Search

The local microenvironment where tumors develop can shape cancer progression and therapeutic outcome. Emerging evidence demonstrate that the efficacy of immune-checkpoint blockade (ICB) is undermined by fibrotic tumor microenvironment (TME). The majority of hepatocellular carcinoma (HCC) develops in liver fibrosis, in which the stromal and immune components may form a barricade against immunotherapy. Here, we report that nanodelivery of a programmed death-ligand 1 (PD-L1) trap gene exerts superior efficacy in treating fibrosis-associated HCC when compared with the conventional monoclonal antibody (mAb). In two fibrosis-associated HCC models induced by carbon tetrachloride and a high-fat, high-carbohydrate diet, the PD-L1 trap induced significantly larger tumor regression than mAb with no evidence of toxicity. Mechanistic studies revealed that PD-L1 trap, but not mAb, consistently reduced the M2 macrophage proportion in the fibrotic liver microenvironment and promoted cytotoxic interferon gamma (IFNγ)

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic lipids and metabolic stress-induced liver injury. There are currently no approved effective pharmacological treatments for NAFLD. Traditional Chinese medicine (TCM) has been used for centuries to treat patients with chronic liver diseases without clear disease types and mechanisms. More recently, TCM has been shown to have unique advantages in the treatment of NAFLD. We performed a systematic review of the medical literature published over the last two decades and found that many TCM formulas have been reported to be beneficial for the treatment of metabolic dysfunctions, including Potentilla discolor Bunge (PDB). PDB has a variety of active compounds, including flavonoids, terpenoids, organic acids, steroids and tannins. Many compounds have been shown to exhibit a series of beneficial effects for the treatment of NAFLD, including anti-oxidative and anti-inflammatory functions, improvement of lipid metabolism and reversal of insulin resistance. In this review, we summarize potential therapeutic effects of TCM formulas for the treatment of NAFLD, focusing on the medicinal properties of natural active compounds from PDB and their underlying mechanisms. We point out that PDB can be classified as a novel candidate for the treatment and prevention of NAFLD.

Hepatocellular carcinoma (HCC) is resistant to current immunotherapy. This poor outcome mainly results from the immunosuppressive characteristics of tumor microenvironment (TME). Accumulating evidence indicates that some chemotherapy agents trigger immunogenic cell death (ICD), providing a promising strategy to remodel the immunosuppressive TME. The role of Plumbagin (PLB, a naphthoquinone compound from Plumbago zeylanica L.) as the ICD inducer for HCC cells was confirmed in this study. Dihydrotanshinone I (DIH, a phenanthraquinone compound of Salvia miltiorrhiza) functioned as the ICD enhancer by generating the reactive oxygen species (ROS). A poly(D,L-lactic-co-glycolic acid) (PLGA)-based nanoparticle (NP) was used to co-encapsulate PLB, DIH and NH

Several probes containing benzothiazole-guided conjugated systems (BGCS) were designed and synthesized, and two molecules (BGCS5 and BGCS6) of which were discovered as selective probes targeting c-MYC Pu22 G-quadruplex DNA. The fluorescence intensity of BGCS5 and BGCS6 in the presence of c-MYC Pu22 far exceeds that of the typical G4 probe TO1. Especially, the fluorescence of BGCS6 increased almost 193-fold in the presence of c-MYC Pu22 G4 compared to that alone in aqueous buffer condition with almost no fluorescence and 10–30 folds than those in the presence of other DNAs, which will be useful tools for disease detection in mammals.

Constitutionally adaptive chemistry of selenium-containing crown ethers (CEs) offers a new platform for controlling/switching the hydration of bolaamphiphile skeletons in water in an effective and simple manner by the virtue of covalent bonding. The adaptive behaviour of the macrocyclic bolaamphiphiles (transformations between C7SeBola and C7SeOBola) in response to redox environment was found to be a decisive factor.

Lead-free BiFeO3–BaTiO3–Bi(Mg2/3Nb1/3)O3 (BFBT-BMN) ceramics with different grain sizes were fabricated by using a conventional solid-state reaction. The high-energy ball milling technique was utilized to obtain the fine-grained ceramics. The grain size reduction lowers the remanent polarization (Pr) and enhances the dielectric breakdown strength (Eb) leading to a drastic increase of the recoverable energy storage density (Wre). For the fine-grained BFBT-BMN ceramics, Wre greatly increases by 8 times from 0.16 J/cm3 to 1.27 J/cm3, compared to the coarse-grained BFBT-BMN ceramics. Transmission electron microscopy (TEM) and piezo-response force microscopy (PFM) measurements revealed the occurrence of the polar nanoregions (PNRs) in the fine-grained BFBT-BMN ceramics. The dynamic and weakly correlated PNRs structure is responsible for the enhancement of recoverable energy storage density in the fined-grained BFBT-BMN ceramics. This work indicates that the grain size reduction is an effective way to modify the energy storage properties of BiFeO3-based ferroelectric ceramics.

Percutaneous coronary intervention (PCI) is an effective treatment for acute myocardial infarction, but the postoperative in-stent re-stenosis (ISR) remains a major risk factor that affects the prognosis of PCI. Clinically, drug-eluting stents (DES) are widely applied to prevent and treat ISR. However, only a few stent coating drugs are currently available for clinical use, including paclitaxel and rapamycin (sirolimus) and their derivatives. These stent-coated drugs have led to a decrease in restenosis rates, but the major adverse outcomes, such as delayed endothelial healing and increased in-stent thrombosis, seriously reduce their therapeutic effects.Herein, we explored the potential efficacy of Euonymine (Euo), an alkaloid extracted from Tripterygium Hypoglaucum (Levl) Hutch (THH, Lei gong Teng), for the prevention against ISR after PCI.Our study depicts the potential efficacy of Euo in treating ISR and explores its mechanism with in vitro and in vivo models.Primary vascular smooth muscle cells (VSMCs) from the rabbit thoracic aorta were cultured, and the proliferation and migration of VSMCs were monitored. Apoptosis was measured by Transmission Electron Microscopy and TUNEL staining assay. Protein and gene levels were measured to explore the underlying molecular mechanisms. In vivo models of porcine coronary implantation and rabbit carotid balloon injury are used to validate the efficacy of Euo in inhibiting ISR after PCI.With an ox-LDL-injured cell model, we showed that Euo suppressed the proliferation and migration of the rabbit thoracic aorta primary VSMCs, while inducing their apoptosis. We next established a rabbit carotid balloon injury model in which the phosphorylation levels of PI3K and AKT1 (Ser473) as well as mTOR activity were significantly elevated compared to the sham-operated control. These activities were significantly attenuated by the Euo intervention. Additionally, the balloon angioplasty significantly increased the expression of Bcl-2, while decreased the expression of Bax and caspase-3. Euo intervention significantly increased the ratio of Bax/Bcl-2 and the level of caspase-3. Taken together, Euo may enhance the VSMCs contractile phenotype by modulating the PTEN/AKT/mTOR signaling pathway. Furthermore, with two in vivo models, the porcine coronary artery implantation model, and the rabbit carotid balloon injury model, we demonstrated that Euo-eluting stents indeed inhibited ISR after PCI.For the first time, this study delineates the potential efficacy of Euo, derived from Tripterygium Hypoglaucum (Levl) Hutch, in ameliorating ISR after PCI with two in vivo models. The phytochemical targets PTEN/AKT/mTOR signaling pathway to increase the contractile phenotype of VSMCs and exerts anti-proliferative, anti-migratory as well as pro-apoptotic effects, thereby inhibiting the ISR.

Fenitrothion (FN) residue in food is a serious threat to public health. Consequently, a sensitive, cost-effective, and convenient immunoassay for FN urgently needs to be fabricated to safeguard human health. Herein, a nanobody-alkaline phosphatase fusion protein (Nb-ALP)-based fluorescent ELISA using red emissive carbon dots (r-CDs) anchored cobalt oxyhydroxide nanosheet (CoOOH NS) composite was developed for detecting FN. Briefly, a Nb-ALP was obtained by autoinduction expression and employed as a recognition, signal transduction, and amplification element. As the fluorescence signal source, r-CDs were assembled with CoOOH NS to yield the r-CDs@CoOOH NS composite, leading to the fluorescence quenching of r-CDs via Förster resonance energy transfer (FRET). After competitive immunoreaction, the Nb-ALP bounded to the immobilized antigen can mediate the production of ascorbic acid, which can reduce the CoOOH NS to Co

In view of that existing opening technologies of front cover for rocket launch canister have disadvantages such as causing damage on the ground equipment, not being reused and easily broken. A novel reusable non-separation spring-driven opening scheme is proposed to achieve rapid and reliable opening of the front cover. The mathematical model of the opening process of the front cover is established by the rigid body dynamics theory. To establish a response surface model to optimize the opening scheme, three main influencing factors of the opening process are obtained through the designed experiments, including the pre-compression, the stiffness of the thrust spring, and the thrust spring force arm length. In addition, the prescribed kinematic law was taken as constraint, and the smaller thrust spring preliminary pressure and angular velocity was taken as optimization expectations. The results show that the opening scheme meets the design requirements on opening process well. It also shows that the optimized scheme can reduce the kinetic energy of the front cover, and the impact on the canister effectively, achieving a reliable and rapid opening of the front cover. Keywords: Canister covers, Spring-driven, Non-separation, Optimized opening scheme, Rocket launch canisters, Launch safety

In an effort to develop novel Bax activators for breast cancer treatment, a series of diverse analogues have been designed and synthesized based on lead compound SMBA1 through several strategies, including introducing various alkylamino side chains to have a deeper access to S184 pocket, replacing carbon atoms with nitrogen, and reducing the nitro group of 9H-fluorene scaffold. Compounds 14 (CYD-2-11) and 49 (CYD-4-61) have been identified to exhibit significantly improved antiproliferative activity compared to SMBA1, with IC50 values of 3.22 μM and 0.07 μM against triple-negative breast cancer MDA-MB-231 and 3.81 μM and 0.06 μM against ER-positive breast cancer MCF-7 cell lines, respectively. Mechanism of action studies of compound 49 indicated that it can activate Bax protein to induce cytochrome c release and regulate apoptotic biomarkers, leading to cancer cell apoptosis. Further in vivo efficacy studies of compounds 14 and 49 in nude mice bearing MDA-MB-231 tumor xenografts demonstrated that these drug candidates can significantly suppress tumor growth, indicating their therapeutic potential for the treatment of breast cancer.

Co-existing of arsenate (As(V)) and arsenite (As(III)) in aquatic environment have posed a great threat to humans due to the high mobility and toxicity. Developing practical methods for the removal of arsenic contamination in water source is vital for improving human wellbeing. Here, a novel nanostructured Fe-Ti-Mn composite oxide (FTMO) for the efficient removal of arsenic was synthesized using a simultaneous oxidation and co-precipitation method. The adsorbent was amorphous or poorly crystallized and was aggregated from heterogeneous nano-sized particles, with a high specific surface area of 434.3 m2/g. Batch experimental results showed that the FTMO effectively removed both As(V) and As(III), and the maximal adsorption capacities of arsenic species at 25 °C were 74.4 mg/g (As(V)) and 122.3 mg/g (As(III)), respectively. The arsenic removal process was endothermic and spontaneous, and the uptake of arsenic was highly pH-dependent. The inhibitive influence of competitive substances on the adsorption behavior followed by the order of: SO42−

Objective: Extracellular vesicles (EVs) are currently a popular treatment for myocardial injury. This work was purposed to uncover the effects of mesenchymal stem cells (MSCs)-secreted EVs miR-200b-3p on oxidative stress and cardiac function after myocardial infarction (MI) through targeting Bcl-2-like protein 11 (BCL2L11). Methods: MI mice models were established. MSCs were isolated and transfected with miR-200b-3p mimic, and MSCs-EVs were isolated. miR-200b-3p-modified MSCs-EVs, along with down-regulated or up-regulated BCL2L11 were injected into MI mice. Afterwards, pathological features, collagen volume fraction, cardiomyocyte apoptosis, cardiac function and oxidative stress were assessed in MI mice. miR-200b-3p, BCL2L11, and NACHT, LRR, and PYD domains-containing protein 1 (NLRP1) expression were measured. Results: miR-200b-3p expression was decreased in MI. BCL2L11 was targeted by miR-200b-3p and bound to NLRP1. MSCs-EVs effectively improved cardiac function and suppress oxidative stress in MI mice, and miR-200b-3p-modified MSCs-EVs attenuated MI-induced injury in mice. Down-regulating BCL2L11 enhanced MSCs-EVs-mediated attenuation of MI in mice, while up-regulating BCL2L11 caused the opposite consequence. Up-regulation of BCL2L11 negated the role of miR-200b-3p-modified MSCs-EVs in MI mice. Conclusion: A summary was obtained that miR-200b-3p-encapsulated MSCs-EVs protected against MI-induced cardiac dysfunction and oxidative stress via suppressing BCL2L11. Funding: Presidential Foundation of Nanfang hospital, China (Grant No. 2019B005). Declaration of Interest: The authors declare that they have no conflicts of interest. Ethical Approval: All animals were treated following the "Guidelines for the Care and Use of Laboratory Animals", and all experiments were conducted with the guidelines of the Ethics Committee of Nanfang Hospital, Southern Medical University.

The emergence of novel plasmid-mediated high-level tigecycline resistance genes tet(X) in the Enterobacteriaceae has increased public health risk for treating severe bacterial infections. Despite growing reports of tet(X)-positive isolates detected in animal sources, the epidemiological association of animal- and environment-derived isolates with human-derived isolates remains unclear. Here, we performed a comprehensive analysis of tet(X4)-positive Escherichia coli isolates collected in a hospital in Guangdong province, China. A total of 48 tet(X4)-positive E. coli isolates were obtained from 1001 fecal samples. The tet(X4)-positive E. coli isolates were genetically diverse but certain strains that belonged to ST48, ST10, and ST877 etc. also have clonally transmitted. Most of the tet(X4) genes from these patient isolates were located on conjugative plasmids that were successfully transferred (64.6%) and generally coexisted with other antibiotic resistance genes including aadA, floR, blaTEM and qnrS. More importantly, we found the IncX1 type plasmid was a common vector for tet(X4) and was prevalent in these patient-derived strains (31.3%). This plasmid type has been detected in animal-derived strains from different species in different regions demonstrating its strong transmission ability and wide host range. Furthermore, phylogenetic analysis revealed that certain strains of patient and animal origin were closely related indicating that the tet(X4)-positive E. coli isolates were likely to have cross-sectorial clonal transmission between humans, animals, and farm environments. Our research greatly expands the limited epidemiological knowledge of tet(X4)-positive strains in clinical settings and provides definitive evidence for the epidemiological link between human-derived tet(X4)-positive isolates and animal-derived isolates.

Introduction A general view in previous research is that employees are reluctant to follow safe work procedures when confronting the shortage of self-control resources. However, this argument is constrained by the restricted view of ego depletion. To fill this gap, this study constructs the nonlinear relationship between ego depletion and safety compliance drawing from the perspective of dual-process theory. Method Regression analysis and hierarchical linear model are used to test our hypothesis. Results By investigating 241 medical staffs, we find that the relationship between ego depletion and safety compliance is U-shaped. This U-shaped relationship is replicated through 221 daily data for 50 medical staffs. In addition, the U-shaped relationship between ego depletion and safety compliance can be enhanced by rumination. Discussions Findings of our study contribute to providing a nuanced explanation about the effect of ego depletion on safety compliance. Also, this study has important implications for High Reliability Organizations to motivate depleted employees to engage in safety compliance behaviors.

(0.75-x)BiFeO3-0.25PbTiO3-xBa(Zr0.25Ti0.75)O3 (BF-PT-BZT) ternary solid solutions were prepared by the solid state reaction method. It was found from X-ray diffraction analysis that the morphotropic phase boundary (MPB) between tetragonal(T) and rhombohedral(R) phases occurred at the composition range of x from 0.13 to 0.28. For BF-PT-base ceramics, the addition of BZT can effectively decreased the tetragonality (c/a) and improved the ferroelectric as well as piezoelectric properties. The maximum value of piezoelectric constant d33 and electromechanical coupling factor kp were 182 pC/N and 0.34, respectively. Also, the ferroelectric transition temperature (Tc) of BF-PT-BZT ceramics varied in the range of 550–298 °C. It is believed that the BF-PT-BZT ternary solid solutions could be a good candidate for high-temperature applications.

A cloud-based analysis system of cardiac images is constructed to realize the remote sharing of cardiac images and related computing services. In its core service, a novel image post-processing approach is presented to obtain information on individual in vivo myocardial fibers. This approach is based on the anisotropic decomposition of the local deformation using tagged magnetic resonance (tMR) images of the heart. The local sine wave model (SinMod) is used in our approach to trace the motion in image sequences. Within this motion framework, a pair of anisotropic deformation components for each pixel is then extracted by Poisson orthogonal composition, which can represent exactly the local Poisson Effect. Based on these pair components, the direction structure (by the major deformation vector field) and the elastic property (by Poisson ratio) of myocardial fiber can be estimated. The experimental results demonstrate that our proposed approach is useful in analyzing information of in vivo myocardial fibers. It will have potential to provide the valuable cloud computing service for remote cardiac diagnosis and treatment.

Aging is a key problem in our daily life which demands more technology such as the terrain classification recognition for the detailed path planning. In this article, a six-axis accelerometer was placed on the base of a walking stick to capture walking gait vibration information. The signal features in the collected information were used to reflect the terrain. We used a matching tracking method to decompose the signal data into linear combinations of Gabor atoms and a joint time-frequency analysis method to perform analysis on the topographic features in a three-dimensional space. Three types of terrains were classified from space-time data. Results show that the proposed algorithm could achieve an average accuracy rate of 88.6%, which is 4% higher than conventional methods.