bluuebunny/crossref_metadata_2025_split huggingface dataset:
Attenuation of Ovalbumin‐induced Airway Inflammation by Compound of Portulaca oleracea L. Extract through Regulating Mast Cell‐Mediated Inflammatory Responses
Authors: Lee Soyoung 
Published: June 2021

Asthma is a chronic airway inflammatory condition characterized by breathing difficulty due to bronchial and mucosal inflammation, which reduces the patient's life quality, and needs continuous pharmacological treatments. Therefore, drug development for the treatment of asthma contributes to healthy life. It has been previously reported that Portulaca oleracea L. have beneficial effects such as anti‐cancer, anti‐oxidant. The compound of Portulaca oleracea L. extracts (CPL) is derivatives of compound isolated from Portulaca oleracea L. extract. The aim of present study was to elucidate whether CPL modulates the asthma and to study its possible mechanisms of action using ovalbumin (OVA)‐induced airway inflammatory mouse model, and cell‐based in vitro models. In mouse model, CPL treated groups were reduced airway constriction and immune cell infiltration in the lung. CPL treated groups were inhibited the release of β‐hexosaminidase, and the level of pro‐inflammatory cytokines in bronchoalveolar lavage fluid. Moreover, CPL treated groups were alleviated the level of immunoglobulin (Ig) such as IgE, OVA‐specific IgE, IgG1 and IgG2a in serum, and the level of pro‐inflammatory cytokines in the lung. These symptoms are associated with the immune response of mast cell, RBL‐2H3 cells were used to evaluate for the effecting mechanism of CPL. In RBL‐2H3 cells, pre‐treatment of CPL suppressed the release of histamine and β‐hexosaminidase, and the expression of pro‐inflammatory cytokines. Taken together, our findings suggest that CPL could facilitate the prevention or treatment of asthma‐like allergic inflammatory diseases.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Biphenylindanone A, a prototypical mGlu2 positive allosteric modulator, alleviates dyskinesia and psychosis in the parkinsonian marmoset
Authors: Hamadjida Adjia , Nuara Stephen , Gourdon Jim , Huot Philippe 
Published: June 2021

ObjectiveTo determine the effect of the prototypical and selective metabotropic glutamate 2 (mGlu2) receptor positive allosteric modulator (PAM) biphenylindanone A (BINA) on L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced psychosis‐like behaviours (PLBs) and dyskinesia in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned marmoset model of Parkinson's disease (PD).BackgroundPsychosis and dyskinesia undermine the quality of life of as many as 50–95% of patients with advanced PD. Available therapies are few, and they may elicit important side effects. We have recently demonstrated that activation of mGlu2 receptors with another prototypical PAM, LY‐487,379, reduces both PLBs and dyskinesia in the MPTP‐lesioned primate. Here, we seek to determine the effects of PAM BINA on these 2 treatment‐related complications, in the MPTP‐lesioned marmoset.MethodsSix common marmosets (Callithrix jacchus) were rendered parkinsonian by MPTP injection. Following repeated administration of L‐DOPA/benserazide (L‐DOPA) to elicit stable PLBs and dyskinesia, they were administered acute challenges of BINA (0.1, 1 and 10 mg/kg) or vehicle, in combinaison with L‐DOPA after which the severity of PLBs, dyskinesia and parkinsonian disability was rated.ResultsBINA (0.1, 1 and 10 mg/kg) significantly reduced the severity of peak dose PLBs, by ≈33.3%, ≈ 55.6 and ≈ 61.1% (P < 0.05, P < 0.01 and P < 0.01), respectively when compared to L‐DOPA/vehicle. Severity of peak dose dyskinesia was also reduced, by ≈ 28.9%, ≈ 52.3 and ≈57.8% (P < 0.05, P < 0.01 and P < 0.01), respectively, when BINA (0.1, 1 and 10 mg/kg) was added to L‐DOPA, compared to L‐DOPA/vehicle. The anti‐psychotic and anti‐dyskinetic effects of BINA were achieved without interfering with the therapeutic effect of L‐DOPA on parkinsonian disability.ConclusionsBINA is the second mGlu2 PAM that was effective at alleviating PLBs and dyskinesia in the gold‐standard animal model of PD, the parkinsonian primate. The results presented here further add to the increasing data suggesting that mGlu2 positive allosteric modulation may be effective to diminish both PD psychosis and L‐DOPA‐induced dyskinesia.Support or Funding InformationFonds de Recherche Québec ‐ Santé, Parkinson Canada, Natural Sciences and Engineering Research Council of Canada, Weston Brain Institute, Michael J Fox Foundation for Parkinson's Research, Healthy Brains for Healthy Lives.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Electroacupuncture Inhibits Opioid‐induced Hyperalgesia in a Mouse Model of Thermal Nociception
Authors: Lee Ming Tatt , Chen Yi‐Hung , Chiou Lih‐Chu 
Published: June 2021

Opioids remain the gold standard for the treatment of moderate to severe acute pain, however, repeated administration of opioids would inflict pain sensitization to the patients, a condition termed opioid‐induced hyperalgesia (OIH). One of the strategies to prevent OIH in clinical practice is by co‐administration of non‐opioid analgesics. We have recently revealed an unprecedented non‐opioid‐mediated analgesic effect induced by electroacupuncture at PC6 (Neiguan) acupoint (EA‐PC6), which overlays the median nerve, in mice.1 Briefly, EA‐PC6 at low frequency (2 Hz, 2 mA, 0.15 ms) can trigger orexin release from the lateral hypothalamus into the ventrolateral periaqueductal gray (vlPAG), a midbrain region for initiating descending pain inhibition. Orexin then activates postsynaptic orexin 1 receptors (OX1Rs), a Gq proteincoupled receptor family, in the vlPAG, resulting in synthesis of 2‐arachydonoylglycerol (2‐AG), an endocannabinoid that produces retrograde inhibition of GABA release by activating presynaptic cannabinoid 1 receptors (CB1Rs), leading to disinhibition of the vlPAG and ultimately inducing analgesia. Importantly, this EA‐PC6‐induced analgesic effect (EA‐PC6‐IA) is not blocked by naloxone, a non‐selective opioid receptor antagonist. Given the opioid‐independent nature of EA‐PC6‐IA, we further examined whether EA‐PC6 can prevent the development of OIH in male mice on thermal nociception test. OIH in mice were induced via repeated injection of morphine (twice/day, 10 mg/kg each, i.p.) over the course of 3 days, and a final dose (10mg/kg, i.p.) on the 4th day. Immediately after the final morphine injection, EA‐PC6 was given for 20 min in OIH‐induced mice, The mice were subsequently subjected to hotplate test. The control groups included the negative control group which received isoflurane anesthesia only, the sham group with needle insertion at PC6 without electrostimulation and the non‐acupoint group (electrostimulation at the deltoid muscle where there are very few acupoints). The results showed that EA‐PC6 inhibited repeated morphine injection‐induced thermal hyperalgesia. Importantly, this analgesic effect was blocked by a pre‐treatment of either SB334867 (an OX1R antagonist, 15 mg/kg, i.p.) or AM251 (an CB1R antagonist, 1.1 mg/kg, i.p.). These findings suggest that EA‐PC6 is a potential novel pain management strategy in OIH‐inflicted patients, such as terminal cancer patients.Support or Funding InformationThis study was supported by Ministry of Science and Technology, Taiwan (MOST107‐2321‐B‐002‐010, MOST107‐2811‐B‐002‐008), National Health Research Institutes, Taiwan (NHRI‐EX107‐10733NI) and Ministry of Education, Taiwan.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A Novel Drug Target for Migraine: The GABAA Receptor α6 Subtype in Trigeminal Ganglia
Authors: Chiou Lih‐Chu , Tzeng Hung‐Ruei , Fan Pi‐Chuan , Sieghart Werner , Ernst Margot , Knutson Daniel E , Cook James 
Published: June 2021

Migraine, an unmet medical need, is due to an overactive trigeminovascular system (TGVS). The trigeminal ganglion (TG), a hub of the TGVS, transmits the pain signals arising from neurogenic inflammation in the meninges to the brainstem. Previously, we have revealed an unprecedented role of the α6 subunit‐containing GABAA receptor (the GABAA receptor α6 subtype, α6GABAAR) on TG in the neuropathogenesis of migraine using the α6GABAAR‐specific positive allosteric modulators (PAMs)1 we developed. In a rat model of migraine induced by intracisternal injection of capsaicin, we showed that Compound 6, a potent α6GABAAR‐selective PAM via acting on TG, attenuated TGVS activation‐induced peripheral and central responses, using immunohistochemical approaches.2 Here, we further investigated whether positive modulating TG α6GABAARs would attenuate migraine‐related nociceptive behaviors induced by repetitive injections of nitroglycerin (NTG), which induces headache in human due to dural vasodilatation. We gave NTG (10 mg/kg, i.p.) to mice (6–8 weeks, male ICR) once every two days for 5 times. The mouse grimace scale (MGS) was used to score, from 0–2, the headache‐like behaviors, including orbital tightening, nose bulge, cheek bulge, and the changes of ear position and whisker. The severity of migraine was assessed by the MGS on day 9 (the 5th session). To evaluate the abortive treatment efficacy of α6GABAAR PAMs, drug were administered 20 min after NTG injection on day 9. For their prevention efficacy, drugs were given 30 min before NTG injection in each session. Repeated NTG injections significantly increased MGS. Compound 6 and its deuterated derivative that has a longer half‐life, DK‐56‐I, significantly attenuated the elevated MGS induced by NTG. Importantly, the effect of the α6GABAAR‐selective PAM was antagonized by i.p. injection of furosemide (20 mg/kg), an α6GABAA R‐selective antagonist that is blood‐brain barrier‐impermeable. It was mimicked by sumatriptan, an effective drug for migraine abortion. Besides, we found that DK‐56‐I was effective in preventing repeated NTG‐induced elevation of MGS, like topiramate, an effective drug for migraine prevention. We also found that α6GABAARs are expressed in TG neurons and satellite glial cells of mice. These results suggest that the TG α6GABAAR is a novel therapeutic target for migraine and that the α6GABAAR‐selective PAM is a novel treatment for migraine abortion and prevention.Support or Funding InformationSupported grants: MOST 107‐2321‐B‐002‐010 and NHRI‐EX107‐10733NI.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Reversal of the Development of Antinociceptive Effects to Chronic Morphine in Mice by Fecal Microbiota Transplantation (FMT)
Authors: Kang James Minho , Dewey William L , Akbarali Hamid I 
Published: June 2021

Morphine remains one of the most frequently prescribed drugs for the treatment of moderate to severe pain, including pain due to cancer or surgery. However, the long‐term use of this excellent pain reliever in man is limited by side‐effects that include analgesic tolerance, dependence and constipation. We have previously shown that depletion of gut bacteria by oral vancomycin results in the loss of antinociceptive tolerance, decreases epithelial permeability and reduces colonic inflammation by chronic morphine. The aim of this study was to investigate the effect of colonizing the gut with non‐opioid commensal microbiome on reversal of morphine‐induced antinociceptive tolerance. Gut bacteria were collected from 5 day placebo and morphine pelleted mice from fecal pellets designated as donor mice groups (PP‐FMT and MP‐FMT). The microbiome was then orally gavaged (1×109 cells/dose) daily for 5 days to placebo (PP) and morphine (MP) pelleted (75 mg pellet, 5 days) recipient mice groups, and the presence of antinociceptive tolerance was determined by morphine challenge (10 mg/kg, s.c.) in the tail immersion and hot plate tests. Daily gavage of the microbiome from morphine pelleted mice to the morphine‐pelleted recipient mice (MP+MP‐FMT) resulted in antinociceptive tolerance to morphine challenge. However, gavage of the microbiome from placebo pelleted donor mice to the morphine pelleted recipient mice (PP+MP‐FMT), prevented the development of antinociceptive tolerance. We further investigated whether an exogenous microbiome could reverse chronic morphine induced antinociceptive tolerance development. In these studies, oral gavage of gut microbiome was commenced after development of tolerance to morphine. Similar to the induction of tolerance, oral gavage of placebo microbiome to morphine tolerant mice (MP+PP‐FMT) reversed antinociceptive tolerance. In order to determine if transplantation of the gut microbiome also prevents the loss of epithelial integrity by chronic morphine treatment, intestinal permeability was measured by oral administration of FITC (Fluorescein isothiocyanate)‐dextran (44 mg/kg, p.o.) in placebo or morphine pelleted mice for 5 days. FITC levels were significantly higher in morphine pelleted mice (MP) treated with the microbiome from morphine donors (MP‐FMT) than placebo pelleted controls (PP, p<0.0001). However, the epithelial integrity was maintained in morphine pelleted mice (MP) treated with the commensal microbiome from placebo donors (PP‐FMT). These studies define a novel microbiome‐gut‐brain interaction in the development of opioid tolerance.Support or Funding InformationNIH R01 DA036975 and NIH T32 DA007027This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of Order of Fixed Ratio Presentation on Demand for Self‐administered Remifentanil in Rats
Authors: Maguire David R , Minervini Vanessa , France Charles P 
Published: June 2021

Behavioral economics has been used extensively to study factors that control operant behavior, including quantification of reinforcing effectiveness of drugs. Consumption of a commodity decreases with increasing price, and the rate of decrease reflects demand elasticity, which is inversely related to reinforcing effectiveness; drugs with low elasticity have greater effectiveness than those with higher elasticity. Price is often manipulated by varying the number of responses required to obtain an infusion (e.g., fixed ratio [FR] schedule); however, many studies present price using only one order, which could introduce sequence effects that influence estimates of demand. This study examined the impact of the order of FR presentation on demand for the mu opioid receptor agonist remifentanil (0.0032 mg/kg/infusion) using a within‐subjects, reversal design. Seven male rats lever pressed for iv infusions. The FR varied across 3‐session blocks, yielding a demand curve. During the first and third phases of the study, FR values were presented in a strictly ascending order; during the second phase, FR values were presented in a mixed order. Rats obtained more than 60 infusions on average per session under baseline conditions (i.e., FR1) during each of the three phases, and the number of infusions decreased systematically with increasing FR values. Estimates of elasticity (i.e., reinforcing effectiveness) were not statistically different across the three phases indicating that the order of ratio presentation did not alter estimates of demand and further demonstrating the marked robustness of price as a source of control over operant behavior, including behavior maintained by drug reinforcers.Support or Funding InformationThis study was supported, in part, by the Welch Foundation (AQ‐0039).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
CHARACTERIZATION OF EXPRESSION PATTERN OF SOMATOSTATIN 4 RECEPTOR IN THE MOUSE BRAIN
Authors: Pohóczky Krisztina , Kecskés Angéla , Bakai Rita , Kormos Viktória , Szentes Nikolett , Szőke Éva , Bölcskei Kata , Udvarácz Ildikó , Ábrahám István , Varga Zoltán , Gaszner Balázs , Helyes Zsuzsanna 
Published: June 2021

Somatostatin is a cyclic neuropeptide which is expressed in brain regions related to pain‐ and mood regulation. It has 5 inhibitory G‐protein coupled receptors, and subtype 4 (sst4) mediates analgesic, anti‐inflammatory and antidepressant effects without endocrine actions. It was suggested to be a novel drug target for chronic neuropathic pain. However, its central nervous system distribution and mechanism of the inhibitory actions are not known due to the lack of specific antibody.We mapped sst4 expression using β‐galactosidase immunohistochemistry in the brain of Sst4 knockout (KO) mice where sst4 was replaced by the lacZ gene. Since KO mice are not appropriate for determining functional changes and co‐localization, we also performed ultrasensitive RNAscope‐based in situ hybridization and neurochemical characterization on formalin‐fixed, paraffin‐embedded coronal sections of wild type mice. Sst4 mRNA was also quantified by qPCR in the positive regions.Strong sst4‐related β‐galactosidase immunopositivity was detected in the hippocampus, moderate in the medial septum, amygdala, habenula in both sexes. Remarkably more intensive signal was seen in the primary somatosensory cortex of male mice compared to females. Sst4 mRNA was abundant in the hippocampal CA1 region, amygdala, spinal cord, sensory and motor cortices (layer 5). It was co‐localized with vesicular glutamate transporter 1 in most regions and choline‐acetyl transferase in the habenula. Sst4 mRNA was significantly higher in the dorsal root ganglia compared the spinal cord. These are the first data for sst4 expression in glutamatergic and cholinergic excitatory neurons of the nociceptive pathway. This might explain its unique value to simultaneously inhibit chronic pain and depression.Support or Funding InformationÚNKP17‐3‐III‐PTE‐166, GINOP‐2.3.3.‐15‐2016‐00050, GINOP‐2.3.3.‐15‐2016‐00048, EFOP‐3.6.2‐16‐2017‐00008, KTIA_NAP_13‐2‐2014‐0022, KTIA_NAP_13‐1‐2013‐0001, 207653/2018/FEKUTSTRATThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Investigating the role of endothelial cell‐specific p110β isoform of PI3K as a potential target for anti‐angiogenic therapy
Authors: Azad Abul Kalam , Zhabyeyev Pavel , Oudit Gavin , Moore Ronald , Murray Allan 
Published: June 2021

IntroductionAngiogenesis‐inhibitor drugs targeting Vascular Endothelial Growth Factor (VEGF) signalling to the endothelial cell (EC) are used to treat various cancers. However, tumors become resistant to this therapy due to the recruitment of alternative growth factors, acting via cognate EC receptor tyrosine kinases (RTK) or g‐protein coupled receptors (GPCR), to cue neo‐angiogenesis. In ECs, the PI3 kinase p110β isoform is uniquely coupled to both RTKs and GPCRs. Endothelial‐specific p110β inactivation impairs angiogenic sprouting and tip cell marker gene expression in vitro. These data indicate that p110β mediates pro‐angiogenic signals. We hypothesize that EC PI3 kinase‐β activity mediates tumor angiogenesis escape from sunitinib therapy.MethodsMouse Lewis lung carcinoma (LLC1) or B16F10 melanoma cells were implanted subcutaneously in EC‐specific p110β knockout (ECβKO) or control mice. Sunitinib (40mg/kg/day) treatment was initiated when the tumors reached an average volume of 200 mm3, then tumor growth was monitored, and all mice were euthanized when the average tumor volume reached 1500 mm3. Second, to model metastasis, B16F10 cells were injected intravenously in ECβKO or control mice, then treated with sunitinib for 20 days. Pimonidazole was administrated 1 hour before euthanasia. Immunohistochemical analyses were performed for CD31‐positive vessels and pimonidazole‐positive hypoxic areas.ResultsEC‐specific p110β loss with sunitinib treatment decreases the growth of subcutaneous LLC1 and B16F10 melanoma cells among syngeneic mice vs the sunitinib alone‐treated control mice. Similarly, EC p110β loss with sunitinib decreases B16F10 metastases in the lung, and the overall tumor area in lung cross‐section, vs sunitinib‐treated control mice. Further, subcutaneous primary and metastatic tumors had a marked decrease in CD31‐positive microvessels in ECβKO vs control mice, accompanied by a significant reduction in tip cell marker gene expression. Surprisingly, pimonidazole‐positive hypoxic area in the tumors was normalized in ECβKO vs control mice. We found that inactivation of EC‐p110β increased NG2‐positive pericyte coverage of tumor microvessels and arterioles.ConclusionsThese findings demonstrate that EC‐specific inactivation of p110β in combination with sunitinib decreases primary tumor growth and tumor metastasis vs sunitinib treatment alone. The density of the tumor vasculature and tip cell gene expression is reduced, but tumor oxygen delivery is normalized. Inhibition of endothelial p110β may be useful as adjuvant therapy with sunitinib, and may facilitate delivery and/or response of the tumor to conventional chemotherapy agents.Support or Funding InformationCanadian Cancer SocietyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Chemotherapeutic Potential of Novel Selenium (Se) Analog of Histone Deacetylase (HDAC) Inhibitor, Suberoylanilide Hydroxamic Acid (SAHA) in Experimental Colorectal Cancer
Authors: Kaushal Naveen , Ghanghas Preety , Desai Dhimant , Raza Kaisar , Bhalla Aman 
Published: June 2021

Colorectal cancer (CRC), one of the leading causes of cancer related deaths worldwide is an outcome of both genetic and epigenetic changes in colonic epithelia leading to the formation of adenocarcinomas. Histone deacetylases (HDACs) through their key roles in regulation of cellular processes, are associated with the development and progression of cancer. Thus, in this regard, HDAC inhibitors have become promising therapeutic targets. These inhibitors induce cell cycle arrest, differentiation, autophagy and apoptotic cell death by inhibiting multiple signaling pathways. Suberoylanilide hydroxamic acid (SAHA), a second generation HDAC inhibitor has been approved by US‐FDA for the treatment of cutaneous T‐Cell lymphoma, however its anti‐cancerous effects against colorectal cancer is still unknown. Also, essential dietary element Selenium (Se) has been found to have an important role in CRC prevention via modulating redox sensitive molecular pathways. Therefore, the present study aimed to explore the anti‐tumorigenic role of SAHA and its Se analog namely, SelSA‐1 (25 mg/kg) in DMH induced experimental colon cancer model in Balb/c mice. The toxicity studies and pharmacokinetic characterization of SelSA‐1 exhibited better tolerance, absorption and elimination rate than SAHA. Further, histological and morphological analyses showed that SelSA‐1 has better/comparable chemotherapeutic potential compared to SAHA at lower doses than SAHA. Further, the positive redox modulatory effects of SelSA‐1 and SAHA in CRC associated oxidative stress were also noteworthy, projecting the plausible use of similar analogs as compounds of choice for cancer treatments based on their safety profiles, efficacy and specificity in terms of chemotherapeutic potential.Support or Funding InformationDepartment of Science and Technology (DST), Govt. of India, New Delhi; University Grant Commission (UGC), Govt. of India, New DelhiThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.