RESUMO
Introduction: Cigarette smoke (CS) exacerbates the severity of diseases not only in lungs, but also in systemic organs having no direct contact with smoke. In addition, smoking during pregnancy can have severe health consequences for both the mother and the fetus. Therefore, our aim was to evaluate effects of prenatal exposure to CS on acetaminophen (APAP)-induced acute liver injury (ALI) in offspring. Methods: Female C57BL/6 mice on day 6 of gestation were exposed to mainstream CS (MSCS) at 0, 150, 300, or 600 µg/L for 2 h a day, 5 days a week for 2 weeks using a nose-only exposure system. At four weeks old, male offspring mice were injected intraperitoneally with a single dose of APAP at 300 mg/kg body weight to induce ALI. Results: Maternal MSCS exposure significantly amplified pathological effects associated with ALI as evidenced by elevated serum alanine aminotransferase levels, increased hepatocellular apoptosis, higher oxidative stress, and increased inflammation. Interestingly, maternal MSCS exposure reduced microRNA (miR)-34a-5p expression in livers of offspring. Moreover, treatment with a miR-34a-5p mimic significantly mitigated the severity of APAP-induced hepatotoxicity. Overexpression of miR-34a-5p completely abrogated adverse effects of maternal MSCS exposure in offspring with ALI. Mechanistically, miR-34a-5p significantly decreased expression levels of hepatocyte nuclear factor 4 alpha, leading to down-regulated expression of cytochrome P450 (CYP)1A2 and CYP3A11. Discussion: Prenatal exposure to MSCS can alter the expression of miRNAs, even in the absence of additional MSCS exposure, potentially increasing susceptibility to APAP exposure in male offspring mice.
RESUMO
Introduction: The effects of pre-anesthetic single-dose oral pimobendan during inhalational anesthesia, including the comparison with the effects of single intravenous pimobendan under anesthesia, remain unexplored. Therefore, this study aimed to determine changes in hemodynamic and echocardiographic parameters induced by pre-anesthetic administration of oral pimobendan under isoflurane general anesthesia and to compare them with those induced by intravenous pimobendan. Methods: Thirteen clinically normal dogs (4 laboratory and 9 client-owned dogs) with no clinical signs and not on any medical treatment were included. Anesthesia was performed three times: no pimobendan (Control), oral pimobendan (PIMO PO, 0.3 mg/kg), and intravenous pimobendan (PIMO IV, 0.15 mg/kg). Echocardiographic and hemodynamic parameters were monitored at 30-min intervals in all groups. Results: Compared to the Control group, end-systolic volume index (ESVI) and normalized left ventricular internal diameter at end-systole (LVIDSN) were significantly lower, and fractional shortening (FS) and ejection fraction (EF) were significantly higher in the PIMO PO and IV groups (p < 0.001). Global radial strain (GRS) was significantly higher in the PIMO PO and IV groups (p = 0.015). Conclusion: Under general anesthesia, oral pimobendan preserved LV systolic and myocardial function in a manner comparable to intravenous pimobendan. Pre-anesthetic administration of oral pimobendan can be used to compensate for cardiac systolic function in dogs who require therapeutic and diagnostic procedures under general anesthesia with potential risk of circulatory failure.
RESUMO
[This corrects the article DOI: 10.1007/s43188-023-00223-y.].
RESUMO
African swine fever, caused by African swine fever virus (ASFV), is a highly contagious and fatal disease that poses a significant threat to the global pig industry. The limited information on ASFV pathogenesis and ASFV-host interactions has recently prompted numerous transcriptomic studies. However, most of these studies have focused on elucidating the transcriptome profiles of ASFV-infected porcine alveolar macrophages in vitro. Here, we analyzed dynamic transcriptional patterns in vivo in nine organ tissues (spleen, submandibular lymph node, mesenteric lymph node, inguinal lymph node, tonsils, lungs, liver, kidneys, and heart) obtained from pigs in the early stages of ASFV infection (1 and 3 d after viremia). We observed rapid spread of ASFV to the spleen after viremia, followed by broad transmission to the liver and lungs and subsequently, the submandibular and inguinal lymph nodes. Profound variations in gene expression patterns were observed across all organs and at all time-points, providing an understanding of the distinct defence strategies employed by each organ against ASFV infection. All ASFV-infected organs exhibited a collaborative response, activating immune-associated genes such as S100A8, thereby triggering a pro-inflammatory cytokine storm and interferon activation. Functional analysis suggested that ASFV exploits the PI3K-Akt signalling pathway to evade the host immune system. Overall, our findings provide leads into the mechanisms underlying pathogenesis and host immune responses in different organs during the early stages of infection, which can guide further explorations, aid the development of efficacious antiviral strategies against ASFV, and identify valuable candidate gene targets for vaccine development.
Assuntos
Vírus da Febre Suína Africana , Febre Suína Africana , Transcriptoma , Animais , Vírus da Febre Suína Africana/genética , Vírus da Febre Suína Africana/fisiologia , Suínos , Febre Suína Africana/virologia , Perfilação da Expressão Gênica , Linfonodos/virologia , Baço/virologia , Baço/metabolismo , Viremia , Pulmão/virologia , Fígado/virologia , Fígado/metabolismoRESUMO
A free-living female Korean water deer (Hydropotes inermis argyropus) was found with swelling in the left femur. Radiographic and histopathologic examination confirmed distal femoral osteosarcoma with metastases to the inguinal lymph node and the lungs; there are no previous reports of osteosarcoma in water deer.
Assuntos
Cervos , Osteossarcoma , Animais , Osteossarcoma/veterinária , Osteossarcoma/patologia , Feminino , Neoplasias Ósseas/veterinária , Neoplasias Ósseas/patologia , Neoplasias Pulmonares/veterinária , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/patologia , Fêmur/patologia , Neoplasias Femorais/veterinária , Neoplasias Femorais/patologia , Metástase LinfáticaRESUMO
Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening viral zoonosis. The causative agent of this disease is the Dabie bandavirus, which is usually known as the SFTS virus (SFTSV). Although the role of vertebrates in SFTSV transmission to humans remains uncertain, some reports have suggested that dogs could potentially transmit SFTSV to humans. Consequently, preventive measures against SFTSV in dogs are urgently needed. In the present study, dogs were immunized three times at two-week intervals with formaldehyde-inactivated SFTSV with two types of adjuvants. SFTSV (KCD46) was injected into all dogs two weeks after the final immunization. Control dogs showed viremia from 2 to 4 days post infection (dpi), and displayed white pulp atrophy in the spleen, along with a high level of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay (TUNEL) positive area. However, the inactivated SFTSV vaccine groups exhibited rare pathological changes and significantly reduced TUNEL positive areas in the spleen. Furthermore, SFTSV viral loads were not detected at any of the tested dpi. Our results indicate that both adjuvants can be safely used in combination with an inactivated SFTSV formulation to induce strong neutralizing antibodies. Inactivated SFTSV vaccines effectively prevent pathogenicity and viremia in dogs infected with SFTSV. In conclusion, our study highlighted the potential of inactivated SFTSV vaccination for SFTSV control in dogs.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Doenças do Cão , Phlebovirus , Febre Grave com Síndrome de Trombocitopenia , Vacinas de Produtos Inativados , Vacinas Virais , Animais , Cães , Phlebovirus/imunologia , Vacinas Virais/imunologia , Vacinas Virais/administração & dosagem , Febre Grave com Síndrome de Trombocitopenia/virologia , Febre Grave com Síndrome de Trombocitopenia/prevenção & controle , Febre Grave com Síndrome de Trombocitopenia/imunologia , Febre Grave com Síndrome de Trombocitopenia/veterinária , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Doenças do Cão/virologia , Doenças do Cão/prevenção & controle , Doenças do Cão/imunologia , Viremia , Carga Viral , Baço/virologia , Baço/patologia , Baço/imunologia , Adjuvantes Imunológicos/administração & dosagem , Vacinação/veterináriaRESUMO
Smoking is a well-established risk factor for various pathologies, including pulmonary diseases, cardiovascular disorders, and cancers. The toxic effects of cigarette smoke (CS) are mediated through multiple pathways and diverse mechanisms. A key pathogenic factor is oxidative stress, primarily induced by excessive formation of reactive oxygen species. However, it remains unclear whether smoking directly induces systemic oxidative stress or if such stress is a secondary consequence. This study aimed to determine whether short-term inhalation exposure to CS induces oxidative stress in extrapulmonary organs in addition to the lung in a murine model. In the experiment, 3R4F reference cigarettes were used to generate CS, and 8-week-old male BALB/c mice were exposed to CS at a total particulate matter concentration of either 0 or 800 µg/L for four consecutive days. CS exposure led to an increase in neutrophils, eosinophils, and total cell counts in bronchoalveolar lavage fluid. It also elevated levels of lactate dehydrogenase and malondialdehyde (MDA), markers indicative of tissue damage and oxidative stress, respectively. Conversely, no significant changes were observed in systemic oxidative stress markers such as total oxidant scavenging capacity, MDA, glutathione (GSH), and the GSH/GSSG ratio in blood samples. In line with these findings, CS exposure elevated NADPH oxidase (NOX)-dependent superoxide generation in the lung but not in other organs like the liver, kidney, heart, aorta, and brain. Collectively, our results indicate that short-term exposure to CS induces inflammation and oxidative stress in the lung without significantly affecting oxidative stress in extrapulmonary organs under the current experimental conditions. NOX may play a role in these pulmonary-specific events.
RESUMO
Severe fever with thrombocytopenia syndrome (SFTS), a tick-borne zoonotic disease, is caused by infection with SFTS virus (SFTSV). A previous study reported that human-to-human direct transmission of SFTSV can occur. However, potential animal-to-animal transmission of SFTSV without ticks has not been fully clarified. Thus, the objective of this study was to investigate potential mice-to-mice transmission of SFTSV by co-housing three groups of mice [i.e., wild-type mice (WT), mice injected with an anti-type I interferon-α receptor-blocking antibody (IFNAR Ab), and mice with knockout of type I interferon-α receptor (IFNAR KO)] as spreaders or recipients with different immune competence. As a result, co-housed IFNAR Ab and IFNAR KO mice showed body weight loss with SFTS viral antigens detected in their sera, extracorporeal secretions, and various organs. Based on histopathology, white pulp atrophy in the spleen was observed in all co-housed mice except WT mice. These results obviously show that IFNAR Ab and IFNAR KO mice, as spreaders, exhibited higher transmissibility to co-housed mice than WT mice. Moreover, IFNAR KO mice, as recipients, were more susceptible to SFTSV infection than WT mice. These findings suggest that type I interferon signaling is a pivotal factor in mice intraspecies transmissibility of SFTSV in the absence of vectors such as ticks.
Assuntos
Infecções por Bunyaviridae , Interferon Tipo I , Phlebovirus , Febre Grave com Síndrome de Trombocitopenia , Doenças Transmitidas por Carrapatos , Humanos , Animais , CamundongosRESUMO
Inhalation of polyhexamethylene guanidine phosphate (PHMG) can cause pulmonary fibrosis. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) are enzymes that produce reactive oxygen species, which may be involved in tissue damage in various lung diseases. To investigate whether the Nox2 isoform of Nox is involved in the progression of PHMG-induced lung damage, we studied the contribution of Nox2 in PHMG-induced lung injury in Nox2-deficient mice. We treated wild-type (WT) and Nox2 knockout mice with a single intratracheal instillation of 1.1 mg/kg PHMG and sacrificed them after 14 days. We analyzed lung histopathology and the number of total and differential cells in the bronchoalveolar lavage fluid. In addition, the expressions of cytokines, chemokines, and profibrogenic genes were analyzed in the lung tissues. Based on our results, Nox2-deficient mice showed less PHMG-induced pulmonary damage than WT mice, as indicated by parameters such as body weight, lung weight, total cell count, cytokine and chemokine levels, fibrogenic mediator expression, and histopathological findings. These findings suggest that Nox2 may have the potential to contribute to PHMG-induced lung injury and serves as an essential signaling molecule in the development of PHMG-induced pulmonary fibrosis by regulating the expression of profibrogenic genes.
RESUMO
Amlexanox is an anti-inflammatory and anti-allergic agent used clinically for the treatment of aphthous ulcers, allergic rhinitis, and asthma. Recent studies have demonstrated that amlexanox, a selective inhibitor of IkB kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1), suppresses a range of diseases or inflammatory conditions, such as obesity-related metabolic dysfunction and type 2 diabetes. However, the effects of amlexanox on neuroinflammatory responses to amlexanox have not yet been comprehensively studied. In this study, we investigated the novel therapeutic effect of amlexanox on LPS-induced neuroinflammation in vivo, and intraperitoneal injection of amlexanox markedly reduced LPS-induced IKKε levels, proinflammatory cytokines, and microglial activation, as evidenced by ionized calcium-binding adapter molecule 1 (Iba1) immunostaining. Furthermore, amlexanox significantly reduced proinflammatory cytokines and chemokines in LPS-induced bone marrow-derived macrophages (BMDM), murine BV2, and human HMC3 microglial cells. This data provided considerable evidence that amlexanox can be used as a preventive and curative therapy for neuroinflammatory and neurodegenerative diseases. In terms of mechanism aspects, our results demonstrated that the anti-inflammatory action of amlexanox in BV2 microglial cells was through the downregulation of NF-κB and STAT3 signaling pathways. In addition, the combination of amlexanox and SPI (a STAT3 selective inhibitor) showed high efficiency in inhibiting the production of neurotoxic and pro-inflammatory mediators. Overall, our data provide rational insights into the mechanisms of amlexanox as a potential therapeutic strategy for neuroinflammation-related diseases.
Assuntos
Aminopiridinas , Diabetes Mellitus Tipo 2 , NF-kappa B , Humanos , Camundongos , Animais , NF-kappa B/metabolismo , Microglia/metabolismo , Lipopolissacarídeos/metabolismo , Quinase I-kappa B/metabolismo , Doenças Neuroinflamatórias , Diabetes Mellitus Tipo 2/metabolismo , Transdução de Sinais , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Anti-Inflamatórios/uso terapêutico , Citocinas/metabolismo , Fator de Transcrição STAT3/metabolismoRESUMO
All pigs in the Republic of Korea are given the foot-and-mouth disease virus (FMDV) vaccine intramuscularly (IM) as part of the country's vaccination policy. However, the IM administration of the FMDV vaccine to pig results in residual vaccine components in the muscle and undesirable changes in muscle and soft tissues, causing economic losses in swine production. In this study, we evaluated whether intradermal (ID) vaccination could be proposed as an alternative to IM administration. ID vaccination (0.2 mL on each side of the neck muscle) and IM vaccination (2 mL on each side of the neck muscle) were performed twice, separated by 14 days, using a commercial FMD vaccine in specific-pathogen-free pigs. We observed growth performance, gross and microscopic lesions at the inoculation site, FMDV-specific antibodies, and neutralizing antibodies for 35 days after vaccination. Side effects on the skin grossly appeared following ID administration, but most were reduced within two weeks. All ID-vaccinated pigs showed inflammatory lesions limited to the dermis, but IM-vaccinated pigs had abnormal undesirable changes and pus in the muscle. ID-vaccinated pigs performed comparably to IM-vaccinated pigs in terms of growth, FMD virus-specific antibodies, protection capability against FMDV, and T-cell induction. This study demonstrated that the ID inoculation of the inactivated FMD vaccine induced immune responses comparable to an IM injection at 1/10 of the inoculation dose and that the inoculation lesion was limited to the dermis, effectively protecting against the formation of abnormal undesirable changes in muscle and soft tissues.
RESUMO
BACKGROUND: Porcine circovirus, a non-enveloped single-stranded DNA virus belonging to the genus Circovirus of the family Circoviridae, is a major pathogen of porcine circovirus-associated disease. Porcine circovirus 3, a novel porcine circovirus, has been identified in individuals with clinical symptoms. OBJECTIVES: The prevalence of porcine circovirus 2 and porcine circovirus 3 and the confirmation of diagnosis of this emerging viral disease have not been fully studied yet. Therefore, the objective of the present study was to investigate the prevalence of porcine circovirus 2 and porcine circovirus 3 in slaughtered pigs and wild boars in Korea between 2018 and 2019. METHODS: Lungs and hilar lymph nodes of healthy pigs slaughtered in slaughterhouses and captured wild pigs were collected, and viruses were detected by multiplex quantitative polymerase chain reaction and two staining methods (in situ hybridization and immunohistochemistry) to confirm the presence of porcine circovirus 2 and porcine circovirus 3. RESULTS: Positive rates of porcine circovirus 2 in lungs and hilar lymph nodes were 78.1% (75/96) and 89.5% (86/96) in slaughtered pigs, respectively. They were 18.0% (30/167) and 46.3% (24/55) in wild boars, respectively. Positive rates of porcine circovirus 3 in lungs and hilar lymph nodes were 30.2% (29/96) and 13.5% (13/96) in slaughtered pigs, respectively. They were 4.2% (7/167) and 5.5% (3/55) in wild boars, respectively. At the farm level, positive rates of porcine circovirus 2 and porcine circovirus 3 were 97.9% (47/48) and 54.2% (26/48), respectively. Positive rates of porcine circovirus 2 and porcine circovirus 3 decreased in spring. Immunohistochemistry and in situ hybridization confirmed the presence of porcine circovirus 2 and porcine circovirus 3 in lungs, but not porcine circovirus 3 in the hilar lymph nodes. CONCLUSION: These results suggest that the prevalence of porcine circovirus 2 and porcine circovirus 3 might vary depending on the season and the type of sample. Wild boars might play a role in the epidemiology of porcine circovirus 2 and porcine circovirus 3 in South Korea. Continuous surveillance and further study are needed for this emerging disease.
Assuntos
Infecções por Circoviridae , Circovirus , Doenças dos Suínos , Suínos , Animais , Circovirus/genética , Doenças dos Suínos/epidemiologia , Prevalência , Infecções por Circoviridae/epidemiologia , Infecções por Circoviridae/veterinária , República da Coreia/epidemiologia , Sus scrofaRESUMO
IMPORTANCE: Viruses are constantly evolving to promote propagation in the host. Here, we show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes host RAD51 for replication. Silencing of RAD51 impaired SARS-CoV-2 propagation. Viral RNA colocalized with RAD51 in the cytoplasm of SARS-CoV-2-infected cells, suggesting that both viral RNA and RAD51 may form a replication complex. We, therefore, evaluated RAD51 inhibitors as possible therapeutic agents against SARS-CoV-2. Indeed, RAD51 inhibitors exerted antiviral activities against not only Wuhan but also variants of SARS-CoV-2. Molecular docking model shows that RAD51 inhibitors impede SARS-CoV-2 propagation by interfering with dimerization of RAD51. These data suggest that RAD51 may represent a novel host-based drug target for coronavirus disease 2019 treatment.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/metabolismo , COVID-19/virologia , Simulação de Acoplamento Molecular , Rad51 Recombinase/antagonistas & inibidores , Rad51 Recombinase/metabolismo , RNA Viral , SARS-CoV-2/fisiologia , Interações Hospedeiro-PatógenoRESUMO
Natural products and herbal medicine have been widely used in drug discovery for treating infectious diseases. Recent outbreak of COVID-19 requires various therapeutic strategies. Here, we used YSK-A, a mixture of three herbal components Boswellia serrata, Commiphora myrrha, and propolis, to evaluate potential antiviral activity against SARS-CoV-2. We showed that YSK-A inhibited SARS-CoV-2 propagation with an IC50 values of 12.5 µg/ml and 15.42 µg/ml in Vero E6 and Calu-3 cells, respectively. Using transcriptome analysis, we further demonstrated that YSK-A modulated various host gene expressions in Calu-3 cells. Among these, we selected 9 antiviral- or immune-related host genes for further study. By siRNA-mediated knockdown experiment, we verified that MUC5AC, LIF, CEACAM1, and GDF15 host genes were involved in antiviral activity of YSK-A. Therefore, silencing of these genes nullified YSK-A-mediated inhibition of SARS-CoV-2 propagation. These data indicate that YSK-A displays an anti-SARS-CoV-2 activity by targeting multiple antiviral genes. Although the exact antiviral mechanism of each constituent has not been verified yet, our data indicate that YSK-A has an immunomodulatory effect on SARS-CoV-2 and thus it may represent a novel natural product-derived therapeutic agent for treating COVID-19.
Assuntos
Produtos Biológicos , COVID-19 , Plantas Medicinais , Chlorocebus aethiops , Animais , SARS-CoV-2 , Produtos Biológicos/farmacologia , Antivirais/farmacologia , Células VeroRESUMO
BACKGROUND: Infectious diseases transmitted by wild animals are major threats to public health. This study aimed to investigate the potential of rescued wild animals that died of unknown causes as reservoirs of infectious agents. From 2018 to 2019, 121 dead wild animals (55 birds and 66 mammals) were included in this study. All wild animals died during treatment after anthropogenic events. After deaths of animals, necropsies were performed and trachea, lungs, large intestine (including stool), and spleen were collected to determine causes of deaths. A high-throughput screening (HTS) quantitative polymerase chain reaction (qPCR) designed to detect 19 pathogens simultaneously against 48 samples in duplicate was performed using nucleic acids extracted from pooled tissues and peripheral blood samples. If positive, singleplex real-time PCR was performed for individual organs or blood samples. RESULTS: The HTS qPCR showed positive results for Campylobacter jejuni (10/121, 8.3%), Campylobacter coli (1/121, 0.8%), Mycoplasma spp. (78/121, 64.5%), and Plasmodium spp. (7/121, 5.7%). Singleplex real-time PCR confirmed that C. jejuni was detected in the large intestine but not in the blood. C. coli was only detected in the large intestine. Mycoplasma spp. were detected in all organs, having the highest proportion in the large intestine and lowest in the blood. Plasmodium spp. was also detected in all organs, with proportions being were similar among organs. CONCLUSIONS: This study shows that wild animals can become carriers of infectious agents without showing any clinical symptoms.
Assuntos
Campylobacter jejuni , Mycoplasma , Animais , Animais Selvagens , Ensaios de Triagem em Larga Escala/veterinária , República da Coreia , Autopsia/veterinária , MamíferosRESUMO
Natural products are continuously being researched to develop safe and effective treatment options for cervical cancer, the fourth most common cancer in women. Piperlongumine (PL), an amide alkaloid mainly present in long pepper, exhibits neuroprotective and anti-cancer properties. However, the specific effect of PL in cervical cancer and the relationship between the anti-cancer pathway and autophagy remain unclear. Therefore, we aimed to investigate PL-induced apoptosis in KB human cervical cancer cells and the relationship between apoptosis and autophagy therein. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and wound-healing assays showed that PL treatment suppressed KB cell viability and proliferation. Apoptosis was identified through 4',6-diamidino-2-phenylindole and annexin V-propidium iodide staining, increased cleaved-poly (ADP-ribose) polymerase and Bcl-2 associated X levels, and decreased B cell lymphoma 2 levels. Acridine orange staining and increased microtubule-associated protein 1A/1B-light chain 3-II and Beclin-1 levels confirmed autophagy. We determined that KB cell-related autophagy exerted cytoprotective effects using the autophagy inhibitors 3-methyladenine and hydroxychloroquine. PL treatment promoted apoptosis by inhibiting the phosphatidylinositol-3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin pathway in KB cells; inhibiting the pathway using PI3K inhibitors increased autophagy. We suggest that PL is a potential natural anticancer agent for cervical cancer treatment.
RESUMO
BACKGROUND: Toll-like receptor 7 (TLR7) is an endosomal TLR activated by single-stranded RNA, including endogenous microRNAs. Although TLR7 is known to promote inflammatory responses in pathophysiological conditions, its role in renal fibrosis has not been investigated. Here, we aim to investigate the inflammatory roles of TLR7 in kidney inflammation and fibrosis. METHODS: TLR7 knockout mice (Tlr7 -/-) subjected to AD-induced kidney injury were utilized to examine the role of TLR7 in kidney fibrosis. To elucidate the role of TLR7 in renal epithelial cells, NRK52E rat renal tubule epithelial cells were employed. RESULTS: Under fibrotic conditions induced by an adenine diet (AD), TLR7 was significantly increased in damaged tubule epithelial cells, where macrophages were highly infiltrated. TLR7 deficiency protected against AD-induced tubular damage, inflammation, and renal fibrosis. Under in vitro conditions, TLR7 activation increased NF-κB activity and induced chemokine expression, whereas TLR7 inhibition effectively blocked NF-κB activation. Furthermore, among the known TLR7 endogenous ligands, miR-21 was significantly upregulated in the tubular epithelial regions. In NRK52E cells, miR-21 treatment induced pro-inflammatory responses, which could be blocked by a TLR7 inhibitor. When the TLR7 inhibitor, M5049, was administered to the AD-induced renal fibrosis model, TLR7 inhibition significantly attenuated AD-induced renal inflammation and fibrosis. CONCLUSIONS: Overall, activation of TLR7 by endogenous miR-21 in renal epithelial cells contributes to inflammatory responses in a renal fibrosis model, suggesting a possible therapeutic target for the treatment of renal fibrosis. Video Abstract.
Assuntos
Nefropatias , MicroRNAs , Receptor 7 Toll-Like , Animais , Camundongos , Ratos , Adenina , Células Epiteliais , Inflamação , MicroRNAs/genética , NF-kappa B , Transdução de Sinais , Nefropatias/genética , Nefropatias/patologia , FibroseRESUMO
Introduction: Bovine herpesvirus 4 (BoHV-4) is a bovine Rhadinovirus not associated with a specific pathological lesion or disease and experimentally employed as a viral vector vaccine. BoHV-4-based vector (BoHV-4-BV) has been shown to be effective in immunizing and protecting several animal species when systemically administrated through intramuscular, subcutaneous, intravenous, or intraperitoneal routes. However, whether BoHV-4-BV affords respiratory disease protection when administered intranasally has never been tested. Methods: In the present study, recombinant BoHV-4, BoHV-4-A-S-ΔRS-HA-ΔTK, was constructed to deliver an expression cassette for the SARS-CoV-2 spike glycoprotein, and its immunogenicity, as well as its capability to transduce cells of the respiratory tract, were tested in mice. The well-established COVID-19/Syrian hamster model was adopted to test the efficacy of intranasally administered BoHV-4-A-S-ΔRS-HA-ΔTK in protecting against a SARS-CoV-2 challenge. Results: The intranasal administration of BoHV-4-A-S-ΔRS-HA-ΔTK elicited protection against SARS-CoV-2, with improved clinical signs, including significant reductions in body weight loss, significant reductions in viral load in the trachea and lungs, and significant reductions in histopathologic lung lesions compared to BoHV-4-A-S-ΔRS-HA-ΔTK administered intramuscularly. Discussion: These results suggested that intranasal immunization with BoHV-4-BV induced protective immunity and that BoHV-4-BV could be a potential vaccine platform for the protection of other animal species against respiratory diseases.
Assuntos
COVID-19 , Herpesvirus Bovino 4 , Vacinas Virais , Animais , Camundongos , Cricetinae , COVID-19/prevenção & controle , SARS-CoV-2 , Administração IntranasalRESUMO
Concanavalin A (ConA) is a plant lectin that can induce immune-mediated liver damage. ConA induced liver damage animal model is a widely accepted model that can mimic clinical acute hepatitis and immune-mediated liver injury in humans. Toll-like receptor-7 (TLR7), a member of the TLR family, plays a key role in pathogen recognition and innate immune activation. The aim of this study was to examine the role of TLR7 in the pathogenesis of ConA-induced liver injury. Acute liver injury was induced by intravenous injection with ConA in WT (wild-type) and TLR7 knockout (KO) mice. Results showed that attenuated liver injury in TLR7-deficient mice, as indicated by increased survival rate, decreased aminotransferase levels, and reduced pathological lesions, was associated with decreased release of pro-inflammatory cytokines in livers. Consistently, significantly decreased proliferation of CD4+ T cell was detected in ConA-stimulated TLR7-deficient splenocytes, but not in CD3/CD28 stimulated TLR7-deficient CD4+ T cells. Moreover, TLR7 deficiency in KCs specifically suppressed the expression of TNF-α (tumor necrosis factor-α). Depletion of KCs abolished the detrimental role of TLR7 in ConA-induced liver injury. Taken together, these results demonstrate that TLR7 can regulate the expression of TNF-α in KCs, which is necessary for the full progression of ConA-induced liver injury.
Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Células de Kupffer , Receptor 7 Toll-Like , Animais , Humanos , Camundongos , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Concanavalina A/efeitos adversos , Células de Kupffer/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVE: To determine pulmonary anthracosis in zoo, wildlife, and companion animals of Jeollabuk-do Province, South Korea. ANIMALS: A total of 350 animals of 61 different species, belonging to 3 classes (mammals: n = 38; avian: 21; and reptiles: 2) from different habitats in Jeollabuk-do Province, were examined. PROCEDURES: Gross lung examination and tissue sampling were done at postmortem, and histopathological analysis was microscopically done on hematoxylin and eosin-stained slides. RESULTS: Macroscopic analysis of anthracotic lung tissue revealed minute (pinpoint size) spots and black pigmentation in a scattered and/or coalescing fashion. The presence of carbon particles was noted in 154 (44%, 154/350) cases. Based on habitation, zoo animals had the highest frequency of anthracosis in the lung (55.2%, 69/125), followed by companion animals (45.2%, 56/124) and wildlife animals (28.7%, 29/101). There was an association between habitation and the presence of anthracosis (P < .05). CLINICAL RELEVANCE: This study revealed evidence that the presence of anthracosis is associated with the environmental air quality of zoo, wildlife, and companion animals in Jeollabuk-do Province, South Korea. Air pollution may affect the respiratory health of the endangered species at the Jeonju Zoo as well as the human population. Continuous monitoring of particulate matter and establishing policies that control industrialization around the province would enable quick action to curb any potential respiratory health risks to animals kept in the urban cities of the province.