Doença granulomatosa crônica: características clínicas, seguimento e terapêutica de cinco pacientes pediátricos / Chronic granulomatous disease: clinical characteristics, follow-up, and therapy of 5 pediatric patients

Introdução: A doença granulomatosa crônica (DGC) é caracterizada por um defeito na capacidade microbicida das células fagocíticas (monócitos e neutrófilos), com alta mortalidade se não diagnosticada precocemente. Os pacientes apresentam infecções recorrentes ou graves, suscetibilidade a granulomas em órgãos profundos, doenças autoimunes e doença inflamatória intestinal. Objetivo e Método: Relato de aspectos clínicos e do tratamento de cinco pacientes com doença granulomatosa crônica. Resultados: Cinco pacientes, três meninos, medianas de idade no início dos sintomas e diagnóstico de 8 meses e 48 meses, respectivamente, foram estudados por um período de 10 anos. Pneumonia (5/5) e doença micobacteriana (3/5) foram as manifestações iniciais mais comuns. Alterações pulmonares foram observadas em todos os casos. Mutações nos genes CYBB e NCF1 foram identificadas em três casos. Antibioticoprofilaxia foi instituída em todos os pacientes e três foram submetidos ao transplante de células tronco-hematopoiéticas (TCH), aos 7, 18 e 19 anos e com sobrevida atual entre 4 a 5 anos. Conclusão: O monitoramento cuidadoso de infecções graves com tratamento imediato foi crucial para a sobrevivência. O TCH, mesmo ao final da adolescência, promoveu a cura da DGC em três pacientes.

Introduction: Chronic granulomatous disease (CGD) is characterized by a defective microbicidal capacity of phagocytic cells (monocytes and neutrophils) with high mortality if not early diagnosed. Patients have recurrent or severe infections and are susceptible to granulomas in visceral organs, autoimmune diseases, and inflammatory bowel diseases. Objective and Method: To report the clinical features and treatment of 5 patients with CGD. Results: Five patients, 3 boys, with median ages at symptom onset and diagnosis of 8 months and 48 months, respectively, were followed for 10 years. Pneumonia (5/5) and mycobacterial disease (3/5) were the most common initial manifestations. Pulmonary changes were observed in all cases. Mutations in the CYBB and NCF1 genes were identified in 3 cases. All patients received antibiotic prophylaxis. Three patients underwent a hematopoietic stem cell transplant (HSCT) at 7, 18, and 19 years, with current survival of 4 to 5 years. Conclusion: Careful monitoring for severe infection with prompt treatment was crucial for survival. Even though HSCT was performed in late adolescence, it promoted the cure of CGD in 3 patients.

Ginsenoside Rg1 attenuates palmitate-induced HMCs fibrosis by inhibiting NOX4/MAPK pathways / 中国药理学通报

Aim To investigate the inhibitory effect of ginsenoside Rg1 on sodium palmitate induced fibrosis in human glomerullar mesangial cells (HMCs) and its mechanism. Methods (1) HMCs were treated with different concentrations of PA for 24 h, the intracellular lipid accumulation was observed by oil red staining, and the intracellular ROS production was detected by H2DCFDA kit; (2) HMCs were divided into control, PA (160 μmol·L

Implications of lysyl oxidase-like protein 3 expression in the periodontium of diabetic rats

Abstract Objectives Diabetes has been strongly associated with periodontal diseases. The periodontal ligament (PDL) has an abundant extracellular matrix (ECM). Lysyl oxidases (LOXs) are closely associated with various diseases caused by abnormal ECM functions, however, the role of LOXs in periodontal diseases induced by diabetes remains unclear. Methodology In this study, 8-week-old Zucker diabetic fatty rats were used to establish a type 2 diabetes mellitus (T2DM) model. After 9 and 16 weeks, hematoxylin and eosin (H&E), Masson's trichrome, and immunohistochemical staining were performed. Results After 9 weeks, loose collagen fibers were found in the interradicular area of the diabetic group, in opposition to the control group. There were no significant differences in LOX expression between the diabetic and control groups (p>0.05). However, after 16 weeks, the diabetic group presented a disordered arrangement of the PDL, showing decreased collagen content and significantly increased lysyl oxidase-like protein 3 (LOXL3) expression when compared with the control group (p<0.05). This suggests that LOXL3 plays a significant role in periodontal histopathological changes in diabetic rats. Conclusion Our study showed elevated LOXL3 expression in the PDL of diabetic rats after 16 weeks, suggesting that LOXL3 may be involved in the occurrence and development of periodontal histopathological changes in diabetic rats. LOXL3 could be further used as an indicator for the early diagnosis of diabetic periodontitis in T2DM patients in clinical settings.

Pterostilbeno Reduz o Estresse Oxidativo no Pulmão e no Ventrículo Direito Induzido por Infarto do Miocárdio Experimental / Pterostilbene Reduces Experimental Myocardial Infarction-Induced Oxidative Stress in Lung and Right Ventricle

Resumo Fundamento O pterostilbeno (PS), um composto polifenólico natural e antioxidante, surge como uma intervenção promissora para minimizar danos do infarto agudo do miocárdio (IAM). Objetivo Este estudo teve como objetivo avaliar o desempenho do PS na promoção da homeostase redox nos pulmões e no ventrículo direito (VD) de animais infartados. Métodos Ratos Wistar machos (60 dias de idade) foram randomizados em três grupos: SHAM, IAM (infarto) e IAM+PS (IAM + pterostilbeno). Sete dias após o procedimento de IAM, os ratos foram tratados com PS (100 mg/kg/dia) por gavagem por oito dias. Os animais foram depois sacrificados e os pulmões e VD foram coletados para análise do balanço redox (diferenças foram consideradas significativas quando p<0,05). Resultados Nossos resultados mostram que o IAM desencadeia a interrupção redox no VD e nos pulmões, o que pode contribuir para danos induzido pelo IAM nesses órgãos. Consistentemente, o PS mitigou o estresse oxidativo e restaurou as defesas antioxidantes (Glutationa - GSH nos pulmões: SHAM = 0,79 ± 0,07; IAM = 0,67 ± 0,05; IAM + PS = 0,86 ± 0,14; p<0,05), indicando seu papel protetor neste cenário. Conclusão Nosso trabalho evidencia o potencial do uso de PS como abordagem terapêutica adjuvante após IAM para proteção dos tecidos pulmonares e cardíacos direitos.

Abstract Background Pterostilbene (PS), a natural and antioxidant polyphenolic compound emerges as a promising intervention in improving the myocardial infarction (MI) damages. Objetives This study aimed to evaluate PS actions in promoting redox homeostasis in lungs and right ventricle (RV) of infarcted animals. Methods Male Wistar rats (60 day-old) were randomized into three groups: SHAM, MI (infarcted), and MI+PS (MI+pterostilbene). Seven days after MI procedure, rats were treated with PS (100 mg/kg/day) via gavage for eight days. Animals were euthanized and the lungs and RV were harvested for analyses of redox balance (Differences were considered significant when p<0.05). Results Our results show that MI triggers a redox disruption scenario in RV and lungs, which can contribute to MI-induced damage on these organs. Consistently, PS mitigated oxidative stress and restored antioxidant defenses (GSH in lungs: SHAM= 0.79±0.07; MI=0.67±0.05; MI+PS=0.86±0.14; p<0.05), indicating its protective role in this scenario. Conclusions Our work evidences the PS potential use as an adjuvant therapeutic approach after MI focusing on protecting pulmonary and right-sided heart tissues.

Mini review: immunologic functions of dual oxidases in mucosal systems of vertebrates / Minirrevisão: funções imunológicas de oxidases duplas em sistemas mucosos de vertebrados

Abstract Mucosal epithelial cells act as the first immunologic barrier of organisms, and contact directly with pathogens. Therefore, hosts must have differential strategies to combat pathogens efficiently. Reactive oxygen species (ROS), as a kind of oxidizing agents, participates in the early stage of killing pathogens quickly. Recent reports have revealed that dual oxidase (DUOX) plays a key role in mucosal immunity. And the DUOX is a transmembrane protein which produces ROS as their primary enzymatic products. This process is an important pattern for eliminating pathogens. In this review, we highlight the DUOX immunologic functions in the respiratory and digestive tract of vertebrates.

Resumo As células epiteliais da mucosa atuam como a primeira barreira imunológica dos organismos e entram em contato direto com os patógenos. Portanto, os hospedeiros devem ter estratégias diferenciadas para combater os patógenos de forma eficiente. Trabalhos recentes revelaram que a oxidase dupla (DUOX) desempenha um papel fundamental para a imunidade da mucosa. A DUOX é uma proteína transmembrana geradora de espécies reativas de oxigênio (EROs) como seus principais produtos enzimáticos. Nesta revisão, apresentaremos as funções imunológicas da DUOX no trato respiratório e digestivo dos vertebrados.

Application of MAO-A/B subtype activity detection in diagnosis and treatment of neurological diseases / 中国临床药理学与治疗学

The abnormal expression of monoamine oxidases (MAOs), which distributed on the outer mitochondrial membrane can cause the dysfunction of neurotransmitter delivery and related to mental and neurodegenerative diseases. Therefore, the specific detection of MAOs (MAO-A/B) and the regulation of their activities will contribute to the diagnosis and treatment of neurological diseases. In order to distinguish the two subtypes of MAO-A/B, fluorescence detection and imaging techniques with highly specific and sensitive properties have important biological relevance. Herein, our research group based on the concept of "spatial configuration conversion" have designed the two-photon small molecule fluorogenic probes of U1 and F1, which capable of specific fluorescence "Switch-ON" behaviour, and combined with two-photon fluorescence microscopic imaging technology to realize the activity detection of endogenous MAO-B/A in cells and tissues. It is hoped that this works will benefit the understanding of physiological function about MAOs and developing innovative inhibitors, as well as diagnosing and treating in neurological diseases.

Influence of Oxygen Supply on Growth and Laccases Production by Pleurotus sajor-caju PS-2001 in Submerged Process

Abstract (1) Background: Oxygen supply is an important parameter to be considered in submerged cultures. This study evaluated the influence of different conditions for dissolved oxygen (DO) concentration on laccases activities and growth of Pleurotus sajor-caju PS-2001 in submerged process in stirred-tank bioreactor. (2) Methods: Initially, three different conditions were tested: uncontrolled DO and minimum levels of 30% and 80% of saturation, with the pH controlled between 4.5 and 7.0. (3) Results: Best results were observed at 30% DO (26 U mL-1 of laccases at 96 h), whereas higher mycelial biomass was observed at 30% and 80% DO (above 4.5 g L-1). Four different conditions of DO (uncontrolled, 10%, 30% and 50% of saturation) were tested at pH 6.5, with higher laccases activity (80 U mL-1 at 66 h) and lower mycelial growth (1.36 g L-1 at 90 h) being achieved with DO of 30%. In this test, the highest values for volumetric productivity and specific yield factor were determined. Under the different pH conditions tested, the production of laccases is favoured at DO concentration of 30% of saturation, while superior DO levels favours fungal growth. (4) Conclusion: The results indicate that dissolved oxygen concentration is a critical factor for the culture of P. sajor-caju PS-2001 and has important effects not only on laccases production but also on fungal growth.

Significance of NADPH oxidases Nox2 and Nox4 expression in DSS induced mouse colitis / 安徽医科大学学报

Objective To investigate the expression and significance of NADPH oxidases Nox2 and Nox4 in mouse colitis. Methods Mouse colitis model was established by using six-to-eight-week-old 129S /SV mice. Mice were randomly divided into 3 groups: control group,1. 5％ dextran sulfate sodium (DSS) group and 3. 0％ DSS group (n = 10 for each group). All of them were fed for 7 days to adapt to the environment. After then,the control group was given drinking water only,colitis was induced by giving drinking water consisted of 1. 5％ DSS or 3. 0％ DSS for 6 days. Weight loss,disease activity index (DAI) and histology were used to quantify the severity of colon inflammation. Oxidative stress indicator,malondialdehyde (MDA) in serum was measured by biochemical methods. The mRNA levels of pro-inflammation cytokines (IL-1β,IL-6 and TNF-α) were quantified by real-time PCR. The protein and mRNA expression of Nox2 and Nox4 in colon tissue of mice was evaluated by immunohistochemistry and real-time PCR,respectively. Results There was no colitis in the control group,while mild and severe enteritis was found in mice in the 1. 5％ DSS group and 3. 0％ DSS group,respectively. The number of goblet cells was decreased significantly in the 1. 5％ DSS group than that of control group (P < 0. 05),and further reduced in the 3. 0％ DSS group (P < 0. 05). MDA was enhanced along with the increased concentration of DSS (P < 0. 05 for both). The expression of Nox2 and Nox4 protein and mRNA was different with the severity of inflammation. The expression of protein and mRNA of both Nox2 and Nox4 were increased in 1. 5％ DSS group compared with the control group (P < 0. 05),and further reduced in the 3. 0％ DSS group (P < 0. 05). Nox2 mostly expressed in the phagocytes and neutrophils; Nox4 mostly expressed in the neutrophils and lymphocytes. Conclusion Nox2 and Nox4 play an important role in the occurrence of mouse colitis.

The effects of NOX1 and NF-κB on TNF-α induced oxidative damage in A549 cells / 中国职业医学

OBJECTIVE: To investigate the effects of nicotinamide adenine dinucleoside phosphate oxidases 1(NOX1) and nuclear factor-kappa B(NF-κB) in tumor necrosis factor-α(TNF-α)-induced oxidative damage in A549 cells. METHODS: i) TNF-α was used to stimulated A549 cells at the concentrations of 0.0, 10.0, 25.0 and 50.0 μg/L. Cell inhibition rate in each group was tested by CCK-8 assay to select the appropriate concentration. ii) A549 cells in logarithmic growth phase were divided into blank control group, solvent control group, TNF-α group, diphenylene iodine(DPI) group and TNF-α+DPI group for NOX1 inhibitor experiment. Logarithmic growth phase A549 cells were divided into blank control group, TNF-α group, BAY11-7082 group and TNF-α+BAY11-7082 group for NF-κB inhibitor experiment. The relative expression of NOX1 and p65 protein in each group was detected by Western blot method. The relative expression of intracellular reactive oxygen species(ROS) were detected by flow cytometry. RESULTS: i) The inhibition rate of A549 cells increased with the increase of TNF-α dose(P<0.05), and 25.0 μg/L was selected as the stimulation dose of TNF-α in subsequent experiments. ii) The relative expression of NOX1, p65 protein and ROS in the TNF-α group was higher than that in the blank control group, solvent control group and DPI group, respectively(P<0.05). The above indexes in TNF-α+DPI group were lower than that in TNF-α group(P<0.05), but higher than that in DPI group(P<0.05). The relative expression of NOX1, p65 protein and ROS in the TNF-α group were higher than that in the blank control group and the BAY11-7082 group(P<0.05), while the above indicators in the TNF-α+BAY11-7082 group were lower than that in the TNF-α group(P<0.05). CONCLUSION: Inhibition of NOX1 or NF-κB can alleviate the oxidative damage induce by TNF-α in A549 cells.

Thermal Inactivation of Crude Polyphenol Oxidases and Peroxidase from Three Tissues of Yellow-fleshed Cassava (Manihot esculenta Crantz) Root cv. Bocou 2

Aims: The objective of this work was to study the thermal inactivation of the polyphenol oxidase (PPO) and peroxidase (POD) activities of cassava (Manihot esculentaCrantz) root cv. Bocou 2 in order to preventenzymatic browning.Study Design: Crude PPO and POD from yellow-fleshed cassava root were subjected to heat treatment and their thermal inactivation characteristics were examined.Place and Duration of the Study: The study was conducted at Biocatalysisand Bioprocesses Laboratory, Food Science and Technology Unit, Nangui Abrogoua University Abidjan, Côte d’Ivoire, between January and December 2015.Methodology: The crude PPO and POD were extracted from three tissues (cortex, cambium and central pith) ofyellow-fleshed cassava root cv. Bocou 2. The thermal inactivation of these enzymatic activities was evaluated between 50 and 70 °C. The kinetic data of thermal inactivation and thermodynamics were analysed. Results: The t1/2-and D-values decreased with increasing temperature, indicating a faster inactivation of PPO and POD at higher temperatures. Z-values ranged from 16.10 to 27.70 °C and activation energy (Ea) from 73.37 to 129.66 kJ mol-1. Thermodynamic investigations indicated that the oxidation reactions involving these enzyme activities were: not spontaneous (?G > 0), slightly endothermic (?H > 0) and reversible (?S < 0).Conclusion: The PPO and POD activities from yellow-fleshed cassava root decreased due to heat denaturation with increasing temperature from 60 to 70 °C. These kinetic data can be used to prevent enzymatic browning in cassava roots.

Alcohol promotes renal fibrosis by activating Nox-mediated DNA methylation of Smad7 / 中国药理学与毒理学杂志

OBJECTIVE Alcohol is mainly metabolized through liver and excreted by kidney in the body. Kidney damage has been considered as the secondary to liver injury and kidney dysfunction is common in hospitalized patients with severe alcoholic hepatitis. Both acute and chronic alcoholism accumulation can compromise kidney function, although alcoholic kidney disease has drawn much more attention recently,the methodology for establishing the in vivo and in vitro alcoholic renal fibrosis models are still lacking,and the underlying mechanisms are to be determined. METHODS and RESULTS Mice were feed with a liquid diet containing alcohol for 4 weeks, 8 weeks and 12 weeks respectively, results of Masson′s Trichrome staining showed that kidney fibrosis peaked in 8-week model group, which consistent with the results of albumin assay,Western blot,immunostaining and real-time PCR of collagen I and α-SMA.In vitro study also confirmed that ethanol upregulated the level of fibrotic index-es,including collagen I and α-SMA,in tubular epithelial cells(HK2 cells).Additionally,both in vivo and in vitro studies showed that Smad7 was decreased and Smad3 was highly activated. Then we further detected the underlying mechanisms by which alcohol induced the imbalance of Smad7 and Smad3. Results of Genome-wide methylation sequencing found DNA methylation of Smad7 in the alcoholic fibrosis kidney,which may be mainly mediated by DNA methyltransferase 1(DNMT1),because knock-down of DNMT1,but not DNMT2 and 3,largely restored Smad7 level in ethanol-treated HK2 cells.Con-sequently, we found that NADPH Oxidases (nox)-mediated oxidative stress is the major force upregu-lating DNMT1,since knockdown of Nox2 and 4 could both decrease DNMT1 while rebalancing Smad7/Smad3 axis, and thereby relieved ethanol-induced fibrotic response in HK2 cells. More importantly, intraperitoneal injection of apocynin,an inhibitor of NADPH oxidoreductase,attenuated renal fibrosis in alcoholic kidney fibrosis mouse model. CONCLUSION By establishing the novel in vivo and in vitro models,we found that through activating oxidative stress-induced DNA methylation of Smad7,alcohol induces renal fibrosis by breaking the balance between Smad7 and Smad3.Elimination of Nox-mediated oxidative stress may be a potential therapy for treatment of long-term alcohol abuse-induced kidney fibrosis.

Mini review: immunologic functions of dual oxidases in mucosal systems of vertebrates

Abstract Mucosal epithelial cells act as the first immunologic barrier of organisms, and contact directly with pathogens. Therefore, hosts must have differential strategies to combat pathogens efficiently. Reactive oxygen species (ROS), as a kind of oxidizing agents, participates in the early stage of killing pathogens quickly. Recent reports have revealed that dual oxidase (DUOX) plays a key role in mucosal immunity. And the DUOX is a transmembrane protein which produces ROS as their primary enzymatic products. This process is an important pattern for eliminating pathogens. In this review, we highlight the DUOX immunologic functions in the respiratory and digestive tract of vertebrates.

Resumo As células epiteliais da mucosa atuam como a primeira barreira imunológica dos organismos e entram em contato direto com os patógenos. Portanto, os hospedeiros devem ter estratégias diferenciadas para combater os patógenos de forma eficiente. Trabalhos recentes revelaram que a oxidase dupla (DUOX) desempenha um papel fundamental para a imunidade da mucosa. A DUOX é uma proteína transmembrana geradora de espécies reativas de oxigênio (EROs) como seus principais produtos enzimáticos. Nesta revisão, apresentaremos as funções imunológicas da DUOX no trato respiratório e digestivo dos vertebrados.

Tripterygium glycosides suppress colitis via NOXs-ROS-NLRP3 inflamma-tory signaling pathways / 中国病理生理杂志

AIM: To observe the effect of Tripterygium glycosides on NOXs-ROS-NLRP3 inflammatory signa-ling pathways in the colon tissue in dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) mice, and to investi-gate the underlying mechanisms.METHODS: BALB/c mice were used and the mouse model of UC was established by DSS induction.The mice were randomly divided into 5 groups (model group, low-, medium-and high-dose Tripterygium glycosides groups, and normal group).The colon tissues were collected 21 d after Tripterygium glycosides gavage.The mRNA expression of NLRP3, ASC and caspase-1 in the colon tissues was detected by real-time PCR.The caspase-1 ex-pression in the colorectal mucosa was observed by immunohistochemical method.ELISA was used to detect the protein le- vels of IL-1α, TNF-αand IL-13.The production of reactive oxygen species (ROS) was measured by chemiluminescence technique, and the consumption rate of NADPH, which was inhibited by DPI, was analyzed to determine the activity of NADPH oxidases (NOXs).The neutrophils were isolated, and the ROS production, NOXs activity, and the mRNA ex-pression of NLRP3, ASC and caspase-1 were also detected.RESULTS: The colon tissues were abnormal with different de-grees in Tripterygium glycosides groups, and histopathological scores were lower than that in model group.In Tripterygium glycosides groups, in addition to the mRNA expression levels of caspase-1 in the colon tissues between normal group and high-dose group, ROS production, NOXs activity and the mRNA expression levels of NLRP3, ASC and caspase-1 in the colon tissues and colon-isolated neutrophils were lower than those in model group (P <0.05), and higher than those in normal group (P <0.05).The results of pairwise comparison for the efficacy of Tripterygium glycosides administration showed that the above indexes were statistically significant except the mRNA expression levels of caspase-1 between middle-dose group and high-dose group.Tripterygium glycosides administration significantly decreased the expression levels of proinflammatory cytokines IL-1αand TNF-αin the homogenates of colon tissues in the model mice (P <0.05).No differ-ence of IL-13 expression among the groups was observed.CONCLUSION: Tripterygium glycosides inhibits NOXs-ROS-NLRP3 inflammatory signaling pathways to reduce the expression of IL-1α, TNF-αand other proinflammatory cytokines, and attenuates DSS-induced ulcerative colitis in mice, by which the neutrophils might be involved in the process.

Expression of vascular adhesion protein-1 in severe hemorrhagic shock and resuscitation in rats / 第二军医大学学报

Objective To observe the expression and activity changes of vascular adhesion protein-1 (VAP-1) in the small intestine and serum of rats during severe hemorrhagic shock and resuscitation, and to study its influence on shock prognosis. Methods Fifty rats were evenly randomized into sham group, hemorrhagic shock group, shock resuscitation group, control recovery group and the experimental recovery group. Rat models of severe hemorrhagic shock and resuscitation were established. Before shock, 1 hour after shock and 1 hour after resuscitation, the expressions of VAP-1 protein and mRNA in the intestinal tissues of rats were examined by Western blotting analysis and real-time RT-PCR, respectively; and the serum levels of VAP-1 and its activities were determined by ELISA kit. Rats in the experimental recovery group was resuscitated by injection of 20 mg/kg 2-bromoethylamine and those in the control recovery group were given 1 mL/kg normal saline, and then the blood pressure, intestinal mucosa injury (Chiu’s score), small intestinal epithelial cell apoptosis (TUNEL detection) and 24-hour survival rates were compared between the two recovery groups. Results The intestinal VAP-1 protein and mRNA expressions and the serum VAP-1 and its activities in the severe hemorrhagic shock group were significantly higher than those in the sham shock group (P<0.05). Compared with the shock group, the above parameters were decreased in the recovery group, but were still higher than those in the sham group. Compared with the saline control group, 20 mg/kg 2-bromoethylamine significantly increased the blood pressure of animals 1 h and 24 h after recovery (P = 0.010, 0.039), significantly improved the Chiu’s score and apoptosis index of small intestinal epithelial cells (P = 0.022, P = 0.002), and improved the 24-hour survival rates of rats(90% to 60%). Conclusion The levels of VAP-1 and its activities are increased in severe hemorrhagic shock rats, and fluid resuscitation can inhibit this increase. Inhibition of VAP-1 activities can improve the low blood pressure, intestinal mucosa injury and apoptosis of small intestinal mucosa cells after the severe hemorrhagic shock and resuscitation, improving the 24-hour survival rates of rats.

Research progress of targeting HO-1/NOX2 pathway for the treatment of Parkinson's disease / 中国药学杂志

Accumulating evidence strongly supports the involvement of oxidative stress in the etiology of Parkinson's disease (PD). ROS derived from the NOX2-containing NADPH oxidase play important role in the pathogenesis of PD. Our intent was to review the research history about the role of NOX2-containing NADPH oxidase in PD. Neuroprotective effect of heme oxygenase-1 (HO-1) in protecting neurons against PD-related neurotoxin-induced oxidative stress dependant injury, and a major emphasis has been on the relationship between HO-1 and NOX2-containing NADPH oxidase. Specific activation of HO-1 gene expression by pharmacological modulation may represent a novel target for therapeutic treatment of PD through inhibiting NOX/ROS. A new target for PD therapy through inhibiting NOX/ROS, thereby modulating HO-1/NOX2 axis is highlighted.

Snake venom L-amino acid oxidases: an overview on their antitumor effects

The L-amino acid oxidases (LAAOs) constitute a major component of snake venoms and have been widely studied due to their widespread presence and various effects, such as apoptosis induction, cytotoxicity, induction and/or inhibition of platelet aggregation, hemorrhage, hemolysis, edema, as well as antimicrobial, antiparasitic and anti-HIV activities. The isolated and characterized snake venom LAAOs have become important research targets due to their potential biotechnological applications in pursuit for new drugs of interest in the scientific and medical fields. The current study discusses the antitumor effects of snake venom LAAOs described in the literature to date, highlighting the mechanisms of apoptosis induction proposed for this class of proteins.

Snake venom L-amino acid oxidases: an overview on their antitumor effects

The L-amino acid oxidases (LAAOs) constitute a major component of snake venoms and have been widely studied due to their widespread presence and various effects, such as apoptosis induction, cytotoxicity, induction and/or inhibition of platelet aggregation, hemorrhage, hemolysis, edema, as well as antimicrobial, antiparasitic and anti-HIV activities. The isolated and characterized snake venom LAAOs have become important research targets due to their potential biotechnological applications in pursuit for new drugs of interest in the scientific and medical fields. The current study discusses the antitumor effects of snake venom LAAOs described in the literature to date, highlighting the mechanisms of apoptosis induction proposed for this class of proteins.

Flavoproteínas que actúan como amino-oxidasas: Estructura, función e importancia clínica / Flavoproteins acting as amine oxidases: Structure, function and clinical significance / Flavoproteínas atuando como amina oxidases: Estrutura, função e significado clínico

Se destaca la actividad de las flavoenzimas como amino-oxidasas, que intervienen en el metabolismo de las aminas biogénicas como biorreguladores, especialmente en el crecimiento y la diferenciación celular. La clasificación de las amino-oxidasas incluye flavoenzimas y quinoenzimas. Se analizan las amino-oxidasas que son flavoproteínas, como las monoamino-oxidasas y las poliamino-oxidasas. Se discuten las isoformas, estructuras y función de ambas, sus sustratos e inhibidores, la expresión de MAO-A y MAO-B en tejidos humanos y sus implicancias clínicas. MAO plaquetaria es un biomarcador de desórdenes mentales y neurodegenerativos. Los inhibidores selectivos de MAO-A resultaron ser eficaces antidepresivos, mientras que algunos de MAO-B se utilizan en el tratamiento de enfermedades de Parkinson y de Alzheimer. La identificación de elevadas concentraciones de poliaminas en varias enfermedades, desde cáncer y psoriasis hasta infecciones parasitarias, hace que la manipulación de su metabolismo sea un blanco terapéutico o preventivo en ciertas enfermedades. Se discute además qué poliamino-oxidasas actúan en el metabolismo de las poliaminas en humanos, frente a las presentes en plantas, bacterias y protistas. Las poliaminas y las enzimas de su metabolismo desempeñan funciones relevantes en los procesos de envejecimiento y en algunas enfermedades, como cáncer, diabetes mellitus, accidentes cerebro-vasculares, insuficiencia renal y trastornos psiquiátricos.

The activity of flavoenzymes as amine oxidases involved in the metabolism of biogenic amines as bioregulators is highlighted, particularly for cell growth and differentiation. The classification of amine oxidases includes flavoenzymes and quinoenzymes. Amine oxidases that are flavoproteins, such as monoamine oxidases and polyamine oxidases, are analyzed herein. The isoforms, structures and functions of both enzyme families, their substrates and inhibitors, the expression of MAO-A and MAO-B in human tissues, and their clinical implications are discussed. Platelet MAO is a biomarker of mental and neurodegenerative disorders. Selective MAO-A inhibitors proved to be effective antidepressants, while some MAO-B inhibitors are used for treatment of Parkinson's and Alzheimer's diseases. The identification of high concentrations of polyamines in a variety of diseases, from psoriasis to cancer and parasitic infections, makes handling their metabolism a therapeutic or preventive target for the treatment of some diseases. Also polyamine oxidase activity on polyamine metabolism in humans, compared to those present in plants, bacteria and protists,is discussed. Polyamines and the enzymes involved in their metabolism play important roles in the aging processes, as well as in certain diseases such as cancer, diabetes mellitus, stroke, kidney failure, and defined psychiatric disorders.

Foi enfatizada a atividade de flavoenzimas como as amina oxidases envolvidas no metabolismo de aminas biogênicas como biorreguladores, especialmente no crescimento e diferenciação celular. A classificação das amina oxidases inclui flavoenzimas e quinoenzimas. Amina oxidases que são flavoproteínas, tais como monoamina oxidases e poliamina oxidases, são analisadas. Isoformas, estrutura e função das duas oxidases são discutidas, os seus substratos e inibidores, a expressão de MAO-A e MAO-B em tecidos humanos e suas implicações clínicas. MAO plaquetária é um biomarcador de desordens mentais e neurodegenerativas. Os inibidores selectivos da MAO-A resultaram ser eficazes antidepressivos, embora alguns dos MAO-B sejam utilizados no tratamento da doença de Parkinson e de Alzheimer. A identificação de elevadas concentrações de poliaminas em várias doenças, desde câncer e psoríase a infecções parasitárias, faz com que a manipulação do seu metabolismo seja um alvo terapêutico ou preventivo em certas doenças. Também se discute que a poliamina oxidase atua sobre o metabolismo das poliaminas no ser humano, em comparação com aquelas presentes em plantas, bactérias e protistas. As poliaminas e enzimas do seu metabolismo desempenham papéis relevantes nos processos de envelhecimento e em algumas doenças, tais como câncer, diabetes miellitus, acidente vascular cerebral, insuficiência renal e perturbações psiquiátricas.

Hydrogen/rydride ion relay - a mechanism for early electron transfer in cytochrome c oxidases / El reléuónico hidrógeno-hidruro: un mecanismo de transferencia temprana de electrones en las citocromo c oxidasas

Cytochrome c oxidase (COX) employs electrons obtained from cytochrome c to bring about the reduction of oxygen to water. It is known that the electrons originate from the haem edge of cytochrome c and enters bovine COX at Trp-104. It is also known that Tyr-105, Glu-198 and Asp-158 of COX subunit II play roles in the enzyme's catalysis but how these roles are linked to electron transfer remain unclear. Recently, we proposed that electrons travel from the haem edge of cytochrome c to CuA, the first metal redox centre of COX, by a hydrogen/hydride ion relay using six residues. Now using a similar computer assisted approach, we investigate the extent to which this hydride/hydrogen ion mechanism is common amongst oxidases. The crystal structures of COX from P denitrificans, R sphaeroides and T thermophilus and quinol oxidase from E coli were downloaded and their binding domains analysed. As with bovine, all four oxidases had only nine amino acid residues in that region and both the sequences and three-dimensional structures were highly conserved. We propose that these residues function as a hydrogen/hydride ion relay, participating directly in electron transfer to CuA. We further suggest that this electron transfer mechanism might be a common feature in oxidases.

La citocromo c oxidasa (COX) emplea electrones obtenidos del citocromo c para producir la reducción del oxígeno a agua. Se sabe que los electrones originan a partir del hemo del citocromo c, y entran en la COX bovina en Trp-104. También se conoce que Tyr-105, Glu-198 y Asp-158 de la subunidad II de COX, desempeñan papeles en la catálisis de la enzima, pero no hay todavía claridad en cuanto a cómo estos papeles se hallan vinculados con la transferencia de electrones. Recientemente, sugerimos que los electrones viajan del borde del hemo del citocromo c al CuA, el primer centro metálico de reacción redox de la COX, por un relé iónico hidrógeno-hidruro, usando seis residuos. Ahora, usando un enfoque similar computarizado, investigamos hasta que punto este mecanismo de iones hidrógeno/hidruro es común entre las oxidasas. Se bajaron y analizaron los dominios de unión de las estructuras cristalinas de la COX de P denitrificans, R sphaeroides, y T thermophilus, y de la quinol oxidasa de la E coli. Como en el caso de la bovina, las cuatro oxidasas tenían sólo nueve residuos de aminoácido en esa región, y tanto las secuencias como las estructuras tridimensionales presentaban un alto grado de conservación. Proponemos que estos residuos funcionan como un relé iónico hidrógeno-hidruro, participando directamente en una transferencia de electrones al CuA. Asimismo, sugerimos que este mecanismo de transferencia de electrones podría ser un rasgo común de las oxidasas.

Línea básica de susceptibilidad y efecto sinérgico a los insecticidas malation y pirmifos-metil en adultos de Culex spp. Say, 1823 (Díptera: Culicidae) del municipio Mario Briceño Iragorry del estado Aragua, Venezuela / Baseline susceptibility and synergistic effect to the insecticides malathion and pirmiphos-methyl in adults of Culex spp. Say, 1823 (Diptera: Culicidae) Mario Briceño Iragorry municipality, Aragua state, Venezuela

Se evaluó la respuesta a los insecticidas organofosforados malatión y pirimifos-metil en poblaciones de campo de adultos Culex spp. del Municipio Mario Briceño Iragorry del Estado Aragua. Se realizaron los bioensayos en botellas tratadas con insecticidas. La determinación del tiempo-mortalidad, permitió obtener la línea base de susceptibilidad de los insecticidas evaluados. Se definió la dosis diagnóstica como la menor dosis que mata el mayor porcentaje de los insectos expuestos. El número de sobrevivientes a los 60 minutos de exposición a dichas dosis fue considerado como criterio de resistencia definiéndose dicho tiempo, como el umbral de resistencia. Los mosquitos resultaron resistentes a malatión a las concentraciones 0,1; 1 y 5 μg/mL con valores de TL100= 90; 90 y 75 minutos respectivamente y susceptibles a pirimifos-metil a las concentraciones 1 y 5 μg/mL con valores TL100= 30 y 15 minutos respectivamente, a la concentración 0,1 μg/mL se obtuvo TL100= 75 lo cual no se estimó por ser una dosis baja. Las concentraciones 5 μg/mL de malatión, 0, μg/ml de pirimifos-metil se sugieren como dosis referenciales. Se identificaron mecanismos de resistencia con el sinergista butóxido de piperonilo (PB) a las concentraciones de malatión 1 y 5 μg/mL con FS = 2 y 2,5 respectivamente. Las enzimas de multifunción oxidasa (MFO) juegan un papel importante en la resistencia al insecticida malation. Los resultados obtenidos, aportan información básica para futuros programas de control de Culex spp., si fuese necesario, debido a su importancia como plaga de ambientes turísticos y como vector de Filariasis (bancroftiasis) y Fiebre del Nilo.

We evaluated the response to the organophosphorus insecticides malathion and pirimiphos-methyl in field populations of adult Culex spp. Mario Briceño Iragorry Municipality Aragua state. Bioassays were carried out using the bottles treated with insecticides. The time-mortality determination allowed us to obtain the baseline susceptibility of the insecticides evaluated. Diagnostic dose was defined as the lowest dose that kills the highest percentage of exposed insects. Survivors after 60 minutes of exposure to these doses was considered as resistance criterion defining this time, as the threshold of resistance. The mosquitoes were resistant to malathion at concentrations 0.1; 1 and 5 μg/mL with values of TL100= 90; 90 and 75 minutes respectively and susceptible to pirimiphos-methyl at concentrations 1 and 5 μg/mL with values of TL100= 30 and 15 minutes respectively, was obtained at the concentration 0.1 μg /mL TL100= 75 which was not considered to be a low dose. The concentrations 5 μg /mL of malathion, 0.1 μg / ml of pirimiphos-methyl are suggested as a reference dose. Resistance mechanisms were identified with the synergist piperonyl butoxide (PB) at concentrations of malathion 1 and 5 μg/mL with FS = 2 and 2.5 respectively. Multifunction oxidase enzymes (MFO) play an important role in resistance to the insecticide malathion. The obtained results provide basic information for future monitoring programs of Culex spp, if necessary, due to its importance as a pest of tourist environments and as a vector of Filariasis (bacroftiosis) and West Nile Fever.