scholarly journals Prostaglandin D2 and the role of the DP1, DP2 and TP receptors in the control of airway reflex events

2014 ◽  
Vol 45 (4) ◽  
pp. 1108-1118 ◽  
Author(s):  
Sarah A. Maher ◽  
Mark A. Birrell ◽  
John J. Adcock ◽  
Michael A. Wortley ◽  
Eric D. Dubuis ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Receptor Agonist ◽  
Sensory Nerve ◽  
Sensory Nerves ◽  
Vagal Afferents ◽  
Prostaglandin D2 ◽  
Airway Reflex ◽  
Guinea Pig Model

Prostaglandin D2 (PGD2) causes cough and levels are increased in asthma suggesting that it may contribute to symptoms. Although the prostaglandin D2 receptor 2 (DP2) is a target for numerous drug discovery programmes little is known about the actions of PGD2 on sensory nerves and cough.We used human and guinea pig bioassays, in vivo electrophysiology and a guinea pig conscious cough model to assess the effect of prostaglandin D2 receptor (DP1), DP2 and thromboxane receptor antagonism on PGD2 responses.PGD2 caused cough in a conscious guinea pig model and an increase in calcium in airway jugular ganglia. Using pharmacology and receptor-deficient mice we showed that the DP1 receptor mediates sensory nerve activation in mouse, guinea pig and human vagal afferents. In vivo, PGD2 and a DP1 receptor agonist, but not a DP2 receptor agonist, activated single airway C-fibres. Interestingly, activation of DP2 inhibited sensory nerve firing to capsaicin in vitro and in vivo.The DP1 receptor could be a therapeutic target for symptoms associated with asthma. Where endogenous PGD2 levels are elevated, loss of DP2 receptor-mediated inhibition of sensory nerves may lead to an increase in vagally associated symptoms and the potential for such adverse effects should be investigated in clinical studies with DP2 antagonists.

Capsaicin-sensitive afferent nerves activate submucosal secretomotor neurons in guinea pig ileum

1995 ◽  
Vol 269 (2) ◽  
pp. G203-G209 ◽  
Author(s):  
S. Vanner ◽  
W. K. MacNaughton
Keyword(s):  
Guinea Pig ◽  
Ion Transport ◽  
Short Circuit ◽  
Ussing Chamber ◽  
Sensory Nerve ◽  
Nerve Fibers ◽  
Sensory Nerves ◽  
Guinea Pig Ileum ◽  
Secretomotor Neurons

This study examined whether capsaicin-sensitive sensory nerves regulate intestinal ion transport using both Ussing chamber and intracellular recording techniques in in vitro submucosal preparations from the guinea pig ileum. In Ussing chamber studies, serosal application of capsaicin (20 nM-20 microM) evoked a biphasic dose-dependent increase in short-circuit current (Isc) (maximal effective concentration 200 nM and 2 microM, respectively). In chloride-free buffer, capsaicin responses were significantly reduced. Capsaicin evoked little or no response when extrinsic sensory nerve fibers had been surgically removed and tetrodotoxin and low-calcium and high-magnesium solutions blocked responses to capsaicin. In epithelial preparations devoid of submucosal neurons, capsaicin had virtually no effect, suggesting that responses evoked by capsaicin-sensitive nerves result from activation of submucosal secretomotor neurons. Intracellular recordings from single submucosal neurons demonstrated that superfusion with capsaicin (2 microM) depolarized neurons with an associated decreased conductance. Depolarizations were completely desensitized when capsaicin was reapplied, but synaptic inputs were unaffected. This study suggests that capsaicin-sensitive nerves can regulate ion transport in the gastrointestinal tract by release of neurotransmitter(s) that activate submucosal secretomotor neurons.

scholarly journals Bronchodilatory effect of Myxopyrum serratulum in animal model

2017 ◽  
Vol 12 (1) ◽  
pp. 84
Author(s):  
Vijayalakshmi Maruthamuthu ◽  
Ruckmani Kandasamy
Keyword(s):  
Guinea Pig ◽  
Methanolic Extract ◽  
Relaxation Effect ◽  
Inhibitory Effect ◽  
Chlorpheniramine Maleate ◽  
Relaxant Effect ◽  
Significant Inhibitory Effect ◽  
Guinea Pig Model

<p class="Abstract">The plant <em>Myxopyrum </em>serratulum is traditionally claimed to relieve asthma and cough. The present study was undertaken to evaluate the bronchodilatory effect of the methanolic extract of <em>M. </em>serratulum on histamine-induced bronchospasm by <em>in vivo</em> and the inhibitory effect of the extract on histamine-contracted tracheal chain and ileum by <em>in vitro</em> guinea pig model. Additionally, the relaxant effect of four cumulative concentrations of the extract (0.25, 0.5, 0.7 and 1.0 g%) was assessed using precontracted tracheal chain under different conditions. The extract (400 mg/kg) prolonged the preconvulsive time to 102.3 ± 3.8 sec when compared to saline and standard chlorpheniramine maleate as 121.3 ± 4.5 sec (p&lt;0.05). The extract also possessed significant inhibitory effect on histamine-contracted guinea pig ileum and tracheal chain and also exhibited significant relaxation effect on precontracted tracheal chain of guinea pig models contracted by 60 mM KCl (p&lt;0.001) and 10 µM methacholine (p&lt;0.001) when compared with standard theophylline.</p>

scholarly journals 672. Activity of Ibrexafungerp (Formerly SCY-078) Against Candida auris: In vitro, In Vivo, and Clinical Case Studies of Candidemia

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S307-S307
Author(s):  
Stephen Barat ◽  
Katyna Borroto-Esoda ◽  
Mahmoud Ghannoum ◽  
Elizabeth Berkow ◽  
David A Angulo
Keyword(s):  
Guinea Pig ◽  
Murine Model ◽  
The United States ◽  
In Vitro Studies ◽  
Pig Model ◽  
Cutaneous Infection ◽  
Candida Auris ◽  
Guinea Pig Model

Abstract Background Candida auris is a growing global threat; a pathogen associated with high mortality (up to 60%), multidrug resistance, the ability to spread from person-to-person and surface-to-person, presenting high risk for outbreaks in healthcare facilities. Ibrexafungerp is a novel IV/oral glucan synthase inhibitor (triterpenoid) antifungal with activity against Candida, Aspergillus, and Pneumocystis spp., in Phase 3 development. Methods In vitro studies tested ibrexafungerp against >100 clinical isolates of C. auris. Other in vitro studies evaluated the effects of ibrexafungerp against C. auris biofilms. In vivo activity against C. auris was evaluated using a disseminated murine model and a cutaneous infection guinea pig model. In humans, an ongoing open-label trial of ibrexafungerp for treatment of patients with infections caused by C. auris (the CARES study) has been initiated in the United States and India. Results In vitro and in vivo studies demonstrated that ibrexafungerp is active against C. auris, including MDR strains. The MIC mode for ibrexafungerp was 1 μg/mL and the MIC50 and MIC90 were 0.5 and 1 μg/mL, respectively. Many echinocandin-resistant C. auris isolates have shown susceptibility to ibrexafungerp. Furthermore, ibrexafungerp has been shown to reduce biofilm thickness. In animal models of C. auris infection, treatment with ibrexafungerp resulted in improved survival and reduced fungal burden in both the murine model of disseminated infection and the guinea pig model of cutaneous infection as compared with untreated controls. In humans, two patients with difficult to treat C. auris candidemias were enrolled in the CARES study and responded positively to oral ibrexafungerp with eradication of the infection. Conclusion These data demonstrate that ibrexafungerp possess potent in vitro and in vivo activity as well as promising clinical activity. Therefore, continued clinical evaluation of ibrexafungerp as an option to treat C. auris infections is warranted. Disclosures All authors: No reported disclosures.

Olorofim effectively eradicates dermatophytes in vitro and in vivo

2021 ◽  
Author(s):  
Esmat Mirbzadeh Ardakani ◽  
Atefeh Sharifirad ◽  
Nasrin Pashootan ◽  
Mahsa Nayebhashemi ◽  
Mozhgan Zahmatkesh ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Skin Lesions ◽  
Growth Patterns ◽  
Pig Model ◽  
Antifungal Compound ◽  
Post Inoculation ◽  
Microsporum Gypseum ◽  
Guinea Pig Model

Superficial fungal infections are prevalent worldwide, with dermatophytes, as the most common cause. Various antifungal agents including azoles and allylamines are commonly used to treat dermatophytosis. However, their overuse has yielded drug-resistant strains, calling for the development of novel anti-mycotic compounds. Olorofim, is a newly developed antifungal compound, which targets pyrimidine biosynthesis in molds. The purpose of this study was to determine the in vitro and in vivo antifungal effects of olorofim against common dermatophytes. The in vitro activity of olorofim against dermatophytes was assessed by microtiter broth dilution method. Bioinformatic analysis of olorofim binding to dihydroorotate dehydrogenase (DHODH) of dermatophytes was also performed, using Aspergillus fumigatus DHODH as a template. The in vivo efficacy of the drug was investigated, using a guinea pig model, experimentally infected with Microsporum gypseum. Microtiter assays confirmed the high in vitro sensitivity of dermatophytes to olorofim (MIC= 0.015-0.06 mg/L). Amino acid sequence analysis indicated that DHODH is highly conserved among dermatophytes. The critical residues, in dermatophytes, involved in olorofim binding, were similar to their counterparts in A. fumigatus DHODH, which explains their susceptibility to olorofim. Typical skin lesions of dermatophyte infection, were observed in the guinea pig model, at seven days post-inoculation. Following one week of daily topical administration of olorofim, similar to the clotrimazole group, the skin lesions were resolved and normal hair growth patterns appeared. In light of the in vitro and in vivo activity of olorofim against dermatophytes, this novel agent may be considered as a treatment of choice, against dermatophytosis.

In vivo induction of neutrophil extracellular traps by Mycobacterium tuberculosis in a guinea pig model

2017 ◽  
Vol 23 (7) ◽  
pp. 625-637 ◽  
Author(s):  
Georgina Filio-Rodríguez ◽  
Iris Estrada-García ◽  
Patricia Arce-Paredes ◽  
María M Moreno-Altamirano ◽  
Sergio Islas-Trujillo ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Guinea Pig ◽  
Neutrophil Extracellular Traps ◽  
Post Inoculation ◽  
Extracellular Traps ◽  
Guinea Pig Model ◽  
In Vivo Induction ◽  
Proteins And Peptides

In 2004, a novel mechanism of cellular death, called ‘NETosis’, was described in neutrophils. This mechanism, different from necrosis and apoptosis, is characterized by the release of chromatin webs admixed with microbicidal granular proteins and peptides (NETs). NETs trap and kill a variety of microorganisms. Diverse microorganisms, including Mycobacterium tuberculosis, are NET inducers in vitro. The aim of this study was to examine whether M. tuberculosis can also induce NETs in vivo and if the NETs are bactericidal to the microorganism. Guinea pigs were intradermally inoculated with M. tuberculosis H37Rv, and the production of NETs was investigated at several time points thereafter. NETs were detected as early as 30 min post-inoculation and were clearly evident by 4 h post-inoculation. NETs produced in vivo contained DNA, myeloperoxidase, elastase, histones, ROS and acid-fast bacilli. Viable and heat-killed M. tuberculosis, as well as Mycobacterium bovis BCG were efficient NET inducers, as were unilamellar liposomes prepared with lipids from M. tuberculosis. In vitro, guinea pig neutrophils also produced NETs in response to M. tuberculosis. However, neither the in vivo nor the in vitro-produced NETs were able to kill M. tuberculosis. Nevertheless, in vivo, neutrophils might propitiate recruitment and activation of more efficient microbicidal cells.

Schistosoma mansoni: in vivoandin vitrostudies of immunity using the guinea-pig model

Parasitology ◽  
1983 ◽  
Vol 87 (3) ◽  
pp. 465-479 ◽  
Author(s):  
E. J. Pearce ◽  
Diane J. McLaren
Keyword(s):  
Guinea Pig ◽  
Schistosoma Mansoni ◽  
Guinea Pigs ◽  
Time Course ◽  
Immune Status ◽  
Challenge Infection ◽  
Cytotoxicity Assays ◽  
Guinea Pig Model

SummaryIn vivoandin vitroparameters of immunity have been assessed in guinea-pigs sensitized with 500 normal or 500 radiation-attenuated cercariae ofSchistosoma mansoni. High levels of resistance to a challenge infection developed in both the chronic and irradiated vaccine model, but immunity was expressed earlier (week 4) and reached higher levels (90%) in the latter case. Vaccinated guinea-pigs have thus been shown to achieve greater resistance than the more commonly used rodent hosts.In vitrocytotoxicity assays have demonstrated that antibodies capable of participating in complement-dependent (lethal antibody) or eosinophil-mediated schistosomular killing, develop in the serum of guinea-pigs immunized with either normal or irradiated cercariae. The time course of development of the eosinophil adherence promoting antibody approximated in both models, the development of immunityin vivo, but the lethal antibody response paralleled the immune status of the animal only in the irradiated vaccine model

Spatial transcriptomics reveals a role for sensory nerves in preserving cranial suture patency through modulation of BMP/TGF-β signaling

2021 ◽  
Vol 118 (42) ◽  
pp. e2103087118
Author(s):  
Robert J. Tower ◽  
Zhu Li ◽  
Yu-Hao Cheng ◽  
Xue-Wei Wang ◽  
Labchan Rajbhandari ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Sensory Nerve ◽  
Positive Association ◽  
Sensory Nerves ◽  
Cranial Bone ◽  
Morphogenetic Protein ◽  
Proliferation And Differentiation ◽  
Microfluidic Chambers

The patterning and ossification of the mammalian skeleton requires the coordinated actions of both intrinsic bone morphogens and extrinsic neurovascular signals, which function in a temporal and spatial fashion to control mesenchymal progenitor cell (MPC) fate. Here, we show the genetic inhibition of tropomyosin receptor kinase A (TrkA) sensory nerve innervation of the developing cranium results in premature calvarial suture closure, associated with a decrease in suture MPC proliferation and increased mineralization. In vitro, axons from peripheral afferent neurons derived from dorsal root ganglions (DRGs) of wild-type mice induce MPC proliferation in a spatially restricted manner via a soluble factor when cocultured in microfluidic chambers. Comparative spatial transcriptomic analysis of the cranial sutures in vivo confirmed a positive association between sensory axons and proliferative MPCs. SpatialTime analysis across the developing suture revealed regional-specific alterations in bone morphogenetic protein (BMP) and TGF-β signaling pathway transcripts in response to TrkA inhibition. RNA sequencing of DRG cell bodies, following direct, axonal coculture with MPCs, confirmed the alterations in BMP/TGF-β signaling pathway transcripts. Among these, the BMP inhibitor follistatin-like 1 (FSTL1) replicated key features of the neural-to-bone influence, including mitogenic and anti-osteogenic effects via the inhibition of BMP/TGF-β signaling. Taken together, our results demonstrate that sensory nerve-derived signals, including FSTL1, function to coordinate cranial bone patterning by regulating MPC proliferation and differentiation in the suture mesenchyme.

scholarly journals Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo guinea pig model

2015 ◽  
Vol 96 (12) ◽  
pp. 3484-3492 ◽  
Author(s):  
Stuart D. Dowall ◽  
Andrew Bosworth ◽  
Robert Watson ◽  
Kevin Bewley ◽  
Irene Taylor ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Ebola Virus ◽  
Pig Model ◽  
Human Populations ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Highly Pathogenic ◽  
Guinea Pig Model

Ebola virus (EBOV) is highly pathogenic, with a predisposition to cause outbreaks in human populations accompanied by significant mortality. Owing to the lack of approved therapies, screening programmes of potentially efficacious drugs have been undertaken. One of these studies has demonstrated the possible utility of chloroquine against EBOV using pseudotyped assays. In mouse models of EBOV disease there are conflicting reports of the therapeutic effects of chloroquine. There are currently no reports of its efficacy using the larger and more stringent guinea pig model of infection. In this study we have shown that replication of live EBOV is impaired by chloroquine in vitro. However, no protective effects were observed in vivo when EBOV-infected guinea pigs were treated with chloroquine. These results advocate that chloroquine should not be considered as a treatment strategy for EBOV.

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