The Experts below are selected from a list of 19992 Experts worldwide ranked by ideXlab platform
Leo Feferman - One of the best experts on this subject based on the ideXlab platform.
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abstract 4698 increased chst15 expression follows declines in arylsulfatase b arsb and dkk3 and disinhibition of non canonical wnt signaling
Cancer Research, 2020Co-Authors: Leo FefermanAbstract:CHST15 (carbohydrate sulfotransferase 15; Chondroitin 4-Sulfate-6-sulfotransferase), is the sulfotransferase enzyme which adds 6-Sulfate to Chondroitin 4-Sulfate to make Chondroitin 4,6-Sulfate, known as CSE. Increased CHST15 expression has been identified in malignant pancreas, renal, colon, ovary, and prostate tissues. We now report a pathway by which expression of CHST15 is increased following decline in the enzyme ARSB (arylsulfatase B; N-acetylgalactosamine-4-sulfatase), which is required for removal of 4-Sulfate groups from Chondroitin 4-Sulfate (C4S). Previous work has shown that decline in ARSB and the resulting increase in C4S leads to decline in activity of SHP2, a ubiquitous non-receptor tyrosine phosphatase, due to enhanced binding of SHP2 with C4S when ARSB is reduced. Decline in SHP2 leads to enhanced ERK1/2 phosphorylation and subsequent downstream effects, including hypermethylation of the DKK (Dickkopf WNT signaling pathway inhibitor)3 promoter and suppressed DKK3 expression. Since DKK3 acts to inhibit Wnt signaling, Wnt signaling is enhanced in prostate epithelium when ARSB is reduced. Experiments were performed to identify the pathway by which CHST15 expression is up-regulated when ARSB is reduced and to assess the role of Wnt. The impact of ARSB silencing on CHST15 expression was determined in normal and malignant human prostate cells, in normal and malignant prostate tissue obtained by laser-capture microdissection, in HepG2 cells, and in prostate tissue of the ARSB-null mouse. Effects of selective inhibitors of Wnt and MAPK signaling pathways on CHST15 expression were evaluated. CHST15 expression was increased in malignant prostate epithelial tissue, in ARSB-null mouse prostate tissue, and following ARSB silencing in human prostate epithelial cells. The activation of Wnt signaling which followed declines in ARSB and DKK3 was required for increased CHST15 expression. Inhibition of Wnt3A blocked the increase in CHST15 expression in prostate epithelial cells co-cultured with prostate stromal cells, whereas DKK3 antibody increased CHST15. Inhibition of Rac-1 GTPase and of phospho-p38 MAPK signaling blocked the observed increase in CHST15 expression, whereas inhibition of JNK, Sp1, or of Rho kinase had no effect. These results indicate that the increase in epithelial CHST15 occurred in the malignant prostate cells and tissue due to effects of non-canonical Wnt signaling leading to enhanced phospho-p38 MAPK. The resultant increase in CHST15 when ARSB activity is reduced may contribute to determination of epithelial vs. stromal characteristics. Citation Format: Joanne Kramer Tobacman, Sumit Bhattacharyya, Leo Feferman. Increased CHST15 expression follows declines in Arylsulfatase B (ARSB) and DKK3 and disinhibition of non-canonical WNT signaling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4698.
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abstract 4699 decline in arylsulfatase b arsb increases pd l1 expression in melanoma hepatic prostate and mononuclear cells
Cancer Research, 2020Co-Authors: Leo FefermanAbstract:Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) is the enzyme that removes 4-Sulfate groups from Chondroitin 4-Sulfate (C4S) and dermatan Sulfate. In previous work, we have shown decline in ARSB with increasing aggressiveness of melanoma cell lines and in association with more aggressive prostate cancers. As ARSB decreases, Chondroitin 4-Sulfate increases, leading to increased binding of SHP2 (PTP11; non-receptor tyrosine phosphatase) and reduced binding of galectin-3. Subsequent effects include increase in phospho-ERK1/2 and transcriptional effects, including hypermethylation of the DKK3 promoter and reduced expression of DKK (Dickkopf WNT pathway signaling inhibitor) 3, leading to activation of Wnt signaling. Other transcriptional events following silencing of ARSB include: increased expression of CSPG4 and MMP-2 in melanoma cells; increased expression of versican in prostate epithelial cells; increased expression of Wnt9A in colonic epithelial cells; and increased MITF-mediated expression of GPNMB in hepatic cells. Invasiveness of cultured melanoma cells increased when ARSB was silenced by siRNA. To further address the role of ARSB, metastatic melanoma tissue was obtained from the biorepository of the University of Illinois at Chicago. Expression of CSPG4 and MMP2 was increased in the metastatic tissues and SHP2 activity was reduced. When ARSB was silenced by siRNA in cultured normal melanocytes (PCS 200-013, ATCC), Programmed Death-Ligand (PD-L)1 increased from 78 ± 7 pg/mg protein to 128 ± 11 pg/mg protein (ELISA assay; p Citation Format: Joanne Kramer Tobacman, Sumit Bhattacharyya, Leo Feferman. Decline in Arylsulfatase B (ARSB) increases PD-L1 expression in melanoma, hepatic, prostate, and mononuclear cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4699.
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increased chst15 follows decline in arylsulfatase b arsb and disinhibition of non canonical wnt signaling potential impact on epithelial and mesenchymal identity
Oncotarget, 2020Co-Authors: Sumit Bhattacharyya, Leo Feferman, Xiaorui Han, Ke Xia, Fuming Zhang, Robert J Linhardt, Joanne K TobacmanAbstract:Expression of CHST15 (carbohydrate sulfotransferase 15; Chondroitin 4-Sulfate-6-sulfotransferase; BRAG), the sulfotransferase enzyme that adds 6-Sulfate to Chondroitin 4-Sulfate (C4S) to make Chondroitin 4,6-diSulfate (Chondroitin Sulfate E, CSE), was increased in malignant prostate epithelium obtained by laser capture microdissection and following arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) silencing in human prostate epithelial cells. Experiments in normal and malignant human prostate epithelial and stromal cells and tissues, in HepG2 cells, and in the ARSB-null mouse were performed to determine the pathway by which CHST15 expression is up-regulated when ARSB expression is reduced. Effects of Wnt-containing prostate stromal cell spent media and selective inhibitors of WNT, JNK, p38, SHP2, β-catenin, Rho, and Rac-1 signaling pathways were determined. Activation of WNT signaling followed declines in ARSB and Dickkopf WNT Signaling Pathway Inhibitor (DKK)3 and was required for increased CHST15 expression. The increase in expression of CHST15 followed activation of non-canonical WNT signaling and involved Wnt3A, Rac-1 GTPase, phospho-p38 MAPK, and nuclear DNA-bound GATA-3. Inhibition of JNK, Sp1, β-catenin nuclear translocation, or Rho kinase had no effect. Consistent with higher expression of CHST15 in prostate epithelium, disaccharide analysis showed higher levels of CSE and Chondroitin 6-Sulfate (C6S) disaccharides in prostate epithelial cells. In contrast, Chondroitin 4-Sulfate (C4S) disaccharides were greater in prostate stromal cells. CSE may contribute to increased C4S in malignant epithelium when GALNS (N-aceytylgalactosamine-6-Sulfate sulfatase) is increased and ARSB is reduced. These effects increase Chondroitin 4-Sulfates and reduce Chondroitin 6-Sulfates, consistent with enhanced stromal characteristics and epithelial-mesenchymal transition.
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arylsulfatase b is reduced in prostate cancer recurrences
Cancer Biomarkers, 2017Co-Authors: Leo Feferman, Peter H Gann, Ryan Deaton, Hui Xie, Jonathan MelamedAbstract:BACKGROUND Arylsulfatase B (ARSB) removes the 4-Sulfate group from Chondroitin 4-Sulfate (C4S) and dermatan Sulfate and is required for their degradation. Prior work showed that ARSB immunohistochemical scores were lower in malignant prostate tissue, and were associated with higher Gleason scores and recurrence. OBJECTIVE This study aims to confirm that ARSB immunostaining of prostate tissue obtained at the time of radical prostatectomy is prognostic for prostate cancer recurrence. METHODS Intensity and distribution of ARSB immunostaining were digitally analyzed in a large, well-annotated, prostate cancer tissue microarray (TMA). Scores were calculated for stroma and epithelium and compared for 191 cases, including 36 recurrences, defined as PSA > 0.2 ng/ml. RESULTS Epithelial scores were significantly lower in the recurrences (p= 0.010), and among subgroups with age > 60, initial PSA > 6 ng/ml, or Gleason grade = 7. ARSB score did not improve the prediction of recurrence in multifactorial analysis. CONCLUSIONS Study findings validate previous findings and provide further evidence that lower ARSB is associated with prostate cancer recurrence. Additional studies are required to assess if there are specific cutoff values that may help predict recurrence.
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decline in arylsulfatase b leads to increased invasiveness of melanoma cells
Oncotarget, 2017Co-Authors: Leo Feferman, Kaoru Terai, Arkadiusz Z DudekAbstract:// Sumit Bhattacharyya 1, 2 , Leo Feferman 1, 2 , Kaoru Terai 1 , Arkadiusz Z. Dudek 1, 2 , Joanne K. Tobacman 1, 2 1 Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA 2 Jesse Brown VA Medical Center, Chicago, IL 60612, USA Correspondence to: Joanne K. Tobacman, email: jkt@uic.edu Keywords: arylsulfatase B, Chondroitin 4-Sulfate, galectin-3, invasiveness, malignant melanoma Received: August 29, 2016 Accepted: November 21, 2016 Published: December 01, 2016 ABSTRACT Arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase) is reduced in several malignancies, but levels in melanoma have not been investigated previously. Experiments were performed in melanoma cell lines to determine ARSB activity and impact on melanoma invasiveness. ARSB activity was reduced ~50% in melanoma cells compared to normal melanocytes. Silencing ARSB significantly increased the mRNA expression of Chondroitin Sulfate proteoglycan(CSPG)4 and pro-matrix metalloproteinase(MMP)-2, known mediators of melanoma progression. Also, invasiveness and MMP activity increased when ARSB was reduced, and recombinant ARSB inhibited invasiveness and MMP activity. Since the only known function of ARSB is to remove 4-Sulfate groups from the N-acetylgalactosamine 4-Sulfate residue at the non-reducing end of Chondroitin 4-Sulfate (C4S) or dermatan Sulfate, experiments were performed to determine the transcriptional mechanisms by which expression of CSPG4 and MMP2 increased. Promoter activation of CSPG4 was mediated by reduced binding of galectin-3 to C4S when ARSB activity declined. In contrast, increased pro-MMP2 expression was mediated by increased binding of the non-receptor tyrosine phosphatase SHP2 to C4S. Increased phospho-ERK1,2 resulted from SHP2 inhibition. Combined effects of increased C4S, CSPG4, and MMP2 increased the invasiveness of the melanoma cells, and therapy with recombinant ARSB may inhibit melanoma progression.
Marina Guizzetti - One of the best experts on this subject based on the ideXlab platform.
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decline in arylsulfatase b and increase in Chondroitin 4 sulfotransferase combine to increase Chondroitin 4 Sulfate in traumatic brain injury
Journal of Neurochemistry, 2015Co-Authors: Xiaolu Zhang, Leo Feferman, Frank C Tortella, David Johnson, Marina GuizzettiAbstract:In an established rat model of penetrating ballistic-like brain injury (PBBI), arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase) activity was significantly reduced at the ipsilateral site of injury, but unaffected at the contralateral site or in sham controls. In addition, the ARSB substrate Chondroitin 4-Sulfate (C4S) and total Sulfated glycosaminoglycans increased. The mRNA expression of Chondroitin 4-sulfotransferase 1 (C4ST1; CHST11) and the sulfotransferase activity rose at the ipsilateral site of injury (PBBI-I), indicating contributions from both increased production and reduced degradation to the accumulation of C4S. In cultured, fetal rat astrocytes, following scratch injury, the ARSB activity declined and the nuclear hypoxia inducible factor (HIF)-1α increased significantly. In contrast, sulfotransferase activity and Chondroitin 4-sulfotransferase expression increased following astrocyte exposure to TGF-β1, but not following scratch. These different pathways by which C4S increased in the cell preparations were both evident in the response to injury in the PBBI-I model. Hence, findings support effects of injury due to mechanical disruption inhibiting ARSB and to chemical mediation by TGF-β1 increasing CHST11 expression and sulfotransferase activity. The increase in C4S following TBI is due to contributions from impaired degradation and enhanced synthesis of C4S which combine in the pathogenesis of the glial scar.
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decline in arylsulfatase b and increase in Chondroitin 4 sulfotransferase combine to increase Chondroitin 4 Sulfate in traumatic brain injury
Journal of Neurochemistry, 2015Co-Authors: Leo Feferman, Frank C Tortella, Xiaolu Zhang, David Johnson, Marina GuizzettiAbstract:In an established rat model of penetrating ballistic-like brain injury (PBBI), arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase) activity was significantly reduced at the ipsilateral site of injury, but unaffected at the contralateral site or in sham controls. In addition, the ARSB substrate Chondroitin 4-Sulfate (C4S) and total Sulfated glycosaminoglycans increased. The mRNA expression of Chondroitin 4-sulfotransferase 1 (C4ST1; CHST11) and the sulfotransferase activity rose at the ipsilateral site of injury (PBBI-I), indicating contributions from both increased production and reduced degradation to the accumulation of C4S. In cultured, fetal rat astrocytes, following scratch injury, the ARSB activity declined and the nuclear hypoxia inducible factor-1α increased significantly. In contrast, sulfotransferase activity and Chondroitin 4-sulfotransferase expression increased following astrocyte exposure to TGF-β1, but not following scratch. These different pathways by which C4S increased in the cell preparations were both evident in the response to injury in the PBBI-I model. Hence, findings support effects of injury because of mechanical disruption inhibiting ARSB and to chemical mediation by TGF-β1 increasing CHST11 expression and sulfotransferase activity. The increase in C4S following traumatic brain injury is because of contributions from impaired degradation and enhanced synthesis of C4S which combine in the pathogenesis of the glial scar. This is the first report of how two mechanisms contribute to the increase in Chondroitin 4-Sulfate (C4S) in TBI. Following penetrating ballistic-like brain injury in a rat model and in the scratch model of injury in fetal rat astrocytes, Arylsulfatase B activity declined, leading to accumulation of C4S. TGF-β1 exposure increased expression of Chondroitin 4-sulfotransferase. Hence, the increase in C4S in TBI is attributable to both impaired degradation and enhanced synthesis, combining in the pathogenesis of the glial scar.
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arylsulfatase b modulates neurite outgrowth via astrocyte Chondroitin 4 Sulfate dysregulation by ethanol
Glia, 2014Co-Authors: Xiaolu Zhang, Marina Guizzetti, Handojo Kusumo, Charles R GoodlettAbstract:In utero ethanol exposure causes Fetal Alcohol Spectrum Disorders, associated with reduced brain plasticity; the mechanisms of these effects are not well understood, particularly with respect to glial involvement. Astrocytes release factors that modulate neurite outgrowth. We explored the hypothesis that ethanol inhibits neurite outgrowth by increasing the release of inhibitory Chondroitin Sulfate proteoglycans (CSPGs) from astrocytes. Astrocyte treatment with ethanol inhibited the activity of arylsulfatase B (ARSB), the enzyme that removes Sulfate groups from Chondroitin-4-Sulfate (C4S) and triggers the degradation of C4S, increased total Sulfated glycosaminoglycans (GAGs), C4S, and neurocan core-protein content and inhibited neurite outgrowth in neurons co-cultured with ethanol-treated astrocytes in vitro, effects reversed by treatment with recombinant ARSB. Ethanol also inhibited ARSB activity and increased Sulfate GAG and neurocan levels in the developing hippocampus after in vivo ethanol exposure. ARSB silencing increased the levels of Sulfated GAGs, C4S, and neurocan in astrocytes and inhibited neurite outgrowth in co-cultured neurons, indicating that ARSB activity directly regulates C4S and affects neurocan expression. In summary, this study reports two major findings: ARSB modulates Sulfated GAG and neurocan levels in astrocytes and astrocyte-mediated neurite outgrowth in co-cultured neurons; and ethanol inhibits the activity of ARSB, increases Sulfated GAG, C4S, and neurocan levels, and thereby inhibits astrocyte-mediated neurite outgrowth. An unscheduled increase in CSPGs in the developing brain may lead to altered brain connectivity and to premature decrease in neuronal plasticity and therefore represents a novel mechanism by which ethanol can exert its neurodevelopmental effects.
Xiaolu Zhang - One of the best experts on this subject based on the ideXlab platform.
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decline in arylsulfatase b and increase in Chondroitin 4 sulfotransferase combine to increase Chondroitin 4 Sulfate in traumatic brain injury
Journal of Neurochemistry, 2015Co-Authors: Xiaolu Zhang, Leo Feferman, Frank C Tortella, David Johnson, Marina GuizzettiAbstract:In an established rat model of penetrating ballistic-like brain injury (PBBI), arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase) activity was significantly reduced at the ipsilateral site of injury, but unaffected at the contralateral site or in sham controls. In addition, the ARSB substrate Chondroitin 4-Sulfate (C4S) and total Sulfated glycosaminoglycans increased. The mRNA expression of Chondroitin 4-sulfotransferase 1 (C4ST1; CHST11) and the sulfotransferase activity rose at the ipsilateral site of injury (PBBI-I), indicating contributions from both increased production and reduced degradation to the accumulation of C4S. In cultured, fetal rat astrocytes, following scratch injury, the ARSB activity declined and the nuclear hypoxia inducible factor (HIF)-1α increased significantly. In contrast, sulfotransferase activity and Chondroitin 4-sulfotransferase expression increased following astrocyte exposure to TGF-β1, but not following scratch. These different pathways by which C4S increased in the cell preparations were both evident in the response to injury in the PBBI-I model. Hence, findings support effects of injury due to mechanical disruption inhibiting ARSB and to chemical mediation by TGF-β1 increasing CHST11 expression and sulfotransferase activity. The increase in C4S following TBI is due to contributions from impaired degradation and enhanced synthesis of C4S which combine in the pathogenesis of the glial scar.
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decline in arylsulfatase b and increase in Chondroitin 4 sulfotransferase combine to increase Chondroitin 4 Sulfate in traumatic brain injury
Journal of Neurochemistry, 2015Co-Authors: Leo Feferman, Frank C Tortella, Xiaolu Zhang, David Johnson, Marina GuizzettiAbstract:In an established rat model of penetrating ballistic-like brain injury (PBBI), arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase) activity was significantly reduced at the ipsilateral site of injury, but unaffected at the contralateral site or in sham controls. In addition, the ARSB substrate Chondroitin 4-Sulfate (C4S) and total Sulfated glycosaminoglycans increased. The mRNA expression of Chondroitin 4-sulfotransferase 1 (C4ST1; CHST11) and the sulfotransferase activity rose at the ipsilateral site of injury (PBBI-I), indicating contributions from both increased production and reduced degradation to the accumulation of C4S. In cultured, fetal rat astrocytes, following scratch injury, the ARSB activity declined and the nuclear hypoxia inducible factor-1α increased significantly. In contrast, sulfotransferase activity and Chondroitin 4-sulfotransferase expression increased following astrocyte exposure to TGF-β1, but not following scratch. These different pathways by which C4S increased in the cell preparations were both evident in the response to injury in the PBBI-I model. Hence, findings support effects of injury because of mechanical disruption inhibiting ARSB and to chemical mediation by TGF-β1 increasing CHST11 expression and sulfotransferase activity. The increase in C4S following traumatic brain injury is because of contributions from impaired degradation and enhanced synthesis of C4S which combine in the pathogenesis of the glial scar. This is the first report of how two mechanisms contribute to the increase in Chondroitin 4-Sulfate (C4S) in TBI. Following penetrating ballistic-like brain injury in a rat model and in the scratch model of injury in fetal rat astrocytes, Arylsulfatase B activity declined, leading to accumulation of C4S. TGF-β1 exposure increased expression of Chondroitin 4-sulfotransferase. Hence, the increase in C4S in TBI is attributable to both impaired degradation and enhanced synthesis, combining in the pathogenesis of the glial scar.
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arylsulfatase b modulates neurite outgrowth via astrocyte Chondroitin 4 Sulfate dysregulation by ethanol
Glia, 2014Co-Authors: Xiaolu Zhang, Marina Guizzetti, Handojo Kusumo, Charles R GoodlettAbstract:In utero ethanol exposure causes Fetal Alcohol Spectrum Disorders, associated with reduced brain plasticity; the mechanisms of these effects are not well understood, particularly with respect to glial involvement. Astrocytes release factors that modulate neurite outgrowth. We explored the hypothesis that ethanol inhibits neurite outgrowth by increasing the release of inhibitory Chondroitin Sulfate proteoglycans (CSPGs) from astrocytes. Astrocyte treatment with ethanol inhibited the activity of arylsulfatase B (ARSB), the enzyme that removes Sulfate groups from Chondroitin-4-Sulfate (C4S) and triggers the degradation of C4S, increased total Sulfated glycosaminoglycans (GAGs), C4S, and neurocan core-protein content and inhibited neurite outgrowth in neurons co-cultured with ethanol-treated astrocytes in vitro, effects reversed by treatment with recombinant ARSB. Ethanol also inhibited ARSB activity and increased Sulfate GAG and neurocan levels in the developing hippocampus after in vivo ethanol exposure. ARSB silencing increased the levels of Sulfated GAGs, C4S, and neurocan in astrocytes and inhibited neurite outgrowth in co-cultured neurons, indicating that ARSB activity directly regulates C4S and affects neurocan expression. In summary, this study reports two major findings: ARSB modulates Sulfated GAG and neurocan levels in astrocytes and astrocyte-mediated neurite outgrowth in co-cultured neurons; and ethanol inhibits the activity of ARSB, increases Sulfated GAG, C4S, and neurocan levels, and thereby inhibits astrocyte-mediated neurite outgrowth. An unscheduled increase in CSPGs in the developing brain may lead to altered brain connectivity and to premature decrease in neuronal plasticity and therefore represents a novel mechanism by which ethanol can exert its neurodevelopmental effects.
Joanne K Tobacman - One of the best experts on this subject based on the ideXlab platform.
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increased expression of Chondroitin sulfotransferases following angii may contribute to pathophysiology underlying covid 19 respiratory failure impact may be exacerbated by decline in arylsulfatase b activity
bioRxiv, 2020Co-Authors: Sumit Bhattacharyya, Kumar Kotlo, Joanne K TobacmanAbstract:Abstract The spike protein of SARS-CoV-2 binds to respiratory epithelium through the ACE2 receptor, an endogenous receptor for Angiotensin II (AngII). The mechanisms by which this viral infection leads to hypoxia and respiratory failure have not yet been elucidated. Interactions between the Sulfated glycosaminoglycans heparin and heparan Sulfate and the SARS-CoV-2 spike glycoprotein have been identified as participating in viral adherence and infectivity. In this brief report, we present data indicating that stimulation of vascular smooth muscle cells by AngII leads to increased expression of two Chondroitin sulfotransferases (CHST11 and CHST15), which are required for the synthesis of the Sulfated glycosaminoglycans Chondroitin 4-Sulfate (C4S) and Chondroitin 4,6-diSulfate (CSE). We suggest that increased expression of these Chondroitin sulfotransferases and the ensuing production of Chondroitin Sulfates may contribute to viral adherence to bronchioalveolar cells and to the progression of respiratory disease in Covid-19. The enzyme Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase), which removes 4-Sulfate groups from the non-reducing end of Chondroitin 4-Sulfate residues, is required for degradation of C4S and CSE. In hypoxic conditions or following treatment with chloroquine, ARSB activity is reduced. Decline in ARSB can contribute to ongoing accumulation and airway obstruction by C4S and CSE. Decline in ARSB leads to increased expression of Interleukin(IL)-6 in human bronchial epithelial cells, and IL-6 is associated with cytokine storm in Covid-19. These findings indicate how Chondroitin Sulfates, Chondroitin sulfotransferases, and Chondroitin sulfatases may participate in the progression of hypoxic respiratory insufficiency in Covid-19 disease and suggest new therapeutic targets.
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increased chst15 follows decline in arylsulfatase b arsb and disinhibition of non canonical wnt signaling potential impact on epithelial and mesenchymal identity
Oncotarget, 2020Co-Authors: Sumit Bhattacharyya, Leo Feferman, Xiaorui Han, Ke Xia, Fuming Zhang, Robert J Linhardt, Joanne K TobacmanAbstract:Expression of CHST15 (carbohydrate sulfotransferase 15; Chondroitin 4-Sulfate-6-sulfotransferase; BRAG), the sulfotransferase enzyme that adds 6-Sulfate to Chondroitin 4-Sulfate (C4S) to make Chondroitin 4,6-diSulfate (Chondroitin Sulfate E, CSE), was increased in malignant prostate epithelium obtained by laser capture microdissection and following arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) silencing in human prostate epithelial cells. Experiments in normal and malignant human prostate epithelial and stromal cells and tissues, in HepG2 cells, and in the ARSB-null mouse were performed to determine the pathway by which CHST15 expression is up-regulated when ARSB expression is reduced. Effects of Wnt-containing prostate stromal cell spent media and selective inhibitors of WNT, JNK, p38, SHP2, β-catenin, Rho, and Rac-1 signaling pathways were determined. Activation of WNT signaling followed declines in ARSB and Dickkopf WNT Signaling Pathway Inhibitor (DKK)3 and was required for increased CHST15 expression. The increase in expression of CHST15 followed activation of non-canonical WNT signaling and involved Wnt3A, Rac-1 GTPase, phospho-p38 MAPK, and nuclear DNA-bound GATA-3. Inhibition of JNK, Sp1, β-catenin nuclear translocation, or Rho kinase had no effect. Consistent with higher expression of CHST15 in prostate epithelium, disaccharide analysis showed higher levels of CSE and Chondroitin 6-Sulfate (C6S) disaccharides in prostate epithelial cells. In contrast, Chondroitin 4-Sulfate (C4S) disaccharides were greater in prostate stromal cells. CSE may contribute to increased C4S in malignant epithelium when GALNS (N-aceytylgalactosamine-6-Sulfate sulfatase) is increased and ARSB is reduced. These effects increase Chondroitin 4-Sulfates and reduce Chondroitin 6-Sulfates, consistent with enhanced stromal characteristics and epithelial-mesenchymal transition.
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Schematic illustration of signaling pathway from ↓ARSB → ↑Chondroitin 4-Sulfate → ↑SHP2 bound → ↓SHP2 activity → ↑phospho-p38 → ↑MITF → ↑GPNMB.
2016Co-Authors: Sumit Bhattacharyya, Leo Feferman, Joanne K TobacmanAbstract:(A) When ARSB activity is normal, the 4-Sulfate group at the non-reducing end of the C4S chain is removed from C4S and the binding of SHP2 to C4S is not increased. Hence, SHP2 can remove tyrosine phosphate from p38. (B) When ARSB is reduced and Chondroitin 4-sulfation is increased, SHP2 binding to C4S is increased and SHP2 activity is reduced. There is inhibition of removal of tyrosine phosphate from p38, leading to increased phosphorylation of p38 and of MITF, leading to activation of the GPNMB promoter. [ARSB = arylsulfatase B; C4S = Chondroitin 4-Sulfate; GPNMB = glycoprotein (transmembrane) NMB; MITF = microphthalmia-associated transcription factor; P = phosphate; S = Sulfate]
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Increase in SHP2 that co-immunoprecipitates with C4S following ARSB knockdown.
2016Co-Authors: Sumit Bhattacharyya, Leo Feferman, Joanne K TobacmanAbstract:(A) Western blot of SHP2 co-immunoprecipitated with C4S shows increased band density following ARSB silencing compared to control silencing (n = 2). The C4S content increased following ARSB silencing, with similar protein. (B) Densitometry showed increased intensity of the immunoprecipitated bands following ARSB silencing (p = 0.007, unpaired t-test, two-tailed; n = 2). (C) HepG2 cells were treated with PHSP1, a chemical SHP2 inhibitor and with DN, CA, or WT SHP2 DNA vectors. These exposures had no effect on the ARSB activity. (p>0.05, one-way ANOVA with Tukey-Kramer post-test; n = 3). (D) Treatment with PHSP1 or with DN. CA, or WT SHP2 DNA vectors did not modify the Chondroitin 4-Sulfate in the HepG2 cells. [ARSB = arylsulfatase B; CA = constitutively active; con si = control siRNA; DN = dominant negative; Inh = inhibitor; N.D. = no difference; OE = overexpression; si = siRNA; Vcon = vector control; WT = wild-type]
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molecular signature of kappa carrageenan mimics Chondroitin 4 Sulfate and dermatan Sulfate and enables interaction with arylsulfatase b
Journal of Nutritional Biochemistry, 2012Co-Authors: Sumit Bhattacharyya, Joanne K TobacmanAbstract:The common food additive kappa-carrageenan (κ-CGN) is a Sulfated polysaccharide that resembles Chondroitin-4-Sulfate (C4S) and dermatan Sulfate (DS). All have a Sulfate group on C4 of a glycoside (galactose for CGN and N-acetylgalactosamine for C4S), and the Sulfate-bearing glycoside is linked in a β-1,4-configuration to an unSulfated, six-carbon sugar (galactose for CGN, glucuronate for C4S and iduronate for DS). The enzyme arylsulfatase B (ARSB; N-acetylgalactosamine-4-Sulfate) is the highly selective enzyme that removes the four-Sulfate group from the nonreducing terminus of C4S and DS, thereby regulating subsequent degradation. In this report, κ-CGN is shown to be a substrate for recombinant human ARSB (rhARSB). Sulfate was generated from both C4S and κ-CGN following incubation with rhARSB. Exposure of human colonic epithelial cells to κ-CGN, but not to C4S, produced reactive oxygen species (ROS) and increased interleukin (IL)-8 secretion. The ROS production from κ-CGN was reduced by exposure to rhARSB, but increased by competition from C4S or DS, but not from Chondroitin-6-Sulfate. Prior treatment of either lambda- or iota-CGN with rhARSB had no impact on ROS, IL-8 or inorganic Sulfate production, demonstrating a specific effect of the molecular configuration of κ-CGN. By mimicry of C4S and DS and by interaction with ARSB, κ-CGN can directly interfere with the normal cellular functions of C4S, DS and ARSB. Since C4S and DS are present in high concentration in tissues, the impact of κ-CGN exposure may be due to some extent to interference with the normal biological functions of ARSB, C4S and DS.
Channe D Gowda - One of the best experts on this subject based on the ideXlab platform.
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molecular architecture and domain arrangement of the placental malaria protein var2csa suggests a model for carbohydrate binding
Journal of Biological Chemistry, 2020Co-Authors: Maria C Bewley, Channe D Gowda, Lovely Gautam, Mashanipalya G Jagadeeshaprasad, John M FlanaganAbstract:VAR2CSA is the placental-malaria–specific member of the antigenically variant Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family. It is expressed on the surface of Plasmodium falciparum-infected host red blood cells and binds to specific Chondroitin-4-Sulfate chains of the placental proteoglycan receptor. The functional ∼310 kDa ectodomain of VAR2CSA is a multidomain protein that requires a minimum 12-mer Chondroitin-4-Sulfate molecule for specific, high affinity receptor binding. However, it is not known how the individual domains are organized and interact to create the receptor-binding surface, limiting efforts to exploit its potential as an effective vaccine or drug target. Using small angle X-ray scattering and single particle reconstruction from negative-stained electron micrographs of the ectodomain and multidomain constructs, we have determined the structural architecture of VAR2CSA. The relative locations of the domains creates two distinct pores that can each accommodate the 12-mer of Chondroitin-4-Sulfate, suggesting a model for receptor binding. This model has important implications for understanding cytoadherence of infected red blood cells and potentially provides a starting point for developing novel strategies to prevent and/or treat placental malaria.
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targeted disruption of a ring infected erythrocyte surface antigen resa like export protein gene in plasmodium falciparum confers stable Chondroitin 4 Sulfate cytoadherence capacity
Journal of Biological Chemistry, 2014Co-Authors: Suchi Goel, Arivalagan Muthusamy, Jun Miao, Liwang Cui, Ali Salanti, Elizabeth A Winzeler, Channe D GowdaAbstract:The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family proteins mediate the adherence of infected erythrocytes to microvascular endothelia of various organs, including the placenta, thereby contributing to cerebral, placental, and other severe malaria pathogenesis. Several parasite proteins, including KAHRP and PfEMP3, play important roles in the cytoadherence by mediating the clustering of PfEMP1 in rigid knoblike structures on the infected erythrocyte surface. The lack of a subtelomeric region of chromosome 2 that contains kahrp and pfemp3 causes reduced cytoadherence. In this study, microarray transcriptome analysis showed that the absence of a gene cluster, comprising kahrp, pfemp3, and four other genes, results in the loss of parasitized erythrocytes adhering to Chondroitin 4-Sulfate (C4S). The role of one of these genes, PF3D7_0201600/PFB0080c, which encodes PHISTb (Plasmodium helical interspersed subtelomeric b) domain-containing RESA-like protein 1 expressed on the infected erythrocyte surface, was investigated. Disruption of PFB0080c resulted in increased var2csa transcription and VAR2CSA surface expression, leading to higher C4S-binding capacity of infected erythrocytes. Further, PFB0080c-knock-out parasites stably maintained the C4S adherence through many generations of growth. Although the majority of PFB0080c-knock-out parasites bound to C4S even after culturing for 6 months, a minor population bound to both C4S and CD36. These results strongly suggest that the loss of PFB0080c markedly compromises the var gene switching process, leading to a marked reduction in the switching rate and additional PfEMP1 expression by a minor population of parasites. PFB0080c interacts with VAR2CSA and modulates knob-associated Hsp40 expression. Thus, PFB0080c may regulate VAR2CSA expression through these processes. Overall, we conclude that PFB0080c regulates PfEMP1 expression and the parasite's cytoadherence.
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structural interactions in Chondroitin 4 Sulfate mediated adherence of plasmodium falciparum infected erythrocytes in human placenta during pregnancy associated malaria
Biochemistry, 2008Co-Authors: Rajeshwara N Achur, Keiichi Takagaki, Subbarao V Madhunapantula, Suchi Goel, Ikuko Kakizaki, Kaoru Kojima, Atul Goyal, Misato Ohta, Sanjeev Kumar, Channe D GowdaAbstract:Infection with Plasmodium falciparum during pregnancy results in the adherence of infected red blood cells (IRBCs) in placenta, causing pregnancy-associated malaria with severe health complications in mothers and fetuses. The Chondroitin 4-Sulfate (C4S) chains of very low Sulfated Chondroitin Sulfate proteoglycans (CSPGs) in placenta mediate the IRBC adherence. While it is known that partially Sulfated but not fully Sulfated C4S effectively binds IRBCs, structural interactions involved remain unclear and are incompletely understood. In this study, structurally defined C4S oligosaccharides of varying Sulfate contents and sizes were evaluated for their ability to inhibit the binding of IRBCs from different P. falciparum strains to CSPG purified from placenta. The results clearly show that, with all parasite strains studied, dodecasaccharide is the minimal chain length required for the efficient adherence of IRBCs to CSPG and two 4-Sulfated disaccharides within this minimal structural motif are sufficient for maximal binding. Together, these data demonstrate for the first time that the C4S structural requirement for IRBC adherence is parasite strain-independent. We also show that the carboxyl group on nonreducing end glucuronic acid in dodecasaccharide motif is important for IRBC binding. Thus, in oligosaccharides containing terminal 4,5-unsaturated glucuronic acid, the nonreducing end disaccharide moiety does not interact with IRBCs due to the altered spatial orientation of carboxyl group. In such C4S oligosaccharides, 14-mer but not 12-mer constitutes the minimal motif for inhibition of IRBC binding to placental CSPG. These data have important implications for the development and evaluation of therapeutics and vaccine for placental malaria.
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developmental stage and cell cycle number dependent changes in characteristics of plasmodium falciparum infected erythrocyte adherence to placental Chondroitin 4 Sulfate proteoglycan
Infection and Immunity, 2007Co-Authors: Subbarao V Madhunapantula, Rajeshwara N Achur, Channe D GowdaAbstract:The adherence of Plasmodium falciparum-infected red blood cells (IRBCs) in the human placenta is mediated by Chondroitin-4-Sulfate (C4S). Although IRBC binding to C4S has been unequivocally established, the adherence characteristics of IRBCs at different stages of parasite development and through successive parasite generations after selection for C4S adherence are not known. Here we show that IRBCs acquire a significant capacity to bind to C4S at as early as 14 h and exhibit maximum binding at 22 to 26 h postinvasion. Surprisingly, the IRBC binding ability decreases by ∼50% at the late trophozoite and schizont stages. The binding strength of the IRBCs also gradually decreases during successive generations after selection for C4S binding, and at the 32nd generation, the binding capacity was only ∼31% of that of IRBCs at the 2nd generation, suggesting that IRBCs eventually lose their C4S-adherent capacity. We also tested the susceptibility of the adhesive protein(s) on the IRBC surface to trypsin treatment at different stages of parasite development. The data show that IRBCs with late trophozoites are more resistant to trypsin treatment than those containing early trophozoites, indicating that parasite proteins expressed on the IRBC surface during trophozoite maturation partially mask accessibility of adhesive protein for binding to C4S. These data provide important insights into the expression pattern of the C4S-adhesive protein(s) on the IRBC surface, emphasizing the need for understanding the regulation of genes involved in IRBC binding to C4S. Our data also define the parasite stage at which IRBCs are suitable for studying structural interactions with C4S.
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structural basis for the adherence of plasmodium falciparum infected erythrocytes to Chondroitin 4 Sulfate and design of novel photoactivable reagents for the identification of parasite adhesive proteins
Journal of Biological Chemistry, 2007Co-Authors: A Prakasha S Gowda, Subbarao V Madhunapantula, Rajeshwara N Achur, V P Bhavanandan, Manojkumar Valiyaveettil, Channe D GowdaAbstract:Abstract A dodecasaccharide motif of the low-Sulfated Chondroitin 4-Sulfate (C4S) mediate the binding of Plasmodium falciparum-infected red blood cells (IRBCs) in human placenta. Here we studied the detailed C4S structural requirements by assessing the ability of chemically modified C4S to inhibit IRBC binding to the placental Chondroitin Sulfate proteoglycan. Replacement of the N-acetyl groups with bulky N-acyl or N-benzoyl substituents had no effect on the inhibitory activity of C4S, whereas reduction of the carboxyl groups abrogated the activity. Dermatan Sulfates showed ∼50% inhibitory activity when compared with C4Ss with similar Sulfate contents. These data demonstrate that the C4S carboxyl groups and their equatorial orientation but not the N-acetyl groups are critical for IRBC binding. Conjugation of bulky substituents to the reducing end N-acetylgalactosamine residues of C4S dodecasaccharide had no effect on its inhibitory activity. Based on these results, we prepared photoaffinity reagents for the identification of the parasite proteins involved in C4S binding. Cross-linking of the IRBCs with a radioiodinated photoactivable C4S dodecasaccharide labeled a ∼22-kDa novel parasite protein, suggesting strongly for the first time that a low molecular weight IRBC surface protein rather than a 200–400-kDa PfEMP1 is involved in C4S binding. Conjugation of biotin to the C4S dodecasaccharide photoaffinity probe afforded a strategy for the isolation of the labeled protein by avidin affinity precipitation, facilitating efforts to identify the C4S-adherent IRBC protein(s). Our results also have broader implications for designing oligosaccharide-based photoaffinity probes for the identification of proteins involved in glycosaminoglycan-dependent attachment of microbes to hosts.