bluuebunny/crossref_metadata_2025_split huggingface dataset:
What Is Known About Users Of Medical Cannabis Against Chronic Musculoskeletal Pain? A Scoping Review Of The Literature
Authors: Soliz Daniela Furrer , Dionne Clermont E , Marcotte Martine , Jauvin Nathalie , Bélanger Richard , Ware Mark , Foldes‐Busque Guillaume , Aubin Michèle , Pluye Pierre , Kröger Edeltraut 
Published: June 2021

IntroductionChronic musculoskeletal pain (CMP) is one of the most common causes of chronic pain that leads to reduced physical function. Currently, the pharmacotherapeutic options against CMP are limited and consist mainly in pain management with gabapentinoids or with opioids, which may have major adverse effects. Although the effectiveness of cannabis for medical purposes (or “medical cannabis”, MC) in the treatment of chronic pain still lacks evidence, a number of patients suffering from CMP are exploring this new therapeutic option. Knowledge regarding MC users suffering from CMP is quite limited but necessary to guide prescribers and policy makers considering this treatment as well as researchers planning rigorous randomized clinical trials on the effectiveness of MC.MethodsWe conducted a scoping literature review to describe the views and perceptions of patients who had consumed MC to relieve CMP, including demographic characteristics, patterns of MC use and perceived positive, negative or adverse effects.ResultsForty‐six studies were included in the present scoping review: 21 were conducted in the US, nine in Canada, ten in Europe, two in Australia, one in Israel, and three included data from several countries (up to 43) in Europe and North America. Our review shows that currently typical MC users are mainly young or middle‐aged men (mean age: 28–61), and the preferred form of use is smoking. A majority of the participants of included studies reported that MC use was helpful in reducing chronic pain with only minor adverse effects; in addition, they reported improved psychological well‐being.ConclusionsAlthough the information described in the included studies is still exploratory, MC use seems, from the perspective of persistent MC users suffering from chronic pain, to produce more benefits than harms.Support or Funding InformationThis study was supported by the Canadian Institutes of Health Research (CIHR).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Protective Role of the Somatostatin Receptor Subtype 4 in the Indomethacin‐Induced Gastrointestinal Mucosal Injury Model
Authors: Csekő Kata , Kormos Viktória , Horváth Ádám , Sudalina Maria , Iarushkina Natalia , Zelena Dóra , Filaretova Ludmila , Helyes Zsuzsanna 
Published: June 2021

Since gastrointestinal ulceration is still associated with high mortality despite advancements in the endoscopic and pharmacological management, precise understanding of the mucosal defensive and protective mechanisms is important. The neuropeptide somatostatin is present in the endocrine cells and sensory nerves, is analogues were shown to reduce mucosal blood flow, pepsin and gastric acid secretion. Its endocrine functions are mediated by the receptors sst2,3,5, and our group discovered that the anti‐inflammatory and analgesic actions are exerted via the sst4 receptor. Sst4 agonists are preclinically tested as novel drug candidates in theses areas. Therefore, we investigated the role of sst4 in gastrointestinal injury.Sst4 gene‐deleted (sst4 −/−) mice and wildtype counterparts (sst4 +/+) were treated s.c. with 35 mg/kg indomethacine (IDM) or its vehicle. Macroscopic and microscopic mucosal lesions in the stomach and small intestine were evaluated by the ImageJ program and semiquantitative histopathological scoring after 4 and 48 h, respectively. Small intestinal length, thymus, adrenal glands, spleen weight and plasma glucose levels were measured. Neutrophil myeloperoxidase (MPO) activity and plasma extravasation were measured by bioluminescent/fluorescent ex vivo imaging after 24 h.Macroscopic lesion area and MPO activity in the gastric mucosa were significantly greater in IDM‐treated sst4−/− mice than in wildtypes 4 h and 24 h after IDM administration, respectively. Similar tendency was observed in the duodenum and jejunum even after 48 h. However, IDM did not induce mucosal plasma extravasation in either group at the 24 h timepoint. Thymus weight was significantly less in sst4−/− mice than in sst4+/+ ones. Histopathological scores, small intestinal length, adrenal and spleen weight, and plasma glucose level were not altered by the sst4 deletion.These results provide evidence for a protective role of the sst4 receptor against chemical injury‐induced gastrointestinal mucosal damage. This shows the safety of sst4 agonist drug candidates in the gastrointestinal tract, and even highlights their potential use for gastroprotective indication.Support or Funding InformationGINOP‐2.3.2‐15‐2016‐00050 – PEPSYS, GINOP‐2.3.2 STAY ALIVE, EFOP‐3.6.2‐16‐2017‐00008, ÚNKP‐18‐3 New National Excellence Program of the Ministry of Human CapacitiesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Allosteric and orthosteric activation of mGlu2 receptors to alleviate dyskinesia and psychosis in the parkinsonian marmoset
Authors: Hamadjida Adjia , Nuara Stephen , Gourdon Jim , Huot Philippe 
Published: June 2021

ObjectiveTo determine the effect of combined allosteric and orthosteric activation of metabotropic glutamate 2 (mGlu2) receptors 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).BackgroundWe have previously demonstrated that activation of mGlu2 receptors via positive allosteric modulation with LY‐487,379 or orthosteric stimulation with LY‐354,740 alleviates PLBs and dyskinesia in experimental parkinsonism. Here, we seek to determine if synergy ensues when mGlu2 positive allosteric modulation and orthosteric stimulation are combined, in the MPTP‐lesioned marmoset.MethodsSix common marmosets 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 LY‐487,379 (1 mg/kg), LY‐354,740 (1 mg/kg), LY‐487,379/LY‐354,740 (each 1 mg/kg) or vehicle, in combination with L‐DOPA, after which the severity of each of PLBs, dyskinesia and parkinsonian disability was rated.ResultsLY‐487,379, LY‐354,740 and LY‐487,379/LY‐354,740 each significantly reduced the severity of the global dyskinesia score, by ≈ 42%, 55% and 64% (each P < 0.001), when compared to L‐DOPA/vehicle. The combination LY‐487,379/LY‐354,740 was significantly more effective than either treatment alone (both P < 0.05). The severity of the global PLB score was also significantly reduced by each of LY‐487,379, LY‐354,740 and LY‐487,379/LY‐354,740, by ≈ 51%, 44% and 56% (each P < 0.001), when compared to L‐DOPA/vehicle. The combination LY‐487,379/LY‐354,740 was significantly more effective than LY‐487,379 (P < 0.01), but not LY‐354,740 (P > 0.05). The benefits on dyskinesia and PLBs were achieved without compromising the therapeutic effect of L‐DOPA on parkinsonism.ConclusionsOur results confirm mGlu2 activation, via both positive allosteric modulation and orthosteric stimulation, is a promising strategy to reduce dyskinesia and psychosis in PD. Moreover, they suggest that the combination of a positive allosteric modulator and an orthosteric agonist may lead to a synergistic effect, thereby providing greater anti‐dyskinetic and anti‐psychotic effects.Support or Funding InformationFonds de Recherche Québec ‐ Santé, Natural Sciences and Engineering Research Council of Canada, Parkinson 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.
Selective Sensitization of Transduction pathways in Carotid Body Glomus Cells of Spontaneously Hypertensive Rats (SHR)
Authors: Tan Zhiyong , Lu Yongjun , Whiteis Carol , Chapleau Mark , Abboud Francois 
Published: June 2021

We have reported that the non‐voltage gated Acid‐Sensing Ion (Na+) Channels (ASICs) and the Tandem pore‐domain Acid‐Sensitive K+ channels (TASK) are low pH sensors in isolated rat glomus cells causing an initial rapid depolarization, and a sustained (Sust.) depolarization, respectively (Circ. Res. 2007; 101:1009‐19). TASK also mediate glomus cells' responses to hypoxia and to the mitochondrial inhibitor cyanide (Cn) (J Physiol. 2004; 556:175‐91).In the present study we tested whether hypersensitivity to low pH (6.0), which we had noted in glomus cells of young (4‐6 weeks) prehypertensive SHR (Hypertension, 2008; see table below), would also be evident with Cn‐induced mitochondrial inhibition. Our hypothesis was that the responses would be equally enhanced with Cn since both low pH and Cn inhibit TASK channels.Using real‐time PCR and western blot analyses we found significant increases in mRNA and protein expression of both ASIC3 and TASK1 in carotid bodies of SHR compared to WKY. However, the enhanced depolarizations (ΔmV) seen at low pH (6.0) in SHR compared to WKY (*P<0.05) were not seen with Cn (2 mM).We conclude that the non‐voltage gated Na+ (ASICs) and K+ (TASK) channels are significantly more sensitive to low pH than to inhibition of mitochondrial electron transport in SHR. The possibility of alternative transduction pathways for low pH vs. hypoxia or Cn remains to be determined.
Angiotensin II induces upregulation of AT1 receptors via the sequential activation of transcription factors NFkB, Elk‐1 and AP‐1 in Cath.a cells
Authors: Mitra Amit Kumar , Gao Lie , Zucker Irving H 
Published: June 2021

It has been clearly established that increased circulating Angiotensin II (Ang II) with concurrent upregulation of brain and peripheral Angiotensin 1‐receptors (AT1R) are important mediators in the pathophysiology of heart failure. In this study we aim to determine the role of sequential activation of transcription factors NFκB, AP‐1 and Elk‐1 in AT1R upregulation. We used Cath.a cells as our neuronal cell model which was treated with Ang II (100nM) over a time course. Western blotting was done for protein expression. Following Ang II activation, there was a temporal increase of the p65 subunit of NFkB. There was a concomitant decrease of IκB and increased IκK expression and AT1R expression. The activation of NFκB was blocked by using the inhibitor Parthenolide leading to a decrease in AT1R expression. The expression of Elk‐1 was upregulated following Ang II activation and was decreased following NFκB inhibition. Gene silencing using p65‐siRNA had similar effects as Parthenolide. The data are presented in the table. Our results suggest a combined role of NFκB, Elk‐1 and AP‐1 in the upregulation AT‐1R in Cath.a cells.Table showing fold change in protein expression compared to control. *p<0.01 vs. control.
High resolution duplex visualization details development of normal and exaggerated luminal stenosis following endarterectomy
Authors: Brown Aliza , Luo Shaoke , Howard Carol , Eidt John , Moursi Mohammed 
Published: June 2021

Reparative surgical procedures in the carotid are limited by intimal hyperplasia. To understand initial patterns of hyperplasia development, we studied circumferential measurements of luminal narrowing, arterial peak systolic velocity (PSV) and end diastolic velocity (EDV) measurements in a rat carotid endarterectomy (CEA).Three male Sprague Dawley rats (450 g BW) served as a normal hyperplasia development group (CON) and N=4 rats had dietary 4.5 g/kg DL‐homocystine (HCYS) added for exaggerated proliferation. Carotids were visualized in real time and duplexed pre‐operatively and 4, 9 and 14 days post‐CEA (Pre‐OP or D4, D9 and D14). PSV/EDV measurements and lesion development was noted longitudinally and circumferential measurements were taken across the suture line. Volume calculations measured lumenal narrowing and were compared to Pre‐Op.Post‐Op PSV/EDV measurements were increased above Pre‐Op levels at D4 through D14 at p<0.05. In HCYS both PSV/EDV were higher at D14 vs. CON at p=0.051 and p=0.018, respectively. Along the anastomosis lumenal narrowing was indicated for both CON and HCYS in Pre‐OP vs. Post‐Op beginning at D4 (p=0.0241 and p=0.0450, respectively). At D14, there was more luminal narrowing in HCYS rats vs. CON at p=0.0001.We observed by duplex that lumenal stenosis is dynamic and changes occur as early as D4 with concomitant influences on arterial pressure. Funded by US Gov, VA Merit Review.
Oxidative stress contributes to increased susceptibility to renal injury induced by mild ischemia‐reperfusion in low birth weight
Authors: Ojeda Norma B 
Published: June 2021

The risk for renal disease is increased in low birth weight (LBW). Susceptibility to renal injury is increased in a rat model of LBW; however, the mechanism(s) involved is not clear. We hypothesize that oxidative stress contributes to LBW susceptibility to renal injury. To investigate rats were treated with vehicle (UT) or superoxide dismutase mimetic (Tempol, 30mg/k, T) starting 15 min prior to mild ischemia (15 min) and during reperfusion (2 hr). Treatment ameliorated the increase in mean arterial pressure (MAP) and renal vascular resistance (RVR), and the decrease in glomerular filtration rate (GFR), and renal blood flow (RBF), and the increase in renal oxidative stress in LBW (Table). Therefore, this data suggest that oxidative stress may contribute to increased susceptibility to renal injury in LBW.* P < 0.05 vs. Control† P < 0.05 vs. UT Counterpart
Intra‐Renal Delivery of Progenitor Cells Improves Systemic Inflammation, Oxidative Stress, and Myocardial Microvascular Function in Experimental Renovascular Disease
Authors: Urbieta Victor Hugo , Zhu Xiangyang , Chade Alejandro , Krier James D , Lerman Amir , Lerman Lilach O 
Published: June 2021

Renovascular disease (RVD) and hypertension (HT) are cardiovascular risk factors, but if recovery of renal function can reverse cardiac dysfunction remained unclear.We hypothesized that improved stenotic kidney function would rescue myocardial microvascular (MMV) function in renovascular HT by reducing oxidative stress and inflammation.Single‐kidney hemodynamics and function and MMV permeability were assessed in pigs in vivo using CT after 6 weeks of RVD. Autologous endothelial progenitor cells (EPC) were then infused intra‐renally, and studies repeated 4 weeks later (RVD+EPC, n=7). Normal and untreated RVD (n=7 each) served as controls.Blood pressure was similarly increased in RVD and RVD+EPC pigs. Compared to normal, RVD showed elevated systemic TNF‐alpha (142.3± 3.7 vs 43.3 ± 3.5 pg/ml, p<0.001) and oxidized‐LDL, blunted glomerular filtration rate (47.9±10.1 vs 70.8 ± 4.3 ml/min, p<0.05), decreased MMV volume fraction, increased MMV permeability, and myocardial fibrosis.EPC were rarely observed in myocardium. However, RVD+EPC showed a decrease in TNF‐alpha (90.5± 2.9, p<0.01 vs RVD) and oxidized‐LDL, implying decreased inflammation and oxidative stress. Furthermore, not only renal, but also MMV function were significantly improved in RVD+EPC.In conclusion, selective improvement in renal function reduces oxidative stress and inflammation and preserves remote MMV function, underscoring functionally important cardiorenal crosstalk.
THE PATHOGENESIS OF HEREDITARY HEMOCHROMATOSIS
Authors: Ramos Emilio , Ganz Tomas , Nemeth Elizabeta 
Published: June 2021

Hereditary hemochromatosis (HH) is an iron overload disease which can result from mutations in HFE, transferrin receptor 2 (TfR2), hemojuvelin (HJV) or hepcidin, all of which lead to inadequate synthesis of the iron‐regulatory hormone hepcidin. Hepcidin deficiency in HH results in excessive iron absorption. In normal homeostasis, hepcidin production is increased by iron loading. In HH, however, hepcidin is inappropriately low for the degree of iron load suggesting that HFE, TfR2 and HJV may be involved in hepcidin regulation by iron.We explored hepcidin regulation by iron in three mouse models of HH: TfR2 mutants, HFE ‐/‐ and HJV‐/‐. HFE−/− and TfR2m/m had a dramatically blunted response to 1 d iron feeding. HFE‐/‐ also failed to increase hepcidin even after 21 d on iron diet but TfR2m/m increased hepcidin comparable to wt mice. This suggests there are two types of iron signals regulating hepcidin, one likely involving circulating iron and depending on both HFE and TfR2 (acute signal) and the other involving HFE but not TfR2 (chronic signal). HJV−/− mice, which had extremely low hepcidin mRNA expression, were not able to increase hepcidin after 1, 7 or 21 d of iron diet, indicating that apart from setting hepcidin baseline, HJV may also be necessary for hepcidin regulation by iron. HH can thus result from both decreased hepcidin baseline and the loss of hepcidin response to acute or chronic changes in iron levels.
HuR and AUF1 Competitively Bind to the JunD mRNA and Regulate its Stability in Intestinal Epithelial Cells
Authors: Zou Tongtong , Rao Jaladanki N , Liu Lan , Xiao Lan , Yu Tingxi , Wang Pengyuan , Zhang Xian , Gorospe Myriam , Wang Jian‐Ying 
Published: June 2021

JunD is an AP‐1 transcription factor and plays an important role in regulating intestinal epithelial integrity, but the mechanism underlying JunD expression remains unclear. RNA‐binding proteins HuR and AUF1 associate with labile mRNAs bearing AU‐rich elements (AREs) and modulate their turnover and translation. This study determined if HuR and AUF1 regulate JunD expression by interacting with its 3′‐untranslated region (3'UTR).MethodsStudies were conducted in intestinal crypt cells. RNA‐binding was examined by biotin pull‐down and RNP‐IP assays. JunD mRNA stability was examined by its half‐life and the chimeric Luc‐JunD‐3'UTR reporter assays. HuR and AUF1 functions were tested by their silencing and overexpression.ResultsHuR and AUF bound to JunD mRNA via AREs in its 3'UTR. Studies mapping JunD 3'UTR revealed that HuR specifically bound to the fragments (F) 3 and 5 that contain high ARE levels, whereas AUF1 interacted with the F5 only. HuR competitively inhibited AUF1 binding to JunD mRNA; HuR silencing not only decreased its binding to JunD 3'UTR but also induced AUF1 affinity for JunD mRNA. Increased HuR stabilized JunD mRNA by both increasing its interaction with the JunD 3'UTR and decreasing AUF1 binding to JunD mRNA.ConclusionsThese results indicate that HuR and AUF1 competitively bind to the JunD 3'UTR and that the ratios of HuR and AUF1 bound to JunD mRNA permit dynamic control of JunD mRNA stability.
In vitro effects of lactic acid on bioelectric properties of equine nonglandular squamous mucosa
Authors: Andrews Frank Michael , Buchanan Benjamin R , Elliott Sarah B , Jassim Rafat Al , McGowan Catherine , Saxton Arnold 
Published: June 2021

Equine gastric ulcers are common in the nonglandular (NG) region and volatile fatty acids (VFAs), byproducts of carbohydrate fermentation by resident gastric bacteria, have been implicated. Lactic acid (LA), also produced by bacteria, may cause ulcers.Our objective was to investigate the in vitro effects of LA on NG mucosal bioelectric properties. Equine gastric tissues (n=13) were studied in Ussing chambers to measure short‐circuit current (Isc) and potential difference (PD). Electrical resistance (R) and conductance (G) were calculated after addition of HCl and LA (5, 10, 20, or 40 mM) in normal Ringer's Solution. Tissues were examined for histopathology.Mucosa exposed to HCl in NRS at pH 1.5 and 4.0 had a significant decrease in Isc and PD; whereas tissues exposed to LA (5, 10, and 20 mM) did not demonstrate significant decreases in Isc and PD. However, mucosa exposed to LA (40 mM), at pH 1.5 demonstrated increased G and decreased R. Histologic changes were consistent with HCl‐induced damage.HCl induced alterations in bioelectric properties of equine NG mucosa, whereas addition of LA (5, 10, 20 mM) did not. However, 40 mM LA at pH 1.5 increased tissue permeability. Lactic acid, produced by resident gastric bacteria, may increase equine NG mucosal permeability by a different mechanism than VFAs which may be important in gastric ulcer pathogenesis.Funded by the Comparative Gastroenterology Society.
Increased BNP during Myocardial Injury Decreases Gastric Emptying and Gastrointestinal Absorption
Authors: Addisu Anteneh , Gower William R. , Dietz John R. 
Published: June 2021

We have shown that B‐type Natriuretic peptide (BNP) decreases gastric emptying and absorption in mice. We examined whether acute myocardial injury which releases BNP also affects gastric emptying and absorption. Wild‐type (WT) and NPR‐A receptor knockout (KO) mice were anesthetized with isoflurane. A 2 mm incision was made between the 4th and 5th intercostal space and a probe cooled in liquid nitrogen applied directly to the left ventricle to induce cryo‐infarction. In WT mice, gastric emptying (%) one week after MI was 68 ± 6 vs. 89 ± 3 in sham (n=5, P<0.05). Two weeks after MI, emptying was 82 ± 1 vs. 98 ± 1, MI vs. sham (n=5, P<0.05). Absorption, (relative plasma fluorescence) was 350 ± 79 vs. 632 ± 121; (n=6, P< 0.05) MI vs. sham. KO mice showed no significant difference in emptying or absorption. Echocardiography showed left ventricular (LV) ejection fraction of 48 ± 3 vs. 64 ± 2 % (P<0.05), fractional shortening of 24 ± 2 vs. 35 ± 2 % (P<0.01), LV systolic volume (μl) of 51 ± 7 vs. 26 ± 3 (P<0.05), LV posterior wall thickness (mm) of 0.76 ± 0.10 vs. 1.15 ± 0.10 (P<0.05), MI vs. sham respectively. BNP levels (pg/ml) were 4292 ± 276 one week after MI vs. 105 ± 11 in sham (n=5, p<0.05). BNP levels were 1965 ± 755 two weeks after MI, (n=5, p<0.05).ConclusionsElevated plasma BNP following acute myocardial injury decreases gastric emptying and absorption in mice. (Support: VA Merit Award to William R. Gower Jr. & NSF/IGERT, Grant to A. Addisu)
CHARACTERIZATION OF MYOCARDIAL CONTRACTILE DYSFUNCTION IN TYPE 2 DIABETES MOUSE MODEL
Authors: Fricovsky Eduardo Santiago , Ihm Sang , Suarez Jorge , Scott Brian , Belke Darrell , Oyeleye Mary , Villarreal Francisco , Dillmann Wolfgang H 
Published: June 2021

CHARACTERIZATION OF MYOCARDIAL CONTRACTILE DYSFUNCTION IN TYPE 2 DIABETES MOUSE MODELEduardo Fricovsky, Sang Ihm, Jorge Suarez, Brian Scott, Francisco Villarreal, , Darrell Belke, Mary O. Oyeleye, Wolfgang DillmannUniversitty of California, San Diego, La Jolla California.Type 2 diabetes mellitus (DMII) contributes to cardiac dysfunction. Characterization of the development of cardiac dysfunction in DMII animal models has been incompletely explored. Currently, it is unknown if cardiac dysfunction occurs in DMII mouse even with mild hyperglycemia and insulin resistance. DMII was induced in mice by feeding a high fat diet (60% fat) and administering a single low dose of streptozotocin (75 mg/Kg). Echocardiography was performed at 2, 4, and 6 months post treatment and diastolic and systolic parameters, as well as biochemical analysis were assessed. Our results show that DMII mice have slightly increased fasting blood glucose compared with control mice (DMII: 124±13 vs. Control: 90±2.0mg/dL). Insulin serum levels were 3 fold increased starting at 2 months in DMII mice suggesting insulin resistance. At 6 months of DMII SERCA2a protein levels was significantly decreased by 50% in hearts. Echo results also showed that at 6 months of DMII mouse hearts already exhibited significant cardiac dysfunction. Fractional Shortening was significantly reduced (DMII: 30.8±6.1% vs. Control: 40.8±4.5%) and LV diastolic (DMII: 3.59±0.16mm vs. Control: 4.03±0.14mm) and systolic (DMII: 2.13±0.2mm vs. Control: 2.79±0.3mm) dimensions were decreased. In conclusion, this data indicates that cardiac dysfunction can develop in DMII mouse hearts even with mild hyperglycemia.