Discussion on the Mechanism of Action of High-frequency Drugs for Treating Heart Failure Based on Network Pharmacology

Objective:To explore the target and mechanism of Astragalus membranaceus,poria,salvia miltiorrhiza and semen leiocarpa in the treatment of heart failure by network pharmacology.Methods:The active components of traditional Chinese medicine and the target of heart failure were screened by multi-platform,and the standard gene was transformed by Uniprot.CytoCasp 3.6.1 was used to draw the network diagram of traditional Chinese medicine・component-target.Go and KEGG analysis were performed by Metascape.Results:A total of 36 predictive target sites of Radix Astragalus,Fuling poria,Salvia miltiorrhiza and Draba nemorosa were screened for treatment of heart failure,mainly involving nerve and factor pathways:ADRB2,ADRA1B and AChE.Cancer pathway:TP53,TNF;Pathways of inflammation:IL1B,PTSG2,PTSG1;Sex hormone pathway:ESRI,AR,PGR;Others:SCN5A,HIF1A,etc.The results of GO and KEGG enrichment suggested that the treatment of heart failure with the top four drugs involved cancer pathway,calcium signaling pathway,HIF-1 signaling pathway,and involved in blood circulation,cell proliferation and other processes.Conclusion:This study combines the pharmacological studies of Chinese medicine and western medicine to reveal the mechanism of multi-target and multi-channel regulation of body balance in Chinese medicine treatment.

Climate change and Aedes albopictus risks in China:current impact and future projection

Background Future distribution of dengue risk is usually predicted based on predicted climate changes using general circulation models(GCMs).However,it is difficult to validate the GCM results and assess the uncertainty of the predictions.The observed changes in climate may be very different from the GCM results.We aim to utilize trends in observed climate dynamics to predict future risks of Aedes albopictus in China.Methods We collected Ae.albopictus surveillance data and observed climate records from 80 meteorological stations from 1970 to 2021.We analyzed the trends in climate change in China and made predictions on future climate for the years 2050 and 2080 based on trend analyses.We analyzed the relationship between climatic variables and the prevalence of Ae.albopictus in different months/seasons.We built a classification tree model(based on the average of 999 runs of classification and regression tree analyses)to predict the monthly/seasonal Ae.albopictus distribution based on the average climate from 1970 to 2000 and assessed the contributions of different climatic variables to the Ae.albopictus distribution.Using these models,we projected the future distributions of Ae.albopictus for 2050 and 2080.Results The study included Ae.albopictus surveillance from 259 sites in China found that winter to early spring(November–February)temperatures were strongly correlated with Ae.albopictus prevalence(prediction accuracy ranges 93.0–98.8%)—the higher the temperature the higher the prevalence,while precipitation in summer(June–September)was important predictor for Ae.albopictus prevalence.The machine learning tree models predicted the current prevalence of Ae.albopictus with high levels of agreement(accuracy>90%and Kappa agreement>80%for all 12 months).Overall,winter temperature contributed the most to Ae.albopictus distribution,followed by summer precipitation.An increase in temperature was observed from 1970 to 2021 in most places in China,and annual change rates varied substantially from-0.22℃/year to 0.58℃/year among sites,with the largest increase in temperature occurring from February to April(an annual increase of 1.4–4.7℃ in monthly mean,0.6–4.0℃ in monthly minimum,and 1.3–4.3℃ in monthly maximum temperature)and the smallest in November and December.Temperature increases were lower in the tropics/subtropics(1.5–2.3℃ from February–April)compared to the high-latitude areas(2.6–4.6℃ from February–April).The projected temperatures in 2050 and 2080 by this study were approximately 1–1.5℃ higher than those projected by GCMs.The estimated current Ae.albopictus risk distribution had a northern boundary of north-central China and the southern edge of northeastern China,with a risk period of June–September.The projected future Ae.albopictus risks in 2050 and 2080 cover nearly all of China,with an expanded risk period of April–October.The current at-risk population was estimated to be 960 million and the future at-risk population was projected to be 1.2 billion.Conclusions The magnitude of climate change in China is likely to surpass GCM predictions.Future dengue risks will expand to cover nearly all of China if current climate trends continue.

Fe_3O_4@C nanoparticles as high-performance Fenton-like catalyst for dye decoloration

Water pollution has become serious environmental problem nowadays. Advanced oxidation processes(AOP) have been widely applied in water treatment.However, traditional Fenton reaction based on Fe2﹢-H2O2 system has obvious drawbacks, which limit its applications In this study, magnetic Fe3O4core-C shell nanoparticles(Fe3O4@C NPs) were prepared for the decoloration of methylene blue(MB) via the co-precipitation followed by the hydrothermal dehydrogenation of glucose. Fe3O4@C NPs showed high catalytic activity of the decoloration of MB through the decomposition of H2O2 in Fenton-like reactions. Fe3O4@C NPs had much higher activity than bare Fe3O4 cores, suggesting the coating of carbon enhanced the catalytic activity. The performance of Fe3O4@C NPs was better at lower pH and higher temperature, but was significantly inhibited in the presence of radical scavenger tertiary butanol. Fe3O4@C NPs could be magnetic separated and regenerated, and maintained with very good catalytic activity. The implication for the applications of Fe3O4@C NP-catalyzed Fenton-like reactions in water treatment was discussed.

The EGFR-P38 MAPK axis up-regulates PD-L1 through miR-675-5p and down-regulates HLA-ABC via hexokinase-2 in hepatocellular carcinoma cells

Background:Immunotherapy has been shown to be a promising strategy against human cancers.A better understanding of the immune regulation in hepatocellular carcinoma(HCC)could help the development of immunotherapy against HCC.The epidermal growth factor receptor(EGFR)signaling is frequently activated in HCC and plays important roles in tumorigenesis.However,its role in HCC immunity is still largely unknown.This study aimed to investigate the impact of EGFR signaling on programmed death-ligand 1(PD-L1)and human leukocyte antigen class-I(HLA-I)expression in HCC cells and its underlying mechanisms.Methods:The expression of phosphorylated EGFR(p-EGFR),PD-L1,and HLAI(HLA-ABC)in HCC specimens was detected by immunohistochemistry,and their correlations were analyzed.PD-L1 and HLA-ABC expression in EGFRactivated HCC cells were detected by quantitative real-time PCR,Western blotting,and flow cytometry,and T cell-mediated lysis was performed to test the immunosuppressive effects of PD-L1 and HLA-ABC alterations in HCC cells.Furthermore,the underlying mechanisms of EGFR activation-induced PD-L1 up-regulation and HLA-ABC down-regulation were explored by animal experiments,luciferase reporter assay,and gene gain-and loss-of-function studies.Results:p-EGFR was positively correlated with PD-L1 and negatively correlated with HLA-ABC expression in HCCs.EGFR activation by its ligand EGF up-regulated PD-L1 and down-regulated HLA-ABC in HCC cells,which was functionally important and could be abolished by the EGFR inhibitor,gefitinib,both in vitro and in vivo.Mechanistically,enhanced P38 mitogenactivated protein kinase(MAPK)activation down-regulated microRNA-675-5p(miR-675-5p)and up-regulated glycolysis-related enzyme hexokinase 2(HK2);miR-675-5p down-regulation enhanced the stability of PD-L1 mRNA probably via the 3’-untranslated region(3’-UTR)of PD-L1 and thereby caused PD-L1 accumulation,and HK2 up-regulation enhanced aerobic glycolysis and mediated a decrease in HLA-ABC.Conclusions:The EGFR-P38 MAPK axis could up-regulate PD-L1 through miR-675-5p and down-regulate HLA-ABC via HK2 in HCC cells.Our study reveals a novel signaling network that may cause immune suppression in HCC and suggests that EGFR signaling can be targeted for HCC immunotherapy.

PEGylation of Double-Walled Carbon Nanotubes for Increasing Their Solubility in Water

Polyethylene glycol(PEG)functionalized double-walled carbon nanotubes(DWNTs)have been synthesized by a[2+1]cycloaddition reaction and characterized by transmission electron microscopy,atomic force microscopy,Raman spectroscopy,thermal gravimetric analysis,and UV-visible spectroscopy.Functionalization affords a large increase in the aqueous solubility of DWNTs.The saturated concentrations of DWNTs functionalized with diazido-terminated PEG800(with a molecular weight of 800)and azido-terminated PEG750 monomethylether(with a molecular weight of 750)are very similar-0.36 and 0.37 mg/mL(DWNTs equivalent concentration),respectively.

Interaction of multi-walled carbon nanotubes and zinc ions enhances cytotoxicity of zinc ions

More and more nanomaterials enter the environment along with their production, application and deposal. They may alter the biological effect of pollutants already existing in the real environment by different interactions. Therefore efforts should also be paid to investigate the combined toxicity of nanomaterials and pollutants. Herein, we studied the combined toxicity of oxi- dized multi-walled carbon nanotubes （O-MWCNTs） and zinc ions on ceils. It is found that cytotoxicity of the combined O-MWCNTs and zinc ions elevates significantly, compared with O-MWCNTs or zinc ions alone. This result comes from the assays of cell morphology, cell viability and proliferation, cell membrane integrity, mitochondrial membrane potential and cell apoptosis. Mechanism studies indicate that O-MWCNTs absorb zinc ions and form slight aggregation. These enhance remark- ably the cellular uptake of O-MWCNTs, and thus induce the death of cells by bringing in more zinc ions into cells. Our study indicates that the existence of nanomaterials could change the bioconsequence of other pollutants and emphasizes the im- portance of the combined toxicity research in the presence of nanomaterials.

Stable isotope labeling of nanomaterials for biosafety evaluation and drug development

Quantitative information,such as environmental migration,absorption,biodistribution,biotransformation,and elimination,is fundamental and essential for the nanosafety evaluations of nanomaterials.Due to the complexity of biological and environmental systems,it is challenging to develop quantitative approaches and tools that could characterize intrinsic behaviors of nanomaterials in the organisms.The isotopic tracers are ideal candidates to tune the physical properties of nanomaterials while preserving their chemical properties.In this review article,we summarized the stable isotope labeling methods of nanomaterials for evaluating their environmental and biological effects.The skeleton labeling protocols of carbon nanomaterials and metal/metal oxide nanoparticles were introduced.The advantages and disadvantages of stable isotope labeling were discussed in comparison with other quantitative methods for nanomaterials.The quantitative information of nanomaterials in environmental and biological systems was summarized along with the biosafety data.The benefits for drug development of nanomedicine were analyzed based on the targeting effects,persistent accumulation,and safety.Finally,the challenges and future perspectives of stable isotope labeling in nanoscience and nanotechnology were discussed.

Direct Imaging of Titania Nanotubes Located in Mouse Neural Stem Cell Nuclei

Titania nanotubes(TiO2-NTs)are a potential drug vehicle for use in nanomedicine.To this end,a preliminary study of the interaction of a model cell with TiO2-NTs has been carried out.TiO2-NTs were first conjugated with a fl uorescent label,fl uorescein isothiocyanate(FITC).FITC-conjugated titania nanotubes(FITC-TiO2-NTs)internalized in mouse neural stem cells(NSCs,line C17.2)can be directly imaged by confocal microscopy.The confocal imaging showed that FITC-TiO2-NTs readily entered into the cells.After co-incubation with cells for 24 h,FITC-TiO2-NTs localized around the cell nucleus without crossing the karyotheca.More interestingly,the nanotubes passed through the karyotheca entering the cell nucleus after co-incubation for 48 h.Atomic force microscopy(AFM)and transmission electron microscopy(TEM)were also employed in tracking the nanotubes in the cell.These results will be of benefit in future studies of TiO2-NTs for use as a drug vehicle,particularly for DNA-targeting drugs.

Neurodegeneration-associated FUS is a novel regulator of circadian gene expression

Background:Circadian rhythms are oscillating physiological and behavioral changes governed by an internal molecular clock,and dysfunctions in circadian rhythms have been associated with ageing and various neurodegenerative diseases.However,the evidence directly connecting the neurodegeneration-associated proteins to circadian control at the molecular level remains sparse.Methods:Using meta-analysis,synchronized animals and cell lines,cells and tissues from FUS R521C knock-in rats,we examined the role of FUS in circadian gene expression regulation.Results:We found that FUS,an oscillating expressed nuclear protein implicated in the pathogenesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),exerted a novel feedback route to regulate circadian gene expression.Nr1d1-encoded core circadian protein REV-ERBαbound the Fus promoter and regulated the expression of Fus.Meanwhile,FUS was in the same complex as PER/CRY,and repressed the expression of E box-containing core circadian genes,such as Per2,by mediating the promoter occupancy of PSF-HDAC1.Remarkably,a common pathogenic mutant FUS(R521C)showed increased binding to PSF,and caused decreased expression of Per2.Conclusions:Therefore,we have demonstrated FUS as a modulator of circadian gene expression,and provided novel mechanistic insights into the mutual influence between circadian control and neurodegeneration-associated proteins.

Intestinal lysozyme releases Nod2 ligand(s) to promote the intestinal mucosal adjuvant activity of cholera toxin

Commensal bacteria boost serum IgG production in response to oral immunization with antigen and cholera toxin(CT)in a manner that depends on Nod2(nucleotide-binding oligomerization domain-containing protein 2).In this study,we examined the role of intestinal lysozyme(Lyz1)in adjuvant activity of CT.We found that Lyz1 released Nod2 ligand(s)from bacteria.Lyz1 deficiency reduced the level of circulating Nod2 ligand in mice.Lyz1 deficiency also reduced the production of IgG and T-cellspecific cytokines after oral immunization in mice.Supplementing Lyz1-deficient mice with MDP restored IgG production.Furthermore,overexpression of Lyz1 in intestinal epithelium boosted the antigen-specific IgG response induced by CT.Collectively,our results indicate that Lyz1 plays an important role in mediating the immune regulatory effect of commensal bacteria through the release of Nod2 ligand(s).

Mild hyperthermia synergized chemotherapy by Bi_(2)Se_(3)/MoSe_(2)nanosaucers for cancer treatment with negligible thermal resistance

Harsh photothermal temperatures(>50℃)caused heating damage to the normal tissues and induced thermal resistance in cancer cells,which significantly limited the safety and efficacy of photothermal therapy(PTT)in cancer treatment.Mild hyperthermia(<42℃)combined with chemotherapy might solve this issue.Herein,a novel transition metal dichalcogenides nanostructure,namely,Bi_(2)Se_(3)/MoSe_(2)nanosaucers(BMNSs),was designed to produce mild photo-hyperthermia(mPTT)and combined with chemotherapy to improve the overall antitumor efficacy.The BMNSs were constituted by Bi_(2)Se_(3)hexagonal nanoplates and enclosed with MoSe_(2)nanosheets evenly.While the MoSe_(2)moiety endowed the nanoplatform with excellent photothermal efficacy,the Bi_(2)Se_(3)substrates provided large specific surface area to anchor more doxorubicin(DOX)molecules as chemotherapeutic agent.Under the stimuli of mPTT/tumor acidic microenvironment,the tumor-specific drug release and the enhanced chemotherapy could be realized,showing impressive therapeutic outcomes against 4T1 cells.The synergetic therapeutic mechanism might be attributed to the mPTT induced cell membrane permeability,and interestingly,the expression of heat shock proteins 70 was not elevated obviously after the synergetic therapy,thus to avoid the tumor thermal resistance and further improve the therapeutic effect.The in vivo anti-tumoral performance of the BMNSs was further studied and complete tumor eradication was achieved without any recurrence and biotoxicity.Not only demonstrating a paradigm of high therapeutic efficacy of mild hyperthermia and synergistic chemotherapy for precise cancer therapy,our findings proved that the cancer therapeutic effect can be improved with minimal side effects through exquisite designing of the microstructures and the physiochemical properties of the nanoplatform.

Silica nanoparticle with a single His-tag for addressable functionalization, reversible assembly, and recycling

For many biomedical and catalytic applications, such as encapsulation of proteins/enzymes in nanopartides （NPs）, it is preferable to have well-dispersed small NPs that are stable in solution and behave quasi-homogeneously. However, conventional liquid phase methods for small-NP synthesis and functionalization usually face great difficulties in separation/purification and recycling. In addition, controlling the orientation of proteins inside NPs is also a crucial issue to maximize the activity of the encapsulated proteins. Herein, we report a solid phase method to solve these problems. Using His-tagged proteins as cores, well-dispersed core-sheU silica NPs are facilely synthesized and functionalized in a column. The core His-tagged proteins are kept bound on the surface of the resIn beads in the column during the entire process, making the separation/purification of NPs and their precursors during the multiple-step process as simple as a few-minutes procedure of draining and washing the column. Each obtained silica NP has an adjustable eccentric core-shell structure with only one His-tag sticking out of the particle. This single His-tag on the surface of each NP not only makes it easy for addressable and stoichiometric functionalization of the NP but also provides an easy way to reversibly assemble NPs into dimers or be oriented on the surface of large particles. Notably, this solid phase approach also provides a versatile means to control the orientation of proteins inside NPs, and the His-tag makes it easy to recycle those well-dispersed small NPs.