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Hemolin is a distinctive immunoglobulin superfamily member involved in invertebrate immune events. Although it is believed that hemolin regulates hemocyte phagocytosis and microbial agglutination in insects, little is known about its contribution to the humoral immune system. In the present study, we focused on hemolin in Antheraea pernyi ( Ap -hemolin) by studying its pattern recognition property and humoral immune functions. Tissue distribution analysis demonstrated the mRNA level of Ap -hemolin was extremely immune-inducible in different tissues. The results of western blotting and biolayer interferometry showed recombinant Ap -hemolin bound to various microbes and pathogen-associated molecular patterns. In further immune functional studies, it was detected that knockdown of hemolin regulated the expression level of antimicrobial peptide genes and decreased prophenoloxidase activation in the A. pernyi hemolymph stimulated by microbial invaders. Together, these data suggest that hemolin is a multifunctional pattern recognition receptor that plays critical roles in the humoral immune responses of A. pernyi .

The depressant β toxin anti-neuroexcitation peptide (ANEP) from the Chinese scorpion Buthus martensii Karsch has analgesic activity by interacting with receptor site 4 of the voltage-gated sodium channels (VGSCs). Here, with molecular dynamics simulations, we examined the binding modes between ANEP and the site 4 of mice sodium channel 1.7 (mNav1.7), a subtype of VGSCs related to peripheral pain. Homology modeling, molecular mechanics, and molecular dynamics in the biomembrane environment were adopted. The results suggested that ANEP bound to the resting site 4 mainly by amino acid residues in the β2–β3 loop and the ‘NC’ domains, and the activate site 4 mainly by amino acid residues in the hydrophobic domain of N-groove and residues in the ‘pharmacophore’. Effects analysis of 14 mutants in the predicted functional domains of ANEP on mouse twisting models showed that the analgesic activity of mutants L15 and E24 of the ‘pharmacophore’, W36, T37, W38, and T39 forming the loop between the β2- and β3-strands and N8, V12, C60, and K64 in the NC domain increased distinctly after these residues were substituted for Ala, respectively. The binding modes and the active sites predicted were consistent with available mutagenesis data, and which is meaningful to understand the related mechanisms of ANEP for Nav1.7.

The purpose of this study is to investigate the anti-angiogenic activities of NSK-01105, a novel sorafenib derivative, in in vitro, ex vivo and in vivo models, and explore the potential mechanisms. NSK-01105 significantly inhibited vascular endothelial growth factor (VEGF)-induced migration and tube formation of human umbilical vein endothelial cells at non-cytotoxic concentrations as shown by wound-healing, transwell migration and endothelial cell tube formation assays, respectively. Cell viability and invasion of LNCaP and PC-3 cells were significantly inhibited by cytotoxicity assay and matrigel invasion assay. Furthermore, NSK-01105 also inhibited ex vivo angiogenesis in matrigel plug assay. Western blot analysis showed that NSK-01105 down-regulated VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2) and the activation of epidermal growth factor receptor (EGFR). Tumor volumes were significantly reduced by NSK-01105 at 60 mg/kg/day in both xenograft models. Immunohistochemical staining demonstrated a close association between inhibition of tumor growth and neovascularization. Collectively, our results suggest a role of NSK-01105 in treatment for human prostate tumors, and one of the potential mechanisms may be attributed to anti-angiogenic activities.

Ly‐GDI, Rho GTPase dissociation inhibitor beta, was found to be expressed parallel to the GM3 level in mouse B16 cells whose GM3 contents were modified by B4galt6 sense, B4galt6 antisense cDNA, or St3galt5 siRNA transfection. Ly‐GDI expression was increased on GM3 addition to these cells and decreased with D‐PDMP treatment, a glucosylceramide synthesis inhibitor. Suppression of GM3 or Ly‐GDI by RNAi was concomitantly associated with an increase in anchorage‐independent growth in soft agar. These results clearly indicate that GM3 suppresses anchorage‐independent growth through Ly‐GDI. GM3 signals regulating Ly‐GDI expression was inhibited by LY294002, siRNA against Akt1 and Akt2 and rapamycin, showing that GM3 signals are transduced via the PI3K/Akt/mTOR pathway. Either siRNA towards Rictor or Raptor suppressed Ly‐GDI expression. The Raptor siRNA suppressed the effects of GM3 on Ly‐GDI expression and Akt phosphorylation at Thr308, suggesting GM3 signals to be transduced to mTOR‐Raptor and Akt‐Thr308, leading to Ly‐GDI stimulation. siRNA targeting Pdpk1 reduced Akt phosphorylation at Thr308 and rendered the cells insensitive to GM3 stimulation, indicating that Akt‐Thr308 plays a critical role in the pathway. The components aligned in this pathway showed similar effects on anchorage‐independent growth as GM3 and Ly‐GDI. Taken together, GM3 signals are transduced in B16 cells through PI3K, Pdpk1, AktThr308 and the mTOR/Raptor pathway, leading to enhanced expression of Ly‐GDI mRNA, which in turn suppresses anchorage‐independent growth in melanoma B16 cells. (Cancer Sci 2011; 102: 1476–1485)

As a typical mimic of natural enzymes, carbon-based peroxidase-like nanozymes have developed vigorously recent years, which are widely used in biomedical research. In this paper, borocarbonitride nanotubes (BCNNTs) were synthesized via assembly and pyrolysis of small organic molecules achieving boron (B) and nitrogen (N) co-doping in carbon nanotubes. As non-metallic nanozymes, BCNNTs exhibited high peroxidase-like activity and photothermal conversion capability, which were applied to bacterial colorimetric point-of-care testing (POCT) and in situ synergistic inactivation. By BCNNTs functionalized with specific antibody of Staphylococcus aureus , sensitive visible and rapid POCT of Staphylococcus aureus was accomplished. Right after the bacterial assay, the bacterial inactivation proceeded efficiently owing to both the catalytic decomposition of H 2 O 2 and photothermal disinfection induced by BCNNT nanozymes, that eliminated bacterial contamination and further transmission without delay. The multifunctional BCNNT nanozymes possessed high peroxidase-like activity, photothermal property, good biocompatibility and stability, which had great potentials in food safety testing, environmental monitoring, and microbial control and therapy.

A facile colorimetric Pb2+ assay system has been developed based on the visible color change of gold nanoparticles (GNPs) modified with α2-microglobulin (α2M) protein. The α2M protein is a soluble and high-affinity receptor for Pb2+, which is well studied and regarded as the comparable positive control in Pb-binding protein researches. It was obtained through purifying recombinant protein from the expression of recombinant plasmids in Escherichia coli and was attached on GNPs to form GNPs-α2M sensor nanoparticles for detecting Pb2+, which has never been used for sensing Pb2+ in previous studies. When Pb2+ was introduced into the assay system, GNPs-α2M sensor nanoparticles can be triggered aggregation with the color change from pink to blue. The detection system exhibited good selectivity and sensitivity, which was attributed to the receptor specificity of α2M protein. Using this assay system, it can be distinguished 1.00 μM concentration of Pb2+ or more by naked eyes clearly. Furthermore, the UV-Vis absorbance ratio between 620 and 523 nm exhibited linearity relationship with the concentration of Pb2+ from 0.05 to 3 μM in assay system. In this research, GNPs-α2M sensor nanoparticles have highly specific capability to recognize Pb2+. The assay system constituted by GNPs-α2M sensor nanoparticles displays excellent convenience, selectivity, and sensitivity that provide promising potentials for on-site rapid test of Pb2+.

Vanillin holds significant importance as a flavoring agent in various industries, including food, pharmaceuticals, and cosmetics. The CoA-dependent pathway for the biosynthesis of vanillin from ferulic acid involved feruloyl-CoA synthase (Fcs) and enoyl-CoA hydratase/lyase (Ech). In this research, the Fcs and Ech were derived from Streptomyces sp. strain V-1. The sequence conservation and structural features of Ech were analyzed by computational techniques including sequence alignment and molecular dynamics simulation. After detailed study for the major binding modes and key amino acid residues between Ech and substrates, a series of mutations (F74W, A130G, A130G/T132S, R147Q, Q255R, ΔT90, ΔTGPEIL, ΔN1-11, ΔC260-287) were obtained by rational design. Finally, the yield of vanillin produced by these mutants was verified by whole-cell catalysis. The results indicated that three mutants, F74W, Q147R, and ΔN1-11, showed higher yields than wild-type Ech. Molecular dynamics simulations and residue energy decomposition identified the basic residues K37, R38, K561, and R564 as the key residues affecting the free energy of binding between Ech and feruloyl-coenzyme A (FCA). The large changes in electrostatic interacting and polar solvating energies caused by the mutations may lead to decreased enzyme activity. This study provides important theoretical guidance as well as experimental data for the biosynthetic pathway of vanillin.

Gangliosides are important components of the neuronal cell membrane and play a vital role in the development of neurons and the brain. They participate in neurotransmission and are considered as the structural basis of learning and memory. Gangliosides participate in several and important physiological processes, such as cell differentiation, cell signaling, neuroprotection, nerve regeneration and apoptosis. The stability of ion concentration in excitable cells is particularly important in the maintenance of a steady state of cells and in the regulation of physiological functions. Ion concentration has been found to be related to the ganglioside’s regulation in many neurological diseases, and several studies have found that they can stabilize intracellular ion concentration by regulating ion channels, which highlights their important regulatory role in neuronal excitability and synaptic transmission. Gangliosides can influence some forms of ion transport, by directly binding to ion transporters or through indirect binding and activation of transport proteins via appropriate signaling pathways. Therefore, the important and special role of gangliosides in the homeostasis of ion concentration is becoming a hot topic in the field and a theoretical basis in promoting help gangliosides use as key drugs for the treatment of nervous system diseases.

: Immunotherapy has emerged as a crucial component in cancer treatment, particularly for the long-term reduction of cancer metastasis and recurrence. However, its development is hindered by limited activation of cellular immune response and suboptimal delivery of vaccine to antigen-presenting cells. : The vaccine was encapsulated within mesoporous silica nanoparticles, followed by functionalization by mannose and phenylboronate ester (MSN-NH-DPM), which facilitates targeting antigen-presenting cells via mannose receptors and enables intracellular delivery through endosomal escape, thereby activating cellular immunity. The nanoparticles were then integrated into chitosan microneedle patches (MNs), which are engineered to deliver the nanoparticles into the skin that is abundant in immune cells, and improve the immune response through the adjuvant properties of chitosan. : The chitosan MNs incorporating MSN-NH-DPM (CTS-MN@MSN-NH-DPM) significantly activated the cellular immune response through the MHC-I pathway. The antigen-presenting cells that uptake the vaccine migrated to nearby lymph nodes, inducing systemic immunity to eliminate cancer cells. Compared with subcutaneous injection, the application of CTS-MN@MSN-NH-DPM significantly inhibited the growth of B16/OVA melanoma tumors and extended the survival time of the melanoma mouse model. : The MNs with targeted and intracellular delivery represent a promising platform for various vaccines to improve the cellular immune response, thus providing a potential solution for cancer treatment.

Human Cav1.3 (hCav1.3) is of great interest as a potential target for Parkinson’s disease. However, common medications like dihydropyridines (DHPs), a kind of classic calcium channel blocker, have poor selectivity to hCav1.3 in clinical treatment, mainly due to being implicated in cardiovascular side-effects mediated by human Cav1.2 (hCav1.2). Recently, pyrimidine-2,4,6-triones (PYTs) have received extensive attention as prominent selective inhibitors to hCav1.3. In this study, we describe the selectivity mechanism of PYTs for hCav1.2 and hCav1.3 based on molecular dynamic simulation methods. Our results reveal that the van der Waals (vdW) interaction was the most important force affecting selectivity. Moreover, the hydrophobic interaction was more conducive to the combination. The highly hydrophobic amino acid residues on hCav1.3, such as V162 (IR1), L303 (IR2), M481 (IR3), and F484 (IR3), provided the greatest contributions in the binding free energy. On the other hand, the substituents of a halogen-substituted aromatic ring, cycloalkyl and norbornyl on PYTs, which are pertinent to the steric hindrance of the compounds, played core roles in the selectivity and affinity for hCav1.3, whereas strong polar substituents needed to be avoided. The findings could provide valuable information for designing more effective and safe medicines for Parkinson’s disease.