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Anatomy Physiology Pharmacology Analysis

View attached explanation and answer. Let me know if you have any questions.1Medical Health ExpertiseMedical Health ExpertiseStudent NameCourse TitleProfessorDate2Medical Health ExpertiseMedical health expertiseINTRODUCTIONWhen your body detects and recognizes pathogens. It defends itself against it. Various immuneresponses vary depending on the type of pathogen. In some scenarios, the body may startfighting its healthy tissues, causing a condition called Rheumatoid arthritis. The exact cause ofthis condition is not well determined. There is no cure for this condition; however, the body takesthe initiative to deal with such a condition before it arises. Various immune responses exist in thebody that fight autoimmune responses causing this condition. RA majorly invades joints, but itcould also spread to other body tissues such as skin, heart, blood vessels, etc. In the most recentstudies, Rheumatoid arthritis is associated with a genetic compilation that transduces stressstimuli such as oxidative stress, cold weather, etc. It is, however, confirmed that theinflammatory disorder RA is not directly carried in the genes. The immune system consists ofmany mechanisms that work together to fight pathogens. For example, macrophages are innateimmune sentinels that reside in tissues. They are uniquely equipped to sense and respond totissue invasion by various pathogens. Neutrophils are effector cells in circulation-not just in thetissues that constantly patrol the body to detect and fight any pathogen. Various immune sentinel(i.e., the two mentioned above) work together in phagocytosis.What is Rheumatoid arthritis-pathology, why is it invaded?It is a chronic inflammatory illness caused by its immune system erroneously attacking itshealthy tissues. It can affect joints and lungs, eyes, skin, heart, and blood vessels. It affects thejoints lining, causing a painful swelling leading to bone erosion alongside joint deformation inthe long run. It is characterized by the presence of autoantibodies called RF- RheumatoidFactors and ACPA-anti-citrullinated peptide antibodies.The disease is autoimmune. Investigations have not revealed what starts the process. It is,however, associated with genetic composition. The disease is not carried in the genes, but genescan increase the likelihood of body reaction to the environmental factors, i.e., viruses andbacteria, which may stimulate the diseaseThe disorder has no cure. However, medication and physiotherapy help slow the disease sprogress. Medications called anti-rheumatic drugs (DMARDS) can be used to manage mostcases. Chemicals released during the inflammation- including tumor necrosis factor-alpha (TNF ), fibroblast growth factor (FGF), transforming growth factor-beta (TGF- ), platelet-derivedgrowth factor, and Interleukin (IL)-1, IL-6, IL-8 lead to tumor growth.3Medical Health ExpertiseAnti-rheumatic DrugsThe type of medications recommended for someone with Rheumatoid arthritis are Conventional DMARDs-which handicap the progress of rheumatoid arthritis, hence helpprevent permanent damage of joints and other tissues. Common DMARDs includemethotrexate (Trexall, Otrexup, others), hydroxychloroquine (Plaquenil) and sulfasalazine(Azulfidine). Associated side effects include severe lung infections alongside liver damage Steroids- Like prednisone prevent inflammation alongside pain. Additionally, they helphandicap joint damage. Associated side effects are diabetes, bone thinning, and weightgaining. It is often recommended for quick pain relief. Nonsteroidal anti-inflammatory drugs NSAIDs- inflammation reduction and pain relief.Naproxen sodium and ibuprofen are over-the-counter NSAIDs drugs.Stronger NSAIDs may be issued under prescription, and associated side effects includekidney damage, stomach irritation, and heart problems. Biologic agents. They also popular as biologic modifiers response. It is a newer classof DMARDs. They include adalimumab (Humira), abatacept (Orencia), certolizumab(Cimzia), anakinra (Kineret), etanercept (Enbrel), golimumab (Simponi), infliximab(Remicade), tocilizumab (Actemra), sarilumab (Kevzara) and rituximab (Rituxan),They have proven highly effective when combined with a conventional DMARD, likemethotrexate and sulfasalazine4Medical Health ExpertiseWhen medications fail, the following surgical operations may be applied to help restore stabilityand prevent or slow down joint damage-Joint Fusion- Is a surgical procedure done to hold a born into position permanentlySynovectomy- Synovectomy is a surgery done to eliminate joint inflamed tissue (synovium) thatcauses unbearable pain, hinders the ability to function, or hinders range of motion. Theprocedure of carrying out a synovectomy is done using arthroscopy.- Tendon repair Are band-like tissue cells that are soft and connect bone and muscles. Uponmuscles contraction, pulling of the bones by the tendons cause the joints to move. Surgery canrepair tendon through mending a torn or damaged tendon. They help bring back the normalmovement to a joint.- Total joint replacement- Mostly, both knee and hip joints are often substituted. An artificialjoint is used in its place. A device called a prosthesis is used, and it can be ceramic, plastic, ormetallic1. Th1 and TH17 immune responsesTh1and Th17 immune responses are generated by Th1 and Th17 cells, respectively.The main Th1 cytokine is the interferon-gamma.Th17 cells require exact cytokines, i.e., transformation multiplication factor- (TGF- ) mixedwith IL-6 or IL-21 for its differentiation (31)They are responsible for producing pro-inflammatory responses responsible for killingintracellular parasites and for perpetuating autoimmune responses.Th1 and Th17 cells produced parallel to each other and can cause inflammation and autoimmunedisease.2. What is the function of monocytes and macrophages?Monocytes (Mo) alongside macrophages (M ) are vital components comprising the innateimmune system alongside actively regulate the process of early stages, development, andresolution of many inflammatory illnesses. Macrophages are monocytes that have migrated intobody tissues from the bloodstream.5Medical Health ExpertiseMacrophages in the body tissues become hyperplastic and lead to inflammation of the synovialmembrane. Macrophages are split into three subsets, M1 macrophages, M2 macrophages, andregulatory macrophages. M2 macrophages can further split into M2a, M2b, and M2c.M1 macrophages are accompanied with a higher capacity to secrete cytokines like IL-1 , TNF,IL-12, alongside IL-18Macrophage polarization produces distinct functional Phenotypes by macrophages as a reactionto specific micro-environmental stimuli. Macrophages are polarized into M macrophages thenactivated to M2 macrophages3. What growth stimuli activate MAPK pathways? What receptors are involved? bywhat MechanismMitogen-catalyzed protein kinases (MAPKs) are serine-threonine protein kinases whichtransduce the signal from the cell surface to the nucleus.They are activated by cellular stresses, i.e., UV irradiation, high osmotic stress, heat shock,lipopolysaccharide, protein synthesis inhibitors, and pro-inflammatory cytokines (i.e., IL-1)The gonadotropin-releasing hormone (GnRH) receptor is involved in the activation ofMAPK Pathways. It uses the Gq protein for its downstream signaling. GnRH activates all fourMAPK cascades by a PKC-dependent mechanism.MKPs are involved in the inactivation of MAPK to avoid the excessive and inappropriatesignaling that may result in a defect in the normal cellular operations.MAPK pathway helps in the regulation of cellular growth, gene expansion, and survival.However, abnormal MAPK signaling may result in increased or uncontrolled cell proliferationand resistance to apoptosis. The application of MAPK Pathways is in some cancer research.P38 is the major MAPK involved in Rheumatoid arthritis. It makes a big contribution to theproduction of inflammatory mediatorsERK1/2 is also a member of mitogen-activated protein kinase and plays a significant role indelivering the extracellular signals to the nucleus. These signals further regulate cellproliferation, cell development and, cell cycle.6Medical Health Expertise4. What are stress stimuli important in Rheumatoid arthritis?The various stress stimuli important in Rheumatoid arthritis are overdoing an activity or traumato the joint, repetitive motions, bone spurs, stress, an infection, cold weather, a change inbarometric pressure, weight gain, and oxidative stress.ROS- reactive oxygen species is a condition in which the pool of reactive oxygen speciesincreases over time, either by the reduction in antioxidant defenses, their augmented production,or the combination of bothStudies have located that: Stress tends to worsen and make RA symptoms. People with posttraumatic stress disorder (PTSD) have a higher risk of developing RA and other autoimmunediseases. Mood disorders, i.e., anxiety and depression, are major risk factors for aggravation ofthe disease, both independently and in association with other provoking factors. Depression andanxiety increase pain perception as well.ROS play an important part in cellular activities such as signaling transduction, genetranscription, and immune responsesThe excessive production of ROS can cause oxidative stress, which damages protein, lipids,matrix components, and nucleic acids. They also serve as important intracellular signalingmolecules that amplify the synovial inflammatory causing Rheumatoid arthritisROS plays a big role in macrophage-mediated immunity. They direct antimicrobial activityagainst bacteria and parasites as well as redox-regulation of immune signaling. They as wellinduce inflammatory activation; this is to assist the host against pathogens.Studies have established that Rheumatoid arthritis can reduce an individual s life span by about10 to 16 years, despite majority of individuals who live with the symptoms past 80 years of age.Factors affecting the illness include a person s lifestyle, age, behaviors such as smoking, andbeing overweight.5. How does ROS impact macrophage activation and Phenotype?ROS is a mediator for the activation of pro-inflammatory signaling pathways. Induced ROSproduction favors the induction of inflammatory macrophages at the onset and during theprogression of diabetes. An in-depth understanding of ROS and macrophages are important inthe discovery for treatment of diabetes6. How many macrophage phenotypes are there?Macrophage phenotypes are divided into M1 Phenotype and M2 Phenotype and are activated bylipopolysaccharide (LPS) or IFN- . They produce pro-inflammatory cytokines, phagocytize7Medical Health Expertisemicrobes, and initiate an immune response. M1 macrophages produce nitric oxide (NO) orreactive oxygen intermediates (ROI) to protect against viruses and bacteria.M2 macrophages are alternatively activated by exposure to certain cytokines such as IL-4, IL-10,or IL-13. M2 macrophage phenotypes produce either proline to induce collagen production orpolyamines to induce proliferation. These macrophages are linked to wound healing and repairfor tissue. They do not produce Nitric Oxide but facilitate formation of extracellular matrix7. A figure Showing were drugs in molecular pathways during Rheumatoid Arthritis8. What are glycosaminoglycansGlycosaminoglycans (GAGs) are molecules made of long, un-branched chains of negativelycharged sugars. They are made up of a repeating disaccharide unit8Medical Health ExpertiseThey are found throughout the body, including joints, blood plasma, skin, and various organs mucous membranes. Each GAG has its function and benefit in the bodyThey play a big part in the cell signaling process, for example, controlled cell growth, facilitatingcell adhesion, wound repair , anticoagulation, proliferation , and skin generationThe most common GAGs are hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparansulfate, heparin, and keratan sulfate with chondroitin sulfate (CS), being the most abundant GAGin the bodyGAGs provoke autoimmune dysfunctions that involve the expansion of GAG-binding cells.These cells shift to anatomical sites predominant in GAGs promoting inflammation andpathology seen in human Rheumatoid Arthritis.9. How are sulfate disaccharides formed in vivo?Sulfate disaccharides are formed in vivo through enzymatic digestion with chondroitinase-ABC.Chondroitinase ABC is an unsaturated disaccharide with two sulfate residues derived fromchondroitin sulfate of the ultimate squid cartilage. Various data, particularly the formation of 2acetamido-2-deoxy-3-O-( -D-glucose-4-enepyranosyluronic acid)-4-O-sulfo-D-galactose and its6-O-sulfate isomer by hydrolysis with chondro-6-sulfatase and chondro-4-sulfatase, respectively,and the formation of 2-acetamido-2-deoxy-4,6-di-O-sulfo-D-galactose by mild acid hydrolysis,The two sulfate residues are located at positions 6 and 4 of the hexosamine moiety.10. What is the major sulfated disaccharide formed in the joints? Is this formedelsewhere in other inflammation conditions?Chondroitin Sulfate is the major sulfated disaccharide formed in the joints. CS is a vitalcomponent of joint ECM and assumes a crucial task in developing and facilitating joint/cartilagepathologies.Chondroitin Sulfate forms a vital part of cartilage. It gives elasticity to the cartilage by helping itretain water, reduces the activity of enzymes and substances that break down collagen in jointsIt helps manage osteoarthritis, a common bone disorder that affects the cartilage surroundingyour joints. Taking CS supplements increases the synthesis of various cartilage componentswhile also preventing cartilage breakdown.In cases of inflammation, chondroitin Sulfate elicits an anti-inflammatory effect on the chondraland synovial levels preventing joint swelling and effusion.9Medical Health Expertise11. Can you expand on the bell-shaped response curve and the impact at a highconcentration of sulfated disaccharide? How does it propagate these effects?A bell-shaped curve is a stimulus-response curve. It shows the change in response to increasingstimulus. At a high concentration of sulfated disaccharide, there s efficacy rise to a certain point.In addition, much more concentration led to decreased efficacyThe first part of the curve shows the basic, uncomplicated dose-response relationship of theseantidepressants, whereas the second, decreasing part remains to be explained. We hypothesizethat a negative feedback pathway through 5-HT1A auto-receptors decreases the efficacy ofselective serotonin reuptake inhibitors with increasing dose, thereby creating the second strangepart of the dose-response curve. This effect can also account for the so-called therapeuticwindow of such antidepressants12. What are receptors for these sulfated disaccharides? How does sulfation affect theirbinding properties?Receptors for the sulfated disaccharides are toll-like receptor (TLR) 9 ligands. TLRs arepathogen-associated molecular patterns that exist as evolutionarily conserved proteins. The manytypes of TLRs range from TLRS 1-TLRS9.TLR 9 is activated in response to DNA. It detects foreign DNA signatures TLR9 can sense,hence determining certain viruses or bacteria inside the cell resulting in stimulation of animmune response.TLR9 plays a key role in the activation of the immune and inflammatory responses to differentmicrobial components. It binds DNA present in viruses and bacteria and triggers signalingcascades that lead to a pro-inflammatory cytokine responseSulfation is a process of conjugation, and it is involved in various body processes, from thebiotransformation/detox pathways to the biosynthesis of some proteins. The sulfation ofhormones allows the transport of hormones in the blood to target tissues. Sulfation enhances thebinding of DNA present in bacteria and viruses, triggering pro-inflammatory responses.13. Have the other groups demonstrated the anti-inflammatory properties of sulfateddisaccharides?Only TLR9 receptors have demonstrated anti-inflammatory properties of Sulfated disaccharides.The other TRLs ranging from TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, and TLR8have not demonstrated any anti-inflammatory properties of Sulfated disaccharides.10Medical Health Expertise14. Why focus on p2 in macrophage and not neutrophilPurinergic Receptors refer to ATP receptors. They are divided into two types, P2X and P2Y.P2X receptors are ATP-activated channels that allow the passage of ions across cell membranes,whereas P2Y receptors are ATP activated G protein-coupled receptors (GPCRs) they initiate anintracellular chain of reactions.P2Y receptors can be both pro-inflammatory and anti-inflammatory. They control macrophageinflammation. Stress-sensing receptors, including purinergic P2X and P2Y receptors, areimportant for macrophages to express various stresses that respond to extracellular nucleotidesand their sugar derivatives.Neutrophils are granulocytes- they work as phagocytes only in circulation macrophages areagranulocytes -they work as phagocytes inside the tissuesThe mingling between neutrophils alongside monocytes/macrophages equip the host indefending against and preventing foreign pathogens efficiently. In macrophages, the focus is onP2 because the Purinergic Receptors act as pro-inflammatory and anti-inflammatory. They arealso not on neutrophils because they are granulocytes and only work in circulation, not in thetissues.View attached explanation and answer. Let me know if you have any questions.1Medical Health ExpertiseMedical Health ExpertiseStudent NameCourse TitleProfessorDate2Medical Health ExpertiseMedical health expertiseINTRODUCTIONWhen your body detects and recognizes pathogens. It defends itself against it. Various immuneresponses vary depending on the type of pathogen. In some scenarios, the body may startfighting its healthy tissues, causing a condition called Rheumatoid arthritis. The exact cause ofthis condition is not well determined. There is no cure for this condition; however, the body takesthe initiative to deal with such a condition before it arises. Various immune responses exist in thebody that fight autoimmune responses causing this condition. RA majorly invades joints, but itcould also spread to other body tissues such as skin, heart, blood vessels, etc. In the most recentstudies, Rheumatoid arthritis is associated with a genetic compilation that transduces stressstimuli such as oxidative stress, cold weather, etc. It is, however, confirmed that theinflammatory disorder RA is not directly carried in the genes. The immune system consists ofmany mechanisms that work together to fight pathogens. For example, macrophages are innateimmune sentinels that reside in tissues. They are uniquely equipped to sense and respond totissue invasion by various pathogens. Neutrophils are effector cells in circulation-not just in thetissues that constantly patrol the body to detect and fight any pathogen. Various immune sentinel(i.e., the two mentioned above) work together in phagocytosis. Stress and trauma are some of theother triggers to Rheumatoid Arthritis. Study shows that individuals with depression and anxietyissues are more susceptible to Rheumatoid Arthritis than individuals without. The disorder canbe curbed using conventional DMARDS, steroids, biologic agents etc. In severe cases or insituations where these medical applications fail, surgical operation such as tendon repair andtendon fusion would be applied. Below is a more detailed discussion on rheumatoid arthritis-anauto-immune inflammatory disorder.What is Rheumatoid arthritis-pathology, why is it invaded?It is a chronic inflammatory illness caused by its immune system erroneously attacking itshealthy tissues. It can affect joints and lungs, eyes, blood vessels, skin, and heart. It affects jointlining, resulting to swellings that are painful consequently resulting to erosion of both the boneand joint deformation in the long run. It is characterized by the presence of autoantibodies calledRF- Rheumatoid Factors and ACPA-anti-citrullinated peptide antibodies.The disease is autoimmune. Investigations have not revealed what starts the process. It is,however, associated with genetic composition. The disease is not carried in the genes, but genescan increase the likelihood of body reaction to the environmental factors, i.e., viruses andbacteria, which may stimulate the diseaseThe disorder has no cure. However, medication and physiotherapy help slow the disease sprogress. Medications called anti-rheumatic drugs (DMARDS) can be used to manage most3Medical Health Expertisecases. Chemicals released during the inflammation- including tumor necrosis factor-alpha (TNF ), fibroblast development factor (FGF), generating development of factor-beta (TGF- ),platelet-derivative development factor, and Interleukin (IL)-1, IL-6, IL-8 lead to tumordevelopment.Anti-rheumatic DrugsThe type of medications recommended for someone with Rheumatoid arthritis are Conventional DMARDs-which handicap the progress of rheumatoid arthritis, hence helpprevent permanent damage of tissue and joints. Popular DMARDs consist of sulfasalazine(Azulfidine), hydroxychloroquine (Plaquenil) and methotrexate (Trexall, Otrexup, others).Associated side effects are severe lung infections alongside liver damage Steroids- Like prednisone prevent inflammation alongside pain. Additionally, they helphandicap joint damage. Associated side effects are diabetes, bone thinning, and weightgaining. It is often recommended for quick pain relief. Nonsteroidal anti-inflammatory drugs NSAIDs- inflammation reduction and pain relief.Naproxen sodium and ibuprofen are over-the-counter NSAIDs drugs.Stronger NSAIDs may be issued under prescription, and associated side effects includekidney damage, stomach irritation, and heart problems. Biologic agents. They also popular as biologic modifiers response. It is a newer classof DMARDs. They include adalimumab (Humira), abatacept (Orencia), certolizumab(Cimzia), anakinra (Kineret), etanercept (Enbrel), golimumab (Simponi), infliximab(Remicade), tocilizumab (Actemra), sarilumab (Kevzara) and rituximab (Rituxan),They have proven highly effective when combined with a conventional DMARD, likemethotrexate and sulfasalazine4Medical Health ExpertiseWhen medications fail, the following surgical operations may be applied to help restore stabilityand prevent or slow down joint damage-Joint Fusion- Is a surgical procedure done to hold a born into position permanentlySynovectomy- Synovectomy is a surgery done to eliminate joint inflamed tissue (synovium) thatcauses unbearable pain, hinders the ability to function, or hinders range of motion. Theprocedure of carrying out a synovectomy is done using arthroscopy.- Tendon repair Are band-like tissue cells that are soft and connect bone and muscles. Uponmuscles contraction, pulling of the bones by the tendons cause the joints to move. Surgery canrepair tendon through mending a torn or damaged tendon. They help bring back the normalmovement to a joint.- Total joint replacement- Mostly, both knee and hip joints are often substituted. An artificialjoint is used in its place. A device called a prosthesis is used, and it can be ceramic, plastic, ormetallic1. Th1 and TH17 immune responsesTh1and Th17 immune responses are generated by Th1 and Th17 cells, respectively.The main Th1 cytokine is the interferon-gamma.5Medical Health ExpertiseTh17 cells require exact cytokines, i.e., transformation multiplication factor- (TGF- ) mixedwith IL-6 or IL-21 for its differentiation (31)They are responsible for producing responses that are pro-inflammatory which are responsiblefor eliminating intracellular parasites as well as preserve autoimmune responses.Th1 and Th17 cells produced parallel to each other and can cause inflammation and autoimmunedisease.2. What is the function of monocytes and macrophages?Monocytes (Mo) alongside macrophages (M ) are vital components comprising the innateimmune system alongside actively regulate the process of early stages, development, andresolution of many inflammatory illnesses. Macrophages are monocytes that have migrated intobody tissues from the bloodstream.Macrophages in the body tissues become hyperplastic and lead to inflammation of the synovialmembrane. Macrophages are split into three subsets, M1 macrophages, M2 macrophages, andregulatory macrophages. M2 macrophages can further split into M2a, M2b, and M2c.M1 macrophages are accompanied with a higher capacity to secrete cytokines like IL-1 , TNF,IL-12, alongside IL-18Macrophage polarization produces distinct functional Phenotypes by macrophages as a reactionto specific micro-environmental stimuli. Macrophages are polarized into M macrophages thenactivated to M2 macrophages3. What growth stimuli activate MAPK pathways? What receptors are involved? bywhat MechanismMitogen-catalyzed protein kinases (MAPKs) are serine-threonine protein kinases whichtransduce the signal from the cell surface to the nucleus.They are activated by cellular stresses, i.e., UV irradiation, high osmotic stress, heat shock,lipopolysaccharide, protein synthesis inhibitors, and pro-inflammatory cytokines (i.e., IL-1)The gonadotropin-releasing hormone (GnRH) receptor is involved in the activation ofMAPK Pathways. It utilizes Gq protein to facilitate downstream signaling. GnRH facilitates allMAPK cascades through a mechanism known as the PKC-dependent.MKPs are involved in the inactivation of MAPK to avoid the excessive and inappropriatesignaling that may result in a defect in the normal cellular operations.6Medical Health ExpertiseMAPK pathway helps in the regulation of cellular growth, gene expansion, and survival.However, abnormal MAPK signaling may result in increased or uncontrolled cell proliferationand resistance to apoptosis. The application of MAPK Pathways is in some cancer research.P38 is the major MAPK involved in Rheumatoid arthritis. It makes a big contribution to theproduction of inflammatory mediatorsERK1/2 is also a constituent of mitogen-catalyzed protein kinase which plays a significant taskin delivery of extracellular signals up to nucleus. The signals further regulate cell proliferation,development and, cycle.4. What are stress stimuli important in Rheumatoid arthritis?The various stress stimuli important in Rheumatoid arthritis are overworking activities or jointtrauma, stress, repetitive motions, spurs of the bone, an infection, chilly weather, a variation ofbarometric pressure, oxidative stress and weight gain.ROS- reactive oxygen species is a condition in which the pool of reactive oxygen speciesincreases over time, either by the reduction in antioxidant defenses, their augmented production,or the combination of bothStudies have located that: Stress tends to worsen and make RA symptoms. Probability ofindividuals with post-traumatic stress disorder (PTSD) contracting RA and other autoimmunediseases is very. Mood disorders, i.e., anxiety and depression, are major risk factors foraggravation of the disease, both independently and in association with other provoking factors.Depression and anxiety increase pain perception as well.ROS play an important part in cellular activities such as signaling transduction, genetranscription, and responses to immuneThe increased generation of ROS likely causes oxidative stress, which damages protein, matrixcomponents, lipids, and nucleic acids. ROS also serve as essential intracellular signalmolecules which amplify synovial inflammatory causing Rheumatoid arthritisROS plays a big role in macrophage-mediated immunity. They facilitate antimicrobial activityfrom bacteria alongside parasites and redox-regulation of immune signal. They as well induceinflammatory activation; this is to assist the host against pathogens.Studies have established that Rheumatoid arthritis can reduce an individual s life span by about10 to 16 years, despite majority of individuals who live with the symptoms past 80 years of age.Factors affecting the illness include a person s lifestyle, age, behaviors such as smoking, andbeing overweight.7Medical Health Expertise5. How does ROS impact macrophage activation and Phenotype?ROS is a mediator for the activation of pro-inflammatory signaling pathways. Induced ROSproduction favors the induction of inflammatory macrophages at the onset and during theprogression of diabetes. An in-depth understanding of ROS and macrophages are important inthe discovery for treatment of diabetes6. How many macrophage phenotypes are there?Macrophage phenotypes are divided into M1 Phenotype and M2 Phenotype and are activated bylipopolysaccharide (LPS) or IFN- . They produce pro-inflammatory phagocytize microbes ,instantiate immune response and cytokines. M1 macrophages release nitric oxide (NO) toprovide protection from viruses and bacteria.Bacteria exposure to various cytokines like IL-4, IL-10, or IL-13 activate M2 macrophage. Thelatter phenotypes generate either proline to stimulate collagen production or polyamines totrigger proliferation. The macrophages are linked to tissue repair and healing wounds. They donot produce Nitric Oxide but facilitate formation of extracellular matrix7. A figure Showing were drugs in molecular pathways during Rheumatoid Arthritis8Medical Health Expertise8. What are glycosaminoglycansGlycosaminoglycans (GAGs) are molecules made of long, un-branched chains of negativelycharged sugars. They are made up of a repeating disaccharide unitThey are found throughout the body, including joints, blood plasma, skin, and various organs mucous membranes. Each GAG has its function and benefit in the bodyThey play a big part in the cell signaling process, for example, controlled cell growth, facilitatingcell adhesion, wound repair, anticoagulation, proliferation, and skin generationThe most common GAGs are heparin, heparan sulfate, chondroitin sulfate and keratan sulfatewith chondroitin sulfate, being the most abundant GAG in the bodyGAGs trigger autoimmune dysfunctions which involve the success of GAG-combined cells.These cells shift to anatomical places predominant within GAGs promoting inflammation andpathology seen in human Rheumatoid Arthritis.9. How are sulfate disaccharides formed in vivo?Sulfate disaccharides are formed in vivo through enzymatic digestion with chondroitinase-ABC.Chondroitinase ABC is an immiscible disaccharide with two residues that are sulfate deducedfrom chondroitin of the final cartilage sulfate. Different statistics, especially generation of 2acetamido-2-deoxy-3-O-( -D-glucose-4-enepyranosyluronic acid)-4-O-sulfo-D-galactosealongside its 6-O-sulfate isomer by hydrolysis with chondro-6-sulfatase and chondro-4-sulfatase,9Medical Health Expertiserespectively, as well as the generation of 2-acetamido-2-deoxy-4,6-di-O-sulfo-D-galactose byweak acid hydrolysis, residual sulfate found at positions 6 and 4 of the hexosamine component.10. What is the major sulfated disaccharide formed in the joints? Is this formedelsewhere in other inflammation conditions?Chondroitin Sulfate is the major sulfated disaccharide formed in the joints. CS is a vitalcomponent of joint ECM and assumes a crucial task in developing and facilitating joint/cartilagepathologies.Chondroitin Sulfate forms a vital part of cartilage. It gives elasticity to the cartilage by helping itretain water, reduces the activity of enzymes and substances that break down collagen in jointsIt helps manage osteoarthritis, a common bone disorder that affects the cartilage surroundingyour joints. Taking CS supplements increases the synthesis of various cartilage componentswhile also preventing cartilage breakdown.In cases of inflammation, chondroitin Sulfate elicits an anti-inflammatory effect on the chondraland synovial levels preventing joint swelling and effusion.11. Can you expand on the bell-shaped response curve and the impact at a highconcentration of sulfated disaccharide? How does it propagate these effects?A bell-shaped curve is a stimulus-response curve. It shows the change in response to increasingstimulus. At a high concentration of sulfated disaccharide, there s efficacy rise to a certain point.In addition, much more concentration led to decreased efficacyThe first part of the curve shows the basic, simple relationship of the highlighted antidepressants,while the second, declining section remains unexplained. We hypothesize that a negated reviewof pathway through 5-HT1A auto-receptors reduces efficacy of chosen serotonin reuptakeinhibitors with rising dose, therefore leading to creation of the second strange portion of the bellshaped curve. This could result into therapeutic window of the anti-depressantsWhat are receptors for these sulfated disaccharides? How does sulfation affect theirbinding properties?Receptors for the sulfated disaccharides are receptor displaying toll-like properties (TLR) 9ligands. TLRs are pathogen-linked molecular patterns that exist as evolutionarily conservedproteins. The many types of TLRs range from TLRS 1-TLRS9.10Medical Health ExpertiseTLR 9 is activated in response to DNA. It detects rare DNA signatures TLR9 sense, hencedetermining either some viruses or bacteria within the cell resulting in stimulation of an immuneresponse.TLR9 assumes an important role in the activation of both immune alongside inflammatoryresponses to different microbial components. It combines DNA in viruses alongside bacteriawhich triggers signal cascading that leads to a response of pro-inflammatory cytokine.Sulfation process involves conjugation, in which different body processes, starting frombiotransformation/detox pathways up to the biosynthesis of various proteins. Hormone sulfationallows transportation of hormones through the blood to aim tissues. It enhances the binding ofDNA present in bacteria and viruses, triggering pro-inflammatory responses.12. Have the other groups demonstrated the anti-inflammatory properties of sulfateddisaccharides?Only TLR9 receptors have demonstrated anti-inflammatory properties of Sulfated disaccharides.The other TRLs ranging from TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, and TLR8have not demonstrated any anti-inflammatory properties of Sulfated disaccharides.13. Why focus on p2 in macrophage and not neutrophilPurinergic Receptors refer to ATP receptors. They are split into two types, P2Y and P2X. Thelatter are ATP-activated receptor channels which allow the ions passage across membranes ofthe cell, while P2Y receptors are G protein-coupled receptors (GPCRs) ATP activated.P2Y receptors can both be anti-inflammatory as well as pro-inflammatory. They controlmacrophage inflammation. Receptors that sense stress, include P2X and P2Y receptors. They aresignificant for macrophages to express various stresses that act upon extracellular nucleotidesand its sugar derivatives.Neutrophils are granulocytes- they function as phagocytes strictly in propagating macrophagesand are agranulocytes meaning they operate as phagocytes within the tissuesThe mingling between neutrophils alongside monocytes/macrophages equip the host indefending against and preventing foreign pathogens efficiently. In macrophages, the focus is onP2 because the Purinergic Receptors act as pro-inflammatory and anti-inflammatory. They arealso not on neutrophils because they are granulocytes and only work in circulation, not in thetissues.11Medical Health ExpertiseView attached explanation and answer. Let me know if you have any questions.1Medical Health ExpertiseMedical Health ExpertiseStudent NameCourse TitleProfessorDateMedical health expertiseINTRODUCTION2Medical Health ExpertiseWhen your body detects and recognizes pathogens. It defends itself against it. Various immuneresponses vary depending on the type of pathogen. In some scenarios, the body may startfighting its healthy tissues, causing a condition called Rheumatoid arthritis. The exact cause ofthis condition is not well determined. There is no cure for this condition; however, the body takesthe initiative to deal with such a condition before it arises. Various immune responses exist in thebody that fight autoimmune responses causing this condition. RA majorly invades joints, but itcould also spread to other body tissues such as skin, heart, blood vessels, etc. In the most recentstudies, Rheumatoid arthritis is associated with a genetic compilation that transduces stressstimuli such as oxidative stress, cold weather, etc. It is, however, confirmed that theinflammatory disorder RA is not directly carried in the genes. The immune system consists ofmany mechanisms that work together to fight pathogens. For example, macrophages are innateimmune sentinels that reside in tissues. They are uniquely equipped to sense and respond totissue invasion by various pathogens. Neutrophils are effector cells in circulation-not just in thetissues that constantly patrol the body to detect and fight any pathogen. Various immune sentinel(i.e., the two mentioned above) work together in phagocytosis. Stress and trauma are some of theother triggers to Rheumatoid Arthritis. Study shows that individuals with depression and anxietyissues are more susceptible to Rheumatoid Arthritis than individuals without. The disorder canbe curbed using conventional DMARDS, steroids, biologic agents etc. In severe cases or insituations where these medical applications fail, surgical operation such as tendon repair andtendon fusion would be applied. Below is a more detailed discussion on rheumatoid arthritis-anauto-immune inflammatory disorder.It is caused by the body s immune system erroneously attacking its healthy tissues. It can affectjoints and lungs, eyes, blood vessels, skin, and heart. It affects joint lining, resulting to swellingsthat are painful consequently resulting to erosion of both the bone and joint deformation in thelong run. It is characterized by the presence of autoantibodies called RF- Rheumatoid Factorsand ACPA-anti-citrullinated peptide antibodies.Rheumatoid arthritis (RA) is a painful crippling chronic autoimmune inflammatory disease,affecting 1:100 of the global population with a female preponderance (3:1 female: males)(Edwards, et al., 1999). It is a chronic inflammatory illness caused by the body s immunesystem erroneously attacking its healthy tissues. It can affect joints and lungs, eyes, bloodvessels, skin, and heart. It affects joint lining, resulting to swellings that are painful consequentlyresulting to erosion of both the bone and joint deformation in the long run. It is characterized bythe presence of autoantibodies called RF- Rheumatoid Factors and ACPA-anti-citrullinatedpeptide antibodies.It has become significant socio-economic burden on society as it increases the risk ofother potential diseases such as cardiovascular diseases, depression and fatigue (Dayer &3Medical Health ExpertiseChoy, 2010 and Pollard et al., 2005) whilst transformative, the mortality rate of RA patients ishigher (Buch and Emery 2002, Wolfe et al., 1994).Characteristically the small joints of the hands, wrists and feet are affected first in a symmetricalfashion but any synovial joint can be involved. There are three forms of clinical presentation intowhich most cases of RA can broadly be recognized. A chronic progressive form in which thedisease begins with minimal joint involvement and then progresses slowly over a period of yearsto multiple joint disease with severe functional limitation. This is the most common pattern ofarthritis seen. Second form is an intermittent course which is punctuated by acute episodes ofarthritis with periods of remission in between. The third form is an explosive onset with multiplejoint involvement and acute synovitis which may go into partial remission after three years or so.This pattern of RA is more commonly seen when RA begins in the elderly patient. (Clin GeriatrMed. 2005)Cells of the myelomonocytic lineage can differentiate into numerous cell types that are involvedin disease for instance monocytes, macrophages, osteoclasts and dendritic cells and activation ofthese cells leads to the production of cytokines and mediators responsible for inflammation.Monocytes are central to the RA pathology as they accumulate in the blood and continuouslymigrate into the inflamed joints where they acquire an activated phenotype and candifferentiate into inflammatory macrophages, dendritic cells and osteoclasts (Ammari et al.,2018 and Goudot et al., 2017). As a consequence of their marked plasticity, the differentiationpathways can be influenced by excess or imbalance of particular pathophysiological stimuli suchas cytokines or growth factors, resulting in altered differentiation or maturation if regulatorymechanisms fail. Different immune modulators such as cytokines and effector cells andsignalling pathways are known to involve in the pathophysiology of RA (Smolen andSteiner, 2003). The complex interaction ofThe disease is autoimmune. Investigations have not revealed what starts the process. It is,however, associated with genetic composition. The disease is not carried in the genes, but genescan increase the likelihood of body reaction to the environmental factors, i.e., viruses andbacteria, which may stimulate the diseaseThe disorder has no cure. However, medication and physiotherapy help slow the disease sprogress. Medications called anti-rheumatic drugs (DMARDS) can be used to manage mostcases. Chemicals released during the inflammation- including tumor necrosis factor-alpha (TNF ), fibroblast development factor (FGF), generating development of factor-beta (TGF- ),platelet-derivative development factor, and Interleukin (IL)-1, IL-6, IL-8 lead to tumordevelopment.4Medical Health ExpertiseCells of the myelomonocytic lineage can differentiate into numerous cell types that are involvedin disease for instance monocytes, macrophages, osteoclasts and dendritic cells and activation ofthese cells leads to the production of cytokines and mediators responsible for inflammation.Monocytes are central to the RA pathology as they accumulate in the blood and continuouslymigrate into the inflamed joints where they acquire an activated phenotype and candifferentiate into inflammatory macrophages, dendritic cells and osteoclasts (Ammari et al.,2018 and Goudot et al., 2017). As a consequence of their marked plasticity, the differentiationpathways can be influenced by excess or imbalance of particular pathophysiological stimuli suchas cytokines or growth factors, resulting in altered differentiation or maturation if regulatorymechanisms fail. Different immune modulators such as cytokines and effector cells andsignalling pathways are known to involve in the pathophysiology of RA (Smolen andSteiner, 2003). The complex interaction of cytokines and effector cells are accountable forthe joint damage that begins at the synovial membrane (Smolen and Steiner, 2003).RA is represented as pannus formation, synovitis, bone erosions and joint destruction. Thejoint is contained within a joint capsule which surrounds joints such as hand, wrists, elbow,ankle and foot. Synovial inflammation is a defensive cellular response against invadingpathogens but defects in normal mechanisms give rise to RA (Fig.1 and Fig.2). The majorcharacteristic of RA is symmetric polyarticular inflammation of the synovial membranewhich is a connective tissue that lines the inner surface of joint capsules (Kunisch et al., 2004).5Medical Health ExpertiseFigure 1. Schematic view of normal joint (a) and a RA affected joint (b) (Adapted from, Smolenand Steiner, 2003).

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