bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2023‒09‒03
seven papers selected by
Jonathan Wolf Mueller, University of Birmingham

  1. Adv Biol (Weinh). 2023 Aug 27. e2300249
      Cartilage injury is a common disease in daily life. Especially in aging populations, the incidence of osteoarthritis is increasing. However, due to the poor regeneration ability of cartilage, most cartilage injuries cannot be effectively repaired. Even cartilage tissue engineering still faces many problems such as complex composition and poor integration of scaffolds and host tissues. In this study, chondroitin sulfate, one of the main components of extracellular matrix (ECM), is chosen as the main natural component of the material, which can protect cartilage in a variety of ways. Moreover, the results show that the addition of chondroitin sulfate improves the mechanical properties of gelatin methacrylate (GelMA) hydrogel, making it able to effectively bear mechanical loads in vivo. Further, chondroitin sulfate is modified to obtain the oxidized chondroitin sulfate (OCS) containing aldehyde groups via sodium periodate. This special group improves the interface integration and adhesion ability of the hydrogel to host cartilage tissue through schiff base reactions. In summary, GelMA/OCS hydrogel is a promising candidate for cartilage regeneration with good biocompatibility, mechanical properties, tissue integration ability, and excellent cartilage repair ability.
    Keywords:  cartilage regeneration; chondroitin sulfate; hydrogels; schiff base reaction; tissue engineering
  2. Cell Chem Biol. 2023 Aug 12. pii: S2451-9456(23)00244-1. [Epub ahead of print]
      Indoxyl sulfate is a microbially derived uremic toxin that accumulates in late-stage chronic kidney disease and contributes to both renal and cardiovascular toxicity. Indoxyl sulfate is generated by the metabolism of indole, a compound created solely by gut microbial tryptophanases. Here, we characterize the landscape of tryptophanase enzymes in the human gut microbiome and find remarkable structural and functional similarities across diverse taxa. We leverage this homology through a medicinal chemistry campaign to create a potent pan-inhibitor, (3S) ALG-05, and validate its action as a transition-state analog. (3S) ALG-05 successfully reduces indole production in microbial culture and displays minimal toxicity against microbial and mammalian cells. Mice treated with (3S) ALG-05 show reduced cecal indole and serum indoxyl sulfate levels with minimal changes in other tryptophan-metabolizing pathways. These studies present a non-bactericidal pan-inhibitor of gut microbial tryptophanases with potential promise for reducing indoxyl sulfate in chronic kidney disease.
    Keywords:  Gut-derived uremic toxins; indoxyl sulfate; mechanism-based inhibitor; microbiome-targeted inhibition; tryptophanase
  3. J Neurosci. 2023 Aug 30. pii: JN-RM-2307-22. [Epub ahead of print]
      Neuronal Kv7 voltage-gate potassium channels generate the M-current and regulate neuronal excitability. Here, we report that dehydroepiandrosterone sulfate (DHEAS) is an endogenous Kv7 channel modulator that attenuates Gq-coupled receptor induced M-current suppression. DHEAS reduced muscarinic agonist-induced Kv7-current suppression of either Kv7.1, Kv7.2, Kv7.4 or Kv7.5 homomeric currents and endogenous M-currents in rat sympathetic ganglion neurons. However, DHEAS per se did not alter the voltage-dependence of these Kv7 homomeric channels or the m1 receptor-induced activation of phospholipase C or protein kinase C. DHEAS treated Kv7.2 homomeric currents became resistant to depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) induced by voltage-activated phosphatase, Ci-VSP or eVSP. Our computational models predicted a novel binding site for DHEAS in the cytoplasmic domain of Kv7 subunits. A single point mutation of the predicted key histidine into cysteine in the rat Kv7.2 subunit, rKv7.2(H558C), resulted in a loss of effects of DHEAS on muscarinic Kv7 current suppression. Furthermore, in vivo administration of DHEAS in mice of both sexes reduced late phase pain responses in the formalin paw test. However, it did not have effects on early phase responses in the formalin paw test or responses in the hot plate test. Co-administration of a selective Kv7 inhibitor, XE991, and DHEAS eliminated analgesic effects of DHEAS in late phase responses in the formalin paw test. Collectively, these results suggest that DHEAS attenuates M-current suppression by stabilizing PIP2-Kv7 subunit interaction and can mitigate inflammatory pain.Significance StatementM-current suppression induced by stimulation of Gq-coupled receptors is a form of Kv7 current modulation that can reversibly increase neuronal excitability. This study demonstrates that DHEAS, an endogenous steroid hormone, is a novel Kv7 channel modulator that can attenuate M-current suppression without affecting basal Kv7 channel kinetics. Administration of DHEAS in vivo alleviated inflammatory pain in rodents. These results suggest that the degree of M-current suppression can be dynamically regulated by small molecules. Therefore, this novel form of Kv7 channel regulation holds promising potential as a therapeutic target for sensitized nervous activities such as inflammatory pain.
  4. Sci Rep. 2023 08 28. 13(1): 14044
      The consequence of chronic kidney disease is the accumulation of metabolic products called uremic toxins in the body. Indoxyl sulfate (IS) is a toxin with a high affinity for proteins. This study focuses on the deleterious effect of IS, especially apoptosis induction, in mononuclear blood cells (MNCs). Thus, in MNCs treated with IS at three different concentrations for 24 h, the survival, mitochondrial potential, caspases activity and expression, Bcl-2 and Bax protein expression, DNA damage, and PARP degradation were estimated. The study showed a decrease in survival and mitochondrial potential of MNCs treated with IS compared to the control. IS increased the activity of caspase 2-, 3-, 9-, and the expression of caspase 3-, and 9- in MNCs but does not affect the activity of caspase 6- and 8. The treatment of MNCs with IS also increased DNA damage and degradation of PARP. Indoxyl sulfate significantly influences the expression of Bcl-2 and Bax proteins. Indoxyl sulfate induces the programmed death of MNCs through the intrinsic mitochondrial apoptotic pathway. The observed cellular changes are mostly dose-dependent.
  5. Dental Press J Orthod. 2023 ;pii: S2176-94512023000400301. [Epub ahead of print]28(4): e2322277
      OBJECTIVE: The aim of this in-vivo study was to assess the salivary dehydroepiandrosterone sulphate (DHEAS) and cortisol levels, and their correlation to the Cervical Vertebrae Maturation method (CVM) in males and females at pre-pubertal, pubertal and post-pubertal growth stages.METHODS: 48 patients (24 males, 24 females) who were to undergo routine orthodontic treatment were screened according to the inclusion and exclusion criteria. Then subjects were grouped according to CVM stages, using lateral cephalogram, in pre-pubertal, pubertal and post-pubertal groups. Unstimulated saliva from the selected subjects was collected. DHEAS and cortisol levels in the salivary samples were estimated by Enzyme-Linked Immunosorbent assay (ELISA). Then they were compared to Cervical Vertebrae Maturation Method stages. One-way ANOVA test followed by Tukey's post-hoc test was used to compare the salivary DHEAS and cortisol levels between different CVM stages in males and females. Independent Student t-test was used to compare the mean salivary DHEAS and cortisol levels between different males and females in each CVM stage.
    RESULT: There was a progressive increase in salivary DHEAS and cortisol concentration as skeletal maturation progressed from CVM stages 1 and 2, CVM stages 3 and 4, reaching the highest value at CVM stages 5 and 6. Their levels were higher in males than females.
    CONCLUSION: The salivary DHEAS and cortisol levels can be useful as a potential indicator of skeletal maturation, to aid in the assessment of pubertal status.
  6. J Am Chem Soc. 2023 Aug 30.
      Sulfation widely exists in the eukaryotic proteome. However, understanding the biological functions of sulfation in peptides and proteins has been hampered by the lack of methods to control its spatial or temporal distribution in the proteome. Herein, we report that fluorosulfate can serve as a latent precursor of sulfate in peptides and proteins, which can be efficiently converted to sulfate by hydroxamic acid reagents under physiologically relevant conditions. Photocaging the hydroxamic acid reagents further allowed for the light-controlled activation of functional sulfopeptides. This work provides a valuable tool for probing the functional roles of sulfation in peptides and proteins.
  7. Alcohol. 2023 Aug 24. pii: S0741-8329(23)00262-8. [Epub ahead of print]
      Ethanol exposure during pregnancy is an important problem and is the cause of fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorder (FASD). The etiology of FAS and FASD can be elucidated using animal models. Recently, a novel model, the zebrafish (Danio rerio), has garnered the interest of researchers. This study confirmed the negative influence of ethyl alcohol (0.5%, 1.5%, and 2.5% v/v) on the development of zebrafish embryos. The observed malformations included pericardial and yolk sac edema, increased body curvature, tail edema, and a decreased embryo hatching rate. The differences in body length, body width, and heart rate were statistically significant. Due to the similarities in the quantity and function of ethanol biotransformation enzymes between zebrafish and mammals, this study investigated the nonoxidative metabolites of ethanol-ethyl glucuronide (EtG) and ethyl sulfate (EtS)-in zebrafish following ethanol exposure. This research confirmed that EtG and EtS concentrations can be measured in zebrafish embryos, and the levels of these metabolites appear to be associated with the ethyl alcohol concentration in the medium.
    Keywords:  Ethanol exposure; Ethyl glucuronide; Ethyl sulfate; Fetal alcohol syndrome; Zebrafish