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Drug re-positioning for tuberculosis infection in HIV/ADS patients
- 1. Anti-tuberculosis drugs for HIV patients Prepared by Anton Yuryev, Ph.D., Elsevier Professional Services on February 15th 2018 Disclaimer: Data in Pathway Studio and in PharmaPendium is regular updated by Elsevier. Therefore the reproduction of workflows from this report may produce additional findings that are different from the results in this report. Contents Mechanism for development of tuberculosis (TB) in HIV patients...............................................................1 Finding drugs inhibiting both HIV infection and TB in Pathway Studio........................................................2 Figure 1: Chemical compounds known to inhibit both TB and HIV found in Pathway Studio..............2 Figure 2: Approved drugs inhibiting HIV infection, tuberculosis infection and activating macrophages are on the top row .........................................................................................................3 Finding drugs inhibiting HIV infection of alveolar macrophages using Pathway Studio curated pathway collection.......................................................................................................................................................3 Finding proteins expressed in alveolar macrophages...............................................................................3 Finding proteins expressed in alveolar macrophages inhibiting HIV infection.........................................3 Figure 3: Proteins expressed in alveolar macrophages regulating HIV infection ................................4 Identification of curated pathways inhibiting HIV infection in alveolar macrophages and corresponding drug agonists.............................................................................................................................................4 Table 1: Drugs activating âAlveolar Macrophages Dysfunctionâ pathway...............................................5 Finding HIV-inhibiting macrophage-activating proteins and drugs outside curated pathways ...................5 Figure 4: NFE2L2 agonists found in Pathway Studio.................................................................................5 Finding drugs positively regulating concepts related to Macrophage Activation and M2 Polarization in Pathway Studio .............................................................................................................................................6 Figure 5: Additional drugs activating macrophages not found by previous workflows .......................6 Conclusion.....................................................................................................................................................6 Table2: Pathway Studio concepts relevant to Macrophage Activation and M2 Polarization ......................8 Table 3: Complete list of drugs inhibiting HIV infection of macrophages found by this white paper........12 Mechanism for development of tuberculosis (TB) in HIV patients Mechanism of TB-HIV interaction is well understood on cellular level. In brief, HIV can infect T-cells and macrophages using CD4 and CCR2/4/5 receptors for entry. HIV infection of immune cell leads to the attenuation of their function and globally compromised immune system. TB uses alveolar macrophages for entry into the organism. If macrophages are healthy TB infection becomes latent and bacteria can live capsulized inside alveolar macrophage phagosomes for years without causing health problems. HIV-
- 2. compromised macrophages cannot control TB replication and allow its malignant spreading into many organs where TB forms granulomas from immune cells around infected resident macrophages. Granulomas subsequently transform into tubercles. It is known that TB does not enter macrophages in certain organs such as heart, skeletal muscles, pancreas, or thyroid. HIV does not infect M2 polarized anti-inflammatory macrophages in all tissues, however, prolonged M2 polarization leads to the accumulation of IL10 which causes macrophages deactivation and increases CCR5 expression on monocytes. Down-regulation of macrophages and T-cells by HIV eventually leads to immune system failure and AIDS. IL10 is also known to facilitate pathogen survival in macrophages thus promoting TB infection. Therefore, drugs against TB infection in HIV patient must activate macrophage function, or prevent virus infection of macrophages, or inhibit IL10 production. Finding drugs inhibiting both HIV infection and TB in Pathway Studio To find drugs inhibiting both types of infection letâs first find relevant disease entities in Pathway Studio. Search for HIV using basic search box located on top of Pathway Studio interface finds several hundred molecules, pathways and diseases. You can sort search results by âTotal connectivityâ column to find most informative HIV-related disease concepts: âHIV infectionâ, âHIV-1 infectionâ, âAcquired Immunodeficiency Syndromeâ. Move them into empty pathway, perform another basic search for âtuberculosisâ and move âTuberculosisâ disease entity into the same pathway with HIV entities. Select one of HIV-related diseases and âTuberculosisâ disease entity and find drugs inhibiting both diseases using Add->Network builder dialog with settings âCommon regulatorsâ filtered for entity Small Molecule and relation type ClinicalTrial or Regulation with Effect negative. Repeat âCommon regulatorsâ search for all pairs of âTuberculosisâ with another HIV-related entity. The approach should yield more than 200 chemical entities as shown on Figure 1. Figure 1: Chemical compounds known to inhibit both TB and HIV found in Pathway Studio To select only approved drugs in this pathway you can either add column âPharmaPendium IDâ to Entity view table of the pathway or paste the following advanced graphical language query into advanced search âSearch queryâ box: objectType='Small Molecule' AND "PharmaPendium ID" != null AND MemberOf (select Network WHERE Name = 'TB+HIV drugs') Make sure to replace 'TB+HIV drugs' with the name of your pathway. To find drugs inhibiting TB infection in HIV patients through activation of macrophages find relevant âMacrophageâ Cell entities
- 3. using basic search and add them to the same pathway and use Network builder option âFind direct interactionsâ option with filter for Regulation relation type with Effect positive. Filtering results for macrophage activators should find at least 27 chemical entities. 18 of them are true drugs and nine are metabolites that are also approved for therapeutic applications and therefore have PharmaPendium ID. Figure 2: Approved drugs inhibiting HIV infection, inhibiting tuberculosis, and activating macrophages are shown in the top row Finding drugs inhibiting HIV infection of alveolar macrophages using Pathway Studio curated pathway collection Finding proteins expressed in alveolar macrophages To find proteins expressed in alveolar macrophages add âAlveolar macrophagesâ entity to new pathway and use Add->Network Builder option âExpand pathwayâ filtered for entity types: Protein, Functional Class, Complex and filtered for Relation type âCellExpressionâ. This search will find more than 100 proteins. Finding alveolar macrophages proteins that inhibit HIV infection Some alveolar macrophages proteins contribute to HIV infection while others prevent it. Drugs that can inhibit proteins contributing to HIV infection are likely immune-suppressants inhibiting macrophage function. They can only further weaken immune system that is already handicapped by HIV and TB infection. Therefore you should search for drugs that activate proteins preventing HIV infection. To find such proteins add HIV-related diseases to the pathway containing proteins expressed in alveolar macrophages. Select âHIV infectionâ, âHIV-1 infectionâ, âAcquired Immunodeficiency Syndromeâ on the pathway and use menu option Add->Relation between selected and unselected entities to connect them with proteins expressed in alveolar macrophages. To find proteins that inhibit HIV infection visualize Effect sign in relations using menu option Style->Color relations->By Effect. Align all red-colored relations with Effect negative horizontally using Align menu option. Align all green-colored relations with Effect positive horizontally using Align menu option in a different row. Inspect sentences supporting all remaining grayed-out relations to find which effect a
- 4. protein has on HIV infection. Move all proteins inhibiting HIV next to the proteins linked by red-colored relations. Reading supporting sentence is often enough to understand the nature of effect but sometime you will need to open the original article containing the sentence to gain an insight about effect sign. This effort should yield you more than 35 proteins expressed in alveolar macrophages that negatively affect HIV infection. While curating for effect is the longest step in this workflow it effectively substitutes for browsing several hundred scientific articles. It will take less than one hour in Pathway Studio compared with days of reading thus improving your reading productivity more than 10 times. Figure 3: Proteins expressed in alveolar macrophages regulating HIV infection Proteins contributing to HIV infection are shown at the top of the diagram. Proteins preventing HIV infection are shown at the bottom of the diagram. Identification of curated pathways inhibiting HIV infection in alveolar macrophages and their drug agonists To find curated pathways containing proteins inhibiting HIV infection in alveolar macrophages select these proteins in the pathway and use Tools->Enrichment analysis of selected entities menu option. Because alveolar macrophages are components of both blood and lung organ systems you should specify both of these systems in Gene Set Categories box by browsing to Organ systems taxonomy branch in Anatomical Index pathway classification. This search should find more than 70 curated pathways. You should look through top 10-20 hits in the search results to find most relevant pathways. For this white paper two pathways were selected for finding drugs: âAnti-Inflammatory Function of Macrophage M2 Lineageâ and âAlveolar Macrophages Dysfunctionâ. Macrophage M2 polarization pathway has been expected from the mechanism of TB-HIV interaction described above. âAlveolar Macrophages Dysfunctionâ pathway belongs to COPD (Chronic Obstructive Pulmonary Disease) pathway collection. The Notes section in the Properties for this pathway says that âMacrophages are believed to play a pivotal role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Their numbers are increased (5-10 fold) in the airways, lung parenchyma, bronchoalveolar lavage fluid, and sputum of smokers and patients with COPDâ. Thus, this pathway depicts how macrophages are chronically activated in COPD by various endogenous signals provoked by tobacco smoking and air pollutants.
- 5. To find drugs activating alveolar macrophages or their M2 polarization select receptors responsible for signal transduction into macrophages on both pathways and expand using Add->Network Builder option âExpand pathwayâ filtered for Small Molecules and DirectRegulation with Effect positive. Receptors in âAnti-Inflammatory Function of Macrophage M2 Lineageâ pathway have not yielded any drugs for this tutorial, while receptors responsible for chronic macrophage activation in COPD have drug agonists listed in Table 1. Table 1: Drugs activating âAlveolar Macrophages Dysfunctionâ pathway Name Target in pathway Reported anti-HIV activity URN PharmaPendium ID ivermectin P2RX5 4 publications, 1 clinical trial urn:agi-cas:70288-86-7 Ivermectin polymyxin B P2RX7 1 clinical trial urn:agi-cas:1404-26-8 Polymyxin B isoflurane P2RX7 urn:agi-cas:26675-46-7 Isoflurane hemin TLR2 3 publications urn:agi-cas:16009-13-5 Hemin bleomycin TLR2 12 clinical trials urn:agi-cas:11056-06-7 Bleomycin paclitaxel TLR4 4 publications, 1 clinical trial against AIDS-Kaposi's sarcoma urn:agi-cas:33069-62-4 Paclitaxel imiquimod TLR4 2 clinical trials against AIDS-anal cancer urn:agi-cas:99011-02-6 Imiquimod Finding drugs for HIV-inhibiting macrophage-activating proteins not included in curated pathways More drugs activating alveolar macrophages can be found by inspecting individual proteins from the bottom of Figure 3 that do not belong to âanti-Inflammatory Function of Macrophage M2 Lineageâ or âAlveolar Macrophages Dysfunctionâ pathways. For example, activation of NFE2L2 protein was recently shown to protect macrophages from HIV infection by inhibiting oxidative stress caused by HIV. NFE2L2 agonists can be found in Pathway Studio by expanding NFE2L2 using Add->Network Builder towards Small Molecules by DirectRegulation relation with Effect=positive. Figure 4 shows NFE2L2 agonists that are cheap and can be readily available in poor countries. Additionally, one publication suggests that NFE2L2 activation may help macrophages to also combat TB infection. Figure 4: NFE2L2 agonists found in Pathway Studio
- 6. Finding drugs positively regulating other concepts related to Macrophage Activation and M2 Polarization in Pathway Studio Additional drugs activating macrophages or their M2 polarization can be found by expanding relevant concepts using Add->Network builder towards Small Molecules by Regulation relation with Effect=positive or as inhibitors of the concepts opposing macrophage activation and M2 polarization Table 2 shows 165 concepts relevant for macrophage function that can be expanded towards drug. You should expand only towards Small molecules than have PharmaPendium ID. Use âAdd conditionâ link in Network builder dialog to add âPharmaPendium IDâ != null condition to your query. Alternatively, you can create a group of all PharmaPendium drugs and then use filter for Specific Pathways or Entity List available on the last page of Network builder dialog. Figure 5: Additional drugs activating macrophages not found by previous workflows Conclusion We found 61 drugs, 20 food supplements from plants, and 24 human metabolites that potentially can reduce risk of TB infection in HIV patients (Table 3). They activate alveolar macrophages and reduce risk of their HIV infection which in turn hampers macrophages resistance to TB. Not all potential drugs have been found by this tutorial. However, the tutorial demonstrates and validates principals for finding ant- TB drugs for HIV patients. The approach was validated by finding Vitamin D3, which is the standard supplement in combating TB infection in HIV patients. Tutorial also found Interferon gamma-1b that was tested as aerosol treatment to activate alveolar macrophages in HIV patients. The workflow can be repeated in Pathway Studio for other proteins and concepts that were omitted from the consideration in this white paper to find even more potential anti-TB drugs for HIV patients.
- 7. Not every drug found by this tutorial can be used against HIV. Additional filtering criteria should be applied to select the best drugs. For example, imiquimod can only be applied topically and therefore cannot activate macrophages in the lung. DMSO is only approved for organ transplant conservation. TB infection is wide-spread among HIV patients in the developing countries. Therefore drug availability and cost must be additional criteria for drug selection. Food supplements and metabolites may be the cheapest way to prevent tuberculosis in HIV positive population in poor countries.
- 8. Table2: Pathway Studio concepts relevant to Macrophage Activation and M2 Polarization Name Object Type Total Connectivity Drug action alveolar macrophage Cell 2410 must activate M1 macrophage Cell 843 must activate M2 macrophage Cell 1370 must activate macrophage Cell 12605 must activate monocyte-macrophage precursor cell Cell 9 must activate alveolar macrophage adhesion Cell Process 7 must activate alveolar macrophage aggregation Cell Process 6 must activate alveolar macrophage apoptosis Cell Process 50 must inhibit alveolar macrophage autophagy Cell Process 2 must activate alveolar macrophage chemotaxis Cell Process 10 must activate alveolar macrophage count Cell Process 87 must activate alveolar macrophage cytotoxicity Cell Process 6 must activate alveolar macrophage damage Cell Process 9 must inhibit alveolar macrophage death Cell Process 20 must inhibit alveolar macrophage destruction Cell Process 2 must inhibit alveolar macrophage development Cell Process 17 must activate alveolar macrophage differentiation Cell Process 9 must activate alveolar macrophage distribution Cell Process 2 must activate alveolar macrophage division Cell Process 4 must activate alveolar macrophage fate commitment Cell Process 2 must activate alveolar macrophage formation Cell Process 5 must activate alveolar macrophage function Cell Process 121 must activate alveolar macrophage growth Cell Process 7 must activate alveolar macrophage homeostasis Cell Process 7 must activate alveolar macrophage infiltration Cell Process 13 must activate alveolar macrophage interaction Cell Process 6 must activate alveolar macrophage invasion Cell Process 3 must activate alveolar macrophage localization Cell Process 2 must activate alveolar macrophage migration Cell Process 21 must activate alveolar macrophage motility Cell Process 5 must activate alveolar macrophage phagocytosis Cell Process 74 must activate alveolar macrophage phenotype Cell Process 41 must activate alveolar macrophage polarity Cell Process 18 must activate alveolar macrophage population Cell Process 29 must activate alveolar macrophage priming Cell Process 7 must activate alveolar macrophage proliferation Cell Process 18 must activate alveolar macrophage proliferative response Cell Process 2 must activate alveolar macrophage ratio Cell Process 3
- 9. alveolar macrophage recognition Cell Process 3 must activate alveolar macrophage regeneration Cell Process 2 must activate alveolar macrophage renewal Cell Process 2 must activate alveolar macrophage repertoire Cell Process 3 must activate alveolar macrophage sequestration Cell Process 3 must activate alveolar macrophage size Cell Process 3 must activate alveolar macrophage spreading Cell Process 5 must activate alveolar macrophage structure Cell Process 2 must activate alveolar macrophage survival Cell Process 9 must activate alveolar macrophage viability Cell Process 7 must activate M1 macrophage chemotaxis Cell Process 4 must activate M1 macrophage count Cell Process 32 must activate M1 macrophage cytotoxicity Cell Process 3 must activate M1 macrophage dedifferentiation Cell Process 2 must inhibit M1 macrophage development Cell Process 14 must activate M1 macrophage differentiation Cell Process 20 must activate M1 macrophage formation Cell Process 15 must activate M1 macrophage function Cell Process 23 must activate M1 macrophage infiltration Cell Process 31 must activate M1 macrophage migration Cell Process 6 must activate M1 macrophage phenotype Cell Process 70 must activate M1 macrophage polarity Cell Process 148 must activate M1 macrophage population Cell Process 11 must activate M1 macrophage proliferation Cell Process 4 must activate M1 macrophage ratio Cell Process 7 must activate M1 macrophage repertoire Cell Process 4 must activate M1 macrophage stress Cell Process 2 must inhibit M1 macrophage survival Cell Process 6 must activate M2 macrophage apoptosis Cell Process 2 must inhibit M2 macrophage count Cell Process 60 must activate M2 macrophage death Cell Process 3 must inhibit M2 macrophage development Cell Process 44 must activate M2 macrophage differentiation Cell Process 56 must activate M2 macrophage formation Cell Process 33 must activate M2 macrophage function Cell Process 38 must activate M2 macrophage growth Cell Process 2 must activate M2 macrophage infiltration Cell Process 14 must activate M2 macrophage migration Cell Process 11 must activate M2 macrophage phenotype Cell Process 132 must activate M2 macrophage polarity Cell Process 237 must activate M2 macrophage population Cell Process 24 must activate M2 macrophage proliferation Cell Process 12 must activate
- 10. M2 macrophage ratio Cell Process 5 must activate M2 macrophage regeneration Cell Process 3 must activate M2 macrophage repertoire Cell Process 2 must activate M2 macrophage survival Cell Process 3 must activate macrophage activation Cell Process 1694 must activate macrophage adhesion Cell Process 403 must activate macrophage agglutination Cell Process 2 must activate macrophage aggregation Cell Process 66 must activate macrophage antigen processing and presentation Cell Process 0 must activate macrophage apoptosis Cell Process 850 must inhibit macrophage architecture Cell Process 2 must activate macrophage autophagy Cell Process 60 must activate macrophage chemotaxis Cell Process 407 must activate macrophage clonal anergy Cell Process 2 must inhibit macrophage communication Cell Process 7 must activate macrophage compartmentalization Cell Process 2 must activate macrophage contact Cell Process 11 must activate macrophage count Cell Process 820 must activate macrophage cytotoxicity Cell Process 58 must activate macrophage damage Cell Process 77 must inhibit macrophage death Cell Process 322 must inhibit macrophage dedifferentiation Cell Process 3 must inhibit macrophage destruction Cell Process 13 must inhibit macrophage development Cell Process 286 must activate macrophage diapedesis Cell Process 6 must activate macrophage differentiation Cell Process 789 must activate macrophage disruption Cell Process 11 must inhibit macrophage distribution Cell Process 25 must activate macrophage division Cell Process 33 must activate macrophage elongation Cell Process 8 must activate macrophage enlargement Cell Process 2 must activate macrophage extravasation Cell Process 31 must activate macrophage fate Cell Process 25 must activate macrophage fate commitment Cell Process 17 must activate macrophage fate specification Cell Process 4 must activate macrophage formation Cell Process 194 must activate macrophage function Cell Process 1471 must activate macrophage fusion Cell Process 141 must activate macrophage growth Cell Process 141 must activate macrophage homeostasis Cell Process 44 must activate macrophage homing Cell Process 45 must activate macrophage infiltration Cell Process 726 must activate
- 11. macrophage interaction Cell Process 121 must activate macrophage invasion Cell Process 162 must activate macrophage lifespan Cell Process 2 must activate macrophage localization Cell Process 23 must activate macrophage mediated cytotoxicity Cell Process 20 must activate macrophage migration Cell Process 950 must activate macrophage migration inhibition Cell Process 43 must inhibit macrophage morphogenesis Cell Process 2 must activate macrophage motility Cell Process 143 must activate macrophage motion Cell Process 50 must activate macrophage phagocytosis Cell Process 556 must activate macrophage phenotype Cell Process 596 must activate macrophage polarity Cell Process 709 must activate macrophage population Cell Process 438 must activate macrophage priming Cell Process 64 must activate macrophage proliferation Cell Process 471 must activate macrophage proliferative response Cell Process 5 must activate macrophage ratio Cell Process 19 macrophage recognition Cell Process 75 must activate macrophage regeneration Cell Process 7 must activate macrophage renewal Cell Process 15 must activate macrophage repertoire Cell Process 39 must activate macrophage response Cell Process 287 must activate macrophage selection Cell Process 3 must activate macrophage senescence Cell Process 4 must activate macrophage sequestration Cell Process 63 must activate macrophage size Cell Process 24 must activate macrophage spreading Cell Process 120 must activate macrophage stress Cell Process 12 must activate macrophage structure Cell Process 4 must activate macrophage survival Cell Process 256 must activate macrophage tethering Cell Process 5 must activate macrophage transdifferentiation Cell Process 7 must activate macrophage transendothelial migration Cell Process 63 must activate macrophage transepithelial migration Cell Process 6 must activate macrophage viability Cell Process 157 must activate macrophage volume Cell Process 4 must activate monocyte macrophage differentiation Cell Process 139 must activate myeloblast macrophage differentiation Cell Process 2 must activate myeloid cell macrophage differentiation Cell Process 13 must activate myeloid progenitor cell macrophage differentiation Cell Process 2 must activate neutrophil macrophage differentiation Cell Process 3 must activate
- 12. stem cell macrophage differentiation Cell Process 2 must activate Table 3: Complete list of drugs inhibiting HIV infection of macrophages found in this white paper Name Connectivity Class Target HIV inhibition TB inhibition albendazole 486 Drug Macrophage Yes Yes amikacin 324 Drug Macrophage Yes Yes atorvastatin 2553 Drug Macrophage Yes Yes azithromycin 1201 Drug Macrophage Yes Yes caspofungin 268 Drug Macrophage Yes Yes CGP 75355 235 Drug Macrophage Yes Yes cisplatin 5050 Drug Macrophage Yes Yes dexamethasone 7253 Drug Macrophage Yes Yes DMSO 2255 Drug Macrophage Yes Yes doxorubicin 4635 Drug Macrophage Yes Yes erythromycin 1147 Drug Macrophage Yes Yes iohexol 212 Drug Macrophage Yes Yes isoniazid 574 Drug Macrophage Yes Yes ivermectin 587 Drug P2RX4 Yes Yes lentinan 303 Drug Macrophage Yes Yes prednisolone 2330 Drug Macrophage Yes Yes prednisone 2134 Drug Macrophage Yes Yes primaquine 264 Drug Macrophage Yes Yes pyrazinamide 205 Drug Macrophage Yes Yes rifabutin 166 Drug Macrophage Yes Yes ritonavir 830 Drug Macrophage Yes Yes sulfasalazine 877 Drug Macrophage Yes Yes valproic acid 3771 Drug Macrophage Yes Yes warfarin 1127 Drug Macrophage Yes Yes curcumin 4678 Supplement NFE2L2 Yes Yes epigallocatechin-3-gallate 3052 Supplement NFE2L2 Yes Yes genistein 3547 Supplement NFE2L2 Yes Yes arginine 4584 Metabolite Macrophage Yes Yes ascorbic acid 4373 Metabolite Macrophage Yes Yes cysteine 3316 Metabolite Macrophage Yes Yes folate 2940 Metabolite Macrophage Yes Yes interferon gamma-1b 86 Metabolite Macrophage Yes Yes lactate 4227 Metabolite Macrophage Yes Yes niacin 1402 Metabolite Macrophage Yes Yes
- 13. polylactic acid 289 Metabolite Macrophage Yes Yes prostaglandin E2 6120 Metabolite Macrophage Yes Yes vitamin D3 2076 Metabolite Macrophage Yes Yes bleomycin 1909 Drug TLR2 Yes colchicine 1937 Drug Macrophage Yes dimethyl fumarate 711 Drug NFE2L2 Yes D-penicillamine 617 Drug Macrophage Yes exenatide 1505 Drug Macrophage Yes haloperidol 1801 Drug Macrophage Yes imiquimod 1066 Drug TLR4 Yes irinotecan 1040 Drug Macrophage Yes lenalidomide 1060 Drug Macrophage Yes levamisole 697 Drug Macrophage Yes paclitaxel 3552 Drug TLR4 Yes pioglitazone 2345 Drug Macrophage Yes polymyxin B 623 Drug P2RX7 Yes rapamycin 5459 Drug Macrophage Yes simvastatin 3207 Drug Macrophage Yes sulforaphane 1548 Drug NFE2L2 Yes tert-butylhydroquinone 511 Drug NFE2L2 Yes fisetin 810 Supplement NFE2L2 Yes pterostilbene 536 Supplement NFE2L2 Yes pyridostigmine 404 Supplement Macrophage Yes resveratrol 4647 Supplement NFE2L2 Yes rosiglitazone 2782 Supplement Macrophage Yes 9-cis-retinoic acid 877 Metabolite Macrophage Yes cadmium 3573 Metabolite NFE2L2 Yes estradiol 6534 Metabolite Macrophage Yes heme 2115 Metabolite NFE2L2 Yes hemin 1221 Metabolite TLR2 Yes lipoic acid 1764 Metabolite NFE2L2 Yes melatonin 5009 Metabolite NFE2L2 Yes methionine 2264 Metabolite Macrophage Yes retinoic acid 6995 Metabolite Macrophage Yes deferoxamine 1539 Drug Macrophage Yes quercetin 3203 Supplement NFE2L2 Yes glutamine 3099 Metabolite Macrophage Yes 3H-1,2-dithiole-3-thione 174 Drug NFE2L2 bardoxolone 63 Drug NFE2L2 clioquinol 309 Drug Macrophage dichloroacetate 738 Drug Macrophage diethyl maleate 310 Drug NFE2L2
- 14. docetaxel 1501 Drug Macrophage everolimus 1641 Drug Macrophage FTY720 1780 Drug Macrophage gadodiamide 114 Drug Macrophage glatiramer acetate 633 Drug Macrophage isoflurane 1666 Drug P2RX7 isoproterenol 2563 Drug Macrophage lixisenatide 136 Drug Macrophage MG132 2544 Drug NFE2L2 nitrogen mustard 380 Drug Macrophage oltipraz 325 Drug NFE2L2 paraquat 1139 Drug NFE2L2 thiazolidinediones 1483 Drug Macrophage triamcinolone acetonide 724 Drug Macrophage butylated hydroxyanisole 468 Supplement NFE2L2 carnosic acid 479 Supplement NFE2L2 CDDO-Im 261 Supplement NFE2L2 CDDO-Me 491 Supplement NFE2L2 cinnamaldehyde 565 Supplement NFE2L2 ellagic acid 868 Supplement Macrophage hydroxytyrosol 446 Supplement NFE2L2 indigo carmine 95 Supplement Macrophage isoliquiritigenin 546 Supplement NFE2L2 phenethyl isothiocyanate 587 Supplement NFE2L2 urethane 495 Supplement Macrophage 15d-PGJ2 1313 Metabolite NFE2L2 4-hydroxynonenal 1163 Metabolite NFE2L2 calcitriol 4333 Metabolite Macrophage triiodothyronine 3131 Metabolite Macrophage