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1.
Cell Commun Signal ; 17(1): 168, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842909

RESUMO

BACKGROUND: Our previous study has demonstrated that NAD(P)H: quinone oxidoreductase 1 (NQO1) is significantly upregulated in human liver cancer where it potentiates the apoptosis evasion of liver cancer cell. However, the underlying mechanisms of the oncogenic function of NQO1 in HCC have not been fully elucidated. METHODS: Expression of NQO1, SIRT6, AKT and X-linked inhibitor of apoptosis protein (XIAP) protein were measured by western blotting and immunohistochemistry. Additionally, the interaction between NQO1 and potential proteins were determined by immunoprecipitation assays. Furthermore, the effect of NQO1 and SIRT6 on tumor growth was determined in cell model and orthotopic tumor implantation model. RESULTS: We found that NQO1 overexpression in HCC enhanced SIRT6 protein stability via inhibiting ubiquitin-mediated 26S proteasome degradation. High level of SIRT6 reduced acetylation of AKT which resulted in increased phosphorylation and activity of AKT. Activated AKT subsequently phosphorylated anti-apoptotic protein XIAP at Ser87 which determined its protein stability. Reintroduction of SIRT6 or AKT efficiently rescued NQO1 knock-out-mediated inhibition of growth and induction of apoptosis. In orthotopic mouse model, NQO1 knock-out inhibited tumor growth and induced apoptosis while this effect was effectively rescued by SIRT6 overexpression or MG132 treatment partially. CONCLUSIONS: Collectively, these results reveal an oncogenic function of NQO1 in sustaining HCC cell proliferation through SIRT6/AKT/XIAP signaling pathway.

2.
Front Pharmacol ; 10: 1270, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31708789

RESUMO

Hepatitis B virus (HBV) is a major public health threat and anti-HBV drugs are limited to nucleos(t)ide analogs (NAs) and pegylated interferon alpha (Peg-IFNα). Toward identifying an effective compound for HBV treatment is important to suppress and eradicate HBV. In this study, we explored the anti-viral effect of Sirtuin 6 (SIRT6) inhibitor, OSS_128167, in HBV transcription and replication. Firstly, we found that OSS_128167 could decrease the level of HBV core deoxyribonucleic acid (DNA) and 3.5-Kb ribonucleic acid (RNA) in vitro. Furthermore, the level of HBV DNA and 3.5-Kb RNA were also markedly suppressed by OSS_128167 administration in HBV transgenic mice. In addition, we found that depletion of SIRT6 inhibited HBV transcription and replication in HepG2.2.15 and HBV-infected HepG2-sodium taurocholate cotransporting polypeptide cells, whereas overexpression of SIRT6 enhanced HBV transcription and replication. Importantly, the positive effect of SIRT6 overexpression on HBV transcription could be blocked by OSS_128167 treatment. Further mechanism studies showed that HBV core promoter was significantly activated by SIRT6 through upregulating peroxisome proliferator-activated receptors α (PPARα) expression. And ectopical expression of SIRT6 or PPARα relieved the restriction of HBV transcription mediated by OSS_128167. In summary, our results showed that OSS_128167 might serve as a potential antiviral agent for HBV therapy and SIRT6 played a pivotal role in HBV transcription and replication.

3.
Trials ; 20(1): 644, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31775839

RESUMO

BACKGROUND: Obesity has become a major public health hazard with epidemic proportions, affecting adults, adolescents, and children of both genders. Previous studies have suggested that acupoint catgut embedding (ACE) might be a potential therapeutic approach for obesity. The purpose of this study is to conduct a rigorous and normative trial to determine the efficacy of ACE for obesity. METHODS/DESIGN: A total of 99 eligible patients diagnosed with obesity will be recruited in this study. They will be randomly allocated to either the verum ACE group, sham ACE group, or waiting list (WL) group, with 33 patients in each group. Each patient in the two ACE-based groups will receive eight sessions of treatment, lasting over 8 weeks. The primary outcome is the reduction of body mass index (BMI) after treatment. Secondary outcomes will include waist circumference (WC), hip circumference (HC), waist:hip ratio, body fat percentage, blood lipid level, subcutaneous fat area, visceral fat area, and World Health Organization Quality of Life (WHOQOL). All the outcomes will be evaluated at baseline, at the end of the 8 weeks of treatments, and at 3 months of follow-up. The evaluators and data analyzers will be blinded to group allocation. DISCUSSION: The findings of this randomized, sham-, and WL-controlled trial will help to investigate the influence of ACE on clinical variables as well as visceral fat area of obesity, which will provide high-quality evidence on the efficacy of ACE for obesity. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800020248. Registered on December 21, 2018.

4.
EBioMedicine ; 49: 232-246, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31680002

RESUMO

BACKGROUND: Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed. METHODS: In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model. FINDINGS: 6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production. INTERPRETATION: We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agent.

5.
Phys Rev Lett ; 123(12): 121102, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31633968

RESUMO

We study the gravothermal evolution of dark matter halos in the presence of dissipative dark matter self-interactions. Dissipative interactions are present in many particle-physics realizations of the dark-sector paradigm and can significantly accelerate the gravothermal collapse of halos compared to purely elastic dark matter self-interactions. This is the case even when the dissipative interaction timescale is longer than the free-fall time of the halo. Using a semianalytical fluid model calibrated with isolated and cosmological N-body simulations, we calculate the evolution of the halo properties-including its density profile and velocity dispersion profile-as well as the core-collapse time as a function of the particle model parameters that describe the interactions. A key property is that the inner density profile at late times becomes cuspy again. Using 18 dwarf galaxies that exhibit a corelike dark matter density profile, we derive constraints on the strength of the dissipative interactions and the energy loss per collision.

6.
Technol Cancer Res Treat ; 18: 1533033819851833, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31570091

RESUMO

OBJECTIVE: To investigate the role of miR-26a-5p in cell proliferation and doxorubicin sensitivity in hepatocellular carcinoma. METHODS: We evaluated miR-26a-5p expression in hepatocellular carcinoma tissues and cell lines by reverse transcription polymerase chain reaction. Cell Counting Kit-8 was used to examine cell proliferation. Relationship between miR-26a-5p and aurora kinase A was evaluated by luciferase report system. Western blot was used to detect expression of aurora kinase A. RESULTS: In this study, we observed miR-26a-5p was downregulated in hepatocellular carcinoma tissues and cell lines. Gain-of-function experiments showed that proliferation rate of hepatocellular carcinoma cells decreased under condition of miR-26a-5p mimics. We found miR-26a-5p mimics could enhance doxorubicin sensitivity of hepatocellular carcinoma cells. Further study showed that aurora kinase A was target gene of miR-26a-5p. Suppression of aurora kinase A could lead to lower cell proliferation and higher doxorubicin sensitivity of hepatocellular carcinoma cells. CONCLUSION: Our study found that miR-26a-5p could inhibit cell proliferation and enhance doxorubicin sensitivity in hepatocellular carcinoma cells by targeting aurora kinase A.

7.
J Ind Microbiol Biotechnol ; 46(7): 937-949, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30937555

RESUMO

Traditional amino acid producers typically exhibit the low glucose uptake rate and growth deficiency, resulting in a long fermentation time because of the accumulation of side mutations in breeding of strains. In this study, we demonstrate that the efficiency of L-lysine production in traditional L-lysine producer Corynebacterium glutamicum ZL-9 can be improved by rationally engineering glucose uptake systems. To do this, different bypasses for glucose uptake were investigated to reveal the best glucose uptake system for L-lysine production in traditional L-lysine producer. This study showed that overexpression of the key genes in PTSGlc or non-PTSGlc increased the glucose consumption, growth rate, and L-lysine production. However, increasing the function of PTSGlc in glucose uptake led to the increase of by-products, especially for plasmid-mediated expression system. Increasing the participation of non-PTSGlc in glucose utilization showed the best glucose uptake system for L-lysine production. The final strain ZL-92 with increasing the expression level of iolT1, iolT2 and ppgK could produce 201.6 ± 13.8 g/L of L-lysine with a productivity of 5.04 g/L/h and carbon yield of 0.65 g/(g glucose) in fed-batch culture. This is the first report of a rational modification of glucose uptake systems that improve the efficiency of L-lysine production through increasing the participation of non-PTSGlc in glucose utilization in traditional L-lysine producer. Similar strategies can be also used for producing other amino acids or their derivatives.


Assuntos
Corynebacterium glutamicum/metabolismo , Glucose/metabolismo , Lisina/biossíntese , Técnicas de Cultura Celular por Lotes , Transporte Biológico , Corynebacterium glutamicum/genética , Engenharia Metabólica/métodos
8.
Cancer Lett ; 452: 90-102, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30914208

RESUMO

Invasion and metastasis are the predominant causes of lethal outcomes in patients with hepatocellular carcinoma (HCC). However, the molecular mechanism underlying the invasive or metastatic process are still insufficiently understood. Here, we first integrated several public databases and identified a novel protein kinase, PDZ-binding kinase (PBK) that was frequently upregulated and correlated with poor prognosis in patients with HCC. Gain- or loss-of-function analysis revealed that PBK promoted migration and invasion of HCC cells both in vitro and in vivo. Mechanistically, PBK enhanced uPAR expression by activating its promoter activity. Chromatin immunoprecipitation (ChIP) assay showed that ETV4 directly bound to the core region of uPAR promoter while PBK could enhance the binding of ETV4 to uPAR promoter. In orthotopic mouse model, PBK knockdown markedly inhibited the lung metastasis of HCC cells, while this effect was significantly restored by uPAR overexpression. Finally, there was a positive correlation between PBK and uPAR, ETV4 and uPAR in HCC clinical samples. Collectively, these findings revealed that PBK acted as a crucial kinase by promoting invasion and migration via the ETV4-uPAR signaling pathway, and it therefore could be a promising diagnostic biomarker and therapeutic target for HCC metastasis.

9.
Cancer Lett ; 451: 156-167, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30867140

RESUMO

NAD(P)H: quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme which is associated with poor prognosis in human breast, colon, lung and liver cancers. However, the molecular mechanisms underlying the pro-tumorigenic function of NQO1 remains unclear. This study investigated the function of NQO1 in the context of hepatocellular carcinoma (HCC) development. We found that NQO1 was frequently up-regulated in human liver cancer, and its high expression level was correlated with the tumor stage and low survival rate of HCC patients. Loss-of-function of NQO1 inhibited growth in HCC cells with increased apoptosis in vitro, and suppressed orthotopic tumorigenicity in vivo. Mechanistically, high level of NQO1 in HCC cells enhanced protein stability of X-linked inhibitor of apoptosis protein (XIAP) by increasing its phosphorylation at Ser 87. Reintroduction of wile type XIAP and the phospho-mimic mutants XIAPS87D significantly reversed NQO1 knock-down/out induced growth inhibition and apoptosis. In mouse model with orthotopically implanted hepatocarcinoma, NQO1 suppression and NQO1 inhibitor suppressed tumor growth and induced apoptosis. NQO1 plays an important role in sustaining HCC cell proliferation and may thus act as a potential therapeutic target in HCC treatment.

10.
Artigo em Inglês | MEDLINE | ID: mdl-30826550

RESUMO

Overdevelopment of adipose tissue in cultured fish is one of the biggest issues plaguing current aquaculture industry, leading to unhealthy status of fishes and production losses. Diet supplemented with 0.30% arachidonic acid (ARA) has been found to reduce adipogenesis and inflammation in grass carp, but the potential mechanism is not comprehensively understood. To fully reveal the effects of dietary ARA on the mRNA profiles of adipose tissue, transcriptome techniques were applied in this study. A 10-weeks feeding experiment was performed using two isonitrogenous and isoenergetic purified diets, namely ARA-free (control) and 0.30% ARA (ARA group). Results showed increased ARA content and decreased intraperitoneal fat index and adipocyte size in the adipose tissue of fish fed ARA (P < 0.05). A total of 611 and 973 genes of the adipose tissue were significantly up-regulated and down-regulated, respectively, in fish fed ARA (P < 0.05). Dietary ARA upregulated LOX pathway but downregulated CYP450 pathway annotated genes expression. A total of 65 cell development annotated genes including 30 adipocyte proliferation, 21 adipocyte differentiation, and 14 cell apoptosis annotated genes were down-regulated in the ARA group. In addition, 19 lipid catabolism annotated genes were increased. The mRNA expression levels of 5 chemokines, 10 cytokines, 26 cytokine and chemokine receptors, 15 cell adhesion, 6 oxidative stress, and 6 angiogenesis annotated genes were all down-regulated in fish fed ARA. Finally, dietary ARA also decreased the expression of transcripts annotated with glucose transportation, glycolysis and gluconeogenesis. Overall, our results demonstrate that dietary ARA has a fat reducing role, and tends to retard adipocyte development and attenuate chronic inflammation based on these adipose transcript expression results in grass carp.

11.
Proc Natl Acad Sci U S A ; 116(11): 5154-5159, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30804206

RESUMO

A high-fat diet (HFD) causes obesity-associated morbidities involved in macroautophagy and chaperone-mediated autophagy (CMA). AMPK, the mediator of macroautophage, has been reported to be inactivated in HFD-caused renal injury. However, PAX2, the mediator for CMA, has not been reported in HFD-caused renal injury. Here we report that HFD-caused renal injury involved the inactivation of Pax2 and Ampk, and the activation of soluble epoxide hydrolase (sEH), in a murine model. Specifically, mice fed on an HFD for 2, 4, and 8 wk showed time-dependent renal injury, the significant decrease in renal Pax2 and Ampk at both mRNA and protein levels, and a significant increase in renal sEH at mRNA, protein, and molecular levels. Also, administration of an sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea, significantly attenuated the HFD-caused renal injury, decreased renal sEH consistently at mRNA and protein levels, modified the renal levels of sEH-mediated epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) as expected, and increased renal Pax2 and Ampk at mRNA and/or protein levels. Furthermore, palmitic acid (PA) treatment caused significant increase in Mcp-1, and decrease in both Pax2 and Ampk in murine renal mesangial cells (mRMCs) time- and dose-dependently. Also, 14(15)-EET (a major substrate of sEH), but not its sEH-mediated metabolite 14,15-DHET, significantly reversed PA-induced increase in Mcp-1, and PA-induced decrease in Pax2 and Ampk. In addition, plasmid construction revealed that Pax2 may positively regulate Ampk transcriptionally in mRMCs. This study provides insights into and therapeutic target for the HFD-mediated renal injury.


Assuntos
Adenilato Quinase/metabolismo , Dieta Hiperlipídica , Epóxido Hidrolases/antagonistas & inibidores , Rim/lesões , Fator de Transcrição PAX2/metabolismo , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Eicosanoides/metabolismo , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/metabolismo , Hipertrofia , Rim/patologia , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Células Mesangiais/patologia , Camundongos , Ácido Palmítico , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Solubilidade , Fatores de Tempo , Ganho de Peso
12.
J Asian Nat Prod Res ; 21(9): 887-894, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30614271

RESUMO

Three new phenylspirodrimanes derivatives named stachybotrysins H and I (1 and 2) and stachybotrin E (3), together with one known compound stachybotrylactam (4), were isolated from Stachybotrys chartarum CGMCC 3.5365. Their structures were determined by extensive NMR data and mass spectroscopic analysis. Compounds 1 and 2 showed inhibitory effect towards potassium channel Kv1.3 with IC50 values of 13.4 and 10.9 µM, respectively.

13.
Hepatology ; 69(5): 1885-1902, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30614547

RESUMO

Hepatitis B virus (HBV) infection is a common infectious disease, in which nuclear covalently closed circular DNA (cccDNA) plays a key role in viral persistence, viral reactivation after treatment withdrawal, and drug resistance. A recent genome-wide association study has identified that the ubiquitin conjugating enzyme E2 L3 (UBE2L3) gene is associated with increased susceptibility to chronic HBV (CHB) infection in adults. However, the association between UBE2L3 and children with CHB and the underlying mechanism remain unclear. In this study, we performed two-stage case-control studies including adults and independent children in the Chinese Han population. The rs59391722 allele in the promoter of the UBE2L3 gene was significantly associated with HBV infection in both adults and children, and it increased the promoter activity of UBE2L3. Serum UBE2L3 protein levels were positively correlated with HBV viral load and hepatitis B e antigen (HBeAg) levels in children with CHB. In an HBV infection cell model, UBE2L3 knockdown significantly reduced total HBV RNAs, 3.5-kb RNA, as well as cccDNA in HBV-infected HepG2-Na+ /taurocholate cotransporting polypeptide cells and human primary hepatocytes. A mechanistic study found that UBE2L3 maintained cccDNA stability by inducing proteasome-dependent degradation of apolipoprotein B mRNA editing enzyme catalytic subunit 3A, which is responsible for the degradation of HBV cccDNA. Moreover, interferon-α (IFN-α) treatment markedly decreased UBE2L3 expression, while UBE2L3 silencing reinforced the antiviral activity of IFN-α on HBV RNAs, cccDNA, and DNA. rs59391722 in UBE2L3 was correlated with HBV DNA suppression and HBeAg loss in response to IFN-α treatment of children with CHB. Conclusion: These findings highlight a host gene, UBE2L3, contributing to the susceptibility to persistent HBV infection; UBE2L3 may be involved in IFN-mediated viral suppression and serve as a potential target in the prevention and treatment of HBV infection.

14.
Fish Physiol Biochem ; 45(1): 287-298, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30238219

RESUMO

Sodium butyrate (SB) can be coated with fatty acid matrix. In this study, the effects of three SB forms, being zero-lipid-coated (SB-A), half-lipid-coated (SB-B), and 2/3 lipid-coated (SB-C) (w/w), on growth, lipid metabolism, and health status of grass carp (Ctenopharyngodon idella) were investigated. The three forms of SB were added to a control diet to form three SB diets, Con., SB-A, SB-B, and SB-C, where the pure SB in each SB diet was kept at the same level (500 mg kg-1). A total of 216 C. idella (14.10 ± 0.60 g/fish) were allotted into four groups (triplicate per group) and fed the four diets respectively for 56 days, and then fish were sampled and determined. Fish growth was not affected by any of the three forms of SB. Viscerosomatic index, intraperitoneal fat index, and crude lipid of hepatopancreas and muscle were significantly decreased and villus height of intestine and mRNA expression of MyD88 and TLR22 in hepatopancreas were significantly improved in SB diets compared with control (p < 0.05), respectively. MiSeq sequencing of the V3-V4 region of bacterial 16S rRNA gene revealed that SB increased the relative abundances of intestinal healthy bacteria, Fusobacteria and Bacteroides, and the abundances of Cetobacterium decreased in the SB-C group. In conclusion, the present results showed that three forms of SB, without affecting the growth of fish, respectively decreased lipid accumulation and probably have a beneficial effect on health of C. idella.


Assuntos
Ração Animal/análise , Ácido Butírico/farmacologia , Carpas/crescimento & desenvolvimento , Dieta/veterinária , Metabolismo dos Lipídeos/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição Animal , Animais , Ácido Butírico/administração & dosagem , Ácido Butírico/química , Carpas/metabolismo , Regulação da Expressão Gênica , Nível de Saúde , Intestinos/microbiologia , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo
15.
Oncol Rep ; 41(3): 1649-1657, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30592290

RESUMO

The present study investigated the expression and potential influence of SHC SH2 domain­binding protein 1 (SHCBP1) in gastric cancer (GC) cells. SHCBP1 is closely related to cell proliferation and cell cycle progression, but its role in GC remains unclear. The TCGA database revealed that SHCBP1 is highly expressed in GC tissues. Furthermore, SHCBP1 was revealed to be highly expressed in GC cell lines MGC­803 and SGC­7901 cells, and downregulation of SHCBP1 significantly inhibited GC cell proliferation. Furthermore, SHCBP1 expression promoted cell cycle progression and inhibition of apoptosis. Since the CDK4, cyclin D1 and caspase family proteins play important roles in cell cycle and apoptosis regulation, it was examined whether there was an association between SHCBP1 and these signaling pathways in GC. Our results revealed that SHCBP1 promoted cell cycle progression by regulating the CDK4­cyclin D1 cascade and suppressed caspase­3, caspase PARP­dependent apoptotic pathways. Cell invasion and metastasis experiments also revealed that SHCBP1 promoted tumor growth and invasiveness. These tumor­promoting functions of SHCBP1 may provide a potential molecular basis for the diagnosis and targeted therapy of GC.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Neoplasias Gástricas/patologia , Apoptose , Biomarcadores Tumorais/genética , Caspase 3/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , RNA Interferente Pequeno/metabolismo , Proteínas Adaptadoras da Sinalização Shc/genética , Transdução de Sinais , Estômago/patologia , Neoplasias Gástricas/diagnóstico
16.
Artigo em Inglês | MEDLINE | ID: mdl-30593870

RESUMO

Fatty acid metabolism is crucial for maintaining energy homeostasis in aquatic vertebrates experiencing environmental stress. Both sterol regulatory element-binding protein 1 (SREBP-1) and peroxisome proliferator-activated receptor α (PPARα) are the key regulators of fatty acid metabolism. In this study, the coding sequences (CDS) of SREBP-1 and PPARα were firstly identified and characterized from Onychostoma macrolepis, encoding peptides of 1136 and 470 amino acids, respectively. The functional domains in O. macrolepis SREBP-1 and PPARα proteins retained the high similarity with those of other animals, at 74.69% and 77.29%, respectively. The mRNA encoding SREBP-1 was primarily expressed in the muscle and PPARα was highly expressed in the liver and intestine. Under thermal exposure, the content of non-esterified fatty acid (NEFA) decreased gradually after 1 h in the liver and muscle of O. macrolepis, which might be due to that the organism meet more energy expenditure via fatty acid ß-oxidation. Furthermore, the mRNA expression level of SREBP-1 decreased, while the mRNA expression level of PPARα increased from 0 h to 6 h in the liver. And we found that the mRNA expression levels of both SREBP-1 and PPARα decreased significantly at 48 h (P < .05) in the muscle, which was in accordance with the significant decrease of target gene FAS and CPT1A mRNA expression levels, respectively. It might be the physiological adjustment that the fish adapted to thermal exposure at the end of experiment. These results illustrate that O. macrolepis SREBP-1 and PPARα-mediated fatty acid metabolism is a fundamental requirement for thermal adaptation.

17.
PLoS One ; 13(11): e0207948, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30481215

RESUMO

Biogenesis of membrane proteins is controlled by the protein homeostasis (proteostasis) network. We have been focusing on protein quality control of γ-aminobutyric acid type A (GABAA) receptors, the major inhibitory neurotransmitter-gated ion channels in mammalian central nervous system. Proteostasis deficiency in GABAA receptors causes loss of their surface expression and thus function on the plasma membrane, leading to epilepsy and other neurological diseases. One well-characterized example is the A322D mutation in the α1 subunit that causes its extensive misfolding and expedited degradation in the endoplasmic reticulum (ER), resulting in autosomal dominant juvenile myoclonic epilepsy. We aimed to correct misfolding of the α1(A322D) subunits in the ER as an approach to restore their functional surface expression. Here, we showed that application of BIX, a specific, potent ER resident HSP70 family protein BiP activator, significantly increases the surface expression of the mutant receptors in human HEK293T cells and neuronal SH-SY5Y cells. BIX attenuates the degradation of α1(A322D) and enhances their forward trafficking and function. Furthermore, because BiP is one major target of the two unfolded protein response (UPR) pathways: ATF6 and IRE1, we continued to demonstrate that modest activations of the ATF6 pathway and IRE1 pathway genetically enhance the plasma membrane trafficking of the α1(A322D) protein in HEK293T cells. Our results underlie the potential of regulating the ER proteostasis network to correct loss-of-function protein conformational diseases.


Assuntos
Retículo Endoplasmático/metabolismo , Proteostase , Receptores de GABA-A/metabolismo , Sequência de Aminoácidos , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Complexo de Golgi/efeitos dos fármacos , Complexo de Golgi/metabolismo , Células HEK293 , Humanos , Mutação , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Conformação Proteica , Transporte Proteico/efeitos dos fármacos , Proteostase/efeitos dos fármacos , Receptores de GABA-A/genética , Tiocianatos/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos
18.
Int J Med Sci ; 15(12): 1356-1364, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30275764

RESUMO

Sirtuin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD +)-dependent class III histone deacetylase. We have reported that HBx (hepatitis B virus X protein)-elevated SIRT2 promotes HBV replication and hepatocarcinogenesis. However, the potential anti-HBV effect of AGK2, a selective inhibitor of SIRT2, has not been reported. Here, the role of AGK2 on HBV replication was examined in the HepAD38 and HepG2-NTCP cell lines. The HBV genome was stably integrated in HepAD38 cell line which expresses HBV under the control of tetracycline. The HepG2-NTCP cells expressing the sodium taurocholate cotransporting polypeptide (NTCP) receptor are susceptible to HBV infection. We found that AGK2 exhibited a robust anti-HBV activity with minimal hepatotoxicity. AGK2 inhibited the expression of HBV total and 3.5kb RNAs, DNA replicative intermediates and HBV core protein (HBc). Moreover, AGK2 treatment suppressed the secretion of the hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg). Importantly, AGK2 treatment inhibited serum HBV DNA, HBeAg and HBsAg levels as well as hepatic HBV DNA, RNA and HBc in the HBV transgenic mice. The results indicated that AGK2, as a SIRT2 inhibitor, might be a new therapeutic option for controlling HBV infection.


Assuntos
Furanos/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Quinolinas/farmacologia , Sirtuína 2/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Animais , Células Hep G2 , Hepatite B/tratamento farmacológico , Antígenos de Superfície da Hepatite B , Antígenos E da Hepatite B , Humanos , Camundongos
19.
Phys Rev Lett ; 121(2): 021304, 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30085724

RESUMO

We search for nuclear recoil signals of dark matter models with a light mediator in PandaX-II, a direct detection experiment in the China Jinping underground laboratory. Using data collected in 2016 and 2017 runs, corresponding to a total exposure of 54 ton day, we set upper limits on the zero-momentum dark matter-nucleon cross section. These limits have a strong dependence on the mediator mass when it is comparable to or below the typical momentum transfer. We apply our results to constrain self-interacting dark matter models with a light mediator mixing with standard model particles, and set strong limits on the model parameter space for the dark matter mass ranging from 5 GeV to 10 TeV.

20.
Fish Physiol Biochem ; 44(4): 1019-1026, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29725939

RESUMO

Cytochrome P450 enzymes (CYP enzymes) catalyze important metabolic reactions of exogenous and endogenous substrates, including fatty acid. In this study, we cloned the complete CDS of the cytochrome P450 2AA (CYP2AA) gene from the grass carp (Ctenopharyngodon idella) for the first time. CYP2AA consisted of 1500 bp, which encoded a predicted protein of 499 amino acids. The identities of CYP2AA between C. idella and zebrafish were 86%. It consists of the conserved heme-binding motif FXXGXXXCXG. Quantitative real-time PCR analysis indicated that CYP2AA mRNA in C. idella was highly expressed in liver and adipose tissue. The effects of fish oil and lard oil in diets on expression of CYP2AA mRNA in vivo were also investigated. The fish oil (FO) group exhibited significantly higher CYP2AA expression in adipose tissue than the lard oil (LO) group (P < 0.01), whereas the mRNA expression of CYP2AA was not notably different in liver. It suggested that the high abundance of CYP2AA mRNA expression in adipose tissue could be induced by fish oil. Our findings provided molecular characterization and expression profile of CYP2AA, and enhanced our understanding of CYP2AA in fish lipid metabolism.


Assuntos
Carpas/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Dieta , Proteínas de Peixes/genética , Transcriptoma , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Sequência de Bases , Carpas/crescimento & desenvolvimento , Clonagem Molecular , Gorduras na Dieta/administração & dosagem , Óleos de Peixe/administração & dosagem , Regulação da Expressão Gênica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Especificidade de Órgãos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Homologia de Sequência
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