bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic Sustained Hypoxic Exposure Can Improve Glucose Metabolism in Mice
Authors: Park Yeram , Hwang Deunsol , Kim Jisu , Lim Kiwon 
Published: April 2020

PurposeHypoxic therapy has been reported to improve glucose metabolism. In previous studies, there were many studies that determined whether hypoxia regulate glucose metabolism. However, it is still unclear whether hypoxia would only affect whole‐body energy expenditure and energy utilization. In addition, along with energy metabolism, it needs to confirm the gene expression associated with glucose metabolism. Therefore, the purpose of the present study was to investigate the effects of hypoxia exposure on resting metabolic rate, changes of protein expression related to glucose metabolism and mitochondrial biogenesis in muscle tissue.MethodsSeven‐week‐old ICR male mice (n=16) were divided into two groups: normoxia pair‐fed to hypoxia (Nor), chronic hypoxia (Chr). Normoxia group was exposed to 21% O2 and chronic hypoxia group was 12% O2 for 3 weeks. After 3 weeks, we confirmed resting metabolic rate (RMR), body composition, and protein expression related to glucose metabolism for hexokinase 2 (HXK2), pyruvate dehydrogenase (PDH) and mitochondrial biogenesis for peroxisome proliferator‐activated receptor gamma coactivator‐1 alpha (PGC‐1α). RMR was measured using an open circuit calorimetry system.ResultsIn resting metabolic rate, carbohydrate oxidation and energy expenditure were significantly higher in the Chr group than in the Nor group. In soleus muscle, PDH protein level was higher in the Chr group than Nor (p=0.015) group. HXK 2 protein level tended to be higher about 21% in the Chr group (p=0.09). PGC1α protein level was higher in the Chr group than Nor group (p=0.032).ConclusionOur data shows that chronic sustained hypoxia significantly improved energy metabolism. Especially, carbohydrate oxidation and protein levels related to glucose metabolism and mitochondrial biogenesis were higher than normoxia group. These observations suggest that chronic exposure for 3 weeks could serve as an effective therapy for glucose metabolic disorder. In the future study, it would be necessary to elucidate whether hypoxia exposure could improve glucose metabolism through diabetic mice model.
FUT2 deficiency may influence the pathogenesis of inflammatory bowel diseases through gut microbiome
Authors: Cheng Sijing , Hu Jun , Wu Xianrui , Jiao Na , Li Yichen , Huang Yibo , Zhu Ruixin , Zhi Min , Zhu Lixin , Lan Ping 
Published: April 2020

Background & AimsNon‐functional fucosyltransferase 2 (FUT2) polymorphisms are associated with inflammatory bowel diseases (IBDs). FUT2 is required for the proper production of oligosaccharides and glycoproteins. These free or attached oligosaccharides have a large impact on the gut microbiota. In this study, we investigated the role of the gut microbiota in IBD pathogenesis with FUT2 deficiency.MethodWe recruited 56 Crohn’s disease (CD) and 25 ulcerative colitis (UC) patients with endoscopically confirmed disease from the IBD clinic in 6th Affiliated Hospital of Sun Yat‐sen University in Guangzhou, China between March 2016 and July 2018. Individuals were asked to provided stool and blood samples respectively. To determine the genotypes of the patients at rs1047781 (A418T) and rs601338 (G461A) of the FUT2 gene, blood DNA was extracted and FUT2 coding sequence was sequenced. For microbiome study, fecal DNA was collected and the V5–V6 region of the 16S rDNA was sequenced with a MiSeq platform.ResultThe incidence of wild‐type, heterozygous and homozygous non‐functional mutations of FUT2, were found to be 32% (26), 49% (40) and 18% (15), respectively, in IBD patients. Significant structural and functional difference were observed at every taxonomic levels among these three groups. Interestingly, the abundance of butyrate producing Dorea, Coprococcus and Ruminococcus was significantly higher in the group carrying homozygous non‐functional FUT2 than those of the other groups (wild‐type and heterozygous non‐functional FUT2, P<0.05). The PICRUSt functional analysis based on the 16S data showed that several carbohydrate synthesis pathways including UDP‐2,3‐diacetamido‐2,3‐dideoxy‐α‐D‐mannuronate biosynthesis and sucrose biosynthesis pathways were enriched in IBD patients with homozygous non‐functional mutation of FUT2 (P<0.05).DiscussionOur results indicated that FUT2 non‐functional mutation was associated with elevated butyrate producing microbiota, which is in concert with elevated gut microbial capacity for carbohydrate production. FUT2 homozygous mutations may lead to the compensatory increase of carbohydrate production, providing fermentation substrate for the production of short‐chain fatty acids by intestinal flora. Our results may provide a theoretical basis for IBD treatment based on microbiome intervention.Support or Funding Information1.National Natural Science Foundation of China 81774152, 31200986, 41530105, 81770571,81970452. 2.Guangzhou laboratory clinical innovation project 2018GZR0201005. 3.National Postdoctoral Program for Innovative Talents of China BX20190393. 4.Natural Science Foundation of Shanghai 16ZR1449800. 5.the University at Buffalo Community of Excellence in Genome, Environment and Microbiome (GEM).
A Rank‐based Longitudinal Correction for Student Self‐selection When Quantifying the Effects of a Voluntary Study Reinforcement Intervention on Exam Performance
Authors: Witchel Harry J. 
Published: April 2020

The quantitative effects of voluntary online study interventions are difficult to ascribe causality to because student self‐selection can confound the analysis. An ideal solution would employ counterfactuals to link the intervention to the effect.OBJECTIVETo determine whether engaging with an online self‐testing platform improved examination performance.METHODInstitution ethical approval was received as was informed consent. A cohort of first‐year undergraduate medical students were provided with a basic online self‐test opportunity on a voluntary basis. Detailed engagement statistics were provided by the online platform, and these were compared to exam performance data over the year for exams and other assessments that normally are produced. As the same students participated in three modules, whereas only one module had the learning intervention, student’s ranks on each final examination were compared in consideration with the engagement with the learning intervention. An anonymized feedback form regarding the self‐test platform was also incorporated.RESULTSFifty of 158 students in the cohort chose to take part and use the platform. Student feedback suggested that the self‐test platform was well liked (4.06 ± 0.10 /5) and helped them learn more (4.10 ± 0.10 /5). Students who used the platform had a trend for scoring higher on the final examination than those who did not (Cohen’s d = 0.25, unpaired t test, P < 0.10); however, there was no direct correlation between use of the intervention and examination score for the relevant module (beta = −0.0054, R‐squared = 0.029). Furthermore, in the longitudinal analysis, the comparative improvement in examination score rank for students who used the intervention (when compared to their ranks when the intervention was not available) was minimal (beta = 0.73 rank increase per 100 questions practiced, R‐squared = 0.0098).CONCLUSIONSImproved cross‐sectional performance of those students who chose to participate in the intervention is likely due to self‐selection of engaged students. The lack of clear benefits of this learning intervention when analyzed longitudinally may be due to the intervention’s focus on a small part of the curriculum that was poorly represented on the exam as well as to other known limitations in the intervention.
Protective Role of P62/SQSTM1 on Acute Ischemia‐Induced Arrhythmia Susceptibility
Authors: Hwang Hyun Seok , Rodriguez Jose , Koh Yeojung , Parvatiyar Michelle S. , Salazar Gloria 
Published: April 2020

IntroductionCardiac ischemia diminishes the intracellular defenses of myocardial cells, resulting in contractile dysfunction, and often leads to ventricular arrhythmias. Recently, we have reported that autophagy adapter protein, p62, modulates the oxidant‐induced cellular Ca handling in myocytes isolated from a mouse with chronic ischemia. Here we investigated the effect of p62 suppression on ventricular arrhythmias after acute ischemia injury in intact heart preparations.MethodsIsolated hearts from wild‐type (WT), heterozygote p62 (HET), and homozygote p62 (HOM) mice (n=6–8 per group, both sexes at 10–12 weeks of age) were prepared for global ischemia (15 min steady‐state, 30 min ischemia, and 60 min reperfusion) with electrocardiogram recording. At the end of the experiment, hearts were harvested for biochemical analysis.ResultsThe steady‐state heart rates (HR) were not different among groups. The HR during the reperfusion tended to decrease in HOM hearts (HR, bpm; WT, 322±36, HET, 302±33, HOM, 249±20). The level of p62 protein expression decreased up to 60% in HET hearts compared to WT hearts. The frequency of ventricular arrhythmias reduced in the HET hearts, and further decreased in the HOM hearts during 60 min of reperfusion (Premature ventricular contraction, PVC/min; WT, 2.71±1.16, HET, 0.61±0.18, HOM 0.26±0.10*, * <0.05 vs. WT). The suppression of the p62 gene has a protective effect on acute ischemia‐induced ventricular arrhythmias in intact hearts.DiscussionOur results suggest that p62 protein may directly contribute to ventricular arrhythmogenesis via intrinsic beta‐adrenergic signaling in the intact heart after acute ischemia.Support or Funding InformationResearch Support: Florida State University
pH‐responsive nanoparticles for Pt (II) delivery to ovarian cancer cells.
Authors: Mieszawska Aneta Joanna , Wlodarczyk Marek T. , Dragulska Sylwia A. , Poursharifi Mina , Chen Ying , Martignetti John A. 
Published: April 2020

Platinum‐based agents represent the most widely used chemotherapy against cancer cells. The effectiveness of Pt (II) treatment depends upon two major factors: 1) cellular accumulation and 2) cellular recognition of the platinum‐induced damage leading to cancer cell apoptosis. Limitations of Pt (II) therapy include inappropriate drug activation in the blood compartment and interaction of Pt (II) agents with plasma proteins. Together these factors result in systemic toxicity, decreased targeted cancer cell delivery, and ultimately, leads to treatment failure. To overcome these major limitations, our work has focused on the synthesis of lipid/polymer nanoparticles (NPs) encapsulating Pt (II) therapy. The NP’s core consists of Pt (II) modified poly(lactic‐co‐glycolic) acid (PLGA‐Pt) polymer. The drug payload within PLGA‐Pt NPs is 5 wt. %, and the NPs are 180 nm in diameter with low polydispersity of 0.115. We explore DNA aptamers as active targeting ligands, which are a part of the NP’s coating. The pH‐responsive polyethylene glycol (PEG) masks the targeting ligands at physiological pH but exposes them at tumoral pH conditions. Proof‐of‐priniciple studies in ovarian cancer (OvCa) models demonstrate enhanced internalization of the PLGA‐Pt NPs when targeting surface ligands. The NPs are highly efficacious in vitro, lowering OvCa cell viability better than the clinical Pt (II) analog, and reveal tumor targeting in vivo in an OvCa mouse model. Taken together our results demonstrate a novel method of delivering Pt‐based drugs, which can overcome current clinically‐relevant limitations.Support or Funding InformationNIH/NCI1R01CA238539‐01
Histamine may directly contract urinary bladder smooth muscle
Authors: Jones B. Malique , Vega Rodríguez Osvaldo J. , Mingin Gerald C. , Tykocki Nathan R. 
Published: April 2020

Mast cell degranulation and histamine release contribute to painful bladder syndrome, urinary tract infections, interstitial cystitis and other bladder disorders. The effects of histamine are well‐studied in other tissues, but little is known about the role of histamine and histamine receptors within the bladder. Since other smooth muscle cells express H1 (contractile) and H2 (relaxant) histamine receptors, we tested the hypothesis that histamine causes contraction of the urinary bladder smooth muscle in mice. All procedures followed institutional guidelines and were approved by the Institutional Animal Care and Use Committees of Michigan State University. Six to 12‐week‐old C57Bl/6 mice were euthanized and dissected bladders were cut into approximately 2 mm wide bladder strips, with or without the urothelium attached, for isometric contractility experiments. Both histamine H1 and H2 receptors were expressed in bladder smooth muscle cells. Increasing concentrations of histamine (100 nM – 300 μM) did not contract strips without urothelium and minimally contracted bladder strips with urothelium. However, bolus administration of 200 μM histamine caused a rapid but transient contraction in strips with and without urothelium. The H1 receptor blocker fexofenadine (5 – 10 μM) blocked these contractions (P<0.05; N=5), whereas the H2 receptor blocker cimetidine (5 – 10 μM) had no effect. In addition, transient receptor potential vanilloid 1 (TRPV1) channel blocker capsazepine significantly reduced histamine‐induced contractions only in bladder strips without urothelium, whereas the Na+ channel blocker tetrodotoxin (TTX) had no effect in any tissue (P < 0.05; N= 3–5). The mast cell activator compound 48/80 (10 μg/ml) contracted urinary bladder smooth muscle, and this contraction was also unaffected by TTX. These results indicate that H1 receptors on urinary bladder smooth cells likely modulate histamine‐induced bladder contraction, and sufficient amounts of histamine can be released from mast cells to cause a contraction.Support or Funding InformationThis research is supported by NIH K01‐DK103840 (NRT) and NIH R01‐DK119615 (NRT & GCM).
The effects of kynurenine metabolites on skeletal muscle in vivo and in vitro
Authors: Kaiser Helen , Ding Ke-Hong , Isales Carlos , Hamrick Mark 
Published: April 2020

The cellular and molecular mechanisms underlying loss of muscle mass and strength with age (sarcopenia) are not well‐understood. Kynurenine (KYN) is a circulating tryptophan metabolite that is generated by the enzyme Indoleamine, 2, 3 dioxygenase (IDO), is known to increase with age, and is implicated in several age‐related pathologies. We have previously shown that an increase in KYN in young mice increased oxidative stress and decreased skeletal muscle mass, whereas inhibition of KYN using a small‐molecule inhibitor of IDO 1‐methyl‐D‐tryptophan (1MT) protected mice against the loss of muscle mass and strength with age. There are, however, a number of downstream metabolites of kynurenine, and it is not entirely clear whether the effects of kynurenine are direct or via these various metabolites. To further elucidate the mechanism by which KYN affects skeletal muscle we treated 22 month old male C57Bl/6 mice with two established metabolites of kynurenine; quinolinic acid (qa) and picolinic acid (pa). Qa was fed 1ppm for 8 weeks, and pa was fed 700ppm for 8 weeks. We then measured quadriceps femoris fiber size, weight, and muscle‐specific hydrogen peroxide levels at the end of the treatment period. In vivo QA and PA did not change skeletal muscle size, weight, or oxidative stress levels. We then pursued in vitro studies to evaluate other KYN metabolites that might contribute to muscle loss with aging. We treated C2C12 myoblasts with 10um of KYN, kynurenic acid, anthranillic acid, cinnabarinic acid, quinolinic acid, picolinic acid, nicotinic acid, and nicotinamide, and measured cell death and hydrogen peroxide levels. Cell death was increased by 10% in all groups compared to control (ANOVA P<.0001). Hydrogen peroxide was increased 2 fold in all groups compared to control (ANOVA P<.05). Cinnabarinic acid increased cell death by 25%, and increased hydrogen peroxide by 2.5 fold. These results suggest that some metabolites may be more potent than others, and these metabolites may be involved in age‐related muscle loss. Furthermore, the data suggest that enzymes downstream of IDO may be potential therapeutic targets for the prevention of sarcopenia and possibly other age‐associated conditions associated with KYN accumulation such as bone loss and neurodegeneration.Support or Funding InformationNIA P01 AG036675
GSK3 Activity is Decreased in The Hippocampus of Male Mice Supplemented with Low‐Dose Lithium in Drinking Water
Authors: Fenech Rachel K. , Ryan Chantal R. , Roy Brian , Fajardo Val A. , MacPherson Rebecca E. K. 
Published: April 2020

Sporadic Alzheimer’s disease (AD) is a neurodegenerative disease characterized by neurofibrillary tangles composed of hyperphosphorylated tau proteins and amyloid‐beta (Aβ) plaques. Together, these two histopathological detriments in the brain lead to progressive cognitive decline. Glycogen synthase kinase‐3 β (GSK3β), a kinase found abundantly in the brain, has been implicated in the development of these AD pathologies. GSK3β remains constituently active until phosphorylated at its inhibitory Ser9 residue. When active, GSK3β is capable of inducing tau hyperphosphorylation and can phosphorylate amyloid‐precursor protein (APP), influencing greater levels of Aβ peptide production. Lithium (Li), a GSK3β inhibitor, has been suggested as an AD prophylaxis. However, Li has also been associated with several dose‐dependent adverse side effects. The purpose of this study was thus to examine the effects of a prophylactic low‐dose Li supplementation on brain GSK3β signaling and activity. C57BL/6J male mice were given 10mg/kg/day Li or no Li in their drinking water for 6 weeks (n=12/group) and the prefrontal cortex (PFC) and hippocampal (HIP) tissues were collected for GSK3 activity assay and western blot analyses. Li mice had increased serum Li concentrations (p<0.0001) and decreased hippocampal GSK3 activity (p=0.06) as compared to control mice. pAkt Thr308 phosphorylation, a kinase immediately upstream of GSK3β capable of inducing inhibitory pGSK3β Ser9 phosphorylation, was increased in the PFC of Li mice compared to control mice (p<0.05). However, no differences in pGSK3β Ser9 or Tyr216, an activating residue, were observed between control and Li mice in both the PFC and HIP. Changes in GSK3 activity without changes in inhibitory Ser9 phosphorylation may suggest that a longer supplementation is needed to affect significant changes in the brain. Furthermore, these results demonstrate that the phosphorylation status of GSK3β may not always be a direct translation of its activity. This highlights the importance of measuring GSK3β activity alongside of measures of upstream kinases (i.e. PI3K/Akt signaling) and downstream targets to obtain a better indication of GSK3β’s overall activity within the brain. Overall, this initial work provides evidence that Li can inhibit hippocampal GSK3 activity and alter the phosphorylation status of upstream kinases at a low‐dose. Future work will examine Li’s potential prophylactic effects in a diseased model which better mimics AD (i.e. aged and metabolically‐distressed mice). This is important to further elucidate the efficacy of low‐dose Li in the prevention of AD pathologies.Support or Funding InformationThis work is supported by the Alzheimer Society of Brant, Haldimand Norfolk, Hamilton Halton and NSERC.
The Role of Xanthine Dehydrogenase (XDH) and Uric Acid in the Kidney Development and Renal Injury
Authors: Dissanayake Lashodya Vindana , Spires Denisha R. , Levchenko Vladislav , Khedr Sherif , Palygin Oleg , Staruschenko Alexander 
Published: April 2020

Uric acid is the end product of purine catabolism in humans and is capable of acting as both an antioxidant scavenging reactive oxygen species and conditionally a pro‐oxidant. Pathophysiological changes in serum uric acid levels (hyperuricemia and hypouricemia) are associated with prevalent diseases, including hypertension and chronic kidney disease as well as rare disorders, such as hereditary xanthinuria. Despite the clear association between uric acid dysregulation and pathology, the mechanisms involved remain unclear. XDH and xanthine oxidase (XO) (together known as Xanthine oxidoreductase (XOR)) is a complex enzyme group that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid. To assess the role of this pathway beyond purine catabolism, we created a genetic ablation of the Xdh gene in the Dahl salt‐sensitive rat background (SSXdh−/−). Sequencing of SSXdh−/− genomic DNA confirmed a 7‐base‐pair‐deletion in exon 4 of the Xdh gene located on chromosome 6. The absence of Xdh protein expression in homozygotes and a reduction in heterozygotes was confirmed by both Western blot and immunohistochemistry analyses. SSXdh−/− rats exhibited early mortality with 7 out of 28 rats not surviving till 6 weeks of age compared to SSXdh+/− and SSXdh+/+ littermates, all of whom survived. Plasma uric acid of 6 weeks old male rats was 0.25±0.03 mg/dl (N=6) in SSXdh+/+ rats and decreased to a level out of the detectable range by the test in the SSXdh−/− group. The 24hr uric acid excretion was also dramatically decreased in SSXdh−/− rats compared to SSXdh+/+ littermates. Masson’s Trichrome staining revealed severe renal damage with an increase in fibrosis (1 and 14% (N=3 and 2 for male SSXdh+/+ and SSXdh−/−, respectively), and dilated tubules in the SSXdh−/− rats. Total body weight was decreased in SSXdh−/− rats, indicating a failure to thrive compared to control rats (190 ± 4 and 58 ± 8 g; N=6 and 4 for male SSXdh+/+ and SSXdh−/−). Additionally, In SSXdh−/− rats at 6 weeks, Western blot analysis showed a lack of connective tissue growth factor (CTGF), which is known to be critical in the nephrogenesis. No apparent sex‐specific differences in development or kidney injury were identified. Our results suggest that the genetic ablation of Xdh caused uric acid depletion and severe renal damage. Therefore, XOR may be essential for the development of the kidney and survival of the rats by regulating purine catabolism.Support or Funding InformationSupported by the Department of Veteran Affairs Grant I01 BX004024 and the National Institutes of Health Grants R35 HL‐135749.