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Viperin is a multifunctional interferon-inducible protein that is directly induced in cells by human cytomegalovirus (HCMV) infection. The viral mitochondrion-localized inhibitor of apoptosis (vMIA) interacts with viperin at the early stages of infection and translocates it from the endoplasmic reticulum to the mitochondria, where viperin modulates the cellular metabolism to increase viral infectivity. Viperin finally relocalizes to the viral assembly compartment (AC) at late stages of infection. Despite the importance of vMIA interactions with viperin during viral infection, their interacting residues are unknown. In the present study, we showed that cysteine residue 44 (Cys44) of vMIA and the N-terminal domain (amino acids [aa] 1 to 42) of viperin are necessary for their interaction and for the mitochondrial localization of viperin. In addition, the N-terminal domain of mouse viperin, which is structurally similar to that of human viperin, interacted with vMIA. This indicates that the structure, rather than the sequence composition, of the N-terminal domain of viperin, is required for the interaction with vMIA. Recombinant HCMV, in which Cys44 of vMIA was replaced by an alanine residue, failed to translocate viperin to the mitochondria at the early stages of infection and inefficiently relocalized it to the AC at late stages of infection, resulting in the impairment of viperin-mediated lipid synthesis and a reduction in viral replication. These data indicate that Cys44 of vMIA is therefore essential for the intracellular trafficking and function of viperin to increase viral replication. Our findings also suggest that the interacting residues of these two proteins are potential therapeutic targets for HCMV-associated diseases. IMPORTANCE Viperin traffics to the endoplasmic reticulum (ER), mitochondria, and viral assembly compartment (AC) during human cytomegalovirus (HCMV) infection. Viperin has antiviral activity at the ER and regulates cellular metabolism at the mitochondria. Here, we show that Cys44 of HCMV vMIA protein and the N-terminal domain (aa 1 to 42) of viperin are necessary for their interaction. Cys44 of vMIA also has a critical role for viperin trafficking from the ER to the AC via the mitochondria during viral infection. Recombinant HCMV expressing a mutant vMIA Cys44 has impaired lipid synthesis and viral infectivity, which are attributed to mislocalization of viperin. Cys44 of vMIA is essential for the trafficking and function of viperin and may be a therapeutic target for HCMV-associated diseases.
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Proteínas Inmediatas-Precoces , Proteína Viperina , Proteínas Virales , Virosis , Animales , Humanos , Ratones , Cisteína/metabolismo , Citomegalovirus/metabolismo , Proteínas Inmediatas-Precoces/metabolismo , Lípidos , Mitocondrias/metabolismo , Virosis/metabolismo , Proteína Viperina/metabolismo , Proteínas Virales/metabolismoRESUMEN
Throughout the recent COVID-19 pandemic, South Korea led national efforts to develop vaccines and therapeutics for SARS-CoV-2. The project proceeded as follows: 1) evaluation system setup (including Animal Biosafety Level 3 (ABSL3) facility alliance, standardized nonclinical evaluation protocol, and laboratory information management system), 2) application (including committee review and selection), and 3) evaluation (including expert judgment and reporting). After receiving 101 applications, the selection committee reviewed pharmacokinetics, toxicity, and efficacy data and selected 32 final candidates. In the nonclinical efficacy test, we used golden Syrian hamsters and human angiotensin-converting enzyme 2 transgenic mice under a cytokeratin 18 promoter to evaluate mortality, clinical signs, body weight, viral titer, neutralizing antibody presence, and histopathology. These data indicated eight new drugs and one repositioned drug having significant efficacy for COVID-19. Three vaccine and four antiviral drugs exerted significant protective activities against SARS-CoV-2 pathogenesis. Additionally, two anti-inflammatory drugs showed therapeutic effects on lung lesions and weight loss through their mechanism of action but did not affect viral replication. Along with systematic verification of COVID-19 animal models through large-scale studies, our findings suggest that ABSL3 multicenter alliance and nonclinical evaluation protocol standardization can promote reliable efficacy testing against COVID-19, thus expediting medical product development.
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COVID-19 , Animales , Cricetinae , Ratones , Humanos , SARS-CoV-2 , Pandemias , Anticuerpos Neutralizantes , Mesocricetus , Modelos Animales de EnfermedadRESUMEN
Viperin is an interferon (IFN)-inducible multifunctional protein. Recent evidence from high-throughput analyses indicates that most IFN-inducible proteins, including viperin, are intrinsically expressed in specific tissues; however, the respective intrinsic functions are unknown. Here we show that the intrinsic expression of viperin regulates adipose tissue thermogenesis, which is known to counter metabolic disease and contribute to the febrile response to pathogen invasion. Viperin knockout mice exhibit increased heat production, resulting in a reduction of fat mass, improvement of high-fat diet (HFD)-induced glucose tolerance, and enhancement of cold tolerance. These thermogenic phenotypes are attributed to an adipocyte-autonomous mechanism that regulates fatty acid ß-oxidation. Under an HFD, viperin expression is increased, and its function is enhanced. Our findings reveal the intrinsic function of viperin as a novel mechanism regulating thermogenesis in adipose tissues, suggesting that viperin represents a molecular target for thermoregulation in clinical contexts.
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Tejido Adiposo/metabolismo , Regulación de la Expresión Génica , Proteínas/genética , Termogénesis/genética , Adipocitos/metabolismo , Animales , Metabolismo Energético/genética , Masculino , Ratones , Ratones NoqueadosRESUMEN
PURPOSE: To evaluate the long-term cure and complication rates of the canal transobturator tape (TOT) procedure for stress urinary incontinence (SUI) in females and assess how to reduce mesh erosion in TOT surgery. MATERIALS AND METHODS: The canal TOT procedure was developed in 2009 and was effective in mitigating the complications of the original TOT procedure in the short-term follow-up. This study was designed for a long-term follow-up. Between October 2006 and December 2010, 232 consecutive women with stress and mixed urinary incontinence underwent the canal TOT procedure. All patients were followed up by urological examination and self-assessment questionnaires. We performed urodynamic studies in patients with pure SUI symptoms and pelvic examination for all patients 5 years post-surgery. RESULTS: A minimum 5 years follow-up data were available for 144 patients. Complications were evaluated according to the Clavien-Dindo classification. Vaginal mesh erosion was reported in 2 patients (1.4%), and the mesh was surgically removed. No bladder or urethral mesh erosion were observed. The subjective and objective cure rates at 5 years were 77.8 and 94.5% respectively. CONCLUSIONS: Canal TOT procedure is an effective minimally invasive procedure with satisfactory results for female SUI in the long term. Compared to the rate of mesh erosion after the original TOT procedure, this technique might be useful in preventing mesh erosion because the mesh is always anatomically well positioned.
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Complicaciones Posoperatorias/epidemiología , Cabestrillo Suburetral , Mallas Quirúrgicas , Incontinencia Urinaria de Esfuerzo/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Falla de Equipo/estadística & datos numéricos , Femenino , Humanos , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Estudios Prospectivos , Mallas Quirúrgicas/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Procedimientos Quirúrgicos Urológicos/instrumentaciónRESUMEN
UV-UV hole burning and IR dip spectra of l-ß3-homotryptophan were measured by a laser desorption supersonic jet technique as a bottom-up approach to understand the secondary structures of ß-peptides. 14 conformers were found by UV-UV hole burning spectroscopy. The conformers were classified into three groups depending on their hydrogen bonding patterns observed in their conformer-specific IR spectra, and tentatively assigned by comparing with quantum chemical calculations. Group 1 had free OH stretch but no NH2 anti-symmetric stretch vibrational transition and was assigned to NH-π hydrogen bonded structures. Group 2, including the most abundant conformer, showed both free OH and NH2 anti-symmetric stretch vibrations, and belonged to NH-O hydrogen bonded conformations. Group 3 of conformers had hydrogen-bonded OH stretch IR transition and had OH-N hydrogen bonds. The internal hydrogen bond of group 3 is a C6 hydrogen bond due to the additional carbon atom at the ß position and shows a shorter bond length than that of a C5 hydrogen bond. While the OH-N C6 hydrogen bond is stronger than NH-O, the entropic effect prefers the more flexible NH-O hydrogen bonded structure. It is expected that the unnatural C6 hydrogen bond influences the conformations of ß-peptides and builds totally different secondary structures than those of α-peptides.
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Triptófano/análogos & derivados , Triptófano/química , Entropía , Enlace de Hidrógeno , Modelos Moleculares , Conformación Molecular , Teoría Cuántica , Espectrofotometría Infrarroja/métodosRESUMEN
STUDY OBJECTIVE: To present our initial experience with reduced-port robotic surgery (RPRS) for myomectomy using the Octo-Port system (DalimSurgNet, Seoul, Korea). DESIGN: Prospective and noncomparative study (Canadian Task Force classification II-3). SETTING: University hospital. PATIENTS: Nineteen consecutive patients with symptomatic uterine myomas desiring conservative minimally invasive robotic surgery from October 2015 to December 2016. INTERVENTIONS: An 8.5-mm or 12-mm robotic camera cannula was inserted through 1 of the Octo-Port channels and an 8-mm conventional robotic port was inserted into a 10-mm channel of the Octo-Port through a 3-cm transumbilical incision. An additional 8-mm conventional robotic port was inserted into a typical robotic port site in the patient's right abdomen. MEASUREMENTS AND MAIN RESULTS: Feasibility and operative outcomes of RPRS myomectomy. The median docking time and console time were 10 minutes (range, 4-22) and 90 minutes (range, 29-198). The largest myoma was located on the anterior uterine wall in 11 patients (57.9%). The median myoma size and weight were 7.2 cm (range, 4.1-10.5) and 141 g (range, 42-590), respectively. Median operative blood loss and change in hemoglobin were 100 mL (range, 30-700) and 2.6 mg/dL (range, .1-3.8), respectively. The procedure was successfully performed via RPRS in 89.5% of patients; 2 patients required placement of 1 to 2 additional robotic ports, resulting in a return to traditional multiport robotic surgery. There were no major postoperative complications or postoperative hernias. CONCLUSION: Our experience demonstrated the feasibility of RPRS for myomectomy using the Octo-Port system in selected patients.
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Leiomioma/cirugía , Procedimientos Quirúrgicos Robotizados/instrumentación , Procedimientos Quirúrgicos Robotizados/métodos , Miomectomía Uterina/instrumentación , Miomectomía Uterina/métodos , Neoplasias Uterinas/cirugía , Adulto , Pérdida de Sangre Quirúrgica , Estudios de Factibilidad , Femenino , Humanos , Laparoscopía/instrumentación , Laparoscopía/métodos , Persona de Mediana Edad , Procedimientos Quirúrgicos Mínimamente Invasivos , Complicaciones Posoperatorias/cirugía , República de CoreaRESUMEN
The aim of this study was to determine whether the different phases of the menstrual cycle could affect operative bleeding in women undergoing laparoscopic hysterectomy. This was a retrospective comparative study. Based on the adjusted day of menstrual cycle, 212 women who underwent laparoscopic hysterectomy were classified into three groups: the follicular phase (n = 51), luteal phase group (n = 125), and menstruation group (n = 36). The primary outcome measure was the operative bleeding. There was no difference in the baseline characteristics of the patients belonging to the three groups. For the groups, there were no significant differences in operative bleeding (p = .469) and change in haemoglobin (p = .330), including operative time, length of hospital stay and complications. The menstrual cycle did not affect the operative bleeding and other parameters. Therefore, no phase of the menstrual cycle could be considered as an optimal timing for performing laparoscopic hysterectomy with minimal operative bleeding. Impact statement What is already known on this subject: the menstrual cycle results in periodic changes in haemostasis and blood flow in the reproductive organs. What the results of this study add: the menstrual cycle did not affect the operative bleeding and other operative parameters during laparoscopic hysterectomy. What the implications are of these findings for clinical practice and/or further research: no phase of the menstrual cycle could be considered as an optimal timing for performing laparoscopic hysterectomy with minimal operative bleeding.
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Pérdida de Sangre Quirúrgica , Fase Folicular , Histerectomía/métodos , Fase Luteínica , Menstruación , Hemorragia Posoperatoria/prevención & control , Factores de Tiempo , Femenino , Humanos , Histerectomía/efectos adversos , Laparoscopía , Tiempo de Internación , Persona de Mediana Edad , Tempo Operativo , Estudios RetrospectivosRESUMEN
AIM: To investigate the feasibility and safety of single port laparoscopic surgery (SP-LS) for ectopic pregnancy, irrespective of type of ectopic pregnancy and hemodynamic stability. METHODS: A prospective case-control study of 106 women who underwent SP-LS or conventional LS for a suspected ectopic pregnancy was performed at a university teaching hospital from January 2009 to March 2012. Twenty-six women underwent SP-LS (SP-LS group) and 80 women underwent conventional LS (conventional LS group). RESULTS: There were no statistical differences between the groups in terms of demographic characteristics, operating time, hemoglobin change, return of bowel activity, hospital stay or complication rate. There were no cases of additional trocar use or conversion to laparotomy. Of five women with heterotopic pregnancy, one underwent SP-LS, and three underwent conventional LS for tubal pregnancy, which all resulted in vaginal delivery without obstetric complication; one woman received SP-LS for cornual pregnancy and had an ongoing pregnancy. CONCLUSION: SP-LS for ectopic pregnancy is feasible and safe regardless of the type of ectopic pregnancy and hemodynamic stability. However, further work is needed to confirm this conclusion and to demonstrate any advantage of SP-LS for ectopic pregnancy.
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Procedimientos Quirúrgicos Ginecológicos/métodos , Laparoscopía/métodos , Embarazo Ectópico/cirugía , Adolescente , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Tiempo de Internación , Tempo Operativo , Embarazo , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Epidermal growth factor (EGF) has been known to induce epithelial-mesenchymal transition (EMT) and prostate cancer cell progression. However, a detailed underlying mechanism by which EGF induces EMT and prostate cancer cell progression remained to be answered. Hypoxia-inducible factor (HIF)-1α and TWIST1 are transcription factors implicated in EMT and cancer metastasis. The purpose of this study is to determine the underlying mechanism of EGF-induced TWIST1 expression and prostate cancer invasion. METHODS: siRNAs were used to silence genes. Immunoblotting, quantitative RT-PCR and immunofluorescence analysis were used to examine protein or mRNA expression. Modified Boyden chamber and invasion assay kit with Matrigel-coated inserts were used to determine prostate cancer cell migration and invasion, respectively. RESULTS: We observed that EGF induced HIF-1α expression and morphological change of prostate cancer epithelial cells to mesenchymal cells. Silencing HIF-1α expression dramatically reduced EGF-induced TWIST1 expression and prostate cancer cell EMT. Conversely, transfection of the cells with HIF-1α siRNA reversed the reduced E-cadherin expression by EGF. Pretreatment of the cells with pharmacological inhibitors of reactive oxygen species [ROS, N-acetylcysteine (NAC)] and STAT3 (WP1066) but not p38 MAPK (SB203580) significantly reduced EGF-induced HIF-1α mRNA and protein expression. Further, pretreatment of the cells with NAC attenuated EGF-induced STAT3 phosphorylation. In addition, we showed that TWIST1 mediated EGF-induced N-cadherin expression, leading to prostate cancer invasion. CONCLUSIONS: We demonstrate a mechanism by which EGF promotes prostate cancer cell progression through a ROS/STAT3/HIF-1α/TWIST1/N-cadherin signaling cascade, providing novel biomarkers and promising therapeutic targets for prostate cancer cell progression.
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Factor de Crecimiento Epidérmico/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Invasividad Neoplásica/patología , Proteínas Nucleares/metabolismo , Neoplasias de la Próstata/patología , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/fisiología , Proteína 1 Relacionada con Twist/metabolismo , Acetilcisteína/farmacología , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Masculino , Proteínas Nucleares/genética , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Neoplasias de la Próstata/metabolismo , ARN Interferente Pequeño , Factor de Transcripción STAT3/genética , Transducción de Señal/efectos de los fármacos , Proteína 1 Relacionada con Twist/genéticaRESUMEN
Bioresorbable neural implants based on emerging classes of biodegradable materials offer a promising solution to the challenges of secondary surgeries for removal of implanted devices required for existing neural implants. In this study, we introduce a fully bioresorbable flexible hybrid opto-electronic system for simultaneous electrophysiological recording and optogenetic stimulation. The flexible and soft device, composed of biodegradable materials, has a direct optical and electrical interface with the curved cerebral cortex surface while exhibiting excellent biocompatibility. Optimized to minimize light transmission losses and photoelectric artifact interference, the device was chronically implanted in the brain of transgenic mice and performed to photo-stimulate the somatosensory area while recording local field potentials. Thus, the presented hybrid neural implant system, comprising biodegradable materials, promises to provide monitoring and therapy modalities for versatile applications in biomedicine.
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Implantes Absorbibles , Depresores del Sistema Nervioso Central , Animales , Ratones , Optogenética , Artefactos , Encéfalo , Electrónica , Ratones TransgénicosRESUMEN
Intranasal infection is commonly used to establish a SARS-CoV-2 mouse model due to its non-invasive procedures and a minimal effect from the operation itself. However, mice intranasally infected with SARS-CoV-2 have a high mortality rate, which limits the utility of this model for exploring therapeutic strategies and the sequelae of non-fatal COVID-19 cases. To resolve these limitations, an aerosolised viral administration method has been suggested. However, an in-depth pathological analysis comparing the two models is lacking. Here, we show that inhalation and intranasal SARS-CoV-2 (106 PFU) infection models established in K18-hACE2 mice develop unique pathological features in both the respiratory and central nervous systems, which could be directly attributed to the infection method. While the inhalation-infection model exhibited relatively milder pathological parameters, it closely mimicked the prevalent chest CT pattern observed in COVID-19 patients with focal, peripheral lesions and fibrotic scarring in the recuperating lung. We also found the evidence of direct neuron-invasion from the olfactory receptor neurons to the olfactory bulb in the intranasal model and showed the trigeminal nerve as an alternative route of transmission to the brain in inhalation infected mice. Even after viral clearance confirmed at 14 days post-infection, mild lesions were still found in the brain of inhalation-infected mice. These findings suggest that the inhalation-infection model has advantages over the intranasal-infection model in closely mimicking the pathological features of non-fatal symptoms of COVID-19, demonstrating its potential to study the sequelae and possible interventions for long COVID.
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COVID-19 , Modelos Animales de Enfermedad , Pulmón , SARS-CoV-2 , Animales , COVID-19/patología , COVID-19/virología , Ratones , Pulmón/patología , Pulmón/virología , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Bulbo Olfatorio/patología , Bulbo Olfatorio/virología , Humanos , Administración Intranasal , Femenino , Neuronas Receptoras Olfatorias/virología , Neuronas Receptoras Olfatorias/metabolismoRESUMEN
Viral load and the duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important determinants of the transmission of coronavirus disease 2019. In this study, we examined the effects of viral doses on the lung and spleen of K18-hACE2 transgenic mice by temporal histological and transcriptional analyses. Approximately, 1×105 plaque-forming units (PFU) of SARS-CoV-2 induced strong host responses in the lungs from 2 days post inoculation (dpi) which did not recover until the mice died, whereas responses to the virus were obvious at 5 days, recovering to the basal state by 14 dpi at 1×102 PFU. Further, flow cytometry showed that number of CD8+ T cells continuously increased in 1×102 PFU-virus-infected lungs from 2 dpi, but not in 1×105 PFU-virus-infected lungs. In spleens, responses to the virus were prominent from 2 dpi, and number of B cells was significantly decreased at 1×105 PFU; however, 1×102 PFU of virus induced very weak responses from 2 dpi which recovered by 10 dpi. Although the defense responses returned to normal and the mice survived, lung histology showed evidence of fibrosis, suggesting sequelae of SARS-CoV-2 infection. Our findings indicate that specific effectors of the immune response in the lung and spleen were either increased or depleted in response to doses of SARS-CoV-2. This study demonstrated that the response of local and systemic immune effectors to a viral infection varies with viral dose, which either exacerbates the severity of the infection or accelerates its elimination.
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BACKGROUND: The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to approximately 500 million cases and 6 million deaths worldwide. Previous investigations into the pathophysiology of SARS-CoV-2 primarily focused on peripheral blood mononuclear cells from patients, lacking detailed mechanistic insights into the virus's impact on inflamed tissue. Existing animal models, such as hamster and ferret, do not faithfully replicate the severe SARS-CoV-2 infection seen in patients, underscoring the need for more relevant animal system-based research. METHODS: In this study, we employed single-cell RNA sequencing (scRNA-seq) with lung tissues from K18-hACE2 transgenic (TG) mice during SARS-CoV-2 infection. This approach allowed for a comprehensive examination of the molecular and cellular responses to the virus in lung tissue. FINDINGS: Upon SARS-CoV-2 infection, K18-hACE2 TG mice exhibited severe lung pathologies, including acute pneumonia, alveolar collapse, and immune cell infiltration. Through scRNA-seq, we identified 36 different types of cells dynamically orchestrating SARS-CoV-2-induced pathologies. Notably, SPP1+ macrophages in the myeloid compartment emerged as key drivers of severe lung inflammation and fibrosis in K18-hACE2 TG mice. Dynamic receptor-ligand interactions, involving various cell types such as immunological and bronchial cells, defined an enhanced TGFß signaling pathway linked to delayed tissue regeneration, severe lung injury, and fibrotic processes. INTERPRETATION: Our study provides a comprehensive understanding of SARS-CoV-2 pathogenesis in lung tissue, surpassing previous limitations in investigating inflamed tissues. The identified SPP1+ macrophages and the dysregulated TGFß signaling pathway offer potential targets for therapeutic intervention. Insights from this research may contribute to the development of innovative diagnostics and therapies for COVID-19. FUNDING: This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2020M3A9I2109027, 2021R1A2C2004501).
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COVID-19 , Melfalán , gammaglobulinas , Animales , Cricetinae , Ratones , Humanos , SARS-CoV-2 , Leucocitos Mononucleares , Hurones , Bronquios , Factor de Crecimiento Transformador beta , Ratones Transgénicos , Modelos Animales de Enfermedad , PulmónRESUMEN
Soil contamination is associated with a high potential for health issues. This study aimed to investigate the bioaccumulation of heavy metals and its associated health impact among residents near a mining area. We performed environmental monitoring by analyzing lead (Pb), cadmium (Cd), and arsenic (As) levels in soil and rice samples, as well as biomonitoring by analyzing blood and urine samples from 58 residents living near the mine. Additionally, concentration trends were investigated among 26 participants in a 2013 study. The Cd and As levels in the soil samples and Cd levels in the rice samples exceeded the criteria for concern. The geometric mean blood Cd level (2.12 µg/L) was two times higher than that in the general population aged > 40 years. The blood Cd level showed decreasing trends from the previous measurements of 4.56-2.25 µg/L, but was still higher than that in the general population. The blood and urine Cd levels were higher in those with a low estimated glomerular filtration rate (eGFR) than in those with normal eGFR. In conclusion, heavy metals from mining areas can accumulate in soil and rice, adversely impacting human health. Continuous environmental monitoring and biomonitoring are required to ensure the safety of residents.
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Atopic dermatitis (AD) is characterized as a multi-factorial inflammatory skin disease that has been increasing worldwide. Previously, we demonstrated that FPG, which is Platycodon grandiflorum (PG) fermented by Lactobacillus plantarum (LP), increases the level of interferon (IFN)-gamma in mouse splenocytes in vitro. In this study, we investigated the effects of FPG in an animal model of AD, with a particular emphasis on its effects on T helper (Th)1 and Th2 immune responses. To assess the potential use of FPG for the inhibition of AD, we established a model of AD-like skin lesions in NC/Nga mice. Immunoglobulin isotypes (Igs) and Th1/Th2 cytokines in the sera and spleens of AD-like mice were examined. In addition, histological examination was also performed. AD symptoms in skin lesions improved following oral administration of FPG. IgE secretion was significantly down-regulated, and this was accompanied by decreased levels of interleukin (IL)-4 and IgG1 and increased serum levels of IL-12p40 and IgG2a in FPG-treated animals. In splenocytes, the production of the Th1 cytokines IL-12p40 and IFN-gamma was up-regulated, while the levels of the Th2 cytokines IL-4 and 5 were down-regulated by FPG treatment. These results suggest that FPG inhibits the development of AD-like skin lesions in NC/Nga mice by suppressing the Th2 cell response and increasing the Th1 cell responses. Our results indicate that FPG is safe and effective for the prevention of AD-like skin lesions.
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Dermatitis Atópica/tratamiento farmacológico , Inmunoglobulina E/metabolismo , Lactobacillus plantarum , Fitoterapia , Preparaciones de Plantas/uso terapéutico , Platycodon , Balance Th1 - Th2/efectos de los fármacos , Animales , Citocinas/metabolismo , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Modelos Animales de Enfermedad , Fermentación , Inmunoglobulina G/sangre , Masculino , Ratones , Ratones Endogámicos , Preparaciones de Plantas/farmacología , Piel/efectos de los fármacos , Bazo/citología , Bazo/metabolismo , Células TH1/metabolismo , Células Th2/metabolismoRESUMEN
To examine the prevalence of the Type D construct using the Korean version of the Type D Personality-14 (DS14) on the Korean youth population and to identify relationships between the Type D construct and other mental health measures. Adolescent participants aged 13-18 years were recruited from 12 schools (7 middle schools and 5 high schools) in Ansan city, located in the southwest area of Gyeonggi-do province, Korea. A total of 4,899 students were assessed with the Korean version of the DS14, Beck depression inventory (BDI), Korean Eppendorf Schizophrenia Inventory (K-ESI), Adolescent Mental health Problem behavior Questionnaire (AMPQ), and Alcohol Use Disorders Identification Test-Korean version (AUDIT-K). We found significant differences in all the measured scales and subscale scores between two groups, those with Type D personality and those without (BDI: p < 0.001, K-ESI: p < 0.001, AMPQ: p < 0.001, AUDIT-K: p < 0.001). When comparing the distributions of the high risk participants identified by the results of BDI, K-ESI, AMPQ, and AUDIT-K between participants with either Type D or non-Type D personality, a significantly higher proportion of high risk participants were in the Type D personality group according to all measures (BDI: p < 0.001, K-ESI: p < 0.001, AMPQ: p < 0.001, AUDIT-K: p < 0.001). In conclusions, Type D adolescents experience various and more severe mental health problems. Type D personality was more related with internalizing symptoms in Korean adolescents. DS14 can be useful in a community mental health program designed for adolescents.
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Pueblo Asiatico/psicología , Personalidad , Adolescente , Depresión , Femenino , Encuestas Epidemiológicas , Humanos , Inhibición Psicológica , Masculino , República de Corea/epidemiología , Conducta SocialRESUMEN
Metabolic reprogramming is an important cancer hallmark. However, the mechanisms driving metabolic phenotypes of cancer cells are unclear. Here, we show that the interferon-inducible (IFN-inducible) protein viperin drove metabolic alteration in cancer cells. Viperin expression was observed in various types of cancer and was inversely correlated with the survival rates of patients with gastric, lung, breast, renal, pancreatic, or brain cancer. By generating viperin knockdown or stably expressing cancer cells, we showed that viperin, but not a mutant lacking its iron-sulfur cluster-binding motif, increased lipogenesis and glycolysis via inhibition of fatty acid ß-oxidation in cancer cells. In the tumor microenvironment, deficiency of fatty acids and oxygen as well as production of IFNs upregulated viperin expression via the PI3K/AKT/mTOR/HIF-1α and JAK/STAT pathways. Moreover, viperin was primarily expressed in cancer stem-like cells (CSCs) and functioned to promote metabolic reprogramming and enhance CSC properties, thereby facilitating tumor growth in xenograft mouse models. Collectively, our data indicate that viperin-mediated metabolic alteration drives the metabolic phenotype and progression of cancer.
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Interferones , Neoplasias , Humanos , Ratones , Animales , Interferones/genética , Interferones/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias/patología , Glucólisis , Células Madre Neoplásicas/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Microambiente TumoralRESUMEN
BACKGROUND: As the number of large-scale studies involving multiple organizations producing data has steadily increased, an integrated system for a common interoperable format is needed. In response to the coronavirus disease 2019 (COVID-19) pandemic, a number of global efforts are underway to develop vaccines and therapeutics. We are therefore observing an explosion in the proliferation of COVID-19 data, and interoperability is highly requested in multiple institutions participating simultaneously in COVID-19 pandemic research. RESULTS: In this study, a laboratory information management system (LIMS) approach has been adopted to systemically manage various COVID-19 non-clinical trial data, including mortality, clinical signs, body weight, body temperature, organ weights, viral titer (viral replication and viral RNA), and multiorgan histopathology, from multiple institutions based on a web interface. The main aim of the implemented system is to integrate, standardize, and organize data collected from laboratories in multiple institutes for COVID-19 non-clinical efficacy testings. Six animal biosafety level 3 institutions proved the feasibility of our system. Substantial benefits were shown by maximizing collaborative high-quality non-clinical research. CONCLUSIONS: This LIMS platform can be used for future outbreaks, leading to accelerated medical product development through the systematic management of extensive data from non-clinical animal studies.
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[This corrects the article DOI: 10.3389/fimmu.2022.1055811.].
RESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has been a global health concern since 2019. The viral spike protein infects the host by binding to angiotensin-converting enzyme 2 (ACE2) expressed on the cell surface, which is then processed by type II transmembrane serine protease. However, ACE2 does not react to SARS-CoV-2 in inbred wild-type mice, which poses a challenge for preclinical research with animal models, necessitating a human ACE2 (hACE2)-expressing transgenic mouse model. Cytokeratin 18 (K18) promoter-derived hACE2 transgenic mice [B6.Cg-Tg(K18-ACE2)2Prlmn/J] are widely used for research on SARS-CoV-1, MERS-CoV, and SARS-CoV-2. However, SARS-CoV-2 infection is lethal at ≥105 PFU and SARS-CoV-2 target cells are limited to type-1 alveolar pneumocytes in K18-hACE2 mice, making this model incompatible with infections in the human lung. Hence, we developed lung-specific SARS-CoV-2 infection mouse models with surfactant protein B (SFTPB) and secretoglobin family 1a member 1 (Scgb1a1) promoters. After inoculation of 105 PFU of SARS-CoV-2 to the K18-hACE2, SFTPB-hACE2, and SCGB1A1-hACE2 models, the peak viral titer was detected at 2 days post-infection and then gradually decreased. In K18-hACE2 mice, the body temperature decreased by approximately 10°C, body weight decreased by over 20%, and the survival rate was reduced. However, SFTPB-hACE2 and SCGB1A1-hACE2 mice showed minimal clinical signs after infection. The virus targeted type I pneumocytes in K18-hACE2 mice; type II pneumocytes in SFTPB-hACE2 mice; and club, goblet, and ciliated cells in SCGB1A1-hACE2 mice. A time-dependent increase in severe lung lesions was detected in K18-hACE2 mice, whereas mild lesions developed in SFTPB-hACE2 and SCGB1A1-hACE2 mice. Spleen, small intestine, and brain lesions developed in K18-hACE2 mice but not in SFTPB-hACE2 and SCGB1A1-hACE2 mice. These newly developed SFTPB-hACE2 and SCGB1A1-hACE2 mice should prove useful to expand research on hACE2-mediated respiratory viruses.