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Savarino V, Visaggi P, Marabotto E, Bertin L, Pasta A, Calabrese F, Zentilin P, Ghisa M, Ribolsi M, Mari A, Tolone S, de Bortoli N, Savarino EV. Topical Protection of Esophageal Mucosa as a New Treatment of GERD. J Clin Gastroenterol 2025; 59:197-205. [PMID: 39777899 DOI: 10.1097/mcg.0000000000002128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 12/08/2024] [Indexed: 01/11/2025]
Abstract
Among the various factors implicated in the pathogenesis of gastroesophageal reflux disease (GERD), visceral hypersensitivity and mucosal resistance have been recently re-evaluated in relation to the increasing phenomenon of proton pump inhibitor failure, particularly in patients with nonerosive reflux disease (NERD). Intensive research has allowed us to understand that noxious substances contained in the refluxate are able to interact with esophageal epithelium and to induce the elicitation of symptoms. The frequent evidence of microscopic esophagitis able to increase the permeability of the mucosa, the proximity of sensory afferent nerve fibers to the esophageal lumen favoring the higher sensitivity to noxious substances and the possible activation of inflammatory pathways interacting with sensory nerve endings are pathophysiological alterations confirming that mucosal resistance is impaired in GERD patients. Accordingly, the reinforcement of protective mechanisms of esophageal mucosa by topical therapies has become a novel treatment target. Alginate, the combination of hyaluronic acid+chondroitin sulphate and Poliprotect have been shown to adhere to esophageal mucosa and to have good protective properties. Several placebo-controlled clinical trials have shown that these compounds, given alone or as add-on therapy for short periods, enable to relieve symptoms and to improve the quality of life in NERD patients. Further studies are needed to confirm the above results and to find new mucosal protectants in order to improve the management of NERD patients.
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Affiliation(s)
- Vincenzo Savarino
- Department of Internal Medicine, Gastroenterology Unit, University of Genoa, Genoa
| | - Pierfrancesco Visaggi
- Department of Translational Research and New Technologies in Medicine and Surgery, Gastroenterology Unit, University of Pisa, Pisa
| | - Elisa Marabotto
- Department of Internal Medicine, Gastroenterology Unit, University of Genoa, Genoa
| | - Luisa Bertin
- Department of Surgery, Oncology and Gastroenterology, University of Padua
- Gastroenterology Unit, Azienda Ospedale Università di Padova, Padua
| | - Andrea Pasta
- Department of Internal Medicine, Gastroenterology Unit, University of Genoa, Genoa
| | - Francesco Calabrese
- Department of Internal Medicine, Gastroenterology Unit, University of Genoa, Genoa
| | - Patrizia Zentilin
- Department of Internal Medicine, Gastroenterology Unit, University of Genoa, Genoa
| | - Matteo Ghisa
- Department of Surgery, Oncology and Gastroenterology, University of Padua
- Gastroenterology Unit, Azienda Ospedale Università di Padova, Padua
| | - Mentore Ribolsi
- Department of Digestive Diseases, Campus Bio Medico University of Rome, Roma
| | - Amir Mari
- Department of Gastroenterology, Azrieli Faculty of Medicine, Nazareth EMMS Hospital, Bar Ilan University, Safed, Israel
| | - Salvatore Tolone
- School of Medicine Naples, Università degli Studi della Campania, Naples, Italy
| | - Nicola de Bortoli
- Department of Translational Research and New Technologies in Medicine and Surgery, Gastroenterology Unit, University of Pisa, Pisa
| | - Edoardo V Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padua
- Gastroenterology Unit, Azienda Ospedale Università di Padova, Padua
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Hong GW, Wan J, Park Y, Yoo J, Cartier H, Garson S, Haykal D, Yi KH. Manufacturing Process of Hyaluronic Acid Dermal Fillers. Polymers (Basel) 2024; 16:2739. [PMID: 39408450 PMCID: PMC11479139 DOI: 10.3390/polym16192739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/16/2024] [Accepted: 09/23/2024] [Indexed: 10/20/2024] Open
Abstract
Hyaluronic acid (HA) fillers are extensively utilized in aesthetic medicine due to their biocompatibility, reversibility, and effectiveness in enhancing skin hydration, volume, and overall appearance. These fillers are predominantly produced through microbial fermentation, followed by a critical cross-linking process that enhances their longevity by resisting enzymatic degradation. This review provides a thorough examination of the manufacturing processes that differentiate HA fillers, with particular attention to the distinctions between biphasic and monophasic variants. Unlike previous studies, this review emphasizes the specific cross-linking techniques and their substantial impact on the fillers' rheological properties, such as elasticity and cohesiveness, which are crucial to their clinical performance and patient outcomes. Additionally, the review offers a comprehensive comparison of HA fillers with non-HA alternatives, including calcium hydroxylapatite, poly-l-lactic acid, and polymethyl methacrylate, highlighting the unique advantages and potential complications associated with each type. By presenting novel insights into the latest advancements and challenges in filler technology, this review aims to provide clinicians with a deeper understanding of filler properties, thereby guiding them in making informed decisions to optimize patient safety and aesthetic results.
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Affiliation(s)
- Gi-Woong Hong
- Samskin Plastic Surgery Clinic, Seoul 06577, Republic of Korea;
| | - Jovian Wan
- Asia Pacific Aesthetic Academy, Hong Kong;
| | | | - Jane Yoo
- Department of Dermatology, Mount Sinai School of Medicine, New York, NY 10029, USA;
| | | | | | - Diala Haykal
- Centre Laser Palaiseau, 91120 Palaiseau, France;
| | - Kyu-Ho Yi
- BK21 FOUR Project, Division in Anatomy and Developmental Biology, Department of Oral Biology, Human Identification Research Institute, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
- Maylin Clinic (Apgujeong), Seoul 06005, Republic of Korea
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Huang T, Zeng Y, Li C, Zhou Z, Xu J, Wang L, Yu DG, Wang K. Application and Development of Electrospun Nanofiber Scaffolds for Bone Tissue Engineering. ACS Biomater Sci Eng 2024; 10:4114-4144. [PMID: 38830819 DOI: 10.1021/acsbiomaterials.4c00028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2024]
Abstract
Nanofiber scaffolds have gained significant attention in the field of bone tissue engineering. Electrospinning, a straightforward and efficient technique for producing nanofibers, has been extensively researched. When used in bone tissue engineering scaffolds, electrospun nanofibers with suitable surface properties promote new bone tissue growth and enhance cell adhesion. Recent advancements in electrospinning technology have provided innovative approaches for scaffold fabrication in bone tissue engineering. This review comprehensively examines the utilization of electrospun nanofibers in bone tissue engineering scaffolds and evaluates the relevant literature. The review begins by presenting the fundamental principles and methodologies of electrospinning. It then discusses various materials used in the production of electrospun nanofiber scaffolds for bone tissue engineering, including natural and synthetic polymers, as well as certain inorganic materials. The challenges associated with these materials are also described. The review focuses on novel electrospinning techniques for scaffold construction in bone tissue engineering, such as multilayer nanofibers, multifluid electrospinning, and the integration of electrospinning with other methods. Recent advancements in electrospinning technology have enabled the fabrication of precisely aligned nanofiber scaffolds with nanoscale architectures. These innovative methods also facilitate the fabrication of biomimetic structures, wherein bioactive substances can be incorporated and released in a controlled manner for drug delivery purposes. Moreover, they address issues encountered with traditional electrospun nanofibers, such as mechanical characteristics and biocompatibility. Consequently, the development and implementation of novel electrospinning technologies have revolutionized scaffold fabrication for bone tissue engineering.
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Affiliation(s)
- Tianyue Huang
- School of Materials and Chemistry, University of Shanghai for Science and Technology 516 Jungong Road, Shanghai 200093, China
| | - YuE Zeng
- Department of Neurology, RuiJin Hospital Lu Wan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Chaofei Li
- Department of General Surgery, RuiJin Hospital Lu Wan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhengqing Zhou
- School of Materials and Chemistry, University of Shanghai for Science and Technology 516 Jungong Road, Shanghai 200093, China
| | - Jie Xu
- School of Materials and Chemistry, University of Shanghai for Science and Technology 516 Jungong Road, Shanghai 200093, China
| | - Lean Wang
- School of Materials and Chemistry, University of Shanghai for Science and Technology 516 Jungong Road, Shanghai 200093, China
| | - Deng-Guang Yu
- School of Materials and Chemistry, University of Shanghai for Science and Technology 516 Jungong Road, Shanghai 200093, China
| | - Ke Wang
- School of Materials and Chemistry, University of Shanghai for Science and Technology 516 Jungong Road, Shanghai 200093, China
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Gehrke NR, Feng D, Ayub Ali M, Maalouf MA, Holstein SA, Wiemer DF. α-Amino bisphosphonate triazoles serve as GGDPS inhibitors. Bioorg Med Chem Lett 2024; 102:129659. [PMID: 38373465 PMCID: PMC10981527 DOI: 10.1016/j.bmcl.2024.129659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/31/2024] [Accepted: 02/14/2024] [Indexed: 02/21/2024]
Abstract
Depletion of cellular levels of geranylgeranyl diphosphate by inhibition of the enzyme geranylgeranyl diphosphate synthase (GGDPS) is a potential strategy for disruption of protein transport by limiting the geranylgeranylation of the Rab proteins that regulate intracellular trafficking. As such, there is interest in the development of GGDPS inhibitors for the treatment of malignancies characterized by abnormal protein production, including multiple myeloma. Our previous work has explored the structure-function relationship of a series of isoprenoid triazole bisphosphonate-based GGDPS inhibitors, with modifications having impact on enzymatic, cellular and in vivo activities. We have synthesized a new series of α-amino bisphosphonates to understand the impact of modifying the alpha position with a moiety that is potentially linkable to other agents. Bioassays evaluating the enzymatic and cellular activities of these compounds demonstrate that incorporation of the α-amino group affords compounds with GGDPS inhibitory activity which is modulated by isoprenoid tail chain length and olefin stereochemistry. These studies provide further insight into the complexity of the structure-function relationship and will enable future efforts focused on tumor-specific drug delivery.
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Affiliation(s)
- Nathaniel R Gehrke
- Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, US
| | - Dan Feng
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, US
| | - Md Ayub Ali
- Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, US; Department of Chemistry, Bangladesh University of Engineering and Technology (BUET), Dhaka-1000, Bangladesh
| | - Mona A Maalouf
- Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, US
| | - Sarah A Holstein
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, US; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, US
| | - David F Wiemer
- Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, US; Department of Pharmacology, University of Iowa, Iowa City, IA 52242-1109, US.
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McCracken JM, Calderon GA, Kumar LA, Balaji S, Rivas F, Erxleben D, Hall A, Hakim JC. Unveiling Vaginal Fibrosis: A Novel Murine Model Using Bleomycin and Epithelial Disruption. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.18.572175. [PMID: 38187720 PMCID: PMC10769241 DOI: 10.1101/2023.12.18.572175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Objective Develop, validate, and characterize a fibrotic murine vaginal wound healing model using bleomycin instillations and epithelial disruption. Approach We tested the effect of repeated bleomycin instillations with mucosal layer disruption on induction of vaginal fibrosis. Tissue samples collected at various time points were analyzed for fibrosis-related gene expression changes and collagen content. Results Low (1.5U/kg) and high-dose (2.5U/kg) bleomycin instillations alone did not induce fibrosis, but when high-dose bleomycin was combined with epithelial disruption, increased pro-fibrotic gene expression and trichrome staining were observed. To evaluate spatial and temporal changes in the ECM structure and gene expression, tissue samples were collected at 1 day, 3 weeks, and 6 weeks after bleomycin and epithelial disruption. Data analyses revealed a significant decrease in matrix metabolizing genes and an increase in pro-fibrotic genes and inhibitors of matrix metabolizing genes in the bleomycin plus epithelial disruption group at 3 weeks. Elevated levels of the profibrotic genes Acta2 , Col1a1 , and Col3a were exclusively detected in this group at 3 weeks, and trichrome staining confirmed increased collagen content after 3 weeks. Hydroxyproline levels showed a tendency towards elevation at 3 weeks (p=0.12) and 6 weeks (p=0.14), indicating fibrosis manifestation at 3 weeks and resolution by 6 weeks post-instillation and epithelial disruption. Innovation We combined bleomycin instillations with epithelial disruption to induce fibrosis and understand the mechanisms of the vaginal repair process. Conclusions Epithelial disruption combined with bleomycin induces murine vaginal fibrosis within three weeks, characterized by increased collagen synthesis. Remarkably, the vaginal tissue fully recovers within six weeks, elucidating the regenerative capacity of the vagina.
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Margara A, Haykal D, Musella D, Bellia G, Boriani F. Hyaluronan Hybrid Cooperative Complexes Injection as a Biostimulation for Postobese Skin Laxity in the Arm: A Histopathologic Study. Aesthet Surg J Open Forum 2023; 6:ojad110. [PMID: 38887212 PMCID: PMC11181863 DOI: 10.1093/asjof/ojad110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/20/2024] Open
Abstract
Background The Hybrid Cooperative Complexes of high and low molecular weight hyaluronic acids (HHCC) improve skin structure and bioactivity. Massive weight loss damages cellular composition and morphological structure of skin. An injective treatment of postobese skin consisting of HHCC may have a role in counteracting these histopathological alterations. Objectives To analyze the histological effects of HHCC injection in the cutaneous tissues of massive weight loss patients suffering from arm laxity. Methods Nine ex-obese patients with postweight-loss-related arm laxity and ptosis requiring brachioplasty were prospectively recruited at the first author's department. HHCC injection was performed on only 1 arm, which included 2 injective sessions separated by 30 days. One month posttreatment, patients underwent a bilateral brachioplasty, and the surgical specimens were histologically examined, searching for any variation in the cutaneous connective tissue following injections. Histology on treated specimens showed a statistically significant increased density of elastic fibers along with a lower fragmentation of the same fibers compared to the untreated tissue. Fibroblasts demonstrated a swollen appearance as if involved in a bioactivation process. Results Treatment with HHCC increases the number of elastin fibers and determines a more regular elastin deposition and architecture, as well as the bioactivation of fibroblasts. The contralateral untreated area showed an irregular structure with elastosis and elastolysis. Conclusions More studies are necessary, but histologically proven benefits are demonstrated in the HHCC-treated skins when compared with basal controlateral skin. These data support the use of HHCC formulations for the treatment of postobese skin laxity. Level of Evidence 5
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Affiliation(s)
| | - Diala Haykal
- Corresponding Author: Dr Diala Haykal, 49 Ter Rue de Paris, 91120 Palaiseau, France. E-mail: ; Instagram: @centre_laser_palaiseau; Twitter: @drdialahaykal
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Sintusek P, Mutalib M, Thapar N. Gastroesophageal reflux disease in children: What's new right now? World J Gastrointest Endosc 2023; 15:84-102. [PMID: 37034973 PMCID: PMC10080553 DOI: 10.4253/wjge.v15.i3.84] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/15/2023] [Accepted: 02/08/2023] [Indexed: 03/16/2023] Open
Abstract
Gastroesophageal reflux (GER) in children is very common and refers to the involuntary passage of gastric contents into the esophagus. This is often physiological and managed conservatively. In contrast, GER disease (GERD) is a less common pathologic process causing troublesome symptoms, which may need medical management. Apart from abnormal transient relaxations of the lower esophageal sphincter, other factors that play a role in the pathogenesis of GERD include defects in esophageal mucosal defense, impaired esophageal and gastric motility and clearance, as well as anatomical defects of the lower esophageal reflux barrier such as hiatal hernia. The clinical manifestations of GERD in young children are varied and nonspecific prompting the necessity for careful diagnostic evaluation. Management should be targeted to the underlying aetiopathogenesis and to limit complications of GERD. The following review focuses on up-to-date information regarding of the pathogenesis, diagnostic evaluation and management of GERD in children.
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Affiliation(s)
- Palittiya Sintusek
- Thai Pediatric Gastroenterology, Hepatology and Immunology Research Unit (TPGHAI), Division of Gastroenterology, Department of Pediatrics, King Chulalongkorn Memorial Hospital and Thai Red Cross, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Bangkok, Thailand
| | - Mohamed Mutalib
- Department of Paediatric Gastroenterology, Pediatric and Gastroenterology Services, Evelina London Children’s Hospital, London SE1 7EH, United Kingdom
| | - Nikhil Thapar
- Department of Gastroenterology, Hepatology and Liver Transplant, Queensland Children’s Hospital, Brisbane, Queensland 4101, Australia
- School of Medicine, University of Queensland, Brisbane, Queensland 4006, Australia
- Woolworths Centre for Child Nutrition Research, Queensland University of Technology, Brisbane, Queensland 4101, Australia
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SPARAVIGNA A, MUSELLA D, CICERONE M, GIORI AM, BELLIA G. Hybrid cooperative complexes of high and low molecular weight hyaluronans (96 mg/3 mL) for the treatment of skin laxity of the inner arm and abdomen. GAZZETTA MEDICA ITALIANA ARCHIVIO PER LE SCIENZE MEDICHE 2022. [DOI: 10.23736/s0393-3660.22.04826-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Efficacy and Tolerability of Hybrid Complexes of High- and Low-Molecular-Weight Hyaluronan Intradermal Injections for the Treatment of Skin Roughness and Laxity of the Neck. ScientificWorldJournal 2022; 2022:4497176. [PMID: 36164489 PMCID: PMC9509274 DOI: 10.1155/2022/4497176] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 03/10/2022] [Accepted: 08/01/2022] [Indexed: 11/23/2022] Open
Abstract
This study aimed to evaluate the efficacy of a well-characterized formulation of hyaluronic acid (HA), Profhilo®, in the treatment of roughness and laxity of the neck skin. The study was performed on 25 subjects ranging in age from 40 to 65 years. Two injections of the studied product at 30-day intervals were performed, with evaluations conducted 1 and 4 months after the first injection. The efficacy was determined by clinical and multilevel instrumental evaluations. In addition, at the end of the study, the subjects completed a questionnaire related to the efficacy and tolerability of the product. The studied product was shown to induce a clear and statistically significant improvement in the skin of the neck in all the subjects, with concordant results between the clinical, instrumental, and subjects' evaluations. The positive effects, present after the first injection, were further increased in the second and last evaluation. Notably, the product was reported to have a very high tolerability by both clinicians and subjects. In conclusion, two injections of the studied product safely induced skin amelioration in subjects with mild to moderate neck skin roughness and laxity.
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Romano C, Scarpignato C. Pharmacologic treatment of GERD in adolescents: Is esophageal mucosal protection an option? Therap Adv Gastroenterol 2022; 15:17562848221115319. [PMID: 36004307 PMCID: PMC9393348 DOI: 10.1177/17562848221115319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 07/07/2022] [Indexed: 02/04/2023] Open
Abstract
Background Gastroesophageal reflux disease (GERD) is still a challenging and difficult to treat condition in children. Although acid suppression represents the mainstay of treatment in adolescents, it is not devoid of adverse events, especially in the long-term. Objectives In this investigation we explored a new therapeutic avenue in GERD, that is esophageal mucosal protection. Design To this end, we performed an investigator-initiated, retrospective study to evaluate the efficacy and safety of a short-term treatment with Esoxx™ medical device in 25 adolescents with GERD-related symptoms. This mucoadhesive formulation contains two natural mucopolysaccharides (sodium hyaluronate and chondroitin sulphate) and adheres to the esophageal mucosa, exerting a protective effect against refluxed gastric contents and allowing mucosal healing. Methods Heartburn, epigastric burning and post-prandial regurgitation were scored with a pain VAS scale and re-evaluated after 3-week treatment with Esoxx (one stick post-prandially, three times daily). Results All patients completed the treatment without adverse effects and with good tolerability and compliance. All the three major symptoms significantly (p<0.001) improved after treatment. No patient required additional investigation (i.e. upper Gastrointestinal endoscopy) or medication (i.e. antisecretory drugs). Conclusion The results of this pilot study suggest that esophageal mucosal protection is a promising therapeutic avenue for GERD also in children. Provided, these data be confirmed by a large, randomized clinical trial, this medical device can enter our therapeutic armamentarium against this challenging disease.
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Affiliation(s)
- Claudio Romano
- Pediatric Gastroenterology and Cystic Fibrosis
Unit, Department of Human Pathology in Adulthood and Childhood “G. Barresi”,
University of Messina, Messina, Italy
| | - Carmelo Scarpignato
- United Campus of Malta, Msida, Malta
- University of Nantes, Nantes, France
- Chinese University of Hong Kong, Hong
Kong
- University of Parma, Parma, Italy
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Huang X, Zheng C, Ding K, Li M, Zhang S, Wu B, Wei Q, Lei Y, Wang Y. Hyaluronic Acid-Grafted Bioprosthetic Heart Valves Achieved by Copolymerization Exhibited Improved Anticalcification and Antithrombogenicity. ACS Biomater Sci Eng 2022; 8:3399-3410. [PMID: 35839344 DOI: 10.1021/acsbiomaterials.2c00367] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Bioprosthetic heart valves (BHVs) are widely used in clinic, but they still have problems of calcification, thrombogenicity, and cytotoxicity. The reported techniques based on glutaraldehyde (Glut) crosslinking have difficulty in solving these problems simultaneously. In this study, we grafted Glut-crosslinked porcine pericardium (GA) with hyaluronic acid (HA) by radical copolymerization to improve its anticalcification and antithrombotic properties. Partially methacrylated poly-ε-lysine was used to introduce methacryl groups into GA. Then, HA-grafted porcine pericardium (GA-HA) was obtained by radical copolymerization. Rat's subcutaneous implantation results showed that the calcium content of GA-HA was significantly lower than that of GA (37 ± 29 μg/mg vs 188 ± 7 μg/mg), and the platelets adhering to the surface of GA-HA decreased by approximately 41% compared with GA. In conclusion, grafting porcine pericardium with HA by copolymerization might be feasible to improve the anticalcification and antithrombotic properties of BHVs.
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Affiliation(s)
- Xueyu Huang
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, P. R. China
| | - Cheng Zheng
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, P. R. China
| | - Kailei Ding
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, P. R. China
| | - Meiling Li
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, P. R. China
| | - Shumang Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, P. R. China
| | - Binggang Wu
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, P. R. China.,Department of Cardiovascular Surgery, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu 610041 P.R. China
| | - Qingrong Wei
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, P. R. China
| | - Yang Lei
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, P. R. China
| | - Yunbing Wang
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, P. R. China
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Spontaneous regression rates of actinic keratosis: a systematic review and pooled analysis of randomized controlled trials. Sci Rep 2022; 12:5884. [PMID: 35393452 PMCID: PMC8990007 DOI: 10.1038/s41598-022-09722-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 03/21/2022] [Indexed: 12/01/2022] Open
Abstract
Actinic keratosis (AK) are precancerous lesions of the skin which may progress to invasive squamous cell carcinoma. However, single lesions may also persist or even regress and heal spontaneously. Until now, evidence on the natural course of AK including spontaneous regression is limited. We aimed to synthesize regression rates of AK. We performed a systematic literature research in Medline, Embase, and CENTRAL for eligible trials until 3rd March 2020. Spontaneous regression rates were pooled using a random-effects model to calculate pooled proportions of participant-specific and lesion-specific complete clearance rates reported for the placebo arms of randomized controlled trials. Subgroup analyses were performed to dissect differences according to the type of placebo, immunocompetence of the participants, and localization of the lesions. Data from 38 records was included. The pooled participant-specific clearance rate was 8% (95% CI 6–10%, I2 = 71%) while the lesion-specific clearance rate was 23% (95% CI 16–31%, I2 = 97%). The highest participant- and lesion-specific clearance rates were achieved 12 weeks after the end of treatment (12% and 33%, respectively). Subgroup analysis revealed participant- as well as lesion-specific clearance rates of 0% for organ transplant recipients (OTR). We conclude that only a few participants achieve complete regression of their AK without any active treatment. Besides, the results underline that lesion clearance without active treatment is unlikely in OTR. Thus, early and consequent treatment of AK is recommended. Special attention should be paid when treating AK of OTR.
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Garantziotis S. Modulation of hyaluronan signaling as a therapeutic target in human disease. Pharmacol Ther 2021; 232:107993. [PMID: 34587477 DOI: 10.1016/j.pharmthera.2021.107993] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 12/14/2022]
Abstract
The extracellular matrix is an active participant, modulator and mediator of the cell, tissue, organ and organismal response to injury. Recent research has highlighted the role of hyaluronan, an abundant glycosaminoglycan constituent of the extracellular matrix, in many fundamental biological processes underpinning homeostasis and disease development. From this basis, emerging studies have demonstrated the therapeutic potential of strategies which target hyaluronan synthesis, biology and signaling, with significant promise as therapeutics for a variety of inflammatory and immune diseases. This review summarizes the state of the art in this field and discusses challenges and opportunities in what could emerge as a new class of therapeutic agents, that we term "matrix biologics".
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Affiliation(s)
- Stavros Garantziotis
- Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
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Juncan AM, Moisă DG, Santini A, Morgovan C, Rus LL, Vonica-Țincu AL, Loghin F. Advantages of Hyaluronic Acid and Its Combination with Other Bioactive Ingredients in Cosmeceuticals. Molecules 2021; 26:molecules26154429. [PMID: 34361586 PMCID: PMC8347214 DOI: 10.3390/molecules26154429] [Citation(s) in RCA: 131] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 07/14/2021] [Accepted: 07/20/2021] [Indexed: 02/07/2023] Open
Abstract
This study proposes a review on hyaluronic acid (HA) known as hyaluronan or hyaluronate and its derivates and their application in cosmetic formulations. HA is a glycosaminoglycan constituted from two disaccharides (N-acetylglucosamine and D-glucuronic acid), isolated initially from the vitreous humour of the eye, and subsequently discovered in different tissues or fluids (especially in the articular cartilage and the synovial fluid). It is ubiquitous in vertebrates, including humans, and it is involved in diverse biological processes, such as cell differentiation, embryological development, inflammation, wound healing, etc. HA has many qualities that recommend it over other substances used in skin regeneration, with moisturizing and anti-ageing effects. HA molecular weight influences its penetration into the skin and its biological activity. Considering that, nowadays, hyaluronic acid has a wide use and a multitude of applications (in ophthalmology, arthrology, pneumology, rhinology, aesthetic medicine, oncology, nutrition, and cosmetics), the present study describes the main aspects related to its use in cosmetology. The biological effect of HA on the skin level and its potential adverse effects are discussed. Some available cosmetic products containing HA have been identified from the brand portfolio of most known manufacturers and their composition was evaluated. Further, additional biological effects due to the other active ingredients (plant extracts, vitamins, amino acids, peptides, proteins, saccharides, probiotics, etc.) are presented, as well as a description of their possible toxic effects.
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Affiliation(s)
- Anca Maria Juncan
- Department of Toxicology, Faculty of Pharmacy, “Iuliu Hațieganu” University of Medicine and Pharmacy, 6 Pasteur Str., 400349 Cluj-Napoca, Romania;
- SC Aviva Cosmetics SRL, 71A Kövari Str., 400217 Cluj-Napoca, Romania
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga Str., 550169 Sibiu, Romania; (L.-L.R.); (A.L.V.-Ț.)
- Correspondence: or (A.M.J.); (D.G.M.); (C.M.)
| | - Dana Georgiana Moisă
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga Str., 550169 Sibiu, Romania; (L.-L.R.); (A.L.V.-Ț.)
- Correspondence: or (A.M.J.); (D.G.M.); (C.M.)
| | - Antonello Santini
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy;
| | - Claudiu Morgovan
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga Str., 550169 Sibiu, Romania; (L.-L.R.); (A.L.V.-Ț.)
- Correspondence: or (A.M.J.); (D.G.M.); (C.M.)
| | - Luca-Liviu Rus
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga Str., 550169 Sibiu, Romania; (L.-L.R.); (A.L.V.-Ț.)
| | - Andreea Loredana Vonica-Țincu
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga Str., 550169 Sibiu, Romania; (L.-L.R.); (A.L.V.-Ț.)
| | - Felicia Loghin
- Department of Toxicology, Faculty of Pharmacy, “Iuliu Hațieganu” University of Medicine and Pharmacy, 6 Pasteur Str., 400349 Cluj-Napoca, Romania;
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15
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Radtsig EY, Konstantinov DI. Extraesophageal signs of gastroesophageal reflux disease: otorhinolaryngologist’s view. TERAPEVT ARKH 2021; 93:521-525. [DOI: 10.26442/00403660.2021.04.200814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 06/03/2021] [Indexed: 11/22/2022]
Abstract
The data on association between various pathologies of the ENT organs and gastroesophageal reflux disease (GERD) is analysed in the article. The variety of extraesophageal signs of GERD in children and adults is given, what is advisable to inform physicians of different specialties about the possibilities of antireflux therapy. These options are expanded with the emergence of a unique new drug, Alfasoxx. Its bioadhesive formula is based on hyaluronic acid and chondroitin sulphate thereby protecting the esophageal mucosa. Alfasoxx acts on the surface of the esophageal mucosa without penetrating into the systemic bloodstream and it also has a low allergenic potential, which has been confirmed by numerous studies. With its healing and repairing effect on erosive lesions of the esophageal epithelium, Alfasoxx in combination with proton pump inhibitors is more effective in achieving regression of clinical manifestations of the disease and improving patients quality of life (according to SF-36 questionnaire) compared to proton pump inhibitors monotherapy.
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16
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Attia YA, Al Nazawi AM, Elsayed H, Sadik MW. Carbon nanotubes catalyzed UV-trigger production of hyaluronic acid from Streptococcus equi. Saudi J Biol Sci 2021; 28:484-491. [PMID: 33424331 PMCID: PMC7783678 DOI: 10.1016/j.sjbs.2020.10.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 10/05/2020] [Accepted: 10/19/2020] [Indexed: 01/15/2023] Open
Abstract
Hyaluronic acid (HA) has great importance in biomedical applications. In this work, a novel nanoparticle-based method that stimulates the hyaluronic acid (HA) production by the bacteria Streptococcus equi subsp. Zooepidemicus has been reported. CNTs with diameters of 40-50 nm and lengths of about 20 mm were used at four different concentrations (0, 10, 25, 50, and 100 μg) to the bacteria and determined the mass of the produced HA in dependence on the exposure time under UV-irradiation. The results clearly showed that the exposure for one minute with low power UV light (254 nm) and 100 µg (CNTs) treatments steadily increased HA production from the control (0.062 g/L) to the highest value (0.992) g/L of HA. The incubation of the streptococci with CNTs led to an increase of the HA production by a factor of 4.23 after 300S exposure time under UV light, whereas the HA production was no significant enhancement under visible light. It is explained that the CNTs nanoparticle-stimulated increase of the HA production with the internalization of the nanoparticles by the bacteria since they "serve as co-enzymes" under induced mutation by UV-irradiation. Transformation process was carried out and showed that the major protein band of Streptococcus equi was observed in the Streptococcus DH5α. RAPD analysis indicates that the amplified DNA fragments and the percentage of polymorphism was similar between Streptococcus equi and Streptococcus DH50α. The chemical structure and molecular weight of the photoproduced HA from Streptococcus equi was similar to the chemical structure of the standard sample.
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Affiliation(s)
- Yasser A. Attia
- National Institute of Laser Enhanced Sciences, Cairo University, Giza 12613, Egypt
| | - Ashwaq M. Al Nazawi
- Preventive Medicine Department, Public Health Directorate, Ministry of Health, Jeddah 22246, Saudi Arabia
| | - Hassan Elsayed
- Department of Microbial Biotechnology, Genetic Engineering and Biotechnology Division, National Research Centre, Dokki, Giza 12622, Egypt
| | - Mahmoud W. Sadik
- Microbiology Department, Faculty of Agriculture, Cairo University, Giza 12613, Egypt
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17
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Bakulina NV, Simanenkov VI, Vorobyev SL, Tikhonov SV, Lishchuk NB, Bakulin IG. The eosinophilic esophagitis and IgG4-related disease involving the esophagus. TERAPEVT ARKH 2020; 92:100-107. [DOI: 10.26442/00403660.2020.08.000792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Indexed: 11/22/2022]
Abstract
The study of eosinophilic esophagitis has become a dynamic field with an evolving understanding of the pathogenesis, diagnosis, and treatment. Immunoglobulin G4 (IgG4)-related disease exhibits systemic involvement but very rarely involves the esophagus. The article presents a clinical case: the history of ulcer and stricture of the esophagus in a young man of 17 years. The patient was finally diagnosed with IgG4-related and eosinophilic esophagitis and showed a good response to corticosteroid therapy. We herein report a rare case of dysphagia associated with IgG4-related disease and eosinophilic. We presented a review of modern data on the relationship of eosinophilic esophagitis and pathological IgG4-response.
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18
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Boarino V, Raguzzi I, Marocchi M, Merighi A. Symptomatic response to GERDOFF® in patients with gastro-esophageal reflux disease and poor response to alginates: an exploratory, post-market, open-label study. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 31:466-473. [PMID: 32721918 DOI: 10.5152/tjg.2020.19327] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND/AIMS A novel medical device based on hyaluronic acid, chondroitin sulphate plus aluminum hydroxide (GERDOFF®, melt-in-mouth tablets) showed efficacy in reducing GER-related symptoms. This exploratory, open-label study evaluated symptomatic effects of a 14-day treatment with GERDOFF® in GERD patients. MATERIALS AND METHODS GERD Impact Scale (GIS) questionnaire was filled at baseline visit, after 7 and 14 days of treatment; patients' Global Satisfaction was evaluated at the final visit. Primary endpoint was the reduction of heartburn episodes per week; secondary endpoints were GERD-related symptoms, patients' satisfaction, and safety. RESULTS Forty patients were included, 22 were on stable therapy with proton pump inhibitor (PPI). Compared to baseline, the days with heartburn episodes and the GIS score progressively decreased during the first (p<0.0001) and the second week of treatment (p<0.0001). Heartburn episodes per week (p<0.0001) and the GIS score (p<0.0001) decreased in the first and the last 7 days of 14-day treatment and did not differ between patients on and off PPI. The treatment was safe and well-tolerated, and it was rated as very good (46.2%) or good (43.6%) on the satisfaction questionnaire. CONCLUSION GERDOFF® could effectively treat GER symptoms in patients not responding to PPI or alginate-based formulation. ISRCTN_15143752.
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Affiliation(s)
- Valentina Boarino
- Department of Gastroenterology and Digestive Endoscopy, University of Modena, Modena, Italy
| | - Ivana Raguzzi
- Department of Gastroenterology and Digestive Endoscopy, Hospital of Cernusco sul Naviglio, Milan, Italy
| | - Margherita Marocchi
- Department of Gastroenterology and Digestive Endoscopy, University of Modena, Modena, Italy
| | - Alberto Merighi
- Department of Gastroenterology and Digestive Endoscopy, University of Modena, Modena, Italy
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19
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Lee M, Rizzo R, Surman F, Zenobi-Wong M. Guiding Lights: Tissue Bioprinting Using Photoactivated Materials. Chem Rev 2020; 120:10950-11027. [DOI: 10.1021/acs.chemrev.0c00077] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Mihyun Lee
- Tissue Engineering + Biofabrication HPL J22, ETH Zürich, Otto-Stern-Weg 7, 8093 Zürich, Switzerland
| | - Riccardo Rizzo
- Tissue Engineering + Biofabrication HPL J22, ETH Zürich, Otto-Stern-Weg 7, 8093 Zürich, Switzerland
| | - František Surman
- Tissue Engineering + Biofabrication HPL J22, ETH Zürich, Otto-Stern-Weg 7, 8093 Zürich, Switzerland
| | - Marcy Zenobi-Wong
- Tissue Engineering + Biofabrication HPL J22, ETH Zürich, Otto-Stern-Weg 7, 8093 Zürich, Switzerland
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20
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Guan L, Zhang L, Xue Y, Yang J, Zhao Z. Molecular pathogenesis of the hyaluronic acid capsule of Pasteurella multocida. Microb Pathog 2020; 149:104380. [PMID: 32645423 DOI: 10.1016/j.micpath.2020.104380] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 07/02/2020] [Accepted: 07/02/2020] [Indexed: 12/20/2022]
Abstract
Pasteurella multocida possesses a viscous capsule polysaccharide on the cell surface, which is a critical structural component and virulence factor. Capsular polysaccharides are structurally similar to vertebrate glycosaminoglycans, providing an immunological mechanism for bacterial molecular mimicry, resistance to phagocytosis, and immune evasion during the infection process. Based on the capsular antigen, P. multocida is divided into A, B, D, E, and F five serogroups. Previously, we systematically reported the biosynthesis and regulation mechanisms of the P. multocida capsule. In this paper, we take serogroup A capsular polysaccharide as the representative, systematically illuminating the P. multocida capsular virulence and epidemiology, molecular camouflage, adhesion and colonization, anti-phagocytosis, anti-complement system, cell invasion and signal transduction mechanism, to provide a theoretical basis for the research of molecular pathogenic mechanism of P. multocida capsule and the development of polysaccharides vaccine.
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Affiliation(s)
- Lijun Guan
- Laboratory of Veterinary Biologics Engineering, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471023, China; Key-Disciplines Lab of Safety of Environment and Animal Product, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471023, China
| | - Lin Zhang
- Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Science, Wuhan, 430223, China
| | - Yun Xue
- Laboratory of Veterinary Biologics Engineering, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471023, China; Key-Disciplines Lab of Safety of Environment and Animal Product, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471023, China
| | - Jinqian Yang
- Laboratory of Veterinary Biologics Engineering, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471023, China; Key-Disciplines Lab of Safety of Environment and Animal Product, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471023, China
| | - Zhanqin Zhao
- Laboratory of Veterinary Biologics Engineering, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471023, China; Key-Disciplines Lab of Safety of Environment and Animal Product, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471023, China.
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21
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Zhang X, Shu W, Yu Q, Qu W, Wang Y, Li R. Functional Biomaterials for Treatment of Chronic Wound. Front Bioeng Biotechnol 2020; 8:516. [PMID: 32582657 PMCID: PMC7283526 DOI: 10.3389/fbioe.2020.00516] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 05/01/2020] [Indexed: 12/30/2022] Open
Abstract
The increasing number of patients with chronic wounds caused by diseases, such as diabetes, malignant tumors, infections, and vasculopathy, has caused severe economic and social burdens. The main clinical treatments for chronic wounds include the systemic use of antibiotics, changing dressings frequently, operative debridement, and flap repair. These routine therapeutic strategies are characterized by a long course of treatment, substantial trauma, and high costs, and fail to produce satisfactory results. Biomaterial dressings targeting the different stages of the pathophysiology of chronic wounds have become an active research topic in recent years. In this review, after providing an overview of the epidemiology of chronic wounds, and the pathophysiological characteristics of chronic wounds, we highlight the functional biomaterials that can enhance chronic wound healing through debridement, anti-infection and antioxidant effects, immunoregulation, angiogenesis, and extracellular matrix remodeling. It is hoped that functional biomaterials will resolve the treatment dilemma for chronic wounds and improve patient quality of life.
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Affiliation(s)
- Xi Zhang
- Department of Hand Surgery, The Second Hospital of Jilin University, Changchun, China.,Department of Burn Surgery, The First Hospital of Jilin University, Changchun, China
| | - Wentao Shu
- Department of Biobank, Division of Clinical Research, The First Hospital of Jilin University, Changchun, China
| | - Qinghua Yu
- Department of Burn Surgery, The First Hospital of Jilin University, Changchun, China
| | - Wenrui Qu
- Department of Hand Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Yinan Wang
- Department of Biobank, Division of Clinical Research, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Organ Regeneration and Transplantation, The First Hospital of Jilin University, Changchun, China
| | - Rui Li
- Department of Hand Surgery, The Second Hospital of Jilin University, Changchun, China
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22
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La Gatta A, Schiraldi C, Zaccaria G, Cassuto D. Hyaluronan Dermal Fillers: Efforts Towards a Wider Biophysical Characterization and the Correlation of the Biophysical Parameters to the Clinical Outcome. Clin Cosmet Investig Dermatol 2020; 13:87-97. [PMID: 32095081 PMCID: PMC6995295 DOI: 10.2147/ccid.s220227] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 11/20/2019] [Indexed: 12/21/2022]
Abstract
Introduction Hyaluronic Acid (HA) fillers are among the most used products in cosmetic medicine. Companies offer different formulations to allow full facial treatment and/or remodeling. Gels are being studied to establish the biophysical properties behind the specific clinical use and a correlation between the gel biophysical properties and their clinical performance. Clinicians' awareness is growing about the potential benefit deriving from such biophysical characterization. Aim The Aliaxin® line of HA dermal fillers is the object of this study. The study aimed to widen the biophysical characterization of these gels by investigating a variety of properties to better support their optimal use. Further, we aimed to provide some clinical findings to gain a deeper insight into the correlation between filler features and clinical outcome. Methods The four gels of the line were investigated, for the first time, for their cohesivity and stability to Reactive Oxygen Species (ROS). Additional secondary rheological parameters; evidence of relative water-uptake ability; and some clinical findings on product safety, palpability and duration of the aesthetic effect are provided. Results and conclusion The gels proved highly cohesive and sensitive to ROS action with stability declining with the decrease in the overall gel elasticity. The G* and complex viscosity values at clinically relevant frequencies and gel water-uptake ability are consistent with the relative clinical indication related to gel projection and hydration capacity. Clinical outcomes showed the safety of the products and a perception of palpability well correlating with the cohesive/viscosity properties of the gels. A similar duration of the aesthetic effect (up to 1 year) was observed despite the diverse in vitro gel stability. The results broaden our knowledge of these gels and may contribute to optimize their clinical use towards the improvement of patient safety and satisfaction. Initial clinical observation indicated that gel biophysical properties allow for a reliable prediction of gel palpability, while in vitro data on gel stability cannot be related to the duration of the observed skin improvement. The latter finding further corroborates the idea of a skin restoration process activated by the gels besides the physical volumetric action.
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Affiliation(s)
- Annalisa La Gatta
- Department Experimental Medicine, Section of Biotechnology, Medical Histology and Molecular Biology, School of Medicine, University of Campania "L. Vanvitelli", Naples 80138, Italy
| | - Chiara Schiraldi
- Department Experimental Medicine, Section of Biotechnology, Medical Histology and Molecular Biology, School of Medicine, University of Campania "L. Vanvitelli", Naples 80138, Italy
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23
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Bhuiyan NH, Varney ML, Bhattacharya DS, Payne WM, Mohs AM, Holstein SA, Wiemer DF. ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors. Bioorg Med Chem Lett 2019; 29:126633. [PMID: 31474482 DOI: 10.1016/j.bmcl.2019.126633] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 08/20/2019] [Indexed: 02/08/2023]
Abstract
The enzyme geranylgeranyl diphosphate synthase (GGDPS) is a potential therapeutic target for multiple myeloma. Malignant plasma cells produce and secrete large amounts of monoclonal protein, and inhibition of GGDPS results in disruption of protein geranylgeranylation which in turn impairs intracellular protein trafficking. Our previous work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. To explore the possibility of selective delivery of such compounds to plasma cells, new analogues with an ω-hydroxy group have been synthesized and examined for their enzymatic and cellular activity. These studies demonstrate that incorporation of the ω-hydroxy group minimally impairs GGDPS inhibitory activity. Furthermore conjugation of one of the novel ω-hydroxy GGDPS inhibitors to hyaluronic acid resulted in enhanced cellular activity. These results will allow future studies to focus on the in vivo biodistribution of HA-conjugated GGDPS inhibitors.
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Affiliation(s)
- Nazmul H Bhuiyan
- Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, United States
| | - Michelle L Varney
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Deep S Bhattacharya
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - William M Payne
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Aaron M Mohs
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, United States; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Sarah A Holstein
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - David F Wiemer
- Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, United States; Department of Pharmacology, University of Iowa, Iowa City, IA 52242-1109, United States.
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Maev IV, Andreev DN, Kucheryavyy YA, Shaburov RI. [Current advances in the treatment of gastroesophageal reflux disease: a focus on esophageal protection]. TERAPEVT ARKH 2019; 91:4-11. [PMID: 32598747 DOI: 10.26442/00403660.2019.08.000387] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Indexed: 02/07/2023]
Abstract
Gastroesophageal reflux disease (GERD) is characterized by high morbidity and a significant decrease in the quality of life of patients, and is a major risk factor for esophageal adenocarcinoma. Nowadays, antisecretory therapy with proton pump inhibitors (PPI) is the "gold standard" of conservative treatment of GERD, but in some cases this therapy is unsuccessful. According to various studies, the prevalence of refractory GERD can reach 30-40%. The latest scientific data in the field of genetics and pathophysiology of GERD demonstrate that a disruption of the barrier function of the esophageal mucosa and an increase of its permeability can be the leading causes of refractoriness. Thus, the optimal therapy for patients with GERD should not only suppress the secretion of hydrochloric acid, but also restore the barrier function of the mucous membrane, providing an esophagoprotective effect. To achieve these goals, Alfasoxx was developed, which consists of a mixture of low molecular weight hyaluronic acid and low molecular weight chondroitin sulfate dissolved in a bioadhesive carrier (poloxamer 407). The clinical efficacy of this product has been confirmed by three prospective, randomized, placebo - controlled trials. Alfasoxx has a healing and restorative effect towards the esophageal epithelium and due to high ability for bioadhesion provides long - term protection of the mucous membrane of the esophagus. Combination therapy for GERD with the use of PPI and an esophagoprotector offers new perspectives for the treatment of patients with GERD.
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Affiliation(s)
- I V Maev
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - D N Andreev
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - Y A Kucheryavyy
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - R I Shaburov
- Yevdokimov Moscow State University of Medicine and Dentistry
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25
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Ullah S, Khalil AA, Shaukat F, Song Y. Sources, Extraction and Biomedical Properties of Polysaccharides. Foods 2019; 8:E304. [PMID: 31374889 PMCID: PMC6723881 DOI: 10.3390/foods8080304] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 07/27/2019] [Accepted: 07/28/2019] [Indexed: 12/14/2022] Open
Abstract
In the recent era, bioactive compounds from plants have received great attention because of their vital health-related activities, such as antimicrobial activity, antioxidant activity, anticoagulant activity, anti-diabetic activity, UV protection, antiviral activity, hypoglycemia, etc. Previous studies have already shown that polysaccharides found in plants are not likely to be toxic. Based on these inspirational comments, most research focused on the isolation, identification, and bioactivities of polysaccharides. A large number of biologically active polysaccharides have been isolated with varying structural and biological activities. In this review, a comprehensive summary is provided of the recent developments in the physical and chemical properties as well as biological activities of polysaccharides from a number of important natural sources, such as wheat bran, orange peel, barely, fungi, algae, lichen, etc. This review also focused on biomedical applications of polysaccharides. The contents presented in this review will be useful as a reference for future research as well as for the extraction and application of these bioactive polysaccharides as a therapeutic agent.
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Affiliation(s)
- Samee Ullah
- Colin Ratledge Center for Microbial Lipids, Center for Functional Foods and Health, School of Agriculture Engineering and Food Science, Shandong University of Technology, Zibo 255049, China
- University Institute of Diet and Nutritional Sciences, Faculty of Allied Health Sciences, The University of Lahore, Lahore 54000, Pakistan
| | - Anees Ahmed Khalil
- University Institute of Diet and Nutritional Sciences, Faculty of Allied Health Sciences, The University of Lahore, Lahore 54000, Pakistan
| | - Faryal Shaukat
- Colin Ratledge Center for Microbial Lipids, Center for Functional Foods and Health, School of Agriculture Engineering and Food Science, Shandong University of Technology, Zibo 255049, China
| | - Yuanda Song
- Colin Ratledge Center for Microbial Lipids, Center for Functional Foods and Health, School of Agriculture Engineering and Food Science, Shandong University of Technology, Zibo 255049, China.
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26
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Chen RF, Wang CT, Chen YH, Chien CM, Lin SD, Lai CS, Wang CJ, Kuo YR. Hyaluronic Acid-Povidone-Iodine Compound Facilitates Diabetic Wound Healing in a Streptozotocin-Induced Diabetes Rodent Model. Plast Reconstr Surg 2019; 143:1371-1382. [PMID: 30807498 DOI: 10.1097/prs.0000000000005504] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND This study investigated whether a hyaluronic acid-povidone-iodine compound can enhance diabetic wound healing. METHODS A dorsal skin defect (6 × 5 cm) in a streptozotocin-induced diabetes rodent model was used. Seventy male Wistar rats were divided into seven groups: I, normal control; II, diabetic control, no treatment; III, diabetic rats, lower molecular weight (100 kDa) hyaluronic acid; IV, rats, higher molecular weight (1000 kDa) hyaluronic acid; V, rats, 0.1% povidone-iodine; VI, rats, lower molecular weight hyaluronic acid plus povidone-iodine; and VII, rats, higher molecular weight hyaluronic acid plus povidone-iodine. Histologic examination was performed with hematoxylin and eosin staining. CD45, Ki-67, prolyl 4-hydroxylase, and vascular endothelial growth factor were evaluated with immunohistochemical staining. RESULTS Compared with the control, higher molecular weight hyaluronic acid plus povidone-iodine-treated rats had significantly reduced wound area (p < 0.001). Higher molecular weight hyaluronic acid plus povidone-iodine increased wound healing time when compared with higher molecular weight hyaluronic acid, povidone-iodine, or lower molecular weight hyaluronic acid plus povidone-iodine. Histology revealed significantly increased neovessels and suppressed inflammatory response in the higher molecular weight hyaluronic acid plus povidone-iodine group when compared with the control group. Immunohistochemical staining revealed significantly increased Ki67, prolyl 4-hydroxylase, and vascular endothelial growth factor expression, and suppressed CD45 expression in the higher molecular weight hyaluronic acid plus povidone-iodine group when compared with the other groups. CONCLUSION Higher molecular weight hyaluronic acid plus povidone-iodine complex dressing significantly facilitated diabetic wound healing via increasing neovascularization and tissue regeneration and suppressing a proinflammatory response.
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Affiliation(s)
- Rong-Fu Chen
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital; the Department of Healthcare Materials, Material and Chemical Research Laboratories, Industrial Technology Research Institute; the Department of Orthopaedics, Kaohsiung Chang Gung Memorial Hospital; the Faculty of Medicine, College of Medicine, Orthopaedic Research Center, Kaohsiung Medical University; and the Department of Biological Sciences, National Sun Yat-sen University
| | - Chun-Ting Wang
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital; the Department of Healthcare Materials, Material and Chemical Research Laboratories, Industrial Technology Research Institute; the Department of Orthopaedics, Kaohsiung Chang Gung Memorial Hospital; the Faculty of Medicine, College of Medicine, Orthopaedic Research Center, Kaohsiung Medical University; and the Department of Biological Sciences, National Sun Yat-sen University
| | - Yu-Hua Chen
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital; the Department of Healthcare Materials, Material and Chemical Research Laboratories, Industrial Technology Research Institute; the Department of Orthopaedics, Kaohsiung Chang Gung Memorial Hospital; the Faculty of Medicine, College of Medicine, Orthopaedic Research Center, Kaohsiung Medical University; and the Department of Biological Sciences, National Sun Yat-sen University
| | - Ching-Ming Chien
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital; the Department of Healthcare Materials, Material and Chemical Research Laboratories, Industrial Technology Research Institute; the Department of Orthopaedics, Kaohsiung Chang Gung Memorial Hospital; the Faculty of Medicine, College of Medicine, Orthopaedic Research Center, Kaohsiung Medical University; and the Department of Biological Sciences, National Sun Yat-sen University
| | - Sin-Daw Lin
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital; the Department of Healthcare Materials, Material and Chemical Research Laboratories, Industrial Technology Research Institute; the Department of Orthopaedics, Kaohsiung Chang Gung Memorial Hospital; the Faculty of Medicine, College of Medicine, Orthopaedic Research Center, Kaohsiung Medical University; and the Department of Biological Sciences, National Sun Yat-sen University
| | - Chung-Sheng Lai
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital; the Department of Healthcare Materials, Material and Chemical Research Laboratories, Industrial Technology Research Institute; the Department of Orthopaedics, Kaohsiung Chang Gung Memorial Hospital; the Faculty of Medicine, College of Medicine, Orthopaedic Research Center, Kaohsiung Medical University; and the Department of Biological Sciences, National Sun Yat-sen University
| | - Ching-Jen Wang
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital; the Department of Healthcare Materials, Material and Chemical Research Laboratories, Industrial Technology Research Institute; the Department of Orthopaedics, Kaohsiung Chang Gung Memorial Hospital; the Faculty of Medicine, College of Medicine, Orthopaedic Research Center, Kaohsiung Medical University; and the Department of Biological Sciences, National Sun Yat-sen University
| | - Yur-Ren Kuo
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital; the Department of Healthcare Materials, Material and Chemical Research Laboratories, Industrial Technology Research Institute; the Department of Orthopaedics, Kaohsiung Chang Gung Memorial Hospital; the Faculty of Medicine, College of Medicine, Orthopaedic Research Center, Kaohsiung Medical University; and the Department of Biological Sciences, National Sun Yat-sen University
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Hyaluronan biology: A complex balancing act of structure, function, location and context. Matrix Biol 2019; 78-79:1-10. [PMID: 30802498 DOI: 10.1016/j.matbio.2019.02.002] [Citation(s) in RCA: 229] [Impact Index Per Article: 38.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/09/2019] [Accepted: 02/11/2019] [Indexed: 02/07/2023]
Abstract
Cell-matrix interactions are fundamental to many developmental, homeostatic, immune and pathologic processes. Hyaluronan (HA), a critical component of the extracellular matrix (ECM) that regulates normal structural integrity and development, also regulates tissue responses during injury, repair, and regeneration. Though simple in its primary structure, HA regulates biological responses in a highly complex manner with balanced contributions from its molecular size and concentration, synthesis versus enzymatic and/or oxidative-nitrative fragmentation, interactions with key HA binding proteins and cell associated receptors, and its cell context-specific signaling. This review highlights the different, but inter-related factors that dictate the biological activity of HA and introduces the overarching themes that weave throughout this special issue of Matrix Biology on hyaluronan.
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Zhou T, Yu Z, Jian MY, Ahmad I, Trempus C, Wagener BM, Pittet JF, Aggarwal S, Garantziotis S, Song W, Matalon S. Instillation of hyaluronan reverses acid instillation injury to the mammalian blood gas barrier. Am J Physiol Lung Cell Mol Physiol 2018; 314:L808-L821. [PMID: 29368549 DOI: 10.1152/ajplung.00510.2017] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Acid (HCl) aspiration during anesthesia may lead to acute lung injury. There is no effective therapy. We hypothesized that HCl instilled intratracheally in C57BL/6 mice results in the formation of low-molecular weight hyaluronan (L-HA), which activates RhoA and Rho kinase (ROCK), causing airway hyperresponsiveness (AHR) and increased permeability. Furthermore, instillation of high-molecular weight hyaluronan (H-HA; Yabro) will reverse lung injury. We instilled HCl in C57BL/6 wild-type (WT), myeloperoxidase gene-deficient (MPO-/-) mice, and CD44 gene-deficient (CD44-/-) mice. WT mice were also instilled intranasally with H-HA (Yabro) at 1 and 23 h post-HCl. All measurements were performed at 1, 5, or 24 h post-HCl. Instillation of HCl in WT but not in CD44-/- resulted in increased inflammation, AHR, lung injury, and L-HA in the bronchoalveolar lavage fluid (BALF) 24 h post-HCl; L-HA levels and lung injury were significantly lower in HCl-instilled MPO-/- mice. Isolated perfused lungs of HCl instilled WT but not of CD44-/- mice had elevated values of the filtration coefficient ( Kf). Addition of L-HA on the apical surface of human primary bronchial epithelial cell monolayer decreased barrier resistance ( RT). H-HA significantly mitigated inflammation, AHR, and pulmonary vascular leakage at 24 h after HCl instillation and mitigated the increase of Kf and RT, as well as ROCK2 phosphorylation. Increased H- and L-HA levels were found in the BALF of mechanically ventilated patients but not in healthy volunteers. HCl instillation-induced lung injury is mediated by the L-HA-CD44-RhoA-ROCK2 signaling pathway, and H-HA is a potential novel therapeutic agent for acid aspiration-induced lung injury.
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Affiliation(s)
- Ting Zhou
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham , Birmingham, Alabama.,Department of Critical Care Medicine, Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Zhihong Yu
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | - Ming-Yuan Jian
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | - Israr Ahmad
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | - Carol Trempus
- Matrix Biology Group, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences , Research Triangle Park, North Carolina
| | - Brant M Wagener
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | - Jean-Francois Pittet
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | - Saurabh Aggarwal
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | - Stavros Garantziotis
- Matrix Biology Group, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences , Research Triangle Park, North Carolina
| | - Weifeng Song
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | - Sadis Matalon
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham , Birmingham, Alabama
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Li D, Qin J, Lv J, Yang J, Yan G. “Turn on” room-temperature phosphorescent biosensors for detection of hyaluronic acid based on manganese-doped ZnS quantum dots. RSC Adv 2018; 8:2873-2879. [PMID: 35541178 PMCID: PMC9077376 DOI: 10.1039/c7ra11858a] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 01/08/2018] [Indexed: 01/28/2023] Open
Abstract
Biosensors based on excellent optical properties of quantum dots (QDs) nanohybrids are efficient for biological detection. In this work, a room-temperature phosphorescent (RTP) PDAD–Mn–ZnS QDs biosensor was constructed with poly(diallyldimethylammonium chloride) (PDAD) as the modifier of MPA-capped Mn–ZnS QDs, and used to detect hyaluronic acid (HA). The newly-added HA induced severe electrostatic interaction with PDAD–Mn–ZnS QDs, leading to the aggregation between PDAD–Mn–ZnS QDs and HA and thereby enhancing RTP. The enhancement of RTP was proportional to the HA concentrations within certain ranges. On this basis, a high-performance HA sensor was built and this sensor had a detection limit of 0.03 μg mL−1 and a detection range of 0.08–2.8 μg mL−1. This proposed RTP sensor can avoid interferences from the background fluorescence or scattering light of the matrix that are encountered in spectrofluorometry. Thus, this biosensor is potentially suitable for detection of HA in real samples without complicated pretreatment. Fabricating PDAD–Mn–ZnS QDs nanohybrids as a facile room-temperature phosphorescent biosensor for detection of hyaluronic acid.![]()
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Affiliation(s)
- Dongxia Li
- Shanxi Normal University
- Linfen 041004
- PR China
| | - Jin Qin
- Shanxi Normal University
- Linfen 041004
- PR China
| | - Jinzhi Lv
- Shanxi Normal University
- Linfen 041004
- PR China
| | - Jiajia Yang
- Shanxi Normal University
- Linfen 041004
- PR China
| | - Guiqin Yan
- Shanxi Normal University
- Linfen 041004
- PR China
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Savarino E, Zentilin P, Marabotto E, Pellegatta G, Coppo C, Brunacci M, Dulbecco P, Savarino V. Drugs for improving esophageal mucosa defense: where are we now and where are we going? Ann Gastroenterol 2017; 30:585-591. [PMID: 29118552 PMCID: PMC5670277 DOI: 10.20524/aog.2017.0187] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 07/24/2017] [Indexed: 12/12/2022] Open
Abstract
In the past, the attention of physiologists and doctors has been mainly focused on the key role of acid in the pathogenesis of gastroesophageal reflux disease (GERD), but increasing evidence that 20-40% of reflux patients respond not at all or only partially to proton pump inhibitors (PPIs) has underlined the concept that factors other than acid are implicated in its development and the elicitation of symptoms. Among these, impaired mucosal integrity, particularly in most patients with non-erosive reflux disease, has recently been reincluded and the reinforcement of defensive mechanisms and/or its protection has been reappointed as a renewed therapeutic target for the management of GERD patients. In this review we will summarize the existing knowledge of the old and novel compounds able to produce this therapeutic effect, including sucralfate, alginate-based drugs, and a new medical device consisting of hyaluronic acid and chondroitin sulfate dispersed in a bioadhesive carrier, together with the potential indications for their use. It is to be stressed, however, that, although these compounds may represent a real alternative to PPI therapy in GERD, the combination of mucosal protection with acid suppression may help manage many cases with a partial or unsatisfactory response to PPIs alone.
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Affiliation(s)
- Edoardo Savarino
- Gastrointestinal Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua (Edoardo Savarino), Italy
| | - Patrizia Zentilin
- Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa (Patrizia Zentillin, Elisa Marabotto, Gaia Pellegatta, Claudia Coppo, Matteo Brunacci, Pietro Dulbecco, Vincenzo Savarino), Italy
| | - Elisa Marabotto
- Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa (Patrizia Zentillin, Elisa Marabotto, Gaia Pellegatta, Claudia Coppo, Matteo Brunacci, Pietro Dulbecco, Vincenzo Savarino), Italy
| | - Gaia Pellegatta
- Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa (Patrizia Zentillin, Elisa Marabotto, Gaia Pellegatta, Claudia Coppo, Matteo Brunacci, Pietro Dulbecco, Vincenzo Savarino), Italy
| | - Claudia Coppo
- Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa (Patrizia Zentillin, Elisa Marabotto, Gaia Pellegatta, Claudia Coppo, Matteo Brunacci, Pietro Dulbecco, Vincenzo Savarino), Italy
| | - Matteo Brunacci
- Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa (Patrizia Zentillin, Elisa Marabotto, Gaia Pellegatta, Claudia Coppo, Matteo Brunacci, Pietro Dulbecco, Vincenzo Savarino), Italy
| | - Pietro Dulbecco
- Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa (Patrizia Zentillin, Elisa Marabotto, Gaia Pellegatta, Claudia Coppo, Matteo Brunacci, Pietro Dulbecco, Vincenzo Savarino), Italy
| | - Vincenzo Savarino
- Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa (Patrizia Zentillin, Elisa Marabotto, Gaia Pellegatta, Claudia Coppo, Matteo Brunacci, Pietro Dulbecco, Vincenzo Savarino), Italy
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Lane RS, St. Ange K, Zolghadr B, Liu X, Schäffer C, Linhardt RJ, DeAngelis PL. Expanding glycosaminoglycan chemical space: towards the creation of sulfated analogs, novel polymers and chimeric constructs. Glycobiology 2017; 27:646-656. [PMID: 28334971 PMCID: PMC5458544 DOI: 10.1093/glycob/cwx021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 02/11/2017] [Accepted: 02/27/2017] [Indexed: 02/01/2023] Open
Abstract
Glycosaminoglycans (GAGs) have therapeutic potential in areas ranging from angiogenesis, inflammation, hemostasis and cancer. GAG bioactivity is conferred by intrinsic structural features, such as disaccharide composition, glycosidic linkages and sulfation pattern. Unfortunately, the in vitro enzymatic synthesis of defined GAGs is quite restricted by a limited understanding of current GAG synthases and modifying enzymes. Our work provides insights into GAG-active enzymes through the creation of sulfated oligosaccharides, a new polysaccharide and chimeric polymers. We show that a C6-sulfonated uridine diphospho (UDP)-glucose (Glc) derivative, sulfoquinovose, can be used as an uronic acid donor, but not as a hexosamine donor, to cap hyaluronan (HA) chains by the HA synthase from the microbe Pasteurella multocida. However, the two heparosan (HEP) synthases from the same species, PmHS1 and PmHS2, could not employ the UDP-sulfoquinovose under similar conditions. Serendipitously, we found that PmHS2 co-polymerized Glc with glucuronic acid (GlcA), creating a novel HEP-like polymer we named hepbiuronic acid [-4-GlcAβ1-4-Glcα1-]n. In addition, we created chimeric block polymers composed of both HA and HEP segments; in these reactions GlcA-, but not N-acetylglucosamine-(GlcNAc), terminated GAG acceptors were recognized by their noncognate synthase for further extension, likely due to the common β-linkage connecting GlcA to GlcNAc in both of these GAGs. Overall, these GAG constructs provide new tools for studying biology and offer potential for future sugar-based therapeutics.
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Affiliation(s)
- Rachel S Lane
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Kalib St. Ange
- Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
| | - Behnam Zolghadr
- Department of NanoBiotechnology, NanoGlycobiology Unit, Universität für Bodenkultur Wien, Muthgasse 11, A-1190 Vienna, Austria
| | | | - Christina Schäffer
- Department of NanoBiotechnology, NanoGlycobiology Unit, Universität für Bodenkultur Wien, Muthgasse 11, A-1190 Vienna, Austria
| | - Robert J Linhardt
- Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
- Department of Biology
- Department of Chemical and Biological Engineering
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
| | - Paul L DeAngelis
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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Beldman TJ, Senders ML, Alaarg A, Pérez-Medina C, Tang J, Zhao Y, Fay F, Deichmöller J, Born B, Desclos E, van der Wel NN, Hoebe RA, Kohen F, Kartvelishvily E, Neeman M, Reiner T, Calcagno C, Fayad ZA, de Winther MPJ, Lutgens E, Mulder WJM, Kluza E. Hyaluronan Nanoparticles Selectively Target Plaque-Associated Macrophages and Improve Plaque Stability in Atherosclerosis. ACS NANO 2017; 11:5785-5799. [PMID: 28463501 PMCID: PMC5492212 DOI: 10.1021/acsnano.7b01385] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 05/02/2017] [Indexed: 05/18/2023]
Abstract
Hyaluronan is a biologically active polymer, which can be formulated into nanoparticles. In our study, we aimed to probe atherosclerosis-associated inflammation by using hyaluronan nanoparticles and to determine whether they can ameliorate atherosclerosis. Hyaluronan nanoparticles (HA-NPs) were prepared by reacting amine-functionalized oligomeric hyaluronan (HA) with cholanic ester and labeled with a fluorescent or radioactive label. HA-NPs were characterized in vitro by several advanced microscopy methods. The targeting properties and biodistribution of HA-NPs were studied in apoe-/- mice, which received either fluorescent or radiolabeled HA-NPs and were examined ex vivo by flow cytometry or nuclear techniques. Furthermore, three atherosclerotic rabbits received 89Zr-HA-NPs and were imaged by PET/MRI. The therapeutic effects of HA-NPs were studied in apoe-/- mice, which received weekly doses of 50 mg/kg HA-NPs during a 12-week high-fat diet feeding period. Hydrated HA-NPs were ca. 90 nm in diameter and displayed very stable morphology under hydrolysis conditions. Flow cytometry revealed a 6- to 40-fold higher uptake of Cy7-HA-NPs by aortic macrophages compared to normal tissue macrophages. Interestingly, both local and systemic HA-NP-immune cell interactions significantly decreased over the disease progression. 89Zr-HA-NPs-induced radioactivity in atherosclerotic aortas was 30% higher than in wild-type controls. PET imaging of rabbits revealed 6-fold higher standardized uptake values compared to the muscle. The plaques of HA-NP-treated mice contained 30% fewer macrophages compared to control and free HA-treated group. In conclusion, we show favorable targeting properties of HA-NPs, which can be exploited for PET imaging of atherosclerosis-associated inflammation. Furthermore, we demonstrate the anti-inflammatory effects of HA-NPs in atherosclerosis.
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Affiliation(s)
- Thijs J. Beldman
- Experimental
Vascular Biology, Department of Medical Biochemistry,
and Cellular Imaging, AMC
Core Facility, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands
| | - Max L. Senders
- Experimental
Vascular Biology, Department of Medical Biochemistry,
and Cellular Imaging, AMC
Core Facility, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands
| | - Amr Alaarg
- Department of Radiology, Mount Sinai School of Medicine, New York, New York 10029, United States
- Department
of Biomaterials Science and Technology, MIRA Institute for Biomedical
Technology and Technical Medicine, University
of Twente, Enschede 7522 NB, The Netherlands
| | - Carlos Pérez-Medina
- Department of Radiology, Mount Sinai School of Medicine, New York, New York 10029, United States
| | - Jun Tang
- Department of Radiology, Mount Sinai School of Medicine, New York, New York 10029, United States
- Department of Radiology, Memorial Sloan
Kettering Cancer Center, New York, New York 10065, United States
| | - Yiming Zhao
- Department of Radiology, Mount Sinai School of Medicine, New York, New York 10029, United States
| | - Francois Fay
- Department of Radiology, Mount Sinai School of Medicine, New York, New York 10029, United States
| | - Jacqueline Deichmöller
- Department of Biological Regulation and Department of Chemical Research
Support, Weizmann Institute of Science, Rehovot 7610001, Israel
- Physical Chemistry II, Ruhr-Universität Bochum, Bochum 44801, Germany
| | - Benjamin Born
- Department of Biological Regulation and Department of Chemical Research
Support, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Emilie Desclos
- Experimental
Vascular Biology, Department of Medical Biochemistry,
and Cellular Imaging, AMC
Core Facility, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands
| | - Nicole N. van der Wel
- Experimental
Vascular Biology, Department of Medical Biochemistry,
and Cellular Imaging, AMC
Core Facility, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands
| | - Ron A. Hoebe
- Experimental
Vascular Biology, Department of Medical Biochemistry,
and Cellular Imaging, AMC
Core Facility, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands
| | - Fortune Kohen
- Department of Biological Regulation and Department of Chemical Research
Support, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Elena Kartvelishvily
- Department of Biological Regulation and Department of Chemical Research
Support, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Michal Neeman
- Department of Biological Regulation and Department of Chemical Research
Support, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Thomas Reiner
- Department of Radiology, Memorial Sloan
Kettering Cancer Center, New York, New York 10065, United States
- Department of Radiology, Weill Cornell Medical College, New York, New York 10065, United States
| | - Claudia Calcagno
- Department of Radiology, Mount Sinai School of Medicine, New York, New York 10029, United States
| | - Zahi A. Fayad
- Department of Radiology, Mount Sinai School of Medicine, New York, New York 10029, United States
| | - Menno P. J. de Winther
- Experimental
Vascular Biology, Department of Medical Biochemistry,
and Cellular Imaging, AMC
Core Facility, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands
- Institute for Cardiovascular Prevention, Ludwig Maximilians University, Munich 80336, Germany
| | - Esther Lutgens
- Experimental
Vascular Biology, Department of Medical Biochemistry,
and Cellular Imaging, AMC
Core Facility, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands
- Institute for Cardiovascular Prevention, Ludwig Maximilians University, Munich 80336, Germany
| | - Willem J. M. Mulder
- Experimental
Vascular Biology, Department of Medical Biochemistry,
and Cellular Imaging, AMC
Core Facility, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands
- Department of Radiology, Mount Sinai School of Medicine, New York, New York 10029, United States
| | - Ewelina Kluza
- Experimental
Vascular Biology, Department of Medical Biochemistry,
and Cellular Imaging, AMC
Core Facility, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands
- E-mail: . Tel: +31(0)205665296
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Savarino V, Pace F, Scarpignato C, the Esoxx Study Group. Randomised clinical trial: mucosal protection combined with acid suppression in the treatment of non-erosive reflux disease - efficacy of Esoxx, a hyaluronic acid-chondroitin sulphate based bioadhesive formulation. Aliment Pharmacol Ther 2017; 45:631-642. [PMID: 28116754 PMCID: PMC5347926 DOI: 10.1111/apt.13914] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 10/04/2016] [Accepted: 12/04/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Several studies have shown that patients with non-erosive reflux disease (NERD) are less responsive to proton pump inhibitors (PPIs) than those with erosive disease as they belong to different subgroups, in whom factors other than acid can trigger symptoms. AIM To evaluate whether combined therapy (mucosal protection plus acid suppression) would improve symptom relief compared to PPI treatment alone. METHODS In a multicenter, randomised, double-blind trial, 154 patients with NERD were randomised to receive Esoxx (Alfa Wassermann, Bologna, Italy), a hyaluronic acid-chondroitin sulphate based bioadhesive formulation, or placebo, in addition to acid suppression with standard dose PPIs for 2 weeks. Symptoms (heartburn, acid regurgitation, retrosternal pain and acid taste in the mouth) and health-related quality of life (HRQL) were evaluated before and after treatment. The primary endpoint was the proportion of patients with at least a 3-point reduction in the total symptom score. RESULTS At the end of treatment, the primary endpoint was reached by 52.6% of patients taking Esoxx compared to 32.1% of those given placebo (P < 0.01). The same was true also for HRQL, evaluated by means of the Short Form-36 questionnaire, which improved with both treatments, but some items were significantly better after Esoxx plus PPI therapy. CONCLUSION The synergistic effect of Essox with PPI treatment suggests that mucosal protection added to acid suppression could improve symptoms and HRQL in NERD patients.
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Affiliation(s)
- V. Savarino
- Gastroenterology & Digestive Endoscopy UnitDepartment of Internal MedicineUniversity of GenoaGenovaItaly
| | - F. Pace
- Division of Gastroenterology & Digestive EndoscopyBolognini Teaching HospitalMilanoItaly
| | - C. Scarpignato
- Clinical Pharmacology & Digestive Pathophysiology UnitDepartment of Clinical & Experimental MedicineUniversity of ParmaParmaItaly
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Nestor G, Sandström C. NMR study of hydroxy and amide protons in hyaluronan polymers. Carbohydr Polym 2017; 157:920-928. [DOI: 10.1016/j.carbpol.2016.10.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 10/03/2016] [Accepted: 10/04/2016] [Indexed: 11/26/2022]
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Fu X, Shang W, Wang S, Liu Y, Qu J, Chen X, Wang PG, Fang J. A general strategy for the synthesis of homogeneous hyaluronan conjugates and their biological applications. Chem Commun (Camb) 2017; 53:3555-3558. [DOI: 10.1039/c6cc09431g] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Here, we developed a general strategy for synthesizing homogeneous HA conjugates, and generated homogeneous HA–pNP, HA–biotin, and HA–oroxylin conjugates to investigate the relationships between HA chain length and its diverse biological functions.
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Affiliation(s)
- Xuan Fu
- National Glycoengineering Research Center
- Shandong Provincial Key Laboratory of Glycochemistry and Glycobiology
- Shandong University
- Jinan
- People's Republic of China
| | - Wenjing Shang
- National Glycoengineering Research Center
- Shandong Provincial Key Laboratory of Glycochemistry and Glycobiology
- Shandong University
- Jinan
- People's Republic of China
| | - Shuaishuai Wang
- Department of Chemistry and Center of Diagnostics & Therapeutics
- Georgia State University
- Atlanta
- USA
| | - Yunpeng Liu
- Department of Chemistry and Center of Diagnostics & Therapeutics
- Georgia State University
- Atlanta
- USA
| | - Jingyao Qu
- National Glycoengineering Research Center
- Shandong Provincial Key Laboratory of Glycochemistry and Glycobiology
- Shandong University
- Jinan
- People's Republic of China
| | - Xi Chen
- Department of Chemistry
- University of California
- Davis
- USA
| | - Peng George Wang
- National Glycoengineering Research Center
- Shandong Provincial Key Laboratory of Glycochemistry and Glycobiology
- Shandong University
- Jinan
- People's Republic of China
| | - Junqiang Fang
- National Glycoengineering Research Center
- Shandong Provincial Key Laboratory of Glycochemistry and Glycobiology
- Shandong University
- Jinan
- People's Republic of China
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Li C, Wang LX. Endoglycosidases for the Synthesis of Polysaccharides and Glycoconjugates. Adv Carbohydr Chem Biochem 2016; 73:73-116. [PMID: 27816108 DOI: 10.1016/bs.accb.2016.07.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Recent advances in glycobiology have implicated essential roles of oligosaccharides and glycoconjugates in many important biological recognition processes, including intracellular signaling, cell adhesion, cell differentiation, cancer progression, host-pathogen interactions, and immune responses. A detailed understanding of the biological functions, as well as the development of carbohydrate-based therapeutics, often requires structurally well-defined oligosaccharides and glycoconjugates, which are usually difficult to isolate in pure form from natural sources. To meet with this urgent need, chemical and chemoenzymatic synthesis has become increasingly important as the major means to provide homogeneous compounds for functional glycocomics studies and for drug/vaccine development. Chemoenzymatic synthesis, an approach that combines chemical synthesis and enzymatic manipulations, is often the method of choice for constructing complex oligosaccharides and glycoconjugates that are otherwise difficult to achieve by purely chemical synthesis. Among these, endoglycosidases, a class of glycosidases that hydrolyze internal glycosidic bonds in glycoconjugates and polysaccharides, are emerging as a very attractive class of enzymes for synthetic purposes, due to their transglycosylation activity and their capability of transferring oligosaccharide units en bloc in a single step, in contrast to the limitation of monosaccharide transfers by common glycosyltransferases. In this chapter, we provide an overview on the application of endoglycosidases for the synthesis of complex carbohydrates, including oligosaccharides, polysaccharides, glycoproteins, glycolipids, proteoglycans, and other biologically relevant polysaccharides. The scope, limitation, and future directions of endoglycosidase-catalyzed synthesis are discussed.
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Affiliation(s)
- Chao Li
- University of Maryland, College Park, MD, United States
| | - Lai-Xi Wang
- University of Maryland, College Park, MD, United States
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Pan W, Qin M, Zhang G, Long Y, Ruan W, Pan J, Wu Z, Wan T, Wu C, Xu Y. Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery. Int J Nanomedicine 2016; 11:4037-50. [PMID: 27578973 PMCID: PMC4998035 DOI: 10.2147/ijn.s108545] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Tacrolimus (FK506), an effective immunosuppressant for treating inflammatory skin diseases, hardly penetrates into and through the skin owing to its high hydrophobicity and molecular weight. The aim of this study was to develop a hybrid system based on nicotinamide (NIC) and nanoparticles (NPs) encapsulating FK506, such as FK506–NPs–NIC, for facilitating percutaneous delivery, which exploited virtues of both NIC and NPs to obtain the synergetic effect. Solubility and percutaneous permeation studies were carried out. The results showed that NIC could increase the solubility and permeability of FK506 and that 20% (w/v) NIC presented higher FK506 permeability and was thus chosen as the hydrotropic solution to solubilize FK506 and prepare FK506–NPs–NIC. Hyaluronic acid (HA) was chemically conjugated with cholesterol (Chol) to obtain amphiphilic conjugate of HA–Chol, which self-assembled NPs in 20% NIC solution containing FK506. The particle size, zeta potential, and morphology of NPs were characterized. The encapsulation efficiency and in vitro percutaneous permeation of NPs were evaluated in the presence and absence of NIC. The results demonstrated that hydrotropic solubilizing FK506 was readily encapsulated into NPs with a higher encapsulation efficiency of 79.2%±4.2%, and the combination of NPs with NIC exhibited a significantly synergistic effect on FK506 deposition within the skin (2.39±0.53 μg/cm2) and penetration through the skin (13.38±2.26 μg/cm2). The effect of the combination of NPs with NIC on drug permeation was further visualized by confocal laser scanning microscope through in vivo permeation studies, and the results confirmed that NPs–NIC synergistically enhanced the permeation of the drug into the skin. The cellular uptake performed in HaCaT cells presented a promoting effect of NPs on cellular uptake. These overall results demonstrated that HA–Chol–NPs–NIC can synergistically improve the percutaneous delivery of FK506, and it is a novel potential strategy based on a nano-sized carrier for FK506 to treat skin diseases.
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Affiliation(s)
- Wenhui Pan
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Mengyao Qin
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Guoguang Zhang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Yueming Long
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Wenyi Ruan
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jingtong Pan
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Zushuai Wu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Tao Wan
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Chuanbin Wu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Yuehong Xu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
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Mende M, Bednarek C, Wawryszyn M, Sauter P, Biskup MB, Schepers U, Bräse S. Chemical Synthesis of Glycosaminoglycans. Chem Rev 2016; 116:8193-255. [DOI: 10.1021/acs.chemrev.6b00010] [Citation(s) in RCA: 190] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Marco Mende
- Institute
of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany
| | - Christin Bednarek
- Institute
of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany
| | - Mirella Wawryszyn
- Institute
of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany
| | - Paul Sauter
- Institute
of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany
| | - Moritz B. Biskup
- Division
2—Informatics, Economics and Society, Karlsruhe Institute of Technology (KIT), Kaiserstraße 12, D-76131 Karlsruhe, Germany
| | - Ute Schepers
- Institute
of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, D-76344 Eggenstein-Leopoldshafen, Germany
| | - Stefan Bräse
- Institute
of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany
- Institute
of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, D-76344 Eggenstein-Leopoldshafen, Germany
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Arnal-Pastor M, Tallà Ferrer C, Herrero Herrero M, Martínez-Gómez Aldaraví A, Monleón Pradas M, Vallés-Lluch A. Scaffolds based on hyaluronan and carbon nanotubes gels. J Biomater Appl 2016; 31:534-543. [DOI: 10.1177/0885328216644535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Physico-chemical and mechanical properties of hyaluronic acid/carbon nanotubes nanohybrids have been correlated with the proportion of inorganic nanophase and the preparation procedure. The mass fraction of -COOH functionalized carbon nanotubes was varied from 0 to 0.05. Hyaluronic acid was crosslinked with divinyl sulfone to improve its stability in aqueous media and allow its handling as a hydrogel. A series of samples was dried by lyophilization to obtain porous scaffolds whereas another was room-dried allowing the collapse of the hybrid structures. The porosity of the former, together with the tighter packing of hyaluronic acid chains, results in a lower water absorption and lower mechanical properties in the swollen state, because of the easier water diffusion. The presence of even a small amount of carbon nanotubes (mass fraction of 0.05) limits even more the swelling of the matrix, owing probably to hybrid interactions. These nanohybrids do not seem to degrade significantly during 14 days in water or enzymatic medium.
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Affiliation(s)
- M Arnal-Pastor
- Centre for Biomaterials and Tissue Engineering, Universitat Politècnica de València, Spain
| | - C Tallà Ferrer
- Centre for Biomaterials and Tissue Engineering, Universitat Politècnica de València, Spain
| | - M Herrero Herrero
- Centre for Biomaterials and Tissue Engineering, Universitat Politècnica de València, Spain
| | | | - M Monleón Pradas
- Centre for Biomaterials and Tissue Engineering, Universitat Politècnica de València, Spain
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, Valencia, Spain
| | - A Vallés-Lluch
- Centre for Biomaterials and Tissue Engineering, Universitat Politècnica de València, Spain
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The Importance of CD44 as a Stem Cell Biomarker and Therapeutic Target in Cancer. Stem Cells Int 2016; 2016:2087204. [PMID: 27200096 PMCID: PMC4856920 DOI: 10.1155/2016/2087204] [Citation(s) in RCA: 197] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Accepted: 03/27/2016] [Indexed: 02/07/2023] Open
Abstract
CD44 is a cell surface HA-binding glycoprotein that is overexpressed to some extent by almost all tumors of epithelial origin and plays an important role in tumor initiation and metastasis. CD44 is a compelling marker for cancer stem cells of many solid malignancies. In addition, interaction of HA and CD44 promotes EGFR-mediated pathways, consequently leading to tumor cell growth, tumor cell migration, and chemotherapy resistance in solid cancers. Accumulating evidence indicates that major HA-CD44 signaling pathways involve a specific variant of CD44 isoforms; however, the particular variant almost certainly depends on the type of tumor cell and the stage of the cancer progression. Research to date suggests use of monoclonal antibodies against different CD44 variant isoforms and targeted inhibition of HA/CD44-mediated signaling combined with conventional radio/chemotherapy may be the most favorable therapeutic strategy for future treatments of advanced stage malignancies. Thus, this paper briefly focuses on the association of the major CD44 variant isoforms in cancer progression, the role of HA-CD44 interaction in oncogenic pathways, and strategies to target CD44-overexpressed tumor cells.
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Chen KL, Yeh YY, Lung J, Yang YC, Yuan K. Mineralization Effect of Hyaluronan on Dental Pulp Cells via CD44. J Endod 2016; 42:711-6. [PMID: 26975415 DOI: 10.1016/j.joen.2016.01.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Revised: 01/13/2016] [Accepted: 01/15/2016] [Indexed: 12/25/2022]
Abstract
INTRODUCTION CD44 is a cell-surface glycoprotein involved in various cellular functions. Recent studies have suggested that CD44 is involved in early mineralization of odontoblasts. Hyaluronic acid (HA) is the principal ligand for receptor CD44. Whether and how HA regulated the mineralization process of dental pulp cells were investigated. METHODS The effects of high-molecular-weight HA on differentiation and mineral deposition of dental pulp cells were tested by using alkaline phosphatase (ALP) activity assay and alizarin red S staining. Osteogenesis real-time polymerase chain reaction array, quantitative polymerase chain reaction, and Western blotting were performed to identify downstream molecules involved in the mineralization induction of HA. CD44 was knocked down and examined to confirm whether the mineralization effect of HA was mediated by receptor CD44. Immunohistochemistry was used to understand the localization patterns of CD44 and the identified downstream proteins in vivo. RESULTS Pulse treatment of HA enhanced ALP activity and mineral deposition in dental pulp cells. Tissue-nonspecific ALP, bone morphogenetic protein 7 (BMP7), and type XV collagen (Col15A1) were upregulated via the HA-CD44 pathway in vitro. Immunohistochemistry of tooth sections showed that the staining pattern of BMP7 was very similar to that of CD44. CONCLUSIONS Results of this study indicated that high-molecular-weight HA enhanced early mineralization of dental pulp cells mediated via CD44. The process involved important mineralization-associated molecules including tissue-nonspecific ALP, BMP7, and Col15A1. The findings may help develop new strategies in regenerative endodontics.
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Affiliation(s)
- Kuan-Liang Chen
- Department of Endodontics, ChiMei Medical Center, Tainan, Taiwan; Department of Dental Laboratory Technology, Min-Hwei College of Healthcare Management, Tainan, Taiwan
| | - Ying-Yi Yeh
- Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jrhau Lung
- Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yu-Chi Yang
- Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kuo Yuan
- Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Stomatology, National Cheng Kung University Hospital, Tainan, Taiwan.
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Yuan F, Lin LX, Zhang HH, Huang D, Sun YL. Effect of carbodiimide-derivatized hyaluronic acid gelatin on preventing postsurgical intra-abdominal adhesion formation and promoting healing in a rat model. J Biomed Mater Res A 2016; 104:1175-81. [DOI: 10.1002/jbm.a.35653] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Revised: 12/22/2015] [Accepted: 01/08/2016] [Indexed: 12/27/2022]
Affiliation(s)
- Fang Yuan
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences; Shenzhen Guangdong 518055 China
| | - Long-Xiang Lin
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences; Shenzhen Guangdong 518055 China
| | - Hui-Hui Zhang
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences; Shenzhen Guangdong 518055 China
| | - Dan Huang
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences; Shenzhen Guangdong 518055 China
| | - Yu-Long Sun
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences; Shenzhen Guangdong 518055 China
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Jadhav S, Käkelä M, Mäkilä J, Kiugel M, Liljenbäck H, Virta J, Poijärvi-Virta P, Laitala-Leinonen T, Kytö V, Jalkanen S, Saraste A, Roivainen A, Lönnberg H, Virta P. Synthesis and In Vivo PET Imaging of Hyaluronan Conjugates of Oligonucleotides. Bioconjug Chem 2015; 27:391-403. [PMID: 26517303 DOI: 10.1021/acs.bioconjchem.5b00477] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Synthesis for (68)Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-chelated oligonucleotide hyaluronan (HA) tetra- and hexasaccharide conjugates is described. A solid-supported technique is used to introduce NOTA-chelator into the 3'-terminus of oligonucleotides and a copper-free strain promoted azide alkyne cycloaddition (SPAAC) to HA/oligonucleotide conjugation. Protecting group manipulation, required for the HA-moieties, is carried out after the SPAAC-conjugation. Positron emission tomography (PET) is used (1) in the whole-body distribution kinetic studies of the conjugates in healthy rats and (2) to show the potential of hyaluronan-induced targeting of oligonucleotides into the infarcted area of rats with myocardial infarction.
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Affiliation(s)
- Satish Jadhav
- Department of Chemistry, University of Turku , FI-20014 Turku, Finland
| | | | | | | | | | | | | | | | | | | | | | | | - Harri Lönnberg
- Department of Chemistry, University of Turku , FI-20014 Turku, Finland
| | - Pasi Virta
- Department of Chemistry, University of Turku , FI-20014 Turku, Finland
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44
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Utilization of Glycosaminoglycans/Proteoglycans as Carriers for Targeted Therapy Delivery. Int J Cell Biol 2015; 2015:537560. [PMID: 26448753 PMCID: PMC4581573 DOI: 10.1155/2015/537560] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Revised: 01/19/2015] [Accepted: 02/15/2015] [Indexed: 02/07/2023] Open
Abstract
The outcome of patients with cancer has improved significantly in the past decade with the incorporation of drugs targeting cell surface adhesive receptors, receptor tyrosine kinases, and modulation of several molecules of extracellular matrices (ECMs), the complex composite of collagens, glycoproteins, proteoglycans, and glycosaminoglycans that dictates tissue architecture. Cancer tissue invasive processes progress by various oncogenic strategies, including interfering with ECM molecules and their interactions with invasive cells. In this review, we describe how the ECM components, proteoglycans and glycosaminoglycans, influence tumor cell signaling. In particular this review describes how the glycosaminoglycan hyaluronan (HA) and its major receptor CD44 impact invasive behavior of tumor cells, and provides useful insight when designing new therapeutic strategies in the treatment of cancer.
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Tokatlian T, Cam C, Segura T. Porous hyaluronic acid hydrogels for localized nonviral DNA delivery in a diabetic wound healing model. Adv Healthc Mater 2015; 4:1084-91. [PMID: 25694196 DOI: 10.1002/adhm.201400783] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Revised: 01/18/2015] [Indexed: 01/08/2023]
Abstract
The treatment of impaired wounds requires the use of biomaterials that can provide mechanical and biological queues to the surrounding environment to promote angiogenesis, granulation tissue formation, and wound closure. Porous hydrogels show promotion of angiogenesis, even in the absence of proangiogenic factors. It is hypothesized that the added delivery of nonviral DNA encoding for proangiogenic growth factors can further enhance this effect. Here, 100 and 60 μm porous and nonporous (n-pore) hyaluronic acid-MMP hydrogels with encapsulated reporter (pGFPluc) or proangiogenic (pVEGF) plasmids are used to investigate scaffold-mediated gene delivery for local gene therapy in a diabetic wound healing mouse model. Porous hydrogels allow for significantly faster wound closure compared with n-pore hydrogels, which do not degrade and essentially provide a mechanical barrier to closure. Interestingly, the delivery of pDNA/PEI polyplexes positively promotes granulation tissue formation even when the DNA does not encode for an angiogenic protein. And although transfected cells are present throughout the granulation tissue surrounding, all hydrogels at 2 weeks, pVEGF delivery does not further enhance the angiogenic response. Despite this, the presence of transfected cells shows promise for the use of polyplex-loaded porous hydrogels for local gene delivery in the treatment of diabetic wounds.
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Affiliation(s)
- Talar Tokatlian
- Department of Chemical and Biomolecular Engineering; University of California, Los Angeles; 5531 Boelter Hall, 420 Westwood Plaza Los Angeles CA 90095-1592 USA
| | - Cynthia Cam
- Department of Bioengineering; University of California, Los Angeles; 5531 Boelter Hall, 420 Westwood Plaza Los Angeles CA 90095-1592 USA
| | - Tatiana Segura
- Department of Chemical and Biomolecular Engineering; University of California, Los Angeles; 5531 Boelter Hall, 420 Westwood Plaza Los Angeles CA 90095-1592 USA
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Witting M, Boreham A, Brodwolf R, Vávrová K, Alexiev U, Friess W, Hedtrich S. Interactions of hyaluronic Acid with the skin and implications for the dermal delivery of biomacromolecules. Mol Pharm 2015; 12:1391-401. [PMID: 25871518 DOI: 10.1021/mp500676e] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Hyaluronic acid (HA) hydrogels are interesting delivery systems for topical applications. Besides moisturizing the skin and improving wound healing, HA facilitates topical drug absorption and is highly compatible with labile biomacromolecules. Hence, in this study we investigated the influence of HA hydrogels with different molecular weights (5 kDa, 100 kDa, 1 MDa) on the skin absorption of the model protein bovine serum albumin (BSA) using fluorescence lifetime imaging microscopy (FLIM). To elucidate the interactions of HA with the stratum corneum and the skin absorption of HA itself, we combined FLIM and Fourier-transform infrared (FTIR) spectroscopy. Our results revealed distinct formulation and skin-dependent effects. In barrier deficient (tape-stripped) skin, BSA alone penetrated into dermal layers. When BSA and HA were applied together, however, penetration was restricted to the epidermis. In normal skin, penetration enhancement of BSA into the epidermis was observed when applying low molecular weight HA (5 kDa). Fluorescence resonance energy transfer analysis indicated close interactions between HA and BSA under these conditions. FTIR spectroscopic analysis of HA interactions with stratum corneum constituents showed an α-helix to β-sheet interconversion of keratin in the stratum corneum, increased skin hydration, and intense interactions between 100 kDa HA and the skin lipids resulting in a more disordered arrangement of the latter. In conclusion, HA hydrogels restricted the delivery of biomacromolecules to the stratum corneum and viable epidermis in barrier deficient skin, and therefore seem to be potential topical drug vehicles. In contrast, HA acted as an enhancer for delivery in normal skin, probably mediated by a combination of cotransport, increased skin hydration, and modifications of the stratum corneum properties.
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Affiliation(s)
- Madeleine Witting
- †Department of Pharmaceutical Sciences, Ludwig-Maximilians-Universität, Munich, Germany
| | - Alexander Boreham
- ‡Department of Physics, Institute of Experimental Physics, Freie Universität Berlin, Berlin, Germany
| | - Robert Brodwolf
- ‡Department of Physics, Institute of Experimental Physics, Freie Universität Berlin, Berlin, Germany
| | - Kateřina Vávrová
- §Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Ulrike Alexiev
- ‡Department of Physics, Institute of Experimental Physics, Freie Universität Berlin, Berlin, Germany
| | - Wolfgang Friess
- †Department of Pharmaceutical Sciences, Ludwig-Maximilians-Universität, Munich, Germany
| | - Sarah Hedtrich
- †Department of Pharmaceutical Sciences, Ludwig-Maximilians-Universität, Munich, Germany.,∥Institute for Pharmaceutical Sciences, Freie Universität Berlin, Berlin, Germany
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Abstract
Vascular integrity or the maintenance of blood vessel continuity is a fundamental process regulated by endothelial cell-cell junctions. Defects in endothelial barrier function are an initiating factor in several disease processes including tumor angiogenesis and metastasis. The glycosaminoglycan, hyaluronan (HA), maintains vascular integrity through specific mechanisms including HA-binding protein signaling in caveolin-enriched microdomains, a subset of lipid rafts. Certain disease states, including cancer, increase enzymatic hyaluronidase activity and reactive oxygen species generation, which break down high molecular weight HA (HMW-HA) to low molecular weight fragments (LMW-HA). LMW-HA can activate specific HA-binding proteins during tumor progression to promote disruption of endothelial cell-cell contacts. In contrast, exogenous administration of HMW-HA promotes enhancement of vascular integrity. This review focuses on the roles of HA in regulating angiogenic and metastatic processes based on its size and the HA-binding proteins present. Further, potential therapeutic applications of HMW-HA in treating cancer are discussed.
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Affiliation(s)
- Patrick A Singleton
- Department of Medicine, Section of Pulmonary and Critical Care, Chicago, Illinois, USA; Department of Anesthesia and Critical Care, The University of Chicago, Chicago, Illinois, USA.
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Korogiannaki M, Guidi G, Jones L, Sheardown H. Timolol maleate release from hyaluronic acid-containing model silicone hydrogel contact lens materials. J Biomater Appl 2015; 30:361-76. [PMID: 25887216 DOI: 10.1177/0885328215581507] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
This study was designed to assess the impact of a releasable wetting agent, such as hyaluronic acid (HA), on the release profile of timolol maleate (TM) from model silicone hydrogel contact lens materials. Polyvinylpyrrolidone (PVP) was used as an alternative wetting agent for comparison. The model lenses consisted of a hydrophilic monomer, either 2-hydroxyethyl methacrylate or N,N-dimethylacrylamide and a hydrophobic silicone monomer of methacryloxypropyltris (trimethylsiloxy) silane. The loading of the wetting and the therapeutic agent occurred during the synthesis of the silicone hydrogels through the method of direct entrapment. The developed materials were characterized by minimal changes in the water uptake, while lower molecular weight of HA improved their surface wettability. The transparency of the examined silicone hydrogels was found to be affected by the miscibility of the wetting agent in the prepolymer mixture as well as the composition of the developed silicone hydrogels. Sustained release of TM from 4 to 14 days was observed, with the drug transport occurring presumably through the hydrophilic domains of the silicone hydrogels. The release profile was strongly dependent on the hydrophilic monomer composition, the distribution of hydrophobic (silane) domains, and the affinity of the therapeutic agent for the silicone hydrogel matrix. Noncovalent entrapment of the wetting agent did not change the in vitro release duration and kinetics of TM, however the drug release profile was found to be controlled by the simultaneous release of TM and HA or PVP. In the case of HA, depending on the HA:drug ratio, the release rate was decreased and controlled by the release of HA, likely due to electrostatic interactions between protonated TM and anionic HA. Overall, partitioning of the drug within the hydrophilic domains of the silicone hydrogels as well as interactions with the wetting agent determined the drug release profile.
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Affiliation(s)
- Myrto Korogiannaki
- Department of Chemical Engineering, McMaster University, Hamilton, ON, Canada
| | - Giuliano Guidi
- Department of Chemical Engineering, McMaster University, Hamilton, ON, Canada
| | - Lyndon Jones
- Department of Chemical Engineering, McMaster University, Hamilton, ON, Canada School of Optometry and Vision Science, University of Waterloo, Waterloo, ON, Canada
| | - Heather Sheardown
- Department of Chemical Engineering, McMaster University, Hamilton, ON, Canada School of Optometry and Vision Science, University of Waterloo, Waterloo, ON, Canada
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Cross D, Jiang X, Ji W, Han W, Wang C. Injectable Hybrid Hydrogels of Hyaluronic Acid Crosslinked by Well-Defined Synthetic Polycations: Preparation and Characterization In Vitro and In Vivo. Macromol Biosci 2015; 15:668-81. [DOI: 10.1002/mabi.201400491] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Revised: 12/31/2014] [Indexed: 11/06/2022]
Affiliation(s)
- Daisy Cross
- Department of Biomedical Engineering; University of Minnesota; 7-105 Hasselmo Hall, 312 Church Street S. E. Minneapolis Minnesota 55455 USA
| | - Xiaoze Jiang
- Department of Biomedical Engineering; University of Minnesota; 7-105 Hasselmo Hall, 312 Church Street S. E. Minneapolis Minnesota 55455 USA
| | - Weihang Ji
- Department of Biomedical Engineering; University of Minnesota; 7-105 Hasselmo Hall, 312 Church Street S. E. Minneapolis Minnesota 55455 USA
| | - Wenqing Han
- Department of Biomedical Engineering; University of Minnesota; 7-105 Hasselmo Hall, 312 Church Street S. E. Minneapolis Minnesota 55455 USA
| | - Chun Wang
- Department of Biomedical Engineering; University of Minnesota; 7-105 Hasselmo Hall, 312 Church Street S. E. Minneapolis Minnesota 55455 USA
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Liu J, Willför S, Xu C. A review of bioactive plant polysaccharides: Biological activities, functionalization, and biomedical applications. ACTA ACUST UNITED AC 2015. [DOI: 10.1016/j.bcdf.2014.12.001] [Citation(s) in RCA: 334] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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