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1.
J Proteomics ; : 103683, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32058041

RESUMO

Obese subjects with non-alcoholic fatty liver disease (NAFLD) and considered metabolically healthy have not been well differentiated. In this study, obese subjects were divided into metabolic healthy obesity (MHO) and NAFLD groups. Liver tissues were sampled from these two types of subjects undergoing bariatric surgery, and proteins in the liver tissues that expressed differently between the two groups of subjects were identified by Tandem Mass Tags (TMT) assay. Compared with the MHO group, 132 proteins were found to be upregulated and 84 proteins were found to be downregulated (mainly localized in mitochondria) in NAFLD group. The KEGG pathway analysis showed that significantly upregulated metabolic pathways include PPAR signaling, ECM-receptor interaction and oxidative phosphorylation was significantly downregulated. The GO analysis revealed that upregulated proteins were involved in extracellular structure organization, extracellular matrix organization and downregulated proteins took part in the oxidation-reduction process and so on. FBLN5 and DHRS2 were further validated by Western blot, immunohistochemistry and ELISA. All results demonstrate that FBLN5 expression was significantly upregulated but DHRS2 was significantly downregulated. SIGNIFICANCE: The variation between MHO and NAFLD was studied by mass spectroscopy to evaluate the mechanism with which MHO subjects resist the harmful effects induced by obesity.

2.
Cell Mol Life Sci ; 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32088728

RESUMO

Hypoxia-inducible factors (HIFs) mediate metabolic reprogramming in response to hypoxia. However, the role of HIFs in branched-chain amino acid (BCAA) metabolism remains unknown. Here we show that hypoxia upregulates mRNA and protein levels of the BCAA transporter LAT1 and the BCAA metabolic enzyme BCAT1, but not their paralogs LAT2-4 and BCAT2, in human glioblastoma (GBM) cell lines as well as primary GBM cells. Hypoxia-induced LAT1 protein upregulation is mediated by both HIF-1 and HIF-2 in GBM cells. Although both HIF-1α and HIF-2α directly bind to the hypoxia response element at the first intron of the human BCAT1 gene, HIF-1α is exclusively responsible for hypoxia-induced BCAT1 expression in GBM cells. Knockout of HIF-1α and HIF-2α significantly reduces glutamate labeling from BCAAs in GBM cells under hypoxia, which provides functional evidence for HIF-mediated reprogramming of BCAA metabolism. Genetic or pharmacological inhibition of BCAT1 inhibits GBM cell growth under hypoxia. Together, these findings uncover a previously unrecognized HIF-dependent metabolic pathway that increases GBM cell growth under conditions of hypoxic stress.

3.
Cell Death Dis ; 11(2): 113, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041941

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

4.
Mol Genet Genomic Med ; : e1048, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31962008

RESUMO

BACKGROUND: Acute pancreatitis in pregnancy (APIP) is a life-threatening disease for both mother and fetus. To date, only three patients with recurrent hypertriglyceridemia-induced APIP (HTG-APIP) have been reported to carry rare variants in the lipoprotein lipase (LPL) gene, which encodes the key enzyme responsible for triglyceride (TG) metabolism. Coincidently, all three patients harbored LPL variants on both alleles and presented with complete or severe LPL deficiency. METHODS: The entire coding regions and splice junctions of LPL and four other TG metabolism genes (APOC2, APOA5, GPIHBP1, and LMF1) were analyzed by Sanger sequencing in a Han Chinese patient who had experienced two episodes of HTG-APIP. The impact of a novel LPL missense variant on LPL protein expression and activity was analyzed by transient expression in HEK293T cells. RESULTS: A novel heterozygous LPL missense variant, p.His210Leu (c.629A > T), was identified in our patient. This variant did not affect protein synthesis but significantly impaired LPL secretion and completely abolished the enzymatic activity of the mutant protein. CONCLUSION: This report describes the first identification and functional characterization of a heterozygous variant in the LPL that predisposed to recurrent HTG-APIP. Our findings confirm a major genetic contribution to the etiology of individual predisposition to HTG-APIP.

6.
Int J Oncol ; 56(1): 337-347, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746419

RESUMO

Hepatitis B virus (HBV) x protein (HBx) has been reported as the primary pathogenic factor involved in HBV­related liver cancer; however, the mechanisms underlying how HBx promotes tumor­associated invasion and metastasis remain unclear. Long noncoding RNA activated by transforming growth factor (TGF)­ß (lncRNA­ATB) is a novel oncogenic lncRNA stimulated by TGF­ß, which is closely associated with the invasion and metastasis of liver cancer. In the present study, whether lncRNA­ATB was involved in HBx­mediated hepatocarcinogenesis was investigated. The expression of lncRNA­ATB in 26 primary liver cancer tissues and lentivirus transfected HBx­HepG2 cell lines was detected, and it was revealed that more advanced tumor­node­metastasis staging and increased expression of lncRNA­ATB in liver cancer tissues were significantly associated with HBV infection. It was further demonstrated that the expression levels of lncRNA­ATB and TGF­ß were elevated in HepG2 cells following HBx­vector transfection, which was accompanied with increased autophagy. Conversely, knockdown of lncRNA­ATB or TGF­ß could suppress this effect. Furthermore, such suppression on autophagy in HepG2 cells could be alleviated by the induction of starvation. In addition, the invasive and migration abilities of HBx­HepG2 cells were increased compared with HepG2 cells, while knockdown of lncRNA­ATB or TGF­ß could reduce these abilities. In conclusion, the results of the present study revealed that HBx was closely associated with oncogenic lncRNA­ATB. HBx­induced autophagy could upregulate the expression of TGF­ß and lncRNA­ATB. This may be considered to be a potential mechanism underlying HBV­induced hepatocarcinogenesis.

7.
Arch Oral Biol ; 109: 104555, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31550570

RESUMO

OBJECTIVES: To assess the association between the promoter region of serotonin transporter (5-HTTLPR) gene polymorphism and recurrent aphthous stomatitis (RAS) occurrence. DESIGNS: We performed the meta-analysis to determine the potential association between 5-HTTLPR polymorphism and RAS. We retrieved revelant studies from the PubMed, Scopus, Embase, Web of Science and Cochrane Library databases up to January 2019. Data were analyzed for odd ratios with 95% confidence intervals using Revman 5.3 software. RESULTS: There were 4 studies in the meta-analysis, which included 291 RAS cases and 286 controls. It indicated a substantially augmented threat of RAS with respect to S vs. L (P =  0.005), SS vs. LL+LS (P < 0.0001) and SS vs. LL models (P < 0.00001), respectively. No heterogeneity was found between studies in all comparisons. CONCLUSIONS: The current meta-analysis provides evidence to prove the association between 5-HTTLPR polymorphism and RAS. Further studies should be performed to clarify the biochemical function and pathological role of 5-HTTLPR in the risk of RAS.


Assuntos
Regiões Promotoras Genéticas , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Estomatite Aftosa/genética , Genótipo , Humanos , Polimorfismo Genético , Recidiva
8.
Int J Cancer ; 146(2): 475-486, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31107971

RESUMO

Long noncoding RNAs (lncRNAs) promote cell proliferation, migration, invasion and castration resistance in prostate cancer (PCa). Understanding the inherited molecular mechanisms by which lncRNAs contribute to the progression of PCa to a lethal disease could have an important impact on cancer detection, diagnosis and prognosis. In our study, PCa-associated lncRNA transcripts from RNA-seq data were identified and screened via bioinformatics analysis, NCBI annotations and literature review. We identified a novel lncRNA, lncAPP (lncRNA activated in PCa progression), which activates in PCa progression and is expressed in primary tumor tissues and urine samples of patients with localized or advanced PCa. Urinary-based lncAPP is a promising biomarker for predicting PCa progression. In vitro and in vivo studies demonstrated that lncAPP enhanced cell proliferation and promoted migration and invasion. The underlying mechanism of lncRNA was investigated by RNA immunoprecipitation, dual-luciferase reporter system assay, etc. Upregulation of lncAPP promoted cell migration and invasion via competitively binding miR218 to facilitate ZEB2/CDH2 expression. In addition, in vivo subcutaneous tumor xenograft models and tail intravenously injection metastatic models were constructed to evaluate lncRNA function. Targeting lncAPP/miR218 axis in cell lines and tumor xenografts restrained tumor progression properties both in vitro and in vivo. These results establish that lncAPP/miR218 axis plays a critical role in PCa progression, and they also suggest new strategies to prevent tumor progression for therapeutic purposes.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias da Próstata/genética , RNA Longo não Codificante/metabolismo , Animais , Antígenos CD/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/urina , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , MicroRNAs/metabolismo , Gradação de Tumores , Invasividade Neoplásica/genética , Análise de Sequência com Séries de Oligonucleotídeos , Próstata/patologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/urina , RNA Longo não Codificante/genética , RNA Longo não Codificante/urina , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
9.
J Exp Clin Cancer Res ; 38(1): 489, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831037

RESUMO

BACKGROUND: Ischemia reperfusion injury (IRI) has been shown to increase the risk of tumor recurrence after liver surgery. Also, nonalcoholic fatty liver disease (NAFLD) is associated with increased HCC recurrence. ALOX12-12-HETE pathway is activated both in liver IRI and NASH. Also, ALOX12-12-HETE has been shown to mediate tumorigenesis and progression. Therefore, our study aims to investigate whether the ALOX12-12-HETE-GPR31 pathway involved in IRI induced HCC recurrence in NAFLD. METHODS: HCC mouse model was used to mimic the HCC recurrence in NAFLD. Western Blot, qPCR, Elisa and Immunofluorescence analysis were conducted to evaluate the changes of multiple signaling pathways during HCC recurrence, including ALOX12-12-HETE axis, EMT, MMPs and PI3K/AKT/NF-κB signaling pathway. We also measured the expression and functional changes of GPR31 by siRNA. RESULTS: ALOX12-12-HETE pathway was activated in liver IRI and its activation was further enhanced in NAFLD, which induced more severe HCC recurrence in fatty livers than normal livers. Inhibition of ALOX12-12-HETE by ML355 reduced the HCC recurrence in fatty livers. In vitro studies showed that 12-HETE increased the expression of GPR31 and induced epithelial-mesenchymal transition (EMT) and matrix metalloprotein (MMPs) by activating PI3K/AKT/NF-κB pathway. Furthermore, knockdown of GPR31 in cancer cells inhibited the HCC recurrence in NAFLD. CONCLUSIONS: ALOX12-12-HETE-GPR31 played an important role in HCC recurrence and might be a potential therapeutic target to reduce HCC recurrence after surgery in fatty livers.

10.
Cell Death Differ ; 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31857702

RESUMO

The treatment of castration-resistant prostate cancer (CRPC) still faces many challenges. Docetaxel is a chemotherapeutic drug commonly used in CRPC patients. However, docetaxel-based chemotherapy usually causes docetaxel resistance, partially due to the resistance of CRPC cells to docetaxel-induced apoptosis. Here, we report that the deubiquitinating enzyme ubiquitin-specific protease 33 (USP33) inhibits docetaxel-induced apoptosis of prostate cancer cells, including androgen-independent prostate cancer cells. USP33 is overexpressed in prostate cancer cells and tissues. We found that knockdown or knockout of USP33 enhanced docetaxel-induced apoptosis of prostate cancer cells, accompanied by increased phosphorylation of the cJUN NH2-terminal kinase (JNK). After blocking docetaxel-induced JNK activation using the JNK inhibitor SP600125 or siRNA targeting JNK, the USP33 knockout-enhanced apoptosis was reversed. Furthermore, we found that USP33 could interact with the phosphatase DUSP1 to negatively regulate the activation of JNK, while USP33 knockdown promoted the proteasomal degradation of DUSP1. Mechanistically, we found that USP33 could inhibit the Lys48 (K48)-linked polyubiquitination of DUSP1. More importantly, DUSP1 overexpression could reverse the USP33 knockdown-induced JNK activation and apoptosis in docetaxel-treated prostate cancer cells. Therefore, USP33 overexpression in prostate cancer may contribute to docetaxel resistance by inhibiting the degradation of its partner DUSP1, leading to impaired JNK activation and apoptosis. Our study suggests that USP33-DUSP1-JNK may be a key signalling module mediating the docetaxel resistance of CRPC, indicating that USP33 is a potential novel therapeutic target in CRPC.

11.
Curr Pharm Des ; 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31880242

RESUMO

BACKGROUND: Ghrelin (GHRL) is a polypeptide, which can specifically bind to the GHSR. The expression of GHSR has significant differences in human normal and prostate cancer tissues. It is meaningful to find an effective diagnostic method for the diagnosis and prognosis of invasive/neuroendocrine prostate cancer. METHODS: GHRL and GHSR mRNAs level were determined by quantitative real-time polymerase chain reaction in PC tissues. The expression of GHRL and GHSR proteins were assessed respectively by western blot and immunohistochemistry. GHRL polypeptide probe was synthesized through standard solid-phase synthesis of polypeptide, and labeled with Alexa Fluor 660. Confocal microscope was used to capture fluorescence images. Living imaging analysis show tumor areas of different invasiveness in mice models. RESULTS: The level of GHRL and GHSR copy number amplification and mRNA expression were increased in invasive/neuroendocrine prostate cancer, and the protein expression of GHRL and GHSR were similarly boosting in NEPC. The GHRL polypeptide probe could effectively bind to GHSR. In PC3, we found that GHRL probe specifically bind to GHSR on cell membrane and accumulated in cells through internalization after binding. Living imaging in mice models showed that there were different signal intensities in tumor areas of different invasiveness. CONCLUSION: The GHSR and GHRL might be used to the molecular imaging diagnosis for invasive/neuroendocrine prostate cancer in future.

12.
J Phys Chem Lett ; 10(21): 6512-6517, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31597419

RESUMO

We report a comprehensive in-situ phase-change study on polycrystalline Sn0.98Se via high-temperature X-ray diffraction and in-situ high-voltage transmission electron microscopy from room temperature to 843 K. The results clearly demonstrate a continuous phase transition from Pnma to Cmcm starting from 573 to 843 K, rather than a sudden transition at 800 K. We also find that the thermal-conductivity rise at high temperature after the phase transition, as commonly seen in pristine SnSe, does not occur in Sn0.98Se, leading to a high thermoelectric figure of merit. Density functional theory calculations reveal the origin to be the suppression of bipolar thermal conduction in the Cmcm phase of Sn0.98Se due to the enlarged bandgap. This work fills the gap of in-situ characterization on polycrystalline Sn0.98Se and provides new insights into the outstanding thermoelectric performance of polycrystalline Sn0.98Se.

13.
Med Sci Monit ; 25: 7488-7498, 2019 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-31587011

RESUMO

BACKGROUND Osteoarthritis (OA) is a joint disease characterized by articular cartilage degeneration and inflammation. We have previously clarified that a xanthan gum (XG) preparation exerts ameliorating effect on a rabbit OA model by regulating matrix metalloproteinase (MMP)-1 and MMP-3, which are critical proteins in the Wnt3a/ß-catenin pathway. Thus, it is reasonable to predict that the Wnt3a/ß-catenin pathway is involved in the treatment of OA with XG. MATERIAL AND METHODS The effect of XG in OA model animals were observed by hematoxylin and eosin staining (HE), Safranin O staining, and Fast Green staining. Articular cartilage degradation on the medial plateau sides was quantified using the modified Pritzker OARSI score. The levels of IL-6, TNF-alpha, and IL-1ß in synovial fluid were determined with ELISA. The protective effect of XG in rat chondrocytes was assessed by CCK8 assay. Moreover, activation of the Wnt3a/ß-catenin pathway and the expression of MMP13, ADAMTS5, aggrecan, and collagen II under the influence of XG was measured by Western blot and qRT-PCR. RESULTS Our results showed that XG reduced the OARSI score and the concentration of inflammatory cytokines in OA after intra-articular injection. XG acted on Wnt3a/ß-catenin in ATDC5 cells in a dose-dependent manner and exhibited a protective effect. XG also decreased the expression of MMP13 and ADAMTS5 and rescued the inhibition of aggrecan and collagen II expression in SNP-stimulated chondrocytes. CONCLUSIONS These results indicate that the effects of XG are related to the Wnt3a/ß-catenin pathway and XG suppresses matrix degradation by inhibiting the expression of MMPs and ADAMTS and promotes aggrecan and collagen II content in the ECM, indicating its favorable potential for use in OA therapy.

14.
Exp Ther Med ; 18(4): 3177-3183, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31555390

RESUMO

The aim of the present study was to determine the prognostic value of peroxisome proliferator-activated receptor-γ (PPAR-γ) and phosphatase and tensin homologue deleted on chromosome ten (PTEN) for bladder cancer. Data were collected from The Cancer Genome Atlas (TCGA), a public database, and were analyzed to assess PTEN and PPAR-γ heterogeneity as well as distinct trends in bladder cancers. Furthermore, PPAR-γ and PTEN expression levels and their association with one another were evaluated. Finally, the prognostic significance of PPAR-γ and PTEN for bladder cancer was validated in vivo using clinical samples. Based on the TCGA database, PTEN levels were significantly increased in bladder cancers (P<0.001); whereas PPAR-γ expression was downregulated in the same samples (P<0.05). Furthermore, linear correlation analysis indicated that in bladder cancers, PPAR-γ and PTEN are inversely correlated (P<0.001). The assessment and analysis of clinical samples revealed that PPAR-γ was significantly elevated in tumor tissues (P<0.001); however, PTEN was downregulated in cancer tissues (P<0.001). Furthermore, PPAR-γ expression determined by immunohistochemistry grey level (P=0.002) was also elevated in high-grade and invasive bladder cancers compared with low-grade and superficial tumors, whereas PTEN levels exhibited the opposite in this analysis (P=0.001). In individuals with lymphoid metastasis, PPAR-γ was significantly increased (P<0.001), and PTEN was significantly decreased (P<0.001). Pearson analysis revealed a significant negative correlation between PPAR-γ and PTEN expression (r=-0.604, P<0.05). In conclusion, tissue heterogeneity was observed with respect to PPAR-γ and PTEN expression in bladder cancer. PTEN and PPAR-γ expression are negatively correlated and may be excellent indicators of bladder cancer tumorigenesis and progression.

15.
Cancer Med ; 8(15): 6614-6623, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31517445

RESUMO

BACKGROUND: The use of alpha-fetoprotein (AFP) testing for the surveillance, diagnosis, and prognosis of hepatocellular carcinoma (HCC) remains controversial. Here, we compared AFP testing rates, elevated AFP rates, factors associated with elevated AFP levels, and prognostic factors associated with overall survival (OS) in HCC patients from different ethnic groups. METHODS: Patients with HCC were identified from the Surveillance, Epidemiology, and End Results registries. Race was categorized as white, black, and others. AFP testing rates and elevated AFP rates were analyzed. Multivariable logistic regression and Cox regression analyses were used to identify independent factors associated with elevated AFP levels and prognosis, respectively. All statistical tests were two sided. RESULTS: A proportion of 79.2% of total HCC patients had AFP testing reports; 77.3% of white, 79.7% of black, and 81.2% of other races underwent AFP testing. Compared with white and other races, black HCC patients had a higher rate of elevated AFP levels among all patients and the early-stage HCC patient cohort. Elevated AFP level was a significant prognostic factor for all HCC patients in different race groups. Factors associated with elevated AFP level and prognostic factors associated with OS varied significantly by race. CONCLUSIONS: AFP testing, elevated AFP rates, predictors of elevated AFP level, and prognostic factors associated with OS differed significantly according to race after adjusting for AFP levels among the three groups. AFP testing for the surveillance, diagnosis, and prognosis of HCC patients is strongly recommended, although racial disparities need to be considered.

16.
Biomed Res Int ; 2019: 9306803, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534967

RESUMO

Prostate cancer (PCa) incidence has been rising in Chinese population. Current PSA-based biopsy has limited positive rate. Our research focused on development of serum markers for the diagnosis of PCa in patients with elevated PSA. miRNAs are found to be aberrantly expressed in many types of cancer. They are readily detectable in plasma and serum. Currently, miRNAs are being evaluated as potential prognostic and diagnostic tools for many types of cancer. We first profiled global serum miRNAs in a pilot set of PCa and benign prostatic hyperplasia (BPH) cases undergoing TRUS-guided prostate biopsy due to elevated PSA levels. A total of 20 differentially expressed miRNAs were discovered by high throughput microarray for further testing using qRT-PCR. In the training phase with 78 PCa and 77 BPH cases, miR-365a-3p, miR-4286, miR-424-5p, miR-27a-3p, and miR-29b-3p were found to have potential diagnostic value. The Logistics regression equation was established by 5 parameters including PSA, prostate volume, miR-4286, miR-27a-3p, and miR-29b-3p and ROC analysis of this model was made with AUC up to 0.892 (95% CI: 0.832-0.937, sensitivity 78.95%, and specificity 92.21%). The panel had excellent diagnostic performance and its significance was confirmed in 100 serum samples in the validation cohort. Overall, we found a panel of serum microRNAs that have considerable clinical significance in detecting early-stage prostate cancer. When combined with PSA and prostate volume, these microRNAs exhibit favorable diagnostic potency.

17.
ACS Appl Mater Interfaces ; 11(34): 31237-31244, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31397997

RESUMO

Porous structure possesses full potentials to develop high-performance thermoelectric materials with low lattice thermal conductivity. In this study, the n-type porous nanostructured Bi2Te3 pellet is fabricated by sintering Bi2Te3 nanoplates synthesized with a facile solvothermal method. With adequate sublimations of Bi2TeO5 during the spark plasma sintering, homogeneously distributed pores and dense grain boundaries are successfully introduced into the Bi2Te3 matrix, causing strong phonon scatterings, from which an ultralow lattice thermal conductivity of <0.1 W m-1 K-1 is achieved in the porous nanostructured Bi2Te3 pellet. With the well-maintained decent electrical performance, a power factor of 10.57 µW cm-1 K-2 at 420 K, as well as the reduced lattice thermal conductivity, secured a promising zT value of 0.97 at 420 K, which is among the highest values reported for pure n-type Bi2Te3. This study provides the insight of realizing ultralow lattice thermal conductivity by synergistic phonon scatterings of pores and nanostructure in the n-type Bi2Te3-based thermoelectric materials.

18.
Redox Biol ; 26: 101302, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31442911

RESUMO

Activation of hepatic stellate cells (HSC) is a hallmark event in liver fibrosis. Accumulation of reactive oxygen species (ROS) serves as a driving force for HSC activation. The regulatory subunits of the NOX complex, NCF1 (p47phox) and NCF2 (p67phox), are up-regulated during HSC activation contributing to ROS production and liver fibrosis. The transcriptional mechanism underlying NCF1/2 up-regulation is not clear. In the present study we investigated the role of serum response factor (SRF) in HSC activation focusing on the transcriptional regulation of NCF1/2. We report that compared to wild type littermates HSC-conditional SRF knockout (CKO) mice exhibited a mortified phenotype of liver fibrosis induced by thioacetamide (TAA) injection or feeding with a methionine-and-choline deficient diet (MCD). More importantly, SRF deletion attenuated ROS levels in HSCs in vivo. Similarly, SRF knockdown in cultured HSCs suppressed ROS production in vitro. Further analysis revealed that SRF deficiency resulted in repression of NCF1/NCF2 expression. Mechanistically, SRF regulated epigenetic transcriptional activation of NCF1/NCF2 by interacting with and recruiting the histone acetyltransferase KAT8 during HSC activation. In conclusion, we propose that SRF integrates transcriptional activation of NCF1/NCF2 and ROS production to promote liver fibrosis.

19.
Cancer Cell ; 36(2): 179-193.e11, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31378681

RESUMO

Liver cancers are highly heterogeneous with poor prognosis and drug response. A better understanding between genetic alterations and drug responses would facilitate precision treatment for liver cancers. To characterize the landscape of pharmacogenomic interactions in liver cancers, we developed a protocol to establish human liver cancer cell models at a success rate of around 50% and generated the Liver Cancer Model Repository (LIMORE) with 81 cell models. LIMORE represented genomic and transcriptomic heterogeneity of primary cancers. Interrogation of the pharmacogenomic landscape of LIMORE discovered unexplored gene-drug associations, including synthetic lethalities to prevalent alterations in liver cancers. Moreover, predictive biomarker candidates were suggested for the selection of sorafenib-responding patients. LIMORE provides a rich resource facilitating drug discovery in liver cancers.

20.
Cell Death Dis ; 10(8): 555, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324751

RESUMO

Neuroinflammation is initiated in response to ischemic stroke, generally with the hallmarks of microglial activation and collateral brain injury contributed by robust inflammatory effects. Triggering receptor expressed on myeloid cells (TREM)-1, an amplifier of the innate immune response, is a critical regulator of inflammation. This study identified that microglial TREM-1 expression was upregulated following cerebral ischemic injury. After pharmacologic inhibition of TREM-1 with synthetic peptide LP17, ischemia-induced infarction and neuronal injury were substantially alleviated. Moreover, blockade of TREM-1 can potentiate cellular proliferation and synaptic plasticity in hippocampus, resulting in long-term functional improvement. Microglial M1 polarization and neutrophil recruitment were remarkably abrogated as mRNA levels of M1 markers, chemokines, and protein levels of myeloperoxidase and intracellular adhesion molecule-1 (ICAM-1) were decreased by LP17. Mechanistically, both in vivo and in vitro, we delineated that TREM-1 can activate downstream pro-inflammatory pathways, CARD9/NF-κB, and NLRP3/caspase-1, through interacting with spleen tyrosine kinase (SYK). In addition, TREM-1-induced SYK initiation was responsible for microglial pyroptosis by elevating levels of gasdermin D (GSDMD), N-terminal fragment of GSDMD (GSDMD-N), and forming GSDMD pores, which can facilitate the release of intracellular inflammatory factors, in microglia. In summary, microglial TREM-1 receptor yielded post-stroke neuroinflammatory damage via associating with SYK.

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