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  5. 有关低分子透明质酸HA35的科研文章

有关低分子透明质酸HA35的科研文章

文献检索@lucky~发表于 2026年03月02日 13:215阅读
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罗列出有关低分子透明质酸HA35的所有科研文章

根据您提供的文献，以下是所有关于低分子透明质酸HA35的科研文章列表：

  1. PMID: 26978861 标题: Hyaluronic Acid in Inflammation and Tissue Regeneration. 摘要: 本文综述了透明质酸（HA）在组织再生中的作用，并提到其性质取决于分子大小。高分子量HA具有抗炎和免疫抑制特性，而低分子量HA是有效的促炎分子。该综述也讨论了HA在伤口愈合的两个主要阶段：炎症和血管生成过程中的作用，并探讨了HA的抗氧化特性及其可能的临床应用。虽然这篇综述没有专门研究HA35，但它对不同分子量HA的特性进行了总体分类，其中低分子量HA的描述与HA35相关联。

  2. PMID: 34299024 标题: Mechanisms of Action and Efficacy of Hyaluronic Acid, Corticosteroids and Platelet-Rich Plasma in the Treatment of Temporomandibular Joint Osteoarthritis-A Systematic Review. 摘要: 这项系统综述旨在探讨透明质酸（HA）、皮质类固醇（CS）和富血小板血浆（PRP）治疗颞下颌关节骨关节炎（TMJ OA）的作用机制和疗效。研究发现，单纯关节穿刺术能有效减轻疼痛并改善TMJ OA患者的下颌功能。在关节穿刺术结束后额外注射低分子量（LMW）HA或高分子量（HMW）HA，或CS，并不能改善最终临床结果。CS对关节软骨有多种负面影响。虽然这篇综述提及了低分子量HA，但未具体到HA35。

  3. PMID: 37004799 标题: Hyaluronic acid and HA-modified cationic liposomes for promoting skin penetration and retention. 摘要: 本研究探讨了透明质酸（HA）对皮肤渗透的影响因素和潜在机制，并设计了HA修饰的十一碳酰苯丙氨酸（UP）脂质体（HA-UP-LPs）作为有效透皮给药策略的原理验证，以增强皮肤渗透和滞留。体外渗透测试（IVPT）显示，低分子量HA（LMW-HA，5 kDa和8 kDa）可以穿透角质层（SC）屏障进入表皮和真皮层，而高分子量HA（HMW-HA）则停留在角质层表面。机制研究表明，LMW-HA可以与角质层中的角蛋白和脂质相互作用，并发挥显著的皮肤水合作用，这可能部分解释了其渗透优势。HA35（35 kDa）属于低分子量HA的范畴，因此这篇文献关于LMW-HA渗透性的发现可能对其有参考价值。

  4. PMID: 25877232 标题: Human skin penetration of hyaluronic acid of different molecular weights as probed by Raman spectroscopy. 摘要: 本研究使用拉曼光谱微成像技术监测不同分子量透明质酸（HA）在皮肤中的渗透情况。结果显示，低分子量HA（20-300 kDa）可以穿透角质层，而高分子量HA（1000-1400 kDa）则无法渗透。这篇文献证实了低分子量HA相对于高分子量HA在皮肤渗透方面的优势，而HA35（35 kDa）属于低分子量HA范围，因此该发现对HA35的皮肤渗透性有直接的启示。

  5. PMID: 39028477 标题: Profhilo® Structura, Current Status and Future Perspectives: A Practical Review. 摘要: Profhilo® Structura 是一种新型的基于HA的产品，利用纳米混合协同复合物（NAHYCO）®技术，由高分子量和低分子量HA组成，旨在恢复面部脂肪组织。虽然这篇文献提到了高低分子量HA的混合应用，但并未具体到HA35。

  6. PMID: 38542191 标题: Intradermal Injection of Hybrid Complexes of High- and Low-Molecular-Weight Hyaluronan: Where Do We Stand and Where Are We Headed in Regenerative Medicine? 摘要: 这篇综述总结了关于高分子量和低分子量透明质酸混合协同复合物（HCC）的体外研究和体内应用，涵盖了从面部和身体年轻化到皮肤伤口愈合、皮肤病学和泌尿生殖系统病症的未来前景。虽然提到了低分子量HA，但未具体到HA35。

  7. PMID: 37314014 标题: Intra-articular Hyaluronic Acid Treatments for Knee Osteoarthritis: A Systematic Review of Product Properties. 摘要: 这项系统综述总结了关于关节内透明质酸（IA-HA）产品差异的现有证据，并评估这些差异是否影响临床结果。结果显示，低分子量（LMW）和高分子量（HMW）HA在滑液中的变化以及与关节空间受体的相互作用存在差异。临床结果的荟萃分析表明，HMW HA在缓解疼痛方面优于LMW HA。虽然此文提及了低分子量HA，但未特指HA35，且结论指出HMW HA在膝骨关节炎治疗中效果更佳。

  8. PMID: 39508297 标题: Viscoelastic High-Molecular-Weight Hyaluronic Acid Hydrogels Support Rapid Glioblastoma Cell Invasion with Leader-Follower Dynamics. 摘要: 本研究探讨了高分子量（HMW）和低分子量（LMW）透明质酸（HA）水凝胶对胶质母细胞瘤（GBM）肿瘤侵袭的影响。结果显示，GBM细胞在HMW HA水凝胶中的侵袭速度远快于LMW HA水凝胶，并表现出独特的“先导-跟随”动态。虽然本文对比了高分子量和低分子量HA，但其低分子量HA的分子量为60 kDa，与HA35（35 kDa）有所不同。

  9. PMID: 36574533 标题: 35kDa hyaluronan ameliorates ethanol driven loss of anti-microbial defense and intestinal barrier integrity in a TLR4-dependent manner. 摘要: 急性和慢性酒精暴露会损害肠道上皮完整性。本研究检验了35 kDa透明质酸（HA35）是否能改善乙醇诱导的肠道损伤。结果显示，口服HA35能够改善慢性乙醇对小鼠近端小肠（空肠）中C型凝集素抗微生物肽（AMPs）表达的降低，以及紧密连接蛋白表达的减少和细菌易位到肠系膜淋巴结的增加。体外实验也证实HA35能阻止乙醇诱导的AMPs表达降低和屏障完整性受损。重要的是，HA35的保护作用需要HA受体TLR4的参与，而非CD44或TLR2。这些数据表明，HA35在恢复乙醇驱动的肠道损伤早期阶段的肠道上皮完整性和防御方面具有治疗潜力。

  10. PMID: 28978412 标题: Layilin is critical for mediating hyaluronan 35kDa-induced intestinal epithelial tight junction protein ZO-1 in vitro and in vivo. 摘要: 本研究旨在探究HA35是否通过与肠道上皮的直接相互作用来增强ZO-1表达，并确定HA35介导结肠上皮ZO-1诱导的HA受体。结果表明，HA35处理增加了小鼠肠道上皮类器官中ZO-1的表达，而2000kDa的大分子HA未被细胞内化。免疫荧光数据显示，Layilin（而非TLR-4或CD44）介导了HA35在体外和体内诱导的结肠上皮ZO-1表达。此外，使用Layilin缺陷小鼠的研究证实，Layilin在健康小鼠和葡聚糖硫酸钠（DSS）诱导的结肠炎期间介导HA35诱导的ZO-1。该研究强调了Layilin作为HA受体，介导口服HA35对肠道上皮的影响，提示HA35有望作为强化肠道屏障防御的简单膳食补充剂。

  11. PMID: 27845198 标题: Hyaluronan 35kDa treatment protects mice from Citrobacter rodentium infection and induces epithelial tight junction protein ZO-1 in vivo. 摘要: 本研究调查了平均分子量约35 kDa的生物合成透明质酸（HA35）在健康小鼠以及感染了 Citrobacter rodentium 的小鼠肠道上皮中的保护功能。结果表明，HA35治疗能够保护小鼠免受 Citrobacter 感染，并增强上皮屏障功能。特别是，免疫荧光和蛋白质印迹分析显示，HA35在健康小鼠和 Citrobacter 感染小鼠中均能诱导紧密连接蛋白ZO-1的表达。此外，我们发现HA35治疗在葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎早期阶段增强了ZO-1的表达并降低了肠道通透性。这些数据表明，HA35治疗增加了紧密连接的表达和功能，提示了一种保护免受 Citrobacter 感染的新机制。

  12. PMID: 29290146 标题: Multifunctional Role of 35 Kilodalton Hyaluronan in Promoting Defense of the Intestinal Epithelium. 摘要: 本研究报告了35 kDa透明质酸（HA35）在促进肠道上皮防御中的多功能作用。此前实验室研究表明，人乳中分离的HA能诱导β-防御素表达并抵抗沙门氏菌感染，而商业HA35也能诱导β-防御素，上调紧密连接蛋白ZO-1表达，并减轻小鼠Citrobacter rodentium感染。本研究进一步证明，HA35在消化道中基本保持完整并具有生物活性，直接诱导β-防御素表达，并减轻小鼠沙门氏菌感染以及下调渗漏性紧密连接蛋白Claudin-2的表达。因此，HA35在宿主先天免疫防御中具有双重作用，即诱导抗菌肽产生和阻止病原体引起的肠漏。HA35有望成为治疗成人和新生儿细菌性结肠炎的潜在疗法。

  13. PMID: 39093812 标题: Low molecular weight 35 kDa hyaluronan fragment HA35 in the treatment of bone metastasis pain: A case report. 摘要: 这是一份关于使用35 kDa低分子量透明质酸片段（HA35）治疗骨转移癌痛的病例报告。一名52岁直肠恶性肿瘤伴多发性骶骨和肺部转移的患者，出现骨转移痛，尽管接受放疗，疼痛缓解仍不满意。在HA35治疗前，她的疼痛数字评分量表（NRS）为10分。通过腹部深层脂肪组织皮下注射100 mg/5 mL的HA35，每3天一次。首次注射后20分钟，疼痛评分降至6分，缓解40%；40分钟后降至4分，缓解60%。经过50次注射后，疼痛持续控制在3分左右。研究结论认为，HA35腹部脂肪组织皮下注射能有效缓解对常规治疗耐药的癌症和骨转移患者的疼痛，同时有助于缓解焦虑和疲劳，改善饮食和睡眠，为晚期癌症患者提供重要的姑息治疗。

  14. PMID: 39684390 标题: Network-Based Bioinformatics Highlights Broad Importance of Human Milk Hyaluronan. 摘要: 人乳富含生物活性因子，促进产后小肠发育和微生物组成熟，并对坏死性小肠结肠炎（NEC）具有保护作用。本研究团队此前已证明35 kDa透明质酸（HA35）能促进小鼠新生儿肠道成熟并保护其免受两种不同NEC模型的影响。本研究通过对HA35处理的小鼠（P7至P14）回肠转录组进行网络和功能分析，发现HA35处理导致间质细胞、Paneth细胞、成熟肠细胞和祖细胞的增加。基因集富集和通路分析显示，HA35上调了与抗氧化和生长通路相关的关键过程，如核因子红细胞2相关因子介导的氧化应激反应、缺氧诱导因子-1α、雷帕霉素靶蛋白，并下调了细胞凋亡信号。这些数据提示，HA35诱导的促生长和分化信号可能是这种人乳生物活性因子抵御NEC的新机制。

  15. PMID: 35565748 标题: Hyaluronic Acid 35 kDa Protects against a Hyperosmotic, Formula Feeding Model of Necrotizing Enterocolitis. 摘要: 坏死性小肠结肠炎（NEC）是早产儿常见的胃肠道急症。本研究旨在验证HA35治疗是否能在一个结合配方喂养的NEC小鼠模型中减少组织学损伤和死亡率。通过地噻宗诱导的Paneth细胞功能障碍和口服啮齿动物乳替代品，在14日龄小鼠中诱导NEC样损伤。结果显示，HA35显著降低了该模型中疾病的严重程度，并有降低死亡率的趋势。RNA-Seq分析表明，HA35上调了与杯状细胞功能和先天免疫相关的基因。这些小肠关键保护和修复机制的激活可能在HA处理的幼鼠在次级NEC模型中病理减轻和生存率提高中发挥作用，为人类早产儿疾病提供了潜在的翻译靶点。

  16. PMID: 39187208 标题: Hyperglycemic environments directly compromise intestinal epithelial barrier function in an organoid model and hyaluronan (∼35 kDa) protects via a layilin dependent mechanism. 摘要: 本研究探讨了高血糖环境对肠道屏障完整性的影响以及35 kDa低分子量透明质酸（HA35）通过Layilin依赖机制提供的保护作用。在高糖环境下，结肠类器官中两种关键屏障蛋白（ZO-1和Occludin）的表达和空间分布均降低。HA35阻止了ZO-1的降解或丢失，并维持了ZO-1和Occludin在高血糖应激下的空间分布。功能上，HA35在高糖条件下对上皮屏障具有保护作用。研究发现，HA受体Layilin参与阻止屏障蛋白丢失（ZO-1）以及维持ZO-1和Occludin的空间分布。蛋白质组学分析显示，在高糖应激下HA35处理的类器官中，细胞死亡和存活是主要上调的通路。HA35通过Layilin调节细胞凋亡，并介导黏着斑激酶（FAK）和F-肌动蛋白的空间组织。这些结果强调了HA35通过其受体Layilin和对细胞凋亡的调节在高糖应激下对肠道屏障功能的保护作用。

  17. PMID: 31121841 标题: Safety of Hyaluronan 35 in Healthy Human Subjects: A Pilot Study. 摘要: 本项初步研究评估了口服HA35（平均分子量约35 kDa）在健康人体中的安全性、耐受性、对代谢、肠道通透性和微生物组组成的影响。20名健康受试者每日口服140毫克HA35（连续七天）。结果显示，HA35在所有受试者中均具有良好的耐受性，没有发生严重不良事件。在28天的研究期间，人口统计学、临床、生化实验室检测、代谢功能或微生物组组成方面均未观察到统计学差异。研究结论认为，口服HA35（140毫克/天）在健康个体中是安全的治疗方法，不影响代谢、炎症或微生物组参数。

  18. PMID: 29142263 标题: Hyaluronic acid 35 normalizes TLR4 signaling in Kupffer cells from ethanol-fed rats via regulation of microRNA291b and its target Tollip. 摘要: 慢性乙醇喂养后，肝巨噬细胞中TLR4信号传导增加。本研究发现，用小分子量HA35处理慢性乙醇喂养大鼠的肝巨噬细胞，可以使TLR4信号传导正常化。通过下一代测序分析发现，miR291b在乙醇作用下上调，而HA35处理后下调。生物信息学分析表明Tollip是miR291b的靶点，Tollip是TLR4的负调节因子。乙醇喂养大鼠肝巨噬细胞中Tollip表达降低，但HA35治疗或转染miR291b发夹抑制剂可恢复Tollip表达并使TLR4刺激的TNFα表达正常化。在酒精性肝炎患者的外周血单核细胞中，HA35预处理可使LPS刺激的TNFα表达降低50%以上。这些结果表明，HA35通过正常化miR291b→Tollip通路，缓解了乙醇诱导的巨噬细胞/单核细胞TLR4信号传导敏感化，提示HA35可能成为酒精性肝病治疗的新型治疗剂。

  19. PMID: 35943893 标题: Effect of Hyaluronic Acid 35 kDa on an In Vitro Model of Preterm Small Intestinal Injury and Healing using Enteroid-derived Monolayers. 摘要: 本研究描述了从非人灵长类动物末端回肠肠隐窝衍生的类器官生成二维（2D）单层的方案，并利用这些类器官衍生的单层在体外划痕伤口实验中，测试35 kDa透明质酸（HA35）促进上皮伤口边缘细胞迁移和增殖的能力。结果显示，体外HA35能加速小肠类器官单层伤口愈合，这可能通过伤口边缘细胞增殖和向伤口区域迁移的结合实现。这些方法可能被用作探索早产人类小肠再生的模型。

  20. PMID: 31237689 标题: Specifically Sized Hyaluronan (35 kDa) Prevents Ethanol-Induced Disruption of Epithelial Tight Junctions Through a layilin-Dependent Mechanism in Caco-2 Cells. 摘要: 本研究旨在探究HA35是否也保护肠道其他区域，以及这种保护作用是由于HA35与肠道上皮的直接或间接相互作用。结果显示，短期乙醇暴露并未引起肠道大体形态的明显改变，但近端和远端结肠中ZO-1和Occludin在紧密连接处的共定位减少。HA35阻止了乙醇的这些影响。在分化的Caco-2细胞中，乙醇降低了ZO-1和Occludin在紧密连接处的定位，并增加了FITC-葡聚糖的通透性。较高浓度的乙醇也降低了跨上皮电阻（TEER）。HA35预处理阻止了这些变化。当Caco-2细胞中的透明质酸受体Layilin被敲除时，HA35不再保护细胞免受乙醇诱导的紧密连接丢失。这些数据表明，HA35通过与肠道上皮细胞上的Layilin相互作用，在短期乙醇暴露期间维持肠道紧密连接的完整性。

References

1Hyaluronic Acid in Inflammation and Tissue Regeneration.PubMed

Malgorzata Litwiniuk, Alicja Krejner, Marcus S Speyrer, et al.
Wounds. 2016 Mar;28(3):78-88.
Hyaluronic acid (HA), the main component of extracellular matrix, is considered one of the key players in the tissue regeneration process. It has been proven to modulate via specific HA receptors, inflammation, cellular migration, and angiogenesis, which are the main phases of wound healing. Studies have revealed that most HA properties depend on its molecular size. High molecular weight HA displays anti-inflammatory and immunosuppressive properties, whereas low molecular weight HA is a potent proinflammatory molecule. In this review, the authors summarize the role of HA polymers of different molecular weight in tissue regeneration and provide a short overview of main cellular receptors involved in HA signaling. In addition, the role of HA in 2 major steps of wound healing is examined: inflammation and the angiogenesis process. Finally, the antioxidative properties of HA are discussed and its possible clinical implication presented.

2Mechanisms of Action and Efficacy of Hyaluronic Acid, Corticosteroids and Platelet-Rich Plasma in the Treatment of Temporomandibular Joint Osteoarthritis-A Systematic Review.PubMed

Marcin Derwich, Maria Mitus-Kenig, Elzbieta Pawlowska
Int J Mol Sci. 2021 Jul 9;22(14):7405. doi: 10.3390/ijms22147405.
Temporomandibular joint osteoarthritis (TMJ OA) is a low-inflammatory disorder with multifactorial etiology. The aim of this review was to present the current state of knowledge regarding the mechanisms of action and the efficacy of hyaluronic acid (HA), corticosteroids (CS) and platelet-rich plasma (PRP) in the treatment of TMJ OA.: The PubMed database was analyzed with the keywords: "(temporomandibular joint) AND ((osteoarthritis) OR (dysfunction) OR (disorders) OR (pain)) AND ((treatment) OR (arthrocentesis) OR (arthroscopy) OR (injection)) AND ((hyaluronic acid) OR (corticosteroid) OR (platelet rich plasma))". After screening of 363 results, 16 studies were included in this review. Arthrocentesis alone effectively reduces pain and improves jaw function in patients diagnosed with TMJ OA. Additional injections of HA, either low-molecular-weight (LMW) HA or high-molecular-weight (HMW) HA, or CS at the end of the arthrocentesis do not improve the final clinical outcomes. CS present several negative effects on the articular cartilage. Results related to additional PRP injections are not consistent and are rather questionable. Further studies should be multicenter, based on a larger group of patients and should answer the question of whether other methods of TMJ OA treatment are more beneficial for the patients than simple arthrocentesis.

3Hyaluronic acid and HA-modified cationic liposomes for promoting skin penetration and retention.PubMed

Chang Ni, Zijun Zhang, Yuling Wang, et al.
J Control Release. 2023 May;357:432-443. doi: 10.1016/j.jconrel.2023.03.049. Epub 2023 Apr 18.
Hyaluronic acid (HA) has been widely used in cosmetics and topical preparations owing to its favorable moisturizing property and potential in enhancing drugs' skin permeability. Here, the influencing factors and underlying mechanism of HA on skin penetration were carefully investigated, and HA-modified Undecylenoyl-Phenylalanine (UP) liposomes (HA-UP-LPs) were designed as a proof of principle for efficacious transdermal drug delivery strategy to enhance the skin penetration and retention. An in vitro penetration test (IVPT) of HA with different molecular weights showed that low molecular weight HA (LMW-HA, 5 kDa and 8 kDa) could pass through the stratum corneum (SC) barrier and enter into the epidermis and dermis layers, whereas its high molecular counterparts (HMW-HA) were trapped on the SC surface. Mechanistic studies revealed that LMW-HA could interact with keratin and lipid in the SC meanwhile exerted a substantial skin hydration effect, which may partially contribute to the SC penetration benefit. In addition, the surface decoration of HA drove an energy-dependent caveolae/lipid raft-mediated endocytosis of the liposomes through direct binding to the CD44 receptors widely expressed on skin cell membranes. Notably, IVPT showed a 1.36-fold and 4.86-fold increase in skin retention of UP and a 1.62-fold and 5.41-fold increase in skin penetration of UP with HA-UP-LPs over UP-LPs and free UP at 24 h, respectively. As a result, the anionic HA-UP-LPs (-30.0 mV) showed enhanced drug skin penetration and retention compared with conventional cationic bared UP-LPs (+21.3 mV) on both in vitro mini-pig skin as well as in vivo mouse skin. Overall, the usage of LMW-HA might offer opportunities in developing novel topical preparations and skin care products with improved transdermal penetration and retention.

4Human skin penetration of hyaluronic acid of different molecular weights as probed by Raman spectroscopy.PubMed

M Essendoubi, C Gobinet, R Reynaud, et al.
Skin Res Technol. 2016 Feb;22(1):55-62. doi: 10.1111/srt.12228. Epub 2015 Apr 16.
BACKGROUND: Topical delivery of molecules into the human skin is one of the main issues in dermatology and cosmetology. Several techniques were developed to study molecules penetration into the human skin. Although widely accepted, the conventional methods such as Franz diffusion cells are unable to provide the accurate localization of actives in the skin layers. A different approach based on Raman spectroscopy has been proposed to follow-up the permeation of actives. It presents a high molecular specificity to distinguish exogenous molecules from skin constituents. METHODS: Raman micro-imaging was applied to monitor the skin penetration of hyaluronic acids (HA) of different molecular weights. The first step, was the spectral characterization of these HA. After, we have determined spectral features of HA by which they can be detected in the skin. In the second part, transverse skin sections were realized and spectral images were recorded. RESULTS: Our results show a difference of skin permeation of the three HA. Indeed, HA with low molecular weight (20-300 kDa) passes through the stratum corneum in contrast of the impermeability of high molecular weight HA (1000-1400 kDa). CONCLUSION: Raman spectroscopy represents an analytical, non-destructive, and dynamic method to evaluate the permeation of actives in the skin layers.

5Profhilo® Structura, Current Status and Future Perspectives: A Practical Review.PubMed

Riccardo Forte, Giovanni Salti, Antonello Tateo
Plast Aesthet Nurs (Phila). 2024;44(3):213-219. doi: 10.1097/PSN.0000000000000571. Epub 2024 Jul 3.
Hyaluronic acid (HA)-based injectables continue to grow in popularity and are used worldwide to improve facial changes associated with aging. Profhilo® Structura (IBSA Farmaceutici Italia, Lodi, Italy) is a novel HA-based product that uses nano hybrid complex of hyaluronic acid (NAHYCO)® technology to create hybrid cooperative complexes consisting of high and low molecular weight HA. Profhilo® Structura's high concentration (45 mg of total HA) and rheological properties (ie, viscosity [resistance to flow] and elasticity [stickiness]) have been specially formulated to restore facial adipose tissue. Because of their early involvement in the facial aging process, the superficial medial and lateral-temporal cheek fat compartments are good candidates for treatment. However, recommendations and guidelines are necessary to ensure that treatment is safe and effective. Three experts were invited to IBSA Farmaceutici Italia Srl to discuss clinical rationale, optimal injection techniques, and clinical outcomes for treating the superficial medial and lateral-temporal cheek fat compartments with Profhilo® Structura. These techniques were developed using patients presenting with either initial hypotrophy of fat compartments within the preauricular area (ie, sinkers) or jowl sagging due to hypotrophy within the preauricular and zygomatic areas (ie, saggers). Targeting these areas using the optimal injection site can maximize product diffusion and minimize the risk for vascular compromise. Targeting these areas also leads to lateral tightening and lipolifting effects due to adipose tissue restoration. The experts agreed that Profhilo® Structura is currently the first and only HA-based injectable treatment that can integrate and restore the adipose tissue in these affected fat compartments.

6Intradermal Injection of Hybrid Complexes of High- and Low-Molecular-Weight Hyaluronan: Where Do We Stand and Where Are We Headed in Regenerative Medicine?PubMed

Dalvi Humzah, Beatriz Molina, Giovanni Salti, et al.
Int J Mol Sci. 2024 Mar 12;25(6):3216. doi: 10.3390/ijms25063216.
Hyaluronic acid (HA) is a remarkably multifaceted biomacromolecule, playing a role in regulating myriad biological processes such as wound healing, tissue regeneration, anti-inflammation, and immunomodulation. Crosslinked high- and low-molecular-weight hyaluronic acid hydrogels achieve higher molar concentrations, display slower degradation, and allow optimal tissue product diffusion, while harnessing the synergistic contribution of different-molecular-weight hyaluronans. A recent innovation in the world of hyaluronic acid synthesis is represented by NAHYCO Hybrid Technology, a thermal process leading to hybrid cooperative hyaluronic acid complexes (HCC). This review summarizes the current literature on the in vitro studies and in vivo applications of HCC, from facial and body rejuvenation to future perspectives in skin wound healing, dermatology, and genitourinary pathologies.

7Intra-articular Hyaluronic Acid Treatments for Knee Osteoarthritis: A Systematic Review of Product Properties.PubMed

Eric Ferkel, Ajay Manjoo, Damion Martins, et al.
Cartilage. 2023 Dec;14(4):424-432. doi: 10.1177/19476035231154530. Epub 2023 Jun 14.
INTRODUCTION: There are many intra-articular hyaluronic acid (IA-HA) products on the market that have known intrinsic differences in molecular size, source, and structure. The current review summarizes existing evidence describing and assessing these differences, while also identifying whether these differences have an impact on clinical outcomes. METHODS: This systematic review summarized all literature that specifically addresses IA-HA product differences. Included studies summarized basic science and mechanism of action comparisons of IA-HA product differences, or systematic reviews that assess differences in clinical outcomes between IA-HA product differences. RESULTS: A total of 20 investigations assessed basic science differences between IA-HA products, while 20 investigations provided assessments of the clinical outcome differences between IA-HA product characteristics. The published basic science literature provided a differentiation between low molecular weight (LMW) and high molecular weight (HMW) HA with regard to changes within the synovial fluid, driven by the interactions that these molecules have with receptors in the joint space. These differences in receptor interaction manifest within clinical outcomes, as meta-analyses comparing pain relief after IA-HA suggest that pain reduction is superior in patients who receive HMW HA as opposed to LMW HA. CONCLUSION: This review highlights differences between IA-HA characteristics, and how important the molecular weight, derivation of the product, and structure are to variances in reported clinical outcomes to treat osteoarthritis (OA) of the knee. HMW IA-HAs have shown greater efficacy compared to the alternative of LMW products, while avian-derived and cross-linked products have potentially demonstrated an increase in inflammatory events over non-avian-derived, non-cross-linked HAs.

8Viscoelastic High-Molecular-Weight Hyaluronic Acid Hydrogels Support Rapid Glioblastoma Cell Invasion with Leader-Follower Dynamics.PubMed

Emily M Carvalho, Erika A Ding, Atul Saha, et al.
Adv Mater. 2024 Dec;36(50):e2404885. doi: 10.1002/adma.202404885. Epub 2024 Nov 7.
Hyaluronic acid (HA), the primary component of brain extracellular matrix, is increasingly used to model neuropathological processes, including glioblastoma (GBM) tumor invasion. While elastic hydrogels based on crosslinked low-molecular-weight (LMW) HA are widely exploited for this purpose and have proven valuable for discovery and screening, brain tissue is both viscoelastic and rich in high-MW (HMW) HA, and it remains unclear how these differences influence invasion. To address this question, hydrogels comprised of either HMW (1.5 MDa) or LMW (60 kDa) HA are introduced, characterized, and applied in GBM invasion studies. Unlike LMW HA hydrogels, HMW HA hydrogels relax stresses quickly, to a similar extent as brain tissue, and to a greater extent than many conventional HA-based scaffolds. GBM cells implanted within HMW HA hydrogels invade much more rapidly than in their LMW HA counterparts and exhibit distinct leader-follower dynamics. Leader cells adopt dendritic morphologies similar to invasive GBM cells observed in vivo. Transcriptomic, pharmacologic, and imaging studies suggest that leader cells exploit hyaluronidase, an enzyme strongly enriched in human GBMs, to prime a path for followers. This study offers new insight into how HA viscoelastic properties drive invasion and argues for the use of highly stress-relaxing materials to model GBM.

935kDa hyaluronan ameliorates ethanol driven loss of anti-microbial defense and intestinal barrier integrity in a TLR4-dependent manner.PubMed

Semanti Ray, Emily Huang, Gail A West, et al.
Matrix Biol. 2023 Jan;115:71-80. doi: 10.1016/j.matbio.2022.11.008. Epub 2022 Nov 26.
Acute and chronic alcohol exposure compromise intestinal epithelial integrity, due to reduced expression of anti-microbial peptides (AMP) and loss of tight junction integrity. Ameliorating gut damage is beneficial in preventing associated distant organ pathologies. Orally administered purified hyaluronan (HA) polymers with an average size of 35 kDa have multiple protective effects in the gut and are well-tolerated in humans. Therefore, we tested the hypothesis that HA35 ameliorates ethanol-induced gut damage. Specifically, mechanisms that restore epithelial barrier integrity and normalize expression of the Reg3 class of C-type lectin AMPs (i.e. Reg3β and Reg3γ) were investigated. Chronic ethanol feeding to mice reduced expression of C-type lectin AMPs in the proximal small intestine (jejunum), reduced expression of tight junction proteins and increased bacterial translocation to the mesenteric lymph node. Oral consumption of HA35 during the last 6 days of ethanol exposure ameliorated the effects of chronic ethanol. Similarly, in vitro challenge of isolated intestinal organoids from murine jejunum with ethanol reduced the expression of C-type lectin AMPs and impaired barrier integrity; these ethanol-induced responses were prevented by pre-treatment with HA35. Importantly, HA receptor null jejunum-derived organoids demonstrated that the HA receptor Tlr4, but not Cd44 nor Tlr2, was required for the protective effect of HA35. Consistent with the data from organoids, HA35 did not protect Tlr4-deficient mice from chronic ethanol-induced intestinal injury. Together, these data suggest therapeutic administration of HA35 is beneficial in restoring gut epithelial integrity and defense during the early stages of ethanol-driven intestinal damage.

10Layilin is critical for mediating hyaluronan 35kDa-induced intestinal epithelial tight junction protein ZO-1 in vitro and in vivo.PubMed

Yeojung Kim, Gail A West, Greeshma Ray, et al.
Matrix Biol. 2018 Mar;66:93-109. doi: 10.1016/j.matbio.2017.09.003. Epub 2017 Oct 1.
Tight junction proteins are critical in maintaining homeostatic intestinal permeability. Multiple intestinal inflammatory diseases are correlated with reduced expression of tight junction proteins. We have recently reported that oral treatment of mice with Hyaluronan 35kDa (HA35) increases colonic expression of tight junction protein zonula occludens-1 (ZO-1). Here, we investigate whether HA35 treatment enhances ZO-1 expression by direct interaction with intestinal epithelium in vitro and have identified the HA receptor responsible for HA35-mediated ZO-1 induction in colonic epithelium in vitro and in vivo. Our results reveal that HA35 treatment increases ZO-1 expression in mouse intestinal epithelial organoids, while large HA 2000kDa is not internalized into the cells. Our immunofluorescence data indicate that layilin, but neither toll-like receptor-4 (TLR-4) nor CD44, mediate the HA35-induced ZO-1 expression in colonic epithelium in vitro and in vivo. Additionally, using layilin null mice we have determined that layilin mediates HA35 induction of ZO-1 in healthy mice and during dextran sulfate sodium (DSS)-induced colitis. Furthermore, we find that while ZO-1 expression levels are reduced, layilin expression levels are equivalent in inflammatory bowel disease (IBD) patients and non-IBD controls. Together, our data suggest that layilin is an important HA receptor, that mediates the effect of oral HA35 treatment on intestinal epithelium. HA35 holds promise as a simple dietary supplement to strengthen gut barrier defense.

11Hyaluronan 35kDa treatment protects mice from Citrobacter rodentium infection and induces epithelial tight junction protein ZO-1 in vivo.PubMed

Yeojung Kim, Sean P Kessler, Dana R Obery, et al.
Matrix Biol. 2017 Oct;62:28-39. doi: 10.1016/j.matbio.2016.11.001. Epub 2016 Nov 11.
Maintaining a healthy intestinal barrier, the primary physical barrier between intestinal microbiota and the underlying lamina propria, is critical for optimal health. Epithelial integrity is essential for the prevention of the entrance of luminal contents, such as bacteria and their products, through the large intestinal barrier. In this study, we investigated the protective functions of biosynthetic, specific sized, hyaluronan around 35kDa (HA35) on intestinal epithelium in healthy mice, as well as mice infected Citrobacter rodentium, an established model that mimics infection with a serious human pathogen, enteropathogenic E. coli (EPEC). Our results reveal that treatment with HA35 protects mice from Citrobacter infection and enhances the epithelial barrier function. In particular, we have found that HA35 induces the expression of tight junction protein zonula occludens (ZO)-1 in both healthy and Citrobacter infected mice, as demonstrated by immunoflurorescence and Western blot analyses. Furthermore, we determined that HA35 treatment enhances ZO-1 expression and reduces intestinal permeability at the early stages of dextran sulfate sodium (DSS)-induced colitis in mice. Together, our data demonstrate that the expression and functionality of tight junctions, are increased by HA35 treatment, suggesting a novel mechanism for the protection from Citrobacter infection.

12Multifunctional Role of 35 Kilodalton Hyaluronan in Promoting Defense of the Intestinal Epithelium.PubMed

Sean P Kessler, Dana R Obery, Kourtney P Nickerson, et al.
J Histochem Cytochem. 2018 Apr;66(4):273-287. doi: 10.1369/0022155417746775. Epub 2018 Jan 1.
Intestinal epithelium plays a critical role in host defense against orally acquired pathogens. Dysregulation of this protective barrier is a primary driver of inflammatory bowel diseases (Crohn's and ulcerative colitis) and also infant gastrointestinal infections. Previously, our lab reported that hyaluronan (HA) isolated from human milk induces the expression of the antimicrobial peptide β-defensin in vivo and protects against Salmonella Typhimurium infection of epithelial cells in vitro. In addition, we demonstrated that commercially available 35 kDa size HA induces the expression of β-defensin, upregulates the expression of tight junction protein zonula occludens-1 (ZO-1), and attenuates murine Citrobacter rodentium infection in vivo. In this current study, we report that HA35 remains largely intact and biologically active during transit through the digestive tract where it directly induces β-defensin expression upon epithelial cell contact. We also demonstrate HA35 abrogation of murine Salmonella Typhimurium infection as well as downregulation of leaky tight junction protein claudin-2 expression. Taken together, we propose a dual role for HA in host innate immune defense at the epithelial cell surface, acting to induce antimicrobial peptide production and also block pathogen-induced leaky gut. HA35 is therefore a promising therapeutic in the defense against bacterially induced colitis in compromised adults and vulnerable newborns.

13Low molecular weight 35 kDa hyaluronan fragment HA35 in the treatment of bone metastasis pain: A case report.PubMed

Zongchun Zhang, Xiaoxiao Jia, Dylan Treger, et al.
Medicine (Baltimore). 2024 Aug 2;103(31):e39145. doi: 10.1097/MD.0000000000039145.
RATIONALE: Late-stage cancer patients often experience severe pain due to bone metastasis, caused by structural damage and cancer-induced inflammation. Hyaluronan, known to alleviate pain by blocking the TRVP1 calcium channel, faces limitations due to its high molecular weight. However, 35 kDa low molecular weight hyaluronan fragment (HA35) have shown promise in relieving various pains, including cancer-related pain. Nonetheless, evidence regarding their efficacy in bone metastasis pain remains scarce. PATIENTS CONCERNS: A 52-year-old female with a rectal malignant tumor and multiple secondary tumors in the sacrum and lungs, accompanied by bone metastasis pain. Despite undergoing radiotherapy, her pain relief was unsatisfactory. Before treatment with HA35, her numerical rating scale score was 10, severely affecting her sleep, appetite, and daily activities. DIAGNOSES: The patient was diagnosed with rectal malignant tumor with multiple metastases, presenting symptoms such as sacral metastasis pain, anal pain, lower limb pain, and anterior abdominal pain. Sacral metastasis pain and lower limb pain indicated a clear diagnosis of bone metastasis pain. INTERVENTIONS: Treatment involved subcutaneous injection into the deep fat tissue layer of the abdomen. A subcutaneous injection of 100 mg/5 mL of HA35 was administered once into the deep fat tissue of the abdomen, with subsequent injections repeated every 3 days. OUTCOMES: Following 1 injection, the patient's pain score decreased to 6 points within 20 minutes, providing 40% pain relief. After 40 minutes, the score further dropped to 4 points, with 60% pain relief. After 50 injections, pain was consistently controlled at around 3 points. LESSONS SUBSECTIONS: Subcutaneous injection of HA35 into the abdominal fat tissue effectively alleviates pain in cancer and bone metastasis patients resistant to conventional treatments. Additionally, it helps alleviate anxiety and fatigue, and improves diet and sleep, thereby offering crucial palliative care for advanced cancer patients.

14Network-Based Bioinformatics Highlights Broad Importance of Human Milk Hyaluronan.PubMed

Kathryn Y Burge, Hua Zhong, Adam P Wilson, et al.
Int J Mol Sci. 2024 Nov 26;25(23):12679. doi: 10.3390/ijms252312679.
Human milk (HM) is rich in bioactive factors promoting postnatal small intestinal development and maturation of the microbiome. HM is also protective against necrotizing enterocolitis (NEC), a devastating inflammatory condition predominantly affecting preterm infants. The HM glycosaminoglycan, hyaluronan (HA), is present at high levels in colostrum and early milk. Our group has demonstrated that HA with a molecular weight of 35 kDa (HA35) promotes maturation of the murine neonatal intestine and protects against two distinct models of NEC. However, the molecular mechanisms underpinning HA35-induced changes in the developing ileum are unclear. CD-1 mouse pups were treated with HA35 or vehicle control daily, from P7 to P14, and we used network and functional analyses of bulk RNA-seq ileal transcriptomes to further characterize molecular mechanisms through which HA35 likely influences intestinal maturation. HA35-treated pups separated well by principal component analysis, and cell deconvolution revealed increases in stromal, Paneth, and mature enterocyte and progenitor cells in HA35-treated pups. Gene set enrichment and pathway analyses demonstrated upregulation in key processes related to antioxidant and growth pathways, such as nuclear factor erythroid 2-related factor-mediated oxidative stress response, hypoxia inducible factor-1 alpha, mechanistic target of rapamycin, and downregulation of apoptotic signaling. Collectively, pro-growth and differentiation signals induced by HA35 may present novel mechanisms by which this HM bioactive factor may protect against NEC.

15Hyaluronic Acid 35 kDa Protects against a Hyperosmotic, Formula Feeding Model of Necrotizing Enterocolitis.PubMed

Kathryn Burge, Jeffrey Eckert, Adam Wilson, et al.
Nutrients. 2022 Apr 24;14(9):1779. doi: 10.3390/nu14091779.
Necrotizing enterocolitis (NEC), an inflammatory disease of the intestine, is a common gastrointestinal emergency among preterm infants. Intestinal barrier dysfunction, hyperactivation of the premature immune system, and dysbiosis are thought to play major roles in the disease. Human milk (HM) is protective, but the mechanisms underpinning formula feeding as a risk factor in the development of NEC are incompletely understood. Hyaluronic acid 35 kDa (HA35), a bioactive glycosaminoglycan of HM, accelerates intestinal development in murine pups during homeostasis. In addition, HA35 prevents inflammation-induced tissue damage in pups subjected to murine NEC, incorporating Paneth cell dysfunction and dysbiosis. We hypothesized HA35 treatment would reduce histological injury and mortality in a secondary mouse model of NEC incorporating formula feeding. NEC-like injury was induced in 14-day mice by dithizone-induced disruption of Paneth cells and oral gavage of rodent milk substitute. Mortality and histological injury, serum and tissue cytokine levels, stool bacterial sequencing, and bulk RNA-Seq comparisons were analyzed. HA35 significantly reduced the severity of illness in this model, with a trend toward reduced mortality, while RNA-Seq analysis demonstrated HA35 upregulated genes associated with goblet cell function and innate immunity. Activation of these critical protective and reparative mechanisms of the small intestine likely play a role in the reduced pathology and enhanced survival trends of HA-treated pups subjected to intestinal inflammation in this secondary model of NEC, providing potentially interesting translational targets for the human preterm disease.

16Hyperglycemic environments directly compromise intestinal epithelial barrier function in an organoid model and hyaluronan (∼35 kDa) protects via a layilin dependent mechanism.PubMed

Samreen Jatana, Amina Abbadi, Gail A West, et al.
Matrix Biol. 2024 Nov;133:116-133. doi: 10.1016/j.matbio.2024.08.007. Epub 2024 Aug 24.
BACKGROUND: Metabolic syndrome and diabetes in obese individuals are strong risk factors for development of inflammatory bowel disease (IBD) and colorectal cancer. The pathogenic mechanisms of low-grade metabolic inflammation, including chronic hyperglycemic stress, in disrupting gut homeostasis are poorly understood. In this study, we sought to understand the impact of a hyperglycemic environment on intestinal barrier integrity and the protective effects of small molecular weight (35 kDa) hyaluronan on epithelial barrier function. METHODS: Intestinal organoids derived from mouse colon were grown in normal glucose media (5 mM) or high glucose media (25 mM) to study the impact of hyperglycemic stress on the intestinal barrier. Additionally, organoids were pretreated with 35 kDa hyaluronan (HA35) to investigate the effect of hyaluronan on epithelial barrier under high glucose stress. Immunoblotting as well as confocal imaging was used to understand changes in barrier proteins, quantitative as well as spatial distribution, respectively. Alterations in barrier function were measured using trans-epithelial electrical resistance and fluorescein isothiocyanate flux assays. Untargeted proteomics analysis was performed to elucidate mechanisms by which HA35 exerts a protective effect on the barrier. Intestinal organoids derived from receptor knockout mice specific to various HA receptors were utilized to understand the role of HA receptors in barrier protection under high glucose conditions. RESULTS: We found that high glucose stress decreased the protein expression as well as spatial distribution of two key barrier proteins, zona occludens-1 (ZO-1) and occludin. HA35 prevented the degradation or loss of ZO-1 and maintained the spatial distribution of both ZO-1 and occludin under hyperglycemic stress. Functionally, we also observed a protective effect of HA35 on the epithelial barrier under high glucose conditions. We found that HA receptor, layilin, was involved in preventing barrier protein loss (ZO-1) as well as maintaining spatial distribution of ZO-1 and occludin. Additionally, proteomics analysis showed that cell death and survival was the primary pathway upregulated in organoids treated with HA35 under high glucose stress. We found that XIAP associated factor 1 (Xaf1) was modulated by HA35 thereby regulating apoptotic cell death in the intestinal organoid system. Finally, we observed that spatial organization of both focal adhesion kinase (FAK) as well as F-actin was mediated by HA35 via layilin. CONCLUSION: Our results highlight the impact of hyperglycemic stress on the intestinal barrier function. This is of clinical relevance, as impaired barrier function has been observed in individuals with metabolic syndrome. Additionally, we demonstrate barrier protective effects of HA35 through its receptor layilin and modulation of cellular apoptosis under high glucose stress.

17Safety of Hyaluronan 35 in Healthy Human Subjects: A Pilot Study.PubMed

Annette Bellar, Sean P Kessler, Dana R Obery, et al.
Nutrients. 2019 May 22;11(5):1135. doi: 10.3390/nu11051135.
. Hyaluronan (HA) is a naturally occurring glycosaminoglycan polymer produced in all vertebrates, and usually present at the high molecular weight (>10 Da). Low molecular weight HA has signaling properties, and fragments ~35 kDa size (HA35) have biological activity in eliciting epithelial β-defensins and tight junction proteins, notably ZO1, important components of innate host defense arsenal of the gut barrier in preclinical models. Safety, tolerability, impact on metabolism, gut permeability, and microbiome composition in healthy human subjects were all evaluated prospectively. . Pharmaceutical grade HA35 (140 mg in water once daily for seven days), was administered orally to 20 healthy subjects (30.7 ± 5.6 years). Demographical, clinical, biochemical laboratory tests, metabolic function and stool microbiome composition were measured on Day 0, 8 and 28. . HA35 was tolerated well in all subjects with no serious adverse events in any subjects. No statistical differences in any of the measurements were seen among the study group over the course of the trial. In aggregate there were no changes in demographical, clinical, biochemical laboratory tests, and metabolic function or microbiome composition during the 28-day study. . Oral HA35 administration (140 mg/day) is a safe treatment in healthy individuals and does not affect metabolic, inflammatory or microbiome parameters.

18Hyaluronic acid 35 normalizes TLR4 signaling in Kupffer cells from ethanol-fed rats via regulation of microRNA291b and its target Tollip.PubMed

Paramananda Saikia, Sanjoy Roychowdhury, Damien Bellos, et al.
Sci Rep. 2017 Nov 15;7(1):15671. doi: 10.1038/s41598-017-15760-4.
TLR4 signaling in hepatic macrophages is increased after chronic ethanol feeding. Treatment of hepatic macrophages after chronic ethanol feeding with small-specific sized hyaluronic acid 35 (HA35) normalizes TLR4 signaling; however, the mechanisms for HA35 action are not completely understood. Here we used Next Generation Sequencing of microRNAs to identify negative regulators of TLR4 signaling reciprocally modulated by ethanol and HA35 in hepatic macrophages. Eleven microRNAs were up-regulated by ethanol; only 4 microRNAs, including miR291b, were decreased by HA35. Bioinformatics analysis identified Tollip, a negative regulator of TLR4, as a target of miR291b. Tollip expression was decreased in hepatic macrophages from ethanol-fed rats, but treatment with HA35 or transfection with a miR291b hairpin inhibitor restored Tollip expression and normalized TLR4-stimulated TNFα expression. In peripheral blood monocytes isolated from patients with alcoholic hepatitis, expression of TNFα mRNA was robustly increased in response to challenge with lipopolysaccharide. Importantly, pre-treatment with HA35 reduced TNFα expression by more than 50%. Taken together, we have identified miR291b as a critical miRNA up-regulated by ethanol. Normalization of the miR291b → Tollip pathway by HA35 ameliorated ethanol-induced sensitization of TLR4 signaling in macrophages/monocytes, suggesting that HA35 may be a novel therapeutic agent in the treatment of ALD.

19Effect of Hyaluronic Acid 35 kDa on an In Vitro Model of Preterm Small Intestinal Injury and Healing using Enteroid-derived Monolayers.PubMed

Adam Wilson, Kathryn Burge, Jeffrey Eckert, et al.
J Vis Exp. 2022 Jul 28(185). doi: 10.3791/63758.
In vitro scratch wound assays are commonly used to investigate the mechanisms and characteristics of epithelial healing in a variety of tissue types. Here, we describe a protocol to generate a two-dimensional (2D) monolayer from three-dimensional (3D) non-human primate enteroids derived from intestinal crypts of the terminal ileum. These enteroid-derived monolayers were then utilized in an in vitro scratch wound assay to test the ability of hyaluronan 35 kDa (HA35), a human milk HA mimic, to promote cell migration and proliferation along the epithelial wound edge. After the monolayers were grown to confluency, they were manually scratched and treated with HA35 (50 µg/mL, 100 µg/mL, 200 µg/mL) or control (PBS). Cell migration and proliferation into the gap were imaged using a transmitted-light microscope equipped for live-cell imaging. Wound closure was quantified as percent wound healing using the Wound Healing Size Plugin in ImageJ. The scratch area and rate of cell migration and the percentage of wound closure were measured over 24 h. HA35 in vitro accelerates wound healing in small intestinal enteroid monolayers, likely through a combination of cell proliferation at the wound edge and migration to the wound area. These methods can potentially be used as a model to explore intestinal regeneration in the preterm human small intestine.

20Specifically Sized Hyaluronan (35 kDa) Prevents Ethanol-Induced Disruption of Epithelial Tight Junctions Through a layilin-Dependent Mechanism in Caco-2 Cells.PubMed

Damien A Bellos, Dhara Sharma, Megan R McMullen, et al.
Alcohol Clin Exp Res. 2019 Sep;43(9):1848-1858. doi: 10.1111/acer.14140. Epub 2019 Jul 16.
BACKGROUND: Specific-sized species of the carbohydrate hyaluronan elicit a variety of cellular responses mediating tissue integrity and repair, as well as regulating inflammatory responses. Orally provided hyaluronan with an average molecular weight of 35 kDa (HA35) protects mice from short-term ethanol (EtOH)-induced liver injury. This protection was associated with maintenance of the colocalization of zonula occludens-1 (ZO-1) and occludin at tight junctions in the proximal colon. However, it is not known whether HA35 also protects other regions of the intestine or whether protection is due to a direct and/or indirect interaction of HA35 with the intestinal epithelium. METHODS: Female C57BL/6J mice were fed an EtOH containing diet or pair-fed control diet (4 days) and treated with or without HA35 via daily gavage during the last 3 days of EtOH feeding. Intestinal morphology and tight junction integrity were assessed. Differentiated Caco-2 cells were transfected or not with scrambled siRNA or siRNA targeting layilin, a hyaluronan receptor. Caco-2 cells were treated with or without HA35 prior to challenge with EtOH. Localization of tight junction proteins, fluorescein isothiocyanate (FITC)-dextran permeability, and transepithelial electrical resistance (TEER) were evaluated. RESULTS: While short-term EtOH did not result in any apparent changes in the gross morphology of the intestine, colocalization of ZO-1 and occludin at tight junctions was decreased in the proximal and distal colon. HA35 prevented these effects of EtOH. In differentiated Caco-2 cells, EtOH decreased the localization of ZO-1 and occludin at tight junctions and increased permeability of FITC-dextran. At higher concentrations, EtOH also decreased TEER. Pretreatment with HA35 prevented these changes. When the hyaluronan receptor layilin was knocked down in Caco-2 cells, HA35 no longer protected cells from EtOH-induced loss of tight junctions. CONCLUSIONS: Taken together, these data indicate that HA35 interacts with layilin on intestinal epithelial cells and maintains intestinal tight junction integrity during short-term EtOH exposure.
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