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Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that places a heavy strain on public health. Host susceptibility to Mtb is modulated by macrophages, which regulate the balance between cell apoptosis and necrosis. However, the role of molecular switches that modulate apoptosis and necrosis during Mtb infection remains unclear. Here, we show that Mtb-susceptible mice and TB patients have relatively low miR-342-3p expression, while mice with miR-342-3p overexpression are more resistant to Mtb. We demonstrate that the miR-342-3p/SOCS6 axis regulates anti-Mtb immunity by increasing the production of inflammatory cytokines and chemokines. Most importantly, the miR-342-3p/SOCS6 axis participates in the switching between Mtb-induced apoptosis and necrosis through A20-mediated K48-linked ubiquitination and RIPK3 degradation. Our findings reveal several strategies by which the host innate immune system controls intracellular Mtb growth via the miRNA-mRNA network and pave the way for host-directed therapies targeting these pathways.
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MicroARNs , Mycobacterium tuberculosis , Tuberculosis , Animales , Muerte Celular , Humanos , Inflamación/genética , Ratones , MicroARNs/genética , Mycobacterium tuberculosis/genética , Proteínas Supresoras de la Señalización de Citocinas , Tuberculosis/genéticaRESUMEN
Inflammation underlies a variety of physiological and pathological processes and plays an essential role in shaping the ensuing adaptive immune responses and in the control of pathogens. However, its physiological functions are not completely clear. Using a LPS-treated RAW264.7 macrophage inflammation model, we found that the production of inflammatory cytokines in ISOC1-deficient cells was significantly higher than that in the control group. It was further proved that ISOC1 deficiency could activate AKT1, and the overactivation of AKT1 could reduce the stability of PEX11B through protein modification, thereby reducing the peroxisome biogenesis and thus affecting inflammation. In this study, we reported for the first time the role of ISOC1 in innate immunity and elucidated the mechanism by which ISOC1 regulates inflammation through AKT1/PEX11B/peroxisome. Our results defined a new role of ISOC1 in the regulatory mechanism underlying the LPS-induced inflammatory response.
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Hidrolasas/metabolismo , Lipopolisacáridos , Peroxisomas , Animales , Citocinas/metabolismo , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Macrófagos/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Peroxisomas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
The purpose of this study was to investigate whether/how digital media exposure influences people's intention to influenza vaccination. Through an anonymous online survey, we collected data on Chinese people's exposure to influenza and influenza vaccine information on digital media platforms and their attitudes toward influenza vaccines (N = 600). The structural equation model analysis results strongly support to the research hypotheses and the proposed model. The findings reveal three major themes: (1) digital media exposure significantly influence the susceptibility and severity of influenza. (2) After exposure to digital media, it is helpful to understand the vaccine's benefits, reduce the barriers to vaccination, and finally improve the intention to vaccination. (3) Users receive cues to action from digital media, and their vaccination intention tends to be positive. These findings explore how digital media exposure influences influenza vaccination intention and may provide insights into vaccine promotion efforts in countries. Research has shown that digital media exposure contributes to getting vaccinated against influenza.
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Objective: To explore whether/how the willingness of Chinese college students to receive the influenza vaccines in the sample is affected by different information channels. Participants: Two hundred and four volunteers were recruited to participate in an anonymous online survey. All participants were college students, mainly undergraduates (81.86%), with a higher proportion of women (56.86%). Methods: Participants answered anonymous questionnaires through the website, including demographic data (age, gender, education, etc.), media exposure channels and frequency, views and attitudes toward influenza vaccines, etc. An ordered logistic regression analysis was conducted to explore the effects of different information sources on influenza vaccination among college students. Results: Exposure to traditional media, digital media, and interpersonal communication promotes college students' understanding of influenza vaccines. Exposure to digital media alleviates college students' hesitation to vaccinate, while interpersonal interaction and digital media exposure promote college students' willingness to vaccinate. Conclusions: Digital media is increasingly important in the lives of Chinese college students to promote healthy behaviors such as influenza vaccinations.
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Vitamin C (VC), in regard to its effectiveness against tumors, has had a controversial history in cancer treatment. However, the anticancer mechanisms of VC are not fully understood. Here, we reported that VC exerted an anticancer effect on cancer cell and xenograft models via inhibiting HIF-1α-dependent cell proliferation and promoting p53-dependent cell apoptosis. To be specific, VC modulated the competitive binding of HIF-1α and p53 to their common E3 ubiquitin ligase CBL, thereby inhibiting tumorigenesis. Moreover, VC treatment activated SIRT1, resulting in p53 deacetylation and CBL-p53 complex dissociation, which in turn facilitated CBL recruitment of HIF-1α for ubiquitination in a proteasome-dependent manner. Altogether, our results provided a mechanistic rationale for exploring the therapeutic use of VC in cancer therapy.
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Neoplasias de la Mama , Ubiquitina-Proteína Ligasas , Ácido Ascórbico/farmacología , Unión Competitiva , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Sirtuina 1/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Introduction: On December 31, 2020, the Chinese government announced that the domestic coronavirus disease-2019 (COVID-19) vaccines have obtained approval for conditional marketing and are free for vaccination. This release drove the attention of the public and intense debates on social media, which reflected public attitudes to the domestic vaccine. This study examines whether the public concerns and public attitudes to domestic COVID-19 vaccines changed after the official announcement. Methods: This article used big data analytics in the research, including semantic network and sentiment analysis. The purpose of the semantic network is to obtain the public concerns about domestic vaccines. Sentiment analysis reflects the sentiments of the public to the domestic vaccines and the emotional changes by comparing the specific sentiments shown on the posts before and after the official announcement. Results: There exists a correlation between the public concerns about domestic vaccines before and after the official announcement. According to the semantic network analysis, the public concerns about vaccines have changed after the official announcement. The public focused on the performance issues of the vaccines before the official approval, but they cared more about the practical issues of vaccination after that. The sentiment analysis showed that both positive and negative emotions increased among the public after the official announcement. "Good" was the most increased positive emotion and indicated great public appreciation for the production capacity and free vaccination. "Fear" was the significantly increased negative emotion and reflected the public concern about the safety of the vaccines. Conclusion: The official announcement of the approval for marketing improved the Chinese public acceptance of the domestic COVID-19 vaccines. In addition, safety and effectiveness are vital factors influencing public vaccine hesitancy.
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COVID-19 , Vacunas , Vacunas contra la COVID-19 , China , Humanos , SARS-CoV-2 , Web Semántica , Análisis de Sentimientos , Vacunación , Vacilación a la VacunaciónRESUMEN
In July 2021, breakthrough cases were reported in the outbreak of COVID-19 in Nanjing, sparking concern and discussion about the vaccine's effectiveness and becoming a trending topic on Sina Weibo. In order to explore public attitudes towards the COVID-19 vaccine and their emotional orientations, we collected 1542 posts under the trending topic through data mining. We set up four categories of attitudes towards COVID-19 vaccines, and used a big data analysis tool to code and manually checked the coding results to complete the content analysis. The results showed that 45.14% of the Weibo posts (n = 1542) supported the COVID-19 vaccine, 12.97% were neutral, and 7.26% were doubtful, which indicated that the public did not question the vaccine's effectiveness due to the breakthrough cases in Nanjing. There were 66.47% posts that reflected significant negative emotions. Among these, 50.44% of posts with negative emotions were directed towards the media, 25.07% towards the posting users, and 11.51% towards the public, which indicated that the negative emotions were not directed towards the COVID-19 vaccine. External sources outside the vaccine might cause vaccine hesitancy. Public opinions expressed in online media reflect the public's cognition and attitude towards vaccines and their core needs in terms of information. Therefore, online public opinion monitoring could be an essential way to understand the opinions and attitudes towards public health issues.
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COVID-19 , Medios de Comunicación Sociales , Vacunas contra la COVID-19 , Brotes de Enfermedades/prevención & control , Humanos , SARS-CoV-2 , Vacilación a la Vacunación , Eficacia de las VacunasRESUMEN
Sepsis is an unusual systemic infection caused by bacteria, which is a life-threatening organ dysfunction. The innate immune system plays an important role in this process; however, the specific mechanisms remain unclear. Using the LPS + treated mouse model, we found that the survival rate of Tgm2-/- mice was lower than that of the control group, while the inflammation was much higher. We further showed that Tgm2 suppressed apoptosis by inhibiting the JNK/BCL-2 signaling pathway. More importantly, Tgm2 interacted with Aga and regulated mitochondria-mediated apoptosis induced by LPS. Our findings elucidated a protective mechanism of Tgm2 during LPS stimulation and may provide a new reference target for the development of novel anti-infective drugs from the perspective of host immunity.
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Aspartilglucosilaminasa/metabolismo , Macrófagos/patología , Proteína Glutamina Gamma Glutamiltransferasa 2/metabolismo , Sepsis/inmunología , Animales , Apoptosis/inmunología , Modelos Animales de Enfermedad , Humanos , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Macrófagos/inmunología , Ratones , Ratones Noqueados , Proteína Glutamina Gamma Glutamiltransferasa 2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Sepsis/patologíaRESUMEN
Recently, COVID-19 caused by the novel coronavirus SARS-CoV-2 has brought great challenges to the world. More and more studies have shown that patients with severe COVID-19 may suffer from cytokine storm syndrome; however, there are few studies on its pathogenesis. Here we demonstrated that SARS-CoV-2 coding protein open reading frame 8 (ORF8) acted as a contributing factor to cytokine storm during COVID-19 infection. ORF8 could activate IL-17 signaling pathway and promote the expression of pro-inflammatory factors. Moreover, we demonstrated that treatment of IL17RA antibody protected mice from ORF8-induced inflammation. Our findings are helpful to understand the pathogenesis of cytokine storm caused by SARS-CoV-2 and provide a potential target for the development of COVID-19 therapeutic drugs.
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Acute liver failure (ALF) is a rare but life-threatening systemic disorder. The innate immune regulation has an important role in this process; however, the specific mechanisms are not completely clear. Using the LPS + D-GalN-induced ALF mouse model, we found that the survival rate of PTPN14-deficient mice was higher than that of the control group, while the release of inflammatory factors was significantly lower. We further showed that PTPN14 interacted with SOCS7, and promoted the degradation of SOCS7 through ubiquitination at K11 and K48, thereby reducing the protein level of SOCS7 and weakening the inhibitory effects on inflammatory factors. More importantly, SOCS7 blocked the NF-κB signaling pathway by preventing the activity of the IKK complex, and then reduced the expression of downstream inflammatory factors. In this study, we firstly reported the inhibitory effect of SOCS7 on the NF-κB pathway in the ALF mouse model and elucidated the mechanism of PTPN14-SOCS7-NF-κB axis in the regulation of inflammation. These results provide new insights into the clinical treatment of ALF.
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Inflamación/genética , Fallo Hepático Agudo/genética , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Fallo Hepático Agudo/metabolismo , Masculino , RatonesRESUMEN
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that poses threats to the public. M. tuberculosis survives in macrophages by escaping from immune surveillance and clearance, which exacerbates the bacterial proliferation. However, the molecular mechanisms of this immune escape have not yet been fully understood. Using multiple cell and mouse models, we found that microRNA-325-3p (miR-325-3p) is upregulated after M. tuberculosis infection and Mir325-deficient mice show resistance to M. tuberculosis We demonstrated that miR-325-3p directly targets LNX1, an E3 ubiquitin ligase of NEK6, and that this hampers the proteasomal degradation of NEK6 in macrophages. The abnormal accumulation of NEK6 leads to the activation of STAT3 signaling, thus inhibiting the process of apoptosis and promoting the intracellular survival of M. tuberculosis Our findings not only reveal a new immune escape pathway of M. tuberculosis but also may provide new insights into the development of therapeutic approaches for drug-resistant TB.IMPORTANCE Intracellular survival of Mycobacterium tuberculosis results in bacterial proliferation and the spread of infection in lungs, consequently deteriorating the conditions of tuberculosis (TB) patients. This research discovers a new immune escape pathway of M. tuberculosis by modulating host miR-325-3p expression, thus leading to the intracellular survival of M. tuberculosis These findings make a contribution to the understanding of the immune escape of M. tuberculosis, and they provide a theoretical basis for the development of therapeutic approaches for drug-resistant TB.