Sergei A Grando

University of California, Irvine, Irvine, California, United States

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Publications (151)577.19 Total impact

  • BMC Cancer 12/2015; 15(1). DOI:10.1186/s12885-015-1158-4 · 3.32 Impact Factor
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    ABSTRACT: Recent research has demonstrated that the nicotinergic signaling network of mammary epithelium can both mediate the physiological control of normal breast epithelial cells (BECs) and exhibit tumor-promoting effects on malignant BECs. Therefore, mammary nicotinic acetylcholine (ACh) receptors (nAChRs) may become a specific target for novel anti-breast cancer therapies. Toward this goal, we investigated the difference in the ACh receptor repertoires between normal and malignant BECs, determined effects of nicotinic ligands on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-dependent activation of ERK1/2 and tumorigenic transformation of MCF10A cells, and characterized reciprocal effects of NNK and SLURP (secreted mammalian Ly-6/urokinase plasminogen activator receptor related protein-1)-1 on the expression of nAChR subunits and several oncogenes and tumor-suppressing genes in BECs. Both the non-malignant MCF10A and malignant MCF7 breast cells expressed α3, α5, α7, α9, α10, β1, β2, γ, δ and ε nAChR subunits and M1, M3, M4 and M5 muscarinic receptor subtypes. The malignancy was associated with expression of α1, α4 and β4 nAChR subunits and M2 subtype. Malignant transformation of BECs was also associated with overexpression of α7-, and α9-made nAChRs. NNK upregulated ERK1/2 phosphorylation, stimulated expression of the gene encoding the tumor-promoter HGF, downregulated expression of the tumor suppressor gene CDKN2A, and induced tumorigenic transformation of MCF10A cells. Compared to the canonical nAChR antagonists, SLURP-1 showed the highest ability to abolish the nAChR-mediated effects of NNK in both cell-signaling and cell-transformation assays and reversed many effects of NNK on gene expression. SLURP-1 also markedly upregulated the tumor suppressor genes CDKN2B, RUNX3 and TP73. Altogether, the obtained results provided new insight into the molecular mechanisms of nAChR-mediated oncogenic effects of NNK on BECs and demonstrated the ability to abolish or reverse these effects by SLURP-1.
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    ABSTRACT: Corneal epithelial erosion is one of the most common problems in clinical ophthalmology. Despite significant progress in understanding how the cornea heals, clinically available pharmacological therapies that can promote repair and prevent visual complications remain limited. We have recently demonstrated that the acetylcholine (ACh) axis of corneal epithelium plays an important role in regulation and coordination of distinct activities of corneal epithelial cells (CEC) mediating re-epithelialization, but mechanisms remained unclear. We hypothesized that the grounds for synergistic effects of corneal ACh receptors lie within the signaling pathways linking different receptors to specific elements of the CEC pro-epithelialization activities. In this study, we sought to elucidate the molecular mechanisms of cooperation of corneal muscarinic and nicotinic ACh receptors (mAChRs and nAChRs) in upregulation of E-cadherin expression. The roles of individual corneal mAChRs and nAChRs subtypes were investigated by in-cell western assay of the ACh-treated CEC, in which different ACh receptor genes were silenced by receptor-specific shRNAs. Functional inactivation of M3, but not M4, mAChR subtype, or α3 or α7, but not α9, nAChR subunit significantly inhibited E-cadherin expression. To gain a mechanistic insight, we blocked the key steps of the downstream signaling pathways. Results demonstrated that cholinergic agonists can upregulate E-cadherin expression by activating M3 mAChR, and α3β2 and α7 nAChRs via the common signaling cascade Ca(2+)-CaMKII-PKC-Ras-Raf-MEK-ERK. Activation of α7 nAChR can launch the Ras-Raf-MEK-ERK cascade both indirectly, through the Ca(2+)-CaMKII-PKC step, and directly, perhaps, due to its direct interaction with Ras. Although the biological significance of such redundancy remained to be elucidated, results of the present study point to a new direction to pharmacologically accelerate corneal re-epithelialization, and should have salient clinical implication. Copyright © 2015 Elsevier B.V. All rights reserved.
    International immunopharmacology 05/2015; DOI:10.1016/j.intimp.2015.04.036 · 2.71 Impact Factor
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    ABSTRACT: Immunobullous diseases mediated by IgA are often difficult to manage, but to date no mechanism has been proposed. Rituximab is an anti-CD20 monoclonal antibody that has demonstrated good efficacy in the treatment of refractory mucous membrane pemphigoid. However, not all cases of mucous membrane pemphigoid respond to rituximab. Herein we present a case of treatment-refractory mucous membrane pemphigoid and propose a mechanism to explain the lack of response to therapy. Before treatment, direct immunofluorescent examination of a biopsy sample from the patient's perilesional skin demonstrated linear deposition of IgG and IgA along the dermoepidermal junction. After a multidrug immunosuppressive regimen that included rituximab, results of a second biopsy demonstrated only IgA along the dermoepidermal junction. This finding correlated well with flow cytometry data from the same patient that demonstrated a persistent population of IgA-secreting plasmablasts/plasma cells, despite depletion of CD20+ cells. In addition, results of immunohistochemical analysis of the perilesional skin remained positive for CD19 and CD138 immune cells (plasmablast/plasma cell markers). These findings suggest that current available immunosuppressive medications, including rituximab, cannot eliminate IgA-secreting plasmablasts/plasma cells, which are likely central to the pathophysiology of IgA-mediated immunobullous diseases. Future studies are needed to develop alternative therapeutic strategies that target autoreactive IgA-secreting plasmablasts/plasma cells.
    04/2015; DOI:10.1001/jamadermatol.2015.59
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    ABSTRACT: Cutaneous lupus erythematosus (CLE) is a chronic inflammatory autoimmune skin disease. Evidence-based therapy for CLE is lacking in the most part. Intravenous immunoglobulin (IVIg) is being increasingly utilized as off-label therapy for a variety of autoimmune and inflammatory conditions, especially in dermatology. The usefulness of IVIg in CLE is not well established. The goal of the present study was to obtain the proof-of-concept evidence that IVIg can control acute CLE and thus replace current systemic immunosuppressive therapy that causes severe side effects and adverse reactions. Sixteen patients who tried and failed various systemic treatments for CLE were screened and consented to use IVIg as a monotherapy. The IVIg was administered at 500 mg/kg/day on 4 consecutive days up to a total of 2 g/kg/month for 3 months, and the subjects were monitored for additional 6 months off any drug for a possible relapse. The cumulative results revealed an overall improvement, as evinced by a decrease of both objective and subjective measures of disease activity. The most sensitive and specific objective and subjective instruments for assessment of the therapeutic effect of IVIg were CLASI-A (Cutaneous Lupus Erythematosus Disease Area and Severity Index) measuring disease activity and Skindex-29 scores, respectively. The CLASI-A score dropped down from the initial value taken as 100%, and remained in the range of approximately 70% until the last visit. Three patients (18.8%) had a temporary flare of CLE symptoms but recovered within a month from the relapse. No serious side effects and adverse reactions occurred. Thus, IVIg monotherapy in CLE allowed to achieve: i) rapid and persistent decreased in disease activity; ii) steady improvement of patients' quality of life assessed by Skindex-29; iii) low relapse rate; and iv) mild nature and short duration of relapses. Since healing was maintained for months after IVIg treatment, it is possible that the IVIgtriggered molecular events mediating the therapeutic action of IVIg that continued to unfold after the end of therapy.
    03/2015; 7(1):5804. DOI:10.4081/dr.2015.5804
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    ABSTRACT: To determine the efficacy and safety of interventions for pemphigus vulgaris (PV). We conducted a systematic review from 2003 to 2013 according to the Cochrane Collaboration methodology. Randomized controlled trials (RCTs) or controlled clinical trials (CCTs) and observational studies were conducted along with diagnosis confirmed by clinical, histopathologic, and immunofluorescence criteria. Primary outcomes were disease remission and mortality; several relevant secondary outcomes were also included. Fourteen RCTs or CCTs and 110 observational studies were included in the final analyses. RCTs or CCTs demonstrated considerable heterogeneity in outcome measures, and all had a high risk of bias for at least 1 of 8 domains. Of the studies, 96.8% (120) described the use of oral corticosteroids. Azathioprine and mycophenolate-mofetil were the most commonly cited treatments. An increasing number of studies described biologic therapies (rituximab, intravenous immunoglobulin [IVIg]). Evidence supporting recent comprehensive treatment guidelines was reviewed. We found persisting wide variations in treatment practice and inadequate quality of research supporting optimal PV treatment. Copyright © 2015 Elsevier Inc. All rights reserved.
    Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 03/2015; DOI:10.1016/j.oooo.2015.01.022 · 1.46 Impact Factor
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    ABSTRACT: To determine the efficacy and safety of interventions for mucous membrane pemphigoid (MMP). We conducted a systematic review from 2003 to 2013 according to the Cochrane Collaboration methodology. Randomized controlled trials (RCTs) or controlled clinical trials and observational studies were included, with diagnosis confirmed by clinical, histopathologic, and immunofluorescence criteria. The primary outcome was lesion remission or healing; several relevant secondary outcomes were also included. In the final analysis, 1 RCT and 32 observational studies were included. The one included RCT with a high risk of bias in multiple domains found limited evidence that pentoxifylline, combined with corticosteroid and cyclophosphamide, was more effective than standard therapy (corticosteroid + cyclophosphamide alone) for ocular MMP. We summarize here the outcomes from 32 observational studies examining 242 patients across 19 unique treatments. Interventions that show promise include rituximab and intravenous immunoglobulin. This systematic review is the most recent since 2003-2009. There is still lack of high-quality research providing evidence-based MMP treatments. Copyright © 2015 Elsevier Inc. All rights reserved.
    03/2015; DOI:10.1016/j.oooo.2015.01.024
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    ABSTRACT: Purpose: Since cholinergic drugs are used in ophthalmology and since cholinergic stimulation has been shown to facilitate epithelialization of mucocutaneous wounds, we performed a systematic analysis of components of the cholinergic network of human and murine corneal epithelial cells (CEC) and determined the role of autocrine and paracrine acetylcholine (ACh) in regulation of CEC motility. Methods: We investigated the expression of ACh receptors at the mRNA and proteins levels in human immortalized CEC, localization of cholinergic molecules in normal and wounded murine cornea, and the effects of cholinergic drugs on CEC directional and random migration in vitro, intercellular adhesion and expression of integrin αV and E-cadherin. Results: We demonstrated that corneal epithelium expresses the ACh synthesizing enzyme choline acetyltransferase, the ACh-degrading enzyme acetylcholinesterase, two muscarinic ACh receptors (mAChRs), M3 and M4, and several nicotinic ACh receptors (nAChRs), including both α7- and α9-made homomeric nAChRs and predominantly the α3β2±α5 subtype of heteromeric nAChRs. Wounding affected the expression patterns of cholinergic molecules in the murine corneal epithelium. Constant stimulation of CEC through both muscarinic and nicotinic signaling pathways was essential for CEC survival and both directional and random migration in vitro. Both α7 and non-α7 nAChRs elicited chemotaxis, with the α7 signaling exhibiting a stronger chemotactic effect. Cholinergic stimulation of CEC upregulated expression of the integrin and cadherin molecules involved in epithelialization. We found synergy between the pro-epithelialization signals elicited by different ACh receptors expressed in CEC. Conclusions: Simultaneous stimulation of mAChRs and nAChRs by ACh may be required to synchronize and balance ionic and metabolic events in a single cell.
    Investigative Ophthalmology &amp Visual Science 09/2014; 55(10). DOI:10.1167/iovs.14-14667 · 3.66 Impact Factor
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    ABSTRACT: Abstract: Elevated levels of histone deacetylases (HDACs) have been indicated in the development of some cancers. HDAC has been imaged using 18F-FAHA and may serve as a marker to study epigenetics. We report evaluation of 18F-FAHA as a probe in the early diagnosis of lung cancer using 18F-FAHA PET/CT studies of A/J mice treated with NNK. 18F-FAHA radiosynthesis was carried out in specific activity of ~2 Ci/μmol. A/J mice were divided into 2 groups: 1. Controls; 2. NNK treatment group with NNK (100 mg/kg, ip, weekly for 4 wks). Mice were injected 100-200 μCi i.v. 18F-FAHA and then scanned in Inveon PET/CT under anesthesia using 2.0% isoflurane. Midbrain, cerebellum and brainstem uptake of 18F-FAHA was displaced by the known HDAC inhibitor, suberanilohydroxamic acid (SAHA) with less than 10% activity remaining. CT revealed presence of lung nodules in 8 to 10-month old NNK mice while control mice were free of tumors. Little uptake of 18F-FAHA was observed in the control mice lungs while significant 18F-FAHA uptake occurred in the lungs of NNK-treated mice with tumor/nontumor >2.0. Ex vivo scans of the excised NNK and control mice lungs confirmed presence of extensive amounts of lung nodules seen by CT and confirmed by 18F-FAHA in the NNK mice with tumor/nontumor >6.0. Our preliminary imaging studies with A/J mice lung cancer model suggest 18F-FAHA PET may allow the study of epigenetic mechanisms involved in NNK-induced tumorigenesis in the lungs.
    American Journal of Nuclear Medicine and Molecular Imaging 06/2014; 4(4):324-332. · 3.25 Impact Factor
  • Sergei A Grando
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    ABSTRACT: This Opinion article discusses emerging evidence of direct contributions of nicotine to cancer onset and growth. The list of cancers reportedly connected to nicotine is expanding and presently includes small-cell and non-small-cell lung carcinomas, as well as head and neck, gastric, pancreatic, gallbladder, liver, colon, breast, cervical, urinary bladder and kidney cancers. The mutagenic and tumour-promoting activities of nicotine may result from its ability to damage the genome, disrupt cellular metabolic processes, and facilitate growth and spreading of transformed cells. The nicotinic acetylcholine receptors (nAChRs), which are activated by nicotine, can activate several signalling pathways that can have tumorigenic effects, and these receptors might be able to be targeted for cancer therapy or prevention. There is also growing evidence that the unique genetic makeup of an individual, such as polymorphisms in genes encoding nAChR subunits, might influence the susceptibility of that individual to the pathobiological effects of nicotine. The emerging knowledge about the carcinogenic mechanisms of nicotine action should be considered during the evaluation of regulations on nicotine product manufacturing, distribution and marketing.
    Nature Reviews Cancer 05/2014; DOI:10.1038/nrc3725 · 29.54 Impact Factor
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    ABSTRACT: A search for novel and more efficient therapeutic modalities of inflammatory bowel disease (IBD) is one of the most important tasks of contemporary medicine. The anti-inflammatory action of nicotine in IBD might be therapeutic, but its toxicity due to off-target and nonreceptor effects limited its use and prompted a search for nontoxic nicotinergic drugs. We tested the hypothesis that SLURP-1 and -2-the physiological nicotinergic substances produced by the human intestinal epithelial cells (IEC) and immunocytes-can mimic the anti-inflammatory effects of nicotine. We used human CCL-241 enterocytes, CCL-248 colonocytes, CCRF-CEM T-cells, and U937 macrophages. SLURP-1 diminished the TLR9-dependent secretion of IL-8 by CCL-241, and IFN γ -induced upregulation of ICAM-1 in both IEC types. rSLURP-2 inhibited IL-1 β -induced secretion of IL-6 and TLR4- and TLR9-dependent induction of CXCL10 and IL-8, respectively, in CCL-241. rSLURP-1 decreased production of TNF α by T-cells, downregulated IL-1 β and IL-6 secretion by macrophages, and moderately upregulated IL-10 production by both types of immunocytes. SLURP-2 downregulated TNF α and IFN γ R in T-cells and reduced IL-6 production by macrophages. Combining both SLURPs amplified their anti-inflammatory effects. Learning the pharmacology of SLURP-1 and -2 actions on enterocytes, colonocytes, T cells, and macrophages may help develop novel effective treatments of IBD.
    BioMed Research International 05/2014; 2014:609086. DOI:10.1155/2014/609086 · 2.71 Impact Factor
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    ABSTRACT: Grover's disease (GD) is a transient or persistent, monomorphous, papulovesicular, asymptomatic or pruritic eruption classified as non-familial acantholytic disorder. Contribution of autoimmune mechanisms to GD pathogenesis remains controversial. The purpose of this study was to investigate antibody-mediated autoimmunity in 11 patients with GD, 4 of which were positive for IgA and/or IgG anti-keratinocyte antibodies by indirect immunofluorescence. We used the most sensitive proteomic technique for an unbiased analysis of IgA- and IgG-autoantibody reactivities. Multiplex analysis of autoantibody responses revealed autoreactivity of all 11 GD patients with cellular proteins involved in the signal transduction events regulating cell development, activation, growth, death, adhesion and motility. Semi-quantitative fluorescence analysis of cultured keratinocytes pretreated with sera from each patient demonstrated decreased intensity of staining for desmoglein 1 and/or 3 and PCNA, whereas 4 of 10 GD sera induced BAD expression, indicating that binding of autoantibodies to keratinocytes alters expression/function of their adhesion molecules and activates apoptosis. We also tested the ability of GD sera to induce visible alterations of keratinocyte shape and motility in vitro but found no specific changes. Thus, our results demonstated that humoral autoimmunity in GD can be mediated by both IgA and IgG autoantibodies. At this point, however, it is impossible to conclude whether these autoantibodies cause or are caused by the disease. Anti-desmoglein antibodies may be triggered by exposure to immune system of sequestered antigens due to disintegration of desmosomes during primary acantholysis. Clarifying etiology of GD will help improve treatment, which currently is symptomatic and of marginal effectiveness. This article is protected by copyright. All rights reserved.
    Experimental Dermatology 10/2013; 22(12). DOI:10.1111/exd.12266 · 4.12 Impact Factor
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    ABSTRACT: Development of novel methods of early diagnosis of lung cancer is one of the major tasks of contemporary clinical and experimental oncology. In this study, we utilized the tobacco nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung cancer in A/J mice as an animal model for development of a new imaging technique for early diagnosis of lung cancer. Lung cancer cells in A/J mice overexpress nicotinic acetylcholine receptors. Longitudinal CT scans were carried out over a period of 8 months after NNK treatment, followed by PET/CT scans with 18F-Nifene that binds to α4-made nicotinic receptors with high affinity. PET/CT scans of lungs were also obtained ex vivo. CT revealed the presence of lung nodules in 8-month NNK-treated mice, while control mice had no tumors. Imaging of live animals prior to necropsy allowed correlation of results of tumor load via PET/CT and histopathological findings. Significant amount of 18F-Nifene was seen in the lungs of NNK-treated mice, whereas lungs of control mice showed only minor uptake of 18F-Nifene. Quantitative analysis of the extent and amount of 18F-Nifene binding in lung in vivo and ex vivo demonstrated a higher tumor/nontumor ratio due to selective labeling of tumor nodules expressing abundant α4 nicotinic receptor subunits. For comparison, we performed PET/CT studies with 18F-FDG, which is used for the imaging diagnosis of lung cancer. The tumor/nontumor ratios for 18F-FDG were lower than for 18F-Nifene. Thus, we have developed a novel diagnostic imaging approach to early diagnosis of lung cancer using 18F-Nifene PET/CT. This technique allows quantitative assessment of lung tumors in live mice, which is critical for establishing tumor size and location, and also has salient clinical implications.
    06/2013; 1(4):128-137. DOI:10.14312/2052-4994.2013-20
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    ABSTRACT: The development of non-hormonal treatment of pemphigus vulgaris (PV) has been hampered by a lack of clear understanding of the mechanisms leading to keratinocyte (KC) detachment and death in pemphigus. In this study, we sought to identify changes in the vital mitochondrial functions in KCs treated with the sera from PV patients and healthy donors. PV sera significantly increased proton leakage from KCs, suggesting that PV IgGs increase production of reactive oxygen species (ROS). Indeed, measurement of intracellular ROS production showed a drastic increase of cell staining in response to treatment by PV sera, which was confirmed by FACS analysis. Exposure of KCs to PV sera also caused dramatic changes in the mitochondrial membrane potential detected with the JC-1 dye. These changes can trigger the mitochondria-mediated intrinsic apoptosis. While sera from different PV patients elicited unique patterns of mitochondrial damage, the mitochondria-protecting drugs nicotinamide, minocycline and cyclosporine A exhibited a uniform protective effect. Their therapeutic activity was validated in the passive transfer model of PV in neonatal BALB/c mice. The highest efficacy of mitochondrial protection of the combination of these drugs found in mitochondrial assay was consistent with the ability of the same drug combination to abolish acantholysis in mouse skin. These findings provide a theoretical background for clinical reports of the efficacy of mitochondria-protecting drugs in PV patients. Pharmacological protection of mitochondria and/or compensation of an altered mitochondrial function may therefore become a novel approach to development of personalized non-hormonal therapies of patients with this potentially lethal autoimmune blistering disease.
    Journal of Biological Chemistry 04/2013; DOI:10.1074/jbc.M113.472100 · 4.60 Impact Factor
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    ABSTRACT: Pemphigus vulgaris (PV) is a mucocutaneous blistering disease characterized by IgG autoantibodies against the stratified squamous epithelium. Current understanding of PV pathophysiology does not explain the mechanism of acantholysis in patients lacking desmoglein antibodies, which justifies a search for novel targets of pemphigus autoimmunity. We tested 264 pemphigus and 138 normal control sera on the multiplexed protein array platform containing 701 human genes encompassing many known keratinocyte cell-surface molecules and members of protein families targeted by organ-non-specific PV antibodies. The top 10 antigens recognized by the majority of test patients' sera were proteins encoded by the DSC1, DSC3, ATP2C1, PKP3, CHRM3, COL21A1, ANXA8L1, CD88 and CHRNE genes. The most common combinations of target antigens included at least one of the adhesion molecules DSC1, DSC3 or PKP3 and/or the acetylcholine receptor CHRM3 or CHRNE with or without the MHC class II antigen DRA. To identify the PV antibodies most specific to the disease process, we sorted the data based on the ratio of patient to control frequencies of antigen recognition. The frequency of antigen recognition by patients that exceeded that of control by 10 and more times were the molecules encoded by the CD33, GP1BA, CHRND, SLC36A4, CD1B, CD32, CDH8, CDH9, PMP22 and HLA-E genes as well as mitochondrial proteins encoded by the NDUFS1, CYB5B, SOD2, PDHA1 and FH genes. The highest specificity to PV showed combinations of autoantibodies to the calcium pump encoded by ATP2C1 with C5a receptor plus DSC1 or DSC3 or HLA-DRA. The results identified new targets of pemphigus autoimmunity. Novel autoantibody signatures may help explain individual variations in disease severity and treatment response, and serve as sensitive and specific biomarkers for new diagnostic assays in PV patients.
    PLoS ONE 03/2013; 8(3):e57587. DOI:10.1371/journal.pone.0057587 · 3.53 Impact Factor
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    ABSTRACT: There is increasing evidence that serotonin (5-hydroxytryptamine [5-HT]) and distinct 5-HT receptors are involved in the pathogenesis of systemic sclerosis. The aim of this study was to test the hypothesis that tropisetron, a routinely used antiemetic agent previously characterized as a 5-HT(3/4) receptor-modulating agent, can directly affect collagen synthesis in vitro and attenuate experimentally induced fibrosis in vivo. Functional in vitro studies were performed using human dermal fibroblasts (HDFs). Signal transduction studies included immunofluorescence analysis, Western immunoblotting, promoter reporter assays, cAMP/Ca(2+) measurements, and use of pharmacologic activators and inhibitors. Gene silencing was performed using small interfering RNA. Putative receptors of tropisetron were detected by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. The murine model of bleomycin-induced scleroderma was used to assess the antifibrogenic and antifibrotic effects of tropisetron in vivo. Collagen expression in vitro, ex vivo, and in situ was determined by real-time RT-PCR analysis, Western immunoblotting, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and immunohistochemical analysis. Tropisetron suppressed collagen synthesis induced by transforming growth factor β1 (TGFβ1). This effect was independent of 5-HT(3/4) receptor but was mediated via α7 nicotinic acetylcholine receptor (α7nAChR). Suppression of TGFβ1-induced collagen synthesis occurred via an unknown molecular mechanism not involving modulation of the Smad, cAMP, Akt, c-Jun, or MAPK pathway. In vivo, tropisetron not only prevented skin fibrosis but also reduced the collagen content in established dermal fibrosis induced by bleomycin. Tropisetron directly reduces collagen synthesis in HDFs via an α7nAChR-dependent mechanism. The antifibrogenic and antifibrotic effects of this agent observed in a mouse model of bleomycin- induced scleroderma indicate the future potential of tropisetron in the treatment of fibrotic diseases such as scleroderma.
    Arthritis & Rheumatology 03/2013; 65(3):792-804. DOI:10.1002/art.37809 · 7.87 Impact Factor
  • Life sciences 11/2012; 91(21-22):969-72. DOI:10.1016/j.lfs.2012.10.004 · 2.30 Impact Factor
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    ABSTRACT: The nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), an important carcinogen found in tobacco products, causes lung cancer in genetically susceptible animals. In addition to mutations of the K-Ras gene, NNK has non-mutagenic effects that include alterations in gene expression and immunomodulation in the lung. Here we report the identification of two gene sets associated with NNK-induced pulmonary tumourigenesis. First, to identify genes involved in the susceptibility to NNK, we compared the lung transcriptomes of NNK-resistant C3H mice with that of the NNK-susceptible A/J mice, identifying differential expression of genes related to innate immunity and inflammation. Second, to identify gene expression induced by NNK, we compared the lung transcriptomes of C3H and A/J mice post-treatment. The Resistin-like alpha (Retnla) gene was highly upregulated in response to NNK only in susceptible mice. This gene product is known to recruit immune cells to the lung, and accumulation of CD45 positive cells in A/J lungs correlated with increased Retnla expression. Genetic susceptibility to NNK-induced lung tumourigenesis may relate in part to gene expression changes and alterations in the immune response to create a pro-tumourigenic environment, acting in concert with NNK's mutagenic effects.
    European journal of cancer (Oxford, England: 1990) 09/2012; 49(3). DOI:10.1016/j.ejca.2012.08.027 · 4.82 Impact Factor
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    ABSTRACT: Restoration of epidermal barrier (epithelialization), is a major component of cutaneous response to stress imposed by wounding. Learning physiologic regulation of epithelialization may lead to novel treatments of chronic wounds. The non-canonical ligands of nicotinic acetylcholine receptors SLURP (secreted mammalian Ly-6/urokinase-type plasminogen activator receptor-related proteins)-1 and -2 are produced by keratinocytes (KCs) and inflammatory cells to augment physiologic responses to non-neuronal acetylcholine, suggesting that they can affect wound epithelialization and inflammation. In this study, recombinant (r)SLURP-1 and -2 exhibited dose dependent effects on migration of cultured KCs, and monoclonal antibodies inactivating auto/paracrine SLURPs in mouse skin delayed wound epithelialization. While effects of rSLURPs on migration were opposite, with rSLURP-1 inhibiting and rSLURP-2 stimulating migration of KCs, each anti-SLURP antibody produced a negative effect on epithelialization in vivo suggesting their more extensive than regulation of keratinocyte migration involvement in wound repair. Since inflammation plays an important role in stress response to wounding, we measured inflammation biomarkers in wounds treated with anti-SLURP antibodies. Both anti-SLURP-1 and -2 antibodies, or their mixture, caused significant elevation of wound myeloperoxidase, IL-1β, IL-6 and TNFα. Taken together, results of this study demonstrated that SLURP-1 slows crawling locomotion of KCs, and exhibits a strong anti-inflammatory activity in wound tissue. In contrast, SLURP-2 facilitates lateral migration of KCs, but shows a lesser anti-inflammatory capacity. Thus, combined biologic activities of both SLURPs may be required for normal stress response to skin wounding, which favors clinical trial of rSLURP-1 and -2 in wounds that fail to heal.
    07/2012; 4(3):324-30. DOI:10.4161/derm.22594
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    ABSTRACT: AIMS: To evaluate the pathobiologic effects of long-term treatment with nicotine of A/J mice susceptible to tobacco-induced lung carcinogenesis. MAIN METHODS: Experimental group of mice received subcutaneous injections of the LD(50) dose of (-)nicotine hydrogen tartrate of 3mg/kg/day, 5days per week for 24months, and control group received the vehicle phosphate-buffered saline. KEY FINDINGS: Nicotine treated mice, 78.6%, but none of control of mice, developed neoplasms originating from the uterus or skeletal muscle. Examination of the uterine neoplasms revealed leiomyosarcomas, composed of whorled bundles of smooth-muscle like cells with large and hyperchromatic nuclei. Sections of the thigh neoplasms revealed densely cellular tumors composed of plump spindle cells, with occasional formation of 'strap' cells, containing distorted striations. Both neoplasms were positive for desmin staining. A solitary pulmonary adenoma with papillary architecture also occurred in one nicotine treated mouse. Experimental mice also developed transient balding starting as small patches of alopecia that progressed to distinct circumscribed areas of complete hair loss or large areas of diffuse hair loss. SIGNIFICANCE: We demonstrate for the first time that chronic nicotine treatment can induce the development of muscle sarcomas as well as transient hair loss. These findings may help explain the association of childhood rhabdomyosarcoma with parental smoking and earlier onset of balding in smokers. It remains to be determined whether the pathobiologic effects of nicotine result from its receptor-mediated action and/or its tissue metabolites cotinine and N'-nitrosonornicotine, or toxic effects of reactive oxygen species activated due to possible intracellular accumulation of nicotine.
    Life sciences 04/2012; DOI:10.1016/j.lfs.2012.03.041 · 2.30 Impact Factor

Publication Stats

5k Citations
577.19 Total Impact Points

Institutions

  • 2007–2015
    • University of California, Irvine
      • • Department of Dermatology
      • • Cancer Research Institute
      • • Institute for Immunology
      Irvine, California, United States
    • CSU Mentor
      Long Beach, California, United States
  • 1997–2008
    • University of California, Davis
      • • Department of Dermatology
      • • Center for Health and the Environment (CHE)
      Davis, CA, United States
  • 2006
    • Universität Heidelberg
      • Department of Dermatology, Venereology and Allergology
      Heidelburg, Baden-Württemberg, Germany
  • 2003–2005
    • Baylor College of Medicine
      • Department of Molecular & Human Genetics
      Houston, Texas, United States
  • 1994–1996
    • University of Minnesota Duluth
      • Department of Chemistry and Biochemistry
      Duluth, Minnesota, United States