BACKGROUND
Hepatitis E virus (HEV) is a leading cause of acute hepatitis. The long-term efficacy of a hepatitis E vaccine needs to be determined.


METHODS
In an initial efficacy study, we randomly assigned healthy adults 16 to 65 years of age to receive three doses of either a hepatitis E vaccine (vaccine group; 56,302 participants) or a hepatitis B vaccine (control group; 56,302 participants). The vaccines were administered at 0, 1, and 6 months, and the participants were followed for 19 months. In this extended follow-up study, the treatment assignments of all participants remained double-blinded, and follow-up assessments of efficacy, immunogenicity, and safety were continued for up to 4.5 years.


RESULTS
During the 4.5-year study period, 60 cases of hepatitis E were identified; 7 cases were confirmed in the vaccine group (0.3 cases per 10,000 person-years), and 53 cases in the control group (2.1 cases per 10,000 person-years), representing a vaccine efficacy of 86.8% (95% confidence interval, 71 to 94) in the modified intention-to-treat analysis, rather than (95% confidence interval, 71 to 84) [corrected]. Of the participants who were assessed for immunogenicity and were seronegative at baseline, 87% of those who received three doses of the hepatitis E vaccine maintained antibodies against HEV for at least 4.5 years; HEV antibody titers developed in 9% in the control group. The rate of adverse events was similar in the two groups.


CONCLUSIONS
Immunization with this hepatitis E vaccine induced antibodies against HEV and provided protection against hepatitis E for up to 4.5 years. (Funded by the Chinese Ministry of Science and Technology and others; ClinicalTrials.gov number, NCT01014845.).

Long-Term Efficacy of a Hepatitis E Vaccine ; 戊型肝炎疫苗的长期保护效果

This study aims to gain deeper insight into HEV-induced innate immunity by characterizing the crosstalk between the virus and the host factor guanylate-binding protein 1 (GBP1). We observe that the amount of GBP1 is elevated upon infection, although number of transcripts is decreased, which is explained by a prolonged protein half-life. Modulation of GBP1 levels via overexpression significantly inhibits the viral life cycle. Use of various GBP-1 mutants revealed that the antiviral effect of GBP-1 on HEV is independent from the GTPase-activity, but depends on the capacity of GBP-1 to form GBP1 homodimers. This connects GBP-1 to the autophagosomal pathway. Indeed, dimerization competent GBP1 targets the viral capsid protein to the lysosomal compartment leading to inactivation of the viral particle. Most importantly, silencing of GBP1 abolishes the antiviral effect of IFNγ on HEV. In IFNγ treated cells the virus is targeted to lysosomal structures and destroyed therein. This process depends in part on GBP1. These observations about the relevance of GBP1 for type II interferon-mediated innate immunity against HEV could be a base for tailoring novel antivirals and improvement of disease management.IMPORTANCE Although HEV represents a worldwide public health problem with 20 million infections and 44.000 death cases per year, there are still no specific antivirals available and many aspects of the viral life cycle are not well understood. Here we identify the guanylate binding protein 1 (GBP1) as a restriction factor affecting life cycle of HEV. Surprisingly, the antiviral effect of GBP1 does not depend on its GTPase function, but on its capacity to homodimerize. We revealed that GBP1 exerts its antiviral activity by targeting HEV to the lysosomal compartment where the virus is inactivated. Most importantly, we observed that the antiviral effect of interferon-γ on HEV strongly depends on GBP1. Our observation that GBP1 impairs HEV and is crucial for the antiviral effect of interferons on HEV extends understanding of host defense-mechanisms. As the interferon-system represents a universal defense-mechanism, our study could help to design novel antivirals targeting.

Identification of the interferon-inducible GTPase GBP1 as major restriction factor for the Hepatitis E virus.

Chronic hepatitis B virus (HBV) infection is an international health problem with extremely high mortality and morbidity rates. Although current clinical chronic hepatitis B (CHB) treatment strategies can partly inhibit and eliminate HBV, viral breakthrough may result due to non-adherence to treatment, the emergence of viral resistance, and a long treatment cycle. Persistent CHB infection arises as a consequence of complex interactions between the virus and the host innate and adaptive immune systems. Therefore, understanding the immune escape mechanisms involved in persistent HBV infection is important for designing novel CHB treatment strategies to clear HBV and achieve long-lasting immune control. This review details the immunological and biological characteristics and escape mechanisms of HBV and the novel immune-based therapies that are currently used for treating HBV.

Innate and adaptive immune escape mechanisms of hepatitis B virus

Hepatitis B virus (HBV) is a major aetiology associated with the development and progression of hepatocellular carcinoma (HCC), the most common primary liver malignancy. Over the past few decades, direct and indirect mechanisms have been identified in the pathogenesis of HBV‐associated HCC which include altered signaling pathways, genome integration, mutation‐induced genomic instability, chromosomal deletions and rearrangements. Intertwining of the HBV counterparts with the host cellular factors, though well established, needs to be systemized to understand the dynamics of host‐HBV crosstalk and its consequences on HCC progression. Existence of a vast array of protein–protein and protein‐nucleic acid interaction databases has led to the uncoiling of the compendia of genes/gene products associated with these interactions. This review covers the existing knowledge about the HBV‐host interplay and brings it down under one canopy emphasizing on the HBV‐host interactomics; and thereby highlights new strategies for therapeutic advancements against HBV‐induced HCC.

The HBV web: An insight into molecular interactomes between the hepatitis B virus and its host en route to hepatocellular carcinoma

Inflammasomes, particularly the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 (NLRP3) inflammasome, apparently serve as crucial regulators of the inflammatory response through the activation of Caspase-1 and induction of pro-inflammatory cytokines and pyroptotic cell death. Pyroptosis is a type of programmed cell death mediated by Caspase-1 cleavage of Gasdermin D and the insertion of its N-terminal fragment into the plasma membrane, where it forms pores, enabling the release of different pro-inflammatory mediators. Pyroptosis is considered not only a pro-inflammatory pathway involved in liver pathophysiology but also an important pro-fibrotic mediator. Diverse molecular mechanisms linking oxidative stress, inflammasome activation, pyroptosis, and the progression of liver pathologies have been documented. Numerous studies have indicated the protective effects of several antioxidants, with the ability to induce nuclear factor erythroid 2-related factor 2 (Nrf2) activity on liver inflammation and fibrosis. In this review, we have summarised recent studies addressing the role of the NLRP3 inflammasome and pyroptosis in the pathogenesis of various hepatic diseases, highlighting the potential application of Nrf2 inducers in the prevention of pyroptosis as liver protective compounds.

/pdf/nlrp3-inflammasome-and-pyroptosis-in-liver-pathophysiology-3utmaoe6.pdf

NLRP3 Inflammasome and Pyroptosis in Liver Pathophysiology: The Emerging Relevance of Nrf2 Inducers

Hepatitis B virus (HBV) has four open reading frames (ORFs) of which ORF C is consists of the pre Core and Core genes encodes the Hepatitis B core antigen (HBcAg) and Hepatitis B e antigen (HBeAg). Studies have shown that HBeAg significantly inhibits the NLRP3 inflammasome activation and interleukin-1β (IL-1β) production. However, the role of HBcAg and ORF C proteins (in this paper, ORF C proteins = HBcAg + HBeAg) were remain unclear. Our study aims to assess whether HBcAg and ORF C proteins can affect the NLRP3 inflammasome pathway. Vectors expressing ORF C proteins and HBcAg were designed and transfected into HepG2 cells. And then, cells were stimulated with lipopolysaccharide (LPS). Activation of the NLRP3 inflammasome and the levels of IL-1β and IL-18 were evaluated by Western blot analysis, quantitative reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunofluorescence. The expression of NLRP3 and IL-1β peaked when HepG2 cells were stimulated with 1000 ng/mL LPS for 18 to 24 hours. HBcAg, but not ORF C proteins, promoted LPS-induced NLRP3 inflammasome activation and IL-1β production. These findings provide a novel mechanism on how the HBV causes liver inflammation and may provide insights into the search for new therapeutic strategies.

Hepatitis B core antigen can regulate NLRP3 inflammasome pathway in HepG2 cells.

Background & aims Hepatitis B virus (HBV) infection is the most critical factor underlying liver cirrhosis and hepatocellular carcinoma worldwide. IL-1β and IL-18, generated by activation of the inflammasome/caspase-1 signaling pathway, play important roles in the control and clearance of HBV. However, the specific relationship between the inflammasome response and IFN-α resistance or viral persistence is yet to be established. Methods Blood samples of patients and supernatant fractions of HBV cell lines were collected for analysis and the effects on inflammasome activation and IL-1β production evaluated via enzyme-linked immunosorbent assay (ELISA), western blot, quantitative RT-PCR and immunofluorescence. Results IL-1β and IL-18 levels produced in sera of IFN-α non-responders were significantly lower than those of responders and normal donors. Additionally, expression of IL-1β and inflammasome components was decreased in peripheral blood mononuclear cells (PBMC) of non-responders, compared with those of responders. In vitro experiments on HepG2, HepG2.2.15 and HepAD38 cell lines showed that HBV induces a significant decrease in IL-1β production through inhibiting activation of the NF-κB signaling and inflammasome/caspase-1 pathways. And hepatitis B virus polymerase (HBV-Pol) appeared crucial for these inhibitory effects of HBV. Conclusion IL-1β production is suppressed in HBV carriers and IFN-α non-responders. HBV induces a significant decrease in IL-1β production through inhibiting the NF-κB signaling and inflammasome pathways, for which HBV-Pol is a crucial requirement. Trial approval number: 20 173 402.

HBV-Pol is crucial for HBV-mediated inhibition of inflammasome activation and IL-1β production.

To study the clinical effects of Ω toenail correction in the treatment of paronychia. One hundred thirty-six cases of 130 patients during the period from August 2018 to August 2021 were treated with Ω toenail correction according to clinical stages, the clinical therapeutic effects of which were evaluated in terms of the operation time, the time to resume movement, treatment cycle, 1-y recurrence rate, and visual analogue scale (VAS) scores before and after treatment. The clinical efficacy was analyzed and compared of Ω toenail correction in treating paronychia of different clinical stages. It has been demonstrated that there was no significant difference in operation time, time to resume movement, treatment cycle and recurrence rate among different stages of paronychia, while there existed the significant difference (p < .05) in VAS score of resting-state pain before and after correction which stood at 6.43 ± 0.29 points with the after-treatment VAS scores at 1.10 ± 0.22. There is a statistical difference (p < .05) in VAS score of movement-evoked pain between before and after treatment. The VAS scores of movement-evoked pain stood at 7.55 ± 0.42, which is in contrast with the after-treatment VAS at 1.74 ± 0.93. It has been concluded that Ω toenail correction characterized by easy operation can relieve the pain immediately, which can achieve satisfactory clinical efficacy for treating paronychia of different stages. 

A Study on the Efficacy of Ω Toenail Correction Treating paronychia.

Fracture of the os peroneum is rare, and displacement of the fracture can be indicative of a tear in the peroneal longus tendon. A fifth metatarsal base fracture is a common injury caused by sudden inversion and plantar flexion of the hindfoot. We observed a rare case of a fifth metatarsal base zone I fracture combined with a displaced os peroneum fracture in a 34-year-old woman. The patient was treated with resection of the os peroneum and repair of the peroneal longus tendon, as well as open reduction and internal fixation of the fifth metatarsal base. After exposing the fragment of the fifth metatarsal base, the distal part of the fractured os peroneum was found to be located just under the fracture site. There were no complications or discomfort of the foot or ankle at 2 years postoperatively. Resection of the os peroneum and direct repair of the peroneal longus tendon were easily performed after the fifth metatarsal base fragment was exposed. This was an innovative method for performing peroneal longus tendon repair in the deep portion of the midfoot.

Fifth Metatarsal Base Fracture Combined With Fracture of the Os Peroneum

Hepatitis E is the most common type of acute hepatitis prevalent worldwide. The open reading frame 3 protein of HEV (HEV ORF3) is proposed to create a favorable environment for viral replication and pathogenesis. However, the mechanisms by which HEV overcomes the effects of host immunity, particularly the role of ORF3, remain to be established. Expression of IFNα and IFNβ in supernatant and cell samples was examined via ELISA and quantitative RT-PCR. The protein levels of specific signaling factors in cells overexpressing HEV ORF3 were examined via western blot. Analyses of cells transfected with vectors expressing ORF3 demonstrated that HEV ORF3 significantly impairs the generation of endogenous type I interferon through downregulating TLR3 and TLR7 as well as their corresponding downstream signaling pathways. Moreover, inhibition of NFκB, JAK/STAT and JNK/MAPK signaling pathways contributed significantly to suppression of increased levels of TLR7. Levels of p-P65, p-STAT1 and p-JNK were markedly impaired in ORF3-expressing cells, even upon treatment with the respective agonists. HEV ORF3 inhibits the production of endogenous type I interferon through downregulation of TLR3 and TLR7. Furthermore, suppression of TLR7 is achieved through impairment of multiple signaling pathways, including NFκB, JAK/STAT and JNK/MAPK.

HEV ORF3 downregulates TLR7 to inhibit the generation of type I interferon via impairment of multiple signaling pathways.

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