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Abstract Background The combination of berberine (BER) and curcumin (CUR) has been verified with ameliorative effects on non-alcohol fatty liver disease (NAFLD). However, discrepant bioavailability and biodistribution of BER and CUR remained an obstacle to achieve synergistic effects. Multilayer nanovesicles have great potential for the protection and oral delivery of drug combinations. Therein lies bile salts inserted liposomes, named as bilosomes, that possesses long residence time in the gastrointestinal tract (GIT) and permeability across the small intestine. Diethylaminoethyl dextran (DEAE-DEX) is generally used as an outside layer on the nanovesicles to increase the mucinous stability and promote oral absorption. Herein, we developed a DEAE-DEX-coated bilosome with BER and CUR encapsulated (DEAE-DEX@LSDBC) for the treatment of NAFLD. Results DEAE-DEX@LSDBC with 150 nm size exhibited enhanced permeation across mucus and Caco-2 monolayer. In vivo pharmacokinetics study demonstrated that DEAE-DEX@LSDBC profoundly prolonged the circulation time and improved the oral absorption of both BER and CUR. Intriguingly, synchronized biodistribution of BER and CUR and highest biodistribution at liver was achieved by DEAE-DEX@LSDBC, which contributed to the optimal ameliorative effects on NAFLD. It was further verified to be mainly mediated by anti-oxidation and anti-inflammation related pathways Conclusion DEAE-DEX coated bilosome displayed promoted oral absorption, prolonged circulation and synchronized biodistribution of BER and CUR, leading to improved ameliorative effects on NAFLD in mice, which provided a promising strategy for oral administration of drug combinations. Graphic abstract

Antimalarial drugs Dihydroartemisinin (DHA) and chloroquine phosphate (CQ) exhibit evident anti-cancer activity, particularly as combination therapy. DHA and CQ combination therapy has been proved to exhibit higher cytotoxic effect in tumor cells and lower toxicity to normal cells than combination of artemisinin derivatives (ARTs) and anticancer chemotherapy drugs. However, different physiochemical properties of DHA and CQ, leading to distinctive in vivo outcomes, considerably limited their synergistic effect in cancer treatment. Herein, we developed a lipid nanoparticle (LNP) for co-delivery of DHA and CQ to inhibit proliferation and metastasis of colorectal cancer. Considering the beneficial effects of acid/reactive oxide species (ROS)-sensitive phospholipids and targeting ligands for colorectal cancer cells, an RGD peptide-modified pH/ROS dual-sensitive LNP loaded with DHA and CQ (RLNP/DC) was prepared. It exhibited optimal cytotoxicity and suppression of invasion and metastasis in HCT116 cells in vitro, attributable to irreversible upregulation of intracellular ROS levels, downregulation of VEGF expression, and upregulation of paxillin expression. A mouse model of orthotopic metastasis of colorectal cancer was established to evaluate anti-proliferation and anti-metastasis effects of RLNP/DC in vivo. Thus, an optimized nanoplatform for DHA and CQ combination therapy was developed in this study that offered potential antitumor efficacy against colorectal cancer.

The combination of chemotherapy with natural products is a common strategy to enhance anticancer effects while alleviating the dose-dependent adverse effects of cancer treatment. Oxymatrine (OMT) has been extensively reported as having anticancer activity. Doxorubicin (DOX) is a chemotherapeutic DNA-damaging agent used for the treatment of carcinoma. In this study, we investigated whether synergistic effects exist with the combination treatment with OMT and DOX using human colorectal cancer cell (CRC) lines and the potential mechanisms involved in in vitro and in vivo activities. The MTT and colony formation assay results showed that compared to either OMT or DOX monotherapy, the combination of OMT + DOX markedly inhibited the growth of HT-29 and SW620 cells. Wound healing assays showed significant inhibition of cell migration with co-treatment, supported by the change in E-cadherin and N-cadherin expressions in Western blotting. Furthermore, flow cytometry analysis revealed that OMT + DOX co-treatment enhanced cell apoptosis as a result of ROS generation, whereas NAC attenuated OMT + DOX–induced apoptosis. Similarly, the apoptosis-related proteins (cleaved caspase-3, cleaved caspase-9, and the ratio of Bax/Bcl-2) were determined by Western blotting, which showed that the expressions of these markers were notably increased in the co-treatment group. Furthermore, co-administration of a low dose of DOX and OMT inhibited xenograft tumor growth in a dose-dependent manner. TUNEL assay and Ki67 staining images indicated more apoptosis and less proliferation occurred in OMT plus DOX-treated xenograft tumors. Meanwhile, the combination strategy decreased cardiotoxicity, which is the most serious side effect of DOX. RNA sequencing was performed to explore the precise molecular alterations involved in the combination group. Among the numerous differentially expressed genes, downregulated FHL-2 and upregulated cleaved SPTAN1 were validated in both mRNA and protein levels of HT-29 and SW620 cells. These two proteins might play a pivotal role involving in OMT + DOX synergistic activity. Overall, OMT in combination with DOX presented an outstanding synergistic antitumor effect, indicating that this beneficial combination may offer a potential therapy for CRC patients.

Inspired by large and medium-sized birds, two kinds of flapping-wing flying robots with wingspans beyond 2 meters were developed. They have the appearance of a hawk and a phoenix respectively, so they are called HIT-Hawk and HIT-Phoenix. In this paper, the bionic concept, theoretical analysis, design and manufacturing are introduced in detail. Firstly, the flight principle and characteristics of large and medium-sized birds were summarized. Then, the aerodynamics was modeled based on the thin airfoil theory, and the main design basis was established. Secondly, the mechanical structures of HIT-Hawk and HIT-Phoenix were designed to ensure the lateral and longitudinal stability and have optimized flight performance. Moreover, an autonomous flight control method was proposed and realized in highly integrated on-onboard controller; it satisfies the strict restrictions on mass, size, power and shape. Finally, the prototypes were fabricated and verified through practical flight experiments. The wingspans of these two flapping wing aircrafts are 2.0 m and 2.3 m respectively, the take-off weights are 1.15 kg and 0.86 kg, and the maximum stable endurance is 65 min (with battery of 3S LiPo, 4300 mAh) and 8 min (with battery of 3S LiPo, 800 mAh). Their wind resistance can both reach level 4. Compared with the small and micro flapping-wing aerial vehicles that mimic insects or small birds, they both have strong load capacity, strong wind resistance and long endurance.

In recent years, it is a trend to integrate the ideas in game theory into the research of multi-robot system. In this paper, a team-competition model is proposed to solve a dynamic multi-robot task allocation problem. The allocation problem asks how to assign tasks to robots such that the most suitable robot is selected to execute the most appropriate task, which arises in many real-life applications. To be specific, we study multi-round team competitions between two teams, where each team selects one of its players simultaneously in each round and each player can play at most once, which defines an extensive-form game with perfect recall. We also study a common variant where one team always selects its player before the other team in each round. Regarding the robots as the players in the first team and the tasks as the players in the second team, the sub-game perfect strategy of the first team computed via solving the team competition gives us a solution for allocating the tasks to the robots—it specifies how to select the robot (according to some probability distribution if the two teams move simultaneously) to execute the upcoming task in each round, based on the results of the matches in the previous rounds. Throughout this paper, many properties of the sub-game perfect equilibria of the team competition game are proved. We first show that uniformly random strategy is a sub-game perfect equilibrium strategy for both teams when there are no redundant players. Secondly, a team can safely abandon its weak players if it has redundant players and the strength of players is transitive. We then focus on the more interesting case where there are redundant players and the strength of players is not transitive. In this case, we obtain several counterintuitive results. For example, a player might help improve the payoff of its team, even if it is dominated by the entire other team. We also study the extent to which the dominated players can increase the payoff. Very similar results hold for the aforementioned variant where the two teams take actions in turn.

Pulmonary emphysema is a fatal lung disease caused by the progressive thinning, enlargement and destruction of alveoli that is closely related to inflammation and oxidative stress. Oxymatrine (OMT), as a bioactive constituent of traditional Chinese herbal Sophora flavescens, has great potential to alleviate pulmonary emphysema via its anti-inflammatory and antioxidative activities. Pulmonary administration is the most preferable way for the treatment of lung diseases. To improve the in vivo stability and pulmonary retention of OMT, OMT-loaded liposome with carboxymethyl chitosan (CMCS) modification was developed. The CMCS was modified on the surface of OMT liposomes via electrostatic attraction and covalent conjugation to obtain Lipo/OMT@CMCS and CMCS-Lipo/OMT, respectively. A porcine pancreatic elastase (PPE)-induced emphysema mice model was established to evaluate the alleviation effects of OMT on alveolar expansion and destruction. CMCS-modified liposomal OMT exhibited superior ameliorative effects on emphysema regardless of the preparation methods, and higher sedimentation and longer retention in the lung were observed in the CMCS-Lipo group. The mechanisms of OMT on emphysema were related to the downregulation of inflammatory cytokines and the rebalancing of antioxidant/oxidation via the Nrf2/HO-1 and NF-κB/IκB-α signaling pathways, leading to reduced cell apoptosis. Moreover, the OMT liposomal preparations further enhanced its anti-inflammatory and antioxidative effects. In conclusion, pulmonary administration of OMT is a potential strategy for the treatment of emphysema and the therapeutic effects can be further improved by CMCS-modified liposomes.

Pose (position and attitude) measurement of a space non-cooperative target is very important for on-orbital servicing tasks, including malfunctioning target repairing, space debris removal, and so on. However, such targets are generally non-cooperative, i.e., no markers are mounted on it and there is no prior knowledge. Therefore, the identification and measurement of a non-cooperative target is very challenging. In this paper, we propose an efficient method to recognize the natural objects with circular or near-circular shapes on the target, reducing the computation load and improving accuracy. First, the geometry properties of a practical non-cooperative target are analyzed. A stereo vision system is correspondingly designed to measure the relative pose of the target. Second, the error sources and time-consuming factors of the traditional method are analyzed. Then, a solution concept is proposed. Third, the efficient method is detailed to solve the geometry equation and determine the pose information, reducing the calculation complexity and increasing the accuracy. The image pre-processing and target detecting algorithms are realized on FPGAs, further accelerating the calculation speed. Finally, we develop an experiment system and verify the proposed method through practical experiments. The experiment system is composed of satellite mockup, binocular camera, and high precision laser tracker. The experiment results show that the proposed method has high accuracy and efficiency.

The present treatments for HIV transfection include chemical agents and gene therapies. Although many chemical drugs, peptides and genes have been developed for HIV inhibition, a variety of non-ignorable drawbacks limited the efficiency of these materials. In this review, we discuss the application of dendrimers as both therapeutic agents and non-viral vectors of chemical agents and genes for HIV treatment. On the one hand, dendrimers with functional end groups combine with the gp120 of HIV and CD4 molecule of host cell to suppress the attachment of HIV to the host cell. Some of the dendrimers are capable of intruding into the cell and interfere with the later stages of HIV replication as well. On the other hand, dendrimers are also able to transfer chemical drugs and genes into the host cells, which conspicuously increase the anti-HIV activity of these materials. Dendrimers as therapeutic tools provide a potential treatment for HIV infection.

Macrophages are the most abundant cell group in atherosclerosis (AS) lesions and play a vital role in all stages of AS progression. Recent research has shown that reactive oxygen species (ROS) generation from photodynamic therapy (PDT) induces macrophage autophagy to improve abnormal lipid metabolism and inflammatory environment. Especially in macrophage-derived foam cells, which has become a potential strategy for the treatment of AS. In this study, we prepared the conjugate (DB) of dextran (DEX) and bovine serum albumin (BSA). The DB was used as the emulsifier to prepare nanoemulsion loaded with upconversion nanoparticles (UCNPs) and chlorin e6 (Ce6) (UCNPs-Ce6@DB). The DEX modified on the surface of the nanoemulsion can recognise and bind to the scavenger receptor class A (SR-A) highly expressed on macrophages and promote the uptake of macrophage-derived foam cells in AS plates through SR-A-mediated endocytosis. In addition, UCNPs-Ce6@DB-mediated PDT enhanced ROS generation and induced autophagy in macrophage-derived foam cells, enhanced the expression of ABCA 1, a protein closely related to cholesterol efflux, and inhibited the secretion of pro-inflammatory cytokines. Ultimately, UCNPs-Ce6@DB was shown to inhibit plaque formation in mouse models of AS. In conclusion, UCNPs-Ce6@DB offers a promising treatment for AS. [ABSTRACT FROM AUTHOR]