bims-supasi 2023-07-30 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2023–07–30
eight papers selected by
Jonathan Wolf Mueller, University of Birmingham

Chondrocyte Homeostasis and Differentiation: Transcriptional Control and Signaling in Healthy and Osteoarthritic Conditions.
Assimilation behaviors and metabolite formations of estrone sulfate sodium (E1-3S) and 17β-estradiol-3-O-sulfate sodium (E2-3S) in the wheat.
Suppression of Indoxyl Sulfate Accumulation Reduces Renal Fibrosis in Sulfotransferase 1a1-Deficient Mice.
ADY tripeptide is a minimum sequence for Tyrosylprotein sulfotransferases 1 and 2 substrate recognition.
Photobiomodulation inhibits the expression of chondroitin sulfate proteoglycans after spinal cord injury via the Sox9 pathway.
Analysis of evolutionary and functional features of the bullfrog SULT1 family.
Gut Microbiome and Microbiome-Derived Metabolites in Patients with End-Stage Kidney Disease.
Placing steroid hormones within the human ABCC3 transporter reveals a compatible amphiphilic substrate-binding pocket.

Life (Basel). 2023 Jun 28. pii: 1460. [Epub ahead of print]13(7):

Chondrocyte Homeostasis and Differentiation: Transcriptional Control and Signaling in Healthy and Osteoarthritic Conditions.

Yara M Michelacci, Raquel Y A Baccarin, Nubia N P Rodrigues.

  Chondrocytes are the main cell type in articular cartilage. They are embedded in an avascular, abundant, and specialized extracellular matrix (ECM). Chondrocytes are responsible for the synthesis and turnover of the ECM, in which the major macromolecular components are collagen, proteoglycans, and non-collagen proteins. The crosstalk between chondrocytes and the ECM plays several relevant roles in the regulation of cell phenotype. Chondrocytes live in an avascular environment in healthy cartilage with a low oxygen supply. Although chondrocytes are adapted to anaerobic conditions, many of their metabolic functions are oxygen-dependent, and most cartilage oxygen is supplied by the synovial fluid. This review focuses on the transcription control and signaling responsible for chondrocyte differentiation, homeostasis, senescence, and cell death and the changes that occur in osteoarthritis. The effects of chondroitin sulfate and other molecules as anti-inflammatory agents are also approached and analyzed.

Keywords:  apoptosis; chondrocyte transcription control; chondroitin sulfate; differentiation; osteoarthritis

DOI:  https://doi.org/10.3390/life13071460
J Environ Manage. 2023 Jul 26. pii: S0301-4797(23)01454-8. [Epub ahead of print]345 118666

Assimilation behaviors and metabolite formations of estrone sulfate sodium (E1-3S) and 17β-estradiol-3-O-sulfate sodium (E2-3S) in the wheat.

Shengwei Zhang, Jing Li, Yanxia Li, Linshu Jiang, Yan Zhao, Xiaoman Jiang, Xuelian Zhang, Wenzhuo Shi.

  The conjugated steroid estrogens (CSEs), including estrone sulfate sodium (E1-3 S) and 17β-estradiol-3-O-sulfate sodium (E2-3 S), exhibit distinct metabolic behaviors in the aqueous and soil environments. However, their assimilation behaviors and metabolite formations in plant bodies (shoots and roots) remain poorly understood. Therefore, this study used a modified plant hydroponic system to explore the efficiency with which wheat (Triticum acstivnm L.) assimilated the two estrogen conjugates, E1-3 S and E2-3 S. Results indicated the potential of wheat to absorb E1-3 S and E2-3 S, with their assimilation in the root being significantly higher (104-105 ng/g dw) than in the shoot (103-104 ng/g dw). E1-3 S de-sulfated and transformed to estrone (E1) at a rate of 4%-45% in the root's oxidative environment, whereas E2-3 S converted to E1-3 S at 210%-570%. However, the root-to-shoot transfer was impeded by a less potent metabolic activity within the shoot system. The co-exposure treatment revealed that E1 or 17β-estradiol (E2) affects the assimilation of E1-3 S and E2-3 S by wheat, with E1 inhibiting E1-3 S assimilation and E2 promoting E2-3 S assimilation in wheat bodies. Nonetheless, free-form steroid estrogens (FSEs), which typically have a significant hormone action, can oxidative-damage the wheat tissues, producing a progressive wilting of wheat leaf and so limiting the transpiration process. Co-exposure initially increased the assimilation amounts of E1-3 S (particularly in shoots) and E2-3 S (in both roots and shoots), but these values rapidly declined as exposure duration increased. The combined effects of E1-3 S and E2-3 S exposure also increased their assimilation. These findings suggest the need for further investigation into the cumulative impact of environmental estrogen contaminants. The findings of present study can potentially guide the development of strategies to prevent and manage steroid estrogen contamination in agricultural contexts.

Keywords:  Assimilation; Conjugated steroid estrogen; Hydroponics; Metabolic formations; Wheat

DOI:  https://doi.org/10.1016/j.jenvman.2023.118666
Int J Mol Sci. 2023 Jul 11. pii: 11329. [Epub ahead of print]24(14):

Suppression of Indoxyl Sulfate Accumulation Reduces Renal Fibrosis in Sulfotransferase 1a1-Deficient Mice.

Huixian Hou, Mai Horikawa, Yuki Narita, Hirofumi Jono, Yutaka Kakizoe, Yuichiro Izumi, Takashige Kuwabara, Masashi Mukoyama, Hideyuki Saito.

  Renal fibrosis is the final manifestation of chronic kidney disease (CKD); its prevention is vital for controlling CKD progression. Indoxyl sulfate (IS), a typical sulfate-conjugated uremic solute, is produced in the liver via the enzyme sulfotransferase (SULT) 1A1 and accumulates significantly during CKD. We investigated the toxicopathological role of IS in renal fibrosis using Sult1a1-KO mice and the underlying mechanisms. The unilateral ureteral obstruction (UUO) model was created; kidney IS concentrations, inflammation, and renal fibrosis were assessed on day 14. After UUO treatment, inflammation and renal fibrosis were exacerbated in WT mice, with an accumulation of IS in the kidney. However, they were significantly suppressed in Sult1a1-KO mice. CD206+ expression was upregulated, and β-catenin expression was downregulated in Sult1a1-KO mice. To confirm the impact of erythropoietin (EPO) on renal fibrosis, we evaluated the time-dependent expression of EPO. In Sult1a1-KO mice, EPO mRNA expression was improved considerably; UUO-induced renal fibrosis was further attenuated by recombinant human erythropoietin (rhEPO). Thus, UUO-induced renal fibrosis was alleviated in Sult1a1-KO mice with a decreased accumulation of IS. Our findings confirmed the pathological role of IS in renal fibrosis and identified SULT1A1 as a new therapeutic target enzyme for preventing and attenuating renal fibrosis.

Keywords:  indoxyl sulfate; renal fibrosis; sulfotransferase 1a1-deficient mice

DOI:  https://doi.org/10.3390/ijms241411329
Biochem Biophys Res Commun. 2023 Jul 17. pii: S0006-291X(23)00883-5. [Epub ahead of print]676 73-77

ADY tripeptide is a minimum sequence for Tyrosylprotein sulfotransferases 1 and 2 substrate recognition.

Yuta Hasegawa, Sayaka Tonsho, Taiyo Nakazawa, Tadashi Kainuma, Kaori Kagasaki, Shota Sakurai, Kouki Kitagawa, Shinichi Asada.

  Tyrosylprotein sulfotransferases (TPSTs) catalyze the transfer of a sulphonate moiety from 3'-Phosphoadenosine 5'-Phosphosulfate (PAPS) to the hydroxyl group of a tyrosine residue in substrate proteins. The positively charged substrate binding region of TPST homodimer interacts with acidic residues located in N-terminal region from the sulfated tyrosine in substrates. However, the sequence pattern in TPST substrate recognition remains unclear. Therefore, we aimed to determine the minimum recognition chain length required for tyrosine sulfation. We prepared His-tagged polypeptide, His-TPST143-370 and His-TPST243-377, form 43-370 of TPST1 and 43-377 of TPST2. Next, we prepared a series of synthesized ADYAE peptides and used a combination of reverse phase high-performance liquid chromatography (RP-HPLC) and mass spectrometric analysis to show that the tripeptide amino acid sequence, ADY, was sulfated by TPST1 and TPST2. Furthermore, we found that the acidic residue, located two residues C-terminal region from the tyrosine residue, may be involved in the TPST-induced sulfation regulation. The results in our study propose that proteins with the ADY sequence may be useful for searching the novel TPST tyrosine sulfated substrates.

Keywords:  Synthetic peptide; Tyrosine sulfation; Tyrosylprotein sulfotransferases

DOI:  https://doi.org/10.1016/j.bbrc.2023.07.026
Neural Regen Res. 2024 Jan;19(1): 180-189

Photobiomodulation inhibits the expression of chondroitin sulfate proteoglycans after spinal cord injury via the Sox9 pathway.

Zhihao Zhang, Zhiwen Song, Liang Luo, Zhijie Zhu, Xiaoshuang Zuo, Cheng Ju, Xuankang Wang, Yangguang Ma, Tingyu Wu, Zhou Yao, Jie Zhou, Beiyu Chen, Tan Ding, Zhe Wang, Xueyu Hu.

  Both glial cells and glia scar greatly affect the development of spinal cord injury and have become hot spots in research on spinal cord injury treatment. The cellular deposition of dense extracellular matrix proteins such as chondroitin sulfate proteoglycans inside and around the glial scar is known to affect axonal growth and be a major obstacle to autogenous repair. These proteins are thus candidate targets for spinal cord injury therapy. Our previous studies demonstrated that 810 nm photobiomodulation inhibited the formation of chondroitin sulfate proteoglycans after spinal cord injury and greatly improved motor function in model animals. However, the specific mechanism and potential targets involved remain to be clarified. In this study, to investigate the therapeutic effect of photobiomodulation, we established a mouse model of spinal cord injury by T9 clamping and irradiated the injury site at a power density of 50 mW/cm2 for 50 minutes once a day for 7 consecutive days. We found that photobiomodulation greatly restored motor function in mice and downregulated chondroitin sulfate proteoglycan expression in the injured spinal cord. Bioinformatics analysis revealed that photobiomodulation inhibited the expression of proteoglycan-related genes induced by spinal cord injury, and versican, a type of proteoglycan, was one of the most markedly changed molecules. Immunofluorescence staining showed that after spinal cord injury, versican was present in astrocytes in spinal cord tissue. The expression of versican in primary astrocytes cultured in vitro increased after inflammation induction, whereas photobiomodulation inhibited the expression of versican. Furthermore, we found that the increased levels of p-Smad3, p-P38 and p-Erk in inflammatory astrocytes were reduced after photobiomodulation treatment and after delivery of inhibitors including FR 180204, (E)-SIS3, and SB 202190. This suggests that Smad3/Sox9 and MAPK/Sox9 pathways may be involved in the effects of photobiomodulation. In summary, our findings show that photobiomodulation modulates the expression of chondroitin sulfate proteoglycans, and versican is one of the key target molecules of photobiomodulation. MAPK/Sox9 and Smad3/Sox9 pathways may play a role in the effects of photobiomodulation on chondroitin sulfate proteoglycan accumulation after spinal cord injury.

Keywords:  Erk; MAPK; P38; Smad3; Sox9; chondroitin sulfate proteoglycans; photobiomodulation; principal component analysis; spinal cord injury; versican

DOI:  https://doi.org/10.4103/1673-5374.374136
Gen Comp Endocrinol. 2023 Jul 24. pii: S0016-6480(23)00154-5. [Epub ahead of print] 114349

Analysis of evolutionary and functional features of the bullfrog SULT1 family.

Kosuke Sato, Kiyoshi Yamauchi, Akinori Ishihara.

We identified the bullfrog Rana catesbeiana sulfotransferase 1 (SULT1) family from the BLAST search tool of the public databases based on the SULT1 families of Nanorana parkeri, Xenopus laevis, and Xenopus tropicalis as queries, revealing the characteristics of the anuran SULT1 family. The results showed that the anuran SULT1 family comprises six subfamilies, four of which were related to the mammalian SULT1 subfamily. Additionally, the bullfrog has two SULT1Cc subfamily members that are consistent with the characteristics of the expanded Xenopus SULT1C subfamily. Several members of the bullfrog SULT1 family were suggested to play important roles in sulfation during metamorphosis. Among these, cDNAs encoding SULT1Cc1 and SULT1Y1 were cloned, and the sulfation activity was analyzed using recombinant proteins. The affinity for 2-naphthol and 3'-phosphoadenosine 5'-phosphosulfate (PAPS) and the enzymatic reaction rate were higher in SULT1Cc1 than in SULT1Y1. Both the enzymes showed inhibitory effect of many thyroid hormones (THs) analogs on the sulfation of 2-naphthol. The potency of sulfation activities of SULT1Cc1 and SULT1Y1 against T4 indicated their possible role in the intracellular T4 clearance during metamorphosis.

DOI: https://doi.org/10.1016/j.ygcen.2023.114349
Int J Mol Sci. 2023 Jul 14. pii: 11456. [Epub ahead of print]24(14):

Gut Microbiome and Microbiome-Derived Metabolites in Patients with End-Stage Kidney Disease.

Takeo Koshida, Tomohito Gohda, Takuya Sugimoto, Takashi Asahara, Rin Asao, Isao Ohsawa, Hiromichi Gotoh, Maki Murakoshi, Yusuke Suzuki, Yuichiro Yamashiro.

  The composition of the gut microbiome is altered in patients with chronic kidney disease (CKD). Dysbiosis leads to decreased levels of stool organic acids (OAs) and systemic inflammation, followed by accumulation of uremic toxins (UTs) and the development of end-stage kidney disease (ESKD). We assessed the relationship between the microbiome and UT levels or the development of ESKD by comparing patients undergoing hemodialysis (HD) and those with normal renal function (NRF). This cross-sectional study recruited 41 patients undergoing HD and 38 sex- and age-matched patients with NRF, and gut microbiome, levels of plasma UTs, inflammatory markers, and stool OAs were compared. The indices of beta-diversity differed significantly between patients with NRF and those undergoing HD, and between patients undergoing HD with and without type 2 diabetes. The levels of stool total OA, inflammatory markers, and UTs differed significantly between the patients with NRF and those undergoing HD. The combined main effects of type 2 diabetes and kidney function status were accumulation of indoxyl sulfate and p-cresyl sulfate. The relative abundances of Negativicutes and Megamonas were associated with development of ESKD and with the levels of UTs, even after adjustment for factors associated with the progression of ESKD. The present study indicates that the gut environment differs between patients with NRF and those undergoing HD and between patients undergoing HD with and without type 2 diabetes. Moreover, ESKD patients with diabetes accumulate more UTs derived from the gut microbiome, which might be associated with cardio-renal diseases and poor prognosis.

Keywords:  diabetic kidney disease; microbiome; uremic toxin

DOI:  https://doi.org/10.3390/ijms241411456
EMBO J. 2023 Jul 24. e113415

Placing steroid hormones within the human ABCC3 transporter reveals a compatible amphiphilic substrate-binding pocket.

Jie Wang, Xu Li, Fang-Fang Wang, Meng-Ting Cheng, Yao-Xu Mao, Shu-Cheng Fang, Liang Wang, Cong-Zhao Zhou, Wen-Tao Hou, Yuxing Chen.

  The human ABC transporter ABCC3 (also known as MRP3) transports a wide spectrum of substrates, including endogenous metabolites and exogenous drugs. Accordingly, it participates in multiple physiological processes and is involved in diverse human diseases such as intrahepatic cholestasis of pregnancy, which is caused by the intracellular accumulation of bile acids and estrogens. Here, we report three cryogenic electron microscopy structures of ABCC3: in the apo-form and in complexed forms bound to either the conjugated sex hormones β-estradiol 17-(β-D-glucuronide) and dehydroepiandrosterone sulfate. For both hormones, the steroid nuclei that superimpose against each other occupy the hydrophobic center of the transport cavity, whereas the two conjugation groups are separated and fixed by the hydrophilic patches in two transmembrane domains. Structural analysis combined with site-directed mutagenesis and ATPase activity assays revealed that ABCC3 possesses an amphiphilic substrate-binding pocket able to hold either conjugated hormone in an asymmetric pattern. These data build on consensus features of the substrate-binding pocket of MRPs and provide a structural platform for the rational design of inhibitors.

Keywords:  ABCC3; cryo-EM; hormone; multidrug resistance; substrate-binding pattern

DOI:  https://doi.org/10.15252/embj.2022113415