- Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer's Disease. [Review]
- PRPPAR Res 2018; 2018:2010675
- Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidenc...
Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARγ more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARγ agonists influence various pathologies in AD with emphasis on development of novel selective PPARγ modulators.
- Managing diabetes and liver disease association. [Review]
- AJArab J Gastroenterol 2018 Nov 09
- There is strong association between liver diseases and diabetes (DM) which is higher than expected by a chance association of two very common disorders. It can be classified into three categories: Li...
There is strong association between liver diseases and diabetes (DM) which is higher than expected by a chance association of two very common disorders. It can be classified into three categories: Liver disease related to diabetes, hepatogenous diabetes (HD), and liver disease occurring coincidentally with DM. The criteria for the diagnosis of diabetes associating liver disease are the same for primary diabetes. Two hours post glucose load is a better screening test for HD. HbA1c may not be suitable for diagnosis or monitoring of diabetes associating advanced liver disease. Apart from the increased cardiovascular risk in patients with type 2 DM (T2 DM) and NAFLD, the cardiovascular and retinopathy risk is low in HD. Patients with metabolic derangement should be screened for NAFLD which in turn may predict T2 DM development. Similarly, patients with established T2 DM should also be screened for NAFLD which further contributes to diabetes worsening. Diabetes is a significant risk factor for progression of the chronic liver disease. It is associated with poor patient survival. Treatment of diabetes associating liver disease appears beneficial. Metformin, if tolerated and not contraindicated, is recommended as a first-line therapy for patients with diabetes and chronic liver disease (CLD). If the hepatic disease is severe, insulin secretagogues should be avoided because of the increased risk of hypoglycaemia. Pioglitazone may be useful in patients with fatty liver disease. DPP-4 inhibitors showed effectiveness and safety for the treatment of T2 DM in CLD patients up to those with child B stage. GLP-1 receptor agonists and SGLT-2 inhibitors exhibit positive effects on weight and are associated with minimal risk of hypoglycaemia. Insulin must be used with caution, as hypoglycaemia may be a problem. Insulin analogues are preferred in the context of hypoglycaemia Statins can be used to treat dyslipidaemia in NAFLD, also the use of angiotensin II receptor antagonist for hypertension is safe and beneficial Given the clear association between diabetes mellitus and hepatocellular carcinoma, the strict control of glycaemia with insulin sensitizers can be essential in its prevention. The addition of DM to the currently used scores (Child-Pugh and MELD scores) may enhance the sensitivity and the specificity for prediction of morbidity and mortality rates in cirrhotic patients. In the new era of directly acting antiviral agents (DAAs) for HCV treatment, it is recommended to follow up lipid profile and blood sugar levels following SVR in order to adjust doses of medications used in diabetic (SVR is associated with reduction in insulin requirements) and dyslipidaemic patients (rebound increase in the lipid profile after clearing the virus may increase risk of cardiovascular disease (CVD)). The issues of post liver transplant diabetes and relation between DM and chronic HBV are highlighted. This narrative review and Consensus-based practice guidance (under revision and criticism) are based on a formal review and analysis of the recently published world literature on the topic (Medline search up to September 2017); and the experience of the authors and independent reviewers.
- Bitter taste receptor ligand improves metabolic and reproductive functions in a murine model of PCOS. [Journal Article]
- EEndocrinology 2018 Nov 09
- Polycystic ovary syndrome (PCOS) results from functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Cultured theca cells from polycystic ovaries of women with the most commo...
Polycystic ovary syndrome (PCOS) results from functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Cultured theca cells from polycystic ovaries of women with the most common form of PCOS overexpress most androgen producing enzymes, particularly CYP450c17. This study used a murine model of PCOS induced by chronic feeding with high fat content diet that exhibits the reproductive, hyperandrogenic, and metabolic constellation of symptoms of PCOS seen in women. Oral administration of KDT501, a hops-derived bitter taste receptor (Tas2R 108) isohumulone ligand resulted in resolution of PCOS-associated endocrine and metabolic disturbances and restored reproductive function. Pioglitazone, a PPARγ agonist, also improved metabolic and reproductive function, though not to the same degree as KDT501. Specifically, treatment of the murine PCOS model with KDT 501 resulted in reduced testosterone and androstenedione in the absence of significant changes in luteinizing or follicle stimulating hormones, improved glucose tolerance, improved lipid metabolism, a reduction in hepatic lipid infiltration and a reduction in adiposity. There was a significant improvement in estrous cyclicity and an increase in the number of ovarian corpora lutea indicative of improved reproductive function after exposure to KDT 501. Finally, ex vivo exposure of murine ovaries to KDT 501 attenuated androgen production and ovarian expression of CYP450c17. Interestingly, the ovaries were found to express Tas2R 108 suggesting a potential regulation of ovarian steroidogenesis through this chemosensory receptor family. In summary, this study suggests that a therapeutic strategy for PCOS can include direct influences on ovarian steroidogenesis that are independent from gonadotrophic hormone regulation.
- Safety of pioglitazone during and after radiation therapy in patients with brain tumors: a phase I clinical trial. [Journal Article]
- JCJ Cancer Res Clin Oncol 2018 Nov 12
- CONCLUSIONS: Pioglitazone was well tolerated by brain tumor patients undergoing RT. 45 mg is a safe dose to use in future efficacy trials.
- Present and emerging pharmacotherapies for non-alcoholic steatohepatitis in adults. [Journal Article]
- EOExpert Opin Pharmacother 2018 Nov 09; :1-14
- Multiple parallel factors are implicated in the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). Currently recommended therapies for NAS...
Multiple parallel factors are implicated in the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). Currently recommended therapies for NASH include vitamin E and pioglitazone, besides dietary and lifestyle changes. Areas covered: This review focuses on the clinical development of several emerging drugs for the treatment of NASH and the impact of these drugs on current treatment standards. Expert opinion: Four drug classes (FXR agonists, CCR2/CCR5 antagonists, ASK1 inhibitors, and PPARα/δ agonists) have moved into phase 3 trials for their investigation as NASH treatments. Results from phase 2 trials of other therapeutic agents with other pharmacological actions are also expected. The importance of combinational therapies with synergistic benefits engaging different targets, is now understood. Furthermore, studies have determined that the Mediterranean diet is beneficial for patients with NAFLD, while the traditional Okinawan diet is also considered useful. In the future, it will be important to establish new biomarkers to assess NAFLD activity, furthermore non-invasive diagnostic methods will promote the development of new drugs for NASH.
- Efficacy and safety of pioglitazone plus phototherapy vs. phototherapy in patients with plaque type psoriasis: a double blinded randomized controlled trial. [Journal Article]
- JDJ Dermatolog Treat 2018 Nov 03; :1-15
- CONCLUSIONS: Pioglitazone can vastly enhance the effectiveness of phototherapy in plaque psoriasis patients without causing any important adverse effect and with no success in improving the score of DLQI.
- PPAR gamma agonist, pioglitazone, rescues liver damage induced by renal ischemia/reperfusion injury. [Journal Article]
- TAToxicol Appl Pharmacol 2018 Oct 26; 362:86-94
- Remote organ damage is the major cause of death in patients with acute kidney injury (AKI) due to renal ischemia reperfusion (IR). Liver is one of the vital organs which are profoundly affected by AK...
Remote organ damage is the major cause of death in patients with acute kidney injury (AKI) due to renal ischemia reperfusion (IR). Liver is one of the vital organs which are profoundly affected by AKI. The present study aims to investigate the role of peroxisome proliferator activator receptor gamma (PPARγ) in liver damage induced by IR injury in rats. Renal IR was induced by right nephrectomy, occlusion of left renal pedicle for 45 min to induce ischemia, and then reperfusion for 6 or 24 h. The PPARγ agonist, pioglitazone, was given orally for 7 days before renal IR procedure. Animals receiving pioglitazone showed improvement in renal and hepatic functions when compared to IR groups. Renal IR increased renal, hepatic and serum levels of tumor necrosis factor-α (TNF-α) and induced apoptotic cell death in liver. These effects were diminished with pioglitazone. In addition, pioglitazone reduced renal IR-induced oxidative stress in liver. Pioglitazone reduced malondialdehyde (MDA) content and NADPH oxidase mRNA expression and induced further increase in nuclear factor erythroid 2-related factor 2 (Nrf2) expression when compared to IR groups. Furthermore, pioglitazone increased the expression of PPARγ target genes such as renal and hepatic PPARγ1 (Pparg1), hepatic hemoxygenase-1 (Hmox1), and hepatic thioredoxin (TRx). Histological profiles for kidney and liver were also ameliorated with pioglitazone. Hence, PPARγ is a potential target to protect liver in patients with renal IR injury.
- Early life adversity blunts responses to pioglitazone in depressed, overweight adults. [Journal Article]
- EPEur Psychiatry 2018 Oct 29; 55:4-9
- CONCLUSIONS: We conclude that a history of early life adversity may impair the body's ability to respond to insulin sensitizing pharmacotherapy, and furthermore that its contribution to resistant depression may function in part via the generation of an insulin resistant phenotype.
- Safety and efficacy of low dose pioglitazone compared with standard dose pioglitazone in type 2 diabetes with chronic kidney disease: A randomized controlled trial. [Journal Article]
- PlosPLoS One 2018; 13(10):e0206722
- CONCLUSIONS: Pioglitazone 7.5 mg once daily treatments presented similar glycemic control to standard dose pioglitazone and exhibited beneficial effects on weight gain and fluid retention among patients with type 2 diabetes and CKD.
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- A systematic review of observational studies of the association between pioglitazone use and bladder cancer. [Journal Article]
- DMDiabet Med 2018 Oct 30
- CONCLUSIONS: Given existing data, it is not appropriate to pool the outcomes of highly heterogeneous studies and further rigorously conducted observational research is needed to clarify the role of pioglitazone use on the incidence of bladder cancer. This article is protected by copyright. All rights reserved.