Browsing by Author "Pheiffer, Carmen"

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    Adipose tissue as a possible therapeutic target for polyphenols : a case for Cyclopia extracts as anti-obesity nutraceuticals
    (Elsevier, 2019) Jack, Babalwa U.; Malherbe, Christiaan J.; Mamushi, Mokadi Peggy; Muller, Christo J. F.; Joubert, Elizabeth; Louwa, Johan; Pheiffer, Carmen
    ENGLISH ABSTRACT: Obesity is a significant contributor to increased morbidity and premature mortality due to increasing the risk of many chronic metabolic diseases such as type 2 diabetes, cardiovascular disease and certain types of cancer. Lifestyle modifications such as energy restriction and increased physical activity are highly effective first-line treatment strategies used in the management of obesity. However, adherence to these behavioral changes is poor, with an increased reliance on synthetic drugs, which unfortunately are plagued by adverse effects. The identification of new and safer anti-obesity agents is thus of significant interest. In recent years, plants and their phenolic constituents have attracted increased attention due to their health-promoting properties. Amongst these, Cyclopia, an endemic South African plant commonly consumed as a herbal tea (honeybush), has been shown to possess modulating properties against oxidative stress, hyperglycemia, and obesity. Likewise, several studies have reported that some of the major phenolic compounds present in Cyclopia spp. exhibit anti-obesity effects, particularly by targeting adipose tissue. These phenolic compounds belong to the xanthone, flavonoid and benzophenone classes. The aim of this review is to assess the potential of Cyclopia extracts as an anti-obesity nutraceutical as underpinned by in vitro and in vivo studies and the underlying cellular mechanisms and biological pathways regulated by their phenolic compounds.
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    Blood-based DNA methylation biomarkers for type 2 diabetes : potential for clinical applications
    (Frontiers Media, 2018) Willmer, Tarryn; Johnson, Rabia; Louw, Johan; Pheiffer, Carmen
    ENGLISH ABSTRACT: Type 2 diabetes (T2D) is a leading cause of death and disability worldwide. It is a chronic metabolic disorder that develops due to an interplay of genetic, lifestyle, and environmental factors. The biological onset of the disease occurs long before clinical symptoms develop, thus the search for early diagnostic and prognostic biomarkers, which could facilitate intervention strategies to prevent or delay disease progression, has increased considerably in recent years. Epigenetic modifications represent important links between genetic, environmental and lifestyle cues and increasing evidence implicate altered epigenetic marks such as DNA methylation, the most characterized and widely studied epigenetic mechanism, in the pathogenesis of T2D. This review provides an update of the current status of DNA methylation as a biomarker for T2D. Four databases, Scopus, Pubmed, Cochrane Central, and Google Scholar were searched for studies investigating DNA methylation in blood. Thirty-seven studies were identified, and are summarized with respect to population characteristics, biological source, and method of DNA methylation quantification (global, candidate gene or genome-wide). We highlight that differential methylation of the TCF7L2, KCNQ1, ABCG1, TXNIP, PHOSPHO1, SREBF1, SLC30A8, and FTO genes in blood are reproducibly associated with T2D in different population groups. These genes should be prioritized and replicated in longitudinal studies across more populations in future studies. Finally, we discuss the limitations faced by DNA methylation studies, which include including interpatient variability, cellular heterogeneity, and lack of accounting for study confounders. These limitations and challenges must be overcome before the implementation of blood-based DNA methylation biomarkers into a clinical setting. We emphasize the need for longitudinal prospective studies to support the robustness of the current findings of this review.
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    DNA methylation of FKBP5 in South African women : associations with obesity and insulin resistance
    (BMC, 2020-09) Willmer, Tarryn; Goedecke, Julia H.; Dias, Stephanie; Louw, Johan; Pheiffer, Carmen
    Background: Disruption of the hypothalamic-pituitary-adrenal (HPA) axis, a neuroendocrine system associated with the stress response, has been hypothesized to contribute to obesity development. This may be mediated through epigenetic modulation of HPA axis-regulatory genes in response to metabolic stressors. The aim of this study was to investigate adipose tissue depot-specific DNA methylation differences in the glucocorticoid receptor (GR) and its co-chaperone, FK506-binding protein 51 kDa (FKBP5), both key modulators of the HPA axis. Methods: Abdominal subcutaneous adipose tissue (ASAT) and gluteal subcutaneous adipose tissue (GSAT) biopsies were obtained from a sample of 27 obese and 27 normal weight urban-dwelling South African women. DNA methylation and gene expression were measured by pyrosequencing and quantitative real-time PCR, respectively. Spearman's correlation coefficients, orthogonal partial least-squares discriminant analysis and multivariable linear regression were performed to evaluate the associations between DNA methylation, messenger RNA (mRNA) expression and key indices of obesity and metabolic dysfunction. Results: Two CpG dinucleotides within intron 7 of FKBP5 were hypermethylated in both ASAT and GSAT in obese compared to normal weight women, while no differences in GR methylation were observed. Higher percentage methylation of the two FKBP5 CpG sites correlated with adiposity (body mass index and waist circumference), insulin resistance (homeostasis model for insulin resistance, fasting insulin and plasma adipokines) and systemic inflammation (c-reactive protein) in both adipose depots. GR and FKBP5 mRNA levels were lower in GSAT, but not ASAT, of obese compared to normal weight women. Moreover, FKBP5 mRNA levels were inversely correlated with DNA methylation and positively associated with adiposity, metabolic and inflammatory parameters. Conclusions: These findings associate dysregulated FKBP5 methylation and mRNA expression with obesity and insulin resistance in South African women. Additional studies are required to assess the longitudinal association of FKBP5 with obesity and associated co-morbidities in large population-based samples.
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    DNA methylation of FKBP5 in South African women : associations with obesity and insulin resistance
    (BMC (part of Springer Nature), 2020-09-21) Willmer, Tarryn; Goedecke, Julia H.; Dias, Stephanie; Louw, Johan; Pheiffer, Carmen
    Background: Disruption of the hypothalamic–pituitary–adrenal (HPA) axis, a neuroendocrine system associated with the stress response, has been hypothesized to contribute to obesity development. This may be mediated through epigenetic modulation of HPA axis-regulatory genes in response to metabolic stressors. The aim of this study was to investigate adipose tissue depot-specific DNA methylation differences in the glucocorticoid receptor (GR) and its co-chaperone, FK506-binding protein 51 kDa (FKBP5), both key modulators of the HPA axis. Methods: Abdominal subcutaneous adipose tissue (ASAT) and gluteal subcutaneous adipose tissue (GSAT) biopsies were obtained from a sample of 27 obese and 27 normal weight urban-dwelling South African women. DNA methylation and gene expression were measured by pyrosequencing and quantitative real-time PCR, respectively. Spearman’s correlation coefficients, orthogonal partial least-squares discriminant analysis and multivariable linear regression were performed to evaluate the associations between DNA methylation, messenger RNA (mRNA) expression and key indices of obesity and metabolic dysfunction. Results: Two CpG dinucleotides within intron 7 of FKBP5 were hypermethylated in both ASAT and GSAT in obese compared to normal weight women, while no differences in GR methylation were observed. Higher percentage methylation of the two FKBP5 CpG sites correlated with adiposity (body mass index and waist circumference), insulin resistance (homeostasis model for insulin resistance, fasting insulin and plasma adipokines) and systemic inflammation (c-reactive protein) in both adipose depots. GR and FKBP5 mRNA levels were lower in GSAT, but not ASAT, of obese compared to normal weight women. Moreover, FKBP5 mRNA levels were inversely correlated with DNA methylation and positively associated with adiposity, metabolic and inflammatory parameters. Conclusions: These findings associate dysregulated FKBP5 methylation and mRNA expression with obesity and insulin resistance in South African women. Additional studies are required to assess the longitudinal association of FKBP5 with obesity and associated co-morbidities in large population-based samples.
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    The effect of adiponectin in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and the potential role of polyphenols in the modulation of adiponectin signaling
    (Elsevier Masson SAS, 2020-09) Shabalala, Samukelisiwe C.; Dludla, Phiwayinkosi V.; Mabasa, Lawrence; Kappo, Abidemi P.; Basson, Albertus K.; Pheiffer, Carmen; Johnson, Rabia
    Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, as it affects up to 30 % of adults in Western countries. Moreover, NAFLD is also considered an independent risk factor for cardiovascular diseases. Insulin resistance and inflammation have been identified as key factors in the pathophysiology of NAFLD. Although the mechanisms associated with the development of NAFLD remain to be fully elucidated, a complex interaction between adipokines and cytokines appear to play a crucial role in the development of this condition. Adiponectin is the most common adipokine known to be inversely linked with insulin resistance, lipid accumulation, inflammation and NAFLD. Consequently, the focus has been on the use of new therapies that may enhance hepatic expression of adiponectin downstream targets or increase the serum levels of adiponectin in the treatment NAFLD. While currently used therapies show limited efficacy in this aspect, accumulating evidence suggest that various dietary polyphenols may stimulate adiponectin levels, offering potential protection against the development of insulin resistance, inflammation and NAFLD as well as associated conditions of metabolic syndrome. As such, this review provides a better understanding of the role polyphenols play in modulating adiponectin signaling to protect against NAFLD. A brief discussion on the regulation of adiponectin during disease pathophysiology is also covered to underscore the potential protective effects of polyphenols against NAFLD. Some of the prominent polyphenols described in the manuscript include aspalathin, berberine, catechins, chlorogenic acid, curcumin, genistein, piperine, quercetin, and resveratrol.
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    Genome-wide DNA methylation in mixed ancestry individuals with diabetes and prediabetes from South Africa
    (Hindawi Publishing Corporation, 2016) Matsha, Tandi E.; Pheiffer, Carmen; Humphries, Stephen E.; Gamieldien, Junaid; Erasmus, Rajiv T.; Kengne, Andre P.
    Aims. To conduct a genome-wide DNA methylation in individuals with type 2 diabetes, individuals with prediabetes, and control mixed ancestry individuals from South Africa. Methods. We used peripheral blood to perform genome-wide DNA methylation analysis in 3 individuals with screen detected diabetes, 3 individuals with prediabetes, and 3 individuals with normoglycaemia from the Bellville South Community, Cape Town, South Africa, who were age-, gender-, body mass index-, and duration of residency-matched. Methylated DNA immunoprecipitation (MeDIP) was performed by Arraystar Inc. (Rockville, MD, USA). Results. Hypermethylated DMRs were 1160 (81.97%) and 124 (43.20%), respectively, in individuals with diabetes and prediabetes when both were compared to subjects with normoglycaemia. Our data shows that genes related to the immune system, signal transduction, glucose transport, and pancreas development have altered DNA methylation in subjects with prediabetes and diabetes. Pathway analysis based on the functional analysis mapping of genes to KEGG pathways suggested that the linoleic acid metabolism and arachidonic acid metabolism pathways are hypomethylated in prediabetes and diabetes. Conclusions. Our study suggests that epigenetic changes are likely to be an early process that occurs before the onset of overt diabetes. Detailed analysis of DMRs that shows gradual methylation differences from control versus prediabetes to prediabetes versus diabetes in a larger sample size is required to confirm these findings.
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    Glucose tolerance, MTHFR C677T and NOS3 G894T polymorphisms, and global DNA methylation in mixed ancestry African individuals
    (Hindawi, 2016-08-14) Matsha, Tandi E.; Pheiffer, Carmen; Mutize, Tinashe; Erasmus, Rajiv T.; Kengne, Andre P.
    ENGLISH ABSTRACT: The aim of this study is to quantify global DNA methylation and investigate the relationship with diabetes status and polymorphisms in MTHFR C677T and NOS3 G894T genes in mixed ancestry subjects from South Africa. Global DNA methylation was measured, and MTHFR rs1801133 and NOS3 rs1799983 polymorphisms were genotyped using high throughput real-time polymerase chain reaction and direct DNA sequencing. Of the 564 participants, 158 (28%) individuals had T2DM of which 97 (17.2%) were screen-detected cases. Another 119 (21.1%) had prediabetes, that is, impaired fasting glucose, impaired glucose tolerance, or the combination of both, and the remainder 287 (50.9%) had normal glucose tolerance. Global DNA methylation was significantly higher in prediabetes and screen-detected diabetes than in normal glucose tolerance (both ) and in screen-detected diabetes compared to known diabetes on treatment (). There was no difference in global DNA methylation between known diabetes on treatment and normal glucose tolerance (). In multivariable linear regression analysis, only NOS3 was associated with increasing global DNA methylation (; 95% CI: 0.286 to 1.560). The association of global DNA methylation with screen-detected diabetes but not treated diabetes suggests that glucose control agents to some extent may be reversing DNA methylation. The association between NOS3 rs1799983 polymorphisms and DNA methylation suggests gene-epigenetic mechanisms through which vascular diabetes complications develop despite adequate metabolic control.
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    Intimate partner violence: a risk factor for gestational diabetes
    (MDPI, 2020-10) Pheiffer, Carmen; Dias, Stephanie; Adam, Sumaiya
    The early detection and management of gestational diabetes mellitus (GDM) is an important public health goal. GDM, which is defined as a glucose intolerance that develops during pregnancy, affects about 14% of pregnancies globally, and without effective treatment, it is associated with adverse short- and long-term maternal and neonatal outcomes. Risk-factor screening is an acceptable and affordable strategy to enable risk stratification and intervention. However, common biological risk factors such as overweight or obesity, excessive gestational weight gain, and family history of diabetes often have poor predictive ability, failing to identify a large proportion of women at risk of developing GDM. Accumulating evidence implicate psychosocial factors in contributing to GDM risk. As such, intimate partner violence (IPV), through its contributing effects on maternal stress and depression, presents a plausible risk factor for GDM. Experiencing IPV during pregnancy may dysregulate the hypothalamus-pituitary-adrenal (HPA) axis, leading to increased cortisol secretion and insulin resistance. These effects may exacerbate the insulin-resistant environment characteristic of pregnancy, thus increasing GDM risk. This review explores the relationship between IPV and GDM. We highlight studies that have linked IPV with GDM and propose a biological mechanism that connects IPV and GDM. Recommendations for IPV screening strategies to prevent GDM are discussed.
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    Investigation of Mycobacterium tuberculosis protein expression and analysis of humoral immune responses of TB patients
    (Stellenbosch : Stellenbosch University, 2004-12) Pheiffer, Carmen; Van Helden, Paul; Betts, Joanna; Stellenbosch University. Faculty of Medicine & Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics.
    ENGLISH ABSTRACT: New agents for the diagnosis, prevention and treatment of tuberculosis are urgently required. Yet, despite extensive tuberculosis research over recent years, no new drugs, vaccines or diagnostics have been identified to date. It is widely speculated that the major obstacle to the identification of new therapies is the lack of understanding of the hostpathogen interaction. This study has investigated whether patterns of antigen expression correlate with molecular epidemiological data and strain virulence through the analysis of protein expression and antigen recognition profiles of different M tuberculosis clinical isolates. Using polyacrylamide gel electrophoresis, enzyme-linked immunosorbent assay, and Western blotting, protein expression and antigen recognition by two genotypically different clinical strains that differed in their frequency in the study population have been compared. In addition to differences in protein expression and antigen recognition between the clinical strains and the reference strain H37Rv, protein expression differences between the clinical strains themselves were observed which may relate to strain frequency and virulence. Differential protein expression by M tuberculosis strains, may explain the heterogeneous host humoral immune response and why no fully effective serodiagnostic test has been developed to date. To explore this hypothesis, the potential of serodiagnosis in this community, where patients are infected with a wide variety of genotypically distinct strains, was investigated. IgG levels to three mycobacterial antigens showed that serodiagnosis of TB is possible in this community, despite infection by a wide variety of genotypically different M tuberculosis strains. Disease episode affected antibody levels, suggesting that care should be taken when evaluating serological diagnosis for repeat episode patients. This study has shown that M tuberculosis protein expression is dynamic and that the bacillus presents a hypervariabie array of antigens to the host immune system. It is likely that different antigens become immunodominant as antituberculosis chemotherapy progresses, and that these differentially expressed antigens may be tracked as predictors of treatment outcome. This hypothesis was tested by correlating Ag85-specific IgG with treatment response, as assessed by sputum smear conversion after two months of antimycobacterial chemotherapy. No significant correlation between antibody levels and treatment responses was observed, suggesting that antibodies may not be useful surrogate markers or that the incorrect antibody type or mycobacterial antigen were selected. Results were consistent with previous findings where patient-to-patient variation dictated the host humoral response. The results obtained in this study have demonstrated that although bacteriological factors may influence strain prevalence due to antigen variation and immune evasion, both bacteriological and host factors affect humoral immunity. Differential protein expression by M tuberculosis strains has potentially important implications for serodiagnosis and the development of subunit or DNA vaccines, by suggesting that multi-antigen cocktails should be used. Differential protein expression may also explain why patients do not develop adequate protective immunity and are susceptible to reinfection.
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    Linking LOXL2 to Cardiac Interstitial Fibrosis
    (MDPI, 2020-08) Erasmus, Melisse; Samodien, Ebrahim; Lecour, Sandrine; Cour, Martin; Lorenzo, Oscar; Dludla, Phiwayinkosi; Pheiffer, Carmen; Johnson, Rabia
    Cardiovascular diseases (CVDs) are the leading causes of death worldwide. CVD pathophysiology is often characterized by increased stiffening of the heart muscle due to fibrosis, thus resulting in diminished cardiac function. Fibrosis can be caused by increased oxidative stress and inflammation, which is strongly linked to lifestyle and environmental factors such as diet, smoking, hyperglycemia, and hypertension. These factors can affect gene expression through epigenetic modifications. Lysyl oxidase like 2 (LOXL2) is responsible for collagen and elastin cross-linking in the heart, and its dysregulation has been pathologically associated with increased fibrosis. Additionally, studies have shown that, LOXL2 expression can be regulated by DNA methylation and histone modification. However, there is a paucity of data on LOXL2 regulation and its role in CVD. As such, this review aims to gain insight into the mechanisms by which LOXL2 is regulated in physiological conditions, as well as determine the downstream effectors responsible for CVD development.
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    Physical exercise potentially targets epicardial adipose tissue to reduce cardiovascular disease risk in patients with metabolic diseases : oxidative stress and inflammation emerge as major therapeutic targets
    (MDPI, 2021-11-04) Nyawo, Thembeka A.; Pheiffer, Carmen; Mazibuko-Mbeje, Sithandiwe E; Mthembu, Sinenhlanhla X. H.; Nyambuya, Tawanda M.; Nkambule, Bongani B.; Sadie-Van Gijsen, Hanel; Strijdom, Hans; Tiano, Luca; Dludla, Phiwayinkosi V.
    ENGLISH ABSTRACT: Excess epicardial adiposity, within a state of obesity and metabolic syndrome, is emerging as an important risk factor for the development of cardiovascular diseases (CVDs). Accordingly, increased epicardial fat thickness (EFT) implicates the exacerbation of pathological mechanisms involving oxidative stress and inflammation within the heart, which may accelerate the development of CVDs. This explains increased interest in targeting EFT reduction to attenuate the detrimental effects of oxidative stress and inflammation within the setting of metabolic syndrome. Here, we critically discuss clinical and preclinical evidence on the impact of physical exercise on EFT in correlation with reduced CVD risk within a setting of metabolic disease. This review also brings a unique perspective on the implications of oxidative stress and inflammation as major pathological consequences that link increased EFT to accelerated CVD risk in conditions of metabolic disease.
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    The prevalence of type 2 diabetes in South Africa : a systematic review protocol
    (BMJ Publishing Group, 2018-06) Pheiffer, Carmen; Pillay-Van Wyk, Victoria; Joubert, Jane D.; Levitt, Naomi; Nglazi, Mweete D.; Bradshaw, Debbie
    Introduction Type 2 diabetes mellitus is a major source of morbidity and mortality in South Africa, spurred by increased urbanisation and unhealthy lifestyle factors. Local epidemiological data are required to inform health planning and policy. The purpose of this systematic review is to identify, collate and synthesise all studies reporting the prevalence of diabetes in South Africa. A secondary aim is to report the prevalence of impaired glucose tolerance and impaired fasting glucose, conditions which are associated with an increased risk of progression to overt diabetes, and the prevalence of undiagnosed diabetes. Methods and analysis Multiple databases will be searched for diabetes prevalence studies conducted in South Africa between 1997 and 2018. Two authors will independently select studies that meet the inclusion criteria, extract data and appraise studies using a risk of bias tool for prevalence studies. Studies with low or moderate risk of bias will be included. Sources of heterogeneity will be explored using subgroup analysis. Ethics and dissemination The systematic review does not require ethics clearance since published studies with non-identifiable data will be used. This review will provide best estimates to inform the Second National Burden of Disease study which can guide health and policy planning.