Dual-Mechanism Glycolipidpeptide with High Antimicrobial Activity, Immunomodulatory Activity, and Potential Application for Combined Antibacterial Therapy.

Bacterial drug resistance is becoming increasingly serious, and it is urgent to develop effective antibacterial drugs. Antimicrobial peptides (AMPs), as potential candidates against bacteria, have a broad prospect for development. Herein, a series of AMPs with biological characteristics (net positive charge, amphiphilicity, and α-helix), an AXA motif recognized by membrane bound serine protease type I signal peptidases (SPase I), an FLPII motif to reduce hemolysis, and a monosaccharide motif to improve the stability and activity were designed and synthesized, and among which, the glycolipidpeptide GLP6 (glycosylated LP6 lipopeptide) had excellent antibacterial and immunomodulatory activity, good stability and biocompatibility, and excellent biofilm eradication and membrane penetrating activity. The positively charged spherical aggregates formed by self-assembly of GLP6 could encapsulate tetracycline (TC) to form GLP6@TC with a sustained-release effect, which could enhance the sensitivity of bacteria to the antibiotic and realize combined sterilization. The results of acute peritonitis and bacterial keratitis showed that GLP6@TC had a good combined antibacterial effect and the ability to inhibit interleukin-2 (IL-2), which could significantly reduce the inflammatory response while treating bacterial infection, and it had great potential for application. The results of computer molecular docking showed the AXA motif could effectively bind to SPase I, which was consistent with the results of biological experiments. In general, the study could provide a perspective for the design of AMPs and combined antibacterial therapy.

Development of KLA-RGD integrated lipopeptide with the effect of penetrating membrane which target the αvß3 receptor and the application of combined antitumor.

Herein, an amphiphilic cationic anticancer lipopeptide P17 with α-helical structure was synthesized based on the integration of KLA and RGD peptide which could bind with the receptor of integrin αvß3. P17 could self assemble into stable spherical aggregates in aqueous solution, and which could encapsulate the anticancer drugs (Such as Dox) to form P17 @ Anticancer drug nanomedicine (P17 @ Dox nanomedicine) which could play the combined therapy of P17 and anticancer drugs (Dox). The encapsulation efficiency of P17 aggregates to Dox was 80.4 ± 3.2 %, and the release behavior of P17 @ Dox nanomedicine in vitro had the characteristics of slow-release and pH responsiveness. The experiments in vitro showed that P17 lipopeptide had low cytotoxicity, high serum stability, low hemolysis and strong penetrating membrane ability. The release of Dox from P17 @ Dox in cells was time-dependment, and the P17 @ Dox nanomedicine had a good anticancer effect. The experiments in vivo showed that P17 and P17 @ Dox nanomedicine both had low hemolysis, and P17 @ Dox nanomedicine could effectively inhibit tumor growth and significantly reduce the toxic and side effects of Dox. Molecular docking experiments showed that P17 could effectively interact with the receptor of integrin αvß3. In conclusion, P17 lipopeptide could be used as an excellent drug carrier and play the combined anticancer effect of P17 and anticancer drugs.

Will Joining Cooperative Promote Farmers to Replace Chemical Fertilizers with Organic Fertilizers?

This study examines whether cooperatives can assist more than 200 million farmers in China, who are facing tightening resources and environmental constraints, in adopting green farming practices. A framework for counterfactual analysis was established to quantify the impact of farmers joining cooperatives on the reduction in chemical fertilizer consumption and the use of organic fertilizers. The study's conclusions are based on data from 712 farmers in four counties in Shandong and Henan provinces. Joining a cooperative can have a positive impact on farmers' selection of environmentally friendly production methods, which increases the likelihood of farmers reducing chemical fertilizer application by 35.6% and organic fertilizer application by 22.0%. It can also reduce the cost of chemical fertilizer application by an average of $209.2/ha. The extent to which smallholder farmers use chemical and organic fertilizers after joining cooperatives depends on the size of their farming operations and their perception of green production.

Development of Drug Carriers with Biocompatibility Based On Human Serum Albumin and ß-Cyclodextrin Molecules and Study of Anticancer Activity.

Herein, a novel molecule S4, which could form a uniform S4 spherical aggregate in water, was synthesized, and the S4 aggregate was used to load Dox to prepare the S4@Dox nanomedicine. The loading efficiency was 80.0 ± 4.5%. The pH response and slow release of Dox were the typical characteristics of the S4@Dox nanomedicine. In vitro experiments showed that cancer cells could successfully phagocytose S4 aggregates and the S4@Dox nanomedicine. The toxicity of S4 aggregates to MCF-7, HepG2, and H22 cells was low, and the S4@Dox nanomedicine had better antitumor activity and specific targeting, especially to the MCF-7 cells. The antitumor activity in vivo and in the tissue section showed that the S4@Dox nanomedicine could significantly reduce Dox toxicity, effectively induce the apoptosis of cancer cells, and effectively inhibit tumor growth, which showed that the nanomedicine had better antitumor activity.

[Innovation and development of Chinese Osteosynthesis].

Chinese Osteosynthesis is a fracture treatment system of integrated Traditional Chinese medicine and Western medicine.Starting from our country reality, according to the traditional theory, highlight the characteristics of traditional Chinese medicine and using modern science and technology, under the guidance of the new fracture treatment principles, after a lot of clinical practice and continuous summary, the integrated Chinese and western medicine fracture treatment system with manual reduction and local external fixation is formed.This paper systematically reviews its development history, which provides enlightenment for our innovation and development today.

Development of anticancer peptides with low hemolysis, high penetrating membrane activity, certain analgesic activity and the synergistic anticancer effect.

Herein, an amphiphilic cationic α-helical anticancer lipopeptide, P10 with low toxicity and high penetrating membrane activity was developed. This lipopeptide could self-assemble into stable spherical aggregates in aqueous solution and encapsulate Dox with a hydrophobic structure to form the P10@Dox nanomedicine. The Dox encapsulation efficiency was 81.3% ± 3.48% and its release from the P10@Dox nanomedicine had the characteristics of slow release and pH response. The in vitro experiments showed that the P10 lipopeptide had low toxicity, excellent membrane penetrating activity and high serum stability, the release of Dox from P10@Dox in cells was time and concentration dependent, and the P10@Dox nanomedicine played a good anti-cancer role. The animal experiments and tissue sections showed that the P10 lipopeptide and P10@Dox nanomedicine both had low hemolysis, and P10@Dox nanomedicine not only greatly reduced the toxicity and side effects of Dox, but also effectively inhibited the tumor growth. Additionally, it was surprising that P10 exhibited certain analgesic activity, which could reduce the accompanying cancer pain, while playing an effective role in cancer therapy. Thus, the results showed that the P10 lipopeptide can be used as an ideal drug carrier and it has great application potential in the field of clinical cancer therapy.

Development of antibacterial peptides with efficient antibacterial activity, low toxicity, high membrane disruptive activity and a synergistic antibacterial effect.

The development of new antimicrobial drugs is urgently required to overcome bacterial resistance which is a serious threat to human health. Antimicrobial peptides (AMPs) which are ideal substitutes for traditional antibiotics have a unique mechanism of action and do not easily cause bacterial resistance. Herein, a series of new AMPs were designed and synthesized based on the biological characteristics of natural AMPs (such as the positive charge, α-helical structure and amphiphilicity). Biological screening of the AMPs provided an antimicrobial lipopeptide LP21 with efficient antimicrobial activity, serum stability, low cytotoxicity and high membrane-disruptive activity. Besides, LP21 could self-assemble into spherical aggregates in aqueous solutions which encapsulated TC to form LP21@TC nanomedicine, and the encapsulation efficiency was about 50.03 ± 3.03%. More impressively, both LP21 and LP21@TC nanomedicine displayed significant therapeutic effects in vivo, and the LP21@TC nanomedicine could exert a synergistic antimicrobial effect. This work is expected to provide a new research vision for the design of AMPs and synergistic antibacterial sensitization treatment.

pH-Responsive Self-Assemblies from the Designed Folic Acid-Modified Peptide Drug for Dual-Targeting Delivery.

Targeting delivery is a promising technique for the therapy of cancers. A molecule FA-EEYSV-NH2, which consists of target recognition site folic acid (FA), dipeptide linker, and peptide drug, was designed as a novel anticancer prodrug. The molecules could self-assemble into nanoparticles at pH 7.0 and nanofibers at pH 5.0. By the aid of pH-responsiveness, the self-assemblies were used purposefully as targeted vehicles of self-delivery prodrugs. The results of cell toxicity and internalization assays have proved that the self-assemblies have good cancer cell selectivity. The selection was mainly attributed to the pH-responsive structure transition of self-assemblies and the FA active-targeting effect. We hope that our work could provide a useful strategy for finely tuning the properties and activities of peptide-based supramolecular nanomaterials, thus optimizing nanomedicines with enhanced performance.

Construction of a Drug Delivery System and Photodynamic Therapy Reagent Based on the Biotin-HSA-DDA-TCPP Molecules and the Application of Synergistic Antitumor Effect.

A biotin-HSA-DDA-TCPP molecule, which can be used as a photodynamic therapeutic agent and drug carrier, was synthesized. The molecule can self-assemble into spherical aggregates, which can be loaded with Dox to form biotin-HSA-DDA-TCPP-Dox nanoparticles in aqueous solution, and the Dox loading efficiency was 86.6 ± 1.76%. The Dox's release behavior was pH responsive and has a sustained release. Cell experiments showed that biotin-HSA-DDA-TCPP-Dox nanoparticles could effectively induce cancer cell apoptosis to exert anticancer and photodynamic therapy effects. The results of animal experiments, tissue sections, and blood biochemistry tests showed that the biotin-HSA-DDA-TCPP-Dox nanoparticles could exert the effect of photodynamic therapy and antitumor, which is similar to Dox after laser irradiation, and achieve a synergistic antitumor effect. The nanoparticles can significantly reduce the Dox toxicity and increase the circulation time of the drug in the body. In summary, the biotin-HSA-DDA-TCPP molecule, which combines the advantages of photodynamic therapy and drug carrier, has great potential in clinical application.

Synthesis of ß-cyclodextrin-PEG-G molecules to delay tumor growth and application of ß-cyclodextrin-PEG-G aggregates as drug carrier.

The clinical use of many chemotherapeutic drugs is considerably greatly limited due to their serious side effects. This problem can be solved by using a low-toxic or nontoxic drug carrier that exhibits excellent performance in entrapping chemotherapeutic drugs. Accordingly, ß-cyclodextrin-PEG-guanosine (ß-CD-PEG-G) molecule was first synthesized. The molecules can self-assemble into negatively charged spherical aggregates (called ß-CD-PEG-G aggregates) that can stably exist in an aqueous solution and entrap doxorubicin (Dox) to form ß-CD-PEG-G-Dox nanomedicine. Dox encapsulation efficiency is approximately 79 ± 6.3%. Dox from ß-CD-PEG-G-Dox nanomedicine exhibits sustained release and pH responsiveness. Cell and animal experiments showed that ß-CD-PEG-G-Dox nanomedicine could effectively induce cancer cell apoptosis to exert antitumor activity. Unexpectively, the animal experiment and tissue sections demonstrated that ß-CD-PEG-G aggregates exhibit certain antitumor activity that could delay the tumor growth. Therefore, the ß-CD-PEG-G molecule has high potential as a drug carrier candidate.

Preparation of ß-CD-DPPE-Dox Nanomedicine and Its' Application as the Anticancer and Antitumor Drug.

ß-CD-DPPE molecule was synthesized through the conjugation of ß-CD-NH2 and the DPPE molecule, and its' water-solubility was more excellent than the traditional phospholipid molecule. The spherical micelles was formed by ß-CD-DPPE molecule in aqueous solution, and the ß-CD-DPPE-Dox nanomedicine can be prepared through loading Dox (Doxorubicin) into the micelles, and the Dox loading ratio was about 82.3 ± 7.27%. At the same time the Dox release behavior from the nanomedicine was sustained-release and pH controlled release, and the release test in vitro showed that the release rate of the Dox at the lower pH was faster than that of normal pH (pH = 7.4), which indicated that the rate of release in the tumor microenvironment is faster than in the normal tissue. Biological test showed that the micelles was low cytotoxicity, and the cytotoxicity of ß-CD-DPPE-Dox nanomedicine was lower than the Dox under the same Dox concentration, and the ß-CD-DPPE-Dox nanomedicine could effectively induce cancer cell apoptosis and inhibit the tumor growth.

Anticancer Properties of Lipidated Peptide Drug Supramolecular Self-Assemblies with Enhanced Stability.

Molecular modification and self-assembly are clinically proved successful strategies in drug design to enhance the treatment efficiency. Herein, the lipidation method is used to modify the anticancer tripeptides tyoservaltide (YSV) into lipidated YSV, C16-EEYSV-NH2, and C16-KKYSV-NH2. We found the lipidated YSV performed better aggregation property from the critical aggregation concentration (CAC) measurements, transmission electron microscope (TEM) and atomic force microscope (AFM) observation. The cytotoxicity experiments showed that the lipidated YSV had better anticancer efficiency due to their excellent self-assembly. Meantime, the lipidated YSV shows superior biostability and cells internalization which can be proved by high performance liquid chromatography (HPLC), inverted fluorescence microscope, and flow cytometry (FCM). For in vivo experiments, the results also showed that lipidated YSV have better performance, and the final histology analysis shows low toxicity to the body organs. Considering the advantages of lipidated YSV, we hope that our study would demonstrate a powerful strategy to improve the application of peptide drugs.

A liposome preparation based on ß-CD-LPC molecule and its application as drug-delivery system.

AIM: The ß-CD-LPC molecule was synthesized based on the conjugation of LPC and ß-CD molecules and it could self-assemble into liposome which was used to encapsulate the Dox to form nanomedicine for the cancer therapy. MATERIALS & METHODS: The anticancer and antitumor effect of ß-CD-LPC-Dox nanomedicine was studied with the vitro and vivo experimental methods. RESULTS: The result showed that ß-CD-LPC liposome had high Dox drug-loading rate and a good sustained-release effect. Cell experiment showed that the ß-CD-LPC-Dox nanomedicine could effectively induce cancer cell apoptosis and in vivo experiments showed that ß-CD-LPC-Dox liposome could effectively inhibit tumor growth and had an effective anticancer activity with lower biotoxicity. CONCLUSION: The ß-CD-LPC-Dox nanomedicine could be applied as a candidate drug to therapy the cancer.

Ordered DNA-Surfactant Hybrid Nanospheres Triggered by Magnetic Cationic Surfactants for Photon- and Magneto-Manipulated Drug Delivery and Release.

Here we construct for the first time ordered surfactant-DNA hybrid nanospheres of double-strand (ds) DNA and cationic surfactants with magnetic counterion, [FeCl3Br](-). The specificity of the magnetic cationic surfactants that can compact DNA at high concentrations makes it possible for building ordered nanospheres through aggregation, fusion, and coagulation. Cationic surfactants with conventional Br(-) cannot produce spheres under the same condition because they lose the DNA compaction ability. When a light-responsive magnetic cationic surfactant is used to produce nanospheres, a dual-controllable drug-delivery platform can be built simply by the applications of external magnetic force and alternative UV and visible light. These nanospheres obtain high drug absorption efficiency, slow release property, and good biocompatibility. There is potential for effective magnetic-field-based targeted drug delivery, followed by photocontrollable drug release. We deduce that our results might be of great interest for making new functional nucleic-acid-based nanomachines and be envisioned to find applications in nanotechnology and biochemistry.

Fluorescent hydrogels with tunable nanostructure and viscoelasticity for formaldehyde removal.

Hydrogels with ultrahigh water content, ∼99 wt %, and highly excellent mechanical strength were prepared by 4'-para-phenylcarboxyl-2,2':6',2″-terpyridine (PPCT) in KOH aqueous solution. The self-assembled structure, rheological properties, and the gel-sol transformation temperature (Tgel-sol) of PPCT/KOH hydrogels that depend on PPCT and KOH concentrations were studied, indicating easily controllable conditions for producing hydrogels in PPCT and KOH mixtures. An important finding was that the hydration radius (Rh) of cations (M(+) = Li(+), Na(+), K(+), Cs(+), NH4(+), (CH3)4N(+), (CH3CH2)4N(+), (CH3CH2CH2)4N(+), (CH3CH2CH2CH2)4N(+)) plays a vital role in gelation of PPCT/MOH systems. To produce hydrogels in PPCT/MOH systems, the Rh of M(+) must be in a suitable region of 3.29 to 3.58 Å, e.g., K(+), Na(+), Cs(+), and the capability of M(+) for inducing PPCT to form hydrogels is K(+) > Na(+) > Li(+), which is followed by the Hofmeister series. The hydrogels of PPCT and KOH mixtures are responsive to external stimuli including temperature and shearing force, and present gelation-induced enhanced fluorescence emission property. The states of being sensitive to the stimuli can readily recover to the original hydrogels, which are envisaged to be an attracting candidate to produce self-healing materials. A typical function of the hydrogels of PPCT and KOH mixtures is that formaldehyde (HCHO) can speedily be adsorbed via electrostatic interaction and converted into nontoxic salts (HCOOK and CH3OK), making it a promising candidate material for HCHO removal in home furnishings to reduce indoor environmental pollutants.

Multiple DNA architectures with the participation of inorganic metal ions.

Here we develop a synthetic protocol for assembling DNA with participating metal ions into multiple shapes. DNA molecules first form coordination complexes with metal ions and these coordination complexes become nucleation sites for primary crystals of metal inorganic salt, and then elementary units of space-filling architectures based on specific geometry form, and finally elementary units assemble into variously larger multiple architectures according to different spatial configurations. We anticipate that our strategy for self-assembling various custom architectures is applicable to most biomolecules possessing donor atoms that can form coordination complexes with metal ions. These multiple architectures provide a general platform for the engineering and assembly of advanced materials possessing features on the micrometer scale and having novel activity.

Preparation and functions of hybrid membranes with rings of Ag NPs anchored at the edges of highly ordered honeycomb-patterned pores.

We report a new, simple strategy to apply honeycomb films for the patterning of colloidal particles. By combination of a "bottom-up" breath figure method and the electrochemical properties of the honeycomb films of ferrocenyl-based oligomers, highly ordered hybrid membranes coated with ring-like patterning of 0D- and 1D-Ag nanoparticles (NPs) have been fabricated. One interesting phenomenon is that the nucleation and adsorption of Ag dots occurred preferentially at the edges of the micropores. The hybrid membranes exhibited richly electrochemical activities towards reduction of iodate and enhanced effectively catalytic reduction of organic dyes. We believe that this method can be used to decorate and/or assemble functional metal NPs such as Au, Pd, and Cu on honeycomb-patterned materials for the further applications of photonics, sensors, and catalysis.

Multiresponsive viscoelastic vesicle gels of nonionic C12EO4 and anionic AzoNa.

Viscoelastic vesicle gels were prepared by mixing a nonionic surfactant, tetraethylene glycol monododecyl ether (C12EO4), and an anionic dye, sodium 4-phenylazobenzoic acid (AzoNa). The gels, which were composed of multilamellar vesicles, were analyzed by cryogenic transmission electron microscopy (cryo-TEM), freeze-fracture transmission electron microscopy (FF-TEM), ²H NMR spectroscopy, and small-angle X-ray scattering (SAXS). The mechanism of vesicle-gel formation is explained by the influence of anionic molecules on the bilayer bending modulus. Interestingly, the vesicle gels were observed to be sensitive to temperature, pH, and light. The viscoelastic vesicle gels respond to heat; they thin at lower temperatures and become thicker at higher temperatures. The vesicle gels are only stable from pH 7 to 11, and the gels become thinner outside of this range. UV light can also trigger a structural phase transition from micelles to multilamellar vesicle gels.

Covalent modification of reduced graphene oxide by means of diazonium chemistry and use as a drug-delivery system.

Under acidic conditions, reduced graphene oxide (rGO) was functionalized with p-aminobenzoic acid, which formed the diazonium ions through the diazotization with a wet-chemical method. Surfactants or stabilizers were not applied during the diazotization. After the functionalized rGO was treated through mild sonication in aqueous solution, these functionalized rGO sheets were less than two layers, which was determined by atomic force microscopy (AFM) imaging. The water solubility of functionalized rGO after the introduction of polyethyleneimine (PEI) was improved significantly; it was followed by covalent binding of folic acid (FA) molecules to the functionalized rGO to allow us to specifically target CBRH7919 cancer cells by using FA as a receptor. The loading and release behaviors of elsinochrome A (EA) and doxorubicin (DOX) on the functionalized rGO sheets were investigated. The EA loading ratio onto rGO-C(6)H(4)-CO-NH-PEI-NH-CO-FA (abbreviated rGO-PEI-FA, the weight ratio of drug loaded onto rGO-PEI-FA) was approximately 45.56 %, and that of DOX was approximately 28.62 %. It was interesting that the drug release from rGO-PEI-FA was pH- and salt-dependent. The results of cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry (FCM) assays, as well as cell morphology observations) clearly showed that the concentration of rGO-PEI-FA as the drug-delivery composite should be less than 12.5 mg L(-1). The conjugation of DOX and rGO-PEI-FA can enhance the cancer-cell apoptosis effectively and can also push the cancer cells to the vulnerable G2 phase of the cell cycle, which is most sensitive and susceptible to damage by drugs or radiation.

The synthesis of highly water-dispersible and targeted CdS quantum dots and it is used for bioimaging by confocal microscopy.

Synthesis of a highly dispersed hydrophilic CdS nanocrystals and their use as fluorescence labeling for live cell imaging is reported here. By carefully manipulating the surface of CdS nanocrystals, the dispersions of CdS-MAA-PEI-FA nanocrystals with high photostability is prepared. The receptor-mediated delivery of folic acid conjugated quantum dots into folate-receptor-positive cell lines such as CBRH7919 liver cancer cells was demonstrated by confocal microscopy. In the future, the further modified CdS nanoparticles can be used for the tissue imaging in vivo studies.