Search Results (83)

Skin photoaging, marked by structural and functional changes, is mainly caused by long-term ultraviolet (UV) exposure. This study sought to create hydroxytyrosol (HT)-loaded soluble microneedles (HT MNs) and thoroughly assess their anti-photoaging effects and underlying mechanisms in vitro and in vivo. The optimized HT MNs, featuring tips with 10% HT + 5% hyaluronic acid (HA) and a backing layer of 10% polyvinyl pyrrolidone (PVP), demonstrated robust mechanical strength (withstanding an axial force of 10 N without fracture), adequate penetration depth (>200 μm), and efficient skin self-recovery post-removal. In vitro, HT MNs notably boosted cell viability, reduced reactive oxygen species (ROS) levels, and suppressed senescence-associated β-galactosidase (A-β-Gal) expression in UVA-exposed human skin fibroblasts (HSF). In vivo, in a UVA + UVB-irradiated mouse model, HT MNs significantly enhanced skin hydration and elasticity, increased collagen density (confirmed by Masson staining), decreased malondialdehyde (MDA) content, and elevated the activities of glutathione (GSH), catalase (CAT), and glutathione peroxidase (GSH-Px). Western blot analysis further revealed that HT MNs upregulated the expression of collagen type I alpha 1 (COL1A1), elastin (ELN), hyaluronan synthase 2 (HAS2), and filaggrin (FLG), while downregulating matrix metalloproteinase 1. Overall, these findings suggest that HT MNs effectively mitigate UV-induced photoaging through antioxidant, anti-senescence, and extracellular matrix (ECM)-regulating mechanisms, underscoring their potential as a novel transdermal anti-photoaging therapy. Full article

Natural compounds, as honey-derived flavonoids and phenolic compounds, are increasingly investigated for their potential to mitigate skin aging and prevent oxidative stress-induced cellular damages. In this context, a dynamic cell culture model was employed to assess the protective influence of honey pre-treatment on stem cell–associated genes and the Wingless-related integration site (Wnt) signaling pathway following ultraviolet (UV)-induced aging. Using a bioreactor, skin stem cells (SSCs) derived from healthy skin biopsies and human skin fibroblasts (HFF1) were pre-treated with 1% honey for 48 h and then exposed to UV. Real-time quantitative polymerase chain reaction (RT-qPCR) analyses were performed on Wnt signaling and anti-aging molecular responses. Honey pre-treatment enhanced the expression of pluripotency markers (Octamer-binding transcription factor 4 (Oct4); SRY-box transcription factor 2 (Sox2)) and reduced senescence-related cell cycle regulators (cyclin-dependent kinase inhibitor 2A (p16); cyclin-dependent kinase inhibitor 1A (p21); tumor protein 53 (p53)) in SSCs. In UV-damaged SSCs, honey also significantly increased Wnt3a expression. In fibroblasts, honey pre-treatment upregulated Heat shock protein 70 (Hsp70) and Hyaluronan synthase 2 (HAS2) expression, while downregulating caspase-8 (CASP8), indicating a protective role against UV-mediated cellular stress. We also analyzed nitric oxide release and the total antioxidant capacity of cells after treatment. Collectively, these findings suggest that honey may safeguard skin stem cells from UV-induced aging by modulating pluripotency and senescence-associated genes and regulating differentiation through alterations in Wnt signaling. Furthermore, Hsp70 upregulation in fibroblasts appears to strengthen cellular stress responses and support homeostatic stability. Full article

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a small neuropeptide detected first in the hypothalamo–hypophyseal system; recently, it has also been identified in peripheral organs and in tumours. It is well demonstrated that PACAP exerts cell- and tissue-protecting effects in various stressful conditions and helps to maintain tissue homeostasis. In melanoma, the anti-invasive effect of PACAP has been demonstrated; however, there is also existing sporadic data which proves PACAP plays a role in melanoma progression. The major goal of our study was to investigate the signalling targets of PACAP in A2058 and WM35 melanoma cell lines in vitro. Various molecular players of melanocyte differentiation and function responded to PACAP application. SOX9 expression increased while SOX10 expression decreased and CREB signalling did not change. The expression level of TYRP1 decreased, while DCT elevated, and MITF expression showed changes at the mRNA level and in its subcellular localisation. In contrast, the amount of hyaluronan (HA) and expressions of its synthases, as well as RHAMM, increased, indicating the role of PACAP in secretion of an HA-rich matrix. In parallel with these results, we detected elevated hyaluronidase2 (Hyal2) expression in the presence of PACAP. On the other hand, alfaV and beta3 integrin expressions did not alter significantly. Our results demonstrate that exogenous PACAP modulates the expression of multiple target molecules in melanoma cells. Some of the significantly responding molecules take part in hyaluronan homeostasis, suggesting an effect of PACAP on tumour matrix composition, through which it can modulate invasiveness of melanoma cells. 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

Skin aging is influenced by both internal and external factors, resulting in wrinkles, decreased elasticity and irregular pigmentation. Hyaluronic acid (HA), a key component of the extracellular matrix, is essential for skin hydration and structural support. Peptides, short amino acid chains, have gained attention in cosmetics due to their multifunctional biological activities. This study explored the moisturizing and metal-chelating properties of Chrono Control Penta (S-Cannabis Sativa-pentapeptide-1), a novel plant-derived peptide whose sequence is WVSPL. In vitro, it chelated iron ions up to 17.86 ± 2.50% and copper ions up to 47.08 ± 1.49% at 10 mM and 3 mM, respectively. Western blot and Enzyme-Linked Immunosorbent Assay (ELISA) analysis showed that, under H₂O₂-induced stress, Chrono Control Penta increased hyaluronan synthase 2 (HAS2) production by 81.72% in BJ-5ta fibroblasts and enhanced HA secretion by 20.11% compared to simulated aging conditions alone, respectively. Furthermore, experiments carried out with the Franz diffusion cell and human full thickness skin demonstrated the peptide’s ability to penetrate the skin layers and even diffuse laterally with a quantified peptide skin biodistribution accounting for 0.095/0.06 nM/mg in 6 h. Advanced AI-based modeling (AlphaFold2, RosettaFold) and docking analysis revealed stable peptide-peptide transporter 2 (PEPT2) interactions, supporting carrier-mediated skin permeation and linking computational predictions with experimental diffusion data. Hence, this study extends previous evidence on the cosmetic efficacy of Chrono Control Penta by (i) adding mechanistic insights into metal chelation and HAS2/HA modulation, (ii) rigorously quantifying local skin penetration and lateral diffusion with HPLC-MS/MS, and (iii) providing a plausible mechanistic link between skin biodistribution and PEPT2-mediated transport based on deep learning structural models. Full article

Ultraviolet B (UV-B) radiation significantly contributes to skin photoaging, which is characterized by epidermal thickening, collagen degradation, wrinkle formation, barrier dysfunction, and oxidative stress. Nicotinamide mononucleotide (NMN), a key precursor of nicotinamide adenine dinucleotide, regulates cellular energy metabolism and antioxidant defense and demonstrates anti-aging effects in animal models. Here, we investigated the protective effects of oral NMN supplementation against UV-B-induced photoaging in SKH-1 hairless mice. Over a 10-week experimental period, oral NMN administration significantly alleviated epidermal hypertrophy, reduced wrinkle formation and skin surface roughness, improved hydration and elasticity, and restored transepidermal water loss to near-normal levels. Histological analyses revealed marked preservation of collagen fiber density and attenuation of dermal matrix degradation. Furthermore, NMN supplementation inhibited the phosphorylation of MAPK signaling components (ERK, JNK, and p38), suppressed pro-inflammatory cytokine (TNF-α and IL-6) and matrix-degrading enzyme (MMP-1) expression, and restored hyaluronan synthase (HAS-1 and HAS-2) expression. Additionally, NMN enhanced the systemic antioxidant defense, as indicated by the restored superoxide dismutase activity. Thus, NMN has multi-layered protective effects against UV-B–induced skin aging by modulating oxidative stress, inflammatory signaling, extracellular matrix remodeling, and hyaluronic acid metabolism. Full article

CaMK4, a calcium/calmodulin-dependent protein kinase, is an important mediator of cellular signal transduction, yet its role in the regulation of skeletal muscle satellite cells (MuSCs) in goats has remained unclear. In this study, CaMK4 overexpression and knockdown models were established, and integrated transcriptomic and proteomic analyses were performed to systematically elucidate its regulatory network. CaMK4 overexpression altered key pathways associated with cell proliferation and muscle development, including cAMP, PI3K-Akt, and actin cytoskeleton regulation, while proteomic data highlighted calcium signaling and JAK-STAT pathways. Conversely, CaMK4 knockdown enhanced MuSC proliferation by upregulating cell cycle-related genes and proteins. Integrated analyses further identified that Galectin-9 (LGALS9), Collagen triple helix repeat containing-1 (CTHRC1), Hyaluronan Synthase 1 (HAS1), and L-Threonine Dehydrogenase (TDH) may serve as potential key nodes regulating cell cycle, apoptosis, and metabolic control. This suggests a regulatory role for CaMK4. Collectively, these findings provide a mechanistic framework for understanding CaMK4 function in ruminant muscle development and may offer insights for improving goat muscle growth, meat quality traits, and production efficiency. Full article

While normal fibroblasts suppress tumor growth, during cancer initiation and progression, this capacity can be lost and even switched to tumor-promoting, for reasons that are not understood. In this study, we aimed to determine differences between patient-derived cancer-associated fibroblasts and fibroblasts from healthy breast tissue to identify if and how these changes stimulate Triple-negative breast cancer (TNBC). Two-dimensional and three-dimensional mono and co-cultures of TNBC cells with fibroblasts from healthy breast or TNBC were analyzed for cell contractility, migration, distribution, proliferation, and hyaluronan production by traction force microscopy, live cell imaging, flow cytometry, Western blot, and ELISA. In 3D spheroid co-culture, CAFs migrated into the tumor mass, mixing with tumor cells, whereas normal fibroblasts remained separate. In 2D, CAFs showed increased cell migration and contractile force, and, in both 2D and 3D co-culture, CAFs increased the proliferation of TNBC cells. CAFs showed increased production of hyaluronan, as compared to normal fibroblasts, and loss of hyaluronan synthase 2 reduced CAF-induced stimulation of TNBC proliferation. These findings suggest that increased production of hyaluronan by TNBC CAFs enhances their capacity to mix with and induce the proliferation of cancer cells, and that the production of hyaluronan by CAFs can be a future therapeutic target against TNBC. Full article

Hyaluronic acid (HA)-based urethral bulking agents are promising for the treatment of stress urinary incontinence (SUI), but migration risks to distant organs remain a concern. This study evaluated the migration and cytotoxicity of Zhoabex G^®, an HA-based bulking agent, in a female rabbit model. Twenty-seven female New Zealand white rabbits were randomized into control (no injection), sham (saline), and experimental (Zhoabex G^®) groups (n = 9 each). After 5 months, tissues from the kidney, lung, liver, and spleen were analyzed using quantitative RT-PCR for hyaluronan synthase (HAS1, HAS2, HAS3) and hyaluronidase (HYAL2) gene expression, and ELISA for HA concentrations. No significant differences in gene expression were observed across groups (p ≥ 0.05, range: 0.166–0.997), with experimental fold change values near sham baselines (e.g., kidney HAS2: 0.987 ± 0.071, p = 0.422). Similarly, HA concentrations showed no group differences (p = 0.577; e.g., kidney: 119.2–121.8 ng/mL), reflecting organ-specific basal levels. These findings indicate that Zhoabex G^® remains localized at the urethral injection site, with no evidence of migration or cytotoxicity in distant organs. The biodegradable and non-particulate nature of Zhoabex G^® further supports its safety for SUI treatment, warranting further clinical investigation. Full article

Facial aging is a multifactorial process involving changes in bone, fat compartments, ligaments, muscles, and skin. Collagen biostimulators, including synthetic agents and autologous platelet concentrates, have gained attention for facial rejuvenation. Injectable platelet-rich fibrin (i-PRF), a second-generation autologous concentrate, has shown promising regenerative properties due to its natural composition and growth factors. Cosmetic peptides, such as palmitoyl pentapeptide-4 (Matrixyl) and Tetrapeptide-21 (GEKG), are also studied for their ability to stimulate collagen synthesis and remodel the extracellular matrix. This in vitro study examined the potential synergistic effects of i-PRF combined with Matrixyl or GEKG on human dermal fibroblast viability, proliferation, and ECM-related gene expression. Fibroblasts were cultured under six conditions: control, i-PRF alone, Matrixyl alone, GEKG alone, i-PRF + Matrixyl, and i-PRF + GEKG. Viability and proliferation were assessed via MTT, crystal violet, and RealTime-Glo™ assays. Gene expression of COL1A1, FN1, and HAS1 was measured using RT-qPCR. The combinations, especially i-PRF + GEKG, led to increased cell viability and upregulated ECM-related genes at 72 h. These effects were stronger than the individual treatments, suggesting synergistic effects, especially with GEKG. These findings highlight the clinical potential of combining autologous platelet concentrates with bioactive peptides for dermal regeneration. Further preclinical and clinical studies are warranted. Full article

Recent studies have demonstrated that the coumarin derivative 4-Methylumbelliferone (4MU) has an antidiabetic effect in rodent models. 4MU is known to decrease the availability of hyaluronan (HA) substrates and inhibit the activity of different HA synthases. Nevertheless, it has been observed that 4MU may also affect cellular metabolism. In this study, we utilize the rat insulinoma beta cell line (INS-1E) cultured in both two-dimensional (2D) and three-dimensional (3D) experimental settings (pseudo islets), as an in vitro model to study beta cell functionality. For the first time, we observed that treating INS1E cells with 4MU results in improved insulin secretion. Additionally, we discovered that 4MU treatment elicited morphological changes from multilayer to monolayer conditions, along with a varied distribution of insulin granules and cell adhesion properties. Notably, we found that insulin secretion is not correlated with HA production. The same result was observed in co-culture experiments involving INS-1E cells and stromal vascular fraction (SVF) from adipose tissue. These experiments aim to investigate the effects of 4MU on beta cells in the context of its potential use in early-stage type 1 diabetes and in enhancing islet transplantation outcomes. Full article

Bassia scoparia (Syn. Kochia scoparia (L.) Schrad.) is a medicinal plant whose fruit, Kochiae Fructus, has been extensively studied for its dermatological applications. This study focused on extracts from the whole plant B. scoparia (WPBS), excluding fruits, to address the research gap regarding the medicinal properties of non-fruit parts. The diverse skin benefits of WPBS, including its anti-photoaging, moisturizing, wound healing, anti-inflammatory, and anti-angiogenic effects, were investigated. The WPBS extract enhanced the viability of keratinocytes (HaCaT) without inducing cytotoxic effects. WPBS significantly reduced matrix metalloproteinase-1 (MMP-1) levels and increased collagen type I alpha 1 (COL1A1) levels (p < 0.01) in fibroblasts exposed to ultraviolet B (UVB) radiation, indicating strong anti-photoaging effects. WPBS upregulated skin hydration markers such as aquaporin-3 (AQP3) and hyaluronan synthase-3 (HAS3) and effectively accelerated fibroblast wound closure compared to the positive control. Furthermore, WPBS substantially downregulated the expression of inflammatory (COX-2 and IL-1β) and angiogenic markers (VEGF). Transcriptome analysis (RNA-seq) confirmed that WPBS suppressed inflammation-related and UV-induced gene expression pathways. Overall, these findings expand the therapeutic scope of B. scoparia beyond its traditional fruit use and suggest that WPBS is a promising botanical ingredient for various skin applications. Full article

In a susceptible individual, persistent, low-level injury to the airway epithelium initiates an exaggerated wound repair response, ultimately leading to idiopathic pulmonary fibrosis (IPF). The mechanisms driving this fibroproliferative response are not fully understood. Here, we review recent spatially resolved transcriptomics and proteomics studies that provide insight into two distinct matricellular microenvironments important in this pathological fibroproliferation. First, in response to alveolar epithelial injury, alveolar differentiation intermediate (ADI) basal cells arising from Secretoglobin (Scgb1a1) progenitors re-populate the injured alveolus remodeling the extracellular matrix (ECM). ADI cells exhibit an interconnected cellular stress response involving the unfolded protein response (UPR), epithelial–mesenchymal transition (EMT) and senescence pathways. These pathways reprogram cellular metabolism to support fibrillogenic ECM remodeling. In turn, the remodeled ECM tonically stimulates EMT in the ADI population, perpetuating the transitional cell state. Second, fibroblastic foci (FF) are a distinct microenvironment composed of activated aberrant “basaloid” cells supporting transition of adjacent mesenchyme into hyaluronan synthase (HAS^hi)-expressing fibroblasts and myofibroblasts. Once formed, FF are the major matrix-producing factories that invade and disrupt the alveolar airspace, forming a mature scar. In both microenvironments, the composition and characteristics of the ECM drive persistence of atypical epithelium sustaining matrix production. New approaches to monitor cellular trans-differentiation and matrix characteristics using positron emission tomography (PET)–magnetic resonance imaging (MRI) and optical imaging are described, which hold the potential to monitor the effects of therapeutic interventions to modify the ECM. Greater understanding of the bidirectional interrelationships between matrix and cellular phenotypes will identify new therapeutics and diagnostics to affect the outcomes of this lethal disease. Full article

Hyaluronan, a key component of the extracellular matrix, plays a crucial role in joint development and maintenance. In order to determine the role of hyaluronan function in joint development and homeostasis, conditional loss-of-function experiments of Hyaluronan Synthase 2 (Has2) were carried out in mice. Has2 depletion in limb mesenchymal cells led to severely shortened limbs with appendicular joints that are deformed, decreased proteoglycan content as characterized by Safranin-O staining, and severely pitted epiphyseal ends of long bones and deformed joints as viewed by micro-CT reconstructions. The embryonic deletion of Has2 in mesoderm mesenchyme of limbs by Prx1-Cre confirmed its involvement in joint development, while in situ hybridization and hyaluronan staining confirmed Has2 expression and abundant accumulation of hyaluronan in the onset of joint formation, the joint interzone. These findings position Has2 as the main hyaluronan-making enzyme in articular cartilage and highlight its essential function in joint formation and retention of proteoglycans of the extracellular matrix of the cartilage. Full article