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1.
Med Hypotheses ; 143: 110127, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32759008

RESUMO

Fenofibrate, which is a PPAR-alfpha agonist, increases the level of sulfatide. In this letter we hypothesize on the background of various findings that this is beneficial against COVID-19. Fenofibrate has been used for decades against hypercholesterolemia and has no serious side effects. Therefore, a trial giving fenofibrate to patients with corona virus infection is recommended.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Fenofibrato/farmacologia , Hipolipemiantes/farmacologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Sulfoglicoesfingolipídeos/sangue , Adulto , Envelhecimento/sangue , Criança , Reposicionamento de Medicamentos , Fenofibrato/uso terapêutico , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Hipertensão/sangue , Hipertensão/complicações , Hipolipemiantes/uso terapêutico , PPAR alfa/antagonistas & inibidores , Internalização do Vírus
2.
Fundam Clin Pharmacol ; 34(5): 530-547, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32603486

RESUMO

Patients with COVID-19 are sometimes already being treated for one or more other chronic conditions, especially if they are elderly. Introducing a treatment against COVID-19, either on an outpatient basis or during hospitalization for more severe cases, raises the question of potential drug-drug interactions. Here, we analyzed the potential or proven risk of the co-administration of drugs used for the most common chronic diseases and those currently offered as treatment or undergoing therapeutic trials for COVID-19. Practical recommendations are offered, where possible.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Medicamentos sob Prescrição/farmacologia , Analgésicos/farmacologia , Antiasmáticos/farmacologia , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Anticoagulantes/farmacologia , Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Antivirais/farmacologia , Betacoronavirus , Fármacos Cardiovasculares/farmacologia , Interações Medicamentosas , Humanos , Hidroxicloroquina/farmacologia , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Interferon beta-1b/farmacologia , Pandemias , Medicamentos sob Prescrição/farmacocinética , Psicotrópicos/farmacologia , Receptores de Interleucina/antagonistas & inibidores , Medição de Risco , Hormônios Tireóideos/farmacologia
3.
Food Chem ; 333: 127478, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32663752

RESUMO

Moringa oleifera Lam. (M. oleifera) leaves have long been consumed as both nutritive vegetable and popular folk medicine for hyperglycemia and hyperlipidemia in Kenya communities. In the current study, in vitro inhibition by M. oleifera leaf extract (MOLE, 90% (v/v) ethanol) of α-glucosidase and pancreatic lipase was demonstrated, followed by determination of the effects of MOLE on both glucose consumption and lipid levels (TC, TG, HDL-C and LDL-C) in 3T3-L1 cells. Potential ligands in MOLE were fast screened using affinity ultrafiltration LC-MS, and 14 and 10 components displayed certain binding affinity to α-glucosidase and pancreatic lipase, respectively. Docking studies revealed the binding energies and hydrogen bonds between potential ligands and enzymes. This study suggests that M. oleifera leaves may be a promising natural source for the prevention and treatment of hyperglycemia and hyperlipidemia as well as a functional food or other product for health care in the near future.


Assuntos
Moringa oleifera/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Células 3T3-L1 , Animais , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Lipase/antagonistas & inibidores , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos
4.
Chem Biol Interact ; 330: 109167, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32603660

RESUMO

Recently, it has been shown that drimane-type sesquiterpenoids isolated from Zygogynum pancheri, a species native to New Caledonia, possessed significant α-amylase inhibitory activities. To further explore their antidiabetic potential, we investigated the effect of 1ß-O-(E-cinnamoyl)-6α-hydroxy-9epi-polygodial (D) and 1ß-E-O-p-methoxycinnamoyl-bemadienolide (L), two of the most active compounds of the series, on diabetic model rats. Compounds D and L (2 mg kg/day) were daily and orally administrated for 30 days to streptozotocin (STZ) (150 mg/kg) induced male diabetic Wistar rats. Animals were allocated into five groups of six rats. Comparatively to diabetic rats, treatments with D and L compounds were able to significantly (P < 0.05) decrease Fasting Blood Glucose (FBG) (70.15%, 71.02%), serum total cholesterol (46.27% and 39.38%), triglycerides (56.60% and 58.15%), creatinine (37.31% and 36.49%) and uric acid levels (67.76% and 69.68%), respectively. Compounds D and L also restored the altered plasma enzyme (aspartate aminotransferase, AST (47.83% and 43.20%), alanine aminotransferase, ALT (49.76% and 48.35%, alkaline phosphatase, ALP (72.78% and 73.21%)) and lactate dehydrogenase, LDH (47.95% and 53.93%) levels to near normal, respectively. Administration of Glymepiride, significantly (p < 0.05) reduced FBG (73.94%) in STZ induced diabetic rats. Additionally, the compounds D and L exhibited inhibitory effects in vivo on lipase activity of diabetic rats (54.83% and 52.25%), respectively. The outcomes of this study suggested that these two drimanes could be considered as efficient hypoglycemic, hypolipidemic and antiobesity agents for diabetes management and its complications.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Fitoterapia/métodos , Extratos Vegetais/farmacologia , Sesquiterpenos Policíclicos/isolamento & purificação , Animais , Fármacos Antiobesidade/isolamento & purificação , Fármacos Antiobesidade/farmacologia , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Hipolipemiantes/isolamento & purificação , Hipolipemiantes/farmacologia , Masculino , Nova Caledônia , Extratos Vegetais/química , Sesquiterpenos Policíclicos/farmacologia , Ratos , Ratos Wistar , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Winteraceae/química
5.
Arterioscler Thromb Vasc Biol ; 40(9): 2084-2094, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32673528

RESUMO

OBJECTIVE: Increased postprandial lipemia (PPL) is an independent risk factor for atherosclerotic cardiovascular diseases. PCSK9 (Proprotein convertase subtilisin kexin type 9) is an endogenous inhibitor of the LDLR (low-density lipoprotein receptor) pathway. We previously showed that PCSK9 inhibition in mice reduces PPL. However, the relative contribution of intracellular intestinal PCSK9 or liver-derived circulating PCSK9 to this effect is still unclear. Approach and Results: To address this issue, we generated the first intestine-specific Pcsk9-deficient (i-Pcsk9-/-) mouse model. PPL was measured in i-Pcsk9-/- as well as in wild-type and streptozotocin-induced diabetic mice following treatment with a PCSK9 monoclonal antibody (alirocumab). Blocking the circulating form of PCSK9 with alirocumab significantly reduced PPL, while overexpressing human PCSK9 in the liver of full Pcsk9-/- mice had the opposite effect. Alirocumab regulated PPL in a LDLR-dependent manner as this effect was abolished in Ldlr-/- mice. In contrast, i-Pcsk9-/- mice did not exhibit alterations in plasma lipid parameters nor in PPL. Finally, PPL was highly exacerbated by streptozotocin-induced diabetes mellitus in Pcsk9+/+ but not in Pcsk9-/- mice, an effect that was mimicked by the use of alirocumab in streptozotocin-treated Pcsk9+/+ mice. CONCLUSIONS: Taken together, our data demonstrate that PPL is significantly altered by full but not intestinal PCSK9 deficiency. Treatment with a PCSK9 monoclonal antibody mimics the effect of PCSK9 deficiency on PPL suggesting that circulating PCSK9 rather than intestinal PCSK9 is a critical regulator of PPL. These data validate the clinical relevance of PCSK9 inhibitors to reduce PPL, especially in patients with type 2 diabetes mellitus.


Assuntos
Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Hiperlipidemias/sangue , Intestinos/enzimologia , Lipídeos/sangue , Pró-Proteína Convertase 9/sangue , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Hiperlipidemias/enzimologia , Hiperlipidemias/genética , Hiperlipidemias/prevenção & controle , Hipolipemiantes/farmacologia , Intestinos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Período Pós-Prandial , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/deficiência , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo
6.
Curr Atheroscler Rep ; 22(5): 18, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32458077

RESUMO

PURPOSE OF REVIEW: To revise the clinical evidence supporting the use of volanesorsen as new lipid-lowering drug and to assess the efficacy and safety of volanesorsen (ISIS 304801) through a systematic review of the literature and a meta-analysis of the available phase 2 and phase 3 clinical studies. RECENT FINDINGS: The meta-analysis of three clinical studies comprising 11 arms (N = l 156 subjects, with 95 in the active-treated arm and 61 in the control one) shows that volanesorsen significantly affects plasma levels of triglycerides (TG) [MD = - 67.90%, 95%CI = - 85.32, - 50.48, P < 0.001], high-density lipoprotein cholesterol (HDL-C) [MD = 40.06%, 95%CI: 32.79, 47.34, P < 0.001], very-low-density lipoprotein cholesterol (VLDL-C) [MD = - 72.90%, 95%CI = - 82.73, - 63.07, P < 0.001], apolipoprotein B (Apo B) [MD = 8%, 95%CI = 2.17, 13.84, P = 0.007], Apo B-48 [MD = - 64.63, 95%CI = - 105.37, - 23.88, P = 0.002], ApoCIII [MD = - 74.83%, 95%CI = - 85.93, - 63.73, P < 0.001], and VLDL ApoCIII [MD = - 83.69%, 95%CI = - 94.08, - 73.29, P < 0.001], without significant impact on LDL-C [MD = 47.01%, 95%CI = - 1.31, 95.33, P = 0.057] levels. Treatment with volanesorsen was associated with an higher risk of injection site reaction (OR = 32.89, 95%CI = 7.97,135,74, P < 0.001) and with an increased risk of upper respiratory tract infections (OR = 10.58, 95%CI = 1.23, 90.93, P < 0.05) when compared to placebo. Volanesorsen has a relevant impact on plasma TG and related parameters without affecting LDL cholesterolemia and is associated with an acceptable safety profile.


Assuntos
Apolipoproteína C-III/antagonistas & inibidores , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/efeitos adversos , Hipolipemiantes/uso terapêutico , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/uso terapêutico , Adulto , Idoso , Animais , Apolipoproteína C-III/biossíntese , HDL-Colesterol/sangue , Feminino , Humanos , Hipolipemiantes/farmacologia , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos/farmacologia , Triglicerídeos/sangue , Adulto Jovem
7.
Adv Exp Med Biol ; 1177: 133-148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32246446

RESUMO

Coronary artery disease (CAD) is one of the leading causes of death worldwide. It is well known that dyslipidemia is a major pathogenic risk factor for atherosclerosis and CAD, which results in cardiac ischemic injury and myocardial infarction. Lipid-modifying drugs can effectively improve lipid abnormalities including reducing low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) or increasing high-density lipoprotein cholesterol (HDL-C), and eventually decrease the incidence of cardiovascular events. This chapter will review basic principles of lipid metabolism and focus on the therapeutic strategies of lipids modifying drugs (statins, proprotein convertase subtilisin/kexin type 9 inhibitors, ezetimibe, niacin, polyunsaturated fatty acids, and so on) in patients with arteriosclerotic cardiovascular disease. Meanwhile, the challenges and perspectives of the lipid-lowering agents currently in clinical practice as well as their limitations will be outlined.


Assuntos
Hipolipemiantes/farmacologia , Lipídeos/sangue , Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , LDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia
8.
Invest Ophthalmol Vis Sci ; 61(3): 54, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32232349

RESUMO

Purpose: To investigate the effects and mechanisms of the peroxisome proliferator-activated receptor alpha (PPAR-α) agonist fenofibrate on the formation of ocular surface squamous metaplasia induced by topical benzalkonium chloride (BAC) in a mouse model. Methods: Ocular surface squamous metaplasia was induced in 16 days by topical BAC application in mice. During the period of induction, mice were divided into four groups: no additional treatment (BAC+UT), topical vehicle (BAC+Vehicle), topical fenofibrate (BAC+Feno), or topical fenofibrate plus intraperitoneal injection of MK886 (BAC+Feno+MK886). The parameters of tear film were evaluated on day 16, and eye specimens were collected. Histologic investigation; PAS assays; immunostaining for cytokeratin 10 (K10), Ki67, and F4/80; and PCR assays for TNF-α and IL-6 were performed. Cell Counting Kit 8 (CCK-8) assays were performed to evaluate the inhibitory effects of fenofibrate on RAW264.7 cells. Results: Fenofibrate suppressed the formation of BAC-induced instable tear film. In the BAC+Feno group, the expression of K10 and Ki67 was lower than in the other three groups. The number of goblet cells was reduced in eyes of the BAC+UT and BAC+Vehicle groups but was maintained in eyes of the BAC+Feno group. The number of F4/80-positive cells and the levels of TNF-α and IL-6 mRNA were significantly reduced in the cornea of the BAC+Feno group. These effects of fenofibrate could be attenuated by MK886. The cell viability of RAW264.7 cells could be significantly inhibited by fenofibrate in a dose-dependent pattern. Conclusions: Topical application of fenofibrate suppressed the formation of ocular surface squamous metaplasia, which might be mediated through the PPAR-α signaling pathway.


Assuntos
Epitélio Anterior/efeitos dos fármacos , Fenofibrato/farmacologia , Hipolipemiantes/farmacologia , PPAR alfa/agonistas , Animais , Anti-Infecciosos Locais/toxicidade , Compostos de Benzalcônio/toxicidade , Proteínas de Ligação ao Cálcio/metabolismo , Contagem de Células , Linhagem Celular , Sobrevivência Celular , Modelos Animais de Doenças , Epitélio Anterior/metabolismo , Epitélio Anterior/patologia , Humanos , Imuno-Histoquímica , Interleucina-6/genética , Queratina-10/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Metaplasia/induzido quimicamente , Metaplasia/tratamento farmacológico , Metaplasia/metabolismo , Metaplasia/patologia , Camundongos , Camundongos Endogâmicos BALB C , Reação em Cadeia da Polimerase em Tempo Real , Receptores Acoplados a Proteínas-G/metabolismo , Fator de Necrose Tumoral alfa/genética
9.
Metabolism ; 107: 154221, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32240727

RESUMO

BACKGROUND: Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) particle containing apolipoprotein(a) (apo(a)) covalently linked to apolipoprotein B-100 (apoB). Statin-treated patients with elevated Lp(a) have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Recent trials show that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition decreases Lp(a) and cardiovascular events, particularly in high risk patients with elevated Lp(a). We investigated the kinetic mechanism whereby alirocumab, a PCSK9 inhibitor, lowers Lp(a) in statin-treated patients with high Lp(a) and ASCVD. METHODS: The effects of 12-week alirocumab treatment (150 mg every 2 weeks) on apo(a) kinetics were studied in 21 patients with elevated Lp(a) concentration (>0.5 g/L). Apo(a) fractional catabolic rate (FCR) and production rate (PR) were determined using intravenous D3-leucine administration, mass spectrometry and compartmental modelling. All patients were on long-term statin treatment. RESULTS: Alirocumab significantly decreased plasma concentrations of total cholesterol (-39%), LDL-cholesterol (-67%), apoB (-56%), apo(a) (-25%) and Lp(a) (-22%) (P< 0.001 for all). Alirocumab also significantly lowered plasma apo(a) pool size (-26%, P <0.001) and increased the FCR of apo(a) (+28%, P< 0.001), but did not alter apo(a) PR, which remained significantly higher relative to a reference group of patients on statins with normal Lp(a) (P< 0.001). CONCLUSIONS: In statin-treated patients, alirocumab lowers elevated plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. This may be consequent on marked upregulation of hepatic receptors (principally for LDL) and/or reduced competition between Lp(a) and LDL particles for these receptors; the mechanism could contribute to the benefit of PCSK9 inhibition with alirocumab on cardiovascular outcomes.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/farmacologia , Lipoproteína(a)/metabolismo , Pró-Proteína Convertase 9/antagonistas & inibidores , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Apoproteína(a)/sangue , Colesterol/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Feminino , Humanos , Hipolipemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Int J Nanomedicine ; 15: 705-715, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32099359

RESUMO

Background: Bezafibrate is a BCS class II drug as it presents very low solubility in water; therefore, its bioavailability after oral administration is very poor. The aim of this work was to enhance solubility and dissolution rate of bezafibrate in water in order to enhance its oral bioavailability. Methods: Several formulations were prepared using PVP K30 and Cremophor ELP employing the solvent-evaporation method and the electrospraying technique. Solubility, release rate, bioavailability in male Sprague Dawley rats, and lipid profile attributes in Wistar rats were assessed in comparison with bezafibrate plain powder. Solid-state characterization was carried out using X-ray diffraction (XRD) analysis, differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM). Results: All the formulations exerted positive effect towards the desired goal. In particular, the optimized formulation furnished about 14-fold enhanced solubility and 85.48 ± 10.16% drug was released in 10 min as compared with bezafibrate alone (4.06 ± 2.59%). The drug existed in the amorphous state in the prepared sample as confirmed by XRD and DSC, whilst no drug-excipient interactions were observed through FTIR analysis. Moreover, SEM revealed smooth-surfaced spherical particles of the optimized formulation. A 5.5-fold higher oral bioavailability was achieved with the optimized formulation in comparison with bezafibrate plain powder. Also, TG, LDL and TC were decreased, and HDL was increased considerably in HFD-treated rats. Conclusion: The optimized formulation consisting of bezafibrate, PVP K30 and cremophor ELP (1/12/1.5, w/w/w) might be a capable drug delivery system for orally administering poorly water-soluble bezafibrate with improved bioavailability and antihyperlipidemic effects.


Assuntos
Bezafibrato/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Hipolipemiantes/farmacologia , Nanosferas/química , Polímeros/química , Administração Oral , Animais , Bezafibrato/administração & dosagem , Bezafibrato/sangue , Bezafibrato/farmacocinética , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Interações Hidrofóbicas e Hidrofílicas , Hipolipemiantes/administração & dosagem , Hipolipemiantes/sangue , Hipolipemiantes/farmacocinética , Lipídeos/química , Masculino , Nanosferas/ultraestrutura , Polietilenoglicóis/química , Povidona/química , Pós , Ratos Sprague-Dawley , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
11.
Am J Physiol Renal Physiol ; 318(3): F826-F834, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32036700

RESUMO

Excessive fructose intake causes metabolic syndrome and lipid accumulation in the kidney and leads to renal dysfunction and damage. Exercise (Ex) improves lipids regulation, but the mechanisms are unclarified in the kidney. In the present study, male Sprague-Dawley rats were allocated to groups fed with control or high-fructose (HFr) diet. Part of rats in each group underwent aerobic treadmill Ex for 12 wk. Drug treatment was performed as the fenofibrate gavage during the last 4 wk on HFr diet-fed rats. Renal function, histological changes, and expression of regulators involved in fatty acid (FA) metabolism were assessed. In CON diet-fed groups, Ex did not affect renal function or histology and significantly increased renal expression of FA ß-oxidation regulators including acyl-CoA dehydrogenases (CADs), acyl-CoA oxidase, peroxisome proliferator-activated receptor (PPAR)-α, and PPAR-γ coactivator (PGC)-1α and lipogenic factors including acetyl-CoA carboxylase (ACCα), FA synthase (FAS), and sterol regulatory element-binding protein 1c. HFr caused albuminuria, lipid accumulation, and renal pathohistological changes, which were attenuated by Ex but not by fenofibrate. HFr decreased renal expression of medium- and short-chain CADs and PPAR-α and increased renal expression of ACCα, FAS, and sterol regulatory element-binding protein 1c. Ex increased expression of CADs, carnitine palmitoyltransferase type I, acyl-CoA oxidase, PPAR-α, and PGC-1α and decreased renal expression of ACCα and FAS in HFr diet-fed rats. The Ex-induced FA metabolism alteration was similar to that in the fenofibrate-treated group. In conclusion, the present study indicates that Ex enhanced renal FA metabolism, which might protect the kidney in lipid dysregulation diseases.


Assuntos
Ácidos Graxos/metabolismo , Fenofibrato/farmacologia , Frutose/administração & dosagem , Rim/fisiologia , Atividade Motora , Ração Animal , Animais , Dieta , Carboidratos da Dieta , Fenofibrato/administração & dosagem , Hipolipemiantes/administração & dosagem , Hipolipemiantes/farmacologia , Masculino , Oxirredução , Ratos , Ratos Sprague-Dawley , Regulação para Cima
12.
J Orthop Res ; 38(2): 297-310, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31471919

RESUMO

Giant cell tumor of bone (GCTB) is a locally aggressive destructive bone lesion. The management of pulmonary metastasis and local recurrence after the surgical treatment of GCTB remains a challenge. Pathologically, stromal cells in GCTB are known as primary neoplastic cells and are recognized as incompletely differentiated preosteoblasts. Therefore, inducing GCTB stromal cells to differentiate into cells with a mature osteoblastic phenotype may stop tumor growth and recurrence. In this study, we aimed to investigate how simvastatin, a clinically approved and commonly used statin that has been known to promote the maturation of cells of the osteogenic lineage, affects GCTB stromal cells. We found that simvastatin effectively inhibited cell viability by suppressing proliferation and by inducing apoptosis in GCTB stromal cells. Moreover, simvastatin treatment upregulated the expression of genes related to osteogenic maturation, such as runt-related transcription factor 2, osteopontin, and osteocalcin, and increased the mineralization of the extracellular matrix in GCTB stromal cells. Ingenuity pathway analysis was used to discover that the vitamin D receptor pathway was involved in the simvastatin-induced osteogenic differentiation of GCTB stromal cells by upregulating the 1,25-dihydroxyvitamin D metabolism. Taken together, this in vitro study demonstrates the antitumor and differentiation-promoting effects of simvastatin on GCTB stromal cells and suggests the possibility of using simvastatin as an adjuvant therapy for GCTB. These findings support further clinical investigation of the efficacy of using simvastatin as an adjuvant therapy for GCTB to reduce recurrence and distant metastasis after surgical treatment. © 2019 Orthopedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:297-310, 2020.


Assuntos
Tumor de Células Gigantes do Osso/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Sinvastatina/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Tumor de Células Gigantes do Osso/metabolismo , Humanos , Hipolipemiantes/farmacologia , Sinvastatina/farmacologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Vitamina D/análogos & derivados , Vitamina D/metabolismo
13.
J Ethnopharmacol ; 247: 112273, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31586692

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Luohanguo (LHG), a traditional Chinese medicine, could clear heat, moisten the lung, soothe the throat, restore the voice, and lubricate intestine and open the bowels. LHG has been utilized for the treatment of sore throats and hyperglycemia in folk medicine as a homology of medicine and food. The hypoglycemic pharmacology of LHG has attracted considerable attention, and mogrosides have been considered to be active ingredients against diabetes mellitus. We have found that these mogrosides could be metabolized into their secondary glycosides containing 1-3 glucose residues in type 2 diabetes mellitus (T2DM) rats in previous studies. These metabolites may be the antidiabetic components of LHG in vivo. Thus far, no reports have been found on reducing blood glucose of mogrosides containing 1-3 glucose residues. AIMS OF THE STUDY: The aim of this study was to confirm that mogrosides containing 1-3 glucose residues were the active components of LHG for antidiabetic effects and to understand their potential mechanisms of action. MATERIALS AND METHODS: First, the special fraction of mogrosides containing 1-3 glucose residues was separated from a 50% ethanol extract of LHG, and the chemical components were identified by ultra-performance liquid chromatography (UPLC) and named low-polar Siraitia grosvenorii glycosides (L-SGgly). Second, the antidiabetic effects of L-SGgly were evaluated by HFD/STZ-induced (high-fat diet and streptozocin) obese T2DM rats by indexing fasting blood glucose (FBG), fasting insulin (FINS), and insulin resistance, and then compared with other fractions in the separation process. The changes in serum lipid levels were also detected. Finally, possible mechanisms of antidiabetic activity of L-SGgly were identified as increasing GLP-1 levels and activating liver AMPK in T2DM rats. RESULTS: The chemical analysis of L-SGgly showed that they contain 11-oxomogroside V, mogroside V, mogroside III, mogroside IIE, mogroside IIIA1, mogroside IIA1, and mogroside IA1, respectively. The total content of the mogrosides in L-SGgly was 54.4%, including 15.7% mogroside IIA1 and 12.6% mogroside IA1. L-SGgly showed excellent effects on obese T2DM rats compared with the other fractions of LHG extract, including significantly reducing the levels of FBG (p < 0.001) and modifying insulin resistance (p < 0.05). Meanwhile, they could significantly decrease the content of triglyceride (p < 0.01), total cholesterol (p < 0.01), low-density lipoprotein cholesterol (p < 0.01) and free fatty acid (p < 0.001) and increase the content of high-density lipoprotein cholesterol (p < 0.001) in serum of T2DM rats. Moreover, L-SGgly can significantly increase (p < 0.01) GLP-1 levels and decrease (p < 0.01) IL-6 levels in T2DM rat serum. AMPK-activating activity in T2DM rats was also upregulated by L-SGgly, but no statistical significance was shown. CONCLUSION: L-SGgly, fractions separated from LHG extract, were verified to have obvious anti-hyperglycemic and anti-hyperlipidemic effects on T2DM rats. Furthermore, L-SGgly regulated insulin secretion in T2DM rats by increasing GLP-1 levels. These findings provide an explanation for the antidiabetic role of LHG.


Assuntos
Cucurbitaceae/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Glicosídeos/farmacologia , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Obesidade/tratamento farmacológico , Triterpenos/farmacologia , Administração Oral , Animais , Glicemia/análise , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Fracionamento Químico , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glicosídeos/análise , Glicosídeos/isolamento & purificação , Glicosídeos/uso terapêutico , Humanos , Hipoglicemiantes/análise , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/análise , Hipolipemiantes/isolamento & purificação , Hipolipemiantes/uso terapêutico , Insulina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Obesidade/sangue , Obesidade/etiologia , Ratos , Estreptozocina/toxicidade , Triterpenos/análise , Triterpenos/isolamento & purificação , Triterpenos/uso terapêutico
14.
Eur J Pharmacol ; 868: 172871, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31846627

RESUMO

Niacin has been widely used as an antihyperlipidemic drug, but the flushing effect restricted its clinical application. Here, we developed novel niacin-lipoic acid dimers which lead to better lipid modulation, higher synergistic effects and less side effects. We utilized molecular docking simulation to design a novel series of niacin-lipoic acid dimers. The compound N-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)nicotinamide (N2L) was selected for the in vitro and in vivo evaluation, including the agonist activity in CHO-hGPR109A cells, cell protective effects in HT22 and HUVECs cells, flushing effect in guinea pigs and rats, lipid modulation in C57BL/6 mice and high fat diet-rats and atherosclerotic lesions regulation in apolipoprotein E null mice. N2L worked as potent and selective agonists for the high affinity niacin receptor GPR109A. N2L retained antioxidation and cytoprotection of lipoic acid. In addition, N2L displayed a good therapeutic index regarding lipid modulation and atherosclerotic lesions regulation, and minimized niacin-induced vasodilation (flushing) effect in vivo. N2L showed effective treatment regarding to lipid regulation and atherosclerosis inhibition effects, also with excellent antioxidant effects, safety profiles and non-flushing. All these results suggest N2L promising application prospects in the drug development for the treatment of atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Rubor/prevenção & controle , Hipolipemiantes/farmacologia , Animais , Aterosclerose/sangue , Aterosclerose/diagnóstico , Linhagem Celular , Cricetulus , Dimerização , Modelos Animais de Doenças , Desenho de Fármacos , Dislipidemias/sangue , Dislipidemias/diagnóstico , Feminino , Rubor/induzido quimicamente , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipolipemiantes/química , Hipolipemiantes/uso terapêutico , Lipídeos/sangue , Masculino , Camundongos , Camundongos Knockout para ApoE , Simulação de Acoplamento Molecular , Niacina/química , Niacina/farmacologia , Niacina/uso terapêutico , Ratos , Ácido Tióctico/química , Ácido Tióctico/farmacologia , Ácido Tióctico/uso terapêutico
15.
Zhongguo Zhong Yao Za Zhi ; 44(21): 4552-4559, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31872647

RESUMO

Hyperlipidemia,as one of the severe risk factors of cardiovascular disease,could easily trigger atherosclerosis,coronary heart disease,peripheral vascular disease,pancreatitis,etc.,and could also increase the incidence of type 2 diabetes and fatty liver disease. Improving dyslipidemia could slow down the progression of atherosclerosis and reduce the risk of coronary heart disease. This is of great importance for prevention and treatment of cardiovascular disease. Phytosterols are natural active ingredients in plants. Many researches have shown that phytosterols have significant lipid-lowering activity,which could effectively lower blood cholesterol and triglyceride levels. Foods containing phytosterols have been widely used as therapeutic diets for improving dyslipidemia. In the early years,it was believed that the lipid-lowering effect of phytosterols was achieved by competitively inhibiting the absorption of dietary cholesterol in the intestine since phytosterols had similar chemical structures with cholesterol. In further researches in recent years,more progress has been made in the lipid-lowering mechanisms of phytosterols. In this paper,PubMed and Web of Science were used to review the cholesterol-lowering and triglyceride-lowering mechanisms of phytosterols according to the available data published,so as to use phytosterols more rationally in clinical application to improve hyperlipidemia and other induced diseases.


Assuntos
Diabetes Mellitus Tipo 2 , Hiperlipidemias , Hipolipemiantes/farmacologia , Fitosteróis/farmacologia , Colesterol , Humanos , Triglicerídeos
16.
Expert Opin Investig Drugs ; 28(12): 1059-1079, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752565

RESUMO

Introduction: Elevated triglyceride (TG) level is a prevalent condition in the general population and in patients with cardiovascular (CV) risk even under statin therapy. Severe hypertriglyceridemia (HTG) puts patients at risk for acute pancreatitis. Several TG-lowering drugs failed in clinical trials, but subgroup analyses suggest that high-risk patients, such as those with atherogenic dyslipidemia or diabetes, benefit from TG lowering.Areas covered: We review advances for TG-lowering drugs in clinical development. These include selective PPARα modulators, omega-3 fatty acid formulations that have been approved for severe HTG, and inhibitors of apolipoprotein C-III, angiopoietin-like-3 or microsomal transfer protein. Lessons learned from the success of the phase 3 trial REDUCE-IT with high-dose icosapent ethyl are also reviewed.Expert opinion: We believe that TG-lowering therapies are coming of age as they will allow to treat patients with high CV risk and moderate HTG, including T2D subjects, as well as patients with severe HTG or even homozygous familial hypercholesterolemia, all of which being 'optimally' treated with a statin. More studies on the impact of therapy on quality of life in patients with severe HTG should be conducted with the help of patient registries.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/farmacologia , Animais , Doenças Cardiovasculares/etiologia , Desenvolvimento de Medicamentos , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacologia , Humanos , Hipertrigliceridemia/complicações , Hipolipemiantes/administração & dosagem , Índice de Gravidade de Doença , Triglicerídeos/sangue
17.
J Environ Pathol Toxicol Oncol ; 38(3): 205-216, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679308

RESUMO

Artemisia vulgaris is a traditional Chinese herb believed to have a wide range of healing properties; it is traditionally used to treat numerous health ailments. The plant is commonly called mugwort or riverside wormwood. The plant is edible, and in addition to its medicinal properties, it is also used as a culinary herb in Asian cooking in the form of a vegetable or in soup. The plant has garnered the attention of researchers in the past few decades, and several research studies have investigated its biological effects, including antioxidant, anti-inflammatory, anticancer, hypolipidemic, and antimicrobial properties. In this review, various studies on these biological effects are discussed along with the tests conducted, compounds involved, and proposed mechanisms of action. This review will be of interest to the researchers working in the field of herbal medicine, pharmacology, medical sciences, and immunology.


Assuntos
Artemisia/química , Fitoterapia , Extratos Vegetais/farmacologia , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Hipolipemiantes/farmacologia , Plantas Medicinais/química
18.
Biomed Khim ; 65(5): 403-406, 2019 Aug.
Artigo em Russo | MEDLINE | ID: mdl-31666413

RESUMO

An imidazole derivative cramizol, has lipid-lowering and anti-atherogenic effects. Cramizol reduces blood levels of cholesterol and triglycerides, and also reduces the atherogenic index in animals with acute hyperlipidemia induced by Triton WR-1339. Cramizol and the lipid-lowering drug fenofibrate exhibited similar effectiveness as hypolipidemic agents. Cramizol also restores the expression of the Apoa1 gene in rats with experimentally induced hyperlipidemia to normal values. This may be a basis of its hypolipidemic and anti-atherogenic action.


Assuntos
Apolipoproteína A-I/genética , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/farmacologia , Imidazóis/farmacologia , Animais , Colesterol/sangue , Fenofibrato , Hiperlipidemias/genética , Ratos , Triglicerídeos/sangue
19.
Lipids Health Dis ; 18(1): 179, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31639005

RESUMO

BACKGROUND: Ceramide plays pathogenic roles in nonalcoholic fatty liver disease (NAFLD) via multiple mechanisms, and as such inhibition of ceramide de novo synthesis in the liver may be of therapeutically beneficial in patients with NAFLD. In this study, we aimed to explore whether inhibition of ceramide signaling by myriocin is beneficial in animal model of NAFLD via regulating autophagy. METHODS: Sprague Dawley rats were randomly divided into three groups: standard chow (n = 10), high-fat diet (HFD) (n = 10) or HFD combined with oral administration of myriocin (0.3 mg/kg on alternate days for 8 weeks) (n = 10). Liver histology and autophagy function were measured. HepG2 cells were incubated with fatty acid with or without myriocin treatment. Lipid accumulation and autophagy markers in the HepG2 cells were analyzed. Serum ceramide changes were studied in 104 subjects consisting healthy adults, liver biopsy-proven patients with NAFLD and liver biopsy-proven patients with chronic hepatitis B (CHB). RESULTS: Myriocin reversed the elevated body weight and serum transaminases and alleviated dyslipidemia in HFD fed rats. Myriocin treatment significantly attenuated liver pathology including steatosis, lobular inflammation and ballooning. By qPCR analysis, it was revealed that myriocin corrected the expression pattern of fatty acid metabolism associated genes including Fabp1, Pparα, Cpt-1α and Acox-2. Further, myriocin also restored the impaired hepatic autophagy function in rats with HFD-induced NASH, and this has been verified in HepG2 cells. Among the sphingolipid species that we screened in lipidomic profiles, significantly increased ceramide was observed in NASH patients as compared to the controls and non-NASH patients, regardless of whether or not they have active CHB. CONCLUSIONS: Ceramide may play an important regulatory role in the autophagy function in the pathogenesis of NASH. Hence, blockade of ceramide signaling by myriocin may be of therapeutically beneficial in NASH. TRIAL REGISTRATION: Registration ID: ChiCTR-DDT-13003983 . Data of registration: 13 May, 2013, retrospectively registered.


Assuntos
Autofagia/efeitos dos fármacos , Ceramidas/metabolismo , Dislipidemias/tratamento farmacológico , Ácidos Graxos Monoinsaturados/farmacologia , Hipolipemiantes/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Adulto , Animais , Autofagia/genética , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Estudos de Casos e Controles , Ceramidas/antagonistas & inibidores , Dieta Hiperlipídica/efeitos adversos , Dislipidemias/etiologia , Dislipidemias/genética , Dislipidemias/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Hepatite B Crônica/genética , Hepatite B Crônica/metabolismo , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Metabolismo dos Lipídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ácido Oleico/antagonistas & inibidores , Ácido Oleico/farmacologia , Oxirredutases/genética , Oxirredutases/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Ácido Palmítico/antagonistas & inibidores , Ácido Palmítico/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
20.
Food Funct ; 10(11): 7378-7386, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31651924

RESUMO

Previous studies have shown that 7S protein is the active ingredient responsible for the plasma cholesterol-lowering activity of soybean. It is hypothesized that isoflavones in soybean could enhance the blood cholesterol-lowering activity of 7S protein. Forty-eight hamsters were divided into six groups and fed a non-cholesterol diet or one of the five high-cholesterol diets containing 12.1% 7S protein with 0-15.62 mg g-1 isoflavones. The results showed that addition of isoflavones in diets dose-dependently enhanced the plasma total cholesterol-lowering activity of 7S protein. Addition of isoflavones in 7S protein-based diets significantly reduced hepatic cholesterol accumulation by 12.6-26.1%, compared with the high cholesterol control diet. Isoflavones could also facilitate excretion of neutral sterols in a dose-dependent manner. Supplementation of isoflavones in diets favourably modulated mRNA expression and the protein mass of HMG-CoA reductase. It was concluded that the enhancing effect of isoflavones on the blood cholesterol-lowering activity of 7S protein was mediated by inhibiting the cholesterol absorption and de novo cholesterol synthesis in hypercholesterolemic hamsters.


Assuntos
Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/farmacologia , Isoflavonas/farmacologia , Proteínas de Plantas/farmacologia , Ração Animal/análise , Animais , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Colesterol/metabolismo , Cricetinae , Dieta/veterinária , Fezes/química , Regulação da Expressão Gênica/efeitos dos fármacos , Hipolipemiantes/química , Isoflavonas/química , Fígado/química , Fígado/metabolismo , Masculino , Proteínas de Plantas/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Soja/química
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