سرکاری عہدید اران کی تقررری، نگرانی اور محاسبہ عہد خلفائے راشدین کے تناظر میں

The period of the rightly guided caliphate is the best role model after the time of the Prophet of Islām, Muḥammad (S. A. W). The rightly guided caliphs crafted the best honest governing mechanism. They understood their commitment with their Lord, Allāh, and the people. They took up the responsibility for providing for the basic needs of their people, like food, shelter, education, peace, stipends of children, married and unmarried persons, social security and justice, etc. The caliphs would appoint the tax collectors, governors and other government officials on the basis of merit: their honesty, qualifications, experience, physical fitness, etc. Further, they, at the time of their appointment, would advise their officials in an open gathering to better use their abilities, resources and powers for the welfare of the masses. Moreover, the government prepared a list of the assets and the properties of their government officials at the time of their appointments. It they found, later, significant increase in the assets, it was investigated and asked for an explanation. If the officials failed to justify the means of the increase in their assets, the additional assets and properties were confiscated by government. In this research study, the author highlights the measures adopted by the rightly guided Caliphs to ensure honest conduct of affairs by the appointed officials of the government.

Phytochemical and Pharmacological Evaluation of Fraxinus Xanthoxyloides Wall. Ex Dc

Secondary metabolites present in medicinal plants are a golden hallmark to combat challenges of the modern world e.g. cancer, infections, diabetes, neurodegenerative and cardiovascular diseases etc. Traditionally different parts of Fraxinus xanthoxyloides Wall. ex DC (Oleaceae) are used for the treatment of pneumonia, pain, jaundice, bone fracture, malaria and also in the treatment of internal wounds. In response to these conditions of infection, injury and trauma the internal protective and essential mechanisms of the organism activated. But if inflammation sustain for longer times it leads to inflammatory disorders. The present investigation was carried out for phytochemical and pharmacological evaluation of F. xanthoxyloides Wall. ex DC leave extract/fractions for the first time considering it as a potential source of inflammation and cancer related drugs. Powder of F. xanthoxyloides leaves was extracted with methanol to obtain the crude extract (FXM) and the resultant was fractionated with solvents in escalating polarity; n-hexane (FXH), chloroform (FXC), ethyl acetate (FXE), n-butanol (FXB) and the residual aqueous (FXA) fraction. GC-MS studies of crude methanol extract revealed the presence of various classes of which terpenoids (26.61%), lactam (16.47%), esters (15.81%), phenols (8.37%), and steroid (6.91%) constituted the major categories. Qualitative investigation of crude methanol extract/fractions of F. xanthoxyloides expressed the presence of terpenoids, coumarins, flavonoids, tannins and quinones while the saponins, anthraquinones and alkaloids were not detected. Quantitative study showed the maximum concentration of terpenoids in chloroform fraction while the highest quantity of coumarins, flavonoids, phenolics and tannins was recorded in ethyl acetate fraction. Presence of terpenoids was not detected in n-butanol and aqueous fraction. Presence of different concentrations of rutin and caffeic acid were observed in HPLC profile of methanol extract/fractions. As far as antioxidant potential is concerned in case of DPPH and hydroxyl radical scavenging assay the best activity was shown by n-butanol fraction. Ethyl acetate fraction has also shown most potent total antioxidant and ferrous ion chelating activity. Methanol extract and chloroform fraction were best in their ferric ion reducing power and nitric oxide scavenging activity respectively. During analgesic studies the chloroform fraction significantly (p < 0.001) increased the percent latency time (76.13±4.49%) in hot plate test after 120 min and decreased (p < 0.001) the count of writhes (77.23±5.64%) as compared to other extracts. The in vitro anti-inflammatory studies indicated that chloroform fraction at 15 μg/ml more effectively inhibited the TNF-α induced synthesis of NFkB (85.0±8.12%, IC50 =5.98 μg/ml) and LPS-instigated nitric oxide (78.23±2.39%, IC50=6.59 μg/ml) synthesis. Although all the extract/fractions showed a dose dependent increase in inhibition of edema formation however, chloroform fraction (4th hour=77.64±3.04%) at 200 mg/kg body weight exhibited relatively higher (p < 0.001) anti-inflammatory activity in carrageenan-induced paw edema in rat. Moreover, chloroform fraction had the ability to decrease (p < 0.001) the influx of leukocytes and the concentration of inflammatory mediators; TNF-α, NO, IL-6 and PGE2 in air pouch exudate. Chloroform fraction of F. xanthoxyloides exhibited the highest anti-leishmanial activity with LD50 of 15.23±0.9 μg/ml to that of glucantime (LD50 = 5.6±2.4 μg/ml) a reference drug. In case of insecticidal studies again chloroform fraction showed the best activity, (LD50 = 28.15±1.8 μg/ml). Correlation analysis exhibited a strong association (p < 0.05) between the terpenoids and the anti-leishmanial activity and a second but non-significant association (p > 0.05) with the insecticidal activity. After in vitro cancer chemopreventive and cytotoxic studies we concluded that chloroform fraction showed maximum aromatase inhibition i.e. 72.2% at 20 μg/ml with IC50 = 13.2 μg/ml. Chloroform fraction also depicted the most potent cytotoxic activity against 1c1c7, MYCN-2 and MCF-7 with survival rate less than 50% i.e. 4.1%, 10.8%, 23.7% respectively and also strong anticoagulant activity. During in vivo studies we observed that in CCl4 treated rats the level of alanine transaminase, aspartate transaminase, total bilirubin, blood urea nitrogen, Creatine kinase, Creatin kinase-MB and globulin was significantly increased while the albumin concentration in serum was decreased as compared to control group. The level of tissue antioxidant enzymes, catalase, peroxidase, superoxide dismutase, glutathione- S-transferase and glutathione reductase was significantly decreased against the control group. Further, significant decrease in GSH while increase in lipid peroxides, H2O2, DNA damages and comet length was induced with CCl4 in different tissues of rat. In contrast, co-administration of FXM restored the biochemical and histological status of the liver, kidney lung and heart tissues. Following bioassay-guided fractionation by column chromatography of F. xanthoxyloides extract/fractions for reduction of DPPH and cytotoxicity against brine shrimps; purified compounds obtained were characterized by 1H, 13C, COSY, HSQC, HMBC and NOESY. Isolated compounds were characterized as Plactranthoic acid, Nummularic acid (NA) with cytotoxic properties and Rutin which showed good antioxidant potential. Antiprolifirative effect of NA was validated through BrdU assay on DU145 and C4-2 prostate cancer cell lines. IC50 values at 24 and 48 hour time period for DU145 were 68.81 μM and 35.93 μM and for C4-2 were 38.98 μM and 26 μM respectively. Clonogenic assays confirmed these findings, where selected concentrations 20 μM and 40 μM showed a dose-dependent inhibition of colony formation relative to untreated controls. NA was not able to significantly halt the migration of DU145 cells. But there was a significant dose dependent decrease (p < 0.001) in the migration of C4-2 cells when compared to untreated controls this was also confirmed by wound scratch assay. We observed the significant (p < 0.001) elevated levels of cellular ADP/ATP in dose and time dependent manner in both the cell lines after NA treatment. High levels of lactate depicting the glycolysis rate were produced in NA as compared to control and we also concluded that NA causes a significant reversible decrease in oxygen consumption rate at 20 μM concentration thus inhibiting mitochondrial activity and reduce mitochondrial ATP production. In both DU145 and C4-2 cells there was a dose-dependent increase (19% and 32.8%) and (8.72% and 49.5%) respectively in apoptotic cell population in NA treated cells as compared to untreated controls. In metformin treated cells there was also a prominent increase in apoptosis. Western blot analysis of whole cell lysates showed an increase in phosphorylation of AMPKα, this was associated with increase in phosphorylation of acetyl CoA carboxylase. Decrease in levels of pS6 thus decrease in cell cycle progression after NA treatment was also observed. Lipid (oil red O) staining showed that there was a dose dependent decrease in number of oil droplets in NA treated prostate cancer cells. We also concluded that NA was able to affect the glycolysis by depleting the level of intermediates and tricarboxylic acid cycle by increasing the level of its intermediates.