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Phototherapy, such as photothermal therapy (PTT) and photodynamic therapy (PDT), has been considered an elegant solution to eradicate tumors due to its minimal invasiveness and low systemic toxicity. Nevertheless, it is still challenging for phototherapy to achieve ideal outcomes and clinical translation due to its inherent drawbacks. Owing to the unique biological functions, diverse gases have attracted growing attention in combining with phototherapy to achieve super-additive therapeutic effects. Specifically, gases such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H 2 S) have been proven to kill tumor cells by inducing mitochondrial damage in synergy with phototherapy. Additionally, several gases not only enhance the thermal damage in PTT and the reactive oxygen species (ROS) production in PDT but also improve the tumor accumulation of photoactive agents. The inflammatory responses triggered by hyperthermia in PTT are also suppressed by the combination of gases. Herein, we comprehensively review the latest studies on gas-synergized phototherapy for cancer therapy, including (1) synergistic mechanisms of combining gases with phototherapy; (2) design of nanoplatforms for gas-synergized phototherapy; (3) multimodal therapy based on gas-synergized phototherapy; (4) imaging-guided gas-synergized phototherapy. Finally, the current challenges and future opportunities of gas-synergized phototherapy for tumor treatment are discussed. 1. The novelty and significance of the work with respect to the existing literature. (1) Strategies to design nanoplatforms for gas-synergized anti-tumor phototherapy have been summarized for the first time. Meanwhile, the integration of various imaging technologies and therapy modalities which endow these nanoplatforms with advanced theranostic capabilities has been summarized. (2) The mechanisms by which gases synergize with phototherapy to eradicate tumors are innovatively and comprehensively summarized. 2. The scientific impact and interest. This review elaborates current trends in gas-synergized anti-tumor phototherapy, with special emphases on synergistic anti-tumor mechanisms and rational design of therapeutic nanoplatforms to achieve this synergistic therapy. It aims to provide valuable guidance for researchers in this field. [Display omitted] [ABSTRACT FROM AUTHOR]

Utilization of the intestinal lymphatic pathway will allow extraordinary gains in lymph and tumors cascade-targeted delivery of oral drugs and awakening the innate/adaptive immunity of the body and the lesion microenvironment, in addition to improving oral bioavailability relative to other means of delivery of oral drugs. Here, inspired by the specific invasion route of intestinal microorganisms, we pioneered an immune-awakening Saccharomyces -inspired mesoporous silicon nanoparticle (yMSN) for the ingenious cascade-targeted delivery of therapeutic cancer vaccines and antitumor drugs to lymph and tumors via the intestinal lymphatic pathway. Encouragingly, yMSN high-loaded tumor-specific antigens (OVA, 11.9%) and anti-tumor drugs (Len, 28.6%) with high stability, namely Len/OVA/yMSN, efficiently co-delivered OVA and Len to their desired target sites. Moreover, yMSN concomitantly awakened the innate antitumor immunity of dendritic cells and macrophages, strengthening vaccine-induced adaptive immune responses and reversing macrophage-associated immunosuppression in the tumor microenvironment. Surprisingly, Len/OVA/yMSN treatment resulted in excellent synergistic antitumor efficacy and long-term antitumor memory in OVA-Hepa1-6-bearing mice. This high-performance nanocarrier provides a novel approach for lesion-targeting delivery of oral drugs accompanied with awakening of the innate/adaptive immunity of the lesion environment, and also represents a novel path for the oral delivery of diverse therapeutic agents targeting other lymph-mediated diseases. A Saccharomyces -inspired nanocarrier brings an ingenious cascade-target-delivery of therapeutic cancer vaccines and antitumor drugs respectively to lymph and tumors via intestinal lymphatic pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

• We introduced R-CIEM, merging RSR and CIEM to enhance information use and aid in Soft Voting learner selection. • We introduced GACEMV, enhancing base learner accuracy with GA and providing optimal combinations for a high-precision ensemble model using R-CIEM. • Using SHAP, we revealed the black box of EL and identified several risk factors. The accurate prediction of the severity and prognosis of COVID-19 patients is essential in order to select the ideal treatment plan, which can help reduce mortality rates associated with the virus. Artificial intelligence (AI)-based disease prediction models show potential in diagnosing and prognosis COVID-19 patients. However, their black-box nature, overfitting, and low accuracy limit their application. To address these challenges, this study proposes a GACEMV ensemble learning framework for building practical and high-precision COVID-19 patient diagnosis models. The GACEMV utilizes genetic algorithm to optimize the hyperparameters of base learners in order to enhance their predictive ability. Additionally, a comprehensive evaluation method is adopted to select the optimal combination of base learners, reducing performance differences and avoiding interference from noisy models. The Ensemble learning model constructed by GACEMV achieved good accuracy in predicting the severity and prognosis of COVID-19 patients through external data sets. Further ablation experiments confirm the necessity of genetic algorithm and comprehensive evaluation method for GACEMV. Moreover, the Ensemble learning model shows outstanding performance in identifying suspected COVID-19 patients in a specific data set, validating its identification ability. Furthermore, the SHAP method identifies a set of biomarkers associated with the severity and prognosis of COVID-19 patients, which are consistent with previous reports. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to develop spherical mesocellular foam (MCF) loaded with a poorly water-soluble drug, intended to be orally administered, able to improve the dissolution rate and enhance the drug loading capacity. Spherical MCF with a continuous 3-D pore system was synthesized using Pluronic 123 triblock polymer (P123) as a surfactant coupled with cetyltrimethyl ammonium bromide (CTAB) as a co-surfactant. A model drug, simvastatin (SV), was loaded onto spherical MCF via a procedure involving a combination of adsorption equilibrium and solvent evaporation. The drug release rate and the drug loading efficiency of spherical MCF were compared with those of fibrous SBA-15. Investigations using nitrogen adsorption, scanning electron microscopy (SEM), transmission electron microscopy (TEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and HPLC demonstrated the successful incorporation of SV into the MCF host. It was found that spherical MCF has a high drug loading efficiency up to 37.5%, and higher than that of fibrous SBA-15 with a pore diameter of 6.5nm. It is worth noting that fast release rate of SV was obtained from spherical MCF compared with SBA-15 and pure crystalline SV using enzyme-free simulated intestinal fluid (SIF, pH 6.8). [Copyright &y& Elsevier]

Arsenic and nickel are common contaminants that usually co-exist in many contaminated natural and mining environments. More research on the interaction of these two contaminants is needed such as their coordination structure and occurrence state at mineral-water interfaces. In this study, we investigated the structure of surface complexes and surface precipitates formed by co-existing As(V) and Ni(II) ions at the ferrihydrite-water interface by varying the order of adsorption processes, pH, aging time and Ni(II) concentration using attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). ATR-FTIR analysis revealed the presence of complexed As O Ni bonds which produced ternary surface complexes. These ternary As O Ni surface complexes formed through a layer by layer alternative coordination on top of the binary As O Fe surface site complexes of ferrihydrite. Such multilayer surface complexes formed as initial surface precipitates which were found to refine their surface structure from amorphous to crystalline phases and were a function of incubation time, coverage of multilayer surface complexes, Ni(II) concentration and pH. Our results presented here can well explain the formation process of surface precipitates on the molecular scale and are of use to forecast the fate and mobility of commonly As(V) and Ni(II) species at the ferrihydrite-water interface commonly found in natural or mine tailings water-soil environments. [ABSTRACT FROM AUTHOR]

Pattern recognition receptors (PRRs) are employed in insects to defend against infectious pathogens by triggering various immune responses. Peptidoglycan recognition proteins (PGRPs), a vital family of PRRs, are widely distributed and highly conserved from vertebrates to invertebrates. To date, five PGRP genes have been identified in Antheraea pernyi , but their biochemical roles still remain unknown. In this study, we focused on the immune functions of PGRP-SA in A. pernyi ( Ap PGRP-SA), which was confirmed to be immune-related according to its significantly up-regulated expression level post microbial injection. In addition, the binding properties of Ap PGRP-SA were investigated using a recombinant protein produced in a prokaryotic expression system, revealing that r Ap PGRP-SA displayed a multi-binding ability to various microbes, including the Gram-positive bacteria Staphylococcus aureus and Micrococcus luteus , Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa , and fungus Candida albicans, together with their surface pathogen associated molecular patterns (PAMPs). Further studies showed that after recognition, the mixture of r Ap PGRP-SA/PAMP remarkably stimulated prophenoloxidase (PPO) activation in the hemolymph of A. pernyi in vitro , while the ds-PGRP-SA-treated hemolymph exhibited a lower sensitivity to PAMPs in comparison to the native sample. Moreover, the transcriptional level of the three antimicrobial peptides was also decreased in PGRP-SA knock-down larvae in response to immune-challenge. In summary, we conclude that Ap PGRP-SA is a novel identified PGRP in A. pernyi that might act as a broad-spectrum pattern recognition receptor and is involved in the PPO activation system as well as antimicrobial peptide production. [ABSTRACT FROM AUTHOR]

Scorpion venom is composed of a large number of bioactive peptides which display important pharmacological activities. In this study we have carried out a study of the functional role of the arginine residue at position 58 in the site RC comprising the reverse turn (8–12) and C-terminal residues 58–64. A polymerase chain reaction was used to substitute this arginine residue with a single amino acid such as alanine, glycine and lysine. The mutants were expressed in soluble form in E. coli , and purified by affinity chromatography. After target peptide purity identification, the recombinant peptides underwent a circular dichroism analysis and a study of their analgesic activity in mice. The results indicated that a single residue modification can affect the pharmacological activity. Our efforts establish a sound basis for further study of the structure-function determinants of the analgesic effect. [ABSTRACT FROM AUTHOR]

Apolipoproteins are protein components of lipoprotein particles, and are increasingly recognized to be functioning in the innate immune systems of both insects and mammals. Mammalian apolipoprotein B (apoB) is associated with a diverse range of innate immune defenses including suppression of bacterial pathogenesis, virus toxicity neutralization, and inhibition of cytokine releases from immune cells. However, little is known about apoB homologous insect apolipophorin-II/I (apoLp-II/I) in controlling of specific pathogen-host encounters such as microbial infections. In the present study, we describe cDNA cloning and characterization of an apoLp-II/I from Chinese oak silk worm, Antheraea pernyi . The apoLp-II/I cDNA is 10237bp in length, which possesses an open reading frame encoding 3305 amino acids. A consensus cleavage site RGRR presenting from Arg 710 to Arg 713 implies posttranslational cleavage of this protein. Ap -apoLp-II/I shares high sequence identities with apoLp-II/I in lepidoptera and other insects. In addition, considerable similarities also exist between Ap -apoLp-II/I and human apoB, which basically positioned in first 1000 residues of the amino termini. Tissue distribution and time-course expression results demonstrate that Ap -apoLp-II/I transcripts were detected predominantly in the fat body, less in epidermis and rarely in midgut, while the synthetic apoLp-II/I protein was abundant in hemocytes and plasma instead of the fatbody. Expression of Ap -apoLp-II/I was stimulated in response to bacterial challenge. In addition, our preliminary studies established a novel role for Ap -apoLp-II/I in regulating prophenoloxidase activation system. Taken together, apoLp-II/I may play an essential role in innate responses of Antheraea pernyi . [ABSTRACT FROM AUTHOR]

Scorpion toxins are invaluable source of therapeutic leads and pharmacological tools which produce influence on the voltage gated sodium channels. In the previous study, our group has reported BmK AGP-SYPU1 (64 amino acids), one scorpion toxin with both potential α-type and β-type scorpion characteristics and analgesic activity in vivo , act as an activator to hNa v 1.4 and hNa v 1.5. Additionally, conserved aromatic amino acids Tyr5 and Tyr42 played important roles in bioactivity of BmK AGP-SYPU1 on hNa v 1.4 and hNa v 1.5. However, the anti-nonceptitor mechanisms of BmK AGP-SYPU1 referred in vivo have not been clarified yet. The roles of Tyr5 and Tyr42 have still kept unclear in the interaction of BmK AGP-SYPU1 with other VGSCs. In this study, in order to give a deep insight into the relationship of structure and function, the effects of BmK AGP-SYPU1 and its two mutants (Y5F and Y42F) on hNa v 1.7, which has emerged as a key molecule involved in pain processing, were examined by using Na + -specialized fluorescent dye and the whole-cell patch clamp. The data showed that BmK AGP-SYPU1 also displayed as an activator to hNa v 1.7 with the potential characteristic of α-type and β-type scorpion toxin. Both Tyr5 and Tyr42 were the key amino acids to the functional properties of BmK AGP-SYPU1 when interacting with hNa v 1.7, and the Tyr42 was involved in the preferences of the toxin to distinct action sites of hNa v 1.7. On the whole, these data provided more information about the structure of BmK AGP-SYPU1 related to its function upon hNa v 1.7, and may bring some clues for engineering scorpion toxins to achieve high bioactivity with lower side effects. [ABSTRACT FROM AUTHOR]

Serpins are a superfamily of proteins engaged in various physiological processes in all kingdoms of life. To date, many striking results have demonstrated serpins are involved in the invertebrate immune system by regulating the proteolytic cascades. However, in most insect species, the immune functions of serpins in response against pathogen invasion remain obscure. In this study, we identified a full-length cDNA sequence of serpin, named serpin-3, from the Chinese oak silkworm Antheraea pernyi . Sequence alignments have indicated that Ap serpin-3 might regulate the melanization reaction via inhibiting prophenoloxidases-activating protease(s) in plasma. Furthermore, it was detected to be primarily transcribed within the fat body, epidermis and hemocytes with significant induction following immune-challenge. Further studies have shown that the knockdown of serpin-3 up-regulated the prophenoloxidases cascade stimulated by pathogen in hemolymph, while the addition of recombinant serpin-3 along with the same elicitor led to the suppressed activation of prophenoloxidase. Besides, the injection of dsRNA of serpin-3 caused the elevated expression of antimicrobial peptides. Altogether, we arrived at a conclusion that serpin-3 might act as a negative-regulator in prophenoloxidases activation and inhibit the production of antimicrobial peptides in Antheraea pernyi larvae. [ABSTRACT FROM AUTHOR]

Apolipophorin-III (apoLp-III) is an exchangeable apolipoprotein found in many insect species and functions as a lipid transport vehicle. Recent studies have shown that apoLp-III is a multifunctional molecule involved in not only lipid transportation but also innate immune responses. In the present study, the pattern recognition properties of Antheraea pernyi apoLp-III were investigated. Recombinant Ap -apoLp-III was bound to different species of microbes and further study showed the r Ap -apoLp-III is capable of interacting with pathogen associated molecular patterns (PAMPs) on the microbial cell surface. In addition, an Ap -apoLp-III/PAMP mixture stimulated the prophenoloxidase (PPO) activation of A. pernyi hemolymph in vitro , to a greater extent than PAMP alone while Ap -apoLp-III itself failed to activate the PPO system, indicating that Ap -apoLp-III up-regulates PPO activation by combining with PAMP. After pathogen invasion following an injection of Staphylococcus aureus , RNAi-mediated silencing of apoLp-III decreased the transcriptional abundance of three antimicrobial peptide genes. These data suggest that apoLp-III is a versatile pattern recognition receptor and may play important roles in the innate immune responses of Antheraea pernyi . [ABSTRACT FROM AUTHOR]

Gangliosides, sialic acid-containing glycosphingolipids, have been considered to be involved in the development, differentiation, and function of nervous systems in vertebrates. However, the mechanisms for anti-inflammation caused by gangliosides are not clear. In this paper, we investigated the anti-inflammation effects of ganglioside GD1a by using RAW264.7 macrophages. Our data demonstrated that treatment of macrophages with lipopolysaccharide significantly increased the production of NO and pro-inflammatory cytokines. GD1a suppressed the induction of iNOS and COX-2 mRNA and protein expression and secretory pro-inflammatory cytokines in culture medium, such as TNFα, IL-1α and IL-1β. In addition, LPS-induced phosphorylation of mitogen-activating protein kinases and IκBα degradation followed by translocation of the NF-κB from the cytoplasm to the nucleus were attenuated after GD1a treatment. Furthermore, GD1a probably inhibited LPS binding to macrophages and LPS-induced accumulation between TLR4 and MyD88. Taken together, the results demonstrated that ganglioside GD1a inhibited LPS-induced inflammation in RAW 264.7 macrophages by suppressing phosphorylation of mitogen-activating protein kinases and activation of NF-κB through repressing the Toll-like receptor 4 signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the study is to investigate the direct angiogenic activities of SMND-309, a novel metabolite of salvianolic acid B, on human umbilical vein endothelial cells (HUVEC) in vitro and its potential molecular mechanisms. Effects of SMND-309 on proliferation and adhesion of HUVEC were measured using sulforhodamine B assay and cell adhesion assay kit, respectively. Effects of SMND-309 on migration and differentiation of HUVEC were examined through wound-healing assay and tube formation on matrigel method, respectively. Expressions of erythropoietin (EPO), EPO receptor, phosphorylated EPO receptor, signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 and vascular endothelial growth factor (VEGF) were detected by Western blot. Knocking down EPO receptor gene and blocking the epidermal growth factor (EGF) receptor/Janus kinase 2 (JAK2) pathways were used to explore the potential mechanisms in SMND-309 induced angiogenesis. SMND-309 strongly induced the proliferation of HUVEC in a concentration-dependent manner within the concentrations of 1–30μg/ml and significantly promoted the adhesion of HUVEC to different extracellular matrix at 30μg/ml. SMND-309 at doses of 3, 10, 30μg/ml significantly enhanced the migration, capillary-like structure formation, and the levels of VEGF, phosphorylated EPO receptor and phosphorylated STAT3. Results from further experiments using HUVECEPO receptor− and AG-490 showed that SMND-309 activated EPO receptor first, and then stimulated JAK2/STAT3, which up-regulated the expression of VEGF, and resulted in the angiogenesis. These results clearly show that SMND-309 has powerful angiogenic activity on HUVEC, which is mostly correlated with the up-regulation of VEGF through EPO receptor/STAT3 signal pathways. [Copyright &y& Elsevier]

Abstract: A novel starch-derived porous silica monolith (PSM) and porous starch foam (PSF) were developed as a carrier in order to improve the dissolution of lovastatin. PSM was prepared by the starch gel template method and PSF was prepared by the solvent exchange method. The morphology and structure of PSM and PSF were characterized by scanning electron microscopy (SEM) and nitrogen adsorption/desorption analysis. Lovastatin was loaded into PSM and PSF by immersion/solvent evaporation. Nano-pore spatial confinement effect on the drug dissolution was systematically studied by SEM, Fourier transform infrared spectroscopy (FTIR), thermogravametric analysis (TGA), x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and in-vitro drug dissolution studies. Lovastatin adsorbed in PSM was amorphous and lovastatin absorbed on PSF was partially present as microcrystal in the pores of PSF and partially in crystalline form distributed on the surface of PSF. PSM and PSF allowed immediate release of lovastatin and enhanced the dissolution rate. These results provide important information about the mechanism of drug adsorption and release. Accordingly, PSM and PSF have a promising future as a vehicle for the oral delivery of poorly water soluble drugs. Moreover, the effect of PSM is better than that of PSF. [Copyright &y& Elsevier]

Abstract: Residue 54 has been shown to be important for bioactivity in several toxins. However, its role in the antinociceptive activity of toxins has not been evaluated yet. In this study, site-directed mutagenesis and mouse acetic acid writhing test were used to investigate the role of Ser54 in the antinociceptive activity of BmK9 neurotoxin from the Buthus martensii Karsch scorpion. Detailed mutagenesis analysis revealed that substitution of Ser54 by various polar amino acids produced no significant change in the antinociceptive activity, while all substitutions of nonpolar amino acid for Ser54 led to a significant loss of antinociceptive activity. Following the conformational analysis, it was suggested that Ser54 in BmK9 plays a functional role in the antinociceptive activity, the residue exerts its effect by means of a side-chain hydrogen bond. [Copyright &y& Elsevier]

Abstract: The evaluation of N-trimethyl chitosan (TMC)-coated liposomes containing Coenzyme Q10 as potential ophthalmic drug delivery system was carried out. Firstly, transcorneal permeation studies were conducted at 34°C using a side-by-side diffusion apparatus. The transport process of the fluorescent marker, rhodamine B, across the corneal epithelium was visualized with confocal laser scanning microscopy. Secondly, the human lens epithelial cells (HLECs) were cultured without or with Coenzyme Q10 followed by addition of H2O2. The cell viability and apoptosis were evaluated. The permeability coefficient for rhodamine B with TMC-coated liposomes increased more than two times in comparison with the value obtained for solution as control, from (0.42±0.018)×105 cms−1 to (1.31±0.030)×105 cms−1. Confocal laser scanning microscopy revealed that a TMC coating enhanced the transepithelial transport, dependent on the TMC concentration and contacting time. Coenzyme Q10 elevated the cell viability and reduced the oxidative damage with the decreased percentage of apoptotic cells in a positive concentration-dependent manner. The ATP content of liposome-treated cells was increased about 2-fold compared with that of H2O2-treated cells. Together, our findings demonstrate that with the enhanced permeation effect of the TMC coating, Coenzyme Q10-loaded TMC-coated liposomes appear to be a promising ophthalmic drug delivery carrier with an efficacy in protecting HLECs against H2O2-induced oxidative damage. [ABSTRACT FROM AUTHOR]

Abstract: A biodegradable porous starch foam (BPSF) was developed for the first time as a carrier in order to improve the dissolution and enhance the oral bioavailability of lovastatin – defined as a model poorly water soluble BCS type II drug. In this paper, BPSF was prepared by the solvent exchange method and characterized by scanning electron microscopy (SEM) and nitrogen adsorption/desorption analysis in order to perform the morphological and structural characterization of BPSF. Lovastatin was loaded by immersion/solvent evaporation into the BPSF which provided a stable hydrophilic matrix with a nano-porous structure. The solid state properties of the loaded BPSF samples were characterized by SEM, Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). In vitro and in vivo drug release studies showed that when BPSF was used as a carrier it allowed immediate release of lovastatin and enhanced the dissolution rate in comparison with crystalline lovastatin and commercial capsules. These results provide important information about the mechanism of drug adsorption and release from BPSF as a carrier. Accordingly, BPSF has a promising future as a device for the oral delivery of poorly water soluble drugs. [ABSTRACT FROM AUTHOR]

Abstract: The genomic DNA sequence encoding an antitumor-analgesic peptide was amplified from the genome of Chinese scorpion Buthus martensii Karsch (BmKAGAP), then cloned and sequenced. An intron, with a high A + T content (61.6%), splits a glycine codon near the end of the precursor signal peptide and the consensus GT/AG splice junction was identified in the BmKAGAP gene. Using PCR amplification, we confirmed the identity of our cloned cDNA, and found that the BmKAGAP gene contained an intron of 506 bp in length, which was almost identical to that of the characterized scorpion sodium channel ligands in size, consensus junctions, putative branch point and A + T content. This is the first report of using a statistical method for Chinese scorpion B. martensii Karsch genomic sequence analysis, involving the extraction of some putative transcription regulatory factors. Moreover, it establishes a theoretical foundation for studying the relationship between scorpion evolution, gene expression and protein function. [Copyright &y& Elsevier]

Abstract: Anti-neuroexcitation peptide (ANEP) is a promising candidate for the treatment of neuroexcitation-associated diseases. N-Trimethyl chitosan (TMC) with different degrees of quaternization was synthesized, characterized and evaluated as a brain-targeting delivery vehicle for ANEP. ANEP-loaded TMC nanoparticles were prepared by ionic crosslinking of TMC with tripolyphosphate (TPP). The optimized formulation of nanoparticles consisted of TMC with a degree of quaternization (DQ) of 36.1% and TPP solution with a concentration of 0.6mg/mL. The mean encapsulation efficiency and loading capacity of the optimum formulation was 80.63% and 185.4μg/mL, respectively, while the mean particle size, zeta potential, and pH value were 255nm, 32.0mV and 6.61, respectively. ANEP was labeled with FITC for in vivo tissue distribution experiments. The results showed that the targetability of ANEP to brain was significantly increased by TMC nanoparticles. Absorptive-mediated transcytosis was believed to be the main pathway for the brain-targeting of FITC–ANEP–TMC/NPs. These findings demonstrate that TMC nanoparticles are potentially useful brain-targeting delivery systems for ANEP. [Copyright &y& Elsevier]

Serpins are known to be necessary for the regulation of several serine protease cascades. However, the mechanisms of how serpins regulate the innate immune responses of invertebrates are not well understood due to the uncertainty of the identity of the serine proteases targeted by the serpins. We recently reported the molecular activation mechanisms of three serine protease-mediated Toll and melanin synthesis cascades in a large beetle, Tenebrio molitor. Here, we purified three novel serpins (SPN4O, SPN55, and SPN48) from the hemolymph of T. molitor. These serpins made specific serpin-serine protease pairs with three Toll cascade-activating serme proteases, such as modular serine protease, Spätzle-processing enzyme-activating enzyme, and Spätzle-processing enzyme and cooperatively blocked the Toll signaling cascade and β-1,3-glucanmediated melanin biosynthesis. Also, the levels of SPN4O and SPN55 were dramatically increased in vivo by the injection of a Toll ligand, processed Spätzle, into Tenebrio larvae. This increase in SPN40 and SPN55 levels indicates that these serpins function as inducible negative feedback inhibitors. Unexpectedly, SPN55 and SPN48 were cleaved at Tyr and Glu residues in reactive center loops, respectively, despite being targeted by trypsin-like Spatzleprocessing enzyme-activating enzyme and Spätzle-processing enzyme. These cleavage patterns are also highly similar to those of unusual mammalian serpins involved in blood coagulation and blood pressure regulation, and they may contribute to highly specific and timely inactivation of detrimental serine proteases during innate immune responses. Taken together, these results demonstrate the specific regulatory evidences of innate immune responses by three novel serpins. [ABSTRACT FROM AUTHOR]

Abstract: Dietary flavonols have been found to possess preventive and therapeutic potential against several kinds of cancers. This study is conducted to investigate the anti-proliferation effects of kaempferol, a major component of food flavonols, against colon cancer cells. In the human HCT116 colon cancer cell line, kaempferol induced p53-dependent growth inhibition and apoptosis. Furthermore, kaempferol was found to induce cytochrome c release from mitochondria and activate caspase-3 cleavage. The Bcl-2 family proteins including PUMA were involved in this process. Kaempferol also induced ATM and H2AX phosphorylation in HCT116 cells, inhibition of ATM by a chemical inhibitor resulted in abrogation of the downstream apoptotic cascades. These findings suggest kaempferol could be a potent candidate for colorectal cancer management. [Copyright &y& Elsevier]

Non-steroidal Anti-inflammatory Drugs (NSAIDs) are widely used because of their excellent anti-inflammatory and analgesic effects. However, NSAIDs could cause certain cardiac side effects, such as myocardial infarction, heart failure, atrial fibrillation, arrhythmia and sudden cardiac death. Therefore, meloxicam, nimesulide, piroxicam, and diclofenac were selected and the whole cell patch clamp technique was used to investigate the electrophysiological regulatory effects of them on the sodium channel hNav1.5 and potassium channel hKv11.1, which were closely associated to the biotoxicity of cardiac, and to explore the potential cardiac risk mechanism. The results showed that the four NSAIDs could inhibit the peak currents of hNav1.5 and hKv11.1. Furthermore, the four NSAIDs could affect both the activation and inactivation processes of hNav1.5 with I–V curves left-shifted to hyperpolarized direction in activation phase. These data indicate that the inhibition effects of Nav1.5 and Kv11.1 by meloxicam, nimesulide, piroxicam, and diclofenac might contribute to their potential cardiac risk. These findings provide a basis for the discovery of other potential cardiac risk targets for NSAIDs. [Display omitted] • NSAIDs act as inhibitors of hNav1.5 and hERG. • Nav1.5 and hERG might be involved in the cardiac side effects of NSAIDs. • Diclofenac showed the least inhibition effects on both hNav1.5 and hERG channels. • Minor perturbations of piroxicam and meloxicam lead to major changes in hNav1.5. [ABSTRACT FROM AUTHOR]