RESUMO
Monitoring of SARS-CoV-2 RNA in wastewater has revealed the role of mobility in the transmission of coronavirus disease (COVID-19), and the surveillance of airport wastewater in cities across the world has demonstrated how travel entry points can give an indication of trends in transmission. This study undertook wastewater surveillance at the Cape Town International Airport (CTIA) to assess the use of a WBE approach to provide supplementary information on the presence of COVID-19 at a key air travel entry point in South Africa. Grab wastewater samples (n = 55) were collected from the CTIA wastewater pump station and analysed using quantitative real-time polymerase chain reaction (qRT-PCR) method. The study found a correlation between the wastewater data and clinical cases reported in the City of Cape Town during various time periods and during the peak of a COVID-19 wave. Highly elevated viral loads in the wastewater were observed at times there was increased mobility through the airport. The study also revealed elevated viral load levels at the airport despite the stricter restrictions and through the lower restrictions. The study findings indicate wastewater surveillance and airports can provide supplementary information to airport authorities to assess the impacts of imposed travel restrictions.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , Águas Residuárias , Aeroportos , Cidades , RNA Viral , Vigilância Epidemiológica Baseada em Águas Residuárias , África do Sul/epidemiologiaRESUMO
This study was one of the first to detect Omicron sublineages BA.4 and BA.5 in wastewater from South Africa. Spearman rank correlation analysis confirmed a strong positive correlation between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA in wastewater samples and clinical cases (r = 0.7749, P < .0001). SARS-CoV-2 viral load detected in wastewater, resulting from the Delta-driven third wave, was significantly higher than during the Omicron-driven fourth wave. Whole-genome sequencing confirmed presence of Omicron lineage defining mutations in wastewater with the first occurrence reported 23 November 2021 (BA.1 predominant). The variant spread rapidly, with prevalence of Omicron-positive wastewater samples rising to >80% by 10 January 2022 with BA.2 as the predominant sublineage by 10 March 2022, whilst on 18 April 2022 BA.4 and BA.5 were detected in selected wastewater sites. These findings demonstrate the value of wastewater-based epidemiology to monitor the spatiotemporal spread and potential origin of new Omicron sublineages.
Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/epidemiologia , Humanos , Prevalência , RNA Viral/genética , SARS-CoV-2/genética , África do Sul/epidemiologia , Águas ResiduáriasRESUMO
Metformin is considered a safe anti-hyperglycemic drug for patients with type 2 diabetes (T2D); however, information on its impact on heart failure-related outcomes remains inconclusive. The current systematic review explored evidence from randomized clinical trials (RCTs) reporting on the impact of metformin in modulating heart failure-related markers in patients with or without T2D. Electronic databases such as MEDLINE, Cochrane Library, and EMBASE were searched for eligible studies. Included studies were those assessing the use of metformin as an intervention, and also containing the comparison group on placebo, and all articles had to report on measurable heart failure-related indices in individuals with or without T2D. The modified Downs and Black checklist was used to evaluate the risk of bias. Overall, nine studies met the inclusion criteria, enrolling a total of 2486 patients. Although summarized evidence showed that metformin did not affect left ventricular function, this antidiabetic drug could improve myocardial oxygen consumption concomitant to reducing prominent markers of heart failure such as n-terminal pro-brain natriuretic peptide and low-density lipoprotein levels, inconsistently between diabetic and nondiabetic patients. Effective modulation of some heart failure-related outcomes with metformin treatment was related to its beneficial effects in ameliorating insulin resistance and blocking pro-inflammatory markers such as the aging-associated cytokine CCL11 (C-C motif chemokine ligand 11). Overall, although such beneficial effects were observed with metformin treatment, additional RCTs are necessary to improve our understanding on its modulatory effects on heart failure-related outcomes especially in diabetic patients.
Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Metformina , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Metformin is a widely used glucose-lowering drug, although its impact on adipose tissue function remains elusive. Adipose tissue-derived molecules regulate diverse physiological mechanisms, including energy metabolism, insulin sensitization, and inflammatory response. Alternatively, it has remained relevant to understand the therapeutic regulation of adipokines in efforts to alleviate inflammation in conditions associated with the metabolic syndrome. The current qualitative analysis of available literature focused on randomized clinical trials (RCTs) assessing the association between administration of metformin and adipokine regulation in individuals with metabolic syndrome. The major electronic databases such as MEDLINE, Cochrane Library, Scopus, and EMBASE were searched for eligible RCTs. Overall, 13 RCTs met the inclusion criteria, with a total of 4605 participants. Patients with metabolic syndrome were characterized by a state of obesity, impaired glucose tolerance, insulin resistance, and type 2 diabetes. Cumulative evidence from these RCTs supported the blood glucose lowering effects of metformin, in addition to promoting weight loss, ameliorating insulin resistance, and reducing pro-inflammatory markers such as interleukin-6 and tumor necrosis factor-α in patients with metabolic syndrome. Importantly, these therapeutic effects are associated with the upregulation of adiponectin and suppression of leptin and resistin.
Assuntos
Adipocinas/metabolismo , Hipoglicemiantes/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Metformina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Resistência à Insulina , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Metformina/farmacologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Rooibos (Aspalathus linearis) has various health benefits. Two case studies have associated chronic Rooibos consumption with conventional prescription medications, including atorvastatin (ATV), with hepatotoxicity. Statins act by inhibiting hydroxymethylglutaryl-coenzyme A reductase, a rate-limiting enzyme in cholesterol synthesis. Although rare, statins are potentially hepatotoxic. The aim was to investigate interactions between aspalathin-rich Rooibos extract GRT™ and ATV-induced hepatotoxicity in C3A liver cells cultured with and without palmitate. Effects of co-treatment of GRT + ATV on cell viability, oxidative stress, apoptosis, mitochondrial integrity, and cellular reactive oxygen species (ROS) production were assessed. Significantly increased ROS production was observed in cells exposed to ATV and palmitate. Combination therapy of GRT + ATV also showed significant increases in ROS production. Under palmitate-treated conditions, ATV-induced significant apoptosis which was not ameliorated by GRT + ATV co-treatment. Despite studies purporting hepatoprotection from Rooibos, our study showed that GRT was unable to modulate ATV-induced hepatotoxic effects in this model.
Assuntos
Atorvastatina/farmacologia , Hepatócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Fígado/efeitos dos fármacos , Fitoterapia/métodos , Espécies Reativas de Oxigênio/metabolismoRESUMO
OBJECTIVE: To evaluate T-helper cytokine responses in a short-term high fat diet (HFD) induced impaired glucose metabolism. To further evaluate the modulation of T-helper 1 (Th1) and T-helper 2 (Th2) cytokines using short-term low-dose aspirin in combination with metformin. DESIGN: Two experiments were carried out in this study in order to evaluate the T-helper cytokine profiles in a state of impaired glucose metabolism. A total of 28 six-week-old male C57BL/6 mice were used in this study. In the first experiment, mice were fed either a high fat diet or low fat diet for a duration of 10 weeks. We then determined the Th1, Th2 and T-helper 17 (Th17) cytokine profiles. In the second experiment, we evaluated whether the short term 6-week treatment with low-dose aspirin in combination with metformin modulates T-helper cytokine profiles of the HFD-fed mice. MEASUREMENTS: In the first experiment, we measured the body weights, blood glucose levels, insulin levels, lipid profiles and haematological parameters. We further performed oral glucose tolerance testing following an 8-hour fast and serum Th1, Th2 and Th17 cytokine levels were also determined following short-term 8-week diet-feeding and 6-week low-dose aspirin and combined metformin with low-dose aspirin treatment. RESULTS: High fat diet-feeding caused a marked increase in circulating peripheral blood lymphocytes, which was attenuated by short-term low-dose aspirin treatment. Moreover, the HFD feeding resulted in 2-fold increase in total cholesterol and a 4-fold increase in low-density lipoprotein cholesterol when compared to the low-fat diet-fed group (p < 0.05). In the high fat diet group, impaired glucose metabolism was associated with skewed Th2 responses without alterations in the Th1 and Th17 cytokine profiles. Interestingly the short-term treatment with low-dose aspirin showed no effect on the selected T-helper 1 cytokine IFN-Ƴ (P > 0.05). While the combination of low-dose aspirin with metformin considerably reduced the levels of serum IFN-Ƴ (P < 0.05). Furthermore low-dose aspirin treatment showed the modest attenuation of the selected Th2 cytokines, IL-10 and IL-13 when compared to low-dose aspirin with metformin (P < 0.01). CONCLUSION: The early immunological and metabolic changes that occur in a state impaired glucose tolerance are accompanied by the increased production of Th2 cell cytokines. The short-term treatment using low-dose aspirin combined with metformin may provide therapeutic benefits in preventing complications associated with dysregulated Th2 cell responses.
Assuntos
Aspirina/farmacologia , Citocinas/metabolismo , Metformina/farmacologia , Células Th2/efeitos dos fármacos , Animais , Quimioterapia Combinada/métodos , Intolerância à Glucose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Células Th2/metabolismoRESUMO
The T-helper (Th1/Th2) paradigm is widely studied for its role in modulating an adaptive immune response, especially in relation to the onset of various autoimmune diseases. In fact, emerging evidence clearly shows an inverse relationship between Th1/Th2 cytokines and the development of type 2 diabetes (T2D) complications, which is accelerated by an exacerbated inflammatory state. Here, relevant studies reporting on any association between the levels of Th1/Th2 cytokines and the development of T2D were retrieved through major electronic databases such as The Cochrane Library, Embase and PubMed. Extracted evidence which mostly involved animal models and human subjects with T2D or metabolic syndrome was assessed for quality and risk of bias using the Downs and Black checklist and Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. Results strongly correlated raised Th1/Th2 cytokines such as interferon-gamma (IFN-γ)/interleukin (IL)-5 and IL-2/IL-5 ratios to T2D, and this was positively linked with the other complications including retinopathy and cardiovascular complications. Further, logistic regression analysis demonstrated that the Th1/Th2 ratios were significantly associated with impaired glucose homeostasis, abnormally enhanced lipid profiles, and insulin resistance. Although more studies making use of a larger sample size are required, current data suggest that optimal modulation of Th1/Th2 cytokines may be an important aspect in the management of T2D and its associated complications.
Assuntos
Citocinas/sangue , Diabetes Mellitus Tipo 2/patologia , Células Th1/imunologia , Equilíbrio Th1-Th2/fisiologia , Células Th2/imunologia , Adulto , Animais , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/patologia , Citocinas/metabolismo , Retinopatia Diabética/patologia , Feminino , Humanos , Resistência à Insulina/fisiologia , Masculino , Síndrome Metabólica/patologia , Camundongos , Pessoa de Meia-IdadeRESUMO
Isoorientin is a natural C-glucosyl flavone that is generating a lot of interest due to its multiple pharmacological activities. Increasing experimental data have shown that the robust antioxidant and anti-inflammatory properties of isoorientin remain important in ameliorating a number of metabolic complications. In fact, plants rich in isoorientin have demonstrated strong ameliorative properties against complications such as hyperglycemia, hyperlipidemia, and insulin resistance. However, while such evidence is accumulating, it has not been reviewed to better inform on the therapeutic potential of this flavone in improving human health. This review examines and extrapolates available literature on the potential beneficial or detrimental effects associated with the use of isoorientin in mitigating metabolic diseases, with a specific focus on diabetes, obesity, and insulin resistance, including associated complications. The discussion includes effective doses in various experimental settings and proposed molecular mechanisms by which isoorientin may exert its therapeutic effects. In addition, the protective effects of extracts of a number of isoorientin-rich plants against metabolic complications will be highlighted.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/uso terapêutico , Luteolina/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Animais , Diabetes Mellitus/dietoterapia , Diabetes Mellitus/tratamento farmacológico , Dieta , Humanos , Resistência à Insulina , Doenças Metabólicas/dietoterapia , Estresse Oxidativo/efeitos dos fármacosRESUMO
The increased use of herbal supplements as complementary or alternative medicines has become a clinical conundrum due to the potential for herb-drug interactions. This is exacerbated by an increased supply of new herbal supplements in the market claiming various health advantages. These herbal supplements are available as over-the-counter self-medications. Herbal supplements are generally perceived as efficacious without side effects commonly associated with conventional drugs. However, despite regulations, claims related to their therapeutic effects are mostly unsupported by scientific evidence. These products often lack suitable product quality controls, labelled inadequately and with batch to batch variations, potentially compromising the safety of the consumer. Amongst health practitioners, the greatest concern is related to the lack of chemical characterization of the active compounds of the herbal supplements. The interaction between these different active components and their concomitant effects on other conventional drugs is generally not known. This review will focus on herbal supplements with the potential to effect pharmacokinetic and pharmacodynamic properties of oestrogen-based oral contraceptives. The use of herbal supplements for weight management, depression, and immune boosting benefits were selected as likely herbal supplements to be used concomitantly by women on oral contraceptives.
Assuntos
Anticoncepcionais Orais/química , Suplementos Nutricionais/análise , Estrogênios/metabolismo , Interações Ervas-Drogas/fisiologia , Feminino , Humanos , MasculinoRESUMO
Evidence from randomized controlled trials (RCTs) suggests that coenzyme Q10 (CoQ10) can regulate adipokine levels to impact inflammation and oxidative stress in conditions of metabolic syndrome. Here, prominent electronic databases such as MEDLINE, Cochrane Library, and EMBASE were searched for eligible RCTs reporting on any correlation between adipokine levels and modulation of inflammation and oxidative stress in individuals with metabolic syndrome taking CoQ10. The risk of bias was assessed using the modified Black and Downs checklist, while the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool was used to evaluate the quality of evidence. Results from the current meta-analysis, involving 318 participants, showed that CoQ10 supplementation in individuals with metabolic syndrome increased adiponectin levels when compared to those on placebo (SMD: 1.44 [95% CI: -0.13, 3.00]; I2 = 96%, p < 0.00001). Moreover, CoQ10 supplementation significantly lowered inflammation markers in individuals with metabolic syndrome in comparison to those on placebo (SMD: -0.31 [95% CI: -0.54, -0.08]; I2 = 51%, p = 0.07). Such benefits with CoQ10 supplementation were related to its ameliorative effects on lipid peroxidation by reducing malondialdehyde levels, concomitant to improving glucose control and liver function. The overall findings suggest that optimal regulation of adipokine function is crucial for the beneficial effects of CoQ10 in improving metabolic health.
Assuntos
Adipocinas/metabolismo , Biomarcadores , Suplementos Nutricionais , Peroxidação de Lipídeos/efeitos dos fármacos , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Ubiquinona/análogos & derivados , Animais , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Viés de Publicação , Ubiquinona/administração & dosagemRESUMO
Evidence on the beneficial effects of resveratrol supplementation on cardiovascular disease-related profiles in patients with type 2 diabetes (T2D) is conflicting, while its impact on renal function and blood pressure measurements remains to be established in these patients. The current meta-analysis included randomized controlled trials (RCTs) reporting on the impact of resveratrol supplementation on markers of renal function and blood pressure in patients with T2D on hypoglycemic medication. Electronic databases such as MEDLINE, Cochrane Library, Scopus, and EMBASE were searched for eligible studies from inception up to June 2020. The random and fixed effects model was used in the meta-analysis. A total of five RCTs met the inclusion criteria and involved 388 participants with T2D. Notably, most of the participants were on metformin therapy, or metformin in combination with other hypoglycemic drugs such as insulin and glibenclamide. Pooled estimates showed that resveratrol supplementation in patients with T2D lowered the levels of fasting glucose (SMD: -0.06 [95% CI: -0.24, 0.12]; I2 = 4%, p = 0.39) and insulin (SMD: -0.08 [95% CI: -0.50, 0.34], I2 = 73%, p = 0.002) when compared to those on placebo. In addition, supplementation significantly lowered systolic blood pressure (SMD: -5.77 [95% CI: -8.61, -2.93], I2 = 66%, p = 0.02) in these patients. Although resveratrol supplementation did not affect creatinine or urea levels, it reduced the total protein content (SMD: -0.19 [95% CI: -0.36, -0.02]; I2 = 91%, p = 0.001). In all, resveratrol supplementation in hypoglycemic therapy improves glucose control and lowers blood pressure; however, additional evidence is necessary to confirm its effect on renal function in patients with T2D.
Assuntos
Biomarcadores/análise , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Suplementos Nutricionais , Hipoglicemiantes/administração & dosagem , Nefropatias/prevenção & controle , Resveratrol/uso terapêutico , Antioxidantes/uso terapêutico , Pressão Sanguínea , Quimioterapia Combinada , Humanos , Testes de Função RenalRESUMO
The current study explored the effect of isoorientin on the metabolic activity and lipid accumulation in fully differentiated 3T3-L1 adipocytes. To achieve this, the 3T3-L1 pre-adipocytes were differentiated for eight days and treated with various concentrations of isoorientin (0.1-100 µM) for four hours. Subsequently, the metabolic activity, lipid accumulation, and mitochondrial respiration were assessed. Furthermore, to unravel the molecular mechanisms that might elucidate the bioactivity of isoorientin, protein expression of the genes involved in insulin signaling and energy expenditure, such as AKT and AMPK, were investigated. The results showed that isoorientin, at different doses, could block lipid storage and enhance glycerol release, with a concomitant improvement of the metabolic activity and mitochondrial function. Although the observed beneficial effects of isoorientin on these cultured 3T3-L1 adipocytes were not consistent at all concentrations, it was clear that doses between 1 and 10 µM were most effective compared to the untreated control. Moreover, the activity of isoorientin was comparable to tested positive controls of CL-316,2431, isoproterenol, insulin, and metformin. Mechanistically, protein expression of AKT and AMPK, was enhanced with isoorientin exposure, suggesting their partial role in modulating lipid metabolism and mitochondrial biogenesis. Indeed, our results showed that isoorientin has the ability to enhance mitochondrial respiration, as we observed an increase in the ATP and oxygen consumption rate. Therefore, we concluded that isoorientin has a potential to impact mitochondrial activity, lipid metabolism and energy expenditure using an in vitro experimental model of obesity.
Assuntos
Adipócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Luteolina/farmacologia , Mitocôndrias/efeitos dos fármacos , Obesidade/metabolismo , Células 3T3-L1 , Quinases Proteína-Quinases Ativadas por AMP , Trifosfato de Adenosina/metabolismo , Adipócitos/metabolismo , Animais , Dioxóis/farmacologia , Glucose/metabolismo , Insulina/metabolismo , Insulina/farmacologia , Isoproterenol/farmacologia , Metformina/farmacologia , Camundongos , Mitocôndrias/metabolismo , Obesidade/tratamento farmacológico , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Blood pressure (BP) is a complex trait that is regulated by multiple physiological pathways and include but is not limited to extracellular fluid volume homeostasis, cardiac contractility, and vascular tone through renal, neural, or endocrine systems. Uncontrolled hypertension (HTN) has been associated with an increased mortality risk. Therefore, understanding the genetics that underpins and influence BP regulation will have a major impact on public health. Moreover, uncontrolled HTN has been linked to inter-individual variation in the drugs' response and this has been associated with an individual's genetics architecture. However, the identification of candidate genes that underpin the genetic basis of HTN remains a major challenge. To date, few variants associated with inter-individual BP regulation have been identified and replicated. Research in this field has accelerated over the past 5 years as a direct result of on-going genome-wide association studies (GWAS) and the progress in the identification of rare gene variants and mutations, epigenetic markers, and the regulatory pathways involved in the pathophysiology of BP. In this review we describe and enhance our current understanding of how genetic variants account for the observed variability in BP response in patients on first-line antihypertensive drugs, amlodipine and hydrochlorothiazide.
Assuntos
Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Hidroclorotiazida/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/genética , Variantes Farmacogenômicos/genética , Adulto , Anlodipino/farmacocinética , Anti-Hipertensivos/farmacocinética , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Humanos , Hidroclorotiazida/farmacocinética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Excessive adiposity in an obese state is known to drive the onset of metabolic dysregulations, mostly involving chronic immune activation and oxidative stress. Prolonged inflammation and oxidative stress have been linked to impaired adipose tissue function and the development of the metabolic syndrome. Currently available therapies offer minimal prophylactic effects, while substantial experimental evidence supports the ameliorative effects of N-acetylcysteine (NAC) against various metabolic complications associated with obesity. The current review provides a comprehensive synthesis of studies published in major search engines such as PubMed, Cochrane library, Embase, and Google Scholar assessing the therapeutic effect of NAC against obesity associated complications. Overwhelming literature included in this review supports the ameliorative effects of NAC against such complications in both in vitro and in vivo models of obesity. In addition to attenuating an abnormal pro-inflammatory response and limiting oxidative damage, NAC could inhibit lipid accumulation by targeting adipogenic transcription factors such as peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein beta (C/EBPß), and improve insulin sensitivity through augmenting phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. Although necessary evidence informing on its optimal dose and its comparative effect with other well-studied pharmacological compounds is demonstrated, it is clear that future investigations are required to confirm the therapeutic effect of NAC in obese human subjects.
Assuntos
Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Obesidade/tratamento farmacológico , Animais , Humanos , Inflamação/metabolismo , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fatores de Transcrição/metabolismoRESUMO
Background/Objective: Recently, several studies have reported that DNA methylation changes in tissue are reflected in blood, sparking interest in the potential use of global DNA methylation as a biomarker for gestational diabetes mellitus (GDM). This study investigated whether global DNA methylation is associated with GDM in South African women. Methods: Global DNA methylation was quantified in peripheral blood cells of women with (n = 63) or without (n = 138) GDM using the MDQ1 Imprint® DNA Quantification Kit. Results: Global DNA methylation levels were not different between women with or without GDM and were not associated with fasting glucose or insulin concentrations. However, levels were 18% (p = 0.012) higher in obese compared to non-obese pregnant women and inversely correlated with serum adiponectin concentrations (p = 0.005). Discussion: Contrary to our hypothesis, global DNA methylation was not associated with GDM in our population. These preliminary findings suggest that despite being a robust marker of overall genomic methylation that offers opportunities as a biomarker, global DNA methylation profiling may not offer the resolution required to detect methylation differences in the peripheral blood cells of women with GDM. Moreover, global DNA methylation in peripheral blood cells may not reflect changes in placental tissue. Further studies in a larger sample are required to explore the candidacy of a more targeted approach using gene-specific methylation as a biomarker for GDM in our population.
Assuntos
Biomarcadores/sangue , Metilação de DNA/genética , Diabetes Gestacional/genética , Obesidade/genética , Adulto , População Negra/genética , Células Sanguíneas , Diabetes Gestacional/sangue , Diabetes Gestacional/patologia , Feminino , Humanos , Insulina/sangue , Obesidade/sangue , Obesidade/patologia , Gravidez , África do SulRESUMO
Increasing evidence implicate altered DNA methylation in the pathophysiology of gestational diabetes mellitus (GDM). This exploratory study probed the association between GDM and peripheral blood DNA methylation patterns in South African women. Genome-wide DNA methylation profiling was conducted in women with (n = 12) or without (n = 12) GDM using the Illumina Infinium HumanMethylationEPIC BeadChip array. Functional analysis of differentially methylated genes was conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. A total of 1046 CpG sites (associated with 939 genes) were differentially methylated between GDM and non-GDM groups. Enriched pathways included GDM-related pathways such as insulin resistance, glucose metabolism and inflammation. DNA methylation of the top five CpG loci showed distinct methylation patterns in GDM and non-GDM groups and was correlated with glucose concentrations. Of these, one CpG site mapped to the calmodulin-binding transcription activator 1 (CAMTA1) gene, which have been shown to regulate insulin production and secretion and may offer potential as an epigenetic biomarker in our population. Further validation using pyrosequencing and conducting longitudinal studies in large sample sizes and in different populations are required to investigate their candidacy as biomarkers of GDM.
Assuntos
Metilação de DNA , Diabetes Gestacional/genética , Adulto , Biomarcadores/sangue , Proteínas de Ligação ao Cálcio/genética , Ilhas de CpG , Diabetes Gestacional/sangue , Diabetes Gestacional/diagnóstico , Feminino , Genoma Humano , Humanos , Gravidez , África do Sul , Transativadores/genéticaRESUMO
We previously demonstrated that an aspalathin-enriched green rooibos extract (GRE) reversed palmitate-induced insulin resistance in C2C12 skeletal muscle and 3T3-L1 fat cells by modulating key effectors of insulin signalling such as phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK). However, the effect of GRE on hepatic insulin resistance is unknown. The effects of GRE on lipid-induced hepatic insulin resistance using palmitate-exposed C3A liver cells and obese insulin resistant (OBIR) rats were explored. GRE attenuated the palmitate-induced impairment of glucose and lipid metabolism in treated C3A cells and improved insulin sensitivity in OBIR rats. Mechanistically, GRE treatment significantly increased PI3K/AKT and AMPK phosphorylation while concurrently enhancing glucose transporter 2 expression. These findings were further supported by marked stimulation of genes involved in glucose metabolism, such as insulin receptor (Insr) and insulin receptor substrate 1 and 2 (Irs1 and Irs2), as well as those involved in lipid metabolism, including Forkhead box protein O1 (FOXO1) and carnitine palmitoyl transferase 1 (CPT1) following GRE treatment. GRE showed a strong potential to ameliorate hepatic insulin resistance by improving insulin sensitivity through the regulation of PI3K/AKT, FOXO1 and AMPK-mediated pathways.
Assuntos
Proteínas Quinases Ativadas por AMP/genética , Chalconas/farmacologia , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Resistência à Insulina , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Células 3T3 , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aspalathus/química , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular , Chalconas/isolamento & purificação , Dieta Hiperlipídica/efeitos adversos , Açúcares da Dieta/efeitos adversos , Regulação da Expressão Gênica , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hiperglicemia/etiologia , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hipoglicemiantes/isolamento & purificação , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Camundongos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Ácido Palmítico/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transdução de SinaisRESUMO
Type 2 diabetic patients possess a two to four fold-increased risk for Cardiovascular Diseases (CVD). Hyperglycemia, oxidative stress associated with endothelial dysfunction and dyslipidemia are regarded as pro-atherogenic mechanisms of CVD. In this study, high-fat diet-induced diabetic and non-diabetic vervet monkeys were treated with 90 mg/kg of aspalathin-rich green rooibos extract (Afriplex GRT) for 28 days, followed by a 1-month wash-out period. Supplementation showed improvements in both the intravenous glucose tolerance test (IVGTT) glycemic area under curve (AUC) and total cholesterol (due to a decrease of the low-density lipoprotein [LDL]) values in diabetics, while non-diabetic monkeys benefited from an increase in high-density lipoprotein (HDL) levels. No variation of plasma coenzyme Q10 (CoQ10) were found, suggesting that the LDL-lowering effect of Afriplex GRT could be related to its ability to modulate the mevalonate pathway differently from statins. Concerning the plasma oxidative status, a decrease in percentage of oxidized CoQ10 and circulating oxidized LDL (ox-LDL) levels after supplementation was observed in diabetics. Finally, the direct correlation between the amount of oxidized LDL and total LDL concentration, and the inverse correlation between ox-LDL and plasma CoQ10 levels, detected in the diabetic monkeys highlighted the potential cardiovascular protective role of green rooibos extract. Taken together, these findings suggest that Afriplex GRT could counteract hyperglycemia, oxidative stress and dyslipidemia, thereby lowering fundamental cardiovascular risk factors associated with diabetes.
Assuntos
Chalconas/farmacologia , LDL-Colesterol/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Biomarcadores , Glicemia/efeitos dos fármacos , Chlorocebus aethiops , Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Lipídeos/sangue , Lipoproteínas LDL/sangue , Masculino , Extratos Vegetais/farmacologia , Ubiquinona/análogos & derivados , Ubiquinona/sangueRESUMO
Accumulative evidence shows that chronic hyperglycaemia is a major factor implicated in the development of pancreatic ß-cell dysfunction in diabetic patients. Furthermore, most of these patients display impaired insulin signalling that is responsible for accelerated pancreatic ß-cell damage. Indeed, prominent pathways involved in glucose metabolism such as phosphatidylinositol 3-kinase/ protein kinase B (PI3-K/AKT) and 5' AMP-activated protein kinase (AMPK) are impaired in an insulin resistant state. The impairment of this pathway is associated with over production of reactive oxygen species and pro-inflammatory factors that supersede pancreatic ß-cell damage. Although several antidiabetic drugs can improve ß-cell function by modulating key regulators such as PI3-K/AKT and AMPK, evidence of their ß-cell regenerative and protective effect is scanty. As a result, there has been continued exploration of novel antidiabetic therapeutics with abundant antioxidant and antiinflammatory properties that are essential in protecting against ß-cell damage. Such therapies include triterpenes, which have displayed robust effects to improve glycaemic tolerance, insulin secretion, and pancreatic ß-cell function. This review summarises most relevant effects of various triterpenes on improving pancreatic ß-cell function in both in vitro and in vivo experimental models. A special focus falls on studies reporting on the ameliorative properties of these compounds against insulin resistance, oxidative stress and inflammation, the well-known factors involved in hyperglycaemia associated tissue damage.
Assuntos
Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Triterpenos/uso terapêutico , Animais , Diabetes Mellitus/tratamento farmacológico , Humanos , Resistência à Insulina , Estresse Oxidativo/efeitos dos fármacosRESUMO
Myocardial remodeling and dysfunction caused by accelerated oxidative damage is a widely reported phenomenon within a diabetic state. Altered myocardial substrate preference appears to be the major cause of enhanced oxidative stress-mediated cell injury within a diabetic heart. During this process, exacerbated free fatty acid flux causes an abnormal increase in mitochondrial membrane potential leading to the overproduction of free radical species and subsequent cell damage. Uncoupling proteins (UCPs) are expressed within the myocardium and can protect against free radical damage by modulating mitochondrial respiration, leading to reduced production of reactive oxygen species. Moreover, transgenic animals lacking UCPs have been shown to be more susceptible to oxidative damage and display reduced cardiac function when compared to wild type animals. This suggests that tight regulation of UCPs is necessary for normal cardiac function and in the prevention of diabetes-induced oxidative damage. This review aims to enhance our understanding of the pathophysiological mechanisms relating to the role of UCPs in a diabetic heart, and further discuss known pharmacological compounds and hormones that can protect a diabetic heart through the modulation of UCPs.