ACE2: From Renoprotection to a Potential
Therapy for Coronavirus Infection
ACE2: From Renoprotection to a Potential
Therapy for Coronavirus Infection
by Daniel Batlle MD
RAS Inhibitors in Hypertension and Heart Failure:
TRUTHS AND MISTRUTHS
OF TREATMENT IN THE
COVID-19 ERA
by J o r d y C o h e n , M D , M S C E
From Hypertension 2020 , American Heart Association
Copy RIght to Hypertension Session 2020 in American Heart Association
Human organoid are miniature sized, self-organized structures, that are derived from stem cells or tissues in culture. The progress, potential, limitations and challenges are discussed.
This document discusses potential biologic therapies for autoimmune diseases. It outlines several cytokines and pathways that are implicated in autoimmune diseases, such as IL-6, TNFα, IL-15, IL-1, and IFNβ. For each one, it describes the biological effects and evidence from animal and human studies that inhibiting these pathways may help treat diseases like rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and type 1 diabetes. The document also discusses potential new therapies targeting IL-23, cell adhesion molecules, and B cell survival factors, and concludes that biologic therapies offer the potential for specifically modulating the immune system to treat autoimmune diseases, but also carry risks of adverse effects.
For better view, press F5.
As we go through our lives each of us will have very different needs for our own healthcare.
Scientist's are constantly researching to make medical care treatment more personalized.
One way they are doing this is by-
Stem Cells therapy
Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition.
It is also known as regenerative medicine, promotes the reparative response of diseased, dysfunctional or injured tissue using stem cells or their derivatives.
It is the next chapter of organ transplantation and uses cells instead of donor organs, which are limited in supply.
What are Stem cells?
Stem cells are called “master cells”
Stem cells are cells that are undifferentiated.
What are Stem cells?
Steam cells have the potential to become all other kinds of cells in our body.
What are Stem cells?
Types of Stem cells
How stem cell therapy works?
Disease cured by stem cell therapy.
Spinal Cord Injuries
Stem cell treatment of Diabetes mellitus type 1 & 2
Stem cell treatment of Stroke
Cancer treatment
Heart damage
Baldness
Tooth implanting
Deafness and blindness
Have stem cells already been used to treat diseases?
Ethical Consideration of Stem Cell Therapy
As the research method mainly focused on Embryonic Stem Cells, which involves taking tissue from an aborted embryo to get proper material to study. This is typically done just days after conception or between the 5th and 9th week.
Since then, researchers have moved on to more ethical study methods, such as Induced Pluripotent Stem Cells (iPS). iPS is artificially derived from a non-pluripotent cell, such as adult somatic cells.
Nowadays stem cell treatment has been spreaded throughout the world. It has also been grown commercially in developed countries.
It is thought that one day it may be the major key to treat various diseases.
Using stem cells to conduct medical research and treat disease is acceptable?
Don’t know
No
Yes
Do you approve of the extraction of stem cells from human embryos for medical research?
Don’t know
No
Yes
This document summarizes the structures and types of immunoglobulins. It discusses the five classes of immunoglobulins - IgG, IgM, IgA, IgD, and IgE - and their properties, including what percentage of serum each class comprises and their roles in binding antigens, fixing complement, and inducing immune responses. It also covers immunoglobulin subclasses defined by minor amino acid differences, as well as kappa and lambda light chain types.
3D In Vitro Model for Drug Efficiency Testingjudoublen
This document discusses the potential advantages of using 3D in vitro models compared to traditional 2D models for drug testing. It notes that 3D cultures more closely mimic the in vivo microenvironment and cell morphology. This allows 3D cultures to better predict cellular responses to drugs and provide more accurate models of disease. The document outlines several applications of 3D cultures, such as studying tumor development, evaluating drug sensitivity, and developing organs-on-chips microfluidic devices that model human organ functions.
Tissue Engineering is the reconstruction of cells to differential cell into the desired tissue or organ in an attempt to improve their structural functions.
Regenerative medicine is an aspect of tissue engineering that uses bioengineering principles to solve healthcare challenges using new innovative ideas, methods and mode of synthesis of different biomaterials construct.
Tissue Regenerative Medicine uses scaffolding development to guide cells into differentiating in to desired tissue or organ.
Scaffolding provides an extracellular matrix for the cells, this extracellular matrix serve and act as the guides for their proper differentiation. (Hynes R.O, 2009)
Other Emerging fields; Protein / Genetic / Clinical Engineering
This presentation describes in detail the various types and sources of stem cells. it also describes the stem cell therapies used to treat various diseases.
you can find out all types of VEGF in this ppt and it is about physiological and path-physiological significance of VEGF and its possible targeting manoeuvering
Human organoid are miniature sized, self-organized structures, that are derived from stem cells or tissues in culture. The progress, potential, limitations and challenges are discussed.
This document discusses potential biologic therapies for autoimmune diseases. It outlines several cytokines and pathways that are implicated in autoimmune diseases, such as IL-6, TNFα, IL-15, IL-1, and IFNβ. For each one, it describes the biological effects and evidence from animal and human studies that inhibiting these pathways may help treat diseases like rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and type 1 diabetes. The document also discusses potential new therapies targeting IL-23, cell adhesion molecules, and B cell survival factors, and concludes that biologic therapies offer the potential for specifically modulating the immune system to treat autoimmune diseases, but also carry risks of adverse effects.
For better view, press F5.
As we go through our lives each of us will have very different needs for our own healthcare.
Scientist's are constantly researching to make medical care treatment more personalized.
One way they are doing this is by-
Stem Cells therapy
Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition.
It is also known as regenerative medicine, promotes the reparative response of diseased, dysfunctional or injured tissue using stem cells or their derivatives.
It is the next chapter of organ transplantation and uses cells instead of donor organs, which are limited in supply.
What are Stem cells?
Stem cells are called “master cells”
Stem cells are cells that are undifferentiated.
What are Stem cells?
Steam cells have the potential to become all other kinds of cells in our body.
What are Stem cells?
Types of Stem cells
How stem cell therapy works?
Disease cured by stem cell therapy.
Spinal Cord Injuries
Stem cell treatment of Diabetes mellitus type 1 & 2
Stem cell treatment of Stroke
Cancer treatment
Heart damage
Baldness
Tooth implanting
Deafness and blindness
Have stem cells already been used to treat diseases?
Ethical Consideration of Stem Cell Therapy
As the research method mainly focused on Embryonic Stem Cells, which involves taking tissue from an aborted embryo to get proper material to study. This is typically done just days after conception or between the 5th and 9th week.
Since then, researchers have moved on to more ethical study methods, such as Induced Pluripotent Stem Cells (iPS). iPS is artificially derived from a non-pluripotent cell, such as adult somatic cells.
Nowadays stem cell treatment has been spreaded throughout the world. It has also been grown commercially in developed countries.
It is thought that one day it may be the major key to treat various diseases.
Using stem cells to conduct medical research and treat disease is acceptable?
Don’t know
No
Yes
Do you approve of the extraction of stem cells from human embryos for medical research?
Don’t know
No
Yes
This document summarizes the structures and types of immunoglobulins. It discusses the five classes of immunoglobulins - IgG, IgM, IgA, IgD, and IgE - and their properties, including what percentage of serum each class comprises and their roles in binding antigens, fixing complement, and inducing immune responses. It also covers immunoglobulin subclasses defined by minor amino acid differences, as well as kappa and lambda light chain types.
3D In Vitro Model for Drug Efficiency Testingjudoublen
This document discusses the potential advantages of using 3D in vitro models compared to traditional 2D models for drug testing. It notes that 3D cultures more closely mimic the in vivo microenvironment and cell morphology. This allows 3D cultures to better predict cellular responses to drugs and provide more accurate models of disease. The document outlines several applications of 3D cultures, such as studying tumor development, evaluating drug sensitivity, and developing organs-on-chips microfluidic devices that model human organ functions.
Tissue Engineering is the reconstruction of cells to differential cell into the desired tissue or organ in an attempt to improve their structural functions.
Regenerative medicine is an aspect of tissue engineering that uses bioengineering principles to solve healthcare challenges using new innovative ideas, methods and mode of synthesis of different biomaterials construct.
Tissue Regenerative Medicine uses scaffolding development to guide cells into differentiating in to desired tissue or organ.
Scaffolding provides an extracellular matrix for the cells, this extracellular matrix serve and act as the guides for their proper differentiation. (Hynes R.O, 2009)
Other Emerging fields; Protein / Genetic / Clinical Engineering
This presentation describes in detail the various types and sources of stem cells. it also describes the stem cell therapies used to treat various diseases.
you can find out all types of VEGF in this ppt and it is about physiological and path-physiological significance of VEGF and its possible targeting manoeuvering
This document summarizes the achievements and work of an expert in regenerative medicine. In three sentences:
The expert has received national and international awards for outstanding work in regenerative medicine. They have treated over 2,000 patients using cellular medicine and have published extensively in the field. The expert focuses on stem cells and their role in tissue regeneration, and has represented their country at international conferences on shifting medicine from a traditional to cellular model.
This document discusses the relationship between gut microbiota and diabetes. It begins by defining microbiota and describing the bacterial composition in different body sites. Environmental factors like breastfeeding, antibiotics, and diet impact the development of gut microbiota. Dysbiosis, or an imbalance in the normal microbiota, has been linked to various diseases like obesity, metabolic syndrome, and both type 1 and type 2 diabetes. A high-fat diet can cause dysbiosis and metabolic endotoxemia, increasing inflammation and insulin resistance. Probiotics, prebiotics, and dietary fiber may help maintain a healthy microbiota and prevent diabetes. Both genetic and environmental factors contribute to the complex relationship between the gut, immune system, and development of
This document summarizes a presentation on innate immunity. It defines innate immunity and outlines the evolution of the immune system from early pioneers like Jenner and Pasteur. It then describes the components of the innate system including physical and chemical barriers, pattern recognition receptors, phagocytic cells, toll-like receptors, complement system, and inflammation. It also discusses two case scenarios involving innate immunity and provides references for further information.
The Artificial Pancreas Device System is a system of devices that closely mimics the glucose regulating function of a healthy pancreas.
It sense the blood glucose level, determining the amount of insulin needed, and then delivering the appropriate amount of insulin.
Sometimes an artificial pancreas device system is referred to as a "closed-loop" system, an "automated insulin delivery" system, or an "autonomous system for glycemic control."
The first hybrid closed loop system, the Medtronic's MiniMed 670G System is the first FDA approved artificial pancreas.
The FDA approved it for treating type 1 diabetes in people age 14 and older.
Artificial pancreases hit the market in 2016.
Three key points are summarized:
1. Three-dimensional cell cultures provide a more natural environment for cells compared to traditional 2D cultures, allowing cells to behave more like they do in vivo.
2. 3D cell culture technology is used for applications like tissue engineering, drug discovery, and analysis of cell biology. It involves engineering scaffolds and growth factors to direct cell differentiation.
3. Mathematical modeling is important for understanding the complex biological and physical factors influencing 3D cell cultures, but optimization of cultures remains an ongoing area of research due to the large number of tunable parameters.
This document discusses the role of Sirtuin 1 (SIRT1) in longevity and aging. It describes how SIRT1 is activated by caloric restriction and exercise in tissues like muscle and liver, where it regulates genes involved in gluconeogenesis. However, the key to longevity may be SIRT1 in the hypothalamus. When overexpressed in the dorsomedial and lateral hypothalamic nuclei, SIRT1 promotes youthful physiology and longevity, while overexpression in other hypothalamic nuclei induces weight gain and obesity. The role of SIRT1 in longevity has been controversial, but it appears to be regulated differently in various tissues and brain regions.
This document discusses the use of organoid cultures in cancer research. It begins with an overview of what organoids are and provides a simple definition of organoids as miniature organs grown in vitro. The document then discusses how three-dimensional culture techniques have enabled the real-time study of mammalian tissues by allowing independent manipulation of genetic and microenvironmental factors. Examples are provided of different cellular inputs used in 3D cultures as well as different culture formats. The roles of 3D cultures in advancing cancer therapeutics through predictive and prognostic testing of preclinical treatments are also summarized.
Stem cells are undifferentiated cells that can differentiate into specialized cells and can self-renew. There are several types of stem cells including embryonic, adult, and fetal stem cells. Embryonic stem cells are the most versatile but also raise ethical issues, while adult stem cells are more limited in their differentiation potential. Stem cell therapy works by stem cells differentiating into the type of cells needed to repair damaged tissue when transplanted into the body. Current applications of stem cell therapy include treating diseases like cancer, diabetes, and Parkinson's disease.
Pre and probiotics in colorectal cancer Prevention By Dalia Khamis El-DeebDalia Deeb
This document discusses prebiotics, probiotics, and their potential role in preventing colon cancer. It begins with definitions of prebiotics as selectively fermented ingredients that change the gastrointestinal microflora to benefit health. Probiotics are live microorganisms that colonize the intestines and exert beneficial effects. The document explores how gut microbiota can contribute to carcinogenesis and the mechanisms by which probiotics and their short-chain fatty acid products may prevent colon cancer, such as decreasing pH, modulating compounds, and inducing apoptosis in altered cells. It concludes that while studies have shown potential, more research is still needed to fully understand mechanisms and generate conclusive evidence on using prebiotics and probiotics to prevent and manage colon
B cells produce antibodies against foreign antigens. Antibodies are secreted by plasma cells and found in body fluids where they help defend against bacteria, viruses, and toxins. Memory B cells remain after an infection to allow a faster response if the same pathogen is encountered again. Macrophages present antigens to B cells to activate antibody production and secrete chemicals that promote B cell cloning and antibody secretion.
1. Introduction & Pathophysiology of Liver fibrosis
2. Experimental Models of Hepatic fibrosis
3. Timeline of development of Fibrotic models
4. Surgically developed models for Fibrosis
5. Chemically Induced Models for Fibrosis
6. Diet Induced Models for Fibrosis
7. Infection based models
8. Extra points
9. Conclusion
10. References
This document summarizes stem cell transplantation for heart failure, discussing the types of stem cells tested, delivery methods, and clinical trials. It describes how bone marrow mononuclear cells, mesenchymal stem cells, and cardiac progenitor cells have shown potential benefits in reducing scarring and improving cardiac function in preclinical and early clinical studies of ischemic and nonischemic heart failure. The most common delivery methods have been intramyocardial via endocardial or epicardial approaches and intracoronary infusion, with endomyocardial delivery being the most widely used technique clinically. Larger clinical trials are still needed to determine which cell types and delivery methods are most effective for treating heart failure.
This document discusses methods for clinical testing, specifically 3D cell culture and organ-on-chip technologies. It notes that animal testing is time-consuming, costly, and often does not predict human outcomes. Organ-on-chip technologies use microfabrication and microfluidics to create microenvironments that better simulate human physiology and organs. This allows for testing of drugs and toxins using human cells in a way that may replace animal models. Examples discussed include a lung-on-a-chip to study pulmonary edema and a proposed "body on a chip" with 3D printed miniature organs to improve drug development and reduce costs.
This document summarizes the current status of stem cell research and therapy for cardiac repair. It discusses the types of stem cells used, including embryonic, bone marrow-derived, and resident cardiac stem cells. Methods of stem cell delivery like intravenous, intracoronary, and direct injection are presented. The mechanisms by which stem cells home to the heart and differentiate are described. Clinical trials using mesenchymal stem cells for acute myocardial infarction and heart failure are mentioned. While benefits are seen, long-term effects and several unresolved issues are still being investigated.
The document discusses the major histocompatibility complex (MHC) and its role in immune recognition. It notes that Gorer and Snell in the 1930s discovered that mouse skin grafts were rejected between mice of different blood groups, showing tissue recognition is based on genetics. They coined the term MHC to describe the genes controlling this tissue recognition. MHC molecules present peptides and are highly polymorphic within and between species, allowing an organism to distinguish self from non-self. The MHC in humans is called the HLA complex.
This document discusses organs-on-chips technology for evaluating drug efficacy and activity in vivo. It describes how organs-on-chips can model the absorption, distribution, metabolism, and excretion (ADME) processes using microfluidic cell culture chips that simulate organ functions. Specifically, it outlines efforts to develop intestinal, kidney, and liver chips to evaluate absorption, metabolism, and clearance. Linked organ chips are also discussed as a way to model organ crosstalk and better understand systemic drug effects. The technology shows promise for reducing animal testing and aiding drug development but challenges remain around replicating full organ complexity and quantifying kinetics.
The document discusses organoids, which are 3D clusters of cells grown in vitro to mimic organ structures. It describes the 5 basic steps to make an organoid: 1) obtain a tissue sample, 2) dissociate it into single cells, 3) isolate stem cells using a cell sorter, 4) add the stem cells to a gel-like substance called Matrigel, and 5) allow the cells to grow over 1-90 days. Various types of organoids are listed, and potential uses discussed, including testing medical/chemical agents, aiding drug development by reducing animal testing, and regenerative medicine by growing replacement organs.
The document discusses the need for an artificial pancreas to help regulate blood glucose levels for diabetics. A natural pancreas fails to produce the proper amount of insulin needed to counter changing blood sugar levels. Maintaining diabetes is difficult and expensive, requiring frequent blood glucose monitoring and insulin injections or pump therapy. The FDA has been working with medical companies to advance artificial pancreas technology. The MiniMed 670G system is highlighted as the first integrated insulin pump and continuous glucose monitoring system that automatically adjusts insulin delivery based on the user's lifestyle and daily activities. The document outlines the phased development of artificial pancreas technology from early integrated pump and CGM systems to current hybrid closed loop systems and future fully automated closed loop systems in development
This document discusses the use of monoclonal antibodies in cancer treatment. It begins by introducing monoclonal antibodies and their benefits over conventional chemotherapy, including homogeneity, specificity, fewer side effects, and the ability to be tagged with other compounds. It then describes naked monoclonal antibodies that work alone and conjugated monoclonal antibodies that are joined to chemotherapy drugs or radioactive particles. Several FDA-approved monoclonal antibodies for different cancer types are listed. The mechanisms of action of rituximab, trastuzumab emtansine, and other monoclonal antibodies are described. Current clinical trials and limitations of monoclonal antibody therapy are also summarized.
Triglytza: Counter-Regulation of RAAS and COVID-19 TreatmentRavi Kumar, Ph.D.
TriGlytza is a proprietary dual combination product of ARKAY Therapeutics. It is custom-designed for treatment and mitigation of ARDS and MODS associated with COVID-19.
This document summarizes the achievements and work of an expert in regenerative medicine. In three sentences:
The expert has received national and international awards for outstanding work in regenerative medicine. They have treated over 2,000 patients using cellular medicine and have published extensively in the field. The expert focuses on stem cells and their role in tissue regeneration, and has represented their country at international conferences on shifting medicine from a traditional to cellular model.
This document discusses the relationship between gut microbiota and diabetes. It begins by defining microbiota and describing the bacterial composition in different body sites. Environmental factors like breastfeeding, antibiotics, and diet impact the development of gut microbiota. Dysbiosis, or an imbalance in the normal microbiota, has been linked to various diseases like obesity, metabolic syndrome, and both type 1 and type 2 diabetes. A high-fat diet can cause dysbiosis and metabolic endotoxemia, increasing inflammation and insulin resistance. Probiotics, prebiotics, and dietary fiber may help maintain a healthy microbiota and prevent diabetes. Both genetic and environmental factors contribute to the complex relationship between the gut, immune system, and development of
This document summarizes a presentation on innate immunity. It defines innate immunity and outlines the evolution of the immune system from early pioneers like Jenner and Pasteur. It then describes the components of the innate system including physical and chemical barriers, pattern recognition receptors, phagocytic cells, toll-like receptors, complement system, and inflammation. It also discusses two case scenarios involving innate immunity and provides references for further information.
The Artificial Pancreas Device System is a system of devices that closely mimics the glucose regulating function of a healthy pancreas.
It sense the blood glucose level, determining the amount of insulin needed, and then delivering the appropriate amount of insulin.
Sometimes an artificial pancreas device system is referred to as a "closed-loop" system, an "automated insulin delivery" system, or an "autonomous system for glycemic control."
The first hybrid closed loop system, the Medtronic's MiniMed 670G System is the first FDA approved artificial pancreas.
The FDA approved it for treating type 1 diabetes in people age 14 and older.
Artificial pancreases hit the market in 2016.
Three key points are summarized:
1. Three-dimensional cell cultures provide a more natural environment for cells compared to traditional 2D cultures, allowing cells to behave more like they do in vivo.
2. 3D cell culture technology is used for applications like tissue engineering, drug discovery, and analysis of cell biology. It involves engineering scaffolds and growth factors to direct cell differentiation.
3. Mathematical modeling is important for understanding the complex biological and physical factors influencing 3D cell cultures, but optimization of cultures remains an ongoing area of research due to the large number of tunable parameters.
This document discusses the role of Sirtuin 1 (SIRT1) in longevity and aging. It describes how SIRT1 is activated by caloric restriction and exercise in tissues like muscle and liver, where it regulates genes involved in gluconeogenesis. However, the key to longevity may be SIRT1 in the hypothalamus. When overexpressed in the dorsomedial and lateral hypothalamic nuclei, SIRT1 promotes youthful physiology and longevity, while overexpression in other hypothalamic nuclei induces weight gain and obesity. The role of SIRT1 in longevity has been controversial, but it appears to be regulated differently in various tissues and brain regions.
This document discusses the use of organoid cultures in cancer research. It begins with an overview of what organoids are and provides a simple definition of organoids as miniature organs grown in vitro. The document then discusses how three-dimensional culture techniques have enabled the real-time study of mammalian tissues by allowing independent manipulation of genetic and microenvironmental factors. Examples are provided of different cellular inputs used in 3D cultures as well as different culture formats. The roles of 3D cultures in advancing cancer therapeutics through predictive and prognostic testing of preclinical treatments are also summarized.
Stem cells are undifferentiated cells that can differentiate into specialized cells and can self-renew. There are several types of stem cells including embryonic, adult, and fetal stem cells. Embryonic stem cells are the most versatile but also raise ethical issues, while adult stem cells are more limited in their differentiation potential. Stem cell therapy works by stem cells differentiating into the type of cells needed to repair damaged tissue when transplanted into the body. Current applications of stem cell therapy include treating diseases like cancer, diabetes, and Parkinson's disease.
Pre and probiotics in colorectal cancer Prevention By Dalia Khamis El-DeebDalia Deeb
This document discusses prebiotics, probiotics, and their potential role in preventing colon cancer. It begins with definitions of prebiotics as selectively fermented ingredients that change the gastrointestinal microflora to benefit health. Probiotics are live microorganisms that colonize the intestines and exert beneficial effects. The document explores how gut microbiota can contribute to carcinogenesis and the mechanisms by which probiotics and their short-chain fatty acid products may prevent colon cancer, such as decreasing pH, modulating compounds, and inducing apoptosis in altered cells. It concludes that while studies have shown potential, more research is still needed to fully understand mechanisms and generate conclusive evidence on using prebiotics and probiotics to prevent and manage colon
B cells produce antibodies against foreign antigens. Antibodies are secreted by plasma cells and found in body fluids where they help defend against bacteria, viruses, and toxins. Memory B cells remain after an infection to allow a faster response if the same pathogen is encountered again. Macrophages present antigens to B cells to activate antibody production and secrete chemicals that promote B cell cloning and antibody secretion.
1. Introduction & Pathophysiology of Liver fibrosis
2. Experimental Models of Hepatic fibrosis
3. Timeline of development of Fibrotic models
4. Surgically developed models for Fibrosis
5. Chemically Induced Models for Fibrosis
6. Diet Induced Models for Fibrosis
7. Infection based models
8. Extra points
9. Conclusion
10. References
This document summarizes stem cell transplantation for heart failure, discussing the types of stem cells tested, delivery methods, and clinical trials. It describes how bone marrow mononuclear cells, mesenchymal stem cells, and cardiac progenitor cells have shown potential benefits in reducing scarring and improving cardiac function in preclinical and early clinical studies of ischemic and nonischemic heart failure. The most common delivery methods have been intramyocardial via endocardial or epicardial approaches and intracoronary infusion, with endomyocardial delivery being the most widely used technique clinically. Larger clinical trials are still needed to determine which cell types and delivery methods are most effective for treating heart failure.
This document discusses methods for clinical testing, specifically 3D cell culture and organ-on-chip technologies. It notes that animal testing is time-consuming, costly, and often does not predict human outcomes. Organ-on-chip technologies use microfabrication and microfluidics to create microenvironments that better simulate human physiology and organs. This allows for testing of drugs and toxins using human cells in a way that may replace animal models. Examples discussed include a lung-on-a-chip to study pulmonary edema and a proposed "body on a chip" with 3D printed miniature organs to improve drug development and reduce costs.
This document summarizes the current status of stem cell research and therapy for cardiac repair. It discusses the types of stem cells used, including embryonic, bone marrow-derived, and resident cardiac stem cells. Methods of stem cell delivery like intravenous, intracoronary, and direct injection are presented. The mechanisms by which stem cells home to the heart and differentiate are described. Clinical trials using mesenchymal stem cells for acute myocardial infarction and heart failure are mentioned. While benefits are seen, long-term effects and several unresolved issues are still being investigated.
The document discusses the major histocompatibility complex (MHC) and its role in immune recognition. It notes that Gorer and Snell in the 1930s discovered that mouse skin grafts were rejected between mice of different blood groups, showing tissue recognition is based on genetics. They coined the term MHC to describe the genes controlling this tissue recognition. MHC molecules present peptides and are highly polymorphic within and between species, allowing an organism to distinguish self from non-self. The MHC in humans is called the HLA complex.
This document discusses organs-on-chips technology for evaluating drug efficacy and activity in vivo. It describes how organs-on-chips can model the absorption, distribution, metabolism, and excretion (ADME) processes using microfluidic cell culture chips that simulate organ functions. Specifically, it outlines efforts to develop intestinal, kidney, and liver chips to evaluate absorption, metabolism, and clearance. Linked organ chips are also discussed as a way to model organ crosstalk and better understand systemic drug effects. The technology shows promise for reducing animal testing and aiding drug development but challenges remain around replicating full organ complexity and quantifying kinetics.
The document discusses organoids, which are 3D clusters of cells grown in vitro to mimic organ structures. It describes the 5 basic steps to make an organoid: 1) obtain a tissue sample, 2) dissociate it into single cells, 3) isolate stem cells using a cell sorter, 4) add the stem cells to a gel-like substance called Matrigel, and 5) allow the cells to grow over 1-90 days. Various types of organoids are listed, and potential uses discussed, including testing medical/chemical agents, aiding drug development by reducing animal testing, and regenerative medicine by growing replacement organs.
The document discusses the need for an artificial pancreas to help regulate blood glucose levels for diabetics. A natural pancreas fails to produce the proper amount of insulin needed to counter changing blood sugar levels. Maintaining diabetes is difficult and expensive, requiring frequent blood glucose monitoring and insulin injections or pump therapy. The FDA has been working with medical companies to advance artificial pancreas technology. The MiniMed 670G system is highlighted as the first integrated insulin pump and continuous glucose monitoring system that automatically adjusts insulin delivery based on the user's lifestyle and daily activities. The document outlines the phased development of artificial pancreas technology from early integrated pump and CGM systems to current hybrid closed loop systems and future fully automated closed loop systems in development
This document discusses the use of monoclonal antibodies in cancer treatment. It begins by introducing monoclonal antibodies and their benefits over conventional chemotherapy, including homogeneity, specificity, fewer side effects, and the ability to be tagged with other compounds. It then describes naked monoclonal antibodies that work alone and conjugated monoclonal antibodies that are joined to chemotherapy drugs or radioactive particles. Several FDA-approved monoclonal antibodies for different cancer types are listed. The mechanisms of action of rituximab, trastuzumab emtansine, and other monoclonal antibodies are described. Current clinical trials and limitations of monoclonal antibody therapy are also summarized.
Triglytza: Counter-Regulation of RAAS and COVID-19 TreatmentRavi Kumar, Ph.D.
TriGlytza is a proprietary dual combination product of ARKAY Therapeutics. It is custom-designed for treatment and mitigation of ARDS and MODS associated with COVID-19.
Renin - Angiotensin - Aldosterone System Inhibitors in Patients with Covid-19Valentina Corona
This document summarizes the current understanding of how medications that inhibit the renin-angiotensin-aldosterone system (RAAS), such as ACE inhibitors and angiotensin receptor blockers (ARBs), may impact COVID-19. It notes that while animal studies have found mixed results on how these drugs affect ACE2 levels, human studies provide little evidence they increase ACE2. It also raises the possibility that ACE2 may be beneficial rather than harmful for lung injury in COVID-19. The document concludes more research is needed to understand the complex interactions between SARS-CoV-2 and the RAAS system in humans before making recommendations about RAAS inhibitor use in COVID-19 patients.
This webinar discusses immunometabolism and its relationship to COVID-19. It explores how elevated glucose levels can favor SARS-CoV-2 infection by inducing viral replication and cytokine expression through a HIF-1α/glycolysis pathway. Insulin treatment is also discussed and its association with increased mortality in COVID-19 patients with diabetes. The role of mitochondria in producing reactive oxygen species during infection is covered, as is the potential for antioxidants and dietary changes like ketogenic diets to impact the immune response. Biomarkers of immunometabolism are proposed for monitoring clinical outcomes.
The document discusses kidney involvement in COVID-19 patients. It notes that acute kidney injury (AKI) occurs in 3-9% of early COVID-19 patients, rising to 19-50% of ICU patients. AKI is associated with higher mortality, between 35-90% among those with COVID-19. Pathological findings include collapsing glomerulopathy and acute tubular injury. Viral particles have been found in podocytes and tubular cells on postmortem and kidney biopsy studies.
This document discusses preserving homeostasis in patients with COVID-19 by modulating the renin-angiotensin system (RAS). It describes how SARS-CoV-2 infection can dysregulate RAS, leading to overactivation of angiotensin II and oxidative stress. The use of angiotensin receptor blockers like losartan is proposed to counteract this and inhibit virus replication by distorting the binding of the virus to ACE2 receptors. Studies in cell cultures found losartan treatment before and after infection reduced viral replication. Maintaining RAS homeostasis is proposed as a promising therapeutic strategy for COVID-19 given the dysregulatory impacts of viral infections.
Inflammation and Vascular Damage in HypertensionInsideScientific
Dr. Ana Briones presents her research on the effects and potential therapeutic targets of excessive inflammation and vascular damage in hypertension.
Inflammation is a typical feature of many cardiovascular diseases such as atherosclerosis, aneurysms, obesity, or hypertension. In hypertension, excessive inflammation from innate and adaptative immune systems associated with elevated levels of local and circulating proinflammatory cytokines and oxidative stress, plays a key role in endothelial dysfunction, vascular remodeling, and augmented vascular stiffness associated to this pathology.
Excessive inflammation can result from elevated cytokines production, but unresolved or inefficient resolution of inflammation might also contribute to the augmented inflammatory milieu found in the vasculature of different cardiovascular diseases. Resolution of inflammation is mediated by a family of specialized pro-resolving mediators (lipoxins, resolvins, protectins, maresins), that limit immune cell infiltration and initiate tissue repair mechanisms.
Dr. Briones will show the latest advances on the role of novel proinflammatory mediators associated to vascular damage in hypertension. Moreover, she will discuss the potential beneficial effects of boosting resolution of inflammation as a new therapeutic approach for the treatment of hypertension and vascular alterations.
Key Topics Include:
- To understand the contribution of excessive inflammation to vascular damage in hypertension
- To understand the effects of proresolvin lipid mediators at the vascular level
- To consider resolution of inflammation as a new therapeutic approach for the management of vascular damage associated to hypertension
Renin angiotensin system inhibitors improve the clinical outcomes of covid 19...gisa_legal
This study evaluated the effects of renin-angiotensin system (RAS) inhibitors on COVID-19 patients with hypertension. The study found that:
1) Patients receiving ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) had lower rates of severe disease and lower levels of the inflammatory marker IL-6 compared to those receiving other hypertension drugs.
2) ACEI/ARB therapy was associated with higher CD3 and CD8 T cell counts and lower peak viral loads.
3) The results suggest that continuing or prioritizing ACEIs/ARBs for hypertension treatment may improve clinical outcomes for COVID-19 patients with hypertension by reducing inflammation and modulating
COVID-19; Updates on Pathophysiology and Laboratory InvestigationsAbdulsalam Al-Ani
This document discusses the pathophysiology and laboratory investigations of COVID-19. It begins with an overview of the objectives and then discusses the direct viral infection process, the immune response, and COVID-19 induced coagulopathy as they relate to the pathophysiology. It also discusses several diagnostic and prognostic laboratory parameters including viral detection methods, antibody detection, and hematological parameters seen in complete blood counts. Specifically, it notes the role of hypoxia-inducible factors, inflammation, and endothelial injury in driving the coagulopathy seen in COVID-19 patients.
Angiotensin receptor blockers as tentative sars co v-2gisa_legal
This document proposes using angiotensin receptor blockers (ARBs) like losartan to treat COVID-19 infections based on the following:
- SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as its receptor, similarly to the SARS virus.
- ARBs have been shown to upregulate ACE2 expression in animal and human studies.
- While increasing the virus' receptor seems counterintuitive, upregulating ACE2 may help reduce lung injury by blocking angiotensin signaling and increasing protective vasodilator peptides.
- The proposal warrants further study by analyzing clinical records to assess if ARB use is associated with better COVID-19
SARS–CoV–2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination I...Guy Boulianne
This document summarizes a research study that investigated how the SARS-CoV-2 spike protein affects DNA damage repair and adaptive immunity. The main findings are:
1) The SARS-CoV-2 spike protein significantly inhibited DNA damage repair in in vitro cell line experiments by impeding the recruitment of key DNA repair proteins like BRCA1 and 53BP1 to damage sites.
2) DNA damage repair is required for effective V(D)J recombination, which generates antibody diversity in B cells and T cell receptors in T cells. Inhibiting DNA damage repair could therefore impair adaptive immunity.
3) The spike protein was found to localize in the cell nucleus, where it could interfere with DNA repair
Co-Chairs, Sean Pokorney, MD, MBA, and Emily P. Zeitler, MD, MHS, FACC, FHRS, prepared useful Practice Aids pertaining to nonvalvular atrial fibrillation for this CME/MOC/NCPD/CPE activity titled “Critical Conversations on Atrial Fibrillation: A MasterClass Series.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/NCPD/CPE information, and to apply for credit, please visit us at https://bit.ly/3us6D2T. CME/MOC/NCPD/CPE credit will be available until April 3, 2024.
Eduardo Marbán, MD, PhD gives a deep dive into the complexities of regenerative cardiovascular medicine and the future directions for cell therapies.
Dr. Marbán’s lab has found several noncoding RNA (ncRNA) species, including short Y RNAs, which themselves have intriguing biological actions. The ncRNA within extracellular vesicles can either be used as they occur naturally or serve as bioinspiration for new chemical entities. The next generations of cell-free biologics (extracellular vesicles and noncoding RNAs) may provide, or even transcend, the benefits of cell therapy without the intrinsic limitations.
Key Topics Include:
- Understand the current status of cell therapy for heart disease
- Review the mechanisms whereby cells exert their therapeutic benefits
- Explore the future of RNA drugs inspired by the contents of extracellular vesicles
The document summarizes the roles of ACE2 and TMPRSS2 in SARS-CoV-2 infection. It explains that SARS-CoV-2 relies on ACE2 to enter cells and TMPRSS2 to prime the viral spike protein. ACE2 catalyzes the conversion of angiotensin II and plays a role in cardiovascular function, while TMPRSS2 is involved in prostate cancer. It further discusses how ADAM17 and TMPRSS2 regulate ACE2 shedding and how their balance may impact viral infection and constitute a natural barrier when more shedding occurs. The document provides references for further reading on related topics like genetic influences on COVID-19 susceptibility and severity.
International Journal of Engineering Research and Applications (IJERA) is an open access online peer reviewed international journal that publishes research and review articles in the fields of Computer Science, Neural Networks, Electrical Engineering, Software Engineering, Information Technology, Mechanical Engineering, Chemical Engineering, Plastic Engineering, Food Technology, Textile Engineering, Nano Technology & science, Power Electronics, Electronics & Communication Engineering, Computational mathematics, Image processing, Civil Engineering, Structural Engineering, Environmental Engineering, VLSI Testing & Low Power VLSI Design etc.
Using SARS-CoV-2 to Teach Physiology and ScienceInsideScientific
Join Dr. Dee Silverthorn for a discussion on how the sudden appearance of the global pandemic of COVID-19 provides a unique opportunity to show students science in action as researchers and healthcare professionals around the world scramble to understand the virus and its effects on the human body. This is the third webinar in this 4-part series on how science education has evolved in the face of new challenges.
In this presentation we will explore some of the ways that we can incorporate today’s headlines into the curriculum by discussing the pathophysiology and pathology of SARS-CoV-2 infection and how it demonstrates the integration of body function across multiple organ systems. Teaching about the coronavirus pandemic also creates opportunities to have students critically analyze research studies and news reports, and to discuss ethical dilemmas such as the distribution of limited amounts of vaccine or the triage of critically ill patients when lifesaving equipment is limited. One important goal of teaching about the coronavirus pandemic is to have students learn to tolerate ambiguity, and to understand that today’s “facts” are simply our best models of what we know.
Role of ACE-2 Receptors in Multi-Systemic Manifestations of COVID-19semualkaira
The severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) virus, which was first discovered in late 2019, is currently wreaking havoc around the world. The most common symptom of this illness is a type of extreme acute respiratory distress
syndrome. Aside from the pulmonary manifestations, the virus is
known to affect several other organs.
Role of ACE-2 Receptors in Multi-Systemic Manifestations of COVID-19semualkaira
The severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) virus, which was first discovered in late 2019, is currently wreaking havoc around the world. The most common symptom of this illness is a type of extreme acute respiratory distress
syndrome. Aside from the pulmonary manifestations, the virus is
known to affect several other organs.
Impact of Newer Glucose-Lowering Agents in CVD & HF , and Novel Therapeutic Strategies
Han Naung Tun
MBBS, MD, FACTM, FACC, FESC
UVM Medical Centre
Larner College of Medicine , University of Vermont ,VT , USA
Latest Trials on CAD from 2020 ESC Congress Han Naung Tun
LoDoCo2 Trial: low-dose colchicine reduced the risk of major cardiovascular events in patients with CAD
ATPCI: Trimetazidine in Angina Patients With Recent Successful Percutaneous Coronary Intervention
RAPID CTCA :Early Coronary CT Angiography in Patients With Suspected or Provisionally Diagnosed Acute Coronary Syndrome
OCT and MRI Find an MI Cause in 85% of Women With MINOCA: HARP
Ventricular septal rupture with cardiogenic shock follows by Inferior AMIHan Naung Tun
This document describes the case of a 58-year-old man who presented with chest pain and was diagnosed with an inferoposterior myocardial infarction complicated by ventricular septal rupture and cardiogenic shock. Initial treatment included medications, percutaneous coronary intervention to open the blocked artery, and supportive care. Despite intensive medical management, the patient's condition deteriorated with the development of ventricular septal defect. Surgical repair was considered but the patient expired from cardiogenic shock before a procedure could be performed. The key learning points are the importance of early recognition of pre-shock states, the high mortality of ventricular septal rupture, and the need for a multidisciplinary approach and care at an experienced center to manage such complex cases.
Updated and Overview of HF Trials in ESC 2020Han Naung Tun
This document summarizes several late-breaking trials presented at the ESC 2020 conference on heart failure (HF) management. It discusses the EMPEROR-Reduced trial which found that empagliflozin reduced cardiovascular death and HF hospitalization in HF patients regardless of diabetes status. It also mentions the EXPLORER-HCM trial on HFpEF and the PARALLAX trial which found sacubitril/valsartan did not reduce cardiac failure events in HFpEF patients compared to ACE/ARB therapy. Finally, it summarizes the DAPA-CKD trial results showing that dapagliflozin delayed kidney failure in patients with chronic kidney disease with and without diabetes.
Hospital Readmission of Heart Failure Patients And Its Precipitated Factors a...Han Naung Tun
Hypertension is one of the most prevalent modifiable risk factor for the development of heart failure (HF). Chronic heart failure (CHF) is the most common cause of readmission for patients in worldwide
How To Recognise and Manage a Pre Shock SettingHan Naung Tun
This document discusses the recognition and management of pre-shock in the context of anterior ST-elevation myocardial infarction (STEMI). Pre-shock, also known as SCAI shock stages A-B, involves persistent hemodynamic compromise without fully meeting shock criteria and these patients are prone to rapid deterioration. The case describes a 65-year-old man with anterior STEMI who did not improve after percutaneous coronary intervention on the culprit lesion, meeting some but not all criteria for cardiogenic shock. Invasive hemodynamic monitoring showed features of pre-shock and upfront use of an intra-aortic balloon pump provided immediate hemodynamic support, preventing further deterioration. Early recognition of pre-shock using both clinical and invasive parameters can guide
Top Five Clinical Trials of PCI in 2019 Han Naung Tun
"My five top trials in #interventionalcardiology in 2019". View this extensive slideset by Andreas Baumbach @EAPCIPresident where he covers the potential impact of these trials on clinical practice & their relevance for practice guidelines ow.ly/G64930q7R1K
#ESC
#EuroPCR
The document discusses the benefits of exercise for mental health. Regular physical activity can help reduce anxiety and depression and improve mood and cognitive functioning. Exercise boosts blood flow, releases endorphins, and promotes changes in the brain which help enhance one's emotional well-being and mental clarity.
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Pre operative assessment of patient with liver diseaseHan Naung Tun
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Cardiac CT Angiography to detect Myocardial Bridging Han Naung Tun
CTCA is a reliable non-invasive tool for detecting myocardial bridging in coronary artery disease. [The study] found an 8.2% frequency of myocardial bridging in 219 patients with coronary artery disease who underwent CTCA. CTCA allows for visualization of the length and depth of the bridging artery and measurement of stenosis. While myocardial bridging can be clinically significant when associated with hemodynamic changes, in most cases it remains asymptomatic. CTCA is an emerging alternative to other invasive tests for diagnosing myocardial bridging.
1) Current treatments for HFpEF have not been shown to reduce morbidity or mortality, though trials are investigating new drug classes like ARNIs, soluble guanylate cyclase stimulators, and SGLT2 inhibitors.
2) Lifestyle modifications including exercise training, weight loss, and salt restriction may help symptoms. Exercise training in particular may improve exercise capacity.
3) Screening for underlying causes like myocardial ischemia, atrial fibrillation, amyloidosis, and treating associated conditions is recommended. The ATTR-ACT trial found tafamidis reduced cardiovascular hospitalizations and mortality in transthyretin amyloid cardiomyopathy.
Universal Definition of Myocardial Infarct Han Naung Tun
1) The document summarizes the 4th Universal Definition of Myocardial Infarction from 2018, outlining 5 types of MI (myocardial infarction).
2) It describes the criteria for each type of MI, including Type 1 due to plaque rupture, Type 2 due to oxygen supply/demand imbalance, and Type 3 where the patient dies before biomarkers can be obtained.
3) It also discusses MI associated with procedures like PCI (Type 4) and CABG (Type 5), and conditions like MINOCA where the coronary arteries are non-obstructive.
Thrombolysis and thrombectomy for acute ischaemic strokeHan Naung Tun
Reperfusion by intravenous thrombolysis or endovascular
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after stroke, but benefit for both treatment modalities is highly
time-dependent. Maximum benefit requires minimisation
of onset-to-treatment times. The safety and efficacy of IV
rtPA is established across a broad range of clinical scenarios.
Endovascular treatment now offers greatly improved outcome
among patients with poor response to IV rtPA but efficacy
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This document provides a history and timeline of cardiac catheterization and percutaneous coronary intervention (PCI):
- In 1929, Werner Forssmann performed the first human cardiac catheterization on himself in Germany, though it was very painful. He shared the 1956 Nobel Prize for this work.
- In 1958, William Sones performed the first selective coronary angiogram, inadvertently discovering coronary anatomy.
- In 1977, Andreas Gruentzig developed the first functioning balloon catheter and performed the first successful non-operative coronary artery dilation.
- Major advances over the subsequent decades included over-the-wire balloon technology, coronary stenting, drug-eluting stents, and treatment of in-stent rest
- Biomarkers such as troponins, copeptin, and natriuretic peptides have become indispensable diagnostic tools in cardiology over the past 60 years.
- Troponins are the gold standard for diagnosing myocardial infarction, while copeptin allows for very early rule-out of MI.
- New biomarkers continue to be discovered through advances in genomics, epigenetics, and other 'omics' fields, with microRNAs showing promise to improve risk stratification and precision medicine for cardiovascular disease.
- Biomarkers have transformed cardiology practice and decision-making, with troponins in particular demonstrating their ability to guide therapies and intervention timing for conditions like ACS.
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
Does Over-Masturbation Contribute to Chronic Prostatitis.pptxwalterHu5
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Histololgy of Female Reproductive System.pptxAyeshaZaid1
Dive into an in-depth exploration of the histological structure of female reproductive system with this comprehensive lecture. Presented by Dr. Ayesha Irfan, Assistant Professor of Anatomy, this presentation covers the Gross anatomy and functional histology of the female reproductive organs. Ideal for students, educators, and anyone interested in medical science, this lecture provides clear explanations, detailed diagrams, and valuable insights into female reproductive system. Enhance your knowledge and understanding of this essential aspect of human biology.
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
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ACE2 , Hypertension and SARS Cov2
1. ACE2: From Renoprotection to a Potential
Therapy for Coronavirus Infection
Daniel Batlle MD
Earle, del Greco
Levin Professor of Medicine
Division of Nephrology and Hypertension
Northwestern University Feinberg School of Medicine
Chicago IL
2. DISCLOSURES
• Dr. Batlle is a co-inventor of a patent entitled ‘Active Low Molecular
Weight Variants of Angiotensin Converting Enzyme 2’ and has submitted
patent applications on ‘’Novel ACE2 proteins for coronavirus
infection” and ‘’Active low molecular weight variant of Angiotensin
Converting Enzyme 2 for the treatment of diseases and conditions of the
eye ’’
• Dr. Batlle is Founder and majority shareholder of ‘Angiotensin
Therapeutics Inc’.
• Dr. Batlle has received consultant fees from Relypsa , Tricida and Astra
Zeneca.
3. 3
Before…
After…
Modified from Danser , Epstein and Batlle Hypertension 2020
ACE2: From Renoprotection to a Potential Therapy for Coronavirus Infection
4. What is ACE2 ?
• Angiotensin Converting Enzyme II is a
monocarboxypepetidase that hydrolyzesAngiotensin
II and other peptides.
• The name ofACE2 was given when it was discovered
in 2000 because of considerable homology with
Angiotensin Converting Enzyme (ACE) ( 61%
homology)
• UnlikeACE,ACE2 does not convert angiotensin I to
angiotensin II, and moreoverACE inhibitors do not
block its activity
4
Monika Rella, Richard Jackson, Tony Turner
5. Amino acid sequences and ACE/ACE2 cleavage sites of various peptides
Eriksson et al. Current Biology 2002
6. PheProHisILeTyrValArgAsp
1 2 3 4 5 6 7 8
N C
ProHisILeTyrValArgAsp
1 2 3 4 5 6 7
N C
Phe
ACE2
Ang II (1-8)
Ang-(1-7)
ACE2 catalyzes the conversion of Ang II to Ang ( 1-7)
8. Native Soluble ACE2 740 aa (100-110 kDa)
Transmembrane domain
Signal peptide
Catalytic domain
Full length ACE2 805 aa (>110 kDa)
N- -C
ACE2 is a tissue enzyme widely distributed preferentially in epithelial cells .
Where is ACE2 located ?
From Davidson ,Wysocki and Batlle Hypertension 2020 , in press.
9. 9
Serfozo et al. Hypertension 2019
POP = Prolyl endopeptidase ( also known as PEP)
10.
11. Immunofluorescence staining of ACE; green; and ACE2 (red; middle) in proximal tubules.
Minghao Ye et al. JASN 2006;17:3067-3075
In polarized epithelia like kidney , lungs and intestine ACE2 is localized in the apical site
Normallung tissue
Type IIalveolarcells
Hamming J pathol. 2004 jun; 203:631-637
12. ACE2 and ACE immunogold labeling in glomeruli.
Minghao Ye et al. JASN 2006;17:3067-3075
13. Triple immunofluorescence staining of ACE (green; A), ACE2 (red; D), and the endothelial cell
marker platelet-endothelial cell adhesion molecule (PECAM-1; blue; B and E).
Minghao Ye et al. JASN 2006;17:3067-3075
14. Fig. 1. (ACE) (green; A) and ACE2 (red; B) in a kidney arteriole from mouse kidney. Merging both images show no
colocalization of ACE and ACE2 (C). By contrast, neighboring tubules (see arrow) stain in yellow
Soler et at AJP 2008 DOI: (10.1152/ajprenal.90488.2008)
19. 19Mizuri et al. AJKD 2008
Expression of ACE and ACE2 in control individuals (left) and with diabetic kidney disease ( right)
20. ACE2 inhibitors
• MLN- 4760 ( MILLENIUM )
• DX-600
• In vivo MLN-4760 can cause worsening of kidney disease ( Ye et al. Hypertension 2012 , Soler et al. Kidney int. 2007)
22. 22Oudit et al. Diabetes 2010
Human Recombinant ACE2 Reduces the Progression of Diabetic Nephropathy (Akita mice)
23. Effect of ACE2 Fc in a Renin Transgenic Mice: a model of Ang II dependent
hypertension
23Liu et al. Kidney Int. 2008
24. ACE2 amplification using native ACE2 failed to improve early DKD caused
by STZ administration
Wysocki et al. Kidney Int. 2017
25. ACE2 activity after native ACE2 administration
Wysocki et al. Kidney int. 2017
26. Native ACE2
740 aa (100-110 kDa)
Catalytic domain
??? aa kDa
Short ACE2 Catalytic domain
Shortening of native soluble ACE2
-C
Jan Wysocki MD , PhD
27. Native Soluble ACE2
1-740 aa
1-605 aa
(~100-110 kD)
(~50 kD)1-522 aa
(~69 kD)
Recombinant ACE2 constructs
Truncations from the C-terminus
1-650 aa (~75 kD)
Full length ACE2
805 aa (>110 kD)
1-619 aa (~71 kD)
1-805 aa
- No Enzymatic Activity
28. Short ACE2 variants are filterable whereas native ACE2 is not
Mina Shirazi et al. ASN 2019
31. Highlights
Study of the ACE2 receptor for SARS-CoV1
• ACE2 as a Functional receptor for the SARS-CoV1. Wenhui Li et al, Nature, 2003.
• SARS-CoV1 binding domain with ACE2 Receptor. Fang Li et al, Science, 2005.
• SARS-CoV1 binding Affinity to ACE2 receptor. Fang Li et al, Antiviral Research , 2013.
Structure of SARS Coronavirus spike receptor-binding domain complexed with ACE2 receptor
A. ACE2 (green), RBD (cyan) and RBM (red).
B. Distribution of tyrosines (magneta) and Cysteines (yellow)
Fang Li et al, SCIENCE; Sep 2005.
32. • Receptor recognition by SARS-CoV2 to ACE2 Receptor. Fang Li et al, Journal of Virology , Jan 2020.
• SARS-CoV2 uses ACE2 receptor and TMPRSS2 for entry into target cells. Hoffmann, Biorxiv, Jan 2020.
• Cryo-EM structure of the SARS-CoV-2 spike in the prefusion conformation. Wrapp et al, Science, Mar 2020.
• Structure of the SARS-CoV-2 spike RBD bound with ACE2 receptor Lan et al, Nature, Mar 2020.
• Structural basis for the recognition of the SARS-CoV2 by ACE2 Receptor. Yan et al, Science, Mar 2020.
• Structure, Function, and Antigenicity of the SARS- CoV-2 Spike Glycoprotein . Walls et al, Cell, Apr 2020.
• SARS-CoV C-terminal domain with ACE2 receptor. Wang et al, Jama, Apr 2020.
Highlights of ACE2 as receptor for SARS-CoV2
Crystal structure of the SARS-CoV-2 bound with the ACE2
receptor
Overall structure of SARS-CoV-2 RBD bound with
ACE2.
1. ACE2 (green)
2. Receptor-binding domain (cyan)
3. Receptor-binding motif (red)
Lan et al, Nature , Mar 2020.
33. SARS-CoV2 bind to the human ACE2 Receptor and priming by TMPRSS2
Binding
1. ACE2 Receptor (Blue).
2. Spike Protein (Green).
3. TMPRSS2 (Red).
Activation
TMPRSS2*
Fusion
* TMPRSS2: Transmembrane protease , serine 2.
From Davidson ,Wysocki and Batlle Hypertension 2020 , in press.
34. (From Batlle et al. Clinical Science 2020 )
Proposed mechanism whereby soluble ACE2 attenuates viral cell entry by
competing with full length ACE2 in the plasma membrane
35. 35
Animal models of SARS-CoV-2
• Transgenic mice
• Syrian Hamsters
• Ferrets and Cats
• Nonhuman primates
42. 42
What about the use of Ang II as a vasopressor in COVID patients ?
Courtesy of Dr Matthew Sparks
The COVID-19 and ACE2 in Cardiovascular, Lung, and Kidney Working Group
43. Angiotensin II is increased in Acute Lung Injury (experimental)
43
Imai et al, Nature,2005
44. Effect of Ang II on ACE2 in a cell model
Deshotels et al Hypertension 2014
45. Ghallager et al. Am J Physiol Cell 2004
Regulation of ACE2 protein by Ang II
47. The renin-angiotensin-aldosterone system
Vaughan, DE JCI 1995
Vaughan DE Am J Cardiol 2001
Dzau et al. Am j cardiol 2001
Vaduganathan NEJM 2020
Wan et al J Virol 2020
Kuba Nat Med 2005
ACE
Angiotensinogen
Angiotensin-I
RENIN
Angiotensin-II
Angiotensin-I – 7
Angiotensin-1- 9
ACE2
Spike
protein
ACE2
fibrinolysis
Hypercoagulable
State
Acute lung injury
Inflammation
Platelet
activation
Courtesy of Dr Hau Kwaan
48. Prognosis of Acute Organ Injury
Incidence(%) 28-day mortality (%)
Overall 28-day mortality: 35.4%
↑SCr ≥100% or RRT
Gupta et al. JAMA July 2020
49. Targeting of ACE2 by SARS-CoV-2 results in angiotensin dysregulation, innate and adaptive
immune pathway activation, and hypercoagulation to result in organ injury and AKI associated
with COVID-19.
Daniel Batlle on behalf of the The COVID-19 and ACE2 in
Cardiovascular, Lung, and Kidney Working Group et al. JASN
doi:10.1681/ASN.2020040419
50. Marquez A. and Batlle D. , Kidney Int. 2019
What does ACE2 do ?
51. B.
Short ACE2 variant improves AKI in the ischemia reperfusion model
Mina Shirazi et al. ASN 2019
52. Tilman Muller and Alonso Marquez Jeannette Tang
Gvantca Gulua and Mina Shirazi
Peter Serfozo
Benedikt Marahrens
Enrique Lores
Jan Wysocki MD , PhD Minghao Ye , MD
54. RAS Inhibitors in
Hypertension and
Heart Failure:
TRUTHS AND MISTRUTHS
OF TREATMENT IN THE
COVID-19 ERA
J o r d y C o h e n , M D , M S C E
A s s i s t a n t P r o f e s s o r o f M e d i c i n e a n d E p i d e m i o l o g y
R e n a l - E l e c t r o l y t e a n d H y p e r t e n s i o n D i v i s i o n
P e r e l m a n S c h o o l o f M e d i c i n e , U n i v e r s i t y o f P e n n s y l v a n i a
@ j o r d y _ b c
55. Disclosure information
•Funding: NIH (NHLBI) K23-HL133843
•Disclosures: I have no financial relationships with commercial interests to disclose. I am co-PI and
chair of the DCC of the Randomized Elimination or Prolongation of ACE Inhibitors and ARB in
Coronavirus Disease 2019 (REPLACE COVID) trial (NCT04338009) and a contributor to
nephjc.com/news/covidace2
•Off-Label Use: My presentation includes cautionary discussion of off-label or investigational use of
ACE Inhibitors and ARBs in COVID-19
58. … a hypothesis
emerged
•“The most frequent comorbidities reported in… studies of
patients with COVID-19 are often treated with angiotensin-
converting enzyme (ACE) inhibitors”
•SARS-CoV and SARS-CoV-2 bind to their target cells through ACE2,
which is expressed by epithelial cells of the lung, intestine, kidney,
and blood vessels
•ACE2 is “upregulated” by ACEIs and ARBs
•“We suggest that patients with cardiac diseases, hypertension,
or diabetes, who are treated with ACE2-increasing drugs, are
at higher risk for severe COVID-19 infection and, therefore,
should be monitored for ACE2-modulating medications, such
as ACE inhibitors or ARBs”
Fang L et al, Lancet Resp Med 2020;8(4):E21
59. •49,556,127 US adults are taking medication
for the treatment of hypertension
•Among those, 41,329,810 (83%) are taking an
ACEI or ARB
National Health and Nutrition Examination Survey data, c/o Bress AP
The gravity of
the hypothesis
65. Hierarchy of
quality of evidence
•Case series fall somewhere
between expert opinion and
ecological studies
Meta
RCTs
Cohortstudies
Case-control studies
Cross-sectional studies
E c o l o g i c a l s t u d i e s
Case reports & case series
E x p e r t o p i n i o n & e d i t o r i a l s
Ho PM et al, Circ 2008;118(16):1675–1684
67. Hypertension
and aging
•>75% of individuals over age
75 have a diagnosis of
hypertension
Whelton PK et al. J Am Coll Cardiol 2018; 71(19)
SBP/DBP ≥130/80 mm Hg or
Antihypertensive Medication
SBP/DBP ≥140/90 mm Hg or
Antihypertensive Medication
Overall, crude 46% 32%
Men
(n=4717)
Women
(n=4906)
Men
(n=4717)
Women
(n=4906)
Overall, age-sex
adjusted
48% 43% 31% 32%
Age group, years
20–44 30% 19% 11% 10%
45–54 50% 44% 33% 27%
55–64 70% 63% 53% 52%
65–74 77% 75% 64% 63%
75+ 79% 85% 71% 78%
68. Hypertension
and aging
•>75% of individuals over age
75 have a diagnosis of
hypertension
Garg S et al, MMWR 2020 69(15);458–464
70. ACE2ACE
Mas
Renin
AT2RAT1R
Angiotensinogen
Ang IIAng I Ang-(1-7)
Vasoconstriction
Renal sodium and water reabsorption
Oxidative stress
Inflammation
Fibrosis
Impaired fibrinolysis
ACEI
ARB
Cohen JB et al, J Clin Hypertens 2020, in press
71. South AM et al, Nat Rev Nephrol 2020;16:305-307
72. South AM et al, Nat Rev Nephrol 2020;16:305-307
74. Summary of
the evidence in
March 2020
•Case series showed many patients with concomitant COVID-19
and hypertension (which could potentially be explained by age)
•In some experimental models, ACEIs and ARBs increase ACE2
expression
• This could potentially lead to increased SARS-CoV-2 virulence
• However, these findings are not consistent across studies, and have not been
corroborated in humans
•Alternatively, animal models of SARS-CoV-1 suggest that
overexpression of ACE2 protects against lung injury
• ACEIs and ARBs could improve mechanisms of host defense or
hyperinflammation
Sparks MA et al, Clin J Am Soc Nephrol 2020 7;15(5):714-716
75. •“We suggest that patients with cardiac diseases, hypertension, or diabetes,
who are treated with ACE2-increasing drugs, are at higher risk for severe
COVID-19 infection and, therefore, should be monitored for ACE2-modulating
medications, such as ACE inhibitors or ARBs”
Fang L et al, Lancet Resp Med 2020;8(4):E21
80. … and the medical societies (thankfully) reacted
Society Summary of recommendations
American Heart Association, Heart Failure Society of
America, American College of Cardiology
Continue ACEis/ARBs for all patients already prescribed them
European Society of Hypertension Continue ACEis/ARBs due to lack of evidence to support differential use in COVID-19 patients
In those with severe symptoms or sepsis, antihypertensive decisions should be made on a case-by-case
basis
Hypertension Canada Continue ACEis/ARBs due to lack of evidence that patients with hypertension or those treated with
ACEis/ARBs are at higher risk of adverse outcomes from COVID-19 infection
Canadian Cardiovascular Society Continue ACEis/ARBs and Angiotensin Receptor Neprilysin Inhibitors due to a lack of clinical evidence to
support withdrawal of these agents
The Renal Association, United Kingdom Continue ACEis/ARBs due to unconvincing evidence that these medications increase risk
International Society of Hypertension Routine use of ACEis/ARBs to treat hypertension should not be influenced by concerns about COVID-19
in the absence of compelling data
American College of Physicians Continue ACEis/ARBs because there is no evidence linking them to COVID-19 disease severity, and
discontinuation of antihypertensive therapy without medical indication could in some circumstances
result in harm
British and Irish Hypertension Society All patients taking ACEi/ARBs should continue to do so during the COVID-19 pandemic; patients could
be put at risk by stopping these medications until we have more information
Sparks MA and Hiremath S et al, nephjc.com/news/covidace2
83. Clinical trials for RAS blockade and COVID-19
Continuing or discontinuing ongoing RAS blockade
Study Identifier Target N
Country
Population Interventions Primary Outcome
NCT04329195
(ACORES-2)
554
France
Hospitalized with COVID-19 Discontinue ACEI/ARB
Comparator: Continue ACEI/ARB (open-label)
Time to 2-point improvement on WHO
scale or discharged alive up to day 28
NCT04338009
(REPLACE COVID)
152
United States
(International)
Hospitalized with COVID-19 Discontinue ACEI/ARB during hospitalization
(resumed on discharge)
Comparator: Continue ACEI/ARB throughout
hospitalization (open-label)
Composite global rank score for death,
mechanical ventilation, and multiorgan
dysfunction
NCT04351581
(RASCOVID-19)
215
Denmark
Hospitalized with COVID-19 Continue ACEI/ARB at the same dose
throughout hospitalization
Comparator: Discontinue ACEI/ARB during
admission for up to 30 days (open-label)
Days alive and out of hospital by day 14
NCT04364893
(BRACE-CORONA)
500
Brazil
Hospitalized with COVID-19 Continue ACEI/ARB for 30 days
Comparator: Stop ACEI/ARB for 30 days
(open-label)
Median days alive and out of the hospital
from enrolment to day 30
NCT04353596
(ACEI-COVID)
208
Austria and
Germany
Outpatient or hospitalized with COVID-19 Discontinue ACEI/ARB
Comparator: Continue ACEI/ARB (open-label)
SOFA score and death at 30 days
Sparks MA and Hiremath S et al, nephjc.com/news/covidace2
84. De novo RAS blockade
Study Identifier Target N
Country
Population Interventions Primary Outcome
NCT04340557 200
United States
Hospitalized with COVID-19 requiring
supplemental oxygen
Losartan 12.5 mg twice daily for up to 10
days
Comparator: No losartan (open-label)
Mechanical ventilation up to day 45
NCT04351724
(ACOVACT substudy B)
500
Austria
Outpatient or hospitalized with COVID-19 Candesartan titrated to BP <120/80 mm Hg
Comparator: Non-ACEI/ARB
antihypertensive (open-label)
Time to sustained improvement >48
hours on the WHO scaleup to day 29
NCT04311177 580
United States
Outpatient with COVID-19 Losartan 25 mg daily
Comparator: Placebo (blinded)
Hospitalization within 15 days
NCT04328012
(COVIDMED group 3)
4000
United States
Hospitalized with confirmed COVID-19 Losartan 25 mg daily for 5-14 days
Comparator: Placebo (blinded)
NIAID COVID-19 ordinal severity scale at
day 60
NCT04335786
(PRAETORIAN-COVID)
651
Netherlands
Hospitalized with confirmed COVID-19 Valsartan 160 mg twice daily up to 14 days
Comparator: Placebo (blinded)
ICU admission, mechanical ventilation or
death within 14 days
Clinical trials for RAS blockade and COVID-19
Sparks MA and Hiremath S et al, nephjc.com/news/covidace2
89. Observational
data of RAS
blockade in
COVID-19
Death
Death
? ACEI/ARB
Hospitalization for
COVID-19
No ACEi/ARB
ACEI/ARBNo ACEi/ARB
Cohen JB et al, Circ Res 2020 5;126(12):e140-e141
91. Observational
data of RAS
blockade in
COVID-19
Cohen JB et al, under review
Paper Design Question
Mehta N et al, JAMA
Cardiol doi:10.1001/
jamacardio.2020.1855
Prospective cohort
18,472 patients tested for COVID-19
2,285 (12%) on ACEI/ARB
ACEI/ARB use and risk of COVID-19 test
positivity
Mancia G et al, N Engl J
Med 2020; 382:2431-
2440
Case-control study
6,272 cases and 30,759 controls
8,071 (22%) on ACEI/ARB
ACEI/ARB use and risk of COVID-19 test
positivity and severe COVID-19
Reynolds et al, N Engl J
Med 2020; 382:2441-
2448
Retrospective cohort
12,594 patients tested for COVID-19
4,564 (36%) on ACEI/ARB
ACEI/ARB use and risk of COVID-19 test
positivity and severe COVID-19
de Abajo PFJ et al,
Lancet 2020; 395:1705-
1714
Case-control study
1,139 cases and 11,390 controls
2,432 (19%) on ACEI/ARB
ACEI/ARB use and risk of COVID-19
hospitalization
92. Observational
data of RAS
blockade in
COVID-19
Cohen JB et al, under review
Paper Findings
Approach to
confounding
Selection/
Collider Bias
Mehta N et al, JAMA
Cardiol doi:10.1001/
jamacardio.2020.1855
OR 0.97; 95% CI 0.81, 1.15 for test
positivity
P-score weighting Conditioned on
being tested
Mancia G et al, N Engl J
Med 2020; 382:2431-
2440
ACEI: OR 0.96; 95% CI 0.87, 1.07
ARB: OR 0.95, 95% CI 0.86, 1.05 for
test positivity
Matching
Adjustment
Conditioned cases
on a positive test
Reynolds et al, N Engl J
Med 2020; 382:2441-
2448
Median % difference likelihood
ACEI: 0.1, 95% CI -4.3, 4.5
ARB: 1.6, 95% CI 2.6, 5.8 for test
positivity
P-score matching Conditioned on
being tested and on
having a positive
test
de Abajo PFJ et al,
Lancet 2020;
395:1705-1714
OR 0.94; 95% CI 0.77, 1.15 for COVID-
19 hospitalization
Matching
Adjustment
Conditioned cases
on hospitalization
for COVID-19
93. Observational
data of RAS
blockade in
COVID-19
Flacco ME et al, Heart 2020 0:1–6. doi:10.1136/heartjnl-2020-317336
Mackey K et al, Ann Intern Med 2020;173:195-203. doi:10.7326/M20-1515
94. Early RAS
blockade RCT
data
Duarte M, et al. medRxiv 2020.08.04.20167205; doi: 10.1101/2020.08.04.20167205
Telmisartan for treatment of Covid-
19 patients: an open randomized
clinical trial. Preliminary report.
•Telmisartan 80 mg bid during
14 days plus standard care vs.
standard care alone for 14
days
•78 patients were included in
the interim analysis
•Telmisartan treated patients
had lower time to discharge
(median time to discharge
control group=15 days;
telmisartan group=9 days)
Interpret with caution
95. Lung and kidney
ACE2
expression with
ACEI/ARB
therapy
Wysocki J et al, JASN 2020; 31, DOI: 10.1681/ASN.2020050667
Kidney
Lung
96. Summary
•Pandemics bring out some of the best the best and worst in medical publications and journalism
•Early case series pointed towards a high prevalence of hypertension, diabetes, and CVD in patients hospitalized with
COVID-19, which led to speculation about RAS blockade as a potential culprit
• None of these studies were adjusted for age
•We’ve learned new information about hypertension, RAS blockade, and COVID-19
• Observational evidence suggests no association of ACEI/ARB use and risk and severity of COVID-19, but these studies have
limitations
• RCTs are ongoing; not all RCTs are created equally. Consider the design and reporting when interpreting results
• ACEI/ARBs do not seem to increase ACE2 expression in the kidneys and lungs in mice
•Premature or unnecessary discontinuation of ACEIs/ARBs could elevate BP and cause decompensation of chronic
health conditions. De novo initiation of ACEIs/ARBs for use in treating COVID-19 is not recommended at this time.