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García-García RM, Jaramillo-Flores ME. Effect of Arthrospira maxima Phycobiliproteins, Rosiglitazone, and 17β-Estradiol on Lipogenic and Inflammatory Gene Expression during 3T3-L1 Preadipocyte Cell Differentiation. Int J Mol Sci 2024; 25:7566. [PMID: 39062809 PMCID: PMC11277109 DOI: 10.3390/ijms25147566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/01/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024] Open
Abstract
The study evaluated the effects of Arthrospira maxima phycobiliproteins (PBPs), rosiglitazone (RSG), and 17β-estradiol (E) on the differentiation process of 3T3-L1 cells and on their regulation of lipogenic and inflammatory gene expression at different stages of the process. The results showed that phycobiliproteins promoted cell proliferation after 24 h of treatment. Furthermore, for all three treatments, the regulation of the highest number of markers occurred on days 6 and 12 of differentiation, regardless of when the treatment was applied. Phycobiliproteins reduced lipid droplet accumulation on days 3, 6, 10, and 13 of the adipogenic process, while rosiglitazone showed no differences compared to the control. On day 6, both phycobiliproteins and rosiglitazone positively regulated Acc1 mRNA. Meanwhile, all three treatments negatively regulated Pparγ and C/ebpα. Phycobiliproteins and estradiol also negatively regulated Ucp1 and Glut4 mRNAs. Rosiglitazone and estradiol, on the other hand, negatively regulated Ppara and Il-6 mRNAs. By day 12, phycobiliproteins and rosiglitazone upregulated Pparγ mRNA and negatively regulated Tnfα and Il-1β. Additionally, phycobiliproteins and estradiol positively regulated Il-6 and negatively regulated Ppara, Ucp2, Acc1, and Glut4. Rosiglitazone and estradiol upregulate C/ebpα and Ucp1 mRNAs. The regulation exerted by phycobiliproteins on the mRNA expression of the studied markers was dependent on the phase of cell differentiation. The results of this study highlight that phycobiliproteins have an anti-adipogenic and anti-inflammatory effect by reducing the expression of adipogenic, lipogenic, and inflammatory genes in 3T3-L1 cells at different stages of the differentiation process.
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Affiliation(s)
| | - María Eugenia Jaramillo-Flores
- Ingeniería Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City CP 07738, Mexico;
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Guo J, Xie Z, Ruan W, Tang Q, Qiao D, Zhu W. Thiazole-based analogues as potential antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA) and their SAR elucidation. Eur J Med Chem 2023; 259:115689. [PMID: 37542993 DOI: 10.1016/j.ejmech.2023.115689] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/07/2023]
Abstract
In recent years, the overuse of antibiotics has resulted in the emergence of antibiotic resistance, which is a serious global health problem. Methicillin-resistant Staphylococcus aureus (MRSA) is a common and virulent bacterium in clinical practice. Numerous researchers have focused on developing new candidate drugs that are effective, less toxic, and can overcome MRSA resistance. Thiazole derivatives have been found to exhibit antibacterial activity against drug-sensitive and drug-resistant pathogens. By hybridizing thiazole with other antibacterial pharmacophores, it is possible to obtain more effective antibacterial candidate drugs. Thiazole derivatives have shown potential in developing new drugs that can overcome drug resistance, reduce toxicity, and improve pharmacokinetic characteristics. This article reviews the recent progress of thiazole compounds as potential antibacterial compounds and examines the structure-activity relationship (SAR) in various directions. It covers articles published from 2018 to 2023, providing a comprehensive platform to plan and develop new thiazole-based small MRSA growth inhibitors with minimal side effects.
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Affiliation(s)
- Jiaojiao Guo
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China
| | - Zhouling Xie
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China
| | - Wei Ruan
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China
| | - Qidong Tang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China
| | - Dan Qiao
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China.
| | - Wufu Zhu
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China.
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Nelson ML, Pfeifer JA, Hickey JP, Collins AE, Kalisch BE. Exploring Rosiglitazone's Potential to Treat Alzheimer's Disease through the Modulation of Brain-Derived Neurotrophic Factor. BIOLOGY 2023; 12:1042. [PMID: 37508471 PMCID: PMC10376118 DOI: 10.3390/biology12071042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 06/24/2023] [Accepted: 07/21/2023] [Indexed: 07/30/2023]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that debilitates over 55 million individuals worldwide. Currently, treatments manage and alleviate its symptoms; however, there is still a need to find a therapy that prevents or halts disease progression. Since AD has been labeled as "type 3 diabetes" due to its similarity in pathological hallmarks, molecular pathways, and comorbidity with type 2 diabetes mellitus (T2DM), there is growing interest in using anti-diabetic drugs for its treatment. Rosiglitazone (RSG) is a peroxisome proliferator-activated receptor-gamma agonist that reduces hyperglycemia and hyperinsulinemia and improves insulin signaling. In cellular and rodent models of T2DM-associated cognitive decline and AD, RSG has been reported to improve cognitive impairment and reverse AD-like pathology; however, results from human clinical trials remain consistently unsuccessful. RSG has also been reported to modulate the expression of brain-derived neurotrophic factor (BDNF), a protein that regulates neuroplasticity and energy homeostasis and is implicated in both AD and T2DM. The present review investigates RSG's limitations and potential therapeutic benefits in pre-clinical models of AD through its modulation of BDNF expression.
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Affiliation(s)
- Mackayla L Nelson
- Department of Biomedical Sciences and Collaborative Specialization in Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Julia A Pfeifer
- Department of Biomedical Sciences and Collaborative Specialization in Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Jordan P Hickey
- Department of Biomedical Sciences and Collaborative Specialization in Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Andrila E Collins
- Department of Biomedical Sciences and Collaborative Specialization in Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Bettina E Kalisch
- Department of Biomedical Sciences and Collaborative Specialization in Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1, Canada
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Tseng CH. Rosiglitazone Does Not Affect the Risk of Inflammatory Bowel Disease: A Retrospective Cohort Study in Taiwanese Type 2 Diabetes Patients. Pharmaceuticals (Basel) 2023; 16:ph16050679. [PMID: 37242462 DOI: 10.3390/ph16050679] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/27/2023] [Accepted: 04/29/2023] [Indexed: 05/28/2023] Open
Abstract
Human studies on the effect of rosiglitazone on inflammatory bowel disease (IBD) are still lacking. We investigated whether rosiglitazone might affect IBD risk by using the reimbursement database of Taiwan's National Health Insurance to enroll a propensity-score-matched cohort of ever users and never users of rosiglitazone. The patients should have been newly diagnosed with diabetes mellitus between 1999 and 2006 and should have been alive on 1 January 2007. We then started to follow the patients from 1 January 2007 until 31 December 2011 for a new diagnosis of IBD. Propensity-score-weighted hazard ratios were estimated with regards to rosiglitazone exposure in terms of ever users versus never users and in terms of cumulative duration and cumulative dose of rosiglitazone therapy for dose-response analyses. The joint effects and interactions between rosiglitazone and risk factors of psoriasis/arthropathies, dorsopathies, and chronic obstructive pulmonary disease/tobacco abuse and the use of metformin were estimated by Cox regression after adjustment for all covariates. A total of 6226 ever users and 6226 never users were identified and the respective numbers of incident IBD were 95 and 111. When we compared the risk of IBD in ever users to that of the never users, the estimated hazard ratio (0.870, 95% confidence interval: 0.661-1.144) was not statistically significant. When cumulative duration and cumulative dose of rosiglitazone therapy were categorized by tertiles and hazard ratios were estimated by comparing the tertiles of rosiglitazone exposure to the never users, none of the hazard ratios reached statistical significance. In secondary analyses, rosiglitazone has a null association with Crohn's disease, but a potential benefit on ulcerative colitis (UC) could not be excluded. However, because of the low incidence of UC, we were not able to perform detailed dose-response analyses for UC. In the joint effect analyses, only the subgroup of psoriasis/arthropathies (-)/rosiglitazone (-) showed a significantly lower risk in comparison to the subgroup of psoriasis/arthropathies (+)/rosiglitazone (-). No interactions between rosiglitazone and the major risk factors or metformin use were observed. We concluded that rosiglitazone has a null effect on the risk of IBD, but the potential benefit on UC awaits further investigation.
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Affiliation(s)
- Chin-Hsiao Tseng
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 10051, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan
- National Institute of Environmental Health Sciences of the National Health Research Institutes, Zhunan 35053, Taiwan
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Dyhring T, Jansen-Olesen I, Christophersen P, Olesen J. Pharmacological Profiling of K ATP Channel Modulators: An Outlook for New Treatment Opportunities for Migraine. Pharmaceuticals (Basel) 2023; 16:225. [PMID: 37259373 PMCID: PMC9966414 DOI: 10.3390/ph16020225] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/28/2023] [Accepted: 01/30/2023] [Indexed: 12/23/2023] Open
Abstract
Migraine is a highly disabling pain disorder with huge socioeconomic and personal costs. It is genetically heterogenous leading to variability in response to current treatments and frequent lack of response. Thus, new treatment strategies are needed. A combination of preclinical and clinical data indicate that ATP-sensitive potassium (KATP) channel inhibitors could be novel and highly effective drugs in the treatment of migraine. The subtype Kir6.1/SUR2B is of particular interest and inhibitors specific for this cranio-vascular KATP channel subtype may qualify as future migraine drugs. Historically, different technologies and methods have been undertaken to characterize KATP channel modulators and, therefore, a head-to-head comparison of potency and selectivity between the different KATP subtypes is difficult to assess. Here, we characterize available KATP channel activators and inhibitors in fluorescence-based thallium-flux assays using HEK293 cells stably expressing human Kir6.1/SUR2B, Kir6.2/SUR1, and Kir6.2/SUR2A KATP channels. Among the openers tested, levcromakalim, Y-26763, pinacidil, P-1075, ZM226600, ZD0947, and A-278637 showed preference for the KATP channel subtype Kir6.1/SUR2B, whereas BMS-191095, NN414, and VU0071306 demonstrated preferred activation of the Kir6.2/SUR1 subtype. In the group of KATP channel blockers, only Rosiglitazone and PNU-37783A showed selective inhibition of the Kir6.1/SUR2B subtype. PNU-37783A was stopped in clinical development and Rosiglitazone has a low potency for the vascular KATP channel subtype. Therefore, development of novel selective KATP channel blockers, having a benign side effect profile, are needed to clinically prove inhibition of Kir6.1/SUR2B as an effective migraine treatment.
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Affiliation(s)
| | - Inger Jansen-Olesen
- Danish Headache Center, Department of Neurology, University of Copenhagen, 2600 Glostrup, Denmark
| | | | - Jes Olesen
- Danish Headache Center, Department of Neurology, University of Copenhagen, 2600 Glostrup, Denmark
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Galaz J, Romero R, Arenas-Hernandez M, Farias-Jofre M, Motomura K, Liu Z, Kawahara N, Demery-Poulos C, Liu TN, Padron J, Panaitescu B, Gomez-Lopez N. Clarithromycin prevents preterm birth and neonatal mortality by dampening alarmin-induced maternal–fetal inflammation in mice. BMC Pregnancy Childbirth 2022; 22:503. [PMID: 35725425 PMCID: PMC9210693 DOI: 10.1186/s12884-022-04764-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 05/12/2022] [Indexed: 11/10/2022] Open
Abstract
Background One of every four preterm neonates is born to a woman with sterile intra-amniotic inflammation (inflammatory process induced by alarmins); yet, this clinical condition still lacks treatment. Herein, we utilized an established murine model of sterile intra-amniotic inflammation induced by the alarmin high-mobility group box-1 (HMGB1) to evaluate whether treatment with clarithromycin prevents preterm birth and adverse neonatal outcomes by dampening maternal and fetal inflammatory responses. Methods Pregnant mice were intra-amniotically injected with HMGB1 under ultrasound guidance and treated with clarithromycin or vehicle control, and pregnancy and neonatal outcomes were recorded (n = 15 dams each). Additionally, amniotic fluid, placenta, uterine decidua, cervix, and fetal tissues were collected prior to preterm birth for determination of the inflammatory status (n = 7–8 dams each). Results Clarithromycin extended the gestational length, reduced the rate of preterm birth, and improved neonatal mortality induced by HMGB1. Clarithromycin prevented preterm birth by interfering with the common cascade of parturition as evidenced by dysregulated expression of contractility-associated proteins and inflammatory mediators in the intra-uterine tissues. Notably, clarithromycin improved neonatal survival by dampening inflammation in the placenta as well as in the fetal lung, intestine, liver, and spleen. Conclusions Clarithromycin prevents preterm birth and improves neonatal survival in an animal model of sterile intra-amniotic inflammation, demonstrating the potential utility of this macrolide for treating women with this clinical condition, which currently lacks a therapeutic intervention. Supplementary Information The online version contains supplementary material available at 10.1186/s12884-022-04764-2.
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Garikapati KK, Kiran AVVVR, Thaggikuppe Krishnamurthy P, S T N, B B, Nagappan K. Quantification of rosiglitazone in rat plasma and tissues via LC-MS/MS - method development, validation, and its application in pharmacokinetic and tissue distribution studies. Biomed Chromatogr 2022; 36:e5326. [PMID: 34993979 DOI: 10.1002/bmc.5326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 12/23/2021] [Accepted: 12/27/2021] [Indexed: 11/05/2022]
Abstract
A bioanalytical method for the quantification of rosiglitazone on rat plasma and tissues (adipose tissue, heart, brain, bone, and kidney) using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was developed and validated. Chromatographic separation was achieved on Gemini C18 column (50mm x 4.6mm, 3μm) using mobile phase consists of 10mM ammonium formate (pH 4.0) and acetonitrile (10:90, v/v) at a flow rate of 0.8 mL/min and injection volume of 10μL (Internal standard - Pioglitazone). LC-MS detection was performed with multiple reaction monitoring mode (MRM) using target ions at m/z→358.0 and m/z → 357.67 for rosiglitazone and pioglitazone (IS) respectively. The calibration curve showed a good correlation coefficient (r2 ) over the concentration range of 1-10000 ng/mL. The mean percentage recoveries of rosiglitazone were found to be over the range of 92.54-96.64 % with detection and lower quantification limit of 0.6 ng/mL and 1.0 ng/mL, respectively. The developed method was validated as per USFDA guidelines and successfully utilized to measure rosiglitazone in plasma and tissue samples. Further, the developed method can be utilized for validating specific organ targeting delivery systems of rosiglitazone in addition to conventional dosage forms.
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Affiliation(s)
- Kusuma Kumari Garikapati
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research) Ooty, Nilgiris, India
| | - Ammu V V V Ravi Kiran
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research) Ooty, Nilgiris, India
| | | | - Narenderan S T
- Department of Pharmaceutical Analysis, JSS College of Pharmacy, JSS Academy of Higher Education & Research) Ooty, Nilgiris, India
| | - Babu B
- Department of Pharmaceutical Analysis, JSS College of Pharmacy, JSS Academy of Higher Education & Research) Ooty, Nilgiris, India
| | - Krishnaveni Nagappan
- Department of Pharmaceutical Analysis, JSS College of Pharmacy, JSS Academy of Higher Education & Research) Ooty, Nilgiris, India
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Ma Y, Du X, Zhao D, Tang K, Wang X, Guo S, Li X, Mei S, Sun N, Liu J, Jiang C. 18:0 Lyso PC, a natural product with potential PPAR-γ agonistic activity, plays hypoglycemic effect with lower liver toxicity and cardiotoxicity in db/db mice. Biochem Biophys Res Commun 2021; 579:168-174. [PMID: 34607170 DOI: 10.1016/j.bbrc.2021.09.059] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/18/2021] [Accepted: 09/23/2021] [Indexed: 12/22/2022]
Abstract
Rosiglitazone, a specific agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ), displays a robust hypoglycemic action in patients with type 2 diabetes mellitus (T2DM) and elicits serious adverse reactions, especially hepatotoxicity and cardiotoxicity. Here, we aims to find a new natural PPAR-γ agonist with less adverse reactions than rosiglitazone in db/db mice. The method of virtual screening was used to identify a PPAR-γ agonist 18:0 Lyso PC from an in-house natural product library. We verified its pharmacological effects and adverse reactions comparing with rosiglitazone in vivo and in vitro. 18:0 Lyso PC exhibited pharmacological effects similar to those of rosiglitazone in db/db mice. Moreover, 18:0 Lyso PC showed a lower extent of liver injury and cardiotoxicity in db/db mice. The mechanism, by which this natural compound alleviates metabolic syndrome, involves a reduction in fatty acid synthesis mediated by activation of the phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase-alpha (AMPKα) and acetyl-CoA carboxylase (ACC) and an increase expression of uncoupled protein 1 (UCP1) and PPAR-γ coactivator-1 alpha (PGC1-α). 18:0 Lyso PC, a natural compound, can show a similar hypoglycemic effect to rosiglitazone by activating PPAR-γ, while eliciting markedly fewer adverse reactions than rosiglitazone.
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Affiliation(s)
- Yiming Ma
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry, Peking Union Medical College, Beijing, 100005, China
| | - Xinyi Du
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry, Peking Union Medical College, Beijing, 100005, China
| | - Dandan Zhao
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry, Peking Union Medical College, Beijing, 100005, China
| | - Kegong Tang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry, Peking Union Medical College, Beijing, 100005, China
| | - Xiaona Wang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry, Peking Union Medical College, Beijing, 100005, China
| | - Shaoting Guo
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry, Peking Union Medical College, Beijing, 100005, China
| | - Xiaobei Li
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry, Peking Union Medical College, Beijing, 100005, China
| | - Song Mei
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry, Peking Union Medical College, Beijing, 100005, China
| | - Na Sun
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry, Peking Union Medical College, Beijing, 100005, China
| | - Jiaqi Liu
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry, Peking Union Medical College, Beijing, 100005, China
| | - Chengyu Jiang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry, Peking Union Medical College, Beijing, 100005, China.
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Youssef MI, Ma J, Chen Z, Hu WW. Potential therapeutic agents for ischemic white matter damage. Neurochem Int 2021; 149:105116. [PMID: 34229025 DOI: 10.1016/j.neuint.2021.105116] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 06/24/2021] [Indexed: 11/19/2022]
Abstract
Ischemic white matter damage (WMD) is increasingly being considered as one of the major causes of neurological disorders in older adults and preterm infants. The functional consequences of WMD triggers a progressive cognitive decline and dementia particularly in patients with ischemic cerebrovascular diseases. Despite the major stride made in the pathogenesis mechanisms of ischemic WMD in the last century, effective medications are still not available. So, there is an urgent need to explore a promising approach to slow the progression or modify its pathological course. In this review, we discussed the animal models, the pathological mechanisms and the potential therapeutic agents for ischemic WMD. The development in the studies of anti-oxidants, free radical scavengers, anti-inflammatory or anti-apoptotic agents and neurotrophic factors in ischemic WMD were summarized. The agents which either alleviate oligodendrocyte damage or promote its proliferation or differentiation may have potential value for the treatment of ischemic WMD. Moreover, drugs with multifaceted protective activities or a wide therapeutic window may be optimal for clinical translation.
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Affiliation(s)
- Mahmoud I Youssef
- Department of Pharmacology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China
| | - Jing Ma
- Department of Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, PR China.
| | - Zhong Chen
- Department of Pharmacology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China; Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, PR China.
| | - Wei-Wei Hu
- Department of Pharmacology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China.
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Gong L, Jin H, Li Y, Quan Y, Yang J, Tang Q, Zou Z. Rosiglitazone ameliorates skeletal muscle insulin resistance by decreasing free fatty acids release from adipocytes. Biochem Biophys Res Commun 2020; 533:1122-1128. [PMID: 33036752 DOI: 10.1016/j.bbrc.2020.09.144] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 09/30/2020] [Indexed: 01/07/2023]
Abstract
Skeletal muscle and white adipose tissue are important organs of glucose-lipid metabolism. However, excessive lipolysis and free fatty acids (FFA) release in adipocytes elevate plasma FFA, leading to insulin resistance in skeletal muscle. Here, we investigated effects of insulin-resistant adipocytes on skeletal muscle in vitro by simulating body environment using a transwell coculture method. Insulin-resistant 3T3-L1 adipocytes increased lipolysis and FFA release, which reduced insulin sensitivity in the cocultured C2C12 myotubes. Rosiglitazone (RSG) decreased excessive lipolysis by reducing expression of adipose triglyceride lipase (ATGL) and activity of hormone-sensitive lipase (HSL), which led to decrease of FFA release from insulin-resistant 3T3-L1 adipocytes. Meanwhile, insulin resistance in C2C12 myotubes cocultured with insulin-resistant 3T3-L1 adipocytes was ameliorated after RSG treatment. Taken together, our present study provided direct evidence to better understand insulin resistance between skeletal muscle and adipose tissue in type 2 diabetes.
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MESH Headings
- 3T3-L1 Cells
- Adipocytes/drug effects
- Adipocytes/metabolism
- Animals
- Asialoglycoproteins/genetics
- Asialoglycoproteins/metabolism
- Cell Communication/physiology
- Coculture Techniques
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/metabolism
- Fatty Acids, Nonesterified/blood
- Fatty Acids, Nonesterified/metabolism
- Hypoglycemic Agents/pharmacology
- Insulin Resistance/physiology
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Lipase/genetics
- Lipase/metabolism
- Lipid Metabolism/drug effects
- Lipolysis/drug effects
- Lipolysis/physiology
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Mice
- Muscle Fibers, Skeletal/drug effects
- Muscle Fibers, Skeletal/metabolism
- Muscle, Skeletal/drug effects
- Muscle, Skeletal/metabolism
- Rosiglitazone/pharmacology
- Sterol Esterase/genetics
- Sterol Esterase/metabolism
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Affiliation(s)
- Longlong Gong
- MOE Key Laboratory of Laser Life Science, Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Huan Jin
- MOE Key Laboratory of Laser Life Science, Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Yonghua Li
- MOE Key Laboratory of Laser Life Science, Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Yingyao Quan
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai Hospital of Jinan University, Zhuhai People's Hospital, Zhuhai, Guangdong, 519000, China
| | - Jichun Yang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
| | - Qing Tang
- MOE Key Laboratory of Laser Life Science, Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Zhengzhi Zou
- MOE Key Laboratory of Laser Life Science, Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
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A New Co-Crystal of Synthetic Drug Rosiglitazone with Natural Medicine Berberine: Preparation, Crystal Structures, and Dissolution. Molecules 2020; 25:molecules25184288. [PMID: 32962058 PMCID: PMC7570454 DOI: 10.3390/molecules25184288] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/15/2020] [Accepted: 09/15/2020] [Indexed: 11/16/2022] Open
Abstract
A co-crystal of rosiglitazone (Rsg) with berberine (Bbr), Rsg-Bbr, was prepared by the solvent evaporation method and characterized. The results showed that the electrostatic attraction existed between the nitrogen anion of rosiglitazone and the quaternary ammonium cation of berberine, and C-H···O hydrogen bonds were formed between Rsg and Bbr. In the crystal structure, rosiglitazone molecules stack into a supramolecular layer through π-π interactions while π-π interactions between berberine cations also result in a similar layer. The co-crystal presented a low moisture adsorption curve in the range of 0−95% relative humidity values at 25 °C. The improved dissolution rate of rosiglitazone in pH = 6.8 buffer solution could be achieved after forming co-crystal.
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De Vries MC, Brown DA, Allen ME, Bindoff L, Gorman GS, Karaa A, Keshavan N, Lamperti C, McFarland R, Ng YS, O'Callaghan M, Pitceathly RDS, Rahman S, Russel FGM, Varhaug KN, Schirris TJJ, Mancuso M. Safety of drug use in patients with a primary mitochondrial disease: An international Delphi-based consensus. J Inherit Metab Dis 2020; 43:800-818. [PMID: 32030781 PMCID: PMC7383489 DOI: 10.1002/jimd.12196] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/18/2019] [Accepted: 11/19/2019] [Indexed: 12/29/2022]
Abstract
Clinical guidance is often sought when prescribing drugs for patients with primary mitochondrial disease. Theoretical considerations concerning drug safety in patients with mitochondrial disease may lead to unnecessary withholding of a drug in a situation of clinical need. The aim of this study was to develop consensus on safe medication use in patients with a primary mitochondrial disease. A panel of 16 experts in mitochondrial medicine, pharmacology, and basic science from six different countries was established. A modified Delphi technique was used to allow the panellists to consider draft recommendations anonymously in two Delphi rounds with predetermined levels of agreement. This process was supported by a review of the available literature and a consensus conference that included the panellists and representatives of patient advocacy groups. A high level of consensus was reached regarding the safety of all 46 reviewed drugs, with the knowledge that the risk of adverse events is influenced both by individual patient risk factors and choice of drug or drug class. This paper details the consensus guidelines of an expert panel and provides an important update of previously established guidelines in safe medication use in patients with primary mitochondrial disease. Specific drugs, drug groups, and clinical or genetic conditions are described separately as they require special attention. It is important to emphasise that consensus-based information is useful to provide guidance, but that decisions related to drug prescribing should always be tailored to the specific needs and risks of each individual patient. We aim to present what is current knowledge and plan to update this regularly both to include new drugs and to review those currently included.
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Affiliation(s)
- Maaike C. De Vries
- Radboudumc Amalia Children's HospitalRadboud Center for Mitochondrial MedicineNijmegenThe Netherlands
| | - David A. Brown
- Department of Human Nutrition, Foods, and Exercise and the Virginia Tech Center for Drug DiscoveryVirginia TechBlacksburgVirginia
| | - Mitchell E. Allen
- Department of Human Nutrition, Foods, and Exercise and the Virginia Tech Center for Drug DiscoveryVirginia TechBlacksburgVirginia
| | - Laurence Bindoff
- Department of Clinical MedicineUniversity of BergenBergenNorway
- Department of NeurologyHaukeland University HospitalBergenNorway
| | - Gráinne S. Gorman
- Wellcome Centre for Mitochondrial Research, Institute of NeuroscienceNewcastle UniversityNewcastle upon TyneUK
- The Newcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
| | - Amel Karaa
- Genetics Unit, Massachusetts General HospitalHarvard Medical SchoolBostonMassachusetts
| | - Nandaki Keshavan
- Mitochondrial Research GroupUCL Great Ormond Street Institute of Child HealthLondonUK
- Metabolic UnitGreat Ormond Street Hospital NHS Foundation TrustLondonUK
| | - Costanza Lamperti
- Unit of Medical Genetics and NeurogeneticsFondazione IRCCS Istituto Neurologico Carlo BestaMilanItaly
| | - Robert McFarland
- Wellcome Centre for Mitochondrial Research, Institute of NeuroscienceNewcastle UniversityNewcastle upon TyneUK
- The Newcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
| | - Yi Shiau Ng
- Wellcome Centre for Mitochondrial Research, Institute of NeuroscienceNewcastle UniversityNewcastle upon TyneUK
- The Newcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
| | - Mar O'Callaghan
- Department of Neurology, Metabolic UnitHospital Sant Joan de DéuBarcelonaSpain
- CIBERERInstituto de Salud Carlos IIIBarcelonaSpain
| | - Robert D. S. Pitceathly
- Department of Neuromuscular DiseasesUCL Queen Square Institute of Neurology and The National Hospital for Neurology and NeurosurgeryLondonUK
| | - Shamima Rahman
- Mitochondrial Research GroupUCL Great Ormond Street Institute of Child HealthLondonUK
- Metabolic UnitGreat Ormond Street Hospital NHS Foundation TrustLondonUK
| | - Frans G. M. Russel
- Department of Pharmacology and ToxicologyRadboud Institute for Molecular Life Sciences, Radboud Center for Mitochondrial Medicine, RadboudumcNijmegenThe Netherlands
| | - Kristin N. Varhaug
- Department of Clinical MedicineUniversity of BergenBergenNorway
- Department of NeurologyHaukeland University HospitalBergenNorway
| | - Tom J. J. Schirris
- Department of Pharmacology and ToxicologyRadboud Institute for Molecular Life Sciences, Radboud Center for Mitochondrial Medicine, RadboudumcNijmegenThe Netherlands
| | - Michelangelo Mancuso
- Department of Clinical and Experimental Medicine, Neurological InstituteUniversity of PisaPisaItaly
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Improving Dissolution and Cytotoxicity by Forming Multidrug Crystals. Molecules 2020; 25:molecules25061343. [PMID: 32188020 PMCID: PMC7144552 DOI: 10.3390/molecules25061343] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/11/2020] [Accepted: 03/13/2020] [Indexed: 12/13/2022] Open
Abstract
Both rosiglitazone and metformin have effects on blood glucose regulation and the proliferation of liver cancer cells. Combination therapy with these two drugs is common and effective for the treatment of diabetes in the clinic, however, the application of these two drugs is influenced by the poor dissolution of rosiglitazone and the gastrointestinal side-effect of metformin resulting from a high solubility. The formation of a multidrug crystal form (Rsg-Met) by a solvent evaporation method can solve the solubility issue. Crystal structure data and intramolecular hydrogen bonds were detected by X-ray diffraction and infrared spectroscopy. Surprisingly, Rsg-Met shortens the time spent in solubility equilibrium and multiplies the dissolution rate of Rsg. Finally, we found that a low concentration of Rsg-Met enhanced the proliferation inhibition effect on liver cancer cells (HepG2, SK-hep1) compared with rosiglitazone, without affecting the human normal cell line LO2.
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Zhao F, Wang H, Wei P, Jiang G, Wang W, Zhang X, Ru S. Impairment of bisphenol F on the glucose metabolism of zebrafish larvae. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2018; 165:386-392. [PMID: 30218961 DOI: 10.1016/j.ecoenv.2018.09.017] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 08/25/2018] [Accepted: 09/02/2018] [Indexed: 06/08/2023]
Abstract
Bisphenol F (BPF) is a substitute of bisphenol A in the production of epoxy resin and polycarbonate. Its extensive use in consumer products leads to a wide human exposure at high levels. Although the adverse effects of BPF on animal health are of increasing public concern, its risks on systematic glucose metabolism and blood glucose concentrations still remain largely unknown. Using zebrafish larvae as the model animal, we investigated the disturbance of BPF exposure on glucose metabolism and the underlying mechanisms. Zebrafish larvae at 96 h post fertilization were exposed to 0.1, 1, 10, and 100 μg/L of BPF for 48 h. Compared with the control group, glucose levels of larvae increased significantly in the 10 and 100 μg/L exposure groups, which are associated with enhancement of gluconeogenesis and suppression of glycolysis induced by high doses of BPF. Additionally, both mRNA expressions and protein levels of insulin increased significantly in the 10 and 100 μg/L exposure groups, while transcription levels of genes encoding insulin receptor substrates decreased significantly in these groups, indicating a possibly decreased insulin sensitivity due to impairment of insulin signaling transduction downstream of insulin receptor. Further, compared with BPF alone, co-exposure of larvae to BPF and rosiglitazone, an insulin sensitizer, significantly attenuates increases in both glucose levels and mRNA expressions of a key gluconeogenesis enzyme. Our data therefore indicate impairing insulin signaling transduction may be the main mechanism through which BPF disrupts glucose metabolism and induces hyperglycemia. Results of the present study inform the health risk assessment of BPF and also suggest the use of zebrafish larvae in large-scale screening of chemicals with possible glucose metabolism disturbing effect.
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Affiliation(s)
- Fei Zhao
- Marine Life Science College, Ocean University of China, 5 Yushan Road, Qingdao 266003, Shandong Province, PR China
| | - Hongfang Wang
- Marine Life Science College, Ocean University of China, 5 Yushan Road, Qingdao 266003, Shandong Province, PR China
| | - Penghao Wei
- Marine Life Science College, Ocean University of China, 5 Yushan Road, Qingdao 266003, Shandong Province, PR China
| | - Guobin Jiang
- Marine Life Science College, Ocean University of China, 5 Yushan Road, Qingdao 266003, Shandong Province, PR China
| | - Wei Wang
- Marine Life Science College, Ocean University of China, 5 Yushan Road, Qingdao 266003, Shandong Province, PR China
| | - Xiaona Zhang
- Marine Life Science College, Ocean University of China, 5 Yushan Road, Qingdao 266003, Shandong Province, PR China
| | - Shaoguo Ru
- Marine Life Science College, Ocean University of China, 5 Yushan Road, Qingdao 266003, Shandong Province, PR China.
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Digenio A, Pham NC, Watts LM, Morgan ES, Jung SW, Baker BF, Geary RS, Bhanot S. Antisense Inhibition of Protein Tyrosine Phosphatase 1B With IONIS-PTP-1B Rx Improves Insulin Sensitivity and Reduces Weight in Overweight Patients With Type 2 Diabetes. Diabetes Care 2018; 41:807-814. [PMID: 29439147 DOI: 10.2337/dc17-2132] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 01/17/2018] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To evaluate safety and efficacy of IONIS-PTP-1BRx, a second-generation 2'-O-methoxyethyl antisense inhibitor of protein tyrosine phosphatase 1B, as add-on therapy in overweight patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea therapy. RESEARCH DESIGN AND METHODS In this phase II, double-blind, randomized, placebo-controlled, multicenter trial, overweight and obese patients (BMI ≥27 kg/m2) with type 2 diabetes (HbA1c ≥7.5% [58 mmol/mol] and ≤10.5% [91 mmol/mol]) on a stable dose of metformin alone or with sulfonylurea were randomized 2:1 to IONIS-PTP-1BRx 200 mg (n = 62) or placebo (n = 30) once weekly for 26 weeks. RESULTS Mean baseline HbA1c was 8.6% (70 mmol/mol) and 8.7% (72 mmol/mol) in placebo and active treatment, respectively. At week 27, IONIS-PTP-1BRx reduced mean HbA1c levels by -0.44% (-4.8 mmol/mol; P = 0.074) from baseline and improved leptin (-4.4 ng/mL; P = 0.007) and adiponectin (0.99 μg/mL; P = 0.026) levels compared with placebo. By week 36, mean HbA1c was significantly reduced (-0.69% [-7.5 mmol/mol]; P = 0.034) and accompanied by reductions in fructosamine (-33.2 μmol/L; P = 0.005) and glycated albumin (-1.6%; P = 0.031) versus placebo. Despite both treatment groups receiving similar lifestyle counseling, mean body weight significantly decreased from baseline to week 27 with IONIS-PTP-1BRx versus placebo (-2.6 kg; P = 0.002) independent of HbA1c reduction (R2 = 0.0020). No safety concerns were identified in the study. CONCLUSIONS Compared with placebo, IONIS-PTP-1BRx treatment for 26 weeks produced prolonged reductions in HbA1c, improved medium-term glycemic parameters, reduced leptin and increased adiponectin levels, and resulted in a distinct body weight-reducing effect.
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Yim CS, Jeong YS, Lee SY, Pyeon W, Ryu HM, Lee JH, Lee KR, Maeng HJ, Chung SJ. Specific Inhibition of the Distribution of Lobeglitazone to the Liver by Atorvastatin in Rats: Evidence for a Rat Organic Anion Transporting Polypeptide 1B2-Mediated Interaction in Hepatic Transport. Drug Metab Dispos 2017; 45:246-259. [PMID: 28069721 DOI: 10.1124/dmd.116.074120] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 01/05/2017] [Indexed: 12/17/2022] Open
Abstract
Cytochrome P450 enzymes and human organic anion transporting polypeptide (OATP) 1B1 are reported to be involved in the pharmacokinetics of lobeglitazone (LB), a new peroxisome proliferator-activated receptor γ agonist. Atorvastatin (ATV), a substrate for CYP3A and human OATP1B1, is likely to be coadministered with LB in patients with the metabolic syndrome. We report herein on a study of potential interactions between LB and ATV in rats. When LB was administered intravenously with ATV, the systemic clearance and volume of distribution at steady state for LB remained unchanged (2.67 ± 0.63 ml/min per kg and 289 ± 20 ml/kg, respectively), compared with that of LB without ATV (2.34 ± 0.37 ml/min per kg and 271 ± 20 ml/kg, respectively). Although the tissue-to-plasma partition coefficient (Kp) of LB was not affected by ATV in most major tissues, the liver Kp for LB was decreased by ATV coadministration. Steady-state liver Kp values for three levels of LB were significantly decreased as a result of ATV coadministration. LB uptake was inhibited by ATV in rat OATP1B2-overexpressing Madin-Darby canine kidney cells and in isolated rat hepatocytes in vitro. After incorporating the kinetic parameters for the in vitro studies into a physiologically based pharmacokinetics model, the characteristics of LB distribution to the liver were consistent with the findings of the in vivo study. It thus appears that the distribution of LB to the liver is mediated by the hepatic uptake of transporters such as rat OATP1B2, and carrier-mediated transport is involved in the liver-specific drug-drug interaction between LB and ATV in vivo.
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Affiliation(s)
- Chang-Soon Yim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.)
| | - Yoo-Seong Jeong
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.)
| | - Song-Yi Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.)
| | - Wonji Pyeon
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.)
| | - Heon-Min Ryu
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.)
| | - Jong-Hwa Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.)
| | - Kyeong-Ryoon Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.)
| | - Han-Joo Maeng
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.)
| | - Suk-Jae Chung
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.)
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Guldiken S, Turgut B, Demir M, Arikan E, Kara M, Vural O, Tugrul A, Fareed J. The Effects of Rosiglitazone Treatment on the Fibrinolytic System in Patients with Type 2 Diabetes Mellitus. Clin Appl Thromb Hemost 2016; 12:55-60. [PMID: 16444435 DOI: 10.1177/107602960601200109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Patients with type 2 diabetes mellitus (DM) are at risk for the development of cardiovascular diseases, which can in part be explained by disturbances in the hemostatic and fibrinolytic systems. The effects of rosiglitazone treatment on the fibrinolytic system and insulin sensitivity in patients with type 2 DM were assessed. Twenty-four patients with type 2 DM and 28 healthy subjects were enrolled in the study. Plasma global fibrinolytic capacity (GFC), tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) levels were measured. Insulin resistance was calculated by hoemostasis model assessment. Patients with type 2 DM then were placed on rosiglitazone (4 mg/day, for 12 weeks) in addition coexistent medication, and baseline tests were repeated. There was no difference between mean t-PA levels of the two groups. PAI-1 levels were higher in diabetic patients than control subjects (p < 0.01). Diabetic patients had lower GFC and t-PA/PAI-1 levels than control subjects (p < 0.05, p < 0.05). PAI-1 levels were positively correlated with waist circumference in diabetic group (r = 0.4, p < 0.05). After rosiglitazone treatment, there was no difference in mean plasma levels of GFC, t-PA, PAI-1 and t-PA/PAI-1 in diabetics. Insulin sensitivity significantly improved after the addition of rosiglitazone treatment in diabetic patients (p < 0.01). The short-term and low-dose treatment with rosiglitazone in type 2 diabetic patients has no effects on the fibrinolytic system, although it improves insulin sensitivity.
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Affiliation(s)
- Sibel Guldiken
- Division of Endocrinology, Trakya University School of Medicine, Edirne, Turkey
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Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes. Bioorg Med Chem Lett 2016; 26:2947-2951. [DOI: 10.1016/j.bmcl.2016.04.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 04/05/2016] [Accepted: 04/07/2016] [Indexed: 12/11/2022]
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Padmanabhan V, Veiga-Lopez A, Herkimer C, Abi Salloum B, Moeller J, Beckett E, Sreedharan R. Developmental Programming: Prenatal and Postnatal Androgen Antagonist and Insulin Sensitizer Interventions Prevent Advancement of Puberty and Improve LH Surge Dynamics in Prenatal Testosterone-Treated Sheep. Endocrinology 2015; 156:2678-92. [PMID: 25919188 PMCID: PMC4475717 DOI: 10.1210/en.2015-1235] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Prenatal T excess induces maternal hyperinsulinemia, early puberty, and reproductive/metabolic defects in the female similar to those seen in women with polycystic ovary syndrome. This study addressed the organizational/activational role of androgens and insulin in programming pubertal advancement and periovulatory LH surge defects. Treatment groups included the following: 1) control; 2) prenatal T; 3) prenatal T plus prenatal androgen antagonist, flutamide; 4) prenatal T plus prenatal insulin sensitizer, rosiglitazone; 5) prenatal T and postnatal flutamide; 6) prenatal T and postnatal rosiglitazone; and 7) prenatal T and postnatal metformin. Prenatal treatments spanned 30-90 days of gestation and postnatal treatments began at approximately 8 weeks of age and continued throughout. Blood samples were taken twice weekly, beginning at approximately 12 weeks of age to time puberty. Two-hour samples after the synchronization with prostaglandin F2α were taken for 120 hours to characterize LH surge dynamics at 7 and 19 months of age. Prenatal T females entered puberty earlier than controls, and all interventions prevented this advancement. Prenatal T reduced the percentage of animals having LH surge, and females that presented LH surge exhibited delayed timing and dampened amplitude of the LH surge. Prenatal androgen antagonist, but not other interventions, restored LH surges without normalizing the timing of the surge. Normalization of pubertal timing with prenatal/postnatal androgen antagonist and insulin sensitizer interventions suggests that pubertal advancement is programmed by androgenic actions of T involving insulin as a mediary. Restoration of LH surges by cotreatment with androgen antagonist supports androgenic programming at the organizational level.
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Affiliation(s)
| | | | - Carol Herkimer
- Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48105
| | - Bachir Abi Salloum
- Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48105
| | - Jacob Moeller
- Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48105
| | - Evan Beckett
- Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48105
| | - Rohit Sreedharan
- Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48105
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Jain MR, Giri SR, Trivedi C, Bhoi B, Rath A, Vanage G, Vyas P, Ranvir R, Patel PR. Saroglitazar, a novel PPARα/γ agonist with predominant PPARα activity, shows lipid-lowering and insulin-sensitizing effects in preclinical models. Pharmacol Res Perspect 2015; 3:e00136. [PMID: 26171220 PMCID: PMC4492752 DOI: 10.1002/prp2.136] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 02/10/2015] [Accepted: 02/12/2015] [Indexed: 01/08/2023] Open
Abstract
Saroglitazar is a novel nonthiazolidinediones (TZD) and nonfibric acid derivative designed to act as dual regulator of lipids and glucose metabolism by activating peroxisome proliferator-activated receptors (PPAR). These studies evaluate the efficacy and safety profile of Saroglitazar in preclinical in vitro and in vivo models. The EC50 values of Saroglitazar assessed in HepG2 cells using PPAR transactivation assay for hPPARα and hPPARγ were 0.65 pmol/L and 3 nmol/L, respectively. In db/db mice, 12-day treatment with Saroglitazar (0.01–3 mg/kg per day, orally) caused dose-dependent reductions in serum triglycerides (TG), free fatty acids (FFA), and glucose. The ED50 for these effects was found to be 0.05, 0.19, and 0.19 mg/kg, respectively with highly significant (91%) reduction in serum insulin and AUC-glucose following oral glucose administration (59%) at 1 mg/kg dose. Significant reduction in serum TG (upto 90%) was also observed in Zucker fa/fa rats, Swiss albino mice, and in high fat -high cholesterol (HF-HC)-fed Golden Syrian hamsters. LDL cholesterol was significantly lowered in hApoB100/hCETP double transgenic mice and HF-HC diet fed Golden Syrian Hamsters. Hyperinsulinemic-Euglycemic clamp study in Zucker fa/fa rats demonstrated potent insulin-sensitizing activity. Saroglitazar also showed a significant decrease in SBP (22 mmHg) and increase (62.1%) in serum adiponectin levels in Zucker fa/fa rats. A 90-day repeated dose comparative study in Wistar rats and marmosets confirmed efficacy (TG lowering) potential of Saroglitazar and has indicated low risk of PPAR-associated side effects in humans. Based on efficacy and safety profile, Saroglitazar appears to have good potential as novel therapeutic agent for treatment of dyslipidemia and diabetes.
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Affiliation(s)
- Mukul R Jain
- Zydus Research Centre, Cadila Healthcare Limited Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad, 382 213, Gujarat, India
| | - Suresh R Giri
- Zydus Research Centre, Cadila Healthcare Limited Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad, 382 213, Gujarat, India
| | - Chitrang Trivedi
- Zydus Research Centre, Cadila Healthcare Limited Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad, 382 213, Gujarat, India
| | - Bibhuti Bhoi
- Zydus Research Centre, Cadila Healthcare Limited Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad, 382 213, Gujarat, India
| | - Akshyaya Rath
- Zydus Research Centre, Cadila Healthcare Limited Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad, 382 213, Gujarat, India
| | - Geeta Vanage
- National Institute for Research in Reproductive Health Parel, Mumbai, India
| | - Purvi Vyas
- Zydus Research Centre, Cadila Healthcare Limited Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad, 382 213, Gujarat, India
| | - Ramchandra Ranvir
- Zydus Research Centre, Cadila Healthcare Limited Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad, 382 213, Gujarat, India
| | - Pankaj R Patel
- Zydus Research Centre, Cadila Healthcare Limited Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad, 382 213, Gujarat, India
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Valenti R, Pantoni L, Markus HS. Treatment of vascular risk factors in patients with a diagnosis of Alzheimer's disease: a systematic review. BMC Med 2014; 12:160. [PMID: 25385407 PMCID: PMC4226862 DOI: 10.1186/s12916-014-0160-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2014] [Accepted: 08/20/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Increasing evidence suggests vascular risk factors (VRF) play a role in the pathogenesis of Alzheimer's disease (AD). Epidemiological studies have found associations between VRF and risk of AD. Treating VRF in patients with AD offers a potential treatment option but ineffective treatments should be avoided in this group who are frequently on multiple medications and in whom compliance may be challenging. METHODS Studies containing information on the treatment of VRF in patients with a diagnosis of AD were identified using a defined search strategy. Randomised controlled trials and observational studies were included. RESULTS The pre-specified search strategy retrieved 11,992 abstract articles, and 25 papers including those identified on review of reference lists and reviews met the inclusion criteria. Of these, 11 were randomised controlled trials (RCTs) and 14 observational studies. Observational studies suggested that a VRF package and treatment of hypertension and statin therapy may be associated with improved outcome but these studies suffered from potential bias. The few RCTs performed were mostly small with short duration follow-up, and do not provide clear evidence either way. CONCLUSIONS Observational data raises the possibility that treating VRF could alter the rate of decline in AD. However RCT data are not yet available to support this hypothesis and to alter clinical practice. RCTs in larger numbers of individuals with longer follow-up, ideally in the early stages of AD, are required to address this potentially important treatment question.
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Affiliation(s)
| | | | - Hugh S Markus
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
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22
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Ding H, Zhang Y, Xu C, Hou D, Li J, Zhang Y, Peng W, Zen K, Zhang CY, Jiang X. Norathyriol reverses obesity- and high-fat-diet-induced insulin resistance in mice through inhibition of PTP1B. Diabetologia 2014; 57:2145-54. [PMID: 24985145 DOI: 10.1007/s00125-014-3315-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 06/06/2014] [Indexed: 12/17/2022]
Abstract
AIM/HYPOTHESIS Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signalling. PTP1B deficiency improves obesity-induced insulin resistance and consequently improves type 2 diabetes in mice. Here, the small molecule norathyriol reversed obesity- and high-fat-diet-induced insulin resistance by inhibiting PTP1B. METHODS The inhibitory mode of PTP1B was evaluated by using the double-reciprocal substrate in the presence of norathyriol. Primary cultured hepatocytes, myoblasts and white adipocytes were used to investigate the effect of norathyriol on insulin signalling. Glucose homeostasis and insulin sensitivity were characterised by glucose and insulin tolerance tests. RESULTS Norathyriol was identified as a competitive inhibitor of PTP1B, with an IC50 of 9.59 ± 0.39 μmol/l. In cultured hepatocytes and myoblasts, norathyriol treatment blocked the PTP1B-mediated dephosphorylation of the insulin receptor. Intraperitoneal injection of norathyriol inhibited liver and muscle PTP1B activity in mice, thus contributing to the improved glucose homeostasis and insulin sensitivity. However, these beneficial effects were abolished in PTP1B-deficient mice. Notably, oral administration of norathyriol protected mice from diet-induced obesity and insulin resistance through inhibition of hypothalamic PTP1B activity. CONCLUSIONS/INTERPRETATION Our results indicate that the small molecule norathyriol is a potent PTP1B inhibitor with good cell permeability and oral availability.
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Affiliation(s)
- Hanying Ding
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210093, Nanjing, Jiangsu, People's Republic of China
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Rana S, Blowers EC, Natarajan A. Small molecule adenosine 5'-monophosphate activated protein kinase (AMPK) modulators and human diseases. J Med Chem 2014; 58:2-29. [PMID: 25122135 DOI: 10.1021/jm401994c] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Adenosine 5'-monophosphate activated protein kinase (AMPK) is a master sensor of cellular energy status that plays a key role in the regulation of whole-body energy homeostasis. AMPK is a serine/threonine kinase that is activated by upstream kinases LKB1, CaMKKβ, and Tak1, among others. AMPK exists as αβγ trimeric complexes that are allosterically regulated by AMP, ADP, and ATP. Dysregulation of AMPK has been implicated in a number of metabolic diseases including type 2 diabetes mellitus and obesity. Recent studies have associated roles of AMPK with the development of cancer and neurological disorders, making it a potential therapeutic target to treat human diseases. This review focuses on the structure and function of AMPK, its role in human diseases, and its direct substrates and provides a brief synopsis of key AMPK modulators and their relevance in human diseases.
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Affiliation(s)
- Sandeep Rana
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center , Omaha, Nebraska 68198-6805, United States
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24
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Kumar V, Mundra V, Mahato RI. Nanomedicines of Hedgehog inhibitor and PPAR-γ agonist for treating liver fibrosis. Pharm Res 2013; 31:1158-69. [PMID: 24249038 DOI: 10.1007/s11095-013-1239-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Accepted: 10/20/2013] [Indexed: 01/01/2023]
Abstract
PURPOSE Hedgehog (Hh) and peroxisome proliferator-activated receptor gamma (PPAR-γ) are major signaling pathways involved in the pathogenesis of liver fibrosis. Since Hh inhibitor, vismodegib (GDC) and PPAR-γ agonist, rosiglitazone (RSG) have poor water solubility, our objective was to formulate biodegradable polymeric nanoparticles encapsulating GDC and RSG for treating liver fibrosis. METHODS Methoxy-polyethylene-glycol-b-poly(carbonate-co-lactide) [mPEG-b-p(CB-co-LA)] was synthesized and characterized using (1)H NMR. Nanoparticles were prepared using this polymer by emulsification/solvent evaporation method to encapsulate GDC and RSG either alone or in combination. Nanoparticles were characterized for particle size, drug loading, drug release, and anti-fibrotic efficacy after tail vein injection into common bile duct ligated (CBDL) fibrotic rats. RESULTS mPEG-b-p(CB-co-LA) copolymer has molecular weight of 30,000 Da as determined by (1)H NMR. Nanoparticles were monodisperse with a mean particle size of 120-130 nm. Drug loading was 5% and 2% w/w for GDC and RSG, respectively. Nanoparticles carrying both GDC and RSG were formulated at half of their individual drug loading. Systemic administration of drug loaded nanoparticles protected liver injury in CBDL rats by suppressing the activation of hepatic stellate cells, and decreasing inflammatory cytokines. CONCLUSION Polymeric nanoparticles for co-delivery of Hh inhibitor and PPAR-γ agonist have the potential to treat liver fibrosis by intervening complex fibrotic cascade.
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Affiliation(s)
- Virender Kumar
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, 38163, USA
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25
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So WY, Cheng Q, Chen L, Evans-Molina C, Xu A, Lam KS, Leung PS. High glucose represses β-klotho expression and impairs fibroblast growth factor 21 action in mouse pancreatic islets: involvement of peroxisome proliferator-activated receptor γ signaling. Diabetes 2013; 62:3751-9. [PMID: 23897951 PMCID: PMC3806592 DOI: 10.2337/db13-0645] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Circulating fibroblast growth factor 21 (FGF21) levels are elevated in diabetic subjects and correlate directly with abnormal glucose metabolism, while pharmacologically administered FGF21 can ameliorate hyperglycemia. The pancreatic islet is an FGF21 target, yet the actions of FGF21 in the islet under normal and diabetic conditions are not fully understood. This study investigated the effects of high glucose on islet FGF21 actions in a diabetic mouse model by investigating db/db mouse islet responses to exogenous FGF21, the direct effects of glucose on FGF21 signaling, and the involvement of peroxisome proliferator-activated receptor γ (PPARγ) in FGF21 pathway activation. Results showed that both adult db/db mouse islets and normal islets treated with high glucose ex vivo displayed reduced β-klotho expression, resistance to FGF21, and decreased PPARγ expression. Rosiglitazone, an antidiabetic PPARγ ligand, ameliorated these effects. Our data indicate that hyperglycemia in type 2 diabetes mellitus may lead to FGF21 resistance in pancreatic islets, probably through reduction of PPARγ expression, which provides a novel mechanism for glucose-mediated islet dysfunction.
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Affiliation(s)
- Wing Yan So
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Qianni Cheng
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Lihua Chen
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Carmella Evans-Molina
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Aimin Xu
- Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
| | - Karen S.L. Lam
- Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
| | - Po Sing Leung
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- Corresponding author: Po Sing Leung,
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Zhang Y, Wang S, Wu S, Zhu S, Dong G, Miao Z, Yao J, Zhang W, Sheng C, Wang W. Facile construction of structurally diverse thiazolidinedione-derived compounds via divergent stereoselective cascade organocatalysis and their biological exploratory studies. ACS COMBINATORIAL SCIENCE 2013; 15:298-308. [PMID: 23614347 DOI: 10.1021/co400022r] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In this article, we present a new approach by merging two powerful synthetic tactics, divergent synthesis and cascade organocatalysis, to create a divergent cascade organocatalysis strategy for the facile construction of new "privileged" substructure-based DOS (pDOS) library. As demonstrated, notably 5 distinct molecular architectures are produced facilely from readily available simple synthons thiazolidinedione and its analogues and α,β-unsaturated aldehydes in 1-3 steps with the powerful strategy. The beauty of the chemistry is highlighted by the efficient formation of structurally new and diverse products from structurally close reactants under the similar reaction conditions. Notably, structurally diverse spiro-thiazolidinediones and -rhodanines are produced from organocatalytic enantioselective 3-component Michael-Michael-aldol cascade reactions of respective thiazolidinediones and rhodanines with enals. Nevertheless, under the similar reaction conditions, reactions of isorhodanine via a Michael-cyclization cascade lead to structurally different fused thiopyranoid scaffolds. This strategy significantly minimizes time- and cost-consuming synthetic works. Furthermore, these molecules possess high structural complexity and functional, stereochemical, and skeletal diversity with similarity to natural scaffolds. In the preliminary biological studies of these molecules, compounds 4f, 8a, and 10a exhibit inhibitory activity against the human breast cancer cells, while compounds 8a, 9a, and 9b display good antifungal activities against Candida albicans and Cryptococcus neoformans. Notably, their structures are different from clinically used triazole antifungal drugs. Therefore, they could serve as good lead compounds for the development of new generation of antifungal agents.
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Affiliation(s)
- Yongqiang Zhang
- Department of Medicinal Chemistry,
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Shengzheng Wang
- Department of Medicinal Chemistry,
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Shanchao Wu
- Department of Medicinal Chemistry,
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Shiping Zhu
- Department of Medicinal Chemistry,
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Guoqiang Dong
- Department of Medicinal Chemistry,
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Zhenyuan Miao
- Department of Medicinal Chemistry,
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Jianzhong Yao
- Department of Medicinal Chemistry,
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Wannian Zhang
- Department of Medicinal Chemistry,
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Chunquan Sheng
- Department of Medicinal Chemistry,
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China
| | - Wei Wang
- Department of Chemistry and
Chemical Biology, University of New Mexico, Albuquerque, New Mexico 87131-0001, United States
- School of Pharmacy, East China University of Science and Technology, Shanghai
200237, P. R. China
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27
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Mannino GC, Sesti G. Individualized therapy for type 2 diabetes: clinical implications of pharmacogenetic data. Mol Diagn Ther 2013; 16:285-302. [PMID: 23018631 DOI: 10.1007/s40291-012-0002-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, abnormally elevated hepatic glucose production, and reduced glucose-stimulated insulin secretion. Treatment with antihyperglycemic agents is initially successful in type 2 diabetes, but it is often associated with a high secondary failure rate, and the addition of insulin is eventually necessary for many patients, in order to restore acceptable glycemic control and to reduce the risk of development and progression of disease complications. Notably, even patients who appear to have similar requirements of antidiabetic regimens show great variability in drug disposition, glycemic response, tolerability, and incidence of adverse effects during treatment. Pharmacogenomics is a promising area of investigation and involves the search for genetic polymorphisms that may explain the interindividual variability in antidiabetic therapy response. The initial positive results portend that genomic efforts will be able to shed important light on variability in pharmacologic traits. In this review, we summarize the current understanding of genetic polymorphisms that may affect the responses of subjects with T2DM to antidiabetic treatment. These genes belong to three major classes: genes involved in drug metabolism and transporters that influence pharmacokinetics (including the cytochrome P450 [CYP] superfamily, the organic anion transporting polypeptide [OATP] family, and the polyspecific organic cation transporter [OCT] family); genes encoding drug targets and receptors (including peroxisome proliferator-activated receptor gamma [PPARG], the adenosine triphosphate [ATP]-sensitive potassium channel [K(ATP)], and incretin receptors); and genes involved in the causal pathway of T2DM that are able to modify the effects of drugs (including adipokines, transcription factor 7-like 2 (T cell specific, HMG-box) [TCF7L2], insulin receptor substrate 1 [IRS1], nitric oxide synthase 1 (neuronal) adaptor protein [NOS1AP], and solute carrier family 30 (zinc transporter), member 8 [SLC30A8]). In addition to these three major classes, we also review the available evidence on novel genes (CDK5 regulatory subunit associated protein 1-like 1 [CDKAL1], insulin-like growth factor 2 mRNA binding protein 2 [IGF2BP2], potassium voltage-gated channel, KQT-like subfamily, member 1 [KCNQ1], paired box 4 [PAX4] and neuronal differentiation 1 [NEUROD1] transcription factors, ataxia telangiectasia mutated [ATM], and serine racemase [SRR]) that have recently been proposed as possible modulators of therapeutic response in subjects with T2DM.
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Affiliation(s)
- Gaia Chiara Mannino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
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28
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Kim KA, Park PW, Kim HK, Ha JM, Park JY. Effect of Quercetin on the Pharmacokinetics of Rosiglitazone, a CYP2C8 Substrate, in Healthy Subjects. J Clin Pharmacol 2013; 45:941-6. [PMID: 16027405 DOI: 10.1177/0091270005278407] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Previous in vitro studies have demonstrated that quercetin inhibits CYP2C8, but there are no available data to indicate that quercetin inhibits CYP2C8 in vivo. The effect of long-term use of quercetin on the pharmacokinetics of rosiglitazone was evaluated. After administration of quercetin or matched placebo for 3 weeks in a crossover manner, rosiglitazone 4 mg was administered, and the pharmacokinetics of rosiglitazone and N-desmethylrosiglitazone were determined. For AUCinfinity, AUClast, and Cmax, the geometric mean ratios (90% confidence interval) for (quercetin + rosiglitazone/placebo + rosiglitazone) were 0.98 (0.92, 1.05), 0.99 (0.92, 1.05), and 1.01 (0.88, 1.14), respectively. Metabolic conversion based on the AUC ratio of N-desmethylrosiglitazone/rosiglitazone in the quercetin phase (0.49 +/- 0.17) was similar to that of the placebo phase (0.47 +/- 0.14) (P = .574). Even though the acute interaction that would occur during the first few days of concurrent administration of quercetin cannot be excluded, these results indicate that long-term use of quercetin does not inhibit CYP2C8 activity, and the usage has little possibility of interacting with drugs that are metabolized by CYP2C8, including rosiglitazone.
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Affiliation(s)
- Kyoung-Ah Kim
- Department of Pharmacology, Gil Medical Center, Gachon Medical School, 1198 Kuwoldong, Namdong-gu, Incheon 405-760, Korea
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Goel A, Parihar A, Mishra P, Varshney S, Nag P, Beg M, Gaikwad A, Rath SK. Design and synthesis of novel pyranone-based insulin sensitizers exhibiting in vivo hepatoprotective activity. MEDCHEMCOMM 2013. [DOI: 10.1039/c3md00178d] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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30
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Schaalan MF. Effects of pioglitazone and/or simvastatin on circulating TNFα and adiponectin levels in insulin resistance. J Immunotoxicol 2012; 9:201-9. [DOI: 10.3109/1547691x.2012.660998] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
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Allstadt Frazier S, McKemie DS, Guerrero TA, LaChapelle H, Skorupski KA, Kass PH, Rodriguez CO. Phase I clinical trial of oral rosiglitazone in combination with intravenous carboplatin in cancer-bearing dogs. Vet Comp Oncol 2012; 12:1-9. [DOI: 10.1111/j.1476-5829.2012.00322.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Affiliation(s)
- S. Allstadt Frazier
- Veterinary Medical Teaching Hospital; University of California; Davis CA USA
- Department of Veterinary Surgical and Radiological Sciences; University of California; Davis CA USA
| | - D. S. McKemie
- Department of Molecular Biosciences; University of California; Davis CA USA
| | - T. A. Guerrero
- Department of Veterinary Surgical and Radiological Sciences; University of California; Davis CA USA
| | - H. LaChapelle
- Veterinary Medical Teaching Hospital; University of California; Davis CA USA
| | - K. A. Skorupski
- Veterinary Medical Teaching Hospital; University of California; Davis CA USA
- Department of Veterinary Surgical and Radiological Sciences; University of California; Davis CA USA
| | - P. H. Kass
- Department of Population, Health & Reproduction; University of California; Davis CA USA
| | - C. O. Rodriguez
- Veterinary Medical Teaching Hospital; University of California; Davis CA USA
- Department of Veterinary Surgical and Radiological Sciences; University of California; Davis CA USA
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Furukawa A, Arita T, Fukuzaki T, Satoh S, Mori M, Honda T, Matsui Y, Wakabayashi K, Hayashi S, Araki K, Ohsumi J. Substituents at the naphthalene C3 position of (−)-Cercosporamide derivatives significantly affect the maximal efficacy as PPARγ partial agonists. Bioorg Med Chem Lett 2012; 22:1348-51. [DOI: 10.1016/j.bmcl.2011.12.066] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2011] [Revised: 12/11/2011] [Accepted: 12/13/2011] [Indexed: 10/14/2022]
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El-Enany NM, Abdelal AA, Belal FF, Itoh YI, Nakamura MN. Development and validation of a repharsed phase- HPLC method for simultaneous determination of rosiglitazone and glimepiride in combined dosage forms and human plasma. Chem Cent J 2012; 6:9. [PMID: 22277722 PMCID: PMC3292994 DOI: 10.1186/1752-153x-6-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2011] [Accepted: 01/26/2012] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Rosiglitazone (ROZ) and glimepiride (GLM) are antidiabetic agents used in the treatment of type 2 diabetes mellitus. A survey of the literature reveals that only one spectrophotometric method has been reported for the simultaneous determination of ROS and GLM in pharmaceutical preparations. However the reported method suffers from the low sensitivity, for this reason, our target was to develop a simple sensitive HPLC method for the simultaneous determination of ROZ and GLM in their combined dosage forms and plasma. RESULTS A simple reversed phase high performance liquid chromatographic (RP-HPLC) method was developed and validated for the simultaneous determination of Rosiglitazone (ROS) and Glimepiride (GLM) in combined dosage forms and human plasma. The separation was achieved using a 150 mm × 4.6 mm i.d., 5 μm particle size Symmetry® C18 column. Mobile phase containing a mixture of acetonitrile and 0.02 M phosphate buffer of pH 5 (60: 40, V/V) was pumped at a flow rate of 1 mL/min. UV detection was performed at 235 nm using nicardipine as an internal standard. The method was validated for accuracy, precision, specificity, linearity, and sensitivity. The developed and validated method was successfully used for quantitative analysis of Avandaryl™ tablets. The chromatographic analysis time was approximately 7 min per sample with complete resolution of ROS (tR = 3.7 min.), GLM (tR = 4.66 min.), and nicardipine (tR, 6.37 min). Validation studieswas performed according to ICH Guidelines revealed that the proposed method is specific, rapid, reliable and reproducible. The calibration plots were linear over the concentration ranges 0.10-25 μg/mL and 0.125-12.5 μg/mL with LOD of 0.04 μg/mL for both compounds and limits of quantification 0.13 and 0.11 μg/mL for ROS and GLM respectively. CONCLUSION The suggested method was successfully applied for the simultaneous analysis of the studied drugs in their co-formulated tablets and human plasma. The mean percentage recoveries in Avandaryl™ tablets were 100.88 ± 1.14 and 100.31 ± 1.93 for ROS and GLM respectively. Statistical comparison of the results with those of the reference method revealed good agreement and proved that there were no significant difference in the accuracy and precision between the two methods respectively. The interference likely to be introduced from some co-administered drugs such as glibenclamide, gliclazide, metformine, pioglitazone and nateglinide was investigated.
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Affiliation(s)
- Nahed M El-Enany
- Department of Analytical Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, 35516, Egypt.
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Nishihara M, Sudo M, Kamiguchi H, Kawaguchi N, Maeshiba Y, Kiyota Y, Takahashi J, Tagawa Y, Kondo T, Asahi S. Metabolic Fate of Sipoglitazar a Novel Oral PPAR Agonist with Activities for PPAR-γ, -α and -δ, in Rats and Monkeys and Comparison with Humans In Vitro. Drug Metab Pharmacokinet 2012; 27:223-31. [DOI: 10.2133/dmpk.dmpk-11-rg-061] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Avogaro A, Federici M, Betteridge J, Bonadonna R, Campbell IW, Schernthaner GH, Staels B, Farinaro E, Crepaldi G. Which is the eligible patient to be treated with pioglitazone? The expert view. J Endocrinol Invest 2011; 34:781-7. [PMID: 22234178 DOI: 10.1007/bf03346725] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Pioglitazone has an important role in the treatment of patients with Type 2 diabetes. The drug can help patients to achieve sustained glycemic control and may delay the requirement for insulin. Pioglitazone may provide benefits beyond its effects on glycemia, with data suggesting it may confer anti-atherosclerotic and cardioprotective properties. Attention should be given to possible side effects relating to class effects of TZD, and selection of appropriate patients to be prescribed pioglitazone will enable optimum benefits to be derived from pioglitazone treatment.
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Affiliation(s)
- A Avogaro
- Department of Clinical and Experimental Medicine, University of Padua, Via Giustiniani 2, 35128 Padua, Italy.
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Common binding requirements of PPAR-α/δ/γ pan agonists: quantitative structure–activity relationship analysis of indanylacetic acid derivatives carrying 4-thiazolyl-phenoxy tail group. Med Chem Res 2011. [DOI: 10.1007/s00044-011-9599-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Frazier SA, McKemie DS, Guerrero TA, Skorupski KA, Rodriguez CO. Evaluation of an extractionless high-performance liquid chromatography-tandem mass spectrometry method for detection and quantitation of rosiglitazone in canine plasma. Am J Vet Res 2011; 72:263-70. [PMID: 21281203 DOI: 10.2460/ajvr.72.2.263] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To develop a simple extractionless method for detection of rosiglitazone in canine plasma and test the method in a pharmacokinetic study after oral administration of rosiglitazone in dogs. ANIMALS 3 client-owned dogs with cancer. PROCEDURES High-performance liquid chromatography-tandem mass spectrometry was performed on canine plasma. The 3 dogs with cancer in the pharmacokinetic study were assessed via physical examination and clinicopathologic evaluation and considered otherwise healthy. Food was withheld for 12 hours, and dogs were administered a single dose (4 mg/m²) of rosiglitazone. Plasma was collected at various times, processed, and analyzed for rosiglitazone. RESULTS The developed method was robust and detected a minimum of 0.3 ng of rosiglitazone/mL. Mean ± SD maximum plasma concentration was 205.2 ± 79.1 ng/mL, which occurred at 3 ± 1 hours, and mean ± SD elimination half-life was 1.4 ± 0.4 hours. The area under the plasma rosiglitazone concentration-versus-time curve varied widely among the 3 dogs (mean ± SD, 652.2 ± 351.3 ng/h/mL). CONCLUSIONS AND CLINICAL RELEVANCE A simple extractionless method for detection of rosiglitazone in canine plasma was developed and was validated with excellent sensitivity, accuracy, precision, and recovery. The method enabled unambiguous evaluation and quantitation of rosiglitazone in canine plasma. This method will be useful for pharmacokinetic, bioavailability, or drug-drug interaction studies. Oral rosiglitazone administration was well tolerated in the dogs.
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Affiliation(s)
- Sara Allstadt Frazier
- Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, USA
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Wang L, Munsick C, Chen S, Bonacorsi S, Cheng PT, Humphreys WG, Zhang D. Metabolism and disposition of 14C-labeled peliglitazar in humans. Drug Metab Dispos 2011; 39:228-38. [PMID: 20978103 DOI: 10.1124/dmd.110.035089] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
The metabolism and disposition of dual (14)C-labeled peliglitazar, a dual α/γ peroxisome proliferator-activated receptor activator, was investigated in 10 healthy male subjects with and without bile collection (groups 1 and 2) after a single 10-mg oral dose. Serial blood samples, urine, and feces (0-240 h) as well as bile samples (3-8 h after dosing from group 2 subjects) were collected. The maximum plasma concentration (C(max)) of drug was reached at approximately 1 h and the elimination half-life (t(1/2)) was approximately 3.5 h. The exposure to drug metabolites (C(max) and area under the plasma concentration versus time curve) was not significantly different between the two groups. The parent compound and its 1-O-β-acyl-glucuronide conjugate were the major components in plasma; other circulating metabolites, including several other glucuronide conjugates, were minor components at all time points. The major portion of the radioactive dose was recovered in feces (94% for group 1 and 32% for group 2). Approximately 24% of the radioactive dose was recovered in the bile from group 2 subjects, nearly all of which was assigned as glucuronides of peliglitazar and its oxidative metabolites (M14, M14a, M14b, M15, M15a, M15b, and M17). In contrast, fecal samples contained peliglitazar and its oxidative metabolites resulting from aliphatic/aryl hydroxylation, and O-demethylation. These results suggested that the major clearance pathway of peliglitazar was through biliary elimination of glucuronide conjugates, which were hydrolyzed to peliglitazar and its oxidative metabolites in the intestines before excretion.
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Affiliation(s)
- Lifei Wang
- Pharmaceutical Candidate Optimization, Discovery and Development, Bristol-Myers Squibb, Princeton, NJ 08543-4000, USA.
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Ushiroda K, Maruta K, Kitoh M, Iwai K, Nagamine J, Tsuchida A, Taiji M, Nagata R. Development of a new class of benzoylpyrrole-based PPARα/γ activators. Bioorg Med Chem Lett 2011; 21:220-4. [PMID: 21130649 DOI: 10.1016/j.bmcl.2010.11.032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Revised: 11/02/2010] [Accepted: 11/04/2010] [Indexed: 12/14/2022]
Abstract
Starting with a subtle blood glucose-lowering effect of a TGF-β inhibitor, we designed and synthesized a series of benzoylpyrrole-based carboxylic acids as PPARs activators. Among these compounds, 10sNa exhibited favorable blood glucose-lowering effect without body weight gain. We assume that the beneficial effect of 10sNa is attributed to not only its compound PPARα agonistic activity but also its PPARγ partial agonistic activity.
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Affiliation(s)
- Kantaro Ushiroda
- Dainippon Sumitomo Pharma Co, Ltd, Drug Research Division, Chemistry Research Laboratories, Osaka, Japan
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Gold M, Alderton C, Zvartau-Hind M, Egginton S, Saunders AM, Irizarry M, Craft S, Landreth G, Linnamägi Ü, Sawchak S. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord 2010; 30:131-46. [PMID: 20733306 PMCID: PMC3214882 DOI: 10.1159/000318845] [Citation(s) in RCA: 264] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/21/2010] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND/AIMS A phase II study of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone extended release (RSG XR) in mild-to-moderate Alzheimer's disease (AD) detected a treatment benefit to cognition in apolipoprotein E(APOE)-ε4-negative subjects. The current phase III study with prospective stratification by APOE genotype was conducted to confirm the efficacy and safety of RSG XR in mild-to-moderate AD. An open-label extension study assessed the long-term safety and tolerability of 8 mg RSG XR. METHODS This double-blind, randomized, placebo-controlled study enrolled 693 subjects. Within 2 APOE allelic strata (ε4-positive, ε4-negative), subjects were randomized (2:2:2:1) to once-daily placebo, 2 mg RSG XR, 8 mg RSG XR or 10 mg donepezil (control). Coprimary endpoints were change from baseline to week 24 in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) score, and week 24 Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+). RESULTS At week 24, no significant differences from placebo in change from baseline in coprimary endpoints were detected with either the RSG XR dose in APOE-ε4-negative subjects or overall. For donepezil, no significant treatment difference was detected in ADAS-Cog; however, a significant difference was detected (p = 0.009) on the CIBIC+. Peripheral edema was the most common adverse event for 8 mg RSG XR (15%) and placebo (5%), and nasopharyngitis for 2 mg RSG XR (7%). CONCLUSION No evidence of efficacy of 2 mg or 8 mg RSG XR monotherapy in cognition or global function was detected in the APOE-ε4-negative or other analysis populations. The safety and tolerability of RSG XR was consistent with its known pharmacology.
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Affiliation(s)
- Michael Gold
- Neurosciences Medicines Development Center, GlaxoSmithKline, Stockley Park, Harlow, UK.
| | - Claire Alderton
- Neurosciences Medicines Development Center, GlaxoSmithKline, Stockley Park, UK
| | - Marina Zvartau-Hind
- Neurosciences Medicines Development Center, GlaxoSmithKline, Stockley Park, UK
| | - Sally Egginton
- Neurosciences Medicines Development Center, GlaxoSmithKline, Harlow, UK
| | - Ann M. Saunders
- Deane Drug Discovery Institute, Division of Neurology, Duke University Medical Center, Durham, N.C., USA
| | - Michael Irizarry
- Neurosciences Medicines Development Center, GlaxoSmithKline, Research Triangle Park, N.C., USA
| | - Suzanne Craft
- Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System and Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Wash., USA
| | - Gary Landreth
- Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Ülla Linnamägi
- Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia
| | - Sharon Sawchak
- Neurosciences Medicines Development Center, GlaxoSmithKline, Research Triangle Park, N.C., USA
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Calixto LA, Bonato PS. Simultaneous determination of rosiglitazone and its metabolites in rat liver microsomal fraction using hollow-fiber liquid-phase microextraction for sample preparation. J Sep Sci 2010; 33:2872-80. [DOI: 10.1002/jssc.201000380] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Gamboa J, Blankenship DA, Niemi JP, Landreth GE, Karl M, Hilow E, Sundararajan S. Extension of the neuroprotective time window for thiazolidinediones in ischemic stroke is dependent on time of reperfusion. Neuroscience 2010; 170:846-57. [PMID: 20691766 DOI: 10.1016/j.neuroscience.2010.07.063] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2009] [Revised: 07/19/2010] [Accepted: 07/30/2010] [Indexed: 12/23/2022]
Abstract
Stroke is a leading cause of death and disability but has limited therapeutic options. Thiazolidinediones (TZDs), agonists for the nuclear receptor, peroxisome proliferator-activated receptor (PPAR)γ, reduce infarct volume and improve neurologic function following transient middle cerebral artery occlusion (MCAO) in rats. Translation of these findings into clinical therapy will require careful assessment of dosing paradigms and effective time windows for treatment. Understanding the mechanisms by which TZDs protect the brain provides insight into how time windows for neuroprotection might be extended. We find that two TZDs, pioglitazone and rosiglitazone, significantly reduce infarct volume at doses similar to those used clinically (1 mg/kg for pioglitazone and 0.1 mg/kg for rosiglitazone). We also find that pioglitazone reduces infarction volume in a transient, but not a permanent MCAO model suggesting that reperfusion plays an important role in TZD mediated neuroprotection. Since PPARγ agonists reduce inflammation and oxidative stress, both of which are exacerbated by reperfusion, we hypothesized that TZDs would be most effective if administered prior to reperfusion. We administered TZDs 3 h after MCAO and found that infarction volume and neurologic function are significantly improved in animals reperfused at 3 h and 15 min (after TZD treatment), but not in animals reperfused at 2 h (before TZD treatment) when assessed either 24 h or 3 weeks after MCAO. While TZDs reduce intercellular adhesion molecule (ICAM) expression to a similar extent regardless of the time of reperfusion, leukocyte entry into brain parenchyma is more dramatically reduced when reperfusion is delayed until after drug treatment. The finding that delaying reperfusion until after TZD treatment is beneficial despite a longer period of ischemia, is dramatic given the widely held view that duration of ischemia is the most important determinate of injury.
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Affiliation(s)
- J Gamboa
- Department of Clinical Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
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Paliwal S, Yadav D, Yadav R, Paliwal S. In silico structure-based drug design approach to develop novel pharmacophore model of human peroxisome proliferator-activated receptor γ agonists. Med Chem Res 2010. [DOI: 10.1007/s00044-010-9370-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Spectrofluorimetric and spectrophotometric determination of rosiglitazone maleate in pharmaceutical preparations and biological fluids. Pharm Chem J 2010. [DOI: 10.1007/s11094-010-0383-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Choi J, Ko Y, Lee HS, Park YS, Yang Y, Yoon S. Identification of (β-carboxyethyl)-rhodanine derivatives exhibiting peroxisome proliferator-activated receptor γ activity. Eur J Med Chem 2010; 45:193-202. [DOI: 10.1016/j.ejmech.2009.09.042] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2009] [Revised: 09/22/2009] [Accepted: 09/24/2009] [Indexed: 11/29/2022]
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Önal A. Spectrophotometric and HPLC determinations of anti-diabetic drugs, rosiglitazone maleate and metformin hydrochloride, in pure form and in pharmaceutical preparations. Eur J Med Chem 2009; 44:4998-5005. [DOI: 10.1016/j.ejmech.2009.09.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2009] [Revised: 08/12/2009] [Accepted: 09/01/2009] [Indexed: 10/20/2022]
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Simultaneous quantification of rosiglitazone and its two major metabolites, N-desmethyl and p-hydroxy rosiglitazone in human plasma by liquid chromatography/tandem mass spectrometry: Application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877:1951-6. [DOI: 10.1016/j.jchromb.2009.05.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2009] [Revised: 04/17/2009] [Accepted: 05/01/2009] [Indexed: 11/20/2022]
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Kumar A, Maurya RA, Sharma S, Ahmad P, Singh A, Tamrakar A, Srivastava AK. Design and synthesis of 3,5-diarylisoxazole derivatives as novel class of anti-hyperglycemic and lipid lowering agents. Bioorg Med Chem 2009; 17:5285-92. [DOI: 10.1016/j.bmc.2009.05.033] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2009] [Revised: 05/12/2009] [Accepted: 05/13/2009] [Indexed: 11/16/2022]
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Acton JJ, Akiyama TE, Chang CH, Colwell L, Debenham S, Doebber T, Einstein M, Liu K, McCann ME, Moller DE, Muise ES, Tan Y, Thompson JR, Wong KK, Wu M, Xu L, Meinke PT, Berger JP, Wood HB. Discovery of (2R)-2-(3-{3-[(4-Methoxyphenyl)carbonyl]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl}phenoxy)butanoic Acid (MK-0533): A Novel Selective Peroxisome Proliferator-Activated Receptor γ Modulator for the Treatment of Type 2 Diabetes Mellitus with a Reduced Potential to Increase Plasma and Extracellular Fluid Volume. J Med Chem 2009; 52:3846-54. [DOI: 10.1021/jm900097m] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- John J. Acton
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Taro E. Akiyama
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Ching H. Chang
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Lawrence Colwell
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Sheryl Debenham
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Thomas Doebber
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Monica Einstein
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Kun Liu
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Margaret E. McCann
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - David E. Moller
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Eric S. Muise
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Yugen Tan
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - John R. Thompson
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Kenny K. Wong
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Margaret Wu
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Libo Xu
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Peter T. Meinke
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Joel P. Berger
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
| | - Harold B. Wood
- Merck Research Laboratories, Merck & Co., Inc., RY800-C114, P.O. Box 2000, Rahway, New Jersey 07065
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Schaalan M, El-Abhar HS, Barakat M, El-Denshary ES. Westernized-like-diet-fed rats: effect on glucose homeostasis, lipid profile, and adipocyte hormones and their modulation by rosiglitazone and glimepiride. J Diabetes Complications 2009; 23:199-208. [PMID: 18407527 DOI: 10.1016/j.jdiacomp.2008.02.003] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2007] [Revised: 01/20/2008] [Accepted: 02/09/2008] [Indexed: 01/11/2023]
Abstract
Wersternized diet, containing high fat diet intake combined with high consumption of softdrinks, is accused with the emerge of modern epidemic obesity and diabesity. Therefore, we aimed to study the effect of this diet combination on the homeostasis of glucose, lipids, and some adipohormones in rats and to simulate the metabolic perturbations induced by the unhealthy Westernized diet intake, leading to the development of type 2 diabetes. To achieve this, we divided male Wistar rats (80-120 g) into two main groups: the first was fed commercial normal fat diet and the second received an in-house-prepared high-fat diet (HFD), combined with fructose in drinking water for a period of 6 weeks, followed by a subdiabetogenic dose of streptozotocin (STZ) (35 mg/kg) to produce frank hyperglycemia. The effect of this diet alone or after 2 weeks of treatment with rosiglitazone or glimepiride on glucose homeostasis, lipid profile, and levels of resistin and leptin was studied. The HFD/fructose/STZ diet elevated fasting plasma glucose, fructosamine, insulin, and homeostasis model assessment (HOMA) index, as well as serum triglycerides (TGs), total cholesterol (TC), and low-density lipoprotein cholesterol, with a decrease in high-density lipoprotein cholesterol. Hepatic TG and TC levels, as well as serum activities of aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH), were increased, suggesting a diet-induced hepatic steatosis, beside the increased levels of serum resistin and leptin. Rosiglitazone corrected the altered parameters measured, except for liver TGs; similarly, glimepiride reinstated the inverted parameters but raised insulin level and, consequently, the HOMA index. These results show that this diet could be used to induce an effect that mimics human type 2 diabetes with its metabolic disturbances and is suitable for screening the antidiabetic agents used for management of this disease.
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Affiliation(s)
- Mona Schaalan
- Biochemistry Department, Faculty of Pharmacy, Misr International University (MIU), Cairo, Egypt.
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