bims-supasi 2024-03-03 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024‒03‒03
seven papers selected by
Jonathan Wolf Mueller, University of Birmingham

Chondroitin sulfate-modified antiangiogenic peptide conjugate induces cell apoptosis via the mitochondria-mediated pathway to perform antitumor activity.
Dimethyl sulfate and diisopropyl sulfate as practical and versatile O-sulfation reagents.
SULTR2;1 Adjusts the Bolting Timing by Transporting Sulfate from Rosette Leaves to the Primary Stem.
Investigation of inhibitory effect of sulfated chitosan oligomer on human heparanase enzyme: in silico and in vitro studies.
Detoxification of Hyperglycemia-induced Glucose Toxicity by the Hexosamine Biosynthetic Pathway.
The influence of uremic toxins on low bone turnover disease in chronic kidney disease.
An integrated investigation of sulfotransferases (SULTs) in hepatocellular carcinoma and identification of the role of SULT2A1 on stemness.

Int J Biol Macromol. 2024 Jan 27. pii: S0141-8130(24)00474-4. [Epub ahead of print] 129671

Chondroitin sulfate-modified antiangiogenic peptide conjugate induces cell apoptosis via the mitochondria-mediated pathway to perform antitumor activity.

Yan Li, Jiaai Fu, Huiwen Hou, Wen Tang, Zengmei Liu, Didi Gao, Feiyan Zhao, XinQing Gao, Feng Sun, Haining Tan.

  Tumor growth and metastasis heavily rely on angiogenesis, crucial for solid tumor development. Inhibiting angiogenesis associated with tumors emerges as a potent therapeutic approach. Our previous work synthesized the chondroitin sulfate-modified antiangiogenic peptide CS-ES2-AF (CS-EA), which exhibited better antiangiogenic activity, longer half-life, and more robust targeting. In this work, we further evaluated the stability in vitro, cellular uptake mechanism, cell apoptosis mechanism, antitumor activity in vivo, and safety of CS-EA. The stability of CS-EA was consistently superior to that of EA at different temperatures and in different pH ranges. Furthermore, CS-EA mainly entered EAhy926 cells through the clathrin-mediated endocytosis pathway. CS-EA inhibited endothelial cell proliferation, and induced cell apoptosis through downregulating the Bcl-2, reducing mitochondria membrane potential, upregulating cytochrome c, Caspase 3, and reactive oxygen species levels. CS-EA showed better antitumor activity in the B16 xenografted tumor model, with a tumor inhibition rate 1.92 times higher than EA. Simultaneously, it was observed that CS-EA did not cause any harmful effects on the vital organs of the mice. These findings indicate that CS-EA holds significant promise for the treatment of tumors.

Keywords:  Antiangiogenic peptide; Antitumor; Chondroitin sulfate; Mechanism; Stability

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.129671
Nat Commun. 2024 Feb 29. 15(1): 1861

Dimethyl sulfate and diisopropyl sulfate as practical and versatile O-sulfation reagents.

Shuaishuai Yue, Guoping Ding, Ye Zheng, Chunlan Song, Peng Xu, Biao Yu, Jiakun Li.

O-Sulfation is a vital post-translational modification in bioactive molecules, yet there are significant challenges with their synthesis. Dialkyl sulfates, such as dimethyl sulfate and diisopropyl sulfate are commonly used as alkylation agents in alkaline conditions, and result in the formation of sulfate byproducts. We report herein a general and robust approach to O-sulfation by harnessing the tunable reactivity of dimethyl sulfate or diisopropyl sulfate under tetrabutylammonium bisulfate activation. The versatility of this O-sulfation protocol is interrogated with a diverse range of alcohols, phenols and N-OH compounds, including carbohydrates, amino acids and natural products. The enhanced electrophilicity of the sulfur atom in dialkyl sulfates, facilitated by the interaction with bisulfate anion (HSO4-), accounts for this pioneering chemical reactivity. We envision that our method will be useful for application in the comprehension of biological functions and discovery of drugs.

DOI: https://doi.org/10.1038/s41467-024-46214-x
Plant Cell Physiol. 2024 Mar 01. pii: pcae020. [Epub ahead of print]

SULTR2;1 Adjusts the Bolting Timing by Transporting Sulfate from Rosette Leaves to the Primary Stem.

Khamsalath Soudthedlath, Toshiki Nakamura, Tsukasa Ushiwatari, Jutarou Fukazawa, Keishi Osakabe, Yuriko Osakabe, Akiko Maruyama-Nakashita.

  Sulfur (S) is an essential macronutrient for plant growth and metabolism. SULTR2;1 is a low-affinity sulfate transporter facilitating the long-distance transport of sulfate in Arabidopsis. The physiological function of SULTR2;1 in the plant life cycle still needs to be determined. Therefore, we analyzed the sulfate transport, S-containing metabolites accumulation, and plant growth using Arabidopsis SULTR2;1 disruption lines, sultr2;1-1 and sultr2;1-2, from seedling to mature growth stages to clarify the metabolic and physiological roles of SULTR2;1. We observed that sulfate distribution to the stems was affected in sultr2;1 mutants resulting in decreased levels of sulfate, cysteine, glutathione (GSH), and total S in the stems, flowers, and siliques; however, the GSH levels increased in the rosette leaves. This suggested the essential role of SULTR2;1 in sulfate transport from rosette leaves to the primary stem. In addition, sultr2;1 mutants unexpectedly bolted earlier than the wild-type without affecting the plant biomass. Correlation between GSH levels in rosette leaves and the bolting timing suggested the rosette leaf GSH levels or limited sulfate transport to the early stem can trigger bolting. Overall, this study demonstrated the critical roles of SULTR2;1 in maintaining the S metabolite levels in the aerial part and transitioning from the vegetative to the reproductive growth phase.

Keywords:   Arabidopsis thaliana ; 1; bolting timing; plant growth and development; sulfate assimilation; sulfate transporter SULTR2; sulfate uptake and distribution

DOI:  https://doi.org/10.1093/pcp/pcae020
J Biomol Struct Dyn. 2024 Feb 27. 1-9

Investigation of inhibitory effect of sulfated chitosan oligomer on human heparanase enzyme: in silico and in vitro studies.

Samet Kocabay, M Abdullah Alagöz, Birnur Akkaya.

  Deaths from cancer are widespread worldwide and the numbers continue to increase day by day. During the disease progression of cancer in cells, many of its metabolic activities change. Increased heparanase enzyme release is just one example. Following heparanase enzyme activity, many molecules interact with the remodeling of glycosaminoglycan structures, which triggers the release of different enzymes, cytokines, and growth factors, including fibroblast growth factors (FGF1 and FGF2), vascular endothelial growth factor (VEGF), hepatocyte growth factor, transforming growth factor β and platelet-derived growth factor. These are the most important factors in metastasis due to the formation of new vascular structures caused by those elements. To reduce tumor growth and metastasis, various drugs have been designed by modifying chitosan and its derivatives. In this study, we used chitosan oligomer (A), sulfated chitosan oligomer (ShCsO) (B), heparin (C), phosphate monomer (D1) of PI-88 and sulfate monomer (D2) of PI-88 as heparanase inhibitors. We modified the chitosan oligomer with chlorosulfonic acid to synthesize ShCsO to investigate its inhibitory effects on human serum heparanase. Also examined were molecular docking; molecular dynamics (MD); adsorption, distribution, metabolism, elimination and toxicity (ADMET); and target prediction. ShCsO decreased enzyme activity at a concentration of 0.0001 mg/mL. The docking scores of A, B and C from in silico studies were -6.254, -6.936 and -6.980 kcal/mol, respectively, and the scores for the two different PI-88 monomers were -5.741 and -5.824 kcal/mol. These results show that ShCsO may be a potential drug candidate for treating cancer.Communicated by Ramaswamy H. Sarma.

Keywords:  Cancer; angiogenesis; chitosan; heparanase; metastasis; sulfated chitosan

DOI:  https://doi.org/10.1080/07391102.2024.2317421
Front Biosci (Landmark Ed). 2024 Feb 21. 29(2): 71

Detoxification of Hyperglycemia-induced Glucose Toxicity by the Hexosamine Biosynthetic Pathway.

Andrew Jun Wang, Aimin Wang, Vincent Hascall.

  The abnormal intermediate glucose metabolic pathways induced by elevated intracellular glucose levels during hyperglycemia often establish the metabolic abnormality that leads to cellular and structural changes in development and to progression of diabetic pathologies. Glucose toxicity generally refers to the hyperglycemia-induced irreversible cellular dysfunctions over time. These irreversible cellular dysfunctions in diabetic nephropathy include: (1) inflammatory responses, (2) mesangial expansion, and (3) podocyte dysfunction. Using these three cellular events in diabetic nephropathy as examples of glucose toxicity in the diabetic complications, this review focuses on: (1) the molecular and cellular mechanisms associated with the hexosamine biosynthetic pathway that underly glucose toxicity; and (2) the potential therapeutic tools to inhibit hyperglycemia induced pathologies. We propose novel therapeutic strategies that directly shunts intracellular glucose buildup under hyperglycemia by taking advantage of intracellular glucose metabolic pathways to dampen it by normal synthesis and secretion of hyaluronan, and/or by intracellular chondroitin sulfate synthesis and secretion. This could be a useful way to detoxify the glucose toxicity in hyperglycemic dividing cells, which could mitigate the hyperglycemia induced pathologies in diabetes.

Keywords:  4MU-xyloside; Hep-Tri; O-Glycosylation; diabetic nephropathy; glucose toxicity; heparin; hexosamine biosynthetic pathway; hyperglycemia; intracellular hyaluronan

DOI:  https://doi.org/10.31083/j.fbl2902071
Tzu Chi Med J. 2024 Jan-Mar;36(1):36(1): 38-45

The influence of uremic toxins on low bone turnover disease in chronic kidney disease.

Giou-Teng Yiang, Wen-Lin Su, Cai-Mei Zheng, Min-Tser Liao, Tong-Hong Cheng, Chien-Lin Lu, Kuo-Cheng Lu.

  Uremic toxins play a crucial role in the development of low bone turnover disease in chronic kidney disease (CKD) through the induction of oxidative stress. This oxidative stress disrupts the delicate balance between bone formation and resorption, resulting in a decline in both bone quantity and quality. Reactive oxygen species (ROS) activate nuclear factor kappa-B and mitogen-activated protein kinase signaling pathways, promoting osteoclastogenesis. Conversely, ROS hinder osteoblast differentiation by facilitating the binding of Forkhead box O proteins (FoxOs) to β-catenin, triggering apoptosis through FoxOs-activating kinase phosphorylation. This results in increased osteoblastic receptor activator of nuclear factor kappa-B ligand (RANKL) expression and decreased nuclear factor erythroid 2-related factor 2 levels, compromising antioxidant defenses against oxidative damage. As CKD progresses, the accumulation of protein-bound uremic toxins such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS) intensifies oxidative stress, primarily affecting osteoblasts. IS and PCS directly inhibit osteoblast viability, induce apoptosis, decrease alkaline phosphatase activity, and impair collagen 1 and osteonectin, impeding bone formation. They also reduce cyclic adenosine 3',5'-monophosphate (cAMP) production and lower parathyroid hormone (PTH) receptor expression in osteoblasts, resulting in PTH hyporesponsiveness. In summary, excessive production of ROS by uremic toxins not only reduces the number and function of osteoblasts but also induces PTH hyporesponsiveness, contributing to the initiation and progression of low bone turnover disease in CKD.

Keywords:  Chronic kidney disease; Low bone turnover disease; Oxidative stress; Uremic toxins

DOI:  https://doi.org/10.4103/tcmj.tcmj_212_23
Apoptosis. 2024 Feb 27.

An integrated investigation of sulfotransferases (SULTs) in hepatocellular carcinoma and identification of the role of SULT2A1 on stemness.

Hao Peng, Kun Feng, Weilu Jia, Yunxin Li, Qingpeng Lv, Yewei Zhang.

  The cytosolic sulfotransferases (SULTs) are phase II conjugating enzymes, which are widely expressed in the liver and mainly mediate the sulfation of numerous xenobiotics and endogenous compounds. However, the role of various SULTs genes has not been reported in hepatocellular carcinoma (HCC). This study aims to analyze the expression and potential functional roles of SULTs genes in HCC and to identify the role of SULT2A1 in HCC stemness as well as the possible mechanism. We found that all of the 12 SULTs genes were differentially expressed in HCC. Moreover, clinicopathological features and survival rates were also investigated. Multivariate regression analysis showed that SULT2A1 and SULT1C2 could be used as independent prognostic factors in HCC. SULT1C4, SULT1E1, and SULT2A1 were significantly associated with immune infiltration. SULT2A1 deficiency in HCC promoted chemotherapy resistance and stemness maintenance. Mechanistically, silencing of SULT2A1 activated the AKT signaling pathway, on the one hand, promoted the expression of downstream stemness gene c-Myc, on the other hand, facilitated the NRF2 expression to reduce the accumulation of ROS, and jointly increased HCC stemness. Moreover, knockdown NR1I3 was involved in the transcriptional regulation of SULT2A1 in stemness maintenance. In addition, SULT2A1 knockdown HCC cells promoted the proliferation and activation of hepatic stellate cells (HSCs), thereby exerting a potential stroma remodeling effect. Our study revealed the expression and role of SULTs genes in HCC and identified the contribution of SULT2A1 to the initiation and progression of HCC.

Keywords:  CAFs; HCC; HSCs; Immune infiltration; Stemness; Sulfotransferases; TME

DOI:  https://doi.org/10.1007/s10495-024-01938-5