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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.
Terpenoids in Treatment of Liver Disease
Published in Dijendra Nath Roy, Terpenoids Against Human Diseases, 2019
Sujan Chatterjee, Debajyoti Patra, Pujita Ghosh, Akash Prasad, Kaustav Dutta Chowdhury
Lutein, one of hundreds of known naturally oxygenated carotenoids, is abundantly present in vegetables, fruits and egg yolks. Lutein consists of a carbon chain with nine conjugated dienes and a hydroxylated cyclic hexenyl structure at each side; owing to its special chemical structure, it has potential anti-oxidant properties and has decreased oxidative stress–mediated liver injury (Souza-Mello et al. 2015). It has effectively augmented mRNA and protein levels of key molecules related to insulin signalling, which were suppressed by a high fat diet. PPAR-α plays an important role in the regulation of hepatic lipid metabolism given that the inhibition of PPAR-α might induce hepatic steatosis (Souza-Mello et al. 2015). Lutein supplementation reversed such PPAR-α inhibition effectively by restoring the expression of SIRT1, which is associated with insulin signalling. All of these results suggest the beneficial effects of lutein on NAFLD. Guinea pigs that were pre-treated with lutein displayed no such significant alteration even after being fed an hypercholesterolaemic diet. Data comparing treated and untreated mice suggests a reduction in TBARS content and nuclear localization of NF-κβ followed by DNA binding. Besides beneficial effects in the presence of a high cholesterol diet, lutein exerts both anti-oxidant and anti-inflammatory effects that can be explained by attenuated NF-κB DNA binding activity (Souza-Mello et al. 2015). Lutein pre-treatment also reduced ALT, AST, alkaline phosphatase (ALP) and LDH production and release to plasma. Reports also indicate that lutein is capable of reducing cyclooxygenase (COX)-2 and iNOS protein expression and stimulating Nrf2 nuclear localization. Accordingly, it may be concluded that in addition to the maintenance of inherent anti-oxidant properties it protects the liver from alcoholic, hyperglycaemic or hypercholesterolaemic stress.
Diabetes and Antidiabetic Therapy: Control of Glucose
Published in Richard J. Sundberg, The Chemical Century, 2017
The fibrates are believed to be activators of PPAR-α, one of a family of transcription factors that regulate lipid and carbohydrate metabolism. PPAR-α is particularly associated with the liver, muscle, and heart. The fibrates reduce triglyceride levels and modestly improve HDL/LDL ratios. They also appear to improve the resistance of the endothelium to inflammation and plaque formation.
Intermittent fasting and probiotics in non-alcoholic fatty liver in rats: interplay between FGF19 and FGF21
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Yomna M yehya, Zeinab H. El-Said, Mohamed Adel, Basma H Othman, Atef A Mansour, Sabry M Gad
FGF21 has direct anti-inflammatory and anti-fibrotic effects and regulates the activation of hepatic stellate cells independent of either insulin resistance or obesity [43]. In this study, both serum FGF21 levels and FGF21 gene expression in liver tissue were in close correlation with each other; FGF21 was significantly increased with HFD, which suggests that FGF21 action may be impaired as a previous study stated that FGF21 receptors were downregulated, like states of hormone resistance in NAFLD [44]. Upregulation of FGF21 is likely an adaptive response to energy disruption in this metabolic state [45]. Surprisingly, FGF21 levels increased more and more in the PR, IF, and IP groups when compared to HFD, with no significant difference among them. In consistent with this result, a study conducted in 2019 by Zhao and his colleagues stated a rise in FGF21 after fructose induced NAFLD especially after probiotics application in the last 4 weeks of the experiment. They proved that FGF21 is required for the beneficial effects of probiotics in regulating the gut-adipose-liver axis to reduce NAFLD [45]. Zhang et al., 2020 declared that IF improved insulin sensitivity via upregulating FGF21 secretion, which downregulates inflammation signaling and activates insulin signaling [14]. Moreover, PPARα plays a central role in the fasting response by directly stimulating the transcription of genes involved in fatty acid oxidation and ketone-body production and inducing the hormone FGF21 in liver [46].
Oleanolic acid suppresses pentylenetetrazole-induced seizure in vivo
Published in International Journal of Environmental Health Research, 2023
Canan Akünal Türel, Oruç Yunusoğlu
Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-regulated nuclear receptors that are present in the brain and include PPAR-α, PPAR-β/δ, and PPAR-γ (Puligheddu et al. 2013; Yunusoğlu 2021b, Yunusoğlu et al. 2022; Komali et al. 2021). PPARs are thought to be a potential target for treating neurological diseases such as epilepsy (Adabi et al. 2012; Puligheddu et al. 2013; Peng et al. 2019). A series of recent examinations showed that PPAR agonists decreased epileptic seizures (Adabi et al. 2012; Puligheddu et al. 2013; Peng et al. 2019). In previous scientific studies, it has been shown that oleanolic acid affects the PPAR system (Kang et al. 2017; Wang et al. 2018; Loza-Rodríguez et al. 2020). Oleanolic acid may contribute to the reduction of anti-seizures by activating PPAR receptors.
Flavonoids fractions of Adansonia digitata L. fruits protects adult Wistar rats from mercury chloride-induced hepatorenal toxicity: histopathological and biochemical studies
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Wusa Makena, Yomi Samson Aribiyun, Aisha Aminu, Barka Ishaku, Ayuba Yohana, Ekwere Eke Inemesit
The histopathological study revealed the architectural changes (liver and kidney) of the flavonoid’s fractions and HgCl2 administered rats (Figures 4 and 5). As previously stated, HgCl2 causes oxidative stress in the liver and kidney, resulting in pathological changes [43]. Mercury chloride transport in the kidney has been studied, and it has been discovered that it is taken up by proximal tubular cells [44]. Also, in this study, rats exposed to only HgCl2 developed renal tubular damage, as well as vascular congestion and mild Bowman’s space enlargement. Flavonoid has been shown to preserve histological integrity in damaged renal tissue with necrosis in the renal parenchyma, and tubular dilatations [45]. The PPARs appear to be promising targets for treating liver disease. Nuclear receptors known as PPARas are involved in mitigating liver inflammation by inhibiting NF-κB and reducing C-reactive protein expression [46]. PPARα stimulation is expected to reduce steatosis by stimulating β-oxidation and reducing inflammation by inhibiting NF-kB [47]. Flavonoids have been shown to stimulate PPAR in several studies [48,49]. Other studies have found that flavonoids increase the PPAR gene expression and protein expression [50,51]. Furthermore, Flavonoids have renoprotective effects [52] by modulating the Nrf2 signaling pathway, which favors the translocation of the transcription factor Nrf2 to the nucleus, where it binds to AREs and activates the transcription of genes encoding phase II antioxidant and detoxifying enzymes [53]. The vital histological findings of this study were that flavonoids treatment resulted in hepatic and renal architecture recovery.