ReverseFX® and autoimmune joint pain

“In a sea of possibilities – pattern recognition is the key to unlocking the door to new therapeutic interventions” Joey Phillips

Rheumatoid Arthritis & Systemic Lupus Erythematosus (SLE)

ReverseFX contains upwards of 90% of the compounds listed in the medical research in relation to Autoimmune Joint Pain / Rheumatoid Arthritis and SLE.

Autoimmune arthritis is the name given to a group of arthritis types where a person’s immune system attacks itself. The most common example is rheumatoid arthritis. When the immune system attacks itself, the result is inflammation in a joint that can cause pain, stiffness, and mobility problems.[1]

Several autoimmune diseases can cause joint pain and other symptoms that mimic rheumatoid arthritis (RA). These diseases most commonly include lupus, systemic scleroderma, and polymyalgia rheumatic.[2]

For the purpose of this research, we will be discussing RA and Lupus.

This research, may at times be highly technical. We will offer insights, but more importantly, we will point to what the research has to say about possible solutions. If consuming technical data is difficult for you, then our suggestion is to focus on what the research has to say about the possible remedies.

Autoimmune joint pain involves primarily four genes:

  • PTPN22 (main gene)

  • PADI4

  • CIITA

  • IL10

These genes all are held in common with the top 10 diseases associated with RA. Therefore, if we can scientifically discover the “ins and outs” of these genes, and their associated networks, we may be able to impact their epigenetic expression.

RA and SLE share the EXACT same gene, which is PTPN22 (Protein Tyrosine Phosphatase Non-Receptor Type 22).

Put those science hats on. Ready…set…let’s go!

Rheumatoid Arthritis (RA)[3]

Rheumatoid arthritis is a disease that causes chronic abnormal inflammation, primarily affecting the joints. The most common signs and symptoms are pain, swelling, and stiffness of the joints. Small joints in the hands and feet are involved most often, although larger joints (such as the shoulders, hips, and knees) may become involved later in the disease. Joints are typically affected in a symmetrical pattern; for example, if joints in the hand are affected, both hands tend to be involved. People with rheumatoid arthritis often report that their joint pain and stiffness is worse when getting out of bed in the morning or after a long rest. Rheumatoid arthritis can also cause inflammation of other tissues and organs, including the eyes, lungs, and blood vessels. Additional signs and symptoms of the condition can include a loss of energy, a low fever, weight loss, and a shortage of red blood cells (anemia). Some affected individuals develop rheumatoid nodules, which are firm lumps of noncancerous tissue that can grow under the skin and elsewhere in the body. The signs and symptoms of rheumatoid arthritis usually appear in mid- to late adulthood. Many affected people have episodes of symptoms (flares) followed by periods with no symptoms (remissions) for the rest of their lives. In severe cases, affected individuals have continuous health problems related to the disease for many years. Abnormal inflammation can lead to severe joint damage, which limits movement and can cause significant disability.

Systemic Lupus Erythematosus (SLE)[4][5]

What is lupus? Lupus is an autoimmune disease. This means that your immune system attacks healthy cells and tissues by mistake. This can damage many parts of the body, including the joints, skin, kidneys, heart, lungs, blood vessels, and brain. There are several kinds of lupus Systemic lupus erythematosus (SLE) is the most common type. It can be mild or severe and can affect many parts of the body.

Systemic lupus erythematosus (SLE) is a chronic disease that causes inflammation in connective tissues, such as cartilage and the lining of blood vessels, which provide strength and flexibility to structures throughout the body. The signs and symptoms of SLE vary among affected individuals, and can involve many organs and systems, including the skin, joints, kidneys, lungs, central nervous system, and blood-forming (hematopoietic) system. SLE is one of a large group of conditions called autoimmune disorders that occur when the immune system attacks the body’s own tissues and organs.

SLE may first appear as extreme tiredness (fatigue), a vague feeling of discomfort or illness (malaise), fever, loss of appetite, and weight loss. Most affected individuals also have joint pain, typically affecting the same joints on both sides of the body, and muscle pain and weakness. Skin problems are common in SLE. A characteristic feature is a flat red rash across the cheeks and bridge of the nose, called a “butterfly rash” because of its shape. The rash, which generally does not hurt or itch, often appears or becomes more pronounced when exposed to sunlight. Other skin problems that may occur in SLE include calcium deposits under the skin (calcinosis), damaged blood vessels (vasculitis) in the skin, and tiny red spots called petechiae. Petechiae are caused by a shortage of cells involved in clotting (platelets), which leads to bleeding under the skin. Affected individuals may also have hair loss (alopecia) and open sores (ulcerations) in the moist lining (mucosae) of the mouth, nose, or, less commonly, the genitals.

About a third of people with SLE develop kidney disease (nephritis). Heart problems may also occur in SLE, including inflammation of the sac-like membrane around the heart (pericarditis) and abnormalities of the heart valves, which control blood flow in the heart. Heart disease caused by fatty buildup in the blood vessels (atherosclerosis), which is very common in the general population, is even more common in people with SLE. The inflammation characteristic of SLE can also damage the nervous system, and may result in abnormal sensation and weakness in the limbs (peripheral neuropathy); seizures; stroke; and difficulty processing, learning, and remembering information (cognitive impairment). Anxiety and depression are also common in SLE.

People with SLE have episodes in which the condition gets worse (exacerbations) and other times when it gets better (remissions). Overall, SLE gradually gets worse over time, and damage to the major organs of the body can be life-threatening.

An important gene associated with Systemic Lupus Erythematosus is PTPN22 (Protein Tyrosine Phosphatase Non-Receptor Type 22), and among its related pathways/superpathways are Systemiclupus erythematosus and Innate Immune System.

An important gene associated with Rheumatoid Arthritis is PTPN22 (Protein Tyrosine Phosphatase Non-Receptor Type 22), and among its related pathways/superpathways are Rheumatoid arthritis and NF-kappaB Signaling.[6]

Diseases related to Rheumatoid Arthritis via text searches within MalaCards or GeneCards Suite gene sharing:

Top Affiliating Genes

1. arthritis

2. PTPN22 PADI4 IRF5 IL10 CIITA

palindromic rheumatism

PTPN22 PADI4

3. autoimmune disease

PTPN22 PADI4 MIR146A IRF5 IL10 CIITA

4. rheumatic disease

PADI4 MIR155 MIR146A IL10

5crohn’s disease

SLC22A4 PTPN22 IRF5 IL10

6. alpha/beta t-cell lymphopenia with gamma/delta t-cell expansion, severe cytomegalovirus infection, and autoimmunity

PTPN22 IL10

7. systemic lupus erythematosus

PTPN22 PADI4 MIR155 MIR150 MIR146A MALAT1

8bone inflammation disease

PTPN22 PADI4 MIR155 MIR146A IL10

9. lymphoproliferative syndrome

MIR146A IL10 CD244

10. multiple sclerosis

PTPN22 PADI4 MIR155 IL10 CIITA

Most held in common amongst these diseases: PTPN22, PADI4, IL10, CIITA

Drugs (Compounds) for Rheumatoid Arthritis (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB)[7]:

  • Orange (related to bioflavonoids such as Vitamin C, Hesperidin, Rutin)

  • Artichoke

  • Strawberry (related to Fisetin)

  • Heparin (Nattokinase has Heparin Binding properties[8]; bacillus subtilis is derived from Nattokinase)

  • Calcium (may be found in Fulvic/Humic acid)

  • Maleic acid (related to citrus)

  • Epinephryl borate (related to Boron; may also be found in Fulvic/Humic acid)

  • Omega 3 Fatty Acid (may be found also in Sea buckthorn[9], with close to 200 properties)

  • Vincristine (Vinpocetine)

  • Acetylcholine (PC)

  • Selenium (may be found in Fulvic/Humic acid)

  • Acetylcysteine (NAC)

  • Capsaicin

  • Vitamin A

  • Niacin (Vitamin B3)

  • Carnitine (Acetylcarnitine)

  • Ginger

  • Curcumin

  • Borage oil

  • Methylcobalamin – Hydroxocobalamin – Cyanocobalamin

  • Mannitol (Bladderwrack[10])

  • Zinc (may be found in Fulvic/Humic acid)

  • Indian frankincense (Boswellia)

  • Glycine (DMG)

  • Tyrosine

  • Citric acid (related to bioflavonoids such as Vitamin C, Hesperidin, Rutin)

  • Puerarin (Kudzu root – Kudzu contains isoflavones, including puerarin (about 60% of the total isoflavones), daidzein, daidzin (structurally related to genistein), mirificin, and salvianolic acid, among numerous others identified.[11])

  • Andrographolide (Andrographis)

  • Evening Primrose

  • DHEA (Dehydroepiandrosterone)

  • Reishi

  • Bifidobacterium

  • Ginkgo biloba

  • Olive (Olive leaf extract)

  • Grape (Grapeseed extract, Resveratrol)

  • Caffeine (Caffeic acid, Caffeic acid phenethyl ester (CAPE), Propolis[12])

  • Menadione – Menaquinone (Vitamin K2, found in Nattokinase[13])

  • Tomato (Lycopene)

  • Blackberry

  • Blueberry

  • Tannic acid (may be found in Prunella Vulgaris/Self-Heal[14])

  • Hyaluronic acid

  • Iodine (found in Bladderwrack and Fulvic/Humic acid)

  • Glucosamine (N-Acetyl Glucosamine)

  • Melatonin

  • Creatine

  • Pyridoxine (B-6)

  • Taurine

  • Vitamin E (found in Sea buckthorn)

  • Arachidonic acid (found in Sea buckthorn)

  • Pomegranate

  • Red yeast rice

  • Soy Bean (Nattokinase; Kudzu root contains isoflavones, including puerarin (about 60% of the total isoflavones), daidzein, daidzin (structurally related to genistein), mirificin, and salvianolic acid, among numerous others identified.)

  • Sunflower (Sunflower lecithin – Phosphatidylcholine)

  • Passionflower

  • Rose Hips

  • Lycium (Goji berries)

  • Chrysanthemum (Mums)

  • Acidophilus

  • Calamus (Sweet flag)

  • Whey Protein

  • Mandelic acid (bitter almonds)

  • Serotonin

  • Cod liver oil

PTPN22 (Protein Tyrosine Phosphatase Non-Receptor Type 22)[15] Assessment

Associates with the molecular adapter protein CBL and may be involved in regulating CBL function in the T-cell receptor signaling pathway. Mutations in this gene may be associated with a range of autoimmune disorders including Type 1 Diabetes, rheumatoid arthritis, systemic lupus erythematosus and Graves’ disease.

Among its related pathways are Class I MHC mediated antigen processing and presentation and Translocation of ZAP-70 to Immunological synapse.

Acts as negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules (PubMed:16461343, PubMed:18056643).

Positively regulates toll-like receptor (TLR)-induced type 1 interferon production (PubMed:23871208). Promotes host antiviral responses mediated by type 1 interferon (By similarity). Regulates NOD2-induced pro-inflammatory cytokine secretion and autophagy (PubMed:23991106).

Top Transcription factor binding sites by QIAGEN in the PTPN22 gene promoter:

  • AML1a

  • GATA-3

  • PPAR-gamma1/2 (Needs PPAR Agonist – linoleic acid (sea buckthorn), oleic acid (sea buckthorn) Resveratrol, cannabidiol, alpha-linolenic acid (sea buckthorn), Fish oil, Omega-3 fatty acids (sea buckthorn), Palmitic Acid (sea buckthorn & MTC coconut), Capric acid (MTC coconut), Curcumin, arachidonic acid (sea buckthorn), Butyric Acid, Myristic acid (MTC coconut), Berberine.

Interacting Proteins for PTPN22 Gene STRING Interaction Network [16]

SKAP2

Src kinase-associated phosphoprotein 2; May be involved in B-cell and macrophage adhesion processes. In B-cells, may act by coupling the B-cell receptor (BCR) to integrin activation. May play a role in src signaling pathway; Belongs to the SKAP family (359 aa)

CSK

Tyrosine-protein kinase CSK; Non-receptor tyrosine-protein kinase that plays an important role in the regulation of cell growth, differentiation, migration, and immune response. Phosphorylates tyrosine residues located in the C-terminal tails of Src-family kinases (SFKs) including LCK, SRC, HCK, FYN, LYN or YES1. Upon tail phosphorylation, Src-family members engage in intramolecular interactions between the phosphotyrosine tail and the SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is recruited to the plasma membrane via binding to transmembrane proteins or ada […] (450 aa)

SULT2A1

Bile salt sulfotransferase; Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfonation of steroids and bile acids in the liver and adrenal glands; Sulfotransferases, cytosolic (285 aa

CBL

E3 ubiquitin-protein ligase CBL; Adapter protein that functions as a negative regulator of many signaling pathways that are triggered by activation of cell surface receptors. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Recognizes activated receptor tyrosinekinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, EGFR, CSF1R, EPHA8 and KDR and terminates signaling. Recognizes membrane-bound HCK, SRC and other kinases of the SRC family […] (906 aa)

ZAP70

Tyrosine-protein kinase ZAP-70; Tyrosine kinase that plays an essential role in the regulation of the adaptive immune response. Regulates motility, adhesion and cytokine expression of mature T-cells, aswell as thymocyte development. Contributes also to the development and activation of primary B-lymphocytes. When antigen-presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylations leads to the recruitment of ZAP70 to the doubly phosphorylated TCR component CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated T […] (619 aa)

IGF1R

Insulin-like growth factor 1 receptor; Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cells. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc […] (1367 aa)

EGFR

Epidermal growth factor receptor; Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates […] (1210 aa)

INSR

Insulin receptor; Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL, and other signaling intermediates. Each of these phosphorylated proteins serves as docking proteins for other signaling proteins that contain Src- homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosine residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the acti […] (1382 aa)

LCK

Tyrosine-protein kinase Lck; Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T- cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein […] (509 aa)

VCP

Transitional endoplasmic reticulum ATPase; Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional elements of the endoplasmic reticulum (tER). Vesicle budding from the tER is an ATP-dependent process. The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is neces […] (806 aa)

PTPN22

Tyrosine-protein phosphatase non-receptor type 22; Acts as a negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules. Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating ’Tyr-394’ residue. Dephosphorylates ZAP70 at its activating ’Tyr- 493’ residue. Dephosphorylates the immune system activator SKAP2. Positively regulates toll-like receptor (TLR)-induced type 1 interferon production. Promotes host […] (807 aa)

CD3e

T-cell surface glycoprotein CD3 epsilon chain; Part of the TCR-CD3 complex present on the T-lymphocyte cell surface that plays an essential role in the adaptive immune response. When antigen-presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of […] (207 aa)

CD247

T-cell surface glycoprotein CD3 zeta chain; Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response. When antigen-presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of do […] (164 aa)

ACTA1

Actin, alpha skeletal muscle; Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells (377 aa)

SPTA1

Spectrin alpha chain, erythrocytic 1; Spectrin is the major constituent of the cytoskeletal network underlying the erythrocyte plasma membrane. It associates with band 4.1 and actin to form the cytoskeletal superstructure of the erythrocyte plasma membrane; EF-hand domain-containing (2419 aa)

INSRR

Insulin receptor-related protein; Receptor with tyrosine-protein kinase activity. Functions as a pH sensing receptor which is activated by increased extracellular pH. Activates an intracellular signaling pathway that involves IRS1 and AKT1/PKB (1297 aa)

PREP

Prolyl endopeptidase; Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long; Belongs to the peptidase S9A family (710 aa)

SLITRK2

SLIT and NTRK-like protein 2; It is involved in synaptogenesis and promotes excitatory synapse differentiation. Suppresses neurite outgrowth (By similarity) (845 aa)

SLITRK1

SLIT and NTRK-like protein 1; It is involved in synaptogenesis and promotes excitatory synapse differentiation. Enhances neuronal dendrite outgrowth (696 aa)

GRB2

Growth factor receptor-bound protein 2; Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway; SH2 domain containing (217 aa)

PRKCD

Protein kinase C delta type; Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell death and cell survival by functioning as a pro-apoptotic protein during DNA damage-induced apoptosis, but acting as an anti-apoptotic protein during cytokine receptor- initiated cell death, is involved in tumor suppression as well as survival of several cancers, is required for oxygen radical production by NADPH oxidase and acts as positive or negative regulator in platelet functional responses. Negatively regulates B c […] (676 aa)

MATK

Megakaryocyte-associated tyrosine-protein kinase; Could play a significant role in the signal transduction of hematopoietic cells. May regulate tyrosine kinase activity of SRC-family members in brain by specifically phosphorylating their C-terminal regulatory tyrosine residue which acts as a negative regulatory site. It may play an inhibitory role in the control of T-cell proliferation (508 aa)

PSTPIP2

Proline-serine-threonine phosphatase-interacting protein 2; Binds to F-actin. May be involved in regulation of the actin cytoskeleton (By similarity); F-BAR domain containing (334 aa)

PSTPIP1

Proline-serine-threonine phosphatase-interacting protein 1; Involved in regulation of the actin cytoskeleton. May regulate WAS actin-bundling activity. Bridges the interaction between ABL1 and PTPN18 leading to ABL1 dephosphorylation. May play a role as a scaffold protein between PTPN12 and WAS and allow PTPN12 to dephosphorylate WAS. Has the potential to physically couple CD2 and CD2AP to WAS. Acts downstream of CD2 and CD2AP to recruit WAS to the T-cell-APC contact site so as to promote the actin polymerization required for synapse induction during T-cell activation (By similarity). […] (416 aa)

TRAF3

TNF receptor-associated factor 3; Regulates pathways leading to the activation of NF- kappa-B and MAP kinases, and plays a central role in the regulation of B-cell survival. Part of signaling pathways leading to the production of cytokines and interferon. Required for normal antibody isotype switching from IgM to IgG. Plays a role T-cell dependent immune responses. Plays a role in the regulation of antiviral responses. Is an essential constituent of several E3 ubiquitin-protein ligase complexes. May have E3 ubiquitin-protein ligase activity and promote ’Lys-63’-linked ubiquitination of […] (568 aa)

VAV1

Proto-oncogene vav; Couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or proliferation; Pleckstrin homology domain containing (845 aa)

Regulating the ‘first shell interactor’ makes a major impact on the function of the aforementioned gene, in this case, SKAP2 ànd PTPN22.

The first shell of interactor (red node) of PTPN22 (Note: red nodes regulate the function of the mentioned gene):

SKAP2 Gene[17] (red node)

Adaptor protein that is thought to play an essential role in the Src signaling pathway, and in regulating proper activation of the immune system.

Drugs (Compounds) for SKAP2 Gene – From: ApexBio and Novoseek:

  • Kaempferol – Common foods that contain kaempferol include: apples, grapes, tomatoes, green tea, potatoes, onions, broccoli, Brussels sprouts, squash, cucumbers, lettuce, green beans, peaches, blackberries, raspberries, and spinach. Plants that are known to contain kaempferol include Aloe vera, Coccinia grandis, Cuscuta chinensis, Euphorbia pekinensis, Glycine max (Nattokinase[18]), Hypericum perforatum, Pinus sylvestris, Moringa oleifera, Rosmarinus officinalis (Rosmarinic acid – Prunella Vulgaris[19]), Sambucus nigra, and Toona sinensis, and Ilex. It also is present in endive.[20]

Kaempferol Inhibits the Migration and Invasion of Rheumatoid Arthritis Fibroblast-Like Synoviocytes by Blocking Activation of the MAPK Pathway[21]

Kaempferol Targeting on the Fibroblast Growth Factor Receptor 3-ribosomal S6 Kinase 2 Signaling Axis Prevents the Development of Rheumatoid Arthritis[22]

Kaempferol Inhibits IL-1β-induced Proliferation of Rheumatoid Arthritis Synovial Fibroblasts and the Production of COX-2, PGE2 and MMPs[23]

Kaempferol targeting on the fibroblast growth factor receptor 3-ribosomal S6 kinase 2 signaling axis prevents the development of rheumatoid arthritis[24]

ZAP70 (as previously mentioned above)

Translocation of ZAP-70 to Immunological synapse (SuperPathway related to PTPN22 Gene)

ZAP70 (Viral Target Gene)[25]-[26]-[27]

Destroying cells infected by viruses…ZAP70 gene

Autoimmunity Eczema Eczematoid dermatitis Respiratory tract infection Pneumonia Recurrent fungal infections Inflammatory abnormality of the skin Abnormality of the digestive system Abnormality of immune system physiology Abnormal inflammatory response T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection

The ZAP70 gene provides instructions for making a protein called zeta-chain-associated protein kinase. This protein is part of a signaling pathway that directs the development of and turns on (activates) immune system cells called T cells. T cells identify foreign substances and defend the body against infection.

The ZAP70 gene is important for the development and function of several types of T cells. These include cytotoxic T cells (CD8+ T cells), whose functions include destroying cells infected by viruses. The ZAP70 gene is also involved in the activation of helper T cells (CD4+ T cells). These cells direct and assist the functions of the immune system by influencing the activities of other immune system cells.

Diseases associated with ZAP70 include Immunodeficiency 48 and Autoimmune Disease, Multisystem, Infantile-Onset, 2.

Among its related pathways are Class I MHC mediated antigen processing and presentation and CREB Pathway.

ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface.

Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR).

Drugs (Compounds) for ZAP70 Gene – From DrugBank, DGIdb, HMDB, and Novoseek:

  • ATP

  • Fostamatinib – a SYK inhibitor (Syk is a protein tyrosine kinase associated with various inflammatory cells, including macrophages, which are presumed to be the cells responsible for ITP platelet clearance. When FcγRs I, IIA, and IIIA bind to their ligands, the receptor complex becomes activated and triggers the phosphorylation of the immunoreceptor-activating motifs (ITAMs). This leads to various genes becoming activated, which causes a cytoskeletal rearrangement that mediates phagocytosis in cells of the monocyte/macrophage lineage. Because Syk plays an important role in FcγR-mediated signal transduction and inflammatory propagation, it is considered a good target for the inhibition of various autoimmune conditions, including rheumatoid arthritis and lymphoma.)

  • Staurosporine – an indolocarbazole (found in blue-green algae)

  • ALOISINE – an inhibitor of CDK1, CDK2, CDK5, GSK-3 alpha, and JNK.

Other Mechanisms of Actions:

  • Protein kinase inhibitor

  • SYK INHIBITOR

Other natural SKY Inhibitors:

  • Piceatannol, a natural stilbene (Resveratrol)

  • tanshinone I (Dan Shen)

  • Ginger

  • Liquorice

  • Saussurea lappa

  • Angelica decursiva

  • Chinese skullcap

  • White mulberry

  • Curcumin

  • Cloves

  • Burdock root

  • Rhubarb

  • Sesame

Discovery of a Natural Syk Inhibitor from Chinese Medicine through a Docking-Based Virtual Screening and Biological Assay Study[28]

Class I MHC mediated antigen processing and presentation[29] (SuperPathway related to PTPN22 Gene)

Red Node: PSMA4 Gene

PSMA4 Gene[30]

The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).

Among its related pathways are Regulation of degradation of deltaF508 CFTR in CF

Drugs (Compounds) for CFTR Gene – From: DrugBank, PharmGKB, ClinicalTrials, ApexBio, DGIdb, IUPHAR, HMDB, Tocris, and Novoseek[31]:

  • Capsaicin

  • Curcumin

  • Tannic acid (Prunella Vulgaris/Self-Heal)

  • Citric acid

  • Apigenin (Flavonols – kaempferol, quercetin, luteolin)

  • Chloride ion (Shilajit/Fulvic acid)

  • Genistein (structurally similar to Kudzu. Also found in Nattokinase)

  • Calcium (Shilajit/Fulvic acid)

  • Resveratrol[32]

Drugs for PSMA4 Gene – From: DrugBank, PharmGKB, and DGIdb:

Mechanism of Action: 20S Proteasome Inhibitor

20S Proteasome Inhibitors[33]-[34][35]:

  • Resveratrol

  • Ginger

  • Withania somnifera or Ashwagandha

  • ECGC

  • Apigenin (Flavonols – kaempferol, quercetin, luteolin)

  • Quercetin – found in Prunella Vulgaris[36]

  • Genistein (found in Nattokinase, and Kudzu – similar compound)

  • Curcumin

*PSMA4 regulates Class I MHC mediated antigen processing and presentation to which 20S Proteasome Inhibitors modulate.*

Genes held in common with diseases related to Rheumatoid Arthritis via text searches within MalaCards or GeneCards Suite gene sharing:

Top Affiliating Genes – PADI4, IRF5, IL10, CIITA

PADI4 Gene[37][38]

This gene is a member of a gene family that encodes enzymes responsible for the conversion of arginine residues to citrulline residues. This gene may play a role in granulocyte and macrophage development leading to inflammation and immune response. [provided by RefSeq, Jul 2008]

Acts as a key regulator of stem cell maintenance by mediating citrullination of histone H1 thereby promoting pluripotency and stem cell maintenance. Promotes profound chromatin decondensation during the innate immune response to infection in neutrophils.

Health conditions associated: Rheumatoid arthritis (RA)

Drugs (Compounds for PADI4 Gene – From: DrugBank, DGIdb, HMDB, and Novoseek:

  • Citrulline

  • Calcium

  • Arginine

  • Water

The first shell of interactor protein (red node)[39]:

  • TP53 – The Guardian of the Genome

TP53 Gene[40]

Drugs (Compounds) for TP53 Gene – From: DrugBank, PharmGKB, ClinicalTrials, ApexBio, DGIdb, Tocris, and Novoseek:

  • Vincristine (Vinpocetine)

  • Zinc (Shilajit/Fulvic acid)

  • Betulinic acid (found in Prunella Vulgaris/Self-Heal[41])

Other TP53 Compounds:

  • D-Mannose + Fucose/Fucoidan (Bladderwrack) + N-Acetyl Glucosamine combined[42]

  • Chondroitin Sulfate[43]

  • Propolis[44]

  • Danshen[45]

  • Resveratrol[46]

  • Pomegranate[47]

  • Ginger[48]

  • Ashwagandha[49]

  • β-glucan[50]

  • Kudzu[51]

  • Nattokinase[52]

  • Sea Buckthorn[53][54]

  • Shilajit[55]

  • Phosphatidylcholine[56]

Studies connecting p53 to RA through PADI4:

  • p53 predominantly regulates IL-6 production and suppresses synovial inflammation in fibroblast-like synoviocytes and adjuvant-induced arthritis[57]

  • p53 in rheumatoid arthritis: friend or foe?[58]

  • Expression of p53 Protein in Rheumatoid Arthritis Synovium. An Immunohistochemical Analysis[59]

  • p53 Expression in rheumatoid and psoriatic arthritis synovial tissue and association with joint damage[60]

  • p53, proto-oncogene and rheumatoid arthritis[61]

  • p53 in rheumatoid arthritis synovial fibroblasts at sites of invasion[62]

Study:

Curative remedies for rheumatoid arthritis: Herbal informatics approach for rational based selection of natural plant products[63]

CIITA[64]

A “master control factor” for class II major histocompatibility complex gene transcription.

The first shell protein:

SIRT1 is an enzyme that deacetylates proteins that contribute to cellular regulation (reaction to stressors, longevity).[66]

SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors.

PGC-1α is the master regulator of mitochondrial biogenesis.[67]

PGC-1α is a transcriptional coactivator that regulates the genes involved in energy metabolism. This protein interacts with the nuclear receptor PPAR-γ, which permits the interaction of this protein with multiple transcription factors. This protein can interact with, and regulate the activities of, cAMP response element-binding protein (CREB) and nuclear respiratory factors (NRFs). It provides a direct link between external physiological stimuli and the regulation of mitochondrial biogenesis, and is a major factor causing slow-twitch rather than fast-twitch muscle fiber types.

Massage therapy appears to increase the amount of PGC-1α which leads to the production of new mitochondria.

PGC-1α and beta has furthermore been implicated in polarization to anti-inflammatory M2 macrophages by interaction with PPARγ. (see PPAR Agonists above). PGC-1 inhibits proinflammatory cytokine production.

SIRT1 has been shown to deacetylate the p53 protein. (See p53 compounds above).

Human aging is characterized by a chronic, low-grade inflammation level, and NF-κB is the main transcriptional regulator of genes related to inflammation. SIRT1 inhibits NF-κB-regulated gene expression.

Resveratrol increases the expression of SIRT1, meaning that it does increase the activity of SIRT1, though not necessarily by direct activation. However, resveratrol was later shown to directly activate Sirtuin 1 against non-modified peptide substrates. Resveratrol also enhances the binding between Sirtuin 1 and Lamin A. In addition to resveratrol, a range of other plant-derived polyphenols have also been shown to interact with SIRT1.

Drugs (Compounds) for SIRT1 Gene – From: DrugBank, ClinicalTrials, ApexBio, DGIdb, HMDB, Tocris, and Novoseek[68]:

  • Resveratrol

  • Nicotinamide

  • NADH

  • Hydrogen peroxide

  • Progesterone

  • Melatonin

  • Quercetin

  • Catalase

Other SIRT1 Compounds[69]-[70]-[71]:

  • Astragalus

  • Panax ginseng

  • Bupleurum

  • Omega-3 fatty acids (Sea Buckthorn)

  • Docosahexaenoic acid (DHA)

  • Fisetin

  • Luteolin (Prunella Vulgaris/Self-Heal)

  • Rutin

  • Curcumin

  • Myricetin (Sea Buckthorn) – contains bioactive compounds, including vitamin C, minerals, monosaccharides, organic acids, carotenoids, vitamin E, tannins, and flavonoids such as quercetin, myricetin, and kaempferol.[72]

  • Apigenin (Flavonols – kaempferol, quercetin, luteolin)

  • Epigallocatechin gallate

  • Fenugreek

  • Naringenin

  • Daidzein (Kudzu)

Potential SIRT1 Inhibitors[73]:

  • PPAR gamma (see above)

  • Genistein/ Daidzein (Kudzu)

Note* – the key here is to balance SIRT1 (modulate), as overactivation may exuberate autoimmune reactions.

This is why combining Sea Buckthorn, Kudzu, and Resveratrol work in a synergistic fashion to accomplish a balance.

IL10 gene

This cytokine has pleiotropic effects in immunoregulation and inflammation. It down-regulates the expression of Th1 cytokines, MHC class II Ags, and costimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production. This cytokine can block NF-kappa Bactivity, and is involved in the regulation of the JAK-STAT signaling pathway. Knockout studies in mice suggested the function of this cytokine as an essential immunoregulator in the intestinal tract. Mutations in this gene are associated with an increased susceptibility to HIV-1 infection and rheumatoid arthritis.[provided by RefSeq, May 2011][74]

Major immune-regulatory cytokine that acts on many cells of the immune system where it has profound anti-inflammatory functions, limiting excessive tissue disruption caused by inflammation.

Targets antigen-presenting cells (APCs) such as macrophages and monocytes and inhibits their release of pro-inflammatory cytokines including granulocyte-macrophage colony-stimulating factor /GM-CSF, granulocyte colony-stimulating factor/G-CSF, IL-1 alpha, IL-1 beta, IL-6, IL-8 and TNF-alpha(PubMed:1940799, PubMed:7512027, PubMed:11564774). Interferes also with antigen presentation by reducing the expression of MHC-class II and co-stimulatory molecules, thereby inhibiting their ability to induce T cell activation (PubMed:8144879). In addition, controls the inflammatory response of macrophages by reprogramming essential metabolic pathways including mTOR signaling (By similarity).

Extensive IL-10 locus remodeling is observed in monocytes upon stimulation of TLR or Fc receptor pathways[75]. (See SYK Inhibitors above)

A study in mice has shown that IL-10 is also produced by mast cells, counteracting the inflammatory effect that these cells have at the site of an allergic reaction.

IL-10 is linked to the myokines, as exercise provokes an increase in circulating levels of IL-1ra, IL-10, and sTNF-R, suggesting that physical exercise fosters an environment of anti-inflammatory cytokines.

Lower levels of IL-10 have been observed in individuals diagnosed with multiple sclerosis when compared to healthy individuals. Due to a decrease in IL-10 levels, TNFα levels are not regulated effectively as IL-10 regulates the TNF-α-converting enzyme. As a result, TNFα levels rise and result in inflammation. TNFα itself induces demyelination of the oliodendroglial via TNF receptor 1, while chronic inflammation has been linked to demyelination of neurons.

Drugs (Compounds) for TNF Gene – From: DrugBank, PharmGKB, ClinicalTrials, ApexBio, DGIdb, HMDB, Tocris, and Novoseek[76]:

  • Glucosamine (NAG)

  • Curcumin

  • Glycyrrhizin (Licorice)

  • Vinpocetine

  • Zinc (Shilajit)

  • Folate (Sea Buckthorn[77])

  • Butyric Acid

  • Andrographis

  • Magnolia

  • Tanshinone IIA (Danshen)

Drugs (Compounds) for IL10 Gene – From: DrugBank, PharmGKB, ClinicalTrials, and Novoseek[78]:

  • Nicotinamide/Niacin

  • Heparin (Heparin binding Nattokinase)

  • Zinc (Shilajit)

  • Folate (Sea Buckthorn)

  • B-12 (Liver Extracts)

  • Acidophilus

  • Bifidobacterium

  • Vitamin B Complex

  • Antioxidant Action of Vitamin-C (Sea Buckthorn + Self-Heal) targets IL-10RA[79]

The NR3C1 Gene (Glucocorticoid Receptor) directly cross talks with IL-10.

The Glucocorticoid Receptor (NR3C1) is the major target of Prednisone!!!

Glucocorticoid receptor agonist:

  • Progesterone

Glucuronidation Agonist:

  • Androgens [R]

  • Bilirubin [R]

  • Bile acids [R]

  • Sulforaphane [R, R]

  • Nrf2 (R, R)

  • Genistein/Kudzu root [R]

  • Green tea [R, R]

  • Dandelion [R]

  • Rooibos tea [R]

  • Honeybush tea [R]

  • Rosemary (Rosmarinic acid/ Prunella Vulgaris/Self-Heal) [R]

  • Ellagic acid (Pomegranate) [R]

  • Ferulic acid [R]

  • Quercetin (Prunella Vulgaris/Self-Heal) [R]

  • Tannic acid (Prunella Vulgaris/Self-Heal) [R]

  • Coumarin [R]

  • Fumaric acid [R]

  • Curcumin[R]

  • Flavone [R]

  • Astaxanthin/ Bladderwrack [R]

Serum/Glucocorticoid Regulated Kinase (SGK) Inhibitor:

  • Dracorhodin perchlorate (DP), one of the main compositions of Dragon’s blood (R)

  • Chloride ion (Shilajit) (R)

  • Flavin mononucleotide (FMN), or riboflavin-5′-phosphate, is a biomolecule produced from riboflavin (vitamin B2) (R)

  • Resveratrol (R)

  • Celastrol – Tripterygium wilfordii (Thunder god vine) (R)

  • Baicalin (Skullcap) (R)

Heat shock proteins (hsp90 and hsp70) communicate with NR3C1 Gene (Glucocorticoid Receptor) through Peptidyl-prolyl cis-trans isomerase FKBP4, which is involved with protein folding and trafficking.[80]-[81]

The isomerase activity of FKBP4 controls neuronal growth cones via regulation of TRPC1 channel opening. Acts also as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly. May have a protective role against oxidative stress in mitochondria.

Heat shock protein 70 modulator:

  • Ginger[82]

Heat shock protein 90 modulator:

  • Ashwagandha[83]

Microtubule Inhibitor:

  • Resveratrol (R)

  • Vinca alkaloid/Periwinkle/Vinpocetine (R)(R)(R)(R)

Drugs (Compound) for TRPC1 Gene – From: ApexBio, DGIdb, IUPHAR, HMDB, and Novoseek[84]:

  • Calcium (Shilajit/Fulvic acid))

  • IP3 receptor antagonist

BCL-2 Modulators ARE IP3 receptor antagonist:

  • BCL-2 Modulators (R):

  • Luteolin (strongest) (Prunella Vulgaris/Self-Heal)(R)

  • Fisetin (second strongest) (R)

  • Resveratrol (R)

  • Marine Algae / Bladderwrack (R)

  • Genistein/Kudzu root (R)

  • Berberine (R)

  • Vinpocetine (R)

  • Withaferin-A/Ashwagandha (R)

  • Lauric Acid/Monolaurin/MTC coconut (R)

  • Sea buckthorn Oil (R)

  • Astaxanthin/Bladderwrack (R)

  • Apigenin (Flavonols – kaempferol, quercetin, luteolin) (R)

  • Galangin (R)

  • Astragalus (R)

  • Beta glucans (R)

  • Quercetin (Prunella Vulgaris/Self-Heal) (R)

  • EGCG (R)

  • Curcumin (R)

  • DIM (Diindolylmethane) (R)

  • Garlic/Allicin (R)

  • Forskolin (R)

Summary:

ReverseFX contains upwards of 90% of the compounds listed above in relation to autoimmune joint pain / Rheumatoid Arthritis.

And, because most these genes with (RA) cross-talk with the same genes as Lupus, it may also be effective and assist the body for this as well.

Kill two birds with one stone!

RA and Lupus have the same main gene…PTPN22!

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[1] https://www.medicalnewstoday.com/articles/322975

[2] https://www.arthritis-health.com/types/rheumatoid/my-joint-pain-caused-rheumatoid-arthritis-ra-or-another-autoimmune-disorder

[3] https://ghr.nlm.nih.gov/condition/rheumatoid-arthritis

[4] https://www.malacards.org/card/systemic_lupus_erythematosus

[5] https://ghr.nlm.nih.gov/condition/systemic-lupus-erythematosus

[6] https://www.malacards.org/card/rheumatoid_arthritis

[7] https://www.malacards.org/card/rheumatoid_arthritis?limit[MaladiesUnifiedCompounds]=697#MaladiesUnifiedCompounds-table

[8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654648/

[9] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438513/

[10] https://en.wikipedia.org/wiki/Fucus_vesiculosus

[11] https://en.wikipedia.org/wiki/Kudzu#Phytochemicals_and_uses

[12] https://www.hindawi.com/journals/bmri/2014/145342/

[13] https://www.scientificamerican.com/article/vitamin-k-and-natto-what-s-the-connection/

[14] https://en.wikipedia.org/wiki/Prunella_vulgaris

[15] https://www.genecards.org/cgi-bin/carddisp.pl?gene=PTPN22

[16] https://version11.string-db.org/cgi/network.pl?taskId=PBGRqrf9Ek6s

[17] https://www.genecards.org/cgi-bin/carddisp.pl?gene=SKAP2

[18] https://rasayanjournal.co.in/vol-4/issue-2/26.pdf

[19] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2795400/

[20] https://en.wikipedia.org/wiki/Kaempferol

[21] https://pubmed.ncbi.nlm.nih.gov/29268189/

[22] https://pubmed.ncbi.nlm.nih.gov/29540697/

[23] https://pubmed.ncbi.nlm.nih.gov/23934131/

[24] https://www.nature.com/articles/s41419-018-0433-0

[25] https://en.wikipedia.org/wiki/ZAP70

[26] https://ghr.nlm.nih.gov/gene/ZAP70

[27] https://www.genecards.org/cgi-bin/carddisp.pl?gene=ZAP70

[28] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320911

[29] https://pathcards.genecards.org/card/class_i_mhc_mediated_antigen_processing_and_presentation

[30] https://www.genecards.org/cgi-bin/carddisp.pl?gene=PSMA4

[31] https://www.genecards.org/cgi-bin/carddisp.pl?gene=CFTR

[32] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828912/

[33] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303152/

[34] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791234/

[35] https://www.nature.com/articles/cddis2013294

[36] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6259167/

[37] https://ghr.nlm.nih.gov/gene/PADI4

[38] https://www.genecards.org/cgi-bin/carddisp.pl?gene=PADI4

[39] https://version11.string-db.org/cgi/network.pl?taskId=U4Mik8XWFjjP

[40] https://www.genecards.org/cgi-bin/carddisp.pl?gene=TP53

[41] https://en.wikipedia.org/wiki/Prunella_vulgaris

[42] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495572/

[43] https://pubs.acs.org/doi/pdf/10.1021/acs.accounts.7b00473?__cf_chl_js chl_tk__= 2a71cfde dc2758124f7a3a 491bc519237193939b-1586631049-0-AXO3RfR0ho UwpGYWp8L5iPp 0sQW5gd0ID4qr20pQWBPWcIfe-Yqxig4uPoYzeiC k cwkwmbuAZ1Lo4Qtv4AY7c4 Tn0qWn5OMuGehKIog_SLR2M-U1uGUA urvm 11iKnEK pQ1Ce4oN rzkIfQ MOcu3A fq_7ovljmBP xMHP0tchbpN3DFWH-xVKEic7W2sJ 0yUb Fnztq1SjzO7Oy9uz1 wdtFqFkhcngvlqW6nt9TGY8_8DnvddEtEG7roVEFmTlmg1XTAG2beEbQsjTS77Dx4RVyOsQjXS1B3 TSik_PvH8I2VcthFkeBC9xlcIn606Uhg9INeEg

[44] http://www.eurekaselect.com/node/175102/article/chemoprotective-effects-of-propolis-on-aflatoxin-b1-induced-hepatotoxicity-in-rats-oxidative-damage-and-hepatotoxicity-by-modulating-tp53-oxidative-stress

[45] https://www.dovepress.com/anticancer-potential-of-salvia-miltiorrhiza-and-its-tanshinones-a n-eff-peer-reviewed-fulltext-article-BTAT

[46] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195383/

[47] https://pubmed.ncbi.nlm.nih.gov/24085032/

[48] https://pubmed.ncbi.nlm.nih.gov/23300887/

[49] https://pubmed.ncbi.nlm.nih.gov/30808373/

[50] https://www.nature.com/articles/srep28802

[51] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017674/

[52] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043915/

[53] https://www.spandidos-publications.com/10.3892/ol.2018.9575

[54]https://www.sciencedirect.com/science/article/pii/S1319562X16000061

[55]https://pubmed.ncbi.nlm.nih.gov/26530234/

[56] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2915541/

[57] https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-016-1161-4

[58] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC129999/

[59] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531907/

[60] https://ard.bmj.com/content/64/2/183

[61] https://www.sciencedirect.com/science/article/abs/pii/S0049017202783157

[62] https://ard.bmj.com/content/62/12/1139

[63]https://www.researchgate.net/publication/312010 568_Curative_rem edies_for_rheum atoid_art hritis_Herbal_in formatics_appro ach_for_rational_b ased_selection_of_natural_plant_products/link/586b5ea908ae329d6211e5d7/download

[64] https://www.genecards.org/cgi-bin/carddisp.pl?gene=CIITA

[65] https://version11.string-db.org/cgi/network.pl?taskId=Vlx6yDr8Sw0S

[66] https://en.wikipedia.org/wiki/Sirtuin_1

[67] https://en.wikipedia.org/wiki/PPARGC1A

[68] https://www.genecards.org/cgi-bin/carddisp.pl?gene=SIRT1

[69] https://www.hindawi.com/journals/omcl/2016/4206392/

[70] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727669/

[71] https://www.preprints.org/manuscript/202001.0324/v1/download

[72] http://www.jmb.or.kr/submission/Journal/027/JMB027-07-07_FDOC_2.pdf

[73] https://selfhacked.com/blog/nad-and-sirt1-their-role-in-chronic-health-issues/

[74] https://ghr.nlm.nih.gov/gene/IL10

[75] https://en.wikipedia.org/wiki/Interleukin_10

[76] https://www.genecards.org/cgi-bin/carddisp.pl?gene=TNF

[77] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438513/

[78] https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL10

[79]https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL10RA

[80] https://version11.string-db.org/cgi/network.pl?taskId=kngXOPdD8nSn

[81] https://www.genecards.org/cgi-bin/carddisp.pl?gene=FKBP4

[82] https://pubmed.ncbi.nlm.nih.gov/21864631/

[83] https://en.wikipedia.org/wiki/Withaferin_A

[84] https://www.genecards.org/cgi-bin/carddisp.pl?gene=TRPC1

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