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H. Nagase - One of the best experts on this subject based on the ideXlab platform.
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Gene expression levels of Gamma-Glutamyl Hydrolase in tumor tissues may be a useful biomarker for the proper use of S-1 and tegafur-uracil/leucovorin in preoperative chemoradiotherapy for patients with rectal cancer
Cancer Chemotherapy and Pharmacology, 2017Co-Authors: Sotaro Sadahiro, T. Suzuki, A. Tanaka, K. Okada, G. Saito, H. Miyakita, T. Ogimi, H. NagaseAbstract:Purpose Preoperative chemoradiotherapy (CRT) using 5-fluorouracil (5-FU)-based chemotherapy is the standard of care for rectal cancer. The effect of additional chemotherapy during the period between the completion of radiotherapy and surgery remains unclear. Predictive factors for CRT may differ between combination chemotherapy with S-1 and with tegafur-uracil/leucovorin (UFT/LV). Methods The subjects were 54 patients with locally advanced rectal cancer who received preoperative CRT with S-1 or UFT/LV. The pathological tumor response was assessed according to the tumor regression grade (TRG). The expression levels of 18 CRT-related genes were determined using RT-PCR assay. Results A pathological response (TRG 1-2) was observed in 23 patients (42.6%). In a multivariate logistic regression analysis for pathological response, the overall expression levels of four genes, HIF1A, MTHFD1, GGH and TYMS, were significant, and the accuracy rate of the predictive model was 83.3%. The effects of the gene expression levels of GGH on the response differed significantly according to the treatment regimen. The total pathological response rate of both high-GGH patients in the S-1 group and low-GGH patients in the UFT/LV group was 58.3%. Conclusion Additional treatment with 5-FU-based chemotherapy during the interval between radiotherapy and surgery is not beneficial in patients who have received 5-FU-based CRT. The expression levels of four genes, HIF1A, MTHFD1, GGH and TYMS, in tumor tissues can predict the response to preoperative CRT including either S-1 or UFT/LV. In particular, the gene expression level of GGH in tumor tissues may be a useful biomarker for the appropriate use of S-1 and UFT/LV in CRT.
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Gene expression levels of Gamma-Glutamyl Hydrolase in tumor tissues may be a useful biomarker for the proper use of S-1 and tegafur-uracil/leucovorin in preoperative chemoradiotherapy for patients with rectal cancer.
Cancer chemotherapy and pharmacology, 2017Co-Authors: Sotaro Sadahiro, T. Suzuki, A. Tanaka, G. Saito, H. Miyakita, T. Ogimi, Ken-ichi Okada, H. NagaseAbstract:Purpose Preoperative chemoradiotherapy (CRT) using 5-fluorouracil (5-FU)-based chemotherapy is the standard of care for rectal cancer. The effect of additional chemotherapy during the period between the completion of radiotherapy and surgery remains unclear. Predictive factors for CRT may differ between combination chemotherapy with S-1 and with tegafur-uracil/leucovorin (UFT/LV).
Thomas J. Ryan - One of the best experts on this subject based on the ideXlab platform.
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Gamma-Glutamyl Hydrolase and drug resistance.
Clinica Chimica Acta, 2006Co-Authors: Erasmus Schneider, Thomas J. RyanAbstract:Gamma-Glutamyl Hydrolase (GGH) is a lysosomal enzyme involved in the metabolism of folates and anti-folates. It acts as an endo- and/or exo-peptidase to cleave Gamma-polyglutamate chains that are attached to folates and anti-folates after they enter a mammalian cell. Whereas the addition of multiple glutamates is necessary to enable the cell to retain folates and anti-folates, hydrolysis of the polyglutamate tails by GGH has the opposite effect of making (anti)-folates exportable again. Thus, GGH plays an important role in the cellular homeostasis of folate. Furthermore, high levels of GGH have been associated with cellular resistance to anti-folates, in particular methotrexate. Consequently, GGH also has pharmacological importance. In addition to the intracellular GGH, carboxypeptidase II (also called intestinal folate conjugase, prostate specific membrane antigen or N-acetyl-alpha-linked acidic dipeptidase) is another enzyme with Gamma-Glutamyl Hydrolase activity; it resides, however, in the cellular membrane. Although genetically and biochemically distinct, this enzyme too appears to play a major role in folate homeostasis, by cleaving polyglutamates from extracellular folate-polyglutamates, so that they can be imported into the cell. Finally, there have been reports suggesting that Gamma-Glutamyl Hydrolase plays a role as a tumor marker in breast and lung cancer.
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Identification of single nucleotide polymorphisms in the human γ-Glutamyl Hydrolase gene and characterization of promoter polymorphisms
Gene, 2003Co-Authors: Karen J. Chave, Thomas J. Ryan, Stacey E Chmura, John GalivanAbstract:Gamma-Glutamyl Hydrolase (GGH) plays a central role in folate metabolism and antifolate action. Increased GGH activity has been found in rat hepatoma cells resistant to the cancer drug methotrexate (MTX). The aim of this study was to identify polymorphisms in the GGH gene that modulate GGH activity and that may affect methotrexate resistance. Exons of the human Gamma-Glutamyl Hydrolase (hGGH) gene were amplified by polymerase chain reaction (PCR) from breast cancer tissue and leukemia cell lines. Single-stranded conformational polymorphism (SSCP) analysis was performed, and PCR products containing different patterns were cloned and sequenced. Six single nucleotide polymorphisms (SNPs) were identified, at bases -401C>T, -354G>T, -124T>G, +16T>C, +452C>T, and +1102A>G, relative to the A of the translation start codon being considered as +1. The SNP at +16, which changes codon -19 (relative to the start of the mature hGGH protein) in the endoplasmic reticulum targeting sequence of hGGH protein from cysteine to arginine, has previously been identified in this laboratory. The SNP at +452 changes the conserved hGGH protein codon 127 from threonine to isoleucine. The functions of SNPs in the promoter of the hGGH gene were studied by site-directed mutagenesis of a 516-bp region of the hGGH gene promoter in a luciferase reporter vector and transfection into HepG2 and MCF-7 cells. All of the promoter polymorphisms enhanced the production of luciferase compared to the wild-type hGGH gene promoter in HepG2 cells, and -401C>T and -124T>G enhanced luciferase expression in MCF-7 cells, suggesting that polymorphisms in the hGGH gene promoter may increase expression of hGGH protein.
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three dimensional structure of human Gamma Glutamyl Hydrolase a class i glatamine amidotransferase adapted for a complex substate
Journal of Biological Chemistry, 2002Co-Authors: Thomas J. Ryan, Karen J. Chave, Patrick Van RoeyAbstract:Abstract γ-Glutamyl Hydrolase catalyzes the cleavage of the γ-Glutamyl chain of folylpoly-γ-Glutamyl substrates and is a central enzyme in folyl and antifolyl poly-γ-glutamate metabolism. The crystal structure of human γ-Glutamyl Hydrolase, determined at 1.6-A resolution, reveals that the protein is a homodimer. The overall structure of human γ-Glutamyl Hydrolase contains 11 α-helices and 14 β-strands, with a fold in which a central eight-stranded β-sheet is sandwiched by three and five α-helices on each side. The topology is very similar to that of the class I glutamine amidotransferase domains, with the only major differences consisting of extensions in four loops and at the C terminus. These insertions are important for defining the substrate binding cleft and/or the dimer interface. Two sequence motifs are found in common between human γ-Glutamyl Hydrolase and the class I glutamine amidotransferase family and include the catalytically essential residues, Cys-110 and His-220. These residues are located in the center of a largel-shaped cleft that is closed at one end and open at the other. Several conserved residues, including Glu-114, His-171, Gln-218, and Lys-223, may be important for substrate binding. Modeling of a methotrexate thioester intermediate, based on the corresponding complex of the glutamate thioester intermediate of Escherichia coli carbamoyl-phosphate synthetase, indicates that the substrate binds in an orientation with the pteroyl group toward the open end of the cleft.
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Glutamyl Hydrolase: pharmacological role and enzymatic characterization
Pharmacology & therapeutics, 2000Co-Authors: John Galivan, Thomas J. Ryan, Rong Yao, Karen J. Chave, Myung S. Rhee, Dezhong YinAbstract:Gamma-Glutamyl Hydrolase (GH, EC 3.4.19.9) is a lysosomal and secreted glycoprotein that hydrolyzes the Gamma-Glutamyl tail of antifolate and folate polyglutamates. Tumor cells that have high levels of GH are inherently resistant to classical antifolates, and further resistance can be acquired by elevations in GH following exposure to this class of antitumor agents. The highest level of expression in normal tissues occurs in the liver and kidney in humans. When panels of tumors are compared with normal tissues, GH expression is elevated in cancerous hepatic and breast tissue. A second poly-Gamma-glutamate hydrolyzing enzyme, glutamate carboxypeptidase II, is a transmembrane protein whose active site is on the outside of the cell, occurring in the prostate gland, small intestine, brain, kidney, and tumor neovasculature. It is a high-affinity (nanomolar), low-turnover, zinc co-catalytic enzyme. In contrast, GH is a low-affinity (micromolar), high-turnover enzyme that has a cysteine at the active site. Data are presented suggesting that Cys110 is the nucleophile that attacks the Gamma-amide linkage and causes hydrolysis. GH is being evaluated as an intracellular target for inhibition in order to enhance the therapeutic activity of antifolates and fluorouracil.
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Site-directed mutagenesis establishes cysteine-110 as essential for enzyme activity in human Gamma-Glutamyl Hydrolase.
Biochemical Journal, 1999Co-Authors: Karen J. Chave, John Galivan, Thomas J. RyanAbstract:Gamma-Glutamyl Hydrolase (GH), which hydrolyses the Gamma-Glutamyl conjugates of folic acid, is a key enzyme in the maintenance of cellular folylpolyglutamate concentrations. The catalytic mechanism of GH is not known. Consistent with earlier reports that GH is sulphydryl-sensitive, we found that recombinant human GH is inhibited by iodoacetic acid, suggesting that at least one cysteine is important for activity [Rhee, Lindau-Shepard, Chave, Galivan and Ryan (1998) Mol. Pharmacol. 53, 1040-1046]. Using site-directed mutagenesis, the cDNA for human GH was altered to encode four different proteins each with one of four cysteine residues changed to alanine. Three of the mutant proteins had activities similar to wild-type GH and were inhibited by iodoacetic acid, whereas the C110A mutant had no activity. Cys-110 is conserved among the human, rat and mouse GH amino acid sequences. The wild-type protein and all four mutants had similar intrinsic fluorescence spectra, indicating no major structural changes had been introduced. These results indicate that Cys-110 is essential for enzyme activity and suggest that GH is a cysteine peptidase. These studies represent the first identification of the essential Cys residue in this enzyme and provide the beginning of a framework to determine the catalytic mechanism, important in defining GH as a therapeutic target.
John Galivan - One of the best experts on this subject based on the ideXlab platform.
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Identification of single nucleotide polymorphisms in the human γ-Glutamyl Hydrolase gene and characterization of promoter polymorphisms
Gene, 2003Co-Authors: Karen J. Chave, Thomas J. Ryan, Stacey E Chmura, John GalivanAbstract:Gamma-Glutamyl Hydrolase (GGH) plays a central role in folate metabolism and antifolate action. Increased GGH activity has been found in rat hepatoma cells resistant to the cancer drug methotrexate (MTX). The aim of this study was to identify polymorphisms in the GGH gene that modulate GGH activity and that may affect methotrexate resistance. Exons of the human Gamma-Glutamyl Hydrolase (hGGH) gene were amplified by polymerase chain reaction (PCR) from breast cancer tissue and leukemia cell lines. Single-stranded conformational polymorphism (SSCP) analysis was performed, and PCR products containing different patterns were cloned and sequenced. Six single nucleotide polymorphisms (SNPs) were identified, at bases -401C>T, -354G>T, -124T>G, +16T>C, +452C>T, and +1102A>G, relative to the A of the translation start codon being considered as +1. The SNP at +16, which changes codon -19 (relative to the start of the mature hGGH protein) in the endoplasmic reticulum targeting sequence of hGGH protein from cysteine to arginine, has previously been identified in this laboratory. The SNP at +452 changes the conserved hGGH protein codon 127 from threonine to isoleucine. The functions of SNPs in the promoter of the hGGH gene were studied by site-directed mutagenesis of a 516-bp region of the hGGH gene promoter in a luciferase reporter vector and transfection into HepG2 and MCF-7 cells. All of the promoter polymorphisms enhanced the production of luciferase compared to the wild-type hGGH gene promoter in HepG2 cells, and -401C>T and -124T>G enhanced luciferase expression in MCF-7 cells, suggesting that polymorphisms in the hGGH gene promoter may increase expression of hGGH protein.
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Characterization of the human γ-Glutamyl Hydrolase promoter and its gene expression in human tissues and cancer cell lines
Gene, 2003Co-Authors: Dezhong Yin, John Galivan, Rong YaoAbstract:Human Gamma-Glutamyl Hydrolase (hGH) plays an important role in the metabolism of folic acid and the pharmacology of antifolates such as methotrexate. We have previously cloned and characterized hGH cDNA and its gene. We report here that the levels of hGH gene expression are high in tissues such as liver, kidney, and placenta as determined by Northern blot and RT-PCR analyses. In contrast, hGH expression is relatively low in spleen, lung, small intestine, and peripheral blood leukocytes. In addition, high levels of hGH mRNA were detected in most cancer cell lines examined. There was no significant difference in hGH mRNA levels between breast cancer tissues and their normal counterparts, although breast cancer tissues generally appeared to have heterogeneous expression of hGH mRNA. Deletion analysis and transient transfection assays were performed. A positive regulatory element located from -52 to +4 relative to the transcriptional start site was found to be required for basal promoter activity in both HepG2 and MCF-7 cells. Also, transcriptional inhibitory elements were found at -96 to-52 and +88 to+104 in MCF-7 cells, but not in HepG2 cells. These data provide novel insights into the regulation of hGH gene transcription in HepG2 and MCF-7 cells.
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Glutamyl Hydrolase: pharmacological role and enzymatic characterization
Pharmacology & therapeutics, 2000Co-Authors: John Galivan, Thomas J. Ryan, Rong Yao, Karen J. Chave, Myung S. Rhee, Dezhong YinAbstract:Gamma-Glutamyl Hydrolase (GH, EC 3.4.19.9) is a lysosomal and secreted glycoprotein that hydrolyzes the Gamma-Glutamyl tail of antifolate and folate polyglutamates. Tumor cells that have high levels of GH are inherently resistant to classical antifolates, and further resistance can be acquired by elevations in GH following exposure to this class of antitumor agents. The highest level of expression in normal tissues occurs in the liver and kidney in humans. When panels of tumors are compared with normal tissues, GH expression is elevated in cancerous hepatic and breast tissue. A second poly-Gamma-glutamate hydrolyzing enzyme, glutamate carboxypeptidase II, is a transmembrane protein whose active site is on the outside of the cell, occurring in the prostate gland, small intestine, brain, kidney, and tumor neovasculature. It is a high-affinity (nanomolar), low-turnover, zinc co-catalytic enzyme. In contrast, GH is a low-affinity (micromolar), high-turnover enzyme that has a cysteine at the active site. Data are presented suggesting that Cys110 is the nucleophile that attacks the Gamma-amide linkage and causes hydrolysis. GH is being evaluated as an intracellular target for inhibition in order to enhance the therapeutic activity of antifolates and fluorouracil.
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Site-directed mutagenesis establishes cysteine-110 as essential for enzyme activity in human Gamma-Glutamyl Hydrolase.
Biochemical Journal, 1999Co-Authors: Karen J. Chave, John Galivan, Thomas J. RyanAbstract:Gamma-Glutamyl Hydrolase (GH), which hydrolyses the Gamma-Glutamyl conjugates of folic acid, is a key enzyme in the maintenance of cellular folylpolyglutamate concentrations. The catalytic mechanism of GH is not known. Consistent with earlier reports that GH is sulphydryl-sensitive, we found that recombinant human GH is inhibited by iodoacetic acid, suggesting that at least one cysteine is important for activity [Rhee, Lindau-Shepard, Chave, Galivan and Ryan (1998) Mol. Pharmacol. 53, 1040-1046]. Using site-directed mutagenesis, the cDNA for human GH was altered to encode four different proteins each with one of four cysteine residues changed to alanine. Three of the mutant proteins had activities similar to wild-type GH and were inhibited by iodoacetic acid, whereas the C110A mutant had no activity. Cys-110 is conserved among the human, rat and mouse GH amino acid sequences. The wild-type protein and all four mutants had similar intrinsic fluorescence spectra, indicating no major structural changes had been introduced. These results indicate that Cys-110 is essential for enzyme activity and suggest that GH is a cysteine peptidase. These studies represent the first identification of the essential Cys residue in this enzyme and provide the beginning of a framework to determine the catalytic mechanism, important in defining GH as a therapeutic target.
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CHARACTERIZATION OF HUMAN CELLULAR Gamma -Glutamyl Hydrolase
Molecular pharmacology, 1998Co-Authors: Myung S. Rhee, Karen J. Chave, John Galivan, B. Lindau-shepard, Thomas J. RyanAbstract:A previously identified cDNA encoding a human γ-Glutamyl Hydrolase was expressed in a baculovirus system. The expressed protein had molecular mass of 37 kDa. Treatment of the protein with PNGase F produced a protein of molecular mass of 30 kDa, indicating that the protein contained asparagine-linked glycosylation. Sequence analysis of the expressed protein indicated that a 24-amino-acid signal peptide had been removed. A polyclonal antibody to the expressed enzyme was used in Western blot analysis of partially purified lysates of HL-60 promyeloid leukemia cells and MCF-7 breast cancer cells. The HL-60 and MCF-7 enzymes appeared as two closely spaced bands with a molecular mass of 37 kDa. Treatment of the HL-60 enzyme with PNGase F produced a protein with a molecular mass of 30 kDa. The activities of the expressed enzyme and the enzyme from HL-60 cells were similar on methotrexate polyglutamates. Methotrexate-γ-Glu is a poor substrate for the human enzyme relative to methotrexate γ-Glu2–5. During hydrolysis of methotrexate-γ-Glu4, all possible pterin-containing cleavage products (methotrexate and methotrexate-γ-Glu1–3) appear. The results demonstrated that the human enzyme cleaves both the ultimate and penultimate γ-linkages of methotrexate polyglutamates. Glutamate was released as either glutamic acid or γ-Glu2. Longer chain species of γ-Glun>2 were not observed. Inhibition by iodoacetic acid suggested that both the expressed enzyme and the HL-60 enzyme may contain a catalytically essential cysteine. These results indicate that the identified cDNA encodes the intracellular γ-Glutamyl Hydrolase found in a variety of human tumor cells and that the baculovirus-expressed enzyme is a suitable model for further structural and enzymatic studies.
Sotaro Sadahiro - One of the best experts on this subject based on the ideXlab platform.
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Gene expression levels of Gamma-Glutamyl Hydrolase in tumor tissues may be a useful biomarker for the proper use of S-1 and tegafur-uracil/leucovorin in preoperative chemoradiotherapy for patients with rectal cancer
Cancer Chemotherapy and Pharmacology, 2017Co-Authors: Sotaro Sadahiro, T. Suzuki, A. Tanaka, K. Okada, G. Saito, H. Miyakita, T. Ogimi, H. NagaseAbstract:Purpose Preoperative chemoradiotherapy (CRT) using 5-fluorouracil (5-FU)-based chemotherapy is the standard of care for rectal cancer. The effect of additional chemotherapy during the period between the completion of radiotherapy and surgery remains unclear. Predictive factors for CRT may differ between combination chemotherapy with S-1 and with tegafur-uracil/leucovorin (UFT/LV). Methods The subjects were 54 patients with locally advanced rectal cancer who received preoperative CRT with S-1 or UFT/LV. The pathological tumor response was assessed according to the tumor regression grade (TRG). The expression levels of 18 CRT-related genes were determined using RT-PCR assay. Results A pathological response (TRG 1-2) was observed in 23 patients (42.6%). In a multivariate logistic regression analysis for pathological response, the overall expression levels of four genes, HIF1A, MTHFD1, GGH and TYMS, were significant, and the accuracy rate of the predictive model was 83.3%. The effects of the gene expression levels of GGH on the response differed significantly according to the treatment regimen. The total pathological response rate of both high-GGH patients in the S-1 group and low-GGH patients in the UFT/LV group was 58.3%. Conclusion Additional treatment with 5-FU-based chemotherapy during the interval between radiotherapy and surgery is not beneficial in patients who have received 5-FU-based CRT. The expression levels of four genes, HIF1A, MTHFD1, GGH and TYMS, in tumor tissues can predict the response to preoperative CRT including either S-1 or UFT/LV. In particular, the gene expression level of GGH in tumor tissues may be a useful biomarker for the appropriate use of S-1 and UFT/LV in CRT.
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Gene expression levels of Gamma-Glutamyl Hydrolase in tumor tissues may be a useful biomarker for the proper use of S-1 and tegafur-uracil/leucovorin in preoperative chemoradiotherapy for patients with rectal cancer.
Cancer chemotherapy and pharmacology, 2017Co-Authors: Sotaro Sadahiro, T. Suzuki, A. Tanaka, G. Saito, H. Miyakita, T. Ogimi, Ken-ichi Okada, H. NagaseAbstract:Purpose Preoperative chemoradiotherapy (CRT) using 5-fluorouracil (5-FU)-based chemotherapy is the standard of care for rectal cancer. The effect of additional chemotherapy during the period between the completion of radiotherapy and surgery remains unclear. Predictive factors for CRT may differ between combination chemotherapy with S-1 and with tegafur-uracil/leucovorin (UFT/LV).
Zepeng Ping - One of the best experts on this subject based on the ideXlab platform.
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serum protein Gamma Glutamyl Hydrolase ig Gamma 3 chain c region and haptoglobin are associated with the syndromes of pulmonary tuberculosis in traditional chinese medicine
BMC Complementary and Alternative Medicine, 2015Co-Authors: Tingting Jiang, Chong Wang, Liliang Wei, Liying Shi, Zhongliang Chen, Zepeng PingAbstract:Traditional Chinese Medicine (TCM) has been applied in treating tuberculosis (TB) based on the TCM syndromes with the effects of inhibiting Mycobacterium, strengthening the body immune system, and reducing the pulmonary toxicity. We used bioinformatic methods to study the clinical and pathological characteristics of pulmonary TB patients with TCM syndromes. Isobaric tags for relative and absolute quantification - coupled two dimensional liquid chromatography-tandem mass spectrometry (iTRAQ-2DLC-MS/MS) methods were applied to screen differentially expressed serum proteins. Pulmonary TB cases were divided into four distinctive TCM syndromes: pulmonary Yin deficiency (PYD) syndrome, hyperactivity of fire due to Yin deficiency (HFYD) syndrome, deficiency of Qi and Yin (DQY) syndrome, and deficiency of Yin and Yang (DYY) syndrome. The serum samples from 214 pulmonary TB patients were collected, and the clinical and pathological data was analyzed by using iTRAQ-2DLC-MS/MS. Finally, the differentially expressed proteins were screened and tested by ELISA. Only 5 patients with DYY syndrome were recruited in 3 years, which were not enough for further research. The DQY cases had higher erythrocyte sedimentation rate (ESR) compared to the PYD and HFYD cases (P = 0.0178). 94.44 % (12 PYD, 18 HFYD, and 4 DQY before anti-TB treatment) of 36 treated TB cases were transformed to PYD accompanied with the reduction of ESR and absorption of pulmonary lesions. A total of 39 differentially expressed proteins (ratios of >1.3 or <0.75) were found among the three TCM syndromes. Proteomic studies revealed that Gamma-Glutamyl Hydrolase (GGH), Ig Gamma-3 chain C region (IGHG3), and haptoglobin (HPT) were specifically over-expressed in PYD (P < 0.01), HFYD (P < 0.001), and DQY cases (P < 0.01), respectively. Furthermore, GGH was significantly higher in PYD cases compared to the HFYD and DQY cases (P < 0.01, P < 0.001, respectively), whereas IGHG3 was significantly higher in HFYD cases than PYD and DQY cases (P < 0.001, P < 0.01, respectively). The results suggest that TCM syndromes are significantly correlated with the pulmonary lesions and ESR. GGH was associated with folate metabolism in PYD cases, IGHG3 was linked to the control of Mycobacterium infection in HFYD patients, and HPT was involved in hypoxia in DQY patients. The present study provides new biological basis to understand the pathological changes and proteomic differences of TB syndromes.
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Serum protein Gamma-Glutamyl Hydrolase, Ig Gamma-3 chain C region, and haptoglobin are associated with the syndromes of pulmonary tuberculosis in traditional Chinese medicine.
BMC complementary and alternative medicine, 2015Co-Authors: Tingting Jiang, Chong Wang, Liliang Wei, Liying Shi, Zhongliang Chen, Zepeng PingAbstract:Traditional Chinese Medicine (TCM) has been applied in treating tuberculosis (TB) based on the TCM syndromes with the effects of inhibiting Mycobacterium, strengthening the body immune system, and reducing the pulmonary toxicity. We used bioinformatic methods to study the clinical and pathological characteristics of pulmonary TB patients with TCM syndromes. Isobaric tags for relative and absolute quantification - coupled two dimensional liquid chromatography-tandem mass spectrometry (iTRAQ-2DLC-MS/MS) methods were applied to screen differentially expressed serum proteins. Pulmonary TB cases were divided into four distinctive TCM syndromes: pulmonary Yin deficiency (PYD) syndrome, hyperactivity of fire due to Yin deficiency (HFYD) syndrome, deficiency of Qi and Yin (DQY) syndrome, and deficiency of Yin and Yang (DYY) syndrome. The serum samples from 214 pulmonary TB patients were collected, and the clinical and pathological data was analyzed by using iTRAQ-2DLC-MS/MS. Finally, the differentially expressed proteins were screened and tested by ELISA. Only 5 patients with DYY syndrome were recruited in 3 years, which were not enough for further research. The DQY cases had higher erythrocyte sedimentation rate (ESR) compared to the PYD and HFYD cases (P = 0.0178). 94.44 % (12 PYD, 18 HFYD, and 4 DQY before anti-TB treatment) of 36 treated TB cases were transformed to PYD accompanied with the reduction of ESR and absorption of pulmonary lesions. A total of 39 differentially expressed proteins (ratios of >1.3 or
