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Item Determinant of metabolic syndrome and its cardiovascular complications among people of African ancestry(2024) Eluwole, Omotayo AlabaCardiovascular disease is now a leading cause of death globally. However, metabolic syndrome is an extremely critical healthcare issue worldwide due to progressive increase in obesity and its related factors. Obesity is strongly associated with insulin resistance and other components of metabolic syndrome. There is discrepancy in the use of parameters for the diagnostic criteria of metabolic syndrome due to genetic and environmental variability in different ethnicity. Body mass index and waist circumference (WC) are commonly used in the assessment of central obesity and abdominal obesity respectively. Fahed et al observed that waist circumference was employed because measurement was easy, however, waist circumference alone is inconclusive of abdominal adiposity and must be interpreted with body mass index. The two measurements (WC and BMI) have been documented to be strongly related to insulin resistance. (Fahed et al., 2022). However, there is controversial assessment of metabolic syndrome using either waist circumference (WC) or body mass index (BMI) or waist hip ratio (WHR) or combination of two measurements (Kassi et al., 2011; Fahed et al., 2022). Our study assessed the prevalence of metabolic syndrome among apparently healthy 1516 participants from African ancestry using seven established diagnostic criteria (NCEP-ATPIII- National Cholesterol Education Program Adult Treatment Panel III, WHO- World Health Organization, IDF-International Diabetes Federation, AHA/NHLBIAmerican Heart Association/National Heart, Lung and Blood Institute, EGIR - European Group for the study of Insulin Resistance, AACE- American Association of Clinical Endocrinology). The result revealed highest prevalence of metabolic syndrome when modified NCEP-ATPIII [National Cholesterol Education Program Adult Treatment Panel III (ATP III)] was considered. The predictive assessment of blood pressure and arterial stiffness may be useful in achieving early detection and prevention of target organ damage. This study further compared clinic blood pressure, ambulatory blood pressure and central pressure using conventional blood pressure monitor, Spacelabs 90207 (Spacelabs Inc., Redmond, Washington, USA) and applanation tonometry Sphygmocor device respectively. The findings revealed that central blood pressure and ambulatory blood pressure are more predictive of cardiovascular events among people of African ancestry. Our findings are pointers to cardiovascular risk in the study population. Additionally, this study provides new insights to the role of obesity in the perturbation of left ventricular geometry of people of African ancestry with metabolic syndrome; using quantitative and comprehensive evaluation of biochemical and echocardiographic profile. Aldosterone produced locally in adipose tissue, heart, kidney and vasculature increase the expression of cytokines and other fibrotic factors. Thus, role of the local renin angiotensin aldosterone system (RAAS) in the pathophysiology of atherosclerosis and cardio-renal fibrosis was evaluated in animal study. With high prevalence of metabolic syndrome and obesity in Africans, elevated aldosterone from diet may likely predispose African community to diastolic dysfunction; this may be a pointer to increased incidence of heart failure in groups of African ancestry. Hence, this study lends insights into the potential role of TRPM7; a novel non selective cation channel and chanzyme in aldosterone-induced cardiovascular fibrosis. This study concluded that modified NCEP-ATPIII has suitable components for the diagnosis of MS in people of African ancestry. Metabolic syndrome in people of African ancestry is strongly associated with factors such as sex, smoking and alcohol. Consequently, MS and other risk factors such as obesity, aldosterone and insulin resistance may lead to left diastolic dysfunction among individuals with MS. Experimentally, aldosterone-salt induced cardio-renal fibrosis, aggravated by TRPM7 might be the underlying pathogenesis of MS and its cardiovascular complications in Africans; thus suggests TRMP7 inhibitors has potential anti-fibrotic agents.Item Genetic influences on methylation of the mu-opioid receptor gene in black South African nyaope users(2024) Masiangwako, TsholofeloBackground: Nyaope is a highly addictive heroin derivative that elicits its effects through interaction with the µ-opioid receptor. Genetic and epigenetic mechanisms, such as mutations and (cytosine-phospho-guanosine) CpG methylation, alter the function of the mu-opioid receptor gene (OPRM1) and protein. The single nucleotide polymorphisms (SNP) rs1799971 (118 A>G) and intronic rs3778150 (T>C) in the OPRM1 have previously been associated with heroin use. The SNP 118 A>G can influence methylation levels of OPRM1 and alter mRNA and protein expression. This study compared the degree of OPRM1 methylation and frequency of SNPs 118 A>G and SNP rs3778150 in peripheral blood samples of black South African male nyaope users (n=200) to age-and-gender-matched screened controls (n=55) in a South African population. Method: DNA was extracted from whole blood samples, bisulfite converted, amplified by methylation-specific PCR and sequenced to determine individual and total methylation levels across a total of 29 CpGs within the OPRM1 promoter region (chr6: 154331689- 154332224bp). The sequencing data was analysed by each of the two methods, methylation assignment bias and partial methylation bias methods. Results: We found that the total methylation levels were lower in nyaope-users than in controls when using the methylation assignment bias method. Only CpG 29 sites showed substantial methylation in the control group in both approaches. In the partial methylation bias method, our main findings showed no differences in the total methylation levels between the two groups while most CpGs displayed significantly higher levels of partial methylation in nyaope-users while controls exhibited significantly higher unmethylation sites at some CpGs. The AG genotype frequency for SNP 118 A>G, was higher in controls than in nyaope-users while other genotypes (AA & GG) for SNP rs1799971 and (TT, CT, CC) SNP rs3778150 were broadly similar in both groups. While the TT genotype SNP rs3778150 occurred more frequently in the control group, there was no haplotype relationship between SNP rs1799971 and rs3778150. Neither was there any correlation observed between nyaope consumption and the presence of SNP rs1799971 and/or rs3778150 in the study populations. Conclusion: This study provided evidence that methylation may not be associated with nyaope addiction and that SNPs rs1799971 and rs3778150 did not alter the methylation status of the OPRM1 promoter or contribute to nyaope addiction in a black South African male population. The findings of this study are a novel contribution to the body of literature as, to the best of our knowledge, this is the first study to investigate OPRM1 gene methylation patterns and the frequency of these specific SNPs in a South African population of nyaope users.Item Prehypertension and target organ changes in an African population(2021) Mokwena, Caroline MotheoHypertension (HT) remains the leading risk factor for cardiovascular diseases (CVDs) and a leading cause of death globally. It is estimated that HT causes 10.4 million deaths annually. Studies showed that even individuals who are in the normotensive( NT) range show indications of target organ damage. This gave rise to a new category of HT called pre-hypertension(pre-HT). Prior 2017, HTwas defined as a blood pressure (BP) ≥ 140/90 mm Hg and pre-HT was defined as a BP of 120 mm Hg to 139 mm Hg. In 2017 these guidelines were revised by the American College of Cardiology (ACC) and the American Heart Association (AHA). According to these new guidelines, HTis defined as BP≥ 130 mm Hg and pre-HTas BP of 120 mm Hg to 129 mm Hg. However, both the South African Hypertension Society (SAHA) and European Society of Cardiology/European Society of Hypertension (ESC/ESH) do not recommend these new guidelines. Both organisations still recommend the definition of HTas a BP ≥ 140/90. Even though the ESC/ESH guidelines are accepted by the SAHA, there is no evidence to indicate which of the guidelines are more appropriate for African communities since all the studies were conducted in western countries like the United States of America (USA) and the United Kingdom (UK). Therefore, in this study we recruited South African peoplefrom South Africa, determined the prevalence of HT and pre-HT assessed cardiovascular target organ changes.We recruited 1211 participants of African ancestry and measured both conventional and ambulatory blood pressure (ABP). To asses cardiac changes we used echocardiography to measure early-to-late diastolic filling and left ventricular wall thickness. To measure vascular changes we used the SphygmoCorto measure pulse wave velocity (PWV). Blood samples were collected to measure plasma hormone concentrations and 24-hour urine samples were collected to measure urinary electrolyte excretion. Anthropometric measurements were taken and body mass index (BMI) was calculated as weight divided by height squared. A standardised questionnaire was administered to determine intake of medication and lifestyle habits like alcohol intake and cigarette smoking. Our results indicate that the average age of the population was 44.05±18.29 years. There were more female(65%) participants than male (5%). The overall population was overweight with a BMI of 29.47±8 kg/m2. Fifteen percent (15%) of the sample population were smokers. Participants who consumed alcohol were 21%. When the AHA guidelines were used, more participants were hypertensive (41.5%) compared to those who were pre-hypertensive (18.6%). On the other hand when the ESC/ESH guidelines were used, more participants were pre-hypertensive (34.2%) compared to those who were hypertensive (25.9%). The night-time BP of the pre-hypertensives and grade-1 (HT1) was within normal range while the night-time BP of the grade 2 (HT2) and grade 3 (HT3) was elevated. The pre-hypertensives and the three HT groups had an attenuated decline in nocturnal BP. Compared to the NT, the PWV and left ventricular mass index (LVMI) of all the HT groups, including the pre-HT were significantly higher. As the HT stages progressed there was a reduction in diastolic function observed.In conclusion our results indicate that according to the SAHS/ESH that are currently applied in SA, pre-HT is overestimated while HT is underestimated. Furthermore, using the AHA guidelines, our findings indicate that cardiovascular target organ changes increase significantly fromthe pre-HTto the HT1 stage. Since both stages (pre-HT and HT1) are considered NT according to the SAHS/ESC/ESH guidelines, by the time they reach HT2 stage which is the first stage considered as hypertensive, target organ damage may have progressed significantly. Therefore, these results indicate that the AHA/ACC guidelines are more appropriate for the SA population. If these guidelines can be adopted for HT treatment, CVD target organ damage can be significantly reduced.Item The effect of a high fructose diet and glucocorticoids intervention on cardiac structure and function in male Sprague Dawley rats(2024) Mokoena, Thobekile SiboneloThe impact of glucocorticoids on left ventricular (LV) morphology and function in animal models and their interaction with metabolic syndrome (MetS) remain unclear. This study aimed to determine the effects of glucocorticoids on LV structure and function and whether MetS exacerbates these effects. Male Sprague Dawley rats were assigned to control, glucocorticoids (GC), high fructose (HF) and glucocorticoids + high fructose (GC+HF) groups (n=10each). HF and GC+HF groups received a 20% fructose solution, while GC and GC+HF groups received 10mg/kg intraperitoneal injections of methylprednisolone daily for 10 weeks. After 10 weeks, LV function was assessed, and cardiac collagen content was determined. Relative wall thickness was greater in the GC group compared to the control (p=0.01). The heart weight indexed to body mass, LV weight indexed to body mass and the relative wall thickness were greater in the GC+HF compared to the control (p=0.04; p=0.009; and p=0.01 respectively). The LV end-diastolic volume was lower in the GC+HF group compared to the control (p=0.007) and the HF(p=0.01). The lateral e’ was lower in the GC and GC+HF groups compared to the control (p=0.001 and p=0.005 respectively) and HF (p<0001 and p=0.0001). The E/e’ was greater in GC and GC+HF rats compared to control (p<0.0001 and p=0.004, respectively) and HF (p<0.0001 and p=0.02, respectively). Cardiac collagen content was greater in GC and GC+HF groups compared to control (p=0.001 and p<0.0001 respectively). In conclusion, glucocorticoid administration induced cardiac remodelling, impaired LV relaxation and increased LV diastolic filling pressures. The presence of MetS resulted in concentric hypertrophy, but did not worsen LV diastolic dysfunction.Item The potential of zingerone to protect against ethanol-induced liver disease(2024) Asiedu, BerniceAlcohol can cross the placental blood-barrier and can also be secreted into breast milk. This can affect developing foetuses and/or nursing neonates negatively, thus impacting on metabolic health in early or later life. Zingerone (ZO) has anti-oxidant, anti-diabetic, anti-inflammatory, hypolipidaemic and hepato-protective properties. I hypothesised that neonatal oral administration of ZO could programme for protection against alcohol-induced metabolic derangements in suckling Sprague-Dawley (SD) rat pups mimicking human neonates that indirectly consume alcohol through their mother’s breast milk. The first experiment evaluated ZO’s potential to protect suckling rat pups against alcohol-induced metabolic derangements. Seventy 10-day old SD rat pups (males = 35; females = 35) were randomly assigned to four groups and administered treatments daily from postnatal (PND) 12-21: group 1-nutritive milk (NM), group 2-1 g/kg body mass ethanol (Eth), group 3- 40 mg/kg body mass ZO and group 4 - NM+Eth+ZO. Terminal body mass, blood glucose concentration, lipid profile and hepatic antioxidant status were determined. Zingerone and ethanol had no effect on pups’ growth performance, blood glucose, total cholesterol, HDL- and LDL-cholesterol and hepatic thiobarbituric acid (TBARs), superoxide dismutase and catalase concentrations (p > 0.05). Ethanol decreased plasma triglyceride concentration in female rat pups (p = 0.04) but increased hepatic cytochrome P450E21 (CYP2E1) and decreased total glutathione (tGSH) concentration in male rat pups (p < 0.05). Zingerone increased tGSH in male rat pups (p = 0.003). A combination of ZO and ethanol increased (p = 0.047) hepatic CP2E1 concentration in male rat pups compared to control but had no effect (p = 0.717) on tGSH concentration. Neonatal orally administered ethanol induced hepatic oxidative stress which ZO, administered during the suckling period, failed to protect against In experiment II, 123 SD rat pups (males = 60; females = 63) were administered the same neonatal interventions as in experiment I but from PDN22 they were grown to adolescence (PND45) with ad libitum access to normal rat chow and tap water. From PND 46-100, rats from each of the four neonatal groups were divided into two subgroups: subgroup I had tap water and subgroup II had ethanol solution as drinking fluids, for eight weeks. Body mass, feed, fluid and caloric intake were measured. Blood glucose concentration, plasma alanine transaminase and aspartate transaminase (ALT and AST) activities, adiponectin (ADP), leptin (LEP) and insulin (INS), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and cytochrome P4502E1 (CYP2E1) concentrations were measured. HOMA-IR was computed. Visceral fat mass, hepatic fat content and histomorphometry were assessed. Hepatic TBARs and mRNA expressions of peroxisome proliferator activator receptor-alpha (PPAR-α), sterol regulatory element binding protein 1c (SREBP1c), nuclear factor kappa beta (NF-Kβ) and TNF-α were measured. Ethanol consumption in adulthood decreased feed and fluid intake but increased calorie intake and plasma CYP2E1 concentration (p < 0.05 vs control). It decreased blood glucose concentration of male rats (p = 0.026). A late single- and a double-alcohol hit had no effect on body and visceral fat mass of the rats (p > 0.05). Neonatal orally administered zingerone and ethanol and consumption of ethanol in adulthood had no effect on body mass, plasma lipid profile, adiponectin, leptin and insulin concentrations, HOMA-IR, AST and ALT activities, IL-6, TNF-α and hepatic TBARS and mRNA expression of NF-KB and TNF-α (p > 0.05). A late single hit with ethanol increased hepatic fat content of male rats only (p = 0.014). A double and or late single ethanol hit increased liver fat content in female rats (p < 0.05). Both a late single and double ethanol hit downregulated PPAR-α but upregulated SREBP1c expression in male and female rats (p < 0.05) and it caused the development of large droplet macrosteatosis. A combination of neonatal orally administered ZO and a late single ethanol hit decreased visceral fat mass of female rats (p = 0.045 vs control) but it did not affect the blood glucose concentration of male rats (p > 0.05). Neonatal orally administered ZO with either a late single- or a double-ethanol hit caused hepatic macrosteatosis, but it had no effect on mRNA expression of PPAR-α of the rats (p > 0.05). However, neonatal orally administered ZO in combination with a late single ethanol hit did not affect SREBP1c expression of the rats but a combination of neonatal orally aministered ZO with a double ethanol hit increased SREBP1c expression of female rats (p = 0.005). The responses of the rats to interventions showed sexual dimorphism: ethanol consumption in adulthood decreased blood glucose concentration of male rats only and an early single ethanol hit caused microsteatosis only in female rats. Zingerone protected male rats against ethanol-induced hepatic fat accumulation. It attenuated the ethanol-induced upregulation of hepatic SREPB1c expression in males but not in females. Ethanol (late single and/or double hit) downregulated the hepatic PPAR-α expression in the rats which was mitigated by ZO. Neonatal orally administered ZO attenuated the late single- and double-hit ethanol-induced macrosteatosis in the rats. Thus, neonatal orally administered ZO can potentially be used as a prophylactic agent against ethanolinduced hepatic lipid accumulation in males and steatosis in both males and females.