Genomic sequencing revealed recombination event between clade 1 and clade 2 occurs in circulating varicella-zoster virus in China.

Varicella-zoster virus (VZV), a member of the Alphaherpesvirinae subfamily, causes varicella in primary infections and establishing a latent stage in sensory ganglia. Upon reactivation, VZV causes herpes zoster with severe neuralgia, especially in elderly patients. The mutation rate for VZV is comparatively lower than the other members of other alpha herpesviruses. Due to geographic isolation, different genotypes of VZV are circulating on separate continents. Here, we successfully isolated a VZV from the vesicular fluid of a youth zoster patient. Based on the single-nucleotide polymorphism profiles of different open reading frames that define the genotype, this newly isolated VZV primarily represents genotype clade 2 but also has characteristics of genotype clade 1. The next-generation sequencing provided a nearly full-length sequence, and further phylogenetic analysis revealed that this VZV isolate is distinct from clades 1 and 2. The Recombination Detection Program indicates that a possible recombinant event may occur between the VZV isolate and clade 1. In summary, we found that there is a circulating VZV isolate in China that may represent a recombinant between clade 1 and clade 2, providing new concerns that need to be considered in the future VZV vaccination program.

Dihydropyridine-derived calcium channel blocker as a promising anti-hantavirus entry inhibitor.

Hantaviruses, the causative agent for two types of hemorrhagic fevers, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), are distributed from Eurasia to America. HFRS and HPS have mortality rates of up to 15% or 45%, respectively. Currently, no certified therapeutic has been licensed to treat hantavirus infection. In this study, we discovered that benidipine hydrochloride, a calcium channel blocker, inhibits the entry of hantaviruses in vitro. Moreover, an array of calcium channel inhibitors, such as cilnidipine, felodipine, amlodipine, manidipine, nicardipine, and nisoldipine, exhibit similar antiviral properties. Using pseudotyped vesicular stomatitis viruses harboring the different hantavirus glycoproteins, we demonstrate that benidipine hydrochloride inhibits the infection by both HFRS- and HPS-causing hantaviruses. The results of our study indicate the possibility of repurposing FDA-approved calcium channel blockers for the treatment of hantavirus infection, and they also indicate the need for further research in vivo.

Corrigendum: Remdesivir (GS-5734) Impedes Enterovirus Replication Through Viral RNA Synthesis Inhibition.

[This corrects the article DOI: 10.3389/fmicb.2020.01105.].

Remdesivir (GS-5734) Impedes Enterovirus Replication Through Viral RNA Synthesis Inhibition.

Human enteroviruses are responsible for diverse diseases, from mild respiratory symptoms to fatal neurological complications. Currently, no registered antivirals have been approved for clinical therapy. Thus, a therapeutic agent for the enterovirus-related disease is urgently needed. Remdesivir (GS-5734) is a novel monophosphoramidate adenosine analog prodrug that exhibits potent antiviral activity against diverse RNA virus families, including positive-sense Coronaviridae and Flaviviridae and negative-sense Filoviridae, Paramyxoviridae, and Pneumoviridae. Currently, remdesivir is under phase 3 clinical development for disease COVID-19 treatment. Here, we found that remdesivir impeded both EV71 viral RNA (vRNA) and complementary (cRNA) synthesis, indicating that EV71 replication is inhibited by the triphosphate (TP) form of remdesivir. Moreover, remdesivir showed potent antiviral activity against diverse enteroviruses. These data extend the remdesivir antiviral activity to enteroviruses and indicate that remdesivir is a promising antiviral treatment for EV71 and other enterovirus infections.

The differential expression of novel circular RNAs in an acute lung injury rat model caused by smoke inhalation

Acute lung injury caused by smoke inhalation is a common severe clinical syndrome. This study aimed to investigate the potential expression of circular RNAs during acute lung injury triggered by smoke inhalation. The acute lung injury rat model was established with smoke inhalation from a self-made smoke generator. The occurrence of acute lung injury was validated by an analysis of the bronchoalveolar lavage fluid and hematoxylin-eosin (HE) staining of lung tissues. Next-generation sequencing and quantitative PCR were performed to identify the differentially expressed circular RNAs associated with acute lung injury that was caused by smoke inhalation. The circular form of the identified RNAs was finally verified by multiple RT-PCR-based assays. The bronchoalveolar lavage fluid (BALF) and lung tissue analysis showed that smoke inhalation successfully induced acute injury in rats, as evidenced by the significantly altered cell numbers, including macrophages, neutrophils, and red blood cells, disrupted cell lining, and increased levels of interleukin-1β, tumor necrosis factor-alpha, and IL-8 in lung tissues. Ten significantly differentially expressed circular RNAs were identified with next-generation sequencing and RT-PCR. The circular form of these RNAs was verified by multiple RT-PCR-based assays. In conclusion, the identified circular RNAs were prevalently and differentially expressed in rat lungs after acute lung injury caused by smoke inhalation

The differential expression of novel circular RNAs in an acute lung injury rat model caused by smoke inhalation.

Acute lung injury caused by smoke inhalation is a common severe clinical syndrome. This study aimed to investigate the potential expression of circular RNAs during acute lung injury triggered by smoke inhalation. The acute lung injury rat model was established with smoke inhalation from a self-made smoke generator. The occurrence of acute lung injury was validated by an analysis of the bronchoalveolar lavage fluid and hematoxylin-eosin (HE) staining of lung tissues. Next-generation sequencing and quantitative PCR were performed to identify the differentially expressed circular RNAs associated with acute lung injury that was caused by smoke inhalation. The circular form of the identified RNAs was finally verified by multiple RT-PCR-based assays. The bronchoalveolar lavage fluid (BALF) and lung tissue analysis showed that smoke inhalation successfully induced acute injury in rats, as evidenced by the significantly altered cell numbers, including macrophages, neutrophils, and red blood cells, disrupted cell lining, and increased levels of interleukin-1ß, tumor necrosis factor-alpha, and IL-8 in lung tissues. Ten significantly differentially expressed circular RNAs were identified with next-generation sequencing and RT-PCR. The circular form of these RNAs was verified by multiple RT-PCR-based assays. In conclusion, the identified circular RNAs were prevalently and differentially expressed in rat lungs after acute lung injury caused by smoke inhalation.

P110ß Inhibition Reduces Histone H3K4 Di-Methylation in Prostate Cancer.

INTRODUCTION AND AIMS: Epigenetic alteration plays a major role in the development and progression of human cancers, including prostate cancer. Histones are the key factors in modulating gene accessibility to transcription factors and post-translational modification of the histone N-terminal tail including methylation is associated with either transcriptional activation (H3K4me2) or repression (H3K9me3). Furthermore, phosphoinositide 3-kinase (PI3 K) signaling and the androgen receptor (AR) are the key determinants in prostate cancer development and progression. We recently showed that prostate-targeted nano-micelles loaded with PI3 K/p110beta specific inhibitor TGX221 blocked prostate cancer growth in vitro and in vivo. Our objective of this study was to determine the role of PI3 K signaling in histone methylation in prostate cancer, with emphasis on histone H3K4 methylation. METHODS: PI3 K non-specific inhibitor LY294002 and p110beta-specific inhibitor TGX221 were used to block PI3 K/p110beta signaling. The global levels of H3K4 and H3K9 methylation in prostate cancer cells and tissue specimens were evaluated by Western blot assay and immunohistochemical staining. A synthetic androgen R1881 was used to stimulate AR activity in prostate cancer cells. A castration-resistant prostate cancer (CRPC) specific human tissue microarray (TMA) was used to assess the global levels of H3K4me2 methylation by immunostaining approach. RESULTS: Our data revealed that H3K4me2 levels were significantly elevated after androgen stimulation. With RNA silencing and pharmacology approaches, we further defined that inhibition of PI3 K/p110beta activity through gene-specific knocking down and small chemical inhibitor TGX221 abolished androgen-stimulated H3K4me2 methylation. Consistently, prostate cancer-targeted delivery of TGX221 in vivo dramatically reduced the global levels of H3K4me2 as assessed by immunohistochemical staining on tissue section of mouse xenografts from CRPC cell lines 22RV1 and C4-2. Finally, immunostaining data revealed a strong H3K4me2 immunosignal in CRPC tissues compared to primary tumors and benign prostate tissues. CONCLUSIONS: Taken together, our results suggest that PI3 K/p110beta-dependent signaling is involved in androgen-stimulated H3K4me2 methylation in prostate cancer, which might be used as a novel biomarker for disease prognosis and targeted therapy. Prostate 77:299-308, 2017. © 2016 Wiley Periodicals, Inc.

Addition and Subtraction Theory of TCM Using Xiao-Chaihu-Decoction and Naturopathy in Predicting Survival Outcomes of Primary Liver Cancer Patients: A Prospective Cohort Study.

To investigate the therapeutic effect of combined Xiao-Chaihu-Decoction and naturopathic medicine therapy on survival outcomes of patients' PLC. In XCHD group (n = 76), patients were treated with Xiao-Chaihu-Decoction in accordance with the addition and subtraction theory of TCM; in NM group (n = 89), patients were managed by naturopathic medicine; in combined group (n = 70), the same volume of Xiao-Chaihu-Decoction combined with naturopathic medicine procedures was applied. There were no evident statistical differences of age, gender, KPS score, body weight, smoking status, AFP levels, HbsAg status, TBIL levels, tumor diameters, and numbers among different groups, showing comparability among groups. No significant difference was found regarding the total remission rate and stability rate of tumors in patients treated by Xiao-Chaihu-Decoction and naturopathic medicine, except the combined therapy. KPS scores were significantly improved after treatment among groups. After treatment, 52.8% cases maintained a stable or slight increase in weight, of which 42.1%, 48.3%, and 70.0% cases maintained weight stably in the XCHD group, NM group, and combined treatment group, respectively. Xiao-Chaihu-Decoction associated with naturopathy may predict improved prognostic outcomes in PLC patients, along with improved remission and stability rates, increased KPS scores, and stable weight maintenance.

Protective role of adiponectin in a rat model of intestinal ischemia reperfusion injury.

AIM: To determine the potential protective role of adiponectin in intestinal ischemia reperfusion (I/R) injury. METHODS: A rat model of intestinal I/R injury was established. The serum level of adiponectin in rats with intestinal I/R injury was determined by enzyme-linked immunosorbent assay (ELISA). The serum levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α were also measured by ELISA. Apoptosis of intestinal cells was detected using the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The production of malondialdehyde (MDA) and superoxide dismutase (SOD) and villous injury scores were also measured. RESULTS: Adiponectin was downregulated in the serum of rats with intestinal I/R injury compared with sham rats. No significant changes in the expression of adiponectin receptor 1 and adiponectin receptor 2 were found between sham and I/R rats. Pre-treatment with recombinant adiponectin attenuated intestinal I/R injury. The production of pro-inflammatory cytokines, including IL-6, IL-1ß, and TNF-α, in rats with intestinal I/R injury was reduced by adiponectin pre-treatment. The production of MDA was inhibited, and the release of SOD was restored by adiponectin pre-treatment in rats with intestinal I/R injury. Adiponectin pre-treatment also inhibited cell apoptosis in these rats. Treatment with the AMP-activated protein kinase (AMPK) signaling pathway inhibitor, compound C, or the heme oxygenase 1 (HO-1) inhibitor, Snpp, attenuated the protective effects of adiponectin against intestinal I/R injury. CONCLUSION: Adiponectin exhibits protective effects against intestinal I/R injury, which may involve the AMPK/HO-1 pathway.

[Management of colonic injuries in the setting of damage control surgery].

OBJECTIVE: To compare the safety of anastomosis and ostomy following 2-stage definitive colonic resection when severe colonic injuries treated in the setting of damage control surgery(DCS). METHODS: Clinical data of 67 patients with severely traumatic colonic injuries undergoing DCS at the Third Affiliated Hospital of Sun Yat-sen University between 2005 and 2013 were analyzed retrospectively. Patients were divided into the anastomosis group undergoing colonic resection and anastomosis (n=40), and the ostomy group undergoing anastomosis with a protecting proximal ostomy (n=27). Postoperative complications were compared between these two groups. The risk factors of colonic anastomosis leakage were analyzed. RESULTS: Demographics, injury severity, physiological imbalance on admission, transfusion during the first operative procedure were similar in the two groups (all P>0.05). Rates of anastomotic leakage, intra-abdominal abscess, enterocutaneous fistula, and would infection after definitive resection were not statistically different between the two groups (all P>0.05). Colonic anasomotic leakage rates were 15.0% (6/40) in anastomosis group and 11.1% (3/27) in ostomy group without significant difference (P>0.05). Left-sided colon injuries occurred in 7 out of 9 patients with anatomotic leakage, whose proportion was significantly higher than that in those without anastomotic leakage (7/9 vs. 24/58, 77.8% vs. 41.4%, P<0.05). A prolonged peritoneal closure was also observed in patients with anastomotic leakage (median, 10 days vs. 2 days, P<0.05). CONCLUSIONS: A strategy of diverting ostomy is not the first choice for patients suffering from severe colonic injuries in the setting of DCS. Peritoneal closure at early stage may decrease the risk of colonic anastomotic leakage.

Clinicopathological significance of RUNX3 gene hypermethylation in hepatocellular carcinoma.

Emerging evidence indicates that RUNX3 is a candidate tumor suppressor in several types of human tumors including hepatocellular carcinoma (HCC). However, the correlation between RUNX3 hypermethylation and incidence of HCC remains unclear. Here, we conducted a systematic review and meta-analysis aiming to comprehensively assess the potential role of RUNX3 hypermethylation in the pathogenesis of HCC. A detailed literature search was made from PubMed, EMBASE, and ISI web of knowledge to identify studies for related research publications. Methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analysis of pooled data was performed. Odds ratio (OR) was calculated and summarized, respectively. Final analysis of 821 HCC patients from 14 eligible studies was performed. We observed that RUNX3 hypermethylation was significantly higher in HCC than in normal liver tissue, the pooled OR from eight studies including 382 HCC and 161 normal liver tissue (OR = 39.32, 95 % confidence interval (CI) = 13.72-112.7, p < 0.00001). The pooled analysis showed significantly increased OR of RUNX3 hypermethylation (OR = 5.4, 95 % CI = 2.06-14.17, p < 0.00001) in HCC tissues and non-tumor liver tissues. In addition, statistically significant OR of RUNX3 hypermethylation was obtained from non-tumorous liver tissue of HCC patients and normal liver tissue (OR = 12.57, 95 % CI = 3.56-44.35, p < 0.0001). The results of this meta-analysis suggest that RUNX3 hypermethylation may be implicated in the pathogenesis of HCC. Thus, detection of RUNX3 hypermethylation may be a helpful and valuable biomarker for diagnosis of HCC.

[The clinical study on chronic hepatitis B treated by the four-step therapeutics of Traditional Chinese Medicine].

OBJECTIVE: To observe the clinical curative effect of chronic hepatitis B treated by the four-step therapeutics of Traditional Chinese Medicine (TCM). METHODS: 120 patients with mild or moderate Chronic Hepatitis B (CHB) were randomly divided into two groups: 80 patients in treatment group and 40 in control group. All enrolled cases accorded with the enroll standard. In treatment group, the patients were divided into mild moderate and severe degree of immune intervention based on the ALT level and treated with four-step therapeutics according to the dialectical theory. In control group, all patients were administered 100mg Lamivudine orally daily for two years. RESULTS: The loss rates of HBeAg, HBV-DNA, precore mutation were 58.9%, 78.9% in treatment group respectively, and 33.3%, 38.9% in control group. There were significant defferences between them. The total effectiveness ratio of two groups has no significant difference. After the treatment, the value of HA, PCIII, IV. C,LN decreased dramatically in treatment group and the antihepatic fibrosis results of treatment group were superior to those of control group. The four-step therapeutics of TCM could improve the ALT value and the ALT value declined to normal after the virus indexes' loss. The response rate in treatment group of ALT-elevating patients was higher than those of no ALT- elevating patients. CONCLUSION: The four-step therapeutics of TCM is effective in treating the CHB patients.

[Quantitative analysis on Radix Salviae miltiorrhizae by NIR].

OBJECTIVE: Rapid nondestructive determination of salvianolic acid B and tanshinone IIA in Radix Salviae Miltiorrhizae with near-infrared reflectance spectroscopy. METHOD: A quantitive model was built up with near-infrared diffuse reflectance spectroscopy. RESULTS: The RMSEP in quantitative calibration model for salvianolic acid B and tanshinone IIA were 0.259 and 0.0232 respectively. CONCLUSION: NIR technique can dispose the samples without complicated pretreatment. You can achieve the results rapidly and correctly. It owns many remarkable advantages that cannot be displayed by traditional analysis methods. It is qualified to rapidly analyze traditional Chinese medicine whose components are complex. NIR can control the quality in production process of traditional Chinese medicine.

[Clinical observations on effects on prognostic factor treating hepatitis B-related cirrhosis with purification purgation dispersion tonicity].

OBJECTIVE: With prognostic factors as assessment standards, the effects of combination of TCM(purification purgation dispersion tonicity) and western medicine treating hepatitis B-related cirrhosis and its complications were assessed. METHODS: In this study, study group and control group were divided, the number of each group was 30. In order to keep balance between the two groups, matching control design was adopted with Wang's 8 prognostic factors as matching conditions. RESULTS: In study group, except Hb, TBIL, ALB and PT had statistic difference, and the complications of cirrhosis such as ascites, HEP and UGH were treated with significant effects. Between study group and control group, in all of prognostic factors only TBIL had statistical diffirence. CONCLUSIONS: It suggested the effects were significant treating hepatitis B-related cirrhosis and its complications with combination of TCM(purification purgation dispersion tonicity) and western medicine. It also suggested that TCM therapy combining purification, purgation, dispersion and tonicity had significant effects on reducing jaundice.