New treatment approaches targeting cutaneous leishmaniasis (CL) are required since conventional drugs exhibit limitations due to their several adverse effects and toxicity. In this study, we aimed to evaluate the in vivo intralesional treatment efficacy of five isoxazole derivatives previously synthesized and effective in vitro against intracellular amastigote forms of Leishmania (L.) amazonensis. Among the tested analogues, 7 exhibited relevant in vivo therapeutic effects. The in silico predictions provided interesting information about the toxicity, suggesting the safety of analogue 7. Experiments performed with Salmonella typhimurium strains (TA98, TA100, and TA102) showed a non-mutagenicity profile of 7. The treatment of Leishmania-infected BALB/c mice with isoxazole 7 showed remarkably smaller CL lesions and decreased the parasitism (by 98.4%) compared to the control group. Hence, analogue 7 is a promising drug candidate and alternative treatment for CL caused by L. amazonensis.

The variability of SARS-CoV-2 appeared to be higher than expected, the emergence of new variants raises concerns. The aim of the work was to compare the pathogenicity of the Wuhan and BA.1.1/Omicron variants in BALB/c mice and Syrian hamsters.
The study used strains of SARS-CoV-2: Dubrovka phylogenetically close to Wuhan-Hu-1, and LIA phylogenetically close to Omicron, BALB/c mice, transgenic mice B6.Cg-Tg(K18-ACE2)2Prlmn/HEMI Hemizygous for Tg(K18-ACE2)2Prlmn, Syrian golden hamsters. Animals were infected intranasally, pathogenicity was estimated by a complex of clinical, pathomorphological and virological methods.
Comparative studies of SARS-CoV-2 Dubrovka and LIA strains on animal models demonstrated their heterogeneous pathogenicity. In parallel infection of BALB/c mice with Dubrovka and LIA variants, the infection proceeded without serious clinical signs and lung damage. Infection with the LIA strain resulted to a systemic disease with a high concentration of viral RNA in the lungs and brain tissues of animals. The presence of viral RNA in mice infected with the Dubrovka strain was transient and undetectable in the lungs by day 7 post-infection. Unlike the mouse model, in hamsters, the Dubrovka strain had a greater pathogenicity than the LIA strain. In hamsters infected with the Dubrovka strain lung lesions were more significant, and the virus spread through organs, in particular in brain tissue, was observed. In hamsters infected with the LIA strain virus was not detected in brain tissue.
The study of various variants of SARS-CoV-2 in species initially unsusceptible to SARS-CoV-2 infection is important for monitoring zoonotic reservoirs that increase the risk of spread of new variants in humans.
Введение. Изменчивость SARS-CoV-2 оказалась выше ожидаемой, а появление новых вариантов вызывает обеспокоенность об их потенциально более высокой вирулентности, трансмиссивности, способности уклоняться от иммунных реакций, вызванных предыдущей инфекцией или вакцинацией. В связи с этим важно изучение патогенеза таких вариантов на экспериментальных моделях SARS-CoV-2. Цель работы сравнение патогенности вариантов Ухань и BA.1.1 (омикрон) у мышей BALB/c и сирийских хомяков. Материал и методы. В исследовании использованы штаммы SARS-CoV-2 Dubrovka, филогенетически близкий к штамму Wuhan-Hu-1, и LIA, филогенетически близкий к штамму омикрон, мыши BALB/c, трансгенные мыши B6.Cg-Tg(K18-ACE2)2Prlmn/HEMI Hemizygous for Tg(K18-ACE2)2Prlmn, сирийские золотистые хомяки. Заражение животных проводили интраназально, определение вирулентности выполняли посредством комплекса клинических, патоморфологических и вирусологических методов. Результаты. Сравнительные исследования штаммов SARS-CoV-2 Dubrovka (Ухань-подобного) и LIA (омикрон-подобного) на моделях животных продемонстрировали их различную патогенность. При параллельном заражении мышей BALB/c вариантами Dubrovka и LIA инфекция протекала без серьёзных клинических признаков и повреждений лёгких. Заражение штаммом LIA приводило к системному заболеванию с высоким содержанием вирусной РНК в лёгких и тканях мозга животных. Вирусная РНК у мышей при заражении штаммом Dubrovka была преходящей и не обнаруживалась в лёгких уже на 7-й день после заражения. Напротив, у хомяков штамм Dubrovka обладал большей патогенностью, чем штамм LIA. При инфицировании штаммом Dubrovka поражения лёгких были значительнее, наблюдались потеря массы тела и распространение вируса по органам, в частности в ткани головного мозга, в то время как при заражении штаммом LIA вирус в тканях головного мозга не определялся. Заключение. Изучение различных вариантов SARS-CoV-2 у видов, изначально невосприимчивых к инфекции, важно для мониторинга зоонозных резервуаров, создающих риск распространения новых вариантов у людей.

OBJECTIVE: Pentavalent antimonials are the standard treatment for cutaneous leishmaniasis (CL), however, treatment failures are frequent. Nimodipine, a calcium channel blocker is known to show promising antiprotozoal effects. Here, we investigated the antileishmanial effect of Nimodipine in both in vitro and in vivo BALB/c mice model of CL. We also compared the in vivo effect with amphotericin B and meglumine antimoniate in the experimental CL mice model.
METHODS: Colorimetric alamar blue assay and J774 A.1 mouse macrophage cells were used to determine the effect of nimodipine on promastigotes and amastigotes viability, respectively. Then, the in vivo activity of nimodipine was compared to that of conventional therapies in both the early and established courses of Leishmania major infection in susceptible non-healing BALB/c mice.
RESULTS: Nimodipine was highly active against promastigotes and amastigotes of L. major with IC50 values of 49.40 and 15.03 μM, respectively. In the early model, the combination therapy with meglumine antimoniate and nimodipine showed no parasites in the spleen or footpad of animals. The footpad thickness was significantly lower in mice treated with either nimodipine (1 mg/kg or 2.5 mg/kg) or amphotericin B compared to the control group in the established lesions model. However, no complete remission was observed in the footpad lesion of any of the treatment groups (nimodipine, amphotericin B, meglumine antimoniate, and combination therapy).
CONCLUSIONS: The effect of nimodipine was comparable to that of amphotericin B and meglumine antimoniate in early and established CL lesion models. Since nimodipine is more cost-effective than conventional therapies, our results merit further investigation in other animal models and voluntary human subjects.

Tuberculosis represents a major global health problem for which improved approaches are needed to shorten the course of treatment and to combat the emergence of resistant strains. The development of effective and safe nanobead-based interventions can be particularly relevant for increasing the concentrations of antitubercular agents within the infected site and reducing the concentrations in the general circulation, thereby avoiding off-target toxic effects. In this work, rifampicin, a first-line antitubercular agent, was encapsulated into biocompatible and biodegradable polyester-based nanoparticles. In a well-established BALB/c mouse model of pulmonary tuberculosis, the nanoparticles provided improved pharmacokinetics and pharmacodynamics. The nanoparticles were well tolerated and much more efficient than an equivalent amount of free rifampicin.

Mesenchymal stromal cells (MSCs) possess self-renewal and multilineage differentiation potential, indicating their prospects as cellular therapeutic agents for regenerative medicine. Although adult bone marrow (BM) is the major source of these cells for clinical use, harvesting requires invasive procedures. Therefore, alternative sources, such as peripheral blood (PB), are needed. The objective of the current study was to compare PB-MSCs and BM-MSCs with regard to their biological characteristics. PB-MSCs and BM-MSCs were isolated from 4-week-old BALB/c white mice by density gradient centrifugation and cultured in DMEM + 10% fetal bovine serum until passage four. Morphological features, proliferation, cell surface marker expression and trilineage differentiation potential were assessed for both PB-MSCs and BM-MSCs. No significant differences in morphological features were observed. BM-MSCs had a higher proliferative capability than PB-MSCs as measured by XTT assays. Both PB-MSCs and BM-MSCs had broadly similar cell surface marker expression, but PB-MSCs had positive expression of cluster of differentiation (CD)146 and CD140b. Both PB-MSCs and BM-MSCs were capable of trilineage differentiation. Although BM-MSCs had a greater capacity for osteogenic and chondrogenic differentiation than PB-MSCs, PB-MSCs had a better capability for adipogenic differentiation than BM-MSCs. In conclusion, PB-MSCs and BM-MSCs have very similar biological characteristics. Thus, PB is a promising source for easily obtaining MSCs in mice.

Rubella vaccine was not part of national immunization programs (NIP) in several countries in the Middle East and North Africa (MENA), South-East Asia (SEA), and South Africa regions until the year 2000. Therefore, immunization coverage of females older than 20 years old in these countries has been the focus of national campaigns for rubella elimination in developing countries. Vaccines against human papillomavirus (HPV) are not part of NIPs in developing countries. To enhance the advantages of rubella-directed immunization campaigns and to increase HPV vaccine uptake in developing countries, this study aimed to test the stability, potency, efficacy and safety of a combined rubella and HPV vaccine. Female BALB/c mice were immunized subcutaneously with proposed combined HPV16/HPV18 VLP and rubella vaccine at weeks (W) 0, 3 then with HPV vaccine at W 7. Immunized mice developed antigen-specific antibodies against rubella and HPV significantly higher than mice immunized with rubella or HPV vaccine alone. The combined vaccine induced significantly higher splenocyte proliferation than control groups. In addition, pro-inflammatory cytokines IL-4, IL-6, IL-2, and IFNγ levels were significantly higher in mice immunized with the combined vaccine than control groups. Overall, the combined vaccine was safe and immunogenic offering antibody protection as well as eliciting a cellular immune response against rubella and HPV viruses in a single vaccine. This combined vaccine can be of great value to females above 20 years old in the SEA, MENA and South Africa regions offering coverage to rubella vaccine and a potential increase in HPV vaccine uptake rates after appropriate clinical testing.

Some important adverse effects of local and regional anaesthesia including injection-site infection, epidural abscess and meningitis, are usually caused by bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa. These infections can even cause the patient\'s death in severe cases. In the present study, the antimicrobial activity of tramadol was investigated on S. aureus and P. aeruginosa in BALB/c-sensitive mice. This experimental multigroup research study evaluated the effect of two different concentrations of injectable tramadol (12.5 and 25 mg/mL) on local infections caused by S. aureus and P. aeruginosa in BALB/c mice within 24 and 48 hours. The results showed that tramadol injection in the specified doses did not have a significant impact on the diameter of lesions caused by local infections due to these organisms. However, the diameter of inflammation resulting from local infection with P. aeruginosa had statistically increased in the two doses after 48 hours (p 0.019). Subcutaneous injection of tramadol reduced the growth of S. aureus through enhancing phagocytes and tissue inflammation; however, it did not help eliminate P. aeruginosa, and at a dose of 25 mg/mL it also increased the growth and spread of the bacteria. It seems that the observed difference was due to the different characteristics of these two bacteria.

Although silver nanoparticles (AgNPs) are widely disseminated and show great potential in the biomedical field, there is a recognized need to better understand their action at the metabolic and functional levels. In this work, we have used NMR metabolomics, together with conventional clinical chemistry and histological examination, to characterize multi-organ and systemic metabolic responses to AgNPs intravenously administered to mice at 8 mg/kg body weight (a dose not eliciting overt toxicity). The major target organs of AgNPs accumulation, liver and spleen, showed the greatest metabolic changes, in a clear 2-stage response. In particular, the liver of dosed mice was found to switch from glycogenolysis and lipid storage, at 6 h postinjection, to glycogenesis and lipolysis, at subsequent times up to 48 h. Moreover, metabolites related to antioxidative defense, immunoregulation and detoxification seemed to play a crucial role in avoiding major hepatic damage. The spleen showed several early changes, including depletion of several amino acids, possibly reflecting impairment of hemoglobin recycling, while only a few differences remained at 48 h postinjection. In the heart, the metabolic shift towards TCA cycle intensification and increased ATP production possibly reflected a beneficial adaptation to the presence of AgNPs. On the other hand, the TCA cycle appeared to be down regulated in the lungs of injected mice, which showed signs of inflammation. Thekidneys showed the mildest metabolic response to AgNPs. Overall, this study has shown that NMR metabolomics is a powerful tool to monitor invivo metabolic responses to nanoparticles, revealing unforeseen effects.

The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3+, CD4+, CD8+, and CD19+) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs.

The disorders of iron overload due to primary or secondary cause are one of the important human diseases leading to high mortality if untreated. To understand this, an animal model has been extensively studied. The source of iron administered to the mode of iron administration that can mimic the iron overload in humans has been studied. A safe and orally active iron chelator is still needed as many of the existing compounds have different types of complications and toxicity associated. Hence having a simple animal model which can be availed quickly and can be used to study various compounds for its iron chelating activity would likely to have immense utility for pharmacological studies. In this review we have shown how, using a simple procedure, a large number of small iron overloaded animals can be produced easily for various studies.