPH Oxidase Organizer 1 (NOXO1) to properly form. By inhibiting this assembly process, an opportunity for reducing the production of catalytic ROS is possible, especially during high ROS conditions that occur under prolonged UV exposure. We designed a series of small molecules and evaluated their inhibitory effects on NOXO2 using in-silico docking methods in the 1WLP crystal structure. We show that the NOX_inh_5 inhibitor was successful in a variety of experiments using primary skin models from various skin tones. NOX_inh_5 proved to be non-cytotoxic while also improving the viability of primary human skin primary cells under UV exposure. Biophysical studies with NOX_inh_5 using an Isothermal calorimetric (ITC) binding and heteronuclear single quantum coherence (HSQC-NMR) exhibited inhibition of complex formation between NOXO2 and CYBA. Authentic human skin explants, treated with and without NOX_inh_5 and UV exposure, decreased p53 stabilization and decreased UV-induced DNA damage as quantified through cyclobutane dimer formation.

Oxalate enhanced aniline degradation by goethite: Structural dependent activity, hydroxyl radicals generation and toxicity evaluation

A photochemical system combining iron (hydr)oxides and oxalate (Ox) shows application prospects in wastewater treatment due to the abundance of reactive oxygen species (ROS) generation. Nevertheless, it is a challenge to the investigate photochemical activity of iron (hydr)oxides/Ox systems with varying structural properties. Herein, the photochemical behaviors of Ox on goethite (Gt) surface from the view of structural dependent activity, containment degradation, and ROS generation were explored in detail. Results confirmed that bidentate mononuclear was formed on Gt surface after complexing Ox. Combined with density functional theory calculation and pH time evolution during aniline degradation, the photochemical activity of the Gt/Ox system fell in between that of ferrihydrite/Ox and hematite/Ox systems. After irradiating 120 min visible light, 96.5% aniline was degraded by 1.0 mM Ox and 0.2 g/L Gt. The amount of •OH in vis/Gt/Ox system could be up to 309.3 μM and its generation was closely associated with Fe(II) while slightly affected by the generated H2O2. Moreover, as revealed by high-performance liquid chromatography with mass spectrometric and Ecological Structure Activity Relationships software, the toxicity of the intermediates of aniline degradation in the vis/Gt/Ox system towards fish and green algae increased first but then declined accompanied by the generation of non-toxic ring-opening products at the end of reaction. According to the findings in the presented study, it could be concluded that vis/Gt/Ox is a promising approach to wiping out aniline wastewater.

MTH1 protects platelet mitochondria from oxidative damage and regulates platelet function and thrombosis

Human MutT Homolog 1 (MTH1) is a nucleotide pool sanitization enzyme that hydrolyzes oxidized nucleotides to prevent their mis-incorporation into DNA under oxidative stress. Expression and functional roles of MTH1 in platelets are not known. Here, we show MTH1 expression in platelets and its deficiency impairs hemostasis and arterial/venous thrombosis in vivo. MTH1 deficiency reduced platelet aggregation, phosphatidylserine exposure and calcium mobilization induced by thrombin but not by collagen-related peptide (CRP) along with decreased mitochondrial ATP production. Thrombin but not CRP induced Ca2+-dependent mitochondria reactive oxygen species generation. Mechanistically, MTH1 deficiency caused mitochondrial DNA oxidative damage and reduced the expression of cytochrome c oxidase 1. Furthermore, MTH1 exerts a similar role in human platelet function. Our study suggests that MTH1 exerts a protective function against oxidative stress in platelets and indicates that MTH1 could be a potential therapeutic target for the prevention of thrombotic diseases.

The role of P21-activated kinase (Pak1) in sinus node function

Sinoatrial node (SAN) dysfunction (SND) and atrial arrhythmia frequently occur simultaneously with a hazard ratio of 4.2 for new onset atrial fibrillation (AF) in SND patients. In the atrial muscle attenuated activity of p21-activated kinase 1 (Pak1) increases the risk for AF by enhancing NADPH oxidase 2 dependent production of reactive oxygen species (ROS). However, the role of Pak1 dependent ROS regulation in SAN function has not yet been determined. We hypothesize that Pak1 activity maintains SAN activity by regulating the expression of the hyperpolarization activated cyclic nucleotide gated cation channel (HCN).To determine Pak1 dependent changes in heart rate (HR) regulation we quantified the intrinsic sinus rhythm in wild type (WT) and Pak1 deficient (Pak1−/−) mice of both sexes in vivo and in isolated Langendorff perfused hearts. Pak1−/− hearts displayed an attenuated HR in vivo after autonomic blockage and in isolated hearts. The contribution of the Ca2+ clock to pacemaker activity remained unchanged, but Ivabradine (3 μM), a blocker of HCN channels that are a membrane clock component, eliminated the differences in SAN activity between WT and Pak1−/− hearts. Reduced HCN4 expression was confirmed in Pak1−/− right atria. The reduced HCN activity in Pak1−/− could be rescued by class II HDAC inhibition (LMK235), ROS scavenging (TEMPOL) or attenuation of Extracellular Signal-Regulated Kinase (ERK) 1/2 activity (SCH772984). No sex specific differences in Pak1 dependent SAN regulation were determined.Our results establish Pak1 as a class II HDAC regulator and a potential therapeutic target to attenuate SAN bradycardia and AF susceptibility.

Empagliflozin prevents oxidative stress induced by acute hyperglycemia in cardiac myocytes.

Empagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, has shown to improve cardiovascular outcomes in patients with diabetes and heart failure. Empagliflozin has also been shown to provide advantageous effects in excised hearts and isolated cardiomyocytes despite SGLT-2 expression lacking in cardiac myocytes. This suggests empagliflozin may have important off-target effects. Previous studies suggested that empagliflozin effects may include attenuation of both reactive oxygen species (ROS) and Ca/calmodulin-dependent kinase II activation, but exact signaling details remained unclear. Using transgenic mice expressing glutaredoxin 1-coupled redox-sensitive green fluorescent protein 2 (Grx1-roGFP2) sensor localized to either the cytosol or mitochondria, we tested for empagliflozin effect on oxidative stress in myocytes bathed in high-glucose (30 mmol/L) containing Tyrode's solution. To assess the changes in redox potential, we exposed each cell to H2O2 and dithiothreitol to calibrate the sensor. We found acute hyperglycemia induced significant increases in ROS over a 3-5min of perfusion, specifically in the cytosolic compartment. This is in line with previous report showing that hyperglycemia activates CaMKII by intracellular O-GlcNAcylation, then the active CaMKII promotes cytosolic ROS production via NAPDH oxidase 2 (NOX2). Importantly, cells preincubated with empagliflozin were fully protected against the hyperglycemia-induced increase in ROS. We also extended our studies on angiotensin II (AngII)-dependent ROS production because AngII activates NOX2, and the excess ROS promotes oxidation- dependent CaMKII activation. Myocytes pretreated with the selective CaMKII inhibitor autocamtide-2-relative inhibitory peptide (cell-permeable myristoylated form) were used to test the role of CaMKII in ROS production by either hyperglycemia or Ang-II. These studies could reveal whether empagliflozin acts on glucose uptake, CaMKII activation, or via direct antioxidant mechanisms. Our findings may provide a mechanistic basis for the positive effects of empagliflozin in myocytes under conditions relevant to heart disease.

Anu Taila, an herbal nasal-drop, delays spore germination in Cunninghamella bertholletiae by reducing cAMP-PKA dependent ROS in mucorale pathogen and extrinsic ROS in human host cells.

The rare, fastest-germinating, frequently invasive mucorale, Cunninghamella bertholletiae, is intractable due to its imprecise etiology. Cunninghamella bertholletiae spores can infect both immunocompromised and immunocompetent individuals to cause mucormycosis. Sub-optimal drug-susceptibility further limits its treatment options. The classical nasal drop, Anu Taila, is reported to be effective against the rather prevalent mucorales, Mucor spp., making its anti-mucormycotic effect against C. bertholletiae worth testing. The inhibitory effect of Anu Taila against C. bertholletiae was manifested as microstructural alterations of the spores and their delayed germination. Anu Taila reduced the germination-promoting reactive oxygen species (ROS) levels in both the pathogen, C. bertholletiae, and the human host lung epithelial A549 cells. Expressions of structural (chitin synthase, trehalose synthase) and functional (cAMP-PKA) markers of spore germination were regulated by Anu Taila. cAMP-PKA expression and ROS generation are well-correlated, implicating the role of Anu Taila in delaying C. bertholletiae spore germination by targeting cAMP-PKA-mediated ROS generation. In conclusion, this study demonstrates that Anu Taila can create an opportunity for the host immune system to tackle the onset of C. bertholletiae infection by delaying its pathogenesis. This can be further leveraged to reinforce the host immune system through combinatorial treatment to prevent the establishment of the mucormycosis infection.

Natural sunlight driven photocatalytic dye degradation by biogenically synthesized tin oxide (SnO2) nanostructures using Tinospora crispa stem extract and its anticancer and antibacterial applications.

In the present study, tin oxide (SnO2) was synthesized by advocating the principles of green chemistry for the photo-mediated degradation of pollutants, antimicrobial, and as an antitumor agent. Bioactive SnO2 (nanorods & nanospheres) were fabricated using Tinospora crispa stem extract (TCSE) via sol-gel technique and characterized extensively. XRD, UV-VIS, FTIR, and XPS studies confirmed the formation of crystalline and well stoichiometric pure phase of SnO2 nanostructures with optical bandgap 3.2 to 3.5eV. The transmission electron microscopy (TEM) results demonstrated the effect of secondary phytoconstituents on the shape of SnO2 in a concentration dependent manner. The morphological variations in the obtained nanostructures attributed to the nucleation density and coalescence effect leading to the formation of nanorods with an average diameter 23-25nm whereas the average particle size of the nanospheres obtained was found to be 23-30nm. The zeta potential value of SnO2 nanorods was high (- 58.9mV) indicating the higher stability compared to nanospheres (- 15.6mV). The SnO2 nanostructures were investigated for the simultaneous degradation of methylene blue with degradation efficiency of 92.3% and 47.3% for rhodamine B in mono system and 72.3%, 47.7% respectively for binary dye system. The anticancer activity of SnO2 nanorods explored against human breast cancer (MCF-7) cells revealed a concentration dependent cytotoxic effect reactive oxygen species (ROS) induced cell death. Additionally, efficient antibacterial activity of SnO2 was established using E.coli. Multifaceted applications of Tinospora crispa stem extract mediated SnO2 nanostructures.

ROS-directed activation of Toll/NF-κB in the hematopoietic niche triggers benzene-induced emergency hematopoiesis.

Hematopoietic stem cells/progenitor cells (HSC/HPCs) orchestrate the hematopoietic process, effectively regulated by the hematopoietic niche under normal and stressed conditions. The hematopoietic niche provides various soluble factors which influence the differentiation and self-renewal of HSC/HSPs. Unceasing differentiation/proliferation/high metabolic activity of HSC/HPCs makes them susceptible to damage by environmental toxicants like benzene. Oxidative stress, epigenetic modifications, and DNA damage in the HSC/HPCs are the key factors of benzene-induced hematopoietic injury. However, the role of the hematopoietic niche in benzene-induced hematopoietic injury/response is still void. Therefore, the current study aims to unravel the role of the hematopoietic niche in benzene-induced hematotoxicity using a genetically tractable model, Drosophila melanogaster. The lymph gland is a dedicated hematopoietic organ in Drosophila larvae. A group of 30-45cells called the posterior signaling center (PSC) in the lymph gland acts as a niche that regulates Drosophila HSC/HPCs maintenance. Benzene exposure to Drosophila larvae (48h) resulted in aberrant hemocyte production, especially hyper-differentiation of lamellocytes followed by premature lymph gland dispersal and reduced adult emergence upon developmental exposure. Subsequent genetic experiments revealed that benzene-induced lamellocyte production and premature lymph gland dispersal were PSC mediated. The genetic experiments further showed that benzene generates Dual oxidase (Duox)-dependent Reactive Oxygen Species (ROS) in the PSC, activating Toll/NF-κB signaling, which is essential for the aberrant hemocyte production, lymph gland dispersal, and larval survival. Together, the study establishes a functional perspective of the hematopoietic niche in a benzene-induced hematopoietic emergency in a genetic model, Drosophila, which might be relevant to higher organisms.

Topical, immunomodulatory epoxy-tiglianes induce biofilm disruption and healing in acute and chronic skin wounds.

The management of antibiotic-resistant, bacterial biofilm infections in chronic skin wounds is an increasing clinical challenge. Despite advances in diagnosis, many patients do not derive benefit from current anti-infective/antibiotic therapies. Here, we report a novel class of naturally occurring and semisynthetic epoxy-tiglianes, derived from the Queensland blushwood tree (Fontainea picrosperma), and demonstrate their antimicrobial activity (modifying bacterial growth and inducing biofilm disruption), with structure/activity relationships established against important human pathogens. In vitro, the lead candidate EBC-1013 stimulated protein kinase C (PKC)-dependent neutrophil reactive oxygen species (ROS) induction and NETosis and increased expression of wound healing-associated cytokines, chemokines, and antimicrobial peptides in keratinocytes and fibroblasts. In vivo, topical EBC-1013 induced rapid resolution of infection with increased matrix remodeling in acute thermal injuries in calves. In chronically infected diabetic mouse wounds, treatment induced cytokine/chemokine production, inflammatory cell recruitment, and complete healing (in six of seven wounds) with ordered keratinocyte differentiation. These results highlight a nonantibiotic approach involving contrasting, orthogonal mechanisms of action combining targeted biofilm disruption and innate immune induction in the treatment of chronic wounds.

NCF4 dependent intracellular reactive oxygen species regulate plasma cell formation

Defective reactive oxygen species (ROS) production by genetically determined variants of the NADPH oxidase 2 (NOX2) complex component, NCF4, leads to enhanced production of autoantibodies to collagen type II (COL2) and severe collagen-induced arthritis (CIA) in mice. To further understand this process, we used mice harboring a mutation in the lipid endosomal membrane binding site (R58A) of NCF4 subunit. This mutation did not affect the extracellular ROS responses but showed instead decreased intracellular responses following B cell stimulation. Immunization with COL2 led to severe arthritis with increased antibody levels in Ncf458A mutated animals without significant effects on antigen presentation, autoreactive T cell activation and germinal center formation. Instead, plasma cell formation was enhanced and had altered CXCR3/CXCR4 expression. This B cell intrinsic effect was further confirmed with chimeric B cell transfer experiments and in vitro LPS or CD40L with anti-IgM stimulation. We conclude that NCF4 regulates the terminal differentiation of B cells to plasma cells through intracellular ROS.

Interfacial dependent reactive oxygen species generation over Pt-ZrO2 nanoparticles for catalytic oxidation of formaldehyde at room temperature

Producing the strong metal-support interaction (SMSI) interface and highly reactive oxygen species is a great challenge for catalytic oxidation of formaldehyde (HCHO) at room temperature over supported metal catalysts. Herein, we report a conceptual oxygen vacancy (VO) associated SMSI interface of Pt-ZrO2 nanoparticles for HCHO catalysis at room temperature, exhibiting interfacial dependent reactive oxygen species (O*) formation. The VO on the ZrO2 support captures and activates the molecular O2, then proceeds to generating the reactive oxygen atom (O*) with a lower activation barrier of 0.3 eV. The generated O* tends to link the (110) surface of ZrO2 and the (111) surface of Pt as an electronic transmission channel for the selective catalytic oxidation of HCHO adsorbed on the (110) surface of ZrO2, accelerating the direct generation of formate species and mineralization of HCHO. The Pt-VO-ZrO2 achieves high HCHO removal and HCHO conversion (>95%) at 20 °C. These findings will consolidate the fundamental theories of room temperature catalytic reactions via constructing the SMSI interface engineering for wide environmental applications.

Rice (Oryza sativa L.) cytochrome P450 protein 716A subfamily CYP716A16 regulates disease resistance

BackgroundThe sustainable development of rice production is facing severe threats by a variety of pathogens, such as necrotrophic Rhizoctonia solani and hemibiotrophic Xanthomonas oryzae pv. oryzae (Xoo). Mining and applying resistance genes to increase the durable resistance of rice is an effective method that can be used to control these diseases.ResultsIn this research, we isolated and characterized CYP716A16, which is a positive regulator of rice to R. solani AG1-IA and Xoo, and belongs to the cytochrome P450 (CYP450) protein 716A subfamily. Overexpression (OE) of CYP716A16 resulted in enhanced resistance to R. solani AG1-IA and Xoo, while RNA interference (RNAi) of CYP716A16 resulted in increased susceptibility compared with wild-type (WT) plants. Additionally, jasmonic acid (JA)-dependent defense responses and reactive oxygen species (ROS) were activated in the CYP716A16-OE lines after R. solani AG1-IA inoculation. The comparative transcriptomic and metabolomics analysis of CYP716A16-OE and the WT lines showed that OE of CYP716A16 activated the biosynthesis of flavonoids and increased the amounts of narcissoside, methylophiopogonanone A, oroxin A, and amentoflavone in plants.ConclusionBased on these results, we suggest that JA-dependent response, ROS level, multiple resistance-related proteins, and flavonoid contents play an important role in CYP716A16-regulated R. solani AG1-IA and Xoo resistance. Our results broaden our knowledge regarding the function of a P450 protein 716A subfamily in disease resistance and provide new insight into the molecular mechanism of rice immune response.

Migraine-Associated Mutation in the Na,K-ATPase Leads to Disturbances in Cardiac Metabolism and Reduced Cardiac Function.

BackgroundMutations in ATP1A2 gene encoding the Na,K‐ATPase α2 isoform are associated with familial hemiplegic migraine type 2. Migraine with aura is a known risk factor for heart disease. The Na,K‐ATPase is important for cardiac function, but its role for heart disease remains unknown. We hypothesized that ATP1A2 is a susceptibility gene for heart disease and aimed to assess the underlying disease mechanism.Methods and ResultsMice heterozygous for the familial hemiplegic migraine type 2–associated G301R mutation in the Atp1a2 gene (α2 +/G301R mice) and matching wild‐type controls were compared. Reduced expression of the Na,K‐ATPase α2 isoform and increased expression of the α1 isoform were observed in hearts from α2 +/G301R mice (Western blot). Left ventricular dilation and reduced ejection fraction were shown in hearts from 8‐month‐old α2 +/G301R mice (cardiac magnetic resonance imaging), and this was associated with reduced nocturnal blood pressure (radiotelemetry). Cardiac function and blood pressure of 3‐month‐old α2 +/G301R mice were similar to wild‐type mice. Amplified Na,K‐ATPase–dependent Src kinase/Ras/Erk1/2 (p44/42 mitogen‐activated protein kinase) signaling was observed in hearts from 8‐month‐old α2 +/G301R mice, and this was associated with mitochondrial uncoupling (respirometry), increased oxidative stress (malondialdehyde measurements), and a heart failure–associated metabolic shift (hyperpolarized magnetic resonance). Mitochondrial membrane potential (5,5´,6,6´‐tetrachloro‐1,1´,3,3´‐tetraethylbenzimidazolocarbocyanine iodide dye assay) and mitochondrial ultrastructure (transmission electron microscopy) were similar between the groups. Proteomics of heart tissue further suggested amplified Src/Ras/Erk1/2 signaling and increased oxidative stress and provided the molecular basis for systolic dysfunction in 8‐month‐old α2 +/G301R mice.ConclusionsOur findings suggest that ATP1A2 mutation leads to disturbed cardiac metabolism and reduced cardiac function mediated via Na,K‐ATPase–dependent reactive oxygen species signaling through the Src/Ras/Erk1/2 pathway.

Important Functions and Molecular Mechanisms of Mitochondrial Redox Signaling in Pulmonary Hypertension

Mitochondria are important organelles that act as a primary site to produce reactive oxygen species (ROS). Additionally, mitochondria play a pivotal role in the regulation of Ca2+ signaling, fatty acid oxidation, and ketone synthesis. Dysfunction of these signaling molecules leads to the development of pulmonary hypertension (PH), atherosclerosis, and other vascular diseases. Features of PH include vasoconstriction and pulmonary artery (PA) remodeling, which can result from abnormal proliferation, apoptosis, and migration of PA smooth muscle cells (PASMCs). These responses are mediated by increased Rieske iron–sulfur protein (RISP)-dependent mitochondrial ROS production and increased mitochondrial Ca2+ levels. Mitochondrial ROS and Ca2+ can both synergistically activate nuclear factor κB (NF-κB) to trigger inflammatory responses leading to PH, right ventricular failure, and death. Evidence suggests that increased mitochondrial ROS and Ca2+ signaling leads to abnormal synthesis of ketones, which play a critical role in the development of PH. In this review, we discuss some of the recent findings on the important interactive role and molecular mechanisms of mitochondrial ROS and Ca2+ in the development and progression of PH. We also address the contributions of NF-κB-dependent inflammatory responses and ketone-mediated oxidative stress due to abnormal regulation of mitochondrial ROS and Ca2+ signaling in PH.

Acute exposure to gold nanoparticles aggravates lipopolysaccharide-induced liver injury by amplifying apoptosis via ROS-mediated macrophage-hepatocyte crosstalk

BackgroundGold nanoparticles (AuNPs) are increasingly utilized in industrial and biomedical fields, thereby demanding a more comprehensive knowledge about their safety. Current toxicological studies mainly focus on the unfavorable biological impact governed by the physicochemical properties of AuNPs, yet the consequences of their interplay with other bioactive compounds in biological systems are poorly understood.ResultsIn this study, AuNPs with a size of 10 nm, the most favorable size for interaction with host cells, were given alone or in combination with bacterial lipopolysaccharide (LPS) in mice or cultured hepatic cells. The results demonstrated that co exposure to AuNPs and LPS exacerbated fatal acute liver injury (ALI) in mice, although AuNPs are apparently non-toxic when administered alone. AuNPs do not enhance systemic or hepatic inflammation but synergize with LPS to upregulate hepatic apoptosis by augmenting macrophage-hepatocyte crosstalk. Mechanistically, AuNPs and LPS coordinate to upregulate NADPH oxidase 2 (NOX2)-dependent reactive oxygen species (ROS) generation and activate the intrinsic apoptotic pathway in hepatic macrophages. Extracellular ROS generation from macrophages is then augmented, thereby inducing calcium-dependent ROS generation and promoting apoptosis in hepatocytes. Furthermore, AuNPs and LPS upregulate scavenger receptor A expression in macrophages and thus increase AuNP uptake to mediate further apoptosis induction.ConclusionsThis study reveals a profound impact of AuNPs in aggravating the hepatotoxic effect of LPS by amplifying ROS-dependent crosstalk in hepatic macrophages and hepatocytes.Graphical

Oxidative stress in the skin: Impact and related protection.

Skin, our first interface to the external environment, is subjected to oxidative stress caused by a variety of factors such as solar ultraviolet, infrared and visible light, environmental pollution, including ozone and particulate matters, and psychological stress. Excessive reactive species, including reactive oxygen species and reactive nitrogen species, exacerbate skin pigmentation and aging, which further lead to skin tone unevenness, pigmentary disorder, skin roughness and wrinkles. Besides these, skin microbiota are also a very important factor ensuring the proper functions of skin. While environmental factors such as UV and pollutants impact skin microbiota compositions, skin dysbiosis results in various skin conditions. In this review, we summarize the generation of oxidative stress from exogenous and endogenous sources. We further introduce current knowledge on the possible roles of oxidative stress in skin pigmentation and aging, specifically with emphasis on oxidative stress and skin pigmentation. Meanwhile, we summarize the science and rationale of using three well-known antioxidants, namely vitamin C, resveratrol and ferulic acid, in the treatment of hyperpigmentation. Finally, we discuss the strategy for preventing oxidative stress-induced skin pigmentation and aging.

Oleanolic Acid Improves Obesity-Related Inflammation and Insulin Resistance by Regulating Macrophages Activation.

The chronic low-grade inflammation of adipose tissues, primarily mediated by adipose tissue macrophages (ATMs), is the key pathogenic link between obesity and metabolic disorders. Oleanolic acid (OA) is a natural triterpenoid possessing anti-diabetic and anti-inflammation effects, but the machinery is poorly understood. This study investigated the detailed mechanisms of OA on adipose tissue inflammation in obese mice. C57BL/6J mice were fed with high-fat diet (HFD) for 12 weeks, then daily intragastric administrated with vehicle, 25 and 50 mg/kg OA for 4 weeks. Comparing with vehicle, OA administration in obese mice greatly improved insulin resistance, and reduced adipose tissue hypertrophy, ATM infiltration as well as the M1/M2 ratio. The pro-inflammatory markers were significantly down-regulated by OA in both adipose tissue of obese mice and RAW264.7 macrophages treated with interferon gamma/lipopolysaccharide (IFN-γ/LPS). Furthermore, it was found that OA suppressed activation of mitogen-activated protein kinase (MAPK) signaling and NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome through decreasing voltage dependent anion channels (VDAC) expression and reactive oxygen species (ROS) production. This is the first report that oleanolic acid exerts its benefits by affecting mitochondrial function and macrophage activation.

Dual oxidase-dependent reactive oxygen species are involved in the regulation of UGT overexpression-mediated clothianidin resistance in the brown planthopper, Nilaparvata lugens.

Uridine diphosphate-glycosyltransferases (UGTs) are phase II metabolic enzymes involved in metabolism of toxins and resistance to insecticides in insect pests. Reactive oxygen species (ROS) induced by xenobiotics are important for activation of detoxification pathways. However, relationships between ROS and UGTs involved in toxin metabolism and insecticide resistance remain unclear. Here, involvement of dual oxidase (Duox)-dependent ROS in regulating UGT expression-mediated insecticide resistance in the brown planthopper (Nilaparvata lugens) was investigated. The overexpression of NlUGT386F2 contributed to the resistance of N. lugens to clothianidin. Furthermore, the ROS inhibitor (N-acetylcysteine) significantly reduced the expression of NlUGT386F2 and increased the susceptibility of N. lugens to clothianidin. Silencing the ROS producer Duox significantly increased the susceptibility of N. lugens to clothianidin through the down-regulation of NlUGT386F2 expression. NlDuox-dependent ROS regulates NlUGT386F2 expression-mediated clothianidin resistance in brown planthopper. These observations further our understanding of the metabolism of toxins and of insecticide-resistance in insect pests.

The antibacterial activities of MoS2 nanosheets towards multi-drug resistant bacteria.

We demonstrated that molybdenum disulfide (MoS2) nanosheets can be an excellent solar disinfection agent for multi-drug resistant (MDR) bacteria with disinfection efficiencies >99.9999% in only 30 min. Distinct from other reactive oxygen species (ROS)-dependent photocatalysts, both ROS generation and size decrease contributed to the high antibacterial efficiencies of MoS2.

Trimethylamine N-Oxide increases soluble fms-like tyrosine Kinase-1 in human placenta via NADPH oxidase dependent ROS accumulation

BackgroundsPreeclampsia (PE) is characterized as placental vascular disturbance and excessive secretion of soluble fms-like tyrosine kinase 1 (sFlt-1) into the maternal circulation. Trimethylamine N-oxide (TMAO, a gut microbe-derived metabolite) is strongly associated with various cardiovascular and cerebrovascular diseases. Recently, we observe that higher maternal circulating TMAO and sFlt-1 in patients with PE. The aims of the present study are to explore the effects of TMAO on placental sFlt-1 production and the underlying mechanism in human placenta. MethodsHuman placental explants, human placental primary trophoblasts and the extravillous trophoblasts (EVT) cell line (HRT-8/SVneo) were exposured to various concentrations of TMAO (100, 150, 300, and 600 μM). The mRNA expression and protein secretion of sFlt-1 in placental explants, primary trophoblasts and HRT-8/SVneo cells were determined with qPCR and ELISA, respectively. The levels of intracellular reactive oxygen species (ROS) production in primary trophoblasts and HRT-8/SVneo cells were measured by peroxide-sensitive fluorescent probe dichlorofluorescein diacetate. ResultsExposure of placental explants, primary trophoblasts and HRT-8/SVneo cells to TMAO significantly enhanced sFlt-1 at both mRNA and protein levels in a dose dependent manner. Moreover, inhibition of NADPH oxidase with apocynin significantly attenuated TMAO-induced ROS production in primary trophoblasts and HRT-8/SVneo, and suppressed sFlt-1 secretion in placental explants, primary trophoblasts and HRT-8/SVneo. ConclusionsOur findings indicated the NADPH oxidase dependent ROS pathway played a critical role in mediating TMAO-induced sFlt-1 generation in human placenta. TMAO may become a potential novel target for pharmacological or dietary interventions to reduce the risk of developing PE.