Matrix Metalloproteinase Research Articles

Mechanisms of drug resistance to neoadjuvant chemotherapy in breast cancer

Aim. Тo study the molecular genetic characteristics of the tumor microenvironment and the mechanisms of cell death in resistant locally advanced breast cancer.Materials and methods. The study included 48 patients with breast cancer T2–4N0–3M0–1 (mean age 55.6 ± 9.8 years), and 29 patients of comparable age with breast fibroadenoma. According to the design of the study, patients were divided into groups: Group 1 included women with breast cancer resistant to neoadjuvant chemotherapy (n = 23), Group 2 – with breast cancer and a complete response to neoadjuvant chemotherapy (n = 25), control Group – with fibroadenoma (n = 29). The expression of markers CD4+, CD8+, CD20+, CD68+, tumor necrosis factor α (TNF-α), vascular endothelial growth factor A (VEGF A), Ang-2, matrix metalloproteinase 12 (MMP-12), inducible nitric oxide synthase (iNOS), bcl-2, p53, CD95 was assessed using immunohistochemistry.Results. When phenotyping immune cells, the following differences were obtained: in the tumor tissue of patients in Group 1, a significant decrease in the number of cytotoxic CD8+ cells was noted compared to Group 2 (p = 0.001) and control (p = 0.032). In Group 2, a significant increase in the number of CD68+ cells was revealed in relation to Group 1 (p = 0.027). The cytokine profile of the tumor microenvironment in Group 1 is characterized by statistically significant overexpression of TNF-α compared to Group 2 (p >0.001) and the control Group (p = 0.01). With regard to apoptotic factors, noteworthy is the significant decrease in the expression of bcl-2 and p53 in Group 1 compared to Group 2 (p = 0.001 and p = 0.02 accordingly).Conclusion. The presented results can serve as the basis for the creation of diagnostic algorithms that have predictive value regarding the effectiveness of NCT, and also to help identify new targets to justify the use of combined breast cancer treatments in the early stage.

Platelet-rich plasma ameliorates cartilage degradation in rat models of osteoarthritis via the OPG/RANKL/RANK system.

Osteoarthritis (OA) is one of the most common degenerative joint diseases in the elderly, which is featured by the degradation of articular cartilage. Recently, platelet-rich plasma (PRP) injection into the affected joint has become one biological therapy for OA treatment. The OPG/RANKL/ RANK signalling has been reported to mediate OA progression. Our study aimed to confirm whether PRP injection retards OA development through the regulation of the OPG/RANKL/RANK system. The OA rat models were induced by medial menisci resection combined with anterior cruciate ligament transection. Four weeks after surgery, OA-induced rats received intra- articular injection with 50 μL PRP once a week for 6 weeks. Rats were euthanised one week after the 6th injection. Rat knee joints were subjected to histopathological examination by haematoxylin- eosin (H&E) and safranin O staining. Osteoprotegerin (OPG), receptor activator of nuclear factor kappa B (RANK), and RANK ligand (RANKL) in the articular cartilage of rats were tested through immunofluorescence staining and western blotting. Serum interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels were measured by enzyme-linked immunosorbent assay (ELISA). Matrix metalloproteinase- 13 (MMP-13), aggrecan, collagen α, IL-1β, IL-6, tumour necrosis factor-alpha (TNF-α), and nuclear factor kappa-B (NF-κB) mRNA and protein expression in rat articular cartilage were examined by real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. Intra-articular injections of PRP significantly improved the structural integrity of the articular cartilage and enhanced the synthesis of glycosaminoglycans. PRP reduced MMP-13 protein level but increased aggrecan and collagen α protein levels in articular cartilage of OA rats. OA-induced increase in serum IL-1β, IL-6, and TNF-α concentrations as well as increased MMP-13, and decreased collagen II mRNA levels were reversed by the administration of PRP. OA increased IL-1β, TNF-α, and NF-κB mRNA expression in rat articular cartilage whereas PRP administration ameliorated these changes. Moreover, in the articular tissue of OA-induced rats the increased OPG protein level was further elevated by PRP injections whereas the protein level of RANK did not change. The increase in the protein level of RANKL in OA-induced articular tissue was offset by PRP administration. PRP elevated OPG mRNA expression and the OPG/RANKL mRNA ratio, but reduced RANKL mRNA expression and the RANKL/RANK mRNA ratio in the articular tissue of OA-induced rats. PRP mitigates cartilage degradation and inflammation in experimental knee OA by regulating the OPG/RANKL/RANK signalling system.

Epidemiology and pathogenesis of osteoarthritis

Background: Osteoarthritis (OA) is the most common form of arthritis and poses a considerable socioeconomic burden, contributing to disability and decreased quality of life, particularly in older adults. However, the current treatment for OA is limited to pain relief, and it is necessary to develop disease-modifying OA drugs that target specific molecular mechanisms of its pathogenesis.Current Concepts: The prevalence of OA increases with age, with the incidence being higher in individuals aged over 60 years. Furthermore, women are more likely to develop knee and hand OA, whereas hip OA is more common in men. The global burden of OA is increasing, driven by an aging population and increasing obesity. The main pathological feature of OA is the degradation of the cartilage extracellular matrix by catabolic proteases such as matrix metalloproteinase 13 (MMP13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (Adamts5), which are regulated by various signaling pathways and transcription factors. The metabolic shift towards glycolysis, which is associated with mitochondrial dysfunction, increases oxidative stress, ultimately leading to chondrocyte senescence and apoptosis. Chondrocytes in the superficial zone have stem cell-like properties and secrete anabolic proteins such as lubricin and fibulin-3. Subchondral bone remodeling and chondrocyte senescence have emerged as critical mechanisms of OA progression.Discussion and Conclusion: The understanding of OA has markedly evolved in recent years, shifting from the traditional view of OA as a “wear and tear” disease to a multifaceted condition with a complex pathogenesis. This paradigm shift could contribute to the development of novel strategies to halt OA progression.

Cellular and Molecular Mechanisms of Hypertrophy of Ligamentum Flavum.

Hypertrophy of the ligamentum flavum (HLF) is a common contributor to lumbar spinal stenosis (LSS). Fibrosis is a core pathological factor of HLF resulting in degenerative LSS and associated low back pain. Although progress has been made in HLF research, the specific molecular mechanisms that promote HLF remain to be defined. The molecular factors involved in the onset of HLF include increases in inflammatory cytokines such as transforming growth factor (TGF)-β, matrix metalloproteinases, and pro-fibrotic growth factors. In this review, we discuss the current understanding of the mechanisms involved in HLF with a particular emphasis on aging and mechanical stress. We also discuss in detail how several pathomechanisms such as fibrosis, proliferation and apoptosis, macrophage infiltration, and autophagy, in addition to several molecular pathways involving TGF-β1, mitogen-activated protein kinase (MAPKs), and nuclear factor-κB (NF-κB) signaling, PI3K/AKT signaling, Wnt signaling, micro-RNAs, extracellular matrix proteins, reactive oxygen species (ROS), etc. are involved in fibrosis leading to HLF. We also present a summary of the current advancements in preclinical animal models for HLF research. In addition, we update the current and potential therapeutic targets/agents against HLF. An improved understanding of the molecular processes behind HLF and a novel animal model are key to developing effective LSS prevention and treatment strategies.

Secretion of endoplasmic reticulum protein VAPB/ALS8 requires topological inversion

VAMP-associated protein (VAP) is a type IV integral transmembrane protein at the endoplasmic reticulum (ER). Mutations in human VAPB/ALS8 are associated with amyotrophic lateral sclerosis (ALS). The N-terminal major sperm protein (MSP) domain of VAPB (Drosophila Vap33) is cleaved, secreted, and acts as a signaling ligand for several cell-surface receptors. Although extracellular functions of VAPB are beginning to be understood, it is unknown how the VAPB/Vap33 MSP domain facing the cytosol is secreted to the extracellular space. Here we show that Vap33 is transported to the plasma membrane, where the MSP domain is exposed extracellularly by topological inversion. The externalized MSP domain is cleaved by Matrix metalloproteinase 1/2 (Mmp1/2). Overexpression of Mmp1 restores decreased levels of extracellular MSP domain derived from ALS8-associated Vap33 mutants. We propose an unprecedented secretion mechanism for an ER-resident membrane protein, which may contribute to ALS8 pathogenesis.

Simple theranostics nanoagent for precision suppression of tumor growth and metastasis: A traditional fermented product having a novel functional breakthrough

Biomass-based nanoagents constitute a focal point in the clinical development of tumor nanotheranostics, characterized by their high biocompatibility, biodegradability, controllability, and sustainability. However, achieving satisfactory nanoagents with biological safety and high theranostic efficacy for clinical translation remains a significant challenge. Herein, based on the design concept of medicine food homology, we developed a simple, mass-produced theranostics nanoagent (HSAVMn@CM NA) using Shanxi aged vinegar (SAV) as the raw material, enabling second near-infrared fluorescence/photoacoustic (NIR-II FL/PA) imaging-guided photo/catalytic/chemodynamic synergistic tumor therapy. A novel strategy involving the hydrolysis of SAV (HSAV) via the hydrolysis-acidification method has been developed to enhance NIR-II FL imaging performance. The HSAVMn@CM NAs have improved tumor-targeted efficiency through biomimetic modification of tumor membranes. Guided by NIR-II FL/PA dual-modal imaging, the HSAVMn@CM NAs achieve targeted photothermal/photodynamic synergistic phototherapy. Notably, the employment of a single laser source for simultaneous photothermal/photodynamic therapy has led to an enhancement in the efficacy of phototherapy. Moreover, the HSAVMn@CM NAs effectively chelated Zn2+ ions within the tumor microenvironment, to inhibit matrix metalloproteinase 2/9 (MMP 2/9) activity, thereby synergistically suppressing primary tumor growth and metastasis. Taken together, this research provides a novel design strategy for biomass-based nanoagents with potential clinical translation in precise tumor theranostics.

Transglutaminase 2 promotes epithelial-to-mesenchymal transition by regulating the expression of matrix metalloproteinase 7 in colorectal cancer cells via the MEK/ERK signaling pathway

Tissue transglutaminase 2 (TGM2) and matrix metalloproteinase 7 (MMP7) are suggested to be involved in cancer development and progression, however, their specific role in colon cancer remains elusive. The present study investigated whether TGM2 and MMP7 influence epithelial-mesenchymal-transition (EMT) processes of colon cancer cells.TGM2 was either overexpressed or knocked down in SW480 and HCT-116 cells, and MMP7 expression and activity analyzed. Conversely, MMP7 was silenced and its correlation with TGM2 expression and activity examined. Co-immunoprecipitation served to evaluate TGM2-MMP7-interaction. TGM2 and MMP7 expression were correlated with invasion, migration, EMT marker expression (E-cadherin, N-cadherin, Slug, Snail), and ERK/MEK signaling.TGM2 overexpression enhanced MMP7 expression and activity, promoted cell invasion, migration and EMT, characterized by increased N-cadherin and Snail/Slug expression. TGM2 knockdown resulted in the opposite effects. Knocking down MMP7 was associated with reduced TGM2 protein expression, cell invasion and migration. Down-regulation of MMP7 diminished ERK/MEK signaling, whereas its up-regulation activated this pathway. The ERK-inhibitor GDC-0994 blocked phosphorylation of MEK/ERK and suppressed TGM2 and MMP7.TGM2 communicates with MMP7 in colon cancer cells forces cell migration and invasion by the MEK/ERK signaling pathway and triggers EMT. Inhibiting TGM2 could thus offer new therapeutic options to treat patients with colon cancer, particularly to prevent metastatic progression.

Prodrug Nanomedicine for Synovium Targeted Therapy of Inflammatory Arthritis: Insights from Animal Model and Human Synovial Joint Fluid.

Many patients cannot tolerate low-dose weekly methotrexate (MTX) therapy for inflammatory arthritis treatment due to life-threatening toxicity. Although biologics offer a target-specific therapy, it raises the risk of serious infections and even cancer due to immune system suppression. We introduce an anti-inflammatory arthritis MTX ester prodrug using a long-circulating biocompatible polymeric macromolecule: folic acid (FA) functionalized hyperbranched polyglycerol (HPG). In vitro the drug MTX is incrementally released through pH and enzymatic degradation over 2 weeks. The role of matrix metalloproteinases (MMPs) in site-specific prodrug activation was verified using synovial fluid (SF) of 26 rheumatology patients and 4 healthy controls. Elevated levels of specific MMPs-markers of joint inflammation-positively correlated with enhanced prodrug release explained by acid-catalyzed hydrolysis of esters by proteases. Intravenously administered 111In-radiolabeled prodrug confirmed by SPECT/CT imaging that it accumulated preferentially in inflamed joints while reducing off-target side-effects in a mouse model of rheumatoid arthritis (RA). Added FA as a targeting vector prolonged prodrug action; prodrug with 4x less MTX applied every 2 weeks was as effective as weekly MTX therapy. The preclinical results suggest a prodrug-based strategy for the treatment of inflammatory joint diseases, with potential for other chronic inflammatory diseases and cancer.

Exploring the Bioactive Potential of Taraxacum officinale F.H. Wigg Aerial Parts on MDA Breast Cancer Cells: Insights into Phytochemical Composition, Antioxidant Efficacy, and Gelatinase Inhibition within 3D Cellular Models

In this work, aerial parts of Taraxacum officinale F.H. Wigg. produced in Umbria, Italy, were chemically investigated by solid-phase microextraction/gas chromatography–mass spectrometry (SPME/GC-MS) to describe their volatile profile. The results obtained showed the preponderant presence of monoterpenes, with limonene and 1,8-cineole as the main components. Further analyses by GC/MS after derivatization reaction were performed to characterize the non-volatile fraction highlighting the presence of fatty acids and di- and triterpenic compounds. T. officinale methanol and dichloromethane extracts, first analyzed by HRGC/MS, were investigated to evaluate the antioxidant activity, cytotoxicity, and antiproliferative properties of MDA cells on the breast cancer cell line and MCF 10A normal epithelial cells as well as the antioxidant activity by colorimetric assays. The impact on matrix metalloproteinases MMP-9 and MMP-2 was also explored in 3D cell systems to investigate the extracts’ efficacy in reducing cell invasiveness. The extracts tested showed no cytotoxic activity with EC50 > 250 µg/mL on both cell lines. The DPPH assay revealed higher antioxidant activity in the MeOH extract compared with the DCM extract, while the FRAP assay showed a contrasting result, with the DCM extract exhibiting slightly greater antioxidant capacity. After treatment for 24 h with a non-cytotoxic concentration of 500 µg/mL of the tested extracts, gelatin zymography and Western blot analyses demonstrated that both MeOH and DCM extracts influenced the expression of MMP-9 and MMP-2 in MDA cells within the 3D cell model, leading to a significant decrease in the levels of these gelatinases, which are crucial markers of tumor invasiveness.

Clinical and morphological features of the myometrium in patients with placental adherent and invasive pathology

BACKGROUND: The fast increase in the frequency of placental adherent and invasive pathology worldwide accounts for the growing interest in studying the pathogenesis of placenta accreta. According to the literature, the clinical and morphological features of the myometrium from the placental attachment area in placental adherent and invasive pathology are described in single articles. Study of morphological features using proteolytic markers in the myometrium from the placenta accreta area could help in understanding the pathogenesis of placental adherent and invasive pathology. For the first time in this study, the clinical and morphological features of the myometrium from the placental attachment area in patients with uterine scar and placental adherent and invasive pathology are compared with the myometrium of women with uterine scar without placenta accreta and intact myometrium. AIM: The aim of this study was to evaluate the expression of matrix metalloproteinase 2 and tissue inhibitors of matrix metalloproteinases 1 and 2 in myometrial biopsies in placental adherent and invasive pathology. MATERIALS AND METHODS: This study included 15 myometrial biopsies from the placental site, which were divided into three groups according to the clinical diagnosis of the patients: group 1 (main group), with a uterine scar after cesarean section and placental adherent and invasive pathology (n = 5); group 2 (comparison group), with a uterine scar after cesarean section (n = 5); group 3 (control group), with a normal pregnancy without a uterine scar (n = 5). Histological examination was carried out using the standard procedure. Immunohistochemical study was performed using antibodies to matrix metalloproteinase 2 and tissue inhibitors of matrix metalloproteinases 1 and 2 (Abcam, USA). Morphometry was carried out using the VideoTesT-Morphology 5.2 program (Videotest Ltd., Russia). The statistical analysis was performed using the IBM SPSS Statistics 26.0 software. RESULTS: In the biopsies of the main group, we verified terminal chorionic villi with hypervascularization and uneven plethora of the vascular bed among hypertrophied muscle fibers, a basal plate with lumen ectasia of unevenly full-blooded vessels, and the absence of a decidual membrane, in contrast to groups 2 and 3. The matrix metalloproteinase 2 expression area in the main group was higher than in the comparison and control groups (p = 0.008; p1–2 = 0.049*, p1–3 = 0.011), the matrix metalloproteinase 2 optical density not differing between the groups (p = 0.122). The tissue inhibitors of matrix metalloproteinases 1 expression area was higher in the comparison group compared to the main group (p = 0.035; p2–3 = 0.032), and the tissue inhibitors of matrix metalloproteinases 1 and 2 optical density was higher in the comparison group compared to control (p = 0.008; p2–3 = 0.005). CONCLUSIONS: In myometrial biopsies of patients with a uterine scar and placental adherent and invasive pathology, we verified pathology of the basal plate of the placenta, increased matrix metalloproteinase 2 expression and decreased tissue inhibitors of matrix metalloproteinases 1 expression, which may indicate the peculiarities of the inflammatory response in the myometrium in placental adherent and invasive pathology.

Unwinding the Threads of Mesoporous Silica Nanoparticles as Cutting-Edge for the Management of Inflammation: An Updated Review.

Inflammation serves as a protective response to combat cellular and tissue damage. There is currently a wide array of synthetic and traditional therapies available for the treatment of inflammatory diseases. However, it is necessary to create a drug delivery system based on nanotechnology that can improve the solubility, permeability, and bioavailability of current treatments. Mesoporous silica nanoparticles (MSNPs) are inorganic materials known for their organised porous interiors, high pore volumes, substantial surface area, exceptional selectivity, permeability, low refractive index, and customisable pore sizes. This review offers concise insights into the progression of the pathophysiology of inflammation, as well as the inducers, mediators, and effectors that are involved in the inflammatory pathway. This study focuses on the growing significance of MSNPs in the treatment of neuroinflammation, inflammatory bowel disease, arthritic inflammation, lung inflammation, and wound healing applications. This review also presents the latest information on the crucial role of MSNPs in delivering herbal medicines for the treatment of inflammation. A comprehensive literature search was conducted for this aim, utilising the Google Scholar, PubMed, and ScienceDirect databases. A systematic review was undertaken utilising scholarly articles published in peer-reviewed journals from 2000 to 2024. The inflammatory mediators involved in the pathophysiology of inflammation include platelet-activating factor, lipoxygenase, cyclooxygenase, Interferon-α, interleukin-6, interleukin- 1β, matrix metalloproteinases, inducible nitric oxide synthase, nuclear factor-κB, prostaglandins, nitric oxide, and phospholipase A2. MSNPs have the potential to be used in the treatment of neuroinflammation, inflammatory bowel disease, arthritic inflammation, lung inflammation, and wound healing. The investigation of the MSNPs of plant-based compounds such as berberine, tetrahydrocannabinol, curcumin, and resveratrol has shown successful results in recent years for the purpose of managing inflammation. This review demonstrates that MSNPs have a strong potential to play a positive role in delivering synthetic and plant-based therapies for the treatment of inflammatory illnesses.

Molecular mechanism of mechanical pressure induced changes in the microenvironment of intervertebral disc degeneration.

Lower back pain, as a typical clinical symptom of spinal degenerative diseases, is emerging as a major social problem. According to recent researches, the primary cause of this problem is intervertebral disc degeneration (IVDD). IVDD is closely associated with factors such as age, genetics, mechanical stimulation (MS), and inadequate nutrition. In recent years, an increasing number of studies have further elucidated the relationship between MS and IVDD. However, the exact molecular mechanisms by which MS induces IVDD remain unclear, highlighting the need for in-depth exploration and study of the relationship between MS and IVDD. Search for relevant literature on IVDD and MS published from January 1, 2010, to the present in the PubMed database. One of the main causes of IVDD is MS, and loading modalities have an impact on the creation of matrix metalloproteinase, the metabolism of the cellular matrix, and other biochemical processes in the intervertebral disc. Nucleus pulposus cell death induced by MS, cartilage end-plate destruction accompanied by pyroptosis, apoptosis, iron death, senescence, autophagy, oxidative stress, inflammatory response, and ECM degradation interact with one another to form a cooperative signaling network. This review discusses the molecular mechanisms of the changes in the microenvironment of intervertebral discs caused by mechanical pressure, explores the interaction between mechanical pressure and IVDD, and provides new insights and approaches for the clinical prevention and treatment of IVDD.

Comparison of tear Matrix Metalloproteinase 9 (MMP-9) estimation with Schirmer's test in Ocular Surface Disorders.

Ocular surface disorder (OSD) is a vexed eye problem and a diagnostic conundrum. Diagnosis has traditionally depended upon symptoms and tests like Schirmer's, TBUT, staining with dyes, and tear meniscus height. Schirmer's test is the most popular. However, the test strips irritate with reflex tearing - producing false high results. Matrix Metalloproteinase 9 (MMP) in the tear is believed to be expressed by stressed epithelial cells of the corneal surface - a key pathology in dry eye disease. This study attempts to compare the results of Schirmer's test and MMP-9 so that the test can individually or severally add to a more definite diagnosis of dry eye disease. 100 eyes of 50 symptomatic patients underwent MMP-9 estimation and were divided into two groups (MMP-9+ve and MMP-9-ve). They were then sub-grouped as per DEWS-2007 based on Schirmer test levels and Ocular Symptomatology Score (OSS). The two groups were compared for severity of dry eye based on Schirmer's test and OSS. Mean Schirmer's value was 12.85 (SD 7.07) for MMP-9+ve and 19.18 (SD 8.94) for MMP-9-ve patients. 80% of patients with severe dry eye and 55.6% of moderate dry eye patients were positive for MMP-9. 85% of the MMP-9 patients had OSS values of 2 or 3. A higher OSDI and positive MMP-9 were shown to be correlated in a statistically remarkable way (p<0.001). The OSDI values of 0-12 for 3/44 (6.8%) positive results, 13-22 for 2/8 (25%) positive results, 23-32 for 4/14 (28.6%) positive results, and 33-100 for 13/35 (37.1%) positive results all showed an increase in MMP-9 positivity along with a rise in the subjective severity of the illness. MMP-9 compares well with Schirmer's values and DED categories based on Schirmer's. The result pointed towards the usefulness of this test in diagnosing patients who may have not yet manifested symptoms.

SENP7 inhibits glioblastoma metastasis and invasion by dissociating SUMO2/3 binding to specific target proteins.

The poor surgical efficacy and recurrence of glioblastoma (GBM) are due to its lack of visible infiltrative features. Our bioinformatics study suggests that low expression of small ubiquitin-like modifier (SUMO)-specific protease 7 (SENP7) indicates poor prognosis in GBM. This study investigated the effect of SENP7 expression on the invasion, migration, and proliferation of GBM cells and aims to identify the SUMO target proteins affected by SENP7. SENP7 expression was analyzed in eight GBM tumor samples and four GBM cell lines, comparing them to normal brain tissue. The effect of SENP7 overexpression on GBM LN229 cell migration, invasion, and proliferation was examined through in vitro assays. Furthermore, four SUMO target proteins involved in tumor invasion and proliferation (CDK6, matrix metalloproteinase-9 [MMP9], AKT, and HIF-1α) were studied to explore SENP7's molecular mechanism. SENP7 expression was significantly lower in GBM tumors compared to normal tissue. SENP7 overexpression in LN229 cells inhibited migration and invasion without affecting proliferation. Overexpression reduced the levels of MMP9, AKT, and HIF-1α, but not CDK6. Immunohistochemical analysis showed decreased MMP9 and CD31 levels, suggesting reduced tumor invasion and angiogenesis. However, SENP7 overexpression did not affect tumor growth in vivo. SENP7 inhibits GBM invasion by dissociating proteins associated with tumor invasion from SUMO2/3, providing a potential target for future GBM therapies.

Effective extraction of Xuetongsu and its role in preventing RA synovial hyperplasia by targeting synovial cell migration and apoptosis

Kadsura heteroclita (Roxb) Craib also named Xuetong in Tujia ethnomedicine in China, has been traditionally employed in rheumatoid arthritis (RA) treatment. Our preceding investigations have elucidated that Xuetongsu (XTS), a triterpenoid compound predominant in Xuetong, showed excellent anti-RA-fibroblast-like synoviocytes (RAFLS) proliferation effect. However, XTS belongs to the trace components of the Xuetong plant, which poses certain limitations to the research. In this study, we designed a method that enhanced the extraction yield of XTS and explored the mechanism of its inhibition of RAFLS cell proliferation and migration in the treatment of RA. The results displayed that XTS reduced RAFLS cell proliferation, with an IC50 value of 4.68 ± 0.65 µM. A series of experimental techniques were utilized to show that XTS induce apoptosis in RAFLS cells at concentrations ranging from 4.5 to 18 µM, including wound healing assay, flow cytometry, and western blot analysis. Moreover, XTS at dosages of 0.42–0.84 mg/kg markedly attenuated paw swelling and synovial hyperplasia in arthritic rats, primarily through the inhibition of RAFLS migration and promotion of RAFLS apoptosis via High mobility group box 1 (HMGB-1)/Matrix metalloproteinase-9 (MMP-9)/MMP-13 signaling pathway and Bcl-2/Bax/Caspase-3 signaling pathway, respectively.

Role of Inflammation and Motility Disorders in the Development, Course and Consequences of Functional Gastrointestinal and Biliary Tract Diseases (Literature Review and Expert Panel Resolution)

Aim: to present the results of the Expert Panel with a discussion of modern concepts of the pathogenesis of functional gastrointestinal diseases and the possibilities of multitarget therapy with trimebutine. Key points. Low-grade inflammation can be considered as a morphological substrate of functional diseases with an increase in activated mastocytes and eosinophils, T-helpers 2 and T-helpers 17 in the gastrointestinal mucosa. In the development in the content of visceral hypersensitivity, the functional connection between mastocytes and TRPV1-positive sensory endings of the vagus nerve is of great importance. Proinflammatory cytokines and matrix metalloproteinases can enter the systemic circulation, provoking the development of systemic manifestations. Increased levels of proinflammatory cytokines are supported by altered intestinal permeability and microbiota. Functional diseases are believed to modify the symptoms and course of concomitant organic diseases of the gastrointestinal tract (for example, functional diseases of the biliary tract may contribute to the development of cholelithiasis, pancreatitis). The peripheral μ-, κ- and δ-receptor agonist trimebutine (Trimedat®) regulates the production of enterohormones, modulates motility throughout the gastrointestinal tract and normalizes visceral sensitivity. The effectiveness of trimebutine in the treatment of functional disorders has been shown in various studies. Trimebutine helps reduce the production of proinflammatory cytokines, including interleukin-6. Conclusion. In the treatment of functional diseases of the gastrointestinal tract, trimebutine can be considered as a multitarget agent, since the drug helps to normalize motility, reduces the degree of visceral hypersensitivity, exhibits anti-inflammatory and neuroregenerative effects, and can also increase the effectiveness of treatment of concomitant diseases.

The Role of Macrophages in the Pathogenesis of Celiac Disease

Aim: to present data on the involvement of macrophages in the pathogenesis of celiac disease and the development of possible treatment methods for this disease aimed at changing the function of macrophages.Key points. Celiac disease is an autoimmune disease with a characteristic serological (antibodies to tissue transglutaminase, endomysium, deamidated gliadin peptides) and histological profile (inflammatory infiltration of the villous epithelium by lymphocytes and their atrophy, crypt hyperplasia) caused by gluten consumption in genetically predisposed individuals. Macrophages, as key cells that provide a link between innate and adaptive immunity, are of significant importance in the pathogenesis of celiac disease. Gliadin peptides stimulate the activation of macrophages according to the proinflammatory phenotype with the production of cytokines, which causes the immune response of T-helpers 1 and T-helpers 17. The result of these processes is the development of an inflammatory reaction and damage to the intestinal mucosa due to the production of matrix metalloproteinases and reactive oxygen species by macrophages. Therapeutic tactics for celiac disease today include a gluten-free diet, which is not so easy to follow. Of interest is the study of the possibility of using polyphenols in celiac disease, which are capable of precipitating gliadins and inhibiting the polarization of macrophages towards a proinflammatory phenotype, while simultaneously stimulating an increase in the population of macrophages of an anti-inflammatory phenotype associated with a decrease in tissue damage.Conclusion. Impaired macrophage function/differentiation results in either inadequate, excessive immune activation or failure to mount effective protective immune responses against pathogens, which may result in the development of gastrointestinal diseases. Studying the involvement of macrophages at different stages of celiac disease progression is important for the development of new treatments for this disease.

Acne and rosacea: similarities and differences. A review

Acne and rosacea are frequently encountered in the clinical practice of a dermatologist. These diseases can develop simultaneously in the same patient. Most often, the erythematous form of rosacea is combined with acne. Because of the similarity of clinical manifestations with acne, the diagnosis of rosacea can be easily missed. Common pathogenetic factors in the 2 diseases are thought to be genetics, alterations in the microbiome, immune disorders, and skin barrier dysfunction. There are few works addressing the relationship between acne and rosacea. A recent study identified a number of common differentially expressed genes, including interleukin-1B and matrix metalloproteinase 9, and showed that gamma delta T cells may play an important role in the development of both diseases. Despite the common pathogenesis and the similarity of some clinical manifestations (papules and pustules), acne and rosacea must be distinguished. In rosacea, there is persistent facial erythema induced by vasoregulatory neutropeptides, whereas in acne, the inflammatory process is due to excess sebum and changes in the skin microbiome. Isotretinoin is used for systemic therapy of both diseases. The drug affects the level of some cytokines, including inhibiting the expression of matrix metalloproteinase 9. In addition, it reduces sebum production in acne, and due to its ability to alter the skin microenvironment, it can reduce Propionibacterium acnes in acne and Demodex folliculorum in rosacea. Daily and cumulative doses for rosacea and acne will differ, as will topical therapy for these conditions. For acne, the combination of clindamycin and benzoyl peroxide is well established for the treatment of acne, allowing rapid meaningful clinical effect. In rosacea, metronidazole in cream form, which has better tolerability, is recommended as a topical agent. In patients suffering from both diseases simultaneously, a combination of clindamycin and benzoyl peroxide should be used to relieve acute inflammation, after which it is possible to switch to metronidazole.

Collaborative Effect of Matrix Metalloproteinases on Type I Collagen Degradation and Muscle Softening in Sea Bass (Lateolabrax japonicus) during Cold Storage.

Matrix metalloproteinases (MMPs) play critical roles in the degradation of collagens, while their mechanism remains unclear. In the present study, the involvement of matrix metalloproteinases (MMPs) in collagen degradation of sea bass muscle during cold storage was explored. Immunohistochemical staining results showed significant degradation of type I collagen in the connective tissue of muscle endomysium during cold storage, thus affecting the muscle structural integrity and quality. Western blot analysis revealed an increment in the α1 chain and a decrease in the β and γ chains of type I collagen. Immunofluorescence staining showed that MMP-2, MMP-9, and MMP-13 were distributed in the endomysium surrounding the muscle fibers. Additionally, the catalytic domains of MMP-2, MMP-9, and MMP-13 with biological activities were successfully expressed. The degradation trend of type I collagen by MMPs under 4 °C was similar to that of muscle collagen during cold storage, suggesting that the degradation of type I collagen was attributed to the cooperative action of the MMPs. In conclusion, our study elucidated that the MMPs-engaged degradation of type I collagen is quite possibly the leading cause of sea bass muscle softening during cold storage.

S100A9 induces tissue remodeling of human nasal epithelium in chronic rhinosinusitis with nasal polyp.

Chronic inflammation triggers tissue remodeling in human nasal epithelial (HNE) cells. S100A9, a protein secreted by inflammatory cells, exhibits potent proinflammatory activity. However, its effect on HNE cell remodeling, such as squamous metaplasia, remains unclear. Therefore, this study aimed to determine the effects and underlying pathways of S100A9 on HNE cell remodeling and investigate its clinical implications in chronic rhinosinusitis (CRS). Cultured HNE cells were treated with S100A9. Bulk RNA sequencing was performed to analyze gene ontology (GO). Ingenuity pathway analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were also analyzed. Additionally, immunohistochemistry and multiplex immunofluorescence were performed on tissue samples obtained from 60 patients, whose clinical informations were also reviewed. GO enrichment analysis indicated that S100A9 induced tissue remodeling in HNE cells toward squamous metaplasia. IPA and KEGG commonly showed that S100A9 affected HNE cells associated with the IL-17 signaling pathway, including target molecules such as matrix metalloproteinase 1 (MMP1) and small proline-rich protein 2A (SPRR2A). Squamous metaplasia with a marked expression of S100A9 was observed in 50% of CRS with nasal polyps (CRSwNPs). In addition, in multiplex immunofluorescence, the S100A9 in sub-epithelium was co-expressed with myeloperoxidase, a neutrophil marker, and MMP1 and SPRR2A were strongly expressed in epithelial remodeling. Clinically, the expression of S100A9 correlated with sino-nasal outcome test-22 (r=0.294, p=0.022) and Lund-Mackay scores (r=0.348, p=0.006). S100A9 induces tissue remodeling in HNE cells. Its increased expression in CRSwNP, particularly squamous epithelium, correlates with disease severity. This suggests the clinical potential of S100A9 as a biomarker for CRS severity.