John Thomas Pinto
Ph.D., (Biochemistry), University of Medicine and Dentistry of NJ, 1974
Post-doctoral studies (Nutrition), Columbia University, 1975-78
CHAPTERS IN BOOKS: 2013 (Life time chapters published 14)
Pinto JT and Rivlin RS. Riboflavin. IN: Handbook of the Vitamins. Nutritional, Biochemical, and Clinical Aspects. Gregory J, Stover P, Suttie JW and Zempleni J., eds. (New York, Taylor and Francis, Inc., Fifth Edition), 2013.
Aquilato A, Lopez V, Doonan B, Hsieh T-C, Pinto JT, Wu E and Wu JM. BRAF Mutation in Melanoma and Dietary Polyphenols as Adjunctive Treatment Strategy. Chapter 102. IN: Polyphenols in Human Health and Disease: Vol 2; Watson RR, Preedy VR, and Zibadi S. eds. (Elsevier: San Diego, CA,) 2013.Cooper AJL, Dorai T, Dorai B, Krasnikov BF, Li JY, Hallen A, and Pinto JT. Role of glutamine transaminases in nitrogen, sulfur, selenium and 1-carbon metabolism: Glutamine Transaminases in normal and cancer Cells. IN: Glutamine in Health and Disease. Rajendram R, Preedy VR, and Patel VB. (Eds.) (Springer, New York) 2013.
JOURNAL ARTICLES PUBLISHED IN 2010-2014 (Life time publication 117 peer-reviewed manuscripts)
Cooper AJL, Krasnikov BF, Pinto JT, Bruschi SA. Measurement of cysteine S-conjugate β-lyase activity. Current Protocols Toxicol., 44: Chapter 4: Unit 4.36.1-16, 2010.
Cooper AJL, Krasnikov BF, Niatsetskaya ZV, Pinto JT, Callery PS, Villa MT, Artigues A, Bruschi SA. Cysteine S-conjugate β-lyases: Important roles in the metabolism of naturally occurring sulfur-and selenium-containing compounds, xenobiotics and anticancer agents. Amino Acids 41(1): 7-27, 2011.
Pinto JT, Lee J-I, Sinha R, MacEwan M., Cooper AJL. Chemopreventive mechanisms of α- keto acid metabolites of naturally occurring organoselenium compounds. Amino Acids 41(1): 29-41, 2011.
Chua CO, Vinukonda G, Hu F, Labinskyy N, Zia MT, Pinto J, Csiszar A, Ungvari Z , Ballabh P. Effect of Hyperoxic Resuscitation on Propensity of Germinal Matrix Hemorrhage and Cerebral Injury. Neuropathol Appl Neurobiol 36(5): 448-458, 2010.
Facompre N., El-Bayoumy K, Sun Y-W, Pinto J, Sinha R. 1,4-phenylenebis(methylene)-selenocyanate (p-XSC) but not selenomethionine inhibits multiple signaling pathways in human prostate cancer cells. Cancer Prev Res 3(8): 975-984, 2010.
Ungvari Z, Gautam T, Koncz P, Henthorn JC, Pinto JT, Ballabh P, Yan H, Mitschelen M, Farley J, Sonntag WE, Csiszar A. Vasoprotective effects of lifespan-extending peripubertal GH replacement in Lewis dwarf rats. J Gerontol A Biol Sci Med Sci 65(11): 1145-1156, 2010.
Ungvari Z, Bailey-Downs L, Gautam T, Sosnowska D, Wang M, Monticone RE, Telljohann R, Pinto JT, de Cabo R, William E. Sonntag WE, Lakatta E, Csiszar A. Age-associated vascular oxidative stress, Nrf2 dysfunction and NF-kB activation in the non-human primate Macaca mulatta. J Gerontol A Biol Sci Med Sci 66(8): 866-875, 2011.
Cooper AJL, Pinto JT, Callery PS. Reversible and irreversible protein glutathionylation: biological and clinical aspects. Expert Opin Drug Metab Toxicol 7(7): 891-910, 2011. Review. Erratum in: Expert Opin Drug Metab Toxicol 7(9): 1183, 2011.
Smirnova NA, Haskew-Layton RE, Basso M, Hushpulian DM, Payappillya JB, Speer RE, Ahn Y-H, Rakhman I, Cole PA, Pinto JT, Ratan RR, Gazaryan IG. Development of Neh2-luciferase reporter and its application for high throughput screening and real-time monitoring of Nrf2 activators. Chem Biol 18(6): 752-765, 2011.
Bailey-Downs LC, Mitschelen M, Sosnowska D, Toth P, Pinto JT, Ballabh P, Valcarce N, Farley J, Koller A, Henthorn JC, Bass C, Sonntag WE, Ungvari Z, Csiszar A. Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: A novel model of vascular aging. J Gerontol A Biol Sci Med Sci. 67(4): 313-329, 2012.
Sinha I, Null K, Wolter W, Suckow MA, King T, Pinto JT and Sinha R. Methylseleninic acid down regulates hypoxia inducible growth factor-1a in invasive prostate cancer. Int J Cancer. 130(6): 1430-1439, 2012.
Bridges CC, Krasnikov BF, Joshee L, Pinto JT, Hallen A, Li J, Zalups RK, Cooper AJL. New insights into the metabolism of organomercury compounds: Mercury-containing cysteine S-conjugates are substrates of human glutamine transaminase K and potent inactivators of cystathionine g-lyase. Arch Biochem Biophys 517(1): 20-29, 2012.
Facompre ND, El-Bayoumy K, Sun Y-W, Pinto JT and Sinha R. Remarkable inhibition of mTOR signaling by the combination of rapamycin and 1,4-phenylenebis(methylene) selenocyanate in human prostate cancer cells. Int J Cancer. 131(9):2134-42, 2012.
Csiszar A, Podlutsky AJ, Podlutskaya N, Sonntag WE, Merlin SZ, Philipp EER, Doyle K, Davila A, Recchia FA, Ballabh P, Pinto JT, Ungvari Z. Testing the oxidative stress hypothesis of aging in primate fibroblasts: Is there a correlation between species longevity and cellular ROS production? Gerontol A Biol Sci Med Sci 67(8): 841-852, 2012.
Cooper AJL, Krasnikov BF, Pinto JT, Kung HF, Li J-Y Ploessl K. Comparative enzymology of (2S,4R)4-fluoroglutamine and (2S,4R)4-fluoroglutamate. Comp Biochem Physiol B Biochem Mol Biol 163: 108-120, 2012.
Khomenko T, Kolodney J, Pinto JT, McLaren GD, Deng X, Chen L, Tolstanova G, Paunovic B, Krasnikov BF, Hoa N, Cooper AJL, Szabo S. New mechanistic explanation for the localization of ulcers in the rat duodenum: Role of iron and selective uptake of cysteamine. Arch Biochem Biophys 525: 60-70, 2012.
Tsikas D, Evans CE, Denton TT, Mitschke A, Gutzki FM, Pinto JT, Khomenko T, Szado S, Cooper AJL. Stable-isotope GC-MS/MS determination of aminoethylcysteine ketimine decarboxylated dimer in biological samples. Anal Biochem. 430(1):4-15, 2012.
Pinto JT, Cooper AJL. From cholesterogenesis to steroidogenesis: Role of riboflavin and flavoenzymes in the biosynthesis of vitamin D. Adv. Nutr. 5: 1–20, 2014.
Sinha I, Allen J, Pinto JT, and Sinha R. Methylseleninic acid elevates REDD1 and inhibits prostate cancer cell growth despite AKT activation and mTOR dysregulation in hypoxia. Int J Cancer: 2014
a. Naturally-occurring organoselenium compounds
Our laboratory has identified mechanisms whereby naturally occurring organoselenium compounds exhibit chemopreventive effects on prostate and colon cancers. We discovered novel metabolic conversions of diet-derived selenoamino acids, Se-methyl-L-selenocysteine (MSC) and L-selenomethionine (SM), to their respective selenoketo acid metabolites, methylselenopyruvate (MSP) and ketomethylselenobutyrate (KMSB). Metabolism of MSC and SM and hence their chemopreventive qualities, were previously thought to occur primarily through β- and γ-lyase reactions. The lyase pathways were hypothesized to generate highly reactive and short-lived, methylselenol, a metabolite that has not been measured nor identified to exist within tissues. Our work shows that the selenoketo acids, derived from MSC and SM, but not MSC and SM themselves, exhibit potent inhibitory effects on a variety of histone deacetylases. This information has significantly altered our basic understanding of the chemopreventive activity associated with diet-derived organoselenium compounds. We have also identified the specific transaminases responsible for the transamination of selenoamino acids to their corresponding keto acids as well as the selectivity of the tissue types capable transamination of each selenoamino acid. Accordingly, glutamine transaminase K (kidney, GTK) selectively converts MSC to MSP and has less than 0.1% the activity with SM. GTK is a ubiquitous enzyme and displays varying degrees of activity in various tissues. By contrast, glutamine transaminase L (Liver, GTL) selectively metabolizes SM to KMSB exhibiting much less activity toward MSC (5-10% that observed with SM). This enzyme is present in liver and is marginally found in other tissues such as pancreas. The significance of this information resides in issues surrounding the aborted nation-wide, clinical study SELECT. Androgen responsive and non-responsive prostate cancer cells do not possess GTL but rather GTK and thus SM, which was provided to SELECT volunteers, was NOT effective in prostate cancer prevention perhaps for these reasons. By contrast, prostate cells do exhibit adequate activity of GTK and thus would have exhibited a response if methylselenocysteine had been used. This remains a viable issue and, in this investigator’s opinion, should evoke further studies.
In both human prostate and colon cancer cells in culture, acetylated histone H3 levels increase during the period 5-24 h after treatment with direct addition of the selenoketo acids (MSP or KMSB). The proportion of cells occupying G2/M phase of the cell cycle increases at 10-50 µM MSP and KMSB, and apoptosis is induced, as evidenced by morphological changes, Annexin V staining, and increased cleaved caspase-3, -6, -7-, -9, and poly(ADP-ribose)polymerase. P21WAF1, a target used by investigators studying clinically-approved HDAC inhibitors, increases in MSP- and KMSB-treated colon cancer cells. Thus, in addition to targeting redox-sensitive signaling factors, selenoketo acids inhibit HDAC activity and nuclear status of acetylated histones.
b. Organoselenium compounds
In additional investigations on organoselenium compounds, we showed that another potential metabolite of methylselenocysteine promotes apoptosis in invasive prostate cancer cells in part by down regulating hypoxia inducible factor-1α (HIF-1α). Accordingly, we demonstrate that methylseleninic acid activates or stabilizes REDD1 (Regulated in Development and DNA Damage Response 1), a conserved mitochondrial stress-response protein whose over-expression inhibits the mTOR (mammalian target of rapamycin) pathway, a critical regulator of tumor cell proliferation. REDD1 has been suggested to act by binding to and sequestering 14-3-3 proteins away from tumor suppressor TSC2 (tuberous sclerosis complex subunit 2) thus leading to TSC2-dependent inhibition of the mTOR pathway. Endogenous REDD1 is required for both dissociation of endogenous TSC2/14-3-3 and inhibition of mTORC1 in response to HIF-1α and hypoxia. Thus, methylseleninic acid activates REDD1 in metastatic prostate cancer cells and significantly inhibits expression of factors that activate the PI3K/PKB and mTOR/p70S6K1 signaling pathways even under hypoxic conditions. In brief, phosphatidylinositol-3-kinase (PI3K) transmits a mitogenic signal through protein kinase B and mammalian target of rapamycin (mTOR) to p70S6K1. The mTOR inhibitor, rapamycin, is recognized to inhibit cells in G1 cell cycle progression and to block expression of cyclin D1, CDK4, CDC25A, and retinoblastoma phosphorylation. Our data suggest that methylseleninic induces REDD1 and inhibits prostate cancer cell growth in hypoxia despite activation of PKB and dysregulation of mTOR which are viable therapeutic targets in control of prostate cancer pathologies.
c. Naturally-occurring organosulfur compounds
Our studies show that S-allylmercaptocysteine (SAMC), a garlic-derived compound, inhibits growth, arrests cells in G2/M, and induces apoptosis in LNCaP, LNCaP C4-2, and PC-3 human prostate carcinoma cells as well as in SW480 and HT29 human colon cancer cells. Indirect immunofluorescent staining for microtubules (MTs) reveal that treatment of colon cancer cells or NIH3T3 fibroblasts with varying doses of SAMC causes MT depolymerization and MT cytoskeleton disruption in interphase cells, and interferes with the spindle assembly in mitotic cells.
Our investigations of signaling pathways involved in SAMC-induced apoptosis found that SAMC causes rapid and sustained induction of c-Jun NH2-terminal kinase-1 (JNK1) activity. SAMC also activates caspase-3, as evidenced by the cleavage of a fluorogenic tetrapeptide substrate and of poly(ADP-ribose) polymerase. Conclusions thus far are that garlic-derived SAMC exerts anti-proliferative effects, at least in part, by disrupting MT assembly thus arresting cells in mitosis and triggering JNK1 and caspase-3 signaling pathways that lead to apoptosis. By investigating the regulatory role displayed by garlic-derived allylsulfides on expression of inducible redox sensitive signal proteins and enzymes and on the overall antioxidant potential of the cell, our studies summarize newly identified mechanisms by which garlic-derived allylsulfide constituents may contribute significantly to cancer prevention and control.
These studies provide novel paradigms by which diet-derived organoselenium and organosulfur compounds might protect against prostate, colon, and a variety of other cancers.
HBSV 5011: Advanced nutrition II
In-depth review of current knowledge and research on the biochemical and physiological aspects of vitamins, minerals, and phytonutrients; applications to diet.