The TIMP protein family: diverse roles in pathophysiology.

The tissue inhibitors of matrix metalloproteinases (TIMPs) are a family of four matrisome proteins classically defined by their roles as the primary endogenous inhibitors of metalloproteinases (MPs). Their functions however are not limited to MP inhibition, with each family member harboring numerous MP-independent biological functions that play key roles in processes such as inflammation and apoptosis. Because of these multifaceted functions, TIMPs have been cited in diverse pathophysiological contexts. Herein, we provide a comprehensive overview of the MP-dependent and -independent roles of TIMPs across a range of pathological conditions. The potential therapeutic and biomarker applications of TIMPs in these disease contexts are also considered, highlighting the biomedical promise of this complex and often misunderstood protein family.

NDRG2 alleviates photoreceptor apoptosis by regulating the STAT3/TIMP3/MMP pathway in mice with retinal degenerative disease.

Photoreceptor apoptosis is the main pathological feature of retinal degenerative diseases; however, the underlying molecular mechanism has not been elucidated. Recent studies have shown that N-myc downstream regulated gene 2 (NDRG2) exerts a neuroprotective effect on the brain and spinal cord. In addition, our previous studies have confirmed that NDRG2 is expressed in mouse retinal photoreceptors and counteracts N-methyl-N-nitrosourea (MNU)-induced apoptosis. However, the underlying molecular mechanism remains unclear. In this study, we observed that the expression of NDRG2 was not only significantly inhibited in photoreceptors after MNU treatment but also after hydrogen peroxide treatment, and photoreceptor apoptosis was alleviated or aggravated after overexpression or knockdown of NDRG2 in the 661W photoreceptor cell line, respectively. The apoptosis inhibitor Z-VAD-FMK rescued photoreceptor apoptosis induced by MNU after NDRG2 knockdown. Next, we screened and identified tissue inhibitor of metalloproteinases 3 (TIMP3) as the downstream molecule of NDRG2 in 661W cells by using quantitative real-time polymerase chain reaction. TIMP3 exerts a neuroprotective effect by inhibiting the expression of matrix metalloproteinases (MMPs). Subsequently, we found that signal transducer and activator of transcription 3 (STAT3) mediated the NDRG2-associated regulation of TIMP3. Finally, we overexpressed NDRG2 in mouse retinal tissues by intravitreally injecting an adeno-associated virus with mouse NDRG2 in vivo. Results showed that NDRG2 upregulated the expression of phospho-STAT3 (p-STAT3) and TIMP3, while suppressing MNU-induced photoreceptor apoptosis and MMP expression. Our findings revealed how NDRG2 regulates the STAT3/TIMP3/MMP pathway and uncovered the molecular mechanism underlying its neuroprotective effect on mouse retinal photoreceptors.

Relative ability of aqueous humor from dogs with and without primary angle-closure glaucoma and ADAMTS10 open-angle glaucoma to catalyze or inhibit collagenolysis.

OBJECTIVE: The objective of the study was to compare the ability of aqueous humor (AH) from dogs with primary angle-closure glaucoma (CPACG), companion dogs without overt evidence of CPACG, and Beagles with and without ADAMTS10 open-angle glaucoma (ADAMTS10-OAG) to catalyze or inhibit collagenolysis. ANIMALS STUDIED: Seventeen normal pet dogs, 27 dogs with CPACG, 19 Beagles with ADAMTS10-OAG, and 4 unaffected Beagles. PROCEDURES: A fluorescein-based substrate degradation assay was used to assess AH proteolytic capacity. Samples were then assayed using the same substrate degradation assay, with recombinant activated matrix metalloproteinase-2 (MMP-2) added to measure protease inhibition effects. RESULTS: For the protease activity assay, relative fluorescence (RF) for AH from normal pet dogs was 13.28 ± 2.25% of control collagenase while RF for AH from dogs with CPACG was 17.47 ± 4.67%; RF was 8.57 ± 1.72% for ADAMTS10-OAG Beagles and 7.99 ± 1.15% for unaffected Beagles. For the MMP-2 inhibition assay, RF for AH from normal dogs was 34.96 ± 15.04% compared to MMP-2 controls, while RF from dogs with CPACG was 16.69 ± 7.95%; RF was 85.85 ± 13.23% for Beagles with ADAMTS10-OAG and 94.51 ± 8.36% for unaffected Beagles. Significant differences were found between dogs with CPACG and both normal pet dogs and dogs with ADAMTS10-OAG and between normal pet dogs and both groups of Beagles. CONCLUSIONS: AH from dogs with CPACG is significantly more able to catalyze proteolysis and inhibit MMP-2 than AH from normal dogs or dogs with ADAMTS10-OAG. Results suggest that pathogenesis may differ between CPACG and ADAMTS10-OAG.

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.

Correlation of TIMP1-MMP2/MMP9 Gene Expression Axis Changes with Treatment Efficacy and Survival of NSCLC Patients.

In the course of lung cancer, normal cells are transformed into cancerous ones, and changes occur in the microenvironment, including the extracellular matrix (ECM), which is not only a scaffold for cells, but also a reservoir of cytokines, chemokines and growth factors. Metalloproteinases (MMPs) are among the elements that enable ECM remodeling. The publication focuses on the problem of changes in the gene expression of MMP2, MMP9 and tissue inhibitor of metalloproteinases (TIMP1) in the blood of NSCLC patients during therapy (one year after surgical resection of the tumor). The paper also analyzes differences in the expression of the studied genes in the tumor tissue, as well as data collected in publicly available databases. The results of blood tests showed no differences in the expression of the tested genes during therapy; however, changes were observed in cancerous tissue, which was characterized by higher expression of MMP2 and MMP9, compared to non-cancerous tissue, and unchanged expression of TIMP1. Nevertheless, higher expression of each of the studied genes was associated with shorter patient survival. Interestingly, it was not only the increased expression of metalloproteinase genes, but also the increased expression of the metalloproteinase inhibitor (TIMP1) that was unfavorable for patients.

Biomarkers of lung alveolarization and microvascular maturation in response to intermittent hypoxia and/or early antioxidant/fish oil supplementation in neonatal rats.

OBJECTIVE: Extremely preterm infants experience frequent intermittent hypoxia (IH) episodes during oxygen therapy which causes significant damage to the lungs and curtails important signaling pathways that regulate normal lung alveolarization and microvascular maturation. We tested the hypothesis that early supplementation with fish oil and/or antioxidants in rats exposed to neonatal IH improves expression of lung biomarkers of alveolarization and microvascular maturation, and reduces IH-induced lung injury. STUDY DESIGN/METHODS: From birth (P0) to P14, rat pups were exposed to room air (RA) or neonatal IH during which they received daily oral supplementation with either: (1) olive oil (OO) (control); (2) Coenzyme Q10 (CoQ10) in OO; (3) fish oil; (4) glutathione nanoparticles (nGSH); or (5) fish oil +CoQ10. At P14 pups were placed in RA until P21 with no further treatment. RA controls were similarly treated. Lung growth and alveolarization, histopathology, apoptosis, oxidative stress and biomarkers of alveolarization and microvascular maturation were determined. RESULTS: Neonatal IH was associated with reduced lung weights and severe histopathological outcomes. These effects were curtailed with fish oil and nGSH. nGSH was also protective against apoptosis, while CoQ10 prevented IH-induced ROS production. Of all treatments, nGSH and CoQ10 + fish oil-induced vascular endothelial growth factor165 and CD31 (Platelet endothelial cell adhesion molecule-1), which are associated with angiogenesis. CoQ10 + fish oil improved alveolarization in RA and IH despite evidence of hemorrhage. CONCLUSIONS: The benefits of nGSH and CoQ10 + fish oil suggest an antioxidant effect which may be required to curtail IH-induced lung injury. Further clinical assessment of the effectiveness of nGSH is warranted.

PhosY-secretome profiling combined with kinase-substrate interaction screening defines active c-Src-driven extracellular signaling.

c-Src tyrosine kinase is a renowned key intracellular signaling molecule and a potential target for cancer therapy. Secreted c-Src is a recent observation, but how it contributes to extracellular phosphorylation remains elusive. Using a series of domain deletion mutants, we show that the N-proximal region of c-Src is essential for its secretion. The tissue inhibitor of metalloproteinases 2 (TIMP2) is an extracellular substrate of c-Src. Limited proteolysis-coupled mass spectrometry and mutagenesis studies verify that the Src homology 3 (SH3) domain of c-Src and the P31VHP34 motif of TIMP2 are critical for their interaction. Comparative phosphoproteomic analyses identify an enrichment of PxxP motifs in phosY-containing secretomes from c-Src-expressing cells with cancer-promoting roles. Inhibition of extracellular c-Src using custom SH3-targeting antibodies disrupt kinase-substrate complexes and inhibit cancer cell proliferation. These findings point toward an intricate role for c-Src in generating phosphosecretomes, which will likely influence cell-cell communication, particularly in c-Src-overexpressing cancers.

Matrix Metalloproteinases/Tissue Inhibitors of Metalloproteinases Ratio: A Biomarker of Bone Resorption in Geriatric Osteoporosis?

BACKGROUND: Matrix metalloproteinases (MMPs) play an important role in bone resorption and are regulated by tissue inhibitors of metalloproteinases (TIMPs). We investigated the use of MMP2/TIMP2 and MMP9/TIMP1 ratios as biomarkers of bone resorption in geriatric osteoporosis and evaluated the relationship between osteoporosis and geriatric syndromes. METHODS: This analytical cross-sectional study involved 87 patients (41 with osteoporosis) treated at the geriatric outpatient clinic of a university hospital. The demographic characteristics, comprehensive geriatric assessment scores, laboratory findings, and bone mineral density of the patients were recorded. Serum MMP9, TIMP1, MMP2, and TIMP2 levels were analyzed by enzyme-linked immunosorbent assay (ELISA). RESULTS: We enrolled 41 and 46 patients with and without osteoporosis, respectively. The groups showed no significant differences in MMP2/TIMP2 and MMP9/TIMP1 ratios (p=0.569 and p=0125, respectively). While the basic activities of daily life (BADL) scores in the osteoporosis group were higher than those in the group without osteoporosis, the instrumental activities of daily life (IADL) scores were significantly lower (p=0.001 and p=0.007, respectively). No significant differences were observed in Mini-Nutritional Assessment, Mini-Mental State Examination, and Geriatric Depression Scale scores (p=0.598, p=0.898, and p=0.287, respectively). CONCLUSION: This is the first study to examine the relationship between osteoporosis and several geriatric syndromes, as well as the relationship between osteoporosis and serum MMP, TIMP values, and MMP/TIMP ratios in geriatric patients. Our results showed that osteoporosis causes dependency in both BADLs and IADLs, and that the MMP2/TIMP2 and MMP9/TIMP1 ratios provided no additional benefit in demonstrating bone resorption in geriatric osteoporosis.

Plasma Levels of MMPs and TIMP-1 in Patients with Osteoarthritis After Recovery from COVID-19.

BACKGROUND: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPS) play a key role in the pathogenesis of osteoarthritis (OA). Recent research showed the involvement of some MMPs in COVID-19, but the results are limited and contradictory. OBJECTIVE: In this study, we investigated the levels of MMPs (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10) and TIMP-1 in the plasma of patients with OA after recovery from COVID- 19. METHODS: The experiment involved patients aged 39 to 80 diagnosed with knee OA. All study participants were divided into three research groups: the control group included healthy individuals, the group OA included patients with enrolled cases of OA, and the third group of OA and COVID-19 included patients with OA who recovered from COVID-19 6-9 months ago. The levels of MMPs and TIMP-1 were measured in plasma by enzyme-linked immunosorbent assay. RESULTS: The study showed a change in the levels of MMPs in patients with OA who had COVID- 19 and those who did not have a history of SARS-CoV-2 infection. Particularly, patients with OA who were infected with coronavirus established an increase in MMP-2, MMP-3, MMP-8, and MMP-9, compared to healthy controls. Compared to normal subjects, a significant decrease in MMP-10 and TIMP-1 was established in both groups of patients with OA and convalescent COVID-19. CONCLUSION: Thus, the results suggest that COVID-19 can affect the proteolysis-antiproteolysis system even after a long postinfectious state and may cause complications of existing musculoskeletal pathologies.

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.

Matrix metalloproteinases as biomarkers and therapeutic targets in colitis-associated cancer.

Colorectal cancer (CRC) remains a major cause of morbidity and mortality. Therapeutic approaches for advanced CRC are limited and rarely provide long-term benefit. Enzymes comprising the 24-member matrix metalloproteinase (MMP) family of zinc- and calcium-dependent endopeptidases are key players in extracellular matrix degradation, a requirement for colon tumor expansion, invasion, and metastasis; hence, MMPs are an important research focus. Compared to sporadic CRC, less is known regarding the molecular mechanisms and the role of MMPs in the development and progression of colitis-associated cancer (CAC) - CRC on a background of chronic inflammatory bowel disease (IBD) - primarily ulcerative colitis and Crohn's disease. Hence, the potential of MMPs as biomarkers and therapeutic targets for CAC is uncertain. Our goal was to review data regarding the role of MMPs in the development and progression of CAC. We sought to identify promising prognostic and therapeutic opportunities and novel lines of investigation. A key observation is that since MMPs may be more active in early phases of CAC, using MMPs as biomarkers of advancing neoplasia and as potential therapeutic targets for adjuvant therapy in those with advanced stage primary CAC rather than overt metastases may yield more favorable outcomes.

Treponema pallidum protein Tp0136 promoting MMPs/TIMPs imbalance via PI3K, MAPK and NF-κB signalling pathways in HDVSMCs.

The invasive capability of Treponema. pallidum is central to its infection process. Matrix metalloproteinases (MMPs), which are specifically inhibited by the tissue inhibitors of metalloproteinases (TIMPs), play a pivotal role in promoting pathogenic invasion by destroying tissue barriers within the body. This study aimed to explore the effect of T. pallidum protein Tp0136 on the balance of MMPs/TIMPs in human dermal vascular smooth muscle cells (HDVSMCs) and the related underlying mechanisms. A number of in vitro studies were conducted to access the impact of recombinant Tp0136 protein on the balance of MMPs/TIMPs in HDVSMCs. The involvement of the PI3K, MAPK, and NF-κB signaling pathways in this process was also investigated. Tp0136 induced the mRNA and protein expressions of MMP1 in HDVSMCs in a concentration-dependent way. In addition, MMP1/TIMP1 and MMP1/TIMP2 ratios were also increased. Furthermore, the study demonstrated that treatment of HDVSMCs with Tp0136 activated the PI3K, MAPK, and NF-κB signaling pathways. Inhibition of PI3K, JNK, P38, and NF-κB, suppressed MMP1 expression and reduced the induction of MMP1/TIMP1 and MMP1/TIMP2 ratios by Tp0136. These findings demonstrate that Tp0136 enhanced the expression of MMP1 involving the PI3K, MAPK, and NF-κB signaling pathways in HDVSMCs, and thus generated the unbalance of MMPs/TIMP, which could contribute to the early spread of T. pallidum and pathogenesis of syphilis.

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.

Role of matrix metalloproteinases in diabetic foot ulcers: Potential therapeutic targets.

Diabetic foot ulcers (DFUs) are pathological states of tissue destruction of the foot or lower extremity in diabetic patients and are one of the serious chronic complications of diabetes mellitus. Matrix metalloproteinases (MMPs) serve crucial roles in both pathogenesis and wound healing. The primary functions of MMPs are degradation, which involves removing the disrupted extracellular matrix (ECM) during the inflammatory phase, facilitating angiogenesis and cell migration during the proliferation phase, and contracting and rebuilding the tissue during the remodeling phase. Overexpression of MMPs is a feature of DFUs. The upregulated MMPs in DFUs can cause excessive tissue degradation and impaired wound healing. Regulation of MMP levels in wounds could promote wound healing in DFUs. In this review, we talk about the roles of MMPs in DFUs and list potential methods to prevent MMPs from behaving in a manner detrimental to wound healing in DFUs.

Matrix Metalloproteinases in Dental and Periodontal Tissues and Their Current Inhibitors: Developmental, Degradational and Pathological Aspects.

OBJECTIVES: This review article aims to describe some of the roles of Matrix metalloproteinases (MMPs) in enamel, dentine, dental caries, hybrid layer degradation, pulp and periodontal tissues, throwing light on their current inhibitors. The article addresses the potential of MMPs to serve as biomarkers with diagnostic and therapeutic value. DESIGN: The sections of this review discuss MMPs' involvement in developmental, remodeling, degradational and turnover aspects of dental and periodontal tissues as well as their signals in the pathogenesis, progress of different lesions and wound healing of these tissues. The literature was searched for original research articles, review articles and theses. The literature search was conducted in PubMed and MEDLINE for articles published in the last 20 years. RESULTS: 119 published papers, two textbooks and two doctoral theses were selected for preparing the current review. CONCLUSIONS: MMPs are significant proteases, of evident contribution in dental and periapical tissue development, health and disease processes, with promising potential for use as diagnostic and prognostic disease biomarkers. Continuing understanding of their role in pathogenesis and progress of different dental, periapical and periodontal lesions, as well as in dentine-pulp wound healing could be a keystone to future diagnostic and therapeutic regimens.

Matrix metalloproteinase-induced cervical extracellular matrix remodelling in pregnancy and cervical cancer.

Abstract: The phenomenal extracellular matrix (ECM) remodelling of the cervix that precedes the myometrial contraction of labour at term or preterm appears to share some common mechanisms with the occurrence, growth, invasion and metastasis of cervical carcinoma. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that are pivotal to the complex extracellular tissue modulation that includes degradation, remodelling and exchange of ECM components, which contribute to homeostasis under normal physiological conditions such as cervical remodelling during pregnancy and puerperium. However, in cancer such as that of the uterine cervix, this extensive network of extracellular tissue modulation is altered leading to disrupted cell-cell and cell-basement membrane adhesion, abnormal tissue growth, neovascularization and metastasis that disrupt homeostasis. Cervical ECM remodelling during pregnancy and puerperium could be a physiological albeit benign neoplasm. In this review, we examined the pathophysiologic differences and similarities in the role of MMPs in cervical remodelling and cervical carcinoma. Lay summary: During pregnancy and childbirth, the cervix, which is the barrel-shaped lower portion of the womb that connects to the vagina, gradually softens, shortens and opens to allow birth of the baby. This process requires structural and biochemical changes in the cervix that are stimulated by enzymes known as matrix metalloproteinases. Interestingly, these enzymes also affect the structural and biochemical framework of the cervix during cervical cancer, although cervical cancers usually occur after infection by human papillomavirus. This review is intended to identify and explain the similarities and differences between the structural and chemical changes in the cervix during pregnancy and childbirth and the changes seen in cervical cancer.

Tissue inhibitor of metalloproteinases 1 is involved in ROS-mediated inflammation via regulating matrix metalloproteinase 1 expression in the sea cucumber Apostichopus japonicus.

Tissue inhibitors of metalloproteinases (TIMPs) serve as matrix metalloproteinase (MMP) inhibitors in the pathogenesis of inflammatory diseases in vertebrates. We cloned and characterised the TIMP1 gene from Apostichopus japonicus using RACE approaches (designated as AjTIMP1). For Vibrio splendidus-challenged sea cucumbers, the peak expression of AjTIMP1 mRNAs in coelomocytes was detected at 24 h (23.44-fold) and remained at high levels (4.01-fold) until 72 h. Similarly, AjTIMP1 expression was upregulated in primary coelomocytes exposed to 10 µg mL-1 LPS. AjTIMP1 was expressed in all tissues, and the highest expression was observed in the body wall. Functional investigation revealed an imbalance in the ratio of AjMMP1/AjTIMP1 in the skin ulceration syndrome (SUS) diseased group; it was sharply up-regulated to 3.97:1 compared with the healthy group. Furthermore, when AjTIMP1 was knocked down using small interfering RNA (siRNA-KD) to 0.4-fold, AjMMP1 and AjMMP19 were upregulated to 1.99- and 1.85-fold, respectively. AjTIMP1 siRNA-KD can promote ROS production by 26.2%, whereas AjMMP1 siRNA-KD can eliminate the increase in ROS. In inflamed tissues, collagen I and III levels were decreased by 33.1% and 33.6%, respectively, in the AjTIMP1 siRNA group at 24 h AjTIMP1 was involved in the inflammatory response by mediating ROS formation and collagen degradation.

Matrix metalloproteinases and their inhibitors - pleiotropic functions in insect immunity and metamorphosis.

Matrix metalloproteinases (MMPs) enable tissue remodeling and immune responses by degrading extracellular matrix proteins. They are regulated by tissue inhibitors of metalloproteinases (TIMPs). Mammals produce more than 20 MMPs but insects produce fewer than 3, at odds with the extensive tissue remodeling required during metamorphosis and inflammation. Addressing this apparent paradox, Liu et al. demonstrate the pleiotropic functions of silkworm MMPs and TIMP. They measured expression levels during pupation and during a response to viral infection in transgenic overexpression and knockout lines for selected MMP/TIMP genes. This confirmed the multiple roles of these key enzymes in insect immunity and metamorphosis. Comment on https://doi.org/10.1111/febs.16313.

Comprehensive analysis of matrix metalloproteinases and their inhibitors in head and neck squamous cell carcinoma.

Objective: This study aimed to explore the association of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) with cancer progression and prognosis in head and neck squamous cell carcinoma (HNSCC).Methods: Differentially expressed genes (DEGs) were identified by LIMMA package using R software. The correlation between the expression levels of MMPs and TIMPs in HNSCC cancer samples and adjacent normal tissue samples was performed using Pearson correlation analysis. The Kruskal-Wallis test (H-test) was used to determine the association between the expression level of MMPs/TIMPs and HNSCC clinical stage. The survival result was expressed as a KM curve, and the log-rank test was used for statistical analysis. Lasso regression and multivariate Cox regression analyses were used to examine whether the gene signature based on MMPs and TIMPs was an independent prognostic factor in patients with HNSCC.Results: Among the top 10 most up-regulated genes in HNSCC cancer tissues when compared with normal tissues, six genes belonged to the MMPs. Spearman correlation analysis revealed that only MMP11 and MMP23B were positively correlated with tumor stage. Survival analysis showed that patients with a high expression of MMP14, MMP20, TIMP1, and TIMP4 had a worse prognosis than low expression patients. Additionally, a novel five-gene (MMP3, MMP17, MMP19, MMP24, and TIMP1) signature was constructed and significantly associated with prognosis as an independent prognostic signature.Conclusions: Our data show that the accuracy of a single gene of MMP or TIMP as predictors of progression and prognosis of HNSCC is limited, although some studies have proposed that MMPs act as driving factors for cancer progression. The prediction performance of the five-gene signature prediction model was much better than that of the gene signatures based on every single gene in prognosis prediction.

Comprehensive characterization of the postoperative pericardial inflammatory response: Potential implications for clinical outcomes.

Objective: There is a paucity of data on the inflammatory response that takes place in the pericardial space after cardiac surgery. This study provides a comprehensive assessment of the local postoperative inflammatory response. Methods: Forty-three patients underwent cardiotomy, where native pericardial fluid was aspirated and compared with postoperative pericardial effluent collected at 4, 24, and 48 hours' postcardiopulmonary bypass. Flow cytometry was used to define the levels and proportions of specific immune cells. Samples were also probed for concentrations of inflammatory cytokines, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs). Results: Preoperatively, the pericardial space mainly contains macrophages and T cells. However, the postsurgical pericardial space was populated predominately by neutrophils, which constituted almost 80% of immune cells present, and peaked at 24 hours. When surgical approaches were compared, minimally invasive surgery was associated with fewer neutrophils in the pericardial space at 4 hours' postsurgery. Analysis of the intrapericardial concentrations of inflammatory mediators showed interleukin-6, MMP-9, and TIMP-1 to be highest postsurgery. Over time, MMP-9 concentrations decreased significantly, whereas TIMP-1 levels increased, resulting in a significant reduction of the ratio of MMP:TIMP after surgery, suggesting that active inflammatory processes may influence extracellular matrix remodeling. Conclusions: These results show that cardiac surgery elicits profound alterations in the immune cell profile in the pericardial space. Defining the cellular and molecular mediators that drive pericardial-specific postoperative inflammatory processes may allow for targeted therapies to reduce immune-mediated complications.