March 2022 Member Publications
- Wang X, Chen X, Zhou W, Men H, Bao T, Sun Y, Wang Q, Tan Y, Keller BB, Tong Q, Zheng Y, Cai L. Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways. Acta Pharm Sin B. 2022 Feb;12(2):708-722. doi: 10.1016/j.apsb.2021.10.005. Epub 2021 Oct 15. PMID: 35256941; PMCID: PMC8897044.
Impact Statement: The role of ferroptosis in the pathogenesis of diabetic cardiomyopathy (DCM) was comprehensively examined by examining the expression of key regulators of ferroptosis in type 2 diabetic mice with cardiomyopathy and a new ex vivo DCM model. Diabetes or AGEs was found to induce ferroptosis, reflected through increased levels of Ptgs2 and lipid peroxides and decreased ferritin and SLC7A11 levels and typically morphological changes in cardiomyocytes, and inhibition of ferroptosis with ferrostatin-1 and deferoxamine, as well as Nrf2 activator, sulforaphane, prevented cardiac remodeling and dysfunction. These findings suggest that ferroptosis plays an essential role in the pathogenesis of DCM; sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation.
- Wise JTF, Salazar-González RA, Habil MR, Doll MA, Hein DW. Expression of arylamine N-acetyltransferase 2 activity in immortalized human bronchial epithelial cells. Toxicol Appl Pharmacol. 2022 Mar 27;442:115993. doi: 10.1016/j.taap.2022.115993. Epub ahead of print. PMID: 35353990.
Impact Statement: A recent meta-analysis reported N-acetyltransferase 2 (NAT2) slow and intermediate phenotypes had a significantly increased risk of lung cancer. NAT2 activity in humans is thought to be restricted to liver and gastrointestinal tract, and no studies to our knowledge have reported the expression of NAT2 activity in immortalized human lung epithelial cells. Given the importance of NAT2 in cancer and inhalation of various carcinogens directly into the lungs, we investigated NAT2 activity and documented that it is expressed and functional in human lung epithelial cells.
Hein DW, Doll MA, Habil MR. Human N-Acetyltransferase 1 and 2 Differ in Affinity Towards Acetyl-Coenzyme A Cofactor and N-Hydroxy-Arylamine Carcinogens. Front Pharmacol. 2022 Feb 25;13:821133. doi: 10.3389/fphar.2022.821133. PMID: 35281898; PMCID: PMC8914035.
Impact Statement: Following recombinant expression in bacteria, yeast, and mammalian cells, we report significant differences in affinity between human N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) for its required co-factor acetyl coenzyme A, as well as for N-hydroxy-arylamines activated via O-acetylation. The findings provide important information to understand the relative contribution of human NAT1 vs NAT2 towards N-acetylation and O-acetylation reactions in human hepatic and extrahepatic tissues.
- Doll MA, Hein DW. 560G>A (rs4986782) (R187Q) Single Nucleotide Polymorphism in Arylamine N-Acetyltransferase 1 Increases Affinity for the Aromatic Amine Carcinogens 4-Aminobiphenyl and N-Hydroxy-4-Aminobiphenyl: Implications for Cancer Risk Assessment. Front Pharmacol. 2022 Feb 22;13:820082. doi: 10.3389/fphar.2022.820082. PMID: 35273499; PMCID: PMC8902414.
Impact Statement: Human arylamine N-acetyltransferase 1 (NAT1) catalyzes the N-acetylation of arylamine carcinogens such as 4-aminobiphenyl (ABP), and following N-hydroxylation, the O-acetylation of N-hydroxy-arylamine carcinogens such as N-hydroxy-ABP (N-OH-ABP). The effects of individual single nucleotide polymorphisms (SNPs) in the NAT1 coding exon on Michaelis-Menten kinetic constants was assessed for ABP N-acetyltransferase and N-OH-ABP O-acetyltransferase activity following transfection of human NAT1 into COS-1 cells. 560G>A (rs4986782) (R187Q) significantly reduced the apparent Km for ABP and N-OH-ABP a finding that was not observed with any of the other NAT1 SNPs tested. These findings suggest that the role of the 560G>A (rs4986782) (R187Q) SNP cancer risk assessment may be modified by exposure level to aromatic amine carcinogens such as ABP.
- Latif RK, Clifford SP, Ghafghazi S, Phipps Z, Chen JJ, Sangroula D, Khan AZ, Saleem J, Farah I, Huang J, Businger JR. Echocardiography and Management for Cardiac Trauma. J Cardiothorac Vasc Anesth. 2022 Feb 12:S1053-0770(22)00120-3. doi: 10.1053/j.jvca.2022.02.010. Epub ahead of print. PMID: 35305892.
Impact Statement: This review article aims to analyze the pathophysiology of cardiac injuries in patients with trauma and the role of echocardiography for the accurate diagnosis of cardiac injury in trauma. This review, additionally, will offer a patient-centered, team-based, early management plan with a treatment algorithm to help improve the quality of care among these patients with cardiac trauma.
- Lu L, Che J, Cheng W, Dong R, Huang J, Yang Z, Lu J. A Retrospective Study of the Relationship Between Blood Transfusion and 30-Day Postoperative Outcomes in Patients Undergoing Isolated Off-Pump Coronary Artery Bypass Grafting. Braz J Cardiovasc Surg. 2022 Mar 3. doi: 10.21470/1678-9741-2021-0031. Epub ahead of print. PMID: 35244374.
Impact Statement: Perioperative blood transfusion increases the risks of postoperative pulmonary infection and short-term mortality in off-pump coronary artery bypass grafting patients.
- Fulghum KL, Audam TN, Lorkiewicz PK, Zheng Y, Merchant M, Cummins TD, Dean WL, Cassel TA, Fan TWM, Hill BG. In vivo deep network tracing reveals phosphofructokinase-mediated coordination of biosynthetic pathway activity in the myocardium. J Mol Cell Cardiol. 2022 Jan;162:32-42. doi: 10.1016/j.yjmcc.2021.08.013. Epub 2021 Sep 3. PMID: 34487754; PMCID: PMC8766935.
Impact Statement: This study tested how phosphofructokinase-1 (PFK1) activity controls the fate of glucose-derived carbon in murine hearts in vivo. PFK1 activity was regulated by cardiac-specific overexpression of kinase- or phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgenes in mice (termed GlycoLo or GlycoHi mice, respectively). Stable isotope (C13) labeled glucose and deep network metabolic tracing revealed that low rates of PFK1 activity, potentially regulated by physical channeling, promoted selective routing of glucose-derived carbon to the purine synthesis pathway to form 5-aminoimidazole-4-carboxamide ribonucleotide. Additionally, PFK1 influenced glucose-derived carbon deposition in glycogen, but did not affect hexosamine biosynthetic pathway activity. These studies demonstrate the utility of deep network tracing to identify metabolic channeling and changes in biosynthetic pathway activity in the heart in vivo and present new potential mechanisms by which metabolic branch point reactions modulate biosynthetic pathways.
- Dongfeng Wu, Shesh N. Rai and Albert Seow. Estimation of preclinical state onset age and sojourn time for heavy smokers in lung cancer. Statistics and Its Interface. 15 (3), 2022. Published Feb 14, 2022.
Impact Statement: Using the pre-existing large data, we have devolved model to predict onset of early- stage of lung cancer in heavy smokers. The mean age (in years) to make the transition into the preclinical state was 70.94 or 71.15 for male and female heavy smokers respectively. About 90% of heavy smokers who are at risk for lung cancer would enter the preclinical state in age interval (55.7, 85.8) for males and (54.2, 87.7) for females, and the transition peaked around age 69 for both genders. Based on the result, low-dose CT should be started at age 55 and ended before 85 for heavy smokers. This provided important information to policy makers.
- Jessica Sparks, Xiaoyong Wu, Mika Kessans Knable, Shesh N. Rai, Vivek Sharma. Predictors of thrombosis in patients treated with bevacizumab. Thrombosis Update. 6, 2022 (DOI: https://doi.org/10.1016/j.tru.2021.100095). Published March, 2022.
Impact Statement: We study the predictors of thrombosis in cancer patients treated with bevacizumab using a single center comprehensive retrospective cohort. The thrombotic events occurred in 24/116 (20.7%) of the hypertension cohort compared to 8/87 (9.2%) of the normotensive patients (p = 0.026) and in 15/52 (28.8%) of hyperlipidemic patients vs 17/151 (11.3%) of those with normal lipids (p = 0.003). The Khorana score was not a significant predictor in this population. In further analyzing our data, we found increasing thrombotic events with each addition of the most telling predictors of thromboses in our population: hypertension, hyperlipidemia, and greater than trace proteinuria, such that patients with all three risk factors present vs none had an odds ratio of 6.786 (p = 0.004). Incorporating these three risk factors into a clinical risk score may help stratify patients into lower and higher risk categories which may assist clinicians in making decisions about the use of prophylactic anticoagulation in this population.
States JC, Peters JM. 2020-2021 Toxicological Sciences Paper of the Year. Toxicol Sci. 2022 Mar 28;186(2):177-178. doi: 10.1093/toxsci/kfac020. PMID: 35348797.
This editorial announced the SOT Paper of the Year.
- Xiong L, Bin Zhou, Young JL, Wintergerst K, Cai L. Exposure to low-dose cadmium induces testicular ferroptosis. Ecotoxicol Environ Saf. 2022 Mar 7;234:113373. doi: 10.1016/j.ecoenv.2022.113373. Epub ahead of print. PMID: 35272187.
Impact Statement: As an environmental pollutant, cadmium (Cd) has been widely reported to induce male infertility due to its gonadotoxicity. This study found for the first time that exposure to 5 ppm Cd significantly decreased the expression of SLC7A11, a marker of ferroptosis in mice, along with the expression of SLC40A1 mRNA and ferritin heavy chain (FTH) protein, whereas there was no obvious change in the mRNA expression of Tfrc, ZIP8, ZIP14, and NCOA4, suggesting that 5 ppm Cd exposure increased testicular ferroptosis, probably due to the reduction of stored iron export potency.