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Piperine is reported to ameliorate common metabolic diseases, however, its molecular mechanism is still unclear. In the present study, we examined whether piperine could stimulate glucagon-like peptide-1 (GLP-1) secretion in a human enteroendocrine cell line, Caco-2, and explored the potential mechanisms from the activation of human bitter taste receptors (TAS2Rs). It was found that TAS2R14 was highly expressed in Caco-2 cells, far more than TAS2R4 and TAS2R10. Piperine and flufenamic acid (FA, a known TAS2R14 agonist) markedly increased intracellular calcium mobilization and significantly enhanced the GLP-1 secretion, accompanied by elevated levels of proglucagon mRNA in Caco-2 cells compared with the control. Moreover, piperine and FA activated TAS2R14 signaling as evidenced by the increased mRNA and protein levels of TAS2R14, and the protein expression of its downstream key molecules including phospholipase C β2 (PLCβ2) and a transient receptor potential channel melastatin 5 (TRPM5). On the other hand, a G protein βγ subunit inhibitor Gallein or a PLC inhibitor U73122 alleviated piperine-stimulated GLP-1 secretion in Caco-2 cells. In the meantime, a flavanone hesperetin significantly attenuated piperine and FA induced the intracellular calcium mobilization and GLP-1 secretion. Furthermore, TAS2R14 knockdown reversed the piperine-triggered up-regulation of PLCβ2 and TRPM5 as well as increased the GLP-1 secretion in Caco-2 cells by TAS2R14 shRNA transfection. In summary, our findings demonstrated that piperine promoted the GLP-1 secretion from enteroendocrine cells through the activation of TAS2R14 signaling. Moreover, TAS2R14 was likely a target of piperine in the alleviation of metabolic diseases.

The 230Th dating (238U–234U–230Th dating method) has become one of the most important dating methods for Quaternary research. However, the 230Th/232Th ratio of 4.4 ± 2.2ⅹ10−6 is widely used for age correction in 230Th dating method. Here, we collected active speleothems with exactly known age and zero-year-old calcium carbonate from caves and dated them by 230Th dating. Our data indicated that the initial 230Th/232Th ratio can be one order of magnitude higher than the ratio of 4.4 ± 2.2 × 10−6. High initial 230Th/232Th ratio may result in false and comparatively old calculated age than the real age of young samples with low 238U concentration. So, the accurate initial 230Th/232Th ratio of active speleothem deposited in the same cave, instead of the general initial 230Th/232Th ratio, is essential for the precise age correction of young speleothem samples of low 238U concentration. Finally, we proposed a procedure to correlate modern observation and speleothem based paleoclimate reconstruction, on the basis of precise 230Th age which corrected by the true initial 230Th/232Th ratio.

Sirt6, a class III NAD+-dependent deacetylase of the sirtuin family, is a highly specific H3 deacetylase and plays important roles in regulating cellular growth and death. The induction of oxidative stress and death is the critical mechanism involved in cardiomyocyte injury and cardiac dysfunction in doxorubicin-induced cardiotoxicity, but the regulatory role of Sirt6 in the fate of DOX-impaired cardiomyocytes is poorly understood. In the present study, we exposed Sirt6 heterozygous (Sirt6+/−) mice and their littermates as well as cultured neonatal rat cardiomyocytes to DOX, then investigated the role of Sirt6 in mitigating oxidative stress and cardiac injury in the DOX-treated myocardium. Sirt6 partial knockout or silencing worsened cardiac damage, remodeling, and oxidative stress injury in mice or cultured cardiomyocytes with DOX challenge. Cardiomyocytes infected with adenoviral constructs encoding Sirt6 showed reversal of this DOX-induced damage. Intriguingly, Sirt6 reduced oxidative stress injury by upregulating endogenous antioxidant levels, interacted with oxidative stress-stirred p53, and acted as a co-repressor of p53 in nuclei. Sirt6 was recruited by p53 to the promoter regions of the target genes Fas and FasL and further suppressed p53 transcription activity by reducing histone acetylation. Sirt6 inhibited Fas/FasL signaling and attenuated both Fas-FADD-caspase-8 apoptotic and Fas-RIP3 necrotic pathways. These results indicate that Sirt6 protects the heart against DOX-induced cardiotoxicity by upregulating endogenous antioxidants, as well as suppressing oxidative stress and cell death signaling pathways dependent on ROS-stirred p53 transcriptional activation, thus reducing Fas–FasL-mediated apoptosis and necrosis.

Polyetheretherketone (PEEK) is one of the semi-crystalline thermoplastic polymers with excellent machinability and chemical stability applied to precise structural plates and electronic components. This study installed multiple sensors to analyze the machining characteristics in the PEEK drilling. According to the time domain signals, the effects of spindle speed and feed rate on the machining characteristics of cutting force and vibration were investigated. In addition, an infrared thermography was installed to record the temperature variation within the drilling area. The experimental hole was 2-mm diameter with a 4.5-mm depth. Experimental results showed that the effect of the feed rate on thrust force is greater than the spindle speed; drilling by a low-level spindle speed with a low-level feed rate can obtain the smallest cutting force and acceleration amplitude in the spindle axis; the temperature within the drilling area is inverse to the feed rate and a high-level feed rate is helpful for forming regular curl chips. When adequate airflow was applied during the drilling operation, the hole’s shrinkage ratio and roundness can be decreased. The data presented in this paper provide valuable references for realizing the drilling of the thermoplastic—PEEK.

Tumor necrosis factor (TNF)-α-induced protein 8-like 2 (TIPE2) is a newly discovered negative immunoregulatory protein that is involved in various cellular immune responses to infections. However, the underlying mechanism by which TIPE2 affects the immune function of dendritic cells (DCs) is not yet understood. This study aimed to determine the correlations among DCs TIPE2 expression, autophagic activity and immune function in the context of sepsis. In addition, the signaling pathway by which TIPE2 regulates autophagy in DCs was investigated. We reported for the first time that TIPE2 overexpression (knock-in, KI) exerted an inhibitory effect on autophagy in DCs and markedly suppressed the immune function of DCs upon septic challenge both in vitro and in vivo. In addition, TIPE2 knockout (KO) in DCs significantly enhanced autophagy and improved the immune response of DCs in sepsis. Of note, we found that the transforming growth factor-β (TGF-β)-activated kinase-1 (TAK1)/c-Jun N-terminal kinase (JNK) pathway was inhibited by TIPE2 in DCs, resulting in downregulated autophagic activity. Collectively, these results suggest that TIPE2 can suppress the autophagic activity of DCs by inhibiting the TAK1/JNK signaling pathway and further negatively regulate the immune function of DCs in the development of septic complications.

Style length is a major determinant of breeding strategies in flowering plants and can vary dramatically between and within species. However, little is known about the genetic and developmental control of style elongation. We characterized the role of two classes of leaf adaxial-abaxial polarity factors, SUPPRESSOR OF GENE SILENCING3 (SGS3) and the YABBY family transcription factors, in the regulation of style elongation in Mimulus lewisii. We also examined the spatiotemporal patterns of auxin response during style development. Loss of SGS3 function led to reduced style length via limiting cell division, and downregulation of YABBY genes by RNA interference resulted in shorter styles by decreasing both cell division and cell elongation. We discovered an auxin response minimum between the stigma and ovary during the early stages of pistil development that marks style differentiation. Subsequent redistribution of auxin response to this region was correlated with style elongation. Auxin response was substantially altered when both SGS3 and YABBY functions were disrupted. We suggest that auxin signaling plays a central role in style elongation and that the way in which auxin signaling controls the different cell division and elongation patterns underpinning natural style length variation is a major question for future research.

Ferroptosis is a nonapoptotic form of programmed cell death triggered by the accumulation of reactive oxygen species (ROS) depended on iron overload. Although most investigations focus on the relationship between ferroptosis and cancer, neurodegenerative diseases, and ischemia/reperfusion injury, research on ferroptosis induced by immune-related inflammatory diseases, especially sepsis, is scarce. Sestrin2 (Sesn2), a highly evolutionary and stress-responsive protein, is critically involved in defense against oxidative stress challenges. Upregulated expression of Sesn2 has been observed in preliminary experiments to have an antioxidative function in the context of an inflammatory response. Nevertheless, the underlying function of Sesn2 in inflammation-mediated ferroptosis in the immune system remains uncertain. The current study aimed to demonstrate the protective effect of Sesn2 on ferroptosis and even correlations with ferroptosis and the functions of ferroptotic-dendritic cells (DCs) stimulated with lipopolysaccharide (LPS). The mechanism underlying DCs protection from LPS-induced ferroptosis by Sesn2 was further explored in this study. We found that the immune response of DCs assessed by co-stimulatory phenotypes was gradually enhanced at the peak time of 12 h upon 1 μg/ml LPS stimulation while ferroptosis in DCs treated with LPS at 24 h was significantly detected. LPS-induced ferroptosis showed a suppressive impact on DCs in phenotypic maturation, which was conversely relieved by the ferroptotic inhibitor. Compared with wild-type (WT) mice, DCs in genetic defective mice of Sesn2 (Sesn2−/−) exhibited exacerbated ferroptosis. Furthermore, the protective effect of Sesn2 on ferroptosis was noticed to be associated with the ATF4-CHOP-CHAC1 pathway, eventually exacerbating ferroptosis by degrading of glutathione. These results indicate that Sesn2 can suppress the ferroptosis of DCs in sepsis by downregulating the ATF4-CHOP-CHAC1 signaling pathway, and it might play an antioxidative role.

The dissociation of H2O is a crucial aspect for the water-gas shift reaction, which often occurs on the vacancies of a reducible oxide support. However, the vacancies sometimes run off, thus inhibiting H2O dissociation. After high-temperature treatment, the ceria supports were lacking vacancies because of sintering. Unexpectedly, the in situ generation of surface oxygen vacancies was observed, ensuring the efficient dissociation of H2O. Due to the surface reconstruction of ceria nanorods, the copper species sustained were highly dispersed on the sintered support, on which CO was adsorbed efficiently to react with hydroxyls from H2O dissociation. In contrast, no surface reconstruction occurred in ceria nanoparticles, leading to the sintering of copper species. The sintered copper species were averse to adsorb CO, so the copper-ceria nanoparticle catalyst had poor reactivity even when surface oxygen vacancies could be generated in situ.

In order to study the cobalt-rich-crust cutting mechanism of conical picks under conditions of different types of joints, a simulation model of cobalt-rich-crust cutting is establish based on the d...

Summary The field of all-polymer solar cells (all-PSCs) has experienced rapid development during the past few years, mainly driven by the design of efficient polymer acceptors (PAs). However, the polymer/polymer blend systems still lag far behind polymer/small molecule acceptor counterparts in power conversion efficiencies (PCEs). Here, we designed a near-infrared PA PY2F-T and paired it with polymer donor PM6 to fabricate all-PSCs with 15.0% PCE. Afterwards, PYT as the third component was introduced into the PM6:PY2F-T host system. Because of the complementary absorption bands and finely tuned microstructures of the ternary blend, the PCE is improved up to 17.2%, with the external quantum efficiency over 80% in visible and near-infrared spectral regions. Impressively, the ternary blend exhibited less energy loss, better light-soaking and photo-thermal stabilities than did the corresponding binary systems. This work promotes the development of high-performance ternary all-polymer systems and heralds a brighter future for accelerating the possible applications of all-PSCs.

Non‐small‐cell lung cancer (NSCLC), with its aggressive biological behavior, is one of the most diagnosed cancers. Tumor‐associated inflammatory cells play important roles in the interaction between chronic inflammation and lung cancer, however the mechanisms involved are far from defined. In the present study, by developing an orthotopic NSCLC mouse model based on chronic inflammation, we proved that an inflammatory microenvironment accelerated the growth of orthotopic xenografts in vivo. Tumor‐associated macrophages, the most abundant population of inflammatory cells, were identified. Treatment with macrophage‐conditioned medium (MCM) promoted the growth and migration of NSCLC cells. Using bioinformatics analysis, we identified downregulated PP2Ac expression in NSCLC cells upon treatment with MCM. We further confirmed that this downregulation was executed in an NF‐κB pathway‐dependent manner. As IκB kinase (IKK) has been proved to be a substrate of PP2Ac, inhibition on PP2Ac could result in amplification of NF‐κB pathway signaling. Overexpression of PP2Ac, or the dominant‐negative forms of IKK or IκB, attenuated the acceleration of growth and metastasis by MCM. Using bioinformatics analysis, we further identified that CXCL1 and COL6A1 could be downstream of NF‐κB/PP2Ac pathway. Luciferase assay and ChIP assay further confirmed the location of response elements on the promoter regions of CXCL1 and COL6A1. Elevated CXCL1 facilitated angiogenesis, whereas upregulated COL6A1 promoted proliferation and migration., Tumor‐associated macrophages, the prominent type of inflammatory cells in non‐small‐cell lung cancer, can promote the growth and metastasis of cancer cells. Overexpression of PP2Ac, or the dominant‐negative forms of IKK or IκB, attenuated the acceleration on cancer cell growth and metastasis by TAMs. CXCL1 and COL6A1 could be downstream of NF‐κB/PP2Ac pathway. Elevated CXCL1 facilitated angiogenesis, whereas upregulated COL6A1 promoted cancer cell proliferation and migration.

Sarsasapogenin (Sar), a natural steroidal compound, shows neuroprotection, cognition-enhancement, antiinflammation, antithrombosis effects, and so on. However, whether Sar has ameliorative effects on diabetes-associated cognitive impairment remains unknown. In this study, we found that Sar ameliorated diabetes-associated memory impairment in streptozotocin-induced diabetic rats, evidenced by increased numbers of crossing platform and percentage of time spent in the target quadrant in Morris water maze tests, and suppressed the nucleotide-binding domain and leucine-rich repeat containing protein 1 (NLRP1) inflammasome in hippocampus and cerebral cortex. Furthermore, Sar inhibited advanced glycation end-products and its receptor (AGEs/RAGE) axis and suppressed up-regulation of thrombin receptor protease-activated receptor 1 (PAR-1) in cerebral cortex. On the other hand, Sar mitigated high glucose-induced neuronal damages, NLRP1 inflammasome activation, and PAR-1 up-regulation in high glucose-cultured SH-SY5Y cells, but did not affect thrombin activity. Moreover, the effects of Sar were similar to those of a selective PAR-1 antagonist vorapaxar. Further studies indicated that activation of the NLRP1 inflammasome and NF-κB mediated the effect of PAR-1 up-regulation in high glucose condition by using PAR-1 knockdown assay. In summary, this study demonstrated that Sar prevented memory impairment caused by diabetes, which was achieved through suppressing neuroinflammation from activated NLRP1 inflammasome and NF-κB regulated by cerebral PAR-1. HIGHLIGHTS: Sarsasapogenin ameliorated memory impairment caused by diabetes in rats. Sarsasapogenin mitigated neuronal damages and neuroinflammation by down-regulating cerebral PAR-1. The NLRP1 inflammasome and NF-κB signaling mediated the pro-inflammatory effects of PAR-1. Sarsasapogenin was a pleiotropic neuroprotective agent and memory enhancer in diabetic rodents.

Although the significant progress in the power conversion efficiencies (PCEs) of non‐fullerene polymer solar cells (PSCs) has proved their commercial potential, the development of efficient photovoltaic materials from easily available raw materials and simple chemical synthesis is still lagging. In this work, three copolymers donors (PTEI‐H, PTEI‐F, and PTEI‐Cl) based on easily synthesized (Z)‐3‐(thiophen‐2‐yl‐methylene)‐indolin‐2‐one (TEI) as electron‐deficient unit were synthesized and characterized. As compared to the polymer PTEI‐H, the fluorinated and chlorinated polymers (PTEI‐F and PTEI‐Cl) show broader band gaps and deeper HOMO energy levels. However, after blending with small molecule acceptor Y6, the as‐cast PTEI‐H devices exhibit a PCE of 8.27%, outperforming those of the PTEI‐F devices (7.22%) and PTEI‐Cl devices (6.50%). The relatively high photovoltaic performance of the PTEI‐H devices are associated with their increased short‐circuit current density and fill factor values, resulting from the efficient exciton dissociation and charge generation, balanced charge transport properties, and reduced recombination loss. In consideration of the merits of the structural simplicity and synthetic accessibility of TEI unit, we believe it is a potential electron‐deficient moiety in developing high‐performance polymer donors for possible mass‐production of non‐fullerene PSCs.

Matrix stiffness is a key physical characteristic of the tumor microenvironment and correlates tightly with tumor progression. Here, we explored the association between matrix stiffness and glioma development. Using atomic force microscopy, we observed higher matrix stiffness in highly malignant glioma tissues than in low-grade/innocent tissues. In vitro and in vivo analyses revealed that culturing glioma cells on stiff polyacrylamide hydrogels enhanced their proliferation, tumorigenesis and CD133 expression. Greater matrix stiffness could obviously up-regulated the expression of BCL9L, thereby promoting the activation of Wnt/β-catenin signaling and ultimately increasing the stemness of glioma cells. Inhibiting Wnt/β-catenin signaling using gigantol consistently improved the anticancer effects of chemotherapy and radiotherapy in mice with subcutaneous glioma tumors. These findings demonstrate that a stiffer matrix increases the stemness of glioma cells by activating BCL9L/Wnt/β-catenin signaling. Moreover, we have provided a potential strategy for clinical glioma treatment by demonstrating that gigantol can improve the effectiveness of traditional chemotherapy/radiotherapy by suppressing Wnt/β-catenin signaling.

One of the most promising approaches to achieving high-performance all-polymer solar cells (all-PSCs) is to develop near-infrared polymer acceptors (PAs) constructed from n-type fused-ring electron...

Protein post-translational modifications (PTMs) play important roles in the regulation of protein functions and cellular processes, which cannot be easily analyzed due to a large number of obstacles, such as the substoichiometric level of PTM proteins, the diversity and complexity of PTM proteins, and the high-intensity interference from ordinary proteins. Therefore, the selective and effective separation of trace amounts of PTM peptides from complex samples is the first crucial step for PTMs. In order to meet the aforesaid requirements, magnetic polymer nanomaterials have emerged as highly effective agents for sample pretreatment in PTM proteomics. In the present review, the recent design of magnetic polymer nanomaterials and their applications in two typical types of protein PTMs (glycosylation and phosphorylation) are summarized. In addition, the development trend of magnetic polymer nanomaterials in PTM proteomics is discussed.

In vitro liquid biopsy based on exosomes offers promising opportunities for fast and reliable detection of lung cancers. In this work, we present a fluorescence resonance energy transfer (FRET) magnetic aptamer-sensor for magnetic enrichment of exosomes with aptamers and detection of cancerous-surface proteins based on a light-up FRET strategy. Fluorescent quantum dots (QDs) and aptamers were introduced onto magnetic nanoparticles and the fluorescence emission turned down when the aptamers were paired with their complementary DNA on the surface of Au nanoparticles. Later, competitive binding of exosomes with the aptamers expelled the Au nanoparticles resulting in an exosome concentration-dependent linear increase of QD fluorescence intensity in a broad exosome concentration range (5 × 102-5 × 109 particles per mL). As found in our work, this system behaved ultra-sensitively and the calculated detection limit of this FRET magnetic aptamer-sensor was as low as 13 particles per mL. Furthermore, taking epithelial cancer-specific antigen (epithelial cell adhesion molecule, EpCAM) screening as a typical example, our built FRET magnetic aptamer-sensor allowed a rapid and efficient distinction of all the epithelial cancer cases (7 lung cancers and 5 other cancers) from health volunteers with 100% accuracy.

Abnormal protein glycosylation is associated with many diseases including cardiovascular disease, diabetes, and cancer. Therefore, selective capturing of glycoproteins under physiological or weak acid conditions (tumor microenvironment) is vital for disease diagnosis and further comprehensive analysis. Here, we propose a strategy of intermolecular B-N bond-based phenylboronic acid affinity to capture glycoproteins under neutral and slightly acidic conditions. Surprisingly, the captured glycoproteins were released in alkaline solution. This is contrary to the traditional phenylboric acid affinity, and we studied this from the perspective of materials, proteins, and incubation conditions. We identified the synergistic effect of intermolecular B-N bond-based phenylboronic acid affinity, electrostatic interaction, and polymer brush structure-based glycoprotein adsorption under slightly acidic conditions. The electrostatic repulsion between Fe3O4@SiO2@poly (2-aminoethyl methacrylate hydrochloride)-4-carboxyphenylboronic acid (Fe3O4@SiO2@PAMA-CPBA) nanoparticles and transferrin (TRF) was far greater than the specific binding between phenylboric acid of CPBA and glycosylation residues of TRF resulting in the release of the captured glycoproteins in alkaline solution. Fe3O4@SiO2@PAMA-CPBA nanoparticles exhibited different selectivity capabilities toward different glycoproteins in multiprotein solutions due to protein interactions. These results may pave a new way for the design of phenylboric acid-based materials towards glycoprotein adsorption in a physiological environment.

Two-dimensional graphene-like hexagonal borophene sheets (HBSs) have a thermodynamically unsteady configuration since boron has one electron less than the carbon in graphene. To overcome this problem, we proposed a novel 2D graphene-like HBS oxide (h-B3O) in theory, which is designed by substituting partial boron atoms in a HBS with oxygen atoms. Molecular dynamics simulations indicate that h-B3O has good thermal stability. Besides, we also explored the potential of h-B3O monolayers as anodes for Li-ion batteries (LIBs) and Na-ion batteries (NIBs) by using first-principles calculations. The results indicated that the h-B3O monolayer has high adsorption energies (-2.33/-1.70 eV for Li/Na), low diffusion barriers (0.67/0.42 eV for Li/Na) and suitable average open-circuit voltages (0.36/0.32 V for LIBs/NIBs). Particularly, h-B3O has a large theoretical specific capacity of 1161 mA h g-1 for LIBs. Thus, benefiting from these characteristics, the h-B3O monolayer is considered as a promising candidate for an anode material for LIBs/NIBs.

Considering the inherent properties of glycopeptides, such as glycan structure, size, and hydrophilicity, affinity materials possessing suitable functional molecule–glycan interactions, matched channels with size exclusion, and surfaces with hydrophilic interactions are preferred for glycopeptide separation in biological samples. Here, a novel boronic-acid-functionalized magnetic covalent organic framework was prepared through epitaxial growth and multi-ligand strategies. The multi-ligand strategy was firstly employed to prepare functionalized magnetic covalent organic framework without any post-functionalization protocol. Notably, the proposed strategy was found to be time saving, robust, and reproducible. The versatile magnetic covalent organic framework nanocomposite was endowed with phenylboronic acid functional molecules, strong hydrophilic features, mesoporous channels, fast magnetic responsiveness, and a large surface area. Benefitting from multiple affinity interactions, namely, synergistic reversible covalent interactions and hydrophilic affinity interactions, the nanocomposite presented extremely high performance in the recognition of intact N-glycopeptides. The inherent properties endowed the nanocomposite with excellent enrichment performance for N-glycopeptides: excellent selectivity (1 : 2000, IgG/BSA, m/m), an ultralow detection limit (0.05 fmol μL−1), and a good size-exclusion effect (1 : 500, IgG digests/BSA, m/m). More excitingly, a total of 1921 unique intact glycopeptides assigned to 1154 glycoproteins were identified from rat liver tissue; this performance is superior to that of commercial products. Additionally, the nanocomposite was successfully applied to enrich intact glycopeptides of exosomes extracted from healthy individuals and renal failure patients, providing a novel concept for the design of materials using a synergistic affinity strategy for sample preparation in glycoproteomics.

Amygdalin is widely distributed in the plant kingdom. Oral delivery of amygdalin releases hydrogen cyanide upon endogenous enzymes causing potential toxic effects to humans. Here, we fabricate Fmoc-Tyr–OH–amygdalin hydrogel (FTOA) which represents L-tyrosine derived low molecular weight hydrogelator entrapping amygdalin. Fourier Transform Infrared Spectroscopy and the Fluorescent Emission Spectrum elucidated the complexation process between the amygdalin and Fmoc-Tyr-OH (FTO). Amygdalin was sustainably released from FTOA at different pH buffer. The rheological behavior similar to the brain supported that the hydrogel tended to be a preferable neural scaffold. Moreover, animal studies showed FTOA significantly promoted neural-functional recovery. This hydrogel achieved a great decrease in damage volume according to H&E staining. Additionally, we found that FTOA enhanced tissue recovery. Simultaneously, the released amygdalin gave a markedly neural inflammatory suppression. Taken together, this study highlights that Fmoc-based gelator encapsulate amygdalin forming a stable hydrogel to perform sustained-release and improve efficacy with minimal side effects.

Context Rosmarinic acid (RA) dose-dependently ameliorates acetaminophen (APAP) induced hepatotoxicity in rats. However, whether RA hepatoprotective effect is by regulating RACK1 and its downstream signals is still unclear. Objective This study explores the RA protective effect on APAP-induced ALI and its mechanism. Materials and methods Sixty Kunming mice 6–8 weeks old were randomly separated into six groups (n = 10) and pre-treated with normal saline, ammonium glycyrrhetate (AG) or RA (10, 20 or 40 mg/kg i.p./day) for two consecutive weeks. Then, APAP (300 mg/kg, i.g.) was administrated to induce ALI, except for the control. Serum alanine/aspartate aminotransferases (ALT and AST), malondialdehyde (MDA), superoxide dismutase (SOD) and histopathology were used to authenticate RA effect. The liver RACK1 and TNF-α were measured by western blot. Results Compared with the APAP group, different dosages RA significantly decreased ALT (52.09 ± 7.98, 55.13 ± 10.19, 65.08 ± 27.61 U/L, p

Single-nucleotide polymorphisms (SNPs), insertion/deletion (indel) polymorphisms, and DNA methylation are the most frequent types of genetic variations. As such, DNA polymorphisms play significant roles in genetic mapping and diagnostics. Thus, analytical methods enabling DNA polymorphism detection will provide an invaluable means for early disease diagnosis. However, no single electrochemical nucleic acid-based sensor has achieved the detection of the three major polymorphisms (SNPs, indel polymorphisms, and DNA methylation) with sufficient specificity and sensitivity. In response, we explore the utilization of a catalytic reaction between methylene blue (MB) covalently linked to surface-bound nucleic acid and freely diffusing ferricyanide (Fe(CN)63-) to improve specificity and sensitivity of DNA polymorphism detection. We find that the dynamics of the nucleic acid tether is an additional rate-limiting factor for the electrocatalytic reaction, in addition to the more traditional kinetic and excess factors. Our proof-of-concept experiments demonstrate that the use of electrocatalysis enables differentiation of the three polymorphisms when target sequences are present at 10 nM. We hypothesize that this ability is a result of the distinct dynamics of the DNA probe with each respective polymorphism. In addition to the specificity the sensor displays, the sensor achieves a 20 pM limit of detection. We believe that the electrocatalysis between nucleic acid-tethered MB and Fe(CN)63- is highly promising for electrochemical nucleic acid-based sensors to achieve better specificity and sensitivity.

We designed and synthesized a series of fused-ring electron acceptors (FREAs) based on naphthalene-fused octacyclic cores end-capped by 3-(1,1-dicyanomethylene)-5,6-difluoro-1- indanone (NOICs) using a bottom-up approach. The NOIC series shares the same end groups and side chains, as well as similar fused-ring cores. The butterfly effects, arising from different methoxy positions in the starting materials, impact the design of the final FREAs, as well as their molecular packing, optical and electronic properties, charge transport, film morphology, and performance of organic solar cells. The binary-blend devices based on this NOIC series show power conversion efficiencies varying from 7.15% to 14.1%, due to the different intrinsic properties of the NOIC series, morphologies of blend films, and voltage losses of devices.

Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small‐molecule palladium complex, can inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukaemia and multiple myeloma. Given that this compound is particularly active against B‐cell malignancies, we have been suggested that it can alleviate immune complexes (ICs)–mediated conditions, especially IgA nephropathy (IgAN). The therapeutic effects of Tris DBA on glomerular cell proliferation and renal inflammation and mechanism of action were examined in a mouse model of IgAN. Treatment of IgAN mice with Tris DBA resulted in markedly improved renal function, albuminuria and renal pathology, including glomerular cell proliferation, neutrophil infiltration, sclerosis and periglomerular inflammation in the renal interstitium, together with (Clin J Am Soc Nephrol. 2011, 6, 1301‐1307) reduced mitochondrial ROS generation; (Am J Physiol‐Renal Physiol. 2011. 301, F1218‐F1230) differentially regulated autophagy and NLRP3 inflammasome; (Clin J Am Soc Nephrol. 2012, 7, 427‐436) inhibited phosphorylation of JNK, ERK and p38 MAPK signalling pathways, and priming signal of the NLRP3 inflammasome; and (Free Radic Biol Med. 2013, 61, 285‐297) blunted NLRP3 inflammasome activation through SIRT1‐ and SIRT3‐mediated autophagy induction, in renal tissues or cultured macrophages. In conclusion, Tris DBA effectively ameliorated the mouse IgAN model and targeted signalling pathways downstream of ICs‐mediated interaction, which is a novel immunomodulatory strategy. Further development of Tris DBA as a therapeutic candidate for IgAN is warranted.

Doxorubicin cardiotoxicity is frequently reported in patients undergoing chemotherapy. The present study investigates whether cardiomyopathy induced by doxorubicin can be improved by the natural flavone acacetin in a mouse model and uncovers the potential molecular mechanism using cultured rat cardiomyoblasts. It was found that the cardiac dysfunction and myocardial fibrosis induced by doxorubicin were significantly improved by acacetin in mice with impaired Nrf2/HO‐1 and Sirt1/pAMPK molecules, which is reversed by acacetin treatment. Doxorubicin decreased cell viability and increased ROS production in rat cardiomyoblasts; these effects are significantly countered by acacetin (0.3‐3 μM) in a concentration‐dependent manner via activating Sirt1/pAMPK signals and enhancing antioxidation (Nrf2/HO‐1 and SOD1/SOD2) and anti‐apoptosis. These protective effects were abolished in cells with silencing Sirt1. The results demonstrate for the first time that doxorubicin cardiotoxicity is antagonized by acacetin via Sirt1‐mediated activation of AMPK/Nrf2 signal molecules, indicating that acacetin may be a drug candidate used clinically for protecting against doxorubicin cardiomyopathy.

More than 80,000 angiosperm species produce flowers with petals fused into a corolla tube. As an important element of the tremendous diversity of flower morphology, the corolla tube plays a critical role in many specialized interactions between plants and animal pollinators (e.g., beeflies, hawkmoths, hummingbirds, nectar bats), which in turn drives rapid plant speciation. Despite its clear significance in plant reproduction and evolution, the corolla tube remains one of the least understood plant structures from a developmental genetics perspective. Through mutant analyses and transgenic experiments, here we show that the tasiRNA-ARF pathway is required for corolla tube formation in the monkeyflower speciesMimulus lewisii. Loss-of-function mutations in theM. lewisiiorthologs ofARGONAUTE7andSUPPRESSOR OF GENE SILENCING 3cause a dramatic decrease in abundance ofTAS3-derived small RNAs and a moderate up-regulation ofAUXIN RESPONSE FACTOR 3(ARF3) andARF4, which lead to inhibition of lateral expansion of the bases of petal primordia and complete arrest of the upward growth of the inter-primordial regions, resulting in unfused corollas. By using an auxin reporter construct, we discovered that auxin distribution is continuous along the petal primordium base and the inter-primordial region during the critical stage of corolla tube formation in the wild-type, and that this auxin distribution is much weaker and more restricted in the mutant. Together, these results suggest a new conceptual model highlighting the central role of auxin directed synchronized growth of the petal primordium base and the inter-primordial region in corolla tube formation.

Modulation of the key immune cell subsets by biomaterial has emerged as a potential target to promote tissue repair and regeneration. Based on calcium alginate (Alg) and glycol chitosan (GC), an injectable double-network (DN) hydrogel has been developed as a scaffold for cell delivery and cell cocultured system. Previous studies have documented the interaction between dendritic cells (DCs) and GC or Alg hydrogel, but the potential effect of DN hydrogel on activation of DCs still remains unclear. This research was conducted to explore the immunomodulatory influence and underlying mechanisms of GC/Alg DN hydrogel on DCs in vitro and in vivo. Stimulation of DCs with DN hydrogel obviously induced the maturation of DCs in vitro. In vivo, DN hydrogel did not have obvious influence on the maturation of splenic DCs on postimplantation days 3, 10, and 30. Mechanistically, we found that DN hydrogel induced the maturation of DCs via phosphorylation of phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin in vitro. It provides a novel understanding of the immunomodulatory property of DN hydrogel on DCs, which may serve as potential target for designing immune-mediated regenerative strategies.

Sepiapterin reductase, a homodimer composed of two subunits, plays an important role in the biosynthesis of tetrahydrobiopterin. Furthermore, sepiapterin reductase exhibits a wide distribution in different tissues and is associated with many diseases, including brain dysfunction, chronic pain, cardiovascular disease and cancer. With regard to drugs targeting sepiapterin reductase, many compounds have been identified and provide potential methods to treat various diseases. However, the underlying mechanism of sepiapterin reductase in many biological processes is unclear. Therefore, this article summarized the structure, distribution and function of sepiapterin reductase, as well as the relationship between sepiapterin reductase and different diseases, with the aim of finding evidence to guide further studies on the molecular mechanisms and the potential clinical value of sepiapterin reductase. In particular, the different effects induced by the depletion of sepiapterin reductase or the inhibition of the enzyme suggest that the non‐enzymatic activity of sepiapterin reductase could function in certain biological processes, which also provides a possible direction for sepiapterin reductase research.

The field of all-polymer solar cells (all-PSCs) has experienced rapid development during the past few years, mainly driven by the development of efficient polymer acceptors. However, the power conversion efficiencies (PCEs) of the all-PSCs are still limited by insufficient light absorption of the donor/acceptor blend and large energy loss in devices. We herein designed a polymer acceptor PYT1 constructed n-type molecular acceptor Y5-C20 as the key building block and blended it with a polymer donor PM6 to obtain an all-polymer photoactive layer. The optimized PM6:PYT1 all-PSCs achieved a record higher PCE of 13.43% with a very low energy loss of 0.47 eV and a photoresponse of up to 900 nm compared with the Y5-C20 based device with a best PCE of 9.42%. Furthermore, the PCEs of the PM6:PYT1 all-PSCs are relatively insensitive to the 1-chloronaphthalene (CN) additive contents and active layer thickness. Our results also highlight the effect of CN additive on PM6:PYT1 morphology, i.e. , charge generation, and transport find an optimized balance, and radiative and non-radiative loss is simultaneously reduced in the blend. This work promotes the development of high-performance polymer acceptors and heralds a brighter future of all-PSCs for commercial applications.

IgA nephropathy (IgAN), the most common primary glomerular disorder, has a relatively poor prognosis yet lacks a pathogenesis-based treatment. Compound K (CK) is a major absorbable intestinal bacterial metabolite of ginsenosides, which are bioactive components of ginseng. The present study revealed promising therapeutic effects of CK in two complementary IgAN models: a passively induced one developed by repeated injections of IgA immune complexes and a spontaneously occurring model of spontaneous grouped ddY mice. The potential mechanism for CK includes 1) inhibiting the activation of NLRP3 inflammasome in renal tissues, macrophages and bone marrow–derived dendritic cells, 2) enhancing the induction of autophagy through increased SIRT1 expression, and 3) eliciting autophagy-mediated NLRP3 inflammasome inhibition. The results support CK as a drug candidate for IgAN.

Two p-type small molecules BDTT-TR and TBFT-TR with benzo[1,2-b′:4,5-b′]dithiophene (BDT) and thieno[2,3-f]benzofuran (TBF) as central core units are synthesized and used as donors in all-small-molecule organic solar cells (all-SMOSCs) with a narrow-bandgap small molecule Y6 (2,2′-((2Z,2′Z)-((12,13-bis(2-ethylhexyl)-3,9-diundecyl-12,13-dihydro-[1,2,5]thiadiazolo [3,4-e]thieno[2″,3’′:4’,5′]thieno[2′,3′: 4,5]pyrrolo[3,2-g]thieno[2′,3′:4,5]thieno[3,2-b]indole-2,10-diyl)bis(methanylylidene))bis (5,6- difluoro-3-oxo-2,3-dihydro-1H-indene-2,1-diylidene))dimalononitrile) as the acceptor. In comparison to BDTT-TR with centrosymmetric BDT as the central unit, TBFT-TR with asymmetric TBF as the central unit shows red-shifted absorption, higher charge-carrier mobility and better charge pathway in blend films. The power conversion efficiency (PCE) of the all-SMOSCs based on TBFT-TR:Y6 reaches 14.03% with a higher short-circuit current density of 24.59 mA cm−2 and a higher fill factor of 72.78% compared to the BDTT-TR:Y6 system. The PCE of 14.03% is among the top efficiencies of all-SMOSCs reported in the literature to date.

Background Non-virus genetic treatment for Parkinson’s disease (PD) via plasmid glial cell-line derived neurotrophic factor (pGDNF) has shown potential for repairing damaged dopaminergic neurons. However, development of this gene therapy is largely hampered by the insufficient transfection efficiency as a result of the cell membrane, lysosome, and cytoskeleton meshwork. Methods In this study, we propose the use of polyethylenimine (PEI)-superparamagnetic iron oxide-plasmid DNA (pDNA)-loaded microbubbles (PSp-MBs) in conjunction with focused ultrasound (FUS) and two-step magnetic navigation to provide cavitation, proton sponge effect and magnetic effects to increase the efficiency of gene delivery. Results The gene transfection rate in the proposed system was 2.2-fold higher than that of the commercial agent (TransIT®-LT1). The transfection rate could be boosted ∼11%, ∼10%, and 6% by cavitation-magnetic hybrid enhanced cell membrane permeabilization, proton sponge effect, and magnetic-assisted cytoskeleton-reorganization, respectively. In vivo data suggested that effective gene delivery with this system results in a 3.2-fold increase in recovery of dopaminergic neurons and a 3.9-fold improvement in the motor behavior when compared to untreated genetic PD mice. Conclusions We proposed that this novel FUS-magnetic hybrid gene delivery platform could be integrated with a variety of therapeutic genes for treating neurodegenerative diseases in the future.

Summary Recent advances in the development of polymer acceptors and the investigation of molecular mass have boosted the power conversion efficiency (PCE) of all-polymer solar cells (all-PSCs) to approximately 11%. Here, a fused-aromatic-ring-constructed polymer acceptor PYT (Poly[(2,2′-((2Z,2′Z)-((12,13-bis(2-octyldodecyl)-3,9-diundecyl-12,13-dihydro[1,2,5]thiadiazolo[3,4e]thieno[2″,3″:4′,5′]thieno[2′,3′:4,5]pyrrolo[3,2-g]thieno[2′,3′:4,5]thieno[3,2-b]-indole-2,10-diyl)bis(methanylylidene))bis(3-oxo-2,3-dihydro-1H-indene-2,1-diylidene)) dimalononitrile-alt-2,5-thiophene)]) is reported, while a series of PYT polymers with different molecular masses (designated as PYTL, PYTM, and PYTH) are prepared to fine-tune the molecular crystallinity and miscibility. Benefiting from the advantages of PYT series, which possess broad absorption with a narrow band of 1.40–1.44 eV and high absorption coefficients of over 1.00 × 105 cm−1, we investigated the blend miscibility and device performance of all-PSCs based on a wide-band-gap polymer donor, PM6. The PYTM-based all-PSCs exhibit an excellent PCE of 13.44%, outperforming those with PYTL (12.55%) and PYTH (8.61%). Our results provide insight into polymer acceptor backbone and molecular mass and suggest guidelines to rationally select polymers for all-PSCs.

Three fused-ring electron acceptors (FXIC-1, FXIC-2, and FXIC-3) were designed and synthesized. This FXIC series has similar electron-rich central units and the same electron-poor termini. Due to the different steric structures of fluorene, bifluorenylidene, and spirobifluorene, FXIC-1 is a one-dimensional (1D) crystal, while FXIC-2 and FXIC-3 are multidimensional (MD) amorphous materials. The conformations of the FXIC series have a slight impact on their absorption and energy levels. FXIC-1 has higher electron mobility than FXIC-2 and FXIC-3. When blending with different polymer donors (PTB7-Th, J71, and PM7), the FXIC-1-based organic solar cells have efficiencies higher than those of the FXIC-2/FXIC-3-based cells. Meanwhile, the ternary-blend cells based on PTB7-Th:F8IC with FXIC-1, FXIC-2, and FXIC-3 show similar efficiencies, which are all better than those of the binary-blend devices.

The crucial roles of the ionization state and counterion presence on the phase behavior of fatty acid in aqueous solutions are well-established. However, the effects of counterions on the adsorption and morphological state of fatty acid on nanoparticle surfaces are largely unknown. This knowledge gap exists due to the high complexity of the interactions between nanoparticles, counterions, and fatty acid molecules in aqueous solution. In this study, we use adsorption isotherms, small angle neutron scattering, and all-atom molecular dynamic simulations to investigate the effect of addition of ethanolamine as a counterion on the adsorption and self-assembly of decanoic acid onto aminopropyl-modified silica nanoparticles. We show that the morphology of the fatty acid assemblies on silica nanoparticles changes from discrete surface patches to a continuous bilayer by increasing concentration of the counterion. This morphological behavior of fatty acid on the oppositely charged nanoparticle surface alters the interfacial activity of the fatty acid–nanoparticle complex and thus governs the stability of the foam formed by the mixture. Our study provides new insights into the structure–property relationship of fatty acid–nanoparticle complexes and outlines a framework to program the stability of foams formed by mixtures of nanoparticles and amphiphiles.

Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small-molecule palladium complex, has been shown to inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukemia, and multiple myeloma. In the current study, we examined the therapeutic effects of Tris DBA on glomerular cell proliferation, renal inflammation, and immune cells. Treatment of accelerated and severe lupus nephritis (ASLN) mice with Tris DBA resulted in improved renal function, albuminuria, and pathology, including measurements of glomerular cell proliferation, cellular crescents, neutrophils, fibrinoid necrosis, and tubulointerstitial inflammation in the kidneys as well as scoring for glomerulonephritis activity. The treated ASLN mice also showed significantly decreased glomerular IgG, IgM, and C3 deposits. Furthermore, the compound was able to 1) inhibit bone marrow–derived dendritic cell–mediated T cell functions and reduce serum anti-dsDNA autoantibody levels; 2) differentially regulate autophagy and both the priming and activation signals of the NLRP3 inflammasome; and 3) suppress the phosphorylation of JNK, ERK, and p38 MAPK signaling pathways. Tris DBA improved ASLN in mice through immunoregulation by blunting the MAPK (ERK, JNK)-mediated priming signal of the NLRP3 inflammasome and by regulating the autophagy/NLRP3 inflammasome axis. These results suggest that the pure compound may be a drug candidate for treating the accelerated and deteriorated type of lupus nephritis.

The incredible diversity of floral color and pattern in nature is largely determined by the transcriptional regulation of anthocyanin and carotenoid biosynthetic genes. While the transcriptional control of anthocyanin biosynthesis is well understood, little is known about the factors regulating the carotenoid biosynthetic pathway in flowers. Here, we characterize the Reduced Carotenoid Pigmentation 2 (RCP2) locus from two monkeyflower (Mimulus) species, the bumblebee-pollinated M. lewisii and hummingbird-pollinated M. verbenaceus. We show that loss-of-function mutations of RCP2 cause drastic down-regulation of the entire carotenoid biosynthetic pathway in these species. Through bulk segregant analysis and transgenic experiments, we have identified the causal gene underlying RCP2, encoding a tetratricopeptide repeat (TPR) protein that is closely related to the Arabidopsis Reduced Chloroplast Coverage (REC) proteins. RCP2 appears to regulate carotenoid biosynthesis independently of RCP1, a previously identified R2R3-MYB master regulator of carotenoid biosynthesis. We show that RCP2 is required for chromoplast development and suggest that it most likely regulates the expression of carotenoid biosynthetic genes through chromoplast-to-nucleus retrograde signaling. Furthermore, we demonstrate that M. verbenaceus is just as amenable to chemical mutagenesis and in planta transformation as the more extensively studied M. lewisii, making these two species an excellent platform for comparative developmental genetics studies of two closely related species with dramatic phenotypic divergence.