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1.
Int J Mol Sci ; 22(18)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34576091

RESUMO

Among lifestyle-related diseases, fatty liver is the most common liver disease. To date, mammalian models have been used to develop methods for inhibiting fatty liver progression; however, new, more efficient models are expected. This study investigated the creation of a new model to produce fatty liver more efficiently than the high-fat diet medaka model that has been used to date. We compared the GAN (Gubra-Amylin nonalcoholic steatohepatitis) diet, which has been used in recent years to induce fatty liver in mice, and the high-fat diet (HFD). Following administration of the diets for three months, enlarged livers and pronounced fat accumulation was noted. The GAN group had large fat vacuoles and lesions, including ballooning, compared to the HFD group. The GAN group had a higher incidence of lesions. When fenofibrate was administered to the fatty liver model created via GAN administration and liver steatosis was assessed, a reduction in liver fat deposition was observed, and this model was shown to be useful in drug evaluations involving fatty liver. The medaka fatty liver model administered with GAN will be useful in future fatty liver research.


Assuntos
Dieta Hiperlipídica , Frutose/administração & dosagem , Polipeptídeo Amiloide das Ilhotas Pancreáticas/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/patologia , Oryzias/fisiologia , Ácido Palmítico/administração & dosagem , Animais , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Fenofibrato/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Oryzias/genética , PPAR alfa/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo
2.
Nat Commun ; 12(1): 5203, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471141

RESUMO

Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). However, resistance to therapy remains a critical issue. By integration of transcriptome, chromatin immunoprecipitation sequencing (CHIP-seq), Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), proteomic and metabolite screening followed by carbon tracing and extracellular flux analyses we show that genetic and pharmacological AURKA inhibition elicits metabolic reprogramming mediated by inhibition of MYC targets and concomitant activation of Peroxisome Proliferator Activated Receptor Alpha (PPARA) signaling. While glycolysis is suppressed by AURKA inhibition, we note an increase in the oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO), which was accompanied by an increase of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Combining AURKA inhibitors with inhibitors of FAO extends overall survival in orthotopic GBM PDX models. Taken together, these data suggest that simultaneous targeting of oxidative metabolism and AURKAi might be a potential novel therapy against recalcitrant malignancies.


Assuntos
Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Efeito Warburg em Oncologia , Linhagem Celular Tumoral , Proliferação de Células , Ácidos Graxos/metabolismo , Glicólise/efeitos dos fármacos , Humanos , PPAR alfa/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteômica , Transdução de Sinais/efeitos dos fármacos , Transcriptoma , Efeito Warburg em Oncologia/efeitos dos fármacos
3.
Biomed Res Int ; 2021: 9066938, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34540999

RESUMO

The peroxisome proliferator-activated receptor (PPAR) α/γ-adenosine 5'-monophosphate- (AMP-) activated protein kinase- (AMPK-) sirtuin-1 (SIRT1) pathway and fatty acid metabolism are reported to be involved in influenza A virus (IAV) replication and IAV-pneumonia. Through a cell-based peroxisome proliferator responsive element- (PPRE-) driven luciferase bioassay, we have investigated 145 examples of traditional Chinese medicines (TCMs). Several TCMs, such as Polygonum cuspidatum, Rheum officinale Baillon, and Aloe vera var. Chinensis (Haw.) Berg., were found to possess high activity. We have further detected the anti-IAV activities of emodin (EMO) and its analogs, a group of common important compounds of these TCMs. The results showed that emodin and its several analogs possess excellent anti-IAV activities. The pharmacological tests showed that emodin significantly activated PPARα/γ and AMPK, decreased fatty acid biosynthesis, and increased intracellular ATP levels. Pharmaceutical inhibitors, siRNAs for PPARα/γ and AMPKα1, and exogenous palmitate impaired the inhibition of emodin. The in vivo test also showed that emodin significantly protected mice from IAV infection and pneumonia. Pharmacological inhibitors for PPARα/γ and AMPK signal and exogenous palmitate could partially counteract the effects of emodin in vivo. In conclusion, emodin and its analogs are a group of promising anti-IAV drug precursors, and the pharmacological mechanism of emodin is linked to its ability to regulate the PPARα/γ-AMPK pathway and fatty acid metabolism.


Assuntos
Emodina/uso terapêutico , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Células A549 , Adenilato Quinase/efeitos dos fármacos , Adenilato Quinase/metabolismo , Animais , China , Cães , Emodina/análogos & derivados , Emodina/metabolismo , Ácidos Graxos/metabolismo , Humanos , Vírus da Influenza A/patogenicidade , Metabolismo dos Lipídeos , Células Madin Darby de Rim Canino , Medicina Tradicional Chinesa/métodos , PPAR alfa/efeitos dos fármacos , PPAR alfa/metabolismo , PPAR gama/efeitos dos fármacos , PPAR gama/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/efeitos dos fármacos , Sirtuína 1/metabolismo
4.
Eur J Neurosci ; 54(6): 5932-5950, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34396611

RESUMO

The peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that has been linked to the modulation of several physiological functions, including the sleep-wake cycle. The PPARα recognizes as endogenous ligands the lipids oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which in turn, if systemically injected, they exert wake-promoting effects. Moreover, the activation of PPARα by the administration of OEA or PEA increases the extracellular contents of neurotransmitters linked to the control of wakefulness; however, the role of PPARα activated by OEA or PEA on additional biochemicals related to waking regulation, such as acetylcholine (ACh) and 5-hydroxytryptamine (5-HT), has not been fully studied. Here, we have investigated the effects of treatments of OEA or PEA on the contents of ACh and 5-HT by using in vivo microdialysis techniques coupled to HPLC means. For this purpose, OEA or PEA were systemically injected (5, 10 or 30 mg/kg; i.p.), and the levels of ACh and 5-HT were collected from the basal forebrain, a wake-related brain area. These pharmacological treatments significantly increased the contents of ACh and 5-HT as determined by HPLC procedures. Interestingly, PPARα antagonist MK-886 (30 mg/kg; i.p.) injected before the treatments of OEA or PEA blocked these outcomes. Our data suggest that the activation of PPARα by OEA or PEA produces significant changes on ACh and 5-HT levels measured from the basal forebrain and support the conclusion that PPARα is a suitable molecular element involved in the regulation of wake-related neurotransmitters.


Assuntos
PPAR alfa , Serotonina , Acetilcolina , Amidas , Encéfalo/metabolismo , Endocanabinoides , Etanolaminas , Ácidos Oleicos , PPAR alfa/metabolismo , Ácidos Palmíticos
5.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445672

RESUMO

In mammalian cells, two cellular organelles, mitochondria and peroxisomes, share the ability to degrade fatty acid chains. Although each organelle harbors its own fatty acid ß-oxidation pathway, a distinct mitochondrial system feeds the oxidative phosphorylation pathway for ATP synthesis. At the same time, the peroxisomal ß-oxidation pathway participates in cellular thermogenesis. A scientific milestone in 1965 helped discover the hepatomegaly effect in rat liver by clofibrate, subsequently identified as a peroxisome proliferator in rodents and an activator of the peroxisomal fatty acid ß-oxidation pathway. These peroxisome proliferators were later identified as activating ligands of Peroxisome Proliferator-Activated Receptor α (PPARα), cloned in 1990. The ligand-activated heterodimer PPARα/RXRα recognizes a DNA sequence, called PPRE (Peroxisome Proliferator Response Element), corresponding to two half-consensus hexanucleotide motifs, AGGTCA, separated by one nucleotide. Accordingly, the assembled complex containing PPRE/PPARα/RXRα/ligands/Coregulators controls the expression of the genes involved in liver peroxisomal fatty acid ß-oxidation. This review mobilizes a considerable number of findings that discuss miscellaneous axes, covering the detailed expression pattern of PPARα in species and tissues, the lessons from several PPARα KO mouse models and the modulation of PPARα function by dietary micronutrients.


Assuntos
Ácidos Graxos/metabolismo , PPAR alfa/metabolismo , Peroxissomos/metabolismo , Acil-CoA Oxidase/metabolismo , Animais , Humanos , Fígado/metabolismo , Oxirredução , Oxirredutases/metabolismo , PPAR alfa/fisiologia , Proliferadores de Peroxissomos , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores do Ácido Retinoico/metabolismo , Elementos de Resposta/genética , Receptores X de Retinoides/metabolismo , Ativação Transcricional/genética
6.
Nutrients ; 13(8)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34444660

RESUMO

Dietary protamine can ameliorate hyperlipidemia; however, the protamine-derived active peptide and its hypolipidemic mechanism of action are unclear. Here, we report the discovery of a novel anti-obesity and hypocholesterolemic peptide, RPR (Arg-Pro-Arg), derived from protamine in mice fed a high-fat diet for 50 days. Serum cholesterol levels were significantly lower in the protamine and RPR groups than in the control group. White adipose tissue weight was significantly decreased in the protamine and RPR groups. The fecal excretion of cholesterol and bile acid was significantly higher in the protamine and RPR groups than in the control group. We also observed a significant decrease in the expression of hepatic SCD1, SREBP1, and adipocyte FAS mRNA, and significantly increased expression of hepatic PPARα and adipocyte PPARγ1 mRNA in the protamine group. These findings demonstrate that the anti-obesity effects of protamine are linked to the upregulation of adipocyte PPARγ1 and hepatic PPARα and the downregulation of hepatic SCD1 via SREBP1 and adipocyte FAS. RPR derived from protamine has a crucial role in the anti-obesity action of protamine by evaluating the effective dose of adipose tissue weight loss.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Anticolesterolemiantes/farmacologia , Colesterol/sangue , Obesidade/tratamento farmacológico , Oligopeptídeos/farmacologia , Protaminas/farmacologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/fisiopatologia , Adiposidade/efeitos dos fármacos , Animais , Biomarcadores/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Perda de Peso/efeitos dos fármacos
7.
Cell Death Dis ; 12(7): 710, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34267188

RESUMO

Alcohol-related liver disease (ALD), a condition caused by alcohol overconsumption, occurs in three stages of liver injury including steatosis, hepatitis, and cirrhosis. DEP domain-containing protein 5 (DEPDC5), a component of GAP activities towards Rags 1 (GATOR1) complex, is a repressor of amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. In the current study, we found that aberrant activation of mTORC1 was likely attributed to the reduction of DEPDC5 in the livers of ethanol-fed mice or ALD patients. To further define the in vivo role of DEPDC5 in ALD development, we generated Depdc5 hepatocyte-specific knockout mouse model (Depdc5-LKO) in which mTORC1 pathway was constitutively activated through loss of the inhibitory effect of GATOR1. Hepatic Depdc5 ablation leads to mild hepatomegaly and liver injury and protects against diet-induced liver steatosis. In contrast, ethanol-fed Depdc5-LKO mice developed severe hepatic steatosis and inflammation. Pharmacological intervention with Torin 1 suppressed mTORC1 activity and remarkably ameliorated ethanol-induced hepatic steatosis and inflammation in both control and Depdc5-LKO mice. The pathological effect of sustained mTORC1 activity in ALD may be attributed to the suppression of peroxisome proliferator activated receptor α (PPARα), the master regulator of fatty acid oxidation in hepatocytes, because fenofibrate (PPARα agonist) treatment reverses ethanol-induced liver steatosis and inflammation in Depdc5-LKO mice. These findings provide novel insights into the in vivo role of hepatic DEPDC5 in the development of ALD.


Assuntos
Fígado Gorduroso Alcoólico/metabolismo , Proteínas Ativadoras de GTPase/deficiência , Fígado/metabolismo , PPAR alfa/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/patologia , Fígado Gorduroso Alcoólico/prevenção & controle , Feminino , Proteínas Ativadoras de GTPase/genética , Mediadores da Inflamação , Fígado/efeitos dos fármacos , Fígado/ultraestrutura , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Knockout , Naftiridinas/farmacologia , Oxirredução , Estresse Oxidativo , PPAR alfa/genética , Transdução de Sinais
8.
Am J Physiol Endocrinol Metab ; 321(2): E292-E304, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34229476

RESUMO

We have generated the transgenic mouse line LTCFDN in which dominant negative TCF7L2 (TCF7L2DN) is specifically expressed in the liver during adulthood. Male but not female LTCFDN mice showed elevated hepatic and plasma triglyceride (TG) levels, indicating the existence of estrogen-ß-cat/TCF signaling cascade that regulates hepatic lipid homeostasis. We show here that hepatic fibroblast growth factor 21 (FGF21) expression was reduced in male but not in female LTCFDN mice. The reduction was not associated with altered hepatic expression of peroxisome proliferator-activated receptor α (PPARα). In mouse primary hepatocytes (MPH), Wnt-3a treatment increased FGF21 expression in the presence of PPARα inhibitor. Results from our luciferase-reporter assay and chromatin immunoprecipitation suggest that evolutionarily conserved TCF binding motifs (TCFBs) on Fgf21 promoter mediate Wnt-3a-induced Fgf21 transactivation. Female mice showed reduced hepatic FGF21 production and circulating FGF21 level following ovariectomy (OVX), associated with reduced hepatic TCF expression and ß-catenin S675 phosphorylation. Finally, in MPH, estradiol (E2) treatment enhanced FGF21 expression, as well as binding of TCF7L2 and ribonucleic acid (RNA) polymerase II to the Fgf21 promoter; and the enhancement can be attenuated by the G-protein-coupled estrogen receptor 1 (GPER) antagonist G15. Our observations hence indicate that hepatic FGF21 is among the effectors of the newly recognized E2-ß-cat/TCF signaling cascade.NEW & NOTEWORTHY FGF21 is mainly produced in the liver. Therapeutic effect of FGF21 analogues has been demonstrated in clinical trials on reducing hyperlipidemia. We show here that Fgf21 transcription is positively regulated by Wnt pathway effector ß-cat/TCF. Importantly, hepatic ß-cat/TCF activity can be regulated by the female hormone estradiol, involving GPER. The investigation enriched our understanding on hepatic FGF21 hormone production, and expanded our view on metabolic functions of the Wnt pathway in the liver.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Fígado/metabolismo , Via de Sinalização Wnt , Animais , Células Cultivadas , Estrogênios/metabolismo , Feminino , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , PPAR alfa/metabolismo
9.
Phytomedicine ; 91: 153648, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34332287

RESUMO

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease. Deposition of amyloid ß plaques (Aß) and neurofibrillary tangles (NFTs) is the key pathological hallmark of AD. Accumulating evidence suggest that impairment of autophagy-lysosomal pathway (ALP) plays key roles in AD pathology. PURPOSE: The present study aims to assess the neuroprotective effects of Qingyangshen (QYS), a Chinese herbal medicine, in AD cellular and animal models and to determine its underlying mechanisms involving ALP regulation. METHODS: QYS extract was prepared and its chemical components were characterized by LC/MS. Then the pharmacokinetics and acute toxicity of QYS extract were evaluated. The neuroprotective effects of QYS extract were determined in 3XTg AD mice, by using a series of behavioral tests and biochemical assays, and the mechanisms were examined in vitro. RESULTS: Oral administration of QYS extract improved learning and spatial memory, reduced carboxy-terminal fragments (CTFs), amyloid precursor protein (APP), Aß and Tau aggregates, and inhibited microgliosis and astrocytosis in the brains of 3XTg mice. Mechanistically, QYS extract increased the expression of PPARα and TFEB, and promoted ALP both in vivo and in vitro. CONCLUSION: QYS attenuates AD pathology, and improves cognitive function in 3XTg mice, which may be mediated by activation of PPARα-TFEB pathway and the subsequent ALP enhancement. Therefore, QYS may be a promising herbal material for further anti-AD drug discovery.


Assuntos
Doença de Alzheimer , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , PPAR alfa/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Proteínas tau
10.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202590

RESUMO

Neuropathic pain is a chronic pain condition persisting past the presence of any noxious stimulus or inflammation. Zerumbone, of the Zingiber zerumbet ginger plant, has exhibited anti-allodynic and antihyperalgesic effects in a neuropathic pain animal model, amongst other pharmacological properties. This study was conducted to further elucidate the mechanisms underlying zerumbone's antineuropathic actions. Research on therapeutic agents involving cannabinoid (CB) and peroxisome proliferator-activated receptors (PPARs) is rising. These receptor systems have shown importance in causing a synergistic effect in suppressing nociceptive processing. Behavioural responses were assessed using the von Frey filament test (mechanical allodynia) and Hargreaves plantar test (thermal hyperalgesia), in chronic constriction injury (CCI) neuropathic pain mice. Antagonists SR141716 (CB1 receptor), SR144528 (CB2 receptor), GW6471 (PPARα receptor) and GW9662 (PPARγ receptor) were pre-administered before the zerumbone treatment. Our findings indicated the involvement of CB1, PPARα and PPARγ in zerumbone's action against mechanical allodynia, whereas only CB1 and PPARα were involved against thermal hyperalgesia. Molecular docking studies also suggest that zerumbone has a comparable and favourable binding affinity against the respective agonist on the CB and PPAR receptors studied. This finding will contribute to advance our knowledge on zerumbone and its significance in treating neuropathic pain.


Assuntos
Neuralgia , PPAR alfa/antagonistas & inibidores , PPAR gama/antagonistas & inibidores , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores , Sesquiterpenos/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Neuralgia/patologia , PPAR alfa/metabolismo , PPAR gama/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo
11.
J Neuroimmunol ; 358: 577654, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34265624

RESUMO

Increasing evidence suggests that SARS-CoV-2, the virus responsible for the COVID-19 pandemic, is associated with increased risk of developing neurological or psychiatric conditions such as depression, anxiety or dementia. While the precise mechanism underlying this association is unknown, aberrant activation of toll-like receptor (TLR)3, a viral recognizing pattern recognition receptor, may play a key role. Synthetic cannabinoids and enhancing cannabinoid tone via inhibition of fatty acid amide hydrolase (FAAH) has been demonstrated to modulate TLR3-induced neuroimmune responses and associated sickness behaviour. However, the role of individual FAAH substrates, and the receptor mechanisms mediating these effects, are unknown. The present study examined the effects of intracerebral or systemic administration of the FAAH substrates N-oleoylethanolamide (OEA), N-palmitoylethanolamide (PEA) or the anandamide (AEA) analogue meth-AEA on hyperthermia and hypothalamic inflammatory gene expression following administration of the TLR3 agonist, and viral mimetic, poly I:C. The data demonstrate that meth-AEA does not alter TLR3-induced hyperthermia or hypothalamic inflammatory gene expression. In comparison, OEA and PEA attenuated the TLR3-induced hyperthermia, although only OEA attenuated the expression of hyperthermia-related genes (IL-1ß, iNOS, COX2 and m-PGES) in the hypothalamus. OEA, but not PEA, attenuated TLR3-induced increases in the expression of all IRF- and NFκB-related genes examined in the hypothalamus, but not in the spleen. Antagonism of PPARα prevented the OEA-induced attenuation of IRF- and NFκB-related genes in the hypothalamus following TLR3 activation but did not significantly alter temperature. PPARα agonism did not alter TLR3-induced hyperthermia or hypothalamic inflammatory gene expression. These data indicate that OEA may be the primary FAAH substrate that modulates TLR3-induced neuroinflammation and hyperthermia, effects partially mediated by PPARα.


Assuntos
Etanolaminas/farmacologia , Hipertermia Induzida/métodos , Mediadores da Inflamação/metabolismo , PPAR alfa/metabolismo , Receptor 3 Toll-Like/administração & dosagem , Amidoidrolases/farmacologia , Animais , Feminino , Expressão Gênica , PPAR alfa/agonistas , PPAR alfa/antagonistas & inibidores , Poli I-C/toxicidade , Ratos , Ratos Sprague-Dawley
12.
Eur J Med Chem ; 223: 113665, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34192642

RESUMO

New types of antidiabetic agents are continually needed with diabetes becoming the epidemic in the world. Indole alkaloids play an important role in natural products owing to their variable structures and versatile biological activities like anticonvulsant, anti-inflammatory, antidiabetic, antimicrobial, and anticancer activities, which are a promising source of novel antidiabetic drugs discovery. The synthesized indole derivatives possess similar properties to natural indole alkaloids. In the last two decades, more and more indole derivatives have been designed and synthesized for searching their bioactivities. This present review describes comprehensive structures of indole compounds with the potential antidiabetic activity including natural indole alkaloids and the synthetic indole derivatives based on the structure classification, summarizes their approaches isolated from natural sources or by synthetic methods, and discusses the antidiabetic effects and the mechanisms of action. Furthermore, this review also provides briefly synthetic procedures of some important indole derivatives.


Assuntos
Hipoglicemiantes/química , Indóis/química , Carbolinas/química , Carbolinas/metabolismo , Carbolinas/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/metabolismo , Hipoglicemiantes/uso terapêutico , Indóis/metabolismo , Indóis/uso terapêutico , PPAR alfa/química , PPAR alfa/metabolismo , PPAR gama/química , PPAR gama/metabolismo , Terpenos/química , Terpenos/metabolismo , Terpenos/uso terapêutico
13.
Molecules ; 26(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073584

RESUMO

PPARα is a ligand-dependent transcription factor and its activation is known to play an important role in cell defense through anti-inflammatory and antioxidant effects. MHY3200 (2-[4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy]-2,2-difluoroacetic acid), a novel benzothiazole-derived peroxisome proliferator-activated receptor α (PPARα) agonist, is a synthesized PPARα activator. This study examined the beneficial effects of MHY3200 on age-associated alterations in reactive oxygen species (ROS)/Akt/forkhead box (FoxO) 1 signaling in rat kidneys. Young (7-month-old) and old (22-month-old) rats were treated with MHY3200 (1 mg/kg body weight/day or 3 mg/kg body weight/day) for two weeks. MHY3200 treatment led to a notable decrease in triglyceride and insulin levels in serum from old rats. The elevated kidney ROS level, serum insulin level, and Akt phosphorylation in old rats were reduced following MHY3200 treatment; moreover, FoxO1 phosphorylation increased. MHY3200 treatment led to the increased level of FoxO1 and its target gene, MnSOD. MHY3200 suppressed cyclooxygenase-2 expression by activating PPARα and inhibiting the activation of nuclear factor-κB (NF-κB) in the kidneys of old rats. Our results suggest that MHY3200 ameliorates age-associated renal inflammation by regulating NF-κB and FoxO1 via ROS/Akt signaling.


Assuntos
Acetatos/farmacologia , Envelhecimento/efeitos dos fármacos , Inflamação/tratamento farmacológico , Rim/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , PPAR alfa/agonistas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tiazóis/farmacologia , Acetatos/uso terapêutico , Animais , Peso Corporal , Regulação da Expressão Gênica , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Rim/patologia , Masculino , PPAR alfa/metabolismo , Fosforilação , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiazóis/uso terapêutico , Fatores de Tempo , Triglicerídeos/metabolismo
14.
Nat Commun ; 12(1): 3660, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135321

RESUMO

The mechanistic target of rapamycin complex 1 (mTORC1) integrates cellular nutrient signaling and hormonal cues to control metabolism. We have previously shown that constitutive nutrient signaling to mTORC1 by means of genetic activation of RagA (expression of GTP-locked RagA, or RagAGTP) in mice resulted in a fatal energetic crisis at birth. Herein, we rescue neonatal lethality in RagAGTP mice and find morphometric and metabolic alterations that span glucose, lipid, ketone, bile acid and amino acid homeostasis in adults, and a median lifespan of nine months. Proteomic and metabolomic analyses of livers from RagAGTP mice reveal a failed metabolic adaptation to fasting due to a global impairment in PPARα transcriptional program. These metabolic defects are partially recapitulated by restricting activation of RagA to hepatocytes, and revert by pharmacological inhibition of mTORC1. Constitutive hepatic nutrient signaling does not cause hepatocellular damage and carcinomas, unlike genetic activation of growth factor signaling upstream of mTORC1. In summary, RagA signaling dictates dynamic responses to feeding-fasting cycles to tune metabolism so as to match the nutritional state.


Assuntos
Jejum/metabolismo , Fígado/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Transdução de Sinais , Animais , Modelos Animais de Doenças , Glucose/metabolismo , Homeostase , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Proteínas Monoméricas de Ligação ao GTP/genética , Nutrientes/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Fenótipo , Proteômica , Transdução de Sinais/efeitos dos fármacos , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Transcrição Genética/efeitos dos fármacos , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo
15.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069420

RESUMO

Selenium-binding protein 1 (Selenbp1) is a 2,3,7,8-tetrechlorodibenzo-p-dioxin inducible protein whose function is yet to be comprehensively elucidated. As the highly homologous isoform, Selenbp2, is expressed at low levels in the kidney, it is worthwhile comparing wild-type C57BL mice and Selenbp1-deficient mice under dioxin-free conditions. Accordingly, we conducted a mouse metabolomics analysis under non-dioxin-treated conditions. DNA microarray analysis was performed based on observed changes in lipid metabolism-related factors. The results showed fluctuations in the expression of numerous genes. Real-time RT-PCR confirmed the decreased expression levels of the cytochrome P450 4a (Cyp4a) subfamily, known to be involved in fatty acid ω- and ω-1 hydroxylation. Furthermore, peroxisome proliferator-activated receptor-α (Pparα) and retinoid-X-receptor-α (Rxrα), which form a heterodimer with Pparα to promote gene expression, were simultaneously reduced. This indicated that reduced Cyp4a expression was mediated via decreased Pparα and Rxrα. In line with this finding, increased levels of leukotrienes and prostaglandins were detected. Conversely, decreased hydrogen peroxide levels and reduced superoxide dismutase (SOD) activity supported the suppression of the renal expression of Sod1 and Sod2 in Selenbp1-deficient mice. Therefore, we infer that ablation of Selenbp1 elicits oxidative stress caused by increased levels of superoxide anions, which alters lipid metabolism via the Pparα pathway.


Assuntos
Metabolismo dos Lipídeos/genética , Proteínas de Ligação a Selênio/metabolismo , Animais , Citocromo P-450 CYP4A/metabolismo , Expressão Gênica , Rim/patologia , Lipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/genética , PPAR alfa/metabolismo , PPAR alfa/fisiologia , RNA Mensageiro/genética , Receptor X Retinoide alfa/metabolismo , Receptor X Retinoide alfa/fisiologia , Proteínas de Ligação a Selênio/genética , Fatores de Transcrição/metabolismo
16.
Molecules ; 26(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067839

RESUMO

Recent work has shown that bilirubin has a hormonal function by binding to the peroxisome proliferator-activated receptor-α (PPARα), a nuclear receptor that drives the transcription of genes to control adiposity. Our previous in silico work predicted three potential amino acids that bilirubin may interact with by hydrogen bonding in the PPARα ligand-binding domain (LBD), which could be responsible for the ligand-induced function. To further reveal the amino acids that bilirubin interacts with in the PPARα LBD, we harnessed bilirubin's known fluorescent properties when bound to proteins such as albumin. Our work here revealed that bilirubin interacts with threonine 283 (T283) and alanine 333 (A333) for ligand binding. Mutational analysis of T283 and A333 showed significantly reduced bilirubin binding, reductions of 11.4% and 17.0%, respectively. Fenofibrate competitive binding studies for the PPARα LBD showed that bilirubin and fenofibrate possibly interact with different amino acid residues. Furthermore, bilirubin showed no interaction with PPARγ. This is the first study to reveal the amino acids responsible for bilirubin binding in the ligand-binding pocket of PPARα. Our work offers new insight into the mechanistic actions of a well-known molecule, bilirubin, and new fronts into its mechanisms.


Assuntos
Bilirrubina/metabolismo , PPAR alfa/metabolismo , Bilirrubina/fisiologia , Ligação Competitiva , Células HEK293 , Humanos , Ligantes , PPAR alfa/fisiologia , Ligação Proteica/fisiologia
17.
Biomed Pharmacother ; 140: 111778, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34062416

RESUMO

Liraglutide has been demonstrated to alleviate hepatic steatosis in clinical practice, but the underlying mechanism remains unclear. Our previous study indicated that the HIF-2α/PPARα pathway was involved in hepatic lipid accumulation induced by hypoxia.We aimed to investigate whether liraglutide could alleviate lipid-induced hepatic steatosis via the HIF-2α/PPARα pathway. Whole-body HIF-2α heterozygous knockout (HIF-2α+/-) mice and littermate wild-type (WT) mice were successfully established. Male mice challenged with a high-fat diet were treated with liraglutide (0.6 mg/kg/d) or normal saline by intraperitoneal injection for 4 weeks. We observed that, compared with WT mice, many indicators of HIF-2α+/- mice improved, including GTT, ITT, fasting blood glucose, body weight, liver weight, and lipid profile in serum or liver lipid deposition, and the expression level of PPARα, mitochondrial function genes, and fatty acid oxidation genes were upregulated, while those of HIF-2α and lipogenesis genes were downregulated significantly. After liraglutide treatment in WT mice, we found that significant improvements were observed in the fat mass, GTT, ITT, fasting blood glucose, body weight, liver weight, lipid profile in serum or liver lipid deposition; the ß-oxidation genes were upregulated and the lipogenesis genes were downregulated; and the abundance of intestinal Akkermansia muciniphila increased significantly. However, the effects of liraglutide on WT mice were not observed in HIF-2α+/- mice. In addition, in the HepG2 steatotic hepatocyte model, liraglutide alleviated lipid deposits by repressing lipid synthesis and enhancing fatty acid ß-oxidation, which were substantially suppressed by the HIF-2α modulators. Therefore, the HIF-2α/PPARα pathway is essential for liraglutide-alleviated lipid-induced hepatic steatosis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hipoglicemiantes/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Liraglutida/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR alfa/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Dieta Hiperlipídica , Microbioma Gastrointestinal/genética , Células Hep G2 , Humanos , Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Masculino , Camundongos Transgênicos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/microbiologia , RNA Bacteriano/genética , RNA Ribossômico 16S/genética
18.
J Surg Res ; 265: 223-232, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33957574

RESUMO

BACKGROUND: Long non-coding RNAs (lncRNAs) have been demonstrated to be involved in the progression of sepsis-induced acute kidney injury (AKI). In this study, we aimed to explore the functions of lncRNA cancer susceptibility candidate 2 (CASC2) in sepsis-induced AKI. METHODS: The sepsis cell models were established by exposing HK2 and HEK293 cells into lipopolysaccharide (LPS). Quantitative real-time polymerase chain reaction (qRT-PCR) assay was conducted to determine the expression of CASC2, miR-545-3p and peroxisome proliferator-activated receptor-α (PPARA) mRNA. Cell Counting Kit-8 (CCK-8) assay, flow cytometry analysis and wound healing assay were employed for cell viability, apoptosis and migration, respectively. Western blot assay was conducted for the protein levels of E-cadherin, α-SMA and PPARA. The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by specific kits. The relationship between miR-545-3p and CASC2 or PPARA was verified by dual-luciferase reporter assay. RESULTS: CASC2 level was decreased in sepsis patients' serums and LPS-treated HK2 and HEK293 cells. CASC2 overexpression facilitated cell viability and restrained cell apoptosis, migration, epithelial-mesenchymal transition (EMT) and oxidative stress in LPS-triggered HK2 and HEK293 cells. CASC2 was identified as a sponge for miR-545-3p to regulate PPARA expression. MiR-545-3p overexpression restored the impact of CASC2 on LPS-induced injury in HK2 and HEK293 cells. Moreover, miR-545-3p overexpression aggravated LPS-induced cell injury in HK2 and HEK293 cells by targeting PPARA. CONCLUSION: CASC2 overexpression relieved the damage of HK2 and HEK293 cells mediated by LPS treatment through regulating miR-545-3p/PPARA axis.


Assuntos
Injúria Renal Aguda/metabolismo , MicroRNAs/metabolismo , PPAR alfa/metabolismo , Sepse/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Injúria Renal Aguda/etiologia , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Sepse/complicações , Adulto Jovem
19.
J Cell Mol Med ; 25(12): 5404-5416, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33955677

RESUMO

Gestational and postpartum high-fat diets (HFDs) have been implicated as causes of obesity in offspring in later life. The present study aimed to investigate the effects of gestational and/or postpartum HFD on obesity in offspring. We established a mouse model of HFD exposure that included gestation, lactation and post-weaning periods. We found that gestation was the most sensitive period, as the administration of a HFD impaired lipid metabolism, especially fatty acid oxidation in both foetal and adult mice, and caused obesity in offspring. Mechanistically, the DNA hypermethylation level of the nuclear receptor, peroxisome proliferator-activated receptor-α (Pparα), and the decreased mRNA levels of ten-eleven translocation 1 (Tet1) and/or ten-eleven translocation 2 (Tet2) were detected in the livers of foetal and adult offspring from mothers given a HFD during gestation, which was also associated with low Pparα expression in hepatic cells. We speculated that the hypermethylation of Pparα resulted from the decreased Tet1/2 expression in mothers given a HFD during gestation, thereby causing lipid metabolism disorders and obesity. In conclusion, this study demonstrates that a HFD during gestation exerts long-term effects on the health of offspring via the DNA demethylation of Pparα, thereby highlighting the importance of the gestational period in regulating epigenetic mechanisms involved in metabolism.


Assuntos
Desmetilação , Dieta Hiperlipídica/efeitos adversos , Obesidade/patologia , PPAR alfa/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Feminino , Idade Gestacional , Metabolismo dos Lipídeos , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismo , PPAR alfa/genética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo
20.
Life Sci ; 277: 119487, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33862107

RESUMO

AIMS: Nonalcoholic fatty liver disease (NAFLD) is a lipid metabolism disorder. Naringin (a main active ingredient in Ganshuang granules) is a flavanone that has been demonstrated to exert hepatoprotective and antifibrotic effects. The present study aimed to use a novel tissue-engineered fatty liver model to assess the effects and mechanisms of naringin on NAFLD. MAIN METHODS: Intracellular triglyceride (TG) was examined by oil red O staining and commercial kits. The proteins associated with lipid metabolism were measured by western blotting and/or qPCR. Very low-density lipoprotein (VLDL) was measured by ELISA. A CCK8 assay was used to assess the cytotoxicity of naringin. Molecular docking was used to predict the interactions and binding patterns between naringin and target proteins. KEY FINDINGS: Naringin significantly reduced intracellular TG accumulation by 52.7% in tissue-engineered fatty (TEF) livers, and also the level of pyruvate dehydrogenase kinase 4. Naringin downregulated CD36 and proliferator activated-receptor γ expression, reducing the uptake of FFAs; naringin also downregulated de novo liposynthetases by reducing acetyl CoA carboxylase, fatty acid synthetase etc. in TEF livers. Moreover, naringin increased the expression of proliferator activated-receptor α (PPAR-α) and carnitine palmitoyltransferase 1 to improve the oxidation of fatty acids. The levels of VLDL secreted from TEF livers were reduced by 24.7% after naringin treatment. Molecular docking analyses determined the bioactivity of naringin through its specific binding to CD36 and PPAR-α. SIGNIFICANCE: Naringin improved lipid metabolism disorders in TEF livers by reducing fatty acid uptake and de novo lipogenesis and increasing fatty acid oxidation. CD36 and PPAR-α might be specific targets of naringin.


Assuntos
Flavanonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Acetil-CoA Carboxilase/metabolismo , Animais , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Flavanonas/metabolismo , Células Hep G2 , Humanos , Lipogênese , Lipoproteínas VLDL/metabolismo , Fígado/metabolismo , Masculino , Simulação de Acoplamento Molecular , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Oxirredução , PPAR alfa/metabolismo , Ratos , Ratos Sprague-Dawley , Triglicerídeos/metabolismo
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