Beta-Adrenergic Blockers as a Potential Treatment for COVID-19 Patients

More than 15 million people have been affected by coronavirus disease 2019 (COVID-19) and it has caused 640 016 deaths as of July 26, 2020. Currently, no effective treatment option is available for COVID-19 patients. Though many drugs have been proposed, none of them has shown particular efficacy in clinical trials. In this article, the relationship between the Adrenergic system and the renin-angiotensin-aldosterone system (RAAS) is focused in COVID-19 and a vicious circle consisting of the Adrenergic system-RAAS-Angiotensin converting enzyme 2 (ACE2)-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (which is referred to as the “ARAS loop”) is proposed. Hyperactivation of the ARAS loop may be the underlying pathophysiological mechanism in COVID-19, and beta-adrenergic blockers are proposed as a potential treatment option. Beta-adrenergic blockers may decrease the SARS-CoV-2 cellular entry by decreasing ACE2 receptors expression and cluster of differentiation 147 (CD147) in various cells in the body. Beta-adrenergic blockers may decrease the morbidity and mortality in COVID-19 patients by preventing or reducing acute respiratory distress syndrome (ARDS) and other complications. Retrospective and prospective clinical trials should be conducted to check the validity of the hypothesis. Also see the video abstract here https://youtu.be/uLoy7do5ROo .     

Prognostic factors and predictors of outcome in patients with COVID-19 and related pneumonia: a retrospective cohort study

The aim of the present study was to simultaneously assess several potential predictors of outcome (co-morbidity, previous and in-hospital treatment, radiologic Brixia score) in patients with COVID-19.This retrospective cohort study included 258 consecutive patients with confirmed COVID-19 admitted to a medical ward at Montichiari Hospital, Brescia, Italy from February 28th to April 30rd, 2020. Patients had SARS-CoV-2 related pneumonia with respiratory failure, and were treated with hydroxychloroquine and lopinavir plus ritonavir. In some patients, additional treatment with tocilizumab, dexamethasone and enoxaparin was adopted. Outcomes (death or recovery) were assessed at the end of the discharge period or at the end of the follow-up (August 2020).During hospitalization, 59 patients died, while 6 died after discharge. The following variables were demonstrated to be associated with a worse prognosis: Radiologic Brixia score higher than 8, presence at baseline of hypertension, diabetes, chronic obstructive pulmonary disease, heart disease, cancer, previous treatment with ACE-inhibitors or anti-platelet drugs. Anticoagulant treatment during hospital admission with enoxaparin at a dose higher than 4000 U once daily was associated with a better prognosis.In conclusion, our study demonstrates that some co-morbidities and cardiovascular risk factors may affect prognosis. The radiologic Brixia score may be a useful tool to stratify the risk of death at baseline. Anticoagulant treatment with enoxaparin might be associated to a clinical benefit in terms of survival in patients with COVID-19.     

Retracted: The promoting effect of MMP13 on mediating the development of HFLS-RA by the target of miR-19a through IL-17 signaling pathway

By investigating the expression profiles of miR-19a and metalloproteinases (MMP13) in human fibroblast-like synoviocytes-rheumatoid arthritis (HFLS-RA) and HFL cells lines, this study intends to confirm the directly target connection between them and reveal the effect of suppressing MMP13 on HLFS-RA migration, invasion and apoptosis. After screening the abnormal expressed messenger RNAs and microRNAs in synovial tissues of patients with RA, the underlying pathway was determined by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The HFLS-RA cell line was transfected for the following experiments with pcDNA3.1(+) served as vector. The directly target association between miR-19a and MMP13 was confirmed by Luciferase reporter assay. Microarray analysis suggested that MMP13 was upregulated while miR-19a was downregulated in HFLS of RA tissues compared with the healthy control group. MMP13 was related to many proteins in protein-protein interaction network, which might be the main influencing factor of RA. KEGG pathway analysis identified that interleukin (IL)-17 pathway was activated in the regulation of MMP13 in the development of RA. Through observing the alteration of luciferase activity, miR-19a could indeed bind to the 3′UTR of the downstream of MMP13, the target association was then confirmed. The proliferation and invasion of HFLS-RA were promoted by overexpressing MMP13 protein. miR-19a could function as a suppressor of MMP13 and thereby retard the severity of RA. The results showed that miR-19a could regulate the expression of MMP13 in HFLS-RA by mediating the proliferation and invasion of HFLS-RA through IL-17 signaling pathway, thereby participating in the degradation of chondrocytes in the progression of RA.     

Different Binding Modes of Spermine to A-T and G-C Base Pairs Modulate the Bending and Stiffening of the DNA Double Helix

Abstract

The influence of base composition (and sequence) on the process of interaction between synthetic polynucleotides and spermine, has been investigated using ultraviolet (including second derivative) spectroscopy, and electric dichroism.

Different binding modes of spermine to poly(dG-dC) as compared to A-T containing polynucleotides, were evidenced. An interaction with the N7 and 06 of guanine is probably partially involved in the former case while simple electrostatic interaction with the phosphate groups would dominate in the latter.

In the intermediate binding range (spermine over DNA phosphate molar ratios Sp/P of the order of 0.1 to 0.2), the complexes with poly(dA) · poly(dT) and those with poly(dA-dT) displayed an important contribution of a permanent dipole moment to the orientation mechanism, as detected by the application of bipolar pulses in electric dichroism experiments. Just prior to precipitation (at Sp/P slightly larger than 0.3), these polynucleotides show electric dichroism and relaxation times characteristics corresponding to toroidal particles formation resulting from a bending of their chains. This implies asymmetric binding to phosphate sites on A-T containing polynucleotides. At low Sp/P ratios, spermine induced a stiffening of poly (dG-dC). No influence of spermine on the orientation mechanism of this polynucleotide was detected for Sp/P values ranging from zero to 0.35. The spermine-induced bending of A-T rich regions thus appears to be essential for DNA condensation into toroidal particles.     

Sources of Thought Two 19th-century Chronobiologists: Thomas Laycock and Edward Smith

This article describes the works of two 19th-century chronobiologists. Thomas Laycock (1812-1876), who held the Chair of Medicine in Edinburgh from 1855-1876, published a series of seven articles in Lancet, all dedicated to periodicities in “vital phenomena.” Laycock considered the understanding of periodicities essential for the advancement of the treatment of diseases. Edward Smith (1818-1874) was a pioneer in experimental chronobiology. In his 1861 book entitled: Health and disease as influenced by daily, seasonal and other cyclical changes in the human, Smith summarized a large number of experiments in which he investigated the occurrence of periodicities in pulse rate, urine flow, urea excretion, and respiration. From his experimental results and those of others, Smith drew practical conclusions regarding patients' care, the timing of drug administration, and the design of night work.     

Reflux induces DNA strand breaks and expression changes of MMP1+9+14 in a human miniorgan culture model

Gastroesophageal reflux disease has been implicated in the pathogenesis of adenocarcinoma of the oesophagus. The same applies to laryngopharyngeal reflux (LPR) and squamous cell cancer of the head and neck, but so far, this link has not been proven. The impact of low pH and bile acids has not been studied extensively in cells other than oesophageal cancer cell lines and tissue. The aims of this study were to investigate the pathogenic potential of reflux and its single components on the mucosa of the upper respiratory tract. We measured DNA stability in human miniorgan cultures (MOCs) and primary epithelial cell cultures (EpCs) in response to reflux by the alkaline comet assay. As matrix metalloproteinases (MMPs) are involved in extracellular matrix remodelling processes and may contribute to cancer progression, we studied the expression of MMP1, -9, and -14 in MOCs, EpC, UM-SCC-22B, and FADU_DD. DNA strand breaks (DNA-SBs) increased significantly at low pH and after incubation with human or artificial gastric juice. Single incubation with glycochenodeoxycholic acid also showed a significant increase in DNA-SBs. In epithelial cell cultures, human gastric juice increased the number of DNA-SBs at pH 4.5 and 5.5. Artificial gastric juice significantly up regulated the gene expression of MMP9. Western blot analysis confirmed the results of gene expression analysis, but the up regulation of MMP1, -9, and -14 was donor-specific. Reflux has the ability to promote genomic instability and may contribute to micro environmental changes suitable for the initiation of malignancy. Further functional gene analysis may elucidate the role of laryngopharyngeal reflux in the development of head neck squamous cell carcinoma (HNSCC).     

The multiple forms of bovine seminal ribonuclease: Structure and stability of a C-terminal swapped dimer

Bovine seminal ribonuclease (BS-RNase) acquires an interesting anti-tumor activity associated with the swapping on the N-terminal. The first direct experimental evidence on the formation of a C-terminal swapped dimer (C-dimer) obtained from the monomeric derivative of BS-RNase, although under non-native conditions, is here reported. The X-ray model of this dimer reveals a quaternary structure different from that of the C-dimer of RNase A, due to the presence of three mutations in the hinge peptide 111–116. The mutations increase the hinge peptide flexibility and decrease the stability of the C-dimer against dissociation. The biological implications of the structural data are also discussed.     

Cationic antioxidants as a powerful tool against mitochondrial oxidative stress

This review describes evidence that mitochondrial reactive oxygen species (mROS) are of great importance under many physiological and pathological conditions. The most demonstrative indications favoring this conclusion originate from recent discoveries of the in vivo effects of mitochondria-targeted antioxidants (MitoQ and SkQs). The latter compounds look promising in treating several incurable pathologies as well as aging.