Matrix Metalloproteinase Research Articles

Limited Alleviation of Lysosomal Acid Lipase Deficiency by Deletion of Matrix Metalloproteinase 12.

Lysosomal acid lipase (LAL) is the only known enzyme that degrades cholesteryl esters and triglycerides at an acidic pH. In LAL deficiency (LAL-D), dysregulated expression of matrix metalloproteinase 12 (MMP-12) has been described. The overexpression of MMP-12 in myeloid lineage cells causes an immune cell dysfunction resembling that of Lal knockout (Lal KO) mice. Both models develop progressive lymphocyte dysfunction and expansion of myeloid-derived suppressor (CD11b+ Gr-1+) cells. To study whether MMP-12 might be a detrimental contributor to the pathology of LAL-D, we have generated Lal/Mmp12 double knockout (DKO) mice. The phenotype of Lal/Mmp12 DKO mice closely resembled that of Lal KO mice, while the weight and morphology of the thymus were improved in Lal/Mmp12 DKO mice. Cytological examination of blood smears showed a mildly reversed lymphoid-to-myeloid shift in DKO mice. Despite significant decreases in CD11b+ Ly6G+ cells in the peripheral blood, bone marrow, and spleen of Lal/Mmp12 DKO mice, the hematopoietic bone marrow progenitor compartment and markers for neutrophil chemotaxis were unchanged. Since the overall severity of LAL-D remains unaffected by the deletion of Mmp12, we conclude that MMP-12 does not represent a viable target for treating the inflammatory pathology in LAL-D.

Results of surgical treatment of chronic pancreatitis with a high risk of developing pancreatic cancer

Objective. To analyze the results of surgical treatment of patients with pancreatic insufficiency and a high risk of developing pancreatic cancer. Materials and methods. The study included 39 patients treated in 2019–2023. In 20 (51%) patients, it was difficult to clearly differentiate between chronic pancreatitis and pancreatic cancer. In 19 (49%) patients, the diagnosis of chronic pancreatitis was not in doubt. All patients with complicated forms of chronic pancreatitis and suspected pancreatic tumor underwent a set of laboratory tests, and routine screening methods of instrumental diagnostics were used. In addition to standard methods of examination, the levels of matrix metalloproteinases and tissue inhibitor of metalloproteinases in the blood plasma were studied. Results. The method of intraoperative multiple biopsy, improved by us, was an obligatory component of surgical care for a clear differential diagnosis of chronic pancreatitis and pancreatic cancer. In the presence of complicated chronic pancreatitis, during surgery, the biopsy was taken using a special punch instrument that resembles a pen, along the entire length of the main pancreatic duct along the upper and lower edges of the dissection in a checkerboard pattern. There were no complications of punch biopsy. Of the 20 patients in whom it was not possible to clearly differentiate between chronic pancreatitis and pancreatic cancer, 12 (60%) were diagnosed with diabetes mellitus. The characteristic changes in the pancreatic tissue gave grounds for performing extended resection interventions in these patients. In the remaining 8 (40%) patients without morphological changes inherent in malignancy, Whipple operation (2), longitudinal pancreaticoduodenectomy (2), Frey operation (2), and our proposed central pancreatic resection with preservation of the left anatomical segment (2) were performed. Drainage and resectional surgical interventions were performed in 19 (49%) patients with complicated forms of chronic pancreatitis. After radical surgical interventions for pancreatic cancer, 1 patient developed gastrostasis, and on the 11th day he underwent a relaparotomy with reconstruction of the gastroenteroanastomosis, and on the 30th day a subhepatic abscess was diagnosed in 1 patient, who underwent drainage with a subcostal mini–access with a positive effect. In 2 patients, after left–sided pancreatic resection, subdiaphragmatic abscesses were diagnosed on the left, they were treated minimally invasively with punctures and drainage under ultrasound control. Multiple organ failure occurred in 1 patient after surgery for internal pancreatic fistula, infected ascites as a complication of neglected chronic pancreatitis. The patient died. Infection of the median laparotomy wound occurred in 4 patients, and healing was achieved by controlled primary tension. Class B pancreatic fistulas occurred in 3 patients: 2 – after left–sided pancreatic resection, 1 – after longitudinal pancreaticoduodenostomy. In 1 patient, a class C permanent pancreatic fistula was formed after a combined (resection and drainage) intervention. Relaparotomy, subtotal resection with Roux–en–Y loop closure was performed. Conclusions. Morphological changes in the pancreatic tissue in chronic pancreatitis in combination with diabetes mellitus, corresponding to the development of PanIN, are direct predictors of adenocarcinoma. Multiple intraoperative pancreatic biopsies are effective in verifying pancreatic malignancy. Pre– and intraoperative diagnostics make it possible to optimize the surgical treatment of complicated forms of chronic pancreatitis and prevent the development of postoperative pancreatic fistula.

Impacts of Hyperglycemia on Epigenetic Modifications in Human Gingival Fibroblasts and Gingiva in Diabetic Rats

Periodontal disease is considered one of the diabetic complications with high morbidity and severity. Recent studies demonstrated the involvement of the epigenome on diabetic complications. Histone modifications change chromatin architecture and gene activation. Histone modifications have been reported to alter chromatin structure and regulate gene transcription. In this study, we investigated the impacts of H3 lysine 4 trimethylation (H3K4me3) and specific histone methyltransferases of H3K4 methylation, su(var)3-9, enhancer-of-zeste, and trithorax domain 1A (SETD1A) on periodontal tissue affected by the diabetic condition. We observed the increase in H3K4me3 and SETD1A in gingival tissue of diabetic rats compared with the normal rats. Cultured human fibroblasts (hGFs) confirmed a high glucose-induced increase in H3K4me3 and SETD1A. We further demonstrated that high glucose increased the gene expression of matrix metalloproteinase (MMP) 1 and MMP13, which were canceled by sinefungin, an SETD1A inhibitor. Our investigation suggests that diabetes triggers histone modifications in the gingival tissue, resulting in gingival inflammation. Histone modifications may play crucial roles in the development of periodontal disease in diabetes.

Development of a Bioactive Titanium Surface via Alkalinization and Naringenin Coating for Peri-Implant Repair: In Vitro Study

This study assessed the effects of titanium (Ti) surface modification with sodium hydroxide (NaOH) associated or not with Naringenin (NA) citrus flavonoid-coating on osteoblastic-like cells (Ob) metabolism. Ti discs were submitted to alkalinization by NaOH solution (5 M, 60 °C) for 24 h; then, the discs were impregnated or not with 100 µg/mL of NA and dried for 1 h at room temperature. The chemical composition, surface topography, and NA release were evaluated. For the biological assays, the discs were placed on 24-well cell culture plates and Ob (Saos-2; ATCC HTB-85) was seeded onto the discs. After different periods, cell adhesion and viability, alkaline phosphatase activity (ALP), and mineralized nodules deposition (MND) were assessed. In addition, cells stimulated with tumor necrosis factor-alpha (TNF-α) were submitted to matrix metalloproteinase (MMP)-2 synthesis and ALP gene expression assessment. Since data presented normal distribution and homogeneity (Shapiro-Wilk; Levene), Student’s t-test or one-way ANOVA/post-hoc tests were selected for data analysis (α = 0.05). Higher roughness was observed on Ti discs submitted to NaOH treatment, while the chemical and NA release evaluations indicated the successful adsorption of NA to alkali-treated Ti surface. Higher cell adhesion, cell viability (after 7 days of culture), ALP activity, and MND were observed on Ti NaOH coated with NA compared to the control group (Ti NaOH) (p < 0.05). Moreover, NA coating also promoted decreased MMP-2 synthesis and increased ALP gene expression in the presence of the inflammatory stimulus TNF-α (p < 0.05). The modification of Ti disks with NaOH associated with NA-coating enhanced bone cell metabolism, suggesting that this type of surface modification has a promising potential to accelerate bone repair and formation around dental implants.

Degradation of pathogenic amyloids induced by matrix metalloproteinase-9

Over the past decade, the greatest promise for treating severe and currently incurable systemic and neurodegenerative diseases has turned to agents capable of effectively degrading pathological amyloid deposits without causing side effects. Specifically, amyloid destruction observed in immunotherapy is hypothesized to occur through activation of proteolytic enzymes. This study examines poorly understood effects of an immune enzyme, extracellular matrix metalloproteinase-9 (MMP9), on amyloids associated with Alzheimer's and Parkinson's diseases, lysozyme, insulin, and dialysis-related amyloidoses. The study establishes the universality of MMP9's effect on various amyloids, with its efficacy largely depending on the fibrillar cluster size. Irreversible amyloid degradation by MMP9 is attributed to the destruction of intramolecular interactions rather than intermolecular hydrogen bonds in the fibril backbone. This process results in the loss of ordered fiber structure without reducing aggregate size or increasing cytotoxicity. Thus, MMP9 can mitigate side effects of anti-amyloid therapy associated with the formation of low-molecular-weight degradation products that may accelerate fibrillogenesis and amyloid propagation between tissues and organs. MMP9 shows promise as a component of safe anti-amyloid drugs by enhancing the accessibility of binding sites through “loosening” amyloid clusters, which facilitates subsequent fragmentation and monomerization by other enzymes.

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.

Forkhead box C1 promotes the pathology of osteoarthritis in subchondral bone osteoblasts via the Piezo1/YAP axis

Subchondral bone sclerosis is a key characteristic of osteoarthritis (OA). Prior research has shown that Forkhead box C1 (FoxC1) plays a role in the synovial inflammation of OA, but its specific role in the subchondral bone of OA has not been explored. Our research revealed elevated expression levels of FoxC1 and Piezo1 in OA subchondral bone tissues. Further experiments on OA subchondral bone osteoblasts with FoxC1 or Piezo1 overexpression showed increased cell proliferation activity, expression of Yes-associated Protein 1 (YAP) and osteogenic markers, and secretion of proinflammatory factors. Mechanistically, the overexpression of FoxC1 through Piezo1 activation, in combination with downstream YAP signaling, led to increased levels of alkaline phosphatase (ALP), collagen type 1 (COL1) A1, RUNX2, Osteocalcin, matrix metalloproteinase (MMP) 3, and MMP9 expression. Notably, inhibition of Piezo1 reversed the regulatory function of FoxC1. The binding of FoxC1 to the targeted area (ATATTTATTTA, residues +612 to +622) and the activation of Piezo1 transcription were verified by the dual luciferase assays. Additionally, Reduced subchondral osteosclerosis and microangiogenesis were observed in knee joints from FoxC1-conditional knockout (CKO) and Piezo1-CKO mice, indicating reduced lesions. Collectively, our study reveals the significant involvement of FoxC1 in the pathologic process of OA subchondral bone via the Piezo1/YAP signaling pathway, potentially establishing a novel therapeutic target.

Determining key residues of engineered scFv antibody variants with improved MMP-9 binding using deep sequencing and machine learning

Given the crucial role of specific matrix metalloproteinases (MMPs) in the extracellular matrix, an imbalance in the regulation of activation of matrix metalloproteinase-9 (MMP-9) zymogen and inhibition of the enzyme can result in various diseases, such as cancer, neurodegenerative, and gynecological diseases. Thus, developing novel therapeutics that target MMP-9 with single-chain antibody fragments (scFvs) is a promising approach. We used fluorescent-activated cell sorting (FACS) to screen a synthetic scFv antibody library displayed on yeast for enhanced binding to MMP-9. The screened scFv mutants demonstrated improved binding to MMP-9 compared to the natural inhibitor of MMPs, tissue inhibitor of metalloproteinases (TIMPs). To identify the molecular determinants of these engineered scFv variants that affect binding to MMP-9, we used next-generation DNA sequencing and computational protein structure analysis. Additionally, a deep-learning language model was trained on the screened scFv library of variants to predict the binding affinities of scFv variants based on their CDR-H3 sequences.

Placenta may exert fetal protection against maternal high salt diet intake via renin-angiotensin-aldosterone system

ObjectiveThis study investigated the effects of high compared to normal dietary salt intake on fetoplacental vascular function, activity of renin-angiotensin-aldosterone system (RAAS), placental pro- and anti-angiogenic factors and biomarkers of placental remodeling and oxidative stress during healthy uncomplicated pregnancy. Materials and methodsBased on their 24-h sodium excretion pregnant women (37–40 weeks’ gestation) were categorized into three groups: normal salt (NS, <5.75 g/day, N = 12), high salt (HS, 5.75–10.25 g/day, N = 36), and very high salt (VHS, >10.25 g/day, N = 17). Pulsatility (PI) and resistive index of middle cerebral artery (MCA) and umbilical artery, plasma renin activity (PRA), serum aldosterone, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) concentrations, as well as placental vascular endothelial growth factor C (VEGF-C), oxidative/antioxidative stress markers (TBARS/FRAP) and matrix metalloproteinase 9 (MMP-9) concentration were measured. ResultsPI MCA was significantly decreased in HS/VHS groups compared to NS group. HS/VHS intake did not suppress PRA and aldosterone concentration. Serum PlGF concentration was significantly increased while sFlt-1 concentration and sFlt-1/PlGF ratio were significantly decreased in VHS group compared to NS group. MMP-9, VEGF-C concentration, TBARS and FRAP in placental tissue were similar between study groups. ConclusionsHS/VHS diet does not suppress RAAS during pregnancy; however, it is associated with decreased PI MCA, a significantly decreased sFlt-1/PlGF ratio and unchanged biomarkers of placental remodeling or oxidative stress in healthy pregnant women, suggesting the presence of a possible protective or compensatory mechanism aimed at preserving placental function and pregnancy outcome itself in terms of maternal HS intake.

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.

The Analysis Study of Interventions of Dry Eye: A Comprehensive Systematic Review

Introduction : Dry eye disease (DED) is a common, multifactorial condition affecting the tear film and ocular surface, leading to discomfort, visual disturbances, and progressive ocular damage if untreated. DED involves a complex interplay among anatomical structures, inflammatory pathways, and environmental factors. It is classified into aqueous-deficient and evaporative types, often presenting as mixed forms. DED significantly affects quality of life, daily functionality, and psychological well-being. This systematic review synthesizes current evidence on DED pathophysiology, classification, diagnosis, and management while highlighting recent advancements in therapeutic strategies. Methods :This review adhered to PRISMA 2020 guidelines, focusing on original research published since 2018. Inclusion criteria targeted studies on DED’s inflammatory mechanisms, diagnostic tools, and treatment approaches. Databases searched included PubMed, ScienceDirect, Embase, Cochrane Library, and Web of Science. Keywords such as “dry eye disease,” “ocular surface inflammation,” and “meibomian gland dysfunction” were employed. Following a rigorous screening process, eight studies met the inclusion criteria for comprehensive analysis. Results : The analysis reaffirmed the central role of inflammation in DED pathophysiology, driven by cytokines and matrix metalloproteinases. Emerging diagnostics, such as tear osmolarity tests and meibography, enhance disease identification. Treatment advancements emphasize anti-inflammatory therapies, artificial tears, and meibomian gland support. The review highlights the burden of DED on quality of life and identifies gaps in addressing work-related and environmental stressors. Conclusion : DED is a complex disorder requiring a multidisciplinary approach. Future research should prioritize innovative therapies targeting underlying mechanisms, comprehensive patient education, and integration of mental health support. Holistic management can mitigate the burden of DED and improve patient outcomes.

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 &gt; 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.