The Emerging Role of Epigenetic Mechanisms in the Causation of Aberrant MMP Activity during Human Pathologies and the Use of Medicinal Drugs

Matrix metalloproteinases (MMPs) cleave extracellular matrix proteins, growth factors, cytokines, and receptors to influence organ development, architecture, function, and the systemic and cell-specific responses to diseases and pharmacological drugs. Conversely, many diseases (such as atherosclerosis, arthritis, bacterial infections (tuberculosis), viral infections (COVID-19), and cancer), cholesterol-lowering drugs (such as statins), and tetracycline-class antibiotics (such as doxycycline) alter MMP activity through transcriptional, translational, and post-translational mechanisms. In this review, we summarize evidence that the aforementioned diseases and drugs exert significant epigenetic pressure on genes encoding MMPs, tissue inhibitors of MMPs, and factors that transcriptionally regulate the expression of MMPs. Our understanding of human pathologies associated with alterations in the proteolytic activity of MMPs must consider that these pathologies and their medicinal treatments may impose epigenetic pressure on the expression of MMP genes. Whether the epigenetic mechanisms affecting the activity of MMPs can be therapeutically targeted warrants further research.

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The role of PCSK9 in infectious diseases.

Current Medicinal Chemistry ◽

10.2174/0929867328666210714160343 ◽

2021 ◽

Vol 28 ◽

Author(s):

Laura Magnasco ◽

Chiara Sepulcri ◽

Roberta Maria Antonello ◽

Stefano Di Bella ◽

Laura Labate ◽

...

Keyword(s):

Infectious Diseases ◽

Malaria Infection ◽

Bacterial Infections ◽

Viral Infections ◽

Physiological Role ◽

Protective Role ◽

Loss Of Function ◽

Pcsk9 Inhibition ◽

Sepsis And Septic Shock

Background: In recent years, many aspects of the physiological role of PCSK9 have been elucidated, particularly regarding its role in lipid metabolism, cardiovascular risk, and its role in innate immunity. Increasing evidence is available about the involvement of PCSK9 in the pathogenesis of viral infections, mainly HCV, and the regulation of host response to bacterial infections, primarily sepsis and septic shock. Moreover, the action of PCSK9 has been investigated as a crucial step in the pathogenesis of malaria infection and disease severity. Objective: This paper aims to review the available published literature on the role of PCSK9 in a wide array of infectious diseases. Conclusion: Besides the ongoing investigation on PCSK9 inhibition among HIV-infected patients to treat HIV- and ART-related hyperlipidemia, preclinical studies indicate how PCSK9 is involved in reducing the replication of HCV. Interestingly, high plasmatic PCSK9 levels have been described in patients with sepsis. Moreover, a protective role of PCSK9 inhibition has also been proposed against dengue and SARS-CoV-2 viral infections. Finally, a loss of function in the PCSK9-encoding gene has been reported to reduce malaria infection mortality.

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An analysis of culmination in Dictyostelium using prestalk and stalk-specific cell autonomous markers

Development ◽

10.1242/dev.111.3.779 ◽

1991 ◽

Vol 111 (3) ◽

pp. 779-787 ◽

Cited By ~ 19

Author(s):

K.A. Jermyn ◽

J.G. Williams

Keyword(s):

Gene Expression ◽

Extracellular Matrix ◽

Dictyostelium Discoideum ◽

Tube Formation ◽

Matrix Proteins ◽

Specific Cell ◽

Primary Role ◽

Fusion Genes ◽

Spore Mass

The ecmA (pDd63) and ecmB (pDd56) genes encode extracellular matrix proteins of the slime sheath and stalk tube of Dictyostelium discoideum. Using fusion genes containing the promoter of one or other gene coupled to an immunologically detectable reporter, we previously identified two classes of prestalk cells in the tip of the migrating slug; a central core of pstB cells, which express the ecmB gene, surrounded by pstA cells, which express the ecmA gene. PstB cells lie at the position where stalk tube formation is initiated at culmination and we show that they act as its founders. As culmination proceeds, pstA cells transform into pstB cells by activating the ecmB gene as they enter the stalk tube. The prespore region of the slug contains a population of cells, termed anterior-like cells (ALC), which have the characteristics of prestalk cells. We show that the ecmA and ecmB genes are expressed at a low level in ALC during slug migration and that their expression in these cells is greatly elevated during culmination. Previous observations have shown that ALC sort to surround the prespore cells during culmination (Sternfeld and David, 1982 Devl Biol. 93, 111–118) and we find just such a distribution for pstB cells. We believe that the ecmB protein plays a structural role in the stalk tube and its presence, as a cradle around the spore head, suggests that it may play a further function, perhaps in ensuring integrity of the spore mass during elevation. If this interpretation is correct, then a primary role of anterior-like cells may be to form these structures at culmination. We previously identified a third class of prestalk cells, pstO cells, which lie behind pstA cells in the slug anterior and which appeared to express neither the ecmA nor the ecmB gene. Using B-galactosidase fusion constructs, which give more sensitive detection of gene expression, we now find that these cells express the ecmA gene but at a much lower level than pstA cells. We also show that expression of the ecmA gene becomes uniformly high throughout the prestalk zone when slugs are allowed to migrate in the light. Overhead light favours culmination and it may be that increased expression of the ecmA gene in the pst ‘O’ region is a preparatory step in the process.

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Exploring the role of extracellular matrix proteins to develop biomarkers of plaque vulnerability and outcome

Journal of Internal Medicine ◽

10.1111/joim.13034 ◽

2020 ◽

Vol 287 (5) ◽

pp. 493-513 ◽

Cited By ~ 4

Author(s):

S. Holm Nielsen ◽

L. Jonasson ◽

K. Kalogeropoulos ◽

M. A. Karsdal ◽

A. L. Reese‐Petersen ◽

...

Keyword(s):

Extracellular Matrix ◽

Extracellular Matrix Proteins ◽

Matrix Proteins ◽

Plaque Vulnerability

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The Role of Structural Extracellular Matrix Proteins in Urothelial Bladder Cancer (Review)

Biomarker Insights ◽

10.4137/bmi.s294 ◽

2007 ◽

Vol 2 ◽

pp. BMI.S294 ◽

Cited By ~ 14

Author(s):

Andrea Brunner ◽

Alexandar Tzankov

Keyword(s):

Extracellular Matrix ◽

Cancer Cells ◽

Cell Invasion ◽

Matrix Proteins ◽

Urothelial Bladder Cancer ◽

Ecm Proteins ◽

Cancer Review ◽

Urothelial Bladder ◽

Carcinoma Of The Bladder

The extracellular matrix (ECM) plays a key role in the modulation of cancer cell invasion. In urothelial carcinoma of the bladder (UC) the role of ECM proteins has been widely studied. The mechanisms, which are involved in the development of invasion, progression and generalization, are complex, depending on the interaction of ECM proteins with each other as well as with cancer cells. The following review will focus on the pathogenetic role and prognostic value of structural proteins, such as laminins, collagens, fibronectin (FN), tenascin (Tn-C) and thrombospondin 1 (TSP1) in UC. In addition the role of integrins mediating the interaction of ECM molecules and cancer cells will be addressed, since integrin-mediated FN, Tn-C and TSP1 interactions seem to play an important role during tumor cell invasion and angiogenesis.

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