Pak-US Strategic Partnership in the War on Terror to Curb Militant Bloodbath

Pakistan’s involvement in the US war on terrorism was a tragic decision. No option was left for the ruling elite of Pakistan except to join the global war on terrorism and to take a U-turn from the support of Taliban’s regime in Afghanistan which was duly recognized by Pakistan’s government in 1996. It was expected by the policy-makers of the US that the alliance with Pakistan would provide extraordinary strength in combating the Al-Qaeda and other affiliated conglomerates in Afghanistan as well as in borderland area. However, after fifteen years of war, the alliance has enfeebled despite their mutual understanding regarding the objectives envisaged in the Strategic Partnership. The war on terrorism has now been escalated from Afghanistan to Pakistan and it has provided space to religious extremism, militancy, intolerance, ethnic division and sectarianism. There is no denial to the fact that religious extremism and terrorism are common threat and have damaged both the countries yet Pakistan has sacrificed more than the US in terms of human and material loss. Nevertheless, blame game and trust deficit is on the rise from both sides. This article focuses first on the joint ventures that the US and Pakistan mutually initiated to curb militant bloodbath in Afghanistan as well as in the border region. Secondly, it will explore factors responsible for increasing trust deficit between the partners. The study will not only provide deep understanding about the prevailing issues between Pakistan and the US but will also give true pictures to streamline the methodology for negotiating with each other in  future.

Evaluation of Biological Potential of Quercus Dilatata L. and Isolation of Active Compounds

Natural products have been the mainstay in treating debilitating and multipronged diseases since the dawn of medicine. The current study was designed to isolate and characterize biologically active lead compounds from an underexplored medicinal folklore Quercus dilatata L. Total 42 extracts from each of the aerial parts, nut shells and galls were prepared using sonication aided maceration as the extraction procedure. The extract library was subjected to a range of phytochemical and in vitro bioassays in order to identify most functional plant part and extraction solvent for preparative extraction. Phytochemical investigation comprised of standard colorimetric assays to determine phenolic and flavonoid contents while, RP-HPLC was carried out to establish polyphenolic profile. MTT assay was employed to determine leishmanicidic activity against Leishmania tropica whereas disc diffusion assay was performed to elucidate antibacterial, antifungal and protein kinase inhibitory spectrum. Starch-iodine chromogenic assay determined the α-amylase inhibitory potential while brine shrimp lethality. MTT and SRB assays were used to find cytotoxic potential of the subject plant. Among all extracts, maximum gallic acid equivalent phenolics and quercetin equivalent flavonoids were quantified in distilled water-acetone aerial parts extract (21.37±0.21 μg GAE/mg DW) and methanol-ethyl acetate galls extract (5.28±0.30 µg QE/mg DW) respectively. RP-HPLC revealed the presence of substantial amount of various phenolics (from 0.049±0.01 to 15.336±1.55 μg/mg extract) including pyrocatechol, gallic acid, catechin, chlorogenic acid, pcoumaric acid, ferulic acid and quercetin in aerial parts extracts. Maximum reducing power potential and total antioxidant capacity was recorded in methanol-ethyl acetate and distilled water extract of galls i.e. 50.76±1.0 and 48.57±1.1 µg AAE/mg DW respectively. Highest free radical scavenging efficiency was exhibited by methanolethyl acetate aerial parts extract (IC50 8.1±0.5 µg/ml). A noteworthy leishmanicidic potential (IC50 12.91 μg/ml) was exhibited by the ethyl acetate-acetone aerial parts extract whereas, maximum antibacterial activity against Staphylococcus aureus (MIC 12.5 µg/ml) was manifested by ethyl acetate aerial parts extract. Substantial protein kinase (PK) inhibition (28±0.35 mm of bald zone of inhibition) was exhibited by methanol extract of aerial parts. Ethyl acetate galls extract showed 52.5±2.75% inhibition of α-amylase activity. Chloroform-methanol aerial parts extract showed maximum cytotoxicity against brine shrimp larvae with IC50 value of 34.54 μg/ml while significant cytotoxicity against THP-1 and Hep G2 cells was shown by nhexane and ethanol aerial part extracts with inhibition of 46.73±0.85% and 82.52±1.45% respectively. Keeping in view the abovementioned results, aerial part was selected for preparative extraction with chloroform-methanol (1:1) as its extraction solvent. Preparative extract (QDC) was partitioned through solvent-solvent extraction and the resulting fractions (QDN, QDE, QDB, QDA) were biologically evaluated to prospect fraction hits for lead development. Maximum α-amylase and leishmanisidic activities were revealed by QDE i.e. 52.44±3.21% and 83.0±2.35% respectively. QDN was found to possess maximum cytotoxic activities against MCF-7 (50.7±3.24%), MDA-MB 231 (40.0±2.31%) and Hep G2 (46.3±1.54%) cell lines whereas, QDB had the highest free radical scavenging potential (IC50 17.55 µg/ml). Maximum inhibition of TNF-α activated NF-κB (67.90±3.27%) and NO production in LPS-activated murine macrophage RAW 264.7 cells (84.90±2.01%) was shown by QDE. QDN was found to be most active in aromatase inhibition assay (61.11±3.76%) and quinone reductase 1 induction assay (induction ratio=7). On the basis of aforementioned results, QDN was selected as hit fraction for leads isolation and was subjected to normal phase gravity and medium pressure liquid column chromatography to yield 4 compounds (QDN2, QDN4, QDN5 and QDN9). Biological evaluation of compounds suggested that maximum α-amylase, PK and antipromastigote activities were presented in case of QDN5 i.e. 19.5±2.30%, 6.5±0.10 mm ZOI and 48.0±2.30% respectively. Likewise, QDN5 showed maximum inhibition against MCF-7 (54.2±1.54%), MDA-MB-231 (43.7±2.40%) and Hep G2 (45.2±3.50%) cancer cell lines. QDN5 showed maximum cancer chemopreventive proficiency via inhibition of NF-κB (65.42±9.70%) and NO production (78.0±1.10%) assays followed by QDN2 with 63.0±5.30 and 65.1±3.20% inhibition of NO production and NF-κB respectively. X-ray crystallographic and spectroscopic studies characterized the structure of QDN2, QDN4 QDN5 and QDN9 as friedelin, 3epifriedelinol, glutinol and taraxerol respectively. In principle, the results of the current study endorses Q. dilatata as a substantial source of bioactive lead compounds.