Hesperetin, a Selective Phosphodiesterase 4 Inhibitor, Effectively Suppresses Ovalbumin-Induced Airway Hyperresponsiveness without Influencing Xylazine/Ketamine-Induced Anesthesia

Hesperetin, a selective phosphodiesterase (PDE)4 inhibitor, is present in the traditional Chinese medicine, “Chen Pi.” Therefore, we were interested in investigating its effects on ovalbumin- (OVA-) induced airway hyperresponsiveness, and clarifying its rationale for ameliorating asthma and chronic obstructive pulmonary disease (COPD). Hesperetin was revealed to have a therapeutic (PDE4H/PDE4L) ratio of >11. Hesperetin (10 ~ 30 μmol/kg, intraperitoneally (i.p.)) dose-dependently and significantly attenuated the airway hyperresponsiveness induced by methacholine. It also significantly suppressed the increases in total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, and levels of cytokines, including interleukin (IL)-2, IL-4, IL-5, interferon-γ, and tumor necrosis factor-α in bronchoalveolar lavage fluid (BALF). It dose-dependently and significantly suppressed total and OVA-specific immunoglobulin E levels in the BALF and serum. However, hesperetin did not influence xylazine/ketamine-induced anesthesia, suggesting that hesperetin has few or no emetic effects. In conclusion, the rationales for ameliorating allergic asthma and COPD by hesperetin are anti-inflammation, immunoregulation, and bronchodilation

Hyperbaric oxygen upregulates cochlear constitutive nitric oxide synthase

<p>Abstract</p> <p>Background</p> <p>Hyperbaric oxygen therapy (HBOT) is a known adjuvant for treating ischemia-related inner ear diseases. Controversies still exist in the role of HBOT in cochlear diseases. Few studies to date have investigated the cellular changes that occur in inner ears after HBOT. Nitric oxide, which is synthesized by nitric oxide synthase (NOS), is an important signaling molecule in cochlear physiology and pathology. Here we investigated the effects of hyperbaric oxygen on eardrum morphology, cochlear function and expression of NOS isoforms in cochlear substructures after repetitive HBOT in guinea pigs.</p> <p>Results</p> <p>Minor changes in the eardrum were observed after repetitive HBOT, which did not result in a significant hearing threshold shift by tone burst auditory brainstem responses. A differential effect of HBOT on the expression of NOS isoforms was identified. Upregulation of constitutive NOS (nNOS and eNOS) was found in the substructures of the cochlea after HBOT, but inducible NOS was not found in normal or HBOT animals, as shown by immunohistochemistry. There was no obvious DNA fragmentation present in this HBOT animal model.</p> <p>Conclusions</p> <p>The present evidence indicates that the customary HBOT protocol may increase constitutive NOS expression but such upregulation did not cause cell death in the treated cochlea. The cochlear morphology and auditory function are consequently not changed through the protocol.</p

Drastic population fluctuations explain the rapid extinction of the passenger pigeon

To assess the role of human disturbances in species' extinction requires an understanding of the species population history before human impact. The passenger pigeon was once the most abundant bird in the world, with a population size estimated at 3-5 billion in the 1800s; its abrupt extinction in 1914 raises the question of how such an abundant bird could have been driven to extinction in mere decades. Although human exploitation is often blamed, the role of natural population dynamics in the passenger pigeon's extinction remains unexplored. Applying high-throughput sequencing technologies to obtain sequences from most of the genome, we calculated that the passenger pigeon's effective population size throughout the last million years was persistently about 1/10,000 of the 1800's estimated number of individuals, a ratio 1,000-times lower than typically found. This result suggests that the passenger pigeon was not always super abundant but experienced dramatic population fluctuations, resembling those of an "outbreak" species. Ecological niche models supported inference of drastic changes in the extent of its breeding range over the last glacial-interglacial cycle. An estimate of acorn-based carrying capacity during the past 21,000 y showed great year-to-year variations. Based on our results, we hypothesize that ecological conditions that dramatically reduced population size under natural conditions could have interacted with human exploitation in causing the passenger pigeon's rapid demise. Our study illustrates that even species as abundant as the passenger pigeon can be vulnerable to human threats if they are subject to dramatic population fluctuations, and provides a new perspective on the greatest human-caused extinction in recorded history

Oncolytic viruses-modulated immunogenic cell death, apoptosis and autophagy linking to virotherapy and cancer immune response

Recent reports have revealed that oncolytic viruses (OVs) play a significant role in cancer therapy. The infection of OVs such as oncolytic vaccinia virus (OVV), vesicular stomatitis virus (VSV), parvovirus, mammalian reovirus (MRV), human adenovirus, Newcastle disease virus (NDV), herpes simplex virus (HSV), avian reovirus (ARV), Orf virus (ORFV), inactivated Sendai virus (ISV), enterovirus, and coxsackievirus offer unique opportunities in immunotherapy through diverse and dynamic pathways. This mini-review focuses on the mechanisms of OVs-mediated virotherapy and their effects on immunogenic cell death (ICD), apoptosis, autophagy and regulation of the immune system

Gingyo-San Enhances Immunity and Potentiates Infectious Bursal Disease Vaccination

The purpose of the present study was to investigate the effects of Gingyo-san (GGS), a traditional Chinese medical formula, on peripheral lymphocyte proliferation and serum antibody titers in chickens vaccinated against the infectious bursal disease (IBD) virus. Treatment groups were fed one of three doses of GGS in their diet (0.5%, 1.0% and 2.0%, w/w), and the IBD vaccine was administered at 1 and 3 weeks of age. At Weeks 8, 12 and 16, changes in serum IBD antibody titers were measured via the micro-method and T cell proliferation. In gene expression experiments, GGS-treated peripheral T lymphocytes were stimulated with concanavalin A (ConA) for 24 h. The mRNA expression of interleukin-2 (IL-2), interferon-γ (IFN-γ), interleukin-4 (IL-4) and interleukin-12 (IL-12) was determined using a semi-quantitative RT-PCR assay. The results showed that a low dose of GGS could significantly raise the antibody titers. Medium and high doses of GGS enhanced IL-2 and IFN-γ production. GGS altered the expression of IL-4 and IL-12 in T lymphocytes. CD4+ T lymphocyte development was also skewed towards the Th1 phenotype. GGS enhanced cell-mediated immunity and augmented the effects of IBD vaccination in strengthening subsequent anti-viral responses

Pioglitazone, a PPAR-γ Activator, Stimulates BKCa but Suppresses IKM in Hippocampal Neurons

Pioglitazone (PIO), a thiazolidinedone, was reported to stimulate peroxisome proliferator-activated receptor-γ (PPAR-γ) with anti-inflammatory, anti-proliferative, anti-diabetic, and antidepressive activities. However, whether this compound exerts any perturbations on Ca2+-activated K+ and M-type K+ currents in central neurons remains largely unresolved. In this study, we investigated the effects of PIO on these potassium currents in hippocampal neurons (mHippoE-14). In whole-cell current recordings, the presence of PIO (10 μM) increased the amplitude of Ca2+-activated K+ current [IK(Ca)] in mHippoE-14 cells. PIO-induced stimulation of IK(Ca) observed in these cells was reversed by subsequent addition of paxilline, yet not by TRAM-39 or apamin. In inside-out current recordings, PIO applied to the bath concentration-dependently increased the activity of large-conductance Ca2+-activated K+ (BKCa) channels with an EC50 value of 7.6 μM. Its activation of BKCa channels in mHippoE-14 cells was voltage-dependent and accompanied by both a lengthening in mean open time and a shortening in slow component of mean closed time. The activation curve of BKCa channels after addition of PIO was shifted to less depolarized potential without any change in the gating charge. PIO also suppressed the amplitude of M-type K+ currents inherently in mHippoE-14 neurons. Taken together, in addition to its agonistic action on PPAR-γ, PIO-induced perturbation of these potassium channels may be responsible for its widely pharmacological actions on hippocampal neurons

High yield expression in a recombinant E. coli of a codon optimized chicken anemia virus capsid protein VP1 useful for vaccine development

<p>Abstract</p> <p>Background</p> <p>Chicken anemia virus (CAV), the causative agent chicken anemia, is the only member of the genus <it>Gyrovirus </it>of the <it>Circoviridae </it>family. CAV is an immune suppressive virus and causes anemia, lymph organ atrophy and immunodeficiency. The production and biochemical characterization of VP1 protein and its use in a subunit vaccine or as part of a diagnostic kit would be useful to CAV infection prevention.</p> <p>Results</p> <p>Significantly increased expression of the recombinant full-length VP1 capsid protein from chicken anemia virus was demonstrated using an <it>E. coli </it>expression system. The VP1 gene was cloned into various different expression vectors and then these were expressed in a number of different <it>E. coli </it>strains. The expression of CAV VP1 in <it>E. coli </it>was significantly increased when VP1 was fused with GST protein rather than a His-tag. By optimizing the various rare amino acid codons within the N-terminus of the VP1 protein, the expression level of the VP1 protein in <it>E. coli </it>BL21(DE3)-pLysS was further increased significantly. The highest protein expression level obtained was 17.5 g/L per liter of bacterial culture after induction with 0.1 mM IPTG for 2 h. After purification by GST affinity chromatography, the purified full-length VP1 protein produced in this way was demonstrated to have good antigenicity and was able to be recognized by CAV-positive chicken serum in an ELISA assay.</p> <p>Conclusions</p> <p>Purified recombinant VP1 protein with the gene's codons optimized in the N-terminal region has potential as chimeric protein that, when expressed in <it>E. coli</it>, may be useful in the future for the development of subunit vaccines and diagnostic tests.</p