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1.
Int. j. morphol ; 41(1): 79-84, feb. 2023. ilus, graf
Article in English | LILACS | ID: biblio-1430536

ABSTRACT

SUMMARY: Paracetamol (known as acetaminophen, or APAP) poisoning causes acute liver damage that can lead to organ failure and death. We sought to determine that APAP overdose can augment tumor necrosis factor-alpha (TNF-α)/ nuclear factor kappa B (NF-kB)/induced nitic oxide synthase (iNOS) axis-mediated hepatotoxicity in rats, and the anti-inflammatory polyphenolic compounds, quercetin (QUR) plus resveratrol (RES) can ameliorate these parameters. Therefore, we induced acute hepatotoxicity in rats using APAP overdose (2 g/kg, orally) and the protective group of rats were treated with 50 mg/kg QUR plus 30 mg/kg RES for one week before APAP ingestion. Animals were killed at day 8. APAP poisoning caused the induction of hepatic tissue levels of TNF-α, NF-kB, and iNOS, which were significantly (p<0.05) decreased by QUR+RES. QUR+RES, also inhibited liver injury biomarkers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, a link between liver injury and TNF-α /NF-kB / iNOS axis mediated hepatotoxicity was observed. Thus, the presented data backing the conclusion that intoxication by paracetamol increases TNF-α / NF-kB / iNOS axis -mediated hepatotoxicity, and is protected by a combination of quercetin and resveratrol.


El envenenamiento por paracetamol (conocido como acetaminofeno o APAP) causa daño hepático agudo que puede provocar una insuficiencia orgánica y la muerte. El objetivo de este trabajo fue determinar si la sobredosis de APAP puede aumentar la hepatotoxicidad mediada por el eje del factor de necrosis tumoral alfa (TNF-α)/factor nuclear kappa B (NF-kB)/óxido nítico sintasa inducida (iNOS) en ratas, y si el polifenólico antiinflamatorio compuesto por quercetina (QUR) más resveratrol (RES) pueden mejorar estos parámetros. Por lo tanto, inducimos hepatotoxicidad aguda en ratas usando una sobredosis de APAP (2 g/kg, por vía oral). El grupo protector de ratas se trató con 50 mg/ kg de QUR más 30 mg/kg de RES durante una semana antes de la ingestión de APAP. Los animales se sacrificaron el día 8. El envenenamiento con APAP en el tejido hepático provocó la inducción de niveles de TNF-α, NF-kB e iNOS, que se redujeron significativamente (p<0,05) con QUR+RES. QUR+RES, también inhibió los biomarcadores de daño hepático, la alanina aminotransferasa (ALT) y el aspartato aminotransferasa (AST). Además, se observó una relación entre la lesión hepática y la hepatotoxicidad mediada por el eje TNF-α /NF-kB/iNOS. Por lo tanto, los datos presentados respaldan la conclusión de que la intoxicación por paracetamol aumenta la hepatotoxicidad mediada por el eje TNF-α /NF-kB / iNOS, y está protegida por una combinación de quercetina y resveratrol.


Subject(s)
Animals , Rats , Quercetin/administration & dosage , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Resveratrol/administration & dosage , Acetaminophen/toxicity , Acute Disease , NF-kappa B/antagonists & inhibitors , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Rats, Sprague-Dawley , Nitric Oxide Synthase/antagonists & inhibitors , Protective Agents , Drug Therapy, Combination , Drug Overdose
2.
Chinese Medical Journal ; (24): 2521-2537, 2023.
Article in English | WPRIM | ID: wpr-1007613

ABSTRACT

Long-chain acyl-coenzyme A (CoA) synthase 4 (ACSL4) is an enzyme that esterifies CoA into specific polyunsaturated fatty acids, such as arachidonic acid and adrenic acid. Based on accumulated evidence, the ACSL4-catalyzed biosynthesis of arachidonoyl-CoA contributes to the execution of ferroptosis by triggering phospholipid peroxidation. Ferroptosis is a type of programmed cell death caused by iron-dependent peroxidation of lipids; ACSL4 and glutathione peroxidase 4 positively and negatively regulate ferroptosis, respectively. In addition, ACSL4 is an essential regulator of fatty acid (FA) metabolism. ACSL4 remodels the phospholipid composition of cell membranes, regulates steroidogenesis, and balances eicosanoid biosynthesis. In addition, ACSL4-mediated metabolic reprogramming and antitumor immunity have attracted much attention in cancer biology. Because it facilitates the cross-talk between ferroptosis and FA metabolism, ACSL4 is also a research hotspot in metabolic diseases and ischemia/reperfusion injuries. In this review, we focus on the structure, biological function, and unique role of ASCL4 in various human diseases. Finally, we propose that ACSL4 might be a potential therapeutic target.


Subject(s)
Humans , Ferroptosis , Apoptosis , Phospholipids/metabolism , Nitric Oxide Synthase
3.
Int. j. morphol ; 39(2)abr. 2021. 659^c666
Article in English | LILACS | ID: biblio-1385365

ABSTRACT

SUMMARY: The aim of this study was to determine the relationship of autophagy-enhancing rapamycin (RAPA) and autophagy- inhibitor 3-methyladenine (3-MA) with Nitric oxide synthases (NOS) in Cisplatin (CIS)-induced neurotoxicity in rats. Rats were divided into 4 groups (n=10): Control was applied saline, CIS (a single dose of 8mg/kg intraperitoneal (i.p.) on 7th day of experiment), RAPA+CIS (2 mg/kg/i.p. RAPA per day and 8 mg/kg/i.p. CIS on 7th day), 3-MA+CIS (15 mg/kg/i.p. 3-MA per day and 8 mg/kg/i.p. CIS on 7th day). Rats were sacrificed under anesthesia. Brain tissues were evaluated histopathologically. eNOS, Inos, nNOS and MAP 2 immunostaining were performed to determine the expression levels of these proteins among groups. Superoxide dismutase (SOD), Catalase (CAT), Malondialdehyde (MDA) and Interleukin IL-6 levels in brain tissue and serum nitric oxide (NO) level were measured by ELISA assay. In histopathological evaluation, neurodegeneration was seen in the CIS group. There was an increase in eNOS, iNOS and nNOS immunostaining in CIS group. While MAP2 immunostaining of the CIS group decreased. There was a decrease in SOD and CAT levels of brain tissue in CIS group. However, there was an increase in MDA, IL-6 and NO levels of brain tissue in CIS group. We found that antioxidant capacity increase while, inflammation and nitric oxide levels decreased in the RAPA-treated group. 3-MA does not have a significant effect. We suggest that CIS-induced neurotoxicity is more effective than Rapa 3-MA and may also be linked to NOS enzymes.


RESUMEN: El objetivo de este estudio fue determinar la relación de la rapamicina potenciadora de la autofagia (RAPA) y el inhibidor de la autofagia 3-metiladenina (3-MA) con óxido nítrico sintasas (NOS) en la neurotoxicidad inducida por cisplatino (CIS) en ratas. Las ratas se dividieron en 4 grupos (n = 10): grupo control se aplicó solución salina, CIS (una dosis única de 8 mg / kg intraperitoneal (ip) el día 7 del experimento), RAPA + CIS (2 mg / kg / ipRAPA por día y 8 mg / kg / ip CIS el día 7), 3-MA + CIS (15 mg / kg / ip 3-MA por día y 8 mg / kg / ip CIS el día 7). Las ratas se sacrificaron bajo anestesia y los tejidos cerebrales fueron analizados histopatológicamente. Se realizaron inmunotinciones con eNOS, Inos, nNOS y MAP 2 para determinar los niveles de expre- sión de estas proteínas entre los grupos. Se midieron los niveles de superóxido dismutasa (SOD), catalasa (CAT), malondialdehído (MDA) e interleucina IL-6 en el tejido cerebral y el nivel de óxido nítrico (NO) en suero mediante ensayo ELISA. En la evaluación histopatológica, se observó neurodegeneración en el grupo CIS. Hubo un aumento en la inmunotinción de eNOS, iNOS y nNOS en el grupo CIS. Mientras que la inmunotinción de MAP2 del grupo CIS disminuyó. Hubo una disminución en los niveles de SOD y CAT del tejido cerebral en el grupo CIS, sin embargo, hubo un aumento en los niveles de MDA, IL-6 y NO en el tejido cerebral en el grupo CIS. Observamos que la capacidad antioxidante aumentó, mientras que la inflamación y los niveles de óxido nítrico disminuyeron en el grupo tratado con RAPA. 3-MA no tiene un efecto significativo. Sugerimos que la neurotoxicidad inducida por CIS es más eficaz que Rapa 3-MA y también puede estar relacio- nada con las enzimas NOS.


Subject(s)
Animals , Male , Rats , Adenine/analogs & derivatives , Cisplatin/toxicity , Nitric Oxide Synthase/drug effects , Sirolimus/pharmacology , Neurotoxicity Syndromes , Superoxide Dismutase , Enzyme-Linked Immunosorbent Assay , Immunohistochemistry , Adenine/pharmacology , Catalase , Interleukin-6 , Rats, Wistar , Malondialdehyde , Antineoplastic Agents/toxicity
4.
West Indian med. j ; 69(1): 26-31, 2021. tab
Article in English | LILACS | ID: biblio-1341861

ABSTRACT

ABSTRACT Objective: Right-heart function is a major determinant of clinical outcome in patients with elevated pulmonary artery pressure due to pulmonary venous hypertension (PVH) and pulmonary arterial hypertension (PAH). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. This study aimed to evaluate if different types of pulmonary hypertension (PH) would cause the same effect on right-heart functions and serum ADMA levels in female patients. Methods: This study included patients with PAH as group I, patients with PVH due to mitral stenosis (mitral valve area ≤ 1.5 cm2, without any additional valve or left-heart disease and systolic pulmonary artery pressure ≥ 50 mmHg in transthoracic echocardiography) as group II, and healthy control subjects as group III. Transthorasic echocardiographic evaluations for right-heart functions were performed according to the guidelines of the American Society of Echocardiography. Venous blood samples were collected, and the serum ADMA concentrations were obtained with the ELISA kit (DRG® International Inc., Springfield, NJ, USA). Results: Patients in groups I and II had higher ADMA levels than healthy control subjects. Right-atrium area and dimensions, right-ventricular (RV) volumes, grade of tricuspid regurgitation, systolic pulmonary arterial pressure, RV wall thickness, and RV outflow tract diameters were significantly higher in group I patients than in group II patients. Right-ventricular myocardial performance index was lower, and RV fractional area change and tricuspid valve systolic tissue Doppler velocity were higher in group II patients than in group I patients. Conclusion: This study demonstrated that both PAH and PVH caused increase in right-heart dimensions and impairment in right-heart functions.


Subject(s)
Humans , Female , Adolescent , Adult , Middle Aged , Aged , Young Adult , Arginine/analogs & derivatives , Nitric Oxide Synthase , Hypertension, Pulmonary/physiopathology , Echocardiography , Ventricular Dysfunction, Right
5.
Acta cir. bras ; 36(8): e360806, 2021. graf
Article in English | LILACS, VETINDEX | ID: biblio-1339008

ABSTRACT

ABSTRACT Purpose: To assess the biochemical, histological, histomorphometric and molecular effects of biliary duct ligation (BDL) induced liver cirrhosis in the heart and kidneys. Methods: Thirty-two weaning rats (21 days old, 50-70 g) underwent BDL and were divided in four groups (euthanasia after two, four, six, and eight weeks, respectively) and compared to control groups. Results: The animals' hearts of group 3 were bigger than those of the control group (p=0.042), including thinner right ventricle wall, decreased internal diameter of ventricles, and increased perivascular collagen deposition in left ventricle, as well as increased interstitial collagen in right ventricle after six weeks. In the kidneys of groups 3 and 4, bilirubin impregnation in the tubules, hydropic degeneration, loss of nuclei and lack of plasmatic membrane limits were noted. Nitric oxide synthase (NOS) gene expressions were higher in group 1 (p=0.008), and endothelial nitric oxide synthase (eNOS) gene expressions were elevated in all experimental groups (p=0.008, p=0.001, p=0.022, and p=0.013, respectively). In the heart, a decreased expression of eNOS in group 1 (p=0.04) was observed. Conclusions: Liver cirrhosis leads to histological and histomorphometric alterations in the heart and kidneys, with changes in the NOS and eNOS gene expressions, that may suggest a role in the associated myocardial and renal manifestations.


Subject(s)
Animals , Rats , Nitric Oxide Synthase , Liver Cirrhosis , Rats , Rats, Sprague-Dawley , Disease Models, Animal , Nitric Oxide Synthase Type III , Kidney
6.
Mem. Inst. Oswaldo Cruz ; 116: e200417, 2021. tab, graf
Article in English | LILACS | ID: biblio-1154880

ABSTRACT

BACKGROUND Toxoplasma gondii causes toxoplasmosis and is controlled by activated macrophages. However, infection of macrophages by tachyzoites induces TGF-β signaling (TGF-s) inhibiting nitric oxide (NO) production. NO inhibition may be a general escape mechanism of distinct T. gondii strains. OBJECTIVES To evaluate in activated macrophages the capacity of T. gondii strains of different virulence and genetics (RH, type I; ME-49, type II; VEG, type III; P-Br, recombinant) to evade the NO microbicidal defense system and determine LC3 loading to the parasitophorous vacuole. METHODS Activated peritoneal macrophages were infected with the different T. gondii strains, NO-production was evaluated by the Griess reagent, and inducible nitric oxide synthase expression, TGF-s, and LC3 localisation assayed by immunofluorescence. FINDINGS Only RH persisted in macrophages, while VEG was more resistant than P-Br and ME-49. All strains induced TGF-s, degradation of inducible nitric oxide synthase, and NO-production inhibition from 2 to 24 h of infection, but only RH sustained these alterations for 48 h. By 24 h of infection, TGF-s lowered in macrophages infected by ME-49, and P-Br, and NO-production recovered, while VEG sustained TGF-s and NO-production inhibition longer. LC3 loading to parasitophorous vacuole was strain-dependent: higher for ME-49, P-Br and VEG, lower for RH. All strains inhibited NO-production, but only RH sustained this effect probably because it persisted in macrophages due to additional evasive mechanisms as lower LC3 loading to parasitophorous vacuole. MAIN CONCLUSIONS These results support that T. gondii can escape the NO microbicidal defense system at the initial phase of the infection, but only the virulent strain sustain this evasion mechanism.


Subject(s)
Animals , Mice , Toxoplasma/physiology , Macrophages, Peritoneal/parasitology , Nitric Oxide Synthase/metabolism , Macrophages/parasitology , Nitric Oxide/biosynthesis , Toxoplasmosis, Animal/parasitology , Macrophages/metabolism
7.
Int. j. morphol ; 38(5): 1217-1222, oct. 2020. graf
Article in English | LILACS | ID: biblio-1134428

ABSTRACT

SUMMARY: Repeated stress is a risk factor for memory impairment and neurological abnormalities in both humans and animals. We sought to investigate the extent of (i) brain tissue injury; (ii) nitrosative and oxidative stress in brain tissue homogenates; (iii) apoptotic and survival biomarkers in brain tissue homogenates; and (iv) immobility and climbing abilities, induced over a period of three weeks by chronic unpredictable stress (CUS). Wistar rats were either left untreated (Control group) or exposed to a variety of unpredictable stressors daily before being sacrificed after 3 weeks (model group). Assessment of depression-like behavior was performed and animals were then culled and harvested brain tissues were stained with basic histological staining and examined under light microscopy. In addition, brain tissue homogenates were prepared and assayed for these parameters; inducible nitric oxide synthase (iNOS), malondialdehyde (MDA), superoxide dismutase (SOD), caspase-3, and B-cell lymphoma 2 (Bcl-2). Histology images showed CUS induced profound damage to the cerebral cortex as demonstrated by severe neuronal damage with shrunken cells, disrupted atrophic nuclei, perineuronal vacuolation and swollen glial cells. CUS also significantly (p<0.05) induced iNOS, MDA, and caspase-3, whereas SOD and Bcl-2 brain tissue levels were inhibited by CUS. In addition, data from the depression-like behavior, forced swimming test showed significant (p<0.05) increase in animal immobility and decrease in climbing ability in the model group of rats. Thus, here we demonstrated a reliable rat model of chronic stress-induced brain injury, which can further be used to investigate beneficial drugs or agents used for a period of three weeks to protect against CUS-induced brain damage.


RESUMEN: El estrés crónico es un factor de riesgo para el deterioro de la memoria y las anomalías neurológicas tanto en humanos como en animales. Intentamos investigar el alcance de lesión del tejido cerebral; (ii) estrés nitrosativo y oxidativo en homogeneizados de tejido cerebral; (iii) biomarcadores apoptóticos y de supervivencia en homogeneizados de tejido cerebral; y (iv) inmovilidad y habilidades de escalada, inducidas durante un período de tres semanas por estrés crónico impredecible (ECI). Se dejaron sin tratamiento (grupo control) ratas Wistar, o se expusieron a una variedad de factores estresantes impredecibles diariamente antes de ser sacrificadas después de 3 semanas (grupo modelo). Se realizó una evaluación del comportamiento similar a la depresión y luego se sacrificaron los animales y se tiñeron los tejidos cerebrales con tinción histológica básica y se examinaron con microscopía óptica. Además, se prepararon homogeneizados de tejido cerebral y se analizaron los siguientes parámetros; óxido nítrico sintasa inducible (iNOS), malondialdehído (MDA), superóxido dismutasa (SOD), caspasa- 3 y linfoma de células B 2 (Bcl-2). Las imágenes histológicas mostraron que el CUS indujo un daño profundo en la corteza cerebral como lo demuestra el daño neuronal severo con células encogidas, núcleos atróficos alterados, vacuolación perineuronal y células gliales inflamadas. ECI también indujo significativamente (p <0,05) iNOS, MDA y caspase-3, mientras que los niveles de tejido cerebral SOD y Bcl-2 fueron inhibidos por ECI. Además, los datos del comportamiento similar a la de- presión, la prueba de natación forzada mostró un aumento significativo (p <0,05) en la inmovilidad animal y una disminución en la capacidad de escalada en el grupo modelo de ratas. Por lo tanto, aquí demostramos un modelo confiable de daño cerebral crónico en rata inducido por el estrés, que se puede utilizar para investigar medicamentos o agentes beneficiosos usados durante un período de tres semanas para proteger el daño cerebral inducido por ECI.


Subject(s)
Animals , Male , Rats , Stress, Psychological/complications , Brain Damage, Chronic/pathology , Superoxide Dismutase/analysis , Behavior, Animal , Brain Injuries/metabolism , Biomarkers , Cerebral Cortex , Chronic Disease , Analysis of Variance , Rats, Wistar , Apoptosis , Oxidative Stress , Nitric Oxide Synthase/analysis , Proto-Oncogene Proteins c-bcl-2 , Depression , Disease Models, Animal , Caspase 3/analysis , Nitrosative Stress , Malondialdehyde/analysis
8.
Acta cir. bras ; 35(2): e202000205, 2020. graf
Article in English | LILACS | ID: biblio-1130618

ABSTRACT

Purpose To investigate the effects of induction of selective liver hypothermia in a rodent model. Methods Seven male Wistar rats were subjected to 90 minutes of partial 70% liver ischemia and topic liver 26°C hypothermia (H group). Other seven male Wistar rats were subjected to 90 minutes of partial 70% normothermic liver ischemia (N group). Five additional rats underwent a midline incision and section of liver ligaments under normothermic conditions and without any liver ischemia (sham group). All animals were sacrificed 24-h after reperfusion, and livers were sampled for analyses. Pathology sections were scored for sinusoidal congestion, ballooning, hepatocelllular necrosis and the presence of neutrophilic infiltrates. Results At the end of the experiment, liver tissue expressions of TNF-ɑ, IL-1β, iNOS and TNF-ɑ/IL-10 ratio were significantly reduced in the H group compared to N group, whereas IL-10 and eNOS were significantly increased in H group. Histopathological injury scores revealed a significant decrease in ischemia/reperfusion (I/R) injuries in H group. Conclusion Selective liver hypothermia prevented I/R injury by inhibiting the release of inflammatory cytokines, preserves microcirculation, prevents hepatocellular necrosis and leukocyte infiltration, allowing maintenance of the liver architecture.


Subject(s)
Animals , Male , Rats , Reperfusion Injury/prevention & control , Acute Lung Injury/prevention & control , Hypothermia, Induced/methods , Liver/blood supply , Body Temperature , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Cytokines/metabolism , Tumor Necrosis Factor-alpha , Rats, Wistar , Inflammation Mediators/metabolism , Nitric Oxide Synthase/metabolism , Disease Models, Animal , Acute Lung Injury/pathology , Ischemia/pathology , Liver/pathology , Necrosis/pathology , Nitric Oxide/metabolism
9.
Braz. J. Pharm. Sci. (Online) ; 56: e18636, 2020. tab, graf
Article in English | LILACS | ID: biblio-1132060

ABSTRACT

This study was initiated to determine whether 2 structurally related flavonoids found in Cyclopia subternata-vicenin-2 (VCN) and scolymoside (SCL)-could modulate renal functional damage in a mouse model of sepsis, and to elucidate the relevant underlying mechanisms. The potential of VCN and SCL treatment to reduce renal damage induced by cecal ligation and puncture (CLP) surgery in mice was measured via assessment of serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, total glutathione, glutathione peroxidase activity, catalase activity, and superoxide dismutase activity. Treatment with either VCN or SCL resulted in elevated plasma levels of BUN and creatinine, and of protein in the urine of mice with CLP-induced renal damage. Moreover, both VCN and SCL inhibited nuclear factor κB activation and reduced the induction of nitric oxide synthase and excessive production of nitric acid. VCN and SCL treatment also reduced the plasma levels of interleukin-6, and tumor necrosis factor-α, reduced lethality due to CLP-induced sepsis, increased lipid peroxidation, and markedly enhanced the antioxidant defense system by restoring the levels of superoxide dismutase, glutathione peroxidase, and catalase in kidney tissues. The present results suggest that VCN and SCL protect mice from sepsis-triggered renal injury


Subject(s)
Animals , Male , Mice , Flavonoids , Antioxidants/analysis , Wounds and Injuries/classification , Blood Urea Nitrogen , Catalase/adverse effects , Tumor Necrosis Factor-alpha , Sepsis/chemically induced , Nitric Oxide Synthase/pharmacology , Creatinine , Kidney
10.
Braz. j. med. biol. res ; 53(3): e8761, 2020. tab, graf
Article in English | LILACS | ID: biblio-1089339

ABSTRACT

Nitric oxide (NO) inhibition by high-dose NG-nitro-L-arginine methyl ester (L-NAME) is associated with several detrimental effects on the cardiovascular system. However, low-dose L-NAME increases NO synthesis, which in turn induces physiological cardiovascular benefits, probably by activating a protective negative feedback mechanism. Aerobic exercise, likewise, improves several cardiovascular functions in healthy hearts, but its effects are not known when chronically associated with low-dose L-NAME. Thus, we tested whether the association between low-dose L-NAME administration and chronic aerobic exercise promotes beneficial effects to the cardiovascular system, evaluating the cardiac remodeling process. Male Wistar rats were randomly assigned to control (C), L-NAME (L), chronic aerobic exercise (Ex), and chronic aerobic exercise associated to L-NAME (ExL). Aerobic training was performed with progressive intensity for 12 weeks; L-NAME (1.5 mg·kg-1·day-1) was administered by orogastric gavage. Low-dose L-NAME alone did not change systolic blood pressure (SBP), but ExL significantly increased SBP at week 8 with normalization after 12 weeks. Furthermore, ExL promoted the elevation of left ventricle (LV) end-diastolic pressure without the presence of cardiac hypertrophy and fibrosis. Time to 50% shortening and relaxation were reduced in ExL, suggesting a cardiomyocyte contractile improvement. In addition, the time to 50% Ca2+ peak was increased without alterations in Ca2+ amplitude and time to 50% Ca2+ decay. In conclusion, the association of chronic aerobic exercise and low-dose L-NAME prevented cardiac pathological remodeling and induced cardiomyocyte contractile function improvement; however, it did not alter myocyte affinity and sensitivity to intracellular Ca2+ handling.


Subject(s)
Animals , Male , Physical Conditioning, Animal/physiology , Calcium/analysis , Nitric Oxide Synthase/drug effects , NG-Nitroarginine Methyl Ester/pharmacology , Enzyme Inhibitors/pharmacology , Myocardial Contraction/drug effects , Body Weight/physiology , Rats, Wistar , Ventricular Pressure/drug effects , Nitric Oxide Synthase/metabolism , NG-Nitroarginine Methyl Ester/administration & dosage , Models, Animal , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/physiology , Enzyme Inhibitors/administration & dosage , Adiposity , Hemodynamics , Motor Activity/physiology , Myocardium/pathology
11.
Acta bioquím. clín. latinoam ; 53(2): 167-173, jun. 2019. tab
Article in Spanish | LILACS | ID: biblio-1019250

ABSTRACT

La esclerosis múltiple remitente-recurrente (EM-RR) es una enfermedad desmielinizante del sistema nervioso central. A fin de entender la asociación del estrés oxidativo a nivel periférico con la recaída de la enfermedad se determinaron los niveles de marcadores de estrés oxidativo en plasma de pacientes en la recaída o brote y una semana después de la misma. Se analizaron muestras de 60 personas (20 pacientes con recaída, 20 pacientes sin recaída y 20 controles sanos). Se cuantificaron mediante métodos espectrofotométricos las actividades enzimáticas de óxido nítrico sintasa (ONS), glutatión peroxidasa (GPx), los niveles de lipoperóxidos y nitritos-nitratos y la fluidez de membrana. En el brote de la enfermedad aumentan significativamente los niveles de las actividades enzimáticas de ONS y GPx y los niveles de nitritos-nitratos y lipoperóxidos (p<0,01 en todos los casos), al ser comparados con los de individuos sanos. Dichos parámetros disminuyeron significativamente una semana después de iniciado el brote. Además, los parámetros evaluados se mantuvieron elevados en pacientes que no experimentaron un brote de la enfermedad cuando se los comparó con individuos sanos. La fluidez de membrana en los pacientes con y sin brote fue similar a la de los controles. En conclusión, el estrés oxidativo es un componente importante en los pacientes con esclerosis múltiple.


Recurrent-remitting multiple sclerosis (RR-MS) is a demyelinating disease of the central nervous system. In order to understand the association of oxidative stress at the peripheral level with the relapse of the disease, the levels of oxidative stress markers in plasma of patients in the relapse or outbreak and one week after relapse were determined. Samples of 60 subjects were analyzed (20 patients in relapse, 20 patients without relapse, and 20 healthy controls). The enzymatic activities of nitric oxide synthase (NOS), glutathione peroxidase (GPx), lipoperoxides and nitrite-nitrate levels and membrane fluidity were quantified by spectrophotometric methods. In relapse, the levels of enzymatic activities of NOS and GPx, and the levels of lipoperoxides and nitrites-nitrates were significantly increased (p<0.01, in all cases), compared with healthy individuals. These parameters decreased significantly 1 week after the start of the outbreak. In addition, the parameters evaluated remained high in patients who did not experience an outbreak of the disease compared to healthy subjects. The membrane fluidity in the patients with and without outbreak was similar to that of the controls. In conclusion, oxidative stress is an important component in patients with multiple sclerosis.


A esclerose múltipla recorrente-remitente (EM-RR) é uma doença desmielinizante do sistema nervoso central. Para compreender a associação do estresse oxidativo a nível periférico com a recaída da doença foram determinados os níveis de marcadores de estresse oxidativo em plasma de doentes na recaída ou surto e uma semana após a recaída. Foram analisadas a amostras de 60 pessoas (20 pacientes com recaída, 20 pacientes sem recaída e 20 controles saudáveis). As atividades enzimáticas de óxido nítrico sintase (ONS), glutationa peroxidase (GPX), os níveis de lipoperóxidos e nitritos-nitratos e a fluidez de membrana foram quantificadas por métodos espectrofotométricos. No surto da doença aumentam em forma significativa os níveis da atividade enzimática de ONS e GPX, e os níveis de nitritos-nitratos e lipoperóxidos (p<0,01 em todos os casos), em comparação com os indivíduos saudáveis. Esses parâmetros diminuíram significativamente uma semana após o início do surto. Além disso, os parâmetros avaliados permaneceram elevados em pacientes que não experimentaram um surto da doença quando comparados com indivíduos saudáveis. A fluência de membrana nos pacientes com e sem surto foi semelhante à dos controles. Em conclusão, o estresse oxidativo é um componente importante nos pacientes com esclerose múltipla.


Subject(s)
Humans , Male , Female , Adolescent , Adult , Middle Aged , Young Adult , Biomarkers/blood , Oxidative Stress , Multiple Sclerosis, Relapsing-Remitting/blood , Nitric Oxide Synthase/blood , Glutathione Peroxidase/blood , Lipid Peroxides/blood
12.
Experimental Neurobiology ; : 516-528, 2019.
Article in English | WPRIM | ID: wpr-763776

ABSTRACT

We have previously demonstrated that the neurosteroid dehydroepiandrosterone sulfate (DHEAS) induces functional potentiation of N-methyl-D-aspartate (NMDA) receptors via increases in phosphorylation of NMDA receptor GluN1 subunit (pGluN1). However, the modulatory mechanisms responsible for the expression of the DHEA-synthesizing enzyme, cytochrome P450c17 following peripheral nerve injury have yet to be examined. Here we determined whether oxidative stress induced by the spinal activation of nitric oxide synthase type II (NOS-II) modulates the expression of P450c17 and whether this process contributes to the development of neuropathic pain in rats. Chronic constriction injury (CCI) of the sciatic nerve induced a significant increase in the expression of NOS-II in microglial cells and NO levels in the lumbar spinal cord dorsal horn at postoperative day 5. Intrathecal administration of the NOS-II inhibitor, L-NIL during the induction phase of neuropathic pain (postoperative days 0~5) significantly reduced the CCI-induced development of mechanical allodynia and thermal hyperalgesia. Sciatic nerve injury increased the expression of PKC- and PKA-dependent pGluN1 as well as the mRNA and protein levels of P450c17 in the spinal cord at postoperative day 5, and these increases were suppressed by repeated administration of L-NIL. Co-administration of DHEAS together with L-NIL restored the development of neuropathic pain and pGluN1 that were originally inhibited by L-NIL administration alone. Collectively these results provide strong support for the hypothesis that activation of NOS-II increases the mRNA and protein levels of P450c17 in the spinal cord, ultimately leading to the development of central sensitization and neuropathic pain induced by peripheral nerve injury.


Subject(s)
Animals , Rats , Central Nervous System Sensitization , Constriction , Cytochromes , Dehydroepiandrosterone , Dehydroepiandrosterone Sulfate , Hyperalgesia , N-Methylaspartate , Neuralgia , Nitric Oxide Synthase Type II , Nitric Oxide Synthase , Nitric Oxide , Oxidative Stress , Peripheral Nerve Injuries , Phosphorylation , RNA, Messenger , Rodentia , Sciatic Nerve , Spinal Cord , Spinal Cord Dorsal Horn
13.
Biomolecules & Therapeutics ; : 241-253, 2019.
Article in English | WPRIM | ID: wpr-763020

ABSTRACT

Flavonoids are major plant constituents with numerous biological/pharmacological actions both in vitro and in vivo. Of these actions, their anti-inflammatory action is prominent. They can regulate transcription of many proinflammatory genes such as cyclooxygenase-2/inducible nitric oxide synthase and many cytokines/chemokines. Recent studies have demonstrated that certain flavonoid derivatives can affect pathways of inflammasome activation and autophagy. Certain flavonoids can also accelerate the resolution phase of inflammation, leading to avoiding chronic inflammatory stimuli. All these pharmacological actions with newly emerging activities render flavonoids to be potential therapeutics for chronic inflammatory disorders including arthritic inflammation, meta-inflammation, and inflammaging. Recent findings of flavonoids are summarized and future perspectives are presented in this review.


Subject(s)
Autophagy , Flavonoids , In Vitro Techniques , Inflammasomes , Inflammation , Nitric Oxide Synthase , Plants
14.
Annals of Surgical Treatment and Research ; : 271-281, 2019.
Article in English | WPRIM | ID: wpr-762721

ABSTRACT

PURPOSE: To determine the potential protective and therapeutic effects and action mechanism of ruscogenin on cerulein-induced acute pancreatitis (AP) model in rats. METHODS: Overall, 32 rats were attenuated to the sham (2-mL/kg/day isotonic solution for 4 weeks), control (20-µg/kg cerulein-induced AP for 12 hours), prophylaxis groups (cerulein-induced AP following 3-mL/kg/day ruscogenin for 4 weeks) and treatment (3-mL/kg/day ruscogenin following cerulein-induced AP for 12 hours). Blood samples were collected for biochemical analysis of nitric oxide synthase 1 (NOS1/neuronal NOS), malondialdehyde (MDA) and intercellular adhesion molecule 1 (ICAM-1). After sacrification, pancreas tissues were collected and prepared for light microscopic (hematoxylin and eosin), immunohistochemical (nuclear factor kappa B) and biochemical analysis (tumor necrosis factor-alpha [TNF-α], interleukin-6 and 1β [IL-6 and IL-1β], CRP, high-sensitivity CRP [hs-CRP] amylase, lipase, and ICAM-1). Ultrastructural analysis was performed by transmission electron microscopy. RESULTS: The protective and therapeutic actions of ruscogenin were accomplished by improvements in histopathology, by decreasing blood cytokine levels of CRP, hs-CRP levels, TNF-α, IL-6, IL-1β, ICAM-1, by reducing the pancreatic enzymes amylase and lipase in blood, and by suppressing the expression of nuclear factor kappa B, ICAM-1, and NOS-1, but not MDA in pancreatic tissues. Ruscogenin also improved cerulein-induced ultrastructural degenerations in endocrine and exocrine cells, especially in treatment group. CONCLUSION: The present findings have demonstrated the beneficial protective and therapeutical effects of ruscogenin, nominating it as a highly promising supplementary agent to be considered in the treatment of AP, and even as a protective agent against the damages induced by disease.


Subject(s)
Animals , Rats , Amylases , Ceruletide , Intercellular Adhesion Molecule-1 , Interleukin-6 , Lipase , Malondialdehyde , Microscopy, Electron, Transmission , Necrosis , NF-kappa B , Nitric Oxide Synthase , Pancreas , Pancreatitis , Therapeutic Uses
15.
Journal of Neurogastroenterology and Motility ; : 589-601, 2019.
Article in English | WPRIM | ID: wpr-765965

ABSTRACT

BACKGROUND/AIMS: Interstitial cells play important roles in gastrointestinal (GI) neuro-smooth muscle transmission. The underlying mechanisms of colonic dysmotility have not been well illustrated. We established a partial colon obstruction (PCO) mouse model to investigate the changes of interstitial cells and the correlation with colonic motility. METHODS: Western blot technique was employed to observe the protein expressions of Kit, platelet-derived growth factor receptor-α (Pdgfra), Ca²⁺-activated Cl⁻ (Ano1) channels, and small conductance Ca²⁺- activated K⁺ (SK) channels. Colonic migrating motor complexes (CMMCs) and isometric force measurements were employed in control mice and PCO mice. RESULTS: PCO mice showed distended abdomen and feces excretion was significantly reduced. Anatomically, the colon above the obstructive silicone ring was obviously dilated. Kit and Ano1 proteins in the colonic smooth muscle layer of the PCO colons were significantly decreased, while the expression of Pdgfra and SK3 proteins were significantly increased. The effects of a nitric oxide synthase inhibitor (L-NAME) and an Ano1 channel inhibitor (NPPB) on CMMC and colonic spontaneous contractions were decreased in the proximal and distal colons of PCO mice. The SK agonist, CyPPA and antagonist, apamin in PCO mice showed more effect to the CMMCs and colonic smooth muscle contractions. CONCLUSIONS: Colonic transit disorder may be due to the downregulation of the Kit and Ano1 channels and the upregulation of SK3 channels in platelet-derived growth factor receptor-α positive (PDGFRα⁺) cells. The imbalance between interstitial cells of Cajal-Ano1 and PDGFRα-SK3 distribution might be a potential reason for the colonic dysmotility.


Subject(s)
Animals , Mice , Abdomen , Apamin , Blotting, Western , Chloride Channels , Colon , Down-Regulation , Feces , Interstitial Cells of Cajal , Muscle, Smooth , Myoelectric Complex, Migrating , Nitric Oxide Synthase , Platelet-Derived Growth Factor , Silicon , Silicones , Small-Conductance Calcium-Activated Potassium Channels , Up-Regulation
16.
Journal of Neurogastroenterology and Motility ; : 316-331, 2019.
Article in English | WPRIM | ID: wpr-765928

ABSTRACT

BACKGROUND/AIMS: Interstitial cells of Cajal (ICC) and their special calcium-activated chloride channel, anoctamin-1 (ANO1) play pivotal roles in regulating colonic transit. This study is designed to investigate the role of ICC and the ANO1 channel in colonic transit disorder in dextran sodium sulfate (DSS)-treated colitis mice. METHODS: Colonic transit experiment, colonic migrating motor complexes (CMMCs), smooth muscle spontaneous contractile experiments, intracellular electrical recordings, western blotting analysis, and quantitative polymerase chain reaction were applied in this study. RESULTS: The mRNA and protein expressions of c-KIT and ANO1 channels were significantly decreased in the colons of DSS-colitis mice. The colonic artificial fecal-pellet transit experiment in vitro was significantly delayed in DSS-colitis mice. The CMMCs and smooth muscle spontaneous contractions were significantly decreased by 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), an ANO1 channel blocker, and NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME), an inhibitor of nitric oxide synthase activity, in DSS-colitis mice compared with that of control mice. Intracellular electrical recordings showed that the amplitude of NPPB-induced hyperpolarization was more positive in DSS-colitis mice. The electric field stimulation-elicited nitric-dependent slow inhibitory junctional potentials were also more positive in DSS-colitis mice than those of control mice. CONCLUSION: The results suggest that colonic transit disorder is mediated via downregulation of the nitric oxide/ICC/ANO1 signalling pathway in DSS-colitis mice.


Subject(s)
Animals , Mice , Blotting, Western , Chloride Channels , Colitis , Colon , Dextrans , Down-Regulation , In Vitro Techniques , Interstitial Cells of Cajal , Muscle, Smooth , Myoelectric Complex, Migrating , NG-Nitroarginine Methyl Ester , Nitric Oxide Synthase , Polymerase Chain Reaction , RNA, Messenger , Sodium
17.
The Korean Journal of Pain ; : 256-263, 2019.
Article in English | WPRIM | ID: wpr-761714

ABSTRACT

BACKGROUND: Antinociceptive anti-inflammatory drugs have many adverse effects. The goal of this investigation is to study the probable anti-inflammatory and analgesic effects of verapamil and N-acetylcysteine (NAC) in experimental rats. METHODS: Adult male Wistar rats were randomly divided into 4 groups in the antinociceptive study, each containing 6 rats; the normal control group, which received saline (1 mL/kg); the diclofenac group, which received diclofenac sodium (5 mg/kg); the NAC group, which received NAC (125 mg/kg); and the verapamil group, which received verapamil (8 mg/kg). In the anti-inflammatory study, 5 groups were used, the 4 previous groups with the addition of an edema control group, received saline and were subjected to formalin test. Hot plate latency time was recorded for antinociceptive evaluation. Paw edema thickness and biochemical parameters were recorded for anti-inflammatory evaluation. RESULTS: Administration of NAC showed significant prolongation of hot plate latency time at 1 hour when compared to the control group while verapamil showed a significant prolongation of hot plate latency time at 1 and 2 hours when compared to the control group and NAC group values. Administration of NAC and verapamil significantly decreased paw edema thickness at 2, 4, and 8 hours when compared to edema control values. Regarding biochemical markers, NAC and verapamil significantly decreased serum nitric oxide synthase, C-reactive protein, and cyclooxygenase-2 levels compared to the edema control value. In accordance, a marked improvement of histopathological findings was observed with both drugs. CONCLUSIONS: NAC and verapamil have antinociceptive and anti-inflammatory effects comparable to diclofenac sodium.


Subject(s)
Adult , Animals , Humans , Male , Rats , Acetylcysteine , Anti-Inflammatory Agents , Biomarkers , C-Reactive Protein , Cyclooxygenase 2 , Diclofenac , Edema , Nitric Oxide Synthase , Pain Measurement , Rats, Wistar , Verapamil
18.
Natural Product Sciences ; : 16-22, 2019.
Article in English | WPRIM | ID: wpr-741650

ABSTRACT

Inula helenium L. is rich source of eudesmane-type sesquiterpene lactones, mainly alantolactone and isoalantolactone, which have the various pharmacological functions. In this study, we examined the inhibitory effects of nitric oxide (NO) production of hexane, methylene chloride, ethyl acetate, butanol, and water fractions from I. helenium and investigated the anti-inflammatory effect of hexane fraction of I. helenium (HFIH) in LPS-induced RAW 264.7 cells. Quantification of alantolactone and isoalantolactone from HFIH was carried out for the standardization by multiple reaction monitoring using triple quadrupole mass spectrometer. HFIH significantly inhibited inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) protein as well as their downstream products NO and prostaglandin E₂ (PGE₂) in LPS-stimulated RAW 264.7 cells. Moreover, HFIH suppressed NF-κB transcriptional activity by decreasing the translocation of p65 to the nucleus. The in vivo study further confirmed that HFIH attenuated the paw edema induced by carrageenan in an acute inflammation model. These findings suggest that HFIH may be useful as a promising phytomedicine for inflammatory-associated diseases.


Subject(s)
Carrageenan , Cyclooxygenase 2 , Edema , Inflammation , Inula , Lactones , Methylene Chloride , Nitric Oxide , Nitric Oxide Synthase , Staphylococcal Protein A , Water
19.
Natural Product Sciences ; : 34-37, 2019.
Article in English | WPRIM | ID: wpr-741647

ABSTRACT

Phytochemical studies were performed to identify the active principles of Phryma leptostachya var. asiatica (Phyrymaceae) for anti-inflammation. The anti-inflammatory activity was assessed by measuring the inhibition rate on nitric oxide (NO) formation in lipopolysaccharide (LPS)-activated macrophage 264.7 cells. Of the five compounds including ursolic acid, phrymarolin I, harpagide, haedoxancoside A, and acteoside isolated from this plant, ursolic acid showed the most prominent inhibition of NO formation. Therefore, ursolic acid may be the anti-inflammatory principle of Phryma leptostachya var. asiatica.


Subject(s)
Macrophages , Nitric Oxide Synthase , Nitric Oxide , Plants
20.
Immune Network ; : e9-2019.
Article in English | WPRIM | ID: wpr-740219

ABSTRACT

Staphylococcus aureus, a Gram-positive pathogen, can cause severe inflammation in humans, leading to various life-threatening diseases. The lipoprotein is a major virulence factor in S. aureus-induced infectious diseases and is responsible for excessive inflammatory mediators such as nitric oxide (NO). Short-chain fatty acids (SCFAs) including butyrate, propionate, and acetate are microbial metabolites in the gut that are known to have anti-inflammatory effects in the host. In this study, we investigated the effects of SCFAs on S. aureus lipoprotein (Sa.LPP)-induced NO production in mouse macrophages. Butyrate and propionate, but not acetate, inhibited Sa.LPP-induced production of NO in RAW 264.7 cells and bone marrow-derived macrophages. Butyrate and propionate inhibited Sa.LPP-induced expression of inducible NO synthase (iNOS). However, acetate did not show such effects under the same conditions. Furthermore, butyrate and propionate, but not acetate, inhibited Sa.LPP-induced activation of NF-κB, expression of IFN-β, and phosphorylation of STAT1, which are essential for inducing transcription of iNOS in macrophages. In addition, butyrate and propionate induced histone acetylation at lysine residues in the presence of Sa.LPP in RAW 264.7 cells. Moreover, Sa.LPP-induced NO production was decreased by histone deacetylase (HDAC) inhibitors. Collectively, these results suggest that butyrate and propionate ameliorate the inflammatory responses caused by S. aureus through the inhibition of NF-κB, IFN-β/STAT1, and HDAC, resulting in attenuated NO production in macrophages.


Subject(s)
Animals , Humans , Mice , Acetylation , Butyrates , Communicable Diseases , Diethylpropion , Fatty Acids, Volatile , Histone Deacetylase Inhibitors , Histone Deacetylases , Histones , Inflammation , Lipoproteins , Lysine , Macrophages , Nitric Oxide Synthase , Nitric Oxide , Phosphorylation , Staphylococcus aureus , Virulence
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