Background

Dr. Cai received his MD in 1983 and Ph.D. in 1990 from Jilin University (formally Norman Bethune University of Medical Sciences), China. He has had his postdoctoral training in the University of Western Ontario and McGill University (1993 – 1999), Canada.

Dr. Cai is tenured Professor of Departments of Pediatrics, Radiation Oncology and Pharmacology and Toxicology, and Director of Pediatric Research Institute, the University of Louisville School of Medicine.  Dr. Cai has served on the many special grant review panels and committees at the NIH, Department of Defense, American Diabetes Association, and American Heart Association.  He is author and co-author of more than 370 publications including peer-reviewed articles and/or book chapters, etc. He has been a member of the several societies or associations, including the Society of Toxicology, American Diabetes Association, American Heart Association, Radiation Research Society, and Dose-Response.  Currently, he also serves as the Editor-in-Chief for the World Journal of Diabetes and Journal of Microbial & Biochemical Technology, Senior Editor for Cardiovascular Toxicology and Radiation Medicine and Protection, and Associate Editor for Frontier in Endocrinology (specifically for Cardiovascular Endocrinology).

Research Interests:

• Understanding the cellular and molecular mechanisms of diabetes-induced cardiovascular diseases, particularly Diabetic Cardiomyopathy.
• Special interest in the role of oxidative stress, Nrf2, and antioxidants in the pathogenesis of diabetic cardiomyopathy, and radiation damage.
• Roles of trace elements such as zinc and iron and related metallothionein in the development of diabetic complications.
• Environmental contaminations of heavy metals such as cadmium and associate health effects.
• Understanding the effect of low dose radiation and associated hormesis and adaptive responses.
• Understanding the mechanisms for and possible protection from radiation-induced damage

Current Projects and Grants

• Role of oxidative stress in diabetic complications
• Antioxidant prevention and therapy for diabetic complication via various transgenic mouse models
• Prevention of diabetic complications with sulforaphane, and broccoli sprout extracts via activation of Nrf2 or metallothionein
• Impact of maternal exposure to environmental metals on the offspring health.
• NIH/NIEHS 1R21ES033327-01.  John Wise, JR (PI).  09/01/2021 – 06/30/2023.  NIH/NIEHS 1R21ES033327-01 Cr(VI)-Induced DNA Damage Contributes to Brain Aging Role: Co-PI
• CIEHS NIH/NIEHS P30 ES030283 (J. Christopher States (PI), Pilot Project (Haixun Guo (PI)), 01/01/2023 – 12/31/2023, “64Cu-PET metallomics for non-invasively tracing copper distribution in response to cadmium and/or HFD”, Role: Co-investigator
• NIH/NIEHS, P30 ES030283 (J. Christopher States (PI)), 07/01/2020 – 06/30/2025 “University of Louisville Center for Integrated Environmental Health Sciences”, Role: Leader for the Multi-Organs Interesting group (MOL RIG); Director of Metallomics Shared Resource for Omics & Exposure Facility Core.
• NIH/NIDDK, 1 R01 DK132163-01.  Yi Tan, PhD (PI).  10/2021-09/2026. “Fibroblast growth factor 1 prevents hyperlipidemia and atherosclerosis”  Major Goals: This project is to define how FGF1 protects against atherosclerosis. Role: Co-PI

Selected Publications and Manuscripts in Progress

Studies related to diabetic cardiomyopathy:

1. Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways. Wang X, Chen X, Zhou W, Men H, Bao T, Sun Y, Wang Q, Tan Y, Keller BB, Tong Q, Zheng Y, Cai L. Acta Pharm Sin B. 2022 Feb; 12(2): 708-722. PMID: 35256941
2. Engineered cardiac tissues: a novel in vitro model to investigate the pathophysiology of mouse diabetic cardiomyopathy. Wang X, Chen XX, Yu HT, Tan Y, Lin Q, Keller BB, Zheng Y, Cai L. Acta Pharmacol Sin. 2021 Jun; 42(6): 932-941. PMID: 33037406
3. Emerging roles of microRNA-208a in cardiology and reverse cardio-oncology. Wang X, Chen X, Xu H, Zhou S, Zheng Y, Keller BB, Cai L. Med Res Rev. 2021 Jul; 41(4): 2172-2194. PMID: 33533026
4. Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence.  Tan Y, Zhang Z, Zheng C, Wintergerst KA, Keller BB, Cai L.  Nat Rev Cardiol. 2020 Aug; 22(2): 603-611PMID: 32080423
5. Protective effects of sulforaphane on type 2 diabetes-induced cardiomyopathy via AMPK-mediated activation of lipid metabolic pathways and NRF2 function. Sun Y, Zhou S, Guo H, Zhang J, Ma T, Zheng Y, Zhang Z, Cai L. Metabolism. 2020 Jan; 102: 154002. PMID: 31706979.
6. The regulatory roles of p53 in cardiovascular health and disease. Men H, Cai H, Cheng Q, Zhou W, Wang X, Huang S, Zheng Y, Cai L. Cell Mol Life Sci. 2020 Mar; 78(5): 2001-2018. PMID: 33179140
7. Metallothionein Preserves Akt2 Activity and Cardiac Function via Inhibiting TRB3 in Diabetic Hearts. Gu J, Yan X, Dai X, Wang Y, Lin Q, Xiao J, Zhou S, Zhang J, Wang K, Zeng J, Xin Y, Barati MT, Zhang C, Bai Y, Li Y, Epstein PN, Wintergerst KA, Li X, Tan Y, Cai L.  Diabetes. 2018 Mar; 67(3): 507-517. PMID: 29079702
8. Metallothionein Is Downstream of Nrf2 and Partially Mediates Sulforaphane Prevention of Diabetic Cardiomyopathy.  Gu J, Cheng Y, Wu H, Kong L, Wang S, Xu Z, Zhang Z, Tan Y, Keller BB, Zhou H, Wang Y, Xu Z, Cai L  Diabetes. 2017 Feb; 66(2): 529-542. PMID: 27903744.
9. Inhibition of JNK phosphorylation by a novel curcumin analog prevents high glucose-induced inflammation and apoptosis in cardiomyocytes and the development of diabetic cardiomyopathy.  Pan Y, Wang Y, Zhao Y, Peng K, Li W, Wang Y, Zhang J, Zhou S, Liu Q, Li X, Cai L, Liang G.  Diabetes. 2014 Oct; 63(10): 3497-511. PMID: 24848068.
10. A novel mechanism by which SDF-1β protects cardiac cells from palmitate-induced endoplasmic reticulum stress and apoptosis via CXCR7 and AMPK/p38 MAPK-mediated interleukin-6 generation.  Zhao Y, Tan Y, Xi S, Li Y, Li C, Cui J, Yan X, Li X, Wang G, Li W, Cai L.  Diabetes. 2013 Jul; 62(7): 2545-58. PMID: 23423573.
11. Angiotensin II plays a critical role in alcohol-induced cardiac nitrative damage, cell death, remodeling, and cardiomyopathy in a protein kinase C/nicotinamide adenine dinucleotide phosphate oxidase-dependent manner.  Tan Y, Li X, Prabhu SD, Brittian KR, Chen Q, Yin X, McClain CJ, Zhou Z, Cai L.  J Am Coll Cardiol. 2012 Apr 17; 59(16): 1477-86. PMID: 22497828
12. Inactivation of GSK-3beta by metallothionein prevents diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling  Wang Y, Feng W, Xue W, Tan Y, Hein DW, Li XK, Cai L.  Diabetes. 2009 Jun; 58(6): 1391-402. PMID: 19324938
13. Metallothionein suppresses angiotensin II-induced nicotinamide adenine dinucleotide phosphate oxidase activation, nitrosative stress, apoptosis, and pathological remodeling in the diabetic heart.  Zhou G, Li X, Hein DW, Xiang X, Marshall JP, Prabhu SD, Cai L.  J Am Coll Cardiol. 2008 Aug 19; 52(8): 655-66. PMID: 18702970
14. Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy.  Cai L, Wang Y, Zhou G, Chen T, Song Y, Li X, Kang YJ.  J Am Coll Cardiol. 2006 Oct 17; 48(8): 1688-97. PMID: 17045908
15. Cardiac metallothionein induction plays the major role in the prevention of diabetic cardiomyopathy by zinc supplementation.  Wang J, Song Y, Elsherif L, Song Z, Zhou G, Prabhu SD, Saari JT, Cai L.  Circulation. 2006 Jan 31; 113(4): 544-54. PMID: 16432057
16. Inhibition of superoxide generation and associated nitrosative damage is involved in metallothionein prevention of diabetic cardiomyopathy.  Cai L, Wang J, Li Y, Sun X, Wang L, Zhou Z, Kang YJ.  Diabetes. 2005 Jun; 54(6): 1829-37. PMID: 15919806
17. Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway.  Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ.  Diabetes. 2002 Jun;51(6):1938-48. PMID: 12031984
    

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Studies related to heavy metal toxicity:

1. Cardiovascular effects of environmental metal antimony: Redox dyshomeostasis as the key pathogenic driver. Tan Y, El-Kersh K, Watson SE, Wintergerst KA, Huang J, Cai L. Antioxid Redox Signal. 2023 Apr; 38(10-12): 803-823. PMID: 36424825
2. Does maternal low-dose cadmium exposure increase the risk of offspring to develop metabolic syndrome and/or type 2 diabetes? Saedi S, Watson SE, Young JL, Tan Y, Wintergerst KA, Cai L. Life Sci. 2023 Feb 15; 315: 121385. PMID: 36634865
3. Current understanding of hexavalent chromium [Cr(VI)] neurotoxicity and new perspectives. Wise JP Jr, Young JL, Cai J, Cai L. Environ Int. 2022 Jan; 158: 106877. PMID: 34547640
4. Plasma level of antimony correlates with pulmonary arterial hypertension severity. El-Kersh K, Danielle Hopkins C, Wu X, Rai SN, Cai L, Huang J. Curr Res Toxicol. 2022 Jun 27; 3:100080.  eCollection 2022. PMID: 35800661
5. Overview of the cardiovascular effects of environmental metals: New preclinical and clinical insights. Huang J, El-Kersh K, Mann KK, James KA, Cai L. Toxicol Appl Pharmacol. 2022 Nov 1; 454: 116247. PMID: 36122736
6. Effects of whole-life exposure to low-dose cadmium with post-weaning high-fat diet on offspring testes in a male mouse model. Xiong L, Zhou B, Young JL, Xu J, Wintergerst K, Cai L.Chem Biol Interact. 2022 Feb 1; 353: 109797. PMID: 34998821
7. Whole life exposure to low dose cadmium alters diet-induced NAFLD. Young JL, Cave MC, Xu Q, Kong M, Xu J, Lin Q, Tan Y, Cai L. Toxicol Appl Pharmacol. 2022 Feb 1; 436: 115855. PMID: 3499072
8. Sex differences in the effects of whole-life, low-dose cadmium exposure on postweaning high-fat diet-induced cardiac pathogeneses. Zhou W, Young JL, Men H, Zhang H, Yu H, Lin Q, Xu H, Xu J, Tan Y, Zheng Y, Cai L. Sci Total Environ. 2022 Feb 25; 809: 152176. PMID: 34875320
9. Exposure to low-dose cadmium induces testicular ferroptosis. Xiong L, Bin Zhou, Young JL, Wintergerst K, Cai L. Ecotoxicol Environ Saf. 2022 April 1; 234:113373. PMID: 35272187
10. Early-Life Exposure to Low-Dose Cadmium Accelerates Diethylnitrosamine and Diet-Induced Liver Cancer. Men H, Young JL, Zhou W, Zhang H, Wang X, Xu J, Lin Q, Tan Y, Zheng Y, Cai L. Oxid Med Cell Longev. 2021 Nov 28; 2021: 1427787. PMID: 34876963
11. Comprehensive Review of Cadmium Toxicity Mechanisms in Male Reproduction and Therapeutic Strategies. Xiong L, Zhou B, Liu H, Cai L. Rev Environ Contam Toxicol. 2021; 258:151-193. PMID: 34618232
12. Zinc as a countermeasure for cadmium toxicity. Yu HT, Zhen J, Leng JY, Cai L, Ji HL, Keller BB.  Acta Pharmacol Sin. 2021 Mar;42(3):340-346.PMID: 32284539 Review.
13. Cadmium and High-Fat Diet Disrupt Renal, Cardiac and Hepatic Essential Metals.Young JL, Yan X, Xu J, Yin X, Zhang X, Arteel GE, Barnes GN, States JC, Watson WH, Kong M, Cai L, Freedman JH. Sci Rep. 2019 Oct 11;9(1):14675. PMID: 31604971
14. Gender Differences in Cardiac Remodeling Induced by a High-Fat Diet and Lifelong, Low-Dose Cadmium Exposure.  Liang Y, Young JL, Kong M, Tong Y, Qian Y, Freedman JH, Cai L.  Chem Res Toxicol. 2019 Jun 17;32(6):1070-1081. PMID: 30912652
15. Neonatal Murine Engineered Cardiac Tissue Toxicology Model: Impact of Metallothionein Overexpression on Cadmium-Induced Injury.  Yu H, Ye F, Yuan F, Cai L, Ji H, Keller BB.  Toxicol Sci. 2018 Oct 1;165(2):499-511. PMID: 29982767
16. Inhibition of DNA methylation attenuates low-dose cadmium-induced cardiac contractile and intracellular Ca(2+) anomalies.  Turdi S, Sun W, Tan Y, Yang X, Cai L, Ren J.  Clin Exp Pharmacol Physiol. 2013 Oct; 40(10):706-12.  PMID: 23902534
17. The late and persistent pathogenic effects of cadmium at very low levels on the kidney of rats. Wang B, Luo Q, Shao C, Li X, Li F, Liu Y, Sun L, Li Y, Cai L. Dose Response. 2013;11(1):60-81. PMID: 23550262
18. Low-dose Cd induces hepatic gene hypermethylation, along with the persistent reduction of cell death and increase of cell proliferation in rats and mice. Wang B, Li Y, Tan Y, Miao X, Liu XD, Shao C, Yang XH, Turdi S, Ma LJ, Ren J, Cai L. PLoS One. 2012;7(3): e33853.  PMID: 22457795
19. Proteomic characterization of the late and persistent effects of cadmium at low doses on the rat liver. Wang B, Wang S, Shao C, Wang G, Li Y, Cai L. J Appl Toxicol. 2013 Jul;33(7):546-57. PMID: 22081424