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1.
Nat Commun ; 15(1): 995, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38307868

RESUMO

The development of effective SARS-CoV-2 vaccines has been essential to control COVID-19, but significant challenges remain. One problem is intramuscular administration, which does not induce robust mucosal immune responses in the upper airways-the primary site of infection and virus shedding. Here we compare the efficacy of a mucosal, replication-competent yet fully attenuated virus vaccine, sCPD9-ΔFCS, and the monovalent mRNA vaccine BNT162b2 in preventing transmission of SARS-CoV-2 variants B.1 and Omicron BA.5 in two scenarios. Firstly, we assessed the protective efficacy of the vaccines by exposing vaccinated male Syrian hamsters to infected counterparts. Secondly, we evaluated transmission of the challenge virus from vaccinated and subsequently challenged male hamsters to naïve contacts. Our findings demonstrate that the live-attenuated vaccine (LAV) sCPD9-ΔFCS significantly outperformed the mRNA vaccine in preventing virus transmission in both scenarios. Our results provide evidence for the advantages of locally administered LAVs over intramuscularly administered mRNA vaccines in preventing infection and reducing virus transmission.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Animais , Cricetinae , Masculino , Humanos , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas de mRNA , SARS-CoV-2 , Mesocricetus , Anticorpos Antivirais , Anticorpos Neutralizantes
2.
Parasitol Res ; 123(2): 135, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38363354

RESUMO

Opisthorchis viverrini infection is endemic in the lower Mekong subregion. The liver is an organ that worms are drawn to and cause damage. However, the immune-related susceptibility in the liver is poorly understood. In this study, we investigated T helper (Th) cell responses in the liver of BALB/c mice and golden Syrian hamsters during 2-28 days post-infection (DPI). We found that Th cell responses were distinct between mice and hamsters in terms of dynamics and polarization. Mice exhibited the early induction of Th1, Th2, Th17, and regulatory T (Treg) cells responses after the presence of O. viverrini worms at 2 DPI. In hamsters, the late induction of Th1/Th17, downregulation of Th2/Treg responses and early elevation of suppressive cytokine interleukin (IL)-10 were found together with swift reduction of Th cell numbers. Interestingly, expressions of IL-4 (Th2 functional cytokine) and Foxp3 (Treg lineage) were completely different between mice and hamsters which elevated in mice but suppressed in hamsters. These results suggest that early induction and well-regulation are related to host resistance. In contrast, late induction of Th cell response might allow immature worms to develop in the host. Our findings provide a greater understanding in Th cell response-related susceptibility in O. viverrini infection which would be targeting immunity for the development of immune-based intervention such as vaccine.


Assuntos
Opistorquíase , Opisthorchis , Cricetinae , Animais , Camundongos , Opistorquíase/prevenção & controle , Mesocricetus , Citocinas , Linfócitos T Auxiliares-Indutores/metabolismo
3.
Int J Mol Sci ; 25(2)2024 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-38256071

RESUMO

Patients with COVID-19 have been reported to experience neurological complications, although the main cause of death in these patients was determined to be lung damage. Notably, SARS-CoV-2-induced pathological injuries in brains with a viral presence were also found in all fatal animal cases. Thus, an appropriate animal model that mimics severe infections in the lungs and brain needs to be developed. In this paper, we compared SARS-CoV-2 infection dynamics and pathological injuries between C57BL/6Smoc-Ace2em3(hACE2-flag-Wpre-pA)Smoc transgenic hACE2-C57 mice and Syrian hamsters. Importantly, the greatest viral distribution in mice occurred in the cerebral cortex neuron area, where pathological injuries and cell death were observed. In contrast, in hamsters, viral replication and distribution occurred mainly in the lungs but not in the cerebrum, although obvious ACE2 expression was validated in the cerebrum. Consistent with the spread of the virus, significant increases in IL-1ß and IFN-γ were observed in the lungs of both animals. However, in hACE2-C57 mice, the cerebrum showed noticeable increases in IL-1ß but only mild increases in IFN-γ. Notably, our findings revealed that both the cerebrum and the lungs were prominent infection sites in hACE2 mice infected with SARS-CoV-2 with obvious pathological damage. Furthermore, hamsters exhibited severe interstitial pneumonia from 3 dpi to 5 dpi, followed by gradual recovery. Conversely, all the hACE2-C57 mice experienced severe pathological injuries in the cerebrum and lungs, leading to mortality before 5 dpi. According to these results, transgenic hACE2-C57 mice may be valuable for studying SARS-CoV-2 pathogenesis and clearance in the cerebrum. Additionally, a hamster model could serve as a crucial resource for exploring the mechanisms of recovery from infection at different dosage levels.


Assuntos
COVID-19 , Cérebro , Humanos , Cricetinae , Camundongos , Animais , Camundongos Endogâmicos C57BL , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/genética , Camundongos Transgênicos , Interleucina-1beta , Mesocricetus , Pulmão
4.
PLoS Pathog ; 20(1): e1011805, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38198521

RESUMO

Hybrid immunity (vaccination + natural infection) to SARS-CoV-2 provides superior protection to re-infection. We performed immune profiling studies during breakthrough infections in mRNA-vaccinated hamsters to evaluate hybrid immunity induction. The mRNA vaccine, BNT162b2, was dosed to induce binding antibody titers against ancestral spike, but inefficient serum virus neutralization of ancestral SARS-CoV-2 or variants of concern (VoCs). Vaccination reduced morbidity and controlled lung virus titers for ancestral virus and Alpha but allowed breakthrough infections in Beta, Delta and Mu-challenged hamsters. Vaccination primed for T cell responses that were boosted by infection. Infection back-boosted neutralizing antibody responses against ancestral virus and VoCs. Hybrid immunity resulted in more cross-reactive sera, reflected by smaller antigenic cartography distances. Transcriptomics post-infection reflects both vaccination status and disease course and suggests a role for interstitial macrophages in vaccine-mediated protection. Therefore, protection by vaccination, even in the absence of high titers of neutralizing antibodies in the serum, correlates with recall of broadly reactive B- and T-cell responses.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Cricetinae , Humanos , Vacina BNT162 , Infecções Irruptivas , COVID-19/prevenção & controle , Mesocricetus , Anticorpos Neutralizantes , Complicações Pós-Operatórias , RNA Mensageiro/genética , Imunidade , Anticorpos Antivirais , Vacinação
5.
Vaccine ; 42(4): 738-744, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38238112

RESUMO

In the quest for heightened protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, we engineered a prototype vaccine utilizing the plant expression system of Nicotiana benthamiana, to produce a recombinant SARS-CoV-2 virus-like particle (VLP) vaccine presenting the S-protein from the Beta (B.1.351) variant of concern (VOC). This innovative vaccine, formulated with either a squalene oil-in-water emulsion or a synthetic CpG oligodeoxynucleotide adjuvant, demonstrated efficacy in a golden Syrian Hamster challenge model. The Beta VLP vaccine induced a robust humoral immune response, with serum exhibiting neutralization not only against SARS-CoV-2 Beta but also cross-neutralizing Delta and Omicron pseudoviruses. Protective efficacy was demonstrated, evidenced by reduced viral RNA copies and mitigated weight loss and lung damage compared to controls. This compelling data instills confidence in the creation of a versatile platform for the local manufacturing of potential pan-sarbecovirus vaccines, against evolving viral threats.


Assuntos
COVID-19 , Animais , Cricetinae , Humanos , COVID-19/prevenção & controle , Mesocricetus , SARS-CoV-2 , Vacinas contra COVID-19/genética , Glicoproteína da Espícula de Coronavírus , Anticorpos Antivirais , Anticorpos Neutralizantes
6.
Viruses ; 16(1)2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38257789

RESUMO

BACKGROUND: SARS-CoV-2 continues to impact human health globally, with airborne transmission being a significant mode of transmission. In addition to tools like vaccination and testing, countermeasures that reduce viral spread in indoor settings are critical. This study aims to assess the efficacy of UV-C light, utilizing the Violett sterilization device, as a countermeasure against airborne transmission of SARS-CoV-2 in the highly susceptible Golden Syrian hamster model. METHODS: Two cohorts of naïve hamsters were subjected to airborne transmission from experimentally infected hamsters; one cohort was exposed to air treated with UV-C sterilization, while the other cohort was exposed to untreated air. RESULTS: Treatment of air with UV-C light prevented the airborne transmission of SARS-CoV-2 from the experimentally exposed hamster to naïve hamsters. Notably, this protection was sustained over a multi-day exposure period during peak viral shedding by hamsters. CONCLUSIONS: These findings demonstrate the efficacy of the UV-C light to mitigate against airborne SARS-CoV-2 transmission. As variants continue to emerge, UV-C light holds promise as a tool for reducing infections in diverse indoor settings, ranging from healthcare facilities to households. This study reinforces the urgency of implementing innovative methods to reduce airborne disease transmission and safeguard public health against emerging biological threats.


Assuntos
COVID-19 , Animais , Cricetinae , Humanos , COVID-19/prevenção & controle , Aerossóis e Gotículas Respiratórios , SARS-CoV-2 , Mesocricetus , Saúde Pública
7.
Viruses ; 16(1)2024 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-38257822

RESUMO

Since the emergence of the first omicron SARS-CoV-2 variant at the end of 2021, several sub-variants have evolved and become predominant in the human population, showing enhanced transmissibility and ability to (partly) escape the adaptive immune response. The XBB sub-variants (e.g., EG.5.1) have become globally dominant. Besides the XBB sub-variants, a phylogenetically distinct variant, i.e., BA.2.86, is also circulating; it carries several mutations in the spike protein as compared to its parental BA.2 variant. Here, we explored the infectivity of the BA.2.86 and EG.5.1 sub-variants compared to the preceding BA.5 sub-variant in Syrian hamsters. Such preclinical models are important for the evaluation of updated vaccine candidates and novel therapeutic modalities. Following intranasal infection with either variant, throat swabs and lung samples were collected on days 3 and 4 post infection. No significant differences in viral RNA loads in throat swabs were observed between these sub-variants. However, the infectious virus titers in the lungs of EG.5.1- and BA.2.86-infected animals were significantly lower compared to the BA.5-infected ones. The lung pathology scores of animals infected with EG.5.1 and BA.2.86 were also markedly lower than that of BA.5 sub-variant. Together, we show that EG.5.1 and BA.2.86 sub-variants exhibit an attenuated replication in hamsters' lungs as compared to the BA.5 sub-variant.


Assuntos
COVID-19 , Animais , Cricetinae , Humanos , Mesocricetus , SARS-CoV-2/genética , Mutação
8.
J Immunol ; 212(4): 576-585, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38180084

RESUMO

SARS-CoV-2 variants of concern (VOCs) continue to evolve and reemerge with chronic inflammatory long COVID sequelae, necessitating the development of anti-inflammatory therapeutic molecules. Therapeutic effects of the receptor for advanced glycation end products (RAGE) were reported in many inflammatory diseases. However, a therapeutic effect of RAGE in COVID-19 has not been reported. In the present study, we investigated whether and how the RAGE-Ig fusion protein would have an antiviral and anti-inflammatory therapeutic effect in the COVID-19 system. The protective therapeutic effect of RAGE-Ig was determined in vivo in K18-hACE2 transgenic mice and Syrian golden hamsters infected with six VOCs of SARS-CoV-2. The underlying antiviral mechanism of RAGE-Ig was determined in vitro in SARS-CoV-2-infected human lung epithelial cells (BEAS-2B). Following treatment of K18-hACE2 mice and hamsters infected with various SARS-CoV-2 VOCs with RAGE-Ig, we demonstrated (1) significant dose-dependent protection (i.e., greater survival, less weight loss, lower virus replication in the lungs); (2) a reduction of inflammatory macrophages (F4/80+/Ly6C+) and neutrophils (CD11b+/Ly6G+) infiltrating the infected lungs; (3) a RAGE-Ig dose-dependent increase in the expression of type I IFNs (IFN-α and IFN-ß) and type III IFN (IFNλ2) and a decrease in the inflammatory cytokines (IL-6 and IL-8) in SARS-CoV-2-infected human lung epithelial cells; and (4) a dose-dependent decrease in the expression of CD64 (FcgR1) on monocytes and lung epithelial cells from symptomatic COVID-19 patients. Our preclinical findings revealed type I and III IFN-mediated antiviral and anti-inflammatory therapeutic effects of RAGE-Ig protein against COVID-19 caused by multiple SARS-CoV-2 VOCs.


Assuntos
COVID-19 , Melfalan , SARS-CoV-2 , gama-Globulinas , Cricetinae , Humanos , Camundongos , Animais , Mesocricetus , Receptor para Produtos Finais de Glicação Avançada/genética , Síndrome Pós-COVID-19 Aguda , Camundongos Transgênicos , Antivirais/farmacologia , Antivirais/uso terapêutico , Modelos Animais de Doenças , Pulmão
9.
Phytomedicine ; 125: 155295, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38277945

RESUMO

BACKGROUND: Geniposidic acid (GPA) alleviates oxidative stress and inflammation in mice However, whether it can effectively regulate lipid accumulation and prevent hyperlipidemia requires further investigation. PURPOSE: This study combined the untargeted metabolomics of cells and a Caenorhabditis elegans model to evaluate the anti-hyperlipidemic potential of GPA by modulating oxidative stress and regulating lipid metabolism. A golden hamster model of hyperlipidemia was used to further validate the lipid-lowering effect and mechanism of action of GPA. METHODS: Chemical staining, immunofluorescence, and flow cytometry were performed to examine the effects of GPA on lipid accumulation and oxidative stress. Untargeted metabolomic analysis of cells and C. elegans was performed using ultra-performance liquid chromatography coupled with quadrupole electrostatic field Orbitrap high-resolution mass spectrometry (UPLC-Q-Orbitrap MS) to identify biomarkers altered by GPA action, analyze the affected metabolic pathways, and validate the mechanisms by which GPA regulates lipid metabolism and oxidative stress. A golden hamster model of hyperlipidemia was established to test the lipid-lowering effects of GPA. Body weight, biochemical markers, rate-limiting enzymes, and key proteins were assessed. Hematoxylin and eosin (H&E) and Oil Red O staining were performed. RESULTS: Phenotypic data showed that GPA decreased free fatty acid (FFA)-induced lipid buildup and high reactive oxygen species (ROS) levels, reversed the decrease in mitochondrial membrane potential (MMP), and increased the cellular reduced glutathione/oxidized glutathione disulfide (GSH/GSSG) ratio. GPA also reduces high glucose-induced lipid build-up and ROS production in C. elegans. Metabolomic analysis showed that GPA affected purine, lipid, and amino acid metabolism. Moreover, GPA inhibited xanthine oxidase (XOD), glutamate dehydrogenase (GLDH), fatty acid synthase (FAS), phosphorylation of P38 MAPK, and upregulated the expression of SIRT3 and CPT1A protein production to control lipid metabolism and produce antioxidant benefits in cells and golden hamsters. CONCLUSION: Current evidence suggests that GPA can effectively regulate lipid metabolism and the oxidative stress response, and has the potential to prevent hyperlipidemia. This study also provided an effective method for evaluating the mechanism of action of GPA.


Assuntos
Caenorhabditis elegans , Hiperlipidemias , Glucosídeos Iridoides , Cricetinae , Animais , Camundongos , Humanos , Caenorhabditis elegans/metabolismo , Células Hep G2 , Espécies Reativas de Oxigênio/metabolismo , Mesocricetus , Metabolômica , Hiperlipidemias/tratamento farmacológico , Lipídeos , Metabolismo dos Lipídeos
10.
EBioMedicine ; 100: 104960, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38232633

RESUMO

BACKGROUND: SARS-CoV-2-neutralizing antibodies (nABs) showed great promise in the early phases of the COVID-19 pandemic. The emergence of resistant strains, however, quickly rendered the majority of clinically approved nABs ineffective. This underscored the imperative to develop nAB cocktails targeting non-overlapping epitopes. METHODS: Undertaking a nAB discovery program, we employed a classical workflow, while integrating artificial intelligence (AI)-based prediction to select non-competing nABs very early in the pipeline. We identified and in vivo validated (in female Syrian hamsters) two highly potent nABs. FINDINGS: Despite the promising results, in depth cryo-EM structural analysis demonstrated that the AI-based prediction employed with the intention to ensure non-overlapping epitopes was inaccurate. The two nABs in fact bound to the same receptor-binding epitope in a remarkably similar manner. INTERPRETATION: Our findings indicate that, even in the Alphafold era, AI-based predictions of paratope-epitope interactions are rough and experimental validation of epitopes remains an essential cornerstone of a successful nAB lead selection. FUNDING: Full list of funders is provided at the end of the manuscript.


Assuntos
COVID-19 , SARS-CoV-2 , Cricetinae , Animais , Humanos , Feminino , Epitopos , Pandemias , Inteligência Artificial , Anticorpos Antivirais , Anticorpos Neutralizantes , Mesocricetus
11.
Behav Brain Res ; 462: 114881, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38272188

RESUMO

It has been hypothesized that oxytocin increases the salience of social stimuli, whether the valence is positive or negative, through its interactions with the ventral tegmental area (VTA). Indeed, oxytocin neurons project to the VTA and activate dopamine neurons that are necessary for social experiences with positive valence. Surprisingly, though, there has not been an investigation of the role of oxytocin in the VTA in mediating social experiences with negative valence (e.g., social stress). Given that there are sex differences in how oxytocin regulates the salience of positively-valenced social interactions, we hypothesized that oxytocin acting in the VTA also alters the salience of social stress in a sex-dependent manner. To test this, female and male Syrian hamsters were site-specifically infused with either saline, oxytocin (9 µM), or oxytocin receptor antagonist (90 µM) into the VTA. Subjects were then exposed to either no defeat or a single, 15 min defeat by one RA. The day following social defeat, subjects underwent a 5 min social avoidance test. There was an interaction between sex and drug treatment, such that the oxytocin antagonist increased social avoidance compared to saline treatment in socially stressed females, while oxytocin decreased social avoidance compared to saline treatment in socially stressed males. Contrary to expectations, these results suggest that oxytocin signaling generally acts to decrease social avoidance, regardless of sex. These sex differences in the efficacy of oxytocin and oxytocin receptor antagonists to alter negatively-valenced social stimuli, however, should be considered when guiding pharmacotherapies for disorders involving social deficits.


Assuntos
Ocitocina , Área Tegmentar Ventral , Cricetinae , Animais , Feminino , Masculino , Humanos , Ocitocina/farmacologia , Ocitocina/fisiologia , Receptores de Ocitocina , Comportamento Social , Mesocricetus , Antagonistas de Hormônios/farmacologia , Estresse Psicológico , Neurônios Dopaminérgicos
12.
Antiviral Res ; 222: 105799, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38190973

RESUMO

Adenovirus infections of immunocompromised humans are a significant source of morbidity and mortality. Presently, there is no drug specifically approved for the treatment of adenovirus infections by the FDA. The state-of-the-art treatment of such infections is the off-label use of cidofovir, an acyclic nucleotide phosphonate. While cidofovir inhibits adenovirus replication, it has dose-limiting kidney toxicity. There is an apparent need for a better compound to treat adenovirus infections. To this end, we have been developing acyclic nucleotide phosphonate prodrugs that utilize an amino acid scaffold equipped with a lipophilic modifier. Here, we compare the antiviral potential of two prodrugs of HPMPA that differ only in the amino acid-based promoiety: USC-087, based on an N-hexadecyl tyrosinamide, and USC-093, based on an N-hexadecyl serinamide. Oral administration of both compounds was very efficacious against disseminated HAdV-C6 infection in immunosuppressed Syrian hamsters, suppressing virus replication and mitigating pathology even when treatment was withheld until 4 days after challenge. We saw only marginal efficacy after respiratory infection of hamsters, which may reflect suboptimal distribution to the lung. Importantly, neither compound induced intestinal toxicity, which was observed as the major adverse effect in clinical trials of brincidofovir, a prodrug of cidofovir which also contains a C-16 modifier. Notably, we found that there was a significant difference in the nephrotoxicity of the two compounds: USC-087 caused significant kidney toxicity while USC-093 did not, at effective doses. These findings will be valuable guidepoints in the future evolution of this new class of potential prodrugs to treat adenovirus infections.


Assuntos
Adenina/análogos & derivados , Infecções por Adenoviridae , Infecções por Adenovirus Humanos , Organofosfonatos , Pró-Fármacos , Tirosina/análogos & derivados , Cricetinae , Animais , Humanos , Infecções por Adenovirus Humanos/tratamento farmacológico , Cidofovir/farmacologia , Cidofovir/uso terapêutico , Mesocricetus , Antivirais/uso terapêutico , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Adenoviridae , Replicação Viral , Organofosfonatos/farmacologia , Organofosfonatos/uso terapêutico , Infecções por Adenoviridae/tratamento farmacológico , Citosina/farmacologia , Citosina/uso terapêutico , Aminoácidos/farmacologia , Nucleotídeos/uso terapêutico
13.
Antiviral Res ; 222: 105814, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38272321

RESUMO

Since the start of the SARS-CoV-2 pandemic, the search for antiviral therapies has been at the forefront of medical research. To date, the 3CLpro inhibitor nirmatrelvir (Paxlovid®) has shown the best results in clinical trials and the greatest robustness against variants. A second SARS-CoV-2 protease inhibitor, ensitrelvir (Xocova®), has been developed. Ensitrelvir, currently in Phase 3, was approved in Japan under the emergency regulatory approval procedure in November 2022, and is available since March 31, 2023. One of the limitations for the use of antiviral monotherapies is the emergence of resistance mutations. Here, we experimentally generated mutants resistant to nirmatrelvir and ensitrelvir in vitro following repeating passages of SARS-CoV-2 in the presence of both antivirals. For both molecules, we demonstrated a loss of sensitivity for resistance mutants in vitro. Using a Syrian golden hamster infection model, we showed that the ensitrelvir M49L mutation, in the multi-passage strain, confers a high level of in vivo resistance. Finally, we identified a recent increase in the prevalence of M49L-carrying sequences, which appears to be associated with multiple repeated emergence events in Japan and may be related to the use of Xocova® in the country since November 2022. These results highlight the strategic importance of genetic monitoring of circulating SARS-CoV-2 strains to ensure that treatments administered retain their full effectiveness.


Assuntos
Anti-Infecciosos , COVID-19 , Animais , Cricetinae , Inibidores de Proteases/farmacologia , SARS-CoV-2/genética , Inibidores Enzimáticos , Antivirais/farmacologia , Mesocricetus
14.
Acta Trop ; 250: 107100, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38101765

RESUMO

The liver fluke Opisthorchis felineus is a foodborne zoonotic pathogen endemic to Russia, Kazakhstan, and several European countries. The adult flukes affect the hepatobiliary system of piscivorous mammals and humans, thereby causing numerous complications, including liver fibrosis. Detailing the mechanisms of progression of the fibrotic complications is a hot topic in the field of research on opisthorchiasis pathogenesis. Pathologic angiogenesis appears to be associated with the fibrogenic progression due to active participation in the recruitment of inflammatory cells and many factors involved in the modulation of the extracellular matrix. The aim of the study was to evaluate neoangiogenesis and amyloid deposits in liver tissues of model animals and patients with confirmed chronic opisthorchiasis. In addition, we assessed a possible correlation of neoangiogenesis with liver fibrosis. We found a significant increase in the number of newly formed vessels and amyloid deposits in the liver of people with chronic opisthorchiasis compared to that of uninfected ones. Thus, for the first time we have demonstrated neoangiogenesis and amyloid deposits during O. felineus infection in a Mesocricetus auratus model. Regression analysis showed that CD34+ newly formed vessels correlate with fibrosis severity in the course of the infection. Our results indicate the potential contribution of angiogenesis to the progression of liver fibrosis, associated with O. felineus infection.


Assuntos
Opistorquíase , Opisthorchis , Cricetinae , Animais , Humanos , Opistorquíase/epidemiologia , Mesocricetus , Placa Amiloide/complicações , Cirrose Hepática/complicações
15.
Physiol Behav ; 273: 114410, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37977252

RESUMO

Social stress plays an important role in the etiology of many neuropsychiatric disorders and can lead to a variety of behavioral deficits such as social withdrawal. One way that social stress may contribute to psychiatric disorders is by reducing social motivation and the rewarding properties of social interactions. We investigated the impact of social stress on social reward in the context of winning versus losing agonistic encounters in Syrian hamsters (Mesocricetus auratus). First, we tested the hypothesis that social stress resulting from either stable low, or subordinate, social status or from social defeat reduces the rewarding properties of social interactions. Using an Operant Social Preference (OSP) task to measure social reward/motivation, we found that both subordinate and socially defeated males made significantly fewer entries into chambers containing novel, same-sex conspecifics compared to males who were dominant (i.e., stably won the agonistic encounters). In females, however, there were no differences in social entries between winners and losers. In a second experiment, we found more activation of the mesolimbic dopamine system (MDS) as assessed with cFos immunohistochemistry in the lateral ventral tegmental area (lVTA) and the nucleus accumbens (NAc) shell of male winners compared to losers. In females, however, there were no differences in activation in the lVTA between winners and losers. Surprisingly, however, winning females displayed significantly more activation in the NAc shell as compared to losing females, despite the lack of behavioral differences. Thus, behavioral and histological data suggest that there are sex differences in the impact of social status on social reward and associated mesolimbic activation.


Assuntos
Caracteres Sexuais , Status Social , Cricetinae , Animais , Masculino , Feminino , Humanos , Recompensa , Mesocricetus , Núcleo Accumbens/fisiologia , Área Tegmentar Ventral/fisiologia
16.
Front Immunol ; 14: 1291972, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38124756

RESUMO

Most COVID-19 vaccines are based on the SARS-CoV-2 Spike glycoprotein (S) or their subunits. However, S shows some structural instability that limits its immunogenicity and production, hampering the development of recombinant S-based vaccines. The introduction of the K986P and V987P (S-2P) mutations increases the production and immunogenicity of the recombinant S trimer, suggesting that these two parameters are related. Nevertheless, S-2P still shows some molecular instability and it is produced with low yield. Here we described a novel set of mutations identified by molecular modeling and located in the S2 region of the S-2P that increase its production up to five-fold. Besides their immunogenicity, the efficacy of two representative S-2P-based mutants, S-29 and S-21, protecting from a heterologous SARS-CoV-2 Beta variant challenge was assayed in K18-hACE2 mice (an animal model of severe SARS-CoV-2 disease) and golden Syrian hamsters (GSH) (a moderate disease model). S-21 induced higher level of WH1 and Delta variants neutralizing antibodies than S-2P in K18-hACE2 mice three days after challenge. Viral load in nasal turbinate and oropharyngeal samples were reduced in S-21 and S-29 vaccinated mice. Despite that, only the S-29 protein protected 100% of K18-hACE2 mice from severe disease. When GSH were analyzed, all immunized animals were protected from disease development irrespectively of the immunogen they received. Therefore, the higher yield of S-29, as well as its improved immunogenicity and efficacy protecting from the highly pathogenic SARS-CoV-2 Beta variant, pinpoint the S-29 mutant as an alternative to the S-2P protein for future SARS-CoV-2 vaccine development.


Assuntos
COVID-19 , SARS-CoV-2 , Cricetinae , Animais , Humanos , Camundongos , SARS-CoV-2/genética , Mesocricetus , COVID-19/prevenção & controle , Vacinas contra COVID-19
17.
Nutrients ; 15(24)2023 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-38140315

RESUMO

Atherosclerotic cardiovascular disease is the leading cause of mortality worldwide, and hypercholesterolemia is a central risk factor for atherosclerosis. This study evaluated the effects of Totum-070, a plant-based polyphenol-rich supplement, in hamsters with high-fat diet (HFD)-induced dyslipidemia. The molecular mechanisms of action were explored using human Caco2 enterocytes. Totum-070 supplementation reduced the total cholesterol (-41%), non-HDL cholesterol (-47%), and triglycerides (-46%) in a dose-dependent manner, compared with HFD. HFD-induced hepatic steatosis was also significantly decreased by Totum-070, an effect associated with the reduction in various lipid and inflammatory gene expression. Upon challenging with olive oil gavage, the post-prandial triglyceride levels were strongly reduced. The sterol excretion in the feces was increased in the HFD-Totum-070 groups compared with the HFD group and associated with reduction of intestinal cholesterol absorption. These effects were confirmed in the Caco2 cells, where incubation with Totum-070 inhibited cholesterol uptake and apolipoprotein B secretion. Furthermore, a microbiota composition analysis revealed a strong effect of Totum-070 on the alpha and beta diversity of bacterial species and a significant decrease in the Firmicutes to Bacteroidetes ratio. Altogether, our findings indicate that Totum-070 lowers hypercholesterolemia by reducing intestinal cholesterol absorption, suggesting that its use as dietary supplement may be explored as a new preventive strategy for cardiovascular diseases.


Assuntos
Aterosclerose , Hipercolesterolemia , Hiperlipidemias , Cricetinae , Animais , Humanos , Hipercolesterolemia/etiologia , Extratos Vegetais/farmacologia , Extratos Vegetais/metabolismo , Dieta Hiperlipídica/efeitos adversos , Polifenóis/farmacologia , Polifenóis/metabolismo , Células CACO-2 , Mesocricetus , Colesterol/metabolismo , Hiperlipidemias/metabolismo , Triglicerídeos/metabolismo , Aterosclerose/etiologia , Aterosclerose/prevenção & controle , Aterosclerose/metabolismo , Fígado/metabolismo
18.
Viruses ; 15(12)2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-38140522

RESUMO

Cardiovascular disease is one of many risk factors that have been linked to increased severity or mortality in coronavirus disease 2019 (COVID-19) patients; however, the exact role of SARS-CoV-2 in the pathogenesis of cardiac inflammatory injury has not been established. A previous study reported that SARS-CoV-2 causes more severe disease with cardiomyopathy in a J2N-k animal model. Here, we investigated the sensitivity of J2N-k hamsters, as a cardiomyopathy animal model, to a delta strain of SARS-CoV-2 compared to J2N-n control animals. We found that J2N-k hamsters were less susceptible to this delta strain than J2N-n animals, and we found no evidence that cardiomyopathy is a risk factor in this animal model. Since the previous study reported that SARS-CoV-2 causes more severe disease with cardiomyopathy in the same animal model, further analysis of the relationship between cardiomyopathy and SARS-CoV-2 infection is needed.


Assuntos
COVID-19 , Cardiomiopatias , Humanos , Cricetinae , Animais , SARS-CoV-2 , COVID-19/complicações , Cardiomiopatias/etiologia , Modelos Animais de Doenças , Mesocricetus
19.
Vopr Virusol ; 68(6): 513-525, 2023 Dec 26.
Artigo em Russo | MEDLINE | ID: mdl-38156567

RESUMO

INTRODUCTION: At the beginning of December 2019, humanity has faced a new problem caused by coronavirus. In Hubei province of central China, epidemic events associated with severe primary viral pneumonia in humans began to develop. The isolated etiological agent was identified as a representative of Coronaviridae family. The global pandemic associated with the new coronavirus infection, acute respiratory syndrome type 2 (Severe acute respiratory syndrome 2, SARS-CoV-2), has become a challenge for humanity. OBJECTIVE: In our work, we assessed the replicative ability and pathogenesis of the SARS-CoV-2 virus in hamsters. MATERIALS AND METHODS: Syrian hamsters (n=16) randomly divided into two groups were used in experiment. The first group was infected intranasally with the SARS-CoV-2 virus, strain SARS-CoV-2/human/KAZ/KZ_Almaty/2020 deposited in GenBank under number MZ379258.1. The second group remained as a control group. Clinical manifestations of the disease in hamsters were observed within 14 days. Samples were collected on days 3, 5, 7, 9, 12, and 14 postinfection. The obtained samples were tested for viral isolation in cell culture, histological examination and analysis of viral RNA by RT-PCR. RESULTS: SARS-CoV-2 virus isolates showed efficient replication in the lungs of hamsters, causing pathological lung lesions in animals infected intranasally. Clinical manifestations of the disease in hamsters infected with this virus were characterized by a decrease in temperature and body weight, wetness and ruffled fur, and frequent stroking of the nasal planum. High virus titers were observed following the virus isolation in cell cultures from nasal, oral swabs and lungs of animals infected intranasally. Pathological autopsy demonstrated pathological changes in the lungs. Moreover, transmission by airborne droplets has been established when a healthy hamster was kept together with animals infected using the intranasal method. CONCLUSION: In conclusion, our study showed that the Syrian hamster model is a useful tool for studying the SARS-CoV-2 pathogenesis, as well as testing vaccine candidates against acute respiratory syndrome type 2.


Assuntos
COVID-19 , Coronaviridae , Pneumonia Viral , Cricetinae , Animais , Humanos , SARS-CoV-2 , COVID-19/patologia , Pulmão , Mesocricetus , Modelos Animais de Doenças
20.
Viruses ; 15(11)2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-38005839

RESUMO

Pibrentasvir (PIB) has been demonstrated to block exonuclease activity of the SARS-CoV-2 polymerase, protecting favipiravir (FVP) and remdesivir (RDV) from post-incorporation excision and eliciting antiviral synergy in vitro. The present study investigated the chemoprophylactic efficacy of PIB, FVP, RDV, FVP with PIB, or RDV with PIB dosed intranasally twice a day, using a Syrian golden hamster contact transmission model. Compared to the saline control, viral RNA levels were significantly lower in throat swabs in FVP (day 7), RDV (day 3, 5, 7), and RDV+PIB (day 3, 5) treatment groups. Similarly, findings were evident for nasal turbinate after PIB and RDV treatment, and lungs after PIB, FVP, and FVP+PIB treatment at day 7. Lung viral RNA levels after RDV and RDV+PIB treatment were only detectable in two animals per group, but the overall difference was not statistically significant. In situ examination of the lungs confirmed SARS-CoV-2 infection in all animals, except for one in each of the RDV and RDV+PIB treatment groups, which tested negative in all virus detection approaches. Overall, prevention of transmission was observed in most animals treated with RDV, while other agents reduced the viral load following contact transmission. No benefit of combining FVP or RDV with PIB was observed.


Assuntos
COVID-19 , SARS-CoV-2 , Cricetinae , Animais , Mesocricetus , COVID-19/prevenção & controle , Pulmão , Nucleotidiltransferases , RNA Viral , Antivirais/farmacologia , Antivirais/uso terapêutico
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