The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform
Enrique Rozengurt - One of the best experts on this subject based on the ideXlab platform.
-
[d-ARG1,d-Trp5,7,9,Leu11]Substance P Inhibits Bombesin-induced Mitogenic Signal Transduction Mediated by Both Gq and G12 in Swiss 3T3 Cells
The Journal of biological chemistry, 2000Co-Authors: James Sinnett-smith, Chintda Santiskulvong, Javier Duque, Enrique RozengurtAbstract:Abstract Substance P (SP) analogues including [d-ARG1,d-Trp5,7,9,Leu11]SP are broad spectrum neuropeptide antagonists and potential anticancer agents, but their mechanism of action is not fully understood. Here, we examined the mechanism of action of [d-ARG1,d-Trp5,7,9,Leu11]SP as an inhibitor of G protein-coupled receptor (GPCR)-mediated signal transduction and cellular DNA synthesis in Swiss 3T3 cells. Addition of [d-ARG1,d-Trp5,7,9,Leu11]SP, at 10 μm, caused a striking rightward shift in the dose-response curves of DNA synthesis induced by bombesin, bradykinin, or vasopressin and markedly inhibited the activation of p42mapk (ERK-2) and p44mapk (ERK-1) induced by these GPCR agonists. In addition, this SP analogue also prevented the protein kinase C-dependent activation of protein kinase D induced by these agonists. [d-ARG1,d-Trp5,7,9,Leu11]SP, at a concentration (10 μm) that inhibited these Gq-mediated events, also prevented GPCR agonist-induced responses mediated through the G proteins of the G12subfamily. These include bombesin-induced assembly of focal adhesions, formation of parallel arrays of actin stress fibers, increase in the tyrosine phosphorylation of focal adhesion kinase (FAK), p130Cas, and paxillin, and formation of a complex between FAK and Src. We conclude that [d-ARG1,d-Trp5,7,9,Leu11]SP acts as a mitogenic antagonist of neuropeptide GPCRs blocking signal transduction via both Gq and G12.
-
[D-ARG1,D-Trp5,7,9,Leu11]Substance P coordinately and reversibly inhibits bombesin- and vasopressin-induced signal transduction pathways in Swiss 3T3 cells.
The Journal of biological chemistry, 1996Co-Authors: Michael J. Seckl, Theresa Higgins, Enrique RozengurtAbstract:Abstract The novel substance P (SP) analogue, [D-ARG1,D-Trp5,7,9,Leu11]SP like [D-ARG1,D-Phe5,D-Trp7,9,Leu11]SP inhibited DNA synthesis induced by bombesin, vasopressin, and bradykinin, but did not interfere with the mitogenic response induced by other growth factors or pharmacological agents in Swiss 3T3 cells. [D-ARG1,D-Trp5,7,9,Leu11]SP reversibly inhibited bombesin-induced DNA synthesis, causing a 6-fold greater rightward shift in the bombesin dose response than [D-ARG1,D-Phe5,D-Trp7,9,Leu11]SP at identical concentrations (10 μM). We found that the new, more potent, SP analogue coordinately and reversibly inhibited bombesin-induced Ca2+ mobilization and protein kinase C (PKC) and mitogen-activated protein (MAP) kinase activation. The dose-response curves for bombesin-induced Ca2+ mobilization and MAP kinase activation were similarly displaced (51- and 40-fold, respectively) by [D-ARG1,D-Trp5,7,9,Leu11]SP. In addition, [D-ARG1,D-Trp5,7,9,Leu11]SP reversibly inhibited bombesin-induced tyrosine phosphorylation of Mr 110,000-130,000 and 70,000-80,000 bands as well as p125 focal adhesion kinase. [D-ARG1,D-Trp5,7,9,Leu11]SP also reversibly and coordinately inhibited vasopressin-induced Ca2+ mobilization, PKC stimulation, MAP kinase activation, tyrosine phosphorylation, and DNA synthesis in Swiss 3T3 cells. Surprisingly, deletion of the terminal Leu of [D-ARG1,D-Phe5,D-Trp7,9,Leu11]SP to yield [D-ARG1,D-Phe5,D-Trp7,9]SP1-10 resulted in a selective loss of inhibitory activity of this analogue against bombesin- but not vasopressin-stimulated DNA synthesis, Ca2+ mobilization, and MAP kinase activation. Collectively, these results suggest that SP analogues act at the receptor level to coordinately and reversibly antagonize bombesin- or vasopressin-induced signal transduction in Swiss 3T3 cells.
-
Metabolism of the broad-spectrum neuropeptide growth factor antagonist: [D-ARG1, D-Phe5, D-Trp7,9, Leu11]-substance P.
British journal of cancer, 1996Co-Authors: Da Jones, Enrique Rozengurt, J Cummings, Aj Maclellan, T Higgins, Simon P. Langdon, John F. SmythAbstract:Broad-spectrum neuropeptide growth factor antagonists, such as [D-ARG1, D-Phe5, D-Trp7,9, Leu11]substance P (antagonist D) and [Arg6, D-Trp7,9, NmePhe8]substance P(6-11) (antagonist G), are currently being investigated as possible anti-tumour agents. These compounds are hoped to be effective against neuropeptide-driven cancers such as small-cell lung cancer. Antagonist D possesses a broader antagonistic spectrum than antagonist G and hence may be of greater therapeutic use. The in vitro metabolism of antagonist D has been characterised and the structures of two major metabolites have been elucidated by amino acid analysis and mass spectrometry. Metabolism was confined to the C-terminus where serine carboxypeptidase action produced [deamidated]-antagonist D (metabolite 1) and [des-Leu11]-antagonist D (metabolite 2) as the major metabolites. Biological characterisation of the metabolites demonstrated that these relatively minor changes in structure resulted in a loss of antagonist activity. These results provide some of the first structure-activity information on the factors that determine which neuropeptides these compounds inhibit and on the relative potency of that inhibition.
John F. Smyth - One of the best experts on this subject based on the ideXlab platform.
-
Processing of [D-ARG1,D-Phe5,D-Trp7,9,Leu11]substance P in xenograft bearing Nu/Nu mice.
Peptides, 1997Co-Authors: Da Jones, J Cummings, Aj Maclellan, Simon P. Langdon, Alison Ritchie, John F. SmythAbstract:Abstract JONES, D. A., A. J. MacLELLAN, J. CUMMINGS, A. A. RITCHIE, S. P. LANGDON AND J. F. SMYTH. Processing of [ d-ARG1,d -Phe5, d -Trp7,9,Leu11]substance P in xenograft bearing Nu/Nu mice. PEPTIDES 18(7) 1073–1077, 1997.—[ d -ARG1, d -Phe5, d -Trp7,9,Leu11]Substance P is a broad-spectrum neuropeptide growth factor antagonist that has exhibited in vitro activity against a range of human cancer cell lines. The fate of this compound in vivo following IP administration at 12 μg/g to nu/nu mice bearing the H69 small-cell lung cancer xenograft has been studied. Metabolism was confined to the C-terminus producing [ d -ARG1, d -Phe5, d -Trp7,9,Leu11]substance P acid and [ d -ARG1, d -Phe5, d -Trp7,9]substance P(1–10). The peptide had a long half-life in plasma (45.9 min) and became widely distributed among the tissues studied with the highest accumulation observed in the liver (AUC 1102 μg/g × min) and the lowest in the brain (5 μg/g × min). Uptake into the tumor xenograft was poor (AUC 189 μg/g × min); however, uptake into the lungs was much greater (AUC 507 μg/g × min), offering encouragement that therapeutic concentrations may be targeted to primary lung tumors.
-
Metabolism of the broad-spectrum neuropeptide growth factor antagonist: [D-ARG1, D-Phe5, D-Trp7,9, Leu11]-substance P.
British journal of cancer, 1996Co-Authors: Da Jones, Enrique Rozengurt, J Cummings, Aj Maclellan, T Higgins, Simon P. Langdon, John F. SmythAbstract:Broad-spectrum neuropeptide growth factor antagonists, such as [D-ARG1, D-Phe5, D-Trp7,9, Leu11]substance P (antagonist D) and [Arg6, D-Trp7,9, NmePhe8]substance P(6-11) (antagonist G), are currently being investigated as possible anti-tumour agents. These compounds are hoped to be effective against neuropeptide-driven cancers such as small-cell lung cancer. Antagonist D possesses a broader antagonistic spectrum than antagonist G and hence may be of greater therapeutic use. The in vitro metabolism of antagonist D has been characterised and the structures of two major metabolites have been elucidated by amino acid analysis and mass spectrometry. Metabolism was confined to the C-terminus where serine carboxypeptidase action produced [deamidated]-antagonist D (metabolite 1) and [des-Leu11]-antagonist D (metabolite 2) as the major metabolites. Biological characterisation of the metabolites demonstrated that these relatively minor changes in structure resulted in a loss of antagonist activity. These results provide some of the first structure-activity information on the factors that determine which neuropeptides these compounds inhibit and on the relative potency of that inhibition.
Da Jones - One of the best experts on this subject based on the ideXlab platform.
-
Processing of [D-ARG1,D-Phe5,D-Trp7,9,Leu11]substance P in xenograft bearing Nu/Nu mice.
Peptides, 1997Co-Authors: Da Jones, J Cummings, Aj Maclellan, Simon P. Langdon, Alison Ritchie, John F. SmythAbstract:Abstract JONES, D. A., A. J. MacLELLAN, J. CUMMINGS, A. A. RITCHIE, S. P. LANGDON AND J. F. SMYTH. Processing of [ d-ARG1,d -Phe5, d -Trp7,9,Leu11]substance P in xenograft bearing Nu/Nu mice. PEPTIDES 18(7) 1073–1077, 1997.—[ d -ARG1, d -Phe5, d -Trp7,9,Leu11]Substance P is a broad-spectrum neuropeptide growth factor antagonist that has exhibited in vitro activity against a range of human cancer cell lines. The fate of this compound in vivo following IP administration at 12 μg/g to nu/nu mice bearing the H69 small-cell lung cancer xenograft has been studied. Metabolism was confined to the C-terminus producing [ d -ARG1, d -Phe5, d -Trp7,9,Leu11]substance P acid and [ d -ARG1, d -Phe5, d -Trp7,9]substance P(1–10). The peptide had a long half-life in plasma (45.9 min) and became widely distributed among the tissues studied with the highest accumulation observed in the liver (AUC 1102 μg/g × min) and the lowest in the brain (5 μg/g × min). Uptake into the tumor xenograft was poor (AUC 189 μg/g × min); however, uptake into the lungs was much greater (AUC 507 μg/g × min), offering encouragement that therapeutic concentrations may be targeted to primary lung tumors.
-
Metabolism of the broad-spectrum neuropeptide growth factor antagonist: [D-Arg^1, D-Phe^5, D-Trp^7,^9, Leu^11]-substance P
British Journal of Cancer, 1996Co-Authors: Da Jones, J Cummings, Sp Langdon, Aj Maclellan, T Higgins, E Rozengurt, Jf SmythAbstract:Broad-spectrum neuropeptide growth factor antagonists, such as [D-ARG1, D-Phe5, D-Trp7,9, Leu11]substance P (antagonist D) and [Arg6, D-Trp7,9, NmePhe8]substance P(6-11) (antagonist G), are currently being investigated as possible anti-tumour agents. These compounds are hoped to be effective against neuropeptide-driven cancers such as small-cell lung cancer. Antagonist D possesses a broader antagonistic spectrum than antagonist G and hence may be of greater therapeutic use. The in vitro metabolism of antagonist D has been characterised and the structures of two major metabolites have been elucidated by amino acid analysis and mass spectrometry. Metabolism was confined to the C-terminus where serine carboxypeptidase action produced [deamidated]-antagonist D (metabolite 1) and [des-Leu11]-antagonist D (metabolite 2) as the major metabolites. Biological characterisation of the metabolites demonstrated that these relatively minor changes in structure resulted in a loss of antagonist activity. These results provide some of the first structure-activity information on the factors that determine which neuropeptides these compounds inhibit and on the relative potency of that inhibition.
-
Metabolism of the broad-spectrum neuropeptide growth factor antagonist: [D-ARG1, D-Phe5, D-Trp7,9, Leu11]-substance P.
British journal of cancer, 1996Co-Authors: Da Jones, Enrique Rozengurt, J Cummings, Aj Maclellan, T Higgins, Simon P. Langdon, John F. SmythAbstract:Broad-spectrum neuropeptide growth factor antagonists, such as [D-ARG1, D-Phe5, D-Trp7,9, Leu11]substance P (antagonist D) and [Arg6, D-Trp7,9, NmePhe8]substance P(6-11) (antagonist G), are currently being investigated as possible anti-tumour agents. These compounds are hoped to be effective against neuropeptide-driven cancers such as small-cell lung cancer. Antagonist D possesses a broader antagonistic spectrum than antagonist G and hence may be of greater therapeutic use. The in vitro metabolism of antagonist D has been characterised and the structures of two major metabolites have been elucidated by amino acid analysis and mass spectrometry. Metabolism was confined to the C-terminus where serine carboxypeptidase action produced [deamidated]-antagonist D (metabolite 1) and [des-Leu11]-antagonist D (metabolite 2) as the major metabolites. Biological characterisation of the metabolites demonstrated that these relatively minor changes in structure resulted in a loss of antagonist activity. These results provide some of the first structure-activity information on the factors that determine which neuropeptides these compounds inhibit and on the relative potency of that inhibition.
Alan G. Hinnebusch - One of the best experts on this subject based on the ideXlab platform.
-
mcm1p binding sites in ARG1 positively regulate gcn4p binding and swi snf recruitment
Biochemical and Biophysical Research Communications, 2009Co-Authors: Sungpil Yoon, Alan G. HinnebuschAbstract:Transcription of the arginine biosynthetic gene ARG1 is activated by Gcn4p, a transcription factor induced by starvation for any amino acid. Previously, we showed that Gcn4p binding stimulates the recruitment of Mcm1p and co-activator SWI/SNF to ARG1 in cells via Gcn4p induction through amino acid starvation. Here, we report that Gcn4p binding is reduced by point mutations of the Mcm1p binding site and increased by overexpression of Mcm1p. This result suggests that Mcm1p plays a positive role in recruiting activator Gcn4p to ARG1, similar to the previously described cooperative interaction of Mcm1p with sequence-specific transcription factors at their promoters. In addition, the mutational analysis of Mcm1p binding sites showed that recruitment of the co-activator SWI/SNF correlated more closely with binding of Mcm1p than of Gcn4p at ARG1. Consistent with this, SWI/SNF co-immunoprecipitated with Mcm1p, but not with Gcn4p. These results support that Mcm1p increases the SWI/SNF recruitment at ARG1, a Gcn4p target promoter. The interaction between Mcm1p and SWI/SNF was abolished in a snf2 deletion strain containing an intact SWI/SNF sub-complex, suggesting that Mcm1p targets the catalytic subunit, which has ATPase activity, during SWI/SNF recruitment. We propose that Mcm1p contributes to active transcription at the ARG1 promoter by increasing the binding of the activator Gcn4p and by recruiting the co-activator complex SWI/SNF at ARG1 under Gcn4p-induced conditions.
-
Mcm1p binding sites in ARG1 positively regulate Gcn4p binding and SWI/SNF recruitment.
Biochemical and biophysical research communications, 2009Co-Authors: Sungpil Yoon, Alan G. HinnebuschAbstract:Transcription of the arginine biosynthetic gene ARG1 is activated by Gcn4p, a transcription factor induced by starvation for any amino acid. Previously, we showed that Gcn4p binding stimulates the recruitment of Mcm1p and co-activator SWI/SNF to ARG1 in cells via Gcn4p induction through amino acid starvation. Here, we report that Gcn4p binding is reduced by point mutations of the Mcm1p binding site and increased by overexpression of Mcm1p. This result suggests that Mcm1p plays a positive role in recruiting activator Gcn4p to ARG1, similar to the previously described cooperative interaction of Mcm1p with sequence-specific transcription factors at their promoters. In addition, the mutational analysis of Mcm1p binding sites showed that recruitment of the co-activator SWI/SNF correlated more closely with binding of Mcm1p than of Gcn4p at ARG1. Consistent with this, SWI/SNF co-immunoprecipitated with Mcm1p, but not with Gcn4p. These results support that Mcm1p increases the SWI/SNF recruitment at ARG1, a Gcn4p target promoter. The interaction between Mcm1p and SWI/SNF was abolished in a snf2 deletion strain containing an intact SWI/SNF sub-complex, suggesting that Mcm1p targets the catalytic subunit, which has ATPase activity, during SWI/SNF recruitment. We propose that Mcm1p contributes to active transcription at the ARG1 promoter by increasing the binding of the activator Gcn4p and by recruiting the co-activator complex SWI/SNF at ARG1 under Gcn4p-induced conditions.
-
Activator Gcn4p and Cyc8p/Tup1p Are Interdependent for Promoter Occupancy at ARG1 In Vivo
Molecular and cellular biology, 2005Co-Authors: Soon-ja Kim, Mark J. Swanson, Hongfang Qiu, Chhabi K. Govind, Alan G. HinnebuschAbstract:The Cyc8p/Tup1p complex mediates repression of diverse genes in Saccharomyces cerevisiae and is recruited by DNA binding proteins specific for the different sets of repressed genes. By screening the yeast deletion library, we identified Cyc8p as a coactivator for Gcn4p, a transcriptional activator of amino acid biosynthetic genes. Deletion of CYC8 confers sensitivity to an inhibitor of isoleucine/valine biosynthesis and impairs activation of Gcn4p-dependent reporters and authentic amino acid biosynthetic target genes. Deletion of TUP1 produces similar but less severe activation defects in vivo. Although expression of Gcn4p is unaffected by deletion of CYC8, chromatin immunoprecipitation assays reveal a strong defect in binding of Gcn4p at the target genes ARG1 and ARG4 in cyc8Δ cells and to a lesser extent in tup1Δ cells. The defects in Gcn4p binding and transcriptional activation in cyc8Δ cells cannot be overcome by Gcn4p overexpression but are partially suppressed in tup1Δ cells. The impairment of Gcn4p binding in cyc8Δ and tup1Δ cells is severe enough to reduce recruitment of SAGA, Srb mediator, TATA binding protein, and RNA polymerase II to the ARG1 and ARG4 promoters, accounting for impaired transcriptional activation of these genes in both mutants. Cyc8p and Tup1p are recruited to the ARG1 and ARG4 promoters, consistent with a direct role for this complex in stimulating Gcn4p occupancy of the upstream activation sequence (UAS). Interestingly, Gcn4p also stimulates binding of Cyc8p/Tup1p at the 3′ ends of these genes, raising the possibility that Cyc8p/Tup1p influences transcription elongation. Our findings reveal a novel coactivator function for Cyc8p/Tup1p at the level of activator binding and suggest that Gcn4p may enhance its own binding to the UAS by recruiting Cyc8p/Tup1p.
-
activator gcn4p and cyc8p tup1p are interdependent for promoter occupancy at ARG1 in vivo
Molecular and Cellular Biology, 2005Co-Authors: Soon-ja Kim, Mark J. Swanson, Hongfang Qiu, Chhabi K. Govind, Alan G. HinnebuschAbstract:The Cyc8p/Tup1p complex mediates repression of diverse genes in Saccharomyces cerevisiae and is recruited by DNA binding proteins specific for the different sets of repressed genes. By screening the yeast deletion library, we identified Cyc8p as a coactivator for Gcn4p, a transcriptional activator of amino acid biosynthetic genes. Deletion of CYC8 confers sensitivity to an inhibitor of isoleucine/valine biosynthesis and impairs activation of Gcn4p-dependent reporters and authentic amino acid biosynthetic target genes. Deletion of TUP1 produces similar but less severe activation defects in vivo. Although expression of Gcn4p is unaffected by deletion of CYC8, chromatin immunoprecipitation assays reveal a strong defect in binding of Gcn4p at the target genes ARG1 and ARG4 in cyc8Δ cells and to a lesser extent in tup1Δ cells. The defects in Gcn4p binding and transcriptional activation in cyc8Δ cells cannot be overcome by Gcn4p overexpression but are partially suppressed in tup1Δ cells. The impairment of Gcn4p binding in cyc8Δ and tup1Δ cells is severe enough to reduce recruitment of SAGA, Srb mediator, TATA binding protein, and RNA polymerase II to the ARG1 and ARG4 promoters, accounting for impaired transcriptional activation of these genes in both mutants. Cyc8p and Tup1p are recruited to the ARG1 and ARG4 promoters, consistent with a direct role for this complex in stimulating Gcn4p occupancy of the upstream activation sequence (UAS). Interestingly, Gcn4p also stimulates binding of Cyc8p/Tup1p at the 3′ ends of these genes, raising the possibility that Cyc8p/Tup1p influences transcription elongation. Our findings reveal a novel coactivator function for Cyc8p/Tup1p at the level of activator binding and suggest that Gcn4p may enhance its own binding to the UAS by recruiting Cyc8p/Tup1p.
Sabir Hussain - One of the best experts on this subject based on the ideXlab platform.
-
association analysis between ARG1 gene polymorphisms and idiopathic dilated cardiomyopathy
Medicine, 2019Co-Authors: Syed Fawad Ali Shah, Tahir Iqbal, Sumaira Akram, Muhammad Arshad Rafiq, Sadia Nawaz, Sabir HussainAbstract:The current study aimed at investigate the potential association of ARG1 polymorphisms in subjects affected by idiopathic dilated cardiomyopathy (IDCM).We have investigated 352 subjects affected by IDCM and 352 population-matched healthy controls by exploiting case-control study. The serum lipids were quantified using spectrophotometric assay, serum arginase activity was done by enzyme colorimetric assay and 2 polymorphisms (rs2781666 and rs2781667) in ARG1 were typed by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) to find out disease associate allele/haplotype segregating in subjects affected by IDCM.Significantly high arginase activity was found to be associated with IDCM subjects when compared with population-matched healthy controls (P < .0001). The higher arginase level in IDCM subjects is negatively correlated with nitrite and nitrate (r = -0.4687, and r = -0.6435, respectively) in our study. There was a significant difference in the distribution of rs2781666 and rs2781667 genotypes of ARG1 polymorphism in patients and controls (P < .0001). Similarly, variant allele T at both loci showed a significant association with the disease phenotypes (P < .0001). Haplotype TT at rs2781666G/T and rs2781667C/T also showed a significantly association (P < .0001).To our knowledge, this is the first report to show a significant involvement of ARG1 polymorphisms to produce IDCM symptoms in subjects originating in Pakistan.
-
Association analysis between ARG1 gene polymorphisms and idiopathic dilated cardiomyopathy.
Medicine, 2019Co-Authors: Syed Fawad Ali Shah, Tahir Iqbal, Sumaira Akram, Muhammad Arshad Rafiq, Sadia Nawaz, Sabir HussainAbstract:The current study aimed at investigate the potential association of ARG1 polymorphisms in subjects affected by idiopathic dilated cardiomyopathy (IDCM).We have investigated 352 subjects affected by IDCM and 352 population-matched healthy controls by exploiting case-control study. The serum lipids were quantified using spectrophotometric assay, serum arginase activity was done by enzyme colorimetric assay and 2 polymorphisms (rs2781666 and rs2781667) in ARG1 were typed by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) to find out disease associate allele/haplotype segregating in subjects affected by IDCM.Significantly high arginase activity was found to be associated with IDCM subjects when compared with population-matched healthy controls (P
-
ARG1 single nucleotide polymorphisms rs2781666 and rs2781665 confer risk of Type 2 diabetes mellitus.
EXCLI journal, 2018Co-Authors: Syed Fawad Ali Shah, Tahir Iqbal, Nasreen Naveed, Sumaira Akram, Muhammad Arshad Rafiq, Sabir HussainAbstract:Genetic polymorphisms mapped in the ARG1 locus (chr6:131894344-131905472) and their functional effects on type 2 diabetes mellitus (T2DM) have not been thoroughly elucidated to date. The present study aimed to investigate an association between variant alleles at ARG1 locus and T2DM in patients. Two ARG1 single nucleotide polymorphisms (SNPs) were characterized in a representative sample of 500 patients with T2DM and 500 healthy volunteers. Serum lipid profile was studied by spectrophotometric analysis, while serum arginase-1 concentrations were determined by an enzyme-linked immunosorbent assay. The regions, encompassing target SNPs (rs2781665 and rs2781666), were amplified by polymerase chain reaction and genotypes were assigned by restriction digestions. A statistically significant increase was observed in the serum hs-CRP and arginase-1 levels in the subjects with T2DM than in controls (P
-
ARG1 single nucleotide polymorphisms rs2781666 and rs2781665 confer risk of type 2 diabetes mellitus
Excli Journal, 2018Co-Authors: Syed Fawad Ali Shah, Tahir Iqbal, Nasreen Naveed, Sumaira Akram, Muhammad Arshad Rafiq, Sabir HussainAbstract:Genetic polymorphisms mapped in the ARG1 locus (chr6:131894344-131905472) and their functional effects on type 2 diabetes mellitus (T2DM) have not been thoroughly elucidated to date. The present study aimed to investigate an association between variant alleles at ARG1 locus and T2DM in patients. Two ARG1 single nucleotide polymorphisms (SNPs) were characterized in a representative sample of 500 patients with T2DM and 500 healthy volunteers. Serum lipid profile was studied by spectrophotometric analysis, while serum arginase-1 concentrations were determined by an enzyme-linked immunosorbent assay. The regions, encompassing target SNPs (rs2781665 and rs2781666), were amplified by polymerase chain reaction and genotypes were assigned by restriction digestions. A statistically significant increase was observed in the serum hs-CRP and arginase-1 levels in the subjects with T2DM than in controls (P <0.0001; for each). The variant genotypes of rs2781666 and rs2781665 were significantly associated with T2DM when compared with controls (P< 0.0001). Moreover, type 2 diabetic patients showed higher frequencies of T allele at rs2781666 and rs2781665 compared to the controls (OR = 1.7; 95 % CI=1.31-2.13; P <0.0001, and OR = 1.9; 95 % CI=1.45-2.38; P <0.0001, respectively). Haplotype T-T (chr6: 131893247-131893559) mapped at rs2781665-A/T and rs2781666-G/T displays higher frequency in the subjects when compared to the healthy ethnically-matched control samples (P <0.0001). We wish to propose, the first ever observation to our knowledge that concluding high levels of arginase-1 and the ARG1 polymorphisms are possible causes to confer/augment the risk of T2DM in subjects originates in Pakistan.