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1.
Theranostics ; 14(1): 75-95, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38164137

RESUMEN

Background and objective: Epithelial ovarian cancer (EOC) is associated with latent onset and poor prognosis, with drug resistance being a main concern in improving the prognosis of these patients. The resistance of cancer cells to most chemotherapeutic agents can be related to autophagy mechanisms. This study aimed to assess the therapeutic effect of MK8722, a small-molecule compound that activates AMP-activated protein kinase (AMPK), on EOC cells and to propose a novel strategy for the treatment of EOC. Purpose: To explore the therapeutic effects of MK8722 on EOC cells, and to elucidate the underlying mechanism. Methods and results: It was found that MK8722 effectively inhibited the malignant biological behaviors of EOC cells. In vitro experiments showed that MK8722 targeted and decreased the lipid metabolic pathway-related fatty acid synthase (FASN) expression levels, causing the accumulation of lipid droplets. In addition, transmission electron microscopy revealed the presence of autophagosome-affected mitochondria. Western blotting confirmed that MK8722 plays a role in activating autophagy upstream (PI3K/AKT/mTOR) and inhibiting autophagy downstream via FASN-dependent reprogramming of lipid metabolism. Plasmid transient transfection demonstrated that MK8722 suppressed late-stage autophagy by blocking autophagosome-lysosome fusion. Immunofluorescence and gene silencing revealed that this effect was achieved by inhibiting the interaction of FASN with the SNARE complexes STX17-SNP29-VAMP8. Furthermore, the antitumor effect of MK8722 was verified using a subcutaneous xenograft mouse model. Conclusion: The findings suggest that using MK8722 may be a new strategy for treating EOC, as it has the potential to be a new autophagy/mitophagy inhibitor. Its target of action, FASN, is a molecular crosstalk between lipid metabolism and autophagy, and exploration of the underlying mechanism of FASN may provide a new research direction.


Asunto(s)
Metabolismo de los Lípidos , Neoplasias Ováricas , Humanos , Femenino , Ratones , Animales , Fosfatidilinositol 3-Quinasas/metabolismo , Autofagia , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/farmacología , Carcinoma Epitelial de Ovario , Acido Graso Sintasa Tipo I/metabolismo
2.
Biol Pharm Bull ; 46(11): 1558-1568, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37914358

RESUMEN

This study was designed to evaluate the potential protective impact of estrogen and estrogen receptor against diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in rats. The levels of liver injury serum biomarkers, liver content of interleukin-6 (IL-6), relative liver weight and distortion of liver histological pictures were significantly increased in ovariectomized (OVX) rats and SHAM rats that received DEN alone and were further exaggerated when DEN was combined with fulvestrant (F) compared to non-DEN treated rats. The OVX rats showed higher insults than SHAM rats. The tapering impact on these parameters was clear in OVX rats that received estradiol benzoate (EB), silymarin (S) or orlistat (ORS). The immunohistochemistry and/or Western blot analysis of liver tissues showed a prominent increase in fatty acid synthase (FASN) and cluster of differentiation 36 (CD36) expressions in OVX and SHAM rats who received DEN and/ or F compared to SHAM rats. In contrast to S, treatment of OVX rats with EB mitigated DEN-induced expression of FASN and CD36 in liver tissue, while ORS improved DEN-induced expression of FASN. In conclusion, the protective effect against HCC was mediated via estrogen receptor alpha (ER-α) which abrogates its downstream genes involved in lipid metabolism namely FASN and CD36 depriving the tumor from survival vital energy source. In addition, ORS induced similar mitigating effect against DEN-induced HCC which could be attributed to FASN inhibition and anti-inflammatory effect. Furthermore, S alleviated DEN-induced HCC, independent of its estrogenic effect.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Femenino , Ratas , Carcinoma Hepatocelular/metabolismo , Dietilnitrosamina/toxicidad , Dietilnitrosamina/metabolismo , Estrógenos/metabolismo , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/farmacología , Interleucina-6/metabolismo , Hígado/metabolismo , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/prevención & control , Receptores de Estrógenos/metabolismo
3.
Cancer Sci ; 114(9): 3553-3567, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37302809

RESUMEN

Pancreatic neuroendocrine neoplasms (pNENs) are among the most frequently occurring neuroendocrine neoplasms (NENs) and require targeted therapy. High levels of fatty acid binding protein 5 (FABP5) are involved in tumor progression, but its role in pNENs remains unclear. We investigated the mRNA and protein levels of FABP5 in pNEN tissues and cell lines and found them to be upregulated. We evaluated changes in cell proliferation using CCK-8, colony formation, and 5-ethynyl-2'-deoxyuridine assays and examined the effects on cell migration and invasion using transwell assays. We found that knockdown of FABP5 suppressed the proliferation, migration, and invasion of pNEN cell lines, while overexpression of FABP5 had the opposite effect. Co-immunoprecipitation experiments were performed to clarify the interaction between FABP5 and fatty acid synthase (FASN). We further showed that FABP5 regulates the expression of FASN via the ubiquitin proteasome pathway and both proteins facilitate the progression of pNENs. Our study demonstrated that FABP5 acts as an oncogene by promoting lipid droplet deposition and activating the WNT/ß-catenin signaling pathway. Moreover, the carcinogenic effects of FABP5 can be reversed by orlistat, providing a novel therapeutic intervention option.


Asunto(s)
Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Vía de Señalización Wnt , Línea Celular Tumoral , Metabolismo de los Lípidos/genética , beta Catenina/genética , beta Catenina/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Tumores Neuroendocrinos/genética , Ácido Graso Sintasas/genética , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/farmacología , Proliferación Celular/genética , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Unión a Ácidos Grasos/metabolismo , Proteínas de Unión a Ácidos Grasos/farmacología , Acido Graso Sintasa Tipo I/genética , Acido Graso Sintasa Tipo I/metabolismo
4.
Oral Dis ; 29(2): 649-660, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34510641

RESUMEN

OBJECTIVES: To investigate the potential effect of fatty acid synthase (FASN) inhibitor orlistat to enhance the effectiveness of chemotherapy drugs widely used to treat oral squamous cell carcinomas (OSCC), such as 5-fluorouracil, cisplatin, and paclitaxel. METHODS: The OSCC SCC-9 LN-1 metastatic cell line, which expresses high levels of FASN, was used for drug combination experiments. Cell viability was analyzed by crystal violet staining and automatic cell counting. Apoptosis and cell cycle were analyzed by flow cytometry with Annexin-V/7-AAD and propidium iodide staining, respectively. Cyclin B1, Cdc25C, Cdk1, FASN, and ERBB2 levels were assessed by Western blotting. Finally, cell scratch and transwell assays were performed to assess cell migration and invasion. RESULTS: Inhibition of FASN with orlistat sensitized SCC-9 LN-1 cells to the cytotoxic effects of paclitaxel and cisplatin, but not 5-fluorouracil, which was accompanied by a significant reduction in cyclin B1. The suppression of proliferation, migration, and invasion of SCC-9 LN-1 cells induced by orlistat plus cisplatin or paclitaxel was not superior to the effects of chemotherapy drugs alone. CONCLUSION: Our results suggest that orlistat enhances the chemosensitivity of SCC-9 LN-1 cells to cisplatin and paclitaxel by downregulating cyclin B1.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Cisplatino/farmacología , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Orlistat/farmacología , Orlistat/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello , Ciclina B1/farmacología , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/farmacología , Neoplasias de la Boca/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Fluorouracilo/farmacología , Línea Celular Tumoral , Apoptosis , Proliferación Celular , Acido Graso Sintasa Tipo I
5.
J Tradit Chin Med ; 42(6): 940-947, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36378052

RESUMEN

OBJECTIVE: To study the mechanism of Dangfei Liganning capsule in the treatment of rats with metabolic associated fatty liver disease (MAFLD). METHODS: Totally 48 specific pathogen free Sprague-Dawley male rats were randomly divided into normal Group, model group, Dangfei Liganning high, moderate, and low-dose groups and Essentiale group which were fed with high fat diet for 8 weeks, and gavage and molding were carried out simultaneously. Dangfei Liganning high, middle and low-dose group were given 0.27, 0.135 and 0.0675 g·kg·d respectively by gavage, Essentiale group was given 0.123 g·kg·d by gavage, the same amount of distilled water was given by gavage in the normal group and the model group. The rats were weighed at the 0th week, 2nd week, 4th week, 6th week and 8th weekend respectively. The rats were sacrificed at the end of the 8th week. Serum levels of alanine aminotransferase (ALT), alanine aminotransferase (AST), triglyceride (TG), total cholesterol (CHO), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein (LDL-C), total protein (TP), albumin (Alb), globulin (GLB), total bilirubin (TBIL), direct bilirubin (DBIL), tumor necrosis factor-α(TNF-α) and interleukin-6 (IL-6) were measured. The levels of liver tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and liver pathology [hematoxylin and eosin (HE) staining, oil red O staining] were detected. The expression levels of liver X receptor α (LXRα), steroid regulatory element binding protein-1 (SREBP-1) and fatty acid synthase (FAS) were detected by immunohistochemistry, Western blot and reverse transcription-polymerase chain reaction reverse transcription-polymerase chain reaction. RESULTS: From the beginning to the 8th week, the growth rate of body weight in the Dangfei Liganning high-dose group was slower than all other groups. There was no significant difference in ALB level in all groups ( 0.05). Compared with the model group, the levels of ALT, AST, LDL-C, TG, CHO, TP, GLB, TBIL, DBIL, IL-6, TNF-α were significantly decreased and HDL-C were significantly increased in Dangfei Liganning high-dose group (0.01, < 0.05). HE and oil red O staining showed that the fatty lesions in rat liver were alleviated, while the expressions of LXRα, SREBP-1, FAS mRNA and protein were significantly decreased (0.01). CONCLUSIONS: Dangfei Liganning capsule can slow down the increase of body weight of MAFLD rats, reduce the levels of transaminase, Lipid and inflammatory factors in MAFLD rats, promote the synthesis of liver protein and bile metabolism, and improve the liver fatty lesion of MAFLD rats, among which the Dangfei Liganning high-dose group is more effective. The mechanism of action may be through blocking LXR-SREBP-1-FAS signal pathway.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Ratas , Masculino , Animales , Receptores X del Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/farmacología , Interleucina-6/genética , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ratas Sprague-Dawley , Alanina Transaminasa/metabolismo , LDL-Colesterol , Hígado , Transducción de Señal , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/farmacología , Ácido Graso Sintasas/uso terapéutico , Bilirrubina , Peso Corporal
6.
Artículo en Inglés | MEDLINE | ID: mdl-36231391

RESUMEN

Bioactive compounds provide new insights into the prevention and treatment of obesity. Lycium barbarum polysaccharide (LBP), a biological macromolecule extracted from Goji berry, has displayed potential for regulating lipid metabolism. However, the relationship between gut microbiota regulation and lipid metabolism is not entirely clear. In the present study, 50, 100, and 150 mg/kg LBP were intragastrically administered to C57BL/6J male mice fed with a high-fat diet simultaneously lasting for twelve weeks. The results showed that 150 mg/kg LBP showed significant results and all doses of LBP feeding (50, 100, 150 mg/kg) remarkably decreased both serum and liver total cholesterol (TC) and triglyceride (TG) levels. Treatment of 150 mg/kg LBP seems to be more effective in weight loss, lowering free fatty acid (FFA) levels in serum and liver tissues of mice. LBP feeding increased the gene expression of adiponectin and decreased the gene expression of peroxisome proliferator-activated receptor γ, Cluster of Differentiation 36, acetyl-coA carboxylase, and fatty acid synthase in a dose-dependent manner. In addition, the 16s rDNA Sequencing analysis showed that 150 mg/kg LBP feeding may significantly increase the richness of gut microbiota by up-regulation of the ACE and Chao1 index and altered ß-diversity among groups. Treatment of 150 mg/kg LBP feeding significantly regulated the microbial distribution by decreasing the relative abundance of Firmicutes and increasing the relative abundance of Bacteroidetes at the phylum level. Furthermore, the relative abundance of Faecalibaculum, Pantoea, and uncultured_bacterium_f_Muribaculaceae at the genus level was significantly affected by LBP feeding. A significant correlation was observed between body weight, TC, TG, FFA and bile acid and phyla at the genus level. The above results indicate that LBP plays a vital role in preventing obesity by co-regulating lipid metabolism and gut microbiota, but its effects vary with the dose.


Asunto(s)
Microbioma Gastrointestinal , Lycium , Acetil-CoA Carboxilasa/metabolismo , Acetil-CoA Carboxilasa/farmacología , Adiponectina/metabolismo , Animales , Ácidos y Sales Biliares , Colesterol , ADN Ribosómico , Dieta Alta en Grasa , Medicamentos Herbarios Chinos , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/farmacología , Ácidos Grasos no Esterificados/farmacología , Metabolismo de los Lípidos , Lycium/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/metabolismo , PPAR gamma/metabolismo , Triglicéridos
7.
Hum Exp Toxicol ; 41: 9603271221129852, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36137816

RESUMEN

Lipid metabolism is an important biochemical process in the body. Recent studies have found that environmental endocrine disruptors play an important role in the regulation of lipid metabolism. Bisphenol A (BPA), a common environmental endocrine disruptor, has adverse effects on lipid metabolism, but the mechanism is still unclear. This study aimed to investigate the effects of gestational BPA exposure on hepatic lipid metabolism and its possible mechanism in male offspring. The pregnant Sprague-Dawley rats were exposed to BPA (0, 0.05, 0.5, 5 mg/kg/day) from day 5 to day 19 of gestation to investigate the levels of triglyceride (TG) and total cholesterol (TC), and the expression of liver lipid metabolism-related genes in male offspring rats. The results showed that compared with the control group, the TG and TC levels in serum and liver in BPA-exposed groups was increased. And the expressions of liver fatty acid oxidation related genes, such as peroxisome proliferators-activated receptor α (PPARα) and carnitine palmitoyl transferase 1α (CPT1α), were down-regulated. However, the expressions of fatty acid synthesis related genes, such as sterol regulatory element binding proteins 1 (SREBP-1), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD-1), were up-regulated. The increased protein levels of mTOR and p-CRTC2 suggested that CREB-regulated transcription coactivator 2 (CRTC2) might be an important mediator in the mTOR/SREBP-1 pathway. In conclusion, these results demonstrated that mTOR/CRTC2/SREBP-1 could be affected by gestational BPA exposure, which may involve in the lipid metabolic disorders in later life.


Asunto(s)
Disruptores Endocrinos , Metabolismo de los Lípidos , Acetil-CoA Carboxilasa/metabolismo , Acetil-CoA Carboxilasa/farmacología , Animales , Compuestos de Bencidrilo , Carnitina/farmacología , Colesterol , Disruptores Endocrinos/toxicidad , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/farmacología , Ácidos Grasos/farmacología , Femenino , Hígado , Masculino , PPAR alfa/metabolismo , Proliferadores de Peroxisomas/metabolismo , Proliferadores de Peroxisomas/farmacología , Fenoles , Embarazo , Ratas , Ratas Sprague-Dawley , Estearoil-CoA Desaturasa/metabolismo , Estearoil-CoA Desaturasa/farmacología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Transferasas/metabolismo , Transferasas/farmacología , Triglicéridos
8.
Toxicol In Vitro ; 85: 105477, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36122805

RESUMEN

Precision-cut tissue slices (PCTS) are frequently used in mammalian research, but its application in the area of aquatic toxicology is still humble. This work proposes the use of PCTS to investigate the effects of the antimicrobial triclosan (TCS) in the mussel Mytilus galloprovincialis. PCTS sectioned from the digestive gland (400 µm) were exposed to 10, 100, and 500 nM TCS for 24 h, and the expression of selected genes, together with the biomarkers, carboxylesterases (CbE) and glutathione S-transferases (GST), and the analysis of lipids in PCTS and culture medium, were used to investigate the molecular initiating events of triclosan in the digestive gland of mussels. Significant dysregulation in the expression of phenylalanine-4-hydroxylase (PAH), glutamate dehydrogenase (GDH), fatty acid synthase (FASN), and 7-dehydrocholesterol reductase (DHCR7), involved in energy, phenylalanine and lipid metabolism, were detected. The analysis of lipids evidenced significant changes in cholesteryl esters (CEs) and membrane lipids in the culture medium of exposed PCTS, suggesting dysregulation of energy and lipid metabolism that can affect lipid dynamics in mussels exposed to triclosan.


Asunto(s)
Antiinfecciosos , Mytilus , Triclosán , Contaminantes Químicos del Agua , Animales , Triclosán/toxicidad , Glutamato Deshidrogenasa/metabolismo , Glutamato Deshidrogenasa/farmacología , Ésteres del Colesterol/metabolismo , Ésteres del Colesterol/farmacología , Glutatión/metabolismo , Biomarcadores/metabolismo , Hidrolasas de Éster Carboxílico/metabolismo , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/farmacología , Fenilalanina/farmacología , Oxigenasas de Función Mixta/metabolismo , Transferasas , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/metabolismo , Mamíferos/metabolismo
9.
Cell Stress Chaperones ; 27(5): 499-511, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35779187

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is a major health concern. Endoplasmic reticulum (ER) stress, inflammation, and metabolic dysfunctions may be targeted to prevent the progress of nonalcoholic fatty liver disease. Sulforaphane (SFN), a sulfur-containing compound that is abundant in broccoli florets, seeds, and sprouts, has been reported to have beneficial effects on attenuating metabolic diseases. In light of this, the present study was designed to elucidate the mechanisms by which SFN ameliorated ER stress, inflammation, lipid metabolism, and insulin resistance - induced by a high-fat diet and ionizing radiation (IR) in rats. In our study, the rats were randomly divided into five groups: control, HFD, HFD + SFN, HFD + IR, and HFD + IR + SFN groups. After the last administration of SFN, liver and blood samples were taken. As a result, the lipid profile, liver enzymes, glucose, insulin, IL-1ß, adipokines (leptin and resistin), and PI3K/AKT protein levels, as well as the mRNA gene expression of ER stress markers (IRE-1, sXBP-1, PERK, ATF4, and CHOP), fatty acid synthase (FAS), peroxisome proliferator-activated receptor-α (PPAR-α). Interestingly, SFN treatment modulated the levels of proinflammatory cytokine including IL-1ß, metabolic indices (lipid profile, glucose, insulin, and adipokines), and ER stress markers in HFD and HFD + IR groups. SFN also increases the expression of PPAR-α and AMPK genes in the livers of HFD and HFD + IR groups. Meanwhile, the gene expression of FAS and CHOP was significantly attenuated in the SFN-treated groups. Our results clearly show that SFN inhibits liver toxicity induced by HFD and IR by ameliorating the ER stress events in the liver tissue through the upregulation of AMPK and PPAR-α accompanied by downregulation of FAS and CHOP gene expression.


Asunto(s)
Estrés del Retículo Endoplásmico , Insulinas , Isotiocianatos , Enfermedad del Hígado Graso no Alcohólico , Sulfóxidos , Proteínas Quinasas Activadas por AMP/genética , Animales , Citocinas/metabolismo , Dieta Alta en Grasa , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ácido Graso Sintasas/genética , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/farmacología , Glucosa/metabolismo , Insulinas/genética , Insulinas/metabolismo , Insulinas/farmacología , Isotiocianatos/farmacología , Isotiocianatos/uso terapéutico , Leptina , Lípidos/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptores Activados del Proliferador del Peroxisoma/genética , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Receptores Activados del Proliferador del Peroxisoma/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/metabolismo , Ratas , Resistina/genética , Resistina/metabolismo , Resistina/farmacología , Sulfóxidos/farmacología , Sulfóxidos/uso terapéutico , Regulación hacia Arriba
10.
Chem Biodivers ; 19(9): e202200495, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35856892

RESUMEN

OBJECT: Edible Brown Seaweed Sargassum fusiforme (Harvey) Setchell, 1931 abbreviated as Sargassum fusiforme was used for folk medical therapy in East Asia countries over five hundred years. Saringosterol acetate (SA) was isolated from S. fusiforme in our previous study and indicated various effects. However, anti-obesity activity of SA and its mechanism still unknown. METHOD: The inhibitory effect of SA, isolated from S. fusiforme, on adipogenesis in 3T3-L1 adipocytes was investigated in vitro and in zebrafish model. Cell toxicity, differentiation, signaling pathway, and lipid accumulation of SA treated 3T3-L1 adipocytes were determined. The body weight and triglyceride content of diet-induced obese (DIO) adult male zebrafish were measured from 12 to 17 weeks after fertilization. RESULT: SA attenuated the differentiation of cells and reduced lipid accumulation, and triglyceride content in the 3T3-L1 adipocytes. During the differentiation of adipocytes, SA suppressed fat accumulation and decreased the expression of signal factors responsible for adipogenesis. In SA-treated adipocytes, while fatty acid synthetase was downregulated, AMP-activated protein kinase (AMPK) was upregulated. Furthermore, SA suppressed body weight and triglyceride content in DIO zebrafish. CONCLUSION: SA is a potential therapeutic agent in the management of metabolic disorders, such as obesity.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Pez Cebra , Células 3T3-L1 , Proteínas Quinasas Activadas por AMP/metabolismo , Acetatos/farmacología , Adipogénesis , Animales , Peso Corporal , Dieta Alta en Grasa , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/farmacología , Ácido Graso Sintasas/uso terapéutico , Masculino , Ratones , Obesidad/tratamiento farmacológico , Estigmasterol/análogos & derivados , Estigmasterol/farmacología , Triglicéridos/metabolismo , Pez Cebra/metabolismo
11.
FEBS Lett ; 596(24): 3191-3202, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35689495

RESUMEN

Previously, we revealed the dual enhancing effect of netoglitazone, an agonist of the peroxisome proliferator-activated receptor γ, on adipogenesis and osteoblastogenesis, and reported that fatty acid synthase (FASN) knockdown selectively repressed its pro-adipogenic effect. Here, we examined if a FASN inhibitor, C75, could selectively repress the pro-adipogenic effect of netoglitazone. Surprisingly, C75 promoted the adipogenic differentiation of multipotent C3H10T1/2 cells but inhibited 3T3-L1 preadipocytes. By identifying glycogen synthase kinase-3ß and intracellular cAMP levels as regulatory targets of C75, we ultimately found the differential expression of adenosine receptor 3 (AR3) and AR2a on these cells. Inhibition of AR3 on C3H10T1/2 and AR2a on 3T3-L1 inhibited the effects of C75 on the differentiation of these cells. Our findings imply that cell-type-specific AR expression might account for the differential adipogenic effects of C75.


Asunto(s)
Adipocitos , Adipogénesis , Ratones , Animales , Adipocitos/metabolismo , Diferenciación Celular , Ácido Graso Sintasas/genética , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/farmacología , PPAR gamma/genética , PPAR gamma/metabolismo , PPAR gamma/farmacología , Células 3T3-L1
12.
J Food Biochem ; 46(10): e14265, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35661366

RESUMEN

There are no medical drugs that provide an acceptable weight loss with minimal adverse effects. This study evaluated the Moringa peregrina (MP) seed extract's anti-obesity effect. Twenty-four (6/each group) male Sprague Dawley rats were divided into group Ι (control), group ΙΙ (high-fat diet [HFD]), group ΙΙΙ (HFD+ MP [250 mg/kg b.wt]), and group ΙV (HFD+ MP [500 mg/kg b.wt]). MP administration significantly ameliorated body weight gains and HFD induced elevation in cholesterol, triglycerides, LDL, and reduced HDL. Moreover, MP seed oil showed high free radical-scavenging activity, delayed ß-carotene bleaching and inhibited lipoprotein and pancreatic lipase enzymes. High-performance liquid chromatography (HPLC) revealed three major active components: crypto-chlorogenic acid, isoquercetin, and astragalin. Both quantitative Real-time PCR (RT-PCR) and western blotting revealed that MP seeds oil significantly decreased the expression of lipogenesis-associated genes such as peroxisome proliferator-activated receptors gamma (PPARγ) and fatty acid synthase (FAS) and significantly elevated the expression of lipolysis-associated genes (acetyl-CoA carboxylase1, ACCl). The oil also enhanced phosphorylation of AMP-activated protein kinase alpha (AMPK-α) and suppressed CCAAT/enhancer-binding protein ß (C/EBPß). In conclusion, administration of M. peregrina seeds oil has anti-obesity potential in HFD-induced obesity in rats. PRACTICAL APPLICATIONS: M. peregrina seeds oil had a potential anti-obesity activity that may be attributed to different mechanisms. These included decreasing body weight, and body mass index and improving lipid levels by decreasing total cholesterol, triglycerides and LDL-C, and increasing HDL-C. Also, M. peregrina seeds oil regulated adipogenesis-associated genes, such as downregulating the expression of (PPARγ, C/EBPα, and FAS) and improving and upregulating the expression and phosphorylation of AMPKα and ACCl. Despite that M. peregrina extract has reported clear anti-obesity potential through animal and laboratory studies, the available evidence-based on human clinical trials are very limited. Therefore, further studies are needed that could focus on clinical trials investigating anti-obesity potential different mechanisms of M. peregrina extract in humans.


Asunto(s)
Dieta Alta en Grasa , Moringa , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/farmacología , Acetilcoenzima A/metabolismo , Acetilcoenzima A/farmacología , Acetilcoenzima A/uso terapéutico , Adipocitos , Animales , Antioxidantes/metabolismo , Peso Corporal , Ácido Clorogénico/metabolismo , Colesterol/metabolismo , LDL-Colesterol/metabolismo , Dieta Alta en Grasa/efectos adversos , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/farmacología , Ácido Graso Sintasas/uso terapéutico , Radicales Libres/metabolismo , Radicales Libres/farmacología , Radicales Libres/uso terapéutico , Humanos , Lipasa/metabolismo , Masculino , Moringa/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/etiología , PPAR gamma/genética , PPAR gamma/metabolismo , Extractos Vegetales/metabolismo , Extractos Vegetales/farmacología , Aceites de Plantas/metabolismo , Ratas , Ratas Sprague-Dawley , Semillas/metabolismo , Triglicéridos/metabolismo , beta Caroteno
13.
An Acad Bras Cienc ; 94(2): e20210670, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35507982

RESUMEN

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.


Asunto(s)
Neoplasias del Cuello Uterino , Apoptosis , Línea Celular Tumoral , Supervivencia Celular , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/farmacología , Femenino , Humanos , Orlistat/farmacología , Neoplasias del Cuello Uterino/tratamiento farmacológico
14.
Mol Cancer Ther ; 21(1): 206-216, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34667110

RESUMEN

Our previous matched case-control study of postmenopausal women with resected early-stage breast cancer revealed that only anastrozole, but not exemestane or letrozole, showed a significant association between the 6-month estrogen concentrations and risk of breast cancer. Anastrozole, but not exemestane or letrozole, is a ligand for estrogen receptor α. The mechanisms of endocrine resistance are heterogenous and with the new mechanism of anastrozole, we have found that treatment of anastrozole maintains fatty acid synthase (FASN) protein level by limiting the ubiquitin-mediated FASN degradation, leading to increased breast cancer cell growth. Mechanistically, anastrozole decreases the guided entry of tail-anchored proteins factor 4 (GET4) expression, resulting in decreased BCL2-associated athanogene cochaperone 6 (BAG6) complex activity, which in turn, prevents RNF126-mediated degradation of FASN. Increased FASN protein level can induce a negative feedback loop mediated by the MAPK pathway. High levels of FASN are associated with poor outcome only in patients with anastrozole-treated breast cancer, but not in patients treated with exemestane or letrozole. Repressing FASN causes regression of breast cancer cell growth. The anastrozole-FASN signaling pathway is eminently targetable in endocrine-resistant breast cancer.


Asunto(s)
Anastrozol/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Ácido Graso Sintasas/uso terapéutico , Anastrozol/farmacología , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Proliferación Celular , Ácido Graso Sintasas/farmacología , Femenino , Humanos
15.
J Urol ; 180(2): 729-36, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18555493

RESUMEN

PURPOSE: Fatty acid synthase has been shown to be over expressed in a wide range of cancers and it has emerged as a therapeutic target. We examined whether fatty acid synthase could be a novel therapeutic target for renal cell carcinoma using the pharmacological fatty acid synthase inhibitor C75 (Cayman Chemical, Ann Arbor, Michigan). MATERIALS AND METHODS: The effects of C75 on cell viability and proliferation in human renal cancer 769P (ATCC(R)), Caki-1 and KU20-01 cells were examined by MTS assay and cell counts. Cell cycle distribution was analyzed by flow cytometry and cell invasiveness was assessed by wound healing and Matrigel(trade mark) invasion assays. Fatty acid synthase expression and the effects of C75 on intracellular signaling pathways were analyzed by Western blotting. The antitumor efficacy of C75 was examined using Caki-1 cell xenografts. RESULTS: All renal cancer cell lines expressed detectable fatty acid synthase. C75 (10 mug/ml) significantly inhibited cell viability and growth by arresting the cell cycle at the G2/M phase and inducing apoptosis (p <0.01). The covered area in the wound and the number of cells invading through a Matrigel chamber were significantly smaller for cells treated with C75 than they were for control cells treated with vehicle (p <0.001). C75 suppressed Her2 and epidermal growth factor receptor expression as well as STAT3 phosphorylation, while increasing p53 and p21(Waf1/Cip1) expression. Intraperitoneal administration of C75 at doses of 20 mg/kg per week for 28 days significantly reduced the tumor volume of Caki-1 xenografts (p <0.05). CONCLUSIONS: Pharmacological inhibition of fatty acid synthase could be an effective strategy for treating renal cell carcinoma.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dimetilsulfóxido/farmacología , Ácido Graso Sintasas/antagonistas & inhibidores , Análisis de Varianza , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Western Blotting , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Recuento de Células , Modelos Animales de Enfermedad , Ácido Graso Sintasas/farmacología , Humanos , Inyecciones Intraperitoneales , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Masculino , Ratones , Ratones Desnudos , Invasividad Neoplásica/patología , Probabilidad , Sensibilidad y Especificidad , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/fisiología , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Int J Biochem Cell Biol ; 35(3): 391-400, 2003 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12531252

RESUMEN

Fatty acid synthase (FAS; acyl-CoA:malonyl-CoA C-acyltransferase [decarboxylating, oxoacyl- and enoyl-reducing and thioester-hydrolyzing], EC 2.3.1.85) is an important enzyme participating in energy metabolism in vivo which is related to adiposis and cancer [Cancer Lett. 167 (1) (2001) 99; Nat. Med. 8 (4) (2002) 335]. Tests of fast- and slow-binding inhibitions showed that fatty acid synthase of chicken liver is rapidly and irreversibly inactivated by low Zn(2+) concentrations. Electrophoresis and FPLC results showed that FAS cross-links occurred in the presence of high Zn(2+) concentrations (>4 microM) which may be another reason that FAS lost its activity. The modification velocity of FAS by DTNB decreased with increasing Zn(2+) concentration, which confirmed that Zn(2+) interacted with SH groups. Substrate protective experiments and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) showed that all three substrates tested had some protective effects on FAS in the presence of Zn(2+), and malonyl-CoA was the most effective of the three substrates. In the presence of malonyl-CoA, the activity loss of FAS decreased sharply and almost no cross-link was observed in SDS-PAGE. This suggests that the phosphopantetheine SH group is the critical group in the cross-link and inhibition of FAS in the presence of Zn(2+).


Asunto(s)
Ácido Graso Sintasas/farmacología , Iones , Hígado/metabolismo , Zinc/farmacología , Animales , Unión Competitiva , Pollos , Cromatografía , Cromatografía Liquida , Reactivos de Enlaces Cruzados/farmacología , Electroforesis en Gel de Poliacrilamida , Ácido Graso Sintasas/química , Hígado/efectos de los fármacos , Malonil Coenzima A/metabolismo , Factores de Tiempo , Zinc/metabolismo
18.
Biochim Biophys Acta ; 1046(2): 111-9, 1990 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-2223852

RESUMEN

Acyl carrier protein (ACP) from Escherichia coli has been shown to form complexes with melittin, a cationic peptide from bee venom. ACP is a small (Mr 8847), acidic, Ca2(+)-binding protein, which possesses some characteristics resembling those of regulatory Ca2(+)-binding proteins including interaction with melittin. Complexing between melittin and ACP which occurred both in the presence and absence of Ca2+ was evident by chemical cross-linking the two peptides, fluorescence changes (including anisotropy measurements), and inhibition by melittin of the activity of a nonaggregated fatty acid synthetase from Euglena. Also, anti-Apis mellifera antibodies which contained antibodies against melittin specifically inhibited the same enzyme system activity relative to non-immune IgG.


Asunto(s)
Proteína Transportadora de Acilo/metabolismo , Escherichia coli/análisis , Meliteno/metabolismo , Animales , Anticuerpos/farmacología , Venenos de Abeja/inmunología , Western Blotting , Calcio/farmacología , Reactivos de Enlaces Cruzados , Dimetil Suberimidato , Euglena/enzimología , Ácido Graso Sintasas/farmacología , Meliteno/antagonistas & inhibidores , Meliteno/inmunología , Peso Molecular , Espectrometría de Fluorescencia
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