RESUMEN
Rheumatoid arthritis (RA) is the most common autoimmune disease, affecting the joints of the hands and feet. Several chemokines and their receptors are crucial in RA pathogenesis through immune cell recruitment. C-X-C Motif Chemokine Ligand 1 (CXCL1), a chemokine for the recruitment of various immune cells, can be upregulated in patients with RA. However, the discussion on the role of CXCL1 in RA pathogenesis is insufficient. Here, we found that CXCL1 promoted cyclooxygenase-2 (COX-II) expression in a dose- and time-dependent manner in rheumatoid arthritis synovial fibroblasts (RASFs). CXCL1 overexpression in RASFs led to a significant increase in COX-II expression, while the transfection of RASFs with the shRNA plasmid resulted in a noticeable decrease in COX-II expression. Next, we delineated the molecular mechanism underlying CXCL1-promoted COX-II expression and noted that CXC chemokine receptor 2 (CXCR2), phospholipase C (PLC), and protein kinase C (PKC) signal transduction were responsible for COX-II expression after CXCL1 incubation for RASFs. Finally, we confirmed the transcriptional activation of nuclear factor κB (NF-κB) in RASFs after incubation with CXCL1. In conclusion, the current study provided a novel insight into the role of CXCL1 in RA pathogenesis.
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Artritis Reumatoide , FN-kappa B , Humanos , FN-kappa B/metabolismo , Receptores de Interleucina-8B/metabolismo , Membrana Sinovial/patología , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Fosfolipasas de Tipo C/metabolismo , Transducción de Señal , Quimiocinas/metabolismo , Fibroblastos/metabolismo , Células Cultivadas , Quimiocina CXCL1/metabolismoRESUMEN
BACKGROUND: Topical non-steroidal anti-inflammatory drugs (NSAIDs) have lower risks for cardiovascular disease and gastrointestinal adverse effects compared to oral NSAIDs, but there are little data regarding their kidney risks in chronic kidney disease (CKD). We evaluated the risk of adverse acute kidney outcomes in CKD according to route of NSAID administration. METHODS: Retrospective cohort study of adults with CKD (eGFR less than 60 ml/min/1.73 m2) who received prescriptions between 2015 and 2017 from a major healthcare cluster in Singapore. The adverse acute kidney outcomes were acute kidney injury (AKI) and need for nephrology specialist consult within 30 days. RESULTS: Among 6298 adults with CKD (mean age 72.1 ± 13.3 years and eGFR 41.9 ± 12.2 ml/min/1.73 m2), systemic and topical NSAIDs were prescribed in 16.7% and 32.0%, respectively. Incident AKI (any severity), KDIGO Stage 2 or 3 AKI, and need for nephrology specialist consult occurred in 16.7%, 2.6%, and 10.6% of the study cohort, respectively. After adjusting for age, diabetes, recent cardiovascular hospitalization, baseline eGFR, RAAS blocker and diuretic, systemic NSAIDs, and topical NSAIDs, compared with the no-NSAID group, were independently associated with incident AKI [adjusted OR 1.77 (95% CI 1.46-2.15) and 1.38 (1.18-1.63), respectively]. Moderate and severe AKI (adjusted OR 1.68, 95% CI 1.09-2.58, p = 0.02) and need for nephrology consults (adjusted OR 1.41, 95% CI 1.09-1.82, p = 0.008) were also increased in systemic NSAIDs. CONCLUSION: Among adults with CKD, both systemic and topical NSAIDs were independently associated with acute adverse kidney outcomes.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Adulto , Humanos , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Estudios Retrospectivos , Antiinflamatorios no Esteroideos/uso terapéutico , Riñón , Insuficiencia Renal Crónica/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamenteRESUMEN
Background and aim: Secretory diarrhea is the most common type of diarrhea. This study aimed at exploring the possible mechanism of antisecretory action of Annona senegalensis stem bark and to identify the bioactive compounds. Experimental procedure: The ability of three crude extract; aqueous, dichloromethane and hexane stem bark extracts to inhibit castor oil-induced stooling in albino rats were assessed. Bioactivity guided fractionation of the most active extract was done using solvent-solvent partitioning (with hexane, dichloromethane, ethylacetate) and column chromatography. In vitro antioxidant activity of the most active sub-fraction was done using standard methods. The most active sub-fraction (25 mg/kg b. wt.) was administered to castor oil-induced diarrheal rats. Diarrheal rats small intestinal malondialdehyde concentration, antioxidant enzyme, cyclooxygenase II and Na+- K+ ATPase activities were determined using standard procedures. GC-MS analysis was done to identify the chemical compounds in the sub-fraction. Result and conclusion: Aqueous extract significantly decreased the number of wet stools. Sub-fraction 1 of ethylacetate fraction of aqueous stem bark extract (EFAS1) showed the highest stool inhibition. The H2O2 scavenging activity of EFAS1 was significantly greater than ascorbic acid. The sub-fraction significantly increased (p < 0.05) the activity of catalase and Na+- K+ ATPase activities but significantly decreased the concentration of malondialdehyde and cyclooxygenase II activity. GC-MS analysis revealed that EFAS1 is rich in catechol, n-hexadecanoic acid and ethyl-5,8,11,14,17-icosapentanoate. The sub-fraction exerts its antisecretory activity by its antioxidative, inhibition of prostaglandin synthesis and stimulation of Na+- K+ ATPase properties due to the presence of catechol, n-hexedecanoic acid and ethyl-5,8,11,14,17-icosapentanoate.
RESUMEN
Cinnamon is one of the herbal resources belonging to the Lauraceae family, is commonly used in traditional medicine and as a flavoring agent. It has antioxidant and anti-inflammatory activities. Therefore, the present study was performed to evaluate the gastroprotective effect of cinnamon on ethanol-induced gastric ulcer in comparison to omeprazole. In Wistar rats, gastric ulcers were induced using one oral dose of 70% ethanol (5 ml/kg b. w.) Cinnamon oil at doses of 2.5 ml/kg body weight and omeprazole (a reference drug) at a dose of 20 mg/kg body weight were orally administrated daily for 7 days before ulcer induction. 1 h after ethanol administration blood samples were collected and then the stomachs of sacrificed rats were subjected to biochemical, macroscopic and histological, and immunohistochemical studies. Oral administration of cinnamon oil significantly attenuated gastric ulcer as revealed by a significant increase in the gastric levels of enzymatic and non-enzymatic antioxidants namely CAT, SOD, GSH-Px, and GSH with a concomitant reduction in MDA level compared with those in the ethanol group. Pre-treatment of cinnamon oil markedly improved the level of TNF-α and PGE content. Furthermore, cinnamon oil pre-treatment significantly increased the immunoreactivity of VEGF while decreasing the immunoreactivity of COX-II. These results were further supported by histopathological findings which revealed the curing effect of cinnamon oil on the microscopic changes induced by ethanol toxicity. Cinnamon oil showed a potential gastroprotective effect on ethanol-induced gastric ulcer comparable to the gastroprotective effect of omeprazole, and its effect may be mediated through suppression of oxidative stress and gastric inflammation and promotion of angiogenesis.
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Úlcera Gástrica , Animales , Antioxidantes/farmacología , Peso Corporal , Cinnamomum zeylanicum , Etanol/efectos adversos , Omeprazol/efectos adversos , Estrés Oxidativo , Ratas , Ratas Wistar , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/patologíaRESUMEN
In a previous study, we reported the alterations of primary antioxidant enzymes and decreased citrate synthase (CS) activities in different grades of human astrocytoma tissues. Here, we further investigated coenzyme Q10 (CoQ10) levels and protein levels of polyprenyl diphosphate synthase subunit (PDSS2) and several COQ proteins required for CoQ10 biosynthesis in these tissues. We found that the level of endogenous CoQ10, but not of exogenous α-tocopherol, was higher in nontumor controls than in all grades of astrocytoma tissues. The levels of COQ3, COQ5, COQ6, COQ7, COQ8A, and COQ9, but not of COQ4, were lower in Grade IV astrocytoma tissues than in controls or low-grade (Grades I and II) astrocytomas, but PDSS2 levels were higher in astrocytoma tissues than in controls. Correlation analysis revealed that the levels of CoQ10 and COQ proteins were negatively correlated with malignancy degree and positively correlated with CS activity, whereas PDSS2 level was positively correlated with malignancy. Moreover, lower level of mitochondrial DNA-encoded cytochrome c oxidase subunit 2 was not only associated with a higher malignancy degree but also with lower level of all COQ proteins detected. The results revealed that mitochondrial abnormalities are associated with impaired CoQ10 maintenance in human astrocytoma progression.
Asunto(s)
Astrocitoma , Ubiquinona , Astrocitoma/metabolismo , ADN Mitocondrial/metabolismo , Humanos , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismoRESUMEN
BACKGROUND: Individuals with diabetes mellitus (DM) may be susceptible to non-steroidal anti-inflammatory drug (NSAID)-induced acute kidney injury (AKI) but data on NSAID-related adverse renal events is sparse. OBJECTIVE: We aimed to evaluate the risk of acute kidney injury and/or hyperkalemia after systemic NSAID among individuals with DM and diabetic chronic kidney disease (CKD). METHODS: Retrospective cohort study of 3896 adults with DM with incident prescriptions between July 2015 and December 2017 from Singapore General Hospital and SingHealth Polyclinics. Laboratory, hospitalization and medication data were retrieved from electronic medical records. The primary outcome was the incidence of AKI and/ or hyperkalemia within 30 days after prescription. RESULTS: AKI and/or hyperkalemia occurred in 13.5% of all DM and 15.8% of diabetic CKD. The association between systemic NSAID >14 days and 30-day risk of AKI and/or hyperkalemia failed to reach statistical significance in unselected DM (adjusted OR 1.62, 95% CI 0.99-2.65, p = 0.05) and diabetic CKD (adjusted OR 0.64, 95% CI 0.15-2.82, p = 0.64), but the odds of AKI and/or hyperkalemia were markedly and significantly increased when NSAID was prescribed with renin-angiotensin-aldosterone system (RAAS) blocker (adjusted OR 4.17, 95% CI 1.74-9.98, p = 0.001) or diuretic (adjusted OR 3.31, 95% CI 1.09-10.08, p = 0.04) and in the absence of diabetic CKD (adjusted OR 1.98, 95% CI 1.16-3.36, p = 0.01). CONCLUSION: NSAID prescription >14 days in individuals with DM with concurrent RAAS blockers or diuretics was associated with higher 30-day risk of AKI and/or hyperkalemia.
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Lesión Renal Aguda , Diabetes Mellitus , Nefropatías Diabéticas , Hiperpotasemia , Insuficiencia Renal Crónica , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/epidemiología , Adulto , Antiinflamatorios no Esteroideos/efectos adversos , Diabetes Mellitus/inducido químicamente , Diabetes Mellitus/tratamiento farmacológico , Nefropatías Diabéticas/inducido químicamente , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/epidemiología , Diuréticos/efectos adversos , Femenino , Humanos , Hiperpotasemia/inducido químicamente , Hiperpotasemia/tratamiento farmacológico , Hiperpotasemia/epidemiología , Masculino , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/epidemiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
A new homoisoflavan, identified as (3 R)-7-hydroxy-3',4'-methylenedioxyhomoisoflavan, was isolated from Dracaena cinnabari Balf. f. resin. The structure was elucidated by one- and two-dimensional NMR spectroscopy as well as high resolution mass spectrometry. In addition, a diverse group of flavonoids were isolated, representing homoisoflavans, flavans, flavanones, chalcones and dihydrochalcones. The compounds were evaluated for their α-glucosidase and COX-II inhibition activity. The obtained IC50 values of the tested flavonoids gave an insight about some key structural features to their α-glucosidase and COX-II inhibitory activity. For α-glucosidase inhibitory activity, a flavanone skeleton was favorable over a flavan. For COX-II inhibition, the introduction of a fused heterocyclic ring at the homoisoflavan skeleton enhanced the activity.
Asunto(s)
Chalconas , Dracaena , Chalconas/química , Chalconas/farmacología , Inhibidores de la Ciclooxigenasa 2 , Dracaena/química , Flavonoides/farmacología , Inhibidores de Glicósido Hidrolasas , Extractos Vegetales/química , Resinas de Plantas/química , alfa-GlucosidasasRESUMEN
Cytochrome c oxidase (COX) deficiency is known to be associated with Leigh syndrome (LS), however there are limited studies on genetic screening of mitochondrial (mt) DNA encoding COX genes as well as the functional validation of identified variants. In our previous studies, we cared for total 165 LS patients and analyzed the nucleotide variations across entire mt genome. We observed a high level of genetic heterogeneity in these patients. We identified various reported and novel variation across entire genome including COX genes. In our present study we have further studied and functionally validated the selected novel nucleotide variant of COX I and COX II gene using different in-silico tools and trans mitochondrial cybrid based assays. As a result of our study, G6036A (G45S) variant of COX I gene, reduced the COX activity in both spectrophotometric as well as In-gel BN-PAGE assays. FACS analysis also revealed this variant to affect the mitochondrial membrane potential in the respective cybrids. Interestingly most of our in-silico studies indicated that this variant might affect the secondary structure and confirmation of COX I protein. Thus we report the first missense mutation in the COX I gene of LS patients and justify its pathogenic role in these patients by different assays. Variant A7746G (N54K) in COX II gene was also predicted to affect the secondary structure as well as stability of COX II protein. Though, the effect of this variant was not significant, however it will be interesting to investigate its significance by other assays in future.
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Ciclooxigenasa 1 , Enfermedad de Leigh , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Humanos , Enfermedad de Leigh/genética , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Mutación , Mutación Missense , TiaminaRESUMEN
BACKGROUND: A novel series of 2-(Morpholin-4-yl)-N-phenylquinazolin-4- amine derivatives were synthesized and confirmed with spectral and elemental techniques. METHODS: The compounds were tested for analgesic and anti-inflammatory activity by various pain models in rodents whereas the selectivity towards COX-2 receptor is determined by in vitro assay. RESULTS: Screening results of compounds exhibited comparable biological activity with that of standard compound Indomethacin used for study. Compound 5d was found to be significantly potent with respect to its anti-inflammatory and analgesic activity with substantial COX-II selectivity. CONCLUSION: In silico analysis by molecular docking and 3D-QSAR studies justifies activity profile of compound 5d, suggesting that it may have potential for further evaluation and development as lead molecule for therapy in pain management.
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Analgésicos/síntesis química , Antiinflamatorios/síntesis química , Dolor/prevención & control , Analgésicos/química , Analgésicos/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Desarrollo de Medicamentos , Humanos , Ratones , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad Cuantitativa , Quinazolinas/síntesis química , Quinazolinas/química , Ratas WistarRESUMEN
Doxorubicin (DOX) is a widely used anthracycline antibiotic for the management of carcinoma. However, it is associated with cardiotoxicity. Fisetin is a plant flavonoid reported to have anti-inflammatory and antiapoptotic potential. To evaluate the cardioprotective potential of fisetin in DOX-induced cardiotoxicity in experimental rats. Sprague-Dawley rats were pre-treated with either fisetin (10, 20 and 40 mg/kg) or sitagliptin (10 mg/kg, p.o.) for 7 days. Cardiac toxicity was induced in rats (except the normal group) by doxorubicin (15 mg/kg i.p.) on 8th day. Various behavioral, biochemical, molecular and histological parameters were assessed in cardiac tissue. DOX-induced alterations in electrocardiographic, hemodynamic and left ventricular function were significantly (p < 0.05) inhibited by fisetin (20 and 40 mg/kg) treatment. Fisetin significantly decrease (p < 0.05) DOX-induced elevated serum CK-MB, LDH, AST, ALT and ALP levels. DOX-induced elevated cardiac oxido-nitrosative (SOD, GSH, MDA and NO) was significantly inhibited (p < 0.05) by fisetin. Up-regulated cardiac caspase-3, COX-II, cTn-I, iNOs, TNF-α, and IL-1ß mRNA, as well as protein expressions were significantly decreased (p < 0.05) by fisetin treatment. It also significantly (p < 0.05) attenuated DOX-induced histopathological alterations in cardiac tissue. In conclusion, the fisetin exerts its cardioprotective potential against DOX-induced toxicity via inhibition of multiple pathways including oxidative stress (SOD, GSH, MDA and NO), inflammation (COX-II, TNF-α, and IL-1ß), and apoptosis (Caspase-3). Therefore, fisetin can be considered as a potential cardioprotective agent during the management of carcinoma using doxorubicin anthracyclines.
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Cardiotoxicidad/tratamiento farmacológico , Flavonoides/metabolismo , Flavonoides/farmacología , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Cardiotónicos/farmacología , Cardiotoxicidad/fisiopatología , Caspasa 3/efectos de los fármacos , Caspasa 3/metabolismo , Ciclooxigenasa 2/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Doxorrubicina/efectos adversos , Doxorrubicina/farmacología , Flavonoles , Corazón , Inflamación/patología , Masculino , Miocardio/metabolismo , Óxido Nítrico Sintasa de Tipo II/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Troponina I/efectos de los fármacos , Troponina I/metabolismo , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The Oroxylum indicum is used traditionally to treat fever, colic, stomach ulcers, constipation, indigestion, intestinal worms, strangury, asthma, cough, hiccough, diarrhea, dysentery and wounds by the herbal healers of Mizoram and it is also part of Ayurvedic formulations. AIMS OF THE STUDY: The wound healing activity of Oroxylum indicum has not been investigated. Therefore, the present study was undertaken to evaluate the ability of different concentrations of ethanol extract of stem bark of Oroxylum indicum in the deep dermal excision wounds of mice. MATERIALS AND METHODS: The deep dermal excision wound was created on the shaved dorsum of Swiss albino mice. Each excision wound was topically applied with 5%, 10%, 20% or 30% gel of stem bark ethanol extract of Oroxylum indicum (OIE) and wound contraction, mean wound healing time (MHT), collagen and DNA syntheses were studied. The expression of NF-κB and COX-II were evaluated in the regenerating wound granulation tissues of mice. RESULTS: Topical application of different concentrations of OIE resulted in a concentration dependent rise in wound contraction and MHT and the highest wound contraction was recorded for 10% OIE. Similarly, topical application of different concentrations of OIE increased the DNA and neocollagen syntheses in a dose dependent manner at all post wounding days and the greatest acceleration in DNA and neocollagen formation was observed for 10% OIE. The evaluation of lipid peroxidation (LOO) showed a dose dependent decline in LOO, which was lowest for 10% OIE. The study of molecular mechanisms revealed the suppression of NF-κB and COX-II in a dose dependent manner in the regenerating wound of mice with a maximum inhibition at 10% OIE. CONCLUSIONS: The present study demonstrates that OIE accelerated the wound contraction and reduced mean wound healing time in mice, which may be due to increased collagen and DNA syntheses, reduced lipid peroxidation coupled by NF-κB and COX-II suppression by OIE in the regenerating wounds of mice.
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Bignoniaceae , Inhibidores de la Ciclooxigenasa 2/farmacología , Extractos Vegetales/farmacología , Cicatrización de Heridas/efectos de los fármacos , Administración Tópica , Animales , Colágeno/metabolismo , ADN/metabolismo , Etanol/química , Femenino , Masculino , Ratones , FN-kappa B/metabolismo , Corteza de la Planta , Piel/efectos de los fármacos , Piel/lesiones , Piel/metabolismo , Solventes/química , Pruebas de Toxicidad AgudaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Araucaria bidwillii Hook., the bunya pine, is an evergreen plant belonging to family Araucariaceae. Traditionally, its leaves and oleoresins have been used as herbal remedies to alleviate pain and inflammation. Based upon the frequent adverse effects accompanying synthetic anti-inflammatory drugs, this study will assess the anti-inflammatory activity of both the total methanol extract and the polyphenolic-rich fraction of A. bidwillii leaves. MATERIALS AND METHODS: The anti-inflammatory activity was assessed in vitro using phytohaemagglutinin-stimulated human peripheral blood mononuclear cells (PBMCs). Isolation of the major compounds was conducted using various chromatographic techniques. Molecular modelling studies are performed on tumor necrosis factor-α (TNF-α), cyclooxygenase-II (COX-II) and 5-lipooxygenase (5-LOX). RESULTS: Both the total methanol extract of Araucaria bidwillii leaves and its fraction revealed a dose-dependent manner in lowering the levels of IL-1ß, IL-6 and TNF-α with an equivalent activity to that of indomethacin. In addition, the phytochemical investigation of the polyphenolic-rich fraction results in identification of agathisflavone-4',7''-dimethyl ether (1), 7-O-methyl-6-hydroxyapigenin (2) and 4',4'-di-O-methylamentoflavone (3) as the main components. In silico molecular modelling showed that agathisflavone-4',7''-dimethyl ether (1) exhibited the fittest binding in TNF-α active sites, while 7-O-methyl-6-hydroxyapigenin (2) showed the highest inhibition in COX-II whereas 4',4'-di-O-methylamentoflavone (3) is the most potent 5-LOX inhibitor. CONCLUSION: Thus, the leaves of Araucaria bidwillii could afford a potent anti-inflammatory agent that effectively ameliorates inflammation and its related hazards. This in turn consolidates the fact of using the leaves of Araucaria bidwillii to sooth inflammation in traditional medicine.
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Antiinflamatorios/farmacología , Extractos Vegetales/farmacología , Polifenoles/farmacología , Tracheophyta , Citocinas/metabolismo , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Modelos Moleculares , Fitohemaglutininas , Hojas de la PlantaRESUMEN
Overdose of acetaminophen (APAP) is often associated with hepatotoxicity. Carfilzomib (CFZ) shows multiple pharmacological activities including anti-inflammatory potential. Therefore, this study was undertaken to evaluate the possible therapeutic effects of CFZ against APAP-induced hepatotoxicity. Hepatotoxicity was induced by administration of APAP (350 mg/kg, intraperitoneal). Mice were given CFZ (0.125, 0.25, or 0.5 mg/kg, intraperitoneal) 1.5 h after APAP administration. Animals were sacrificed on 6 h and blood and liver tissue samples were collected for analysis. In CFZ-post-treated group, there was significant and dose-dependent decrease in serum alanine aminotransferase levels. The level of tumor necrosis factor-α (TNF-α), reactive oxygen species, and NO decreased, whereas glutathione increased significantly by CFZ post-treatment. Upregulated mRNA expression of COX-II and iNOS were significantly downregulated by CFZ post-treatment. CFZ may exert its hepatoprotective action by alleviating inflammatory, oxidative, and nitrosative stress via inhibition of TNF-α, COX-II, and iNOS.
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Acetaminofén/toxicidad , Hígado/efectos de los fármacos , Oligopéptidos/uso terapéutico , Inhibidores de Proteasoma/uso terapéutico , Acetaminofén/administración & dosificación , Acetaminofén/efectos adversos , Animales , Ciclooxigenasa 2/efectos de los fármacos , Ciclooxigenasa 2/genética , Regulación de la Expresión Génica , Glutatión , Inflamación/tratamiento farmacológico , Inyecciones Intraperitoneales , Hígado/metabolismo , Masculino , Ratones , Óxido Nítrico Sintasa de Tipo II/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/genética , Oligopéptidos/administración & dosificación , Oligopéptidos/farmacología , Estrés Oxidativo/efectos de los fármacos , Inhibidores de Proteasoma/farmacología , Especies Reactivas de OxígenoRESUMEN
CONTEXT: Overdose of acetaminophen (APAP) is common in humans and is often associated with hepatic damage. Withania somnifera (L.) Dunal (Solanaceae) shows multiple pharmacological activities including antioxidant and anti-inflammatory potential. OBJECTIVE: To evaluate the possible mechanism of hepatoprotective activity of withanolide-rich fraction (WRF) isolated from a methanolic extract of Withania somnifera roots. MATERIALS AND METHODS: Hepatotoxicity was induced by oral administration of APAP (750 mg/kg, p.o.) for 14 d. The control group received the vehicle. APAP-treated animals were given either silymarin (25 mg/kg) or graded doses of WRF (50, 100 and 200mg/kg) 2 h prior to APAP administration. Animals were killed on 15th day and blood and liver tissue samples were collected for the further analysis. RESULTS: In WRF-treated group, there was significant and dose-dependent (p < 0.01 and p < 0.001) decrease in serum bilirubin, ALP, AST and ALT levels with significant and dose-dependent (p < 0.01 and p < 0.001) increase in hepatic SOD, GSH and total antioxidant capacity. The level of MDA and NO decreased significantly (p < 0.01) by WRF treatment. Up-regulated mRNA expression of TNF-α, IL-1ß, COX-II and iNOS was significantly down-regulated (p < 0.001) by WRF. Histological alternations induced by APAP in liver were restored to near normality by WRF pretreatment. CONCLUSION: WRF may exert its hepatoprotective action by alleviating inflammatory and oxido-nitrosative stress via inhibition of TNF-α, IL-1ß, COX-II and iNOS.
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Acetaminofén/toxicidad , Hígado/efectos de los fármacos , Extractos Vegetales/farmacología , Withania , Witanólidos/farmacología , Animales , Ciclooxigenasa 2/genética , Inhibidores de la Ciclooxigenasa 2/farmacología , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/genética , Lípidos/sangre , Hígado/metabolismo , Hígado/patología , Masculino , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/genética , ARN Mensajero/análisis , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética , Withania/químicaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Madhuca indica J. F. Gmel. (Sapotaceae) has shown antioxidant, anti-inflammatory, analgesic, anti-diabetic and hepatoprotective potential. It has been traditionally used as laxative, tonic, anti-burn, anti-earthworm, wound healing and headache. AIM OF THE STUDY: To investigate the efficacy and possible mechanism of Madhuca indica J. F. Gmel. leaves methanolic extract (MI-ALC) and its isolated chloroform fraction (D3) against experimental induced gastric ulcers. MATERIALS AND METHODS: D3 was isolated from MI-ALC, well characterized (HPTLC, FT-IR, (1)H-NMR and LC-MS) and evaluated for its gastroprotective activity by using acetic acid induced ulcer in male Wistar rats (150-200g). D3 (2.5, 5 and 10mg/kg, p.o.) were administered for the period of 14 days. At the end of treatment, rats were sacrificed to collect the stomach sample for evaluation of antioxidant (SOD, GSH, and MDA) enzyme, oxido-inflammatory (TNF-α, IL-1, iNOs) and prostaglandins (COX-II) markers by using RT-PCR. RESULTS: The structure and molecular weight (MW) of the isolated compound (D3) were confirmed by 1D and 2D spectral data and characterized as 3,5,7,3',4'-Pentahydroxy flavone with MW C15H10O7. Administration of 3,5,7,3',4'-Pentahydroxy flavone (5 and 10mg/kg) significantly and dose-dependently inhibited (P<0.01 and P<0.001) acetic acid induced an alteration in the antioxidant enzyme. It also significantly and dose-dependently down-regulated gastric oxido-inflammatory and prostaglandins markers. Histopathological aberration induced in the stomach also attenuated by 3,5,7,3',4'-Pentahydroxy flavone treatment. CONCLUSION: Finding of present investigation suggests that MI-ALC possessed potent antiulcer activity due to the presence of 3,5,7,3',4'-Pentahydroxy flavone via its oxido-inflammatory and prostaglandins modulatory potential.
Asunto(s)
Antiulcerosos , Madhuca , Quercetina , Úlcera Gástrica/tratamiento farmacológico , Ácido Acético , Animales , Antiulcerosos/aislamiento & purificación , Antiulcerosos/farmacología , Antiulcerosos/uso terapéutico , Biomarcadores/metabolismo , Ciclooxigenasa 2/genética , Mucosa Gástrica/metabolismo , Glutatión/metabolismo , Interleucina-1beta/genética , Masculino , Malondialdehído/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Fitoterapia , Hojas de la Planta/química , Prostaglandinas/metabolismo , Quercetina/aislamiento & purificación , Quercetina/farmacología , Quercetina/uso terapéutico , Ratas Wistar , Estómago/efectos de los fármacos , Estómago/patología , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patología , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
One of the most invasive species worldwide, Solenopsis invicta Buren, has been described in China since 2003. Recent studies have suggested that China populations are the result of introductions from the USA; however, detailed molecular studies need to be performed in order to understand the expansion and potential multiple introductions from other countries into China. As there were populations of red imported fire ant, S. invicta in different areas and with different methods of introduction, mitochondrial cytochrome oxidase I gene was used as a marker from 12 populations in four cities in Fujian Province, China, to determine the relationship of invasion among these populations. The three most common haplotypes previously describe in invasive populations of S. invicta: H5, H22 and H36, were found in Fujian. However, frequencies in each city were different. For instance, three populations from Longyan city which invaded with waste plastics, shared haplotype H5. Populations from Xiamen city and Jinjiang city which dispersed with nursery stock, sward and scrap leather, shared haplotype H22. The population from Nanyan village of Xinluo district, Longyan city, bore haplotype H36. Mitochondrial data reveals that the invasion history of S. invicta in Fujian Province is complex, including multiple invasions probably from other provinces within China. Security measures to prevent S. invicta spreading within China are as important as from overseas.
Asunto(s)
Hormigas/genética , Especies Introducidas , Animales , China , ADN Mitocondrial/genética , Genética de Población , Haplotipos , Control de Insectos/métodos , FilogeografíaRESUMEN
Diabetic complications cause noticeable liver damage, which finally progresses to diabetic hepatopathy. Nutritive antioxidants not only reduce the liver damage, but also prevent it by modulating the release of various proteins involved in apoptotic signaling cascades. This study explores the molecular mechanisms underlying diabetes-induced liver damage and its modulation by naringenin. Antioxidant status, liver & kidney biomarker enzymes, reactive oxygen species (ROS) generation, mitochondrial membrane potential, expression of apoptotic proteins like Bax (bcl-2 associated X), Bcl-2 (b-cell Lymhoma-2), Caspase-3, Caspase-9, AIF (Apoptosis inducing factor) and Endo-G (Endonuclease-G) were studied in streptozotocin induced diabetic rats. Significant hyperglycemia, disturbed antioxidant status, altered carbohydrate metabolizing enzymes, increased ROS and lipid peroxidation; decreased mitochondrial membrane potential and enhanced release of AIF and Endo-G were observed. Hyperglycemia also affected apoptosis and its related genes at both transcriptional and translational level (Caspase-3 & 9, Bax and Bcl-2) in the liver of diabetic rats. Naringenin, a flavonone, exerted anti-hyperglycemic effect and was able to prevent oxidative stress and resultant apoptotic events caused due to diabetes-induced hepatotoxicity. Thus, our study shows, a protective effect of naringenin against diabetes induced liver damage and redox imbalance, which could further be exploited for the management of diabetic hepatopathy.
RESUMEN
BACKGROUND: Cinnamomi cortex has wide varieties of pharmacological actions such as anti-inflammatory action, anti-platelet aggregation, and improving blood circulation. In this study, we tested to determine whether the Cinnamomi cortex extract has antioxidant activities. MATERIALS AND METHODS: Antioxidative actions were explored by measuring free radical scavenging activity, NO levels, and reducing power. The mechanism of antioxidative action of Cinnamomi cortex was determined by measuring iNOS and COX-II expression in lipopolysaccharide (LPS) stimulated Raw cells. RESULTS: Seventy percent methanolic extract of Cinnamomi cortex exerted significant 1,1-diphenyl--2--picrylhydrazyl (DPPH) free radicals and NO scavenging activities in a dose-dependent manner. More strikingly, the Cinnamomi cortex extract exerted dramatic reducing power activity (13-fold over control). Production of iNOS induced by LPS was significantly inhibited by the Cinnamomi cortex extract, suggesting that it inhibits NO production by suppressing iNOS expression. Additionally, COX-2 induced by LPS was dramatically inhibited by the Cinnamomi cortex extract. CONCLUSION: These results suggest that 70% methanolic extract of Cinnamomi cortex exerts significant antioxidant activity via inhibiting iNOS and COX-II induction.