bims-supasi 2024-12-29 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024–12–29
thirteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Fucosylated chondroitin sulfate, an intriguing polysaccharide from sea cucumber: past, present, and future.
Chondroitin Sulfate Nanovectorized by LC-PUFAs Nanocarriers Extracted from Salmon (Salmo salar) by Green Process with Decreased Inflammatory Marker Expression in Interleukin-1β-Stimulated Primary Human Chondrocytes In Vitro Culture.
Identification and Characterization of Two Aryl Sulfotransferases from Deep-Sea Marine Fungi and Their Implications in the Sulfation of Secondary Metabolites.
Heparan sulfate regulates the fate decisions of human pluripotent stem cells.
Fabrication and evaluation of chondroitin sulfate based hydrogels loaded with chitosan nanoparticles for oral delivery of vildagliptin.
Detection of Oral Testsosterone Undecanoate Administration in UGT2B17 del/del and del/ins Individuals. Part II: Urinary Endogenous Steroid Sulfate Markers.
Retention of indoxyl sulfate in different genotypes of ABCC2 may explain variation in tacrolimus pharmacokinetics.
Virus adaptation to heparan sulfate comes with capsid stability tradeoff.
Impaired renal transporter gene expression and uremic toxin excretion as aging hallmarks in cats with naturally occurring chronic kidney disease.
Conjugate Position of Glucuronide and Sulfate in Piceatannol Derivatives Affects the Stability and Hydrolytic Resistance of the Conjugate in Biological Matrices.
The Choice of Anti-Inflammatory Influences the Elimination of Protein-Bound Uremic Toxins.
The Ability of AST-120 to Lower the Serum Indoxyl Sulfate Level Improves Renal Outcomes and the Lipid Profile in Diabetic and Nondiabetic Animal Models of Chronic Kidney Disease: A Meta-Analysis.
Heparin in sepsis: current clinical findings and possible mechanisms.

Glycobiology. 2024 Dec 21. pii: cwae098. [Epub ahead of print]

Fucosylated chondroitin sulfate, an intriguing polysaccharide from sea cucumber: past, present, and future.

Adriani L Felix, Suzane M Penno, Francisco F Bezerra, Paulo A S Mourão.

  Fucosylated chondroitin sulfate (FCS) is a unique polysaccharide, first described nearly four decades ago, and found exclusively in sea cucumbers. It is a component of the extracellular matrix, possibly associated with peculiar properties of the invertebrate tissue. The carbohydrate features a chondroitin sulfate core with branches of sulfated α-Fuc linked to position 3 of the β-GlcA. FCSs from different species of sea cucumbers share a similar chondroitin sulfate core but the structure of the sulfated α-Fuc branches varies significantly. The predominant pattern consists of a single unit of sulfated α-Fuc, though some species exhibit branches with multiple α-Fuc units. This comprehensive review focuses on four major aspects of FCS. Firstly, we describe the initial approaches to elucidate the structure of FCS using classical methods of carbohydrate chemistry. Secondly, we highlight the impact of two-dimensional NMR methods in consolidating and revealing further details about the structure of FCS. These studies were conducted by various researchers across different countries and involving multiple species of sea cucumbers. Thirdly, we summarize the biological activities reported for FCS. Our survey identified 104 publications involving FCS from 42 species of sea cucumbers, reporting 10 types of biological activities. Most studies focused on anticoagulant and antithrombotic activities. Finally, we discuss future perspectives for studies related to FCS. These studies aim to clarify the evolutionary advantage for sea cucumbers in developing such a peculiar fucosylated glycosaminoglycan. Additionally, there is a need to identify the enzymes and genes involved in the metabolism of this unique carbohydrate.

Keywords:  Chondroitin sulfate; fucose-rich polysaccharide; glycosaminoglycan; marine invertebrates

DOI:  https://doi.org/10.1093/glycob/cwae098
Mar Drugs. 2024 Dec 20. pii: 571. [Epub ahead of print]22(12):

Chondroitin Sulfate Nanovectorized by LC-PUFAs Nanocarriers Extracted from Salmon (Salmo salar) by Green Process with Decreased Inflammatory Marker Expression in Interleukin-1β-Stimulated Primary Human Chondrocytes In Vitro Culture.

Louis Pruvost, Maureen Gerlei, Cédric Paris, Émilie Velot, Cyril J-F Kahn, Arnaud Bianchi, Michel Linder.

  Chondroitin sulfate (CS), a glycosaminoglycan, supports health through various physiological functions, including tissue protection, bone growth, and skin aging prevention. It also contributes to anticoagulant or anti-inflammatory processes, with its primary clinical use being osteoarthritis treatment. This study presents the results of the valorization of lipids and CS, both extracted from salmon co-products through enzymatic processes. The polar lipids, naturally rich in long-chain fatty acids (docosahexaenoic acid DHA C22:6 n-3 and eicosapentaenoic acid EPA C20:5 n-3), and the CS, primarily located in the nasal cartilage, were separated and concentrated before being characterized using various techniques to determine functional and lipid composition. These compounds were then used to formulate liposomes of 63 to 95 nm in size composed of 19.38% of DHA and 7.44% of EPA and encapsulating CS extract with a Δdi-4S/Δdi-6S ratio of 0.53 at 2 weight masses (10-30 kDa and >30 kDa) or CS standard all at two different concentrations. Liposomes were tested on human chondrocytes in inflamed conditions. Thus, compatibility tests, the expression of various inflammation markers at transcriptional and molecular levels, nitrites, and the amount of collagenase produced were analyzed. The results showed that CS, in synergy with the liposomes, played a positive role in combating chondrocyte inflammation even at a low concentration.

Keywords:  Salmo salar; anti-inflammatory; chondroitin sulfate; encapsulation; enzymatic hydrolysis; liposome; phospholipid

DOI:  https://doi.org/10.3390/md22120571
Mar Drugs. 2024 Dec 20. pii: 572. [Epub ahead of print]22(12):

Identification and Characterization of Two Aryl Sulfotransferases from Deep-Sea Marine Fungi and Their Implications in the Sulfation of Secondary Metabolites.

Nicolas Graziano, Beatriz Arce-López, Tristan Barbeyron, Ludovic Delage, Elise Gerometta, Catherine Roullier, Gaëtan Burgaud, Elisabeth Poirier, Laure Martinelli, Jean-Luc Jany, Nolwenn Hymery, Laurence Meslet-Cladiere.

  Sulfation plays a critical role in the biosynthesis of small molecules, regulatory mechanisms such as hormone signaling, and detoxification processes (phase II enzymes). The sulfation reaction is catalyzed by a broad family of enzymes known as sulfotransferases (SULTs), which have been extensively studied in animals due to their medical importance, but also in plant key processes. Despite the identification of some sulfated metabolites in fungi, the mechanisms underlying fungal sulfation remain largely unknown. To address this knowledge gap, we conducted a comprehensive search of available genomes, resulting in the identification of 174 putative SULT genes in the Ascomycota phylum. Phylogenetic analysis and structural modeling revealed that these SULTs belong to the aryl sulfotransferase family, and they are divided into two potential distinct clusters of PAPS-dependent SULTs within the fungal kingdom. SULT genes from two marine fungi isolated from deep-sea hydrothermal vents, Hortaea werneckii UBOCC-A-208029 (HwSULT) and Aspergillus sydowii UBOCC-A-108050 SULT (AsSULT), were selected as representatives of each cluster. Recombinant proteins were expressed in Escherichia coli and biochemically characterized. HwSULT demonstrated high and versatile activity, while AsSULT appeared more substrate-specific. Here, HwSULT was used to sulfate the mycotoxin zearalenone, enhancing its cytotoxicity toward healthy feline intestinal cells.

Keywords:  cytotoxic activity; enzymatic sulfation; marine fungi; sulfated metabolites; sulfated mycotoxin; sulfotransferases

DOI:  https://doi.org/10.3390/md22120572
Stem Cell Reports. 2024 Dec 24. pii: S2213-6711(24)00328-X. [Epub ahead of print] 102384

Heparan sulfate regulates the fate decisions of human pluripotent stem cells.

Deepsing Syangtan, Deena Al Mahbuba, Sayaka Masuko, Qiao Li, Andrew C Elton, Yefim Zaltsman, Paul J Wrighton, Ke Xia, Xiaorui Han, Yilan Ouyang, Fuming Zhang, Robert J Linhardt, Laura L Kiessling.

  Heparan sulfate (HS) is an anionic polysaccharide generated by all animal cells, but our understanding of its roles in human pluripotent stem cell (hPSC) self-renewal and differentiation is limited. We derived HS-deficient hPSCs by disrupting the EXT1 glycosyltransferase. These EXT1-/- hPSCs maintain self-renewal and pluripotency under standard culture conditions that contain high levels of basic fibroblast growth factor(bFGF), a requirement for sufficient bFGF signaling in the engineered cells. Intriguingly, Activin/Nodal signaling is also compromised in EXT1-/- hPSCs, highlighting HS's previously unexplored involvement in this pathway. As a result, EXT1-/- hPSCs fail to differentiate into mesoderm or endoderm lineages. Unexpectedly, HS is dispensable for early ectodermal differentiation of hPSCs but still critical in generating motor neurons. Those derived from HS-deficient hPSCs lack proper neuronal projections and show alterations in axonogenesis gene expression. Thus, our study uncovers expected and unexpected mechanistic roles of HS in hPSC fate decisions.

Keywords:  CRISPR; EXT1; bFGF; basic fibroblast growth factor; ectoderm; glycan; glycosyltransferase; heparan sulfate; mesendoderm; neuron; nodal

DOI:  https://doi.org/10.1016/j.stemcr.2024.11.014
Int J Biol Macromol. 2024 Dec 19. pii: S0141-8130(24)09822-2. [Epub ahead of print]290 139011

Fabrication and evaluation of chondroitin sulfate based hydrogels loaded with chitosan nanoparticles for oral delivery of vildagliptin.

Muhammad Fahad, Shefaat Ullah Shah, Muhammad Danish Saeed, Kifayat Ullah Shah, Usra Nazir, Nauman Rahim Khan, Kifayat Ullah Shah, Mohammad Asad.

  Vildagliptin is a drug of choice in type II diabetes mellitus that suffers from limitations like short half-life with reduced bioavailability. To improve the therapeutic performance of vildagliptin, this study aimed to synthesize chitosan nanoparticles (NPs) loaded hydrogel by using biological polysaccharides like sodium alginate (SA) and chondroitin sulfate (CS). The NPs were prepared by ionic gelation method and various characterization tests like surface morphology, size and zeta potential, entrapment efficiency, and in-vitro drug release studies were performed. Results indicated that NPs were round in geometry with an average particle size of 213 nm, having drug encapsulation efficiency of 65 % and controlled drug release within 6-8 h. The optimized NPs (F2) loaded hydrogel showed a good dynamic swelling with gel fraction of 96 %. The hydrogels released 96 % of vildagliptin in 72 h via a non-Fickian diffusion mechanism. The optimized formulation was thermally stable. Formulation showed greater swelling at slight basic pH 7.4 as compared to acidic medium. Moreover, acute toxicity study results demonstrated that the developed NPs loaded hydrogel were safe for oral delivery. The overall results suggested that vildagliptin-loaded NPs loaded hydrogel can serve as an alternative novel dosage form for oral controlled drug delivery.

Keywords:  Chitosan nanoparticles; Controlled release; Hydrogels; Toxicity profile; Vildagliptin

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.139011
Drug Test Anal. 2024 Dec 23.

Detection of Oral Testsosterone Undecanoate Administration in UGT2B17 del/del and del/ins Individuals. Part II: Urinary Endogenous Steroid Sulfate Markers.

Sergi Coll, Sho Shiomura, Élida Alechaga, Claudia Bressan, Núria Monfort, Masato Okano, Rosa Ventura.

  The detection of endogenous anabolic androgenic steroids misuse in Asian population using the Steroidal Module of the Athlete Biological Passport (ABP) is a challenge due to the high prevalence of UGT2B17 gene deletion polymorphism with low levels of testosterone (T) glucuronide. In this study, the capabilities of different approaches based on urine analysis for the detection of oral T undecanoate administration were evaluated in 13 Asian volunteers, including 11 subjects with del/del genotype and 2 subjects with del/ins genotype. In the first part of the work, the effect on the urinary steroid profile (SP) and on the isotope ratio mass spectrometry markers was evaluated. In this second part, the effect on endogenous sulfate markers was evaluated. Results showed that the oral T administration is detected for a much longer period of time with sulfate markers than with the conventional urinary SP markers. Androstanediol sulfate 1 (Diol-S1)/dehydroandrosterone sulfate (DHA-S) and epiandrosterone sulfate (epiA-S)/DHA-S ratios were the most diagnostic parameters for longitudinal monitoring, as reported for Caucasian volunteers in a previous work. For most subjects, sulfate markers allowed the detection of suspicious samples up to 144 h. Combinations of sulfate and glucuronide markers improved the sensitivity in comparison with the conventional SP markers, but yielded poorer results than the best sulfate ratios. Based on the results of this study and previous works, sulfate EAAS metabolites provide a consistent improvement in the detectability of T administration in both Caucasian and Asian populations. Their incorporation into the ABP should be considered.

Keywords:  LC–MS/MS; doping; endogenous; glucuronides; steroids; sulfates

DOI:  https://doi.org/10.1002/dta.3845
PeerJ. 2024 ;12 e18729

Retention of indoxyl sulfate in different genotypes of ABCC2 may explain variation in tacrolimus pharmacokinetics.

Jing Wang, Siqi Huang, Yuanchen Li, Qiu Fang, Min Wang, Huaijun Zhu.

   Background: Microbiota-derived toxins indoxyl sulfate and hippuric acid were previously reported to be associated with altered pharmacokinetics of the immunosuppressant tacrolimus in liver transplant recipients, and ABC transporter proteins are likely to be involved in the transport of such substances, but the in vivo role has not been elucidated. The aim of this study was to assess the retention of indoxyl sulfate and hippuric acid in the plasma of liver transplantation subjects carrying different genotypes of ABCB1 and ABCC2 (changes in transporter activity due to genetic variation), and to explore whether genetic variation is involved in altering the relationship between microbe-derived toxins and tacrolimus pharmacokinetics.
Methods: Liver transplantation subjects treated with the immunosuppressive regimen tacrolimus, corticosteroids, and mycophyolate mofetil were included and divided into normal renal function group and chronic kidney disease group. The plasma concentrations of indoxyl sulfate and hippuric acid in two groups of liver transplantation subjects carrying different genotypes of ABCB1 and ABCC2 were compared. For genotype carriers with significant differences, the Pearson Correlation Coefficient method was further used to investigate the correlation between plasma indoxyl sulfate level and tacrolimus dose-corrected trough concentration in patients with different renal function status.
Results: Carriers of the rs717620-24T variant exhibited high plasma indoxyl sulfate retention in patients with normal renal function, and furthermore, chronic kidney disease patients and patients with normal renal function exhibited indoxyl sulfate and tacrolimus in the ABCC2 normal function (β = -0.740, p = 0.020) and reduced function groups (β = -0.526, p = 0.005), respectively, showing a strong correlation with tacrolimus.
Conclusion: ABCC2 may be one of the pathways by which tacrolimus pharmacokinetics is altered by indoxyl sulfate.

Keywords:  ABCC2; Indoxyl sulfate; Liver transplantation; Single nucleotide polymorphisms; Tacrolimus pharmacokinetics

DOI:  https://doi.org/10.7717/peerj.18729
Elife. 2024 Dec 23. pii: e98441. [Epub ahead of print]13

Virus adaptation to heparan sulfate comes with capsid stability tradeoff.

Han Kang Tee, Simon Crouzet, Arunima Muliyil, Gregory Mathez, Valeria Cagno, Matteo Dal Peraro, Aleksandar Antanasijevic, Sophie Clément, Caroline Tapparel.

  Because of high mutation rates, viruses constantly adapt to new environments. When propagated in cell lines, certain viruses acquire positively charged amino acids on their surface proteins, enabling them to utilize negatively charged heparan sulfate (HS) as an attachment receptor. In this study, we used enterovirus A71 (EV-A71) as model and demonstrated that unlike the parental MP4 variant, the cell-adapted strong HS-binder MP4-97R/167G does not require acidification for uncoating and releases its genome in the neutral or weakly acidic environment of early endosomes. We experimentally confirmed that this pH-independent entry is not associated with the use of HS as an attachment receptor but rather with compromised capsid stability. We then extended these findings to another HS-dependent strain. In summary, our data indicate that acquisition of capsid mutations conferring affinity for HS come together with decreased capsid stability and allow EV-A71 to enter the cell via a pH-independent pathway. This pH-independent entry mechanism boosts viral replication in cell lines but may prove deleterious in vivo, especially for enteric viruses crossing the acidic gastric environment before reaching their primary replication site, the intestine. Our study thus provides new insight into the mechanisms underlying the in vivo attenuation of HS-binding EV-A71 strains. Not only are these viruses hindered in tissues rich in HS due to viral trapping, as generally accepted, but our research reveals that their diminished capsid stability further contributes to attenuation in vivo. This underscores the complex relationship between HS-binding, capsid stability, and viral fitness, where increased replication in cell lines coincides with attenuation in harsh in vivo environments like the gastrointestinal tract.

Keywords:  infectious disease; microbiology; viruses

DOI:  https://doi.org/10.7554/eLife.98441
Aging (Albany NY). 2024 Dec 20. 16

Impaired renal transporter gene expression and uremic toxin excretion as aging hallmarks in cats with naturally occurring chronic kidney disease.

Qinghong Li, James A Holzwarth, Bethany Smith, Sonia Karaz, Mathieu Membrez, Vincenzo Sorrentino, Stacie Summers, Julie Spears, Eugenia Migliavacca.

  Aging leads to nephron senescence and chronic kidney disease (CKD). In cats, indoxyl sulfate (IxS) has been previously quantified and associated with CKD, and little is known about tubular transporters. Two cohorts of cats aged 6 to 21 years were enrolled. Cohort 1 included 41 colony cats with 28 control and 13 CKD cats. Cohort 2 had 30 privately-owned cats with 10 control and 20 CKD cats. In cohort 1, serum concentrations of IxS, trimethylamine N-oxide (TMAO), p-cresol sulfate (PCS), and phenyl sulfate were higher in CKD vs. control cats (all P<0.05). This observation was independently validated in cohort 2. Renal cortical and medullar tissues were collected from a third cohort of cats euthanized for humane reasons unrelated to the study. We provided the evidence that renal tubular transporter genes, OAT1, OAT4, OATP4C1, and ABCC2, but not OAT3, were expressed in the kidneys of cats, and their expressions were downregulated in CKD (all FDR<0.1). Cats and humans share 90.9%, 77.8%, and 82.5% identities in OAT1, OATP4C1, and ABCC2 proteins, respectively. In healthy cats, circulating TMAO and IxS are significantly correlated with age. Our study reveals impaired uremic toxin secretion and tubular transporter expression in cats with CKD.

Keywords:  ABCC2; OAT1; OATP4C1; indoxyl sulfate; trimethylamine N-oxide

DOI:  https://doi.org/10.18632/aging.206176
J Agric Food Chem. 2024 Dec 22.

Conjugate Position of Glucuronide and Sulfate in Piceatannol Derivatives Affects the Stability and Hydrolytic Resistance of the Conjugate in Biological Matrices.

Miyu Nishikawa, Mai Nakayama, Keisuke Fukaya, Daisuke Urabe, Shinichi Ikushiro.

  Piceatannol, a stilbene compound, undergoes a comprehensive phase II metabolism mediated by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) in humans. Despite their well-documented beneficial effects on health, their detailed pharmacokinetic fate, including the metabolite structure and properties, is poorly understood. Thus, we determined the structure of seven glucuronides and six sulfates transformed from piceatannol and its methylated derivatives in recombinant yeast cells expressing UGTs or SULTs. We evaluated their properties in human and rat plasma samples. The conjugate that was substituted at the 3'- or 4'-catecholic hydroxy moiety exhibited increased stability. The sulfatase-mediated hydrolysis assay results in incomplete digestion or compound degradation of certain sulfates, suggesting a potential risk of underestimation by using indirect quantification methods. These findings emphasize the importance of an authentic standard for accurate pharmacokinetic studies of phase II metabolites that will be useful for understanding the mechanisms underlying the functional contribution of piceatannol in the body.

Keywords:  UDP-glucuronosyltransferase; deconjugation; hydrolysis; piceatannol; sulfotransferase

DOI:  https://doi.org/10.1021/acs.jafc.4c08072
Toxins (Basel). 2024 Dec 16. pii: 545. [Epub ahead of print]16(12):

The Choice of Anti-Inflammatory Influences the Elimination of Protein-Bound Uremic Toxins.

Víctor Joaquín Escudero-Saiz, Elena Cuadrado-Payán, María Rodriguez-Garcia, Gregori Casals, Lida María Rodas, Néstor Fontseré, María Del Carmen Salgado, Carla Bastida, Nayra Rico, José Jesús Broseta, Francisco Maduell.

  Pain is a frequent and disturbing symptom among hemodialysis patients. Protein-bound uremic toxins (PBUTs) are related to cardiovascular and overall mortality, and they are difficult to remove with current hemodialysis treatments. The PBUT displacers, such as furosemide, tryptophan, or ibuprofen, may be promising new strategies for improving their clearance. This study aims to compare ibuprofen versus other analgesic drugs in PBUT removal. A prospective study was carried out in 23 patients. Patients underwent four dialysis sessions with routine dialysis parameters, except for analgesic drugs administered (lysine acetylsalicylic acid, acetaminophen, dexketoprofen, and ibuprofen). The reduction ratios (RRs) of a wide range of molecular weight molecules were assessed, including total p-cresyl sulfate and total indoxyl-sulfate. There were no complications related to the administered drug, and pain was controlled independently of the drug. There were no differences in the RR of small-size and medium-sized molecules between all four study treatments. However, indoxyl sulfate and p-cresyl sulfate RRs when ibuprofen was administered were significantly higher than lysine acetylsalicylic acid, acetaminophen, and dexketoprofen treatments. In conclusion, patients with pain may benefit from treatment with ibuprofen instead of lysine acetylsalicylic acid, paracetamol, or dexketoprofen, since in addition to improving pain, it increases the removal of PBUTs.

Keywords:  dialysis efficiency; hemodiafiltration; indoxyl sulfate; p-cresyl sulfate; pain; protein-bound toxins; uremic toxins

DOI:  https://doi.org/10.3390/toxins16120545
Toxins (Basel). 2024 Dec 16. pii: 544. [Epub ahead of print]16(12):

The Ability of AST-120 to Lower the Serum Indoxyl Sulfate Level Improves Renal Outcomes and the Lipid Profile in Diabetic and Nondiabetic Animal Models of Chronic Kidney Disease: A Meta-Analysis.

Hande O Altunkaynak, Eda Karaismailoglu, Ziad A Massy.

  The therapeutic benefit of the oral adsorbent drug AST-120 in chronic kidney disease (CKD) is related to an indoxyl sulfate (IS)-lowering action. Diabetes and dyslipidemia might worsen kidney damage in CKD. However, it is not known whether AST-120 influences lipid abnormalities as well as renal function in patients with CKD and diabetes. The objective of the present meta-analysis was to evaluate the efficacy of AST-120 treatment in CKD using data from preclinical studies. Mixed-effect or random-effect models were used to estimate the standardized mean difference (SMD) and the 95% confidence interval (CI). Publication bias was assessed with a funnel plot and Egger's test. The potential influence of some variables (the dose and duration of AST-120 treatment, the animal species, and the CKD model's diabetic status) was evaluated in subgroup analyses. Treatment with AST-120 was associated with a significantly lower IS level in animals with CKD (SMD = -1.75; 95% CI = -2.00, -1.49; p < 0.001). Significant improvements in markers of renal function and the lipid profile were also observed. In subgroup analyses of the cholesterol level, the diabetic status, the AST-120 dose, and the animal species were found to be influential factors. AST-120 lowered serum IS and triglyceride levels and improved renal function in animal models of CKD independent of diabetes status. However, AST-120's ability to lower the total cholesterol level was more prominent in animals with diabetic CKD.

Keywords:  AST-120; cholesterol; chronic kidney disease; diabetes; indoxyl sulfate; meta-analysis; mouse; rat; renal function markers; triglyceride

DOI:  https://doi.org/10.3390/toxins16120544
Front Immunol. 2024 ;15 1495260

Heparin in sepsis: current clinical findings and possible mechanisms.

Sihan Yu, Yawen Chi, Xiaochun Ma, Xu Li.

  Sepsis is a clinical syndrome resulting from the interaction between coagulation, inflammation, immunity and other systems. Coagulation activation is an initial factor for sepsis to develop into multiple organ dysfunction. Therefore, anticoagulant therapy may be beneficial for sepsis patients. Heparin possesses a variety of biological activities, so it has a broad prospect in sepsis. Previous studies suggested that patients with sepsis-induced disseminated intravascular coagulation and high disease severity might be suitable for anticoagulant therapy. With the development of artificial intelligence (AI), recent studies have shown that patients with severe coagulation activation represent the targeted patients for anticoagulant therapy in sepsis. However, it remains necessary to accurately define the relevant biomarkers indicative of this phenotype and validate their clinical utility by large randomized controlled trials (RCTs). Analyses of data from early small RCTs, subgroup analyses of large RCTs and meta-analyses have collectively suggested that anticoagulant therapy, particularly the use of heparin, may be an effective approach for managing sepsis patients. Concurrently, debate persists regarding the optimal selection of anticoagulants, proper timing, usage and dosage of administration that should be employed to assess treatment efficacy. The primary mechanisms of heparin are acting on heparan sulfate, histones, high mobility group box 1 and heparin-binding protein, which interfere with the regulation of inflammation, vascular permeability, coagulation, endothelial function and other biological activities. However, the underlying pathophysiological processes mediating the potential therapeutic effects of heparin in the context of sepsis remain incompletely understood and warrant additional rigorous investigation to establish the mechanism more conclusively.

Keywords:  anticoagulant; coagulation; heparin; mechanism; sepsis

DOI:  https://doi.org/10.3389/fimmu.2024.1495260