Browsing by Author "Nadar, Anand."

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Biomarkers and histopathologic changes in rats with monocrotaline-induced pulmonary hypertension following administration of antiretroviral medications.
(2020) Adeoti, Adekunle Olatayo.; Nadar, Anand.
Pulmonary hypertension (PH) is a progressive life-threatening vasculopathy characterized by dysregulated pulmonary vascular remodelling that results in an increased pulmonary vascular resistance, right ventricular hypertrophy, right heart failure and untimely death. Human Immunodeficiency Virus (HIV) is a recognized cause of PH with a relatively stable prevalence of HIV associated PH of 0.5% in most developed countries. One of the animal models of PH is comprises a once off monocrotaline (MCT) in rats, which leads to PH that mimics typical PH presentation observed in humans. Early administration of antiretroviral medication has been shown to prevent the development of PH in human subjects, however, in advanced cases no significant improvement was reported. The impact of antiretroviral medications is controversial; however, nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors (PI) have been shown to improve outcome in PH animal models. A potential connection between combination antiretroviral and PH in human subjects has been established which was contrary the protective effects of solely administer NRTI. The study was conducted to test the hypothesis that antiretroviral medications could ameliorate MCT induced PH in rat models and identify potential biomarker for PH. An approval was given by the Animal Research Ethics Committee of the institution (AREC/066/018M) of University of KwaZulu-Natal, Durban, South Africa, to conduct the study. Forty adult male Sprague-Dawley rats (body weight: 200-250 g) were randomly divided into five groups (n=8 per group). The treatment groups received a single intraperitoneal injection of MCT (60 mg kg-1) while the control group received an equivalent volume of intraperitoneal saline injection. Zidovudine (100 mg kg-1), ritonavir (30 mg kg-1), or combination of both drugs (zidovudine 100 mg kg-1 and ritonavir 30 mg kg-1) were administrated daily for the study period of 28 days to the rats in three of the four groups with MCT for 28 days respectively. On the twenty-eighth day of the study, rats were sacrificed, and the harvested lungs and hearts organ were analyzed. Gene expression was conducted using RT-PCR for the antioxidant’s enzymes, ASK-1 and a laboratory assay for lipid peroxidation was performed. A significantly higher mRNA gene expression of catalase, superoxide dismutase, and glutathione peroxidase in the heart tissue of the antiretroviral treated rats was observed and compared to the untreated groups. There was an increase in malondialdehyde (MDA) in the heart tissues of untreated rats (37.01±1.16 nmol/g, p<0.0001) compared to the control group (3.46±0.97 nmol/g) with an associated reduction in MDA by the antiretrovirals. Furthermore, an increase in the total antioxidant capacity (TAC) in AZT (0.85±0.02 nmol/g, p<0.0001), RTV (0.63±0.03 nmol/g, p<0.0001) and combination of AZT/RTV (0.77±0.06 nmol/g, p<0.0001) compared to untreated (0.28±0.025) rats. Furthermore, lower relative mRNA gene expression of ASK-1 was observed in the heart of the treated rats with zidovudine (2.67 ± 0.09, p < 0.0001), ritonavir (2.57 ±0.11, p < 0.0001) and a combination of both (2.75 ± 0.06, p < 0.0001) when compared to rats in the untreated group. An overexpressed mRNA gene of ASK-1 in the untreated rats (12.0 ± 0.90, p < 0.0001) when compared to the control. This study shows evidence that zidovudine and ritonavir ameliorate MCT-induced PH in rats by suppressing oxidative stress. Also, ASK-1 is a potential biomarker for anti-apoptotic characteristics of PH. Our findings indicate the antioxidative role of antiretroviral medications in PH and the role of biomarkers in PH.
Effects of moderate treadmill activity on cardiovascular factors in spontaneously hypertensive rats.
(2016) Mwewa, Kibwe.; Nadar, Anand.; Channa, Mahendra Lala.
Hypertension is a major health problem throughout the world because of its high prevalence and its association with increased risk of cardiovascular disease. Oxidative stress due to either increase of reactive oxygen species (ROS) or a compromised antioxidant status has also been positively correlated with cardiovascular diseases. The beneficial effect of physical activity has been well documented in the literature but studies have shown that in the SHR physical activity leads to oxidative stress. The SHR is an excellent model of essential hypertension and hence the present study was designed to investigate the effect of moderate treadmill activity on various cardiovascular factors in SHR. Sixteen male SHR and male Wistar rats (n=16) weighing between 70 and 90 g were used and they were randomly divided into four groups: The SHR exercised group (n=8), Wistar exercised group (n=8), SHR group (n=8) and Wistar (n=8). All the rats in exercised group were subjected to a weekly increase in the rate of activity on the treadmill. Blood pressure, blood glucose and body mass were recorded weekly. At the end of the 8 week experimental protocol, animals were fasted for 12 hours, anaesthetized with halothane and blood and tissue samples harvested. The C-reactive protein (CRP) and antioxidant-associated trace elements such as copper (Cu), iron (Fe), manganese (Mn), selenium (Se), and zinc (Zn) were measured in the blood, brain and skeletal muscle. Cardiotrophin-1 (CT-1) was determined in the plasma, total antioxidant capacity (TAC) and malonyldialdehyde (MDA) were determined in blood and skeletal muscle, plasma TAC levels was also measured. The superoxide dismutase (SOD), IkB and nuclear factor-kappa (NF-kB) gene expression were also measured in skeletal muscle and liver. Kidney sections were stained with Haematoxylin-Eosin (H&E) and sections of aorta were stained with Verhoeff-van Gieson (VVG). The results show that physical activity did not significantly change both the systolic and diastolic blood pressures in SHR. Plasma levels of CRP and NF-kB mRNA expression were increased in both SHR and Wistar exercised groups. An increase in oxidative stress due to physical activity was evident by an increase in TAC and MDA levels in the skeletal muscle. A significant decrease in blood TAC and SOD mRNA expression was also evident in the SHR exercise group. Physical activity also resulted in significant shifts in trace elements that are associated with a compromised antioxidant system.
Evaluation of the potential benefits of L-ergothioneine on selected complications associated with type-2 diabetes in a rat model.
(2021) Dare, Ayobami.; Nadar, Anand.; Channa, Mahendra Lala.
Several pathogenic factors promote type-2 diabetic complications in patients, including cardiomyopathy, nephropathy, and non-alcoholic fatty liver disease (NAFLD). Specific nutraceuticals from food may act as a medicinal adjuvant in managing diabetic complications. L-ergothioneine (L-egt), a bioactive compound obtained from medicinal mushrooms, beans and some meat products, has been shown to reduce lipid accumulation, provide cytoprotection in tissue injury and enhances therapeutic efficacy when used as adjuvant. This study investigated the effect of L-ergothioneine with or without metformin on pathogenic metabolic pathways and biomarkers associated with selected diabetic complications in a type-2 diabetic rat model. Ninety (90) adult male Sprague-Dawley (175±20)g rats were divided into three study groups [study 1 (36), study 2 (30) and study 3 (24)]. A 10% fructose solution was provided ad libitum to adult male Sprague- Dawley (175±20)g rats for 14 days followed by a single intraperitoneal injection of low dose streptozotocin (STZ 40mg/kg bwt, i.p) to induce type-2 diabetes after which the animals were randomly divided into six, five, and four groups (n=6) in studies 1 (liver), 2 (kidney), and 3 (heart), respectively. The control groups were administered 1ml/100g distilled water, while L-egt (35mg/kg bwt), metformin (500mg/kg bwt), and losartan (20mg/kg bwt) were administered in the other groups. At the end of each study, animals were euthanized via decapitation, blood samples were collected, while the heart, kidney, and liver tissue were excised and used for biochemical, RT-qPCR, ELISA, western blotting, and histopathological analysis. An in-silico study was done to evaluate the molecular antioxidant mechanism of L-egt. Administration of L-egt, with or without metformin, to diabetic animals positively altered selected biomarkers of hepatic, renal, and cardiac dysfunction and prevented structural damage in these tissues. This treatment regimen mitigated oxidative stress, inflammation, and fibrosis by downregulating (p<0.05) SREBP1c, FAS, NF-kB, fibronectin, TGFβ1, and Keap1 expression and upregulating (p<0.05) Nrf2, Sirt1, NQO1, and HO1 expression compared with the diabetic control animals. Interestingly, co-administration of L-egt and metformin improved glucose homeostasis and reduced HOMA-IR. The in-silico study showed that L-egt binds to the active site of Nrf2 and may serve as a ligand to activate this potent antioxidant molecule. The overall result from this study showed the potential benefits of L-ergothioneine in the management of selected complications associated with type-2 diabetes. This bioactive compound may be an effective adjuvant to attenuate hypertriglyceridemia, oxidative stress, and inflammation, thereby protecting vital organs associated with diabetic complications against injury and improving glycemic control when coadministered with metformin to delay the onset of diabetic complications.
Impact of quercetin-3-0-rutinoside on biochemical and reproductive profile of rats prenatally exposed to high fat diet.
(2020) Adeyemi, Toluwalope Esther.; Nadar, Anand.; Channa, Mahendra Lala.
The increasing prevalence of infertility and obesity over the last few decades have become a major public health challenge among individuals within the reproductive age. Consumption of a high-fat diet (HFD) is a harbinger for many metabolic alterations and diseases including infertility and subfertility. Studies have shown that the reproductive health of an individual can be programmed prior birth since exposure to certain environmental factors especially during intrauterine life play significant roles in transcriptional and epigenetic alterations in pivotal genes. However, understanding the molecular mechanisms linking oxidative stress caused by adverse environmental conditions to intrauterine alterations at critical periods of development might help in the clinical management of diet-induced infertility problems. This study therefore aimed at investigating the impact of maternal HFD consumption on sex-linked differences in the reproductive hormone profiles of diet unexposed offspring and examined the therapeutic potential of 150 mg/kg Quercetin-3-O-rutinoside (QR) against the HFD-induced biological changes. Adult female Sprague Dawley rats were randomly divided into two groups and fed either 45% HFD or normal diet (ND) for eight weeks before mating with male rats fed ND. Thereafter, the pregnant rats were divided into four dietary treatment groups: ND, HFD, ND+QR, and HFD+QR. At gestation day 19 (GD19), n=7 animals per group were sacrificed. Blood and tissue samples were collected and stored at -800C for biochemical and molecular analyses. The remaining dams were allowed to litter naturally and sacrificed. The pups were also sacrificed at postnatal day (PND) 21, 28 and 35. Blood and tissue samples were collected and stored for subsequent analyses. Using standard laboratory procedures, we measured oxidative changes in the liver, placenta and brain tissues by assessing levels of malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), catalase and nitric oxide (NO). Concentrations of hypothalamic gonadotropin releasing hormone (GnRH), serum luteinizing hormone (LH), testicular testosterone, and brain tumour necrosis factor (TNF-α) and glucagon-like peptide 1 (GLP-1) were assessed via enzyme linked immunosorbent assay (ELISA) technique. HFD-induced transcriptional changes in chemerin, chemokine-like receptor (CMKLR 1), TNF-α, GLP-1, interleukin-1 (IL-1β) and nuclear factor kappa B (NFκB) in the hypothalamic and testicular tissues were assessed by reverse transcriptase polymerase chain reaction (RT-PCR). After eight weeks of maternal HFD consumption, lipogram test indicated decreased plasma total cholesterol (TC) level, hypertriglyceridemia and increased low-density lipoprotein (LDL) levels. Our findings also showed that offspring of HFD-fed dams had delayed fur appearance and lower body weight compared to those from the control (ND) dams. These morphological changes were accompanied by elevated MDA levels in placenta, liver and brain tissues of HFD-fed dams and their diet-naïve offspring. Furthermore, there was evidence of hepatic nitrosative stress, time-dependent and sex-linked differences in hepatic SOD and brain GSH levels in the offspring. Also, hypothalamic GnRH and serum LH levels were significantly reduced at PND 28 and 35 in the offspring. Moreover, testicular testosterone was decreased at PND 35 in offspring of HFD-fed dams. Upregulation of chemerin, TNF-α, IL-1β mRNA transcripts in the hypothalamic-gonadal axis of male offspring indicates possible HFD-induced tissue inflammation and consequences for dysregulated steroidogenic and/or reproductive functions. Elevated brain GLP-1 may be linked to activated bioenergetic and homeostatic responses to HFD-induced oxidative stress. Overall, maternal HFD exposure led to induced oxidative stress, low-grade tissue inflammation and decreased levels of gonadotropins and androgens in their diet naïve offspring, whereas QR has little or no significant effects on these parameters.
The interrelationship of dietary cholesterol, copper and zinc on plasma lipids and tissue copper and zinc levels in the rat.
(1992) Nadar, Anand.; Burger, F. J.
No abstract available.
An investigation into the neurochemical and behavioural patterns of C57Bl6 mice exposed to "Sugars" and its constituents.
(2020) Chetty, Yvette Yolanda.; Nadar, Anand.; Naidoo, Panjasaram.
“Sugars” is an illicit drug cocktail that is a low-grade mixture of heroin and other opioids. The composition of this cocktail is highly varied as other ingredients are added during its manufacturing process to add bulk to the mixture and possibly increase profits of the suppliers. This highly addictive cocktail requires only a single use to initiate dependence and if not used timeously thereafter, severe withdrawal symptoms occur as soon as four hours after the last use. Due to the highly variable composition of this drug cocktail, it has been difficult to create a rehabilitation program with a low relapse rate as the physiological mechanisms of action of this cocktail have not been previously investigated. This study therefore aimed to investigate the physiological effects of “Sugars” and its ingredients in an animal model. This would provide novel findings on the pharmacological actions of the components of “Sugars” in the body as well as the physiological changes that may result during administration and withdrawal of the drug. This thesis is comprised of four manuscripts viz. one review paper that discusses the psychosocial issues of “Sugars” from an ethnographic standpoint and three experimental papers that focus on neurophysiology, behaviour, and immunology. The first experimental paper focuses on dopamine concentrations which were analysed using an ELISA assay and the sucrose preference test which can be used to assess the anhedonic behaviour in an animal model. The second paper focuses on the changes in memory function which was assessed using the Morris water maze and hippocampal mass and the third paper discusses changes in circulating immune cells following the analysis of blood samples with a heamotology analyser . The major findings emanating from this study were that administration of “Sugars” resulted in substantial changes in the dopaminergic system, cognitive abilities and haematological parameters involved in immunity; however, it was also observed that these changes were potentially reversed following a withdrawal period of 10 days in a mouse model. The extent of the effects observed may have also been influenced by the ratio of the ingredients in the cocktail. These novel findings can therefore assist in the formation of a targeted rehabilitation program that factors in the changes in the various physiological systems as discussed in this thesis. Key words: “Sugars”, illicit drug cocktail, dopamine, heroin, hippocampus
Oxidative stress of tissue in hypertensive rats.
(2006) Govender, Melvin M.; Nadar, Anand.
Oxidative stress, resulting from an antioxidant/free radical imbalance, is considered to be an important etiologic factor in the patho-physiological changes associated with salt sensitive hypertension. An important unresolved issue in hypertension research is the mechanism for organ damage during the development of the syndrome. Reactive oxygen species (ROS) such as the superoxide radical (02) , hydrogen peroxide (H202), and the hydroxyl radical (OH), may playa critical role in the pathogenesis of hypertension by targeting the very tissue that is responsible for regulating blood pressure, during the hypertensive state. Thus, this study was undertaken to evaluate the antioxidant and free radical status in the DSS rat strain, which has been shown to be an excellent model of salt sensitive hypertension. The antioxidant status was evaluated on the basis of the vascular superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels, and the free radical status was evaluated on the basis of the plasma H20 2 concentration. The levels of malonyldialdehyde (MDA), which is a bio-marker for lipid peroxidation was used to determine the level of oxidative stress in the kidney, liver and brain. The kidney and liver were also subjected to an induced free radical mediated lipid peroxidation, by exposing the tissue to increasing known concentrations of H202 (2.5mM - 15mM). The level of lipid peroxidation was used to assess the tissues antioxidant buffering capacity to an induced free radical "attack". The results have shown that the DSS strain may have a compensatory increase in vascular SOD levels, to counter an increase in 02-. SOD levels were significantly lower during salt loading. The GPx levels were significantly lower in the DSS strain, and showed a slight increase during salt loading. The results demonstrate that the DSS strain has a compromised antioxidant status compared to the DSR strain. The plasma H202concentration displayed non-significant changes in the DSS strain, however salt loading did result in a non-significant increase in the plasma H202 concentration in the DSS strain. The GPx : HZ02 ratio, demonstrated an inadequate increase in GPx levels during salt loading to neutralise this non-significant increase in HzOz concentration. The kidney showed an increased level of in vivo lipid peroxidation, which could implicate increased tissue damage, and thus confirm the kidney as being a target organ during the hypertensive state. The liver and brain showed non-significant differences in the level of in vivo lipid peroxidation and are therefore thought not to be target tissue in the hypertensive state. The kidney displayed a decreased antioxidant buffering capacity to the induced free radical "attack", thereby demonstrating the tissue's decreased ability to neutralise an increased free radical level. Although the liver displayed a "normal" level of in vivo lipid peroxidation, it also displayed a decreased antioxidant buffering capacity to an induced free radical "attack", showing that the liver is able to cope with in vivo free radical levels, but at higher free radical levels, its loses its ability to quench a free radical "attack" and thereby minimise lipid peroxidation. The in vivo lipid peroxidation levels of the kidney, liver and brain have shown that tissues have varying abilities to cope with tissue oxidative stress, and behave differently, in their free radical quenching abilities. These results have shown that a compromised free radical and antioxidant status results in oxidative damage to the tissue responsible for regulating blood pressure.
The role of angiotensin ll and oxidative stress in the spontaneously hypertensive rat.
(2011) Govender, Melvin M.; Nadar, Anand.
Oxidative stress resulting from an imbalance between free radicals and antioxidants is considered to be an important etiological factor in the development and maintenance of hypertension. Angiotensin II (Ang II) has been shown to be an important regulator of blood pressure and acts to elevate blood pressure by its pressor effects. The pressor effects of Ang II are well documented but recent evidence has suggested another possible role of Ang II in elevating blood pressure, whereby it acts via an independent mechanism that is directly linked with oxidative stress. The spontaneously hypertensive rat (SHR) is a widely used model in the investigation of the pathophysiological mechanisms involved in hypertension. This study was therefore undertaken to determine whether Ang II acts as a causative factor via oxidative stress in the development and maintenance of hypertension in the SHR. This was elucidated by evaluating the role of both the endogenous in vivo levels of Ang II as well as an exogenous sub-pressor dose of Ang II, on oxidative stress and its associated parameters. The parameters evaluated included, the antioxidant status of the model on the basis of the levels of the major antioxidant enzymes viz. SOD, GPx and catalase; the free radical generating capacity, by assessing the activity of the membrane bound enzyme NADPH oxidase and the levels of H2O2. The study also evaluated the levels of the endogenous vasodilator nitric oxide (NO), remodelling of the vasculature and the level of tissue oxidative stress in the kidney. The results show that the SHR has an elevated plasma Ang II level and an elevated level of oxidative stress, thus showing that in this model there is an intimate link between oxidative stress and Ang II. The SHR also shows depleted levels of NO and thus a decreased vasodilatory capacity and increased remodelling of the vasculature. The kidney showed an increased level of lipid peroxidation, which was due to the elevated levels of oxidative stress. All of these pathophysiological changes contribute to the elevation in blood pressure in this model. The long term infusion of the sub-pressor dose of Ang II affected the SHR to a greater extent than the Wistar. Although the dose of Ang II elevated the blood pressure in both models, the degree of the pathophysiological changes associated with the elevation in blood pressure was greater in the SHR. The Ang II infusion in both these models demonstrated that in the SHR which is genetically predisposed to hypertension, adjustments are made to the antioxidant system, that result in an elevated level of protection against oxidative stress. These results show that Ang II acts as a causative factor in the pathogenesis of hypertension in the SHR via its well documented pressor effects, as well as via a multitude of independent mechanisms that are linked to oxidative stress. This is substantiated by the significant decrease in NO that is caused by the elevated oxidative stress, as well as the previously described pathophysiological changes. This study has therefore shown that Ang II has an intimate causative link with oxidative stress that results in parallel mechanisms that work concomitantly with each other in hypertension in this model.
The role of antioxidants in atherogenesis and salt-sensitive hypertension.
(2003) Nadar, Anand.; Somova, Liliana I.
Abstract available in PDF file.
“Sugars”: the chemical characterization of a prevalent illicit drug cocktail in South Africa.
(2016) Chetty, Yvette Yolanda.; Nadar, Anand.
ABSTRACT Introduction “Sugars” is an illicit drug cocktail that is thought to be a mixture of heroin, cocaine and other substances in order to add bulk to the final product. Since its emergence in a local KwaZulu-Natal community known as Chatsworth in 2006, the use of the drug has spread to other provinces in South Africa and has currently become a popular drug amongst the youth. The affordability of the cocktail has allowed it to become rampant in low income communities and this coupled with its accessibility further reinforces “Sugars” as the preferred drug of choice. The use of the drug allows the user to experience euphoria, however once the effects wear off, the pain of the resulting withdrawal or “roster” drives the individual to continue using the drug. The withdrawal symptoms range from common cold and flu-like symptoms to extreme bone pain, stomach cramps, constipation and nausea. There have been attempts at rehabilitating “Sugars” addicts however, due to the lack of knowledge of a precise chemical composition of the cocktail, it is difficult to effectively maintain therapeutic interventions. Aim The aim of this study was therefore to chemically characterize the composition of “Sugars”, thereby allowing for the development of targeted treatment options for rehabilitation centres. Method Batches of samples of the mixture were sourced from 3 independent suppliers in the Durban South area of KwaZulu-Natal, South Africa. Chromatographic techniques were used to separate the individual constituents of the mixture and determine molecular weights of these compounds. Nuclear magnetic imaging was used to identify the compounds. Results and discussion The tests confirmed the presence of heroin, papaverine and noscapine in the “Sugars” samples analysed. However, there was variance noted in the composition between the different sources of the drug. We hypothesize that “Sugars” was therefore not heroin that is bulked up with other substances, but may be the waste product of the final purification process in the illicit heroin manufacturing process. Conclusion It was concluded that “Sugars” contained heroin, noscapine and papaverine. The variance in composition of heroin in the samples suggests independence between suppliers. The presence of papaverine and noscapine, which are impurities that are usually removed during the final purification of heroin, supports the hypothesis that “Sugars” is the waste product of the manufacture of heroin. Noscapine and papaverine are costly pharmaceutical products and we therefore speculate that it would not be economically viable to bulk up a cheap low grade drug cocktail with these compounds.