Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 157
Filtrar
2.
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.

3.
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.

4.
Zhen Ci Yan Jiu ; 46(9): 775-81, 2021 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-34558244

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) on the expression of NF-κB p65 in hippocampus and the morphology of hippocampus in rats with chronic fatigue syndrome (CFS), so as to explore its mechanism in improving cognitive dysfunction of CFS. METHODS: Forty-eight SD rats were randomly divided into control, model, EA and inhibitor groups (n=12 in each group). The CFS model was established by multi-factor compound stress stimulation method. Rats of the EA group received EA (50 Hz, 1 mA) at "Baihui" (GV20), Emotional Area I and bilateral Sensory Area for 30 min, once daily for 15 days. For rats in the inhibitor group, pyrrolidine dithiocarbamate (100 mg·kg-1·d-1) was injected intraperitoneally, once a day for 15 days. Learning and memory ability was evaluated by Morris water maze test. HE staining was used to observe the morphology of hippocampus. Western blot was used to determine the expression level of NF-κB p65 in hippocampus. RESULTS: After mode-ling, the general status score was increased (P<0.01), the escape latency was prolonged(P<0.01), the times of crossing the platform was decreased(P<0.01), and the expression level of NF-κB p65 in hippocampus tissue was significantly increased (P<0.05) in the model group compared with the control group. Compared with the model group, the general status score was decreased (P<0.01), the escape latency was shortened(P<0.01), the times of crossing the platform was increased(P<0.01), and the expression level of NF-κB p65 in hippocampus tissue was significantly decreased (P<0.05) in the EA and inhibitor groups. HE staining showed that in the model group, the hippocampal nerve cells were arranged disorderly, the structure was loose, and the number of apoptotic bodies and inflammatory cells was significantly increased. The degree of tissue damage of the EA and inhibitor groups was milder than that of the model group. CONCLUSION: EA can improve the cognitive function in CFS rats, which may be associated with its effect in inhibiting the expression of NF-κB and reducing the inflammation response in hippocampus.


Assuntos
Doença de Alzheimer , Eletroacupuntura , Síndrome de Fadiga Crônica , Animais , Cognição , Síndrome de Fadiga Crônica/genética , Síndrome de Fadiga Crônica/terapia , Hipocampo , NF-kappa B/genética , Ratos , Ratos Sprague-Dawley
5.
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.

6.
Hepatology ; 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34297426

RESUMO

BACKGROUND AND AIMS: NASH is currently one of the most common causes of liver transplantation and hepatocellular carcinoma. Thus far, there is still no effective pharmacological therapy for this disease. Recently, Gastrodin has demonstrated hepatoprotective effects in a variety of liver diseases. The aim of this study is to investigate the function of Gastrodin in NASH. APPROACH AND RESULTS: In our study, Gastrodin showed potent therapeutic effects on NASH both in vivo and in vitro. In high-fat diet or high-fat and high-cholesterol diet-fed mice, the liver weight, hepatic and serum triglyceride and cholesterol contents, and serum alanine aminotransferase and aspartate aminotransferase activity levels were markedly reduced by Gastrodin treatment as compared with the corresponding vehicle groups. Notably, Gastrodin showed minimal effects on the function and histological characteristics of other major organs in mice. We further examined the effects of Gastrodin on lipid accumulation in primary mouse hepatocytes and human hepatocyte cell line and observed that Gastrodin showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress. Furthermore, RNA-sequencing analysis systemically indicated that Gastrodin suppressed the pathway and key regulators related to lipid accumulation, inflammation, and fibrosis in the pathogenesis of NASH. Mechanistically, we found that Gastrodin protected against NASH by activating the adenosine monophosphate-activated protein kinase (AMPK) pathway, which was supported by the result that the AMPK inhibitor Compound C or AMPK knockdown blocked the Gastrodin-mediated hepatoprotective effect. CONCLUSIONS: Gastrodin attenuates steatohepatitis by activating the AMPK pathway and represents a therapeutic for the treatment of NASH.

7.
Hepatology ; 2021 Jul 07.
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.

8.
Adv Mater ; 33(33): e2100972, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34247423

RESUMO

Understanding light-matter interactions in nanomaterials is crucial for optoelectronic, photonic, and plasmonic applications. Specifically, metal nanoparticles (NPs) strongly interact with light and can undergo shape transformations, fragmentation and ablation upon (pulsed) laser excitation. Despite being vital for technological applications, experimental insight into the underlying atomistic processes is still lacking due to the complexity of such measurements. Herein, atomic resolution electron tomography is performed on the same mesoporous-silica-coated gold nanorod, before and after femtosecond laser irradiation, to assess the missing information. Combined with molecular dynamics (MD) simulations based on the experimentally determined 3D atomic-scale morphology, the complex atomistic rearrangements, causing shape deformations and defect generation, are unraveled. These rearrangements are simultaneously driven by surface diffusion, facet restructuring, and strain formation, and are influenced by subtleties in the atomic distribution at the surface.

9.
Ann Palliat Med ; 10(7): 7329-7339, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34263624

RESUMO

BACKGROUND: This study aimed to build a radiomics model with deep learning (DL) and human auditing and examine its diagnostic value in differentiating between coronavirus disease 2019 (COVID-19) and community-acquired pneumonia (CAP). METHODS: Forty-three COVID-19 patients, whose diagnoses had been confirmed with reverse-transcriptase polymerase-chain-reaction (RT-PCR) tests, and 60 CAP patients, whose diagnoses had been confirmed with sputum cultures, were enrolled in this retrospective study. The candidate regions of interest (ROIs) on the computed tomography (CT) images of the 103 patients were determined using a DL-based segmentation model powered by transfer learning. These ROIs were manually audited and corrected by 3 radiologists (with an average of 12 years of experience; range 6-17 years) to check the segmentation acceptance for the radiomics analysis. ROI-derived radiomics features were subsequently extracted to build the classification model and processed using 4 different algorithms (L1 regularization, Lasso, Ridge, and Z test) and 4 classifiers, including the logistic regression (LR), multi-layer perceptron (MLP), support vector machine (SVM), and extreme Gradient Boosting (XGboost). A receiver operating characteristic curve (ROC) analysis was conducted to evaluate the performance of the model. RESULTS: Quantitative CT measurements derived from human-audited segmentation results showed that COVID-19 patients had significantly decreased numbers of infected lobes compared to patients in the CAP group {median [interquartile range (IQR)]: 4 [3, 4] and 4 [4, 5]; P=0.031}. The infected percentage (%) of the whole lung was significantly more elevated in the CAP group [6.40 (2.77, 11.11)] than the COVID-19 group [1.83 (0.65, 4.42); P<0.001], and the same trend applied to each lobe, except for the superior lobe of the right lung [1.81 (0.09, 5.28) for COVID-19 vs. 1.32 (0.14, 7.02) for CAP; P=0.649]. Additionally, the highest proportion of infected lesions were observed in the CT value range of (-470, -370) Hounsfield units (HU) in the COVID-19 group. Conversely, the CAP group had a value range of (30, 60) HU. Radiomic model using corrected ROIs exhibited the highest area under ROC (AUC) of 0.990 [95% confidence interval (CI): 0.962-1.000] using Lasso for feature selection and MLP for classification. CONCLUSIONS: The proposed radiomics model based on human-audited segmentation made accurate differential diagnoses of COVID-19 and CAP. The quantification of CT measurements derived from DL could potentially be used as effective biomarkers in current clinical practice.


Assuntos
COVID-19 , Aprendizado Profundo , Computadores , Humanos , Estudos Retrospectivos , SARS-CoV-2
10.
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.

11.
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.

12.
Cell Metab ; 33(7): 1372-1388.e7, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34146477

RESUMO

Nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma and liver disorders have become the leading causes for the need of liver transplantation in developed countries. Lipotoxicity plays a central role in NASH progression by causing endoplasmic reticulum stress and disrupting protein homeostasis. To identify key molecules that mitigate the detrimental consequences of lipotoxicity, we performed integrative multiomics analysis and identified the E3 ligase tripartite motif 16 (TRIM16) as a candidate molecule. In particular, we found that lipid accumulation and inflammation in a mouse NASH model is mitigated by TRIM16 overexpression but aggravated by its depletion. Multiomics analysis showed that TRIM16 suppressed NASH progression by attenuating the activation of the mitogen-activated protein kinase (MAPK) signaling pathway; specifically, by preferentially interacting with phospho-TAK1 to promote its degradation. Together, these results identify TRIM16 as a promising therapeutic target for the treatment of NASH.

13.
Cell Metab ; 33(8): 1640-1654.e8, 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34107313

RESUMO

Obesity is characterized by the excessive accumulation of the white adipose tissue (WAT), but healthy expansion of WAT via adipocyte hyperplasia can offset the negative metabolic effects of obesity. Thus, identification of novel adipogenesis regulators that promote hyperplasia may lead to effective therapies for obesity-induced metabolic disorders. Using transcriptomic approaches, we identified transmembrane BAX inhibitor motif-containing 1 (TMBIM1) as an inhibitor of adipogenesis. Gain or loss of function of TMBIM1 in preadipocytes inhibited or promoted adipogenesis, respectively. In vivo, in response to caloric excess, adipocyte precursor (AP)-specific Tmbim1 knockout (KO) mice displayed WAT hyperplasia and improved systemic metabolic health, while overexpression of Tmbim1 in transgenic mice showed the opposite effects. Moreover, mature adipocyte-specific Tmbim1 KO did not affect WAT cellularity or nutrient homeostasis. Mechanistically, TMBIM1 binds to and promotes the autoubiquitination and degradation of NEDD4, which is an E3 ligase that stabilizes PPARγ. Our data show that TMBIM1 is a potent repressor of adipogenesis and a potential therapeutic target for obesity-related metabolic disease.

14.
Mol Med Rep ; 24(1)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33955514

RESUMO

A hypertrophic scar (HPS) is characterized by abnormal cell proliferation and the overproduction of extracellular matrix. Currently, the treatment options available for this remain unsatisfactory. Innovative treatments are required to attenuate or prevent hypertrophic scarring and the present study searched for a drug capable of becoming a new preventative and therapeutic strategy. Although the underlying mechanisms have not been fully clarified; it is widely accepted that the TGF­ß1/SMAD3 signaling pathway serves an essential role in HPS formation. In the present study, a compound library consisting of clinically used drugs was screened for their inhibitory activity against the SMAD3 protein. The results indicated that ivermectin was able to suppress the phosphorylation of SMAD3. Therefore, the present study further investigated whether ivermectin exhibited antifibrotic effects on HPS fibroblasts. The results demonstrated that ivermectin inhibited the proliferation of HPS fibroblasts and significantly decreased the production of type I collagen, α­smooth muscle actin and cellular communication network factor 2, as determined by analyzing the mRNA and protein expression levels. In conclusion, the results of the present study suggested that ivermectin may be a promising therapeutic agent for HPS.


Assuntos
Actinas/metabolismo , Cicatriz Hipertrófica/tratamento farmacológico , Cicatriz Hipertrófica/metabolismo , Colágeno Tipo I/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Fibroblastos/metabolismo , Ivermectina/farmacologia , Actinas/genética , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/genética , Fator de Crescimento do Tecido Conjuntivo/genética , Regulação para Baixo/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Cultura Primária de Células , Proteína Smad3/antagonistas & inibidores , Proteína Smad3/metabolismo
15.
Cancer Med ; 10(12): 4164-4173, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33963688

RESUMO

BACKGROUND: Microsatellite instability (MSI) predetermines responses to adjuvant 5-fluorouracil and immunotherapy in rectal cancer and serves as a prognostic biomarker for clinical outcomes. Our objective was to develop and validate a deep learning model that could preoperatively predict the MSI status of rectal cancer based on magnetic resonance images. METHODS: This single-center retrospective study included 491 rectal cancer patients with pathologically proven microsatellite status. Patients were randomly divided into the training/validation cohort (n = 395) and the testing cohort (n = 96). A clinical model using logistic regression was constructed to discriminate MSI status using only clinical factors. Based on a modified MobileNetV2 architecture, deep learning models were tested for the predictive ability of MSI status from magnetic resonance images, with or without integrating clinical factors. RESULTS: The clinical model correctly classified 37.5% of MSI status in the testing cohort, with an AUC value of 0.573 (95% confidence interval [CI], 0.468 ~ 0.674). The pure imaging-based model and the combined model correctly classified 75.0% and 85.4% of MSI status in the testing cohort, with AUC values of 0.820 (95% CI, 0.718 ~ 0.884) and 0.868 (95% CI, 0.784 ~ 0.929), respectively. Both deep learning models performed better than the clinical model (p < 0.05). There was no statistically significant difference between the deep learning models with or without integrating clinical factors. CONCLUSIONS: Deep learning based on high-resolution T2-weighted magnetic resonance images showed a good predictive performance for MSI status in rectal cancer patients. The proposed model may help to identify patients who would benefit from chemotherapy or immunotherapy and determine individualized therapeutic strategies for these patients.

16.
Cell Metab ; 33(6): 1171-1186.e9, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33951476

RESUMO

Antihyperglycemic therapy is an important priority for the treatment of type 2 diabetes (T2D). Excessive hepatic glucose production (HGP) is a major cause of fasting hyperglycemia. Therefore, a better understanding of its regulation would be important to develop effective antihyperglycemic therapies. Using a gluconeogenesis-targeted kinome screening approach combined with transcriptome analyses, we uncovered Nemo-like kinase (NLK) as a potent suppressor of HGP. Mechanistically, NLK phosphorylates and promotes nuclear export of CRTC2 and FOXO1, two key regulators of hepatic gluconeogenesis, resulting in the proteasome-dependent degradation of the former and the inhibition of the self-transcriptional activity and expression of the latter. Importantly, the expression of NLK is downregulated in the liver of individuals with diabetes and in diabetic rodent models and restoring NLK expression in the mouse model ameliorates hyperglycemia. Therefore, our findings uncover NLK as a critical player in the gluconeogenic regulatory network and as a potential therapeutic target for T2D.

17.
Hepatology ; 74(3): 1319-1338, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33894019

RESUMO

BACKGROUND AND AIMS: NAFLD has become the most common liver disease worldwide but lacks a well-established pharmacological therapy. Here, we aimed to investigate the role of an E3 ligase SH3 domain-containing ring finger 2 (SH3RF2) in NAFLD and to further explore the underlying mechanisms. METHODS AND RESULTS: In this study, we found that SH3RF2 was suppressed in the setting of NAFLD across mice, monkeys, and clinical individuals. Based on a genetic interruption model, we further demonstrated that hepatocyte SH3RF2 deficiency markedly deteriorates lipid accumulation in cultured hepatocytes and diet-induced NAFLD mice. Mechanistically, SH3RF2 directly binds to ATP citrate lyase, the primary enzyme promoting cytosolic acetyl-coenzyme A production, and promotes its K48-linked ubiquitination-dependent degradation. Consistently, acetyl-coenzyme A was significantly accumulated in Sh3rf2-knockout hepatocytes and livers compared with wild-type controls, leading to enhanced de novo lipogenesis, cholesterol production, and resultant lipid deposition. CONCLUSION: SH3RF2 depletion in hepatocytes is a critical aggravator for NAFLD progression and therefore represents a promising therapeutic target for related liver diseases.

18.
ACS Omega ; 6(13): 9188-9195, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33842787

RESUMO

Although gold nanorods capped with hexadecyltrimethylammonium bromide (CTAB) have been prepared through the seed-mediated method for their use in diagnostics and therapeutics, the toxicity of AuNRs@CTAB limits their practical applications in the biomedical field. In this work, the synthesis and tuning of gold nanorods at very low concentrations of CTAB (as low as 0.008 M) was successfully achieved by using the seed-mediated method. Furthermore, we managed to optimize the growth conditions by changing the amount of seeds, AgNO3, and/or HCl. At low CTAB concentrations, gold nanorods with tunable size and aspect ratio, high monodispersity, and high purity were obtained and studied by UV-vis spectroscopy, transmission electron microscopy, and Mie-Gans theoretical calculations. This work revealed a method of nanoparticle growth that may be extended to synthesize other nanomaterials such as Ag, Cu, Pd, and Pt at such low CTAB concentrations.

19.
Hepatology ; 74(3): 1300-1318, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33768585

RESUMO

BACKGROUND AND AIMS: NAFLD prevalence has increased rapidly and become a major global health problem. Tumor necrosis factor α-induced protein 8-like 2 (TIPE2) plays a protective role in a cluster of liver diseases, such as autoimmune hepatitis, hepatitis B, and hepatocellular carcinoma. However, the function of TIPE2 in NAFLD remains unknown. Here, we investigated the role of TIPE2 in the development of NAFLD. APPROACH AND RESULTS: Our study found that in vitro overexpression or knockout of TIPE2 significantly ameliorated or aggravated lipid accumulation and inflammation in hepatocytes exposed to metabolic stimulation, respectively. Consistently, in vivo hepatic steatosis, insulin resistance, inflammation, and fibrosis were alleviated in hepatic Tipe2-transgenic mice but exaggerated in hepatic Tipe2-knockout mice treated by metabolic challenges. RNA sequencing revealed that TIPE2 was significantly associated with the mitogen-activated protein kinase pathway. Mechanistic experiments demonstrated that TIPE2 bound with transforming growth factor beta-activated kinase 1 (TAK1), prevented tumor necrosis factor receptor-associated factor 6-mediated TAK1 ubiquitination and subsequently inhibited the TAK1 phosphorylation and activation of TAK1-c-Jun N-terminal kinase (JNK)/p38 signaling. Further investigation showed that blocking the activity of TAK1 reversed the worsening of hepatic metabolic disorders and inflammation in hepatic-specific Tipe2-knockout hepatocytes and mice treated with metabolic stimulation. CONCLUSIONS: TIPE2 suppresses NAFLD advancement by blocking TAK1-JNK/p38 pathway and is a promising target molecule for NAFLD therapy.

20.
ACS Omega ; 6(10): 7034-7046, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33748617

RESUMO

Bimetallic nanorods are important colloidal nanoparticles for optical applications, sensing, and light-enhanced catalysis due to their versatile plasmonic properties. However, tuning the plasmonic resonances is challenging as it requires a simultaneous control over the particle shape, shell thickness, and morphology. Here, we show that we have full control over these parameters by performing metal overgrowth on gold nanorods within a mesoporous silica shell, resulting in Au-Ag, Au-Pd, and Au-Pt core-shell nanorods with precisely tunable plasmonic properties. The metal shell thickness was regulated via the precursor concentration and reaction time in the metal overgrowth. Control over the shell morphology was achieved via a thermal annealing, enabling a transition from rough nonepitaxial to smooth epitaxial Pd shells while retaining the anisotropic rod shape. The core-shell synthesis was successfully scaled up from micro- to milligrams, by controlling the kinetics of the metal overgrowth via the pH. By carefully tuning the structure, we optimized the plasmonic properties of the bimetallic core-shell nanorods for surface-enhanced Raman spectroscopy. The Raman signal was the most strongly enhanced by the Au core-Ag shell nanorods, which we explain using finite-difference time-domain calculations.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...