scholarly journals Dihydroartemisinin Ameliorates Chronic Nonbacterial Prostatitis and Epithelial Cellular Inflammation by Blocking the E2F7/HIF1α Pathway

2021 ◽  
Author(s):  
Yan Zhou ◽  
Jun-hao Wang ◽  
Jian-peng Han ◽  
Jian-yong Feng ◽  
Kuo Guo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Inflammatory Factors ◽  
Protective Effects ◽  
Epithelial Cell Proliferation ◽  
Chronic Nonbacterial Prostatitis ◽  
Cellular Inflammatory Response ◽  
Nonbacterial Prostatitis

Abstract Objective: Chronic nonbacterial prostatitis (CNP) has remained one of the most prevalent urological diseases, particularly in older men. Dihydroartemisinin (DHA) has been identified as a semi-synthetic derivative of artemisinin that exhibits broad protective effects. However, the role of DHA in inhibiting CNP inflammation and prostatic epithelial cell proliferation remains largely unknown. Materials and Methods: CNP mice model was induced by carrageenan and Haemotoxylin Eosin (HE) ,immunofluorescence and immunochemistry staining were used to confirm CNP and E2F7 expression. Human prostatic epithelial cells (HPECs) and RWPE-1 was induced by lipopolysaccharide (LPS) to mimic CNP model in vitro. Real-time quantitative PCR and Western blot were used to detect proliferation and inflammatory genes expression. Cell proliferation was determined using MTT assay.Results: DHA significantly alleviated the rough epithelium and inhibited multilamellar cell formation in the prostatic gland cavity and prostatic index induced by carrageenan. In addition, DHA decreased the expression of TNF-α and IL-6 inflammatory factors in prostatitis tissues and in LPS-induced epithelial cells. Upregulation of transcription factor E2F7, which expression was inhibited by DHA, was found in CNP tissues, human BPH tissues and LPS-induced epithelial cells inflammatory response. Mechanically, we found that depletion of E2F7 by shRNA inhibited epithelial cell proliferation and LPS-induced inflammation while DHA further enhance these effects. Furthermore, HIF1α was transcriptional regulated by E2F7 and involved in E2F7-inhibited CNP and cellular inflammatory response. Interestingly, we found that inhibition of HIF1α blocks E2F7-induced cell inflammatory response but does not obstruct E2F7-promoted cell growth.Conclusion: The results revealed that DHA inhibits the CNP and inflammation by blocking the E2F7/HIF1α pathway. Our findings provide new evidence for the mechanism of DHA and its key role in CNP, which may provide an alternative solution for the prevention and treatment of CNP.

scholarly journals c-Src inactivation reduces renal epithelial cell-matrix adhesion, proliferation, and cyst formation

2011 ◽  
Vol 301 (2) ◽  
pp. C522-C529 ◽  
Author(s):  
Justine Elliott ◽  
Nadezhda N. Zheleznova ◽  
Patricia D. Wilson
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Collecting Duct ◽  
Specific Inhibitor ◽  
Cell Phenotype ◽  
Epithelial Cell Proliferation ◽  
Matrix Adhesion ◽  
Cyst Lining

c-Src is a non-receptor tyrosine kinase whose activity is induced by phosphorylation at Y418 and translocation from the cytoplasm to the cell membrane. Increased activity of c-Src has been associated with cell proliferation, matrix adhesion, motility, and apoptosis in tumors. Immunohistochemistry suggested that activated (pY418)-Src activity is increased in cyst-lining autosomal dominant polycystic kidney disease (ADPKD) epithelial cells in human and mouse ADPKD. Western blot analysis showed that SKI-606 (Wyeth) is a specific inhibitor of pY418-Src without demonstrable effects on epidermal growth factor receptor or ErbB2 activity in renal epithelia. In vitro studies on mouse inner medullary collecting duct (mIMCD) cells and human ADPKD cyst-lining epithelial cells showed that SKI-606 inhibited epithelial cell proliferation over a 24-h time frame. In addition, SKI-606 treatment caused a striking statistically significant decrease in adhesion of mIMCD and human ADPKD to extracellular collagen matrix. Retained viability of unattached cells was consistent with a primary effect on epithelial cell anchorage dependence mediated by the loss of extracellular matrix (ECM)-attachment due to α2β1-integrin function. SKI-606-mediated attenuation of the human ADPKD hyperproliferative and hyper-ECM-adhesive epithelial cell phenotype in vitro was paralleled by retardation of the renal cystic phenotype of Pkd1 orthologous ADPKD heterozygous mice in vivo. This suggests that SKI-606 has dual effects on cystic epithelial cell proliferation and ECM adhesion and may have therapeutic potential for ADPKD patients.

Changes in human bladder epithelial cell gene expression associated with interstitial cystitis or antiproliferative factor treatment

2003 ◽  
Vol 14 (2) ◽  
pp. 107-115 ◽  
Author(s):  
Susan Keay ◽  
Francoise Seillier-Moiseiwitsch ◽  
Chen-Ou Zhang ◽  
Toby C. Chai ◽  
Jialu Zhang
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Interstitial Cystitis ◽  
Expression Patterns ◽  
Epithelial Cell Proliferation ◽  
Normal Cells ◽  
Bladder Epithelial Cell ◽  
Normal Bladder

Explanted bladder epithelial cells from patients with interstitial cystitis (IC) have been shown to differ from explanted control cells in several ways, including production of an antiproliferative factor (APF), altered production of certain epithelial growth factors, and rate of proliferation. To better understand the role of the APF in abnormal bladder epithelial cell proliferation in IC, we studied gene expression patterns in normal bladder epithelial cells treated with APF vs. mock APF and compared them to expression patterns in IC vs. normal cells using microarray analysis. Oligo-dT-primed total cellular RNA was labeled with [33P]dCTP and hybridized to GeneFilter GF211 microarray membranes (Research Genetics) containing cDNA for 3,964 human genes. Thirteen genes that function in epithelial cell proliferation or differentiation were consistently differentially expressed in both IC (compared with control) and APF-treated (compared with mock APF-treated) normal bladder epithelial cells. The general pattern of gene expression in IC and APF-treated cells suggested a less proliferative phenotype, with increased expression of E-cadherin, phosphoribosylpyrophosphate synthetase-associated protein 39, and SWI/SNF complex 170-kDa subunit, and decreased expression of vimentin, α2-integrin, α1-catenin, cyclin D1, and jun N-terminal kinase 1; these findings were confirmed for the structural gene products (E-cadherin, vimentin, α2-integrin, and α-catenin) by immunohistochemistry. These results are compatible with the previously noted decreased proliferation rate of IC and APF-treated normal cells, and indicate that the mechanism whereby APF inhibits cell proliferation may involve both downregulation of genes that stimulate cell proliferation along with upregulation of genes that inhibit cell growth.

Estrogen-dependent responses of the mammary fat pad in prepubertal dairy heifers

2006 ◽  
Vol 190 (3) ◽  
pp. 819-827 ◽  
Author(s):  
M J Meyer ◽  
A V Capuco ◽  
Y R Boisclair ◽  
M E Van Amburgh
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Epithelial Cell Proliferation ◽  
Fat Pad ◽  
Dairy Heifers ◽  
Ovarian Status ◽  
Mammary Fat Pad ◽  
Igf I

Ovaries are absolutely required for development of the mammary parenchyma (PAR) in cattle, reflecting estrogen-dependent epithelial cell proliferation. However, the estrogen receptor (ER) that mediates the mammary estrogen effects, ERα, is absent in proliferating epithelial cells. In the mouse, this discrepancy is explained in part by the ability of the mammary fat pad (MFP) to synthesize epithelial cell mitogens such as IGF-I in response to estrogen. Consistent with a similar role for the bovine MFP, 30% of its fibroblasts and adipocytes were immunoreactive for ERα in prepubertal dairy heifers. To assess estrogen-dependent gene expression in the MFP, 16 prepubertal dairy heifers were randomly assigned to a 2×2 factorial. The first factor was ovarian status, with heifers undergoing bilateral ovariectomy or left intact at 4.6 months of age. The second factor was applied 30 days after surgery and consisted of injection of estrogen or excipient. After 3 days of injection, heifers were administered an intrajugular bolus of bromodeoxyuridine (BrdU) and slaughtered 2 h later. The estrogen injection, but not ovarian status, caused significant increases in the fraction of epithelial cells labeled with BrdU and produced tissue-specific effects on gene expression. In the PAR, estrogen injection increased IGF-I gene expression by twofold despite reductions of 50% or more in ERα mRNA abundance and the fraction of epithelial cells immunoreactive for ERα. The estrogen-dependent increase in IGF-I mRNA was greater in the MFP, presumably because estrogen failed to downregulate ERα expression in this mammary compartment. Finally, estrogen-responsiveness of the MFP appears unique among the bovine fat depots as estrogen injection did not induce IGF-I expression in its s.c. counterpart. Our data demonstrate that the bovine MFP is highly responsive to exogenous estrogen, consistent with a role for this tissue compartment in communicating its effects on epithelial cell proliferation.

412. The role of macrophages in regulating uterine epithelial cell proliferation

2008 ◽  
Vol 20 (9) ◽  
pp. 92
Author(s):  
A. S. Care ◽  
W. V. Ingman ◽  
M. J. Jasper ◽  
SA Robertson
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Diphtheria Toxin ◽  
Functional Markers ◽  
Epithelial Cell Proliferation ◽  
Uterine Epithelial Cells ◽  
Uterine Epithelial Cell ◽  
Macrophage Depletion ◽  
Embryo Attachment

During the oestrous cycle, uterine epithelial cells respond to ovarian steroid hormones by producing an array of cytokines and chemokines that cause macrophage recruitment into the uterus and regulate macrophage activation phenotype. In turn, growth factors and cytokines synthesised by macrophages potentially impact epithelial cell proliferation, secretory function and receptivity to embryo attachment. To investigate the hypothesis that uterine macrophages are essential contributors to the proliferation of uterine epithelial cells, we have used an ovariectomy and steroid replacement model in CD11b-DTR ‘Mac-terminator' mice. These mice are engineered for CD11b promoter-driven expression of the monkey diphtheria toxin (DT) receptor, allowing acute systemic ablation of macrophages by administration of human diphtheria toxin (DT). CD11b-DTR mice were ovariectomised, then 2–4 weeks later were primed with E 2, followed by administration of DT (25 ng/g, ip) to effect macrophage depletion, and BrDU to label proliferating cells. Control mice were given PBS instead of DT. Uterine tissues were stained with F4/80 to detect macrophages, and anti-BrDU to detect BrDU+ epithelial cell nuclei. DT treatment was associated with a depletion of >90% of F4/80+ uterine macrophages. However, the numbers of BrDU+ epithelial cells and the architecture of the luminal epithelial surface and abundance of epithelial glands were similar in control and DT-treated uterine tissues. These data suggest that resident macrophages may not be essential for oestrogen-driven uterine epithelial cell proliferation. In ongoing experiments we are assessing the effect of macrophage depletion on epithelial cell expression of functional markers including those involved in regulation of embryo attachment.

scholarly journals Bronchial epithelial cell growth regulation in fibroblast cocultures: the role of hepatocyte growth factor

2007 ◽  
Vol 293 (1) ◽  
pp. L69-L76 ◽  
Author(s):  
Grzegorz Skibinski ◽  
J. Stuart Elborn ◽  
Madeleine Ennis
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Proliferative Activity ◽  
Neutralizing Antibodies ◽  
Bronchial Epithelial Cell ◽  
Bronchial Epithelial Cells ◽  
Epithelial Cell Proliferation ◽  
Bronchial Epithelial ◽  
Hepatocyte Growth

Proliferation of bronchial epithelial cells is an important biological process in physiological conditions and various lung diseases. The objective of this study was to determine how bronchial fibroblasts influence bronchial epithelial cell proliferation. The proliferative activity in cocultures was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and direct cells counts. Concentration of cytokines was measured in cell culture supernatants by means of ELISA. In primary cell cocultures, fibroblasts or fibroblast-conditioned medium enhanced 1.85-fold the proliferation of primary bronchial epithelial cells ( P < 0.02) compared with bronchial epithelial cells cultured alone. The proliferative activity in cocultures and in fibroblast-conditioned medium was reduced by neutralizing antibody to hepatocyte growth factor (HGF) and HGF receptor c-met. Neutralizing antibodies to FGF-7 and IGF-1 had no effect. Treatment of fibroblast-epithelial cocultures with anti-IL-6 and anti-TNF-α neutralizing antibodies and with indomethacin decreased production of HGF. These results indicate that cytokines and PGE2may indirectly mediate epithelial cell proliferation via the regulation of HGF in bronchial stromal cells and that HGF plays a crucial role in proinflammatory cytokine-induced proliferation in the experimental system studied.

Cysteinyl leukotrienes enhance growth of human airway epithelial cells

1990 ◽  
Vol 259 (4) ◽  
pp. L255-L261 ◽  
Author(s):  
G. D. Leikauf ◽  
H. E. Claesson ◽  
C. A. Doupnik ◽  
S. Hybbinette ◽  
R. C. Grafstrom
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Epithelial Cell Proliferation ◽  
Leukotriene C4 ◽  
Cysteinyl Leukotrienes ◽  
Human Airway ◽  
Human Airway Epithelial Cells

Epithelial inflammation may play an obligatory role in the pathogenesis of a number of chronic pulmonary diseases such as asthma or bronchitis and has been implicated during the promotion phase of multistage carcinogenesis. At sites of inflammation, bioactive lipid mediators are released and activate a wide range of pathophysiological responses including bronchospasm. Previous studies suggest that one class of inflammatory mediators, the eicosanoids, can also influence cell growth. Epithelial cell proliferation and hyperplasia are common sequelae to irritation and inflammation, and because the lung has a high capacity to produce eicosanoids, we investigated the effects of a group of these compounds, the cysteinyl leukotrienes, on growth of human airway epithelial cells. Leukotrienes were found to be mitogenic in a concentration-dependent manner and exhibit a structure-activity relationship, with leukotriene C4 being more potent than its sequential metabolites leukotriene D4 and E4. The potency of leukotriene C4 is striking, stimulating colony-forming efficiency in concentrations as low as 10 fM. These findings suggest a new physiological role for leukotrienes in the lung that links inflammation with epithelial cell proliferation.

scholarly journals SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Hua Geng ◽  
Saravanan Subramanian ◽  
Longtao Wu ◽  
Heng-Fu Bu ◽  
Xiao Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Viral Infection ◽  
Human Lung ◽  
Lung Epithelial Cells ◽  
Lung Epithelial Cell ◽  
Accessory Protein ◽  
Epithelial Cell Proliferation ◽  
Lung Epithelial

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a disease that involves significant lung tissue damage. How SARS-CoV-2 infection leads to lung injury remains elusive. The open reading frame 8 (ORF8) protein of SARS-CoV-2 (ORF8SARS-CoV-2) is a unique accessory protein, yet little is known about its cellular function. We examined the cellular distribution of ORF8SARS-CoV-2 and its role in the regulation of human lung epithelial cell proliferation and antiviral immunity. Using live imaging and immunofluorescent staining analyses, we found that ectopically expressed ORF8SARS-CoV-2 forms aggregates in the cytosol and nuclear compartments of lung epithelial cells. Using in silico bioinformatic analysis, we found that ORF8SARS-CoV-2 possesses an intrinsic aggregation characteristic at its N-terminal residues 1-18. Cell culture did not reveal any effects of ORF8SARS-CoV-2 expression on lung epithelial cell proliferation and cell cycle progression, suggesting that ORF8SARS-CoV-2 aggregates do not affect these cellular processes. Interestingly, ectopic expression of ORF8SARS-CoV-2 in lung epithelial cells suppressed basal expression of several antiviral molecules, including DHX58, ZBP1, MX1, and MX2. In addition, expression of ORF8SARS-CoV-2 attenuated the induction of antiviral molecules by IFNγ but not by IFNβ in lung epithelial cells. Taken together, ORF8SARS-CoV-2 is a unique viral accessory protein that forms aggregates when expressing in lung epithelial cells. It potently inhibits the expression of lung cellular anti-viral proteins at baseline and in response to IFNγ in lung epithelial cells, which may facilitate SARS-CoV-2 escape from the host antiviral innate immune response during early viral infection. In addition, it seems that formation of ORF8SARS-CoV-2 aggregate is independent from the viral infection. Thus, it would be interesting to examine whether any COVID-19 patients exhibit persistent ORF8 SARS-CoV-2 expression after recovering from SARS-CoV-2 infection. If so, the pathogenic effect of prolonged ORF8SARS-CoV-2 expression and its association with post-COVID symptoms warrant investigation in the future.

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