RESUMEN
BACKGROUND: Recent studies have demonstrated that side population (SP) cells isolated from various cancer cell lines and primary tumors possess stem cell-like properties. Sesamin, a food-derived agent, possesses anti-cancer activities both in vitro and in vivo. The present study was designed to determine whether sesamin also have effects on cancer stem-like SP cells from gallbladder cancer (GBC). METHODS: In this study, we sorted SP cells by flow cytometry. SP cells were cultured and treated with sesamin. Tumor-sphere formation, colony formation, Matrigel invasion and tumorigenic potential were determined. Expression of nuclear NF-κB, IL-6, p-Stat3, Twist, E-cadherin and Vimentin was measured by Western blot, immunofluorescence staining or RT-PCR analysis. Nuclear NF-κB activity and IL-6 protein level were assessed with ELISA. Xenograft tumors were generated in nude mice. RESULTS: After treated with sesamin, SP cells differentiated into cells expressing the epithelial marker (E-cadherin). Sesamin effectively affected SP cells stem cell-like characteristics (i.e., tumor-sphere formation, colony-formation, Matrigel invasion), weakened the drug-resistance of SP cells and inhibited tumor growth both in vitro and in vivo. Treatment with sesamin significantly reduced the expression of nuclear NF-κB, IL-6, p-Stat3, Twist and Vimentin (a mesenchymal marker) in SP cells. Nuclear NF-κB activity and IL-6 level were also decreased after treatment with sesamin. CONCLUSION: Food-derived sesamin directs the epithelial differentiation of cancer stem-like SP cells from GBC, which is associated with attenuation of NF-κB-IL-6-Stat3-Twist signal pathway.
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Dioxoles/farmacología , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/patología , Lignanos/farmacología , Células Madre Neoplásicas/efectos de los fármacos , Células de Población Lateral/efectos de los fármacos , Análisis de Varianza , Animales , Cadherinas/metabolismo , Carcinoma/tratamiento farmacológico , Carcinoma/metabolismo , Carcinoma/patología , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Neoplasias de la Vesícula Biliar/metabolismo , Humanos , Interleucina-6/metabolismo , Ratones , Ratones Desnudos , FN-kappa B/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Células de Población Lateral/metabolismo , Células de Población Lateral/patología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Sesamin (Ses) is a natural lignan abundantly present in sesame and sesame oil. Pyroptosis, a newly identified type of pro-inflammatory programmed necrosis, contributes to the development of non-alcoholic steatohepatitis (NASH) when hepatocyte pyroptosis is excessive. In this study, Ses treatment demonstrated an improvement in hepatic damage in mice with high-fat, high-cholesterol diet-induced NASH and palmitate (PA)-treated mouse primary hepatocytes. Notably, we discovered, for the first time, that Ses could alleviate hepatocyte pyroptosis both in vivo and in vitro. Furthermore, treatment with phorbol myristate acetate, a protein kinase Cδ (PKCδ) agonist, increased PKCδ phosphorylation and attenuated the protective effects of Ses against pyroptosis in PA-treated mouse primary hepatocytes. Mechanistically, Ses treatment alleviated hepatocyte pyroptosis in NASH, which was associated with the regulation of the PKCδ/nod-like receptor family CARD domain-containing protein 4/caspase-1 axis. This study introduces a novel concept and target, suggesting the potential use of functional factors in food to alleviate liver damage caused by NASH.
RESUMEN
Nonalcoholic fatty liver disease (NAFLD) is the primary complication of type 2 diabetes (T2DM)-related liver disease, lacking effective treatment options. Metformin (Met), a widely prescribed anti-hyperglycemic medication, has been found to protect against NAFLD. Ferroptosis, a newly discovered form of cell death, is associated with the development of NAFLD. Despite this association, the extent of Met's protective effects on NAFLD through the modulation of ferroptosis has yet to be thoroughly investigated. In the present study, the administration of erastin or Ras-selective lethal 3 (RSL3), both known ferroptosis inducers, resulted in elevated cell mortality and reduced cell viability in AML12 hepatocytes. Notably, Met treatment demonstrated the capacity to mitigate these effects. Furthermore, we observed increased ferroptosis levels in both AML12 hepatocytes treated with palmitate and oleate (PA/OA) and in the liver tissue of db/db mice. Met treatment demonstrated significant reductions in iron accumulation and lipid-related reactive oxygen species production, simultaneously elevating the glutathione/glutathione disulfide ratio in both PA/OA-treated AML12 hepatocytes and the liver tissue of db/db mice. Interestingly, the anti-ferroptosis effects of Met were significantly reversed with the administration of RSL3, both in vitro and in vivo. Mechanistically, Met treatment regulated the glutathione peroxidase 4/solute carrier family 7 member 11/acyl-CoA synthetase long-chain family member 4 axis to alleviate ferroptosis in NAFLD hepatocytes. Overall, our findings highlight the crucial role of ferroptosis in the development of T2DM-related NAFLD and underscore the potential of Met in modulating key factors associated with ferroptosis in the context of NAFLD.
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Diabetes Mellitus Tipo 2 , Ferroptosis , Indanos , Metformina , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Metformina/farmacología , Metformina/uso terapéutico , Disulfuro de Glutatión , Ratones EndogámicosRESUMEN
Metformin (Met) is the recommended first-line therapeutic drug for type 2 diabetes mellitus (T2DM) and exerts protective effects on ß-cell damage. Ferroptosis, a new form of cell death, is associated with pancreatic islet injury in patients with T2DM. However, the protective effects of Met treatment against ß-cell damage through ferroptosis modulation remain under-reported. This study investigated the in vivo effects of Met treatment on pancreatic ß-cell ferroptosis using two different diabetic mouse models, namely, low-dose streptozotocin (STZ) and high-fat diet (HFD)-induced diabetic mice and db/db mice. Met treatment significantly restored insulin release, reduced cell mortality, and decreased the overproduction of lipid-related reactive oxygen species in the islets of both STZ/HFD-induced diabetic mice and db/db mice. Administration of the Ras-selective lethal 3 injection significantly attenuated the antiferroptosis effects of Met. Mechanistically, Met treatment alleviated ß-cell ferroptosis in T2DM, which was associated with the regulation of the GPX4/ACSL4 axis in the islets. In conclusion, our findings highlight the significance of ferroptosis in T2DM ß-cell damage and provide novel insights into the protective effects of Met against islet ß cells.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ferroptosis , Células Secretoras de Insulina , Metformina , Humanos , Ratones , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Metformina/farmacología , Metformina/uso terapéutico , Metformina/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismoRESUMEN
Ferroptosis, a new type of cell death, is associated with pancreatic ß cell damage. However, the role of glucolipotoxicity in inducing ß cell ferroptosis remains unclear. Metformin (Met), exenatide (Exe), and saxagliptin (Sax) are frequently used anti-hyperglycaemic drugs. However, their protective effects on ß cells through ferroptosis modulation are not well-established. In this study, we observed significant ferroptosis in NIT-1 cells and primary mouse islets after exposure to high glucose and palmitate (HG/PA). Compared to Exe and Sax, Met significantly alleviated glucolipotoxicity-induced pancreatic ß cell ferroptosis. Blocking the activity of glutathione peroxidase 4 (GPX4) with Ras-selective lethal 3 or inhibiting its expression by small interfering RNA transfection significantly attenuated the anti-ferroptosis effects of Met. Mechanistically, Met alleviates HG/PA-induced ß cell ferroptosis by regulating the GPX4/ACSL4 axis. Collectively, our findings highlight the significance of ferroptosis in pancreatic ß cell glucolipotoxicity-induced injury and provide novel insights into the protective effects of Met on islet ß cells.
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Ferroptosis , Células Secretoras de Insulina , Islotes Pancreáticos , Metformina , Animales , Ratones , Muerte Celular , Células Secretoras de Insulina/metabolismo , Metformina/farmacologíaRESUMEN
Three different inorganic-organic hetero-junctions (A: ITO/SiO2/Alq3/Al, B: ITO/Alq3/SiO2/Al and C: ITO/SiO2/Alq3/SiO2/Al) were fabricated. The emission can be observed only under positive bias in devices A and B, but under both biases in device C according to their brightness waveforms. With increasing voltage, the increase in blue emission in devices B and C is faster than that in green emission. This is because that the recombination of hot electrons and holes, i.e., electron-hole pairs, produced blue emission in devices B and C, and the recombination of electrons injected from Al with the accumulated holes, which are excited by hot electrons, produced green emission in device A. Hence, the emissions of the devices are attributed to not only the recombination of electrons and accumulated holes, but also the cathodoluminescence-like (CL-like) emission.
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Single-drug therapy for cancer is greatly hampered by its non-specific delivery to the target tissue, limited efficacies, poor tolerability, and resistance profiles. In order to overcome these limitations, we developed a new targeted nanoparticle platform for co-delivery of two different anticancer drugs. A conjugate based on carboxymethylcellulose (CMC) was first synthesized by introducing hydrophilic molecules (PEG), target molecules (folate), and drug molecules (betulinic acid) into CMC. Then another anticancer drug hydroxycamptothecine (HCPT) was encapsulated into the nanoparticles from the conjugate using a simple nanoprecipitation method. The obtained nanoparticles possessed appropriate size (â¼180 nm), high drug loading efficiency (â¼23 wt% BA, 21.15 wt% HCPT), a slow drug release rate, higher blood circulation half-time of free BA (6.4-fold) and HCPT (6.0-fold), and high synergetic activity of BA and HCPT toward cancer cells. Furthermore, the targeted nanoparticles showed rapid cellular uptake by tumor cells. The antitumor effect of the nanoparticles in a mouse tumor xenograft model exhibited a much better tumor inhibition efficacy and fewer side effects than that of BA and HCPT, strongly supporting their application as efficient carriers for anticancer therapy.
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Advanced glycation end products (AGEs), the direct modulators of ß-cells, have been shown to cause insulin-producing ß-cell dysfunction and apoptosis through increase of intracellular reactive oxygen species (ROS) production. Sesamin has been demonstrated to possess antioxidative activity. This study was designed to investigate whether sesamin protects against AGEs-evoked ß-cell damage via its antioxidant property. The effects of sesamin were examined in C57BL/6J mice and MIN6 cell line. In in vivo studies, mice were intraperitoneally injected with AGEs (120 mg/kg) and orally treated with sesamin (160 mg/kg) for four weeks. Intraperitoneal glucose tolerance and insulin releasing tests were performed. Insulin content, ROS generation and ß-cell apoptosis in pancreatic islets were also measured. In in vitro studies, MIN6 cells were pretreated with sesamin (50 or 100 µM) and then exposed to AGEs (200 mg/L) for 24 h. Insulin secretion, ß-cell death, ROS production as well as expression and activity of NADPH oxidase were determined. Sesamin treatment obviously ameliorated AGE-induced ß-cell dysfunction and apoptosis both in vivo and in vitro. These effects were associated with decreased ROS production, down-regulated expression of p67(phox) and p22(phox), and reduced NADPH oxidase activity. These results suggest that sesamin protects ß-cells from damage caused by AGEs through suppressing NADPH oxidase-mediated oxidative stress.
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Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Dioxoles/farmacología , Productos Finales de Glicación Avanzada/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Lignanos/farmacología , Animales , Células Cultivadas , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: The blood pressure lowering effect of sesamin has been demonstrated to be associated with the increase in vascular nitric oxide (NO) biological activity by our previous studies and others. The present study was designed to explore the underlying mechanisms involved in the effect of sesamin on aortic NO bioactivity in spontaneously hypertensive rats (SHRs). METHODS: Sesamin was orally administered for 8 consecutive weeks in SHRs. Systolic blood pressure (SBP) was measured using the tail-cuff method. The aortas were isolated and in vitro vascular reactivity studies were performed. Superoxide anion production in carotid arteries was assessed by dihydroethidium fluorescence staining. The protein expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (P-eNOS), dihydrofolate reductase (DHFR), nicotinamide adenine dinucleotide phosphate oxidase subunit p47phox, and copper, zinc superoxide dismutase (Cu/Zn-SOD) in aortas was detected by Western blotting. The dimeric form of eNOS in aortas was determined by low-temperature sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Aortic level of nitrotyrosine and activities of antioxidant enzymes, namely, total SOD (T-SOD), glutathione peroxidase (GPx) and catalase were also detected. RESULTS: In SHRs, sesamin treatment reduced SBP, improved vascular relaxation induced by acetylcholine and enhanced aortic NO bioactivity. Sesamin treatment enhanced NO biosynthesis in SHR aortas was due to upregulated P-eNOS and suppressed eNOS uncoupling, and the latter effect might be attributed to decreased nitrotyrosine and upregulated DHFR. Sesamin also reduced the NO oxidative inactivation and decreased the superoxide anion production through downregulation of p47(phox) and amelioration of eNOS uncoupling. In addition, sesamin treatment did not alter the levels of GPx and catalase activity but obviously reduced the compensatory elevated T-SOD activity and Cu/Zn-SOD protein expression. CONCLUSION: Chronic treatment with sesamin could reduce hypertension and improve endothelial dysfunction through enhancement of NO bioactivity in SHR aortas.
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Antihipertensivos/farmacología , Aorta/efectos de los fármacos , Dioxoles/farmacología , Lignanos/farmacología , Óxido Nítrico/metabolismo , Animales , Antioxidantes/metabolismo , Aorta/metabolismo , Presión Sanguínea/efectos de los fármacos , Western Blotting , Regulación hacia Abajo/efectos de los fármacos , Electroforesis en Gel de Poliacrilamida , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Masculino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Superóxido Dismutasa/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The present study was designed to evaluate the possible in vivo protective effects of sesamin on hypertension and endothelial function in two-kidney, one-clip renovascular hypertensive rats fed with a high-fat, high-sucrose diet (2K1C rats on HFS diet). Sesamin was orally administered for 8 weeks in 2K1C rats on HFS diet. Then, the serum malondialdehyde level was determined. The protein expression of endothelial nitric oxide synthase (eNOS), nitrotyrosine and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47(phox) in aortas was detected by Western blotting. Vasorelaxation response to acetylcholine and nitroprusside, and functional assessment of nitric oxide (NO) bioactivity were also determined in aortic rings. Sesamin treatment reduced systolic blood pressure, improved vasodilatation induced by acetylcholine and enhanced NO bioactivity in the thoracic aortas. These changes were associated with increased eNOS, decreased malondialdehyde content, and reduced nitrotyrosine and p47(phox) protein expression. All these results suggest that chronic treatment with sesamin reduces hypertension and improves endothelial dysfunction through upregulation of eNOS expression and reduction of NO oxidative inactivation in 2K1C rats on HFS diet.