Exploring the mechanism of metformin action in Alzheimer's disease and type 2 diabetes based on network pharmacology, molecular docking, and molecular dynamic simulation.

Background: Metformin, which has been shown to be highly effective in treating type 2 diabetes (T2D), is also believed to be valuable for Alzheimer's disease (AD). Computer simulation techniques have emerged as an innovative approach to explore mechanisms. Objective: To study the potential mechanism of metformin action in AD and T2D. Methods: The chemical structure of metformin was obtained from PubChem. The targets of metformin were obtained from PubChem, Pharm Mapper, Batman, SwissTargetPrediction, DrugBank, and PubMed. The pathogenic genes of AD and T2D were retrieved from the GeneCards, OMIM, TTD, Drugbank, PharmGKB, and DisGeNET. The intersection of metformin with the targets of AD and T2D is represented by a Venn diagram. The protein-protein interaction (PPI) and core targets networks of intersected targets were constructed by Cytoscape 3.7.1. The enrichment information of GO and Kyoto Encyclopedia of Gene and Genomics (KEGG) pathways obtained by the Metascape was made into a bar chart and a bubble diagram. AutoDockTools, Pymol, and Chem3D were used for the molecular docking. Gromacs software was used to perform molecular dynamics (MD) simulation of the best binding target protein. Results: A total of 115 key targets of metformin for AD and T2D were obtained. GO analysis showed that biological process mainly involved response to hormones and the regulation of ion transport. Cellular component was enriched in the cell body and axon. Molecular function mainly involved kinase binding and signal receptor regulator activity. The KEGG pathway was mainly enriched in pathways of cancer, neurodegeneration, and endocrine resistance. Core targets mainly included TP53, TNF, VEGFA, HIF1A, IL1B, IGF1, ESR1, SIRT1, CAT, and CXCL8. The molecular docking results showed best binding of metformin to CAT. MD simulation further indicated that the CAT-metformin complex could bind well and converge relatively stable at 30 ns. Conclusion: Metformin exerts its effects on regulating oxidative stress, gluconeogenesis and inflammation, which may be the mechanism of action of metformin to improve the common pathological features of T2D and AD.

Exploring the mechanism of ellagic acid against gastric cancer based on bioinformatics analysis and network pharmacology.

Ellagic acid (EA) is a natural polyphenolic compound. Recent studies have shown that EA has potential anticancer properties against gastric cancer (GC). This study aims to reveal the potential targets and mechanisms of EA against GC. This study adopted methods of bioinformatics analysis and network pharmacology, including the weighted gene co-expression network analysis (WGCNA), construction of protein-protein interaction (PPI) network, receiver operating characteristic (ROC) and Kaplan-Meier (KM) survival curve analysis, Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, molecular docking and molecular dynamics simulations (MDS). A total of 540 EA targets were obtained. Through WGCNA, we obtained a total of 2914 GC clinical module genes, combined with the disease database for screening, a total of 606 GC-related targets and 79 intersection targets of EA and GC were obtained by constructing Venn diagram. PPI network was constructed to identify 14 core candidate targets; TP53, JUN, CASP3, HSP90AA1, VEGFA, HRAS, CDH1, MAPK3, CDKN1A, SRC, CYCS, BCL2L1 and CDK4 were identified as the key targets of EA regulation of GC by ROC and KM curve analysis. The enrichment analysis of GO and KEGG pathways of key targets was performed, and they were mainly enriched in p53 signalling pathway, PI3K-Akt signalling pathway. The results of molecular docking and MDS showed that EA could effectively bind to 13 key targets to form stable protein-ligand complexes. This study revealed the key targets and molecular mechanisms of EA against GC and provided a theoretical basis for further study of the pharmacological mechanism of EA against GC.

Exploring the Potential Molecular Mechanism of the Shugan Jieyu Capsule in the Treatment of Depression through Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation.

BACKGROUND: Shugan Jieyu Capsule (SJC) is a pure Chinese medicine compound prepared with Hypericum perforatum and Acanthopanacis Senticosi. SJC has been approved for the clinical treatment of depression, but the mechanism of action is still unclear. OBJECTIVE: Network pharmacology, molecular docking, and molecular dynamics simulation (MDS) were applied in the present study to explore the potential mechanism of SJC in the treatment of depression. METHODS: TCMSP, BATMAN-TCM, and HERB databases were used, and related literature was reviewed to screen the effective active ingredients of Hypericum perforatum and Acanthopanacis Senticosi. TCMSP, BATMAN-TCM, HERB, and STITCH databases were used to predict the potential targets of effective active ingredients. GeneCards database, DisGeNET database, and GEO data set were used to obtain depression targets and clarify the intersection targets of SJC and depression. STRING database and Cytoscape software were used to build a protein-protein interaction (PPI) network of intersection targets and screen the core targets. The enrichment analysis on the intersection targets was conducted. Then the receiver operator characteristic (ROC) curve was constructed to verify the core targets. The pharmacokinetic characteristics of core active ingredients were predicted by SwissADME and pkCSM. Molecular docking was performed to verify the docking activity of the core active ingredients and core targets, and molecular dynamics simulations were performed to evaluate the accuracy of the docking complex. RESULTS: We obtained 15 active ingredients and 308 potential drug targets with quercetin, kaempferol, luteolin, and hyperforin as the core active ingredients. We obtained 3598 targets of depression and 193 intersection targets of SJC and depression. A total of 9 core targets (AKT1, TNF, IL6, IL1B, VEGFA, JUN, CASP3, MAPK3, PTGS2) were screened with Cytoscape 3.8.2 software. A total of 442 GO entries and 165 KEGG pathways (P<0.01) were obtained from the enrichment analysis of the intersection targets, mainly enriched in IL-17, TNF, and MAPK signaling pathways. The pharmacokinetic characteristics of the 4 core active ingredients indicated that they could play a role in SJC antidepressants with fewer side effects. Molecular docking showed that the 4 core active components could effectively bind to the 8 core targets (AKT1, TNF, IL6, IL1B, VEGFA, JUN, CASP3, MAPK3, PTGS2), which were related to depression by the ROC curve. MDS showed that the docking complex was stable. CONCLUSION: SJC may treat depression by using active ingredients such as quercetin, kaempferol, luteolin, and hyperforin to regulate targets such as PTGS2 and CASP3 and signaling pathways such as IL-17, TNF, and MAPK, and participate in immune inflammation, oxidative stress, apoptosis, neurogenesis, etc.

Exploring the Potential Mechanism of Action of Ursolic Acid against Gastric Cancer and COVID-19 using Network Pharmacology and Bioinformatics Analysis.

BACKGROUND: Patients with gastric cancer (GC) are more likely to be infected with 2019 coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the prognosis is worse. It is urgent to find effective treatment methods. OBJECTIVE: This study aimed to explore the potential targets and mechanism of ursolic acid (UA) on GC and COVID-19 by network pharmacology and bioinformatics analysis. METHODS: The online public database and weighted co-expression gene network analysis (WGCNA) were used to screen the clinical related targets of GC. COVID-19-related targets were retrieved from online public databases. Then, a clinicopathological analysis was performed on GC and COVID-19 intersection genes. Following that, the related targets of UA and the intersection targets of UA and GC/COVID-19 were screened. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome Analysis (KEGG) pathway enrichment analyses were performed on the intersection targets. Core targets were screened using a constructed protein-protein interaction network. Finally, molecular docking and molecular dynamics simulation (MDS) of UA and core targets were performed to verify the accuracy of the prediction results. RESULTS: A total of 347 GC/COVID-19-related genes were obtained. The clinical features of GC/COVID-19 patients were revealed using clinicopathological analysis. Three potential biomarkers (TRIM25, CD59, MAPK14) associated with the clinical prognosis of GC/COVID-19 were identified. A total of 32 intersection targets of UA and GC/COVID-19 were obtained. The intersection targets were primarily enriched in FoxO, PI3K/Akt, and ErbB signaling pathways. HSP90AA1, CTNNB1, MTOR, SIRT1, MAPK1, MAPK14, PARP1, MAP2K1, HSPA8, EZH2, PTPN11, and CDK2 were identified as core targets. Molecular docking revealed that UA strongly binds to its core targets. The MDS results revealed that UA stabilizes the protein-ligand complexes of PARP1, MAPK14, and ACE2. CONCLUSION: This study found that in patients with gastric cancer and COVID-19, UA may bind to ACE2, regulate core targets such as PARP1 and MAPK14, and the PI3K/Akt signaling pathway, and participate in antiinflammatory, anti-oxidation, anti-virus, and immune regulation to exert therapeutic effects.

Preparation and Application of Nanozymes with Uricase-Like Activity Based on Molecularly Imprinted Polymers.

Nanozymes have advantages over natural enzymes in terms of efficiency, stability, and economy. MVSM (Mixed Valence State MOF) is a nano-oxidase with uricase-like activity that may catalyze uric acid (UA) in the body into allantoin and H2 O2 to treat gout and hyperuricemia by substituting natural uricase. However, it cannot specifically identify and choose UA. To increase the selectivity and affinity of MVSM for UA, the composite material MVSM@MIP is innovatively synthesized using a new synthetic approach termed the "two-step synthesis method," which may prevent UA from being oxidized by MVSM during manufacture in this study. At the same time, this study also provides experimental proof of the effective creation of the material, the advantages of the "two-step synthesis approach," and the high selectivity and affinity of MVSM@MIP for UA. Based on these findings, the suggested technique may be used to effectively catalyze uric acid in human urine with high activity.

Recent Advances in Construction and Application of Metal-Nanozymes in Pharmaceutical Analysis.

Nanozymes, made of emerging nanomaterials, have similar activity to natural enzyme and exhibit promising applications in in the fields of environment, biology and medicine, and food safety science. In recent years, with the deep finding and research to nanozymes by researchers, its application in field of pharmaceutical analysis has emerged gradually, possessing great significance in drug safety evaluation and quality control. This review summarizes the construction of metal nanozymes, strategies to improve their performance and their application in pharmaceutical detection and analysis, especially in detection of target analytes consisting of small molecule medicine macromolecule, toxic and others, which proposes theoretical foundation for development of nanozymes in this field. At the same time, it also provides opportunities and challenges for the construction and application of new nanozymes.

Exploration of the main active components and pharmacological mechanism of Yerba Mate based on network pharmacology.

INTRODUCTION: Yerba mate is widely consumed in South American countries and is gaining popularity around the world. Long-term consumption of yerba mate has been proven to have health-care functions and therapeutic effects on many diseases; however, its underlying mechanism has not been clearly elucidated. In this research, we explored the pharmacological mechanism of yerba mate through a network pharmacological approach. MATERIAL AND METHODS: The bioactive components of yerba mate were screened from published literature and the Traditional Chinese Medicine System Pharmacology Database (TCMSP), and the targets and related diseases were retrieved by TCMSP. Furthermore, the component-target-disease network an protein-protein interaction (PPI) network were constructed, and combined with gene ontology (GO) functional analysis and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis to explore the pharmacological mechanism of yerba mate. RESULTS: As a result, 16 bioactive components of yerba mate were identified, which acted on 229 targets in total. Yerba mate can be used to treat 305 diseases, such as breast cancer, asthma, Alzheimer's disease, osteoarthritis, diabetes mellitus, atherosclerosis, and obesity. Protein kinase B (AKT1), signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase 1 (MAPK1), transcription factor AP-1 (JUN), cellular tumour antigen (p53) TP53, tumour necrosis factor (TNF), transcription factor p65 (RELA), interleukin-6 (IL6), amyloid-beta precursor protein (APP), and vascular endothelial growth factor A (VEGFA) were identified as the key targets of yerba mate playing pharmacological roles. The signalling pathways identified by KEGG pathway enrichment analysis that were most closely related to the effects of yerba mate included pathways in cancer, fluid shear stress and atherosclerosis, and human cytomegalovirus infection. CONCLUSION: the results of our study preliminarily verify the basic pharmacological action and possible mechanism of yerba mate and provide a reference for the further development of its medicinal value.

Degradation study of rutin as template from magnetic composite molecularly imprinted polymer supernatant samples by liquid chromatography-mass spectrometry.

Compound structure change of the template molecule from rutin samples might affect the selectivity and adsorption of molecularly imprinted polymers based on magnetic halloysite nanotubes (MHNTs@MIPs). In the present study, not only MHNTs@MIPs were successfully characterized by TEM, SEM, EDS, FT-IR, TGA and VSM, but related compounds and potential degradation factors of template molecule rutin were also investigated in the polymerization and elution process of MHNTs@MIPs by high-performance liquid chromatography together with photodiode array and tandem mass spectrometry (HPLC-PDA-MS/MS) in negative ion mode. Nine flavonol components were detected in rutin active pharmaceutical ingredient samples, such as rutin, isoquercetrin, kaempferol-3-O-rutoside, isorhamnetin-3-O-rutoside, quercetin, kaempferol, isorhamnetin and two unknown triglycosides. Under acidic, basic, oxidative and solvent conditions, two common degradants with negative ESI-MS ions at m/z 317 and 349 were found. Meanwhile, protocatechuic acid and methyl ester were also observed as two characteristic oxidative degradants. Compared to above degradation results, rutin-dimethylsulfoxide adduct and oxidative degradant were observed in the synthesis supernatant, which demonstrated that appropriate solvents and strict control of the oxygen level were critical in the synthesis process. Therefore, degradation studies provide a solid foundation for the optimization of MHNT@MIP synthesis with rutin as a template, which can be potentially applied to other templates for further material performance investigation.

Novel composite nanomaterials based on magnetic molecularly imprinted polymers for selective extraction and determination of rutin in fruit juice.

In this work, with the attempt to further improve the selectivity, magnetism and loading proportion of existing adsorbents, a novel composite (MGO/MHNTs@MIPs) was synthesized by electrostatically combining molecularly imprinted polymer based on the surface of magnetic halloysite nanotubes (MHNTs@MIPs) with magnetic graphene oxide (MGO). Then some characterizations were done to prove its successful synthesis. Besides, the bonding experiment showed that it possessed a loading capacity of up to 132 mg·g-1, and the adsorption behavior of MGO/MHNTs@MIPs was elucidated by Langmuir isotherm model and Pseudo-second order model. By comparing its adsorption capacity to analogues, we concluded that the MGO/MHNTs@MIPs with the MHNTs@MIPs as basic elements exhibited higher selectivity (imprinting factor = 2.25) than that of MGO/MHNTs@NIPs based on MHNTs@NIPs for template rutin. Furthermore, a series of solid phase extraction conditions were optimized, and then the materials were used for the extraction and detection of rutin in fruit juice under the optimal conditions.

Systematic Review and Network Meta-Analysis of Noninvasive Brain Stimulation on Dysphagia after Stroke.

Background: Dysphagia is a common sequelae after stroke. Noninvasive brain stimulation (NIBS) is a tool that has been used in the rehabilitation process to modify cortical excitability and improve dysphagia. Objective: To systematically evaluate the effect of NIBS on dysphagia after stroke and compare the effects of two different NIBS. Methods: Randomized controlled trials about the effect of NIBS on dysphagia after stroke were retrieved from databases of PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang Data, VIP, and CBM, from inception to June 2021. The quality of the trials was assessed, and the data were extracted according to the Cochrane Handbook for Systematic Reviews of Interventions. A statistical analysis was carried out using RevMan 5.3 and ADDIS 1.16.8. The effect size was evaluated by using the standardized mean difference (SMD) and a 95% confidence interval (CI). Results: Ultimately, 18 studies involving 738 patients were included. Meta-analysis showed that NIBS could improve the dysphagia outcome and severity scale (DOSS) score (standard mean difference (SMD) = 1.44, 95% CI 0.80 to 2.08, P < 0.05) and the water swallow test score (SMD = 6.23, 95% CI 5.44 to 7.03, P < 0.05). NIBS could reduce the standardized swallowing assessment (SSA) score (SMD = -1.04, 95% CI -1.50 to -0.58, P < 0.05), the penetration-aspiration scale (PAS) score (SMD = -0.85, 95% CI -1.33 to -0.36, P < 0.05), and the functional dysphagia scale score (SMD = -1.05, 95% CI -1.48 to -0.62, P < 0.05). Network meta-analysis showed that the best probabilistic ranking of the effects of two different NIBS on the DOSS score is rTMS (P = 0.52) > tDCS (P = 0.48), the best probabilistic ranking of the SSA score is rTMS (P = 0.72) > tDCS (P = 0.28), and the best probabilistic ranking of the PAS score is rTMS (P = 0.68) > tDCS (P = 0.32). Conclusion: Existing evidence showed that NIBS could improve swallowing dysfunction and reduce the occurrence of aspiration after stroke, and that rTMS is better than tDCS. Limited by the number of included studies, more large-sample, multicenter, double-blind, high-quality clinical randomized controlled trials are still needed in the future to further confirm the results of this research.

Study on performance of mimic uricase and its application in enzyme-free analysis.

Nanozymes were the novel research field to replace natural enzymes because of stability and low cost. However, the research on nanozymes was mainly focused on peroxidase, and there was little research about nanozymes with oxidase-like activity, especially mimic oxidase of small molecules related to human physiology. High levels of uric acid (UA) in the body can cause hyperuricemia and gout. And natural uricase cured this disease because it could oxidize UA. The oxidase-like activity of mixed valence state metal organic frameworks with cerium (MVSM) had been studied, but MVSM was found to have uricase-like activity in this article. The catalytic process of UA with MVSM was studied by a variety of analytical methods, which was similar to the natural uricase except for further oxidation of H2O2. The catalytic activity constants of MVSM were acquired by the Michaelis-Menten equation. MVSM had a better ability to catalyze UA in in vivo and in vitro experiments. An enzyme-free analysis-based mimic uricase for UA was established. All the experimental results proved that MVSM had a good prospect to replace the natural uricase. A nanomaterial, mixed valence state Ce-MOF (MVSM), with uricase-like activity has been found in vivo and in vitro. This material has potential to be a fluorescent analysis for detecting uric acid without uricase.

Effect of dapagliflozin on diabetic patients with cardiovascular disease via MAPK signalling pathway.

Clinical studies have shown that dapagliflozin can reduce cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM), but the exact mechanism is unclear. In this study, we used the molecular docking and network pharmacology methods to explore the potential mechanism of dapagliflozin on T2DM complicated with cardiovascular diseases (CVD). Dapagliflozin's potential targets were predicted via the Swiss Target Prediction platform. The pathogenic targets of T2DM and CVD were screened by the Online Mendelian Inheritance in Man (OMIM) and Gene Cards databases. The common targets of dapagliflozin, T2DM and CVD were used to establish a protein-protein interaction (PPI) network; the potential protein functional modules in the PPI network were found out by MCODE. Metascape tool was used for Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis. A potential protein functional module with the best score was obtained from the PPI network and 9 targets in the protein functional module all showed good binding properties when docking with dapagliflozin. The results of KEGG pathway enrichment analysis showed that the underlying mechanism mainly involved AGE-RAGE signalling pathway in diabetic complications, TNF signalling pathway and MAPK signalling pathway. Significantly, the MAPK signalling pathway was considered as the key pathway. In conclusion, we speculated that dapagliflozin played a therapeutic role in T2DM complicated with CVD mainly through MAPK signalling pathway. This study preliminarily reveals the possible mechanism of dapagliflozin in the treatment of T2DM complicated with CVD and provides a theoretical basis for future clinical research.

Nanozyme based on graphene oxide modified with Fe3O4, CuO, and cucurbit[6]uril for colorimetric determination of homocysteine.

A nanozyme based on graphene oxide modified with Fe3O4 NPs, CuO NPs, and cucurbit[6]uril has been successfully fabricated by a simple sonochemical technique. By employing CB[6] as a specific binding pocket and Fe3O4@CuO-GO as a peroxidase mimic, this novel nanozyme (BN I) is equipped with molecular recognition ability and enhanced peroxidase-like activity. On the basis of the inhibition effect of homocysteine (Hcy) towards the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) catalyzed by BN I, a simple colorimetric method is established for the sensitive and selective determination of Hcy. This proposed method displays a good linear response in the range 5-200 µM with a detection limit of 1.8 µM. In the practical assay of human plasma samples, the relative standard deviations (RSD) are lower than 11% and the recoveries are between 98.0 and 104.9%. In the assay of human urine samples, the RSD are below 9.0% and the recoveries range from 94.0 to 103.5%. The colorimetric method presented offers a convenient and accurate way for the determination of biomarkers in point-of-care testing (POCT).

ZnO nanorods/Fe3O4-graphene oxide/metal-organic framework nanocomposite: recyclable and robust photocatalyst for degradation of pharmaceutical pollutants.

Nanosized semiconductors are widely utilized as solar energy based photocatalyst. However, the deficiencies such as poor adsorption toward contaminants and recyclability issues, rapid recombination of photo-introduced radicals, and deactivation by scavengers are still be the obstacle. To addressing those obstacles, zeolitic imidazolate framework-8 (ZIF-8), photosensitive ZnO, and paramagnetic Fe3O4 were anchored on conductive graphene oxide (GO) to prepare a nanocomposite photocatalyst ZnO/Fe3O4-GO/ZIF. The photocatalyst showed good robustness to scavengers of hydroxyl radicals (OH•), superoxide radicals (O2•-), and hole (h+) with hydrophobic ZIF-8 modified surface. Finally, four pharmaceuticals (sulfamethazine, metronidazole, norfloxacin, and 4-acetaminophen) were degraded rapidly under simulated solar irradiation for 1 h, and the photocatalyst could be recycled at least ten times without obvious deactivation. The final results show that combination of semiconductor, graphene oxide and ZIF-8 is a good idea for construction of efficient photocatalyst. It offers new views in interface modification of nanomaterials, photocatalysis, and adsorption.

Non-invasive Brain Stimulation for Neuropathic Pain After Spinal Cord Injury: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: This study aims to systematically evaluate the effect of non-invasive brain stimulation (NIBS) on neuropathic pain (NP) after spinal cord injury and compare the effects of two different NIBS. METHODS: Randomized controlled trials (RCTs) about the effect of NIBS on NP after spinal cord injury (SCI) were retrieved from the databases of PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang Data, VIP, and CBM from inception to September 2021. The quality of the trials was assessed, and the data were extracted according to the Cochrane handbook of systematic review. Statistical analysis was conducted with Stata (version 16) and R software (version 4.0.2). RESULTS: A total of 17 studies involving 507 patients were included. The meta-analysis showed that NIBS could reduce the pain score (SMD = -0.84, 95% CI -1.27 -0.40, P = 0.00) and the pain score during follow-up (SMD = -0.32, 95%CI -0.57 -0.07, P = 0.02), and the depression score of the NIBS group was not statistically significant than that of the control group (SMD = -0.43, 95%CI -0.89-0.02, P = 0.06). The network meta-analysis showed that the best probabilistic ranking of the effects of two different NIBS on the pain score was repetitive transcranial magnetic stimulation (rTMS) (P = 0.62) > transcranial direct current stimulation (tDCS) (P = 0.38). CONCLUSION: NIBS can relieve NP after SCI. The effect of rTMS on NP is superior to that of tDCS. We suggest that the rTMS parameters are 80-120% resting motion threshold and 5-20 Hz, while the tDCS parameters are 2 mA and 20 min. However, it is necessary to carry out more large-scale, multicenter, double-blind, high-quality RCT to explore the efficacy and mechanism of NIBS for NP after SCI.

Cucurbiturils regulating Fe3O4-Au nanoparticles as a multi-functional platform for Cd2+ sensing and nitrocompound catalysis.

Herein, through the interfacial regulation of cucurbiturils (CBs) on Fe3O4-Au nanoparticles, a novel multifunctional platform is constructed for the sensitive detection of Cd2+ and the selective catalytic reduction (SCR) of nitrocompounds. The reported surface modification strategy provides an efficient approach to prepare a new platform for multiple purposes.