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Aim This study investigates the effects of ginsenoside Rb1 (GsRb1) on methamphetamine (METH)-induced toxicity in SH-SY5Y neuroblastoma cells and METH-induced conditioned place preference (CPP) in adult Sprague-Dawley rats. It also examines whether GsRb1 can regulate these effects through the NR2B/ERK/CREB/BDNF signaling pathways. Methods SH-SY5Y cells were pretreated with GsRb1 (20 μM and 40 μM) for 1 h, followed by METH treatment (2 mM) for 24 h. Rats were treated with METH (2 mg/kg) or saline on alternating days for 10 days to allow CPP to be examined. GsRb1 (5, 10, and 20 mg/kg) was injected intraperitoneally 1 h before METH or saline. Western blot was used to examine the protein expression of NR2B, ERK, P-ERK, CREB, P-CREB, and BDNF in the SH-SY5Y cells and the rats' hippocampus, nucleus accumbens (NAc), and prefrontal cortex (PFC). Results METH dose-dependently reduced the viability of SH-SY5Y cells. Pretreatment of cells with 40 μM of GsRb1 increased cell viability and reduced the expression of METH-induced NR2B, p-ERK, p-CREB and BDNF. GsRb1 also attenuated the expression of METH CPP in a dose-dependent manner in rats. Further, GsRb1 dose-dependently reduced the expression of METH-induced NR2B, p-ERK, p-CREB, and BDNF in the PFC, hippocampus, and NAc of rats. Conclusion GsRb1 regulated METH-induced neurotoxicity in vitro and METH-induced CPP through the NR2B/ERK/CREB/BDNF regulatory pathway. GsRb1 could be a therapeutic target for treating METH-induced neurotoxicity or METH addiction.

The effects of tool-workpiece relative positions on the microstructures and mechanical properties of 1-mm-thick 6061-T6 aluminum to T2 copper friction stir welds are systematically investigated in this research. Compared with the case of placing Cu sheet on advancing side, placing the Al sheet on advancing side can promote the flow of nugget material and expand the volume of the mixing zone, which is more conducive to obtain high-quality dissimilar Al-Cu welds. Based on this, the 1-mm tool offset toward Cu side is found to yield higher hardness and more defects due to the formation of Cu9Al4, leading to poor tensile properties and a brittle fracture feature of the joint. When the tool axis moves 1 mm toward the Al side, the decrease in Cu content in the stir zone not only limits the adhesion of material to the shoulder surface but also prevents the phase transformation from CuAl2 to Cu9Al4 and induces thin lamellar structures in the weld, which improves the fracture patterns and leads to good tensile properties of joint. The present study is expected to clarify the process characteristics of the dissimilar FSW of Al and Cu thin sheets and thus to promote the high-quality application of Al and Cu materials in electrical and electronic technology.

To investigate the fractioning of chlorpyrifos, omethoate, cypermethrin, and deltamethrin during wheat milling and the fate of four pesticides during Chinese steamed bread (CSB) processing, wheat samples, which were sprayed twice with chlorpyrifos, omethoate, cypermethrin, and deltamethrin at three levels of concentrations during the grain‐filling stage, were milled, and wheat flour was processed to CSB. The residues of four pesticides in the milling products, kneaded dough, fermented dough, and CSB were determined with GC‐MS/MS. The concentrations of chlorpyrifos, omethoate, cypermethrin, and deltamethrin in bran were 1.46–1.57, 1.85–2.13, 1.27–1.86, and 1.63–2.33 times higher than those in wheat, respectively, while the residues of the four pesticides in shorts decreased approximately 27.97% to 57.02% for chlorpyrifos, 6.22% to 44.77% for cypermethrin, and 13.13% to 61.15% for deltamethrin compared with the residues in wheat (p, Milling process decreased chlorpyrifos, omethoate, cypermethrin, and deltamethrin levels in flour. Cypermethrin and deltamethrin levels showed various degrees of increases during Chinese steamed bread processing. Changes of chlorpyrifos, omethoate, cypermethrin, and deltamethrin during Chinese steamed bread making process were firstly detailed reported.

Shini Feng,1 Yajing Ren,1 Hui Li,1 Yunfei Tang,1 Jinyu Yan,1 Zeyuan Shen,1 Huijie Zhang,2 Fuxue Chen1 1School of Life Sciences, Shanghai University, Shanghai, 200444, People’s Republic of China; 2School of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214122, People’s Republic of ChinaCorrespondence: Fuxue ChenSchool of Life Sciences, Shanghai University, Shanghai, 200444, People’s Republic of ChinaTel/Fax +86-21-6613-5167Email chenfuxue@staff.shu.edu.cnPurpose: Nanomaterial-based drug-delivery systems allowing for effective targeted delivery of smallmolecule chemodrugs to tumors have revolutionized cancer therapy. Recently, as novel nanomaterials with outstanding physicochemical properties, boron nitride nanospheres (BNs) have emerged as a promising candidate for drug delivery. However, poor dispersity and lack of tumor targeting severely limit further applications. In this study, cancer cell–membrane biomimetic BNs were designed for targeted anticancer drug delivery.Methods: Cell membrane extracted from HeLa cells (HM) was used to encapsulate BNs by physical extrusion. Doxorubicin (Dox) was loaded onto HM-BNs as a model drug.Results: The cell-membrane coating endowed the BNs with excellent dispersibility and cytocompatibility. The drug-release profile showed that the Dox@HM-BNs responded to acid pH, resulting in rapid Dox release. Enhanced cellular uptake of Dox@HM-BNs by HeLa cells was revealed because of the homologous targeting of cancer-cell membranes. CCK8 and live/dead assays showed that Dox@HM-BNs had stronger cytotoxicity against HeLa cells, due to self-selective cellular uptake. Finally, antitumor investigation using the HeLa tumor model demonstrated that Dox@HM-BNs possessed much more efficient tumor inhibition than free Dox or Dox@BNs.Conclusion: These findings indicate that the newly developed HM-BNs are promising as an efficient tumor-selective drug-delivery vehicle for tumor therapy.Keywords: boron nitride nanospheres, cancer-cell membrane, targeted drug delivery, chemotherapy, biomimetic

Background and aims Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of excessive triglycerides (TGs) in hepatocytes. Obesity is a major risk factor for developing fatty liver, although the intracellular molecular basis remains largely unclear. N6 -methyladenosine (m6 A) RNA methylation is the most common internal modification in eukaryotic mRNA. Approach and results In the present study, by m6 A sequencing and RNA sequencing, we found that both m6 A enrichment and mRNA expression of lipogenic genes were significantly increased in leptin-receptor-deficient db/db mice. Importantly, our results showed that YT521-B homology domain-containing 2 (Ythdc2), an m6 A reader, was markedly down-regulated in livers of obese mice and NAFLD patients. Suppression of Ythdc2 in livers of lean mice led to TG accumulation, whereas ectopic overexpression of Ythdc2 in livers of obese mice improved liver steatosis and insulin resistance. Mechanistically, we found that Ythdc2 could bind to mRNA of lipogenic genes, including sterol regulatory element-binding protein 1c, fatty acid synthase, stearoyl-CoA desaturase 1, and acetyl-CoA carboxylase 1, to decrease their mRNA stability and inhibit gene expression. Conclusions Our findings describe an important role of the m6 A reader, Ythdc2, for regulation of hepatic lipogenesis and TG homeostasis, which might provide a potential target for treating obesity-related NAFLD.

Friction stir repair welding of the lap structure of 2-mm-thick 7B04-T74 aluminum alloy is investigated in this study. A groove on the bottom plate surface was used to simulate the defect formed by the lap structure failure, by which an attempt was made to investigate the friction stir lap repair welding technology. The results show that the lap structure turns to butt–lap coexistent structure for the repair welding, leading to the variations of material flow patterns and weld formation features. Compared with the initial lap joint, both effective sheet thickness and effective lap width are improved in the repaired joints, and the hook tips of repaired joints are better metallurgically bonded. The nugget zone of repaired joint possesses significantly higher hardness than the initial joint. In addition, the fracture strength of the repaired joints is largely improved for advancing side loading configuration.

MnO2 has the highest potential as a supercapacitor electrode; however, its disadvantage in electronic conductivity hinders its widespread use. This study reports the excellent electrochemical performance of MnMC/NF (MnO2 and ZIF-derived nanoporous carbon on nickel foam) composites. MnMC/NF composites are produced when leaf-like Co-ZIF is annealed on nickel foam, followed by potassium permanganate treatment. When the annealing temperature reaches 700 °C, the maximum specific capacitance of 531 F/g is achieved at 1 A/g (456 F/g at 20 A/g) with a rate capability of 85.5%. MnMC/NF700 has a long cyclic stability, and the capacitance retention was 82% after 5000 cycles. The energy density of an assembled device using MnMC/NF700 composite as positive electrodes can reach 38.8 Wh/kg. This is due to the combined effect of nickel substrate's 3D porous structure and the excellent electronic conductivity of ZIF-derived nanoporous carbon. The unique configuration of MnMC/NF composites may provide a referable design for energy storage systems, including materials that have the highest potential for use as supercapacitor electrodes.

Cancer exhibits diverse heterogeneity with a complicated molecular basis that usually harbors genetic and epigenetic abnormality, which poses a big challenge for single-target agents. In the current work, we proposed a hybrid strategy by incorporating pharmacophores that bind to the acetylated lysine binding pocket of BET proteins with a typical kinase hinge binder to generate novel polypharmacological inhibitors of BET and kinases. Through elaborating the core structure of 6-(pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-one, we demonstrated that this rational design can produce high potent inhibitors of CDK9 and BET proteins. In this series, compound 40 was identified as the potential lead compound with balanced activities of BRD4 (IC50 = 12.7 nM) and CDK9 (IC50 = 22.4 nM), as well as good antiproliferative activities on a small cancer cell panel. Together, the current study provided a new method for the discovery of bromodomain and kinase dual inhibitors rather than only being discovered by serendipity.

1060 Al and Al0.1CoCrFeNi are friction stir lap welded in this study in order to improve the microstructure and mechanical property of the high-entropy alloy by adding Al element into the alloy through friction stir processing. The results indicate that a crescent-shaped aluminum-addition zone featured by limited upward material flow is formed in the high-entropy alloy. The aluminum-addition friction stir processing leads to the formation of fine and homogeneously distributed microstructures and the occurrence of body-centered cubic phases in the high-entropy alloy. Owing to the synthetical strengthening effects caused by friction stir modification and Al content increase, the hardness of the Al0.1CoCrFeNi alloy is increased significantly from 100 Hv to an average value over 400 Hv and a maximum value of 600 Hv. The present study is able to provide an effective approach for the preparation and strengthening of high-entropy alloys.

The inflammatory proliferation of fibroblast-like synoviocytes (FLSs) and functional imbalances in T lymphocytes play critical roles in the pathogenesis of rheumatoid arthritis (RA). The clinical efficacy of Huayu Tongbi Fang (HYTB, a traditional herbal formula) in RA treatment has been validated. In this study, we aimed to explore the regulatory mechanisms of HYTB on the proliferation and differentiation of T lymphocytes, and the inhibitory effect of HYTB on inflammatory proliferation of FLSs. The RCS-364 (Rat FLSs) cells were cocultured with rat splenic lymphocytes that were induced by interleukin-1β in Transwell chambers. After freeze-dried HYTB powder treatment, the percentage of T-cell subset and apoptosis rates of FLSs were measured using flow cytometry. Furthermore, protein expression of key molecules of NF-κB and JAK/STAT signaling pathways was quantified using Western blot. The granulocyte-macrophage colony-stimulating factor (GM-CSF) was measured using enzyme-linked immunosorbent assay. The results showed that HYTB could inhibit the inflammatory proliferation of FLSs through inducing cell apoptosis. Additionally, HYTB treatment could intervene in the proliferation and differentiation of T lymphocytes and regulate protein expression of key molecules in NF-κB and JAK/STAT cell signaling pathways. Moreover, it could inhibit FLS activation by suppressing GM-CSF production by T cells and FLSs. Therefore, the HYTB formula should be used as a traditional medicine against RA in modern complementary and alternative therapies.

Heparosan is a natural precursor of heparin biosynthesis in mammals. It is stable in blood circulation but can be degraded in lysosomes, showing good biocompatibility and long circulation features. So heparosan can be designed as anticancer drug carriers to increase tumor selectivity and improve the therapeutic effect. A novel redox-sensitive heparosan-cystamine-vitamin E succinate (KSV) micelle system was constructed for intracellular delivery of doxorubicin (DOX). Simultaneously, the redox-insensitive heparosan-adipic acid dihydrazide-vitamin E succinate copolymer (KV) was synthesized as control. DOX-loaded micelles (DOX/KSV) with an average particle size of 90–120 nm had good serum stability and redox-triggered depolymerization. In vitro drug release test showed that DOX/KSV micelles presented obvious redox-triggered release behavior compared with DOX/KV. Cytotoxicity and cell uptake were investigated using MGC80-3 tumor cells and COS7 fibroblast-like cells. The cell survival rate of blank micelles was more than 90%, and the cytotoxicity of DOX/KSV in MGC80-3 cells was higher than in COS7 cells, indicating that the carrier has better biocompatibility and less toxicity side effect. The cytotoxicity of DOX/KSV against MGC80-3 cells was significantly greater than that of free DOX and DOX/KV. Furthermore, compared with DOX/KV in MGC80-3 cells, DOX/KSV micelles uptook more anticancer drugs and then released DOX faster into the cell nucleus. The micelles were endocytosed by multiple pathways, but clathrin-mediated endocytosis was the main pathway. Therefore, heparosan polysaccharide could be a potential option as anticancer carrier for enhancing efficacy and mitigating toxicity., Graphical abstract Redox-sensitive amphiphilic KSV copolymer was designed to deliver DOX. After passive targeted and uptaken by tumor cells, DOX was released rapidly into the nucleus in the intracellular reduced environment.Image, graphical abstract

Background Radix Astragali and Radix Angelicae Sinensis are two herbs that compose Danggui Buxue Tang (an herbal formula for treatment of anemia diseases). In this study, we explored the molecular mechanism and effective targets to immune destruction of bone marrow (BM) cells treated with Radix Astragali, Radix Angelicae Sinensis or a combination of two agents. The potential synergic advantages of two herbs should also be explored. Methods The constituents of Radix Astragali and Radix Angelicae Sinensis were analyzed by high performance liquid chromatography-electrospray ionization/mass spectrometer system BM cells were separated from limbs of BALB/c mice, and immune destruction was induced with IFN-γ. The percentages of hematopoietic stem cells (HSCs) and CD3+ T cells were detected by flow cytometry. The distribution of T-bet and changes in the combination of SAP and SLAM in BM cells were observed by immunofluorescence. Western blotting was used to assay the expression of key molecules of the eIF2 signaling pathway in BM cells. Results Seven constituents of Radix Astragali and six constituents of Radix Angelicae Sinensis were identified. The percentages of HSCs increased significantly after treatment with Radix Angelicae Sinensis, especially at high concentrations. The percentages of CD3+ T cells were significantly decreased after Radix Astragali and Radix Angelicae Sinensis treatment. However, the synergistic function of two-herb combinations was superior to that of the individual herbs alone. The distribution of T-bet in BM cells was decreased significantly after Radix Angelicae Sinensis treatment. The number of SLAM/SAP double-stained cells was increased significantly after Radix Astragali treatment at low concentrations. The phosphorylation levels of eIF2α were also reduced after Radix Astragali and Radix Angelicae Sinensis treatment. Conclusions Radix Astragali and Radix Angelicae Sinensis could intervene in the immunologic balance of T lymphocytes, inhibit the apoptosis of BM cells induced by immune attack, restore the balance of the T cell immune response network and recover the hematopoietic function of HSCs. The synergistic effects of Radix Astragali and Radix Angelicae Sinensis were superior to those of each herb alone.

Hole-transport material-free (HTM-free) perovskite solar cells (PSCs) have the advantages of low manufacturing cost and excellent stability, however, the power conversion efficiencies (PCEs) of these PSCs are relatively low due to the high recombination rate at charge transport interface contacts. Herein, a novel bilayer electron-transport scaffold of SiO2/NaYF4:Yb,Er@SiO2 modified TiO2 nanorods was designed to improve the performance of HTM-free PSCs. Facilitated by the 1D nanorods structure of underneath TiO2 scaffold, photogenerated charges can be quickly transported out of perovskite film with reduced recombination, and the NaYF4:Yb,Er@SiO2 insulating capping layer can further inhibit the charge recombination by removing charge shorting pathways caused by the tangle of TiO2 nanorods with carbon back contact. Moreover, NaYF4:Yb,Er can upconvert near-infrared light into visible region that can be directly used by perovskite materials to improve the current density of corresponding PSCs. Our PSCs have an average PCE of 14.01 ± 0.53%. We demonstrated that up-conversion of light at 980 nm was possible but up-conversion made no statistical improvement in performance.

BackgroundDiabetic kidney disease (DKD) is the leading cause of end-stage kidney disease worldwide. Epidemiological evidence of the association between urinary sodium excretion and the presence of DKD in patients with type 2 diabetes mellitus (T2DM) has not yet been well established.MethodsWe performed a cross-sectional study of 1545 patients with T2DM over aged 20 years old from January 2018 to December 2020. Urinary sodium excretion was measured by 24-hour urine samples in inpatients and morning fasting urine samples in outpatients. The associations between urinary sodium excretion and the risks of DKD were examined using stepwise regression analysis, logistic regression analysis and multivariable-adjusted restricted cubic splines (RCS).ResultsRegression analysis showed that urinary sodium was independently associated with urinary albumin to creatinine ratio (UACR) level (P = 0.006) and the risks of DKD (P = 0.042). In multivariable-adjusted RCS analysis, urinary sodium excretion was significantly associated with UACR in all patients (P = 0.008), and exhibited a J-shaped relationship. Logistic regression analysis showed that increased urinary sodium excretion was significantly associated with increased risks of DKD [OR (95% CI); 1.56 (1.07-2.27); P = 0.020]. However, the relationships between urinary sodium excretion and the risks of DKD and albuminuria showed no significance, after further adjustment for HOMA-IR and ba-PWV (brachial-ankle pulse wave velocity) (Both P > 0.05).ConclusionsHigher urinary sodium excretion level was associated with increased risks of DKD among patients with T2DM, dependent of vascular sclerosis and insulin resistance.

Arsenic is one of the most common environmental pollutants. Neurotoxicity induced by arsenic has become a major public health concern. However, the effects of arsenic-induced neurotoxicity in the brain and the underlying molecular mechanisms are not well understood. N-acetyl-cysteine (NAC) is a thiol-based antioxidant that can antagonize heavy metal-induced neurotoxicity by scavenging reactive oxygen species (ROS). Here, we used the mouse oligodendrocyte precursor cell (OPC) line Oli-neu to explore the neurotoxic effects of arsenic and the protective effects of NAC. We found that arsenic exposure decreased cell viability, increased oxidative stress, caused mitochondrial dysfunction, and led to apoptosis of Oli-neu cells. Furthermore, we revealed that NAC treatment reversed these neurotoxic effects of arsenic. TMEM179, a key membrane protein, was found highly expressed in OPCs and to be an important factor in maintaining mitochondrial functions. We found that TMEM179 played a critical role in mediating the neurotoxic effects of arsenic and the protective role of NAC. PKCβ is a downstream factor through which TMEM179 regulates the expression of apoptosis-related proteins. This study improves our understanding of the neurotoxic effects and mechanisms of arsenic exposure and the protective effects of NAC. It also identifies a potential molecular target, TMEM179, for the treatment of arsenic-induced neurotoxicity.

Proteins achieve efficient energy storage and conversion through electron transfer along a series of redox cofactors. Multiheme cytochromes are notable examples. These proteins transfer electrons over distance scales of several nanometers to >10 μm and in so doing they couple cellular metabolism with extracellular redox partners including electrodes. Here we report pump-probe spectroscopy that provides a direct measure of the intrinsic rates of heme-heme electron transfer in this fascinating class of proteins. Our study took advantage of a spectrally unique His/Met ligated heme introduced at a defined site within the decaheme extracellular MtrC protein of Shewanella oneidensis. We observed rates of heme-to-heme electron transfer on the order of 109 s-1 (3.7-4.3 A edge-to-edge distance), in good agreement with predictions based on density functional and molecular dynamics calculations. These rates are amongst the highest reported for ground state electron transfer in biology. Yet, some fall 2-3 orders of magnitude below the Moser-Dutton ruler because electron transfer at these short distances is through-space and therefore associated with a higher tunneling barrier than the through-protein tunneling scenario that is usual at longer distances. Moreover, we show that the His/Met ligated heme creates an electron sink that stabilizes the charge separated state on the 100 microsecond time scale. This feature could be exploited in future designs of multiheme cytochromes as components of versatile photosynthetic biohybrid assemblies.

GATA6 antisense RNA 1 (GATA6-AS1) has been reported to be involved in the progression of several types of cancer. In the present study, the role of GATA6-AS1 in ovarian cancer (OC) was explored. Reverse transcription quantitative PCR was used to detect the expression of GATA6-AS1, microRNA (miR)-19a-5p and tet methylcytosine dioxygenase 2 (TET2) in OC and adjacent normal tissues. Furthermore, OC cells with GATA-AS1 either knocked down or overexpressed were established. The Cell Counting Kit-8 assay was used to evaluate cell proliferation and a Transwell assay was used to assess the migratory and invasive abilities of OC cells. A dual luciferase reporter gene assay was used to determine whether GATA6-AS1 and miR-19a-5p, and miR-19a-5p and TET2, may interact with each other. The results demonstrated that GATA6-AS1 expression level was decreased in OC tissues and cells compared with control groups. In addition, GATA6-AS1 overexpression significantly inhibited the proliferation and migratory and invasive abilities of OC cells, whereas GATA6-AS1 downregulation had the opposite effects. Furthermore, GATA6-AS1 adsorbed miR-19a-5p to repress its expression and GTA6-AS1 indirectly upregulated TET2 expression. Taken together, the findings from this study suggested that GATA6-AS1 could inhibit the proliferation and migratory and invasive abilities of OC cells via regulation of the miR-19a-5p/TET2 axis.

Polydatin, an active ingredient from the roots of Polygonum cuspidatum, is considered to have protective effects on the cardiovascular system and liver. In this study, we demonstrated that polydatin has antitumor activity against human cervical cancer. Polydatin efficiently inhibited cervical cancer cell proliferation by regulating cell cycle-related proteins including p21, p27, CDK2, CDK4, Cyclin D1, and Cyclin E1. Furthermore, polydatin suppressed cell invasion and migration by regulating epithelial–mesenchymal transition (EMT) markers, including E-cadherin, N-cadherin, Snail and Slug. The c-Myc, as a proto-oncogene, is considered to be closely associated with the proliferation and metastasis of tumor cells. After polydatin treatment, the protein expression of c-Myc showed a significant decrease. Based on these data, we overexpressed c-Myc in cervical cancer cells and observed that the overexpression of c-Myc rescued the inhibitory effect of polydatin on cell proliferation and metastasis. These results indicated that polydatin can inhibit cell proliferation and metastasis through suppressing the c-Myc expression in human cervical cancer.

Polybrominated diphenyl ethers (PBDEs) are present in biosolids and other solid wastes, as well as being detected in landfill leachates. As sand-bentonite mixtures are extensively used as basal liner materials for landfills, a sand-bentonite mixture was investigated by swelling tests and leaching column tests to determine whether it can effectively contain and/or immobilize PBDEs in landfill leachate. Leaching column tests were conducted with permeants consisting of biosolids’ leachates diluted to 50% by volume and spiked with 50 μg/mL of a pentaBDE mixture solution. The results showed that the sand-bentonite retained up to 45–66% of the total PBDEs in the permeant; however, the concentration of PBDEs in the effluent increased continuously and reached a significant level during a 3-week period. PBDEs probably sorbed onto both fine and ultra-fine organic particles. During leaching, a compacted sand-bentonite admix could stop fine particles from passing, but at the same time, ultra-fine organic particles carried PBDEs through the barrier materials. The hydraulic conductivity, k, of the sand-bentonite was negatively affected by shrinkage of the clay interlayer caused by the permeant hydrophobicity. However, the hydraulic conductivity changed only to a limited extent, remaining at a magnitude of 10−9 cm/s, probably because the PBDE concentrations were low. Therefore, caution is needed when sand-bentonite is applied to landfill liners as a barrier for PBDEs.

Background: Drug delivery systems (DDS) capable of targeting both cell and organelle levels are highly desirable for effective cancer therapy. In this study, we developed a novel enzyme-responsive, multistage-targeted anticancer DDS based on mesoporous silica nanoparticles (MSNs), which possessed both CD44-targeting and mitochondrial-targeting properties. Materials and methods: Triphenylphosphine (TPP), a mitochondria-targeting compound, was grafted onto the surface of MSNs firstly. Then, Doxorubicin (Dox) was encapsulated into the pore of MSNs, followed by capping with tumor-targeting molecules hyaluronic acid (HA) through electrostatic interactions to form the final product consist of Dox loaded, TPP attached, HA capped mesoporous silica nanoparticles (MSN-DPH). Results: Our results suggested that MSN-DPH was preferentially taken up by cancer cells via CD44 receptor-mediated endocytosis. Moreover, MSN-DPH mainly accumulated in mitochondria owing to the mitochondrial-targeting ability of TPP. Degradation of HA by overexpressed HAase facilitated the release of Dox in cancer cells. Thus, MSN-DPH efficiently killed the cancer cells while exhibited much lower cytotoxicity to normal cells. Conclusion: This study demonstrates a promising multistage-targeted DDS for cancer chemotherapy.

The zigzag line has significant and complicated effects on the mechanical properties of friction-stir-welded aluminum alloys. The zigzag line feature and its affecting characteristic on joint property are largely related to welding speed. In this paper, an Al-Zn-Mg aluminum alloy was butt friction-stir-welded, and the effects of welding speed on zigzag line feature and joint property were studied in detail in order to reveal the intrinsic correlations between the critical process parameter and the weld quality and, consequently, to provide guidance for the process optimization. The results indicate that at high welding speed of 300 mm/min, the loose and dilute distribution of the oxide layer fragments induces the relatively ambiguous zigzag line feature; the joint does not fail through the zigzag line during tensile test and shows superior tensile properties. With decreasing welding speed to 175 and 50 mm/min, the zigzag line feature is not weakened by the severer tool stirring action, as widely reported by previous studies, but is strengthened gradually due to the enhancement of the collective flow and more concentrated redistribution of broken oxide particles, leading to joint failure at zigzag lines and the degradation of tensile properties of joints.

An inorganic caesium cation was incorporated into perovskite to improve the performance and stability of solar cells with a hole-transport-material free structure in ambient air. A triple cation device with a champion power conversion efficiency of over 15% was achieved, exhibiting superior thermal, long-term and operational stabilities.

Redox-active films are advantageous matrices for the immobilization of photosynthetic proteins, due to their ability to mediate electron transfer as well as to achieve high catalyst loading on an electrode for efficient generation of electricity or solar fuels., Redox-active films are advantageous matrices for the immobilization of photosynthetic proteins, due to their ability to mediate electron transfer as well as to achieve high catalyst loading on an electrode for efficient generation of electricity or solar fuels. A general challenge arises from various charge recombination pathways along the light-induced electron transfer chain from the electrode to the charge carriers for electricity production or to the final electron acceptors for solar fuel formation. Experimental methods based on current measurement or product quantification are often unable to discern between the contributions from the photocatalytic process and the detrimental effect of the short-circuiting reactions. Here we report on a general electrochemical model of the reaction–diffusion processes to identify and quantify the “bottlenecks” present in the fuel or current generation. The model is able to predict photocurrent–time curves including deconvolution of the recombination contributions, and to visualize the corresponding time dependent concentration profiles of the product. Dimensionless groups are developed for straightforward identification of the limiting processes. The importance of the model for quantitative understanding of biophotoelectrochemical processes is highlighted with an example of simulation results predicting the effect of the diffusion coefficient of the charge carrier on photocurrent generation for different charge recombination kinetics.

The difficulty of dispersing nanofillers and the insufficient of flexibility remains major obstacle to the expansion of nanocomposite applications. In this study, silk fibroin (SF) based nanocomposite materials were obtained using glycerol plasticized SF as the matrix and short polymer nanofibers as the reinforcing phase. Highly flexible SF films with silk I structure were fabricated by using glycerol as a plasticizer. More importantly, plasticizer glycerol significantly improved the homogeneous dispersion of short PVA-co-PE nanofibers in SF films through interfacial interactions, forming flexible and robust nanofiber-reinforced composite films. FTIR and XRD results showed that no significant change was found on secondary structure and crystal structure of SF protein after adding PVA-co-PE nanofibers. It was found that nanofiber content showed significant influence on the mechanical behavior of nanocomposite films, where the addition of 5–10% short PVA-co-PE nanofibers is preferred for achieving enhanced flexibility and strength. This study provides new options for the fabrication of robust and flexible SF nanocomposites for functional applications.

Leveraging physical factors in cellular microenvironments to promote adipose tissue-derived stem cell (ADSC) osteogenic differentiation has emerged as a new strategy in the development of scaffolds for bone tissue engineering. Anisotropicity is one of those factors of interest; however, the utilization of anisotropicity to promote ADSC osteogenic differentiation is still not efficient. In this study, we designed a substrate with a dual anisotropic structure fabricated via a combination of 3D printing and magnetic field-induced magnetic nanoparticle assembly techniques. These dual anisotropic structures have a scale hierarchy, and the scale of the magnetic nanoparticle assemblies matches that of a single ADSC. This is in contrast to conventional anisotropic osteogenic induction scaffolds that have anisotropic structures at only one scale and at an order of magnitude different from single ADSCs. ADSCs cultured on substrates with such structures have significantly higher osteogenic marker expression, e.g., ALP, at both the protein and mRNA levels, and more calcium nodule formation was also found, suggesting a stronger tendency toward osteogenic differentiation of ADSCs. RNA-seq data revealed that alterations in kinase signaling pathway transduction, cell adhesion, and cytoskeletal reconstruction may account for the elevated osteogenic induction capacity. These data support our hypothesis that such a structure could maximize the anisotropicity that ADSCs can sense and therefore promote ADSC osteogenic differentiation. In this work, a substrate with dual anisotropy were prepared by combination of 3D printing and magnetic field-induced magnetic nanoparticle assembly. ADSCs cultured on this substrates have significantly higher osteogenic markers expression and more calcium nodules formation was also found, suggesting a stronger tendency of toward osteogenic differentiation of ADSCs. RNA-seq data revealed alteration of that alterations in kinase signaling pathway transduction, cell adhesion and cytoskeletalon reconstruction may account for the elevated osteogenic induction capacity.

Arsenic stress causes rapid transcriptional responses in plants. However, transcriptional regulators of arsenic-induced gene expression in plants remain less well known. To date, forward genetic screens have proven limited for dissecting arsenic response mechanisms. We hypothesized that this may be due to the extensive genetic redundancy present in plant genomes. To overcome this limitation, we pursued a forward genetics screen for arsenite tolerance using a randomized library of plants expressing >2,000 artificial microRNAs (amiRNAs). This library was designed to knock-down diverse combinations of homologous gene family members within sub-clades of transcription factor and transporter gene families. We identified six transformant lines showing an altered response to arsenite in root growth assays. Further characterization of an amiRNA line targeting closely homologous CBF and ERF transcription factors show that the CBF1,2 and 3 transcription factors negatively regulate arsenite sensitivity. Furthermore, the ERF34 and ERF35 transcription factors are required for cadmium resistance. Generation of CRISPR lines, higher-order T-DNA mutants, and gene expression analyses, further support our findings. These ERF transcription factors differentially regulate arsenite sensitivity and cadmium tolerance.

CpG oligodeoxynucleotides (ODNs) have attracted increasing attention as immunotherapeutic agents. However, efficient transfection of CpG ODNs into the immune cells remains a big challenge. In this study, for the first time, we reported that silk fibroin (SF) could function as an efficient carrier for CpG ODNs. A novel strategy was developed to prepare SF-CpG ODNs nanoparticles (NPs) based on self-assembly of SF. The as-prepared SF-CpG NPs were spherical in shape and were uniformly dispersed. SF-CpG NPs exhibited good stability and biocompatibility. SF-CpG NPs possessed significantly enhanced (7 folds) cellular uptake compared with CpG ODNs. Release of CpG ODNs from SF-CpG NPs was accelerated in environment-mimicking TLR9-localized endo/lysosome. SF-CpG NPs stimulated about four folds higher levels of immune cytokines and nitric oxide compared with CpG ODNs. Our results suggested that SF notably improved the CpG ODNs delivery. SF-CpG NPs have strong potential in immunotherapy.

Arsenic stress causes rapid transcriptional responses in plants. However, transcriptional regulators of arsenic-induced gene expression in plants remain less well known. To date, forward genetic screens have proven limited for dissecting arsenic response mechanisms. We hypothesized that this may be due to the extensive genetic redundancy present in plant genomes. To overcome this limitation, we pursued a forward genetics screen for arsenite tolerance using a randomized library of plants expressing >2,000 artificial microRNAs (amiRNAs). This library was designed to knock-down diverse combinations of homologous gene family members within sub-clades of transcription factor and transporter gene families. We identified six transformant lines showing an altered response to arsenite in root growth assays. Further characterization of an amiRNA line targeting closely homologous CBF and ERF transcription factors show that the CBF1,2 and 3 transcription factors negatively regulate arsenite sensitivity. Furthermore, the ERF34 and ERF35 transcription factors are required for cadmium resistance. Generation of CRISPR lines, higher-order T-DNA mutants, and gene expression analyses, further support our findings. These ERF transcription factors differentially regulate arsenite sensitivity and cadmium tolerance.

Multidrug resistance (MDR) is the main challenge faced by cancer chemotherapy. Drug-conjugate offers a promising strategy for breast cancer therapy. In this regard, we developed a DNVM multifunctional drug delivery system by crosslinking doxorubicin (DOX) and vitamin E succinate (VES) with a pH-sensitive hydrazone bond and then encapsulated the DOX-NN-VES prodrug into pH-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine (HOD) micelles. DOX resistant MCF-7/ADR cell were adopted as a model to study the capability and mechanism of MDR reversal. DNVM exhibited much higher cytotoxicity and cell uptake efficiency compared with that of acid-insensitive DOX-VES loaded HOD micelles (DVSM) and DOX loaded HOD micelles (DOXM), indicating the better capacity of DNVM for the reversal of MDR. Moreover, DNVM prevented drug efflux more effectively, inhibited the expression of P-gp, induced excessive production of reactive oxygen species and affected the expression of apoptosis-related proteins. In vivo experiments showed that DNVM significantly inhibited the tumor growth with no obvious changes in the body weight of MCF-7/ADR cells-bearing nude mice. The results suggested that the “double gain” DNVM can synergistically enhance the efficacy of chemotherapeutics for DOX resistant tumor cells and has the potential to overcome tumor MDR.

Uncontrollable bleeding poses considerable fatality risks by large-volume blood losses. Current emergency antibleeding handlings including either compression with gauze or "passive" blood transfusion are thus far from ideal, while most recently developed hemostatic agents still share common limitations without considering the subsequent tissue repairing and antibacterial activity after treatment. Herein, we introduce a novel bioinspired aggregated collagen nanofiber-based biocompatible and efficient hemostatic hydrogel material (TS-Gel-Ag-col) prepared by the integration of multifunctional compounds of muco-mimetic poloxamer, polyvinylpyrrolidone, and dencichine/chitosan dialdehyde synergistic crosslinked aggregated collagen nanofibers decorated with silver nanoparticles. Comprehensive material characterization and in vitro and in vivo studies of TS-Gel-Ag-col demonstrate that these materials possess effective antihemorrhagic and antibacterial wound protection effects. Moreover, TS-Gel-Ag-col can facilitate the tissue repairing of skin wounds by promoting revascularization. TS-Gel-Ag-col holds great promise for next-generation collagen-based absorbable hemostatic materials and for the development of smart artificial skins.

Nuclear receptors (NRs) are a superfamily of transcription factors which sense hormonal signals or nutrients to regulate various biological events, including development, reproduction, and metabolism. Here, this study identifies nuclear receptor subfamily 2, group F, member 6 (NR2F6), as an important regulator of hepatic triglyceride (TG) homeostasis and causal factor in the development of non‐alcoholic fatty liver disease (NAFLD). Adeno‐associated virus (AAV)‐mediated overexpression of NR2F6 in the liver promotes TG accumulation in lean mice, while hepatic‐specific suppression of NR2F6 improves obesity‐associated hepatosteatosis, insulin resistance, and methionine and choline‐deficient (MCD) diet‐induced non‐alcoholic steatohepatitis (NASH). Mechanistically, the fatty acid translocase CD36 is identified as a transcriptional target of NR2F6 to mediate its steatotic role. NR2F6 is able to bind directly onto the CD36 promoter region in hepatocytes and increases the enrichment of nuclear receptor coactivator 1 (SRC‐1) and histone acetylation at its promoter. Of pathophysiological significance, NR2F6 is significantly upregulated in the livers of obese mice and NAFLD patients. Moreover, treatment with metformin decreases NR2F6 expression in obese mice, resulting in suppression of CD36 and reduced hepatic TG contents. Therefore, these results provide evidence for an unpredicted role of NR2F6 that contributes to liver steatosis and suggest that NR2F6 antagonists may present a therapeutic strategy for reversing or treating NAFLD/NASH pathogenesis., NR2F6 (nuclear receptor subfamily 2, group F, member 6) is increased in the livers of obese mice and patients with non‐alcoholic fatty liver disease. It transcriptionally upregulates the fatty acid transporter CD36 to enhance fatty acid uptake in hepatocytes, thereby promoting liver steatosis. These findings identify an important role for NR2F6 in the regulation of hepatic lipid homeostasis.

Lithium-sulfur batteries (LSBs) have been considered as the future potential energy storage system with advantages of high energy density (2600 Wh kg-1), eco-friendliness and low cost. However, the poor conductivity and serious shuttle effects of polysulfides block their application. Herein, g-C3N4/carbon heterostructure on graphene nanosheet (PCNG) is constructed via phenyl-modified strategy and in-situ thermal polycondensation, which has a unique electron cloud distribution with excellent sulfur immobilization ability as well as good electroconductivity. As a result, Li-S cells with simple S/C cathodes and PCNG interlayers show a high initial capacity of 1192 mAh g-1 at 0.1 C, and an ultra-long lifespan with a slow capacity attenuation of 0.050% per cycle after 800 cycles. The cell with PCNG/PP separator also has a stable cycle performance at high area sulfur loading of 7 mg cm-2. These findings provide a new sight on functionalizing g-C3N4 for application in Li-S electrochemistry.

Caulis Lonicerae, the dried stem of Lonicera japonica, has been confirmed to have antiinflammatory and antioxidant therapeutic effects. In the present study, we aimed to evaluate the functional mechanism of glycosides extracted from Caulis Lonicerae on the inflammatory proliferation of interleukin-1 beta (IL-1β)-mediated fibroblast-like synoviocytes (FLSs) from rats. Rat FLSs (RSC-364) co-cultured with lymphocytes induced by IL-1β were used as a cell model. Glycosides in a freeze-dried powder of aqueous extract from Caulis Lonicerae were identified using high-performance liquid chromatography-electrospray ionization/mass spectrometry. After treatment with glycosides, the inflammatory proliferation of FLS, induced by IL-1β, decreased significantly. Flow cytometry analysis showed that treatment with glycosides restored the abnormal balance of T cells by intervening in the proliferation and differentiation of helper T (Th) cells. Glycosides also inhibited the activation of Janus kinase signal transducer and activator of transcription (JAK-STAT) and nuclear factor (NF)-κB signaling pathways by suppressing the protein expression of key molecules in these pathways. Therefore, we concluded that the glycosides of Caulis Lonicerae can intervene in the differentiation of Th cells, suppressing the activation of JAK-STAT and NF-κB signaling pathways, contributing to the inhibitory effect on inflammatory proliferation of FLS co-cultured with lymphocytes induced by pro-inflammatory cytokines.

Strawberries are highly popular around the world because of their juicy flesh and unique taste. However, they are delicate and extremely susceptible to peroxidation of their membrane lipids during storage, which induces water loss and rotting of the fruit. This study investigated the effects of ozone treatment on the physiological traits, active oxygen metabolism, and the antioxidant properties of postharvest strawberry. The results revealed that the weight loss (WL) and respiration rate (RR) of strawberry were inhibited by ozone treatment (OT), while the decline of firmness (FIR) and total soluble solids (TSS) were delayed. Ozone also reduced the generation rate of superoxide radical anions , and the content of hydrogen peroxide (H2O2) enhanced the activity of superoxidase (SOD), catalase (CAT), ascorbate peroxidase (APX), and monodehydroascorbate reductase (MDHAR), as well as promoted the accumulation of ascorbic acid (ASA), glutathione (GSH), and ferric reducing/antioxidant power (FRAP). In addition, a total of 29 antioxidant-related proteins were changed between the OT group and control (CK) group as detected by label-free proteomics during the storage time, and the abundance associated with ASA–GSH cycle was higher in the OT group at the later stage of storage, and the qRT-PCR results were consistent with those of proteomics. The improvement of the antioxidant capacity of postharvest strawberry treated with ozone may be achieved by enhancing the activity of the antioxidant enzymes and increasing the expression of the antioxidant proteins related to the ascorbic acid–glutathione (ASA–GSH) cycle.

Silk is extensively investigated in bone tissue engineering due to its extraordinary mechanical properties and ability to regulate biomineralization. Protein templates regulate biomineralization process through chemical interaction with ions. However, the effect of structural differences in silk fibroin on biomineralization has not been studied in detail. In this study, Antheraea pernyi silk fibroin (ASF) and Bombyx mori silk fibroin (BSF) fibers were used as templates to study the effect of silk species on biomineralization. The results showed that silk fibroin could induce the formation of calcium-deficient hydroxyapatite in simulated body fluid (SBF), and the SBF treatment resulted in the formation of silk I crystals. Compared with BSF, ASF exhibited a higher ability to induce mineralization, which may depend on the differences in hydrophilic amorphous fractions between ASF and BSF. The amorphous fractions of ASF contain more acidic amino acids, which can provide more nucleation sites in the initial stage of mineralization, resulting in faster mineralization process and more mineral deposits. This study decodes the key role of silk fibroin fractions on biomineralization, and provides deeper insights for the study of silk fibroin as biomineralization template and bone repair materials.

Heavy metals affect male reproductive function by impairing reproductive organs, disturbing reproductive hormone levels or directly affecting sperm quality. However, little attention has been given to the effect of environmental heavy metals on reproductive function in wild male birds. The present study investigated the alterations of reproductive function in male tree sparrows (Passer montanus) exposed to environments contaminated by heavy metals in terms of testis parameters, reproductive hormone levels and sperm movement characteristics. Two plots, Baiyin (BY, mainly polluted by copper, zinc, lead and cadmium) and Liujiaxia (LJX, a relatively unpolluted area) were selected as sampling sites. The results showed that tree sparrows from BY (1) accumulated higher levels of cadmium in the testes, (2) showed lower superoxide dismutase (SOD) activity and malondialdehyde level, with higher total antioxidant capacity and apoptosis level in the testes, (3) showed higher plasma levels of estrogen, follicle stimulating hormone and luteinizing hormone (LH), and (4) had better sperm movement performance. Additionally, we found that testis size, SOD activity in testes and LH levels were decisive factors in sperm movement performance in tree sparrows. Heavy metal concentrations in testes negatively correlated with testis size, SOD activity in testes, and estrogen levels in tree sparrows. The present study indicates that heavy metals accumulating in testes of tree sparrows adversely affected some key indicators of male reproductive function. However, testicular function, reproductive hormone levels and sperm quality showed adaptive responses that tended to partially compensate for the negative effects in the heavy metal polluted area. This study further indicated that the regulation of testicular function and reproductive hormone levels was the main factor for better sperm quality in tree sparrows exposed to environments contaminated by heavy metals.

Ozone treatment was found to delay the postharvest cantaloupe melon decay and improve its intrinsic quality during the cold storage. The transcriptomes of cantaloupe peel and pulp in response to ozone treatment were investigated to reveal the mechanisms using a high-throughput RNA sequencing approach. Results showed that 570 and 313 differentially expressed genes were identified in peel and pulp, respectively. According to these identified genes, the gene ontology and pathway enrichment analysis indicated that the ozone treatment could maintain the firmness of the cantaloupe by changing pectin metabolites and reduction of the ethylene production by regulating relevant genes especially in the peel. The total flavonoid content changes in peel and pulp related to the regulation of phenylalanine ammonia lyase, 4-coumarate-CoA ligase and P450 family genes which further leading to the inhibition of phenylalanine metabolic pathway in peel but promotion of secondary metabolism in pulp. The qRT-PCR results were in accordance with our RNA sequencing results which validated the conclusions. The present study for the first time reveals the mechanism of cantaloupe in response to ozone treatment at a transcriptome level which is of importance for cantaloupe storage.

Iron homeostasis is essential for maintaining cellular function in a wide range of cell types. However, whether iron affects the thermogenic properties of adipocytes is currently unknown. Using integrative analyses of multi‐omics data, transferrin receptor 1 (Tfr1) is identified as a candidate for regulating thermogenesis in beige adipocytes. Furthermore, it is shown that mice lacking Tfr1 specifically in adipocytes have impaired thermogenesis, increased insulin resistance, and low‐grade inflammation accompanied by iron deficiency and mitochondrial dysfunction. Mechanistically, the cold treatment in beige adipocytes selectively stabilizes hypoxia‐inducible factor 1‐alpha (HIF1α), upregulating the Tfr1 gene, and thermogenic adipocyte‐specific Hif1α deletion reduces thermogenic gene expression in beige fat without altering core body temperature. Notably, Tfr1 deficiency in interscapular brown adipose tissue (iBAT) leads to the transdifferentiation of brown preadipocytes into white adipocytes and muscle cells; in contrast, long‐term exposure to a low‐iron diet fails to phenocopy the transdifferentiation effect found in Tfr1‐deficient mice. Moreover, mice lacking transmembrane serine protease 6 (Tmprss6) develop iron deficiency in both inguinal white adipose tissue (iWAT) and iBAT, and have impaired cold‐induced beige adipocyte formation and brown fat thermogenesis. Taken together, these findings indicate that Tfr1 plays an essential role in thermogenic adipocytes via both iron‐dependent and iron‐independent mechanisms., A role of transferrin receptor 1 (Tfr1) in brown/beige adipocytes is reported. Ablation of Tfr1 in adipose tissue attenuates the thermogenic capacity and induces transdifferentiation of brown adipocytes via distinct mechanisms. The findings shed light on how Tfr1 and iron homeostasis affect thermogenesis, suggesting the Tfr1 and iron metabolic pathway as potential targets for preventing metabolic diseases.

We reported the conversion of deoxynivalenol-3-glucoside (D3G) to deoxynivalenol (DON) during Chinese steamed bread (CSB) processing by artificial D3G contamination. Meanwhile, the effects of enzymes in wheat flour and those produced from yeast, along with the two main components in wheat flour&mdash, wheat starch and wheat gluten&mdash, on the conversion profiles of D3G were evaluated. The results showed D3G could convert to DON during CSB processing, and the conversion began with dough making and decreased slightly after fermentation and steaming. However, there was no significant difference in three stages. When yeast was not added, or enzyme-deactivated wheat flour was used to simulate CSB process, and whether yeast was added or not, D3G conversion could be observed, and the conversion was significantly higher after dough making. Likewise, D3G converted to DON when wheat starch and wheat gluten were processed to CSB, and the conversion in wheat starch was higher.