Inhibition of cellular factor TM6SF2 suppresses secretion pathways of Hepatitis B, Hepatitis C and Hepatitis D viruses.

Chronic viral hepatitis is caused by hepatitis B virus, hepatitis C virus or hepatitis D virus (HBV, HCV, and HDV). Despite different replication strategies, all these viruses rely on secretion through the host endoplasmic reticulum-Golgi pathway, providing potential host targets for antiviral therapy. Knockdown of transmembrane 6 superfamily member 2 (TM6SF2) in virus cell culture models reduced secretion of infectious HCV virions, HDV virions and HBV subviral particles. Moreover, in a cohort of people with hepatitis B a TM6SF2 polymorphism (rs58542926 CT/TT, which causes protein misfolding and reduced TM6SF2 in the liver) correlated with lower concentrations of subviral particles in blood, complementing our previous work showing decreased HCV viral load in people with this polymorphism. In conclusion, the host protein TM6SF2 plays a key role in secretion of HBV, HCV and HDV, providing the potential for novel pan-viral agents to treat people with chronic viral hepatitis.

High Prevalence of Chronic Viral Hepatitis and Liver Fibrosis Among Mongols in Southern California.

BACKGROUND: Mongolia is a highly endemic region for chronic hepatitis B (HBV), hepatitis delta (HDV), and hepatitis C (HCV) infections. Aim of this study was to comprehensively characterize chronic viral hepatitis among Mongols living in Southern California. METHODS: Three screening events were conducted between August and November 2018, with 528 adult Mongols tested for HBV and HCV. HBsAg (+) individuals (CHB) underwent additional testing for HDV RNA and anti-HDV. Liver tests, platelet count, and FibroScan™ were performed on CHB and chronic HCV (CHC) individuals. RESULTS: Fifty-one out of 534 were HBsAg reactive (9.7%), and all were foreign-born. Mean age of CHB individuals was 37.8 (range 18-69) years. Forty-six out of 51 were HBeAg (-). HBV genotypes were exclusively D2 or A1. Twenty-one out of 51 (41.2%) were anti-HDV (+) and 17/51 (33.3%) were HDV RNA (+). HDV RNA (+) individuals had significantly higher ALT, fibrosis-4 score, and liver stiffness compared to HDV RNA (-) individuals. Incidence of advanced fibrosis was higher in HDV RNA (+) individuals (57% vs. 13%, p = 0.013). Forty-eight (9.1%) individuals were anti-HCV (+) and 19 (3.6%) were HCV RNA (+). Mean age of CHC individuals was 40.2 (range 28-71) years. Prevalence of anti-HCV (+) was higher among those born between 1945 and 1965 versus those born after 1965 (18.8% vs. 7.9%, p = 0.025). Genotype 1b was predominant. Incidence of cirrhosis was 7% among all participants. CONCLUSIONS: Mongols living in the USA are at high risk for CHB and CHC infections. One-third of CHB individuals had CHD superinfection with advanced fibrosis. Universal screening for viral hepatitis in Mongols in the USA is mandatory.

Synthesis, Structural Characterization, and Bioactivity of the Stable Peptide RCB-1 from Ricinus communis.

The Ricinus communis biomarker peptides RCB-1 to -3 comprise homologous sequences of 19 (RCB-1) or 18 (RCB-2 and -3) amino acid residues. They all include four cysteine moieties, which form two disulfide bonds. However, neither the 3D structure nor the biological activity of any of these peptides is known. The synthesis of RCB-1, using microwave-assisted, Fmoc-based solid-phase peptide synthesis, and a method for its oxidative folding are reported. The tertiary structure of RCB-1, subsequently established using solution-state NMR, reveals a twisted loop fold with antiparallel ß-sheets reinforced by the two disulfide bonds. Moreover, RCB-1 was tested for antibacterial, antifungal, and cytotoxic activity, as well as in a serum stability assay, in which it proved to be remarkably stable.

Peripheral B cells from patients with hepatitis C virus-associated lymphoma exhibit clonal expansion and an anergic-like transcriptional profile.

Chronic HCV infection remains a global health concern due to its involvement in hepatic and extrahepatic diseases, including B cell non-Hodgkin lymphoma (BNHL). Clinical and epidemiological evidence support a causal role for HCV in BNHL development, although mechanistic insight is lacking. We performed RNA-sequencing on peripheral B cells from patients with HCV alone, BNHL alone, and HCV-associated BNHL to identify unique and shared transcriptional profiles associated with transformation. In patients with HCV-associated BNHL, we observed the enrichment of an anergic-like gene signature and evidence of clonal expansion that was correlated with the expression of epigenetic regulatory genes. Our data support a role for viral-mediated clonal expansion of anergic-like B cells in HCV-associated BNHL development and suggest epigenetic dysregulation as a potential mechanism driving expansion. We propose epigenetic mechanisms may be involved in both HCV-associated lymphoma and regulation of B cell anergy, representing an attractive target for clinical interventions.

Travel Tales of a Worldwide Weed: Genomic Signatures of Plantago major L. Reveal Distinct Genotypic Groups With Links to Colonial Trade Routes.

Retracing pathways of historical species introductions is fundamental to understanding the factors involved in the successful colonization and spread, centuries after a species' establishment in an introduced range. Numerous plants have been introduced to regions outside their native ranges both intentionally and accidentally by European voyagers and early colonists making transoceanic journeys; however, records are scarce to document this. We use genotyping-by-sequencing and genotype-likelihood methods on the selfing, global weed, Plantago major, collected from 50 populations worldwide to investigate how patterns of genomic diversity are distributed among populations of this global weed. Although genomic differentiation among populations is found to be low, we identify six unique genotype groups showing very little sign of admixture and low degree of outcrossing among them. We show that genotype groups are latitudinally restricted, and that more than one successful genotype colonized and spread into the introduced ranges. With the exception of New Zealand, only one genotype group is present in the Southern Hemisphere. Three of the most prevalent genotypes present in the native Eurasian range gave rise to introduced populations in the Americas, Africa, Australia, and New Zealand, which could lend support to the hypothesis that P. major was unknowlingly dispersed by early European colonists. Dispersal of multiple successful genotypes is a likely reason for success. Genomic signatures and phylogeographic methods can provide new perspectives on the drivers behind the historic introductions and the successful colonization of introduced species, contributing to our understanding of the role of genomic variation for successful establishment of introduced taxa.

Sensitivity and specificity of commercially available rapid diagnostic tests for viral hepatitis B and C screening in serum samples.

Early diagnosis of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is pivotal for optimal disease management. Sensitivity and specificity of 19 rapid diagnostic test (RDT) kits by different manufacturers (ABON, CTK Biotech, Cypress Diagnostics, Green Gross, Human Diagnostic, Humasis, InTec, OraSure, SD Bioline, Wondfo) were assessed on serum samples of 270 Mongolians (90 seropositive for hepatitis B surface antigen (HBsAg), 90 seropositive for hepatitis C antibody (HCV-Ab), 90 healthy subjects). All tested RDTs for detection of HBsAg performed with average sensitivities and specificities of 100% and 99%, respectively. Albeit, overall sensitivity and specificity of RDTs for detection of HCV-Ab was somewhat lower compared to that of HBsAg RDTs (average sensitivity 98.9%, average specificity 96.7%). Specificity of RDTs for detection of HCV-Ab was dramatically lower among HBsAg positive individuals, who were 10.2 times more likely to show false positive test results. The results of our prospective study demonstrate that inexpensive, easy to handle RDTs are a promising tool in effective HBV- and HCV-screening especially in resource-limited settings.

Hypertension prevalence and control in Ulaanbaatar, Mongolia.

This study examines the prevalence, awareness, treatment, and control of hypertension in Ulaanbaatar, Mongolia, using both the American Heart Association and conventional thresholds (130/80 and 140/90 mm Hg, respectively). In this randomized cross-sectional study, two-stage cluster sampling was used to obtain a sample of 4515 individuals aged ≥20 years. Hypertension was defined by the use of antihypertensives in the last 2 weeks or a blood pressure at or above the thresholds of 140/90 and 130/80 mm Hg. The mean age of the participants was 41.1 ± 14.0 years and 54.5% were women. Hypertension prevalence was 25.6% (using 140/90 mm Hg) and 46.5% (using 130/80 mm Hg). Prevalence increased with age and below 50 years men were consistently more likely to be hypertensive. Among hypertensive participants, the rates of awareness, treatment, and control were 69.7%, 46.8%, and 24.0% (using 140/90 mm Hg) and 49.1%, 25.8%, and 6.4% (using 130/80 mm Hg, respectively). Men had lower rates of awareness, treatment, and control compared with women, with the most pronounced differences at younger ages. This study shows that awareness, treatment, and control rates in Ulaanbaatar are better than in most low- and middle-income countries but are still suboptimal. The largest "care gap" was in young men where a regulatory requirement for annual workplace blood pressure screening has the potential to enhance care. A major hypertension control program has just been initiated in Ulaanbaatar.

Antigenotoxic and antioxidant effects of the Mongolian medicinal plant Leptopyrum fumarioides (L): an in vitro study.

ETHNOPHARMACOLOGICAL RELEVANCE: Leptopyrum fumarioides has been used in the traditional medicine of Mongolia for the treatment of various diseases, including drug intoxications. However, since there is only sparse information about its chemistry, active components, and pharmacological and toxicological effects, the major aim of the present study employing mouse lymphoma cells was to evaluate the genotoxic and antigenotoxic/antioxidative effects of extracts and components isolated from this plant. MATERIAL AND METHODS: A crude methanol extract was separated into three different sub-extracts: dichloromethane, n-butanol, and water. The major constituent of the n-butanol extract, i.e., the flavone luteolin-7-O-glucoside and a mixture of the most abundant compounds in the dichloromethane sub-extract were then isolated. DNA damage was evaluated using the comet assay; the antioxidant activity was evaluated using the DPPH radical scavenging assay. RESULTS: The crude methanol extract, the dichloromethane sub-extract and the mixture of compounds isolated from the latter fraction, increased the level of DNA damage after three hours of exposure. In contrast, no increase in DNA damage was observed in the cells that had been exposed to the n-butanol and water sub-extracts, or to the pure flavone. When non-DNA damaging concentrations of extracts and compounds were tested together with the DNA damaging agent catechol, all sub-extracts were found to reduce the catechol-induced DNA damage (the flavone was then found to be the most effective protective agent). The n-butanol sub-extract and the flavone were also found to have the most prominent antioxidative effects. CONCLUSION: Based on the results from the present study, components in Leptopyrum fumarioides were found to protect the DNA damage induced by catechol, probably by acting as potent antioxidants.