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Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Glitazones, PPAR-γ agonists, are one of the earlier drugs used for treatment of T2DM (Nanjan et al., 2018). Ciglitazone (2a, Fig. 11.11) was discovered by Takeda in 1982, but rapidly discontinued (Gale, 2001). Troglitazone 2b was approved by FDA for T2DM in 1997, but after 6 weeks of its launch by Glaxo Welcome was withdrawn due to hepatotoxicity, and finally retired in 2000 (Nanjan et al., 2018). There are three marketed TZDs: pioglitazone (2c, Actos™ or Glustin™, Takeda Pharma USA and Eli Lilly), rosiglitazone (2d, Avandia™, GlaxoSmithKline), and lobeglitazone (2e, Duvie™, Chong Kun Dang), whose chemical structures are shown in Fig. 11.11. There are concerns about cardiovascular risks associated to rosiglitazone 2d, so that FDA placed some restrictions on it use, while EMA (European Medicine Agency) recommended its suspension from the market (Nanjan et al., 2018). On the other hand, the risk of developing bladder cancer associated to the use of pioglitazone 2c has been also reported (Shukla and Kalra, 2011). Lobeglitazone 2e was approved by the Ministry of Food and Drug Safety of Korea in 2013 (Lee et al., 2015), although the postmarketing surveillance is planned to finish in 2019. Chemical structure of glitazones.
Pharmacological treatment for transforming growth factor beta induced corneal dystrophies: what is the way forward?
Published in Expert Review of Clinical Pharmacology, 2023
Gabriella Guo Sciriha, Janet Sultana, Joseph Borg
TGFBI expression is controlled directly by the TGF-beta/SMAD signaling pathway [8]. Furthermore, indirect modulation of TGFBI expression also occurs via the JNK signaling cascade [9], the PI3-K/AKT and the cAMP/PKA cascades. Attempts at generating CD animal models which may subsequently be used to test the relevance of potential drugs have been scarce. However, 16 potential drugs that can theoretically reduce the levels of mutant TGFBIp in human corneal cells have been identified in literature [10]. These can be categorized into five groups [10]: compounds targeting TGF-beta/Smad and Akt/GSK-3 signaling cascades (Group a: lithium, tranilast, 2,4-diamino-5-(1-hydroxynaphthalen-2-yl)-5 H-chromeno[2,3-b] pyriine-3-carbonitrile, histone deacetylase (HDAC) inhibitors: vorinostat and givinostat (ITF2357), doxycycline, lobeglitazone, halofuginone, glucosamine, nitric oxide, SB431542 and SP600125); compounds targeting JNK signaling cascade (Group b: SP600125, doxycycline); compounds inhibiting DNA synthesis and function (Group c: MMC); compounds inducing increased elimination of TGFBIp (Group d: 4-PBA, melatonin and Torin1) and compounds binding to mutant TGFBIp (Group e: MO07617, RJF00203, BTB05094, RJF00203 and BTB05094 [11]) (Table 1).
Close association of PFASs exposure with hepatic fibrosis than steatosis: evidences from NHANES 2017–2018
Published in Annals of Medicine, 2023
Wenli Cheng, Min Li, Luyun Zhang, Cheng Zhou, Xinyu Zhang, Chenyu Zhu, Luyi Tan, Hui Lin, Wenjuan Zhang, Wenji Zhang
In this study, the associations were investigated between several serum PFASs and NAFLD based on liver ultrasound transient elastography and other non-invasive biomarkers. The GLM and RCS were constructed to reveal there was no significant association between PFASs and CAP. The results of hepatic steatosis-related indicators FLI, LFS and FSI also demonstrated that PFASs had no significant correlation with hepatic steatosis based on ANOVA and Spearman’s tests. But PFASs exposure was indeed closely related to glucose and lipid metabolism. Serum TG has positive correlations with PFHxS, PFNA, PFOA and PFOS while FPG had positive correlations with all of the PFASs in the study. PFASs structurally resembled fatty acids and activated the peroxisome proliferators-activated receptors (PPARs) signaling pathway, responsible for perturbations of glucose and lipid homeostasis partially [39]. A new study showed serum albumin mediated the effects of PFASs on serum lipid levels [40]. PFASs had shown a strong binding affinity to serum proteins and were positively associated with serum albumin [41], which was bound to PFASs and transported to target organs that regulate serum lipid levels [40]. In addition, we also found that PFASs were negatively correlated with BMI and positively correlated with HDL which was also reported in a previous study among European teenagers [42]. But a high level of PFOA (median level = 1635.96 ng/mL) was reported to negatively associate with HDL in workers of a fluorochemical plant [43]. These evidences suggested that the effects of PFASs on hepatic steatosis appeared to be a double-edged sword and associated with the exposure concentration. The activation of PPARs induced genes in both lipogenesis/uptake and fatty acid oxidation pathways. But targeting PPARs was also an emerging strategy for the treatment of steatosis and inflammation. The agonists of PPARα (fenofibrate) and PPARγ (pioglitazone, lobeglitazone) had been shown to reduce hepatic steatosis in both animal studies and clinical trials. Additionally, the lipid metabolism pathways might be influenced by the feedback loop [44]. As previously mentioned, PFOS and PFOA were found to relieve steatosis in mice with diet induce-fatty liver [14, 15]. The molecular mechanisms of the switch between lipogenic and lipid oxidation effects induced by PFASs are not fully understood.