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Vascular calcification (VC) is one of the major causes of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). VC is a complex process expressing similarity to bone metabolism in onset and progression. VC in CKD is promoted by various factors not limited to hyperphosphatemia, Ca/Pi imbalance, uremic toxins, chronic inflammation, oxidative stress, and activation of multiple signaling pathways in different cell types, including vascular smooth muscle cells (VSMCs), macrophages, and endothelial cells. In the current review, we provide an in-depth analysis of the various kinds of VC, the clinical significance and available therapies, significant contributions from multiple cell types, and the associated cellular and molecular mechanisms for the VC process in the setting of CKD. Thus, we seek to highlight the key factors and cell types driving the pathology of VC in CKD in order to assist in the identification of preventative, diagnostic, and therapeutic strategies for patients burdened with this disease.
Prabhatchandra Dube; Armelle DeRiso; Mitra Patel; Dhanushya Battepati; Bella Khatib-Shahidi; Himani Sharma; Rajesh Gupta; Deepak Malhotra; Lance Dworkin; Steven Haller; David Kennedy. Vascular Calcification in Chronic Kidney Disease: Diversity in the Vessel Wall. Biomedicines 2021, 9, 404 .
AMA StylePrabhatchandra Dube, Armelle DeRiso, Mitra Patel, Dhanushya Battepati, Bella Khatib-Shahidi, Himani Sharma, Rajesh Gupta, Deepak Malhotra, Lance Dworkin, Steven Haller, David Kennedy. Vascular Calcification in Chronic Kidney Disease: Diversity in the Vessel Wall. Biomedicines. 2021; 9 (4):404.
Chicago/Turabian StylePrabhatchandra Dube; Armelle DeRiso; Mitra Patel; Dhanushya Battepati; Bella Khatib-Shahidi; Himani Sharma; Rajesh Gupta; Deepak Malhotra; Lance Dworkin; Steven Haller; David Kennedy. 2021. "Vascular Calcification in Chronic Kidney Disease: Diversity in the Vessel Wall." Biomedicines 9, no. 4: 404.
Viral entry mechanisms for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are an important aspect of virulence. Proposed mechanisms involve host cell membrane-bound angiotensin-converting enzyme 2 (ACE2), type II transmembrane serine proteases (TTSPs), such as transmembrane serine protease isoform 2 (TMPRSS2), lysosomal endopeptidase Cathepsin L (CTSL), subtilisin-like proprotein peptidase furin (FURIN), and even potentially membrane bound heparan sulfate proteoglycans. The distribution and expression of many of these genes across cell types representing multiple organ systems in healthy individuals has recently been demonstrated. However, comorbidities such as diabetes and cardiovascular disease are highly prevalent in patients with Coronavirus Disease 2019 (COVID-19) and are associated with worse outcomes. Whether these conditions contribute directly to SARS-CoV-2 virulence remains unclear. Here, we show that the expression levels of ACE2, TMPRSS2 and other viral entry-related genes, as well as potential downstream effector genes such as bradykinin receptors, are modulated in the target organs of select disease states. In tissues, such as the heart, which normally express ACE2 but minimal TMPRSS2, we found that TMPRSS2 as well as other TTSPs are elevated in individuals with comorbidities compared to healthy individuals. Additionally, we found the increased expression of viral entry-related genes in the settings of hypertension, cancer, or smoking across target organ systems. Our results demonstrate that common comorbidities may contribute directly to SARS-CoV-2 virulence and we suggest new therapeutic targets to improve outcomes in vulnerable patient populations.
Joshua Breidenbach; Prabhatchandra Dube; Subhanwita Ghosh; Belal Abdullah; Nikolai Modyanov; Deepak Malhotra; Lance Dworkin; Steven Haller; David Kennedy. Impact of Comorbidities on SARS-CoV-2 Viral Entry-Related Genes. Journal of Personalized Medicine 2020, 10, 146 .
AMA StyleJoshua Breidenbach, Prabhatchandra Dube, Subhanwita Ghosh, Belal Abdullah, Nikolai Modyanov, Deepak Malhotra, Lance Dworkin, Steven Haller, David Kennedy. Impact of Comorbidities on SARS-CoV-2 Viral Entry-Related Genes. Journal of Personalized Medicine. 2020; 10 (4):146.
Chicago/Turabian StyleJoshua Breidenbach; Prabhatchandra Dube; Subhanwita Ghosh; Belal Abdullah; Nikolai Modyanov; Deepak Malhotra; Lance Dworkin; Steven Haller; David Kennedy. 2020. "Impact of Comorbidities on SARS-CoV-2 Viral Entry-Related Genes." Journal of Personalized Medicine 10, no. 4: 146.
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.
The burden of cardiovascular disease and death in chronic kidney disease (CKD) outpaces that of the other diseases and is not adequately described by traditional risk factors alone. Diminished activity of paraoxonase (PON)-1 is associated with increased oxidant stress, a common feature underlying the pathogenesis of CKD. We aimed to assess the prognostic value of circulating PON-1 protein and PON lactonase activity on adverse clinical outcomes across various stages and etiologies of CKD. Circulating PON-1 protein levels and PON lactonase activity were measured simultaneously in patients with CKD as well as a cohort of apparently healthy non-CKD subjects. Both circulating PON-1 protein levels and PON lactonase activity were significantly lower in CKD patients compared to the non-CKD subjects. Similarly, across all stages of CKD, circulating PON-1 protein and PON lactonase activity were significantly lower in patients with CKD compared to the non-CKD controls. Circulating PON lactonase activity, but not protein levels, predicted future adverse clinical outcomes, even after adjustment for traditional risk factors. The combination of lower circulating protein levels and higher activity within the CKD subjects were associated with the best survival outcomes. These findings demonstrate that diminished circulating PON lactonase activity, but not protein levels, predicts higher risk of future adverse clinical outcomes in patients with CKD.
Chrysan J. Mohammed; Yanmei Xie; Pamela S. Brewster; Subhanwita Ghosh; Prabhatchandra Dube; Tiana Sarsour; Andrew L. Kleinhenz; Erin L. Crawford; Deepak Malhotra; Richard W. James; Philip A. Kalra; Steven T. Haller; David J. Kennedy. Circulating Lactonase Activity but Not Protein Level of PON-1 Predicts Adverse Outcomes in Subjects with Chronic Kidney Disease. Journal of Clinical Medicine 2019, 8, 1034 .
AMA StyleChrysan J. Mohammed, Yanmei Xie, Pamela S. Brewster, Subhanwita Ghosh, Prabhatchandra Dube, Tiana Sarsour, Andrew L. Kleinhenz, Erin L. Crawford, Deepak Malhotra, Richard W. James, Philip A. Kalra, Steven T. Haller, David J. Kennedy. Circulating Lactonase Activity but Not Protein Level of PON-1 Predicts Adverse Outcomes in Subjects with Chronic Kidney Disease. Journal of Clinical Medicine. 2019; 8 (7):1034.
Chicago/Turabian StyleChrysan J. Mohammed; Yanmei Xie; Pamela S. Brewster; Subhanwita Ghosh; Prabhatchandra Dube; Tiana Sarsour; Andrew L. Kleinhenz; Erin L. Crawford; Deepak Malhotra; Richard W. James; Philip A. Kalra; Steven T. Haller; David J. Kennedy. 2019. "Circulating Lactonase Activity but Not Protein Level of PON-1 Predicts Adverse Outcomes in Subjects with Chronic Kidney Disease." Journal of Clinical Medicine 8, no. 7: 1034.
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.