الباب الثالث: الشاعرة المعروفة بروين شاکر
بروین شاکر شاعرۃ أردیۃ معروفۃ، ولدت، وتعلمت في کراتشي، وھي أکبر شاعرات الباکستان، ولکن أصل أجدادھا من الھند، وسنتحدث في ھذا الباب عن ھذہِ الشاعرۃ المعروفۃ من حیث ولادتھا، نشأتھا، تعلیمھا، زواجھا، دواوینھا، عملھا الأدبي، أولادھا، أعمالھا غیر الأدبیۃ ثقافتھا، ثم وفاتھا، وأھم مؤلفاتھا الشعریۃ، وأهمية قصائدھا بین الشاعرات الأخریات باعتبارها من أعظم شاعرات الغزل الأردو الحر والحزین ومکانتھا بین الشعراء والشاعرات وفکرتھا عن العشق وأسلوبھا في الشعر۔
Syncretic and shared religious spaces have long been perceived as reflections of tolerance. This does not imply that tolerance is completely liberated from multiple clashing components and the coexistence of interfaith practices do not suggest that hostility is entirely missing. In recent times, a transformation is taking place at the shared space of the Jhule Lal by the dominant religious group. However, there remains an appearance of tolerance at the shared space of the Jhule Lal among believers of both Islam and Hinduism, which blinds the observer of the deep internal contestation and process of transformation between both Sindhi Hindus and Sindhi Muslims who revere the same saint of the Jhule Lal. A syncretic space does not simply absorb different religious groups, and by studying the practices, rituals and interactions of the custodians, visitors and devotees at the shrine, this paper aims to unearth the processes through which shrine is contested in multiple identities, discourse (written, textual, verbal) authority, and belief systems.
Drug development has multiple stages of drug designing and evaluation in pharmacological models for desired clinical outcomes. The unmet need to completely eradicate cancer and leishmaniasis drives researchers to continue the struggle for safer and effective medicines. Along these lines, a library of 78 organic synthetic compounds including organotin (IV) (39), indoline (15), hydrazide (4), diazole (2) and ferrocene (18) derivatives were studied against Leishmania and cancer using in vitro, in silico and in vivo models. Cytotoxicity against DU145, THP-1 and isolated lymphocytes was shown by 36 (> 70%), 21 (> 50-70%), and 18 (least IC50 2.23 μg/ml) organotins and 1 (75.72%), 4 (50.2-82.3%) and 2 (least IC50 13 μg/ml) indolines, respectively. Only 5 (50.08-81.7%) hydrazides/diazoles and 9 (least IC50 6.66 μg/ml) ferrocenes were cytotoxic to THP-1 cells and lymphocytes, respectively. A total of 38 (least MIC 0.0122 μg/disc) organotins, 1 (least MIC 3.125 μg/disc) indoline, 3 (least MIC 1.5625 μg/disc) diazole/hydrazides and 17 (least MIC 0.74 μg/disc) ferrocenes demonstrated protein kinase (PK) inhibition activity in Streptomyces 85E. Next, in silico analysis of selected 36 organotin (IV) compounds, comparatively more cytotoxic to cancer cells, showed that these were drug-like to mid structures, have low to high blood brain barrier penetration and human intestinal absorption (caco2 cell permeability 17.6-35.09 nm/sec) and were metabolized by phase I and phase II reactions. Organotins were also predicted to target multiple enzymes, transcription factors, receptors, transporters, ion channels and other proteins. Subsequently, in vitro cytotoxicity analysis in prostate cancer cell lines and fibroblasts provided least IC50 values of 0.17 μM (PC3M) and 1.67 μM (fibroblasts) for triphenyltin (IV); 0.63 μM (PC3M) and 0.12 μM (fibroblasts) for tributyltin (IV); 0.33 μM (PC3M) and 2.55 μM (fibroblasts) for dibutyltin (IV) and 6.06 μM (PC3M) and 4.29 μM (fibroblasts) for tribenzyltin (IV) compounds after 72 h of treatment. Eventually, in-depth study of two most active compounds namely dibutylstannanediyl (2Z,2’Z)-bis(4-(benzylamino)-4-oxobut-2-enoate (Ch-620) and triphenylstannyl 2-(benzylcarbamoyl) benzoate (Ch-319), showed that both compounds were more cytotoxic to prostate cancer and melanoma cells as compared to normal cells, restricted their colony forming capacity and migration, induced cell cycle arrest and caspase mediated apoptosis and disrupted associated regulatory proteins. Ch-620 resulted in phosphorylation of p38 MAPK and ERK1/2, upregulation of PPARα, decreased expression of SMAD4 and ITGB5 and reduced tumor proliferation as observed by proteomics, in vitro and in vivo xenograft studies. Treatment of cancer cells and transgenic Pten knockout mice with Ch-319 downregulated PI3K/Akt signaling associated with elevation of FOXO3a expression. In addition, Ch-319 decreased expression of epithelial-mesenchymal transition markers N-cadherin and Vimentin with concomitant increase in E-cadherin in in vitro. Immunohistochemical examination of tumor sections also depicted reduction of proliferation markers. Moreover, evaluation of 78 compounds against Leishmania tropica kwh showed that 37, 5 and 1 organotin, indoline and ferrocene compounds, respectively inhibited growth of promastigotes. The selected 43 compounds predominantly organotin (IV) derivatives, halted the growth of Leishmania promastigotes partially by producing reactive oxygen species. Antileishmanial activity was reduced by 4.1-6.9 and 1.4-7.96% in triphenyltin (IV), 3.3-14.22 and 6.3-11.2% in tribenzyltin (IV), 5.2-34.38 and 1.8-38.2% in tributyltin (IV) and 7.9-15.7 and 5.2-15.4% in dibutyltin (IV) compounds in the presence of sodium azide and mannitol, respectively. Indolines and ferrocenes demonstrated antileishmanial activity reduction maximally in the presence of mannitol by 5.3 and 6.22%, respectively. Considering all these results, it is proposed that Ch-319 and Ch-620 have potential to be developed as anticancer agents against prostate cancer. Furthermore, organotin (IV) compounds in particular are also potent antileishmanial agents and detailed analysis on their mechanism is recommended.