| Metabolic syndrome (MS) is a risk factor for many chronic diseases including cardiovasculardiseases, chronic kidney diseases and pulmonary diseases. It is associated with thyroiddysfunction ascribed to the role of thyroid hormones in metabolism, blood pressure regulation,and in enhancing generation of reactive oxygen species (ROS) leading to oxidative stress.Oxidative stress has been identified as its possible unifying pathological mechanism. There is nosingle effective treatment for MS currently. Patients are given3-5concomitant medications totreat each MS component. This is associated with poor compliance and increased risks of drug-drug interactions. A possible intervention strategy is to target health promotions towards highrisk population groups for prevention and control, and to develop monotherapy for simultaneoustreatment of components. Mitochondria-targeted antioxidants developed as pharmaceuticals arebeneficial in reducing cardiovascular risks and attenuating oxidative stress. While the role ofLipoic acid (LA), Resveratrol (R) and Quercetin (Q) are recognized, the mechanisms for theirameliorative effects are partially understood. Therefore, the objective of this study was todetermine the prevalence of MS among University workers, examine the relationship withthyroid function and mechanisms for protective effects of LA, Resveratrol and Quercetin on theheart, kidney and lungs. Both cross-sectional and experimental studies were conducted.In the cross-sectional study, a total of2273University workers (male-1198; female-1075) aged22-60years participated. Anthropometric measurements (weight and height), blood pressure,fasting plasma glucose (FPG), lipids, liver and kidney function tests, thyroid stimulatinghormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), total antioxidant capacity (T-AOC), lipid peroxidation products, malondialdehyde (MDA), advanced oxidation proteinproducts (AOPP) and dityrosine levels were measured. In the experimental study, mice were fedhigh-fat diet (HFD) to induce obesity and supplemented with antioxidants to examine protectiveeffects. Female C57BL/6mice were fed HFD, HFD+LA, HFD+R, HFD+Q and normal dietfor26weeks. Mice body weight, tissue weight (heart, kidney, lung), blood pressure, heart pulserate, plasma TSH, T4, T3, FT4, FT3, tissue angiotensin converting enzyme (ACE), nitric oxidesynthase (NOS), Ca(2+)-ATPase, Na+/K+-ATPase activity, ROS, T-AOC, reduced glutathione(GSH)/oxidised glutathione (GSSG) ratio, catalase activity, MDA were measured, and thecardiac, renal and lung genes analyzed by reverse transcription polymerase chain reaction. The overall prevalence MS among University workers was6.1%, increased with age, and wassignificantly (P<0.01) higher in males (5.1%) than females (1.1%). The most prevalent MScomponents in all participants were hypertension (37.9%) and hypertryglyceridemia (20.8%),corresponding rates in males were28.3%and16.1%while females had a prevalence of9.6%and4.7%. After adjustment for age, administrative work was associated (P<0.05) with increasedhypertension [odds ratio (OR)=1.474;95%confidence interval (CI),1.146-1.896] andhyperglycemia (OR=1.469;95%CI,1.082-1.993) in male workers, and with hypertension(OR=1.492;95%CI,1.071-2.080) in females. However, hypertryglyceridemia was lower(OR=0.390;95%CI,0.204-0.746) in female administrators compared to those in academics. Inboth sexes, no difference (P>0.05) was found in reduced high density lipoprotein cholesterol(HDL) and elevated triglycerides in males.Evaluation of thyroid function in792males and358females (30–60years) indicated a positiveassociation (P<0.05) of subclinical hypothyroidisms (SCH) with MS components in males. TSHassociated with increased triglycerides (β=0.108, P=0.020) and FPG (β=0.130, P=0.006) insubclinical hypothyroid males after adjustment for age and body mass index (BMI) while noassociation (P>0.05) of TSH with MS components was found in euthyroid group. In females,TSH was not correlated (P>0.05) with MS components in both euthyroid and subclinicalhypothyroid groups. Comparisons by occupation showed higher (P<0.05) TSH (5.23±0.52mU/l)and FT4(19.02±2.40pmol/l) in subclinical hypothyroid male workers in administrationcompared with those in academic (TSH,5.12±0.52mU/l; FT4,18.57±2.46pmol/l) whichresulted in elevated blood pressure, FPG, total cholesterol, triglycerides and HDL. In females,TSH, FT4, BMI, blood pressure, triglycerides and FPG were significantly (P<0.05) higher insubclinical hypothyroid administrators than those in academics.A further evaluation of oxidative stress markers in SCH compared with normal thyroid functionshowed marked differences. Among middle-aged men with SCH (n=467), MDA concentrations(8.11±1.39nmol/ml) were significantly higher (P<0.05) compared with euthyroid controls (7.34±1.31nmol/ml; n=190) while AOPP, dityrosine and T-AOC levels were not different. MDAwas not associated with TSH (β=-0.019, P=0.759), FT4(β=-0.062, P=0.323) and FT3(β=-0.018,P=0.780) in SCH while levels increased with elevated total cholesterol (β=0.229, P=0.001), LDL (β=0.203, P=0.009) and triglycerides (β=0.159, P=0.036) after adjustment for age and BMI. T-AOC reduced (β=-0.327, P=0.030) with increased MDA in euthyroids and not in SCH (β=-0.068, P=0.349) while levels increased with elevated triglycerides in both groups.In mice, high fat-feeding induced obesity at six weeks and was accompanied by alteration inplasma TSH, thyroid hormones, high blood pressure, increased heart pulse rate, hypertrophy andoxidative stress. Tissue activity of ACE, Na+/K+-ATPase and Ca (2+)-ATPase increased in theheart and kidney of HFD mice while NOS activity decreased due to increased expression of ACEgene, Na+/K+ATPase gene (ATP1B1) and reduced NOS3, respectively. Fibrotic genes (Cjal1,VEGF), hypoxia gene (HIF-1α), pro-apoptotic gene (Bax) increased while anti-apoptotic gene,Bcl-2reduced. Supplementation with antioxidants inhibited weight gain, restored T3levels,improved endothelial function, and reduced blood pressure, heart pulse rate, hypertrophy, andoxidative stress in the heart, kidney and lungs. Antioxidants reduced oxidative stress byattenuating ROS, improving antioxidant capacity, GSH levels and increasing catalase activity; byrestoring T3levels via reducing TRα1and increasing DIO1expression in the heart and kidney;by inhibiting ACE and AT1a expression with subsequent reduction in angiotensin II activity inthe heart and kidney; reducing NF-κB in the lung; improving K+and Ca2+homeostasis, and byinhibiting GSK3β via PI3K/AKT pathway. Consequently, fibrosis and apoptosis was reduced.In conclusion, the study has identified a population group with a high risk of MS, and providedpotential therapeutic intervention. It was demonstrated that prevalence of MS components washigh among University workers with the main risk factors being; increasing age, gender,occupation type and reduced thyroid function. Workers in administration with SCH hadincreased cardiovascular risks. Moreover, oxidative stress was markedly increased in individualswith SCH. Nevertheless, antioxidant supplementation reduced obesity and attenuated oxidativestress. Therefore, assessment of thyroid function in individuals with MS components may befavourable. Targeting thyroid hormone restoration, inhibition of ACE and GSK3β via PI3K/AKTsignalling pathway using LA, Resveratrol and Quercetin are potential novel therapeuticapproaches for developing pharmaceuticals that could aid in MS treatment. |
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