Vasoactive intestinal peptide prevents PKCε-induced intestinal epithelial barrier disruption during EPEC infection

2015 ◽  
Vol 308 (5) ◽  
pp. G389-G402 ◽  
Author(s):  
V. Morampudi ◽  
V. S. Conlin ◽  
U. Dalwadi ◽  
X. Wu ◽  
K. C. Marshall ◽  
...  
Keyword(s):  
Vasoactive Intestinal Peptide ◽  
Critical Role ◽  
Term Treatment ◽  
Epithelial Barrier ◽  
Protective Effects ◽  
Short Term Treatment ◽  
Barrier Integrity ◽  
Barrier Disruption ◽  
Long Term Treatment

We previously showed that vasoactive intestinal peptide (VIP) protects against bacterial pathogen-induced epithelial barrier disruption and colitis, although the mechanisms remain poorly defined. The aim of the current study was to identify cellular pathways of VIP-mediated protection with use of pharmacological inhibitors during enteropathogenic Escherichia coli (EPEC) infection of Caco-2 cell monolayers and during Citrobacter rodentium-induced colitis. EPEC-induced epithelial barrier disruption involved the PKC pathway but was independent of functional cAMP, Rho, and NF-κB pathways. VIP mediated its protective effects by inhibiting EPEC-induced PKC activity and increasing expression of the junctional protein claudin-4. Short-term treatment with TPA, which is known to activate PKC, was inhibited by VIP pretreatment, while PKC degradation via long-term treatment with TPA mimicked the protective actions of VIP. Immunostaining for specific PKC isotypes showed upregulated expression of PKCθ and PKCε during EPEC infection. Treatment with specific inhibitors revealed a critical role for PKCε in EPEC-induced barrier disruption. Furthermore, activation of PKCε and loss of barrier integrity correlated with claudin-4 degradation. In contrast, inhibition of PKCε by VIP pretreatment or the PKCε inhibitor maintained membrane-bound claudin-4 levels, along with barrier function. Finally, in vivo treatment with the PKCε inhibitor protected mice from C. rodentium-induced colitis. In conclusion, EPEC infection increases intracellular PKCε levels, leading to decreased claudin-4 levels and compromising epithelial barrier integrity. VIP inhibits PKCε activation, thereby attenuating EPEC-induced barrier disruption.

In vivo administration of a GnRH antagonist to male mice: effects on pituitary gonadotropin secretion in vitro

1989 ◽  
Vol 120 (3) ◽  
pp. 308-314
Author(s):  
A. M. Ultee-van Gessel ◽  
G.J. van Steenbrugge ◽  
F. G. Leemborg ◽  
F. H. Schroeder ◽  
F. H. de Jong
Keyword(s):  
Gnrh Antagonist ◽  
Term Treatment ◽  
Plasma Testosterone ◽  
High Dose ◽  
Male Mice ◽  
Short Term Treatment ◽  
Gonadotropin Secretion ◽  
Long Term Treatment

Abstract. The potent luteinizing hormone-releasing hormone antagonist [N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]GnRH (4 mg/kg) was administered sc once or daily for 21 days to immune-deficient (nude) and normal immune-competent (NIC) male mice derived from the same genetic background. Effects of in vivo pretreatment with the antagonist on gonadotropin secretion from hemipituitary glands from both types of mice were studied in vitro in the presence or absence of synthetic GnRH. Treatment with the GnRH antagonist caused differential effects on release of FSH and LH from and amounts of FSH and LH in hemipituitary glands. Pituitary FSH secretion was effectively inhibited, whereas effects on pituitary LH were less evident or nonsignificant under these experimental conditions. Long-term treatment with the antagonist caused larger effects on pituitary secretion and content of FSH, when compared with short-term treatment. No significant effects of duration of treatment on secretion or pituitary content of LH were detected. Addition of synthetic GnRH to the incubation medium caused stimulation of gonadotropin release. Therefore, it was concluded that the high doses of this GnRH antagonist were not able to block GnRH receptors effectively in the pituitary glands of nude and NIC male mice. The incomplete suppression of LH secretion by this high dose of the GnRH antagonist may partly explain the inability of the antagonist to suppress plasma testosterone levels and the growth of androgen-dependent tumours in male mice.

scholarly journals Effects of Gintonin-Enriched Fraction on Methylmercury-Induced Neurotoxicity and Organ Methylmercury Elimination

2020 ◽  
Vol 17 (3) ◽  
pp. 838
Author(s):  
Hyeon-Joong Kim ◽  
Sun-Hye Choi ◽  
Na-Eun Lee ◽  
Hee-Jung Cho ◽  
Hyewhon Rhim ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Neural Progenitor Cells ◽  
Term Treatment ◽  
Dependent Manner ◽  
Protective Effects ◽  
Independent Manner ◽  
Long Term Treatment ◽  
Liver And Kidney

Gintonin is a newly discovered ingredient of ginseng and plays an exogenous ligand for G protein-coupled lysophosphatidic acid receptors. We previously showed that gintonin exhibits diverse effects from neurotransmitter release to improvement of Alzheimer’s disease-related cognitive dysfunctions. However, previous studies did not show whether gintonin has protective effects against environmental heavy metal. We investigated the effects of gintonin-enriched fraction (GEF) on methylmercury (MeHg)-induced neurotoxicity and learning and memory dysfunction and on organ MeHg elimination. Using hippocampal neural progenitor cells (hNPCs) and mice we examined the effects of GEF on MeHg-induced hippocampal NPC neurotoxicity, on formation of reactive oxygen species (ROS), and on in vivo learning and memory functions after acute MeHg exposure. Treatment of GEF to hNPCs attenuated MeHg-induced neurotoxicity with concentration- and time-dependent manner. GEF treatment inhibited MeHg- and ROS inducer-induced ROS formations. Long-term treatment of GEF also improved MeHg-induced learning and memory dysfunctions. Oral administration of GEF decreased the concentrations of MeHg in blood, brain, liver, and kidney. This is the first report that GEF attenuated MeHg-induced in vitro and in vivo neurotoxicities through LPA (lysophosphatidic acids) receptor-independent manner and increased organ MeHg elimination. GEF-mediated neuroprotection might achieve via inhibition of ROS formation and facilitation of MeHg elimination from body.

scholarly journals Budesonide promotes airway epithelial barrier integrity following double-stranded RNA challenge

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260706
Author(s):  
Clara Rimmer ◽  
Savas Hetelekides ◽  
Sophia I. Eliseeva ◽  
Steve N. Georas ◽  
Janelle M. Veazey
Keyword(s):  
Barrier Function ◽  
Large Fraction ◽  
Beta Agonist ◽  
Epithelial Barrier ◽  
Airway Epithelial ◽  
Barrier Dysfunction ◽  
Double Stranded Rna ◽  
Barrier Integrity ◽  
Barrier Disruption

Airway epithelial barrier dysfunction is increasingly recognized as a key feature of asthma and other lung diseases. Respiratory viruses are responsible for a large fraction of asthma exacerbations, and are particularly potent at disrupting epithelial barrier function through pattern recognition receptor engagement leading to tight junction dysfunction. Although different mechanisms of barrier dysfunction have been described, relatively little is known about whether barrier integrity can be promoted to limit disease. Here, we tested three classes of drugs commonly prescribed to treat asthma for their ability to promote barrier function using a cell culture model of virus-induced airway epithelial barrier disruption. Specifically, we studied the corticosteroid budesonide, the long acting beta-agonist formoterol, and the leukotriene receptor antagonist montelukast for their ability to promote barrier integrity of a monolayer of human bronchial epithelial cells (16HBE) before exposure to the viral mimetic double-stranded RNA. Of the three, only budesonide treatment limited transepithelial electrical resistance and small molecule permeability (4 kDa FITC-dextran flux). Next, we used a mouse model of acute dsRNA challenge that induces transient epithelial barrier disruption in vivo, and studied the effects budesonide when administered prophylactically or therapeutically. We found that budesonide similarly protected against dsRNA-induced airway barrier disruption in the lung, independently of its effects on airway inflammation. Taken together, these data suggest that an under-appreciated effect of inhaled budesonide is to maintain or promote airway epithelial barrier integrity during respiratory viral infections.

Anticancer Effects & Comparative Study of Thymoquinone, Cordyceps, Spirulina, Ganoderma Lucidium, Poria Cocos, and Lion’s Mane on Human Nasal Cancer Cells (RPMI-2650)

2020 ◽  
pp. 62-78
Author(s):  
سعيد مزعل موازي ◽  
يحيى فائق حسين ◽  
عبد المنعم دولاني ◽  
سيف يوسف عبدالله السويدي
Keyword(s):  
Term Treatment ◽  
Epithelial Cell Line ◽  
Anticancer Effect ◽  
Short Term Treatment ◽  
Poria Cocos ◽  
Nasal Cancer ◽  
Antineoplastic Effect ◽  
Long Term Treatment ◽  
High Concentrations

Recently, many studies have been conducted to discover or improve cancers treatment. The current study aims to investigate the anticancer effect of thymoquinone, cordyceps, spirulina, ganoderma lucidium, poria cocos, and lion’s mane in four different concentrations 4, 8, 16, and 32 ug (equivalent to 1 mg/mL) in two different time treatments (48 and 96 hours) on human nasal epithelial cell line RPMI 2650. By using cell culture cytotoxicity techniques and assay, the highest anticancer effect on RPMI 2650 was obtained by thymoquinone. The lowest anticancer effect was demonstrated by poria cocos and cordyceps. However, these two medications showed higher anticancer effect when given in short-term treatment (48 hours) compared to long-term treatment (96 hours). Ganoderma lucidium and spirulina showed better impact than poria cocos, cordyceps, and lion’s mane in term of cells cytotoxicity. Mild to moderate antineoplastic effect was seen by utilizing lion’s mane treatment compared other drugs. Therefore, adopting a long-term treatment of high concentrations and doses of thymoquinone, cordyceps, spirulina, ganoderma lucidium, poria cocos, and lion’s mane can be more effective in the treatment of nasal cancer. In conclusion, these drugs were found to be a promising cancer remedy; therefore, they can be utilized as alternative treatment for nasal cancer or any other type of cancer therapy.

scholarly journals Sunitinib treatment promotes metastasis of drug-resistant renal cell carcinoma via TFE3 signaling pathway

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Luchao Li ◽  
Shuo Zhao ◽  
Zhengfang Liu ◽  
Nianzhao Zhang ◽  
Shuo Pang ◽  
...  
Keyword(s):  
Renal Cell ◽  
Cell Cancer ◽  
Acquired Resistance ◽  
Resistant Cell ◽  
Term Treatment ◽  
Acquired Drug Resistance ◽  
Sunitinib Treatment ◽  
Long Term Treatment

AbstractReceptor tyrosine kinase (RTK) inhibitors, such as sunitinib and sorafenib, remain the first-line drugs for the treatment of mRCC. Acquired drug resistance and metastasis are the main causes of treatment failure. However, in the case of metastasis Renal Cell Cancer (mRCC), which showed a good response to sunitinib, we found that long-term treatment with sunitinib could promote lysosome biosynthesis and exocytosis, thereby triggering the metastasis of RCC. By constructing sunitinib-resistant cell lines in vivo, we confirmed that TFE3 plays a key role in the acquired resistance to sunitinib in RCC. Under the stimulation of sunitinib, TFE3 continued to enter the nucleus, promoting the expression of endoplasmic reticulum (ER) protein E-Syt1. E-Syt1 and the lysosomal membrane protein Syt7 form a heterodimer, which induces ER fragmentation, Ca2+ release, and lysosomal exocytosis. Lysosomal exocytosis has two functions: pumping sunitinib out from the cytoplasm, which promotes resistance to sunitinib in RCC, releasing cathepsin B (CTSB) into the extracellular matrix (ECM), which can degrade the ECM to enhance the invasion and metastasis ability of RCC. Our study found that although sunitinib is an effective drug for the treatment of mRCC, once RCC has acquired resistance to sunitinib, sunitinib treatment will promote metastasis.

scholarly journals The plant secondary compound swainsonine reshapes gut microbiota in plateau pikas (Ochotona curzoniae)

2021 ◽  
Author(s):  
Shien Ren ◽  
Chao Fan ◽  
Liangzhi Zhang ◽  
Xianjiang Tang ◽  
Haibo Fu ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Artificial Diet ◽  
Alpha Diversity ◽  
Term Treatment ◽  
Short Term Treatment ◽  
Ochotona Curzoniae ◽  
Rdna Sequencing ◽  
Long Term Treatment ◽  
Significant Difference ◽  
Herbivorous Mammals

Abstract Plants produce various plant secondary compounds (PSCs) to deter the foraging of herbivorous mammals. However, little is known about whether PSCs can reshape gut microbiota and promote gut homeostasis of hosts. Using 16S rDNA sequencing to investigate the effects of PSCs on the gut microbiota of small herbivorous mammals, we studied plateau pikas (Ochotona curzoniae) fed diets containing swainsonine (SW) extracted from Oxytropis ochrocephala. Our results showed that both long- and short-term treatment of a single artificial diet in the laboratory significantly reduced alpha diversity and significantly affected beta diversity, core bacteria abundance, and bacterial functions in pikas. After SW was added to the artificial diet, the alpha diversity significantly increased in the long-term treatment, and core bacteria (e.g., Akkermansiaceae) with altered relative abundances in the two treatments showed no significant difference compared with pikas in the wild. The complexity of the co-occurrence network structure was reduced in the artificial diet, but it increased after SW was added in both treatments. Further, the abundances of bacteria related to altered alanine, aspartate, and glutamate metabolism in the artificial diet were restored in response to SW. SW further decreased the concentration of short-chain fatty acids (SCFAs) in both treatments. Our results suggest that PSCs play a key role in regulating gut microbiota community and intestinal homeostasis, thereby maintaining host health. Key points • Swainsonine improves the intestinal bacterial diversity of plateau pikas. • Swainsonine promotes the recovery of core bacterial abundances in the gut of plateau pikas. • Swainsonine promotes the restoration of intestinal bacterial functions of plateau pikas.

scholarly journals Evaluation of cytotoxicity and mutagenicity of the benzodiazepine flunitrazepam in vitro and in vivo

2014 ◽  
Vol 50 (2) ◽  
pp. 251-256
Author(s):  
Igor Vivian de Almeida ◽  
Giovana Domingues ◽  
Lilian Capelari Soares ◽  
Elisângela Düsman ◽  
Veronica Elisa Pimenta Vicentini
Keyword(s):  
Rattus Norvegicus ◽  
Bone Marrow Cells ◽  
Micronucleus Test ◽  
Term Treatment ◽  
Genotoxic Effects ◽  
Short Term ◽  
Short Term Treatment ◽  
Chromosomal Aberration Test

Flunitrazepam (FNZ) is a sedative benzodiazepine prescribed for the short-term treatment of insomnia. However, there are concerns regarding possible carcinogenic or genotoxic effects of this medicine. Thus, the aim of this study was to evaluate the cytotoxic, clastogenic and aneugenic effects of FNZ in hepatoma cells from Rattus norvegicus (HTC) in vitro and in bone marrow cells of Wistar rats in vivo. These effects were examined in vitro following treatment with 0.2, 1.0, 5.0 or 10 μg/mL FNZ using a micronucleus test with a cytokinesis block or in vivo using a chromosomal aberration test following treatment with 7, 15 or 30 μg/mL/kg body weight. The results showed that the benzodiazepine concentrations tested were not cytotoxic, aneugenic or clastogenic. However, considering the adverse effects of using this benzodiazepine, more studies are required.

Fluvoxamine in the Treatment of Trichotillomania: An 8-Week, Open-Label Study

CNS Spectrums ◽  
1998 ◽  
Vol 3 (9) ◽  
pp. 64-71 ◽  
Author(s):  
Gary A. Christenson ◽  
Scott J. Crow ◽  
James E. Mitchell ◽  
Thomas B. Mackenzie ◽  
Ross D. Crosby ◽  
...  
Keyword(s):  
Treatment Response ◽  
Term Treatment ◽  
Hair Pulling ◽  
Short Term ◽  
Open Label ◽  
Short Term Treatment ◽  
Open Label Study ◽  
Label Study ◽  
Long Term Treatment

AbstractThis short-term, open-label study investigates short- and long-term effects of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine for the treatment of trichotillomania (TTM). Additionally, this study aimed to test the hypothesis that the presence of hair pulling compulsiveness is predictive of SSRI response. Nineteen subjects meeting the Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised, (DSM-III-R) criteria for TTM were treated with fluvoxamine at doses up to 300 mg/day. Random regression analysis of change across time for patients who completed the study (n=14) and those who dropped out (n=5) revealed statistically significant improvements in Physician Rating Scale, hair-pulling episodes, Trichotillomania Impairment Scale, and Trichotillomania Symptom Severity Scale, but not in estimated amount of hair pulled. In addition, the percentage of patients' focused or compulsive hair-pulling symptoms was predictive of treatment response. Unfortunately, all three subjects who entered long-term treatment displayed substantial movement back toward baseline by the end of 6 months. We concluded that fluvoxamine produces moderate reductions in symptoms during the short-term treatment of TTM and that the presence of focused or compulsive hair pulling may be predictive of treatment response. However, responses may be short lived when treatment is extended.

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