TIM22 and TIM29 inhibit HBV replication by up-regulating SRSF1 expression.

Hepatitis B virus (HBV) infection is a serious global health problem. After the viruses infect the human body, the host can respond to the virus infection by coordinating various cellular responses, in which mitochondria play an important role. Evidence has shown that mitochondrial proteins are involved in host antiviral responses. In this study, we found that the overexpression of TIM22 and TIM29, the members of the inner membrane translocase TIM22 complex, significantly reduced the level of intracellular HBV DNA and RNA and secreted HBV surface antigens and E antigen. The effects of TIM22 and TIM29 on HBV replication and transcription is attributed to the reduction of core promoter activity mediated by the increased expression of SRSF1 which acts as a suppressor of HBV replication. This study provides new evidence for the critical role of mitochondria in the resistance of HBV infection and new targets for the development of treatment against HBV infection.

Antibody-secreting cells as a source of NR1-IgGs in N-methyl-D-aspartate receptor-antibody encephalitis.

BACKGROUND: The pathogenicity of NR1-IgGs in N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis is known, but the immunobiological mechanisms underlying their production remain unclear. METHODS: For the first time, we explore the origin of NR1-IgGs and evaluate the contribution of B-cells to serum NR1-IgGs levels. Peripheral blood mononuclear cells (PBMCs) were obtained from patients and healthy controls (HCs). Naïve, unswitched memory (USM), switched memory B cells (SM), antibody-secreting cells (ASCs), and PBMC depleted of ASCs were obtained by fluorescence-activated cell sorting and cultured in vitro. RESULTS: For some patients, PBMCs spontaneously produced NR1-IgGs. Compared to the patients in PBMC negative group, the positive group had higher NR1-IgG titers in cerebrospinal fluid and Modified Rankin scale scores. The proportions of NR1-IgG positive wells in PBMCs cultures were correlated with NR1-IgGs titers in serum and CSF. The purified ASCs, SM, USM B cells produced NR1-IgGs in vitro. Compared to the patients in ASCs negative group, the positive group exhibited a worse response to second-line IT at 3-month follow-up. Naïve B cells also produce NR1-IgGs, implicating that NR1-IgGs originate from naïve B cells and a pre-germinal centres defect in B cell tolerance checkpoint in some patients. For HCs, no NR1-IgG from cultures was observed. PBMC depleted of ASCs almost eliminated the production of NR1-IgGs. CONCLUSIONS: These collective findings suggested that ASCs might mainly contribute to the production of peripheral NR1-IgG in patients with NMDAR-antibody encephalitis in the acute phase. Our study reveals the pathogenesis and helps develop tailored treatments (eg, anti-CD38) for NMDAR-antibody encephalitis.

Calcitriol suppresses gastric cancer progression and cisplatin resistance by inhibiting glycolysis and M2 macrophage polarization through inhibition of mTOR activation.

The tumor microenvironment (TME) plays a critical role in tumor progression, with macrophages and tumor cells interacting within the TME, influencing cancer development. Despite the known anticancer properties of calcitriol, its role in the TME remains uncertain. This study aimed to explore the effects of calcitriol on macrophages and cancer cells in the TME and its impact on gastric cancer cell proliferation and cisplatin resistance. In vitro TME models were established using conditioned medium from gastric cancer cells (CCM) and macrophages (MCM) treated with or without calcitriol. The results revealed that calcitriol treatment suppressed the expression of glycolysis-related genes and proteins (GLUT1, HKII, LDHA) in MCM-induced gastric cancer cells, leading to increased cancer cell apoptosis and reduced viability, along with decreased Cyclin D1 gene expression. Moreover, calcitriol treatment inhibited mTOR activation in MCM-induced gastric cancer cells. Additionally, calcitriol hindered CCM-induced M2 macrophage polarization by reducing CD206 expression and increasing TNFα gene expression in THP1-derived macrophages, attenuating cisplatin resistance. These findings suggest that calcitriol may impede gastric cancer progression by targeting glycolysis and M2 macrophage polarization through the regulation of mTOR activation in the TME.

Fucoxanthin induces human melanoma cytotoxicity by thwarting the JAK2/STAT3/BCL-xL signaling axis.

Melanoma is the most lethal skin malignancy. Fucoxanthin is a marine carotenoid with significant anticancer activities. Intriguingly, Fucoxanthin's impact on human melanoma remains elusive. Signal Transducer and Activator of Transcription 3 (STAT3) represents a promising target in cancer therapy due to its persistent activation in various cancers, including melanoma. Herein, we revealed that Fucoxanthin is cytotoxic to human melanoma cell lines A2758 and A375 while showing limited cytotoxicity to normal human melanocytes. Apoptosis is a primary reason for Fucoxanthin's melanoma cytotoxicity, as the pan-caspase inhibitor z-VAD-fmk drastically abrogated Fucoxanthin-elicited clonogenicity blockage. Besides, Fucoxanthin downregulated tyrosine 705-phosphorylated STAT3 (p-STAT3 (Y705)), either inherently present in melanoma cells or inducible by interleukin 6 (IL-6) stimulation. Notably, ectopic expression of STAT3-C, a dominant-active STAT3 mutant, abolished Fucoxanthin-elicited melanoma cell apoptosis and clonogenicity inhibition, supporting the pivotal role of STAT3 blockage in Fucoxanthin's melanoma cytotoxicity. Moreover, Fucoxanthin lowered BCL-xL levels by blocking STAT3 activation, while ectopic BCL-xL expression rescued melanoma cells from Fucoxanthin-induced killing. Lastly, Fucoxanthin was found to diminish the levels of JAK2 with dual phosphorylation at tyrosine residues 1007 and 1008 in melanoma cells, suggesting that Fucoxanthin impairs STAT3 signaling by blocking JAK2 activation. Collectively, we present the first evidence that Fucoxanthin is cytotoxic selectively against human melanoma cells while sparing normal melanocytes. Mechanistically, Fucoxanthin targets the JAK2/STAT3/BCL-xL antiapoptotic axis to provoke melanoma cell death. This discovery implicates the potential application of Fucoxanthin as a chemopreventive or therapeutic strategy for melanoma management.

Diagnosis of an epidermoid retroperitoneal cyst via ultrasound: A case report.

Retroperitoneal cysts (RPCs) are rare types of cyst in the retroperitoneal space that are frequently misdiagnosed as gynecological tumors. This case report details, an epidermoid RPC, identified through 2D ultrasound, with attempts to visualize its rendered images using 3D ultrasound. A 39-year-old female patient was admitted to the hospital following the detection of a pelvic mass during a routine physical examination. Initially, the lesion was suspected to be an ovarian tumor, but subsequent ultrasound investigations suggested an epidermoid RPC. This diagnosis was later confirmed by pelvic magnetic resonance imaging. The definitive diagnosis was made following laparoscopic exploration and pathological examination. This case is shared to analyze the ultrasound characteristics of epidermoid RPCs.

Double-balloon enteroscopy for the detection of GIST in a patient with neurofibromatosis type 1.

NF1 is an autosomal dominant hereditary disease, with a prevalence of at least 1 in 4000-5000 population. The diagnosis criteria of NF1 included typical manifestations such as café-au-lait spots, frecking in the axilla or inguinal region, multiple neurofibromas, Lisch nodeules, and distinctive osseous lesions. Genetic testing shows NF1 mutation. It is essential for tumor surveillance in NF1 patients because their life expectancy is about 54 years due to malignancy. A case of NF-1 patient receive laparoscopic small bowel resection and finally diagnosed as adenocarcinoma and ganglioneuroma. About 25% of NF1 patients had GISTs , most of them were asymptomatic and some may manifest with abdominal pain, bowel obstruction, or gastrointestinal bleeding. CT and MRI are commonly used imaging modalities for GIST in NF1, while they may be negative sometimes. As DBE a more practical and non-invasive method now, we consider it is a valuable method for screening and early detecting small intestine disease for NF1 patients.

Wound healing and postoperative management in paediatric patients following 27-Gauge Transconjunctival Sutureless Vitrectomy for vitreoretinal conditions.

The utilization of 27-G TSV, or 27-Gauge Transconjunctival Sutureless Vitrectomy, poses distinct difficulties in the context of paediatric patients, particularly those younger than 14 years old, on account of the dearth of exhaustive documentation concerning the efficacy and results of these operations. Therefore, this retrospective study was to evaluate the safety and efficacy of 27-G TSV in paediatric patients, with emphasis on management of intraoperative and postoperative complications and postoperative wound healing. A total of 54 eyes of 52 paediatric patients who underwent 27-G TSV at Sichuan Provincial People's Hospital were included in the study. The average duration of follow-up was 9.32 ± 3.35 months. The complication with the highest incidence rate was Rhegmatogenous Retinal Detachment (RRD), which was detected in 27.8% cases. Familial Exudative Vitreoretinopathy (FEVR) and Persistent Fetal Vasculature (PFV) each accounted for 16.7% of the cases. Retinopathy of Prematurity (ROP) and Vitreous Haemorrhage (VH) constituted 11.1% and 14.8%, respectively, of the reported cases. Lens injury (1.9%), cannula slippage (7.4%) and wound leakage (5.6%) were intraoperative complications. Iatrogenic retinal detachment occurred at 3.7%. Hypotony (10.8% of patients), vitreous haemorrhage (9.3%), cataract formation (9.3%), ocular hypertension (8.1%) and retinal detachment (5.6%) were postoperative complications. Effective management strategies were executed, such as performing in situ trocar puncture to address cannula slippage and promptly suturing to address wound leakage. 27-G TSV exhibited promise as the therapeutic alternative for range of vitreoretinal disorders in paediatric patients, accompanied by complications that were controllable during and after the procedure. Strict preoperative planning and precise surgical technique are indispensable in order to maximize patient outcomes and guarantee effective wound healing and recovery within this particular demographic.

Whole fresh fruit intake and risk of incident diabetes in different glycemic stages: a nationwide prospective cohort investigation.

PURPOSE: Fruit intake is beneficial to several chronic diseases, but controversial in diabetes. We aimed to investigate prospectively the associations of whole fresh fruit intake with risk of incident type 2 diabetes (T2D) in subjects with different glucose regulation capacities. METHODS: The present study included 79,922 non-diabetic participants aged ≥ 40 years from an ongoing nationwide prospective cohort in China. Baseline fruit intake information was collected by a validated food frequency questionnaire. Plasma HbA1c, fasting and 2 h post-loading glucose levels were measured at both baseline and follow-up examinations. Cox proportional hazards models were used to calculate hazard ratio (HR) and 95% confidence intervals (CI) for incident diabetes among participants with normal glucose tolerance (NGT) and prediabetes, after adjusted for multiple confounders. Restricted cubic spline analysis was applied for dose-response relation. RESULTS: During a median 3.8-year follow-up, 5886 (7.36%) participants developed diabetes. Overall, we identified a linear and dose-dependent inverse association between dietary whole fresh fruit intake and risk of incident T2D. Each 100 g/d higher fruit intake was associated with 2.8% lower risk of diabetes (HR 0.972, 95%CI [0.949-0.996], P = 0.0217), majorly benefiting NGT subjects with 15.2% lower risk (HR 0.848, 95%CI [0.766-0.940], P = 0.0017), while not significant in prediabetes (HR 0.981, 95%CI 0.957-4.005, P = 0.1268). Similarly, the inverse association was present in normoglycemia individuals with a 48.6% lower risk of diabetes when consuming fruits > 7 times/week comparing to those < 1 time/week (HR 0.514, 95% CI [0.368-0.948]), but not in prediabetes (HR 0.883, 95% CI [0.762-1.023]). CONCLUSION: These findings suggest that higher frequency and amount of fresh fruit intake may protect against incident T2D, especially in NGT, but not in prediabetes, highlighting the dietary recommendation of higher fresh fruit consumption to prevent T2D in normoglycemia population.

Mitochondrial diversity and genetic structure of common carp (Cyprinus carpio) in Pearl River and Nandujiang River.

Common carp (Cyprinus carpio) is an important valuable cyprinid in China and has been a popular cultured aquaculture species around the globe. Understanding the genetic diversity of wild native common carp not only provides basic data for the protection and utilisation of common carp resources but also assesses the effect of human activities on the genetic diversity of this species. In this study, genetic diversity and population structure of the common carp from 15 sampling populations in the Pearl River and Nandujiang River were determined using a coalescent mitochondrial locus (MLS), including mitochondrial cytochrome b gene (Cytb) and a control region (D-loop) segment. The haplotype diversity and nucleotide diversity were 0.962 and 0.00628 in the Pearl River and 0.808 and 0.00376 in the Nandujiang River, respectively. Phylogenetic and haplotype network analyses indicated that three sub-species (a) C. c. rubrofuscus, (b) C. c. haematopterus and (c) C. c. carpio all occur in both rivers. AMOVA revealed that the variation within populations (86.2%) was the main source of the total variation. Statistically significant genetic differentiation among different Pearl River populations of C. c. rubrofuscus (Fst  = 0.05-0.25) and relatively high genetic differentiation between the Nandujiang River population and the Pearl River populations (Fst  > 0.238) are apparent. Bayesian clustering analyses detected that global populations consisted of eight genetic clusters and examined that Nandujiang River population included relatively pure genetic clusters. Neutrality tests suggested that native populations experienced recent population expansion, and Extended Bayesian Skyline Plot indicated that the common carp populations likely experienced a historical expansion during 0.125-0.250 MYA. Artificial fish propagation and release, escape from fish farms and Fang Sheng may explain the invasion of non-native sub-species in many river sections, such as Laibin, Rongjiang, Huizhou, Heyuan and Zhaoqing. To conserve the native common carp populations, release station should be established to culture native common carp fry. Overall, the findings can be contributed to complementing scientific knowledge for conservation and management of the wild native common carp.

Nicotinamide N-Methyltransferase inhibits HBV replication by suppressing NR5A1 expression invitro.

Chronic hepatitis B virus (HBV) infection can lead to fibrosis, liver cirrhosis, and primary hepatocellular carcinoma. Investigating host factors that regulate HBV replication helps to identify antiviral targets. In the current study, we identified Nicotinamide N-Methyltransferase gene (NNMT) as a novel factor that regulates HBV transcription. NNMT is up-regulated at both the mRNA and protein levels in HepG2.2.15 cells compared to HepG2 cells. Overexpression of NNMT reduces HBV replication in several cell models, while knockdown of NNMT enhances HBV DNA levels. Mechanistically, NNMT suppresses HBV DNA replication by inhibiting HBV RNA transcription. The region required for the inhibitory effect of NNMT was narrowed to nt 1672-1708 in enhancer II by luciferase assays. On the other hand, ChIP assays and EMSA results showed that NNMT does not bind to this region substantially, either directly or indirectly. Next, a collection of hepatic nuclear receptor transcription factors was screened to determine whether they were affected by NNMT overexpression. NR5A1, a positive regulator of HBV replication, decreased significantly after NNMT overexpression. Collectively, the findings of this study shed light on the regulation of HBV transcription.

Analysis of the efficacy of autologous peripheral blood stem cell transplantation in high-risk neuroblastoma.

Objective: This study aimed to analyze the efficacy of autologous peripheral blood stem cell transplantation for high-risk neuroblastoma in China. Methods: The data of 90 high-risk neuroblastoma patients treated with the CCCG-NB 2015 regimen were reviewed. The baseline clinicopathological characteristics and prognosis were analyzed and compared. In addition, the prognoses of tandem autologous stem cell transplantation and single autologous stem cell transplantation groups were compared. Results: The results of survival analysis showed that autologous peripheral blood stem cell transplantation based on this pretreatment regimen significantly improved the prognosis of children in the high-risk group. The 3-year event-free survival (EFS) and overall survival (OS) rates for the transplantation group and the nontransplantation group were 65.5% vs. 41.3% (p=0.023) and 77.1% vs. 57.9% (p=0.03), respectively. There was no difference in the distribution of baseline clinical case characteristics between the single transplantation group and the tandem transplantation group (p>0.05), and there was no significant difference in EFS and OS between the two groups (p>0.05). Conclusion: Based on this pretreatment programme, autologous peripheral blood stem cell transplantation is safe and tolerable and significantly improves the prognosis of children in the high-risk group. The value of tandem autologous stem cell transplantation is worthy of further discussion, which should consider various aspects such as the transplantation medication regimen and the patient's state.

Co-production of biogas and humic acid using rice straw and pig manure as substrates through solid-state anaerobic fermentation and subsequent aerobic composting.

Compared with wet anaerobic digestion, solid-state fermentation possesses many merits such as low water consumption, high biogas yield and low processing cost. In this work, co-producing biogas and humic acid (HA) by two-step solid-state fermentation was innovatively investigated using rice straw and pig manure as materials. The result indicates that C/N ratio, straw particle size, and total solid content (TS%) caused significant effects on the solid-state fermentation process. At the first step for anaerobic biogas fermentation, the optimal fermentation conditions included C/N ratio of 27.5, straw particle size of 0.85 mm and TS% of 25%. The maximal biogas productivity and methane content were up to 0.43 m3/(m3·d) and 64.88%, respectively. This means that biogas production was significantly improved by adjusting C/N ratio during the co-fermentation of rice straw and pig manure. Following, the digested residue was aerobically composted for HA biosynthesis to improve the fertilizer efficiency of the fermented substrate. The optimal aeration rate of 0.75 L/min was obtained, and the volatile solid (VS) degradation rate, HA content, and the germination index (GI) value were up to 19.16%, 100.89 mg/g, and 103.07%, respectively, which indicates that HA biosynthesis and compost maturity were significantly enhanced. Therefore, the co-production of biogas and HA using rice straw and pig manure as fermentation materials was achieved by adopting the two-step solid-state fermentation, and the bioconversion efficiencies of livestock manure and straw were significantly improved.

[Research progress of Angelicae Sinensis Radix and predictive analysis on its quality markers].

Angelicae Sinensis Radix, as a medicinal and edible Chinese medicinal herb, is widely used in clinical practice. It is mainly cultivated in Minxian, Tanchang, Zhangxian and Weiyuan counties of Gansu province. In recent years, with the comprehensive and in-depth study of Angelicae Sinensis Radix in China and abroad, its chemical composition, pharmacological effects and application and development have attracted much attention. In this study, the chemical composition, traditional efficacy, and modern pharmacological effects of Angelicae Sinensis Radix were summarized. On this basis, combined with the core concept of quality markers(Q-markers), the Q-markers of Angelicae Sinensis Radix were discussed from the aspects of mass transfer and traceability and chemical composition specificity, availability, and measurability, which provided scientific basis for the quality evaluation of Angelicae Sinensis Radix.

Longitudinal Dynamics of the Neutralizing Antibody Response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic with no licensed vaccine or specific antiviral agents for therapy. Little is known about the longitudinal dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific neutralizing antibodies (NAbs) in patients with COVID-19. METHODS: Blood samples (n = 173) were collected from 30 patients with COVID-19 over a 3-month period after symptom onset and analyzed for SARS-CoV-2-specific NAbs using the lentiviral pseudotype assay, coincident with the levels of IgG and proinflammatory cytokines. RESULTS: SARS-CoV-2-specific NAb titers were low for the first 7-10 days after symptom onset and increased after 2-3 weeks. The median peak time for NAbs was 33 days (interquartile range [IQR], 24-59 days) after symptom onset. NAb titers in 93.3% (28/30) of the patients declined gradually over the 3-month study period, with a median decrease of 34.8% (IQR, 19.6-42.4%). NAb titers increased over time in parallel with the rise in immunoglobulin G (IgG) antibody levels, correlating well at week 3 (r = 0.41, P < .05). The NAb titers also demonstrated a significant positive correlation with levels of plasma proinflammatory cytokines, including stem cell factor (SCF), TNF-related apoptosis-inducing ligand (TRAIL), and macrophage colony-stimulating factor (M-CSF). CONCLUSIONS: These data provide useful information regarding dynamic changes in NAbs in patients with COVID-19 during the acute and convalescent phases.

Dicoumarol, an NQO1 inhibitor, blocks cccDNA transcription by promoting degradation of HBx.

BACKGROUND & AIMS: Current antiviral therapies help keep HBV under control, but they are not curative, as they are unable to eliminate the intracellular viral replication intermediate termed covalently closed circular DNA (cccDNA). Therefore, there remains an urgent need to develop strategies to cure CHB. Functional silencing of cccDNA is a crucial curative strategy that may be achieved by targeting the viral protein HBx. METHODS: We screened 2,000 small-molecule compounds for their ability to inhibit HiBiT-tagged HBx (HiBiT-HBx) expression by using a HiBiT lytic detection system. The antiviral activity of a candidate compound and underlying mechanism of its effect on cccDNA transcription were evaluated in HBV-infected cells and a humanised liver mouse model. RESULTS: Dicoumarol, an inhibitor of NAD(P)H:quinone oxidoreductase 1 (NQO1), significantly reduced HBx expression. Moreover, dicoumarol showed potent antiviral activity against HBV RNAs, HBV DNA, HBsAg and HBc protein in HBV-infected cells and a humanised liver mouse model. Mechanistic studies demonstrated that endogenous NQO1 binds to and protects HBx protein from 20S proteasome-mediated degradation. NQO1 knockdown or dicoumarol treatment significantly reduced the recruitment of HBx to cccDNA and inhibited the transcriptional activity of cccDNA, which was associated with the establishment of a repressive chromatin state. The absence of HBx markedly blocked the antiviral effect induced by NQO1 knockdown or dicoumarol treatment in HBV-infected cells. CONCLUSIONS: Herein, we report on a novel small molecule that targets HBx to combat chronic HBV infection; we also reveal that NQO1 has a role in HBV replication through the regulation of HBx protein stability. LAY SUMMARY: Current antiviral therapies for hepatitis B are not curative because of their inability to eliminate covalently closed circular DNA (cccDNA), which persists in the nuclei of infected cells. HBV X (HBx) protein has an important role in regulating cccDNA transcription. Thus, targeting HBx to silence cccDNA transcription could be an important curative strategy. We identified that the small molecule dicoumarol could block cccDNA transcription by promoting HBx degradation; this is a promising therapeutic strategy for the treatment of chronic hepatitis B.

HOMEOBOX PROTEIN52 Mediates the Crosstalk between Ethylene and Auxin Signaling during Primary Root Elongation by Modulating Auxin Transport-Related Gene Expression.

The gaseous hormone ethylene participates in many physiological processes in plants. Ethylene-inhibited root elongation involves PIN-FORMED2 (PIN2)-mediated basipetal auxin transport, but the molecular mechanisms underlying the regulation of PIN2 function by ethylene (and therefore auxin distribution) are poorly understood. Here, we report that the plant-specific and ethylene-responsive HD-Zip gene HB52 is involved in ethylene-mediated inhibition of primary root elongation in Arabidopsis thaliana Biochemical and genetic analyses demonstrated that HB52 is ethylene responsive and acts downstream of ETHYLENE-INSENSITIVE3 (EIN3). HB52 knockdown mutants displayed an ethylene-insensitive phenotype during primary root elongation, while its overexpression resulted in short roots, as observed in ethylene-treated plants. In addition, root auxin distribution and gravitropism were impaired in HB52 knockdown and overexpression lines. Consistent with these findings, in vitro and in vivo binding experiments showed that HB52 regulates the expression of auxin transport-related genes, including PIN2, WAVY ROOT GROWTH1 (WAG1), and WAG2 by physically binding to their promoter regions. These findings suggest that HB52 functions in the ethylene-mediated inhibition of root elongation by modulating the expression of auxin transport components downstream of EIN3, revealing a mechanism in which HB52 acts as an important node in the crosstalk between ethylene and auxin signaling during plant growth and development.

SIRT7 restricts HBV transcription and replication through catalyzing desuccinylation of histone H3 associated with cccDNA minichromosome.

Chronic hepatitis B virus (HBV) infection is a significant public health burden worldwide. HBV covalently closed circular DNA (cccDNA) organized as a minichromosome in nucleus is responsible for viral persistence and is the key obstacle for a cure of chronic hepatitis B (CHB). Recent studies suggest cccDNA transcription is epigenetically regulated by histone modifications, especially histone acetylation and methylation. In the present study, we identified transcriptionally active histone succinylation (H3K122succ) as a new histone modification on cccDNA minichromosome by using cccDNA ChIP-Seq approach. Silent mating type information regulation 2 homolog 7 (SIRT7), as an NAD+-dependent histone desuccinylase, could bind to cccDNA through interaction with HBV core protein where it catalyzed histone 3 lysine 122 (H3K122) desuccinylation. Moreover, SIRT7 acts cooperatively with histone methyltransferase, suppressor of variegation 3-9 homolog 1 (SUV39H1) and SET domain containing 2 (SETD2) to induce silencing of HBV transcription through modulation of chromatin structure. Our data improved the understanding of histone modifications of the cccDNA minichromosome, thus transcriptional silencing of cccDNA may represent a novel antiviral strategy for the prevention or treatment of HBV infection.

Phytochemical Profile and Anti-Inflammatory Activity of the Fraction from Artemisia lavandulaefolia.

Artemisia lavandulaefolia, a traditional herbal medicine, has been utilized as anti-inflammatory and analgesia agent in clinic. Bioassay-guided fractionation resulted in a fraction (ALDF) with anti-inflammatory effect obtained from A. lavandulaefolia. Its main constituents were analyzed and identified by UPLC-ESI-Q-TOF-MS technology. ALDF showed the strong inhibitory activity on the nitrogen oxide (NO) production in LPS-induced RAW 264.7 macrophages with an IC50 value of 1.64±0.41 µg/mL. Further results displayed that ALDF also significantly suppressed the secretion of key pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2 ) and interleukin-1ß (IL-1ß), and the increase of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression induced by LPS stimulation. Mechanism study indicated that ALDF was able to block NF-κB signaling pathway through inhibiting IκB and p65 phosphorylation, as well as NF-κB p65 nuclear translocation. Furthermore, in vivo results in mice revealed that treatments with ALDF evoked significant inhibition on ear edema induced by xylene and on the writhing responses induced by acetic acid. These results suggest that ALDF holds great potential in the prevention and treatment of inflammatory disorders.

A Functional Variant in Ubiquitin Conjugating Enzyme E2 L3 Contributes to Hepatitis B Virus Infection and Maintains Covalently Closed Circular DNA Stability by Inducing Degradation of Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit 3A.

Hepatitis B virus (HBV) infection is a common infectious disease, in which nuclear covalently closed circular DNA (cccDNA) plays a key role in viral persistence, viral reactivation after treatment withdrawal, and drug resistance. A recent genome-wide association study has identified that the ubiquitin conjugating enzyme E2 L3 (UBE2L3) gene is associated with increased susceptibility to chronic HBV (CHB) infection in adults. However, the association between UBE2L3 and children with CHB and the underlying mechanism remain unclear. In this study, we performed two-stage case-control studies including adults and independent children in the Chinese Han population. The rs59391722 allele in the promoter of the UBE2L3 gene was significantly associated with HBV infection in both adults and children, and it increased the promoter activity of UBE2L3. Serum UBE2L3 protein levels were positively correlated with HBV viral load and hepatitis B e antigen (HBeAg) levels in children with CHB. In an HBV infection cell model, UBE2L3 knockdown significantly reduced total HBV RNAs, 3.5-kb RNA, as well as cccDNA in HBV-infected HepG2-Na+ /taurocholate cotransporting polypeptide cells and human primary hepatocytes. A mechanistic study found that UBE2L3 maintained cccDNA stability by inducing proteasome-dependent degradation of apolipoprotein B mRNA editing enzyme catalytic subunit 3A, which is responsible for the degradation of HBV cccDNA. Moreover, interferon-α (IFN-α) treatment markedly decreased UBE2L3 expression, while UBE2L3 silencing reinforced the antiviral activity of IFN-α on HBV RNAs, cccDNA, and DNA. rs59391722 in UBE2L3 was correlated with HBV DNA suppression and HBeAg loss in response to IFN-α treatment of children with CHB. Conclusion: These findings highlight a host gene, UBE2L3, contributing to the susceptibility to persistent HBV infection; UBE2L3 may be involved in IFN-mediated viral suppression and serve as a potential target in the prevention and treatment of HBV infection.

Serum Lysyl Oxidase Is a Potential Diagnostic Biomarker for Kidney Fibrosis.

BACKGROUND: Kidney fibrosis is the ultimate consequence of advanced stages of chronic kidney disease (CKD); however, there are currently no reliable biomarkers or noninvasive diagnostic tests available for the detection of kidney fibrosis. Lysyl oxidase (LOX) promotes collagen cross-linking, and serum LOX levels have been shown to be elevated in patients with fibrosis of the heart, lungs, and liver. However, serum LOX levels have not been reported in patients with kidney fibrosis. We explored whether serum LOX levels are associated with kidney fibrosis. METHOD: Overall, 202 patients with kidney disease underwent renal biopsy, scoring of kidney fibrosis, and determination of the area of kidney fibrosis. LOX levels were measured in serum and in kidney tissues. We analyzed the association of circulating LOX and tissue LOX levels with the scores and areas of kidney fibrosis. LOX expression was also investigated with in vitro and in vivo kidney fibrosis models. RESULTS: Serum LOX levels were higher in patients with kidney fibrosis than in those without kidney fibrosis (p < 0.001) and higher in patients with moderate-severe kidney fibrosis than in patients with mild kidney fibrosis (p < 0.001). Both serum LOX and renal tissue LOX levels correlated with the area of kidney fibrosis (r = 0.748, p < 0.001; r = 0.899, p < 0.001, respectively). Receiver operating characteristic curve analysis of serum LOX levels showed an area under the curve of 0.80 (95% CI: 0.74-0.86). The optimal serum LOX level cutoff point was 253.34 pg/mL for the prediction of kidney fibrosis and 306.56 pg/mL for the prediction of moderate-severe kidney fibrosis. LOX expression levels were significantly upregulated (2.3-2.6 and 6-fold, respectively) in in vitro and in vivo interstitial fibrosis models. CONCLUSIONS: Both serum LOX and tissue LOX levels correlated with the presence and degree of kidney fibrosis in patients with CKD. These results suggest that serum LOX levels could potentially serve as a noninvasive diagnostic biomarker for kidney fibrosis and may further potentially serve as a stratified biomarker for the identification of mild and moderate-severe kidney fibrosis.