Search Results (2,686)

Introduction: Osteoarthritis (OA), a leading cause of disability among the elderly, is characterized by progressive joint tissue destruction. Fucoidan, a sulfated polysaccharide with known anti-inflammatory and antioxidant properties, has been investigated for its potential to protect against interleukin-1 beta (IL-1β)-induced articular tissue damage. Methods: Human primary chondrocytes and synovial fibroblasts were pre-treated with 100 μg/mL fucoidan before stimulation with 1 ng/mL of IL-1β. The protective effects of fucoidan were assessed by measuring oxidative stress markers and catabolic enzyme levels. These in vitro findings were corroborated using a rat anterior cruciate ligament transection-induced OA model. To explore the underlying mechanisms, particularly the interaction between microRNAs (miRs) and heme oxygenase-1 (HO-1), five candidate miRs were identified in silico and experimentally validated. Luciferase reporter assays were used to confirm direct interactions. Results: Fucoidan exhibited protective effects against IL-1β-induced oxidative stress and catabolic processes in both chondrocytes and synovial fibroblasts, consistent with in vivo observations. Fucoidan treatment restored HO-1 expression while reducing inducible nitric oxide synthase and matrix metalloproteinase levels in IL-1β-stimulated cells. Notably, this study revealed that fucoidan modulates the miR-22/HO-1 pathway, a previously uncharacterized mechanism in OA. Specifically, miR-22 was upregulated by IL-1β and subsequently attenuated by fucoidan. Luciferase reporter assays confirmed a direct interaction between miR-22 and HO-1. Conclusion: The results demonstrate that fucoidan mitigates OA-related oxidative stress in chondrocytes and synovial fibroblasts through the novel modulation of the miR-22/HO-1 axis. The miR-22/HO-1 pathway represents a crucial therapeutic target for OA, and fucoidan may offer a promising therapeutic intervention. Full article

Objectives: Saccharomyces boulardii CNCM I-745, a probiotic yeast, is effectively used for the treatment of acute diarrhea as well as for the prevention and treatment of traveller‘s diarrhea and diarrhea under tube feeding. The underlying mechanisms are not fully elucidated. Both antitoxic and regulatory effects on the intestinal barrier, mediated either by the yeast or yeast-derived substrates, have been discussed. Methods: To examine the effects of Saccharomyces boulardii released substrates (S.b.S) on gastrointestinal (GI) barrier function, a murine small intestinal organoid cell model under stress was used. Stress was induced by lipopolysaccharide (LPS) exposure or withdrawal of growth factors from cell culture medium (GF_Red). Stressed organoids were treated with S.b.S (200 µg/mL), and markers of GI barrier and inflammatory response were assessed. Results: GF_Red-induced stress was characterized by disturbances in selected tight junction (TJ) (p < 0.05), adherent junction (AJ) (p < 0.001), and mucin (Muc) formation (p < 0.01), measured by gene expressions, whereby additional S.b.S treatment was found to reverse these effects by increasing Muc2 (from 0.22 to 0.97-fold change, p < 0.05), Occludin (Ocln) (from 0.37 to 3.5-fold change, p < 0.0001), and Claudin (Cldn)7 expression (from 0.13 ± 0.066-fold change, p < 0.05) and by decreasing Muc1, Cldn2, Cldn5, and junctional adhesion molecule A (JAM-A) expression (all p < 0.01). Further, S.b.S normalized expression of nucleotide binding oligomerization domain (Nod)2- (from 44.5 to 0.51, p < 0.0001) and matrix metalloproteinase (Mmp)7-dependent activation (from 28.3 to 0.02875 ± 0.0044 ** p < 0.01) of antimicrobial peptide defense and reduced the expression of several inflammatory markers, such as myeloid differentiation primary response 88 (Myd88) (p < 0.01), tumor necrosis factor α (Tnfα) (p < 0.01), interleukin (IL)-6 (p < 0.01), and IL-1β (p < 0.001). Conclusions: Our data provide new insights into the molecular mechanisms by which Saccharomyces boulardii CNCM I-745-derived secretome attenuates inflammatory responses and restores GI barrier function in small intestinal organoids. Full article

Background: Metastatic melanoma is a highly aggressive malignancy with poor prognoses and frequent resistance to conventional chemotherapy. Approximately 40% of melanoma cases carry the BRAF^V600E mutation, for which vemurafenib, a selective BRAF^V600E inhibitor, is approved. Despite initial clinical benefits, vemurafenib often leads to drug resistance and relapse, highlighting the need for improved therapeutic strategies. Objectives, methods: In this study, we designed, synthesized, and characterized five novel vemurafenib analogs—RF-86A, RF-87A, RF-94A, RF-94B, and RF-96B—with the aim of enhancing anti-proliferative and anti-metastatic effects against human melanoma cells. Results: All compounds induced apoptosis in BRAF^V600E-mutated A375 cells, with RF-86A displaying the lowest IC₅₀ value among the series, comparable to that of vemurafenib. Moreover, RF-86A exhibited the highest selectivity index, as determined using HEK293T cells as a non-tumorigenic control. Additionally, migration assays and gelatin zymography demonstrated that the analogs, unlike vemurafenib, significantly inhibited matrix metalloproteinases MMP-2 and MMP-9, key enzymes involved in tumor invasion and metastasis. Conclusions: These findings suggest that structural modifications to the vemurafenib scaffold may improve therapeutic efficacy and offer a promising strategy to overcome acquired resistance. 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

The matrix metalloproteinase (MMP) family includes several membrane-bound enzymes. Membrane-type 5 matrix metalloproteinase (MT5-MMP) is unique amongst the MMP family in being primarily expressed in the brain and during development. It is proposed to contribute to synaptic plasticity and is implicated in several pathologies, including multiple cancers and Alzheimer’s disease. In cancer, MT5-MMP expression has been correlated to cancer progression, but a distinct mechanistic role has yet to be uncovered. In Alzheimer’s disease, MT5-MMP exhibits pro-amyloidogenic activity, functioning as an η-secretase that cleaves amyloid precursor protein (APP), ultimately generating two synaptotoxic fragments, Aη-α and Aη-β. Several intracellular binding partners for MT5-MMP have been identified, and of these, N4BP2L1, EIG121, BIN1, or TMX3 binding to MT5-MMP results in a significant increase in MT5-MMP η-secretase activity. Beyond direct effects on APP, MT5-MMP may also facilitate APP trafficking to endosomal/lysosomal compartments and enhance proinflammatory responses. Overall, the substrate profile of MT5-MMP has not been well defined, and selective inhibitors of MT5-MMP have not been described. These advances will be needed for further consideration of MT5-MMP as a therapeutic target in Alzheimer’s disease and other pathologies. Full article

Photoaging, predominantly induced by ultraviolet radiation, is a primary driver of premature skin aging, characterized by complex molecular mechanisms including oxidative stress, inflammation, matrix metalloproteinase activation, and extracellular matrix degradation. Consequently, there is growing scientific interest in identifying effective natural agents to counteract skin aging and photoaging. Djulis (Chenopodium formosanum), an indigenous Taiwanese pseudocereal from the Amaranthaceae family, has emerged as a promising candidate for skincare applications because of its rich phytochemicals and diverse bioactivities. This review describes the current understanding of the molecular mechanisms underlying photoaging and examines the therapeutic potential of djulis extract as a multifunctional agent for skin aging. Its mechanisms of action include enhancing antioxidant defenses, modulating inflammatory pathways, preserving the extracellular matrix, and inhibiting the formation of advanced glycation end products. Bioactive constituents of djulis extract, including phenolic compounds, flavonoids, and betanin, are known to exhibit potent antioxidant and photoprotective activities by modulating multiple molecular pathways essential for skin protection. The bioactivities of djulis in in vitro and animal studies, and four skin clinical trials of djulis extract products are presented in this review article. Ultimately, this review provides an overview that supports the potential of djulis extract in the development of evidence-based skincare formulations for the prevention and treatment of skin aging. Full article

According to the World Health Organization, musculoskeletal injuries affect more than 1.71 billion people around the world. These injuries are a major public health issue and the leading cause of disability. There has been a recent interest in hydrogels as a potential biomaterial for musculoskeletal tissue regeneration. This is due to their high water content (70–99%), ECM-like structure, injectability, and controllable degradation rates. Recent preclinical studies indicate that they can enhance regeneration by modulating the release of bioactive compounds, growth factors, and stem cells. Composite hydrogels that combine natural and synthetic polymers, like chitosan and collagen, have compressive moduli that are advantageous for tendon–bone healing. Some of these hydrogels can even hold up to 0.8 MPa of tensile strength. In osteoarthritis models, functionalized systems such as microspheres responsive to matrix metalloproteinase-13 have demonstrated disease modulation and targeted drug delivery, while intelligent in situ hydrogels have exhibited a 43% increase in neovascularization and a 50% enhancement in myotube production. Hydrogel-based therapies have been shown to restore contractile force by as much as 80%, increase myofiber density by 65%, and boost ALP activity in bone defects by 2.1 times in volumetric muscle loss (VML) models. Adding TGF-β3 or MSCs to hydrogel systems improved GAG content by about 60%, collagen II expression by 35–50%, and O’Driscoll scores by 35–50% in cartilage regeneration. Full article

Cartilage degradation is a key feature of osteoarthritis (OA), a joint disease that significantly impacts the quality of life of the elderly population. While advanced age is recognized as one of the major risk factors for OA, the underlying mechanisms are not fully understood. Research involving cartilage from aged animals has improved our understanding of the changes associated with aging. However, studies with aged animals can be time-consuming and costly. In this study, we investigate the use of human sera from older donors as a stressor to induce aging-like changes in cultured human chondrocytes. First, we assess the expression levels of markers related to chondrogenesis, hypertrophy, fibrosis, and inflammation in human chondrocytes treated with sera from younger or older human donors. Next, we evaluate the regenerative potential of these sera-treated chondrocytes by stimulating them with the anabolic factor transforming growth factor (TGF)-β3. The results show that treatment with sera from older donors induced an aging-like phenotype in chondrocytes and impaired their ability to generate new cartilage. These findings provide insight into the role of systemic factors (serum) in cartilage aging and offer a novel in vitro model for studying age-related changes in chondrocytes. Full article

Advanced glycation end-products (AGEs) are formed by the non-enzymatic glycation of proteins, lipids, and nucleic acids due to the consumption of high-carbohydrate diets; their production is also promoted by a sedentary lifestyle as well as cigarette smoking. Elevated levels of AGEs in the circulatory system and internal organs of the body are commonly observed in a number of cardiovascular diseases such as hypertension, diabetes, atherosclerosis, coronary artery disease, aortic aneurysm, atrial fibrillation, myocardial infarction, and heart failure, which are associated with the development of oxidative stress and myocardial inflammation. The adverse effects of AGEs on the cardiovascular system are elicited by both non-receptor mechanisms involving the cross-linking of extracellular and intracellular proteins, and by receptor-mediated mechanisms involving the binding of AGEs with advanced glycation end-product receptors (RAGEs) on the cell membrane. AGE–RAGE interactions along with the cross-linking of proteins promote the generation of oxidative stress, the production of inflammation, the occurrence of intracellular Ca²⁺-overload, and alterations in the extracellular matrix leading to the development of cardiovascular dysfunction. AGEs also bind with two other protein receptors in the circulatory system: soluble RAGEs (sRAGEs) are released upon the proteolysis of RAGEs due to the activation of matrix metalloproteinase, and endogenous secretory RAGEs (esRAGEs) are secreted as a spliced variant of endogenous RAGEs. While the AGE–RAGE signal transduction axis serves as a pathogenic mechanism, both sRAGEs and esRAGEs serve as cytoprotective interventions. The serum levels of sRAGEs are decreased in ischemic heart disease, vascular disease, and heart failure, as well as in other cardiovascular diseases, but are increased in chronic diabetes and renal disease. Several interventions which can reduce the formation of AGEs, block the AGE–RAGE axis, or increase the levels of circulating sRAGEs have been shown to exert beneficial effects in diverse cardiovascular diseases. These observations support the view that the AGE–RAGE axis not only plays a critical role in pathogenesis, but is also an excellent target for the treatment of cardiovascular disease. Full article

Background: Cerebral aneurysm (CA) is a focal or diffuse pathological dilation of the cerebral arterial wall that arises due to various etiological factors. It represents a serious vascular condition, particularly affecting the elderly, and carries a high risk of rupture and neurological morbidity. Clonidine (CL), an α2-adrenergic receptor agonist, has been reported to suppress aneurysm progression; however, its underlying molecular mechanisms, especially in relation to cerebral endothelial dysfunction, remain unclear. This study aimed to investigate the potential of CL to mitigate CA development by modulating apoptosis, inflammation, and oxidative stress in an Angiotensin II (Ang II)-induced endothelial injury model. Methods: Human brain microvascular endothelial cells (HBMECs) were used to establish an in vitro model of endothelial dysfunction by treating cells with 1 µM Ang II for 48 h. CL was administered 2 h prior to Ang II exposure at concentrations of 0.1, 1, and 10 µM. Cell viability was assessed using the MTT assay. Oxidative stress markers, including reactive oxygen species (ROS) and Nitric Oxide (NO), were measured using 2′,7′–dichlorofluorescin diacetate (DCFDA). Gene expression levels of vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP-2 and MMP-9), high mobility group box 1 (HMGB1), and nuclear factor kappa B (NF-κB) were quantified using RT-qPCR. Levels of proinflammatory cytokines; tumor necrosis factor-alpha (TNF-α), Interleukin-6 (IL-6), and interferon-gamma (IFN-γ); were measured using commercial ELISA kits. Results: Ang II significantly increased ROS production and reduced NO levels, accompanied by heightened proinflammatory cytokine release and endothelial dysfunction. MTT assay revealed a marked decrease in cell viability following Ang II treatment (34.18%), whereas CL preserved cell viability in a concentration-dependent manner: 44.24% at 0.1 µM, 66.56% at 1 µM, and 81.74% at 10 µM. CL treatment also significantly attenuated ROS generation and inflammatory cytokine levels (p < 0.05). Furthermore, the expression of VEGF, HMGB1, NF-κB, MMP-2, and MMP-9 was significantly downregulated in response to CL. Conclusions: CL exerts a protective effect on endothelial cells by reducing oxidative stress and suppressing proinflammatory signaling pathways in Ang II-induced injury. These results support the potential of CL to mitigate endothelial injury in vitro, though further in vivo studies are required to confirm its translational relevance. Full article

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease predominantly of the small airways and parenchyma. COPD lungs exhibit an influx of circulating innate immune cells, which, when isolated, display impaired functions, including imbalanced protease secretion. In addition to immune cells, the extracellular matrix (ECM) plays a crucial role in COPD pathology. Remodeling of the ECM can generate ECM fragments, which can be released into circulation and subsequently induce pro-inflammatory responses. COPD is a heterogeneous disease, and serological biomarkers can be used to sub-categorize COPD patients for targeted treatments and optimal recruitment in clinical trials. This study evaluated fragments of calprotectin, collagen type VI, and versican, generated by neutrophil elastase and matrix metalloproteinases (MMP-) 2 and 12, respectively, as potential biomarkers of COPD disease, severity, and endotypes. Lower plasma levels of a neoepitope marker of calprotectin, indicative of activated neutrophils (nordicCPa9-HNETM), were detected in COPD donors compared to controls. CPa9-HNE was associated with milder disease, higher degree of air-trapping, and higher serum levels of MMP-2. Deposition of CPa9-HNE levels in lung tissue revealed no differences between groups. Taken together, CPa9-HNE was found to be a potential marker of mild COPD, but further studies are warranted to validate our findings. Full article

Craniofacial development is a complex, highly conserved process involving multiple tissue types and molecular pathways, with perturbations resulting in congenital defects that often require invasive surgical interventions to correct. Remarkably, some species, such as Xenopus laevis, can correct some craniofacial abnormalities during pre-metamorphic stages through thyroid hormone-independent mechanisms. However, the full scope of factors mediating remodeling initiation and coordination remain unclear. This study explores the differential remodeling responses of craniofacial defects by comparing the effects of two pharmacological agents, thioridazine-hydrochloride (thio) and ivermectin (IVM), on craniofacial morphology in X. laevis. Thio-exposure reliably induces a craniofacial defect that can remodel in pre-metamorphic animals, while IVM induces a permanent, non-correcting phenotype. We examined developmental changes from feeding stages to hindlimb bud stages and mapped the effects of each agent on the patterning of craniofacial tissue types including: cartilage, muscle, and nerves. Our findings reveal that thio-induced craniofacial defects exhibit significant consistent remodeling, particularly in muscle, with gene expression analysis revealing upregulation of key remodeling genes, matrix metalloproteinases 1 and 13, as well as their regulator, prolactin.2. In contrast, IVM-induced defects show no significant remodeling, highlighting the importance of specific molecular and cellular factors in pre-metamorphic craniofacial correction. Additionally, unique neuronal profiles suggest a previously underappreciated role for the nervous system in tissue remodeling. This study provides novel insights into the molecular and cellular mechanisms underlying craniofacial defect remodeling and lays the groundwork for future investigations into tissue repair in vertebrates. Full article

Diabetic wounds are a devastating complication that cause chronic pain, recurrent infections, and limb amputations due to impaired healing. Despite advances in wound care, existing therapies often fail to address the underlying molecular dysregulation, highlighting the need for innovative and safe therapeutic approaches. Among these, D-amino acids such as D-tryptophan (D-Trp) have emerged as key regulators of cellular processes; however, their therapeutic potential in diabetic wounds remains largely unexplored. Here, we investigate the therapeutic potential of D-Trp in streptozotocin (STZ)-induced diabetic mice, comparing it with phosphate-buffered saline (PBS) controls and vascular endothelial growth factor (VEGF) as a positive control. Wound healing, inflammation, and histopathology were assessed. Protein and gene expression were analyzed via Western blot and RT-qPCR, respectively. Biolayer interferometry (BLI) measured the binding of D-Trp to hypoxia-inducible factor-1α (HIF-1α). D-Trp accelerated wound healing by modulating extracellular matrix (ECM) remodeling, signaling, and apoptosis. It upregulated matrix metalloproteinases (MMP1, MMP3, MMP-9), Janus kinase 2 (JAK2), and mitogen-activated protein kinase (MAPK) proteins while reducing pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], IL-6). D-Trp also suppressed caspase-3 and enhanced angiogenesis through HIF-1α activation. These findings suggest that D-Trp promotes healing by boosting ECM turnover, reducing inflammation, and activating MAPK/JAK pathways. Thus, D-Trp is a promising therapeutic for diabetic wounds. Full article

This study characterized collagen remodeling in an electron-beam-sterilized porcine acellular dermal matrix (E-PADM) by evaluating host response kinetics during wound healing. E-PADM (n = 6 lots/time point) was implanted in an abdominal wall bridging defect in nonhuman primates (N = 24). Histological, immunohistochemical, and biochemical assessments were conducted. Pro-inflammatory tissue cytokines peaked 1 month post-implantation and subsided to baseline by 6 months. E-PADM-specific serum immunoglobulin G antibodies increased by 213-fold from baseline at 1 month, then decreased to <10-fold by 6–9 months. The mean percentage tissue area staining positively for matrix metalloproteinase-1 plateaued at 3 months (40.3 ± 16.9%), then subsided by 6 months (16.3 ± 11.1%); tissue inhibitor matrix metalloproteinase-1 content plateaued at 1 month (39.0 ± 14.3%), then subsided by 9 months (13.0 ± 8.8%). Mean E-PADM thickness (1.7 ± 0.2 mm pre-implant) increased at 3 months (2.9 ± 1.5 mm), then decreased by 9 months (1.9 ± 1.1; equivalent to pre-implant). Histology demonstrated mild inflammation between 1–3 months, then a peak in host tissue deposition, with ≈75%–100% E-PADM collagen turnover, and fibroblast infiltration and neovascularization between 3–6 months. Picrosirius red staining revealed that mature E-PADM collagen was replaced by host-associated neo-collagen by 6 months. E-PADM implantation induced wound healing, which drove dermal E-PADM collagen remodeling to native, functional fascia-like tissue at the implant site. Full article

There are currently no approved therapeutic treatments targeting metabolic dysfunction-associated steatotic liver disease (MASLD). Albumin, a liver-produced plasma protein with anti-inflammatory and antioxidant properties, is reduced in advanced liver disease. Considering the role of chronic obesity-induced inflammation in MASLD pathogenesis, we investigated whether albumin administration could prevent disease progression to metabolic dysfunction-associated steatohepatitis (MASH). MASLD was induced in mice using a high-fat and high-cholesterol (PC) treatment for 8 weeks, followed by treatment with bovine serum albumin (BSA; 0.8 mg/kg) every three days for another 8 weeks. This regimen prevented time-dependent weight gain, regardless of diet, with 57% and 27% reductions in mice fed a standard chow (Std Chow) or PC diet, respectively. Further, supplementation reduced nuclear factor kappa B (NF-κB) activation by 2.8-fold (p = 0.0328) in PC-fed mice, consistent with albumin’s known anti-inflammatory properties. Unexpectedly, albumin also reduced hepatic neutral lipid accumulation and circulating non-esterified fatty acids. While PC-fed mice did not exhibit full progression to MASH, albumin treatment significantly increased hepatic matrix metalloproteinase-2 expression, suggesting the inhibition of early fibrotic signalling. While further studies are needed to elucidate the underlying mechanisms, these findings offer new insight into the potential of albumin, either alone or in combination with other therapies, to reduce hepatic steatosis in MASLD. Full article