Controlling the Mechanical Myofibroblast via SRC: A Potential Drug Discovery Platform

2010 ◽  
Author(s):  
W. David Merryman ◽  
Joshua D. Hutcheson
Keyword(s):  
Smooth Muscle ◽  
Drug Discovery ◽  
Connective Tissue ◽  
Cell Membrane ◽  
Genetic Mutation ◽  
Fibroblast Cells ◽  
Potential Drug ◽  
Fibrotic Disease ◽  
Tissue Fibrosis ◽  
Myofibroblast Phenotype

Connective tissue makes up a large portion of our bodies, with collagen constituting ∼30% of the protein of connective tissue. Any tissue that undergoes fibrosis, either due to a genetic mutation or with age or use, typically falls into the ubiquitous category of ‘connective tissue fibrosis’. There are multiple potential contributors to connective tissue fibrosis; however, two dominate the literature — mechanical stress/strain and cytokines. Both stimuli lead to activation of fibroblast cells to a myofibroblast phenotype, the cellular hallmark of fibrotic disease. The myofibroblast phenotype is indicated by the expression of smooth muscle α-actin (αSMA), which associates with myosin to form actin-myosin contractile elements and generates intracellular force that is transduced to the ECM via cell membrane integrins.

scholarly journals The Fine Structure of the Epithelial Cells of the Mouse Prostate

1960 ◽  
Vol 7 (3) ◽  
pp. 511-513 ◽  
Author(s):  
David Brandes ◽  
Adolfo Portela
Keyword(s):  
Endoplasmic Reticulum ◽  
Smooth Muscle ◽  
Fine Structure ◽  
Epithelial Cells ◽  
Connective Tissue ◽  
Cell Membrane ◽  
Secretory Cells ◽  
Ventral Lobe ◽  
Cytoplasmic Matrix ◽  
Mouse Prostate

The fine structure of the epithelial cells of one component of the prostatic complex of the mouse—the ventral lobe—has been investigated by electron microscopy. This organ is composed of small tubules, lined by tall simple cuboidal epithelium, surrounded by smooth muscle and connective tissue. Electron micrographs of the epithelial cells of the ventral lobe show these to be limited by a cell membrane, which appears as a continuous dense line. The nucleus occupies the basal portion of the cell and the nuclear envelope consists of two membranes. The cytoplasmic matrix is of moderately low density. The endoplasmic reticulum consists of elongated, circular, and oval profiles representing the cavities of this system bounded by rough surfaced membranes. The Golgi apparatus appears localized in a region between the apical border and the nucleus, and is composed of the usual elements found in secretory cells (3, 9). At the base of the cells, a basement membrane is visible in close contact with the outer aspect of the cell membrane. A space of varying width, which seems to be occupied by connective tissue, separates the epithelial cells from the surrounding smooth muscle fibers and the blood vessels. Bodies with the appearance of portions of the cytoplasm, mitochondria, or profiles of the endoplasmic reticulum can be seen in the lumina of the acini and on the bases of these pictures and others of the apical region the mechanism of secretion by these cells is discussed. The fine structural organization of these cells is compared with that of another component of the mouse prostate—the coagulating gland.

Applications of Biomembranes in Drug Discovery

MRS Bulletin ◽  
2006 ◽  
Vol 31 (7) ◽  
pp. 541-545 ◽  
Author(s):  
Ye Fang ◽  
Yulong Hong ◽  
Brian Webb ◽  
Joydeep Lahiri
Keyword(s):  
Drug Discovery ◽  
Cell Membrane ◽  
Therapeutic Intervention ◽  
Parallel Analysis ◽  
Pharmaceutical Companies ◽  
Potential Drug ◽  
Drug Compounds ◽  
Membrane Bound ◽  
Pharmacologically Active

Molecules in the cell membrane are key targets for therapeutic intervention. Technologies that enable the preservation of membrane-bound targets in their biomimetic and pharmacologically active states for screening of potential drug compounds are of great interest to bio-pharmaceutical companies. This review discusses emerging biomembrane technologies with a focus on biomembrane microarrays that enable the parallel analysis of multiple membrane-bound targets.

Some Conditions Necessary for Pinocytosis

1968 ◽  
Vol 26 ◽  
pp. 142-143
Author(s):  
M. W. Brightman
Keyword(s):  
Smooth Muscle ◽  
Cell Membrane ◽  
Toxic Effects ◽  
Cytological Evidence ◽  
Cell Processes

The cytological evidence for pinocytosis is the focal infolding of the cell membrane to form surface pits that eventually pinch off and move into the cytoplasm. This activity, which can be inhibited by oxidative and glycolytic poisons, is performed only by cell processes that are at least 300A wide. However, the interpretation of such toxic effects becomes equivocal if the membrane invaginations do not normally lead to the formation of migratory vesicles, as in some endothelia and in smooth muscle. The present study is an attempt to set forth some conditions under which pinocytosis, as distinct from the mere inclusion of material in surface invaginations, can take place.

Sitagliptin: a potential drug for the treatment of SARS-CoV-2?

2020 ◽  
Author(s):  
Sanaa Bardaweel
Keyword(s):  
Clinical Trials ◽  
Drug Discovery ◽  
Antimalarial Drug ◽  
Drug Repurposing ◽  
Spike Protein ◽  
Diabetic Patients ◽  
Potential Drug ◽  
Chemokine Production ◽  
Drug Discovery And Development ◽  
Sequence Identity

Recently, an outbreak of fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. As the coronavirus pandemic rages, drug discovery and development become even more challenging. Drug repurposing of the antimalarial drug chloroquine and its hydroxylated form had demonstrated apparent effectiveness in the treatment of COVID-19 associated pneumonia in clinical trials. SARS-CoV-2 spike protein shares 31.9% sequence identity with the spike protein presents in the Middle East Respiratory Syndrome Corona Virus (MERS-CoV), which infects cells through the interaction of its spike protein with the DPP4 receptor found on macrophages. Sitagliptin, a DPP4 inhibitor, that is known for its antidiabetic, immunoregulatory, anti-inflammatory, and beneficial cardiometabolic effects has been shown to reverse macrophage responses in MERS-CoV infection and reduce CXCL10 chemokine production in AIDS patients. We suggest that Sitagliptin may be beneficial alternative for the treatment of COVID-19 disease especially in diabetic patients and patients with preexisting cardiovascular conditions who are already at higher risk of COVID-19 infection.

Biochemical Fingerprint of Greek Sideritis spp.: Implications for Potential Drug Discovery and Advanced Breeding Strategies

2019 ◽  
Vol 08 (04) ◽  
Author(s):  
Fotini Trikka ◽  
Sofia Michailidou ◽  
Antonios M. Makris ◽  
Anagnostis Argiriou
Keyword(s):  
Drug Discovery ◽  
Breeding Strategies ◽  
Potential Drug

Expression of alpha-smooth muscle actin, TGF-β1 and TGF-β type II receptor during connective tissue contraction

1997 ◽  
Vol 33 (8) ◽  
pp. 622-627 ◽  
Author(s):  
M. Reza Ghassemifar ◽  
Roy W. Tarnuzzer ◽  
Nasser Chegini ◽  
Erkki Tarpila ◽  
Gregory S. Schultz ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Connective Tissue ◽  
Smooth Muscle Actin ◽  
Type Ii ◽  
Muscle Actin ◽  
Alpha Smooth Muscle Actin ◽  
Tissue Contraction ◽  
Tgf Β1

Regulation of human lung fibroblast phenotype and function by vitronectin and vitronectin integrins

2001 ◽  
Vol 114 (19) ◽  
pp. 3507-3516 ◽  
Author(s):  
Amelia K. Scaffidi ◽  
Yuben P. Moodley ◽  
Markus Weichselbaum ◽  
Philip J. Thompson ◽  
Darryl A. Knight
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Monoclonal Antibodies ◽  
Human Lung ◽  
Stress Fibers ◽  
Collagen Gels ◽  
Human Lung Fibroblast ◽  
Myofibroblast Phenotype ◽  
And Function ◽  
Blocking Antibodies

Myofibroblasts, characterised by high expression of α-smooth muscle actin (α-SMA), are important and transient cells in normal wound healing but are found in increased number in various pathological conditions of the lung including asthma and pulmonary fibrosis. The mechanisms that regulate the myofibroblast phenotype are unknown but are likely to involve signals from the extracellular matrix transmitted via specific integrins. Vitronectin is a glycoprotein released during inflammation and has been shown to regulate the phenotype of vascular smooth muscle cells via αv and β1 integrins. In the current study we have examined whether vitronectin influences the phenotype and function of normal human lung fibroblasts (HFL-1). Incubation of HFL-1 cells with vitronectin induced a concentration-dependent reduction in α-SMA expression. By contrast, function-blocking monoclonal antibodies to the vitronectin integrins αv, β1, αvβ3 and αvβ5 induced the expression of α-SMA and its organization into stress fibers. Expression of α-SMA induced by all function-blocking monoclonal antibodies was abrogated by inhibition of protein kinase C and phosphatidylinositol-3 kinase, but the effects of inhibition of other signalling pathways was integrin dependent. Exposure to other extracellular matrix proteins such as fibronectin, collagen or their integrins did not influence expression of α-SMA. The expression and organization of α-SMA induced by exposure to function-blocking antibodies was translated into an augmented capacity of HFL-1 cells to contract fibroblast populated collagen gels. By contrast, contraction of collagen gels following incubation with vitronectin was not significantly different to control. This study has shown that vitronectin influences the phenotype and behaviour of HFL-1 cells by downregulating the expression of α-SMA and reducing their contractile ability. By contrast, occupancy of specific integrins by function-blocking antibodies upregulated the expression of α-SMA and induced the formation of functional stress fibers capable of contracting collagen gels. These results suggest that vitronectin modulates the fibroblast-myofibroblast phenotype, implying an important role in the remodelling process during lung development or response to injury.

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