Nicotinamide Adenine Dinucleotide Phosphate Hydrogen Research Articles

Nicotinamide adenine dinucleotide phosphate oxidase in pancreatic diseases: Mechanisms and future perspectives.

Pancreatitis and pancreatic cancer (PC) stand as the most worrisome ailments affecting the pancreas. Researchers have dedicated efforts to unraveling the mechanisms underlying these diseases, yet their true nature continues to elude their grasp. Within this realm, oxidative stress is often believed to play a causal and contributory role in the development of pancreatitis and PC. Excessive accumulation of reactive oxygen species (ROS) can cause oxidative stress, and the key enzyme responsible for inducing ROS production in cells is nicotinamide adenine dinucleotide phosphate hydrogen oxides (NOX). NOX contribute to pancreatic fibrosis and inflammation by generating ROS that injure acinar cells, activate pancreatic stellate cells, and mediate macrophage polarization. Excessive ROS production occurs during malignant transformation and pancreatic carcinogenesis, creating an oxidative microenvironment that can cause abnormal apoptosis, epithelial to mesenchymal transition and genomic instability. Therefore, understanding the role of NOX in pancreatic diseases contributes to a more in-depth exploration of the exact pathogenesis of these diseases. In this review, we aim to summarize the potential roles of NOX and its mechanism in pancreatic disorders, aiming to provide novel insights into understanding the mechanisms underlying these diseases.

Oxidative Stress in Parasitic Diseases-Reactive Oxygen Species as Mediators of Interactions between the Host and the Parasites.

Oxidative stress plays a significant role in the development and course of parasitic infections, both in the attacked host organism and the parasite organism struggling to survive. The host uses large amounts of reactive oxygen species (ROS), mainly superoxide anion (O2•-) and hydrogen peroxide (H2O2), to fight the developing parasitic disease. On the other hand, the parasite develops the most effective defense mechanisms and resistance to the effects of ROS and strives to survive in the host organism it has colonized, using the resources and living environment available for its development and causing the host's weakening. The paper reviews the literature on the role of oxidative stress in parasitic diseases, which are the most critical epidemiological problem worldwide. The most common parasitosis in the world is malaria, with 300-500 million new cases and about 1 million deaths reported annually. In Europe and Poland, the essential problem is intestinal parasites. Due to a parasitic infection, the concentration of antioxidants in the host decreases, and the concentration of products of cellular components oxidation increases. In response to the increased number of reactive oxygen species attacking it, the parasites have developed effective defense mechanisms, including primarily the action of antioxidant enzymes, especially superoxide dismutase and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-dependent complexes glutathione and thioredoxin.

Fisetin Treats Kidney Oxidative Stress, Inflammation, and Apoptosis in Rat Diarrhea.

Diarrhea is the increase in the excretion of human water; meanwhile, fisetin, a bioactive flavonol molecule, is widely used in the treatment/prevention of gastrointestinal disorders. The purpose of this study is to investigate the anti-diarrheal activity of fisetin by restoring kidney function, antioxidant activity, inflammatory markers, Na+/K+-ATPase level, apoptosis, and protein content in diarrheal rats. A total of 36 male rats were distributed into two groups (18 rats/group): normal and diarrheal. The normal group was further divided into three subgroups (6 rats/subgroup): Control, fisetin, and desmopressin drug subgroups, consisting of normal rats orally treated once a day for 4 weeks with 1 mL distilled water, 50 mg/kg fisetin, and 1 mg/kg desmopressin drug, respectively. A lactose diet containing 35% lactose was fed to the normal rats for a month. The diarrheal rats were also divided into three subgroups (6 rats/subgroup): diarrheal rats, diarrheal rats + fisetin, and diarrheal rats + desmopressin drug groups, whereby the diarrheal rats were orally treated once a day for 4 weeks with 1 mL distilled water, 50 mg/kg fisetin, and 1 mg/kg desmopressin drug, respectively. Fisetin significantly decreased serum urea (41.20 ± 2.6-29.74 ± 2.65), creatinine (1.43 ± 0.05-0.79 ± 0.06), and urinary volume (1.30 ± 0.41-0.98 ± 0.20), while significantly increasing kidney weight (0.48 ± 0.03-0.67 ± 0.07), sodium, potassium, and chloride balance in both serum and urine. Fisetin significantly increased the antioxidant activity (superoxide dismutase (1170 ± 40-3230 ± 50), glutathione peroxidase (365 ± 18-775 ± 16), catalase (0.09 ± 0.03-0.14 ± 0.06), and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase activity (8.6 ± 1.31-10.5 ± 1.25), while significantly decreasing malondialdehyde (19.38 ± 0.54-9.54 ± 0.83), conjugated dienes (1.86 ± 0.24-1.64 ± 0.19), and oxidative index (0.62 ± 0.04-0.54 ± 0.05)), alongside the inflammatory markers (tumor necrosis factor-α (65.2 ± 2.59-45.3 ± 2.64), interleukin-1β, interleukin-6 (107 ± 4.5-56.1 ± 7.2), and interleukin-10) in the diarrheal rats to values approaching the control values. Fisetin also restored the Na+/K+-ATPase level, apoptosis, protein content, and kidney architecture in diarrheal rats to be near the control group. Fisetin treated diarrhea in rats by restoring kidney function, antioxidant activity, inflammatory markers, apoptosis, proteome content, and histology.

The nonessential amino acid cysteine is required to prevent ferroptosis in acute myeloid leukemia

AbstractCysteine is a nonessential amino acid required for protein synthesis, the generation of the antioxidant glutathione, and for synthesizing the nonproteinogenic amino acid taurine. Here, we highlight the broad sensitivity of leukemic stem and progenitor cells to cysteine depletion. By CRISPR/CRISPR-associated protein 9–mediated knockout of cystathionine-γ-lyase, the cystathionine-to-cysteine converting enzyme, and by metabolite supplementation studies upstream of cysteine, we functionally prove that cysteine is not synthesized from methionine in acute myeloid leukemia (AML) cells. Therefore, although perhaps nutritionally nonessential, cysteine must be imported for survival of these specific cell types. Depletion of cyst(e)ine increased reactive oxygen species (ROS) levels, and cell death was induced predominantly as a consequence of glutathione deprivation. nicotinamide adenine dinucleotide phosphate hydrogen oxidase inhibition strongly rescued viability after cysteine depletion, highlighting this as an important source of ROS in AML. ROS-induced cell death was mediated via ferroptosis, and inhibition of glutathione peroxidase 4 (GPX4), which functions in reducing lipid peroxides, was also highly toxic. We therefore propose that GPX4 is likely key in mediating the antioxidant activity of glutathione. In line, inhibition of the ROS scavenger thioredoxin reductase with auranofin also impaired cell viability, whereby we find that oxidative phosphorylation–driven AML subtypes, in particular, are highly dependent on thioredoxin-mediated protection against ferroptosis. Although inhibition of the cystine-glutamine antiporter by sulfasalazine was ineffective as a monotherapy, its combination with L-buthionine-sulfoximine (BSO) further improved AML ferroptosis induction. We propose the combination of either sulfasalazine or antioxidant machinery inhibitors along with ROS inducers such as BSO or chemotherapy for further preclinical testing.

Individual and combinative effect of NaCl and γ-radiation on NADPH-generating enzymes activity in corn (Zea mays L.) sprouts

Being a universal reducing agent nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) plays an important role in the cellular metabolism and the implementation of anti-stress reactions in plants. There are only a few enzymes that ensure the NADPH pool formation in cells. Among them, the most important are glucose-6-phosphate dehydrogenase (G6PDH, EC 1.1.1.49), malate dehydrogenase decarboxylating (DMDH, malic enzyme, EC 1.1.1.40) and NADP-isocitrate dehydrogenase (NADP-IDH, EC 1.1.1.42). The presented investigation is devoted to studying the influence of the individual and combinative effects of NaCl and γ-radiation as abiotic stress factors on biometric indicators and activity of these NADPH-generating enzymes, on organic content, and the formation of paramagnetic centers as defense reaction in corn (Zagatala-68 genotype) sprouts. It was found that 100 mM NaCl had an inhibitory effect on the development of sprouts. Relatively lower doses (50 Gy and 100 Gy) of γ-radiation had a positive, but its higher doses (150 Gy and 200 Gy) had a negative effect on this process. 500 Gy was a lethal dose (LD) for the corn sprouts. Combinative stress in all cases considerably delayed the development of sprouts. G6PDH showed the highest activity in the first, whereas, NADP-IDH showed the same activity in the last days of the experiment. All three enzymes, especially the G6PDH, have been activated in both root and stem tissues under the influence of stress factors (either radiation or salt). Combinative stress (γ-radiation + salt) also led to an induction of these activities which was necessary to neutralize the negative consequences of stress factors. Stress factors in all cases also had a negative effect on the content of organic matter in seedlings. Ionizing gamma radiation, which resulted in the formation of new paramagnetic centers as an anti-stress defense reaction in many cases was observed in wheat seedlings, but not in corn sprouts, which clearly shows that there are some differences in the protective mechanisms of these C3- and C4-types of plants to γ-radiation.

Phenyllactic acid maintains the storage quality of ‘Zaosu’ pears by regulating respiration and energy metabolism

Respiration and energy metabolism are intricately linked to the quality and senescence of fruit after harvest. This investigation was carried out to examine alternations in quality parameters, respiration, and energy metabolism of ‘Zaosu’ pears subsequent to phenyllactic acid immersion. Results demonstrated that phenyllactic acid treatment led to a reduction in L* , a* , b* values, ΔE, and mass loss. Additionally, it maintained ascorbic acid, reducing sugar, soluble sugar, soluble solids, and chlorophyll contents; delayed the decrease in flesh firmness and titratable acidity of pears. The activities and gene expressions of glucose-6-phosphate dehydrogenase, glucose phosphate isomerase, hexokinase, nicotinamide adenine dinucleotide kinase, cytochrome C oxidase, and succinate dehydrogenasepears in pears were enhanced by phenyllactic acid. Moreover, phenyllactic acid promoted PbPK, PbAOX, PbH+-ATPase, and PbCa2+-ATPase expressions, while inhibiting malate dehydrogenase activity and the expressions of PbPFK and PbMDH in pears. Phenyllactic acid also led to a decrease in the levels of nicotinamide adenine dinucleotide hydrogen and nicotinamide adenine dinucleotide, while causing an increase in the levels of nicotinamide adenine dinucleotide phosphate hydrogen and nicotinamide adenine dinucleotide phosphate within the fruit. Collectively, postharvest phenyllactic acid treatment can effectively preserve the storage quality of ‘Zaosu’ pears by regulating the activity and gene expression of the key enzymes involved in respiration and energy metabolism.

The correlation between oxidative stress markers and increasing intracranial pressure: a study of Malondialdehyde (MDA), Superoxide Dismutase (MnSOD), Nicotinamide Adenine Dinucleotide Phosphate Hydrogen (NADPH), and catalase

Link of Video Abstract: https://youtu.be/nINFPi4uVow Background: Abnormalities in the neurosurgical field concerning cranial structure are almost always followed by increased intracranial pressure (ICP), which causes cerebral hypoxia and disrupts the whole cellular system. This study analyzes the correlation between ICP changes and oxidative stress markers, in subjects with various anatomical pathology abnormalities who underwent surgery. Methods: This was a cross sectional study of 24 subjects with ICP conducted in the Department of Neurosurgery, Cipto Mangunkusumo Hospital, Jakarta, from November to December 2009. In this study, ANOVA analysis has been done to measure the mean difference oxidative stress (MnSOD, NADPH, MDA, and catalase) in subjects with various changes in ICP who have undergone surgery and Spearman analysis to measure the correlation between each oxidative stress markers. Oxidative stress markers were measured from normal brain tissue taken intra-operatively, cerebrospinal fluid (CSF) taken while doing ventriculostomy, and peripheral blood taken from a central vein catheter (CVC). Results: The results showed that MDA concentrations in blood were significantly correlated with MDA in brain tissue (P = 0.029) in all of the ICP groups, CSF MnSOD concentration and CSF NADPH concentrations correlated with brain tissue NAPDH (p= 0.000) in congenital group and CSF catalase concentration correlated with brain tissue catalase (p = 0.00) in congenital group. Conclusion: Increased ICP caused by various pathological conditions causes changes in oxidative stress markers in brain cells, CSF and blood. Oxidative stress markers in blood and CSF are correlated strongly with the brain. It is suggested that it could be used to predict intracranial high pressure in all cases with intracranial abnormalities.

Engineering co-utilization of glucose and xylose for chemical overproduction from lignocellulose.

Bio-refining lignocellulose could provide a sustainable supply of fuels and fine chemicals; however, the challenges associated with the co-utilization of xylose and glucose typically compromise the efficiency of lignocellulose conversion. Here we engineered the industrial yeast Ogataea polymorpha (Hansenula polymorpha) for lignocellulose biorefinery by facilitating the co-utilization of glucose and xylose to optimize the production of free fatty acids (FFAs) and 3-hydroxypropionic acid (3-HP) from lignocellulose. We rewired the central metabolism for the enhanced supply of acetyl-coenzyme A and nicotinamide adenine dinucleotide phosphate hydrogen, obtaining 30.0 g l-1 of FFAs from glucose, with productivity of up to 0.27 g l-1 h-1. Strengthening xylose uptake and catabolism promoted the synchronous utilization of glucose and xylose, which enabled the production of 38.2 g l-1 and 7.0 g l-1 FFAs from the glucose-xylose mixture and lignocellulosic hydrolysates, respectively. Finally, this efficient cell factory was metabolically transformed for 3-HP production with the highest titer of 79.6 g l-1 in fed-batch fermentation in mixed glucose and xylose.

NOX4–TIM23 interaction regulates NOX4 mitochondrial import and metabolic reprogramming

Pulmonary fibrosis is a progressive lung disease characterized by macrophage activation. Asbestos-induced expression of nicotinamide adenine dinucleotide phosphate hydrogen oxidase 4 (NOX4) in lung macrophages mediates fibrotic progression by the generation of mitochondrial reactive oxygen species (ROS), modulating mitochondrial biogenesis, and promoting apoptosis resistance; however, the mechanism(s) by which NOX4 localizes to mitochondria during fibrosis is not known. Here, we show that NOX4 localized to the mitochondrial matrix following asbestos exposure in lung macrophages via direct interaction with TIM23. TIM23 and NOX4 interaction was found in lung macrophages from human subjects with asbestosis, while it was absent in mice harboring a conditional deletion of NOX4 in lung macrophages. This interaction was localized to the proximal transmembrane region of NOX4. Mechanistically, TIM23 augmented NOX4-induced mitochondrial ROS and metabolic reprogramming to oxidative phosphorylation. Silencing TIM23 decreased mitochondrial ROS and oxidative phosphorylation. These observations highlight the important role of the mitochondrial translocase TIM23 interaction with NOX4. Moreover, this interaction is required for mitochondrial redox signaling and metabolic reprogramming in lung macrophages.

Enzyme histochemical characterization of orbital glands in fetuses of Indian buffalo (Bubalus bubalis).

The orbital glands, viz. lacrimal gland, superficial and deep gland of third eyelid (LG, SGT and HG), are important for normal eye functions. These glands have different functions in various animals. The information about the enzyme histochemical nature of prenatal orbital glands in Indian buffalo seems to be unavailable. Therefore, the study was planned on orbital glands of six full term recently died fetuses from animals with dystocia. The frozen sections of all these glands were subjected to standard localization protocols for Alkaline Phosphatase (AKPase), Glucose 6 phosphatase (G-6-Pase), Lactate dehydrogenase (LDH), Succinate dehydrogenase (SDH), Glucose 6 phosphate dehydrogenase (G-6-PD), Nicotinamide Adenine Dinucleotide Hydrogen Diaphorase (NADHD), Nicotinamide Adenine Dinucleotide Phosphate Hydrogen diaphorase (NADPHD), Dihydroxy phenylalanine oxidase (DOPA-O), Tyrosinase, non-specific esterase (NSE) and Carbonic anhydrase (CAse). The results revealed a mixed spectrum of reaction for the above enzymes in LG, SGT and HG which ranged from moderate (for LDH in SGT) to intense (for most of the enzymes in all three glands). However, DOPA-O, Tyrosinase and CAse did not show any reaction. From the present study, it can be postulated that the orbital glands of fetus have a high activity of metabolism as it has many developmental and functional activities which were mediated with the higher activity of the enzymes involved.

The potential role of vitamin E in patients with glucose-6-phosphate dehydrogenase deficiency: A systematic review and meta-analysis.

As an antioxidant, vitamin E (VitE) may benefit the erythrocytes by protecting glutathione from oxidation by free radicals and peroxide-generating processes. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines when reporting this systematic review. We searched 6 electronic databases (PubMed, Scopus, Web of Science, and Cochrane Library) until May 8, 2022. We included all relevant studies. According to the study design, the Cochrane assessment tool (Risk of Bias 2), Risk Of Bias In Non-randomized Studies - of Interventions checklists, and National Institutes of Health tools were used to assess the risk of bias.Continuous data were pooled as a mean difference (MD) with a relative 95% confidence interval. The protocol was registered on PROSPERO (CRD42022333848). Six studies were included in the meta-analysis with a total of 181 patients. Compared with the control group, VitE significantly improved the hemoglobin level for chronic hemolysis (MD = 2.72 g/dL, P < .0001) and for acute hemolysis (MD = 1.18 g/dL, P < .0001). It also decreased the reticulocyte level for chronic hemolysis (MD = -1.39 P < .0001) and for acute hemolysis (MD = -1.42%, P < .0001). For before and after studies, the use of VitE significantly improved the level of packed cell volume (MD = 0.56%, P < .00001), red blood cell half-life (MD = 2.19 days, P < .0001), and decreased the reticulocytes level (MD = -1.41%, P < .00001). Among patients with glucose-6-phosphate dehydrogenase deficiency, VitE might provide benefits such as increasing the hemoglobin, packed cell volume levels, red blood cell half-life, and decreasing the reticulocyte level, so reducing hemolysis. Further high-quality, well-designed randomized controlled trials are recommended.

A neutrophil-biomimic platform for eradicating metastatic breast cancer stem-like cells by redox microenvironment modulation and hypoxia-triggered differentiation therapy

Metastasis accounts for 90% of breast cancer deaths, where the lethality could be attributed to the poor drug accumulation at the metastatic loci. The tolerance to chemotherapy induced by breast cancer stem cells (BCSCs) and their particular redox microenvironment further aggravate the therapeutic dilemma. To be specific, therapy-resistant BCSCs can differentiate into heterogeneous tumor cells constantly, and simultaneously dynamic maintenance of redox homeostasis promote tumor cells to retro-differentiate into stem-like state in response to cytotoxic chemotherapy. Herein, we develop a specifically-designed biomimic platform employing neutrophil membrane as shell to inherit a neutrophil-like tumor-targeting capability, and anchored chemotherapeutic and BCSCs-differentiating reagents with nitroimidazole (NI) to yield two hypoxia-responsive prodrugs, which could be encapsulated into a polymeric nitroimidazole core. The platform can actively target the lung metastasis sites of triple negative breast cancer (TNBC), and release the escorted drugs upon being triggered by the hypoxia microenvironment. During the responsiveness, the differentiating agent could promote transferring BCSCs into non-BCSCs, and simultaneously the nitroimidazole moieties conjugated on the polymer and prodrugs could modulate the tumor microenvironment by depleting nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and amplifying intracellular oxidative stress to prevent tumor cells retro-differentiation into BCSCs. In combination, the BCSCs differentiation and tumor microenvironment modulation synergistically could enhance the chemotherapeutic cytotoxicity, and remarkably suppress tumor growth and lung metastasis. Hopefully, this work can provide a new insight in to comprehensively treat TNBC and lung metastasis using a versatile platform.

A profitable function ofCeriporia lacerataHG2011 on nodulation and biological nitrogen fixation of green bean (Phaseolus vulgaris L.)

Green bean (Phaseolus vulgaris L.) is a popular vegetable worldwide. The use of beneficial fungi is a simple and effective way to improve the biological nitrogen fixation (BNF) of this leguminous vegetable. A micro-plot was conducted to investigate the enhancement of BNF using 15N natural abundance technology and agronomic performances of green bean caused by wood-rot fungus Ceriporia lacerata HG2011. The results showed the soil for frequently growing green bean featured abundant native rhizobia, and newly inoculated rhizobia may have to compete with them in nodulation and only highly competitive rhizobia can succeed. The addition of C. lacerata HG2011 to the soil increased the population of ammonia oxidizers, nitrifiers, and phosphorus (P)-mobilizing microbes in rhizosphere, accelerated nitrification and P mobilization, creating a favorable soil environment with high P and low ammonia for BNF. Green bean received C. lacerata HG2011 had higher dehydrogenase activity in roots and higher nodulation rate and large nodules. These phenomena implied abundant supplies of adenosine triphosphate, nicotinamide adenine dinucleotide hydrogen, or nicotinamide adenine dinucleotide phosphate hydrogen for BNF in the roots, a large proportion of N2 fixation tissues, and a greater sink for receiving photosynthates. As a result, C. lacerata HG2011 considerably increased the percentage of N derived from the atmosphere, BNF, and plant nutrient uptake (including N, P, and potassium), leading to 15.58%-28.51% of biomass increasment and 9.82%-17.03% of peapod yield increasment along with quality improvement compared with non-fungal application. C. lacerata HG2011 increased the nodulation and BNF of green bean, accelerated the nutrient uptake (NPK) and therefore improved the yield and peapod quality of green bean. The study demonstrates that C. lacerata HG2011 could be used as a biofertilizer for BNF improvement of legumes.

NOX as a Therapeutic Target in Liver Disease.

The nicotinamide adenine dinucleotide phosphate hydrogen oxidase (NADPH oxidase or NOX) plays a critical role in the inflammatory response and fibrosis in several organs such as the lungs, pancreas, kidney, liver, and heart. In the liver, NOXs contribute, through the generation of reactive oxygen species (ROS), to hepatic fibrosis by acting through multiple pathways, including hepatic stellate cell activation, proliferation, survival, and migration of hepatic stellate cells; hepatocyte apoptosis, enhancement of fibrogenic mediators, and mediation of an inflammatory cascade in both Kupffer cells and hepatic stellate cells. ROS are overwhelmingly produced during malignant transformation and hepatic carcinogenesis (HCC), creating an oxidative microenvironment that can cause different and various types of cellular stress, including DNA damage, ER stress, cell death of damaged hepatocytes, and oxidative stress. NOX1, NOX2, and NOX4, members of the NADPH oxidase family, have been linked to the production of ROS in the liver. This review will analyze some diseases related to an increase in oxidative stress and its relationship with the NOX family, as well as discuss some therapies proposed to slow down or control the disease’s progression.

RONS and Oxidative Stress: An Overview of Basic Concepts

Oxidative stress (OS) has greatly interested the research community in understanding damaging processes occurring in cells. OS is triggered by an imbalance between reactive oxygen species (ROS) production and their elimination by the antioxidant system; however, ROS function as second messengers under physiological conditions. ROS are produced from endogenous and exogenous sources. Endogenous sources involve mitochondria, nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), oxidases (NOXs), endoplasmic reticulum (ER), xanthine oxidases (XO), endothelial nitric oxide synthase (eNOs), and others. In contrast, exogenous ROS might be generated through ultraviolet (UV) light, ionizing radiation (IR), contaminants, and heavy metals, among others. It can damage DNA, lipids, and proteins if OS is not controlled. To avoid oxidative damage, antioxidant systems are activated. In the present review, we focus on the basic concepts of OS, highlighting the production of reactive oxygen and nitrogen species (RONS) derived from internal and external sources and the last elimination. Moreover, we include the cellular antioxidant system regulation and their ability to decrease OS. External antioxidants are also proposed as alternatives to ameliorate OS. Finally, we review diseases involving OS and their mechanisms.

Anti-Inflammatory Effects of Auranamide and Patriscabratine-Mechanisms and In Silico Studies.

Auranamide and patriscabratine are amides from Melastoma malabathricum (L.) Smith. Their anti-inflammatory activity and nuclear factor erythroid 2-related factor 2 (NRF2) activation ability were evaluated using Escherichia coli lipopolysaccharide (LPSEc)-stimulated murine macrophages (RAW264.7) and murine hepatoma (Hepa-1c1c7) cells, respectively. The cytotoxicity of the compounds was assessed using a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. The anti-inflammatory activity was determined by measuring the nitric oxide (NO) production and pro-inflammatory cytokines (Interleukin (IL)-1β, Interferon (IFN)-γ, tumour necrosis factor (TNF)-α, and IL-6) and mediators (NF-κB and COX-2). NRF2 activation was determined by measuring the nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) quinone oxidoreductase 1 (NQO1), nuclear NRF2 and hemeoxygenase (HO)-1. In vitro metabolic stability was assessed using the mouse, rat, and human liver microsomes. The compounds were non-toxic to the cells at 10 μM. Both compounds showed dose-dependent effects in downregulating NO production and pro-inflammatory cytokines and mediators. The compounds also showed upregulation of NQO1 activity and nuclear NRF2 and HO-1 levels. The compounds were metabolically stable in mouse, rat and human liver microsomes. The possible molecular targets of NRF2 activation by these two compounds were predicted using molecular docking studies and it was found that the compounds might inhibit the Kelch domain of KEAP1 and GSK-3β activity. The physicochemical and drug-like properties of the test compounds were predicted using Schrodinger small molecule drug discovery suite (v.2022-2).

Effect of histone deacetylase inhibitor (vorinostat) on new-onset diabetes induced by tacrolimus

ObjectiveThe immunosuppressant tacrolimus is a major cause of new-onset diabetes after transplantation. The aim of this study was to evaluate whether a low dose of the histone-deacetylase inhibitor (vorinostat) might ameliorate tacrolimus-induced new-onset diabetes. MethodsThirty 8-week-old male Wistar rats were randomly divided into five groups: a control group, tacrolimus group (1.5 mg/kg intraperitoneally for 28 days), vorinostat group (15 mg/kg orally for 28 days), a group receiving tacrolimus with vorinostat for 28 days; and a group receiving coadministration of tacrolimus for 28 days and vorinostat for 14 days. Diabetes development was assessed on the basis of serum glucose, insulin, HOMA-IR and C-peptide. To investigate the mechanism of vorinostat, we assessed inflammatory markers (tumor necrosis factor-α and interleukin-1β), an antioxidant marker (glutathione), an oxidant marker (nicotinamide adenine dinucleotide phosphate hydrogen oxidase) and an apoptosis marker (caspase-3). Kidney functions (creatinine and blood urea nitrogen) were also assessed. ResultsThe administration of tacrolimus for 28 days resulted in significantly increased serum glucose and decreased C-peptide and insulin levels than those in the control group. However, coadministration of vorinostat significantly decreased hyperglycemia and increased C-peptide and insulin levels. Moreover, combined treatment with tacrolimus and vorinostat, compared with tacrolimus treatment alone, resulted in significantly reduced inflammatory and oxidant markers, and increased glutathione. Additionally, vorinostat improved the kidney parameters. ConclusionVorinostat at a low dose (15 mg/kg) induces anti-inflammatory and antioxidative effects that protect the pancreas and kidney against the development of new-onset diabetes due to tacrolimus in rats. This experimental study provides insights supporting further clinical trials to improve the post-kidney transplantation protocol through addition of vorinostat to the immunosuppressive regimen.

A Mixture of Topical Forms of Polydeoxyribonucleotide, Vitamin C, and Niacinamide Attenuated Skin Pigmentation and Increased Skin Elasticity by Modulating Nuclear Factor Erythroid 2-like 2.

It is well-known that increased oxidative stress caused by ultraviolet B (UV-B) radiation induces melanogenesis and activates metalloproteinases (MMPs), which degrade collagen and elastin fibers, leading to decreased skin elasticity. Various antioxidant agents, such as vitamin C and niacinamide, have been evaluated for use as treatments for photoaging or skin pigmentation. In this study, we evaluated the ability of a topical liquid formula of polydeoxyribonucleotide (PDRN), vitamin C, and niacinamide (PVN) delivered via a microneedling therapy system (MTS) to attenuate photoaging and pigmentation by increasing nuclear factor erythroid 2-like 2 (NRF2)/heme oxygenase-1 (HO-1) and decreasing MMP expression in a UV-B-radiated animal model. The effects of the PVN were compared with those of individual PDRN and hydroquinone (HQ) compounds. The expression of NRF2/HO-1 significantly increased in response to HQ, PDRN, and PVN in UV-B-radiated animal skin. The activity of nicotinamide adenine dinucleotide phosphate hydrogen oxidase decreased in response to HQ, PDRN, and PVN, and the superoxide dismutase activity increased. The expression of tumor protein p53 and microphthalmia-associated transcription factor and tyrosinase activity decreased in response to HQ, PDRN, and PVN, and this decrease was accompanied by decreased melanin content in the skin. The expression of nuclear factor kappa-light-chain enhancer of activated B cells and MMP2/3/9 decreased in response to HQ, PDRN, and PVN in UV-B-radiated skin. However, the expression of collagen type I α1 chain and the amount of collagen fibers that were evaluated by Masson’s trichrome staining increased in response to HQ, PDRN, and PVN. The contents of elastin fibers, fibrillin 1/2 and fibulin 5 increased in response to HQ, PDRN, and PVN. In conclusion, PVN delivered via MTS led to decreased melanogenesis and destruction of collagen and elastin fibers by MMPs, and, thus, PVN decreased skin pigmentation and increased skin elasticity.

Increasing nicotinamide adenine dinucleotide phosphate hydrogen levels via pentose phosphate pathway promotes phyenylpropanoid metabolism of fresh-cut white mushroom (Agaricus bisporus) under high O2/CO2 storage

Cutting usually shortens white mushroom shelf life due to wounding stress. The metabolic activities including phenylpropanoid metabolism can promote wound-healing ability in white mushroom, thus alleviating the negative effect of its cutting process. However, few reports have reported on the relationship between phenylpropanoid metabolism and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) content. In this study, the effects of high O2/CO2 treatment on the phenylpropanoid metabolism and NADPH level produced via the pentose phosphate pathway (PPP) in white mushroom slices were analyzed. White mushroom slices were first treated with 80% O2+20% CO2 controlled atmosphere for 3 h. The results showed that high O2/CO2 treatment enhanced phenylpropanoid metabolism, which is demonstrated by higher total phenol, flavonoid, and lignin content. High O2/CO2 treatment also reduced the total respiratory rate. However, it increased PPP and tricarboxylic acid cycle rates; inhibited decline in ATP content and improved NAD+ kinase activity. Moreover, NAD+ and NADH contents decreased, whereas NADP+ and NADPH contents increased. To further investigate the relationship between respiratory metabolism and phenylpropanoid metabolism, whole white mushroom were immersed in 0.1 mol L−1 Na3PO4 (a PPP inhibitor) and then the slices were treated with 80% O2+20% CO2 for 3 h. This led to lower key enzyme activity and metabolic product content in the phenylpropanoid metabolism compared with no Na3PO4 treatment. These results demonstrated that high oxygen treatment can effectively induce phenylpropanoid metabolism by increasing NADPH levels via stimulating the PPP. In conclusion, the PPP might play an important role of phenylpropanoid metabolism in fresh-cut white mushroom.

Protocatechualdehyde restores endothelial dysfunction in streptozotocin-induced diabetic rats.

BackgroundThe present study was conducted with the aim of clarifying the effects of protocatechualdehyde (PCA) on the endothelial function in streptozotocin (STZ)-induced diabetic rats.MethodsSprague Dawley (SD) rats were intraperitoneally injected with STZ (single dose of 60 mg/kg). Diabetic model rats were given PCA (25 mg/kg/day) via gavage feeding for 6 weeks. Vascular function was studied; superoxide anion and nitrotyrosine levels were assessed; and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase as well as total superoxide dismutase (SOD) activity were detected. Protein expression of phosphorylated endothelial nitric oxide synthase (P-eNOS), total endothelial nitric oxide synthase (T-eNOS), p22phox, p47phox and Cu/Zn-SOD were measured by Western blot analysis.ResultsPCA treatment significantly ameliorated the impairment of acetylcholine- evoked endothelium-dependent relaxation, with no obvious effects observed on the blood glucose or body weight in the STZ-induced diabetic rats. Expression levels of aortic P-eNOS/T-eNOS and endothelial nitric oxide synthase (eNOS) activity were decreased in STZ-induced diabetic rats while they remained unchanged in PCA-treated rats. However, PCA treatment improved oxidative inactivation of nitric oxide (NO) and decreased the levels of superoxide anion and nitrotyrosine in the aorta of STZ-induced diabetic rats; these were achieved by reducing the level of nitrotyrosine and down-regulating p47phox and p22phox expression, as well as up-regulating Cu/Zn-SOD protein expression. Consistently, the effects observed were associated with a decrease in NADPH oxidase activity and an increase in total SOD activity.ConclusionsOur results indicate that the administration of PCA may be protective against oxidative stress and may restore endothelial function by improving vascular NO oxidative inactivation in diabetic condition.