The British Colonial Encounter with the Pukhtuns: An Appraisal of Faqir Ippi’s Struggle against the British Raj (1936-1947)

The North-West Frontier region of the British Empire in India during the Great Game was part of the ‘Ring Fence Strategy’, framed by the Raj against its adversaries and rivals in Central and South Asia. To protect her ‘Jewel in the Crown’- India, the British Raj made several moves in the strategically placed Pukhtun1 land. The Pukhtun populace, adherent to their centuries old code of conduct, Puḳhtūnwali, consistently resisted the British encroachment of their territory. Mirza Ali Khan, popularly known as Faqir Ippi, was one of the many freedom fighters who challenged the imperialist power in this region. Taking notice of Islam Bibi’s case, a Hindu Convert, Faqir Ippi mobilized the Pukhtuns of Waziristan in defying and fighting the British. He was a serious contestant to the British authority with his well-known fighting skills, effective planning and guerilla tactics in one of the most difficult terrains. The entire Tribal Belt, especially Waziristan, proved to be a ‘turbulent frontier’ for nearly eleven years, i.e. 1936-1947. This insurgency started bringing bad name to the crown and encouraging others to rise against the British. To contain and end Faqir Ippi’s resistance, Governor George Cunningham hired the locals to instigate and bribe his followers to rise and fight against him. The aim of this paper is a critical evaluation of the British strategy in this region and an appraisal of Faqir Ippi’s response and assessment of how successful he was in invigorating Pukhtun resistance to defend their motherland, using both colonial and local sources.

Role of Hepatitis-C Virus Non Structural Proteins in the Induction of Insulin Resistance

Hepatitis C Virus is one of the lethal infections prevailing throughout the world. There are approximately 8.5 million individuals that are infected with this deadly virus in Pakistan. Hepatitis C virus is responsible for acute and chronic viral infection. Chronic hepatitis C virus infection causes persistent inflammation that leads to liver fibrosis, insulin resistance/type 2 diabetes mellitus, liver cirrhosis and finally hepatocellular carcinoma (HCC). There is strong evidence that insulin resistance has a major role in metabolic syndrome, and is a risk factor for increased liver fibrosis in patients with chronic hepatitis C virus infection. However the underlying mechanism of insulin resistance in chronic hepatitis C virus infection is not well known. The present study describes the molecular mechanism of HCV nonstructural protein 5A (NS5A) induced insulin resistance. In this study, we elucidated the molecular mechanism involved in HCV nonstructural protein 5A (NS5A) induced insulin resistance. In the present study human hepatoma cell line Huh 7.5 was transfected with HCV NS5A (Huh 7.5/NS5A) as well as HCV (JFH-1) genomic RNA was transfected into Huh 7.5 cell line (Huh 7.5/HCV) to discern the effect of HCV and HCV NS5A protein upon modulation of insulin signaling pathway. Here, we demonstrated that an increased serine phosphorylation of insulin receptor substrate-1 (pSer307) and Akt (pSer473) in Huh 7.5/HCV infected cells compared to mock infected cells. Interestingly, the Huh 7.5/NS5A cell line showed an increased serine phosphorylation of pSer307 IRS-1 and pSer473 Akt, compared to the mock transfected cells, which is a critical step defining the downstream insulin signaling pathway. Glycogen synthase kinase-3 (GSK-3), the downstream target of Akt, is known to favor gluconeogenesis. Our results revealed a diminished phosphorylation level of GSK-3 in Huh 7.5/NS5A expressing hepatoma cells compared to the mock transfected cells, thereby favoring gluconeogenesis. Forkhead transcription factor (FOX-01) which is another important downstream target of insulin signaling pathway, was shown to undergo reduced phosphorylation level (pSer 256) in Huh 7.5/NS5A expressing hepatoma cells compared to the mock transfected cells. Collectively, these findings suggest a molecular mechanism by which ectopic expression of Huh 7.5/NS5A modulates the insulin signaling pathway at post translational level. There are several gluconeogenic and lipogenic markers lying downstream to the insulin mediated signaling molecules (pSer307IRS-1, pSer473Akt, pSer256Fox-01 and GSK-3). In this study, we observed that Huh 7.5/HCV infected hepatoma cells as well as ectopic expression of Huh 7.5/NS5A leads to enhanced gluconeogenesis through up regulating the mRNA levels of gluconeogenic genes i.e. Phosphoenol pyruvate carboxy kinase (PEPCK) and Glucose-6-phosphatase (G6P) compared to their controls. In the similar way, an elevated mRNA level of Diacyl glycerol acyltransferase (DGAT), a key lipogenic marker, was also observed in Huh 7.5/HCV infected as well as Huh 7.5/NS5A expressing hepatoma cells compared to their controls. Based on these results, we deduce a mechanism through which HCV NS5A is potentially capable of modulating the entire insulin signaling pathway at mRNA and post-translational level thereby paving a way towards insulin resistance, a metabolic syndrome.