Muhammad Imran Arshad

French Institute of Health and Medical Research, Lutetia Parisorum, Île-de-France, France

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Publications (15)72.54 Total impact

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    ABSTRACT: IL-33 is crucially involved in liver pathology and drives hepatoprotective functions. However, the regulation of IL-33 by cytokines of the Interleukin-6 family, including Oncostatin M (OSM) and IL-6, is not well studied. The aim of the present study was to determine whether OSM mediates regulation of IL-33 expression in liver cells. Intramuscular administration in mice of an adenovirus encoding OSM (AdOSM) leads to increase in expression of OSM in muscles, liver and serum of AdOSM infected mice compared to control mice. The increase of circulating OSM markedly regulated mRNA of genes associated with blood vessel biology, chemotaxis, cellular death, induction of cell adhesion molecules and the alarmin cytokine IL-33 in liver. Steady state IL-33 mRNA was up-regulated by OSM at an early phase (8h) following AdOSM infection. At the protein level, the expression of IL-33 was significantly induced in liver endothelial cells (LSEC and VEC) with a peak at 8 days of post AdOSM-infection in mice. In addition, we found OSM-stimulated human microvascular endothelial HMEC-1 cells and human liver sinusoidal endothelial cells/TRP3 cells showed a significant increase in expression of IL-33 mRNA in a dose dependent manner in cell culture. The OSM mediated over-expression of IL-33 was associated with the activation/enrichment of CD4(+)ST2(+) cells in liver of AdOSM infected mice compared to AdGFP-treated control mice. In summary, these data suggest that the cytokine OSM regulates the IL-33 expression in liver endothelial cells in vivo and in HMEC-1/TRP3 cells in vitro and may specifically expands the target CD4(+)ST2(+) cells in liver. Copyright © 2014, American Journal of Physiology- Gastrointestinal and Liver Physiology.
    AJP Gastrointestinal and Liver Physiology 08/2015; DOI:10.1152/ajpgi.00398.2014 · 3.74 Impact Factor
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    ABSTRACT: Interleukin-27 (IL-27) belongs to the IL-6/IL-12 family of cytokines, associated with different inflammatory diseases and orchestrates its biological activity via common heterodimeric receptor composed of WSX-1 (IL-27Rα) and gp130. The present study was aimed to investigate the regulation of CXCL9, CXCL10, and CXCL11 chemokines in hepatic cells (human LX-2 cell line derived from normal human stellate cells (HSC), primary human hepatocytes, HSC, and HepG2 cells) and concanavalin A (ConA)-induced liver inflammation. We demonstrated that IL-27, but not IL-6, induced/up-regulated CXCR3 ligand genes (CXCL9, CXCL10, and CXCL11; out of 26 selected genes) in a STAT1-dependent manner in hepatic cells in vitro both at transcript and protein levels. In ConA-induced T cell-mediated hepatic model, we showed that soluble IL-27/IFNγ was elevated following ConA hepatitis in association with increased CXCL9, CXCL10, and CXCL11 expression in the liver. The exogenous IL-27 administration induced CXCR3 ligands in mouse liver at 4 h with any significant effect on recruitment of CXCR3(+) immune cells in the liver. The neutralization of IL-27 during ConA hepatitis differentially modulated (transcript vs protein expression) CXCR3 ligands and IFNγ during ConA-induced hepatitis with down-regulated expression of CXCL9 and CXCL10 at transcript level. The IFNγ, complementary regulated the expression of CXCR3 ligands as their up-regulation during ConA hepatitis, was abolished in IFNγ KO mice. In summary, IL-27 up-regulated the CXCL9, CXCL10, and CXCL11 chemokine expression in hepatic cells. IL-27 regulated CXCR3 ligand expression in IFNγ-dependent manner during acute hepatitis suggesting a complementary role of IL-27 and IFNγ to moderate liver inflammation via regulation of CXCR3 ligands. IL-27 up-regulated CXCR3 ligand expression in human hepatic cells in vitro. IL-27 up-regulated CXCR3 ligand expression and secretion in ConA hepatitis in vivo. CXCR3 ligand expression was down-regulated by blocking IL-27 or IFNγ deficiency. IL-27 modulated liver injury by regulation of CXCR3 ligands in IFNγ-dependent manner.
    Journal of Molecular Medicine 07/2015; DOI:10.1007/s00109-015-1319-6 · 4.74 Impact Factor
  • Journal of Hepatology 04/2015; 62:S487-S488. DOI:10.1016/S0168-8278(15)30674-7 · 10.40 Impact Factor
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    ABSTRACT: Interleukin-33 (IL-33), a cytokine belonging to the IL-1 family, is crucially involved in inflammatory pathologies including liver injury and linked to various modes of cell death. However, a link between IL-33 and necroptosis or programmed necrosis in liver pathology remains elusive. We aimed to investigate the regulation of IL-33 during necroptosis-associated liver injury. The possible regulation of IL-33 during liver injury by receptor-interacting protein kinase 1 (RIPK1) and poly(ADP-ribose) polymerase 1 (PARP-1) was investigated in mice in vivo and in hepatic stellate cells in vitro. The liver immunohistopathology, flow cytometry, serum transaminase measurement, ELISA, and qPCR-based cytokine measurement were carried out. By using a chemical approach, we showed that pretreatment of mice with Necrostatin-1 (Nec-1) (inhibitor of RIPK1) and/or PJ34 (inhibitor of PARP-1) significantly protected mice against concanavalin A (ConA) liver injury (aspartate amino-transferase (AST)/alanine amino-transferase (ALT)) associated with down-regulated hepatocyte-specific IL-33 expression. In contrast, the expression level of most systemic cytokines (except for IL-6) or activation of liver immune cells was not altered by chemical inhibitors rather an increased infiltration of neutrophils in the liver. During polyinosine-polycytidylic acid (Poly(I:C))-induced acute hepatitis, liver injury and hepatocyte-specific IL-33 expression was also inhibited by PJ34 without any protective effect of PJ34 in CCl4-induced liver injury. Moreover, PJ34 down-regulated the protein expression of IL-33 in activated hepatic stellate cells by cocktail of cytokines or staurosporine in vitro. In conclusion, we evidenced that the Nec-1/PJ34 is a potent inhibitor of liver injury and Nec-1/PJ34 down-regulated hepatocyte-specific IL-33 expression in the liver in vivo or in hepatic stellate cells in vitro, suggesting IL-33 as a possible readout of necroptosis-involved liver pathologies. Necroptosis inhibitors can protect mice against liver injury induced by ConA or Poly(I:C). IL-33 expression in liver injury in vivo is inhibited by PJ34. IL-33 expression in hepatic stellate cells in vitro is inhibited by PJ34. Hepatocyte-specific IL-33 expression is down-regulated by Nec-1/PJ34 during hepatitis. IL-33 is a new marker of necroptosis-associated liver injuries.
    Journal of Molecular Medicine 03/2015; 93(8). DOI:10.1007/s00109-015-1270-6 · 4.74 Impact Factor
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    ABSTRACT: The interleukin-33 (IL-33) has now emerged as a cytokine with diverse and pleiotropic functions in various infectious and inflammatory diseases. IL-33 is expressed by epithelial, endothelial cells, fibroblasts and hepatocytes. The target cells of IL-33 are the Th2 cells, basophils, dendritic cells, mast cells, macrophages, NKT cells and newly discovered nuocytes/natural helper cells/innate lymphoid cells bearing ST2 receptor. IL-33 has dual function both as a traditional cytokine and as a nuclear factor regulating gene transcription. IL-33 functions as an 'alarmin' released following cell death, as a biomarker, vaccine adjuvant, having pro-inflammatory and protective effects during various infections. The exacerbated or protective role of IL-33/ST2 axis during different infections is dependent upon the organ involved, type of infectious agent, acute or chronic infection, invasiveness of infectious agent, host immune compartment, cellular and cytokine microenvironment. In this review, we focus on the recent advances in understanding of the role of IL-33/ST2 axis in various viral, bacterial, fungal, helminth and protozoal infectious diseases in animal model and human patient studies. The functional role of IL-33 and ST2 during experimentally induced infections has been summarized by accumulating the data of IL-33 and ST2 deficient mice or exogenously administered IL-33. In summary exploring the crucial and diverse role of IL-33/ST2 axis during infections may help for therapeutic intervention across a wide range of infectious diseases. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Infection and Immunity 02/2015; 83(5). DOI:10.1128/IAI.02908-14 · 4.16 Impact Factor
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    ABSTRACT: Phytotoxic ability of aqueous extracts of new and old mango leaves at different concentrations i.e., 2.5, 5.0, 7.5 and 10% against canary grass and wheat were tested In vitro and In vivo. Results revealed that all the extracts significantly inhibited the germination and growth of canary grass In vitro as well as In vivo. Maximum inhibition i.e. more than 80% to all the parameters of canary grass was observed by 10% extract In vitro. In pot experiment 66% reduction, in the dry weight of canary grass was observed when the old leaves water extract was applied before emergence. All the treatments showed non significant results about the germination of wheat In vivo. Old mango leaves extract was found better as compared to new ones, because it moderately enhanced the wheat germination and growth, while new mango leaves induced some reduction regarding the shoot length and grain weight of wheat. Total phenolic contents were higher in new mango leaves as compared to old ones. 4-hydroxybenzaldehyde, m-coumaric, p-coumaric, 4-hydroxy benzoic, vanillic, caffeic, gallic and protocatechuic acids were phenolic compounds identified through Mass Spectrometry and High Performance Liquid Chromatography analyses of mango leaves. It has been concluded that old mango leaves extract could be used as a herbicide to suppress canary grass and to enhance wheat growth.
    Pakistan Journal of Botany 10/2013; 45:1527-1535. · 1.21 Impact Factor
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    ABSTRACT: The IL-33/ST2 axis is known to be involved in liver pathologies. Although, the IL-33 levels increased in sera of viral hepatitis patients in human, the cellular sources of IL-33 in viral hepatitis remained obscure. Therefore, we aimed to investigate the expression of IL-33 in murine fulminant hepatitis induced by a Toll like receptor (TLR3) viral mimetic, poly(I:C) or by pathogenic mouse hepatitis virus (L2-MHV3). The administration of poly(I:C) plus D-galactosamine (D-GalN) in mice led to acute liver injury associated with the induction of IL-33 expression in liver sinusoidal endothelial cells (LSEC) and vascular endothelial cells (VEC), while the administration of poly(I:C) alone led to hepatocyte specific IL-33 expression in addition to vascular IL-33 expression. The hepatocyte-specific IL-33 expression was down-regulated in NK-depleted poly(I:C) treated mice suggesting a partial regulation of IL-33 by NK cells. The CD1d KO (NKT deficient) mice showed hepatoprotection against poly(I:C)-induced hepatitis in association with increased number of IL-33 expressing hepatocytes in CD1d KO mice than WT controls. These results suggest that hepatocyte-specific IL-33 expression in poly(I:C) induced liver injury was partially dependent of NK cells and with limited role of NKT cells. In parallel, the L2-MHV3 infection in mice induced fulminant hepatitis associated with up-regulated IL-33 expression as well as pro-inflammatory cytokine microenvironment in liver. The LSEC and VEC expressed inducible expression of IL-33 following L2-MHV3 infection but the hepatocyte-specific IL-33 expression was only evident between 24 to 32h of post infection. In conclusion, the alarmin cytokine IL-33 was over-expressed during fulminant hepatitis in mice with LSEC, VEC and hepatocytes as potential sources of IL-33.
    PLoS ONE 09/2013; 8(9):e74278. DOI:10.1371/journal.pone.0074278 · 3.23 Impact Factor
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    ABSTRACT: Interleukin (IL)-33, a member of the IL-1 cytokine family, positively correlates with acute hepatitis and chronic liver failure in mice and humans. IL-33 is expressed in hepatocytes and is regulated by natural killer T (NKT) cells during concanavalin A (ConA)-induced acute liver injury. Here, we investigated the molecular mechanisms underlying the expression of IL-33 during acute hepatitis. The expression of IL-33 and its regulation by death receptor pathways was investigated after the induction of ConA-acute hepatitis in wildtype (WT), perforin(-/-) , tumor necrosis factor related apoptosis inducing ligand (TRAIL)(-/-) , and NKT cell-deficient (CD1d(-/-) ) mice. In addition, we used a model of acute liver injury by administering Jo2/Fas-antibody or D-galactosamine-tumor necrosis factor alpha (TNFα) in WT mice. Finally, the effect of TRAIL on IL-33 expression was assessed in primary cultured murine hepatocytes. We show that IL-33 expression in hepatocytes is partially controlled by perforin during acute liver injury, but not by TNFα or Fas ligand (FasL). Interestingly, the expression of IL-33 in hepatocytes is blocked during ConA-acute hepatitis in TRAIL-deficient mice compared to WT mice. In contrast, administration of recombinant murine TRAIL associated with ConA-priming in CD1d-deficient mice or in vitro stimulation of murine hepatocytes by TRAIL but not by TNFα or Jo2 induced IL-33 expression in hepatocytes. The IL-33-deficient mice exhibited more severe ConA liver injury than WT controls, suggesting a protective effect of IL-33 in ConA-hepatitis. Conclusion: The expression of IL-33 during acute hepatitis is dependent on TRAIL, but not on FasL or TNFα. (HEPATOLOGY 2012).
    Hepatology 12/2012; 56(6). DOI:10.1002/hep.25893 · 11.19 Impact Factor
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    ABSTRACT: Interleukin-33 (IL-33), a cytokine of IL-1 family, is primarily expressed by several cell types and recently IL-33/ST2 axis was found to be crucial in liver pathology [1] and [2]. IL-33 interacts via its specific receptors, ST2 and IL-1RAcP, which are mainly expressed by immune cells. Beside, IL-33 is thought to be released during cellular death and it is hypothesized that IL-33 can act as an alarmin cytokine during acute phase of disease, like HMGB1 is known.Methods We investigated the expression and regulation of IL-33 in hepato-cellular death way in mice in developing several models of acute hepatitis, including concanavalin A (ConA), anti-Fas/Jo2 and D-GalN-TNF-α induced hepatitis. Further, by using TRAIL, CD1d and IL-33 deficient mice in ConA-induced liver injury, we studied the expression and function of IL-33.ResultsWe show that IL-33 was present at low levels constitutively in vascular endothelial and sinusoidal endothelial cells while it was clearly induced in these cells after ConA, Fas/Jo2 and D-GalN-TNF-α administration. Interestingly, the hepatocytes strongly expressed nuclear IL-33 specifically in ConA-induced hepatitis compared to other models. We show that the regulation of IL-33 in hepatocytes was via NKT cells [3] and also TRAIL as injection of recombinant TRAIL in CD1d-/- mice after ConA priming induced IL-33 in hepatocytes. Finally, the IL-33 deficient mice exhibited more severe ConA liver injury than WT controls suggesting a protective effect of IL-33 in ConA-hepatitis.Conclusion In conclusion, we demonstrate that the expression of IL-33 during acute hepatitis is dependent on NKT cells and TRAIL.
    Cytokine 09/2012; 59(3):549. DOI:10.1016/j.cyto.2012.06.182 · 2.87 Impact Factor
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    ABSTRACT: Although TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand) is a well-known apoptosis inducer, we have previously demonstrated that acidic extracellular pH (pHe) switches TRAIL-induced apoptosis to regulated necrosis (or necroptosis) in human HT29 colon and HepG2 liver cancer cells. Here, we investigated the role of RIPK1 (receptor interacting protein kinase 1), RIPK3 and PARP-1 (poly (ADP-ribose) polymerase-1) in TRAIL-induced necroptosis in vitro and in concanavalin A (Con A)-induced murine hepatitis. Pretreatment of HT29 or HepG2 with pharmacological inhibitors of RIPK1 or PARP-1 (Nec-1 or PJ-34, respectively), or transient transfection with siRNAs against RIPK1 or RIPK3, inhibited both TRAIL-induced necroptosis and PARP-1-dependent intracellular ATP depletion demonstrating that RIPK1 and RIPK3 were involved upstream of PARP-1 activation and ATP depletion. In the mouse model of Con A-induced hepatitis, where death of mouse hepatocytes is dependent on TRAIL and NKT (Natural Killer T) cells, PARP-1 activity was positively correlated with liver injury and hepatitis was prevented both by Nec-1 or PJ-34. These data provide new insights into TRAIL-induced necroptosis with PARP-1 being active effector downstream of RIPK1/RIPK3 initiators and suggest that pharmacological inhibitors of RIPKs and PARP-1 could be new treatment options for immune-mediated hepatitis.Cell Death and Differentiation advance online publication, 20 July 2012; doi:10.1038/cdd.2012.90.
    Cell death and differentiation 07/2012; 19(12). DOI:10.1038/cdd.2012.90 · 8.39 Impact Factor
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    Muhammad I Arshad · Claire Piquet-Pellorce · Michel Samson
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    ABSTRACT: 'Alarmins' are a group of proteins or molecules that are released from cells during cellular demise to alert the host immune system. Two of them, Interleukin-33 (IL-33) and high-mobility group box-1 (HMGB1), share many similarities of cellular localization, functions and involvement in various inflammatory pathologies including hepatitis. The expressions of IL-33 and HMGB1, and their receptors ST2 and receptor for advanced glycation end products (RAGE), are substantially up-regulated during acute and chronic hepatitis. Recent data evidence a possible protective role of IL-33/ST2 axis during liver injury. A contrast in expression of IL-33 and HMGB1 alarmins were associated with type of hepatocellular death mediated by immune cells or hepato-toxic agents. The massive release of active form of IL-33 from hepatocytes may affect the recruitment and activation of its ST2-positive target immune cells in the liver to confer its alarmin functions. This review highlights the emerging roles of alarmin proteins in various liver pathologies, by focusing on classical HMGB1 and a newly discovered alarmin, the IL-33.
    Liver international: official journal of the International Association for the Study of the Liver 04/2012; 32(8):1200-10. DOI:10.1111/j.1478-3231.2012.02802.x · 4.41 Impact Factor
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    ABSTRACT: Inclusion body hepatitis-hydropericardium syndrome (IBH-HPS) in broilers is caused by an adenovirus, here referred to as inclusion body hepatitis-hydropericardium syndrome virus (IBH-HPSV). Th is study describes the immune status of broiler chickens experimentally inoculated with an isolate of fowl adenovirus-4 serotype-1, involved in IBH-HPS in various trials. When compared with the unchallenged controls, IBH-HPSV-inoculated broilers had signifi cantly higher atrophy of the bursa of Fabricius (BF) by up to 2-fold, as well as of the thymus (up to 9-fold) and spleen (up to 1.5-fold) (P < 0.05), with up to 60% mortality. Upon challenge with sheep red blood cells (SRBCs), IBH-HPSV-inoculated birds had from 2-to 3-log lower anti-SRBC antibody titers than the control. Response to phytohemagglutinin-P (PHA-P) was signifi cantly reduced in IBH-HPSV-inoculated birds (P < 0.05) as compared to the control. Results of the studies revealed that the immune status of broilers is compromised signifi cantly during IBH-HPSV infection in terms of lymphoid organ integrity, humoral, and cell-mediated immune responses, respectively. Th ese fi ndings suggest that immune dysfunction could be a contributing factor in the increased mortality of birds aff ected by IBH-HPS, which renders the birds immunosuppressed for the rest of their lives.
    Turkish Journal of Veterinary and Animal Sciences 01/2012; 36(3). DOI:10.3906/vet-0807-21 · 0.32 Impact Factor
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    ABSTRACT: Interleukin-33 (IL-33) is thought to be released during cellular death as an alarming cytokine during the acute phase of disease, but its regulation in vivo is poorly understood. We investigated the expression of IL-33 in two mouse models of acute hepatitis by administering either carbon tetrachloride (CCl(4) ) or concanavalin A (ConA). IL-33 was overexpressed in both models but with a stronger induction in ConA-induced hepatitis. IL-33 was weakly expressed in vascular and sinusoidal endothelial cells from normal liver and was clearly induced in CCl(4) -treated mice. Surprisingly, we found that hepatocytes strongly expressed IL-33 exclusively in the ConA model. CD1d knock-out mice, which are deficient in NKT cells and resistant to ConA-induced hepatitis, no longer expressed IL-33 in hepatocytes following ConA administration. Interestingly, invariant NKT (iNKT) cells adoptively transferred into ConA-treated CD1d KO mouse restored IL-33 expression in hepatocytes. This strongly suggests that NKT cells are responsible for the induction of IL-33 in hepatocytes.
    European Journal of Immunology 08/2011; 41(8):2341-8. DOI:10.1002/eji.201041332 · 4.52 Impact Factor
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    ABSTRACT: A cryosection of the liver taken from a mouse treated with concanavalin A to induce acute hepatitis features on this issue's cover; the section is stained with Hoechst, Texas red-phalloidin and anti-mIL-33 goat IgG/Cy5-conjugated secondary antibody, identifying the nuclei in blue, F-actin filaments in orange and IL-33-expressing cells in green respectively. The image is taken from the article by Arshad et al. (pp. 2341-2349) in which the induction of IL-33 expression in hepatocytes in concanavalin A-induced hepatitis is suggested to be driven by NKT cells.
    European Journal of Immunology 08/2011; 41(8). DOI:10.1002/eji.201190050 · 4.52 Impact Factor
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    ABSTRACT: IL-33, a novel IL-1 family member, is crucially expressed and involved in pulmonary diseases, but its regulation in viral diseases such as influenza A virus (IAV) remains unclear. This study aimed to characterize the expression and release of IL-33 in lungs of IAV-infected mice in vivo and in murine respiratory epithelial cells (MLE-15) in vitro. Our results provide evidence of up-regulation of IL-33 mRNA in IAV-infected murine lungs, compared with noninfected control mice. The overexpression of IL-33 was positively correlated with a significant increase in mRNA encoding the proinflammatory cytokines TNF-α, IFN-γ, IL-1β, and IL-6, and was also associated with an increase in IFN-β mRNA. A profound overexpression of IL-33 protein was evident in IAV-infected murine lungs and bronchoalveolar lavages of influenza-infected mice, compared with low concentrations in naive lungs in vivo. Immunolocalization highlighted the cellular expression of IL-33 in alveolar epithelial and endothelial cells, along with increased infiltrate cells in virus-infected lungs. Further in vitro experiments showed an induction of IL-33 transcript-in MLE-15 cells and human epithelial cells (A549) infected with different strains of IAV in comparison with noninfected cells. In conclusion, our findings evidenced a profound expression of IL-33 in lungs during both in vivo and in vitro IAV infections, suggesting a role for IL-33 in virus-induced lung infections.
    American Journal of Respiratory Cell and Molecular Biology 06/2011; 45(6):1125-32. DOI:10.1165/rcmb.2010-0516OC · 4.11 Impact Factor

Publication Stats

145 Citations
72.54 Total Impact Points

Institutions

  • 2012–2015
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • University of Agriculture Faisalabad
      • Institute of Microbiology
      Shah Faisalabad, Punjab, Pakistan
  • 2011–2015
    • Université de Rennes 1
      • UMR S 1085 - Institut de recherche en santé, environnement et travail (IRSET)
      Roazhon, Brittany, France
  • 2013
    • Nuclear Institute for Agriculture and Biology
      Shah Faisalabad, Punjab, Pakistan