bluuebunny/crossref_metadata_2025_split huggingface dataset:
microRNA 103‐1 exerts a neuroprotective effect in stroke by enhancing ncx1 expression in the brain (654.1)
Authors: Pignataro Giuseppe , Vinciguerra Antonio , Cerullo Pierpaolo , Cuomo Ornella , Formisano Luigi , Guida Natascia , Di Renzo Gianfranco , Annunziato Lucio 
Published: June 2021

Background and purpose: MicroRNAs (miRNA) are single‐stranded short RNA molecules that regulate gene expression by either degradation or translational repression of mRNA. Recent studies showed that cerebral ischemia significantly alter cerebral miRNA profiles, mediating profound effect on the disease outcome. In that scenario the Na+/Ca2+ exchanger, by mediating Ca2+ and Na+ fluxes in a bidirectional way across the synaptic plasma membrane, may play a pivotal role in the events leading to anoxic damage. The objective of this study was to set up a valid therapeutical strategy able to contrast the role of specific miRNAs that downregulate NCX expression under experimental conditions mimicking stroke.Methods: NCX protein expression was evaluated after miRNA and atimiRNA cell trasfection. AntimiRNA 103‐1 was intracerebroventricularly administered in ischemic rat to prevent mir‐103‐1 detrimental action on NCX1.Results: NCX1 physiological expression was dramatically reduced when cells were treated with mir‐103‐1. Conversely, the in vivo approach showed that antimiRNA‐103‐1 protected from brain ischemia by up‐regulating the neurobeneficial protein NCX1.Conclusions: The present findings support the idea that blocking mir‐103‐1 by microRNA inhibitors is a reasonable strategy to stop neurodetrimental downregulation of NCX occurring during ischemic conditions.
Doxorubicin inhibits lymphatic function in vitro and in vivo (655.1)
Authors: Stolarz Amanda , Pathan Asif , Versluis Rachel , Fletcher Terry , Stimers Joseph , Galanzha Ekaterina , Rusch Nancy 
Published: June 2021

Doxorubicin (DOX) is an independent risk factor for lymphedema in breast cancer patients after surgery and/or radiation therapy. The mechanisms by which DOX contributes to lymphedema are unclear. We hypothesized that DOX directly inhibits lymphatic contractions and lymph flow by a mechanism distinct from its cytotoxic action. Isolated rat mesenteric lymph vessels (LVs) were cannulated, pressurized (4‐5 mm Hg) and equilibrated in a no‐flow system using physiological salt solution (37°C) until spontaneous contractions were stable. An edge‐detection system recorded changes in external diameter. Adding DOX into the bath at increasing concentrations (0.5 to 20 µmol/L; n=7) progressively attenuated the amplitude and area under the curve (AUC) of LV contractions, culminating in reductions of ~55% (amplitude) and ~60% (AUC). Washout of DOX partially restored contractile activity. High‐resolution, intravital optical imaging of rat mesenteric LVs in vivo also revealed that DOX (10 µmol/L) inhibits LV spontaneous contractions and reduces lymph flow (n=2). DOX reduced lymph flow by ~66% (t=10 min) and 100% (t=30 min) from baseline. Thus, DOX may contribute to lymphedema by directly inhibiting LV contractile function as an off‐target effect.Grant Funding Source: Partially supported by a Rho Chi‐AFPE Graduate Fellowship (AS)
In vitro and in vivo evaluation of doxorubicin‐based anti‐cancer treatment in combination with the herbal medicine black cohosh (655.3)
Authors: Szeffler Agata , Stawarz Andrew , Slania Stephanie , Kalinowski Leszek , Dobrucki Lawrence , Dobrucki Iwona 
Published: June 2021

Many breast cancer patients use herbal extracts of black cohosh (BC) in combination with doxorubicin (DOX). In this study we evaluated the synergistic effects of BC and DOX on: (1) in vitro viability, colony formation of human breast cancer cells (MCF‐7), and (2) in vivo evaluation of tumor growth and metabolism.For viability study, MCF‐7 were incubated with DOX (1‐100μM for 2hrs) and BC (100xdose for 6hrs) alone or combined. To assess the MCF‐7 survival, we used a clonogenic assay. MCF‐7 were incubated with DOX (0.1‐10μM for 2hrs) and BC (10‐100x dose for 6hrs) alone or combined, and cultured for 2wks. Colonies were scanned with a digital stereoscope and counted.In vivo experiments were performed on OVEX nude mice injected with MCF‐7. After 6wks of tumor growth, animals were divided into groups: a control and those receiving DOX (4mg/kg/wk), BC (20mg/kg/d) or both DOX and BC. Tumor growth was measured twice a week using digital calipers. We performed PET‐CT imaging with 18F‐FDG at baseline, 2 and 6 wks after the treatment. PET‐CT images were analyzed and tumor activity expressed as %ID/g.We observed significant increase in the number of apoptotic cells after incubation with both DOX and BC vs. control. DOX altered the potential of MCF‐7 cells to form colonies, however co‐incubation with BC did not affect this process. In vivo PET‐CT revealed significant reduction in tumor metabolism after treatment with DOX (40%) and BC (20%) alone. However, we did not observe any synergistic effects when treated with DOX and BC. Both DOX and BC inhibited tumor growth by 20% and 12%, respectively. DOX and BC treatment resulted in a 57% reduction in tumor size.BC exerts synergistic effects on DOX cytotoxicity resulting in reduction in tumor size, but this change is independent of in vitro ability of MCF‐7 to form colonies, and in vivo tumor glucose metabolism. Further studies are necessary to establish which mechanism underlies these effects and to examine potential clinical implications in management of breast cancer patients.Grant Funding Source: UIUC Research Board Award (Dobrucki, I.T.)
Vomiting in docetaxel chemotherapy: which to blame, dose or gene? (655.4)
Authors: Jabir Rafid , Ho Gwo , Anuar Muhammad Azrif , Stanslas Johnson 
Published: June 2021

The adverse effects (AEs) of docetaxel are major limiting factors of its success in the battle against cancer. AEs can be hematological and non‐hematological (nausea, vomiting, diarrhea, rash and mucositis). Eventually, the dose is often reduced or regimen is diverted. Single nucleotide polymorphisms (SNPs) of genes encoding for proteins involved in the transport of docetaxel (ABCB1 and SLCO1B3) could potentially cause accumulation of the drug and consequent AEs. Therefore, we investigated the association between the SNPs (ABCB1 3435CT and SLCO1B3 334TG) and docetaxel AEs in seventy five Malaysian breast cancer patients receiving docetaxel as a single agent chemotherapy at 90‐100 mg/m2 and 75 mg/m2 in the adjuvant and metastatic settings, respectively. The SNPs were analyzed using PCR‐RFLP technique followed by DNA sequencing of selected samples. The patients were Chinese 37 (49%), Malays 32 (43%) and Indians 6 (8%). We found no significant association between the doses given and development of vomiting. However, Indian patients having ABCB1 3435TT (mutant) had a significant association with the development of vomiting (p=0.03). The SNPs‐AEs association is an essential step in the achievement of personalized docetaxel chemotherapy milestones.Grant Funding Source: Malaysian Ministry of Higher Education‐FRGS (04‐04‐10‐848FR) and University Malaya HIR‐UM.C/625/1
Glucocorticoid receptor in locus coeruleus mediates the repetitive treatment of corticosterone‐induced sleep disorders (656.6)
Authors: Wang Zi‐Jun , Zhang Xue‐Qiong , Cui Xiang‐Yu , Cui Su‐Ying , Zhang Yong‐He 
Published: June 2021

Constantly increased cortisol level resulted from stress can cause serious physical or psychological disorders, but the mechanism of stress‐induced sleep disorders remains unclear. Here we described a novel model, which enables us to investigate stress mimicked sleep disorders induced by repetitive administration of corticosterone (CORT). Rats were treated with CORT for 7 days and the sleep parameters were assessed by EEG. In this model, we observed significant decrease in total sleep time and increase in REM sleep time. Meanwhile, the glucocorticoid receptor(GR) level was notably lowered in Locus coeruleus(LC). We also observed the activation of noradrenergic neurons in LC and the suppression of GABAergic neurons activity in ventrolateral preoptic area(VLPO). Otherwise, no significant changes were found in other sleep regulating nuclei. In addition, we observed remarkable increase of NE in LC, VLPO and hypothalamus and increase of tyrosine hydroxylase in LC and decrease of glutamic acid decarboxylase in VLPO. Microinjection of GR antagonist, RU486 into LC reversed the sleep changes. These results suggested that GR in LC may play a role in the stress mimicked sleep disorders and support the hypothesis that the repetitive treatment of CORT may lower the GR level and induce the activation of noradrenergic neurons in LC, then inhibit GABAergic neurons in VLPO and consequently induced sleep disorders.Grant Funding Source: Supported by National Natural Science Foundation of China (No. 81173031, 81202511 and 81302746)
Euphol from Euphorbia tirucalli induces human gastric cancer death through the degradation of TGFβR in lipid raft membrane microdomain (657.12)
Authors: Lin Ming‐wei , Huang Yaw‐Bin , Hsieh Chia‐Yuan , Wu Deng‐Chyang , Chang Fang‐Rong , Chen Chun‐Lin 
Published: June 2021

Transforming growth factor‐β (TGF‐β) is correlated with poorer prognosis in gastric cancer. Therefore, inhibition of the TGF‐β pathway is an attractive strategy for the treatment of cancer. In this study, we demonstrated that euphol, a euphane‐type triterpene alcohol, attenuated TGF‐β‐induced smad2 phosphorylation, and induced gastric cancer cell death through mitochondrial‐dependent apoptosis. Euphol enriched TGF‐β receptors expression in cell membrane lipid raft microdomain within an hour, and promoted them degradation within 24 hours. The interaction of lipid membrane and euphol was confirmed by liquid chromatography‐mass spectrometry and Biacore‐surface plasmon resonance analysis. In conclusion, our results suggest that euphol may distribute membrane protein TGF‐β receptors in lipid rafts, and these membrane modifications may induce cancer cell death.Grant Funding Source: Supported by Grant from the Department of Health, Executive Yuan, ROC (DOH100‐TD‐C‐111‐002)
Phytochemical study and antinociceptive effect of the hexanic extract of leaves from Combretum duarteanum and friedelin in orofacial nociceptive models (657.14)
Authors: Brito Renan , Quintans Jullyana , Costa Emmanoel , Tavares Josean , Estevam Charles , Barison Andersson , Silva Marcelo , Quintans‐Júnior Lucindo 
Published: June 2021

We investigated the antinociceptive effects of the hexanic extract (HE) of leaves from C. duarteanum and friedelin, its mainly compound, in formalin‐, glutamate‐ and capsaicin‐ induced orofacial nociception models. In order to isolate of friedelin from HE, flash chromatography technique was used. Male Swiss mice (n=8/group) were pretreated with HE (100, 200 or 400 mg/kg; p.o.), friedelin (50 mg/kg, p.o.), vehicle (Tween 80 0.2%; p.o.) or morphine (5 mg/kg; i.p.) before the injection of algogen agents into the right upper lip (perinasal area). The test of formalin‐induced orofacial nociception showed that HE and friedelin significantly reduced nociception (p<0.001), in both phases of testing, when compared with the vehicle. In the glutamate and capsaicin‐induced orofacial nociception tests, pre‐treatment with HE produced a significant orofacial anti‐nociception (p<0.001), at all doses tested, when compared with the control group. The results suggest the HE and friedelin possess antinociceptive effects in models of orofacial nociception in rodents.Grant Funding Source: Suported by CAPES/Brazil, CNPq/Brazil and FAPITEC/Brazil
Anti‐asthma and anti‐peritonitis effects of O‐methylthioangeloylsencathenone (657.8)
Authors: Im Dong‐Soon , Lee Kyoung‐Pil , Park Soo‐Jin , Kang Saeromi , Noh Dae‐Young , Kim Jung‐Min , Lee Young‐Geun , Choi Young‐Whan 
Published: June 2021

To elucidate the anti‐allergic and anti‐inflammatory effects of Petasites genus, we have studied effect of o‐methylthioangeloylsencathenone, a sesquiterpene from Petasites genus on lipopolysaccharide‐induced peritonitis model mouse and ovulalbumin‐induced asthma model mouse. O‐methylthioangeloylsencathenone inhibited antigen‐induced degranulation of β‐hexosamidase in RBL‐2H3 mast cells. In an ovalbumin‐induced mouse asthma model, o‐methylthioangeloylsencathenone inhibited accumulation of eosinophils, macrophages, and lymphocytes significantly in bronchioalveolar fluids (BALF) of asthma mouse. O‐methylthioangeloylsencathenone inhibited also lipopolysaccharide (LPS)‐induced mRNA induction of cyclooxygenase 2 (COX‐2) and inducible nitric oxide synthase (iNOS), detected by RT‐PCR in mouse peritoneal macrophages. O‐methylthioangeloylsencathenone also inhibited LPS‐induced protein induction of COX‐2 and iNOS, detected by Western blotting in mouse peritoneal macrophages. Furthermore, o‐methylthio angeloylsencathenone inhibited production of nitrites, the enzyme product of iNOS in a concentration‐dependent manner in the macrophages. Furthermore, o‐methylthioangeloylsencathenone significantly inhibited migration of neutrophils in the peritoneum in LPS‐induced mouse peritonitis model. In summary, o‐methylthioangeloylsencathenone in Petasites genus acts as an anti‐asthma and anti‐inflammatory constituent.Grant Funding Source: This research was supported by High Value‐added Food Technology Development (111135‐03‐2‐SB030)
Identification of a novel anti‐inflammatory compound from Schisandra chinesis (657.9)
Authors: Im Dong‐Soon , Lee Kyoung‐Pil , Kang Saeromi , Park Soo‐Jin , Noh Dae‐Young , Kim Jung‐Min , Lee Young‐Geun , Choi Young‐Whan 
Published: June 2021

To elucidate the anti‐inflammatory and anti‐allergic effects of Schisandra chinensis, we studied the effect of a novel compound isolated from S. chinensis. The compound M isolated from Schisandra chinensis fruits is a novel sesquiterpine, a derivative of α‐cubebene.We found that the compound M concentration‐dependently inhibited antigen‐induced degranulation, which was measured in RBL‐2H3 mast cells by measuring β‐hexosamidase activity. The compound M also inhibited the inductions of inducible nitric oxide synthase and cyclooxygenase 2 at mRNA and protein levels, which was measured by Western blotting in mouse peritoneal macrophages. And LPS‐induced productions of nitric oxide and prostaglandin E2 were inhibited by the compound M. The compound M modulated LPS‐induced activations of ERK, JNK, and p38MAPK in mouse peritoneal macrophages. Furthermore, the compound M strongly inhibited the accumulation of neutrophils, eosinophils, and basophils to peritoneal fluid in a LPS‐induced peritonitis model. The compound M has suppressive properties for inflammatory responses and may be utilized as a potent agent for the treatment of inflammatory diseases.Grant Funding Source: This research was supported by High Value‐added Food Technology Development (111135‐03‐2‐SB030)
Effects of opioids and cannabinoids during chronic morphine treatment in rhesus monkeys (658.3)
Authors: Zanettini Claudio , Gerak Lisa , France Charles 
Published: June 2021

Opioids remain the drugs of choice for treating moderate‐severe pain, although concerns about abuse and dependence limit their use. Therapeutic utility might be improved by combining opioids with other drugs to enhance analgesic effects, but only if other (adverse) effects of opioids are not similarly enhanced. This study examined changes in the antinociceptive (warm water tail withdrawal) effects of morphine and the cannabinoid receptor agonist WIN‐55,212 resulting from twice daily treatment with 3.2 mg/kg morphine in 4 monkeys. Before treatment, morphine and WIN‐55,212 increased tail withdrawal latency with similar potency (ED50= 1.2 and 0.8 mg/kg, respectively); during treatment dose‐effect curves of both drugs were significantly shifted rightward (12.9‐ and 3.4‐fold, respectively). Acute discontinuation of treatment increased heart rate and observable signs that can be indicative of withdrawal (yawning, vocalization, and twitching); these effects were reversed when morphine treatment resumed. These results demonstrate robust tolerance to the antinociceptive effects of morphine under conditions that generate modest physical dependence (withdrawal). That chronic morphine treatment might confer reduced potency of a cannabinoid receptor agonist raises concerns regarding the therapeutic utility of combining opioids and cannabinoids to treat pain.Grant Funding Source: Supported by R01DA005018 and K05DA17918
VTA GABA(A) receptors mediate maladaptive disinhibition of dopamine release in the NAc ő a potential mechanism for increased risk taking behavior following adolescent voluntary alcohol intake (658.9)
Authors: Schindler Abigail , Tsusui Kimberly , Clark Jeremy 
Published: June 2021

Alcohol is the most commonly abused drug among adolescents and shows the highest liability of all abused drugs. We have previously demonstrated that voluntary alcohol consumption by adolescent rats results in maladaptive risk‐taking behavior and phasic dopamine release in adulthood, as assessed by a probability discounting task and fast scan cyclic voltammetry (FSCV). These findings suggest that adolescent alcohol exposure‐induced changes in striatal dopamine release could bias choice by assigning greater value to the risky option, but the underlying mechanisms remain unknown. GABAA receptors located in the VTA are a potential candidate for mediating these effects. Using electrical stimulation of PPT glutamatergic afferents to VTA DA neurons, here we demonstrate that adult rats previously exposed to alcohol during adolescence show increased phasic dopamine release in the NAc, as compared to controls. PPT stimulation elicits GABAA receptor dependent current in VTA DA neurons, raising the possibility that adolescent alcohol intake produces this increased phasic dopamine release through downregulation of GABAA receptors on VTA DA neurons. Systemic administration of L‐838,417, a GABAA receptor α2, α3, and α5 subunit allosteric agonist, causes a dose‐dependent decrease in phasic DA release elicited by PPT stimulation in control rats, and this decrease is enhanced in rats exposed to alcohol during adolescence. Additionally, imaging flow cytometry was used to measure expression of GABAA receptor subunits on neurons of the ventral midbrain. Preliminary results suggest that GABAA receptor α3, but not α1, subunit surface expression is decreased following adolescent alcohol intake. Taken together, these results provide unique insight into the potential role that GABAergic modulation of dopamine neurons plays in the maladaptive risk taking behavior seen following adolescent alcohol exposure and highlights new potential therapeutic targets.Grant Funding Source: R01AA021121 and T32AA07455
Endomorphin analogs with analgesic actions mediated through exon 11 variants of the mu opioid receptor (MOR‐1) (659.10)
Authors: Marrone Gina , Grinnell Stephen , Pan Ying‐Xian , Pintar John , Majumdar Susruta , Pasternak Gavril 
Published: June 2021

Multiple mu opioid receptors (MOR‐1) have been confirmed with the cloning of several mu splice variants. These variants are generated by distinct promoters associated with exon 1 and exon 11. Previously, our lab (Pan et al., 2009, PNAS) observed that the potency of morphine‐6β‐glucuronide, heroin, and fentanyl analgesia was significantly reduced in mice lacking truncated 6 transmembrane (6TM) exon 11 variants of MOR‐1. In contrast, morphine analgesia was intact. We now present evidence that the mu selective peptides endomorphin‐1 and endomorphin‐2 also require exon 11 variants for their analgesic actions supraspinally. An endomorphin‐2 analog, DAPP (dmt‐DAla‐Phe‐Phe‐NH2), produces analgesia via exon 11 variants of MOR‐1 as well. In vitro, approximately 50% of [125I]DAPP binding was lost in the brains of exon 11 knockout mice, whereas almost no specific binding was detected in triple knockout mice lacking MOR‐1 exon 1 variants, delta (DOR‐1), and kappa (KOR‐1). Consistent with our previous behavioral findings, morphine‐6β‐glucuronide, 6‐acetyl‐morphine, and fentanyl were less potent competitors of [125I]DAPP in the brains of exon 11 knockout mice compared to C57/B6 wild type mice. Overall, our findings provide further evidence for the functional role of truncated 6TM variants of MOR‐1. These results also suggest that mu analgesics, including peptides, can be subclassified based on their affinities to exon 11 associated splice variants.Grant Funding Source: NIDA DA02615, DA06142 and DA07242
Abundant sigma‐1 receptor expression in the rat dorsal root ganglion (659.14)
Authors: Kim HungTae , Duellman Tyler , Mavlyutov Tim , Ruoho Arnold , Yang Jay 
Published: June 2021

Intrathecal administration of Sigma‐1 receptor (S1R) antagonists attenuate the pain behavior of rodents in both inflammatory and neuropathic pain models. However, the S1R localization in the spinal cord shows a selective ventral horn motor neuron distribution suggesting the high likelihood of S1R in the dorsal root ganglion (DRG) mediating the pain relief by intrathecally administered drugs. Here, we demonstrate the presence of a strong S1R immuno‐fluorescence in all rat DRG neurons co‐localizing with the NSE marker but not in the GFAP‐positive satellite cells At the protein level, Western blots confirmed that the DRG demonstrated a significantly greater S1R expression per ug of total protein compared to liver, heart, spinal cord or cortex. However, qPCR demonstrated greater expression of the S1R mRNA in the liver and heart compared to the DRG indicating the presence of a potential organ‐specific translational or post‐translational regulation of S1R expression. We hope to exploit this and other mechanisms for down regulating S1R expression in the DRG as potential anatomically‐targeted therapeutic strategy for the treatment of inflammatory and neuropathic pain.Grant Funding Source: Supported by NIH R01 Grant
The role of GABA in hyperbaric oxygen‐induced acute antinociception in mice (659.16)
Authors: Liu Shulin , Shirachi Donald , Quock Raymond 
Published: June 2021

Earlier we reported that mice responded with an acute antinociceptive effect during an 11‐min treatment with HBO2 at 3.5 atmospheres absolute (ATA) (Ohgami et al., NeuroReport 20:1325, 2009). We endeavored to explore the possible role of GABA in this HBO2‐induced effect by pretreating different groups of male NIH Swiss mice, 20‐30 g, intracerebroventricularly (i.c.v.) or intrathecally (i.t.) with various drugs that influenced GABA neurotransmission. The pretreatment drugs were the GABAA antagonist SR 95531, the GABAB antagonist CGP 35348 and the GABA neuronal uptake‐inhibitor (±)‐nipecotic acid. Antinociceptive responsiveness to HBO2 was assessed using the acetic acid‐induced abdominal constriction test conducted in a small animal hyperbaric chamber. HBO2 at 3.5 ATA evoked a strong antinociceptive effect that was antagonized in dose‐related manner by i.c.v.‐ or i.t.‐administered SR 95531. I.c.v. and i.t. pretreatment with CGP 35348 or nipecotic acid potentiated HBO2‐induced antinociception at higher doses. These data strongly suggest that GABA is involved in the acute antinociceptive response of mice to HBO2.Grant Funding Source: Supported by NIH Grant AT‐007222 and the Allen I. White Distinguished Professorship.