bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sustained Delivery of Dihydrotestosterone Impact on the Pathophysiology of Isolated Endothelial and Smooth Muscle Cells
Authors: Benghuzzi Hamed a , Tucci Michelle a 
Published: June 2021

Sex steroid hormones appear to be a risk factor for the development of atherosclerosis. Proliferation of vascular smooth muscle cells (SMC) was documented to be a mediator in atherosclerotic plaque formation. The objective of this study was to investigate the effect of sustained delivery of dihydrotestosterone (DHT) on the growth of cultured aortic endothelial cells (EC) and SMC incubated individually, or in combination. The SMC were explanted from the media and intima of the abdominal and thoracic aorta of adult male rabbits, and EC were prepared by trypsinization of the vessel. Cells were seeded and grown undisturbed for up to 6 weeks in culture. A total of four equal (n=4 wells) groups was used in Phase I. Groups 1–3 were plated with EC, SMC, and EC+SMC, respectively. Group IV served as control. Half of the wells (n=4 per group) in each group were exposed to tricalcium phosphates capsules loaded with 40 mg DHT (release profile: 3–5 ng/ml/day) and second half was exposed to sham capsules. Resultes revealed that sustained release of DHT to EC+SMC cultures induced greater cellular proliferation than in control wells, as determined by cell counts after 96 hours of culture. In contrast, the number of cells/well of a single cell type, grown in the presence of DHT, did not differ from the control wells. In the second phase of this investigation, various capsules releasing different concentrations of DHT were used. The release rate of 10 ng/ml/day of DHT regressed the proliferation rate by approximately 40% compared to other lower doses (2.4, or 6 ng/ml/day). Results of this investigation suggest that: (1) sustained delivery of a physiological dose of DHT to combined cultures of EC+SMC significantly increased cellular growth, while the exposure of DHT to EC or SMC grown individually had no effect on the rate of cellular proliferation, and (2) the effect of sustained delivery of DHT on vascular smooth muscle cells was found to be dose dependent.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Methamphetamine and cocaine administration increases CRF‐R2 and decreases S100‐beta astrocytic immunoreactivity in the VTA
Authors: Trzeciak Marta , Sharpe Amanda L. , Douglas Phillip , Beckstead Michael J. 
Published: June 2021

Dopamine neurons in the ventral tegmental area (VTA) play a crucial role in the reinforcing properties of abused drugs including methamphetamine and cocaine. However, there is evidence suggesting the involvement of non‐dopaminergic transmitters, including glutamate and corticotropin‐releasing factor (CRF), on psychostimulant effects in the VTA. Astrocytes can express a large variety of receptors for neurotransmitters such as glutamate which could indirectly influence neurotransmission in the VTA. Additionally, corticotropin‐releasing factor (CRF) receptors have been reported on astrocytes in the cerebellum, although no one has yet identified them on astrocytes in the VTA. CRF in the VTA plays a role in stress‐induced relapse and drug‐seeking behavior, but the localization of its effects are not completely understood. Although tissue from mouse VTA shows a high level of CRF1 receptor transcript and lower levels of CRF2 receptor transcript, both receptors play a functional role in regulating VTA synaptic activity.Here, we aimed to use immunofluorescence to identify the effect of methamphetamine and cocaine administration on astrocytic glutamate and CRF receptors. We treated adult male mice with i.p. injections of methamphetamine (3 mg/kg), cocaine (10 mg/kg), or saline (vehicle) for 12 days. Brains were then removed and sectioned (40 μm thickness) in the coronal plane. The tissue was then processed for immunofluorescence using tyrosine hydroxylase as a dopaminergic cell marker and S100‐beta as a marker for astrocytes. We examined the level of glutamate and glutamate/aspartate transporters (GLT‐1 and GLAST) and CRF receptors. Images were captured using fluorescent microscopy and processed using ImageJ software. The results showed a ~30% decrease in GLT‐1 and GLAST immunofluorescence in brains of mice treated with cocaine or methamphetamine compared to saline. In addition, we observed increased labelling of CRF2 receptors in drug‐treated groups, a decrease of S100beta, and an increase of co‐staining of these markers. Our results suggest that administration of either methamphetamine or cocaine increases immunoreactivity for CRF2 receptors in the VTA, an effect that is most pronounced in S100‐ beta positive cells.Support or Funding InformationThis work was supported by National Institute on Aging grant R01 AG052606.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sex Differences in High Fat Diet‐Induced Enhanced Sensitivity to Methamphetamine and Dopamine D1 Receptor Agonist SKF 82958
Authors: Hardin Ethan , Ramos Jeremiah , Serafine Katherine 
Published: June 2021

Eating a diet high in fat can lead to obesity and insulin resistance. Further, eating high fat laboratory chow enhances sensitivity of rats to the behavioral effects of drugs acting on dopamine systems (e.g., methamphetamine). For example, male rats eating high fat chow are more sensitive to the locomotor stimulating effects of methamphetamine than rats eating standard chow. The locomotor‐stimulating effects of methamphetamine are due, in part, to increased action of dopamine at dopamine D1 receptors; however, it is not known if diet enhances sensitivity of rats to the behavioral effects of dopamine D1 receptor agonists (e.g., SKF 82958). To test the hypothesis that eating a high fat diet enhances sensitivity rats to locomotion induced by dopaminergic drugs, male and female Sprague‐Dawley rats ate either standard (17% kcal from fat) or high fat (60% kcal from fat) chow and were tested once per week with SKF 82958 (0.01–3.2 mg/kg) or methamphetamine (0.1–3.2 mg/kg) using a cumulative dosing procedure for 6 weeks. Male and female rats eating high fat chow were more sensitive to the locomotor‐stimulating effects methamphetamine than control rats eating standard chow. Female rats eating high fat chow, but not males, were also more sensitive to the locomotor stimulating effects of SKF 82958 than female rats eating standard chow. Taken together with previous research, these results suggest that among females, eating high fat chow might impact sensitivity to methamphetamine via dopamine D1 receptor specific changes, while among males, high fat diet‐induced enhanced sensitivity to methamphetamine might be due to dopamine D2 receptor specific changes. Future experiments will examine differences in dopamine receptor expression among male and female rats eating different diets.Support or Funding InformationUTEP COURIThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Possible Role of Chitin‐Like Proteins in the Etiology of Alzheimer's Disease
Authors: Prancan Arthur , Lomiguen Christine , Vidal Luis , Kozlowski Piotr 
Published: June 2021

Chitin is a β‐linked straight chain carbohydrate matrix monopolymer prominent in invertebrates, from fungi to arthropods. Surprisingly, chitin is now documented in vertebrates, including humans, a component of vertebrate physiology that has been neglected until now. Chitin levels are elevated in Alzheimer's disease (AD) patients, not only in the central nervous system but also in the cerebrospinal fluid and plasma. Elevated levels of chitin lectin have been reported in patients with AD. Chitinase activity varies widely in the human population. Chitin levels can increase in individuals with intrinsically low chitinase activity. Elevated amounts of chitin can reflect accumulation of the small chitin fragments that remain wherever rapid hyaluronan synthesis occurs. Another source of chitin may be from remote fungal infections. Chitin can be toxic for neurons, and its accumulation may lead to the development of AD. We present new suggestions for animal models and treatment modalities that could prove useful in future research endeavors. An unexpected connection with Gaucher's disease patients and their heterozygote relatives is also identified. These chitin‐related mechanisms are novel approaches to AD whose etiology until now has defied explication.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Icariin ameliorates learning and memory function via improving cerebral glucose metabolism disorder in APP/PS1/Tau triple transgenic Alzheimer's disease mice
Authors: Jin Feng , Zhang Ying , Nie Jing , Shi Jingshan 
Published: June 2021

OBJECTIVETo investigate whether icariin (ICA), a flavonoid extracted from the Chinese herb (Berberidaceae epimedium L), can ameliorate learning and memory function via improving cerebral glucose metabolism disorder in APP/PS1/Tau triple transgenic Alzheimer's disease mice (3×Tg‐AD mice).METHODSThree‐month‐old male 3×Tg‐AD mice were randomly divided into three groups (n=10 per group): 3×Tg group, 3×Tg + ICA 30 mg/kg group, 3×Tg + ICA 60 mg/kg group, and age‐matched male wild type (WT) mice were randomly divided into two groups (n=10 per group): WT control group, WT+ ICA 60 mg/kg group. ICA in vehicle (0.5% Tween‐80 in distilled water) was given orally once a day for five months in the 3×Tg+ICA groups, 3×Tg and WT control groups were given an equal volume vehicle. Morris water maze was used to detect the learning and memory function of mice. Brain glucose metabolism in 3×Tg‐AD mice was observed by 18F‐FDG microPET imaging technique. Nissl staining and HE staining were used to evaluate the survival neurons in hippocampus of mice. Glucose oxidase assay was used to detect glucose contents in cortex of mice. The protein expression of APP, Aβ1‐40, Aβ1‐42 , glucose transporter 1 (GLUT1) and GLUT3, and the phosphorylation level of tau protein at multiple sites in hippocampus were detected by Western Blot.RESULTSBehavioral examination revealed a profound decrease learning and memory function, accompanied by a decrease in number of neuronal cells in 3×Tg‐AD mice. Moreover, the cerebral 18F‐FDG uptake rate per gram tissue was reduced, the glucose contents in the hippocampus and cortex were increased in 3×Tg‐AD mice. In addition, Western blot analysis showed that the expression of APP, Aβ1‐40, Aβ1‐42 proteins and the levels of tau protein phosphorylation at Ser199/202 and PHF‐1 (Ser396/404) sites were increased significantly, followed by a decrease of GLUT1 and GLUT3 expression in hippocampus of 3×Tg‐AD mice. All of these changes in behavioral functions, 18F‐FDG uptake rate, glucose contents, neuronal loss and the related protein expression were reversed when mice were treated with ICA.CONCLUSIONICA can improve the learning and memory ability of AD model mice, the mechanism may be related to the improvement of cerebral glucose metabolism dysfunction by increasing the expression of GLUT.Support or Funding InformationThis work was supported by the National Natural Science Foundation of China (81660599), the Foundation of Zunyi Medical University (2013F‐686, F‐738), The Postgraduate Education Foundation of Guizhou Province (KYJJ2017008).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
RNA‐Seq Reveals Potential Mechanisms of Baicalein in Improving Cognition in SAMP8 Mice
Authors: Li Jiaqi , Du Guanhua , Gao Li , Qin Xuemei 
Published: June 2021

ObjectiveAlthough baicalein has shown benefits for an array of human diseases including dementia, the effects and mechanisms underlying the neuroprotective effect of baicalein have not been fully explored in senescence‐accelerated mouse prone 8 (SAMP8).MethodsIn the present work, 8‐month‐old SAMP8 mice were intragastrically administrated with 200 mg/kg baicalein once a day for eight weeks, and age‐matched SAMR1 mice were used as control group. The effects of baicalein on hypomnesis in SAMP8 mice were evaluated by behavioral tests including Morris water maze, Novel object recognition test, and Olfactory memory test, and the mechanisms were explored by RNA‐seq technology combined with network pharmacology and quantitative real‐time PCR (qRT‐PCR).ResultsThe results showed that treatment with baicalein improved the cognitive functions of the SAMP8 mice, including spatial learning and memory, object recognition memory, and olfactory memory. The RNA‐seq results showed that 1035 differentially expressed genes (DEGs) were found in 10‐month‐old SAMP8 mice versus the age‐matched SAMR1 mice. Treatment of baicalein altered 654 DEGs in the SAMP8 mice and among them, 214 DEGs could be reversely regulated by baicalein resulting in similar RNA levels to SAMR1 mice. Based on the DEGs, a gene network was constructed containing 908 nodes and 3771 edges. Fifty hub DEGs and eight signaling pathways including Jak‐STAT signaling pathway and PI3K‐Akt signaling pathway were regulated by baicalein through network pharmacology analysis and KEGG pathway analysis. The hub DEGs in Jak‐STAT signaling pathway and PI3K‐Akt signaling pathway including Prlr, Gh, Il7, Il20rb, Il5, Comp, Ibsp, Gm5741 were verified through qRT‐PCR.ConclusionOur results indicate that the effects of baicalein on improving cognitive impairments of SAMP8 mice might be attributed to modulation of Jak‐STAT signaling pathway and PI3K‐Akt signaling pathway.Support or Funding InformationThis project was supported by the National Natural Science Foundation of China (81603319), and partly supported by Science and Technology Innovation Team of Shanxi Province (201605D131045‐18), and Key laboratory of Effective Substances Research and Utilization in TCM of Shanxi province (201705D111008‐21).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Klotho Improves Alzheimer's Disease‐like Pathology and Cognitive Deficits in APP/PS1 Mice
Authors: Du Junrong , Zeng Chenye , Yang Tingting , Zhou Hongjing 
Published: June 2021

Alzheimer's disease (AD) is the most common type of senile dementia. The anti‐aging gene Klotho is reported to decline in the brain of AD patients and animals. However, the role of Klotho in the progression of AD remains elusive. The present study explored the effects and underlying mechanism of Klotho in a mouse model of AD. The upregulation of cerebral Klotho expression was mediated by an intracerebroventricular injection of a lentiviral vector that encoded Klotho (LV‐KL) in 7‐month‐old APP/PS1 transgenic mice. Three months later, LV‐KL significantly induced Klotho overexpression in the brain and effectively ameliorated cognitive deficit and Alzheimer's disease‐like pathology in APP/PS1 mice. LV‐KL induced autophagy activation both in AD mice and BV2 murine microglia. These results suggest that the upregulation of Klotho expression in the brain may promote the autophagic clearance of Aβ and protect against cognitive deficits in AD mice. These findings highlight the preventive and therapeutic potential of Klotho for the treatment of AD.Support or Funding InformationThis work was supported by the National Science Foundation of China (81473219), and partly by targeting drug delivery system of Sichuan Province Youth Science and Technology Innovation Team (2016TD0001) and 111 Project of the National Ministry of Education (B18035).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Delta‐9‐tetrahydrocannabinol (THC) Enhances Heroin‐Induced Antinociception and Disruptions of Learning and Performance in Rhesus Macaques
Authors: Nilges Mark R , Grace Joseph A , Winsauer Peter J 
Published: June 2021

Cannabinoid administration prior to opioid administration can produce opioid‐sparing antinociceptive effects in several species by reducing the dosage of opioid needed to produce effective antinociception. These potentially valuable clinical effects could be undermined, however, if the cannabinoids also enhance the disruptive effects of opioids on neurobehavioral function. To address this question, the combined effects of THC and heroin were examined in nonhuman primates (rhesus macaques, n=4) responding in a learning and performance task and concurrently exposed to a tail‐withdrawal antinociception procedure. Testing in this case was facilitated by examining 4 discrete cycles of acquisition and performance that were separated by timeout periods to facilitate tail‐withdrawal tests and cumulative dosing. Each cycle included a 10‐min time out period for drug onset, a 15‐min acquisition component, and a 5‐min performance component. In the learning and performance task, subjects acquired a new 5‐response key‐sequence, or emitted a well‐rehearsed 5‐response key‐sequence, respectively. Responding in both components of the task was reinforced with a food pellet after every three completions of the sequence (i.e., a second‐order fixed‐ratio [FR3] schedule of food reinforcement). Warm‐water tail‐withdrawal antinociception was measured using three water temperatures (40°, 50°, and 55°C). Heroin alone dose‐dependently decreased response rates in the acquisition and performance components without markedly increasing percent errors. When the opioid antagonist naltrexone (1 mg/kg) preceded the cumulative heroin injections, the heroin dose‐effect curves for both the behavioral disruptions and antinociception were shifted rightward indicating both effects were mediated by mu‐opioid receptors. In contrast, THC alone disrupted both behaviors at doses that had no antinociceptive effect, but it shifted the heroin dose‐effect curves for learning, performance, and antinociception leftward. Overall, these data demonstrate that THC produces its opioid‐sparing antinociceptive effects at doses that are behaviorally disruptive alone and in combination with heroin.Support or Funding InformationThis work was supported by a National Institute of Drug Abuse Fellowship (F32DA47013‐01)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Comparing the Neuroprotective Efficacy of P7C3‐A20 to Novel P7C3 Derivatives in a Rodent Model of Paclitaxel‐Induced Peripheral Neuropathy
Authors: Smith Hudson R. , LoCoco Peter M. , Chavera Teresa A. , Zamora Joshua C. , Jennings Elaine M. , Pando Miryam M. , Berg Kelly A. , Clarke William P. 
Published: June 2021

Chemotherapy‐induced peripheral neuropathy (CIPN) is a prevalent adverse effect of anti‐cancer chemotherapeutics like paclitaxel (PTX), a microtubule targeting agent known to induce severe and persistent neuropathic pain. The development of CIPN not only diminishes the quality of life of cancer patients, but also downgrades their cancer prognosis as dose reduction or cessation of their anti‐cancer regimen are the only clinical interventions currently available for CIPN. Thus, the development of a pharmacological intervention that limits the neuropathic side‐effects of anti‐cancer chemotherapy is urgently needed. Here we tested the neuroprotective effects of the aminopropyl carbazole, P7C3‐A20 (A20), and several A20 derivatives in a rat model of paclitaxel‐induced peripheral neuropathy. All experiments were done by investigators blinded to the drug treatments. Racemic A20 (2.2, 6.6, 20 mg/kg, i.p., q.d.), or vehicle, was administered daily to male Sprague‐Dawley rats over a 14‐day period beginning 2 days before PTX treatment (11.7 mg/kg/day, i.p.; every other day for 3 injections). A20 dose‐dependently attenuated PTX‐induced mechanical allodynia in rats. Evaluation of intraepidermal nerve fiber (IENF) density in rat paw biopsies using immunohistochemical staining revealed that treatment with PTX produced a profound loss in IENF density that was prevented by treatment with A20. Further, statistical analysis indicated strong correlations between IENF density, a diagnostic marker of CIPN in humans, and nociceptive threshold to mechanical stimuli. Enantiomer specific mixtures of A20 (20 mg/kg, i.p., q.d.), racemic A20 (20 mg/kg, i.p., q.d.), or vehicle were then administered utilizing the same behavioral paradigm and PTX dosing schedule as above. Consistent with our previous data, racemic A20 attenuated PTX‐induced mechanical allodynia and the S‐enantiomer was identified as the active component of the racemic mixture. We have also tested the neuroprotective efficacy of four novel A20 derivatives coded as compounds A through D. The A20 derivatives were administered daily at 20 mg/kg by i.p. injection and mechanical allodynia was assayed as described above. One compound, Drug C, provided robust protection against PTX‐induced mechanical allodynia, whereas the compounds A, B, and D demonstrated limited neuroprotective efficacy. Taken together, A20 and perhaps its derivatives are an exciting new class of pharmacological agents that may have clinical utility for alleviating peripheral neuropathies caused by various anti‐cancer chemotherapeutics.Support or Funding InformationSupported in part by Calico Life Sciences and Proneurotech.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.