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1.
Molecules ; 26(16)2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34443516

RESUMO

Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases such as atherosclerosis and neurodegeneration. Thus, the design of multifunctional compounds that can concurrently tackle two or more therapeutic targets is an appealing approach. In this study, the basic NSAID structure was fused with the antioxidant moieties 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHB), its reduced alcohol 3,5-di-tert-butyl- 4-hydroxybenzyl alcohol (BHBA), or 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox), a hydrophilic analogue of α-tocopherol. Machine learning algorithms were utilized to validate the potential dual effect (anti-inflammatory and antioxidant) of the designed analogues. Derivatives 1-17 were synthesized by known esterification methods, with good to excellent yields, and were pharmacologically evaluated both in vitro and in vivo for their antioxidant and anti-inflammatory activity, whereas selected compounds were also tested in an in vivo hyperlipidemia protocol. Furthermore, the activity/binding affinity of the new compounds for lipoxygenase-3 (LOX-3) was studied not only in vitro but also via molecular docking simulations. Experimental results demonstrated that the antioxidant and anti-inflammatory activities of the new fused molecules were increased compared to the parent molecules, while molecular docking simulations validated the improved activity and revealed the binding mode of the most potent inhibitors. The purpose of their design was justified by providing a potentially safer and more efficient therapeutic approach for multifactorial diseases.


Assuntos
Antioxidantes/química , Aterosclerose/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Inibidores de Lipoxigenase/química , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/química , Antioxidantes/síntese química , Antioxidantes/farmacologia , Aterosclerose/patologia , Cromanos/química , Cromanos/farmacologia , Desenho de Fármacos , Humanos , Hiperlipidemias/patologia , Hipolipemiantes/síntese química , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Inflamação/patologia , Lipoxigenase/química , Lipoxigenase/efeitos dos fármacos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacologia , Simulação de Acoplamento Molecular , Degeneração Neural/tratamento farmacológico , Degeneração Neural/patologia , Estresse Oxidativo/efeitos dos fármacos , Parabenos/química , Parabenos/farmacologia , Relação Estrutura-Atividade
2.
Molecules ; 26(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299638

RESUMO

The endoplasmic reticulum (ER) plays a multifunctional role in lipid biosynthesis, calcium storage, protein folding, and processing. Thus, maintaining ER homeostasis is essential for cellular functions. Several pathophysiological conditions and pharmacological agents are known to disrupt ER homeostasis, thereby, causing ER stress. The cells react to ER stress by initiating an adaptive signaling process called the unfolded protein response (UPR). However, the ER initiates death signaling pathways when ER stress persists. ER stress is linked to several diseases, such as cancer, obesity, and diabetes. Thus, its regulation can provide possible therapeutic targets for these. Current evidence suggests that chronic hyperglycemia and hyperlipidemia linked to type II diabetes disrupt ER homeostasis, thereby, resulting in irreversible UPR activation and cell death. Despite progress in understanding the pathophysiology of the UPR and ER stress, to date, the mechanisms of ER stress in relation to type II diabetes remain unclear. This review provides up-to-date information regarding the UPR, ER stress mechanisms, insulin dysfunction, oxidative stress, and the therapeutic potential of targeting specific ER stress pathways.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Estresse do Retículo Endoplasmático , Estresse Oxidativo , Transdução de Sinais , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia
3.
Biomed Pharmacother ; 139: 111668, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243630

RESUMO

Metabolic Syndrome (MetS) is a complex and multifactorial condition often characterised by obesity, hypertension, hyperlipidaemia, insulin resistance, glucose intolerance and fasting hyperglycaemia. Collectively, MetS can increase the risk of atherosclerotic-cardiovascular disease, which is the leading cause of death worldwide. However, no animal model currently exists to study MetS in the context of atherosclerosis. In this study we developed a pre-clinical mouse model that recapitulates the spectrum of MetS features while developing atherosclerosis. When BPHx mice were placed on a western type diet for 16 weeks, all the classical characteristics of MetS were observed. Comprehensive metabolic analyses and atherosclerotic imaging revealed BPHx mice to be obese and hypertensive, with elevated total plasma cholesterol and triglyceride levels, that accelerated atherosclerosis. Altogether, we demonstrate that the BPHx mouse has all the major components of MetS, and accelerates the development of atherosclerosis.


Assuntos
Aterosclerose/patologia , Dieta/efeitos adversos , Hipertensão/patologia , Síndrome Metabólica/patologia , Animais , Aterosclerose/sangue , Aterosclerose/metabolismo , Glicemia/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Hiperglicemia/sangue , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Hipertensão/sangue , Hipertensão/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/metabolismo , Obesidade/patologia , Triglicerídeos/sangue
4.
Chem Biodivers ; 18(8): e2100049, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34118114

RESUMO

We aimed to investigate the impact of apigenin on LOX-1, Bcl-2, and Bax expression in hyperlipidemia rats and explore the possible molecular pathological mechanism of apigenin in improving hyperlipidemia and preventing atherosclerosis. In hyperlipidemia models, the levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c) and the LOX-1 protein expression were apparently increased (P<0.01), while the high-density lipoprotein cholesterol (HDL-c) levels and the ratio of Bcl-2/Bax were reduced significantly (P<0.01) in comparison with the standard control group. After the treatment of apigenin, the levels of TC, TG, LDL-c, and the LOX-1 protein expression were noticeably decreased (P<0.01), while the levels of HDL-c and the Bcl-2/Bax ratio were increased (P<0.01). The intima was thickened and had protrusions in the hyperlipidemia model group compared to the normal control group. In comparison with the atherosclerosis model group, the degree of aortic lesions in the low-dose, middle-dose, high-dose groups was alleviated. Apigenin can reduce the level of blood lipid, improve hyperlipidemia, and prevent atherosclerosis in hyperlipidemia rats. The molecular mechanism may be related to inhibiting LOX-1 gene expression and increasing the Bcl-2/Bax ratio.


Assuntos
Apigenina/farmacologia , Expressão Gênica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores Depuradores Classe E/metabolismo , Proteína X Associada a bcl-2/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Apigenina/uso terapêutico , Colesterol/sangue , Modelos Animais de Doenças , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/patologia , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ratos , Ratos Sprague-Dawley , Receptores Depuradores Classe E/genética , Triglicerídeos/sangue , Proteína X Associada a bcl-2/genética
5.
Eur J Med Chem ; 221: 113522, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33984804

RESUMO

Statins play an important role in the treatment of hyperlipidemia, but drug resistance and adverse effects greatly limits their application. To discover new lipid-lowering drugs, three different series of tetrahydroprotoberberine derivatives (THPBs) were designed and synthesized. These compounds were first tested for their effects on viability of HepG2 cells and 21 compounds with the percent of cell viability over 90% were further screened to evaluate their ability to reduce total cholesterol (TC) and triglyceride (TG) levels. Among these derivatives, two compounds displayed significant down-regulation both intracellular of TC and TG content, especially compound 49 exhibited the greatest efficacy. Mechanistically, compound 49 promoted proteasomal degradation of SREBPs. Importantly, compound 49 displayed superior bioavailability (F = 65.1%) and obvious efficacy in the treatment of high fat diet induced obesity in vivo. Therefore, compound 49 is a promising candidate to develop new treatment of hyperlipidemia.


Assuntos
Antineoplásicos/farmacologia , Alcaloides de Berberina/farmacologia , Desenho de Fármacos , Hiperlipidemias/tratamento farmacológico , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 2/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Alcaloides de Berberina/síntese química , Alcaloides de Berberina/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Estrutura Molecular , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Relação Estrutura-Atividade
6.
PLoS One ; 16(3): e0247638, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33764994

RESUMO

CONTEXT: Obesity, is a state of chronic inflammation, characterized by elevated lipids, insulin resistance and relative hypogonadotropic hypogonadism. We have defined the accompanying decreased Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), ovarian steroids and reduced pituitary response to Gonadotropin-releasing Hormone (GnRH) as Reprometabolic syndrome, a phenotype that can be induced in healthy normal weight women (NWW) by acute infusion of free fatty acids and insulin. OBJECTIVE: To identify potential mediators of insulin and lipid-related reproductive endocrine dysfunction. DESIGN, SETTING, PARTICIPANTS: Secondary analysis of crossover study of eumenorrheic reproductive aged women of normal Body Mass Index (BMI) (<25 kg/m2) at an academic medical center. INTERVENTION: Participants underwent 6-hour infusions of either saline/heparin or insulin plus fatty acids (Intralipid plus heparin), in the early follicular phase of sequential menstrual cycles, in random order. Euglycemia was maintained by glucose infusion. Frequent blood samples were obtained. MAIN OUTCOME MEASURES: Pooled serum from each woman was analyzed for cytokines, interleukins, chemokines, adipokines, Fibroblast Growth Factor-21 (FGF-21) and markers of endoplasmic reticulum (ER) stress (CHOP and GRP78). Wilcoxon signed-rank tests were used to compare results across experimental conditions. RESULTS: Except for Macrophage Inflammatory Protein-1ß (MIP-1ß), no significant differences were observed in serum levels of any of the inflammatory signaling or ER stress markers tested. CONCLUSION: Acute infusion of lipid and insulin, to mimic the metabolic syndrome of obesity, was not associated with an increase in inflammatory markers. These results imply that the endocrine disruption and adverse reproductive outcomes of obesity are not a consequence of the ambient inflammatory environment but may be mediated by direct lipotoxic effects on the hypothalamic-pituitary-ovarian (HPO) axis.


Assuntos
Ácidos Graxos não Esterificados/administração & dosagem , Hiperinsulinismo/metabolismo , Hiperlipidemias/metabolismo , Insulina/administração & dosagem , Síndrome Metabólica/metabolismo , Transdução de Sinais , Centros Médicos Acadêmicos , Adolescente , Adulto , Índice de Massa Corporal , Estudos Cross-Over , Citocinas/genética , Citocinas/metabolismo , Estresse do Retículo Endoplasmático , Emulsões Gordurosas Intravenosas/administração & dosagem , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Hormônio Foliculoestimulante/genética , Hormônio Foliculoestimulante/metabolismo , Expressão Gênica , Aptidão Genética/efeitos dos fármacos , Aptidão Genética/genética , Técnica Clamp de Glucose , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Hiperinsulinismo/induzido quimicamente , Hiperinsulinismo/genética , Hiperinsulinismo/patologia , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/genética , Hiperlipidemias/patologia , Hormônio Luteinizante/genética , Hormônio Luteinizante/metabolismo , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo
7.
Dokl Biochem Biophys ; 496(1): 10-13, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33689066

RESUMO

It was established that the administration of an aqueous solution of bis(µ-tartrato)di(µ-hydroxy) germanate (IV) triethanolammonium to animals daily for 2 months at a dose of the active substance of 10 mg/kg of the animal's weight leads to inhibition of the total activity of the alkaline phospholipase A2 of mononuclear cells. The results of the study can be used to correct lipid metabolism in the development of disorders in hyperlipidemia. This makes it possible to expand the scope of use of the studied substance and create new pharmaceuticals based on bis(µ-tartrato)di(µ-hydroxy) germanate (IV) triethanolammonium prevent and inhibit the development of hyperlipidemia.


Assuntos
Etanolaminas/farmacologia , Hiperlipidemias/tratamento farmacológico , Compostos Organometálicos/farmacologia , Inibidores de Fosfolipase A2/farmacologia , Fosfolipases A2/metabolismo , Animais , Colesterol/sangue , Germânio/química , Germânio/farmacologia , Hiperlipidemias/enzimologia , Hiperlipidemias/patologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/enzimologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Fosfolipases A2/sangue , Coelhos
8.
Metabolism ; 119: 154768, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33775647

RESUMO

BACKGROUND: Reducing serum low-density lipoprotein cholesterol (LDL-C) in hyperlipemia is recognized as an effective strategy to minimize the risk of atherosclerotic cardiovascular disease (ASCVD). MiR-337-3p has already been discovered to play regulatory roles in tumor proliferation and metastasis, adipocyte browning and ischemic brain injury, etc. However, the association between miR-337-3p and LDL-C is unknown. METHODS: Gene Expression Omnibus (GEO) dataset and two hyperlipidemic murine models were used to analyze the potential relationship between miR-337-3p and LDL-C. AAV-mediated liver-directed miRNA overexpression in high fat diet (HFD)-fed mouse model was used to examine the effect of miR-337-3p on LDL-C and WB/RT-PCR/ELISA/luciferase assays were used to investigate the underlying mechanism. RESULTS: The expressions of miR-337-3p were obviously lower in multiple hyperlipidemic mouse models and had a negative correlation with serum LDL-C levels. After confirming the effect of miR-337-3p on the improvement of serum LDL-C in vivo, we discovered PCSK9 might be a possible target of miR-337-3p, which was further proved by in vitro experiments. MiR-337-3p could directly interact with both the PCSK9 3'UTR and promoter to inhibit PCSK9 translation and transcription. Furthermore, the result from DiI-LDL uptake assay under the knockdown of PCSK9 demonstrated that miR-337-3p promoting the absorption of LDL-C in HepG2 cells was dependent on PCSK9, and the result from LDLR-/- mouse model indicated that miR-337-3p regulating LDL-C was dependent on PCSK9/LDLR pathway. CONCLUSION: We discovered a new function of miR-337-3p in regulating PCSK9 expression and LDL-C absorption, suggesting miR-337-3p might be a new therapeutic target for the development of antihyperlipidemic drug.


Assuntos
LDL-Colesterol/sangue , Hiperlipidemias/genética , MicroRNAs/fisiologia , Pró-Proteína Convertase 9/genética , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Regulação da Expressão Gênica , Células HEK293 , Células Hep G2 , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/complicações , Hiperlipidemias/patologia , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética
9.
FEBS J ; 288(14): 4249-4266, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33452755

RESUMO

Viral infection is a significant burden to health care worldwide. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, are widely used as cholesterol-lowering drugs. Recently, long-term statin therapy was shown to reduce the antiviral immune response; however, the underlying molecular mechanisms are unclear. Here, we found that simvastatin decreased polyinosinic-polycytidylic acid [poly(I:C)]-induced expression of antiviral interferon (IFN)-ß and IFN-stimulated genes (ISGs) in the bronchoalveolar lavage fluid (BALF) and lungs of mice with high-fat diet-induced hyperlipidemia. Macrophages were the dominant cell type in the BALF of poly(I:C)-treated mice. We examined the effects of simvastatin in primary lung macrophages and found that simvastatin suppressed poly(I:C)-induced expression of IFN-ß and ISGs. We examined the molecular mechanisms of statin-mediated inhibition of antiviral gene expression using murine macrophage-like cell line, J774.1/JA-4. Simvastatin and pitavastatin decreased poly(I:C)-induced expression of IFN-ß and ISGs. Moreover, they repressed poly(I:C)-induced phosphorylation of IFN regulatory factor (IRF) 3 and signal transducers and activators of transcription (STAT) 1, which is involved in Janus kinase (JAK)/STAT signaling. Mevalonate and geranylgeranyl pyrophosphate (GGPP), but not cholesterol, counteracted the negative effect of statins on IFN-ß and ISG expression and phosphorylation of IRF3 and STAT1. The geranylgeranyltransferase inhibitor suppressed poly(I:C)-induced expression of IFN-ß and ISGs and phosphorylation of IRF3 and STAT1. These results suggest that statins suppressed the expression of IFN-ß and ISGs in poly(I:C)-treated hyperlipidemic mice and murine macrophages and that these effects occurred through the inhibition of IRF3 and JAK/STAT signaling in macrophages. Furthermore, GGPP recovered the statin-suppressed IRF3 and JAK/STAT signaling in poly(I:C)-treated macrophages.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hiperlipidemias/tratamento farmacológico , Fatores Reguladores de Interferon/metabolismo , Interferon beta/metabolismo , Macrófagos/efeitos dos fármacos , Poli I-C/toxicidade , Animais , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Indutores de Interferon/toxicidade , Fator Regulador 3 de Interferon/antagonistas & inibidores , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Fatores Reguladores de Interferon/genética , Interferon beta/genética , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Janus Quinases/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
10.
Life Sci ; 269: 119048, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33453246

RESUMO

AIMS: The present study investigated the potential effects of pterostilbene (PT) on glycemic and lipid profiles, fat storage, cardiovascular indices, and hepatic parameters of rats fed with sucrose solution. MAIN METHODS: 24 male Wistar rats received either drinking water or a 40% sucrose solution over a period of 140 days. After this period, animals were randomly allocated into four groups (n = 6): Control (C), C + Pterostilbene (PT), Sucrose (S), and S + PT. Pterostilbene (40 mg/kg) was given orally for 45 consecutive days. KEY FINDINGS: Pterostilbene did not influence morphometric and nutritional parameters. The insulin sensitivity index TyG was elevated in the C + PT group (p < 0.01) and reduced in S + PT group (p < 0.05). Basal glucose levels were lower in the S + PT group (p < 0.05), and the glycemic response was improved with PT treatment in glucose provocative tests. Conversely, rats from the C + PT group showed impaired glucose disposal during those tests. Lipid profile was partially improved by PT treatment. Hepatic oxidative stress in the S group was improved after PT treatment. In the C group, PT reduced SOD activity, glutathione levels, and increased catalase activity. Collagen content was reduced by PT treatment. SIGNIFICANCE: PT effects depends on the type of diet the animals were submitted. In rats fed with sucrose-solution, PT confirmed its positive effects, improving glucose and lipid profile, and acting as a potent antioxidant. The effects of PT on rats that consumed a normal diet were very discrete or even undesirable. We suggest caution with indiscriminate consume of natural compounds by healthy subjects.


Assuntos
Antioxidantes/farmacologia , Sacarose na Dieta/toxicidade , Hiperglicemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estilbenos/farmacologia , Animais , Glicemia/metabolismo , Hiperglicemia/induzido quimicamente , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Oxirredução , Ratos , Ratos Wistar
11.
Chem Biol Interact ; 333: 109323, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33212049

RESUMO

As hyperlipidemia was a pathological progress by lipid dysfunctions, the present object was to investigate the hypolipidemic and hepatoprotective effects of Auricularia auricular residue polysaccharides (RPS) against HFE (high-fat emulsion) toxicities in mice. The structure analysis showed that the RPS was pyranose-polysaccharides mainly composed of glucose with the weight-average molecular weight of 2.00 × 105 Da. The in vivo experiments demonstrated that the RPS had potential hepatoprotections by enhancing the antioxidant and anti-hyperlipidaemia status, and could inhibit the increasing body weights. Besides, the RPS could improve the glucose utilization with the oral glucose tolerance test (120 min) of 5.04 ± 0.12 mmol/L at the dose of 400 mg/kg bw. The results in present study demonstrated that RPS could be used as a functional foods and natural medicines against the HFE-induced hyperlipidemia and its complications.


Assuntos
Antioxidantes/farmacologia , Auricularia/química , Citoproteção/efeitos dos fármacos , Polissacarídeos Fúngicos/farmacologia , Hipolipemiantes/farmacologia , Fígado/efeitos dos fármacos , Adiponectina/sangue , Animais , Antioxidantes/uso terapêutico , Peso Corporal/efeitos dos fármacos , Polissacarídeos Fúngicos/uso terapêutico , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/patologia , Hipolipemiantes/uso terapêutico , Insulina/sangue , Leptina/sangue , Fígado/patologia , Masculino , Camundongos
12.
Arch. Soc. Esp. Oftalmol ; 95(12): 611-614, dic. 2020. ilus
Artigo em Espanhol | IBECS | ID: ibc-197761

RESUMO

CASO CLÍNICO: Presentamos tres casos de pacientes con hiperquilomicronemia familiar y lipemia retinalis, y analizamos de forma comparada las características fundoscópicas de cada uno de ellos. DISCUSIÓN: El aspecto característico del fondo retiniano en color salmón-pálido corresponde con grados severos de lipemia retinalis. Los hallazgos relativos a la tonalidad del árbol vascular en segmentos distales constituyen probablemente el dato exploratorio que mejor orienta el diagnóstico oftalmológico en niveles inferiores de hipertrigliceridemia


CASES REPORT: Three cases are presented of patients with familial hyperchylomicronaemia and lipaemia retinalis, in whom an analysis is made of the fundoscopic characteristics of each of them. DISCUSSION: The typical appearance of the retinal fundus is pale salmon coloured and corresponds to levels of severe lipaemia retinalis. As regards the findings, the vascular tree tonality is probably the best exploratory evidence to help in the ophthalmological diagnosis


Assuntos
Humanos , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Hiperlipoproteinemia Tipo I/diagnóstico por imagem , Oftalmoscopia/métodos , Hiperlipidemias/diagnóstico por imagem , Doenças Retinianas/diagnóstico por imagem , Hiperlipoproteinemia Tipo I/patologia , Hiperlipidemias/patologia , Doenças Retinianas/patologia , Fundo de Olho
13.
PLoS One ; 15(11): e0238407, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33237915

RESUMO

Calcific aortic valve disease (CAVD) is a deadly disease that is rising in prevalence due to population aging. While the disease is complex and poorly understood, one well-documented driver of valvulopathy is serotonin agonism. Both serotonin overexpression, as seen with carcinoid tumors and drug-related agonism, such as with Fenfluramine use, are linked with various diseases of the valves. Thus, the objective of this study was to determine if genetic ablation or pharmacological antagonism of the 5-HT2B serotonin receptor (gene: Htr2b) could improve the hemodynamic and histological progression of calcific aortic valve disease. Htr2b mutant mice were crossed with Notch1+/- mice, an established small animal model of CAVD, to determine if genetic ablation affects CAVD progression. To assess the effect of pharmacological inhibition on CAVD progression, Notch1+/- mice were treated with the 5-HT2B receptor antagonist SB204741. Mice were analyzed using echocardiography, histology, immunofluorescence, and real-time quantitative polymerase chain reaction. Htr2b mutant mice showed lower aortic valve peak velocity and mean pressure gradient-classical hemodynamic indicators of aortic valve stenosis-without concurrent left ventricle change. 5-HT2B receptor antagonism, however, did not affect hemodynamic progression. Leaflet thickness, collagen density, and CAVD-associated transcriptional markers were not significantly different in any group. This study reveals that genetic ablation of Htr2b attenuates hemodynamic development of CAVD in the Notch1+/- mice, but pharmacological antagonism may require high doses or long-term treatment to slow progression.


Assuntos
Valva Aórtica/patologia , Colesterol/metabolismo , Hemodinâmica/genética , Receptor Notch1/genética , Receptor 5-HT2B de Serotonina/genética , Animais , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/patologia , Calcinose/genética , Calcinose/patologia , Dieta , Modelos Animais de Doenças , Progressão da Doença , Ecocardiografia/métodos , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/patologia , Hemodinâmica/fisiologia , Hipercolesterolemia/genética , Hipercolesterolemia/patologia , Hiperlipidemias/genética , Hiperlipidemias/patologia , Camundongos
14.
PLoS One ; 15(11): e0242422, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33237943

RESUMO

Statins are used to lower cholesterol and prevent cardiovascular disease. Musculoskeletal side effects known as statin associated musculoskeletal symptoms (SAMS), are reported in up to 10% of statin users, necessitating statin therapy interruption and increasing cardiovascular disease risk. We tested the hypothesis that, when exposed to statins ex vivo, engineered human skeletal myobundles derived from individuals with (n = 10) or without (n = 14) SAMS and elevated creatine-kinase levels exhibit statin-dependent muscle defects. Myoblasts were derived from muscle biopsies of individuals (median age range of 62-64) with hyperlipidemia with (n = 10) or without (n = 14) SAMS. Myobundles formed from myoblasts were cultured with growth media for 4 days, low amino acid differentiation media for 4 days, then dosed with 0 and 5µM of statins for 5 days. Tetanus forces were subsequently measured. To model the change of tetanus forces among clinical covariates, a mixed effect model with fixed effects being donor type, statin concentration, statin type and their two way interactions (donor type*statin concentration and donor type* statin type) and the random effect being subject ID was applied. The results indicate that statin exposure significantly contributed to decrease in force (P<0.001) and the variability in data (R2C [R square conditional] = 0.62). We found no significant differences in force between myobundles from patients with/without SAMS, many of whom had chronic diseases. Immunofluorescence quantification revealed a positive correlation between the number of straited muscle fibers and tetanus force (R2 = 0.81,P = 0.015) and negative correlation between number of fragmented muscle fibers and tetanus force (R2 = 0.482,P = 0.051) with no differences between donors with or without SAMS. There is also a correlation between statin exposure and presence of striated fibers (R2 = 0.833, P = 0.047). In patient-derived myobundles, statin exposure results in myotoxicity disrupting SAA organization and reducing force. We were unable to identify differences in ex vivo statin myotoxicity in this system. The results suggest that it is unlikely that there is inherent susceptibility to or persistent effects of statin myopathy using patient-derived myobundles.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/induzido quimicamente , Idoso , Aminoácidos/farmacologia , Células Cultivadas , Meios de Cultura/farmacologia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/patologia , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Contração Muscular/efeitos dos fármacos , Fadiga Muscular/fisiologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/fisiopatologia , Doenças Musculares/fisiopatologia , Mioblastos/efeitos dos fármacos , Músculo Quadríceps/citologia , Método Simples-Cego , Engenharia Tecidual
15.
Biomed Res Int ; 2020: 4878704, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33178827

RESUMO

Hyperlipidemia is a risk factor for cardiac damage and cardiovascular disease. Increasing evidence has shown that dyslipidemia-related cardiac damage is associated with lipid accumulation, oxidative stress, and inflammation. Thymoquinone (TQ) is the major constituent of Nigella sativa, commonly known as black seed or black cumin, and is globally used in folk (herbal) medicine for treating and preventing a number of diseases and conditions. Several studies have shown that TQ can protect against cardiac damage. This study is aimed at investigating the possible protective effects of TQ on hyperlipidemia-induced cardiac damage in low-density lipoprotein receptor-deficient (LDL-R-/-) mice. Eight-week-old male LDL-R-/- mice were randomly divided into normal diet (ND), high-fat diet (HFD), and HFD and TQ (HFD+TQ) groups and were fed the different diets for eight weeks. Blood samples were obtained from the inferior vena cava in serum tubes and stored at -80°C until use. Some cardiac tissues were fixed in 10% formalin and then embedded in paraffin for histological evaluation. The remainder of the cardiac tissues was snap-frozen in liquid nitrogen for mRNA preparation or immunoblotting. The levels of metabolism-related factors, such as total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), and high-sensitivity C-reactive protein (hs-CRP), were decreased in the HFD+TQ group compared with those in the HFD group. Periodic acid-Schiff staining demonstrated that lipid deposition was lower in the HFD+TQ group than in the HFD group. The expression of pyroptosis indicators (NOD-like receptor 3 (NLRP3), interleukin- (IL-) 1ß, IL-18, and caspase-1), proinflammatory factors (IL-6 and tumor necrosis factor alpha (TNF-α)), and macrophage markers (cluster of differentiation (CD) 68) was significantly downregulated in the HFD+TQ group compared with that in the HFD group. Our results indicate that TQ may serve as a potential therapeutic agent for hyperlipidemia-induced cardiac damage.


Assuntos
Anti-Inflamatórios/uso terapêutico , Benzoquinonas/uso terapêutico , Cardiotônicos/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Miocárdio/patologia , Piroptose , Receptores de LDL/deficiência , Animais , Anti-Inflamatórios/farmacologia , Benzoquinonas/farmacologia , Cardiotônicos/farmacologia , Citocinas/metabolismo , Dieta Hiperlipídica , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hiperlipidemias/genética , Hiperlipidemias/patologia , Mediadores da Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Modelos Biológicos , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Piroptose/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de LDL/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
J Oleo Sci ; 69(10): 1287-1295, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33028753

RESUMO

Policosanol, a mixture of long-chain alcohols found in animal and plant waxes, has several biological effects including lipid-lowering that have been extensively studied. However, its bioavailability is low. To investigate the effect of nanoemulsified rice bran wax policosanol (NPOL) on plasma homocysteine, heart and liver histology in hyperlipidemic rats, high-fat diet containing 2.5% cholesterol was used to induce hyperlipidemia in Sprague Dawley rats. The hyperlipidemic rats were treated with NPOL and rice bran wax policosanol (POL) in comparison with normal diet (ND), high-cholesterol diet (HCD) and simvastatin-treated rats. Plasma homocysteine, heart and liver histology, and hepatic mRNA expression of peroxisome proliferator-activated receptor gamma (PPARG) were evaluated. The NPOL group, similar to the simvastatin group, showed reduced plasma homocysteine, preserved heart and liver histology, and down-regulated hepatic PPARG mRNA in comparison to the control group, and was better than the POL group. The results suggest that the modest effect of NPOL on homocysteine and preservation of heart and liver histology could be through the regulation of PPARG expression on a background of increased assimilation of rice bran wax policosanol.


Assuntos
Cardiotônicos , Álcoois Graxos/farmacologia , Álcoois Graxos/uso terapêutico , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Fígado/metabolismo , Fígado/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Oryza/química , PPAR gama/genética , PPAR gama/metabolismo , Fitoterapia , Ceras/química , Animais , Dieta Hiperlipídica/efeitos adversos , Expressão Gênica/efeitos dos fármacos , Homocisteína/sangue , Hiperlipidemias/etiologia , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley
17.
Sci Rep ; 10(1): 15443, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963259

RESUMO

In the context of failure of treatment for non alcoholic fatty liver disease (NAFLD)-mediated systemic damages, recognition of novel and successful characteristic drug to combat these anomalous situations is earnestly required. The present study is aimed to evaluate protective value of ethanol extract of Coccinia grandis leaves (EECGL), naturally occurring medicinal plant, on NAFLD-mediated systemic damage induced by high lipid diet along with monosodium glutamate (HM)-fed rats. Our study uncovered that EECGL significantly ameliorates HM-induced hyperlipidemia, increased lipogenesis and metabolic disturbances (via up regulation of PPAR-α and PPAR-γ), oxidative stress (via reducing the generation of reactive oxygen species and regulating the redox-homeostasis) and inflammatory response (via regulating the pro-inflammatory and anti-inflammatory factors with concomitant down regulation of NF-kB, iNOS, TNF-α and up regulation of eNOS). Furthermore, EECGL significantly inhibited HM-induced increased population of cells in sub G0/G1 phase, decreased Bcl2 expression and thereby loss of mitochondrial membrane potential with over expression of Bax, p53, p21, activation of caspase 3 and 9 indicated the apoptosis and suppression of cell survival. It is perhaps the first comprehensive study with a mechanistic approach which provides a strong unique strategy for the management of HM-induced systemic damage with effective dose of EECGL.


Assuntos
Cucurbitaceae/química , Dieta Hiperlipídica/efeitos adversos , Hiperlipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Síndrome Metabólica/tratamento farmacológico , Extratos Vegetais/farmacologia , Glutamato de Sódio/toxicidade , Animais , Biomarcadores/análise , Regulação da Expressão Gênica , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Estresse Oxidativo , Ratos , Ratos Wistar
18.
Biochim Biophys Acta Mol Cell Res ; 1867(12): 118850, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32918982

RESUMO

It is known that hyperlipidemia is a risk factor for sensorineural hearing loss. However, the biological mechanisms underlying hyperlipidemia and hearing impairment have not been completely elucidated in the cochlea. Based on our previous study of human subjects, elderly people taking drugs for hyperlipidemia showed better hearing than those not taking any medications. We hypothesized that drugs for hyperlipidemia, such as statins, may have the potential to prevent hearing impairment. The aim of this study was to investigate the correlation between hyperlipidemia and hearing impairment and the hearing preservation effect of atorvastatin using a hyperlipidemic mouse model with diet-induced obesity (DIO). Here, we demonstrate that DIO mice had a significant hearing impairment as well as increased levels of reactive oxygen species (ROS) and hair cell death due to reduced levels of pAKT and superoxide dismutase 2 (SOD2). However, these changes were significantly prevented by atorvastatin. Oxidative stress-induced intrinsic apoptosis was decreased by the high expression of Nrf2 and antioxidant genes, which improved mitochondrial function and ROS via activation of the PI3K-pAKT pathway by atorvastatin. Therefore, atorvastatin has the potential to prevent hearing impairment via redox balance in the presence of hyperlipidemia.


Assuntos
Atorvastatina/farmacologia , Perda Auditiva/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Idoso , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cóclea/efeitos dos fármacos , Cóclea/metabolismo , Cóclea/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Perda Auditiva/etiologia , Perda Auditiva/genética , Perda Auditiva/patologia , Humanos , Hiperlipidemias/complicações , Hiperlipidemias/genética , Hiperlipidemias/patologia , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
PLoS One ; 15(9): e0239934, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32997716

RESUMO

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is a target for cardiovascular prevention. Contemporary equations for LDL-C estimation have limited accuracy in certain scenarios (high triglycerides [TG], very low LDL-C). OBJECTIVES: We derived a novel method for LDL-C estimation from the standard lipid profile using a machine learning (ML) approach utilizing random forests (the Weill Cornell model). We compared its correlation to direct LDL-C with the Friedewald and Martin-Hopkins equations for LDL-C estimation. METHODS: The study cohort comprised a convenience sample of standard lipid profile measurements (with the directly measured components of total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], and TG) as well as chemical-based direct LDL-C performed on the same day at the New York-Presbyterian Hospital/Weill Cornell Medicine (NYP-WCM). Subsequently, an ML algorithm was used to construct a model for LDL-C estimation. Results are reported on the held-out test set, with correlation coefficients and absolute residuals used to assess model performance. RESULTS: Between 2005 and 2019, there were 17,500 lipid profiles performed on 10,936 unique individuals (4,456 females; 40.8%) aged 1 to 103. Correlation coefficients between estimated and measured LDL-C values were 0.982 for the Weill Cornell model, compared to 0.950 for Friedewald and 0.962 for the Martin-Hopkins method. The Weill Cornell model was consistently better across subgroups stratified by LDL-C and TG values, including TG >500 and LDL-C <70. CONCLUSIONS: An ML model was found to have a better correlation with direct LDL-C than either the Friedewald formula or Martin-Hopkins equation, including in the setting of elevated TG and very low LDL-C.


Assuntos
LDL-Colesterol/sangue , Aprendizado de Máquina , Adulto , Idoso , HDL-Colesterol/sangue , Interpretação Estatística de Dados , Feminino , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/patologia , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue
20.
Am J Forensic Med Pathol ; 41(4): e61-e63, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32969849

RESUMO

The autopsy findings for 3 cases of SARS-(CoV-2) pneumonia-related deaths are reported with pulmonary histology and immunohistochemistry findings. In 2 cases (cases 1 and 2), the time interval from presentation to death was approximately 1 week, whereas for case 3, the time interval from presentation to death was hours. Case 1 and case 2 presented with shortness of breath, cough, and flu-like symptoms. The decedent from case 3 died shortly after presenting to a local emergency room with high fever, chest and abdominal pain, and shortness of breath. All 3 cases had 1 or more comorbidities. The postmortem interval for cases 1 and 2 was 2 weeks as they died at sea and were stored on board within the respective cruise ships' refrigeration units, whereas case 3 was examined within 24 hours of death. The autopsies were conducted at the Miami-Dade County Medical Examiners Department under routine infectious precautions. Salient clinical history and autopsy findings are summarized. Microscopic examination revealed pneumonia with associated atypical endovascular cells.


Assuntos
Betacoronavirus , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Adulto , Autopsia , COVID-19 , Cardiomegalia/complicações , Cardiomegalia/patologia , Círculo Arterial do Cérebro/patologia , Comorbidade , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/patologia , Infecções por Coronavirus/complicações , Complicações do Diabetes/patologia , Evolução Fatal , Feminino , Humanos , Hiperlipidemias/complicações , Hiperlipidemias/patologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Nasofaringe/virologia , Obesidade/complicações , Obesidade/patologia , Pandemias , Pneumonia Viral/complicações , Edema Pulmonar/complicações , Edema Pulmonar/patologia , SARS-CoV-2 , Uso de Tabaco/patologia
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