Matrix metalloproteinases (MMPs) are enzymes that degrade components of the extracellular matrix. They are implicated in various neurological conditions and play important roles in processes like synaptic remodeling. More recently, MMPs have been shown to regulate neural stem cell biology and remyelination, suggesting their importance in nervous system regeneration. While MMPs serve beneficial functions, their upregulation in conditions like neuroinflammation and neurodegeneration can also contribute to tissue damage.
Matrix metalloproteinases (MMPs) are a family of calcium-dependent zinc-containing endopeptidases that are responsible for tissue remodeling and degradation of the extracellular matrix. MMPs are excreted by connective tissue and inflammatory cells and play a role in both physiological and pathological processes such as angiogenesis. MMPs degrade various components of the extracellular matrix, including collagens, and their activation leads to tissue remodeling and degradation involved in conditions like cancer.
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that degrade extracellular matrix components. MMPs play important roles in tissue remodeling during processes like wound healing and organ development by breaking down collagen, elastin, fibronectin and other matrix proteins. Their activity is regulated by tissue inhibitors of metalloproteinases (TIMPs). Abnormal MMP activity is associated with diseases like cancer, atherosclerosis, and rheumatoid arthritis by facilitating tissue invasion or destruction.
Toll-like receptors (TLRs) play a key role in the innate immune system by recognizing molecular patterns from pathogens. TLRs are expressed on immune cells like macrophages and dendritic cells. They recognize pathogen-associated molecular patterns and activate signaling pathways that induce inflammatory responses and adaptive immunity. There are 10 human TLRs that recognize different ligands from bacteria, viruses, and fungi. TLR signaling involves either a MyD88-dependent or independent pathway leading to cytokine production and immune cell activation. Dysregulation of TLRs has been implicated in various diseases.
Inflammasomes: Guardian Angels of the bodyVarij Nayan
"Generally speaking, the inflammasome depends on the assembly of a sensor(e.g. NLRP), with an adaptor, ASC (apoptosis-associated Speck-like protein containing a CARD), allowing the recruitment and activation of an inflammatory caspase, Caspase-1"
This lecture discusses how the immune system responds to tumors and how tumors evade the immune system. It covers various types of tumor antigens recognized by the immune system, including products of mutated genes, overexpressed proteins, and oncofetal antigens. The immune system mounts cellular and humoral responses against tumors through cytotoxic T cells, NK cells, macrophages, and antibodies. However, tumors have developed mechanisms to evade the immune system, such as antigen loss, lack of costimulation, immunosuppression, and inducing T cell apoptosis. Understanding the immune response and evasion is crucial for developing immunotherapies against cancer.
The immune system plays an important role in tumor immunity by recognizing and destroying tumor cells. However, tumors have developed several mechanisms to evade the immune system. Tumors express a variety of tumor antigens that can elicit an immune response, but they often downregulate antigen expression or lose antigenicity over time. Additionally, tumors employ immunosuppressive strategies like increasing immunosuppressive cytokines or reducing co-stimulatory molecules to avoid immune detection and destruction. While immune surveillance exists, tumors have found ways to circumvent it through immune escape mechanisms.
Matrix metalloproteinases (MMPs) are a family of calcium-dependent zinc-containing endopeptidases that are responsible for tissue remodeling and degradation of the extracellular matrix. MMPs are excreted by connective tissue and inflammatory cells and play a role in both physiological and pathological processes such as angiogenesis. MMPs degrade various components of the extracellular matrix, including collagens, and their activation leads to tissue remodeling and degradation involved in conditions like cancer.
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that degrade extracellular matrix components. MMPs play important roles in tissue remodeling during processes like wound healing and organ development by breaking down collagen, elastin, fibronectin and other matrix proteins. Their activity is regulated by tissue inhibitors of metalloproteinases (TIMPs). Abnormal MMP activity is associated with diseases like cancer, atherosclerosis, and rheumatoid arthritis by facilitating tissue invasion or destruction.
Toll-like receptors (TLRs) play a key role in the innate immune system by recognizing molecular patterns from pathogens. TLRs are expressed on immune cells like macrophages and dendritic cells. They recognize pathogen-associated molecular patterns and activate signaling pathways that induce inflammatory responses and adaptive immunity. There are 10 human TLRs that recognize different ligands from bacteria, viruses, and fungi. TLR signaling involves either a MyD88-dependent or independent pathway leading to cytokine production and immune cell activation. Dysregulation of TLRs has been implicated in various diseases.
Inflammasomes: Guardian Angels of the bodyVarij Nayan
"Generally speaking, the inflammasome depends on the assembly of a sensor(e.g. NLRP), with an adaptor, ASC (apoptosis-associated Speck-like protein containing a CARD), allowing the recruitment and activation of an inflammatory caspase, Caspase-1"
This lecture discusses how the immune system responds to tumors and how tumors evade the immune system. It covers various types of tumor antigens recognized by the immune system, including products of mutated genes, overexpressed proteins, and oncofetal antigens. The immune system mounts cellular and humoral responses against tumors through cytotoxic T cells, NK cells, macrophages, and antibodies. However, tumors have developed mechanisms to evade the immune system, such as antigen loss, lack of costimulation, immunosuppression, and inducing T cell apoptosis. Understanding the immune response and evasion is crucial for developing immunotherapies against cancer.
The immune system plays an important role in tumor immunity by recognizing and destroying tumor cells. However, tumors have developed several mechanisms to evade the immune system. Tumors express a variety of tumor antigens that can elicit an immune response, but they often downregulate antigen expression or lose antigenicity over time. Additionally, tumors employ immunosuppressive strategies like increasing immunosuppressive cytokines or reducing co-stimulatory molecules to avoid immune detection and destruction. While immune surveillance exists, tumors have found ways to circumvent it through immune escape mechanisms.
Fibroblasts are mesenchymal cells that form connective tissue and play important roles in health and disease. In health, fibroblasts are involved in organ development and maintenance through secretion of extracellular matrix proteins and growth factors. In disease, fibroblasts contribute to tissue repair after injury but can also cause fibrosis and promote tumor progression. The document discusses fibroblast anatomy, functions in various organs, roles in wound healing, inflammation and fibrosis, and tumors that can arise from fibroblasts. It provides examples of how fibroblasts are involved in both normal tissue functions and a wide range of pathological conditions.
Toll-like receptors (TLRs) are a key part of the innate immune system. They recognize structural patterns in pathogens and activate immune responses. TLRs are expressed in immune cells and tissues exposed to the external environment. They recognize pathogen-associated molecular patterns and signal through either a MyD88-dependent or TRIF-dependent pathway to induce inflammatory responses and help activate adaptive immunity. TLR signaling leads to cytokine production, phagocytosis, cell apoptosis, and interferon release. This helps link innate and adaptive immunity through effects on dendritic cells.
The complement system is an important part of the innate immune system that activates through three pathways - classical, lectin, and alternative. Activation leads to the formation of C3 and C5 convertases that generate inflammatory molecules like C3a and C5a, and opsonins like C3b that promote phagocytosis. It ultimately forms the membrane attack complex that lyses target cells. Complement is tightly regulated to prevent damage to host cells and excessive inflammation. Deficiencies in complement components can increase risk of certain infections.
Mast cells (MCs) play a broad role in both physiology and disease beyond just allergy. MCs originate from bone marrow progenitor cells and develop in tissues where they exist in different phenotypes. MCs can be activated through various stimuli to degranulate and release mediators that impact wound healing, homeostasis, the nervous system, host defense against parasites, bacteria, viruses, and venoms, as well as diseases like allergy, asthma, vascular disease, and fibrosis. MCs contribute to inflammation in conditions such as inflammatory bowel disease and some autoimmune/autoinflammatory diseases.
The document discusses various types of tumor antigens recognized by T cells and immune mechanisms of tumor rejection. It covers tumor-associated antigens and tumor-specific antigens, and describes four main categories of tumor antigens: 1) abnormally expressed but unmutated cellular proteins, 2) products of mutated self genes, 3) oncogenes and mutated tumor suppressor genes, and 4) antigens of oncogenic viruses. It also discusses how tumors can evade immune responses through mechanisms like antigen loss, inhibiting immune molecules, regulatory T cells, and secreting immunosuppressive factors. Novel immunotherapies discussed include therapeutic cancer vaccines, monoclonal antibodies, immune checkpoint inhibitors, adoptive cell therapies, and oncolytic viruses.
Epithelial and mesenchymal transition in invasion and metastasisAshwini Gowda
This document discusses neoplasia and the process of metastasis. It defines neoplasia as new, uncontrolled growth and describes the hallmarks of cancer cells, including autonomous growth, loss of differentiation, invasion and metastasis. It explains the multi-step process of metastasis, beginning with local invasion of tumor cells into surrounding tissue facilitated by degradation of the extracellular matrix and migration of cells. The document then discusses the vascular dissemination of tumor cells and colonization at distant sites, outlining several theories for how metastatic potential arises in tumors. Key genes and pathways involved in epithelial-mesenchymal transition and the generation of cancer stem cells are also reviewed.
dendritic cells are part of innate immune system, antigen presenting cells in skin, activation of t cells and inducing and maintaining immune tolerance, 4 types- langerhans cells, dermal dendritic cells, merkel cells, melanocytes
Metastatic cascade and Epithelial Mesenchymal TransitionShruti Dogra
This document provides an overview of cancer metastasis and the epithelial-mesenchymal transition (EMT) process. It discusses the metastatic cascade, which involves tumor cell invasion, intravasation into blood vessels, transport through circulation, extravasation and homing to distant sites, and formation of secondary tumors. EMT is described as a key step in metastasis that allows epithelial cells to detach from primary tumors and migrate. The molecular and cellular changes involved in EMT include loss of epithelial markers like E-cadherin and gain of mesenchymal markers. Transcription factors such as Snail, Slug, Twist, and ZEB play important roles in inducing EMT. Understanding metastasis and EMT can help develop strategies to prevent cancer spread
Mast cells play important roles in allergic diseases through their development, activation, and release of mediators. They develop from hematopoietic stem cells under the influence of stem cell factor and local tissue factors. Activated through IgE-dependent or non-IgE dependent mechanisms, mast cells degranulate and release preformed mediators like histamine and proteases, as well as synthesize new mediators. They contribute to allergen sensitization by influencing dendritic cells and promoting Th2 responses. In anaphylaxis, mast cell tryptase is the predominant mediator released systemically.
Cytokines are small soluble proteins that are important mediators of the inflammatory response. They are produced by immune cells like lymphocytes and monocytes and act as signaling molecules between cells. The document defines cytokines and provides classifications of cytokines. It describes the roles of key cytokines like IL-1 and IL-2 in innate immunity and leukocyte recruitment during the early immune response. Cytokines function through binding to specific cell surface receptors and activating intracellular signaling pathways.
Neutrophils are specialized white blood cells that play a key role in the innate immune system's defense against pathogens. They are the most abundant type of white blood cell and circulate in the bloodstream, migrating to sites of infection through a multi-step process involving rolling, adhesion, transmigration, and chemotaxis. At the site of infection, neutrophils phagocytose and kill pathogens using granules containing antimicrobial enzymes and reactive oxygen species. They also form neutrophil extracellular traps (NETs) composed of DNA and antimicrobial proteins to ensnare and kill microbes. Uncontrolled activation of neutrophils can cause tissue damage and contribute to chronic inflammatory diseases.
The document discusses immunological tolerance and its breakdown which can lead to autoimmunity and autoimmune diseases. It explains the mechanisms of central and peripheral tolerance that normally prevent immune responses against self-antigens. Failure of these tolerance mechanisms can occur through various causes like a breakdown of T cell anergy or loss of regulatory T cells, resulting in an immune response against self-tissues and the development of autoimmune conditions.
This is a PowerPoint presentation of DIF in Dermatology and its clinical importance. This PPT is made by Dr. Jerriton Brewin, 1st year PG in DVL at SVMCH, Pondy.
This document discusses mast cells, including their role in health and disease. It begins by describing mast cell activation through IgE receptors or other stimuli, which causes the release of mediators like histamine. These mediators contribute to wound healing, angiogenesis, and defense against infection. However, mast cell activation also causes immediate hypersensitivity reactions and exacerbates conditions like arthritis and coronary disease. The document concludes by discussing mast cell disorders like mastocytosis.
This document discusses the structure and function of desmosomes, which are the major cellular structures that maintain cell-cell adhesion in the epidermis. Desmosomes are composed of three major protein families: plakins (including desmoplakin), armadillo proteins, and desmosomal cadherins. Desmoplakin links the desmosomal cadherins to the keratin intermediate filaments inside the cell. Mutations in desmosomal proteins can cause skin fragility disorders and cardiomyopathies. The document also briefly summarizes other epidermal junctional complexes including adherens junctions, tight junctions, and gap junctions.
This document summarizes key information about Toll-like receptors (TLRs):
- TLRs are pattern recognition receptors that recognize pathogens and activate immune responses. They play a role in both innate and adaptive immunity.
- TLRs recognize specific microbial ligands and signal through either MyD88-dependent or MyD88-independent pathways to induce inflammatory responses.
- Genetic variations in TLRs have been linked to susceptibility or resistance to various diseases like leprosy, tuberculosis, and cancer. Targeting TLR pathways may offer therapeutic approaches for neurological diseases like Alzheimer's disease.
This document summarizes the key stages in B-lymphocyte maturation, generation, and activation. It discusses how B cells develop from progenitor cells in the bone marrow, where they undergo antigen-independent maturation including immunoglobulin gene rearrangement and positive and negative selection to remove self-reactive cells. Mature B cells then leave the bone marrow equipped with B cell receptors. The document also describes how B cells are activated upon binding of antigen to their receptor, requiring co-stimulation by T helper cells to initiate the antibody response.
This document summarizes matrix metalloproteinases (MMPs), a family of enzymes that degrade the extracellular matrix and are involved in tissue remodeling. It groups MMPs into collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and others. For each group, it lists the MMP names and their protein substrates. It also describes two pathways for activating MMPs at the cell surface, and discusses transcriptional regulation, activation of precursors, substrate specificity, inhibitors like TIMPs and α2-macroglobulins, and classes of pharmacological MMP inhibitors.
An undergraduate lecture on immunologic tolerance, it's various types and how a breakdown of tolerance contributes to the pathogenesis of autoimmune diseases. Additionally a small quiz at the end to gauge the students' learning.
The role of matrix metalloproteinase 2 (mmp 2Feng-wei Yeh
The document discusses the role of matrix metalloproteinase 2 (MMP-2) in chronic periodontitis. MMP-2 degrades extracellular matrix proteins and collagen fibers. Due to its gelatinase function, MMP-2 may be associated with tooth mobility caused by periodontitis. Smoking is a major risk factor for chronic periodontitis by worsening inflammation. Tetracycline and doxycycline can inhibit MMPs and reduce periodontal inflammation by functioning as tissue inhibitors of metalloproteinases.
The role of matrix metalloproteinase 2 Feng-wei Yeh
This document discusses the role of matrix metalloproteinase 2 (MMP-2) in chronic periodontitis. MMP-2 is a gelatinase found in gingival crevicular fluid and periodontal tissue that can degrade proteins and collagen fibers. Increased levels of MMP-2 may be associated with the symptoms of chronic periodontitis such as inflammation, tissue destruction, and tooth mobility. Quantifying MMP-2 levels in gingival crevicular fluid could help diagnose chronic periodontitis and monitor the effects of treatment. Natural compounds that inhibit MMP-2 may offer alternative therapies to antibiotics for treating chronic periodontitis.
Fibroblasts are mesenchymal cells that form connective tissue and play important roles in health and disease. In health, fibroblasts are involved in organ development and maintenance through secretion of extracellular matrix proteins and growth factors. In disease, fibroblasts contribute to tissue repair after injury but can also cause fibrosis and promote tumor progression. The document discusses fibroblast anatomy, functions in various organs, roles in wound healing, inflammation and fibrosis, and tumors that can arise from fibroblasts. It provides examples of how fibroblasts are involved in both normal tissue functions and a wide range of pathological conditions.
Toll-like receptors (TLRs) are a key part of the innate immune system. They recognize structural patterns in pathogens and activate immune responses. TLRs are expressed in immune cells and tissues exposed to the external environment. They recognize pathogen-associated molecular patterns and signal through either a MyD88-dependent or TRIF-dependent pathway to induce inflammatory responses and help activate adaptive immunity. TLR signaling leads to cytokine production, phagocytosis, cell apoptosis, and interferon release. This helps link innate and adaptive immunity through effects on dendritic cells.
The complement system is an important part of the innate immune system that activates through three pathways - classical, lectin, and alternative. Activation leads to the formation of C3 and C5 convertases that generate inflammatory molecules like C3a and C5a, and opsonins like C3b that promote phagocytosis. It ultimately forms the membrane attack complex that lyses target cells. Complement is tightly regulated to prevent damage to host cells and excessive inflammation. Deficiencies in complement components can increase risk of certain infections.
Mast cells (MCs) play a broad role in both physiology and disease beyond just allergy. MCs originate from bone marrow progenitor cells and develop in tissues where they exist in different phenotypes. MCs can be activated through various stimuli to degranulate and release mediators that impact wound healing, homeostasis, the nervous system, host defense against parasites, bacteria, viruses, and venoms, as well as diseases like allergy, asthma, vascular disease, and fibrosis. MCs contribute to inflammation in conditions such as inflammatory bowel disease and some autoimmune/autoinflammatory diseases.
The document discusses various types of tumor antigens recognized by T cells and immune mechanisms of tumor rejection. It covers tumor-associated antigens and tumor-specific antigens, and describes four main categories of tumor antigens: 1) abnormally expressed but unmutated cellular proteins, 2) products of mutated self genes, 3) oncogenes and mutated tumor suppressor genes, and 4) antigens of oncogenic viruses. It also discusses how tumors can evade immune responses through mechanisms like antigen loss, inhibiting immune molecules, regulatory T cells, and secreting immunosuppressive factors. Novel immunotherapies discussed include therapeutic cancer vaccines, monoclonal antibodies, immune checkpoint inhibitors, adoptive cell therapies, and oncolytic viruses.
Epithelial and mesenchymal transition in invasion and metastasisAshwini Gowda
This document discusses neoplasia and the process of metastasis. It defines neoplasia as new, uncontrolled growth and describes the hallmarks of cancer cells, including autonomous growth, loss of differentiation, invasion and metastasis. It explains the multi-step process of metastasis, beginning with local invasion of tumor cells into surrounding tissue facilitated by degradation of the extracellular matrix and migration of cells. The document then discusses the vascular dissemination of tumor cells and colonization at distant sites, outlining several theories for how metastatic potential arises in tumors. Key genes and pathways involved in epithelial-mesenchymal transition and the generation of cancer stem cells are also reviewed.
dendritic cells are part of innate immune system, antigen presenting cells in skin, activation of t cells and inducing and maintaining immune tolerance, 4 types- langerhans cells, dermal dendritic cells, merkel cells, melanocytes
Metastatic cascade and Epithelial Mesenchymal TransitionShruti Dogra
This document provides an overview of cancer metastasis and the epithelial-mesenchymal transition (EMT) process. It discusses the metastatic cascade, which involves tumor cell invasion, intravasation into blood vessels, transport through circulation, extravasation and homing to distant sites, and formation of secondary tumors. EMT is described as a key step in metastasis that allows epithelial cells to detach from primary tumors and migrate. The molecular and cellular changes involved in EMT include loss of epithelial markers like E-cadherin and gain of mesenchymal markers. Transcription factors such as Snail, Slug, Twist, and ZEB play important roles in inducing EMT. Understanding metastasis and EMT can help develop strategies to prevent cancer spread
Mast cells play important roles in allergic diseases through their development, activation, and release of mediators. They develop from hematopoietic stem cells under the influence of stem cell factor and local tissue factors. Activated through IgE-dependent or non-IgE dependent mechanisms, mast cells degranulate and release preformed mediators like histamine and proteases, as well as synthesize new mediators. They contribute to allergen sensitization by influencing dendritic cells and promoting Th2 responses. In anaphylaxis, mast cell tryptase is the predominant mediator released systemically.
Cytokines are small soluble proteins that are important mediators of the inflammatory response. They are produced by immune cells like lymphocytes and monocytes and act as signaling molecules between cells. The document defines cytokines and provides classifications of cytokines. It describes the roles of key cytokines like IL-1 and IL-2 in innate immunity and leukocyte recruitment during the early immune response. Cytokines function through binding to specific cell surface receptors and activating intracellular signaling pathways.
Neutrophils are specialized white blood cells that play a key role in the innate immune system's defense against pathogens. They are the most abundant type of white blood cell and circulate in the bloodstream, migrating to sites of infection through a multi-step process involving rolling, adhesion, transmigration, and chemotaxis. At the site of infection, neutrophils phagocytose and kill pathogens using granules containing antimicrobial enzymes and reactive oxygen species. They also form neutrophil extracellular traps (NETs) composed of DNA and antimicrobial proteins to ensnare and kill microbes. Uncontrolled activation of neutrophils can cause tissue damage and contribute to chronic inflammatory diseases.
The document discusses immunological tolerance and its breakdown which can lead to autoimmunity and autoimmune diseases. It explains the mechanisms of central and peripheral tolerance that normally prevent immune responses against self-antigens. Failure of these tolerance mechanisms can occur through various causes like a breakdown of T cell anergy or loss of regulatory T cells, resulting in an immune response against self-tissues and the development of autoimmune conditions.
This is a PowerPoint presentation of DIF in Dermatology and its clinical importance. This PPT is made by Dr. Jerriton Brewin, 1st year PG in DVL at SVMCH, Pondy.
This document discusses mast cells, including their role in health and disease. It begins by describing mast cell activation through IgE receptors or other stimuli, which causes the release of mediators like histamine. These mediators contribute to wound healing, angiogenesis, and defense against infection. However, mast cell activation also causes immediate hypersensitivity reactions and exacerbates conditions like arthritis and coronary disease. The document concludes by discussing mast cell disorders like mastocytosis.
This document discusses the structure and function of desmosomes, which are the major cellular structures that maintain cell-cell adhesion in the epidermis. Desmosomes are composed of three major protein families: plakins (including desmoplakin), armadillo proteins, and desmosomal cadherins. Desmoplakin links the desmosomal cadherins to the keratin intermediate filaments inside the cell. Mutations in desmosomal proteins can cause skin fragility disorders and cardiomyopathies. The document also briefly summarizes other epidermal junctional complexes including adherens junctions, tight junctions, and gap junctions.
This document summarizes key information about Toll-like receptors (TLRs):
- TLRs are pattern recognition receptors that recognize pathogens and activate immune responses. They play a role in both innate and adaptive immunity.
- TLRs recognize specific microbial ligands and signal through either MyD88-dependent or MyD88-independent pathways to induce inflammatory responses.
- Genetic variations in TLRs have been linked to susceptibility or resistance to various diseases like leprosy, tuberculosis, and cancer. Targeting TLR pathways may offer therapeutic approaches for neurological diseases like Alzheimer's disease.
This document summarizes the key stages in B-lymphocyte maturation, generation, and activation. It discusses how B cells develop from progenitor cells in the bone marrow, where they undergo antigen-independent maturation including immunoglobulin gene rearrangement and positive and negative selection to remove self-reactive cells. Mature B cells then leave the bone marrow equipped with B cell receptors. The document also describes how B cells are activated upon binding of antigen to their receptor, requiring co-stimulation by T helper cells to initiate the antibody response.
This document summarizes matrix metalloproteinases (MMPs), a family of enzymes that degrade the extracellular matrix and are involved in tissue remodeling. It groups MMPs into collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and others. For each group, it lists the MMP names and their protein substrates. It also describes two pathways for activating MMPs at the cell surface, and discusses transcriptional regulation, activation of precursors, substrate specificity, inhibitors like TIMPs and α2-macroglobulins, and classes of pharmacological MMP inhibitors.
An undergraduate lecture on immunologic tolerance, it's various types and how a breakdown of tolerance contributes to the pathogenesis of autoimmune diseases. Additionally a small quiz at the end to gauge the students' learning.
The role of matrix metalloproteinase 2 (mmp 2Feng-wei Yeh
The document discusses the role of matrix metalloproteinase 2 (MMP-2) in chronic periodontitis. MMP-2 degrades extracellular matrix proteins and collagen fibers. Due to its gelatinase function, MMP-2 may be associated with tooth mobility caused by periodontitis. Smoking is a major risk factor for chronic periodontitis by worsening inflammation. Tetracycline and doxycycline can inhibit MMPs and reduce periodontal inflammation by functioning as tissue inhibitors of metalloproteinases.
The role of matrix metalloproteinase 2 Feng-wei Yeh
This document discusses the role of matrix metalloproteinase 2 (MMP-2) in chronic periodontitis. MMP-2 is a gelatinase found in gingival crevicular fluid and periodontal tissue that can degrade proteins and collagen fibers. Increased levels of MMP-2 may be associated with the symptoms of chronic periodontitis such as inflammation, tissue destruction, and tooth mobility. Quantifying MMP-2 levels in gingival crevicular fluid could help diagnose chronic periodontitis and monitor the effects of treatment. Natural compounds that inhibit MMP-2 may offer alternative therapies to antibiotics for treating chronic periodontitis.
1) The study examined the role of MMP-2 in astrocytoma growth and found that MMP-2 surprisingly attenuates brain tumour growth, in contrast to previous beliefs.
2) MMP-2 was found to promote macrophage recruitment and vascular repair in brain tumours, limiting their growth. Lack of MMP-2 reduced macrophage recruitment and promoted tumour growth.
3) MMP-2 is not involved in vascular destabilization commonly associated with malignant brain tumours, but rather is part of a tissue repair response that constrains tumour growth. Therefore, MMP-2 is not a suitable target for brain cancer treatment.
Molecular Mechanisms in Urothelial Cancer – Invasiveness: Systems Approach
This document discusses molecular pathways involved in the progression of urothelial carcinoma from non-invasive to invasive stages. It describes alterations in key pathways such as p53 and Rb that control cell cycle regulation and apoptosis. Proteases like MMPs degrade the extracellular matrix and promote angiogenesis, facilitating tumour invasion and metastasis. The interactions between pathways that regulate the extracellular environment, cell proliferation and cell death determine the invasiveness of urothelial carcinoma.
1) Neutrophil-derived MMP-9, when not complexed with TIMP-1, promotes both physiological angiogenesis and tumor-induced angiogenesis in avian and mouse models.
2) MMP-9 derived from tumor cells or other cell types is usually complexed with TIMP-1 and does not induce angiogenesis, but neutrophil MMP-9 can rescue dampened tumor angiogenesis.
3) Neutrophil MMP-9 may facilitate tumor metastasis by enhancing tumor angiogenesis and making FGF-2 bioavailable, thereby promoting processes in the metastasis cascade like intravasation.
This document summarizes research on estrogen and cancer. It discusses the three main forms of estrogen, their molecular mechanisms of action, and role in carcinogenesis. Estrogen exerts its effects by binding to estrogen receptors, and can influence genes related to cell proliferation, apoptosis, and angiogenesis. Main cancer therapies that target estrogen include selective estrogen receptor modulators (SERMs) like tamoxifen and aromatase inhibitors. Resistance to these therapies can develop through various molecular changes. Future areas of research include exploring other cancer types that may be treated with anti-estrogen therapies and identifying new drug targets.
Id4 suppresses MMP2-mediated invasion of glioblastoma-derived cells by direc...Ahmad Usama
Id4 expression suppresses glioblastoma invasion by directly inhibiting Twist1 function. The study found that Id4 overexpression in glioblastoma cell lines attenuated cellular invasion without affecting motility. Id4 was shown to regulate expression of MMP2, a matrix metalloproteinase involved in invasion, by forming an inhibitory complex with Twist1, preventing it from binding to and activating the MMP2 promoter. High Id4 expression in glioblastoma patients correlated with improved overall and disease-free survival and inversely correlated with MMP2 expression. The study demonstrates a novel mechanism where Id4 inhibits glioblastoma invasion by disrupting Twist1 activation of MMP2.
Pediatric soft tissue lesions/certified fixed orthodontic courses by Indian d...Indian dental academy
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
RECENT ADVANCES IN TREATMENT OF NEOPLASMS IN ANIMALSAjjanagi Bhimappa
Recent advances in treatment of neoplasms in animals include surgery, radiation therapy, immunotherapy, chemotherapy, and other targeted therapies. Surgery remains a primary treatment and can be curative for early stage localized tumors. Radiation therapy provides local control for certain tumor types. Immunotherapy seeks to stimulate the immune system to attack tumors and includes vaccines, cytokines, and other immunomodulators. Chemotherapy utilizes cytotoxic drugs to damage rapidly dividing tumor cells. Newer targeted therapies are also showing promise for some cancers. Effective treatment often requires a multi-modal approach tailored to each individual patient and tumor characteristics.
Pitfalls in diagnosis of soft tissue tumors of childhoodSonic V S
The document discusses several potential pitfalls in the diagnosis of soft tissue tumors in children. It covers:
1) Misclassification of specific sarcomas like rhabdomyosarcoma subtypes and non-rhabdomyosarcoma soft tissue sarcomas.
2) Benign lesions that can be misdiagnosed as sarcomas, and sarcomas that can be misdiagnosed as benign.
3) Misgrading the aggressiveness of sarcomas.
4) Non-soft tissue tumors that are sometimes misdiagnosed as soft tissue sarcomas. Careful histology, immunohistochemistry, cytogenetics and molecular analysis are needed to arrive at
5. Carcinoid Tumour Biochemical And Radiological Testingensteve
Carcinoid tumours are rare, slow-growing neuroendocrine tumours that can be detected through biochemical markers like 5-HIAA and chromogranin A in urine and blood, as well as through various radiological imaging techniques. Common imaging methods discussed are 111In-pentetreotide scintigraphy, MIBG scintigraphy, CT, MRI, ultrasound, and newer techniques like PET scans using different tracers. Biochemical markers and radiological imaging can help detect primary tumours, metastases, and monitor treatment response.
Dr. Natasha Tiffany has nearly a decade of experience treating cancer patients with targeted therapies as a physician at Hematology Oncology of Salem. Targeted therapy utilizes either antibody drugs that mimic immune system proteins targeting cancer cells or smaller molecule drugs, and has become a major resource in cancer treatment. Some examples of targeted therapy drugs include Gleevec, which is used to treat gastrointestinal stromal tumors and certain leukemias, Iressa for non-small-cell lung cancer with epidermal growth factor receptor mutations, and Sutent and Velcade for kidney cancer and multiple myeloma respectively.
Gene therapy is an experimental technique that uses genes to treat disease by inserting genes into patients' cells instead of using drugs or surgery. Recent research has shown promising advances in gene therapy to treat various diseases. However, gene therapy still faces technical challenges such as safely delivering genes to target cells and tissues, potential immune responses, and difficulty treating complex multigenic disorders. While still experimental, gene therapy offers hope for treating currently incurable conditions.
This document discusses host modulation therapies for the treatment of periodontal disease. It first introduces concepts of host modulation and describes how therapies aim to downregulate destructive aspects of the host inflammatory response. A major focus is on matrix metalloproteinases (MMPs), which degrade connective tissue during periodontal disease. The document outlines various stages of MMP inhibition that could be targeted therapeutically, including inhibiting MMP induction, activation of latent MMPs, and upregulating natural MMP inhibitors. It provides extensive details on the mechanisms and clinical studies of sub-antimicrobial doses of doxycycline, one of the few approved host modulation drugs for treating periodontitis.
Carcinoid tumors arise from neuroendocrine cells in the gastrointestinal tract. They most commonly occur in the appendix, ileum, and rectum. While often asymptomatic, they may secrete serotonin and cause carcinoid syndrome in rare cases. Diagnosis involves urinary tests for serotonin metabolites and imaging exams. Treatment of localized tumors is surgical resection, while metastatic tumors may also require chemotherapy. Prognosis is generally good if the tumor is localized but worsens with increased size and spread.
This document discusses neuroendocrine tumors (NETs), which arise from neuroendocrine cells derived from neural crest cells. NETs were previously called APUDomas and carcinoids but are now classified as neuroendocrine gastroenteropancreatic tumors. Specific NETs discussed include insulinomas, glucagonomas, gastrinomas, vipomas, and somatostatinomas. Diagnosis and treatment options are described for each tumor type. The document also covers carcinoid syndrome, typical and atypical carcinoid tumors, and treatment approaches for NETs such as surgery, medical therapy, peptide receptor radionuclide therapy, and hepatic artery embolization.
Introduction to Targeted Therapies in OncologyMohamed Abdulla
Describes the molecular background which represents the core for developing targeted therapies against specific biological events in malignant cellular clones.
This document discusses targeted cancer therapy and provides several examples. It compares chemotherapy to targeted therapy, noting targeted therapy drugs inhibit more specific targets and include many oral agents. Examples discussed include Gleevec for CML targeting BCR-ABL fusion, EGFR mutations in lung cancer treated by drugs like Iressa, ALK rearrangements in lung cancer treated by crizotinib, BRAF mutations in melanoma treated by vemurafenib, and HER2-positive breast cancers treated by Herceptin. New immunotherapies and antibody-drug conjugates are also mentioned.
This document discusses host modulation therapy for treating periodontal disease. It defines host modulation therapy as aiming to reduce tissue destruction and stabilize or regenerate the periodontium by modifying the host response. Host modulation therapies are pharmaceuticals that are prescribed as adjuncts to conventional treatments like scaling and root planing. Both systemically and locally administered agents are discussed that can restore the balance between proinflammatory and antiinflammatory mediators in periodontal diseases.
1. Metaloproteinases (MMPs) are enzymes that maintain and degrade the extracellular matrix during tissue repair and remodeling. MMPs participate in wound healing, angiogenesis, and cancer metastasis.
2. MMPs are classified into subgroups based on their protein targets, such as collagens, gelatinases, and matrilysins. They have domains for signaling, catalytic activity, and substrate binding.
3. MMP activity is regulated by tissue inhibitors of metalloproteinases (TIMPs) and imbalanced MMP/TIMP expression contributes to cancer progression and metastasis by continuously remodeling the extracellular matrix.
This document discusses a study examining the role of metallothionein-I/II (MT-I/II) in promoting axonal regeneration in the central nervous system after injury. The key findings are:
1) MT-I/II can overcome inhibition by myelin and myelin-associated glycoprotein (MAG) to promote neurite outgrowth from cortical, hippocampal and dorsal root ganglion neurons in vitro.
2) Intrathecal delivery of MT-I/II to dorsal root ganglion neurons promotes neurite outgrowth in the presence of MAG.
3) Mice deficient in MT-I/II show reduced neurite outgrowth on MAG and fail to regener
Regulation of Glycolysis downstream of mTOReadvisor
The document discusses regulation of glycolysis downstream of mTOR. It notes that activation of the PI3K/AKT/mTOR pathway leads to increased cell growth and proliferation by increasing glucose uptake and glycolysis. Cancer cells upregulate key glycolytic enzymes and switch to the M2 isoform of pyruvate kinase, which differs from isoforms expressed in normal adult tissues. The M2 isoform preferentially binds to phosphorylated tyrosine residues and its expression is important for cell growth.
This study investigated the relationship between MMP-9, TIMP-1, and sialic acid (NANA) in a human glial cell line and the effects of NANA on the expression of these genes. The study found that NANA upregulated the expression of both MMP-9 and TIMP-1 at lower concentrations in a way that maintained the MMP-9/TIMP-1 balance. However, at higher concentrations of 1000μM NANA, MMP-9 expression was upregulated to a significantly greater degree than TIMP-1 expression, causing an imbalance similar to reports in neurodegenerative diseases. This suggests NANA may be involved in signaling pathways regulating the expression of these genes linked to neuroinfl
1. Metaloproteinase matriks-2 (MMP-2) is a zinc-dependent endopeptidase encoded by the MMP2 gene that degrades gelatin, collagen types IV, V, VII, IX and X, and plays a role in tissue remodeling.
2. MMP-2 is secreted as an inactive proenzyme and can be activated extracellularly by proteases or intracellularly via S-glutathiolation without protease removal of its prodomain.
3. Mutations in the MMP2 gene have been associated with Winchester syndrome and Nodulosis-Arthropathy-Osteolysis syndrome.
Discuss the concept and rationale of host modulationOdeyemiKolade
This document discusses host modulation therapy for periodontal disease. It defines host modulation therapy as aiming to reduce tissue damage and stabilize or regenerate the periodontium by modifying destructive and upregulating protective host responses. It outlines various concepts of HMT, including targeting proinflammatory cytokines, matrix metalloproteinases, and arachidonic acid metabolites. Classes of HMT agents that act on these targets are described, including nonsteroidal anti-inflammatories, tetracyclines, and cytokine antagonists.
1) p53 activation through nutlin-3a treatment suppressed M2 macrophage polarization by downregulating M2 marker genes like c-MYC, IRF4 and FIZZ1.
2) Loss of p53 increased M2 macrophage polarization both in vitro and in vivo by increasing the expression of M2 marker genes.
3) p53 was found to suppress M2 macrophage polarization by directly binding to the promoter region of c-MYC gene, reducing its expression and influencing the expression of downstream M2 genes.
I. The document summarizes research on matrix metalloproteinases (MMPs), a family of enzymes that degrade extracellular matrix and participate in vascular remodeling. It discusses 12 MMPs and their roles in atherosclerotic plaque development and rupture.
II. Studies have shown several MMPs (MMP-1, -2, -3, -9, -12) present in atherosclerotic plaques and implicated in plaque development and rupture. MMP-8 was also found to be associated with collagen degradation in plaque shoulders, a site of rupture.
III. The document concludes that MMP-3 and its inhibitor, TIMP-3, are overexpressed in aneurysmal aorta, suggesting inhibition of MMP3
I. The document summarizes research on matrix metalloproteinases (MMPs), a family of enzymes that degrade extracellular matrix and participate in vascular remodeling. It discusses 12 MMPs and their roles in atherosclerotic plaque development and rupture.
II. Studies have shown several MMPs (MMP-1, -2, -3, -9, -12) present in atherosclerotic plaques and implicated in plaque development and rupture. MMP-8 was also found to be associated with collagen degradation in plaque shoulders, a site of rupture.
III. The document concludes that MMP-3 and its inhibitor, TIMP-3, are overexpressed in aneurysmal aorta, suggesting inhibition of MMP3
I. The document summarizes research on matrix metalloproteinases (MMPs), a family of enzymes that degrade extracellular matrix and participate in vascular remodeling. It discusses 12 MMPs and their roles in atherosclerotic plaque development and rupture.
II. Studies have shown several MMPs (MMP-1, -2, -3, -9, -12) present in atherosclerotic plaques and implicated in plaque development and rupture. MMP-8 was also found to be associated with collagen degradation in rupture-prone shoulder regions of plaques.
III. The document concludes that MMP-3 and its inhibitor, TIMP-3, are overexpressed in aneurysmal aorta, suggesting inhibition of
Immunomodulators can stimulate or suppress the immune system. There are several classes of immunomodulators including glucocorticoids, calcineurin inhibitors, antiproliferatives, and biologicals. Glucocorticoids have broad anti-inflammatory effects and work by binding to receptors that regulate gene transcription. Calcineurin inhibitors like tacrolimus and cyclosporine inhibit T cell activation. Antiproliferatives such as azathioprine, mycophenolate mofetil, and methotrexate inhibit lymphocyte proliferation. Biologicals include monoclonal antibodies that target specific molecules. Immunomodulators are used to prevent transplant rejection and treat autoimmune disorders but can have side
The document discusses several studies related to atherosclerosis and cardiovascular disease:
1) A study finds that a polymorphism in the Fas gene promoter region is a genetic risk factor for myocardial infarction by modulating Fas expression.
2) Immunoglobulin treatment suppresses atherosclerosis in mice via its Fc portion by reducing macrophage accumulation in lesions.
3) Inhibition of NF-kB reduces inflammatory molecule expression and attenuates atherosclerosis in mice.
4) MMP-8 may represent a new collagenolytic pathway in acute plaque disruption based on its levels in carotid plaques from patients.
This document summarizes the development of cardiac mesoderm from lateral plate mesoderm. It discusses how signaling pathways like BMP, Wnt, and noggin regulate this process through inhibition and activation of genes. BMP activates Mesp1, which inhibits Wnt and allows cardiac mesoderm to form. Noggin inhibits BMP to allow mmp-3 to activate cardiac genes. The current model has gaps, like how noggin increases mmp-3. Future experiments aim to fill these gaps, like seeing cardiogenesis without BMP or noggin.
Canine oncoprotein targets for Melanoma, Breast Cancer, OsteosarcomaSnehal Salunkhe
We can acquire the basic knowledge about canine oncoprotein targets specifically for Melanoma, Osteosarcoma and Breast cancer. I haven't mentioned all the proteins and their targets involved, but just a general overview of these targets with the drugs involved in their treatment/clinical trials.
DNA methylation is an epigenetic mechanism that involves the addition of a methyl group to cytosine residues in DNA. It is catalyzed by DNA methyltransferase enzymes and plays a key role in gene expression and cellular differentiation. Aberrant DNA methylation, including both hypermethylation and hypomethylation, has been associated with cancer development by disrupting gene expression. Detection of DNA methylation patterns can provide insights into cancer biology and may have applications as a diagnostic tool.
This document provides an overview of the host immune response to microbial pathogens, focusing on periodontal bacteria. It discusses how microbe-associated molecular patterns (MAMPs) from bacteria are recognized by pattern recognition receptors (PRRs) like Toll-like receptors (TLRs) and Nucleotide-binding oligomerization domain-like receptors (NLRs). TLR2, TLR4, and TLR9 recognize bacterial lipoproteins, lipopolysaccharide, and CpG-DNA, respectively. NLRs like NOD1 and NOD2 detect peptidoglycan. This interaction stimulates proinflammatory cytokine production and activates innate and adaptive immunity. Recognition of MAMPs is important for the host
Immunosuppressive drugs used to treat transplant rejection include calcineurin inhibitors like cyclosporine and tacrolimus, mTOR inhibitors like sirolimus and everolimus, anti-proliferatives like azathioprine and mycophenolic acid, corticosteroids like prednisolone and hydrocortisone, and antibodies like the monoclonal anti-IL-2Rα receptor antibodies basiliximab and daclizumab or polyclonal anti-T-cell antibodies like anti-thymocyte globulin. The IL-2 receptor antagonist daclizumab is approved for use in renal, cardiac transplant, and multiple sclerosis.
Melatonin is a hormone produced in the body that regulates sleep cycles. It is produced in the pineal gland and levels rise at night in response to darkness. As a supplement, melatonin is used to treat sleep disorders like jet lag or shift work disorder by helping to realign the body's circadian rhythm. It may also help with sleep quality, headaches, and depression. While generally safe at low doses, melatonin can cause side effects like drowsiness if taken too close to bedtime or in high amounts.
This slide is special for master students (MIBS & MIFB) in UUM. Also useful for readers who are interested in the topic of contemporary Islamic banking.
Exploiting Artificial Intelligence for Empowering Researchers and Faculty, In...Dr. Vinod Kumar Kanvaria
Exploiting Artificial Intelligence for Empowering Researchers and Faculty,
International FDP on Fundamentals of Research in Social Sciences
at Integral University, Lucknow, 06.06.2024
By Dr. Vinod Kumar Kanvaria
How to Manage Your Lost Opportunities in Odoo 17 CRMCeline George
Odoo 17 CRM allows us to track why we lose sales opportunities with "Lost Reasons." This helps analyze our sales process and identify areas for improvement. Here's how to configure lost reasons in Odoo 17 CRM
LAND USE LAND COVER AND NDVI OF MIRZAPUR DISTRICT, UPRAHUL
This Dissertation explores the particular circumstances of Mirzapur, a region located in the
core of India. Mirzapur, with its varied terrains and abundant biodiversity, offers an optimal
environment for investigating the changes in vegetation cover dynamics. Our study utilizes
advanced technologies such as GIS (Geographic Information Systems) and Remote sensing to
analyze the transformations that have taken place over the course of a decade.
The complex relationship between human activities and the environment has been the focus
of extensive research and worry. As the global community grapples with swift urbanization,
population expansion, and economic progress, the effects on natural ecosystems are becoming
more evident. A crucial element of this impact is the alteration of vegetation cover, which plays a
significant role in maintaining the ecological equilibrium of our planet.Land serves as the foundation for all human activities and provides the necessary materials for
these activities. As the most crucial natural resource, its utilization by humans results in different
'Land uses,' which are determined by both human activities and the physical characteristics of the
land.
The utilization of land is impacted by human needs and environmental factors. In countries
like India, rapid population growth and the emphasis on extensive resource exploitation can lead
to significant land degradation, adversely affecting the region's land cover.
Therefore, human intervention has significantly influenced land use patterns over many
centuries, evolving its structure over time and space. In the present era, these changes have
accelerated due to factors such as agriculture and urbanization. Information regarding land use and
cover is essential for various planning and management tasks related to the Earth's surface,
providing crucial environmental data for scientific, resource management, policy purposes, and
diverse human activities.
Accurate understanding of land use and cover is imperative for the development planning
of any area. Consequently, a wide range of professionals, including earth system scientists, land
and water managers, and urban planners, are interested in obtaining data on land use and cover
changes, conversion trends, and other related patterns. The spatial dimensions of land use and
cover support policymakers and scientists in making well-informed decisions, as alterations in
these patterns indicate shifts in economic and social conditions. Monitoring such changes with the
help of Advanced technologies like Remote Sensing and Geographic Information Systems is
crucial for coordinated efforts across different administrative levels. Advanced technologies like
Remote Sensing and Geographic Information Systems
9
Changes in vegetation cover refer to variations in the distribution, composition, and overall
structure of plant communities across different temporal and spatial scales. These changes can
occur natural.
This presentation includes basic of PCOS their pathology and treatment and also Ayurveda correlation of PCOS and Ayurvedic line of treatment mentioned in classics.
বাংলাদেশের অর্থনৈতিক সমীক্ষা ২০২৪ [Bangladesh Economic Review 2024 Bangla.pdf] কম্পিউটার , ট্যাব ও স্মার্ট ফোন ভার্সন সহ সম্পূর্ণ বাংলা ই-বুক বা pdf বই " সুচিপত্র ...বুকমার্ক মেনু 🔖 ও হাইপার লিংক মেনু 📝👆 যুক্ত ..
আমাদের সবার জন্য খুব খুব গুরুত্বপূর্ণ একটি বই ..বিসিএস, ব্যাংক, ইউনিভার্সিটি ভর্তি ও যে কোন প্রতিযোগিতা মূলক পরীক্ষার জন্য এর খুব ইম্পরট্যান্ট একটি বিষয় ...তাছাড়া বাংলাদেশের সাম্প্রতিক যে কোন ডাটা বা তথ্য এই বইতে পাবেন ...
তাই একজন নাগরিক হিসাবে এই তথ্য গুলো আপনার জানা প্রয়োজন ...।
বিসিএস ও ব্যাংক এর লিখিত পরীক্ষা ...+এছাড়া মাধ্যমিক ও উচ্চমাধ্যমিকের স্টুডেন্টদের জন্য অনেক কাজে আসবে ...
3. MMPs have following functional characteristics: Proteinases that degrade at least one component of the extracellular matrix Contain a zinc ion & are inhibited by chelating agents Secreted in latent form, requiring activation for proteolytic activity Inhibited by tissue inhibitors of metalloproteinases (TIMPs) Share common amino acid sequences
5. Increase in research activity pertaining to MMPs & A disintegrin & metalloproteinases (ADAMs), in nervous system Implicated in myriad of neurological conditions, & also associated with important neurophysiological functions, including synaptic remodeling & long-term potentiation (LTP) More recently, demonstration that MMPs regulate neural stem cell biology & remyelination suggests their importance in regeneration of nervous system MMPs & ADAMs are important in neuroinflammation, & recently they are linked to neurodegenerative disorders
8. GENERAL PROPERTIES OF MMPs There are 24 mammalian MMP members (MMP1–28), each product of different gene MMP4–6 are no longer used,MMP18 only been cloned from Xenopus, MMP22 is present in chickens & two versions of human MMP23 These can be subdivided on basis of domain structure With exception of the six membrane-type MMPs (MT-MMPs), MMP family members are generally secreted from cells
9.
10. Signal peptide & propeptide region form part of cysteine switch, which folds over zinc in catalytic site & maintains latent state Cleavage site enables proconvertase furin to activate MMP by cleaving propeptide FN binding site is present in MMP2 & 9, connecting them with basal lamina. Catalytic zinc site is present in all MMPs Haemopexin domain is joined to catalytic site by hinge region. MMP14 (an MT-MMP) has TMD
11. Collagenases Key feature is ability to cleave interstitial collagens I, II, and III at a specific site three-fourths from N-terminus It can also digest number of other ECM & non-ECM molecules Gelatinases Gelatinase A (MMP-2) & gelatinase B (MMP-9) digest denatured collagens, gelatins & no. of ECM including native type IV, V, XI collagen, laminin Stromelysins Besides digesting ECM components, MMP-3 activates a number of proMMPs, & its action on partially processed proMMP-1 is critical for generation of fully active MMP-1
12. Matrilysins Matrilysin 1 (MMP-7) & matrilysin 2 (MMP-26), also called endometase, are in this group Besides ECM components, MMP-7 processes cell surface molecules such as pro–-defensin, Fas-ligand, pro–tumor necrosis factor (TNF)-, & E-cadherin to generate soluble forms hence acting as ‘sheddases’ Membrane-Type MMPs (6) 4 are type I transmembrane proteins (MMP-14,15, 16,& 24),& 2 are GPI anchored proteins (MMP-17 & 25) With exception of MT4-MMP, all capable of activating proMMP-2 & digest number of ECM molecules, & MT1-MMP has collagenolytic activity on type I, II, & III collagens
13. ADAMs Transmembrane proteins that bind to integrins & important in intracellular signaling & cell adhesion Chara. function - proteolytic processing of membrane-anchored precursors & subsequent release of mature proteins .This process is referred to as ‘protein ECTODOMAIN SHEDDING’ Proteins modulated include cell-surface receptor Notch & its ligand Delta, important in CNS development, amyloid precursor protein implicated in AD(ADAM-10 an α- secretase) ,TNF-α (ADAM-17 known as TACE- TNF-α converting enzyme), & ligands of EGF receptor ADAMs are implicated in cellular proliferation, migration, differentiation, & survival, in axonal growth & myelination
14.
15. TIMPs TIMPs are small proteins & these enzymes are codified by highly conserved genes and have overlapping functions Four TIMPs have been identified TIMPs are inhibitory against most MMPs with some predilections: TIMP1 inhibits MMP9, TIMP2 inhibits MMP2 &, paradoxically, contributes to activation of pro-MMP2 TIMP3 has role in cellular growth, cellular death, & tissue repair
19. Activation of ProMMPs MMPs can be activated by proteinases or in vitro by chemical agents, such as thiol-modifying agents Activation of proMMPs by plasmin is relevant in vivo Activated MMPs can participate in processing other MMPs Fine regulatory mechanisms to control destructive enzymes, TIMPs may interfere with activation by interacting with intermediate MMP before it is fully activated
24. MMPs regulate CNS development – MMP’s are expressed during nervous system ontogeny & CNS abnormalities occur when their activity is perturbed or impaired In particular role in neurogenesis ,angiogenesis, development of oligodendrocytes & myelin MMPs have beneficial role in healthy CNS - Within adult CNS MMPs function in remodeling ECM. ECM will in turn regulate cell migration & survival Neurons remodel their synaptic connections in response to various stimuli. Synaptic environment including ECM , play imp role in neuronal plasticity & learning & memory
25.
26. 3. MMPs in repair of adult CNS – It is important that following initial & likely detrimental up regulation of several MMPs after injury, delayed, subtle & restricted expression of specific MMPs have beneficial role MMP-9 expressed 7 days after demyelinating insult to the spinal cord of mice promotes maturation of oligodendrocytes & their formation of myelin Delayed expression of MMP-2 after traumatic spinal cord is necessary for ECM remodeling & functional recovery.
29. Neuroinflammation CNS injury initiates cascade of events defined as neuroinflammation Cytokine & chemokine response associated with production of free radicals & proteases TNFα, interleukin 1β, & chemokines, are implicated and tissue responses differ with specific Injury Factors that affect outcome of inflammatory process include presence of hypoxia–ischemia, duration of injury, presence of infection & types of cells involved
30.
31. MMPs in hypoxia–ischemia Basal lamina around cerebral blood vessels contains ECM proteins, including laminin, fibronectin, heparan sulphate, & type IV collagen Proteolysis of BBB by MMPs results in loss of basal lamina proteins, which increases the risk of hemorrhage MMP2, MMP3, and MMP9 increase permeability of BBB. Inhibitors of MMPs can reduce damage to BBB In ischemia with reperfusion, MMPs are induced & disrupt BBB; for instance, in Mmp9 knockout model, focal ischemic lesions decreased the damage to the blood–brain barrier & infarct size
32.
33. MMP In autoimmune disorder & infection Immunological or infectious pathogen, main injury site is blood vessels alone. Whenever BBB is affected, MMP9 is key factor in injury process Exacerbation of acute MS increases MMP9 concentrations in CSF & treatment with steroid reduces MMP9 concentrations Treatment with MMP inhibitor GM-6001 suppresses development of clinical experimental allergic encephalomyelitis in mice In rats with experimental allergic neuritis, a broad spectrum MMP inhibitor, BB-1101, which also inhibits TACE, reduces damage to nerves
34. Metalloproteinases regulate myelinogenesis. A. MMP9/12 in maturation of oligodendrocytes precursor cells to oligodendrocytes & extension of their processes MMP9 and 12 are known to influence myelin formation during development, this is achieved through effect of these MMPs on bioavailability ofIGF1. IGFBP6,. B. Demyelination in adult mouse spinal cord, MMP9 regulates remyelination. mechanism is clearance of NG2 proteoglycans, which constitutes an inhibitory barrier for maturation of oligodendrocytes & their subsequent reformation of myelin.
37. MMP in vascular cognitive impairment MMPs are induced by hypoxic hypoperfusion in white matter During hypoxia, HIF1α increases, leading to expression of many genes implicated in injury & repair Furin contributes to activation of MMPs implicated in injury HIF1α stimulates expression of substances that mediate repair, including VEGF & TGFβ In rat model of VCI , hypoxic hypoperfusion induces MMPs & thus increases permeability of BBB in white matter
38. Possible mechanism for white matter injury in vascular cognitive impairment HIF1α concentration, turns on cassettes of genes associated with injury such as FURIN, & increases expression of VEGF and TGFβ, which are important in repair. Furin leads to activation of MMP2 through activation of MT-MMP. MMP2 can disrupt tight junction proteins & open the BBB, leading to edema. Edema might also cause demyelination. Additionally, MMP2 might attack myelin and can activate endothelin 1, which causes vasoconstriction through calcium metabolism in small muscle. Vasoconstriction aggravates hypoxic state. Conversely, on the repair side, VEGF and TGFβ activate angiopoietin 2, which acts through the secretion of MMPs to initiate angiogenesis and neurogenesis.
39. (E) Immunostaining with antibodies to MMP3 detects an immunoreactive astrocytes (arrow). (F) Immunostaining with antibodies to MMP3 detects an MMP3-positive macrophage around a fibrotic blood vessel in demyelinated area (arrow).
40. MMPs & ADAMs in AD MMPs participate in formation & clearance of amyloid-β peptides (Aβ) MMPs are induced endogenously by amyloid molecules in blood vessels, astrocytes, & microglia Astrocytes exposed to Aβ1-40 secrete MMP2,3 & 9 When Aβ is deposited in tissues around plaques, there is activation of microglia & astrocytosis, this inflammatory response might contribute to neuronal Death Increase in expression of MMPs in brain tissue & blood of patients with AD is probably part of inflammatory response
41. ADAMs are part of α- secretase α-secretase cleaves APP molecule, soluble fragment of APP is produced (APPsα), which can be further metabolized by proteases & cleared from brain across BBB. However, if β-secretase initiates cleavage of APP to form interim product that γ-secretase cleaves, then the Aβ molecule is formed. Most common form of Aβ is Aβ1-40, which is degraded by MMPs cleared through BBB : a smaller amount of Aβ1-42 is formed, but this can clump into fibrils that accumulate in amyloid plaques. MMP2 and MMP9 degrade Aβ & aid in its clearance from brain across BBB. Furthermore, microglia are activated by Aβ, adding to the amount of MMP9 available. Aβ=am
42. MMPs in Parkinson’s disease In vitro, apoptotic dopaminergic neurons release MMP3, which activates microglia , suggesting that, MMP3 is signalling molecule in addition. TNFα released from microglia leads to neuronal death; Primary mouse mesencephalic cells in culture die when treated with BH4 (tetrahydrobiopterin), selective dopaminergic neuronal toxin; treatment with MMP3 inhibitor NNGH (N-isobutyl-N-[4-methoxyphenylsulfonyl]-glycylhydroxamic acid) prolongs cell survival by decreasing TNFα release from activated microglia.
44. At least 3 factors contribute Stage of CNS injury – it is likely that in early phase after insult, when many metalloproteinases are induced or released into milieu that normally has low levels of protease MMPs are detrimental Indeed, in rodents, early & short-term treatment (for 3 days) of spinal cord injury or intracerebral hemorrhage with metalloproteinase inhibitors attenuates extent of neurotoxicity & subsequent loss of function More latterly after injury, when metalloproteinases are expressed discreetly and locally
45. Type of injury inflicted Type of injury affects profile of inflammatory cells at injury site & available MMP substrates expressed in that microenvironment chronic diseases such as MS & EAE entail significant representation by T lymphocytes, which promote inflammation & neurotoxicity, whereas in acute spinal cord injury, injury site is infiltrated with neutrophils & macrophages rather than T cells In different cellular contexts, & with differences in gene expression in these cell types, substrates for,& functions of, MMP differ
46. 3. Pathophysiology of disorder involved In EAE, recovery from disease depends on switch of CD4+ T lymphocytes from proinflammatory Th1 subset to Th2 environment in order for inflammation to subside MMP12 may be required for this switch,& its absence results in animals with more inflamed CNS & greater EAE severity By contrast, in cord injury, which represents insult less dependent on T cells, MMP12 may not be required to alter this ratio Rather, MMP12 expression increases activation of microglia/ macrophages, which exacerbate damage to injured cord
50. MMP inhibitors Early recognition that excessive MMP expression contributes to diseases such as cancer led to active development of inhibitors One of first hydroxamates developed was batimastat (BB94). Marimastat second generation hydroxamate with increased bioavailability after oral intake,& has been tested in gliomas Tetracycline antibiotics inhibits MMP enzymatic activity has led to use of these & chemically modified tetracyclines without anti-microbial activity (CMTs) as MMP inhibitors Only compound approved for use based on its ability to inhibit MMPs is low-dose doxycycline formulation, Periostat
52. One of most potent tetracyclines to inhibit gelatinases, is minocycline. minocycline in EAE reduces disease activity Minocycline was found to reduce relapse rate & gad enhancing MRI lesions in pilot trial in RRMS CMT as MMP inhibitors acts by binding Zn2+ &Ca2+, latter being required to maintain proper enzyme conformation CMTs also down regulate expression of MMPs, & to decrease oxidative activation of pro-MMPs into active enzymes Statins, are also described to reduce production of MMPs by cells or to inhibit MMP activity
56. Antibodies to MMPs & broad-spectrum MMP inhibitors, BB-94, 1101, & GM-6001, reduce BBB damage, infarct size, & cell death Protect brain from hemorrhagic complications of alteplase by reducing permeability of BBB & preventing alteplase from entering brain & activating MMPs MMP inhibitors in stroke needs to be given early in first few days after injury to prevent blocking recovery phase MRI has shown in rats that, although BB-1101 blocked early opening of BBB at 3hr after 90-min MCA occlusion with reperfusion, inhibitor had no effect on lesion size at 48 h, & recovery over 3 weeks was slowed
59. MMP inhibitors were beneficial in animal studies of MS,GBS , meningitis & vascular dementia MMPs in bacterial meningitis contribute to damage seen in children with meningitis despite use of appropriate antibiotics Water-soluble inhibitor of MMPs & TACE, TNF-484, is effective in animals Doxycycline blocks secondary damage in experimental bacterial meningitis in rodents Doxycycline has been used in treatment of MMP-mediated vascular diseases & reduced vascular damage in animal model
60. Even more speculative is possible use of MMP inhibitors in treatment of Alzheimer’s disease Role of MMPs & ADAMs in AD is complex because of their dual function Theoretically, treatment with MMP inhibitors could impede amyloid clearance because MMP9 seems to facilitate removal of the amyloid peptides Use of MMP inhibitors in PD might show great promise as death of dopaminergic neurons seems to be associated with release of MMPs by the activated cells around them
63. Major obstacle is low specificity & poor solubility particularly those with hydroxymate base Other obstacle is poor understanding of time to initiate & time to stop treatment Need to assess beneficial & deleterious effects in detail Selective inhibition VS broad spectrum inhibition Side effects
64. CONCLUSIONS Metalloproteinases have both beneficial and detrimental functions in the CNS Issue of MMPs as causative factors in disease is active area of investigation, but their possible role as facilitators of CNS recovery needs greater consideration. Research needed to understand diverse roles of proteases to design specific drugs & devise therapeutic strategies The potential use of MMP inhibitors to treat CNS diseases is an exciting prospect, but it is important to balance risk with the benefits of this treatment