Publications by authors named "William L Neumann"

44 Publications

Sphingosine-1-phosphate receptor subtype 1 activation in the central nervous system contributes to morphine withdrawal in rodents.

J Neuroinflammation 2020 Oct 22;17(1):314. Epub 2020 Oct 22.

Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, 1402 South Grand Blvd, St. Louis, MO, 63104, USA.

Opioid therapies for chronic pain are undermined by many adverse side effects that reduce their efficacy and lead to dependence, abuse, reduced quality of life, and even death. We have recently reported that sphingosine-1-phosphate (S1P) 1 receptor (S1PR1) antagonists block the development of morphine-induced hyperalgesia and analgesic tolerance. However, the impact of S1PR1 antagonists on other undesirable side effects of opioids, such as opioid-induced dependence, remains unknown. Here, we demonstrate that naloxone-precipitated morphine withdrawal in mice altered de novo sphingolipid metabolism in the dorsal horn of the spinal cord and increased S1P that accompanied the manifestation of several withdrawal behaviors. Blocking de novo sphingolipid metabolism with intrathecal administration of myriocin, an inhibitor of serine palmitoyltransferase, blocked naloxone-precipitated withdrawal. Noteworthy, we found that competitive (NIBR-15) and functional (FTY720) S1PR1 antagonists attenuated withdrawal behaviors in mice. Mechanistically, at the level of the spinal cord, naloxone-precipitated withdrawal was associated with increased glial activity and formation of the potent inflammatory/neuroexcitatory cytokine interleukin-1β (IL-1β); these events were attenuated by S1PR1 antagonists. These results provide the first molecular insight for the role of the S1P/S1PR1 axis during opioid withdrawal. Our data identify S1PR1 antagonists as potential therapeutics to mitigate opioid-induced dependence and support repurposing the S1PR1 functional antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct.
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http://dx.doi.org/10.1186/s12974-020-01975-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584082PMC
October 2020

Clinicopathologic Features of Varicella Zoster Virus Infection of the Upper Gastrointestinal Tract.

Am J Surg Pathol 2021 02;45(2):209-214

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York Presbyterian Hospital.

Reactivation of latent varicella zoster virus (VZV) may be limited to a dermatome or involve multiple organs, including the gastrointestinal tract. Although gastrointestinal manifestations of disseminated zoster have been likened to those of herpes simplex virus (HSV), histologic features of VZV-related injury to the tubular gut are not well-documented. We performed this study to describe the clinicopathologic features of VZV-related gastrointestinal injury. We identified 6 such patients with VZV infection. All involved the upper gastrointestinal tract, affecting the esophagus (n=3), stomach (n=2), or both (n=1). All patients were immunocompromised adults with hematologic malignancies (n=5) or a heart transplant (n=1); 3 with hematologic malignancies had received stem cell transplants. Five patients had cutaneous and gastrointestinal zoster; 1 had gastrointestinal disease alone. When compared with 14 HSV-related esophagitis controls, there were several notable differences. VZV caused hemorrhagic ulcers with nodularity or erythema, whereas HSV produced round, shallow ulcers on a background of nearly normal mucosa (P=0.01). VZV-related ulcers featured fibrin-rich, pauci-inflammatory exudates compared with the macrophage-rich exudates of HSV (P=0.003). The cytopathic changes of VZV were present at all levels of the squamous epithelium, especially in a peripapillary distribution. In contrast, HSV inclusions were located in the superficial layers (P=0.003) and detached keratinocytes. Unlike HSV, VZV involved the stomach, producing hemorrhage accompanied by striking apoptosis in the deep glands. We conclude that VZV produces unique patterns of gastrointestinal injury that facilitate its diagnosis. Recognition of gastrointestinal VZV infection is important because it heralds potentially life-threatening disseminated disease.
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http://dx.doi.org/10.1097/PAS.0000000000001576DOI Listing
February 2021

Myeloperoxidase instigates proinflammatory responses in a cecal ligation and puncture rat model of sepsis.

Am J Physiol Heart Circ Physiol 2020 09 7;319(3):H705-H721. Epub 2020 Aug 7.

Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri.

Myeloperoxidase (MPO)-derived hypochlorous (HOCl) reacts with membrane plasmalogens to yield α-chlorofatty aldehydes such as 2-chlorofatty aldehyde (2-ClFALD) and its metabolite 2-chlorofatty acid (2-ClFA). Recent studies showed that 2-ClFALD and 2-ClFA serve as mediators of the inflammatory responses to sepsis by as yet unknown mechanisms. Since no scavenger for chlorinated lipids is available and on the basis of the well-established role of the MPO/HOCl/chlorinated lipid axis in inflammatory responses, we hypothesized that treatment with MPO inhibitors (-acetyl lysyltyrosylcysteine amide or 4-aminobenzoic acid hydrazide) would inhibit inflammation and proinflammatory mediator expression induced by cecal ligation and puncture (CLP). We used intravital microscopy to quantify in vivo inflammatory responses in Sham and CLP rats with or without MPO inhibition. Small intestines, mesenteries, and lungs were collected to assess changes in MPO-positive staining and lung injury, respectively, as well as free 2-ClFA and proinflammatory mediators levels. CLP caused neutrophil infiltration, 2-ClFA generation, acute lung injury, leukocyte-/platelet-endothelium interactions, mast cell activation (MCA), plasminogen activator inhibitor-1 (PAI-1) production, and the expression of several cytokines, chemokines, and vascular endothelial growth factor, changes that were reduced by MPO inhibition. Pretreatment with a PAI-1 inhibitor or MC stabilizer prevented CLP-induced leukocyte-endothelium interactions and MCA, and abrogated exogenous 2-ClFALD-induced inflammatory responses. Thus, we provide evidence that MPO instigates these inflammatory changes in CLP and that chlorinated lipids may serve as a mechanistic link between the enzymatic activity of MPO and PAI-1- and mast cell-dependent adhesive interactions, providing a rationale for new therapeutic interventions in sepsis. Using two distinct myeloperoxidase (MPO) inhibitors, we show for the first time that MPO plays an important role in producing increases in free 2-chlorofatty aldehyde (2-ClFALD)-a powerful proinflammatory chlorinated lipid in plasma and intestine-a number of cytokines and other inflammatory mediators, leukocyte and platelet rolling and adhesion in postcapillary venules, and lung injury in a cecal ligation and puncture model of sepsis. In addition, the use of a plasminogen activator inhibitor-1 (PAI-1) inhibitor or a mast cell stabilizer prevented inflammatory responses in CLP-induced sepsis. PAI-1 inhibition also prevented the proinflammatory responses to exogenous 2-ClFALD superfusion. Thus, our study provides some of the first evidence that MPO-derived free 2-ClFA plays an important role in CLP-induced sepsis by a PAI-1- and mast cell-dependent mechanism.
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http://dx.doi.org/10.1152/ajpheart.00440.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509276PMC
September 2020

Activation of sphingosine-1-phosphate receptor subtype 1 in the central nervous system contributes to morphine-induced hyperalgesia and antinociceptive tolerance in rodents.

Pain 2020 Sep;161(9):2107-2118

Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, United States.

Abstract: Morphine-induced alterations in sphingolipid metabolism in the spinal cord and increased formation of the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) have been implicated in the development of morphine-induced hyperalgesia (OIH; increased pain sensitivity) and antinociceptive tolerance. These adverse effects hamper opioid use for treating chronic pain and contribute to dependence and abuse. S1P produces distinct effects through 5 G-protein-coupled receptors (S1PR1-5) and several intracellular targets. How S1P exerts its effects in response to morphine remains unknown. Here, we report that S1P contributes to the development of morphine-induced hyperalgesia and tolerance through S1P receptor subtype 1 (S1PR1) signaling in uninjured male and female rodents, which can be blocked by targeting S1PR1 with S1PR1 antagonists or RNA silencing. In mouse neuropathic pain models, S1PR1 antagonists blocked the development of tolerance to the antiallodynic effects of morphine without altering morphine pharmacokinetics and prevented prolonged morphine-induced neuropathic pain. Targeting S1PR1 reduced morphine-induced neuroinflammatory events in the dorsal horn of the spinal cord: increased glial marker expression, mitogen-activated protein kinase p38 and nuclear factor κB activation, and increased inflammatory cytokine expression, such as interleukin-1β, a cytokine central in the modulation of opioid-induced neural plasticity. Our results identify S1PR1 as a critical path for S1P signaling in response to sustained morphine and reveal downstream neuroinflammatory pathways impacted by S1PR1 activation. Our data support investigating S1PR1 antagonists as a clinical approach to mitigate opioid-induced adverse effects and repurposing the functional S1PR1 antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct.
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http://dx.doi.org/10.1097/j.pain.0000000000001888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554181PMC
September 2020

Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis.

Gut 2020 Nov 28;69(11):1928-1938. Epub 2020 Feb 28.

Department of Medicine, Baylor Scott and White Research Institute, Dallas, Texas, USA

Objective: Although perturbations in mitochondrial function and structure have been described in the intestinal epithelium of Crohn's disease and ulcerative colitis patients, the role of epithelial mitochondrial stress in the pathophysiology of inflammatory bowel diseases (IBD) is not well elucidated. Prohibitin 1 (PHB1), a major component protein of the inner mitochondrial membrane crucial for optimal respiratory chain assembly and function, is decreased during IBD.

Design: Male and female mice with inducible intestinal epithelial cell deletion of ( ) or Paneth cell-specific deletion of ( ) and control mice were housed up to 20 weeks to characterise the impact of PHB1 deletion on intestinal homeostasis. To suppress mitochondrial reactive oxygen species, a mitochondrial-targeted antioxidant, Mito-Tempo, was administered. To examine epithelial cell-intrinsic responses, intestinal enteroids were generated from crypts of or mice.

Results: mice exhibited spontaneous ileal inflammation that was preceded by mitochondrial dysfunction in all IECs and early abnormalities in Paneth cells. Mito-Tempo ameliorated mitochondrial dysfunction, Paneth cell abnormalities and ileitis in ileum. Deletion of specifically in Paneth cells ( ) was sufficient to cause ileitis. Intestinal enteroids generated from crypts of or mice exhibited decreased viability and Paneth cell defects that were improved by Mito-Tempo.

Conclusion: Our results identify Paneth cells as highly susceptible to mitochondrial dysfunction and central to the pathogenesis of ileitis, with translational implications for the subset of Crohn's disease patients exhibiting Paneth cell defects.
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http://dx.doi.org/10.1136/gutjnl-2019-319523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483170PMC
November 2020

Inhibition of protein nitration prevents cisplatin-induced inactivation of STAT3 and promotes anti-apoptotic signaling in organ of Corti cells.

Exp Cell Res 2019 08 9;381(1):105-111. Epub 2019 May 9.

Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, USA; Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, MI, USA. Electronic address:

JAK/STAT pathway is one among the several oxidative stress-responsive signaling pathways that play a critical role in facilitating cisplatin-induced ototoxicity. Cisplatin treatment decreases the levels of cochlear LMO4, which acts as a scaffold for IL6-GP130 protein complex. Cisplatin-induced nitration and degradation of LMO4 could destabilize this protein complex, which in turn could compromise the downstream STAT3-mediated cellular defense mechanism. Here, we investigated the link between cisplatin-induced nitrative stress and STAT3-mediated apoptosis by using organ of Corti cell cultures. SRI110, a peroxynitrite decomposition catalyst that prevented cisplatin-induced decrease in LMO4 levels and ototoxicity, was used to inhibit nitrative stress. Immunoblotting and immunostaining indicated that cisplatin treatment decreased the expression levels, phosphorylation, and nuclear localization of STAT3 in UB/OC1 cells. Inhibition of nitration by SRI110 co-treatment prevented cisplatin-induced inactivation of STAT3 and promoted its nuclear localization. SRI110 co-treatment reversed the cisplatin-induced changes in the expression levels of Bcl2l1, Ccnd1, Jak2, Jak3, and Src and significantly attenuated the changes in the expression levels of Cdkn1a, Egfr, Fas, Il6st, Jak1, Stat3, and Tyk2. Collectively, these results suggest that the inhibition of cisplatin-induced nitration prevents the inactivation of STAT3, which in turn enables the transcription of anti-apoptotic genes and thereby helps to mitigate cisplatin-induced toxicity.
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http://dx.doi.org/10.1016/j.yexcr.2019.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546436PMC
August 2019

Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain.

Proc Natl Acad Sci U S A 2019 05 8;116(21):10557-10562. Epub 2019 May 8.

Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 63104;

Neuropathic pain afflicts millions of individuals and represents a major health problem for which there is limited effective and safe therapy. Emerging literature links altered sphingolipid metabolism to nociceptive processing. However, the neuropharmacology of sphingolipid signaling in the central nervous system in the context of chronic pain remains largely unexplored and controversial. We now provide evidence that sphingosine-1-phosphate (S1P) generated in the dorsal horn of the spinal cord in response to nerve injury drives neuropathic pain by selectively activating the S1P receptor subtype 1 (S1PR1) in astrocytes. Accordingly, genetic and pharmacological inhibition of S1PR1 with multiple antagonists in distinct chemical classes, but not agonists, attenuated and even reversed neuropathic pain in rodents of both sexes and in two models of traumatic nerve injury. These S1PR1 antagonists retained their ability to inhibit neuropathic pain during sustained drug administration, and their effects were independent of endogenous opioid circuits. Moreover, mice with astrocyte-specific knockout of did not develop neuropathic pain following nerve injury, thereby identifying astrocytes as the primary cellular substrate of S1PR1 activity. On a molecular level, the beneficial reductions in neuropathic pain resulting from S1PR1 inhibition were driven by interleukin 10 (IL-10), a potent neuroprotective and anti-inflammatory cytokine. Collectively, our results provide fundamental neurobiological insights that identify the cellular and molecular mechanisms engaged by the S1PR1 axis in neuropathic pain and establish S1PR1 as a target for therapeutic intervention with S1PR1 antagonists as a class of nonnarcotic analgesics.
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http://dx.doi.org/10.1073/pnas.1820466116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534990PMC
May 2019

Kinetics of Tetracaine Solvolysis in Propylene Glycol.

Int J Pharm Compd 2018 Jul-Aug;22(4):329-334

SIUE School of Pharmacy, Edwardsville, Illinois.

Tetracaine is a potent ester-type local anesthetic. Recent publications describe the use of TC free base in topical anesthetic formulations containing propylene glycol. While solvolysis of tetracaine in propylene glycol solutions has been reported, there are no detailed reports on the kinetics of tetracaine reaction with propylene glycol. The objectives of the study were to characterize the kinetics and temperature dependence of tetracaine solvolysis in PG solutions. In this study, products of tetracaine degradation in propylene glycol solution at 60°C were collected and analyzed by high-performance liquid chromatographymass spectrometry and nuclear magnetic resonance. The kinetics of tetracaine reaction with propylene glycol was studied at 22°C, 30°C, 40°C, and 60°C. The reaction of tetracaine with n-propanol and isopropanol was also studied. Analysis was performed by high-performance liquid chromatography-mass spectrometry with ultraviolet detection using a gradient elution method. Tetracaine concentrations were quantitated using a four-point standard curve. Tetracaine degradation rates were consistent with apparent first order kinetics at all temperatures studied. The data indicated that tetracaine degrades via transesterification with propylene glycol. The rate constants ranged from 2.26 x 10 d at 22°C to 7.06 x 10 d at 60°C. Arrhenius analysis indicated an activation energy for the reaction of 74.1 kJ/mol, which is similar to published values for the hydrolysis of pharmaceutical esters.
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September 2018

Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain.

J Exp Med 2018 05 27;215(5):1301-1313. Epub 2018 Apr 27.

Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO

The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain. Mice with astrocyte-specific alterations of did not develop neuropathic pain and lost their ability to respond to S1PR1 inhibition, strongly implicating astrocytes as a primary cellular substrate for S1PR1 activity. At the molecular level, S1PR1 engaged astrocyte-driven neuroinflammation and altered glutamatergic homeostasis, processes blocked by S1PR1 antagonism. Our findings establish S1PR1 as a target for therapeutic intervention and provide insight into cellular and molecular pathways. As FTY720 also shows promising anticancer potential and is FDA approved, rapid clinical translation of our findings is anticipated.
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http://dx.doi.org/10.1084/jem.20170584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940258PMC
May 2018

Synthesis of 3-(3-hydroxyphenyl)pyrrolidine dopamine D receptor ligands with extended functionality for probing the secondary binding pocket.

Bioorg Med Chem Lett 2018 06 4;28(10):1897-1902. Epub 2018 Apr 4.

Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, 220 University Park Drive, Edwardsville, IL 62026, USA. Electronic address:

A series of 3-(3-hydroxyphenyl)pyrrolidine analogues which incorporate N-alkyl groups and N-butylamide-linked benzamide functionality have been synthesized and their in vitro binding affinities at human dopamine receptors have been evaluated. Our ligand design strategy was to take the 3-(3-hydroxyphenyl)pyrrolidine scaffold and extend functionality from the orthosteric binding site to the secondary binding pocket for enhancing affinity and selectivity for the D receptor. The N-alkyl analogues constitute a homologous series from N-pentyl to N-decyl to probe the length/bulk tolerance of the secondary binding pocket of the D receptor. Enantiomeric 3-(3-hydroxyphenyl)pyrrolidine analogues were also prepared in order to test the chirality preference of the orthosteric binding site for this scaffold. Benzamide analogues were prepared to enhance affinity and/or selectivity based upon the results of the homologous series.
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http://dx.doi.org/10.1016/j.bmcl.2018.03.084DOI Listing
June 2018

2-Chlorofatty acids induce Weibel-Palade body mobilization.

J Lipid Res 2018 01 22;59(1):113-122. Epub 2017 Nov 22.

Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104

Endothelial dysfunction is a hallmark of multiple inflammatory diseases. Leukocyte interactions with the endothelium have significant effects on vascular wall biology and pathophysiology. Myeloperoxidase (MPO)-derived oxidant products released from leukocytes are potential mediators of inflammation and endothelial dysfunction. 2-Chlorofatty acids (2-ClFAs) are produced as a result of MPO-derived HOCl targeting plasmalogen phospholipids. Chlorinated lipids have been shown to be associated with multiple inflammatory diseases, but their impact on surrounding endothelial cells has not been examined. This study tested the biological properties of the 2-ClFA molecular species 2-chlorohexadecanoic acid (2-ClHA) on endothelial cells. A synthetic alkyne analog of 2-ClHA, 2-chlorohexadec-15-ynoic acid (2-ClHyA), was used to examine the subcellular localization of 2-ClFA in human coronary artery endothelial cells. Click chemistry experiments revealed that 2-ClHyA localizes to Weibel-Palade bodies. 2-ClHA and 2-ClHyA promote the release of P-selectin, von Willebrand factor, and angiopoietin-2 from endothelial cells. Functionally, 2-ClHA and 2-ClHyA cause neutrophils to adhere to and platelets to aggregate on the endothelium, as well as increase permeability of the endothelial barrier which has been tied to the release of angiopoietin-2. These findings suggest that 2-ClFAs promote endothelial cell dysfunction, which may lead to broad implications in inflammation, thrombosis, and blood vessel stability.
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http://dx.doi.org/10.1194/jlr.M080200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748502PMC
January 2018

Targeting nitrative stress for attenuating cisplatin-induced downregulation of cochlear LIM domain only 4 and ototoxicity.

Redox Biol 2016 12 31;10:257-265. Epub 2016 Oct 31.

Department of Pharmaceutical Sciences, Southern Illinois University Edwardsville, Edwardsville, IL 62026, USA.

Cisplatin-induced ototoxicity remains a primary dose-limiting adverse effect of this highly effective anticancer drug. The clinical utility of cisplatin could be enhanced if the signaling pathways that regulate the toxic side-effects are delineated. In previous studies, we reported cisplatin-induced nitration of cochlear proteins and provided the first evidence for nitration and downregulation of cochlear LIM domain only 4 (LMO4) in cisplatin ototoxicity. Here, we extend these findings to define the critical role of nitrative stress in cisplatin-induced downregulation of LMO4 and its consequent ototoxic effects in UBOC1 cell cultures derived from sensory epithelial cells of the inner ear and in CBA/J mice. Cisplatin treatment increased the levels of nitrotyrosine and active caspase 3 in UBOC1 cells, which was detected by immunocytochemical and flow cytometry analysis, respectively. The cisplatin-induced nitrative stress and apoptosis were attenuated by co-treatment with SRI110, a peroxynitrite decomposition catalyst (PNDC), which also attenuated the cisplatin-induced downregulation of LMO4 in a dose-dependent manner. Furthermore, transient overexpression of LMO4 in UBOC1 cells prevented cisplatin-induced cytotoxicity while repression of LMO4 exacerbated cisplatin-induced cell death, indicating a direct link between LMO4 protein levels and cisplatin ototoxicity. Finally, auditory brainstem responses (ABR) recorded from CBA/J mice indicated that co-treatment with SRI110 mitigated cisplatin-induced hearing loss. Together, these results suggest that cisplatin-induced nitrative stress leads to a decrease in the levels of LMO4, downregulation of LMO4 is a critical determinant in cisplatin-induced ototoxicity, and targeting peroxynitrite could be a promising strategy for mitigating cisplatin-induced hearing loss.
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http://dx.doi.org/10.1016/j.redox.2016.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099269PMC
December 2016

Primary Colonic Eosinophilia and Eosinophilic Colitis in Adults.

Am J Surg Pathol 2017 Feb;41(2):225-233

*Miraca Life Sciences Research Institute, Irving †University of Texas Southwestern Medical Center ‡Baylor University Medical Center, Dallas §Baylor College of Medicine, Houston, TX.

The normal content of eosinophils in the adult colon and the criteria for the histopathologic diagnosis of eosinophilic colitis remain undefined. This study aimed at: (1) establishing the numbers of eosinophils in the normal adult colon; and (2) proposing a clinicopathologic framework for the diagnosis of primary colonic eosinophilia and eosinophilic colitis. To accomplish these goals, we counted the eosinophils in the right, transverse, and left colon of 159 adults with normal colonic histology. Using a database of 1.2 million patients with colonic biopsies, we extracted all adults with a diagnosis of colonic eosinophilia. We reviewed the slides from all cases and captured demographic, clinical, and pathologic data, including information about eosinophilia in other organs. We then compared the clinical manifestations of the study patients (those with no identifiable cause of eosinophilia) to those of patients with other types of colitis. The normal eosinophil counts (per mm) were 55.7±23.4 in the right, 41.0±18.6 in the transverse, and 28.6±17.2 in the left colon. Of the 194 study patients (eosinophil counts 166-5050/mm), 63 were asymptomatic and had a normal colonoscopy. Diarrhea and abdominal pain were the commonest indications for colonoscopy (38% and 27%, respectively) among the 131 patients who had symptoms, endoscopic abnormalities, or both. Neither clinical manifestations nor endoscopic appearance were sufficiently characteristic to elicit the suspicion of colonic eosinophilia. In conclusion, primary colonic eosinophilia was extremely rare in this series (<1 in 6000 patients); one third of these patients were asymptomatic. Their clinical manifestations were not distinctive and could not have led clinicians to suspect this condition; one third of the patients were asymptomatic. We suggest that regularly reporting high colonic eosinophilia may result in increased opportunities for clinicopathologic studies that might lead to a better definition of this still elusive entity.
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http://dx.doi.org/10.1097/PAS.0000000000000760DOI Listing
February 2017

The cystine/glutamate antiporter system xc- drives breast tumor cell glutamate release and cancer-induced bone pain.

Pain 2016 11;157(11):2605-2616

Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.

Bone is one of the leading sites of metastasis for frequently diagnosed malignancies, including those arising in the breast, prostate and lung. Although these cancers develop unnoticed and are painless in their primary sites, bone metastases result in debilitating pain. Deeper investigation of this pain may reveal etiology and lead to early cancer detection. Cancer-induced bone pain (CIBP) is inadequately managed with current standard-of-care analgesics and dramatically diminishes patient quality of life. While CIBP etiology is multifaceted, elevated levels of glutamate, an excitatory neurotransmitter, in the bone-tumor microenvironment may drive maladaptive nociceptive signaling. Here, we establish a relationship between the reactive nitrogen species peroxynitrite, tumor-derived glutamate, and CIBP. In vitro and in a syngeneic in vivo model of breast CIBP, murine mammary adenocarcinoma cells significantly elevated glutamate via the cystine/glutamate antiporter system xc. The well-known system xc inhibitor sulfasalazine significantly reduced levels of glutamate and attenuated CIBP-associated flinching and guarding behaviors. Peroxynitrite, a highly reactive species produced in tumors, significantly increased system xc functional expression and tumor cell glutamate release. Scavenging peroxynitrite with the iron and mangano-based porphyrins, FeTMPyP and SRI10, significantly diminished tumor cell system xc functional expression, reduced femur glutamate levels and mitigated CIBP. In sum, we demonstrate how breast cancer bone metastases upregulate a cystine/glutamate co-transporter to elevate extracellular glutamate. Pharmacological manipulation of peroxynitrite or system xc attenuates CIBP, supporting a role for tumor-derived glutamate in CIBP and validating the targeting of system xc as a novel therapeutic strategy for the management of metastatic bone pain.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065056PMC
http://dx.doi.org/10.1097/j.pain.0000000000000681DOI Listing
November 2016

Oral administration of SR-110, a peroxynitrite decomposing catalyst, enhances glucose homeostasis, insulin signaling, and islet architecture in B6D2F1 mice fed a high fat diet.

Arch Biochem Biophys 2016 04 10;596:126-37. Epub 2016 Mar 10.

School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL, 62026, USA. Electronic address:

Peroxynitrite has been implicated in type 2 diabetes and diabetic complications. As a follow-up study to our previous work on SR-135 (Arch Biochem Biophys 577-578: 49-59, 2015), we provide evidence that this series of compounds are effective when administered orally, and their mechanisms of actions extend to the peripheral tissues. A more soluble analogue of SR-135, SR-110 (from a new class of Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes) was orally administered for 2 weeks to B6D2F1 mice fed a high fat-diet (HFD). Mice fed a HFD for 4 months gained significantly higher body weights compared to lean diet-fed mice (52 ± 1.5 g vs 34 ± 1.3 g). SR-110 (10 mg/kg daily) treatment significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control or vehicle (peanut butter) group. SR-110 treatment enhanced insulin signaling in the peripheral organs, liver, heart, and skeletal muscle, and reduced lipid accumulation in the liver. Furthermore, SR-110 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration. These results suggest that a peroxynitrite decomposing catalyst is effective in improving glucose homeostasis and restoring islet morphology and β-cell insulin content under nutrient overload.
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http://dx.doi.org/10.1016/j.abb.2016.03.002DOI Listing
April 2016

Cisplatin-induced apoptosis in auditory, renal, and neuronal cells is associated with nitration and downregulation of LMO4.

Cell Death Discov 2015;1. Epub 2015 Nov 9.

Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan, USA - 48202; Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, Michigan, USA - 48201.

Cytotoxic effects of cisplatin occur primarily through apoptosis. Though several pro- and anti-apoptotic signaling molecules have been identified to play an important role in mediating the ototoxic, nephrotoxic, and neurotoxic side-effects of cisplatin, the underlying mechanism is yet to be fully characterized. We reported that nitration of LIM domain only 4 (LMO4), a transcriptional regulator, facilitates cochlear apoptosis in cisplatin-induced ototoxicity. However, its role in cisplatin-mediated nephrotoxicity and neurotoxicity is poorly understood. Therefore, HK2, and SH-SY5Y cells were employed along with UBOC1 cells, to investigate the perturbations of LMO4 in cisplatin-induced cytotoxicity, in renal, neuronal, and auditory cells, respectively. Cisplatin induced an increase in the expression of active caspase-3, indicating cellular apoptosis, and increased the nitration of proteins, 24 h post-treatment. Immunostaining with anti-nitrotyrosine and anti-LMO4 indicated that nitrotyrosine co-localized with LMO4 protein in cisplatin treated cells. Immunoblotting with anti-LMO4 indicated that cisplatin induced a decrease in LMO4 protein levels. However, a corresponding decrease in LMO4 gene levels was not observed. Inhibition of protein nitration with SRI110, a peroxynitrite decomposition catalyst, attenuated cisplatin-induced downregulation of LMO4. More importantly, overexpression of LMO4 mitigated the cytotoxic effects of cisplatin in UBOC1 cells while a dose-dependent decrease in LMO4 protein strongly correlated with cell viability in UBOC1, HK2, and SH-SY5Y cells. Collectively, these findings suggested a potential role of LMO4 in facilitating the cytotoxic effects of cisplatin in auditory, renal, and neuronal cells.
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http://dx.doi.org/10.1038/cddiscovery.2015.52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4765951PMC
November 2015

SR-135, a peroxynitrite decomposing catalyst, enhances β-cell function and survival in B6D2F1 mice fed a high fat diet.

Arch Biochem Biophys 2015 Jul 29;577-578:49-59. Epub 2015 Apr 29.

School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL 62026, United States. Electronic address:

Peroxynitrite has been implicated in β-cell dysfunction and insulin resistance in obesity. Chemical catalysts that destroy peroxynitrite, therefore, may have therapeutic value for treating type 2 diabetes. To this end, we have recently demonstrated that Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes, SR-135 and its analogs, can effectively catalyze the decomposition of peroxynitrite in vitro and in vivo through a 2-electron mechanism (Rausaria et al., 2011). To study the effects of SR-135 on glucose homeostasis in obesity, B6D2F1 mice were fed with a high fat-diet (HFD) for 12 weeks and treated with vehicle, SR-135 (5mg/kg), or a control drug SRB for 2 weeks. SR-135 significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control, vehicle or SRB. SR-135 also enhanced glucose-stimulated insulin secretion based on ex vivo studies. Moreover, SR-135 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration and apoptosis. These results suggest that a peroxynitrite decomposing catalyst enhances β-cell function and survival under nutrient overload.
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http://dx.doi.org/10.1016/j.abb.2015.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533897PMC
July 2015

The development and maintenance of paclitaxel-induced neuropathic pain require activation of the sphingosine 1-phosphate receptor subtype 1.

J Biol Chem 2014 Jul;289(30):21082-97

The ceramide-sphingosine 1-phosphate (S1P) rheostat is important in regulating cell fate. Several chemotherapeutic agents, including paclitaxel (Taxol), involve pro-apoptotic ceramide in their anticancer effects. The ceramide-to-S1P pathway is also implicated in the development of pain, raising the intriguing possibility that these sphingolipids may contribute to chemotherapy- induced painful peripheral neuropathy, which can be a critical dose-limiting side effect of many widely used chemotherapeutic agents.We demonstrate that the development of paclitaxel-induced neuropathic pain was associated with ceramide and S1P formation in the spinal dorsal horn that corresponded with the engagement of S1P receptor subtype 1 (S1PR(1))- dependent neuroinflammatory processes as follows: activation of redox-sensitive transcription factors (NFκB) and MAPKs (ERK and p38) as well as enhanced formation of pro-inflammatory and neuroexcitatory cytokines (TNF-α and IL-1β). Intrathecal delivery of the S1PR1 antagonist W146 reduced these neuroinflammatory processes but increased IL-10 and IL-4, potent anti-inflammatory/ neuroprotective cytokines. Additionally, spinal W146 reversed established neuropathic pain. Noteworthy, systemic administration of the S1PR1 modulator FTY720 (Food and Drug Administration- approved for multiple sclerosis) attenuated the activation of these neuroinflammatory processes and abrogated neuropathic pain without altering anticancer properties of paclitaxel and with beneficial effects extended to oxaliplatin. Similar effects were observed with other structurally and chemically unrelated S1PR1 modulators (ponesimod and CYM-5442) and S1PR1 antagonists (NIBR-14/15) but not S1PR1 agonists (SEW2871). Our findings identify for the first time the S1P/S1PR1 axis as a promising molecular and therapeutic target in chemotherapy-induced painful peripheral neuropathy, establish a mechanistic insight into the biomolecular signaling pathways, and provide the rationale for the clinical evaluation of FTY720 in chronic pain patients.
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http://dx.doi.org/10.1074/jbc.M114.569574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110312PMC
July 2014

Stability of non-aqueous topical tetracaine and clotrimazole solutions in polypropylene droptainer bottles.

Int J Pharm Compd 2013 Nov-Dec;17(6):508-11

SIUE School of Pharmacy, Edwardsville, Il 62026, USA.

Tetracaine topical solution may improve patient adherence with topical clotrimazole therapy for fungal otitis externa. The chemical stability of tetracaine 1% and combination clotrimazole 1% with tetracaine 1% topical solutions was determined using a stability-indicating high-performance liquid chromatography assay. Propylene glycol and polyethylene glycol 400 were used as anhydrous solvents. Standard curves for tetracaine and clotrimazole were linear with r2 > or = 0.999. Clotrimazole did not degrade in either propylene glycol or polyethylene glycol 400 throughout the 90-day study period. Tetracaine degraded significantly in propylene glycol but not in polyethylene glycol 400. A beyond-use date of 90 days is supported for tetracaine and the combination clotrimazole-tetracaine solution in polyethylene glycol 400. A beyond-use date of 60 days is supported for tetracaine and the combination clotrimazole-tetracaine in propylene glycol.
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May 2014

Autoimmune atrophic gastritis--pathogenesis, pathology and management.

Nat Rev Gastroenterol Hepatol 2013 Sep 18;10(9):529-41. Epub 2013 Jun 18.

Miraca Life Sciences Research Institute, 6655 North MacArthur Boulevard, Irving, TX 75039, USA.

Autoimmune gastritis is a chronic progressive inflammatory condition that results in the replacement of the parietal cell mass by atrophic and metaplastic mucosa. A complex interaction of autoantibodies against the parietal cell proton pump and sensitized T cells progressively destroy the parietal cells, inducing hypochlorhydria and then achlorhydria, while autoantibodies against the intrinsic factor impair the absorption of vitamin B₁₂. The resulting cobalamin deficiency manifests with megaloblastic anaemia and neurological and systemic signs and symptoms collectively known as pernicious anaemia. Previously believed to be predominantly a disease of elderly women of Northern European ancestry, autoimmune gastritis has now been recognized in all populations and ethnic groups, but because of the complexity of the diagnosis no reliable prevalence data are available. For similar reasons, as well as the frequent and often unknown overlap with Helicobacter pylori infection, the risk of gastric cancer has not been adequately assessed in these patients. This Review summarizes the epidemiology, pathogenesis and pathological aspects of autoimmune metaplastic atrophic gastritis. We also provide practical advice for the diagnosis and management of patients with this disease.
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http://dx.doi.org/10.1038/nrgastro.2013.101DOI Listing
September 2013

Spinal mitochondrial-derived peroxynitrite enhances neuroimmune activation during morphine hyperalgesia and antinociceptive tolerance.

Pain 2013 Jul 27;154(7):978-86. Epub 2013 Feb 27.

St. Louis University School of Medicine, St. Louis, MO, USA.

Treatment of severe pain by morphine, the gold-standard opioid and a potent drug in our arsenal of analgesic medications, is limited by the eventual development of hyperalgesia and analgesic tolerance. We recently reported that systemic administration of a peroxynitrite (PN) decomposition catalyst (PNDC) or superoxide dismutase mimetic attenuates morphine hyperalgesia and antinociceptive tolerance and reduces PN-mediated mitochondrial nitroxidative stress in the spinal cord. These results suggest the potential involvement of spinal PN signaling in this setting; which was examined in the present study. PN removal with intrathecal delivery of manganese porphyrin-based dual-activity superoxide/PNDCs, MnTE-2-PyP(5+) and the more lipophilic MnTnHex-2-PyP(5+), blocked hyperalgesia and antinociceptive tolerance in rats. Noteworthy is that intrathecal MnTnHex-2-PyP(5+) prevented nitration and inactivation of mitochondrial manganese superoxide dismutase. Mitochondrial manganese superoxide dismutase inactivation enhances the superoxide-to-PN pathway by preventing the dismutation of superoxide to hydrogen peroxide, thus providing an important enzymatic source for PN formation. Additionally, intrathecal MnTnHex-2-PyP(5+) attenuated neuroimmune activation by preventing the activation of nuclear factor kappa B, extracellular-signal-regulated kinase and p38 mitogen activated protein kinases, and the enhanced levels of proinflammatory cytokines, interleukin (IL)-1β and IL-6, while increasing anti-inflammatory cytokines, IL-4 and IL-10. The role of PN was further confirmed using intrathecal or oral delivery of the superoxide-sparing PNDC, SRI-110. These results suggest that mitochondrial-derived PN triggers the activation of several biochemical pathways engaged in the development of neuroinflammation in the spinal cord that are critical to morphine hyperalgesia and tolerance, further supporting the potential of targeting PN as an adjunct to opiates to maintain pain relief.
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http://dx.doi.org/10.1016/j.pain.2013.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874243PMC
July 2013

Supraspinal peroxynitrite modulates pain signaling by suppressing the endogenous opioid pathway.

J Neurosci 2012 Aug;32(32):10797-808

Saint Louis University School of Medicine, Saint Louis, Missouri 63104, USA.

Peroxynitrite (PN, ONOO(-)) is a potent oxidant and nitrating agent that contributes to pain through peripheral and spinal mechanisms, but its supraspinal role is unknown. We present evidence here that PN in the rostral ventromedial medulla (RVM) is essential for descending nociceptive modulation in rats during inflammatory and neuropathic pain through PN-mediated suppression of opioid signaling. Carrageenan-induced thermal hyperalgesia was associated with increased 3-nitrotyrosine (NT), a PN biomarker, in the RVM. Furthermore, intra-RVM microinjections of the PN decomposition catalyst Fe(III)-5,10,15,20-tetrakis(N-methyl-pyridinium-4-yl)porphyrin (FeTMPyP(5+)) dose-dependently reversed this thermal hyperalgesia. These effects of FeTMPyP(5+) were abrogated by intra-RVM naloxone, implicating potential interplay between PN and opioids. In support, we identified NT colocalization with the endogenous opioid enkephalin (ENK) in the RVM during thermal hyperalgesia, suggesting potential in situ interactions. To address the functional significance of such interactions, we exposed methionine-enkephalin (MENK) to PN and identified the major metabolite, 3-nitrotyrosine-methionine-sulfoxide (NSO)-MENK, using liquid chromatography-mass spectrometry. Next, we isolated, purified, and tested NSO-MENK for opioid receptor binding affinity and analgesic effects. Compared to MENK, this NSO-MENK metabolite lacked appreciable binding affinity for δ, μ, and κ opioid receptors. Intrathecal injection of NSO-MENK in rats did not evoke antinociception, suggesting that PN-mediated chemical modifications of ENK suppress opioid signaling. When extended to chronic pain, intra-RVM FeTMPyP(5+) produced naloxone-sensitive reversal of mechanical allodynia in rats following chronic constriction injury of the sciatic nerve. Collectively, our data reveal the central role of PN in RVM descending facilitation during inflammatory and neuropathic pain potentially through anti-opioid activity.
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http://dx.doi.org/10.1523/JNEUROSCI.6345-11.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511865PMC
August 2012

Prohibitin attenuates colitis-associated tumorigenesis in mice by modulating p53 and STAT3 apoptotic responses.

Cancer Res 2012 Nov 6;72(22):5778-89. Epub 2012 Aug 6.

Department of Internal Medicine, Division of Gastroenterology, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas 75246, USA.

Although inflammatory bowel disease is associated with higher risk of colorectal cancer, the precise pathogenic mechanisms underlying this association are not completely understood. Prohibitin 1 (PHB), a protein implicated in the regulation of proliferation, apoptosis, and transcription, is decreased in intestinal inflammation. In this study, we have established a key function for PHB in mediating colitis-associated cancer. Wild-type and transgenic (Tg) mice specifically overexpressing PHB in intestinal epithelial cells were subjected to a classical two-stage protocol of colitis-associated carcinogenesis. In addition, wild-type and p53 null human cell models were used to assess PHB interaction with STAT3 and p53. Wild-type mice exhibited decreased mucosal PHB protein expression during colitis-associated carcinogenesis. Tg mice exhibited decreased susceptibility in a manner associated with increased apoptosis, p53, Bax, and Bad expression plus decreased Bcl-xL and Bcl-2 expression. PHB overexpression in wild-type but not p53 null human cells increased expression of Bax, Bad, and caspase-3 cleavage. In wild-type p53 cells, PHB overexpression decreased basal and interleukin-6-induced STAT3 activation and expression of the STAT3 responsive genes Bcl-xL and Bcl-2. PHB coimmunoprecipitated with phospho-STAT3 in addition to p53 in cultured cell lysates and colon mucosa. This is the first study to show interaction between PHB and STAT3 in vivo. In summary, our findings suggest that PHB protects against colitis-associated cancer by modulating p53- and STAT3-mediated apoptosis. Modulation of PHB expression in intestinal epithelial cells may offer a potential therapeutic approach to prevent colitis-associated carcinogenesis.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-0603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3500430PMC
November 2012

Inverse association of esophageal eosinophilia and Barrett esophagus.

J Clin Gastroenterol 2012 Oct;46(9):752-7

Miraca Research Institute, Miraca Life Sciences, Irving, TX 75039, USA.

Background: The high frequency of gastroesophageal reflux symptoms reported in patients with eosinophilic esophagitis has suggested that the two disorders may be associated; however, few studies have systematically addressed this issue.

Goals: To determine the frequency of the simultaneous occurrence of esophageal eosinophilia and Barrett esophagus and define the clinical characteristics of patients with both conditions.

Study: From a national pathology database of patients who had esophagogastroduodenoscopy with mucosal biopsies we extracted patients with a diagnosis of Barrett mucosa, eosinophilic esophagitis pattern of injury [(≥15 eosinophils/high-power field (HPF)], or both. We then evaluated their respective clinicopathologic associations.

Results: Among 233,662 unique patients evaluated during the study period, Barrett mucosa without increased eosinophils was diagnosed in 29,733 patients (12.7%; median age 63 y; 67.6% male); eosinophil counts of ≥15/HPF were recorded in 9509 patients without Barrett mucosa (4.1%; median age 44 y; 63.9% male). A simultaneous diagnosis of Barrett mucosa and ≥15 eosinophils/HPF in the squamous epithelium and was made in 404 unique patients (0.17%; median age 56 y; 79.5% male). The observed prevalence of the simultaneous occurrence of the two conditions was one third of that expected if they occurred independently (odds ratio 0.29; 95% confidence interval, 0.27-0.33; P<0.0001).

Conclusions: These data suggest a strong inverse relationship between Barrett metaplasia and eosinophilic infiltrates in the esophageal mucosa. Although the influence of diagnostic bias cannot be excluded, the possibility that eosinophilic infiltrates in the esophageal mucosa prevent subsequent metaplastic changes may deserve to be explored.
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http://dx.doi.org/10.1097/MCG.0b013e3182568792DOI Listing
October 2012

Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain.

J Neurosci 2012 May;32(18):6149-60

Department of Pharmacological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.

Chemotherapy-induced peripheral neuropathy (CIPN) accompanied by chronic neuropathic pain is a major dose-limiting side effect of a large number of antitumoral agents including paclitaxel (Taxol). Thus, CIPN is one of most common causes of dose reduction and discontinuation of what is otherwise a life-saving therapy. Neuropathological changes in spinal cord are linked to CIPN, but the causative mediators and mechanisms remain poorly understood. We report that formation of peroxynitrite (PN) in response to activation of nitric oxide synthases and NADPH oxidase in spinal cord contributes to neuropathological changes through two mechanisms. The first involves modulation of neuroexcitatory and proinflammatory (TNF-α and IL-1β) and anti-inflammatory (IL-10 and IL-4) cytokines in favor of the former. The second involves post-translational nitration and modification of glia-derived proteins known to be involved in glutamatergic neurotransmission (astrocyte-restricted glutamate transporters and glutamine synthetase). Targeting PN with PN decomposition catalysts (PNDCs) not only blocked the development of paclitaxel-induced neuropathic pain without interfering with antitumor effects, but also reversed it once established. Herein, we describe our mechanistic study on the role(s) of PN and the prevention of neuropathic pain in rats using known PNDCs (FeTMPyP(5+) and MnTE-2-PyP(5+)). We also demonstrate the prevention of CIPN with our two new orally active PNDCs, SRI6 and SRI110. The improved chemical design of SRI6 and SRI110 also affords selectivity for PN over other reactive oxygen species (such as superoxide). Our findings identify PN as a critical determinant of CIPN, while providing the rationale toward development of superoxide-sparing and "PN-targeted" therapeutics.
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http://dx.doi.org/10.1523/JNEUROSCI.6343-11.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752044PMC
May 2012

Exogenous fluorescent tracer agents based on pegylated pyrazine dyes for real-time point-of-care measurement of glomerular filtration rate.

Bioorg Med Chem 2012 Apr 10;20(8):2490-7. Epub 2012 Mar 10.

Covidien Pharmaceuticals, 675 McDonnell Boulevard, Hazelwood, MO 63042, USA.

Novel pyrazine carboxamides bearing hydrophilic poly(ethylene glycol) (PEG) moieties were designed, synthesized, and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, compounds 4d and 5c that contain about 48 ethylene oxide units in the PEG chain exhibited the most favorable physicochemical and renal clearance properties. In vitro studies show that these two compounds have low plasma protein binding, a necessary condition for renal excretion. In vivo animal model results show that 4d and 5c have a higher urine recovery of the injected dose than iothalamate (a commonly considered gold standard GFR agent). Pharmacokinetic studies show that these two compounds exhibit a plasma clearance equivalent to iothalamate, but with a faster (i.e. lower) terminal half-life than iothalamate (possibly from restricted distribution into the extracellular space due to large molecular size and hydrodynamic volume). Furthermore, the plasma clearance of 4d and 5c remained unchanged upon blockage of the tubular secretion pathway with probenecid, a necessary condition for establishment of clearance via glomerular filtration exclusively. Finally, noninvasive real-time monitoring of this class of compounds was demonstrated by pharmacokinetic clearance of 5c by optical measurements in rat model, which correlates strongly with plasma concentration of the tracer. Hence, 4d and 5c are promising candidates for translation to the clinic as exogenous fluorescent tracer agents in real-time point-of-care monitoring of GFR.
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http://dx.doi.org/10.1016/j.bmc.2012.03.015DOI Listing
April 2012

Gastric heterotopia in the proximal oesophagus ("inlet patch"): Association with adenocarcinomas arising in Barrett mucosa.

Dig Liver Dis 2012 Apr 4;44(4):292-6. Epub 2012 Jan 4.

Caris Research Institute, Caris Diagnostics, Irving, TX, USA.

Background: The prevalence of inlet patches and their association with other conditions of the gastrointestinal tract have been studied prospectively in tertiary care facilities; little is known about practice patterns in private outpatient clinics and endoscopy centres.

Aims: To assess prevalence, demographic determinants, and associated clinicopathologic features of inlet patches in patients who had oesophagogastroduodenoscopy in outpatient settings throughout the United States.

Methods: Retrospective analysis of the clinicopathologic records of 487,229 unique patients who had oesophagogastroduodenoscopy with biopsies between January 2008 and December 2010.

Results: There were 870 patients with inlet patches with a prevalence of 0.18%. Significant associations included male gender (OR 1.68), dysphagia (OR 1.34), upper respiratory complaints (OR 2.81), globus (OR 5.39) Barrett oesophagus (OR 1.55), and adenocarcinomas arising in Barrett mucosa (OR 5.64).

Conclusions: The prevalence of inlet patches in a tertiary care setting (0.18%) was considerably lower than reported in prospective studies (3.7% on average). Inlet patches were significantly associated with male gender, dysphagia, upper respiratory complaints, globus, Barrett mucosa, and adenocarcinomas arising in Barrett oesophagus. Further studies will be needed to determine if patients with inlet patches and Barrett mucosa benefit from increased surveillance.
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http://dx.doi.org/10.1016/j.dld.2011.11.008DOI Listing
April 2012

Anti-superoxide and anti-peroxynitrite strategies in pain suppression.

Biochim Biophys Acta 2012 May 19;1822(5):815-21. Epub 2011 Dec 19.

Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Boulevard, St. Louis, MO 63104, USA.

Superoxide (SO, O(2)·(-)) and its reaction product peroxynitrite (PN, ONOO(-)) have been shown to be important in the development of pain of several etiologies. While significant progress has been made in teasing out the relative contribution of SO and PN peripherally, spinally, and supraspinally during the development and maintenance of central sensitization and pain, there is still a considerable void in our understanding. Further research is required in order to develop improved therapeutic strategies for selectively eliminating SO and/or PN. Furthermore, it may be that PN is a more attractive target, in that unlike SO it has no currently known beneficial role. Our group has been at the forefront of research concerning the role of SO and PN in pain, and our current findings have led to the development of two new classes of orally active catalysts which are selective for PN decomposition while sparing SO. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.
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http://dx.doi.org/10.1016/j.bbadis.2011.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478755PMC
May 2012

Retooling manganese(III) porphyrin-based peroxynitrite decomposition catalysts for selectivity and oral activity: a potential new strategy for treating chronic pain.

J Med Chem 2011 Dec 22;54(24):8658-69. Epub 2011 Nov 22.

Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University, Edwardsville, Illinois 62026, United States.

Redox-active metalloporphyrins represent the most well-characterized class of catalysts capable of attenuating oxidative stress in vivo through the direct interception and decomposition of superoxide and peroxynitrite. While many interesting pharmacological probes have emerged from these studies, few catalysts have been developed with pharmaceutical properties in mind. Herein, we describe our efforts to identify new Mn(III)-porphyrin systems with enhanced membrane solubilizing properties. To this end, seven new Mn(III)-tetracyclohexenylporphyin (TCHP) analogues, 7, 10, 12, 15, and 16a-c, have been prepared in which the beta-fused cyclohexenyl rings provide a means to shield the charged metal center from the membrane during passive transport. Compounds 7, 15, and 16a-c have been shown to be orally active and potent analgesics in a model of carrageenan-induced thermal hyperalgesia. In addition, oral administration of compound 7 (10-100 mg/kg, n=5) has been shown to dose dependently reverse mechano-allodynia in the CCI model of chronic neuropathic pain.
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http://dx.doi.org/10.1021/jm201233rDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3240686PMC
December 2011

Influence of nanostructure morphology on host capacity and kinetics of guest release.

Small 2011 Jul 16;7(14):1998-2003. Epub 2011 Jun 16.

Department of Chemistry, Texas A&M University, College Station, TX 77842, USA.

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http://dx.doi.org/10.1002/smll.201100567DOI Listing
July 2011