USP14 promotes K63-linked RIG-I deubiquitination and suppresses antiviral immune responses.

Retinoic acid-inducible gene I (RIG-I) is a critical RNA virus sensor that initiates antiviral immune response through K63-linked ubiquitination. In this study, we demonstrated USP14, a deubiquitinating enzyme, as a negative regulator in antiviral responses by directly deubiquitinating K63-linked RIG-I. USP14 knockdown significantly enhanced RIG-I-triggered type I IFN signaling and inhibited vesicular stomatitis virus (VSV) replication both in mouse peritoneal macrophages and THP1 cells. USP14 overexpression in HeLa cells attenuated RIG-I-triggered IFN-ß expression and promoted VSV replication. Besides, USP14-specific inhibitor, IU1, increased RIG-I-mediated type I IFN production and antiviral responses in vitro and in vivo. In addition, USP14 could interact with RIG-I and remove RIG-I K63-linked polyubiquitination chains. This article is the first to report that USP14 acts as a negative regulator in antiviral response through deubiquitinating K63-linked RIG-I. These findings provide insights into a potential new therapy targeting USP14 for RNA virus-related diseases.

[Screening and antibacterial function of Bacillus amyloliquefaciens X030].

OBJECTIVE: We isolated 339 bacillus strains from 72 soil samples all over the country, then purified their antimicrobial compounds and studied the antibacterial activity, to enrich bacillus resources and explore their second metabolites. METHODS: A bacillus strain with strong antibacterial activity was selected by dilution plate and water bath heating from a soil sample from a peanut plantation in Henan Province; this strain was identified according to morphological observation, physiological and biochemical characteristics, and consequences of 16S rRNA homologous analysis. Antibacterial compound from the identified strain, Bacillus amyloliquefaciens X030, was separated and purified by acetone precipitation, Sephadex chromatography, C18 reverse phase column chromatography. Its molecular weight was analyzed by LC-MS/MS. The antibacterial activity was characterized by disc diffusion and plate two-way cultivation. RESULTS: Bacillus amyloliquefaciens was isolated that not only has antibacterial activity against Staphylococcus aureus, Candida albican and Saccharomycetes; but also against Pyriculariaoryzae, Chili pointed cell anthrax, Gloeosporium eriobotryae speg and Phytophthora parasitica. The compound was confirmed as polypeptide. CONCLUSION: Bacillus amyloliquefaciens X030 can produce a polypeptide that inhibits pathogenic bacteria and plant pathogenic fungi.

A Scale for Measuring Electronic Patient Engagement Behaviors: Development and Validation.

Purpose: Advancements in electronic health (eHealth) technology have profoundly impacted patient engagement. This study aimed to develop and validate the Electronic Patient Engagement Behavior (EPEB) scale to measure the conceptual and underlying framework of patient engagement behaviors in an eHealth context. Patients and Methods: Initial measurement items were generated based on a literature review and qualitative research. Two rounds of surveys, a pilot survey and validation survey, were conducted to evaluate the psychometric properties of the scale. Results: The EPEB scale consists of 15 items in four dimensions: disease information search, physician-patient interaction, social interaction between patients, and disease self-monitoring. In the pilot survey, the exploratory factor analysis revealed a four-factor model, explaining 69.411% of variance. In the validation survey, the Cronbach's α coefficient of each sub-scale was 0.865, 0.904, 0.904, and 0.900 respectively. The Spearman-Brown split coefficient of the scale was 0.963. The results of the cross-sex measurement equivalence test indicate that all fit indices met the measurement criteria. The confirmatory factor analysis indicated second-order 4-factor model fit the data well. The EPEB has a good reliability and validity. Conclusion: The EPEB scale provides a reliable tool for measuring patient engagement behaviors in the eHealth context. The utilization of this scale may yield valuable insights into strategies for enhancing patient engagement and optimizing health outcomes.

MEF2C promotes M1 macrophage polarization and Th1 responses.

The polarization of macrophages to the M1 or M2 phenotype has a pivotal role in inflammation and host defense; however, the underlying molecular mechanism remains unclear. Here, we show that myocyte enhancer factor 2 C (MEF2C) is essential for regulating M1 macrophage polarization in response to infection and inflammation. Global gene expression analysis demonstrated that MEF2C deficiency in macrophages downregulated the expression of M1 phenotypic markers and upregulated the expression of M2 phenotypic markers. MEF2C significantly promoted the expression of interleukin-12 p35 subunit (Il12a) and interleukin-12 p40 subunit (Il12b). Myeloid-specific Mef2c-knockout mice showed reduced IL-12 production and impaired Th1 responses, which led to susceptibility to Listeria monocytogenes infection and protected against DSS-induced IBD in vivo. Mechanistically, we showed that MEF2C directly activated the transcription of Il12a and Il12b. These findings reveal a new function of MEF2C in macrophage polarization and Th1 responses and identify MEF2C as a potential target for therapeutic intervention in inflammatory and autoimmune diseases.

ß-coronavirus infectious diseases: recommended strategies for the prevention and control of transmission.

In recent years, the incidence and mortality of infectious diseases in China are increasing. Infectious diseases, especially new infectious diseases, seriously threaten people's lives. Recent works found that most of the emerging infectious diseases come from wild life. At the same time, the impact of human activities on the environment has further deteriorated the living environment of wildlife. However, with the conducted in-depth research on virus, human beings increase the risk of getting infected. Taking Beta Coronavirus as the example, we analyzed the transmission risks of coronavirus in the prevention and control of the outbreaks of emerging infectious diseases, and recommend the prevention and control strategies before, during and after the viral outbreak. Additional works are urgently needed to better define the biological and epidemiological characteristics of these viruses.

Impact of the Inflow Population From Outbreak Areas on the COVID-19 Epidemic in Yunnan Province and the Recommended Control Measures: A Preliminary Study.

Background: COVID-19 developed into a global pandemic in 2020 and poses challenges regarding the prevention and control capabilities of countries. A large number of inbound travelers from other regions could lead to a renewed outbreak of COVID-19 in the local regions. Globally, as a result of the imbalance in the control of the epidemic, all countries are facing the risk of a renewed COVID-19 outbreak brought about by travelers from epidemic areas. Therefore, studies on a proper management of the inbound travelers are urgent. Methods: We collected a total of 4,733,414 inbound travelers and 174 COVID-19 diagnosed patients in Yunnan province from 21 January 2020 to 20 February 2020. Data on place of origin, travel history, age, and gender, as well as whether they had suspected clinical manifestations for inbound travelers in Yunnan were collected. The impact of inbound travelers on the local epidemic was analyzed with a collinear statistical analysis and the effect of the control measures on the epidemic was evaluated with a sophisticated modeling approach. Results: Of the 174 COVID-19 patients, 60.9% were not from Yunnan, and 76.4% had a history of travel in Hubei. The amount of new daily cases in Yunnan was significant correlated with the number of inbound travelers from Hubei and suspected cases among them. Using Susceptible-Exposed-Infectious-Recovered (SEIR) model analysis, we found that the prevention and control measures dropped the local R0 down to 1.07 in Yunnan province. Conclusions: Our preliminary analysis showed that the proper management of inbound travelers from outbreak areas has a significantly positive effect on the prevention and control of the virus. In the process of resettlement, some effective measures taken by Yunnan province may provide an important reference for preventing the renewed COVID-19 outbreak in other regions.

P22077 inhibits LPS-induced inflammatory response by promoting K48-linked ubiquitination and degradation of TRAF6.

Inflammation is a biological process associated with multiple human disorders such as autoimmune diseases and metabolic diseases. Therefore, alleviation of inflammation is important for disease prevention or treatment. Recently, deubiquitinating enzymes (DUBs), especially ubiquitin specific protease-7 (USP7) attracts increasing attention as a potential drug target for inflammation. As an inhibitor of USP7, P22077 has been used to study the roles of USP7 in inflammatory response and neuroblastoma growth. However, the role and precise mechanism of P22077 in anti-inflammatory is still indistinct. In this study, we demonstrated that P22077 could attenuate the release of pro-inflammatory factors including TNF-α, IL-1ß, IL-6 and NO, suppress mRNA expression of COX-2 and iNOS, and inhibit activation of NF-κB and MAPKs signaling pathways in Raw264.7 cells and mouse peritoneal macrophages after LPS stimulation. In vivo study showed that P22077 could relieve inflammatory response and reduce the lung injury in C57BL/6 mice with LPS-induced endotoxemia. Mechanically, P22077 might play an anti-inflammatory role by promoting tumor necrosis factor receptor-associated factor 6 (TRAF6) degradation via K48-linked polyubiquitination. These findings provide a rationale for the role of the P22077 in anti-inflammatory pathway and the promising clinical application of P22077 to treat inflammatory diseases.

Cirsitakaoside isolated from Premna szemaoensis reduces LPS-induced inflammatory responses in vitro and in vivo.

Cirsitakaoside is a natural compound isolated from Premna szemaoensis. However, the anti-inflammatory effects of cirsitakaoside are poorly understood. We investigated the anti-inflammatory action of cirsitakaoside in lipopolysaccharide (LPS)-stimulated macrophages and mice in vivo. Cirsitakaoside could suppress the production of pro-inflammatory cytokines such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in a dose-dependent manner in LPS-stimulated mouse peritoneal macrophages and RAW264.7 cells. Cirsitakaoside also could inhibit inducible nitric oxide synthase (iNOS) mRNA and cyclooxygenase-2 (COX-2) mRNA expression in LPS-stimulated mouse peritoneal macrophages and RAW264.7 cells. These effects were partially carried out by inactivated nuclear factor-κB (NF-κB) and Mitogen-activated protein kinases (MAPKs) pathway via inhibiting the phosphorylation of the IKKα/ß, IκBα and c-Jun N-terminal kinase/stress-activated protein kinase (JNK) in LPS-stimulated murine macrophages. In vivo, we showed that cirsitakaoside could relieve LPS-induced inflammation response. These results suggest that cirsitakaoside has the potential anti-inflammatory effect for treatment of inflammation diseases.

Teuvincenone F Suppresses LPS-Induced Inflammation and NLRP3 Inflammasome Activation by Attenuating NEMO Ubiquitination.

Inflammation causes many diseases that are serious threats to human health. However, the molecular mechanisms underlying regulation of inflammation and inflammasome activation are not fully understood which has delayed the discovery of new anti-inflammatory drugs of urgent clinic need. Here, we found that the natural compound Teuvincenone F, which was isolated and purified from the stems and leaves of Premna szemaoensis, could significantly inhibit lipopolysaccharide (LPS)-induced pro-inflammatory cytokines production and NLRP3 inflammasome activation. Our results showed that Teuvincenone F attenuated K63-linked ubiquitination of NF-κB-essential modulator (NEMO, also known as IKKγ) to suppress LPS-induced phosphorylation of NF-κB, and inhibited mRNA expression of IL-1ß, IL-6, TNF-α, and NLRP3. In addition, we found that decreased NLRP3 expression by Teuvincenone F suppressed NLRP3 inflammasome activation and IL-1ß/IL-18 maturation. In vivo, we revealed that Teuvincenone F treatment relieved LPS-induced inflammation. In conclusion, Teuvincenone F is a highly effective natural compound to suppress LPS-induced inflammation by attenuating K63-linked ubiquitination of NEMO, highlighting that Teuvincenone F may be a potential new anti-inflammatory drug for the treatment of inflammatory and NLRP3 inflammasome-driven diseases.