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1.
Int J Mol Sci ; 24(22)2023 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-38003345

RESUMO

Phospholipase A2 (PLA2) enzymes influence inflammatory bowel disease in both positive and negative manners depending on the type of PLA2 that is expressed. This study explored the influence of the abundantly expressed Group 1B PLA2 (PLA2G1B) on ulcerative colitis. Wild-type C57BL/6J mice and Pla2g1b-/- mice were treated with dextran sulfate sodium (DSS) for 5 days to induce epithelial injury, followed by another 5 days without DSS for recovery. The Pla2g1b-/- mice displayed significantly less body weight loss, colitis pathology, and disease activity indexes compared to the wild-type mice. The differences in colitis were not due to differences in the colonic lysophospholipid levels, but higher numbers of stem and progenitor cells were found in the intestines of Pla2g1b-/- mice compared to the wild-type mice. The DSS-treated Pla2g1b-/- mice also showed higher expressions of genes that are responsible for epithelial repair and lower expressions of proinflammatory cytokine genes in the colon, as well as reduced inflammatory cytokine levels in the plasma. In vitro experiments revealed the PLA2G1B stimulation of inflammatory cytokine expression by myeloid cells. PLA2G1B inactivation protects against DSS-induced colitis in mice by increasing the intestinal stem cell reservoir for epithelial repair and reducing myeloid cell inflammation in the diseased colon. Thus, PLA2G1B may be a target for colitis management.


Assuntos
Colite Ulcerativa , Colite , Camundongos , Animais , Fosfolipases A2 do Grupo IB/metabolismo , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Colo/patologia , Colite Ulcerativa/metabolismo , Fosfolipases A2/genética , Fosfolipases A2/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Mucosa Intestinal/metabolismo
2.
Am J Physiol Regul Integr Comp Physiol ; 325(1): R55-R68, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37212552

RESUMO

This study explored the role of apoE receptor-2 (apoER2), a unique member of the LDL receptor family proteins with a restricted tissue expression profile, in modulating diet-induced obesity and diabetes. Unlike wild-type mice and humans in which chronic feeding of a high-fat Western-type diet leads to obesity and the prediabetic state of hyperinsulinemia before hyperglycemia onset, the Lrp8-/- mice with global apoER2 deficiency displayed lower body weight and adiposity, slower development of hyperinsulinemia, but the accelerated onset of hyperglycemia. Despite their lower adiposity, adipose tissues in Western diet-fed Lrp8-/- mice were more inflamed compared with wild-type mice. Additional experiments revealed that the hyperglycemia observed in Western diet-fed Lrp8-/- mice was due to impaired glucose-induced insulin secretion, ultimately leading to hyperglycemia, adipocyte dysfunction, and inflammation upon chronic feeding of the Western diet. Interestingly, bone marrow-specific apoER2-deficient mice were not defective in insulin secretion, exhibiting increased adiposity and hyperinsulinemia compared with wild-type mice. Analysis of bone marrow-derived macrophages revealed that apoER2 deficiency impeded inflammation resolution with lower secretion of IFN-ß and IL-10 in response to LPS stimulation of IL-4 primed cells. The apoER2-deficient macrophages also showed an increased level of disabled-2 (Dab2) as well as increased cell surface TLR4, suggesting that apoER2 participates in Dab2 regulation of TLR4 signaling. Taken together, these results showed that apoER2 deficiency in macrophages sustains diet-induced tissue inflammation and accelerates obesity and diabetes onset while apoER2 deficiency in other cell types contributes to hyperglycemia and inflammation via defective insulin secretion.


Assuntos
Hiperglicemia , Hiperinsulinismo , Resistência à Insulina , Animais , Humanos , Camundongos , Tecido Adiposo/metabolismo , Medula Óssea/metabolismo , Dieta , Dieta Hiperlipídica , Hiperglicemia/metabolismo , Hiperinsulinismo/genética , Inflamação/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/metabolismo , Receptores de LDL , Receptor 4 Toll-Like/metabolismo
3.
Int J Mol Sci ; 23(17)2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36077289

RESUMO

A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and polymorphisms with pathogenesis of numerous chronic diseases, including atherosclerosis, obesity/diabetes, and Alzheimer's disease. The human APOE gene is polymorphic with three major alleles, ε2, ε3 and ε4, encoding apoE2, apoE3, and apoE4, respectively. The APOE gene is expressed in many cell types, including hepatocytes, adipocytes, immune cells of the myeloid lineage, vascular smooth muscle cells, and in the brain. ApoE is present in subclasses of plasma lipoproteins, and it mediates the clearance of atherogenic lipoproteins from plasma circulation via its interaction with LDL receptor family proteins and heparan sulfate proteoglycans. Extracellular apoE also interacts with cell surface receptors and confers signaling events for cell regulation, while apoE expressed endogenously in various cell types regulates cell functions via autocrine and paracrine mechanisms. This review article focuses on lipoprotein transport-dependent and -independent mechanisms by which apoE deficiency or polymorphisms contribute to cardiovascular disease, metabolic disease, and neurological disorders.


Assuntos
Apolipoproteínas E/metabolismo , Aterosclerose , Doenças Cardiovasculares , Animais , Apolipoproteína E2/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Aterosclerose/genética , Doenças Cardiovasculares/metabolismo , Humanos , Camundongos , Receptores de LDL/genética
4.
Sci Rep ; 12(1): 1858, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35115621

RESUMO

Climate change impacts the structure, functioning, and distribution of species and ecosystems. It will shift ecosystem boundaries, potentially affecting vulnerable ecosystems, such as tropical Africa's high mountain ecosystems, i.e., afroalpine ecosystems, and their highly susceptible uniquely adapted species. However, ecosystems along these mountains are not expected to respond similarly to the change. The ericaceous woody vegetation, located between the low-elevation broadleaf forests and high-elevation afroalpine vegetation, are anticipated to be affected differently. We hypothesize that projected climate change will result in an upward expansion and increasing dominance of ericaceous vegetation, which will negatively impact the endemic rich afroalpine ecosystems of the extensive Sanetti plateau. Hence, we modeled the impact of future climate change on the distribution of ericaceous vegetation and discussed its effect on bordering ecosystems in the Bale Mountains. We applied four familiar correlative modeling approaches: bioclim, domain, generalized linear methods, and support vector machines. We used WorldClim's bioclimatic variables as environmental predictors and two representative concentration pathways (RCPs) of the IPCC Fifth Assessment Report climate change scenarios, namely RCP4.5 and RCP8.5 for future climate projection. The results indicate increased ericaceous vegetation cover on the midaltitude of northwestern and northern parts of the massif, and the Sanetti plateau. We observed upward range expansion and increase of close ericaceous vegetation in midaltitudes, while receding from the lower range across the massif. Moreover, the current ericaceous vegetation range correlates to the temperature and precipitation trends, reaffirming the critical role of temperature and precipitation in determining species distributions along elevational gradients. The results indicate the high likelihood of considerable changes in this biodiversity hotspot in Eastern Africa.

5.
J Biol Chem ; 297(3): 101106, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34425108

RESUMO

Polymorphisms in the apolipoprotein E (apoE) gene are risk factors for chronic inflammatory diseases including atherosclerosis. The gene product apoE is synthesized in many cell types and has both lipid transport-dependent and lipid transport-independent functions. Previous studies have shown that apoE expression in myeloid cells protects against atherogenesis in hypercholesterolemic ApoE-/- mice. However, the mechanism of this protection is still unclear. Using human APOE gene replacement mice as models, this study showed that apoE2 and apoE4 expressed endogenously in myeloid cells enhanced the inflammatory response via mechanisms independent of plasma lipoprotein transport. The data revealed that apoE2-expressing myeloid cells contained higher intracellular cholesterol levels because of impaired efflux, causing increasing inflammasome activation and myelopoiesis. In contrast, intracellular cholesterol levels were not elevated in apoE4-expressing myeloid cells, and its proinflammatory property was found to be independent of inflammasome signaling and related to enhanced oxidative stress. When ApoE-/- mice were reconstituted with bone marrow from various human APOE gene replacement mice, effective reduction of atherosclerosis was observed with marrow cells obtained from APOE3 but not APOE2 and APOE4 gene replacement mice. Taken together, these results documented that apoE2 and apoE4 expression in myeloid cells promotes inflammation via distinct mechanisms and promotes atherosclerosis in a plasma lipoprotein transport-independent manner.


Assuntos
Apolipoproteína E2/metabolismo , Apolipoproteína E4/metabolismo , Aterosclerose/genética , Animais , Apolipoproteína E2/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/genética , Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Feminino , Humanos , Inflamação , Lipoproteínas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Mieloides/metabolismo , Transdução de Sinais
6.
Curr Opin Lipidol ; 32(5): 301-307, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34310383

RESUMO

PURPOSE OF REVIEW: LDL receptor-related protein 1 (LRP1) is a multifunctional protein with endocytic and signal transduction properties due to its interaction with numerous extracellular ligands and intracellular proteins. This brief review highlights key developments in identifying novel functions of LRP1 in liver, lung, and the central nervous system in disease pathogenesis. RECENT FINDINGS: In hepatocytes, LRP1 complexes with phosphatidylinositol 4-phosphate 5-kinase-1 and its related protein to maintain intracellular levels of phosphatidylinositol (4,5) bisphosphate and preserve lysosome and mitochondria integrity. In contrast, in smooth muscle cells, macrophages, and endothelial cells, LRP1 interacts with various different extracellular ligands and intracellular proteins in a tissue-dependent and microenvironment-dependent manner to either enhance or suppress inflammation, disease progression or resolution. Similarly, LRP1 expression in astrocytes and oligodendrocyte progenitor cells regulates cell differentiation and maturation in a developmental-dependent manner to modulate neurogenesis, gliogenesis, and white matter repair after injury. SUMMARY: LRP1 modulates metabolic disease manifestation, inflammation, and differentiation in a cell-dependent, time-dependent, and tissue-dependent manner. Whether LRP1 expression is protective or pathogenic is dependent on its interaction with specific ligands and intracellular proteins, which in turn is dependent on the cell type and the microenvironment where these cells reside.


Assuntos
Células Endoteliais , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Células Endoteliais/metabolismo , Homeostase , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Macrófagos/metabolismo , Miócitos de Músculo Liso/metabolismo , Receptores de LDL/metabolismo
7.
PLoS Negl Trop Dis ; 15(4): e0009288, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33872307

RESUMO

BACKGROUND: Visceral leishmaniasis (VL) is re-emerging in Armenia since 1999 with 167 cases recorded until 2019. The objectives of this study were (i) to determine for the first time the genetic diversity and population structure of the causative agent of VL in Armenia; (ii) to compare these genotypes with those from most endemic regions worldwide; (iii) to monitor the diversity of vectors in Armenia; (iv) to predict the distribution of the vectors and VL in time and space by ecological niche modeling. METHODOLOGY/PRINCIPAL FINDINGS: Human samples from different parts of Armenia previously identified by ITS-1-RFLP as L. infantum were studied by Multilocus Microsatellite Typing (MLMT). These data were combined with previously typed L. infantum strains from the main global endemic regions for population structure analysis. Within the 23 Armenian L. infantum strains 22 different genotypes were identified. The combined analysis revealed that all strains belong to the worldwide predominating MON1-population, however most closely related to a subpopulation from Southeastern Europe, Maghreb, Middle East and Central Asia. The three observed Armenian clusters grouped within this subpopulation with strains from Greece/Turkey, and from Central Asia, respectively. Ecological niche modeling based on VL cases and collected proven vectors (P. balcanicus, P. kandelakii) identified Yerevan and districts Lori, Tavush, Syunik, Armavir, Ararat bordering Georgia, Turkey, Iran and Azerbaijan as most suitable for the vectors and with the highest risk for VL transmission. Due to climate change the suitable habitat for VL transmission will expand in future all over Armenia. CONCLUSIONS: Genetic diversity and population structure of the causative agent of VL in Armenia were addressed for the first time. Further genotyping studies should be performed with samples from infected humans, animals and sand flies from all active foci including the neighboring countries to understand transmission cycles, re-emergence, spread, and epidemiology of VL in Armenia and the entire Transcaucasus enabling epidemiological monitoring.


Assuntos
Doenças Transmissíveis Emergentes/diagnóstico , Leishmania infantum/genética , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/epidemiologia , Repetições de Microssatélites , Armênia/epidemiologia , Pré-Escolar , Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/parasitologia , Ecossistema , Feminino , Genótipo , Humanos , Lactente , Leishmaniose Visceral/parasitologia , Masculino , Epidemiologia Molecular , Tipagem Molecular , Projetos Piloto , Polimorfismo de Fragmento de Restrição , Medição de Risco
8.
J Biol Chem ; 296: 100370, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33548224

RESUMO

The LDL receptor-related protein 1 (LRP1) is a multifunctional transmembrane protein with endocytosis and signal transduction functions. Previous studies have shown that hepatic LRP1 deficiency exacerbates diet-induced steatohepatitis and insulin resistance via mechanisms related to increased lysosome and mitochondria permeability and dysfunction. The current study examined the impact of LRP1 deficiency on mitochondrial function in the liver. Hepatocytes isolated from liver-specific LRP1 knockout (hLrp1-/-) mice showed reduced oxygen consumption compared with control mouse hepatocytes. The mitochondria in hLrp1-/- mouse livers have an abnormal morphology and their membranes contain significantly less anionic phospholipids, including lower levels of phosphatidylethanolamine and cardiolipin that increase mitochondrial fission and impair fusion. Additional studies showed that LRP1 complexes with phosphatidylinositol 4-phosphate 5-kinase like protein-1 (PIP5KL1) and phosphatidylinositol 4-phosphate 5-kinase-1ß (PIP5K1ß). The absence of LRP1 reduces the levels of both PIP5KL1 and PIP5K1ß in the plasma membrane and also lowers phosphatidylinositol(4,5) bisphosphate (PI(4,5)P2) levels in hepatocytes. These data indicate that LRP1 recruits PIP5KL1 and PIP5K1ß to the plasma membrane for PI(4,5)P2 biosynthesis. The lack of LRP1 reduces lipid kinase expression, leading to lower PI(4,5)P2 levels, thereby decreasing the availability of this lipid metabolite in the cardiolipin biosynthesis pathway to cause cardiolipin reduction and the impairment in mitochondria homeostasis. Taken together, the current study identifies another signaling mechanism by which LRP1 regulates cell functions: binding and recruitment of PIP5KL1 and PIP5K1ß to the membrane for PI(4,5)P2 synthesis. In addition, it highlights the importance of this mechanism for maintaining the integrity and functions of intracellular organelles.


Assuntos
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/deficiência , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Animais , Membrana Celular/metabolismo , Fígado Gorduroso/metabolismo , Hepatócitos/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Fígado/patologia , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Lisossomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Fosfatidilinositóis/metabolismo , Transporte Proteico , Receptores de LDL/metabolismo
9.
J Lipid Res ; 62: 100012, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33500241

RESUMO

The impairment of LDL receptor-related protein-1 (LRP1) in numerous cell types is associated with obesity, diabetes, and fatty liver disease. Here, we compared the metabolic phenotype of C57BL/6J wild-type and LRP1 knock-in mice carrying an inactivating mutation in the distal NPxY motif after feeding a low-fat diet or high-fat (HF) diet with cholesterol supplementation (HFHC) or HF diet without cholesterol supplementation. In response to HF feeding, both groups developed hyperglycemia, hyperinsulinemia, hyperlipidemia, increased adiposity, and adipose tissue inflammation and liver steatosis. However, LRP1 NPxY mutation prevents HFHC diet-induced hypercholesterolemia, reduces adipose tissue and brain inflammation, and limits liver progression to steatohepatitis. Nevertheless, this mutation does not protect against HFHC diet-induced insulin resistance. The selective metabolic improvement observed in HFHC diet-fed LRP1 NPxY mutant mice is due to an apparent increase of hepatic LDL receptor levels, leading to an elevated rate of plasma lipoprotein clearance and lower hepatic cholesterol levels. The unique metabolic phenotypes displayed by LRP1 NPxY mutant mice indicate an LRP1-cholesterol axis in modulating tissue inflammation. The LRP1 NPxY mutant mouse phenotype differs from phenotypes observed in mice with tissue-specific LRP1 inactivation, thus highlighting the importance of an integrative approach to evaluate how global LRP1 dysfunction contributes to metabolic disease development.


Assuntos
Colesterol na Dieta
10.
Epidemics ; 33: 100411, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33130413

RESUMO

Epidemiological models (EMs) are widely used to predict the temporal outbreak risk of vector-borne diseases (VBDs). EMs typically use the basic reproduction number (R0), a threshold quantity, to indicate risk. To provide an overall view of the risk, these model outputs can be transformed into spatial risk maps, using various aggregation methods (e.g. average R0 over time, cumulative number of days with R0 > 1). However, there is no standardized methodology available for this. Depending on the specific aggregation methods used, the yielded spatial risk maps may have considerably different interpretations. Additionally, the method used to visualize the aggregated data also affects the perceived spatial patterns. In this review, we compare commonly used aggregation and visualization methods and discuss the respective interpretation of risk maps. Research publications using epidemiological modelling methods were drawn from Web of Science. Only publications containing maps of R0 transformed from EMs were considered for the analysis. An example EM was applied to illustrate how aggregation and visualization methods affect the final presentations of risk maps. Risk maps can be generated to show duration, intensity and spatio-temporal dynamics of potential outbreak risk of VBDs. We show that 1) different temporal aggregation methods lead to different interpretations; 2) similar spatial patterns do not necessarily bear the same meaning; 3) visualization methods considerably affect how results are perceived, and thus should be applied with caution. We recommend mapping both intensity and duration of the VBD outbreak risk, using small time-steps to show spatio-temporal dynamics when possible.


Assuntos
Monitoramento Epidemiológico , Doenças Transmitidas por Vetores/epidemiologia , Animais , Número Básico de Reprodução , Surtos de Doenças , Humanos , Modelos Estatísticos
11.
J Biol Chem ; 295(14): 4631-4646, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32079675

RESUMO

Increasing hepatic mitochondrial activity through pyruvate dehydrogenase and elevating enterohepatic bile acid recirculation are promising new approaches for metabolic disease therapy, but neither approach alone can completely ameliorate disease phenotype in high-fat diet-fed mice. This study showed that diet-induced hepatosteatosis, hyperlipidemia, and insulin resistance can be completely prevented in mice with liver-specific HCLS1-associated protein X-1 (HAX-1) inactivation. Mechanistically, we showed that HAX-1 interacts with inositol 1,4,5-trisphosphate receptor-1 (InsP3R1) in the liver, and its absence reduces InsP3R1 levels, thereby improving endoplasmic reticulum-mitochondria calcium homeostasis to prevent excess calcium overload and mitochondrial dysfunction. As a result, HAX-1 ablation activates pyruvate dehydrogenase and increases mitochondria utilization of glucose and fatty acids to prevent hepatosteatosis, hyperlipidemia, and insulin resistance. In contrast to the reduction of InsP3R1 levels, hepatic HAX-1 deficiency increases bile salt exporter protein levels, thereby promoting enterohepatic bile acid recirculation, leading to activation of bile acid-responsive genes in the intestinal ileum to augment insulin sensitivity and of cholesterol transport genes in the liver to suppress hyperlipidemia. The dual mechanisms of increased mitochondrial respiration and enterohepatic bile acid recirculation due to improvement of endoplasmic reticulum-mitochondria calcium homeostasis with hepatic HAX-1 inactivation suggest that this may be a potential therapeutic target for metabolic disease intervention.


Assuntos
Ácidos e Sais Biliares/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mitocôndrias/metabolismo , Animais , Glicemia/análise , Cálcio/metabolismo , Dieta Ocidental , Retículo Endoplasmático/metabolismo , Teste de Tolerância a Glucose , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Insulina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Cetona Oxirredutases/metabolismo , Peroxidação de Lipídeos , Lipogênese , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Triglicerídeos/sangue
12.
Arterioscler Thromb Vasc Biol ; 39(10): 2132-2144, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31412739

RESUMO

OBJECTIVE: Genome-wide studies showed that mutation in apoER2 (apolipoprotein E receptor-2) is additive with ε4 polymorphism in the APOE gene on cardiovascular disease risk in humans. ApoE or apoER2 deficiency also accelerates atherosclerosis lesion necrosis in hypercholesterolemic mice and promotes neointima formation after vascular injury. This study tests the hypothesis that apoE and apoER2 modulate vascular occlusive diseases through distinct mechanisms. Approach and Results: Carotid endothelial denudation induced robust neointima formation in both apoE-/- and apoER2-deficient Lrp8-/- mice. The intima in apoE-/- mice was rich in smooth muscle cells, but the intima in Lrp8-/- mice was cell-poor and rich in extracellular matrix. Vascular smooth muscle cells isolated from apoE-/- mice were hyperplastic whereas Lrp8-/- smooth muscle cells showed reduced proliferation but responded robustly to TGF (transforming growth factor)-ß-induced fibronectin synthesis indicative of a senescence-associated secretory phenotype, which was confirmed by increased ß-galactosidase activity, p16INK4a immunofluorescence, and number of multinucleated cells. Western blot analysis of cell cycle-associated proteins showed that apoER2 deficiency promotes cell cycle arrest at the metaphase/anaphase. Coimmunoprecipitation experiments revealed that apoER2 interacts with the catalytic subunit of protein phosphatase 2A. In the absence of apoER2, PP2A-C (protein phosphatase 2A catalytic subunit) failed to interact with CDC20 (cell-division cycle protein 20) thus resulting in inactive anaphase-promoting complex and impaired cell cycle exit. CONCLUSIONS: This study showed that apoER2 participates in APC (anaphase-promoting complex)/CDC20 complex formation during mitosis, and its absence impedes cytokinesis abscission thereby accelerating premature cell senescence and vascular disease. This mechanism is distinct from apoE deficiency, which causes smooth muscle cell hyperplasia to accelerate vascular disease.


Assuntos
Aterosclerose/patologia , Morte Celular/genética , Senescência Celular/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Lesões do Sistema Vascular/patologia , Animais , Células Cultivadas , Citocinese/fisiologia , Modelos Animais de Doenças , Feminino , Citometria de Fluxo/métodos , Humanos , Imunoprecipitação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos de Músculo Liso/metabolismo , Neointima/patologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Valores de Referência , Túnica Íntima/metabolismo , Túnica Íntima/patologia
13.
Ecol Evol ; 9(24): 14417-14429, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31938529

RESUMO

AIM: Due to their longevity and structure, forest ecosystems are particularly affected by climate change with consequences for their biodiversity, functioning, and services to mankind. In the European Union (EU), natural and seminatural forests are protected by the Habitats Directive and the Natura 2000 network. This study aimed to assess the exposure of three legally defined forest habitat types to climate change, namely (a) Tilio-Acerion forests of slopes, screes, and ravines (9180*), (b) bog woodlands (91D0*), and (c) alluvial forests with Alnus glutinosa and Fraxinus excelsior (91E0*). We analyzed possible changes in their Bavarian distribution, including their potential future coverage by Natura 2000 sites. We hypothesized that protected areas (PAs) with larger elevational ranges will remain suitable for the forests as they allow for altitudinal distribution shifts. METHODS: To estimate changes in range size and coverage by PAs, we combined correlative species distribution models (SDMs) with spatial analyses. Ensembles of SDM-algorithms were applied to two climate change scenarios (RCP4.5 and RCP8.5) of the HadGEM2-ES model for the period 2061-2080. RESULTS: Our results revealed that bog woodlands experience the highest range losses (>2/3) and lowest PA coverage (max. 15% of sites with suitable conditions). Tilio-Acerion forests exhibit opposing trends depending on the scenario, while alluvial forests are less exposed to climatic changes. As expected, the impacts of climate change are more pronounced under the "business as usual" scenario (RCP8.5). Additionally, PAs in flat landscapes are more likely to lose environmental suitability for currently established forest habitat types. MAIN CONCLUSIONS: Based on these findings, we advocate the expansion of the Natura 2000 network particularly in consideration of elevational gradients, connectivity, and projected climatic suitability. Nonclimatic stressors on forest ecosystems, especially bog woodlands, should be decreased and climate change mitigation efforts enhanced. We recommend transferring the approach to other habitat types and regions.

14.
Int J Health Geogr ; 17(1): 35, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30314528

RESUMO

BACKGROUND: Usutu virus (USUV) is a mosquito-borne flavivirus, reported in many countries of Africa and Europe, with an increasing spatial distribution and host range. Recent outbreaks leading to regional declines of European common blackbird (Turdus merula) populations and a rising number of human cases emphasize the need for increased awareness and spatial risk assessment. METHODS: Modelling approaches in ecology and epidemiology differ substantially in their algorithms, potentially resulting in diverging model outputs. Therefore, we implemented a parallel approach incorporating two commonly applied modelling techniques: (1) Maxent, a correlation-based environmental niche model and (2) a mechanistic epidemiological susceptible-exposed-infected-removed (SEIR) model. Across Europe, surveillance data of USUV-positive birds from 2003 to 2016 was acquired to train the environmental niche model and to serve as test cases for the SEIR model. The SEIR model is mainly driven by daily mean temperature and calculates the basic reproduction number R0. The environmental niche model was run with long-term bio-climatic variables derived from the same source in order to estimate climatic suitability. RESULTS: Large areas across Europe are currently suitable for USUV transmission. Both models show patterns of high risk for USUV in parts of France, in the Pannonian Basin as well as northern Italy. The environmental niche model depicts the current situation better, but with USUV still being in an invasive stage there is a chance for under-estimation of risk. Areas where transmission occurred are mostly predicted correctly by the SEIR model, but it mostly fails to resolve the temporal dynamics of USUV events. High R0 values predicted by the SEIR model in areas without evidence for real-life transmission suggest that it may tend towards over-estimation of risk. CONCLUSIONS: The results from our parallel-model approach highlight that relying on a single model for assessing vector-borne disease risk may lead to incomplete conclusions. Utilizing different modelling approaches is thus crucial for risk-assessment of under-studied emerging pathogens like USUV.


Assuntos
Surtos de Doenças , Infecções por Flavivirus/epidemiologia , Flavivirus , Modelos Teóricos , Animais , Surtos de Doenças/prevenção & controle , Europa (Continente)/epidemiologia , Infecções por Flavivirus/diagnóstico , Infecções por Flavivirus/transmissão , Humanos , Fatores de Risco
15.
Front Plant Sci ; 9: 715, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29922310

RESUMO

Plant ecosystem engineers are widely used to combat land degradation. However, the ability of those plants to modulate limiting abiotic and biotic resources of other species can cause damage to ecosystems in which they become invasive. Here, we use Lupinus nootkatensis as example to estimate and project the hazardous potential of nitrogen fixing herbaceous plants in a sub-polar oceanic climate. L. nootkatensis was introduced to Iceland in the 1940s to address erosion problems and foster reforestation, but subsequently became a high-latitude invader. In a local field survey, we quantified the impact of L. nootkatensis invasion at three different cover levels (0, 10-50, and 51-100%) upon native plant diversity, richness, and community composition of heath-, wood-, and grasslands using a pairwise comparison design and comparisons of means. Afterward, we scaled impacts up to the ecosystem and landscape level by relating occurrences of L. nootkatensis to environmental and human-mediated variables across Iceland using a species distribution model. Plant diversity was significantly deteriorated under high lupine cover levels of the heath- and woodland, but not in the grassland. Plant species richness of the most diverse habitat, the heathland, linearly decreased with lupine cover level. The abundance of small rosettes, cushion plants, orchids, and small woody long-lived plants of the heath declined with invader presence, while the abundance of late successional species and widespread nitrophilous ruderals in wood- and grasslands increased. Distribution modeling revealed 13.3% of Iceland's land surface area to be suitable lupine habitat. Until 2061-2080, this area will more than double and expand significantly into the Central Highlands due to human mediation and increasingly favorable climatic conditions. Species-rich habitats showed a loss of plant species diversity and richness as well as a change in community composition even in low lupine cover classes. The future increase of suitable lupine habitat might lead to the displacement of cold-adapted native plant species and will certainly challenge conservation as well as restoration of ecosystems in the cold climate of Iceland, but also elsewhere. Lupine invasion speeds up succession, which may be additive with climate change effects, and accelerates ecological change in cold biomes.

16.
Artigo em Inglês | MEDLINE | ID: mdl-29914102

RESUMO

The intensity and extent of transmission of arboviruses such as dengue, chikungunya, and Zika virus have increased markedly over the last decades. Autochthonous transmission of dengue and chikungunya by Aedes albopictus has been recorded in Southern Europe where the invasive mosquito was already established and viraemic travelers had imported the virus. Ae. albopictus populations are spreading northward into Germany. Here, we model the current and future climatically suitable regions for Ae. albopictus establishment in Germany, using climate data of spatially high resolution. To highlight areas where vectors and viraemic travellers are most likely to come into contact, reported dengue and chikungunya incidences are integrated at the county level. German cities with the highest likelihood of autochthonous transmission of Aedes albopictus-borne arboviruses are currently located in the western parts of the country: Freiburg im Breisgau, Speyer, and Karlsruhe, affecting about 0.5 million people. In addition, 8.8 million people live in regions considered to show elevated hazard potential assuming further spread of the mosquito: Baden-Württemberg (Upper Rhine, Lake Constance regions), southern parts of Hesse, and North Rhine-Westphalia (Lower Rhine). Overall, a more targeted and thus cost-efficient implementation of vector control measures and health surveillance will be supported by the detailed maps provided here.


Assuntos
Aedes/virologia , Infecções por Arbovirus/transmissão , Clima , Mosquitos Vetores/virologia , Animais , Alemanha , Humanos , Modelos Biológicos , Dinâmica Populacional , Medição de Risco , Análise Espaço-Temporal
17.
J Biol Chem ; 293(25): 9674-9684, 2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29752404

RESUMO

Reduced low-density lipoprotein receptor-related protein-1 (LRP1) expression in the liver is associated with poor prognosis of liver cirrhosis and hepatocellular carcinoma. Previous studies have shown that hepatic LRP1 deficiency exacerbates palmitate-induced steatosis and toxicity in vitro and also promotes high-fat diet-induced hepatic insulin resistance and hepatic steatosis in vivo The current study examined the impact of liver-specific LRP1 deficiency on disease progression to steatohepatitis. hLrp1+/+ mice with normal LRP1 expression and hLrp1-/- mice with hepatocyte-specific LRP1 inactivation were fed a high-fat, high-cholesterol (HFHC) diet for 16 weeks. Plasma lipid levels and body weights were similar between both groups. However, the hLrp1-/- mice displayed significant increases in liver steatosis, inflammation, and fibrosis compared with the hLrp1+/+ mice. Hepatocyte cell size, liver weight, and cell death, as measured by serum alanine aminotransferase levels, were also significantly increased in hLrp1-/- mice. The accelerated liver pathology observed in HFHC-fed hLrp1-/- mice was associated with reduced expression of cholesterol excretion and bile acid synthesis genes, leading to elevated immune cell infiltration and inflammation. Additional in vitro studies revealed that cholesterol loading induced significantly higher expression of genes responsible for hepatic stellate cell activation and fibrosis in hLrp1-/- hepatocytes than in hLrp1+/+ hepatocytes. These results indicate that hepatic LRP1 deficiency accelerates liver disease progression by increasing hepatocyte death, thereby causing inflammation and increasing sensitivity to cholesterol-induced pro-fibrotic gene expression to promote steatohepatitis. Thus, LRP1 may be a genetic variable that dictates individual susceptibility to the effects of dietary cholesterol on liver diseases.


Assuntos
Colesterol na Dieta/efeitos adversos , Hepatócitos/patologia , Inflamação/etiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores de LDL/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Células Cultivadas , Progressão da Doença , Hepatócitos/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo
18.
PLoS Negl Trop Dis ; 11(9): e0005873, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28880944

RESUMO

BACKGROUND: Cutaneous leishmaniasis (CL) is a major public health problem in Libya. In this paper, we describe the eco-epidemiological parameters of CL during the armed conflict period from January 2011 till December 2012. Current spatiotemporal distributions of CL cases were explored and projected to the future using a correlative modelling approach. In addition the present results were compared with our previous data obtained for the time period 1995-2008. METHODOLOGY/PRINCIPAL FINDINGS: We investigated 312 CL patients who presented to the Dermatology Department at the Tripoli Central Hospital and came from 81 endemic areas distributed in 10 districts. The patients presented with typical localized lesions which appeared commonly on the face, arms and legs. Molecular identification of parasites by a PCR-RFLP approach targeting the ITS1 region of the rDNA was successful for 81 patients with two causative species identified: L. major and L. tropica comprised 59 (72.8%) and 22 (27.2%) cases, respectively. Around 77.3% of L. tropica CL and 57.7% of L. major CL caused single lesions. Five CL patients among our data set were seropositive for HIV. L. tropica was found mainly in three districts, Murqub (27.3%), Jabal al Gharbi (27.3%) and Misrata (13.7%) while L. major was found in two districts, in Jabal al Gharbi (61%) and Jafara (20.3%). Seasonal occurrence of CL cases showed that most cases (74.2%) admitted to the hospital between November and March, L. major cases from November till January (69.4%), and L. tropica cases mainly in January and February (41%). Two risk factors were identified for the two species; the presence of previously infected household members, and the presence of rodents and sandflies in patient's neighborhoods. Spatiotemporal projections using correlative distribution models based on current case data and climatic conditions showed that coastal regions have a higher level of risk due to more favourable conditions for the transmitting vectors. CONCLUSION: Future projection of CL until 2060 showed a trend of increasing incidence of CL in the north-western part of Libya, a spread along the coastal region and a possible emergence of new endemics in the north-eastern districts of Libya. These results should be considered for control programs to prevent the emergence of new endemic areas taking also into consideration changes in socio-economical factors such as migration, conflicts, urbanization, land use and access to health care.


Assuntos
Leishmania major/genética , Leishmania tropica/genética , Leishmaniose Cutânea/epidemiologia , Leishmaniose Cutânea/parasitologia , Análise Espaço-Temporal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Criança , Pré-Escolar , DNA de Protozoário/genética , Feminino , Humanos , Lactente , Leishmania major/isolamento & purificação , Leishmania tropica/isolamento & purificação , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/transmissão , Líbia/epidemiologia , Masculino , Pessoa de Meia-Idade , Psychodidae/parasitologia , Roedores/parasitologia , Adulto Jovem
19.
J Biol Chem ; 291(32): 16610-9, 2016 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-27317662

RESUMO

LRP1 (LDL receptor-related protein-1) is a ubiquitous receptor with both cell signaling and ligand endocytosis properties. In the liver, LRP1 serves as a chylomicron remnant receptor and also participates in the transport of extracellular cathepsin D to the lysosome for prosaposin activation. The current study showed that in comparison with wild type mice, hepatocyte-specific LRP1 knock-out (hLrp1(-/-)) mice were more susceptible to fasting-induced lipid accumulation in the liver. Primary hepatocytes isolated from hLrp1(-/-) mice also accumulated more intracellular lipids and experienced higher levels of endoplasmic reticulum (ER) stress after palmitate treatment compared with similarly treated hLrp1(+/+) hepatocytes. Palmitate-treated hLrp1(-/-) hepatocytes displayed similar LC3-II levels, but the levels of p62 were elevated in comparison with palmitate-treated hLrp1(+/+) hepatocytes, suggesting that the elevated lipid accumulation in LRP1-defective hepatocytes was not due to defects in autophagosome formation but was due to impairment of lipophagic lipid hydrolysis in the lysosome. Additional studies showed increased palmitate-induced oxidative stress, mitochondrial and lysosomal permeability, and cell death in hLrp1(-/-) hepatocytes. Importantly, the elevated cell death and ER stress observed in hLrp1(-/-) hepatocytes were abrogated by E64D treatment, whereas inhibiting ER stress diminished cell death but not lysosomal permeabilization. Taken together, these results documented that LRP1 deficiency in hepatocytes promotes lipid accumulation and lipotoxicity through lysosomal-mitochondrial permeabilization and ER stress that ultimately result in cell death. Hence, LRP1 dysfunction may be a major risk factor in fatty liver disease progression.


Assuntos
Estresse do Retículo Endoplasmático , Fígado Gorduroso , Hepatócitos , Estresse Oxidativo , Ácido Palmítico/toxicidade , Receptores de LDL/deficiência , Proteínas Supressoras de Tumor/deficiência , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Lisossomos/genética , Lisossomos/metabolismo , Lisossomos/patologia , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Permeabilidade
20.
J Biol Chem ; 290(24): 14875-83, 2015 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-25922079

RESUMO

Obesity and metabolic disorders such as insulin resistance and type 2 diabetes have become a major threat to public health globally. The mechanisms that lead to insulin resistance in type 2 diabetes have not been well understood. In this study, we show that mice deficient in MAPK phosphatase 5 (MKP5) develop insulin resistance spontaneously at an early stage of life and glucose intolerance at a later age. Increased macrophage infiltration in white adipose tissue of young MKP5-deficient mice correlates with the development of insulin resistance. Glucose intolerance in MKP5-deficient mice is accompanied by significantly increased visceral adipose weight, reduced AKT activation, enhanced p38 activity, and increased inflammation in visceral adipose tissue when compared with wild-type (WT) mice. Deficiency of MKP5 resulted in increased inflammatory activation in macrophages. These findings thus demonstrate that MKP5 critically controls inflammation in white adipose tissue and the development of metabolic disorders.


Assuntos
Tecido Adiposo/patologia , Inflamação/enzimologia , Resistência à Insulina , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Tecido Adiposo/enzimologia , Animais , Glucose/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética
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