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1.
J Chem Inf Model ; 61(9): 4125-4130, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34516123

RESUMO

A recent publication in Science has proposed that cationic amphiphilic drugs repurposed for COVID-19 typically use phosholipidosis as their antiviral mechanism of action in cells but will have no in vivo efficacy. On the contrary, our viewpoint, supported by additional experimental data for similar cationic amphiphilic drugs, indicates that many of these molecules have both in vitro and in vivo efficacy with no reported phospholipidosis, and therefore, this class of compounds should not be avoided but further explored, as we continue the search for broad spectrum antivirals.


Assuntos
COVID-19 , Lipidoses , Preparações Farmacêuticas , Antivirais/toxicidade , Humanos , Lipidoses/tratamento farmacológico , Fosfolipídeos , SARS-CoV-2
2.
Sci Rep ; 11(1): 16314, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381105

RESUMO

Metabolic disorders, including hepatic lipidosis and ketosis, severely affect animal health status and welfare with a large economic burden in dairy herds. The gold standard for diagnosing hepatic lipidosis is the liver biopsy, which is impractical and invasive for the screening at farm level. Ultrasound (US) imaging is a promising technique for identifying liver dysfunction, but standardized specifications in physiological conditions are needed. Herein, we described the features of four US measurements, namely the liver predicted triacylglycerol (pTAG) content, liver depth (LD), and portal vein area (PVA) and depth (PVD) and we investigated their associations with a set of hematochemical (HC) indicators in 342 clinically healthy Holstein Friesian dairy cows. Liver pTAG content was negatively associated with hematocrit and positively with globulin, whereas PVA was negatively associated with thiol group levels, and LD positively with ceruloplasmin. We found significant interactions between some HC parameters and parity: in particular, creatinine, thiol groups and globulin for PVA, and aspartate aminotransferase, paraoxonase and ceruloplasmin for PVD. This study offers new insights on variations in liver function occurring after calving and pave the way for the potential use of minimally invasive techniques for prompt detection of metabolic disorders in dairy herds.


Assuntos
Fígado/metabolismo , Animais , Bovinos , Doenças dos Bovinos/metabolismo , Lipidoses/metabolismo , Doenças Metabólicas/metabolismo , Triglicerídeos/metabolismo , Ultrassonografia/métodos
3.
Science ; 373(6554): 541-547, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34326236

RESUMO

Repurposing drugs as treatments for COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has drawn much attention. Beginning with sigma receptor ligands and expanding to other drugs from screening in the field, we became concerned that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs. For all of the 23 cationic amphiphilic drugs we tested, including hydroxychloroquine, azithromycin, amiodarone, and four others already in clinical trials, phospholipidosis was monotonically correlated with antiviral efficacy. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the physicochemical properties of drugs and does not reflect specific target-based activities-rather, it may be considered a toxic confound in early drug discovery. Early detection of phospholipidosis could eliminate these artifacts, enabling a focus on molecules with therapeutic potential.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos , Lipidoses/induzido quimicamente , Fosfolipídeos/metabolismo , SARS-CoV-2/efeitos dos fármacos , Células A549 , Animais , Antivirais/química , Antivirais/uso terapêutico , Antivirais/toxicidade , COVID-19/virologia , Cátions , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Testes de Sensibilidade Microbiana , SARS-CoV-2/fisiologia , Tensoativos/química , Tensoativos/farmacologia , Tensoativos/toxicidade , Células Vero , Replicação Viral/efeitos dos fármacos
4.
J Pediatr Hematol Oncol ; 43(4): e525-e528, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32516200

RESUMO

Sclerosing lipogranuloma (SLG) in children is a rare, benign disease of unknown etiology suspected to be due to abnormal fatty tissue reaction. A 13-year-old girl presented with progressively worsening back pain. Cross-sectional imaging identified a retroperitoneal mass compressing the left ureter as well as infrarenal inferior vena cava atresia with extensive venous collaterals and chronic partially occlusive thromboses of the iliac veins. Surgical biopsy was consistent with SLG and it resolved spontaneously. SLG is typically a disease of adulthood but may be seen in children. The association between inferior vena cava atresia with venous thrombosis and development of SLG has not been reported previously.


Assuntos
Lipidoses/patologia , Gordura Subcutânea/patologia , Adolescente , Feminino , Humanos , Inflamação/complicações , Inflamação/patologia , Lipidoses/complicações , Fibrose Retroperitoneal/complicações , Fibrose Retroperitoneal/patologia , Veia Cava Inferior/patologia , Trombose Venosa/complicações , Trombose Venosa/patologia
5.
Cell Death Dis ; 11(12): 1069, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33318479

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder and frequently exacerbates in postmenopausal women. In NAFLD, the endoplasmic reticulum (ER) plays an important role in lipid metabolism, in which salubrinal is a selective inhibitor of eIF2α de-phosphorylation in response to ER stress. To determine the potential mechanism of obesity-induced NAFLD, we employed salubrinal and evaluated the effect of ER stress and autophagy on lipid metabolism. Ninety-five female C57BL/6 mice were randomly divided into five groups: standard chow diet, high-fat (HF) diet, HF with salubrinal, HF with ovariectomy, and HF with ovariectomy and salubrinal. All mice except for SC were given HF diet. After the 8-week obesity induction, salubrinal was subcutaneously injected for the next 8 weeks. The expression of ER stress and autophagy markers was evaluated in vivo and in vitro. Compared to the normal mice, the serum lipid level and adipose tissue were increased in obese mice, while salubrinal attenuated obesity by blocking lipid disorder. Also, the histological severity of hepatic steatosis and fibrosis in the liver and lipidosis was suppressed in response to salubrinal. Furthermore, salubrinal inhibited ER stress by increasing the expression of p-eIF2α and ATF4 with a decrease in the level of CHOP. It promoted autophagy by increasing LC3II/I and inhibiting p62. Correlation analysis indicated that lipogenesis in the development of NAFLD was associated with ER stress. Collectively, we demonstrated that eIF2α played a key role in obesity-induced NAFLD, and salubrinal alleviated hepatic steatosis and lipid metabolism by altering ER stress and autophagy through eIF2α signaling.


Assuntos
Autofagia , Estresse do Retículo Endoplasmático , Fator de Iniciação 2 em Eucariotos/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Transdução de Sinais , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Adiposidade/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Cinamatos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipidoses/complicações , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tioureia/análogos & derivados , Tioureia/farmacologia
6.
JCI Insight ; 5(21)2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-32990683

RESUMO

With an expanding aging population burdened with comorbidities, there is considerable interest in treatments that optimize health in later life. Acarbose (ACA), a drug used clinically to treat type 2 diabetes mellitus (T2DM), can extend mouse life span with greater effect in males than in females. Using a genetically heterogeneous mouse model, we tested the ability of ACA to ameliorate functional, pathological, and biochemical changes that occur during aging, and we determined which of the effects of age and drug were sex dependent. In both sexes, ACA prevented age-dependent loss of body mass, in addition to improving balance/coordination on an accelerating rotarod, rotarod endurance, and grip strength test. Age-related cardiac hypertrophy was seen only in male mice, and this male-specific aging effect was attenuated by ACA. ACA-sensitive cardiac changes were associated with reduced activation of cardiac growth-promoting pathways and increased abundance of peroxisomal proteins involved in lipid metabolism. ACA further ameliorated age-associated changes in cardiac lipid species, particularly lysophospholipids - changes that have previously been associated with aging, cardiac dysfunction, and cardiovascular disease in humans. In the liver, ACA had pronounced effects on lipid handling in both sexes, reducing hepatic lipidosis during aging and shifting the liver lipidome in adulthood, particularly favoring reduced triglyceride (TAG) accumulation. Our results demonstrate that ACA, already in clinical use for T2DM, has broad-ranging antiaging effects in multiple tissues, and it may have the potential to increase physical function and alter lipid biology to preserve or improve health at older ages.


Assuntos
Acarbose/farmacologia , Envelhecimento/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Coração/efeitos dos fármacos , Lipidoses/tratamento farmacológico , Hepatopatias/tratamento farmacológico , Condicionamento Físico Animal , Fatores Etários , Animais , Feminino , Inibidores de Glicosídeo Hidrolases/farmacologia , Lipidoses/metabolismo , Hepatopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Fatores Sexuais
7.
Anal Chem ; 92(16): 11223-11231, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32664717

RESUMO

Lipid droplets (LDs) are organelles that play a major role in regulating the storage of neutral lipids. Dysregulation of LDs is associated with metabolic disorders, such as fatty liver diseases, obesity, diabetes, and atherosclerosis. We have developed LD-selective small-molecule fluorescence probes (probes 3 and 4) that are available for both one- and two-photon microscopy, employing live or fixed cells. We found that probes 3 and 4 sensitively detect the increased LDs in response to oleic acid or endoplasmic reticulum stress, both in cells and tissues of the liver. The narrow absorption and emission bands of probes 3 and 4 allow multicolor imaging for the study of the role of LDs in pathophysiology and LD-associated signaling by the coapplication of the probes for different organelles or antibodies against specific proteins. In addition, we show here, for the first time, that two-photon microscopy imaging using our LD-selective probes with LysoTracker provides a novel method for screening drugs to potentially induce steatosis and/or phospholipidosis.


Assuntos
Fígado Gorduroso/diagnóstico por imagem , Corantes Fluorescentes/química , Gotículas Lipídicas/metabolismo , Lipidoses/diagnóstico por imagem , Animais , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/efeitos da radiação , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado Gorduroso/induzido quimicamente , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Células HeLa , Humanos , Lipidoses/induzido quimicamente , Camundongos , Microscopia de Fluorescência , Fótons
8.
Nutr Diabetes ; 10(1): 20, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32518225

RESUMO

INTRODUCTION: Obesity is a multifactorial chronic inflammatory disease. Consumption of high energy density (HED) diets is associated with hyperphagia, increased body weight and body fat accumulation, and obesity. Our lab has previously shown that short-term (4 weeks) consumption of a HED diet triggers gut microbiota dysbiosis, gut inflammation, and reorganization of the gut-brain vagal communication. OBJETIVES: The aim of this study was to investigate the effect of long-term (6 months) consumption of HED diet on body composition, gut microbiome, hepatocellular lipidosis, microglia activation in the nucleus of the solitary tract, and systemic inflammation. METHODS: Male Sprague-Dawley rats were fed a low energy density (LED) diet for 2 weeks and then switched to a HED diet for 26 weeks. Twenty-four-hour food intake, body weight, and body composition were measured twice a week. Blood serum and fecal samples were collected at baseline, 1, 4, 8, and 26 weeks after introduction of the HED diet. Serum samples were used to measure insulin, leptin, and inflammatory cytokines using Enzyme-linked Immunosorbent Assay. Fecal samples were assessed for 16 S rRNA genome sequencing. RESULTS: HED diet induced microbiota dysbiosis within a week of introducing the diet. In addition, there was significant microglia activation in the intermediate NTS and marked hepatic lipidosis after 4 weeks of HED diet. We further observed changes in the serum cytokine profile after 26 weeks of HED feeding. CONCLUSIONS: These data suggest that microbiota dysbiosis is the first response of the organism to HED diets, followed by increased liver fat accumulation, microglia activation in the brain, and circulating levels of inflammatory markers. To our knowledge, this is the first study to present longitudinal and cross-sectional results on effect of long-term consumption of HED diets on all these parameters in a single cohort of animals.


Assuntos
Dieta/métodos , Disbiose/metabolismo , Lipidoses/metabolismo , Microglia/metabolismo , Núcleo Solitário/metabolismo , Tecido Adiposo/metabolismo , Animais , Composição Corporal , Peso Corporal , Estudos Transversais , Citocinas/sangue , Microbioma Gastrointestinal , Humanos , Inflamação/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Ratos , Ratos Sprague-Dawley
9.
Int J Mol Sci ; 21(8)2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32340283

RESUMO

Drug-induced phospholipidosis (PL) is a storage disorder caused by the formation of phospholipid-drug complexes in lysosomes. Because of the diversity of PL between species, human cell-based assays have been used to predict drug-induced PL in humans. We established three-dimensional (3D) human liver organoids as described previously and investigated their liver characteristics through multiple analyses. Drug-induced PL was initiated in these organoids and in monolayer HepG2 cultures, and cellular changes were systemically examined. Organoids that underwent differentiation showed characteristics of hepatocytes rather than HepG2 cells. The organoids also survived under PL-inducing drug conditions for 48 h and maintained a more stable albumin secretion level than the HepG2 cells. More cytoplasmic vacuoles were observed in organoids and HepG2 cells treated with more potent PL-induced drugs, but to a greater extent in organoids than in HepG2 cells. Lysosome-associated membrane protein 2, a marker of lysosome membranes, showed a stronger immunohistochemical signal in the organoids. PL-distinctive lamellar bodies were observed only in amiodarone-treated organoids by transmission electron microscopy. Human liver organoids are thus more sensitive to drug-induced PL and less affected by cytotoxicity than HepG2 cells. Since PL is a chronic condition, these results indicate that organoids better reflect metabolite-mediated hepatotoxicity in vivo and could be a valuable system for evaluating the phospholipidogenic effects of different compounds during drug development.


Assuntos
Lipidoses/etiologia , Lipidoses/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fosfolipídeos/metabolismo , Albuminas/biossíntese , Biomarcadores , Sobrevivência Celular/efeitos dos fármacos , Suscetibilidade a Doenças , Expressão Gênica , Glicogênio/metabolismo , Células Hep G2 , Humanos , Imuno-Histoquímica , Lipidoses/patologia , Fígado/patologia , Fígado/ultraestrutura , Organoides , Técnicas de Cultura de Tecidos
10.
Bioorg Med Chem Lett ; 30(9): 126933, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32044185

RESUMO

In this paper, we present the phospholipidosis-inducing potential (PLIP) of forty fragment-sized diamines derived from N-benzyl-4-(methylamino)piperidine and discuss the relationship between their PLIP and the physicochemical properties. Our results demonstrate that the previously reported methods are not suitable for predicting the PLIP of fragment-sized diamines; the second basic pKa can distinguish PLIP-positive diamines from PLIP-negative diamines more accurately than ClogP or most basic pKa. To the best of our knowledge, this is the first report describing the relationship between PLIP and second basic pKa.


Assuntos
Diaminas/farmacologia , Lipidoses/induzido quimicamente , Diaminas/efeitos adversos , Diaminas/química , Concentração de Íons de Hidrogênio , Estrutura Molecular , Relação Estrutura-Atividade
11.
Metabolism ; 102: 154002, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706979

RESUMO

BACKGROUND: AMP-activated protein kinase (AMPK), particularly AMPKα2 isoform, plays a critical role in maintaining cardiac homeostasis. It was reported that sulforaphane (SFN) prevented type 2 diabetes (T2D)-induced cardiomyopathy accompanied by the activation of AMPK; In this study, AMPK's pivotal role in SFN-mediated prevention against T2D-induced cardiomyopathy was tested using global deletion of AMPKα2 gene (AMPKα2-KO) mice. METHODS AND RESULTS: T2D was established by feeding 3-month high-fat diet (HFD) to induce insulin resistance, followed by an intraperitoneal injection of streptozotocin (STZ) to induce mild hyperglycemia in both AMPKα2-KO and wild-type (WT) mice. Then both T2D and control mice were subsequently treated with or without SFN for 3 months while continually feeding HFD or normal diet. Upon completion of the 3-month treatment, five mice from each group were sacrificed as a 3-month time-point (3 M). The rest continued normal diet or HFD until terminating study at the sixth month (6 M) of diabetes. Cardiac function was examined with echocardiography before sacrifice at both 3 M and 6 M. SFN prevented T2D-induced progression of cardiac dysfunction, remodeling (hypertrophy and fibrosis), inflammation, and oxidative damage in wild-type diabetic mice, but not in AMPKα2-KO mice. Mechanistically, SFN prevented T2D-induced cardiomyopathy not only by improving AMPK-mediated lipid metabolic pathways, but also enhancing NRF2 activation via AMPK/AKT/GSK3ß pathway. However, these improving effects of SFN were abolished in AMPKα2-KO diabetic mice. CONCLUSIONS: AMPK is indispensable for the SFN-induced prevention of cardiomyopathy in T2D, and the activation of NRF2 by SFN is mediated by AMPK/AKT/GSK3ß signaling pathways.


Assuntos
Cardiotônicos/farmacologia , Diabetes Mellitus Tipo 2/complicações , Cardiomiopatias Diabéticas/prevenção & controle , Isotiocianatos/farmacologia , Lipidoses/prevenção & controle , Fator 2 Relacionado a NF-E2/fisiologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/fisiologia , Animais , Cardiotônicos/uso terapêutico , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/patologia , Isotiocianatos/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Lipidoses/genética , Lipidoses/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Estreptozocina
12.
J Feline Med Surg ; 22(6): 500-505, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31322470

RESUMO

OBJECTIVES: The aim of this study was to evaluate if de novo hepatic lipid synthesis contributes to fatty acid overload in the liver of cats with feline hepatic lipidosis (FHL). METHODS: Lipogenic gene expression of peroxisome proliferator-activated receptor-alpha (PPAR-α), peroxisome proliferator-activated receptor-gamma (PPAR-γ), fatty acid synthase (FASN) and sterol regulatory element-binding factor (SREBF1) were evaluated using quantitative RT-PCR in liver tissue of six cats with FHL and compared with the liver tissue of eight healthy cats. RESULTS: In liver tissue, PPAR-α, PPAR-γ and FASN mRNA expression levels were not significantly different (P >0.12, P >0.89 and P >0.5, respectively) in the FHL group compared with the control group. SREBF1 gene expression was downregulated around 10-fold in the FHL group vs the control group (P = 0.039). CONCLUSIONS AND RELEVANCE: The downregulation of SREBF1 in the liver tissue of cats with FHL does not support the hypothesis that de novo lipogenesis in the liver is an important pathway of fatty acid accumulation in FHL.


Assuntos
Doenças do Gato/genética , Expressão Gênica , Lipidoses/veterinária , Lipogênese/genética , Animais , Doenças do Gato/metabolismo , Gatos , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Lipidoses/genética , Lipidoses/metabolismo , Lipídeos/biossíntese , Fígado/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
13.
J Vet Intern Med ; 34(1): 132-138, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31830357

RESUMO

BACKGROUND: Hepatic lipidosis is increasing in incidence in the Western world, with cats being particularly sensitive. When cats stop eating and start utilizing their fat reserves, free fatty acids (FFAs) increase in blood, causing an accumulation of triacylglycerol (TAG) in the liver. OBJECTIVE: Identifying potential new drugs that can be used to treat hepatic lipidosis in cats using a feline hepatic organoid system. ANIMALS: Liver organoids obtained from 6 cats. METHODS: Eight different drugs were tested, and the 2 most promising were further studied using a quantitative TAG assay, lipid droplet staining, and qPCR. RESULTS: Both T863 (a diacylglycerol O-acyltransferase 1 [DGAT1] inhibitor) and 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR; an adenosine monophosphate kinase activator) decreased TAG accumulation by 55% (P < .0001) and 46% (P = .0003), respectively. Gene expression of perilipin 2 (PLIN2) increased upon the addition of FFAs to the medium and decreased upon treatment with AICAR but not significantly after treatment with T863. CONCLUSIONS AND CLINICAL IMPORTANCE: Two potential drugs useful in the treatment of hepatic lipidosis in cats were identified. The drug T863 inhibits DGAT1, indicating that DGAT1 is the primary enzyme responsible for TAG synthesis from external fatty acids in cat organoids. The drug AICAR may act as a lipid-lowering compound via decreasing PLIN2 mRNA. Liver organoids can be used as an in vitro tool for drug testing in a species-specific system and provide the basis for further clinical testing of drugs to treat steatosis.


Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Doenças do Gato/tratamento farmacológico , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Fígado Gorduroso/veterinária , Lipidoses/veterinária , Organoides/metabolismo , Ribonucleotídeos/farmacologia , Aminoimidazol Carboxamida/farmacologia , Animais , Doenças do Gato/metabolismo , Gatos , Ácidos Graxos não Esterificados/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Lipidoses/tratamento farmacológico , Lipidoses/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia
14.
Int J Med Sci ; 16(12): 1593-1603, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31839747

RESUMO

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its pathogenesis and mechanism are intricate. In the present study, we aimed to evaluate the role of PPAR δ in LPS associated NAFLD and to investigate the signal transduction pathways underlying PPAR δ treatment in vitro. Material and Methods: L02 cells were exposed to palmitic acid (PA) and/or LPS in the absence or presence of PPAR δ inhibition and/or activation. Results: LPS treatment markedly increased lipid deposition, FFA contents, IL-6 and TNF-α levels, and cell apoptosis in PA treatment (NAFLD model). PPAR δ inhibition protects L02 cells against LPS-induced lipidosis and injury. Conversely, the result of PPAR δ activation showed the reverse trend. LPS+PA treatment group significantly decreases the relative expression level of IRS-1, PI3K, AKT, phosphorylation of AKT, TLR-4, MyD88, phosphorylation of IKKα, NF-κB, Bcl-2 and increases the relative expression level of Bax, cleaved caspase 3 and cleaved caspase 8, compared with the cells treated with NAFLD model. PPAR δ inhibition upregulated the related proteins' expression level in insulin resistance and inflammation pathway and downregulated apoptotic relevant proteins. Instead, PPAR δ agonist showed the reverse trend. Conclusion: Our data show that PPAR δ inhibition reduces steatosis, inflammation and apoptosis in LPS-related NAFLD damage, in vitro. PPAR δ may be a potential therapeutic implication for NAFLD.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Lipidoses/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR delta/genética , Substâncias Protetoras/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Hepatócitos/efeitos dos fármacos , Humanos , Lipidoses/genética , Lipidoses/metabolismo , Lipidoses/patologia , Lipídeos/genética , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR delta/agonistas , PPAR delta/antagonistas & inibidores , Ácido Palmítico/toxicidade , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tiazóis/farmacologia
15.
Rev. lab. clín ; 12(4): e21-e33, oct.-dic. 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-187309

RESUMO

Las dislipidemias son alteraciones del metabolismo lipídico que cursan con concentraciones de lípidos alteradas, tanto por exceso como por defecto. Estas alteraciones están fuertemente asociadas con el proceso aterosclerótico, y se ha demostrado que el control de dichas alteraciones consigue disminuir la incidencia de episodios de origen isquémico. Diagnosticar las dislipidemias desde un punto de vista etiológico es muy importante, ya que el riesgo cardiovascular al que predispone cada una de ellas es diferente, dependiendo del tipo de lipoproteína que esté alterada y de su concentración. Por ello es de gran utilidad disponer de algoritmos diagnósticos sencillos que incluyan magnitudes del metabolismo lipídico disponibles en la mayoría de los laboratorios clínicos, con el fin de realizar el diagnóstico inicial del tipo de dislipidemia, en caso de poseer las herramientas diagnósticas adecuadas identificarla y, en caso contrario, disponer de la información apropiada para recomendar la ampliación del estudio en otro centro que disponga de los recursos necesarios para establecer el diagnóstico


Dyslipidaemias are alterations in lipid metabolism that involve an excess, as well as a deficit, in lipid concentrations. These alterations are strongly associated with atherosclerosis, and it has been shown that its control reduces the incidence of episodes of ischaemic origin. Diagnosing dyslipidaemias from an aetiological point of view is very important, since the cardiovascular risk to which each one predisposes is different, and depends on the type of lipoprotein that is altered and its concentration. For this reason, it is very useful to have simple diagnostic algorithms that include the measurements of lipid metabolism that are available in most clinical laboratories in order to make the initial diagnosis of the type of dyslipidaemia. In the case of having the right diagnostic tools, identify it; and if not, to have the appropriate information to recommend the extension of the study in another centre with resources to establish the diagnosis


Assuntos
Humanos , Dislipidemias/diagnóstico , Transtornos do Metabolismo dos Lipídeos/diagnóstico , Hiperlipidemias/diagnóstico , Lipidoses/diagnóstico , Hipercolesterolemia/diagnóstico , Colesterol/sangue , Lipídeos/sangue , Técnicas de Laboratório Clínico/métodos , Guias como Assunto , Metabolismo dos Lipídeos/fisiologia , Dislipidemias/classificação , Diagnóstico Diferencial
16.
Anal Bioanal Chem ; 411(30): 8023-8032, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31776643

RESUMO

Within drug development and pre-clinical trials, a common, significant and poorly understood event is the development of drug-induced lipidosis in tissues and cells. In this manuscript, we describe a mass spectrometry imaging strategy, involving repeated analysis of tissue sections by DESI MS, in positive and negative polarities, using MS and MS/MS modes. We present results of the detected distributions of the administered drug, drug metabolites, lipid molecules and a putative marker of lipidosis, di-docosahexaenoyl (22:6)-bis(monoacylglycerol) phosphate (di-22:6-BMP). A range of strategies have previously been reported for detection, isolation and identification of this compound, which is an isomer of di-docosahexaenoic (22:6 n-3) phosphatidylglycerol (di-22:6 PG), a commonly found lipid that acts as a surfactant in lung tissues. We show that MS imaging using MS/MS can be used to differentiate these compounds of identical mass, based upon the different distributions of abundant fragment ions. Registration of images of these fragments, and detected drugs and metabolites, is presented as a new method for studying drug-induced lipidosis in tissues. Graphical abstract.


Assuntos
Biomarcadores/metabolismo , Lipidoses/induzido quimicamente , Pulmão/diagnóstico por imagem , Espectrometria de Massas/métodos , Amiodarona/efeitos adversos , Animais , Antiarrítmicos/efeitos adversos , Masculino , Ratos Wistar , Roedores
17.
J Theor Biol ; 479: 37-47, 2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31310757

RESUMO

Phospholipidosis is characterized by the presence of excessive accumulation of phospholipids in different tissue types (lungs, liver, eyes, kidneys etc.) caused by cationic amphiphilic drugs. Electron microscopy analysis has revealed the presence of lamellar inclusion bodies as the hallmark of phospholipidosis. Some phospholipidosis causing compounds can cause tissue specific inflammatory/retrogressive changes. Reliable and accurate in silico methods could facilitate early screening of phospholipidosis inducing compounds which can subsequently speed up the pharmaceutical drug discovery pipelines. In the present work, stacking ensembles are implemented for combining a number of different base learners to develop predictive models (a total of 256 trained machine learning models were tested) for phospholipidosis inducing compounds using a wide range of molecular descriptors (ChemMine, JOELib, Open babel and RDK descriptors) and structural alerts as input features. The best model consisting of stacked ensemble of machine learning algorithms with random forest as the second level learner outperformed other base and ensemble learners. JOELib descriptors along with structural alerts performed better than the other types of descriptor sets. The best ensemble model achieved an overall accuracy of 88.23%, sensitivity of 86.27%, specificity of 90.20%, mcc of 0.765, auc of 0.896 with 88.21 g-means. To assess the robustness and stability of the best ensemble model, it is further evaluated using stratified 10×10 fold cross validation and holdout testing sets (repeated 10 times) achieving 84.83% mean accuracy with 0.708 mean mcc and 88.46% mean accuracy with 0.771 mean mcc respectively. A comparison of different meta classifiers (Generalized linear regression, Gradient boosting machines, Random forest and Deep learning neural networks) in stacking ensemble revealed that random forest is the better choice for combining multiple classification models.


Assuntos
Lipidoses/diagnóstico , Modelos Estatísticos , Fosfolipídeos/metabolismo , Área Sob a Curva , Descoberta de Drogas , Humanos , Lipidoses/induzido quimicamente , Lipidoses/etiologia , Aprendizado de Máquina/normas , Sensibilidade e Especificidade
18.
Invest Ophthalmol Vis Sci ; 60(5): 1789-1798, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31022733

RESUMO

Purpose: To determine major differences in lipid profile between human control and glaucomatous optic nerve. To assess major enzymes in lipid pathway if aberration is revealed for a lipid class by profiling. Methods: Optic nerve (ON) samples were obtained from human cadaveric donors [control (n = 11) and primary open-angle glaucoma (POAG; n = 12)]; the lipids were extracted using Bligh and Dyer methods. Control and glaucoma donors were all Caucasians age 72.3 ± 5.9 and 70.3 ± 10.5 (inclusive of both sexes), respectively. Lipids were extracted after weighing the tissue; the protein amounts in the corresponding aqueous phase of organic solvent extraction were recorded. High-resolution mass spectrometry was performed using a Q-exactive mass spectrometer coupled with an EASY-nLC 1000 liquid chromatograph instrument. Bioinformatics and statistical analysis were performed using LipidSearch v.4.1 and MetaboAnalyst 4.0/STATA 14.2. Protein amounts were determined using Bradford's method. Western blot, ELISA, and immunohistochemistry utilized established protocols and were performed for protein quantification and localization, respectively. Additional donor tissues were utilized for Western blot, ELISA, and immunohistochemistry. Results: Principal component analysis (PCA) placed control and glaucomatous ONs in two distinct groups based on analysis of lipid profiles. Total lipid, total phospholipids, total ceramide, and total sphingolipids were similar (without significant difference) between control and glaucoma. However, we found a significant increase in glucosylsphingosine in glaucoma compared to control samples. We found similar levels of glucocerebrosidase (GBA), ceramide glucosyltransferase (UGCG), decreased nonlysosomal glucocerebrosidase (GBA2), and increased lysosomal and nonlysosomal acylsphingosine amidohydrolase (ASAH1 and ASAH2) levels in glaucomatous ON compared to control. Conclusions: We found significant differences in glucosylsphingosine lipids, consistent with decreased GBA and GBA2 and increased ASAH1 and ASAH2 immunoreactivity in glaucoma, suggesting the potential impairment of sphingolipid enzymatic pathways in lysosomal and nonlysosomal cellular compartments.


Assuntos
Glaucoma de Ângulo Aberto/metabolismo , Metabolismo dos Lipídeos , Lipidoses/metabolismo , Nervo Óptico/metabolismo , Psicosina/análogos & derivados , Ceramidase Ácida/metabolismo , Idoso , Western Blotting , Cromatografia Líquida de Alta Pressão , Ensaio de Imunoadsorção Enzimática , Feminino , Glucosilceramidase/metabolismo , Glucosiltransferases/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Espectrometria de Massas , Ceramidase Neutra/metabolismo , Psicosina/metabolismo , beta-Glucosidase/metabolismo
19.
Poult Sci ; 98(9): 3950-3962, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30941423

RESUMO

Hepatic lipidosis (HL) is a well-known disease in fattening and in parent turkey flocks. Among others, dietary effects like (a lack of) essential amino acids (AA) as lipotrophic factors (e.g., methionine) have been considered as potentially predispositing for HL. Several studies have reported abnormal AA profiles in hepatic diseases of humans and other livestock. The ratio of branched-chain amino acids (BCAA) to aromatic amino acids (AAA) in plasma is used to predict hepatic cirrhosis. In this study, the state of supply of AA was investigated by comparing non-affected (NA) animals and those affected by HL. The AA pattern in the liver and blood can provide potential indications of pathogenesis of HL. In cooperation with German poultry veterinarians, 3 cases of HL on 3 different fattening turkey farms were visited (13/14 wk old, "B.U.T. Big 6" and "TP7"). Overall, 73 birds were examined, of which 42 birds suffered from HL and 31 were not affected. Feeding samples of the respective actual feed were taken and analyzed. The selection of animals was carried out (NA randomly) by clinical signs such as apathy and dyspnea and the diagnosis was made at necropsy, which could be confirmed by crude fat content in liver tissue (HL: 309, NA: 155). In liver tissue, the CP and AA contents were lower among animals with HL than among NA (P < 0.05). In blood samples, the sum of AA, ammonia, and urea was more than 3 times higher among animals with HL (431 mg/dL serum) than among NA (114 mg/dL serum; P < 0.01). The ratio of BCAA to AAA was also significantly different between the groups (HL: 0.85, NA: 1.42; P < 0.05). In the case of HL, entire herds were not affected and the "non-affected" ones were comparable with healthy slaughtered animals. There seems to be a clear change in protein and AA metabolism of HL animals, which could lead to an optimization in feeding practice in repeated cases of HL.


Assuntos
Aminoácidos/metabolismo , Lipidoses/veterinária , Hepatopatias/veterinária , Doenças das Aves Domésticas/metabolismo , Perus , Aminoácidos/sangue , Animais , Feminino , Lipidoses/sangue , Lipidoses/etiologia , Lipidoses/metabolismo , Hepatopatias/sangue , Hepatopatias/etiologia , Hepatopatias/metabolismo , Doenças das Aves Domésticas/sangue , Doenças das Aves Domésticas/etiologia
20.
Pharmacol Res ; 141: 189-200, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30593851

RESUMO

Topiramate is an anticonvulsant drug also prescribed for migraine prophylaxis that acts through several mechanisms of action. Several studies indicate that topiramate induces weight loss and a moderate reduction of plasma lipids and glucose. Based on these favourable metabolic effects, aim of this study was to evaluate if topiramate could modulate atherosclerosis development and protect target organs of dysmetabolic conditions. Thirty apoE-deficient mice were divided into three groups and fed for 12 weeks a high fat diet (Control) or the same diet containing topiramate at 0.125% and 0.250%. Body weight, water and food intake were monitored throughout the study. Plasma lipids and glucose levels were measured and a glucose tolerance test was performed. Atherosclerosis development was evaluated in the whole aorta and at the aortic sinus. Histological analysis of liver, kidney and adipose tissue was performed. Topiramate did not affect weight gain and food intake. Glucose tolerance and plasma lipids were not changed and, in turn, atherosclerosis development was not different among groups. Topiramate did not modify liver and adipose tissue histology. Conversely, in the kidneys, the treatment reduced the occurrence of glomerular lipidosis by decreasing foam cells accumulation and reducing the expression of inflammatory markers. Blood urea nitrogen levels were also reduced by treatment. Our results indicate that topiramate does not affect atherosclerosis development, but preserves kidney structure and function. The study suggests that topiramate could be investigated in drug repurposing studies for the treatment of glomerular lipidosis.


Assuntos
Rim/efeitos dos fármacos , Lipidoses/prevenção & controle , Substâncias Protetoras/farmacologia , Topiramato/farmacologia , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Glicemia/análise , Dieta Hiperlipídica , Feminino , Rim/metabolismo , Rim/patologia , Lipidoses/metabolismo , Lipidoses/patologia , Lipídeos/sangue , Camundongos Knockout para ApoE
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