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1.
J Food Biochem ; : e13505, 2020 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-33047361

RESUMEN

Here, we examined the protective effect of ferulic acid (FA) on cadmium chloride (CdCl2 )-mediated reproductive toxicity in male rats. Animals were divided into four groups: control, FA (20 mg/kg), CdCl2 (6.5 mg/kg), and FA + CdCl2 . CdCl2 treatment evoked a significant increase in testis cadmium concentration in addition to obvious increase in testosterone, luteinizing hormone, and follicle-stimulating hormone levels. Moreover, CdCl2 -induced oxidative damage through exhausting the cellular defenses (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione) and downregulating the nuclear factor erythroid 2-related factor 2 (Nrf2) expression accompanied by increases of malondialdehyde and nitric oxide contents. Testicular inflammation was evident indicated by increased levels of interleukin-1ß and tumor necrosis factor-α in CdCl2 -treated rats. CdCl2 exposure also decreased the expression of the proliferating cell nuclear antigen and augmented apoptotic events associated with prominent histopathological alterations. However, FA coadministration mitigated the impaired hormonal level, apoptotic and inflammatory injuries elicited by CdCl2, and maintained the oxidant/antioxidant balance in testicular tissue via Nrf2 activation. PRACTICAL APPLICATIONS: Cadmium is an environmental toxicant and known to cause adverse effects including reproductive toxicity. However, antioxidant application has been found to protect against heavy metals-mediated toxic effects. Here, we examined the potential protective efficacy of ferulic acid against cadmium-mediated testicular impairments through estimating the amount of cadmium in the testis, hormonal profile, oxidative status, inflammatory response, apoptotic and proliferating markers in addition to the histopathological alterations. The obtained findings revealed that ferulic acid supplementation was able to abolish the testicular damages coupled with cadmium exposure. The protective efficiency of ferulic acid may correlated with its strong antioxidant, anti-inflammatory, and antiapoptotic activities; suggesting that ferulic acid may be used to ameliorate cadmium-induced testicular deficits.

2.
IUBMB Life ; 72(10): 2121-2132, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32710811

RESUMEN

Sepsis results from a major systemic inflammatory response and can induce disorders in multiple organs. The present study evaluated the potential protective effects of oleuropein (OLE) against hyperinflammatory responses during lipopolysaccharide (LPS)-induced sepsis in mice. Sixty male Balb/c mice were randomly categorized into five groups of 12 animals each: control, intraperitoneally injected with OLE (50 mg/kg), injected with LPS (10 mg/kg, intraperitoneal), and two groups administered OLE (25 and 50 mg/kg) for 3 days prior to LPS injection. Twenty-four hours after lipopolysaccharide injection, the animals were sacrificed. Serum, liver, and kidney tissue samples were collected for biochemical analyses, histopathological examinations, and investigation of inflammation-related gene expression. OLE pretreatment significantly reduced liver damage parameters (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase) and kidney damage parameters (blood urea nitrogen, creatinine, and kidney injury molecule-1) in the septic mice. OLE pretreatment ameliorated LPS-induced liver and kidney histological changes. OLE significantly mitigated the increased levels of malondialdehyde in the liver and kidneys and reduced levels of reduced glutathione induced by LPS. LPS injection also resulted in increased expression of the proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) and inflammation-related genes (Nos2, Hmgb1, Mpo, Cd46, Map2k4, and Map2k7) in the hepatic and renal tissues. OLE reduced these expressions to ameliorate the inflammatory response. Moreover, OLE pretreatment enhanced the survival rate of septic mice. In conclusion, OLE alleviated the inflammatory response to protect against LPS-induced sepsis in mice.

3.
PLoS One ; 15(6): e0234465, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32544194

RESUMEN

Obesity leads a crucial importance in metabolic disorders, as well as type 2 diabetes mellitus. Our present study was designed to assess the potential role of irisin, adiponectin, leptin and gene polymorphism of PNPLA3, leptin and adiponectin as predictive markers of diabetes associated with obesity. One hundred eighty subjects were distributed to three groups including; healthy non-diabetic non obese volunteers as a control group, diabetic non obese group, and diabetic obese group (n = 60 for each group). Fasting blood samples of all groups were collected to determine fasting blood glucose, insulin levels, insulin resistance, total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triacylglycerol, irisin, adiponectin, leptin; as well as, polymorphism of PNPLA3, adiponectin and leptin. The results showed that glucose, insulin resistance, total cholesterol, irisin, leptin, LDL-C, triacylglycerol concentrations were significantly increased, however, insulin, HDL-C, adiponectin were significantly decreased in diabetic obese patients in relation to diabetic non-obese patients as well as in healthy volunteers. The polymorphism of PNPLA3 rs738409 was linearly related to irisin and leptin but was not related with circulating concentrations of adiponectin. We concluded that increased irisin and leptin levels can predict the insulin resistance in obese patients. Moreover, patients who have mutant genotype of PNPLA3 I148 gene (rs738409) C>G, ADIPOQ gene (rs266729) G>C and LEP gene (rs2167270) G>A showed a significant higher susceptibility rate for DM in obese people than those with wild type. This could be considered as an adjustable retort to counter the impact of obesity on glucose homeostasis.


Asunto(s)
Adiponectina/genética , Diabetes Mellitus Tipo 2/etiología , Predisposición Genética a la Enfermedad , Resistencia a la Insulina/genética , Leptina/genética , Lipasa/genética , Proteínas de la Membrana/genética , Obesidad/complicaciones , Obesidad/genética , Adiponectina/sangre , Adulto , Femenino , Fibronectinas/sangre , Fibronectinas/genética , Marcadores Genéticos , Humanos , Leptina/sangre , Lipasa/sangre , Masculino , Proteínas de la Membrana/sangre , Polimorfismo Genético , Adulto Joven
4.
J Adv Res ; 24: 149-157, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32322420

RESUMEN

Breast cancer (BC) incidence is progressively increasing in Egypt. However, there is insufficient knowledge of the acquired somatic mutations in Egyptian BC patients which limit our understanding of its progression. To the best of our knowledge, this is the first Egyptian cohort to sequence a multiple-gene panel of cancer related genes on BC patients. Four hundred and nine cancer related genes were sequenced in 46 fresh breast tumors of Egyptian BC patients to identify somatic mutations and their frequencies. TP53 and PIK3CA were the most top two frequently mutated genes. We detected 15 different somatic mutations in TP53 and 8 different ones in PIK3CA, each in 27 samples (58.7%). According to Clinvar database; we found 19 pathogenic somatic mutations: 7 in Tp53, 5 in PIK3CA, and single variants of VHL, STK11, AKT1, KRAS, IDH2, PTEN and ERBB2. We also identified 5 variants with uncertain significance (4 in TP53 and 1 in CEBPA) and 4 variants with conflicting interpretations of pathogenicity (2 in TP53 and 1 in each of APC and JAK3). Moreover, one drug response variant (p.P72R) in TP53 was detected in 8 samples. Furthermore, four novel variants were identified in JAK2, MTOR, KIT and EPHB. Further analysis, by Ingenuity Variant Analysis software (IVA), showed that PI3K/AKT signaling is altered in greater than 50% of Egyptian BC patients which implicates PI3K/AKT signaling as a therapeutic target. In this cohort, we shed the light on the most frequently detected somatic mutations and the most altered pathway in Egyptian BC patients.

5.
Biol Trace Elem Res ; 197(2): 606-618, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31845207

RESUMEN

Diabetes mellitus (DM) is a group of metabolic disorders that are characterized by a loss of glucose homeostasis and insufficiency in production or action of insulin. Development of newly antidiabetic molecules using a variety of organic compounds and biomolecules has been in practice for a long time. Recently, nanomaterials are also being used in antidiabetic studies for their unique properties. In this context, zinc nanoparticles have drawn attention due to the relationship between diabetes and imbalance of zinc homeostasis. Few studies have attempted to investigate the effect of zinc oxide nanoparticles (ZON) in microRNA dysregulations in diabetes. To evaluate the therapeutic effect of ZON on streptozotocin (STZ)-induced diabetic rats as well as its role in microRNA dysregulations. Diabetes was induced in rats by 60 mg/kg body weight (bwt) of STZ and then treated with ZON (5 mg/kg bwt) for 15 consecutive days. The levels of glucose, insulin, oxidative stress markers, and microRNAs expression were measured in liver and pancreas tissues. Intraperitoneal injection of 60 mg/kg bwt of STZ to Wistar rats caused significant decreases in the body weight and Zn contents of pancreas, liver, and kidney. Also, STZ injection increased the blood glucose level and oxidative stress (lipid peroxidation (LPO) and nitric oxide (NO). Meanwhile, STZ decreased blood insulin and pancreatic anti-oxidants. STZ also resulted in ß cell dysfunction and destruction and altered the expression of certain pancreatic and liver microRNAs. ZON treatment for 15 days, at a dose of 5 mg/kg bwt resulted in marked improvements in the blood insulin, glucose tolerance, and structure and function of the pancreatic ß cells. Furthermore, ZON administration reduced LPO and NO, and increased the levels of enzymatic and non-enzymatic anti-oxidants in STZ-induced diabetic rats. It was found also that ZON specifically regulated the expression of pancreatic and liver microRNAs that involved in diabetes development. The obtained results revealed that ZON is a promising antidiabetic agent. The antidiabetic effect of ZON was partially mediated by restoring the oxidants/antioxidants balance and by modulating the alerted microRNAs.

6.
Naunyn Schmiedebergs Arch Pharmacol ; 392(6): 685-695, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30759264

RESUMEN

There is increasing evidence of a link between type 2 diabetes mellitus (T2DM) and cognitive decline. T2DM has been recognized as a risk factor for Alzheimer's disease (AD). The aim of this research was to investigate the biochemical and physiological effects of vildagliptin treatment alone, and in combination with memantine, in a rat model of combined T2DM and AD. The experimental study was carried out on 75 male Wistar rats weighing 180-200 g. The rats were divided into five groups (n = 15): normal group, Alzheimer diabetic control, treated with vildagliptin (10 mg/kg/day), treated with memantine (30 mg/kg/day), and treated with combination of drugs. Serum glucose, lipid profile, acetylcholinesterase (AChE), homocysteine (Hcy), and amyloid beta peptide (Aß) were determined. Lipid peroxidation was measured in brain tissue. Expression of amyloid precursor protein (APP) in the brain was assessed by q-PCR, and expression of total and phosphorylated tau was determined by Western Blotting. Vildagliptin alone and in combination with memantine caused a decrease in blood glucose, HOMA-IR, lipid profile, Hcy, malanodialdhyde, and acetylcholinesterase, and an increase in apolipoprotein E. Expression of APP and phosphorylated tau protein was decreased with combined vildagliptin and memantine treatment. In conclusion, vildagliptin treatment, either alone or in combination with memantine, modulates AD-associated biochemical changes and downregulates amyloid precursor protein and phosphorylated tau expression in diabetic rats.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Precursor de Proteína beta-Amiloide/genética , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Memantina/administración & dosificación , Vildagliptina/administración & dosificación , Proteínas tau/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Regulación hacia Abajo , Lípidos/sangre , Masculino , Fosforilación , Ratas , Ratas Wistar , Estreptozocina
7.
Cardiovasc Toxicol ; 19(4): 344-356, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30644033

RESUMEN

This study has been initiated to investigate whether sunitinib (SUN) alters the expression of key genes engaged in mitochondrial transport and oxidation of long chain fatty acids (LCFA), and if so, whether these alterations should be viewed as a mechanism of SUN-induced cardiotoxicity, and to explore the molecular mechanisms whereby carnitine supplementation could attenuate SUN-induced cardiotoxicity. Adult male Wister albino rats were assigned to one of the four treatment groups: Rats in group 1 received no treatment but free access to tap water for 28 days. Rats in group 2 received L-carnitine (200 mg/kg/day) in drinking water for 28 days. Rats in group 3 received SUN (25 mg/kg/day) in drinking water for 28 days. Rats in group 4 received the same doses of L-carnitine and SUN in drinking water for 28 days. Treatment with SUN significantly increased heart weight, cardiac index, and cardiotoxicity enzymatic indices, as well as severe histopathological changes. Moreover, SUN significantly decreased level of adenosine monophosphate-activated protein kinase (AMPKα2), total carnitine, adenosine triphosphate (ATP) and carnitine palmitoyltransferase I (CPT I) expression and significantly increased acetyl-CoA carboxylase-2 (ACC2) expression and malonyl-CoA level in cardiac tissues. Interestingly, carnitine supplementation resulted in a complete reversal of all the biochemical, gene expression and histopathological changes-induced by SUN to the control values. In conclusion, data from this study suggest that SUN inhibits AMPK downstream signaling with the consequent inhibition of mitochondrial transport of LCFA and energy production in cardiac tissues. Carnitine supplementation attenuates SUN-induced cardiotoxicity.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Antineoplásicos/toxicidad , Carnitina/farmacología , Suplementos Dietéticos , Metabolismo Energético/efectos de los fármacos , Cardiopatías/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/toxicidad , Sunitinib/toxicidad , Acetil-CoA Carboxilasa/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Cardiotoxicidad , Carnitina O-Palmitoiltransferasa/metabolismo , Cardiopatías/inducido químicamente , Cardiopatías/enzimología , Masculino , Malonil Coenzima A/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/enzimología , Miocitos Cardíacos/enzimología , Ratas Wistar , Transducción de Señal
8.
BMC Complement Altern Med ; 18(1): 321, 2018 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-30518369

RESUMEN

BACKGROUND: Eugenol is a natural phenolic compound and possesses anticancer and antibacterial activities. Breast cancer is a major global health problem, and most of the chemotherapeutic agents are highly toxic with long-term side effects. Therefore, this study aimed to explore the possibility of using eugenol as an anti-metastatic and anti-proliferative agent against MDA-MB-231 and SK-BR-3 breast cancer cells. METHODS: Breast cancer cell lines MDA-MB-231 and SK-BR-3 were treated with eugenol and cell proliferation was measured using a real-time cell electronic sensing system. Annexin V analysis with flow cytometry was used to detect the effect of eugenol on cell death. In MDA-MB-231 and SK-BR-3 cells, metastatic potential after eugenol treatment was examined using a wound-healing assay. Real-time PCR was used to study the effect of eugenol on the expression of anti-metastatic genes such as MMP2, MMP9, and TIMP-1, and genes involved in apoptosis including Caspase3, Caspase7, and Caspase9. RESULTS: Treatment with 4 µM and 8 µM eugenol for 48 h significantly inhibited cell proliferation of MDA-MB-231, with an inhibition rate of 76.4%, whereas 5 µM and 10 µM of eugenol for 48 h significantly inhibited the proliferation of SK-BR-3 cells with an inhibition rate of 68.1%. Eugenol-treated cells showed significantly decreased MMP2 and MMP9 expression and an insignificant increase in TIMP1 expression in HER2 positive and triple negative breast cancer cells. Eugenol significantly increased the proportion of MDA-MB-231 and SK-BR-3 cells in late apoptosis and increased the expression of Caspase3, Caspase7, and Caspase9. CONCLUSION: To the best of our knowledge, this is the first study to describe the anti-metastatic effect of eugenol against MDA-MB-231 and SK-BR-3 breast cancer cell lines.


Asunto(s)
Antineoplásicos/farmacología , Eugenol/farmacología , Neoplasias de la Mama Triple Negativas/metabolismo , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Neoplasias de la Mama Triple Negativas/genética
9.
Asian Pac J Cancer Prev ; 19(3): 777-783, 2018 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-29582634

RESUMEN

Background: Breast cancer is affected by the immune system in that different cytokines play roles in its initiation and progression. Interleukin-10 (IL-10), an anti-inflammatory cytokine, is an immunosuppressive factor involved in tumorigenesis. The present study was conducted to investigate the gene silencing effect of a small interference RNA (siRNA) targeting IL-10 on the apoptotic pathway in breast cancer cell line. Methods: The siRNA targeting IL-10 and a glyceraldehyde 3-phosphate dehydrogenase (GAPDH) clone were introduced into MDA-MB-231 cells. Real-time PCR assays were used to determine IL-10 and GAPDH gene expression levels, in addition to those for protein kinase B (AKT), phosphoinositide 3-kinase (PI3K), B-cell lymphoma 2 (Bcl2), caspase-3 and caspase-9 genes related to apoptosis. Results: Inhibition of IL-10 by the siRNA accelerated apoptosis and was accompanied by significant increase in caspase-3 and caspase-9 and a significant decrease in PI3K, AKT and Bcl2 expression levels compared to the non-transfected case. Conclusions: In conclusion, the production of IL-10 may represent a new escape mechanism by breast cancer cells to evade destruction by the immune system. IL-10 gene silencing causes down regulation of both PI3K/AKT and Bcl2 gene expression and also increases the Bbc3, BAX caspase3, and caspase 3 cleavage expression levels. IL­10 might represent a promising new target for therapeutic strategies.


Asunto(s)
Apoptosis , Neoplasias de la Mama/patología , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Interleucina-10/antagonistas & inhibidores , ARN Interferente Pequeño/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Proliferación Celular , Femenino , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Transducción de Señal , Células Tumorales Cultivadas
10.
BMC Complement Altern Med ; 17(1): 472, 2017 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-28962559

RESUMEN

BACKGROUND: Cisplatin is widely used chemotherapeutic agent for cancer treatment with limited uses due to its neurotoxic side effect. The aim of this study was to determine the potential preventive effects of rutin on the brain of cisplatin- neurotoxic rat model. METHODS: Forty rats were divided into four groups. Group-1 (control group) was intra-peritoneal (IP) injected with 2.5 ml/kg saline. Group-2 (rutin group) was orally administrated 30 mg/kg rutin dissolved in water for 14 days. Group-3 (cisplatin group) was IP received 5 mg/kg cisplatin single dose. Group-4 (rutin and cisplatin group) was orally administrated 30 mg/kg rutin dissolved in water for 14 days with a single dose of 5 mg/kg cisplatin IP on day ten. Brain tissues from frontal cortex was used to extract RNA, the gene expression levels of paraoxonase-1 (PON-1), PON-2, PON-3, peroxisome proliferator-activated receptor delta (PPAR-δ), and glutathione peroxidase (GPx) was investigated by Real-time PCR. RESULTS: Cisplatin significantly decreased the expression levels of PON-1, PON-3, PPAR-δ and GPX whereas significantly increased PON-2 expression levels. Co-administration of Rutin prevented the cisplatin-induced toxicity by restoring the alteration in the studied genes to normal values as in the control group. CONCLUSION: This study showed that Rutin has neuroprotective effect and reduces cisplatin- neurotoxicity with possible mechanism via the antioxidant pathway.


Asunto(s)
Encéfalo/efectos de los fármacos , Cisplatino/efectos adversos , Fármacos Neuroprotectores/farmacología , Rutina/farmacología , Animales , Peso Corporal/efectos de los fármacos , Encéfalo/enzimología , Encéfalo/metabolismo , Química Encefálica/efectos de los fármacos , Glutatión/metabolismo , Glutatión Peroxidasa/análisis , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , PPAR delta/análisis , PPAR delta/genética , PPAR delta/metabolismo , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo
11.
BMC Nephrol ; 18(1): 194, 2017 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-28619064

RESUMEN

BACKGROUND: Cisplatin (CP) is commonly used in the treatment of different types of cancer but nephrotoxicity has been a major limiting factor. Therefore, the present study aimed to study the possible protective effect of rutin against nephrotoxicity induced by cisplatin in rats. METHODS: Forty male Wistar albino rats were randomly divided into 4 groups. Rats of group 1 control group intraperitoneal (i.p.) received 2.5 ml/kg, group 2 CP group received single dose 5 mg/kg cisplatin i.p. group 3 rutin group orally received 30 mg/kg rutin group 4 (CP plus rutin) received CP and rutin as in group 2 and 3. Kidneys were harvested for histopathology and for the study the gene expression of c-Jun N-terminal kinases (JNK), Mitogen-activated protein kinase 4 (MKK4), MKK7, P38 mitogen-activated protein kinases (P38), tumor necrosis factors alpha (TNF-α), TNF Receptor-Associated Factor 2 (TRAF2), and interleukin-1 alpha (IL-1-α). RESULTS: The cisplatin single dose administration to rats induced nephrotoxicity associated with a significant increase in blood urea nitrogen (BUN) and serum creatinine and significantly increase Malondialdehyde (MDA) in kidney tissues by 230 ± 5.5 nmol/g compared to control group. The animal treated with cisplatin showed a significant increase in the expression levels of the IL-1α (260%), TRFA2 (491%), P38 (410%), MKK4 (263%), MKK7 (412%), JNK (680%) and TNF-α (300%) genes compared to control group. Additionally, histopathological examination showed that cisplatin-induced interstitial congestion, focal mononuclear cell inflammatory, cell infiltrate, acute tubular injury with reactive atypia and apoptotic cells. Rutin administration attenuated cisplatin-induced alteration in gene expression and structural and functional changes in the kidney. Additionally, histopathological examination of kidney tissues confirmed gene expression data. CONCLUSION: The present study suggested that the anti-oxidant and anti-inflammatory effect of rutin may prevent CP-induced nephrotoxicity via decreasing the oxidative stress, inhibiting the interconnected ROS/JNK/TNF/P38 MAPK signaling pathways, and repairing the histopathological changes against cisplatin administration.


Asunto(s)
Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & control , Antineoplásicos/toxicidad , Cisplatino/toxicidad , Lesión Renal Aguda/patología , Animales , Masculino , Ratas , Ratas Wistar , Rutina , Resultado del Tratamiento
12.
Asian Pac J Cancer Prev ; 18(1): 169-176, 2017 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-28240513

RESUMEN

Background: High-risk types of human papillomavirus (HR-HPV) may play a role in the development of epithelial ovarian cancer (EOC). The aim of this study was to determine any HPV genotypes and correlations to CADM1, PAX1, MAL and ADCYAP1 gene methylation in Egyptian EOC patients. Materials and methods: The prevalence of HR-HPV in 100 formalin fixed paraffin embedded EOC tissues was determined using nested polymerase chain reaction (PCR) with MY09/MY11 and GP5+/GP6 + primers to amplify a broad spectrum of HPV genotypes in a single reaction. DNA sequencing was applied to identify HPV genotypes for the positive samples. All samples negative for HPV were re-analyzed for HR-HPV and low-risk HPV subtypes using type specific primers. Results: The prevalence of HPV was 10% in our EOC cases. HPV-16 and HPV-18 were the predominant genotypes followed by HPV−33, all being associated with advanced stages. Other HR-HPV and low risk HPV genotypes were not found. CADM1 was hypermethylated in 100% of patients infected with HPV-16 and HPV-33 and in 75% of patients infected with HPV-18. Hypermethylation of PAX1 was evident in 80% and in 75% of patients infected with HPV-16 and HPV-18 while MAL was hypermethylated in 100% and ADCYAP1 was hypermethylated in 60% and in 75%, respectively. Conclusion: The presence of high risk HPV genotypes among epithelial ovarian carcinoma may reflect an importance of infection in the pathogenesis of EOC. In HR-HPV infected cancers, DNA methylation may be one of the mechanisms triggering the alteration in CADM1, PAX1, MAL and ADCYAP1 gene expression levels.

13.
BMC Complement Altern Med ; 17(1): 45, 2017 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-28086769

RESUMEN

BACKGROUND: Liver diseases are major global health problems. Ginseng extract has antioxidant, immune-modulatory and anti-inflammatory activities. This study investigated the effect of ginseng extract on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. METHODS: Male Wistar rats were divided into four groups: control group, ginseng group, CCl4 group and CCl4 + ginseng group. Liver injury was induced by the intraperitoneal (I.P) injection of 3 ml/kg CCl4 (30% in olive oil) weekly for 8 weeks. The control group was I.P injected with olive oil. The expression of genes encoding transforming growth factor beta (TGF-ß), type I TGF-ß receptor (TßR-1), type II TGF-ß receptor (TßR-II), mothers against decapentaplegic homolog 2 (Smad2), Smad3, Smad4, matrix metalloproteinase 2 (MMP2), MMP9, tissue inhibitor matrix metalloproteinase-1 (TIMP-1), Collagen 1a2 (Col1a2), Collagen 3a1 (Col3a1), interleukin-8 (IL-8) and interleukin -10 (IL-10) were measured by real-time PCR. RESULTS: Treatment with ginseng extract decreased hepatic fat deposition and lowered hepatic reticular fiber accumulation compared with the CCl4 group. The CCl4 group showed a significant increase in hepatotoxicity biomarkers and up-regulation of the expression of genes encoding TGF-ß, TßR-I, TßR-II, MMP2, MMP9, Smad-2,-3, -4, and IL-8 compared with the control group. However, CCl4 administration resulted in the significant down-regulation of IL-10 mRNA expression compared with the control group. Interestingly, ginseng extract supplementation completely reversed the biochemical markers of hepatotoxicity and the gene expression alterations induced by CCl4. CONCLUSION: ginseng extract had an anti-fibrosis effect via the regulation of the TGF-ß1/Smad signaling pathway in the CCl4-induced liver fibrosis model. The major target was the inhibition of the expression of TGF-ß1, Smad2, and Smad3.


Asunto(s)
Cirrosis Hepática/tratamiento farmacológico , Panax/química , Extractos Vegetales/administración & dosificación , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Tetracloruro de Carbono/efectos adversos , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Masculino , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Ratas Wistar , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Smad/genética , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta1/genética
14.
Biochem Pharmacol ; 124: 69-82, 2017 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-27984001

RESUMEN

Psoriasis is an autoimmune inflammatory skin disease characterized by activated IL-23/STAT3/Th17 axis. Recently psoriatic inflammation has been shown to be associated with asthma. However, no study has previously explored how psoriatic inflammation affects airway inflammation. Therefore, this study investigated the effect of imiquimod (IMQ)-induced psoriatic inflammation on cockroach extract (CE)-induced airway inflammation in murine models. Mice were subjected to topical and intranasal administration of IMQ and CE to develop psoriatic and airway inflammation respectively. Various analyses in lung/spleen related to inflammation, Th17/Th2/Th1 cell immune responses, and their signature cytokines/transcription factors were carried out. Psoriatic inflammation in allergic mice was associated with increased airway inflammation with concurrent increase in Th2/Th17 cells/signature cytokines/transcription factors. Splenic CD4+ T and CD11c+ dendritic cells in psoriatic mice had increased STAT3/RORC and IL-23 mRNA expression respectively. This led us to explore the effect of systemic IL-23/STAT3 signaling on airway inflammation. Topical application of STA-21, a small molecule STAT3 inhibitor significantly reduced airway inflammation in allergic mice having psoriatic inflammation. On the other hand, adoptive transfer of IL-23-treated splenic CD4+ T cells from allergic mice into naive recipient mice produced mixed neutrophilic/eosinophilic airway inflammation similar to allergic mice with psoriatic inflammation. Our data suggest that systemic IL-23/STAT3 axis is responsible for enhanced airway inflammation during psoriasis. The current study also suggests that only anti-asthma therapy may not be sufficient to alleviate airway inflammatory burden in asthmatics with psoriasis.


Asunto(s)
Bronquitis/complicaciones , Modelos Animales de Enfermedad , Hipersensibilidad/complicaciones , Interleucina-23/metabolismo , Psoriasis/complicaciones , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Alérgenos/administración & dosificación , Animales , Líquido del Lavado Bronquioalveolar , Linfocitos T CD4-Positivos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C
15.
Asian Pac J Cancer Prev ; 17(11): 4965-4971, 2016 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-28032724

RESUMEN

Objective: Breast cancer is global female health problem worldwide. Most of the currently used agents for breast cancer treatment have toxic side-effects. Ginseng root, an oriental medicine, has many health benefits and may exhibit direct anti-cancer properties. This study was performed to assess the effects of ginseng on breast cancer cell lines. Materials and Methods: Cytotoxicity of ginseng extract was measured by MTT assay after exposure of MDA-MB-231, MCF-10A and MCF-7 breast cancer cells to concentrations of 0.25, 0.5, 1, 1.5, 2 and 2.5 mg/well. Expression levels of p21WAF, p16INK4A, Bcl-2, Bax and P53 genes were analyzed by quantitative real time PCR. Results: The treatment resulted in inhibition of cell proliferation in a dose-and time-dependent manner. p53, p21WAF1and p16INK4A expression levels were up-regulated in ginseng treated MDA-MB-231 and MCF-7 cancer cells compared to untreated controls and in MCF-10A cells. The expression levels of Bcl2 in the MDA-MB-231 and MCF-7 cells were down-regulated. In contrast, that of Bax was significantly up-regulated. Conclusion: The results of this study revealed that ginseng may inhibit breast cancer cell growth by activation of the apoptotic pathway.

16.
Oxid Med Cell Longev ; 2016: 5436745, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27239252

RESUMEN

Background and Objective. High-cholesterol diet (HCD) intends to increase the oxidative stress in liver tissues inducing hepatotoxicity. Rutin is a natural flavonoid (vitamin p) which is known to have antioxidative properties. The aim of the present study was to investigate the potential effects of Rutin on hypercholesterolemia-induced hepatotoxicity in rats. Materials and Methods. Male Wistar rats were divided into four groups: G-I control, G-II Rutin, G-III HCD, and G-IV Rutin + HCD. The liver functions and lipid profile were used to evaluate the HCD-induced hepatotoxicity. Quantitative real time-PCR was carried out to evaluate the expression levels of genes in TGF-ß/Smad signaling pathway. Results. Rutin in combination with HCD showed a significant protective effect against hepatotoxicity. HCD caused significant increase in the mRNA expression of transforming growth factor beta (TGF-ß), Mothers Against Decapentaplegic Homolog 2 (Smad-2), Mothers Against Decapentaplegic Homolog 4 (Smad-4), Bcl-2-binding component 3 (Bbc3), caspase-3, P53 and Interleukin-6 (IL-6) and decrease in the expression levels of Cyclin depended kinase inhibitor (P21) and Interleukin-3 (IL-3) in hepatic cells. Conclusion. TGF-ß/Smad signaling pathway is involved in HCD-induced hepatotoxicity and Rutin inhibits the hepatotoxicity via suppressing this pathway. Therefore, Rutin might be considered as a protective agent for hepatotoxicity.


Asunto(s)
Colesterol/efectos adversos , Dieta Alta en Grasa/efectos adversos , Hepatopatías/tratamiento farmacológico , Rutina/uso terapéutico , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Peso Corporal/efectos de los fármacos , Caspasa 3/metabolismo , Interleucinas/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hepatopatías/sangre , Hepatopatías/enzimología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas Wistar , Rutina/farmacología , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/metabolismo
17.
Asian Pac J Cancer Prev ; 16(14): 5807-15, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26320455

RESUMEN

BACKGROUND: Ovarian cancer is the most common gynecological malignancy and constitutes the fifth leading cause of female cancer death. Some biological parameters have prognostic roles in patients with advanced ovarian cancer and their expression may contribute to tumor progression. The aim of this study was to investigate the potential prognostic value of SKP2, genes P27Kip1, K-ras, c-Myc, COX2 and HER2 genes expression in ovarian cancer. MATERIALS AND METHODS: This study was performed on two hundred formalin fixed paraffin embedded ovarian cancer and normal adjacent tissues (NAT). Gene expression levels were assessed using real time PCR and Western blotting. RESULTS: Elevated expression levels of SKP2, K-ras, c-Myc, HER2 and COX2 genes were observed in 61.5% (123/200), 92.5% (185/200), 74% (148/200), 96 % (192/200), 90% (180/200) and 78.5% (157/200) of cancer tissues, respectively. High expression of SKP2 and down-regulation of P27 was associated with advanced stages of cancer. CONCLUSIONS: The association between high expression of c-Myc and SKP2 with low expression of P27 suggested that the Skp2-P27 pathway may play an important role in ovarian carcinogenesis. Reduced expression of P27 is associated with advanced stage of cancer and can be used as a biological marker in clinical routine assessment and management of women with advanced ovarian cancer.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Neoplasias Ováricas/metabolismo , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Transducción de Señal , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis , Biomarcadores de Tumor/genética , Western Blotting , Proliferación Celular , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Quinasas Asociadas a Fase-S/genética , Células Tumorales Cultivadas , Adulto Joven
18.
Toxicol Mech Methods ; 25(5): 417-23, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26360969

RESUMEN

Riboflavin (vitamin B2) is an easily absorbed micronutrient with a key role in maintaining health in humans and animals. It is the central component of the cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) and is therefore required by all flavoproteins. Riboflavin also works as an antioxidant by scavenging free radicals. The present study was designed to evaluate the effects of riboflavin against acute lungs injury induced by the administration of a single intranasal dose (20 µg/rat) of lipopolysaccharides (LPS) in experimental rats. Administration of LPS resulted in marked increase in malondialdehyde (MDA) level (p < 0.01) and MPO activity (p < 0.001), whereas marked decrease in glutathione (GSH) content (p < 0.001), glutathione reductase (GR) (p < 0.001) and glutathione peroxidase (p < 0.01) activity. These changes were significantly (p < 0.001) improved by treatment with riboflavin in a dose-dependent manner (30 and 100 mg/kg, respectively). Riboflavin (100 mg/kg, p.o.) showed similar protective effects as dexamethasone (1 mg/kg, p.o.). Administration of LPS showed marked cellular changes including interstitial edema, hemorrhage, infiltration of PMNs, etc., which were reversed by riboflavin administration. Histopathological examinations showed normal morphological structures of lungs tissue in the control group. These biochemical and histopathological examination were appended with iNOS and CAT gene expression. The iNOS mRNA expression was increased significantly (p < 0.001) and levels of CAT mRNA expression was decreased significantly (p < 0.001) in the animals exposed to LPS, while treatment with riboflavin significantly (p < 0.01) improved expression of both gene. In conclusion, the present study clearly demonstrated that riboflavin caused a protective effect against LPS-induced ALI. These results suggest that riboflavin may be used to protect against toxic effect of LPS in lungs.


Asunto(s)
Lesión Pulmonar Aguda/prevención & control , Antioxidantes/uso terapéutico , Lipopolisacáridos/toxicidad , Riboflavina/uso terapéutico , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Animales , Antioxidantes/administración & dosificación , Catalasa/genética , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Relación Dosis-Respuesta a Droga , Expresión Génica/efectos de los fármacos , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Óxido Nítrico Sintasa de Tipo II/genética , Ratas Wistar , Riboflavina/administración & dosificación
19.
Biol Res ; 48: 30, 2015 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-26062544

RESUMEN

BACKGROUND: Carbon tetrachloride (CCl4) induces hepatotoxicity in animal models, including the increased blood flow and cytokine accumulation that are characteristic of tissue inflammation. The present study investigates the hepato-protective effect of rutin on CCl4-induced hepatotoxicity in rats. RESULTS: Forty male Wistar rats were divided into four groups. Group I (control group) received 1 mL/kg of dimethyl sulfoxide intragastrically and 3 mL/kg olive oil intraperitoneally twice a week for 4 weeks. Group II received 70 mg/kg rutin intragastrically. Groups III and IV received CCl4 (3 mL/kg, 30 % in olive oil) intraperitoneally twice a week for 4 weeks. Group IV received 70 mg/kg rutin intragastrically after 48 h of CCl4 treatment. Liver enzyme levels were determined in all studied groups. Expression of the following genes were monitored with real-time PCR: interleukin-6 (IL-6), dual-specificity protein kinase 5 (MEK5), Fas-associated death domain protein (FADD), epidermal growth factor (EGF), signal transducer and activator of transcription 3 (STAT3), Janus kinase (JAK), B-cell lymphoma 2 (Bcl2) and B-cell lymphoma-extra-large (Bcl-XL). The CCl4 groups showed significant increases in biochemical markers of hepatotoxicity and up-regulation of expression levels of IL-6, Bcl-XL, MEK5, FADD, EGF, STAT3 and JAK compared with the control group. However, CCl4 administration resulted in significant down-regulation of Bcl2 expression compared with the control group. Interestingly, rutin supplementation completely reversed the biochemical markers of hepatotoxicity and the gene expression alterations induced by CCl4. CONCLUSION: CCl4 administration causes alteration in expression of IL-6/STAT3 pathway genes, resulting in hepatotoxicity. Rutin protects against CCl4-induced hepatotoxicity by reversing these expression changes.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Interleucina-6/metabolismo , Rutina/farmacología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Biomarcadores , Tetracloruro de Carbono , Factor de Crecimiento Epidérmico/metabolismo , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Expresión Génica/efectos de los fármacos , Quinasas Janus/metabolismo , Hígado/efectos de los fármacos , MAP Quinasa Quinasa 5/metabolismo , Masculino , Sustancias Protectoras/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteína bcl-X/metabolismo
20.
Asian Pac J Cancer Prev ; 16(2): 541-9, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25684485

RESUMEN

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) with higher metastatic rate and both local and systemic recurrence compared to non-TNBC. The generation of reactive oxygen species (ROS) secondary to oxidative stress is associated with DNA damage, chromosomal degradation and alterations of both hypermethylation and hypomethylation of DNA. This study concerns differential methylation of promoter regions in specific groups of genes in TNBC and non-TNBC Saudi females in an effort to understand whether epigenetic events might be involved in breast carcinogenesis, and whether they might be used as markers for Saudi BCs. Methylation of glutathione S-transferase P1 (GSTP1), T-cadherin (CDH13), Paired box protein 5 (PAX5), death associated protein kinase (DAPK), twist-related protein (TWIST), DNA-binding protein inhibitor (ID4), High In Normal-1 (HIN-1), cyclin-dependent kinase inhibitor 2A (p16), cyclin D2 and retinoic acid receptor-ß (RARß1) genes was analyzed by methylation specific polymerase chain reaction (MSP) in 200 archival formalin- fixed paraffin embedded BC tissues divided into 3 groups; benign breast tissues (20), TNBC (80) and non-TNBC (100). The relationships between methylation status, and clinical and pathological characteristics of patients and tumors were assessed. Higher frequencies of GSTP1, ID4, TWIST, DAPK, PAX5 and HIN-1 hypermethylation were found in TNBC than in non-TNBC. Hypermethylation of GSTP1, CDH13, ID4, DAPK, HIN-1 and PAX5 increased with tumor grade increasing. Other statistically significant correlations were identified with studied genes. Data from this study suggest that increased hypermethylation of GSTP1, ID4, TWIST, DAPK, PAX5 and HIN-1 genes in TNBC than in non-TNBC can act as useful biomarker for BCs in the Saudi population. The higher frequency of specific hypermethylated genes paralleling tumor grade, size and lymph node involvement suggests contributions to breast cancer initiation and progression.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma Ductal de Mama/genética , Metilación de ADN , Proteínas Quinasas Asociadas a Muerte Celular/genética , Gutatión-S-Transferasa pi/genética , Proteínas Inhibidoras de la Diferenciación/genética , Factor de Transcripción PAX5/genética , Neoplasias de la Mama Triple Negativas/genética , Adulto , Carcinoma Ductal de Mama/patología , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Pronóstico , Arabia Saudita , Neoplasias de la Mama Triple Negativas/patología
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