Naringin abrogates angiotensin-converting enzyme (ACE) activity and podocin signalling pathway in cobalt chloride-induced nephrotoxicity and hypertension.

PurposeThe persistent and alarming rates of increase in cardiovascular and renal diseases caused by chemicals such as cobalt chloride (CoCl2) in mammalian tissues have led to the use of various drugs for the treatment of these diseases. This study aims at evaluating the nephron-protective action of Naringin (NAR), a metal-chelating antioxidant against CoCl2-induced hypertension and nephrotoxicity.MethodsForty-two male Wistar rats were randomly distributed to seven rats of six groups and classified into Group A (Control), Group B (300 part per million; ppm CoCl2), Group C (300 ppm CoCl2 + 80 mg/kg NAR), Group D (300 ppm CoCl2 + 160 mg/kg NAR), Group E (80 mg/kg NAR), and Group F (160 mg/kg NAR). NAR and CoCl2 were administered via oral gavage for seven days. Biomarkers of renal damage, oxidative stress, antioxidant status, blood pressure parameters, immunohistochemistry of renal angiotensin-converting enzyme and podocin were determined.ResultsCobalt chloride intoxication precipitated hypertension, renal damage, and oxidative stress. Immunohistochemistry revealed higher expression of angiotensin-converting enzyme (ACE) and podocin in rats administered only CoCl2.ConclusionTaken together, the antioxidant and metal-chelating action of Naringin administration against cobalt chloride-induced renal damage and hypertension could be through abrogation of angiotensin-converting enzyme and podocin signalling pathway.

Antioxidant and Chemopreventive Effects of Azadirachta indica on Lead Acetate-induced Hepatotoxicity in Male Wistar Rats.

Toxic metals such as lead (Pb) cause severe liver damage in humans and animals, with oxidative stress prominently implicated in the pathogenesis of lead acetate­induced liver injury. Azadirachta indica is hepatoprotective due to its antioxidative effect. This study investigated the antioxidative role of A. indica (AI) and its chemopreventive effect on lead acetate (LA)-induced hepatocellular dysfunction with seventy adult male rats classified into group A- Control (distilled water), group B 0.1% LA only, group C and D- 0.1% LA + 100 mg/kg and 0.1% LA + 200 mg/kg AI respectively, group E- 0.2% LA, group F and G- 0.2% LA + 100 mg/kg and 0.2% LA + 200 mg/kg AI. Oxidative stress markers (MDA and H2O2), antioxidant parameters (GSH, SOD, CAT, GPx, GST), inflammatory markers (MPO and NO), alanine aminotransferase (ALT) and histopathological studies of the liver were evaluated. The results showed that LA administration caused a decrease in GSH, GPx, and GST while AI co-administration increased the activities of the antioxidants. Moreover, LA administration increased MPO, NO, MDA, and H2O2 levels whereas AI significantly reduced (P<0.05) these parameters. Histopathological examination revealed necrosis and mild infiltration by inflammatory cells in LA administered rats, whereas these lesions were absent in AI administered rats. In conclusion, A. indica demonstrates a protective role in lead acetate-induced hepatotoxicity, mainly via oxidative stress inhibition.

Protective effects and chemical composition of Corchorus olitorius leaf fractions against isoproterenol-induced myocardial injury through p65NFkB-dependent anti-apoptotic pathway in rats.

Background The fractions of Corchorus olitorius leaf (COLF) were evaluated against oxidative stress, inflammation and apoptosis in isoproterenol (ISO)-induced myocardial injury (MI) Wistar rats. Methods The n-hexane, dichloromethane, ethylacetate and ethanol fractions were obtained from COLF extract. Male Wistar strains were randomly grouped into 11 groups (n = 6 in each group), which comprises normal control group, MI control group, 4 fraction groups with two doses (50 and 100 mg/kg) and enalapril (10 mg/kg). The sera were obtained for biochemical studies like AOPP (advance oxidized protein product), CRP (C-reactive protein), LDH (lactate dehydrogenase), CKMB (creatine kinase-MB) and myocardial tissue obtained for GSH, p65NFkB, bax, bcl2, p53 and p65NFkB assays. Results The subcutaneous administration of ISO increased the serum level of CRP, LDH and CKMB significantly (p < 0.05) and decreased serum AOPP, tissue GSH and p65NFkB (p < 0.05) in the infarction control rats. Pretreatment with COLF and enalapril increased the tissue GSH and p65NFkB levels (p < 0.05) and significantly reduced serum CRP, AOPP, LDH and CKMB. The dichloromethane fraction (CODCM) being the most active was chosen to evaluate the anti-apoptotic effect. CODCM (50 and 100 mg/kg) and enalapril showed a significant (p < 0.05) effect through severe expression of p65NFkB, which correlates with increased bcl2 protein expression, decreased bax protein and p53 expression. Gas chromatography mass spectrometry revealed the presence of 26 compounds in CODCM. Conclusions From the present study, COLF protected the myocardial tissue against ischemic injury in rats probably via the p65NFkB-dependent anti-apoptotic pathway and attenuation of pro-inflammatory marker level.

Consequences of restricting antimalarial drugs to rapid diagnostic test-positive febrile children in south-west Nigeria.

OBJECTIVES: To investigate the consequence of restricting antimalarial treatment to febrile children that test positive to a malaria rapid diagnostic test (MRDT) only in an area of intense malaria transmission. METHODS: Febrile children aged 3-59 months were screened with an MRDT at health facilities in south-west Nigeria. MRDT-positive children received artesunate-amodiaquine (ASAQ), while MRDT-negative children were treated based on the clinical diagnosis of non-malaria febrile illness. The primary endpoint was the risk of developing microscopy-positive malaria within 28 days post-treatment. RESULTS: 309 (60.5%) of 511 children were MRDT-positive while 202 (39.5%) were MRDT-negative at enrolment. 18.5% (50/275) of MRDT-positive children and 7.6% (14/184) of MRDT-negative children developed microscopy-positive malaria by day 28 post-treatment (ρ = 0.001). The risk of developing clinical malaria by day 28 post-treatment was higher among the MRDT-positive group than the MRDT-negative group (adjusted OR 2.74; 95% CI, 1.4, 5.4). A higher proportion of children who were MRDT-positive at enrolment were anaemic on day 28 compared with the MRDT-negative group (12.6% vs. 3.1%; ρ = 0.001). Children in the MRDT-negative group made more unscheduled visits because of febrile illness than those in MRDT-positive group (23.2% vs. 12.0%; ρ = 0.001). CONCLUSION: Restricting ACT treatment to MRDT-positive febrile children only did not result in significant adverse outcomes. However, the risk of re-infection within 28 days was significantly higher among MRDT-positive children despite ASAQ treatment. A longer-acting ACT may be needed as the first-line drug of choice for treating uncomplicated malaria in high-transmission settings to prevent frequent re-infections.

CONSÉQUENCES DE LA RESTRICTION DES ANTIPALUDIQUES AUX ENFANTS FÉBRILES POSITIFS AU TEST DE DIAGNOSTIC RAPIDE DANS LE SUD-OUEST DU NIGÉRIA: OBJECTIFS: Investiguer la conséquence de restreindre le traitement antipaludéen uniquement à des enfants fébriles avec un résultat positif à un test de diagnostic rapide (TDR) du paludisme dans une zone de forte transmission du paludisme. MÉTHODES: Les enfants fébriles âgés de 3 à 59 mois ont été dépistés avec un TDR du paludisme dans des établissements de santé du sud-ouest du Nigéria. Les enfants avec un TDR positif ont reçu de l'artésunate-amodiaquine (ASAQ), tandis que ceux avec un TDR négatif ont été traités sur la base du diagnostic clinique de maladie fébrile non liée au paludisme. Le critère d'évaluation principal était le risque de développer un paludisme positif au microscope dans les 28 jours suivant le traitement. RÉSULTATS: 309 (60,5%) des 511 enfants étaient positifs au TDR du paludisme tandis que 202 (39,5%) étaient négatifs au moment de leur inscription. 18,5% (50/275) des enfants TDR-positifs et 7,6% (14/184) des enfants TDR-négatifs ont développé un paludisme positif au microscope endéans le jour 28 après le traitement (ρ = 0,001). Le risque de développer un paludisme clinique endéans le 28è jour après le traitement était plus élevé dans le groupe TDR-positif que dans le groupe TDR-négatif (OR ajusté = 2,74; IC95%: 1,4 - 5,4). Une proportion plus élevée d'enfants TDR-positifs au moment de l'inscription étaient anémiques au 28è jour par rapport au groupe TDR-négatif (12,6% contre 3,1%; ρ = 0,001). Les enfants du groupe TDR-négatif ont effectué plus de visites non planifiées en raison d'une maladie fébrile que ceux du groupe TDR-positif (23,2% contre 12,0%; ρ = 0,001). CONCLUSION: Le fait de limiter le traitement de combinaison à l'artémisinine (TCA) aux seuls enfants fébriles présentant un résultat positif au TDR n'a pas eu d'effet indésirable significatif. Cependant, le risque de réinfection dans les 28 jours était significativement plus élevé chez les enfants TDR-positifs malgré le traitement par ASAQ. Un TCA à action prolongée pourrait être nécessaire en tant que médicament de choix en première ligne pour traiter le paludisme sans complications dans les régions à forte transmission afin de prévenir les réinfections fréquentes.

Interaction between rifampicin, amodiaquine and artemether in mice infected with chloroquine resistant Plasmodium berghei.

BACKGROUND: Artemisinin-based combination therapy (ACT) remains the most effective chemotherapeutic strategy in the management of malaria. However, reports of reduced susceptibility of Plasmodium falciparum to the ACT justify the need for continued search for alternative anti-malarial drugs. The use of antibiotics with anti-malarial properties represents a potentially valuable chemotherapeutic option for the management of drug resistant infections. Thus, the intrinsic anti-malarial activity of the combination of clinical doses of rifampicin with amodiaquine and artemether was evaluated in an animal model using Plasmodium berghei. METHODS: A modification of the suppressive tests in vivo was employed. The anti-malarial activity of standard doses of amodiaquine (AQ) with or without artemether (ART) and combined with varying doses of rifampicin (RIF 15 mg/kg or RIF 30 mg/kg body weight) was evaluated in 40 mice sub-divided into eight groups and inoculated intraperitoneally with 1 × 10(7) red blood cells infected with chloroquine-resistant P. berghei ANKA strain. There were two control groups of animals, one group received amodiaquine alone while the other group received saline. Parasiticidal activity and survival of the animals were assessed over 21 days. RESULTS: Parasitaemia in the control animals peaked at 38% on day 9 and all animals died by day 10. The combination of amodiaquine with rifampicin 15 mg/kg body weight was the most effective of all the combinations and more efficacious than amodiaquine alone. The order of superiority of anti-malarial efficacy of the combinations was as follows; AQ + RIF 15 > AQ > AQ + ART + RIF 30 > AQ + ART + RIF 15 > AQ +RIF 30. CONCLUSION: The combination of the clinical dose of rifampicin (15 mg/kg) with amodiaquine represents a potentially valuable treatment option in management of drug resistant malaria. In addition, the role of pharmacokinetic interaction in multiple drug therapy cannot be over-emphasized.