Sustained Activation of Postsynaptic 5-HT2A Receptors Gates Plasticity at Prefrontal Cortex Synapses

Abstract

The prefrontal cortex (PFC) plays a key role in many high-level cognitive processes. It is densely innervated by serotonergic neurons originating from the dorsal and median raphe nuclei, which profoundly influence PFC activity. Among the 5-HT receptors abundantly expressed in PFC, 5-HT_2A receptors located in dendrites of layer V pyramidal neurons control neuronal excitability and mediate the psychotropic effects of psychedelic hallucinogens, but their impact on glutamatergic transmission and synaptic plasticity remains poorly characterized. Here, we show that a 20-min exposure of mouse PFC slices to serotonin or the 5-HT_2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) produces a long-lasting depression of evoked AMPA excitatory postsynaptic currents in layer V pyramidal neurons. DOI-elicited long-term depression (LTD) of synaptic transmission is absent in slices from 5-HT_2A receptor-deficient mice, is rescued by viral expression of 5-HT_2A receptor in pyramidal neurons and occludes electrically induced long-term depression. Furthermore, 5-HT_2A receptor activation promotes phosphorylation of GluA2 AMPA receptor subunit at Ser⁸⁸⁰ and AMPA receptor internalization, indicating common mechanisms with electrically induced LTD. These findings provide one of the first examples of LTD gating under the control of a G protein-coupled receptor that might lead to imbalanced synaptic plasticity and memory impairment following a nonphysiological elevation of extracellular serotonin.

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Altered Cortical and Hippocampal Excitability in TgF344-AD Rats Modeling Alzheimer’s Disease Pathology

Abstract

Current findings suggest that accumulation of amyloid-β (Aβ) and hyperphosphorylated tau in the brain disrupt synaptic function in hippocampal–cortical neuronal networks leading to impairment in cognitive and affective functions in Alzheimer's disease (AD). Development of new disease-modifying AD drugs are challenging due to the lack of predictive animal models and efficacy assays. In the present study we recorded neural activity in TgF344-AD rats, a transgenic model with a full array of AD pathological features, including age-dependent Aβ accumulation, tauopathy, neuronal loss, and cognitive impairments. Under urethane anesthesia, TgF344-AD rats showed significant age-dependent decline in brainstem-elicited hippocampal theta oscillation and decreased theta-phase gamma-amplitude coupling comparing to their age-matched wild-type counterparts. In freely-behaving condition, the power of hippocampal theta oscillation and gamma power during sharp-wave ripples were significantly lower in TgF344-AD rats. Additionally, these rats showed impaired coherence in both intercortical and hippocampal–cortical network dynamics, and increased incidence of paroxysmal high-voltage spindles, which occur during awake, behaviorally quiescent state. TgF344-AD rats demonstrated impairments in sensory processing, having diminished auditory gating and 40-Hz auditory evoked steady-state response. The observed differences in neurophysiological activities in TgF344-AD rats, which mirror several abnormalities described in AD patients, may be used as promising markers to monitor disease-modifying therapies.

https://ift.tt/2leWhjf

Versatile graphene biosensors for enhancing human cell therapy

Publication date: 15 October 2018
Source:Biosensors and Bioelectronics, Volume 117
Author(s): George M. Vlăsceanu, Roxana-Maria Amărandi, Mariana Ioniță, Teddy Tite, Horia Iovu, Luisa Pilan, Jorge S. Burns
Technological advances in engineering and cell biology stimulate novel approaches for medical treatment, in particular cell-based therapy. The first cell-based gene therapy against cancer was recently approved by the US Food and Drug Administration. Progress in cancer diagnosis includes a blood test detecting five cancer types. Numerous stem cell phase I/II clinical trials showing safety and efficacy will soon pursue qualifying criteria for advanced therapy medicinal products (ATMP), aspiring to join the first stem-cell therapy approved by the European Medicines Agency. Cell based therapy requires extensive preclinical characterisation of biomarkers indicating mechanisms of action crucial to the desired therapeutic effect. Quantitative analyses monitoring critical functions for the manufacture of optimal cell and tissue-based clinical products include successful potency assays for implementation. The challenge to achieve high quality measurement is increasingly met by progress in biosensor design. We adopt a cell therapy perspective to highlight recent examples of graphene-enhanced biointerfaces for measurement of biomarkers relevant to cancer treatment, diagnosis and tissue regeneration. Graphene based biosensor design problems can thwart their use for health care transformative point of care testing and real-time applications. We discuss concerns to be addressed and emerging solutions for establishing clinical grade biosensors to accelerate human cell therapy.



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Photodynamic therapy of balloon-injured rat carotid arteries using indocyanine green

Abstract

Photodynamic therapy (PDT) has been used to inhibit intimal hyperplasia in injured arteries. Because of the limited tissue penetration of visible light, an endovascular light source with a guided wire is often required for effective treatment. Indocyanine green (ICG), a near-infrared (NIR) photosensitizer, has been used in PDT for cancers. An extracorporeal light source may be used for shallow tissue because of the better tissue penetration of NIR light. The aim of this study was to evaluate the effect of ICG-PDT using extracorporeal NIR light on the inhibition of intimal hyperplasia in balloon-injured carotid arteries. A balloon injury (BI) model was used to induce intimal hyperplasia of carotid artery. Sprague–Dawley rats were divided into control, BI, BI + 1 × PDT, and BI + 2 × PDT groups. The control group underwent a sham procedure. PDT was performed 7 days after BI. In the BI + 1 × PDT group, ICG was administered 1 h before light irradiation. External illumination with 780-nm light-emitting diode light at a fluence of 4 J/cm² was applied. For the BI + 2 × PDT group, PDT was performed again at day 7, following the first PDT. Hematoxylin and eosin (H & E) staining was performed to assess vessel morphology. Arterial wall thickness was significantly larger in the BI group compared with the control group. ICG-PDT significantly reduced arterial wall thickness compared with the BI group. Repeated PDT further decreased arterial wall thickness to the level of the control group. These findings indicate a promising approach for the treatment of restenosis of carotid arteries.

https://ift.tt/2Myxpz8

Correction to: Electroretinogram evaluation for the treatment of proliferative diabetic retinopathy by short-pulse pattern scanning laser panretinal photocoagulation

The published online version contains incorrect data in Table 2 caption. Argon should not be mentioned in the caption as this is not used in this paper.

https://ift.tt/2JQskAD

Cosmetics, Vol. 5, Pages 38: Screening-Level Safety Assessment of Personal Care Product Constituents Using Publicly Available Data

Cosmetics, Vol. 5, Pages 38: Screening-Level Safety Assessment of Personal Care Product Constituents Using Publicly Available Data

Cosmetics doi: 10.3390/cosmetics5020038

Authors: Ernest S. Fung Derek A. Drechsel Kevin M. Towle Melinda T. Hoang Rachel M. Novick Cayla Poteete Dennis J. Paustenbach Andrew D. Monnot

Organizations recommend evaluating individual ingredients when assessing the safety of personal care or cosmetic products. The goal of this study was to present a screening-level safety assessment methodology to evaluate the safety of a product by identifying individual ingredients, determining their frequency of use in on-market products, and examining published safe-level-of-use information for each ingredient. As a case study, we evaluated WEN by Chaz Dean (WCD) cleansing conditioners since there have been claims of adverse health effects associated with product use. We evaluated 30 ingredients in three on-market WCD cleansing conditioners. We then analyzed the National Library of Medicine’s Household Products Database and the Environmental Working Group’s (EWG) Skin Deep Cosmetic Database, two of the largest publicly available databases, for other on-market personal care and cosmetic products that contained these ingredients. Safe-level-of-use information for each ingredient was obtained by reviewing peer-reviewed literature, the Food and Drug Administration’s (FDA) generally recognized as safe (GRAS) database, available Cosmetic Ingredient Review (CIR) publications, and available product safety publications. The results of this analysis showed that more than 20,000 personal care and cosmetic products contained one or more of the evaluated ingredients used in WCD cleaning conditioners. Published safety information was available for 21 of the 30 evaluated ingredients: seven identified ingredients were designated as GRAS by the FDA and 16 ingredients had safe-level-of-use information available from the CIR. This study presents a screening-level safety assessment methodology that can serve as an initial screening tool to evaluate the safety of an ingredient intended for use in personal care and cosmetic products before a product is launched onto the market. This study provides evidence that the evaluated WCD cleansing conditioner ingredients are commonly used in other personal care and cosmetic products, and ingredients with available safety information are generally considered safe for the intended use. The scope of this analysis is limited to frequency of use information and available toxicological data. Additional testing including in silico, in vitro, and clinical studies may be needed to evaluate the potential toxicity of an ingredient.

https://ift.tt/2MuuM1y

Atypical chest pain in a patient with hydatid cyst of the interventricular septum

We report a 57-year-old man presenting with symptoms of sharp pricking, exertional retrosternal chest pain multiple times, each episode lasting for a few seconds. On evaluation, the ECG of the patient showed normal sinus rhythm with T wave inversions in leads V1–V3. Troponin T test was negative. Transthoracic echocardiography showed a globular mass in the interventricular septum. Cardiac MRI was suspicious of the lesion to be a hydatid cyst. Surgical excision of the lesion followed by histopathology was confirmatory of hydatid cyst.

https://ift.tt/2LTh4UI