bluuebunny/crossref_metadata_2025_split huggingface dataset:
Skin temperature measured by infrared thermography after ultrasound‐guided blockade of the sciatic nerve
Authors: VAN HAREN F. G. A. M. , KADIC L. , DRIESSEN J. J 
Published: August 2013

BackgroundIn the present study, we assessed the relationship between subgluteal sciatic nerve blocking and skin temperature by infrared thermography in the lower extremity. We hypothesized that blocking the sciatic nerve will lead to an increase in temperature, and that this will correlate with existing sensory block tests.MethodsWe studied 18 healthy individuals undergoing orthopaedic surgery of the foot under ultrasound‐guided subgluteal blockade of the sciatic nerve with 30 ml ropivacaine 7.5 mg/ml. Skin temperature was measured on the toes, the dorsal and plantar side of the foot, the malleoli, and the lateral side of the lower leg, just before sciatic nerve blockade and at 10‐min intervals thereafter.ResultsBaseline skin temperatures showed a significant distal‐to‐proximal gradient. After sciatic block, temperatures on the blocked side increased significantly in the toes and foot. When comparing pinprick to skin temperature in a receiver operating curve, there was an AUC of 85.9% (95% confidence interval = 83.7–88.2%, P < 0.001). The medial malleolus (not being innervated by the sciatic nerve) showed no significant difference to the lateral.ConclusionsAfter sciatic nerve block, temperatures of the foot increased significantly. There was a good correlation between pinprick testing and infrared temperature measurement. This makes infrared skin temperature measuring a good test in determining block success when sensory testing is impossible.
Maintenance of muscle mass and load‐induced growth in Muscle RING Finger 1 null mice with age
Authors: Hwee Darren T. , Baehr Leslie M. , Philp Andrew , Baar Keith , Bodine Sue C. 
Published: August 2013

SummaryAge‐related loss of muscle mass occurs to varying degrees in all individuals and has a detrimental effect on morbidity and mortality. Muscle RING Finger 1 (MuRF1), a muscle‐specific E3 ubiquitin ligase, is believed to mediate muscle atrophy through the ubiquitin proteasome system (UPS). Deletion of MuRF1 (KO) in mice attenuates the loss of muscle mass following denervation, disuse, and glucocorticoid treatment; however, its role in age‐related muscle loss is unknown. In this study, skeletal muscle from male wild‐type (WT) and MuRF1 KO mice was studied up to the age of 24 months. Muscle mass and fiber cross‐sectional area decreased significantly with age in WT, but not in KO mice. In aged WT muscle, significant decreases in proteasome activities, especially 20S and 26S β5 (20–40% decrease), were measured and were associated with significant increases in the maladaptive endoplasmic reticulum (ER) stress marker, CHOP. Conversely, in aged MuRF1 KO mice, 20S or 26S β5 proteasome activity was maintained or decreased to a lesser extent than in WT mice, and no increase in CHOP expression was measured. Examination of the growth response of older (18 months) mice to functional overload revealed that old WT mice had significantly less growth relative to young mice (1.37‐ vs. 1.83‐fold), whereas old MuRF1 KO mice had a normal growth response (1.74‐ vs. 1.90‐fold). These data collectively suggest that with age, MuRF1 plays an important role in the control of skeletal muscle mass and growth capacity through the regulation of cellular stress.
Secondary Analysis of Publicly Available Data Reveals Superoxide and Oxygen Radical Pathways are Enriched for Associations Between Type 2 Diabetes and Low‐Frequency Variants
Authors: Yazdanpanah Mojgan , Chen Chuhua , Graham Jinko 
Published: August 2013

SummaryGenome‐wide association studies explain at most 5%‐10% of the heritable components of type 2 diabetes. Some of the “missing type 2 diabetes heritability” could be explained by low‐frequency variants. We examined the associations between low‐frequency variants and type 2 diabetes, using data from 2538 diabetic and 2977 nondiabetic subjects in the publicly available database of Genotypes and Phenotypes. We applied two approaches. First, we combined information from all low‐frequency (1%‐5%) variants at a locus in a gene‐centric analysis of associations with diabetes. Next, we searched for gene ontology (GO) biological processes that were enriched for gene‐centric associations, after correcting for multiple testing to control the false discovery rate (FDR). We found three GO biological processes that were significantly enriched for associations to diabetes: “response to superoxide” (FDR‐adjusted p = 2.7 × 10−3), “response to oxygen radical” (FDR‐adjusted p = 2.7 × 10−3), and “heart contraction” (FDR‐adjusted p = 2.6 × 10−2). There were three genes that contributed to “response to superoxide” and “oxygen radical” pathways, including the SOD1 gene. Gene‐centric tests of association with low‐frequency variants, followed by analysis to evaluate which biological pathways are enriched for these associations has the potential to recover, at least some proportion of, the “missing heritability” of type 2 diabetes.
TAK‐875, a GPR40/FFAR1 agonist, in combination with metformin prevents progression of diabetes and β‐cell dysfunction in Zucker diabetic fatty rats
Authors: Ito R , Tsujihata Y , Matsuda‐Nagasumi K , Mori I , Negoro N , Takeuchi K 
Published: August 2013

Background and PurposeTAK‐875, a selective GPCR40/free fatty acid receptor 1 agonist, improves glycaemic control by increasing glucose‐dependent insulin secretion. Metformin is a first‐line drug for treatment of type 2 diabetes that improves peripheral insulin resistance. Based on complementary mechanism of action, combining these agents is expected to enhance glycaemic control. Here, we evaluated the chronic effects of TAK‐875 monotherapy and combination therapy with metformin in diabetic rats.Experimental ApproachLong‐term effects on glycaemic control and β‐cell function were evaluated using Zucker diabetic fatty (ZDF) rats, which develop diabetes with hyperlipidaemia and progressive β‐cell dysfunction.Key ResultsSingle doses of TAK‐875 (3–10 mg·kg−1) and metformin (50–150 mg·kg−1) significantly improved both postprandial and fasting hyperglycaemia, and additive improvements were observed in their combination. Six‐week treatment with TAK‐875 (10 mg·kg−1, b.i.d.) significantly decreased glycosylated Hb (GHb) by 1.7%, and the effect was additively enhanced by combination with metformin (50 mg·kg−1, q.d.; GHb: −2.4%). This improvement in glycaemic control in the combination group was accompanied by significant 3.2‐fold increase in fasting plasma insulin levels. Pancreatic insulin content was maintained at a level comparable to that in normal rats by combination treatment (vehicle: 26, combination: 67.1; normal lean: 69.1 ng·mg−1 pancreas) without affecting pancreatic glucagon content. Immunohistochemical analyses revealed normal morphology, enhanced pancreas duodenum homeobox‐1 expression and increased PCNA‐positive cells in islets of the combination group.Conclusion and ImplicationsOur results indicate that combination therapy with TAK‐875 and metformin could be a valuable strategy for glycaemic control and β‐cell preservation in type 2 diabetes.
In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects
Authors: Ignatowska‐Jankowska B M , Ghosh S , Crowe M S , Kinsey S G , Niphakis M J , Abdullah R A , Tao Q , O' Neal S T , Walentiny D M , Wiley J L , Cravatt B F , Lichtman A H 
Published: August 2013

Background and PurposeSince monoacylglycerol lipase (MAGL) has been firmly established as the predominant catabolic enzyme of the endocannabinoid 2‐arachidonoylglycerol (2‐AG), a great need has emerged for the development of highly selective MAGL inhibitors. Here, we tested the in vivo effects of one such compound, KML29 (1,1,1,3,3,3‐hexafluoropropan‐2‐yl 4‐(bis(benzo[d][1,3]dioxol‐5‐yl)(hydroxy)methyl)piperidine‐1‐carboxylate).Experimental ApproachIn the present study, we tested KML29 in murine inflammatory (i.e. carrageenan) and sciatic nerve injury pain models, as well as the diclofenac‐induced gastric haemorrhage model. KML29 was also evaluated for cannabimimetic effects, including measurements of locomotor activity, body temperature, catalepsy, and cannabinoid interoceptive effects in the drug discrimination paradigm.Key ResultsKML29 attenuated carrageenan‐induced paw oedema and completely reversed carrageenan‐induced mechanical allodynia. These effects underwent tolerance after repeated administration of high‐dose KML29, which were accompanied by cannabinoid receptor 1 (CB1) receptor desensitization. Acute or repeated KML29 administration increased 2‐AG levels and concomitantly reduced arachidonic acid levels, but without elevating anandamide (AEA) levels in the whole brain. Furthermore, KML29 partially reversed allodynia in the sciatic nerve injury model and completely prevented diclofenac‐induced gastric haemorrhages. CB1 and CB2 receptors played differential roles in these pharmacological effects of KML29. In contrast, KML29 did not elicit cannabimimetic effects, including catalepsy, hypothermia and hypomotility. Although KML29 did not substitute for Δ9‐tetrahydrocannabinol (THC) in C57BL/6J mice, it fully and dose‐dependantly substituted for AEA in fatty acid amide hydrolase (FAAH) (−/−) mice, consistent with previous work showing that dual FAAH and MAGL inhibition produces THC‐like subjective effects.Conclusions and ImplicationsThese results indicate that KML29, a highly selective MAGL inhibitor, reduces inflammatory and neuropathic nociceptive behaviour without occurrence of cannabimimetic side effects.Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐6
ORM‐10103: a significant advance in sodium‐calcium exchanger pharmacology?
Authors: Terracciano C M , Hancox J C 
Published: August 2013

The sodium‐calcium exchanger (NCX) is an electrogenic transporter that is widely expressed in different tissues. In the heart, the NCX plays important roles in calcium ion homeostasis, excitation‐contraction coupling and the electrophysiological properties of cardiac myocytes. Precise determination of the roles of the NCX has somewhat been hampered by a lack of selective small molecule inhibitors. In this issue of the BJP, Jost and colleagues present data on a new NCX inhibitor, ORM‐10103, which has submicromolar EC50 values against cardiac forward and reverse exchange activity. The compound exhibits improved selectivity over existing small molecule NCX inhibitors and, in particular, appears to be without effect on L‐type calcium channels at high concentrations. ORM‐10103 could therefore have significant value for studies of the (patho)physiological roles of the NCX in the heart. Further pharmacological studies are required to investigate the actions of ORM‐10103 on cardiac cells and tissues and to determine its effects on non‐cardiac NCX isoforms.Linked ArticleThis article is a commentary on Jost et al., pp. 768–778 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12228
Treatment with resveratrol attenuates sublesional bone loss in spinal cord‐injured rats
Authors: Wang Hua‐Dong , Shi Ya‐Min , Li Li , Guo Ji‐Dong , Zhang Yu‐Peng , Hou Shu‐Xun 
Published: August 2013

Background and PurposeSublesional osteoporosis predisposes individuals with spinal cord injury (SCI) to an increased risk of low‐trauma fracture. The aim of the present work was to investigate the effect of treatment with resveratrol (RES) on sublesional bone loss in spinal cord‐injured rats.Experimental ApproachComplete SCI was generated by surgical transaction of the cord at the T10–12 level. Treatment with RES (400 mg·kg−1 body mass per day−1, intragastrically) was initiated 12 h after the surgery for 10 days. Then, blood was collected and femurs and tibiae were removed for evaluation of the effects of RES on bone tissue after SCI.Key ResultsTreatment of SCI rats with RES prevented the reduction of bone mass including bone mineral content and bone mineral density in tibiae, preserved bone structure including trabecular bone volume fraction, trabecular number, and trabecular thickness in tibiae, and preserved mechanical strength including ultimate load, stiffness, and energy in femurs. Treatment of SCI rats with RES enhanced femoral total sulfhydryl content, reduced femoral malondialdehyde and IL‐6 mRNA levels. Treatment of SCI rats with RES suppressed the up‐regulation of mRNA levels of PPARγ, adipose‐specific fatty‐acid‐binding protein and lipoprotein lipase, and restored mRNA levels of Wnt1, low‐density lipoprotein‐related protein 5, Axin2, ctnnb1, insulin‐like growth factor 1 (IGF‐1) and receptor for IGF‐1 in femurs and tibiae.Conclusions and ImplicationsTreatment with RES attenuated sublesional bone loss in spinal‐cord‐injured rats, associated with abating oxidative stress, attenuating inflammation, depressing PPARγ signalling, and restoring Wnt/β‐catenin and IGF‐1 signalling.
Levels of heroin and its metabolites in blood and brain extracellular fluid after i.v. heroin administration to freely moving rats
Authors: Gottås A , Øiestad E L , Boix F , Vindenes V , Ripel Å , Thaulow C H , Mørland J 
Published: August 2013

Background and PurposeHeroin, with low affinity for μ‐opioid receptors, has been considered to act as a prodrug. In order to study the pharmacokinetics of heroin and its active metabolites after i.v. administration, we gave a bolus injection of heroin to rats and measured the concentration of heroin and its metabolites in blood and brain extracellular fluid (ECF).Experimental ApproachAfter an i.v. bolus injection of heroin to freely moving Sprague–Dawley rats, the concentrations of heroin and metabolites in blood samples from the vena jugularis and in microdialysis samples from striatal brain ECF were measured by ultraperformance LC‐MS/MS.Key ResultsHeroin levels decreased very fast, both in blood and brain ECF, and could not be detected after 18 and 10 min respectively. 6‐Monoacetylmorphine (6‐MAM) increased very rapidly, reaching its maximal concentrations after 2.0 and 4.3 min, respectively, and falling thereafter. Morphine increased very slowly, reaching its maximal levels, which were six times lower than the highest 6‐MAM concentrations, after 12.6 and 21.3 min, with a very slow decline during the rest of the experiment and only surpassing 6‐MAM levels at least 30 min after injection.Conclusions and ImplicationsAfter an i.v. heroin injection, 6‐MAM was the predominant opioid present shortly after injection and during the first 30 min, not only in the blood but also in rat brain ECF. 6‐MAM might therefore mediate most of the effects observed shortly after heroin intake, and this finding questions the general assumption that morphine is the main and most important metabolite of heroin.
A novel androgen signalling pathway uses dihydrotestosterone, but not testosterone, to activate the EGF receptor signalling cascade in prostate stromal cells
Authors: Oliver V L , Poulios K , Ventura S , Haynes J M 
Published: August 2013

Background and PurposeHuman prostate growth and function are tightly controlled by androgens that are generally thought to exert their effects by regulating gene transcription. However, a rapid, non‐genomic steroid action, often involving an elevation of intracellular calcium ([Ca2+]i), has also been described in a number of cell types. In this study we investigate whether androgens acutely regulate [Ca2+]i in stromal cells derived from the human prostate.Experimental ApproachHuman‐cultured prostatic stromal cells (HCPSCs) were loaded with the calcium‐sensitive fluorophore, fura‐2‐acetoxymethyl ester (FURA‐2AM) (10 μM). Changes in [Ca2+]i in response to the androgens, dihydrotestosterone (DHT) and testosterone, as well as EGF were measured by fluorescence microscopy.Key ResultsDHT, but not testosterone (0.03–300 nM), elicited concentration‐dependent elevations of [Ca2+]i within 1 min of addition. These responses were blocked by the androgen receptor antagonist, flutamide (10 μM); the sarcoplasmic reticulum ATPase pump inhibitor, thapsigargin (1 μM); the inositol trisphosphate receptor inhibitor, 2‐aminoethyldiphenyl borate (50 μM) and the PLC inhibitor, U‐73122 (1 μM). Responses were also blocked by the L‐type calcium channel blocker, nifedipine (1 μM), and by removal of extracellular calcium. A similar transient elevation of [Ca2+]i was elicited by EGF (100 ng·mL−1). The EGF receptor inhibitor, AG 1478 (30 nM), and the MMP inhibitor, marimastat (100 nM), blocked the DHT‐induced elevation of [Ca2+]i.Conclusions and ImplicationsThese studies show that DHT elicits an androgen receptor‐dependent acute elevation of [Ca2+]i in HCPSC, most likely by activating EGF receptor signalling.
Midkine and cytoplasmic maturation of mammalian oocytes in the context of ovarian follicle physiology
Authors: Ikeda Shuntaro , Yamada Masayasu 
Published: August 2013

Midkine (MK) was originally characterized as a member of a distinct family of neurotrophic factors functioning in theCNS. However, it was later discovered that MK is abundantly expressed in ovarian follicles. Since then, the physiological roles of this molecule in the ovary have been steadily investigated. During thein vitromaturation (IVM) of oocytesMKwas shown to promote the cytoplasmic maturation of oocytes, as indicated by post‐fertilization development. This effect ofMKcould be mediated via its pro‐survival (anti‐apoptotic) effects on the cumulus‐granulosa cells that surround oocytes. The oocyte competence‐promoting effects ofMKare discussed in the context of the recently discovered involvement ofMKin the full maturation of ovarian follicles.MKwas at the frontline of a new paradigm for neurotrophic factors as oocytetrophic factors.MKmay promote the developmental competence of oocytes via common signalling molecules with the other neurotrophic factor(s). Alternatively or concomitantly,MKmay also interact with various transmembrane molecules on cumulus‐granulosa cells, which are important for ovarian follicle growth, dominance and differentiation, and act as a unique pro‐survival factor in ovarian follicles, such thatMKpromotes oocyte competence.MK, along with other ovarian neurotrophic factors, may contribute to the optimization of theIVMsystem.Linked ArticlesThis article is part of a themed section on Midkine. To view the other articles in this section visithttp://dx.doi.org/10.1111/bph.2014.171.issue‐4
Endothelial TRPV4 channels mediate dilation of cerebral arteries: impairment and recovery in cerebrovascular pathologies related to Alzheimer's disease
Authors: Zhang Luqing , Papadopoulos Panayiota , Hamel Edith 
Published: August 2013

Background and PurposeTransient receptor potential vanilloid type 4 (TRPV4) channels are expressed in brain endothelial cells, but their role in regulating cerebrovascular tone under physiological and pathological conditions is still largely unknown.Experimental ApproachWild‐type (WT) mice and mice that overexpress a mutated form of the human amyloid precursor protein (APP mice, model of increased amyloid β), a constitutively active form of TGF‐β1 (TGF mice, model of cerebrovascular fibrosis) or both (APP/TGF mice) were used. Dilations to the selective TRPV4 channel opener GSK1016790A (GSK) or to ACh were measured in posterior cerebral artery segments.Key ResultsBoth GSK‐ and ACh‐induced dilations virtually disappeared following endothelium denudation in WT mice. These responses were impaired in vessels from APP, TGF and APP/TGF mice compared with WT. Pre‐incubation of WT vessels with the selective TRPV4 channel blocker HC‐067047, or with small‐conductance (SK channel, apamin) and/or intermediate‐conductance (IK channel, charybdotoxin, ChTx) Ca2+‐sensitive K+ channel blocker abolished GSK‐induced dilations and massively decreased those induced by ACh. These treatments had no or limited effects on ACh‐induced dilation in vessels from APP, TGF or APP/TGF mice, and IK and SK channel function was preserved in transgenic mice. Antioxidant superoxide dismutase or catalase normalized GSK‐ and ACh‐mediated dilations only in APP brain arteries.Conclusion and ImplicationsWe conclude that endothelial TRPV4 channels mediate ACh‐induced dilation in cerebral arteries, that they are impaired in models of cerebrovascular pathology and that they are sensitive, albeit in the reversible manner, to amyloid β‐induced oxidative stress.
Simvastatin induces a central hypotensive effect via Ras‐mediated signalling to cause eNOS up‐regulation
Authors: Cheng Wen‐Han , Ho Wen‐Yu , Chang Chien‐Feng , Lu Pei‐Jung , Cheng Pei‐Wen , Yeh Tung‐Chen , Hong Ling‐Zong , Sun Gwo‐Ching , Hsiao Michael , Tseng Ching‐Jiunn 
Published: August 2013

Background and PurposeClinical studies indicate that statins have a BP‐lowering effect in hypercholesterolemic individuals with hypertension. Specifically, statins modulate BP through the up‐regulation of endothelial NOS (eNOS) activation in the brain. However, the signalling mechanisms through which statins enhance eNOS activation remain unclear. Therefore, we examined the possible signalling pathways involved in statin‐mediated BP regulation in the nucleus tractus solitarii (NTS).Experimental ApproachTo investigate the involvement of Ras and other signalling pathways in simvastatin‐induced effects on BP, BP and renal sympathetic nerve activity (RSNA) were determined in spontaneously hypertensive rats (SHRs) before and after i.c.v. administration of simvastatin in the absence and presence of a Ras‐specific inhibitor (farnesyl thiosalicylic acid, FTS), a geranylgeranyltransferase inhibitor (GGTI‐2133), a PI3K inhibitor (LY294002) or a MAPK‐ERK kinase (MEK) inhibitor (PD98059).Key ResultsFTS significantly attenuated the decrease in BP and increased NO evoked by simvastatin and reversed the decrease in basal RSNA induced by simvastatin. Immunoblotting and pharmacological studies showed that inhibition of Ras activity by FTS significantly abolished simvastatin‐induced phosphorylation of ERK1/2, ribosomal protein S6 kinase (RSK), Akt and decreased eNOS phosphorylation. Likewise, administration of Akt and ERK1/2 signalling inhibitors, LY294002 and PD98059, attenuated the reduction in BP evoked by simvastatin. Furthermore, i.c.v. simvastatin decreased Rac1 activation and the number of ROS‐positive cells in the NTS.Conclusions and ImplicationsSimvastatin modulates central BP control in the NTS of SHRs by increasing Ras‐mediated activation of the PI3K‐Akt and ERK1/2‐RSK signalling pathways, which then up‐regulates eNOS activation.