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In this proof-of-concept study, we used high-content imaging to test a novel panel of dual glycogen synthase kinase 3 beta (GSK-3\u03b2) and histone deacetylase (HDAC) 1 and 6 inhibitor candidates for their efficacy in reducing the growth of green fluorescent protein (GFP)-expressing mycobacteria in human primary macrophages. We demonstrate that all ten test compounds, also including the GSK-3\u03b2 inhibitor SB415286, exhibit an antimycobacterial effect of 20\u201360% at low micromolar doses and are non-toxic to host cells. Mtb growth showed a positive correlation with the respective 50% inhibitory concentration (IC50) values of GSK-3\u03b2, HDAC1, and HDAC6 in each compound, indicating that compounds with a potent IC50 value for HDAC1, in particular, corresponded to higher antimycobacterial activity. Furthermore, the results from multiparametric flow cytometry and a customized multiplex RNA array demonstrated that SB415286 and selected compounds, C02 and C06, could modulate immune polarization and inflammation in Mtb-infected macrophages involving an enhanced expression of CCL2, IL-10 and S100A9, but a decrease in inflammatory mediators including COX-2, TNF-\u03b1, and NF\u03baB. These data suggest that GSK-3\u03b2 inhibition alone can decrease the intracellular growth of mycobacteria and regulate macrophage inflammation, while dual GSK-3\u03b2\/HDAC inhibitors enhance this efficacy. Accordingly, the tailored design of dual GSK-3\u03b2\/HDAC inhibitors could represent an innovative approach to host-directed therapy in TB.<\/jats:p>","DOI":"10.3390\/biom15040550","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T12:05:56Z","timestamp":1744200356000},"page":"550","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dual GSK-3\u03b2\/HDAC Inhibitors Enhance the Efficacy of Macrophages to Control Mycobacterium tuberculosis Infection"],"prefix":"10.3390","volume":"15","author":[{"given":"Sadaf","family":"Kalsum","sequence":"first","affiliation":[{"name":"Center for Infectious Medicine (CIM), Department of Medicine Huddinge, Karolinska Institutet, ANA Futura, 141 52 Huddinge, Sweden"},{"name":"Division of Medical Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Link\u00f6ping University, 581 83 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruilan","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Infectious Medicine (CIM), Department of Medicine Huddinge, Karolinska Institutet, ANA Futura, 141 52 Huddinge, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mira","family":"Akber","sequence":"additional","affiliation":[{"name":"Center for Infectious Medicine (CIM), Department of Medicine Huddinge, Karolinska Institutet, ANA Futura, 141 52 Huddinge, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengjie","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education School of Pharmacy, Jinan University, 855 Xingye Avenue, Guangzhou 510632, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5092-9892","authenticated-orcid":false,"given":"Maria","family":"Lerm","sequence":"additional","affiliation":[{"name":"Division of Medical Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Link\u00f6ping University, 581 83 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqing","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education School of Pharmacy, Jinan University, 855 Xingye Avenue, Guangzhou 510632, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3155-1123","authenticated-orcid":false,"given":"Magda","family":"Lourda","sequence":"additional","affiliation":[{"name":"Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, ANA Futura, 141 52 Huddinge, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education School of Pharmacy, Jinan University, 855 Xingye Avenue, Guangzhou 510632, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8540-153X","authenticated-orcid":false,"given":"Susanna","family":"Brighenti","sequence":"additional","affiliation":[{"name":"Center for Infectious Medicine (CIM), Department of Medicine Huddinge, Karolinska Institutet, ANA Futura, 141 52 Huddinge, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,9]]},"reference":[{"key":"ref_1","unstructured":"(2025, March 06). Global Tuberculosis Report 2024: World Health Organization (WHO). Available online: https:\/\/www.who.int\/teams\/global-tuberculosis-programme\/tb-reports."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e147","DOI":"10.1093\/cid\/ciw376","article-title":"Official American Thoracic Society\/Centers for Disease Control and Prevention\/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis","volume":"63","author":"Nahid","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Stelitano, G., Sammartino, J.C., and Chiarelli, L.R. (2020). Multitargeting Compounds: A Promising Strategy to Overcome Multi-Drug Resistant Tuberculosis. Molecules, 25.","DOI":"10.3390\/molecules25051239"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Kolloli, A., and Subbian, S. (2017). Host-Directed Therapeutic Strategies for Tuberculosis. Front. Med., 4.","DOI":"10.3389\/fmed.2017.00171"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"101672","DOI":"10.1016\/j.smim.2022.101672","article-title":"Inflammation-mediated tissue damage in pulmonary tuberculosis and host-directed therapeutic strategies","volume":"65","author":"Tiwari","year":"2023","journal-title":"Semin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Jeong, E.K., Lee, H.J., and Jung, Y.J. (2022). Host-Directed Therapies for Tuberculosis. Pathogens, 11.","DOI":"10.3390\/pathogens11111291"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101312","DOI":"10.1016\/j.tranon.2021.101312","article-title":"HDAC inhibitors: Targets for tumor therapy, immune modulation and lung diseases","volume":"16","author":"Shanmugam","year":"2022","journal-title":"Transl. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Udinia, S., Suar, M., and Kumar, D. (2023). Host-directed therapy against tuberculosis: Concept and recent developments. J. Biosci., 48.","DOI":"10.1007\/s12038-023-00374-y"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1111\/j.1749-6632.2003.tb05964.x","article-title":"Histone deacetylases: Unique players in shaping the epigenetic histone code","volume":"983","author":"Thiagalingam","year":"2003","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1139\/o05-041","article-title":"Role of histone acetylation in the control of gene expression","volume":"83","author":"Verdone","year":"2005","journal-title":"Biochem. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Eckschlager, T., Plch, J., Stiborova, M., and Hrabeta, J. (2017). Histone Deacetylase Inhibitors as Anticancer Drugs. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071414"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1111\/cei.13192","article-title":"HDAC inhibitors modulate innate immune responses to micro-organisms relevant to chronic mucocutaneous candidiasis","volume":"194","author":"Rosler","year":"2018","journal-title":"Clin. Exp. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1182\/blood-2011-10-292003","article-title":"Histone\/protein deacetylases and T-cell immune responses","volume":"119","author":"Akimova","year":"2012","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1182\/blood-2006-04-019711","article-title":"Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function","volume":"109","author":"Brogdon","year":"2007","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/s41392-019-0095-0","article-title":"Targeting epigenetic regulators for cancer therapy: Mechanisms and advances in clinical trials","volume":"4","author":"Cheng","year":"2019","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/s41576-018-0074-2","article-title":"Clinical epigenetics: Seizing opportunities for translation","volume":"20","author":"Berdasco","year":"2019","journal-title":"Nat. Rev. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1080\/15548627.2015.1075110","article-title":"Phenylbutyrate induces LL-37-dependent autophagy and intracellular killing of Mycobacterium tuberculosis in human macrophages","volume":"11","author":"Rekha","year":"2015","journal-title":"Autophagy"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1093\/infdis\/jiab100","article-title":"Immunomodulatory Agents Combat Multidrug-Resistant Tuberculosis by Improving Antimicrobial Immunity","volume":"224","author":"Ahmed","year":"2021","journal-title":"J. Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Mily, A., Rekha, R.S., Kamal, S.M., Arifuzzaman, A.S., Rahim, Z., Khan, L., Haq, M.A., Zaman, K., Bergman, P., and Brighenti, S. (2015). Significant Effects of Oral Phenylbutyrate and Vitamin D3 Adjunctive Therapy in Pulmonary Tuberculosis: A Randomized Controlled Trial. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0138340"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1111\/joim.12767","article-title":"Daily adjunctive therapy with vitamin D(3) and phenylbutyrate supports clinical recovery from pulmonary tuberculosis: A randomized controlled trial in Ethiopia","volume":"284","author":"Bekele","year":"2018","journal-title":"J. Intern. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1007\/s13277-015-3781-8","article-title":"Phenylbutyrate-a pan-HDAC inhibitor-suppresses proliferation of glioblastoma LN-229 cell line","volume":"37","author":"Kusaczuk","year":"2016","journal-title":"Tumour Biol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Coussens, A.K., Wilkinson, R.J., and Martineau, A.R. (2015). Phenylbutyrate Is Bacteriostatic against Mycobacterium tuberculosis and Regulates the Macrophage Response to Infection, Synergistically with 25-Hydroxy-Vitamin D3. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1005007"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/j.micinf.2013.08.007","article-title":"Treatment with phenylbutyrate in a pre-clinical trial reduces diarrhea due to enteropathogenic Escherichia coli: Link to cathelicidin induction","volume":"15","author":"Mily","year":"2013","journal-title":"Microbes Infect."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9178","DOI":"10.1073\/pnas.0602888103","article-title":"Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic","volume":"103","author":"Raqib","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1128\/IAI.00132-16","article-title":"Beneficial Effects of Sodium Phenylbutyrate Administration during Infection with Salmonella enterica Serovar Typhimurium","volume":"84","author":"Jellbauer","year":"2016","journal-title":"Infect. Immun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"105682","DOI":"10.1016\/j.isci.2022.105682","article-title":"Topical phenylbutyrate antagonizes NF-kappaB signaling and resolves corneal inflammation","volume":"25","author":"Koganti","year":"2022","journal-title":"iScience"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wang, S., Yang, K., Li, C., Liu, W., Gao, T., Yuan, F., Guo, R., Liu, Z., Tan, Y., and Hu, X. (2023). 4-Phenyl-butyric Acid Inhibits Japanese Encephalitis Virus Replication via Inhibiting Endoplasmic Reticulum Stress Response. Viruses, 15.","DOI":"10.3390\/v15020534"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.2174\/1381612821666150105160059","article-title":"Phenylbutyric Acid: Simple structure\u2014multiple effects","volume":"21","author":"Kusaczuk","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1038\/npp.2008.229","article-title":"Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer\u2019s disease mouse model","volume":"34","author":"Ricobaraza","year":"2009","journal-title":"Neuropsychopharmacology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1111\/j.1474-9726.2011.00680.x","article-title":"Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice","volume":"10","author":"Wiley","year":"2011","journal-title":"Aging Cell"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Jacobs, K.M., Bhave, S.R., Ferraro, D.J., Jaboin, J.J., Hallahan, D.E., and Thotala, D. (2012). GSK-3beta: A Bifunctional Role in Cell Death Pathways. Int. J. Cell Biol., 2012.","DOI":"10.1155\/2012\/930710"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1476-9255-9-23","article-title":"Role of glycogen synthase kinase-3 beta in the inflammatory response caused by bacterial pathogens","volume":"9","author":"Juarez","year":"2012","journal-title":"J. Inflamm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"110555","DOI":"10.1016\/j.isci.2024.110555","article-title":"Glycogen synthase kinase 3 inhibition controls Mycobacterium tuberculosis infection","volume":"27","author":"Chao","year":"2024","journal-title":"iScience"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Lauretti, E., Dincer, O., and Pratico, D. (2020). Glycogen synthase kinase-3 signaling in Alzheimer\u2019s disease. Biochim. Biophys. Acta Mol. Cell Res., 1867.","DOI":"10.1016\/j.bbamcr.2020.118664"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1021\/acsmedchemlett.8b00507","article-title":"Discovery of the First-in-Class GSK-3beta\/HDAC Dual Inhibitor as Disease-Modifying Agent To Combat Alzheimer\u2019s Disease","volume":"10","author":"Betari","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Rao Muvva, J., Parasa, V.R., Lerm, M., Svensson, M., and Brighenti, S. (2019). Polarization of Human Monocyte-Derived Cells With Vitamin D Promotes Control of Mycobacterium tuberculosis Infection. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.03157"},{"key":"ref_37","first-page":"e61807","article-title":"Polarization of M1 and M2 Human Monocyte-Derived Cells and Analysis with Flow Cytometry upon Mycobacterium tuberculosis Infection","volume":"163","author":"Mily","year":"2020","journal-title":"J. Vis. Exp."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1021\/jm00079a024","article-title":"Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides","volume":"35","author":"Davis","year":"1992","journal-title":"J. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/S1074-5521(00)00025-9","article-title":"Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription","volume":"7","author":"Coghlan","year":"2000","journal-title":"Chem. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Moreira, J.D., Koch, B.E.V., van Veen, S., Walburg, K.V., Vrieling, F., Mara Pinto Dabes Guimaraes, T., Meijer, A.H., Spaink, H.P., Ottenhoff, T.H.M., and Haks, M.C. (2020). Functional Inhibition of Host Histone Deacetylases (HDACs) Enhances in vitro and in vivo Anti-mycobacterial Activity in Human Macrophages and in Zebrafish. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00036"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s40169-017-0181-2","article-title":"A perspective on multi-target drug discovery and design for complex diseases","volume":"7","author":"Ramsay","year":"2018","journal-title":"Clin. Transl. Med."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Kim, S.Y., Choi, J.A., Choi, S., Kim, K.K., Song, C.H., and Kim, E.M. (2024). Advances in an In Vitro Tuberculosis Infection Model Using Human Lung Organoids for Host-Directed Therapies. PLoS Pathog., 20.","DOI":"10.1371\/journal.ppat.1012295"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.smim.2014.10.002","article-title":"Perspectives on host adaptation in response to Mycobacterium tuberculosis: Modulation of inflammation","volume":"26","author":"Dorhoi","year":"2014","journal-title":"Semin. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Sasindran, S.J., and Torrelles, J.B. (2011). Mycobacterium Tuberculosis Infection and Inflammation: What is Beneficial for the Host and for the Bacterium?. Front. Microbiol., 2.","DOI":"10.3389\/fmicb.2011.00002"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Muefong, C.N., and Sutherland, J.S. (2020). Neutrophils in Tuberculosis-Associated Inflammation and Lung Pathology. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00962"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Ashenafi, S., Loreti, M.G., Bekele, A., Aseffa, G., Amogne, W., Kassa, E., Aderaye, G., and Brighenti, S. (2023). Inflammatory immune profiles associated with disease severity in pulmonary tuberculosis patients with moderate to severe clinical TB or anemia. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1296501"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Hoffmeister, L., Diekmann, M., Brand, K., and Huber, R. (2020). GSK3: A Kinase Balancing Promotion and Resolution of Inflammation. Cells, 9.","DOI":"10.3390\/cells9040820"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/ni1221","article-title":"Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3","volume":"6","author":"Martin","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Etna, M.P., Severa, M., Licursi, V., Pardini, M., Cruciani, M., Rizzo, F., Giacomini, E., Macchia, G., Palumbo, O., and Stallone, R. (2021). Genome-Wide Gene Expression Analysis of Mtb-Infected DC Highlights the Rapamycin-Driven Modulation of Regulatory Cytokines via the mTOR\/GSK-3beta Axis. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.649475"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Nienaber, A., Hayford, F.E.A., Variava, E., Martinson, N., and Malan, L. (2021). The Manipulation of the Lipid Mediator Metabolism as Adjunct Host-Directed Therapy in Tuberculosis. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.623941"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.bcp.2016.07.014","article-title":"Inhibition of GSK-3 reduces prostaglandin E2 production by decreasing the expression levels of COX-2 and mPGES-1 in monocyte\/macrophage lineage cells","volume":"116","author":"Noma","year":"2016","journal-title":"Biochem. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Wang, W., Ning, Y., Wang, Y., Deng, G., Pace, S., Barth, S.A., Menge, C., Zhang, K., Dai, Y., and Cai, Y. (2022). Mycobacterium tuberculosis-Induced Upregulation of the COX-2\/mPGES-1 Pathway in Human Macrophages Is Abrogated by Sulfasalazine. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.849583"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3062","DOI":"10.1038\/s41467-020-16877-3","article-title":"Mesenchymal stem cells offer a drug-tolerant and immune-privileged niche to Mycobacterium tuberculosis","volume":"11","author":"Jain","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Pellegrini, J.M., Martin, C., Morelli, M.P., Schander, J.A., Tateosian, N.L., Amiano, N.O., Rolandelli, A., Palmero, D.J., Levi, A., and Ciallella, L. (2021). PGE2 displays immunosuppressive effects during human active tuberculosis. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-92667-1"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1080\/00207454.2022.2130297","article-title":"Therapeutic implications of glycogen synthase kinase-3beta in Alzheimer\u2019s disease: A novel therapeutic target","volume":"134","author":"Mandlik","year":"2024","journal-title":"Int. J. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1021\/acs.jmedchem.0c00931","article-title":"Glycogen Synthase Kinase 3beta: A New Gold Rush in Anti-Alzheimer\u2019s Disease Multitarget Drug Discovery?","volume":"64","author":"Tumiatti","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1021\/acschemneuro.4c00061","article-title":"First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3beta\/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer\u2019s Disease","volume":"15","author":"Santini","year":"2024","journal-title":"ACS Chem. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.2174\/1568026620666200607190951","article-title":"PTML Modeling for Alzheimer\u2019s Disease: Design and Prediction of Virtual Multi-Target Inhibitors of GSK3B, HDAC1, and HDAC6","volume":"20","author":"Kleandrova","year":"2020","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"19371","DOI":"10.1073\/pnas.1109201108","article-title":"Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes host vacuolar-H+-ATPase to inhibit phagosome acidification","volume":"108","author":"Wong","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.biochi.2019.07.023","article-title":"ATP synthase, an essential enzyme in growth and multiplication is modulated by protein tyrosine phosphatase in Mycobacterium tuberculosis H37Ra","volume":"165","author":"Chatterjee","year":"2019","journal-title":"Biochimie"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Talevi, A. (2015). Multi-target pharmacology: Possibilities and limitations of the \"skeleton key approach\" from a medicinal chemist perspective. Front. Pharmacol., 6.","DOI":"10.3389\/fphar.2015.00205"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e230143","DOI":"10.1590\/0074-02760230143","article-title":"Histone deacetylase (HDAC) inhibitors- based drugs are effective to control Mycobacterium tuberculosis infection and promote the sensibility for rifampicin in MDR strain","volume":"118","year":"2023","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Kalsum, S., Akber, M., Loreti, M.G., Andersson, B., Danielson, E., Lerm, M., and Brighenti, S. (2024). Sirtuin inhibitors reduce intracellular growth of M. tuberculosis in human macrophages via modulation of host cell immunity. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-79136-1"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1016\/j.bpj.2018.03.002","article-title":"Magnetic Field Changes Macrophage Phenotype","volume":"114","author":"Wosik","year":"2018","journal-title":"Biophys. J."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/4\/550\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:13:17Z","timestamp":1760029997000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/4\/550"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,9]]},"references-count":64,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["biom15040550"],"URL":"https:\/\/doi.org\/10.3390\/biom15040550","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,9]]}}}