骨格筋障害の病態学解析および腎障害の新たな評価モデルの構築

広島大学(Hiroshima University)博士(学術)Doctor of Philosophydoctora

Molecular docking and pharmacokinetic studies of phytocompounds from Nigerian Medicinal Plants as promising inhibitory agents against SARS-CoV-2 methyltransferase (nsp16)

Abstract Background Since the index case was reported in China, COVID-19 has led to the death of at least 4 million people globally. Although there are some vaccine cocktails in circulation, the emergence of more virulent variants of SARS-CoV-2 may make the eradication of COVID-19 more difficult. Nsp16 is an S-adenosyl-L-Methionine-dependent methyltransferase that plays an important role in SARS-CoV-2 viral RNA cap formation—a crucial process that confers viral stability and prevents virus detection by cell innate immunity mechanisms. This unique property makes nsp16 a promising molecular target for COVID-19 drug design. Thus, this study aimed to identify potent phytocompounds that can effectively inhibit SARS-CoV-2 nsp16. We performed in silico pharmacokinetic screening and molecular docking studies using 100 phytocompounds—isolated from fourteen Nigerian plants—as ligands and nsp16 (PDB: 6YZ1) as the target. Results We found that only 59 phytocompounds passed the drug-likeness analysis test. However, after the docking analysis, only six phytocompounds (oxopowelline, andrographolide, deacetylbowdensine, 11, 12-dimethyl sageone, sageone, and quercetin) isolated from four Nigerian plants (Crinum jagus, Andrographis paniculata, Sage plants (Salvia officinalis L.), and Anacardium occidentale) showed good binding affinity with nsp16 at its active site with docking score ranging from − 7.9 to − 8.4 kcal/mol. Conclusions Our findings suggest that the six phytocompounds could serve as therapeutic agents to prevent viral survival and replication in cells. However, further studies on the in vitro and in vivo inhibitory activities of these 6 hit phytocompounds against SARS-CoV-2 nsp16 are needed to confirm their efficacy and dose

Serum Amyloid A3 Promoter-Driven Luciferase Activity Enables Visualization of Diabetic Kidney Disease

The early detection of diabetic nephropathy (DN) in mice is necessary for the development of drugs and functional foods. The purpose of this study was to identify genes that are significantly upregulated in the early stage of DN progression and develop a novel model to non-invasively monitor disease progression within living animals using in vivo imaging technology. Streptozotocin (STZ) treatment has been widely used as a DN model; however, it also exhibits direct cytotoxicity to the kidneys. As it is important to distinguish between DN-related and STZ-induced nephropathy, in this study, we compared renal responses induced by the diabetic milieu with two types of STZ models: multiple low-dose STZ injections with a high-fat diet and two moderate-dose STZ injections to induce DN. We found 221 genes whose expression was significantly altered during DN development in both models and identified serum amyloid A3 (Saa3) as a candidate gene. Next, we applied the Saa3 promoter-driven luciferase reporter (Saa3-promoter luc mice) to these two STZ models and performed in vivo bioluminescent imaging to monitor the progression of renal pathology. In this study, to further exclude the possibility that the in vivo bioluminescence signal is related to renal cytotoxicity by STZ treatment, we injected insulin into Saa3-promoter luc mice and showed that insulin treatment could downregulate renal inflammatory responses with a decreased signal intensity of in vivo bioluminescence imaging. These results strongly suggest that Saa3 promoter activity is a potent non-invasive indicator that can be used to monitor DN progression and explore therapeutic agents and functional foods

Identification of natural inhibitor from Aframomum melegueta targeting survivin and mammalian rapamycin signaling pathway in Kidney Cancer

Overactivation of survivin and mammalian rapamycin signaling pathway plays an important role in renal carcinogenesis. Recent studies have shown that extract from Aframomum species produces interesting cytotoxic effects against drug resistance cancer. However, the effect of Aframomum melegueta on renal survivin and mammalian rapamycin signaling pathway have not been studied. In this study, we have described a thorough computational study on the effect of natural compounds from Aframomum melegueta on survivin and mammalian rapamycin target at molecular level. Our results revealed a new class of small molecule inhibitors, namely {1,3}benzodaoxolo{5,6-c} dihydrogingerenone, 5-hydroxy-7-methoxyflavone, apigenin, 3,4-dimethoxyphenylacetone and arctigenin, which effectively inhibit survivin and mammalian rapamycin signaling activity. Furthermore, the ADMET (Adsorption, distribution, metabolism, excretion and toxicological) properties prediction also shows that these compounds had good pharmacological properties with little or no toxicity effect. Collectively, our finding suggests that the natural compounds from Aframomum melegueta reported in this study could serve as a potent therapeutic inhibitor of survivin and mammalian rapamycin in renal cancer cells. Thus, we propose further investigation of these compound to validate our findings

Screen shot of Form Hub page.

<p>Screen shot of Form Hub page.</p

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Screen shot of web dashboard built with python and git hub using PLSQL Database.

<p>Screen shot of web dashboard built with python and git hub using PLSQL Database.</p

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<p>Trend of contact follow-up before and after deployment of Mobile application.</p