RESUMEN
Granulosa cells are somatic cells located inside follicles that play a crucial role in the growth and development of follicles. Quercetin and tanshinone are two key monomers in traditional Chinese medicine that have antioxidant and anti-aging properties. The KGN cell apoptosis model caused by triptolide (TP) was employed in this work to investigate granulosa cell death and medication rescue. Quercetin and tanshinone therapy suppressed KGN cell death and oxidation while also regulating the expression of critical apoptosis and oxidation-related markers such as B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax). Further research revealed that the effects of Quercetin and Tanshinone were accomplished via deacetylation of FOXO3A in the cytoplasm and mitochondria via the SIRT1/SIRT3-FOXO3a axis. In summary, Quercetin and tanshinone protect KGN cells from apoptosis by reducing mitochondrial apoptosis and oxidation via the SIRT1/SIRT3-FOXO3a axis.
Asunto(s)
Abietanos , Sirtuina 3 , Femenino , Humanos , Apoptosis , Autofagia/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Quercetina/farmacología , Sirtuina 1/efectos de los fármacos , Sirtuina 1/metabolismo , Sirtuina 3/efectos de los fármacos , Sirtuina 3/metabolismo , Proteína Forkhead Box O3/efectos de los fármacosRESUMEN
The granulosa cells (GCs) of birds are essential for the reproduction and maintenance of populations in nature. Atrazine (ATR) is a potent endocrine disruptor that can interfere with reproductive function in females and Diaminochlorotriazine (DACT) is the primary metabolite of ATR in the organism. Melatonin (MT) is an endogenous hormone with antioxidant properties that plays a crucial role in development of animal germ cells. However, how ATR causes mitochondrial dysfunction, abnormal secretion of steroid hormones, and whether MT prevents ATR-induced female reproductive toxicity remains unclear. Thus, the purpose of this study is to investigate the protective effect of MT against ATR-induced female reproduction. In the present study, the GCs of quail were divided into 6 groups, as follows: C (Serum-free medium), MT (10 µM MT), A250 (250 µM ATR), MA250 (10 µM MT+250 µM ATR), D200 (200 µM DACT) and MD200 (10 µM MT+200 µM DACT), and were cultured for 24 h. The results revealed that ATR prevented GCs proliferation and decreased cell differentiation. ATR caused oxidative damage and mitochondrial dysfunction, leading to disruption of steroid synthesis, which posed a severe risk to GC's function. However, MT supplements reversed these changes. Mechanistically, our study exhibited that the ROS/SIRT1/STAR axis as a target for MT to ameliorate ATR-induced mitochondrial dysfunction and steroid disorders in GCs, which provides new insights into the role of MT in ATR-induced reproductive capacity and species conservation in birds.
Asunto(s)
Atrazina , Herbicidas , Melatonina , Enfermedades Mitocondriales , Animales , Femenino , Atrazina/toxicidad , Atrazina/metabolismo , Células de la Granulosa/metabolismo , Herbicidas/toxicidad , Herbicidas/metabolismo , Melatonina/farmacología , Enfermedades Mitocondriales/inducido químicamente , Especies Reactivas de Oxígeno/metabolismo , Sirtuina 1/efectos de los fármacos , Sirtuina 1/metabolismo , Esteroides/metabolismo , Codorniz/genética , Codorniz/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Polyalthia longifolia var. angustifolia Thw. (Annonaceae) is commonly used in traditional medicine as a tonic for rejuvenation and exhibiting good antioxidant activities. AIM OF THE STUDY: To evaluate P. longifolia methanolic leaf extract (PLME) antiaging activity at 1 mg/mL in Saccharomyces cerevisiae BY611 yeast. MATERIALS AND METHODS: The antiaging effect of PLME was studied via replicative lifespan assay, antioxidative stress assays, reactive oxygen species (ROS) determination, reduced glutathione (GSH) determination, superoxide dismutase (SOD) and Sirtuin 1 (SIRT1) genes regulation studies and SOD and SIRT1 proteins activities. RESULTS: The PLME treatment increased the growth and prolonged the lifespan of the yeast significantly (p < 0.05) compared to the untreated yeast group. Besides, the PLME also protected the yeast from oxidative stress induced by 4-mM-H2O2 via decreasing (p < 0.05) the ROS from 143.207 to 127.223. The antioxidative action of PLME was proved by spot assay. Phloxine B staining was further confirmed the PLME antioxidative action of PLME, where more whitish-pink live yeast cells were observed. In addition, the PLME also enhanced GSH content significantly (p < 0.05) in yeast treated with PLME from 16.81 to 25.31 µmol. Furthermore, PLME increased the SOD and SIRT1 genes expression significantly (p < 0.05) with ΔCt values of 1.11 and 1.15, respectively. The significantly (p < 0.05) elevated SOD and SIRT1 protein activities were recorded as 51.54 U/mg Prot and 1716 ng/mL, respectively. CONCLUSIONS: PLME exhibited good antiaging activities in S. cerevisiae, by modulating oxidative stress, enhancing GSH content, and increasing SOD and SIRT1 genes expression.
Asunto(s)
Envejecimiento/efectos de los fármacos , Antioxidantes/farmacología , Extractos Vegetales/farmacología , Polyalthia/química , Polifenoles/farmacología , Saccharomyces cerevisiae/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Sirtuina 1/efectos de los fármacos , Superóxido Dismutasa/efectos de los fármacosRESUMEN
The current study investigated the effects of stevia extracts on a PTZ-induced epileptic rat model and its potential mechanism. Thirty male Sprague-Dawley rats were equally subdivided into 3 groups; (1) normal control (NC) group, (2) PTZ-group: received PTZ (50 mg/kg, i.p. every other day) for 2 weeks, and (3) PTZ+ Stevia group: received PTZ and stevia (200 mg/kg orally daily) for 4 weeks (2 weeks before the start of PTZ treatment and 2 weeks with PTZ administration). The first jerk latency and the seizure score were assessed in rats. Also, brain tissue samples were collected by the end of the experiment, and oxidative stress markers (catalase, MDA, and total antioxidant capacity (TAC)) were measured by biochemical analysis in hippocampal brain homogenates. Also, in the hippocampus, the expression of IL6 and Bcl-2 at the mRNA level and expression of Sirt-1, P53, caspase-3, GFAP, and NF-kB in CA3 hippocampal region by immunohistochemistry was investigated. PTZ substantially increased the seizure score and decreased the seizure latency. Also, PTZ significantly increased MDA, GFAP, IL-6, NF-kB, caspase-3, and p53 and significantly reduced Sirt-1, TAC, and Bcl-2 in hippocampal tissues compared to the control group (p < 0.01). However, Stevia Rebaudiana Bertoni (Stevia R.) significantly attenuated the PTZ-induced seizures, improved oxidative stress markers, downregulated GFAP, IL-6, NF-kB, caspase-3, and p53, and upregulated Sirt-1 and Bcl-2 in the CA3 hippocampal region (p < 0.01). In conclusion, Stevia R. exhibits neuroprotective and antiepileptic actions in PTZ-induced epilepsy due to its antioxidant, anti-apoptotic, and anti-inflammatory effects. Additionally, the Sirt-1 pathway might be involved in the antiepileptic and neuroprotective effects of stevia in PTZ-kindled epileptic rat model.
Asunto(s)
Anticonvulsivantes/farmacología , Antioxidantes/farmacología , Epilepsia/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Extractos Vegetales/farmacología , Stevia , Animales , Anticonvulsivantes/administración & dosificación , Antioxidantes/administración & dosificación , Apoptosis , Convulsivantes/farmacología , Modelos Animales de Enfermedad , Epilepsia/inducido químicamente , Epilepsia/inmunología , Epilepsia/metabolismo , Hipocampo/inmunología , Hipocampo/metabolismo , Masculino , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Pentilenotetrazol/farmacología , Extractos Vegetales/administración & dosificación , Ratas , Ratas Sprague-Dawley , Sirtuina 1/efectos de los fármacos , Sirtuina 1/metabolismoRESUMEN
The peroxisome proliferator-activated receptor (PPAR) α/γ-adenosine 5'-monophosphate- (AMP-) activated protein kinase- (AMPK-) sirtuin-1 (SIRT1) pathway and fatty acid metabolism are reported to be involved in influenza A virus (IAV) replication and IAV-pneumonia. Through a cell-based peroxisome proliferator responsive element- (PPRE-) driven luciferase bioassay, we have investigated 145 examples of traditional Chinese medicines (TCMs). Several TCMs, such as Polygonum cuspidatum, Rheum officinale Baillon, and Aloe vera var. Chinensis (Haw.) Berg., were found to possess high activity. We have further detected the anti-IAV activities of emodin (EMO) and its analogs, a group of common important compounds of these TCMs. The results showed that emodin and its several analogs possess excellent anti-IAV activities. The pharmacological tests showed that emodin significantly activated PPARα/γ and AMPK, decreased fatty acid biosynthesis, and increased intracellular ATP levels. Pharmaceutical inhibitors, siRNAs for PPARα/γ and AMPKα1, and exogenous palmitate impaired the inhibition of emodin. The in vivo test also showed that emodin significantly protected mice from IAV infection and pneumonia. Pharmacological inhibitors for PPARα/γ and AMPK signal and exogenous palmitate could partially counteract the effects of emodin in vivo. In conclusion, emodin and its analogs are a group of promising anti-IAV drug precursors, and the pharmacological mechanism of emodin is linked to its ability to regulate the PPARα/γ-AMPK pathway and fatty acid metabolism.
Asunto(s)
Emodina/uso terapéutico , Virus de la Influenza A/efectos de los fármacos , Gripe Humana/tratamiento farmacológico , Células A549 , Adenilato Quinasa/efectos de los fármacos , Adenilato Quinasa/metabolismo , Animales , China , Perros , Emodina/análogos & derivados , Emodina/metabolismo , Ácidos Grasos/metabolismo , Humanos , Virus de la Influenza A/patogenicidad , Metabolismo de los Lípidos , Células de Riñón Canino Madin Darby , Medicina Tradicional China/métodos , PPAR alfa/efectos de los fármacos , PPAR alfa/metabolismo , PPAR gamma/efectos de los fármacos , PPAR gamma/metabolismo , Transducción de Señal/efectos de los fármacos , Sirtuina 1/efectos de los fármacos , Sirtuina 1/metabolismoRESUMEN
Obesity remains a continuing global health concern, as it is associated with an increased risk of many chronic diseases. Atractylodes chinensis Koidz. (Ac) is traditionally used in the treatment of inflammatory diseases, such as arthritis, hepatitis, and gastric ulcers. Despite the diverse pharmacological activities of Ac, scientific evidence for the use of Ac in obesity is still limited. Therefore, the present study aimed to determine the anti-obesity effects of Ac. C57BL/6N mice were divided into five groups as follows: chow diet group (CON), 45% HFD group, HFD + oral administration of orlistat group, and HFD + oral administration of Ac groups. RT-PCR and western blotting were used to examine the expression of molecules relating to obesity progression. Ac-administered mice showed dramatically decreased body weight and weight gain compared to the high-fat diet (HFD)-fed mice. In addition, Ac administration attenuated the protein expression levels of adipogenic transcription factors in the white adipose tissue (WAT) and livers of HFD-fed mice. Furthermore, Ac administration declined the expression levels of lipogenic genes, while enhancing those of the fatty acid oxidation genes in the WAT of HFD-fed mice. Importantly, Ac administration highly upregulated the AMP-activated kinase (AMPK) and sirtuin 1 (SIRT1) expression levels in WAT of the HFD-induced obese mouse model. Our results provide evidence that Ac can effectively ameliorate weight gain and adipose tissue expansion.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Atractylodes/metabolismo , Dieta Alta en Grasa/efectos adversos , Obesidad/tratamiento farmacológico , Extractos Vegetales/farmacología , Sirtuina 1/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Animales , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Ratones , Ratones Obesos , Obesidad/metabolismo , Sirtuina 1/efectos de los fármacos , Sirtuina 1/genética , AguaRESUMEN
Four new C-11 monosaccharide attached dammarane triterpenoid glycosides cypaliurusides SV (1-4), along with nine known dammarane triterpenoid glycosides (5-13) were isolated from a CHCl3-soluble extract of the leaves of Cyclocarya paliurus. All characterized compounds were assayed for their cytotoxicities against HepG2 cells and 10 compounds were evaluated for the agonistic effects on sirtuin1 (SIRT1). The results showed that compounds 1, 5 and 6 were strongly cytotoxic in HepG2 cell line. Two dammarane triterpenoid glycosides 3 and 10 exhibited agonistic activities on SIRT1 with IC50 of 10 µM and 20 µM, respectively.
Asunto(s)
Glicósidos/farmacología , Juglandaceae/química , Sirtuina 1/efectos de los fármacos , Triterpenos/farmacología , China , Glicósidos/aislamiento & purificación , Células Hep G2 , Humanos , Estructura Molecular , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Hojas de la Planta/química , Triterpenos/aislamiento & purificación , DamaranosRESUMEN
The benefits of walnut (Juglans regia) consumption for metabolic health are known, but the molecular background underlying their putative antioxidant and anti-inflammatory/immunomodulatory effects is underexplored. We assessed that walnut supplementation (6 weeks) reverted unfavorable changes of the SIRT1/FoxO3a/MnSOD/catalase axis in the heart induced by fructose-rich diet (FRD). Intriguingly, Nox4 was increased by both FRD and walnut supplementation. FRD increased the cytosolic fraction and decreased the nuclear fraction of the uniquely elucidated ChREBP in the heart. The ChREBP nuclear fraction was decreased in control rats subjected to walnuts. In addition, walnut consumption was associated with a reduction in systolic BP in FRD and a decrease in fatty acid AA/EPA and AA/DHA ratios in plasma. In summary, the protective effect of walnut supplementation was detected in male rats following the fructose-induced decrease in antioxidative/anti-inflammatory capacity of cardiac tissue and increase in plasma predictors of low-grade inflammation. The current results provide a novel insight into the relationship between nutrients, cellular energy homeostasis, and the modulators of inflammatory/immune response in metabolic syndrome, emphasizing the heart and highlighting a track for translation into nutrition and dietary therapeutic approaches against metabolic disease.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Catalasa/efectos de los fármacos , Suplementos Dietéticos/análisis , Ácidos Grasos/sangre , Fructosa/efectos adversos , Corazón/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Juglans/química , Sirtuina 1/efectos de los fármacos , Animales , Antiinflamatorios , Humanos , Ratas , Ratas WistarRESUMEN
Binge drinking (BD) is the main alcohol consumption pattern among teenagers. Recently, oxidative stress (OS) generated by BD exposure has been related to hepatic metabolic deregulation and cardiovascular dysfunction. This study analyzed if BD by generating oxidative stress modulates the alteration in hepatic energy homeostasis through two important regulators of energy metabolism: the NAD+-dependent sirtuin deacetylase (SIRT1) and AMP-activated protein kinase (AMPK) and if supplementation with the antioxidant selenium (Se) improves these metabolic disorders. Four groups of adolescent rats supplemented or not with Se (0.4 ppm) and exposed to intermittent i.p. BD were used. BD rats showed an increased AST/ALT ratio, total bilirubin in serum and lipid peroxidation in the liver. The BD rats also showed a higher abdominal/thoracic ratio and increased levels of TG, gluc, and chol compared to the control group, provoking an increase in mean blood pressure (MBP). This alcohol consumption pattern decreased hepatic Se deposits, cytoplasmic GPx activity, and GSH levels as well as the expressions of two metabolic sensors and the pAMPK/AMPK ratio. Se supplementation restored antioxidant parameters and decreased lipid oxidation, avoiding OS and improving the hepatic expression of pAMPK and SIRT1, contributing to the improvement of metabolic (better lipid profile and IRS-1 expression) and vascular function (lower MBP), and to the increase of hepatic functionality (lower AST/ALT ratio). All these actions decrease cardiometabolic risk factor development in the short and long term and could disrupt the relationship between BD and MS, two problems which are currently affecting adolescents.
Asunto(s)
Conducta del Adolescente , Antioxidantes/administración & dosificación , Consumo Excesivo de Bebidas Alcohólicas , Ácido Selenioso/administración & dosificación , Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Adolescente , Animales , Antioxidantes/farmacología , Suplementos Dietéticos , Humanos , Hígado/metabolismo , Masculino , Modelos Animales , Estrés Oxidativo , Ratas , Ratas Wistar , Ácido Selenioso/farmacología , Sirtuina 1/efectos de los fármacos , Sirtuina 1/metabolismoRESUMEN
Diabetes-induced oxidative stress is vital in initiating neuronal damage in the diabetic retina, leading to diabetic retinopathy (DR). This study investigates the possible effects of coumestrol (CMS) on streptozotocin (STZ)-induced DR. First, we established a rat model of DR by STZ injection and a cell model involving high-glucose (HG) exposure of human retinal microvascular endothelial cells (hRMECs). We characterized the expression patterns of oxidative stress indicators, pro-inflammatory cytokines, and pro-apoptotic proteins in hRMECs. Polymerase chain reaction showed sirtuin 1 (SIRT1) to be poorly expressed in the retinal tissues of STZ-treated rats and HG-exposed hRMECs, but its expression was upregulated upon treatment with CMS treatment. Furthermore, CMS treatment attenuated the STZ-induced pathologies such as oxidative stress, inflammation, and cell apoptosis. Consistent with the in vivo results, CMS activated the expression of SIRT1, thereby inhibiting oxidative stress, inflammation, and apoptosis of HG-treated hRMECs. From these findings, we concluded that CMS ameliorated DR by inhibiting inflammation, apoptosis and oxidative stress through activation of SIRT1.
Asunto(s)
Apoptosis/efectos de los fármacos , Cumestrol/farmacología , Retinopatía Diabética/metabolismo , Células Endoteliales/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fitoestrógenos/farmacología , Retina/efectos de los fármacos , Sirtuina 1/efectos de los fármacos , Animales , Diabetes Mellitus Experimental/metabolismo , Retinopatía Diabética/patología , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Glucosa/toxicidad , Humanos , Inflamación/metabolismo , Ratas , Retina/metabolismo , Retina/patología , Vasos Retinianos/citología , Sirtuina 1/metabolismoRESUMEN
Diabetic nephropathy (DN) is a common complication of diabetes. Yishen capsule, composed of Chinese herbs, improves the clinical outcome in DN patients. However, its therapeutic potential and underlying mechanisms require further elucidation. Hence, our study aimed to investigate the underlying mechanisms and therapeutic potential of Yishen capsule in DN. Streptozotocin-induced DN rats were treated with Yishen capsules (1.25 g/kg/day) for 8 weeks. Then, blood glucose and urine protein levels were measured. Hematoxylin and eosin staining and western blot assays were used to examine the histologic changes and gene expression, respectively, in kidney samples. Mouse podocytes were treated with rat serum containing Yishen capsule and transmission electron microscopy was used to examine autophagosome formation. Cell counting kit-8 assay was performed to examine cell proliferation. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses were conducted to detect changes in gene expression. The localization of SIRT1 was examined in the podocytes using immunocytofluorescence assay. We found that Yishen capsule relieved pathological changes, decreased urine protein, increased SIRT1, LC3-II, and Beclin-1 expression, and reduced acetylated NF-κB p65 expression in vivo. In addition, rat serum containing Yishen capsule showed improved podocyte proliferation, promoted the mRNA and protein levels of LC3-II and Beclin-1, and induced nuclear translocation of SIRT1. Furthermore, it increased SIRT1 expression and decreased mRNA level of NF-κB in the serum. SIRT1 inhibitor increased the mRNA level of NF-κB. Our data suggests that Yishen capsule improves DN by promoting podocyte autophagy via the SIRT1/NF-κB pathway.
Asunto(s)
Autofagia/efectos de los fármacos , Nefropatías Diabéticas/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Podocitos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/patología , Medicamentos Herbarios Chinos/química , Masculino , Ratones , Ratas , Sirtuina 1/efectos de los fármacos , Estreptozocina , Factor de Transcripción ReIA/metabolismoRESUMEN
PURPOSE: Exercise training and some herbal components have an anticancer function and can suppress tumor growth. However, the role of these protective factors in altering breast cancer-related gene expression is still unknown. Thus, this study aimed to assess the effect of 4 wk of high-intensity interval training (HIIT) and saffron (Crocus sativus L.) aqueous extract (SAE) on Sirtuin-1 (SIRT1), human telomerase reverse transcriptase (hTERT), and p53 gene expression in female mice breast tumor tissue induced by 4T1 cell line. METHODS: This study was performed on female BALB/c mice. The 4T1 breast cancer cells were subcutaneously implanted, and mice were randomly sorted into the following groups: control, HIIT, SAE, HIIT + SAE (n = 10 mice per group), and sham (n = 4 mice per group). Mice were sacrificed at the end of the intervention period, and the expression of SIRT-1, hTERT, and p53 was determined by real-time polymerase chain reaction. RESULTS: The mRNA level of SIRT1 was increased in the HIIT + SAE group compared with the HIIT and control groups (P = 0.007 and P = 0.03, respectively). Moreover, the amount of mRNA of p53 was increased after a 4-wk HIIT compared with the control and HIIT + SAE groups in tumor tissue (P = 0.03 and P = 0.02, respectively). No change was found in the mRNA expression of hTERT between groups (P = 0.92). CONCLUSIONS: These findings suggest that HIIT may reduce tumor burden through the upregulation of p53 associated with tumor suppression pathway. In contrast, the combination of HIIT and SAE did not alter p53 and SIRT1 expression levels and may suppress tumor growth by other mechanisms.
Asunto(s)
Crocus , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Mamarias Experimentales/genética , Condicionamiento Físico Animal/métodos , Extractos Vegetales/farmacología , Animales , Neoplasias de la Mama/genética , Línea Celular Tumoral , Femenino , Genes p53/efectos de los fármacos , Humanos , Ratones Endogámicos BALB C , ARN Mensajero/metabolismo , Sirtuina 1/efectos de los fármacos , Telomerasa/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Rikkunshito, a traditional Japanese herbal medicine, improves appetite via activation of gastrointestinal hormone ghrelin pathway. The function of ghrelin is mediated by growth hormone secretagogue receptor (GHSR1a), and ghrelin has been known to possess diverse physiological functions including growth suppression of some cancer cells. Considering that increased ghrelin signaling by Rikkunshito could enhance sirtuin1 (SIRT1) activity in nervous system, we aimed to investigate the effect of Rikkunshito in ovarian cancer cells. Ovarian cancer cell lines were treated with Rikkunshito, and cellular viability, gene expressions and epithelial-mesenchymal transition (EMT) status were investigated. To investigate the involvement of SIRT1 by Rikkunshito in SKOV3 cancer cells, endogenous expression of SIRT1 was depleted using small interfering RNA (siRNA). Treatment with Rikkunshito elevated ghrelin, GHSR1a and SIRT1, while cellular viability was decreased. The treatment of Rikkunshito also inhibited cellular migration and invasion status in a dose-dependent manner, and these effects were translated to the enhanced EMT status, although the role of SIRT1 was not determined. Our study revealed a novel function of Rikkunshito in enhancing EMT status of ovarian cancer cells. Therefore, we would like to propose that Rikkunshito may be used as a novel adjunctive therapy in chemotherapy of ovarian cancer because platinum-based chemotherapy frequently used for the treatment of ovarian cancer inevitably impairs appetite.
Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Ováricas/metabolismo , Receptores de Ghrelina/efectos de los fármacos , Sirtuina 1/efectos de los fármacos , Antígenos CD/efectos de los fármacos , Antígenos CD/metabolismo , Cadherinas/efectos de los fármacos , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Supervivencia Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Femenino , Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Ghrelina/efectos de los fármacos , Ghrelina/metabolismo , Humanos , Neoplasias Ováricas/genética , Receptores de Ghrelina/genética , Receptores de Ghrelina/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Vimentina/efectos de los fármacos , Vimentina/metabolismoRESUMEN
OBJECTIVE: To explore the specific molecular mechanisms of Danshensu (DSS) in the treatment of ischemia reperfusion injury (IRI). METHODS: IRI model was established with isolated rat hearts by performing global ischaemia for 30 min, and then followed by 60 min reperfusion. Also, H9C2 cells were subjected to 4-h hypoxia followed by 3-h reoxygenation. Then 10 µmol/L DSS were added in the reperfusion/reoxygenation step to intervene IRI. Cardiac function, structural change and apoptosis were respectively tested by Langendorff System, hematoxylin and eosin (HE) and terminal-deoxynucleotidyl transferase mediated nick endabeling (TUNEL) stainings. Then lactate dehydrogenase (LDH), reactive oxygen species (ROS), superoxide gasification enzyme (SOD) and glutathione peroxidase (GSH-PX) were detected by enzyme-linked immunosorbent assay (ELISA). Sirt1/FoxO1/Rab7 Signal Pathway was monitored at both protein and mRNA levels. RESULTS: The results showed that IRI not only greatly attenuated cardiac function (LVDP and ±dp/dtmax, P<0.01, P<0.05) and increased the level of the marker enzymes (cardiac troponin T, LDH, P<0.01) from the coronary effluents, but also markedly induced changes in the structure of cardiomyocytes and contributed to apoptosis, which were mediated by boosted endogenous ROS. However, after treatment with DSS all above indexes were improved, which was related to activating Sirt1/FoxO1/Rab7 signal pathway accompanied with the enhancement of antioxidant defense system, such as superoxide gasification enzyme and glutathione peroxidase. CONCLUSION: DSS is able to protect hearts from IRI, which may be attributable to inhibiting excessive ROS through Sirt1/FoxO1/Rab7 signaling.
Asunto(s)
Lactatos/farmacología , Miocitos Cardíacos/efectos de los fármacos , Daño por Reperfusión , Transducción de Señal/efectos de los fármacos , Animales , Antioxidantes/farmacología , Modelos Animales de Enfermedad , Isquemia , L-Lactato Deshidrogenasa/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas del Tejido Nervioso , Estrés Oxidativo/efectos de los fármacos , Ratas , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Sirtuina 1/efectos de los fármacos , Proteínas de Unión al GTP rab/efectos de los fármacos , Proteínas de Unión a GTP rab7RESUMEN
Mounting evidences have demonstrated that diet-induced obesity is associated with cognition impairment via increasing oxidative stress and inflammation in the brain. Atorvastatin (Ator, a HMG-CoA reductase inhibitor) is a cholesterol lowering drug. Studies have reported that Ator can ameliorate the development and progression of cognition impairment. Additionally, silent information regulator 1 (SIRT1) has been demonstrated to be beneficial in cognition impairment. However, the interaction between Ator and SIRT1 activation for cognition impairment remains unclear. This study aimed to identify a relationship between the use of Ator and cognition impairment induced by high-fat diet via Sirt1 activation. A total of 60 healthy male C57BL/6J mice were purchased and then divided into 6 groups, including normal diet group (control), a high-fat diet group (40%HFD, 40% energy from fat), a model group (60%HFD, 60% energy from fat), and model group treated with different doses of Ator (high-dose (80 mg), moderate-dose (40 mg), and low-dose (20 mg) groups). All interventions took place for 7 months. Metabolic phenotypes were characterized for body weight and analysis of serum lipid level. The level of cognition development was examined by Morris water maze (MWM) approach and novel object recognition test (NORT); besides, the expression of Creb1, Gap-43, BDNF, CaMKII, and ERKs of frontal cortex and hippocampus was determined by reverse transcription polymerase chain reaction (RT-PCR). Then, the levels of factors related to inflammation (TNF-a, IL-1ß, HMGB1 and IL-6) and oxidation stress (SOD, MDA, CAT and GSH-Px) were assessed using commercially available kits. Finally, SIRT1 and its downstream molecules (Ac-FoxO1, Ac-p53, Ac-NF-κB, Bcl-2 and Bax) were evaluated by Western blot analysis. Compared with the 60% HFD group, body weight and serum lipid levels were significantly decreased in the Ator treated groups. The results of MWM and NORT, as well as the levels of Creb1, Gap-43, BDNF, CaMKII, and ERKs were markedly reversed in the moderate- and low-dose of Ator treated groups. Meanwhile, the expression of IL-1ß, TNF-a, IL-6, HMGB1, and MDA was notably decreased, whereas the activity of SOD, CAT, and GSH-Px was increased. It was also revealed that the expression of SIRT1 was remarkably unregulated, the level of Bcl-2 was upregulated, and the content of Ac-FoxO1, Ac-p53, Ac-NF-κB, and Bax was downregulated in the moderate- and low-dose of Ator. Furthermore, results showed that the effect of moderate-dose of Ator was significantly greater than the low-dose of Ator. However, these effects were not observed in the high-dose of Ator. Our results showed that moderate- and low-dose of Ator can significantly attenuate cognition impairment induced by HFD through its antioxidant and anti-inflammatory functions related to SIRT1 activation.
Asunto(s)
Atorvastatina/farmacología , Disfunción Cognitiva/tratamiento farmacológico , Dieta Alta en Grasa/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Sirtuina 1/efectos de los fármacos , Animales , Antioxidantes/farmacología , Peso Corporal/efectos de los fármacos , Cognición/efectos de los fármacos , Disfunción Cognitiva/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Masculino , Ratones Endogámicos C57BL , Obesidad/metabolismoRESUMEN
BACKGROUND: Salidroside, an active component from Traditional Chinese Medicine Rhodiola rosea L., has various pharmacological functions including anti-inflammatory, anti-cancer and anti-oxidative properties. However, whether salidroside plays a beneficial role in diabetic nephropathy is still unclear. PURPOSE: The objective of this work was to investigate the potential roles of salidroside against diabetic nephropathy and the underlying molecular mechanisms. METHODS: Streptozocin was given to obese mice to generate diabetic nephropathy animal model. Salidroside was administered to these mice and proteinuria, podocyte integrity, renal morphology and fibrosis, mitochondrial biogenesis were examined. RESULTS: Our results showed that salidroside treatment greatly attenuates diabetic nephropathy as evidenced by decreased urinary albumin, blood urea nitrogen and serum creatinine. Morphological analysis indicated that salidroside improves renal structures in diabetic nephropathy. The decreases in nephrin and podocin expression were markedly reversed by salidroside. Moreover, kidney fibrosis in diabetic nephropathy mice was largely prevented by salidroside. Mechanistically, in salidroside-treated mice, the mitochondrial DNA copy and electron transport chain proteins were significantly enhanced. Meanwhile, the reduced Sirt1 and PGC-1α expression in diabetic nephropathy was almost completely counteracted in the presence of salidroside. CONCLUSIONS: Our data showed that salidroside plays a beneficial role against diabetic nephropathy in mice, which probably via Sirt1/PGC-1α mediated mitochondrial biogenesis.
Asunto(s)
Nefropatías Diabéticas/prevención & control , Glucósidos/farmacología , Fenoles/farmacología , Sirtuina 1/efectos de los fármacos , Factores de Transcripción/efectos de los fármacos , Animales , ADN Mitocondrial/metabolismo , Nefropatías Diabéticas/metabolismo , Modelos Animales de Enfermedad , Transporte de Electrón , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Mitocondrias/metabolismo , Podocitos/metabolismo , Sirtuina 1/metabolismo , Estreptozocina , Factores de Transcripción/metabolismo , Regulación hacia ArribaRESUMEN
The development of novel, efficient and nontoxic photosensitizers (PSs) is a challenging task for photodynamic therapy (PDT). In our previous study, corrole had been demonstrated to be a promising PS in PDT for cancer cells. In this paper, a novel electron-deficient flat phosphorus tris(ethoxycarbonyl) corrole (1-P) was synthesized and characterized. In vitro photodynamic activities and toxicity of 1-P in HepG2 xenograft tumours was evaluated by standard assay. The results shown 1-P displayed a potential efficient and low-toxic PS, which suggesting this kind of corrole is a powerful and promising antitumor PS for PDT. In addition, the potential anti-tumour mechanism study of 1-P was also investigated by the apoptosis antibody array, immunohistochemical and western blotting assay (WB) experiments, we found that the PDT activity of 1-P can degrade SIRT1 (an important deacetylase), and activate the Fas signal pathway to inhibit the growth of liver cancer cells.
Asunto(s)
Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Ratones , Fósforo/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/toxicidad , Porfirinas/farmacología , Sirtuina 1/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Receptor fas/metabolismoRESUMEN
Developmental toxicity of compounds, which women of reproductive age are exposed to, should be assessed to minimize the incidence of miscarriage and birth defects. The present study examined the potential developmental toxicity of resveratrol, a dietary supplement widely marketed with various health claims, using the P19C5 embryoid body (EB) morphogenesis assay, which evaluates adverse effects of chemical exposures on tissue growth and axial elongation. Resveratrol (trans isoform) impaired morphogenesis at 4⯵M and higher, creating smaller and rounder EBs, whereas cis isoform, and glucuronated and sulfonated metabolites did not. Trans-resveratrol also altered expression levels of developmental regulator genes involved in embryonic patterning, such as Wnt3a, Tbx6, and Cyp26a1. To investigate the mechanisms of trans-resveratrol action, the roles of estrogen receptor, sirtuin 1 (SIRT1), and DNA replication in EB morphogenesis were examined. Neither activators of estrogen receptors (diethylstilbestrol [18⯵M] and raloxifene [8⯵M]) nor activator of SIRT1 (SRT1720 [2.4-3.2⯵M]) caused morphological and molecular alterations that are comparable to trans-resveratrol (10⯵M). By contrast, a reduction in the DNA replication rate with aphidicolin (0.4⯵M) or hydroxyurea (40⯵M) created smaller and rounder EBs and altered the expression levels of Wnt3a, Tbx6, and Cyp26a1 in a manner similar to trans-resveratrol. Consistently, trans-resveratrol significantly reduced the rate of EdU incorporation in P19C5 cells. These results suggest that a reduction in the DNA replication rate is one of the mechanisms by which trans-resveratrol impacts EB development. This study provides mechanistic insight for further investigations on the developmental toxicity of trans-resveratrol.
Asunto(s)
Suplementos Dietéticos/toxicidad , Cuerpos Embrioides/efectos de los fármacos , Resveratrol/toxicidad , Línea Celular , Supervivencia Celular/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Cuerpos Embrioides/ultraestructura , Desarrollo Embrionario/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Humanos , Morfogénesis/efectos de los fármacos , Receptores de Estrógenos/efectos de los fármacos , Sirtuina 1/efectos de los fármacos , EstereoisomerismoRESUMEN
Alcohol abuse affects several neurological pathways and causes significant alterations in the brain. Abstention from alcohol causes only a marginal decrease in oxidative stress and neuro inflammation. Our previous studies had shown that an active metabolite of vitamin A, all trans retinoic acid (ATRA), ameliorates alcohol induced toxicity. Hence in the present study we investigated whether ATRA regressed alcohol induced neuroinflammation. We focused on the role of silent mating type information regulation 2 homolog 1(SIRT1) and nuclear factor kappa-B (NFκB). Animals were administered with ethanol at a daily dose of (4 g/kg body weight) for 90 days. On the 91st day ethanol administration was stopped and animals were divided into ethanol abstention (A) and ATRA supplementation group (ATRA + A) (100 µg/kg body weight) and maintained for 30 days. Ethanol exposure increased markers of oxidative stress, inflammation and the activities of alcohol and acetaldehyde dehydrogenases and reduced the expression of SIRT1 in the whole brain.The ethanol induced altered expressions of NFκB and SIRT1 were modulated by supplementation of ATRA. Abstention also reduced toxicity, but to a lower extent in comparison with supplementation of ATRA. Our results seemed to suggest that ATRA regressed the mediators of ethanol induced neuroinflammation by reducing oxidative stress and by regulating the expression of NFκB and SIRT1. The ameliorative potential of ATRA was much higher than abstention.
Asunto(s)
Inflamación/metabolismo , FN-kappa B/efectos de los fármacos , Sirtuina 1/efectos de los fármacos , Tretinoina/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Sirtuina 1/metabolismoRESUMEN
BACKGROUND: Manganese superoxide dismutase (MnSOD) is an important antioxidant enzyme affected in heart/muscle-specific MnSOD-deficient mice (H/M-SOD2-/-), which develop progressive congestive heart failure and exhibit pathology typical of dilated cardiomyopathy. METHODS: In this study we investigated the beneficial effects of epigallocatechin gallate (EGCG) on the cardiac remodeling and telomere biology in H/M-SOD2-/- mice. H/M-SOD2-/- mice were divided into three groups: those receiving normal drinking water (KO), a low dose of EGCG (L: 10mg/L), and a high dose of EGCG (H: 100mg/L) beginning at eight weeks of age and lasting for eight weeks. RESULTS: The mice in the KO group exhibited significantly dilated cardiac remodeling with reduced contractility, which was prevented by the administration of EGCG. Although the mortality of KO mice was about 50% at 16 weeks of age, the mice that received EGCG had a high survival rate. The cardiac dilatation with reduced cardiac contraction in KO mice was prevented by EGCG treatment. The levels of myocardial oxidative stress and free fatty acids were lower in the group treated with EGCG compared with the KO group. The increased expression of nitric oxide synthase 2, nitrotyrosine, fatty acid synthase, Toll-like receptor 4, and Sirt1 in the KO mice were prevented by EGCG treatment. The shortening of the telomere length, decreased telomerase activity in KO mice were also prevented by EGCG. CONCLUSIONS: H/M-SOD2-/- mice receiving EGCG have a lower mortality rate and exhibit less inflammation and a better preserved cardiac function and telomere biology.