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Objective To test the hypotheses that brain networks of patients with epilepsy differ from that of healthy controls and functional interactions in the brain are correlated to the duration of epilepsy. Method The present study recorded Magnetoencephalography (MEG) data from twenty patients with epilepsy and twenty healthy controls, constructed the whole functional brain network based on phase lag index (PLI), compared the differences in functional connectivity and network measures between patients with epilepsy and healthy controls, and analyzed the correlation between network measures and the duration of epilepsy. Results The patients with epilepsy showed significant increase in mean functional connectivity in the alpha band, gamma band and ripple band, significant increase in mean clustering coefficient in the theta band, beta band and ripple band, significant increase in average shortest path length in the theta band and alpha band. Only in the alpha band, a significant negative correlation between mean clustering coefficient and the duration of epilepsy was detected. Conclusions Our results indicated that the alterations of functional brain network are related to a functional imbalance that resulted from epileptic activity and the brain network of patients with epilepsy become more pathological over time. [ABSTRACT FROM AUTHOR]

Previously, we established delayed jellyfish envenomation syndrome (DJES) models and proposed that the hemorrhagic toxins in jellyfish tentacle extracts (TE) play a significant role in the liver and kidney injuries of the experimental model. Further, we also demonstrated that metalloproteinases are the central toxic components of the jellyfish Cyanea capillata ( C. capillata ), which may be responsible for the hemorrhagic effects. Thus, metalloproteinase inhibitors appear to be a promising therapeutic alternative for the treatment of hemorrhagic injuries in DJES. In this study, we examined the metalloproteinase activity of TE from the jellyfish C. capillata using zymography analyses. Our results confirmed that TE possessed a metalloproteinase activity, which was also sensitive to heat. Then, we tested the effect of metalloproteinase inhibitor batimastat (BB-94) on TE-induced hemorrhagic injuries in DJES models. Firstly, using SR-based X-ray microangiography, we found that BB-94 significantly improved TE-induced hepatic and renal microvasculature alterations in DJES mouse model. Secondly, under synchrotron radiation micro-computed tomography (SR-μCT), we also confirmed that BB-94 reduced TE-induced hepatic and renal microvasculature changes in DJES rat model. In addition, being consistent with the imaging results, histopathological and terminal deoxynucleotidyl transferase-mediated UTP end labeling (TUNEL)-like staining observations also clearly corroborated this hypothesis, as BB-94 was highly effective in neutralizing TE-induced extensive hemorrhage and necrosis in DJES rat model. Although it may require further clinical studies in the near future, the current study opens up the possibilities for the use of the metalloproteinase inhibitor, BB-94, in the treatment of multiple organ hemorrhagic injuries in DJES. [ABSTRACT FROM AUTHOR]

Objective To investigate the combination effect using iron chelators deferasirox and cisplatin on A549 cell proliferation and apoptosis and to provide evidences to explore an effective way to treat lung cancer. Methods Lung adenocarcinoma cells were cultured by conventional way, with administration of different concentrations of deferasirox and cisplatin. Cell growth inhibition was observed under an inverted microscope. Proliferation inhibition was evaluated by MTT assay. Morphological changes of cell apoptosis was detected using DAPI, AO/EB straning and flow cytometry. Results After a certain time of incubation with different concentrations of the combined drugs, the cell number reduce significantly, which was counted under invert microscope. Cells were dispersed with each other and adherent cells appear shrunken and poor in refractivity. MTT assay showed that inhibition of cell proliferation was in a concentration-time-dependent manner. Chromatin condensation, nuclear condensation and other typical apoptotic morphology were detected after DAPI and AO/EB straining. Flow cytometry showed that apoptosis increased with rising drug concentration. So combination therapy was significantly pro-apoptotic. Conclusion Deferasirox has the ability to inhibit proliferation of A549 cells and can promote tumor cell apoptosis and enhances cancer cell tolerance when combined with cisplatin. It can also reduce the amount and toxicity of cisplatin. It provides a basis for finding an effective way to treat lung cancer. [ABSTRACT FROM AUTHOR]

Cationic monofunctional platinum(II)-based anticancer agents with a general formula of cis -[Pt(NH 3 ) 2 (N-donor)Cl] + have recently drawn significant attention due to their unique mode of action, distinctive anticancer spectrum, and promising antitumor activity both in vitro and in vivo . Understanding the mechanism of action of novel monofunctional platinum compounds through rational drug design will aid in the further development of active agents. In this study, we synthesized and evaluated a monofunctional platinum-based anticancer agent SA–Pt containing a bulky salicylanilide moiety. The antiproliferative activity of SA–Pt was close to that of cisplatin. Mechanism studies revealed that SA–Pt entered HeLa cells more efficiently than cisplatin, blocked the cell cycle at the S-phase, and induced apoptosis. The compound bound to DNA as effectively as cisplatin, but did not block RNA polymerase II-mediated transcription as strongly as cisplatin, indicating that once the compound formed Pt-DNA lesions, the salicylanilide group was more easily recognized and removed. This study not only enriches the family of monofunctional platinum-based anticancer agents but also guides the design of more potent monofunctional platinum complexes. [ABSTRACT FROM AUTHOR]

BTK plays a critical role in the B cell receptor mediated inflammatory signaling in the rheumatoid arthritis (RA). Through a rational design approach we discovered a highly selective and potent BTK kinase inhibitor (CHMFL-BTK-11) which exerted its inhibitory efficacy through a covalent bond with BTK Cys481. CHMFL-BTK-11 potently blocked the anti-IgM stimulated BCR signaling in the Ramos cell lines and isolated human primary B cells. It significantly inhibited the LPS stimulated TNF-α production in the human PBMC cells but only weakly affecting the normal PBMC cell proliferation. In the adjuvant-induced arthritis rat model, CHMFL-BTK-11 ameliorated the inflammatory response through blockage of proliferation of activated B cells, inhibition of the secretion of the inflammatory factors such as IgG1, IgG2, IgM, IL-6 and PMΦ phagocytosis, stimulation of secretion of IL-10. The high specificity of CHMFL-BTK-11 makes it a useful pharmacological tool to further detect BTK mediated signaling in the pathology of RA.

With the enhanced interoperability of information among vehicles, the demand for collaborative sharing among vehicles increases. Based on blockchain, the classical consensus algorithms in collaborative IoV (Internet of Vehicle), such as PoW (Proof of Work), PoS (Proof of Stake), and DPoS (Delegated Proof of Stake), only consider the node features, which is hard to adapt to the immediacy and flexibility of vehicles. On the other hand, classical consensus algorithms often require mass computing, which undoubtedly increases the communication overhead, resulting in the inability to achieve collaborative IoV under asymmetric networks. Therefore, proposing a low failure rate consensus algorithm that takes into account running time and energy consumption becomes a major challenge in IoV applications. This paper proposes an AI-enabled consensus algorithm with vehicle features, combining vehicle-based metrics and neural networks. First, we introduce vehicle-based metrics such as vehicle online time, performance, and behavior. Then, we propose an integral model and a hierarchical classification method, which combine with a BP neural network to obtain the optimal solution for interconnection. Among them, we also use Informer to predict the future online duration of vehicles, which effectively solves the situation that the primary node vehicle drops off in collaborative IoV. Finally, the experimentations show that the vehicle-based metrics eliminate the problem of the primary node vehicle being offline, which realizes the collaborative IoV considering vehicle features. Meanwhile, it reduces the vehicle network system delay and energy consumption. [ABSTRACT FROM AUTHOR]

Thioredoxins (Trx proteins) are a family of small, highly-conserved and ubiquitous proteins that play significant roles in the resistance of oxidative damage. In this study, a homologue of Trx was identified from the cDNA library of tentacle of the jellyfish Cyanea capillata and named CcTrx1. The full-length cDNA of CcTrx1 was 479 bp with a 312 bp open reading frame encoding 104 amino acids. Bioinformatics analysis revealed that the putative CcTrx1 protein harbored the evolutionarily-conserved Trx active site 31CGPC34 and shared a high similarity with Trx1 proteins from other organisms analyzed, indicating that CcTrx1 is a new member of Trx1 sub-family. CcTrx1 mRNA was found to be constitutively expressed in tentacle, umbrella, oral arm and gonad, indicating a general role of CcTrx1 protein in various physiological processes. The recombinant CcTrx1 (rCcTrx1) protein was expressed in Escherichia coli BL21 (DE3), and then purified by affinity chromatography. The rCcTrx1 protein was demonstrated to possess the expected redox activity in enzymatic analysis and protection against oxidative damage of supercoiled DNA. These results indicate that CcTrx1 may function as an important antioxidant in C. capillata. To our knowledge, this is the first Trx protein characterized from jellyfish species. [ABSTRACT FROM AUTHOR]

Abstract: Inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have shown to be promising in clinical trials against cancer and other diseases, and lots of efforts have been put into the development of organic compounds as more potent PARP-1 inhibitors. Here we describe a strategy to conveniently obtain metal-based PARP-1 inhibitors with enhanced biological activities by conjugating platinum moiety with an original inhibitor, e.g., benzonaphthyridone. Based on the structure–activity relationship analysis of PARP-1 inhibitors, three platinated PARP-1 inhibitors were designed, and the complexes were synthesized and characterized. Complex 3 presented significantly enhanced cytotoxicity against a panel of human cancer cells and a 10-fold increased inhibitory effect against recombinant PARP-1 compared with the original PARP-1 inhibitor. Complex 3 was as cytotoxic as cisplatin and its spectrum of anticancer activity was identical to that of cisplatin. The complex was able to enter into cancer cells efficiently, bind to DNA well, and block cell cycle at G2/M phase, indicating that complex 3 is an effective anticancer agent with a distinct mechanism of action. Our study implies that the conjugation of platinum with PARP-1 inhibitors could be a valid strategy to obtain more potent anticancer agents with improved biological activities. [Copyright &y& Elsevier]

PI3Kδ has been found to be over-expressed in B-Cell-related malignancies. Despite the clinical success of the first selective PI3Kδ inhibitor, CAL-101, inhibition of PI3Kδ itself did not show too much cytotoxic efficacy against cancer cells. One possible reason is that PI3Kδ inhibition induced autophagy that protects the cells from death. Since class III PI3K isoform PIK3C3/Vps34 participates in autophagy initiation and progression, we predicted that a PI3Kδ and Vps34 dual inhibitor might improve the anti-proliferative activity observed for PI3Kδ-targeted inhibitors. We discovered a highly potent ATP-competitive PI3Kδ/Vps34 dual inhibitor, PI3KD/V-IN-01, which displayed 10-1500 fold selectivity over other PI3K isoforms and did not inhibit any other kinases in the kinome. In cells, PI3KD/V-IN-01 showed 30-300 fold selectivity between PI3Kδ and other class I PI3K isoforms. PI3KD/V-IN-01 exhibited better anti-proliferative activity against AML, CLL and Burkitt lymphoma cell lines than known selective PI3Kδ and Vps34 inhibitors. Interestingly, we observed FLT3-ITD AML cells are more sensitive to PI3KD/V-IN-01 than the FLT3 wt expressing cells. In AML cell inoculated xenograft mouse model, PI3KD/V-IN-01 exhibited dose-dependent anti-tumor growth efficacies. These results suggest that dual inhibition of PI3Kδ and Vps34 might be a useful approach to improve the PI3Kδ inhibitor's anti-tumor efficacy.

Ibrutinib, a clinically approved irreversible BTK kinase inhibitor for Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL) etc, has been reported to be potent against EGFR mutant kinase and currently being evaluated in clinic for Non Small Cell Lung Cancer (NSCLC). Through EGFR wt/mutant engineered isogenic BaF3 cell lines we confirmed the irreversible binding mode of Ibrutinib with EGFR wt/mutant kinase via Cys797. However, comparing to typical irreversible EGFR inhibitor, such as WZ4002, the washing-out experiments revealed a much less efficient covalent binding for Ibrutinib. The biochemical binding affinity examination in the EGFR L858R/T790M kinase revealed that, comparing to more efficient irreversible inhibitor WZ4002 (Kd: 0.074 μM), Ibrutinib exhibited less efficient binding (Kd: 0.18 μM). An X-ray crystal structure of EGFR (T790M) in complex with Ibrutinib exhibited a unique DFG-in/c-Helix-out inactive binding conformation, which partially explained the less efficiency of covalent binding and provided insight for further development of highly efficient irreversible binding inhibitor for the EGFR mutant kinase. These results also imply that, unlike the canonical irreversible inhibitor, sustained effective concentration might be required for Ibrutinib in order to achieve the maximal efficacy in the clinic application against EGFR driven NSCLC.

Novel star-shaped poly(è-caprolactone)-b-poly(2-hydroxyethyl methacrylate) (sPCL-b-PHE-MA) with 3 arm and 6 arm was synthesized by a combination of ring-opening polymerization and atom transfer radical polymerization. The structure of copolymers was confirmed by nuclear magnetic resonance (¹H and,13 NMR) and Fourier transform infrared spectros-copy. The thermal behavior was measured by differential scanning calorimetry. The results showed that Tc, Tm, and Xc of the sPCL-b-PHEMA were reduced along with the increase in the length of the PHEMA block. The copolymers could self-assemble into dispersed micelles with quite low (×10-4 mg/mL) critical micelle concentration. The size and morphology of the micelles were characterized by dynamic light scattering and HAADF scan-ning transmission electron microscopy. It was found that the micelles were around 20-70 nm with a regular spherical shape. Moreover, drug loading content and encapsulation efficiency of paclitaxel by 3sPCL-b-PHEMA micelles were much lower than the values of 6sPCL-b-PHEMA micelles. The drug release experiments demonstrated that paclitaxelrelease was two-phase release profile and relative to the structure of sPCL-b-PHEMA.The in vitro cytotoxicity of sPCL-b-PHEMA micelles was evaluated using methylthiazoletetrazolium assay. The results showed no apparent inhibition effect on the Hela cells. These preliminary studies suggest that sPCL-b-PHEMA has a possible application as anticancer drug delivery carriers. [ABSTRACT FROM AUTHOR]

• This report has investigated the local immune landscape when upon exposure to silica nanomaterials. • Systemically administered SiO2 NPs increased the ratio of myeloid cells to T cells in the lung. • The altered immune microenvironment induced malignant cells survival in the lung tissue. Our results indicated systemically administered SiO2 NPs may inadvertently perturbed normal lung microenvironment, which is characterized by T cell-exhaustion signature for a long time, increasing the likelihood of malignant cells metastasis and survive. [Display omitted] In the context of nanomedicine, the inevitable accumulation of systemically administered inorganic nanomaterials in normal tissues and organs (e.g. liver, lung, spleen) may inadvertently perturb the normal immune microenvironment. Here, we investigate the immune microenvironment of the lung, liver, and spleen following the systemic administration of silica nanoparticles (SiO 2 NPs). Using single-cell RNA sequencing technology, we observe a dramatic decrease in the number of T cells in the lung following SiO 2 NPs administration, coupled to the enhanced IL-17-producing γδ T cells frequency, the reduced αβ T population, as well as the greater expression of the T cells dysfunctional markers. We further find that this effect is caused by accumulation of bone-marrow-derived cells in the lung, which are recruited by the SiO 2 NPs. Unexpectedly, in multiple mouse models, tumor metastasis in the lung is found more easily in SiO 2 -treated mice. Our results indicate that systemically administered SiO 2 NPs may inadvertently perturb normal lung microenvironment characterized by T cell-dysfunction signature, which increases the likelihood of malignant cells survival in the lung tissue. [ABSTRACT FROM AUTHOR]

Developing a functional coating for vascular stents with sustainable and tunable NO release remains challenging. In this work, we report a silk fibroin/chitosan-based biopolymer coating incorporating copper ions as a catalyst for NO generation and demonstrate its potential for the surface functionalization of cardiovascular stents. Based on the differences in silk fibroin and chitosan coordinating with copper ions, the loading, bonding, and release of copper ions could be precisely regulated over a wide range by controlling the ratio of silk fibroin and chitosan. This system shows good cytocompatibility for endothelial cells and tunable catalytic activity to decompose S -nitroso- N -acetyl-D-penicillamine (SNAP) for NO generation. Consequently, a functionalized coating with sustainable and tunable NO catalysis generation was developed on the metallic stent. Based on good biocompatibility, tunable NO release, and simple processing, the coating is expected to have great promise in the field of intervention therapy of cardiovascular disease. [Display omitted] [ABSTRACT FROM AUTHOR]