Alzheimer’s-like remodeling of neuronal ryanodine receptor in COVID-19

Reiken, Steve; Dridi, Haikel; Sittenfeld, Leah; Li, Xiaoping; Marks, Andrew R.

doi:10.1101/2021.02.18.431811

Cited by 15 publications

(22 citation statements)

References 45 publications

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“…This lipid mediator prevents oxidation of the RyR ryanodine receptors, a family of Ca 2+ release channels that controls the intracellular calcium exchange and whose oxidation may cause leaks of Ca 2+ and lead to heart failure, pulmonary insufficiency and cognitive dysfunction in COVID-19. 29 Furthermore, TX-B2 was the only prostanoid with an enzymatic origin overexpressed in ICU patients, which agrees with the need for heparin therapy in these patients to prevent microcirculatory damage.…”

Section: Discussionsupporting

confidence: 65%

Plasma oxylipin levels may predict Covid-19 patient outcomes. An observational and retrospective study

Biagini¹,

Franzini²,

Oliveri³

et al. 2021

Preprint

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Background The key role of inflammation in the progression of COVID-19 was evident right from the beginning of the pandemic. Consequently, many authors studied the onset and evolution of the cytokine storm. In contrast, other inflammatory mediators such as oxylipins have received almost no attention. Methods We conducted a monocentric observational and retrospective study (IMPRE-COVID-19) with patients (aged ≥ 18 years) admitted to Pisa University Hospital with COVID-19 related pneumonia. SARS-CoV-2 infection was confirmed by polymerase chain reaction in a nasopharyngeal swab, while pneumonia was demonstrated by CT scan. Oxylipin plasma levels were analysed in a convenient sample of 52 patients randomly selected from those that had a complete set of cytokine values evaluated for clinical purposes. In 12 cases, plasma samples collected on different days were available at the BMS Multispecialistic Biobank of Pisa University Hospital and were analysed to understand the evolution of the oxylipin levels during hospitalization. The two datasets that included oxylipin and cytokine values were analysed by principal component analysis (PCA), computation of Fisher s canonical variable, and a multivariate receiver operating characteristic (ROC) curve. Findings Between March and April 2020, 52 patients were enrolled of which 28 were hospitalised in COVID-19 wards, 20 in ICUs, and 4 who were initially hospitalised in the wards and who were then transferred to the ICUs due to deteriorating health conditions. Plasma samples collected on different days were available from 7 patients in the wards, 1 from an ICU, and 4 from patients who were hospitalised in both. The mean age of participants was 61 years (SD 16), 11 were females (21%), and 41 were males (79%), without significant differences between groups in terms of age and gender. PCA of oxylipin data led to a clear differentiation of samples collected in COVID-19 wards and ICUs. This differentiation had not been obtained with cytokine data. In addition, borderline samples were from patients hospitalised in COVID-19 wards that were about to be transferred to the ICUs, thus suggesting that differentiation is not a consequence of a different treatment, but somehow related to a diverse evolution of the pathology. Computation of Fisher s canonical variable identified the original input variables that were the most effective in discriminating between the two classes. The combination of the two datasets did not improve the discrimination, thus suggesting that oxylipins are more informative than cytokines for this purpose. A multivariate class model built using the four lowest-order principal components as the input variables, and COVID-19 ward samples as the target class, produced a ROC curve with a resulting area under the curve (AUC) equal to 0·92 – which is much higher than most AUC outcomes obtained for individual oxylipins. Interpretation After analysing the metabolic pathways of the most informative oxylipins, we speculate that more severe COVID-19 is associated with a selective deficiency of pro-resolving oxylipins leading to ineffective resolutive mechanisms of inflammation, likely worsened by endothelial damage. We believe that our oxylipin data suggest the possibility to predict the evolution of COVID-19 in individual patients at an early stage. Funding Institutional funds from the University of Pisa supported the study.

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Section: Discussionsupporting

confidence: 65%

Plasma oxylipin levels may predict Covid-19 patient outcomes. An observational and retrospective study

Biagini¹,

Franzini²,

Oliveri³

et al. 2021

Preprint

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“…The TGF-β signaling pathway over-activation by this virus and reactive oxygen species (ROS) production leads to Ca 2+ leak from RyR channels in the sarcoplasmic reticulum (SR). This effect is produced through oxidation and protein kinase A (PKA) phosphorylation, uncoupling the regulating protein calstabin (FKBP12.6) from the RyR channel, destabilizing the closed state and favoring an open state [49]. Another mechanism proposed for RyR channel dysfunction during SARS-CoV-2 infection is through cathepsin L13 (a protease expressed in the host cell's plasma membrane); this enzyme has also been shown to participate in the over-activation of RyR channels, promoting a leaky state.…”

Section: Viral Modifications Of Host Cell Calcium Homeostasismentioning

confidence: 99%

Could Lower Testosterone in Older Men Explain Higher COVID-19 Morbidity and Mortalities?

Montaño

Sommer

Solís‐Chagoyán

et al. 2022

IJMS

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The health scourge imposed on humanity by the COVID-19 pandemic seems not to recede. This fact warrants refined and novel ideas analyzing different aspects of the illness. One such aspect is related to the observation that most COVID-19 casualties were older males, a tendency also noticed in the epidemics of SARS-CoV in 2003 and the Middle East respiratory syndrome in 2012. This gender-related difference in the COVID-19 death toll might be directly involved with testosterone (TEST) and its plasmatic concentration in men. TEST has been demonstrated to provide men with anti-inflammatory and immunological advantages. As the plasmatic concentration of this androgen decreases with age, the health benefit it confers also diminishes. Low plasmatic levels of TEST can be determinant in the infection’s outcome and might be related to a dysfunctional cell Ca2+ homeostasis. Not only does TEST modulate the activity of diverse proteins that regulate cellular calcium concentrations, but these proteins have also been proven to be necessary for the replication of many viruses. Therefore, we discuss herein how TEST regulates different Ca2+-handling proteins in healthy tissues and propose how low TEST concentrations might facilitate the replication of the SARS-CoV-2 virus through the lack of modulation of the mechanisms that regulate intracellular Ca2+ concentrations.

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“…Activation levels of hundreds of genes in all major cell types differed in the COVID-19 patients' brains vs. controls. Many of these genes were associated with inflammatory processes and degenerative neuro diseases such as Alzheimer's and Parkinson's diseases (Yang et al, 2021;Reiken et al, 2022). The findings may help explain the neurological problems of patients with LCS.…”

Section: Brains Of Individuals Who Died Of Covid-19 Are Similar To Al...mentioning

confidence: 88%

Recommendation: Treatment of clinical long COVID encephalopathies with nasal administered mesenchymal stromal cell extracellular vesicles

Askenase

2022

Front. Nanotechnol.

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We propose therapy with extracellular vesicles (EVs) for dominant central nervous system aspects of chronic Long COVID Syndromes (LCS). These clinical conditions have a delayed onset of 1–3 months following the cessation of active SARS-CoV-2 virus infections that cause an acute disease called COVID-19. The therapy of LCS will be achieved by direct access to the central nervous system (CNS) by nasal administration of small EVs derived from Mesenchymal Stromal Cells (MSC). When administered nasally, they target CNS microglia and endothelia involved in LCS encephalopathy, as indicated by experimental animal models and human autopsy and spinal fluid studies. Underlying this approach is the discovery that MSC-sEV treatment for healing neuro injury targets, microglia, and macrophages that then likely release secondary trophic EVs that affect the local capillary endothelial cells to restore vascular integrity. It is postulated that the pathways of endothelial and neural pathologies in acute SARS-CoV-2 virus infections may carry over to produce underlying vascular and neurological defects mediating LCS that are susceptible to this proposed nasal therapy with MSC-sEVs.

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Alzheimer’s-like remodeling of neuronal ryanodine receptor in COVID-19

Cited by 15 publications

References 45 publications

Plasma oxylipin levels may predict Covid-19 patient outcomes. An observational and retrospective study

Plasma oxylipin levels may predict Covid-19 patient outcomes. An observational and retrospective study

Could Lower Testosterone in Older Men Explain Higher COVID-19 Morbidity and Mortalities?

Recommendation: Treatment of clinical long COVID encephalopathies with nasal administered mesenchymal stromal cell extracellular vesicles

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