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With the increased prevalence of nonalcoholic steatohepatitis (NASH) in the world, effective pharmacotherapy in clinical practice is still lacking. Previous studies have shown that dibenzazepine (DBZ), a Notch inhibitor, could alleviate NASH development in a mouse model. However, low bioavailability, poor water solubility, and extrahepatic side effects restrict its clinical application. To overcome these barriers, we developed a reactive oxygen species (ROS)-sensitive nanoparticle based on the conjugation of bilirubin to poly(ethylene glycol) (PEG) chains, taking into account the overaccumulation of hepatic ROS in the pathologic state of nonalcoholic steatohepatitis (NASH). The PEGylated bilirubin can self-assemble into nanoparticles in an aqueous solution and encapsulate insoluble DBZ into its hydrophobic cavity. DBZ nanoparticles (DBZ Nps) had good stability, rapidly released DBZ in response to H2O2, and effectively scavenged intracellular ROS of hepatocytes. After systemic administration, DBZ Nps could accumulate in the liver of the NASH mice, extend persistence in circulation, and improve the bioavailability of DBZ. Furthermore, DBZ Nps significantly improved glucose intolerance, relieved hepatic lipid accumulation and inflammation, and ameliorated NASH-induced liver fibrosis. Additionally, DBZ Nps had no significant extrahepatic side effects. Taken together, our results highlight the potential of the ROS-sensitive DBZ nanoparticle as a promising therapeutic strategy for NASH.
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Lipogênese , Fígado , Camundongos Endogâmicos C57BL , Nanopartículas , Hepatopatia Gordurosa não Alcoólica , Espécies Reativas de Oxigênio , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Nanopartículas/química , Lipogênese/efeitos dos fármacos , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Receptores Notch/metabolismo , Receptores Notch/antagonistas & inibidores , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Bilirrubina , Polietilenoglicóis/química , Modelos Animais de Doenças , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , DibenzazepinasRESUMO
Metabolic diseases are a series of metabolic disorders that include obesity, diabetes, insulin resistance, hypertension, and hyperlipidemia. The increased prevalence of metabolic diseases has resulted in higher mortality and mobility rates over the past decades, and this has led to extensive research focusing on the underlying mechanisms. Xenobiotic receptors (XRs) are a series of xenobiotic-sensing nuclear receptors that regulate their downstream target genes expression, thus defending the body from xenobiotic and endotoxin attacks. XR activation is associated with the development of a number of metabolic diseases such as obesity, nonalcoholic fatty liver disease, type 2 diabetes, and cardiovascular diseases, thus suggesting an important role for XRs in modulating metabolic diseases. However, the regulatory mechanism of XRs in the context of metabolic disorders under different nutrient conditions is complex and remains controversial. This review summarizes the effects of XRs on different metabolic components (cholesterol, lipids, glucose, and bile acids) in different tissues during metabolic diseases. As chronic inflammation plays a critical role in the initiation and progression of metabolic diseases, we also discuss the impact of XRs on inflammation to comprehensively recognize the role of XRs in metabolic diseases. This will provide new ideas for treating metabolic diseases by targeting XRs. SIGNIFICANCE STATEMENT: This review outlines the current understanding of xenobiotic receptors on nutrient metabolism and inflammation during metabolic diseases. This work also highlights the gaps in this field, which can be used to direct the future investigations on metabolic diseases treatment by targeting xenobiotic receptors.
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Diabetes Mellitus Tipo 2 , Doenças Metabólicas , Humanos , Xenobióticos/metabolismo , Inflamação , Obesidade/metabolismoRESUMO
Adipose tissue inflammation, as defined by macrophage accumulation, is proposed to cause insulin resistance and systemic inflammation. Because the strength of this relationship for humans is unclear, we tested whether adipose tissue macrophage (ATM) burden is correlated with these health indicators. Using immunohistochemistry, we measured abdominal subcutaneous CD68+ (total ATM), CD14+ (proinflammatory/M1), and CD206+ (anti-inflammatory/M2) ATM in 97 volunteers (BMI 20-38 kg/m2, in addition to body composition, adipocyte size, homeostasis model assessment of insulin resistance, ADIPO-IR, adipose tissue insulin resistance measured by palmitate, plasma lipids, TNF, and IL-6 concentrations. There were several significant univariate correlations between metabolic parameters to IL-6 and ATM per 100 adipocytes, but not ATM per gram tissue; adipocyte size was a confounding variable. We used matching strategies and multivariate regression analyses to investigate the relationships between ATM and inflammatory/metabolic parameters independent of adipocyte size. Matching approaches revealed that the groups discordant for CD206 but concordant for adipocyte size had significantly different fasting insulin and IL-6 concentrations. However, groups discordant for adipocyte size but concordent for ATM differeded in that visceral fat, plasma triglyceride, glucose, and TNF concentrations were greater in those with large adipocytes. Multivariate regression analysis indicated that indexes of insulin resistance and fasting triglycerides were predicted by body composition; the predictive value of ATM per 100 adipocytes or per gram tissue was variable between males and females. We conclude that the relationship between ATM burden and metabolic/inflammatory variables is confounded by adipocyte size/body composition and that ATM do not predict insulin resistance, systemic inflammation, or dyslipidemia. ATM may primarily play a role in tissue remodeling rather than in metabolic pathology.
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Tecido Adiposo/patologia , Inflamação/patologia , Resistência à Insulina/fisiologia , Macrófagos/patologia , Gordura Abdominal/química , Adipócitos/patologia , Adulto , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Composição Corporal , Índice de Massa Corporal , Feminino , Humanos , Lectinas Tipo C/análise , Receptores de Lipopolissacarídeos/análise , Masculino , Receptor de Manose , Lectinas de Ligação a Manose/análise , Pessoa de Meia-Idade , Obesidade/patologia , Receptores de Superfície Celular/análise , Gordura Subcutânea/químicaRESUMO
The association between the Arg194Trp polymorphism in the XRCC1 gene and the risk of hematological malignancies has been extensively investigated. However, the results were inconsistent. The objective of the current study is to investigate the association by meta-analysis. We searched the PubMed, Embase, CNKI, Wanfang, and Weipu databases, covering all studies until Aug. 7, 2013. Statistical analysis was performed by using the RevMan4.2 software and the Stata10.0 software. A total of 20 case-control studies concerning the Arg194Trp polymorphism were indentified from 19 articles. In total analysis, our results suggested that the Arg194Trp polymorphism was not associated with an increased/decreased risk of hematological malignancies (odds ratio (OR) = 1.01, 95 % confidence interval (CI) = 0.85-1.22, P = 0.87 for Arg/Trp+Trp/Trp vs. Arg/Arg). In the subgroup analysis by ethnicity, no significant association was found either among Asians (OR = 1.04, 95% CI = 0.84-1.29, P = 0.72) or among Europeans (OR = 1.04, 95% CI = 0.72-1.49, P = 0.83); in the subgroup analyses by cancer types, no significant association was found either among leukemia (OR = 1.10, 95% CI = 0.89-1.35, P = 0.39) or in lymphoma (OR = 0.83, 95% CI = 0.57-1.22, P = 0.35). The current meta-analysis indicated that the Arg194Trp polymorphism in the XRCC1 gene might be not a risk factor for hematological malignancies. In the future, more large-scale case-control studies are needed to validate these results.
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Proteínas de Ligação a DNA/genética , Neoplasias Hematológicas/genética , Polimorfismo Genético , Estudos de Casos e Controles , Neoplasias Hematológicas/etiologia , Humanos , Risco , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
The Glu298Asp polymorphism in the NOS3 gene has been implicated as a risk factor for prostate cancer. To date, several studies have evaluated the associations between the Glu298Asp polymorphism and prostate cancer risk; however, the results were inconclusive. The aim of the current study was to perform a meta-analysis to investigate the association between the polymorphism and the risk of prostate cancer. A total of 3,206 cases and 3,880 controls from eight case-control studies were included for data synthesis. The overall results suggested no significant association between the polymorphism and the risk of prostate cancer (OR=1.01, 95% CI=0.92-1.11, p = 0.83 for Asp/Asp+Glu/Asp vs. Glu/Glu). In the stratified analysis according to ethnicity, no significant associations were observed in Asians and Europeans. The current meta-analysis suggested that the Glu298Asp polymorphism of the NOS3 gene might not contribute to the risk of prostate cancer.
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Predisposição Genética para Doença , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo Genético , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Humanos , Masculino , Neoplasias da Próstata/etiologia , RiscoRESUMO
The -786T > C polymorphism in NOS3 gene may affect the DNA repair pathways and be associated with risk of cancer. However, the results of previous studies are inconsistent. The objective of this study is to investigate the association between the -786T > C polymorphism in NOS3 and risk of cancer by meta-analysis. We searched PubMed, Embase, CNKI, and Wanfang databases and the last search was updated on Sept. 20, 2013. Statistical analysis was performed using Revman4.2 and Stata10.0 software. A total of 9 case-control studies concerning 4,089 cases and 3,847 controls were included. The results suggested a significant association between the -786T > C polymorphism in NOS3 and cancer risk (CC vs. TT + CT; OR = 1.30, 95% CI = 1.07-1.57, P = 0.007) in total analysis. In the subgroup analysis by ethnicity and cancer types, significant associations were found in the breast cancer subgroup (OR 1.51, 95% CI 1.07-2.12; P = 0.02) and European subgroup (OR 1.26, 95% CI 1.01-1.58; P = 0.04). The current meta-analysis suggested that the -786T > C polymorphisms in NOS3 may be a risk factor for cancer. In the future, more case-control studies are needed to validate our results.
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Predisposição Genética para Doença , Neoplasias/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo Genético , Estudos de Casos e Controles , Humanos , Neoplasias/etiologia , Fatores de RiscoRESUMO
The Thr241Met polymorphism in XRCC3 gene may affect the DNA repair pathways and be associated with the risk of cancer. However, the results of previous studies are inconsistent in Chinese mainland populations. The objective of this study is to investigate the association between the Thr241Met polymorphism in XRCC3 gene and risk of cancer for the Chinese Mainland populations by meta-analysis. We searched PubMed database, Embase database, CNKI database, and Wanfang database, and the last search was updated on July 24, 2013. Statistical analysis was performed using RevMan4.2 and Stata10.0 software. Finally, a total of 23 case-control studies in 23 articles were included. The results suggested a significant association between the Thr241Met polymorphism in XRCC3 gene and cancer risk in Chinese mainland populations (Met/Met + Thr/Met vs. Thr/Thr: OR = 1.25, 95 % CI = 1.02-1.54, P = 0.04). In the subgroup analyses by cancer types, significant associations were found in cervical cancer and nasopharyngeal cancer. The current meta-analysis suggested that the Thr241Met polymorphism in the XRCC3 gene may be a risk factor for cancer in Chinese mainland populations. In the future, more case-control studies are needed to validate these results.
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Proteínas de Ligação a DNA/genética , Estudos de Associação Genética , Neoplasias/genética , Estudos de Casos e Controles , China , Genética Populacional , Humanos , Neoplasias/patologiaRESUMO
Pregnane X receptor (PXR) has been reported to regulate glycolipid metabolism. The dysfunction of intestinal barrier contributes to metabolic disorders. However, the role of intestinal PXR in metabolic diseases remains largely unknown. Here, we show that activation of PXR by tributyl citrate (TBC), an intestinal-selective PXR agonist, improves high fat diet (HFD)-induced obesity. The metabolic benefit of intestinal PXR activation is associated with upregulation of ß-1,3 galactosyltransferase 5 (B3galt5). Our results reveal that B3galt5 mainly expresses in the intestine and is a direct PXR transcriptional target. B3galt5 knockout exacerbates HFD-induced obesity, insulin resistance and inflammation. Mechanistically, B3galt5 is essential to maintain the integrity of intestinal mucus barrier. B3galt5 ablation impairs the O-glycosylation of mucin2, destabilizes the mucus layer, and increases intestinal permeability. Furthermore, B3galt5 deficiency abolishes the beneficial effect of intestinal PXR activation on metabolic disorders. Our results suggest the intestinal-selective PXR activation regulates B3galt5 expression and maintains metabolic homeostasis, making it a potential therapeutic strategy in obesity.
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Dieta Hiperlipídica , Galactosiltransferases , Resistência à Insulina , Mucosa Intestinal , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade , Receptor de Pregnano X , Animais , Obesidade/metabolismo , Obesidade/genética , Receptor de Pregnano X/metabolismo , Receptor de Pregnano X/genética , Galactosiltransferases/metabolismo , Galactosiltransferases/genética , Camundongos , Dieta Hiperlipídica/efeitos adversos , Mucosa Intestinal/metabolismo , Masculino , Intestinos , HumanosRESUMO
OBJECTIVE: To investigate the expression of 3-mercaptopyruvate sulfurtransferase (3MST) in medulla oblongata of neonatal rats and effects of intrauterine cigarette exposure on its expression. METHODS: Sprague Dawley pregnant rats were randomly divided into 2 groups, control group and cigarette smoke exposure group (n = 8). 3MST mRNA and protein expression in medulla oblongata of neonatal rats were analysed by RT-PCR and Western blot, respectively, and the expression of 3MST in the neurons of respiratory-related nuclei in medulla oblongata of neonatal rats was investigated with immunohistochemical technique. RESULTS: The RT-PCR and Western blot analyses showed that 3MST mRNA and protein were expressed in the medulla oblogata of neonatal rats and intrauterine cigarette exposure promoted their expression (P < 0.05). Immunohistochemical staining indicated that 3MST existed in the neurons of pre-Bötzinger complex (pre-BötC), hypoglossal nucleus (12N), ambiguous nucleus (Amb), facial nucleus (FN) and nucleus tractus solitarius (NTS) in control group of the animals and the mean optical densities of 3MST-positive neurons in the pre-BötC, 12N, Amb and FN, but not NTS, were significantly increased in cigarette smoke exposure group (P < 0.05). CONCLUSIONS: 3MST exists in the neurons of medullary respiratory nuclei of neonatal rats and its expression can be up-regulated by intrauterine cigarette exposure, suggesting that the 3MST-H2S pathway may be involved in protection of medullary respiratory centers against injury induced by intrauterine cigarette exposure.
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Bulbo/enzimologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Sulfurtransferases/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Animais Recém-Nascidos , Feminino , Masculino , Bulbo/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Sprague-Dawley , Sulfurtransferases/genética , Regulação para Cima/efeitos dos fármacosRESUMO
Wound healing is a sophisticated process consisting of serial phases with overlaps, including hemostasis, inflammation, proliferation, and remodeling. The inflammation response is an early response that plays a crucial role in eliminating microbes and clearing damaged cell debris. However, in some pathological circumstances, such as diabetes mellitus, ischemia, trauma, deep burn, etc., abnormal inflammation can cause impaired wound healing. Adipose-derived stem cells (ADSCs) belong to the mesenchymal stem cell (MSC) family and exhibit prospective applications in tissue regeneration and dermatological repairs. ADSC-secreted extracellular vesicles (ADSC-EVs) mimic the functions of ADSCs without the concerns of cell survival, immune response, or ethical issues. Studies have revealed that ADSC-EVs can inhibit abnormal inflammation responses and accelerate wound healing through various mechanisms. Moreover, some studies explored modifications in the cargo components of ADSC-EVs to enhance their therapeutic efficacy. Given the increasing studies focusing on the potential of ADSC-EVs in wound healing, how they interfere with different phases of this process has been investigated in pieces. In this review, we summarized all up-to-date evidence to map a clearer picture of the underlying mechanisms of ADSC-EVs in inflammation response. The applications of ADSC-EVs aiming at inflammation in the healing process were also reviewed to provide therapeutic strategies for future investigators.
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Activated hepatic stellate cells (HSCs) are considered the key driver of excessive extracellular matrix and abnormal angiogenesis, which are the main pathological manifestations of hepatic fibrosis. However, the absence of specific targeting moieties has rendered the development of HSC-targeted drug delivery systems a significant obstacle in the treatment of liver fibrosis. Here we have identified a notable increase in fibronectin expression on HSCs, which positively correlates with the progression of hepatic fibrosis. Thus, we decorated PEGylated liposomes with CREKA, a peptide with high affinity for fibronectin, to facilitate the targeted delivery of sorafenib to activated HSCs. The CREKA-coupled liposomes exhibited enhanced cellular uptake in the human hepatic stellate cell line LX2 and selective accumulation in CCl4-induced fibrotic liver through the recognition of fibronectin. When loaded with sorafenib, the CREKA-modified liposomes effectively suppressed HSC activation and collagen accumulation in vitro. Furthermore. in vivo results demonstrated that the administration of sorafenib-loaded CREKA-liposomes at a low dose significantly mitigated CCl4-induced hepatic fibrosis, prevented inflammatory infiltration and reduced angiogenesis in mice. These findings suggest that CREKA-coupled liposomes have promising potential as a targeted delivery system for therapeutic agents to activated HSCs, thereby providing an efficient treatment option for hepatic fibrosis. STATEMENT OF SIGNIFICANCE: In liver fibrosis, activated hepatic stellate cells (aHSCs) are the key driver of extracellular matrix and abnormal angiogenesis. Our investigation has revealed a significant elevation in fibronectin expression on aHSCs, which is positively associated with the progression of hepatic fibrosis. Thus, we developed PEGylated liposomes decorated with CREKA, a molecule with a high affinity for fibronectin, to facilitate the targeted delivery of sorafenib to aHSCs. The CREKA-coupled liposomes can specifically target aHSCs both in vitro and in vivo. Loading sorafenib into CREKA-Lip significantly alleviated CCl4-induced liver fibrosis, angiogenesis and inflammation at low doses. These findings suggest that our drug delivery system holds promise as a viable therapeutic option for liver fibrosis with minimal risk of adverse effects.
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Células Estreladas do Fígado , Lipossomos , Camundongos , Humanos , Animais , Células Estreladas do Fígado/metabolismo , Lipossomos/química , Fibronectinas/metabolismo , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Cirrose Hepática/metabolismo , Fígado/patologia , Polietilenoglicóis/farmacologiaRESUMO
Background: Cardiovascular diabetology is an emergent field focusing on all aspects of diabetes/cardiovascular interrelationship and metabolic syndrome. High-quality evidence needs to be provided to determine the efficacy and safety of interventions in cardiovascular diabetology. The heterogeneity of outcomes among trials limits the comparison of results, and some outcomes are not always meaningful to end-users. The cardiovascular diabetology core outcome set (COS) study aims to develop a COS of interventions for cardiovascular diabetology. In this paper, we introduce the methodological framework for developing the COS. Methods: The COS development will include the following steps: (a) establish the COS groups of stakeholders, including international steering committee, Delphi survey group, and consensus meeting group; (b) systematic reviews of outcomes used in trials of cardiovascular diabetology; (c) semistructured interview of stakeholders for outcomes of cardiovascular diabetology; (d) generate a list of candidate outcomes and determine the original outcome pool; (e) Delphi survey with stakeholders of cardiovascular diabetology to select potential core outcomes; and (f) review and endorse the cardiovascular diabetology COS by expert consensus meeting. Conclusions: This current study reports the methodological framework to develop a COS in cardiovascular diabetology and will provide evidence for the future development of COS in cardiovascular diabetology.
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Avaliação de Resultados em Cuidados de Saúde , Projetos de Pesquisa , Técnica Delphi , Determinação de Ponto Final , Avaliação de Resultados em Cuidados de Saúde/métodos , ConsensoRESUMO
Liver fibrosis is featured by activation of hepatic stellate cells (HSCs) and excessive accumulation of extracellular matrix (ECM). The Golgi apparatus in HSCs plays a vital role in synthesis and secretion of ECM proteins, while its targeted disruption in activated HSCs could be considered as a promising approach for liver fibrosis treatment. Here, we developed a multitask nanoparticle CREKA-CS-RA (CCR) to specifically target the Golgi apparatus of activated HSCs, based on CREKA (a specific ligand of fibronectin) and chondroitin sulfate (CS, a major ligand of CD44), in which retinoic acid (a Golgi apparatus-disturbing agent) chemically conjugated and vismodegib (a hedgehog inhibitor) encapsulated. Our results showed that CCR nanoparticles specifically targeted activated HSCs and preferentially accumulated in the Golgi apparatus. Systemic administration of CCR nanoparticles exhibited significantly accumulation in CCl4-induced fibrotic liver, which was attributed to specific recognition with fibronectin and CD44 on activated HSCs. CCR nanoparticles loaded with vismodegib not only disrupted Golgi apparatus structure and function but also inhibited the hedgehog signaling pathway, thus markedly suppressing HSC activation and ECM secretion in vitro and in vivo. Moreover, vismodegib-loaded CCR nanoparticles effectively inhibited the fibrogenic phenotype in CCl4-induced liver fibrosis mice without causing obvious toxicity. Collectively, these findings indicate that this multifunctional nanoparticle system can effectively deliver therapeutic agents to the Golgi apparatus of activated HSCs, thus has potential treatment of liver fibrosis with minimal side effects.
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Células Estreladas do Fígado , Nanopartículas , Camundongos , Animais , Proteínas Hedgehog/metabolismo , Fibronectinas/metabolismo , Ligantes , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Nanopartículas/química , Complexo de Golgi/metabolismo , Fígado/patologiaRESUMO
OBJECTIVE: Cholesterol gallstone disease (CGD) is closely related to cholesterol metabolic disorder. Glutaredoxin-1 (Glrx1) and Glrx1-related protein S-glutathionylation are increasingly being observed to drive various physiological and pathological processes, especially in metabolic diseases such as diabetes, obesity and fatty liver. However, Glrx1 has been minimally explored in cholesterol metabolism and gallstone disease. METHODS: We first investigated whether Glrx1 plays a role in gallstone formation in lithogenic diet-fed mice using immunoblotting and quantitative real-time PCR. Then a whole-body Glrx1-deficient (Glrx1-/-) mice and hepatic-specific Glrx1-overexpressing (AAV8-TBG-Glrx1) mice were generated, in which we analyzed the effects of Glrx1 on lipid metabolism upon LGD feeding. Quantitative proteomic analysis and immunoprecipitation (IP) of glutathionylated proteins were performed. RESULTS: We found that protein S-glutathionylation was markedly decreased and the deglutathionylating enzyme Glrx1 was greatly increased in the liver of lithogenic diet-fed mice. Glrx1-/- mice were protected from gallstone disease induced by a lithogenic diet because their biliary cholesterol and cholesterol saturation index (CSI) were reduced. Conversely, AAV8-TBG-Glrx1 mice showed greater gallstone progression with increased cholesterol secretion and CSI. Further studies showed that Glrx1-overexpressing greatly altered bile acid levels and/or composition to increase intestinal cholesterol absorption by upregulating Cyp8b1. In addition, liquid chromatography-mass spectrometry and IP analysis revealed that Glrx1 also affected the function of asialoglycoprotein receptor 1 (ASGR1) by mediating its deglutathionylation, thereby altering the expression of LXRα and controlling cholesterol secretion. CONCLUSION: Our findings present novel roles of Glrx1 and Glrx1-regulated protein S-glutathionylation in gallstone formation through the targeting of cholesterol metabolism. Our data advises Glrx1 significantly increased gallstone formation by simultaneously increase bile-acid-dependent cholesterol absorption and ASGR1- LXRα-dependent cholesterol efflux. Our work suggests the potential effects of inhibiting Glrx1 activity to treat cholelithiasis.
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Cálculos Biliares , Animais , Camundongos , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Cálculos Biliares/metabolismo , Glutarredoxinas/genética , Glutarredoxinas/metabolismo , Glutarredoxinas/farmacologia , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Proteína S/metabolismo , Proteína S/farmacologia , ProteômicaRESUMO
Excessive N-acetyl-p-benzoquinone imine (NAPQI) formation is a starting event that triggers oxidative stress and subsequent hepatocyte necrosis in acetaminophen (APAP) overdose caused acute liver failure (ALF). S-glutathionylation is a reversible redox post-translational modification and a prospective mechanism of APAP hepatotoxicity. Glutaredoxin-1 (Glrx1), a glutathione-specific thioltransferase, is a primary enzyme to catalyze deglutathionylation. The objective of this study was to explored whether and how Glrx1 is associated with the development of ALF induced by APAP. The Glrx1 knockout mice (Glrx1-/-) and liver-specific overexpression of Glrx1 (AAV8-Glrx1) mice were produced and underwent APAP-induced ALF. Pirfenidone (PFD), a potential inducer of Glrx1, was administrated preceding APAP to assess its protective effects. Our results revealed that the hepatic total protein S-glutathionylation (PSSG) increased and the Glrx1 level reduced in mice after APAP toxicity. Glrx1-/- mice were more sensitive to APAP overdose, with higher oxidative stress and more toxic metabolites of APAP. This was attributed to Glrx1 deficiency increasing the total hepatic PSSG and the S-glutathionylation of cytochrome p450 3a11 (Cyp3a11), which likely increased the activity of Cyp3a11. Conversely, AAV8-Glrx1 mice were defended against liver damage caused by APAP overdose by inhibiting the S-glutathionylation and activity of Cyp3a11, which reduced the toxic metabolites of APAP and oxidative stress. PFD precede administration upregulated Glrx1 expression and alleviated APAP-induced ALF by decreasing oxidative stress. We have identified the function of Glrx1 mediated PSSG in liver injury caused by APAP overdose. Increasing Glrx1 expression may be investigated for the medical treatment of APAP-caused hepatic injury.
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CONTEXT: The factors that determine the recycling of free fatty acids (FFA) back into different adipose tissue depots via the direct storage pathway are not completely understood. OBJECTIVE: To assess the interactions between adipocyte factors and plasma FFA concentrations that determine regional FFA storage rates. DESIGN: We measured direct adipose tissue FFA storage rates before and after weight loss under high FFA (intravenous somatostatin and epinephrine) and low (intravenous insulin and glucose) FFA concentrations. SETTING: Mayo Clinic Clinical Research Unit. PATIENTS: Sixteen premenopausal women, body mass index 30 to 37 kg/m2. INTERVENTION: Comprehensive lifestyle weight loss program. MAIN OUTCOME MEASURE: Direct FFA storage rates in upper and lower body subcutaneous fat. RESULTS: Over the entire range of FFA and under isolated conditions of elevated FFA concentrations, the storage rates of FFA into upper and lower body subcutaneous fat per unit lipid were associated with concentrations, not adipocyte fatty acid storage factors. Under low FFA conditions, direct FFA storage rates were related to adipocyte CD36 content, not tissue level content of fatty acid storage factors. Weight loss did not change these relationships. CONCLUSIONS: The regulation of direct FFA storage under low FFA concentration conditions appears to be at the level of the cell/adipocyte content of CD36, whereas under high FFA concentration conditions, direct FFA storage at the tissue level is predicted by plasma FFA concentrations, independent of adipocyte size or fatty acid storage factors. These observations offer novel insights into how adipose tissue regulates direct FFA storage in humans.
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Tecido Adiposo/metabolismo , Índice de Massa Corporal , Antígenos CD36/metabolismo , Diacilglicerol O-Aciltransferase/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Redução de Peso , Adulto , Feminino , Seguimentos , Humanos , Estilo de Vida , MasculinoRESUMO
BACKGROUND: Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (Dâ¯+â¯Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, Dâ¯+â¯Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans. METHODS: In an open label Phase 1 pilot study, we administered 3â¯days of oral D 100â¯mg and Q 1000â¯mg to subjects with diabetic kidney disease (Nâ¯=â¯9; 68·7⯱â¯3·1â¯years old; 2 female; BMI:33·9⯱â¯2·3â¯kg/m2; eGFR:27·0⯱â¯2·1â¯mL/min/1·73m2). Adipose tissue, skin biopsies, and blood were collected before and 11â¯days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed. FINDINGS: Dâ¯+â¯Q reduced adipose tissue senescent cell burden within 11â¯days, with decreases in p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated ß-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16INK4A+ and p21CIP1+ cells were reduced, as were circulating SASP factors, including IL-1α, IL-6, and MMPs-9 and -12. INTERPRETATION: "Hit-and-run" treatment with senolytics, which in the case of Dâ¯+â¯Q have elimination half-lives <11â¯h, significantly decreases senescent cell burden in humans. FUND: NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.
Assuntos
Senescência Celular/efeitos dos fármacos , Dasatinibe/farmacologia , Nefropatias Diabéticas/metabolismo , Quercetina/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Idoso , Biomarcadores , Biópsia , Ensaios Clínicos Fase I como Assunto , Dasatinibe/uso terapêutico , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/tratamento farmacológico , Quimioterapia Combinada , Feminino , Humanos , Imuno-Histoquímica , Testes de Função Renal , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Quercetina/uso terapêuticoRESUMO
We previously demonstrated that hydrogen sulfide (H2S) protected neonatal rat medulla oblongata from prenatal cigarette smoke exposure (CSE) via anti-apoptotic effect. The present work further investigated the involvement of anti-oxidative and anti-inflammatory effects of H2S in the protection. Pregnant Sprague-Dawley rats were randomly divided into NaCl, CSE, CSEâ¯+â¯NaHS (a donor of H2S) and NaHS groups. All the tests were performed with corresponding neonatal rats. Nissl staining revealed that NaHS treatment ameliorated neuronal chromatolysis in the hypoglossal nucleus and nucleus ambiguus resulted from prenatal CSE. Moreover, NaHS eliminated decrease of glutathione level, increase of malondialdehyde content and inhibition of superoxide dismutase activity within neonatal rat medulla oblongata caused by prenatal CSE. NaHS also relieved the up-regulation of tumor necrosis factor-α, interleukin-1ß and interleukin-6 in the medulla oblongata of the neonatal CSE rats. These results suggest that H2S can alleviate prenatal CSE-induced injuries of neonatal rat medulla oblongata through anti-oxidative and anti-inflammatory effects.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Bulbo/efeitos dos fármacos , Fumar/efeitos adversos , Sulfetos/farmacologia , Animais , Animais Recém-Nascidos , Citocinas/genética , Citocinas/metabolismo , Feminino , Glutationa/metabolismo , Sulfeto de Hidrogênio , Malondialdeído/metabolismo , Troca Materno-Fetal , Bulbo/metabolismo , Gravidez , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND: The association between Graves' disease (GD) and thyroid carcinoma remains controversial. This study aimed to investigate incidental thyroid carcinoma (ITC) in surgery-treated hyperthyroid patients with and without GD. MATERIALS AND METHODS: We searched PubMed and EMBASE for cohort studies investigating ITC in surgery-treated hyperthyroid patients without prediagnosed thyroid carcinoma in accordance with the Meta-Analysis of Observational Studies in Epidemiology guidelines. The last search was updated to January 23, 2018. All statistical tests were performed using Review Manager 5.3 and STATA version 12.0. RESULTS: Eleven cohort studies involving 10,743 GD and 3,336 non-GD patients were included. The pooled prevalence of ITC was 7.0% (95% confidence interval [CI] 4.5-9.6), and was comparable in surgery-treated GD and non-GD hyperthyroid patients (GD vs non-GD: pooled odds ratio [OR], 1.0; 95% CI: 0.68-1.46; P=0.98). In the subgroup analysis, toxic adenoma and toxic nodular goiter showed no difference when comparing with GD (pooled OR, 0.53; 95% CI: 0.21-1.36; P=0.18 and pooled OR, 1.01; 95% CI: 0.65-1.57; P=0.95, respectively). CONCLUSION: Our study demonstrated that GD was not associated with increased risk of ITC in surgery-treated hyperthyroid patients.