RESUMO
Serotonin (i.e., 5-hydroxytryptamine [5-HT]) plays a key role in stress responses in vertebrates. In mammals and teleosts, tryptophan hydroxylase (Tph), a rate-limiting enzyme in the biosynthesis of 5-HT, includes two paralogs: Tph 1 and Tph 2. The response of the Tphs to stress has been reported in mammals, but less is known about the responses of these enzymes to stress in fish. In the present study, we examined whether heat stress affects the mRNA expression of these Tphs in the brain of medaka fish (Oryzias latipes). We also determined the concentration of 5-HT in the brain, the mRNA expression of heat shock protein 90 alpha (Hsp90α) in the liver, plasma cortisol concentration, and blood glucose concentration in medaka. Whole-body exposure to repeated heat stress significantly decreased the mRNA expression of Tph1 and Tph2 in male and female medaka, whereas single heat stress did not affect the expression of either of the mRNAs. The 5-HT concentration also decreased significantly after repeated heat stress sessions in both sexes, but did not decrease after a single heat stress session. After single and repeated heat stress sessions, Hsp90α mRNA expression increased in both sexes; however, increments in the concentrations of plasma cortisol and blood glucose occurred in male, but not in female, medaka. These results suggest that both types of Tphs are involved in reducing 5-HT in the brain and are reliable indicators of chronic stress response in both sexes. However, stress responses in plasma cortisol and blood glucose concentrations differ between male and female medaka.
Assuntos
Encéfalo/enzimologia , Resposta ao Choque Térmico , Oryzias/metabolismo , Triptofano Hidroxilase/metabolismo , Animais , Feminino , Regulação Enzimológica da Expressão Gênica , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Triptofano Hidroxilase/genéticaRESUMO
Social interactions regulate the expression of several neuropeptides that have a central role in the reproductive system of mammals. Nonmammalian vertebrates also have these neuropeptides or paralogs, however, studies on the social regulation of reproductive physiology in nonmammalian species are limited. In this study, we examined whether the expression of gonadotropin-releasing hormones (GnRHs) and kisspeptin (Kiss1) is affected by social hierarchy resulting from the outcomes of male-male competition in medaka fish (Oryzias latipes). Four males were introduced to each other in an experimental tank, and classified as the most aggressive dominant or the most submissive subordinate fish, based on the frequency of their aggressive acts during a short-term competition. Dominant and subordinate males maintained their social rank during a long-term competition. Immediately after short-term competition, gonadotropin-releasing hormone-3 (GnRH3) level in the olfactory bulb was significantly higher in subordinate males than in dominant males. After long-term competition, dominant males had high level of gonadotropin-releasing hormone-1 (GnRH1) in the preoptic area, whereas subordinate males had lower Kiss1 level in the nucleus ventral tuberis. On the other hand, the levels of gonadotropin-releasing hormone-2 (GnRH2) in the nucleus lateralis valvulae and Kiss1 in the nucleus posterioris periventricularis, and plasma 11-ketotestosterone (11-KT) concentration did not differ between subordinate and dominant males after the short- and long-term competitions. These results suggest that social hierarchy regulates the expression of GnRH1, GnRH3, and Kiss1 without affecting 11-KT level in male medaka.
Assuntos
Encéfalo/metabolismo , Hormônio Liberador de Gonadotropina/genética , Hierarquia Social , Kisspeptinas/genética , Oryzias/metabolismo , Agressão , Animais , Comportamento Animal , Hormônio Liberador de Gonadotropina/metabolismo , Kisspeptinas/metabolismo , Masculino , Oryzias/sangue , Testosterona/análogos & derivados , Testosterona/sangueRESUMO
Continuing emergence of variants of concern resulting in reduced SARS-CoV-2 vaccine efficacy necessitates additional prevention strategies. The structure of VLPCOV-01, a lipid nanoparticle-encapsulated, self-amplifying RNA COVID-19 vaccine with a comparable immune response to BNT162b2, was revised by incorporating a modified base, 5-methylcytosine, to reduce reactogenicity, and an updated receptor-binding domain derived from the Brazil (gamma) variant. Interim analyses of a phase 1 dose-escalation booster vaccination study with the resulting construct, VLPCOV-02, in healthy, previously vaccinated Japanese individuals (N = 96) are reported (jRCT2051230005). A dose-related increase in solicited local and systemic adverse events was observed, which were generally rated mild or moderate. The most commonly occurring events were tenderness, pain, fatigue, and myalgia. Serum SARS-CoV-2 immunoglobulin titers increased during the 4 weeks post-immunization. VLPCOV-02 demonstrated a favorable safety profile compared with VLPCOV-01, with reduced adverse events and fewer fever events at an equivalent dose. These findings support further study of VLPCOV-02.
RESUMO
In order to improve vaccine effectiveness and safety profile of existing synthetic RNA-based vaccines, we have developed a self-amplifying RNA (saRNA)-based vaccine expressing membrane-anchored receptor binding domain (RBD) of SARS-CoV-2 S protein (S-RBD) and have demonstrated that a minimal dose of this saRNA vaccine elicits robust immune responses. Results from a recent clinical trial with 5-methylcytidine (5mC) incorporating saRNA vaccine demonstrated reduced vaccine-induced adverse effects while maintaining robust humoral responses. In this study, we investigate the mechanisms accounting for induction of efficient innate and adaptive immune responses and attenuated adverse effects induced by the 5mC-incorporated saRNA. We show that the 5mC-incorporating saRNA platform leads to prolonged and robust expression of antigen, while induction of type-I interferon (IFN-I), a key driver of reactogenicity, is attenuated in peripheral blood mononuclear cells (PBMCs), but not in macrophages and dendritic cells. Interestingly, we find that the major cellular source of IFN-I production in PBMCs is plasmacytoid dendritic cells (pDCs), which is attenuated upon 5mC incorporation in saRNA. In addition, we demonstrate that monocytes also play an important role in amplifying proinflammatory responses. Furthermore, we show that the detection of saRNA is mediated by a host cytosolic RNA sensor, RIG-I. Importantly, 5mC-incorporating saRNA vaccine candidate produced robust IgG responses against S-RBD upon injection in mice, thus providing strong support for the potential clinical use of 5mC-incorporating saRNA vaccines.
RESUMO
Several vaccines have been widely used to counteract the global pandemic caused by SARS-CoV-2. However, due to the rapid emergence of SARS-CoV-2 variants of concern (VOCs), further development of vaccines that confer broad and longer-lasting protection against emerging VOCs are needed. Here, we report the immunological characteristics of a self-amplifying RNA (saRNA) vaccine expressing the SARS-CoV-2 Spike (S) receptor binding domain (RBD), which is membrane-anchored by fusing with an N-terminal signal sequence and a C-terminal transmembrane domain (RBD-TM). Immunization with saRNA RBD-TM delivered in lipid nanoparticles (LNP) efficiently induces T-cell and B-cell responses in non-human primates (NHPs). In addition, immunized hamsters and NHPs are protected against SARS-CoV-2 challenge. Importantly, RBD-specific antibodies against VOCs are maintained for at least 12 months in NHPs. These findings suggest that this saRNA platform expressing RBD-TM will be a useful vaccine candidate inducing durable immunity against emerging SARS-CoV-2 strains.
Assuntos
COVID-19 , Vacinas , Animais , Cricetinae , Humanos , SARS-CoV-2/genética , COVID-19/prevenção & controle , Motivo de Reconhecimento de RNA , Glicoproteína da Espícula de Coronavírus/genética , Anticorpos Neutralizantes , Anticorpos AntiviraisRESUMO
VLPCOV-01 is a lipid nanoparticle-encapsulated self-amplifying RNA (saRNA) vaccine that expresses a membrane-anchored receptor-binding domain (RBD) derived from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. A phase 1 study of VLPCOV-01 is conducted (jRCT2051210164). Participants who completed two doses of the BNT162b2 mRNA vaccine previously are randomized to receive one intramuscular vaccination of 0.3, 1.0, or 3.0 µg VLPCOV-01, 30 µg BNT162b2, or placebo. No serious adverse events have been reported. VLPCOV-01 induces robust immunoglobulin G (IgG) titers against the RBD protein that are maintained up to 26 weeks in non-elderly participants, with geometric means ranging from 5,037 (95% confidence interval [CI] 1,272-19,940) at 0.3 µg to 12,873 (95% CI 937-17,686) at 3 µg compared with 3,166 (95% CI 1,619-6,191) with 30 µg BNT162b2. Neutralizing antibody titers against all variants of SARS-CoV-2 tested are induced. VLPCOV-01 is immunogenic following low-dose administration. These findings support the potential for saRNA as a vaccine platform.
Assuntos
COVID-19 , Vacinas , Humanos , Pessoa de Meia-Idade , Vacinas contra COVID-19/efeitos adversos , Vacina BNT162 , SARS-CoV-2/genética , RNA , COVID-19/prevenção & controle , Vacinas de mRNARESUMO
BACKGROUND/AIM: Hepatitis B core (HBc) antibody positivity indicates a history of hepatitis B virus (HBV) infection and latent infection. PATIENTS AND METHODS: We conducted a retrospective case-control study of 512 and 495 head and neck cancer (HNC) and non-HNC patients treated at the Okayama University Hospital, Head and Neck Cancer Center from 2008-2017. Demographic data and risk factors that might affect HNC diagnosis were analyzed to assess their effects. RESULTS: Cancer diagnosis was found to correlate with HBc antibody positivity [odds ratio (OR)=1.50, 95% confidence interval (CI)=1.09-2.08], smoking (OR=3.03, 95%CI=2.16-4.25), and a previous history of cancer (OR=4.12, 95%CI=2.79-6.09). The HBs antigen positivity rate in both groups was very close to that observed in the general Japanese population. The HBc antibody positivity rate was very high only in the HNC group. CONCLUSION: HBc antibody positivity and HNC are epidemiologically correlated.