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1
Rahman, Safikur, Md Tabish Rehman, Gulam Rabbani, Parvez Khan, Mohamed F. AlAjmi, Md Imtaiyaz Hassan, Ghazala Muteeb, and Jihoe Kim. "Insight of the Interaction between 2,4-thiazolidinedione and Human Serum Albumin: A Spectroscopic, Thermodynamic and Molecular Docking Study." International Journal of Molecular Sciences 20, no. 11 (June 3, 2019): 2727. http://dx.doi.org/10.3390/ijms20112727.
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Thiazolidinedione derivatives (TZDs) have attracted attention because of their pharmacological effects. For example, certain TZDs have been reported to ameliorate type II diabetes by binding and activating PPARs (peroxisome proliferator-activated receptors). Nonetheless, no information is available on the interaction between the heterocyclic 2, 4-thiazolidinedione (2,4-TZD) moiety and serum albumin, which could affect the pharmacokinetics and pharmacodynamics of TZDs. In this study, we investigated the binding of 2,4-TZD to human serum albumin (HSA). Intrinsic fluorescence spectroscopy revealed a 1:1 binding stoichiometry between 2,4-TZD and HSA with a binding constant (Kb) of 1.69 ± 0.15 × 103 M−1 at 298 K. Isothermal titration calorimetry studies showed that 2,4-TZD/HSA binding was an exothermic and spontaneous reaction. Molecular docking analysis revealed that 2,4-TZD binds to HSA subdomain IB and that the complex formed is stabilized by van der Waal’s interactions and hydrogen bonds. Molecular dynamics simulation confirmed the stability of the HSA-TZD complex. Further, circular dichroism and 3D fluorescence studies showed that the global conformation of HSA was slightly altered by 2,4-TZD binding, enhancing its stability. The results obtained herein further help in understanding the pharmacokinetic properties of thiazolidinedione.
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Ortmeyer, Heidi K., Noni L. Bodkin, Joseph Haney, Shinji Yoshioka, Hiroyoshi Horikoshi, and Barbara C. Hansen. "A Thiazolidinedione ImprovesIn VivoInsulin Action on Skeletal Muscle Glycogen Synthase in Insulin-Resistant Monkeys." International Journal of Experimental Diabetes Research 1, no. 3 (2000): 195–202. http://dx.doi.org/10.1155/edr.2000.195.
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Thiazolidinediones (TZD) have been shown to have anti-diabetic effects including the ability to decrease fasting hyperglycemia and hyperinsulinemia, increase insulin-mediated glucose disposal rate (M) and decrease hepatic glucose production, but the mechanisms of action are not well established. To determine whether a TZD (R-102380, Sankyo Company Ltd., Tokyo, Japan) could improve insulin action on skeletal muscle glycogen synthase (GS), the rate-limiting enzyme in glycogen synthesis, 4 insulin-resistant obese monkeys were given I mg/kg/ day R-102380 p.o. for a 6-week period. Skeletal muscle GS activity and glucose 6-phosphate (G6P) content were compared between pre-dosing and dosing periods before and during the maximal insulin-stimulation of a euglycemic hyperinsulinemic clamp.Compared to pre-dosing, insulin-stimulated GS activity and G6P content were increased by this TZD: GS independent activity (p= 0.02), GS total activity (p= 0.005), GS fractional activity (p= 0.06) and G6P content (p= 0.02). The change in GS activity induced byin vivoinsulin (insulin-stimulated minus basal) was also increased by this TZD: GS independent activity (p= 0.03) and GS fractional activity (p= 0.04).We conclude that the TZD R-102380 improves insulin action at the skeletal muscle in part by increasing the activity of glycogen synthase. This improvement in insulin sensitivity may be a key factor in the anti-diabetic effect of the thiazolidinedione class of agents.
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Chis, Irina C., Doina Baltaru, Simona Clichici, Ovidiu Oniga, Ileana Cojocaru, and Cristina Nastasa. "The Effects of a 5-Chromene-yl-thiazolidin-2,4-dione Derivative in Alleviating Oxidative Stress in Adjuvant-Induced Arthritis." Revista de Chimie 69, no. 9 (October 15, 2018): 2361–65. http://dx.doi.org/10.37358/rc.18.9.6534.
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Rheumatoid arthritis (RA) is a chronic inflammatory disease that reduces life quality and requires long-life therapy. Quercetin (Que) is a natural flavonoid with antioxidant and anti-inflammatory effects. (3-(2-(4-Chlorophenyl)-2-oxoethyl)-5-((6-methyl-4-oxo-4H-chromen-3-yl)methylene) thiazolidine-2,4-dione (TZD) is a thiazolidinedione derivative synthesized in our laboratory. This study was designed to investigate the antioxidant effects of the Que and TZD derivative administration in adjuvant-induced arthritic (AIA) rats. AIA was induced in Wistar rats by the intraplantar injection of Freund�s complete adjuvant (FCA), unilaterally in the right hind paw. The control non-arthritic rats and the arthritic rats were treated with Que (30 mg/kg/day) or TZD derivative (12 mg/kg/day) for 21 days. The antioxidant effects of 5-chromen-yl- thiazolidinedione were compared to Que. The serum levels of malondialdehyde (MDA) and protein carbonyl (PC) groups, the superoxide dismutase (SOD) and catalase (CAT) activity were assessed. AIA rats showed significatly increased oxidative stress parameter levels in the blood. The results indicated that the TZD derivative decreased the blood oxidative stress parameters in the treated arthritic rats, compared to Que. The antioxidant effects of 5-chromen-yl-thiazolidinedione in AIA suggest its therapeutic properties for the clinical treatment of RA.
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Kim, Won Jun, Jung Hyun Noh, Kyungdo Han, and Cheol-Young Park. "The Association Between Second-Line Oral Antihyperglycemic Medication on Types of Dementia in Type 2 Diabetes: A Nationwide Real-World Longitudinal Study." Journal of Alzheimer's Disease 81, no. 3 (June 1, 2021): 1263–72. http://dx.doi.org/10.3233/jad-201535.
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Background: There are few reports that evaluated the association between various types of dementia and dual oral therapy with antihyperglycemic medication. Objective: The goal of this study was to investigate the association between treatment of dual antihyperglycemic medication and dementia subclass in type 2 diabetes mellitus using the Korean National Health Insurance System. Methods: This study included 701,193 individuals with diabetes prescribed dual oral therapy between 2009 and 2012 from the Korean National Health Insurance Service Database, which were tracked until 2017. All-cause, Alzheimer’s (AD) and vascular dementia (VaD) were investigated by dual oral therapy. Adjustments were made for age, sex, income, diabetes duration, hypertension, dyslipidemia, smoking, drinking, exercise, body mass index, glucose level, and estimated glomerular filtration rate. Results: Dual therapy with metformin (Met) + dipeptidyl peptidase-4 inhibitor (DPP-4i), Met + thiazolidinedione (TZD), and sulfonylurea (SU) + thiazolidinediones (TZD) were significantly associated with all-cause dementia (HR = 0.904, 0.804, and 0.962, respectively) and VaD (HR = 0.865, 0.725, and 0.911, respectively), compared with Met + SU. Met + DPP-4i and Met + TZD were associated with significantly lower risk of AD (HR = 0.922 and 0.812), compared with Met + SU. Dual therapy with TZD was associated with a significantly lower risk of all-cause dementia, AD, and VaD than nonusers of TZD (HR = 0.918, 0.925 and 0.859, respectively). Conclusion: Adding TZD or DPP-4i instead of SU as second-line anti-diabetic treatment may be considered for delaying or preventing dementia. Also, TZD users relative to TZD non-users on dual oral therapy were significantly associated with lower risk of various types of dementia.
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Corigliano, Domenica M., Riyaz Syed, Sebastiano Messineo, Antonio Lupia, Rahul Patel, Chittireddy Venkata Ramana Reddy, Pramod K. Dubey, et al. "Indole and 2,4-Thiazolidinedione conjugates as potential anticancer modulators." PeerJ 6 (August 8, 2018): e5386. http://dx.doi.org/10.7717/peerj.5386.
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Background Thiazolidinediones (TZDs), also called glitazones, are five-membered carbon ring molecules commonly used for the management of insulin resistance and type 2 diabetes. Recently, many prospective studies have also documented the impact of these compounds as anti-proliferative agents, though several negative side effects such as hepatotoxicity, water retention and cardiac issues have been reported. In this work, we synthesized twenty-six new TZD analogues where the thiazolidinone moiety is directly connected to an N-heterocyclic ring in order to lower their toxic effects. Methods By adopting a widely applicable synthetic method, twenty-six TZD derivatives were synthesized and tested for their antiproliferative activity in MTT and Wound healing assays with PC3 (prostate cancer) and MCF-7 (breast cancer) cells. Results Three compounds, out of twenty-six, significantly decreased cellular viability and migration, and these effects were even more pronounced when compared with rosiglitazone, a well-known member of the TZD class of antidiabetic agents. As revealed by Western blot analysis, part of this antiproliferative effect was supported by apoptosis studies evaluating BCL-xL and C-PARP protein expression. Conclusion Our data highlight the promising potential of these TZD derivatives as anti-proliferative agents for the treatment of prostate and breast cancer.
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van de Vyver, M., E. Andrag, I. L. Cockburn, and W. F. Ferris. "Thiazolidinedione-induced lipid droplet formation during osteogenic differentiation." Journal of Endocrinology 223, no. 2 (September 10, 2014): 119–32. http://dx.doi.org/10.1530/joe-14-0425.
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Chronic administration of the insulin-sensitising drugs, thiazolidinediones (TZDs), results in low bone mineral density and ‘fatty bones’. This is thought to be due, at least in part, to aberrant differentiation of progenitor mesenchymal stem cells (MSCs) away from osteogenesis towards adipogenesis. This study directly compared the effects of rosiglitazone, pioglitazone, and netoglitazone treatment on osteogenesis and adipogenesis in MSCs derived from subcutaneous (SC) or visceral (PV) white adipose tissue. MSCs were isolated from adipose tissue depots of male Wistar rats and characterised using flow cytometry. The effects of TZD treatment on osteogenic and adipogenic differentiation were assessed histologically (day 14) and by quantitative PCR analysis (Pparγ2(Pparg2),Ap2(Fabp4), Adipsin(Adps),Msx2, Collagen I(Col1a1), andAlp) on days 0, 7, and 10. Uniquely, lipid droplet formation and mineralisation were found to occur concurrently in response to TZD treatment during osteogenesis. Compared with SC MSCs, PV MSCs were more prone to lipid accumulation under controlled osteogenic and adipogenic differentiation conditions. This study demonstrated that the extent of lipid accumulation is dependent on the nature of thePparligand and that SC and PV MSCs respond differently toin vitroTZD treatment, suggesting that metabolic status can contribute to the adverse effects associated with TZD treatment.
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Rosa, Fernanda, Misagh Moridi, Johan S. Osorio, Jayant Lohakare, Erminio Trevisi, Shelby Filley, Charles Estill, and Massimo Bionaz. "2,4-Thiazolidinedione in Well-Fed Lactating Dairy Goats: II. Response to Intra-Mammary Infection." Veterinary Sciences 6, no. 2 (June 5, 2019): 52. http://dx.doi.org/10.3390/vetsci6020052.
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In a prior experiment, treatment of goats with the putative PPARγ agonist 2,4-thiazolidinedione (2,4-TZD) ameliorated the response to intramammary infection without evidence of PPARγ activation. The lack of PPARγ activation was possibly due to deficiency of vitamin A and/or a poor body condition of the animals. Therefore, the present study hypothesized that activation of PPARγ by 2,4-TZD in goats supplemented with adequate amounts of vitamin A can improve the response to sub-clinical mastitis. Lactating goats receiving a diet that met National Research Council requirements, including vitamin A, were injected with 8 mg/kg BW of 2,4-TZD (n = 6) or saline (n = 6; control (CTR)) daily. Two weeks into treatment, all goats received Streptococcus uberis (IMI) in the right mammary gland. Blood biomarkers of metabolism, inflammation, and oxidative status plus leukocytes phagocytosis were measured. Mammary epithelial cells (MEC) and macrophages were isolated from milk and liver tissue collected for gene expression analysis. Milk fat was maintained by treatment with 2,4-TZD, but decreased in CTR, after IMI. Haptoglobin was increased after IMI only in 2,4-TZD without any effect on negative acute phase proteins, indicating an improved liver function. 2,4-TZD vs. CTR had a greater amount of globulin. The expression of inflammation-related genes was increased by IMI in both macrophages and MEC. Except for decreasing expression of SCD1 in MEC, 2,4-TZD did not affect the expression of measured genes. Results confirmed the successful induction of sub-clinical mastitis but did not confirm the positive effect of 2,4-TZD on the response to IMI in well-fed goats.
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Rosa, Fernanda, Johan S. Osorio, Erminio Trevisi, Francisco Yanqui-Rivera, Charles T. Estill, and Massimo Bionaz. "2,4-Thiazolidinedione Treatment Improves the Innate Immune Response in Dairy Goats with Induced Subclinical Mastitis." PPAR Research 2017 (2017): 1–22. http://dx.doi.org/10.1155/2017/7097450.
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Mastitis is a major disease in dairy cows resulting in significant economic losses. In vitro works suggest that ruminants peroxisome proliferator-activated receptor gamma (PPARγ) can aid in improving the response to mastitis and can control milk fat synthesis. The objectives of the present experiment were to test if treatment with the putative PPARγ agonist 2,4-thiazolidinedione (TZD) improves (1) the response to subclinical mastitis and (2) milk fat production. Lactating goats received daily injections of 8 mg/kg BW of TZD or saline for 3 weeks. After one week of TZD injection, half of the goats in each group received intramammary infusion of Strep. uberis or saline in both halves for a total of 4 groups (n=6/group). TZD treatment did not affect milk fat but had positive effect on milk somatic cells count, blood nonesterified fatty acids, inflammatory markers, and liver function. TZD significantly increased myeloperoxidase but did not affect leukocytes phagocytosis or insulin. TZD increased adipocytes size and had minor effect on expression of PPARγ target genes in mammary epithelial cells but not in adipose tissue. Overall, TZD ameliorated the response to intramammary infection but the effect on milk fat synthesis and expression of related transcripts was less than expected.
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Govindarajan, R., E. R. Siegel, D. L. Simmons, and N. P. Lang. "Thiazolidinedione (TZD) exposure and risk of squamous cell carcinoma of head and neck (SCCHN)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 1511. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.1511.
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1511 Background: Peroxisome proliferator-activated receptor γ (PPARγ), a nucleic acid receptor, heterodimerizes with retinoic acid X receptor (RXR). Ligand activation of RXR leads to decreased proliferation of SCCHN cell lines. TZDs (syn: glitazones), used to treat diabetes mellitus (DM), are ligands for the RXR:PPARγ heterodimer. A retrospective study of diabetics attending the Veterans Affairs (VA) health care system was undertaken to assess the association between TZD exposure and the risk of developing SCCHN. Methods: Data were obtained from the electronic patient database VISN 16 (covering 10 VA institutions) for males aged ≥40 presenting with DM and no prior SCCHN between 10/01/96 and 12/31/03. DM and SCCHN diagnoses were identified using ICD9 codes. Subjects were followed until 12/31/05, and analyzed for SCCHN risk via Cox regression, using time-dependent covariates to model exposure to TZDs, insulin and other anti-DM agents. Results: 130,406 subjects met the study criteria. Median (quartiles) age at DM presentation was 64 (55–72).18.5% were African-American, 61.3% were Caucasian, and 20.2% were other/unknown. The table shows TZD exposure, SCCHN incidence and hazard ratios for SCCHN with exposure to TZD alone or in combination with insulin and other anti-DM agents after adjusting for age, race, BMI, and HbA1C. Conclusions: A 41%-55% reduction in the risk of SCCHN was observed in diabetic subjects treated with TZD alone, with insulin, and with other anti-DM agents. The decrease was statistically significant (P<0.05) for TZD alone and TZD with other agents, but not for TZD with insulin. These findings suggest a protective effect of TZD on the development of SCCHN. The mechanism is not clearly known but possibly mediated through RXR:PPARγ pathway. [Table: see text] No significant financial relationships to disclose.
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Klopper, Joshua P., Vibha Sharma, Reid Bissonnette, and Bryan R. Haugen. "Combination PPARγand RXR Agonist Treatment in Melanoma Cells: Functional Importance of S100A2." PPAR Research 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/729876.
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Nuclear hormone receptors, including RXR and PPARγ, represent novel therapeutic targets in melanoma. We have previously shown that the DRO subline of the amelanotic melanoma A375 responds to rexinoid and thiazolidinedione (TZD) treatmentin vitroandin vivo. We performed microarray analysis of A375(DRO) after TZD and combination rexinoid/TZD treatment in which the calcium binding protein S100A2 had increased expression after rexinoid or TZD treatment and a synergistic increase to combination treatment. Increased S100A2 expression is dependent on an intact PPARγreceptor, but it is not sufficient to mediate the antiproliferative effects of rexinoid/TZD treatment. Over expression of S100A2 enhanced the effect of rexinoid and TZD treatment while inhibition of S100A2 expression attenuated the response to rexinoid/TZD treatment, suggesting that S100A2 is necessary for optimal response to RXR and PPARγactivation by respective ligands. In summary, we have identified potential downstream mediators of rexinoid and TZD treatment in a poorly differentiated melanoma and found that alterations in S100A2 expression affect RXR and PPARγsignaling in A375(DRO) cells. These studies provide insight into potential mechanisms of tumor response or resistance to these novel therapies.
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Jaaf, Shana, Fernanda Rosa, Misagh Moridi, Johan S. Osorio, Jayant Lohakare, Erminio Trevisi, Shelby Filley, Gita Cherian, Charles T. Estill, and Massimo Bionaz. "2,4-Thiazolidinedione in Well-Fed Lactating Dairy Goats: I. Effect on Adiposity and Milk Fat Synthesis." Veterinary Sciences 6, no. 2 (May 17, 2019): 45. http://dx.doi.org/10.3390/vetsci6020045.
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Background: In a prior experiment, treatment of goats with the putative PPARγ agonist 2,4-thiazolidinedione (2,4-TZD) did not affect milk fat or expression of milk-fat related genes. The lack of response was possibly due to deficiency of vitamin A and/or a poor body condition of the animals. In the present experiment, we tested the hypothesis that PPARγ activation affects milk fat synthesis in goats with a good body condition and receiving adequate levels of vitamin A. Methods: Lactating goats receiving a diet that met NRC requirements, including vitamin A, were injected with 8 mg/kg BW of 2,4-TZD (n = 6) or saline (n = 6; CTR) daily for 26 days. Blood metabolic profiling and milk yield and components were measured including fatty acid profile. Expression of genes related to glucose and lipid metabolism was measured in adipose tissue and in mammary epithelial cells (MEC). Size of adipocytes was assessed by histological analysis. Results: NEFA, BHBA, and fatty acids available in plasma decreased while glucose increased in 2,4-TZD vs. CTR. Size of cells and expression of insulin signaling and glucose metabolism-related genes were larger in 2,4-TZD vs. CTR in adipose tissue. In MEC, expression of SCD1 and desaturation of stearate was lower in 2,4-TZD vs. CTR. Conclusions: Overall data revealed a lack of PPARγ activation by 2,4-TZD and no effect on milk fat synthesis despite a strong anti-lipolysis effect on adipose tissue.
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Arévalo-Turrubiarte, M., L. González-Dávalos, A. Yabuta, J. D. Garza, J. L. Dávalos, O. Mora, and A. Shimada. "Effect of 2,4-Thiazolidinedione on Limousin Cattle Growth and on Muscle and Adipose Tissue Metabolism." PPAR Research 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/891841.
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The main adipogenic transcription factor PPARγpossesses high affinity to 2,4-TZD, a member of the Thiazolidinedione family of insulin-sensitizing compounds used as adipogenic agents. We evaluated 2,4-TZD’s effect on bovine growth and PPAR tissue expression. Seventeen Limousin bulls (18 month-old; 350 kg body weight (BW)) were assigned into 2 treatments: control and 2,4-TZD (8 mg/70 kg BW) and were fed until bulls reached 500 kg BW. They were weighed and their blood was sampled. DNA, RNA, and protein were determined in liver; skeletal muscle; subcutaneous (SC), omental, perirenal adipose tissues (AT) to determine protein synthesis rate and cellular size. Expression of PPAR mRNA was measured in liver and muscle (PPARα, -δ, and -γ) and SC adipose tissue (γ) by real-time PCR. No significant differences were found (P>0.1) in weight gain, days on feed, and carcass quality. Muscle synthesis was greater in controls (P<0.05); cell size was larger with 2,4-TZD (P<0.05). PPARα, -δ, and -γexpressions with 2,4-TZD in liver were lower (P<0.01) than in muscle. No differences were found for PPARγmRNA expression in SCAT. The results suggest the potential use of 2,4-TZD in beef cattle diets, because it improves AT differentiation, liver, and muscle fatty acid oxidation that, therefore, might improve energy efficiency.
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Yang, Tianxin, and Sunhapas Soodvilai. "Renal and Vascular Mechanisms of Thiazolidinedione-Induced Fluid Retention." PPAR Research 2008 (2008): 1–8. http://dx.doi.org/10.1155/2008/943614.
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Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor subtypeγ(PPARγ) activators that are clinically used as an insulin sensitizer for glycemic control in patients with type 2 diabetes. Additionally, TZDs exhibit novel anti-inflammatory, antioxidant, and antiproliferative properties, indicating therapeutic potential for a wide variety of diseases associated with diabetes and other conditions. The clinical applications of TZDs are limited by the common major side effect of fluid retention. A better understanding of the molecular mechanism of TZD-induced fluid retention is essential for the development of novel therapies with improved safety profiles. An important breakthrough in the field is the finding that the renal collecting duct is a major site for increased fluid reabsorption in response to rosiglitazone or pioglitazone. New evidence also indicates that increased vascular permeability in adipose tissues may contribute to edema formation and body weight gain. Future research should therefore be directed at achieving a better understanding of the detailed mechanisms of TZD-induced increases in renal sodium transport and in vascular permeability.
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Sethi, Navjot Singh, Deo Nandan Prasad, and Rajesh Kumar Singh. "An Insight into the Synthesis and SAR of 2,4-Thiazolidinediones (2,4-TZD) as Multifunctional Scaffold: A Review." Mini-Reviews in Medicinal Chemistry 20, no. 4 (April 10, 2020): 308–30. http://dx.doi.org/10.2174/1389557519666191029102838.
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2,4-Thiazolidinedione (2,4-TZD) is a versatile pharmacophore, a privileged scaffold, and a remarkable sulphur-containing heterocyclic compound with diverse pharmacological activities. The multifarious biological activities, due to different mechanisms of action, low cost, and easy availability of 2,4-TZD impressed medicinal chemists to integrate this moiety to develop various lead compounds with diverse therapeutic actions. This resulted in the swift development in the last decade for generating different new potential molecules bearing 2,4-TZD. In this review, the authors attempt to shape and present the latest investigations (2012 onwards) going on in generating promising 2,4-TZD containing lead compounds. The data has been collected and analyzed to develop the structure-activity relationship (SAR). The SAR and active pharmacophores of various leads accountable for antidiabetic, anticancer, antimicrobial, and antioxidant activities have also been illustrated. This review also highlighted some of the important chemical synthetic routes for the preparation of various 2,4-TZD derivatives. This review will definitely serve as a useful source of structural information to medicinal chemists and may be utilized for the strategic design of potent 2,4-TZD derivatives in the future.
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Sharma, Vijay Kumar, Anup Barde, and Sunita Rattan. "Design, Synthesis and Characterization of Pyrimidine based Thiazolidinedione Derivatives." Asian Journal of Chemistry 32, no. 5 (2020): 1101–8. http://dx.doi.org/10.14233/ajchem.2020.22565.
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Novel thiazolidine-2,4-dione (TZD) based pyrimidine derivatives have been synthesized by Knoevenagel condensation reaction between thiazolidine-2,4-dione and amino pyrimidinyl aliphatic aldehydes followed by heterogeneous metal reduction. Synthetic strategy involved nucleophillic substitution of hydroxyl protected six membered aliphatic chain on 4,6-dichloropyrimidine followed by Suzuki coupling. This approach is regioselective, efficient and versatile for synthesis of such analogs
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Todd, Mark K., Matthew J. Watt, Jamie Le, Andrea L. Hevener, and Lorraine P. Turcotte. "Thiazolidinediones enhance skeletal muscle triacylglycerol synthesis while protecting against fatty acid-induced inflammation and insulin resistance." American Journal of Physiology-Endocrinology and Metabolism 292, no. 2 (February 2007): E485—E493. http://dx.doi.org/10.1152/ajpendo.00080.2006.
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In the present investigation, we studied the effects of thiazolidinedione (TZD) treatment on insulin-stimulated fatty acid (FA) and glucose kinetics in perfused muscle from high-fat (HF)-fed rats. We tested the hypothesis that TZDs prevent FA-induced insulin resistance by attenuating proinflammatory signaling independently of myocellular lipid levels. Male Wistar rats were assigned to one of three 3-wk dietary groups: control chow fed (CON), 65% HF diet (HFD), or TZD- (troglitazone or rosiglitazone) enriched HF diet (TZD + HFD). TZD treatment led to a significant increase in plasma membrane content of CD36 protein in muscle (red: P = 0.01, and white: P = 0.001) that correlated with increased FA uptake (45%, P = 0.002) and triacylglycerol (TG) synthesis (46%, P = 0.03) during the perfusion. Importantly, whereas HF feeding caused increased basal TG ( P = 0.047), diacylglycerol ( P = 0.002), and ceramide ( P = 0.01) levels, TZD treatment only prevented the increase in muscle ceramide. In contrast, all of the muscle inflammatory markers altered by HF feeding (↑NIK protein content, P = 0.009; ↑IKKβ activity, P = 0.006; ↓IκB-α protein, P = 0.03; and ↑JNK phosphorylation, P = 0.003) were completely normalized by TZD treatment. Consistent with this, HFD-induced decrements in insulin action were also prevented by TZD treatment. Thus our findings support the notion that TZD treatment causes increased FA uptake and TG accumulation in skeletal muscle under insulin-stimulated conditions. Despite this, TZDs suppress the inflammatory response to dietary lipid overload, and it is this mechanism that correlates strongly with insulin sensitivity.
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Phillips, Susan A., Jacqueline Kung, Theodore P. Ciaraldi, Charles Choe, Louis Christiansen, Sunder Mudaliar, and Robert R. Henry. "Selective regulation of cellular and secreted multimeric adiponectin by antidiabetic therapies in humans." American Journal of Physiology-Endocrinology and Metabolism 297, no. 3 (September 2009): E767—E773. http://dx.doi.org/10.1152/ajpendo.00378.2009.
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Adiponectin, an insulin-sensitizing factor secreted from adipose tissue, is decreased in individuals with type 2 diabetes (T2D) and increased in response to thiazolidinedione (TZD) therapy. Changes in its secretion and assembly into higher-order forms affect insulin sensitivity. To determine the relative potency of TZDs on intra-adipocyte multimerization and secretion of adiponectin, we assessed the impact of in vivo low- or high-dose rosiglitazone treatment alone or combined with metformin in subjects with T2D. T2D subjects received high-dose rosiglitazone (8 mg/day), high-dose metformin (2,000 mg/day), or low-dose combination rosiglitazone-metformin therapy (4 mg + 1,000 mg/day) for 4 mo. All subjects were then switched to high-dose rosiglitazone-metformin combination therapy (8 mg + 2,000 mg/day) for another 4 mo. Low-dose rosiglitazone increased serum adiponectin, whereas the high dose increased both adipocyte content and serum adiponectin levels. TZDs selectively increased the percentage of circulating adiponectin in the potent, high-molecular-weight (HMW) form. No TZD effects were evident on multimer distribution in the cell. Expression of the chaperone protein ERp44, which retains adiponectin within the cell, was decreased by TZD treatment. No changes occurred in Ero1-Lα expression. Metformin had no effect on any of these measures. Increases in adiponectin correlated with improvements in insulin sensitivity. In vivo, TZDs have apparent dose-dependent effects on cellular and secreted adiponectin. TZD-mediated improvements in whole body insulin sensitivity are associated with increases in circulating but not cellular levels of the HMW adiponectin multimer. Finally, TZDs promote the selective secretion of HMW adiponectin, potentially, in part, through decreasing the expression of the adiponectin-retaining protein ERp44.
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Verma, Sant Kumar, Yatesh Sharad Yadav, and Suresh Thareja. "2,4-Thiazolidinediones as PTP 1B Inhibitors: A Mini Review (2012-2018)." Mini-Reviews in Medicinal Chemistry 19, no. 7 (March 28, 2019): 591–98. http://dx.doi.org/10.2174/1389557518666181026092029.
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2,4-thiazolidinedione (TZD) scaffold is a synthetic versatile scaffold explored by medicinal chemists for the discovery of novel molecules for the target-specific approach to treat or manage number of deadly ailments. PTP 1B is the negative regulator of insulin signaling cascade, and its diminished activity results in abolishment of insulin resistance associated with T2DM. The present review focused on the seven years journey (2012-2018) of TZDs as PTP 1B inhibitors with the insight into the amendments in the structural framework of TZD scaffold in order to optimize/design potential PTP 1B inhibitors. We have investigated the synthesized molecules based on TZD scaffold with potential activity profile against PTP 1B. Based on the SAR studies, the combined essential pharmacophoric features of selective and potent TZDs have been mapped and presented herewith for further design and synthesis of novel inhibitors of PTP 1B. Compound 46 bearing TZD scaffold with N-methyl benzoic acid and 5-(3-methoxy-4-phenethoxy) benzylidene exhibited the most potent activity (IC50 1.1 µM). Imidazolidine-2,4-dione, isosteric analogue of TZD, substituted with 1-(2,4-dichlorobenzyl)-5-(3-(2,4- dichlorobenzyloxy)benzylidene) (Compound 15) also endowed with very good PTP inhibitory activity profile (IC50 0.57 µM). It is noteworthy that Z-configuration is essential in structural framework around the double bond of arylidene for the designing of bi-dentate ligands with optimum activity.
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Pinelli, Nicole R., Raymond Cha, Morton B. Brown, and Linda A. Jaber. "Addition of Thiazolidinedione or Exenatide to Oral Agents in Type 2 Diabetes: A Meta-Analysis." Annals of Pharmacotherapy 42, no. 11 (October 28, 2008): 1541–51. http://dx.doi.org/10.1345/aph.1l198.
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Background: The introduction of several new therapeutic agents for the treatment of type 2 diabetes mellitus has led to significant challenges for providers in deciding which agent to select during the disease course. Objective: To provide a relative comparison of the efficacy and safety of adding thiazolidinediones (TZDs) or exenatide to oral agents for the management of type 2 diabetes mellitus by performing meta-analyses of relevant published studies. Methods: We systematically searched PubMed, MEDLINE, CINHAL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, EMBASE (inception to March 2008 for all databases), and abstracts presented at the 2006 and 2007 American Diabetes Association conferences to identify all relevant publications. Studies were included in the analysis if they (1) were published in English, (2) were prospective, randomized, and controlled with placebo or comparator, (3) were at least 24 weeks' duration, (4) included nonpregnant adults with type 2 diabetes, (5) were full-text, peer-reviewed articles examining the efficacy of either TZDs (rosiglitazone or pioglitazone) or exenatide in combination with other oral drugs, and (6) included hemoglobin A1C (AIC) outcomes in a manner that allowed data analysis. We evaluated mean change in A1C levels, proportion of subjects reaching A1C goals of less than 7%, mean change in fasting plasma glucose (FPG) and body weight, and the occurrence of nonsevere hypoglycemia and gastrointestinal adverse events. Results: A total of 5212 TZD and 3562 exenatide publications were identified. After critical evaluation, 22 publications met all of the inclusion criteria for the meta-analysis. A1C was reduced from baseline for TZDs (weighted mean difference –0.80%; 95% CI –1.10 to –0.50) and exenaiide (weighted mean difference –0.60%; 95% CI –1.04 to –0.16), Compared with controls, TZD- and exenatide-based therapies had odds ratios greater than 1 for reaching A1C targets of less than 7% (TZD OR 2.27; 95% CI 1.22 to 4.24 and exenatide OR 2.90; 95% CI 1.28 to 6.55). FPG concentrations were reduced significantly from baseline in the TZD-based regimens (weighted mean difference –29.58 mg/dL; 95% CI –39.27 to –19.89), but did not achieve significance in the exenatide trials (weighted mean difference –8.77 mg/dL; 95% CI –28.85 to 11.31). Body weight was reduced with exenatide (weighted mean difference –2.74 kg; 95% CI –4.85 to –0.64) and increased in subgroup analyses for TZDs (weighted mean difference 2.19 kg; 95% CI 1.24 to 3.14). There was no significant association between TZD or exenatide therapy and the risk of nonsevere hypoglycemia. The odds ratios for nausea, vomiting, and diarrhea with exenatide relative to controls were 9.02 (95% CI 3.66 to 22.23), 4.56 (95% CI 3.13 to 6.65), and 2.96 (95% CI 2.05 to 4.26), respectively. Conclusions: TZDs and exenatide have modest but beneficial effects on glycemic control and are relatively safe in regard to the adverse events studied. TZDs produce greater improvement in glycemic control, while exenatide Is associated with reduction in body weight.
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Mamtani, Ronac, Kevin Haynes, Warren B. Bilker, David J. Vaughn, Brian L. Strom, Karen Glanz, and James D. Lewis. "Long-term therapy with thiazolidinediones and the risk of bladder cancer: A cohort study." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 1503. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.1503.
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1503 Background: The US Food and Drug Administration and other regulatory agencies recently warned prescribers that use of pioglitazone, a thiazolidinedione (TZD), may increase the risk of bladder cancer. France and Germany removed the drug from their markets, although the rest of Europe did not. However, no information was available about the risk from alternative TZDs. We aimed to compare bladder cancer risk over time with use of TZDs relative to sulfonylureas (SUs), and between pioglitazone and rosiglitazone. Methods: We conducted a cohort study of patients with type 2 diabetes who initiated treatment with a TZD or SU using The Health Improvement Network (2000-2010), a UK general practitioner medical record database. Incident cancers within the database were identified. We computed hazard ratios (HRs) of bladder cancer for TZDs in comparison to the reference group of SU users. Results: There were 60 incident diagnoses of bladder cancer in the TZD cohort (n=18,459) and 137 in the SU cohort (n=41,396). There was no significant difference in bladder cancer risk between the cohorts (HR 0·93, [95% CI 0·68-1·29]), but most use was short-term use. In contrast, the risk of bladder cancer increased with increasing time since initiation of TZD versus SU therapy (HRs 1·15, 1·40, and 1·72 for 3-4, 4-5, and ≥ 5 years, respectively; P-trend=0·033). Bladder cancer risk also increased with increasing time since initiation of pioglitazone (P-trend<0·001) and rosiglitazone (P-trend=0·006). Direct comparison of pioglitazone to rosiglitazone did not demonstrate significant differences in cancer risk with increasing time since initiation (P-trend=0·12) or duration of therapy (P-trend=0·75). Conclusions: Long-term TZD therapy is associated with an increased risk of bladder cancer, which appears to be a class effect.
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Feldman, Mark, Julia Shenderovich, Eran Lavy, Michael Friedman, and Doron Steinberg. "A Sustained-Release Membrane of Thiazolidinedione-8: Effect on Formation of a Candida/Bacteria Mixed Biofilm on Hydroxyapatite in a Continuous Flow Model." BioMed Research International 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/3510124.
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Thiazolidinediones (TZDs) have been found to act as effective quorum sensing quenchers, capable of preventing biofilm formation. Our previous studies demonstrated a profound antibiofilm effect of the TZD derivative thiazolidinedione-8 (S-8), either in solution or incorporated into a sustained-release membrane (SRM-S-8) under batch conditions. In the present study, we used a constant depth film fermenter model in order to investigate the impact of SRM-S-8 on mixedC. albicans-S. mutansbiofilm development, under flow conditions. We found that essential parameters of cospecies biofilm maintenance and maturation, such as metabolic activity, biofilm thickness, roughness, extracellular polysaccharides production, and morphology of both pathogens, were altered by SRM-S-8 in the flow system. We propose that prolonged and sustained release of S-8 in a flow-through system allows better penetration of the active agent to deeper layers of the mixed biofilm, thereby increasing its activity against both pathogens. In conclusion, the use of a locally applied sustained-release drug delivery system of S-8 can affect the dental polymicrobial biofilm, resulting in clinical improvements and a better patient compliance.
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Li, Wei-Guo, and He-Qun Wang. "Design and synthesis of a novel 5-(aminomethylene)thiazolidine-2,4-dione derivatives as potent hepatitis-B virus polymerase inhibitors." Bangladesh Journal of Pharmacology 10, no. 2 (April 2, 2015): 271. http://dx.doi.org/10.3329/bjp.v10i2.21876.
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<p>A series of novel thiazolidinedione analogues (TZD) were designed and synthesized potent inhibitors of HBV capsid assembly. The synthesis of thiazolidine-2,4-dione derivatives (4a–4o), starting from the condensation of 5-(ethoxymethylene)thiazolidine-2,4-dione (1) with various secondary amines (3) derived from biologically active compounds. The newly synthesized TZD analogues 4a-4o were characterized by <sup>1</sup>H NMR, <sup>13</sup>C NMR, and MS and evaluated for their anti-HBV activity. Most of the compounds inhibited the expression of viral antigens at low concentration. Six compounds, 4g, 4h, 4l, 4m, 4n, and 4o, demonstrated potent inhibition of HBV DNA replication at submicromolar range. Of these five initial hits, compound 4o was the most active when compared with lamivudine.</p><p> </p><p> </p>
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Chiu, Melody, Lucien McBeth, Puneet Sindhwani, and Terry D. Hinds. "Deciphering the Roles of Thiazolidinediones and PPARγin Bladder Cancer." PPAR Research 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/4810672.
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The use of thiazolidinedione (TZD) therapy in type II diabetic patients has proven useful in the lowering of blood glucose levels. However, recent investigations have shown that there may be potential health concerns associated, including the risk of developing bladder cancer as well as complications in the cardiovasculature. TZDs are ligands for the nuclear receptor PPARγ, and activation causes lipid uptake and insulin sensitization, both of which are critical processes for diabetic patients whose bodies are unable to utilize insulin effectively. Several studies have shown that PPARγ/TZDs decrease IGF-1 levels and, thus, reduce cancer growth in carcinomas such as the pancreas, colon, liver, and prostate. However, other studies have shed light on the potential of the receptor as a biomarker for uroepithelial carcinomas, particularly due to its stimulatory effect on migration of bladder cancer cells. Furthermore, PPARγmay provide the tumor-promoting microenvironment by de novo synthesis of nutrients that are needed for bladder cancer development. In this review, we closely examine the TZD class of drugs and their effects on PPARγin patient studies along with additional molecular factors that are positive modulators, such as protein phosphatase 5 (PP5), which may have considerable implications for bladder cancer therapy.
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Weng, J.-R., C.-Y. Chen, J. J. Pinzone, M. D. Ringel, and C.-S. Chen. "Beyond peroxisome proliferator-activated receptor γ signaling: the multi-facets of the antitumor effect of thiazolidinediones." Endocrine-Related Cancer 13, no. 2 (June 2006): 401–13. http://dx.doi.org/10.1677/erc.1.01182.
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Certain members of the thiazolidinedione (TZD) family of the peroxisome proliferator-activated receptor γ (PPARγ) agonists, such as troglitazone and ciglitazone, exhibit antitumor activities; however, the underlying mechanism remains inconclusive. Substantial evidence suggests that the antiproliferative effect of these TZD members in cancer cells is independent of PPARγ activation. To discern the role of PPARγ in the antitumor effects of TZDs, we have synthesized PPARγ-inactive TZD analogs which, although devoid of PPARγ activity, retain the ability to induce apoptosis with a potency equal to that of their parental TZDs in cancer cell lines with varying PPARγ expression status. Mechanistic studies from this and other laboratories have further suggested that troglitazone and ciglitazone mediate antiproliferative effects through a complexity of PPARγ-independent mechanisms. Evidence indicates that troglitazone and ciglitazone block BH3 domain-mediated interactions between the anti apoptotic Bcl-2 (B-cell leukemia/lymphoma 2) members Bcl-2/Bcl-xL and proapoptotic Bcl-2 members. Moreover, these TZDs facilitate the degradation of cyclin D1 and caspase-8-related FADD-like IL-l-converting enzyme (FLICE)-inhibitory protein through proteasome-mediated proteolysis, and down-regulate the gene expression of prostate-specific antigen gene expression by inhibiting androgen activation of the androgen response elements in the promoter region. More importantly, dissociation of the effects of TZDs on apoptosis from their original pharmacological activity (i.e. PPARγ activation) provides a molecular basis for the exploitation of these compounds to develop different types of molecularly targeted anticancer agents. These TZD-derived novel therapeutic agents, alone or in combination with other anticancer drugs, have translational relevance in fostering effective strategies for cancer treatment.
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SUN, LIJUN, HAOYU WANG, HAO XU, JINHONG WEI, LIANG SHI, XIAOGANG LIU, and JIANBAO ZHANG. "EFFECTS OF FLUID SHEAR STRESS AND CIGLITAZONE ON OSTEOBLASTS." Journal of Mechanics in Medicine and Biology 12, no. 04 (September 2012): 1250076. http://dx.doi.org/10.1142/s0219519412005022.
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Long-term use of thiazolidinedione (TZD) antidiabetic agents in patients with type 2 diabetes mellitus has been shown to increase the incidence of osteoporosis. Mechanical loading can enhance bone mass by promoting bone formation and suppressing bone resorption, which may be beneficial to patients with TZD-induced osteoporosis. In this study, we examined the cooperative effect of fluid shear stress (FSS) and ciglitazone (CIG), a type of TZD, on osteoblasts. The proliferation, osteoblast differentiation-related mRNA expression and translocation of nuclear factor κB (NFκB) of osteoblasts were assessed. The results show that CIG significantly decreased the proliferation of osteoblasts, inhibited the translocation of NFκB to the nucleus and reduced the mRNA expression of COX-2, IGF, Runx2 and OCN. At the same time, CIG also increased the mRNA expression of PPARγ. Conversely, FSS significantly increased the proliferation of osteoblasts, promoted the translocation of NFκB to the nucleus and increased the mRNA expression of COX-2, IGF, Runx2 and OCN but decreased the mRNA expression of PPARγ. When FSS and CIG were combined, FSS counteracted the effects of CIG on osteoblasts. Taken together, the current results suggest that FSS is able to arrest the effects of CIG on the proliferation and differentiation of osteoblasts.
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Katafuchi, Takeshi, William L. Holland, Rahul K. Kollipara, Ralf Kittler, David J. Mangelsdorf, and Steven A. Kliewer. "PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice." Proceedings of the National Academy of Sciences 115, no. 48 (November 12, 2018): 12102–11. http://dx.doi.org/10.1073/pnas.1814522115.
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The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation and is the target for the insulin-sensitizing thiazolidinedione (TZD) drugs used to treat type 2 diabetes. In cell-based in vitro studies, the transcriptional activity of PPARγ is inhibited by covalent attachment of small ubiquitin-related modifier (SUMOylation) at K107 in its N terminus. However, whether this posttranslational modification is relevant in vivo remains unclear. Here, using mice homozygous for a mutation (K107R) that prevents SUMOylation at this position, we demonstrate that PPARγ is SUMOylated at K107 in white adipose tissue. We further show that in the context of diet-induced obesity PPARγ-K107R–mutant mice have enhanced insulin sensitivity without the corresponding increase in adiposity that typically accompanies PPARγ activation by TZDs. Accordingly, the PPARγ-K107R mutation was weaker than TZD treatment in stimulating adipocyte differentiation in vitro. Moreover, we found that both the basal and TZD-dependent transcriptomes of inguinal and epididymal white adipose tissue depots were markedly altered in the K107R-mutant mice. We conclude that PPARγ SUMOylation at K107 is physiologically relevant and may serve as a pharmacologic target for uncoupling PPARγ’s beneficial insulin-sensitizing effect from its adverse effect of weight gain.
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Brunmair, Barbara, Katrin Staniek, Zsuzsanna Lehner, Debendranath Dey, Charles W. Bolten, Karin Stadlbauer, Anton Luger, and Clemens Fürnsinn. "Lipophilicity as a determinant of thiazolidinedione action in vitro: findings from BLX-1002, a novel compound without affinity to PPARs." American Journal of Physiology-Cell Physiology 300, no. 6 (June 2011): C1386—C1392. http://dx.doi.org/10.1152/ajpcell.00401.2010.
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The pharmacology of thiazolidinediones (TZDs) seems to be driven not only by activation of peroxisome proliferator-activated receptor-γ (PPARγ), but also by PPARγ-independent effects on mitochondrial function and cellular fuel handling. This study portrayed such actions of the novel hydrophilic TZD compound BLX-1002 and compared them to those of conventional TZDs. Mitochondrial function and fuel handling were examined in disrupted rat muscle mitochondria, intact rat liver mitochondria, and specimens of rat skeletal muscle. BLX-1002 was superior to most other TZDs as an inhibitor of respiratory complex 1 in disrupted mitochondria, but had less effect than any other TZD on oxygen consumption by intact mitochondria and on fuel metabolism by intact tissue. The latter finding was obviously related to the hydrophilic properties of BLX-1002, because high potentials of individual TZDs to shift muscle fuel metabolism from the aerobic into the anaerobic pathway were associated with high ClogP values indicative of high lipophilicity and low hydrophilicity (e.g., % increase in lactate release induced by 10 μmol/l of respective compound: BLX-1002, ClogP 0.39, +10 ± 8%, not significant; pioglitazone, ClogP 3.53, +68 ± 12%, P < 0.001; troglitazone, ClogP 5.58, +157 ± 14%, P < 0.001). The observed specific properties of BLX-1002 could result from relatively strong direct affinity to an unknown mitochondrial target, but limited access to this target. Results suggest 1) that impairment of mitochondrial function and increased anaerobic fuel metabolism are unlikely to account for PPARγ-independent glucose lowering by BLX-1002, and 2) that higher lipophilicity of an individual TZD is associated with stronger acceleration of anaerobic glycolysis.
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Lee, Seoyeon, Kyoung Min Kim, Soo Lim, Ghayoung Lee, Tae Jung Oh, Sung Hee Choi, and Hak Chul Jang. "The effects of lobeglitazone, a novel thiazolidinedione (TZD), on bone mineral density in mice." Diabetes Research and Clinical Practice 120 (October 2016): S113—S114. http://dx.doi.org/10.1016/s0168-8227(16)31204-9.
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Russell, Nicole M., Carlos A. Alvarez, Anthony J. Busti, Lisa M. Chastain, Krystal L. Edwards, R. Shane Greene, and Rick A. Weideman. "107: Combination Thiazolidinedione (TZD) and Fibrate Effect on High Density Lipoprotein Concentration (HDL-C)." Journal of Clinical Lipidology 2, no. 3 (June 2008): 205. http://dx.doi.org/10.1016/j.jacl.2008.04.016.
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Lichtor, Terry, Alessandra Spagnolo, Roberta P. Glick, and Douglas L. Feinstein. "PPAR- Thiazolidinedione Agonists and Immunotherapy in the Treatment of Brain Tumors." PPAR Research 2008 (2008): 1–4. http://dx.doi.org/10.1155/2008/547470.
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Thiazolidinediones (TZDs) are selective agonists of the peroxisome proliferator-activated receptor (PPAR) gamma, a transcription factor belonging to the superfamily of nuclear hormone receptors. Although activation of PPAR by TZDs has been best characterized by its ability to regulate expression of genes associated with lipid metabolism, PPAR agonists have other physiological effects including modulating pro- and anti-inflammatory gene expression and inducing apoptosis in several cell types including glioma cells and cell lines. Immunotherapeutic approaches to reducing brain tumors are focused on means to reduce the immunosuppressive responses of tumors which dampen the ability of cytotoxic T-lymphocytes to kill tumors. Initial studies from our lab show that combination of an immunotherapeutic strategy with TZD treatment provides synergistic benefit in animals with implanted tumors. The potential of this combined approach for treatment of brain tumors is reviewed in this report.
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Higgins, Linda S., and Christos S. Mantzoros. "The Development of INT131 as a Selective PPAR Modulator: Approach to a Safer Insulin Sensitizer." PPAR Research 2008 (2008): 1–9. http://dx.doi.org/10.1155/2008/936906.
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INT131 (formerly T0903131, T131, AMG131) is a potent non-thiazolidinedione (TZD) selective peroxisome proliferator-activated receptor modulator (SPPARM) currently in Phase 2 clinical trials for treatment of type-2 diabetes mellitus (T2DM). This new chemical entity represents a second generation SPPARM approach developed after the first generation PPAR full agonists to address their inherent limitations. INT131 was specifically and carefully designed using preclinical models to exhibit a biological profile of strong efficacy withde minimisside effects compared to PPAR full agonists. As a potent PPAR modulator, INT131 binds to PPAR with high affinity. In pharmacology models of diabetes and in early clinical studies, it achieved a high level of efficacy in terms of antidiabetic actions such as insulin sensitization and glucose and insulin lowering, but had little activity in terms of other, undesired, effects associated with TZD PPAR full agonists such as edema and adipogenesis. Ongoing clinical development is directed at translating these findings into establishing a novel and effective treatment for T2DM patients with an improved safety profile in relation to that currently available.
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Kershaw, Erin E., Michael Schupp, Hong-Ping Guan, Noah P. Gardner, Mitchell A. Lazar, and Jeffrey S. Flier. "PPARγ regulates adipose triglyceride lipase in adipocytes in vitro and in vivo." American Journal of Physiology-Endocrinology and Metabolism 293, no. 6 (December 2007): E1736—E1745. http://dx.doi.org/10.1152/ajpendo.00122.2007.
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Peroxisome proliferator-activated receptor-γ (PPARγ) regulates adipocyte genes involved in adipogenesis and lipid metabolism and is the molecular target for thiazolidinedione (TZD) antidiabetic agents. Adipose triglyceride lipase (ATGL) is a recently described triglyceride-specific lipase that is induced during adipogenesis and remains highly expressed in mature adipocytes. This study evaluates the ability of PPARγ to directly regulate ATGL expression in adipocytes in vitro and in vivo. In fully differentiated 3T3-L1 adipocytes, ATGL mRNA and protein are increased by TZD and non-TZD PPARγ agonists in a dose- and time-dependent manner. Rosiglitazone-mediated induction of ATGL mRNA is rapid and is not inhibited by the protein synthesis inhibitor cycloheximide, indicating that intervening protein synthesis is not required for this effect. Rosiglitazone-mediated induction of ATGL mRNA and protein is inhibited by the PPARγ-specific antagonist GW-9662 and is also significantly reduced following siRNA-mediated knockdown of PPARγ, supporting the direct transcriptional regulation of ATGL by PPARγ. In vivo, ATGL mRNA and protein are increased by rosiglitazone treatment in white and brown adipose tissue of mice with and without obesity due to high-fat diet or leptin deficiency. Thus, PPARγ positively regulates ATGL mRNA and protein expression in mature adipocytes in vitro and in adipose tissue in vivo, suggesting a role for ATGL in mediating PPARγ's effects on lipid metabolism.
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Shukla, Karuna S., Shailendra Pandey, and A. Pooja Chawla. "SYNTHESIS, BIOLOGICAL EVALUATION AND DOCKING STUDIES OF NON HEPATOTOXIC 5-SUBSTITUTED THIAZOLIDINE-2, 4-DIONES AS ANTIDIABETIC, ANTI-HYPERLIPIDEMIC, ANTI-OXIDANT AND CYTOTOXIC AGENTS." INDIAN DRUGS 57, no. 09 (November 5, 2020): 19–37. http://dx.doi.org/10.53879/id.57.09.12186.
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A series of eleven thiazolidine-2, 4-dione (TZD) derivatives, were synthesized and characterized by FT-IR, 1 H NMR and mass spectral analysis. All the synthesized TZD derivatives were screened for their in vitro and in vivo anti-diabetic and antioxidant, activities and cytotoxicity. In vivo antihyperglycemic effect was assessed by measuring plasma glucose (PG) levels in alloxan-induced type II diabetic rat models. The compound 4h exhibited better blood glucose lowering activity than the standard drug rosiglitazone. The synthesized TZD derivatives were evaluated for hepatotoxicity and pancreatic tissue studies. Antioxidant activity was evaluated by DPPH method and H2 O2 method. Compounds 4a and 4b exhibited potent antioxidant activity. Among the tested compounds for cytotoxicity using MTT assay method, compound 4i exhibited better viability and cytotoxicity activity. Thiazolidinedione derivatives were evaluated for their affinity towards target PPARg, using rosiglitazone as the reference compound molecular docking visualization through FlexX docking program. From selected anti-diabetic targets, the proposed derivatives exhibited better interaction with PPARγ receptor, where rosiglitazone showed docking score of -19.891 kJ/ mol, compound 4h exhibited highest docking score of -31.6068 kJ/mol. The study showed that all the studied compounds were showing higher docking score when compared to control drug rosiglitazone and it could be a remarkable starting point to evaluate structure activity relationships to develop new lead molecules with potential anti-diabetic activities.
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Li, Weijie, Julia Tonelli, Preeti Kishore, Randall Owen, Elliot Goodman, Philipp E. Scherer, and Meredith Hawkins. "Insulin-sensitizing effects of thiazolidinediones are not linked to adiponectin receptor expression in human fat or muscle." American Journal of Physiology-Endocrinology and Metabolism 292, no. 5 (May 2007): E1301—E1307. http://dx.doi.org/10.1152/ajpendo.00312.2006.
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Circulating adiponectin levels are increased by the thiazolidinedione (TZD) class of PPARγ agonists in concert with their insulin-sensitizing effects. Two receptors for adiponectin (AdipoR1 and AdipoR2) are widely expressed in many tissues, but their physiological significance to human insulin resistance remains to be fully elucidated. We examined the expression patterns of AdipoR1 and AdipoR2 in fat and skeletal muscle of human subjects, their relationship to insulin action, and whether they are regulated by TZDs. Expression patterns of both AdipoRs were similar in subcutaneous and omental fat depots, with higher expression in adipocytes than in stromal cells and macrophages. To determine the effects of TZDs on AdipoR expression, subcutaneous fat and quadriceps muscle were biopsied in 14 insulin-resistant subjects with type 2 diabetes mellitus after 45 mg pioglitazone or placebo for 21 days. This duration of pioglitazone improved insulin's suppression of glucose production by 41% and enhanced stimulation of glucose uptake by 27% in concert with increased gene expression and plasma levels of adiponectin. Pioglitazone did not affect AdipoR expression in muscle, whole fat, or cellular adipose fractions, and receptor expression did not correlate with baseline or TZD-enhanced insulin action. In summary, both adiponectin receptors are expressed in cellular fractions of human fat, particularly adipocytes. TZD administration for sufficient duration to improve insulin action and increase adiponectin levels did not affect expression of AdipoR1 or AdipoR2. Although TZDs probably exert many of their effects via adiponectin, changes in these receptors do not appear to be necessary for their insulin-sensitizing effects.
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LEVINE, M., and K. GAEBEL. "Impact of formulary policy on thiazolidinedione (TZD) use in the ontario drug benefit (ODB) program." Clinical Pharmacology & Therapeutics 77, no. 2 (February 2005): P72. http://dx.doi.org/10.1016/j.clpt.2004.12.165.
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Bajwa, Poonam J., Jimmy W. Lee, Daniel S. Straus, and Christian Lytle. "Activation of PPARγ by rosiglitazone attenuates intestinal Cl− secretion." American Journal of Physiology-Gastrointestinal and Liver Physiology 297, no. 1 (July 2009): G82—G89. http://dx.doi.org/10.1152/ajpgi.90640.2008.
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The thiazolidinedione (TZD) drugs rosiglitazone (Ro) and pioglitazone (Po) are PPARγ agonists in widespread clinical use as insulin-sensitizing agents in Type 2 diabetes. On the basis of recent evidence implicating PPARγ as a positive modulator of intestinal epithelial differentiation, we hypothesized that TZD drugs might attenuate intestinal secretory function. To evaluate this possibility, we examined the effects of Ro and Po on electrogenic Cl− secretion [short-circuit current ( Isc)] in mouse intestinal segments and in cultured human intestinal epithelial cells (HT29-Cl.19A). As hypothesized, oral administration of Ro (20 mg·kg−1·day−1) to mice for 8 days markedly reduced intestinal Isc responses to cAMP (forskolin)- and Ca2+ (carbachol)-dependent stimuli. In these Ro-treated mice, cholera toxin-induced intestinal fluid accumulation was reduced 65%. With continued Ro treatment, the Isc response to carbachol recovered significantly, whereas that to forskolin remained attenuated. Treatment of HT29 cells for 5 days with 10 μM Ro or Po in vitro brought about a similar hyposecretory state. In HT29 cells, the loss of cAMP-dependent Cl− secretion was attributable to a reduced expression of CFTR Cl− channel, KCNQ1 K+ channel, and Na-K-2Cl cotransporter-1 proteins. The transient loss of Ca2+-dependent Cl− secretion involved an impairment of basolateral Ca2+-stimulated K+ channel activity without a detectable loss of KCa3.1 channel protein. Our results establish TZD drugs as important modulators of intestinal Cl− secretory function.
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Miles, Philip D. G., Yaacov Barak, Ronald M. Evans, and Jerrold M. Olefsky. "Effect of heterozygous PPARγ deficiency and TZD treatment on insulin resistance associated with age and high-fat feeding." American Journal of Physiology-Endocrinology and Metabolism 284, no. 3 (March 1, 2003): E618—E626. http://dx.doi.org/10.1152/ajpendo.00312.2002.
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Peroxisome proliferator-activated receptor-γ (PPARγ) is the target receptor for thiazolidinedione (TZD) compounds, which are a class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. Paradoxically, however, mice deficient in PPARγ ( PPARγ+/− ) are more insulin sensitive than their wild-type (WT) littermates, not less, as would be predicted. To determine whether PPARγ deficiency could prevent the development of the insulin resistance associated with increasing age or high-fat (HF) feeding, insulin sensitivity was assessed in PPARγ+/− and WT mice at 2, 4, and 8 mo of age and in animals fed an HF diet. Because TZDs elicit their effect through PPARγ receptor, we also examined the effect of troglitazone (a TZD) in these mice. Glucose metabolism was assessed by hyperinsulinemic euglycemic clamp and oral glucose tolerance test. Insulin sensitivity declined with age for both groups. However, the decline in the PPARγ+/− animals was substantially less than that of the WT animals, such that, by 8 mo of age, the PPARγ+/− mice were markedly more insulin sensitive than the WT mice. This greater sensitivity in PPARγ+/− mice was lost with TZD treatment. HF feeding led to marked adipocyte hypertrophy and peripheral tissue and hepatic insulin resistance in WT mice but also in PPARγ+/− mice. Treatment of these mice with troglitazone completely prevented the adipocyte hypertrophy and normalized insulin action. In conclusion, PPARγ deficiency partially protects against age-related insulin resistance but does not protect against HF diet-induced insulin resistance.
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Tilekar, Kalpana, Neha Upadhyay, Markus Schweipert, Jessica D. Hess, Lucasantiago Henze Macias, Piotr Mrowka, Franz-Josef Meyer-Almes, et al. "Permuted 2,4-thiazolidinedione (TZD) analogs as GLUT inhibitors and their in-vitro evaluation in leukemic cells." European Journal of Pharmaceutical Sciences 154 (November 2020): 105512. http://dx.doi.org/10.1016/j.ejps.2020.105512.
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Akhavan, Malihe, Naser Foroughifar, Hoda Pasdar, and Ahmadreza Bekhradnia. "Green Synthesis, Biological Activity Evaluation, and Molecular Docking Studies of Aryl Alkylidene 2, 4-thiazolidinedione and Rhodanine Derivatives as Antimicrobial Agents." Combinatorial Chemistry & High Throughput Screening 22, no. 10 (January 16, 2020): 716–27. http://dx.doi.org/10.2174/1386207322666191127103122.
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Aim and Objective: The magic scaffolds rhodanine and thiazolidine are very important heterocyclic compounds in drug design and discovery. Those are important heterocyclic compounds that have attracted a great deal of attention due to the fact that they exhibit a variety of bioactivities including antibacterial, antifungal, antiviral, antimalarial, and anti-inflammatory activities. These agents often exhibit selective toxicity. The goal of this study was molecular docking, green and solvent-free efficient synthesis of a new series of hetero/aromatic substituted rhodanine and thiazolidine analogues and then investigation of their antimicrobial activity. Materials and Methods: To a mixture of TZD or rhodanine (1 mmol) in the presence of ionic liquid ChCl/urea, various aldehyde (1 mmol) was added. After completion of the reaction, obtained crude compound was collected by filtration and products were recrystallized from ethanol. The binding-free energy between all synthesized compounds with 3EEJ protein (C. glabrata enzyme) were obtained by molecular docking studies. These compounds were evaluated using microdilution method against (ATCC 6538) and (ATCC 12228) Gram-negative, (ATCC 8739) and (ATCC 9027) as Gram-positive and (ATCC 1012), (ATCC 339), C. (ATCC 1057), (ATCC 503), (ATCC 340) and (ATCC 194) as fungi. Results: All of the acceptable products were determined by 1H NMR, 13C NMR, Mas and FT-IR spectroscopy. The binding-free energy between compounds 10a and 10b with 3EEJ protein were found to be -8.08 kcal/mol and -8.15 kcal/mol, respectively. These compounds having a heteroaromatic ring attached to the TZD or rhodanine core showed excellent antimicrobial activity with MIC values of 0.25-8 μg/mL (compound 10a) and 0.5-16 μg/mL (compound 10b) against the most tested fungi strains, Gram-positive and Gram-negative bacteria. Conclusion: A convenient and rapid method has been developed for the synthesis of rhodanine and thiazolidine-2,4-dione (TZD) derivatives as efficient antimicrobial agents using a Deep Eutectic Ionic Liquids (DEILs) choline chloride urea under solvent-free condition. Among the newly synthesized compounds, (Z)-5-((quinoxalin-3-yl) methylene) thiazolidine-2, 4-dione (10a) and (Z)- 5- ((quinoxalin-3-yl) methylene)-2-thioxothiazolidin-one (10b) exerted the promising effect and these compounds can be considered to be further probed as inhibitors of cgDHFR enzyme.
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Sikka, Sakshi, Luxi Chen, Gautam Sethi, and Alan Prem Kumar. "Targeting PPARγSignaling Cascade for the Prevention and Treatment of Prostate Cancer." PPAR Research 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/968040.
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The peroxisome proliferator-activated receptor-gamma (PPARγ) is a member of the hormone-activated nuclear receptor superfamily. PPARγcan be activated by a diverse group of agents, such as endogenous polyunsaturated fatty acids, 15-deoxy-Δ12,14-prostaglandin J2(15d-PGJ2), and thiazolidinedione (TZD) drugs. PPARγinduces antiproliferative, antiangiogenic, and prodifferentiation pathways in several tissue types, thus making it a highly useful target for downregulation of carcinogenesis. These TZD-derived novel therapeutic agents, alone or in combination with other anticancer drugs, have translational relevance in fostering effective strategies for cancer treatment. TZDs have been proven for antitumor activity in a wide variety of experimental cancer models, bothin vitroandin vivo, by affecting the cell cycle, inducing cell differentiation and apoptosis, as well as by inhibiting tumor angiogenesis. Angiogenesis inhibition mechanisms of TZDs include direct inhibition of endothelial cell proliferation and migration, as well as reduction in tumor cell vascular endothelial growth factor production. In prostate cancer, PPARγligands such as troglitazone and 15d-PGJ2have also shown to inhibit tumor growth. This paper will focus on current discoveries in PPARγactivation, targeting prostate carcinogenesis as well as the role of PPARγas a possible anticancer therapeutic option. Here, we review PPARγas an antitumor agent and summarize the antineoplastic effects of PPARγagonists in prostate cancer.
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Ohga, Sakiko, Kenichi Shikata, Kosuke Yozai, Shinichi Okada, Daisuke Ogawa, Hitomi Usui, Jun Wada, Yasushi Shikata, and Hirofumi Makino. "Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-κB activation." American Journal of Physiology-Renal Physiology 292, no. 4 (April 2007): F1141—F1150. http://dx.doi.org/10.1152/ajprenal.00288.2005.
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Thiazolidinedione (TZD), a ligand for peroxisome proliferator-activated receptor-γ (PPAR-γ), exerts anti-inflammatory effects independently of the insulin-sensitizing effect. In the present study, we tested the hypothesis that TZD prevents the progression of diabetic nephropathy by modulating the inflammatory process. Five-week-old Sprague-Dawley rats were divided into three groups: 1) nondiabetic control rats (non-DM), 2) diabetic rats (DM), and 3) diabetic rats treated with pioglitazone (DM+pio). Diabetes was induced by injection with streptozotocin (STZ). The DM+pio group received 0.0002% pioglitazone mixed in chow for 8 wk after induction of diabetes. Blood glucose and HbA1c were elevated in diabetic rats but did not change by treatment with pioglitazone. Pioglitazone reduced urinary albumin excretion and glomerular hypertrophy, suppressed the expression of transforming growth factor (TGF)-β, type IV collagen, and ICAM-1, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, renal NF-κB activity was increased in diabetic rats and reduced by pioglitazone. PPAR-γ was expressed in glomerular endothelial cells in the diabetic kidney and in cultured glomerular endothelial cells. High-glucose conditions increased the expression of ICAM-1 and the activation of NF-κB in cultured glomerular endothelial cells. These changes were reduced by pioglitazone, ciglitazone, and pyrrolidine dithiocarbamate, an inhibitor of NF-κB. However, pioglitazone did not show the changes in the presence of PPAR-γ antagonist GW9662. Our results suggest that the preventive effects of pioglitazone may be mediated by its anti-inflammatory actions, including inhibition of NF-κB activation, ICAM-1 expression, and macrophage infiltration in the diabetic kidney.
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Garber, Alan J., Yehuda Handelsman, George Grunberger, Daniel Einhorn, Martin J. Abrahamson, Joshua I. Barzilay, Lawrence Blonde, et al. "CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM – 2020 EXECUTIVE SUMMARY." Endocrine Practice 26, no. 1 (January 2020): 107–39. http://dx.doi.org/10.4158/cs-2019-0472.
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Abbreviations: A1C = hemoglobin A1C; AACE = American Association of Clinical Endocrinologists; ABCD = adiposity-based chronic disease; ACCORD = Action to Control Cardiovascular Risk in Diabetes; ACCORD BP = Action to Control Cardiovascular Risk in Diabetes Blood Pressure; ACE = American College of Endocrinology; ACEI = angiotensin-converting enzyme inhibitor; AGI = alpha-glucosidase inhibitor; apo B = apolipoprotein B; ARB = angiotensin II receptor blocker; ASCVD = atherosclerotic cardiovascular disease; BAS = bile acid sequestrant; BMI = body mass index; BP = blood pressure; CCB = calcium channel blocker; CGM = continuous glucose monitoring; CHD = coronary heart disease; CKD = chronic kidney disease; DKA = diabetic ketoacidosis; DPP4 = dipeptidyl peptidase 4; eGFR = estimated glomerular filtration rate; EPA = eicosapentaenoic acid; ER = extended release; FDA = Food and Drug Administration; GLP1 = glucagon-like peptide 1; HDL-C = high-density-lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; LDL-C = low-density-lipoprotein cholesterol; LDL-P = low-density-lipoprotein particle; Look AHEAD = Look Action for Health in Diabetes; NPH = neutral protamine Hagedorn; OSA = obstructive sleep apnea; PCSK9 = proprotein convertase subtilisin-kexin type 9 serine protease; RCT = randomized controlled trial; SU = sulfonylurea; SGLT2 = sodium-glucose cotransporter 2; SMBG = self-monitoring of blood glucose; T2D = type 2 diabetes; TZD = thiazolidinedione
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Govindarajan, R., E. R. Siegel, D. L. Simmons, and N. P. Lang. "Thiazolidinedione (TZD) exposure and overall survival (OS) in squamous cell carcinoma of the head and neck (SCCHN)." Journal of Clinical Oncology 26, no. 15_suppl (May 20, 2008): 6079. http://dx.doi.org/10.1200/jco.2008.26.15_suppl.6079.
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da Rocha Junior, Laurindo Ferreira, Moacyr Jesus Barreto de Melo Rêgo, Mariana Brayner Cavalcanti, Michelly Cristiny Pereira, Marina Galdino da Rocha Pitta, Priscilla Stela Santana de Oliveira, Sayonara Maria Calado Gonçalves, et al. "Synthesis of a Novel Thiazolidinedione and Evaluation of Its Modulatory Effect on IFN-γ, IL-6, IL-17A, and IL-22 Production in PBMCs from Rheumatoid Arthritis Patients." BioMed Research International 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/926060.
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Rheumatoid arthritis (RA) is an autoimmune disease frequently characterized by chronic synovitis of multiple joints. The pathogenesis of RA is complex and involves many proinflammatory cytokines as Th17 related ones. PPARγis a nuclear receptor activator that represses proinflammatory gene expression. Thus, this work aimed to synthetize a new thiazolidinedione (TZD) analogue based on a well-known anti-inflammatory and PPARγagonist activity of this ring and evaluate its anti-inflammatory activity. After chemical structure confirmation, the compound named 5-(5-bromo-2-methoxy-benzylidene)-3-(2-nitro-benzyl)-thiazolidine-2,4-dione TM17 was submitted to cytokine releasing inhibition and PPARγgenetic modulation assays. The new compound showed no toxicity on human and murine cells, decreasing IL-6 secretion by murine splenocytes and reducing IL-17A, IL-22, and IFN-γexpression in peripheral blood mononuclear cells from patients with RA. TM17 was more efficient in modulating the mRNA expression of PPARγthan its well-used TZD agonist rosiglitazone. Surprisingly, TM17 was efficient on IL-17A and IFN-γreduction, like the positive control methylprednisolone, and presented a better effect on IL-22 levels. In conclusion, PBMCs obtained from RA patients under TM17 treatment present a significant reduction in IL-17A, IL-22, and IFN-γlevels, but not IL-6 when compared with nontreated cells, as well as increase PPARγmRNA expression in absence of stimulus addressing it as a promising molecule in RA treatment.
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Lu, Juu-Chin, Chia-Yun Lu, and Ying-Yu Wu. "THRAP3 depletion reduces PPARγ mRNA and anti-inflammatory action in 3T3-L1 adipocytes." Journal of Molecular Endocrinology 67, no. 3 (October 1, 2021): 149–59. http://dx.doi.org/10.1530/jme-20-0334.
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Peroxisome proliferator-activated receptor γ (PPARγ) is the master transcriptional regulator of adipocytes and the cellular target of thiazolidinedione (TZD) drugs. Suppression of pro-inflammatory actions, including pro-inflammatory gene expression and lipolysis in adipocytes, contributes to PPARγ-mediated anti-diabetic effects of TZDs. However, adverse side effects largely limited the clinical use of TZDs, despite their potent insulin-sensitizing effects. Therefore, it is important to understand how PPARγ is regulated. Thyroid hormone receptor-associated protein 3 (THRAP3) was previously reported to promote diabetic gene expression by acting as a transcriptional coregulator of PPARγ in adipocytes. Therefore, we tested if THRAP3 modulated anti-inflammatory functions of PPARγ in 3T3-L1 adipocytes. THRAP3 depletion increased basal and tumor necrosis factor α (TNFα)-induced lipolysis, pro-inflammatory gene expression, and phosphorylation of extracellular signal-regulated kinases (ERKs), suggesting elevated pro-inflammatory response after THRAP3 depletion in adipocytes. Moreover, TZD-mediated suppression of TNFα-induced lipolysis, pro-inflammatory gene expression, and ERK phosphorylation was attenuated or alleviated after THRAP3 depletion. Interestingly, the mRNA and protein levels of PPARγ were greatly reduced in THRAP3-depleted adipocytes. Actinomycin D treatment revealed that the stability of PPARγ mRNA was greatly reduced by THRAP3 depletion in adipocytes. Thus, in addition to modulating PPARγ function, THRAP3 may directly regulate the transcript of PPARγ in differentiated adipocytes.
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Van Raalte, Daniël H., Renate E. van Genugten, Björn Eliasson, Diane L. Möller-Goede, Andrea Mari, Andrea Tura, Craig Wilson, et al. "The effect of alogliptin and pioglitazone combination therapy on various aspects of β-cell function in patients with recent-onset type 2 diabetes." European Journal of Endocrinology 170, no. 4 (April 2014): 565–74. http://dx.doi.org/10.1530/eje-13-0639.
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ObjectiveType 2 diabetes mellitus (T2DM) management requires continuous treatment intensification due to progressive decline in β-cell function in insulin resistant individuals. Initial combination therapy of a dipeptidyl peptidase (DPP)-4 inhibitor with a thiazolidinedione (TZD) may be rational. We assessed the effects of the DPP4 inhibitor alogliptin (ALO) combined with the TZD pioglitazone (PIO), vs ALO monotherapy or placebo (PBO), on β-cell function and glycemic control in T2DM.Material and methodsA 16-week, two-center, randomized, double-blind, PBO-controlled, parallel-arm intervention study in 71 patients with well-controlled T2DM (age 59.1±6.3 years; A1C 6.7±0.1%) treated with metformin, sulfonylurea, or glinide monotherapy was conducted. Patients were treated with combined ALO 25 mg and PIO 30 mg daily or ALO 25 mg daily monotherapy or PBO. Main outcome measures included change in A1C and fasting plasma glucose (FPG) from baseline to week 16. In addition, change in β-cell function parameters obtained from standardized meal tests at baseline and at week 16 was measured.ResultsALO/PIO and ALO decreased A1C from baseline by 0.9±0.1 and 0.4±0.2% respectively (both P<0.001 vs PBO). FPG was decreased to a greater extent by ALO/PIO compared with ALO monotherapy (P<0.01). ALO/PIO treatment improved β-cell glucose sensitivity (vs PBO; P<0.001) and fasting secretory tone (vs PBO; P=0.001), while ALO monotherapy did not change β-cell function parameters. All treatments were well tolerated.ConclusionShort-term treatment with ALO/PIO or ALO improved glycemic control in well-controlled T2DM patients, but only combined ALO/PIO improved β-cell function. These data support that initial combination therapy with a DPP4 inhibitor and TZD to address multiple core defects in T2DM may be a sensible approach.
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Bourdon, Allen K., Greg Villareal, George Perry, and Clyde F. Phelix. "Alzheimer's and Parkinson's Disease Novel Therapeutic Target." International Journal of Knowledge Discovery in Bioinformatics 7, no. 2 (July 2017): 68–82. http://dx.doi.org/10.4018/ijkdb.2017070104.
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Thiazolidinedione (TZD) drugs (Takeda Pharmaceuticals and Metabolic Solutions Development Company) targeting inhibition of the mitochondrial pyruvate carrier (MPC) are currently being tested in clinical trials to prevent progression into mild cognitive impairment of Alzheimer's disease (AD) or in the pipeline to prevent neurodegeneration in Parkinson's disease (PD). These have Ki values in the µM range. This study was focused on identifying candidate drug precursors of the natural cinnamic acid products that might have good bioavailability in the nM ranges forming covalent thiol bonds with targets. In silico protein homology modeling and ligand docking has demonstrated that binding cysteine residues within the transport channel is a key part of the inhibitory mechanism. These are covalent thiohemiacetal bonds with the alpha-carbon, carboxylate group, off a phenol ring. Like the classic MPC inhibitors, these natural derivatives of hydroxycinnamic acid have a conjugated pi-system used to form thiol bonds with the cysteine residue via Michael addition.
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Kroker, Alice J., and John B. Bruning. "Review of the Structural and Dynamic Mechanisms of PPARγPartial Agonism." PPAR Research 2015 (2015): 1–15. http://dx.doi.org/10.1155/2015/816856.
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PPARγ(peroxisome proliferator activated receptorγ) is a ligand activated transcription factor of the nuclear receptor superfamily that controls the expression of a variety of genes involved in fatty acid metabolism, adipogenesis, and insulin sensitivity. While endogenous ligands of PPARγinclude fatty acids and eicosanoids, synthetic full agonists of the receptor, including members of the thiazolidinedione (TZD) class, have been widely prescribed for the treatment of type II diabetes mellitus (T2DM). Unfortunately, the use of full agonists has been hampered by harsh side effects with some removed from the market in many countries. In contrast, partial agonists of PPARγhave been shown to retain favourable insulin sensitizing effects while exhibiting little to no side effects and thus represent a new potential class of therapeutics for the treatment of T2DM. Partial agonists have been found to not only display differences in transcriptional and cellular outcomes, but also act through distinct structural and dynamic mechanisms within the ligand binding cavity compared to full agonists.
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Huang, Hui-Ling, Ya-Wen Hong, You-Hong Wong, Ying-Nien Chen, Jong-Ho Chyuan, Ching-Jang Huang, and Pei-Min Chao. "Bitter melon (Momordica charantia L.) inhibits adipocyte hypertrophy and down regulates lipogenic gene expression in adipose tissue of diet-induced obese rats." British Journal of Nutrition 99, no. 2 (February 2008): 230–39. http://dx.doi.org/10.1017/s0007114507793947.
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Bitter melon (Momordica charantia; BM) has been shown to ameliorate diet-induced obesity and insulin resistance. To examine the effect of BM supplementation on cell size and lipid metabolism in adipose tissues, three groups of rats were respectively fed a high-fat diet supplemented without (HF group) or with 5 % lyophilised BM powder (HFB group), or with 0·01 % thiazolidinedione (TZD) (HFT group). A group of rats fed a low-fat diet was also included as a normal control. Hyperinsulinaemia and glucose intolerance were observed in the HF group but not in HFT and HFB groups. Although the number of large adipocytes (>180 μm) of both the HFB and HFT groups was significantly lower than that of the HF group, the adipose tissue mass, TAG content and glycerol-3-phosphate dehydrogenase activity of the HFB group were significantly lower than those of the HFT group, implying that BM might reduce lipogenesis in adipose tissue. Experiment 2 was then conducted to examine the expression of lipogenic genes in adipose tissues of rats fed low-fat, HF or HFB diets. The HFB group showed significantly lower mRNA levels of fatty acid synthase, acetyl-CoA carboxylase-1, lipoprotein lipase and adipocyte fatty acid-binding protein than the HF group (P < 0·05). These results indicate BM can reduce insulin resistance as effective as the anti-diabetic drug TZD. Furthermore, BM can suppress the visceral fat accumulation and inhibit adipocyte hypertrophy, which may be associated with markedly down regulated expressions of lipogenic genes in the adipose.
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Benson, Kiara K., Wenxiang Hu, Angela H. Weller, Alexis H. Bennett, Eric R. Chen, Sumeet A. Khetarpal, Satoshi Yoshino, et al. "Natural human genetic variation determines basal and inducible expression of PM20D1, an obesity-associated gene." Proceedings of the National Academy of Sciences 116, no. 46 (October 28, 2019): 23232–42. http://dx.doi.org/10.1073/pnas.1913199116.
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PM20D1 is a candidate thermogenic enzyme in mouse fat, with its expression cold-induced and enriched in brown versus white adipocytes. Thiazolidinedione (TZD) antidiabetic drugs, which activate the peroxisome proliferator-activated receptor-γ (PPARγ) nuclear receptor, are potent stimuli for adipocyte browning yet fail to induce Pm20d1 expression in mouse adipocytes. In contrast, PM20D1 is one of the most strongly TZD-induced transcripts in human adipocytes, although not in cells from all individuals. Two putative PPARγ binding sites exist near the gene’s transcription start site (TSS) in human but not mouse adipocytes. The −4 kb upstream site falls in a segmental duplication of a nearly identical intronic region +2.5 kb downstream of the TSS, and this duplication occurred in the primate lineage and not in other mammals, like mice. PPARγ binding and gene activation occur via this upstream duplicated site, thus explaining the species difference. Furthermore, this functional upstream PPARγ site exhibits genetic variation among people, with 1 SNP allele disrupting a PPAR response element and giving less activation by PPARγ and TZDs. In addition to this upstream variant that determines PPARγ regulation of PM20D1 in adipocytes, distinct variants downstream of the TSS have strong effects on PM20D1 expression in human fat as well as other tissues. A haplotype of 7 tightly linked downstream SNP alleles is associated with very low PMD201 expression and correspondingly high DNA methylation at the TSS. These PM20D1 low-expression variants may account for human genetic associations in this region with obesity as well as neurodegenerative diseases.