Object: The present study screened ideal lead natural compounds that could target and inhibit matrix metalloproteinase 9 (MMP9) protein from the ZINC database to develop drugs for clear cell renal cell carcinoma (CCRCC)-targeted treatment. Methods: Discovery Studio 4.5 was used to compare and screen the ligands with the reference drug, solasodine, to identify ideal candidate compounds that could inhibit MMP9. The LibDock module was used to analyze compounds that could strongly bind to MMP9, and the top 20 compounds determined by the LibDock score were selected for further research. ADME and TOPKAT modules were used to choose the safe compounds from these 20 compounds. The selected compounds were analyzed using the CDOCKER module for molecular docking and feature mapping for pharmacophore prediction. The stability of these compound–MMP9 complexes was analyzed by molecular dynamic simulation. Cell counting kit-8, colony-forming, and scratch assays were used to analyze the anti-CCRCC effects of these ligands. Results: Strong binding to MMP9 was exhibited by 6,762 ligands. Among the top 20 compounds, sappanol and sventenin exhibited nearly undefined blood–brain barrier level and lower aqueous solubility, carcinogenicity, and hepatotoxicity than the positive control drug, solasodine. Additionally, these compounds exhibited lower potential energies with MMP9, and the ligand–MMP9 complexes were stable in the natural environment. Furthermore, sappanol inhibited CCRCC cell migration and proliferation. Conclusion: Sappanol and sventenin are safe and reliable compounds to target and inhibit MMP9. Sappanol can CCRCC cell migration and proliferation. These two compounds may give new thought to the targeted therapy for patients with CCRCC.
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with a poor prognosis and a high recurrence rate. PIK3CA gene is frequently mutated in breast cancer, with PIK3CA H1047R as the hotspot mutation reported in TNBC. We used the ZINC database to screen natural compounds that could be structurally modified to develop drugs targeting the PIK3CA H1047R mutant protein in the PI3K pathway. The LibDock module showed that 2,749 compounds could strongly bind to the PIK3CA H1047R protein. Ultimately, the top 20 natural ligands with high LibDock scores were used for further analyses including assessment of ADME (absorption, distribution, metabolism, and excretion), toxicity, stability, and binding affinity. ZINC000004098448 and ZINC000014715656 were selected as the safest drug candidates with strong binding affinity to PIK3CA H1047R, no hepatotoxicity, less carcinogenicity, better plasma protein binding (PPB) properties, and enhanced intestinal permeability and absorption than the two reference drugs, PKI-402 and wortmannin. Moreover, their lower potential energies than those of PIK3CA H1047R confirmed the stability of the ligand-receptor complex under physiological conditions. ZINC000004098448 and ZINC000014715656 are thus safe and stable leads for designing drugs against PIK3CA H1047R as part of a targeted therapeutic approach for patients with TNBC.
Background: Arteriovenous fistula (AVF) failure can occur in patients undergoing hemodialysis (HD). In this study, we explored the correlation between hyperlipidemia and AVF failure in patients undergoing HD. Moreover, we compared the lipid profiles of patients with chronic kidney disease (CKD) with those of healthy people to provide a basis for lipid-lowering in patients undergoing HD. Method and analysis: We searched PubMed, Web of Science, Embase, the Cochrane library, CNKI, CBM, the China Science Periodical Database, and the China Science and Technology Journal Database. The final search was conducted on August 31, 2021, and the search period was restricted between 2000 and August 31, 2021, without publication restrictions. All studies met the inclusion criteria, and the influences of sex, age, geographical location, diagnosis method, and publication year were excluded. The data were analyzed using the random-effects model and the fixed-effects model. Results: Twenty-eight studies were included in the meta-analysis with 121,666 patients in the CKD group and 1714 patients in the AVF failure group. Triglyceride concentration in patients with CKD was higher than in healthy subjects (MD: −31.56, 95% CI: −41.23 to −21.90, p < 0.00001). A high total cholesterol (TC) concentration (MD: 6.97, 95% CI: 2.19–11.74, p = 0.004) and a high low-density lipoprotein cholesterol (LDL-C) concentration (MD: 23.83, 95% CI: 18.48–29.18, p < 0.00001) were associated with AVF failure. Furthermore, HDL-C was lower in the AVF failure group than in the AVF patency group (MD: −2.68, 95% CI: −4.60 to −0.76, p = 0.006). Conclusion: Our analysis indicates that the AVF failure may be related to the increase of TC/LDL-C and the decrease of HDL-C. Although current guidelines do not consider intensive lipid-lowering therapy as necessary in patients undergoing HD, our research indicates that patients with AVF undergoing HD may need regular TC/LDL-C-lowering therapy to prevent AVF failure. However, this issue still needs well designed prospective trials.
Silica nanoparticles (SiNPs) have multiple applications, particularly in the field of biomedical science. However, SiNPs can cause a multitude of diseases, including chronic kidney disease (CKD). The molecular mechanism of renal toxicity caused by SiNPs is complex and remains to be clarified. Therefore, we examined the role and mechanism of apoptosis via the unfolded protein response (UPR) induced by SiNPs. We utilized an in vitro model of NRK-52E cells and an in vivo rat model with SiNPs administered via tracheal drip. After the NRK-52E cells were exposed to SiNPs, cell viability decreased; the mitochondrial membrane potential, calcium content, reactive oxygen species, and apoptosis rate increased; and light microscopy revealed cell damage. Meanwhile, apoptosis, the UPR, and oxidative stress-related proteins were all increased in NRK-52E cells. Moreover, an increase in the concentration of SiNPs was positively correlated with renal damage, as detected by light microscopy and transmission electron microscopy. As the SiNP concentration increased, apoptosis, the UPR, and oxidative stress-related proteins increased and the activity of antioxidant enzymes decreased in rat kidney. We conclude that the UPR plays a key role in apoptosis induced by SiNPs in the kidney.
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