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1.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498245

RESUMO

Cannabinoids have shown to exert their therapeutic actions through a variety of targets. These include not only the canonical cannabinoid receptors CB1R and CB2R but also related orphan G protein-coupled receptors (GPCRs), ligand-gated ion channels, transient receptor potential (TRP) channels, metabolic enzymes, and nuclear receptors. In this review, we aim to summarize reported compounds exhibiting their therapeutic effects upon the modulation of CB1R and/or CB2R and the nuclear peroxisome proliferator-activated receptors (PPARs). Concomitant actions at CBRs and PPARα or PPARγ subtypes have shown to mediate antiobesity, analgesic, antitumoral, or neuroprotective properties of a variety of phytogenic, endogenous, and synthetic cannabinoids. The relevance of this multitargeting mechanism of action has been analyzed in the context of diverse pathologies. Synergistic effects triggered by combinatorial treatment with ligands that modulate the aforementioned targets have also been considered. This literature overview provides structural and pharmacological insights for the further development of dual cannabinoids for specific disorders.


Assuntos
Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores de Canabinoides/metabolismo , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Animais , Moduladores de Receptores de Canabinoides/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/antagonistas & inibidores
2.
Expert Opin Pharmacother ; 21(8): 953-967, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32237916

RESUMO

INTRODUCTION: There is an unmet medical need for an effective anti-fibrotic treatment for NASH with advanced fibrosis. AREAS COVERED: The authors review the current and novel agents for the treatment of NASH with fibrosis. They also consider the potential future strategies of combination therapies. EXPERT OPINION: Farnesoid X receptor (FXR) agonist (obeticholic acid [OCA]) significantly ameliorated hepatic fibrosis in NASH stage 2/3 fibrosis in an interim analysis of phase 3 trial. Because OCA has several drawbacks such as itching and elevated low-density lipoprotein-cholesterol (LDL-C), non-bile acid FXR agonists are now under development. Selonsertib (apoptosis signaling kinase 1 inhibitor), emricasan (an irreversible pan-caspase inhibitor), and simtsuzumab (a monoclonal antibody against lysyl oxidase-like 2) were discontinued because of no efficacy over placebo. Peroxisome proliferator-activator receptor α/δ agonists, C-C motif chemokine receptor-2/5 antagonists, and thyroid ß receptor agonist are ongoing in phase 3 trials. A variety of agents including fibroblast growth factor (FGF)-21 and FGF-19 agonists, as well as acetyl-CoA carboxylase inhibitors, are also expected. Among antidiabetic agents, semaglutide, a novel GLP-1 RA, is ongoing for NASH stage 1-3 fibrosis in a phase 2 trial. Furthermore, the combination of GLP-RA/glucagon receptor agonist and GLP-RA/gastrointestinal peptide agonist are promising future options.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pioglitazona/uso terapêutico , Vitamina E/uso terapêutico , Ácido Quenodesoxicólico/administração & dosagem , Ácido Quenodesoxicólico/uso terapêutico , Ensaios Clínicos como Assunto , Fatores de Crescimento de Fibroblastos/agonistas , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Pioglitazona/administração & dosagem , Receptores Citoplasmáticos e Nucleares/agonistas , Resultado do Tratamento , Vitamina E/administração & dosagem
3.
Biochim Biophys Acta Mol Basis Dis ; 1866(6): 165727, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32070771

RESUMO

Mitochondrial complex I (CI), the first multiprotein enzyme complex of the OXPHOS system, executes a major role in cellular ATP generation. Consequently, dysfunction of this complex has been linked to inherited metabolic disorders, including Leigh disease (LD), an often fatal disease in early life. Development of clinical effective treatments for LD remains challenging due to the complex pathophysiological nature. Treatment with the peroxisome proliferation-activated receptor (PPAR) agonist bezafibrate improved disease phenotype in several mitochondrial disease mouse models mediated via enhanced mitochondrial biogenesis and fatty acid ß-oxidation. However, the therapeutic potential of this mixed PPAR (α, δ/ß, γ) agonist is severely hampered by hepatotoxicity, which is possibly caused by activation of PPARγ. Here, we aimed to investigate the effects of the PPARα-specific fibrate clofibrate in mitochondrial CI-deficient (Ndufs4-/-) mice. Clofibrate increased lifespan and motor function of Ndufs4-/- mice, while only marginal hepatotoxic effects were observed. Due to the complex clinical and cellular phenotype of CI-deficiency, we also aimed to investigate the therapeutic potential of clofibrate combined with the redox modulator KH176. As described previously, single treatment with KH176 was beneficial, however, combining clofibrate with KH176 did not result in an additive effect on disease phenotype in Ndufs4-/- mice. Overall, both drugs have promising, but independent and nonadditive, properties for the pharmacological treatment of CI-deficiency-related mitochondrial diseases.


Assuntos
Cromanos/farmacologia , Clofibrato/farmacologia , Complexo I de Transporte de Elétrons/deficiência , Longevidade/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Bezafibrato/farmacologia , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Ácidos Graxos/metabolismo , Humanos , Doença de Leigh/tratamento farmacológico , Doença de Leigh/metabolismo , Doença de Leigh/patologia , Camundongos , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Atividade Motora/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/genética
4.
Lancet Gastroenterol Hepatol ; 5(3): 306-315, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31806572

RESUMO

Up to 40% of patients with primary biliary cholangitis have an incomplete response to first-line treatment with ursodeoxycholic acid. Obeticholic acid was approved by the US Food and Drug Administration in 2016 as a second-line treatment for patients with primary biliary cholangitis who are unresponsive to ursodeoxycholic acid; however, approximately 50% of patients might need additional treatments to reach therapeutic goals. A considerable need exists for effective treatment options to prevent progression to liver transplantation or death in these patients. Drugs that might modulate immunological abnormalities in primary biliary cholangitis have been studied but their effectiveness varies. Budesonide, ciclosporin, and rituximab have shown potential in modifying the disease process. Bezafibrate, a pan-peroxisome proliferator-activated receptor agonist, has been shown to ameliorate deranged bile acid homoeostasis and attenuate raised concentrations of liver enzymes associated with primary biliary cholangitis. As the mechanisms underlying the pathogenesis and progression of primary biliary cholangitis are further clarified, specific targeted therapies are under development with promising early results. Various therapeutic target bile acid homeostasis, immune dysfunction, and fibrogenetic pathways are being studied. A better understanding of the biochemical and clinical effects of the therapies in development bear discussion, both to guide the discovery of new therapies and to inform clinicians so that rational treatment regimens can be tailored to patients once they become available.


Assuntos
Homeostase/efeitos dos fármacos , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/tratamento farmacológico , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Bezafibrato/farmacologia , Bezafibrato/uso terapêutico , Ácidos e Sais Biliares/fisiologia , Budesonida/farmacologia , Budesonida/uso terapêutico , Estudos de Casos e Controles , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/química , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/uso terapêutico , Colagogos e Coleréticos/química , Colagogos e Coleréticos/farmacologia , Colagogos e Coleréticos/uso terapêutico , Ensaios Clínicos como Assunto , Ciclosporina/farmacologia , Ciclosporina/uso terapêutico , Progressão da Doença , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Isoxazóis/farmacologia , Isoxazóis/uso terapêutico , Cirrose Hepática Biliar/metabolismo , Cirrose Hepática Biliar/fisiopatologia , Transplante de Fígado/estatística & dados numéricos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Citoplasmáticos e Nucleares/agonistas , Rituximab/farmacologia , Rituximab/uso terapêutico , Resultado do Tratamento , Estados Unidos/epidemiologia , United States Food and Drug Administration/organização & administração , Ácido Ursodesoxicólico/química , Ácido Ursodesoxicólico/farmacologia , Ácido Ursodesoxicólico/uso terapêutico
5.
Nat Rev Gastroenterol Hepatol ; 17(2): 93-110, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31819247

RESUMO

Primary biliary cholangitis is a chronic, seropositive and female-predominant inflammatory and cholestatic liver disease, which has a variable rate of progression towards biliary cirrhosis. Substantial progress has been made in patient risk stratification with the goal of personalized care, including early adoption of next-generation therapy with licensed use of obeticholic acid or off-label fibrate derivatives for those with insufficient benefit from ursodeoxycholic acid, the current first-line drug. The disease biology spans genetic risk, epigenetic changes, dysregulated mucosal immunity and altered biliary epithelial cell function, all of which interact and arise in the context of ill-defined environmental triggers. A current focus of research on nuclear receptor pathway modulation that specifically and potently improves biliary excretion, reduces inflammation and attenuates fibrosis is redefining therapy. Patients are benefiting from pharmacological agonists of farnesoid X receptor and peroxisome proliferator-activated receptors. Immunotherapy remains a challenge, with a lack of target definition, pleiotropic immune pathways and an interplay between hepatic immune responses and cholestasis, wherein bile acid-induced inflammation and fibrosis are dominant clinically. The management of patient symptoms, particularly pruritus, is a notable goal reflected in the development of rational therapy with apical sodium-dependent bile acid transporter inhibitors.


Assuntos
Autoimunidade/imunologia , Di-Hidrolipoil-Lisina-Resíduo Acetiltransferase/imunologia , Cirrose Hepática Biliar/imunologia , Imunidade Adaptativa/imunologia , Animais , Ácidos e Sais Biliares/metabolismo , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , Antiportadores de Cloreto-Bicarbonato/genética , Colagogos e Coleréticos/uso terapêutico , Progressão da Doença , Exposição Ambiental , Epigênese Genética , Humanos , Imunidade Inata/imunologia , Cirrose Hepática , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/metabolismo , MicroRNAs/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Citoplasmáticos e Nucleares/agonistas , Simportadores/antagonistas & inibidores , Ácido Ursodesoxicólico/uso terapêutico
6.
Int J Mol Sci ; 20(24)2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31817347

RESUMO

The browning of white adipose tissue (beige adipocytes) stimulates energy expenditure. Omega-3 fatty acids have been shown to induce thermogenic action in adipocytes via G-protein coupled receptor 120 (GPR120). Atrial natriuretic peptide (ANP) is a peptide hormone that plays the role of maintaining normal blood pressure in kidneys to inhibit Na+ reuptake. Recently, ANP was found to induce adipocyte browning by binding to NPR1, an ANP receptor. However, the expression of ANP in adipocytes has not yet been studied. Therefore, in this study, we investigate the expression of ANP in beige-like adipocytes induced by docosahexaenoic acids (DHA), T3, or a PPAR agonist, rosiglitazone. First, we found that brown adipocyte-specific genes were upregulated in beige-like adipocytes. DHA promoted ANP expression in beige-like cells, whereas DHA-induced ANP expression was abolished by GPR120 knockout. ANP secretion of beige-like adipocytes was increased via PKC/ERK1/2 signaling in the GPR120 pathway. Furthermore, ANP secreted from beige-like adipocytes acted on HEK-293 cells, the recipient cells, leading to increased cGMP activity. After the NPR1 knockdown of HEK-293 cells, cGMP activity was not changed. Taken together, our findings indicate that beige-like adipocytes induce ANP secretion, which may contribute to improving obesity-associated metabolic disease.


Assuntos
Adipócitos Bege/metabolismo , Fator Natriurético Atrial/biossíntese , Ácidos Docosa-Hexaenoicos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células 3T3-L1 , Adipócitos Bege/citologia , Animais , Fator Natriurético Atrial/genética , GMP Cíclico/genética , GMP Cíclico/metabolismo , Técnicas de Inativação de Genes , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Quinase 6 Ativada por Mitógeno/genética , Proteína Quinase 6 Ativada por Mitógeno/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Receptores do Fator Natriurético Atrial/genética , Receptores do Fator Natriurético Atrial/metabolismo
7.
Cells ; 9(1)2019 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31877771

RESUMO

Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic steatohepatitis (NASH). NASH is a severe condition characterized by steatosis and concomitant liver inflammation and fibrosis, for which no drug is yet available. NAFLD is also generally conceived as the hepatic manifestation of the metabolic syndrome. Consequently, well-established drugs that are indicated for the treatment of type 2 diabetes and hyperlipidemia are thought to exert effects that alleviate the pathological features of NASH. One class of these drugs targets peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that play a regulatory role in lipid metabolism and inflammation. Therefore, PPARs are now also being investigated as potential anti-NASH druggable targets. In this paper, we review the mechanisms of action and physiological functions of PPARs and discuss the position of the different PPAR agonists in the therapeutic landscape of NASH. We particularly focus on the PPAR agonists currently under evaluation in clinical phase II and III trials. Preclinical strategies and how refinement and optimization may improve PPAR-targeted anti-NASH drug testing are also discussed. Finally, potential caveats related to PPAR agonism in anti-NASH therapy are stipulated.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Ativados por Proliferador de Peroxissomo/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Chalconas/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Desenvolvimento de Medicamentos , Fígado Gorduroso , Humanos , Hipoglicemiantes/farmacologia , Inflamação/patologia , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Fenilpropionatos/farmacologia , Pioglitazona/farmacologia , Propionatos/farmacologia , Pirróis/farmacologia
8.
Nat Commun ; 10(1): 5291, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31757939

RESUMO

Histone deacetylase 3 (Hdac3) regulates the expression of lipid metabolism genes in multiple tissues, however its role in regulating lipid metabolism in the intestinal epithelium is unknown. Here we demonstrate that intestine-specific deletion of Hdac3 (Hdac3IKO) protects mice from diet induced obesity. Intestinal epithelial cells (IECs) from Hdac3IKO mice display co-ordinate induction of genes and proteins involved in mitochondrial and peroxisomal ß-oxidation, have an increased rate of fatty acid oxidation, and undergo marked remodelling of their lipidome, particularly a reduction in long chain triglycerides. Many HDAC3-regulated fatty oxidation genes are transcriptional targets of the PPAR family of nuclear receptors, Hdac3 deletion enhances their induction by PPAR-agonists, and pharmacological HDAC3 inhibition induces their expression in enterocytes. These findings establish a central role for HDAC3 in co-ordinating PPAR-regulated lipid oxidation in the intestinal epithelium, and identify intestinal HDAC3 as a potential therapeutic target for preventing obesity and related diseases.


Assuntos
Enterócitos/metabolismo , Histona Desacetilases/genética , Metabolismo dos Lipídeos/genética , Obesidade/genética , Animais , Calorimetria , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Deleção de Genes , Regulação da Expressão Gênica , Mucosa Intestinal/metabolismo , Peroxidação de Lipídeos/genética , Lipidômica , Camundongos , Mitocôndrias/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/genética , Triglicerídeos/metabolismo
9.
Int J Mol Sci ; 20(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614690

RESUMO

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner. Pemafibrate, due to its high selectivity, is likely to replace other PPARα agonists for dyslipidemia and cardiovascular diseases. PPARγ agonist pioglitazone showed tremendous promises in many non-metabolic disorders like chronic kidney disease, depression, inflammation, and autoimmune diseases. The clinical niche of PPARß/δ agonists is less well-explored. Interestingly, dual- or pan-PPAR agonists, namely chiglitazar, saroglitazar, elafibranor, and lanifibranor, are gaining momentum with their optimistic outcomes in many diseases including type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and primary biliary cholangitis. Notably, the preclinical and clinical development for PPAR antagonists remains unacceptably deficient. We anticipate the future design of better PPAR modulators with minimal off-target effects, high selectivity, superior bioavailability, and pharmacokinetics. This will open new possibilities for PPAR ligands in medicine.


Assuntos
Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Animais , Disponibilidade Biológica , Proliferação de Células , Ensaios Clínicos como Assunto , Descoberta de Drogas , Metabolismo Energético , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ligantes
10.
J Med Chem ; 62(24): 10995-11003, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31407888

RESUMO

Over the course of the past decade, peroxisome proliferator-activated receptors (PPARs) have been identified as part of the cannabinoid signaling system: both phytocannabinoids and endocannabinoids are capable of binding and activating these nuclear receptors. Fatty acid amide hydrolase (FAAH) hydrolyzes the endocannabinoid anandamide and other N-acylethanolamines. These substances have been shown to have numerous anticancer effects, and indeed the inhibition of FAAH has multiple beneficial effects that are mediated by PPARα subtype and by PPARγ subtype, especially antiproliferation and activation of apoptosis. The substrates of FAAH are also PPAR agonists, which explains the PPAR-mediated effects of FAAH inhibitors. Much like cannabinoid ligands and FAAH inhibitors, PPARγ agonists show antiproliferative effects on cancer cells, suggesting that additive or synergistic effects may be achieved through the positive modulation of both signaling systems. In this Miniperspective, we discuss the development of novel FAAH inhibitors able to directly act as PPAR agonists and their promising utilization as leads for the discovery of highly effective anticancer compounds.


Assuntos
Amidoidrolases/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Animais , Humanos , Neoplasias/metabolismo , Neoplasias/patologia
11.
Molecules ; 24(14)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336903

RESUMO

It has been more than 36 years since peroxisome proliferator-activated receptors (PPARs) were first recognized as enhancers of peroxisome proliferation. Consequently, many studies in different fields have illustrated that PPARs are nuclear receptors that participate in nutrient and energy metabolism and regulate cellular and whole-body energy homeostasis during lipid and carbohydrate metabolism, cell growth, cancer development, and so on. With increasing challenges to human health, PPARs have attracted much attention for their ability to ameliorate metabolic syndromes. In our previous studies, we found that the complex functions of PPARs may be used as future targets in obesity and atherosclerosis treatments. Here, we review three types of PPARs that play overlapping but distinct roles in nutrient and energy metabolism during different metabolic states and in different organs. Furthermore, research has emerged showing that PPARs also play many other roles in inflammation, central nervous system-related diseases, and cancer. Increasingly, drug development has been based on the use of several selective PPARs as modulators to diminish the adverse effects of the PPAR agonists previously used in clinical practice. In conclusion, the complex roles of PPARs in metabolic networks keep these factors in the forefront of research because it is hoped that they will have potential therapeutic effects in future applications.


Assuntos
Metabolismo Energético , Nutrientes/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Animais , Humanos , Especificidade de Órgãos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais
12.
Clin Drug Investig ; 39(6): 553-563, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31037611

RESUMO

BACKGROUND AND OBJECTIVES: Chiglitazar is a novel configuration-restricted non-thiazolidinedione peroxisome proliferator-activated receptor pan-agonist currently in the Phase III clinical development stage for type 2 diabetes mellitus patients. The objective of this Phase I study was to evaluate the pharmacokinetics, safety and tolerability of single and multiple doses of chiglitazar tablets taken orally and the effect of food on its pharmacokinetics in healthy Chinese subjects. METHODS: A single-centre, open-label, randomised, two-stage Phase I study was carried out. In the first-stage study, we evaluated a single dose of 8, 16, or 32 mg, and multiple doses of 16 mg, taken once daily for 9 days. The effect of food consumption was also studied in this stage. In the second-stage study, a greater range of single doses (24, 48 or 72 mg) were further evaluated. Pharmacokinetics, safety and tolerability profiles were assessed at each study stage. RESULTS: After a single oral dose of chiglitazar, at doses ranging from 8 to 72 mg, the maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were proportionally increased (165-1599 ng/mL for the mean Cmax and 1356-12,584 ng·h/mL for the mean AUC0-t), with low inter-subject variability. There were no significant changes in the mean terminal phase half-life (t1/2), which ranged from 9.0 to 11.9 h, and the clearance and volume of distribution were similar for all evaluated doses. The results from the examination of multiple dose of 16 mg once daily for nine consecutive days showed that a steady-state condition was achieved by Day 6. There was no apparent accumulation of chiglitazar observed at Day 9, as compared with the first administration. While food increased the AUC0-t of chiglitazar by about 13%, there were no effects on other parameters, including Cmax, Tmax and t1/2. There were no serious or severe adverse events observed in the single- or multiple-dose studies. CONCLUSIONS: Chiglitazar tablets showed a good dose-dependent linear pharmacokinetic profile in the dose range of 8-72 mg. There was no accumulation after multiple daily administration of chiglitazar at a dose of 16 mg.  High-fat/calorie food increased the absorption of the drug, but there were no significant changes in exposure and other pharmacokinetic parameters. Chiglitazar was safe and well tolerated in healthy Chinese subjects at the dose levels and administration regimens evaluated.


Assuntos
Carbazóis/administração & dosagem , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Propionatos/administração & dosagem , Administração Oral , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Carbazóis/efeitos adversos , Carbazóis/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Propionatos/efeitos adversos , Propionatos/farmacocinética , Comprimidos , Adulto Jovem
13.
Eur J Med Chem ; 176: 326-342, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31112893

RESUMO

Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular disease, obesity, and diabetes. These receptors show a high degree of stereoselectivity towards several classes of drugs. This review covers the most relevant findings that have been made in the last decade and takes into consideration only those compounds in which stereochemistry led to unexpected results or peculiar interactions with the receptors. These cases are reviewed and discussed with the aim to show how enantiomeric recognition originates at the molecular level. The structural characterization by crystallographic methods and docking experiments of complexes formed by PPARs with their ligands turns out to be an essential tool to explain receptor stereoselectivity.


Assuntos
Derivados de Benzeno/química , Derivados de Benzeno/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Acetatos/química , Acetatos/metabolismo , Animais , Sítios de Ligação , Cristalografia por Raios X , Humanos , Indóis/química , Indóis/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Oxazóis/química , Oxazóis/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/antagonistas & inibidores , Receptores Ativados por Proliferador de Peroxissomo/química , Fenilpropionatos/química , Fenilpropionatos/metabolismo , Ligação Proteica , Estereoisomerismo , Relação Estrutura-Atividade , Tirosina/análogos & derivados , Tirosina/metabolismo
14.
Obes Rev ; 20(7): 1057-1069, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31111657

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. Recently, some novel compounds have been investigated for the prevention and treatment of NAFLD. Oleoylethanolamide (OEA), an endogenous PPAR-α agonist, has exhibited a plethora of pharmacological properties for the treatment of obesity and other obesity-associated metabolic complications. This systematic review was performed with a focus on the effects of OEA on the risk factors for NAFLD. PubMed, Scopus, Embase, ProQuest, and Google Scholar databases were searched up to December 2018 using relevant keywords. All articles written in English evaluating the effects of OEA on the risk factors for NAFLD were eligible for the review. The evidence reviewed in this article illustrates that OEA regulates multiple biological processes associated with NAFLD, including lipid metabolism, inflammation, oxidative stress, and energy homeostasis through different mechanisms. In summary, many beneficial effects of OEA have led to the understanding that OEA may be an effective therapeutic strategy for the management of NAFLD. Although a wide range of studies have demonstrated the most useful effects of OEA on NAFLD and the associated risk factors, further clinical trials, from both in vivo studies and in vitro experiments, are warranted to verify these outcomes.


Assuntos
Endocanabinoides/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ácidos Oleicos/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Animais , Relação Dose-Resposta a Droga , Humanos , Camundongos Endogâmicos C57BL , Fatores de Risco
15.
Eur J Med Chem ; 175: 215-233, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082765

RESUMO

α-Santonin, a sesquiterpene lactone isolated from Artemisia Santonica, possesses diverse bioactivities including antioxidant, anti-inflammation, immunosuppressive, anti-roundworm, anti-malaria, etc. However, its bioactivities are not satisfactory and need to be further optimized. Thus, many α-santonin derivatives were synthesized on the basis of rings A, B and C for the discovery of new analogues with prominent bioactivities. Herein, we reviewed and discussed the related synthetic methodologies, diverse bioactivities and structure-activity relationships (SAR) of α-santonin derivatives.


Assuntos
Santonina/química , Santonina/farmacologia , Adjuvantes Imunológicos/farmacologia , Anti-Inflamatórios/farmacologia , Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Herbicidas/farmacologia , Humanos , Inibidores de Lipoxigenase/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Plantas/efeitos dos fármacos , Santonina/síntese química , Relação Estrutura-Atividade , Trichomonas vaginalis/efeitos dos fármacos , Tripanossomicidas/farmacologia
16.
Int J Mol Sci ; 20(7)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30979019

RESUMO

Osteoclasts are the sole bone resorbing cell in the body and their over activity is key in the development of osteoporosis. Osteoclastogenesis is mediated by receptor activator of nuclear factor κB ligand (RANKL) signalling pathways. Unsaturated fatty acids (UFA) are known to inhibit osteoclastogenesis by targeting RANKL signalling. However, the mechanisms of action remain unclear. Peroxisome proliferator activated receptors (PPARs) are a family of nuclear receptors, with three known isoforms (PPAR-α, PPAR-ß/δ and PPAR-γ), that are known to bind UFAs and are expressed in osteoclasts. In this study, we aimed to determine how different families of UFAs activate PPARs and how PPAR activation influences osteoclast signalling. Human CD14+ monocytes were seeded into cluster plates with RANKL and macrophage colony stimulating factor (M-CSF) in the presence of PPAR agonists or different types of UFAs. All the PPAR agonists were shown to upregulate the activity of their respective receptors. Polyunsaturated fatty acids increased PPAR-α to a greater extent than monounsaturated fatty acids (MUFAs), which favoured PPAR-ß/δ activation. All PPAR agonists inhibited osteoclastogenesis. The activation of RANKL signalling pathways and expression of key osteoclast genes were downregulated by PPAR agonists. This study reveals that PPAR activation can inhibit osteoclastogenesis through modulation of RANKL signalling.


Assuntos
Ácidos Graxos Insaturados/metabolismo , Receptores de Lipopolissacarídeos/análise , Monócitos/citologia , Osteoclastos/citologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais , Adolescente , Adulto , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Masculino , Monócitos/metabolismo , Osteoclastos/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Ligante RANK/metabolismo , Adulto Jovem
17.
Curr Opin Gastroenterol ; 35(3): 168-176, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30844893

RESUMO

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the United States and is strongly associated to the metabolic syndrome. In this review, we will discuss the evidence behind the current recommendations on lifestyle modifications and available treatment options for NAFLD. RECENT FINDINGS: The unrelenting rise in obesity and diabetes epidemic has led to a large healthcare burden from NAFLD and it is projected to continue to grow over the next two decades. Lifestyle modification that leads to weight loss is effective at treating NAFLD, but these modifications require a multidisciplinary approach for success in the real world. Multiple pharmacologic treatment options have been studied with promising results, but none have been approved for treatment in the United States. Clinical trials are on-going to study further pharmacologic treatment alternatives. SUMMARY: NAFLD is the most common chronic liver disease in United States, and an independent risk factor for mortality. Implementation of lifestyle modifications through a multidisciplinary approach and careful selection of patients for pharmacologic interventions will be essential for successful management of NAFLD.


Assuntos
Antioxidantes/uso terapêutico , Cirurgia Bariátrica , Dieta Redutora , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Exercício Físico , Hipoglicemiantes/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/terapia , Tiazolidinedionas/uso terapêutico , Chalconas/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , Café , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Propionatos/uso terapêutico , Receptores Citoplasmáticos e Nucleares/agonistas , Sono , Ácido Ursodesoxicólico/uso terapêutico , Vitamina E/uso terapêutico
18.
Chem Pharm Bull (Tokyo) ; 67(3): 199-202, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30827999

RESUMO

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily and include three subtypes (PPARα, PPARδ, and PPARγ). They regulate gene expression in a ligand-dependent manner. PPARα plays an important role in lipid metabolism. PPARγ is involved in glucose metabolism and is a potential therapeutic target in Type 2 diabetes. PPARδ ligands are candidates for the treatment of metabolic disorders. Thus, the detection of PPAR ligands may facilitate the treatment of various diseases. In this study, to identify PPAR ligands, we engineered reporter cell lines that can be used to quantify PPARγ and PPARδ activity. We evaluated several known ligands using these reporter cell lines and confirmed that they are useful for PPAR ligand detection. Furthermore, we evaluated extracts of approximately 200 natural resources and found various extracts that enhance reporter gene activity. Finally, we identified a main alkaloid of the Evodia fruit, evodiamine, as a PPARγ activator using this screening tool. These results suggest that the established reporter cell lines may serve as a useful cell-based screening tool for finding PPAR ligands to ameliorate metabolic syndromes.


Assuntos
Síndrome Metabólica/prevenção & controle , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Linhagem Celular , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Síndrome Metabólica/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/genética , Extratos Vegetais/farmacologia
19.
J Pharmacol Exp Ther ; 369(1): 67-77, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30745416

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a very common chronic hepatic disease, with nonalcoholic steatohepatitis (NASH) as a major and severe subcategory that can lead to cirrhosis and hepatocellular carcinoma, and thereby to a high mortality rate. Currently, there has been no approved drug to treat NAFLD or NASH. The current study has presented RLA8, a novel and balanced quadruple agonist for hepatic lipid metabolism and inflammation-related peroxisome proliferator-activated receptors (PPARs)-α/γ/δ and G protein-coupled receptor 40 (GPR40), as a NASH drug candidate. The efficacy of RLA8 to treat NASH was evaluated in vivo using two mouse models induced by methionine/choline-deficient diet or by high-fat diet, respectively. RLA8 was shown to improve serum alanine aminotransferase and high-density lipoprotein cholesterol levels, reduce hepatic free fatty acid and triglyceride levels, and alleviate insulin resistance. Cytokine and lipoperoxide analysis revealed that RLA8 could reduce oxidative stress and inflammation. Histochemical and morphologic examination of mouse livers showed that RLA8 could improve pathologic changes such as steatosis, ballooning, collagen fiber, and inflammation. Polymerase chain reaction and Western blot analyses proved that RLA8 could result in PPARs and GPR40 activation, accompanied by upregulation of the 5'AMP-activated protein kinase-acetyl-CoA carboxylase pathway and inhibition of the expression of lipogenic genes and proteins, which provided more insights into its action mechanisms. In summary, RLA8 has significantly better efficacy to improve NASH-induced liver damage such as steatosis, inflammation, and fibrosis, and, consequently, it represents a new and highly promising NASH drug candidate that is worthy of further investigation and development.


Assuntos
Cirrose Hepática/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Acoplados a Proteínas-G/agonistas , Estilbenos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR alfa/agonistas , PPAR delta/agonistas , PPAR gama/agonistas , Estilbenos/uso terapêutico
20.
Curr Drug Metab ; 20(1): 15-22, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29886826

RESUMO

BACKGROUND: Diabetes, with an increased prevalence and various progressive complications, has become a significant global health challenge. The concrete mechanisms responsible for the development of diabetes still remain incompletely unknown, although substantial researches have been conducted to search for the effective therapeutic targets. This review aims to reveal the novel roles of Xenobiotic Nuclear Receptors (XNRs), including the Peroxisome Proliferator-Activated Receptor (PPAR), the Farnesoid X Receptor (FXR), the Liver X Receptor (LXR), the Pregnane X Receptor (PXR) and the Constitutive Androstane Receptor (CAR), in the development of diabetes and provide potential strategies for research and treatment of metabolic diseases. METHODS: We retrieved a large number of original data about these five XNRs and organized to focus on their recently discovered functions in diabetes and its complications. RESULTS: Increasing evidences have suggested that PPAR, FXR, LXR ,PXR and CAR are involved in the development of diabetes and its complications through different mechanisms, including the regulation of glucose and lipid metabolism, insulin and inflammation response and related others. CONCLUSION: PPAR, FXR, LXR, PXR, and CAR, as the receptors for numerous natural or synthetic compounds, may be the most effective therapeutic targets in the treatment of metabolic diseases.


Assuntos
Síndrome Metabólica/metabolismo , Síndrome Metabólica/terapia , Receptores Citoplasmáticos e Nucleares/metabolismo , Xenobióticos/metabolismo , Animais , Humanos , Receptores X do Fígado/metabolismo , Síndrome Metabólica/patologia , Terapia de Alvo Molecular , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptor de Pregnano X/metabolismo
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