RESUMEN
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease phenotypes which start with simple steatosis and lipid accumulation in the hepatocytes - a typical histological lesions characteristic. It may progress to non-alcoholic steatohepatitis (NASH) that is characterized by hepatic inflammation and/or fibrosis and subsequent onset of NAFLD-related cirrhosis and hepatocellular carcinoma (HCC). Due to the central role of the liver in metabolism, NAFLD is regarded as a result of and contribution to the metabolic abnormalities seen in the metabolic syndrome. Peroxisome proliferator-activated receptors (PPARs) has three subtypes, which govern the expression of genes responsible for energy metabolism, cellular development, inflammation, and differentiation. The agonists of PPARα, such as fenofibrate and clofibrate, have been used as lipid-lowering drugs in clinical practice. Thiazolidinediones (TZDs) - ligands of PPARγ, such as rosiglitazone and pioglitazone, are also used in the treatment of type 2 diabetes (T2D) with insulin resistance (IR). Increasing evidence suggests that PPARß/δ agonists have potential therapeutic effects in improving insulin sensitivity and lipid metabolism disorders. In addition, PPARs ligands have been considered as potential therapeutic drugs for hypertension, atherosclerosis (AS) or diabetic nephropathy. Their crucial biological roles dictate the significance of PPARs-targeting in medical research and drug discovery. Here, it reviews the biological activities, ligand selectivity and biological functions of the PPARs family, and discusses the relationship between PPARs and the pathogenesis of NAFLD and metabolic syndrome. This will open new possibilities for PPARs application in medicine, and provide a new idea for the treatment of fatty liver and related diseases.
Asunto(s)
Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Síndrome Metabólico , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Síndrome Metabólico/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Hígado/metabolismo , PPAR alfa/metabolismo , Inflamación/metabolismo , Lípidos/uso terapéuticoRESUMEN
Because the excessive apoptosis of articular chondrocytes contributes to extracellular matrix (ECM) loss and cartilage damage in rheumatoid arthritis (RA), inhibiting chondrocyte apoptosis might be a promising strategy for RA. Aquaporin1 (AQP1) is overexpressed in RA cartilage and synovial tissues, and play a vital pathogenic role in RA development. Particularly, we previously reported that acetazolamide (AZ) as an AQP1 inhibitor suppressed secondary inflammation and promoted ECM production in cartilage of adjuvant-induced arthritis rats. Here, we investigated the antiapoptotic effect of AZ on interleukin-1ß (IL-1ß)-induced apoptosis, a classic in vitro model of chondrocyte apoptosis. AZ treatment could inhibit IL-1ß-induced apoptosis, evidenced by increasing cell viability, relieving apoptotic nuclear morphology, decreasing apoptosis rates, and restoring mitochondrial membrane potential. Additionally, AZ reversed IL-1ß-induced decrease of Bcl-2 protein and reduced IL-1ß-induced increases of Bax and caspase 3 protein, accompanied by inhibiting IκBα degradation and phosphorylation in cytoplasm, reducing NF-κB p65 protein level in nucleus and preventing NF-κB p65 translocation from cytoplasm to nucleus. In conclusion, our findings indicated that AZ could effectively attenuate IL-1ß-induced chondrocyte apoptosis mediated by regulating the protein levels of apoptosis-related genes and inhibiting the activation of NF-κB signal pathway, suggesting that AZ might be of potential clinical interest in RA treatment.
Asunto(s)
Acetazolamida/farmacología , Apoptosis/efectos de los fármacos , Inhibidores de Anhidrasa Carbónica/farmacología , Condrocitos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Cartílago Articular/citología , Células Cultivadas , Condrocitos/metabolismo , Interleucina-1beta/metabolismo , Cultivo Primario de Células , Ratas , Ratas Sprague-Dawley , Factor de Transcripción ReIA/metabolismoRESUMEN
G-protein coupled receptor-mediated pathogenesis is of great importance in the development of diabetic complications, but the detailed mechanisms have not yet been clarified. Therefore, we aimed to explore the roles of the prostaglandin E2 receptor 1 (EP1)-mediated signalling pathway and develop a corresponding treatment for diabetic nephropathy (DN). To create the DN model, rats fed a high-fat and high-glucose diet were injected with a single dose of streptozotocin (35 mg/kg, i.p.). Then, rats were either treated or not with berberine (100 mg/kg per day, i.g., 8 weeks). Cells were isolated from the renal cortex and cultured in high-sugar medium with 20% foetal bovine serum. Prostaglandin E2 (PGE2 ) levels were determined by ELISA, and cells were identified by fluorescence immunoassay. We measured the biochemical characteristics and observed morphological changes by periodic-acid-Schiff staining. The expression of the EP1 receptor and the roles of GRK2 and ß-arrestin2 were identified using western blotting and flow cytometry. Downstream proteins were detected by western blot, while molecular changes were assessed by ELISA and laser confocal scanning microscopy. Berberine not only improved the majority of biochemical and renal functional parameters but also improved the histopathological alterations. A significant increase in PGE2 level, EP1 membrane expression and Gαq expression, and concentration of Ca(2+) were observed, accompanied by increased GRK2 and ß-arrestin2 levels soon afterwards. Berberine decreased the abnormal concentration of Ca(2+) , the increased levels of PGE2 , the high expression of EP1 and Gαq and suppressed the proliferation of mesangial cells. The EP1 receptor, a critical therapeutic target of the signalling pathway, contributed to mesangial cell abnormalities, which are linked to renal injury in DN. The observed renoprotective effects of berberine via regulating the PGE2 -EP1-Gαq-Ca(2+) signalling pathway indicating that berberine could be a promising anti-DN medicine in the future.
Asunto(s)
Berberina/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Dinoprostona/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Glomérulos Renales/patología , Células Mesangiales/metabolismo , Sustancias Protectoras/uso terapéutico , Subtipo EP1 de Receptores de Prostaglandina E/metabolismo , Animales , Berberina/farmacología , Biomarcadores/metabolismo , Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Diabetes Mellitus Experimental/patología , Quinasa 2 del Receptor Acoplado a Proteína-G/metabolismo , Pruebas de Función Renal , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/fisiopatología , Masculino , Células Mesangiales/efectos de los fármacos , Sustancias Protectoras/farmacología , Ratas Sprague-Dawley , beta-Arrestinas/metabolismoRESUMEN
Diabetic nephropathy (DN) is a serious complication of diabetes mellitus, and persistent inflammation in circulatory and renal tissues is an important pathophysiological basis for DN. The essence of the microinflammatory state is the innate immune response, which is central to the occurrence and development of DN. Members of the inflammasome family, including both "receptors" and "regulators", are key to the inflammatory immune response. Nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) and other inflammasome components are able to detect endogenous danger signals, resulting in activation of caspase-1 as well as interleukin (IL)-1ß, IL-18 and other cytokines; these events stimulate the inflammatory cascade reaction, which is crucial for DN. Hyperglycaemia, hyperlipidaemia and hyperuricaemia can activate the NLRP3 inflammasome, which then mediates the occurrence and development of DN through the K+ channel model, the lysosomal damage model and the active oxygen cluster model. In this review, we survey the involvement of the NLRP3 inflammasome in various signalling pathways and highlight different aspects of their influence on DN. We also explore the important effects of the NLRP3 inflammasome on kidney function and structural changes that occur during DN development and progression. It is becoming more evident that NLRP3 inflammasome targeting has therapeutic potential for the treatment of DN.
Asunto(s)
Nefropatías Diabéticas/patología , Inflamasomas/inmunología , Riñón/patología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Animales , Nefropatías Diabéticas/inmunología , Nefropatías Diabéticas/fisiopatología , Humanos , Inmunidad Innata , Inflamasomas/análisis , Riñón/inmunología , Riñón/fisiopatología , Proteína con Dominio Pirina 3 de la Familia NLR/análisis , Transducción de SeñalRESUMEN
BACKGROUND: Approaches promoting fibroblast-like synoviocytes (FLS) apoptosis are considered as a meaningful strategy for rheumatoid arthritis (RA) treatment. We have previously reported the anti-arthritic effect of penta-acetyl geniposide ((Ac)5GP, an active derivative of geniposide) on adjuvant-induced arthritis (AIA) rats in vivo. The present study aimed to investigate the pro-apoptotic effect of (Ac)5GP on AIA FLS in vitro and the underlying molecular mechanisms. METHODS: Rat AIA was induced by complete Freund's adjuvant, and FLS were primary-cultured from synovial tissues. AIA FLS were treated with (Ac)5GP (50, 100 and 200⯵M) for 48â¯h and cell proliferation and apoptosis were respectively examined. The involvement of apoptosis-related proteins (Bax, Bcl-2 and caspase 3) and nuclear factor kappa B (NF-κB) signaling pathway was checked. RESULTS: (Ac)5GP inhibited the viability of AIA FLS and reduced the percentage of Ki67-positive cells in AIA FLS. Particularly, (Ac)5GP promoted AIA FLS apoptosis in vitro by inducing apoptotic nuclear morphology, facilitating DNA ladder formation and increasing percentages of both early and late apoptotic cells. (Ac)5GP treatment on AIA FLS decreased Bcl-2 protein level whereas increased the levels of Bax and caspase 3 proteins. Moreover, (Ac)5GP reduced the degradation and phosphorylation of IκBα, down-regulated NF-κB p65 protein level in nucleus and inhibited NF-κB p65 nuclear translocation. CONCLUSIONS: (Ac)5GP had a potent pro-apoptotic effect on AIA FLS in vitro, which is associated with regulating apoptosis-related proteins and inhibiting NF-κB activation.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Iridoides/farmacología , Sinoviocitos/efectos de los fármacos , Factor de Transcripción ReIA/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Artritis Experimental/patología , Caspasa 3/metabolismo , Proliferación Celular/efectos de los fármacos , Fibroblastos , Iridoides/química , Masculino , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Sprague-Dawley , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/metabolismo , Sinoviocitos/metabolismo , Sinoviocitos/patología , Factor de Transcripción ReIA/metabolismoRESUMEN
Previous studies demonstrated that penta-acetyl geniposide ((Ac)5GP, an acetylated derivative of geniposide) exhibited better pharmacological functions than geniposide. This study was aimed to observe the potential effect of (Ac)5GP on adjuvant-induced arthritis (AIA) in rat and explore the involved mechanisms. Rat AIA was induced by complete Freund's adjuvant. (Ac)5GP (30, 60, 120 mg/kg) was given to AIA rats by intragastric administration. Paw swelling, polyarthritis index, serum pro-inflammatory cytokines levels, histological assessments of ankle joint, and proteoglycan expression were respectively measured to evaluate the therapeutic effect of (Ac)5GP on rat AIA. Immunohistochemistry for Ki67 and TUNEL assay were performed to reveal the anti-proliferative and pro-apoptotic effects of (Ac)5GP on AIA synoviocytes in vivo. Protein levels of Bcl-2, Bax, caspase 3, IκBα, p-IκBα, and NF-κB p65 in synovial tissues were detected by Western blot. We found that (Ac)5GP treatment could suppress secondary hind paw swelling, reduce polyarthritis index, decrease TNF-α and IL-1ß serum levels, attenuate pathological damage of ankle joint, and promote proteoglycans expression. (Ac)5GP treatment also could reduce Ki67 positive expression rate and raise the synovial apoptosis index in synovial tissues. Additionally, (Ac)5GP (120 mg/kg) could significantly decrease Bcl-2 protein level, increase Bax and cleaved caspase 3 protein levels, and normalize the ratio of Bcl-2 to Bax. Moreover, (Ac)5GP (120 mg/kg) could inhibit the degradation and phosphorylation of IκBα and reduce NF-κB p65 protein level in nuclear extracts. In conclusion, (Ac)5GP showed a potent anti-arthritic effect on AIA rats via inducing synovial apoptosis and inhibiting NF-κB activation in synovial tissues.
Asunto(s)
Apoptosis/efectos de los fármacos , Artritis Experimental/tratamiento farmacológico , Glucósidos Iridoides/uso terapéutico , FN-kappa B/antagonistas & inhibidores , Membrana Sinovial/patología , Animales , Glucósidos Iridoides/farmacología , Inhibidor NF-kappaB alfa/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Transducción de Señal/efectos de los fármacos , Membrana Sinovial/química , Factor de Transcripción ReIA/efectos de los fármacos , Factor de Transcripción ReIA/metabolismoRESUMEN
In this study, we explored the effect of berberine treatment on the AGEs-RAGE pathway in a rat model of diabetic nephropathy, and we investigated the mechanism by which key factors caused kidney injury and the effects of berberine. In vivo, berberine improved fasting blood glucose, body weight, the majority of biochemical and renal function parameters and histopathological changes in the diabetic kidney. Western blotting and immunohistochemistry revealed significant increases in the levels of AGEs, RAGE, P-PKC-ß and TGF-ß1 in injured kidneys, and these levels were markedly decreased by treatment with berberine. In vitro, berberine inhibited mesangial cell proliferation. Cells treated with berberine showed reduced levels of AGEs, accompanied by decreased RAGE, p-PKC and TGF-ß1 levels soon afterwards. Berberine exhibited renoprotective effects in diabetic nephropathy rats, and the molecular mechanism was associated with changes in the levels and regulation of the AGEs-RAGE-PKC-ß-TGF-ß1 signaling pathway.
Asunto(s)
Berberina/uso terapéutico , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/patología , Productos Finales de Glicación Avanzada/metabolismo , Células Mesangiales/metabolismo , Sustancias Protectoras/uso terapéutico , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Transducción de Señal , Animales , Berberina/farmacología , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/fisiopatología , Regulación hacia Abajo/efectos de los fármacos , Ayuno/sangre , Glucosa/farmacología , Productos Finales de Glicación Avanzada/sangre , Riñón/efectos de los fármacos , Riñón/patología , Riñón/fisiopatología , Pruebas de Función Renal , Masculino , Células Mesangiales/efectos de los fármacos , Células Mesangiales/patología , Fosforilación/efectos de los fármacos , Sustancias Protectoras/farmacología , Proteína Quinasa C beta/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Estreptozocina , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Berberine has proven protective effects on diabetic nephropathy, but the mechanism for its effects has not been comprehensively established. Hence, we aimed to explore the renoprotective mechanism of berberine on the accumulation of extracellular matrix, alterations of its major components and corresponding changes in the regulatory system, including the matrix metalloproteinases/tissue inhibitor of matrix metalloproteinases (MMPs/TIMPs) system, in diabetic nephropathy rats. In the experiments, diabetic nephropathy rats were treated with berberine (0, 50, 100, 200 mg/kg) respectively. The protein levels of transforming growth factor-ß1 were then detected by Western blot, while fibronectin and type IV collagen levels were assessed using immunohistochemistry. Changes in the MMP2/9 and TIMP1/2 levels were detected using two forms simultaneously. In addition, we also measured the characteristics and biochemical indicators of the diabetic nephropathy rats. The results showed that berberine could ameliorate the fasting blood glucose, and the majority of biochemical and renal function parameters, but did not have an effect on body weight. Immunohistochemistry and Western blot examination revealed a significant increase in the MMP9 and TIMP1/2 levels, with an obvious decrease in MMP2 expression in the diabetic nephropathy rats. Berberine (100 and 200 mg/kg) could significantly improve the abnormal changes in the MMPs/TIMPs system. Meanwhile, reductions in the transforming growth factor-ß1, fibronectin and type IV collagen expression levels were observed in the berberine treatment groups. Therefore, the renoprotective effects of berberine on diabetic nephropathy might be associated with changes in the extracellular matrix through the regulation of the MMPs/TIMPs system in the rat kidney.