- Screening for PPAR Non-Agonist Ligands Followed by Characterization of a Hit, AM-879, with Additional No-Adipogenic and cdk5-Mediated Phosphorylation Inhibition Properties. [Journal Article]
- FEFront Endocrinol (Lausanne) 2018; 9:11
- Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of a nuclear receptor superfamily and acts as a ligand-dependent transcription factor, playing key roles in maintenance of adipose...
Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of a nuclear receptor superfamily and acts as a ligand-dependent transcription factor, playing key roles in maintenance of adipose tissue and in regulation of glucose and lipid homeostasis. This receptor is the target of thiazolidinediones, a class of antidiabetic drugs, which improve insulin sensitization and regulate glycemia in type 2 diabetes. Despite the beneficial effects of drugs, such as rosiglitazone and pioglitazone, their use is associated with several side effects, including weight gain, heart failure, and liver disease, since these drugs induce full activation of the receptor. By contrast, a promising activation-independent mechanism that involves the inhibition of cyclin-dependent kinase 5 (CDK5)-mediated PPARγ phosphorylation has been related to the insulin-sensitizing effects induced by these drugs. Thus, we aimed to identify novel PPARγ ligands that do not possess agonist properties by conducting a mini-trial with 80 compounds using the sequential steps of thermal shift assay, 8-anilino-1-naphthalenesulfonic acid fluorescence quenching, and a cell-based transactivation assay. We identified two non-agonist PPARγ ligands, AM-879 and P11, and one partial-agonist, R32. Using fluorescence anisotropy, we show that AM-879 does not dissociate the NCOR corepressorin vitro, and it has only a small effect on TRAP coactivator recruitment. In cells, AM-879 could not induce adipocyte differentiation or positively regulate the expression of genes associated with adipogenesis. In addition, AM-879 inhibited CDK5-mediated phosphorylation of PPARγin vitro. Taken together, these findings supported an interaction between AM-879 and PPARγ; this interaction was identified by the analysis of the crystal structure of the PPARγ:AM-879 complex and evidenced by AM-879's mechanism of action as a putative PPARγ non-agonist with antidiabetic properties. Moreover, we present an optimized assay pipeline capable of detecting ligands that physically bind to PPARγ but do not cause its activation as a new strategy to identify ligands for this nuclear receptor.
- A guide for using experimental design in chromatographic method development: applied to the analysis of selected anti-diabetic pharmaceutical combinations. [Journal Article]
- PPharmazie 2016 Dec 01; 71(12):683-690
- A guide experimental design in chromatographic method development was described and applied successfully to the analysis of different recently approved anti-diabetic pharmaceutical combinations. Enha...
A guide experimental design in chromatographic method development was described and applied successfully to the analysis of different recently approved anti-diabetic pharmaceutical combinations. Enhancement of UHPLC analysis of alogliptin benzoate either with pioglitazone hydrochloride or with metformin hydrochloride was achieved. The optimal chromatographic conditions were not attained by trial and error that requires a large number of experiments. Alternatively, a computer program was used as a systematic optimization strategy for the design of the experiment which accurately predicts the combined effect of different factors simultaneously. Resolution between peaks was studied by the proposed fractional factorial design approach performed by the Minitab® Program using screening and optimization steps. Application of the central composite design was implemented. A Pareto chart was used to exclude the insignificant variables. Linearity ranges were found to be 0.5-40 μg ml-1, 1-20 μg ml-1 and 1-32 μg ml-1 for alogliptin benzoate, pioglitazone hydrochloride and metformin hydrochloride, respectively. The proposed method is applicable for the analysis of six pharmaceutical dosage forms namely, Nesina®, Actos®, Glucophage®, Oseni®, Kazano® and Actoplus MET® tablets.
- Metformin and pioglitazone combination therapy ameliorate polycystic ovary syndrome through AMPK/PI3K/JNK pathway. [Journal Article]
- ETExp Ther Med 2018; 15(2):2120-2127
- Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder, which results in health problems such as menstrual disorders, hyperandrogenism and persistent anovulation. Hyperandrogen...
Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder, which results in health problems such as menstrual disorders, hyperandrogenism and persistent anovulation. Hyperandrogenism and insulin resistance are the basic characteristics of PCOS. To investigate the combined effect of metformin and pioglitazone on POCS and the potential mechanisms, a rat model of PCOS was established by intramuscular injection of estradiol valerate (EV). The effect of metformin and pioglitazone monotherapy or combination therapy in control rats and PCOS rats was evaluated, involving the testosterone level, follicular development and insulin resistance. The potential mechanism for the therapeutic effect of metformin and pioglitazone on POCS was explored through using three inhibitors of the 5'adenosine monophosphate-activated protein kinase (AMPK)/phosphoinositide-3 kinase (PI3K)/c-Jun N-terminal kinase (JNK) pathway (Compound C, Wortmannin and SP600125). The results showed that EV-induced PCOS rats demonstrated hyperandrogenemia, hyperinsulinemia and follicular dysplasia. Metformin or pioglitazone monotherapy significantly suppressed the high level of testosterone, reduced the raised percentage of cystic follicles and primary follicles, promoted the number of early antral follicles, and markedly decreased the high concentration of fasting insulin and homeostatic model assessment for insulin resistance index in PCOS rats. In addition, metformin and pioglitazone combination therapy demonstrated greater efficacy than its individual components. Furthermore, individual or joint treatment with metformin and pioglitazone affected the phosphorylation level of JNK in PCOS rats. Compound C and Wortmannin eliminated the effect of metformin and pioglitazone combination therapy on improving the follicular growth in PCOS rats, whereas SP600125 treatment enhanced this combination therapy effect. These data suggested that metformin and pioglitazone combination therapy demonstrated great efficacy in ameliorating PCOS through regulating the AMPK/PI3K/JNK pathway.
- Impact of regulatory spin of pioglitazone on prescription of antidiabetic drugs among physicians in India: A multicentre questionnaire-based observational study. [Journal Article]
- IJIndian J Med Res 2017; 146(4):468-475
- CONCLUSIONS: Majority of the physicians though were aware of the regulatory changes with regard to pioglitazone, but their prescribing patterns were not changed for this drug. However, it was being used at lower than the recommended dose. There is a need for generating more evidence through improved pharmacovigilance activities and large-scale population-based prospective studies regarding the safety issues of pioglitazone, so as to make effectual risk-benefit analysis for its continual use in T2DM.
- A Combination of the Aerosolized PPAR-γ Agonist Pioglitazone and a Synthetic Surfactant Protein B Peptide Mimic Prevents Hyperoxia-Induced Neonatal Lung Injury in Rats. [Journal Article]
- NNeonatology 2018 Feb 09; 113(4):296-304
- CONCLUSIONS: Nebulized PPAR-γ agonist PGZ with a synthetic lung surfactant accelerates lung maturation and prevents neonatal hyperoxia-induced lung injury more than either modality alone, with the potential to provide more effective prevention of BPD.
- Combination effects of alogliptin and pioglitazone on steatosis and hepatic fibrosis formation in a mouse model of non-alcoholic steatohepatitis. [Journal Article]
- BBBiochem Biophys Res Commun 2018 Feb 09
- This study aimed to evaluate the effects of combination therapy with a dipeptidyl peptidase-4 inhibitor, alogliptin, and a peroxisome proliferator-activated receptor-γ agonist, pioglitazone, in a pre...
This study aimed to evaluate the effects of combination therapy with a dipeptidyl peptidase-4 inhibitor, alogliptin, and a peroxisome proliferator-activated receptor-γ agonist, pioglitazone, in a preclinical model of nonalcoholic steatohepatitis using low-density lipoprotein receptor-knockout mice fed a modified choline-deficient l-amino acid-defined diet. Monotherapy with either alogliptin (10-200 mg/kg) or pioglitazone (6-20 mg/kg) significantly decreased hepatic triglyceride content and fibrosis. The concomitant treatment of alogliptin (30 mg/kg), pioglitazone (20 mg/kg) also decreased hepatic triglyceride and hepatic collagen-I mRNA at greater extent compared to monotherapy. Hepatic expression of CD11b mRNA and monocyte chemoattractant protein-1 were also reduced by the concomitant treatment. These results suggest that via an anti-inflammatory potential in addition to anti-metabolic effects, the combination therapy of alogliptin and pioglitazone may provide therapeutic benefits to type 2 diabetes patients with nonalcoholic steatohepatitis, which will be proven in controlled clinical trials.
- Pleiotropic effects of hypoglycemic agents: implications in asthma and COPD. [Review]
- COCurr Opin Pharmacol 2018 Feb 07; 40:34-38
- Diabetes mellitus (DM) is a complex multifactorial disease due to the interaction between environmental noxae and genetic predisposition. Furthermore, an increased association between DM, especially ...
Diabetes mellitus (DM) is a complex multifactorial disease due to the interaction between environmental noxae and genetic predisposition. Furthermore, an increased association between DM, especially Type 2 diabetes mellitus (T2DM), and the onset of pulmonary function impairment with a bronchial hyperresponsiveness has been documented. DM is a risk factor for accelerated decline in FEV1 and the development of asthma and COPD. The increased blood glucose concentrations along with higher levels of oxidative stress and inflammation can influence the pulmonary function and, since hypoglycemic drugs can act on these different defects we can hypothesize their direct effect on obstructive pulmonary diseases. Metformin, a biguanide, is the molecule having several evidences of its action on asthma and COPD in patients with T2DM. In this population, Metformin can ameliorate pulmonary outcomes reducing high glucose concentrations, inflammation through the activation of the AMP-activated protein kinase, leading to the decreased production of pro-inflammatory cytokines and blunting allergic eosinophilic airway inflammation. There are evidences of Pioglitazone role on asthma, since the activation of PPARγ Pioglitazone might inhibit the synthesis and release of pro-inflammatory cytokines. Indeed, Pioglitazone can improve symptoms associated with asthma reducing episodes of exacerbation and oral steroid prescription. Finally, randomized clinical trials using hypoglycemic agents on patients with asthma and COPD with and without DM should be proposed as well as the implementation of a new formulation of hypoglycemic agents to make it possible to administer it via aerosol.
- Application of a Fast Separation Method for Anti-diabetics in Pharmaceuticals Using Monolithic Column: Comparative Study With Silica Based C-18 Particle Packed Column. [Journal Article]
- JCJ Chromatogr Sci 2018 Feb 07
- Run time is a predominant factor in HPLC for quality control laboratories especially if there is large number of samples have to be analyzed. Working at high flow rates cannot be attained with silica...
Run time is a predominant factor in HPLC for quality control laboratories especially if there is large number of samples have to be analyzed. Working at high flow rates cannot be attained with silica based particle packed column due to elevated backpressure issues. The use of monolithic column as an alternative to traditional C-18 column was tested for fast separation of pharmaceuticals, where the results were very competitive. The performance comparison of both columns was tested for separation of anti-diabetic combination containing Metformin, Pioglitazone and Glimepiride using Gliclazide as an internal standard. Working at high flow rates with less significant backpressure was obtained with the monolithic column where the run time was reduced from 6 min in traditional column to only 1 min in monolithic column with accepted resolution. The structure of the monolith contains many pores which can adapt the high flow rate of the mobile phase. Moreover, peak symmetry and equilibration time were more efficient with monolithic column.
- Del romanticismo y la ficción a la realidad: Dippel, Galvani, Aldini y «el moderno Prometeo». Breve historia del impulso nervioso. [Journal Article]
- GMGac Med Mex 2018; 154(1):105-110
- Mary Wollstonecraft Godwin (1797-1851), mejor conocida como Mary Shelley, con su visión romántica del mundo dio vida a una progenie interminable de historias en la literatura, y su escrito originó el...
Mary Wollstonecraft Godwin (1797-1851), mejor conocida como Mary Shelley, con su visión romántica del mundo dio vida a una progenie interminable de historias en la literatura, y su escrito originó el mito del creador mortal que da vida a partir de la ciencia. Aunque parezca sorprendente, la historia ha llegado a considerarse un mito debido a los actos fundamentados en hechos de cierta forma «verídicos» que ayudaron a su origen, como fueron el galvanismo y el estudio del potencial eléctrico en los seres vivos llevados a cabo por dos italianos: Luigi Galvani y Giovanni Aldini. De igual manera, es posible aseverar la influencia directa sobre la obra por parte del folklore europeo de la época que rodeaba al teólogo, alquimista y médico Johann Konrad Dippel, quien hábitó el Castillo Frankenstein desde su nacimiento y además desarrollo el «elixir de la vida». La similitud que existe entre la novela y la vida de los tres personajes históricos hace pensar que la autora Mary Shelley, al pertenecer a una clase socialmente agraciada y educada, tuvo conocimiento de la disputa científica por el entendimiento de la energía eléctrica. El mundo creativo de Shelley, lleno de matices góticos y románticos, demuestra influencia directa de la alquimia al hablar de la «chispa de la vida», así como de los trabajos publicados por Galvani y Aldini.
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- The peroxisome proliferator-activated receptor agonist pioglitazone and 5-lipoxygenase inhibitor zileuton have no effect on lung inflammation in healthy volunteers by positron emission tomography in a single-blind placebo-controlled cohort study. [Journal Article]
- PlosPLoS One 2018; 13(2):e0191783
- CONCLUSIONS: Endotoxin-induced lung inflammation in humans is not responsive to pioglitazone or zileuton, highlighting the challenge in translating anti-inflammatory drug efficacy results from murine models to humans.