{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:30:43Z","timestamp":1790688643189,"version":"4.1.0"},"reference-count":32,"publisher":"Walter de Gruyter GmbH","issue":"1","license":[{"start":{"date-parts":[[2021,1,1]],"date-time":"2021-01-01T00:00:00Z","timestamp":1609459200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Tuberculosis (TB) caused by\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (\n                    <jats:italic>M. tb<\/jats:italic>\n                    ) still remains a devastating infectious disease in the world. There has been a daunting increase in the incidence of Type 2 Diabetes Mellitus (T2DM) worldwide. T2DM patients are three times more vulnerable to\n                    <jats:italic>M. tb<\/jats:italic>\n                    infection compared to healthy individuals. TB-T2DM coincidence is a challenge for global health control. Despite some progress in the research,\n                    <jats:italic>M. tb<\/jats:italic>\n                    still has unexplored characteristics in successfully evading host defenses. The lengthy duration of treatment, the emergence of multi-drug-resistant strains and extensive-drug-resistant strains of\n                    <jats:italic>M. tb<\/jats:italic>\n                    have made TB treatment very challenging. Previously, we have tested the antimycobacterial effects of everolimus within\n                    <jats:italic>in vitro<\/jats:italic>\n                    granulomas generated from immune cells derived from peripheral blood of healthy subjects. However, the effectiveness of everolimus treatment against mycobacterial infection in individuals with T2DM is unknown. Furthermore, the effectiveness of the combination of\n                    <jats:italic>in vivo<\/jats:italic>\n                    glutathione (GSH) supplementation in individuals with T2DM along with\n                    <jats:italic>in vitro<\/jats:italic>\n                    treatment of isolated immune cells with everolimus against mycobacterial infection has never been tested. Therefore, we postulated that liposomal glutathione (L-GSH) and everolimus would offer great hope for developing adjunctive therapy for mycobacterial infection. L-GSH or placebo was administered to T2DM individuals orally for three months. Study subjects\u2019 blood was drawn pre- and post-L-GSH\/or placebo supplementation, where Peripheral Blood Mononuclear Cells (PBMCs) were isolated from whole blood to conduct\n                    <jats:italic>in vitro<\/jats:italic>\n                    studies with everolimus. We found that\n                    <jats:italic>in vitro<\/jats:italic>\n                    treatment with everolimus, an mTOR (membrane target of rapamycin) inhibitor, significantly reduced intracellular\n                    <jats:italic>M. bovis<\/jats:italic>\n                    BCG infection alone and in conjunction with L-GSH supplementation. Furthermore, we found L-GSH supplementation coupled with\n                    <jats:italic>in vitro<\/jats:italic>\n                    everolimus treatment produced a greater effect in inhibiting the growth of intracellular\n                    <jats:italic>Mycobacterium bovis<\/jats:italic>\n                    BCG, than with the everolimus treatment alone. We also demonstrated the functions of L-GSH along with\n                    <jats:italic>in vitro<\/jats:italic>\n                    everolimus treatment in modulating the levels of cytokines such as IFN-\u03b3, TNF-\u03b1, and IL-2 and IL-6, in favor of improving control of the mycobacterial infection. In summary,\n                    <jats:italic>in vitro<\/jats:italic>\n                    everolimus-treatment alone and in combination with oral L-GSH supplementation for three months in individuals with T2DM, was able to increase the levels of T-helper type 1 (Th1) cytokines IFN-\u03b3, TNF-\u03b1, and IL-2 as well as enhance the abilities of granulomas from individuals with T2DM to improve control of a mycobacterial infection.\n                  <\/jats:p>","DOI":"10.1515\/bmc-2021-0003","type":"journal-article","created":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T23:57:46Z","timestamp":1620777466000},"page":"16-26","source":"Crossref","is-referenced-by-count":15,"title":["The Effects of Oral Liposomal Glutathione and In Vitro Everolimus in Altering the Immune Responses against\n                    <i>Mycobacterium bovis<\/i>\n                    BCG Strain in Individuals with Type 2 Diabetes"],"prefix":"10.1515","volume":"12","author":[{"given":"Kimberly","family":"To","sequence":"first","affiliation":[{"name":"Graduate College of Biomedical Sciences , Western University of Health Sciences , Pomona , CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoqiong","family":"Cao","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific , Western University of Health Sciences , Pomona , CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aram","family":"Yegiazaryan","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific , Western University of Health Sciences , Pomona , CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Owens","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific , Western University of Health Sciences , Pomona , CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayvan","family":"Sasaninia","sequence":"additional","affiliation":[{"name":"Graduate College of Biomedical Sciences , Western University of Health Sciences , Pomona , CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Vaughn","sequence":"additional","affiliation":[{"name":"Graduate College of Biomedical Sciences , Western University of Health Sciences , Pomona , CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohkam","family":"Singh","sequence":"additional","affiliation":[{"name":"Graduate College of Biomedical Sciences , Western University of Health Sciences , Pomona , CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Truong","sequence":"additional","affiliation":[{"name":"Graduate College of Biomedical Sciences , Western University of Health Sciences , Pomona , CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Airani","family":"Sathananthan","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific , Western University of Health Sciences , Pomona , CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishwanath","family":"Venketaraman","sequence":"additional","affiliation":[{"name":"Graduate College of Biomedical Sciences , Western University of Health Sciences , Pomona , CA , USA ; College of Osteopathic Medicine of the Pacific , Western University of Health Sciences , Pomona , CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2021,5,9]]},"reference":[{"key":"2025120518180947432_j_bmc-2021-0003_ref_001","unstructured":"Global tuberculosis report 2020. Geneva: World Health Organization; 2019."},{"key":"2025120518180947432_j_bmc-2021-0003_ref_002","doi-asserted-by":"crossref","unstructured":"Restrepo BI. Diabetes and Tuberculosis. Microbiol Spectr. 2016 Dec;4(6). https:\/\/doi.org\/10.1128\/microbiolspec.TNMI7-0023-2016.","DOI":"10.1128\/microbiolspec.TNMI7-0023-2016"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_003","unstructured":"National Diabetes Statistics Report, 2020. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services; 2020."},{"key":"2025120518180947432_j_bmc-2021-0003_ref_004","unstructured":"Treatment for TB Disease, 2016. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services; 2016."},{"key":"2025120518180947432_j_bmc-2021-0003_ref_005","doi-asserted-by":"crossref","unstructured":"El-Sadr WM, Perlman DC, Denning E, Matts JP, Cohn DL. A review of efficacy studies of 6-month short-course therapy for tuberculosis among patients infected with human immunodeficiency virus: differences in study outcomes. Clin Infect Dis. 2001;32(4):623\u201332.","DOI":"10.1086\/318706"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_006","doi-asserted-by":"crossref","unstructured":"Sharma SK, Sharma A, Kadhiravan T, Tharyan P. Rifamycins (rifampicin, rifabutin and rifapentine) compared to isoniazid for preventing tuberculosis in HIV-negative people at risk of active TB. Cochrane Database Syst Rev. 2013;2013(7):CD007545.","DOI":"10.1002\/14651858.CD007545.pub2"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_007","doi-asserted-by":"crossref","unstructured":"Ramappa V, Aithal GP. Hepatotoxicity Related to Anti-tuberculosis Drugs: Mechanisms and Management. J Clin Exp Hepatol. 2013;3(1):37\u201349.","DOI":"10.1016\/j.jceh.2012.12.001"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_008","doi-asserted-by":"crossref","unstructured":"Singh P, Subbian S. Harnessing the mTOR Pathway for Tuberculosis Treatment. Front Microbiol. 2018;9:70.","DOI":"10.3389\/fmicb.2018.00070"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_009","doi-asserted-by":"crossref","unstructured":"Aderem A, Underhill DM. Mechanisms of phagocytosis in macrophages. Annu Rev Immunol. 1999;17(1):593\u2013623.","DOI":"10.1146\/annurev.immunol.17.1.593"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_010","doi-asserted-by":"crossref","unstructured":"Armstrong JA, Hart PD. Response of cultured macrophages to Mycobacterium tuberculosis, with observations on fusion of lysosomes with phagosomes. J Exp Med. 1971;134(3 Pt 1):713\u201340.","DOI":"10.1084\/jem.134.3.713"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_011","doi-asserted-by":"crossref","unstructured":"Clemens DL, Horwitz MA. Characterization of the Mycobacterium tuberculosis phagosome and evidence that phagosomal maturation is inhibited. J Exp Med. 1995;181(1):257\u201370.","DOI":"10.1084\/jem.181.1.257"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_012","doi-asserted-by":"crossref","unstructured":"Kapoor N, Pawar S, Sirakova TD, Deb C, Warren WL, Kolattukudy PE. Human granuloma in vitro model, for TB dormancy and resuscitation. PLoS One. 2013;8(1):e53657.","DOI":"10.1371\/journal.pone.0053657"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_013","doi-asserted-by":"crossref","unstructured":"Ferlita S, Yegiazaryan A, Noori N, Lal G, Nguyen T, To K, et al. Type 2 Diabetes Mellitus and Altered Immune System Leading to Susceptibility to Pathogens, Especially Mycobacterium tuberculosis. J Clin Med. 2019;8(12):2219.","DOI":"10.3390\/jcm8122219"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_014","doi-asserted-by":"crossref","unstructured":"Roach DR, Bean AG, Demangel C, France MP, Briscoe H, Britton WJ. TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol. 2002;168(9):4620\u20137.","DOI":"10.4049\/jimmunol.168.9.4620"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_015","doi-asserted-by":"crossref","unstructured":"Hu X, Chakravarty SD, Ivashkiv LB. Regulation of interferon and Toll-like receptor signaling during macrophage activation by opposing feedforward and feedback inhibition mechanisms. Immunol Rev. 2008;226(1):41\u201356.","DOI":"10.1111\/j.1600-065X.2008.00707.x"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_016","doi-asserted-by":"crossref","unstructured":"O\u2019Garra A, Britton WJ. \u201cCytokines in Tuberculosis,\u201d in Handbook of Tuberculosis, Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA, 2017, pp. 185\u2013225.","DOI":"10.1002\/9783527611614.ch25"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_017","doi-asserted-by":"crossref","unstructured":"Allen M, Bailey C, Cahatol I, Dodge L, Yim J, Kassissa C, et al. Mechanisms of control of Mycobacterium tuberculosis by NK cells: role of glutathione. Front Immunol. 2015;6(OCT):508.","DOI":"10.3389\/fimmu.2015.00508"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_018","doi-asserted-by":"crossref","unstructured":"Tobin DM. Host-directed therapies for tuberculosis. Cold Spring Harb Perspect Med. 2015;5(10):a021196.","DOI":"10.1101\/cshperspect.a021196"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_019","doi-asserted-by":"crossref","unstructured":"Teskey G, Abrahem R, Cao R, Gyurjian K, Islamoglu H, Lucero M, et al. Glutathione as a Marker for Human Disease. Adv Clin Chem. 2018;87:141\u2013159.","DOI":"10.1016\/bs.acc.2018.07.004"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_020","doi-asserted-by":"crossref","unstructured":"Ballatori N, Krance SM, Notenboom S, Shi S, Tieu K, Hammond CL. Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem. 2009;390(3):191\u2013214.","DOI":"10.1515\/BC.2009.033"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_021","doi-asserted-by":"crossref","unstructured":"Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, et al. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014;6(268):268ra179.","DOI":"10.1126\/scitranslmed.3009892"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_022","doi-asserted-by":"crossref","unstructured":"Ashley D, Hernandez J, Cao R, To K, Yegiazaryan A, Abrahem R, et al. Antimycobacterial Effects of Everolimus in a Human Granuloma Model. J Clin Med. 2020;9(7):2043.","DOI":"10.3390\/jcm9072043"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_023","doi-asserted-by":"crossref","unstructured":"Kern JK, Geier DA, Adams JB, Garver CR, Audhya T, Geier MR. A clinical trial of glutathione supplementation in autism spectrum disorders. Med Sci Monit. 2011;17(12):CR677\u201382.","DOI":"10.12659\/MSM.882125"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_024","doi-asserted-by":"crossref","unstructured":"Ly J, Lagman M, Saing T, Singh MK, Tudela EV, Morris D, et al. Liposomal Glutathione Supplementation Restores TH1 Cytokine Response to Mycobacterium tuberculosis Infection in HIV-Infected Individuals. J Interferon Cytokine Res. 2015;35(11):875\u201387.","DOI":"10.1089\/jir.2014.0210"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_025","doi-asserted-by":"crossref","unstructured":"Valdivia A, Ly J, Gonzalez L, Hussain P, Saing T, Islamoglu H, et al. Restoring Cytokine Balance in HIV-Positive Individuals with Low CD4 T Cell Counts. AIDS Res Hum Retroviruses. 2017;33(9):905\u201318.","DOI":"10.1089\/aid.2016.0303"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_026","doi-asserted-by":"crossref","unstructured":"Teskey G, Cao R, Islamoglu H, Medina A, Prasad C, Prasad R, et al. The synergistic effects of the glutathione precursor, NAC and first-line antibiotics in the granulomatous response against mycobacterium tuberculosis. Front Immunol. 2018 Sep;9(SEP):2069.","DOI":"10.3389\/fimmu.2018.02069"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_027","doi-asserted-by":"crossref","unstructured":"Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO Collaborative Project on Early Detection of Persons with Harmful Alcohol Consumption\u2014II. Addiction. 1993;88(6):791\u2013804.","DOI":"10.1111\/j.1360-0443.1993.tb02093.x"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_028","doi-asserted-by":"crossref","unstructured":"North RJ, Jung YJ. Immunity to tuberculosis. Annu Rev Immunol. 2004;22(1):599\u2013623.","DOI":"10.1146\/annurev.immunol.22.012703.104635"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_029","doi-asserted-by":"crossref","unstructured":"Lagman M, Ly J, Saing T, Kaur Singh M, Vera Tudela E, Morris D, et al. Investigating the causes for decreased levels of glutathione in individuals with type II diabetes. PLoS One. 2015;10(3):e0118436.","DOI":"10.1371\/journal.pone.0118436"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_030","doi-asserted-by":"crossref","unstructured":"Venketaraman V, Millman A, Salman M, Swaminathan S, Goetz M, Lardizabal A, et al. Glutathione levels and immune responses in tuberculosis patients. Microb Pathog. 2008;44(3):255\u201361.","DOI":"10.1016\/j.micpath.2007.09.002"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_031","doi-asserted-by":"crossref","unstructured":"Millman AC, Salman M, Dayaram YK, Connell ND, Venketaraman V. Natural killer cells, glutathione, cytokines, and innate immunity against Mycobacterium tuberculosis. J Interferon Cytokine Res. 2008;28(3):153\u201365.","DOI":"10.1089\/jir.2007.0095"},{"key":"2025120518180947432_j_bmc-2021-0003_ref_032","doi-asserted-by":"crossref","unstructured":"Venketaraman V, Dayaram YK, Talaue MT, Connell ND. Glutathione and nitrosoglutathione in macrophage defense against Mycobacterium tuberculosis. Infect Immun. 2005;73(3):1886\u20139.","DOI":"10.1128\/IAI.73.3.1886-1889.2005"}],"container-title":["Biomolecular Concepts"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/bmc-2021-0003\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/bmc-2021-0003\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T18:48:56Z","timestamp":1764960536000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/bmc-2021-0003\/html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,1]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,5,9]]},"published-print":{"date-parts":[[2021,1,1]]}},"alternative-id":["10.1515\/bmc-2021-0003"],"URL":"https:\/\/doi.org\/10.1515\/bmc-2021-0003","relation":{},"ISSN":["1868-503X","1868-5021"],"issn-type":[{"value":"1868-503X","type":"electronic"},{"value":"1868-5021","type":"print"}],"subject":[],"published":{"date-parts":[[2021,1,1]]}}}