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1.
Ann Agric Environ Med ; 27(3): 407-412, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32955223

RESUMO

INTRODUCTION AND OBJECTIVE: The biochemical and anthropometric consequences of metabolic disorders exert an enormous effect on the functioning of people worldwide. The aim of this study is to assess relationships between biochemical and anthropometric parameters associated with metabolic syndrome, and the presence of the PPAR-γ rs1801282, the FTO rs9939609, and the MC4R rs17782313 polymorphisms in women aged 45-60. MATERIAL AND METHODS: The study included 425 women, aged 45-59 years, from the general population of the West Pomeranian Province in north-west Poland. The research procedure involved a structured interview, anthropometric and blood pressure measurements, biochemical analysis of serum, and genetic analysis. RESULTS: The carriers of the A/A genotype of the FTO polymorphism had higher LDL levels than their counterparts with the T/T genotype (p = 0.01). The carriers of the T/T genotype of the MC4R polymorphism had lower non-HDL levels than those with the C/C and C/T genotypes (p = 0.019). Weight was related to the C/C and the C/G + G/G genotypes of the PPAR-γ gene polymorphism (p = 0.046). The model of inheritance for the MC4R polymorphism had a significant effect on TG (p = 0.039) and non-HDL (p = 0.05) levels. CONCLUSIONS: The genotypes analyzed in the study had only a slight direct effect on the biochemical and anthropometric abnormalities typical of metabolic disorders. Nonetheless, the risk alleles (A allele of the FTO rs9939609 and the C allele of the MC4R rs17782313) were found to be related to lipid metabolism disorders in 45-60-year-old women.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Antropometria , Predisposição Genética para Doença , Síndrome Metabólica/genética , PPAR gama/genética , Receptor Tipo 4 de Melanocortina/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , PPAR gama/metabolismo , Polônia , Polimorfismo de Nucleotídeo Único , Receptor Tipo 4 de Melanocortina/metabolismo
2.
Nat Commun ; 11(1): 4448, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895370

RESUMO

Substance abuse disorders are linked to alteration of circadian rhythms, although the molecular and neuronal pathways implicated have not been fully elucidated. Addictive drugs, such as cocaine, induce a rapid increase of dopamine levels in the brain. Here, we show that acute administration of cocaine triggers reprogramming in circadian gene expression in the striatum, an area involved in psychomotor and rewarding effects of drugs. This process involves the activation of peroxisome protein activator receptor gamma (PPARγ), a nuclear receptor involved in inflammatory responses. PPARγ reprogramming is altered in mice with cell-specific ablation of the dopamine D2 receptor (D2R) in the striatal medium spiny neurons (MSNs) (iMSN-D2RKO). Administration of a specific PPARγ agonist in iMSN-D2RKO mice elicits substantial rescue of cocaine-dependent control of circadian genes. These findings have potential implications for development of strategies to treat substance abuse disorders.


Assuntos
Relógios Circadianos/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Cocaína/efeitos adversos , Núcleo Accumbens/efeitos dos fármacos , PPAR gama/metabolismo , Receptores de Dopamina D2/metabolismo , Administração Oral , Animais , Relógios Circadianos/fisiologia , Cocaína/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Dopamina/metabolismo , Injeções Intraperitoneais , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/fisiopatologia , PPAR gama/agonistas , Pioglitazona/administração & dosagem , Receptores de Dopamina D2/genética , Recompensa , Transdução de Sinais
3.
PLoS One ; 15(8): e0237976, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822399

RESUMO

Environmental exposure to arsenite (As3+) has a strong association with the development of human urothelial cancer (UC) and is the 5th most common cancer in men and the 12th most common cancer in women. Muscle invasive urothelial cancer (MIUC) are grouped into basal or luminal molecular subtypes based on their gene expression profile. The basal subtype is more aggressive and can be associated with squamous differentiation, characterized by high expression of keratins (KRT1, 5, 6, 14, and 16) and epidermal growth factor receptor (EGFR) within the tumors. The luminal subtype is less aggressive and is predominately characterized by elevated gene expression of peroxisome proliferator-activated receptor- gamma (PPARγ) and forkhead box protein A1 (FOXA1). We have previously shown that As3+-transformed urothelial cells (As-T) exhibit a basal subtype of UC expressing genes associated with squamous differentiation. We hypothesized that the molecular subtype of the As-T cells could be altered by inducing the expression of PPARγ and/or inhibiting the proliferation of the cells. Non-transformed and As-T cells were treated with Troglitazone (TG, PPARG agonist, 10 µM), PD153035 (PD, an EGFR inhibitor, 1 µM) or a combination of TG and PD for 3 days. The results obtained demonstrate that treatment of the As-T cells with TG upregulated the expression of PPARγ and FOXA1 whereas treatment with PD decreased the expression of some of the basal keratins. However, a combined treatment of TG and PD resulted in a consistent decrease of several proteins associated with the basal subtype of bladder cancers (KRT1, KRT14, KRT16, P63, and TFAP2A). Our data suggests that activation of PPARγ while inhibiting cell proliferation facilitates the regulation of genes involved in maintaining the luminal subtype of UC. In vivo animal studies are needed to address the efficacy of using PPARγ agonists and/or proliferation inhibitors to reduce tumor grade/stage of MIUC.


Assuntos
Arsenitos/farmacologia , Proliferação de Células/efeitos dos fármacos , PPAR gama/metabolismo , Troglitazona/farmacologia , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Fator 3-alfa Nuclear de Hepatócito/genética , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Queratinas/genética , Queratinas/metabolismo , Camundongos , Camundongos Nus , PPAR gama/agonistas , Quinazolinas/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcriptoma/efeitos dos fármacos , Transplante Heterólogo , Regulação para Cima/efeitos dos fármacos , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
4.
Nat Commun ; 11(1): 4150, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811819

RESUMO

The systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases. A mechanistic understanding of adipocyte dysfunction with age could help to prevent age-related metabolic disorders, but the role of autophagy in aged adipocytes remains unclear. Here we show that, in contrast to other tissues, aged adipocytes upregulate autophagy due to a decline in the levels of Rubicon, a negative regulator of autophagy. Rubicon knockout in adipocytes causes fat atrophy and hepatic lipid accumulation due to reductions in the expression of adipogenic genes, which can be recovered by activation of PPARγ. SRC-1 and TIF2, coactivators of PPARγ, are degraded by autophagy in a manner that depends on their binding to GABARAP family proteins, and are significantly downregulated in Rubicon-ablated or aged adipocytes. Hence, we propose that age-dependent decline in adipose Rubicon exacerbates metabolic disorders by promoting excess autophagic degradation of SRC-1 and TIF2.


Assuntos
Adipócitos/metabolismo , Envelhecimento/fisiologia , Autofagia/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Doenças Metabólicas/metabolismo , Adipócitos/patologia , Adipogenia/genética , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Adiposidade/genética , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/fisiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Técnicas de Inativação de Genes , Glucose/genética , Glucose/metabolismo , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Coativador 1 de Receptor Nuclear/metabolismo , Coativador 2 de Receptor Nuclear/metabolismo , PPAR gama/metabolismo
5.
PLoS One ; 15(8): e0237095, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756599

RESUMO

Regular exercise is an effective strategy that is used to prevent and treat obesity as well as type 2 diabetes. Exercise-induced myokine secretion is considered a mechanism that coordinates communication between muscles and other organs. In order to examine the possibility of novel communications from muscle to adipose tissue mediated by myokines, we treated 3T3-L1 adipocytes with C2C12 myotube electrical pulse stimulation-conditioned media (EPS-CM), using a C2C12 myotube contraction system stimulated by an electrical pulse. Continuous treatment with myotube EPS-CM promoted adipogenesis of 3T3-L1 pre-adipocytes via the upregulation of the peroxisome proliferator-activated receptor-gamma (PPARγ) 2 and PPARγ-regulated gene expression. Furthermore, our results revealed that myotube EPS-CM induces lipolysis and secretion of adiponectin in mature adipocytes. EPS-CM obtained from a C2C12 myoblast culture did not induce such changes in these genes, suggesting that contraction-induced myokine(s) secretion occurs particularly in differentiated myotubes. Thus, contraction-induced secretion of myokine(s) promotes adipogenesis and lipid metabolism in 3T3-L1 adipocytes. These findings suggest the possibility that skeletal muscle communicates to adipose tissues during exercise, probably by the intermediary of unidentified myokines.


Assuntos
Adipócitos/citologia , Diferenciação Celular , Lipólise , Fibras Musculares Esqueléticas/metabolismo , Células 3T3 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia , Adiponectina/metabolismo , Animais , Comunicação Celular , Meios de Cultivo Condicionados/farmacologia , Camundongos , PPAR gama/metabolismo
6.
Gene ; 759: 144981, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32707300

RESUMO

Peroxisome proliferator-activated receptor gamma (PPARG), as a member of the nuclear receptor superfamily, plays an important role in adipocyte differentiation and regulation of lipid and glucose metabolism. In this study, the transcripts of PPARG gene were isolated and identified in buffalo mammary gland. The results showed that two types of transcripts (PPARG1 and PPARG2) of PPARG gene produced by alternative 5' end use were expressed in buffalo mammary gland, and each of them had four different alternative splicing variants. The PPARG1 includes PPARG1a, PPARG1b, PPARG1c and PPARG1d, while the PPARG2 contains PPARG2a, PPARG2b, PPARG2c and PPARG2d. Among them, only PPARG1a, PPARG2a and PPARG2d can encode complete functional proteins with three complete functional domains, and the rest encode truncated proteins with incomplete functional domains. All the eight variants of PPARG protein do not contain transmembrane regions and signal peptides, but their conserved domain, secondary and tertiary structure and subcellular localization were different. Subcellular localization confirmed that the main transcripts PPARG1a and PPARG2a played a functional role in the nucleus, which was consistent with the results by in silico prediction. RT-qPCR analysis of buffalo mammary tissue showed that the mRNA expression levels of PPARG1 and PPARG2 in lactation were higher than those in non-lactation, and the expression levels of transcripts PPARG2d and PPARG1b + PPARG2b in lactating stage were also higher than those in non-lactating stage, but the mRNA abundance of transcripts PPARG1c, PPARG1d and PPARG2c in non-lactating period was higher than that in lactating period. The results of this study suggest that PPARG1 and PPARG2 may play important role in buffalo milk fat synthesis, and the eight alternative splicing variants found here are likely to be related to the post-transcriptional regulation of lactation.


Assuntos
Búfalos/genética , Glândulas Mamárias Animais/metabolismo , PPAR gama/genética , Animais , Feminino , Lactação/genética , Leite/metabolismo , PPAR gama/metabolismo
7.
Life Sci ; 257: 118103, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32681913

RESUMO

Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal (GI) disorder with negative impacts on quality of life of patients. Although the etiology of the disease is still unclear, there are a set of mechanisms and factors involved in IBS pathogenesis. Visceral hypersensitivity, impaired gut barrier, along with minor inflammation and oxidative stress are the most important triggers for IBS induction. Activation of peroxisome proliferator activated receptor-γ (PPAR-γ) has been shown to improve gut barrier, downregulate pro-inflammatory cytokines, reduce free radical production through antioxidative mechanisms, and exert anti-nociceptive effects against somatic pain. An electronic search in PubMed, Google Scholar, Scopus, and Cochrane library was performed and relevant clinical, in vivo and in vitro articles published between 2004 and June 2020 were collected. Search terms included "Irritable Bowel Syndrome" OR "IBS" OR "visceral hypersensitivity" OR "motility dysfunction" AND "peroxisome proliferator activated receptors" OR "PPAR". Herein, the efficacy of PPARγ signaling as a potential target for IBS treatment is reviewed.


Assuntos
Síndrome do Intestino Irritável/metabolismo , PPAR gama/metabolismo , Animais , Humanos , Inflamação/metabolismo , Síndrome do Intestino Irritável/tratamento farmacológico , Estresse Oxidativo
8.
Mol Cell Biol ; 40(17)2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601106

RESUMO

Transcription factors C/EBPß and C/EBPδ are induced within hours after initiation of adipogenesis in culture. They directly promote the expression of master adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα and are required for adipogenesis in vivo However, the mechanism that controls the induction of C/EBPß and C/EBPδ remains elusive. We previously showed that histone methyltransferases MLL3/MLL4 and associated PTIP are required for the induction of PPARγ and C/EBPα during adipogenesis. Here, we show MLL3/MLL4/PTIP-associated protein PAGR1 (also known as PA1) cooperates with phosphorylated CREB and ligand-activated glucocorticoid receptor to directly control the induction of C/EBPß and C/EBPδ in the early phase of adipogenesis. Deletion of Pagr1 in white and brown preadipocytes prevents the induction of C/EBPß and C/EBPδ and leads to severe defects in adipogenesis. Adipogenesis defects in PAGR1-deficient cells can be rescued by the ectopic expression of C/EBPß or PPARγ. Finally, the deletion of Pagr1 in Myf5+ precursor cells impairs brown adipose tissue and muscle development. Thus, by controlling the induction of C/EBPß and C/EBPδ, PAGR1 plays a critical role in adipogenesis.


Assuntos
Adipogenia/fisiologia , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Células 3T3-L1 , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Diferenciação Celular/fisiologia , Histona Metiltransferases/metabolismo , Camundongos , Camundongos Knockout , PPAR gama/metabolismo , Ligação Proteica
9.
Anticancer Res ; 40(6): 3071-3080, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487601

RESUMO

BACKGROUND/AIM: Head and neck squamous cell carcinoma affects nearly 500,000 people annually. Augmenting PPARγ functional activation is linked with multiple anti-carcinogenic processes in aerodigestive cell lines and animal models. PPARγ/RXRα heterodimers may be key partners in this activation. MATERIALS AND METHODS: CA 9-22 and NA cell lines were treated with the PPARγ agonist ciglitazone and/or the RXRα agonist 9-cis-retinoic acid. PPARγ functional activation, cellular proliferation, apoptosis activity, and phenotype were subsequently analyzed. RESULTS: Ciglitazone and 9-cis-retinoic acid independently activated PPARγ and down-regulated the carcinogenic phenotype in vitro. Combination treatment significantly augmented these effects, further decreasing proliferation (p<0.0001), and increasing PPARγ functional activation (p<0.0001), apoptosis (p<0.05), and adipocyte differentiation markers (p<0.0001). CONCLUSION: The efficacy of the combination of ciglitazone and 9-cis-retinoic acid afforded lowering treatment concentrations while maintaining desired therapeutic outcomes, optimistically supporting the feasibility and practicality of this novel treatment option.


Assuntos
Neoplasias Bucais/tratamento farmacológico , PPAR gama/metabolismo , Retinoides/uso terapêutico , Tiazolidinedionas/uso terapêutico , Humanos , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Retinoides/farmacologia , Taxa de Sobrevida , Tiazolidinedionas/farmacologia
10.
Proc Natl Acad Sci U S A ; 117(25): 14280-14291, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513715

RESUMO

In utero mammalian development relies on the establishment of the maternal-fetal exchange interface, which ensures transportation of nutrients and gases between the mother and the fetus. This exchange interface is established via development of multinucleated syncytiotrophoblast cells (SynTs) during placentation. In mice, SynTs develop via differentiation of the trophoblast stem cell-like progenitor cells (TSPCs) of the placenta primordium, and in humans, SynTs are developed via differentiation of villous cytotrophoblast (CTB) progenitors. Despite the critical need in pregnancy progression, conserved signaling mechanisms that ensure SynT development are poorly understood. Herein, we show that atypical protein kinase C iota (PKCλ/ι) plays an essential role in establishing the SynT differentiation program in trophoblast progenitors. Loss of PKCλ/ι in the mouse TSPCs abrogates SynT development, leading to embryonic death at approximately embryonic day 9.0 (E9.0). We also show that PKCλ/ι-mediated priming of trophoblast progenitors for SynT differentiation is a conserved event during human placentation. PKCλ/ι is selectively expressed in the first-trimester CTBs of a developing human placenta. Furthermore, loss of PKCλ/ι in CTB-derived human trophoblast stem cells (human TSCs) impairs their SynT differentiation potential both in vitro and after transplantation in immunocompromised mice. Our mechanistic analyses indicate that PKCλ/ι signaling maintains expression of GCM1, GATA2, and PPARγ, which are key transcription factors to instigate SynT differentiation programs in both mouse and human trophoblast progenitors. Our study uncovers a conserved molecular mechanism, in which PKCλ/ι signaling regulates establishment of the maternal-fetal exchange surface by promoting trophoblast progenitor-to-SynT transition during placentation.


Assuntos
Diferenciação Celular/fisiologia , Isoenzimas/metabolismo , Troca Materno-Fetal/fisiologia , Placenta/metabolismo , Proteína Quinase C/metabolismo , Trofoblastos/fisiologia , Animais , Proteínas de Ligação a DNA/metabolismo , Feminino , Fator de Transcrição GATA2/metabolismo , Humanos , Isoenzimas/genética , Masculino , Camundongos , Camundongos Knockout , Modelos Animais , PPAR gama/metabolismo , Placenta/citologia , Placentação/fisiologia , Gravidez , Proteína Quinase C/genética , Transdução de Sinais , Células-Tronco/citologia , Fatores de Transcrição/metabolismo , Trofoblastos/citologia
11.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(1): 85-89, 2020 Jan 28.
Artigo em Chinês | MEDLINE | ID: mdl-32476378

RESUMO

OBJECTIVE: To observe the effects of resveratrol on body composition in adult catch-up growth rats and to explore the possible mechanism. METHODS: Eight-week-old male SD rats were randomly divided into 6 groups: normal controls for 4 weeks (NC4) group, caloric restriction for 4 weeks (R4) group, calorie restriction meanwhile resveratrol treatment for 4 weeks (R4E) group, normal controls for 12 weeks (NC12) group, catch-up growth (CUG) group and catch-up growth meanwhile resveratrol treatment for 8 weeks (CUGE) group. At the end of the four-week and twelve-week experimental period, the body weight, muscle and fat content of trunk and whole body, the ratio of trunk to whole body fat were detected, and at the end of twelve-week experimental period, the expression of SIRT1 in skeletal muscle and epididymal adipose tissue, and the expression of PPARγ in epididymal adipose tissue were detected. RESULTS: Compared with NC12 group, the fat content of trunk and whole body and trunk to whole body fat ratio in CUG group were increased significantly, along with the expression of PPARγ in epididymal adipose tissue was increased significantly (P<0.05), while the muscle content of trunk and whole body, the expression of SIRT1 in skeletal muscle and epididymal adipose tissue in CUG group were decreased significantly compared with NC12 group (P<0.05 or P<0.01); compared with CUG group, oral administration of resveratrol distinctly reduced the body fat content and trunk to whole body fat ratio in the CUGE groups, and the expression of PPARγ in epididymal adipose tissue of CUGE group was also significantly decreased (P<0.05). Meanwhile, the muscle content and the expression of SIRT1 in skeletal muscle and epididymal adipose tissue in CUGE group were significantly increased compared with the CUG group (P<0.05). CONCLUSION: Resveratrol can decrease body fat content, increase muscle content and improve abdominal fat accumulation in adult catch-up growth rats, and its mechanism may be associated with increasing SIRT1 expression in skeletal muscle and visceral adipose tissue, decreasing PPARγ expression in visceral adipose tissue.


Assuntos
Composição Corporal/efeitos dos fármacos , Resveratrol/farmacologia , Tecido Adiposo , Animais , Restrição Calórica , Gordura Intra-Abdominal , Masculino , Músculo Esquelético , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley , Sirtuína 1/metabolismo
12.
Life Sci ; 256: 117908, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512011

RESUMO

BACKGROUND: Excessive alcohol intake contributes to severe liver damage involving oxidative stress and inflammatory responses, which make them promising therapeutic targets. Previous studies have demonstrated that empagliflozin (EMPA) showed cardiovascular, renal, and cerebral benefits potentially mediated through its antioxidant and anti-inflammatory actions. AIMS: This experiment aimed to evaluate the hepatoprotective effect of EMPA on alcoholic liver disease (ALD) and the possible underlying mechanisms. MATERIALS AND METHODS: Serum biochemical parameters and the liver contents of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Real-time qPCR was conducted to determine the gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (Hmox-1). In addition, ELISA was performed to measure tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, Nrf-2, and PPAR-γ. Nuclear factor-kappa B (NF-κB) was detected by immunohistochemical staining using an anti-NF-κB p65 antibody. KEY FINDINGS: Our results revealed that the serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were significantly reduced by EMPA. EMPA also decreased the content of MDA and NO and increased the activities of SOD and GSH in liver homogenates. Moreover, EMPA inhibited the release of proinflammatory cytokines, including TNF-α, IL-1ß, and IL-6, via the downregulation of NF-κB. These changes were associated with an improvement in histopathological deterioration. The protective effect of EMPA against oxidative stress and inflammation was associated with the upregulation of PPAR-γ, Nrf-2, and their target gene Hmox-1. SIGNIFICANCE: EMPA showed protective activities against ethanol-induced liver injury by suppressing inflammation and oxidative stress via modulation of the NF-κB/Nrf-2/PPAR-γ axis.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Compostos Benzidrílicos/farmacologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/prevenção & controle , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Glucosídeos/farmacologia , NF-kappa B/metabolismo , PPAR gama/metabolismo , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Aspartato Aminotransferases/metabolismo , Compostos Benzidrílicos/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Descoberta de Drogas , Etanol/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/metabolismo , Glutationa/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Interleucinas/metabolismo , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/genética , Superóxido Dismutase/metabolismo
13.
Metabolism ; 110: 154302, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32589900

RESUMO

BACKGROUND: Intracellular lipid accumulation is associated with various diseases, particularly cancer. Mitochondrial dysfunction is considered as a cause of lipid accumulation; however, the related underlying mechanism remains unclear. FINDINGS: We found that Von Hippel-Lindau (VHL)-deficiency led to lipid accumulation and mitochondrial dysfunction in renal cell carcinoma cells. Moreover, VHL downregulated ATP-citrate lyase (ACLY), a key enzyme in de novo lipid synthesis, at the transcriptional level, which inhibited intracellular lipid accumulation in human renal carcinoma tissues. We identified PPARγ as the transcription factor regulating ACLY expression by binding to the cis-regulatory site PPRE on its promoter. VHL directly interacted with and promoted ubiquitination of PPARγ, leading to its degradation both in vitro and in vivo, resulting in the downregulation of ACLY. Furthermore, adenovirus-mediated VHL overexpression substantially ameliorated hepatic steatosis induced by a high-fat diet in db/db mice. Importantly, low VHL expression was associated with high ACLY expression and poor prognosis in human liver carcinoma in a dataset in The Cancer Genome Atlas. CONCLUSIONS: VHL plays role in cellular lipid metabolism via regulating mitochondria and targeting PPARγ, a transcription factor for ACLY independent of hypoxia-inducible factor 1α. A novel VHL-PPARγ-ACLY axis and its implication in fatty liver disease and cancer were uncovered.


Assuntos
ATP Citrato (pro-S)-Liase/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Neoplasias/metabolismo , PPAR gama/metabolismo , Ubiquitinação , Proteína Supressora de Tumor Von Hippel-Lindau/fisiologia , Animais , Linhagem Celular Tumoral , Progressão da Doença , Fígado Gorduroso/metabolismo , Humanos , Camundongos , Complexo de Endopeptidases do Proteassoma/fisiologia , Proteína Supressora de Tumor Von Hippel-Lindau/genética
14.
Toxicol Appl Pharmacol ; 398: 115009, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32353385

RESUMO

Significant attention has been given to the potential of environmental chemicals to disrupt lipid homeostasis at the cellular level. These chemicals, classified as obesogens, are abundantly used in a wide variety of consumer products. However, there is a significant lack of information regarding the mechanisms by which environmental exposure can contribute to the onset of obesity and non-alcoholic fatty liver disease (NAFLD). Several studies have described the interaction of potential obesogens with lipid-related peroxisome proliferator-activated receptors (PPAR). However, no studies have quantified the degree of modification to lipidomic profiles in relevant human models, making it difficult to directly link PPAR agonists to the onset of lipid-related diseases. A quantitative metabolomic approach was used to examine the dysregulation of lipid metabolism in human liver cells upon exposure to potential obesogenic compounds. The chemicals rosiglitazone, perfluorooctanoic acid, di-2-ethylexylphthalate, and tributyltin significantly increased total lipids in liver cells, being diglycerides, triglycerides and phosphatidylcholines the most prominent. Contrarily, perfluorooctane sulfonic acid and the pharmaceutical fenofibrate appeared to lower total lipid concentrations, especially those belonging to the acylcarnitine, ceramide, triglyceride, and phosphatidylcholine groups. Fluorescence microscopy analysis for cellular neutral lipids revealed significant lipid bioaccumulation upon exposure to obesogens at environmentally relevant concentrations. This integrated omics analysis provides unique mechanistic insight into the potential of these environmental pollutants to promote diseases like obesity and NAFLD. Furthermore, this study provides a significant contribution to advance the understanding of molecular signatures related to obesogenic chemicals and to the development of alternatives to in vivo experimentation.


Assuntos
Exposição Ambiental/efeitos adversos , Poluentes Ambientais/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Obesidade/induzido quimicamente , Obesidade/metabolismo , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolômica/métodos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR gama/metabolismo
15.
Ecotoxicol Environ Saf ; 199: 110714, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32446100

RESUMO

Previous studies focused on biocompatibility of graphene oxide (GO) to macrophages, but the impact of GO on lipid profiles in macrophages was less investigated. Herein, we investigated the interactions between THP-1 macrophages and GO of different sizes (GO of size 500-5000 nm, denoted as GO-L; GO of size < 500 nm, denoted as GO-S). We found that after 24 h exposure, the internalization of GO appeared to be minimal, whereas up to 50 µg/mL of GO-L but not GO-S reduced lipid accumulation, accompanying with a significantly reduced release of soluble monocyte chemoattractant protein-1 (MCP-1) but not interleukin-6 (IL-6). Moreover, lipidomic data showed that GO-L decreased the levels of 17 lipid classes, whereas GO-S only decreased the levels of 5 lipid classes. For comparison, 50 µg/mL carbon black (CB) significantly increased lipid accumulation with considerable particle internalization. GO-reduced lipid accumulation was not related with increase of reactive oxygen species (ROS) or induction of autophagy, and modulation of autophagy by chemicals showed no significant effect to alter the effects of GO-L on lipid accumulation. However, exposure to GO reduced the mRNA and protein levels of key components in peroxisome proliferators-activated receptor (PPAR) signaling pathway, a pathway that is related with lipid droplet biogenesis, and the modulation of PPARγ by chemicals altered the effects of GO-L on lipid accumulation. In conclusion, our results suggested that GO size-dependently altered lipid profiles in THP-1 macrophages that might be related with PPAR signaling pathway.


Assuntos
Grafite/química , Grafite/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , PPAR gama/metabolismo , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Células THP-1
16.
Nat Commun ; 11(1): 2123, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358558

RESUMO

Mammals differ in their regeneration potential after traumatic injury, which might be caused by species-specific regeneration programs. Here, we compared murine and human Schwann cell (SC) response to injury and developed an ex vivo injury model employing surgery-derived human sural nerves. Transcriptomic and lipid metabolism analysis of murine SCs following injury of sural nerves revealed down-regulation of lipogenic genes and regulator of lipid metabolism, including Pparg (peroxisome proliferator-activated receptor gamma) and S1P (sphingosine-1-phosphate). Human SCs failed to induce similar adaptations following ex vivo nerve injury. Pharmacological PPARg and S1P stimulation in mice resulted in up-regulation of lipid gene expression, suggesting a role in SCs switching towards a myelinating state. Altogether, our results suggest that murine SC switching towards a repair state is accompanied by transcriptome and lipidome adaptations, which are reduced in humans.


Assuntos
Metabolismo dos Lipídeos/fisiologia , Células de Schwann/citologia , Células de Schwann/metabolismo , Animais , Feminino , Humanos , Lisofosfolipídeos/metabolismo , Masculino , Camundongos , Bainha de Mielina/metabolismo , Regeneração Nervosa/genética , Regeneração Nervosa/fisiologia , Sistema Nervoso/citologia , Sistema Nervoso/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , PPAR gama/metabolismo , Sistema Nervoso Periférico/citologia , Sistema Nervoso Periférico/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo
17.
Zhongguo Zhong Yao Za Zhi ; 45(2): 451-456, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237331

RESUMO

To investigate the efficacy of Huangqin Qingre Chubi Capsules(HQC) in patients with ankylosing spondylitis(AS) and its effect on oxidative stress, and to explore its possible mechanism. Fifty-eight cases of AS patients were randomly divided into HQC group and salazosulfapyridine(SASP) group. Another 30 healthy people were employed as a control group. Superoxide dismutase(SOD), total antioxidant capacity(TAOC), malondialdehyde(MDA), lipid peroxidatio(LPO), interleukin-1ß(IL-1ß), IL-10, IL-4, and tumor necrosis factor-α(TNF-α) were detected by ELISA. The mRNA expression levels of AMP-activated protein kinase(AMPK-α), forkhead box O3a(FOXO3a), manganese superoxide dismutase(MnSOD), and peroxisome proliferator-activated receptor gamma(PPARγ) were detected by Real-time fluorescence quantitative polymerase chain reaction(RT-qPCR). The protein expression levels of AMPK-α, FOXO3a, p-FOXO3a, MnSOD, and PPARγ were detected by Western blot. A questionnaire was used to evaluate the disease activity score and observe the clinical efficacy of HQC in AS patients. The levels of MDA, LPO, TNF-α, and IL-1ß were significantly increased in the peripheral blood of AS patients, and SOD, TAOC, IL-4, IL-10 levels were significantly decreased. After HQC treatment, scores of disease active indexes were all decreased, and its clinical efficacy was significantly higher than that in SASP group. After HQC treatment, TAOC, SOD, IL-4, IL-10 were increased and MDA, LPO, TNF-α, IL-1ß were decreased; mRNA levels of AMPK-α, FOXO3a, MnSOD, PPARγ and protein levels of AMPK-α, FOXO3a, p-FOXO3a, MnSOD, PPARγ were increased(P<0.01 or P<0.05). HQC can effectively improve the clinical symptoms and oxidative stress of AS patients, and its mechanism may be related to activating PPARγ and up-regulating AMPK/FOXO3a signal pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Proteína Forkhead Box O3/metabolismo , Estresse Oxidativo , PPAR gama/metabolismo , Espondilite Anquilosante/tratamento farmacológico , Cápsulas , Humanos , Scutellaria baicalensis/química , Transdução de Sinais , Sulfassalazina/uso terapêutico
18.
Invest Ophthalmol Vis Sci ; 61(4): 30, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32330227

RESUMO

Purpose: Meibomian glands are essential in maintaining the integrity and health of the ocular surface. Meibomian gland dysfunction (MGD), mainly induced by ductal occlusion, is considered as the major cause of dry eye disease. In this study, a novel in vitro model was established for investigating the role of inflammation in the process of MGD. Methods: Mouse tarsal plates were removed from eyelids after dissection and explants were cultured during various time ranging from 24 to 120 hours. Meibomian gland epithelial cells were further enzymatically digested and dissociated from tarsal plates before culturing. Both explants and cells were incubated in different media with or without serum or azithromycin (AZM). Furthermore, explants were treated with IL-1ß or vehicle for 48 hours. Analyses for tissue viability, histology, biomarker expression, and lipid accumulation were performed with hematoxylin and eosin (H&E) staining, immunofluorescence staining, and Western blot. Results: Higher viability was preserved when explants were cultured on Matrigel with immediate addition of culture medium. The viability, morphology, biomarker expression, and function of meibomian glands were preserved in explants cultured for up to 72 hours. Lipid accumulation and peroxisome proliferator-activated receptor γ (PPARγ) expression increased in both explants and cells cultured in media containing serum or AZM. Treatment with IL-1ß induced overexpression of Keratin (Krt) 1 in meibomian gland ducts. Conclusions: Intervention with pro-inflammatory cytokine IL-1ß induces hyperkeratinization in meibomian gland ducts in vitro. This novel organotypic culture model can be used for investigating the mechanism of MGD.


Assuntos
Azitromicina/farmacologia , Síndromes do Olho Seco/patologia , Interleucina-1beta/farmacologia , Disfunção da Glândula Tarsal/patologia , Glândulas Tarsais/citologia , PPAR gama/metabolismo , Análise de Variância , Animais , Western Blotting , Células Cultivadas , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/fisiopatologia , Células Epiteliais/patologia , Feminino , Imunofluorescência , Humanos , Técnicas In Vitro , Masculino , Disfunção da Glândula Tarsal/fisiopatologia , Glândulas Tarsais/patologia , Camundongos , Camundongos Endogâmicos C57BL
19.
Arch Biochem Biophys ; 686: 108365, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32315651

RESUMO

Pelargonidin is a natural compound that exists widely in fruits, and exerts antioxidant, anti-atherosclerotic, anti-inflammatory, anti-hyperglycemic, and anti-diabetic activities. However, there have not been any studies concerning its anti-obesity potential to date. Therefore, we evaluated the anti-obesity potential of pelargonidin via inhibition of adipogenesis in 3T3-L1 cells. The cellular oil droplet content was decreased to 68.14%, 56.75%, and 48.39% and triglyceride accumulation decreased to 74.53%, 61.54%, and 47.86% after incubation with 5 µM, 10 µM, and 20 µM pelargonidin, respectively, when compared with DMSO group. Furthermore, pelargonidin treatment led to decrease in glucose consumption. Western blot assay illustrated that the expression of PPAR-γ was suppressed to 63.25%, 47.52%, and 21.23% after incubation with 5 µM, 10 µM, and 20 µM pelargonidin when compared with DMSO group. Then, we measured the expression of some target proteins of PPAR-γ, and found that pelargonidin decreased the expressions of HMGCR, LPL, Glut4, and A-FABP. Besides, the result of Luciferase Reporter Assay indicated that pelargonidin inhibited PPAR-γ transcription activity. These results indicated that pelargonidin exerts anti-adipogenic activity in 3T3-L1 cells through inhibition of PPAR-γ signaling pathway, and pelargonidin could be used as a potential anti-obesity agent.


Assuntos
Adipogenia/efeitos dos fármacos , Antocianinas/farmacologia , Fármacos Antiobesidade/farmacologia , PPAR gama/metabolismo , Células 3T3-L1 , Animais , Antocianinas/metabolismo , Fármacos Antiobesidade/metabolismo , Regulação para Baixo/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Camundongos , Triglicerídeos/genética , Triglicerídeos/metabolismo
20.
Proc Natl Acad Sci U S A ; 117(16): 9082-9093, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32253301

RESUMO

Current multiple sclerosis (MS) medications are mainly immunomodulatory, having little or no effect on neuroregeneration of damaged central nervous system (CNS) tissue; they are thus primarily effective at the acute stage of disease, but much less so at the chronic stage. An MS therapy that has both immunomodulatory and neuroregenerative effects would be highly beneficial. Using multiple in vivo and in vitro strategies, in the present study we demonstrate that ursolic acid (UA), an antiinflammatory natural triterpenoid, also directly promotes oligodendrocyte maturation and CNS myelin repair. Oral treatment with UA significantly decreased disease severity and CNS inflammation and demyelination in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Importantly, remyelination and neural repair in the CNS were observed even after UA treatment was started on day 60 post immunization when EAE mice had full-blown demyelination and axonal damage. UA treatment also enhanced remyelination in a cuprizone-induced demyelination model in vivo and brain organotypic slice cultures ex vivo and promoted oligodendrocyte maturation in vitro, indicating a direct myelinating capacity. Mechanistically, UA induced promyelinating neurotrophic factor CNTF in astrocytes by peroxisome proliferator-activated receptor γ(PPARγ)/CREB signaling, as well as by up-regulation of myelin-related gene expression during oligodendrocyte maturation via PPARγ activation. Together, our findings demonstrate that UA has significant potential as an oral antiinflammatory and neural repair agent for MS, especially at the chronic-progressive stage.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Imunomodulação/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Remielinização/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Cuprizona/toxicidade , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/patologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/imunologia , Oligodendroglia/patologia , PPAR gama/metabolismo , Triterpenos/uso terapêutico
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