A new canine picornavirus (CanPV) variant, designated as dog/SH1901/CHN/2019, was detected in a pool of various canine fecal samples in the mainland of China using a viral metagenomic analysis, and its nearly complete genome sequence was determined and analyzed. Sequence analyses revealed that it had a standard picornavirus genome organization, a type I internal ribosome entry site (IRES) in the 5'UTR. However, dog/SH1901/CHN/2019 has generated a serial of unique aa mutations and 7aa insertion when compared with the closely related CanPVs. Phylogenetic analysis and pairwise sequence comparisons based on the P1, 2C, 3C, and 3D protein sequences showed that dog/SH1901/ CHN/2019 was closely related to CanPV strains 244 F, 325 F and 6D, which clustered into an independent evolutionary clade and distantly related to CanPV strain A128thr of the genus Mischivirus, which indicated the unclassified CanPV strains may belong to a novel species or genus in the family Picornaviridae. This study extends our knowledge on the evolution and genetic diversity of CanPVs.Ischemic stroke is one of the major diseases that cause mortality and morbidity of human beings, but there is still lack of effective treatment and prevention. We found that 2-(2-Benzofuranyl)-2-Imidazoline (2-BFI) is potently protective against stroke and acute inflammatory immune disease. Moreover, the mammalian target of rapamycin (mTOR) signaling contributes effectively to the modulation of post-stroke neuroinflammatory response. However, whether the protection of 2-BFI against ischemic injury is through mTOR-mediated neuroinflammatory response remains unestablished. Here, we used 2-BFI to treat ischemic rats induced by distal middle cerebral artery occlusion (dMCAO). We found that 2-BFI administration after dMCAO improved the neurological deficits and decreased the infarct volume. 2-BFI reduced phosphorylation of mTOR and p70S6, increased IL-10 and TGF-β, and decreased IFN-γ levels in ischemic rats. Our results demonstrated that 2-BFI attenuates ischemic injury by inhibiting the activation of mTOR signaling and modulating neuroinflammation after stroke in rats.The mechanism underlying the high incidence of remifentanil-induced postoperative hyperalgesia is unclear. Also, no effective prevention method exists. Inflammatory pain-related studies showed that P2X4 purinergic receptors (P2X4Rs) in the dorsal horn of the spinal cord and dorsal root ganglia are essential for maintaining allodynia caused by inflammation. However, little is known about its role in opioid-induced hyperalgesia. This study aimed to determine the role of P2X4R and related signaling pathways in the remifentanil-induced postoperative hyperalgesia (RIH) model. The study simulated the remifentanil infusion and surgical incision during general anesthesia. The mRNA and protein expression level of P2X4R in rats with RIH model increased from 2 h to 48 h after the surgery. The administration of P2X4R inhibitors prevented the occurrence of RIH, resulting in a reduction in mechanical and thermal pain. Moreover, P2X4R was involved in RIH in male and female rats, indicating no sex-specific difference. P2X4R also increased the expression of AMPA receptor subunit GluA1 in a brain-derived neurotrophic factor (BDNF) / tyrosine receptor kinase B (TrkB) dependent manner. The results from whole-cell patch-clamp recording suggested that P2X4R also regulated AMPA receptor-mediated miniature excitatory postsynaptic currents and participated in the synaptic plasticity of spinal dorsal horn neurons. Bioactive Compound Library In summary, P2X4R was involved in AMPAR expression, electrophysiological function, and synaptic plasticity of spinal dorsal horn neurons through BDNF/TrkB signaling. This might be the mechanism underlying RIH, and hence inhibition of P2X4R might be a potential treatment strategy.The testis is a temperature-sensitive organ that needs to be maintained 2-7 °C below core body temperature to ensure the production of normal sperm. Failure to maintain testicular temperature in mammals impairs spermatogenesis and leads to low sperm counts, poor sperm motility and abnormal sperm morphology in the ejaculate. This review discusses the recent knowledge on the response of testicular somatic cells to heat stress and, specifically, regarding the relevant contributions of heat, germ cell depletion and inflammatory reactions on the functions of Sertoli and Leydig cells. It also outlines mechanisms of testicular thermoregulation, as well as the thermogenic factors that impact testicular function.
Heat shock response (HSR), a component of cellular protein quality control mechanisms, is defective in different neurodegenerative conditions such as Parkinson's disease (PD). Forced upregulation of heat shock factor 1 (HSF1), an HSR master regulator, showed therapeutic promise in PD models. Many of the reported small-molecule HSF1 activators have limited functions. Therefore, identification and understanding the molecular bases of action of new HSF1 activating molecules is necessary.
We used a cell-based reporter system to screen Andrographis paniculata leaf extract to isolate andrographolide as an inducer of HSF1 activity. The andrographolide activity was characterized by analyzing its role in different protein quality control mechanisms.
We find that besides ameliorating the PD in MPTP-treated mice, andrographolide upregulated different machineries controlled by HSF1 and NRF2 in both cell and mouse brain. Andrographolide achieves these functions through mTORC1 activated via p38 MAPK and ERK pathways. NRF2 activation is reflected in the upregulation of proteasome as well as autophagy pathways. We further show that NRF2 activation is mediated through mTORC1 driven phosphorylation of p62/sequestosome 1. Studies with different cell types suggested that andrographolide-mediated induction of ROS level underlies all these activities in agreement with the upregulation of mTORC1 and NRF2-antioxidant pathway in mice.
Andrographolide through upregulating HSF1 activity ameliorates protein aggregation induced cellular toxicity.
Our results provide a reasonable basis for use of andrographolide in the therapy regimen for the treatment of PD.
Our results provide a reasonable basis for use of andrographolide in the therapy regimen for the treatment of PD.Bioactive Compound Library
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