bims-supasi 2024-10-20 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024–10–20
seventeen papers selected by
Jonathan Wolf Mueller, University of Birmingham

The accomplices: Heparan sulfates and N-glycans foster SARS-CoV-2 spike:ACE2 receptor binding and virus priming.
Metabolomic analysis reveals the potential of fucosylated chondroitin sulfate from sea cucumber in modulating metabolic homeostasis.
Impact of Chondroitin Sulfate Proteoglycan 4 Pseudogene 12 Genetic Variants on Colorectal Cancer Risk: A Case-Control Study.
Transient CAR T cells with specificity to oncofetal glycosaminoglycans in solid tumors.
Construction and performance evaluation of fully biomimetic hyaline cartilage matrix scaffolds for joint defect regeneration.
Enzyme-Sialylation-Controlled Chemical Sulfation of Glycan Epitopes for Decoding the Binding of Siglec Ligands.
Branched oncolytic peptides target HSPGs, inhibit metastasis, and trigger the release of molecular determinants of immunogenic cell death in pancreatic cancer.
Benzylic C-H Radical Sulfation by Persulfates.
Serotonin, cortisol, and DHEA-S levels in anxious and depressive pregnant women living with HIV.
Sulfated xylogalactofucans from Spatoglossum asperum: Production, structural features and antiviral activity.
Implantable Fluorogenic DNA Biosensor for Stress Detection.
Dengue Envelope Protein as a Cytotoxic Factor Inducing Hemorrhage and Endothelial Cell Death in Mice.
Does the Composition of Gut Microbiota Affect Chronic Kidney Disease? Molecular Mechanisms Contributed to Decreasing Glomerular Filtration Rate.
Time-course remodeling and pathology intervention of α-synuclein amyloid fibril by heparin and heparin-like oligosaccharides.
Pre-Conception Androgen Levels and Obstetric Outcomes in Polycystic Ovary Syndrome: A Single-Center Retrospective Study.
Chondroitin Sulfate Proteoglycan 4 (CSPG4) as an Emerging Target for Immunotherapy to Treat Melanoma.
Structure-Activity Relationships and Target Selectivity of Phenylsulfonylamino-Benzanilide Inhibitors Based on S1647 at the SLC10 Carriers ASBT, NTCP, and SOAT.

Proc Natl Acad Sci U S A. 2024 Oct 22. 121(43): e2404892121

The accomplices: Heparan sulfates and N-glycans foster SARS-CoV-2 spike:ACE2 receptor binding and virus priming.

Giulia Paiardi, Matheus Ferraz, Marco Rusnati, Rebecca C Wade.

  Although it is well established that the SARS-CoV-2 spike glycoprotein binds to the host cell ACE2 receptor to initiate infection, far less is known about the tissue tropism and host cell susceptibility to the virus. Differential expression across different cell types of heparan sulfate (HS) proteoglycans, with variably sulfated glycosaminoglycans (GAGs), and their synergistic interactions with host and viral N-glycans may contribute to tissue tropism and host cell susceptibility. Nevertheless, their contribution remains unclear since HS and N-glycans evade experimental characterization. We, therefore, carried out microsecond-long all-atom molecular dynamics simulations, followed by random acceleration molecular dynamics simulations, of the fully glycosylated spike:ACE2 complex with and without highly sulfated GAG chains bound. By considering the model GAGs as surrogates for the highly sulfated HS expressed in lung cells, we identified key cell entry mechanisms of spike SARS-CoV-2. We find that HS promotes structural and energetic stabilization of the active conformation of the spike receptor-binding domain (RBD) and reorientation of ACE2 toward the N-terminal domain in the same spike subunit as the RBD. Spike and ACE2 N-glycans exert synergistic effects, promoting better packing, strengthening the protein:protein interaction, and prolonging the residence time of the complex. ACE2 and HS binding trigger rearrangement of the S2' functional protease cleavage site through allosteric interdomain communication. These results thus show that HS has a multifaceted role in facilitating SARS-CoV-2 infection, and they provide a mechanistic basis for the development of GAG derivatives with anti-SARS-CoV-2 potential.

Keywords:  ACE2 receptor; SARS-CoV-2; glycoprotein interactions; heparan sulfate; molecular dynamics simulation

DOI:  https://doi.org/10.1073/pnas.2404892121
J Pharm Biomed Anal. 2024 Oct 10. pii: S0731-7085(24)00551-X. [Epub ahead of print]252 116509

Metabolomic analysis reveals the potential of fucosylated chondroitin sulfate from sea cucumber in modulating metabolic homeostasis.

Piaopiao Qiu, Aihua Xia, Xinying Yang, Lin Yi, Yilan Ouyang, Yiming Yao, Haiying Liu, Liang Li, Zhenqing Zhang.

  In this study, we prepared four derivatives of fucosylated chondroitin sulfate (FCS): full-length FCS (flFCS) from Holothuria leucospilota, low molecular weight FCS (lmFCS) derived from flFCS, and their de-branched counterparts, de-branched flFCS (d-flFCS) and de-branched lmFCS (d-lmFCS) via controlled acid treatment. Following structural verification using various analytical techniques, we applied targeted metabolomics to examine the impact of FCS on nutritional efficacy and its structure-activity relationship. Analysis of 225 plasma and feces samples from 75 mice revealed a positive correlation between metabolomic shifts and increased weight gain, underscoring FCS's potential to enhance nutrient absorption and promote growth. The observed linear relationship between the levels of short-chain fatty acids in plasma and feces suggests that FCS may facilitate catabolic activities in the gastrointestinal tract. The comparative study of different FCS derivatives on mouse growth and metabolic homeostasis regulation led to the conclusion that FCS exhibits greater biological activity with a higher degree of branching and larger molecular weight.

Keywords:  Anabolism; Branch; Catabolism; Fucosylated chondroitin sulfate (FCS); Metabolomics; Molecular weight

DOI:  https://doi.org/10.1016/j.jpba.2024.116509
DNA Cell Biol. 2024 Oct 18.

Impact of Chondroitin Sulfate Proteoglycan 4 Pseudogene 12 Genetic Variants on Colorectal Cancer Risk: A Case-Control Study.

Xianlei Zhou, Liwen Guo, Zhenbang Yang, Hongxue Xu, Zhi Zhang, Xuemei Zhang.

  This study aims to investigate the correlation between the chondroitin sulfate proteoglycan 4 pseudogene 12 (CSPG4P12) polymorphism and the risk of colorectal cancer (CRC). This case-control study involved 850 patients with CRC and 850 health controls. The genotypes of CSPG4P12 (rs2880765, rs6496932, and rs8040855) were determined by the TaqMan-MGB probe method. Logistic regression model was employed to evaluate the association of CSPG4P12 single-nucleotide polymorphisms (SNPs) with the risk of CRC by calculating the odds ratio (OR) and 95% confidence interval (CI). The CSPG4P12 exhibited lower expression in CRC tissues. Our data showed that the rs6496932 variant increased CRC risk (CA vs. CC: p = 0.006; CA + AA vs. CC: p = 0.005). In contrast, the rs8040855 variant reduced the risk of CRC (CG vs. CC: p < 0.001; CG + GG vs. CC: p < 0.001). Stratification by gender and age revealed that the rs8040855 variant decreased CRC risk; however, the rs6496932 variant increased CRC risk among males (CA vs. CC: p = 0.024; CA + AA vs. CC: p = 0.014) and younger individuals (CA vs. CC: p = 0.004; CA + AA vs. CC: p = 0.010). When stratified by smoking and drinking status, the rs8040855 variant decreased CRC risk among nonsmokers (CG vs. CC: p < 0.001; CG + GG vs. CC: p < 0.001) and nondrinkers (CA vs. CC: p = 0.002; CA + AA vs. CC: p = 0.004). The rs6496932 variant increased CRC risk among nonsmokers (CA vs. CC: p = 0.016; CA + AA vs. CC: p = 0.036) and nondrinkers (CG vs. CC: p < 0.001; CG + GG vs. CC: p < 0.001). Haplotype analysis showed that the CSPG4P12 Trs2880765Crs6496932Grs8040855 haplotype reduced the risk of CRC compared with the reference haplotype (CSPG4P12 Ars2880765Crs6496932Crs8040855) (OR = 0.46, 95% CI = 0.26-0.82, p = 0.049). These findings highlight the potential of these genetic variants as biomarkers for CRC susceptibility, offering insights into personalized prevention strategies.

Keywords:  CSPG4P12; colorectal cancer; genetic variant; susceptibility

DOI:  https://doi.org/10.1089/dna.2024.0174
EMBO Mol Med. 2024 Oct 15.

Transient CAR T cells with specificity to oncofetal glycosaminoglycans in solid tumors.

Nastaran Khazamipour, Htoo Zarni Oo, Nader Al-Nakouzi, Mona Marzban, Nasrin Khazamipour, Morgan E Roberts, Negin Farivar, Igor Moskalev, Joey Lo, Fariba Ghaidi, Irina Nelepcu, Alireza Moeen, Sarah Truong, Robert Dagil, Swati Choudhary, Tobias Gustavsson, Beibei Zhai, Sabine Heitzender, Ali Salanti, Poul H Sorensen, Mads Daugaard.

  Glycosaminoglycans are often deprioritized as targets for synthetic immunotherapy due to the complexity of glyco-epitopes and limited options for obtaining specific subtype binding. Solid tumors express proteoglycans that are modified with oncofetal chondroitin sulfate (CS), a modification normally restricted to the placenta. Here, we report the design and functionality of transient chimeric antigen receptor (CAR) T cells with selectivity to oncofetal CS. Following expression in T cells, the CAR could be "armed" with recombinant VAR2CSA lectins (rVAR2) to target tumor cells expressing oncofetal CS. While unarmed CAR T cells remained inactive in the presence of target cells, VAR2-armed CAR T cells displayed robust activation and the ability to eliminate diverse tumor cell types in vitro. Cytotoxicity of the CAR T cells was proportional to the concentration of rVAR2 available to the CAR, offering a potential molecular handle to finetune CAR T cell activity. In vivo, armed CAR T cells rapidly targeted bladder tumors and increased the survival of tumor-bearing mice. Thus, our work indicates that cancer-restricted glycosaminoglycans may be exploited as potential targets for CAR T cell therapy.

Keywords:  CAR T Cells; Chondroitin Sulfate; Immunotherapy; Oncofetal CS; Solid Tumor

DOI:  https://doi.org/10.1038/s44321-024-00153-8
Biomed Mater. 2024 Oct 17.

Construction and performance evaluation of fully biomimetic hyaline cartilage matrix scaffolds for joint defect regeneration.

Haidi Sun, Zhonglian Wu, Lihua Liu, Xu Hu, Yurui Zhao, Chirun Wang, Jian Yang, Zehao Gu, Dong-An Wang, Hang Yao.

  Due to the absence of nerves and blood vessels in articular cartilage, its regeneration and repair present a significant and complex challenge in osteoarthritis treatment. Developing a specialized physical and chemical microenvironment supporting cell growth has been difficult in cartilage grafting, especially when aiming for comprehensive biomimetic solutions. Based on previous research, we have designed a tissue-engineered decellularized living hyaline cartilage graft (dLhCG). The study developed a method to improve the hydrophilicity and stiffness of scaffolds by employing chemical grafting techniques and designed a decellularized hyaline cartilage phenotype matrix scaffold for tissue engineering. Here, we reported a method using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride /N-hydroxysuccinimide (EDC/NHS) to achieve the grafting of chondroitin sulfate (CS) onto dLhCG, ultimately producing a tissue-engineered hyaline cartilage graft with the CS (dLhCG/CS). Young's modulus measurements revealed that the cross-linked scaffolds exhibited enhanced mechanical properties. We implanted the cross-linked dLhCG/CS scaffolds into the trochlear region of rat joints and evaluated their functionality through histological analysis and biomechanical tests. After 12 weeks, the dLhCG/CS scaffolds demonstrated excellent bioinductive activity comparable to dLhCG. The regenerated tissue effectively maintained a hyaline cartilage phenotype and exhibited similar mechanical properties, playing a crucial role in cartilage regeneration.

Keywords:  Cartilage matrix; Hyaline phenotype; Joint regeneration; Tissue engineering

DOI:  https://doi.org/10.1088/1748-605X/ad884f
J Am Chem Soc. 2024 Oct 17.

Enzyme-Sialylation-Controlled Chemical Sulfation of Glycan Epitopes for Decoding the Binding of Siglec Ligands.

Shengzhou Ma, Pengfei Zhang, Jinfeng Ye, Yinping Tian, Xiao Tian, Jaesoo Jung, Matthew S Macauley, Jiabin Zhang, Peng Wu, Liuqing Wen.

Widely distributed in nature, sulfated glycan epitopes play important roles in diverse pathophysiological processes. However, due to their structural complexity, the preparation of glycan epitopes with structurally defined sulfation patterns is challenging, which significantly hampers the detailed elucidation of their biological functions at the molecular level. Here, we introduce a strategy for site-specific chemical sulfation of glycan epitopes, leveraging enzymatic sialylation and desialylation processes to precisely control the regio-specificity of sulfation of disaccharide or trisaccharide glycan backbones. Using this method, a sulfated glycan library covering the most common sialylated glycan epitopes was prepared in high yield and efficiency. By screening a microarray prepared with this glycan library, we systematically probed their binding specificity with human Siglecs (sialic acid-binding immunoglobulin-type lectins), many of which function as glyco-immune checkpoints to suppress immune system activation. Our investigation revealed that sulfation and sialylation patterns serve as important determinants of Siglec binding affinity and specificity. Thus, these findings offer new insights for the development of research tools and potential therapeutic agents targeting glyco-immune checkpoints by modulating the Siglec signaling pathway.

DOI: https://doi.org/10.1021/jacs.4c08817
Front Mol Biosci. 2024 ;11 1429163

Branched oncolytic peptides target HSPGs, inhibit metastasis, and trigger the release of molecular determinants of immunogenic cell death in pancreatic cancer.

Alessandro Rencinai, Eva Tollapi, Giulia Marianantoni, Jlenia Brunetti, Tania Henriquez, Alessandro Pini, Luisa Bracci, Chiara Falciani.

  Immunogenic cell death (ICD) can be exploited to treat non-immunoreactive tumors that do not respond to current standard and innovative therapies. Not all chemotherapeutics trigger ICD, among those that do exert this effect, there are anthracyclines, irinotecan, some platinum derivatives and oncolytic peptides. We studied two new branched oncolytic peptides, BOP7 and BOP9 that proved to elicit the release of damage-associated molecular patterns DAMPS, mediators of ICD, in pancreatic cancer cells. The two BOPs selectively bound and killed tumor cells, particularly PANC-1 and Mia PaCa-2, but not cells of non-tumor origin such as RAW 264.7, CHO-K1 and pgsA-745. The cancer selectivity of the two BOPs may be attributed to their repeated cationic sequences, which enable multivalent binding to heparan sulfate glycosaminoglycans (HSPGs), bearing multiple anionic sulfation patterns on cancer cells. This interaction of BOPs with HSPGs not only fosters an anti-metastatic effect in vitro, as demonstrated by reduced adhesion and migration of PANC-1 cancer cells, but also shows promising tumor-specific cytotoxicity and low hemolytic activity. Remarkably, the cytotoxicity induced by BOPs triggers the release of DAMPs, particularly HMGB1, IFN-β and ATP, by dying cells, persisting longer than the cytotoxicity of conventional chemotherapeutic agents such as irinotecan and daunorubicin. An in vivo assay in nude mice showed an encouraging 20% inhibition of tumor grafting and growth in a pancreatic cancer model by BOP9.

Keywords:  danger associated molecular patterns; immunogenic cell death; metastasis; oncolytic peptides; pancreatic cancer

DOI:  https://doi.org/10.3389/fmolb.2024.1429163
Angew Chem Int Ed Engl. 2024 Oct 15. e202413847

Benzylic C-H Radical Sulfation by Persulfates.

Zhen Xia, Zhongyao Ye, Ting Deng, Ze Tan, Chunlan Song, Jiakun Li.

  Sulfation is a highly valuable pathological and physiological process, yet it is often underappreciated considering the rather difficult accessibility of organosulfates. O-sulfonation (O-SO3), a conventional and still common way to make organosulfates, restricts its applicability to hydroxyl compounds and therein lies a major challenge of library construction. Here, we describe a benzylic C-H radical sulfation with persulfates via C-O bond formation. This strategy leverages modular control over the reactivity of persulfates and the stability of sulfate radicals by coutercations. K+/NH4+ stabilized sulfate radicals act as the oxidant to generate carbon-centered radicals from substrates, and activation of persulfates by NBu4+ provides O-O resource pool to facilitate C-OSO3- bond formation via a bimolecular homolytic substitution (SH2) process.

Keywords:  C-H oxidation; C-O Bond; SH2 process; radical chemistry; sulfation

DOI:  https://doi.org/10.1002/anie.202413847
BMC Psychol. 2024 Oct 17. 12(1): 563

Serotonin, cortisol, and DHEA-S levels in anxious and depressive pregnant women living with HIV.

María Del Pilar Meza-Rodríguez, Philippe Leff-Gelman, Diana Medina-Bastidas, Miroslava Avila-García, Ricardo Figueroa-Damián, Ignacio Camacho-Arroyo.

  Pregnancy in women living with human immunodeficiency virus (WLWH) represents an important challenge for maternal-fetal health. Besides, they can also present anxiety (Anx) and depression (Dep). Imbalances in serotonin (5-HT), dehydroepiandrosterone sulfate (DHEA-S), and cortisol (CORT) levels can contribute to Anx and Dep manifestations. Currently, there is not enough data about the neuroendocrine and neurochemical changes in pregnant WLWH with affective disorders. This study aimed to characterize 5-HT, DHEA-S, and CORT plasma levels in Mexican pregnant WLWH presenting Anx/Dep. Forty-two adult pregnant women were recruited during the third trimester of gestation at the National Institute of Perinatology in Mexico during 2019-2022. These patients were divided into three groups: (1) pregnant WLWH with Anx/Dep (n = 16), (2) pregnant without HIV but with Anx/Dep (n = 12), and (3) healthy pregnant women without Anx/Dep (n = 14). WLWH presented a marked reduction in 5-HT (41.33 ± 39.37 ng/dL) compared to non-infected pregnant women with Anx/Dep (220.2 ± 151.8 ng/dL) and the healthy group (370.0 ± 145.3 ng/dL). Anx/Dep infected and uninfected pregnant women showed a significant reduction in DHEA-S levels (86.58 ± 30.59 and 76.9 ± 36.7 µg/dL, respectively) compared to healthy subjects (149.7 ± 44.6 µg/dL). Anx and Dep symptoms were inversely correlated with 5-HT and DHEA-S levels. No significant differences were observed in CORT levels among the three groups (p = 0.094). Our results suggest the presence of a disbalance in 5-HT and DHEA-S levels in pregnant WLWH with affective symptoms.

Keywords:  Anxiety; Cortisol; Dehydroepiandrosterone sulfate; Depression; HIV; Pregnancy; Serotonin

DOI:  https://doi.org/10.1186/s40359-024-02054-4
Carbohydr Res. 2024 Oct 04. pii: S0008-6215(24)00265-9. [Epub ahead of print]545 109286

Sulfated xylogalactofucans from Spatoglossum asperum: Production, structural features and antiviral activity.

Shuvam Mukherjee, Mathias E Chemen, Saikat Pal, Luana E Piccini, Subrata Jana, Elsa B Damonte, Bimalendu Ray, Cybele C Garcia, Sayani Ray.

  In cultured cells, herpes simplex virus (HSV) infectivity is successfully inhibited by sulfated polysaccharides. Herein, we utilized an amalgamated extraction-sulfation procedure to produce two xylogalactofucan sulfates (S203 and S204) from Spatoglossum asperum using ClSO3H.Pyr/DMF and SO3.Pyr/DMF reagents, respectively. Among these xylogalactofucans, the 17 ± 12 kDa polymer (S203) with 14 % sulfate exhibited activity on several HSV variants, including an acyclovir-resistant HSV-1 strain. This is the first report of the anti-HSV activity of a sulfated xylogalactofucan of S. asperum. The effective concentration 50 % (EC50) value of S203 against HSV-1 strain F was 0.6 μg/mL with a selectivity index of 833. The backbone of this polymer (S203) is made up mostly of (1 → 4)-linked-α-l-Fucp units having sulfate groups typically at O-3 and sometimes at O-2 positions. Oligosaccharides containing Xyl, Gal and Fuc units confirms that they are an integral part of a single polymer, another novelty of this study. The EC50 values of the native xylogalactofucan (S202) and the SO3.Pyr/DMF modified polymer (S204), containing 2 % and 6 % sulfates, were >100 and 3.3 μg/mL, respectively. Introduction of sulfate groups enhanced their capability to inhibit the infection of cells by HSV-1. These findings suggest feasibility of inhibiting HSV attachment to cells by blocking viral entry with polysaccharide having specific structure.

Keywords:  Amalgamated extraction/sulfation; Antiviral activity; ClSO(3)H.Pyr/DMF reagent; Mode of action; Spatoglossum asperum; Sulfated xylogalactofucan

DOI:  https://doi.org/10.1016/j.carres.2024.109286
ACS Appl Mater Interfaces. 2024 Oct 17.

Implantable Fluorogenic DNA Biosensor for Stress Detection.

Irina Drachuk, Namrata Ramani, Svetlana Harbaugh, Chad A Mirkin, Jorge L Chávez.

  Implantable sensors that can monitor analytes related to cognitive and physiological status have gained significant focus in recent years. We have developed an implantable biosensor to detect dehydroepiandrosterone sulfate (DHEA-S), a biomarker related to stress. The biosensor strategy was based on the principle of forced intercalation (FIT) aptamers designed to detect subtle intramolecular changes during aptamer-target binding events. By incorporating a steroid-specific fluorogenic aptamer into a hydrogel, the sensitivity and biostability of the FIT biosensor fiber were improved, which were essential for designing implantable sensors to monitor biomarker levels in the living body. The polyethylenimine-based hydrogel chosen for this study produced an optically transparent cross-linked network with optimal microstructure, physicochemical, and mechanical properties, making it suitable for optical biosensors. The in vitro studies showed that the biosensor fiber was successfully activated in human serum and skin analogue, providing a linear response to physiological concentrations of the steroid. We believe that this type of implantable platform can be effective in monitoring more complex biomarkers associated with physiological or psychological health.

Keywords:  FIT biosensor; fluorogenic aptamer; forced-intercalation; hydrogel; stress monitoring

DOI:  https://doi.org/10.1021/acsami.4c08940
Int J Mol Sci. 2024 Oct 09. pii: 10858. [Epub ahead of print]25(19):

Dengue Envelope Protein as a Cytotoxic Factor Inducing Hemorrhage and Endothelial Cell Death in Mice.

Te-Sheng Lien, Der-Shan Sun, Wen-Sheng Wu, Hsin-Hou Chang.

  Dengue virus (DENV) infection, prevalent in tropical and subtropical regions, can progress to dengue hemorrhagic fever (DHF), which increases mortality during secondary infections. DHF is characterized by endothelial damage and vascular leakage. Despite its severity, no specific antiviral treatments exist, and the viral factors responsible for endothelial damage remain unclear. This study examines the role of the DENV envelope protein domain III (EIII) in inducing endothelial apoptosis using a mouse model. Additionally, we aim to explore whether cell death-inducing pathways could serve as drug targets to ameliorate EIII-induced endothelial injury and hemorrhage. In vitro experiments using human endothelial HMEC-1 cells demonstrated that both recombinant EIII (rEIII) and DENV markedly induced caspase-3-mediated endothelial cell death, an effect that was attenuated by co-treatment with chondroitin sulfate B (CSB), N-acetyl cysteine (NAC), and the caspase-3 inhibitor z-DEVD-FMK. In vivo, sequential injections of rEIII and anti-platelet immunoglobulin in mice, designed to mimic the clinical phase of DHF with peak viremia followed by an increase in DENV-induced Ig, including autoantibodies, revealed that these dual treatments markedly triggered caspase-3-dependent apoptosis in vascular endothelial cells at hemorrhage sites. Treatments with z-DEVD-FMK effectively reduced DHF-like symptoms such as thrombocytopenia, hemorrhage, inflammation, hypercoagulation, and endothelial damage. Additionally, CSB and NAC alleviated hemorrhagic symptoms in the mice. These results suggest that targeting EIII, reactive oxygen species, and caspase-3-mediated apoptosis could offer potential therapeutic strategies for addressing EIII-induced hemorrhagic pathogenesis.

Keywords:  N-acetyl cysteine; caspase-3; chondroitin sulfate B; dengue hemorrhagic fever; endothelial cell apoptosis; envelope protein domain III; z-DEVD-FMK

DOI:  https://doi.org/10.3390/ijms251910858
Int J Mol Sci. 2024 Sep 27. pii: 10429. [Epub ahead of print]25(19):

Does the Composition of Gut Microbiota Affect Chronic Kidney Disease? Molecular Mechanisms Contributed to Decreasing Glomerular Filtration Rate.

Ewelina Młynarska, Emilian Budny, Maciej Saar, Ewa Wojtanowska, Justyna Jankowska, Szymon Marciszuk, Marcin Mazur, Jacek Rysz, Beata Franczyk.

  Chronic kidney disease (CKD) is a very prevalent and insidious disease, particularly with initially poorly manifested symptoms that progressively culminate in the manifestation of an advanced stage of the condition. The gradual impairment of kidney function, particularly decreased filtration capacity, results in the retention of uremic toxins and affects numerous molecular mechanisms within the body. The dysbiotic intestinal microbiome plays a crucial role in the accumulation of protein-bound uremic toxins such as p-cresol (pC), indoxyl sulfate (IS), and p-cresyl sulfate (p-CS) through the ongoing fermentation process. The described phenomenon leads to an elevated level of oxidative stress and inflammation, subsequently resulting in tissue damage and complications, particularly an increase in cardiovascular risk, representing the predominant cause of mortality in chronic kidney disease (CKD). Therefore, exploring methods to reduce uremic toxins is currently a pivotal therapeutic strategy aimed at reducing the risk of organ damage in patients with chronic kidney disease (CKD). This review aims to summarize recent discoveries on modifying the composition of the intestinal microbiota through the introduction of special probiotic and synbiotic supplements for CKD therapy. The potential to connect the gut microbiota with CKD opens the possibility for further extensive research in this area, which could lead to the incorporation of synbiotics and probiotics into the fundamental treatment and prevention of CKD.

Keywords:  chronic kidney disease (CKD); gut microbiota; microbiome; prebiotics; probiotics; uremic toxins

DOI:  https://doi.org/10.3390/ijms251910429
Nat Struct Mol Biol. 2024 Oct 17.

Time-course remodeling and pathology intervention of α-synuclein amyloid fibril by heparin and heparin-like oligosaccharides.

Youqi Tao, Peng Xu, Shenqing Zhang, Wei Shangguan, Guang Yang, Kaien Liu, Xiang Li, Yunpeng Sun, Qinyue Zhao, Dan Li, Biao Yu, Cong Liu.

Amyloid fibrils represent a pathological state of protein polymer that is closely associated with various neurodegenerative diseases. Polysaccharides have a prominent role in recognizing amyloid fibrils and mediating their pathogenicity. However, the mechanism underlying the amyloid-polysaccharide interaction remains elusive. We also do not know its impact on the structure and pathology of formed fibrils. Here, we used cryo-electron microscopy to analyze the atomic structures of mature α-synuclein (α-syn) fibrils upon binding with polymeric heparin and heparin-like oligosaccharides. The fibril structure, including the helical twist and conformation of α-syn, changed over time upon the binding of heparin but not oligosaccharides. The sulfation pattern and numbers of saccharide units are important for the binding. Similarly, negatively charged biopolymers typically interact with amyloid fibrils, including tau and various α-syn polymorphs, leading to alterations in their conformation. Moreover, we show that heparin-like oligosaccharides can not only block neuronal uptake and propagation of formed α-syn fibrils but also inhibit α-syn fibrillation. This work demonstrates a distinctive activity of heparin and biopolymers in remodeling amyloid fibrils and suggests the pharmaceutical potential of heparin-like oligosaccharides.

DOI: https://doi.org/10.1038/s41594-024-01407-2
Diagnostics (Basel). 2024 Oct 08. pii: 2241. [Epub ahead of print]14(19):

Pre-Conception Androgen Levels and Obstetric Outcomes in Polycystic Ovary Syndrome: A Single-Center Retrospective Study.

Mónika Orosz, Fanni Borics, Dávid Rátonyi, Beáta Vida, Szilvia Csehely, Attila Jakab, Luca Lukács, Rudolf Lampé, Tamás Deli.

  Hyperandrogenism is a determining diagnostic factor for PCOS. If pregnancy is conceived, it is considered high-risk due to several potential complications, but the correlation between pre-pregnancy androgen levels and obstetric outcomes is poorly characterized.
OBJECTIVE: To determine if pre-pregnancy serum androgen concentrations and androgen indexes differed when certain obstetric and neonatal outcomes appeared in PCOS.
METHODS: A single-center, retrospective study was carried out. All patients were treated between 2012 and 2019. A total of 73 patients had all the endocrine and obstetric data available. Pre-pregnancy hormone levels (total testosterone-T, androstenedione-AD, DHEAS (dehydroepiandrosterone sulfate), SHBG (sex-hormone-binding globulin), and TSH (thyroid-stimulating hormone) were collected, and T/SHBG, AD/SHBG, DHEAS/SHBG, T/AD indexes were calculated and compared.
RESULTS: When miscarriage was present in the history, significantly elevated pre-pregnancy AD levels were observed. Higher pre-pregnancy AD level was noted in PCOS patients delivering female newborns as compared to males. Additionally, a higher T/AD ratio was associated with subsequent preterm delivery, but significance was lost after age adjustment. Maternal age at delivery had a significant negative correlation with pre-pregnancy DHEAS levels and DHEAS/SHBG ratio. Pre-pregnancy SHBG displayed a significant negative correlation, while pre-pregnancy androgen/SHBG ratios exhibited positive correlations with both birth weight and birth weight percentile.
CONCLUSIONS: Based on our data, AD and the T/AD ratio emerge as distinctive factors in certain outcomes, implying a potential specific role of altered 17-β-HSD (17β-hydroxysteroid dehydrogenase) enzyme activity, possibly influencing offspring outcomes. The pre-pregnancy T/SHBG ratio exhibits a potentially stronger correlation with fetal growth potential compared to SHBG alone. DHEAS and maternal age at delivery are strongly correlated in PCOS patients.

Keywords:  androgen levels; gestational diabetes mellitus; in vitro fertilization; obstetric outcomes; polycystic ovary syndrome; pre-pregnancy hormone levels

DOI:  https://doi.org/10.3390/diagnostics14192241
Cancers (Basel). 2024 Sep 25. pii: 3260. [Epub ahead of print]16(19):

Chondroitin Sulfate Proteoglycan 4 (CSPG4) as an Emerging Target for Immunotherapy to Treat Melanoma.

Xinyi Chen, Shabana Habib, Madalina Alexandru, Jitesh Chauhan, Theodore Evan, Joanna M Troka, Avigail Rahimi, Benjamina Esapa, Thomas J Tull, Wen Zhe Ng, Amanda Fitzpatrick, Yin Wu, Jenny L C Geh, Hawys Lloyd-Hughes, Lais C G F Palhares, Rebecca Adams, Heather J Bax, Sean Whittaker, Joanna Jacków-Malinowska, Sophia N Karagiannis.

  Immunotherapies, including checkpoint inhibitor antibodies, have precipitated significant improvements in clinical outcomes for melanoma. However, approximately half of patients do not benefit from approved treatments. Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of immunotherapies directly focused on melanoma cells. This is partly due to few available targets, especially those expressed on the cancer cell surface. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface molecule overexpressed in human melanoma, with restricted distribution and low expression in non-malignant tissues and involved in several cancer-promoting and dissemination pathways. Here, we summarize the current understanding of the expression and functional significance of CSPG4 in health and melanoma, and we outline immunotherapeutic strategies. These include monoclonal antibodies, antibody-drug conjugates (ADCs), chimeric-antigen receptor (CAR) T cells, and other strategies such as anti-idiotypic and mimotope vaccines to raise immune responses against CSPG4-expressing melanomas. Several showed promising functions in preclinical models of melanoma, yet few have reached clinical testing, and none are approved for therapeutic use. Obstacles preventing that progress include limited knowledge of CSPG4 function in human cancer and a lack of in vivo models that adequately represent patient immune responses and human melanoma biology. Despite several challenges, immunotherapy directed to CSPG4-expressing melanoma harbors significant potential to transform the treatment landscape.

Keywords:  antibodies; antibody–drug conjugates (ADCs); chimeric-antigen receptors (CAR) T cells; chondroitin sulfate proteoglycan 4 (CSPG4); immunotherapy; melanoma; vaccines

DOI:  https://doi.org/10.3390/cancers16193260
J Med Chem. 2024 Oct 17.

Structure-Activity Relationships and Target Selectivity of Phenylsulfonylamino-Benzanilide Inhibitors Based on S1647 at the SLC10 Carriers ASBT, NTCP, and SOAT.

Marie Wannowius, Christopher Neelen, Philipp Lotz, Michael Daude, Anita Neubauer, Bärbel Fühler, Wibke E Diederich, Joachim Geyer.

The intestinal bile acid carrier ASBT (SLC10A2), the hepatic bile acid carrier NTCP (SLC10A1), and the steroid sulfate carrier SOAT (SLC10A6), all members of the solute carrier family SLC10, are established drug targets. The ASBT inhibitors odevixibat, maralixibat, and elobixibat are used to treat intrahepatic cholestasis, cholestatic pruritus, and obstipation. The peptide drug bulevirtide blocks binding of the hepatitis B and D viruses to NTCP and thereby inhibits the virus's entry into hepatocytes. Experimental SOAT inhibitors have antiproliferative effects on hormone-dependent breast cancer cells. The phenylsulfonylamino-benzanilide S1647 is an inhibitor of ASBT and SOAT. The present study aimed to comparatively analyze a set of newly synthesized and commercially available S1647 derivatives for their transport inhibition against ASBT, NTCP, and SOAT. Structure-activity relationships were systematically analyzed regarding potency and target specificity to elucidate whether this compound class is worth being further developed in preclinical studies for pharmacological ASBT, NTCP, and/or SOAT inhibition.

DOI: https://doi.org/10.1021/acs.jmedchem.4c01743