Search Results (33)

Despite extensive research on fascial mechanobiology, no unified mechanotransduction framework has been established to explain how mechanical forces translate into adaptive cellular responses in fascial tissue. This narrative review synthesizes evidence from mesenchymal cell and fibroblast research to propose the Ca²⁺–Hyaluronan (CHA) axis as a comprehensive mechanotransduction feedback loop for fascia phenomenology. The CHA framework describes how mechanical stress activates Ca²⁺ channels (Piezo1, TRPV4, P2Y2), triggering HAS2-mediated hyaluronan (HA) synthesis. The molecular weight of synthesized HA then determines receptor signaling outcomes: high-molecular-weight HA binds CD44 to promote tissue stability and quiescence, while low-molecular-weight HA fragments activate RHAMM to drive remodeling and repair—a dynamic oscillation termed “Quiet or Riot.” Three key conclusions emerge: First, the CHA framework is well supported by existing literature on mesenchymal cells, providing a testable model for fascial mechanobiology. Second, HA molecular weight dynamics and CD44/RHAMM oscillation have direct implications for optimizing movement, manual therapy, and rehabilitative interventions. Third, while HA-CD44/RHAMM signaling is broadly implicated in tissue remodeling, Ca²⁺-dependent regulatory mechanisms specific to fasciacytes require experimental validation. A critical translational gap remains: the absence of quantitative mechanical thresholds distinguishing beneficial from pathological loading limits clinical application. Future research should employ 3D matrix models, live imaging, receptor manipulation, and omics profiling to establish these thresholds and validate the CHA framework in fasciacytes. Understanding fascial mechanotransduction through the CHA loop may transform approaches to movement prescription, manual therapy, and treatment of fascial dysfunction. Full article

Hyaluronic acid (HA) is a ubiquitous glycosaminoglycan essential for maintaining tissue hydration, structural integrity, and immunological homeostasis in vertebrates. Although traditionally regarded as a host-derived molecule, HA is also produced by a range of microorganisms, most notably Streptococcus spp., through specialized hyaluronan synthases (HAS). Microbial HA and host-derived HA fragments play key roles not only in tissue physiology but also in infection biology, influencing microbial virulence, biofilm formation, and immune evasion. In bacteria, HA-rich capsules promote adhesion, shield pathogens from complement-mediated opsonization and phagocytosis, and facilitate dissemination through host tissues. Conversely, HA-degrading enzymes and reactive oxygen species generate low-molecular-weight HA fragments that amplify inflammation by activating—toll-like receptor 2 (TLR2)/toll-like receptor 4 (TLR4) signaling, contributing to chronic inflammatory states. Furthermore, microbial HA modulates biofilm organization in both bacterial and fungal pathogens, enhancing persistence and antimicrobial tolerance. Clinically, widespread use of HA-based dermal fillers has generated increasing concern over delayed biofilm-associated infections, diagnostic challenges, and complications arising from microbial contamination and host–microbe interactions. Recent advances in HA engineering, including anti-microbial HA conjugates and receptor-targeted biomaterials, offer promising strategies to mitigate infection risk while expanding therapeutic applications. This review synthesizes current knowledge on HA biosynthesis across biological kingdoms, its dualistic role in health and disease, and its emerging relevance at the interface of microbiology, immunology, and biomedical applications. Full article

Hyaluronic acid (HA) is a major glycosaminoglycan in the hepatic extracellular matrix and pericellular space, playing a critical role in maintaining liver architecture and regulating cell–matrix interactions. In chronic liver disease, regardless of etiology, dysregulated HA metabolism, particularly the generation and accumulation of low-molecular-weight HA (LMW-HA), has been implicated in fibrogenesis, immune dysregulation, and hepatocellular carcinogenesis via receptor-mediated pathways involving lymphocyte homing receptor (CD44), receptor for hyaluronan-mediated motility (RHAMM), and Toll-like receptors (TLRs). This review synthesizes current evidence on HA biosynthesis, turnover, and signaling, emphasizing its dual role as a structural scaffold and as an active modulator of immune responses and tumor progression in chronic liver disease. Given the rising global burden of metabolic liver disease, and in line with our recent findings that small HA fragments are elevated in obesity and promote low-grade, TLR-dependent activation of innate immune cells, we emphasize metabolic dysfunction-associated steatotic liver disease (MASLD) as a highly prevalent and clinically relevant setting to examine HA-driven immunomodulation during progression to advanced fibrosis and hepatocellular carcinoma (HCC) and to consider therapeutic strategies targeting HA synthesis, turnover, or receptor signaling. Full article

YKL-40 is a chitinase-like glycoprotein implicated in various pathological processes, yet its glycosaminoglycan (GAG) binding profile beyond heparin has not been examined. In this study, we performed a Microscale Thermophoresis (MST) analysis on the heparin-binding glycoprotein YKL-40 using low molecular weight GAG oligosaccharides. We identified two new GAG ligands, dermatan sulfate (DS) and hyaluronan (HA), while chondroitin sulfate (CS) showed no detectable binding affinity. The results show that heparin is bound with the strongest affinity, followed by DS and HA. To further investigate these differences, molecular docking was used to evaluate possible binding modes. Molecular docking results indicated that both heparin and DS interacted with the same site on YKL-40, the heparin-binding site at residues 143–149, suggesting a multifunctional binding region that may act as a competitive switch or integration hub for spatially regulated signaling. Together, these findings expand the known ligand profile of YKL-40 and offer new insights into its ECM-context-dependent roles, with implications for targeting YKL-40 in diseases involving chronic inflammation, fibrosis, and cancer progression. Full article

Hyaluronan (HA), a high-molecular-weight polysaccharide naturally found in vertebrate tissues such as skin, joints, and the vitreous body, plays a critical role in various biological processes. Its functionality is highly dependent on molecular weight, with high-molecular-weight HA exhibiting anti-inflammatory and immunosuppressive effects, while low-molecular-weight HA promotes inflammation, immunostimulation, and angiogenesis. Due to its biocompatibility, biodegradability, and tunable properties, HA has gained increasing attention in biomedical applications. This review summarizes recent advances in the encapsulation of HA with other polymers and therapeutic agents in nanosystems, particularly hydrogels and nanoparticles. HA-based formulations demonstrate improved therapeutic outcomes, including drug release sustained up to 7 days, wound closure rates exceeding 90% in animal models, particle size in the range of 50–300 nm, and enhanced bioavailability of encapsulated drugs by 2–3 fold compared with free drugs. Such properties have shown promise in enhancing therapeutic efficacy and targeted drug delivery in the treatment of skin wound healing, diabetes, osteoarthritis, rheumatoid arthritis, and ophthalmic diseases. The review emphasizes how HA’s modifications and composite systems optimize drug release profiles and biological interactions, thereby contributing to the development of next-generation biomedical therapies. Full article

Salvia haenkei (SH-Haenkenium^®), a native plant of Bolivia, is known as strong inhibitor of senescence and recently exploited in wound healing and for its potential anti-inflammatory properties. Hyaluronan at high and low molecular weight (HCC), explored in diverse cell models, and recently used in clinical practice, showed beneficial effects in dermo aesthetic and regenerative injective treatments. In this research work a novel formulation based on HCC coupled SH was tested for its potentiality in counteracting dermal injury. In vitro wound healing has been used to demonstrate HCC + SH capacity to improve keratinocytes migration respects the sole HCC, supported also by positive modulation of remodeling and integrity biomarkers. In addition, an in vitro dehydration test showed its ability to defend the skin from dryness. Moreover, an in vitro inflammation model (with lipopolysaccharides derived from E. coli) was used to assess molecular fingerprint of the pathological model and compare the cell response after treatments. Inflammatory biomarkers (e.g., KRT6, TLR-4 and NF-κB) and specific cytokines (e.g., IL-6, IL-22, IL-23) proved the effect of HCC + SH, in reducing inflammatory mediators. A more complex model, 3D-FT skin, was used to better resemble an in vivo condition, and confirmed the efficacy of novel formulations to counteract inflammation. All results trigger the interest in the novel formulation based on SH extract and hyaluronan complexes for its potential efficacy as natural anti-inflammatory agent for damaged skin, for its healing and regenerative properties. Full article

Wound healing incurs various challenges, making it an important topic in medicine. Short-chain peptides from fish protein hydrolysates possess wound healing properties that may represent a solution. In this study, perch hydrolysates were produced from perch side steams using a designed commercial complex enzyme via a proprietary pressure extraction technique. The average molecular weight of the perch peptides was 1289 kDa, and 62.60% of the peptides had a low molecular weight (≤1 kDa). Similarly to the beneficial amino acid sequence FPSIVGRP, FPSLVRGP accounted for 6.21% abundance may have a potential antihypertensive effect. The concentrations of collagen composition and branched-chain amino acids were 1183 and 1122 mg/100 g, respectively. In a fibroblast model, active perch peptides accelerated wound healing mainly by increasing the secretion of procollagen I, fibronectin, and hyaluronan. In an SD rat model established to mimic human wounds, orally administered perch hydrolysates with a molecular weight below 2.3 kDa accelerated wound healing, which mainly resulted from collagen-forming amino acids, branched-chain amino acids, and matrikine. Collectively, the residue of perch extract can be upcycled via a hydrolysis technique to produce not only bioactive sequences but also short-chain peptides. Considering the therapeutic potential to promote wound healing, such by-products are of great value and may be developed as dietary nutraceuticals. Full article

Hyaluronan (HA) levels are dynamically regulated homeostatically through biosynthesis and degradation. HA homeostasis is often perturbed under disease conditions. HA degradation products are thought to contribute to disease pathology. The hyaluronidase CEMIP requires the presence of living cells for its HA depolymerizing activity. CEMIP is overexpressed in a variety of pathological conditions, and the inhibition of its hyaluronidase activity therefore has therapeutic potential. To identify novel inhibitors of the CEMIP hyaluronidase activity, we established here a cell-compatible, medium-throughput assay for CEMIP-dependent HA depolymerization. The assay employs ultrafiltration plates to separate low- from high-molecular-weight HA, followed by quantification of HA fragments using an HA ELISA-like assay. Using this assay, we tested a range of compounds that have been reported to inhibit other hyaluronidases. Thereby, we identified several sulfated hydrocarbon polymers that inhibit CEMIP more potently than other hyaluronidases. One of these is heparin, a sulfated glycosaminoglycan produced by mast cells that constitutes the first described physiological CEMIP inhibitor. The most potent inhibitor (IC₅₀ of 1.8 nM) is dextran sulfate, a synthetic sulfated polysaccharide. Heparin and dextran sulfate are used in numerous established and experimental biomedical applications. Their ability to inhibit CEMIP needs to be taken into account in these contexts. Full article

Hyaluronic acid (HA) is a remarkably multifaceted biomacromolecule, playing a role in regulating myriad biological processes such as wound healing, tissue regeneration, anti-inflammation, and immunomodulation. Crosslinked high- and low-molecular-weight hyaluronic acid hydrogels achieve higher molar concentrations, display slower degradation, and allow optimal tissue product diffusion, while harnessing the synergistic contribution of different-molecular-weight hyaluronans. A recent innovation in the world of hyaluronic acid synthesis is represented by NAHYCO^® Hybrid Technology, a thermal process leading to hybrid cooperative hyaluronic acid complexes (HCC). This review summarizes the current literature on the in vitro studies and in vivo applications of HCC, from facial and body rejuvenation to future perspectives in skin wound healing, dermatology, and genitourinary pathologies. Full article

Cells and extracts derived from adipose tissue are gaining increasing attention not only in plastic surgery and for aesthetic purposes but also in regenerative medicine. The ability of hyaluronan (HA) to support human adipose stromal cell (hASC) viability and differentiation has been investigated. However, the compatibility of adipose tissue with HA-based formulation in terms of biophysical and rheological properties has not been fully addressed, although it is a key feature for tissue integration and in vivo performance. In this study, the biophysical and biochemical properties of highly concentrated (45 mg/mL) high/low-molecular-weight HA hybrid cooperative complex were assessed with a further focus on the potential application in adipose tissue augmentation/regeneration. Specifically, HA hybrid complex rheological behavior was observed in combination with different adipose tissue ratios, and hyaluronidase-catalyzed degradation was compared to that of a high-molecular-weight HA (HHA). Moreover, the HA hybrid complex’s ability to induce in vitro hASCs differentiation towards adipose phenotype was evaluated in comparison to HHA, performing Oil Red O staining and analyzing gene/protein expression of PPAR-γ, adiponectin, and leptin. Both treatments supported hASCs differentiation, with the HA hybrid complex showing better results. These outcomes may open new frontiers in regenerative medicine, supporting the injection of highly concentrated hybrid formulations in fat compartments, eventually enhancing residing staminal cell differentiation and improving cell/growth factor persistence towards tissue regeneration districts. Full article

It has been reported that hyaluronic acid (HA) with a 35 kDa molecular weight (HA35) acts biologically to protect tissue from injury, but its biological properties are not yet fully characterized. This study aimed to evaluate the cellular effects and biodistribution of HA35 compared to HA with a 1600 kDa molecular weight (HA1600). We assessed the effects of HA35 and HA1600 on cell migration, NO and ROS generation, and gene expression in cultured macrophages, microglia, and lymphocytes. HA35 was separately radiolabeled with ^99mTc and ¹²⁵I and administered to C57BL/6J mice for in vivo biodistribution imaging. In vitro studies indicated that HA35 and HA1600 similarly enhanced cell migration through HA receptor binding mechanisms, reduced the generation of NO and ROS, and upregulated gene expression profiles related to cell signaling pathways in immune cells. HA35 showed a more pronounced effect in regulating a broader range of genes in macrophages and microglia than HA1600. Upon intradermal or intravenous administration, radiolabeled HA35 rapidly accumulated in the liver, spleen, and lymph nodes. In conclusion, HA35 not only exhibits effects on cellular bioactivity comparable to those of HA1600 but also exerts biological effects on a broader range of immune cell gene expression. The findings herein offer valuable insights for further research into the therapeutic potential of HA35 in inflammation-mediated tissue injury. Full article

Macrophages are a highly versatile and heterogenic group of immune cells, known for their involvement in inflammatory reactions. However, our knowledge about distinct subpopulations of macrophages and their specific contribution to the resolution of inflammation remains incomplete. We have previously shown, in an in vivo peritonitis model, that inhibition of the synthesis of the pro-inflammatory lipid mediator prostaglandin E₂ (PGE₂) attenuates efficient resolution of inflammation. PGE₂ levels during later stages of the inflammatory process further correlate with expression of the hyaluronan (HA) receptor Lyve1 in peritoneal macrophages. In the present study, we therefore aimed to understand if PGE₂ might contribute to the regulation of Lyve1 and how this might impact inflammatory responses. In line with our in vivo findings, PGE₂ synergized with dexamethasone to enhance Lyve1 expression in bone marrow-derived macrophages, while expression of the predominant hyaluronan receptor CD44 remained unaltered. PGE₂-mediated Lyve1 upregulation was strictly dependent on PGE₂ receptor EP2 signaling. While PGE₂/dexamethasone-treated macrophages, despite their enhanced Lyve1 expression, did not show inflammatory responses upon stimulation with low (LMW) or high-molecular-weight hyaluronan (HMW)-HA, they were sensitized towards LMW-HA-dependent augmentation of lipopolysaccharide (LPS)-induced inflammatory responses. Thus, Lyve1-expressing macrophages emerged as a subpopulation of macrophages integrating inflammatory stimuli with extracellular matrix-derived signals. Full article

Radiation-induced skin injury (RISI) is a frequent and severe complication with a complex pathogenesis that often occurs during radiation therapy, nuclear incidents, and nuclear war, for which there is no effective treatment. Hyaluronan (HA) plays an overwhelming role in the skin, and it has been shown that UVB irradiation induces increased HA expression. Nevertheless, to the best of our knowledge, there has been no study regarding the biological correlation between RISI and HA degradation and its underlying mechanisms. Therefore, in our study, we investigated low-molecular-weight HA content using an enzyme-linked immunosorbent assay and changes in the expression of HA-related metabolic enzymes using real-time quantitative polymerase chain reaction and a Western blotting assay. The oxidative stress level of the RISI model was assessed using sodium dismutase, malondialdehyde, and reactive oxygen species assays. We demonstrated that low-molecular-weight HA content was significantly upregulated in skin tissues during the late phase of irradiation exposure in the RISI model and that HA-related metabolic enzymes, oxidative stress levels, the MEK5/ERK5 pathway, and inflammatory factors were consistent with changes in low-molecular-weight HA content. These findings prove that HA degradation is biologically relevant to RISI development and that the HA degradation mechanisms are related to HA-related metabolic enzymes, oxidative stress, and inflammatory factors. The MEK5/ERK5 pathway represents a potential mechanism of HA degradation. In conclusion, we aimed to investigate changes in HA content and preliminarily investigate the HA degradation mechanism in a RISI model under γ-ray irradiation, to consider HA as a new target for RISI and provide ideas for novel drug development. Full article

A buildup of reactive oxygen species (ROS) occurs in virtually all pathological conditions. Hyaluronan (HA) is a major extracellular matrix component and is susceptible to oxidation by reactive oxygen species (ROS), yet the precise chemical structures of oxidized HA products (oxHA) and their physiological properties remain largely unknown. This study characterized the molecular weight (MW), structures, and physiological properties of oxHA. For this, high-molecular-weight HA (HMWHA) was oxidized using increasing molar ratios of hydrogen peroxide (H₂O₂) or hypochlorous acid (HOCl). ROS lead to the fragmentation of HA, with the oxHA products produced by HOCl exhibiting an altered chemical structure while those produced by H₂O₂ do not. HMWHA promotes the viability of human corneal epithelial cells (hTCEpi), while low MWHA (LMWHA), ultra-LMWHA (ULMWHA), and most forms of oxHA do not. HMWHA and LMWHA promote hTCEpi proliferation, while ULMWHA and all forms of oxHA do not. LMWHA and some forms of oxHA promote hTCEpi migration, while HMWHA does not. Finally, all native forms of HA and oxHA produced by HOCl promote in vivo corneal wound healing, while oxHA produced by H₂O₂ does not. Taken together, our results show that HA fragmentation by ROS can alter the physiological activity of HA by altering its MW and structure. Full article

The aim of the case series was to determine the efficacy of a new medical device developed for adipose tissue restoration in the face. The medical device used the patented NAHYCO^® Hybrid Technology to deliver 45 mg of high- (1400 ± 200 kDa) and 45 mg of low- (100 ± 20 kDa) molecular-weight hyaluronan, in 2 mL. Patients and methods: Twenty-two volunteers, aged 36–60 years. Two mL of Profhilo^® Structura was injected using a 25 G cannula for each hemiface, into superficial fat compartment along the line from the preauricular area to the mandibular angle. Two injections were performed, and Profhilo Structura’s effect on restoring adipose tissue was evaluated immediately after treatment, and over a 6-month follow-up. The studied medical device revealed a pseudoplastic behavior and consistency that allowed easy extrusion from a syringe. It showed a lower viscosity compared to dermal fillers, based on crosslinked HA. Clinically, the soft tissue thickness increased immediately after injection, and the clinical improvement persisted across a 6-month follow-up. The self-reported satisfaction with the treatment showed an amelioration in the midface of all the subjects enrolled, with no adverse effects. Profhilo^® Structura demonstrated a peculiar fat compartment integration, with a regenerating effect on adipose tissue senescence. The skin thickening and compaction effects were similar to those obtained using chemically crosslinked dermal fillers, while a natural look was preserved, and the use of crosslinking agents was avoided. Full article