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1.
Chem Pharm Bull (Tokyo) ; 67(9): 1006-1014, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474723

RESUMO

Chlorogenic acid (CGA) has been considered as one of important active components in a number of medicinal herbs. Recently our group demonstrated that caffeoyl salicylate scaffold derived from CGA can be employed for the development of novel anti-inflammatory agents. The most active compound D104 can be a very promising starting point for the further structural optimization. A series of novel caffeoyl salicylate analogs were designed, synthesized, and evaluated by preliminary biological evaluation. The obtained results showed that the two compounds B12 and B13 can not only inhibit production of nitric oxide (NO) in RAW264.7 cells induced by lipopolysaccharides (LPS) effectively, but also have high safety in in vitro cytotoxic test, which could be comparable with D104. Molecular docking study on the peroxisome proliferator-activated receptor γ (PPARγ) protein revealed that compounds B12 and B13 can follow the same binding mode with D104, and the carboxyl group of caffeoyl salicylate scaffold might play a key role in the interaction with protein target, which implied the carboxyl group should be retained in the further optimization.


Assuntos
Ácido Clorogênico/química , Óxido Nítrico/metabolismo , Ácido Salicílico/química , Células A549 , Animais , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Ácido Clorogênico/farmacologia , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , PPAR gama/química , PPAR gama/metabolismo , Estrutura Terciária de Proteína , Células RAW 264.7
2.
Cell Biochem Funct ; 37(7): 560-568, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31479167

RESUMO

Annexin A1 (AnxA1) is a protein secreted by phagocytic cells which plays a pivotal role on the resolution of inflammation by enhancing phagocytosis carried out by phagocytes. Which factors and intracellular mechanisms are linked to such actions exerted by AnxA1 are yet to be completely understood. In order to investigate such, BV2 microglial cells were transfected with plasmids aimed at down-modulating AnxA1 expression and also treated with exogenous recombinant rAnxA1; gene and protein expression of proliferated-activated receptor γ (PPARγ) and CD36, STAT6 phosphorylation and phagocytosis of apoptotic neurons were investigated. Down-modulating AnxA1 in BV2 cells impaired gene and protein expression of PPARγ, effects reversed by treatment with recombinant AnxA1 (rAnxA1). Lower levels of CD36 were also verified in AnxA1 down-modulated BV2 cells. AnxA1-mediated phagocytosis of apoptotic cells was abrogated due to blockade of PPARγ activation, and in AnxA1 down-modulated cells exogenous AnxA1 failed to exert any effects on phagocytosis. Lower levels of STAT6/pSTAT6 in AnxA1 down-modulated BV2 cells suggest the involvement of this transcription factor with PPARγ and CD36 synthesis and actions. Data here shown suggest that there is a probable connection between AnxA1, PPARγ, and CD36, which must all act in association in order for efferocytosis to occur properly. AnxA1-mediated phosphorylation of STAT6 is probably involved with intracellular pathways involving PPARγ and CD36 actions. These data evidence that PPARγ/CD36 play a role on AnxA1-mediated efferocytosis in microglial cells. SIGNIFICANCE OF THE STUDY: The findings of this work provide evidence that the glucocorticoid-mediated protein annexin A1 modulates PPARγ expression and that PPARγ is important for annexin A1-mediated efferocytosis. Only recently the interaction between these two factors has begun to be explored, and knowledge on associated cell mechanisms are still scarce. Elucidating how annexin A1 and PPARγ interact with one another provides basis for further research aimed at understanding molecular pathways and cell signaling events involved with these factors, expanding existing knowledge on the anti-inflammatory effects of such factors.


Assuntos
Anexina A1/metabolismo , Microglia/metabolismo , PPAR gama/metabolismo , Fagocitose , Animais , Linhagem Celular , Perfilação da Expressão Gênica , Humanos , Camundongos , Microglia/citologia , PPAR gama/genética , Ratos
3.
Chem Biol Interact ; 311: 108795, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31419397

RESUMO

Citreoviridin (CIT), a mycotoxin and ATP synthase inhibitor, is regarded as one of aetiology factors of cardiac beriberi and Keshan disease. Thiamine (VB1) and selenium (Se) improve the recovery of these two diseases respectively. The underlying mechanisms of cardiotoxic effect of CIT and cardioprotective effect of VB1 and Se have not been fully elucidated. In this study, we found that ectopic ATP synthase was more sensitive to CIT treatment than mitochondrial ATP synthase in H9c2 cardiomyocytes. CIT inhibited the transcriptional activity of peroxisome proliferator activated receptor gamma (PPAR-γ) in mice hearts and H9c2 cells. PPAR-γ agonist attenuated the inhibitory effect of CIT on mechanistic target of rapamycin complex 2 (mTORC2) and stimulatory effect of CIT on autophagy in cardiomyocytes. CIT induced apoptosis through lysosomal-mitochondrial axis in cardiomyocytes. PPAR-γ agonist and autophagy inhibitor alleviated CIT-induced apoptosis and accelerated cardiac biomarker. VB1 and Se accelerated the basal transcriptional activity of PPAR-γ in mice hearts and H9c2 cells. Furthermore, VB1 and Se reversed the effect of CIT on PPAR-γ, autophagy and apoptosis. Our findings defined PPAR-γ-mTORC2-autophagy pathway as the key link between CIT cardiotoxicity and cardioprotective effect of VB1 and Se. The present study would shed new light on the pathogenesis of cardiomyopathy and the cardioprotective mechanism of micronutrients.


Assuntos
Apoptose/efeitos dos fármacos , Aurovertinas/farmacologia , Autofagia/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Selênio/farmacologia , Tiamina/farmacologia , Animais , Aquaporinas/genética , Aquaporinas/metabolismo , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Masculino , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Miocárdio/metabolismo , Miocárdio/patologia , PPAR gama/agonistas , PPAR gama/genética , PPAR gama/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Proteína X Associada a bcl-2/metabolismo
4.
J Agric Food Chem ; 67(37): 10321-10329, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31419115

RESUMO

Pterostilbene (PTS) is a phenolic compound with diverse pharmacologic activities. However, its potential for inhibiting obesity-related colorectal cancer (CRC) remains unclear. Our study evaluated the mechanism of inhibitory effects of PTS on adipocyte conditioned-medium (aCM)-induced malignant transformation in HT-29 colorectal adenocarcinoma cells. The results demonstrated that PTS could downregulate the expression of aCM-induced fatty acid-binding protein 5 (FABP5) and prometastatic factors such as vascular endothelial growth factor, matrix metalloproteinase-2 (MMP2), MMP9, and extracellular tumor necrosis factor α via inhibiting aCM-induced nuclear factor-kappa B (NF-κB), ß-catenin, and peroxisome proliferator-activated receptor γ (PPAR-γ). Moreover, PTS can suppress aCM-stimulated phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinases 1/2 (JNK 1/2) signaling pathways activation that are upstream of NF-κB, ß-catenin, and PPAR-γ. Therefore, we suggest that PTS could alleviate adiposity-induced metastasis in CRC via inhibiting cell migration through downregulating FABP5 gene expression.


Assuntos
Adipócitos/metabolismo , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/fisiopatologia , Meios de Cultivo Condicionados/química , Proteínas de Ligação a Ácido Graxo/metabolismo , Estilbenos/farmacologia , Células 3T3 , Animais , Linhagem Celular , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Meios de Cultivo Condicionados/metabolismo , Regulação para Baixo/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/genética , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Pharm Res ; 36(10): 145, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31396764

RESUMO

PURPOSE: The immediate plasma metabolism and development of chemo-resistance (single agent) severely hampers the clinical effectiveness of Sorafenib (SRF) in liver cancer therapy. MicroRNA27a inhibition is a promising biological strategy for breast cancer therapy. METHODS: In this study, we aimed to prepare SRF and anti-miRNA27a-loaded anti-GPC3 antibody targeted lipid nanoparticles to enhance the therapeutic efficacy against liver cancers. In this study, we have employed a unique cationic switchable lipid (CSL) as a mean to encapsulate miRNA as well as to confer pH-responsiveness to the nanocarrier system. RESULTS: The G-S27LN was nanosized and offered a pH-responsive release of SRF from the carrier system and we have demonstrated the specific affinity of G-S27LN towards the GPC3-overexpressed HepG2 cancer cells. Anti-microRNA27a significantly increased the protein expression of FOXO1 and PPAR-γ which are crucial components involved in proliferation and apoptosis of tumor cells. Combination of SRF and anti-miRNA27a (G-S27LN) resulted in significantly lower cell viability with a marked increase in the apoptosis cell proportion compared to that of free SRF indicating the synergistic anticancer effect. Animal studies in liver cancer xenograft model demonstrated significant suppression of tumor burden, reduced tumor cell and elevated TUNEL positive apoptosis with no toxicity concerns in animals treated with G-S27LN formulation. CONCLUSION: The CSL-based G-S27LN efficiently co-delivered anti-microRNA27a and SRF and therefore represents a promising therapy to treat liver cancer. This study also brings forth a platform strategy for the effective treatment of number of other advanced cancers.


Assuntos
Antagomirs/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Glipicanas/imunologia , Lipídeos/química , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/imunologia , Nanopartículas/química , Sorafenibe/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colesterol/química , Sinergismo Farmacológico , Proteína Forkhead Box O1/metabolismo , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Camundongos Nus , PPAR gama/metabolismo , Fosforilcolina/química , Polietilenoglicóis/química
6.
J Agric Food Chem ; 67(34): 9643-9651, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31390199

RESUMO

Licorice is a traditional Chinese medicine, which is often used as sweetener and cosmetic ingredients in food and pharmaceutical industries. Among them, glycyrrhetic acid is one of the most important agents. Studies have shown that glycyrrhetic acid exhibited antitumor activities as PPARγ agonist. However, the limited number of PPARγ glycyrrhetinic agonists and their high toxicity greatly limit the design based on the structure. Therefore, clarifying the binding mode between PPARγ and small molecules, we focused on the introduction of a natural active piperazine skeleton in the position of glycyrrhetinic acid C-3. According to the Combination Principle and the Structure-Based Drug Design, 19 glycyrrhetic acid derivatives were designed and synthesized as potential PPARγ agonists. Compounds 4c and 4q were screened as high-efficiency and low-toxicity lead compounds.


Assuntos
Antineoplásicos Fitogênicos/química , Medicamentos de Ervas Chinesas/química , Ácido Glicirretínico/análogos & derivados , Glycyrrhiza/química , PPAR gama/antagonistas & inibidores , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Medicamentos de Ervas Chinesas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacologia , Humanos , PPAR gama/metabolismo , Relação Estrutura-Atividade
7.
Life Sci ; 233: 116745, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31404524

RESUMO

Hypertension is one of the major risk factors for cardiovascular disease worldwide and is striking more young people, which is characterized by impaired vascular endothelial function. To find the functional lncRNAs associated with hypertension, high throughput lncRNA microarray were used to analyze expression profile of the lncRNAs in the aortic vascular endothelial cells (VECs) of spontaneously hypertensive rats (SHRs). The tail vein injection of siRNA was used to study the influence of lncRNA AK094457 inhibition on endothelial function in vivo. In vitro, endothelial function was studied in endothelial cells transfected with lncRNA AK094457-overexpressed vectors and siRNAs. pPPARγ and iNOS protein levels were detected with Western blot. Elisa assay was used to analyze the secretion of AngII, ET-1, ROS and LDH level. The nitrite/nitrate (NO2-/NO3-) concentration was measured using a colorimetric assay. LncRNA AK094457 was a most upregulated lncRNA in SHRs. It is showed that downregulation of AK094457 significantly reduced rat arterial pressure, increased activation of endothelial PPARγ, and suppressed serum contents of AngII and NO in vivo. Furthermore, results from gain-and-loss of function in primary aortic endothelial cells indicated that AK094457 negatively regulated activation of PPARγ and promoted AngII-mediated endothelial dysfunction, manifested by decreased capacities of cell proliferation and migration, and increased levels of ROS production and LDH release. In conclusion, lncRNA AK094457 is identified as a key regulator in blood pressure and endothelial function, which can increase AngII-induced hypertension and endothelial dysfunction via suppression of PPARγ.


Assuntos
Angiotensina II/toxicidade , Endotélio Vascular/patologia , Hipertensão/patologia , Músculo Liso Vascular/patologia , PPAR gama/antagonistas & inibidores , RNA Longo não Codificante/genética , Vasoconstritores/toxicidade , Animais , Proliferação de Células , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/genética , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Ratos , Ratos Endogâmicos SHR , Transdução de Sinais , Remodelação Vascular
8.
DNA Cell Biol ; 38(9): 945-954, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31355674

RESUMO

Domestic cattle are an important type of livestock, with beef production playing a major role in the agricultural economy. Adipocyte levels and fat content are interrelated, with meat quality being highly dependent on its fat content and distribution. Acyl-CoA synthetases of long-chain (ACSL) fatty acids (FAs) play an integral role in virtually every metabolic pathway in mammalian biochemistry, including complex lipid biosynthesis, protein modification, and ß-oxidation processes. ACSL3 activity is also known to be associated with adipocyte differentiation; however, its biological mechanism of action is currently unclear. Gene expression in subcutaneous preadipocytes isolated from subcutaneous deposits of Chinese Red Steppe cattle has been studied using in vitro cell transfection, real-time polymerase chain reaction and western blot analysis. The lipid and triglyceride contents of lipid droplets have also been measured to verify the levels of gene expression. These combined studies show that ACSL3 is induced during adipocyte differentiation, with its overexpression promoting an increase in the triglyceride content of lipid droplets. Furthermore, mRNA and protein expression levels for adipocyte differentiation marker genes, such as peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (C/EBPα), were markedly increased during mature adipocyte cell differentiation. Knockdown of ACSL3 expression using ACSL3 small interfering RNAs (siRNAs) resulted in a decrease in lipid content of cattle adipocytes, providing further evidence that ACSL3 plays a key role in the differentiation process.


Assuntos
Adipócitos/citologia , Adipogenia , Bovinos/genética , Coenzima A Ligases/genética , Adipócitos/metabolismo , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Células Cultivadas , Coenzima A Ligases/metabolismo , PPAR gama/genética , PPAR gama/metabolismo
9.
Chem Commun (Camb) ; 55(61): 8919-8922, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31270526

RESUMO

Cancer development is often associated with lipid metabolic reprogramming, including aberrant lipid accumulation. We create novel paradigms endowed with dual functions of anticancer activity and inhibition of lipid accumulation by conjugating the natural product quercetin and synthetic alkylphospholipid drugs, and harnessing the biomedical effects of both. These conjugates offer fresh perspectives in the search for anticancer candidates.


Assuntos
Fármacos Antiobesidade/farmacologia , Antineoplásicos/farmacologia , Éteres Fosfolipídicos/farmacologia , Fosforilcolina/análogos & derivados , Quercetina/análogos & derivados , Quercetina/farmacologia , Fármacos Antiobesidade/síntese química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Gotículas Lipídicas/metabolismo , Receptores X do Fígado/metabolismo , PPAR gama/metabolismo , Éteres Fosfolipídicos/síntese química , Fosforilcolina/síntese química , Fosforilcolina/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quercetina/síntese química , Transdução de Sinais/efeitos dos fármacos
10.
Gene ; 712: 143966, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31279711

RESUMO

BACKGROUND: Acute paracetamol (PCM) toxicity is a clinical problem; can result in a serious liver injury that finally may progress to acute liver failure. Curcumin (CUR) is a prevalent natural compound that can maintain prooxidant/antioxidant balance and thus can help in liver protection; also, Silymarin (SL) is a traditional antioxidant herb, used to treat liver disorders through scavenging free radicals. This study aimed to illustrate the histological, biochemical and molecular changes induced by acute PCM overdose on rats' liver to elucidate the effectiveness of CUR compared to SL in alleviating such changes. MATERIALS AND METHODS: Male Wister Albino rats were divided into 6 groups each comprising 23 rats: control group, curcumin (CUR) treated group received (100 mg CUR/ kg), silymarin treated group received (100 mg SL/kg) for 7 successive days. Paracetamol (PCM) exposed group administered a single dose of PCM (200 mg/kg orally on 8th day). PCM + CUR group and PCM + SL group pretreated with CUR and SL respectively for 7 days then received single PCM dose (200 mg/kg) on the 8th day. Blood and liver tissues were collected for biochemical, histopathological and immunohistochemical analyses using anti-p53 antibody. In addition, real time polymerase chain reaction (RT- PCR) was used to measure Bax, bcl2 and Peroxisome proliferator-activated receptor-gamma (PPAR γ) mRNA expression levels. RESULTS: In the paracetamol overdose group, the liver architecture showed necrotic changes, hydropic degeneration, congestion and dilatation of central veins. This hepatocellular damage was confirmed by a significant increase of AST, ALT levels and by an apparent increase in the number of p53 stained cells. PCM toxicity showed significant elevation of total oxidant status (TOS), oxidant status index (OSI) and decreased total antioxidant capacity (TAC) compared to controls (p < 0.001). Gene expression analysis showed that PCM caused an elevation of bcl2 and a reduction of both Bax and PPARγ mRNA expression. The histological alternation in the liver architecture was markedly improved in (PCM + CUR) group compared to (PCM+ SL) group, with an obvious decrease in the number of P53 stained cells. CUR pretreatment inhibited the elevation of TOS and OSI as well as the reduction of TAC caused by PCM toxicity compared to (PCM + SL) group. CONCLUSION: Both SL and CUR pretreatment prevented the toxic effects of PCM, but CUR is more effective than SL in ameliorating acute PCM induced hepatotoxicity.


Assuntos
Acetaminofen/toxicidade , Curcumina/farmacologia , Falência Hepática Aguda/induzido quimicamente , Fígado/efeitos dos fármacos , Silimarina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Apoptose , Sinergismo Farmacológico , Imuno-Histoquímica , Masculino , Oxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Proteína X Associada a bcl-2/metabolismo
11.
Chem Biol Interact ; 311: 108755, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31319077

RESUMO

Effective control of white adipose tissue accumulation would provide a therapeutic strategy for obesity, which poses a growing global problem. The plant chemical mangiferin stimulates adenosine monophosphate-activated protein kinase (AMPK), which inhibits adipogenesis and has therefore been considered a therapeutic target for obesity and related diseases. We previously reported the anti-inflammatory properties of 6'-O-acetyl mangiferin (OAM). In this study, we evaluated the potential of OAM as an AMPK activator in vitro in 3T3-L1 preadipocytes. OAM inhibited adipogenesis as indicated by lower intracellular lipid and triglyceride accumulation as well as reduced adipogenic gene and protein expression upon treatment. OAM-treated 3T3-L1 cells excreted more glycerol, indicating increased lipolysis, which was supported by increased expression of lipolysis-related genes, including adipose triglyceride lipase and hormone-sensitive lipase. We determined that OAM upregulates lipolysis via phosphorylation-dependent activation of AMPK. Further, OAM upregulated the ß-oxidation pathway as indicated by enhanced expression of phosphorylated acetyl-CoA-carboxylase and long-chain acyl-CoA synthetase 1. In conclusion, OAM markedly decreased intracellular lipid accumulation by enhancing lipolysis via AMPK activation and by upregulating ß-oxidation. Thus, OAM has potential as a drug for the prevention and/or improvement of obesity and related diseases and deserves further study.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipogenia/efeitos dos fármacos , Iris (Planta)/química , Lipólise/efeitos dos fármacos , Xantonas/farmacologia , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Iris (Planta)/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Triglicerídeos/metabolismo
12.
Chem Biol Interact ; 311: 108758, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31348919

RESUMO

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder in children. It is diagnosed by two main behavioral phenotypes i.e. social-communication impairments and repetitive behavior. ASD is complex disorder with unsolved etiology due to multiple genes involvement, epigenetic mechanism and environmental factors. The clinical and preclinical studies have been indicating the association of propionic acid with autism spectrum disorder. Numerous studies suggest the potential therapeutic effects of peroxisome proliferator-activated receptor-gamma (PPAR-γ) in different brain disorders. This research evaluates the utility of selective agonist of PPAR-γ, pioglitazone in postnatal propionic acid induced ASD related symptomatology in male Wistar rats. PPA (250 mg/kg, p.o.) was administered to male offspring for three consecutive days from postnatal 21st day to 23rd day. PPA induced social impairment, repetitive behavior, hyperlocomotion, anxiety and low exploratory activity in rats. Also, postnatal propionic acid-treated rats showed higher levels of oxidative stress (increased in thiobarbituric acid reactive species and decreased in reduced glutathione) as well as inflammation (increased in interleukin-6, tumor necrosis factor-alpha and decreased in interleukin-10) in the cerebellum, brainstem and prefrontal cortex. The rats were treated daily with pioglitazone (10 mg/kg and 20 mg/kg, p.o.) from postnatal 24th day to end of the study. Treatment with pioglitazone, significantly attenuated the postnatal propionic acid-induced social impairment, repetitive behavior, hyperactivity, anxiety and low exploratory activity. Furthermore, pioglitazone also reduced the postnatal propionic acid-induced oxidative stress and neuroinflammation in aforementioned brain regions. Hence, pioglitazone improved the propionic acid-induced neurobehavioral and biochemical impairments in rats.


Assuntos
Transtorno do Espectro Autista/patologia , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/agonistas , Pioglitazona/farmacologia , Animais , Ansiedade/prevenção & controle , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Glutationa/metabolismo , Inflamação/prevenção & controle , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Locomoção/efeitos dos fármacos , Masculino , PPAR gama/metabolismo , Fenótipo , Pioglitazona/uso terapêutico , Propionatos/toxicidade , Ratos , Ratos Wistar
13.
Nat Commun ; 10(1): 2987, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278260

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal disease in which the intricate alveolar network of the lung is progressively replaced by fibrotic scars. Myofibroblasts are the effector cells that excessively deposit extracellular matrix proteins thus compromising lung structure and function. Emerging literature suggests a correlation between fibrosis and metabolic alterations in IPF. In this study, we show that the first-line antidiabetic drug metformin exerts potent antifibrotic effects in the lung by modulating metabolic pathways, inhibiting TGFß1 action, suppressing collagen formation, activating PPARγ signaling and inducing lipogenic differentiation in lung fibroblasts derived from IPF patients. Using genetic lineage tracing in a murine model of lung fibrosis, we show that metformin alters the fate of myofibroblasts and accelerates fibrosis resolution by inducing myofibroblast-to-lipofibroblast transdifferentiation. Detailed pathway analysis revealed a two-arm mechanism by which metformin accelerates fibrosis resolution. Our data report an antifibrotic role for metformin in the lung, thus warranting further therapeutic evaluation.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Lipogênese/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Metformina/farmacologia , Miofibroblastos/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Colágeno/biossíntese , Modelos Animais de Doenças , Humanos , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/patologia , Pulmão/citologia , Pulmão/patologia , Masculino , Metformina/uso terapêutico , Camundongos , Miofibroblastos/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacos
14.
J Food Sci ; 84(8): 2330-2336, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31313321

RESUMO

It has been reported that genistein could improve metabolic syndromes. Our study aimed to investigate the effects and potential mechanisms of genistein on improving cholesterol metabolism in HepG2 cell. HepG2 cells were cultured with 0, 0.01, 1.00, 10.00, and 50.00 µM genistein for 24 hr. The current results showed a dose-dependent manner between genistein and intracellular contents of total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), and cellular apolipoprotein A1 (Apo-A1) secretion. TC was increased by 25.69%, meanwhile HDL-C and Apo-A1 were decreased by 56.00% and 25.93%, respectively, when the dosage of genistein was 1.00 µM. Genistein dose-dependently upregulated the protein and mRNA levels of sterol regulatory element binding proteins-2 (SREBP-2), as well as the mRNA levels of low-density lipoprotein receptor (LDLR) and 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGCR), by 145.91%, 72.29%, 310.23%, and 123.08%, respectively, when we gave 1.00 µM genistein, indicating that intracellular cholesterol synthesis and absorption of exogenous cholesterol were increased. In addition, the mRNA levels of peroxisome proliferator-activated receptor-γ (PPARγ) and liver X receptor (LXRα), lowered by 58.23% and 34.86% at 0.01 µM genistein, were reduced in a dose-dependent manner. LXRα and ATP-binding cassette transporter A1 (ABCA1) protein levels were significantly (P < 0.05) decreased by 50.35% and 11.60% at 1.00 µM genistein, which indicated that cellular cholesterol efflux was inhibited. Taken together, our results suggested that genistein at dosage of more than 1.00 µM was able to increase the intracellular cholesterol levels by up regulating SREBP-2/LDLR/HMGCR pathway and suppressing PPARγ/LXRα/ABCA1 pathway. PRACTICAL APPLICATION: In this study, genistein appeared to be effective in reducing plasma cholesterol levels due to increase the intracellular cholesterol levels by upregulating cholesterol absorption through SREBP-2/LDLR/HMGCR pathway, and also downregulating cholesterol efflux via PPARγ/LXRα/ABCA1 pathway in vitro. In addition, plasma cholesterol is regarded as the key indicator of atherosclerosis; therefore, we believe that our findings could be used for further exploration on a possible therapeutic application of genistein for atherosclerosis.


Assuntos
Colesterol/metabolismo , Genisteína/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , HDL-Colesterol/genética , HDL-Colesterol/metabolismo , Expressão Gênica , Células Hep G2 , Humanos , Metabolismo dos Lipídeos , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
15.
Life Sci ; 231: 116493, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31153818

RESUMO

AIMS: Obestatin regulates water metabolism by inhibiting arginine vasopressin (AVP) release and upregulated obestatin has been detected in patients with chronic heart failure (CHF). However, the significance of obestatin in CHF, particularly with regard to water retention and aquaporin 2 (AQP2) expression, remains unknown. MAIN METHODS: Using a CHF rat model, the effects of 2-week exogenous obestatin administration were evaluated. Expression of AQP2 was evaluated by immunoblotting, immunohistochemical staining, and quantitative real-time PCR (qPCR) in CHF rat model and mouse inner medullary collecting duct (mIMCD) 3 cell line. Moreover, the influence of obestatin on the genetic transcription profile in mIMCD3 cells was evaluated by microarray, and the potential regulatory mechanisms of obestatin on AQP2 were evaluated by RNA silencing of vasopressin receptor 2 (V2R), peroxisome proliferator-activated receptor gamma (PPARG), and G protein-coupled receptor 39 (GPR39). KEY FINDINGS: Obestatin increased urinary output and improved expression of CHF biomarker without significantly altering cardiac function, plasma electrolyte concentrations, or the plasma AVP concentration. AQP2 expression was significantly reduced. The results of microarray analyses and qPCR indicated that mRNA levels of Aqp2, Pparg, and V2r were significantly decreased. Inhibition of V2r and Pparg mRNA further reduced the expression of AQP2, while the inhibitory efficacy of obestatin on AQP2 was significantly offset after Gpr39 knockdown. SIGNIFICANCE: Long-term treatment with obestatin improves water retention in CHF by increasing urinary output through downregulation of AQP2 expression in renal IMCD cells. These effects may be at least partially mediated by regulation of GPR39, V2R and PPARG signaling.


Assuntos
Edema/tratamento farmacológico , Grelina/farmacologia , Insuficiência Cardíaca/metabolismo , PPAR gama/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Vasopressinas/metabolismo , Animais , Aquaporina 2/metabolismo , Arginina Vasopressina , Água Corporal , Linhagem Celular , Edema/metabolismo , Insuficiência Cardíaca/fisiopatologia , Rim/efeitos dos fármacos , Rim/metabolismo , Túbulos Renais Coletores/metabolismo , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Equilíbrio Hidroeletrolítico , Desequilíbrio Hidroeletrolítico
16.
Life Sci ; 232: 116595, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31238053

RESUMO

AIMS: The world's population is becoming aged and the proportion of older persons is growing in almost every country in the world. Ellagic acid (EA) shows abundant pharmacological properties. Therefore, we aimed to determine the mechanism of anti-aging effects of low and high doses of EA. MAIN METHODS: Aging model was induced by d-galactose (DG), and the anti-aging effect of EA alone or in the presence of PPAR-γ antagonist GW9662, and in combination with metformin were evaluated. The activities of ALT, AST, and AChE, the levels of FBS, HbA1c, testosterone and DHEA-SO4, MDA, GSH, TNF-α, IL-6, advanced glycation end products (AGEs), and BDNF were measured in serum, liver or brain. KEY FINDINGS: DG led to increasing in the levels of IL-6, TNF-α, MDA, AChE, AGEs, ALT, AST, FBS, and HbA1c, in which decrease in the levels of body weight, GSH, BDNF, DHEA-SO4 and testosterone. Metformin (300 mg/kg) abrogated the effects of DG-induced aging model. We also found that the low dose of EA (30 mg/kg) decreases the deteriorative effects of DG-induced aging at 10 weeks of treatment only, however, high dose of EA (100 mg/kg) was effective at both 6 and 10 weeks of treatment. The addition of GW9662 completely reversed the effects of the low dose of EA, but not for the high dose, on DG-induced aging model. SIGNIFICANCE: We revealed that daily and oral administration of EA provides anti-aging effects at low dose in a PPAR-γ receptor-dependent fashion, but not at the high dose.


Assuntos
Envelhecimento/efeitos dos fármacos , Ácido Elágico/farmacologia , PPAR gama/metabolismo , Envelhecimento/fisiologia , Anilidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Galactose/farmacologia , Glutationa Peroxidase/metabolismo , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Metformina/farmacologia , Camundongos , Modelos Animais , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
17.
Food Chem Toxicol ; 131: 110552, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31163220

RESUMO

[OBJECTIVE]: Di(2-ethylhexyl) phthalate (DEHP), a widely used plasticizer, may act as an endocrine disruptor and cause developmental toxicity. Differentiated human embryonic stem cells (hESCs) were used to investigate the underlying mechanism of the embryotoxicity induced by DEHP. [Materials and Methods] H9-hESCs were treated with DEHP at different concentrations for 10 days, and the cytotoxicity of DEHP on cell proliferation was determined using a cell-microelectronic sensing technique (Real-Time Cellular Analysis: RTCA). Based on the 50% inhibitory proliferation concentration (IC50), differentiated H9-hESCs were treated with DEHP at 0, 50, 100, and 200 µg/ml for 120 h, followed by measurement of its toxic effects on the transcriptome by mRNA microarray and QuantiGene Plex (QGP). Proteins were detected by the iTRAQ-based proteomics method and the proteins related to the PPARγ/PTEN/Akt pathways were measured by western blotting. The progression of the cell cycle and apoptosis were characterized using flow cytometry (FCM). In other experiments, hESCs were pre-treated with GW9662 (20 µM), a specific PPARγ inhibitor, for 30 min, followed by exposure to GW9662 (20 µM) and DEHP (200 µg/ml) for 120 h to observe the underlying mechanism of DEHP's embryotoxicity. [RESULTS]: DEHP inhibited H9-hESC cell proliferation in a dose-dependent manner, with an IC50 of 165.78 µg/ml. FCM results showed that DEHP could markedly induce cell cycle arrest and increase apoptosis. Gene microarray and QPG array analyses indicated that the peroxisome proliferator-activated receptor γ (PPARγ) was an apparent target for DEHP. We further demonstrated that DEHP could activate the PPARγ and upregulate the expression of PTEN downstream genes, and then play a negative role in the AKT signaling pathway. Cells pretreated with PPARγ inhibitor, GW9662, were shown to restore the effect of DEHP on the PPARγ/PTEN/AKT signaling pathway, and induce the recovery of cell cycle arrest and apoptosis. [CONCLUSION]: DEHP inhibited cell proliferation, promoted cell cycle arrest, and induced apoptosis through the PPARγ/PTEN/AKT signaling pathway in differentiated human embryonic stem cells. It suggested that DEHP exposure possibly cause reproductive or developmental toxicity in humans through the PPARγ signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Bovinos , Proliferação de Células/efeitos dos fármacos , Emulsões/síntese química , Emulsões/química , Humanos , PPAR gama/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Plastificantes/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Soroalbumina Bovina/química , Teratogênios/toxicidade
18.
Food Chem Toxicol ; 131: 110576, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31199990

RESUMO

Ivermectin, a member of the avermectins, is one of the most used anti-parasitic agents, and acts by binding to glutamate-gated chloride channels in invertebrate nerve cells. There is limited information, however, on the effects of ivermectin in non-neural cell, such as adipocytes. The present work aimed to investigate the role of ivermectin in adipogenesis using 3T3-L1 preadipocytes. Ivermectin inhibited the differentiation of preadipocytes and triglyceride (TG) accumulation. In particular, the treatment of ivermectin at the middle to late adipogenic differentiation period (day 2-8) was correlated with the inhibition of fat accumulation. Ivermectin treatment also significantly modulated the mRNA expression of key markers in adipogenesis, fatty acid synthesis, uptake, and oxidation, and enhanced the gene expression of two subunits of the glycine receptor (GlyR). Specifically, the protein levels of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and acetyl-CoA carboxylase (ACC) were reduced. Interestingly, the suppression of TG accumulation by ivermectin was partially abolished by rosiglitazone, a specific PPARγ agonist, but Z-guggulsterone, a selective FXR antagonist, failed to rescue the ivermectin-induced effect on adipogenesis. Lastly, ivermectin prevented adipogenesis induced by permethrin and fipronil. In conclusion, ivermectin inhibits adipogenesis of 3T3-L1 preadipocytes partially via PPARγ & GlyR-dependent, but not FXR-dependent, pathway.


Assuntos
Adipogenia/efeitos dos fármacos , Antiparasitários/farmacologia , Ivermectina/farmacologia , Triglicerídeos/metabolismo , Células 3T3-L1 , Animais , Diferenciação Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Camundongos , PPAR gama/metabolismo , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores da Glicina/metabolismo
19.
Environ Pollut ; 246: 963-971, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31159146

RESUMO

Bisphenol S (BPS) has been widely used as a bisphenol alternative in recent few years. However, with mounting evidence suggesting that the presence of BPS in the environment also poses risks to ecosystems and human health, we decided to use the juvenile common carp (Cyprinus carpio) and its primary macrophages as in vivo and in vitro models to examine if BPS is a safe substitute of BPA. The present study evaluated the immune responses of chronic BPS exposure and their mechanisms of action associated with peroxisome proliferator-activated receptor (PPAR) signaling pathway. Potential oxidative stress and pro-inflammatory effects of BPS exposure were identified in fish liver after 60-day exposure, based on the increased reactive oxygen species (ROS) production, antioxidant capacity, NO production, lipid peroxidation, and induction of inflammatory cytokine expression, as well as acute phase protein levels of C-reactive protein, immunoglobulin M, lysozyme, and complement component 3. Moreover, pparγ, PPAR pathway-associated genes retinoid x receptor α (rxrα) and nuclear factor-κb (nfκb) presented a rough concentration-dependent alteration after BPS exposure. An acute BPS exposure to the isolated primary macrophages from juvenile common carp was performed to help elucidate gene expression patterns of pparγ, rxrα, and nfκb in a typical immune cell model, the results were consistent with what we found in vivo experiments for long-term BPS exposure. Furthermore, with coexposure to BPS and a PPARγ antagonist, the restriction of PPAR signaling pathway significantly inhibited the induction of ROS and the mRNA level of interleukin-1ß, confirming the involvement of PPAR pathway in BPS-induced chronic inflammatory stress in liver.


Assuntos
Poluentes Ambientais/toxicidade , Inflamação/metabolismo , Fígado/efeitos dos fármacos , PPAR gama/metabolismo , Fenóis/toxicidade , Sulfonas/toxicidade , Animais , Carpas/imunologia , Carpas/metabolismo , Inflamação/genética , Fígado/imunologia , Fígado/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
20.
Cell Mol Biol Lett ; 24: 35, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31160894

RESUMO

Background: Pulmonary edema is one of the pathological characteristics of acute respiratory distress syndrome (ARDS). The epithelial sodium channel (ENaC) is thought to be the rate-limiting factor for alveolar fluid clearance (AFC) during pulmonary edema. The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone was shown to stimulate ENaC-mediated salt absorption in the kidney. However, its role in the lung remains unclear. Here, we investigated the role of the PPARγ agonist in the lung to find out whether it can regulate AFC during acute lung injury (ALI). We also attempted to elucidate the mechanism for this. Methods: Our ALI model was established through intratracheal instillation of lipopolysaccharide (LPS) in C57BL/6 J mice. The mice were randomly divided into 4 groups of 10. The control group underwent a sham operation and received an equal quantity of saline. The three experimental groups underwent intratracheal instillation of 5 mg/kg LPS, followed by intraperitoneal injection of 4 mg/kg rosiglitazone, 4 mg/kg rosiglitazone plus 1 mg/kg GW9662, or only equal quantity of saline. The histological morphology of the lung, the levels of TNF-α and IL-1ß in the bronchoalveolar lavage fluid (BALF), the level of AFC, and the expressions of αENaC and serum and glucocorticoid-induced kinase-1 (SGK1) were determined. Type 2 alveolar (AT II) cells were incubated with rosiglitazone (15 µM) with or without GW9662 (10 µM). The expressions of αENaC and SGK1 were determined 24 h later. Results: A mouse model of ALI was successfully established. Rosiglitazone significantly ameliorated the lung injury, decreasing the TNF-α and IL-1ß levels in the BALF, enhancing AFC, and promoting the expressions of αENaC and SGK1 in ALI mice, which were abolished by the specific PPARγ blocker GW9662. In vitro, rosiglitazone increased the expressions of αENaC and SGK1. This increase was prevented by GW9662. Conclusions: Rosiglitazone ameliorated the lung injury and promoted ENaC-mediated AFC via a PPARγ/SGK1-dependent signaling pathway, alleviating pulmonary edema in a mouse model of ALI.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Líquido da Lavagem Broncoalveolar/química , Canais Epiteliais de Sódio/metabolismo , PPAR gama/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Rosiglitazona/farmacologia , Transdução de Sinais , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Animais , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
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