ABSTRACT
There is an urgent need for effective antiviral drugs to alleviate the current COVID-19 pandemic. Here, we rationally designed and developed chimeric antisense oligonucleotides to degrade envelope and spike RNAs of SARS-CoV-2. Each oligonucleotide comprises a 3 antisense sequence for target recognition and a 5-phosphorylated 2-5 poly(A)4 for guided ribonuclease L (RNase L) activation. Since RNase L can potently cleave single strand RNA during innate antiviral response, the improved degradation efficiency of chimeric oligonucleotides was twice as much as classic antisense oligonucleotides in Vero cells, for both SARS-CoV-2 RNA targets. In pseudovirus infection models, one of chimeric oligonucleotides targeting spike RNA achieved potent and broad-spectrum inhibition of both SARS-CoV-2 and its recently reported N501Y and/or {Delta}H69/{Delta}V70 mutants. These results showed that the constructed chimeric oligonucleotides could efficiently degrade pathogenic RNA of SARS-CoV-2 facilitated by immune activation, showing promising potentials as antiviral nucleic acid drugs for COVID-19.
ABSTRACT
<p><b>OBJECTIVE</b>To observe the effects of Sanhuangyinchi decoction (SHYCD) pretreatment on acute hepatic failure (AHF) induced by D-galactosamine and lipopolysaccharide (LPS) in rats and explore the possible mechanisms involving antioxidant stress and cell apoptosis-related protein expression.</p><p><b>METHODS</b>Forty-eight SD rats were randomized equally into control group, AHF model group, high-, medium- and low-dose SHYCD groups, and Bicyclol group. Five days after administration of the corresponding drugs, the rats were challenged with peritoneal D-galactosamine (700 mg/kg) plus LPS (10 ug/kg) injections to induce AHF acute hepatic failure except for those in the control group. At 48 h after the injections, blood samples were collected from the rats to detect the levels of ALT, AST, TBIL, PT, INR and FIB, and pathological changes and superoxide dismutase (SOD) and malondialdehyde (MDA) contents in the liver were examined; immunohistochemistry and western blotting were used to detect caspase-3 protein expression in the liver.</p><p><b>RESULTS</b>The levels of ALT, AST, TBIL, TP and INR in the 3 SHYCD groups and Bicyclol group significantly decreased (P<0.05) while FIB significantly increased in comparison with those in the model group. SHYCD obviously ameliorated the pathological changes, enhanced SOD activity (P<0.05), and decreased MDA levels (P<0.05) and caspase-3 expression (P<0.05) in the liver tissue. SHYCD at the medium dose produced similar effects to Bicyclol (P>0.05) and showed better effects at the high dose than Bicyclol (P<0.05).</p><p><b>CONCLUSION</b>SHYCD pretreatment can dose-dependently ameliorate AHF in rats possibly by suppressing antioxidant stress and caspase-3 expression to decrease hepatic cell apoptosis.</p>
Subject(s)
Animals , Male , Rats , Caspase 3 , Metabolism , Drugs, Chinese Herbal , Therapeutic Uses , Liver Failure, Acute , Drug Therapy , Metabolism , Malondialdehyde , Metabolism , Oxidative Stress , Phytotherapy , Rats, Sprague-Dawley , Superoxide Dismutase , MetabolismABSTRACT
This study was aimed to observe effects of different doses of D-galactosamine (D-GalN) plus lipopoly-saccharide (LPS) and blood coagulation changes among rat model of acute liver failure, in order to establish an ideal model of acute liver failure in rats. SD rats were randomly divided into the control group, D-GalN high, medium and low dose groups, with 10 rats in each group. Except the normal group, rats in other groups were injected with D-GalN plus LPS at different doses to induce acute liver failure. The mortality of rats was observed. The liver function and blood coagulation were detected from rat serum at 0 h, 12 h, 24 h, 48 h, and 72 h. HE stain was used in the observa-tion of changes on liver pathological changes. The results showed that the mortality of D-GalN high, medium and low dose groups within 72 h were 60%, 30%, 10%, respectively. There were significant differences on the serum content level of ALT, AST, TBIL, PT, INR, FIB from different dose groups at different time points and the normal group (P<0.05). However, the comparison among D-GalN high, medium and low dose groups showed no statistical difference on ALT and AST; while there were statistical differences on TBIL, PT, INR and FIB (P < 0.05). It was concluded that coagulation index was more stable in the liver failure model. Through observation on the liver function, blood coagulation and pathological morphology, the model of acute liver failure induced with medium dose of D-GalN plus LPS in SD rats at 48 h was more similar to the clinical symptom of acute liver failure. Therefore, the medium dose was the ideal model inducing dose.
ABSTRACT
The fragmentation pathways of two taxanes drugs have been studied in positive ion mode by Q-TOF with the advantages of high mass accuracy and high resolution analysis. The [M+H] + ions were observed by ESI-MS, from which the molecular weights were obtained. Using the protonated pseudo-molecular ions [M+H]+ as internal reference compounds, the accurate mass and element composition of the fragment ions were determined. The collision induced dissociation (CID) data of the [M+H] ions provided fragmentation pathways of related compounds. Results showed that the major cleavage pathways of paclitaxel and docetaxel were the same that the cleavage of C-O bond between the side chain and taxol skeleton easily occurred, then stripping of the functional groups on the parent ring. Some common fragments were formed, such as m/z 105.033 7, 291.137 3, 309.148 5, 327.159 7, 387.181 2 and 509.217 4, which would provide a basis for future qualitative and quantitative analysis of taxanes in vitro and in vivo.
ABSTRACT
<p><b>OBJECTIVE</b>To investigate the effects of Sanren decoction on the immune function of rats with spleen-stomach damp-heat (DHSS) syndrome.</p><p><b>METHODS</b>Fifty male SD rats were randomly allocated into normal control group, DHSS model group, and 3 Sanren decoction groups (high, medium and low doses). The effects of the decoction on the body mass, rectal temperature (RT), water and food intake, histopathological changes of the gastrointestinal mucosa and serum levels of interleukin (IL)-4 and interferon (IFN)-γ were evaluated.</p><p><b>RESULTS</b>The serum levels of IFN-γ and IL-4 in the model group significantly increased compared with those in the control group (P<0.01), with a slightly increased IFN-γ/IL-4 ratio (P>0.05). Sanren decoction obviously reduced the rectal temperature and significantly decreased the production of both cytokines. High-dose Sanren decoction caused more markedly decreased IL-4 level (P<0.05) to result in a significantly increased IFN-γ/IL-4 ratio (P<0.05).</p><p><b>CONCLUSIONS</b>A shift of Th1/Th2 balance toward Th1 immune response is demonstrated in rats with DHSS syndrome, and Sanren decoction produces a protective effect on the gastrointestinal mucosa by immunoregulation.</p>