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1.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445339

RESUMO

Both agonist studies and loss-of-function models indicate that PPARγ plays an important role in cutaneous biology. Since PPARγ has a high level of basal activity, we hypothesized that epidermal PPARγ would regulate normal homeostatic processes within the epidermis. In this current study, we performed mRNA sequencing and differential expression analysis of epidermal scrapings from knockout mice and wildtype littermates. Pparg-/-epi mice exhibited a 1.5-fold or greater change in the expression of 11.8% of 14,482 identified transcripts. Up-regulated transcripts included those for a large number of cytokines/chemokines and their receptors, as well as genes associated with inflammasome activation and keratinization. Several of the most dramatically up-regulated pro-inflammatory genes in Pparg-/-epi mouse skin included Igfl3, 2610528A11Rik, and Il1f6. RT-PCR was performed from RNA obtained from non-lesional full-thickness skin and verified a marked increase in these transcripts, as well as transcripts for Igflr1, which encodes the receptor for Igfl3, and the 2610528A11Rik receptor (Gpr15). Transcripts for Il4 were detected in Pparg-/-epi mouse skin, but transcripts for Il17 and Il22 were not detected. Down-regulated transcripts included sebaceous gland markers and a number of genes associated with lipid barrier formation. The change in these transcripts correlates with an asebia phenotype, increased transepidermal water loss, alopecia, dandruff, and the appearance of spontaneous inflammatory skin lesions. Histologically, non-lesional skin showed hyperkeratosis, while inflammatory lesions were characterized by dermal inflammation and epidermal acanthosis, spongiosis, and parakeratosis. In conclusion, loss of epidermal Pparg alters a substantial set of genes that are associated with cutaneous inflammation, keratinization, and sebaceous gland function. The data indicate that epidermal PPARγ plays an important role in homeostatic epidermal function, particularly epidermal differentiation, barrier function, sebaceous gland development and function, and inflammatory signaling.


Assuntos
Dermatite/genética , Epiderme/metabolismo , PPAR gama/fisiologia , Fenômenos Fisiológicos da Pele/genética , Animais , Células Cultivadas , Dermatite/metabolismo , Dermatite/patologia , Dermatite/fisiopatologia , Epiderme/fisiologia , Homeostase/genética , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade de Órgãos/genética , PPAR gama/genética , PPAR gama/metabolismo
2.
Wiad Lek ; 74(7): 1617-1621, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34459761

RESUMO

OBJECTIVE: The aim: To study the association between the effectiveness of treatment with pioglitazone non-alcoholic fatty liver disease (NAFLD) in patients with obesity and PPARG rs1801282 (Pro12Ala)-polymorphism in Ukrainians. PATIENTS AND METHODS: Materials and methods: 123 patients with NAFLD in combination with obesity 1, 2, 3 classes were included in comprehensive weight loss program (5 visits, 12-weeks). The case group was treated with pioglitazone 15 mg / day, while the control group received only program. Ultrasound (US) steatometry and genetic testing rs1801282 polymorphism in PPARG gene were performed. RESULTS: Results: Pioglitazone, PPARG rs1801282 genotype, CAP before treatment, previous weight loss attempts, and duration of obesity were associated with the change in controlled attenuation parameter (CAP) during treatment. There was a significant association between the target CAP reduction achievement and pioglitazone treatment (adjusted odds ratio 0.23, 95% CI 0.07-0.73; p = 0.01) with the CC genotype of PPARG gene (adjusted odds ratio 92.9, 95% CI 7.4-1159; p < 0.001) compared to patients with the CG genotype. CONCLUSION: Conclusions: Pioglitazone and PPARG rs1801282 polymorphism could influence on dynamics of CAP reduction during treatment.


Assuntos
Hepatopatia Gordurosa não Alcoólica , PPAR gama , Predisposição Genética para Doença , Genótipo , Humanos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/complicações , Obesidade/genética , PPAR gama/genética , Pioglitazona/uso terapêutico , Polimorfismo de Nucleotídeo Único
3.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445309

RESUMO

In our previous work, we built the model of PPARγ dependent pathways involved in the development of the psoriatic lesions. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor and transcription factor which regulates the expression of many proinflammatory genes. We tested the hypothesis that low levels of PPARγ expression promote the development of psoriatic lesions triggering the IL17-related signaling cascade. Skin samples of normally looking and lesional skin donated by psoriasis patients and psoriatic CD3+ Tcells samples (n = 23) and samples of healthy CD3+ T cells donated by volunteers (n = 10) were analyzed by real-time PCR, ELISA and immunohistochemistry analysis. We found that the expression of PPARγ is downregulated in human psoriatic skin and laser treatment restores the expression. The expression of IL17, STAT3, FOXP3, and RORC in psoriatic skin before and after laser treatment were correlated with PPARγ expression according to the reconstructed model of PPARγ pathway in psoriasis.In conclusion, we report that PPARγ weakens the expression of genes that contribute in the development of psoriatic lesion. Our data show that transcriptional regulation of PPARγ expression by FOSL1 and by STAT3/FOSL1 feedback loop may be central in the psoriatic skin and T-cells.


Assuntos
PPAR gama/metabolismo , Psoríase/metabolismo , Transdução de Sinais , Adulto , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , PPAR gama/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos T/metabolismo
4.
J Agric Food Chem ; 69(32): 9299-9312, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34342980

RESUMO

Ginsenoside F2 (GF2) is a protopanaxdiol saponin from Panax ginseng leaves and possesses many potential pharmacological properties. GF2 may prevent obesity by directly binding to the peroxisome proliferator-activated receptor-γ (PPARγ) and inhibiting adipocyte differentiation. However, the mechanism by which GF2 alleviates obesity is unknown. We therefore explored the anti-adipogenesis and anti-obesity effects of GF2 in vitro and in vivo. GF2 inhibited differentiation and reduced the triglyceride (TG) content of 3T3-L1 preadipocytes in the early stage of adipogenesis. Administration of GF2 (50 and 100 mg/kg) to obese mice for 4 weeks reduced the body weight gain, weight of adipose tissues, adipocyte size, and total cholesterol, TG, and AST levels in serum. RNA sequencing and real-time quantitative PCR indicated that GF2 decreased the expression levels of adipokines, including PPARγ, fatty acid synthase, and adiponectin. KEGG enrichment and western blot analyses demonstrated that GF2 accelerated the phosphorylation of AMPK and ACC in vitro and in vivo. Moreover, GF2 promoted the biosynthesis of mitochondria in 3T3-L1 adipocytes and increased the expression of antioxidant enzymes such as SOD and GSH-Px in the liver of obese mice. Therefore, GF2 suppressed adipogenesis and obesity by regulating the expression of adipokines and activating the AMPK pathway. Hence, the findings suggest that GF2 may have potential therapeutic implications to treat obesity.


Assuntos
Adipogenia , Fármacos Antiobesidade , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Adipogenia/genética , Animais , Fármacos Antiobesidade/farmacologia , Dieta Hiperlipídica , Ginsenosídeos , Camundongos , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/genética , PPAR gama/genética
5.
Fish Physiol Biochem ; 47(4): 1149-1164, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34142329

RESUMO

Diet-induced fatty liver is a considerable threaten to fish aquaculture due to the popularity of the high-fat diet (HFD) feeding. Our study aims to investigate the effects of flavanones from Sedum sarmentosum Bunge (FSSB) on the liver function to identify a potential treatment for HFD-induced fatty liver disease. Physiological and pathological indicators were tested in the liver of Nile tilapia (Oreochromis niloticus) and results showed parameters including lipid metabolites, redox parameters, and inflammatory factors could be adequately restored to normal level by addition of 150 mg/kg FSSB to HFD. Proteomics analysis was performed in liver tissues from tilapia with normal diet (ND), HFD, and HFD+FSSB. Totally, 51 upregulated proteins and 77 downregulated proteins were identified in HFD groups and 67 proteins of them were restored after treated with FSSB. Bioinformatics analysis showed that differentially expressed proteins (DEPs) in HFD+FSSB150 group compared with HFD group are mainly enriched in acety-CoA metabolic process, adenosine-triphosphate (ATP) biosynthetic process, lipid metabolic process, and phospholipid metabolic process. The dysregulated proteins were involved in peroxidosome proliferators-activated receptor (PPAR) signaling pathway, fat digestion and absorption, and immune system. The quantitative real-time PCR (qRT-PCR) assay further revealed that the expression of GST, PPARα, PPARγ, and multiple-inflammatory cytokines could be also reversed in HFD group under the treatment of 150 mg/kg FSSB. Our findings demonstrated FSSB is efficient for the treatment of fatty liver disease through regulation of lipid metabolism and antioxidation in Nile tilapia, providing a new treatment of non-alcoholic fatty liver disease (NAFLD) in fish aquaculture.


Assuntos
Antioxidantes/uso terapêutico , Ciclídeos , Fígado Gorduroso/tratamento farmacológico , Doenças dos Peixes/tratamento farmacológico , Flavanonas/uso terapêutico , Sedum , Animais , Antioxidantes/farmacologia , Colesterol/sangue , Ciclídeos/sangue , Ciclídeos/genética , Ciclídeos/crescimento & desenvolvimento , Dieta Hiperlipídica , Fígado Gorduroso/genética , Fígado Gorduroso/veterinária , Doenças dos Peixes/genética , Proteínas de Peixes/genética , Flavanonas/farmacologia , Glutationa Transferase/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , PPAR alfa/genética , PPAR gama/genética , Triglicerídeos/sangue
6.
J Med Food ; 24(6): 666-669, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34077672

RESUMO

Obesity is defined as excess adipose mass that causes serious health problems. Phenethyl isothiocyanate (PEITC) is a major and relatively nontoxic compound of the isothiocyanates. Although many studies have demonstrated that PEITC is a potent substance with physiological activities, such as anticancer activity, the precise mechanism for the effects of PEITC on inflammation and lipid metabolism in adipose tissue is not clear. Our study aimed to clarify the effects of PEITC supplements on the adipose tissue in obesity induced with a high-fat/cholesterol diet, and the underlying mechanisms. We induced obesity by feeding the mice with high fat with 1% cholesterol diet (HFCD) for 13 weeks. Mice were divided into five groups: normal diet (CON), HFCD, HFCD with 3 mg/(kg·d) gallic acid (HFCD+G), and HFCD with 30 and 75 mg/(kg·d) PEITC (HFCD+P30 and HFCD+P75, respectively). Using western blotting and quantitative polymerase chain reaction (qPCR) analysis of the adipose tissue, we determined the expression of lipid metabolism-related genes and inflammation-related genes. In the HFCD, the expression level of nuclear factor-κB (NF-κB), lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), and cyclooxygenase-2 (COX-2), was higher compared with that in the CON. Moreover, in the HFCD, the expression of p-mechanical targets of the rapamycin (mTOR) was increased, whereas that of p-AMP-activated protein kinase (AMPK) was decreased compared with that in the CON. Nevertheless, these decreased expression levels of p-AMPK and increased levels of LOX-1, p-mTOR, peroxisome proliferator-activated receptor gamma (PPARγ), NF-κB, and COX-2, were alleviated by PEITC supplementation. Therefore, we suggest that PEITC might be a potential preventive agent for ameliorating obesity-induced inflammation and adipogenesis by modulating the mTOR/AMPK/PPARγ pathway.


Assuntos
Metabolismo dos Lipídeos , PPAR gama , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Inflamação/genética , Inflamação/metabolismo , Isotiocianatos/metabolismo , Camundongos , Camundongos Obesos , PPAR gama/genética , PPAR gama/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
7.
Cell Prolif ; 54(7): e13072, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34031939

RESUMO

OBJECTIVES: Induction of deactivation and apoptosis of hepatic stellate cells (HSCs) are principal therapeutic strategies for liver fibrosis. Krüppel-like factor 14 (KLF14) regulates various biological processes, however, roles, mechanisms and implications of KLF14 in liver fibrosis are unknown. MATERIALS AND METHODS: KLF14 expression was detected in human, rat and mouse fibrotic models, and its effects on HSCs were assessed. Chromatin immunoprecipitation assays were utilized to investigate the binding of KLF14 to peroxisome proliferator-activated receptor γ (PPARγ) promoter, and the binding of enhancer of zeste homolog 2 (EZH2) to KLF14 promoter. In vivo, KLF14-overexpressing adenovirus was injected via tail vein to thioacetamide (TAA)-treated rats to investigate the role of KLF14 in liver fibrosis progression. EZH2 inhibitor EPZ-6438 was utilized to treat TAA-induced rat liver fibrosis. RESULTS: KLF14 expression was remarkably decreased in human, rat and mouse fibrotic liver tissues. Overexpression of KLF14 increased LD accumulation, inhibited HSCs activation, proliferation, migration and induced G2/M arrest and apoptosis. Mechanistically, KLF14 transactivated PPARγ promoter activity. Inhibition of PPARγ blocked the suppressive role of KLF14 overexpression in HSCs. Downregulation of KLF14 in activated HSCs was mediated by EZH2-regulated histone H3 lysine 27 trimethylation. Adenovirus-mediated KLF14 overexpression ameliorated TAA-induced rat liver fibrosis in PPARγ-dependent manner. Furthermore, EPZ-6438 dramatically alleviated TAA-induced rat liver fibrosis. Importantly, KLF14 expression was decreased in human with liver fibrosis, which was significantly correlated with EZH2 upregulation and PPARγ downregulation. CONCLUSIONS: KLF14 exerts a critical anti-fibrotic role in liver fibrosis, and targeting the EZH2/KLF14/PPARγ axis might be a novel therapeutic strategy for liver fibrosis.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Cirrose Hepática/patologia , PPAR gama/metabolismo , Animais , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , Fatores de Transcrição Kruppel-Like/genética , Cirrose Hepática/metabolismo , Camundongos , Morfolinas/farmacologia , PPAR gama/antagonistas & inibidores , PPAR gama/genética , Regiões Promotoras Genéticas , Piridonas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Tioacetamida/farmacologia
8.
FASEB J ; 35(6): e21555, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34046947

RESUMO

Preeclampsia (PE) is a life-threatening disease of pregnant women associated with severe hypertension, proteinuria, or multi-organ injuries. Mitochondrial-mediated placental oxidative stress plays a key role in the pathogenesis of PE. However, the underlying mechanism remains to be revealed. Here, we identify Rnd3, a small Rho GTPase, regulating placental mitochondrial reactive oxygen species (ROS). We showed that Rnd3 is down-regulated in primary trophoblasts isolated from PE patients. Loss of Rnd3 in trophoblasts resulted in excessive ROS generation, cell apoptosis, mitochondrial injury, and proton leakage from the respiratory chain. Moreover, Rnd3 overexpression partially rescues the mitochondrial defects and oxidative stress in human PE primary trophoblasts. Rnd3 physically interacts with the peroxisome proliferators-activated receptor γ (PPARγ) and promotes the PPARγ-mitochondrial uncoupling protein 2 (UCP2) cascade. Forced expression of PPARγ rescues deficiency of Rnd3-mediated mitochondrial dysfunction. We conclude that Rnd3 acts as a novel protective factor in placental mitochondria through PPARγ-UCP2 signaling and highlight that downregulation of Rnd3 is a potential factor involved in PE pathogenesis.


Assuntos
Mitocôndrias/patologia , PPAR gama/metabolismo , Placenta/patologia , Pré-Eclâmpsia/patologia , Trofoblastos/patologia , Proteína Desacopladora 2/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Feminino , Humanos , Mitocôndrias/metabolismo , Estresse Oxidativo , PPAR gama/genética , Placenta/metabolismo , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Gravidez , Trofoblastos/metabolismo , Proteína Desacopladora 2/genética , Proteínas rho de Ligação ao GTP/genética
9.
Oncoimmunology ; 10(1): 1906500, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-34026331

RESUMO

Only a small subset of colorectal cancer (CRC) patients benefits from immunotherapies, comprising blocking antibodies (Abs) against checkpoint receptor "programmed-cell-death-1" (PD1) and its ligand (PD-L1), because most cases lack the required mutational burden and neo-antigen load caused by microsatellite instability (MSI) and/or an inflamed, immune cell-infiltrated PD-L1+ tumor microenvironment. Peroxisome proliferator-activated-receptor-gamma (PPARγ), a metabolic transcription factor stimulated by anti-diabetic drugs, has been previously implicated in pre/clinical responses to immunotherapy. We therefore raised the hypothesis that PPARγ induces PD-L1 on microsatellite stable (MSS) tumor cells to enhance Ab-target engagement and responsiveness to PD-L1 blockage. We found that PPARγ-agonists upregulate PD-L1 mRNA/protein expression in human gastrointestinal cancer cell lines and MSS+ patient-derived tumor organoids (PDOs). Mechanistically, PPARγ bound to and activated DNA-motifs similar to cognate PPARγ-responsive-elements (PPREs) in the proximal -2 kb promoter of the human PD-L1 gene. PPARγ-agonist reduced proliferation and viability of tumor cells in co-cultures with PD-L1 blocking Ab and lymphokine-activated killer cells (LAK) derived from the peripheral blood of CRC patients or healthy donors. Thus, metabolic modifiers improved the antitumoral response of immune checkpoint Ab, proposing novel therapeutic strategies for CRC.


Assuntos
Neoplasias Colorretais , PPAR gama , Antígeno B7-H1/genética , Neoplasias Colorretais/tratamento farmacológico , Humanos , Instabilidade de Microssatélites , PPAR gama/genética , Microambiente Tumoral
10.
J Agric Food Chem ; 69(21): 6032-6042, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34008977

RESUMO

Although the health benefits of probiotics have been widely known for decades, there has still been limited use of probiotic bacteria in anti-obesity therapy. Herein, we demonstrated the role of Bifidobacterium longum subsp. infantis YB0411 (YB, which was selected by an in vitro adipogenesis assay) in adipogenic differentiation in 3T3-L1 pre-adipocytes. We observed that YB-treatment effectively reduced triglyceride accumulation and the expression of CCAAT/enhancer-binding protein α, ß, and δ (C/EBPα, C/EBPß, and C/EBPδ), peroxisome proliferator-activated receptor γ (PPARγ), fatty acid-binding protein 4 (aP2), and acetyl-CoA carboxylase (ACC). YB-treatment also reduced the levels of core autophagic markers (p62 and LC3B) in 3T3-L1 pre-adipocytes. Small-interfering-RNA-mediated knockdown and competitive-chemical-inhibition assays showed that AMP-activated protein kinase (AMPK) commenced the anti-adipogenic effect of YB. In addition, YB supplement markedly reduced body weight and fat accretion in mice with high-fat-diet-induced obesity. Our findings suggest that YB may be used as a potential probiotic candidate to ameliorate obesity.


Assuntos
Adipogenia , Bifidobacterium longum , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Adipócitos , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Diferenciação Celular , Camundongos , Obesidade/genética , PPAR gama/genética
11.
Wei Sheng Yan Jiu ; 50(2): 315-319, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33985643

RESUMO

OBJECTIVE: To explore the relationship between the peroxisome proliferator-activated receptor γ(PPARγ) 2 gene Pro12 Ala polymorphism and the risk of obesity in the Chinese population. METHODS: Take "peroxisome proliferator activated receptor gamma2", "PPAR gamma2", "pparg2", "peroxisome proliferator-activated receptor gamma2", "obesity", "Pro12 Ala", "gene polymorphism", "Chinese" as searchable words, Chinese people were selected as study subjects from Chinese databases such as CNKI, Wanfang Database, VIP and foreign language databases such as PubMed, Embase, Cochrane Library and Web of Science, which were published from the establishment of the database until December 31, 2019. RevMan 5. 3 software was used for Meta-analysis of the literature with literature score ≥ 5 points. RESULTS: A total of 12 articles were included, including 2233 cases and 1795 healthy controls. Meta-analysis showed that:(1) Dominant gene model: the risk of obesity for those carrying Ala/Ala+Pro/Ala was 1. 86 times that of those carrying Pro/Pro(OR=1. 86, 95%CI 1. 07-3. 21). (2) Additive gene model: the risk of obesity for those carrying Pro/Ala was 1. 79 times that of those carrying Pro/Pro(OR=1. 79, 95% CI 1. 04-3. 08). (3) Allelic model: the risk of obesity in those carrying the allele Ala was 1. 75 times that of those carrying the allele Pro(OR=1. 75, 95% CI 1. 11-2. 78). The subgroup analysis of different regions showed that the combined OR(95% CI) values of the dominant gene model, additive gene model and allelic model in the southern region were 1. 96(1. 12-3. 42), 2. 02(1. 14-3. 56) and 1. 79(1. 06-3. 03), the combined OR(95% CI) values of the dominant gene model, additive gene model and allele model in the northern region were 1. 89(0. 90-3. 97), 1. 77(0. 85-3. 67) and 1. 80(0. 97-3. 36). CONCLUSION: The polymorphic allele Ala or genotype Ala/Ala or Pro/Ala of PPARγ2 gene may increase the risk of obesity in Chinese population. The correlation between the PPARγ2 gene Pro12 Ala polymorphism and the risk of obesity in the southern population is more obvious.


Assuntos
Predisposição Genética para Doença , PPAR gama , China/epidemiologia , Genótipo , Humanos , Idioma , Obesidade/genética , PPAR gama/genética
12.
J Med Food ; 24(5): 487-496, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34009020

RESUMO

Anacardic acid (AA), a major component of cashew nut shell liquid, has extensive bioactivities. However, little is known about its antiadipogenic properties or the mechanism that underpins them. The aim of this study was to investigate the effect of AA on 3T3-L1 preadipocyte differentiation and its mechanisms of action. AA inhibits lipid accumulation during adipogenesis in 3T3-L1 preadipocyte (IC50 = 25.45 µM). AA abrogates mRNA expressions of the genes implicated in lipogenesis and their transcription factors, especially Pparg and Cebpa. Furthermore, antibody microarray and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis results showed that the proteins implicated in the Akt signaling pathway were most likely altered by AA. Notably, upon AA treatment, heat shock protein 90 (Hsp90), a positive regulator of Akt, was decreased, resulting in Akt degradation. These findings indicate that AA, a natural product that acts as a Hsp90/Akt signaling inhibitor, may be a possible antiadipogenic agent.


Assuntos
Adipogenia , Proteínas Proto-Oncogênicas c-akt , Células 3T3-L1 , Adipócitos/metabolismo , Ácidos Anacárdicos , Animais , Diferenciação Celular , Camundongos , PPAR gama/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
13.
Nat Commun ; 12(1): 2538, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33953160

RESUMO

Group 2 innate lymphoid cells (ILC2s) play a critical role in protection against helminths and in diverse inflammatory diseases by responding to soluble factors such as the alarmin IL-33, that is often overexpressed in cancer. Nonetheless, regulatory factors that dictate ILC2 functions remain poorly studied. Here, we show that peroxisome proliferator-activated receptor gamma (PPARγ) is selectively expressed in ILC2s in humans and in mice, acting as a central functional regulator. Pharmacologic inhibition or genetic deletion of PPARγ in ILC2s significantly impair IL-33-induced Type-2 cytokine production and mitochondrial fitness. Further, PPARγ blockade in ILC2s disrupts their pro-tumoral effect induced by IL-33-secreting cancer cells. Lastly, genetic ablation of PPARγ in ILC2s significantly suppresses tumor growth in vivo. Our findings highlight a crucial role for PPARγ in supporting the IL-33 dependent pro-tumorigenic role of ILC2s and suggest that PPARγ can be considered as a druggable pathway in ILC2s to inhibit their effector functions. Hence, PPARγ targeting might be exploited in cancer immunotherapy and in other ILC2-driven mediated disorders, such as asthma and allergy.


Assuntos
Imunidade Inata/imunologia , Interleucina-33/metabolismo , Linfócitos/metabolismo , Neoplasias/terapia , PPAR gama/metabolismo , Animais , Asma , Citocinas/farmacologia , Técnicas de Silenciamento de Genes , Humanos , Hipersensibilidade , Imunoterapia , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias , Neoplasias/patologia , PPAR gama/genética
14.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946412

RESUMO

Despite the huge body of research on osteogenic differentiation and bone tissue engineering, the translation potential of in vitro results still does not match the effort employed. One reason might be that the protocols used for in vitro research have inherent pitfalls. The synthetic glucocorticoid dexamethasone is commonly used in protocols for trilineage differentiation of human bone marrow mesenchymal stromal cells (hBMSCs). However, in the case of osteogenic commitment, dexamethasone has the main pitfall of inhibiting terminal osteoblast differentiation, and its pro-adipogenic effect is well known. In this work, we aimed to clarify the role of dexamethasone in the osteogenesis of hBMSCs, with a particular focus on off-target differentiation. The results showed that dexamethasone does induce osteogenic differentiation by inhibiting SOX9 expression, but not directly through RUNX2 upregulation as it is commonly thought. Rather, PPARG is concomitantly and strongly upregulated, leading to the formation of adipocyte-like cells within osteogenic cultures. Limiting the exposure to dexamethasone to the first week of differentiation did not affect the mineralization potential. Gene expression levels of RUNX2, SOX9, and PPARG were simulated using approximate Bayesian computation based on a simplified theoretical model, which was able to reproduce the observed experimental trends but with a different range of responses, indicating that other factors should be integrated to fully understand how dexamethasone influences cell fate. In summary, this work provides evidence that current in vitro differentiation protocols based on dexamethasone do not represent a good model, and further research is warranted in this field.


Assuntos
Dexametasona/farmacologia , Glucocorticoides/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , PPAR gama/metabolismo , Fatores de Transcrição SOX9/metabolismo , Adulto , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , PPAR gama/genética , Fatores de Transcrição SOX9/genética
15.
J Med Chem ; 64(10): 6949-6971, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34006099

RESUMO

Monotargeting anticancer agents suffer from resistance and target nonspecificity concerns, which can be tackled with a multitargeting approach. The combined treatment with HDAC inhibitors and PPARγ agonists has displayed potential antitumor effects. Based on these observations, this work involves design and synthesis of molecules that can simultaneously target PPARγ and HDAC. Several out of 25 compounds inhibited HDAC4, and six compounds acted as dual-targeting agents. Compound 7i was the most potent, with activity toward PPARγ EC50 = 0.245 µM and HDAC4 IC50 = 1.1 µM. Additionally, compounds 7c and 7i were cytotoxic to CCRF-CEM cells (CC50 = 2.8 and 9.6 µM, respectively), induced apoptosis, and caused DNA fragmentation. Furthermore, compound 7c modulated the expression of c-Myc, cleaved caspase-3, and caused in vivo tumor regression in CCRF-CEM tumor xenografts. Thus, this study provides a basis for the rational design of dual/multitargeting agents that could be developed further as anticancer therapeutics.


Assuntos
Desenho de Fármacos , Histona Desacetilases/metabolismo , PPAR gama/metabolismo , Proteínas Repressoras/metabolismo , Tiazolidinedionas/química , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos SCID , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , PPAR gama/química , PPAR gama/genética , Proteínas Repressoras/antagonistas & inibidores , Relação Estrutura-Atividade , Tiazolidinedionas/metabolismo , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico , Ativação Transcricional/efeitos dos fármacos , Transplante Heterólogo
16.
Nat Commun ; 12(1): 2876, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001883

RESUMO

Activation of non-shivering thermogenesis is considered a promising approach to lower body weight in obesity. p62 deficiency in adipocytes reduces systemic energy expenditure but its role in sustaining mitochondrial function and thermogenesis remains unresolved. NBR1 shares a remarkable structural similarity with p62 and can interact with p62 through their respective PB1 domains. However, the physiological relevance of NBR1 in metabolism, as compared to that of p62, was not clear. Here we show that whole-body and adipocyte-specific ablation of NBR1 reverts the obesity phenotype induced by p62 deficiency by restoring global energy expenditure and thermogenesis in brown adipose tissue. Impaired adrenergic-induced browning of p62-deficient adipocytes is rescued by NBR1 inactivation, unveiling a negative role of NBR1 in thermogenesis under conditions of p62 loss. We demonstrate that upon p62 inactivation, NBR1 represses the activity of PPARγ, establishing an unexplored p62/NBR1-mediated paradigm in adipocyte thermogenesis that is critical for the control of obesity.


Assuntos
Adipócitos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , PPAR gama/metabolismo , Proteína Sequestossoma-1/deficiência , Termogênese , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/metabolismo , Animais , Animais Recém-Nascidos , Núcleo Celular/metabolismo , Células Cultivadas , Metabolismo Energético/genética , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , PPAR gama/genética , Ligação Proteica , Receptor X Retinoide alfa/genética , Receptor X Retinoide alfa/metabolismo , Proteína Sequestossoma-1/genética
17.
Am J Pathol ; 191(7): 1314-1324, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33887215

RESUMO

Solitary fibrous tumors (SFTs) harbor activating NAB2-STAT6 gene fusions. Different variants of the NAB2-STAT6 gene fusion have been associated with distinct clinicopathologic features. Lipomatous SFTs are a morphologic variant of SFTs, characterized by a fat-forming tumor component. Our aim was to evaluate NAB2-STAT6 fusion variants and to further study the molecular genetic features in a cohort of lipomatous SFTs. A hybrid-capture-based next-generation sequencing panel was employed to detect NAB2-STAT6 gene fusions at the RNA level. In addition, the RNA expression levels of 507 genes were evaluated using this panel, and were compared with a control cohort of nonlipomatous SFTs. Notably, 5 of 11 (45%) of lipomatous SFTs in the current series harbored the uncommon NAB2 exon 4-STAT6 exon 4 gene fusion variant, which is observed in only 0.9% to 1.4% of nonlipomatous SFTs. Furthermore, lipomatous SFTs displayed significant differences in gene expression compared with their nonlipomatous counterparts, including up-regulation of the gene peroxisome proliferator activated receptor-γ (PPARG). Peroxisome proliferator activated receptor-γ is a nuclear receptor regulating adipocyte differentiation, providing a possible explanation for the fat-forming component in lipomatous SFTs. In summary, the current study provides a possible molecular genetic basis for the distinct morphologic features of lipomatous SFTs.


Assuntos
Adipócitos/patologia , PPAR gama/genética , Proteínas Repressoras/genética , Fator de Transcrição STAT6/genética , Tumores Fibrosos Solitários/genética , Adulto , Idoso , Diferenciação Celular/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fusão Oncogênica , Tumores Fibrosos Solitários/patologia , Regulação para Cima
18.
Eur J Vasc Endovasc Surg ; 61(6): 1008-1016, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33858751

RESUMO

OBJECTIVE: Perivascular adipose tissue (PVAT) contributes to vascular homeostasis and is increasingly linked to vascular pathology. PVAT density and volume were associated with abdominal aortic aneurysm (AAA) presence and dimensions on imaging. However, mechanisms underlying the role of PVAT in AAA have not been clarified. This study aimed to explore differences in PVAT from AAA using gene expression and functional tests. METHODS: Human aortic PVAT and control subcutaneous adipose tissue were collected during open AAA surgery. Gene analyses and functional tests were performed. The control group consisted of healthy aorta from non-living renal transplant donors. Gene expression tests were performed to study genes potentially involved in various inflammatory processes and AAA related genes. Live PVAT and subcutaneous adipose tissue (SAT) from AAA were used for ex vivo co-culture with smooth muscle cells (SMCs) retrieved from non-pathological aortas. RESULTS: Adipose tissue was harvested from 27 AAA patients (n [gene expression] = 22, n [functional tests] = 5) and five control patients. An increased inflammatory gene expression of PTPRC (p = .008), CXCL8 (p = .033), LCK (p = .003), CCL5 (p = .004) and an increase in extracellular matrix breakdown marker MMP9 (p = .016) were found in AAA compared with controls. Also, there was a decreased anti-inflammatory gene expression of PPARG in AAA compared with controls (p = .040). SMC co-cultures from non-pathological aortas with PVAT from AAA showed increased MMP9 (p = .033) and SMTN (p = .008) expression and SAT increased SMTN expression in these SMC. CONCLUSION: The data revealed that PVAT from AAA shows an increased pro-inflammatory and matrix metallopeptidase gene expression and decreased anti-inflammatory gene expression. Furthermore, increased expression of genes involved in aneurysm formation was found in healthy SMC co-culture with PVAT of AAA patients. Therefore, PVAT from AAA might contribute to inflammation of the adjacent aortic wall and thereby plays a possible role in AAA pathophysiology. These proposed pathways of inflammatory induction could reveal new therapeutic targets in AAA treatment.


Assuntos
Aneurisma da Aorta Abdominal/genética , Quimiocina CCL5/genética , Interleucina-8/genética , Antígenos Comuns de Leucócito/genética , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/genética , Metaloproteinase 9 da Matriz/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Estudos de Casos e Controles , Quimiocina CCL5/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Feminino , Humanos , Interleucina-8/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , PPAR gama/genética , PPAR gama/metabolismo , RNA Mensageiro/metabolismo
19.
Int J Mol Sci ; 22(8)2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33920138

RESUMO

Alzheimer's disease (AD) is a chronic, neurodegenerative brain disorder affecting millions of Americans that is expected to increase in incidence with the expanding aging population. Symptomatic AD patients show cognitive decline and often develop neuropsychiatric symptoms due to the accumulation of insoluble proteins that produce plaques and tangles seen in the brain at autopsy. Unexpectedly, some clinically normal individuals also show AD pathology in the brain at autopsy (asymptomatic AD, AsymAD). In this study, SWItchMiner software was used to identify key switch genes in the brain's entorhinal cortex that lead to the development of AD or disease resilience. Seventy-two switch genes were identified that are differentially expressed in AD patients compared to healthy controls. These genes are involved in inflammation, platelet activation, and phospholipase D and estrogen signaling. Peroxisome proliferator-activated receptor γ (PPARG), zinc-finger transcription factor (YY1), sterol regulatory element-binding transcription factor 2 (SREBF2), and early growth response 1 (EGR1) were identified as transcription factors that potentially regulate switch genes in AD. Comparing AD patients to AsymAD individuals revealed 51 switch genes; PPARG as a potential regulator of these genes, and platelet activation and phospholipase D as critical signaling pathways. Chemical-protein interaction analysis revealed that valproic acid is a therapeutic agent that could prevent AD from progressing.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Genes de Troca/genética , Inflamação/genética , Envelhecimento/genética , Envelhecimento/patologia , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Proteína 1 de Resposta de Crescimento Precoce/genética , Córtex Entorrinal/patologia , Regulação da Expressão Gênica/genética , Humanos , Inflamação/patologia , PPAR gama/genética , Fosfolipase D/genética , Placa Amiloide , Transdução de Sinais/genética , Software , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Fator de Transcrição YY1/genética
20.
Clin Lab ; 67(4)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33865244

RESUMO

BACKGROUND: Diabetic peripheral neuropathy (DPN) is one of the most common and complex chronic complications of diabetes, but it is clinically lacking effective means for early diagnosis and early treatment. MicroRNA, in the occurrence and development of the disease, has an important regulatory role. Its role in diabetes has been reported more. However, specific research on microRNA in DPN is rare. METHODS: Based on the results of bioinformatics screening, miR-377 and miR-216a, their respective target molecules growth association protein 43 (GAP-43) and angiopoietin-like 4 protein (ANGPTL4), and related pathways peroxisome proliferator activated receptor gamma (PPARG) and chemerin were tested by RT-qPCR and ELISA in blood samples of DPN to analyze the correlation between these differentially expressed molecules and clinico-pathological factors of DPN. RESULTS: In this study, we found that miR-377, miR-216a, GAP-43, ANGPTL4, and PPARG were significantly differentially expressed genes for DPN. The correlation analysis showed that they were closely related to the clinical indicators of DPN suggesting that they may be involved in the development of DPN. In addition, receiver operating characteristic (ROC) curves generated for miR216a, miR377, ANGPTL4, GAP43, PPARG revealed that they can be used as new molecular diagnostic markers of DPN. CONCLUSIONS: miR-216a, miR-377, ANGPTL4, GAP-43, and PPARG could potentially be biomarkers of DPN.


Assuntos
Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas , MicroRNAs , Proteína 4 Semelhante a Angiopoietina/genética , Biomarcadores , Quimiocinas , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Neuropatias Diabéticas/diagnóstico , Neuropatias Diabéticas/genética , Proteína GAP-43 , Humanos , MicroRNAs/genética , PPAR gama/genética
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