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1.
Clin Sci (Lond) ; 135(19): 2243-2263, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34569605

RESUMO

The protein tyrosine kinase inhibitor imatinib is used in the treatment of various malignancies but may also promote beneficial effects in the treatment of diabetes. The aim of the present investigation was to characterize the mechanisms by which imatinib protects insulin producing cells. Treatment of non-obese diabetic (NOD) mice with imatinib resulted in increased beta-cell AMP-activated kinase (AMPK) phosphorylation. Imatinib activated AMPK also in vitro, resulting in decreased ribosomal protein S6 phosphorylation and protection against islet amyloid polypeptide (IAPP)-aggregation, thioredoxin interacting protein (TXNIP) up-regulation and beta-cell death. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) mimicked and compound C counteracted the effect of imatinib on beta-cell survival. Imatinib-induced AMPK activation was preceded by reduced glucose/pyruvate-dependent respiration, increased glycolysis rates, and a lowered ATP/AMP ratio. Imatinib augmented the fractional oxidation of fatty acids/malate, possibly via a direct interaction with the beta-oxidation enzyme enoyl coenzyme A hydratase, short chain, 1, mitochondrial (ECHS1). In non-beta cells, imatinib reduced respiratory chain complex I and II-mediated respiration and acyl-CoA carboxylase (ACC) phosphorylation, suggesting that mitochondrial effects of imatinib are not beta-cell specific. In conclusion, tyrosine kinase inhibitors modestly inhibit mitochondrial respiration, leading to AMPK activation and TXNIP down-regulation, which in turn protects against beta-cell death.

2.
J Oncol ; 2021: 8943353, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34518766

RESUMO

Objective: To explore the application of NRS2002 in preoperative nutritional screening of patients with liver cancer (LC). Methods: 60 LC patients treated in the First Affiliated Hospital of Gannan Medical University (January 2018-May 2021) were chosen as the research objects, and split into group J without nutritional risk and group Q with nutritional risk according to the results of NRS2002 to compare the preoperative situation, surgery-related indexes, hematological indexes, postoperative recovery, and incidence of complications between the two groups. Results: Group J (n = 28) and group Q (n = 32) showed no obvious difference in preoperative situation, and patients' liver function indexes were within the normal range. The duration of surgery in group J was notably shorter compared with group Q (P < 0.05). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin (DBIL), and albumin in group J were notably different from those of group Q (P < 0.001) at 1 day after surgery. ALT and AST in group J were notably different from those of group Q at 3 days after surgery (P < 0.001). No obvious differences were observed in the hematological indexes between the two groups at 5 days after surgery (P > 0.05). The total amount of albumin infusion, postoperative hospitalization time, and hospitalization cost in group J were notably lower compared with group Q (P < 0.001). The incidence of complications in group J was notably lower compared with group Q (P < 0.05). Conclusion: Postoperative recovery of LC patients is closely related to their preoperative nutritional status, and those with poor nutritional status have a high incidence of postoperative complications and long recovery time. NRS2002 can effectively screen the nutritional status of patients and provide reference for prognosis evaluation.

3.
Metabolites ; 11(6)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200685

RESUMO

The pathophysiology of nonalcoholic fatty liver disease (NAFLD) is a complex process involving metabolic and inflammatory changes in livers and other organs, but the pathogenesis is still not well clarified. Two mouse models were established to study metabolic alteration of nonalcoholic fatty liver and nonalcoholic steatohepatitis, respectively. The concentrations of metabolites in serum, liver and intestine content were measured by the AbsoluteIDQ® p180 Kit (Biocrates Life Sciences, Innsbruck, Austria). Multivariate statistical methods, pathway analysis, enrichment analysis and correlation analysis were performed to analyze metabolomic data. The metabolic characteristics of liver, serum and intestine content could be distinctly distinguished from each group, indicating the occurrence of metabolic disturbance. Among them, metabolic alteration of liver and intestine content was more significant. Based on the metabolic data of liver, 19 differential metabolites were discovered between DIO and control, 12 between DIO-CCl4 and DIO, and 47 between DIO-CCl4 and normal. These metabolites were mainly associated with aminoacyl-tRNA biosynthesis, nitrogen metabolism, lipid metabolism, glyoxylate and dicarboxylate metabolism, and amino metabolism. Further study revealed that the intervention of obeticholic acid (OCA) could partly reverse the damage of CCl4. The correlation analysis of metabolite levels and clinical parameters showed that phosphatidylcholines were negatively associated with serum alanine aminotransferase, aspartate aminotransferase, NAFLD activity score, and fibrosis score, while lysophosphatidylcholines, sphingomyelins, amino acids, and acylcarnitines shared the reverse pattern. Our study investigated metabolic alteration among control, NAFLD model, and OCA treatment groups, providing preclinical information to understand the mechanism of NAFLD and amelioration of OCA.

4.
Metabolism ; 120: 154797, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33984334

RESUMO

OBJECTIVE: Obeticholic acid (OCA) has been proved to play potential therapeutic effect on nonalcoholic steatohepatitis (NASH). Up to now, the study of OCA on NLRP3 inflammasome activation in macrophage is still blank and merits great attention. Here, we aimed to better characterize the role and mechanism of OCA on NASH treatment focusing on NLRP3 inflammasome activation in macrophages. METHODS: The effects of OCA on inflammasome activation were investigated in BMDM, Kupffer cell, BMDC and LX2 cell. Preconditioned media from BMDM culture was used to treat primary hepatocytes to explore the effects of macrophage NLRP3 inflammasome activation on the function of hepatocytes. In vivo, high fat diet plus CCl4 (DIO + CCl4) induced murine NASH model and choline-deficient and amino acid-defined (CDA) diet-induced NASH mice were used to verify the inhibitory effect of OCA on inflammasome activation in liver macrophages and recapitulate its protective role on NASH progressing. To clear up the effect of OCA on macrophage is FXR dependent or not, FXR siRNA was introduced into BMDMs. RESULTS: OCA blockaded NLRP3 inflammasome in BMDMs by impacting on the activation stage and disrupting ASC oligomerization. Preconditioned supernatant from LPS + ATP treated BMDMs increased mRNA expression of lipogenic enzymes and lipid content, whereas preconditioned supernatant from OCA treated BMDM blocked these effects in both normal and the FXR knockdown hepatocytes. In DIO + CCl4 mice, the population of inflammatory myeloid lineage cells in livers was decreased upon OCA treatment. Accordingly, the level of IL-1ß and IL-18 in liver, the hepatic expression of ASC, pro-caspase-1 and active caspase-1, the expression of caspase 1 p20 in liver macrophages were also reduced. Similar results were obtained in CDA diet-fed mice. Furthermore, OCA maintained the inhibition on NLRP3 inflammasome activation in FXR knockdown BMDMs, suggesting FXR could be dispensable in this effect. CONCLUSIONS: This finding brings up a new mechanism of OCA on NASH treatment, suggested by direct inhibition on NLRP3 inflammasome activation in macrophage, further suppression on inflammasome activation-elicited hepatic lipid accumulation, and contributing to the amelioration of NASH.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Inflamassomos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Células Cultivadas , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Inflamassomos/metabolismo , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia
5.
Signal Transduct Target Ther ; 6(1): 165, 2021 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-33895786

RESUMO

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). In this study, we developed an integrative drug repositioning framework, which fully takes advantage of machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 can interact with the nucleocapsid (N) protein of SARS-CoV-2 and is able to suppress the LPS-induced production of several inflammatory cytokines that are highly relevant to the prevention of immunopathology induced by SARS-CoV-2 infection.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Simulação por Computador , Reposicionamento de Medicamentos , Modelos Biológicos , SARS-CoV-2/metabolismo , Humanos
6.
Mol Metab ; 41: 101045, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32599076

RESUMO

OBJECTIVE: Salt-induced kinase 1 (SIK1) acts as a key modulator in many physiological processes. However, the effects of SIK1 on gluconeogenesis and the underlying mechanisms have not been fully elucidated. In this study, we found that a natural compound phanginin A could activate SIK1 and further inhibit gluconeogenesis. The mechanisms by which phanginin A activates SIK1 and inhibits gluconeogenesis were explored in primary mouse hepatocytes, and the effects of phanginin A on glucose homeostasis were investigated in ob/ob mice. METHODS: The effects of phanginin A on gluconeogenesis and SIK1 phosphorylation were examined in primary mouse hepatocytes. Pan-SIK inhibitor and siRNA-mediated knockdown were used to elucidate the involvement of SIK1 activation in phanginin A-reduced gluconeogenesis. LKB1 knockdown was used to explore how phanginin A activated SIK1. SIK1 overexpression was used to evaluate its effect on gluconeogenesis, PDE4 activity, and the cAMP pathway. The acute and chronic effects of phanginin A on metabolic abnormalities were observed in ob/ob mice. RESULTS: Phanginin A significantly increased SIK1 phosphorylation through LKB1 and further suppressed gluconeogenesis by increasing PDE4 activity and inhibiting the cAMP/PKA/CREB pathway in primary mouse hepatocytes, and this effect was blocked by pan-SIK inhibitor HG-9-91-01 or siRNA-mediated knockdown of SIK1. Overexpression of SIK1 in hepatocytes increased PDE4 activity, reduced cAMP accumulation, and thereby inhibited gluconeogenesis. Acute treatment with phanginin A reduced gluconeogenesis in vivo, accompanied by increased SIK1 phosphorylation and PDE4 activity in the liver. Long-term treatment of phanginin A profoundly reduced blood glucose levels and improved glucose tolerance and dyslipidemia in ob/ob mice. CONCLUSION: We discovered an unrecognized effect of phanginin A in suppressing hepatic gluconeogenesis and revealed a novel mechanism that activation of SIK1 by phanginin A could inhibit gluconeogenesis by increasing PDE4 activity and suppressing the cAMP/PKA/CREB pathway in the liver. We also highlighted the potential value of phanginin A as a lead compound for treating type 2 diabetes.


Assuntos
Diterpenos/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Caesalpinia/metabolismo , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Extratos Vegetais/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Transdução de Sinais
7.
Acta Pharmacol Sin ; 42(11): 1834-1846, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33574568

RESUMO

Suppression of excessive hepatic gluconeogenesis is an effective strategy for controlling hyperglycemia in type 2 diabetes (T2D). In the present study, we screened our compounds library to discover the active molecules inhibiting gluconeogenesis in primary mouse hepatocytes. We found that SL010110 (5-((4-allyl-2-methoxyphenoxy) methyl) furan-2-carboxylic acid) potently inhibited gluconeogenesis with 3 µM and 10 µM leading to a reduction of 45.5% and 67.5%, respectively. Moreover, SL010110 caused suppression of gluconeogenesis resulted from downregulating the protein level of phosphoenolpyruvate carboxykinase 1 (PEPCK1), but not from affecting the gene expressions of PEPCK, glucose-6-phosphatase, and fructose-1,6-bisphosphatase. Furthermore, SL010110 increased PEPCK1 acetylation, and promoted PEPCK1 ubiquitination and degradation. SL010110 activated p300 acetyltransferase activity in primary mouse hepatocytes. The enhanced PEPCK1 acetylation and suppressed gluconeogenesis caused by SL010110 were blocked by C646, a histone acetyltransferase p300 inhibitor, suggested that SL010110 inhibited gluconeogenesis by activating p300. SL010110 decreased NAD+/NADH ratio, inhibited SIRT2 activity, and further promoted p300 acetyltransferase activation and PEPCK1 acetylation. These effects were blocked by NMN, an NAD+ precursor, suggested that SL010110 inhibited gluconeogenesis by inhibiting SIRT2, activating p300, and subsequently promoting PEPCK1 acetylation. In type 2 diabetic ob/ob mice, single oral dose of SL010110 (100 mg/kg) suppressed gluconeogenesis accompanied by the suppressed hepatic SIRT2 activity, increased p300 activity, enhanced PEPCK1 acetylation and degradation. Chronic oral administration of SL010110 (15 or 50 mg/kg) significantly reduced the blood glucose levels in ob/ob and db/db mice. This study reveals that SL010110 is a lead compound with a distinct mechanism of suppressing gluconeogenesis via SIRT2-p300-mediated PEPCK1 degradation and potent anti-hyperglycemic activity for the treatment of T2D.

8.
Metabolism ; 99: 45-56, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295453

RESUMO

BACKGROUND AND PURPOSE: TGR5 plays an important role in many physiological processes. However, the functions of TGR5 in the regulation of the glucose metabolism and insulin sensitivity in the skeletal muscles have not been fully elucidated. We synthesized MN6 as a potent and selective TGR5 agonist. Here, the effect of MN6 on insulin resistance in skeletal muscles was evaluated in diet-induced obese (DIO) mice and C2C12 myotubes, and the underlying mechanisms were explored. METHODS: The activation of MN6 on human and mouse TGR5 was evaluated by a cAMP assay in HEK293 cell lines stable expressing hTGR5/CRE or mTGR5/CRE cells. GLP-1 secretion was measured in NCI-H716 cells and CD1 mice. The acute and chronic effects of MN6 on regulating metabolic abnormalities were observed in ob/ob and DIO mice. 2-deoxyglucose uptake was examined in isolated skeletal muscles. Akt phosphorylation, glucose uptake and glycogen synthesis were examined to assess the effects of MN6 on palmitate-induced insulin resistance in C2C12 myotubes. RESULTS: MN6 potently activated human and mouse TGR5 with EC50 values of 15.9 and 17.9 nmol/L, respectively, and stimulated GLP-1 secretion in NCI-H716 cells and CD1 mice. A single oral dose of MN6 significantly decreased the blood glucose levels in ob/ob mice. Treatment with MN6 for 15 days reduced the fasting blood glucose and HbA1c levels in ob/ob mice. MN6 improved glucose and insulin tolerance and enhanced the insulin-stimulated glucose uptake of skeletal muscles in DIO mice. The palmitate-induced impairment of insulin-stimulated Akt phosphorylation, glucose uptake and glycogen synthesis in C2C12 myotubes could be prevented by MN6. The effect of MN6 on palmitate-impaired insulin-stimulated Akt phosphorylation was abolished by siRNA-mediated knockdown of TGR5 or by the inhibition of adenylate cyclase or protein kinase A, suggesting that this effect is dependent on the activation of TGR5 and the cAMP/PKA pathway. CONCLUSIONS: Our study identified that a TGR5 agonist could ameliorate insulin resistance by the cAMP/PKA pathway in skeletal muscles; this uncovered a new effect of the TGR5 agonist on regulating the glucose metabolism and insulin sensitivity in skeletal muscles and further strengthened its potential value for the treatment of type 2 diabetes.


Assuntos
Ciclopropanos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Resistência à Insulina , Músculo Esquelético/efeitos dos fármacos , Piridinas/uso terapêutico , Quinoxalinas/uso terapêutico , Receptores Acoplados a Proteínas G/agonistas , Animais , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Células HEK293 , Homeostase , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo
9.
Front Pharmacol ; 9: 476, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867482

RESUMO

The role of phosphodiesterase 3 (PDE3), a cyclic AMP (cAMP)-degrading enzyme, in modulating gluconeogenesis remains unknown. Here, linderane, a natural compound, was found to inhibit gluconeogenesis by activating hepatic PDE3 in rat primary hepatocytes. The underlying molecular mechanism and its effects on whole-body glucose and lipid metabolism were investigated. The effect of linderane on gluconeogenesis, cAMP content, phosphorylation of cAMP-response element-binding protein (CREB) and PDE activity were examined in cultured primary hepatocytes and C57BL/6J mice. The precise mechanism by which linderane activates PDE3 and inhibits the cAMP pathway was explored using pharmacological inhibitors. The amelioration of metabolic disorders was observed in ob/ob mice. Linderane inhibited gluconeogenesis, reduced phosphoenolpyruvate carboxykinase (Pck1) and glucose-6-phosphatase (G6pc) gene expression, and decreased intracellular cAMP concentration and CREB phosphorylation in rat primary hepatocytes under both basal and forskolin-stimulated conditions. In rat primary hepatocytes, it also increased total PDE and PDE3 activity but not PDE4 activity. The suppressive effect of linderane on the cAMP pathway and gluconeogenesis was abolished by the non-specific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the specific PDE3 inhibitor cilostazol. Linderane indirectly activated PDE3 through extracellular regulated protein kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) activation. Linderane improved glucose and lipid metabolism after chronic oral administration in ob/ob mice. Our findings revealed linderane as an indirect PDE3 activator that suppresses gluconeogenesis through cAMP pathway inhibition and has beneficial effects on metabolic syndromes in ob/ob mice. This investigation highlighted the potential for PDE3 activation in the treatment of type 2 diabetes.

10.
J Am Chem Soc ; 140(7): 2485-2492, 2018 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-29394051

RESUMO

Hongkonoids A-D (1-4), the first example of ascorbylated terpenoids featuring a unique 5,5,5-fused tricyclic spiroketal butyrolactone moiety and diterpenoid-derived long chain, were isolated from Dysoxylum hongkongense. Their structures were unambiguously assigned by a combination of spectroscopic data, chemical degradation, X-ray crystallography, CD analysis, and total synthesis. The total syntheses of compounds 1-4 were effectively accomplished by a convergent strategy with the longest linear sequences of 12-14 steps and overall yields of 5.4-9.6%. Notably, we exploited a bioinspired one-pot method to construct the key intermediate 14 from an easily made compound 12 by involving the cascade reactions of an elaborate Claisen rearrangement, deprotections, and a 5-exo-trig cyclization. The desired major epimer 14a was then transformed to the main building block 21. Assembly of 21 and the long chain vinyl iodide 7 was made by an NHK coupling reaction to furnish the framework of 1-4. Some of the hongkonoids and/or synthetic analogs showed significant to moderate inhibitory activities against NF-κB, 11ß-HSD1, and sterol synthesis. The most active NF-κB inhibitor 34 exhibited distinct inhibition on the LPS-induced inflammatory responses in RAW 246.7 and primary BMDM cells.

11.
Chem Biol Drug Des ; 90(6): 1122-1133, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28548386

RESUMO

Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme that mobilizes fatty acids from cellular triglyceride stores. Metabolic syndrome, which refers to a group of abnormalities that occur together and increase the risk of coronary artery disease, stroke, type 2 diabetes, and cachexia, can be treated using ATGL-specific inhibitors. Atglistatin (1) is the first small-molecule inhibitor of ATGL. In this study, we designed and synthesized 29 Atglistatin derivatives and evaluated their inhibition of forskolin-stimulated lipolysis in 3T3-L1 adipocytes as an indicator of their potential to inhibit ATGL in adipose tissues. Among all the tested Atglistatin analogs, we previously found that the thiourea compound 9e showed potent ATGL inhibitory activity in vitro, which was much stronger than that of Atglistatin, and its inhibitory activity in vivo was similar to that of Atglistatin. This tool compound could be used to study the pathophysiology and druggability of ATGL in animal models of metabolic disease and cachexia.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Lipase/antagonistas & inibidores , Compostos de Fenilureia/química , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Colforsina/farmacologia , Inibidores Enzimáticos/farmacologia , Glicerol/metabolismo , Lipase/metabolismo , Lipólise/efeitos dos fármacos , Camundongos , Compostos de Fenilureia/farmacologia , Relação Estrutura-Atividade
12.
Int J Biol Sci ; 13(1): 1-12, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28123341

RESUMO

Dysregulation of lipid metabolism in skeletal muscle is involved in the development of insulin resistance. Mutations in lipin-1, a key lipid metabolism regulator leads to significant systemic insulin resistance in fld mice. However, the function of lipin-1 on lipid metabolism and insulin sensitivity in skeletal muscle is still unclear. Herein we demonstrated that downregulation of lipin-1 in C2C12 myotubes by siRNA transfection suppressed insulin action, characterized by reduced insulin stimulated Akt phosphorylation and glucose uptake. Correspondingly, decreased lipin-1 expression was observed in palmitate-induced insulin resistance in C2C12 myotubes, suggested that lipin-1 might play a role in the etiology of insulin resistance in skeletal muscle. The insulin resistance induced by lipin-1 downregulation was related to the disturbance of lipid homeostasis. Lipin-1 silencing reduced intracellular DAG and TAG levels, but elevated ceramide accumulation in C2C12 myotubes. Moreover, the impaired insulin stimulated Akt phosphorylation and glucose uptake caused by lipin-1 silencing could be blocked by the pretreatment with SPT inhibitor myriocin, ceramide synthase inhibitor FB1, or PP2A inhibitor okadaic acid, suggested that the increased ceramide accumulation might be responsible for the development of insulin resistance induced by lipin-1 silencing in C2C12 myotubes. Meanwhile, decreased lipin-1 expression also impaired mitochondrial function in C2C12 myotubes. Therefore, our study suggests that lipin-1 plays an important role in lipid metabolism and downregulation of lipin-1 induces insulin resistance by increasing intracellular ceramide accumulation in C2C12 myotubes. These results offer a molecular insight into the role of lipin-1 in the development of insulin resistance in skeletal muscle.


Assuntos
Ceramidas/metabolismo , Resistência à Insulina/fisiologia , Fibras Musculares Esqueléticas/metabolismo , Proteínas Nucleares/metabolismo , Fosfatidato Fosfatase/metabolismo , Animais , Western Blotting , Linhagem Celular , Diglicerídeos/metabolismo , Resistência à Insulina/genética , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Proteínas Nucleares/genética , Palmitatos/farmacologia , Fosfatidato Fosfatase/genética , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Triglicerídeos/metabolismo
13.
Int J Biol Sci ; 11(11): 1272-80, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26435693

RESUMO

The role of AMP-activated protein kinase (AMPK) in pancreatic ß-cell apoptosis is still controversial, and the reasons for the discrepancies have not been clarified. In the current study, we observed the effects of two well-known AMPK activators 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and metformin, on apoptosis in rat insulinoma INS-1E cells, and further explored their possible mechanisms. Both AICAR and metformin protected INS-1E cells from palmitate-induced apoptosis, as reflected by decreases in both cleaved caspase 3 protein expression and caspase 3/7 activity, and these protective effects were abrogated by AMPK inhibitor compound C. The protective action of AICAR was probably mediated by the suppression of triacylglycerol accumulation, increase in Akt phosphorylation and decrease in p38 MAPK phosphorylation, while metformin might exert its protective effect on INS-1E cells by decreases in both JNK and p38 MAPK phosphorylation. All these regulations were dependent on AMPK activation. However, under standard culture condition, AICAR increased JNK phosphorylation and promoted INS-1E cell apoptosis in an AMPK-dependent manner, whereas metformin showed no effect on apoptosis. Our study revealed that AMPK activators AICAR and metformin exhibited different effects on INS-1E cell apoptosis under different culture conditions, which might be largely attributed to different downstream mediators. Our results provided new and informative clues for better understanding of the role of AMPK in ß-cell apoptosis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Metformina/farmacologia , Palmitatos/farmacologia , Ribonucleotídeos/farmacologia , Aminoimidazol Carboxamida/farmacologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Metabolismo dos Lipídeos/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos
14.
ACS Med Chem Lett ; 6(4): 386-91, 2015 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-25941553

RESUMO

Analogues of the natural product (-)-arctigenin, an activator of adenosine monophosphate activated protein kinase, were prepared in order to evaluate their effects on 2-deoxyglucose uptake in L6 myotubes and possible use in ameliorating metabolic disorders. Racemic arctigenin 2a was found to display a similar uptake enhancement as does (-)-arctigenin. As a result, the SAR study was conducted utilizing racemic compounds. The structure-activity relationship study led to the discovery of key substitution patterns on the lactone motif that govern 2-deoxyglucose uptake activities. The results show that replacement of the para-hydroxyl group of the C-2 benzyl moiety of arctigenin by Cl has a pronounced effect on uptake activity. Specifically, analogue 2p, which contains the p-Cl substituent, stimulates glucose uptake and fatty acid oxidation in L6 myotubes.

15.
Acta Pharmacol Sin ; 36(3): 343-52, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25732571

RESUMO

AIM: Defects in fatty acid metabolism contribute to the pathogenesis of insulin resistance and obesity. In this study, we investigated the effects of a novel compound yhhu981 on fatty acid metabolism in vitro and in vivo. METHODS: The capacity to stimulate fatty acid oxidation was assessed in C2C12 myotubes. The fatty acid synthesis was studied in HepG2 cells using isotope tracing. The phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) was examined with Western blot analysis. For in vivo experiments, ob/ob mice were orally treated with yhhu981 acutely (300 mg/kg) or chronically (150 or 300 mg·kg(-1)·d(-1) for 22 d). On the last day of treatment, serum and tissue samples were collected for analysis. RESULTS: Yhhu981 (12.5-25 µmol/L) significantly increased fatty acid oxidation and the expression of related genes (Sirt1, Pgc1α and Mcad) in C2C12 myotubes, and inhibited fatty acid synthesis in HepG2 cells. Furthermore, yhhu981 dose-dependently increased the phosphorylation of AMPK and ACC in both C2C12 myotubes and HepG2 cells. Compound C, an AMPK inhibitor, blocked fatty acid oxidation in yhhu981-treated C2C12 myotubes and fatty acid synthesis decrease in yhhu981-treated HepG2 cells. Acute administration of yhhu981 decreased the respiratory exchange ratio in ob/ob mice, whereas chronic treatment with yhhu981 ameliorated the lipid abnormalities and ectopic lipid deposition in skeletal muscle and liver of ob/ob mice. CONCLUSION: Yhhu981 is a potent compound that stimulates fatty acid oxidation, and exerts pleiotropic effects on lipid metabolism by activating AMPK.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Alcinos/farmacologia , Fármacos Antiobesidade/farmacologia , Ativadores de Enzimas/farmacologia , Ácidos Graxos/metabolismo , Fígado/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Obesidade/tratamento farmacológico , Resorcinóis/farmacologia , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Acetil-CoA Carboxilase/metabolismo , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Metabolismo Energético/efeitos dos fármacos , Ativação Enzimática , Células Hep G2 , Humanos , Fígado/enzimologia , Camundongos Obesos , Fibras Musculares Esqueléticas/enzimologia , Obesidade/enzimologia , Oxirredução , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima
16.
Acta Pharmacol Sin ; 33(9): 1195-203, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22922341

RESUMO

AIM: Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a potent and selective inhibitor of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) with the ability to ameliorate metabolic disorders in diet-induced obese mice. In the present study, we investigated the effects of emodin on adipocyte function and the underlying mechanisms in vitro, and its anti-diabetic effects in ob/ob mice. METHODS: 3T3-L1 adipocytes were used for in vitro studies. 11ß-HSD1A activity was evaluated with a scintillation proximity assay. The adipogenesis, glucose uptake, lipolysis and adiponectin secretion were investigated in 3T3-L1 adipocytes treated with emodin in the presence of active (corticosterone) or inactive glucocorticoid (11-dehydrocorticosterone). For in vivo studies, ob/ob mice were administered emodin (25 and 50 mg·kg⁻¹·d⁻¹, ip) for 26 d. On the last day of administration, the serum was collected and the mesenteric and perirenal fat were dissected for analyses. RESULTS: Emodin inhibited the 11ß-HSD1 activity in 3T3-L1 adipocytes in concentration- and time-dependent manners (the IC50 values were 7.237 and 4.204 µmol/L, respectively, after 1 and 24 h treatment. In 3T3-L1 adipocytes, emodin (30 µmol/L) suppressed 11-dehydrocorticosterone-induced adipogenesis without affecting corticosterone-induced adipogenesis; emodin (3 µmol/L) reduced 11-dehydrocorticosterone-stimulated lipolysis, but had no effect on corticosterone-induced lipolysis. Moreover, emodin (3 µmol/L) partly reversed the impaired insulin-stimulated glucose uptake and adiponectin secretion induced by 11-dehydrocorticosterone but not those induced by corticosterone. In ob/ob mice, long-term emodin administration decreased 11ß-HSD1 activity in mesenteric adipose tissues, lowered non-fasting and fasting blood glucose levels, and improved glucose tolerance. CONCLUSION: Emodin improves the inactive glucocorticoid-induced adipose tissue dysfunction by selective inhibition on 11ß-HSD1 in adipocyte in vitro and improves glycemic control in ob/ob mice.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adipócitos/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Emodina/farmacologia , Células 3T3-L1 , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Adiponectina/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/fisiopatologia , Relação Dose-Resposta a Droga , Emodina/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Glucocorticoides/toxicidade , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Concentração Inibidora 50 , Insulina/metabolismo , Lipólise/efeitos dos fármacos , Camundongos , Camundongos Obesos , Fatores de Tempo
17.
Br J Pharmacol ; 161(1): 113-26, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20718744

RESUMO

BACKGROUND AND PURPOSE: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is an attractive therapeutic target of type 2 diabetes and metabolic syndrome. Emodin, a natural product and active ingredient of various Chinese herbs, has been demonstrated to possess multiple biological activities. Here, we investigated the effects of emodin on 11beta-HSD1 and its ability to ameliorate metabolic disorders in diet-induced obese (DIO) mice. EXPERIMENTAL APPROACH: Scintillation proximity assay was performed to evaluate inhibition of emodin against recombinant human and mouse 11beta-HSDs. The ability of emodin to inhibit prednisone- or dexamethasone-induced insulin resistance was investigated in C57BL/6J mice and its effect on metabolic abnormalities was observed in DIO mice. KEY RESULTS: Emodin is a potent and selective 11beta-HSD1 inhibitor with the IC(50) of 186 and 86 nM for human and mouse 11beta-HSD1, respectively. Single oral administration of emodin inhibited 11beta-HSD1 activity of liver and fat significantly in mice. Emodin reversed prednisone-induced insulin resistance in mice, whereas it did not affect dexamethasone-induced insulin resistance, which confirmed its inhibitory effect on 11beta-HSD1 in vivo. In DIO mice, oral administration of emodin improved insulin sensitivity and lipid metabolism, and lowered blood glucose and hepatic PEPCK, and glucose-6-phosphatase mRNA. CONCLUSIONS AND IMPLICATIONS: This study demonstrated a new role for emodin as a potent and selective inhibitor of 11beta-HSD1 and its beneficial effects on metabolic disorders in DIO mice. This highlights the potential value of analogues of emodin as a new class of compounds for the treatment of metabolic syndrome or type 2 diabetes.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Emodina/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Corticosteroides/toxicidade , Animais , Linhagem Celular , Dexametasona/toxicidade , Dieta , Relação Dose-Resposta a Droga , Emodina/administração & dosagem , Humanos , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Obesidade , Prednisona/toxicidade , Ligação Proteica , Conformação Proteica
18.
J Pediatr ; 154(3): 345-50, 350.e1, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19028388

RESUMO

OBJECTIVE: To investigate the increased risk of congenital, neurologic, and endocrine disorders in autistic preschool children and to probe possible cognitive impairment-associated variation in such risks. STUDY DESIGN: Using a population-based longitudinal study, a total of 3440 autistic children born in 1997-1999 and 33,391 age- and residential urbanicity-matched control subjects were identified from the National Health Insurance Research Database in Taiwan. Conditional logistic analyses were performed to estimate the strength of association stratified by the presence of cognitive impairment. RESULTS: Autistic children were found to have greatly elevated risks of congenital anomalies (eg, tuberous sclerosis: adjusted odds ratio [aOR] = 34 approximately 61) and neurologic disorders (eg, epilepsy: aOR = 5 approximately 13) compared with their matched nonautistic peers. The increased risk of medical diseases for mentally retarded autism were approximately 1.6 to 9 times greater than those for isolated autism. CONCLUSIONS: The observed cognitive impairment-related variation in the increased risk of congenital, neurological, and endocrine disorders with autism may provide some clinical and etiologic implications that warrant investigation in the future.


Assuntos
Transtorno Autístico/epidemiologia , Transtornos Cognitivos/epidemiologia , Anormalidades Congênitas/epidemiologia , Doenças do Sistema Endócrino/epidemiologia , Doenças do Sistema Nervoso/epidemiologia , Estudos de Casos e Controles , Pré-Escolar , Cognição , Comorbidade , Feminino , Humanos , Deficiência Intelectual/epidemiologia , Estudos Longitudinais , Masculino , Medição de Risco , Taiwan/epidemiologia
19.
J Stud Alcohol Drugs ; 69(3): 378-87, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18432380

RESUMO

OBJECTIVE: This study examined the extent to which youthful alcohol consumption and the initiation of tobacco, betel nut, and other illegal drugs may differ by their first drinking context in Taiwan-a society with social norms that are more tolerant of underage drinking. METHOD: In 2004, in a nationally representative sample of 11,943 school-attending youth ages 15-18, information pertaining to sociodemographic characteristics, problem behaviors, lifetime experiences of alcohol, tobacco, betel nut, and illegal drugs, as well as psychoactive, drug-specific age of initiation, context at first use, average frequency, and recency of use, was assessed by anonymous questionnaires. RESULTS: Youth who had their first alcoholic beverages in entertainment settings or at friends' houses were more likely to become frequent drinkers. After adjustment for socioeconomic background and problem behaviors, having had the first drink in entertainment settings was associated with a faster progression into the initiation of illegal drugs (hazard ratio [HR]=2.5, 95% confidence interval [CI]: 1.5-4.0) and betel nut (HR=1.5, 95% CI: 1.1-2.1). CONCLUSIONS: Youthful drinking pattern and transition from alcohol to betel nut and illegal drugs may vary modestly by the first drinking context. This context may be recognized as a proxy variable to identify youth at a higher risk for alcohol and other drug problems and to devise context-based educational or prevention programs.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Areca , Drogas Ilícitas , Psicotrópicos , Fumar/epidemiologia , Meio Social , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adolescente , Consumo de Bebidas Alcoólicas/psicologia , Comorbidade , Estudos Transversais , Feminino , Amigos/psicologia , Inquéritos Epidemiológicos , Humanos , Masculino , Fatores de Risco , Fumar/psicologia , Facilitação Social , Fatores Socioeconômicos , Transtornos Relacionados ao Uso de Substâncias/psicologia , Taiwan
20.
Drug Alcohol Depend ; 95(3): 209-18, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18342459

RESUMO

In this study, we examine whether adolescent emotional and behavior problems vary by history of early alcohol experiences. A national sample of 6974 alcohol-naïve and 4337 alcohol-experienced youths aged 15-18 years were identified within the 2004 National Survey of Illegal Drug Use among Adolescents in Taiwan. Four alcohol experience groups were created based on recency and frequency of alcohol use: (1) naïve; never drank alcohol, (2) trial use; first and only consumption of alcohol occurred more than 6 months preceding the assessment, (3) past use; alcohol used on more than one occasion but had not had a drink in the 6 months prior to the assessment, and (4) current use; consumed alcohol more than once and drank within the 6 months preceding the interview. A Chinese adaptation of the Youth Self-Report (YSR) assessed eight behavior syndromes: withdrawn, anxious/depressed, somatic complaints, social problems, thought problems, attention problems, rule-breaking behavior, and aggressive behavior. Multivariate response models (GLM/GEE) were used to examine the relationship of alcohol experiences with emotional and behavior problems. Alcohol-using youth were more likely to experience several specific emotional or behavioral syndromes than their alcohol-naïve counterparts. For example, youth with a history of alcohol use had an estimated 30-60% increase in the odds of experiencing items within the aggressive behavior syndrome as compared with alcohol-naïve youth. The type of early alcohol involvement in adolescence may exert differential effects on emotions and behaviors expressed across and within syndromes; these may warrant distinctions in informing etiological research and preventive efforts.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Transtornos Mentais/epidemiologia , Adolescente , Idade de Início , Criança , Feminino , Humanos , Masculino , Transtornos Mentais/diagnóstico , Transtornos Mentais/psicologia , Vigilância da População/métodos , Prevalência , Inquéritos e Questionários , Taiwan/epidemiologia
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