Search Results (114)

Hyaluronic acid (HA) is a ubiquitous glycosaminoglycan with distinct biological functions, dependent on its molecular weight. High-molecular-weight HA (HMWHA) primarily exhibits structural and anti-inflammatory roles, whereas low-(LMWHA) and very low-molecular-weight HAs (vLMWHA) actively participate in tissue regeneration and angiogenesis. This review highlights the pivotal roles of HA across the female reproductive lifespan, emphasizing how molecular weight dictates its therapeutic potential. In gynecology, LMWHA effectively alleviates symptoms of genitourinary syndrome of menopause, restores vaginal architecture, and mitigates complications following pelvic radiotherapy, improving both tissue integrity and patient quality of life. vLMWHA shows promise in enhancing viral clearance and lesion regression in human papillomavirus (HPV) infections. In obstetrics, HMWHA plays crucial roles in implantation, immunotolerance, and embryogenesis and maintains cervical barrier integrity to prevent ascending infections and preterm birth. Moreover, emerging clinical evidence supports oral HMWHA supplementation for reducing pregnancy complications, such as threatened miscarriage, subchorionic hematomas, and preterm delivery. This review underscores the necessity of considering HA’s molecular weight to optimize interventions in gynecological and obstetric care, offering tailored strategies to support women’s health throughout their lives. Full article

Glycation influences skin aging through non-enzymatic reactions between reducing sugars and proteins, forming advanced glycation end-products (AGEs) that accelerate skin deterioration. This study evaluates the curative anti-glycation effects of an injectable formulation combining dual-molecular-weight hyaluronic acid (low and mid/high) with trehalose in methylglyoxal-induced glycation in human skin explants. Thirty-six human skin explants were allocated across five experimental groups in a 12-day study. Glycation was induced using methylglyoxal (500 μM) on days 1 and 4, followed by curative product administration on day 5. CML (Nε-(carboxymethyl)lysine) immunohistochemistry was performed to assess glycation levels in the reticular dermis at days 6, 8, and 12, with quantitative analysis conducted through standardized image analysis. The formulation significantly reduced CML formation by 60% on day 6 compared to untreated controls (p < 0.001). Under methylglyoxal-induced glycation stress the product showed sustained curative effects, with CML reductions of 69% on day 6 (p = 0.008), 68% on day 8 (p = 0.012), and 61% on day 12 (p = 0.033) compared to methylglyoxal treatment alone. Cell viability remained unaffected throughout the study period across all experimental conditions. The tested injectable formulation exhibits significant and sustained curative anti-glycation properties in human skin explants for 12 days, effectively counteracting methylglyoxal-induced glycation damage without affecting cell viability. These findings advance anti-aging skin interventions, offering a novel approach to address glycation-induced skin damage with potential applications in clinical dermatology and aesthetic medicine. Full article

Background: Cancer ranks as a leading cause of death worldwide. It is urgent to develop intelligent co-delivery systems for cancer chemotherapy to achieve reduced side-effects and enhanced therapeutic efficacy. Methods: We chose oligo-hyaluronic acid (oHA, a low molecular weight of HA) as the carrier, and adriamycin (ADM) and paclitaxel (PTX) as the co-delivered drugs. The oHA-ss-PTX macromolecular prodrug was synthesized by introducing glutathione-stimuli-responsive disulfide bonds through chemical reactions. Then, we constructed ADM-loading micelles (ADM/oHA-ss-PTX) in one step by microfluidic preparation. The delivery efficacy was evaluated comprehensively in vitro and in vivo. The biocompatibility of ADM/oHA-ss-PTX was assessed by hemolysis activity analysis, BSA adsorption testing, and cell viability assay in endothelial cells. Results: The resulting ADM/oHA-ss-PTX micelles possessed a dynamic size (127 ± 1.4 nm, zeta potential −9.0 mV), a high drug loading content of approximately 21.2% (PTX) and 7.6% (ADM). Compared with free ADM+PTX, ADM/oHA-ss-PTX showed enhanced blood stability and more efficiently inhibited cancer cell proliferation. Moreover, due to the CD44-mediated endocytosis pathway, a greater number of ADM/oHA-ss-PTX micelles were absorbed by A549 cells than by oHA-saturated A549 cells. In vivo experiments also showed that ADM/oHA-ss-PTX micelles had excellent therapeutic effects and targeting ability. These results show that ADM/oHA-ss-PTX micelles were a promising platform for co-delivery sequential therapy in CD44-positive cancer. Conclusions: In conclusion, these results convincingly demonstrate that ADM/oHA-ss-PTX micelles hold great promise as a novel platform for co-delivering multiple drugs. Their enhanced properties not only validate the potential of this approach for sequential cancer therapy in CD44-positive cancers but also pave the way for future clinical translation and further optimization in cancer treatment. Full article

Tremella fuciformis is high in polysaccharides, which have a structure made up of a straight chain of (1→3) α-D-mannan and side chains of glucuronic acid, xylose, and fucose. This study aimed to evaluate whether the non-animal hyaluronic acid extracted from Tremella fuciformis can maintain the chemical and physical characteristics of hyaluronic acid that ensure its biological functionality. Chemical and physical analyses such as hyaluronic content, screening of metals, purity, pH, nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (ATR/FTIR), and MALDI-TOF were performed. Chemical characterisation revealed that the most abundant polysaccharide in the extract was hyaluronic acid, accounting for ca. 87.76%, with a molecular weight above 2000 kDa. In addition, ATR/FTIR and NMR spectroscopy and MALDI-TOF analysis confirmed that Tremella fuciformis extract is a source of non-animal hyaluronic acid. In summary, every molecular attribute examined played a significant role in determining the functional qualities of the extract, indicating that a thoughtful choice of extraction technique can enhance its advantages. Full article

Cannabidiol (CBD) and tetrahydrocurcumin (THC) have demonstrated anti-inflammatory activity as well as generating new lymph vessels. We present the formulations and evaluations of CBD and THC loaded in hydrogels for the treatment of lymphedema to promote angiogenesis of lymph vessels and an anti-inflammatory response. Six CBD-THC hydrogel formulations were prepared and evaluated. The hydrodynamic particle sizes were 302.0–545.1 nm and the zeta potentials were from −58.80 to −33.63 mV. The hydrogel pHs were 6.43–6.54. The hydrogel formulations were non-toxic for both CBD (<25 µg/mL) and THC (<12.5 µg/mL). It was observed that high-molecular-weight hyaluronic acid in hydrogel affected collagen production. Hydrogel formulations at 2 µg/mL of CBD and 1 µg/mL of THC induced human dermal lymphatic endothelial cell tube formation. CBD-THC hydrogel formulations showed a notable ability to induce angiogenesis, which suggested its potential effectiveness in promoting new lymphatic vessel formation. Moreover, CBD-THC hydrogels showed anti-inflammatory properties. Further research is needed to ensure these treatments effectively enhance lymphatic repair. Full article

Skin aging is significantly influenced by glycation processes, leading to the formation of Advanced Glycation End-products (AGEs) that compromise dermal structure and function. This study evaluated the protective effects of a novel injectable product based on a combination of two different ranges of Molecular Weights of Hyaluronic Acid (MWHA: LMWHA-Low MWHA, MMWHA-Mid MWHA, and HMWHA-High MWHA) and trehalose against glycation in human skin explants. Using human skin explants with methylglyoxal-induced glycation stress, we assessed the product’s impact on carboxymethyllysine (CML) formation and cell viability in the reticular dermis. The product was administered prophylactically one day before methylglyoxal exposure, and samples were analyzed after six days. Results demonstrated that the product significantly reduced CML formation by 45% (p < 0.01) compared to untreated controls under baseline conditions and maintained a 30% reduction (p < 0.05) in CML formation under methylglyoxal-induced stress. Importantly, the product preserved cell viability throughout the experimental period and maintained CML levels comparable to physiological baseline despite glycation stress. These findings suggest that the synergistic action of hyaluronic acid and trehalose provides effective protection against both baseline and induced glycation in human skin, indicating potential applications in preventing glycation-related skin aging. Full article

Skin aging is a complex and multifactorial process influenced by both intrinsic and extrinsic factors. The periorbital area of the face is particularly susceptible to premature aging signs due to its delicate skin structure, and is a major concern for many individuals. While hyaluronic acid (HA)-based dermal filler products are commonly used for periorbital rejuvenation, novel approaches to effectively locally address the visible signs of aging are available. This study aimed to investigate Innovyal Regenerative Action (IRA), an injectable polynucleotide–HA (PN-HA) regenerative complex designed for periocular prejuvenation. Firstly, PN-HA was compared to other commercially available HA-based dermbooster products (Profhilo^®, Suisselle Cellbooster^® Glow, and NCTF^® 135 HA) in terms of rheological properties, in vitro antioxidant capacity, and total collagen production stimulation in human fibroblasts. Secondly, the clinical effects of the IRA PN-HA complex were evaluated in two case reports (monotherapy for periorbital prejuvenation). It was shown that the PN-HA complex outperformed its comparators in terms of relative rheological behavior (biophysical attributes normalized to polymer contents), intrinsic antioxidant activity (CUPRAC, FRAP, and ORAC assays), as well as total collagen level induction (72-h in vitro dermal fibroblast induction model). Generally, the results of this study provided mechanistic and preliminary clinical insights into the potential benefits of the IRA PN-HA complex for periocular cutaneous treatment. Overall, it was underscored that combining the structural support and regenerative properties of PN with the hydrating and volumizing effects of HA bares tangible potential for multifactorial skin quality enhancement and for periocular prejuvenation in particular. Full article

Background/Objectives: Knee osteoarthritis (OA) is a degenerative chronic disease characterized by a reduction in articular cartilage, as well as pain and functional limitations. We evaluated both the efficacy and safety of cross-linked high-molecular-weight hyaluronic acid in patients with knee OA. Methods: In this observational prospective single-arm study, a cross-linked high-molecular-weight hyaluronic acid (DIART ONE 90 mg in 3 mL) was administered in single injections to 50 patients aged 18–65 years, with a follow-up at 3, 6, and 12 months. Several scores were evaluated, including the Knee Injury and Osteoarthritis Outcome Score as the primary outcome measure and the Visual Analogue Scale, Timed Up and Go Test, Six-Minute Walking Test, General Health Assessment with 36-Item Short Form Health Survey, Zung’s Self-Rating Anxiety Scale, and Zung’s Self-Rating Depression Scale as secondary outcome measures. Both physicians and patients knew the kind of treatment they received. Results: During the follow-ups, we observed a statistically significant improvement in clinical scores at 3 and 6 months, with a decrease in clinical benefit at 12 months. Functional and psychological benefits were significant at 3, 6, and 12 months. No side effects were described except pain associated with the site of injection. Conclusions: In conclusion, we documented that cross-linked high-molecular-weight hyaluronic acid (DIART ONE 90 mg in 3 mL) represents an effective option in the management of mild–moderate osteoarthritis. Full article

Background: This study evaluated the postoperative effects of hyaluronic acid (HA) on pain, swelling, and trismus following mandibular third molar surgery. Material and Methods: Thirty healthy patients with bilateral impacted mandibular third molars underwent two surgeries at 21-day intervals. In a split-mouth design, one extraction socket was treated with 0.2 mL of high-molecular-weight hyaluronic acid gel (Monovisc^® [molecular weight ≈ 1.5–2.2 million Da]), while the contralateral socket received no additional treatment. Perioperative medications, including NSAIDs, were standardized for all patients. Data collection included postoperative pain, swelling (using Gabka and Matsumura’s method), analgesic consumption, and trismus (mouth opening) on designated days. Data were analyzed using the Mann–Whitney U and Wilcoxon signed-rank tests with Bonferroni correction (adjusted significance level: p > 0.0083). Results: The mean VAS pain scores on day 1 were 63.5 ± 22.3 in the HA group and 61.9 ± 12.5 in the control group, decreasing to 3.9 ± 7.6 and 3.3 ± 7.2, respectively, by day 7 (p > 0.0083). The maximum interincisal distance on day 7 was 45.9 ± 7.4 mm in the HA group and 43.5 ± 7.3 mm in the control group, showing a slight improvement (p = 0.002). Swelling, measured using the tragus–pogonion distance, was 164.6 ± 20.7 mm in the HA group and 166.3 ± 18.9 mm in the control group on day 7 (p > 0.0083). Analgesic consumption remained comparable across all postoperative days (p > 0.0083). No statistically significant differences were observed between the HA and the control groups at any evaluated time point. Conclusions: Hyaluronic acid application after mandibular third molar surgery demonstrated a slight improvement in trismus on day 7, but no significant long-term advantages in pain or swelling. While early postoperative improvements in trismus were observed, these findings require further validation. Additional studies are needed to explore HA’s potential clinical applications in oral surgery. Full article

Background/Objectives: Previously, we reported that high molecular weight hyaluronic acid (HMW-HA) exerts chondroprotective effects by enhancing dual specificity protein phosphatase 10/mitogen-activated protein kinase (MAPK) phosphatase 5 (DUSP10/MKP5) expression and suppressing inflammatory cytokine-induced matrix metalloproteinase-13 (MMP13) expression in a human immortalized chondrocyte line (C28/I2 cells) via inhibition of MAPKs. The aim of this study was to elucidate the molecular mechanisms underlying the enhancement of DUSP10/MKP5 expression by HMW-HA in C28/I2 cells. Methods: C28/I2 cells were treated with HMW-HA, and the activation of intracellular signaling molecules was determined using Western blot analysis. The expression levels of mRNAs and microRNAs (miRNAs) were evaluated through real-time quantitative reverse transcription PCR analysis. Results: HMW-HA treatment induced Akt phosphorylation via interaction with CD44, and pretreatment with specific inhibitors of phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt) signaling attenuated the HMW-HA-induced expression of DUSP10/MKP5. HMW-HA suppressed the expression of miR-92a, miR-181a, and miR-181d. Loss-of-function and gain-of-function analyses of these miRNAs indicate that miR-92a, miR-181a, and miR-181d negatively regulate DUSP10/MKP5 expression. Moreover, HMW-HA-induced Akt phosphorylation was partially suppressed by miR-181a and miR-181d mimics. Finally, we found that HMW-HA activates RhoA-associated protein kinase (ROK) signaling, which contributes to Akt phosphorylation. Conclusions: These findings suggest that the induction of DUSP10/MKP5 expression by HMW-HA binding to CD44, leading to MMP13 suppression, involves multiple regulatory mechanisms, including PI3K/Akt and RhoA-activated ROK signaling, in addition to miRNA-mediated regulation. Elucidating these detailed molecular mechanisms may reveal novel biological activities that contribute to the therapeutic efficacy of HMW-HA against osteoarthritis. Full article

Hyaluronic acid (HA), a natural polymer produced through biotechnological processes, is initially synthesized with a high molecular weight, which is subsequently reduced for specific applications. This work aims to develop an experimental laboratory device that enables the controlled depolymerization of HA to achieve a targeted molecular weight. This is accomplished by applying precisely regulated temperature and pressure conditions that facilitate the cleavage of HA polymer chains as they pass through a narrow capillary. The process also allows for a controlled exposure time to elevate the temperature and pressure, with the rapid transition between standard and elevated conditions ensuring temporal stability. A key innovation of this approach is the selective application of an elevated temperature to a designated capillary section, adjustable from 0.5 to 5 m in 0.5 m increments, allowing for a broad range of reaction times. Numerical simulations verified temperature distribution along the capillary during heating and cooling. The device’s effectiveness is demonstrated by cleaving HA chains (initial Mw = 2150 kDa) dissolved in an aqueous solution at a 0.1 mg/mL concentration. Results from a factorial experiment that evaluated the extremes of three main variables show cleavage across a wide molecular weight range, reaching values as low as 8 kDa, with a variance of less than 5%. This study presents a viable device for the selective depolymerization of HA via physical parameters alone, eliminating the need for additional substances such as acids, hydroxides, or enzymes. 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

A novel Bacillus subtilis HB-31 strain was isolated from Gotjawal Wetland in Jeju Island, Republic of Korea. A mucus substance produced by this strain was identified as high-molecular-weight poly-γ-glutamic acid (γ-PGA) using NMR, Fourier transform infrared spectroscopy, and size-exclusion chromatography/multi-angle light scattering analyses. We evaluated whether γ-PGA strengthened the skin barrier using keratinocytes and a reconstructed skin model. In keratinocytes, γ-PGA treatment dose-dependently increased the mRNA expression of skin barrier markers, including filaggrin, involucrin, loricrin, serine palmitoyl transferase, fatty acid synthase, and 3-hydroxy-3-methylglutaryl coenzyme A reductase. γ-PGA also enhanced hyaluronic acid synthesis by upregulating hyaluronic acid synthase-1, -2, and -3 mRNA levels and promoted aquaporin 3 expression, which is involved in skin hydration. In the reconstructed skin model, topical application of 1% γ-PGA elevated filaggrin, involucrin, CD44, and aquaporin 3 expression, compared to the control. These results suggest that the newly isolated HB-31 can be used as a commercial production system of high-molecular-weight γ-PGA, which can serve as an effective ingredient for strengthening the skin barrier and improving moisture retention. Further research is needed to explore the long-term effects of γ-PGA on skin health and its application in treating skin conditions. Full article

Transdermal drug delivery minimizes pain and provides a controlled, stable release of drugs, but its effectiveness is limited by the skin’s natural barriers. Microneedles overcome this problem, enabling minimally invasive drug delivery. Microneedle patches (MNPs) with 80 µm-tall needles composed of hyaluronic acid (HA) were developed and evaluated for their formability, structural integrity, dissolution rate, skin penetration ability, and drug transmission capacity. The influence of the molecular weight of HA on these properties was also investigated. MNPs made from low-molecular-weight HA (30 kDa–50 kDa) demonstrated 12.5 times superior drug permeability in ex vivo human skin compared to needleless patches (NLPs). Furthermore, in the same test, low-molecular-weight HA MNPs had 1.7 times higher drug permeability than high-molecular-weight HA MNPs, suggesting superior transdermal administration. The molecular weight of HA significantly influenced its solubility and permeability, highlighting the potential effectiveness of MNPs as drug delivery systems. Puncture tests demonstrated a penetration depth of 50–60 µm, indicating minimal nerve irritation in the dermis and effective drug delivery to the superficial dermal layer. These results present a manufacturing technique for MNPs incorporating model drug compounds and highlight their potential as a novel and minimally invasive drug delivery method for the biomedical applications of soft gels. Full article

Background: Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin’s lymphoma that primarily affects the skin, rich in hyaluronic acid (HA). HA is a component of the extracellular matrix in the dermis and likely affects the development of CTCL, but the mechanism is poorly understood. Here we show that low-molecular-weight HA (LMWHA) possibly exacerbates CTCL, and bexarotene, already used in CTCL treatment, decreases HA production. Methods: We conducted immunohistochemistry, qRT-PCR, immunoblotting, and HA quantification using both mouse and human specimens to evaluate the impact of HA on CTCL. Additionally, we assessed the effect of bexarotene, which is already used for CTCL treatment, on HA metabolism. Results: HA expression was higher in patients’ serum and skin sections than in healthy controls. HA extracted from the skin of mice inoculated with tumors showed an increase in LMWHA. LMWHA increased lymphoma cell proliferation in vitro and accelerated tumor formation in mice in vivo. LMWHA also created a favorable environment for tumor cells by affecting fibroblasts, vascular endothelial cells, and tumor-associated macrophages. Thus, increased levels of HA, mainly LMWHA, exacerbate CTCL progression by affecting tumor cells and their microenvironment. Bexarotene treatment reduced the amount of total HA in murine tumor-inoculated skin, as well as the supernatant of cultured normal human dermal fibroblasts (NHDFs) and HuT78 cells. Detailed in vitro analyses showed that bexarotene treatment decreased HA synthase (HAS)1 and HAS2 expression in NHDFs and HAS1 and HAS3, and CEMIP expression in HuT78 cells. Chromatin immunoprecipitation assays revealed that bexarotene reduced retinoid X receptor-α binding to the HAS1 and HAS2 promoters in NHDFs. Conclusions: Bexarotene potentially exerts its anti-tumor effect by reducing HA levels through decreased expression of HAS. These findings provide new insights into the process of CTCL development and additional insights regarding bexarotene treatment. Full article