bluuebunny/crossref_metadata_2025_split huggingface dataset:
Opioid growth factor reverses the progression of clinical disease in established relapse‐remitting experimental autoimmune encephalomyelitis ő a model for multiple sclerosis (651.2)
Authors: Hammer Leslie , Zagon Ian , McLaughlin Patricia 
Published: June 2021

Relapse‐remitting multiple sclerosis (RR‐MS) is a chronic disorder involving inflammatory attacks on the CNS in 350,000 people in the U.S. RR‐MS reduces the quality of life, and eventually results in paralysis. OGF, chemically termed [Met5]‐enkephalin, was administered daily to female SJL/J mice with established relapse‐remitting experimental autoimmune encephalomyelitis (RR‐EAE). Mice were immunized with PLP139‐151 in complete Freund’s adjuvant, and beginning 2 days after initial behavioral signs received daily injections of OGF (10 mg/kg) or sterile saline. Within 9 days of treatment with OGF the mice had markedly reduced mean behavior scores relative to controls; the sum of the behavior scores was 140.1±14.4 for the RR‐EAE+Saline group in comparison to 72.2±11.5 for the RR‐EAE+OGF group. Disease severity scores were 16.3± 5 for RR‐EAE+Saline in comparison to 3.6±1.7 for OGF treated mice. No saline‐treated mouse had a complete remission, whereas 83% of OGF mice had complete remissions (behavioral score 蠄 0.5); the total length of time in complete remission was 9.1±3.4 days for the RR‐EAE+OGF animals over the course of the 40‐day experimental period. In summary, treatment with OGF initiated at the time of discernible disease reduced the intensity of the initial flair, reversed the progression of RR‐EAE, and resulted in complete clinical remission, supporting its use as a novel therapy for the treatment of MS.Grant Funding Source: Shockey Family Foundation
Low dose naltrexone inhibits the progression of clinical disease in established relapse‐remitting experimental autoimmune encephalomyelitis ő a model for multiple sclerosis (651.3)
Authors: Zagon Ian , Hammer Leslie , McLaughlin Patricia 
Published: June 2021

Relapse‐remitting multiple sclerosis (RR‐MS) is a chronic disorder involving inflammatory attacks on the CNS. RR‐MS affects about 350,000 people in the U.S. significantly reducing the quality of life. The Opioid Growth Factor (OGF)‐Opioid Growth Factor Receptor (OGFr) pathway has been reported to be involved in experimental autoimmune encephalomyelitis (EAE). Blockade of OGF‐OGFr interaction using low dosages of the opioid antagonist naltrexone (LDN) alters the course of disease. SJL/J mice were immunized with PLP139‐151, and were injected (ip) daily with 0.1 mg/kg naltrexone or saline beginning 2 days after initial signs of disease. Within 9 days of LDN treatment mice had markedly reduced mean behavioral scores compared to controls, with the sum of behavioral scores being 142.9±11.5 for the RR‐EAE+Saline group in comparison to 78.8±9.1for the RR‐EAE+LDN group. In the LDN group, 80% of the mice had complete remission (behavioral scores of 0.5 or less) during the 40 day observation period. Moreover, LDN‐treated mice demonstrated a 4‐fold increase in mild disease scores relative to controls. The results indicate that modulation of the OGF‐OGFr pathway by LDN in established RR‐EAE inhibited the severity of initial flair and limited the progression of clinical disease, with many LDN‐treated mice showing complete remission. These observations support LDN as a non‐toxic/safe biotherapy for the treatment of RR‐MS.Grant Funding Source: Shockey Family Foundation
Nongenomic effects of estrogen mediate the dose‐related myocardial oxidative stress and dysfunction caused by acute ethanol in female rats (652.19)
Authors: El‐Mas Mahmoud , Abdel‐Rahman Abdel 
Published: June 2021

Acute ethanol lowers blood pressure (BP) and cardiac output in proestrus and after chronic estrogen (E2) replacement in ovariectomized (OVX) female rats. However, whether rapid nongenomic effects of E2 mediate these hemodynamic effects of ethanol remained unanswered. To test this hypothesis, we investigated the effect of ethanol (0.5, 1 or 1.5 g/kg; i.v.) on left ventricular (LV) function and oxidative markers in OVX rats pretreated 30 min earlier with 1 μg/kg E2 (OVXE2) or vehicle (OVX) and in proestrus sham‐operated (SO) rats. In SO rats, ethanol caused significant and dose‐ related reductions in BP, rate of rise in LV pressure (LV dP/dtmax), and LV developed pressure (LVDP). The ethanol effects disappeared in OVX rats and were restored in OVXE2 rats suggesting rapid estrogen receptor signaling mediates the detrimental LV effects of ethanol. The E2‐dependent LV dysfunction caused by ethanol was associated with higher LV: (i) generation of reactive oxygen species, (ii) expression of the malondialdehyde and 4‐hydroxynonenal protein adducts, (iii) Akt and ERK1/2, and (iv) catalase activity. Collectively, it is concluded that rapid estrogen receptor signaling is implicated in the cellular events that lead to the generation of aldehyde protein adducts and Akt/ERK1/2 phosphorylation, which ultimately mediate the estrogen‐dependent LV oxidative stress and dysfunction caused by ethanol in female rats. Grant Funding Source: Supported by NIAAA [2R01 AA014441‐07]
Membrane cholesterol and caveolar modulation of cardiac function, ischemic tolerance and opioidergic protection (652.21)
Authors: See Hoe Louise , Schilling Jan , Kellerhals Sarah , Headrick John , Patel Hemal , Peart Jason 
Published: June 2021

Studies support a role for cholesterol‐rich membrane microdomains, caveolae, and caveolins in cardiac tolerance and conditioning to ischemia‐reperfusion (IR). The importance of membrane cholesterol in intrinsic IR tolerance and preconditioning is unclear. We assessed effects of cholesterol depletion vs. lifelong modulation of caveolin‐3 (deletion and overexpression) on myocardial function, IR tolerance and opioid preconditioning. Hearts from male C57/Bl6 mice received methyl‐β‐cyclodextrin (MβCD, 2 μM ‐ 1 mM), depleting membrane cholesterol, prior to ex vivo IR ± acute or sustained opioid receptor preconditioning (SLP). Additionally, cardiac caveolin‐3 (cav‐3) knockout (KO) and overexpressor (OE) hearts were exposed to IR ± SLP. MβCD significantly reduced sarcolemmal cholesterol content by >10‐30%, and induced significant pre‐ and post‐ischemic contractile dysfunction. Cardioprotection with acute morphine (10 μM) was abolished with >20 μM MβCD, yet SLP remained efficacious until 200 μM MβCD. Cav‐3 KO reduced, while cav‐3 OE enhanced IR tolerance. SLP improved post‐ischemic recovery in cav‐3 KO, and protection was additive in cav‐3 OE hearts. Membrane cholesterol plays a key role in intrinsic IR tolerance and conventional and novel preconditioning. Novel SLP is further delineated from conventional preconditioning stimuli, as this phenotype appears independent of cav‐3 protein.Grant Funding Source: Supported by National Heart Foundation Australia (LS) and Australian Research Council (JP)
Screening and identification of the specific microRNAs involved in the protection of morphine preconditioning against hypoxia/reoxygenation injury in rat failing cardiomyocytes (652.6)
Authors: He Shu‐fang , Zhu Hai‐juan , Zhang Ye 
Published: June 2021

This study was designed to investigate the protective effects of morphine preconditioning (MPC) against hypoxia/reoxygenation (H/R) injury in rat failing cardiomyocytes, and to screen and identify the involved microRNAs (miRNAs). The cardiomyocytes isolated from adriamycin‐induced failing rat heart received MPC at different concentrations followed by H/R and then cellular injury was measured. In another experiment, total RNA was extracted from the failing cardiomyocytes after MPC and subjected to miRNA microarray and subsequent bioinfornatics analysis and real‐time RT‐PCR validation. Typblue exclusion and LDH assay results showed that MPC significantly attenuated cell injury caused by H/R in failing cardiomyocytes. The miRNA microarray data showed that many of miRNAs differentially expressed among groups. By Gene Ontology and KEGG pathways analysis, the predicted target genes were enriched in calcium ion transport, apoptosis and MAPK signal pathway. Notably, miR‐133b was obviously downregulated in failing cardiomyocytes while highly expressed under MPC; miR‐6216 and miR‐let‐7 were upregulated in failing cardiomyocytes but decreased by MPC. The miRNA microarray data was further confirmed by real‐time RT‐PCR. In conclusion, miRNAs, especially miR‐133b, miR‐6216 and miR‐let‐7 might be involved in the protection of morphine preconditioning against H/R injury in failing cardiomyocytes.Grant Funding Source: Supported by National Natural Science Foundation of China（81200171）
Chronic Bendavia therapy improves post‐infarction cardiac function and prevents adverse left ventricular remodeling in rats (652.8)
Authors: Dai Wangde , Shi Jianru , Hale Sharon , Kloner Robert 
Published: June 2021

Bendavia (Ben), a mitochondria‐targeting peptide, protects mitochondrial function by enhancing bioenergetics under conditions of oxidative stress, thus inhibiting ROS formation. We hypothesized that Ben therapy would benefit post‐myocardial infarction (MI) cardiac function and remodeling in rats. At 2 hours after left coronary ligation, rats were randomized to receive Ben that was delivered subcutaneously by an Alzet Osmotic Pump (3 mg/kg/day, n=28) or water (n=26). Six weeks later, scar circumference assessed by histology and expressed as percentage of total left ventricular (LV) circumference, was significantly smaller in the Ben group (39.7 ± 2.2 %) versus the water group (47.4 ± 2.5 %, p=0.024). Post‐mortem LV volume was 9.6% smaller in the Ben group (p=0.019). LV fractional shortening by echo was significantly greater in the Ben group (28.8 ± 1.7 %) than in the water group (23.8 ± 1.8 %, p=0.047). LV stroke volume was greater in the Ben group (0.257 ± 0.008 ml) versus the water group (0.231 ± 0.008 ml, p=0.029), and LV ejection fraction assessed by LV ventriculography was greater with Ben (55.3 ± 1.4%) versus water (49.3 ± 1.4%, p=0.005). Ben treatment reversed the down‐regulated expression of mitochondrial energy metabolism‐related genes at the noninfarcted infarct border assessed by PCR array. Chronic Ben therapy improved post‐MI cardiac function, prevented stretching of the scar and adverse remodeling in rats.Grant Funding Source: Supported by Stealth Peptides, Inc., Newton, Mass.
5‐HT disturbs interaction between gut epithelium and commensal bacteria (653.10)
Authors: Regmi Sushil , Shadfar Sina , Neupane Ganesh , Lee Jintae , Lee Jin‐Hyung , Kim Jung‐Ae 
Published: June 2021

The gut is considered as one of immune privilege sites, which is developed by complex interplay between gut microbiome and the intestinal epithelial barrier. The mechanisms regulating gut tolerance to the commensal bacteria also play an important role in the protection of intestine against epithelial injury. Human studies in patients with inflammatory bowel disease (IBD) have implicated aberrant communication between host and gut flora such as inappropriate immune responses against their own flora. In addition to the excessive production of proinflammatory cytokines, serotonin (5‐hydroxytryptamine, 5‐HT), an enteric neurotransmitter and paracrine hormone, is also increased in the gut of IBD patients, suggesting its role in the pathogenesis of IBD. In the present study, we examined the role of 5‐HT in aberrant communication between gut epithelial cells and commensal bacteria (E coli). 5‐HT enhanced adherence of commensal E coli to HT29 colonic epithelial cells without affecting the adherence of pathogenic E coli. At the same time, 5‐HT treatment synergistically increased mRNA expression of IL‐8, TLR‐2, and Nox2 in commensal E coli‐treated‐HT29 cells. Either pretreatment with NADPH oxidase inhibitor (DPI) and antioxidant (vitamin C) or transfection with Nox2 siRNA significantly suppressed the 5‐HT‐induced adhesion of commensal E coli to HT‐29 cells. Taken together, 5‐HT disturbs the interaction between gut epithelium and commensal bacteria, which may alter gut tolerance to commensal bacteria.Grant Funding Source: Supported by Basic Science Research Program through the National Research Foundati
Analysis of ligand bias in functional studies involving the allosteric modulation of G protein‐coupled receptors (654.6)
Authors: Ehlert Frederick , Griffin Michael 
Published: June 2021

The affinity constants of a ligand for active and inactive states of a receptor ultimately determine its ability to activate downstream signaling events. In this report, we describe a reverse‐engineering strategy for estimating these microscopic constants. Our approach involves analyzing responses measured downstream in the signaling pathway of a G protein‐coupled receptor under conditions of partial receptor inactivation and allosteric modulation. The analysis also yields estimates of the isomerization constant of the unoccupied receptor, the sensitivity constant of the signaling pathway, and the more empirical parameters of the receptor population including the observed affinities and efficacies of allosteric and orthosteric ligands ‐ including inverse agonists ‐ and the efficacy of the unoccupied receptor (i.e., constitutive activity). We validate our approach with an analytical proof and by analysis of simulated data. We also use our method to analyze data from the literature. We show that the values of the microscopic constants of orthosteric and allosteric ligands are constant regardless of the allosteric interaction and the nature of the receptor‐signaling pathway as long as the same active state mediates the response. Our analysis is useful for quantifying probe‐dependent allosteric interactions and the selectivity of agonists for different signaling pathways.Grant Funding Source: NIH grant GM 69829
Reversal effects of tetramethylpyrazine on multidrug resistance in hepatocellular carcinoma cells BEL‐7402/ADM by inhibiting calcium pathway (655.6)
Authors: Wang Xuanbin , Liu Ying , Li Hongliang , Liu Ming , Ouyang Lu , Wang Linhai , Xie Yong 
Published: June 2021

P‐glycoprotein (P‐gp) was one of mechanisms of Multidrug resistant (MDR) hepatocellular carcinoma (HCC) . Its activation, at least partially depends on protein kinase Cα (PKCα). Tetramethylpyrazine (TMP) is a bioactive constituent isolated from the root of Ligusticum chuanxiong Hort, a Chinese herb. The present study was to investigate if TMP reverses Human drug resistant hepatocellular carcinoma cells BEL‐7402/ADM by inhibiting calcium pathway. We found that the microscopy showed that the average immunofluorescent intensity of the PKCα level in Bel‐7402/ADM cells treated with TMP was (33.33 ± 1.7) % compared to that of without TMP (P<0.001). The fluorescent intensity of intracellular Ca2+ for BEL‐7402/ADM treated with TMP was 541.67±8.15 versus that of without TMP (665.16±2.89) (P<0.05); CCK‐8 assay showed that when TMP combined with UO126 (ERK blocker) or SP600125(JNK blocker), the IC50 value of doxorubicin on Bel‐7402/ADM was increased. However, when TMP combined with SB203580 (p38 blocker) was treated in Bel‐7402/ADM, the IC50 value was reduced. Furthermore, compared with the control group, the level of intracellular reactive oxygen species (ROS) of TMP group was increased. These suggested that TMP might reversal MDR HCC by downregulating calcium pathway which may be associated with ROS level and MAPK pathway. Grant Funding Source: Supported by Department of Health of Hubei Province, NO. JX5A10;
Metformin with radiotherapy enforces growth retardation of head and neck squamous cell carcinoma (655.9)
Authors: Yeo Jiyoung , Park Eun‐Ji , Kim Kyungmin , Jang Hyung‐Jun , Cho Kwang‐Jae , Kim Min‐Sik 
Published: June 2021

Head and neck (HN) cancer accounts for approximately tenth of all cancers worldwide and radiotherapy is also a common cancer treatment for patients. We investigated synergistic effects of metformin, one of type 2 diabetes mellitus (T2DM) drugs, when treated with radiation treatment in HN cancer models. Metformin was treated as a dose‐dependent manner with/without 8Gy‐irradiation to Fadu, a HN squamous cell line, and supplemented in diet for 2 weeks in human HN cancer xenograft‐bearing Balb/c‐nude mice under radiotherapy. In the metformin‐treated Fadu after irradiation, AMPK was significantly activated compared with each single treatment. With the reduction of Bcl‐2/Bax ratio, cleaved caspases and p53 were up‐regulated and Akt, Erk, and p38MAPK were down‐regulated. Besides, colony formation was strongly attenuated in HUVECs on an AMPK‐dependent manner and effectively inhibited Fadu tumor growth in Balb/c‐nude mice. Therefore, to conclude, combined treatment metformin with radiotherapy contributes to tumor growth retardation via improved apoptosis and inhibited proliferation of HN cancer cell. These finding may describe practical potential to further translational research and clinical trials in HN cancer.Grant Funding Source: supported by the NRF of Korea (No. 2011‐0012555) and Ministry of Health & Welfare (A091205)
A novel N/OFQ antagonist that is potent, selective, orally‐bioavailable, and has demonstrable on‐target actions (656.4)
Authors: Barth Vanessa , Statnick Michael , McKinzie David , Rorick‐Kehn Linda , Kahl Steven , Toledo Miguel , Diaz Nuria , Lafuente Celia , Benito Ana , Jimenez Alma , Martinez‐Grau Maria , Pedregal Concepcion , Witkin Jeffrey 
Published: June 2021

Background: Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or NOP. Agonists and antagonists for the receptor have been designed and employed to help elucidate its biological functions. We now report on a highly potent, selective, and orally‐bio‐available antagonist with documented engagement of NOP receptors in vivo.Methods: Compound 1 was evaluated in in vitro, ex vivo, and in vivo assays to characterize its value as a NOP receptor antagonist research tool. These assays included filtration‐based [3H]‐Noc/OFQ receptor binding, blockade of Noc/OFQ stimulated GTP‐‐[35S] binding, and in vivo measures of N/OFQ receptor occupancy and blockade of Ro64,6198 induced hypothermia in Sprague‐Dawley rats.Results: Compound 1 has a Kb of 0.17nM as an antagonist of N/OFQ‐stimulated G protein activation and a binding affinity (Ki) for N/OFQ receptors of 0.1nM. No intrinsic agonist efficacy was observed in vitro at concentrations up to 10µM. Compound 1 occupies N/OFQ receptors in the rat brain following oral administration; ED80 = 0.3 mg/kg, p.o. In vivo activity was demonstrated by its potent inhibition (minimal effective dose = 0.1 mg/kg, p.o.) of hypothermic effects of an N/OFQ agonist.Conclusions: These data suggest that Compound 1 is as an orally‐active tool for assessments of the functional significance of NOP receptors.
Pharmacokinetic alternation of mitiglinide in depression model rats (657.3)
Authors: Xu Feng 
Published: June 2021

Many diabetes patients suffer from wild to severe depression. It is unclear that depression might alter the drug metabolic process of the hypoglycemic agents or not. We conducted an animal experiment to study the impact. Eighteen Sprague‐Dawley rats were randomized into depression model group and control group. The 9 depression rats were established by exposing to chronic unpredicted mild stresses (CUMS) for 8 weeks. Open‐field test and 5‐HT levels were assayed to evaluate the depression. All rats were given 2.5mg/kg of mitiglinide (MGN) per os. MGN plasma concentration was measured by HPLC‐MS/MS. Statistical moment analysis was processed with DAS software. Open‐field test and 5‐HT levels measurement results confirmed the depression model. Cmax, Tmax, AUC0→∞, MRT0→∞, and T1/2z were reduced while CLz/F was increased in depression model rats compared to control rats. These preliminary results suggest that depression might alter the drug metabolic process of MGN.Grant Funding Source: Supported by Shanghai Fengxian Science and Technology Research Project
From the research on anti‐inflammatory and immunopharmacology of a natural herbaceous peony to discovery of paeoniflorin ‐6'‐O‐ benzene sulfonate (657.4)
Authors: Wei Wei 
Published: June 2021

Objective. Total glucosides of paeony (TGP) were main active constituents of Paeonia lactiﬂora Pall. we have disclosed its antiinﬂammatory and immune effects via regulating balance of cytokines and cellular signaling. TGP was approved for treating rheumatoid arthritis (RA) by SFDA in 1998. TGP is more secure than DMARDs but with weak efficacy, which caused by poor absorption of paeoniflorin(Pae) that is one of main monomer of TGP .Therefore, series derivatives of Pae were screened based on PK/PD study. Pae‐6′‐O‐benzene sulfonate (CP‐25) was selected as a potential medicine. G protein‐coupled receptor (GPCRs) signaling such as EPs are negatively regulated byGRK2, and play an important role in dysfunction of fibroblast‐like synoviocytes (FLS) and immunocytes in RA. The objective is investigating effects of CP‐25 on inflammation and immune response, including the role of GPCR desensitization in functions and interaction of DC, FLS, T and B cells. Methods. Agonist, antagonist, siRNA and site mutation were used as intervention, and molecular biological technology were utilized. Results. We found that CP‐25 inhibited activation of immunocyte and FLS by binding to active sites of GRK2, inhibiting excessive transmembrane of GRK2, and modulating abnormal desensitization of GPCRs. Conclusion. This research offered a foundation for developing CP‐25 as a novel drugs for RA.Grant Funding Source: NSFC81330081
Antinociceptive effects of imidazoline I2 receptor agonists in the formalin test in rats (658.2)
Authors: Thorn David , Zhang Yanan , Li Jun‐Xu 
Published: June 2021

Pain is a significant global public health problem and currently available analgesics are not adequate to meet the clinical needs, leaving a big population with undertreated pain. The imidazoline I2 receptor is an emerging drug target for analgesics as I2 receptor agonists demonstrate antinociceptive effects in rodent models of acute and chronic pain. However, little is known of the neuroanatomical mechanism mediating I2 receptor agonist‐induced antinociception. This study examined the effects of the selective I2 receptor agonists 2‐BFI, BU224, and CR4056 using the formalin test in rats. 2‐BFI (1‐10 mg/kg, i.p.) and BU224 (1‐10 mg/kg, i.p.) dose‐dependently attenuated the spontaneous flinching behavior observed during 10min (phase 1) and 20‐60min (phase 2) following formalin (2%, 50µl) treatment, while CR4056 (1‐32 mg/kg, i.p.) only decreased phase 2 flinching. Local administration of 2‐BFI (1‐10 mg/kg, s.c.) to the hindpaw of rats had no antinociceptive effects. In contrast, centrally delivered 2‐BFI (10‐100 µg, i.c.v.) dose‐dependently attenuated phase 1 and phase 2 flinching. Together, these data suggest that I2 receptor agonists produce significant antinociception via a central mechanism and further supports that I2 receptors may represent a novel drug target to treat pain. (DA034806)Grant Funding Source: Supported by R01 DA034806/DA/NIDA NIH HHS/United States