Abstract
The therapeutic effectiveness of immune checkpoint inhibitors in cancer patients is quite profound. However, it is generally accepted that further progress is curtailed by accompanying adverse events and by low cure rates linked to the tumor microenvironment. The multitudes of immune processes altered by low-molecular-weight thiols published over the past decades suggest they have potential to alter tumor microenvironment processes which could result in an increase in immune checkpoint inhibitor survival rates. Based on one of the most studied and most potent low-molecular-weight thiols, β-mercaptoethanol (BME), it is proposed that clinical assessment be undertaken to identify any BME benefits with relevance for proliferation/differentiation of immune cells, lymphocyte exhaustion, immunogenicity of tumor antigens and inactivation of suppressor cells/factors. The BME alterations projected to be most effective are: maintenance/replacement of glutathione in lymphocytes via facilitation of cysteine uptake, inhibition of suppressor cells/soluble factors and inactivation of free-radical, reactive oxygen species.
References
- 1. . Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161(2), 205–214 (2015).
- 2. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat. Rev. Clin. Oncol. 16(9), 563–580 (2019).
- 3. . Immune checkpoint inhibitors and the liver. From therapeutic efficacy to side effects. Aliment. Pharmacol. Ther. 50(8), 872–884 (2019).
- 4. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 381(16), 1535–1546 (2019).
- 5. . Influences of BRAF inhibitors on the immune microenvironment and the rationale for combined molecular and immune targeted therapy. Curr. Oncol. Rep. 18(7), 42 (2016).
- 6. Quantitative evidence for early metastatic seeding in colorectal cancer. Nat. Genet. 51(7), 1113–1122 (2019).
- 7. . Anticancer activity and chemoprevention of xenobiotic organosulfurs in preclinical model systems. Oncol. Discov. 1, 4 (2013).
- 8. . Implications of plasma thiol redox in disease. Clin. Sci. (Lond.) 132(12), 1257–1280 (2018).
- 9. . Biosynthesis and biological properties of compounds containing highly reactive, reduced sulfane sulfur. Pol. J. Pharmacol. 53(3), 215–225 (2001).
- 10. . Sulfur signaling: is the agent sulfide or sulfane? Anal. Biochem. 413(2), 1–7 (2011).
- 11. . Reduced humoral immune activity in long-lived old mice: an approach to elucidating its mechanisms. Immunology 31(6), 903–911 (1976).
- 12. . Restoration of impaired immune functions in aging animals. III. Effect of mercaptoethanol in enhancing the reduced primary antibody responsiveness in vivo. Mech. Ageing Dev. 11(1), 1–8 (1979).
- 13. . Restoration of impaired immune functions in aging animals. IV. Action of 2-mercaptoethanol in enhancing age-reduced immune responsiveness. Mech. Ageing Dev. 13(4), 367–378 (1980).
- 14. . Effect of dietary 2-mercaptoethanol on the life span, immune system, tumor incidence and lipid peroxidation damage in spleen lymphocytes of aging BC3F1 mice. Mech. Ageing Dev. 27(3), 341–358 (1984).
- 15. . Obesity, longevity, quality of life: alteration by dietary 2-mercaptoethanol. Virulence 1(6), 509–515 (2010).
- 16. . Longevity of SLE-prone mice increased by dietary 2-mercaptoethanol via a mechanism imprinted within the first 28 days of life. Virulence 1(6), 516–522 (2010).
- 17. . Dietary supplemented 2-mercaptoethanol prevents spontaneous and delays virally induced murine mammary tumorigenesis. Cancer Biol. Ther. 14(6), 521–526 (2013).
- 18. . Alteration of radiation-sensitive processes associated with cancer and longevity by dietary 2-mercaptoethanol. J. Cancer Res. Ther. 10(1), 127–132 (2014).
- 19. . Effect of 2-mercaptoethanol on some metabolic indices of ageing of CBA/Ca inbred mice. Mech. Ageing Dev. 45(1), 75–92 (1988).
- 20. . Effect of an antioxidant compound (2-mercaptoethanol) on the nerve terminals of the aging small intestine. Exp. Gerontol. 25(2), 135–140 (1990).
- 21. Effect of 2-mercaptoethanol on posthypoxic and age related biochemical and behavioral changes in mice and rats. Biomed. Biochim. Acta 49(10), 1085–1090 (1990).
- 22. . Effect of cigarette smoke and 2-mercaptoethanol administration on age-related alterations and immunological parameters. Gerontol. 37(6), 326–334 (1991).
- 23. Effects of thiol antioxidant β-mercaptoethanol on diet-induced obese mice. Life Sci. 107(1-2), 32–41 (2014).
- 24. . Enhancement of antibody synthesis in vitro by mercaptoethanol. Cell. Immunol. 3(1), 155–160 (1972).
- 25. . Immune responses in vitro. I. Culture conditions for antibody synthesis. Cell. Immunol. 3(2), 264–276 (1972).
- 26. . Immune responses in vitro. VI. Genetic control of the in vivo–in vitro discrepancies in 19S antibody synthesis. J. Exp. Med. 136(5), 1241–1257 (1972).
- 27. . Immune responses in vitro. VII. Differentiation of H-2 and non-H-2 alloantigens of the mouse by a dual mixed leukocyte culture. Transplant. 16(4), 331–338 (1973).
- 28. . Immune responses in vitro. V. Role of mercaptoethanol in the mixed-leukocyte reaction. Cell. Immunol. 5(3), 410–418 (1972).
- 29. . Immune responses in vitro. II. Mixed leukocyte interaction in a protein-free medium. Eur. J. Immunol. 3(7), 379–385 (1973).
- 30. . Immune responses in vitro. IV. A comparison of the protein-free and mouse serum supplemented mouse mixed lymphocyte interaction assays. Eur. J. Immunol. 3(8), 516–519 (1973).
- 31. . Immune responses in vitro. III. Enhancement of the mouse mixed lymphocyte interaction by isologous and homologous sera. Eur. J. Immunol. 3(7), 385–392 (1973).
- 32. . Augmentation of in vitro antibody response by disulfide compounds. I. Comparison between intermolecular and intramolecular disulfides. Jpn. J. Pharmacol. 37(1), 13–19 (1985).
- 33. . Nonspecific activation of murine lymphocytes. I. Proliferation and polyclonal activation induced by 2-mercaptoethanol and α-thioglycerol. J. Exp. Med. 145(3), 473–489 (1977).
- 34. . Augmentation of the antibody response by lipoic acid in mice. I. Analysis of the mode of action in in vitro culture system. Jpn. J. Pharmacol. 42(1), 135–140 (1986).
- 35. . The effects of mercaptoethanol and of peritoneal macrophages on the antibody-forming capacity of nonadherent mouse spleen cells in vitro. J. Exp. Med. 136(3), 604–617 (1972).
- 36. . The role of fetal calf serum in the primary immune response in vitro. J. Exp. Med. 145(4), 1029–1038 (1977).
- 37. . Augmentation of in vitro antibody response by disulfide compounds. II. T cell-mediated augmentation by oxidized dithiothreitol, an intramolecular disulfide. Immunopharmacology 7(3–4), 159–165 (1984).
- 38. Redox imbalance in cystine/glutamate transporter-deficient mice. J. Biol. Chem. 280(45), 37423–37429 (2005).
- 39. . Macrophage requirement for the in vitro response to TNP-Ficoll: a thymic independent antigen. J. Immunol. 116(6), 1579–1581 (1976).
- 40. PD-1 blockade augments humoral immunity through ICOS-mediated CD4+ T cell instruction. Int. Immunopharmacol. 66(1), 127–138 (2019).
- 41. . Separation of mouse spleen cells by passage through columns of Sephadex G-10. J. Immunol. Methods 5(3), 239–247 (1974).
- 42. . Humoral primary immune response in vitro in a homologous mouse system: replacement of fetal calf serum by a 2-mercaptoethanol or macrophage-activated fraction of mouse serum. J. Immunol. 119(6), 2089–2094 (1977).
- 43. . The in vitro immune response to a T-independent antigen. I. The effect of macrophages and 2-mercaptoethanol. Eur. J. Immunol. 8(11), 776–781 (1978).
- 44. . In vitro induction of polyclonal killer T cells with 2-mercaptoethanol and the essential role of macrophages in this process. J. Immunol. 118(5), 1697–1703 (1977).
- 45. . Secondary in vitro responses of T lymphocytes to non-H-2 alloantigens. J. Exp. Med. 145(4), 802–818 (1977).
- 46. . Primary in vitro cytotoxic T cell response to non-major histocompatibility complex alloantigens in normal mice. J. Exp. Med. 156(2), 610–621 (1982).
- 47. . Generation of cytotoxic T lymphocytes in vitro. I. Response of normal and immune mouse spleen cells in mixed leukocyte cultures. J. Exp. Med. 140(3), 703–717 (1974).
- 48. . Effect of delayed addition of 2-mercaptoethanol on the generation of mouse cytotoxic T lymphocytes in mixed leukocyte cultures. Eur. J. Immunol. 5(3), 223–225 (1975).
- 49. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1(5), 405–413 (1994).
- 50. Enhanced induction of antitumor T-cell responses by cytotoxic T lymphocyte associated molecule-4 blockade: the effect is manifested only at the restricted tumor-bearing stages. Cancer Res. 57(18), 4036–4041 (1997).
- 51. . The mechanism of cell-mediated cytotoxicity. I. Killing by murine cytotoxic T lymphocytes requires cell surface thiols and activated proteases. J. Immunol. 124(2), 870–878 (1980).
- 52. . The extended family of CD1d-restricted NKT cells: sifting through a mixed bag of TCRs, antigens, and functions. Front. Immunol. 6, 362 (2015).
- 53. Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 191(4), 661–668 (2000).
- 54. Type I natural killer T cells suppress tumors caused by p53 loss in mice. Blood 113(25), 6382–6385 (2009).
- 55. iNKT cells control mouse spontaneous carcinoma independently of tumor-specific cytotoxic T cells. PLoS ONE 5(1), e8646 (2010).
- 56. Identification of novel glycol ligands activating a sulfatide-reactive, CD1d-restricted, Type II natural killer T lymphocyte. Eur. J. Immunol. 42(11), 2851–2860 (2012).
- 57. . The regulatory role of invariant NKT cells in tumor immunity. Cancer Immunol. Res. 3(5), 425–435 (2015).
- 58. . Type II NKT cells: a distinct CD1d-restricted immune regulatory NKT cell subset. Immunogenetics 68(8), 665–676 (2016).
- 59. . Cell surface thiols, but not intracellular glutathione, are essential for cytolysis by a cloned murine natural killer cell line. Immunol. Invest. 14(5), 401–414 (1985).
- 60. . The generation of natural killer (NK) cells from NK precursor cells in rat long term bone marrow cultures. J. Exp. Med. 172(1), 303–313 (1990).
- 61. . Induction of lymphokine-activated killer activity in rat splenocyte cultures: the importance of 2-mercaptoethanol and indomethacin. Cancer Immunol. Immunother. 33(1), 28–32 (1991).
- 62. . Role of thiols in human peripheral blood natural killer and killer lymphocyte activities. Experientia 45(2), 180–181 (1989).
- 63. . Requirement of thiol compounds as reducing agents for IL-2-mediated induction of LAK activity and proliferation of human NK cells. J. Immunol. 151(10), 5535–5544 (1993).
- 64. . Fas ligand induction in human NK cells is regulated by redox through a calcineurin-nuclear factors of activated T cell-dependent pathway. J. Immunol. 162(4), 1988–1993 (1999).
- 65. . Thiols prevent Fas (CD95)-mediated T cell apoptosis by down-regulating membrane Fas expression. Eur. J. Immunol. 26(12), 2981–2988 (1996).
- 66. Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance. Nat. Immunol. 20(12), 1656–1667 (2019).
- 67. . Immune exhaustion: past lessons and new insights from lymphocytic choriomeningitis virus. Viruses 11(2), 156 (2019).
- 68. . T-cell exhaustion: characteristics, causes and conversion. Immunology 129(4), 474–481 (2010).
- 69. . Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15(8), 486–499 (2015).
- 70. PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. J. Clin. Invest. 123(6), 2604–2615 (2013).
- 71. . In vitro antioxidant treatment recovers proliferative responses of anergic CD4+ lymphocytes from human immunodeficiency virus-infected individuals. Blood 87(11), 4746–4753 (1996).
- 72. Adult T cell leukemia (ATL)-derived factor/human thioredoxin prevents apoptosis of lymphoid cells induced by L-cystine and glutathione depletion: possible involvement of thiol-mediated redox regulation in apoptosis caused by pro-oxidant state. J. Immunol. 158(7), 3108–3117 (1997).
- 73. . The role of low molecular weight thiols in T lymphocyte proliferation and IL-2 secretion. J. Immunol. 175(12), 7965–7972 (2005).
- 74. . Commentary: The interleukin-2 T cell system: a new cell growth model. Front. Immunol. 6, 414 (2015).
- 75. . Changes in intracellular glutathione levels in stimulated and unstimulated lymphocytes in the presence of 2-mercaptoethanol or cysteine. J. Immunol. 130(1), 362–364 (1983).
- 76. . Requirement for pro-oxidant and antioxidant states in T cell mediated immune responses-Relevance for the pathogenetic mechanisms of AIDS? Klin. Wochenschr. 69(21–23), 1118–1122 (1991).
- 77. . Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives. Am. J. Med. 91(3C), S140–S144 (1991).
- 78. . N-Acetylcysteine – a safe antidote for cysteine/glutathione deficiency. Curr. Opin. Pharmacol. 7(4), 355–359 (2007).
- 79. . Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunological dysfunction. FASEB J. 11(13), 1077–1089 (1997).
- 80. . Regulation of the immune response to tumor antigen. IV. Tumor antigen-specific suppressor factor(s) bear I-J determinants and induce suppressor T cells in vivo. J. Immunol. 121(6), 2144–2147 (1978).
- 81. . Switching on the macrophage-mediated suppressor mechanism by tumor cells to evade host immune surveillance. Proc. Natl Acad. Sci. USA 77(7), 4265–4269 (1980).
- 82. . Defective monocyte accessory function due to surface sulfhydryl oxidation in rheumatoid arthritis. Clin. Exp. Immunol. 56(3), 607–613 (1984).
- 83. Depletion of CD4+ CD25+ regulatory T cells enhances natural killer T cell-mediated anti-tumour immunity in a murine mammary breast cancer model. Clin. Exp. Immunol. 159(1), 93–99 (2010).
- 84. Synergistic effects of CTLA-4 blockade with tremelimumab and elimination of regulatory T lymphocytes in vitro and in vivo. Int. J. Cancer 129(2), 374–386 (2011).
- 85. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210(9), 1695–1710 (2013).
- 86. . Modulation of immune responses by suppressor T cells. Fed. Proc. 37(10), 2361–2364 (1978).
- 87. . Activities of nonspecific and specific suppressor T-cell factors in immune responses. Agents Actions Suppl. 7, 126–133 (1980).
- 88. . Role and function of antigen nonspecific suppressor factors. Crit. Rev. Immunol. 7(2), 93–130 (1987).
- 89. . Induction of specific suppressor T cells in vitro. J. Immunol. 117(1), 313–318 (1976).
- 90. . 2-Mercaptoethanol and N-acetylcysteine enhance T cell colony formation in AIDS and ARC. Clin. Exp. Immunol. 77(1), 7–10 (1989).
- 91. . Ncf1 (p47phox) is essential for direct regulatory T cell mediated suppression of CD4+ effector T cells. PLoS ONE 6(1), e16013 (2011).
- 92. . Suppression of murine natural killer cell activity by adherent cells from aging mice. Mech. Ageing Dev. 31(2), 155–162 (1985).
- 93. . Glycolipid antigen induces long-term natural killer T cell anergy in mice. J. Clin. Invest. 115(9), 2572–2583 (2005).
- 94. . Effect of tumor cells on the generation of cytotoxic T lymphocytes in vitro. I. Accessory cell functions of mouse tumor cells in the generation of cytotoxic T lymphocytes in vitro: replacement of adherent phagocytic cells by tumor cells or 2-mercaptoethanol. Eur. J. Immunol. 7(6), 394–400 (1977).
- 95. Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species. J. Clin. Invest. 117(10), 3020–3028 (2007).
- 96. . Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 70(1), 68–77 (2010).
- 97. . Extracellular redox modulation by regulatory T cells. Nat. Chem. Biol. 5(10), 721–723 (2009).
- 98. . Suppression of immune responses to sheep erythrocytes by the lymphokine soluble immune response suppressor (SIRS) in vivo. J. Immunol. 137(3), 863–867 (1986).
- 99. . Soluble suppressor factors in patients with acquired immune deficiency syndrome and its prodrome. Elaboration in vitro by T lymphocyte-adherent cell interactions. J. Clin. Invest. 72(6), 2072–2081 (1983).
- 100. . Impaired suppressor cell activity due to surface sulphydryl oxidation in rheumatoid arthritis. Br. J. Rheumatol. 31(9), 599–603 (1992).
- 101. . Suppressor T cells in a primary in vitro response to non-major histocompatibility alloantigens. J. Exp. Med. 156(5), 1398–1414 (1982).
- 102. . Strength of TCR-peptide/MHC interactions and in vivo T cell responses. J. Immunol. 186(9), 5039–5045 (2011).
- 103. Redox regulation facilitates optimal peptide selection by MHC class I during antigen processing. Cell 27(2), 369–382 (2006).
- 104. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science 359(6375), 582–587 (2018).
- 105. . The determinants of tumour immunogenicity. Nat. Rev. Cancer 12(4), 307–313 (2012).
- 106. . Neoantigens in cancer immunotherapy. Science 348(6230), 69–74 (2015).
- 107. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375(9), 819–829 (2016).
- 108. . History and genealogy of the H-2Kb mutants from the C57BL/6Kh colony. Immunogenetics 15(2), 177–185 (1982).
- 109. . Immunogenetic and biological aspects of in vitro lymphocyte allotransformation (MLR) in the mouse. Transplant. Rev. 15, 62–88 (1973).
- 110. . Methods for the study of histocompatibility genes. J. Genet. 49, 87–108 (1948).
- 111. . Fine specificity of alloimmune cytotoxic T lymphocytes directed against H-2K. A Study with Kb Mutants. J. Exp. Med. 151(5), 993–1013 (1980).
- 112. . Dermal histocompatibility and in vitro lymphocyte reactions of three new H-2 mutants. Immunogenetics 2, 337–348 (1975).
- 113. . Genetic control of permanently accepted allografts. Transplant. Proc. 19(1 Pt 1), 890–893 (1987).
- 114. Biochemical studies of H-2K antigens from a group of related mutants. I. Identification of a shared mutation in B6-H-2bm5 and B6-H-2bm16. Immunogenetics 17(1), 19–29 (1983).
- 115. . CML typing of serologically identical H-2 mutants. Distinction of 19 specificities on the cells of four mouse strains carrying z1 locus mutations and the strain of origin. lmmunogenetics 5, 43–56 (.1977).
- 116. . T-lymphocyte response to H-2 mutants. I. Proliferation is dependent on Ly 1+2+ cells. J. Exp. Med. 147(5), 1395–1404 (1978).
- 117. . Immune responses in vitro. XIII. MLR detectability of Mlsa, Mlsc, Mlsb, and Mlsd encoded products. J. Immunol. 134(5), 2948–2952 (1985).
- 118. . Evidence that strong Mls determinants are nonpolymorphic. Transplantation 31(5), 376–378 (1981).
- 119. . Immune responses in vitro. XII. Two independently segregating loci control Mls product(s). J. Immunol. 128(4), 1502–1506 (1982).
- 120. . Genetic complexity of Mls. J. Immunogenet. 15(1–3), 39–47 (1988).
- 121. . T cell recognition of Mls: T cell clones demonstrate polymorphism between Mlsa, Mlsc, and Mlsd. J. Immunol. 138(2), 373–379 (1987).
- 122. . Clonal analysis of the Mls system. A reappraisal of polymorphism and allelism among Mlsa, Mlsc, and Mlsd. J. Exp. Med. 165(4), 1113–1129 (1987).
- 123. . The Mlsd-defined primary mixed lymphocyte reaction: a composite response to Mlsa and Mlsc determinants. J. Immunol. 138(12), 4085–4092 (1987).
- 124. . T lymphocytes responding to Mls-locus antigens are Lyt-1+2- and I-A restricted. Immunogenetics 10(5), 481–497 (1980).
- 125. . Bidirectionality of mixed lymphocyte stimulation (Mls) response. Effects of Mlsb stimulator cells on Mlsa helper cells. J. Immunol. 140(8), 2543–2548 (1988).
- 126. . Linkage of Mls genes to endogenous mouse mammary tumour viruses of inbred mice. Nature 349(6309), 526–528 (1991).
- 127. . The open reading frames in the 3′ long terminal repeats of several mouse mammary tumor virus integrants encode V/∼3-specific superantigens. J. Exp. Med. 175(1), 41–47 (1992).
- 128. . Genetics of tissue transplantation. Biology of the Laboratory Mouse. (2nd Edition). Green EL (Ed.). McGraw-Hill, NY, USA, 457 (1966).
- 129. . A new histogenetic method for minor histocompatibility antigen typing. J. Immunol. 118(2), 423–426 (1977).
- 130. . Syngeneic responses by murine thymocytes: a role for non-MHC and non-Mls genes. J. Immunol. 134(1), 10–15 (1985).
- 131. Induction and characterization of minor histocompatibility antigens. Specific primary cytotoxic T lymphocyte responses in vitro. J. Immunol. 140(3), 723–729 (1988).
- 132. . A new cytotoxic lymphocyte defined antigen coded by a gene closely linked to the H-3 locus. Immunogenetics 10(4), 333–341 (1980).
- 133. . Complexity of minor histocompatibility loci. Hum. Immunol. 14(3), 220–233 (1985).
- 134. . Nonspecific activation of murine lymphocytes. II. Parameters of the interaction between splenic lymphocytes and radiolabeled 2-mercaptoethanol in vitro. J. Immunol. 120(5), 1453–1459 (1978).
- 135. . Nonspecific activation of murine lymphocytes. III. Nonspecific activation of murine lymphocytes. III. Cells responding mitogenically to 2-mercaptoethanol are typical unstimulated lymphocytes. J. Immunol. 121(5), 899–1904 (1978).
- 136. . Nonspecific activation of murine lymphocytes. IV. Proliferation of a distinct, late maturing lymphocyte subpopulation induced by 2-mercaptoethanol. J. Immunol. 121(5), 1905–1913 (1978).
- 137. . Nonspecific activation of murine lymphocytes. V. Role of cellular collaboration between T and B lymphocytes in the proliferative and polyclonal responses to 2-mercaptoethanol. J. Immunol. 122(4), 1433–1439 (1979).
- 138. . Nonspecific activation of murine lymphocytes. VI. Mediation of synergistic interaction between T and B lymphocytes by a cell-associated, reciprocally acting lymphocyte proliferation helper. J. Exp. Med. 149(3), 644–657 (1979).
- 139. . Nonspecific activation of murine lymphocytes. VII. Functional correlates of molecular structure of thiol compounds. J. Immunol. 126(1), 20–26 (1981).
- 140. . In vitro induction of polyclonal killer T cells with 2-mercaptoethanol and the essential role of macrophages in this process. J. Immunol. 118(5), 1697–1703 (1977).
- 141. . Cell death-mediated cytokine release and its therapeutic implications. J. Exp. Med. 216(7), 1474–1486 (2019).
- 142. . Presence of impairment of humoral immunity in nonadherent spleen cells of old mice. J. Immunol. 111(5), 1502–1506 (1973).
- 143. . Humoral immunity in aged mice. II. Increased suppressor T cell activity in immunologically deficient old mice. J. Immunol. 116(3), 735–738 (1976).
- 144. Restoration of impaired immune functions in aging animals. VI. Differential potentiating effect of 2-mercaptoethanol on young and old murine spleen cells. Int. J. Immunopharmacol. 4(5), 429–436 (1982).
- 145. . Restoration of impaired immune functions in aging animals. II. Effect of mercaptoethanol in enhancing the reduced primary antibody responsiveness in vitro. Mech. Ageing Dev. 10(5), 325–340 (1979).
- 146. . Preferential enhancement by 2-mercaptoethanol of IL-2 responsiveness of T blast cells from old over young mice is associated with potentiated protein kinase C translocation. Immunol. Lett. 20(2), 149–154 (1989).
- 147. . Alterations in immune function in rats caused by dietary lipotrope deficiency: effect of culture medium, 2-mercaptoethanol and mitogen dose on the in vitro lymphocyte transformation response. J. Nutr. 112(12), 2342–2352 (1982).
- 148. . Glutathione augments in vitro proliferative responses of lymphocytes to concanavalin A to a greater degree in old than in young rats. J. Nutr. 120(12), 1710–1717 (1990).
- 149. . Decline in natural killer cell-mediated immunosurveillance in aging mice – a consequence of reduced cell production and tumor binding capacity. Mech. Ageing Dev. 75(2), 115–129 (1994).
- 150. Genetic control of the decline of natural killer cell activity in aging mice. Growth Dev. Aging 58(1), 3–12 (1994).
- 151. . Tumor-primed NK cells: waiting for the green light. Front. Immunol. 4, e408 (2013).
- 152. . Effects in vitro of several antioxidants on the natural killer function of aging mice. Exp. Gerontol. 34(5), 675–685 (1999).
- 153. . The amount of thiolic antioxidant ingestion needed to improve several immune functions is higher in aged than in adult mice. Free Radic. Res. 36(2), 119–126 (2002).
- 154. . Antioxidant requirements for bovine oocytes varies during in vitro maturation, fertilization and development. Theriogenology 59(3–4), 939–949 (2003).
- 155. Reversal of aging-associated hippocampal synaptic plasticity deficits by reductants via regulation of thiol redox and NMDA receptor function. Aging Cell 9(5), 709–721 (2010).
- 156. . Inhibition by cysteamine-HCl of oncogenesis induced by 7,12-dimethylbenz(alpha)anthracene without affecting toxicity. Cancer Res. 34(12), 3387–3390 (1974).
- 157. . Inhibitory effect of prolonged administration of cysteamine on experimental carcinogenesis in rat stomach induced by N-methyl-N'-nitro-N-nitrosoguanidine. Int. J. Cancer 41(3), 423–426 (1988).
- 158. . Tissue norepinephrine depletion as a mechanism for cysteamine inhibition of colon carcinogenesis induced by azoxymethane in Wistar rats. Int. J. Cancer 44(6), 1008–1011 (1989).
- 159. . Inhibition by cysteamine of hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague–Dawley rats. Int. J. Cancer 44(3), 529–533 (1989).
- 160. . Attenuating effect of the monoamine oxidase inhibitor furazolidone on the anti-carcinogenetic effect of cysteamine on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats. Int. J. Cancer 48(4), 605–608 (1991).
- 161. . Prolongation of the normal life span by radiation protection chemicals. J. Gerontol. 12(3), 257–263 (1957).
- 162. . Aging: overview. Ann. NY Acad. Sci. 928, 1–21 (2001).
- 163. . Suppression of the immune response in tumor-bearing mice. I. Response to virus-producing tumor cells and non-virus-producing tumor cells. J. Natl Cancer Inst. 63(5), 1215–1220 (1979).
- 164. . Agents which block membrane lipid peroxidation enhance mouse spleen cell immune activities in vitro: relationship to the enhancing activity of 2-mercaptoethanol. Eur. J. Immunol. 11(5), 371–376 (1981).
- 165. . Prevention of acetaminophen- and naphthalene-induced cataract and glutathione loss by CySSME. Invest. Ophthalmol. Vis. Sci. 37(5), 923–929 (1996).
- 166. . Protection against acetaminophen-induced hepatotoxicity by L-CySSME and its N-acetyl and ethyl ester derivatives. J. Biochem. Toxicol. 11(6), 289–295 (1996).
- 167. Synergistic effects of glutathione and β-mercaptoethanol treatment during in vitro maturation of porcine oocytes on early embryonic development in a culture system supplemented with L-cysteine. J. Reprod. Dev. 56(6), 575–582 (2010).
- 168. . A review: alteration of in vitro reproduction processes by thiols – emphasis on 2-mercaptoethanol. J. Reprod. Dev. 60(6), 399–405 (2014).
- 169. . Differentiation of human adipose-derived mesenchymal stem cell into insulin-producing cells: an in vitro study. J. Physiol. Biochem. 69(3), 451–458 (2013).
- 170. . Origin and evolution of the free radical theory of aging: a brief personal history, 1954–2009. Biogerontology 10(6), 773–781 (2009).
- 171. . Sulphane sulphur in biological systems: a possible regulatory role. Biochem. J. 264(3), 625–632 (1989).
- 172. Thiol-mediated inhibition of FAS and CD2 apoptotic signaling in activated human peripheral T cells. Int. Immunol. 9(1), 117–125 (1997).
- 173. . Prolonged sulforaphane treatment activates survival signaling in nontumorigenic NCM460 colon cells but apoptotic signaling in tumorigenic HCT116 colon cells. Nutr. Cancer 63(2), 248–255 (2011).
- 174. . Diallyl trisulfide inhibits activation of signal transducer and activator of transcription 3 in prostate cancer cells in culture and in vivo. Cancer Prev. Res. 3(11), 1473–1483 (2010).
- 175. . Hydrogen sulfide: an endogenous mediator of resolution of inflammation and injury. Antioxid. Redox Signal. 17(1), 58–67 (2012).
- 176. Hydrogen sulfide is an endogenous potentiator of T cell activation. J. Biol. Chem. 287(6), 4211–4221 (2012).
- 177. Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation. Proc. Natl Acad. Sci. USA 109(23), 9161–9166 (2012).
- 178. . Evidence for a dithiol-activated signaling pathway in natural killer cell avidity regulation of leukocyte function antigen-1: structural requirements and relationship to phorbol ester- and CD16-triggered pathways. Blood 86(6), 2288–2301 (1995).
- 179. . Targeting allosteric disulphide bonds in cancer. Nat. Rev. Cancer 13(7), 425–431 (2013).
- 180. . Thiols in cancer. In: Nutritional Oncology. Elsevier, Inc., MA, USA, 307–320 (2006).
- 181. . Redox mechanisms in neurodegeneration: from disease outcomes to therapeutic opportunities. Antioxid. Redox Signal. 30(11), 1450–1499 (2019).
- 182. . Involvement and relative importance of at least two distinct mechanisms in the effects of 2-mercaptoethanol on murine lymphocytes in culture. J. Cell. Physiol. 141(1), 40–45 (1989).
- 183. Activated human CD4+ T cells express transporters for both cysteine and cystine. Sci. Rep. 2, 266 (2012).
- 184. . Macrophages regulate intracellular glutathione levels of lymphocytes. Evidence for an immunoregulatory role of cysteine. Cell. Immunol. 129(1), 32–46 (1990).
- 185. Tumor-associated mesenchymal stem cells inhibit naive T cell expansion by blocking cysteine export from dendritic cells. Int. J. Cancer 139(9), 2068–2081 (2016).
- 186. . Antigen presenting cells control T cell proliferation by regulating amino acid availability. Proc. Natl Acad. Sci. USA 99(3), 1107–1109 (2002).
- 187. . Regulation of glutathione levels in mouse spleen lymphocytes by transport of cysteine. J. Cell. Physiol. 133(2), 330–336 (1987).
- 188. Antigen-presenting dendritic cells provide the reducing extracellular microenvironment required for T lymphocyte activation. Proc. Natl Acad. Sci. USA 99(3), 1491–1496 (2002).
- 189. . Mechanism of augmentation of the antibody response in vitro by 2-mercaptoethanol in murine lymphocytes. I. 2-Mercaptoethanol-induced stimulation of the uptake of cystine, an essential amino acid. J. Exp. Med. 155(5), 1277–1290 (1982).
- 190. . Mechanism of augmentation of the antibody response in vitro by 2-mercaptoethanol in murine lymphocytes. II. A major role of the mixed disulfide between 2-mercaptoethanol and cysteine. Cell. Immunol. 79(1), 173–185 (1983).
- 191. Serum free thiols predict cardiovascular events and all-cause mortality in the general population: a prospective cohort study. BMC Med. 18(1), 130 (2020).
- 192. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. J. Affect. Disord. 135(1–3), 389–394 (2011).
- 193. IFIGENIA study group. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N. Engl. J. Med. 353(21), 2229–2242 (2005).
- 194. BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell 178(2), 330–345 (2019).
- 195. . Reduced level of serum thiols in patients with a diagnosis of active disease. J. Anti-Aging Med. 6(4), 327–334 (2003).
- 196. . Serum free thiols in chronic heart failure. Pharmacol. Res. 111, 452–458 (2016).
- 197. Oxidative stress is associated with suspected non-alcoholic fatty liver disease and all-cause mortality in the general population. Liver Int. 40(9), 2148–2159 (2020).
- 198. . Potentialalteration of COVID-19 by beta-mercaptoethanol. Future Microbiol. 15, 1313–1318 (2020).