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The epidermis, the most superficial layer of the human skin, serves a critical barrier function, protecting the body from external pathogens and allergens. Dysregulation of epidermal differentiation contributes to barrier dysfunction and has been implicated in the pathology of various dermatological diseases, including atopic dermatitis (AD). Mucopolysaccharide polysulphate (MPS) is a moisturising agent used to treat xerosis in patients with AD. However, its mechanism of action on keratinocytes, the main constituents of the epidermis, remains unclear. In this study, we investigated the effect of MPS on keratinocytes by subjecting adult human epidermal and three‐dimensional cultured keratinocytes to MPS treatment, followed by transcriptome analysis. The analysis revealed that MPS treatment enhances keratinocyte differentiation and suppresses proliferation. We focused on amphiregulin (AREG), a membrane protein that belongs to the epidermal growth factor (EGF) family and possesses a heparin‐binding domain, as a significant target among the genes altered by MPS. MPS exerted an inhibitory effect directly on AREG, rather than on EGF receptors or other members of the EGF family. Furthermore, AREG leads to a reduction in epidermal barrier function, whereas MPS contributes to barrier enhancement via AREG inhibition. Collectively, these findings suggest that MPS modulates barrier function through AREG inhibition, offering insights into potential therapeutic strategies for skin barrier restoration. [ABSTRACT FROM AUTHOR]

Keita Okoshi,1 Shotaro Ito,1 Megumi Matsuoka,1 Yoshinori Kinugasa,1 Eri Shimizu,2 Kosei Tanaka,2 Joji Okada,3 Takahiro Nishizaka,1 Azumi Nagasawa,1 Tsuyoshi Seki,1 Makoto Iijima,1 Masatoshi Abe,4 Osamu Nemoto4 1Human Health Care Products Research, Kao Corporation, Tokyo, Japan; 2Analytical Science Research, Kao Corporation, Tochigi, Japan; 3Skin Care Products Research, Kao Corporation, Tokyo, Japan; 4Sapporo Skin Clinic, Sapporo, JapanCorrespondence: Azumi Nagasawa, Human Health Care Products Research, Kao Corporation, 2-1-3, Bunka, Sumida-ku, Tokyo, 131-8501, Japan, Tel +81-3-5630-7690, Fax +81-3-5630-9342, Email nagasawa.azumi@kao.comPurpose: Atopic dermatitis is characterized by chronic inflammation and dryness accompanied by severe itching. The combined use of moisturizers and topical anti-inflammatory drugs is essential for alleviating atopic dermatitis. We have developed a topical anti-inflammatory drug with a steroid and a moisturizer with heparinoid, both in lamellar structure-based formulations containing synthetic pseudo-ceramides. Here, assessed the efficacy of this combination in the treatment of atopic dermatitis.Methods: We included 22 patients with mild to moderate atopic dermatitis and subjected them to a seven-week treatment with the test formulations, followed by a four-week post-treatment period.Results: Clinical findings and the quality of life of participants remarkably improved after one week of treatment. Furthermore, skin hydration and transepidermal water loss considerably improved at weeks one and three, respectively. The Cer [NP]/[NS] ratio, an indicator of epidermal turnover, substantially increased during the treatment period and remained elevated even thereafter. The improvement in stratum corneum function was distinctive in participants with lower barrier function.Conclusion: These findings indicated that the combined use of the anti-inflammatory drug and moisturizer, both in lamellar structure-based formulations, is effective in treating atopic dermatitis in patients with fragile barrier function.Keywords: base formulations, lamellar structure, steroid, heparinoid, barrier function, TEWL

Crude anionic polysaccharides extracted from the Pacific starfish Lethasterias fusca were purified by anion-exchange chromatography. The main fraction LF, having MW 14.5 kDa and dispersity 1.28 (data of gel-permeation chromatography), was solvolytically desulfated and giving rise to preparation LF-deS with a structure of dermatan core [→3)-β-d-GalNAc-(1→4)-α-l-IdoA-(1→]n, which was identified according to NMR spectroscopy data. Analysis of the NMR spectra of the parent fraction LF led to identification of the main component as dermatan sulfate LF-Derm →3)-β-d-GalNAc4R-(1→4)-α-l-IdoA2R3S-(1→ (where R was SO3 or H), bearing sulfate groups at O-3 or both at O-2 and O-3 of α-l-iduronic acid, as well as at O-4 of some N-acetyl-d-galactosamine residues. The minor signals in NMR spectra of LF were assigned as resonances of heparinoid LF-Hep composed of the fragments →4)-α-d-GlcNS3S6S-(1→4)-α-l-IdoA2S3S-(1→. The 3-O-sulfated and 2,3-di-O-sulfated iduronic acid residues are very unusual for natural glycosaminoglycans, and further studies are needed to elucidate their possible specific influence on the biological activity of the corresponding polysaccharides. To confirm the presence of these units in LF-Derm and LF-Hep, a series of variously sulfated model 3-aminopropyl iduronosides were synthesized and their NMR spectra were compared with those of the polysaccharides. Preparations LF and LF-deS were studied as stimulators of hematopoiesis in vitro. Surprisingly, it was found that both preparations were active in these tests, and hence, the high level of sulfation is not necessary for hematopoiesis stimulation in this particular case. [ABSTRACT FROM AUTHOR]

Because of the importance of epidermal functions, including stratum corneum hydration and maintenance of permeability barrier homeostasis, in the pathogenesis of a variety of cutaneous and systemic disorders, a wide range of products has been developed to improve epidermal functions. However, the underlying mechanisms whereby certain products, including heparinoid-containing product, are far little understood. In the present study, we assessed the impact of a heparinoid-containing product, Hirudoid® cream, on epidermal permeability barrier function and expression levels of a panel of epidermal mRNA related to the formation/maintenance of the permeability barrier in mouse skin. Our results showed that while the baseline levels of transepidermal water rates remained unchanged, treatment with Hirudoid® cream twice daily for 7 days significantly accelerated permeability barrier recovery and increased stratum corneum hydration. In parallel, expression levels of epidermal mRNA for certain differentiation marker-related proteins, lipid synthetic enzymes, keratinocyte proliferation and antimicrobial peptides also increased significantly. Together, these results provide the underlying mechanisms by which topical Hirudoid® cream improves epidermal permeability barrier and antimicrobial function. Because of its benefits for epidermal functions, heparinoid-containing product could be more useful in the management of skin conditions, characterized by abnormal permeability barrier and antimicrobial function.

Heparinoid, a type of compound that has structures similar to heparin, has been found in marine organisms such as shrimp head. This shrimp waste products were used to prepare, characterize, and evaluate the antithrombotic effect of heparinoid. Two heparinoid compounds were obtained from shrimp head, and the main fraction F1 was →4)-GlcA-(1→3)-GalNAc-(1→ with Ara, while the minor fraction F2 composed mainly of the backbone as →4)-β-D-GlcA (or IdoA)-(1→4)-β-D-GlcN (or GlcNAc)-(1→. Both F1 and F2 could extend activated partial thromboplastin time and thrombin time concentration-dependently, and F2 has stronger activity than F1 at the same concentration. The potential anticoagulant mechanism of F1 and F2 may relate to their combination with more antithrombin III, which binds to and potentiates the action of antithrombin as well as inhibiting coagulation factors Xa and IIa, preventing blood clot formation. Furthermore, heparinoid F1 and F2 were found to have high fibrinolytic capability in vitro and in vivo via activating the self-fibrinolytic system. In conclusion, heparinoids (F1 and F2) derived from shrimp head wastes could be used as candidate compounds to prevent thrombosis while posing a lower hemorrhagic risk. [ABSTRACT FROM AUTHOR]

Heparinoid, a sulfate polysaccharide derived from marine organisms was attracted largely attention due to its versatile activities. A naturally occurring heparinoid (M2) that was extracted from the mollusk Meretrix lusoria and used in this investigation shown strong antithrombotic action. UV–Vis, FT-IR, SAX-HPLC, and NMR were used to explore the structural characteristics of M2, results indicated that M2 similar with heparin, its average molecular weight was 22.58 kDa. Which was primarily made up of→4)-α-IdoA2S-(1→4)-α-GlcNS6S-(1→ (31.19%), →4)-β-GlcA-(1→4)-α-GlcNAc (1→ (23.21%), →4)-β-GlcA-(1→4)-α-GlcNS (1→ (13.87%), →4)-α-IdoA2S-(1→4)-α-GlcNS (1→ (8.95%), →4)-β-GlcA-(1→4)-α-GlcNAc6S (1→ (7.39%) and →4)-β-GlcA-(1→4)-α-GlcNS6S (1→ (7.63%). The antithrombotic activity of M2 was evaluated using measurements of the anticoagulant effect in vitro and the fibrinolytic capability in vitro and in vivo, and M2 has 122.4 U/mg of anticoagulant activity and 1.41 U/mg of fibrinolytic activity, respectively. Additionally, a mouse tail-cutting model was used to assess the bleeding effect in real time, it found that M2 had a reduced hemorrhagic risk than heparin. Consequently, M2 could be exploited to develop functional foods or medications with antithrombotic properties.

Tight junctions (TJs) play important roles in epidermal barrier function and their dysfunction is involved in the pathogenesis of various skin diseases, including atopic dermatitis (AD). Mucopolysaccharide polysulphate (MPS) is the active ingredient of a moisturizing agent used to treat xerosis in patients with AD; however, its mechanism of action on TJ barrier function remains unclear. To elucidate the effects of MPS on TJs, adult human epidermal keratinocyte (HEKa) cells were exposed to MPS, subjected to Western blotting and quantitative PCR analyses for the investigation of TJ‐related factors. MPS treatment significantly increased the mRNA and protein expression of claudin‐1 (CLDN1) and zonula occludens‐1, and significantly increased transepithelial electrical resistance (TEER), which indicates TJ integrity. Conversely, the sulphated and non‐sulphated glycosaminoglycans, chondroitin sulphate and hyaluronic acid, respectively, had little effect on TEER or the expression of mRNAs or TJ‐related proteins. Interestingly, MPS treatment also inactivated the extracellular signal‐regulated kinase signalling pathway, which is known to negatively regulate CLDN1 expression. Furthermore, MPS notably improved the reduction in CLDN1 expression and TEER caused by histamine, which is upregulated in the skin of patients with AD and is known to disrupt the TJ barrier function. Taken together, these findings demonstrate that treatment with the moisturizing agent, MPS, can repair TJ dysfunction and could therefore represent a new therapeutic option for treating patients with AD. [ABSTRACT FROM AUTHOR]

Megumi Matsuoka,1 Keita Okoshi,1 Shotaro Ito,1 Takuji Kume,2 Tsuyoshi Seki,1 Takahiro Nishizaka,1 Joji Okada,3 Azumi Nagasawa,1 Makoto Iijima,1 Masatoshi Abe,4 Osamu Nemoto4 1Health & Wellness Products Research, Kao Corporation, Sumida-ku, Tokyo, Japan; 2Analytical Science Research, Kao Corporation, Wakayama, Japan; 3Skin Care Products Research, Kao Corporation, Sumida-ku, Tokyo, Japan; 4Sapporo Skin Clinic, Sapporo, Hokkaido, JapanCorrespondence: Azumi NagasawaHealth & Wellness Products Research, Kao Corporation, 2-1-3, Bunka, Sumida-ku, Tokyo, 131-8501, JapanTel +81-3-5630-9443Fax +81-3-5630-9342Email nagasawa.azumi@kao.comPurpose: Atopic dermatitis (AD) is characterized by chronic inflammation, which frequently recurs, is exacerbated, and enters remission. A maintenance remission period is important for AD patients. We developed a formulation for use during AD remission, containing heparinoid and pseudo-ceramide that forms a lamellar structure. We evaluated the allergen permeability and examined the formulation’s efficacy in maintaining remission in patients with AD.Materials and Methods: Seventeen AD patients applied a cream containing 0.3% heparinoid and pseudo-ceramide (test cream group, n = 10), or a general cream containing 0.3% heparinoid (control cream group, n = 7) to their arm for four weeks after inducing remission with the application of a steroid cream for two weeks.Results: The lamellar structure of the test cream was confirmed with small- and wide-angle x-ray scattering analysis and observation by transmission electron microscopy. The test cream inhibited the penetration of V8 protease significantly compared to the control cream in vitro. According to AD severity score by dermatologists, the effects remission maintenance of the test cream group were comparable to those of the control cream group. However, the test cream group had a significantly increased skin hydration value compared to the control cream group. A significant decrease in transepidermal water loss, an indicator of skin barrier function, was shown in the test cream group compared to the control cream group.Conclusion: The cream with lamellar structures containing heparinoid and pseudo-ceramides may inhibit allergen penetration. Moreover, skin properties improved during the remission period; thus, the formulation we developed was suitable for use during the AD remission period.Keywords: atopic dermatitis, barrier, lamellar, heparinoid, ceramide, skin hydration, transepidermal water loss

Introduction: Molecular targeted therapies (MTTs) cause skin disorders in patients with cancer, and moisturizers are useful treatments; however, their actual use and costs are unknown. Our purpose was to examine the use and costs of moisturizers prescribed for xerosis (asteatosis) in patients with cancer treated with MTTs. Methods: We used data from a Japanese hospital-based claims database. The index date was the first date of MTT prescription from October 2011 to April 2018 (selection period), and the follow-up period was 1 year from the index date. Patients treated with MTTs during the selection period and who were not prescribed moisturizers in the 6 months before the index date were included as the study cohort. Timing, duration, amount, and costs of the prescribed moisturizers and total medical costs were analyzed. Results: Among the 78,190 patients in the study cohort, 27,906 patients (35.7%) were prescribed moisturizers during follow-up. Moisturizer prescription timing, duration, and volume were inconsistent. The average annual total medical costs for treating patients with MTT who were prescribed moisturizers was JPY 6.165 million (USD 53,797) per patient, and the moisturizer costs were JPY 6033 (USD 53). The number of patients who used moisturizers showed an increasing trend. Conclusion: No consistent patterns were observed for the timing or duration of moisturizer use, which suggests various developmental patterns of skin disorders. Furthermore, medical costs for moisturizers accounted for only a small proportion of the total medical costs required for cancer treatment. [ABSTRACT FROM AUTHOR]

Crude anionic polysaccharides extracted from the Pacific starfish Lethasterias fusca were purified by anion-exchange chromatography. The main fraction LF, having MW 14.5 kDa and dispersity 1.28 (data of gel-permeation chromatography), was solvolytically desulfated and giving rise to preparation LF-deS with a structure of dermatan core [→3)-β-d-GalNAc-(1→4)-α-l-IdoA-(1→]n, which was identified according to NMR spectroscopy data. Analysis of the NMR spectra of the parent fraction LF led to identification of the main component as dermatan sulfate LF-Derm →3)-β-d-GalNAc4R-(1→4)-α-l-IdoA2R3S-(1→ (where R was SO3 or H), bearing sulfate groups at O-3 or both at O-2 and O-3 of α-l-iduronic acid, as well as at O-4 of some N-acetyl-d-galactosamine residues. The minor signals in NMR spectra of LF were assigned as resonances of heparinoid LF-Hep composed of the fragments →4)-α-d-GlcNS3S6S-(1→4)-α-l-IdoA2S3S-(1→. The 3-O-sulfated and 2,3-di-O-sulfated iduronic acid residues are very unusual for natural glycosaminoglycans, and further studies are needed to elucidate their possible specific influence on the biological activity of the corresponding polysaccharides. To confirm the presence of these units in LF-Derm and LF-Hep, a series of variously sulfated model 3-aminopropyl iduronosides were synthesized and their NMR spectra were compared with those of the polysaccharides. Preparations LF and LF-deS were studied as stimulators of hematopoiesis in vitro. Surprisingly, it was found that both preparations were active in these tests, and hence, the high level of sulfation is not necessary for hematopoiesis stimulation in this particular case.

Heparinoid, a type of compound that has structures similar to heparin, has been found in marine organisms such as shrimp head. This shrimp waste products were used to prepare, characterize, and evaluate the antithrombotic effect of heparinoid. Two heparinoid compounds were obtained from shrimp head, and the main fraction F1 was →4)-GlcA-(1→3)-GalNAc-(1→ with Ara, while the minor fraction F2 composed mainly of the backbone as →4)-β-D-GlcA (or IdoA)-(1→4)-β-D-GlcN (or GlcNAc)-(1→. Both F1 and F2 could extend activated partial thromboplastin time and thrombin time concentration-dependently, and F2 has stronger activity than F1 at the same concentration. The potential anticoagulant mechanism of F1 and F2 may relate to their combination with more antithrombin III, which binds to and potentiates the action of antithrombin as well as inhibiting coagulation factors Xa and IIa, preventing blood clot formation. Furthermore, heparinoid F1 and F2 were found to have high fibrinolytic capability in vitro and in vivo via activating the self-fibrinolytic system. In conclusion, heparinoids (F1 and F2) derived from shrimp head wastes could be used as candidate compounds to prevent thrombosis while posing a lower hemorrhagic risk.

Xerosis and pruritus are common in patients undergoing dialysis. These symptoms are treated with moisturizers, but limited evidence supports the efficacy of such treatment. Our exploratory study suggested the effectiveness of a heparinoid‐containing product for xerosis in dialysis patients. We conducted a multicenter, open‐label, randomized, before‐after, parallel‐group comparative study to verify the exploratory study results (Clinical Trial Registry: UMIN000029360). Seventy‐one Japanese patients undergoing dialysis with chronic kidney disease and xerosis were randomly assigned to receive a heparinoid‐containing product for 2 weeks (group A [n = 36]) or 8 weeks (group B [n = 35]). Patients were instructed to apply the study product based on the fingertip unit method. The efficacy endpoints were the water content of the stratum corneum (WCSC), skin dryness score, pruritus visual analog scale score, and Dermatology Life Quality Index. Safety was assessed by monitoring adverse events. The mean WCSC (arbitrary units) was 26.0 ± 9.6 in group A and 25.2 ± 10.0 in group B at the start of treatment (week 0), significantly increased to 39.0±12.5 in group A and 38.5 ± 11.0 in group B (P < 0.0001 for both vs week 0) by week 2, and then decreased only in group A. Thus, the WCSC at week 4 (the primary endpoint) remained significantly higher in group B (36.4 ± 12.2 vs 28.8 ± 10.4; P = 0.0068). Other endpoints improved during treatment with the study product. One patient developed a rash and erythema as treatment‐related adverse events. In conclusion, 8 weeks' application of a heparinoid‐containing product was effective for xerosis in patients undergoing dialysis. [ABSTRACT FROM AUTHOR]

The search and development of direct and rapid anticoagulants used per os, is an urgent problem in physiological and medical science. A number of plants contain heparin-like components with a positive effect on the hemostatic system, both within normal and in some pathological conditions of the body.The aim of the work was to study the complex effect of fibrin, a heparin-like substance (heparinoid) from the roots of Paeonia lactiflora, on fibrinolytic, anticoagulant systems of the body and polymerization processes, when it is administered per os in animals within normal conditions and when modeling the state of prethrombosis.Materials and methods. To carry out the research, the roots of Paeonia lactiflora growing in the Botanical Garden of Moscow State University, and laboratory animals – male Wistar rats – were used. To study the antithrombotic effects of the extract from roots containing heparinoid, the state of prethrombosis was modeled in rats. The determined parameters of hemostasis were: anticoagulant activity according to the tests of activated partial thromboplastin time and thrombin time, fibrinolytic activity according to the test of total fibrinolytic activity, fibrin polymerization according to the test of fibrindepolymerization activity of blood plasma.Results. With repeated (every 24 hours within 3 days) oral administration of the extract containing heparinoid, in animals within normal conditions and with prethrombosis, the following anticoagulant effects were established in the blood: an increase in anticoagulant, fibrindepolymerization and fibrinolytic plasma activity. Possible mechanisms of the activating effect of heparinoid on fibrinolysis and anticoagulant properties of plasma due to the excretion of tissue plasminogen activator into the bloodstream from the endothelium, thrombin inhibition, and fibrin polymerization are described. Moreover, the anticoagulant effect of the use of the extract from the peony roots was equivalent to that of the reference drug of low molecular weight heparin from Celsus (USA). For the first time, it was revealed that when modeling experimental prethrombosis, the administration of heparinoid in rats at the dose of 37.5 IU/kg МЕ/кг body weight restored impaired hemostasis, which requires a further study.Conclusion. The ability of heparinoid from peony roots to normalize the functional state of the anticoagulant system during the development of prethrombosis in animals has been established. The restriction of fibrin polymerization during oral administration of heparinoid from peony in animals by increasing the enzymatic fibrinolytic and fibrindepolymerization activity of blood plasma was revealed. In the future, heparinoid can be used as an antithrombotic agent.

Copyright of Shipin Kexue/ Food Science is the property of Food Science Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: Either systemic or topical glucocorticoids (GCs) can cause significant adverse effects on cutaneous structure and function. Although some products and ingredients can improve GC-induced abnormalities in epidermal permeability barrier, the efficacy is moderate. Prior studies in normal mice showed that topical applications of a heparinoid-containing product, Hirudoid® cream, improve epidermal barrier function by upregulation of epidermal proliferation, expression of mRNA for epidermal differentiation, and lipid production. Objective: The objective of this study was to assess whether topical applications of this product could prevent GC-induced changes in epidermal function in murine skin. Materials and Methods: One group of C57BL/6J mice was treated topically with 0.05% clobetasol propionate twice daily for 6 days, while another group was treated topically with Hirudoid® cream 30 min after each application of clobetasol propionate. Untreated mice served as normal controls. Transepidermal water loss (TEWL) rates, stratum corneum hydration, and skin surface pH were measured using respective probes connected to an MPA5 physiology monitor. qPCR was used to measure the expression levels of mRNA for keratinocyte differentiation-related proteins and lipid synthetic enzymes. Results: Co-applications of Hirudoid ® cream with GC minimally, but significantly, increased skin thickness in comparison to GC treatment alone (p < 0.05), in parallel with increased expression levels of mRNA for PCNA in both the dermis and the epidermis. Moreover, Hirudoid® cream largely prevented GC-induced elevation in basal TEWL (p < 0.001) and delay in barrier recovery (p < 0.05), accompanied by upregulation in the expression levels of mRNA for epidermal involucrin, HMGCoA, and SPT1. However, both stratum corneum hydration and skin surface pH were comparable in the skin treated with GC alone versus GC + Hirudoid® cream. Conclusion: Topical heparinoid-containing product can partially prevent GC-induced alterations in some epidermal functions. [ABSTRACT FROM AUTHOR]

Abstract Recently, heparin-induced thrombocytopenia (HIT) after vaccination with the vaccines manufactured by AstraZeneca and Pfizer–BioNTech has been published in the New England Journal of Medicine. These reports state that heparin was not used around the vaccination period in all cases. HIT after vaccination is more common in women; thus, heparinoid use can be suspected to induce HIT.

Recurrent spontaneous abortion (RSA) is defined as the loss of at least two consecutive pregnancies before the 28th week of gestation. RSA is a complicated pathological condition causedmultiple factors including genetic abnormalities, anatomical factors, endocrine disorders, immune abnormalities, prethrombotic state (PTS) and infection factors. Studies have suggested that anticoagulation and antiplatelet therapy could significantly improve the pregnancy outcomes of RSA patients with PTS and autoimmune abnormalities. Frequently used anticoagulants and antiplatelet drugs are heparin, heparinoid, warfarin, aspirin and clopidogrel. However, the maternal and fetal safety after the of these drugs during pregnancy has long been concerned. Safety of anticoagulants and antiplatelet drugs in patients with recurrent spontaneous abortion during pregnancy is reviewed. [ABSTRACT FROM AUTHOR]

Heparinoids are the starting material for sulodexide production, a drug used as intravenous anti-coagulant, as an alternative to heparin. The origin determination in the starting material for sulodexide, heparin, and derivatives is crucial for safety (including the impact related to bovine spongiform encephalopathy) and efficacy of the final products. Therefore, European countries have decided to approve the production of heparin only from porcine intestinal mucosa. PCR (polymerase chain reaction) methods are available to evaluate the origin species of crude heparin, during heparin production process, while they lack for the same analysis in heparinoids during sulodexide manufacturing processes. Notably, two main critical issues occur during the origin determination by using PCR for heparinoid analysis: first, heparin has been known to inhibit DNA polymerase activity and, second, the DNA amounts are very low in these samples. To overcome these critical issues, our proposed method is based on two fundamental steps, the DNA concentration by glycogen treatment and DNA purification, which occur before and after DNA extraction, respectively. Finally, by applying real-time PCR, we amplify three specific DNA sequences of ruminant species (bovine, ovine, and caprine), to assess possible contamination, and one from swine, to confirm the origin species. To date, such a method is the only one that determines origin species by PCR for heparinoids that guarantee quality, safety, and traceability of heparin-derived pharmaceutical products. In conclusion, our proposed method is an alternative to nuclear magnetic resonance and ELISA methods, because real-time PCR offers significant advantages in sensitivity, specificity, and robustness. [ABSTRACT FROM AUTHOR]

Cutibacterium acnes is an opportunistic pathogen in acne vulgaris. C. acnes produces autoinducer-2 (AI-2）, a signaling molecule used for communication known as quorum sensing (QS）. In C. acnes, QS reportedly upregulates biofilm formation leading to resistance against bactericidal agents. In this study, we analyzed how heparinoid affected QS and biofilm formation of the opportunistic pathogen C. acnes. We also verified whether heparinoid would suppress biofilm formation and enhance the efficacy of the bactericidal agent 4-isopropyl-3-methylphenol (IPMP) against C. acnes biofilms. We ran an AI-2 bioassay using Vibrio harveyi ATCC BBA-1121. Heparinoid exhibited inhibitory activity against AI-2 at concentrations of 0.003-0.005%, suggesting an AI-2 analog-derived or C. acnes culture supernatant-derived inhibition of the AI-2 activity. To evaluate how heparinoid suppresses biofilm formation in C. acnes, we completed a biofilm assay in 96-well plates. We also evaluated the bactericidal activity of IPMP against the C. acnes biofilm prepared with or without heparinoid. Heparinoid inhibited C. acnes biofilm formation and IPMP bactericidal efficacy increased upon heparinoid-mediated suppression of biofilm formation. In this study, we clarified that heparinoid inhibits the AI-2-mediated QS of C. acnes, thereby suppressing biofilm formation and increasing IPMP bactericidal efficacy, potentially suppressing acne vulgaris.

Copyright of Shipin Kexue/ Food Science is the property of Food Science Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: Epidermal keratinocytes initiate skin inflammation by activating immune cells. The skin barrier is disrupted in atopic dermatitis (AD) and epidermal keratinocytes can be exposed to environmental stimuli, such as house dust mite (HDM) allergens. We showed previously that HDM allergens activate the NLRP3 inflammasome of keratinocytes, thereby releasing pro‐inflammatory cytokines. Heparinoid is an effective moisturizer for atopic dry skin. However, a recent report showed that heparinoid treatment can improve inflammation of lichen planus. Therefore, we hypothesized that it acts on epidermal keratinocytes not only as a moisturizer, but also as a suppressant of the triggers of skin inflammation. We found that HDM allergen‐induced interleukin (IL)‐1β release from keratinocytes was inhibited significantly by heparinoid pretreatment without affecting cell viability. However, heparinoid did not affect caspase‐1 release, suggesting that heparinoid did not affect HDM allergen‐induced inflammasome activation. Heparinoid treatment not only decreased intracellular levels of pro‐IL‐1β, but also suppressed IL‐1β messenger RNA (mRNA) expression in keratinocytes. Among the intracellular signalling pathways, the activation of extracellular signal‐regulated kinase and p38 pathways, which are required for IL‐1β expression in keratinocytes, was inhibited by heparinoid treatment. The inhibitory effect of heparinoid on IL‐1β mRNA expression was also confirmed with living skin equivalents. Our results demonstrated that heparinoid suppresses the initiation of keratinocyte‐mediated skin inflammation. [ABSTRACT FROM AUTHOR]

*Visual Abstracts prepared by Dr. Carmen Carina Cabrera Objectives. To evaluate the safety and efficacy of heparinoid supplementation on all-cause mortality and disease progression in diabetic kidney disease (DKD). Methodology. Trials evaluating heparinoid supplementation in DKD were included. Two authors performed a literature search with eligible studies undergoing validity screen, data extraction, and statistical analysis. Results were calculated using the Mantel-Haenszel odds ratio for dichotomous variables and the inverse variance method for continuous variables, and pooled using a random or fixed effects model depending on heterogeneity Results. Twelve trials were included in the analysis. Eight involved sulodexide while two each involved low molecular weight heparin and danaparoid. We found no statistically significant difference between the heparinoid and placebo groups for all-cause mortality (95% CI, HR 0.79 [0.41, 1.53], p=0.49), number of patients reaching therapeutic success (95% CI, OR 0.97 [0.71, 1.33], p=0.87), serum creatinine (95% CI, MD 2.55 umol/L [-0.54, 5.65], p=0.11), and creatinine clearance (95% CI, MD -8.55 mg/min [-18.28, 1.18], p=0.09). We also found no statistically significant difference in urinary albumin excretion rate (UAER) between Type 2 heparinoid-treated DKD patients compared to placebo (95% CI, log transformed MD 0.13 mg/24h [-0.42, 0.68], p=0.65); however, a statistically significant UAER reduction was seen in Type 1 heparinoid-treated DKD patients compared to placebo (95% CI, log-transformed MD -1.5 mg/24h [-2.79, -0.21], p=0.02). This subgroup analysis was performed due to initial heterogeneity (I^2=57%). Conclusion. Heparinoid supplementation was not associated with statistically significant changes in Type 2 DM patients. However, it may be associated with a statistically significant UAER reduction of approximately 31.62 mg/24 h as compared to placebo in Type 1 DM patients. Due to sparse data on hard clinical outcomes, larger studies are recommended.

Background Upon skin injuries, dermal fibroblasts actively produce transforming growth factor-β (TGF-β), which leads to the formation of α-smooth muscle actin (αSMA)-positive granulation tissues. The hyperplasia or incomplete regression of these tissues subsequently causes scar formation in the skin, where sulfated glycosaminoglycans (GAGs), side chains of unique proteoglycans, are supposed to play important roles. Objective The aim of this study is to clarify the effects of sulfated GAGs on dermal cell behaviors triggered by the TGF-β signaling, along with its possible regulators basic fibroblast growth factor (bFGF) and cell surface epimorphin. bFGF and epimorphin might regulate the TGF-β-induced αSMA expression, they could exert such effects only in specific cellular contexts, given that they lack conventional signal sequences for extracellular localization. Methods Human scar-derived dermal fibroblasts (HSFs) were treated with TGF-β alone, TGF-β plus bFGF, and TGF-β plus cell surface expression of epimorphin. The effects of GAGs on the expression of αSMA and the cellular morphology were then investigated. Results A highly sulfated chondroitin sulfate (CS-E) or its substitute (heparinoid) had marked inhibitory effects on TGF-β-mediated changes in HSF behaviors. We found that heparinoid can directly associate with TGF-β, bFGF and epimorphin. We also found that bFGF downregulated αSMA, which was attenuated by heparinoid, whereas epimorphin augmented αSMA expression, which was further amplified by heparinoid. Conclusions TGF-β, bFGF and epimorphin in the extracellular microenvironment cooperatively affect HSF behaviors under the control of a highly sulfated chondroitin sulfate. These results provide important evidence towards understanding the regulation of TGF-β-induced HSF behaviors. [ABSTRACT FROM AUTHOR]

A series of low-molecular-weight polymannuronate (LPM) and polyguluronate (LPG) polyanionic derivatives, including LPM/LPG phosphate (LPMP/LPGP), LPM/LPG H-phosphonate (LPMHP/LPGHP) and LPM/LPG sulfate (LPMS/LPGS), were prepared as heparinoids by chemical modification of LPM and LPG. The structures and characteristics of LPM, LPG and their derivatives were elucidated based on high performance gel permeation chromatography (HPGPC), fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance spectroscopy (NMR) and polyacrylamide gel electrophoresis (PAGE). In order to test the heparin-like activities of these derivatives and to reveal the activities affected by substituent groups and PM/PG polysaccharide backbones, the anticoagulant activities and FGF/FGFR1c signaling activation abilities were evaluated in vitro . The results showed that sulfate group was the best substituent group to improve the heparin-like activities of LPM/LPG compared with the other two anionic groups. The results also showed that sulfated derivative based on PG structure had better activities than that based on PM structure. [ABSTRACT FROM AUTHOR]

Propylene glycol alginate sodium sulfate (PSS) is the world’s first oral heparinoid approved by Chinese Food and Drug Administration in 1987. Propylene glycol alginate sodium sulfate is produced by modifying partially hydrolyzed alginate, one of the most abundant marine polysaccharides isolated from brown algae, by epoxypropane esterification and by chemical sulfation. It is used for treating and preventing cardiovascular-related diseases. The low cost (US$1.29/100 tablets, ∼4 tablets/day), remarkable clinical effects, and convenient oral administration make PSS an ideal long-term prevention drug. Propylene glycol alginate sodium sulfate is available in most drug stores in China, and millions of patients take PSS routinely during the past 27 years. The 22 784 reported clinical cases as well as the structure, preparation, clinical efficacy, adverse reactions, pharmacokinetics, pharmacodynamics, and future perspectives of PSS based on the results of peer-reviewed publications will be discussed. This review should bring the knowledge of PSS gained in China to the world to stimulate in depth academic and clinical studies of PSS. [ABSTRACT FROM AUTHOR]

Background: The use of antithrombotic agents, including anticoagulants, antiplatelet agents, and thrombolytics has increased over the last decade and is expected to continue to rise. Although antithrombotic-associated intracranial hemorrhage can be devastating, rapid reversal of coagulopathy may help limit hematoma expansion and improve outcomes.Methods: The Neurocritical Care Society, in conjunction with the Society of Critical Care Medicine, organized an international, multi-institutional committee with expertise in neurocritical care, neurology, neurosurgery, stroke, hematology, hemato-pathology, emergency medicine, pharmacy, nursing, and guideline development to evaluate the literature and develop an evidence-based practice guideline. Formalized literature searches were conducted, and studies meeting the criteria established by the committee were evaluated.Results: Utilizing the GRADE methodology, the committee developed recommendations for reversal of vitamin K antagonists, direct factor Xa antagonists, direct thrombin inhibitors, unfractionated heparin, low-molecular weight heparin, heparinoids, pentasaccharides, thrombolytics, and antiplatelet agents in the setting of intracranial hemorrhage.Conclusions: This guideline provides timely, evidence-based reversal strategies to assist practitioners in the care of patients with antithrombotic-associated intracranial hemorrhage. [ABSTRACT FROM AUTHOR]

Background and Objectives With the increasing elderly population in Japan, skin problems have become a greater concern. A heparinoid-containing moisturiser is frequently used in Japan, but there is a lack of evidence for its efficacy in treating senile xerosis. To determine whether there is a correlation between age and the hydration state of the stratum corneum ( SC) assessed by skin capacitance, and to evaluate the efficiency of a heparinoid-containing moisturiser and a bed bath to treat senile xerosis. Methods We recruited 73 individuals to assess the hydration state of the SC on their flexor forearm by measuring their skin capacitance. To evaluate the efficacy of a heparinoid-containing moisturiser on senile xerosis, we recruited seven inpatients with an inactive daily life ( IDL) who had senile xerosis. They were treated with the moisturiser in addition to a bed bath in two different protocols, and we measured the skin capacitance on their flexor forearms on days 0, 7 and 14. Results There was a weak negative correlation (−0.3854, P < 0.01) between skin capacitance and age. Following the moisturiser treatments, the seven inpatients had increased hydration of both arms on days 7 and 14. The skin capacitance of the right forearm slightly decreased on day 14, even though it was significantly different from day 0 ( P < 0.05). Conclusions These findings indicate that treatment with a heparinoid-containing moisturiser together with a bed bath is an effective method for treating patients who have senile xerosis and IDL. [ABSTRACT FROM AUTHOR]

The efficacy of adapalene for acne treatment has been established. However, because of local adverse reactions, a fair number of patients discontinue adapalene treatment before experiencing its effects. To examine the usefulness of moisturizers concomitant with adapalene on adherence to treatment and its therapeutic effects in patients, 100 patients with mild to severe acne vulgaris were randomly assigned to one of two groups: group A, in which patients received adapalene in combination with a moisturizer (heparinoid); or group B, in which treatment consisted of adapalene alone and was converted to combination therapy with a moisturizer if local adverse reactions occurred that made adherence to treatment difficult. After 4 weeks of treatment, we compared the proportion of patients who adhered to therapy until the end of week 4, the number of treatment dropouts, and changes in the number of inflammatory eruptions and comedones between the groups. All of the patients in group A and 70% in group B continued the initial therapy until the end of week 4. In group B, three patients withdrew their consent and one patient stopped attending follow-up visits. The treatment period with the initial therapy was significantly elongated by the concomitant use of a moisturizer. No adverse effect of the use of a moisturizer was observed on the number of comedones and inflammatory eruptions. The concomitant use of a moisturizer with adapalene from the beginning of treatment did not affect its therapeutic effects and helped to improve adherence to treatment with adapalene. [ABSTRACT FROM AUTHOR]

Heparinoid, a type of compound that has structures similar to heparin, has been found in marine organisms such as shrimp head. This shrimp waste products were used to prepare, characterize, and evaluate the antithrombotic effect of heparinoid. Two heparinoid compounds were obtained from shrimp head, and the main fraction F1 was →4)-GlcA-(1→3)-GalNAc-(1→ with Ara, while the minor fraction F2 composed mainly of the backbone as →4)-β-D-GlcA (or IdoA)-(1→4)-β-D-GlcN (or GlcNAc)-(1→. Both F1 and F2 could extend activated partial thromboplastin time and thrombin time concentration-dependently, and F2 has stronger activity than F1 at the same concentration. The potential anticoagulant mechanism of F1 and F2 may relate to their combination with more antithrombin III, which binds to and potentiates the action of antithrombin as well as inhibiting coagulation factors Xa and IIa, preventing blood clot formation. Furthermore, heparinoid F1 and F2 were found to have high fibrinolytic capability in vitro and in vivo via activating the self-fibrinolytic system. In conclusion, heparinoids (F1 and F2) derived from shrimp head wastes could be used as candidate compounds to prevent thrombosis while posing a lower hemorrhagic risk.

Heparinoid, a sulfate polysaccharide derived from marine organisms was attracted largely attention due to its versatile activities. A naturally occurring heparinoid (M2) that was extracted from the mollusk Meretrix lusoria and used in this investigation shown strong antithrombotic action. UV-Vis, FT-IR, SAX-HPLC, and NMR were used to explore the structural characteristics of M2, results indicated that M2 similar with heparin, its average molecular weight was 22.58 kDa. Which was primarily made up of→4)-α-IdoA2S-(1→4)-α-GlcNS6S-(1→ (31.19%), →4)-β-GlcA-(1→4)-α-GlcNAc (1→ (23.21%), →4)-β-GlcA-(1→4)-α-GlcNS (1→ (13.87%), →4)-α-IdoA2S-(1→4)-α-GlcNS (1→ (8.95%), →4)-β-GlcA-(1→4)-α-GlcNAc6S (1→ (7.39%) and →4)-β-GlcA-(1→4)-α-GlcNS6S (1→ (7.63%). The antithrombotic activity of M2 was evaluated using measurements of the anticoagulant effect in vitro and the fibrinolytic capability in vitro and in vivo , and M2 has 122.4 U/mg of anticoagulant activity and 1.41 U/mg of fibrinolytic activity, respectively. Additionally, a mouse tail-cutting model was used to assess the bleeding effect in real time, it found that M2 had a reduced hemorrhagic risk than heparin. Consequently, M2 could be exploited to develop functional foods or medications with antithrombotic properties., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)