RESUMO
Endoplasmic reticulum stress is associated with insulin resistance and the development of nonalcoholic fatty liver disease. Deficiency of the endoplasmic reticulum stress response T-cell death-associated gene 51 (TDAG51) (TDAG51-/-) in mice promotes the development of high-fat diet (HFD)-induced obesity, fatty liver, and hepatic insulin resistance. However, whether this effect is due specifically to hepatic TDAG51 deficiency is unknown. Here, we report that hepatic TDAG51 protein levels are consistently reduced in multiple mouse models of liver steatosis and injury as well as in liver biopsies from patients with liver disease compared to normal controls. Delivery of a liver-specific adeno-associated virus (AAV) increased hepatic expression of a TDAG51-GFP fusion protein in WT, TDAG51-/-, and leptin-deficient (ob/ob) mice. Restoration of hepatic TDAG51 protein was sufficient to increase insulin sensitivity while reducing body weight and fatty liver in HFD fed TDAG51-/- mice and in ob/ob mice. TDAG51-/- mice expressing ectopic TDAG51 display improved Akt (Ser473) phosphorylation, post-insulin stimulation. HFD-fed TDAG51-/- mice treated with AAV-TDAG51-GFP displayed reduced lipogenic gene expression, increased beta-oxidation and lowered hepatic and serum triglycerides, findings consistent with reduced liver weight. Further, AAV-TDAG51-GFP-treated TDAG51-/- mice exhibited reduced hepatic precursor and cleaved sterol regulatory-element binding proteins (SREBP-1 and SREBP-2). In vitro studies confirmed the lipid-lowering effect of TDAG51 overexpression in oleic acid-treated Huh7 cells. These studies suggest that maintaining hepatic TDAG51 protein levels represents a viable therapeutic approach for the treatment of obesity and insulin resistance associated with nonalcoholic fatty liver disease.
Assuntos
Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Camundongos , Morte Celular , Dieta Hiperlipídica/efeitos adversos , Hepatócitos/metabolismo , Resistência à Insulina/fisiologia , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Linfócitos T/metabolismo , MasculinoRESUMO
BACKGROUND: TGFß1 is a major profibrotic mediator in chronic kidney disease (CKD). Its direct inhibition, however, is limited by adverse effects. Inhibition of activins, also members of the TGFß superfamily, blocks TGFß1 profibrotic effects, but the mechanism underlying this and the specific activin(s) involved are unknown. METHODS: Cells were treated with TGFß1 or activins A/B. Activins were inhibited generally with follistatin, or specifically with neutralizing antibodies or type I receptor downregulation. Cytokine levels, signaling and profibrotic responses were assessed with ELISA, immunofluorescence, immunoblotting and promoter luciferase reporters. Wild-type or TGFß1-overexpressing mice with unilateral ureteral obstruction (UUO) were treated with an activin A neutralizing antibody. RESULTS: In primary mesangial cells, TGFß1 induces secretion primarily of activin A, which enables longer-term profibrotic effects by enhancing Smad3 phosphorylation and transcriptional activity. This results from lack of cell refractoriness to activin A, unlike that for TGFß1, and promotion of TGFß type II receptor expression. Activin A also supports transcription through regulating non-canonical MRTF-A activation. TGFß1 additionally induces secretion of activin A, but not B, from tubular cells, and activin A neutralization prevents the TGFß1 profibrotic response in renal fibroblasts. Fibrosis induced by UUO is inhibited by activin A neutralization in wild-type mice. Worsened fibrosis in TGFß1-overexpressing mice is associated with increased renal activin A expression and is inhibited to wild-type levels with activin A neutralization. CONCLUSIONS: Activin A facilitates TGFß1 profibrotic effects through regulation of both canonical (Smad3) and non-canonical (MRTF-A) signaling, suggesting it may be a novel therapeutic target for preventing fibrosis in CKD.
Assuntos
Ativinas , Insuficiência Renal Crônica , Camundongos , Animais , Ativinas/metabolismo , Fibrose , Fator de Crescimento Transformador betaRESUMO
OBJECTIVE: Cardiovascular disease is the primary cause of mortality in patients with chronic kidney disease. Vascular calcification (VC) in the medial layer of the vessel wall is a unique and prominent feature in patients with advanced chronic kidney disease and is now recognized as an important predictor and independent risk factor for cardiovascular and all-cause mortality in these patients. VC in chronic kidney disease is triggered by the transformation of vascular smooth muscle cells (VSMCs) into osteoblasts as a consequence of elevated circulating inorganic phosphate (Pi) levels, due to poor kidney function. The objective of our study was to investigate the role of TDAG51 (T-cell death-associated gene 51) in the development of medial VC. METHODS AND RESULTS: Using primary mouse and human VSMCs, we found that TDAG51 is induced in VSMCs by Pi and is expressed in the medial layer of calcified human vessels. Furthermore, the transcriptional activity of RUNX2 (Runt-related transcription factor 2), a well-established driver of Pi-mediated VC, is reduced in TDAG51-/- VSMCs. To explain these observations, we identified that TDAG51-/- VSMCs express reduced levels of the type III sodium-dependent Pi transporter, Pit-1, a solute transporter, a solute transporter, a solute transporter responsible for cellular Pi uptake. Significantly, in response to hyperphosphatemia induced by vitamin D3, medial VC was attenuated in TDAG51-/- mice. CONCLUSIONS: Our studies highlight TDAG51 as an important mediator of Pi-induced VC in VSMCs through the downregulation of Pit-1. As such, TDAG51 may represent a therapeutic target for the prevention of VC and cardiovascular disease in patients with chronic kidney disease.
Assuntos
Transdiferenciação Celular , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Osteogênese , Fatores de Transcrição/metabolismo , Calcificação Vascular/metabolismo , Idoso , Animais , Células Cultivadas , Colecalciferol , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Hiperfosfatemia/induzido quimicamente , Hiperfosfatemia/metabolismo , Hiperfosfatemia/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Fosfatos/metabolismo , Transdução de Sinais , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismo , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Calcificação Vascular/genética , Calcificação Vascular/patologia , Calcificação Vascular/prevenção & controleRESUMO
The worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly. Although this condition is generally benign, accumulating evidence now suggests that patients with NAFLD are also at increased risk of cardiovascular disease (CVD); the leading cause of death in developed nations. Despite the well-established role of the liver as a central regulator of circulating low-density lipoprotein (LDL) cholesterol levels, a known driver of CVD, the mechanism(s) by which hepatic steatosis contributes to CVD remains elusive. Interestingly, a recent study has shown that circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels correlate positively with liver steatosis grade. Given that PCSK9 degrades the LDL receptor (LDLR) and prevents the removal of LDL from the blood into the liver, in the present study we examined the effect of hepatic steatosis on LDLR expression and circulating LDL cholesterol levels. We now report that in a manner consistent with findings in patients, diet-induced steatosis increases circulating PCSK9 levels as a result of de novo expression in mice. We also report the finding that steatosis abrogates hepatic LDLR expression and increases circulating LDL levels in a PCSK9-dependent manner. These findings provide important mechanistic insights as to how hepatic steatosis modulates lipid regulatory genes, including PCSK9 and the LDLR, and also highlights a novel mechanism by which liver disease may contribute to CVD.
Assuntos
Dieta Hiperlipídica , Fígado Gorduroso/patologia , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/metabolismo , Animais , Apolipoproteínas B/sangue , LDL-Colesterol/sangue , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado Gorduroso/metabolismo , Células Hep G2 , Humanos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Compostos Organofosforados/farmacologia , Pró-Proteína Convertase 9/sangue , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismoRESUMO
Digestive system development is orchestrated by combinatorial signaling interactions between endoderm and mesoderm, but how these signals are interpreted in the genome is poorly understood. Here we identified the transcriptomes of Xenopus foregut and hindgut progenitors, which are conserved with mammals. Using RNA-seq and ChIP-seq we show that BMP/Smad1 regulates dorsal-ventral gene expression in both the endoderm and mesoderm, whereas Wnt/ß-catenin acts as a genome-wide toggle between foregut and hindgut programs. Unexpectedly, ß-catenin and Smad1 binding were associated with both transcriptional activation and repression, with Wnt-repressed genes often lacking canonical Tcf DNA binding motifs, suggesting a novel mode of direct repression. Combinatorial Wnt and BMP signaling was mediated by Smad1 and ß-catenin co-occupying hundreds of cis-regulatory DNA elements, and by a crosstalk whereby Wnt negatively regulates BMP ligand expression in the foregut. These results extend our understanding of gastrointestinal organogenesis and of how Wnt and BMP might coordinate genomic responses in other contexts.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Sistema Digestório/metabolismo , Genoma , Proteína Smad1/metabolismo , Transcrição Gênica , Via de Sinalização Wnt/genética , Xenopus laevis/genética , Animais , Sequência de Bases , Padronização Corporal/genética , Cromatina/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Ligação Proteica , Transcriptoma/genética , Xenopus laevis/embriologia , beta Catenina/metabolismoRESUMO
OBJECTIVE: Rosuvastatin has been widely used in the primary and secondary prevention of coronary heart disease. However, its antiatherosclerotic properties have not been tested in a mouse model that could mimic human coronary heart disease. The present study was designed to test the effects of rosuvastatin on coronary artery atherosclerosis and myocardial fibrosis in SR-B1 (scavenger receptor class B type 1) and apoE (apolipoprotein E) double knockout mice. APPROACH AND RESULTS: Three-week-old SR-B1-/-/apoE-/- mice were injected daily with 10 mg/kg of rosuvastatin for 2 weeks. Compared with saline-treated mice, rosuvastatin-treated mice showed increased levels of hepatic PCSK9 (proprotein convertase subtilisin/kexin type-9) and LDLR (low-density lipoprotein receptor) message, increased plasma PCSK9 protein but decreased levels of hepatic LDLR protein and increased plasma total cholesterol associated with apoB (apolipoprotein B) 48-containing lipoproteins. In spite of this, rosuvastatin treatment was associated with decreased atherosclerosis in both the aortic sinus and coronary arteries and reduced platelet accumulation in atherosclerotic coronary arteries. Cardiac fibrosis and cardiomegaly were also attenuated in rosuvastatin-treated SR-B1-/-/apoE-/- mice. Two-week treatment with rosuvastatin resulted in significant decreases in markers of oxidized phospholipids in atherosclerotic plaques. In vitro analysis showed that incubation of bone marrow-derived macrophages with rosuvastatin substantially downregulated cluster of differentiation (CD)36 and inhibited oxidized LDL-induced foam cell formation. CONCLUSIONS: Rosuvastatin protected SR-B1-/-/apoE-/- mice against atherosclerosis and platelet accumulation in coronary arteries and attenuated myocardial fibrosis and cardiomegaly, despite increased plasma total cholesterol. The ability of rosuvastatin to reduce oxidized phospholipids in atherosclerotic plaques and inhibit macrophage foam cell formation may have contributed to this protection.
Assuntos
Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Colesterol/sangue , Doença da Artéria Coronariana/prevenção & controle , Vasos Coronários/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Placa Aterosclerótica , Rosuvastatina Cálcica/farmacologia , Receptores Depuradores Classe B/deficiência , Seio Aórtico/efeitos dos fármacos , Animais , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Biomarcadores/sangue , Células Cultivadas , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Modelos Animais de Doenças , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Células Espumosas/patologia , Lipoproteínas LDL/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Knockout para ApoE , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/metabolismo , Receptores Depuradores Classe B/genética , Seio Aórtico/metabolismo , Seio Aórtico/patologiaRESUMO
Doxorubicin is a widely used chemotherapeutic with deleterious cardiotoxic side effects. HDL has been shown to protect cardiomyocytes in vitro against doxorubicin-induced apoptosis. Scavenger receptor class B type 1 (SR-B1), a high-affinity HDL receptor, mediates cytoprotective signaling by HDL through Akt. Here, we assessed whether increased HDL levels protect against doxorubicin-induced cardiotoxicity in vivo and in cardiomyocytes in culture and explored the intracellular signaling mechanisms involved, particularly the role of SR-B1. Transgenic mice with increased HDL levels through overexpression of human apolipoprotein A1 (apoA1Tg/Tg) and wild-type mice (apoA1+/+) with normal HDL levels were treated repeatedly with doxorubicin. After treatment, apoA1+/+ mice displayed cardiac dysfunction, as evidenced by reduced left ventricular end-systolic pressure and +dP/d t, and histological analysis revealed cardiomyocyte atrophy and increased cardiomyocyte apoptosis after doxorubicin treatment. In contrast, apoA1Tg/Tg mice were protected against doxorubicin-induced cardiac dysfunction and cardiomyocyte atrophy and apoptosis. When SR-B1 was knocked out, however, overexpression of apoA1 did not protect against doxorubicin-induced cardiotoxicity. Using primary neonatal mouse cardiomyocytes and human immortalized ventricular cardiomyocytes in combination with genetic knockout, inhibitors, or siRNA-mediated knockdown, we demonstrated that SR-B1 is required for HDL-mediated protection of cardiomyocytes against doxorubicin-induced apoptosis in vitro via a pathway involving phosphatidylinositol 3-kinase and Akt1/2. Our findings provide proof of concept that raising apoA1 to supraphysiological levels can dramatically protect against doxorubicin-induced cardiotoxicity via a pathway that is mediated by SR-B1 and involves Akt1/2 activation in cardiomyocytes. NEW & NOTEWORTHY We have identified an important role for the scavenger receptor class B type 1 in facilitating high-density lipoprotein-mediated protection of cardiomyocytes against stress-induced apoptosis and shown that increasing plasma high-density lipoprotein protects against the deleterious side effects of the chemotherapeutic and cardiotoxic drug doxorubicin.
Assuntos
Cardiomiopatias/prevenção & controle , Doxorrubicina , Lipoproteínas HDL/metabolismo , Miócitos Cardíacos/enzimologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Depuradores Classe B/metabolismo , Disfunção Ventricular Esquerda/prevenção & controle , Animais , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Apoptose , Atrofia , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/enzimologia , Cardiomiopatias/fisiopatologia , Cardiotoxicidade , Linhagem Celular , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/patologia , Receptores Depuradores Classe B/deficiência , Receptores Depuradores Classe B/genética , Transdução de Sinais , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/enzimologia , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular EsquerdaRESUMO
The low concentration issue is a fundamental challenge when it comes to prebiotic chemistry, as macromolecular systems need to be assembled via intermolecular reactions, and this is inherently difficult in dilute solutions. This is especially true when the reactions are challenging, and reactions that proceeded more rapidly could have dictated chemical evolution. Herein we establish that formaldehyde is capable of catalyzing, via temporary intramolecularity, a challenging reaction in water at low concentrations, thus providing an alternative to other approaches that can either lead to higher concentrations or higher effective molarities.
Assuntos
Evolução Química , Formaldeído/química , Água/química , CatáliseRESUMO
OBJECTIVE: Deficiency of the high-density lipoprotein receptor, scavenger receptor class B, type I (SR-BI), in apolipoprotein E knockout or hypomorphic mice, respectively, results in spontaneous or diet-inducible occlusive coronary artery (CA) atherosclerosis, myocardial infarction, and early death. Here, we examine effects of SR-BI deficiency on cardiovascular phenotypes in low-density lipoprotein receptor (LDLR) knockout mice fed different atherogenic diets. APPROACH AND RESULTS: SR-BI/LDLR double knockout and control LDLR knockout mice were fed atherogenic diets containing different amounts of fat, cholesterol, and sodium cholate. Double knockout mice fed atherogenic diets high in cholesterol exhibited significantly reduced survival compared with LDLR knockout mice fed the same diets. In addition to increased diet-accelerated aortic sinus atherosclerosis, we observed significant diet-induced CA atherosclerosis in double knockout mice and diet-dependent accumulation of platelets in CA atherosclerotic plaques. This was accompanied by substantial myocardial fibrosis in double knockout mice fed high cholesterol diets. Atherogenic diet fed double knockout mice also exhibited higher circulating cytokine levels, monocytosis with increased proportions of Ly6C(hi) and Ly6C(int) monocytes, and higher adhesion molecule expression in CA endothelial cells compared with control LDLR knockout mice. CONCLUSIONS: Diet-accelerated atherosclerosis and occlusive, platelet-rich CA disease in SR-BI/LDLR double knockout mice is affected by amounts of cholesterol and cholate in atherogenic diets and is accompanied by increased expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in CAs and increased Ly6C(hi) and Ly6C(int) monocytes in circulation. The increased vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in CA endothelial cells in SR-BI-deficient mice likely explains their increased susceptibility to atherosclerosis in CAs.
Assuntos
Arteriopatias Oclusivas/epidemiologia , Doença da Artéria Coronariana/epidemiologia , Dieta Aterogênica/efeitos adversos , Infarto do Miocárdio/epidemiologia , Receptores de LDL/deficiência , Receptores Depuradores Classe B/deficiência , Animais , Arteriopatias Oclusivas/metabolismo , Colatos/efeitos adversos , Colesterol na Dieta/efeitos adversos , Doença da Artéria Coronariana/metabolismo , Citocinas/sangue , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Incidência , Molécula 1 de Adesão Intercelular/metabolismo , Camundongos , Camundongos Knockout , Infarto do Miocárdio/metabolismo , Receptores de LDL/genética , Fatores de Risco , Receptores Depuradores Classe B/genética , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Diabetic kidney disease (DKD) is characterized by a progressive increase in albuminuria and typical pathologic features. Recent studies have shown that sex is an important factor to consider in the pathogenesis of DKD. Presently, the hallmarks of this disease have primarily been studied in male rodent models. Here we explored the influence of sex in a murine model of DKD. CD1 mice underwent a right nephrectomy followed by intraperitoneal injection with 200 mg/kg streptozotocin to induce type 1 diabetes. Due to a high mortality rate, females required a reduction in streptozotocin to 150 mg/kg. Mice were followed for 12 weeks. Both sexes developed comparable hyperglycemia, while albuminuria and glomerular volume were increased to a greater degree in females and kidney hypertrophy was only seen in females. Males had a greater increase in blood pressure and glomerular basement membrane thickening, and a greater decrease in endpoint weight. Serum TGFß1 levels were increased only in females. However, both sexes showed a similar increase in induction of kidney fibrosis. T cell and macrophage infiltration were also increased in both sexes. While some differences were observed, overall, both sexes developed clinical and pathologic characteristics of early DKD. Future studies evaluating therapeutic interventions can thus be assessed in both sexes of this DKD model.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Feminino , Masculino , Camundongos , Animais , Modelos Animais de Doenças , Estreptozocina , Albuminúria/etiologia , Nefropatias Diabéticas/patologia , Membrana Basal Glomerular/patologia , Diabetes Mellitus Tipo 2/complicaçõesRESUMO
OBJECTIVE: Metabolic Syndrome (MetS) affects hundreds of millions of individuals and constitutes a major cause of morbidity and mortality worldwide. Obesity is believed to be at the core of metabolic abnormalities associated with MetS, including dyslipidemia, insulin resistance, fatty liver disease and vascular dysfunction. Although previous studies demonstrate a diverse array of naturally occurring antioxidants that attenuate several manifestations of MetS, little is known about the (i) combined effect of these compounds on hepatic health and (ii) molecular mechanisms responsible for their effect. METHODS: We explored the impact of a metabolic enhancer (ME), consisting of 7 naturally occurring antioxidants and mitochondrial enhancing agents, on diet-induced obesity, hepatic steatosis and atherogenic serum profile in mice. RESULTS: Here we show that a diet-based ME supplementation and exercise have similar beneficial effects on adiposity and hepatic steatosis in mice. Mechanistically, ME reduced hepatic ER stress, fibrosis, apoptosis, and inflammation, thereby improving overall liver health. Furthermore, we demonstrated that ME improved HFD-induced pro-atherogenic serum profile in mice, similar to exercise. The protective effects of ME were reduced in proprotein convertase subtilisin/kexin 9 (PCSK9) knock out mice, suggesting that ME exerts it protective effect partly in a PCSK9-dependent manner. CONCLUSIONS: Our findings suggest that components of the ME have a positive, protective effect on obesity, hepatic steatosis and cardiovascular risk and that they show similar effects as exercise training.
Assuntos
Resistência à Insulina , Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Pró-Proteína Convertase 9/metabolismo , Antioxidantes/metabolismo , Dieta Hiperlipídica/efeitos adversos , Obesidade/metabolismo , Fígado/metabolismo , Síndrome Metabólica/etiologia , Síndrome Metabólica/prevenção & controle , Síndrome Metabólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/metabolismo , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVE: Climate change is expected to increase global temperatures. How temperature-related mortality risk will change is not completely understood, and how future demographic changes will affect temperature-related mortality needs to be clarified. We evaluate temperature-related mortality across Canada until 2099, accounting for age groups and scenarios of population growth. METHODS: We used daily counts of non-accidental mortality for 2000 to 2015 for all 111 health regions across Canada, incorporating in the study both urban and rural areas. A two-part time series analysis was used to estimate associations between mean daily temperatures and mortality. First, current and future daily mean temperature time series simulations were developed from Coupled Model Inter-Comparison Project 6 (CMIP6) climate model ensembles from past and projected climate change scenarios under Shared Socioeconomic Pathways (SSPs). Next, excess mortality due to heat and cold and the net difference were projected to 2099, also accounting for different regional and population aging scenarios. RESULTS: For 2000 to 2015, we identified 3,343,311 non-accidental deaths. On average, a net increase of 17.31% (95% eCI: 13.99, 20.62) in temperature-related excess mortality under a higher greenhouse gas emission scenario is expected for Canada in 2090-2099, which represents a greater burden than a scenario that assumed strong levels of greenhouse gas mitigation policies (net increase of 3.29%; 95% eCI: 1.41, 5.17). The highest net increase was observed among people aged 65 and over, and the largest increases in both net and heat- and cold-related mortality were observed in population scenarios that incorporated the highest rates of aging. CONCLUSION: Canada may expect net increases in temperature-related mortality under a higher emissions climate change scenario, compared to one assuming sustainable development. Urgent action is needed to mitigate future climate change impacts.
RéSUMé: OBJECTIF: Les changements climatiques devraient accroître les températures mondiales. La façon dont le risque de mortalité lié à la température évoluera n'est pas entièrement comprise, et la façon dont les changements démographiques futurs influeront sur la mortalité liée à la température doit être clarifiée. Nous étudions la mortalité liée à la température au Canada jusqu'en 2099, en tenant compte des groupes d'âge et des scénarios de croissance démographique. MéTHODES: Nous avons utilisé les nombres quotidiens de mortalité non accidentelle pour 2000 à 2015 pour toutes les 111 régions socio sanitaires du Canada, en intégrant dans l'étude des régions urbaines et rurales. Une analyse en séries chronologiques en deux parties a été utilisée pour estimer les associations entre les températures quotidiennes moyennes et la mortalité. Premièrement, des simulations de séries chronologiques de températures moyennes quotidiennes actuelles et futures ont été élaborées à partir d'ensembles de modèles climatiques du Projet de comparaison croisée 6 (CMIP6) du modèle couplé à partir de scénarios de changements climatiques passés et projetés dans le cadre de voies socioéconomiques partagées (SSP). Ensuite, la surmortalité due à la chaleur et au froid et la différence nette ont été projetées jusqu'en 2099, ce qui tient également compte de différents scénarios régionaux et de vieillissement de la population. RéSULTATS: De 2000 à 2015, nous avons recensé 3 343 311 décès non accidentels. En moyenne, une augmentation nette de 17,31% (eCI à 95%: 13,99, 20,62) de la mortalité excessive liée à la température dans le cadre d'un scénario d'émissions de gaz à effet de serre plus élevées est prévue pour le Canada en 20902099, ce qui représente un fardeau plus lourd qu'un scénario qui suppose des niveaux élevés de politiques d'atténuation des émissions de gaz (augmentation nette de 3,29%; eCI à 95%: 1,41, 5,17). La plus forte augmentation nette a été observée chez les personnes de 65 ans ou plus, et les plus fortes augmentations de la mortalité nette, de mortalité liée à la chaleur et au froid ont été observées dans les scénarios de population qui comprenaient les taux de vieillissement les plus élevés. CONCLUSION: Le Canada pourrait s'attendre à des augmentations nettes de la mortalité liée à la température dans le cadre d'un scénario de changement climatique à émissions plus élevées, comparativement à un scénario de développement durable. Des mesures urgentes sont nécessaires pour atténuer les répercussions futures des changements climatiques.
Assuntos
Gases de Efeito Estufa , Humanos , Temperatura , Mudança Climática , Temperatura Alta , Envelhecimento , Canadá/epidemiologia , MortalidadeRESUMO
Mechanistic investigations on the aldehyde-catalyzed intermolecular hydroamination of allylic amines using N-alkylhydroxylamines are presented. Under the reaction conditions, the presence of a specific aldehyde catalyst allows formation of a mixed aminal intermediate, which permits intramolecular Cope-type hydroamination. The reaction was determined to be first-order in both the aldehyde catalyst (α-benzyloxyacetaldehyde) and the allylic amine. However, the reaction displays an inverse order behavior in benzylhydroxylamine, which reveals a significant off-cycle pathway and highlights the importance of an aldehyde catalyst that promotes a reversible aminal formation. Kinetic isotope effect experiments suggest that hydroamination is the rate-limiting step of this catalytic cycle. Overall, these results enabled the elaboration of a more accurate catalytic cycle and led to the development of a more efficient catalytic system for alkene hydroamination. The use of 5-10 mol % of paraformaldehyde proved more effective than the use of 20 mol % of α-benzyloxyacetaldehyde, leading to high yields of intermolecular hydroamination products within 24 h at 30 °C.
Assuntos
Aldeídos/química , Compostos Alílicos/química , Hidroxilaminas/química , Aminação , Aminas/química , CatáliseRESUMO
The 78 kDa glucose-regulated protein (GRP78) is considered an endoplasmic reticulum (ER)-resident molecular chaperone that plays a crucial role in protein folding homeostasis by regulating the unfolded protein response (UPR) and inducing numerous proapoptotic and autophagic pathways within the eukaryotic cell. However, in cancer cells, GRP78 has also been shown to migrate from the ER lumen to the cell surface, playing a role in several cellular pathways that promote tumor growth and cancer cell progression. There is another insidious consequence elicited by cell surface GRP78 (csGRP78) on cancer cells: the accumulation of csGRP78 represents a novel neoantigen leading to the production of anti-GRP78 autoantibodies that can bind csGRP78 and further amplify these cellular pathways to enhance cell growth and mitigate apoptotic cell death. This review examines the current body of literature that delineates the mechanisms by which ER-resident GRP78 localizes to the cell surface and its consequences, as well as potential therapeutics that target csGRP78 and block its interaction with anti-GRP78 autoantibodies, thereby inhibiting further amplification of cancer cell progression.
RESUMO
High levels of low density lipoprotein (LDL) cholesterol and low levels of high density lipoprotein (HDL) cholesterol are risk factors for cardiovascular disease. Mice that lack genes involved in the clearance of LDL from the bloodstream, such as the LDL receptor and apolipoprotein E, are widely used models of experimental atherosclerosis. Conversely, mice that lack the HDL receptor, scavenger receptor class B type I, and therefore have disrupted HDL functionality, also develop diet-inducible atherosclerosis but are a seldom-used disease model. In this study, we compared atherosclerosis and associated phenotypes in scavenger receptor class B type I knockout mice with those of wild type, LDL receptor knockout, and apolipoprotein E knockout mice after 20 weeks of being fed an atherogenic diet containing sodium cholate. We found that while scavenger receptor class B type I knockout mice had substantially lower plasma cholesterol than LDL receptor and apolipoprotein E knockout mice, they developed atherosclerotic plaques with similar sizes and compositions in their aortic sinuses, and more extensive atherosclerosis in their descending aortas and coronary arteries. This was associated with elevated tumor necrosis factor alpha levels in scavenger receptor class B type I knockout mice compared to wild type and LDL receptor knockout mice, and lymphocytosis, monocytosis, and elevated vascular cell adhesion molecule expression in coronary artery endothelial cells compared to the other mice examined. We conclude that extensive atherosclerosis in arteries that are not generally susceptible to atherosclerosis in scavenger receptor class B type I knockout mice is driven by factors in addition to hypercholesterolemia, including inflammation, dysregulation of the immune system and increased sensitivity of endothelial cells in arteries that are normally resistant to atherosclerosis. Scavenger receptor class B type I knockout mice fed a cholate containing atherogenic diet may prove to be a useful model to study mechanisms of atherosclerosis and evaluate treatments that rely on intact LDL clearance pathways.
RESUMO
INTERVENTION: Ontario's Harmonized Heat Warning and Information System (HWIS) brings harmonized, regional heat warnings and standard heat-health messaging to provincial public health units prior to periods of extreme heat. RESEARCH QUESTION: Was implementation of the harmonized HWIS in May 2016 associated with a reduction in emergency department (ED) visits for heat-related illness in urban locations across Ontario, Canada? METHODS: We conducted a population-based interrupted time series analysis from April 30 to September 30, 2012-2018, using administrative health and outdoor temperature data. We used autoregressive integrated moving average models to examine whether ED rates changed following implementation of the harmonized HWIS, adjusted for maximum daily temperature. We also examined whether effects differed in heat-vulnerable groups (≥65 years or <18 years, those with comorbidities, those with a recent history of homelessness), and by heat warning region. RESULTS: Over the study period, heat alerts became more frequent in urban areas (6 events triggered between 2013 and 2015 and 14 events between 2016 and 2018 in Toronto, for example). The mean rate of ED visits was 47.5 per 100,000 Ontarians (range 39.7-60.1) per 2-week study interval, with peaks from June to July each year. ED rates were particularly high in those with a recent history of homelessness (mean rate 337.0 per 100,000). Although rates appeared to decline following implementation of HWIS in some subpopulations, the change was not statistically significant at a population level (rate 0.04, 95% CI: -0.03 to 0.1, p=0.278). CONCLUSION: In urban areas across Ontario, ED encounters for heat-related illness may have declined in some subpopulations following HWIS, but the change was not statistically significant. Efforts to continually improve HWIS processes are important given our changing Canadian climate.
RéSUMé: INTERVENTION: Le système d'avertissement et d'information de chaleur harmonisé pour l'Ontario (SAIC) transmet des alertes régionales harmonisées sur la chaleur et des messages normalisés sur la chaleur et la santé aux unités de santé publique provinciales, avant les périodes de chaleur extrême. QUESTION DE RECHERCHE: La mise en Åuvre du SAIC harmonisé en mai 2016 a-t-elle été associée à une réduction des visites aux urgences pour des maladies liées à la chaleur dans les zones urbaines de l'Ontario, au Canada? MéTHODES: Nous avons effectué une analyse de séries chronologiques interrompues basée sur la population du 30 avril au 30 septembre, 20122018, en utilisant des données administratives sur la santé et la température extérieure. Nous avons utilisé des modèles autorégressifs à moyenne mobile intégrée pour examiner si le taux de visites des urgences avait changé après la mise en Åuvre du SAIC harmonisé, ajusté pour tenir compte de la température maximale quotidienne. Nous avons également examiné si les effets différaient pour les groupes vulnérables à la chaleur (≥65 ans ou <18 ans, les personnes ayant des comorbidités et les personnes avec un passé récent de sans-abri), et selon la région d'alerte de chaleur. RéSULTATS: Au cours de la période d'étude, les alertes de chaleur sont devenues plus fréquentes dans les zones urbaines (6 événements déclenchés entre 2013 et 2015 et 14 événements déclenchés entre 2016 et 2018 à Toronto, par exemple). Le taux moyen de visites aux urgences était de 47,5 pour 100 000 Ontariens (de 39,7 à 60,1) par intervalle de deux semaines, avec des pointes chaque année en juin et juillet. Le taux de visites aux urgences était particulièrement élevé chez les personnes avec un passé récent de sans-abri (taux moyen de 337,0 pour 100 000). Malgré une baisse du taux après la mise en Åuvre du SAIC dans certaines sous-populations, le changement n'était pas statistiquement significatif au niveau de la population (taux 0,04, IC 95 % : -0,03 à 0,1, p=0,278). CONCLUSION: Dans les zones urbaines de l'Ontario, le nombre de consultations aux urgences pour des maladies liées à la chaleur a diminué dans certaines sous-populations après la mise en place du SAIC, mais le changement n'était pas statistiquement significatif. Les efforts visant à améliorer continuellement les processus du SAIC sont importants compte tenu de l'évolution du climat canadien.
Assuntos
Transtornos de Estresse por Calor , Temperatura Alta , Serviço Hospitalar de Emergência , Transtornos de Estresse por Calor/epidemiologia , Humanos , Sistemas de Informação , Ontário/epidemiologia , Fatores de TempoRESUMO
Background: PCSK9 modulates the uptake of circulating lipids through a range of receptors, including the low-density lipoprotein receptor (LDLR) and CD36. In the kidney, CD36 is known to contribute to renal injury through pro-inflammatory and -fibrotic pathways. In this study, we sought to investigate the role of PCSK9 in modulating renal lipid accumulation and injury through CD36 using a high fat diet (HFD)-induced murine model. Methods: The effect of PCSK9 on the expression of CD36 and intracellular accumulation of lipid was examined in cultured renal cells and in the kidneys of male C57BL/6J mice. The effect of these findings was subsequently explored in a model of HFD-induced renal injury in Pcsk9 -/- and Pcsk9 +/+ littermate control mice on a C57BL/6J background. Results: In the absence of PCSK9, we observed heightened CD36 expression levels, which increased free fatty acid (FFA) uptake in cultured renal tubular cells. As a result, PCSK9 deficiency was associated with an increase in long-chain saturated FFA-induced ER stress. Consistent with these observations, Pcsk9-/- mice fed a HFD displayed elevated ER stress, inflammation, fibrosis, and renal injury relative to HFD-fed control mice. In contrast to Pcsk9-/- mice, pretreatment of WT C57BL/6J mice with evolocumab, an anti-PCSK9 monoclonal antibody (mAb) that binds to and inhibits the function of circulating PCSK9, protected against HFD-induced renal injury in association with reducing cell surface CD36 expression on renal epithelia. Conclusions: We report that circulating PCSK9 modulates renal lipid uptake in a manner dependent on renal CD36. In the context of increased dietary fat consumption, the absence of circulating PCSK9 may promote renal lipid accumulation and subsequent renal injury. However, although the administration of evolocumab blocks the interaction of PCSK9 with the LDLR, this evolocumab/PCSK9 complex can still bind CD36, thereby protecting against HFD-induced renal lipotoxicity.
Assuntos
Antígenos CD36 , Ácidos Graxos não Esterificados , Animais , Anticorpos Monoclonais/farmacologia , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta , Fibrose , Rim/metabolismo , Lipoproteínas LDL/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pró-Proteína Convertase 9/genéticaRESUMO
Evidence suggests that caffeine (CF) reduces cardiovascular disease (CVD) risk. However, the mechanism by which this occurs has not yet been uncovered. Here, we investigated the effect of CF on the expression of two bona fide regulators of circulating low-density lipoprotein cholesterol (LDLc) levels; the proprotein convertase subtilisin/kexin type 9 (PCSK9) and the low-density lipoprotein receptor (LDLR). Following the observation that CF reduced circulating PCSK9 levels and increased hepatic LDLR expression, additional CF-derived analogs with increased potency for PCSK9 inhibition compared to CF itself were developed. The PCSK9-lowering effect of CF was subsequently confirmed in a cohort of healthy volunteers. Mechanistically, we demonstrate that CF increases hepatic endoplasmic reticulum (ER) Ca2+ levels to block transcriptional activation of the sterol regulatory element-binding protein 2 (SREBP2) responsible for the regulation of PCSK9, thereby increasing the expression of the LDLR and clearance of LDLc. Our findings highlight ER Ca2+ as a master regulator of cholesterol metabolism and identify a mechanism by which CF may protect against CVD.
Assuntos
Cafeína/farmacologia , Colesterol/metabolismo , Fígado/metabolismo , Pró-Proteína Convertase 9/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/farmacologia , Animais , LDL-Colesterol/metabolismo , Células Hep G2 , Hepatócitos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Receptores de LDL/metabolismoRESUMO
Herein we describe a catalytic tethering strategy in which simple aldehyde precatalysts enable, through temporary intramolecularity, room-temperature intermolecular hydroamination reactivity and the synthesis of vicinal diamines. The catalyst allows the formation of a mixed aminal from an allylic amine and a hydroxylamine, resulting in a facile intramolecular hydroamination event. The promising enantioselectivities obtained with a chiral aldehyde also highlight the potential of this catalytic tethering approach in asymmetric catalysis and demonstrate that efficient enantioinduction relying only on temporary intramolecularity is possible.