Search Results (4,439)

Inflammation plays a critical role in the pathogenesis of osteoarthritis (OA). The objective of this study was to investigate the anti-inflammatory and chondroprotective properties of Artemisia annua L. water extract (AWE) following the induction of inflammation in cartilage cells (SW1353 cell) through the administration of interleukin-1 beta (IL-1β). We demonstrated significant antioxidant activity, as evidenced by elevated total phenolic and flavonoid content, in addition to robust free radical scavenging capacity, as assessed through DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) assays. Its cytotoxic effects were assessed at a concentration of 200 μg/mL, where no cytotoxic signs were observed in SW1353 cells treated with IL-1β; the levels of reactive oxygen species (ROS) were notably reduced in a dose-dependent manner. The principal inflammatory markers, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), were significantly diminished by AWE treatment. AWE administration led to a dose-dependent reduction in the expression of key proteins involved in the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathways, ultimately resulting in a decrease in the release of matrix metalloproteinases (MMPs), specifically MMP-1 and MMP-13, which are known to contribute to cartilage degradation. Additionally, the levels of degraded collagen type II in the cartilage cells were restored. These findings suggest that reducing oxidative stress and inflammation, along with inhibiting activated MAPK and NF-κB signaling pathways, may ameliorate the progression of IL-1β-induced OA. Furthermore, a molecular docking analysis revealed a strong binding affinity of MMP-13, a critical mediator in the pathogenesis of OA. Six compounds were identified in AWE, corroborating its potential antioxidant and anti-inflammatory effects. Therefore, AWE may serve as a potentially useful therapeutic agent against OA by modulating inflammation-related mechanisms. Full article

Background/Objectives: New anti-tuberculosis compounds are needed to treat patients infected with multi- or extensively drug-resistant Mycobacterium tuberculosis strains. Studies based on spontaneous in vitro mutagenesis can provide insights into the possible modes of action and resistance mechanisms of such new compounds. We evaluated the primary response of M. tuberculosis in vitro to the action of new aroylhydrazones and nitrofuroylamides. Methods: The reference strain H37Rv was cultured on solid media with compounds at increased concentrations relative to MIC. Resistant clones were investigated using whole-genome sequencing and bioinformatics tools to assess the role and potential impact of identified mutations. Results: Some of the mutations are significant (based on in silico analysis), located in essential genes, and therefore of particular interest. Frameshift mutations were observed in (i) Rv2702/ppgK, which is associated with starvation-induced drug tolerance and persistence in mice, and (ii) Rv3696c/glpK, which has been described as a switch on/off mutation associated with drug tolerance. Nonsynonymous substitutions were found in Rv0506/mmpS2, which belongs to the Mmp protein family involved in transport and drug efflux, and in infB, encoding the translation initiation factor IF-2. Conclusions: The primary adaptation of M. tuberculosis to the selective pressure of the tested compounds is complex and multifaceted. It involves multiple unrelated genes and pathways linked to non-specific drug tolerance, efflux systems, or mechanisms counteracting oxidative stress. Full article

Cystic fibrosis (CF) is characterized by chronic respiratory infections and excessive inflammation, driven by both host- and pathogen-derived proteases. The dysregulated activity of proteolytic enzymes such as neutrophil elastase (NE), cathepsin G, and matrix metalloproteases (MMPs) degrades lung tissue, exacerbates airway remodeling, and perpetuates inflammatory cycles. Concurrently, bacterial proteases from pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus contribute to immune evasion and tissue destruction, compounding disease severity. Despite advances in antimicrobial and anti-inflammatory therapies, protease-driven lung damage remains a critical challenge. This review examines the dual role of host and bacterial proteases in CF pathophysiology, highlighting emerging protease-targeted therapies aimed at mitigating lung damage and inflammation. Strategies explored include the inhibition of NE, MMPs, and bacterial proteases, with a focus on innovative therapeutic approaches such as dual-function inhibitors, biologics, and advanced drug delivery systems. By restoring the protease–antiprotease balance, these interventions offer the potential to improve clinical outcomes and quality of life for CF patients. Full article

Ovarian cancer (OC) is one of the most fatal gynecological neoplasms. Meta-analyses have shown that the relationship between body mass index (BMI) and ovarian cancer incidence was detected in some types of ovarian cancer. Chronic inflammation and excessive accumulation of free fatty acids are key adipose tissue-derived factors initiating cancer development. Cancer cells transform adipose-derived stem cells into cancer-associated adipocytes, which produce adipokines and interleukins. It was revealed that adipokines exert a pleiotropic role in ovarian cancer pathogenesis. Chemerin presents both pro-cancer and anti-cancer action in ovarian cancer development. Chemerin induces angiogenesis and increases programmed death ligand-1 (PD-L1) expression, leading to enhanced proliferation and migration of OC cells. Apelin impacts cancer cell migration and acts as a mitogenic factor. Moreover, apelin exerts influence on lipid uptake into cancer cells and accelerates fatty acid oxidation, which provides energy for cancer cells. Visfatin induces matrix metallopeptidase 2 (MMP2) expression involved in extracellular matrix degradation and suppresses claudin 3 and 4 expression. Visfatin also induces a shift to anaerobic glucose metabolism and influences poly-ADP ribose polymerase (PARP). Resistin induces MMP2 and vascular endothelial growth factor (VEGF) expression and contributes to cisplatin-resistance development. A substantial body of evidence indicates that antagonists of adipokines mitigate OC progression, and adipokines are gaining gradual recognition as a potential therapeutic aim in ovarian cancer targeted therapy. Full article

Background/Objectives: Temporary decreases in dermal collagen caused by artificial ultraviolet exposure are largely affected by increased epidermis-derived matrix metalloproteinase (MMP)-1 levels. However, the role of epidermal MMP-1 in dermal tissue remodeling induced by chronic sun exposure remains unclear. This study aimed to clarify the involvement of epidermal and dermal MMP-1 in dermal collagen reduction induced by chronic sun exposure. Methods: Immunofluorescent staining of 30 facial skin tissue samples was performed to visualize MMP-1. The fluorescence intensity of epidermal MMP-1 observed on microscopic images was analyzed in relation to the severity of dermal tissue remodeling and the dermal collagen fiber density. A similar correlation analysis of the number of dermal MMP-1-positive cells was also performed. Results: Epidermal MMP-1 was observed in the stratum spinosum of skin without severe tissue remodeling; however, in skin with severe dermal tissue remodeling, MMP-1 was localized throughout the epidermis. The epidermal MMP-1 signal area and dermal collagen fiber density were negatively correlated (ρ = −0.383; p = 0.0002; n = 90). However, the ratio of dermal MMP-1-positive cells to total dermal cells was only negatively correlated with the collagen fiber density in skin that was not severely remodeled (ρ = −0.746; p = 0.001; n = 15). Conclusions: Epidermal MMP-1 is involved in the tissue remodeling of skin that is subjected to chronic sun exposure and short-term ultraviolet radiation exposure. However, dermal-cell-derived MMP-1 may be involved in biological processes that require an immediate collagen degradation response. The results of this study demonstrate the importance of controlling epidermal MMP-1 to inhibit dermal tissue remodeling induced by chronic sun exposure and provide new insights that are beneficial to the development of anti-photoaging skincare cosmetics. Full article

Repeated exposure to low-level blast overpressure, frequently experienced during explosive breaching and heavy weapons use in training and operations, is increasingly recognised as a serious risk to the neurological health of military personnel. Although research on the underlying pathobiological mechanisms in humans remains limited, this study investigated the effects of such exposure on circulating molecular biomarkers associated with inflammation, neurovascular damage, and endothelial injury. Blood samples from military breachers were analysed for myeloperoxidase (MPO), matrix metalloproteinases (MMPs), and junctional proteins indicative of blood–brain barrier (BBB) disruption and endothelial damage, including occludin (OCLN), zonula occludens-1 (ZO-1), aquaporin-4 (AQP4), and syndecan-1 (SD-1). The results revealed significantly elevated levels of MPO, MMP-3, MMP-9, and MMP-10 in breachers compared to unexposed controls, suggesting heightened inflammation, oxidative stress, and vascular injury. Increased levels of OCLN and SD-1 further indicated BBB disruption and endothelial glycocalyx degradation in breachers. These findings highlight the potential for chronic neurovascular unit damage/dysfunction from repeated blast exposure and underscore the importance of early targeted interventions—such as reducing oxidative stress, reinforcing BBB integrity, and managing inflammation—that could be essential in mitigating the risk of long-term neurological impairment associated with blast exposure. Full article

Growing evidence demonstrates the critical roles of long non-coding RNAs (lncRNAs) in osteoarthritis (OA) pathogenesis. The lncRNA XIST is one of the most commonly studied; however, its function remains unclear. This study aimed to research the molecular mechanism of XIST in human OA chondrocytes. Cells were transfected with small interfering RNA against XIST or with a microRNA (miR)-146a inhibitor in the presence of interleukin (IL)-1β. Viability was detected using MTT; apoptosis using cytometry; and XIST, miR-146a, B-cell lymphoma (BCL)2, and metalloproteinase (MMP)-13 expression using real-time PCR. The analysis of p50 and p65 nuclear factor (NF)-κB was conducted using PCR and immunofluorescence. Our findings showed that XIST was highly expressed in OA chondrocytes when compared to T/C-28a2 lines. Furthermore, XIST silencing significantly promoted survival and limited apoptosis, with a concomitant over expression of BCL2, reduction in MMP-13 mRNA, and NF-κB activation after IL-1β stimulus. Conversely, miR-146a was significantly down-regulated in OA cells, while its levels were increased following XIST silencing; moreover, miR-146a inhibition induced opposite results to those caused by XIST. Finally, the down-regulation of XIST was correlated to the over-expression of miR-146a, with a consequent modulation of BCL2, MMP-13, and NF-κB. This study suggests an influence of the XIST/miR-146a axis on the viability, apoptosis, and matrix degradation occurring in OA. Full article

Currently, the number of e-cigarette and heated tobacco product (HTP) users are steadily increasing, while the number of classic cigarette users are decreasing. The effects of smoking classic cigarettes on human health have been thoroughly described in the literature, but the negative health effects of e-cigarettes and HTPs on the human body are not clearly defined. Among users of different forms of tobacco, those at a particularly high risk of developing particular disease entities should be identified, allowing for the faster implementation of potential treatments, including psychotherapeutic ones. Biomarkers are used for this purpose. This paper summarizes the potential of these compounds from the different exposure groups of classic cigarettes, e-cigarettes, and HTPs, and presents changes in their concentrations in the body fluids of different tobacco users. This review discusses the impact of tobacco use in relation to levels of the following biomarkers: TNF-α, IL-1β, IL-6, IL-8, IL-17, IFN-γ, IL-10, IL-4, Il-13, TGF-β, VEGF EGF, HGF, BDNF, MMP-9, CRP, microplastics, and selected parameters of oxidative stress. This review also includes suggested forms of treatment, including Tobacco Product Use Reduction Programs, to minimize the potential negative effects of the above-mentioned products. Full article

Background: Peripheral artery disease (PAD) is a high-risk vascular condition, and vascular remodeling has become a promising therapeutic approach. Paeoniflorin (PF) is the main bioactive compound in the roots of Paeonia lactiflora Pall, which is commonly used to treat a range of cardiovascular disorders. However, the mechanisms underlying the ameliorating effects of PF on PAD remain unclear. Therefore, the purpose of this study was to explore the therapeutic efficiency of PF on PAD and determine its mechanisms. Methods: The blood flow of mice was detected with a laser Doppler dot scanning imaging system. HE staining was used to observe the morphological changes of ischemic muscle. The changes in the serologic indexes were detected with an automatic biochemical assay, and the capillary density of ischemic gastrocnemius was detected with a Lectin immunofluorescence assay. The expression of angiogenesis-related proteins in ischemic gastrocnemius was detected with Western blotting, and the proportion of macrophages and neutrophils in total cells was detected with flow cytometry. Results: PF significantly increased blood flow, capillary density and protein expressions of vascular endothelial growth factor A (VEGFA), matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 2 (MMP9), and estrogen receptor α (ERα) in mouse ischemic tissue in a PAD model. PF enhances the migration of endothelial cells and promotes the formation of tubular structures, involving the ERα/ROCK2 signaling pathway. Furthermore, PF was found to promote the phenotypic transformation of macrophages and alleviated grave inflammatory responses during vascular remodeling. Conclusions: We determined that PF as a potent compound in promoting angiogenesis and mitigating inflammatory responses during revascularization. Full article

Hypermobile Ehlers–Danlos Syndrome (hEDS) is a hereditary connective tissue disorder characterized by joint hypermobility, skin hyperextensibility, and systemic manifestations such as chronic fatigue, gastrointestinal dysfunction, and neurological symptoms. Unlike other EDS subtypes with known genetic mutations, hEDS lacks definitive markers, suggesting a multifactorial etiology involving both mitochondrial dysfunction and non-mitochondrial pathways. This scoping review, conducted in accordance with the PRISMA-ScR guidelines, highlights mitochondrial dysfunction as a potential unifying mechanism in hEDS pathophysiology. Impaired oxidative phosphorylation (OXPHOS), elevated reactive oxygen species (ROS) levels, and calcium dysregulation disrupt cellular energetics and extracellular matrix (ECM) homeostasis, contributing to the hallmark features of hEDS. We reviewed candidate genes associated with ECM remodeling, signaling pathways, and immune regulation. Protein–protein interaction (PPI) network analyses revealed interconnected pathways linking mitochondrial dysfunction with these candidate genes. Comparative insights from Fabry disease and fragile X premutation carriers underscore shared mechanisms such as RNA toxicity, matrix metalloproteinases (MMP) activation, and ECM degradation. These findings may suggest that mitochondrial dysfunction amplifies systemic manifestations through its interplay with non-mitochondrial molecular pathways. By integrating these perspectives, this review provides a potential framework for understanding hEDS pathogenesis while highlighting latent avenues for future research into its molecular basis. Understanding the potential role of mitochondrial dysfunction in hEDS not only sheds light on its complex molecular etiology but also opens new paths for targeted interventions. Full article

Circulating small extracellular vesicles (sEVs) are emerging as potential biomarkers for glioblastoma progression. This study aimed to compare the levels of matrix metalloproteinases (MMP2 and MMP9), terminal complement complex (C5b-9), and VEGF-A in circulating sEVs in glioblastoma patients (GBMPs) with and without tumor recurrence. Using differential ultracentrifugation, sEVs were isolated from blood samples of GBMPs with no tumor recurrence for over one year (n = 6) and after first relapse (n = 14). The vesicles were characterized and quantified using flow cytometry. In both groups, C5b-9 was predominantly detected on tumor-specific circulating sEVs (glial fibrillary acidic protein (GFAP)-positive sEVs) with high VEGF-A expression, while C5b-9 was significantly less frequent on sEVs with low VEGF-A expression (p < 0.05). GFAP+VEGF+dimMMP2-C5b-9+ vesicles were rarely detected in GBMPs without relapse, suggesting their potential utility as biomarkers for a favorable relapse-free prognosis. In recurrent GBMPs, a positive correlation was observed between GFAP+VEGF+bright MMP2+C5b-9+ sEVs and MGMT gene promoter methylation levels (r = 0.543, p < 0.05). Additionally, a trend toward a negative correlation was found between GFAP+VEGF+bright MMP2+C5b-9- sEVs and mutant p53 expression in primary tumor tissue (r = −0.44, p = 0.114). These findings suggest that sEV profiles may serve as valuable prognostic markers for glioblastoma recurrence and treatment responses. Full article

Cellular senescence plays a crucial role in skin aging, with senescent dermal fibroblasts contributing to reduced skin elasticity and increased inflammation. This study investigated the potential of Ganoderma lucidum (Reishi) ethanol extract to modulate the senescent phenotype of human dermal fibroblasts. Reishi powder of two different vendors was used. The extract was produced by extracting the Reishi powder for at least three weeks in 40% ethanol at room temperature. Etoposide-induced senescent fibroblasts were treated with Reishi extracts from two commercial sources for 14 days. Gene expression analysis was performed using qPCR to assess senescence makers, antioxidant defense, and extracellular matrix remodeling. Results showed that Reishi extracts significantly upregulated antioxidant and cytoprotective genes, including Heme oxygenase 1 (HO-1), γ-Glutamylcysteine synthetase (γGCS-L), and NAD(P)H dehydrogenase [quinone] 1 (NQO1), compared to untreated controls. Importantly, Reishi treatment suppressed the expression of p16^INK4a, a key marker of cellular senescence, while transiently upregulating p21^Cip1. The extracts also demonstrated potential senolytic properties, reducing the percentage of senescent cells as measured by senescence-associated β-galactosidase staining. However, Reishi treatment did not mitigate the upregulation of MMP1 and IL-8 in one Reishi treatment group, indicating differences in the preparations of different vendors. These findings suggest that Ganoderma lucidum extract may help alleviate some aspects of cellular senescence in dermal fibroblasts, primarily through enhanced antioxidant defense and cytoprotection, potentially offering a novel approach to combat skin aging. Full article

In recent years, researchers have been paying special attention to the tumor microenvironment (TME). One of the most important factors contributing to the development and progression of cancer is the destruction of elements of the extracellular matrix (ECM). The most important substances involved in regulating the extracellular matrix degradation process are extracellular matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). In the process of cancer cell migration, chemokines secreted by target tissues, as well as the profile of chemokine receptors presented on cancer cells, play a key role. In the presented work, five components of the TME were selected: MMP-2, MMP-7, TIMP-2, CXCL-9, and CXCL-10. In the years 2018–2021, peripheral blood samples were collected before the start of treatment and then on day 33 of intensive treatment from 31 patients diagnosed with ALL. The results indicate that the levels of MMP-2, MMP-7, and TIMP-2 did not statistically significantly change before and during treatment of ALL patients. The decrease in CXCL-9 and CXCL-10 levels in the patients’ serum on the 33rd day of therapy turned out to be statistically significant. Our study indicates that serum is also a valuable material for the evaluation of these substances. Conclusions: CXCL-9 and CXCL-10 could be used as one of markers for monitoring the response to treatment and a potential marker of ALL recurrence in pediatric patients. The role of MMP-2, MMP-7, and TIMP-2 in the assessment of response to therapy in children with ALL has not been confirmed. Full article

Background/Objectives: Osteoarthritis (OA) is a very common degenerative joint disease that has a significant negative impact on patients’ lives and which can lead to functional limitations and disability. Matrix metalloproteinase 13 (MMP-13) is a key enzyme responsible for the degenerative changes in cartilage occurring during the pathogenesis of OA. This cohort study analyzed the differences in the expression level of MMP13 mRNA in articular cartilage with subchondral bone and in the synovium of patients with OA, according to the disease stage, in order to develop potential markers for OA progression, as well as for the degree of pain perception, in order to discover a molecular biomarker related to pain. Methods: In thirty-one patients (n = 31), the expression level of the studied gene was assessed in the affected and unaffected areas of the knee joint using the qPCR method. Statistical analysis was performed using the Mann–Whitney U test, the Kruskal–Wallis test, and Spearman’s rank correlation coefficient. Results: A significantly higher expression level of MMP13 mRNA was noticed in the OA-affected articular cartilage with subchondral bone compared to the control tissue (p = 0.027, Mann–Whitney U test). The expression level of MMP13 mRNA was higher in patients with stage 4 knee OA than in those with stage 3, but the difference in MMP13 mRNA expression level was statistically insignificant (p > 0.05, Mann–Whitney U test). A higher MMP13 mRNA expression level was noticed in the OA-affected synovium compared to the control tissue (median RQ: 0.068 and 0.037, respectively), but these differences were not significant (p > 0.05, Mann–Whitney U test). A significantly higher MMP13 mRNA expression level was observed in the synovium of stage 4 knee OA patients compared to stage 3 patients (p = 0.015, Mann–Whitney U test). There was no significant difference in the expression level of MMP13 mRNA between both tissues, i.e., the articular cartilage with subchondral bone and the synovium from the stage 3 group and the control tissue (p > 0.05, Mann–Whitney U test); however, a significant difference was found between these tissues in stage 4 and in the control tissue (p = 0.014, Mann–Whitney U test). Conclusions: The results of our pilot study indicated the diagnostic potential of MMP13 mRNA and proved its role in the development and progression of OA. Further studies are needed to verify the potential utility of MMP13 mRNA in the development of molecularly targeted therapy for patients with OA. Full article