Inhalation of 2, 4-di-tert-butylphenol-Loaded micelles suppresses respiratory syncytial virus infection in mice.

Human respiratory syncytial virus (RSV) is a common cause of respiratory infections in infants, young children, and elderly people. However, there are no effective treatments or vaccines available in most countries. In this study, we explored the anti-RSV potential of 2, 4-Di-tert-butylphenol (2, 4-DTBP), a compound derived from Houttuynia cordata Thunb. To overcome the poor solubility of 2, 4-DTBP, we encapsulated it in polymeric micelles and delivered it by inhalation. We found that 2, 4-DTBP-loaded micelles inhibited RSV infection in vitro and improved survival, lung pathology, and viral clearance in RSV-infected mice. Our results suggested that 2, 4-DTBP-loaded micelle is a promising novel therapeutic agent for RSV infection.

Polysaccharides screening for pulmonary mucus penetration by molecular dynamics simulation and in vitro verification.

Mucus penetration is one of the physiologic barriers of inhalation and nanocarriers can effectively facilitate the permeation of drugs. The interactions between the nanocarriers and mucin are crucial for penetration across the mucus layer on the respiratory tract. In this study, we proposed a molecular dynamics (MD) simulation method for the screening of polysaccharides that acted as the surface modification materials for inhalable nano-preparations to facilitate mucus penetration. MD revealed all-atom interactions between the monomers of polysaccharides, including dextran (DEX)/hyaluronic acid (HA)/carboxymethyl chitosan (CMCS) and the human mucin protein MUC5AC (hMUC5AC). The obtained data showed that DEX formed stronger non-covalent bonds with hMUC5AC compared to HA and CMCS, which suggested that HA and CMCS had better mucus permeability than DEX. For the in vitro verification, HA/CMCS-coated liposomes and DEX/PEG-inserted liposomes were prepared. The results of mucin interactions and mucus penetration studies confirmed that HA and CMCS possessed the weakest interactions with mucin and facilitated the mucus penetration, which was in consistent with the data from MD simulation. This work may shed light on the MD simulation-based screening of surface modification materials for inhalable nano-preparations to facilitate mucus penetration.

Automatic artery/vein classification methods for retinal blood vessel: A review.

Automatic retinal arteriovenous classification can assist ophthalmologists in disease early diagnosis. Deep learning-based methods and topological graph-based methods have become the main solutions for retinal arteriovenous classification in recent years. This paper reviews the automatic retinal arteriovenous classification methods from 2003 to 2022. Firstly, we compare different methods and provide comparison tables of the summary results. Secondly, we complete the classification of the public arteriovenous classification datasets and provide the annotation development tables of different datasets. Finally, we sort out the challenges of evaluation methods and provide a comprehensive evaluation system. Quantitative and qualitative analysis shows the changes in research hotspots over time, Quantitative and qualitative analyses reveal the evolution of research hotspots over time, highlighting the significance of exploring the integration of deep learning with topological information in future research.

A biomimetic nanocarrier facilitates glucose consumption and reactive oxide species accumulation in enzyme therapy for colorectal cancer.

Glucose oxidase (GOx)-based enzyme therapeutics are potential alternatives for colorectal cancer (CRC) treatment via glucose consumption and accumulation of hydrogen peroxide (H2O2). Given that H2O2 can be eliminated by cytoprotective autophagy, autophagy inhibitors that can interrupt autolysosome-induced H2O2 elimination are promising combination drugs of GOx. Here, we developed a multifunctional biomimetic nanocarrier for effective co-delivery of an autophagy inhibitor-chloroquine phosphate (CQP) and GOx to exert their synergistic effect by irreversibly upregulating intracellular reactive oxygen species (ROS) levels. Poly (D, l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) were used to encapsulate both GOx and CQP using a W/O/W multi-emulsion method. Calcium phosphate (CaP) was used to "fix" CQP to GOx in the internal water phase, where it served as a pH-sensitive unit to facilitate intracellular drug release. Folic acid-modified red blood cell membranes (FR) were used to camouflage the GOx/CQP/CaP encapsulated PLGA NPs (referred to as PLGA/GCC@FR). In an AOM/DSS-induced CRC mouse model, PLGA/GCC@FR exhibited improved antitumor effects, in which the number of tumor nodes were only a quarter of that in the free drug combination group. The enhanced therapeutic effects of PLGA/GCC@FR were attributed to the prolonged tumor retention which was verified by both dynamic in vivo imaging and drug biodistribution. This multifunctional biomimetic nanocarrier facilitated combined enzyme therapeutics by depleting glucose and augmenting intracellular ROS levels in tumor cells, which exerted a synergistic inhibitory effect on tumor growth. Therefore, this study proposed a novel strategy for the enhancement of combined enzyme therapeutics, which provided a promising method for effective CRC treatment.

Shikonin reverses cancer-associated fibroblast-induced gemcitabine resistance in pancreatic cancer cells by suppressing monocarboxylate transporter 4-mediated reverse Warburg effect.

BACKGROUND: Gemcitabine is a first-line chemotherapeutic agent for pancreatic cancer (PC); however, most patients who receive adjuvant gemcitabine rapidly develop resistance and recurrence. Cancer-associated fibroblasts (CAFs) are a crucial component of the tumor stroma that contribute to gemcitabine-resistance. There is thus an urgent need to find a novel therapeutic strategy to improve the efficacy of gemcitabine in PC cells under CAF-stimulation. PURPOSE: To investigate if shikonin potentiates the therapeutic effects of gemcitabine in PC cells with CAF-induced drug resistance. METHODS: PC cell-stimulated fibroblasts or primary CAFs derived from PC tissue were co-cultured with PC cells to evaluate the ability of shikonin to improve the chemotherapeutic effects of gemcitabine in vitro and in vivo. Glucose uptake assay, ATP content analysis, lactate measurement, real-time PCR, immunofluorescence staining, western blot, and plasmid transfection were used to investigate the underlying mechanism. RESULTS: CAFs were innately resistant to gemcitabine, but shikonin suppressed the PC cell-induced transactivation and proliferation of CAFs, reversed CAF-induced resistance, and restored the therapeutic efficacy of gemcitabine in the co-culture system. In addition, CAFs underwent a reverse Warburg effect when co-cultured with PC cells, represented by enhanced aerobic glycolytic metabolism, while shikonin reduced aerobic glycolysis in CAFs by reducing their glucose uptake, ATP concentration, lactate production and secretion, and glycolytic protein expression. Regarding the mechanism underlying these sensitizing effects, shikonin suppressed monocarboxylate transporter 4 (MCT4) expression and cellular membrane translocation to inhibit aerobic glycolysis in CAFs. Overexpression of MCT4 accordingly reversed the inhibitory effects of shikonin on PC cell-induced transactivation and aerobic glycolysis in CAFs, and reduced its sensitizing effects. Furthermore, shikonin promoted the effects of gemcitabine in reducing the growth of tumors derived from PC cells and CAF co-inoculation in BALB/C mice, with no significant systemic toxicity. CONCLUSION: These results indicate that shikonin reduced MCT4 expression and activation, resulting in inhibition of aerobic glycolysis in CAFs and overcoming CAF-induced gemcitabine resistance in PC. Shikonin is a promising chemosensitizing phytochemical agent when used in combination with gemcitabine for PC treatment. The results suggest that disrupting the metabolic coupling between cancer cells and stromal cells might provide an attractive strategy for improving gemcitabine efficacy.

Targeted treatment of atherosclerosis with protein-polysaccharide nanoemulsion co-loaded with photosensitiser and upconversion nanoparticles.

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 ABCA1, 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.

Fabrication of a protein-dextran conjugates formed oral nanoemulsion and its application to deliver the essential oil from Alpinia zerumbet Fructus.

The injury of vascular endothelial cells caused by high glucose (HG) is one of the driving factors of vascular complications of diabetes. Oral administration is the most common route of administration for the treatment of diabetes and its vascular complications. Essential oil extracts from Chinese medicine possess potential therapeutic effects on vascular endothelial injury. However, low solubility and volatility of essential oils generally result in poor oral absorption. Development of nanocarriers for essential oils is a promising strategy to overcome the physiological barriers of oral absorption. In this study, a nanoemulsion composed of bovine serum albumin (BSA)-dextran sulfate (DS) conjugate and sodium deoxycholate (SD) was constructed. The nanoemulsions were verified with promoted oral absorption and prolonged circulation time. After the primary evaluation of the nanoemulsion, essential oil from Alpinia zerumbet Fructus (EOFAZ)-loaded nanoemulsion (denoted as EOFAZ@BD5/S) was prepared and characterized. Compared to the free EOFAZ, EOFAZ@BD5/S increased the protective effects on HG-induced HUVEC injury in vitro and ameliorative effects on the vascular endothelium disorder and tunica media fibroelastosis in a T2DM mouse model. Collectively, this study provides a nanoemulsion for the oral delivery of essential oils, which holds strong promise in the treatment of diabetes-induced vascular endothelial injury.

Dual-targeting of artesunate and chloroquine to tumor cells and tumor-associated macrophages by a biomimetic PLGA nanoparticle for colorectal cancer treatment.

The regimens on colorectal cancer (CRC) are clinically limited due to the ignorance of tumor-supportive microenvironments. To combine the therapeutic effects on both tumor cells growth and immunosuppressive tumor microenvironments (TME), we propose the artesunate (AS) and chloroquine (CQ) combination and develop a poly (d,l-lactide-co-glycolide) (PLGA)-based biomimetic nanoparticle for dual-targeting delivery of the drug combination. Hydroxymethyl phenylboronic acid conjugated PLGA (HPA) is synthesized to form a reactive oxygen species (ROS)-sensitive core of biomimetic nanoparticles. A mannose-modified erythrocyte membrane (Man-EM) obtained by a novel surface modification method is cloaked on the AS and CQ-loaded HPA core to receive a biomimetic nanoparticle-HPA/AS/CQ@Man-EM. It holds a strong promise in inhibiting the proliferation of CRC tumor cells and reversing the phenotypes of TAMs via targeting both tumor cells and M2-like tumor-associated macrophages (TAMs). Verifying in an orthotopic CRC mouse model, the biomimetic nanoparticles showed improved accumulation at tumor tissues and effectively suppressed the tumor growth via both inhibition of tumor cell growth and repolarization of TAMs. Notably, unbalanced distribution to the tumor cells and TAMs is the key to realize the remarkable anti-tumor effects. This work proposed an effective biomimetic nanocarrier for the CRC treatment.

Fabrication of a Polysaccharide-Protein/Protein Complex Stabilized Oral Nanoemulsion to Facilitate the Therapeutic Effects of 1,8-Cineole on Atherosclerosis.

Atherosclerosis (AS) is a systemic disease characterized by lipid deposition in the blood vessel wall that urgently requires effective and safe therapeutic drugs for long-term treatment. An essential oil monomer-1,8-cineole (CIN) with ameliorative effects on vascular injuries has considerable potential for preventing the progression of AS because of its antioxidant, anti-inflammation, and cholesterol regulatory effects. However, the high volatility and instability of CIN result in low oral bioavailability and a short half-life, thereby limiting its clinical application. We formulated a nanoemulsion using a polysaccharide-protein/protein complex (dextran-bovine serum albumin/protamine, DEX5k-BSA/PTM) as an emulsifier, with vitamin B12 (VB12) as the ligand to facilitate the transportation across the small intestine. An emulsion preparation method using a microjet followed by ultraviolet irradiation was developed to obtain the CIN-loaded oral nanoemulsion CIN@DEX5k-BSA/PTM/VB12. The nanoemulsion improved the stability of CIN both in vitro and in vivo, prolonged the retention time in the gastrointestinal tract (GIT), and enhanced the permeability across the mucus layer and intestinal epithelial cells to increase oral bioavailability and plaque accumulation of CIN. Validated in an AS mouse model, CIN@DEX5k-BSA/PTM/VB12 achieved prominent therapeutic efficacy combating AS. This study highlights the advantages of DEX5k-BSA/PTM and VB12 in the development of nanoemulsions for CIN and provides a promising oral nanoplatform for the delivery of essential oils.

Nanotechnology-based photo-immunotherapy: a new hope for inhibition of melanoma growth and metastasis.

Melanoma is the most aggressive form of skin cancer and there is a need for the development of effective anti-melanoma therapies as it shows high metastatic ability and low response rate. In addition, it has been identified that traditional phototherapy could trigger immunogenic cell death (ICD) to activate antitumor immune response, which could not only effectively arrest primary tumour growth, but also exhibit superior effects in terms of anti-metastasis, anti-recurrence for metastatic melanoma treatment. However, the limited tumour accumulation of photosensitizers/photothermal agents and immunosuppressive tumour microenvironment severely weaken the immune effects. The application of nanotechnology facilitates a higher accumulation of photosensitizers/photothermal agents at the tumour site, which can thus improve the antitumor effects of photo-immunotherapy (PIT). In this review, we summarise the basic principles of nanotechnology-based PIT and highlight novel nanotechnologies that are expected to enhance the antitumor immune response for improved therapeutic efficacy.

Diffusion coefficient of cationic liposomes during lipoplex formation determines transfection efficiency in HepG2 cells.

Cationic lipid-based lipoplexes are well-known for gene delivery. To determine the relationship between physicochemical characteristics and transfection efficiency, cationic liposomes of different sizes were prepared and incubated with plasmid DNA at different temperatures to form lipoplexes. We found that the liposome diffusion coefficient during lipoplex formation strongly correlated with the physicochemical characteristics of lipoplexes, accessibility of plasmid DNA in lipoplexes, and logarithm of gene expression per metabolic activity. Clathrin-mediated endocytosis was the major route for lipoplexes comprising 100 nm-liposomes, as reported previously. As liposome size increased, the major route shifted to lipid raft-mediated endocytosis. In addition, macropinocytosis was observed for all liposome sizes. The role of reactive oxygen species might depend on liposome size and endocytosis. Information from this study would be useful for understanding cationic lipoplex-mediated transfection.

Development of Inhalable Chitosan-Coated Oxymatrine Liposomes to Alleviate RSV-Infected Mice.

Human respiratory syncytial virus (RSV) infection is the most important cause of acute lower respiratory tract infection in infants, neonates, and young children, even leading to hyperinflation and atelectasis. Oxymatrine (OMT), originating from natural herbs, possessed potential antivirus activity against influenza A virus, Coxsackie B3 virus, and RSV, whereas the absence of an in vivo study indicated the difficulties in overcoming the physiological obstacles. Since RSV basically replicated in lung tissue, in this study, we fabricated and characterized a chitosan (CS)-coated liposome with OMT loaded for the treatment of lethal RSV infection via inhalation. The results uncovered that OMT, as a hydrophilic drug, was liable to diffuse in the mucus layer and penetrate through the gas-blood barrier to enter systemic circulation quickly, which might restrict its inhibitory effect on RSV replication. The CS-coated liposome enhanced the distribution and retention of OMT in lung tissue without restriction from mucus, which contributed to the improved alleviative effect of OMT on lethal RSV-infected mice. Overall, this study provides a novel inhalation therapy for RSV infection, and the CS-coated liposome might be a potential inhalable nanocarrier for hydrophilic drugs to prevent pulmonary infections.

Biomimetic engineered nanocarriers inspired by viruses for oral-drug delivery.

Oral administration is the most preferred and simplest route, but it is highly challenging due to the numerous barriers in the gastrointestinal tract. To overcome these barriers, nanocarriers have been developed to protect oral drugs. An increased understanding of viral infection has inspired researchers to mimic the viral structures and functions in the design of drug carriers. The virus-inspired nanoparticles (VINs) have been highly optimized based on the viral specific features to enhance the bioavailability of drugs. Herein, we have reviewed the development and design strategies of VINs, as well as a systematic summary for mechanisms and processes of oral absorption and the application of VINs, providing a new perspective on challenges to the clinical translation of oral nano-carriers.

Inhibition of Mitochondrial Biosynthesis Using a "Right-Side-Out" Membrane-Camouflaged Micelle to Facilitate the Therapeutic Effects of Shikonin on Triple-Negative Breast Cancer.

The mitochondria represent a potential target for the treatment of triple-negative breast cancer (TNBC) and shikonin (SK) has shown remarkable therapeutic effects on TNBC. Herein, it is found that SK possesses potent inhibitory effects on mitochondrial biogenesis via targeting polymerase gamma (POLG). However, its application is restricted by its poor aqueous solubility and stability, and therefore, a biomimetic micelle to aid with tumor lesion accumulation and mitochondria-targeted delivery of SK is designed. A folic acid (FA) conjugated polyethylene glycol derivative (FA-PEG-FA) is inserted onto the external membranes of red blood cells (FP-RBCm) to prepare a "right-side-out" RBCm-camouflaged cationic micelle (ThTM/SK@FP-RBCm). Both FP-RBCm coating and a triphenylphosphine (TPP) moiety on the periphery of micelles contribute to tumor lesion distribution, receptor-mediated cellular uptake, and electrostatic attraction-dependent mitochondrial targeting, thereby maximizing inhibitory effects on mitochondrial biosynthesis in TNBC cells. Intravenous administration of ThTM/SK@FP-RBCm leads to profound inhibition of tumor growth and lung metastasis in a TNBC mouse model with no obvious toxicity. This work highlights the mitochondria-targeted delivery of SK using a "right-side-out" membrane-camouflaged micelle for the inhibition of mitochondrial biogenesis and enhanced therapeutic effects on TNBC.

Carboxymethyl Chitosan Modified Oxymatrine Liposomes for the Alleviation of Emphysema in Mice via Pulmonary Administration.

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.

Targeted Lipid Nanoparticles Encapsulating Dihydroartemisinin and Chloroquine Phosphate for Suppressing the Proliferation and Liver Metastasis of Colorectal Cancer.

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.

Improving the ameliorative effects of berberine and curcumin combination via dextran-coated bilosomes on non-alcohol fatty liver disease in mice.

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.

Oxymatrine Synergistically Enhances Doxorubicin Anticancer Effects in 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.

Dynamic Task Allocation in Multi-Robot System Based on a Team Competition Model.

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.

The ameliorative effect of terpinen-4-ol on ER stress-induced vascular calcification depends on SIRT1-mediated regulation of PERK acetylation.

Endoplasmic reticulum (ER) stress-mediated phenotypic switching of vascular smooth muscle cells (VSMCs) is key to vascular calcification (VC) in patients with chronic kidney disease (CKD). Studies have shown that activation/upregulation of SIRT1 has a protective effect on CKD-VC. Meanwhile, although terpinen-4-ol has been shown to exert a protective effect against cardiovascular disease, its role and underlying mechanism in VC remain unclear. Herein, we explored whether terpinen-4-ol alleviates ER stress-mediated VC through sirtuin 1 (SIRT1) and elucidated its mechanism to provide evidence for its application in the clinical prevention and treatment of VC. To this end, a CKD-related VC animal model and ß-glycerophosphate (ß-GP)-induced VSMC calcification model were established to investigate the role of terpinen-4-ol in ER stress-induced VC, in vitro and in vivo. Additionally, to evaluate the involvement of SIRT1, mouse and VSMC Sirt1-knockdown models were established. Results show that terpinen-4-ol inhibits calcium deposition, phenotypic switching, and ER stress in VSMCs in vitro and in vivo. Furthermore, pre-incubation of VSMCs with terpinen-4-ol or a SIRT1 agonist, decreased ß-GP-induced calcium salt deposition, increased SIRT1 protein level, and inhibited PERK-eIF2α-ATF4 pathway activation, thus, alleviating VC. Similar results were observed in VSMCs induced to overexpress SIRT1 via lentivirus transcription. Meanwhile, the opposite results were obtained in SIRT1-knockdown models. Further, results suggest that SIRT1 physically interacts with, and deacetylates PERK. Specifically, mass spectrometry analysis identified lysine K889 as the acetylation site of SIRT1, which regulates PERK. Finally, inhibition of SIRT1 reduced the effect of terpinen-4-ol on the deacetylation of PERK in vitro and in vivo and weakened the inhibitory effect of terpinen-4-ol against ER stress-mediated VC. Cumulatively, terpinen-4-ol was found to inhibit post-translational modification of PERK at the K889 acetylation site by upregulating SIRT1 expression, thereby ameliorating VC by regulating ER stress. This study provides insights into the underlying molecular mechanism of terpinen-4-ol, supporting its development as a promising therapeutic agent for CKD-VC.