RESUMEN
Obeticholic acid (OCA), a semisynthetic bile acid derivative, was approved for its therapeutic use in primary biliary cirrhosis. OCA has a enterohepatic circulation and host-gut microbiota metabolic interaction, which produce various metabolites. Such metabolites, especially structural isomers of OCA, together with the need to achieve idea lower limit of quantitation (LLOQ) with minimum matrix interference, bring about significant difficulties to the bioanalysis of OCA. Herein, by applying a combination of solid-phase extraction (SPE) and ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), we introduced an approach for the bioanalysis of OCA along with its two major metabolites-glyco-OCA (GOA) and tauro-OCA (TOA) in human plasma, the full validation results of which showed excellent performance. The quantitative range is 0.2506 â¼ 100.2 ng/mL for OCA, 0.2500 â¼ 100.0 ng/mL for GOA, as well as 0.1250 â¼ 50.00 ng/mL for TOA, respectively. This method was successfully applied to the pharmacokinetic studies in healthy subjects following administration of OCA tablets.
Asunto(s)
Ácido Quenodesoxicólico , Límite de Detección , Comprimidos , Espectrometría de Masas en Tándem , Humanos , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida de Alta Presión/métodos , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/sangre , Ácido Quenodesoxicólico/farmacocinética , Ácido Quenodesoxicólico/química , Reproducibilidad de los Resultados , Modelos Lineales , Extracción en Fase Sólida/métodos , MasculinoAsunto(s)
Cirrosis Hepática Biliar , Humanos , Cirrosis Hepática Biliar/tratamiento farmacológico , Cirrosis Hepática Biliar/terapia , Ácido Ursodesoxicólico/uso terapéutico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapéutico , Colagogos y Coleréticos/uso terapéuticoRESUMEN
Acute kidney injury (AKI), a common complication of sepsis, might be caused by overactivated inflammation, mitochondrial damage, and oxidative stress. However, the mechanisms underlying sepsis-induced AKI (SAKI) have not been fully elucidated, and there is a lack of effective therapies for AKI. To this end, this study aimed to investigate whether obeticholic acid (OCA) has a renoprotective effect on SAKI and to explore its mechanism of action. Through bioinformatics analysis, our study confirmed that the mitochondria might be a critical target for the treatment of SAKI. Thus, a septic rat model was established by cecal ligation puncture (CLP) surgery. Our results showed an evoked inflammatory response via the NF-κB signaling pathway and NLRP3 inflammasome activation in septic rats, which led to mitochondrial damage and oxidative stress. OCA, an Farnesoid X Receptor (FXR) agonist, has shown anti-inflammatory effects in numerous studies. However, the effects of OCA on SAKI remain unclear. In this study, we revealed that pretreatment with OCA can inhibit the inflammatory response by reducing the synthesis of proinflammatory factors (such as IL-1ß and NLRP3) via blocking NF-κB and alleviating mitochondrial damage and oxidative stress in the septic rat model. Overall, this study provides insight into the excessive inflammation-induced SAKI caused by mitochondrial damage and evidence for the potential use of OCA in SAKI treatment.
Asunto(s)
Lesión Renal Aguda , Ácido Quenodesoxicólico , Modelos Animales de Enfermedad , Mitocondrias , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Estrés Oxidativo , Ratas Sprague-Dawley , Sepsis , Transducción de Señal , Animales , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/farmacología , Ácido Quenodesoxicólico/uso terapéutico , FN-kappa B/metabolismo , Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control , Transducción de Señal/efectos de los fármacos , Ratas , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Interleucina-1beta/metabolismoRESUMEN
Primary biliary cholangitis is a chronic, autoimmune, cholestatic disease that mainly affects women aged 40-70 years. Recent epidemiological studies have shown an increasing incidence worldwide despite geographical heterogeneity and a decrease in the female-to-male ratio of those the disease affects. Similar to other autoimmune diseases, primary biliary cholangitis occurs in genetically predisposed individuals upon exposure to environmental triggers, specifically xenobiotics, smoking, and the gut microbiome. Notably, the diversity of the intestinal microbiome is diminished in individuals with primary biliary cholangitis. The intricate interplay among immune cells, cytokines, chemokines, and biliary epithelial cells is postulated as the underlying pathogenic mechanism involved in the development and progression of primary biliary cholangitis, and extensive research has been dedicated to comprehending these complex interactions. Following the official approval of obeticholic acid as second-line treatment for patients with an incomplete response or intolerance to ursodeoxycholic acid, clinical trials have indicated that peroxisome proliferator activator receptor agonists are promising additional second-line drugs. Future dual or triple drug regimens might reach a new treatment goal of normalisation of alkaline phosphatase levels, rather than a decrease to less than 1·67 times the upper limit of normal levels, and potentially improve long-term outcomes. Improvement of health-related quality of life with better recognition and care of subjective symptoms, such as pruritus and fatigue, is also an important treatment goal. Promising clinical investigations are underway to alleviate these symptoms. Efforts to facilitate better access to medical care and dissemination of current knowledge should enable diagnosis at an earlier stage of primary biliary cholangitis and ensure access to treatments based on risk stratification for all patients.
Asunto(s)
Ácido Quenodesoxicólico , Humanos , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapéutico , Cirrosis Hepática Biliar/tratamiento farmacológico , Ácido Ursodesoxicólico/uso terapéutico , Femenino , Microbioma Gastrointestinal , Persona de Mediana Edad , Masculino , Colagogos y Coleréticos/uso terapéutico , AncianoRESUMEN
BACKGROUND: Bile acids (BAs) are steroid-derived molecules with important roles in digestion, the maintenance of host metabolism, and immunomodulation. Primary BAs are synthesized by the host, while secondary BAs are produced by the gut microbiome through transformation of the former. The regulation of microbial production of secondary BAs is not well understood, particularly the production of 7-dehydroxylated BAs, which are the most potent agonists for host BA receptors. The 7-dehydroxylation of cholic acid (CA) is well established and is linked to the expression of a bile acid-inducible (bai) operon responsible for this process. However, little to no 7-dehydroxylation has been reported for other host-derived BAs (e.g., chenodeoxycholic acid, CDCA or ursodeoxycholic acid, UDCA). RESULTS: Here, we demonstrate that the 7-dehydroxylation of CDCA and UDCA by the human isolate Clostridium scindens is induced when CA is present, suggesting that CA-dependent transcriptional regulation is required for substantial 7-dehydroxylation of these primary BAs. This is supported by the finding that UDCA alone does not promote expression of bai genes. CDCA upregulates expression of the bai genes but the expression is greater when CA is present. In contrast, the murine isolate Extibacter muris exhibits a distinct response; CA did not induce significant 7-dehydroxylation of primary BAs, whereas BA 7-dehydroxylation was promoted upon addition of germ-free mouse cecal content in vitro. However, E. muris was found to 7-dehydroxylate in vivo. CONCLUSIONS: The distinct expression responses amongst strains indicate that bai genes are regulated differently. CA promoted bai operon gene expression and the 7-dehydroxylating activity in C. scindens strains. Conversely, the in vitro activity of E. muris was promoted only after the addition of cecal content and the isolate did not alter bai gene expression in response to CA. The accessory gene baiJ was only upregulated in the C. scindens ATCC 35704 strain, implying mechanistic differences amongst isolates. Interestingly, the human-derived C. scindens strains were also capable of 7-dehydroxylating murine bile acids (muricholic acids) to a limited extent. This study shows novel 7-dehydroxylation activity in vitro resulting from the presence of CA and suggests distinct bai gene expression across bacterial species.
Asunto(s)
Ácidos y Sales Biliares , Ácido Cólico , Ácido Cólico/metabolismo , Animales , Ácidos y Sales Biliares/metabolismo , Ratones , Humanos , Clostridium/metabolismo , Clostridium/genética , Regulación Bacteriana de la Expresión Génica , Hidroxilación , Operón , Ácido Quenodesoxicólico/metabolismo , Ácido Ursodesoxicólico/metabolismo , Microbioma GastrointestinalRESUMEN
Previous studies have shown that pharmaceutical agents such as lipoic acid have the ability to soften the lens, presenting a promising avenue for treating presbyopia. One obstacle encountered in the preclinical stage of such agents is the need for precise measurements of lens elasticity in experimental models. This study aimed to evaluate the effects of 25-hydroxycholesterol, lipoic acid, and obeticholic acid on the viscoelastic properties of mouse lenses using a custom-built elastometer system. Data were acquired on lenses from C57BL/6J female mice from two age groups: young (age: 8-10 weeks) and old (age: 32-43 weeks). OD lenses were used as the control and OS lenses were treated. Control lenses were immersed in Dulbecco's Modified Eagle Medium (DMEM) and treatment lenses were immersed in a compound solution containing 25-hydroxycholesterol (5 young and 5 old), lipoic acid at 2.35 mM (5 young and 5 old), lipoic acid at 0.66 mM (5 old), or obeticholic acid (5 old) at 37 °C for 18 h. After treatment, the mouse lenses were placed in a DMEM-filled chamber within a custom-built elastometer system that recorded the load and lens shape as the lens was compressed by 600 µm at a speed of 50 µm/s. The load was continuously recorded during compression and during stress-relaxation. The compression phase was fit with a linear function to quantify lens stiffness. The stress-relaxation phase was fit with a 3-term exponential relaxation model providing relaxation time constants (t1, t2, t3), and equilibrium load. The lens stiffness, time constants and equilibrium load were compared for the control and treated groups. Results revealed an increase in stiffness with age for the control group (young: 1.16 ± 0.11 g/mm, old: 1.29 ± 0.14 g/mm) and relaxation time constants decreased with age (young: t1 = 221.9 ± 29.0 s, t2 = 24.7 ± 3.8 s, t3 = 3.12 ± 0.87 s, old: t1 = 183.0 ± 22.0 s, t2 = 20.6 ± 2.6 s and t3 = 2.24 ± 0.43 s). Among the compounds tested, only 25-hydroxycholesterol produced statistically significant changes in the lens stiffness, relaxation time constants, and equilibrium load. In conclusion, older mouse lenses are stiffer and less viscous than young mouse lenses. Notably, no significant change in lens stiffness was observed following treatment with lipoic acid, contrary to previous findings.
Asunto(s)
Ácido Quenodesoxicólico , Elasticidad , Cristalino , Ratones Endogámicos C57BL , Ácido Tióctico , Animales , Ratones , Cristalino/efectos de los fármacos , Femenino , Ácido Tióctico/farmacología , Ácido Tióctico/análogos & derivados , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/farmacología , Viscosidad , Envejecimiento/fisiología , Antioxidantes/farmacología , Hidroxicolesteroles/farmacologíaRESUMEN
Bile acids (BA) are synthesized in the human liver and undergo metabolism by host gut bacteria. In diseased states, gut microbial dysbiosis may lead to high primary unconjugated BA concentrations and significant perturbations to secondary BA. Hence, it is important to understand the microbial-mediated formation kinetics of secondary bile acids using physiologically relevant ex vivo human faecal microbiota models. Here, we optimized an ex vivo human faecal microbiota model to recapitulate the metabolic kinetics of primary unconjugated BA and applied it to investigate the formation kinetics of novel secondary BA metabolites and their sequential pathways. We demonstrated (1) first-order depletion of primary BA, cholic acid (CA) and chenodeoxycholic acid (CDCA), under non-saturable conditions and (2) saturable Michaelis-Menten kinetics for secondary BA metabolite formation with increasing substrate concentration. Notably, relatively lower Michaelis constants (Km) were associated with the formation of deoxycholic acid (DCA, 14.3 µM) and lithocholic acid (LCA, 140 µM) versus 3-oxo CA (>1000 µM), 7-keto DCA (443 µM) and 7-keto LCA (>1000 µM), thereby recapitulating clinically observed saturation of 7α-dehydroxylation relative to oxidation of primary BA. Congruently, metagenomics revealed higher relative abundance of functional genes related to the oxidation pathway as compared to the 7α-dehydroxylation pathway. In addition, we demonstrated gut microbial-mediated hyocholic acid (HCA) and hyodeoxycholic acid (HDCA) formation from CDCA. In conclusion, we optimized a physiologically relevant ex vivo human faecal microbiota model to investigate gut microbial-mediated metabolism of primary BA and present a novel gut microbial-catalysed two-step pathway from CDCA to HCA and, subsequently, HDCA.
Asunto(s)
Ácidos y Sales Biliares , Heces , Humanos , Heces/microbiología , Cinética , Ácidos y Sales Biliares/metabolismo , Microbioma Gastrointestinal , Ácido Quenodesoxicólico/metabolismo , Modelos Biológicos , MicrobiotaRESUMEN
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.
Asunto(s)
Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Receptores Citoplasmáticos y Nucleares , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/metabolismo , Humanos , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/farmacología , Ácido Quenodesoxicólico/química , Ligandos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Unión Proteica , AnimalesRESUMEN
In this study, we developed an effective method for the large-scale synthesis of chenodeoxycholic acid (CDCA) from phocaecholic acid (PhCA). A high total yield of up to 72 % was obtained via five steps including methyl esterification, Ts-protection, bromination, reduction, and hydrolysis. The structures of the intermediates were confirmed by 1H NMR (Nuclear Magnetic Resonance), 13C NMR, HRMS (High Resolution Mass Spectrometry), and IR (Infrared Spectroscopy) spectroscopies. This method offers a new and practical approach to the synthesizing of CDCA.
Asunto(s)
Ácido Quenodesoxicólico , Ácido Quenodesoxicólico/química , Ácido Quenodesoxicólico/síntesis química , Ácido Quenodesoxicólico/análogos & derivados , Espectroscopía de Resonancia MagnéticaRESUMEN
Lipid-lowering drugs, especially statins, are extensively utilized in clinical settings for the prevention of hyperlipidemia. Nevertheless, prolonged usage of current lipid-lowering medications is associated with significant adverse reactions. Therefore, it is imperative to develop novel therapeutic agents for lipid-lowering therapy. In this study, a chenodeoxycholic acid and lactobionic acid double-modified polyethyleneimine (PDL) nanocomposite as a gene delivery vehicle for lipid-lowering therapy by targeting the liver, are synthesized. Results from the in vitro experiments demonstrate that PDL exhibits superior transfection efficiency compared to polyethyleneimine in alpha mouse liver 12 (AML12) cells and effectively carries plasmids. Moreover, PDL can be internalized by AML12 cells and rapidly escape lysosomal entrapment. Intravenous administration of cyanine5.5 (Cy5.5)-conjugated PDL nanocomposites reveals their preferential accumulation in the liver compared to polyethyleneimine counterparts. Systemic delivery of low-density lipoprotein receptor plasmid-loaded PDL nanocomposites into mice leads to reduced levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TC) in the bloodstream without any observed adverse effects on mouse health or well-being. Collectively, these findings suggest that low-density lipoprotein receptor plasmid-loaded PDL nanocomposites hold promise as potential therapeutics for lipid-lowering therapy.
Asunto(s)
Ácido Quenodesoxicólico , Hígado , Nanocompuestos , Polietileneimina , Receptores de LDL , Animales , Polietileneimina/química , Ratones , Hígado/metabolismo , Hígado/efectos de los fármacos , Ácido Quenodesoxicólico/química , Ácido Quenodesoxicólico/farmacología , Receptores de LDL/metabolismo , Receptores de LDL/genética , Nanocompuestos/química , Línea Celular , Masculino , Transfección/métodos , Técnicas de Transferencia de Gen , Plásmidos/genética , Plásmidos/químicaRESUMEN
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.
Asunto(s)
Ácido Quenodesoxicólico , Modelos Animales de Enfermedad , Mucosa Intestinal , Receptores Citoplasmáticos y Nucleares , Síndrome del Intestino Corto , Animales , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/farmacología , Síndrome del Intestino Corto/metabolismo , Síndrome del Intestino Corto/tratamiento farmacológico , Síndrome del Intestino Corto/patología , Ratas , Humanos , Masculino , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/agonistas , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Microbioma Gastrointestinal/efectos de los fármacos , Femenino , Ratas Sprague-Dawley , Apoptosis/efectos de los fármacos , Persona de Mediana Edad , Intestino Delgado/metabolismo , Intestino Delgado/efectos de los fármacos , Intestino Delgado/patología , Adulto , Proteínas de Uniones Estrechas/metabolismoRESUMEN
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.
Asunto(s)
Ácido Quenodesoxicólico , Ácido Quenodesoxicólico/análogos & derivados , Receptores Citoplasmáticos y Nucleares , Humanos , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Ácido Quenodesoxicólico/farmacología , Ácido Quenodesoxicólico/uso terapéutico , Animales , Ácidos y Sales Biliares/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Hígado/efectos de los fármacosRESUMEN
Bile acids play a vital role in modulating host metabolism, with chenodeoxycholic acid (CDCA) standing out as a primary bile acid that naturally activates farnesoid X receptor (FXR). In this study, we investigated the microbial transformations of CDCA by seven human intestinal fungal species. Our findings revealed that hydroxylation and dehydrogenation were the most prevalent metabolic pathways. Incubation of CDCA with Rhizopus microspores (PT2906) afforded eight undescribed compounds (6-13) alongside five known analogs (1-5) which were elucidated by HRESI-MS and NMR data. Notably, compounds 8, 12 and 13 exhibited an inhibitory effect on FXR in contrast to the FXR activation observed with CDCA in vitro assays. This study shone a light on the diverse transformations of CDCA by intestinal fungi, unveiling potential modulators of FXR activity with implications for host metabolism.
Asunto(s)
Biotransformación , Ácido Quenodesoxicólico , Receptores Citoplasmáticos y Nucleares , Humanos , Ácido Quenodesoxicólico/metabolismo , Ácido Quenodesoxicólico/farmacología , Ácido Quenodesoxicólico/química , Receptores Citoplasmáticos y Nucleares/metabolismo , Intestinos/microbiología , Estructura Molecular , Hongos/metabolismo , Hongos/efectos de los fármacos , Rhizopus/metabolismo , Relación Estructura-Actividad , Relación Dosis-Respuesta a DrogaRESUMEN
BACKGROUND: Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline phosphatase [ALP] and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long-term effectiveness of second-line treatments remains uncertain. AIMS: To evaluate the long-term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation). METHODS: We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non-responsive PBC patients (Paris-II criteria) from Spain and Portugal who received OCA ± fibrates. RESULTS: Of 255 patients, median follow-up was 35.1 months (IQR: 20.2-53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE-PBC and 5-year UK-PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension. CONCLUSION: Triple therapy was superior in achieving therapeutic goals in UDCA-nonresponsive PBC. Decompensation was linked to pre-existing portal hypertension.
Asunto(s)
Fosfatasa Alcalina , Ácido Quenodesoxicólico , Colagogos y Coleréticos , Quimioterapia Combinada , Cirrosis Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Ácido Ursodesoxicólico/uso terapéutico , Estudios Longitudinales , Cirrosis Hepática Biliar/tratamiento farmacológico , Anciano , Resultado del Tratamiento , Fosfatasa Alcalina/sangre , Colagogos y Coleréticos/uso terapéutico , Ácidos Fíbricos/uso terapéutico , España , Bilirrubina/sangre , AdultoRESUMEN
Farnesoid X receptor (FXR) plays critical regulatory roles in cardiovascular physiology/pathology. However, the role of FXR agonist obeticholic acid (OCA) in sepsis-associated myocardial injury and underlying mechanisms remain unclear. C57BL/6J mice are treated with OCA before lipopolysaccharide (LPS) administration. The histopathology of the heart and assessment of FXR expression and mitochondria function are performed. To explore the underlying mechanisms, H9c2 cells, and primary cardiomyocytes are pre-treated with OCA before LPS treatment, and extracellular signal-regulated protein kinase (ERK) inhibitor PD98059 is used. LPS-induced myocardial injury in mice is significantly improved by OCA pretreatment. Mechanistically, OCA pretreatment decreased reactive oxygen species (ROS) levels and blocked the loss of mitochondrial membrane potential (ΔΨm) in cardiomyocytes. The expression of glutathione peroxidase 1 (GPX1), superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), and nuclear factor erythroid 2-related factor 2 (NRF-2) increased in the case of OCA pretreatment. In addition, OCA improved mitochondria respiratory chain with increasing Complex I expression and decreasing cytochrome C (Cyt-C) diffusion. Moreover, OCA pretreatment inhibited LPS-induced mitochondria dysfunction via suppressing ERK1/2-DRP signaling pathway. FXR agonist OCA inhibits LPS-induced mitochondria dysfunction via suppressing ERK1/2-DRP signaling pathway to protect mice against LPS-induced myocardial injury.
Asunto(s)
Ácido Quenodesoxicólico , Lipopolisacáridos , Sistema de Señalización de MAP Quinasas , Ratones Endogámicos C57BL , Miocitos Cardíacos , Animales , Lipopolisacáridos/toxicidad , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/farmacología , Ratones , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Masculino , Especies Reactivas de Oxígeno/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Línea Celular , Receptores Citoplasmáticos y NuclearesRESUMEN
BACKGROUND: The relationship between primary sclerosing cholangitis (PSC) and biliary bile acids (BAs) remains unclear. Although a few studies have compared PSC biliary BAs with other diseases, they did not exclude the influence of cholestasis, which affects the composition of BAs. We compared biliary BAs and microbiota among patients with PSC, controls without cholestasis, and controls with cholestasis, based on the hypothesis that alterations in BAs underlie the pathophysiology of PSC. METHODS: Bile samples were obtained using endoscopic retrograde cholangiopancreatography from patients with PSC (n = 14), non-hepato-pancreato-biliary patients without cholestasis (n = 15), and patients with cholestasis (n = 13). RESULTS: The BA profiles showed that patients with PSC and cholestasis controls had significantly lower secondary BAs than non-cholestasis controls, as expected, whereas the ratio of cholic acid/chenodeoxycholic acid in patients with PSC was significantly lower despite cholestasis, and the ratio of (cholic acid + deoxycholic acid)/(chenodeoxycholic acid + lithocholic acid) in patients with PSC was significantly lower than that in the controls with or without cholestasis. The BA ratio in the bile of patients with PSC showed a similar trend in the serum. Moreover, there were correlations between the alteration of BAs and clinical data that differed from those of the cholestasis controls. Biliary microbiota did not differ among the groups. CONCLUSIONS: Patients with PSC showed characteristic biliary and serum BA compositions that were different from those in other groups. These findings suggest that the BA synthesis system in patients with PSC differs from that in controls and patients with other cholestatic diseases. Our approach to assessing BAs provides insights into the pathophysiology of PSC.
Asunto(s)
Ácidos y Sales Biliares , Colangitis Esclerosante , Colestasis , Colangitis Esclerosante/sangre , Colangitis Esclerosante/microbiología , Humanos , Masculino , Ácidos y Sales Biliares/sangre , Ácidos y Sales Biliares/análisis , Ácidos y Sales Biliares/metabolismo , Femenino , Persona de Mediana Edad , Adulto , Colestasis/sangre , Colestasis/microbiología , Colangiopancreatografia Retrógrada Endoscópica , Estudios de Casos y Controles , Anciano , Conductos Biliares/microbiología , Bilis/metabolismo , Bilis/microbiología , Ácido Quenodesoxicólico/análisis , Ácido Cólico/análisis , Ácido Cólico/sangreRESUMEN
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.
Asunto(s)
Ácido Quenodesoxicólico , Ácido Quenodesoxicólico/análogos & derivados , Modelos Animales de Enfermedad , Hígado , Enfermedad del Hígado Graso no Alcohólico , Receptores Citoplasmáticos y Nucleares , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/genética , Ácido Quenodesoxicólico/farmacología , Ácido Quenodesoxicólico/uso terapéutico , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Ratones , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Galectina 3/metabolismo , Galectina 3/genéticaRESUMEN
INTRODUCTION: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid metabolism disorder. It is caused by a defect in the sterol-27-hydroxylase gene, leading to the deposition of cholesteryl and bile alcohol in large amounts, causing a variety of clinical manifestations; however, tremor as the main manifestation of CTX has not been reported. PATIENTS CONCERNS AND CLINICAL FINDINGS: Herein, we report a 27-year-old woman, who developed head and body tremors at the age of 12 years. Many hospitals misdiagnosed her condition as idiopathic tremor and Parkinson disease, with a poor curative effect. PRIMARY DIAGNOSIS AND INTERVENTION: We diagnosed her with CTX and treated with chenodeoxycholic acid and clonazepam. CONCLUSION: The patient's condition considerably improved. This case could help avoid misdiagnosis and mistreatment in clinical practice.
Asunto(s)
Ácido Quenodesoxicólico , Temblor , Xantomatosis Cerebrotendinosa , Humanos , Xantomatosis Cerebrotendinosa/diagnóstico , Xantomatosis Cerebrotendinosa/complicaciones , Xantomatosis Cerebrotendinosa/tratamiento farmacológico , Xantomatosis Cerebrotendinosa/genética , Femenino , Adulto , Temblor/etiología , Temblor/diagnóstico , Ácido Quenodesoxicólico/uso terapéutico , Clonazepam/uso terapéutico , Diagnóstico DiferencialRESUMEN
BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid disorder. Affected patients often remain undiagnosed until the age of 20-30 years, when they have already developed significant neurologic disease that may not be reversible. An elevated plasma cholestanol concentration has been accepted as a diagnostic criterion for CTX for decades. OBJECTIVE: Full biochemical characterization was performed for three genetically and clinically confirmed atypical CTX cases with normal plasma cholestanol levels. METHODS: Clinical assessment and genetic/biochemical testing for patients with CTX was performed by their physician providing routine standard of care. RESULTS: We report three new atypical CTX cases with large extensor tendon xanthomas but normal plasma cholestanol levels. All three cases had marked elevations of bile acid precursors and bile alcohols in plasma and urine that decreased on treatment with chenodeoxycholic acid. We also review eight published cases of atypical CTX with normal/near normal circulating cholestanol levels. CONCLUSION: The atypical biochemical presentation of these cases provides a diagnostic challenge for CTX, a disorder for which cholestanol has been believed to be a sensitive biomarker. These cases demonstrate measurements of plasma cholestanol alone are insufficient to exclude a diagnosis of CTX. The data presented is consistent with the concept that bile acid precursors and bile alcohols are sensitive biomarkers for atypical CTX with normal cholestanol, and that such testing is indicated, along with CYP27A1 gene analyses, in patients presenting with significant tendon and/or tuberous xanthomas and/or neurologic disease in early adulthood despite normal or near normal cholesterol and cholestanol levels.
Asunto(s)
Ácidos y Sales Biliares , Colestanol , Xantomatosis Cerebrotendinosa , Humanos , Xantomatosis Cerebrotendinosa/genética , Xantomatosis Cerebrotendinosa/diagnóstico , Xantomatosis Cerebrotendinosa/sangre , Colestanol/sangre , Ácidos y Sales Biliares/sangre , Ácidos y Sales Biliares/metabolismo , Masculino , Adulto , Femenino , Ácido Quenodesoxicólico/uso terapéutico , Adulto Joven , Colestanoles/sangreRESUMEN
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.