Prophylactic Activity Research Articles

Glutaraldehyde modified red blood cells delivering artesunate to the liver as a dual therapeutic and prophylactic antimalaria strategy.

Malaria can spread quickly in the population and develop rapidly. Patients with malaria usually die due to lack of timely and effective treatment. Artesunate (AS) is a highly effective and low-toxicity antimalarial drug, but its short half-life in the blood makes it difficult to control the malaria infection completely. Red blood cells (RBCs) have great biodegradability and can be employed to encapsulate various drugs. In this work, we employed RBCs as carriers to encapsulate AS and modified them with glutaraldehyde to construct an intelligent response drug delivery system (G-AS-RBCs) targeting the liver for antimalaria therapeutic and prophylactic activity. The G-AS-RBCs had a drug loading amount of 6.56 ± 0.14 mg 10-8 cells, suggesting excellent biocompatibility. G-AS-RBCs exhibited strong liver targeting efforts and can be maintained in the mice for at least 9 days, showing the potential for malaria prevention. The enrichment of AS in the liver was enhanced because of the natural liver targeting of erythrocytes and the enhancement of liver targeting by glutaraldehyde treatment. Furthermore, AS entrapped into RBCs also showed improved slow-release characteristics and achieved a better effect of inhibiting or killing the malaria parasite than free drugs. Therefore, this RBC-based strategy is expected to realize the prevention and treatment of malaria and has good application prospects.

Clinico-pathological changes and performance indices in Eimeria tenella-infected broiler chickens following the prophylactic administration of Ganoderma lucidum, Vernonia amygdalina, and Vitellaria paradoxa methanolic extract

This study assessed the clinico-pathological changes and performance indices in Eimeria tenella-infected broiler chickens following the prophylactic administration of methanol extracts of Ganoderma lucidum, Vernonia amygdalina and Vitellaria paradoxa. One hundred one-day-old Abor acre broiler chicks were randomly divided into 10 groups (A1, B1, C1, D1, A2, B2, C2, D2, E, and F) of 10 birds each. From 14-20 days of age (doa), groups A1 and A2 were administered G. lucidum; B1 and B2 V. amygdalina; C1 and C2 V. paradoxa methanol extracts; D1 and D2 Amprolium; while groups E and F were not administered any extract/medication. At 21 doa, groups A2, B2, C2, D2 and E were challenged with 104 E. tenella sporulated oocysts orally. Clinical signs, morbidity and mortality rates, caecal lesion scores and performance indices were determined. Outcomes revealed mild clinical signs in groups A2, B2, and C2, moderate in D2 but severe in E; 100% morbidity and 0.0% mortality in all groups of chickens. Caecal lesions were mild in groups A2, B2, C2 and D. There was non-significantly (P > 0.05) higher weight gain and lower feed conversion ratio in groups A2, B2, C2 and D2 compared to E. The oocyst decrease ratio and anticoccidial index were higher in A2, B2, C2 and D2 than E. The prophylactic administration of G. lucidum, V. amygdalina leaf and V. paradoxa stem bark methanol extracts decreased the clinical signs, caecal lesions, and histopathological changes, and improved performance in the E. tenella-challenged broiler chickens. The identification of the bioactive substances in these extracts responsible for their prophylactic anticoccidial activities and their possible mechanisms is therefore recommended.

Novel Arylpiperazine Derivatives of Salicylamide with α1-Adrenolytic Properties Showed Antiarrhythmic and Hypotensive Properties in Rats.

Cardiovascular diseases remain one of the leading causes of death worldwide. Unfortunately, the available pharmacotherapeutic options have limited effectiveness. Therefore, developing new drug candidates remains very important. We selected six novel arylpiperazine alkyl derivatives of salicylamide to investigate their cardiovascular effects. Having in mind the beneficial role of α1-adrenergic receptors in restoring sinus rhythm and regulating blood pressure, first, using radioligand binding assays, we evaluated the affinity of the tested compounds for α-adrenergic receptors. Our experiments revealed their high to moderate affinity for α1- but not α2-adrenoceptors. Next, we aimed to determine the antiarrhythmic potential of novel derivatives in rat models of arrhythmia induced by adrenaline, calcium chloride, or aconitine. All compounds showed potent prophylactic antiarrhythmic activity in the adrenaline-induced arrhythmia model and no effects in calcium chloride- or aconitine-induced arrhythmias. Moreover, the tested compounds demonstrated therapeutic antiarrhythmic activity, restoring a normal sinus rhythm immediately after the administration of the arrhythmogen adrenaline. Notably, none of the tested derivatives affected the normal electrocardiogram (ECG) parameters in rodents, which excludes their proarrhythmic potential. Finally, all tested compounds decreased blood pressure in normotensive rats and reversed the pressor response to methoxamine, suggesting that their hypotensive mechanism of action is connected with the blockade of α1-adrenoceptors. Our results confirm the antiarrhythmic and hypotensive activities of novel arylpiperazine derivatives and encourage their further investigation as model structures for potential drugs.

FXR mediates ILC-intrinsic responses to intestinal inflammation

The pleiotropic actions of the Farnesoid X Receptor (FXR) are required for gut health, and reciprocally, reduced intestinal FXR signaling is seen in inflammatory bowel diseases (IBDs). Here, we show that activation of FXR selectively in the intestine is protective in inflammation-driven models of IBD. Prophylactic activation of FXR restored homeostatic levels of pro-inflammatory cytokines, most notably IL17. Importantly, these changes were attributed to FXR regulation of innate lymphoid cells (ILCs), with both the inflammation-driven increases in ILCs, and ILC3s in particular, and the induction of Il17a and Il17f in ILC3s blocked by FXR activation. Moreover, a population of ILC precursor-like cells increased with treatment, implicating FXR in the maturation/differentiation of ILC precursors. These findings identify FXR as an intrinsic regulator of intestinal ILCs and a potential therapeutic target in inflammatory intestinal diseases.

Arsenic trioxide elicits prophylactic and therapeutic immune responses against solid tumors by inducing necroptosis and ferroptosis.

Boosting tumor immunosurveillance with vaccines has been proven to be a feasible and cost-effective strategy to fight cancer. Although major breakthroughs have been achieved in preventative tumor vaccines targeting oncogenic viruses, limited advances have been made in curative vaccines for virus-irrelevant malignancies. Accumulating evidence suggests that preconditioning tumor cells with certain cytotoxic drugs can generate whole-cell tumor vaccines with strong prophylactic activities. However, the immunogenicity of these vaccines is not sufficient to restrain the outgrowth of existing tumors. In this study, we identified arsenic trioxide (ATO) as a wide-spectrum cytotoxic and highly immunogenic drug through multiparameter screening. ATO preconditioning could generate whole-cell tumor vaccines with potent antineoplastic effects in both prophylactic and therapeutic settings. The tumor-preventive or tumor-suppressive benefits of these vaccines relied on CD8+ T cells and type I and II interferon signaling and could be linked to the release of immunostimulatory danger molecules. Unexpectedly, following ATO-induced oxidative stress, multiple cell death pathways were activated, including autophagy, apoptosis, necroptosis, and ferroptosis. CRISPR‒Cas9-mediated knockout of cell death executors revealed that the absence of Rip3, Mlkl, or Acsl4 largely abolished the efficacy of ATO-based prophylactic and therapeutic cancer vaccines. This therapeutic failure could be rescued by coadministration of danger molecule analogs. In addition, PD-1 blockade synergistically improved the therapeutic efficacy of ATO-based cancer vaccines by augmenting local IFN-γ production.

Genomic Landscape Highlights Molecular Mechanisms Involved in Silicate Solubilization, Stress Tolerance, and Potential Growth-Promoting Activity of Bacterium Enterobacter sp. LR6.

Silicon (Si) is gaining widespread attention due to its prophylactic activity to protect plants under stress conditions. Despite Si's abundance in the earth's crust, most soils do not have enough soluble Si for plants to absorb. In the present study, a silicate-solubilizing bacterium, Enterobacter sp. LR6, was isolated from the rhizospheric soil of rice and subsequently characterized through whole-genome sequencing. The size of the LR6 genome is 5.2 Mb with a GC content of 54.9% and 5182 protein-coding genes. In taxogenomic terms, it is similar to E. hormaechei subsp. xiangfangensis based on average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH). LR6 genomic data provided insight into potential genes involved in stress response, secondary metabolite production, and growth promotion. The LR6 genome contains two aquaporins, of which the aquaglyceroporin (GlpF) is responsible for the uptake of metalloids including arsenic (As) and antimony (Sb). The yeast survivability assay confirmed the metalloid transport activity of GlpF. As a biofertilizer, LR6 isolate has a great deal of tolerance to high temperatures (45 °C), salinity (7%), and acidic environments (pH 9). Most importantly, the present study provides an understanding of plant-growth-promoting activity of the silicate-solubilizing bacterium, its adaptation to various stresses, and its uptake of different metalloids including As, Ge, and Si.

Hepatocyte-specific Mas activation enhances lipophagy and fatty acid oxidation to protect against acetaminophen-induced hepatotoxicity in mice

Acetaminophen (APAP) is the most common cause of drug-induced liver injury (DILI); however, treatment options are limited. Mas is a G protein-coupled receptor whose role in APAP-induced hepatotoxicity has not yet been examined. Intrahepatic Mas expression was determined in both human and mouse DILI models. Mas1-/-, AlbcreMas1f/f, Ppara-/-, Mas1-/-Ppara-/- and wild-type mice were challenged with APAP for the in vivo analyses of Mas-AKT-FOXO1 axis-dependent lipophagy and fatty acid oxidation (FAO), using pharmacological compounds and genetic tools. Liver samples were collected for RNA-sequencing, proteomics, metabolomics, lipidomics, and metabolic flux analysis. Live-imaging of liver and histological, biochemical, and molecular studies were performed to evaluate APAP-induced hepatotoxicity in mice. Primary hepatocytes and hepatic cell lines were exposed to APAP for in vitro analysis. Intrahepatic Mas expression was significantly upregulated in human and mouse DILI models. Mice with systemic, liver-specific, or hepatocyte-specific Mas1 deficiency were vulnerable to APAP-induced hepatotoxicity. They exhibited substantially impaired lipophagy and downstream FAO, which was accompanied by the activation of AKT and suppression of FOXO1. In addition, the prophylactic activation of Mas showed unbelievably ideal effects to protect mice from APAP challenge, with remarkably enhanced lipophagy and FAO dependent on the AKT-FOXO1 axis. Moreover, the protective effects of AVE0991 were substantially diminished by the inhibition of either lipophagy or FAO. The activation of Mas on hepatocytes enhanced AKT-FOXO1-dependent lipophagy and downstream FAO to protect mice from APAP-induced hepatotoxicity, suggesting that hepatocyte-specific Mas might be a novel therapeutic target for DILI. Mas signaling arises as a novel therapeutic target for patients with APAP overdose. Mas-AKT/FOXO1-fatty acid degradation pathway is critical for researchers to develop treatment strategies of APAP overdose. When Mas signaling is targeted, the extent of liver injury should be taken into account at the time of administration. These findings obtained from APAP-challenged mice still need to be confirmed in the clinics.

Investigation of the prophylactic and therapeutic effectiveness of oral thyme extract in rats experimentally infected with cryptosporidium parvum.

In this study, the prophylactic and therapeutic activities of thyme extract at different concentrations against experimental Cryptosporidium parvum infection in immunosuppressed rats were investigated. Thyme extract was prepared at four different concentrations (10%, 30%, 50%, and 100%) and administered as a single oral dose of 1 mL for evaluation of its prophylactic efficacy. Five consecutive days after infection was detected in all rats, therapeutic evaluations were also performed. According to the results obtained by daily counting of oocysts in stools, the prophylactic and therapeutic effects of thyme extract administration were significant in comparison to the control group (P˂0.01). Oocyst shedding continued in the control group at high numbers from the beginning to the end of the study, while oocyst counts in the prophylaxis groups remained low throughout the study. On the other hand, oocyst excretion rates were high in the therapeutic groups and decreased rapidly after thyme extract administration. At the end of the study, oocyst excretion had completely stopped for some rats administered thyme extract. There was no group in which oocyst shedding ceased for all rats. No significant differences were observed in the therapeutic or prophylaxis groups regarding the doses administered (P > 0.01). Renal and hepatic functions were monitored by measuring urea, creatinine, alanine transaminase, and aspartate transaminase levels ​​before and after thyme extract administration. As a result, it was concluded that oral thyme extract administration at the doses applied in this study is effective and safe in the prophylactic and therapeutic treatment of experimental cryptosporidiosis in rats.

Studies on candidate genes for lithium prophylaxis performed at the Poznan University of Medical Sciences

Lithium is a drug of choice as a mood-stabilizer for the maintenance treatment of bipolar disorder. The prophylactic efficacy of lithium can be determined by genetic factors, partially related to a predisposition to bipolar disorder. In the field of psychiatric genetics, the first decade of the 21st century was dominated by the "candidate gene" research. In this paper, the studies on candidate genes connected with lithium prophylaxis performed at the Poznań University of Medical Sciences in 2005-2018 are presented. During this time, the polymorphisms of multiple genes have been investigated, many of which are also connected with a predisposition to bipolar illness. The associations with lithium prophylactic efficacy were found for the polymorphisms in 5HTT, ACP1, ARNTL, BDNF, COMT, DRD1, FKBP5, FYN, GLCC, NR3C1, and TIM, genes, but not those in 5HT2A, 5HT2C, DRD2, DRD3, DRD4, GRIN2B, GSK-3β, MMP-9, and NTRK2 genes. The polymorphism of the GSK-3β gene was found to be associated with the kidney side-effects occurring during lithium therapy. Possible roles for these genes in both the mechanism of lithium prophylactic activity and pathogenesis of bipolar mood disorder were discussed.

Amphiphile-CpG vaccination induces potent lymph node activation and COVID-19 immunity in mice and non-human primates

Despite the success of currently authorized vaccines for the reduction of severe COVID-19 disease risk, rapidly emerging viral variants continue to drive pandemic waves of infection, resulting in numerous global public health challenges. Progress will depend on future advances in prophylactic vaccine activity, including advancement of candidates capable of generating more potent induction of cross-reactive T cells and durable cross-reactive antibody responses. Here we evaluated an Amphiphile (AMP) adjuvant, AMP-CpG, admixed with SARS-CoV-2 Spike receptor binding domain (RBD) immunogen, as a lymph node-targeted protein subunit vaccine (ELI-005) in mice and non-human primates (NHPs). AMP-mediated targeting of CpG DNA to draining lymph nodes resulted in comprehensive local immune activation characterized by extensive transcriptional reprogramming, inflammatory proteomic milieu, and activation of innate immune cells as key orchestrators of antigen-directed adaptive immunity. Prime-boost immunization with AMP-CpG in mice induced potent and durable T cell responses in multiple anatomical sites critical for prophylactic efficacy and prevention of severe disease. Long-lived memory responses were rapidly expanded upon re-exposure to antigen. In parallel, RBD-specific antibodies were long-lived, and exhibited cross-reactive recognition of variant RBD. AMP-CpG-adjuvanted prime-boost immunization in NHPs was safe and well tolerated, while promoting multi-cytokine-producing circulating T cell responses cross-reactive across variants of concern (VOC). Expansion of RBD-specific germinal center (GC) B cells in lymph nodes correlated to rapid seroconversion with variant-specific neutralizing antibody responses exceeding those measured in convalescent human plasma. These results demonstrate the promise of lymph-node adjuvant-targeting to coordinate innate immunity and generate robust adaptive responses critical for vaccine efficacy.

The anticancer human mTOR inhibitor sapanisertib potently inhibits multiple Plasmodium kinases and life cycle stages.

Compounds acting on multiple targets are critical to combating antimalarial drug resistance. Here, we report that the human "mammalian target of rapamycin" (mTOR) inhibitor sapanisertib has potent prophylactic liver stage activity, in vitro and in vivo asexual blood stage (ABS) activity, and transmission-blocking activity against the protozoan parasite Plasmodium spp. Chemoproteomics studies revealed multiple potential Plasmodium kinase targets, and potent inhibition of Plasmodium phosphatidylinositol 4-kinase type III beta (PI4Kβ) and cyclic guanosine monophosphate-dependent protein kinase (PKG) was confirmed in vitro. Conditional knockdown of PI4Kβ in ABS cultures modulated parasite sensitivity to sapanisertib, and laboratory-generated P. falciparum sapanisertib resistance was mediated by mutations in PI4Kβ. Parasite metabolomic perturbation profiles associated with sapanisertib and other known PI4Kβ and/or PKG inhibitors revealed similarities and differences between chemotypes, potentially caused by sapanisertib targeting multiple parasite kinases. The multistage activity of sapanisertib and its in vivo antimalarial efficacy, coupled with potent inhibition of at least two promising drug targets, provides an opportunity to reposition this pyrazolopyrimidine for malaria.

Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362.

Plasmepsin X (PMX) is an essential aspartyl protease controlling malaria parasite egress and invasion of erythrocytes, development of functional liver merozoites (prophylactic activity), and blocking transmission to mosquitoes, making it a potential multistage drug target. We report the optimization of an aspartyl protease binding scaffold and the discovery of potent, orally active PMX inhibitors with in vivo antimalarial efficacy. Incorporation of safety evaluation early in the characterization of PMX inhibitors precluded compounds with a long human half-life (t1/2) to be developed. Optimization focused on improving the off-target safety profile led to the identification of UCB7362 that had an improved in vitro and in vivo safety profile but a shorter predicted human t1/2. UCB7362 is estimated to achieve 9 log 10 unit reduction in asexual blood-stage parasites with once-daily dosing of 50 mg for 7 days. This work demonstrates the potential to deliver PMX inhibitors with in vivo efficacy to treat malaria.

Potential therapies against SARS-CoV-2 virus evaluated in large-scale clinical trials

COVID-19 is a viral disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The pathogenesis of SARS-CoV-2 infection in humans manifests as mild symptoms to severe respiratory failure. The development of vaccines against coronaviruses faces several inherent challenges in its establishment as safe and effective, but also in production and distribution. Therefore, supportive treatments are more achievable in a short period of time in controlling the pandemic. Treatment is mainly based on controlling symptoms and inhibiting viral replication. Antivirals are more effective the earlier they are administered during the course of the disease, preferably starting from the first days of evolution; the benefit/risk ratio is the higher the patient has a higher risk of severe evolution. That is why antivirals are primarily administered to patients with nonsevere forms of the disease who have risk factors for severe evolution. Immunomodulatory drugs enhance the immune response against pathogens and may offer a therapeutic approach to treatment of viral diseases, having a significant prophylactic activity in the acute respiratory viral infection. There is a strong scientific rationale which suggest that viral diseases respond to immunomodulatory drugs. People protected with antivirals, immunomodulatory drugs or vaccines often have the disease in a milder or asymptomatic form. In Romania, the latest treatment protocol for COVID-19 includes immunomodulatory, antiviral and anti-inflammatory medication.

Antimalarial Activity of Extract and Fractions of Sauropus androgynus (L.) Merr.

Sauropus androgynus (L.) Merr., in the Indonesian local name known as “Katuk,” is a tropical shrub plant of the family Euphorbiaceae. Based on genus and chemotaxonomic approaches, as well as in vitro testing of Plasmodium falciparum, leaves of S. androgynus are presumed to have an active compound content as an antimalarial. The current study aims to investigate the antimalarial activity of 96% ethanol extract and fractions of S. androgynus leaves. The ethanolic extract was fractionated using the vacuum liquid chromatography (VLC) method with three solvents of different polarities (n-hexane, chloroform, and 96% ethanol). The fraction obtained was then evaluated for antimalarial activity against P. falciparum 3D7 strain. The ethanolic extract was evaluated for antimalarial suppressive and prophylactic activity against P. berghei-infected mice, as well as inhibitory activity against the heme detoxification process in vitro. Fractionation of ethanolic extract resulted in seven combined fractions, with the most active fraction being FV (50% inhibitory concentration (IC50) = 2.042 µg/mL). The ethanolic extract showed good parasitic suppressive (therapeutic) activity with a median effective dose (ED50) value of 15.35 mg/kg body weight. In a prophylactic test, ethanolic extract showed parasite growth inhibitory activity of 67.74 ± 9.21% after the administration of 400 mg/kg body weight for 4 days before infection, and 65.30 ± 10.44% after the administration of 200 mg/kg body weight for 8 consecutive days (4 days before and after infection). The ethanolic extract also showed an effect in inhibiting the formation of β-hematin of about 26.87–79.36% at a concentration of 0.1–4 mg/mL and an IC50 value of 0.479 mg/mL. The S. androgynus leaves were shown to have antimalarial activity in vitro and in vivo, where ethanolic extract were more active compared with the fraction obtained. The antimalarial properties of the extract showed a higher suppressive activity than prophylactic activity.

Study to Identify and Evaluate Predictor Factors for Primary Open-Angle Glaucoma in Tertiary Prophylactic Actions.

The aim of this study is to develop a predictive model with several explanatory variables that can guide ophthalmologists to make a more objective assessment of the evolution of open-angle glaucoma (OAG) during tertiary prevention. Objectives: The evaluation of risk factors and different predictors of symptom progression between patients with POAG and non-glaucoma patients (NG), as well as between primary open-angle glaucoma with high intraocular pressure (POAG) and primary open-angle glaucoma with normal intraocular pressure (NTG), in tertiary prophylactic activities. Methods: This research is an analytical epidemiological study of a prospective cohort. For the study, we took into account personal medical history, physical ophthalmological examination, intraocular pressure (IOP) values, and visual field (VF) parameters, examined with the Opto AP-300 Automated Perimeter using the “fast threshold” strategy. The results of gonioscopy were inconsistently recorded; they were not considered in the study due to missing values, the processing of which would have seriously distorted the statistical analysis. Ophthalmological examination was completed with a dichotomous questionnaire entitled “Symptom Inventory”, made according to the accusations of patients resulting from a “focus group” study. The study was carried out in the ophthalmology office within the Integrated Outpatient Clinic of the Emergency Clinical Hospital of Oradea, Bihor County (IOCECHO) between January–December 2021. The threshold of statistical significance was defined for p value < 0.05. The obtained results were statistically processed with specialized software SPSS 22. Results: The study included 110 people, of which 71 (64.54%) had POAG (IOP > 21 mmHg) and 39 people (35.46%) had NTG (IOP < 21 mmHg), the two groups being statistically significantly different (χ2 = 9.309, df = 1, p = 0.002). For the POAG group, glaucomatous loss was early, AD < −6 dB, according to the staging of glaucomatous disease, HODAPP classification. In addition, the groups of POAG and NTG patients was compared with a group of 110 NG patients, these three groups being statistically significantly different (χ2 = 34.482, df = 2, p = 0.000). Analysis of confounding factors (age, sex, residence, marital status) shows a statistically significant relationship only for age (F = 2.381, df = 40, p = 0.000). Sex ratio for the study groups = 5.11 for OAG and =5.87 for NG. After treatment (prostaglandin analogues and neuroprotective drugs) IOP decreased statistically significantly for both POAG and NTG. Conclusions: this study identified possible predictors of OAG, at the 5% level (risk factors and symptoms as independent variables) using a dichotomous questionnaire tool with a complementary role in tertiary prophylactic activities. The implementation of the focus group interview results as a socio-human research technique will be supportive to clinicians.

Evaluation of anti-malarial potency of new pyrazole-hydrazine coupled to Schiff base derivatives

BackgroundThe search for pharmacologically effective agents among molecules bearing multiple functionalities is commonly practiced. In continuation of the search for new anti-malarial agents, new pyrazole-hydrazine coupled Schiff-base derivatives previously synthesized were screened for anti-malarial property.MethodsHere, in vivo prophylactic and curative activities of the compounds were assessed while their binding affinity for falcipain-2, a crucial enzyme in Plasmodium survival, was done using computational techniques.ResultsThe two derivatives (BepINH and BepBeH) respectively led to a significant (p < 0.05) reduction in parasitaemia count (0.76 ± 1.11 and 0.79 ± 1.19) at day 3 post-treatment relative to the negative control (16.37 ± 1.25). For the prophylactic study, it was observed that the highest parasitaemia suppression level of 95.35% and 95.17% for BepINH and BepBeH at 15 mg/kg was slightly comparable to that obtained for ACT-Lonart (99.38%). In addition, their haematological profiles indicate that they are potentially beneficial in suppressing haemolytic damage to RBC, thereby protecting the body against infection-induced anaemia. Docking calculations on the derivatives toward the Plasmodium falciparum falcipain-2 revealed that they favourably interacted with a binding affinity higher than that of a known cocrystallized inhibitor.ConclusionThis study confirms the relevance of multi-functional molecules in the search for new and effective anti-plasmodial agent and lay the foundation for further development of these compound series to potent anti-plasmodial agent that interacts with falcipain-2.

Effect of α-Tocopheryloxy Acetic Acid on the Infection of Mice with Plasmodium berghei ANKA In Vivo and Humans with P. falciparum In Vitro.

Malarial parasites are susceptible to oxidative stress. The effects of α-tocopheryloxy acetic acid (α-TEA), a vitamin E analog, on infection by Plasmodium berghei ANKA and P. falciparum in mice and human red blood cells (RBCs), respectively, were examined in this study. For in vivo studies in mice, RBCs infected with P. berghei ANKA were inoculated via intraperitoneal injection and α-TEA was administered to C57BL/6J male mice after infection. The blood-brain barrier (BBB) permeability was examined by Evans blue staining in experimental cerebral malaria at 7days after infection. The in vitro inhibitory effect of α-TEA on P. falciparum 3D7 (chloroquine-sensitive strain) and K1 (multidrug-resistant strain) was tested using a SYBR Green I-based assay. When 1.5% α-TEA was administered for 14days after infection, 88% of P. berghei ANKA-infected mice survived during the experimental period. Nevertheless, all the control mice died within 12days of infection. Furthermore, the Evans blue intensity in α-TEA-treated mice brains was less than that in untreated mice, indicating that α-TEA might inhibit the destruction of the BBB and progression of cerebral malaria. The in vitro experiment revealed that α-TEA inhibited the proliferation of both the 3D7 and K1 strains. This study showed that α-TEA is effective against murine and human malaria in vivo and in vitro, respectively. Although α-TEA alone has a sufficient antimalarial effect, future research could focus on the structure-activity relationship to achieve better pharmacokinetics and decrease the cytotoxicity and/or the combined effect of α-TEA with existing drugs. In addition, the prophylactic antimalarial activity of premedication with α-TEA may also be an interesting perspective in the future.

Potent universal beta-coronavirus therapeutic activity mediated by direct respiratory administration of a Spike S2 domain-specific human neutralizing monoclonal antibody.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) marks the third novel β-coronavirus to cause significant human mortality in the last two decades. Although vaccines are available, too few have been administered worldwide to keep the virus in check and to prevent mutations leading to immune escape. To determine if antibodies could be identified with universal coronavirus activity, plasma from convalescent subjects was screened for IgG against a stabilized pre-fusion SARS-CoV-2 spike S2 domain, which is highly conserved between human β-coronavirus. From these subjects, several S2-specific human monoclonal antibodies (hmAbs) were developed that neutralized SARS-CoV-2 with recognition of all variants of concern (VoC) tested (Beta, Gamma, Delta, Epsilon, and Omicron). The hmAb 1249A8 emerged as the most potent and broad hmAb, able to recognize all human β-coronavirus and neutralize SARS-CoV and MERS-CoV. 1249A8 demonstrated significant prophylactic activity in K18 hACE2 mice infected with SARS-CoV-2 lineage A and lineage B Beta, and Omicron VoC. 1249A8 delivered as a single 4 mg/kg intranasal (i.n.) dose to hamsters 12 hours following infection with SARS-CoV-2 Delta protected them from weight loss, with therapeutic activity further enhanced when combined with 1213H7, an S1-specific neutralizing hmAb. As little as 2 mg/kg of 1249A8 i.n. dose 12 hours following infection with SARS-CoV Urbani strain, protected hamsters from weight loss and significantly reduced upper and lower respiratory viral burden. These results indicate in vivo cooperativity between S1 and S2 specific neutralizing hmAbs and that potent universal coronavirus neutralizing mAbs with therapeutic potential can be induced in humans and can guide universal coronavirus vaccine development.

BML-257, a Small Molecule that Protects against Drug-Induced Liver Injury in Zebrafish.

The use of many essential drugs is restricted due to their deleterious effects on the liver. Molecules that can prevent or protect the liver from drug-induced liver injury (DILI) would be invaluable in such situations. We used a transgenic line in zebrafish with a hepatocyte-specific expression of bacterial nitroreductase to cause temporally controlled liver damage. A whole organism-based chemical screen using the transgenic line identified BML-257, a potent small molecule AKT inhibitor, that protected the liver against metronidazole-induced liver injury. BML-257 also showed potent prophylactic and pro-regenerative activity in this liver damage model. BML-257 was tested in two independent toxicological models of liver injury caused by acetaminophen and isoniazid and was found to be protective against damage. This suggests that BML-257 has the potential to protect against multiple kinds of DILI.

Mobile applications for diagnostics, development, and alternative communication for children with language disorders

Problem and goal. Language disorders of different kinds may cause personal issues and prevent the successful development of an individual. Early diagnostics and precise correctional recommendations enable such issues to be resolved efficiently in childhood. A modern speech therapist needs mobile facilities that can both make his/her work with prescribed protocols easier and perform high-quality professional diagnostics. Creating software tools is quite important, especially when dealing with children. The peak of prophylactic and therapeutic activities occurs in pre- and primary school age. Methodology. In the scope of this research, the current state of the problem was observed and analyzed, psycholinguistics part and informatics part of the problem were identified, and their interaction was specified. The results of application of these approaches on the base of several longitude psycho-diagnostic experiments were analyzed and evaluated. Results. The software tools to diagnose child language disorders and to develop language abilities in the case of problems are presented. In addition, a tool for an alternative communication via pictograms is described. These tools implement a playing strategy to decrease stress and improve effectiveness. Conclusion. Experimental evaluation demonstrates that mobile approach reduces time for the therapist’s routine duties and makes diagnostic and correctional process attractive for children.