https://www.nature.com/articles/s41380-020-00965-3.pdf

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https://elifesciences.org/download/aHR0cHM6Ly9jZG4uZWxpZmVzY2llbmNlcy5vcmcvYXJ0aWNsZXMvNjIwNDgvZWxpZmUtNjIwNDgtdjIucGRmP2Nhbm9uaWNhbFVyaT1odHRwczovL2VsaWZlc2NpZW5jZXMub3JnL2FydGljbGVzLzYyMDQ4/elife-62048-v2.pdf

 

 

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Abstract: “To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson’s disease. It was recently observed in a rodent model of Alzheimer’s disease that the interaction between the a7 subtype of nicotinic acetylcholine receptor (a7-nAChR) and sigma-1 receptor (s1-R) could exert neuroprotective effects through the modulation of neuroinflammation which is one of the key components of the pathophysiology of Parkinson’s disease. In this context, the aim of the present study was to assess the effects of the concomitant administration of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-furo[2,3-c]pyridine-5-carboxamide (PHA) 543613 as an a7-nAChR agonist and 2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate (PRE)-084 as a s1-R agonist in a well-characterized 6-hydroxydopamine rat model of Parkinson’s disease. The animals received either vehicle separately or the dual therapy PHA/PRE once a day until day 14 post-lesion. Although no effect was noticed in the amphetamine-induced rotation test, our data has shown that the PHA/PRE treatment induced partial protection of the dopaminergic neurons (15-20%), assessed by the dopamine transporter density in the striatum and immunoreactive tyrosine hydroxylase in the substantia nigra. Furthermore, this dual therapy reduced the degree of glial activation consecutive to the 6-hydroxydopamine lesion, i.e, the 18 kDa translocation protein density and glial fibrillary acidic protein staining in the striatum, and the CD11b and glial fibrillary acidic protein staining in the substantia nigra. Hence, this study reports for the first time that concomitant activation of a7-nAChR and s1-R can provide a partial recovery of the nigro-striatal dopaminergic neurons through the modulation of microglial activation.”

Vetel S, Foucault-Fruchard L, Tronel C, Buron F, Vergote J, Bodard S, Routier S, Sérrière S, Chalon S. Neuroprotective and anti-inflammatory effects of a therapy combining agonists of nicotinic α7 and σ1 receptors in a rat model of Parkinson’s disease. Neural Regen Res. 2021 Jun;16(6):1099-1104. doi: 10.4103/1673-5374.300451. PMID: 33269756.

 

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“The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural–mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.”

Meinhardt, J., Radke, J., Dittmayer, C. et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci (2020). https://doi.org/10.1038/s41593-020-00758-5.

https://www.nature.com/articles/s41593-020-00758-5

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“Do old and damaged cells remember what it was like to be young? That’s the suggestion of new study, in which scientists reprogrammed neurons in mouse eyes to make them more resistant to damage and able to regrow after injury—like the cells of younger mice. The study suggests that hallmarks of aging, and possibly the keys to reversing it, lie in the epigenome, the proteins and other compounds that decorate DNA and influence what genes are turned on or off.

The idea that aging cells hold a memory of their young epigenome “is very provocative,” says Maximina Yun, a regenerative biologist at the Dresden University of Technology who was not involved in the work. The new study “supports that [idea], but by no means proves it,” she adds. If researchers can replicate these results in other animals and explain their mechanism, she says, the work could lead to treatments in humans for age-related disease in the eye and beyond.

Epigenetic factors influence our metabolism, our susceptibility to various diseases, and even the way emotional trauma is passed through generations. Molecular biologist David Sinclair of Harvard Medical School, who has long been on the hunt for antiaging strategies, has also looked for signs of aging in the epigenome. …”

 https://www.sciencemag.org/news/2020/12/researchers-restore-lost-sight-mice-offering-clues-reversing-aging

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Excerpt from text: “…SARS-CoV-2 virions have in fact been observed in the human olfactory bulb (Nampoothiri et al., 2020). SARS-CoV particles have also been found in the human brain (Ding et al., 2004; Gu et al., 2005; Xu et al., 2005). Adding to these observations, brain lesions were observed in a transgenic mouse model expressing the human ACE2 in the nose and infected intranasally with SARS-CoV (Netland et al., 2008). Moreover, a retrospective case study on 214 COVID-19 patients reported neurological manifestations possibly correlated with the severity of the disease (Mao et al., 2020) (with the confounding factor that old people are more likely to develop severe disease). As worrying are suggestions that a subset of patients infected with the virus but lacking respiratory symptoms may exhibit neurologic symptoms (Wang et al., 2020b), and that they may be associated with encelphalitis (Moriguchi et al.,2020…..”

Fodoulian, L., Tuberosa, J., Rossier, D., Boillat, M., Kan, C., Pauli, V., Egervari, K., Lobrinus, J.A., Landis, B.N., Carleton, A., Rodriguez, I., SARS-CoV-2 receptors and entry genes are expressed in the human olfactory neuroepithelium and brain, ISCIENCE (2020), doi: https:// doi.org/10.1016/j.isci.2020.101839.

https://www.cell.com/iscience/pdf/S2589-0042(20)31036-1.pdf

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Abstract

Importance: Coronavirus disease 2019 (COVID-19) may lead to serious illness as a result of an excessive immune response. Fluvoxamine may prevent clinical deterioration by stimulating the σ-1 receptor, which regulates cytokine production.

Objective: To determine whether fluvoxamine, given during mild COVID-19 illness, prevents clinical deterioration and decreases the severity of disease.

Design, setting, and participants: Double-blind, randomized, fully remote (contactless) clinical trial of fluvoxamine vs placebo. Participants were community-living, nonhospitalized adults with confirmed severe acute respiratory syndrome coronavirus 2 infection, with COVID-19 symptom onset within 7 days and oxygen saturation of 92% or greater. One hundred fifty-two participants were enrolled from the St Louis metropolitan area (Missouri and Illinois) from April 10, 2020, to August 5, 2020. The final date of follow-up was September 19, 2020.

Interventions: Participants were randomly assigned to receive 100 mg of fluvoxamine (n = 80) or placebo (n = 72) 3 times daily for 15 days.

Main outcomes and measures: The primary outcome was clinical deterioration within 15 days of randomization defined by meeting both criteria of (1) shortness of breath or hospitalization for shortness of breath or pneumonia and (2) oxygen saturation less than 92% on room air or need for supplemental oxygen to achieve oxygen saturation of 92% or greater.

Results: Of 152 patients who were randomized (mean [SD] age, 46 [13] years; 109 [72%] women), 115 (76%) completed the trial. Clinical deterioration occurred in 0 of 80 patients in the fluvoxamine group and in 6 of 72 patients in the placebo group (absolute difference, 8.7% [95% CI, 1.8%-16.4%] from survival analysis; log-rank P = .009). The fluvoxamine group had 1 serious adverse event and 11 other adverse events, whereas the placebo group had 6 serious adverse events and 12 other adverse events.

Conclusions and relevance: In this preliminary study of adult outpatients with symptomatic COVID-19, patients treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days. However, the study is limited by a small sample size and short follow-up duration, and determination of clinical efficacy would require larger randomized trials with more definitive outcome measures.

Trial registration: ClinicalTrials.gov Identifier: NCT04342663

Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, Miller JP, Yang L, Yingling M, Avidan MS, Reiersen AM: Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA  [ Epub ahead of print, Nov.12,2020 ] e2022760. doi: 10.1001/jama.2020.22760

https://pubmed.ncbi.nlm.nih.gov/33180097/

 

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Summary: “An aspirin to make CSCs go away: Cancer stem cells (CSCs) are tumor cells with stem cell-like qualities that promote tumor progression, adaption to stress, and resistance to chemotherapy. Bhattacharya et al. found that aspirin targets CSCs in a way that may enhance the efficacy of chemotherapy in patients with basal-like breast cancers. In cultured CSCs from invasive breast tumors or in a mouse model of breast cancer, aspirin suppressed the synthesis of the drug efflux pump ABCG2 by relieving the repression of the transcription cofactor SMAR1 by pluripotency factors. Aspirin prevented doxorubicin-induced repression of SMAR1 and proliferation of CSCs, consequently enhancing the cytotoxicity of doxorubicin. Thus, in addition to its current use as an anti-inflammatory for inflammation-driven premalignancies and cancers, aspirin might also be used to target CSCs in invasive breast cancer.”
SMAR1 repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin. Science Signaling 13(654): eaay6077 (Oct.20, 2020); DOI: 10.1126/scisignal.aay6077.
https://stke.sciencemag.org/content/13/654/eaay6077
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https://www.nature.com/articles/d41586-020-02957-3

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Abstract: “The mechanisms by which prenatal immune activation increase the risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs)-which are known to be affected in schizophrenia (SCZ) when matured-from induced pluripotent stem cells (iPSCs) derived from healthy controls (HCs) and individuals with SCZ and co-cultured them with or without activated microglia. Co-culture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analyses, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release. Deficits in mitochondrial function and arborization were reversed by alpha lipoic acid and acetyl-L-carnitine treatments, which boost mitochondrial function. Notably, activated-microglia-conditioned medium altered metabolism in cINs and iPSCs from HCs but not in iPSCs from individuals with SCZ or in glutamatergic neurons. After removal of activated-microglia-conditioned medium, SCZ cINs but not HC cINs showed prolonged metabolic deficits, which suggests that there is an interaction between SCZ genetic backgrounds and environmental risk factors. ”

Park G-H et al: Activated microglia cause metabolic disruptions in developmental cortical interneurons that persist in interneurons from individuals with schizophrenia. Nature Neurosci. 23(11): 1352-1364 (2020).

https://pubmed.ncbi.nlm.nih.gov/33097921/

 

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