Erythropoietin (EPO) is a hormone that regulates red blood cell production but also has neuroprotective properties. It is produced in the kidney and liver in response to hypoxia and its receptor is present in the nervous system. EPO protects neurons from apoptosis, oxidative stress, and excitotoxicity through multiple signaling pathways. It also protects the blood-brain barrier integrity and supports angiogenesis, neurogenesis, and synaptogenesis. The document presents several case studies where EPO was administered to patients with brain injuries such as hemorrhage and ischemia and seemed to improve outcomes.
The document summarizes a study investigating the role of extracellular ATP and the P2X7 receptor (P2X7R) in activating inflammasome signaling in neutrophils. The study finds that:
1) ATP induces IL-1β secretion from mouse and human neutrophils in a dose-dependent manner through activation of the P2X7R and downstream NLRP3 inflammasome.
2) Mouse neutrophils express functional cell surface P2X7Rs, as ATP stimulation induces sustained calcium influx and IL-1β release, which is blocked by P2X7R antagonists.
3) ATP-induced IL-1β secretion and caspase-1 activation requires the NLRP3 inflammasome machinery of NLRP3
The document discusses the endothelium and the role of nitric oxide (NO) in the body. It defines the endothelium as the thin layer of cells lining blood vessels and lymphatic vessels. Endothelial cells release NO, previously called endothelium-derived relaxing factor (EDRF), which modulates blood vessel tone. NO is a gaseous signaling molecule synthesized from L-arginine by nitric oxide synthase (NOS). NO has many roles, including regulating circulation and the nervous, immune, digestive, and reproductive systems. It acts as a vasodilator, neurotransmitter, and plays roles in wound healing and apoptosis.
This document discusses various neurotoxins that can contaminate food, including their sources and effects. It focuses on botulinum toxin, which is produced by Clostridium botulinum bacteria and commonly found in improperly canned foods. It acts by blocking the release of acetylcholine at neuromuscular junctions, causing flaccid paralysis. Other neurotoxins discussed include tetrodotoxin from pufferfish and conotoxins from snails, as well as toxic metals like mercury, aluminum, and lead that can contaminate foods. The document emphasizes that following good manufacturing practices is key to avoiding neurotoxin proliferation in foods.
ENDOPLASMIC RETICULUM STRESS IN DIABETIC COMPLICATIONSBasweshwar Gawali
The document discusses endoplasmic reticulum (ER) stress in diabetic complications. It begins by providing background on diabetes and the role of the ER. The ER is responsible for protein folding, modification and transport. Under stress, misfolded proteins accumulate and activate the unfolded protein response (UPR) pathway involving IRE1, PERK and ATF6. Persistent ER stress can lead to apoptosis and organ dysfunction. Conditions like diabetes with high protein load and misfolding in the pancreas and other tissues cause ER stress. Targeting ER stress pathways may provide novel treatment strategies for diabetes and related complications.
This document summarizes a study examining the relationship between impaired brain insulin signaling, amyloid-beta oligomers (AbOs), tau, and cell cycle reentry (CCR) in Alzheimer's disease (AD) pathogenesis. The study finds that AbOs activate the protein kinase mTORC1, which then phosphorylates tau and induces CCR in neurons. CCR can be prevented by insulin-stimulated activation of lysosomal mTORC1. As AbOs also reduce neuronal insulin signaling, decreased insulin signaling allows the toxic effects of AbOs to cause CCR and neuronal death, contributing to AD progression. The findings help explain how impaired brain insulin signaling may promote AD by unleashing the cell cycle reentry effects of Ab
Prostaglandins were discovered in the 1930s and are locally acting lipid compounds derived from fatty acids. They include prostaglandins, thromboxanes, and leukotrienes. Prostaglandins have diverse physiological functions such as regulating inflammation, inducing labor pains, vasodilation/constriction, and sensitizing neurons to pain. They are synthesized through the cyclooxygenase pathway from arachidonic acid and act through G-protein coupled receptors on target cells. Common therapeutic uses of prostaglandins include induction of labor, treatment of hypertension and peripheral vascular diseases.
Erythropoietin (EPO) is a hormone that regulates red blood cell production but also has neuroprotective properties. It is produced in the kidney and liver in response to hypoxia and its receptor is present in the nervous system. EPO protects neurons from apoptosis, oxidative stress, and excitotoxicity through multiple signaling pathways. It also protects the blood-brain barrier integrity and supports angiogenesis, neurogenesis, and synaptogenesis. The document presents several case studies where EPO was administered to patients with brain injuries such as hemorrhage and ischemia and seemed to improve outcomes.
The document summarizes a study investigating the role of extracellular ATP and the P2X7 receptor (P2X7R) in activating inflammasome signaling in neutrophils. The study finds that:
1) ATP induces IL-1β secretion from mouse and human neutrophils in a dose-dependent manner through activation of the P2X7R and downstream NLRP3 inflammasome.
2) Mouse neutrophils express functional cell surface P2X7Rs, as ATP stimulation induces sustained calcium influx and IL-1β release, which is blocked by P2X7R antagonists.
3) ATP-induced IL-1β secretion and caspase-1 activation requires the NLRP3 inflammasome machinery of NLRP3
The document discusses the endothelium and the role of nitric oxide (NO) in the body. It defines the endothelium as the thin layer of cells lining blood vessels and lymphatic vessels. Endothelial cells release NO, previously called endothelium-derived relaxing factor (EDRF), which modulates blood vessel tone. NO is a gaseous signaling molecule synthesized from L-arginine by nitric oxide synthase (NOS). NO has many roles, including regulating circulation and the nervous, immune, digestive, and reproductive systems. It acts as a vasodilator, neurotransmitter, and plays roles in wound healing and apoptosis.
This document discusses various neurotoxins that can contaminate food, including their sources and effects. It focuses on botulinum toxin, which is produced by Clostridium botulinum bacteria and commonly found in improperly canned foods. It acts by blocking the release of acetylcholine at neuromuscular junctions, causing flaccid paralysis. Other neurotoxins discussed include tetrodotoxin from pufferfish and conotoxins from snails, as well as toxic metals like mercury, aluminum, and lead that can contaminate foods. The document emphasizes that following good manufacturing practices is key to avoiding neurotoxin proliferation in foods.
ENDOPLASMIC RETICULUM STRESS IN DIABETIC COMPLICATIONSBasweshwar Gawali
The document discusses endoplasmic reticulum (ER) stress in diabetic complications. It begins by providing background on diabetes and the role of the ER. The ER is responsible for protein folding, modification and transport. Under stress, misfolded proteins accumulate and activate the unfolded protein response (UPR) pathway involving IRE1, PERK and ATF6. Persistent ER stress can lead to apoptosis and organ dysfunction. Conditions like diabetes with high protein load and misfolding in the pancreas and other tissues cause ER stress. Targeting ER stress pathways may provide novel treatment strategies for diabetes and related complications.
This document summarizes a study examining the relationship between impaired brain insulin signaling, amyloid-beta oligomers (AbOs), tau, and cell cycle reentry (CCR) in Alzheimer's disease (AD) pathogenesis. The study finds that AbOs activate the protein kinase mTORC1, which then phosphorylates tau and induces CCR in neurons. CCR can be prevented by insulin-stimulated activation of lysosomal mTORC1. As AbOs also reduce neuronal insulin signaling, decreased insulin signaling allows the toxic effects of AbOs to cause CCR and neuronal death, contributing to AD progression. The findings help explain how impaired brain insulin signaling may promote AD by unleashing the cell cycle reentry effects of Ab
Prostaglandins were discovered in the 1930s and are locally acting lipid compounds derived from fatty acids. They include prostaglandins, thromboxanes, and leukotrienes. Prostaglandins have diverse physiological functions such as regulating inflammation, inducing labor pains, vasodilation/constriction, and sensitizing neurons to pain. They are synthesized through the cyclooxygenase pathway from arachidonic acid and act through G-protein coupled receptors on target cells. Common therapeutic uses of prostaglandins include induction of labor, treatment of hypertension and peripheral vascular diseases.
we are teleologically cardioprotected. we are already cardioprotected. nature has given us everything we need to be unbreakable.we just have to push the right buttons.
please, pay heed to the turtles! they know best!
Nitric oxide (NO) is produced in the body by nitric oxide synthase (NOS) enzymes from the amino acid L-arginine. NO acts as both an intracellular and extracellular signaling molecule and is involved in many physiological processes like neurotransmission and smooth muscle relaxation. There are three isoforms of NOS - neuronal NOS, inducible NOS, and endothelial NOS. NO stimulates soluble guanylate cyclase which increases cyclic GMP levels and triggers smooth muscle relaxation. In addition to cGMP signaling, NO can also signal through S-nitrosylation of proteins or by forming nitrite and nitrate storage pools.
HIF-1 Gene is transcribed in the nucleus with the help of specific protein .HIF-1 protein with DNA binding activity. Functional HIF transcription factors comprise 2 different subunits, that is, alpha (α) and beta (β). The α subunit, of which there are 3 forms ( HIF-1α, HIF-2α and HIF-3α) out of which HIF-1α and HIF-2α are main, HIF-1α is oxygen sensitive, HIF-1α is expressed in almost all cell types, and transcriptionally upregulates a large number of genes, including those encoding Vascular endothelial growth factor (VEGF), Glucose transporters, Glycolytic pathway enzymes , Insulin-like growth factor-2, Endothelin-1, transferrin, HIF-2 is the primary regulator of EPO production and also plays an important role in enterocyte iron uptake.
HIF-β is continuously transcribed and its mRNA and protein are maintained at constant levels irrespective of oxygen levels, the availability of HIF-α is highly dependent on cellular oxygen levels. Thus, the activity of the HIF transcription factor heterodimer is relatively low under normal tissue oxygen conditions called normaxia however, as cellular oxygen levels decrease called hypoxia, HIF-α concentration increases, making HIF progressively more functionally active.
1. Cell signaling involves the synthesis, release, and transport of signaling molecules like neurotransmitters and hormones that bind to receptors on target cells.
2. This triggers signal transduction pathways inside the cell that cause changes in cell behavior.
3. The cell then responds accordingly through actions like releasing other molecules or changing its activity level.
This document describes the autonomic nervous system (ANS) and its sympathetic and parasympathetic divisions. It discusses the origin, neurotransmitters, receptors, and functions of the sympathetic and parasympathetic nervous systems. Key points include:
- The ANS regulates involuntary functions like cardiac output, respiration, and glandular secretions.
- The sympathetic division originates in the thoracic spinal cord and uses norepinephrine as its neurotransmitter. The parasympathetic division originates in cranial and sacral regions and uses acetylcholine.
- Target organs receive dual innervation from both divisions, with opposing effects. The overall response depends on the balance of activity between the two.
This document provides an overview of a course on HIF (hypoxia-inducible factor) in cell biology and physiology. The course aims to explore how oxygen levels vary both in cell culture and in vivo, understand the molecular basis of the HIF pathway, and consider various factors that contribute to and result from HIF activation. Key points covered include the roles of oxygen transport and tissue oxygenation, the regulation of HIF by prolyl hydroxylases, and the adaptive cellular responses mediated by HIF, such as erythropoiesis and angiogenesis. The impacts of HIF in cancer biology and its complex interactions with other pathways are also briefly discussed.
Epoetin alfa (Epogen) is a 165-amino acid glycoprotein produced using recombinant DNA technology that stimulates red blood cell production. It binds to the erythropoietin receptor and activates pathways involved in erythrocyte differentiation and maintenance of circulating red blood cell mass. Epoetin alfa is used to treat anemia by increasing reticulocyte count within 10 days and red blood cell count, hemoglobin levels within 2 to 6 weeks. Common side effects include headache, body aches, diarrhea, and joint, bone, or muscle pain.
A Powerpoint presentation on the basics of Eicosanoids which includes Prostaglandins, Leukotrienes (LTs) ad Platelete Activating Factors (PAF) suitable for Undergraduate level Medical students.
The document discusses the endoplasmic reticulum (ER), which is an extensive membrane network inside cells. It has two regions: the smooth ER and rough ER. The rough ER is studded with ribosomes and finishes making proteins. It is important for producing proteins that are essential for other organelles to function. The smooth ER produces lipids, engages in metabolism, and makes steroid hormones. It is also involved in detoxification. Dysfunctions of the ER and unfolded protein response are associated with neurodegenerative diseases like Parkinson's and kidney diseases. Treating ER stress may aid in diagnosis and treatment of such diseases.
This document discusses the use of erythropoietin (EPO) to treat hypoxic-ischemic encephalopathy (HIE) in newborns. HIE results from reduced oxygen and blood flow to the brain and can cause death or disabilities. The standard treatment is therapeutic hypothermia within 6 hours, but this only helps some infants. EPO may provide additional neuroprotection when given with hypothermia. Animal studies show EPO improves outcomes when given after brain injury. A clinical trial found better motor outcomes at 12 months for EPO plus hypothermia versus hypothermia alone. The document recommends criteria for giving EPO to babies in low-resource settings who experience HIE, including signs of moderate-
This document summarizes various mediators of inflammation. It describes that mediators are either cell-derived and stored in granules or plasma-derived and activated by proteolytic cleavage. Key cell-derived mediators discussed include histamine from mast cells, prostaglandins and leukotrienes derived from arachidonic acid, and cytokines like TNF and IL-1. Plasma protein systems activated during inflammation are the complement, kinin, and coagulation systems which generate inflammatory peptides like bradykinin, C3a, and thrombin. Reactive oxygen species and nitric oxide are also discussed as mediators with both pro-inflammatory and anti-inflammatory roles.
The document describes the expression of erythropoietin (EPO) in a pET-28a vector. EPO is a glycoprotein that regulates red blood cell production. The author details EPO's structure and function, as well as its commercial importance as a treatment for anemia. She then outlines her methodology for expressing both native EPO and a fusion EPO protein with a histidine tag in E. coli cells. Comparing the expressed proteins to the natural sequence confirms their functionality in vitro.
Today around 47 million people survive with dementia, globally. This number is projected to increase to more than 131 million by 2050. About 2.1 million Alzheimer's patients having age of 85 years or older were reported in year 2017.
Direct conversion of neurons to fibroblastssyed shafiq
The document summarizes a research article that was published in Nature in 2010. The study found that fibroblasts could be directly converted into functional neurons by infecting the cells with viruses containing five transcription factor genes (Ascl1, Brn2, Myt1l, Zic1, and Olig2). The resulting induced neuronal (iN) cells displayed neuronal morphology, membrane properties, and ability to form functional synapses similar to primary neurons. Further experiments showed that Ascl1 alone or Ascl1 combined with Brn2 and Myt1l were able to generate iN cells, demonstrating the key factors required for direct neuronal conversion.
Neuropeptides are small protein-like molecules that neurons use to communicate with each other. They influence various brain and bodily functions. Some peptides act as both hormones and neuropeptides. Neuropeptide Y (NPY) is involved in processes like feeding, learning, and social behavior. It has therapeutic potential for treating obesity and anxiety/depression. Calcitonin gene-related peptide (CGRP) is a vasodilator that may be linked to migraines. Substance P is associated with pain and inflammation. Cholecystokinin is a gut-brain hormone involved in processes like feeding and anxiety. Many neuropeptides act through G-protein coupled receptors and have potential pharmacological applications.
A Critical Role of Erythropoietin Receptor in Neurogenesis and Post-Stroke Re...johnohab
Erythropoietin (EPO) is the principal growth factor regulating the production of red blood cells. Recent studies demonstrated that
exogenous EPO acts as a neuroprotectant and regulates neurogenesis. Using a genetic approach, we evaluate the roles of endogenous EPO
and its classical receptor (EPOR) in mammalian neurogenesis. We demonstrate severe and identical embryonic neurogenesis defects in
animals null for either the Epo or EpoR gene, suggesting that the classical EPOR is essential for EPO action during embryonic neurogenesis.
Furthermore, by generating conditional EpoR knock-down animals, we demonstrate that brain-specific deletion of EpoR leads to
significantly reduced cell proliferation in the subventricular zone and impaired post-stroke neurogenesis. EpoR conditional knockdown
leads to a specific deficit in post-stroke neurogenesis through impaired migration of neuroblasts to the peri-infarct cortex. Our results
suggest that both EPO and EPOR are essential for early embryonic neural development and that the classical EPOR is important for adult
neurogenesis and for migration of regenerating neurons during post-injury recovery.
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 file is all about eicosanoids including prostaglandins,prostacyclins and leukutriens with its mechanism of formation and inhibitors of LOX and COX pathways
Nitric oxide and its role in reproductiondavid sonwani
Nitirc oxide an noble gas signaling molecule present in all types of living organism as an excretory product. has multiple role in body including defense cure and mainly reproduction.
- GnRH neuronal cell bodies are located in the hypothalamus and extend processes to the median eminence where GnRH is released into the hypophyseal portal system.
- The hypophyseal portal system connects hypothalamic GnRH neurons to gonadotropes in the anterior pituitary.
- GnRH stimulates the anterior pituitary to secrete LH and FSH, which then direct gonadal function in the ovaries and testes.
Physiological reduction of the gonadal sex hormones in old ages results in declined neurogenesis especially in the hippocampus with the resultant age dependent memory and executive functions regressions.
Physiological reduction of the gonadal sex hormones in old ages results in declined neurogenesis especially in the hippocampus with the resultant age dependent cognitive impairment and risk of AD
we are teleologically cardioprotected. we are already cardioprotected. nature has given us everything we need to be unbreakable.we just have to push the right buttons.
please, pay heed to the turtles! they know best!
Nitric oxide (NO) is produced in the body by nitric oxide synthase (NOS) enzymes from the amino acid L-arginine. NO acts as both an intracellular and extracellular signaling molecule and is involved in many physiological processes like neurotransmission and smooth muscle relaxation. There are three isoforms of NOS - neuronal NOS, inducible NOS, and endothelial NOS. NO stimulates soluble guanylate cyclase which increases cyclic GMP levels and triggers smooth muscle relaxation. In addition to cGMP signaling, NO can also signal through S-nitrosylation of proteins or by forming nitrite and nitrate storage pools.
HIF-1 Gene is transcribed in the nucleus with the help of specific protein .HIF-1 protein with DNA binding activity. Functional HIF transcription factors comprise 2 different subunits, that is, alpha (α) and beta (β). The α subunit, of which there are 3 forms ( HIF-1α, HIF-2α and HIF-3α) out of which HIF-1α and HIF-2α are main, HIF-1α is oxygen sensitive, HIF-1α is expressed in almost all cell types, and transcriptionally upregulates a large number of genes, including those encoding Vascular endothelial growth factor (VEGF), Glucose transporters, Glycolytic pathway enzymes , Insulin-like growth factor-2, Endothelin-1, transferrin, HIF-2 is the primary regulator of EPO production and also plays an important role in enterocyte iron uptake.
HIF-β is continuously transcribed and its mRNA and protein are maintained at constant levels irrespective of oxygen levels, the availability of HIF-α is highly dependent on cellular oxygen levels. Thus, the activity of the HIF transcription factor heterodimer is relatively low under normal tissue oxygen conditions called normaxia however, as cellular oxygen levels decrease called hypoxia, HIF-α concentration increases, making HIF progressively more functionally active.
1. Cell signaling involves the synthesis, release, and transport of signaling molecules like neurotransmitters and hormones that bind to receptors on target cells.
2. This triggers signal transduction pathways inside the cell that cause changes in cell behavior.
3. The cell then responds accordingly through actions like releasing other molecules or changing its activity level.
This document describes the autonomic nervous system (ANS) and its sympathetic and parasympathetic divisions. It discusses the origin, neurotransmitters, receptors, and functions of the sympathetic and parasympathetic nervous systems. Key points include:
- The ANS regulates involuntary functions like cardiac output, respiration, and glandular secretions.
- The sympathetic division originates in the thoracic spinal cord and uses norepinephrine as its neurotransmitter. The parasympathetic division originates in cranial and sacral regions and uses acetylcholine.
- Target organs receive dual innervation from both divisions, with opposing effects. The overall response depends on the balance of activity between the two.
This document provides an overview of a course on HIF (hypoxia-inducible factor) in cell biology and physiology. The course aims to explore how oxygen levels vary both in cell culture and in vivo, understand the molecular basis of the HIF pathway, and consider various factors that contribute to and result from HIF activation. Key points covered include the roles of oxygen transport and tissue oxygenation, the regulation of HIF by prolyl hydroxylases, and the adaptive cellular responses mediated by HIF, such as erythropoiesis and angiogenesis. The impacts of HIF in cancer biology and its complex interactions with other pathways are also briefly discussed.
Epoetin alfa (Epogen) is a 165-amino acid glycoprotein produced using recombinant DNA technology that stimulates red blood cell production. It binds to the erythropoietin receptor and activates pathways involved in erythrocyte differentiation and maintenance of circulating red blood cell mass. Epoetin alfa is used to treat anemia by increasing reticulocyte count within 10 days and red blood cell count, hemoglobin levels within 2 to 6 weeks. Common side effects include headache, body aches, diarrhea, and joint, bone, or muscle pain.
A Powerpoint presentation on the basics of Eicosanoids which includes Prostaglandins, Leukotrienes (LTs) ad Platelete Activating Factors (PAF) suitable for Undergraduate level Medical students.
The document discusses the endoplasmic reticulum (ER), which is an extensive membrane network inside cells. It has two regions: the smooth ER and rough ER. The rough ER is studded with ribosomes and finishes making proteins. It is important for producing proteins that are essential for other organelles to function. The smooth ER produces lipids, engages in metabolism, and makes steroid hormones. It is also involved in detoxification. Dysfunctions of the ER and unfolded protein response are associated with neurodegenerative diseases like Parkinson's and kidney diseases. Treating ER stress may aid in diagnosis and treatment of such diseases.
This document discusses the use of erythropoietin (EPO) to treat hypoxic-ischemic encephalopathy (HIE) in newborns. HIE results from reduced oxygen and blood flow to the brain and can cause death or disabilities. The standard treatment is therapeutic hypothermia within 6 hours, but this only helps some infants. EPO may provide additional neuroprotection when given with hypothermia. Animal studies show EPO improves outcomes when given after brain injury. A clinical trial found better motor outcomes at 12 months for EPO plus hypothermia versus hypothermia alone. The document recommends criteria for giving EPO to babies in low-resource settings who experience HIE, including signs of moderate-
This document summarizes various mediators of inflammation. It describes that mediators are either cell-derived and stored in granules or plasma-derived and activated by proteolytic cleavage. Key cell-derived mediators discussed include histamine from mast cells, prostaglandins and leukotrienes derived from arachidonic acid, and cytokines like TNF and IL-1. Plasma protein systems activated during inflammation are the complement, kinin, and coagulation systems which generate inflammatory peptides like bradykinin, C3a, and thrombin. Reactive oxygen species and nitric oxide are also discussed as mediators with both pro-inflammatory and anti-inflammatory roles.
The document describes the expression of erythropoietin (EPO) in a pET-28a vector. EPO is a glycoprotein that regulates red blood cell production. The author details EPO's structure and function, as well as its commercial importance as a treatment for anemia. She then outlines her methodology for expressing both native EPO and a fusion EPO protein with a histidine tag in E. coli cells. Comparing the expressed proteins to the natural sequence confirms their functionality in vitro.
Today around 47 million people survive with dementia, globally. This number is projected to increase to more than 131 million by 2050. About 2.1 million Alzheimer's patients having age of 85 years or older were reported in year 2017.
Direct conversion of neurons to fibroblastssyed shafiq
The document summarizes a research article that was published in Nature in 2010. The study found that fibroblasts could be directly converted into functional neurons by infecting the cells with viruses containing five transcription factor genes (Ascl1, Brn2, Myt1l, Zic1, and Olig2). The resulting induced neuronal (iN) cells displayed neuronal morphology, membrane properties, and ability to form functional synapses similar to primary neurons. Further experiments showed that Ascl1 alone or Ascl1 combined with Brn2 and Myt1l were able to generate iN cells, demonstrating the key factors required for direct neuronal conversion.
Neuropeptides are small protein-like molecules that neurons use to communicate with each other. They influence various brain and bodily functions. Some peptides act as both hormones and neuropeptides. Neuropeptide Y (NPY) is involved in processes like feeding, learning, and social behavior. It has therapeutic potential for treating obesity and anxiety/depression. Calcitonin gene-related peptide (CGRP) is a vasodilator that may be linked to migraines. Substance P is associated with pain and inflammation. Cholecystokinin is a gut-brain hormone involved in processes like feeding and anxiety. Many neuropeptides act through G-protein coupled receptors and have potential pharmacological applications.
A Critical Role of Erythropoietin Receptor in Neurogenesis and Post-Stroke Re...johnohab
Erythropoietin (EPO) is the principal growth factor regulating the production of red blood cells. Recent studies demonstrated that
exogenous EPO acts as a neuroprotectant and regulates neurogenesis. Using a genetic approach, we evaluate the roles of endogenous EPO
and its classical receptor (EPOR) in mammalian neurogenesis. We demonstrate severe and identical embryonic neurogenesis defects in
animals null for either the Epo or EpoR gene, suggesting that the classical EPOR is essential for EPO action during embryonic neurogenesis.
Furthermore, by generating conditional EpoR knock-down animals, we demonstrate that brain-specific deletion of EpoR leads to
significantly reduced cell proliferation in the subventricular zone and impaired post-stroke neurogenesis. EpoR conditional knockdown
leads to a specific deficit in post-stroke neurogenesis through impaired migration of neuroblasts to the peri-infarct cortex. Our results
suggest that both EPO and EPOR are essential for early embryonic neural development and that the classical EPOR is important for adult
neurogenesis and for migration of regenerating neurons during post-injury recovery.
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 file is all about eicosanoids including prostaglandins,prostacyclins and leukutriens with its mechanism of formation and inhibitors of LOX and COX pathways
Nitric oxide and its role in reproductiondavid sonwani
Nitirc oxide an noble gas signaling molecule present in all types of living organism as an excretory product. has multiple role in body including defense cure and mainly reproduction.
- GnRH neuronal cell bodies are located in the hypothalamus and extend processes to the median eminence where GnRH is released into the hypophyseal portal system.
- The hypophyseal portal system connects hypothalamic GnRH neurons to gonadotropes in the anterior pituitary.
- GnRH stimulates the anterior pituitary to secrete LH and FSH, which then direct gonadal function in the ovaries and testes.
Physiological reduction of the gonadal sex hormones in old ages results in declined neurogenesis especially in the hippocampus with the resultant age dependent memory and executive functions regressions.
Physiological reduction of the gonadal sex hormones in old ages results in declined neurogenesis especially in the hippocampus with the resultant age dependent cognitive impairment and risk of AD
Yousry Endothelial Vs Erectile Dysfunctionguest5a246c
Endothelial dysfunction is associated with erectile dysfunction. The endothelium normally releases nitric oxide which causes vasodilation and erection by relaxing smooth muscle. However, in endothelial dysfunction the nitric oxide pathway is disrupted, inhibiting vasodilation and leading to erectile dysfunction. Risk factors for developing both endothelial dysfunction and erectile dysfunction include diabetes, smoking, hypertension, hyperlipidemia, and other conditions.
This document discusses neuropeptides, which are small protein molecules that play a role in communication between nervous system cells. Some key points:
- Neuropeptides are produced in nervous system cells and regulate functions like temperature, appetite, circadian rhythms and behavior.
- They are encoded by genes and synthesized as precursor proteins which are processed into shorter peptide chains.
- Common neuropeptides discussed include substance P, CGRP, NPY, oxytocin, and vasopressin. These have various roles like pain signaling, vasodilation, appetite regulation, and social behaviors.
- Neuropeptides act through G-protein coupled receptors and can influence processes like gene expression, synaptogenesis and
This document reports on a study examining how carbon monoxide (CO) induces heme oxygenase-1 (HO-1) expression and inhibits endothelial cell apoptosis triggered by endoplasmic reticulum (ER) stress. The key findings are:
1) CO activates the transcription factor Nrf2 through phosphorylation of the protein kinase R-like ER kinase (PERK), leading to increased HO-1 expression.
2) CO-induced PERK activation results in phosphorylation of eukaryotic translation initiation factor 2α and expression of activating transcription factor 4.
3) CO prevents ER stress-induced expression of X-box binding protein 1 and cleavage of activating transcription factor 6.
4) CO inhibits
Neurochemical transmission in the brain dr lateef 2021lateef khan
This document discusses neurochemical transmission in the brain. It begins by explaining the importance of understanding how drugs act in the central nervous system and the methods that have been developed to study neuropharmacology. These methods include microelectrodes, brain slice techniques, patch clamping, histochemistry, and molecular cloning. The document then describes the major excitatory and inhibitory neurotransmitters in the brain and how neurotransmission occurs. Specific topics covered include glutamate, GABA, receptors, and how drugs can target neurotransmission pathways.
Prion proteins are naturally occurring proteins found in brain cells that play roles in neuronal signaling and protection. When prion proteins misfold, they can influence other prion proteins to misfold as well, leading to prion diseases. Misfolded prion proteins are resistant to the cell's quality control system and cause neurodegeneration. A recent study found that a single misfolded prion protein molecule can be highly toxic, challenging theories that protein aggregates are always required for toxicity. Misfolded proteins may also play a role in diabetes by damaging insulin-producing pancreatic cells and disrupting protein quality control in the endoplasmic reticulum.
Different types of receptors can drugs affect the body through interacting with these receptors.
this presentation is a part from special course in basics of pharmacology .. deep and simple
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.
This slide show has been prepared to be presented in the 4th edition of World Congress on Endocrinology, Diabetes and Metabolism, (EDM 2023 Congress)
Sep 07-08, 2023,
Rome, Italy
The document discusses arterial blood gas (ABG) analysis and its potential use as an indicator of physical endurance following cardiac surgery. It provides background on cardiac rehabilitation programs and exercises that can improve cardiopulmonary function and quality of life after surgery. ABG analysis measures parameters related to ventilation, acid-base balance, and oxygenation. Precise interpretation of ABG results can guide medical management and identify acid-base disorders that may require intervention.
COVID-19 poses a serious global health threat in the 21st century. There are currently no approved vaccines or antiviral treatments for COVID-19. The virus enters cells by binding to the ACE2 receptor and causes severe lung damage. High levels of proinflammatory cytokines are associated with worse outcomes. Blocking the renin-angiotensin system may help attenuate acute respiratory distress syndrome. Computational studies indicate certain molecules may reduce the affinity of SARS-CoV-2 for the ACE2 receptor.
This review article was presented in the 7th International joint cardiovascular congress held on Feb 28-29, 2019, in Convention Center, Shahid Rejaee Heart Hospital, Tehran, Iran
The metabolic syndrome is a constellation of conditions that increases the risk of atherosclerotic cardiovascular disease and type 2 diabetes. It is characterized by central obesity, high blood pressure, high blood sugar, high triglycerides, and low HDL cholesterol. The metabolic syndrome is caused by excess caloric intake and sedentary lifestyle and predisposes patients to insulin resistance. It affects 10-40% of adults worldwide and presents a major health challenge.
Cardiac rehabilitation (CR) is a multidisciplinary program that helps patients restore health and reduce future heart risks after a cardiac event. CR includes exercise training, risk factor modification, and psychosocial support. The goals are to influence the underlying heart disease, optimize physical and mental health, and help patients resume normal activities. CR is delivered in phases from the hospital through long-term maintenance. Exercise training in CR increases cardiovascular fitness and muscle adaptations, lowering heart rate and blood pressure during activity. Arterial blood gases are analyzed to assess respiratory function and acid-base status, and guide safe exercise progression in CR.
The document discusses the role of cytokines in mental status and neurological conditions. It states that cytokines are small signaling proteins released during inflammation that can influence cognition, mood, and behavior. Elevated cytokine levels are associated with depression, anxiety, and stress disorders. Cytokines like IL-1β, TNF-α, and IL-6 are involved in modulating memory and synaptic plasticity in the hippocampus. They have also been linked to delirium, cognitive impairment, and neurodegenerative disorders. While acute inflammation is normal, chronic or dysregulated cytokine activity can negatively impact mental functioning through effects on the brain and neurotransmitter systems.
Cell Therapy Expansion and Challenges in Autoimmune DiseaseHealth Advances
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3. Neuro-protective effects of EPO
Viault (1890)
Carnot and Deflandre (1906)
There must be hormone to increase
erythropoiesis in high altitude, it
regulates erythropoiesis
Jacobson (1957) and Nathan (1964):
the kidney is the major site but not the
sole site of Epo production.
Goldwasser and his team (1977):
prepared 8 mg of highly purified human
Epo
3
4. Neuro-protective effects of EPO
EPO:
Is required for:
survival,
Proliferation,
differentiation
of erythroid progenitor cells in
bone marrow, and
Prevents apoptosis in progenitor
cells
4
5. Neuro-protective effects of EPO
EPO:
Produced by renal interstitial
cells having a neuron-like shape
and express marker antigens
found in neuronal cells
Ito cells in the liver produces
EPO; very similar to the EPO-
producing renal fibroblast-like
interstitial cells,
5
6. Neuro-protective effects of EPO
Epo and Epo-R
EPO-R
belongs to the cytokine receptor superfamily
consists of:
an extracellular domain,
a transmembrane domain,
an intracellular domain.
6
8. Neuro-protective effects of EPO
EPO and EPO-R can be
found in the:
Nervous system,
Cardiovascular system,
Digestive system,
Endocrine system,
Female and male
reproductive system,
Respiratory system
Spleen
8
9. Neuro-protective effects of EPO
EPO production and secretion:
regulated by the tissue oxygen
supply (kidney, liver, brain)
via activation of the hypoxia-
inducible factor 1 (HIF-1)
pathway
9
10. Neuro-protective effects of EPO
HIF:
a heterodimeric protein
α- and β-subunits
HIF α-subunits (1, 2, 3):
regulated by oxygen tension,
in normoxia hydroxylated,
degraded by pVHL
in hypoxia not hydroxylated
HIF β-subunit:
constitutively expressed.
10
11. Neuro-protective effects of EPO
the expression of EPO-R is:
not sensitive to hypoxia???
regulated by:
pro-inflammatory cytokines:
TNFα, IL-1β
erythropoietin
probably other unidentified factors
11
12. Neuro-protective effects of EPO
In EPO or EPO-R knock-out
mice:
Apoptosis increases prior to the
onset of anemia
There seems to be a functional
role of EPO/EPO-R signaling
rather than erythropoiesis
12
14. Neuro-protective effects of EPO
auto-phosphorylation
of JAK-2 results in
activation of several
signaling pathways:
RAS/MAPK with the
ability to activate
STAT5
up-regulating
antiapoptotic proteins
Bcl-2 and Bcl-XL
EPO+EPO-R
activates
JAK-2
RAS/MAPK
STAT5
upregulation of
Bcl-2, Bcl-XL
14
15. Neuro-protective effects of EPO
auto-phosphorylation
of JAK-2 results in
activation of several
signaling pathways:
PI3K/AKT:
inhibits pro-apoptotic
molecules and prevents
release of cytochrome
c from mitochondria
PI3K/AKT
inhibition of
activation of
JAK-2
EPO+EPO-R
GSK-3β
caspase -3/-9
BAD
15
16. Neuro-protective effects of EPO
auto-phosphorylation
of JAK-2 results in
activation of several
signaling pathways:
PI3K/AKT:
Phosphorylation of
GATA-1
Inhibition of BAD, GSK
and caspase-3/-9
results in aborting
apoptosis
PI3K/AKT
inhibition of
activation of
JAK-2
EPO+EPO-R
GSK-3β
caspase -3/-9
BAD
16
17. Neuro-protective effects of EPO
auto-phosphorylation of
JAK-2 results in activation
of several signaling
pathways:
PI3K/AKT:
Down-regulation of NF-ƙB:
suppresses pro-inflammatory
cytokines likeTNF-α and IL-6
and simultaneously
increases anti-inflammatory
cytokine IL-10 level.
EPO+EPO-R
JAK-2
NF-ƙB
downregulation
TNF-α
IL-6
IL-10
anti-
inflammatory
effect
17
18. Neuro-protective effects of EPO
auto-phosphorylation
of JAK-2 results in
activation of several
signaling pathways:
PI3K/AKT:
Expression of eNOS
(endothelial Nitric
Oxide Synthase)
eNOS
PI3K/AKT
EPO+EPO-R
JAK-2
NO
&vasodilatation
NADPH oxidase inhibition
&
ROS
18
19. Neuro-protective effects of EPO
a multicenter double blinded
clinical study in Germany:
EPO had no cell-protective
effect or even might be
hazardous in humans.
Ehrenreich H, Weissenborn K, Prange H.
Recombinant Human Erythropoietin in the
Treatment of Acute Ischemic Stroke. Stroke. 2009;
40: e647-e656
19
20. Neuro-protective effects of EPO
the modulatory effect of EPO
on the central respiratory
commands:
acute (less than 1 hour) and
chronic EPO administration:
attenuated and abolished
hypoxia-induced central
respiratory depression
MEK½ and PI3K pathways
mediates this response
Repir Physiol Neurobiol. 2015; 206: 36-40
20
21. Neuro-protective effects of EPO
The report of a phase II double blinded
placebo controlled study in infants with
moderate to severe hypoxic/ischemic
encephalopathy:
EPO could:
1) diminish MRI brain injury, and
2) improve the motor function of
the infants after 1 year, yet
3) the mortality did not differ
significantly
Pediatrics. 2016; 137(6): e20160191
21
22. Neuro-protective effects of EPO
EPO-R knock-out mice:
Low level of neural progenitor
cells
Low neurogenesis
22
23. Neuro-protective effects of EPO
High baseline concentration
of EPO-R is expressed as an
autocrine/paracrine system
in:
astrocytes that surround
capillaries in white matter,
purkinje neurons,
the choroid plexus
the ependymal cells
limbic system and hippocampus
23
24. Neuro-protective effects of EPO
EPO and EPO-R:
Expressed in low levels in
healthy brain
Increase markedly following
injuries
24
25. Neuro-protective effects of EPO
EPO: Does it pass through BBB?
cannot penetrate BBB:
in hypoxia/ischemia permeability of
BBB increases, and
peripherally administered EPO:
can be found in CSF in rats, primates
and humans.
through the extracellular
pathways.
25
26. Neuro-protective effects of EPO
the absolute source of EPO in the
CNS is not the blood.
it is produced de novo in the CNS
tissue hypoxia in the CNS increases:
EPO concentration
EPO-R expression
26
27. Neuro-protective effects of EPO
EPO expression in the nervous system
is regulated by:
the tissue oxygen supply and via
activation of the (HIF-1) pathway
In non-hypoxic circumstances:
mechanical damage
Infection
metabolic stress (glucose , insulin?)
oxidative stress
elevated temperature
Intense neural activity
enriched environment
pro-inflammatory cytokines
27
28. Neuro-protective effects of EPO
CNS lesions:
primary injury:
Necrotic core, Penumbra
Infiltration of inflammatory
cells
secondary injury:
Propagation of necrotic core
and lesion in the penumbra
Final pathway:
resorption of cellular debris
gliosis vs regenerating a
functional tissue
28
29. Neuro-protective effects of EPO
Ischemic/hypoxic and other
types of brain injuries:
lack of oxygen and nutrients
pro-inflammatory mediators in
neurovascular unit:
TNF-α, IL-6, ICAM-1
brain edema and hemorrhagic
transformation
neural cell apoptosis and death
29
30. Neuro-protective effects of EPO
Reperfusion
restoration of perfusion in
the ischemic lesion
oxygen stress
free radical formation
excitotoxicity,
nitric oxide production
30
31. Neuro-protective effects of EPO
In brain injuries the
leakiness of BBB
due to:
inflammatory
mediators,
reactive oxygen
species (ROS),
VEGF,
MMP,
microRNA
31
32. Neuro-protective effects of EPO
HIF-1α in hypoxic brain
insult:
expression ofVEGF,
VEGFR and MMP-9, AQP-4:
BBB hyer-permeability
Brain edema
inhibition of HIF-1α:
cerebral edema through:
MMP-9 and AQP-4
32
33. Neuro-protective effects of EPO
Neural stem cells in
mammals:
SGZ, SVZ, OB
In cortical injuries:
neuroblasts originating
from SVZ stem/progenitor
cells migrates to the
penumbra:
VEGF, IGF-1, SDF-1/CXCR-4
and Ang-1/Tie-2 signals
33
34. Neuro-protective effects of EPO
MMPs:
With several significant
physiological
potentials involved in:
growth,
development,
tissue repair and wound
healing
synaptic plasticity
neurite growth
myelinogenesis.
34
35. Neuro-protective effects of EPO
MMPs:
up-regulated and activated
in ischemic and other brain
injuries,
Its latent form is activated
by:
Endogenous and exogenous
plasminogen activator
Furin
free radicals
35
36. Neuro-protective effects of EPO
Angiogenesis:
proliferation of mature endothelial and endothelial
progenitor cells (EPC) located in the penumbra in the
first 12-24 hour after the insult
VEGF leads the process
36
37. Neuro-protective effects of EPO
VEGF:
a family of cytokines,
induce angiogenesis
through proliferation,
sprouting, migration of
the endothelial cells and
New vascular tube
formation by these cells.
Found in pericytes in the
border of brain lesions
37
38. Neuro-protective effects of EPO
VEGF:
After binding withVEGFR-2 increases
vascular permeability through activating
cGMP and a NO-dependent pathway
38
39. Neuro-protective effects of EPO
AQP-4
integral membrane proteins
plays important roles in:
mediating water
homeostasis
bidirectional passive trans-
cellular water transfer in
response to osmotic
gradient
the expression of this channel
is modulated by HIF-1 and
VEGF
39
41. Neuro-protective effects of EPO
Strategy against CNS
insults:
Decrease apoptosis and
supporting the cells
restore delivery of
oxygen and nutrients
(angiogenesis)
suppressing edema and
saving the integrity of
BBB, {ASAP}
supporting neurogenesis
and synaptogenesis
(ECM)
41
42. Neuro-protective effects of EPO
hypoxia dose-dependently
makes astrocytes secret
EPO
EPO has a trophic paracrine
effect on:
Neurons,
Astrocytes,
Microglia.
42
43. Neuro-protective effects of EPO
EPO:
Protects the neural
cells against reduced
oxygen tension,
ecitotoxicity and ROS
or other free radicals
43
44. Neuro-protective effects of EPO
EPO
facilitates energy production
in mitochondria:
stabilizing mitochondrial
membrane potential
Inhibiting free radical
production in mitochondria
44
45. Neuro-protective effects of EPO
EPO in the nervous system:
apoptosis,
inflammatory responses
re-establishment of compromised
functions by support of :
1) proliferation,
2) Migration, and
3) differentiation
of progenitor cells to compensate
for the lost or injured cells
45
46. Neuro-protective effects of EPO
rhEPO could protect BBB:
By up-regulating theTJ
proteins
MMP
glial cell inflammatory
reactions,
TNF-α levels and
NF–кβ activation
46
47. Neuro-protective effects of EPO
EPO protects BBB:
againstVEGF-induced injury
and the resulting hyper-
permeability in early phases
of brain insults
have cytoprotective effect
on endothelial cells in
ischemic insults
inhibit AQP-4-induced
astrocyte swelling through
activating JNK and MAPK
47
48. Neuro-protective effects of EPO
Endogenous EPO was
attributed to:
Induce neural
stem/progenitor cells to
proliferate, migrate and
differentiate in addition to
survive
in rats, EPO-R is more
concentrated on neural
progenitor cells (NPCs)
than on the mature ones
48
49. Neuro-protective effects of EPO
astrocyte-derived EPO
anti-apoptotic factor for
microglia:
without having any influence on
pro-inflammatory potentials
dose-dependent proliferative
effect on microglia
Bcl/Bax ratio in the microglia
prevents activation of caspase-
3 and -9
49
50. Neuro-protective effects of EPO
EPO completes the loop of
a physiological feedback
pathway by:
inducing MMP-2 and -9
which promotes angiogenesis
and migration of neuronal
progenitor cells
limiting MMPs activity to a
restricted area throughTIMPs
expression by astrocytes
50
51. Neuro-protective effects of EPO
EPO through activating
PI3K/Akt pathway
regulates:
TIMP-1 gene transcription,
TIMP-1 mRNA induction and
TIMP-1 expression
51
52. Neuro-protective effects of EPO
EPO supports
regenerating neurons
and astroglial cells by:
regulating MMP-2, MMP-9
andVEGF
increasingVEGF receptors
1, 2 and 3 in hypoxia
52
53. Neuro-protective effects of EPO
EPO increases survival of
cultured endothelial cells
through:
activating Akt1 pathway,
stabilizing mitochondrial
membrane potentials and
inhibiting caspase 3 and-9
53
54. Neuro-protective effects of EPO
EPO has pro-angiogenic
property:
Induces endothelial cell to:
proliferate,
migrate,
produce nitric oxide (NO),
degrade ECM delicately,
differentiate
Mobilizes the endothelial
progenitor cells,
54
55. Neuro-protective effects of EPO
Effective synaptogenesis
needs high degree of
plasticity through
regulating the
consistency of perineural
net and ECM remodeling:
Role of MMPs in cognition,
memory, learning
55
56. Neuro-protective effects of EPO
activation of EPOR in
cultured young rat
cerebellar and hippocampal
neurons:
reduces glutamate release
by inhibiting calcium-
dependent exocytosis of this
excitatory amino acid
56
57. Neuro-protective effects of EPO
rhEPO in reperfusion injury:
up-regulation of IL-1β and
IL-18, MMP-2 and MMP-9
protects against oxygen
toxicity and free radicals
(ROS, RNS) through:
pro-inflammatory
mediators
57
58. Neuro-protective effects of EPO
rhEPO attenuates ischemia-
induced inflammation by:
reducing neuronal death
rather than by direct effects
upon EPO-R–expressing
inflammatory cells.
rhEPO rescues neurons
within the penumbra from
apoptosis
58
59. Neuro-protective effects of EPO
EPO :
TNF-α, IL-6, and
monocyte chemo-attractant
protein-1 (MCP-1)
TNF-α, IL-1:
Inhibits EPO production
59
60. Neuro-protective effects of EPO
EPO, in neonatal rats:
after hypoxic/ischemic injury
stimulated:
oligodendrogenesis
attenuated white matter damage
EPO, in adult rats:
after stroke
amplified myelinating oligodendrocytes
increased myelinated axons in peri-infarct
white matter and
improved functional outcome
60
61. Neuro-protective effects of EPO
EPO, in MCAO in adult
mice brains:
reduced demyelination
astrocyte activation, and
decreased the protein level
of β-APP.
inhibited Nogo-A and MAG
protein levels after cerebral
ischemia:
attenuating axonal injury
61
77. Neuro-protective effects of EPO
Now, we have a new vision
of EPO’s effect in the
nervous system:
anti-apoptotic,
anti-oxidant,
anti-inflammatory
neuro-protective by
stimulation of :
Angiogenesis
Neurogenesis
77