Anti-inflammatory drugs and the renin-angiotensin-aldosterone system: Current knowledge and potential effects on early SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of coronavirus disease 19 (COVID-19), and is genetically related to the 2003 SARS and Middle East respiratory syndrome (MERS-CoV) coronaviruses. Recent studies have reported that similar to SARS-CoV, this strain expresses a spike protein (S) with a receptor binding domain (RBD) that binds to angiotensin-converting enzyme 2 (ACE2) - an enzyme expressed mostly in the endothelium, kidneys, heart, gastrointestinal tract and lungs - to facilitate viral entry and intracellular replication. Incidentally, the renin-angiotensin-aldosterone system (RAAS) is integral to physiologic control of both ACE and ACE2 expression, and is an essential system utilized by SARS-CoV-2, albeit with varying schools of thought on how it can affect viral entry. In this paper, we will review current knowledge on the RAAS and how it can be affected by non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroid use at the organ and cellular levels. We will then discuss the relevance of these interactions on organ-specific ACE2 expression, and provide scientific insights on how this mechanism can potentially affect SARS-CoV-2 infection in the early phases of disease. From the standpoint of other known viruses, we will then aim to discuss the potential uses or restrictions of these drugs in viral infection, and provide an update on relevant studies about COVID-19.

Caffeine reduces deficits in mechanosensation and locomotion induced by L-DOPA and protects dopaminergic neurons in a transgenic Caenorhabditis elegans model of Parkinson's disease.

CONTEXT: L-DOPA is the first-line drug for Parkinson's disease (PD). However, chronic use can lead to dyskinesia. Caffeine, which is a known neuroprotectant, can potentially act as an adjunct to minimise adverse effects of L-DOPA. OBJECTIVES: This study determined changes in terms of neurodegeneration, locomotion and mechanosensation in Caenorhabditis elegans (Rhabditidae) strain UA57 overexpressing tyrosine hydroxylase (CAT-2) when treated with caffeine, L-DOPA or their combinations. MATERIALS AND METHODS: Neurodegeneration was monitored via fluorescence microscopy of GFP-tagged dopaminergic neurons in the head and tail regions of C. elegans (n = 20). Meanwhile, mechanosensation and locomotion under vehicle (0.1% DMSO), L-DOPA (60 mM), caffeine (10 mM) or 60 mM L-DOPA + 10 or 20 mM caffeine (60LC10 and 60LC20) treatments were scored for 3 days. RESULTS: L-DOPA (60 mM) reduced CEP and ADE neurons by 4.3% on day 3, with a concomitant decrease in fluorescence by 44.6%. This correlated with reductions in gentle head (-35%) and nose touch (-40%) responses, but improved locomotion (20-75%) compared with vehicle alone. CEP and ADE neuron counts were preserved with caffeine (10 mM) or 60LC10 (98-100%), which correlated with improved mechanosensation (10-23%) and locomotion (18-76%). However, none of the treatments was able to preserve PDE neuron count, reducing the basal slowing response. Discussion and conclusions: Taken together, we show that caffeine can protect DAergic neurons and can reduce aberrant locomotion and loss of sensation when co-administered with L-DOPA, which can potentially impact PD treatment and warrants further investigation.

Cytosolic non-vesicular dopamine accumulation as the predominant mechanism for developing non-DOPA responsive parkinsonism in late-stage Huntington disease.

Disturbances in motor movement can have similar clinical presentations, albeit having different pathways and temporal onset. Hypokinetic movements present with rigidity, resting tremors, postural instability and bradykinesia, as seen in parkinsonism, while hyperkinetic movements typically present with chorea, ballismus, tic, athetosis and dystonia. Nonetheless, movement disorders are thought to be a continuum. Long-term therapy of parkinsonism with L-DOPA or dopamine (DA) agonists leads to late-onset dyskinesia - a hyperkinetic movement disorder, while patients with late-stage Huntington disease (HD) often develop non-DOPA responsive parkinsonism. In this paper, it is proposed that late-onset parkinsonism is driven by the overactivity of the nigrostriatal dopaminergic pathway. The excessive synthesis, storage, release, reuptake and degradation of dopamine in the presynaptic terminal and synaptic clefts lead to cellular stress and damage, resulting to progressive neuroapoptosis aggravated by pro-parkinsonism drugs used to treat hyperkinesia. Glutamate excitotoxicity may provide initial stress to neurons during early HD - but as the disease advances, lower glutamate levels are observed, making it less likely to cause the hypokinetic shift on its own. Over time, dopaminergic neurons are depleted and cholinergic influence to striatal GABA release is unopposed, leading to late-onset parkinsonism that is unresponsive to DOPA challenge, due to drastic DA neuron loss previously masked by the dominating choreic presentation. This paper thus provides a mechanism of action to a common clinical sequela and complication of long-term choreic diseases, whose pathophysiologic mechanism is presently lacking.

Anastasis and the ER stress response: Solving the paradox of the unfolded protein response in cancer.

In recent years, studies have suggested a novel pathway for cell survival, which faces scientific skepticism and interest in its concept of cell 'resurrection' - that is, the anastasis of cells at late-stage apoptosis. While biomarkers have been discovered, many of these are related to the endoplasmic reticulum (ER) stress response - acting also to promote cell survival in the presence of perturbation. The promises of anastasis, if accepted, will greatly impact translational medicine especially in the treatment of cancer, since apoptosis is generally irreversible in the late stages, and chemotherapy is performed to maximize tumor death and minimize off-target effects. As with all new concepts, there is a need to demarcate anastasis from a well-studied survival mechanism - the ER stress response - if the concept is to progress any further. In this article, it is proposed that anastasis and the ER stress response are one and the same mechanism, demarcated only by the presence of persistent stress. Further, anastasis solves the paradox of the unfolded protein response (UPR) in cancer by providing rationale in C/EBP homologous protein (CHOP)-induced tumor survival, such that CHOP-mediated apoptosis initiates genetic alterations in favor of its survival. After which, the cell regenerates through an enhanced ER stress response. Hence, anastatic cell recovery is the ER stress response post-apoptosis.

Molecular interactions with redox sites and salt bridges modulate the anti-aggregatory effect of flavonoid, tannin and cardenolide moieties against amyloid-beta (1-42) in silico.

In this study, the interactions of flavonoid, tannin and cardenolide moieties as well as their known metabolites were docked against the apolar NMR structure of the aggregatory amyloid-beta fragment (Aß1-42). Results showed that the catechin moiety favorably bound Aß1-42 peptide at Asp23, Asn27, Ser26 and Glu22 residues, with chalcone similarly binding the middle region of the peptide. Remarkably, hippuric and ferulic acids exhibited hydrophobic interactions with Aß1-42 at the latter portion of the peptide, possibly blocking the salt bridges formed by Glu22-Lys28 which stabilizes Phe19-Gly25, as well as the ß-sheet Leu34-Gly38 that are known to exist in peptide aggregation. Meanwhile, the metabolites of hydrolyzable tannins, such as urolithin A and gallic acid, exhibited H-bonding interactions with different residues of Aß1-42, including Asp1, Asp23 and hydrophobic interactions by gallic acid planar ring to the Hsd6 residue. The coverage was lessened in pyrogallol, suggesting that gallic acid loses its efficacy when further metabolized. Lastly, the different binding poses of the cardenolide moiety interacted with Hsp6 (protonated His) and Tyr10 via hydrophobic interactions. Due to these interactions, the large polycyclic moiety of the ligand would also block further interactions with Hsd6 (prototropic tautomer of His), Asp7, Ser8 and Gly9 that are integral to His6-His13-His14, Arg5-Asp7and Leu34-Gly38 ß-sheets, salt bridges in Glu22-Lys28 and turn conformation Phe19-Gly25. Together, these data suggest that the known metabolites of anthocyanins and hydrolyzable tannins contribute the most effective anti-aggregatory interactions with Aß1-42, with an unexpected role for cardiac glycosides such as the cardenolie moiety. These bring to light the important role of metabolism in vivo, and suggests further investigation on the effects of these metabolites when concentrated in vivo.