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AbstractProtein dynamic networks play an important role in the regulation of many protein systems. Some residues that are far away from the interface between proteins and their targets have a critical role in modulating the activity of some scorpion toxins. Here, conservation analysis combined with an in vivo experiment has reveals that Met58 is a key residue of BmK scorpion toxin AGP-SYPU2 in the modulation of analgesic activity. Molecular dynamics simulations clearly reveal the conformational changes that allow the loop between the β2 and β3 sheets to be exposed on the toxin surface to interact with its targets. Our results emphasize specific roles for the residue Met58 in the NC domain and our work gives valuable information for further modification of scorpion toxins to obtain new analgesic peptides with enhanced activity. Communicated by Ramaswamy H. Sarma

•PRRs constitute a fundamental and core part of the insect immune system.•Insects take efforts to expand the repertoire of PRRs which is called ‘diversity’ in this review.•The diversity of PRRs includes genetic variability, isoform diversity, and ‘part-time’ PRRs.•PRRs with opsonin function and regulation of signaling pathways also show the diversity of PRRs.

Pain affects approximately 30% of people and places a large economic and social burden on society. Despite the availability of a range of analgesics, complete alleviation of symptoms still rarely occurred. Effective and safe drugs for the treatment of pain are still an unmet clinical need. In recent years, the voltage-gated sodium channels (VGSCs) have been recognized as potential targets for analgesic development. VGSCs are major players in generating and propagating action potentials. They represent an appealing target for the development of new and safer drugs in the treatment of pain. The majority of the research has been focused on Nav1.7 in particular, other VGSC subtypes, such as Nav1.1, Nav1.3, Nav1.6, Nav1.8 and Nav1.9 have recently come to the forefront of analgesic research. Peptides from scorpion have been proved to be a valuable tool in neuroscience, playing a significant role in the identification and characterization of VGSC subtypes and many of them resulting in analgesia in pain. This review assesses the potential of scorpion toxin targeting VGSCs for analgesic development.

Pain affects approximately 30% of people and places a large economic and social burden on society. Despite the availability of a range of analgesics, complete alleviation of symptoms still rarely occurred. Effective and safe drugs for the treatment of pain are still an unmet clinical need. In recent years, the voltage-gated sodium channels (VGSCs) have been recognized as potential targets for analgesic development. VGSCs are major players in generating and propagating action potentials. They represent an appealing target for the development of new and safer drugs in the treatment of pain. The majority of the research has been focused on Nav1.7 in particular, other VGSC subtypes, such as Nav1.1, Nav1.3, Nav1.6, Nav1.8 and Nav1.9 have recently come to the forefront of analgesic research. Peptides from scorpion have been proved to be a valuable tool in neuroscience, playing a significant role in the identification and characterization of VGSC subtypes and many of them resulting in analgesia in pain. This review assesses the potential of scorpion toxin targeting VGSCs for analgesic development.

Multidrug resistance (MDR) is known to be a great obstruction to successful chemotherapy, and considerable efforts have been devoted to reverse MDR including designing various functional drug delivery systems. In this study, hybrid lipid-capped mesoporous silica nanoparticles (LTMSNs), aimed toward achieving stimuli-responsive drug release to circumvent MDR, were specially designated for drug delivery. After modifying MSNs with hydrophobic chains through disulfide bond on the surface, lipid molecules composing polymer d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) with molar ratio of 5:1 were subsequently added to self-assemble into a surrounded lipid layer via hydrophobic interaction acting as smart valves to block the pore channels of carrier. The obtained LTMSNs had a narrow size distribution of ca. 190 nm and can be stably dispersed in body fluids, which may ensure a long circulating time and ideal enhanced permeability and retention effect. Doxorubicin (DOX) was chosen as a model drug to be encapsulated into LTMSNs. Results showed that this hybrid lipid-capped mesoporous silica drug delivery system can achieve redox and pH-responsive release of DOX, thereby avoiding the premature leakage of drug before reaching the specific site and releasing DOX within the cancerous cells. Owing to the presence of TPGS-containing lipid layer, LTMSNs–DOX exhibited higher uptake efficiency, cytotoxicity, and increased intracellular accumulation in resistant MCF-7/Adr cells compared with DOX solution, proving to be a promising vehicle to realize intracellular drug release and inhibit drug efflux.

A redox-responsive delivery system based on colloidal mesoporous silica (CMS) has been developed, in which 6-mercaptopurine (6-MP) was conjugated to vehicles by cleavable disulfide bonds. The oligosaccharide of hyaluronic acid (oHA) was modified on the surface of CMS by disulfide bonds as a targeting ligand and was able to increase the stability and biocompatibility of CMS under physiological conditions. In vitro release studies indicated that the cumulative release of 6-MP was less than 3% in the absence of glutathione (GSH), and reached nearly 80% within 2 h in the presence of 3 mM GSH. Confocal microscopy and fluorescence-activated cell sorter (FACS) methods were used to evaluate the cellular uptake performance of fluorescein isothiocyanate (FITC) labeled CMS, with and without oHA modification. The CMS-SS-oHA exhibited a higher cellular uptake performance via CD44 receptor-mediated endocytosis in HCT-116 (CD44 receptor-positive) cells than in NIH-3T3 (CD44 receptor-negative) cells. 6-MP loaded CMS-SS-oHA exhibited greater cytotoxicity against HCT-116 cells than NIH-3T3 cells due to the enhanced cell uptake behavior of CMS-SS-oHA. This study provides a novel strategy to covalently link bioactive drug and targeting ligand to the interiors and exteriors of mesoporous silica to construct a stimulus-responsive targeted drug delivery system.

The purpose of this study was to develop poly(amidoamine) (PAMAM)-functionalized multi-walled carbon nanotubes (MWNTs) loaded with a poorly water-soluble drug, intended to improve the drug-loading capacity, dissolution and design a sustained release system. MWNTs were modified with a carboxyl group by acid treatment and then complex with PAMAM. PAMAM-MWNTs were investigated as a scaffold for loading the model drug, Carvedilol (CAR), using three different methods (the fusion method, the incipient wetness impregnation method, and the solvent method). The effects of different pore size, specific surface area and physical state were systematically studied using FT-IR, TGA, SEM, DSC, nitrogen adsorption, XPS and XRD. All the samples made by PAMAM-MWNTs to load the drug had a marked effect on the drug-loading capacity as well as drug dissolution, especially the Ⅱ-30%.

A novel spherical nanosilica matrix (SNM) together with chitosan (CTS) encapsulated SNM (CTS-SNM) was developed in order to investigate the feasibility of using chitosan to regulate drug release rate from porous silica and obtain an oral sustained drug delivery system. To achieve this goal, we synthesized a spherical nanosilica matrix (SNM) and incorporated chitosan chains on the SNM surface. Solvent evaporation method was adopted to load the model drug carvedilol into SNM and CTS-SNM. The physicochemical properties of the drug carriers and drug-loaded composites were systematically studied using scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption, X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The structural changes in CTS-SNM in simulated gastrointestinal fluid as well as the relationships between swelling effect of chitosan and in vitro drug release behaviors were investigated. Pharmacokinetic and bioavailability aspects were also discussed. The results showed that the powerful dispersing effect of SNM and the blocking action due to the swelling of chitosan were the two main factors contributing to the sustained drug release behavior. The swelling effect of chitosan in an acidic environment together with the shrinking effect in a relatively alkaline environment allowed regulation of drug release behavior in simulated gastrointestinal fluid. An in vivo study showed that the bioavailability of CAR was improved 182% compared with that of the commercial capsule when SNM was used as the drug carrier. As for CAR-CTS-SNM, the Tmaxof CAR was delayed by about 3.4 h and the bioavailability was slightly increased in comparison with the commercial capsule. We believe that SNM and CTS-SNM developed in this study will help increase the use of polymers and inorganic materials in pharmaceutical applications and stimulate the design of oral drug delivery systems for immediate or sustained release of poorly water-soluble drugs.

Our purpose was to study the formulation and anti‐cataract effects of aqueous eye drops containing a high concentration of zinc diethyldithiocarbamate (Zn‐DDC). A possible mechanism of the anti‐cataract effect of Zn‐DDC was also studied. Zn‐DDC and hydroxypropyl‐β‐cyclodextrin (HPβCD) inclusion complex (Zn‐DDC/HPβCD) was studied using the saturation solution method and characterized by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (IR). Suitable formulations for Zn‐DDC eye drops were established by means of in‐vitro trans‐corneal penetration experiments. The anti‐cataract effect of the selected formulation was demonstrated by the delay in lens opacity development in hereditary shumuya cataract rats (SCRs). Semiquantitative reverse transcription polymerase chain reaction (RT‐PCR) was performed to study the effect of diethyldithiocarbamate (DDC), a metabolite of Zn‐DDC, on the transcription inducible nitric oxide synthase (iNOS) mRNA in human lens epithelial cells (HLEC). In the presence of 22% (w/v) HPβCD, the solubility of Zn‐DDC in water (0.2 mm) was increased almost 850 fold (to 17 mm), by the formation of Zn‐DDC/HPβCD. The stoichiometry of Zn‐DDC inclusion was 1:1. The Zn‐DDC/HPβCD stability constant, K(s) (1:1) was estimated to be 3453 m−1. The ophthalmic preparation containing 0.1% HPMC and 0.1% poloxamer 188 (P188) exhibited better permeability than the others in‐vitro, and significantly delayed cataract formation in SCRs compared with non‐treated SCRs. DDC inhibits the transcription of iNOS mRNA in HLEC. We concluded that this drug delivery system increases both the drug solubility in aqueous eye drops and the permeability of drug through the rabbit cornea, by the formation of a drug‐cyclodextrin inclusion complex and the addition of polymers and penetration enhancers. The preparation effectively prevented the development of cataracts in SCRs. DDC, the metabolite of Zn‐DDC, may be one of the factors in the prevention of cataract formation because it inhibits the transcription of iNOS mRNA.

Our purpose was to study the formulation and anti-cataract effects of aqueous eye drops containing a high concentration of zinc diethyldithiocarbamate (Zn-DDC). A possible mechanism of the anti-cataract effect of Zn-DDC was also studied. Zn-DDC and hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complex (Zn-DDC/HPβCD) was studied using the saturation solution method and characterized by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (IR). Suitable formulations for Zn-DDC eye drops were established by means of in-vitro trans-corneal penetration experiments. The anti-cataract effect of the selected formulation was demonstrated by the delay in lens opacity development in hereditary shumuya cataract rats (SCRs). Semiquantitative reverse transcription polymerase chain reaction (RT-PCR) was performed to study the effect of diethyldithiocarbamate (DDC), a metabolite of Zn-DDC, on the transcription inducible nitric oxide synthase (iNOS) mRNA in human lens epithelial cells (HLEC). In the presence of 22% (w/v) HPβCD, the solubility of Zn-DDC in water (0.2 mm) was increased almost 850 fold (to 17 mm), by the formation of Zn-DDC/HPβCD. The stoichiometry of Zn-DDC inclusion was 1:1. The Zn-DDC/HPβCD stability constant, K(s) (1:1) was estimated to be 3453 m−1. The ophthalmic preparation containing 0.1% HPMC and 0.1% poloxamer 188 (P188) exhibited better permeability than the others in-vitro, and significantly delayed cataract formation in SCRs compared with non-treated SCRs. DDC inhibits the transcription of iNOS mRNA in HLEC. We concluded that this drug delivery system increases both the drug solubility in aqueous eye drops and the permeability of drug through the rabbit cornea, by the formation of a drug-cyclodextrin inclusion complex and the addition of polymers and penetration enhancers. The preparation effectively prevented the development of cataracts in SCRs. DDC, the metabolite of Zn-DDC, may be one of the factors in the prevention of cataract formation because it inhibits the transcription of iNOS mRNA.