The research work presented in this thesis deals with the chemotherapeutic (antiproliferative) and cancer chemopreventive activity of a medicinal plant from Pakistan; Fagonia cretica L. (Zygophyllaceae), based on the traditional claims for its use in folklore medicine in the treatment of different types of cancers and inflammatory conditions. Through a bioactivity guided fractionation approach, the crude extract (FCC), resultant two organic fractions i.e. n-hexane and ethyl acetate (FCN and FCE, respectively) and an aqueous fraction (FCA) were tested for their anti-proliferative and cancer chemopreventive activity by employing different standard bioassays. In this investigation, it was demonstrated that F. cretica extract and fractions have antiproliferative activity towards human breast cancer cells and it can exert cancer chemopreventive effects via NFκB inhibition, iNOS inhibition and QR induction. The most potent fraction was ethyl acetate (FCE) fraction followed by n-hexane fraction (FCN) in this study. Six compounds in total (FCEE1, FCEK2, FCEK3, FCEM4, FCEN5 and FCNC6) were isolated from potent fractions of this medicinal plant using repeated flash column chromatography. Structural elucidation was carried out through a series of spectroscopic experiments (1-D and 2-D NMR). Among these six compounds, one compound (FCEE1) is a triterpene acid, two compounds (FCEK2 and FCEN5) belong to the triterpene saponin class, one compound FCEM4 belongs to steroidal saponin class and two compounds (FCEK3 and FCNC6) belong to phytosterol class of chemical compounds. All the isolated compounds have known structures but these are isolated from this plant species for the first time. All the compounds were evaluated for their anti-proliferative activity against breast cancer cell lines (MCF-7 and MDAMB- 231), non-tumorigenic breast epithelial cell line (MCF-10A) and cervical cancer cell line (HeLa) by using sulforhodamine B (SRB) assay. Cancer chemopreventive potential of compounds was also estimated in different bioassays i.e. TNF-α activated nuclear factor-kappa B (NFκB) assay, inhibition of lipopolysaccharide (LPS)- activated nitric oxide (NO) production in murine macrophage RAW 264.7 cells (iNOS) assay, Aromatase inhibition assay and Quinone reductase 1 (QR1) induction assay. A serial dilution of eight concentrations (0.39, 0.78, 1.56, 3.12, 6.25, 12.5, 25, 50 μM) for each compound was tested. xix Purified compounds were able to reduce cell viability significantly in two phenotypically different breast cancer cell lines (MCF-7 and MDA-MB-231). This activity was markedly reduced in normal mammary epithelial cells (MCF-10A) thus indicating selective toxicity between malignant and normal cells. Among compounds, in NFκB inhibition assay, FCEE1 showed maximum inhibition (IC50, 5.26 μM) while in iNOS inhibition assay, FCEM4 demonstrated best activity (IC50, 0.38 μM). For QR1 induction, FCNC6 was proved to be best compound (CD, 17.07 μM). None of the compounds were active in inhibiting aromatase enzyme. Compound FCEE1, a triterpene acid was the most potent compound in this study followed by FCEM4. Elucidation and characterization of the cytotoxic mechanism was undertaken by cell cycle status, apoptosis and expression of transcription factors and their targets i.e. p53, p21, Bax, γ-H2AX and FOXO3a. Pure compound treatment was able to induce a time and dose-dependent decrease on cell viability of two phenotypically different breast cancer cell lines (MCF-7 and MDA-MB-231), while demonstrating a markedly decreased cytotoxic effect of triterpene acid (FCEE1) and derivatives i.e. triterpene saponins (FCEK2 and FCEN5) on normal mammary epithelial cells (MCF-10A). Cell cycle arrest (expressed by sub-G1 peak) and apoptosis was induced in both MCF-7 and MDA-MB-231 cells. Overall all the purified compounds were more effective against estrogen receptor negative breast cancer (MDA-MB-231) cells. Loss of breast cancer cell viability is associated with induction of DNA double strand breaks which were detected in both cell lines by pure compounds’ treatment. In MCF-7 cells, expression of p53 by FCEE1 seems to induce upregulation of the CDK inhibitor, p21, and pro-apoptotic Bax. In current study, pure compounds’ treatment to human breast cancer cells induced double strand breaks to DNA associated with activation of DNA repair protein γ-H2AX. Compound FCEM4 treatment was able to induce FOXO3a expression in both MCF-7 and MDA-MB-231 cells. This suggests that activation of FOXO3a in the absence of functional p53 plays a vital role in induction of cytotoxicity. The results of this study suggest that FCEE1 is cytotoxic through p53 dependent as well as independent pathways while FCEM4 uses only p53 independent pathway.
The Immensely Merciful to all, The Infinitely Compassionate to everyone.
73:01 a. O Al-Muzzammil! b. O The Enwrapped - Muhammad!
73:02 a. Stay up in worshipful meditation through the late nighttime, b. except for a little while,
73:03 a. - half of it, b. or a little less than that, up to a third,
73:04 a. or even a little more, up to two-thirds. b. And recite The Qur’an in a slow and distinct recitation.
73:05 a. Indeed, soon WE are going to entrust a heavy burden on you - awe-inspiring – b. - The Qur’an.
73:06 a. Surely, the getting up by late nighttime for worshipful meditation is very demanding, b. yet very rewarding for subduing one’s soul, and c. making recitation more effective -
73:07 a. - for, indeed, during the daytime you have extended schedule of engagements.
73:08 a. But recite The Sacred Name of your Rabb - The Lord, b. and devote yourself to HIM exclusively in wholesome devotion.
73:09 a. HE is Rabb - The Lord of the east and the west. b. There is no worshipful entity except HIM. c. So take HIM as your Guardian and Guarantor.
688 Surah 73 * Al-Muzzammil
73:10 a. And bear with patience over what they allege against you and your Divine Mission, b. and keep a distance from them in a gracious manner.
73:11 a. And leave it to ME to deal with the beliers and deniers who have been given the good...
The aim of Hijrah is not to run away from problem that occurred in the process of giving da'wah, but rather to establish the resolve in solving the problem. Hijrah as a movement carried out by the Prophet Muhammad (PBUH) and his companions from Makkah to Madinah, aimed to keep, maintain and uphold the message of Allah, in the form of Islamic aqeedah and shari’a, in order to achieve the mercy and pleasure of Allah SWT. This move, as we can see in the seerah, later brought a great impact to the success of the Islamic da’wah which was increasingly evolving. Hence the fundamental problem that has led to the migration has been solved. In fact, the Hijrah brought a significant impact not just to the Islamic world but also to world civilisation. The story and background of the migration of Rasulullah (PBUH) from Makkah to Madinah is touched in this writing to show that there were a lot of lessons and guidance that can be inferred. It did not merely signify a final destination for Makkah Muslims, but was also the beginning of a continuous effort to establish a strong and resilient ummah. The event of Hijrah in fact had changed the world after that forever. It highlighted the perseverance of the Rasulullah (PBUH) and the early Muslims through the difficult times. Hijrah demonstrates that for people with faith, there is hope for ease after difficulties. There was also a great unity model among Muslims of different backgrounds. The Hijrah had also marked the beginning of the Islamic State under the leadership of Rasulullah (PBUH) which then became a reference for all state governance everywhere in the future
The present study was conducted in the experimental field of Nuclear Institute for Agriculture and Biology (NIAB) and the Department of Plant Breeding and Genetics University of Agriculture, Faisalabad, Pakistan. Seventy two mung × mash inter-specific recombinants were evaluated for various yield traits and for resistance against mungbean yellow mosaic disease (MYMD). Thirty six promising recombinants were selected on the basis of desirability index and these were also confirmed at molecular level. Sixteen male specific recombinant genotypes were selected and evaluated for quality traits. On the basis of overall performance in different experiments, five recombinant genotypes were finally selected and 5 × 5 diallel crosses were attempted. Parents and F1 hybrids were evaluated thereafter for the study of inheritance patterns of different traits. The magnitude of genotypic and phenotypic coefficients of variability ranged from (2.73% to 28.97%) and (3.46% to 31.95%) respectively. Moderate to high Broad sense heritability value was observed, it ranged from (34% to 99%) with greatest value (h2 = 99%) for 100-seed weight. Low to medium genetic advance was observed with highest value of (10.591) for plant height. High heritability values coupled with high genetic advance were observed for clusters per plant, pods per plant, and seed yield per plant indicating the presence of additive gene action. Pods per plant had higher value of genetic advance (46.12%) followed by number of clusters per plant (38.06%) and seed yield (30.82%). Pods per plant had maximum positive and significant genotypic (rg = 0.903) and phenotypic (0.860) correlations with clusters per plant. Days to flower, plant height, pods per plant and cluster per plant appeared to be the most prominent characters as they had highly significant phenotypic and genotypic correlations with seed yield. Pods per plant were also appeared to be the most important secondary trait suggesting greatest improvement in mean seed yield (31%) followed by plant height (24%) and clusters per plant (5%). Selection for number of pods per plant showed promise for greatest improvement in seed yield that was 54% of the improvement possible through direct selection for seed yield followed by clusters per plant and plant height. The aggregate index score of desirability ranged from 4 to 13 and the genotype, MMH 11534 was at the top followed by MMH 53105. Thirty six promising genotypes having high yield potential and disease resistance were selected. Universal Rice Primer (URP) and RAPD markers confirmed 16 recombinants which were also reconfirmed by SSR markers. The primer, SSR VR0111 confirmed maximum number of genotypes as male specific recombinants. Sixteen recombinant genotypes were selected on the basis of their male parent specific banding pattern and diversified PCR. The recombinant genotype, MMH 4224 got improved with respect to all essential amino acid, while MMH 1115, MMH 2112, MMH 7124 and MMH 4255 also exhibited significant improvement. On the basis of overall performance in different experiments, seven recombinant genotypes, viz; MMH 1115, MMH 4224, MMH 4255, MMH 7124, MMH 2112, MMH 4295 and MMH 2225 were observed to be more prominent and hence these were selected as elite lines. These lines were true inter - specific recombinants and possessed excellent nutritional quality coupled with high yield potential and disease resistance. Considering the worth of these elite lines, it was suggested that these may be used for further evaluation in different trials for the release of new commercial cultivars. All the traits studied were under the control of dominant gene action except 100-seed weight. Heterosis breeding was recommended for these traits and recombination breeding was suggested for the improvement of 100-seed weight. The hybrids having positive and significant SCA effects were recommended for heterosis breeding and the hybrids whose parents have significant GCA effects and non- significant SCA effects were recommended for further progeny testing.