Increases in expression of carbohydrate sulfotransferases CHST11 and CHST15 and decline in N-acetylgalactosamine-4-sulfatase (Arylsulfatase B, ARSB) require phospho-p38-MAPK following exposure to SARS-CoV-2 spike protein receptor binding domain in human a

Objective: Immunohistochemistry of post-mortem lung tissue from Covid-19 patients with diffuse alveolar damage demonstrated marked increases in chondroitin sulfate and CHST15 and decline in N-acetylgalactosamine-4-sulfatase. Studies were undertaken to identify the mechanisms involved in these effects. Method(s): Human primary small airway epithelial cells (PCS 301-010;ATCC) were cultured and exposed to the SARSCoV- 2 spike protein receptor binding domain (SPRBD;AA: Lys310-Leu560;Amsbio). Expression of the spike protein receptor, angiotensin converting enzyme 2 (ACE2), was enhanced by treatment with Interferon-beta. Promoter activation, DNA-binding, RNA silencing, QPCR, Western blots, ELISAs, and specific enzyme inhibitors were used to elucidate the underlying molecular mechanisms. Result(s): Treatment of the cultured cells by the SPRBD led to increased CHST15 and CHST11 expression and decline in ARSB expression. Sulfotransferase activity, total chondroitin sulfate, and sulfated glycosaminoglycan (GAG) content were increased. Phospho-T180/T182-p38-MAPK and phospho- S423/S425-Smad3 were required for the activation of the CHST15 and CHST11 promoters. Inhibition by SB203580, a phospho-p38 MAPK inhibitor, and by SIS3, a Smad3 inhibitor, blocked the CHST15 and CHST11 promoter activation. SB203580 reversed the SPRBD-induced decline in ARSB expression, but SIS3 had no effect on ARSB expression or promoter activation. Phospho-p38 MAPK was shown to reduce retinoblastoma protein (RB) S807/S811 phosphorylation and increase RB S249/T252 phosphorylation. E2F-DNA binding declined following exposure to SPRBD, and SB203580 reversed this effect. This indicates a mechanism by which SPRBD, phospho-p38 MAPK, E2F, and RB can regulate ARSB expression and thereby impact on chondroitin 4-sulfate and dermatan sulfate and molecules that bind to these sulfated GAGs, including Interleukin-8, bone morphogenetic protein-4, galectin-3 and SHP-2 (Src homology region 2-containing protein tyrosine phosphatase 2). Conclusion(s): The enzyme ARSB is required for the degradation of chondroitin 4-sulfate and dermatan sulfate, and accumulation of these sulfated GAGs can contribute to lung pathophysiology, as evident in Covid-19. Some effects of the SPRBD may be attributable to unopposed Angiotensin II, when Ang1-7 counter effects are diminished due to binding of ACE2 with the SARS-CoV-2 spike protein and reduced production of Ang1-7. Aberrant cell signaling and activation of the phospho-p38 MAPK and Smad3 pathways increase CHST15 and CHST11 production, which can contribute to increased chondroitin sulfate in infected cells. Decline in ARSB may occur as a consequence of effects of phospho-p38 MAPK on RB phosphorylation and E2F1 availability. Decline in ARSB and the resulting impaired degradation of sulfated GAGs have profound consequences on cellular metabolic, signaling, and transcriptional events. Funding is VA Merit Award.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.

Using heparin molecules to manage COVID-2019.

The coronavirus disease 2019 (COVID-19) pandemic is becoming one of the largest global public health crises in modern history. The race for an effective drug to prevent or treat the infection is the highest priority among health care providers, government officials, and the pharmaceutical industry. Recent evidence reports that the use of low-molecular-weight heparin reduces mortality in patients with severe coronavirus with coagulopathy. Although the full scope of the benefits from heparin for COVID-19 patients is unfolding, encouraging clinical data suggest that heparin-like molecules may represent a useful approach to treat or prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The intent of this article is to offer our opinions on the mechanism(s) by which heparin may attenuate the course of SARS-CoV-2 infection. Furthermore, we propose a novel strategy to treat or prevent SARS-CoV-2 infection using "designer" heparin molecules that are fabricated using a synthetic biology approach.

Anti-SARS-CoV-2 and anticoagulant properties of Pentacta pygmaea fucosylated chondroitin sulfate depend on high molecular weight structures.

Fucosylated chondroitin sulfate (FucCS) is a unique marine glycosaminoglycan that exhibits diverse biological functions including antiviral and anticoagulant activity. In previous work, the FucCS derived from Pentacta pygmaea (PpFucCS) showed moderate anticoagulant effect but high inhibitory activity against the Wuhan strain of severe acute respiratory syndrome coronavirus (SARS-CoV-2). In this study, we perform free-radical depolymerization of PpFucCS by the copper-based Fenton method to generate low molecular weight (MW) oligosaccharides. PpFucCS oligosaccharides were structurally analyzed by 1H nuclear magnetic resonance spectroscopy and used to conduct structure-activity relationship studies regarding their effects against SARS-CoV-2 and clotting. Anticoagulant properties were measured by activated partial thromboplastin time, protease (factors Xa and IIa) inhibition by serine protease inhibitors [antithrombin (AT) and heparin cofactor II (HCII)], and competitive surface plasmon resonance (SPR) assay using AT, HCII and IIa. Anti-SARS-CoV-2 properties were measured by concentration-response inhibitory curves of HEK-293 T-hACE2 cells infected with a baculovirus pseudotyped SARS-CoV-2 Delta variant spike (S)-protein and competitive SPR assays using multiple S-proteins [Wuhan, N501Y (Alpha), K417T/E484K/N501Y (Gamma), L542R (Delta) and Omicron (BA.2 subvariant)]. Cytotoxicity of native PpFucCS and oligosaccharides was also assessed. The PpFucCS-derived oligosaccharide fraction of the highest MW showed great anti-SARS-CoV-2 Delta activity and reduced anticoagulant properties. Results have indicated no cytotoxicity and MW-dependency on both anti-SARS-CoV-2 and anticoagulant effects of PpFucCS as both actions were reduced accordingly to the MW decrease of PpFucCS. Our results demonstrate that the high MW structures of PpFucCS is a key structural element to achieve the maximal anti-SARS-CoV-2 and anticoagulant effects.

Prospects for the Use of Marine Sulfated Fucose-Rich Polysaccharides in Treatment and Prevention of COVID-19 and Post-COVID-19 Syndrome.

Symptoms of the new coronavirus infection that appeared in 2019 (COVID-19) range from low fever and fatigue to acute pneumonia and multiple organ failure. The clinical picture of COVID-19 is heterogeneous and involves most physiological systems; therefore, drugs with a wide spectrum of mechanism of action are required. The choice of the treatment strategy for post-COVID-19 syndrome is still a challenge to be resolved. Polysaccharides with a high fucose content derived from seaweed and marine animals can form the basis for the subsequent development of promising agents for the treatment of COVID-19 and post-COVID-19 syndrome. This class of biopolymers is characterized by a variety of biological activities, including antiviral, antithrombotic, anticoagulant, hemo-stimulating, anti-inflammatory and immune-regulatory. Low molecular weight derivatives of these polysaccharides, as well as synthetic oligosaccharides with a sufficient amount and sulfation type may be considered as the most promising compounds due to their better bioavailability, which undoubtedly increases their therapeutic potential.

Glucocorticoid Effects on Proteoglycans and Glycosaminoglycans.

Glucocorticoids are steroid hormones that play diverse roles in numerous normal and pathological processes. They are actively used to treat a wide variety of diseases, including neurodegenerative and inflammatory diseases, cancers, and COVID-19, among others. However, the long-term use of glucocorticoids is associated with numerous side effects. Molecular mechanisms of these negative side effects are not completely understood. Recently, arguments have been made that one such mechanisms may be related to the influence of glucocorticoids on O-glycosylated components of the cell surface and extracellular matrix, in particular on proteoglycans and glycosaminoglycans. The potential toxic effects of glucocorticoids on these glycosylated macromolecules are particularly meaningful for brain physiology because proteoglycans/glycosaminoglycans are the main extracellular components of brain tissue. Here, we aim to review the known effects of glucocorticoids on proteoglycan expression and glycosaminoglycan content in different tissues, with a specific focus on the brain.

UPDATED RESULTS FROM A NOVEL, LONGITUDINAL, MULTICENTER DISEASE MONITORING PROGRAM (DMP) OF VESTRONIDASE ALFA FOR THE TREATMENT OF MUCOPOLYSACCHARIDOSIS VII (MPS VII)

Background: MPS VII is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by beta-glucuronidase (GUS) enzyme deficiency. Vestronidase alfa (recombinant human GUS) enzyme replacement therapy is approved in the United States, Europe, and parts of Latin America for the treatment of MPS VII. Methods: The Disease Monitoring Program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N ≈ 35 planned) treated with vestronidase alfa or with any other management approach. Investigational sites are centers with expertise in mucopolysaccharidosis treatment. Data will be collected for up to 10 years and include demographics, clinical history, clinical characteristics, cognition, mobility, skeletal disease, pulmonary function, patient and caregiver-reported health-related quality of life, and long-term vestronidase alfa safety and effectiveness. Data are monitored and recorded in compliance with Good Clinical Practice guidelines. Annual individual patient reports will be provided to patients and caregivers. Results: As of 31 May 2021, 20 patients are enrolled: 19 in the treated group and one in the untreated group. Of the 19 treated patients, 14 were treated with vestronidase alfa before DMP enrollment, and five were treated with vestronidase alfa during the DMP. Eleven patients (55%) are male, and 11 patients (55%) are Hispanic or Latino, reflecting that most patients (11 of 20) are enrolled in South America. Mean (SD [range]) age at MPS VII diagnosis was 4.47 (3.99 [0.1-12.0]) years and mean (SD [range]) age at DMP enrollment was 11.08 (7.21 [1.5-26.3]) years. Seven patients (35%) had a history of non-immune hydrops fetalis. For the 14 patients treated prior to DMP enrollment, mean (SD [range]) age at initiation of vestronidase alfa was 9.4 (6.3 [3.0-22.8]) years. For the five patients treated during the DMP, mean (SD [range]) age at initiation of vestronidase alfa was 6.1 (4.5 [2.5-11.5]) years. Three patients who reached two years of treatment in the DMP had an 88% and 75% reduction from baseline in the original (parent) clinical study in dermatan sulfate and chondroitin sulfate uGAG excretion, respectively. Four serious adverse events (SAEs) in two patients have been reported. One SAE, intermittent hypotension, was assessed as an infusion-associated reaction to vestronidase alfa;this SAE did not meet hypersensitivity criteria;this patient had a low positive anti-drug antibody (ADA) titer (1:80) prior to the first administration of vestronidase alfa but did not test ADA positive at any subsequent visit during the DMP. All SAEs were consistent with the known safety profile of vestronidase alfa. No deaths were reported. COVID-19 resulted in travel restrictions for many patients, but only one dose of vestronidase alfa was missed. Nine patients had ADA data analyzed at baseline;of these, four tested positive at initial baseline, but all four subsequently tested negative during the DMP, while three other patients had low positive ADA titers (range: 1:10 to 1:320). All patients with positive ADA samples tested negative for neutralizing ADA, and four had reductions of at least 80% in dermatan sulfate uGAG excretion from baseline in the original (parent) clinical study. Conclusions: Reductions in uGAG demonstrate ongoing effectiveness of vestronidase alfa at DMP Year 2. No new safety concerns were identified, and all patients continue on study. The MPS VII DMP continues to enroll patients and collect data to characterize MPS VII disease presentation, clinical heterogeneity, and progression.

Post-COVID pain syndrome: a review of international observations

The novel coronavirus infection is commonly referred to as COVID-19, sometimes by the name of the causative agent of a respiratory viral infection, as SARS-CoV-2. Frequently, the course of COVID-19 is divided into three main periods: acute COVID-19 (up to 4 weeks), post-acute COVID-19 (from 4 to 12 weeks), post-COVID (post-COVID;from 12 weeks to 6 months). If a more protracted course of COVID (over 6 months) is discussed, the term “long-COVID” is used. All observations demonstrated a high incidence of pain syndromes of various localization in the post-COVID period and long-COVID. According to survey data, 92.3% of patients with COVID-19 reported musculoskeletal problems at the time of admission. Pain syndrome is observed in 56.3% of cases 1 month after hospitalization. Three months after COVID-19, myalgia was observed in 40.55% of cases, joint pain in 39.18%, back pain in 31.62%, and lower back pain in 24.74%. After 6 months, joint pain continues to be observed in 18.59% of patients, myalgia - in 15.09%, back pain - in 14.39%, lower back pain - in 11.23%. In 50.8% of cases, patients reported new-onset pain, of which 38.5% had pain of moderate severity (≥3 points on the visual analog scale). Patients with new-onset pain during COVID had worse quality of life indicators and a negative correlation with the pain syndrome severity, which significantly hampered recovery. Data from a meta-analysis that included 47,910 patients with long-COVID and with a protracted course of COVID indicate that 19% of them had pain in the joints of various localization. The direct cytopathic effect of SARS-CoV-2 and the systemic immune inflammation that occurs in response to infection cause damage to the joint tissue. According to the Guidelines for the Treatment of Patients with the Consequences of COVID-19, it is recommended to use slow acting structure-modifying drugs - SYSADOA - in the pharmacological treatment regimen for patients with osteoarthritis, among which parenteral forms of pharmaceutically standardized drugs - chondroitin sulfate (CS) and glucosamine sulfate (GS) are preferred. GS and CS are inhibitors of the signaling cascade of the nuclear factor NF-κB, which is involved in the realization of biological effects of a pro-inflammatory cytokine (tumor necrosis factor α), the excessive activity of which is associated with the cytokine storm in COVID-19.

Inhibition of SARS-CoV-2 wild-type (Wuhan-Hu-1) and Delta (B.1.617.2) strains by marine sulfated glycans.

The Coronavirus disease pandemic has steered the global therapeutic research efforts toward the discovery of potential anti-severe acute respiratory syndrome coronavirus (SARS-CoV-2) molecules. The role of the viral spike glycoprotein (S-protein) has been clearly established in SARS-CoV-2 infection through its capacity to bind to the host cell surface heparan sulfate proteoglycan (HSPG) and angiotensin-converting enzyme-2. The antiviral strategies targeting these 2 virus receptors are currently under intense investigation. However, the rapid evolution of the SARS-CoV-2 genome has resulted in numerous mutations in the S-protein posing a significant challenge for the design of S-protein-targeted inhibitors. As an example, the 2 key mutations in the S-protein receptor-binding domain (RBD), L452R, and T478K in the SARS-CoV-2 Delta variant (B.1.617.2) confer tighter binding to the host epithelial cells. Marine sulfated glycans (MSGs) demonstrate excellent inhibitory activity against SARS-CoV-2 via competitive disruption of the S-protein RBD-HSPG interactions and thus have the potential to be developed into effective prophylactic and therapeutic molecules. In this study, 7 different MSGs were evaluated for their anti-SARS-CoV-2 activity in a virus entry assay utilizing a SARS-CoV-2 pseudovirus coated with S-protein of the wild-type (Wuhan-Hu-1) or the Delta (B.1.617.2) strain. Although all tested MSGs showed strong inhibitory activity against both strains, no correlations between MSG structural features and virus inhibition could be drawn. Nevertheless, the current study provides evidence for the maintenance of inhibitory activity of MSGs against evolving SARS-CoV-2 strains.

CHEMICALLY DECORATED DECELLULARIZED CORNEA AS FULL-THICKNESS STROMAL SUBSTITUTE

During the ongoing Covid-19 pandemic, collection and donation of human cadaveric corneas are cumbersome. Decellularized corneas (DC) have gained intense popularity as a possible scaffold for corneal remodeling and as an alternative tissue source for corneal replacement. However, DC elicits immune response inspite of elimination of the cellular contents/antigens due to distortion of the collagen fibrils that exposes certain antigenic sites, which often lead to graft rejection. Therefore, here, we tested the hypothesis that cross-linking DC with chondroitin sulfate (CS) may help in restoring distorted conformational changes of the fibrous matrix and would reduce graft rejection. An in vitro immune response study confirmed that the cross-linked DC elicited the least immune response than DC. We implanted three sets of corneal scaffolds obtained from goat, i.e., native, decellularized, and DC conjugated with CS into rabbit stroma. Histology analysis, three months post-implantation confirmed seamless graft integration, cell migration, and no sign of inflammation in the crosslinked cornea. However, so far we have checked the immunogenic potential of decellularized and crosslinked cornea among cross-species(goat to rabbit). Now, before moving to a human clinical trial (patients with infectious keratitis), we are validating the decellularization of the human stromal layer using discarded human corneas not suitable for implantation, for the regeneration of the corneal endothelial layer. The decellularized, chemically decorated cornea will be tectonically strong, offer less immunogenicity, can be sterilized, and will have a longer shelf life. Through this novel study, we can meet the demand for alternative bioengineered human cornea for keratitis patients.

Role of chondroitin sulfate in the regulation of neuroimmunoendocrine network interactions in patients with neurological symptoms in the post-covid period

The review discusses the prospects for the use of chondroitin sulfate and its derivatives for new indications in patients with and myalgic encephalomyelitis/chronic fatigue syndrome after SARS-CoV-2 infection. The epidemiology, clinical manifestations, main mechanisms of the development of the dysregulation of neuroimmunoendocrine network interactions in long-term COVID-19 are considered. Modern data on the relationship between mechanisms of neuroprotective effects of chondroitin sulfate and its derivatives and their chemical structure characteristics have been analyzed. The position is argued according to which chondroitin sulfate and its derivatives can become promising drugs in prevention of the development of neuroimmunoendocrine network interactions disorders in COVID-19. © 2021 Ima-Press Publishing House. All rights reserved.

A review of non-surgical management of hand osteoarthritis

Introduction: Hand osteoarthritis (OA) is a common musculoskeletal condition leading to pain and loss of function. Current treatment aims to target the symptoms of hand OA involving a combination of nonsurgical and surgical interventions. During the COVID-19 pandemic, there has been a renewed interest in conservative management. The purpose of this article is to review non-surgical therapies in hand OA, their mechanism of action and efficacy. Method: An online search of PubMed for articles between 1st January 2004- 1st February 2020 was performed according to specific terms and agreed inclusion criteria. Results: The search produced 289 results of which 28 met the inclusion criteria comprising 13 RCTs, 8 systematic reviews, 5 clinical trials and 2 international guidelines. Conclusions: Topical NSAIDs remain first-line pharmacological agents in the management of hand OA. Increasingly, oral NSAIDs have been recommended however their use must be balanced against their potential adverse effects. Supplementation with chondroitin sulfate may help to delay the structural damage in hand OA, which may reduce the need for oral NSAIDs. Intra-articular injections of hyaluronic acid and corticosteroids are effective treatments and provide longer symptomatic relief, additionally hyaluronic acid may improve function over a longer period of time. Targeted hand exercises are widely recommended however may only provide short-term improvements and vary according to the different subtypes of hand OA. In summary, there are multiple conservative management options for hand OA which should be considered prior to operative intervention given the current restrictions on surgical practice.

Increase in Chondroitin Sulfate and Decline in Arylsulfatase B May Contribute to Pathophysiology of COVID-19 Respiratory Failure.

INTRODUCTION: The potential role of accumulation of chondroitin sulfates (CSs) in the pathobiology of COVID-19 has not been examined. Accumulation may occur by increased synthesis or by decline in activity of the enzyme arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) which requires oxygen for activity. METHODS: Immunostaining of lung tissue from 28 patients who died due to COVID-19 infection was performed for CS, ARSB, and carbohydrate sulfotransferase (CHST)15. Measurements of mRNA expression of CHST15 and CHST11, sulfotransferase activity, and total sulfated glycosaminoglycans (GAGs) were determined in human vascular smooth muscle cells following angiotensin (Ang) II treatment. RESULTS: CS immunostaining showed increase in intensity and distribution, and immunostaining of ARSB was diminished in COVID-19 compared to normal lung tissue. CHST15 immunostaining was prominent in vascular smooth muscle cells associated with diffuse alveolar damage due to COVID-19 or other causes. Expression of CHST15 and CHST11 which are required for synthesis of CSE and chondroitin 4-sulfate, total sulfated GAGs, and sulfotransferase activity was significantly increased following AngII exposure in vascular smooth muscle cells. Expression of Interleukin-6 (IL-6), a mediator of cytokine storm in COVID-19, was inversely associated with ARSB expression. DISCUSSION/CONCLUSION: Decline in ARSB and resulting increases in CS may contribute to the pathobiology of COVID-19, as IL-6 does. Increased expression of CHSTs following activation of Ang-converting enzyme 2 may lead to buildup of CSs.

Structural and kinetic analyses of holothurian sulfated glycans suggest potential treatment for SARS-CoV-2 infection.

Certain sulfated glycans, including those from marine sources, can show potential effects against SARS-CoV-2. Here, a new fucosylated chondroitin sulfate (FucCS) from the sea cucumber Pentacta pygmaea (PpFucCS) (MW ∼10-60 kDa) was isolated and structurally characterized by NMR. PpFucCS is composed of {→3)-ß-GalNAcX-(1→4)-ß-GlcA-[(3→1)Y]-(1→}, where X = 4S (80%), 6S (10%) or nonsulfated (10%), Y = α-Fuc2,4S (40%), α-Fuc2,4S-(1→4)-α-Fuc (30%), or α-Fuc4S (30%), and S = SO3-. The anti-SARS-CoV-2 activity of PpFucCS and those of the FucCS and sulfated fucan isolated from Isostichopus badionotus (IbFucCS and IbSF) were compared with that of heparin. IC50 values demonstrated the activity of the three holothurian sulfated glycans to be ∼12 times more efficient than heparin, with no cytotoxic effects. The dissociation constant (KD) values obtained by surface plasmon resonance of the wildtype SARS-CoV-2 spike (S)-protein receptor-binding domain (RBD) and N501Y mutant RBD in interactions with the heparin-immobilized sensor chip were 94 and 1.8 × 103 nM, respectively. Competitive surface plasmon resonance inhibition analysis of PpFucCS, IbFucCS, and IbSF against heparin binding to wildtype S-protein showed IC50 values (in the nanomolar range) 6, 25, and 6 times more efficient than heparin, respectively. Data from computational simulations suggest an influence of the sulfation patterns of the Fuc units on hydrogen bonding with GlcA and that conformational change of some of the oligosaccharide structures occurs upon S-protein RBD binding. Compared with heparin, negligible anticoagulant action was observed for IbSF. Our results suggest that IbSF may represent a promising molecule for future investigations against SARS-CoV-2.

Axonal Regeneration by Glycosaminoglycan.

Like other biomolecules including nucleic acid and protein, glycan plays pivotal roles in various cellular processes. For instance, it modulates protein folding and stability, organizes extracellular matrix and tissue elasticity, and regulates membrane trafficking. In addition, cell-surface glycans are often utilized as entry receptors for viruses, including SARS-CoV-2. Nevertheless, its roles as ligands to specific surface receptors have not been well understood with a few exceptions such as selectins and siglecs. Recent reports have demonstrated that chondroitin sulfate and heparan sulfate, both of which are glycosaminoglycans, work as physiological ligands on their shared receptor, protein tyrosine phosphatase sigma (PTPσ). These two glycans differentially determine the fates of neuronal axons after injury in our central nervous system. That is, heparan sulfate promotes axonal regeneration while chondroitin sulfate inhibits it, inducing dystrophic endbulbs at the axon tips. In our recent study, we demonstrated that the chondroitin sulfate (CS)-PTPσ axis disrupted autophagy flux at the axon tips by dephosphorylating cortactin. In this minireview, we introduce how glycans work as physiological ligands and regulate their intracellular signaling, especially focusing on chondroitin sulfate.

A glycosaminoglycan microarray identifies the binding of SARS-CoV-2 spike protein to chondroitin sulfate E.

Heparan sulfate (HS), a sulfated glycosaminoglycan (GAG), was reported to be a necessary host attachment factor that promotes SARS-CoV-2 infection. In this study, we developed GAG microarrays based on fluorescence detection for high-sensitivity screening of the GAG-binding specificity of proteins and applied it for the analysis of SARS-CoV-2 spike (S) protein. Among the 20 distinct GAGs, the S protein bound not only to heparin (HEP)/HS but also to chondroitin sulfate E (CSE) in a concentration-dependent manner. We then analyzed the specificity of each subunit of the S protein. While the S1 subunit showed exclusive binding to HEP, the S2 subunit also bound to CSE and HEP/HS. CSE might act as an alternative attachment factor for HS in SARS-CoV-2 infection.

The Inter-α-Trypsin Inhibitor Family: Versatile Molecules in Biology and Pathology.

Inter-α-trypsin inhibitor (IαI) family members are ancient and unique molecules that have evolved over several hundred million years of vertebrate evolution. IαI is a complex containing the proteoglycan bikunin to which heavy chain proteins are covalently attached to the chondroitin sulfate chain. Besides its matrix protective activity through protease inhibitory action, IαI family members interact with extracellular matrix molecules and most notably hyaluronan, inhibit complement, and provide cell regulatory functions. Recent evidence for the diverse roles of the IαI family in both biology and pathology is reviewed and gives insight into their pivotal roles in tissue homeostasis. In addition, the clinical uses of these molecules are explored, such as in the treatment of inflammatory conditions including sepsis and Kawasaki disease, which has recently been associated with severe acute respiratory syndrome coronavirus 2 infection in children.