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1.
An Acad Bras Cienc ; 94(2): e20210670, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35507982

RESUMO

Fatty acid synthase (FASN) is the rate-limiting enzyme for the de novo synthesis of fatty acids in the cytoplasm of tumour cells. Many tumour cells express high levels of FASN, and its expression is associated with a poorer prognosis. Cervical cancer is a major public health problem, representing the fourth most common cancer affecting women worldwide. To date, only a few in silico studies have correlated FASN expression with cervical cancer. This study aimed to investigate in vitro FASN expression in premalignant lesions and cervical cancer samples and the effects of a FASN inhibitor on cervical cancer cells. FASN expression was observed in all cervical cancer samples with increased expression at more advanced cervical cancer stages. The FASN inhibitor (orlistat) reduced the in vitro cell viability of cervical cancer cells (C-33A, ME-180, HeLa and SiHa) in a time-dependent manner and triggered apoptosis. FASN inhibitor also led to cell cycle arrest and autophagy. FASN may be a potential therapeutic target for cervical cancer, and medicinal chemists, pharmaceutical researchers and formulators should consider this finding in the development of new treatment approaches for this cancer type.


Assuntos
Neoplasias do Colo do Útero , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Ácido Graxo Sintases/metabolismo , Ácido Graxo Sintases/farmacologia , Feminino , Humanos , Orlistate/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico
2.
J Adv Res ; 37: 169-184, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35499057

RESUMO

Introduction: The prognosis for cervical cancer (CC) patients with lymph node metastasis (LNM) is extremely poor. Lipid droplets (LDs) have a pivotal role in promoting tumor metastasis. The crosstalk mechanism between LDs and LNM modulated in CC remains largely unknown. Objectives: This study aimed to construct a miRNA-dependent progonostic model for CC patients and investigate whether miR-532-5p has a biological impact on LNM by regualting LDs accumulation. Methods: LASSO-Cox regression was applied to establish a prognostic prediction model. miR-532-5p had the lowest P-value in RNA expression (P < 0.001) and prognostic prediction (P < 0.0001) and was selected for further study. The functional role of the prognostic miR-532-5p-correlated competing endogenous RNA (ceRNA) network was investigated to clarify the crosstalk between LDs and LNM. The underlying mechanism was determined using site-directed mutagenesis, dual luciferase reporter assays, RNA immunoprecipitation assays, and rescue experiments. A xenograft LNM model was established to evaluate the effect of miR-532-5p and orlistat combination therapy on tumor growth and LNM. Results: A novel 5-miRNAs prognostic signature was constructed to better predict the prognosis of CC patient. Further study demonstrated that miR-532-5p inhibited epithelial-mesenchymal transition and lymphangiogenesis by regulating LDs accumulation. Interestingly, we also found that LDs accumulation promoted cell metastasis in vitro. Mechanistically, we demonstrated a miR-532-5p-correlated ceRNA network in which LINC01410 was bound directly to miR-532-5p and effectively functioned as miR-532-5p sponge to disinhibit its target gene-fatty acid synthase (FASN). Combined therapy with miR-532-5p and FASN inhibitor-orlistat further inhibited tumor growth and LNM in vivo. Conclusion: Our findings highlight a LD accumulation-dependent mechanism of miR-532-5p-modulated LNM and support treatment with miR-532-5p/orlistat as novel strategy for treating patients with LNM in CC.


Assuntos
MicroRNAs , Neoplasias do Colo do Útero , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Gotículas Lipídicas/metabolismo , Metástase Linfática , MicroRNAs/genética , MicroRNAs/metabolismo , Orlistate , Prognóstico , Neoplasias do Colo do Útero/genética
3.
Front Endocrinol (Lausanne) ; 13: 824269, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35282441

RESUMO

Background: Orlistat, a reversible inhibitor of pancreatic and gastric lipase, is known to have anti-obesity and antioxidant properties. Cholesterol intermediates and metabolites have diverse and important functions in cardiovascular disease. Therefore, we aimed to evaluate the effect of orlistat on sterol metabolism in overweight and obese adults after weight loss during the intervention or weight loss at 12 weeks. Methods: A total of 51 (27 in the control group and 24 in the experimental group), patients with a BMI of 27 or greater were randomly assigned in a 1:1 ratio to receive either orlistat (120 mg) three times a day plus phentermine hydrochloride (37.5 mg) once daily or a placebo three times a day plus phentermine hydrochloride (37.5 mg) once daily. The primary study outcome was sterol metabolism. Results: The experimental group exhibited significantly decreased metabolic signatures of serum sterols, free cholesterol, sitosterol, 7α-hydroxycholesterol (7α-OHC), and 7ß-OHC at 12 weeks. The experimental group also exhibited significantly decreased metabolic ratios of sitosterol and 7α-OHC to cholesterol at 12 weeks. Regarding changes in sterol signatures from baseline to 6-month follow-up, free cholesterol, plant sterols, and cholesterol precursors tended to decrease with weight loss during the intervention and increase again as the weight was regained in both groups. Conclusion: Orlistat treatment improves oxysterol metabolism in overweight and obese adults. Our findings support that orlistat plays a crucial role in the process of endothelial dysfunction and atherosclerosis via oxysterol modulation.


Assuntos
Fármacos Antiobesidade , Oxisteróis , Adulto , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Colesterol , Método Duplo-Cego , Humanos , Lactonas/farmacologia , Lactonas/uso terapêutico , Lipase/uso terapêutico , Obesidade/induzido quimicamente , Obesidade/complicações , Obesidade/tratamento farmacológico , Orlistate/uso terapêutico , Sobrepeso/complicações , Sobrepeso/tratamento farmacológico , Fentermina/uso terapêutico , Perda de Peso
4.
Cancer Lett ; 536: 215642, 2022 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-35307486

RESUMO

Hepatocellular carcinoma (HCC) is a highly malignant tumor and its progression is associated with altered lipid metabolism in precancerous lesions, such as non-alcoholic fatty liver disease. Here, we identified sperm associated antigen 4 (SPAG4), and explored its oncogenic role in HCC progression. Database analysis and immunohistochemistry indicated increased level of SPAG4 in HCC tissues which was of prognostic value. Gain/loss-of-function experiments showed that SPAG4 exerted oncogenic roles in HCC growth both in vitro and in vivo. RNA sequencing revealed activation of a lipogenic state and SREBP1-mediated pathway following SPAG4 overexpression. Mechanistically, the N-terminal region of SPAG4 bound to lamin A/C, which increased SREBP1 expression, nuclear translocation, and transcriptional activity. Treatment with orlistat, a lipid synthesis inhibitor, reversed SPAG4-mediated oncogenic effects, and its efficacy varied with SPAG4 level. The effect of orlistat was further amplified when combined with sorafenib in tumor xenograft mouse models. Our study provides evidence that SPAG4 mediates HCC progression by affecting lipid metabolism. Administration of orlistat combined with sorafenib reverses SPAG4-mediated oncogenesis in HCC cells and ectopic xenograft tumors in mice, suggesting that this pathway represents a potential target for HCC treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Carcinogênese/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Lamina Tipo A/farmacologia , Lipogênese/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Orlistate/metabolismo , Orlistate/farmacologia , Sorafenibe/farmacologia , Espermatozoides/metabolismo , Espermatozoides/patologia
5.
Clin Ther ; 44(3): e35-e44, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35105470

RESUMO

PURPOSE: Nearly 90% of individuals with type 2 diabetes mellitus (T2DM) are either overweight or obese, placing them at high risk of microvascular and macrovascular complications. The main objective of this study was to assess the use of antiobesity medications and antihyperglycemic agents that produce weight gain among patients with T2DM who qualify for National Institutes of Health guideline-recommended pharmacologic weight loss therapy. METHODS: This study used the 2005-2006 through 2015-2016 biannual cycles of the National Health and Nutrition Examination Survey and included adults aged ≥20 years who reported a diagnosis of T2DM and who qualified for antiobesity treatment (defined as a body mass index ≥27 kg/m2) at the time of physical examination. Antiobesity medication use was defined as use of orlistat, phentermine, diethylpropion, lorcaserin, phentermine/topiramate, bupropion/naltrexone, or liraglutide. Use of weight-inducing antihyperglycemic agents was defined as use of sulfonylureas, thiazolidinediones, or insulin (any type), either alone or in combination with any other antihyperglycemic agent regardless of effect on weight. FINDINGS: Among adults with T2DM who qualified for antiobesity treatment (N = 2910), only 40 participants (2.2%; 95% CI, 1.5-3.3) were on pharmacologic antiobesity treatment within 30 days of survey interview. The only antiobesity medications identified were liraglutide (n = 34 [1.9%]), phentermine (n = 4 [0.2%]), orlistat (n = 1 [0.1%]), and phentermine/topiramate (n = 1 [0.0%]). Among those who were on antihyperglycemic treatment (n = 2401), 1661 (66%; 95% CI, 63.1-68.8) were on weight-inducing antihyperglycemic agents; however, a downward trend in the use of these agents over time was observed (from 78.4% in 2005-2006 to 53.3% in 2015-2016; P < 0.0005). IMPLICATIONS: This is the first national epidemiologic study evaluating the use of antiobesity medications and weight-inducing antihyperglycemic agents among patients with T2DM who qualify for weight loss therapy. This study documents that patients are not on guideline-directed weight loss therapy. Furthermore, weight loss goals are likely compromised by 66% of individuals being on weight-inducing antihyperglycemic therapy. Use of antiobesity medications could play a significant role in promoting weight loss and potentially lead to a healthier lifestyle, which could reduce microvascular and macrovascular complications. Stronger recommendations in using guideline-directed therapy in obesity complicated by T2DM are necessary.


Assuntos
Fármacos Antiobesidade , Diabetes Mellitus Tipo 2 , Adulto , Fármacos Antiobesidade/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Inquéritos Nutricionais , Obesidade/tratamento farmacológico , Obesidade/epidemiologia , Orlistate/uso terapêutico , Fentermina/efeitos adversos , Prevalência , Topiramato/uso terapêutico , Estados Unidos/epidemiologia , Perda de Peso
6.
Biomed Res Int ; 2022: 4145659, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35178447

RESUMO

OBJECTIVE: The present study investigated the effect of the leaves extracts and fractions of Plectranthus glandulosus on the inhibition of pancreatic lipase, cholesterol esterase, adipocytes lipid uptake, and antithrombotic activity which may be important in atherosclerosis development. METHODS: Aqueous, ethanolic, and hydroethanolic extracts of Plactranthus glandulosus were prepared by maceration. The hydroethanolic extract was fractionated into n-hexane, ethylacetate, and n-butanol fractions and their inhibition of pancreatic lipase, cholesterol esterase, adipocytes lipid uptake, and antithrombotic activities measured. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis was carried out to determine phytochemical constituents present in the extracts. RESULTS: The standard orlistat exhibited a higher inhibitory activity on pancreatic lipase and cholesterol esterase (16.31 µg/mL and 15.75 µg/mL, respectively) compared to ethyl acetate fraction (IC50, 17.70 µg/mL and IC50, 24.8 µg/mL, respectively). Among crude extract, hydroethanolic extract showed a better inhibition against pancreatic lipase (IC50, 21.06 µg/mL) and cholesterol esterase (IC50, 25.14 µg/mL) though not comparable to the effect of orlistat. The best lipid uptake inhibition was observed in the hydroethanolic extract (IC50, 45.42 µg/mL) followed by the ethyl acetate fraction (IC50, 47.77 µg/mL). A better antithrombolytic activity was exhibited by the ethyl acetate fraction at all concentrations (50-800 µ/mL), while hydroethanolic extract exhibited the best activity among crude extract. However, these were not comparable to the standard aspirin. The LC-HRMS analysis revealed the presence of 7-O-methyl luteolin 5-O-ß-D-glucopyranoside, chrysoeriol 5-O-ß-D-glucopyranoside, 5,7-dihydroxy-3,2',4'-trimethoxyflavone, and plectranmicin as major compounds in both hydroethanolic extract and ethyl acetate fraction. CONCLUSION: Thus, our finding supports the traditional use of this plant, which might provide a potential source for future antiatherosclerotic drug discovery.


Assuntos
Lamiaceae , Plectranthus , Antioxidantes/farmacologia , Fibrinolíticos/farmacologia , Lipase , Lipídeos/análise , Orlistate/farmacologia , Extratos Vegetais/química , Folhas de Planta/química , Plectranthus/química , Esterol Esterase/análise
7.
Ultrastruct Pathol ; 46(1): 18-36, 2022 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-34979873

RESUMO

BACKGROUND: Obesity is a major universal health issue linked to a majority of illness. AIM: To evaluate the histological and biochemical changes occurred in the duodenal mucosa of high fat diet HFD and orlistat fed rats and to assess the possible protective role of N-acetyl cysteine NAC supplementation. MATERIAL AND METHOD: Sixty male albino rats weighing 180-200 g were classified randomly into control group I and three experimental groups (HFD group II, HFD + orlistat group III, and HFD + orlistat + NAC group IV). All experimental groups received HFD alone/and treatment for 6 weeks. Group III received orlistat (32 mg/kg/day) before meals and group IV received the same regimen as group III in addition to NAC (230 mg/kg/day) after meals. After completion of the experiment, duodenal sections were processed for histological examination, oxidative stress parameters, and semiqualitative real time PCR for proinflammatory mediators TNFα and IL6 evaluation. Also, plasma lipid parameters were assessed and morphometric duodenal results were analyzed statistically. RESULTS: By histological examination of HFD and (HFD + orlistat) groups, we found severe to moderate duodenal structural disturbances, increased goblet cells, collagen fibers, and BAX and iNOS immunostaining. By Biochemical examination, both groups showed increased proinflammatory markers level (TNFα and IL6) with decreased all antioxidant parameters and increased MDA. Moreover, NAC treatment in group IV significantly reduced all structural changes, levels of proinflammatory mediators and increased all antioxidant parameter levels and decreased MDA. CONCLUSION: All findings elucidated that NAC could be accounted to be a useful drug for protection of duodenal mucosa of HFD and orlistat treated animals.


Assuntos
Acetilcisteína , Dieta Hiperlipídica , Acetilcisteína/farmacologia , Animais , Dieta Hiperlipídica/efeitos adversos , Interleucina-6 , Masculino , Membrana Mucosa/efeitos dos fármacos , Orlistate/efeitos adversos , Estresse Oxidativo , Ratos , Fator de Necrose Tumoral alfa
8.
Gynecol Endocrinol ; 38(3): 253-257, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35068315

RESUMO

OBJECTIVE: This retrospective study sought to evaluate the effect of orlistat intervention on the outcome of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) in overweight/obese infertile women. METHODS: Twenty-nine overweight/obese patients undergoing IVF/ICSI for the first time were treated with orlistat intervention (orlistat group). Another 29 patients with matched age and body mass index (BMI) were included in the control group at a ratio of 1:1. Clinical data of both groups were collected, and the clinical baseline data, IVF/ICSI cycle information and embryo transfer outcome were compared between groups by Student's t-test or chi-square test when appropriate. RESULTS: The 29 patients in the orlistat group completed 37 embryo transfer cycles, and the 29 subjects in the control group completed 38 embryo transfer cycles. There was no significant difference in the clinical baseline data or IVF/ICSI cycle data between the two groups (p > .05). In the end, 22 transfer cycles in orlistat group obtained clinical pregnancies, 5 obtained biochemical pregnancies and 10 had non-pregnancies. As for the control group, 15 transfer cycles obtained clinical pregnancies, 15 achieved biochemical pregnancies and 8 had non-pregnancies. The clinical pregnancy rate of the orlistat group was significantly higher than that of the control group (59.46% versus 39.47%, p = .004), but there was no significant difference in the live birth rate between the two groups (54.05% versus 36.84%, p > .05). CONCLUSIONS: Orlistat intervention for overweight/obese infertile women receiving IVF/ICSI treatment will increase the clinical pregnancy rate, without affecting the total amount of gonadotropins, ovarian stimulation time or the follicular output rate (FORT).


Assuntos
Infertilidade Feminina , Injeções de Esperma Intracitoplásmicas , Feminino , Fertilização In Vitro , Humanos , Infertilidade Feminina/terapia , Obesidade/tratamento farmacológico , Obesidade/terapia , Orlistate/uso terapêutico , Sobrepeso/complicações , Sobrepeso/terapia , Gravidez , Taxa de Gravidez , Estudos Retrospectivos
9.
Int J Obes (Lond) ; 46(5): 1002-1008, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35079130

RESUMO

BACKGROUND: Genetically modified probiotics have potential for use as a novel approach to express bioactive molecules for the treatment of obesity. The objective of the present study was to investigate the beneficial effect of genetically modified Escherichia coli Nissle 1917 (EcN-GM) in obese C57BL/6J mice. METHODS: First, an obesity model in C57BL/6J mice was successfully established. Then, the obese mice were randomly assigned into three groups: obese mice (OB), obese mice + EcN-GM (OB + EcN-GM), and obese mice + orlistat (OB + orlistat) (n = 10 in each group). The three groups were gavaged with 0.3 ml of 1010 CFU/ml control EcN, EcN-GM (genetically engineered EcN) and 10 ml/kg orlistat. Body weight, food consumption, fat pad and organ weight, hepatic biochemistry and hepatic histopathological alterations were measured. The effects of EcN-GM on the levels of endocrine peptides and the intestinal microbiota were also analyzed. RESULTS: After supplementation for 8 weeks, EcN-GM was associated with decreases in body weight gain, food intake, fat pad and liver weight, and alleviation hepatocyte steatosis in obese mice. EcN-GM also increased the level of GLP-1 in serum and alleviated leptin and insulin resistance. Moreover, supplementation with EcN-GM increased the α-diversity of the intestinal microbiota but did not significantly influence the relative abundance of Firmicutes and Bacteroidetes. CONCLUSIONS: These results indicated that EcN-GM, a genetically modified E. coli strain, may be a potential therapeutic approach to treat obesity. The beneficial effect of EcN-GM may be independent of the alteration of the diversity and composition of the intestinal microbiota in obese mice.


Assuntos
Escherichia coli , Probióticos , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade , Orlistate/farmacologia , Probióticos/farmacologia
10.
Arch Oral Biol ; 135: 105343, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35026648

RESUMO

OBJECTIVE: Fatty acid synthase levels are associated with aggressiveness, prognosis, and risk of metastasis in oral squamous cell carcinomas. This enzyme contains seven catalytic domains and its inhibition by synthetic or natural drugs has antineoplastic properties such as C75, which is a synthetic inhibitor of the ß- ketoacyl synthase domain, the antibiotic triclosan, ligand of the enoyl reductase domain, and the antiobesity drug orlistat, which inhibits the thioesterase domain. Here, we sought to investigate and compare the in vitro effects of C75, triclosan, and orlistat on malignant phenotypes of the cell line SCC-9: proliferation, cell cycle, apoptosis, adhesion, migration, and invasion. DESIGN: Half-maximal inhibitory concentration (IC50) was determined using cell viability assays. Cell death and cell cycle progression were analyzed by Annexin V-PE/7-ADD-PerCP labeling and propidium iodide staining, respectively. Cell migration and invasion were assayed by transwells assays and cell adhesion using collagen and fibronectin. RESULTS: C75 showed the lowest IC50 and higher inhibition of lipid droplets at low concentrations and reduced cell motility. Triclosan showed the intermediate IC50 value, excellent reduction of lipid bodies at the IC50 when compared with C75 and orlistat. Also, triclosan reduced cell cycle progression, adhesion, migration, and invasion of SCC-9 and induced the highest levels of apoptosis. Orlistat promoted cell cycle arrest, but showed the lowest induction of apoptosis and did not affected invasion and adhesion of SCC-9. CONCLUSION: Altogether, despite the particular effects of the analyzed fatty acid synthase inhibitors, triclosan showed to better interfere in tumorigenic phenotypes of SCC-9 cells.


Assuntos
Ácido Graxo Sintases , Neoplasias Bucais , Apoptose , Linhagem Celular Tumoral , Humanos , Neoplasias Bucais/tratamento farmacológico , Orlistate , Fenótipo
11.
Eur Heart J Cardiovasc Pharmacother ; 8(2): 179-186, 2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33991094

RESUMO

AIMS: The rising prevalence of obesity and its associated comorbidities represent a growing public health issue; in particular, obesity is known to be a major risk factor for cardiovascular disease. Despite the evidence behind the efficacy of orlistat in achieving weight loss in patients with obesity, no study thus far has quantified its long-term effect on cardiovascular outcomes. The purpose of this study is to explore long-term cardiovascular outcomes after orlistat therapy. METHODS AND RESULTS: A propensity-score matched cohort study was conducted on the nation-wide electronic primary and integrated secondary healthcare records of the Clinical Practice Research Datalink (CPRD). The 36 876 patients with obesity in the CPRD database who had completed a course of orlistat during follow-up were matched on a 1:1 basis with equal numbers of controls who had not taken orlistat. Patients were followed up for a median of 6 years for the occurrence of the primary composite endpoint of major adverse cardiovascular events (fatal or non-fatal myocardial infarction or ischaemic stroke), and a number of secondary endpoints including primary endpoint components individually, the occurrence of new-onset heart failure, coronary revascularization, new chronic kidney disease stage III+ (CKD3+), and all-cause mortality. During the median study follow-up of 6 years, the occurrence of major adverse cardiovascular events was lower in the orlistat cohort [hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.66-0.83, P < 0.001]. Patients who took orlistat experienced lower rates of myocardial infarction (HR 0.77; 95% CI 0.66-0.88, P < 0.001) and ischaemic stroke (HR 0.68; 95% CI 0.56 to -0.84, P < 0.001) as well as new-onset heart failure (HR 0.79; 95% CI 0.67-0.94, P = 0.007). There was no differences in revascularization rates (HR 1.12; 95% CI 0.91-1.38, P = 0.27), but a lower rate of both CKD3+ development (HR 0.78; 95% CI 0.73-0.83, P < 0.001) and mortality (HR 0.39, 95% CI 0.36 to -0.41, P < 0.001) was observed. CONCLUSION: In this nation-wide, propensity-score matched study, orlistat was associated with lower rates of overall major adverse cardiovascular events, new-onset heart failure, renal failure, and mortality. This study adds to current evidence on the known improvements in cardiovascular risk factor profiles of orlistat treatment by suggesting a potential role in primary prevention.


Assuntos
Doenças Cardiovasculares , Obesidade , Orlistate , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/etiologia , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Humanos , Obesidade/complicações , Obesidade/diagnóstico , Obesidade/tratamento farmacológico , Obesidade/epidemiologia , Orlistate/efeitos adversos , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia
12.
Clin Endocrinol (Oxf) ; 96(6): 758-780, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34918367

RESUMO

CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous condition affecting women of reproductive age and is associated with increased body weight. OBJECTIVE: To review the literature on the effect of different pharmacological interventions on the anthropometric indices in women with PCOS. DATA SOURCES: We searched PubMed, MEDLINE, Scopus, Embase, Cochrane library, and the Web of Science in April 2020 with an update in PubMed in March 2021. STUDY SELECTION: The study followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)2020. DATA EXTRACTION: Reviewers extracted data and assessed the risk of bias using the Cochrane risk of bias tool. RESULTS: 80 RCTs were included in the meta-analysis. Metformin vs placebo showed significant reduction in the mean body weight (MD: -3.13 kg; 95% confidence interval [CI]: -5.33 to -0.93, I² = 5%) and the mean body mass index (BMI) (MD: -0.75 kg/m2 ; 95% CI: -1.15 to -0.36, I² = 0%). There was a significant reduction in the mean BMI with orlistat versus placebo (MD: -1.33 kg/m²; 95% CI: -2.16 to -0.66, I² = 0.0%), acarbose versus metformin (MD: -1.26 kg/m²; 95% CI: -2.13 to -0.38, I² = 0%), and metformin versus pioglitazone (MD: -0.91 kg/m²; 95% CI: -1.62 to -0.19, I² = 0%). A significant increase in the mean BMI was also observed in pioglitazone versus placebo (MD: + 2.59 kg/m²; 95% CI: 1.78-3.38, I² = 0%) and in rosiglitazone versus metformin (MD: + 0.80 kg/m²; 95% CI: 0.32-1.27, I² = 3%). There was a significant reduction in the mean waist circumference (WC) with metformin versus placebo (MD: -1.21 cm; 95% CI: -3.71 to 1.29, I² = 0%) while a significant increase in the mean WC with pioglitazone versus placebo (MD: + 5.45 cm; 95% CI: 2.18-8.71, I² = 0%). CONCLUSION: Pharmacological interventions including metformin, sitagliptin, pioglitazone, rosiglitazone orlistat, and acarbose have significant effects on the anthropometric indices in women with PCOS.


Assuntos
Metformina , Síndrome do Ovário Policístico , Acarbose/uso terapêutico , Peso Corporal , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Orlistate/uso terapêutico , Pioglitazona/uso terapêutico , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Rosiglitazona/uso terapêutico
13.
Anal Chim Acta ; 1190: 339248, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34857133

RESUMO

Esterase is a large hydrolysis family, and widely distributed in many kinds of cells. It is responsible for multiple physiological and pathological functions including metabolism, gene expression. While abnormality of esterase is associated with many pathological activities in obesity, Wolman's disease, and cancer. Thereby, it is essential to design an effective tool for esterase in situ detection in biological systems. Herein, a novel fluorescent probe Y-1 for monitoring esterase in living cells was rationally designed. Probe Y-1 was synthesized by the conjugation between an acetylation of 4-hydroxy naphthalimide and benzothiazole group. Benzothiazole moiety is a typical Excited-state intramolecular proton transfer (ESIPT) controller. Acetate group was selected as the responsive site and ESIPT initiator. As the acetate group could block the ESIPT effect, the probe emits no fluorescence under the excitation of 455 nm. When binding with esterase, Y-1 shows distinct fluorescence with the peak at 560 nm with short time when ESIPT is on. Y-1 displays high sensitivity (LOD is 0.216 × 10-3 U/mL), fast response (within 5 min), high selectivity and photostability towards esterase. Furthermore, the %RSD (relative standard deviation) of within-day and day-to-day precision was no more than 13.0% and the accuracy ranged from -6.5 to -12.3%. Kinetics performance of Y-1 indicates that esterase has high affinity and hydrolysis to Y-1. For biological applications, our probe is a time-dependent visualizing esterase in living HepG2 and CoLo205 cells within 15 min. After the treatment of orlistat (1 and 5 µM) for inhibiting the activity of esterase, the bright fluorescence has also been detected using our probe. Furthermore, it has been successful in monitoring the esterase in zebrafish, the data were consistent with cellular phenomena. Therefore, all these findings indicate that the robust probe Y-1 is a useful qualitative tool for detecting esterase in biological systems.


Assuntos
Corantes Fluorescentes , Naftalimidas , Animais , Benzotiazóis , Esterases , Células HeLa , Humanos , Orlistate , Espectrometria de Fluorescência , Peixe-Zebra
14.
Zhonghua Nei Ke Za Zhi ; 60(12): 1165-1168, 2021 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-34856689

RESUMO

The aim of this study was to assess the effects of orlistat or metformin treatment on lipid and glucose metabolism, and gonadal function in obese/overweight women with polycystic ovary syndrome (PCOS). A total of 39 patients diagnosed with PCOS were randomly (digital table method) divided into orlistat treatment group (20 cases) and metformin treatment group (19 cases). Compared with those before, treatment with either orlistat or metformin significantly reduced body weight, body mass index (BMI), hip circumferences, and serum insulin levels of the PCOS patients both at the end of 3 months and 6 months (P<0.05). No significant differences could be viewed between orlistat and metformin treated subjects. Moreover, orlistat treatment significantly lowered the levels of low-density lipoprotein cholesterol, total cholesterol, fasting blood glucose, and homeostasis model assessment-insulin resistance (HOMA-IR) (P<0.05), while there were no significant changes in above parameters with metformin treatment. The improvement of menstrual cycle was observed after 6-month treatment in both groups (P<0.05). However, changes in polycystic ovarian morphology by ultrasound were only observed in orlistat treated group. In conclusion, orlistat is comparable with metformin in weight loss and improvement of insulin resistance and menstrual cycle, and is superior to metformin in improvement of lipid metabolism in overweight/obese PCOS patients.


Assuntos
Resistência à Insulina , Metformina , Síndrome do Ovário Policístico , Índice de Massa Corporal , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Obesidade/complicações , Obesidade/tratamento farmacológico , Orlistate , Sobrepeso/complicações , Sobrepeso/tratamento farmacológico , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/tratamento farmacológico
15.
Wiad Lek ; 74(9 cz 1): 2060-2065, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34725276

RESUMO

OBJECTIVE: The aim: To study morphometric and electron microscopic changes in the parenchyma of rat lymph nodes under the action of sodium glutamate and its correction by orlistat. PATIENTS AND METHODS: Materials and methods: The article presents and analyzes the data of an experimental study conducted on 66 white male rats and females of reproductive age. Experimental animals are divided into 4 groups. RESULTS: Results: After six weeks of exposure to monosodium glutamate, there was a significant decrease in the relative area of the cortical substance in the lymph nodes of white male and female rats by 11.95% and 9.31% and, respectively, an increase in the relative area of the medullary substance by 18.76% and 14.7% in compared with an intact group of animals. After six weeks of sodium glutamate and the next six weeks of the standard diet of vivarium and orlistat, the relative area of the cortical substance in the lymph node parenchyma was 2.55% and 0.38% more than the parameters of the intact group of animals, respectively. Accordingly, the relative area of the medullary substance decreased and was 4.01% and 0.59% less compared to the intact group of animals. CONCLUSION: Conclusions: Electron microscopic examination showed that monosodium glutamate causes changes in the parenchyma of the lymph nodes as in a high-calorie diet. The introduction of orlistat (xenical) leads to a partial restoration of the structural organization, and hence the function of this organ.


Assuntos
Elétrons , Glutamato de Sódio , Animais , Feminino , Linfonodos , Masculino , Microscopia Eletrônica , Orlistate , Ratos
16.
Internist (Berl) ; 62(12): 1354-1359, 2021 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-34591131

RESUMO

Obesity and its comorbidities represent a worldwide growing health challenge. In Germany, at least 15 million people are suffering from this disease. To date, lifestyle modification is the most frequently used treatment modality, but offers only limited success concerning both the extent and the sustainability of weight loss, while surgical interventions are restricted to people with severe obesity (body mass index ≥40 kg/m2). For this reason, there are huge efforts to develop pharmacological options for better and clinically meaningful weight management. At present, only a few compounds (orlistat, liraglutide, amfepramon) are available for adjunct drug treatment of obesity in Germany. However, new principles and compounds that could revolutionize obesity management in the years to come are on the horizon. For alternative "slimming drugs", mainly dietary supplements, scientific evidence is lacking on efficacy or clinically meaningful weight loss.


Assuntos
Fármacos Antiobesidade , Drogas Ilícitas , Fármacos Antiobesidade/uso terapêutico , Humanos , Obesidade/tratamento farmacológico , Obesidade/epidemiologia , Orlistate , Perda de Peso
17.
Int J Mol Sci ; 22(18)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34576044

RESUMO

α,ß-amyrenone (ABAME) is a triterpene derivative with many biological activities; however, its potential pharmacological use is hindered by its low solubility in water. In this context, the present work aimed to develop inclusion complexes (ICs) of ABAME with γ- and ß-cyclodextrins (CD), which were systematically characterized through molecular modeling studies as well as FTIR, XRD, DSC, TGA, and SEM analyses. In vitro analyses of lipase activity were performed to evaluate possible anti-obesity properties. Molecular modeling studies indicated that the CD:ABAME ICs prepared at a 2:1 molar ratio would be more stable to the complexation process than those prepared at a 1:1 molar ratio. The physicochemical characterization showed strong evidence that corroborates with the in silico results, and the formation of ICs with CD was capable of inducing changes in ABAME physicochemical properties. ICs was shown to be a stronger inhibitor of lipase activity than Orlistat and to potentiate the inhibitory effects of ABAME on porcine pancreatic enzymes. In conclusion, a new pharmaceutical preparation with potentially improved physicochemical characteristics and inhibitory activity toward lipases was developed in this study, which could prove to be a promising ingredient for future formulations.


Assuntos
Inibidores Enzimáticos/farmacologia , Lipase/antagonistas & inibidores , Triterpenos/farmacologia , beta-Ciclodextrinas/farmacologia , Animais , Varredura Diferencial de Calorimetria , Simulação por Computador , Inibidores Enzimáticos/química , Lipase/química , Orlistate/farmacologia , Solubilidade/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier , Suínos , Triterpenos/síntese química , Triterpenos/química , Difração de Raios X , beta-Ciclodextrinas/química
18.
Hypertension ; 78(5): e38-e50, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34538096

RESUMO

Hypertension is a major risk factor for cardiovascular and renal diseases in the United States and worldwide. Obesity accounts for much of the risk for primary hypertension through several mechanisms, including neurohormonal activation, inflammation, and kidney dysfunction. As the prevalence of obesity continues to increase, hypertension and associated cardiorenal diseases will also increase unless more effective strategies to prevent and treat obesity are developed. Lifestyle modification, including diet, reduced sedentariness, and increased physical activity, is usually recommended for patients with obesity; however, the long-term success of these strategies for reducing adiposity, maintaining weight loss, and reducing blood pressure has been limited. Effective pharmacotherapeutic and procedural strategies, including metabolic surgeries, are additional options to treat obesity and prevent or attenuate obesity hypertension, target organ damage, and subsequent disease. Medications can be useful for short- and long-term obesity treatment; however, prescription of these drugs is limited. Metabolic surgery is effective for producing sustained weight loss and for treating hypertension and metabolic disorders in many patients with severe obesity. Unanswered questions remain related to the mechanisms of obesity-related diseases, long-term efficacy of different treatment and prevention strategies, and timing of these interventions to prevent obesity and hypertension-mediated target organ damage. Further investigation, including randomized controlled trials, is essential to addressing these questions, and emphasis should be placed on the prevention of obesity to reduce the burden of hypertensive cardiovascular and kidney diseases and subsequent mortality.


Assuntos
Cirurgia Bariátrica/métodos , Exercício Físico/fisiologia , Hipertensão/fisiopatologia , Obesidade/fisiopatologia , Perda de Peso/fisiologia , American Heart Association , Fármacos Antiobesidade/uso terapêutico , Depressores do Apetite/uso terapêutico , Humanos , Hipertensão/terapia , Obesidade/prevenção & controle , Orlistate/uso terapêutico , Fentermina/uso terapêutico , Estados Unidos , Perda de Peso/efeitos dos fármacos
19.
ACS Infect Dis ; 7(10): 2876-2888, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34478259

RESUMO

Tetrahydrolipstatin (THL, 1a) has been shown to inhibit both mammalian and bacterial α/ß hydrolases. In the case of bacterial systems, THL is a known inhibitor of several Mycobacterium tuberculosis hydrolases involved in mycomembrane biosynthesis. Herein we report a highly efficient eight-step asymmetric synthesis of THL using a route that allows modification of the THL α-chain substituent to afford compounds 1a through 1e. The key transformation in the synthesis was use of a (TPP)CrCl/Co2(CO)8-catalyzed regioselective and stereospecific carbonylation on an advanced epoxide intermediate to yield a trans-ß-lactone. These compounds are modest inhibitors of Ag85A and Ag85C, two α/ß hydrolases of M. tuberculosis involved in the biosynthesis of the mycomembrane. Among these compounds, 10d showed the highest inhibitory effect on Ag85A (34 ± 22 µM) and Ag85C (66 ± 8 µM), and its X-ray structure was solved in complex with Ag85C to 2.5 Å resolution. In contrast, compound 1e exhibited the best-in-class MICs of 50 µM (25 µg/mL) and 16 µM (8.4 µg/mL) against M. smegmatis and M. tuberculosis H37Ra, respectively, using a microtiter assay plate. Combination of 1e with 13 well-established antibiotics synergistically enhanced the potency of few of these antibiotics in M. smegmatis and M. tuberculosis H37Ra. Compound 1e applied at concentrations 4-fold lower than its MIC enhanced the MIC of the synergistic antibiotic by 2-256-fold. In addition to observing synergy with first-line drugs, rifamycin and isoniazid, the MIC of vancomycin against M. tuberculosis H37Ra was 65 µg/mL; however, the MIC was lowered to 0.25 µg/mL in the presence of 2.1 µg/mL 1e demonstrating the potential of targeting mycobacterial hydrolases involved in mycomembrane and peptidoglycan biosynthesis.


Assuntos
Mycobacterium tuberculosis , Animais , Antituberculosos/farmacologia , Isoniazida , Testes de Sensibilidade Microbiana , Orlistate
20.
Life Sci ; 284: 119896, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34450168

RESUMO

AIM: Abiraterone acetate for metastatic castration-resistant prostate cancer is an acetylated prodrug to be hydrolyzed to abiraterone. Abiraterone acetate is known to be hydrolyzed by pancreatic cholesterol esterase secreted into the intestinal lumen. This study aimed to investigate the possibility that arylacetamide deacetylase (AADAC) expressed in enterocytes contributes to the hydrolysis of abiraterone acetate based on its substrate preference. MATERIALS AND METHODS: Abiraterone acetate hydrolase activity was measured using human intestinal (HIM) and liver microsomes (HLM) as well as recombinant AADAC. Correlation analysis between activity and AADAC expression was performed in 14 individual HIMs. The in vivo pharmacokinetics of abiraterone acetate was examined using wild-type and Aadac knockout mice administered abiraterone acetate with or without orlistat, a pancreatic cholesterol esterase inhibitor. KEY FINDINGS: Recombinant AADAC showed abiraterone acetate hydrolase activity with similar Km value to HIM and HLM. The positive correlation between activity and AADAC levels in individual HIMs supported the responsibility of AADAC for abiraterone acetate hydrolysis. The area under the plasma concentration-time curve (AUC) of abiraterone after oral administration of abiraterone acetate in Aadac knockout mice was 38% lower than that in wild-type mice. The involvement of pancreatic cholesterol esterase in abiraterone formation was revealed by the decreased AUC of abiraterone by coadministration of orlistat. Orlistat potently inhibited AADAC, implying its potential as a perpetrator of drug-drug interactions. SIGNIFICANCE: AADAC is responsible for the hydrolysis of abiraterone acetate in the intestine and liver, suggesting that concomitant use of abiraterone acetate and drugs potently inhibiting AADAC should be avoided.


Assuntos
Acetato de Abiraterona/metabolismo , Hidrolases de Éster Carboxílico/metabolismo , Acetato de Abiraterona/sangue , Acetato de Abiraterona/química , Acetato de Abiraterona/farmacocinética , Adolescente , Adulto , Idoso , Androstenos/sangue , Animais , Carboxilesterase/metabolismo , Feminino , Humanos , Hidrólise , Concentração Inibidora 50 , Intestinos/efeitos dos fármacos , Cinética , Masculino , Camundongos Knockout , Microssomos Hepáticos/metabolismo , Pessoa de Meia-Idade , Orlistate/administração & dosagem , Orlistate/farmacologia , Proteínas Recombinantes/metabolismo
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