Emerging Role of HMGB1 in the Pathogenesis of Schistosomiasis Liver Fibrosis

In chronic schistosomiasis, liver fibrosis is linked to portal hypertension, which is a condition associated with high mortality and morbidity. High mobility group box 1 (HMGB1) was originally described as a nuclear protein that functions as a structural co-factor in transcriptional regulation. However, HMGB1 can also be secreted into the extracellular milieu under appropriate signal stimulation. Extracellular HMGB1 acts as a multifunctional cytokine that contributes to infection, injury, inflammation, and immune responses by binding to specific cell-surface receptors. HMGB1 is involved in fibrotic diseases. From a clinical perspective, HMGB1 inhibition may represent a promising therapeutic approach for treating tissue fibrosis. In this study, we demonstrate elevated levels of HMGB1 in the sera in experimental mice or in patients with schistosomiasis. Using immunohistochemistry, we demonstrated that HMGB1 trafficking in the hepatocytes of mice suffering from acute schistosomiasis was inhibited by Glycyrrhizin, a well-known HMGB1 direct inhibitor, as well as by DIC, a novel and potential anti-HMGB1 compound. HMGB1 inhibition led to significant downregulation of IL-6, IL4, IL-5, IL-13, IL-17A, which are involved in the exacerbation of the immune response and liver fibrogenesis. Importantly, infected mice that were treated with DIC or GZR to inhibit HMGB1 pro-inflammatory activity showed a significant increase in survival and a reduction of over 50% in the area of liver fibrosis. Taken together, our findings indicate that HMGB1 is a key mediator of schistosomotic granuloma formation and liver fibrosis and may represent an outstanding target for the treatment of schistosomiasis

Diabetogenic viruses: linking viruses to diabetes mellitus

Diabetes Mellitus (DM) is a group of chronic metabolic diseases distinguished by elevated glycemia due to the alterations in insulin metabolism. DM is one of the most relevant diseases of the modern world, with high incidence and prevalence worldwide, associated with severe systemic complications and increased morbidity and mortality rates. Although genetic factors and lifestyle habits are two of the main factors involved in DM onset, viral infections, such as enteroviruses, cytomegalovirus, hepatitis C virus, human immunodeficiency virus, severe acute respiratory syndrome coronavirus 2, among others, have been linked as triggers of type 1 (T1DM) and type 2 (T2DM) diabetes. Over the years, various groups identified different mechanisms as to how viruses can promote these metabolic syndromes. However, this field is still poorly explored and needs further research, as millions of people live with these pathologies. Thus, this review aims to ex-plore the different processes of how viruses can induce DM and their contribution to the prevalence and incidence of DM worldwide

Mapping the interactions of dengue virus NS1 protein with human liver proteins using a yeast two-hybrid system: identification of C1q as an interacting partner.

Dengue constitutes a global health concern. The clinical manifestation of this disease varies from mild febrile illness to severe hemorrhage and/or fatal hypovolemic shock. Flavivirus nonstructural protein 1 (NS1) is a secreted glycoprotein that is displayed on the surface of infected cells but is absent in viral particles. NS1 accumulates at high levels in the plasma of dengue virus (DENV)-infected patients, and previous reports highlight its involvement in immune evasion, dengue severity, liver dysfunction and pathogenesis. In the present study, we performed a yeast two-hybrid screen to search for DENV2 NS1-interacting partners using a human liver cDNA library. We identified fifty genes, including human complement component 1 (C1q), which was confirmed by coimmunoprecipitation, ELISA and immunofluorescence assays, revealing for the first time the direct binding of this protein to NS1. Furthermore, the majority of the identified genes encode proteins that are secreted into the plasma of patients, and most of these proteins are classified as acute-phase proteins (APPs), such as plasminogen, haptoglobin, hemopexin, α-2-HS-glycoprotein, retinol binding protein 4, transferrin, and C4. The results presented here confirm the direct interaction of DENV NS1 with a key protein of the complement system and suggest a role for this complement protein in the pathogenesis of DENV infection

Nitrogen-Based Heterocyclic Compounds: A Promising Class of Antiviral Agents against Chikungunya Virus

Arboviruses, in general, are a global threat due to their morbidity and mortality, which results in an important social and economic impact. Chikungunya virus (CHIKV), one of the most relevant arbovirus currently known, is a re-emergent virus that causes a disease named chikungunya fever, characterized by a severe arthralgia (joint pains) that can persist for several months or years in some individuals. Until now, no vaccine or specific antiviral drug is commercially available. Nitrogen heterocyclic scaffolds are found in medications, such as aristeromycin, favipiravir, fluorouracil, 6-azauridine, thioguanine, pyrimethamine, among others. New families of natural and synthetic nitrogen analogous compounds are reported to have significant anti-CHIKV effects. In the present work, we focus on these nitrogen-based heterocyclic compounds as an important class with CHIKV antiviral activity. We summarize the present understanding on this class of compounds against CHIKV and also present their possible mechanism of action

Determination of NS1 positivity using Platelia Dengue NS1 Ag assay.

<p>Determination of NS1 positivity using Platelia Dengue NS1 Ag assay.</p

Cellular localization of DENV2 NS1 interacting-partners identified by yeast two-hybrid screening.

<p>Cellular localization of DENV2 NS1 interacting-partners identified by yeast two-hybrid screening.</p

DENV NS1 directly binds human C1q in an ELISA assay.

<p>(A) Microtiter plates were coated with purified human C1q (10 µg/mL). After incubation with increasing concentrations of purified DENV NS1 that was purified from the supernatant of BHK cells, bound NS1 was detected using a specific conformational monoclonal anti-NS1 antibody. (B) Microtiter plates were coated with purified human C1q (10 µg/mL). After incubation with increasing concentrations of purified DENV NS1 that was purified from <i>E. coli</i> cells, bound NS1 was detected with a specific polyclonal anti-NS1 antibody. Error bars indicate standard deviation from three independent experiments, and asterisks indicate significant difference from the control mock or BSA. *<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001.</p

Demographic, clinical symptoms and serological status of dengue-positive samples.

<p>*The first day after symptoms onset was considered as day 1.</p><p>Demographic, clinical symptoms and serological status of dengue-positive samples.</p

Plasmid linkage assays for transformants identified using DENV2 NS1 as bait in the yeast two-hybrid screening.

<p>Transformants containing the bait and prey plasmids were visualized by their growth on double drop-out media (SD–Leu–Trp; column A). Putative interacting partners were visualized by their growth on triple (SD–His–Leu–Trp; column B) and quadruple drop-out media (SD–Ade–His–Leu–Trp; column C) and by the blue color staining of the colony-lift filter assay (column D) indicating HIS3, ADE2 and <i>lacZ</i> reporter gene activation, respectively. AH109 yeast cells cotransformed with the plasmids pGBKT7-53 (murine p53 fused to the GAL4 DNA-binding domain) and pGADT7-T (SV40 large T-antigen fused to the GAL4 activation domain) served as positive controls (C+). AH109 cotransformed with the plasmids pGBKT7-NS1 and pGADT7-AD (C1), pGBKT7-NS1 and pGADT7-T (C2), pGBKT7 and pGADT7 (C3), pGBKT7 and pGADT7-T (C4), pGBKT7-Lam (laminin C) and pGADT7 (C5), and pGBKT7-Lam and pGADT7-T (C6) served as negative controls. The gene name for each acronym is detailed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057514#pone-0057514-t001" target="_blank">Table 1</a>.</p