RESUMEN
BACKGROUND: Promoter methylation of tumor suppressor genes (TSGs) is a well-reported portent in carcinogenesis; hence, it is worthy to investigate this in high-risk Northeast population of India. The study was designed to investigate methylation status of 94 TSGs in esophageal squamous cell carcinoma (ESCC). Further, the effect of OPCML promoter methylation on gene expression was analyzed by immunohistochemistry. Moreover, in silico protein-protein interactions were examined among 8 TSGs identified in the present study and 23 epigenetically regulated genes reported previously by our group in ESCC. MATERIALS AND METHODS: Methylation profiling was carried out by polymerase chain reaction array and OPCML protein expression was examined by tissue microarray-based immunohistochemistry. RESULTS: OPCML, NEUROG1, TERT, and WT1 genes were found hypermethylated and SCGB3A1, CDH1, THBS1, and VEGFA were hypomethylated in Grade 2 tumor. No significant change in OPCML expression was observed among control, Grade 1, and Grade 2 tumor. Conclusively, hypermethylation of the studied OPCML promoter in Grade 2 tumor produced no effect on expression. Unexpectedly, OPCML expression was downregulated in Grade 3 tumor in comparison to other groups signifying that downregulation of OPCML expression may lead to higher grade of tumor formation at the time of diagnosis of ESCC in patients. Significant interactions at protein level were found as VEGFA:PTK2, CTNNB1:CDH1, CTNNB1:VEGFA, CTNNB1:NEUROG1, CTNND2:CDH1, and CTNNB1:TERT. These interactions are pertinent to Wnt/ß-catenin and TGF-ß-Smad pathways. CONCLUSIONS: Deranged OPCML expression may lead to high-grade ESCC as well as epigenetically regulated genes, that is, CDH1, CTNNB1, CTNND2, THBS1, PTK2, WT1, OPCML, TGFB1, and SMAD4 may alter the Wnt/ß-catenin and TGF-ß-Smad pathways in ESCC. Further study of these genes could be useful to understand the molecular pathology of ESCC with respect to epithelial-mesenchymal transition (EMT) mediated by Wnt/ß-catenin and TGF-ß signaling pathways.
Asunto(s)
Moléculas de Adhesión Celular/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/genética , Regulación Neoplásica de la Expresión Génica , Moléculas de Adhesión Celular/metabolismo , Metilación de ADN/genética , Regulación hacia Abajo , Epigénesis Genética/genética , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Esófago/patología , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Humanos , Masculino , Clasificación del Tumor , Regiones Promotoras Genéticas/genética , Transducción de Señal/genética , Proteínas Smad/metabolismo , Análisis de Matrices Tisulares , Factor de Crecimiento Transformador beta/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMEN
AIM: Scopolamine is known to produce amnesia due to blockade of the cholinergic neurotransmission. The present study investigated the potential of Convolvulus pluricaulis (CP) to attenuate scopolamine (2 mg/kg, i.p) induced increased protein and mRNA levels of tau, amyloid precursor protein (AßPP), amyloid ß (Aß) levels and histopathological changes in rat cerebral cortex. MATERIALS AND METHODS: The study was conducted on male Wistar rats (250 ± 20 g) divided into four groups of eight animals each. Groups 1 and 2 served as controls receiving normal saline and scopolamine for 4 weeks, respectively. Group 3 received rivastigmine (standard) and group 4 received aqueous extract of CP simultaneously with scopolamine. Western blot and RT-PCR analysis were used to evaluate the levels of protein and mRNA of amyloid precursor protein (AßPP) and tau in rat cortex and ELISA was used to measure the amyloid ß (Aß) levels. Histopathology was also performed on cortical section of all groups. RESULT: Oral administration of CP extract (150 mg/kg) to scopolamine treated rats reduced the increased protein and mRNA levels of tau and AßPP levels followed by reduction in Aß levels compared with scopolamine treated group. The potential of extract to prevent scopolamine neurotoxicity was reflected at the microscopic level as well, indicative of its neuroprotective effects. CONCLUSION: CP treatment alleviated neurotoxic effect of scopolamine reflects its potential as potent neuroprotective agent.
Asunto(s)
Precursor de Proteína beta-Amiloide/antagonistas & inhibidores , Encéfalo/efectos de los fármacos , Convolvulus , Extractos Vegetales/farmacología , Escopolamina/toxicidad , Proteínas tau/antagonistas & inhibidores , Precursor de Proteína beta-Amiloide/biosíntesis , Animales , Encéfalo/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Regulación de la Expresión Génica , Masculino , Extractos Vegetales/aislamiento & purificación , Raíces de Plantas , Distribución Aleatoria , Ratas , Ratas Wistar , Proteínas tau/biosíntesisRESUMEN
AIM: To investigate the neuroprotective effect of Convolvulus pluricaulis aqueous extract (AE) against scopolamine (1 mg/kg body weight (bwt))-induced neurotoxicity in the cerebral cortex of male Wistar rats. MATERIALS AND METHODS: The study was carried out on male Wistar rats (age matched, weight 250 ± 20 g). The present study investigated cognitive-enhancing property of AE using Elevated plus maze (EPM) (transfer latency [TL]) and Morris water maze (MWM). Besides evaluating the effect of extract on neurochemical enzymes, in vivo antioxidant and free radical scavenging activities were also screened. All the measured parameters were compared with rivastigmine tartrate (1 mg/kg bwt) which was taken as standard. RESULTS: Pretreatment of rats with AE (150 mg/kg bwt) significantly reduced scopolamine-induced increase in the TL in EPM, whereas in MWM, administration of extract improved the impairment of spatial memory induced by scopolamine. The activity of acetylcholinesterase (AChE) was significantly inhibited by extract within the cortex and hippocampus. Reduced activities or contents of glutathione reductase, superoxide dismutase, and reduced glutathione within the cortex and hippocampus induced by scopolamine were elevated by the extract. Taken together, it could be postulated that extract may exert its potent-enhancing activity through both anti-AChE and antioxidant action. CONCLUSION: AE possesses neuroprotective potential, thus validating its use in alleviating toxic effects of scopolamine.
RESUMEN
AIM OF THE STUDY: Convolvulus pluricaulis (Convolvulaceae) has long been used as traditional herbal medicine in India as nerve tonic. We investigated neuroprotective effects of aqueous extract from Convolvulus pluricaulis (CP) against aluminium chloride induced neurotoxicity in rat cerebral cortex. MATERIAL, METHOD AND RESULT: Daily administration of CP (150 mg/kg) for 3 months along with aluminium chloride (50 mg/kg) decreased the elevated enzymatic activity of acetylcholine esterase and also inhibited the decline in Na(+)/K(+)ATPase activity which resulted from aluminium intake. Beside, preventing accumulation of lipid and protein damage, changes in the levels of endogenous antioxidant enzymes associated with aluminium administration were also rectified. Oral administration of CP preserved the mRNA levels of muscarinic receptor 1 (M1 receptor), choline acetyl transferase (ChAT) and Nerve Growth Factor-Tyrosine kinase A receptor (NGF-TrkA). It also ameliorated the upregulated protein expression of cyclin dependent kinase5 (Cdk5) induced by aluminium. The potential of CPE to inhibit aluminium induced toxicity was compared with rivastigmine tartrate (1mg/kg), which was taken as standard. The potential of the extract to prevent aluminium-induced neurotoxicity was also reflected at the microscopic level, indicative of its neuroprotective effects. CONCLUSION: Convolvulus pluricaulis possesses neuroprotective potential, thus validating its use in alleviating toxic effects of aluminium.
