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An Asian woman with blurred vision
Published in Tim French, Terry Wardle, The Problem-Based Learning Workbook, 2022
Rosiglitazone and pioglitazone also target insulin resistance but through a different mechanism. These drugs are peroxisome proliferator-activated receptor-gamma (PPAR) agonists. PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver.
Glycyrrhiza glabra (Licorice) and Gymnema sylvestre (Gurmar)
Published in Azamal Husen, Herbs, Shrubs, and Trees of Potential Medicinal Benefits, 2022
Jasbir Kaur, Sana Nafees, Mohd Anwar, Jamal Akhtar, Nighat Anjum
Antidiabetic: Insulin dependent type 2 diabetes is an insulin-resistant disorder, an emerging health problem in modern-day society. PPARs (peroxisomal receptor antagonists) are ligand-dependent changes that regulate the expression of a group of genes that play an essential role in glucose metabolism. PPAR receptors are of 3 types: PPAR-α, PPAR-γ, and PPAR-δ. PPAR-α is present in muscles, liver, and kidney; PPAR-γ is found in adrenal glands, fat cells, and small intestine; and PPAR-δ is ubiquitous. PPAR-γ are the primary targets for insulin sensitization like pioglitazone and rosiglitazone. Ethyl acetate extract showed significant binding of PPAR-γ as seen in GAL-4-PPAR-γ-Flue test. This activity is due to the phenolic compounds like glycycoumarin, glycyrin, isolglycyrol, dehydroglyasperin, glyasperin B, and glyasperin D. Pioglitazone and glycine have been shown to prevent elevated blood sugar levels in rats after sucrose exposure in the oral sucrose tolerance test. The potent PPAR-γ agonist, i.e., pioglitazone, improves resistance of insulin, hence improves type 2 diabetes, and glycyrrhizin showed intense activity bound to the PPAR-γ ligand, thus lowering blood sugar in KK-Ay (Knockout diabetes mice). This finding is important because traditionally licorice has been used as an artificial sweetening agent and can help in treating insulin-resistant disorders common in modern society (Takii et al., 2000).
Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
PPAR-α agonists serves as cellular receptor for fibrates, a class of drugs used in the treatment of dyslipidemia, and also used for the treatment of vascular complications associated with Type 2 DM (Verges, 2004; Steiner, 2007). These fibrates possess a common chemical structure (2-methyl-2-aryloxypropionic acids or esters), not displaying any chiral center. In an attempt to obtain an enantiopure PPAR-α agonist, Astra Zeneca synthesized AZD 4619 ((S)-5, Fig. 11.9), an α agonist, by means of an enzymatic dynamic kinetic resolution (DKR) of the corresponding racemic thioester 4, using an organic base to promote the racemization (Brown et al., 2006), as shown in Fig. 11.9. DKR process to synthesize AZD 46919.
Hepatoprotective effects of norgalanthamine on carbon tetrachloride induced-hepatotoxicity in mice
Published in Drug and Chemical Toxicology, 2023
Nayeon Yang, Myungsoon Ko, Meejung Ahn, Taekyun Shin
This study further examined the effects of norgalanthamine on lipid metabolism, which is an important pathological event, and on protective and/or therapeutic targets in liver disease (Musso et al.2017). In the treatment of patients with nonalcoholic steatohepatitis, a molecular target of therapy is the PPAR-mediated increase in the oxidation of free fatty acids (Musso et al.2017). PPAR-γ participates in the modulation of metabolic disorders by activating the expression of genes involved in adipocyte maturation, lipid accumulation, and insulin-sensitive glucose transport (Lee et al. 2017). These findings imply the potential of norgalanthamine as an anti-adipogenic agent, based on its ability to reduce lipid accumulation in the livers of mice with CCl4-induced liver injury.
The roles of hydrogen sulfide in renal physiology and disease states
Published in Renal Failure, 2022
Jianan Feng, Xiangxue Lu, Han Li, Shixiang Wang
PPARs are a class of ligand–activated nuclear transcription factors that belong to the receptor superfamily. Three subtypes of PPARs, PPAR–α, PPAR–β/δ, and PPAR–γ, have been found. Each PPAR subtype can alleviate metabolic abnormalities under the action of agonists; however, their mechanisms of action are different. For example, activation of PPAR–β/δ can significantly improve BP by increasing NO and serve as a new therapeutic target for hypertension [135,136]. Recent studies have shown that the role of H2S in regulating BP might be related to PPARβ/δ activation. H2S is thought to work with NO in synergy to regulate vascular tone. The specific molecular mechanism may involve H2S–mediated upregulation of PPAR–δ expression, increases in protein kinase B or AMPK phosphorylation, and enhancement of eNOS phosphorylation with a consequent increase in NO production [137,138]. In rats, the use of NOS inhibitors, such as Nx–nitro–l–arginine methyl ester, can cause hypertension, which can be reversed by treatment with NaHS [139]. However, in aortic rings of rats, low concentrations of NaHS (10–100 μM) can downregulate NO production and consequently induce vasoconstriction. In contrast, administration of high doses of NaHS has been reported to directly relax aortic rings [140]. These findings suggest a role of H2S/NO crosstalk in BP regulation. The antihypertensive effect of H2S is also dose dependent, but the specific mechanism needs further study [6].
Vitamin D3 intake as modulator for the early biomarkers of myocardial tissue injury in diabetic hyperlipidaemic rats
Published in Archives of Physiology and Biochemistry, 2022
Mohamed M. Elseweidy, Sousou I. Ali, Noura I. Shershir, Abd Elmonem A. Ali, Sally K. Hammad
In our study, vitamin D significantly improved the lipid profile in diabetic rats. This is consistent with other studies, where vitamin D improved the lipid profile not only in experimental animals, but also in patients with type 1 and type 2 diabetes (Jafari et al. 2016, Elseweidy et al. 2017, Hafez et al. 2019). The binding of vitamin D to its receptors regulates key genes involved in lipid metabolism. For example, vitamin D can increase the expression of PPAR-α and CPT-1. PPAR-α is expressed prominently in liver, heart and skeletal muscle and plays a key role in regulating genes that are involved in lipids storage and utilisation such as fatty acid oxidation. On the other hand, CPT-1 is a rate-limiting enzyme of β-oxidation of fatty acids, which takes place in the mitochondria. CPT-1 facilitates the first step of the transport of long-chain fatty acids into mitochondria (Lefebvre et al. 2006, Ning et al. 2015).