Data
Lezione/(Seminario/
Esercitazione)
Presentazione del Corso
Importanza dei legami non-covalenti in Biologia
Importanza del gruppo laterale degli aminoacido e degli atomi coinvolti nel legame peptidico nella struttura tridimensionale delle proteine.
Diapositive legami non-covalenti e struttura proteine
Diapositive legami non-covalenti e struttura proteine 2d/pagina
Non covalent
bonds
The Chemical Components
of a Cell
Hydrogen bonds
Van der Waals
bond
Hydrophobic
effect
Surface tension
The
Chemistry of Water
Structure of protein (database Japan)
Lipidi nelle membrane: Lipidi saturi e insaturi. Glicerofosfolipidi: tipi di code e di testa. Colesterolo: proprietà strutturale e interazione con altri lipidi e proteine. Sfingolipidi: sfingosina, ceramidi con acidi grassi idrossilati e non-idrossilati; sfingomielina; glicolipidi: introduzione.
Lipids (altro sito)
Cell membranes (sito didattico di Nature) [DA ENTRARE CON CREDENZIALI DI ATENEO]
Biological Membranes and the Cell Surface
Structure of the plasma membrane
Sfingolipidi, cont.: classi, ruolo, patologie associate alla deficitaria degradazione nei lisosmi.
Membrana plasmatica: importanza dell'asimmetria dei lipidi nei due foglietti; influenza della forma molecolare dei lipidi sullo spessore e curvatura delle membrane. Introduzione alla versione attualizzata del modello del mosaico fluido: tipi di proteine associate alle membrane. Proteine integrali: importanza della alfa-elica e beta-foglietto per l'attraversamento della membrana. Aminoacidi dell'interfaccia lipide-ambite acquoso: "effeto "snorkeling". Proteine periferiche di membrane: introduzione.
Membrana plasmatica, segue. Proteine periferiche. Ancore lipidiche per ancoraggio di proteine al foglietto citosolico (palmitoilazione, meristilazione, prenilazione) e per l'ancoraggio al foglietto esterno (glicosilfosfatidilinositolo, GPI). Associazione di proteine periferiche alla membrana mediata da domini di riconoscimento di lipidi o lipidi fosforilati, oppure mediate da ioni Calcio. Accenno alle proteine "scaffold".
Diapositive su proteine periferiche e proteine scaffold.
Diapositive membrana, 3a parte (2D/p)
Glicocalice: Introduzione: Glicoproteine N-linked e O-linked. Mucine. (Seminario: Regioni "Variable number of tandem repeat, VNTR" ricche di residui glicosilati nelle mucine; Alterazione delle mucine nei tumori.
Glycosylation Changes in Cancer
Glicocalice, segue: Glicosamino glicani e proteoglicani. Proteoglicani della membrana plasmatica.
Diapositive sulla 2a parte del glicocalice
Diapositive glicvocalice, 2a parte (2D/p)
Introduzione ai rafts lipidici: L'evoluzione del modello del mosaico fluido negli ultimi 40 anni. Organizzazione e stabilizzazione dei componenti dei rafts.
Proteoglycans and Sulfated Glycosaminoglycans
Sito con informazioni e immagini interessanti sui Proteoglicani in particolare quelli di di membrana [SERVIRA' ANCHE PER LE LEZIONI SULLA MATRICE EXTRACELLULARE].
Simons K, Sampaio JL. Membrane organization and lipid rafts. Cold Spring Harb Perspect Biol. 2011
Cartoon, tratto dal filmato "The inner life of a cell", Harvard, che illustra dei rafts lipidici.
Rafts lipidici, cont.:Tipi di rafts, Caveolae. Ruolo degli sfingolipidi nell modellamento della forma di alcune proteine (Rafts come chaperonine). Caratteristiche dei domini tipo V3 che legano gli sfingolipidi presenti in proteine molto diversificate.Importanza dell'idrossilazione dell'acido grasso che lega la sfingosina e dell'isomero beta-galattosio per il legame specifico proteina-sfingolipide. Ruolo dei rafts nella trasduzione dei segnali.
Seminario: Proteine Src. Proteine scaffold
Diapositive 2a parte rafts e Seminari.
Diapositive 2a parte rafts e Seminari (2D/foglio)
Pagina del gruppo di Jacques Fantini dedicata al GalCer
Simons K, Toomre
D. Lipid rafts and signal transduction. Nat Rev Mol Cell
Biol. 2000 Oct;1(1):31-9.
Kai Simons (MPI) Part 1: The role of lipids in organizing the cellular traffic.
Kai Simons (MPI) Part 2: Lipid rafts as a membrane organizing principle
Seminario: RUOLO DEI RAFTS NELL’INFEZIONE PROVOCATA DA TOSSINE, VIRUS, AMILOIDE, E PRIONI
Diapositive del Seminario Rafts & infezione
Modulation of proteolytic processing of amyloid precursor protein (APP) by lipids.
Dolganiuc
A. Alcohol and Viral Hepatitis: Role of Lipid Rafts.
Alcohol Res. 2015;37(2):299-309.
Both alcohol abuse and infection with hepatitis viruses can lead to liver
disease, including chronic hepatitis. Alcohol and hepatitis viruses have
synergistic effects in the development of liver disease. Some of these
involve the cellular membranes and particularly their functionally active
domains, termed lipid rafts, which contain many proteins with essential
roles in signaling and other processes. These lipid rafts play a central
role in the lifecycles of hepatitis viruses. Alcohol's actions at the
lipid rafts may contribute to the synergistic harmful effects of alcohol
and hepatitis viruses on the liver and the pathogenesis of liver disease.
Seminario: RUOLO DEI RAFTS NELL'ATTIVAZIONE DI LINFOCITI E B E DI MAST CELLS.
Diapositive Seminario Rafts & attivazione di linfociti e mast cells
Diapositive Rafts & attivazione linfociti e mast cells (2D/foglio)
Lezione: Vescicole extracellulari: Introduzione: tipi di microvescicole: ectosomi, exosomi, corpi apoptotici.
1a parte microsvescicole (2D/foglio) CORRETTA
Adaptive Immunity: Specific Defenses of the Host
Libro "Immunobiology: The Immune System in Health and Disease" 5th edition.
Janeway CA Jr, Travers P, Walport M, et al., New York: Garland Science; 2001.
http://www.ncbi.nlm.nih.gov/books/NBK10757/?term=ImmunobiologyModel of the role for lipid rafts in B-cell activation. (da: Pierce SK. Lipid rafts and B-cell activation. Nat Rev Immunol. 2002 Feb;2(2):96-105).
Ectosomes (Cocucci, Meldolesi, 2011)
ESERCITAZIONI AL CONFOCALE (FACOLTATIVE) (dott.ssa Patrizia Vaghi)
CENTRO DI SERVIZI INTERDIPARTIMENTALE
'CENTRO GRANDI STRUMENTI'
Cascina Cravino - via Bassi, 21 - 27100 Pavia - Italia
Vescicole extracellulari, cont. Ectosomi: Biogenesi e secrezione. Stimoli per la secrezione (aumento concentrazione intracellulare di Ca). Ruolo pro-coagulante dell'esposizione di "Tissue Factor" (Fattore III della coagulazione) nelle particelle derivate da piastrine o cellule endoteliali attivate.
Exosomi, introduzione: Biogenesi. Via endocitaria, corpi multivescicolari
Diapositive: Microvescicole 2a parte (2D/foglio). CORRETTA [INCLUDE NUOVE DIAPOSITIVE SU FLIPPASI, FLOPPASI E SCRAMBLASI]
Exosomes.gene-quantification.info
(Exosomes and Microvesicles (MV)
... the content and their physiological function)
Exosomi, cont: ruolo di proteine ESCRT e tetraspanine nella formazione dei corpi multivescicolari e nella selezione dei contenuti. Contenuto differenziale di ectosomi ed exosomi. RNA nelle microvescicole.
Diapositive Microvescicole, 3a parte (2d/foglio)
L'interazione delle microvescicole con cellule bersaglio e conseguenze verranno approfondite nella prossima lezione
Buona Pasqua a tutti voi e alle vostre famiglie
Microvescicole, segue: Molecole coinvolte nel riconoscimento, destino nelle cellule ricevitrici.
Diapositive : Microvescicole, 4a parte
Seminari: Ruolo delle microvescicole nel microambiente tumorale, sistema immunitario, fegato, intestino, sistema nervoso.
Biomarkers insights. Exosomes & Microvesicles: http://biomarkerinsights.qiagen.com/category/liquid-biopsy/exosomes-microvesicles/
The science of circulating microvesicles
Lavori che si possono scaricare dalla rete:
1. Zhang
X, Yuan X, Shi H, Wu L, Qian H, Xu W. Exosomes in cancer: small
particle, big player. J Hematol Oncol. 2015 Jul 10;8:83.
Exosomes have emerged as a novel mode of intercellular communication.
Exosomes can shuttle bioactive molecules including proteins, DNA, mRNA,
as well as non-coding RNAs from one cell to another, leading to the exchange
of genetic information and reprogramming of the recipient cells. Increasing
evidence suggests that tumor cells release excessive amount of exosomes,
which may influence tumor initiation, growth, progression, metastasis,
and drug resistance. In addition, exosomes transfer message from tumor
cells to immune cells and stromal cells, contributing to the escape from
immune surveillance and the formation of tumor niche. In this review,
we highlight the recent advances in the biology of exosomes as cancer
communicasomes. We review the multifaceted roles of exosomes, the small
secreted particles, in communicating with other cells within tumor microenvironment.
Given that exosomes are cell type specific, stable, and accessible from
body fluids, exosomes may provide promising biomarkers for cancer diagnosis
and represent new targets for cancer therapy.
2. Basso M, Bonetto V: Extracellular Vesicles and a Novel Form of Communication in the Brain. Front Neurosci. 2016 Mar 31;10:127. doi: 10.3389/fnins.2016.00127. eCollection 2016. In numerous neurodegenerative diseases, the interplay between neurons and glia modulates the outcome and progression of pathology. One particularly intriguing mode of interaction between neurons, astrocytes, microglia, and oligodendrocytes is characterized by the release of extracellular vesicles that transport proteins, lipids, and nucleotides from one cell to another. Notably, several proteins that cause disease, including the prion protein and mutant SOD1, have been detected in glia-derived extracellular vesicles and observed to fuse with neurons and trigger pathology in vitro. Here we review the structural and functional characterization of such extracellular vesicles in neuron-glia interactions. Furthermore, we discuss possible mechanisms of extracellular vesicle biogenesis and release from activated glia and microglia, and their effects on neurons. Given that exosomes, the smallest type of extracellular vesicles, have been reported to recognize specific cellular populations and act as carriers of very specialized cargo, a thorough analysis of these vesicles may aid in their engineering in vitro and targeted delivery in vivo, opening opportunities for therapeutics.
Disponibile in pdf:
Abels ER, Breakefield XO. Introduction to Extracellular Vesicles:
Biogenesis, RNA Cargo Selection, Content, Release, and Uptake.
Cell Mol Neurobiol. 2016 Apr 6. [Epub ahead of print]
Extracellular vesicles are a heterogeneous group of membrane-limited vesicles
loaded with various proteins, lipids, and nucleic acids. Release of extracellular
vesicles from its cell of origin occurs either through the outward budding
of the plasma membrane or through the inward budding of the endosomal
membrane, resulting in the formation of multivesicular bodies, which release
vesicles upon fusion with the plasma membrane. The release of vesicles
can facilitate intercellular communication by contact with or by internalization
of contents, either by fusion with the plasma membrane or by endocytosis
into "recipient" cells. Although the interest in extracellular
vesicle research is increasing, there are still no real standards in place
to separate or classify the different types of vesicles. This review provides
an introduction into this expanding and complex field of research focusing
on the biogenesis, nucleic acid cargo loading, content, release, and uptake
of extracellular vesicles.
Molecole di adesione: Introduzione: Adesione omofilica e eterofilica. Principali famiglie: caderine, selettine, superfamiglia delle immunoglobuline e integrine. Giunzioni di membrana e molecole di adesione coinvolte nei desmosomi a cintura, desmosomi a borchia,
Diapositive introduzione adesione:
Caderine: moduli extracellulari e intracellulari; caderine classiche e non-classiche. Importanza delle proteine citoplasmatiche nel colelgamento al citoscheletro di actina o dei filamenti intermedi. Modulazione dell'adesione e trasduzione del segnale associata alle caderine. Meccanotrasduzione associata alle caderine.
Cadherins
(un altro sito)
Cadherin
superfamily
Potential signalling pathways affected by loss of E-cadherin function.
ATTENZIONE: La "Conversione Epitelio-Mesenchimale" verrà trattato già nella prossima lezione (Martedì 5 Aprile) e non dopo le lezioni sulle molecole di adesione. Sarà seguito da un Seminario su "Struttura dei capillari sanguigni normali e tumorali. Approfondimento del ruolo della VE-caderina". Questi argomenti sono di grande importanza in Patologia e Biologia dello Sviluppo.
Esercitazioni al microscopio confocale (1° e 2° turni) - Centro Grandi Strumenti - Dott.ssa Patrizia Vaghi
Conversione Epitelio-Mesenchima e Mesenchima-Epitelio in situazioni normali e patologiche : tipi e marcatori
Seminario: Struttura dei capillari sanguigni normali e tumorali. Ruolo della VE-caderina.
Epithelial-mesenchymal transition
Epithelial-Mesenchymal Transitions in Human Cancer
Molecular organization of endothelial AJs.
The role of adherens junctions and VE-cadherin in the control of vascular permeability
Adhesion in the stem cell niche: biological roles and regulation
Molecole di adesione, segue: Selectine: Lectine [seminario], selectine (lectine di tipo C) E-, L- e P-, tipi di ligandi. Importanza dell'adesione transiente.
Glycoforum
Lectins
Selectins
C-type lectins
Superfamiglia delle immunoglobuline: domini tipo immunoglobulinico (Ig-like) e domini di tipo III della fibronectina; interazioni omofiliche ed eterofiliche; ICAMs, N-CAMs, V-CAM, PECAM. Importanza dell'acido polisialico delle N-CAM durante lo sviluppo embrionale.
Diapositive sulle molecole di adesione della superfamiglia delle immunoglobuline
The Immunoglobulin Gene Superfamily
N-CAMs Mediate Ca2+-Independent Homophilic Cell-Cell Adhesion.
Neuronal cell adhesion molecules of the immunoglobulin superfamily.
I-type lectins: I-type lectins are glycan-binding proteins that belong to the immunoglobulin superfamily (IgSF), excluding antibodies and T-cell receptors.... the Siglec family of sialic acid-binding lectins is the only well-characterized group of I-type lectins, both structurally and functionally.
Disponibile in .pdf:
- Chistiakov DA, Orekhov AN, Bobryshev YV. Endothelial PECAM-1
and its function in vascular physiology and atherogenic pathology.
Exp Mol Pathol. 2016 Apr 11;100(3):409-415. doi: 10.1016/j.yexmp.2016.03.012.
[Epub ahead of print]
Platelet endothelial cell adhesion molecule (PECAM-1) is highly expressed in vascular cells such as endothelial cells (ECs) and blood-borne cells like platelets and leukocytes. In ECs, this molecule controls junctional and adhesive properties. In physiological conditions, PECAM-1 supports the endothelial barrier function. In inflammation that is observed in vessels affected by atherosclerosis, the function of PECAM-1 is impaired, an event that leads to increased adhesion of neutrophils and other leukocytes to ECs, decreased vascular integrity, and higher leukocyte transmigration to the intima media. PECAM-1 has six extracellular immunoglobulin (Ig)-like domains that support attraction and adhesion of leukocytes to ECs. The cytoplasmic tail of PECAM-1 contains two tyrosine residues (Tyr-663 and Tyr-686) that could be phosphorylated by Src family protein kinases is involved in the intracellular signaling. Actually, those tyrosines are the part of the immunoreceptor tyrosine-based inhibition motifs (ITIMs) that inhibit inflammation. However, in atherosclerosis, the PECAM-1-dependent immune suppression is disturbed. This in turn facilitates recruitment of leukocytes and supports proatherogenic inflammation. - Shimizu T, Kurozumi K, Ishida J, Ichikawa T., Date I. Adhesion
molecules and the extracellular matrix as drug targets for glioma.
Brain Tumor Pathol. 2016 Apr;33(2):97-106. doi: 10.1007/s10014-016-0261-9.
Epub 2016 Mar 18.
The formation of tumor vasculature and cell invasion along white matter tracts have pivotal roles in the development and progression of glioma. A better understanding of the mechanisms of angiogenesis and invasion in glioma will aid the development of novel therapeutic strategies. The processes of angiogenesis and invasion cause the production of an array of adhesion molecules and extracellular matrix (ECM) components. This review focuses on the role of adhesion molecules and the ECM in malignant glioma. The results of clinical trials using drugs targeted against adhesion molecules and the ECM for glioma are also discussed.
LAVORO DISCUSSO DA EDOARDO
ERRICCHIELLO: “Extracellular Vesicles from Trypanosoma
brucei Mediate Virulence Factor Transfer and Cause Host Anemia”
Cell. 2016 Jan 14;164(1-2):246-57. doi: 10.1016/j.cell.2015.11.051.
Szempruch AJ, Sykes SE, Kieft R, Dennison L, Becker AC, Gartrell A,
Martin WJ, Nakayasu ES, Almeida IC, Hajduk SL, Harrington JM.
Intercellular communication between parasites and with host cells provides
mechanisms for parasite development, immune evasion, and disease pathology.
Bloodstream African trypanosomes produce membranous nanotubes that originate
from the flagellar membrane and disassociate into free extracellular
vesicles (EVs). Trypanosome EVs contain several flagellar proteins that
contribute to virulence, and Trypanosoma brucei rhodesiense EVs contain
the serum resistance-associated protein (SRA) necessary for human infectivity.
T. b. rhodesiense EVs transfer SRA to non-human infectious trypanosomes,
allowing evasion of human innate immunity. Trypanosome EVs can also
fuse with mammalian erythrocytes, resulting in rapid erythrocyte clearance
and anemia. These data indicate that trypanosome EVs are organelles
mediating non-hereditary virulence factor transfer and causing host
erythrocyte remodeling, inducing anemia.
Diapositive comunicazione Erricchiello
LAVORO DISCUSSO DA ALICE
SANTONASTASO: "In
Vivo imaging reveals extracellular vesicle-mediated phenocopying of
metastatic behavior.” Cell. 2015 May 21;161(5):1046-57. doi:
10.1016/j.cell.2015.04.042. Zomer A, Maynard C, Verweij FJ, Kamermans
A, Schäfer R, Beerling E, Schiffelers RM, de Wit E, Berenguer J,
Ellenbroek SI, Wurdinger T, Pegtel DM, van Rheenen J.
Most cancer cells release heterogeneous populations of extracellular
vesicles (EVs) containing proteins, lipids, and nucleic acids. In vitro
experiments showed that EV uptake can lead to transfer of functional
mRNA and altered cellular behavior. However, similar in vivo experiments
remain challenging because cells that take up EVs cannot be discriminated
from non-EV-receiving cells. Here, we used the Cre-LoxP system to directly
identify tumor cells that take up EVs in vivo. We show that EVs released
by malignant tumor cells are taken up by less malignant tumor cells
located within the same and within distant tumors and that these EVs
carry mRNAs involved in migration and metastasis. By intravital imaging,
we show that the less malignant tumor cells that take up EVs display
enhanced migratory behavior and metastatic capacity. We postulate that
tumor cells locally and systemically share molecules carried by EVs
in vivo and that this affects cellular behavior.
Molecole di adesion: Integrine: Introduzione: struttura eterodimerica, importanza dei domini extra- e intracellulari, funzioni, suddivisione in famiglie; in particolare in base alle subunità beta; legame con il citoscheletro di actina; attivazione.
Integrins
Beta-2 integrins
(Univ of Virginia)
Molecole di adesione: Integrine, continuazione. Ruolo delle integrine nella trasduzione dei segnali. meccanotrasduzione nelle adesioni focali, Legame con il citoscheletro dei filamenti intermedi negli emi-desmosomi.
Integrins and Signal Transduction
Disponibile in .pdf:
- Mui KL, Chen CS, Assoian RK. The mechanical regulation of
integrin-cadherin crosstalk organizes cells, signaling and forces.
J Cell Sci. 2016 Feb 26. pii: jcs.183699. [Epub ahead of print]
Cadherins and integrins are intrinsically linked through the actin cytoskeleton and share common signaling molecules. Although mechanosensing by the integrin-actin axis has long been appreciated, a growing body of literature now demonstrates that cadherins also transduce and respond to mechanical forces. Mounting evidence shows that mechanically driven crosstalk between integrins and cadherins regulates the spatial distribution of these receptors, their signaling intermediates, the actin cytoskeleton and intracellular forces. This interplay between integrins and cadherins can control fibronectin matrix assembly and signaling, and a fine balance between traction forces at focal adhesions and intercellular tension at adherens junctions is crucial for directional collective cell migration. In this Commentary, we discuss two central ideas: (1) how the dynamic interplay between integrins and cadherins regulates the spatial organization of intracellular signals and the extracellular matrix, and (2) the emerging consensus that intracellular force is a central mechanism that dictates cell behavior, guides tissue development and ultimately drives physiology. - Zeltz C, Gullberg D. The integrin-collagen connection - a
glue for tissue repair? J Cell Sci. 2016 Feb 15;129(4):653-64.
The a1ß1, a2ß1, a10ß1 and a11ß1 integrins constitute a subset of the integrin family with affinity for GFOGER-like sequences in collagens. Integrins a1ß1 and a2ß1 were originally identified on a subset of activated T-cells, and have since been found to be expressed on a number of cell types including platelets (a2ß1), vascular cells (a1ß1, a2ß1), epithelial cells (a1ß1, a2ß1) and fibroblasts (a1ß1, a2ß1). Integrin a10ß1 shows a distribution that is restricted to mesenchymal stem cells and chondrocytes, whereas integrin a11ß1 appears restricted to mesenchymal stem cells and subsets of fibroblasts. The bulk of the current literature suggests that collagen-binding integrins only have a limited role in adult connective tissue homeostasis, partly due to a limited availability of cell-binding sites in the mature fibrillar collagen matrices. However, some recent data suggest that, instead, they are more crucial for dynamic connective tissue remodeling events - such as wound healing - where they might act specifically to remodel and restore the tissue architecture. This Commentary discusses the recent development in the field of collagen-binding integrins, their roles in physiological and pathological settings with special emphasis on wound healing, fibrosis and tumor-stroma interactions, and include a discussion of the most recently identified newcomers to this subfamily - integrins a10ß1 and a11ß1.
Ingber, Donald A: https://tensegrity.wikispaces.com/Ingber,+Donald+A
The Architecture
of Life (D. Ingber): A universal set of building rules seems to guide
the design of organic structures—from simple
carbon compounds to complex cells and tissues
Tensegrity I. Cell structure and hierarchical systems biology (D. Ingber)
Tensegrity II. How structural networks influence cellular information processing networks
Tensegrity-Based Mechanosensing from Macro to Micro (D. Ingber)
Cascata di adesione dei leucociti: Ruolo delle integrine nell'estravasione dei leucociti dai vasi sanguigni verso i tessuti infiammati.
Diapositive estravasione dei leucociti
Introduzione alla matrice extracellulare: composizione e ruolo
Diapositive Introduzione alla matrice (solo aspetti generali)
Diapositive introduzione ai collageni
Diapositive introduzione ai proeoglicani della matrice
Leukocyte Extravasation with explanation
Disponibile in .pdf:
Vestweber D. How leukocytes cross the vascular endothelium. Nat Rev Immunol. 2015 Nov;15(11):692-704. Immune responses depend on the ability of leukocytes to move from the circulation into tissue. This is enabled by mechanisms that guide leukocytes to the right exit sites and allow them to cross the barrier of the blood vessel wall. This process is regulated by a concerted action between endothelial cells and leukocytes, whereby endothelial cells activate leukocytes and direct them to extravasation sites, and leukocytes in turn instruct endothelial cells to open a path for transmigration. This Review focuses on recently described mechanisms that control and open exit routes for leukocytes through the endothelial barrier.
Figura di Frantz: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995612/figure/F1/
Seminario: Motivi, domini e moduli delle proteine
Matrice extracellulare, segue: Collageni: composizione, tipi, sintesi (processi intracellulari ed extracellulari). Patologie associate.
Sculture di Julian Foos: collagene e non solo
Collagen
Collagen:
The Fibrous Proteins of the Matrix
O-LINKED
GLYCANS IN COLLAGENS
Type
IV collagen network formation
Water-Soluble
Vitamins Function As Coenzymes
Matrice extracellulare, segue: Elastina: composizione,
formazione di fibrille, importanza dei legami incrociati bi- e tetrafunzionali
fra le varie molecole di elastina; importanza della fibrillina
Differenze tra collagene ed elastina.
Glicosaminoglicani e proteoglicani della matrice. L'acido ialuronico (ora designato come ialuronato ("hyaluran")): un GAG evoluzionariamente molto antico e importante.Sintesi dell'ialuronato sulla membrana plasmatica (notare che non si svolge nell'apparato di Golgi come avviene per gli altri glicosaminoglicani). Eparina. Proteoglicani: struttura e funzioni. Perlecano e lamina basale.Aggrecano e cartilagine. Ruolo dei proteoglicani nell'idratazione della matrice e nei legami a proteine e peptidi biologicamente attivi.
Diapositive sui glicosaminoglicani e proteoglicani della MECPaganini, How The Great Violinist Was Helped By A Rare Medical Condition
Marfan's Syndrome: Michael Phelps' Blessing or Curse?
Perlecan (HSPG2 (heparan sulfate proteoglycan 2))
Secondary and tertiary structure of hyaluronan in aquous solution. Some biological consequences.
Proteoglycans
Glycosaminoglycans
and Proteoglycans
Basement
membrane proteogycans
Perlecan
Cartilage
Aggrecan
Olczyk
P, Mencner L, Komosinska-Vassev K. Diverse Roles of Heparan Sulfate
and Heparin in Wound Repair. Biomed Res Int. 2015;2015:549417.
Heparan sulfate (HS) and heparin (Hp) are linear polysaccharide chains
composed of repeating (1?4) linked pyrosulfuric acid and 2-amino-2-deoxy
glucopyranose (glucosamine) residue. Mentioned glycosaminoglycans chains
are covalently O-linked to serine residues within the core proteins creating
heparan sulfate/heparin proteoglycans (HSPG). The latter ones participate
in many physiological and pathological phenomena impacting both the plethora
of ligands such as cytokines, growth factors, and adhesion molecules and
the variety of the ECM constituents. Moreover, HS/Hp determine the effective
wound healing process. Initial growth of HS and Hp amount is pivotal during
the early phase of tissue repair; however heparan sulfate and heparin
also participate in further stages of tissue regeneration.
Iozzo
RV, Schaefer L. Proteoglycan form and function: A comprehensive
nomenclature of proteoglycans. Matrix Biol. 2015 Mar;42:11-55.
doi: 10.1016/j.matbio.2015.02.003. Epub 2015 Feb 18.
We provide a comprehensive classification of the proteoglycan gene families
and respective protein cores. This updated nomenclature is based on three
criteria: Cellular and subcellular location, overall gene/protein homology,
and the utilization of specific protein modules within their respective
protein cores. These three signatures were utilized to design four major
classes of proteoglycans with distinct forms and functions: the intracellular,
cell-surface, pericellular and extracellular proteoglycans. The proposed
nomenclature encompasses forty-three distinct proteoglycan-encoding genes
and many alternatively-spliced variants. The biological functions of these
four proteoglycan families are critically assessed in development, cancer
and angiogenesis, and in various acquired and genetic diseases where their
expression is aberrant.
The extracellular matrix (ECM) is a fundamental component of multicellular
organisms that provides mechanical and chemical cues that orchestrate
cellular and tissue organization and functions. Degradation, hyperproduction
or alteration of the composition of the ECM cause or accompany numerous
pathologies. Thus, a better characterization of ECM composition, metabolism,
and biology can lead to the identification of novel prognostic and diagnostic
markers and therapeutic opportunities. The development over the last few
years of high-throughput ("omics") approaches has considerably
accelerated the pace of discovery in life sciences. In this review, we
describe new bioinformatic tools and experimental strategies for ECM research,
and illustrate how these tools and approaches can be exploited to provide
novel insights in our understanding of ECM biology. We also introduce
a web platform "the matrisome project" and the database MatrisomeDB
that compiles in silico and in vivo data on the matrisome, defined as
the ensemble of genes encoding ECM and ECM-associated proteins. Finally,
we present a first draft of an ECM atlas built by compiling proteomics
data on the ECM
Glicoproteine della matrice: Importanza della struttura multimodulare. Fibronectina (struttura e funzione). Laminina: struttura e ruolo nella lamina basale.
Seminario: struttura, ruolo e ligandi cellulari di nidogeno/entactina, trombospondina, tenascina, fattore di von Willebrand, secreted protein acidic and rich in cysteine (SPARC) /osteopontina.
Diapositive sulle glicoproteine della matrice.
Lamina/membrana basale: componenti (laminina, collagene di tipo IV, perlecano, agrina): ruolo strutturale e modulatore dell'attività delle cellule che su di essa poggiano.
Fibronectin
Fibronectin,
an Extracellular Adhesion Molecule
Lavori molto interessanti:
LeBleu VS, Macdonald
B, Kalluri R. Structure and function of basement membranes. Exp Biol
Med (Maywood). 2007 Oct;232(9):1121-9.
Yurchenco PD. Basement membranes: cell scaffoldings and signaling platforms. Cold Spring Harb Perspect Biol. 2011 Feb 1;3(2). doi:pii: a004911. 10.1101/cshperspect.a004911.
Miner JH. Glomerular basement membrane composition and the filtration barrier. Pediatr Nephrol. 2011 Sep;26(9):1413-7. Matsuo I, Kimura-Yoshida C. Extracellular distribution of diffusible growth factors controlled by heparan sulfate proteoglycans during mammalian
embryogenesis. Philos Trans R Soc Lond B Biol Sci. 2014. Disponibile in.pdf: Wang Y, Ni H. Fibronectin maintains the balance between hemostasis and thrombosis. Cell Mol Life Sci. 2016 Apr 21. [Epub ahead of print]
Fibronectin is a dimeric protein widely distributed in solid tissues
and blood. This major extracellular matrix protein is indispensable for
embryogenesis and plays crucial roles in many physiological and pathological
processes. Fibronectin pre-mRNA undergoes alternative splicing to generate
over 20 splicing variants, which are categorized as either plasma fibronectin
(pFn) or cellular fibronectin (cFn). All fibronectin variants contain
integrin binding motifs, as well as N-terminus collagen and fibrin binding
motifs. With motifs that can be recognized by platelet integrins and coagulation
factors, fibronectin, especially pFn, has long been suspected to be involved
in hemostasis and thrombosis, but the exact function of fibronectin in
these processes is controversial. The advances made using intravital microscopy
models and fibronectin deficient and mutant mice have greatly facilitated
the direct investigation of fibronectin function in vivo. Recent studies
revealed that pFn is a vital hemostatic factor that is especially crucial
for hemostasis in both genetic and anticoagulant-induced deficiencies
of fibrin formation. pFn may also be an important self-limiting regulator
to prevent hemorrhage as well as excessive thrombus formation and vessel
occlusion. In addition to pFn, cFn is found to be prothrombotic and may
contribute to thrombotic complications in various diseases. Further investigations
of the role of pFn and cFn in thrombotic and hemorrhagic diseases may
provide insights into development of novel therapeutic strategies (e.g.,
pFn transfusion) for the maintenance of the fine balance between hemostasis
and thrombosis.
Introduzione alla degradazione della matrice extracellulare.
Diapositive introduzione degradazione matrice.
Serina proteasi e loro inibitori "Serpine" Attivatori del plasminogeno di tipo urochinasi e tissutale.
Diapositive sulle serine proteasi
Seminario: Sistemi della coagulazione e fibrinolisi; sistema del complemento; sistema delle chinine: importanza della callicreina nella crescita tumorale.
Diapositive su cascata della coagulazione, fibrinolisi, chinine
Metalloproteasi della matrice: Ruolo dei vari domini: dominio autoinibitorio, dominio catalitico, dominio tipo emopexina. Metallo proteasi della matrice secrete oppure legate alle membrane (MT-MMPs) e loro inibitori tissutali (TIMPs). Proteine ADAMs e importanza nel rilascio di ectodomini di proteine di membrana. Proteine ADAMTs e degradazione dei proteoglicani.
Murphy & Arhtur: Danger outside the cell. The extracellular matrix and diesease.
Role of Matrix Metalloproteinases in Cancer
Lavori disponibili in .pdf:
1) Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression.Nat Rev Cancer. 2002 Mar;2(3):161-74.
Matrix metalloproteinases (MMPs) have long been associated with cancer-cell invasion and metastasis. This provided the rationale for clinical trials of MMP inhibitors, unfortunately with disappointing results. We now know, however, that the MMPs have functions other than promotion of invasion, have substrates other than components of the extracellular matrix, and that they function before invasion in the development of cancer. With this knowledge in hand, can we rethink the use of MMP inhibitors in the clinic?
2) Nagase H, Visse R, Murphy G. Structure and function of matrix
metalloproteinases and TIMPs.Cardiovasc Res. 2006 Feb 15;69(3):562-73.
Matrix metalloproteinases (MMPs), also called matrixins, function in the
extracellular environment of cells and degrade both matrix and non-matrix
proteins. They play central roles in morphogenesis, wound healing, tissue
repair and remodelling in response to injury, e.g. after myocardial infarction,
and in progression of diseases such as atheroma, arthritis, cancer and
chronic tissue ulcers. They are multi-domain proteins and their activities
are regulated by tissue inhibitors of metalloproteinases (TIMPs). This
review introduces the members of the MMP family and discusses their domain
structure and function, proenyme activation, the mechanism of inhibition
by TIMPs and their significance in physiology and pathology.
3) Khokha R, Murthy A, Weiss A. Metalloproteinases and their
natural inhibitors in inflammation and immunity. Nat Rev Immunol.
2013 Sep;13(9):649-65.
Over the past 50 years, steady growth in the field of metalloproteinase
biology has shown that the degradation of extracellular matrix components
represents only a fraction of the functions performed by these enzymes
and has highlighted their fundamental roles in immunity. Metalloproteinases
regulate aspects of immune cell development, effector function, migration
and ligand-receptor interactions. They carry out ectodomain shedding
of cytokines and their cognate receptors. Together with their endogenous
inhibitors TIMPs (tissue inhibitor of metalloproteinases), these
enzymes regulate signalling downstream of the tumour necrosis factor receptor
and the interleukin-6 receptor, as well as that downstream of the epidermal
growth factor receptor and Notch, which are all pertinent for inflammatory
responses. This Review discusses the metalloproteinase family as a crucial
component in immune cell development and function.
Seminario sui tipi di MMPs e ruolo delle MMPs nei tumori e nell'infiammazione.
Peptidi bioattivi derivati dalla degradazione della matrice: Matrichine e matricriptine. Definizione, meccanismi di formazione, effetti biologici. Agenti antiangiogenetici (endostatina, angiostatina).
Diapositive su matrichine e matricriptine
Seminario:
1. Matrichine derivate dai vari componenti della matrice.
3. Altre info sull'angiogenesi tumorale e inibitori dell'angiogenesi
Lavoro disponibile in .pdf:
Antalis TM, Conway GD, Peroutka RJ, Buzza MS.
Membrane-anchored proteases in endothelial cell biology. Curr
Opin Hematol. 2016 May;23(3):243-52.
PURPOSE OF REVIEW: The endothelial cell plasma membrane is a metabolically
active, dynamic, and fluid microenvironment where pericellular proteolysis
plays a critical role. Membrane-anchored proteases may be expressed by
endothelial cells as well as mural cells and leukocytes with distribution
both inside and outside of the vascular system. Here, we will review the
recent advances in our understanding of the direct and indirect roles
of membrane-anchored proteases in vascular biology and the possible conservation
of their extravascular functions in endothelial cell biology. RECENT FINDINGS:
Membrane-anchored proteases belonging to the serine or metalloprotease
families contain amino-terminal or carboxy-terminal domains, which serve
to tether their extracellular protease domains directly at the plasma
membrane. This architecture enables protease function and substrate repertoire
to be regulated through dynamic localization in distinct areas of the
cell membrane. These proteases are proving to be key components of the
cell machinery for regulating vascular permeability, generation of vasoactive
peptides, receptor tyrosine kinase transactivation, extracellular matrix
proteolysis, and angiogenesis. SUMMARY: A complex picture of the interdependence
between membrane-anchored protease localization and function is emerging
that may provide a mechanism for precise coordination of extracellular
signals and intracellular responses through communication with the cytoskeleton
and with cellular signaling molecules.
Lavoro scaricabile da Internet:
Bonnans
C, Chou J, Werb Z. Remodelling the extracellular matrix in development
and disease. Nat Rev Mol Cell Biol. 2014 Dec;15(12):786-801.
The extracellular matrix (ECM) is a highly dynamic structure that is present
in all tissues and continuously undergoes controlled remodelling. This
process involves quantitative and qualitative changes in the ECM, mediated
by specific enzymes that are responsible for ECM degradation, such as
metalloproteinases. The ECM interacts with cells to regulate diverse functions,
including proliferation, migration and differentiation. ECM remodelling
is crucial for regulating the morphogenesis of the intestine and lungs,
as well as of the mammary and submandibular glands. Dysregulation of ECM
composition, structure, stiffness and abundance contributes to several
pathological conditions, such as fibrosis and invasive cancer. A better
understanding of how the ECM regulates organ structure and function and
of how ECM remodelling affects disease progression will contribute to
the development of new therapeutics.
Beginning of angiogenesis research (Judah Folkman, MD and Raghu Kalluri, PhD)
Learn Angiogenesis
Suggerimento lavori su angiogenesis da approfondire per tema esame:
- Jain RK. Taming vessels to treat cancer. Sci Am. 2008 Jan;298(1):56-63.
- Jain RK, Carmeliet P. SnapShot: Tumor angiogenesis. Cell. 2012 Jun 8;149(6):1408-1408.e1.
- Carmeliet P. Angiogenesis in life, disease and medicine. Nature. 2005 Dec 15;438(7070):932-6.
- Wells JM, Gaggar A, Blalock JE. MMP generated matrikines. Matrix Biol. 2015. Jan 28.
- Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014 Nov 10;26(5):605-22. Ten antiangiogenic drugs targeting VEGF or its receptors are approved for cancer treatment. However, these agents, intended to block tumors' blood supply, may cause hypoxia, which may fuel tumor progression and treatment resistance. Emerging clinical data suggest that patients whose tumor perfusion or oxygenation increases in response to these agents may actually survive longer. Hence, strategies aimed at alleviating tumor hypoxia while improving perfusion may enhance the outcome of radiotherapy, chemotherapy, and immunotherapy. Here I summarize lessons learned from preclinical and clinical studies over the past decade and propose strategies for improving antiangiogenic therapy outcomes for malignant and nonmalignant diseases.
- Jain
RK, Martin JD, Stylianopoulos T. The role of mechanical forces
in tumor growth and therapy. Annu Rev Biomed Eng. 2014 Jul
11;16:321-46.
Tumors generate physical forces during growth and progression. These physical forces are able to compress blood and lymphatic vessels, reducing perfusion rates and creating hypoxia. When exerted directly on cancer cells, they can increase cells' invasive and metastatic potential. Tumor vessels-while nourishing the tumor-are usually leaky and tortuous, which further decreases perfusion. Hypoperfusion and hypoxia contribute to immune evasion, promote malignant progression and metastasis, and reduce the efficacy of a number of therapies, including radiation. In parallel, vessel leakiness together with vessel compression causes a uniformly elevated interstitial fluid pressure that hinders delivery of blood-borne therapeutic agents, lowering the efficacy of chemo- and nanotherapies. In addition, shear stresses exerted by flowing blood and interstitial fluid modulate the behavior of cancer and a variety of host cells. Taming these physical forces can improve therapeutic outcomes in many cancers.
Disponibile pdf:
1) Ricard-Blum S, Salza R.: Matricryptins and matrikines: biologically active fragments of the extracellular matrix. Exp Dermatol. 2014 Jul;23(7):457-63.
Numerous extracellular proteins and glycosaminoglycans (GAGs) undergo limited enzymatic cleavage resulting in the release of fragments exerting biological activities, which are usually different from those of the full-length molecules. In this review, we define matrikines and matricryptins, which are bioactive fragments released from the extracellular matrix proteins, proteoglycans and GAGs and report their major biological activities. These fragments regulate a number of physiopathological processes including angiogenesis, cancer, fibrosis, inflammation, neurodegenerative diseases and wound healing. The challenges to translate these fragments from molecules biologically active in vitro and in experimental models to potential drugs are discussed in the last part of the review.
2) Bix G, Iozzo RV. Matrix revolutions: "tails" of
basement-membrane components with angiostatic functions. Trends
Cell Biol. 2005 Jan;15(1):52-60.
Angiogenesis, the creation of neovasculature from native blood vessels,
is a prerequisite for many physiological and pathological processes. Recently,
C-terminal tail fragments of several basement-membrane proteins such as
endostatin, tumstatin and endorepellin have been shown to inhibit angiogenesis.
Although there seems to be little or no homology among them, a common
theme is that these fragments modulate endothelial cells by distinct interactions
with integrins and activate distinct intracellular signaling cascades
that often lead to disruption of the actin cytoskeleton. In this article,
we focus on recent advances regarding the mechanism of action of these
angiostatic fragments and the emerging concept of similarities among them,
with the underlying premise that appreciating these similarities might
lead to improved therapeutics.
3) Ricard-Blum S, Ballut L. Matricryptins derived from collagens and proteoglycans. Front Biosci. 2011 Jan 1;16:674-97.
Controlled proteolysis of extracellular matrix components releases bioactive fragments or unmasks cryptic sites that play key roles in controlling various physio-pathological processes including angiogenesis, tissue remodeling, wound healing, inflammation, tumor growth, and metastasis. We review here the structure and mechanisms of release of i) the proteolytic fragments (matricryptins) cleaved from collagens, proteoglycans and glycosaminoglycans, and ii) the matricryptic sites existing in these molecules. The cell surface receptors and the signaling pathways they trigger to exert their biological activities is discussed with the major physio-pathological processes they control. Their involvement in autoimmune and inherited diseases is reported. Most matricryptins issued from collagens, proteoglycans and glycosaminoglycans exhibit anti-angiogenic and anti-tumor properties and their use as potential drugs and as potential disease markers is discussed. Perspectives for identifying the common structural features, if any, of the matricryptins and their use in combination with chemotherapy and radiotherapy in the treatment of cancer are presented.
4) Burgess JK, Weckmann M. Matrikines and the lungs. Pharmacol Ther. 2012 Jun;134(3):317-37.
The extracellular matrix is a complex network of fibrous and nonfibrous molecules that not only provide structure to the lung but also interact with and regulate the behaviour of the cells which it surrounds. Recently it has been recognised that components of the extracellular matrix proteins are released, often through the action of endogenous proteases, and these fragments are termed matrikines. Matrikines have biological activities, independent of their role within the extracellular matrix structure, which may play important roles in the lung in health and disease pathology. Integrins are the primary cell surface receptors, characterised to date, which are used by the matrikines to exert their effects on cells. However, evidence is emerging for the need for co-factors and other receptors for the matrikines to exert their effects on cells. The potential for matrikines, and peptides derived from these extracellular matrix protein fragments, as therapeutic agents has recently been recognised. The natural role of these matrikines (including inhibitors of angiogenesis and possibly inflammation) make them ideal targets to mimic as therapies. A number of these peptides have been taken forward into clinical trials. The focus of this review will be to summarise our current understanding of the role, and potential for highly relevant actions, of matrikines in lung health and disease.
5) Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Carmeliet P(1), Jain RK. Nat Rev Drug Discov. 2011 Jun;10(6):417-27. doi: 10.1038/nrd3455.
Despite having an abundant number of vessels, tumours are usually hypoxic
and nutrient-deprived because their vessels malfunction. Such abnormal
milieu can
fuel disease progression and resistance to treatment. Traditional anti-angiogenesis
strategies attempt to reduce the tumour vascular supply, but
their success is restricted by insufficient efficacy or development of
resistance. Preclinical and initial clinical evidence reveal that normalization
of the vascular abnormalities is emerging as a complementary therapeutic
paradigm for cancer and other vascular disorders, which affect more than
half a billion
people worldwide. Here, we discuss the mechanisms, benefits, limitations
and possible clinical translation of vessel normalization for cancer and
other
angiogenic disorders.
6) Therapeutic application of anti-angiogenic nanomaterials in cancers. Mukherjee S(1), Patra CR(1).Nanoscale. 2016 Apr 12. [Epub ahead of print]
Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a vital role in physiological and pathological processes (embryonic development, wound healing, tumor growth and metastasis). The overall balance of angiogenesis inside the human body is maintained by pro- and anti-angiogenic signals. The processes by which drugs inhibit angiogenesis as well as tumor growth are called the anti-angiogenesis technique, a most promising cancer treatment strategy. Over the last couple of decades, scientists have been developing angiogenesis inhibitors for the treatment of cancers. However, conventional anti-angiogenic therapy has several limitations including drug resistance that can create problems for a successful therapeutic strategy. Therefore, a new comprehensive treatment strategy using antiangiogenic agents for the treatment of cancer is urgently needed. Recently researchers have been developing and designing several nanoparticles that show anti-angiogenic properties. These nanomedicines could be useful as an alternative strategy for the treatment of various cancers using anti-angiogenic therapy. In this review article, we critically focus on the potential application of anti-angiogenic nanomaterial and nanoparticle based drug/siRNA/peptide delivery systems in cancer therapeutics. We also discuss the basic and clinical perspectives of anti-angiogenesis therapy, highlighting its importance in tumor angiogenesis, current status and future prospects and challenges.
7) Bergers G, Benjamin LE.Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003 Jun;3(6):401-10.
It has become evident that we cannot understand tumour growth without considering components of the stromal microenvironment, such as the vasculature. At the same time, the tumour phenotype determines the nature of the tumour vasculature. Much research is now devoted to determining the impact of angiogenesis on tumour development and progression, and the reciprocal influences of tumour products on the microvasculature. A more detailed understanding of the complex parameters that govern the interactions between the tumour and vascular compartments will help to improve anti-angiogenic strategies-- not only for cancer treatment, but also for preventing recurrence.
8) Ricard-Blum S, Vallet SD. Proteases decode the extracellular
matrix cryptome. Biochimie. 2016 Mar;122:300-13.
The extracellular matrix is comprised of 1100 core-matrisome and matrisome-associated
proteins and of glycosaminoglycans. This structural scaffold contributes
to the organization and mechanical properties of tissues and modulates
cell behavior. The extracellular matrix is dynamic and undergoes constant
remodeling, which leads to diseases if uncontrolled. Bioactive fragments,
called matricryptins, are released from the extracellular proteins by
limited proteolysis and have biological activities on their own. They
regulate numerous physiological and pathological processes such as angiogenesis,
cancer, diabetes, wound healing, fibrosis and infectious diseases and
either improve or worsen the course of diseases depending on the matricryptins
and on the molecular and biological contexts. Several protease families
release matricryptins from core-matrisome and matrisome-associated proteins
both in vitro and in vivo. The major proteases, which decrypt the extracellular
matrix, are zinc metalloproteinases of the metzincin superfamily (matrixins,
adamalysins and astacins), cysteine proteinases and serine proteases.
Some matricryptins act as enzyme inhibitors, further connecting protease
and matricryptin fates and providing intricate regulation of major physiopathological
processes such as angiogenesis and tumorigenesis. They strengthen the
role of the extracellular matrix as a key player in tissue failure and
core-matrisome and matrisome-associated proteins as important therapeutic
targets.
9) Per ruolo di MMPs nella gravidanza:
Sharma S, Godbole G, Modi D. Decidual Control of Trophoblast Invasion.
Am J Reprod Immunol. 2016 Mar;75(3):341-50. doi: 10.1111/aji.12466. Epub
2016 Jan 12.
At the time of implantation, the trophoblast cells of the embryo adhere
and then invade into the maternal endometrium and eventually establish
placentation. The endometrium at the same time undergoes decidualization,
which is essential for successful pregnancy. While the NK cells of the
decidua have been implicated to play a key role in trophoblast invasion,
few evidence are now available to demonstrate a pro-invasive property
of decidual stromal cells. Secretions from decidualized endometrial stromal
cells promote invasion of primary trophoblasts and model cell lines by
activating proteases and altering expression of adhesion-related molecules.
The decidual secretions contain high amounts of pro-invasive factors that
include IL-1ß, IL-5, IL-6, IL-7, IL-8, IL-9, IL-13, IL-15, Eotaxin
CCL11, IP-10 and RANTES, and anti-invasive factors IL-10, IL-12 and VEGF.
It appears that these decidual factors promote invasion by regulating
the protease pathways and integrin expression utilizing the STAT pathways
in the trophoblast cells. At the same time the decidua also seem to secrete
some anti-invasive factors that are antagonist to the matrix metalloproteinases
and/or are activators of tissue inhibitors of metalloproteinases. This
might be essential to neutralize the effects of the invasion-promoting
factors and restrain over-invasion. It is tempting to propose that during
the course of pregnancy, the decidua must balance the production of these
pro and anti-invasive molecules and such harmonizing production would
allow a timely and regulated invasion.
Il Corso è terminato. Mi auguro di essere riuscita a rendere affascinanti gli argomenti trattati e di avervi invogliato ad approfondirli ulteriormente.