scholarly journals Recent insights into natural product inhibitors of matrix metalloproteinases

MedChemComm ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 2024-2037 ◽  
Author(s):  
Geetha B. Kumar ◽  
Bipin G. Nair ◽  
J. Jefferson P. Perry ◽  
David B. C. Martin
Keyword(s):  
Cardiovascular Disease ◽  
Matrix Metalloproteinases ◽  
Matrix Metalloproteinase ◽  
Natural Product ◽  
Human Health ◽  
Neurodegenerative Disorders ◽  
Biological Functions ◽  
Mmp Inhibitors ◽  
The Matrix ◽  
Health And Disease

Members of the matrix metalloproteinase (MMP) family have biological functions that are central to human health and disease, and MMP inhibitors have been investigated for the treatment of cardiovascular disease, cancer and neurodegenerative disorders.

scholarly journals Mitochondrial Iron in Human Health and Disease

2019 ◽  
Vol 81 (1) ◽  
pp. 453-482 ◽  
Author(s):  
Diane M. Ward ◽  
Suzanne M. Cloonan
Keyword(s):  
Human Health ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Biological Functions ◽  
Mitochondrial Homeostasis ◽  
Innate Immune Signaling ◽  
Mitochondrial Iron ◽  
Health And Disease

Mitochondria are an iconic distinguishing feature of eukaryotic cells. Mitochondria encompass an active organellar network that fuses, divides, and directs a myriad of vital biological functions, including energy metabolism, cell death regulation, and innate immune signaling in different tissues. Another crucial and often underappreciated function of these dynamic organelles is their central role in the metabolism of the most abundant and biologically versatile transition metals in mammalian cells, iron. In recent years, cellular and animal models of mitochondrial iron dysfunction have provided vital information in identifying new proteins that have elucidated the pathways involved in mitochondrial homeostasis and iron metabolism. Specific signatures of mitochondrial iron dysregulation that are associated with disease pathogenesis and/or progression are becoming increasingly important. Understanding the molecular mechanisms regulating mitochondrial iron pathways will help better define the role of this important metal in mitochondrial function and in human health and disease.

scholarly journals Unique structural features of the mitochondrial AAA+ protease AFG3L2 reveal the molecular basis for activity in health and disease

2019 ◽  
Author(s):  
Cristina Puchades ◽  
Bojian Ding ◽  
Albert Song ◽  
R. Luke Wiseman ◽  
Gabriel C. Lander ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Structural Data ◽  
Structural Features ◽  
Genetic Mutations ◽  
Biological Functions ◽  
Catalytic Core ◽  
Structural Framework ◽  
Health And Disease

AbstractMitochondrial AAA+ quality control proteases regulate diverse aspects of mitochondrial biology through specialized protein degradation, but the underlying molecular mechanisms that define the diverse activities of these enzymes remain poorly defined. The mitochondrial AAA+ protease AFG3L2 is of particular interest, as genetic mutations localized throughout AFG3L2 are linked to diverse neurodegenerative disorders. However, a lack of structural data has limited our understanding of how mutations impact enzymatic activity. Here, we used cryo-EM to determine a substrate-bound structure of the catalytic core of human AFG3L2. This structure identifies multiple specialized structural features within AFG3L2 that integrate with conserved structural motifs required for hand-over-hand ATP-dependent substrate translocation to engage, unfold and degrade targeted proteins. Mapping disease-relevant AFG3L2 mutations onto our structure demonstrates that many of these mutations localize to these unique structural features of AFG3L2 and distinctly influence its activity and stability. Our results provide a molecular basis for neurological phenotypes associated with different AFG3L2 mutations, and establish a structural framework to understand how different members of the AAA+ superfamily achieve specialized, diverse biological functions.

The gut microbiota at the intersection of diet and human health

Science ◽  
2018 ◽  
Vol 362 (6416) ◽  
pp. 776-780 ◽  
Author(s):  
Christopher L. Gentile ◽  
Tiffany L. Weir
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Human Physiology ◽  
Human Health ◽  
Biological Processes ◽  
Dietary Nutrients ◽  
Metabolic Conditions ◽  
Health And Disease ◽  
The Relationship

Diet affects multiple facets of human health and is inextricably linked to chronic metabolic conditions such as obesity, type 2 diabetes, and cardiovascular disease. Dietary nutrients are essential not only for human health but also for the health and survival of the trillions of microbes that reside within the human intestines. Diet is a key component of the relationship between humans and their microbial residents; gut microbes use ingested nutrients for fundamental biological processes, and the metabolic outputs of those processes may have important impacts on human physiology. Studies in humans and animal models are beginning to unravel the underpinnings of this relationship, and increasing evidence suggests that it may underlie some of the broader effects of diet on human health and disease.

scholarly journals The Pharmacological TAILS of Matrix Metalloproteinases and Their Inhibitors

2020 ◽  
Vol 14 (1) ◽  
pp. 31
Author(s):  
Nabangshu Das ◽  
Colette Benko ◽  
Sean E. Gill ◽  
Antoine Dufour
Keyword(s):  
Clinical Trials ◽  
Matrix Metalloproteinases ◽  
Conformational Changes ◽  
Active Sites ◽  
Inflammatory Diseases ◽  
Phase Iii ◽  
Biological Functions ◽  
Mmp Inhibitors ◽  
Allosteric Control ◽  
Phase Iii Clinical Trials

Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat®, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on the development of more selective inhibitors or targeting other domains than their active sites through specific small molecule inhibitors or monoclonal antibodies. Here, we present some examples that aim to better understand the mechanisms of conformational changes/allosteric control of MMPs functions. In addition to MMP inhibitors, we discuss unbiased global approaches, such as proteomics and N-terminomics, to identify new MMP substrates. We present some examples of new MMP substrates and their implications in regulating biological functions. By characterizing the roles and substrates of individual MMP, MMP inhibitors could be utilized more effectively in the optimal disease context or in diseases never tested before where MMP activity is elevated and contributing to disease progression.

scholarly journals Matrix Metalloproteinase Inhibition in a Murine Model of Cavitary Tuberculosis Paradoxically Worsens Pathology

2018 ◽  
Vol 219 (4) ◽  
pp. 633-636 ◽  
Author(s):  
Alvaro A Ordonez ◽  
Supriya Pokkali ◽  
Julian Sanchez-Bautista ◽  
Mariah H Klunk ◽  
Michael E Urbanowski ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Mycobacterium Tuberculosis ◽  
Matrix Metalloproteinases ◽  
Pulmonary Tuberculosis ◽  
Matrix Metalloproteinase ◽  
Murine Model ◽  
Potent Inhibitor ◽  
Mmp Inhibitors

Abstract Matrix metalloproteinases (MMPs) degrade extracellular matrix and are implicated in tuberculosis pathogenesis and cavitation. In particular, MMP-7 is induced by hypoxia and highly expressed around pulmonary cavities of Mycobacterium tuberculosis–infected C3HeB/FeJ mice. In this study, we evaluated whether administration of cipemastat, an orally available potent inhibitor of MMP-7, could reduce pulmonary cavitation in M. tuberculosis–infected C3HeB/FeJ mice. We demonstrate that, compared with untreated controls, cipemastat treatment paradoxically increases the frequency of cavitation (32% vs 7%; P = .029), immunopathology, and mortality. Further studies are needed to understand the role of MMP inhibitors as adjunctive treatments for pulmonary tuberculosis.

The effect of thymosin β4 on articular cartilage chondrocyte matrix metalloproteinase expression

2002 ◽  
Vol 30 (6) ◽  
pp. 879-882 ◽  
Author(s):  
E. J. Blain ◽  
D. J. Mason ◽  
V. C. Duance
Keyword(s):  
Articular Cartilage ◽  
Matrix Metalloproteinases ◽  
Matrix Metalloproteinase ◽  
Mechanical Loading ◽  
Functional Role ◽  
Fold Increase ◽  
Thymosin Β4 ◽  
Cytoskeletal Organization ◽  
Primary Chondrocytes ◽  
The Matrix

Mechanical loading is paramount in regulating both the anabolic and catabolic activities of articular cartilage chondrocytes, essential for the matrix to retain its functional integrity. We have identified thymosin β4 as a putative mechanically regulated gene that may mediate load-enhanced synthesis and activation of matrix metalloproteinases (MMPs) 2 and 9 in articular cartilage. The objective of this study was to confirm the mechanical regulation of thymosin β4 and determine its effect on cartilage chondrocyte MMP production. Thymosin β4 mRNA expression, analysed by quantitative PCR, revealed a significant 20-fold increase in cartilage loaded for 10 min which was still evident after 30 min of loading. Treatment of primary chondrocytes with 2 and 4 μg · ml-1 thymosin β4 peptide for 4 h significantly increased pro-MMP 9 expression and activation. We postulate a functional role for load-induced thymosin β4 in modulating the cytoskeletal organization of articular cartilage chondrocytes to affect MMP expression.

scholarly journals Matrix Metalloproteases as Influencers of the Cells’ Social Media

2019 ◽  
Vol 20 (16) ◽  
pp. 3847 ◽  
Author(s):  
Daniel Young ◽  
Nabangshu Das ◽  
Anthonia Anowai ◽  
Antoine Dufour
Keyword(s):  
Inflammatory Diseases ◽  
Matrix Metalloproteases ◽  
Phase Iii ◽  
Biological Functions ◽  
Mmp Inhibitors ◽  
Ecm Remodeling ◽  
Surface Receptors ◽  
Phase Iii Clinical Trials ◽  
The Matrix ◽  
The Impact

Matrix metalloproteinases (MMPs) have been studied in the context of cancer due to their ability to increase cell invasion, and were initially thought to facilitate metastasis solely through the degradation of the extracellular matrix (ECM). MMPs have also been investigated in the context of their ECM remodeling activity in several acute and chronic inflammatory diseases. However, after several MMP inhibitors failed in phase III clinical trials, a global reassessment of their biological functions was undertaken, which has revealed multiple unanticipated functions including the processing of chemokines, cytokines, and cell surface receptors. Despite what their name suggests, the matrix aspect of MMPs could contribute to a lesser part of their physiological functions in inflammatory diseases, as originally anticipated. Here, we present examples of MMP substrates implicated in cell signaling, independent of their ECM functions, and discuss the impact for the use of MMP inhibitors.

Association of matrix metalloproteinase 3 and γ-glutamyltransferase 1 gene polymorphisms with the cardio-ankle vascular index in young Russians

2016 ◽  
Vol 26 (6) ◽  
pp. 1238-1240 ◽  
Author(s):  
Alexander V. Sorokin ◽  
Kazuhiko Kotani ◽  
Olga Y. Bushueva
Keyword(s):  
Cardiovascular Disease ◽  
Arterial Stiffness ◽  
Disease Prevention ◽  
Matrix Metalloproteinase ◽  
Gene Polymorphisms ◽  
Specific Gene ◽  
Young Population ◽  
Matrix Metalloproteinase 3 ◽  
Additional Tool ◽  
The Matrix

AbstractSpecific gene polymorphisms are known to be associated with a different arterial physiology in the younger generation. The present study found that young Russians with the matrix metalloproteinase 3 6A/6A and γ-glutamyltransferase 1AA genotypes have lower levels of the cardio-ankle vascular index – a recent measure of arterial stiffness. This observation may serve as an additional tool for cardiovascular disease prevention in the young population.

Abstract 318: Matrix Metalloproteinase 12 is Causally Implicated in Cardiovascular Disease

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Ulf Hedin ◽  
Hovsep Mahdessian ◽  
Ljubica Perisic ◽  
Mariette Lengquist ◽  
Karl Gertow ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Matrix Metalloproteinase ◽  
Mononuclear Cells ◽  
Plasma Concentrations ◽  
Intima Media Thickness ◽  
Proximity Ligation Assay ◽  
Nucleotide Polymorphisms ◽  
Peripheral Blood Mononuclear ◽  
Asymptomatic Patients ◽  
The Matrix

Recent evidence suggests that single nucleotide polymorphisms (SNPs) in the matrix metalloproteinase (MMP) gene cluster located at chromosome 11q22.3 are associated with large-vessel stroke. In the present study, we evaluated and extended the reported association by examining the relationship between MMPs and vascular disease in both clinical and experimental samples. Plasma concentrations of MMP-1, MMP-3, MMP-7, MMP-10 and MMP-12 were measured in 3 394 subjects with high-risk for cardiovascular disease (CVD) using the Olink ProSeek CVD array. Plasma MMP-12 concentration showed association with incident cardiovascular events (199 events over 36 months) and intima-media thickness progression over time (p=3.6x10 -5 ). The SNP variant rs1892971 was strongly associated with plasma MMP-12 concentration (p=8x10 -29 ) and weakly with susceptibility to coronary heart disease in the CardiogramplusC4D consortium study (p=8.8x10 -5 ). The same SNP was also significantly associated with MMP-12 gene expression in peripheral blood mononuclear cells using microarrays from patients with carotid atherosclerosis (n=96; p=1.8x10 -4 ). Expression of MMP-12 was strongly increased in carotid plaques (n=127) compared with undiseased arteries (n=10; p<0.0001) and in plaques from symptomatic (n=87) compared to asymptomatic patients (n=40; p=0.03) and localised to CD68+ macrophages. Using proximity ligation assay MMP-12 and elastin was demonstrated to co-interact in plaques in situ, particularly in regions with moderate to strong MMP-12 expression. Silencing of MMP-12 using siRNA in differentiated THP-1 cells indicated that MMP-12 has a role in macrophage migration. In conclusion, our study suggests that MMP-12 is a causal factor in CVD that is highly upregulated in human atherosclerotic plaques where it interacts with elastin and appears to enhance macrophage invasion.

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