Expression Of Sulfotransferases Research Articles

Cytosolic sulfotransferases in endocrine disruption.

The mammalian cytosolic sulfotransferases (SULTs) catalyze the sulfation of endocrine hormones as well as a broad array of drugs, environmental chemicals, and other xenobiotics. Many endocrine-disrupting chemicals (EDCs) interact with these SULTs as substrates and inhibitors, and thereby alter sulfation reactions responsible for metabolism and regulation of endocrine hormones such as estrogens and thyroid hormones. EDCs or their metabolites may also regulate expression of SULTs through direct interaction with nuclear receptors and other transcription factors. Moreover, some sulfate esters derived from EDCs (EDC-sulfates) may serve as ligands for endocrine hormone receptors. While the sulfation of an EDC can lead to its excretion in the urine or bile, it may also result in retention of the EDC-sulfate through its reversible binding to serum proteins and thereby enable transport to other tissues for intracellular hydrolysis and subsequent endocrine disruption. This mini-review outlines the potential roles of SULTs and sulfation in the effects of EDCs and our evolving understanding of these processes.

Developing liver-targeted naringenin nanoparticles for breast cancer endocrine therapy by promoting estrogen metabolism

Endocrine therapy is standard for hormone receptor–positive (HR+) breast cancer treatment. However, current strategies targeting estrogen signaling pay little attention to estradiol metabolism in the liver and is usually challenged by treatment failure. In a previous study, we demonstrated that the natural compound naringenin (NAR) inhibited HR+ breast cancer growth by activating estrogen sulfotransferase (EST) expression in the liver. Nevertheless, the poor water solubility, low bio-barrier permeability, and non-specific distribution limited its clinical application, particularly for oral administration. Here, a novel nano endocrine drug NAR-cell penetrating peptide-galactose nanoparticles (NCG) is reported. We demonstrated that NCG presented specific liver targeting and increased intestinal barrier permeability in both cell and zebrafish xenotransplantation models. Furthermore, NCG showed liver targeting and enterohepatic circulation in mouse breast cancer xenografts following oral administration. Notably, the cancer inhibition efficacy of NCG was superior to that of both NAR and the positive control tamoxifen, and was accompanied by increased hepatic EST expression and reduced estradiol levels in the liver, blood, and tumor tissue. Moreover, few side effects were observed after NCG treatment. Our findings reveal NCG as a promising candidate for endocrine therapy and highlight hepatic EST targeting as a novel therapeutic strategy for HR+ breast cancer.Graphical

Neuropeptide W protects against ovarian oxidative injury and reinforces ovarian steroidogenic activity via the upregulation of ERα expression.

The aim of this study was to investigate the protective effect of neuropeptide W (NPW) on ovarian ischemia-reperfusion-induced oxidative injury and ovarian steroid metabolism. Rats were randomly divided into control and ischemia groups that received either saline or NPW (0.1 or 5 μg/kg/day). Bilateral ovarian ischemia was performed for 3 h followed by a 72-h reperfusion. Blood, ovary, and uterus samples were collected for biochemical and histological assessments. Treatment with either dose of NPW alleviated oxidative injury of the ovaries with a significant suppression in free radical formation and decreased histopathological injury in both the ovarian and uterine tissues, along with reduced lipid peroxidation and neutrophil accumulation in the uterus. Moreover, NPW treatment reversed the decrease in aromatase expression with a concomitant reduction in the expression of the inactivity enzyme estrogen sulfotransferase. Also, downregulation of estrogen receptor-α (ERα) expression in the injured ovarian tissue was abolished by NPW treatment, which implicates that the protective effect of NPW on the female reproductive system may involve the upregulation of the ERα-mediated signaling pathway. Our study demonstrated for the first time that NPW protects against ovarian oxidative injury and reinforces ovarian steroidogenic activity, which is accompanied by the upregulation of ERα expression in the ovaries.

Jasmonates disrupt carrageenan synthesis during carposporogenesis in the red seaweed Grateloupia imbricata

In this study, we monitored changes in cell wall sulfated galactans in the red seaweed Grateloupia imbricata after the rapid (48 h) induction of cystocarp maturation and carpospore development by the volatile hormone methyl jasmonate (MEJA). Synthesis of sulfated galactans, carrageenans, which requires sulfated UDP galactose, was followed by expression analysis of genes encoding phosphoglucomutase (PGM), galactose-1-phosphate uridyltransferase (GALT), and those responsible for sulfate assimilation (S-transporter and sulfate adenylyltransferase, SAT). In addition, the expression of carbohydrate sulfotransferase and galactose-6-sulfurylase responsible for the addition and removal of sulfate groups to the galactans backbone were evaluated. Structural changes, such as thallus softening, were analyzed using Fourier-transformed infrared spectroscopy (FTIR) spectra, and ploidy was assessed using flow cytometry. The results showed downregulation of most of the genes encoding precursors or those in charge of transformation into sulfated hexoses for cell wall synthesis. Furthermore, alterations in the FTIR spectrum of carrageenan from MEJA-induced fertile thalli, such as the disappearance and flattening of absorption bands, were observed. The promptness of these events and the ploidy of thalli and spores seem to confirm the induction of mitotic production of haploid spores by MEJA.

Altered serum metabolome associated with vascular calcification developed from CKD and the critical pathways.

Vascular calcification (VC) is more likely to be detected in the chronic kidney disease (CKD) population. The mechanism of VC development from CKD is different from that for simple VC and has always been a major research area. The aim of this study was to detect alterations in the metabolome during development of VC in CKD and to identify the critical metabolic pathways and metabolites involved in its pathogenesis. Rats in the model group were given an adenine gavage combined with a high-phosphorus diet to imitate VC in CKD. The aorta calcium content was measured and used to divide the model group into a VC group and non-vascular calcification group (non-VC group). The control group was fed a normal rat diet and given a saline gavage. Ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) was used to determine the altered serum metabolome in the control, VC, and non-VC groups. The identified metabolites were mapped into the Kyoto Encyclopedia of Genes and Genomes (KEGG) database (https://www.genome.jp/kegg/) for pathway and network analyses. There were 14 metabolites that changed significantly in the VC group, with three metabolic pathways playing critical roles in the pathogenesis of VC in CKD: steroid hormone biosynthesis; valine, leucine and isoleucine biosynthesis; and pantothenate and CoA biosynthesis. Our results indicated changes in the expression of steroid sulfatase and estrogen sulfotransferase, and down-regulation of the in situ synthesis of estrogens in the VC group. In conclusion, the serum metabolome alters significantly during the pathogenesis of VC in CKD. The key pathways, metabolites, and enzymes we identified are worth further study and may become a promising therapeutic target for the treatment of VC in CKD.

Qualitative and quantitative analyses in sulfated glycosaminoglycans, chondroitin sulfate/dermatan sulfate, during 3T3-L1 adipocytes differentiation.

Chondroitin sulfate/dermatan sulfate (CS/DS) is a member of glycosaminoglycans (GAGs) found in animal tissues. Major CS/DS subclasses, O, A, C, D, and E units, exist based on the sulfation pattern in d-glucuronic acid (GlcA) and N-acetyl-d-galactosamine repeating units. DS is formed when GlcA is epimerized into l-iduronic acid. Our study aimed to analyze the CS/DS profile in 3 T3-L1 cells before and after adipogenic induction. CS/DS contents, molecular weight (Mw), and sulfation pattern were analyzed by using high-performance liquid chromatography. CS/DS synthesis- and sulfotransferase-related genes were analyzed by reverse transcription real-time PCR. CS/DS amount was significantly decreased in the differentiated (DI) group compared to the non-differentiated (ND) group, along with a lower expression of CS biosynthesis-related genes, chondroitin sulfate N-acetylgalactosaminyltransferase 1 and 2, as well as chondroitin polymerizing factor. GAGs in the DI group also showed lower Mw than those of ND. Furthermore, the A unit was the major CS/DS in both groups, with a proportionally higher CS-A in the DI group. This was consistent with the expression of carbohydrate sulfotransferase 12 that encodes chondroitin 4-O-sulfotransferase, for CS-A formation. These qualitative and quantitative changes in CS/DS and CS/DS-synthases before and after adipocyte differentiation reveal valuable insights into adipocyte development.

CARIES ASSOCIATED WITH RESTORATIONS IN PRIMARY MOLARS –AN 18-MONTHS FOLLOW-UP STUDY

Introduction: According to the scientific literature, sulfur contained in various foods and medicines is almost completely absorbed in the gastrointestinal tract. However, the role of sulfur containing mineral waters as a dietary source of sulfur still remains unrevealed. The focus of this study was the effect of sulfurous mineral water from two public fountains on the territory of Varna town on the expression rates of enzymes involved in the processes of sulfonation in human intestinal cells. Methods: Human intestinal epithelial cells were incubated with different percentage content of sulfurous mineral water in the growth medium. Cell viability was measured by the MTT test, and three concentrations of mineral water were chosen for gene expression analyses. The cells were treated with water samples with different residence times after filling: 24 hours, 3 and 7 days. Messenger RNA levels of two sulfotransferases isoforms (SULT1A1 and SULT1A3) and 3′-phosphoadenosine-5′-phosphosulfate synthase 1 (PAPSS1) were measured. Results: Significantly increased mRNA levels of both sulfotransferases were measured in cells treated with 24-hours samples from the two fountains. This stimulatory effect was dependent on the percentage content of mineral water in the culture medium. Despite the stimulated expression of sulfotransferases, higher volume concentrations of 24-hour samples of mineral water significantly inhibited the gene expression of PAPSS1. It could be suggested that the H2S, as a major active compound in the mineral water, has the potential to modulate the gene expression of the investigated enzymes. Conclusion: Sulfurous mineral water should be considered an important dietary source of sulfur. We believe that the presented results would be of interest to society and health professionals.

Schistosome Sulfotransferases: Mode of Action, Expression and Localization.

Oxamniquine (OXA) is a prodrug activated by a sulfotransferase (SULT) that was only active against Schistosoma mansoni. We have reengineered OXA to be effective against S. haematobium and S. japonicum. Three derivatives stand out, CIDD-0066790, CIDD-0072229, and CIDD-0149830 as they kill all three major human schistosome species. However, questions remain. Is the OXA mode of action conserved in derivatives? RNA-interference experiments demonstrate that knockdown of the SmSULT, ShSULT, and SjSULT results in resistance to CIDD-0066790. Confirming that the OXA-derivative mode of action is conserved. Next is the level of expression of the schistosome SULTs in each species, as well as changes in SULT expression throughout development in S. mansoni. Using multiple tools, our data show that SmSULT has higher expression compared to ShSULT and SjSULT. Third, is the localization of SULT in the adult, multicellular eucaryotic schistosome species. We utilized fluorescence in situ hybridization and uptake of radiolabeled OXA to determine that multiple cell types throughout the adult schistosome worm express SULT. Thus, we hypothesize the ability of many cells to express the sulfotransferase accounts for the ability of the OXA derivatives to kill adult worms. Our studies demonstrate that the OXA derivatives are able to kill all three human schistosome species and thus will be a useful complement to PZQ.

Loss of Hs3st3a1 or Hs3st3b1 enzymes alters heparan sulfate to reduce epithelial morphogenesis and adult salivary gland function

Heparan sulfate 3-O-sulfotransferases generate highly sulfated but rare 3-O-sulfated heparan sulfate (HS) epitopes on cell surfaces and in the extracellular matrix. Previous ex vivo experiments suggested functional redundancy exists among the family of seven enzymes but that Hs3st3a1 and Hs3st3b1 sulfated HS increases epithelial FGFR signaling and morphogenesis. Single-cell RNAseq analysis of control SMGs identifies increased expression of Hs3st3a1 and Hs3st3b1 in endbud and myoepithelial cells, both of which are progenitor cells during development and regeneration. To analyze their in vivo functions, we generated both Hs3st3a1−/- and Hs3st3b1−/- single knockout mice, which are viable and fertile. Salivary glands from both mice have impaired fetal epithelial morphogenesis when cultured with FGF10. Hs3st3b1−/- mice have reduced intact SMG branching morphogenesis and reduced 3-O-sulfated HS in the basement membrane. Analysis of HS biosynthetic enzyme transcription highlighted some compensatory changes in sulfotransferases expression early in development. The overall glycosaminoglycan composition of adult control and KO mice were similar, although HS disaccharide analysis showed increased N- and non-sulfated disaccharides in Hs3st3a1−/− HS. Analysis of adult KO gland function revealed normal secretory innervation, but without stimulation there was an increase in frequency of drinking behavior in both KO mice, suggesting basal salivary hypofunction, possibly due to myoepithelial dysfunction. Understanding how 3-O-sulfation regulates myoepithelial progenitor function will be important to manipulate HS-binding growth factors to enhance tissue function and regeneration.

Exploring the sulfate patterns of chondroitin sulfate/dermatan sulfate and keratan sulfate in human pancreatic cancer

This study was designed to explore the sulfation patterns of chondroitin sulfate (CS)/dermatan sulfate (DS), and keratan sulfate (KS) and the expression of carbohydrate sulfotransferases (CHSTs) in 26 pancreatic tumor and normal tissues. CS/DS and KS profiles were simultaneously determined. Pancreatic tumor tissues exhibited increased ΔDi-0S, ΔDi-4S, and ΔDi-6S levels, with absolute ΔDi-4S content being highest, followed by ΔDi-6S. However, as for the contents of KS-6S and KS-6S,6'S, there were no significant regular change. The expression levels of CHST1 and CHST4 were 37 and 15 times higher than those in normal tissues. PCA and OPLS-DA revealed that ΔDi-4S and ΔDi-6S levels could be reliably used to differentiate between healthy and cancerous tissues. The up-regulation of CHST3, CHST12, CHST13, and CHST15 was directly correlated with C-4 and C-6 sulfation. These data provide a foundation for future studies of the role of ΔDi-4S and ΔDi-6S in the progression of pancreatic cancer.

Endogenous phytosulfokine α (PSKα) signaling delays petals senescence and prolongs vase life of cut rose flowers (Rosa hybrida cv. Angelina)

This study investigated the endogenous phytosulfokine α (PSKα) signaling during opening and senescence in rose flowers. Our results showed that the higher phytosulfokines (PSKs) and tyrosyl protein sulfotransferase (TPST) expression could be responsible for higher endogenous PSKα accumulation in petals during rose flowers opening (stages 2 and 3). By triggering the endogenous PSKα signaling, higher phytosulfokine receptor 1 (PSKR1) expression could be responsible for higher cytosolic cyclic guanosine monophosphate (cGMP) accumulation in petals during rose flowers opening (stages 3 and 4). Higher protein kinase G (PKG) and cyclic nucleotide-gated ion channel 1 (CNGC1) expression accompanying higher plasma membrane intrinsic protein 2 (PIP2) and tonoplast intrinsic protein 1 (TIP1) expression in petals during rose flowers opening may arise from higher cytosolic cGMP accumulation giving rise to higher petals relative water content (RWC) (stage 4). Triggering phosphodiesterase (PDE) expression lay off cytosolic cGMP signaling. Suppressing PKG and CNGC1 expression accompanying lower PIP2 and TIP1 expression accelerates petals senescence in rose flowers representing by deteriorating petals membrane integrity revealed by higher electrolyte leakage and malondialdehyde (MDA) accumulation (stage 5 and 6). For delaying petals senescence and prolonging vase life in cut rose flowers, we employed exogenous PSKα treatment at the commercial harvest stage (stage 3). Our results showed that the suppressing PDE expression in petals by exogenous 150 nM PSKα treatment could be responsible for allowing cytosolic cGMP signaling ongoing for supporting PKG and CNGC1 expression accompanying by higher PIP2 and TIP1 expression. Exogenous 150 nM PSKα treatment, outperforming cut rose flowers by delayed senescence and prolonged vase life to 16 days from 12 days could be ascribed to preserving membrane integrity revealed by lower electrolyte leakage and MDA accumulation. Our results could be proposed that exogenous PSKα treatment and endogenous PSKα signaling for employing in the floriculture industry for delaying petals senescence and prolonging the vase life of cut rose flower.

Effect of Low Nutrition and T-2 Toxin on C28/I2 Chondrocytes Cell Line and Chondroitin Sulfate-Modifying Sulfotransferases.

To investigate the effects of low nutrition and trichothecenes-2 toxin (T-2) on human chondrocytes cell line C28/I2 and the gene expression levels of some chondroitin sulfate (CS)-modifying sulfotransferases. The chondrocytes were divided into 4 intervention groups: (a) control group (Dulbecco's modified Eagle's medium/Nutrient Mixture F-12 [DMEM/F-12] with fetal bovine serum [FBS]), (b) low-nutrition group (DMEM/F-12 without FBS), (c) T-2 group (DMEM/F-12 with FBS plus 20 ng/mL T-2), and (d) combined group (DMEM/F-12 without FBS plus 20 ng/mL T-2). Twenty-four hours postintervention, ultrastructural changes in the chondrocytes were observed by transmission electron microscopy (TEM). Live cell staining and methyl thiazolyl tetrazolium (MTT) assay were performed to observe cell viability. The expression of CS-modifying sulfotransferases, including carbohydrate sulfotransferase 3, 12, 13, 15 (CHST-3, CHST-12, CHST-13, and CHST-15, respectively), and uronyl 2-O-sulfotransferase (UST) were examined by quantitative real-time polymerase chain reaction (RT-qPCR) analysis. The cells in the T-2 group and combined group had significantly lower live cell counts and relative survival rates than the control group. TEM pictures revealed decreased electron density of mitochondria in the low-nutrition group. The T-2 group and combined group both caused mitochondrial swelling, damage, and reduction in mitochondrial number. RT-qPCR showed a trend of altered expression of CHST and increased expression of UST genes under low-nutrition, T-2 toxin and combined interventions. These results show early-stage Kashin-Beck disease chondrocyte pathophysiology, consisting of chondrocyte cell damage and compensatory upregulation of CHST and UST genes.

Increased expression of chondroitin sulfotransferases and proteoglycans follows AngII and may help explain pathophysiology underlying Covid‐19 respiratory failure

The precise mechanisms by which Covid‐19 infection leads to hypoxia and respiratory failure have not yet been elucidated. Interactions between sulfated glycosaminoglycans (GAGs) and the SARS‐CoV‐2 spike glycoprotein have been identified as participating in viral adherence and infectivity. The spike glycoprotein binds to respiratory epithelium through the angiotensin converting enzyme 2 (ACE2) receptor, which endogenously interacts with Angiotensin (Ang) II to yield Angiotensin 1‐7. Stimulation of human vascular smooth muscle cells by Ang II leads to increased mRNA expression of two chondroitin sulfotransferases (CHST11 and CHST15), which are required for synthesis of chondroitin 4‐sulfate (C4S) and chondroitin 4,6‐disulfate (CSE), respectively. Total sulfated GAGs, increased sulfotransferase activity, and increased expression of the proteoglycans biglycan, syndecan‐1, perlecan, and versican followed treatment by Ang II. Candesartan, an Angiotensin II receptor blocker (Arb), largely, but incompletely, inhibited these increases, and the differences from baseline remained significant. These results suggest that another effect of Ang II also contributes to the increased expression of chondroitin sulfotransferases, total sulfated GAGs, and proteoglycans. We hypothesize that activation of ACE2 may contribute to these increases and suggest that the SARS‐CoV‐2 spike glycoprotein interaction with ACE2 may also increase chondroitin sulfotransferases, sulfated GAGs, and proteoglycans and thereby contribute to viral adherence to bronchioalveolar cells and to respiratory compromise in SARS‐CoV‐2 infection.

Genome wide analysis of heparan sulfate assembly

It is well known that the arrangement of the sulfated sugar residues in heparan sulfate specify the location of binding sites for heparan sulfate-binding proteins, and that binding regulates important biological processes including cell proliferation and development. Most of the enzymes involved in heparan sulfate biosynthesis have been cloned, purified and studied biochemically, but there is much less information regarding the mechanisms that control the spatial and temporal expression of heparan sulfate in cells and tissues. To study this question, a lentiviral single guide RNA (sgRNA) library was utilized to knock down gene expression across the entire genome in a human melanoma cell line. High-throughput screening assays based on binding and uptake of guanidino-neomycin, a small molecule ligand that binds to heparan sulfate, was developed. The top hit was the epigenetic factor KDM2B, a histone demethylase. RNAseq revealed that inactivation of KDM2B altered the expression of several sulfotransferases and upregulated the sulfatase SULF1. These changes differentially affected the binding of human fibroblast growth factor 1 (FGF1), FGF7, FGF10, S100 calcium-binding protein A12 and antithrombin, whereas binding of FGF2, interleukin-8 and neuropilin-1 was not affected. ChiPseq analysis showed an increase in H3K4me3 extending from the promoter in SULF1 into the gene body, suggesting that KDM2B normally represses SULF1 expression. Network analysis showed that inactivation of KDM2B also led to marked alterations in the expression of many extracellular matrix genes, suggesting that KDM2B serves as a master regulator of the extracellular matrix.

Profiles of Two Glycaemia Modifying Drugs on the Expression of Rat and Human Sulfotransferases.

To study the effects of blood glucose regulating compounds on human and rat sulfotransferases (SULTs) expressions. Phase-II enzymes, sulfotransferases catalyze the sulfuryl-group-transfer to endogenous/exogenous compounds. The alteration of expressions of SULTs may have influence on the sulfation of its substrate and other biomolecules. The influence of the altered biotransformation might alter different biochemical events, drug-drug interactions and bioaccumulation or excretion pattern of certain drug. In this brief study, diabetes-inducing drug streptozotocin (STZ; 10 or 50 mg/kg to male Sprague Dawley rat for 2 weeks) or hyperglycemia controlling drug tolbutamide (TLB 0.1 or 10μM to human hepato-carcinoma cells, HepG2 for 10 days) was applied and the SULTs expressions were verified. Extensive protein-protein (STa, SULT2A1/DHEAST) interactions were studied by the STRING (Search-Tool-for-the-Retrieval-of-Interacting Genes/Proteins) Bioinformatics-software. Present result suggests that while STZ increased the STa (in rat) (dehydroepiandrosterone catalyzing SULT; DHEAST in human HepG2), tolbutamide decreased PPST (phenol catalyzing SULT) and DHEAST activity in human HepG2 cells. Moderate decreases of MPST (monoamine catalyzing SULT) and EST (estrogen catalyzing) activities are noticed in this case. STa/DHEAST was found to be highly interactive to SHBG/- sex-hormone-binding-globulin; PPARα/lipid-metabolism-regulator; FABP1/fatty-acid-binding-protein. Streptozotocin and tolbutamide, these two glycaemia-modifying drugs demonstrated regulation of rat and human SULTs activities. The reciprocal nature of these two drugs on SULTs expression may be associated with their contrasting abilities in influencing glucose-homeostasis. Possible association of certain SULT-isoform with hepatic fat-regulations may indicate an unfocused link between calorie-metabolism and the glycemic-state of an individual. Explorations of this work may uncover the role of sulfation metabolism of specific biomolecule on cellular glycemic regulation.

Tocopherol Moderately Induces the Expressions of Some Human Sulfotransferases, which are Activated by Oxidative Stress.

Oxidative stress is generated in biological system by several endogenous/exogenous factors like environmental-pollution/toxicity/diseases and by daily-life-stress. We previously showed that oxidative-stress impaired the activities/expressions of phase-II drug-metabolizing enzyme, sulfotransferases (SULTs). The SULT catalyzes sulfation of endogenous/exogenous compounds. Vitamin E is globally consumed by a large number of individuals for the cellular protection from oxidative stress and aging. Here, vitamin E (tocopherol; α/γ and tocotrienol; α/γ; 0, 1, 10, or 100 μM) was tested in human carcinoma cell line, HepG2 for their influences on SULTs expression/(western blotting). The effects of oxidant (glutathione-oxidized/GSSG) or reductant (glutathione-reduced/GSH, Dithiothreitol/DTT) on SULT activities were studied in rat-liver/human intestinal tissues. Results suggest, tocopherol is more inductive to monoamine-SULT (MPST) and Dehydroepiandrosterone-SULT (DHEAST) compared to that of tocotrienol (inconsistent change in PPST, phenol sulfotransferase/MPST/EST, estrogen sulfotransferase). The nuclear-factor constitutive androstane receptor (CAR) was found to be induced moderately. This study overall describes that vitamin E moderately influences SULTs expression. The induction ability of tocopherol should be judged taking into account its long-term consummation. Oxidative stress activates rat and human SULTs activities and expressions. Further studies are necessary in this regard.

Expression of Genes Related to Carrageenan Synthesis during Carposporogenesis of the Red Seaweed Grateloupia imbricata.

Carrageenan, the foremost constituent of extracellular matrix of some rhodophyta, is a galactan backbone with a different number of sulphate groups attached. Variations of degree of sulphation are associated with different types of carrageenans, which vary according to seaweed life cycles, and have consequences for the exploitation of this raw material. In this work, we used three well-recognised stages of development thalli and two stages of cystocarp maturation to analyse genes that encode addition and elimination of sulphate groups to cell-wall galactan of the red seaweed Grateloupia imbricata. Expressions of carbohydrate sulfotransferase and galactose-6 sulfurylase and genes encoding stress proteins such as cytochrome P450 and WD40, were examined. Results showed that transcript expression of carbohydrate sulfotransferase occurs at all stage of thalli development. Meanwhile galactose-6 sulfurylase expressions displayed different roles, which could be related to a temporal regulation of cystocarp maturation. Cytochrome P450 and WD40 are related to the disclosure and maturation of cystocarps of G. imbricata. Our conclusion is that differential expression of genes encoding proteins involved in the sulphation and desulphation of galactan backbone is associated with alterations in thalli development and cystocarp maturation in the red seaweed Grateloupia imbricata. Exploitation of industry-valued carrageenan will depend on insight into gene mechanisms of red seaweeds.

The Role of Sulfotransferases in Liver Diseases.

The cytosolic sulfotransferases (SULTs) are phase II conjugating enzymes that catalyze the transfer of a sulfonate group from the universal sulfate donor 3'-phosphoadenosine-5'-phosphosulfate to a nucleophilic group of their substrates to generate hydrophilic products. Sulfation has a major effect on the chemical and functional homeostasis of substrate chemicals. SULTs are widely expressed in metabolically active or hormonally responsive tissues, including the liver and many extrahepatic tissues. The expression of SULTs exhibits isoform-, tissue-, sex-, and development-specific regulations. SULTs display a broad range of substrates including xenobiotics and endobiotics. The expression of SULTs has been shown to be transcriptionally regulated by members of the nuclear receptor superfamily, such as the peroxisome proliferator-activated receptors, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, liver X receptors, farnesoid X receptor, retinoid-related orphan receptors, estrogen-related receptors, and hepatocyte nuclear factor 4α These nuclear receptors can be activated by numerous xenobiotics and endobiotics, such as fatty acids, bile acids, and oxysterols, many of which are substrates of SULTs. Due to their metabolism of xenobiotics and endobiotics, SULTs and their regulations are implicated in the pathogenesis of many diseases. This review is aimed to summarize the central role of major SULTs, including the SULT1 and SULT2 subfamilies, in the pathophysiology of liver and liver-related diseases. SIGNIFICANCE STATEMENT: Sulfotransferases (SULTs) are indispensable in the homeostasis of xenobiotics and endobiotics. Knowing SULTs and their regulations are implicated in human diseases, it is hoped that genetic or pharmacological manipulations of the expression and/or activity of SULTs can be used to affect the clinical outcome of diseases.

Investigating global gene expression changes in a murine model of cherubism

Cherubism is a rare genetic disorder caused primarily by mutations in SH3BP2 resulting in excessive bone resorption and fibrous tissue overgrowth in the lower portions of the face. Bone marrow derived cell cultures derived from a murine model of cherubism display poor osteogenesis and spontaneous osteoclast formation. To develop a deeper understanding for the potential underlying mechanisms contributing to these phenotypes in mice, we compared global gene expression changes in hematopoietic and mesenchymal cell populations between cherubism and wild type mice. In the hematopoietic population, not surprisingly, upregulated genes were significantly enriched for functions related to osteoclastogenesis. However, these upregulated genes were also significantly enriched for functions associated with inflammation including arachidonic acid/prostaglandin signaling, regulators of coagulation and autoinflammation, extracellular matrix remodeling, and chemokine expression. In the mesenchymal population, we observed down regulation of osteoblast and adventitial reticular cell marker genes. Regulators of BMP and Wnt pathway associated genes showed numerous changes in gene expression, likely implicating the down regulation of BMP signaling and possibly the activation of certain Wnt pathways. Analyses of the cherubism derived mesenchymal population also revealed interesting changes in gene expression related to inflammation including the expression of distinct granzymes, chemokines, and sulfotransferases. These studies reveal complex changes in gene expression elicited from a cherubic mutation in Sh3bp2 that are informative to the mechanisms responding to inflammatory stimuli and repressing osteogenesis. The outcomes of this work are likely to have relevance not only to cherubism, but other inflammatory conditions impacting the skeleton.

Abnormal expression of chondroitin sulfate sulfotransferases in the articular cartilage of pediatric patients with Kashin-Beck disease.

The objective of this study is to investigate the expression of enzymes involved in the sulfation of articular cartilage from proximal metacarpophalangeal (PMC) joint cartilage and distal metacarpophalangeal (DMC) joint cartilage in children with Kashin-Beck disease (KBD). The finger cartilage samples of PMC and DMC were collected from KBD and normal children aged 5-14years old. Hematoxylin and eosin staining as well as immunohistochemical staining were used to observe the morphology and quantitate the expression of carbohydrate sulfotransferase 3 (CHST-3), carbohydrate sulfotransferase 12 (CHST-12), carbohydrate sulfotransferase 13 (CHST-13), uronyl 2-O-sulfotransferase (UST), and aggrecan. In the results, the numbers of chondrocyte decreased in all three zones of PMC and DMC in the KBD group. Less positive staining cells for CHST-3, CHST-12, CHST-13, UST, and aggrecan were observed in almost all three zones of PMC and DMC in KBD. The positive staining cell rates of CHST-12 were higher in superficial and middle zones of PMC and DMC in KBD, and a significantly higher rate of CHST-13 was observed only in superficial zone of PMC in KBD. In conclusion, the abnormal expression of chondroitin sulfate sulfotransferases in chondrocytes of KBD children may provide an explanation for the cartilage damage, and provide therapeutic targets for the treatment.