Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 639
Filtrar
1.
Hepatology ; 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34662438

RESUMO

BACKGROUND & AIMS: Ischemia reperfusion (I/R) injury is an inevitable complication of liver transplantation and compromises its prognosis. Glycosyltransferases have been recognized as promising targets for disease therapy, but their roles remain largely unknown in hepatic I/R injury. Here, we aim to demonstrate the exact function and molecular mechanism of a glycosyltransferase, N-Acetylgalactosaminyltransferase-4 (GALNT4), in hepatic I/R injury. APPROACH & RESULTS: Via an RNA-seq data-based correlation analysis, we found a close correlation between GALNT4 expression and hepatic I/R-related molecular events in murine model. The mRNA and protein expression of GALNT4 were markedly upregulated upon reperfusion surgery in both clinical samples from subjects underwent liver transplantation and mouse model. We found that GALNT4 deficiency significantly exacerbated I/R-induced liver damage, inflammation and cell death, whereas GALNT4 overexpression led to the opposite phenotypes. Our in-depth mechanistic exploration clarified that GALNT4 directly binds to the apoptosis signal-regulating kinase1 (ASK1) to inhibit its N-terminal dimerization and subsequent phosphorylation, leading to a robust inactivation of the downstream c-Jun N-terminal kinase (JNK) / p38 and nuclear factor kappa B (NF-κB) signalling. Intriguingly, the inhibitory capacity of GALNT4 on ASK1 activation is independent of its glycosyltransferase activity. CONCLUSIONS: GALNT4 represents a promising therapeutic target for liver I/R injury and improve liver surgery prognosis by inactivating ASK1-JNK/p38 signalling pathway.

2.
Medicine (Baltimore) ; 100(39): e27332, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596136

RESUMO

ABSTRACT: Growing evidence supports that the tumor microenvironment plays a key role in the development and progression of tumors. But immune microenvironment of hepatocellular carcinoma (HCC) has not yet been fully explored. In the present investigation, the clinical value and prognostic significance of immune-related genes in HCC were investigated.The immune and stromal scores of HCC were calculated through the application of Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data Algorithm based on the Cancer Genome Atlas database. Differentially expressed genes were identified using the "edgeR" package of the R software. Functional annotation and pathway enrichment were performed using "ggplots2" and "clusterProfiler" packages in R software. Protein-protein interaction network was constructed using STRING, and the hub genes were identified through the Cytoscape. Survival analysis was performed using Kaplan-Meier methods. Tumor Immune Estimation Resource algorithm was used to view the immune landscape of the microenvironment in HCC.Firstly, the immune and stromal scores of HCC were calculated and we found that the immune and stromal scores of HCC were closely related to the patients' prognosis. Then the differentially expressed genes were identified respectively stratified by the median value of the immune and stromal scores, and the immune-related genes that related to the prognosis in HCC patients were further identified. Functional enrichment analysis and protein-protein interaction networks further showed that these genes mainly participated in immune-related biological process. In addition, dendritic cells were found to be the most abundant in the microenvironment of HCC through Tumor Immune Estimation Resource algorithm and were significantly associated with the patients' prognosis. To robust the results, the immune-related genes were validated in an independent dataset from the Gene Expression Omnibus database.We arrived at a more comprehensive understanding of the microenvironment of HCC and extracted 7 immune-related genes that were significantly associated with the recurrence survival of HCC.


Assuntos
Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Microambiente Tumoral/imunologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Prognóstico , Mapas de Interação de Proteínas , Células Estromais , Microambiente Tumoral/genética
3.
Medicine (Baltimore) ; 100(36): e27116, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34516503

RESUMO

ABSTRACT: Low bone mineral density (BMD) was significantly related to the fracture of distal radius. Serum brain-derived neurotrophic factor (BDNF) level was closely related to BMD in spine and osteoporotic fractures. In this study, we aimed to explore the association of BDNF polymorphisms (rs6265 and rs7124442) with BMD and the fracture of distal radius.This retrospective study included 152 patients with distal radius fractures and 148 healthy controls. BDNF polymorphisms were detected via TaqMan allelic discrimination assay. BMD was evaluated through X-ray. Difference in features between cases and controls were compared adopting Chi-square test or t test. The associations of BDNF polymorphisms with fracture risk of distal radius and BMD were assessed employing χ2 test and expressed by odd ratios (ORs) with 95% confidence intervals (95% CIs).BMD was significantly decreased in patients with the fracture of distal radius than in healthy controls. The polymorphism rs6265 significantly increased the risk of distal radius fracture (adjustment: GA: OR = 1.724, 95%CI = 1.003 -2.951, P = .049; GG: OR = 2.415, 95%CI = 1.0219 -3.674, P = .005). Moreover, rs6265 genotypes GA (OR = 4.326, 95%CI = 1.725 -11.896, P = .003) and GG (OR = 13.285, 95%CI = 3.659 -51.072, P = .001) significantly increased BMD reduction. However, BDNF polymorphism rs7124442 had no obvious correlation with BMD or fracture risk.BMD was associated with BDNF rs6265 polymorphism. BDNF polymorphism rs6265 could elevate the risk of osteoporosis and distal radius fracture.


Assuntos
Doenças Ósseas Metabólicas/complicações , Predisposição Genética para Doença , Fraturas por Osteoporose/epidemiologia , Fraturas do Rádio/epidemiologia , Absorciometria de Fóton , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , China/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/genética , Fraturas do Rádio/etiologia , Fraturas do Rádio/genética , Estudos Retrospectivos , Fatores de Risco
4.
Cell Metab ; 33(10): 1943-1956.e2, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34478633

RESUMO

Metabolic dysfunction is becoming a predominant risk for the development of many comorbidities. Ischemic heart disease (IHD) still imposes the highest disease burden among all cardiovascular diseases worldwide. However, the contributions of metabolic risk factors to IHD over time have not been fully characterized. Here, we analyzed the global disease burden of IHD and 15 associated general risk factors from 1990 to 2019 by applying the methodology framework of the Global Burden of Disease Study. We found that the global death cases due to IHD increased steadily during that time frame, while the mortality rate gradually declined. Notably, metabolic risk factors have become the leading driver of IHD, which also largely contributed to the majority of IHD-related deaths shifting from developed countries to developing countries. These findings suggest an urgent need to implement effective measures to control metabolic risk factors to prevent further increases in IHD-related deaths.

5.
Cell Metab ; 33(10): 2059-2075.e10, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34536344

RESUMO

Myocardial ischemia-reperfusion (MIR) injury is a major cause of adverse outcomes of revascularization after myocardial infarction. To identify the fundamental regulator of reperfusion injury, we performed metabolomics profiling in plasma of individuals before and after revascularization and identified a marked accumulation of arachidonate 12-lipoxygenase (ALOX12)-dependent 12-HETE following revascularization. The potent induction of 12-HETE proceeded by reperfusion was conserved in post-MIR in mice, pigs, and monkeys. While genetic inhibition of Alox12 protected mouse hearts from reperfusion injury and remodeling, Alox12 overexpression exacerbated MIR injury. Remarkably, pharmacological inhibition of ALOX12 significantly reduced cardiac injury in mice, pigs, and monkeys. Unexpectedly, ALOX12 promotes cardiomyocyte injury beyond its enzymatic activity and production of 12-HETE but also by its suppression of AMPK activity via a direct interaction with its upstream kinase TAK1. Taken together, our study demonstrates that ALOX12 is a novel AMPK upstream regulator in the post-MIR heart and that it represents a conserved therapeutic target for the treatment of myocardial reperfusion injury.

6.
Nucleic Acids Res ; 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34581805

RESUMO

In order to uncover the meanings of 'book of life', 155 different biological language models (BLMs) for DNA, RNA and protein sequence analysis are discussed in this study, which are able to extract the linguistic properties of 'book of life'. We also extend the BLMs into a system called BioSeq-BLM for automatically representing and analyzing the sequence data. Experimental results show that the predictors generated by BioSeq-BLM achieve comparable or even obviously better performance than the exiting state-of-the-art predictors published in literatures, indicating that BioSeq-BLM will provide new approaches for biological sequence analysis based on natural language processing technologies, and contribute to the development of this very important field. In order to help the readers to use BioSeq-BLM for their own experiments, the corresponding web server and stand-alone package are established and released, which can be freely accessed at http://bliulab.net/BioSeq-BLM/.

7.
Nat Nanotechnol ; 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34531557

RESUMO

Converting CO2 emissions, powered by renewable electricity, to produce fuels and chemicals provides an elegant route towards a carbon-neutral energy cycle. Progress in the understanding and synthesis of Cu catalysts has spurred the explosive development of electrochemical CO2 reduction (CO2RR) technology to produce hydrocarbons and oxygenates; however, Cu, as the predominant catalyst, often exhibits limited selectivity and activity towards a specific product, leading to low productivity and substantial post-reaction purification. Here, we present a single-atom Pb-alloyed Cu catalyst (Pb1Cu) that can exclusively (~96% Faradaic efficiency) convert CO2 into formate with high activity in excess of 1 A cm-2. The Pb1Cu electrocatalyst converts CO2 into formate on the modulated Cu sites rather than on the isolated Pb. In situ spectroscopic evidence and theoretical calculations revealed that the activated Cu sites of the Pb1Cu catalyst regulate the first protonation step of the CO2RR and divert the CO2RR towards a HCOO* path rather than a COOH* path, thus thwarting the possibility of other products. We further showcase the continuous production of a pure formic acid solution at 100 mA cm-2 over 180 h using a solid electrolyte reactor and Pb1Cu.

8.
Sensors (Basel) ; 21(18)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34577406

RESUMO

Compressive Sensing (CS) has proved to be an effective theory in the field of image acquisition. However, in order to distinguish the difference between the measurement matrices, the CS imaging system needs to have a higher signal sampling accuracy. At the same time, affected by the noise of the light path and the circuit, the measurements finally obtained are noisy, which directly affects the imaging quality. We propose a dual-optical imaging system that uses the bidirectional reflection characteristics of digital micromirror devices (DMD) to simultaneously acquire CS measurements and images under the same viewing angle. Since deep neural networks have powerful modeling capabilities, we trained the filter network and the reconstruction network separately. The filter network is used to filter the noise in the measurements, and the reconstruction network is used to reconstruct the CS image. Experiments have proved that the method we proposed can filter the noise in the sampling process of the CS system, and can significantly improve the quality of image reconstruction under a variety of algorithms.


Assuntos
Compressão de Dados , Processamento de Imagem Assistida por Computador , Algoritmos , Redes Neurais de Computação , Imagens de Fantasmas
9.
Sensors (Basel) ; 21(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502760

RESUMO

A 3-aminopropyl-triethoxysilane (APES) fiber-optic sensor based on a Mach-Zehnder interferometer (MZI) was demonstrated. The MZI was constructed with a core-offset fusion single mode fiber (SMF) structure with a length of 3.0 cm. As APES gradually attaches to the MZI, the external environment of the MZI changes, which in turn causes change in the MZI's interference. That is the reason why we can obtain the relationships between the APES amount and resonance dip wavelength by measuring the transmission variations of the resonant dip wavelength of the MZI. The optimized amount of 1% APES for 3.0 cm MZI biosensors was 3 mL, whereas the optimized amount of 2% APES was 1.5 mL.


Assuntos
Técnicas Biossensoriais , Hominidae , Animais , Tecnologia de Fibra Óptica , Interferometria , Fibras Ópticas
10.
Hepatology ; 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34482560

RESUMO

BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is a complicated disease characterized by hepatocyte steatosis, inflammation infiltration, and liver fibrosis. Accumulating evidence suggests that the innate immunity plays a key role in NASH progression. Here, we aimed to reveal the role of melanoma-differentiation-associated gene 5 (MDA5, also known as Ifih1), a conventional innate immune regulator upon viral infection, in the progression of NASH and investigate its underlying mechanism. APPROACH AND RESULTS: We first examined the expression of MDA5 and found that MDA5 was markedly downregulated in the livers with NASH in human individuals and mice models. MDA5 overexpression significantly inhibited the free fatty acid (FFA) induced lipid accumulation and inflammation in hepatocyte in vitro, while MDA5 knockdown promotes hepatocyte lipotoxicity. Using hepatocyte-specific Mda5 gene knockout and transgenic mice, we found that diet induced hepatic steatosis, inflammation and liver fibrosis were markedly exacerbated by Mda5 deficiency but suppressed by Mda5 overexpression. Mechanistically, we found that the activation of ASK1-MAPK pathway was significantly inhibited by MDA5 but enhanced by MDA5 deletion. We further validated that MDA5 directly interacted with ASK1 and suppressed its N-terminal dimerization. Importantly, blockage of ASK1 with adenovirus expressing dominant negative ASK1 (dnASK1) obviously reversed the lipid accumulation and ASK1 pathway activation when Mda5 knockout. CONCLUSIONS: These data indicate that MDA5 is an essential suppressor in NASH, the findings support MDA5 as a novel regulator of ASK1 and a promising therapeutic target for NASH.

11.
Artigo em Inglês | MEDLINE | ID: mdl-34409582

RESUMO

Functional autoantibodies directed to the M2 muscarinic acetylcholine receptor (M2R) could affect the heart rate directly by altering cardiac M2R activity and/or indirectly by changing vagal-mediated cardiac M2R activity. We measured M2R autoantibody activity in sera from 10 subjects with postural tachycardia syndrome (POTS) and 5 healthy control subjects using a cell-based bioassay. Half of the POTS subjects demonstrated presence of elevated M2R autoantibody activity, while no significant M2R autoantibody activity was found in the healthy subjects. Serum-derived immunoglobulin G (IgG) from antibody-positive POTS patients induced a dose-dependent activation of M2R, which was blocked by the muscarinic antagonist atropine. Moreover, antibody-positive POTS IgG decreased the responsiveness to oxotremorine, an orthosteric muscarinic agonist, indicating an indirect inhibitory effect. These data suggest that M2R autoantibodies may contribute to the pathophysiology of POTS by increasing the normal vagal withdrawal during upright posture through its negative allosteric modulation of M2R activity. M2 muscarinic receptor-activating autoantibodies are present in a subgroup of patients with POTS and act as a negative allosteric modulator of the orthosteric ligand response.

12.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 50(3): 390-395, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34402254

RESUMO

Atherosclerosis is a common pathological change in cardiovascular disease. Vascular smooth muscle cell is the main source of plaque cell and extracellular matrix, and nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcription factor regulating the function of vascular smooth muscle cell. In the process of atherosclerosis, Nrf2 signaling pathway has the following regulatory effects on vascular smooth muscle cell: regulating the phenotype of vascular smooth muscle cell to change to the direction conducive to the alleviation of disease progression; inhibiting the proliferation and migration of vascular smooth muscle cell; mitigating the level of blood lipid; alleviating vascular smooth muscle cell calcification, aging and apoptosis process. This article reviews the specific mechanisms of Nrf2 regulating atherosclerosis, such as phenotypic transformation, proliferation and migration, lipid metabolism, calcification, aging and apoptosis in atherosclerosis, in order to provide a basis for understanding the molecular mechanism of atherosclerosis development and finding therapeutic targets.


Assuntos
Aterosclerose , Fator 2 Relacionado a NF-E2 , Movimento Celular , Proliferação de Células , Células Cultivadas , Humanos , Músculo Liso Vascular , Miócitos de Músculo Liso , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais
13.
Hepatology ; 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34435375

RESUMO

BACKGROUND & AIMS: Although the prevalence of nonalcoholic fatty liver disease (NAFLD) has risen dramatically to 25% of the adult population worldwide, there are as yet no approved pharmacological interventions for the disease due to uncertainty about the underlying molecular mechanisms. It is known that mitochondrial dysfunction is an important factor in the development of NAFLD. Mitochondrial antiviral signaling protein (MAVS) is a critical signaling adaptor for host defenses against viral infection. However, the role of MAVS in mitochondrial metabolism during NAFLD progression remains largely unknown. APPROACH & RESULTS: Based on expression analysis, we identified a marked downregulation of MAVS in hepatocytes during NAFLD progression. By employing MAVS global knockout and hepatocyte-specific MAVS knockout mice, we found that MAVS is protective against diet-induced NAFLD. MAVS deficiency induces extensive mitochondrial dysfunction during NAFLD pathogenesis which was confirmed as impaired mitochondrial respiratory capacity and membrane potential. Metabolomics data also showed the extensive metabolic disorders after MAVS deletion. Mechanistically, MAVS interacts with the N-terminal stretch of voltage-dependent anion channel 2 (VDAC2), which is required for the ability of MAVS to influence mitochondrial function and hepatic steatosis. CONCLUSIONS: In hepatocytes, MAVS plays an important role in protecting against NAFLD by helping to regulate healthy mitochondrial function. These findings provide new insights regarding the metabolic importance of conventional immune regulators and support the possibility that targeting MAVS may represent a new avenue for treating NAFLD.

14.
Sci Rep ; 11(1): 15305, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315926

RESUMO

An association between angiogenesis/inflammation status and tumor has been reported in various types of cancer. This study sought to assess the role of peripheral blood VEGF and some inflammation biomarkers in evaluating clinical response and prognosis in patients with non-operative esophageal squamous cell carcinoma (ESCC). Peripheral blood of 143 patients with non-operative ESCC at our institute was dynamically collected at 5 time points including 1 day before radiotherapy, during radiotherapy (15f), at the end of radiotherapy, 1 month after radiotherapy, and 3 months after radiotherapy. VEGF expression in the peripheral blood was detected and related inflammation biomarkers such as GPS, CAR and CLR were counted. Logistic regression and Cox regression were implemented respectively to analyze the correlation of each predictor with clinical response and prognosis. The performance of combined testing was estimated using AUCs. Based on independent predictors, a nomogram prediction model was established to predict the probabilities of 1- and 2-year PFS of patients. The effectiveness of the nomogram model was characterized by C-index, AUC, calibration curves and DCA. VEGF and CLR levels at the end of radiotherapy were independent predictors of clinical response, while VEGF and GPS levels at 3 months after radiotherapy were independent prognostic predictors. The efficacy of combined detection of VEGF and CLR is superior to the single detection in evaluating clinical response and prognosis. The nomogram showed excellent accuracy in predicting PFS. The combined detection of VEGF and CLR at the end of radiotherapy can be used to evaluate the clinical response of patients with non-operative ESCC, and the combined detection of VEGF and GPS 3 months after radiotherapy can be used to predict the prognosis. Implemented by nomogram model, it is expected to provide practical and reliable method to evaluate the clinical response and prognosis of patients with non-operative ESCC tool.

15.
Hepatology ; 74(5): 2508-2525, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34231239

RESUMO

BACKGROUND AND AIMS: NAFLD is the most prevalent chronic liver disease without any Food and Drug Administration-approved pharmacological intervention in clinic. Fatty acid synthase (FASN) is one of the most attractive targets for NAFLD treatment because of its robust rate-limiting capacity to control hepatic de novo lipogenesis. However, the regulatory mechanisms of FASN in NAFLD and potential therapeutic strategies targeting FASN remain largely unknown. METHODS AND RESULTS: Through a systematic interactomics analysis of FASN-complex proteins, we screened and identified sorting nexin 8 (SNX8) as a binding partner of FASN. SNX8 directly bound to FASN and promoted FASN ubiquitination and subsequent proteasomal degradation. We further demonstrated that SNX8 mediated FASN protein degradation by recruiting the E3 ligase tripartite motif containing 28 (TRIM28) and enhancing the TRIM28-FASN interaction. Notably, Snx8 interference in hepatocytes significantly deteriorated lipid accumulation in vitro, whereas SNX8 overexpression markedly blocked hepatocyte lipid deposition. Furthermore, the aggravating effect of Snx8 deletion on NAFLD was validated in vivo as hepatic steatosis and lipogenic pathways in the liver were significantly exacerbated in Snx8-knockout mice compared to wild-type controls. Consistently, hepatocyte-specific overexpression of Snx8 in vivo markedly suppressed high-fat, high-cholesterol diet (HFHC)-induced hepatic steatosis. Notably, the protective effect of SNX8 against NAFLD was largely dependent on FASN suppression. CONCLUSIONS: These data indicate that SNX8 is a key suppressor of NAFLD that promotes FASN proteasomal degradation. Targeting the SNX8-FASN axis is a promising strategy for NAFLD prevention and treatment.

17.
Front Genet ; 12: 626710, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194465

RESUMO

The ancestral origin and genomic history of Chinese Hui people remain to be explored due to the paucity of genome-wide data. Some evidence argues that an eastward migration of Central Asians gave rise to modern Hui people, which is referred to as the demic diffusion hypothesis; other evidence favors the cultural diffusion hypothesis, which posits that East Asians adopted Muslim culture to form the modern culturally distinct populations. However, the extent to which the observed genetic structure of the Huis was mediated by the movement of people or the assimilation of Muslim culture also remains highly contentious. Analyses of over 700 K SNPs in 109 western Chinese individuals (49 Sichuan Huis and 60 geographically close Nanchong Hans) together with the available ancient and modern Eurasian sequences allowed us to fully explore the genomic makeup and origin of Hui and neighboring Han populations. The results from PCA, ADMIXTURE, and allele-sharing-based f-statistics revealed a strong genomic affinity between Sichuan Huis and Neolithic-to-modern Northern East Asians, which suggested a massive gene influx from East Asians into the Sichuan Hui people. Three-way admixture models in the qpWave/qpAdm analyses further revealed a small stream of gene influx from western Eurasians into the Sichuan Hui people, which was further directly confirmed via the admixture event from the temporally distinct Western sources to Sichuan Hui people in the qpGraph-based phylogenetic model, suggesting the key role of the cultural diffusion model in the genetic formation of the Sichuan Huis. ALDER-based admixture date estimation showed that this observed western Eurasian admixture signal was introduced into the Sichuan Huis during the historic periods, which was concordant with the extensive western-eastern communication along the Silk Road and historically documented Huis' migration history. In summary, although significant cultural differentiation exists between Hui people and their neighbors, our genomic analysis showed their strong genetic affinity with modern and ancient Northern East Asians. Our results support the hypothesis that the Sichuan Huis arose from a mixture of minor western Eurasian ancestry and predominant East Asian ancestry.

18.
Hepatology ; 2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34272738

RESUMO

BACKGROUND AND AIMS: NAFLD is the most prevalent chronic liver disease worldwide, but no effective pharmacological therapeutics are available for clinical use. NASH is the more severe stage of NAFLD. During this progress, dysregulation of endoplasmic reticulum (ER)-related pathways and proteins is one of the predominant hallmarks. We aimed to reveal the role of ring finger protein 5 (RNF5), an ER-localized E3 ubiquitin-protein ligase, in NASH and to explore its underlying mechanism. APPROACH AND RESULTS: We first inspected the expression level of RNF5 and found that it was markedly decreased in livers with NASH in multiple species including humans. We then introduced adenoviruses for Rnf5 overexpression or knockdown into primary mouse hepatocytes and found that palmitic acid/oleic acid (PAOA)-induced lipid accumulation and inflammation in hepatocytes were markedly attenuated by Rnf5 overexpression but exacerbated by Rnf5 gene silencing. Hepatocyte-specific Rnf5 knockout significantly exacerbated hepatic steatosis, inflammatory response, and fibrosis in mice challenged with diet-induced NASH. Mechanistically, we identified 3-hydroxy-3-methylglutaryl CoA reductase degradation protein 1 (HRD1) as a binding partner of RNF5 by systematic interactomics analysis. RNF5 directly bound to HRD1 and promoted its lysine 48 (K48)-linked and K33-linked ubiquitination and subsequent proteasomal degradation. Furthermore, Hrd1 overexpression significantly exacerbated PAOA-induced lipid accumulation and inflammation, and short hairpin RNA-mediated Hrd1 knockdown exerted the opposite effects. Notably, Hrd1 knockdown significantly diminished PAOA-induced lipid deposition, and up-regulation of related genes resulted from Rnf5 ablation in hepatocytes. CONCLUSIONS: These data indicate that RNF5 inhibits NASH progression by targeting HRD1 in the ubiquitin-mediated proteasomal pathway. Targeting the RNF5-HRD1 axis may provide insights into the pathogenesis of NASH and pave the way for developing strategies for NASH prevention and treatment.

19.
Artigo em Inglês | MEDLINE | ID: mdl-34309996

RESUMO

Abundant and affordable methane is not only a high-quality fossil fuel, it is also a raw material for the synthesis of value-added chemicals. Solar-energy-driven conversion of methane offers a promising approach to directly transform methane to valuable energy sources under mild conditions, but remains a great challenge at present. In this Review, recent advances in the photocatalytic conversion of methane are systematically summarized. Insights into the construction of effective semiconductor-based photocatalysts from the perspective of light-absorption units and active centers are highlighted and discussed in detail. The performance of various photocatalysts in the conversion of methane is presented, with the photooxidation classified according to the oxidant systems. Lastly, challenges and future perspectives in the photocatalytic oxidation of methane are described.

20.
Hepatology ; 74(4): 2133-2153, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34133792

RESUMO

BACKGROUND AND AIMS: Hepatic ischemia/reperfusion (I/R) injury, a common clinical problem that occurs during liver surgical procedures, causes a large proportion of early graft failure and organ rejection cases. The identification of key regulators of hepatic I/R injury may provide potential strategies to clinically improve the prognosis of liver surgery. Here, we aimed to identify the role of tumor necrosis factor alpha-induced protein 3-interacting protein 3 (TNIP3) in hepatic I/R injury and further reveal its immanent mechanisms. APPROACH AND RESULTS: In the present study, we found that hepatocyte TNIP3 was markedly up-regulated in livers of both persons and mice subjected to I/R surgery. Hepatocyte-specific Tnip3 overexpression effectively attenuated I/R-induced liver necrosis and inflammation, but improved cell proliferation in mice, whereas TNIP3 ablation largely aggravated liver injury. This inhibitory effect of TNIP3 on hepatic I/R injury was found to be dependent on significant activation of the Hippo-YAP signaling pathway. Mechanistically, TNIP3 was found to directly interact with large tumor suppressor 2 (LATS2) and promote neuronal precursor cell-expressed developmentally down-regulated 4-mediated LATS2 ubiquitination, leading to decreased Yes-associated protein (YAP) phosphorylation at serine 112 and the activated transcription of factors downstream of YAP. Notably, adeno-associated virus delivered TNIP3 expression in the liver substantially blocked I/R injury in mice. CONCLUSIONS: TNIP3 is a regulator of hepatic I/R injury that alleviates cell death and inflammation by assisting ubiquitination and degradation of LATS2 and the resultant YAP activation.TNIP3 represents a promising therapeutic target for hepatic I/R injury to improve the prognosis of liver surgery.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...