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Microcystins are potent hepatotoxins that have become a global health concern in recent years. Their actions in at-risk populations with pre-existing liver disease is unknown. We tested the hypothesis that the No Observed Adverse Effect Level (NOAEL) of Microcystin-LR (MC-LR) established in healthy mice would cause exacerbation of hepatic injury in a murine model (Leprdb/J) of Non-alcoholic Fatty Liver Disease (NAFLD). Ten-week-old male Leprdb/J mice were gavaged with 50 μg/kg, 100 μg/kg MC-LR or vehicle every 48 h for 4 weeks (n = 15–17 mice/group). Early mortality was observed in both the 50 μg/kg (1/17, 6%), and 100 μg/kg (3/17, 18%) MC-LR exposed mice. MC-LR exposure resulted in significant increases in circulating alkaline phosphatase levels, and histopathological markers of hepatic injury as well as significant upregulation of genes associated with hepatotoxicity, necrosis, nongenotoxic hepatocarcinogenicity and oxidative stress response. In addition, we observed exposure dependent changes in protein phosphorylation sites in pathways involved in inflammation, immune function, and response to oxidative stress. These results demonstrate that exposure to MC-LR at levels that are below the NOAEL established in healthy animals results in significant exacerbation of hepatic injury that is accompanied by genetic and phosphoproteomic dysregulation in key signaling pathways in the livers of NAFLD mice.
Apurva Lad; Robin C. Su; Joshua D. Breidenbach; Paul M. Stemmer; Nicholas J. Carruthers; Nayeli K. Sanchez; Fatimah K. Khalaf; Shungang Zhang; Andrew L. Kleinhenz; Prabhatchandra Dube; Chrysan J. Mohammed; Judy A. Westrick; Erin L. Crawford; Dilrukshika Palagama; David Baliu-Rodriguez; Dragan Isailovic; Bruce Levison; Nikolai Modyanov; Amira F. Gohara; Deepak Malhotra; Steven T. Haller; David J. Kennedy. Chronic Low Dose Oral Exposure to Microcystin-LR Exacerbates Hepatic Injury in a Murine Model of Non-Alcoholic Fatty Liver Disease. Toxins 2019, 11, 486 .
AMA StyleApurva Lad, Robin C. Su, Joshua D. Breidenbach, Paul M. Stemmer, Nicholas J. Carruthers, Nayeli K. Sanchez, Fatimah K. Khalaf, Shungang Zhang, Andrew L. Kleinhenz, Prabhatchandra Dube, Chrysan J. Mohammed, Judy A. Westrick, Erin L. Crawford, Dilrukshika Palagama, David Baliu-Rodriguez, Dragan Isailovic, Bruce Levison, Nikolai Modyanov, Amira F. Gohara, Deepak Malhotra, Steven T. Haller, David J. Kennedy. Chronic Low Dose Oral Exposure to Microcystin-LR Exacerbates Hepatic Injury in a Murine Model of Non-Alcoholic Fatty Liver Disease. Toxins. 2019; 11 (9):486.
Chicago/Turabian StyleApurva Lad; Robin C. Su; Joshua D. Breidenbach; Paul M. Stemmer; Nicholas J. Carruthers; Nayeli K. Sanchez; Fatimah K. Khalaf; Shungang Zhang; Andrew L. Kleinhenz; Prabhatchandra Dube; Chrysan J. Mohammed; Judy A. Westrick; Erin L. Crawford; Dilrukshika Palagama; David Baliu-Rodriguez; Dragan Isailovic; Bruce Levison; Nikolai Modyanov; Amira F. Gohara; Deepak Malhotra; Steven T. Haller; David J. Kennedy. 2019. "Chronic Low Dose Oral Exposure to Microcystin-LR Exacerbates Hepatic Injury in a Murine Model of Non-Alcoholic Fatty Liver Disease." Toxins 11, no. 9: 486.
Inflammatory Bowel Disease (IBD) represents a collection of gastrointestinal disorders resulting from genetic and environmental factors. Microcystin-leucine arginine (MC-LR) is a toxin produced by cyanobacteria during algal blooms and demonstrates bioaccumulation in the intestinal tract following ingestion. Little is known about the impact of MC-LR ingestion in individuals with IBD. In this study, we sought to investigate MC-LR's effects in a dextran sulfate sodium (DSS)-induced colitis model. Mice were separated into four groups: (a) water only (control), (b) DSS followed by water (DSS), (c) water followed by MC-LR (MC-LR), and (d) DSS followed by MC-LR (DSS + MC-LR). DSS resulted in weight loss, splenomegaly, and severe colitis marked by transmural acute inflammation, ulceration, shortened colon length, and bloody stools. DSS + MC-LR mice experienced prolonged weight loss and bloody stools, increased ulceration of colonic mucosa, and shorter colon length as compared with DSS mice. DSS + MC-LR also resulted in greater increases in pro-inflammatory transcripts within colonic tissue (TNF-α, IL-1β, CD40, MCP-1) and the pro-fibrotic marker, PAI-1, as compared to DSS-only ingestion. These findings demonstrate that MC-LR exposure not only prolongs, but also worsens the severity of pre-existing colitis, strengthening evidence of MC-LR as an under-recognized environmental toxin in vulnerable populations, such as those with IBD.
Robin C. Su; Thomas M. Blomquist; Andrew L. Kleinhenz; Fatimah K. Khalaf; Prabhatchandra Dube; Apurva Lad; Joshua D. Breidenbach; Chrysan J. Mohammed; Shungang Zhang; Caitlin E. Baum; Deepak Malhotra; David J. Kennedy; Steven T. Haller. Exposure to the Harmful Algal Bloom (HAB) Toxin Microcystin-LR (MC-LR) Prolongs and Increases Severity of Dextran Sulfate Sodium (DSS)-Induced Colitis. Toxins 2019, 11, 371 .
AMA StyleRobin C. Su, Thomas M. Blomquist, Andrew L. Kleinhenz, Fatimah K. Khalaf, Prabhatchandra Dube, Apurva Lad, Joshua D. Breidenbach, Chrysan J. Mohammed, Shungang Zhang, Caitlin E. Baum, Deepak Malhotra, David J. Kennedy, Steven T. Haller. Exposure to the Harmful Algal Bloom (HAB) Toxin Microcystin-LR (MC-LR) Prolongs and Increases Severity of Dextran Sulfate Sodium (DSS)-Induced Colitis. Toxins. 2019; 11 (6):371.
Chicago/Turabian StyleRobin C. Su; Thomas M. Blomquist; Andrew L. Kleinhenz; Fatimah K. Khalaf; Prabhatchandra Dube; Apurva Lad; Joshua D. Breidenbach; Chrysan J. Mohammed; Shungang Zhang; Caitlin E. Baum; Deepak Malhotra; David J. Kennedy; Steven T. Haller. 2019. "Exposure to the Harmful Algal Bloom (HAB) Toxin Microcystin-LR (MC-LR) Prolongs and Increases Severity of Dextran Sulfate Sodium (DSS)-Induced Colitis." Toxins 11, no. 6: 371.
In 1972 Neal Bricker presented the “trade-off” hypothesis in which he detailed the role of physiological adaptation processes in mediating some of the pathophysiology associated with declines in renal function. In the late 1990’s Xie and Askari published seminal studies indicating that the Na+/K+-ATPase (NKA) was not only an ion pump, but also a signal transducer that interacts with several signaling partners. Since this discovery, numerous studies from multiple laboratories have shown that the NKA is a central player in mediating some of these long-term “trade-offs” of the physiological adaptation processes which Bricker originally proposed in the 1970’s. In fact, NKA ligands such as cardiotonic steroids (CTS), have been shown to signal through NKA, and consequently been implicated in mediating both adaptive and maladaptive responses to volume overload such as fibrosis and oxidative stress. In this review we will emphasize the role the NKA plays in this “trade-off” with respect to CTS signaling and its implication in inflammation and fibrosis in target organs including the heart, kidney, and vasculature. As inflammation and fibrosis exhibit key roles in the pathogenesis of a number of clinical disorders such as chronic kidney disease, heart failure, atherosclerosis, obesity, preeclampsia, and aging, this review will also highlight the role of newly discovered NKA signaling partners in mediating some of these conditions.
Fatimah K. Khalaf; Prabhatchandra Dube; Amal Mohamed; Jiang Tian; Deepak Malhotra; Steven T. Haller; David J. Kennedy. Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase. International Journal of Molecular Sciences 2018, 19, 2576 .
AMA StyleFatimah K. Khalaf, Prabhatchandra Dube, Amal Mohamed, Jiang Tian, Deepak Malhotra, Steven T. Haller, David J. Kennedy. Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase. International Journal of Molecular Sciences. 2018; 19 (9):2576.
Chicago/Turabian StyleFatimah K. Khalaf; Prabhatchandra Dube; Amal Mohamed; Jiang Tian; Deepak Malhotra; Steven T. Haller; David J. Kennedy. 2018. "Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase." International Journal of Molecular Sciences 19, no. 9: 2576.
Cardiotonic steroids (CTS) are Na+/K+-ATPase (NKA) ligands that are elevated in volume-expanded states and associated with cardiac and renal dysfunction in both clinical and experimental settings. We test the hypothesis that the CTS telocinobufagin (TCB) promotes renal dysfunction in a process involving signaling through the NKA α-1 in the following studies. First, we infuse TCB (4 weeks at 0.1 µg/g/day) or a vehicle into mice expressing wild-type (WT) NKA α-1, as well as mice with a genetic reduction (~40%) of NKA α-1 (NKA α-1+/−). Continuous TCB infusion results in increased proteinuria and cystatin C in WT mice which are significantly attenuated in NKA α-1+/− mice (all p < 0.05), despite similar increases in blood pressure. In a series of in vitro experiments, 24-h treatment of HK2 renal proximal tubular cells with TCB results in significant dose-dependent increases in both Collagens 1 and 3 mRNA (2-fold increases at 10 nM, 5-fold increases at 100 nM, p < 0.05). Similar effects are seen in primary human renal mesangial cells. TCB treatment (100 nM) of SYF fibroblasts reconstituted with cSrc results in a 1.5-fold increase in Collagens 1 and 3 mRNA (p < 0.05), as well as increases in both Transforming Growth factor beta (TGFb, 1.5 fold, p < 0.05) and Connective Tissue Growth Factor (CTGF, 2 fold, p < 0.05), while these effects are absent in SYF cells without Src kinase. In a patient study of subjects with chronic kidney disease, TCB is elevated compared to healthy volunteers. These studies suggest that the pro-fibrotic effects of TCB in the kidney are mediated though the NKA-Src kinase signaling pathway and may have relevance to volume-overloaded conditions, such as chronic kidney disease where TCB is elevated.
David J. Kennedy; Fatimah K. Khalaf; Brendan Sheehy; Malory E. Weber; Brendan Agatisa-Boyle; Julijana Conic; Kayla Hauser; Charles M. Medert; Kristen Westfall; Philip Bucur; Olga V. Fedorova; Alexei Y. Bagrov; W. H. Wilson Tang. Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na+/K+-ATPase Profibrotic Signaling Pathways. International Journal of Molecular Sciences 2018, 19, 2566 .
AMA StyleDavid J. Kennedy, Fatimah K. Khalaf, Brendan Sheehy, Malory E. Weber, Brendan Agatisa-Boyle, Julijana Conic, Kayla Hauser, Charles M. Medert, Kristen Westfall, Philip Bucur, Olga V. Fedorova, Alexei Y. Bagrov, W. H. Wilson Tang. Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na+/K+-ATPase Profibrotic Signaling Pathways. International Journal of Molecular Sciences. 2018; 19 (9):2566.
Chicago/Turabian StyleDavid J. Kennedy; Fatimah K. Khalaf; Brendan Sheehy; Malory E. Weber; Brendan Agatisa-Boyle; Julijana Conic; Kayla Hauser; Charles M. Medert; Kristen Westfall; Philip Bucur; Olga V. Fedorova; Alexei Y. Bagrov; W. H. Wilson Tang. 2018. "Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na+/K+-ATPase Profibrotic Signaling Pathways." International Journal of Molecular Sciences 19, no. 9: 2566.