Demethylation of TIMP2 and TIMP3 Inhibits Cell Proliferation, Migration, and Invasion in Pituitary Adenomas.

OBJECTIVE: Tissue inhibitors of matrix metalloproteinases (TIMPs) are prognostic markers in cancers. However, the role of TIMPs in DNA methylation during invasive pituitary adenoma (PA) remains unclear. The purpose of this study was to assess the effects of TIMP2 and TIMP3 promoter demethylation on the proliferation, migration, and invasion of invasive PA cells. METHODS: Methylation-specific polymerase chain reaction (PCR), quantitative PCR, and western blots were used to analyze the promoter methylation and expression of TIMP1-3. Cell counting kit-8 (CCK-8), wound healing, and transwell assays were carried out to determine the effects of TIMP2 and TIMP3 demethylation. RESULTS: TIMP1-3 showed downregulated expression in invasive PA tissues and cell lines (p < 0.05). The low expression of TIMP1-3 was due to promoter methylation of these genes (p < 0.05). The results showed that downregulation of TIMP2 and TIMP3 can promote cell proliferation, migration, and invasion (p < 0.05), whereas overexpression of TIMP2 and TIMP3 can inhibit cell proliferation, migration, and invasion (p < 0.05). After treatment with 5-azacytidine (5-AzaC), the cell activity decreased, the proliferation rate decreased, and the invasion ability weakened (p < 0.05). Treatment with 5-AzaC increased TIMP2 and TIMP3 expression and decreased DNA (cytosine-5-)-methyltransferase 1 (DNMT1), DNMT3a, and DNMT3b expression (p < 0.05). CONCLUSIONS: We showed that DNA methylation causes the silencing of TIMP2 and TIMP3 in invasive PA, it can also lead to malignant cell proliferation and cause pathological changes, whereas the use of 5-AzaC can inhibit the methylation process and can inhibit cell proliferation. Our results provide a novel method for clinical diagnosis and prevention of invasive PA.

Kidney Fibrosis and Matrix Metalloproteinases (MMPs).

Chronic kidney disease (CKD) is a disorder that causes changes in both the structure and function of the kidneys, causing complications such as hypertension, edema, and oliguria. Renal fibrosis is also a common pathological feature of CKD. Matrix metalloproteinases (MMPs) are endopeptidases that degrade extracellular matrix (ECM) proteins. The proteinase domain consists of a zinc ion in the active site, which contributes to its stabilization with another zinc and three calcium structural ions. Many cellular processes are controlled by MMPs, such as cell-cell interactions and various signaling pathways, while they are also involved in degrading substrates on cell surfaces. Tissue inhibitors of metalloproteinases (TIMPs) are key regulators of metalloproteinases, and both are involved in regulating cell turnover, the regulation, and the progression of fibrosis and apoptosis in the tissue. MMPs play a role in renal fibrosis, such as the tubular cell epithelial-mesenchymal transition (TEM), activation of resident fibroblasts, endothelial-mesenchymal transition (EndoMT), and pericyte-myofibroblast transdifferentiation. This review aims to show the mechanisms through which MMPs contribute to renal fibrosis, paying particular attention to MMP-9 and the epithelial-mesenchymal transition.

Exposure to atrazine and endosulfan alters oviductal adenogenesis in the broad-snouted caiman (Caiman latirostris).

The molecular pathways involved in oviductal adenogenesis are highly conserved among vertebrates. In this work, we study the histomorphological changes and molecular pathways involved in Caiman latirostris oviductal adenogenesis and the effects of in ovo exposure to environmentally relevant doses of endosulfan (END) and atrazine (ATZ) on these processes. To this end, the histomorphological changes at epithelial and subepithelial compartments, the protein expressions of ß-catenin and Wnt-7a, and the gene expression of metalloproteinases (MMPs) and its inhibitors (TIMPs) were evaluated as biomarkers of oviductal adenogenesis in prepubertal juvenile C. latirostris. Exposure to END altered adenogenesis-related epithelium characteristics and mRNA expression of MMP2, MMP9, and TIMP1. Exposure to ATZ increased the width of the subepithelial stroma with loosely arranged collagen fibers and increased ß-catenin expression in buds (invaginated structures that precede glands). The results demonstrate that in ovo exposure to ATZ and END alters oviductal adenogenesis at tissue, cellular, and molecular levels. An altered oviductal adenogenesis could impair fertility, raising concern on the effects of pesticide pollution in wildlife and domestic animals.

Laboratory Assessment of the Effects of AGA@4life Multidisciplinary Intervention on the Inflammatory Profile, MMPs, and TIMPs in a Geriatric Population.

In recent years, the world's aging population has increased, contributing to the development of age-related pathologies, which have been aggravated by physical inactivity and excessive fat intake. This study aimed to evaluate the effect of implementing a nutritional program (control group-CG) combined with exercise (intervention group-IG) on the inflammatory profile, MMPs, and TIMPs in a group of 34 elderly participants (IG, n = 18; CG, n = 16). Participants underwent a full multidisciplinary diagnostic evaluation (T0), with the gathering of clinical information and biochemical and hematological determinations being re-evaluated eight weeks later (T1). A diet manual was made, which provided a selection of different types of diets resulting from the nutritional needs of the different users at the center. The aerobic exercise consisted of two sessions per week with a total duration of 1 h. The laboratory evaluation was performed by slot blot. Statistical analysis included a paired sample t-test and Spearman's correlation coefficient. We observed that in the IG, there was a significant increase at T1 of TNF-α (p < 0.05) and MMP-2 (p < 0.05), without changes in IL-6 and MMP-9, showing that the intervention did not cause an exacerbated inflammatory response in exercised elderly people. The intervention program implemented showed potential to contribute to better active aging strategies, taking advantage of the known benefits of exercise without inducing a harmful inflammatory response in elderly participants.

Matrix metalloproteinases are associated with severity of disease among COVID-19 patients: A possible pharmacological target.

COVID-19 is a devastating disease and imbalanced matrix metalloproteinase (MMP) activity may contribute to its pathophysiology. This exploratory study examined whether increased circulating concentrations of MMP-2 and MMP-9, and their endogenous inhibitors, the tissue inhibitors of MMP (TIMP)-1, TIMP-2, TIMP-3 and TIMP-4 are persistently found in patients 2 weeks after their recovery from severe or critical COVID-19 as compared with those in healthy controls. Subjects who had severe (n = 26) or critical (n = 25) PCR-confirmed COVID-19 and healthy controls (n = 21) had blood samples drawn 2 weeks after recovery and serum MMP-2, MMP-9, TIMP-1, TIMP-2, TIMP-3 and TIMP-4 were determined using two Human Luminex® Discovery Assays. Circulating MMP activity was also determined by gel zymography. Patients who had severe or critical COVID-19 had increased circulating MMP-9 and MMP-2 concentrations, with increased MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios indicating increased MMP activity, confirmed by gel zymography (all p < 0.05). Higher circulating MMP-9 (but not MMP-2) concentrations were found in critical versus severe COVID-19 (p < 0.05). We found increased circulating MMP-9 and MMP-2 concentrations and activity many days after recovery from the acute disease, with MMP-9 levels associated with disease severity. These biochemical alterations suggest that MMP-2 and MMP-9 may be important pharmacological targets in COVID-19.

Increased matrix metalloproteinase-2 in ligamentum flavum hypertrophy and the regulation of MMP-2/TIMPs by elastin-derived peptides.

The study aimed to examine matrix metalloproteinase-2 (MMP-2) expression in a rat ligamentum flavum (LF) hypertrophy model in vivo, and the effect of elastin-derived peptides (EDPs) on MMP-2 and tissue inhibitors of metalloproteinases (TIMPs) in rat LF cells in vitro. Surgical destabilization was performed at the rat spinal L3/4 level to induce increased mechanical stress. Rats were killed at 6- and 12-weeks postsurgery for histological staining, immunohistochemical staining, RT-qPCR and western blot. 100 µg/mL EDPs were applied to isolated normal rat LF cells, with or without pretreatment of elastin receptor complex (ERC) inhibitors, to assess the expression of MMP-2, TIMP-1, and TIMP-2. Spinal destabilization led to LF hypertrophy, observed through increased LF thickness and area, along with histological changes of chondrometaplasia and elastic fiber degradation. LF was also stained positively for Col I and Col II, where elastic fiber has broken down. MMP-2 expression was notably elevated in the hypertrophied LF, accompanied by increased TIMP-2 and TIMP-3 levels. EDPs were found to suppress MMP-2 expression and reduce TIMP-1 and TIMP-2 levels in rat LF cells. Interestingly, exposure to EDPs led to a significant rise in MMP-2/TIMP-1 and MMP-2/TIMP-2 ratios, dependent on the ERC. Collectively, the study suggests that increased MMP-2 activity contributes to elastic fiber degradation in hypertrophied LF, generating EDPs that further enhance the MMP-2/TIMPs ratio in LF cells in an ERC-dependent manner. Further research is essential to delve into the mechanisms of EDPs in LF hypertrophy.

Exercise affects high-fat diet-stimulated breast cancer metastasis through irisin secretion by altering cancer stem cell properties.

Background: Regular physical activities reduce the growth of breast cancer, but research on the effects of steady exercise on metastasis and its mechanisms is limited. In this study, the effects of steady exercise on breast cancer metastasis and its possible mechanism were demonstrated. Methods: Experimental metastasis was induced after 8 weeks of steady exercise using a mouse model. Furthermore, one of the myokines, irisin, was studied to elucidate the effects of metastasis-regulating protein expression, and colony and sphere formation, which are cancer stem cell properties. Results: Low- and moderate-intensity exercise significantly reduced the number and volume of metastasized tumors. Among myokines, only irisin was significantly increased by steady exercise but decreased by a high-fat diet. In vitro studies, irisin significantly decreased the number of colonies and sphere formation. Irisin also inhibited cell migration and invasion and suppressed the malignancy of breast cancer cells by reducing the expression of vimentin, MMP-2, MMP-9, and HIF-1 and by increasing the expression of TIMP-1 and TIMP-2. Conclusion: Steady exercise modulates myokine secretions and among them, irisin suppresses breast cancer metastasis by decreasing self-renewal properties and invasion regulating protein expressions. Thus, regular exercise may be beneficial in the prevention of breast tumor metastasis.

Tissue inhibitors of metalloproteinases (TIMPs) modulate platelet ADAM10 activity.

Platelet-specific collagen receptor glycoprotein (GP)VI is stable on the surface of circulating platelets but undergoes ectodomain cleavage on activated platelets. Activation-dependent GPVI metalloproteolysis is primarily mediated by A Disintegrin And Metalloproteinase (ADAM) 10. Regulation of platelet ADAMs activity is not well-defined however Tissue Inhibitors of Metalloproteinases (TIMPs) may play a role. As levels of TIMPs on platelets and the control of ADAMs-mediated shedding by TIMPs has not been evaluated, we quantified the levels of TIMPs on the surface of resting and activated platelets from healthy donors by flow cytometry and multiplex ELISA. Variable levels of all TIMPs could be detected on platelets. Plasma contained significant quantities of TIMP1 and TIMP2, but only trace amounts of TIMP3 and TIMP4. Recombinant TIMP3 strongly ablated resting and activated platelet ADAM10 activity, when monitored using a quenched fluorogenic peptide substrate with ADAM10 specificity. Whilst ADAM10-specific inhibitor GI254023X or ethylenediamine tetraacetic acid (EDTA) could modulate ligand-initiated shedding of GPVI, only recombinant TIMP2 achieved a modest (~20%) inhibition. We conclude that some platelet TIMPs are able to modulate platelet ADAM10 activity but none strongly regulate ligand-dependent shedding of GPVI. Our findings provide new insights into the regulation of platelet receptor sheddase activity.

What do we know? Platelet receptor GPVI initiates platelet adhesion and aggregation and is proteolytically cleaved from the activated platelet surfaceThe metalloproteinases responsible belong to the ADAMs family of enzymes which are inhibited by TIMPsWhat did we discover? Plasma contains significant amounts of TIMP1 and TIMP2Circulating platelets bear significant amounts of TIMPs 1, 2, and 3Recombinant TIMP3 strongly inhibits resting and activated platelet ADAM10 activityExogenous addition of TIMP2 mildly blocked ligand-initiated shedding of GPVIWhat is the impact? TIMPs may modulate ADAM10 activity under resting conditions and stabilize GPVI levels in response to platelet activationAnti-GPVI agents are being evaluated as anti-thrombotic agents, however, acute loss of GPVI in trauma or settings of thrombocytopenia is linked with clinical bleedingUnderstanding how GPVI levels are regulated is important as agents that modulate GPVI function are emerging as important therapeutics for clinical applications in Thrombosis and Hemostasis fields.

TIMP-1 Protects Tight Junctions of Brain Endothelial Cells From MMP-Mediated Degradation.

OBJECTIVE: The blood-brain barrier (BBB) plays a critical role in central nervous system homeostasis, and the integrity of BBB is disrupted in many neurodegenerative diseases. Matrix metalloproteinases (MMPs) degrade the tight junctions (TJs) of endothelial cells and basement membrane components essential to BBB integrity, which leads to increased BBB permeability and allows inflammatory cells and neurotoxic substances to enter the brain. Tissue inhibitors of metalloproteinases (TIMPs), endogenous inhibitors of MMPs, regulate MMP activity, thereby maintaining BBB integrity. METHODS: The disruptive impacts of MMP-3 and MMP-9 on BBB and protective effect of TIMP-1 were investigated in a simplified in vitro model of the BBB, which was generated using rat brain microvascular endothelial cells (RBMEC). The main features of BBB formation, including permeability and the trans-endothelial electrical resistance (TEER), were monitored over time after the addition of MMP-3 and MMP-9 and their complexes with TIMP-1 inhibitor. RESULTS: Our results indicated that MMP-3 and MMP-9 caused a dose-dependent disruption of the BBB, with 1.5 µM MMPs resulting in an over threefold increase in permeability, while TIMP-1 inhibition protected the integrity of the BBB model and recovered TEER and permeability of RBMECs. The disruption and recovery of tight junction proteins of RBMECs after MMP and TIMP treatment were also detected using fluorescent microscopy. CONCLUSION: MMP-9 and MMP-3 disrupt the BBB by degrading tight junctions in endothelial cells, and TIMP-1 could inhibit the disruptive effect of MMP-3 and MMP-9 by showing potential as therapeutic protein against MMP-related diseases where BBB disruption plays a role.

Impact on peri-implant connective tissue of laser treated versus traditional healing abutments: a human clinical trials.

BACKGROUND: Dental implant is the principal treatment for edentulism and the healthiness of the peri-implant tissue has a pivotal role for its longterm success. In addition, it has been shown that also the topography of the healing abutment can influence the outcome of the restoration. The objective of this human clinical trial was to assess the impact of a novel laser-treated healing abutment on peri-implant connective tissue and extracellular matrix proteins compared to the conventional machined surface, which served as the control group. METHODS: During second surgical stage a customized healing abutment were inserted on 30 single dental implants. Healing abutments were realized with two alternated different surface (two side laser-treated surfaces and two side machined surfaces) in order to be considered both as test and control on the same implant and reduce positioning bias. Following the soft tissue healing period (30 ± 7 days) a 5 mm circular biopsy was retrieved. Immuno-histochemical and quantitative real-time PCR (qPCR) analyses were performed on Collagen, Tenascin C, Fibrillin I, Metalloproteinases (MMPs) and their inhibitor (TIMPs). 15 were processed for qPCR, while the other 15 were processed for immunohistochemical analysis. Paired t-test between the two groups were performed. A value of p < 0.05 was considered statistically significant. RESULTS: Results revealed that the connective tissue facing the laser-treated surface expressed statistically significant lower amount of MMPs (p < 0.05) and higher level of TIMPs 3 (p < 0.05), compared to the tissue surrounding the machined implant, which, in turn expressed also altered level of extracellular matrix protein (Tenascin C, Fibrillin I (p < 0.05)) and Collagen V, that are known to be altered also in peri-implantitis. CONCLUSIONS: In conclusion, the laser-treated surface holds promise in positively influencing wound healing of peri-implant connective tissue. Results demonstrated that topographic nature of the healing abutments can positively influence mucosal wound healing and molecular expression. Previous studies have been demonstrated how laser treatment can rightly influence integrity and functionality of the gingiva epithelium and cell adhesion. Regarding connective tissue different molecular expression demonstrated a different inflammatory pattern between laser treated or machined surfaces where laser treated showed better response. Targeted interventions and preventive measures on peri- implant topography could effectively minimize the risk of peri-implant diseases contributing to the long-term success and durability of restoration. However, new studies are mandatory to better understand this phenomenon and the role of this surface in the peri-implantitis process.  TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov Identifier: (Registration Number: NCT05754970 ). Registered 06/03/2023, retrospectively registered.

The Comprehensive Analysis of Specific Proteins as Novel Biomarkers Involved in the Diagnosis and Progression of Gastric Cancer.

Gastric cancer (GC) cases are predicted to rise by 2040 to approximately 1.8 million cases, while GC-caused deaths to 1.3 million yearly worldwide. To change this prognosis, there is a need to improve the diagnosis of GC patients because this deadly malignancy is usually detected at an advanced stage. Therefore, new biomarkers of early GC are sorely needed. In the present paper, we summarized and referred to a number of original pieces of research concerning the clinical significance of specific proteins as potential biomarkers for GC in comparison to well-established tumor markers for this malignancy. It has been proved that selected chemokines and their specific receptors, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), specific proteins such as interleukin 6 (IL-6) and C-reactive protein (CRP), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), as well as DNA- and RNA-based biomarkers, and c-MET (tyrosine-protein kinase Met) play a role in the pathogenesis of GC. Based on the recent scientific literature, our review indicates that presented specific proteins are potential biomarkers in the diagnosis and progression of GC as well as might be used as prognostic factors of GC patients' survival.

13-Butoxyberberine Bromide Inhibits Migration and Invasion in Skin Cancer A431 Cells.

Cancer metastasis is the primary cause of cancer morbidity and mortality. Anti-metastasis mechanism of skin cancer by 13-butoxyberberine bromide, a novel berberine derivative, has not yet been reported. This study investigated the effects of 13-butoxyberberine bromide on migration and invasion of skin cancer A431 cells. The cytotoxicity of 13-butoxyberberine bromide was determined by MTT assay. The effect of 13-butoxyberberine bromide on cell migration and invasion were examined using a wound-healing assay, transwell migration assay, and transwell invasion assay, respectively. The cell adhesion ability was determined by an adhesion assay. Protein expressions that play important roles in cancer migration and invasion were evaluated by Western blot analysis. The results showed that 13-butoxyberberine bromide effectively inhibited cell migration, invasion, and adhesion in A431 cells. Interestingly, 13-butoxyberberine bromide was more effective for cell migration inhibition than berberine. In addition, 13-butoxyberberine bromide showed anti-migration and anti-invasion effects by down-regulated MMP-2 and MMP-9 expression and up-regulated TIMP-1 and TIMP-2 expression in A431 cells. Moreover, pretreatment with 13-butoxyberberine bromide significantly inhibited EGF-induced cell migration and p-EGFR, ERK, p-ERK, STAT3, and p-STAT3 expressions in A431 cells at lower concentrations when compared with the berberine. These findings indicated that 13-butoxyberberine bromide could be further developed as an anticancer agent.

Matrix Metalloproteinases in Chronic Obstructive Pulmonary Disease.

Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade proteins of the extracellular matrix and the basement membrane. Thus, these enzymes regulate airway remodeling, which is a major pathological feature of chronic obstructive pulmonary disease (COPD). Furthermore, proteolytic destruction in the lungs may lead to loss of elastin and the development of emphysema, which is associated with poor lung function in COPD patients. In this literature review, we describe and appraise evidence from the recent literature regarding the role of different MMPs in COPD, as well as how their activity is regulated by specific tissue inhibitors. Considering the importance of MMPs in COPD pathogenesis, we also discuss MMPs as potential targets for therapeutic intervention in COPD and present evidence from recent clinical trials in this regard.

Effect of blood flow-restricted resistance training on myocardial fibrosis in early spontaneously hypertensive rats.

Objective: The purpose of this study was to explore the effect of blood flow-restricted resistance training on myocardial fibrosis in early spontaneously hypertensive rats (SHRs). Methods: Four-week-old male Wistar-Kyoto rats and SHRs were randomly divided into the following groups: normal group (WKY), SHR control (SHR-SED) group, high-intensity resistance training (HIRT) group, low- and medium-intensity resistance training (LMIRT) group, and blood flow-restricted low- and medium-resistance training (BFRT) group. Body weight, hemodynamics, cardiac function, myocardial morphology and fibrosis, and the expression levels of transforming growth factor-beta1-Smad (TGFß-1-Smad) pathway-related proteins in the myocardium were assessed. Results: (1) BFRT lowered blood pressure significantly, decreased left ventricular wall thickness, and improved cardiac function. At the same time, BFRT was superior to traditional resistance training in lowering diastolic blood pressure, and was superior to HIRT in improving left ventricular compliance, reducing heart rate, and reducing left ventricular posterior wall and left ventricular mass (P < 0.05). (2) BFRT decreased collagen I and collagen fiber area in the myocardium, increased the collagen III area, and decreased the collagen I/III ratio (P < 0.05). BFRT produced a better proportion of myocardial collagen fibers than did traditional resistance training (P < 0.05). (3) In the myocardium of the BFRT group compared to the traditional resistance training group, the expression of TGFß-1, Smad2/3/4, p-Smad2/3, CTGF, and TIMP1 was significantly downregulated, MMP2 and TIMP2 were significantly upregulated, the MMP/TIMP ratio significantly increased, and TGFß-1 expression significantly decreased (P < 0.05). Conclusion: BFRT inhibited the TGFß-1-Smad pathway in the myocardium, downregulated the expression of CTGF, and regulated the balance between MMPs and TIMPs, thereby reducing myocardial fibrosis in SHR, and improving cardiac morphology and function. BFRT also lowered blood pressure, and achieved an effect of early prevention and treatment of hypertension. At the same time, BFRT was superior to traditional resistance training in reducing diastolic blood pressure and adjusting the proportion of myocardial collagen fibers.

Relationship between Trace Elements and Matrix Metalloproteinases 2 and 9 and their Tissue Inhibitors in Medullary Thyroid Carcinoma.

Medullary Thyroid Carcinoma (MTC) constitutes around 5% of all thyroid cancers. Trace elements assessment has emerged as a useful strategy in the diagnostics of MTC combined with Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) analysis. The aim of this study was to compare the presence and content of trace elements (i.e., Copper (Cu), Zinc (Zn), Iron (Fe), and Manganese (Mn)) in MTC with respect to control samples and their potential relationship with markers of MTC in tissues. The study included 26 patients who had undergone thyroidectomy, due to the diagnosis of MTC and 17 patients as control. We combined tumour pathology and staging, immunohistochemical analysis of calcitonin, MMPs, and TIMPs, with analytical biochemistry using Inductively Coupled Plasma - Mass Spectrometry (ICP-MS) to determine the levels of trace elements. No differences by MTC type for MMPs and their TIPMs, although strong TIMP-1 and TIMP-2 immunohistochemical expression of MTC were unveiled. Additionally, Zn, Fe, and Mn tended to be decreased, and Cu to be increased in samples presenting MTC with respect to controls. Moreover, Zn was the unique trace element which seemed to be correlated with MMPs and TIMPs. Trace elements such as Zn, Fe, and Mn are decreased in tissues affected by MTC. In addition, Zn may be the trace element which saves more relationship with the proportion and intensity of MMPs, being considered altogether useful biomarkers of MTC. We therefore suggest the analysis of novel and traditional markers of MTC as a novel approach in this pathology.

Bioactive ingredients in activated platelet-rich plasma derived from cord blood and adult blood via Luminex technology: a comparative study / 中国输血杂志

【Objective】 To compare the bioactive ingredients in activated platelet-rich plasma (PRP) from cord blood and adult blood, explore its reasonable indicators reflecting the inflammatory regulation ability, in order to guide the preparation. 【Methods】 PRP was prepared and activated from 63 healthy adults (31 males, 32 females) and 61 neonates (30 males, 31 females), and 20 cytokines were measured using Luminex technology for assessing the age- and sex-based bioactive differences of PRP. High-sensitivity C-reactive protein(hs-CRP), procalcitonin and MMPs/TIMPs from each sample were measured for their correlations with the 10 inflammation-related cytokines. 【Results】 The activated cord blood PRP released 10 growth factors and chemokines more than the adult blood PRP, whereas IGF-1, HGF and 8 pro-inflammatory cytokines lower than the latter. Most cytokines of adult PRP were more in females than in males (P<0.05), except for IGF-1 and HGF, which showed no difference by gender. Compared with hs-CRP and PCT, MMPs/TIMPs ratio was more closely related with the inflammation-related cytokines, which can reflect the inflammatory regulation of PRP. 【Conclusion】 Due to the lower immunocompetence and no age or gender disturbance, cord blood PRP has the rational MMPs/TIMPs ratio and more cytokines which promote the inflammation and wound healing.

Matrix Metalloproteinases and Their Inhibitors as Potential Prognostic Biomarkers in Head and Neck Cancer after Radiotherapy.

Head and neck cancer (HNC) is among the ten most frequent tumours, with 5-year survival rates varying from 30% to 70% depending on the stage and location of the tumour. HNC is traditionally known as head and neck squamous cell carcinoma (HNSCC), since 90% arises from epithelial cells. Metastasis remains a major cause of mortality in patients with HNSCC. HNSCC patients with metastatic disease have an extremely poor prognosis with a survival rate of less than a year. Matrix metalloproteinases (MMPs) have been described as biomarkers that promote cell migration and invasion. Radiotherapy is widely used to treat HNSCC, being a determining factor in the alteration of the tumour's biology and microenvironment. This review focuses on analysing the current state of the scientific literature on this topic. Although few studies have focused on the role of these proteinases in HNC, some authors have concluded that radiotherapy alters the behaviour of MMPs and tissue inhibitors of metalloproteinases (TIMPs). Therefore, more research is needed to understand the roles played by MMPs and their inhibitors (TIMPs) as prognostic biomarkers in patients with HNC and their involvement in the response to radiotherapy.

Complete abrogation of key osteoclast markers with a membrane-anchored tissue inhibitor of metalloproteinase : a novel approach in the prevention of osteoclastogenesis.

AIMS: Tissue inhibitors of metalloproteinases (TIMPs) are the endogenous inhibitors of the zinc-dependent matrix metalloproteinases (MMP) and A disintegrin and metalloproteinases (ADAM) involved in extracellular matrix modulation. The present study aims to develop the TIMPs as biologics for osteoclast-related disorders. METHODS: We examine the inhibitory effect of a high affinity, glycosyl-phosphatidylinositol-anchored TIMP variant named 'T1PrαTACE' on receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced osteoclast differentiation. RESULTS: Osteoclast progenitor cells transduced with T1PrαTACE failed to form tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts or exhibit bone-resorbing activity following treatment with RANKL. At the messenger RNA level, T1PrαTACE strongly attenuated expression of key osteoclast marker genes that included TRAP, cathepsin K, osteoclast stimulatory transmembrane protein (OC-STAMP), dendritic cell-specific transmembrane protein (DC-STAMP), osteoclast-associated receptor (OSCAR), and ATPase H+-transporting V0 subunit d2 (ATP6V0D2) by blocking autoamplification of nuclear factor of activated T cells 1 (NFATc1), the osteoclastogenic transcription factor. T1PrαTACE selectively extended p44/42 mitogen-activated protein kinase activation, an action that may have interrupted terminal differentiation of osteoclasts. Inhibition studies with broad-spectrum hydroxamate inhibitors confirmed that the anti-resorptive activity of T1PrαTACE was not reliant on its metalloproteinase-inhibitory activity. CONCLUSION: T1PrαTACE disrupts the RANKL-NFATc1 signalling pathway, which leads to osteoclast dysfunction. As a novel candidate in the prevention of osteoclastogenesis, the TIMP could potentially be developed for the treatment of osteoclast-related disorders such as osteoporosis.Cite this article: Bone Joint Res 2022;11(11):763-776.

Hepatoprotective Effects of Aureobasidium pullulans Derived ß 1,3-1,6 Glucans in a Murine Model of Non-alcoholic Steatohepatitis.

Background: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are highly prevalent conditions characterized by inflammation and fibrosis of the liver, which can progress to cirrhosis and hepatocellular carcinoma if left untreated. Conventional modalities are mainly symptomatic, with no definite solution. Beta-glucan-based biological response modifiers are a potential strategy in lieu of their beneficial metabolic effects. Aureobasidium pullulans strains AFO-202 and N-163 beta-glucans were evaluated for anti-fibrotic and anti-inflammatory hepatoprotective potentials in a NASH animal model in this study. Methods: In the STAM™ murine model of NASH, five groups were studied for 8 weeks: (1) vehicle (RO water), (2) AFO-202 beta-glucan; (3) N-163 beta-glucan, (4) AFO-202+N-163 beta-glucan, and (5) telmisartan (standard pharmacological intervention). Evaluation of biochemical parameters in plasma and hepatic histology including Sirius red staining and F4/80 immunostaining were performed. Results: AFO-202 beta-glucan significantly decreased inflammation-associated hepatic cell ballooning and steatosis. N-163 beta-glucan decreased fibrosis and inflammation significantly (P value < 0.05). The combination of AFO-202 with N-163 significantly decreased the NAFLD Activity Score (NAS) compared with other groups. Conclusion: This preclinical study supports the potential of N-163 and AFO-202 beta-glucans alone or in combination as potential preventive and therapeutic agent(s), for NASH.

TNF-induced metalloproteinase-9 production is associated with neurological manifestations in HTLV-1-infected individuals.

HTLV-1-infected individuals may develop a neurologic inflammatory condition known as HTLV-1-associated myelopathy (HAM/TSP), in which the high production of TNF is observed. These patients exhibit higher proviral loads, enhanced production of proinflammatory cytokines and lymphocyte proliferation in comparison to asymptomatic HTLV-1 carriers and those presenting overactive bladder (OAB-HTLV-infected). Metalloproteinases (MMPs) are known to degrade the components of the blood-brain barrier, favoring the migration of infected cells into the central nervous system. Moreover, the unbalanced production of MMPs and their inhibitors (TIMPs) has also been associated with tissue damage. The present work studied the production of MMP-9 and TIMPs in HTLV-1-infected individuals with and without neurological manifestations. HAM/TSP patients presented higher concentrations of MMP-9 in peripheral blood mononuclear cell (PBMC) culture supernatants, as well as a higher MMP-9/TIMP-3 ratio when compared to the other groups studied. MMP-9 levels positively correlated with proviral load and TNF in OAB-HTLV-infected individuals, and the in vitro neutralization of TNF significantly decreased MMP-9 levels in PBMC culture supernatants. Our findings indicate an association between MMP-9 production and the proinflammatory state associated with HTLV-1 infection, as well as HAM/TSP.