Veterinary drug Trametin obtained on the basis of Trametes pubescens xylotroph fungi: its effect on the biosynthesis of interferons and its prophylactic activity against calf respiratory diseases

Given the spread of bacterial and viral diseases in young farm animals, the use of interferons and drugs to stimulate their biosynthesis has gained relevance. In a previous study, we examined the effect of a veterinary drug Trametin produced on the basis of Trametes pubescens (Shumach.: Fr.) Pilat. on the biosynthesis of interferons in the blood of mice. The present work is aimed at studying the biosynthesis dynamics of α- and γ-interferons when using Trametin and studying its prophylactic activity in calves. It is shown that a single oral administration of Trametin in doses ranging from 15 to 60 mg/kg causes a dose-dependent induction and production of γ-interferon in the blood of mice, whose maximum content reaches 1337.0±93.0 pg/mL at 48 h after administering a dose of 30 mg/kg. With a Trametin dose increase from 15 to 30 mg/kg, the level of α-interferon production rises to 1388.0±84.0 pg/mL at 48 h after administration. At a Cycloferon dose of 4.5 mg/kg, the production level of α-interferon and γ-interferon amounts to 1455.47±84.2 and 1447.0±90.0 pg/mL, respectively. The immunostimulatory properties of Trametin are confirmed by a scientific and economic experiment conducted using immunocompromised calves. In our studies, an immunological test of calf blood performed prior to and following the administration of Trimetin and Cycloferon constitutes criteria for the prophylactic activity of these drugs. The prophylactic efficacy of Trametin is confirmed by an increase in phagocytic activity by 10.5%, phagocytic index by 61.8%, and phagocytic number by 52.8%. After Trametin administration, the bactericidal activity of the serum increases by 60%. Cycloferon exhibits a similar immunostimulatory effect. Nonspecific prophylaxis using Trametin is shown to reduce the incidence of bacterial and viral respiratory diseases in young calves and generally improve their immunity.

The fifth stage of the research оn the project «Saumal-tour»: results and prospects

The purpose of the article is to determine the impact of the combination of saumal consumption, physical exertion and staying in the middle mountains on the human body. Saumal or fresh mare's milk is an excellent alternative to cow's milk when feeding children or the elderly. The therapeutic properties of mare's milk were used by the ancestors of the Kazakh people 5 thousand years ago. The article provides data on the dosed use of saumal in combination with physical exertion and staying in the middle mountains for 5 years in order to improve the health of older athletes. The research methodology is based on the analysis of tourist and medical literature, system analysis, and also includes a stating experiment. The project is based on a combination of the therapeutic and health-improving potential of the climate of the Middle mountains, technologies of sports and health tourism and ancient traditions of the peoples of Central Asia on the use of saumal. The accumulated experience allows us to draw the following conclusions: 1) as a person stays in mid-mountain conditions, the body's resistance to a lack of oxygen increases, people's well-being improves, body functions stabilize, and efficiency increases; 2) all participants in the collection significantly reduced their weight, blood pressure and heart rate leveled off to the age norm; 3) the working capacity has significantly increased; 4) the prophylactic efficacy of Saumal and the restorative potential for aged athletes who had suffered a stroke and heart attack were revealed; 5) in the process of using saumal, the intellectual activity of the participants increases.

Potential prophylactic efficacy of mast cell stabilizers against COVID-19 vaccine-induced anaphylaxis

To fight against coronavirus disease 2019 (COVID-19), the vaccination is currently the most effective approach. However, in addition to common systemic side effects, the vaccines can cause serious allergic reactions or anaphylaxis. In anaphylaxis, the exposure to the allergen causes a sudden release of chemical mediators from mast cells, for which adrenaline is the drug of first choice. In our previous basic studies, in addition to adrenaline, anti-allergic drugs (olopatadine, loratadine, tranilast and ketotifen), antibiotics (clarithromycin), corticosteroids (hydrocortisone and dexamethasone) and certain food constituents (caffeine and catechin) inhibited the process of exocytosis and showed their effectiveness as highly potent mast cell stabilizers. In these studies, since mast cells were pre-incubated with these drugs or the food constituents before exocytosis was induced, the findings strongly indicated their prophylactic efficacy in stabilizing mast cells. Considering such pharmacological properties of these commonly prescribed medications or the food constituents, their prophylactic use may potentially be beneficial in preventing anaphylaxis caused by COVID-19 vaccination.

Potent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus display remarkable efficacy against authentic B.1.351 virus. Surprisingly, structural analysis has revealed that 58G6 and 13G9 both recognize the steric region S470–495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly binds to another region S450–458 in the RBD. Significantly, 58G6 and 510A5 both demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. Together, we have evidenced 2 potent neutralizing Abs with unique mechanism targeting authentic SARS-CoV-2 mutants, which can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.

Molnupiravir—A Novel Oral Anti-SARS-CoV-2 Agent

Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly resulted in a global pandemic with approximately 4 million deaths. Effective oral antiviral agents are urgently needed to treat coronavirus disease-2019 (COVID-19), block SARS-CoV-2 transmission, and prevent progression to severe illness. Molnupiravir (formerly EIDD-2801), a prodrug of beta-D-N4-hydroxycytidine (EIDD-1931) and an inhibitor of RNA-dependent RNA polymerase, possesses significant activity against SARS-CoV-2. Its prophylactic efficacy has been evidenced in a ferret model. Two phase-I trials (NCT04392219 and NCT04746183) have demonstrated that oral molnupiravir is safe and well-tolerated at therapeutic doses. After five-days of oral molnupiravir therapy, satisfactory efficacies, assessed by eliminating nasopharyngeal virus in patients with early and mild COVID-19, were disclosed in two phase-II trials (NCT04405739 and NCT 04405570). Two phase-II/III trials, NCT04575597 and NCT04575584, with estimated enrollments of 1850 and 304 cases, respectively, are ongoing. The NCT04575597 recently released that molnupiravir significantly reduced the risk of hospitalization or death in adults experiencing mild or moderate COVID-19. To benefit individual and public health, clinical applications of molnupiravir to promptly treat COVID-19 patients and prevent SARS-CoV-2 transmission may be expected.

Treatment of Chikungunya Virus (CHIKV) Using Targeted Immunotherapy

Chikungunya virus (CHIKV) is the most common mosquito-borne Alphavirus infecting humans worldwide. Up to date, there are no antiviral treatments or vaccines approved to treat or prevent CHIKV for which treatments remain symptomatic based on clinical manifestations. Hence, designing effective therapies to either prevent or treat CHIKV infection is of paramount importance. Interestingly, monoclonal antibodies (mAbs) are known to be significantly important in mediating protective immunity in CHIV infection. During the last decades, numerous animal studies have reported the protective and prophylactic efficacy of human and mouse anti-CHIKV mAbs isolated from convalescent patients. However, the therapeutic benefits of these anti-CHIKV mAbs can be limited by multiple factors. Thus, it becomes pertinent to better understand the CHIKV infection dynamics, mitigate the undesired mAbs-associated effects and improve therapies. In this review, we critically discuss CHIKV antiviral infectious mechanisms and address how the improved understanding of the latter may pave the way to better targeted immunotherapies.

A non-bactericidal cathelicidin provides prophylactic efficacy against bacterial infection by driving phagocyte influx

The roles of bactericidal cathelicidins against bacterial infection have been extensively studied. However, the anti-bacterial property and mechanism of action of non-bactericidal cathelicidins are rarely known. Herein, a novel naturally occurring cathelicidin (PopuCATH) from tree frog (Polypedates puerensis) didn’t show any direct anti-bacterial activity in vitro. Intriguingly, intraperitoneal injection of PopuCATH before bacterial inoculation significantly reduced the bacterial load in tree frogs and mice, and reduced the inflammatory response induced by bacterial inoculation in mice. PopuCATH pretreatment also increased the survival rates of septic mice induced by a lethal dose of bacterial inoculation or cecal ligation and puncture (CLP). Intraperitoneal injection of PopuCATH significantly drove the leukocyte influx in both frogs and mice. In mice, PopuCATH rapidly drove neutrophil, monocyte/macrophage influx in mouse abdominal cavity and peripheral blood with a negligible impact on T and B lymphocytes, and neutrophils, monocytes/macrophages, but not T and B lymphocytes, were required for the preventive efficacy of PopuCATH. PopuCATH did not directly act as chemoattractant for phagocytes, but PopuCATH obviously drove phagocyte migration when it was cultured with macrophages. PopuCATH significantly elicited chemokine/cytokine production in macrophages through activating p38/ERK mitogen-activated protein kinases (MAPKs) and NF-κB p65. PopuCATH markedly enhanced neutrophil phagocytosis via promoting the release of neutrophil extracellular traps (NETs). Additionally, PopuCATH showed low side effects both in vitro and in vivo. Collectively, PopuCATH acts as a host-based immune defense regulator that provides prophylactic efficacy against bacterial infection without direct antimicrobial effects. Our findings reveal a non-bactericidal cathelicidin which possesses unique anti-bacterial action, and highlight the potential of PopuCATH to prevent bacterial infection.