Browsing by Author "Sibiya, Ntethelelo Hopewell."

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The acute effects of dioxidovanadium on blood glucose concentration and oxidative stress in the hippocampus of non-diabetic male Sprague Dawley rats and the chronic effects of dioxidovanadium on selected markers associated with hippocampal dysfunction in male streptozotocin-induced diabetic rats.
(2022) Dayanand, Yalka.; Ngubane, Phikelelani Siphosethu.; Khathi, Andile.; Sibiya, Ntethelelo Hopewell.
Diabetes mellitus is a disease associated with derangements in glucose metabolism and chronic hyperglycaemia. Chronic hyperglycaemia induces oxidative stress and inflammation that affect glucose sensitive hippocampal neurons resulting in generation of amyloid plaques and tau tangles. These are the primary markers used in the detection of neurodegenerative diseases such as Alzheimer’s and dementia. Hence, there is a strong correlation between diabetes and memory impairment. Current therapeutic options such as bolus insulin have been successful in the management of the disease. Despite the efficacy of these therapies, they however have been shown to possess undesirable effects that exacerbate the secondary pathological effects of diabetes on the hippocampus thereby contributing to the detriment of cognitive tasks such as learning and memory. Therefore, there is a need to explore alternative treatments. Transition metals have been shown to possess therapeutic effects with vanadium possessing the greatest potency in lowering blood glucose concentrations. However, studies have demonstrated toxic accumulation of vanadium in the hippocampus which result in the generation of oxidative stress and neurodegeneration. In our laboratory, we have synthesised dioxidovanadium (V) complex by attaching organic ligands to reduce the toxicity and improve potency of the metal. This complex has been shown to efficiently reduce blood glucose and elicit cardio and reno-protective properties. Despite these advancements the effects of this complex on the hippocampus and learning and memory are yet to be established. Therefore, in this study the aim was to evaluate the effect of dioxidovanadium complex on selected learning and memory parameters. Methodology The effect of vanadium on the brain was studied acutely and chronically. In the acute study, animals were separated into 2 groups, non-diabetic control group and a non-diabetic animal group which was were treated with vanadium complex (40 mg.kg-1 p.o). The treatment was administered at time 0. Subsequently an n=3 from each group was sacrificed at regular time intervals (1 hour, 2 hours, 6 hours, 24 hours, 5 days, 10 days) in each group. Blood glucose concentration was monitored before sacrificing and hippocampal tissue was harvested for malonaldehyde (MDA) analysis and glutathione peroxidase (GPx1) and tumour necrosis alpha (TNF-α). The second study was conducted over 5 weeks and consisted of an untreated non-diabetic control, a diabetic control, a positive insulin treated group (0.175 mg.kg-1 s.c) and two dioxidovanadium (V) treated groups (40 mg.kg-1 p.o), a non-diabetic and a diabetic group. Blood glucose was monitored weekly and the Morris water maze was conducted on the last week of the study. After 5 weeks the animals were sacrificed and hippocampal tissue was harvested for malonaldehyde (MDA) analysis, glutathione peroxidase (GPx1) tumour necrosis alpha (TNF-α), amyloid beta (Aβ) and hyperphosphorylated tau (pTau) ELISA’s. Results Acutely, dioxidovandium (V) did not lower blood glucose significantly in comparison to the control group. Interestingly, MDA, GPx1 and (TNF-α) were also not significantly different from the control group over all time periods in the study. Chronically, the glucose concentration of the dioxidovandium (V) treated diabetic group was significantly lowered when compared to the untreated group which displayed significantly increased glucose concentration in comparison to the non-diabetic control. The non-diabetic dioxidovanadium (V) treated group did not show a significant difference in glycaemic level. Increased MDA concentration in the diabetic group was significantly lowered by dioxidovanadium(V) treatment. GPx1 concentration in the dioxidovanadium (V) treated group significantly improved in comparison to the diabetic untreated control. The non-diabetic dioxidovandium (V) treated group showed no significant change in MDA and Gpx1 after the 5-week period. There was no significant difference in TNF-α in dioxidovanadium (V) treated groups, diabetic and non-diabetic. The concentration of Amyloid β was significantly lower in the diabetic control when compared to the non-diabetic control. The dioxidovanadium (V) treated groups, both diabetic and non-diabetic did not have a significant difference in comparison to the diabetic control. pTau concentrations in all groups did not significantly differ. Latency times for the last day of training the Morris water maze followed the same trend. The probe test results, which measured spatial memory, for the diabetic untreated and dioxidovanadium (V) treated groups were significantly reduced in comparison to the non-diabetic control group. The non-diabetic untreated and non-diabetic dioxodivanadium (V) treated were not significantly different. Conclusion Dioxidovanadium (V) treatment in non-diabetic animals did not induce hypoglycaemia acutely however reduced blood glucose concentration in diabetic animals when administered chronically. Dioxidovanadium (V) did not induce oxidative stress and may protect against neurodegeneration by enhancing antioxidant status and therefore was considered as a pro-oxidant in the hippocampus.
An investigation on the effects of a rhenium (V) compound with uracil-derived ligands on markers associated with hepatic, cardiovascular and renal complications in diet-induced prediabetic rats = Ucwaningo ngemiphumela yerhenium (V) compound ene-uracil ezifweni eziyamene nesibindi, inhliziyo kanye nezinso emagundaneni ayedla kodwa esengcupheni yesifo sikashukela.
(2023) Siboto, Angezwa.; Khathi, Andile.; Ngubane, Phikelelani Siphosethu.; Sibiya, Ntethelelo Hopewell.
Prediabetes is a metabolic disorder that often precedes the onset of type 2 diabetes mellitus. This development of this asymptomatic condition is associated with chronic consumption of high calorie diets and sedentary lifestyles. Prediabetes results in decreased insulin sensitivity in the peripheral tissues resulting in elevated blood glucose levels that are not high enough for a diagnosis of type 2 diabetes. This moderate hyperglycaemia has been shown to lead to trigger complications such as non-alcoholic fatty liver disease, renal dysfunction and cardiovascular disease which are generally only diagnosed during type 2 diabetes. The current management strategy for prediabetes consists of a combination of pharmacological and lifestyle intervention. The pharmacological agents such as metformin while lifestyle intervention involves dietary modification to lower calorie diets. Studies show that prediabetic patients tend to be more dependent pharmacological intervention and struggle with changing diets thus lowering the efficacy of drugs such as metformin. This often leads to the eventual development of prediabetes. Therefore, there is a need for new pharmacological agents that can remain effective in both the presence and absence of dietary intervention. In our laboratory we have synthesised a novel rhenium (v) compound with uracil-derived ligands that has shown promising biological activities that include anti-hyperglycaemic effects in diet-induced prediabetic rats. This compound was shown to improve insulin sensitivity in peripheral tissues in prediabetic rats. To advance from this knowledge, this study sought to investigate the effects of the rhenium (V) compound with uracil-derived ligands on markers associated with hepatic, cardiovascular and renal complications in diet induced prediabetic rats model. Iqoqa. Isendlalelo: Iziguli ezisengcupheni yokungenwa yisifo sikashukela zibhekene nokuba sengcupheni yokungenwa yizifo ezinhlobonhlobo, okubalwa kuzo isifo sesibindi, isifo senhliziyo, kanye nokulimala kwezinso ngenxa yesifo sikashukela. Uma sesihlahliwe isifo, indlela ephakanyiswayo ibandakanya ukuxutshwa kokwelapha ngemithi kanye nokushintsha indlela yokuphila. Kodwa-ke, kunenkinga eqoshwe phansi yokwahluleka kweziguli ezihluphekayo ukugcina imithetho eyamene nendlela yokudla, bagxile kakhulu ekusebenziseni imithi, okuholela ekutheni imithi ingasebenzi kahle. Ngenxa yalokhu, kunesidingo semithi emisha ezokwazi ukwelapha ngempumelelo ngisho indlela yokudla ingashintshiwe. Lolu cwaningo luhlose ukuhlola umthelela werhenium (V) compound ene-uracil-derived ligands kwabaqokiwe asebecishe bangenwe ushukela, kubhekwa kokubili ukuba khona nokungabi khona kokungenelela ngokudla. Izindlela zokuqhuba ucwaningo: Amagundane ajovwa ngeprediabetes ewuhlobo oluhlala amasonto angama-20 anomsoco wamafutha kanye nezinikamandla. Emuva kokujovwa, amagundane aqokwa ngokuwola afakwa ekulashweni ngemithi ehlukahlukene. Ajovwa ngerhenium (V) compound elinganiselwa ku-15 mg/kg kanye ngosuku, njalo ngosuku lwesithathu Isikhathi esingamasonto ayi-12, kunganakwa ukuthi uhlobo lokudla kunjani. Imiphumela: Engxenyeni yokuqala (1), ukujovwa ngerhenium (V) compound kwadala ukulapheka kwesibindi, ukunonophala komzimba kanye nokwakheka kwamafutha. Okokugcina, lokhu kwelashwa kwavimbela ukonakala kwesibindi okwafakazelwa ukwehla kwama-enzyme biomarkers esibindi. Engxenyeni yesibili (2), ukusebenzisa irhenium (V) compound kwadala ukwehla kokhwantalala kanye namapro-inflammatory cytokines markers. Lokhu kwehla kwayamaniswa nokwehla kwamazinga amatriglycerides anesisindo samafutha esiphansi. Ngaphezu kwalokho, kwaba nokubuyela esimweni kokukhiqizwa kwamafutha anesisindo esiphezulu kulawo magundane afakwa irhenium (V) compound. Engxenyeni yesithathu (3), ukusebenza kwezinso kwabuyela esimweni, okwabonakala ngokwenyuka kweGRF nokwehla kweKIM 1, ipodocin ne-aldosterone. Irhenium (V) compound yathuthukisa ukusebenza kwezinso ngokuvimbela ukhwantalala oluyamene nokwehla kukashukela ezinsweni kukona kokubili ukuba khona nokungabi bikho kokushintsha indlela yokudla. Isiphetho: Imiphumela yakhombisa ukuthi irhenium (V) compound yaphumelela ukuvikela isibindi nezinso, kanti yathuthukisa ukusebenza kwenhliziyo kulawo magundane ayejovwe ngeprediabetic enokudla. Yize kunjalo, lusadingeka ucwaningo oluzocacisa kabanzi ngokusebenza nokulethwa kwemiphumela yalo muthi.
Effects of momordica balsamina on glucose handling in high fat high carbohydrate induced prediabetic rat model and glucose handling in C2C12 induced insulin resistant cell lines: effects on selected metabolic markers.
(2020) Khumalo, Bongiwe.; Ngubane, Phikelelani Siphosethu.; Khathi, Andile.; Sibiya, Ntethelelo Hopewell.
Increased consumption of fat and high carbohydrate coincided with increased prevalence in type 2 diabetes, a condition whose onset is always preceded by prediabetes. Prediabetes is best characterised by hyperglycaemia, insulin resistance and glucose intolerance. Prolong chronic hyperglycaemia exacerbates complications of increased oxidative stress, advanced glycation end products (AGE), dyslipidaemia, hyperinsulinemia and increased inflammatory markers. Once diagnosed, life style and dietary interventions strategies are one of the cornerstones in management of prediabetes. However, patients do not adhere to these life style changes. Hence the present study investigated the effects of Momordica balsamina (MB) on glucose handling in insulin resistance in C2C12 palmitic acid induced insulin resistant cell lines and in high fat high carbohydrate induced prediabetic rat model. Methods Briefly, air-dried MB leaves were extracted with methanol to yield methanolic extracts. The study was divided into 2 experimental series invitro, first series investigated the effects of MB compounds on cell viability in skeletal muscle cell lines. The second series investigated the effects of MB on glucose uptake in palmitic acid induced insulin resistant skeletal muscle cell lines. Invivo studies encompassed HFHC-induced diabetic rats which were divided into untreated and treated groups. The rats were treated with metformin (500 mg kg-1 p.o.) as standard drug and MB (250 mg kg-1 p.o.) a test drug. MB (250 mg kg-1 p.o.) was administered once every third day. Blood glucose concentration, body weight and calorie intake were monitored every fourth week for a period of 12 weeks. Terminally, animals were sacrificed after which blood, liver and skeletal muscle were collected for biochemical analysis. Results MB significantly decreased media glucose concentration whilst glycogen concentration was improved by comparison with insulin resistant cells. Treatment with MB reduced tissue damage which was shown MDA in the plasma while also improving their antioxidant status compared with insulin resistant cells. In vivo study, we measured caloric intake, body weights, ghrelin concentration, OGT response, glycogen concentration, GLUT 4, glycogen synthase, HOMA2- IR value and glycated haemoglobin (HbA1c) concentration. Interestingly, Momordica balsamina coupled with dietary intervention resulted in decreased fasting glucose concentration, suggesting improvement in insulin sensitivity. Reduced caloric intake and restored a steady constant weight growth, thus preventing obesity. This was associated with decreased plasma ghrelin levels. Additionally, there was a significant decrease in HOMA2-IR value. This was further evidenced by decreased levels of glycated haemoglobin in the MB-treated rats. Conclusion The results obtained suggests that Momordica balsamina (MB) possesses anti-hyperglycaemic and protective properties in vivo and in vitro, therefore could be potent in the management of prediabetes, impaired glucose homeostasis induced hyperglycaemia. In addition, these findings provide new scope to comprehensively delineate the medicinal plant, Momordica balsamina mechanism of activity.
The effects of oxidovanadium complexes on glucose metabolism in liver and skeletal muscle cell lines.
(2014) Sibiya, Ntethelelo Hopewell.; Musabayane, Cephas Tagumirwa.
Abstract available in PDF file.
Investigating the effects of bredemolic acid on selected markers of some prediabetes-associated dysfunctions in diet-induced prediabetic rats.
(2019) Akinnuga, Akinjide Moses.; Khathi, Andile.; Sibiya, Ntethelelo Hopewell.; Ngubane, Phikelelani Siphosethu.
Prediabetes is an abnormal glycaemic state between normoglycaemia and chronic hyperglycaemia which is currently prevalent in developing and developed countries due to increased consumption of high caloric diet coupled with sedentary lifestyle. Prediabetes is associated with abnormal glucose metabolism. Additionally, the risk of developing prediabetes-associated complications such as non-alcoholic fatty liver disease (NAFLD), cardiovascular and renal diseases is not only present in overt diabetes mellitus but also in prediabetes. Management of prediabetes involves the combination of dietary and pharmacological interventions, however there is reported low compliance among patients as they tend to become overly dependent on the pharmacological interventions. Consequently, the pharmacological intervention efficacy is reduced as patients still progress to having overt diabetes. Therefore, managing prediabetes with anti-diabetic agents that will remain effective even in the absence of dietary intervention is considered necessary. Triterpenes have been found to have potential as anti-diabetic agents. Bredemolic acid (BA), a pentacyclic triterpene, has been reported to have increased biological activity relative to some other triterpenes. In this study, we sought to investigate the effects of BA on selected markers of some prediabetes-associated dysfunctions such as abnormal glucose homeostasis, hepatic, cardiovascular and renal dysfunctions in a prediabetic rat model in both the presence and absence of dietary intervention. Materials and Methods Thirty six (36) Sprague Dawley male rats that weighed 150 – 180g were divided into two groups: the non-prediabetic (n=6) and the prediabetic groups (n=30) which were fed a normal diet (ND) and high fat high carbohydrate (HFHC) diet respectively for 20 weeks to induce prediabetes. At 20th week, prediabetes was confirmed by assessment of fasting blood glucose (FBG) and oral glucose tolerance test (OGTT). The prediabetic rats were further sub-divided into five groups (n=6) and treated with either BA (80 mg/kg) or metformin (MET, 500 mg/kg) in the presence and absence of diet intervention for 12 weeks. Every 4 weeks of treatment, all the animals were placed in metabolic cages to determine caloric and fluid intake as well as urine output. Also, the body mass index (BMI), waist circumference (WC), blood pressure and heart rate were measured at every 4 weeks of treatment. After the 12 weeks of treatment, the animals were sacrificed, blood samples were collected into EDTA sample bottles and centrifuged to obtain plasma. Also, the skeletal muscle, liver, heart and kidney were collected, weighed, snapped frozen with liquid nitrogen and stored at -80°C before the biochemical analysis of selected markers of glucose homeostasis, hepatic, cardiovascular and renal functions. Results In the first study, the untreated diet-induced prediabetic rats had a significantly increased body weight, increased caloric intake, elevated glycated haemoglobin, increased ghrelin plasma concentration, decreased muscle glycogen concentration, insulin resistance and hyperinsulinaemia compared to the non-prediabetic rats. However, BA treatment with or without diet intervention ameliorated the body weight, caloric intake, glycated haemoglobin, muscle glycogen, glucose tolerance, plasma insulin and increased the expression of glucose transporter 4 (GLUT 4) in the skeletal muscle by comparison to the untreated prediabetic rats. Prediabetic induction in the second study resulted into elevated plasma concentration of liver enzymes, increased liver glycogen and triglyceride concentrations, increased oxidative stress in the liver and decreased sterol regulatory element binding protein (SREBP1c) by comparison to the non-prediabetic animals. Conversely, administration of BA with or without dietary intervention ameliorated liver functions by decreased oxidative stress, decreased liver enzymes, decreased liver glycogen and triglyceride as well as increased hepatic SREBP1c concentration in comparison to the untreated prediabetic animals. The results in the third study showed that the untreated prediabetic rats had a significantly increased body mass index (BMI), waist circumference (WC), blood pressure, heart rate, lipid profile, oxidative stress and inflammatory markers with significantly decreased endothelial nitric oxide synthase (eNOS) by comparison to the non-prediabetic control rats. On the other hand, the administration of BA with or without diet intervention improved cardiovascular functions by a decrease in BMI, WC, total cholesterol concentration, triglyceride concentration, blood pressure, heart rate, oxidative stress and inflammation with significant increase in eNOS plasma concentration in comparison to the untreated prediabetic rats. In the fourth study, the untreated prediabetic rats had a significantly increased fluid intake, urine output, sodium retention, potassium loss, aldosterone concentration, albuminuria, proteinuria, kidney injury molecule (KIM-1) and urinary podocin mRNA expression in comparison to non-prediabetic control and BA treated rats with or without diet intervention. Also, the untreated prediabetic rats presented increased albumin, total protein, urea, uric acid, creatinine and oxidative stress markers concentrations with a significant decrease in glomerular filtration rate (GFR). However, administration of BA with or without diet intervention attenuated oxidative stress, decreased urinary podocin mRNA expression and the aforementioned renal dysfunctions parameters. Conclusion This study showed that long term consumption of high caloric diet-induced prediabetes and resulted in abnormal glucose homeostasis, hepatic, cardiovascular and renal dysfunctions. Also, the results of this study showed that these dysfunctions are not only present during overt type 2 diabetes mellitus but already present at the prediabetic stage due to insulin resistance or hyperinsulinaemia that triggered oxidative stress in the physiological systems that we examined in this study. However, due to amelioration of insulin resistance via improved insulin sensitivity and earlier reported antioxidant activities that are common to all pentacyclic triterpenes, administration of BA significantly ameliorated the prediabetes-associated dysfunctions (abnormal glucose homeostasis, hepatic, cardiovascular and renal dysfunctions) with or without diet intervention in the prediabetic stage.