RESUMO
The human tailless homologue receptor (TLX) is a ligand-activated transcription factor acting as a master regulator of neural stem cell homeostasis. Despite its promising potential in neurodegenerative disease treatment, TLX ligands are rare but required to explore phenotypic effects of TLX modulation and for target validation. We have systematically studied and optimized a TLX agonist scaffold obtained by fragment fusion. Structural modification enabled the development of two TLX agonists endowed with nanomolar potency and binding affinity. Both exhibited favorable chemical tool characteristics including high selectivity and low toxicity. Most notably, the TLX agonists comprise different scaffolds and display high chemical diversity, enabling their use as a set for target identification and validation studies.
Assuntos
Receptores Citoplasmáticos e Nucleares , Humanos , Relação Estrutura-Atividade , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Ligantes , Células HEK293 , Animais , Estrutura Molecular , Receptores Nucleares ÓrfãosRESUMO
The farnesoid X receptor (FXR) is a crucial therapeutic target for treating non-alcoholic steatohepatitis (NASH). Although obeticholic acid (OCA) as a FXR agonist presents good efficacy, the safety data such as severe pruritus should be carefully considered. To discover new medications, we screen and choose the optimal compounds from ZINC15 database that may agonistically interact with FXR. We utilized the DS19 software to assist us in conducting the computer-aided structure based virtual screening to discover potential FXR agonists. After LibDock scores were determined by screening, their absorption, distribution, metabolism, excretion and toxicity predictions were examined. To determine the binding affinity between the chosen drugs and FXR, molecule docking was utilized. Molecular dynamics simulation was utilized to evaluate the stabilization of the ligand-FXR complex in its native environment. Higher binding affinity and stability with FXR were observed for ZINC000013374322 and ZINC000006036327, as two novel natural compounds, with lower rodent carcinogenicity, Ames mutagenicity, no hepatotoxicity and non-inhibitors of CYP2D6. They could stably exist in the environment, possess favorable potential energy and exert pharmacological effects at lower doses. Furthermore, ZINC000006036327 had lower skin irritancy and sensitization potential compared to OCA, also suggest the possibility of improved skin itching occurrence. ZINC000013374322 and ZINC000006036327 were found to be the best leading compounds to be FXR agonists. They are chosen as safe candidates for FXR target medicine, which play comparable pharmacological effects at lower doses.
Assuntos
Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Receptores Citoplasmáticos e Nucleares , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Humanos , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/química , Ligantes , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ligação Proteica , AnimaisRESUMO
Liraglutide, a glucagon-like peptide 1 analog used to treat type 2 diabetes and obesity, is a potential new treatment modality for bile acid (BA) diarrhea. Here, we show that administration of liraglutide significantly decreased total BAs, especially the primary BAs, including cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, and ß-muricholic acid, in the liver and feces. In addition, liraglutide significantly decreased tryptophan metabolites, including L-tryptophan, serotonin, 5-hydroxy indole-3-acetic acid, L-kynurenine, and xanthurenic acid, in the colon, whereas it significantly increased indole-3-propionic acid. Moreover, the administration of liraglutide remarkably decreased the expression of apical sodium-dependent bile acid transporter, which mediates BA uptake across the apical brush border member in the ileum, ileal BA binding protein, and fibroblast growth factor 15 in association with decreased expression of the BA-activated nuclear receptor farnesoid X receptor and the heteromeric organic solute transporter Ostα/ß, which induces BA excretion, in the ileum. Liraglutide acutely decreased body weight and blood glucose levels in association with decreases in plasma insulin and serotonin levels in food-deprived mice. These findings suggest the potential of liraglutide as a novel inhibitor of primary BAs and serotonin in the colon.
Assuntos
Ácidos e Sais Biliares , Colo , Receptor do Peptídeo Semelhante ao Glucagon 1 , Liraglutida , Serotonina , Animais , Liraglutida/farmacologia , Serotonina/metabolismo , Ácidos e Sais Biliares/metabolismo , Camundongos , Colo/metabolismo , Colo/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Masculino , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Triptofano/metabolismo , Triptofano/farmacologia , Triptofano/análogos & derivados , Camundongos Endogâmicos C57BL , Íleo/metabolismo , Íleo/efeitos dos fármacos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Ácidos Cólicos , Proteínas de Membrana Transportadoras , SimportadoresRESUMO
INTRODUCTION: This proof-of-concept, open-label phase 1b study evaluated the safety and efficacy of cilofexor, a potent selective farnesoid X receptor agonist, in patients with compensated cirrhosis due to primary sclerosing cholangitis. METHODS: Escalating doses of cilofexor (30 mg [weeks 1-4], 60 mg [weeks 5-8], 100 mg [weeks 9-12]) were administered orally once daily over 12 weeks. The primary endpoint was safety. Exploratory measures included cholestasis and fibrosis markers and pharmacodynamic biomarkers of bile acid homeostasis. RESULTS: Eleven patients were enrolled (median age: 48 years; 55% men). The most common treatment-emergent adverse events (TEAEs) were pruritus (8/11 [72.7%]), fatigue, headache, nausea, and upper respiratory tract infection (2/11 [18.2%] each). Seven patients experienced a pruritus TEAE (one grade 3) considered drug-related. One patient temporarily discontinued cilofexor owing to peripheral edema. There were no deaths, serious TEAEs, or TEAEs leading to permanent discontinuation. Median changes (interquartile ranges) from baseline to week 12 (predose, fasting) were -24.8% (-35.7 to -7.4) for alanine transaminase, -13.0% (-21.9 to -8.6) for alkaline phosphatase, -43.5% (-52.1 to -30.8) for γ-glutamyl transferase, -12.7% (-25.0 to 0.0) for total bilirubin, and -21.2% (-40.0 to 0.0) for direct bilirubin. Least-squares mean percentage change (95% confidence interval) from baseline to week 12 at trough was -55.3% (-70.8 to -31.6) for C4 and -60.5% (-81.8 to -14.2) for cholic acid. Fasting fibroblast growth factor 19 levels transiently increased after cilofexor administration. DISCUSSION: Escalating doses of cilofexor over 12 weeks were well tolerated and improved cholestasis markers in patients with compensated cirrhosis due to primary sclerosing cholangitis (NCT04060147).
Assuntos
Colangite Esclerosante , Cirrose Hepática , Prurido , Humanos , Colangite Esclerosante/tratamento farmacológico , Colangite Esclerosante/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Prurido/etiologia , Prurido/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Estudo de Prova de Conceito , Resultado do Tratamento , Colestase , Fadiga/etiologia , Fadiga/diagnóstico , Fadiga/induzido quimicamente , Náusea/induzido quimicamente , Idoso , Cefaleia/induzido quimicamente , Ácidos e Sais Biliares/metabolismo , Administração OralRESUMO
AIM: Bile acids (BA) function as signalling molecules regulating glucose-lipid homeostasis and energy expenditure. However, the expression of the apical sodium-dependent bile acid transporter (ASBT) in the kidney, responsible for renal BA reabsorption, is downregulated in patients with diabetic kidney disease (DKD). Using the db/db mouse model of DKD, this study aimed to investigate the effects of rescuing ASBT expression via adeno-associated virus-mediated delivery of ASBT (AAVASBT) on kidney protection. METHODS: Six-week-old male db/db mice received an intraparenchymal injection of AAVASBT at a dose of 1 × 1011 viral genomes (vg)/animal and were subsequently fed a chow diet for 2 weeks. Male db/m mice served as controls. For drug treatment, daily intraperitoneal (i.p.) injections of the farnesoid X receptor (FXR) antagonist guggulsterone (GS, 10 mg/kg) were administered one day after initiating the experiment. RESULTS: AAVASBT treatment rescued renal ASBT expression and reduced the urinary BA output in db/db mice. AAVASBT treatment activated kidney mitochondrial biogenesis and ameliorated renal impairment associated with diabetes by activating FXR. In addition, the injection of FXR antagonist GS in DKD mice would reverse these beneficial effects by AAVASBT treatment. CONCLUSION: Our work indicated that restoring renal ASBT expression slowed the course of DKD via activating FXR. FXR activation stimulates mitochondrial biogenesis while reducing renal oxidative stress and lipid build up, indicating FXR activation's crucial role in preventing DKD. These findings further suggest that the maintenance of renal BA reabsorption could be a viable treatment for DKD.
Assuntos
Nefropatias Diabéticas , Rim , Transportadores de Ânions Orgânicos Dependentes de Sódio , Receptores Citoplasmáticos e Nucleares , Simportadores , Animais , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/etiologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Masculino , Simportadores/metabolismo , Simportadores/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Rim/metabolismo , Rim/patologia , Rim/efeitos dos fármacos , Camundongos , Ácidos e Sais Biliares/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
The diterpene cafestol represents the most potent cholesterol-elevating compound known in the human diet, being responsible for more than 80% of the effect of coffee on serum lipids, with a mechanism still not fully clarified. In the present study, the interaction of cafestol and 16-O-methylcafestol with the stabilized ligand-binding domain (LBD) of the Farnesoid X Receptor was evaluated by fluorescence and circular dichroism. Fluorescence quenching was observed with both cafestol and 16-O-methylcafestol due to an interaction occurring in the close environment of the tryptophan W454 residue of the protein, as confirmed by docking and molecular dynamics. A conformational change of the protein was also observed by circular dichroism, particularly for cafestol. These results provide evidence at the molecular level of the interactions of FXR with the coffee diterpenes, confirming that cafestol can act as an agonist of FXR, causing an enhancement of the cholesterol level in blood serum.
Assuntos
Colesterol , Café , Diterpenos , Receptores Citoplasmáticos e Nucleares , Diterpenos/farmacologia , Diterpenos/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Colesterol/metabolismo , Humanos , Café/química , Simulação de Acoplamento Molecular , Ligação Proteica , Simulação de Dinâmica Molecular , Dicroísmo CircularRESUMO
Nuclear receptors (NRs) regulate transcription in response to ligand binding and NR modulation allows pharmacological control of gene expression. Although some NRs are relevant as drug targets, the NR1 family, which comprises 19 NRs binding to hormones, vitamins, and lipid metabolites, has only been partially explored from a translational perspective. To enable systematic target identification and validation for this protein family in phenotypic settings, we present an NR1 chemogenomic (CG) compound set optimized for complementary activity/selectivity profiles and chemical diversity. Based on broad profiling of candidates for specificity, toxicity, and off-target liabilities, sixty-nine comprehensively annotated NR1 agonists, antagonists and inverse agonists covering all members of the NR1 family and meeting potency and selectivity standards are included in the final NR1 CG set. Proof-of-concept application of this set reveals effects of NR1 members in autophagy, neuroinflammation and cancer cell death, and confirms the suitability of the set for target identification and validation.
Assuntos
Autofagia , Humanos , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Ligantes , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/agonistas , Camundongos , Células HEK293 , Genômica/métodos , Linhagem Celular TumoralRESUMO
Farnesoid X receptor (FXR) was identified as an orphan nuclear receptor resembling the steroid receptor in the late '90s. Activation of FXR is a crucial step in many physiological functions of the liver. A vital role of FXR is impacting the amount of bile acids in the hepatocytes, which it performs by reducing bile acid synthesis, stimulating the bile salt export pump, and inhibiting its enterohepatic circulation, thus protecting the hepatocytes against the toxic accumulation of bile acids. Furthermore, FXR mediates bile acid biotransformation in the intestine, liver regeneration, glucose hemostasis, and lipid metabolism. In this review, we first discuss the mechanisms of the disparate pleiotropic actions of FXR agonists. We then delve into the pharmacokinetics of Obeticholic acid (OCA), the first-in-class selective, potent FXR agonist. We additionally discuss the clinical journey of OCA in humans, its current evidence in various human diseases, and its plausible roles in the future.
Assuntos
Ácido Quenodesoxicólico , Ácido Quenodesoxicólico/análogos & derivados , Receptores Citoplasmáticos e Nucleares , Humanos , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/uso terapêutico , Animais , Ácidos e Sais Biliares/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/efeitos dos fármacosRESUMO
Polycystic ovary syndrome (PCOS), an endocrine disorder afflicting 6-20% of women of reproductive age globally, has been linked to alterations in the gut microbiome. We previously showed that in PCOS, elevation of Bacteroides vulgatus in the gut microbiome was associated with altered bile acid metabolism. Here we show that B. vulgatus also induces a PCOS-like phenotype in female mice via an alternate mechanism independent of bile acids. We find that B. vulgatus contributes to PCOS-like symptoms through its metabolite agmatine, which is derived from arginine by arginine decarboxylase. Mechanistically, agmatine activates the farnesoid X receptor (FXR) pathway to subsequently inhibit glucagon-like peptide-1 (GLP-1) secretion by L cells, which leads to insulin resistance and ovarian dysfunction. Critically, the GLP-1 receptor agonist liraglutide and the arginine decarboxylase inhibitor difluoromethylarginine ameliorate ovarian dysfunction in a PCOS-like mouse model. These findings reveal that agmatine-FXR-GLP-1 signalling contributes to ovarian dysfunction, presenting a potential therapeutic target for PCOS management.
Assuntos
Agmatina , Microbioma Gastrointestinal , Síndrome do Ovário Policístico , Receptores Citoplasmáticos e Nucleares , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Animais , Feminino , Camundongos , Agmatina/farmacologia , Agmatina/metabolismo , Agmatina/uso terapêutico , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de Doenças , Resistência à Insulina , Bacteroides/efeitos dos fármacos , Humanos , Carboxiliases/metabolismoRESUMO
Nuclear receptors such as constitutive androstane receptor (CAR), pregnane X receptor (PXR), and peroxisome proliferator-activated receptor-alpha (PPARα), and transcription factors with nuclear receptor type activity such as aryl hydrocarbon receptor (AhR) function as xenobiotic sensors. Hepatocyte nuclear factor 4alpha (HNF4α) is a highly conserved orphan nuclear receptor essential for liver function. We tested the hypothesis that HNF4α is essential for the function of these 4 major xenosensors. Wild-type (WT) and hepatocyte-specific Hnf4a null (HNF4α-KO) mice were treated with the mouse-specific activators of AhR (TCDD, 30 µg/kg), CAR (TCPOBOP, 2.5 µg/g), PXR, (PCN, 100 µg/g), and PPARα (WY-14643, 1 mg/kg). Blood and liver tissue samples were collected to study receptor activation. TCDD (AhR agonist) treatment did not affect the liver-to-body weight ratio (LW/BW) in either WT or HNF4α-KO mice. Further, TCDD activated AhR in both WT and HNF4α-KO mice, confirmed by increase in expression of AhR target genes. TCPOBOP (CAR agonist) significantly increased the LW/BW ratio and CAR target gene expression in WT mice, but not in HNF4α-KO mice. PCN (a mouse PXR agonist) significantly increased LW/BW ratio in both WT and HNF4α-KO mice however, failed to induce PXR target genes in HNF4α-KO mice. The treatment of WY-14643 (PPARα agonist) increased LW/BW ratio and PPARα target gene expression in WT mice but not in HNF4α-KO mice. Together, these data indicate that the function of CAR, PXR, and PPARα but not of AhR was disrupted in HNF4α-KO mice. These results demonstrate that HNF4α function is critical for the activation of hepatic xenosensors, which are critical for toxicological responses.
Assuntos
Receptor Constitutivo de Androstano , Fator 4 Nuclear de Hepatócito , Fígado , Camundongos Knockout , PPAR alfa , Receptor de Pregnano X , Receptores Citoplasmáticos e Nucleares , Animais , Fator 4 Nuclear de Hepatócito/metabolismo , Fator 4 Nuclear de Hepatócito/genética , Fígado/metabolismo , Fígado/efeitos dos fármacos , PPAR alfa/agonistas , PPAR alfa/metabolismo , PPAR alfa/genética , Receptor de Pregnano X/genética , Receptor de Pregnano X/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Camundongos , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Receptores de Esteroides/agonistas , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Pirimidinas/farmacologia , Dibenzodioxinas Policloradas/toxicidade , Piridinas/farmacologiaRESUMO
Consumption of herbal products containing pyrrolizidine alkaloids (PAs) is one of the major causes for hepatic sinusoidal obstruction syndrome (HSOS), a deadly liver disease. However, the crucial metabolic variation and biomarkers which can reflect these changes remain amphibious and thus to result in a lack of effective prevention, diagnosis and treatments against this disease. The aim of the study was to determine the impact of HSOS caused by PA exposure, and to translate metabolomics-derived biomarkers to the mechanism. In present study, cholic acid species (namely, cholic acid, taurine conjugated-cholic acid, and glycine conjugated-cholic acid) were identified as the candidate biomarkers (area under the ROC curve 0.968 [95% CI 0.908-0.994], sensitivity 83.87%, specificity 96.55%) for PA-HSOS using two independent cohorts of patients with PA-HSOS. The increased primary bile acid biosynthesis and decreased liver expression of farnesoid X receptor (FXR, which is known to inhibit bile acid biosynthesis in hepatocytes) were highlighted in PA-HSOS patients. Furtherly, a murine PA-HSOS model induced by senecionine (50 mg/kg, p.o.), a hepatotoxic PA, showed increased biosynthesis of cholic acid species via inhibition of hepatic FXR-SHP singling and treatment with the FXR agonist obeticholic acid restored the cholic acid species to the normal levels and protected mice from senecionine-induced HSOS. This work elucidates that increased levels of cholic acid species can serve as diagnostic biomarkers in PA-HSOS and targeting FXR may represent a therapeutic strategy for treating PA-HSOS in clinics.
Assuntos
Biomarcadores , Hepatopatia Veno-Oclusiva , Metabolômica , Alcaloides de Pirrolizidina , Receptores Citoplasmáticos e Nucleares , Alcaloides de Pirrolizidina/toxicidade , Animais , Hepatopatia Veno-Oclusiva/induzido quimicamente , Hepatopatia Veno-Oclusiva/metabolismo , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Masculino , Humanos , Biomarcadores/metabolismo , Camundongos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Ácidos e Sais Biliares/metabolismo , Feminino , Pessoa de Meia-Idade , Camundongos Endogâmicos C57BL , Ácido Cólico , AdultoRESUMO
BACKGROUND: Short bowel syndrome (SBS) features nutrients malabsorption and impaired intestinal barrier. Patients with SBS are prone to sepsis, intestinal flora dysbiosis and intestinal failure associated liver disease. Protecting intestinal barrier and preventing complications are potential strategies for SBS treatment. This study aims to investigate the effects of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), have on intestinal barrier and ecological environment in SBS. METHODS AND RESULTS: Through testing the small intestine and serum samples of patients with SBS, impaired intestinal barrier was verified, as evidenced by reduced expressions of intestinal tight junction proteins (TJPs), increased levels of apoptosis and epithelial cell damage. The intestinal expressions of FXR and related downstream molecules were decreased in SBS patients. Then, global FXR activator OCA was used to further dissect the potential role of the FXR in a rat model of SBS. Low expressions of FXR-related molecules were observed on the small intestine of SBS rats, along with increased proinflammatory factors and damaged barrier function. Furthermore, SBS rats possessed significantly decreased body weight and elevated death rate. Supplementation with OCA mitigated the damaged intestinal barrier and increased proinflammatory factors in SBS rats, accompanied by activated FXR-related molecules. Using 16S rDNA sequencing, the regulatory role of OCA on gut microbiota in SBS rats was witnessed. LPS stimulation to Caco-2 cells induced apoptosis and overexpression of proinflammatory factors in vitro. OCA incubation of LPS-pretreated Caco-2 cells activated FXR-related molecules, increased the expressions of TJPs, ameliorated apoptosis and inhibited overexpression of proinflammatory factors. CONCLUSIONS: OCA supplementation could effectively ameliorate the intestinal barrier disruption and inhibit overexpression of proinflammatory factors in a rat model of SBS and LPS-pretreated Caco-2 cells. As a selective activator of FXR, OCA might realize its protective function through FXR activation.
Assuntos
Ácido Quenodesoxicólico , Modelos Animais de Doenças , Mucosa Intestinal , Receptores Citoplasmáticos e Nucleares , Síndrome do Intestino Curto , Animais , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/farmacologia , Síndrome do Intestino Curto/metabolismo , Síndrome do Intestino Curto/tratamento farmacológico , Síndrome do Intestino Curto/patologia , Ratos , Humanos , Masculino , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Feminino , Ratos Sprague-Dawley , Apoptose/efeitos dos fármacos , Pessoa de Meia-Idade , Intestino Delgado/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Adulto , Proteínas de Junções Íntimas/metabolismoRESUMO
Liver fibrosis is a common pathological process in the progression of several chronic liver diseases to cirrhosis and hepatocellular carcinoma. Therefore, the development of medications that can repress the progress of liver fibrosis is essential. We discovered that initially, 12ß-(m-methyl-benzoyl)-11,12-dihydro oleanolic acid (12d-OA), a farnesoid X receptor (FXR) modulator, possessed potential anti-fibrotic properties. Through an in-depth study, we revealed that 12d-OA not only inhibited the expression of fibrogenic markers in the LX-2 cells and HSC-T6 cells but also exhibited significant protective effects against liver injury and liver fibrosis in bile duct ligation (BDL) rats. Further exploration of its molecular mechanism indicated that 12d-OA exerted antifibrotic activity by inhibiting the extracellular signal-regulated kinase (ERK)/stress-activated protein kinase (p38) signaling pathways. Consequently, the great effects of 12d-OA in vitro and in vivo suggest that it may be a good candidate for liver fibrosis.
Assuntos
Cirrose Hepática , Ácido Oleanólico , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Ácido Oleanólico/farmacologia , Ácido Oleanólico/análogos & derivados , Masculino , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/prevenção & controle , Humanos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Linhagem Celular , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ratos , Antifibróticos/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismoRESUMO
The nuclear farnesoid X receptor (FXR), a master regulator of bile acid and metabolic homeostasis, is a key target for treatment of nonalcoholic steatohepatitis (NASH). This study compared efficacy of FXR agonists obeticholic acid (OCA) and INT-787 by liver histopathology, plasma biomarkers of liver damage, and hepatic gene expression profiles in the Amylin liver NASH (AMLN) diet-induced and biopsy-confirmed Lepob/ob mouse model of NASH. Lepob/ob mice were fed the AMLN diet for 12 weeks before liver biopsy and subsequent treatment with vehicle, OCA, or INT-787 for 8 weeks. Hepatic steatosis, inflammation, and fibrosis (liver lipids, galectin-3, and collagen 1a1 [Col1a1], respectively), as well as plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, were assessed. Hepatic gene expression was assessed in Lepob/ob mice that were fed the AMLN diet for 14 weeks then treated with vehicle, OCA, or INT-787 for 2 weeks. INT-787, which is equipotent to OCA but more hydrophilic, significantly reduced liver lipids, galectin-3, and Col1a1 compared with vehicle, and to a greater extent than OCA. INT-787 significantly reduced plasma ALT and AST levels, whereas OCA did not. INT-787 modulated a substantially greater number of genes associated with FXR signaling, lipid metabolism, and stellate cell activation relative to OCA in hepatic tissue. These findings demonstrate greater efficacy of INT-787 treatment compared with OCA in improving liver histopathology, decreasing liver enzyme levels, and enhancing gene regulation, suggesting superior clinical potential of INT-787 for the treatment of NASH and other chronic liver diseases.
Assuntos
Ácido Quenodesoxicólico , Ácido Quenodesoxicólico/análogos & derivados , Modelos Animais de Doenças , Fígado , Hepatopatia Gordurosa não Alcoólica , Receptores Citoplasmáticos e Nucleares , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/genética , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/uso terapêutico , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Camundongos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Galectina 3/metabolismo , Galectina 3/genéticaRESUMO
INTRODUCTION: Up to 40% of Primary biliary cholangitis (PBC) patients have a suboptimal response to Ursodeoxycholic acid (UDCA). Close to half of such patients show a remarkable improvement when additionally treated with Obeticholic acid (OCA) but have a dose-dependent increase of pruritus. This relative success of OCA, a first-in-class Farnesoid receptor (FXR) agonist, has positioned FXR as an attractive target for drug development. Novel candidates have since emerged, providing hope for this subgroup of patients who lack effective and safe treatments. AREAS COVERED: We discussed the role of bile acids in PBC pathogenesis and how the FXR agonists provide therapeutic value by affecting bile acid synthesis and transport. Novel FXR agonists undergoing pre-clinical and clinical trials for PBC were enlisted via literature search by including the terms 'FXR agonists,' 'FXR PBC,' 'PBC clinical trials' on PubMed, MEDLINE via Ovid, and Clinicaltrials.gov. EXPERT OPINION: Novel FXR agonists currently under investigation for PBC improve the disease surrogate markers in early trials. However, as with OCA, pruritus remains a concern with the newer drugs despite targeted chemical modifications to increase FXR specificity. Directing future resources toward studying the molecular mechanisms behind pruritus may lead to better drug design and efficacious yet safer drugs.
Assuntos
Ácido Quenodesoxicólico , Cirrose Hepática Biliar , Receptores Citoplasmáticos e Nucleares , Animais , Humanos , Ácidos e Sais Biliares/metabolismo , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , Colagogos e Coleréticos/farmacologia , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos , Drogas em Investigação/farmacologia , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/fisiopatologia , Prurido/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Ácido Ursodesoxicólico/farmacologiaRESUMO
Farnesoid X receptor (FXR) improves the function of islets, especially in the setting of Roux-en-Y gastric bypass (RYGB). Here we investigated how FXR activation regulates ß-cell proliferation and explored the potential link between FXR signaling and the menin pathway in controlling E2F3 expression, a key transcription factor for controlling adult ß-cell proliferation. Stimulation with the FXR agonist GW4064 or chenodeoxycholic acid (CDCA) increased E2F3 expression and ß-cell proliferation. Consistently, E2F3 knockdown abolished GW4064-induced proliferation. Treatment with GW4064 increased E2F3 expression in ß-cells via enhancing Steroid receptor coactivator-1 (SRC1) recruitment, increasing the pro-transcriptional acetylation of histone H3 at the E2f3 promoter. GW4064 treatment also decreased the association between FXR and menin, leading to the induction of FXR-mediated SRC1 recruitment. Mimicking the impact of FXR agonists, RYGB also increased E2F3 expression and ß-cell proliferation in GK rats and SD rats. These findings unravel the crucial role of the FXR/menin signaling in epigenetically controlling E2F3 expression and ß-cell proliferation, a mechanism possibly underlying RYGB-induced ß-cell proliferation.
Assuntos
Proliferação de Células , Fator de Transcrição E2F3 , Epigênese Genética , Células Secretoras de Insulina , Receptores Citoplasmáticos e Nucleares , Animais , Ratos , Proliferação de Células/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/genética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Fator de Transcrição E2F3/metabolismo , Fator de Transcrição E2F3/genética , Ratos Wistar , Histonas/metabolismo , Isoxazóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologiaRESUMO
Primary sclerosing cholangitis (PSC) is a rare cholestatic disease characterized by biliary infiltration, hepatic fibrosis and bile duct destruction. To date, treatment options for PSC are very limited. Therefore, the current study is aimed to investigate the therapeutic potential of berberine (BBR) against PSC. The disease was induced by feeding the mice with 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine (DDC) for four weeks. The serum biochemistry and liver histology were analyzed. Furthermore, the expression of farnesoid X receptor (FXR) was also evaluated by real-time PCR. The results indicated that berberine prevents the progression of PSC by modulating the expression of FXR which ultimately regulates other genes (including Cyp7A1 and BSEP) thus maintaining bile acids homeostasis. Furthermore, the docking analysis showed that berberine interacts with the binding pocket of FXR to activate the protein thus acting as an FXR agonist. In conclusion, data indicate that berberine protects the liver from PSC-related injury. This effect might be due to the modulation of FXR activity.
Assuntos
Berberina , Colangite Esclerosante , Fígado , Receptores Citoplasmáticos e Nucleares , Berberina/farmacologia , Berberina/uso terapêutico , Colangite Esclerosante/tratamento farmacológico , Colangite Esclerosante/metabolismo , Colangite Esclerosante/patologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Camundongos , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Simulação de Acoplamento Molecular , Progressão da Doença , Ácidos e Sais Biliares/metabolismo , Humanos , Sítios de Ligação , Camundongos Endogâmicos C57BL , Colesterol 7-alfa-Hidroxilase/metabolismo , Colesterol 7-alfa-Hidroxilase/genética , PiridinasRESUMO
Primary biliary cholangitis (PBC) is a rare cholestatic immune-mediated liver disease. The clinical course varies from mild to severe, with a substantial group of patients developing cirrhosis within a decade. These patients are at risk of hepatocellular carcinoma, decompensation and liver failure. First line Ursodeoxycholic acid (UDCA) treatment improves the cholestatic surrogate markers, and was recently associated with a favorable survival free of liver transplantation, even in case of an incomplete biochemical response. However, despite adequate UDCA therapy, patients remain at risk of liver disease progression. Therefore, on-treatment multifactor-based risk stratification is necessary to identify patients in need of additional therapy. This requires a personalized approach; especially as recent studies suggest that complete biochemical normalization as most stringent response criterion might be preferred in selected patients to optimize their outcome. Today, stricter biochemical goals might actually be reachable with the addition of farnesoid X receptor or peroxisome proliferator-activated receptor agonists, or, in highly-selected cases, use of corticosteroids. Randomized controlled trials showed improvements in the key biochemical surrogate markers with the addition of these drugs, which have also been associated with improved clinical outcome. Considering this evolving PBC landscape, with more versatile treatment options and treatment goals, this review recapitulates the recent insight in UDCA therapy, the selection of patients with a residual risk of liver disease progression and the results of the currently available second line treatment options.
Assuntos
Colagogos e Coleréticos , Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Ácido Ursodesoxicólico/uso terapêutico , Cirrose Hepática Biliar/tratamento farmacológico , Colagogos e Coleréticos/uso terapêutico , Progressão da Doença , Receptores Citoplasmáticos e Nucleares/agonistas , Ensaios Clínicos Controlados Aleatórios como Assunto , Transplante de Fígado , Corticosteroides/uso terapêutico , Receptores Ativados por Proliferador de Peroxissomo/agonistasRESUMO
INTRODUCTION: The Farnesoid X receptor (FXR) is a key transcription factor that is involved in the bile acid signaling network. The modulation of the FXR activity influences glucose and lipid homeostasis, reduces obesity and insulin resistance, as well as it regulates the pathogenesis of inflammatory and metabolic disorders. FXR ligands have therefore emerged in drug discovery as promising therapeutic agents for the prevention and treatment of gastrointestinal and liver diseases, including cancer. AREAS COVERED: Recent advances in the field of FXR modulators are reviewed, with a particular attention on patent applications filed in the past 5 years related to both the discovery and development of FXR targeting drugs. EXPERT OPINION: FXR agonists have proven their efficacy and safety in humans and have shown a significant potential as clinical agents to treat metabolic and inflammatory associated conditions. However, several challenges, including adverse events such as pruritus, remain to be solved. Current studies aim to gain insights into the pathophysiological mechanisms by which FXR regulates metabolism and inflammation in terms of tissue/organ/isoform-specificity, post-translational modifications and coregulatory proteins, on the route of novel, improved FXR modulators.
Assuntos
Desenvolvimento de Medicamentos , Hepatopatias , Patentes como Assunto , Receptores Citoplasmáticos e Nucleares , Humanos , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Animais , Ligantes , Hepatopatias/tratamento farmacológico , Hepatopatias/fisiopatologia , Hepatopatias/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/fisiopatologia , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Inflamação/metabolismo , Descoberta de Drogas , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/fisiopatologia , Ácidos e Sais Biliares/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Cilofexor is a nonsteroidal farnesoid X receptor agonist being developed in combination with firsocostat/semaglutide for the treatment of nonalcoholic steatohepatitis. This phase 1 study evaluated the effects of food and acid-reducing agents (ARAs) on the pharmacokinetics of cilofexor (100- or 30-mg fixed-dose combination with firsocostat) in healthy participants. Cohorts 1 (n = 20, 100 mg) and 2 (n = 30, 30 mg) followed a 3-period, 2-sequence crossover design and evaluated effects of light-fat and high-fat meals. Cohort 3 (n = 30, 100 mg fasting) followed a 2-period, 2-sequence crossover design and evaluated the effects of a 40-mg single dose of famotidine. Cohort 4 (n = 18, 100 mg) followed a 3-period, 2-sequence crossover design and evaluated the effects of a 40-mg once-daily regimen of omeprazole administered under fasting conditions or following a light-fat meal. Administration with light-fat or high-fat meals resulted in no change and an â¼35% reduction in cilofexor AUC, respectively, relative to the fasting conditions. Under fasting conditions, famotidine increased cilofexor AUC by 3.2-fold and Cmax by 6.1-fold, while omeprazole increased cilofexor AUC by 3.1-fold and Cmax by 4.8-fold. With a low-fat meal, omeprazole increased cilofexor exposure to a lesser extent (Cmax 2.5-fold, AUC 2.1-fold) than fasting conditions. This study suggests that caution should be exercised when cilofexor is administered with ARAs under fed conditions; coadministration of cilofexor (100 or 30 mg) with ARAs under fasting conditions is not recommended with the current clinical trial formulations.