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1.
Mol Pharm ; 21(6): 2922-2936, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38751169

RESUMEN

With the increased prevalence of nonalcoholic steatohepatitis (NASH) in the world, effective pharmacotherapy in clinical practice is still lacking. Previous studies have shown that dibenzazepine (DBZ), a Notch inhibitor, could alleviate NASH development in a mouse model. However, low bioavailability, poor water solubility, and extrahepatic side effects restrict its clinical application. To overcome these barriers, we developed a reactive oxygen species (ROS)-sensitive nanoparticle based on the conjugation of bilirubin to poly(ethylene glycol) (PEG) chains, taking into account the overaccumulation of hepatic ROS in the pathologic state of nonalcoholic steatohepatitis (NASH). The PEGylated bilirubin can self-assemble into nanoparticles in an aqueous solution and encapsulate insoluble DBZ into its hydrophobic cavity. DBZ nanoparticles (DBZ Nps) had good stability, rapidly released DBZ in response to H2O2, and effectively scavenged intracellular ROS of hepatocytes. After systemic administration, DBZ Nps could accumulate in the liver of the NASH mice, extend persistence in circulation, and improve the bioavailability of DBZ. Furthermore, DBZ Nps significantly improved glucose intolerance, relieved hepatic lipid accumulation and inflammation, and ameliorated NASH-induced liver fibrosis. Additionally, DBZ Nps had no significant extrahepatic side effects. Taken together, our results highlight the potential of the ROS-sensitive DBZ nanoparticle as a promising therapeutic strategy for NASH.


Asunto(s)
Lipogénesis , Hígado , Ratones Endogámicos C57BL , Nanopartículas , Enfermedad del Hígado Graso no Alcohólico , Especies Reactivas de Oxígeno , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ratones , Nanopartículas/química , Lipogénesis/efectos de los fármacos , Masculino , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Receptores Notch/metabolismo , Receptores Notch/antagonistas & inhibidores , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Bilirrubina , Polietilenglicoles/química , Modelos Animales de Enfermedad , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Dibenzazepinas
2.
Drug Metab Dispos ; 51(2): 237-248, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36414407

RESUMEN

Metabolic diseases are a series of metabolic disorders that include obesity, diabetes, insulin resistance, hypertension, and hyperlipidemia. The increased prevalence of metabolic diseases has resulted in higher mortality and mobility rates over the past decades, and this has led to extensive research focusing on the underlying mechanisms. Xenobiotic receptors (XRs) are a series of xenobiotic-sensing nuclear receptors that regulate their downstream target genes expression, thus defending the body from xenobiotic and endotoxin attacks. XR activation is associated with the development of a number of metabolic diseases such as obesity, nonalcoholic fatty liver disease, type 2 diabetes, and cardiovascular diseases, thus suggesting an important role for XRs in modulating metabolic diseases. However, the regulatory mechanism of XRs in the context of metabolic disorders under different nutrient conditions is complex and remains controversial. This review summarizes the effects of XRs on different metabolic components (cholesterol, lipids, glucose, and bile acids) in different tissues during metabolic diseases. As chronic inflammation plays a critical role in the initiation and progression of metabolic diseases, we also discuss the impact of XRs on inflammation to comprehensively recognize the role of XRs in metabolic diseases. This will provide new ideas for treating metabolic diseases by targeting XRs. SIGNIFICANCE STATEMENT: This review outlines the current understanding of xenobiotic receptors on nutrient metabolism and inflammation during metabolic diseases. This work also highlights the gaps in this field, which can be used to direct the future investigations on metabolic diseases treatment by targeting xenobiotic receptors.


Asunto(s)
Diabetes Mellitus Tipo 2 , Enfermedades Metabólicas , Humanos , Xenobióticos/metabolismo , Inflamación , Obesidad/metabolismo
3.
FASEB J ; 36(6): e22349, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35567505

RESUMEN

Excessive lipid accumulation, inflammation, and fibrosis in the liver are the major characteristics of non-alcoholic steatohepatitis (NASH). Mesencephalic astrocyte-derived neurotrophic factor (MANF) plays an important role in metabolic homeostasis, raising the possibility that it is involved in NASH. Here, we reduced and increased MANF levels in mice in order to explore its influence on hepatic triglyceride homeostasis, inflammation, and fibrosis during NASH progression. The MANF expression was decreased in Western diet-induced NASH mice. In vivo, liver-specific MANF knockout exacerbated hepatic lipid accumulation, inflammation, and fibrosis of mice induced by Western diet, while liver-specific MANF overexpression mitigated these NASH pathogenic features. In vitro, knocking down MANF in primary hepatocyte cultures aggravated hepatic steatosis and inflammation, which MANF overexpression markedly attenuated. Studies in vitro and in vivo suggested that MANF regulated hepatic lipid synthesis by modulating SREBP1 expression. Inhibiting SREBP1 in primary hepatocytes blocked lipid accumulation after MANF knockdown. MANF overexpression reversed LXRs agonist GW3965 induced SREBP1 and LIPIN1 expression. MANF decreased the expression of pro-inflammatory cytokines by inhibiting NF-κB phosphorylation. These results suggest that MANF can protect against NASH by regulating SREBP1 expression and NF-κB signaling.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Animales , Astrocitos/metabolismo , Dieta Occidental , Fibrosis , Inflamación/metabolismo , Lípidos , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo
4.
Molecules ; 28(15)2023 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-37570771

RESUMEN

The aberrant expansion of GGGGCC hexanucleotide repeats within the first intron of the C9orf72 gene represent the predominant genetic etiology underlying amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The transcribed r(GGGGCC)n RNA repeats form RNA foci, which recruit RNA binding proteins and impede their normal cellular functions, ultimately resulting in fatal neurodegenerative disorders. Furthermore, the non-canonical translation of the r(GGGGCC)n sequence can generate dipeptide repeats, which have been postulated as pathological causes. Comprehensive structural analyses of r(GGGGCC)n have unveiled its polymorphic nature, exhibiting the propensity to adopt dimeric, hairpin, or G-quadruplex conformations, all of which possess the capacity to interact with RNA binding proteins. Small molecules capable of binding to r(GGGGCC)n have been discovered and proposed as potential lead compounds for the treatment of ALS and FTD. Some of these molecules function in preventing RNA-protein interactions or impeding the phase transition of r(GGGGCC)n. In this review, we present a comprehensive summary of the recent advancements in the structural characterization of r(GGGGCC)n, its propensity to form RNA foci, and its interactions with small molecules and proteins. Specifically, we emphasize the structural diversity of r(GGGGCC)n and its influence on partner binding. Given the crucial role of r(GGGGCC)n in the pathogenesis of ALS and FTD, the primary objective of this review is to facilitate the development of therapeutic interventions targeting r(GGGGCC)n RNA.


Asunto(s)
Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Humanos , Esclerosis Amiotrófica Lateral/metabolismo , Demencia Frontotemporal/genética , Secuencia de Bases , Expansión de las Repeticiones de ADN , ARN/genética , ARN/química , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo
5.
Biochem Biophys Res Commun ; 602: 163-169, 2022 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-35278889

RESUMEN

Paracetamol (APAP), an over-the-counter drug, is normally safe within the therapeutic dose range but can cause irreversible liver damage after an overdose. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress protein and plays a crucial role in metabolic disease. However, the role of MANF in APAP-induced acute hepatotoxicity is still unknown. We used hepatocyte-specific MANF-knockout mice and hepatocyte-specific MANF transgenic mice to investigate the role of hepatocyte-derived MANF in APAP-induced acute liver injury. MANF deficiency was associated with a decreased expression of detoxification enzymes, aggravated glutathione depletion and apoptosis in hepatocytes. Mechanistically, MANF knockout significantly increased PERK-eIF2α-ATF4-CHOP signaling pathway. Blockade of PERK abolished MANF deficiency-over-induced hepatotoxicity after APAP administration. Conversely, hepatocyte-specific MANF overexpression attenuated APAP-induced hepatotoxicity by downregulating the PERK-eIF2α-ATF4-CHOP signaling pathway. Thus, hepatocyte-derived MANF may play a protective role in APAP-induced hepatotoxicity.


Asunto(s)
Acetaminofén , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Acetaminofén/toxicidad , Animales , Apoptosis , Astrocitos/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/tratamiento farmacológico , Estrés del Retículo Endoplásmico , Factor 2 Eucariótico de Iniciación/metabolismo , Ratones , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/metabolismo , Transducción de Señal
6.
Hepatology ; 73(3): 1140-1157, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32535965

RESUMEN

BACKGROUNDS AND AIMS: Activation of hepatic stellate cells (HSCs) is a central driver of fibrosis. This study aimed to elucidate the role of the deacetylase sirtuin 6 (Sirt6) in HSC activation and liver fibrosis. APPROACH AND RESULTS: Gain-of-function and loss-of-function models were used to study the function of Sirt6 in HSC activation. Mass spectrometry was used to determine the specific acetylation site. The lecithin retinol acyltransferase-driven cyclization recombination recombinase construct (CreERT2) mouse line was created to generate HSC-specific conditional Sirt6-knockout mice (Sirt6△HSC ). We found that Sirt6 is most abundantly expressed in HSCs as compared with other liver cell types. The expression of Sirt6 was decreased in activated HSCs and fibrotic livers of mice and humans. Sirt6 knockdown and Sirt6 overexpression increased and decreased fibrogenic gene expression, respectively, in HSCs. Mechanistically, Sirt6 inhibited the phosphorylation and nuclear localization of mothers against decapentaplegic homolog (Smad) 2. Further study demonstrated that Sirt6 could directly interact with Smad2, deacetylate Smad2, and decrease the transcription of transforming growth factor ß/Smad2 signaling. Mass spectrometry revealed that Sirt6 deacetylated conserved lysine 54 on Smad2. Mutation of lysine 54 to Arginine in Smad2 abolished the regulatory effect of Sirt6. In vivo, specific ablation of Sirt6 in HSCs exacerbated hepatocyte injury and cholestasis-induced liver fibrosis in mice. With targeted delivery of the Sirt6 agonist MDL-800, its concentration was 9.28-fold higher in HSCs as compared with other liver cells and alleviated hepatic fibrosis. CONCLUSIONS: Sirt6 plays a key role in HSC activation and liver fibrosis by deacetylating the profibrogenic transcription factor Smad2. Sirt6 may be a potential therapeutic target for liver fibrosis.


Asunto(s)
Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática/metabolismo , Sirtuinas/metabolismo , Proteína Smad2/metabolismo , Animales , Inmunoprecipitación de Cromatina , Técnica del Anticuerpo Fluorescente , Humanos , Cirrosis Hepática/etiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
7.
FASEB J ; 35(3): e21408, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33583107

RESUMEN

Sirtuin 6 (Sirt6), a member of the Sirtuin family, has important roles in maintaining glucose and lipid metabolism. Our previous studies demonstrated that the deletion of Sirt6 in pro-opiomelanocortin (POMC)-expressing cells by the loxP-Cre system resulted in severe obesity and hepatic steatosis. However, whether overexpression of Sirt6 in hypothalamic POMC neurons could ameliorate diet-induced obesity is still unknown. Thus, we generated mice specifically overexpressing Sirt6 in hypothalamic POMC neurons (PSOE) by stereotaxic injection of Cre-dependent adeno-associated viruses into the arcuate nucleus of Pomc-Cre mice. PSOE mice showed increased adiposity and decreased energy expenditure. Furthermore, thermogenesis of BAT and lipolysis of WAT were both impaired, caused by reduced sympathetic nerve innervation and activity in adipose tissues. Mechanistically, Sirt6 overexpression decreasing STAT3 acetylation, thus lowering POMC expression in the hypothalamus underlined the observed phenotypes in PSOE mice. These results demonstrate that Sirt6 overexpression specifically in the hypothalamic POMC neurons exacerbates diet-induced obesity and metabolic disorders via the hypothalamus-adipose axis.


Asunto(s)
Hipotálamo/metabolismo , Neuronas/metabolismo , Obesidad/etiología , Proopiomelanocortina/metabolismo , Sirtuinas/metabolismo , Tejido Adiposo/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Metabolismo Energético/fisiología , Leptina/metabolismo , Ratones Endogámicos C57BL , Obesidad/metabolismo , Proopiomelanocortina/genética
8.
Biochem Biophys Res Commun ; 550: 197-203, 2021 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-33713857

RESUMEN

Alcoholic fatty liver disease (AFLD) is induced by alcohol consumption and may progress to more severe liver diseases such as alcoholic steatohepatitis, fibrosis and cirrhosis, and even hepatocellular carcinoma. Mesencephalic astrocyte-derived neurotrophic factor (MANF) participates in maintaining lipid homeostasis. However, the role of MANF in the pathogenesis of AFLD remains unclear. We established an AFLD mouse model following the US National Institute on Alcohol Abuse and Alcoholism procedure. Both mRNA and protein levels of MANF were significantly increased in the chronic binge alcohol feeding model. Liver-specific knockout of MANF aggravated hepatic lipid accumulation. Similarly, liver-specific overexpression of MANF alleviated AFLD in mouse livers. MANF affected hepatic lipid metabolism by modulating autophagy. The levels of LC3-II and Atg5-Atg12 were decreased in mouse livers with MANF liver-specific knockout and increased with MANF liver-specific overexpression. Furthermore, MANF changed the phosphorylation of Stat3 and its nuclear localization. MANF may have a protective role in the development of AFLD.


Asunto(s)
Autofagia , Hígado Graso Alcohólico/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Autofagia/efectos de los fármacos , Consumo Excesivo de Bebidas Alcohólicas , Etanol/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Factores de Crecimiento Nervioso/deficiencia , Fosforilación
9.
Mol Pharm ; 18(3): 1373-1385, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33544609

RESUMEN

Renal fibrosis is the final manifestation of various chronic kidney diseases. Interstitial myofibroblasts, which are reported to highly express integrin αvß3, are the effector cells in renal fibrogenesis. Since current therapies do not efficiently target these cells, there is no effective therapeutic method for preventing or mitigating the disease. Here, we modified sterically stable PEGylated liposomes with the pentapeptide cRGDfC (RGD-Lip), which has a high affinity for αvß3, to specifically deliver drug to renal interstitial myofibroblasts. Our results showed that attaching cRGDfC to liposomes significantly increased their uptake by activated renal fibroblasts NRK-49F cells, and this effect was greatly abolished by adding excess-free cRGDfC or a knockdown of αvß3. Systemic administration of RGD-Lip gave rise to significant accumulation in a fibrotic kidney, which is ascribed to the specific recognition with integrin αvß3 on interstitial myofibroblasts. When loaded with celastrol, RGD-guided liposomes dramatically depressed the proliferation and activation of NRK-49F cells in vitro. Additionally, celastrol-loaded RGD-Lip markedly attenuated renal fibrosis, injury, and inflammation induced by unilateral ureteral obstruction (UUO) in mice, without inducing significant systemic toxicity. Thus, this liposomal system shows great promise for delivering therapeutic agents to interstitial myofibroblasts for renal fibrosis treatment with minimal side effects.


Asunto(s)
Fibrosis/metabolismo , Integrina alfaVbeta3/metabolismo , Riñón/metabolismo , Miofibroblastos/metabolismo , Animales , Línea Celular , Células Epiteliales/metabolismo , Fibroblastos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Células RAW 264.7 , Ratas , Insuficiencia Renal Crónica/metabolismo , Transducción de Señal/fisiología , Factor de Crecimiento Transformador beta1/metabolismo , Obstrucción Ureteral/metabolismo
10.
Sheng Li Xue Bao ; 73(5): 745-754, 2021 Oct 25.
Artículo en Zh | MEDLINE | ID: mdl-34708231

RESUMEN

SIRT6, a member of the silencing information regulatory protein family, is a nicotinamide adenine dinucleotide-dependent histone deacetylase and an ADP-ribose transferase enzyme. It plays an important role in fundamental physiological and pathological processes, including lipid metabolism, inflammation, oxidative stress and fibrosis, and is considered as a potential therapeutic target for metabolic syndrome. SIRT6 knockout mice displayed severe fatty liver, and the expression of SIRT6 in the liver of nonalcoholic steatohepatitis (NASH) mice was significantly lower than that of normal mice. Overexpression of SIRT6 significantly ameliorated NASH-induced liver damage. It is suggested that SIRT6 may play a key role in protecting against NASH. In this paper, we review the important regulatory functions of SIRT6 in the occurrence and development of NASH.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Sirtuinas , Animales , Hígado , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Estrés Oxidativo , Sirtuinas/genética , Sirtuinas/metabolismo
11.
J Biol Chem ; 294(5): 1579-1589, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30530497

RESUMEN

Sirt6 is an NADH (NAD+)-dependent deacetylase with a critical role in hepatic lipid metabolism. Ketogenesis is controlled by a signaling network of hepatic lipid metabolism. However, how Sirt6 functions in ketogenesis remains unclear. Here, we demonstrated that Sirt6 functions as a mediator of ketogenesis in response to a fasting and ketogenic diet (KD). The KD-fed hepatocyte-specific Sirt6 deficiency (HKO) mice exhibited impaired ketogenesis, which was due to enhanced Fsp27 (fat-specific induction of protein 27), a protein known to regulate lipid metabolism. In contrast, overexpression of Sirt6 in mouse primary hepatocytes promoted ketogenesis. Mechanistically, Sirt6 repressed Fsp27ß expression by interacting with Crebh (cAMP response element-binding protein H) and preventing its recruitment to the Fsp27ß gene promoter. The KD-fed HKO mice also showed exacerbated hepatic steatosis and inflammation. Finally, Fsp27 silencing rescued hypoketonemia and other metabolic phenotypes in KD-fed HKO mice. Our data suggest that the Sirt6-Crebh-Fsp27 axis is pivotal for hepatic lipid metabolism and inflammation. Sirt6 may be a pharmacological target to remedy metabolic diseases.


Asunto(s)
Hepatocitos/metabolismo , Cuerpos Cetónicos/biosíntesis , Proteínas/metabolismo , Sirtuinas/fisiología , Animales , Hepatocitos/citología , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
12.
Gastroenterology ; 157(3): 793-806.e14, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31170413

RESUMEN

BACKGROUND & AIMS: The role of aryl hydrocarbon receptor (AhR) in liver fibrosis is controversial because loss and gain of AhR activity both lead to liver fibrosis. The goal of this study was to investigate how the expression of AhR by different liver cell types, hepatic stellate cells (HSCs) in particular, affects liver fibrosis in mice. METHODS: We studied the effects of AhR on primary mouse and human HSCs, measuring their activation and stimulation of fibrogenesis using RNA-sequencing analysis. C57BL/6J mice were given the AhR agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE); were given carbon tetrachloride (CCl4); or underwent bile duct ligation. We also performed studies in mice with disruption of Ahr specifically in HSCs, hepatocytes, or Kupffer cells. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, and immunoblotting. RESULTS: AhR was expressed at high levels in quiescent HSCs, but the expression decreased with HSC activation. Activation of HSCs from AhR-knockout mice was accelerated compared with HSCs from wild-type mice. In contrast, TCDD or ITE inhibited spontaneous and transforming growth factor ß-induced activation of HSCs. Mice with disruption of Ahr in HSCs, but not hepatocytes or Kupffer cells, developed more severe fibrosis after administration of CCl4 or bile duct ligation. C57BL/6J mice given ITE did not develop CCl4-induced liver fibrosis, whereas mice without HSC AhR given ITE did develop CCl4-induced liver fibrosis. In studies of mouse and human HSCs, we found that AhR prevents transforming growth factor ß-induced fibrogenesis by disrupting the interaction of Smad3 with ß-catenin, which prevents the expression of genes that mediate fibrogenesis. CONCLUSIONS: In studies of human and mouse HSCs, we found that AhR prevents HSC activation and expression of genes required for liver fibrogenesis. Development of nontoxic AhR agonists or strategies to activate AhR signaling in HSCs might be developed to prevent or treat liver fibrosis.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Senescencia Celular , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática Experimental/prevención & control , Hígado/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/agonistas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/deficiencia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proliferación Celular , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Regulación de la Expresión Génica , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/patología , Indoles/farmacología , Hígado/efectos de los fármacos , Hígado/patología , Cirrosis Hepática Experimental/genética , Cirrosis Hepática Experimental/metabolismo , Cirrosis Hepática Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/deficiencia , Receptores de Hidrocarburo de Aril/genética , Transducción de Señal , Proteína smad3/metabolismo , Tiazoles/farmacología , beta Catenina/metabolismo
13.
Biochem Biophys Res Commun ; 523(3): 787-794, 2020 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-31948761

RESUMEN

Telmisartan is a known angiotensin II (Ang II) AT1 receptor blocker (ARB). While the beneficial effect of Telmisartan on glucose and lipid metabolism has been reported, the underlying molecular mechanism remained unclear. The endoplasmic reticulum (ER) stress is considered as one of important factors contributing to insulin resistance. In this study, we found that Telmisartan alleviated diet-induced obesity and insulin resistance, suppressed inflammation in adipose tissue, and alleviated hepatic steatosis. Furthermore, we showed that Telmisartan suppressed ER stress by activating AMP-activated protein kinase (AMPK) signaling pathway in vivo. In differentiated 3T3-L1 adipocytes, Telmisartan also improved palmitate acid (PA) induced ER stress. Compound C, an AMPK inhibitor, could abolish beneficial effect of Telmisartan on ER stress. Our data indicated Telmisartan improved obesity-induced insulin resistance through suppression of ER stress by activation of AMPK. These results provided the evidence that Telmisartan may have therapeutic potential for the treatment of obesity and type II diabetes.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Resistencia a la Insulina , Obesidad/tratamiento farmacológico , Telmisartán/uso terapéutico , Células 3T3-L1 , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Activación Enzimática/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/complicaciones , Obesidad/metabolismo , Telmisartán/farmacología
14.
Mol Pharm ; 17(11): 4152-4162, 2020 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-33089693

RESUMEN

Liver fibrosis is a common outcome of most chronic liver diseases, but there is no clinically approved drug for its treatment. Previous studies have reported the potential of SB431542 as an inhibitor of TGF-ß signaling in the treatment of liver fibrosis, but it shows poor water solubility and low bioavailability. Here, we improve these characteristics of SB431542 by loading it into liposomes (SB-Lips) with two FDA-approved excipients: soya phosphatidyl S100 and Solutol HS15. In vitro, SB-Lips had stronger inhibitory effects on the proliferation and activation of hepatic stellate cells LX-2 than free SB. After an intravenous injection in a CCl4-induced liver fibrosis mouse model, SB-Lips accumulated preferentially in the liver, its area under the concentration-time curve was significantly higher than that of free SB431542, and it alleviated hepatic fibrosis significantly more than free drug, which was associated with greater inhibition of TGF-ß signaling. Furthermore, SB-Lips did not cause significant injury to other organs. These results suggest that our liposomal system is safe and effective for delivering SB431542 to fibrotic liver.


Asunto(s)
Benzamidas/administración & dosificación , Benzamidas/farmacocinética , Dioxoles/administración & dosificación , Dioxoles/farmacocinética , Cirrosis Hepática Experimental/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Animales , Tetracloruro de Carbono/efectos adversos , Línea Celular , Modelos Animales de Enfermedad , Liberación de Fármacos , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Humanos , Liposomas , Cirrosis Hepática Experimental/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Distribución Tisular
15.
J Cell Physiol ; 234(10): 17578-17588, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30793300

RESUMEN

Cardiac hypertrophy is the main cause of heart failure and sudden death in patients. But the pathogenesis is unclear. Angiotensin II may contribute to cardiac hypertrophy in response to pressure overload. In angiotensin II-treated cardiomyocytes, there is a larger cross-sectional area, more apoptosis cells, and a reduction of irisin expression. An increase in P62, an autophagy flux index, as well as LC3II, were observed in cardiomyocytes after angiotensin II-induced injury. Surprisely, irisin supplementation increased LC3II expression and decreased P62 expression, consisted of results of RFP-GFP-LC3B adenovirus transfection, and reduced cardiomyocyte apoptosis, meanwhile, the protection of irisin was reversed by the autophagy inhibitor 3-methyladenine. In animal experiments, overexpression of irisin reduced cardiomyocyte apoptosis and alleviated myocardial hypertrophy caused by pressure overload. The above results indicate that irisin-induced protective autophagy and alleviated the apoptosis signaling pathway in cardiomyocytes, consequently reducing cardiomyocyte apoptosis after angiotensin II-induced injury. Hence, increasing irisin expression may be a new way to improve cardiac function and quality of life in patients with cardiac hypertrophy.


Asunto(s)
Angiotensina II/fisiología , Apoptosis/fisiología , Autofagia/fisiología , Fibronectinas/farmacología , Fibronectinas/fisiología , Miocitos Cardíacos/patología , Miocitos Cardíacos/fisiología , Angiotensina II/farmacología , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Cardiomegalia/etiología , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Células Cultivadas , Regulación hacia Abajo , Fibronectinas/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Miocitos Cardíacos/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Transducción de Señal/efectos de los fármacos
16.
J Hepatol ; 71(1): 212-221, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30871980

RESUMEN

Liver diseases affect millions of people worldwide. In most developed countries, the incidence of viral hepatitis is waning as a result of modern advances in disease prevention, diagnosis, and therapies. Expanded programmes for systematic immunisation against hepatitis B virus have also significantly brought down the number of new cases in many countries, including China. In contrast, with the improvement in living standards, the prevalence of metabolic liver diseases including non-alcoholic fatty liver disease and alcohol-related liver disease is set to rise, ultimately leading to more cases of end-stage liver diseases (liver failure, cirrhosis, and liver cancer). Over the past 30 years, visionary governments of major nations have provided strong incentives for basic/clinical research, vaccination programmes, and drug discovery and development in the field of hepatology. To get rid of her unflattering title as the "leader in liver diseases", China has also made a serious effort to initiate nationwide preventive measures for liver diseases, global partnerships, and mentoring programmes for young hepatologists. Instrumental to such progress is the continuous support of the National Natural Science Foundation of China (NSFC), which has helped hepatology to thrive in virtually all research directions within the country. In this article, we seek to provide stimulating glimpses into the evolving liver disease epidemiology, institutional research profiles, funding landscape, and drug development trends in China, with an attempt to compare her status and achievements with those of the United States, European countries, and Japan.


Asunto(s)
Investigación Biomédica/tendencias , Gastroenterología/métodos , Hepatopatías , China , Carga Global de Enfermedades , Humanos , Hepatopatías/clasificación , Hepatopatías/epidemiología
17.
Wound Repair Regen ; 27(4): 366-374, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30706567

RESUMEN

Sirtuin 6 (Sirt6) is an NAD+-dependent deacetylase that regulates central metabolic functions such as glucose homeostasis, fat metabolism, and cell apoptosis. However, the tissue-specific function of Sirt6 in liver regeneration remains unknown. Here, we show that liver-specific Sirt6 knockout (Sirt6LKO) impaired liver reconstitution after 2/3 partial hepatectomy, which was attributed to an alteration of cell cycle progression. Sirt6 LKO delayed hepatocyte transition into S phase during liver regeneration, as shown by the analysis of cell cycle-related proteins and the immuno staining of Ki-67 and 5-bromo-2-deoxyuridine (BrdU). The delayed cell cycle in Sirt6 LKO mice was attributed to the disruption of m-TOR and Akt activity, which is an important pro-proliferation pathway in liver regeneration. Sirt6 LKO also reduced carbon tetrachloride (CCl4 )-induced liver damage. Our results suggest that Sirt6 LKO impaired liver regeneration via delayed cell cycle and impaired m-TOR and Akt activity.


Asunto(s)
Hepatectomía , Hepatocitos/fisiología , Regeneración Hepática/efectos de los fármacos , Hígado/patología , Sirtuinas/efectos adversos , Animales , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Regeneración Hepática/fisiología , Ratones , Ratones Noqueados
18.
J Mol Cell Cardiol ; 121: 242-255, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30053525

RESUMEN

In hypertrophic hearts, autophagic flux insufficiency is recognized as a key pathology leading to maladaptive cardiac remodeling and heart failure. This study aimed to illuminate the cardioprotective role and mechanisms of a new myokine and adipokine, irisin, in cardiac hypertrophy and remodeling. Adult male wild-type, mouse-FNDC5 (irisin-precursor)-knockout and FNDC5 transgenic mice received 4 weeks of transverse aortic constriction (TAC) alone or combined with intraperitoneal injection of chloroquine diphosphate (CQ). Endogenous FNDC5 ablation aggravated and exogenous FNDC5 overexpression attenuated the TAC-induced hypertrophic damage in the heart, which was comparable to the protection of irisin against cardiomyocyte hypertrophy induced by angiotensin II (Ang II) or phenylephrine (PE). Accumulated autophagosome and impaired autophagy flux occurred in the TAC-treated myocardium and Ang II- or PE-insulted cardiomyocytes. Irisin deficiency caused reduced autophagy and aggravated autophagy flux failure, whereas irisin overexpression or supplementation induced protective autophagy and improved autophagy flux, which were reversed by autophagy inhibitors Atg5 siRNA, 3-MA and CQ. Irisin boosted the activity of only AMPK but not Akt and MAPK family members in hypertrophic hearts and cultured cardiomyocytes and further activated ULK1 at Ser555 but not Ser757 and did not affect the mTOR-S6K axis. Blockage of AMPK and ULK1 with compund C and SBI-0206965, respectively, both abrogated irisin's protection against cardiomyocyte hypertrophic injury and reversed its induction of both autophagy and autophagy flux. Our results suggest that irisin protects against pressure overload-induced cardiac hypertrophy by inducing protective autophagy and autophagy flux via activating AMPK-ULK1 signaling.


Asunto(s)
Proteínas Quinasas Activadas por AMP/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Cardiomegalia/genética , Fibronectinas/genética , Insuficiencia Cardíaca/genética , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Angiotensina II/administración & dosificación , Animales , Autofagia/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/antagonistas & inhibidores , Benzamidas/administración & dosificación , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/patología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/patología , Humanos , Ratones , Ratones Transgénicos , Miocitos Cardíacos/efectos de los fármacos , Fenilefrina/administración & dosificación , Presión , Pirimidinas/administración & dosificación , Transducción de Señal , Serina-Treonina Quinasas TOR/genética
19.
Am J Pathol ; 187(4): 808-818, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28283178

RESUMEN

Cholesterol gallstone disease (CGD) is one of the most common gastrointestinal diseases. Lithogenic hepatic bile secretion precedes the formation of cholesterol gallstones. Constitutive androstane receptor (CAR), a member of nuclear family, plays an important role in cholesterol and bile acid metabolism. To examine whether activation of CAR can prevent cholesterol gallstone formation, we treated C57BL6/J mice maintained on a lithogenic diet with CAR agonist 1,4-bis-[2-(3, 5-dichlorpyridyloxy)] benzene and performed bile duct cannulation to study the dynamics of biliary lipids. We report that activation of CAR decreases the biliary cholesterol concentration and prevents CGD formation. The lower biliary cholesterol level was largely attributed to suppressed Abcg5 and Abcg8 expression in CAR-activated mice. CAR activation also promoted cholesterol conversion into bile acids by increasing the expression of Cyp7a1, a rate-limiting enzyme in bile acid biosynthesis. Activation of CAR enhanced bile acid re-absorption via increasing the expression of bile acid transporters Asbt and Ostß in the ileum. The hepatic steatosis was also improved in the liver of CAR-activated mice. Furthermore, activation of CAR protected the mice against the liver X receptor α-sensitized CGD through suppressing the expression of Abcg5/8. Collectively, CAR plays an important role in maintaining the homeostasis of cholesterol, bile acids, and triglycerides levels, and it might be a promising therapeutic target for preventing or treating CGD.


Asunto(s)
Colesterol/efectos adversos , Cálculos Biliares/metabolismo , Cálculos Biliares/prevención & control , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Bilis/metabolismo , Canalículos Biliares/metabolismo , Transporte Biológico/genética , Colesterol 7-alfa-Hidroxilasa , Receptor de Androstano Constitutivo , Hígado Graso/genética , Hígado Graso/patología , Vesícula Biliar/metabolismo , Vesícula Biliar/patología , Cálculos Biliares/patología , Regulación de la Expresión Génica , Lipogénesis/genética , Hígado/metabolismo , Hígado/patología , Receptores X del Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Fosfolípidos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo
20.
Endocr J ; 64(4): 403-410, 2017 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-28216543

RESUMEN

Evidence has shown that endoplasmic reticulum (ER) stress was involved in the progression to type 2 diabetes mellitus (T2DM) and development of insulin resistance. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel secreted protein upregulated by ER stress. This study aimed to assess serum level of MANF in normal glucose tolerance (NGT) participants and newly diagnosed prediabetic and T2DM patients. A total of 257 participants with NGT, newly diagnosed prediabetes or T2DM were recruited from Yinchao and Hangtian communities of Chengdu, Sichuan, China. Serum MANF level was quantified by enzyme-linked immunosorbent assay (ELISA). The mean age for the 257 participants (147 females) was 62±8 years (range 44-78): 71 with NGT, 115 with newly diagnosed prediabetes and 71 with T2DM. Mean serum MANF level was significantly higher with newly diagnosed prediabetes and T2DM than NGT (2.89±1.09 and 3.03±1.73 vs 2.13±1.37 ng/mL, both p<0.001). MANF level was not correlated with insulin sensitivity indexes (homeostasis model assessment for insulin resistance [HOMA-IR], Matsuda Index and quantitative insulin sensitivity check index [QUICKI]) for NGT and T2DM participants but was correlated with such indexes for prediabetes patients. We concluded that serum MANF level was higher in patients with newly diagnosed prediabetes and T2DM than in NGT controls. MANF appears to be associated with Matsuda Index, QUICKI and HOMA-IR in prediabetes patients.


Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Resistencia a la Insulina , Factores de Crecimiento Nervioso/sangre , Estado Prediabético/sangre , Adulto , Anciano , Pueblo Asiatico , Glucemia/metabolismo , Estudios de Casos y Controles , China , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Intolerancia a la Glucosa/sangre , Humanos , Masculino , Persona de Mediana Edad , Estado Prediabético/diagnóstico
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