Matrix metalloproteinases in aortic dissection.

Aortic dissection, characterized by a high immediate mortality, is primarily caused by excessive bleeding within the walls of the aorta or a severe tear within the intimal layer of the aorta. Inflammation, as well as oxidative stress and the degradation of extracellular matrix (ECM), are significant factors in the development and occurrence of aortic dissection. Matrix metalloproteinases (MMPs) are pivotal enzymes responsible for degrading the ECM. Inflammatory factors and oxidants can interact with MMPs, indicating the potential significance of MMPs in aortic dissection. A substantial body of evidence indicates that numerous MMPs are significantly upregulated in aortic dissection, playing a critical role in ECM degradation and the pathogenesis of aortic dissection. Furthermore, targeting these enzymes has demonstrated potential in facilitating ECM restoration and reducing the incidence of aortic dissection. This review initially provides a brief overview of MMP biology before delving into their expression patterns, regulatory mechanisms, and therapeutic applications in aortic dissection. A profound comprehension of the catabolic pathways associated with aortic dissection is imperative for the future development of potential preventive or therapeutic bio-interventions for aortic dissection.

Skin Malignant Melanoma and Matrix Metalloproteinases: Promising Links to Efficient Therapies.

Skin malignant melanoma (MM) is one of the most frequent and aggressive neoplasia worldwide. Its associated high mortality rates are mostly due to its metastases, while diagnosis and treatment of MM in its early stages is of favorable prognostic. Even skin superficial MMs at incipient local stages can already present with lymph node invasion and distant metastases. Therefore, knowledge of the controllable risk factors and pathogenic mechanisms of MM development, spreading, and metastatic pattern, as well as early diagnosis, are essential to decrease the high mortality rates associated with cutaneous malignant melanoma. Genetic factors are incriminated, although lifetime-acquired genetic mutations appear to be even more frequently involved in the development of MM. Skin melanocytes divide only twice per year and have time to accumulate genetic mutations as a consequence of environmental aggressive factors, such as UV exposure. In the search for more promising therapies, matrix metalloproteinases have become of significant interest, such as MMP-1, MMP-2, MMP-9, and MMP-13, which have been linked to more aggressive forms of cancer and earlier metastases. Therefore, the development of specific synthetic inhibitors of MMP secretion or activity could represent a more promising and effective approach to the personalized treatment of MM patients.

Breaking the Cycle: Matrix Metalloproteinase Inhibitors as an Alternative Approach in Managing Tuberculosis Pathogenesis and Progression.

Mycobacterium tuberculosis (Mtb) has long posed a significant challenge to global public health, resulting in approximately 1.6 million deaths annually. Pulmonary tuberculosis (TB) instigated by Mtb is characterized by extensive lung tissue damage, leading to lesions and dissemination within the tissue matrix. Matrix metalloproteinases (MMPs) exhibit endopeptidase activity, contributing to inflammatory tissue damage and, consequently, morbidity and mortality in TB patients. MMP activities in TB are intricately regulated by various components, including cytokines, chemokines, cell receptors, and growth factors, through intracellular signaling pathways. Primarily, Mtb-infected macrophages induce MMP expression, disrupting the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), thereby impairing extracellular matrix (ECM) deposition in the lungs. Recent research underscores the significance of immunomodulatory factors in MMP secretion and granuloma formation during Mtb pathogenesis. Several studies have investigated both the activation and inhibition of MMPs using endogenous MMP inhibitors (i.e., TIMPs) and synthetic inhibitors. However, despite their promising pharmacological potential, few MMP inhibitors have been explored for TB treatment as host-directed therapy. Scientists are exploring novel strategies to enhance TB therapeutic regimens by suppressing MMP activity to mitigate Mtb-associated matrix destruction and reduce TB induced lung inflammation. These strategies include the use of MMP inhibitor molecules alone or in combination with anti-TB drugs. Additionally, there is growing interest in developing novel formulations containing MMP inhibitors or MMP-responsive drug delivery systems to suppress MMPs and release drugs at specific target sites. This review summarizes MMPs' expression and regulation in TB, their role in immune response, and the potential of MMP inhibitors as effective therapeutic targets to alleviate TB immunopathology.

Unveiling the bidirectional role of MMP9: A key player in kidney injury.

Matrix metalloproteinases (MMPs) are a group of zinc-dependent proteolytic metalloenzymes that are involved in numerous pathological conditions, including nephropathy. MMP9, a member of the MMPs family, is categorized as a constituent of the gelatinase B subgroup, and its involvement in extracellular matrix (ECM) remodeling and renal fibrosis highlights its importance in the development and progression of renal diseases. The exact role of MMP9 in the development of kidney diseases is still controversial. This study investigated the dual role of MMP9 in kidney injury, discussing its implications in the pathogenesis of kidney diseases and investigating the design and mechanism of MMP9 inhibitors based on previous studies. This study provides an effective basis for the development of novel and selective MMP9 inhibitors for treating renal diseases.

Pharmacological Inhibition of MMP-12 Exerts Protective Effects on Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice.

Human abdominal aortic aneurysms (AAAs) are characterized by increased activity of matrix metalloproteinases (MMP), including MMP-12, alongside macrophage accumulation and elastin degradation, in conjunction with superimposed atherosclerosis. Previous genetic ablation studies have proposed contradictory roles for MMP-12 in AAA development. In this study, we aimed to elucidate if pharmacological inhibition of MMP-12 activity with a phosphinic peptide inhibitor protects from AAA formation and progression in angiotensin (Ang) II-infused Apoe-/- mice. Complimentary studies were conducted in a human ex vivo model of early aneurysm development. Administration of an MMP-12 inhibitor (RXP470.1) protected hypercholesterolemia Apoe-/- mice from Ang II-induced AAA formation and rupture-related death, associated with diminished medial thinning and elastin fragmentation alongside increased collagen deposition. Proteomic analyses confirmed a beneficial effect of MMP-12 inhibition on extracellular matrix remodeling proteins combined with inflammatory pathways. Furthermore, RXP470.1 treatment of mice with pre-existing AAAs exerted beneficial effects as observed through suppressed aortic dilation and rupture, medial thinning, and elastin destruction. Our findings indicate that pharmacological inhibition of MMP-12 activity retards AAA progression and improves survival in mice providing proof-of-concept evidence to motivate translational work for MMP-12 inhibitor therapy in humans.

MMPs as potential molecular targets in epithelial-to-mesenchymal transition driven COPD progression.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality globally and the risk of developing lung cancer is six times greater in individuals with COPD who smoke compared to those who do not smoke. Matrix metalloproteinases (MMPs) play a crucial role in the pathophysiology of respiratory diseases by promoting inflammation and tissue degradation. Furthermore, MMPs are involved in key processes like epithelial-to-mesenchymal transition (EMT), metastasis, and invasion in lung cancer. While EMT has traditionally been associated with the progression of lung cancer, recent research highlights its active involvement in individuals with COPD. Current evidence underscores its role in orchestrating airway remodeling, fostering airway fibrosis, and contributing to the potential for malignant transformation in the complex pathophysiology of COPD. The precise regulatory roles of diverse MMPs in steering EMT during COPD progression needs to be elucidated. Additionally, the less-understood aspect involves how these MMPs bi-directionally activate or regulate various EMT-associated signaling cascades during COPD progression. This review article explores recent advancements in understanding MMPs' role in EMT during COPD progression and various pharmacological approaches to target MMPs. It also delves into the limitations of current MMP inhibitors and explores novel, advanced strategies for inhibiting MMPs, potentially offering new avenues for treating respiratory diseases.

Matrix metalloproteinases targeting in prostate cancer.

Prostate cancer (PCa) is one of the most common tumors affecting men all over the world. PCa has brought a huge health burden to men around the world, especially for elderly men, but its pathogenesis is unclear. In prostate cancer, epigenetic inheritance plays an important role in the development, progression, and metastasis of the disease. An important role in cancer invasion and metastasis is played by matrix metalloproteinases (MMPs), zinc-dependent proteases that break down extracellular matrix. We review two important forms of epigenetic modification and the role of matrix metalloproteinases in tumor regulation, both of which may be of significant value as novel biomarkers for early diagnosis and prognosis monitoring. The author considers that both mechanisms have promising therapeutic applications for therapeutic agent research in prostate cancer, but that efforts should be made to mitigate or eliminate the side effects of drug therapy in order to maximize quality of life of patients. The understanding of epigenetic modification, MMPs, and their inhibitors in the functional regulation of prostate cancer is gradually advancing, it will provide a new technical means for the prevention of prostate cancer, early diagnosis, androgen-independent prostate cancer treatment, and drug research.

Matrix Metalloproteinases in Oral Cancer Pathogenesis and their Use in Therapy.

Matrix metalloproteinases (MMPs) are proteolytic enzymes that aid in extracellular matrix (ECM) remodeling. MMPs destroy the extracellular matrix, causing tumor growth and metastasis. MMPs are involved in the spread and metastasis of oral cancer. High levels of MMPs and oral squamous cell carcinoma have been linked to cancer prognosis. Modern medicine aims to prevent the illness from spreading through early intervention and examining changes in MMP genes. MMP gene polymorphism has recently been identified as one of the factors predicting susceptibility or risk in the development of oral carcinoma. This review aims to provide insight into the function of MMP subtypes involved in cancer. The genetic polymorphism in MMP genes and its predictive value in risk evaluation have been elaborated. Novel personalized therapeutic approaches for oral cancer, like the use of MMP inhibitors, nanoparticle-mediated targeting of MMP, or gene silencing by microRNA, can be designed.

Matrix Metalloproteinase-9 inhibitors as therapeutic drugs for traumatic brain injury.

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.

Structure-Based Optimization and Biological Evaluation of Potent and Selective MMP-7 Inhibitors for Kidney Fibrosis.

Matrix metalloproteinase-7 (MMP-7) has been shown to play important roles in pathophysiological processes involved in the development/progression of diseases such as cancer and fibrosis. We discovered selective MMP-7 inhibitors composed of arylsulfonamide, carboxylate, and short peptides by a molecular hybridization approach. These compounds interacted with MMP-7 via multiple hydrogen bonds in the cocrystal structures. To obtain compounds for in vivo evaluation, we attempted structural optimization, particularly targeting Tyr167 at the S3 subsite through structure-based drug design, and identified compound 15 as showing improved MMP-7 potency and MMP subtype selectivity. A novel π-π stacking interaction with Tyr167 was achieved when 4-pyridylalanine was introduced as the P3 residue. Compound 15 suppressed the progression of kidney fibrosis in a dose-dependent manner in a mouse model of unilateral ureteral obstruction. Thus, we demonstrated, for the first time, that potent and selective MMP-7 inhibitors could prevent the progression of kidney fibrosis.

Enzyme-Responsive Nanoparticles for the Targeted Delivery of an MMP Inhibitor to Acute Myocardial Infarction.

Herein, we have developed a drug-loaded matrix metalloproteinase (MMP)-responsive micellar nanoparticle (NP) intended for minimally invasive intravenous injection during the acute phase of myocardial infarction (MI) and prolonged retention in the heart for small-molecule drug delivery. Peptide-polymer amphiphiles (PPAs) bearing a small-molecule MMP inhibitor (MMPi), PD166793, were synthesized via ring-opening metathesis polymerization (ROMP) and formulated into spherical micelles by transitioning to aqueous solution. The resulting micellar NPs underwent MMP-induced aggregation, demonstrating enzyme responsiveness. Using a rat MI model, we observed that these NPs were capable of successfully extravasating into the infarcted region of the heart where they were retained due to the active, enzyme-mediated targeting, remaining detectable after 1 week post administration without increasing macrophage recruitment. Furthermore, in vitro studies show that these NPs demonstrated successful drug release following MMP treatment and maintained drug bioactivity as evidenced by comparable MMP inhibition to free MMPi. This work establishes a targeted NP platform for delivering small-molecule therapeutics to the heart after MI, opening possibilities for myocardial infarction treatment.

Novel Matrix Metalloproteinase-9 (MMP-9) Inhibitors in Cancer Treatment.

Matrix metalloproteinases (MMPs) belong to a family of zinc-dependent proteolytic metalloenzymes. MMP-9, a member of the gelatinase B family, is characterized as one of the most intricate MMPs. The crucial involvement of MMP-9 in extracellular matrix (ECM) remodeling underscores its significant correlation with each stage of cancer pathogenesis and progression. The design and synthesis of MMP-9 inhibitors is a potentially attractive research area. Unfortunately, to date, there is no effective MMP-9 inhibitor that passes the clinical trials and is approved by the FDA. This review primarily focuses on exploring the diverse strategies employed in the design and advancement of MMP-9 inhibitors, along with their anticancer effects and selectivity. To illuminate the essential structural characteristics necessary for the future design of novel MMP-9 inhibitors, the current narrative review highlights several recently discovered MMP-9 inhibitors exhibiting notable selectivity and potency.

Roles of Matrix Metalloproteinases and Their Natural Inhibitors in Metabolism: Insights into Health and Disease.

Matrix metalloproteinases (MMPs) are a family of zinc-activated peptidases that can be classified into six major classes, including gelatinases, collagenases, stromelysins, matrilysins, membrane type metalloproteinases, and other unclassified MMPs. The activity of MMPs is regulated by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). MMPs are involved in a wide range of biological processes, both in normal physiological conditions and pathological states. While some of these functions occur during development, others occur in postnatal life. Although the roles of several MMPs have been extensively studied in cancer and inflammation, their function in metabolism and metabolic diseases have only recently begun to be uncovered, particularly over the last two decades. This review aims to summarize the current knowledge regarding the metabolic roles of metalloproteinases in physiology, with a strong emphasis on adipose tissue homeostasis, and to highlight the consequences of impaired or exacerbated MMP actions in the development of metabolic disorders such as obesity, fatty liver disease, and type 2 diabetes.

Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013-2023).

Matrix metalloproteinases (MMPs) are identifiable members of proteolytic enzymes that can degrade a wide range of proteins in the extracellular matrix (ECM). MMPs can be categorized into six groups based on their substrate specificity and structural differences: collagenases, gelatinases, stromelysins, matrilysins, metalloelastase, and membrane-type MMPs. MMPs have been linked to a wide variety of biological processes, such as cell transformation and carcinogenesis. Over time, MMPs have been evaluated for their role in cancer progression, migration, and metastasis. Accordingly, various MMPs have become attractive therapeutic targets for anticancer drug development. The first generations of broad-spectrum MMP inhibitors displayed effective inhibitory activities but failed in clinical trials due to poor selectivity. Thanks to the evolution of X-ray crystallography, NMR analysis, and homology modeling studies, it has been possible to characterize the active sites of various MMPs and, consequently, to develop more selective, second-generation MMP inhibitors. In this review, we summarize the computational and synthesis approaches used in the development of MMP inhibitors and their evaluation as potential anticancer agents.

The Role of MMP-9 and MMP-9 Inhibition in Different Types of Thyroid Carcinoma.

Matrix metalloproteinase-9 (MMP-9), one of the most investigated and studied biomarkers of the MMPs family, is a zinc-dependent proteolytic metalloenzyme whose primary function is degrading the extracellular matrix (ECM). It has been proved that MMP-9 expression elevates in multiple pathological conditions, including thyroid carcinoma. MMP-9 has a detectable higher level in malignant or metastatic thyroid tumor tissues than in normal or benign tissues and acts as an additional marker to distinguish different tumor stages because of its close correlations with clinical features, such as lymph node metastasis, TNM stage, tumor size and so on. Natural and non-natural MMP-9 inhibitors suppress its expression, block the progression of diseases, and play a role in therapy consequently. MMP-9 inhibitory molecules also assist in treating thyroid tumors by suppressing the proliferation, invasion, migration, metastasis, viability, adhesion, motility, epithelial-mesenchymal transition (EMT), and other risk factors of different thyroid cancer cells. In a word, discovering and designing MMP-9 inhibitors provide great therapeutic effects and promising clinical values in various types of thyroid carcinoma.

Physiological Properties, Functions, and Trends in the Matrix Metalloproteinase Inhibitors in Inflammation-Mediated Human Diseases.

BACKGROUND: Matrix metalloproteinases (MMPs), also known as metalloproteinases, are enzymes that degrade proteins and require the presence of active metal atoms. There are more than 20 types of MMPs, and they promote cell migration through the proteolytic degradation of the extracellular basement. MMPs are upregulated in cancers and inflamed regions. MMPs have three conservation regions: pro-MMP, catalysis, and hemopexin. Through these domains, MMPs cleave matrixes and cell-cell barriers. Consequently, MMPs cleave the whole extracellular matrix (ECM). In other words, they decompose most of the components related to the ECM, in their roles as key enzymes in cellular and pathophysiological events in the body. INTRODUCTION: Zn2+-containing endo-type peptidases directly degrade and remodel the ECM region in the progression of various diseases. MMPs are frequently found in abnormal disease status of inflammatory responses, periodontal lesion, inflammatory pulmonary lesion, arteriosclerotic smooth muscles, arthritis, and tumor metastasis and invasion. They are also known to participate in aging processes-such as wrinkle formation-by destroying collagen in the dermis. In particular, the onset of diseases via the MMP-dependent inflammatory response is caused by the breakdown of proteins in the ECM and the basement membranous region, which are the supporting structures of cells. METHODS: This review describes the developments in the research examining the general and selective inhibitors for MMP associated with various human diseases over the past 20 years in terms of structure remodeling, substrate-recognizing specificities, and pharmacological applicability. RESULTS: Among two similar types of MMPs, MMP-2 is known as gelatinase-A with a 72 kDa, while MMP-9 is termed gelatinase-B with a 92 kDa. Both of these play a key role in this action. Therefore, both enzymatic expression levels coincide during the onset and progression of diseases. Endogenous tissue inhibitors of matrix metalloproteinases (TIMPs) are highly specific for each MMP inhibitor type. The intrinsic factors regulate various MMP types by inhibiting the onset of various diseases mediated by MMP-dependent or independent inflammatory responses. The MMP- 9 and MMP-2 enzyme activity related to the prognosis of diseases associated with the inflammatory response are selectively inhibited by TIMP1 and TIMP2, respectively. The major pathogenesis of MMP-mediated diseases is related to the proliferation of inflammatory cells in various human tissues, which indicates their potential to diagnose or treat these diseases. The discovery of a substance that inhibits MMPs would be very important for preventing and treating various MMP-dependent diseases. CONCLUSION: Considerable research has examined MMP inhibitors, but most of these have been synthetic compounds. Research using natural products as MMP inhibitors has only recently become a subject of interest. This review intends to discuss recent research trends regarding the physiological properties, functions, and therapeutic agents related to MMPs.

Bioactives from Marine Organisms and their Potential Role as Matrix Metalloproteinase Inhibitors.

Recent research has revealed the role of metalloproteinases in a number of severe pathological illnesses, including cardiac, cartilage, neurological, and cancer-related diseases that are fatal to humans. Metalloproteinases are a subclass of endopeptidases that comprise structurally identical enzymes known as Matrix Metalloproteinases (MMPs) that are solely involved in extracellular matrix degradation and play a significant regulatory function in tissue remodeling. Improper regulation and expression of MMPs have been linked to several life-threatening pathological conditions in humans. Hence there is an ever-growing interest in various research communities to identify and report the Matrix Metalloproteinase Inhibitors (MMPIs). In spite of several chemically synthesized MMPIs being available currently, several unpleasant side effects, un-successful clinical trials have made use of synthetic MMPIs as a risky strategy. Several natural product researchers have strongly recommended and reported many natural resources like plants, microorganisms, and animals as greater resources to screen for bioactives that can function as potential natural MMPIs. Marine environment is one of the vast and promising resources that harbor diverse forms of life known to synthesize biologically active compounds. These bioactive compounds from marine organisms have been reported for their unparalleled biological effects and have profound applications in cosmeceutical, nutraceutical, and pharmaceutical research. Several research groups have reported an umpteen number of medicinally unmatched compounds from marine flora and fauna, thus driving researchers to screen marine organisms for natural MMPIs. In this review, our group has reported the potential MMPIs from marine organisms.

Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology.

The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.

Discovery of Aryloxyphenyl-Heptapeptide Hybrids as Potent and Selective Matrix Metalloproteinase-2 Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis.

Matrix metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase that plays important roles in the degradation of extracellular matrix proteins. MMP2 is considered to be an attractive target for the treatment of various diseases such as cancer, arthritis, and fibrosis. In this study, we have developed a novel class of MMP2-selective inhibitors by hybridizing the peptide that binds to a zinc ion and S2-S5 pockets with small molecules that bind to the S1' pocket. Structural modifications based on X-ray crystallography revealed that the introduction of 2,4-diaminobutanoic acid (Dab) at position 4 dramatically enhanced MMP2 selectivity by forming an electrostatic interaction with Glu130. After improving the metabolic and chemical stability, TP0556351 (9) was identified. It exhibited potent MMP2 inhibitory activity (IC50 = 0.20 nM) and extremely high selectivity. It suppressed the accumulation of collagen in a bleomycin-induced idiopathic pulmonary fibrosis model in mice, demonstrating the efficacy of MMP2-selective inhibitors for fibrosis.