Promising Experimental Anti-SARS-CoV-2 Agent "SLL-0197800": The Prospective Universal Inhibitory Properties against the Coming Versions of the Coronavirus.

Isoquinoline derivatives having some nucleosidic structural features are considered as candidate choices for effective remediation of the different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and their following disease, the coronavirus disease 2019 (COVID-19). SLL-0197800 is a recently discovered isoquinoline compound with potential strong universal anticoronaviral activities against SARS-CoV-2 and its previous strains. SLL-0197800 nonspecifically hits the main protease (Mpro) enzyme of the different coronaviruses. Herein in the present study, we tested the probability of the previous findings of this experimental agent to be extended to comprise any coronavirus through concurrently disrupting the mutable-less replication enzymes like the RNA-dependent RNA polymerase (RdRp) protein as well as the 3'-to-5' exoribonuclease (ExoN) protein. The in vitro anti-RdRp/ExoN assay revealed the potent inhibitory activities of SLL-0197800 on the coronaviral replication with minute values of anti-RdRp and anti-RdRp/ExoN EC50 (about 0.16 and 0.27 µM, respectively). The preliminary in silico outcomes significantly supported these biochemical findings. To put it simply, the present important results of these extension efforts greatly reinforce and extend the SLL-0197800's preceding findings, showing that the restraining/blocking actions (i.e., inhibitory activities) of this novel investigational anti-SARS-CoV-2 agent against the Mpro protein could be significantly extended against other copying and multiplication enzymes such as RdRp and ExoN, highlighting the potential use of SLL-0197800 against the coming versions of the homicidal coronavirus (if any), i.e., revealing the probable nonspecific anticoronaviral features and qualities of this golden experimental drug against nearly any coronaviral strain, for instance, SARS-CoV-3.

Electrocardiographic and histopathological characterizations of diabetic cardiomyopathy in rats.

Diabetes is a clinical condition that is associated with insulin deficiency and hyperglycemia. Cardiomyopathy, retinopathy, neuropathy, and nephropathy are well known complications of the elevated blood glucose. Diabetic cardiomyopathy is a clinical disorder that is associated with systolic and diastolic dysfunction along with cardiac fibrosis, inflammation, and elevated oxidative stress. In this study, diabetes was induced by intraperitoneal injection of streptozotocin (STZ) 50 mg/kg. We determined the plasma levels of cardiac troponin-T (cTnT) and creatinine kinase MB (CK-MB) by ELISA. Diabetic rats showed abnormal cardiac architecture and increased collagen production. Significant elevation in ST-segment, prolonged QRS, and QT-intervals and increased ventricular rate were detected. Additionally, diabetic rats showed a prolongation in P wave duration and atrial tachyarrhythmia was observed. Plasma levels of cTnT and CK-MB were elevated. In conclusion, these electrocardiographic changes (elevated ST-segment, prolonged QT interval, and QRS complex, and increased heart rate) along with histopathological changes and increased collagen formation could be markers for the development of diabetic cardiomyopathy in rats.

Impact of interferon ß-1b, interferon ß-1a and fingolimod therapies on serum interleukins-22, 32α and 34 concentrations in patients with relapsing-remitting multiple sclerosis.

Interleukins (ILs)-22, 32α and 34 were monitored in the sera of relapsing-remitting multiple sclerosis (RRMS) patients at different time intervals with or without interferon ß-1b, interferon ß-1a and fingolimod treatments. The results showed that sera of untreated RRMS patients were statistically higher in concentration of IL-22 (P < .001), but not IL-32α and IL-34, than those of healthy individuals. Interestingly, interferon ß-1b, interferon ß-1a and fingolimod treatments led to a significant decrease of serum concentrations of ILs-22 and 32α, but not 34, at 6 and 12 months of treatment, compared to their initial concentrations before initiating therapy. The correlation analysis revealed that the changes of serum IL-22 (r = 0.814) and, to a lesser extent, IL-32α (r = 0.381) concentrations were positively correlated with those of expanded disability status score. In conclusion, serum IL-22 concentration may be a potential marker for MS disease severity and efficacy of treatment.

Valproate-induced liver injury: modulation by the omega-3 fatty acid DHA proposes a novel anticonvulsant regimen.

BACKGROUND: The polyunsaturated, ω-3 fatty acid, docosahexaenoic acid (DHA), claims diverse cytoprotective potentials, although via largely undefined triggers. Thus, we currently first tested the ability of DHA to ameliorate valproate (VPA)-evoked hepatotoxicity, to modulate its anticonvulsant effects, then sought the cellular and molecular basis of such actions. Lastly, we also verified whether DHA may kinetically alter plasma levels/clearance rate of VPA. METHODS AND RESULTS: VPA (500 mg/kg orally for 14 days in rats) evoked prominent hepatotoxicity that appeared as a marked rise (2- to 4-fold) in serum hepatic enzymes (γ-glutamyl transferase [γ-GT], alanine aminotransferase [ALT], and alkaline phosphatase [ALP]), increased hepatic lipid peroxide (LPO) and tumor necrosis factor-alpha (TNFα) levels, as well as myeloperoxidase (MPO) activity (3- to 5-fold), lowering of serum albumin (40 %), and depletion of liver reduced-glutathione (GSH, 35 %). Likewise, histopathologic examination revealed hepatocellular degeneration, replacement by inflammatory cells, focal pericentral necrosis, and micro/macrovesicular steatosis. Concurrent treatment with DHA (250 mg/kg) markedly blunted the elevated levels of liver enzymes, lipid peroxides, TNFα, and MPO activity, while raising serum albumin and hepatic GSH levels. DHA also alleviated most of the cytologic insults linked to VPA. Besides, in a pentylenetetrazole (PTZ) mouse convulsion model, DHA (250 mg/kg) markedly increased the latency in convulsion evoked by VPA, beyond their individual responses. Lastly, pharmacokinetic studies revealed that joint DHA administration did not alter serum VPA concentrations. CONCLUSIONS: DHA substantially ameliorated liver injury induced by VPA, while also markedly boosted its pharmacologic effects. DHA manipulated definite cellular machinery to curb liver oxidative stress and inflammation, without affecting VPA plasma levels. Collectively, these protective and synergy profiles for DHA propose a superior VPA-drug combination regimen.