Immunization with recombinant ORF2 p551 protein protects common marmosets (Callithrix jacchus) against homologous and heterologous hepatitis E virus challenge

Q3 · MEDICINE

Article

Author: Mikhailov, Mikhail ; Lyashenko, Anna ; Gulyaev, Stanislav ; Isaeva, Olga ; Belyakova, Alla ; Ishmukhametov, Aydar ; Kondrashova, Alla ; Chumakov, Alexey ; Bayurova, Ekaterina ; Kyuregyan, Karen ; Karlsen, Anastasia ; Potemkin, Ilya ; Gordeychuk, Ilya ; Morozov, Igor ; Sorokin, Alexey ; Gulyaeva, Tatiana ; Isaguliants, Maria

BACKGROUNDHepatitis E virus (HEV) is a major causative agent of acute hepatitis worldwide, prompting continuous HEV vaccine efforts. Vaccine development is hampered by the lack of convenient animal models susceptible to infection with different HEV genotypes. We produced recombinant open reading frame 2 protein (pORF2; p551) of HEV genotype (GT) 3 and assessed its immunogenicity and protectivity against HEV challenge in common marmosets (Callithrix jacchus, CM).METHODSp551 with consensus sequence corresponding to amino acid residues 110-660 of HEV GT3 pORF2 was expressed in E. coli and purified by affinity chromatography. CMs were immunized intramuscularly with 20 μg of p551 VLPs with alum adjuvant (n = 4) or adjuvant alone (n = 2) at weeks 0, 3, 7 and 19. At week 27, p551-immunized and control animals were challenged with HEV GT1 or GT3 and thereafter longitudinally screened for markers of liver function, anti-HEV IgG and HEV RNA in feces and sera.RESULTSPurified p551 formed VLPs with particle size of 27.71 ± 2.42 nm. Two immunizations with p551 induced anti-HEV IgG mean titer of 1:1810. Immunized CMs challenged with homologous and heterologous HEV genotype did not develop HEV infection during the follow-up. Control CMs infected with both HEV GT1 and GT3 demonstrated signs of HEV infection with virus shedding and elevation of the levels of liver enzymes. High levels of anti-HEV IgG persisted in vaccinated CMs and control CMs that resolved HEV infection, for up to two years post challenge.CONCLUSIONSCMs are shown to be a convenient laboratory animal model susceptible to infection with HEV GT1 and GT3. Immunization with HEV GT3 ORF2/p551 triggers potent anti-HEV antibody response protecting CMs from homologous and heterologous HEV challenge. This advances p551 in VLPs as a prototype vaccine against HEV.

01 Mar 2014·Journal of Cell Communication and SignalingQ2 · BIOLOGY

Grape seed proanthocyanidins and metformin act by different mechanisms to promote insulin signaling in rats fed high calorie diet

Q2 · BIOLOGY

Article

Author: S. Sreeja ; Saravanan Bhuvaneswari ; Baskaran Yogalakshmi ; Carani Venkatraman Anuradha

AbstractKey pathways like insulin signaling, AMP activated kinase (AMPK) activation and inflammatory signaling are involved in the complex pathological network of hepatic insulin resistance. Our aim is to investigate whether grape seed proanthocyanidins (GSP) and metformin (MET) target any of these pathways in insulin resistant rat liver. Albino Wistar rats were rendered insulin resistant by feeding a high fat‐fructose diet (HFFD). Either GSP (100 mg/kg b.w), MET(50 mg/kg b.w) or both were administered to insulin resistant rats as therapeutic options. HFFD‐feeding caused hyperglycemia, hyperinsulinemia, increased gluconeogenesis, decreased tyrosine phosphorylation of insulin receptor‐β(IR‐β) and insulin receptor substrate‐1 (IRS‐1) and increased serine phosphorylation of IRS‐1. The association of p85α subunit of phosphotidyl inositol 3 kinase(PI3K) with IRS‐1 and subsequent Akt phosphorylation were reduced while the expression of mitogen activated protein kinases (MAPK) were increased in HFFD rats. Both MET and GSP reduced hyperglycemia and hyperinsulinemia and improved glycolysis, tyrosine phosphorylation of IR‐β and IRS‐1, IRS‐1‐PI3K association and Akt activation. However, activation of tumor necrosis factor‐α, interleukin‐6, leptin and suppressor of cytokine signaling‐3 and reduction in adiponectin caused by chronic HFFD feeding were reversed by GSP better than by MET. Activation of AMPK by GSP was much less compared to that by MET. These findings suggest that GSP might activate PI3K pathway and promote insulin action by reducing serine kinase activation and cytokine signaling and MET by targeting AMPK. The beneficial effects were enhanced during combination therapy. Thus, combination therapy with MET and GSP may be considered for the management of metabolic syndrome.

01 Jun 1998·Thrombosis ResearchQ3 · MEDICINE

The Antithrombotic Effect of Potent Bifunctional Thrombin Inhibitors Based on Hirudin Sequence, P551 and P532, on He-Ne Laser-Induced Thrombosis in Rat Mesenteric Microvessels

Q3 · MEDICINE

Article

Author: A. Matsuoka ; Y. Okada ; J. Yamamoto ; J.C. Giddings ; T. Yamashita ; Y. Tsuda ; Y. Konishi

The antithrombotic effect of potent synthetic bifunctional non-substrate type thrombin inhibitors based on hirudin sequences, P551 and P532, on Helium-Neon laser-induced thrombosis was investigated in rat mesenteric microvessels and compared with other types of thrombin inhibitors. P551 and P532, when given intravenously, inhibited platelet-rich thrombus formation in both arterioles and venules in a dose-dependent manner. The inhibitory effect was maximal immediately after intravenous administration and persisted for 20-30 minutes in both arterioles and venules. The minimal effective doses of P551 and P532 were 1.0 mg/ kg (intravenously) in both. However, the time course of the antithrombotic effect was not in keeping with the inhibitory effect measured by an activated partial thromboplastin time and was similar to other types of inhibitors in spite of different half-lives. The current findings show that P551 and P532 had significant inhibitory effects on platelet-rich thrombus formation and suggest that these bifunctional thrombin inhibitors could be potent antithrombotic agents.

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Discovery	JP	Hyogo College of Medicine	-

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