Syed Jafar Mehdi

18-β Glycyrrhetinic acid alleviates 2-acetylaminofluorene-induced hepatotoxicity in Wistar rats Role in hyperproliferation, inflammation and oxidative stress

2-Acetylaminofluorene (2-AAF) is a known hepatic carcinogen which leads to tumour formation in rodents. 18-β Glycyrrhetinic acid (18β-GA) derived from liquorice plant has various pharmacological properties such as anti-ulcer, anti-inflammatory, antiviral, hepatoprotective and antioxidant. This study is designed to elucidate the chemopreventive properties of 18β-GA against 2-AAF-induced liver toxicity in Wistar rats and evaluated its effect on inflammatory and tumour promotion marker and activities of different oxidative stress enzymes. Administration of 2-AAF at the dose of (50 mg/kg body weight (b.w.) intraperitoneally (i.p.)) for five consecutive days induces hepatic toxicity, inflammation, oxidative stress and hyperproliferation. Pretreatment with 18β-GA at two different doses (45 and 75 mg kg−1 b.w.) significantly ameliorates 2-AAF-induced increased lipid peroxidation, alanine transaminase and aspartate transaminase, xanthine oxidase activities and activities of phase-II detoxifying enzymes along with the levels of glutathione content. Administration of 18β-GA also significantly restored the expressions of proliferating cell nuclear antigen, cyclooxygenase 2, inducible nitric oxide synthase and nuclear factor κB. Furthermore, histological observations also support the preventive effects of 18β-GA. Our findings suggest that pretreatment with 18β-GA showed potential hepatoprotective effects via attenuation of oxidative stress, inflammation and hyperproliferation.

Breast Metastasis from Non-Small-Cell Lung Carcinoma

Development of metastasis to the breast from lung cancer is very rare and the prognosis for such patients is poor. We present a patient who had metastasis to breast from non-small-cell lung cancer. It is important to distinguish a primary breast cancer from metastasis to the breast, as the therapy offered would be markedly different, with considerably different outcomes.

Angiosarcoma of the Small Intestine: A Possible Role for Thalidomide?

An 85-yr-old male presented with complaints of a 40-lb weight loss and a dull left upper quadrant abdominal pain. He also complained of decreased appetite, generalized weakness, generally not feeling well, and a dull left upper quadrant abdominal pain that was not relieved by food. He had a ventral and a left-sided inguinal hernia. Laboratory investigations revealed iron deficiency anemia, the cause of which was not apparent despite extensive investigation including computerized tomographic scans, esophagogastroduodenoscopy, and small-bowel follow-through examination. Surgical exploration for possible angiodysplasia, malignancy, and/or mesenteric ischemia revealed an incarcerated hernia, and the histopathological examination of the surgical specimen revealed high-grade angiosarcoma. The tumor showed strong positivity for vimentin and CD31 and a focal positivity for Factor VIII and CD34. At that time he was found to have hepatic metastases. He was started on thalidomide as an experimental measure with no change in the performance status and increasing evidence of necrosis in the metastatic lesion.

Allelic Loss of 10q23.3, the PTEN Gene Locus in Cervical Carcinoma from Northern Indian Population

Cervical cancer is one of the most common malignant diseases affecting women worldwide. Studies on loss of heterozygosity have been made for PTEN gene specific microsatellite markers in malignancies like breast, ovary and lungs and the results have shown a significant association. However the role of this gene is not clearly understood in cervical cancer from Indian population. A total of 135 cervical carcinoma tissues samples were analyzed for loss of heterozygosity. DNA was isolated from the samples and their matched control specimens. Polymerase chain reaction was performed using primer specific for two intragenic markers (D10S198 & D10S192) and one marker (D10S541) in flanking region and further electrophoresed on 8% denaturing polyacrylamide gel. Overall, 31 out of 133(23%) informative cases showed loss of heterozygosity in at least one locus in the region examined. The percentage of loss of heterozygosity for these markers ranged from 8% (D10S192) to 13% (D10S198). Loss of heterozygosity was more frequently detected in intragenic region (D10S198 & D10S192) than in flanking region, D10S541 (21% versus 9%). These data argue that PTEN is a tumor suppressor gene whose inactivation may play an important role in the carcinoma of uterine cervix.

PTEN-mediated AKT activation contributes to the reduced apoptosis among Indian oral squamous cell carcinoma patients

PurposeThe tumor suppressor gene PTEN negatively regulates Akt, a downstream mediator phosphoinositol 3-kinase. Several studies have reported the role of PTEN gene in Akt downregulation and apoptosis induction in different cancers and cell lines. However, the role of loss of PTEN expression in Akt activation and spontaneous apoptosis in oral squamous cell carcinoma clinical specimens is not well established.MethodsWe investigated the expression of PTEN and phospho-Akt in 146 formalin-fixed (archived) paraffin-embedded oral squamous cell carcinoma tissue sections through immunohistochemical analysis. Programmed cell death (apoptosis) was determined by Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling assay.ResultsSixty-one percent loss of PTEN expression and 68.5% Akt activation was observed in oral squamous cell carcinoma. A significant correlation was found between loss of PTEN expression and Akt activation. Loss of PTEN expression and Akt activation were further correlated with different clinical parameters and found to be significantly correlated with tumor stage. Apoptotic index was estimated and correlated with PTEN expression and Akt activation. The percentage of apoptotic cells varied from 0.2 to 14.1%. Low apoptotic index was observed in 105 (72%) of samples, and it was found to be significantly related with loss of PTEN expression and phospho-AktConclusionThe present study confirms the contribution of loss of PTEN expression in Akt phosphorylation and spontaneous apoptosis suppression in the specimens of oral cancer. Both PTEN and phospho-Akt are likely to be concerned with oral cancer progression and reduced incidence of spontaneous apoptosis

Phytochemical Composition of Cassia fistula Fruit Extracts and its Anticancer Activity Against Human Cancer Cell Lines

Abstract Cassia fistula Linn. (Fabaceae) fruit has been used in folk medicine and reported for various pharmacological properties. We evaluated the anticancer activity of C. fistula fruit extracts [ethyl acetate extract of pulp (EEP), n-butanol extract of pulp (BEP), ethyl acetate extract of seeds (EES), n-butanol extract of seeds (BES)] against human cervical cancer (SiHa) and breast cancer (MCF-7) cell lines. Phytochemicals analysis revealed that the EEP and EES contained anticancer compounds like 2(3H)-furanone, rhein, thymoland oleic acid. BES contained inositol and palmitic acid, whereas BEP contained inositol and 2-pyrrolidone. IC50 of EEP, EES, BEP and BES against SiHa cells were 415.5±0.19, 435.7±0.11, 535.3±0.32 and 580.2±0.41 µg/mL, whereas against MCF-7 cells were 422.2±0.32, 451.4±0.27, 564.5±0.21 and 575.6±0.47 µg/mL respectively (p ≤ 0.01). At IC50, EEP, EES, BEP and BES treated MCF-7 cells formed colonies of 17.5, 16.3, 22.5 and 18.8 % whereas treated SiHa cells formed colonies of 11.5, 12.8, 19.2 and 16.7 % (p≤0.03). Seeds and pulp treated both cell lines showed up-regulation of p53 and Bax genes, down-regulation of Bcl-2 gene and increased caspase-3, 7 & 10 and -9 enzymes activities. Also, the fragmented genomic DNA in pulp and seeds extracts treated SiHa and MCF-7 cells showed sign of apoptosis.We concluded that the fruit pulp and seeds extracts inhibited MCF-7 and SiHa cells growth and induced cells death by modulating the expression of apoptosis-regulatory genes and caspase enzymes.

HPV typing and its relation with apoptosis in cervical carcinoma from Indian population

Definite progress in understanding the etiology of cervical cancer has been achieved, and some types of human papillomavirus have been established as the central cause of cervical cancer worldwide. This study investigates the human papillomavirus infection and its correlation with apoptosis and clinicopathologic characteristics in squamous cell carcinoma of uterine cervix. Human papillomavirus typing was done by type-specific primers for high-risk human papillomavirus using standard polymerase chain reaction method. Programmed cell death (apoptosis) was determined by terminal deoxynucleotidyl transferase biotin–dUTP nick end labeling assay. Human papillomavirus infection in tissue biopsy of cervical carcinoma was detected in 131 of 135 (97%) cases. Among the positive cases of human papillomavirus, 123 (94%) cases were human papillomavirus type 16, and five (4%) cases were human papillomavirus type 18. Out of 135 cervical carcinoma cases, 81 (60%) cases showed presence of apoptosis. The phenomenon of apoptosis was seen slightly higher in squamous cell carcinoma than in adenocarcinoma (40% in squamous cell carcinoma and 33% in adenocarcinoma). The human papillomavirus infection in cervical cancer might not play any role in the occurrence of apoptosis.

Common Variants in CLDN2 and MORC4 Genes Confer Disease Susceptibility in Patients with Chronic Pancreatitis.

A recent genome-wide association study (GWAS) identified association with variants in X-linked CLDN2 and MORC4, and PRSS1-PRSS2 loci with chronic pancreatitis (CP) in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525—OR 1.71, P = 1.38 x 10-09; rs12008279—OR 1.56, P = 1.53 x 10-04) and 2 variants in MORC4 gene (rs12688220—OR 1.72, P = 9.20 x 10-09; rs6622126—OR 1.75, P = 4.04x10-05) in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10-06) and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31–0.78], P = 0.0027). A variant in the gene MORC4 (rs12688220) showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068) suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10-14). Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients.

Antioxidant Capacity and Phenolic Content of the Aqueous Extract of Commonly Consumed Cucurbits

The antioxidant capacity of commonly consumed cucurbits vegetable was determined by the DPPH, FRAP, Fe3+ reducing power, and hydrogen peroxide scavenging assay. The aqueous extract of Luffa cylindrica showed the highest value of phenolic content and antioxidant capacity based on FRAP, Fe3+ reducing power, and hydrogen peroxide scavenging assay. However, Laginaria siceraria extract showed the highest flavonoid and DPPH scavenging activities among all three cucurbits used in this study. Phenolic content in aqueous extracts of Luffa cylindrica and Laginaria siceraria was almost equal. Cucurbita maxima exhibited the lowest phenolic, flavonoid content, and exhibited the lowest power of antioxidant scavenging. The antioxidant capacity of cucurbits was significantly correlated (P < 0.05) with the phenolic content of their extracts. The antioxidant capacity of Luffa cylindrica and Laginaria siceraria have also shown a significant correlation (P < 0.05).

Protein Kinases and Parkinson’s Disease

Currently, the lack of new drug candidates for the treatment of major neurological disorders such as Parkinson’s disease has intensified the search for drugs that can be repurposed or repositioned for such treatment. Typically, the search focuses on drugs that have been approved and are used clinically for other indications. Kinase inhibitors represent a family of popular molecules for the treatment and prevention of various cancers, and have emerged as strong candidates for such repurposing because numerous serine/threonine and tyrosine kinases have been implicated in the pathobiology of Parkinson’s disease. This review focuses on various kinase-dependent pathways associated with the expression of Parkinson’s disease pathology, and evaluates how inhibitors of these pathways might play a major role as effective therapeutic molecules.