Rapamycin improves the survival of epilepsy model cells by blocking phosphorylation of mTOR base on computer simulations and cellular experiments.

PURPOSE: Epilepsy is a chronic brain dysfunction characterized by recurrent epileptic seizures. Rapamycin is a naturally occurring macrolide from Streptomyces hygroscopicus, and rapamycin may provide a protective effect on the nervous system by affecting mTOR. Therefore, we investigated the pharmacologic mechanism of rapamycin treating epilepsy through bioinformatics analysis, cellular experiments and supercomputer simulation. METHODS: Bioinformatics analysis was used to analyze targets of rapamycin treating epilepsy. We established epilepsy cell model by HT22 cells. RT-qPCR, WB and IF were used to verify the effects of rapamycin on mTOR at gene level and protein level. Computer simulations were used to model and evaluate the stability of rapamycin binding to mTOR protein. RESULTS: Bioinformatics indicated mTOR played an essential role in signaling pathways of cell growth and cell metabolism. Cellular experiments showed that rapamycin could promote cell survival, and rapamycin did not have an effect on mRNA expression of mTOR. However, rapamycin was able to significantly inhibit the phosphorylation of mTOR at protein level. Computer simulations indicated that rapamycin was involved in the treatment of epilepsy through regulating phosphorylation of mTOR at protein level. CONCLUSION: We found that rapamycin was capable of promoting the survival of epilepsy cells by inhibiting the phosphorylation of mTOR at protein level, and rapamycin did not have an effect on mRNA expression of mTOR. In addition to the traditional study that rapamycin affects mTORC1 complex by acting on FKBP12, this study found rapamycin could also directly block the phosphorylation of mTOR, therefore affecting the assembly of mTORC1 complex and mTOR signaling pathway.

Exploring the mechanism of action of dapansutrile in the treatment of gouty arthritis based on molecular docking and molecular dynamics.

Purpose: Dapansutrile is an orally active ß-sulfonyl nitrile compound that selectively inhibits the NLRP3 inflammasome. Clinical studies have shown that dapansutrile is active in vivo and limits the severity of endotoxin-induced inflammation and joint arthritis. However, there is currently a lack of more in-depth research on the effect of dapansutrile on protein targets such as NLRP3 in gouty arthritis. Therefore, we used molecular docking and molecular dynamics to explore the mechanism of dapansutrile on NLRP3 and other related protein targets. Methods: We use bioinformatics to screen active pharmaceutical ingredients and potential disease targets. The disease-core gene target-drug network was established and molecular docking was used for verification. Molecular dynamics simulations were utilized to verify and analyze the binding stability of small molecule drugs to target proteins. The supercomputer platform was used to measure and analyze the binding free energy, the number of hydrogen bonds, the stability of the protein target at the residue level, the radius of gyration and the solvent accessible surface area. Results: The protein interaction network screened out the core protein targets (such as: NLRP3, TNF, IL1B) of gouty arthritis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that gouty arthritis mainly played a vital role by the signaling pathways of inflammation and immune response. Molecular docking showed that dapansutrile play a role in treating gouty arthritis by acting on the related protein targets such as NLRP3, IL1B, IL6, etc. Molecular dynamics was used to prove and analyze the binding stability of active ingredients and protein targets, the simulation results found that dapansutrile forms a very stable complex with IL1B. Conclusion: We used bioinformatics analysis and computer simulation system to comprehensively explore the mechanism of dapansutrile acting on NLRP3 and other protein targets in gouty arthritis. This study found that dapansutrile may not only directly inhibit NLRP3 to reduce the inflammatory response and pyroptosis, but also hinder the chemotaxis and activation of inflammatory cells by regulating IL1B, IL6, IL17A, IL18, MMP3, CXCL8, and TNF. Therefore, dapansutrile treats gouty arthritis by attenuating inflammatory response, inflammatory cell chemotaxis and extracellular matrix degradation by acting on multiple targets.

Exploring the mechanism of action of licorice in the treatment of COVID-19 through bioinformatics analysis and molecular dynamics simulation.

Purpose: The rapid worldwide spread of Corona Virus Disease 2019 (COVID-19) has become not only a global challenge, but also a lack of effective clinical treatments. Studies have shown that licorice can significantly improve clinical symptoms such as fever, dry cough and shortness of breath in COVID-19 patients with no significant adverse effects. However, there is still a lack of in-depth analysis of the specific active ingredients of licorice in the treatment of COVID-19 and its mechanism of action. Therefore, we used molecular docking and molecular dynamics to explore the mechanism of action of licorice in the treatment of COVID-19. Methods: We used bioinformatics to screen active pharmaceutical ingredients and potential targets, the disease-core gene target-drug network was established and molecular docking was used for verification. Molecular dynamics simulations were carried out to verify that active ingredients were stably combined with protein targets. The supercomputer platform was used to measure and analyze stability of protein targets at the residue level, solvent accessible surface area, number of hydrogen bonds, radius of gyration and binding free energy. Results: Licorice had 255 gene targets, COVID-19 had 4,628 gene targets, the intersection gene targets were 101. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene ontology (GO) analysis showed that licorice played an important role mainly through the signaling pathways of inflammatory factors and oxidative stress. Molecular docking showed that Glycyrol, Phaseol and Glyasperin F in licorice may playe a role in treating COVID-19 by acting on STAT3, IL2RA, MMP1, and CXCL8. Molecular dynamics were used to demonstrate and analyze the binding stability of active ingredients to protein targets. Conclusion: This study found that Phaseol in licorice may reduce inflammatory cell activation and inflammatory response by inhibiting the activation of CXCL8 and IL2RA; Glycyrol may regulate cell proliferation and survival by acting on STAT3. Glyasperin F may regulate cell growth by inhibiting the activation of MMP1, thus reducing tissue damage and cell death caused by excessive inflammatory response and promoting the growth of new tissues. Therefore, licorice is proposed as an effective candidate for the treatment of COVID-19 through STAT3, IL2RA, MMP1, and CXCL8.

Molecular docking and molecular dynamics simulation study the mechanism of progesterone in the treatment of spinal cord injury.

PURPOSE: Spinal cord injury can lead to incomplete or complete loss of voluntary movement and sensory function, leading to serious complications. Numerous studies have shown that progesterone exhibits strong therapeutic potential for spinal cord injury. However, the mechanism by which progesterone treats spinal cord injury remains unclear. Therefore, this article explores the mechanism of progesterone in the treatment of spinal cord injury by means of molecular docking and molecular dynamics simulation. METHODS: We used bioinformatics to screen active pharmaceutical ingredients and potential targets, and molecular docking and molecular dynamics were used to validate and analysis by the supercomputer platform. RESULTS: Progesterone had 3606 gene targets, spinal cord injury had 6560 gene targets, the intersection gene targets were 2355. GO and KEGG analysis showed that the abundant pathways involved multiple pathways related to cell metabolism and inflammation. Molecular docking showed that progesterone played a role in treating spinal cord injury by acting on BDNF, AR, NGF and TNF. Molecular dynamics was used to prove and analyzed the binding stability of active ingredients and protein targets, and AR/Progesterone combination has the strongest binding energy. CONCLUSION: Progesterone promotes recovery from spinal cord injury by promoting axonal regeneration, remyelination, neuronal survival and reducing inflammation.

Molecular docking and molecular dynamics study Lianhua Qingwen granules (LHQW) treats COVID-19 by inhibiting inflammatory response and regulating cell survival.

Purpose: 2019 Coronavirus disease (COVID-19) is endangering health of populations worldwide. Latest research has proved that Lianhua Qingwen granules (LHQW) can reduce tissue damage caused by inflammatory reactions and relieve patients' clinical symptoms. However, the mechanism of LHQW treats COVID-19 is currently lacking. Therefore, we employed computer simulations to investigate the mechanism of LHQW treats COVID-19 by modulating inflammatory response. Methods: We employed bioinformatics to screen active ingredients in LHQW and intersection gene targets. PPI, GO and KEGG was used to analyze relationship of intersection gene targets. Molecular dynamics simulations validated the binding stability of active ingredients and target proteins. Binding free energy, radius of gyration and the solvent accessible surface area were analyzed by supercomputer platform. Results: COVID-19 had 4628 gene targets, LHQW had 1409 gene targets, intersection gene targets were 415. Bioinformatics analysis showed that intersection targets were closely related to inflammation and immunomodulatory. Molecular docking suggested that active ingredients (including: licopyranocoumarin, Glycyrol and 3-3-Oxopropanoic acid) in LHQW played a role in treating COVID-19 by acting on CSF2, CXCL8, CCR5, NLRP3, IFNG and TNF. Molecular dynamics was used to prove the binding stability of active ingredients and protein targets. Conclusion: The mechanism of active ingredients in LHQW treats COVID-19 was investigated by computer simulations. We found that active ingredients in LHQW not only reduce cell damage and tissue destruction by inhibiting the inflammatory response through CSF2, CXCL8, CCR5 and IFNG, but also regulate cell survival and growth through NLRP3 and TNF thereby reducing apoptosis.

Author Correction: Arbuscular mycorrhizal fungi promote the growth of plants in the mining associated clay.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Arbuscular mycorrhizal fungi promote the growth of plants in the mining associated clay.

It is urgent to restore the ecological function in open-pit mining areas on grassland in Eastern China. The open-pit mines have abundant of mining associated clay, which is desirable for using as a soil source for ecological restoration. The mining associated clay in Hulunbuir district, Inner Mongolia was selected and mixed with a sandy soil at a ratio of 1:1 (S_C soil). Also, effects of arbuscular mycorrhizal fungi (AMF) inoculation on soil functions were studied. The aboveground and underground biomass of maize in S_C soil was 1.49 and 2.41 times higher than that of clay soil, respectively. In the topsoil and S_C soil, the growth hormone (IAA) and cytokinin (CTK) levels of maize were higher than that of clay, while abscission acid (ABA) levels were lower. The inoculation with AMF could significantly improve the biomass of maize and enhance the stress resistance of plants. Through structural equation model (SEM) analyses, it was found that the soil type and AMF inoculation had the most direct impact on maize growth and biomass content. These finds extend our knowledge regarding a low-cost method for physical and biological improvement of mining associated clay, and to provide theoretical support for large-scale application in the future.

Arbuscular mycorrhizal fungi alleviate root damage stress induced by simulated coal mining subsidence ground fissures.

Coal mining results in surface subsidence and induces the development of ground fissures that damage surrounding plant roots. Very few studies have explored the stress of root damage caused by ground fissures and whether arbuscular mycorrhizal fungi (AMF) can relieve root damage stress induced by ground fissures. In the present study we simulated ground fissure induced root damage, examined the resultant changes in endogenous hormones, root system morphology, leaf area, leaf chlorophyll content, nutrient content and biomass of maize, and examined the ameliorative effects of AMF on maize with root damage. Ground fissures led to significantly higher levels of endogenous abscisic acid (ABA) but significantly reduced levels of indole-3-acetic acid (IAA), gibberellins (GA) and cytokinin (CTK). In addition, ground fissures led to significantly reduced root biomass, total root length, root tip number, total root volume, plant nutrient content, leaf chlorophyll content and leaf area. The shoot biomass of root damaged maize decreased significantly by 46%. By contrast, AMF increased IAA and CTK levels in maize roots, reduced ABA levels, improved the hormone balance of damaged plants, increased total root length, root tip number, total root volume, leaf area and leaf chlorophyll content, increased nutrient content and increased shoot biomass by 34%. Overall, by simulating coal mining subsidence ground fissures, the study investigated the effects of root damage stress on plant biomass, found that AMF can alleviate the mechanical damages to the root system, and provided a theoretical basis for microbial remediation in areas subject to subsidence due to coal mining.