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Modulation of Proliferation and Apoptosis Biomarkers in Oral and Other Cancers

Thesis Info

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Author

Khan, Salman Ahmed

Program

PhD

Institute

University of Karachi

City

Karachi

Province

Sindh

Country

Pakistan

Thesis Completing Year

2017

Thesis Completion Status

Completed

Subject

Molecular Medicine

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/14025/1/Salman_Ahmed_Khan_Molecular_Medicine_HSR_2017_UoK_Karachi.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676726668159

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Cancer, also known as neoplasia, involves uncontrolled cell proliferation leading to malignant tumor formation. Epithelial cancers (or carcinomas, representing about 80% of all cancers) are a group of cancers originating in the epithelial lining of many locations, such as digestive tract, airways, breast, reproductive tracts and oral cavity. Oral cancer is one of the eight most common types of cancer worldwide. It starts from the upper digestive tract, including the larynx, oral and nasal cavities. Whereas lung cancer is the major cause of cancer-related deaths worldwide, representing about 26% to 28% per year. Heavy alcohol consumption, betel nut chewing, smoking, viral infections, occupation hazard and exposure to UV radiation are the major risk factors. Tyrosine kinase receptors (TKs), such as EGFR and Lyn are major regulators of cell growth and survival. In cancer cells, such receptors are constitutively activated and lead to malignant phenotype. Blocking of active TKs efficiently stops proliferation and induces apoptosis in oral and lung cancer cells. In the present study, we selected five TKIs (Genistein, Gefitinib, Erlotinib, Dasatinib, and Imatinib) which acts upon EGFR and Src family tyrosine kinases. Imatinib and Dasatinib are non-optimal TKIs for oral and lung carcinomas, and have to be utilized at relatively high concentrations to display inhibition. Our goal was to select therapeutically suitable small molecules, such as resveratrol (a natural polyphenol) and artemisinin along with its derivatives (synthetic endoperoxides) to potentiate the sub-optimal activity of standard TKIs. The objective of our study was to investigate standard TKIs and the possible adjuvant effects of artemisinin derivatives (endoperoxides, EPs) and resveratrol (natural phenol, NP) on highly malignant lung cancer cells (NCI-H460) and laryngeal cancer cells (KCLB-SNU46) of lower malignancy. Optimal combinations of TKIs and EPs/NP that decrease the proliferative capacity of oral and lung cancer cell lines, and increase their apoptosis potential were thus investigated. The techniques employed were flowcytometry, spectrophotometry, SDS-PAGE and western blotting. Out of five TKIs, Imatinib and Dasatinib at higher concentration and on 48 hours incubation affected the oral cancer cell line (KCLBSNU46). However, the lung cancer cell line (NCI-H460) responded to Gefitinib as well as Imatinib and Dasatinib only after 48 hours. Artemisinin itself didn’t show any effect but its endoperoxide derivatives OD59 and OD66 showed potent anticancer activity (with very low IC50) in both cell lines when compared to that of the standard TKIs. Resveratrol showed no effect on oral cancer cells, but lung cancer cells did respond to high resveratrol concentrations. In combination studies, resveratrol and endoperoxides (OD66 and OD67) showed significant synergistic effects when combined with gefitinib and dasatinib at very low concentrations in both the cell lines. Furthermore it was confirmed that these synergistic combinations induced apoptosis by modulating the phosphorylation of the EGFR and Lyn tyrosine kinases. This study conclude that resistance phenomena in cancer cells can be modulated by combining sub-therapeutic doses of standard TKIs with least effective doses of natural and synthetic compounds. This approach can conveniently reduce the dosage as well as the cytotoxic effects of the clinically used TKIs on cancer patients.
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تعارف ومنہج تفسیر تدبر قران

امین احسن اصلاحی نے تفسیر تدبر قرآن کا آغاز ۱۹۵۹ء میں کیا اور اس کی پہلی جلد ۱۹۵۶ء میں مکمل ہوئی۔نوجلدوں پر مشتمل یہ ضخیم تفسیر اگست۱۹۸۰ء میں پایہ تکمیل تک پہنچی۔ [[1]]

وہ تدبر قرآن کے مقدےمیں تفسیر لکھنے کے مقاصد بیان کرتے ہوئے تحریر کرتے ہیں:

"اس کتاب کو لکھنے سے میرےپیش نظر قرآن کریم کی ایسی تفسیر لکھنا ہے جس میں میری دلی آرزو اور پوری کوشش اس امر کے لئے ہے کہ میں ہر قسم کے بیرونی لوث اور لگاؤ کے تعصب و تخریب سے آزاد اور پاک ہوکر آیت کا وہ مطلب سمجھاؤں جو فی الواقع اور فی الحقیقت اس آیت سے نکلتاہے اس مقصد کے تقاضے سے قدرتی طور پر میں نے اس میں فہم قرآن کے ان وسائل و ذرائع کو اہمیت دی جو خود قرآن کے اندر موجود ہیں"۔[[2]]

امین احسن اصلاحی نےتفسیر تدبر قرآن کے تحریر کرنے میں اپنے استاد حمیدالدین فراہی کے اصول تفسیر و تدبر و تفکر کو بھی سامنے رکھا اور اپنی اس تفسیر کو انہوں نے ایک صدی کے تفکر و تدبر کا نتیجہ قرار دیاہے۔

تفسیر کے مقدمے میں تحریر کرتے ہیں:

"تفسیر تدبر قرآن پر میں نے اپنی زندگی کے پورے ۵۵ سال صرف کیے ہیں جس میں ۲۳ سال صرف کتاب کی تحریر و تسوید کی نذر ہوئے ۔ اگر اس کے ساتھ وہ مدت بھی ملا دی جائے جو استادامام ؒ نے قرآن کے غور و تدبر پر صرف کی ہے اور جس کو میں نے اس کتاب میں سمونے کی کوشش کی ہے تو کم و بیش ایک صدی کا قرآنی فکر ہے جو آپ کے سامنے تفسیر تدبر قرآن کی صورت میں آیا ہے"۔[[3]]

...

مراعاة الفروق الفردية في التوجيهات النبويّة للصحابة رضي الله تعالى عنهم

The aim of this research paper is to identify the extent of advertency the Prophet (peace be on him) made to consider individual differences in educating the companions the teachings of Islam; inAvesting their potentials in serving the invitation unto Allah and spreading Islam on earth. This paper also aims to set apart Islamic perspective of individual differences from that of non-Islamic in terms of treatment and acknowledgement. A significant contribution of this paper is to illustrate the prophetical attention given to individual differences in crises management and utilizing it in rectifying modern Islamic path.

Characterization and Bio-Evaluation of Some Indigenous Legume Protein Isolates for Complementary Foods

In present investigation, extraction, characterization and bio-evaluation of protein isolates from different indigenous legumes i.e. chickpea, lentil, broad and kidney beans were carried out to develop complementary foods. In tested legumes, after inactivation of anti-nutritional factors, protein isolates were prepared through isoelectric precipitation method. The highest protein yield as 80.47±5.71% was estimated in lentil protein isolates (LPI) followed by 73.14±3.44% in chickpea protein isolates (CPI) and 67.58±3.70% in broad bean protein isolates (BPI) while the lowest yield 52.83±3.36% was in kidney bean protein isolates (KPI). Moreover, protein isolates were assessed for their functional properties like bulk density, oil & water absorption, emulsifying & foaming properties etc. Maximum bulk density was revealed in LPI followed by CPI, KPI and BPI. Likewise, higher water absorption capacity was recorded in CPI tracked by LPI and BPI whilst the lowest in KPI. Maximum foaming capacity (FC) was revealed in BPI followed by KPI and LPI, respectively and the minimum in CPI. Electrophorogram through SDS-PAGE showed that legume protein isolates had protein bands in the range of 4 to 70kDa. Amino acid quantification was also performed with reference to requisite profile for the pre-schoolers. Among the essential amino acids, higher lysine content (4.54±0.21g/100g) was found in KPI followed by CPI (3.70±0.09g/100g) and LPI (3.66±0.20g/100g) whilst BPI showed minimum values (3.51±0.21g/100g). Simultaneously, amino acid scores were also determined with values of 39.6, 40.0, 40.0 and 56.0 in CPI, LPI, BPI and KPI, respectively. Bio-evaluation of respective isolates was performed through growth study parameters. Among the resultant protein isolates, the highest values were observed in LPI followed by CPI and BPI while the lowest for KPI regarding protein efficiency ratio (PER), net protein (NPR) and relative net protein ratio (RNPR), respectively for the year 2009-10. Similarly, nitrogen balance study parameters showed the highest values for true digestibility (TD), biological value (BV) & net protein utilization (NPU) in LPI tracked by CPI and BPI whereas the lowest values for these traits were recorded in KPI. However, BV value was high in KPI as compared to BPI. Similar trend for growth and nitrogen balance studies was observed in the next year 2010- 11. On the basis of overall yield, functional properties and bio-evaluation, two best protein isolates namely LPI and CPI were selected along with control for complementary foods preparation. The prepared formulations based on LPI (C1) and CPI (C2) congregated the FAO criteria for supplementary infant foods. The developed weaning foods were analyzed for chemical composition, energy value, bulk density, reconstitution index, viscosity and amino acid profile. Additionally, gross calorific values were observed as 401.70±20.42, 401.15±20.50 and 410.16±20.90kcal/100g for C1, C2 and control complementary foods, respectively. The essential amino acids were found to be sufficient in lentil and chickpea protein supplemented weaning foods. In addition to amino acid quantification for infant formulations, amino acid scores were also estimated. In complementary foods, maximum calorific value was contributed by fat followed by protein. Formulations in current study are capable of delivering 120.22±6.80, 122.49±6.36 and 123.27±6.09kcal per single meal for C1, C2 and control, respectively. Hedonic response regarding various sensory attributes also showed acceptance towards developed complementary foods. The acceptability appraisal of prepared infant formulations was conducted through short term infant feeding trial with the help of nursing mothers. The acceptability remained as 61.40 to 65.00% at the initiation of study and reached to 80.80 to 83.20% at the end of trial. Correlation studies also showed strong association among various variables and refelect their positive and negative contributions. The upshots of this project indicated that indigenous legumes have potential to yield protein isolates with appreciable functional and nutritional quality for application in array of foods with special reference to complementary foods.