bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2022‒08‒21
eleven papers selected by
Jonathan Wolf Mueller
University of Birmingham

  1. Nat Commun. 2022 Aug 13. 13(1): 4760
      Lineage plasticity of prostate cancer is associated with resistance to androgen receptor (AR) pathway inhibition (ARPI) and supported by a reactive tumor microenvironment. Here we show that changes in chondroitin sulfate (CS), a major glycosaminoglycan component of the tumor cell glycocalyx and extracellular matrix, is AR-regulated and promotes the adaptive progression of castration-resistant prostate cancer (CRPC) after ARPI. AR directly represses transcription of the 4-O-sulfotransferase gene CHST11 under basal androgen conditions, maintaining steady-state CS in prostate adenocarcinomas. When AR signaling is inhibited by ARPI or lost during progression to non-AR-driven CRPC as a consequence of lineage plasticity, CHST11 expression is unleashed, leading to elevated 4-O-sulfated chondroitin levels. Inhibition of the tumor cell CS glycocalyx delays CRPC progression, and impairs growth and motility of prostate cancer after ARPI. Thus, a reactive CS glycocalyx supports adaptive survival and treatment resistance after ARPI, representing a therapeutic opportunity in patients with advanced prostate cancer.
  2. Acta Biomater. 2022 Aug 11. pii: S1742-7061(22)00454-8. [Epub ahead of print]
      Reactive oxygen species (ROS) play a critical role in the pathogenesis of osteoarthritis. The injection of a single antioxidant drug is characterized by low drug utilization and short residence time in the articular cavity, limiting the therapeutic effect of antioxidant drugs on osteoarthritis. Currently, the drug circulation half-life can be extended using delivery vehicles such as liposomes and microspheres, which are widely used to treat diseases. In addition, the composite carriers of liposomes and hydrogel microspheres can combine the advantages of different material forms and show stronger plasticity and flexibility than traditional single carriers, which are expected to become new local drug delivery systems. Chondroitin sulfate, a sulfated glycosaminoglycan commonly found in native cartilage, has good antioxidant properties and degradability and is used to develop an injectable chondroitin sulfate hydrogel by covalent modification with photo-cross-linkable methacryloyl groups (ChsMA). Herein, ChsMA microgels anchored with liquiritin (LQ)-loaded liposomes (ChsMA@Lipo) were developed to delay the progression of osteoarthritis by dual antioxidation. On the one hand, the antioxidant drug LQ wrapped in ChsMA@Lipo microgels exhibits significant sustained-release kinetics due to the double obstruction of the lipid membrane and the hydrogel matrix network. On the other hand, ChsMA can eliminate ROS through degradation into chondroitin sulfate monomers by enzymes in vivo. Therefore, ChsMA@Lipo, as a degradable and dual antioxidant drug delivery platform, is a promising option for osteoarthritis treatment. STATEMENT OF SIGNIFICANCE: : Compared with the traditional single carrier, the composite carriers of hydrogel microspheres and liposome can complement the advantages of different materials, which shows stronger plasticity and flexibility, and is expected to become a new and efficient drug delivery system. ChsMA@Lipo not only attenuates IL-1β-induced ECM degradation in chondrocytes but also inhibits the M1 macrophages polarization and the inflammasome activation. The obtained ChsMA@Lipo alleviates the progression of osteoarthritis in vivo, which is promising for osteoarthritis treatment.
    Keywords:  Antioxidation; Drug delivery; Microsphere; Osteoarthritis; Reactive oxygen species
  3. Transl Oncol. 2022 Aug 16. pii: S1936-5233(22)00167-X. [Epub ahead of print]25 101508
      Aberrant metabolism has been proposed as one of the emerging hallmarks of cancer. However, the interplay between metabolic disorders and cancer metastasis remains to be defined. To explore the sophisticated metabolic processes during metastatic progression, we analyzed differentially expressed metabolic genes during the epithelial-mesenchymal transition (EMT) of lung cancer cells and defined the EMT-associated metabolic gene signature in lung adenocarcinoma patients. We found that the glycosaminoglycan (GAG)-chondroitin sulfate (CS) biosynthesis pathway was upregulated in the mesenchymal state of lung cancer and associated with poor prognosis. Notably, carbohydrate sulfotransferase 11 (CHST11), a crucial CS biosynthetic enzyme, was confirmed as a poor prognosis marker in non-small cell lung cancer (NSCLC) by immunohistochemical analysis. Moreover, forced CHST11 expression promoted invasion and metastasis, which was abolished by depleting the final product of CS biosynthesis by chondroitinase ABC treatment or active-domain negative CHST11. In vivo metastasis mouse models showed that CHST11 increased lung colonies number and sulfated mucosubstance expression. Furthermore, microarray analysis revealed ceruloplasmin (CP), which facilitated iron metabolism, was the downstream effector of CHST11. CP was upregulated by CHST11 through interferon-γ signaling pathway stimulation and related to unfavorable prognosis. Both forced CP expression and long-term iron treatment increased invasion and lung colony formation. Furthermore, we found 3-AP, an iron chelator, hampered the CHST11-induced metastasis. Our findings implicate that the novel CHST11-CP-iron axis enhances EMT and may serve as a new therapeutic target to treat NSCLC patients.
    Keywords:  CHST11; EMT; Iron-metabolism; NSCLC
  4. Int J Biol Macromol. 2022 Aug 15. pii: S0141-8130(22)01773-1. [Epub ahead of print]
      The alteration of the extracellular matrix (ECM) homeostasis plays an important role in the development of osteoarthritis (OA). The pathological changes of OA are mainly manifested in the large reduction of components in ECM, like type II collagen and aggrecan, especially hyaluronic acid and chondroitin sulfate and often accompanied by inflammation. Rebuilding ECM and inhibiting inflammation may reverse OA progression. In this work, we developed new magnesium-containing glycosaminoglycans (Mg-GAGs), to create a positive ECM condition for promoting cartilage regeneration and alleviating OA. In vitro results suggested that the introduction of Mg-GAGs contributed to promoting chondrocyte proliferation and facilitated upregulating chondrogenic genes and suppressed inflammation-related factors. Moreover, Mg-GAGs exhibited positive effects on suppressing synovial inflammation, reducing chondrocyte apoptosis and preserving the subchondral bone in the ACLT-induced OA rabbit model. This study provides new insight into ECM-based therapeutic strategy and opens a new avenue for the development of novel OA treatment.
    Keywords:  Extracellular matrix; Glycosaminoglycans; Magnesium
  5. J Aging Phys Act. 2022 Aug 17. 1-22
      Age-related changes affect the ratio between two steroid hormones of the hypothalamic-pituitary-adrenal axis, cortisol and dehydroepiandrosterone (sulfate) (DHEA[S]). Physical activity (PA) may buffer the effects of chronic stress and counteract the aging decline of DHEA(S). Therefore, a systematic review was conducted to understand how PA influences physiological markers of cortisol and/or DHEA(S) and whether there is a difference in observational associations or experimental effects in older adults aged 65 years and older. A narrative synthesis was performed on nine observational studies, and meta-analyses were performed on 22 randomized controlled trials. There was low- to moderate-quality evidence that regular PA beneficially reduces cortisol and increases DHEA(S) levels. Subgroup analyses showed no clinically important differences between men and women, different exercise modalities, or health states. The findings cautiously suggest that regular PA of older adults' own choice that they find enjoyable could be recommended to improve cortisol and/or DHEA(S) levels.
    Keywords:  aged 65 and over; chronic stress; exercise; healthy aging; physical fitness
  6. Oncogenesis. 2022 Aug 15. 11(1): 49
      Heparanase (HPA) is the predominant enzyme that cleaves heparan sulfate and plays a critical role in a variety of pathophysiological processes. HPA activity has been traditionally correlated with tumor metastasis due to participation in the cleavage and remodeling of the extracellular matrix (ECM). Apart from its well-characterized catalytic properties, HPA was noticed to exert biological functions not rely on its enzymatic activity. This feature is supported by studies showing induction of signaling events, such as Src and AKT, by nonenzymatic HPA mutant. We provide evidence here that active HPA and inactive HPA mutant proteins enhance gastric cancer cell growth, possibly attributed to TFEB-mediated autophagy. Similarly, HPA gene silencing resulted in decreased gastric cancer cell proliferation and autophagy. Besides, TFEB inhibition reduced cell growth and autophagy induced by nonenzymatic HPA. Notably, HPA and TFEB were significantly elevated in gastric carcinomas compared with the adjacent gastric tissue. Moreover, the elevation of HPA gene expression and upregulation of TFEB levels have been associated with advanced clinical stage and poor prognosis of gastric cancer, providing strong clinical support for a connection between TFEB and HPA. Thus, neutralizing the nonenzymatic function of HPA and the related TFEB-driven autophagy may profoundly impact gastric cancer progression.
  7. Nat Microbiol. 2022 Aug 18.
      Consumption of dietary lipids, such as cholesterol, modulates the gut microbiome with consequences for host health through the production of microbiome-derived metabolites. Despite the implications for host metabolism, a limited number of specific interactions of the gut microbiome with diet-derived lipids have been characterized. This is partially because obtaining species-level resolution of the responsible taxa can be challenging and additional approaches are needed to identify health-relevant metabolites produced from cholesterol-microbiome interactions. Here we performed bio-orthogonal labelling sort sequence spectrometry, a click chemistry based workflow, to profile cholesterol-specific host-microbe interactions. Mice were exposed to an alkyne-functionalized variant of cholesterol and 16S ribosomal RNA gene amplicon sequencing of faecal samples identified diet-derived cholesterol-interacting microbes from the genera Bacteroides, Bifidobacterium, Enterococcus and Parabacteroides. Shotgun metagenomic analysis provided species-level resolution of diet-derived cholesterol-interacting microbes with enrichment of bile acid-like and sulfotransferase-like activities. Using untargeted metabolomics, we identify that cholesterol is converted to cholesterol sulfate in a Bacteroides-specific manner via the enzyme BT_0416. Mice monocolonized with Bacteroides thetaiotaomicron lacking Bt_0416 showed altered host cholesterol and cholesterol sulfate compared with wild-type mice, identifying a previously uncharacterized microbiome-transformation of cholesterol and a mechanism for microbiome-dependent contributions to host phenotype. Moreover, identification of a cholesterol-responsive sulfotransferase in Bacteroides suggests diet-dependent mechanisms for altering microbiome-specific cholesterol metabolism. Overall, our work identifies numerous cholesterol-interacting microbes with implications for more precise microbiome-conscious regulation of host cholesterol homeostasis.
  8. Nat Microbiol. 2022 Aug 18.
      Members of the human gut microbiome enzymatically process many bioactive molecules in the gastrointestinal tract. Most gut bacterial modifications characterized so far are hydrolytic or reductive in nature. Here we report that abundant human gut bacteria from the phylum Bacteroidetes perform conjugative modifications by selectively sulfonating steroidal metabolites. While sulfonation is a ubiquitous biochemical modification, this activity has not yet been characterized in gut microbes. Using genetic and biochemical approaches, we identify a widespread biosynthetic gene cluster that encodes both a sulfotransferase (BtSULT, BT0416) and enzymes that synthesize the sulfonate donor adenosine 3'-phosphate-5'-phosphosulfate (PAPS), including an APS kinase (CysC, BT0413) and an ATP sulfurylase (CysD and CysN, BT0414-BT0415). BtSULT selectively sulfonates steroidal metabolites with a flat A/B ring fusion, including cholesterol. Germ-free mice monocolonized with Bacteroides thetaiotaomicron ΔBT0416 exhibited reduced gastrointestinal levels of cholesterol sulfate (Ch-S) compared with wild-type B. thetaiotaomicron-colonized mice. The presence of BtSULT and BtSULT homologues in bacteria inhibited leucocyte migration in vitro and in vivo, and abundances of cluster genes were significantly reduced in patients with inflammatory bowel disease. Together, these data provide a mechanism by which gut bacteria sulfonate steroidal metabolites and suggest that these compounds can modulate immune cell trafficking in the host.
  9. Front Oncol. 2022 ;12 918419
      Prostate cancer displays a certain phenotypic plasticity that allows for the transition of cells from the epithelial to the mesenchymal state. This process, known as epithelial-mesenchymal transition (EMT), is one of the factors that give the tumor cells greater invasive and migratory capacity with subsequent formation of metastases. In addition, many cancers, including prostate cancer, are derived from a cell population that shows the properties of stem cells. These cells, called cancer stem cells (CSCs) or tumor-initiating cells, not only initiate the tumor process and growth but are also able to mediate metastasis and drug resistance. However, the impact of EMT and CSCs in prostate cancer progression and patient survival is still far from fully understood. Heparanase (HPSE), the sole mammalian endoglycosidase capable of degrading heparan sulfate (HS), is also involved in prostate cancer progression. We had previously proved that HPSE regulates EMT in non-cancerous pathologies. Two prostate cancer cell lines (DU145 and PC3) were silenced and overexpressed for HPSE. Expression of EMT and stemness markers was evaluated. Results showed that the expression of several EMT markers are modified by HPSE expression in both the prostate cancer cell lines analyzed. In the same way, the stemness markers and features are also modulated by HPSE expression. Taken together, the present findings seem to prove a new mechanism of action of HPSE in sustaining prostate cancer growth and diffusion. As for other tumors, these results highlight the importance of HPSE as a potential pharmacological target in prostate cancer treatment.
    Keywords:  cancer stem cells; epithelial to mesenchymal transition; heparanase; in vitro; prostate cancer
  10. Nat Chem Biol. 2022 Aug 18.
      Adhesion G protein-coupled receptors are elusive in terms of their structural information and ligands. Here, we solved the cryogenic-electron microscopy (cryo-EM) structure of apo-ADGRG2, an essential membrane receptor for maintaining male fertility, in complex with a Gs trimer. Whereas the formations of two kinks were determinants of the active state, identification of a potential ligand-binding pocket in ADGRG2 facilitated the screening and identification of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate and deoxycorticosterone as potential ligands of ADGRG2. The cryo-EM structures of DHEA-ADGRG2-Gs provided interaction details for DHEA within the seven transmembrane domains of ADGRG2. Collectively, our data provide a structural basis for the activation and signaling of ADGRG2, as well as characterization of steroid hormones as ADGRG2 ligands, which might be used as useful tools for further functional studies of the orphan ADGRG2.
  11. Eur J Vasc Endovasc Surg. 2022 Aug 13. pii: S1078-5884(22)00507-X. [Epub ahead of print]
      OBJECTIVES: Females are more prone to complications during non-cardiac arterial procedures (NCAP) than males. The current study investigates the difference in the effect of periprocedural prophylactic heparin in males and females, using the activated clotting time (ACT).DESIGN: Retrospective analysis of a prospective multicentre cohort study.
    METHODS: All patients undergoing elective NCAP using heparin and ACT measurements between January 2016 and March 2020 were included. Two heparin dosage protocols were used: weight-based dosing: 100 IU/kg (international units per kilogram) and a bolus of 5 000 IU. Primary outcome was the anticoagulatory effect of heparin after 5 minutes, measured by the ACT. Secondary outcomes were the effect of heparin after 30 minutes, bleeding complications and arterial thromboembolic complications (ATEC).
    RESULTS: 778 patients were included, 26% were female. After 100 IU/kg (n=300), females more often reached longer ACT (<200 s: 22% versus 25%, p=.62; 200-250 s: 41% versus 53%, p=.058; 251-280 s, 26% versus 15%, p=.030). The mean ACT after 100 IU/kg of heparin was 233 s (95% CI 224-243) for females and 226 s (95% CI 221-231) for males (p=.057). After a bolus of 5 000 IU heparin (n=411), females reached significantly higher levels of anticoagulation than males (mean ACT 204 s versus 190 s: p=<.001; ACT <200 s: 44% versus 66%; p<.001; ACT 200-250 s: 47% versus 30%, p=.001; ACT 251-280 s: 7.8% versus 2.3%, p=.009). Thirty minutes after heparin administration, 58% of all patients had an ACT <200 s. ATEC did not differ between females and males (6.9% versus 5.1%, p=.33) but bleeding complications were higher in females (27% versus 16% (p=.001)).
    CONCLUSIONS: Heparin leads to significant longer ACT in females during NCAP. Further research is needed to investigate whether individual-based heparin protocols lead to less bleeding complications and lower incidence of ATEC.
    Keywords:  activated clotting time; bleeding; female; heparin; sex; vascular surgical procedures