TY  - JOUR
AB  - Phenolic acid-rich fraction from Anisopus mannii (PhAM) contains abundance of ferulic acid, gallic acid, protocatechuic acid, and syringic acid. Among other glycolytic enzymes, in vitro, PhAM counteracted the binding of sodium orthovanadate to phosphofructokinase 1 (PFK-1), improving its activities. In a rat model of diet-induced diabetes, PhAM monotherapy reduced HbA1c by an average of 0.63% and fasting plasma glucose by 25mg/dl. This herb rescued β-cells from streptozotocin-mediated destruction, thereby improving glycemic control. Supported by the preclinical trial, eighty-five patients with type 2 diabetes (T2D) receiving first-line medications were enrolled in a double-blind, randomized, placebo-controlled trial with a 90% power level. Patients were randomized into a placebo group or either of the following two treatment groups: oral administration of 12mg or 20mg/kg body weight of PhAM once every 48h for 6 months. Both treatments were well tolerated. At the endpoint, more than 70% of patients achieved a 0.5 - 2.0 decrease in HbA1c levels and a >20mg/dl decrease in fasting blood glucose, meeting the pre-specified primary outcome. 66% of patients treated with 20mg PhAM achieved the < 7% HbA1c and HOMA-IR of > 1.0 goal. respectively. Our study shows that PhAM can supplement first-line medications to achieve target glycemic control within 6 months. Pan African Clinical Trial Registration number: PACTR202206531545729.
AU  - Amadi, P.U.*
AU  - Osuoha, J.O.*
AU  - Ekweogu, C.N.*
AU  - Jarad, S.J.*
AU  - Efiong, E.E.
AU  - Odika, P.C.*
AU  - Ejiofor, C.*
AU  - Aloy-Amadi, O.*
AU  - Gill, G.S.*
AU  - Adumekwe, C.W.*
AU  - Gaowa, A.*
AU  - Zhang, D.*
AU  - de Courten, B.*
AU  - Agomuo, E.N.*
C1  - 73098
C2  - 56912
CY  - 24-28 Oval Rd, London Nw1 7dx, England
TI  - Phenolic acids from Anisopus mannii modulates phosphofructokinase 1 to improve glycemic control in patients with type 2 diabetes: A double-blind, randomized, clinical trial.
JO  - Pharmacol. Res.
VL  - 212
PB  - Academic Press Ltd- Elsevier Science Ltd
PY  - 2025
SN  - 1043-6618
ER  - 

TY  - JOUR
AB  - Activation of brown adipose tissue (BAT) with the β3-adrenergic receptor agonist CL316,243 protects mice from atherosclerosis development, and the presence of metabolically active BAT is associated with cardiometabolic health in humans. In contrast, exposure to cold or treatment with the clinically used β3-adrenergic receptor agonist mirabegron to activate BAT exacerbates atherosclerosis in apolipoprotein E (ApoE)- and low-density lipoprotein receptor (LDLR)-deficient mice, both lacking a functional ApoE-LDLR pathway crucial for lipoprotein remnant clearance. We, therefore, investigated the effects of mirabegron treatment on dyslipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a humanized lipoprotein metabolism model with a functional ApoE-LDLR clearance pathway. Mirabegron activated BAT and induced white adipose tissue (WAT) browning, accompanied by selectively increased fat oxidation and attenuated fat mass gain. Mirabegron increased the uptake of fatty acids derived from triglyceride (TG)-rich lipoproteins by BAT and WAT, which was coupled to increased hepatic uptake of the generated cholesterol-enriched core remnants. Mirabegron also promoted hepatic very low-density lipoprotein (VLDL) production, likely due to an increased flux of fatty acids from WAT to the liver, and resulted in transient elevation in plasma TG levels followed by a substantial decrease in plasma TGs. These effects led to a trend toward lower plasma cholesterol levels and reduced atherosclerosis. We conclude that BAT activation by mirabegron leads to substantial metabolic benefits in APOE*3-Leiden.CETP mice, and mirabegron treatment is certainly not atherogenic. These data underscore the importance of the choice of experimental models when investigating the effect of BAT activation on lipoprotein metabolism and atherosclerosis.
AU  - Ying, Z.*
AU  - van Eenige, R.*
AU  - Beerepoot, R.*
AU  - Boon, M.R.*
AU  - Kloosterhuis, N.J.*
AU  - Van De Sluis, B.*
AU  - Bartelt, A.
AU  - Rensen, P.C.N.*
AU  - Kooijman, S.*
C1  - 67125
C2  - 53485
CY  - 24-28 Oval Rd, London Nw1 7dx, England
TI  - Mirabegron-induced brown fat activation does not exacerbate atherosclerosis in mice with a functional hepatic ApoE-LDLR pathway.
JO  - Pharmacol. Res.
VL  - 187
PB  - Academic Press Ltd- Elsevier Science Ltd
PY  - 2023
SN  - 1043-6618
ER  - 

TY  - JOUR
AB  - 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.
AU  - Dludla, P.V.*
AU  - Nkambule, B.B.*
AU  - Tiano, L.*
AU  - Louw, J.*
AU  - Jastroch, M.
AU  - Mazibuko-Mbeje, S.E.*
C1  - 54325
C2  - 45513
SP  - 11-24
TI  - Uncoupling proteins as a therapeutic target to protect the diabetic heart.
JO  - Pharmacol. Res.
VL  - 137
PY  - 2018
SN  - 1043-6618
ER  - 

TY  - JOUR
AB  - Infusion of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) causes an elevation of blood pressure and depression of cardiac output. Polymorphisms in the promoter region of the ADMA-degrading enzyme dimethylarginine dimethylaminohydrolase 2 (DDAH2) gene have been associated with elevated ADMA concentrations and adverse outcomes in critically ill patients. We hypothesized that two DDAH2 promoter - 1151 A/C and -449 G/C polymorphisms (rs805304 and rs805305) will be associated with blood pressure levels, hypertension prevalence and measures of cardiac structure and function in the general population. Methods and results: We genotyped rs805304 and rs805305 in 783 participants of the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg S3 study. Plasma ADMA concentrations did not differ by rs805304 and rs805305 genotypes. Both polymorphisms were associated with a higher prevalence of hypertension. The odds ratio (adjusted for age, gender and body mass index) for hypertension was 1.70 (95%CI: 1.22-2.36: p=0.002) for those homozygous (n=348) for the -1151A allele and 1.80 (95%CI: 1.29-2.49, p<0.001) for individuals homozygous for the -449G allele (n=350). However, both polymorphisms were not related to measures of cardiac structure and function (left ventricular [LV] mass, LV wall thickness, LV end-diastolic diameter, ejection fraction, E/A ratio, isovolumetric relaxation time) in multivariable-adjusted models. Conclusion: The present study indicates that the -1151 A/C and -449 G/C polymorphisms in the DDAH2 promoter region are not related to plasma ADMA levels or measures of cardiac structure and function but are associated with an increased prevalence of hypertension. The mechanisms of this association need further investigation.
AU  - Maas, R.*
AU  - Erdmann, J.*
AU  - Luneburg, N.*
AU  - Stritzke, J.*
AU  - Schwedhelm, E.*
AU  - Meisinger, C.
AU  - Peters, A.
AU  - Weil, J.*
AU  - Schunkert, H.*
AU  - Boger, R.H.*
AU  - Lieb, W.*
C1  - 2897
C2  - 26878
CY  - London
SP  - 488-493
TI  - Polymorphisms in the promoter region of the dimethylarginine dimethylaminohydrolase 2 gene are associated with prevalence of hypertension.
JO  - Pharmacol. Res.
VL  - 60
IS  - 6
PB  - Academic Press Ltd- Elsevier Science Ltd
PY  - 2009
SN  - 1043-6618
ER  -