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Cytokine Aug 2023The matrix metalloproteinases (MMPs) are engaged in the degradation and remodeling of the extracellular matrix and vessels, allowing the progression of pathological... (Review)
Review
The matrix metalloproteinases (MMPs) are engaged in the degradation and remodeling of the extracellular matrix and vessels, allowing the progression of pathological processes. Recent studies pointed that MMP -2 and -9 are promising visceral leishmaniasis biomarkers. Thus, the present studystudy aimed to review published scientific literature related to MMP-2 and -9 activity on canine visceral leishmaniasis (CVL). The review followed the PRISMA method, searching for articles in ScienceDirect, PubMed, Scopus, Lilacs, Medline and Google Scholar from inception until 20 March 2022 by employing the following terms: "dog", "matrix metalloproteinases" and "Visceral Leishmaniasis" or "Kala Azar". The selected articles were read in full and only those consistent with the eligibility criteria were included in the review. Of 238 articles from the initial search, only five were deemed eligible, which were conducted between 2010 and 2018. All studies were performed in Brazil. It was observed that there was a higher expression of proMMP-2 in cerebrospinal (CS) fluid and serum and active MMP-2 in different skin areas, mainly in high parasite load areas. As for MMP-9, the pro and active forms were both expressed in CS fluid, serum and different skin areas. The MMP-2 can be considered a biomarker of bad prognostic as it plays an inflammatory role with a greater release in the initial phase of the disease, where MMP-9 is perceived in the chronic phase of CVL. Future research on the subject with greater methodological rigor and bigger sample sizes are mandatory to clarify the role of MMPs on disease progression.
Topics: Dogs; Biomarkers; Leishmaniasis, Visceral; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Risk Factors; Animals
PubMed: 37257306
DOI: 10.1016/j.cyto.2023.156236 -
Kidney International Nov 2023Matrix metalloproteinases (MMPs) cleave matrix components along with multiple other effects. They are integral to virtually all biological processes, including...
Matrix metalloproteinases (MMPs) cleave matrix components along with multiple other effects. They are integral to virtually all biological processes, including inflammation and wound healing. As such, MMPs have been studied in the context of peritoneal membrane injury. MMP10 is a stromelysin and is involved in the degradation of matrix proteoglycans. Ishimura et al. demonstrate that MMP10 is involved in peritoneal membrane fibrosis. The clinical implications of these observations are presently unknown.
Topics: Matrix Metalloproteinase 10; Wound Healing
PubMed: 37863635
DOI: 10.1016/j.kint.2023.09.009 -
Annals of Vascular Surgery Aug 2024Studies have linked matrix metalloproteinases (MMPs) to both thoracic aortic aneurysm and abdominal aortic aneurysm (TAA and AAA). The precise MMPs entailed in this...
BACKGROUND
Studies have linked matrix metalloproteinases (MMPs) to both thoracic aortic aneurysm and abdominal aortic aneurysm (TAA and AAA). The precise MMPs entailed in this procedure, however, were still unknown. This study used a two-sample Mendelian randomization (MR) analysis to look into the causal relationship between MMPs and the risk of TAA and AAA.
METHODS
Eight MMPs, including MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, MMP-12, and MMP-13, were found among people of European ancestry with accessible Genome-Wide Association Studies (GWAS). We employed the findings from Genome-Wide Association Studies (GWAS) for 8 MMPs, and TAA and AAA from the FinnGen consortiums (3,201 cases and 317,899 controls, respectively) were used in a two-sample MR analysis. The primary method of analysis for MR was the inverse variance weighted (IVW) method, along with analyses of heterogeneity and horizontal pleiotropy. 31 single-nucleotide polymorphisms connected to MMP were retrieved.
RESULTS
IVW demonstrated a negative causal association between TAA and AAA and serum MMP-12 levels. The incidence of TAA decreased by 1.031% for every 1 ng/mL increase in serum MMP-12 [odds ratio (OR) = 0.897, 95% confidence interval (CI): 0.831-0.968, P = 0.005]. The incidence of AAA fell by 1.653% (OR = 0.835, 95% CI: 0.752-0.926, P = 0.001) for every 1 ng/mL increase in serum MMP-12. There was no horizontal pleiotropy or heterogeneity in the MR data (P > 0.05).
CONCLUSIONS
The levels of TAA and AAA and serum MMP-12 are causally related. MMP-12 is a factor that reduces the risk of AAA and TTA. Our study suggested that MMP-12 level is causally associated with a decreased risk of TAA and AAA.
Topics: Humans; Mendelian Randomization Analysis; Aortic Aneurysm, Abdominal; Polymorphism, Single Nucleotide; Risk Factors; Genome-Wide Association Study; Genetic Predisposition to Disease; Aortic Aneurysm, Thoracic; Matrix Metalloproteinases; Risk Assessment; Matrix Metalloproteinase 12; Phenotype; Case-Control Studies; Incidence; Protective Factors
PubMed: 38609009
DOI: 10.1016/j.avsg.2024.02.011 -
Expert Opinion on Therapeutic Patents Oct 2023Matrix metalloproteinases (MMPs) are strongly interlinked with the progression and mechanisms of several life-threatening diseases including cancer. Thus, novel MMP... (Review)
Review
INTRODUCTION
Matrix metalloproteinases (MMPs) are strongly interlinked with the progression and mechanisms of several life-threatening diseases including cancer. Thus, novel MMP inhibitors (MMPIs) as promising drug candidates can be effective in combating these diseases. However, no MMPIs are marketed to date due to poor pharmacokinetics and lower selectivity. Therefore, this review was performed to study the newer MMPIs patented after the COVID-19 period for an updated perspective on MMPIs.
AREAS COVERED
This review highlights patents related to MMPIs, and their therapeutic implications published between January 2021 and August 2023 available in the Google Patents, Patentscope, and Espacenet databases.
EXPERT OPINION
Despite various MMP-related patents disclosed up to 2020, newer patent applications in the post-COVID-19 period decreased a lot. Besides major MMPs, other isoforms (i.e. MMP-3 and MMP-7) have gained attention recently for drug development. This may open up newer dimensions targeting these MMPs for therapeutic advancements. The isoform selectivity and bioavailability are major concerns for effective MMPI development. Thus, adopting theoretical approaches and experimental methodologies can unveil the development of novel MMPIs with improved pharmacokinetic profiles. Nevertheless, the involvement of MMPs in cancer, and the mechanisms of such MMPs in other diseases should be extensively studied for novel MMPI development.
Topics: Humans; Antineoplastic Agents; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Patents as Topic; Neoplasms; COVID-19
PubMed: 37982191
DOI: 10.1080/13543776.2023.2284935 -
European Review For Medical and... Aug 2023The aim of this study was to investigate the protective effect and mechanism of action (MOA) of Qiliqiangxin capsule (QL) in the deoxycorticosterone acetate (DOCA)...
OBJECTIVE
The aim of this study was to investigate the protective effect and mechanism of action (MOA) of Qiliqiangxin capsule (QL) in the deoxycorticosterone acetate (DOCA) salt-induced rat heart failure with preserved ejection fraction (HFpEF) model.
MATERIALS AND METHODS
Nono-nephrectomy sixty Sprague Dawley (SD) rats received DOCA salt injection and 1% saline in drinking water for 4 weeks and were randomly divided into four groups on average: Model group (n=15), Sac/Val group (Sacubitril Valsartan 0.02 g/kg, n=15), QL-L group (Qiliqiangxin 0.25 g/kg, n=15) and QL-H group (Qiliqiangxin 1 g/kg, n=15). Another Normal group was set (n=15). Blood pressure, N-terminal pro-brain natriuretic peptide (NT-proBNP), cardiac index, echocardiography, and hemodynamics were measured to evaluate heart function. Masson and Wheat germ agglutinin (WGA) staining was performed to observe the fibrosis deposition and the cross-sectional area (CSA) of cardiomyocytes. The concentration levels of the serum cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-2, IL-6, and IL-10 inflammatory factors, were detected by ELISA; matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), transforming growth factor-β1 (TGF-β1), nuclear factor-κB (NF-κB), Smad homologue 2 (Smad2) and Smad homologue 3 (Smad3) expression were detected by Western-blot.
RESULTS
Compared with the Model group, QL treatment significantly ameliorated the heart function in DOCA salt-induced rat HFpEF model, showing a decrease in cardiac index, an increase of the EF and E/A ratio, a reduction in the left ventricular anterior/posterior wall (LVAW/LVPW), in the time contraction of isovolumic diastolic time (IVRT), -dP/dt Max, and Tau, and the decrease of serum NT-ProBNP. Masson and WGA staining indicated that QL inhibited the fibrosis deposition and the myocardial hypertrophy compared with the Model group, which was consistent in reducing the protein expression levels of cardiac remodeling such as TGF-β1, MMP2, MMP9, Smad2, and Smad3. Moreover, QL treatment inhibited the expression of NF-κB in the heart tissues and decreased the serum concentration of pro-inflammatory cytokines TNF-α and IL-2, instead, increasing the IL-10 concentration.
CONCLUSIONS
QL improved the cardiac function and inhibited the myocardial fibrosis in DOCA salt-induced rat HFpEF by improving diastolic dysfunction, preventing left ventricular hypertrophy, and ameliorating the inflammatory responses model in DOCA salt-induced rat HFpEF model.
Topics: Rats; Animals; Matrix Metalloproteinase 2; Interleukin-10; Desoxycorticosterone Acetate; Matrix Metalloproteinase 9; Transforming Growth Factor beta1; Heart Failure; NF-kappa B; Tumor Necrosis Factor-alpha; Ventricular Remodeling; Rats, Sprague-Dawley; Stroke Volume; Myocytes, Cardiac; Cytokines
PubMed: 37606135
DOI: 10.26355/eurrev_202308_33298 -
Matrix Biology : Journal of the... Nov 2023Extracellular proteolysis and turnover are core processes of tissue homeostasis. The predominant matrix-degrading enzymes are members of the Matrix Metalloproteinase...
Extracellular proteolysis and turnover are core processes of tissue homeostasis. The predominant matrix-degrading enzymes are members of the Matrix Metalloproteinase (MMP) family. MMPs extensively degrade core matrix components in addition to processing a range of other factors in the extracellular, plasma membrane, and intracellular compartments. The proteolytic activity of MMPs is modulated by the Tissue Inhibitors of Metalloproteinases (TIMPs), a family of four multi-functional matrisome proteins with extensively characterized MMP inhibitory functions. Thus, a well-regulated balance between MMP activity and TIMP levels has been described as critical for healthy tissue homeostasis, and this balance can be chronically disturbed in pathological processes. The relationship between MMPs and TIMPs is complex and lacks the constraints of a typical enzyme-inhibitor relationship due to secondary interactions between various MMPs (specifically gelatinases) and TIMP family members. We illustrate a new complexity in this system by describing how MMP9 can cleave members of the TIMP family when in molar excess. Proteolytic processing of TIMPs can generate functionally altered peptides with potentially novel attributes. We demonstrate here that all TIMPs are cleaved at their C-terminal tails by a molar excess of MMP9. This processing removes the N-glycosylation site for TIMP3 and prevents the TIMP2 interaction with latent proMMP2, a prerequisite for cell surface MMP14-mediated activation of proMMP2. TIMP2/4 are further cleaved producing ∼14 kDa N-terminal proteins linked to a smaller C-terminal domain through residual disulfide bridges. These cleaved TIMP2/4 complexes show perturbed MMP inhibitory activity, illustrating that MMP9 may bear a particularly prominent influence upon the TIMP:MMP balance in tissues.
Topics: Matrix Metalloproteinase 9; Proteolysis; Tissue Inhibitor of Metalloproteinases; Gelatinases; Proteins
PubMed: 37804930
DOI: 10.1016/j.matbio.2023.09.002 -
Activation of LXRα attenuates 2-Ethylhexyl diphenyl phosphate (EHDPP) induced placental dysfunction.Ecotoxicology and Environmental Safety Nov 20232-Ethylhexyl diphenyl phosphate (EHDPP) is one of the typical organophosphate flame retardants (OPFRs) and has been widely detected in environmental media. Exposure to...
2-Ethylhexyl diphenyl phosphate (EHDPP) is one of the typical organophosphate flame retardants (OPFRs) and has been widely detected in environmental media. Exposure to EHDPP during pregnancy affects placental development and fetal growth. Liver X receptor α (LXRα) is essential to placental development. However, finite information is available regarding the function of LXRα in placenta damages caused by EHDPP. In present study we investigated to figure out whether LXRα is playing roles in EHDPP-induced placenta toxicity. While EHDPP restrained cell viability, migration, and angiogenesis dose-dependently in HTR-8/SVneo and JEG-3 cells, overexpression or activation by agonist T0901317 of LXRα alleviated the above phenomenon, knockdown or inhibition by antagonist GSK2033 had the opposite effects in vitro. Further study indicated EHDPP decreased LXRα expression and transcriptional activity leading to mRNA, protein expression levels downregulation of viability, migration, angiogenesis-related genes Forkhead box M1 (Foxm1), endothelial nitric oxide synthase (eNos), matrix metalloproteinase-2 (Mmp-2), matrix metalloproteinase-9 (Mmp-9), vascular endothelial growth factor-A (Vegf-a) and upregulation of inflammatory genes interleukin-6 (Il-6), interleukin-1β (Il-1β) and tumor necrosis factor-α (Tnf-α) in vitro and in vivo. Moreover, EHDPP caused decreased placental volume and fetal weight in mice, treatment with LXRα agonist T0901317 restored these adverse effects. Taken together, our study unveiled EHDPP-induced placenta toxicity and the protective role of LXRα in combating EHDPP-induced placental dysfunction. Activating LXRα could serve as a therapeutic strategy to reverse EHDPP-induced placental toxicity.
Topics: Female; Pregnancy; Animals; Mice; Phosphates; Liver X Receptors; Matrix Metalloproteinase 2; Vascular Endothelial Growth Factor A; Cell Line, Tumor; Placenta
PubMed: 37864966
DOI: 10.1016/j.ecoenv.2023.115605 -
Journal of Periodontology Nov 2023Resolvins are endogenous mediators of the resolution of inflammation. They are derived from omega-3 polyunsaturated fatty acid precursors. Resolvin D1 (RvD1) and...
BACKGROUND
Resolvins are endogenous mediators of the resolution of inflammation. They are derived from omega-3 polyunsaturated fatty acid precursors. Resolvin D1 (RvD1) and Resolvin E1 (RvE1) are the best-characterized members for actively promoting periodontal regeneration in experimental animal models. Here, we evaluated the efficacy of RvD1 and RvE1 on cementoblasts, the key cells involved in dental cementum regeneration and the attachment of the tooth to the alveolar bone.
METHODS
Immortalized mouse cementoblasts (OCCM-30) were treated with different concentrations (0.1-1000 ng/mL) of RvD1 and RvE1. Cell proliferation was measured using an electrical impedance-based real-time cell analyzer. Mineralization was evaluated with von Kossa staining. The mRNA expression of mineralized tissue-associated markers of bone sialoprotein (BSP), Type I collagen (COL I), osteocalcin (OCN), osteopontin (OPN), runt-related transcription factor 2 (RunX2), alkaline phosphatase (ALP), osteoprotegerin (OPG), receptor activator of nuclear factor kappa B (NF-κB) (RANK), receptor activator of NF-κB ligand (RANKL), and extracellular matrix-degrading enzymes [matrix metalloproteinase (MMP)-1, MMP-2, MMP-3, MMP-9, and their tissue inhibitors (TIMP-1, TIMP-2)], RvE1 receptor (ChemR23) and RvD1 receptor (ALX/PFR2), cytokines (tumor necrosis factor-alpha {TNF-α}, interleukin {IL}-1β, IL-6, IL-8, IL-10, IL-17), oxidative stress enzymes [superoxide dismutase (SOD), glutathione peroxidase (GPX), and cyclooxygenase-2 (Cox-2)] were analyzed using quantitative polymerase chain reaction (qPCR).
RESULTS
Both RvD1 and RvE1 (10-100 ng/mL) significantly increased the proliferation of cementoblasts and mineralized nodules at all concentrations (p < 0.05). RvE1 increased BSP, RunX2, and ALP compared with the RvD1 dose and time-dependently, while RvD1 and RvE1 differentially regulated COL-I. RvE1 increased OPG mRNA expression, whereas RANK-RANKL mRNA expression decreased by RvE1. MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 expressions were reduced by RvE1 compared with RvD1. Treatment of cementoblasts with RvD1 and RvE1 differentially affected cytokine and oxidative stress enzymes while significantly increasing their receptor expressions (ChemR23 and ALX/PFR2).
CONCLUSIONS
RvD1 and RvE1 regulate proliferation, mineralization, and gene expression in cementoblasts using similar pathways while differentially affecting tissue degradation, suggesting a targeted therapeutic approach for cementum turnover during periodontal regeneration.
Topics: Mice; Animals; Dental Cementum; Tissue Inhibitor of Metalloproteinase-2; Tissue Inhibitor of Metalloproteinase-1; Matrix Metalloproteinase 3; Core Binding Factor Alpha 1 Subunit; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Integrin-Binding Sialoprotein; RNA, Messenger; Docosahexaenoic Acids; Eicosapentaenoic Acid
PubMed: 37322861
DOI: 10.1002/JPER.22-0510 -
Neurochemistry International Jan 2024Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality among young adults and the elderly. In the United States, TBI is responsible for... (Review)
Review
Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality among young adults and the elderly. In the United States, TBI is responsible for around 30 percent of all injuries brought on by injuries in general. Vasogenic cerebral edema due to blood-brain barrier (BBB) dysfunction and the associated elevation of intracranial pressure (ICP) are some of the major causes of secondary injuries following traumatic brain injury. Matrix metalloproteinase-9 (MMP-9) is a therapeutic target for being an enzyme that degrades the proteins that make up a part of the microvascular basal lamina as well as inter-endothelial tight junctions of the blood-brain barrier. MMP-9-mediated BBB dysfunctions and the compromise of the BBB is a major pathway that leads the development of vasogenic cerebral edema, elevation of ICP, poor cerebral perfusion and brain herniation following traumatic brain injury. That makes MMP-9 an effective therapeutic target and endogenous or exogenous MMP-9 inhibitors as therapeutic drugs for preventing secondary brain damage after traumatic brain injury. Although our understanding of the mechanisms that underlie the primary and secondary stages of damage following a TBI has significantly improved in recent years, such information has not yet resulted in the successful development of novel pharmacological treatment options for traumatic brain injury. Recent pre-clinical and/or clinical studies have demonstrated that there are several compounds with specific or non-specific MMP-9 inhibitory properties either directly binding and inhibiting MMP-9 or by indirectly inhibiting MMP-9, with potential as therapeutic agents for traumatic brain injury. This article reviews the efficacy of several such medications and potential agents that include endogenous and exogeneous compounds that are at various levels of research and development. MMP-9-based therapeutic drug development has enormous potential in the pharmacological treatment of cerebral edema and/or neuronal injury resulting from traumatic brain injury.
Topics: Aged; Humans; Blood-Brain Barrier; Brain Edema; Brain Injuries, Traumatic; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors
PubMed: 38008261
DOI: 10.1016/j.neuint.2023.105642 -
Brain Research Bulletin Nov 2023The inhibition of matrix metalloproteinases (MMPs) has shown potential in the treatment of various neurodegenerative diseases, and perioperative neurocognitive disorders...
BACKGROUND
The inhibition of matrix metalloproteinases (MMPs) has shown potential in the treatment of various neurodegenerative diseases, and perioperative neurocognitive disorders (PND) is accompanied by the increased expression of MMP-2 and MMP-9 in the hippocampus. However, the effect of inhibiting MMP-2 and MMP-9 on PND is not clear. In this study we aimed to evaluate the effects of inhibiting MMP-2 and MMP-9 on cognitive function in the aged mice after surgery, in order to find a possible target for the prevention and treatment of PND METHODS: In this study, 14-month-old C57BL/6 mice were used to establish a PND model by tibial fracture surgery and sevoflurane anesthesia. Three days later, part of the mice were subjected to cognitive assessment and the other was sacrificed for biochemical analysis. We used the Novel object recognition test and Fear conditioning test to evaluate the postoperative cognitive function of mice. The expression of mmp-2 and MMP-9 was detected by western blotting. We also examined the expression of claudin-5 and occludin using Western blotting, and the activation of microglia and astrocytes using immunofluorescence.
RESULTS
The results showed that surgery increased the expression of MMP-2 and MMP-9 in the hippocampus of mice, accompanied by cognitive impairment, decreased expression of claudin-5 and occludin, and increased activation of microglia and astrocytes. However, inhibition of MMP-2 and MMP-9 expression by SB-3CT reversed these changes.
CONCLUSIONS
Our study shows that inhibition of MMP-2 and MMP-9 alleviates anesthesia/surgery-induced cognitive decline by increasing BBB integrity and inhibiting glial cell activation.
Topics: Animals; Mice; Blood-Brain Barrier; Claudin-5; Cognitive Dysfunction; Hippocampus; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice, Inbred C57BL; Occludin
PubMed: 37939860
DOI: 10.1016/j.brainresbull.2023.110810