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Background Panax ginseng is a well-known medicinal plant worldwide. As an herbal medicine, ginseng is also known for its long lifecycle, which can reach several decades. WRKY proteins play regulatory roles in many aspects of biological processes in plants, such as responses to biotic or abiotic stress, plant development, and adaptation to environmental challenges. Genome-wide analyses of WRKY genes in P. ginseng have not been reported. Results In this study, 137 PgWRKY genes were identified from the ginseng genome. Phylogenetic analysis showed that the PgWRKYs could be clustered into three primary groups and five subgroups. Most of the PgWRKY gene promoters contained several kinds of hormone- and stress-related cis-regulatory elements. The expression patterns of PgWRKY genes in 14 different tissues were analyzed based on the available public RNA-seq data. The responses of the PgWRKY genes to heat, cold, salt and drought treatment were also investigated. Most of the PgWRKY genes were expressed differently after heat treatment, and expression trends changed significantly under drought and cold treatment but only slightly under salt treatment. The coexpression analysis of PgWRKY genes with the ginsenoside biosynthesis pathway genes identified 11 PgWRKYs that may have a potential regulatory role in the biosynthesis process of ginsenoside. Conclusions This work provides insights into the evolution, modulation and distribution of the WRKY gene family in ginseng and extends our knowledge of the molecular basis along with modulatory mechanisms of WRKY transcription factors in ginsenoside biosynthesis.

Methanol synthesis from CO2 hydrogenation catalyzed by Zn/Cu alloy has been widely studied, but there is still debate on its catalytic active phase and whether the Zn can be oxidized during the reaction process. What is more, as Zn atoms could locate on Zn/Cu alloy surface in forms of both single atom and cluster, how Zn surface distribution affects catalytic activity is still not clear. In this work, we performed a systematic theoretical study to compare the mechanistic natures and catalytic pathways between Zn single atom and small cluster on catalyst surface, where the surface oxidation was shown to play the critical role. Before surface oxidation, the Zn single atom/Cu is more active than the Zn small cluster/Cu, but its surface oxidation is difficult to take place. Instead, after the easy surface oxidation by CO2 decomposition, the oxidized Zn small cluster/Cu becomes much more active, which even exceeds the hardly-oxidized Zn single atom/Cu to become the active phase. Further analyses show this dramatic promotion of surface oxidation can be ascribed to the following factors: i) The O from surface oxidation could preferably occupy the strongest binding sites on the center of Zn cluster. That makes the O intermediates bind at the Zn/Cu interface, preventing their too tight binding for further hydrogenation; ii) The higher positive charge and work function on the oxidized surface could also promote the hydrogenation of O intermediates. This work provided one more example that under certain condition, the metal cluster can be more active than the single atom in heterogeneous catalysis.

Background Pesticide residue and its poor utilization remains problematic in agricultural development. To address the issue, a nano-pesticide has been developed by incorporating pesticide acetamiprid in porous silica nanoparticles. Results This nano-pesticide had an acetamiprid loading content of 354.01 mg g−1. Testing LC50 value against tea aphids of the commercial preparation was three times that of the nano-pesticide. In tea seedlings (Camellia sinensis L.), acetamiprid was transported upward from the stem to the young leaves. On day 30, the average retained concentrations in tea leaves treated with the commercial preparation were about 1.3 times of that in the nano-pesticide preparation. The residual concentrations of dimethyl-acetamiprid in leaves for plants treated with the commercial preparation were about 1.1 times of that in the nano-pesticide preparation. Untargeted metabolomics of by LC–MS on the young leaves of tea seedlings under nano-pesticide and commercial pesticide treatments showed significant numbers of differentially expressed metabolites (P 1). Between the nano-pesticide treatment group and the commercial preparation treatment group there were 196 differentially expressed metabolites 2 h after treatment, 200 (7th day), 207 (21st day), and 201 (30th day) in negative ion mode, and 294 (2nd h), 356 (7th day), and 286 (30th day) in positive ion mode. Preliminary identification showed that the major differentially expressed metabolites were glutamic acid, salicylic acid, p-coumaric acid, ribonic acid, glutamine, naringenin diglucoside, sanguiin H4, PG (34:2) and epiafzelechin. Conclusions This work demonstrated that our nano-pesticide outperformed the conventional pesticide acetamiprid in terms of insecticidal activity and pesticide residue, and the absorption, transportation and metabolism of nano-pesticide in tea plant were different, which pave a new pathway for pest control in agricultural sector. Graphical abstract

Hydrogen storage is one of the key challenges for hydrogen economy. Among various storage candidates, magnesium hydride (MgH2) offers excellent storage capacity and cost performance, but its sluggi...

Formic acid (HCOOH) is one of the most promising chemical fuels that can be produced through CO2 electroreduction. However, most of the catalysts for CO2 electroreduction to HCOOH in aqueous solution often suffer from low current density and limited production rate. Herein, we provide a bismuth/cerium oxide (Bi/CeOx ) catalyst, which exhibits not only high current density (149 mA cm-2 ), but also unprecedented production rate (2600 μmol h-1 cm-2 ) with high Faradaic efficiency (FE, 92 %) for HCOOH generation in aqueous media. Furthermore, Bi/CeOx also shows favorable stability over 34 h. We hope this work could offer an attractive and promising strategy to develop efficient catalysts for CO2 electroreduction with superior activity and desirable stability.

Conversion-type NiO material is attractive due to its high theoretical capacity, and yet it displays inadequate reaction sites, a huge volume expansion, and a sluggish ions/electrons’ transport rat...

Chronic musculoskeletal pain (CMP) is a common occurrence in clinical practice and there are a variety of options for the treatment of it. However, the pharmacological therapy is still considered to be a primary treatment. The recent years have witnessed the emergence of opioid crisis, yet there are no relevant guidelines on how to treat CMP with non-opioid analgesics properly. The Chinese Medical Association for the Study of Pain convened a panel meeting to develop clinical practice consensus for the treatment of CMP with non-opioid analgesics. The purpose of this consensus is to present the application of nonsteroidal anti-inflammatory drugs, serotonin norepinephrine reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, muscle relaxants, ion channel drugs and topical drugs in CMP.

Cross-ply unidirectional laminates made of ultra-high molecular weight polyethylene fibers are widely used as components of bullet-proof vests. To simulate the delamination process of the material under penetration, we constructed a numerical mechanical model, which was validated by tests using 7.62 × 39 mm rifle bullets penetrating laminates of different thicknesses. The results show that the delamination region is essentially diamond-shaped. The simulated delamination region is in good agreement with the experimental data. It is found that the delamination region increases with the compression modulus along the fiber direction. The delamination region increases when the shear strength between the fabric layers decreases; However, it is little influenced by the normal strength. The delamination region of the front face of the laminate is little influenced by the failure strain of the material and the initial velocity of the bullet. The delamination region of the back face increases with the failure strain and decreases with the initial velocity.

Understanding the influence of intermediates to catalytic performance is critical for electrochemical conversion of nitrate to ammonia. In this issue of Chem Catalysis, Peng and co-workers report that electron polarization induced by alloying effect can lead to the change of adsorption sites and affect the formation of intermediates, thus paving a new mechanism for ammonia synthesis from nitrate reduction reaction.

Fluorescent chemosensors based on coordination polymers (CPs) have received particular attention in monitoring the pH values and appropriate analytes in environmental and biological systems owing to their extreme superiorities. Herein, a novel solvent-dependent fluorescent Co(II)-CP, [Co(asba)(2-mmzm)(H2O)2]·3H2O (1), was obtained through the assembly between Co2+ and 2-amino-4-sulfobenzoic acid (H2asba) in the presence of the flexible hydrophobic ligand 1,4-bis[(2-methyl-1H-imidazol-1-yl)methyl]benzene (2-mmzm). 1 is a 1D coordination polymer, which is further linked by a 1D hydrogen-bonded tape into a 3D supramolecular network. 1 shows high hydrolytic stability as well as strong acidic and basic resistance. Remarkably, 1 is a quite rare example that shows dual responsive fluorescence sensing of pH and Cu2+. 1 shows distinct sensing behavior toward pH with interesting different sensing mechanisms in three continuous pH ranges. Moreover, 1 demonstrates high accuracy in determining the pH of artificial gastric juices. 1 could also sensitively and selectively sense Cu2+ ions over a number of interfering metal ions. The limit of detection (LOD) for Cu2+ reaches the 2.4 μM level.

Selective oxidation of propene to acrolein and acrylic acid has been applied in industry for many years. In this work, the density functional theory plus U (DFT+U) method was performed to study the hydrogen abstraction of propene on the MoO3(010) surface. From the most stable chemisorbed propene (di-σ propene), the allyl intermediate is difficult to produce on a perfect MoO3(010) surface because of the high barrier. In general, the barriers of the second hydrogen abstraction are much lower than those of the first one. The conclusion from our slab model calculations is consistent with the experimental results. It is found that the (3 + 2) mechanism exhibits lower barriers than the (5 + 2) mechanism. Oxygen defects facilitate the first dehydrogenation significantly, and π-allyl converts to σ-allyl favorably on defects, in agreement with a previous experimental study. The present study indicates that increasing the surface oxygen defects might be an effective way to promote the activity of MoO3 to propene oxidation.

Chemical hydrogen storage materials such as hydrazine borane (HB) have aroused great interest when the tricky hydrogen storage is still a barrier on the way to sustainable hydrogen energy development. Many efforts have been dedicated to the dehydrogenation of HB, but the catalytic performance is still not sufficient enough. Herein, we develop the synthesis of NiPt–MoOx nanoparticles supported on NH2 functionalized N doped rGO (NiPt–MoOx/NH2–N-rGO) via a green and facile method. Unexpectedly, the supported Ni0.9Pt0.1–MoOx ultrafine nanoparticles (UPs, ∼1.5 nm) show the highest activity by far with 100% selective conversion and a turnover frequency (TOF) of 4412 h−1 at 323 K.

Brain microvascular endothelial cells (BMECs) dysfunction is related to the pathogenesis of neurovascular complication of diabetes mellitus that adversely lead to various CNS disorders. Mitoquinone (MitoQ) is a mitochondria targeted antioxidant that exerts multiple protective effects in many oxidative damage-related diseases. In this study, we determined the protective effects of MitoQ on high glucose (HG)-induced BMECs injury and investigated the underlying mechanism. We found that HG significantly reduced the expression of Nrf2 and HO-1, decreased mitochondrial membrane potential, increased intracellular and mitochondrial reactive oxygen species (ROS) generation, induced cytoskeletal damage and apoptosis in BMECs. In addition, Mito tempol, a mitochondrial ROS scavenger, significantly reduced HG-induced mitochondrial ROS production and attenuated cytoskeletal damage and cell apoptosis, suggesting MtROS production was involved in HG-induced BMECs injury. Moreover, we found that MitoQ treatment significantly upregulated the expression of Nrf2 and HO-1 in HG-induced BMECs, which is accompanied by improved mitochondrial membrane potential and decreased MtROS production. Meanwhile, MitoQ treatment also remarkably attenuated HG-induced cytoskeletal damage and cell apoptosis in BMECs. However, inhibitor of Nrf2 with ML385 impaired the protective effects of MitoQ in HG-induced BMECs. In conclusion, our results suggest that MitoQ exerts protective effect on HG-induced BMECs injury via activating Nrf2/HO-1 pathway.

Pseudomonas aeruginosa is the main conditional pathogen of immunodeficiency individuals. The mechanisms governing immune response to P. aeruginosa infection by macrophages remain incompletely defined. Herein, we demonstrate that protein tyrosine phosphatase-1B (PTP1B) is a critical negative regulator of P. aeruginosa infection response by macrophages. PTP1B-deficient macrophages display greatly enhanced bacterial phagocytosis and killing, accompanied by increased lysosome formation during P. aeruginosa infection. We also found that PTP1B repressed nitric oxide (NO) production and nitric oxide synthase (iNOS) induction following P. aeruginosa infection. PTP1B deficiency tended to upregulate the production of TRIF-interferon (IFN) pathway cytokines and chemokines, including IFN-β and interferon γ-inducible protein 10 (CXCL10, IP-10). Unexpectedly, the phosphorylation level of STAT1 was not regulated by PTP1B. In vivo experiments also confirmed that the regulatory function of PTP1B was not dependent on STAT1. These findings demonstrate that STAT1 is dispensable for negative regulation of P. aeruginosa clearance by macrophages.

This study synthesized the water-permeable and hydrophobic property of water-based polyurethane (WPU) and applied it to nylon fiber-based functional textiles. Specifically, poly-stearyl acrylate (PSA) homopolymers with different molecular weights were used as end-capping agents in the WPU to form water-based polyurethane with acrylate terminal (WPUA). In the WPUA process, dimethylacetamide was adopted as a neutralizing agent to form a stable WPUA emulsion. The effects of the design parameters, such as the hydrophilic ionic group dimethylol propionic acid (DMPA), the PSA molecular weight and content, were set as the control factors and are analyzed by the Taguchi method and gray relational analysis (GRA). The water-repellent characteristic, water vapor permeability (WVP) and fabric flexural rigidity were considered as performance parameters as multi-qualities. The Taguchi method was based on the analysis of variance and implemented orthogonal arrays for experimental design. Each performance parameter was optimized independently. Then, the performance parameters were optimized together with GRA. According to the experimental results, the most important factor for the water-repellent characteristic, WVP and fabric flexural rigidity is the DMPA content, followed by the PSA molecular weight and content. The corresponding results showed that in the optimal parameter combination, the content of DMPA was 30.8 phm (parts per hundred monomer by weight), the PSA molecular weight was 3000 g/mol and the PSA content was 4 phm. After WPUA padding, the water contact angle of the water-repellent nylon was 135.3°, the WVP was 2271.7 g/m2/day and the flexural rigidity was 2.7 cm.

Fruit and leaf possess distinctly different metabolites. Here, metabolites and transcriptome were compared between mature leaves (ML) and juice sacs (JS) of Citrus grandis "Hirado Buntan" to investigate the possible reasons. Results indicated that the remarkable difference in starch, total flavonoids and carotenoids, l-ascorbate, and jasmonic acid between ML and JS was tightly related to the expression levels of their biosynthesis-related genes, while the significant difference in abscisic acid and citrate was mainly related to the gene expression level(s) of 9-cis-epoxycarotenoid dioxygenase and proton pump genes, respectively. In addition, ATP citrate lyase probably plays a key role in the levels of flavonoids between ML and JS via providing different levels of acetyl-CoA. Taken together, these results identified some key candidate genes responsible for the content of a given metabolite and will contribute to research in regulating such metabolite content in citrus fruits.

Rationale: Statin, the most widely used medication in lowering cholesterol, is also associated with increased risk of type 2 diabetes, but its molecular basis remains unclear. Methods: Mice were injected intraperitoneally with statins alone or in combination with sirtuin (Sirt) 6 activator, and blood glucose levels were measured. Liver tissues from patients with statin use were analyzed for the expression of Sirt6. Results: Statin treatment up-regulated the hepatic expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, which was prevented by Sirt6 overexpression. Mechanistically, statin directly repressed Sirt6 expression by induction of microRNA (miR)-495, a novel inhibitor of Sirt6. Pathway analysis for predicted target genes of miR-495 recognized forkhead box protein (Fox)O1 as a key downstream signaling of Sirt6. Statin treatment increased the acetylation and protein stability of FoxO1, which was suppressed by Sirt6 overexpression. Inhibiting miR-495 recovered Sirt6 levels, blocking the ability of statin to increase FoxO1 mediated gluconeogenesis, and thus confirming the role of the miR-495/Sirt6/FoxO1 pathway in controlling gluconeogenesis. Moreover, the Sirt6 activator MDL801 prevented gluconeogenesis and hyperglycemia induced by statin in mice. Equally noteworthy was that human liver tissues obtained from statin users showed a significant decrease in Sirt6 protein levels compared to those of non-users. Conclusion: Statin induces miR-495 to suppress Sirt6 expression, which leads to enhancement of FoxO1-mediated hepatic gluconeogenesis. Thus, Sirt6 activation may offer a promising strategy for preventing statin-induced hyperglycemia.

This study synthesized water-based polyurethane with acrylate terminal group (WPUA) using the long carbon chain of stearyl acrylate to synthesize hydrophobic poly-stearyl acrylate (PSA). The proposed process could minimize environmental pollution caused by fluorine-containing monomers. As a water-based polyurethane (WPU) end-capping agent, the hydrophobic PSA and the hydrophilic and water vapor permeable WPU are copolymerized to form a WPUA functional resin with simultaneous water vapor permeability (WVP) and water repellency. Here, 2-mercaptoethanol was used to control the molecular weight of PSA to prepare the acrylate end-capping agent. PSA was then employed in WPU to form WPUA, which is characterized by the moisture permeability of WPU and water repellency of acrylic resin simultaneously. During the WPUA process, dimethylacetamide was used as a neutralizer to replace the traditional toxic chemical control drug triethylamine. This study set up the material and chemical structure to replace the toxic chemical-controlled drugs and organofluoride in the traditional preparation of moisture permeable and water repellent materials. The proposed process was proven to reduce the consumption of organic solvent, achieve WPUA copolymer stability, and provided moisture permeable and water repellent functions. In addition, Fourier transform infrared spectroscopy was used to determine the structure of WPUA, while thermogravimetry analysis and differential scanning calorimetry were performed to establish the thermal properties of WPUA. After the WPUA was padded on nylon fabric, its water drop contact angle was observed through a scanning electron microscope. The results showed that the contact angle of nylon fabric increased significantly, water repellency was reached, and WVP rises by 23.75%.

Nafion based proton exchange membrane (PEM) has long been used as conventional PEM in direct methanol fuel cell (DMFC) industry. However, the high cost of Nafion membrane and other drawbacks like high methanol crossover hinder the advancement of this industry. This study aims to develop a low cost membrane using sulfonated poly ether ether ketone (SPEEK) polymer. Silica and silicotungstic acid (SiWA) were incorporated into the membrane matrix using solution casting method. The optimum loading of the additives was tuned and it is discovered that the SPEEK membrane containing 10 wt% of silica and 5 wt% of SiWA has the best performance due to its high proton conductivity and moderately low methanol permeability. The performance of the membrane can further be enhanced by adding (3-aminopropyl)triethoxysilane (APTES) and carbonyldiimidazole (CDI) as coupling agents. Inclusion of APTES and CDI in SPEEK could not only improve the compatibility between organic SPEEK and inorganic additives, but also improve the homogeneity and dispersity of the additives. As a result, the resultant membrane with a better dimensional stability achieves high selectivity (10.60 × 104 S.s/cm3) up to 6.5 times more than pristine SPEEK membrane and 1.3 times higher than the commercial Nafion 117 membrane.

Active crystal facets can generate special properties for various applications. Herein, we report a (001) faceted nanosheet-constructed hierarchically porous TiO2/rGO hybrid architecture with unprecedented and highly stable lithium storage performance. Density functional theory calculations show that the (001) faceted TiO2 nanosheets enable enhanced reaction kinetics by reinforcing their contact with the electrolyte and shortening the path length of Li+ diffusion and insertion-extraction. The reduced graphene oxide (rGO) nanosheets in this TiO2/rGO hybrid largely improve charge transport, while the porous hierarchy at different length scales favors continuous electrolyte permeation and accommodates volume change. This hierarchically porous TiO2/rGO hybrid anode material demonstrates an excellent reversible capacity of 250 mAh g–1 at 1 C (1 C = 335 mA g–1) at a voltage window of 1.0–3.0 V. Even after 1000 cycles at 5 C and 500 cycles at 10 C, the anode retains exceptional and stable capacities of 176 and 160 mAh g–1, respectively. Moreover, the formed Li2Ti2O4 nanodots facilitate reversed Li+ insertion-extraction during the cycling process. The above results indicate the best performance of TiO2-based materials as anodes for lithium-ion batteries reported in the literature.

Undifferentiation is a key feature of nasopharyngeal carcinoma (NPC), which presents as a unique opportunity for intervention by differentiation therapy. In this study, we found that SOX1 inhibited proliferation, promoted differentiation, and induced senescence of NPC cells, which depended on its transcriptional function. RNA-Seq-profiling analysis showed that multiple undifferentiated markers of keratin family, including KRT5, KRT13, and KRT19, were reduced in SOX1 overexpressed NPC cells. Interestingly, gene ontology (GO) analysis revealed genes in SOX1 overexpressed cells were enriched in extracellular functions. The data of LC/MS untargeted metabolomics showed that the content of retinoids in SOX1 overexpressed cells and culture medium was both higher than that in the control group. Subsequently, we screened mRNA level of genes in retinoic acid (RA) signaling or metabolic pathway and found that the expression of UDP-glucuronosyltransferases was significantly decreased. Furtherly, UGT2B7 could rescue the differentiation induced by SOX1 overexpression. Inhibition of UGTs by demethylzeylasteral (T-96) could mimic SOX1 to promote the differentiation of NPC cells. Thus, we described a mechanism by which SOX1 regulated the differentiation of NPC cells by activating retinoid metabolic pathway, providing a potential target for differentiation therapy of NPC.

The evidence of combining neoadjuvant chemotherapy with targeted therapy for patients with locally advanced gastric cancer is inadequate. We conducted a single-arm phase II trial to evaluate the efficacy and safety of S-1, oxaliplatin and apatinib (SOXA) in patients with locally advanced gastric adenocarcinoma.Treatment-naïve patients received three preoperative cycles of S-1 (80-120 mg/day on days 1-14) and oxaliplatin (130 mg/mOf 29 patients included, median age was 60 (range, 43-73) years; 20 (69.0%) were male. The pRR was 89.7% (95% confidence interval [CI], 72.7%-97.8%; 26 of 29 patients; P 0.001) with 28 patients treated with surgery. All 29 patients were available for preoperative response evaluation, achieving an objective response rate of 79.3% (95% CI, 60.3%-92.0%) and a disease control rate of 96.6% (95% CI, 82.2%-99.9%). The margin-free resection rate was 96.6% (95% CI, 82.2%-99.9%). The pathologic complete response rate was 13.8% (95%CI, 1.2%-26.3%). Downstaging of overall TNM stage was observed in 16 (55.2%) patients. During neoadjuvant therapy, 10 (34.5%) patients had grade ≥III adverse events. No treatment-related death occurred. Surgery-related complications were observed in 12 of 28 (42.9%) patients.SOXA followed by surgery in patients with locally advanced gastric adenocarcinoma showed favourable activity and manageable safety. A randomised controlled trial in locally advanced gastric or oesophagogastric junction adenocarcinoma is ongoing (ClinicalTrials.gov: NCT04208347).

The urgent demands for high-energy-density rechargeable batteries promote a flourishing development of Li metal anode. However, the uncontrollable dendrites growth and serious side reactions severely limit its commercial application. Herein, an artificial LiF-rich solid electrolyte interphase (SEI) is constructed at molecular-level using one-step photopolymerization of hexafluorobutyl acrylate based solution, where the LiF is in situ generated during photopolymerization process (denoted as PHALF). The LiF-rich layer comprised flexible polymer matrix and inorganic LiF filler not only ensures intimate contact with Li anode and adapts volume fluctuations during cycling but also regulates Li deposition behavior, enabling it to suppress the dendrite growth and block side reactions between the electrolyte and Li metal. Accordingly, the PHALF-Li anode presents superior stable cycling performance over 500 h at 1 mA·cm−2 for 1 mA·h·cm−2 without dendrites growth in carbonate electrolyte. The work provides a novel approach to design and build in situ artificial SEI layer for high-safety and stable Li metal anodes.

This study took nano-silica particles mixed in low-density polyethylene to implement the optimum processing parameters and make abnormal parameter identification for the twin-screw co-rotating extruder used in the manufacturing process. The mixing quality was divided into distribution and dispersion, where distribution was tested by an energy dispersive spectrometer and evaluated using the coefficient of variation. Dispersion was assessed by the surface effect and specific surface equations, as based on the spectrum of scanning electron microscopy. By using the Taguchi method in planning the experiment coupled with an analysis of variance, we conducted the single-quality characteristic analysis of the experimental results of the two quality characteristics, namely the distribution and dispersion. Then, by using the hierarchical architecture of analytic level process, we can obtain the optimized parameter factors and levels and the calculation of the total weighting of various parameter levels, as well as the ranking of the parameter levels. According to the confirmation experimental results, the signal-to-noise ratios of distribution and dispersion fell within 95% confidence intervals, indicating that the experiment can be represented and reliable. The optimum parameters combination is SiO2 addition level 1%, screw speed 60 rpm, mixing time 5 min, temperature (upper) 150℃, temperature (middle), 175℃ and temperature (lower) 190℃. After that, by using the optimal parameters and operation processing parameters for support vector machine classification, the abnormality of the processing parameters can be identified for 100%. The good quality of the production can be guaranteed during the extrusion.

Background/Aim: Essential oils of sunflower receptacles (SEOs) have antibacterial and antioxidant potential. However, the differences of biological activities from the different varieties of sunflowers have not been studied till now. The purpose of this study was to compare the differences of chemical compounds, antioxidant activities, and inhibitory activities against xanthine oxidase (XO) of SEOs from the three varieties of sunflowers including LD5009, SH363, and S606.Methods: SEOs were extracted by using the optimal extraction conditions selected by response surface methodology (RSM). Chemical compounds of SEOs were identified from the three varieties of sunflowers by gas chromatography-mass spectrometry (GC-MS). Antioxidant activities of SEOs were detected by 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and iron ion reduction ability. Inhibitory activities of SEOs against XO were measured by using UV spectrophotometer. XO inhibitors were selected from the main chemical compounds of SEOs by the high-throughput selections and molecular simulation docking.Results: The extraction yields of SEOs from LD5009, SH363, and S606 were 0.176, 0.319, and 0.580%, respectively. A total of 101 chemical compounds of SEOs were identified from the three varieties of sunflowers. In addition, the results of inhibitory activities against XO showed that SEOs can reduce uric acid significantly. Eupatoriochromene may be the most important chemical compounds of SEOs for reducing uric acid. The results of antioxidant activities and inhibitory activities against XO showed that SEOs of LD5009 had the strongest antioxidant and XO inhibitory activities. The Pearson correlation coefficient (r > 0.95) showed that γ-terpinene, (E)-citral, and L-Bornyl acetate were highly correlated with the antioxidant activities and XO inhibitory ability.Conclusion: SEOs had antioxidant activities and XO inhibitory ability. It would provide more scientific information for utilization and selection of varieties of sunflowers, which would increase the food quality of sunflowers and incomes of farmers.

Patients with Coronavirus Disease 2019 (COVID-19), due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection mainly present with respiratory issues and related symptoms, in addition to significantly affected digestive system, especially the intestinal tract. While several studies have shown changes in the intestinal flora of patients with COVID-19, not much information is available on the gut virome of such patients. In this study, we used the viromescan software on the latest gut virome database to analyze the intestinal DNA virome composition of 15 patients with COVID-19 and investigated the characteristic alternations, particularly of the intestinal DNA virome to further explore the influence of COVID-19 on the human gut. The DNA viruses in the gut of patients with COVID-19 were mainly crAss-like phages (35.48%),Myoviridae(20.91%), andSiphoviridae(20.43%) family of viruses. Compared with healthy controls, the gut virome composition of patients with COVID-19 changed significantly, especially the crAss-like phages family, from the first time of hospital admission. A potential correlation is also indicated between the change in virome and bacteriome (likeTectiviridaeandBacteroidaceae). The abundance of the viral and bacterial population was also analyzed through continuous sample collection from the gut of patients hospitalized due to COVID-19. The gut virome is indeed affected by the SARS-CoV-2 infection, and along with gut bacteriome, it may play an important role in the disease progression of COVID-19. These conclusions would be helpful in understanding the gut-related response and contribute to the treatment and prevention strategies of COVID-19.

Shigella flexneri can synthesise polysaccharide chains having complex sugars and a regulated number of repeating units. S. flexneri lipopolysaccharide O antigen (Oag) is synthesised by the Wzy-dependent pathway which is the most common pathway used in bacteria for polysaccharide synthesis. The inner membrane protein WzyB polymerizes the Oag repeat units into chains, while the polysaccharide co-polymerases WzzB and WzzpHS2 determine the average number of repeat units or "the modal length", termed short-type and very long-type. Our data show for the first time a direct interaction between WzyB and WzzpHS2, with and without the use of the chemical cross-linker dithiobis (succinimidyl propionate) (DSP). Additionally mutations, generated via random and site directed mutagenesis, identify a region of WzyB that caused diminished function and significantly decreased very-long Oag chain polymerisation, and that affected the aforementioned interaction. These results provide insight into the mechanisms underlying the regulation of Oag biosynthesis. Importance Complex polysaccharide chains are synthesised by bacteria, usually at a regulated number of repeating units, which has broad implications for bacterial pathogenesis. One example is the O antigen (Oag) component of lipopolysaccharide that is predominantly synthesised by the Wzy-dependent pathway. Our findings show for the first time a direct physical interaction between WzyB and WzzpHS2. Additionally, a set of Wzy mutant constructs were generated revealing a proposed active site/switch region involved in the activity of WzyB and the physical interaction with WzzpHS2. Combined, these findings further the understanding of the Wzy-dependent pathway. The identification of a novel interaction with the polysacchraride co-polymerase WzzpHS2, and the region of WzyB that is involved in this aforementioned interaction and its impact on WzyB Oag synthesis activity, have significant implication for the prevention/treatment of bacterial diseases, and discovery of novel biotechnologies.

Uncontrolled mitosis is one of the most important features of cancer, and mitotic kinases are thought to be ideal targets for anticancer therapeutics. However, despite numerous clinical attempts spanning decades, clinical trials for mitotic kinase-targeting agents have generally stalled in the late stages due to limited therapeutic effectiveness. Alisertib (MLN8237) is a promising oral mitotic aurora kinase A (AURKA, Aurora-A) selective inhibitor, which is currently under several clinical evaluations but has failed in its first Phase III trial due to inadequate efficacy. In this study, we performed genome-wide CRISPR/Cas9-based screening to identify vulnerable biological processes associated with alisertib in breast cancer MDA-MB-231 cells. The result indicated that alisertib treated cancer cells are more sensitive to the genetic perturbation of oxidative phosphorylation (OXPHOS). Mechanistic investigation indicated that alisertib treatment, as well as other mitotic kinase inhibitors, rapidly reduces the intracellular ATP level to generate a status that is highly addictive to OXPHOS. Furthermore, the combinational inhibition of mitotic kinase and OXPHOS by alisertib, and metformin respectively, generates severe energy exhaustion in mitotic cells that consequently triggers cell death. The combination regimen also enhanced tumor regression significantly in vivo. This suggests that targeting OXPHOS by metformin is a potential strategy for promoting the therapeutic effects of mitotic kinase inhibitors through the joint targeting of mitosis and cellular energy homeostasis.

This study developed a nano-size filler as a thermally conductive filler for a silicone thermal pad (STP) by exfoliating hexagonal-boron nitride ( h-BN) with the chemical exfoliation-free radical polymerization method to produce boron nitride nanosheets (BNNSs). We used N,N-dimethylacrylamide as the intercalation agent. After polymerization, it became poly( N,N-dimethylacrylamide) to exfoliate the h-BN layer. BNNSs were taken as a single-filler and hybrid-fillers with Al2O3 and then compared with h-BN to investigate their effect on the silicone composite properties. As the free radical polymerization reaction time increased, the interlayer distance of BNNSs lengthened to 0.35 nm, while the thickness of h-BN sheets decreased. The X-ray diffractometer results showed how the h-BN (002) crystal plane was enhanced and displaced. The Fourier transform infrared spectra showed that the characteristic peaks of 1372 and 812 cm−1 were enhanced, and the Raman results showed that the E2 g displacement and full width at half maximum increased, thus validating the successful preparation of BNNSs. Based on the scanning electron microscope-transmission electron microscope results, BNNSs with 24-hour reaction time offered the best results with a thickness of 5 nm. The highest thermal conductivity reached 3.66 W m−1 K−1 with the addition of 50 wt% BNNSs, and tensile strength of up to 11.30 kg/cm2. Hybrid-fillers showed enhancement of thermal conductivity to 5.28 W m−1 K−1 and tensile strength to 7.32 kg cm−2. Finally, the STP showed that the volume resistance (>1010 Ω cm), withstand voltage (>10 kV mm−1), and flame resistance (V-0) of the STP prepared by this study comply with the industrial application specifications.

Cocrystal modification strategy has been applied to 3,5-dichlorosalicylic acid (DCA) through the addition of various liquid pyrazine derivatives: 2,3-dimethylpyrazine (2,3-DMP); 2,5-dimethylpyrazine (2,5-DMP); and 2,3,5-trimethylpyrazine (TMP). Three new cocrystals (2,3-DMP-DCA = 1:2 for 1; 2,5-DMP-DCA = 1:2 for 2; and TMP-DCA = 1:1 for 3) have been obtained, all of which were characterized by X-ray diffraction analysis, infrared spectroscopy, thermogravimetric analyses and UV–Vis spectroscopy. The Hirshfeld surface analysis has been performed to illustrate the intermolecular interactions. The results revealed that hydrogen bonding and other weaker interactions such as halogen bonding contacts and π···π stacking participated in a cooperative way to stabilize the supramolecular structures and different methyl substitutions changed the bonding mode and intermolecular force of pyrazine derivative cocrystals. Thermodynamic results showed that the stability of liquid pyrazine spices can be improved and the decomposition temperature for cocrystal 3 is higher than the other cocrystals. This work provides an approach to solidification of liquid pyrazine spices for more applications.

Triple‐negative breast cancer (TNBC) has a relatively poor outcome. Acquired chemoresistance is a major clinical challenge for TNBC patients. Previously, we reported that kinase‐dead Aurora kinase A (Aurora‐A) could effectively transactivate the FOXM1 promoter. Here, we demonstrate an additional pathway through which Aurora‐A stabilizes FOXM1 by attenuating its ubiquitin in TNBC. Specifically, Aurora‐A stabilizes FOXM1 in late M phase and early G1 phase of the cell cycle, which promotes proliferation of TNBC cells. Knock‐down of Aurora‐A significantly suppresses cell proliferation in TNBC cell lines and can be rescued by FOXM1 overexpression. We observe that paclitaxel‐resistant TNBC cells exhibit high expression of Aurora‐A and FOXM1. Overexpression of Aurora‐A offers TNBC cells an additional growth advantage and protection against paclitaxel. Moreover, Aurora‐A and FOXM1 could be simultaneously targeted by thiostrepton. Combination of thiostrepton and paclitaxel treatment reverses paclitaxel resistance and significantly inhibits cell proliferation. In conclusion, our study reveals additional mechanism through which Aurora‐A regulates FOXM1 and provides a new therapeutic strategy to treat paclitaxel‐resistant triple‐negative breast cancer.

The electrochemical N2 fixation, which is far from practical application in aqueous solution under ambient conditions, is extremely challenging and requires a rational design of electrocatalytic centers. We observed that bismuth (Bi) might be a promising candidate for this task because of its weak binding with H adatoms, which increases the selectivity and production rate. Furthermore, we successfully synthesized defect-rich Bi nanoplates as an efficient noble-metal-free N2 reduction electrocatalyst via a low-temperature plasma bombardment approach. When exclusively using 1 H NMR measurements with N2 gas as a quantitative testing method, the defect-rich Bi(110) nanoplates achieved a 15 NH3 production rate of 5.453 μg mgBi -1 h-1 and a Faradaic efficiency of 11.68 % at -0.6 V vs. RHE in aqueous solution at ambient conditions.

Methylene-bridged biindoles and 3-formylindoles were selectively synthesized using a new carbon donor N,N-dimethylethanolamine, catalyzed by CuCl2 and CoCl2 respectively. A high conversion rate and good regioselectivity were achieved. Oxygen atmosphere promoted the reaction toward the conversion of 3-formylindoles.

Background: The combination of transarterial chemoembolization (TACE) and apatinib has been used in the treatment of intermediate or advanced hepatocellular carcinoma (HCC). However, its effectiveness and safety are also argued. Methods: Eligible studies were collected from a computer search of literatures published from the database establishment to May 2019 in PubMed, Web of Science, EMBASE, Ovid, the Cochrane Library, Wanfang Database, China National Knowledge Infrastructure, and China Biology Medicine Disc. The objective response rate (ORR), the disease control rate (DCR), survival rate (SR), and the incidences of treatment-related adverse effects (AEs) were collected as the relevant outcomes. Data were analyzed through fixed/random effects of meta-analysis models with RevMan 5.3 software. Results: Eight randomized controlled clinical trials comprising 528 patients and 4 cohort studies comprising 226 patients were eventually included. Compared to the control group treated with TACE solely, combination therapy group, in which intermediate or advanced HCC patients were treated with TACE and apatinib, significantly enhanced ORR (relative risk [RR] 2.06, 95% CI 1.63–2.61, p < 0.001), DCR (RR 1.65, 95% CI 1.24–2.20, p < 0.001), and whole SRs of 6-month (RR 1.52, 95% CI 1.08–2.14, p = 0.02), 1-year (RR 1.52, 95% CI 1.25–1.84, p < 0.001), and 2-year (RR 1.84, 95% CI 1.34–2.54, p < 0.001). The incidence of hand foot syndrome, proteinuria, hypertension, and diarrhea was significantly increased in the combination therapy group compared with the control group (p < 0.05), and the incidence of nausea and vomiting, fever, and myelosuppression, respectively, was similar in 2 groups (p > 0.05). Conclusions: The combination therapy of TACE and apatinib can enhance the clinical effectiveness better than TACE solely in patients with intermediate or advanced HCC, while increase in the AEs is usually tolerable.

Veneering ceramics should be strongly bonded to zirconia core in order to achieve successfully long-term clinical practice. Indeed, to pursue the high zirconia core–veneering ceramic bonding is still a concerned issue. In this regard, this study was to treat zirconia surface using a 3 wt% Si3N4 solution in 4 M NaOH and to investigate the effect of soaking time (5, 10, and 20 days) on the surface properties of zirconia and shear bond strength between zirconia and veneering ceramics. The residual veneering ceramics on zirconia surfaces and failure modes were also examined after fracture. The results showed that the phase composition of zirconia before and after surface modification was not changed. The elemental mapping and depth profiling consistently revealed the soaking-time-dependent Si content on the zirconia surface. The surface roughness of zirconia was significantly (P

BACKGROUND: Gastric cancer (GC) patients with peritoneal metastasis usually have extremely poor prognosis. Intraperitoneal infusion of paclitaxel (PTX) provides an effective treatment, but relapse and PTX-resistance are unavoidable disadvantages, and it is difficult to monitor the occurrence of PTX-resistance. OBJECTIVE: The aim of this study was to explore novel autoantibodies in the ascites of individuals with relapsed PTX-resistant GC with peritoneal metastasis. METHODS: Ascites samples were collected before PTX infusion and after the relapse in 3 GC patients. To determine the expression of significantly changed proteins, we performed autoantibody profiling with immunome protein microarrays and tandem mass tag (TMT) quantitative proteomics, and then, the overlapping proteins were selected. RESULTS: Thirty-eight autoantibodies that were differentially expressed between the ascites in the untreated group and relapsed PTX-resistant group were identified. For confirmation of the results, TMT quantitative proteomics was performed, and 842 dysregulated proteins were identified. Four proteins, TPM3, EFHD2, KRT19 and vimentin, overlapped between these two assays. CONCLUSIONS: Our results first revealed that TPM3, EFHD2, KRT19 and vimentin were novel autoantibodies in the ascites of relapsed PTX-resistant GC patients. These autoantibodies may be used as potential biomarkers to monitor the occurrence of PTX-resistance.

Nerve injury-induced gene expression change in the spinal cord is critical for neuropathic pain genesis. RNA N6-methyladenosine (m6A) modification represents an additional layer of gene regulation. We showed that spinal nerve ligation (SNL) upregulated the expression of matrix metallopeptidase 24 (MMP24) protein, but not Mmp24 mRNA, in the spinal cord neurons. Blocking the SNL-induced upregulation of spinal MMP24 attenuated local neuron sensitization, neuropathic pain development and maintenance. Conversely, mimicking MMP24 increase promoted the spinal ERK activation and produced evoked nociceptive hypersensitivity. Methylated RNA Immunoprecipitation Sequencing (MeRIP-seq) and RNA Immunoprecipitation (RIP) assay indicated the decreased m6A enrichment in the Mmp24 mRNA under neuropathic pain condition. Moreover, fat-mass and obesity-associated protein (FTO) was colocalized with MMP24 in spinal neurons and shown increased binding to the Mmp24 mRNA in the spinal cord after SNL. Overexpression or suppression of FTO correlates with promotion or inhibition of MMP24 expression in cultured spinal cord neurons. In conclusion, SNL promoted the m6A eraser FTO binding to the Mmp24 mRNA, which subsequently facilitated the translation of MMP24 in the spinal cord, and ultimately contributed to neuropathic pain genesis.

This thesis focuses on the design, synthesis and development of dynamic multivalent nanostructures such as supramolecular dendrimers, liposomes and gold-functionalized nanostructures. These structures can be used for drug delivery and molecular sensing applications. This thesis is divided into three parts:In part one, a general introduction to self-assembly, dynamic systems, metalligand exchange, nanostructured dendritic scaffolds, liposomes and gold nanostructures is given.In part two, a microwave approach is presented as an efficient method for the regioselective deuteration of bipyridine scaffolds. Dynamic systems based on transition metal-bipyridine coordination complexes were investigated. The compositional self-adaptation and kinetics of these dynamic systems were successfully assessed by ESI-MS. Based on this amphiphilic dendrimers/metallodendrimers were also designed and synthesized via a convergent strategy. Their ability to self-assemble into supramolecular assemblies and their controlled disassembly was effectively demonstrated.In part three, two types of drug delivery systems based on dynamic multivalent nanostructures of glycodendrimers/metalloglycodendrimers and drugpresenting liposomes were developed. The dynamic self-assembly of these architectures into supramolecular nanostructures with site-specific functionality through interacting carbohydrate or cholesterol moieties was assessed. The host-guest interaction/encapsulation and controlled release with external stimuli were studied using a fluorescent probe, as well as selected drug molecules. The antibacterial property of the drug delivery systems was also evaluated, demonstrating an enhanced bactericidal activity. A new, rapid and simple approach for the functionalization of plasmonic gold nanostructured surfaces was also developed. The optical performance and light-specific sensitivity of the fluorescent probe on the resulting nanostructures were also presented.

Background Perioperative therapy can improve the low survival benefit of surgery alone for locally advanced gastric cancer. The introduction of immunotherapy and its combination with chemotherapy and/or targeted therapy has created more opportunities for optimal treatment. The aim of the present study was to compare the efficacy and safety of S-1 plus oxaliplatin (SOX) combined with apatinib (SOXA) or SOX combined with apatinib and camrelizumab (SOXAP) versus SOX as the perioperative therapy for resectable, locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Methods The study was a multicenter, randomized, open-label, parallel-controlled trial conducted in China. Eligible participants were randomized to the SOX, SOXA, and SOXAP groups. Patients received three pre-operative and three postoperative 3-week cycles of SOX or SOXA or SOXAP, followed by apatinib (SOXA group) or apatinib combined with camrelizumab (SOXAP group) for 3 cycles, which could be continued at the investigator's choice. Overall treatment is up to 1 year of apatinib and up to 17 cycles of camrelizumab. SOX is 130 mg/m2 oxaliplatin on day 1 plus S-1 orally twice daily on days 1 to 14. Apatinib is orally administered at a dose of 500 mg (SOXA group) or 250 mg (SOXAP group) on days 1 to 21, and camrelizumab 200 mg is given intravenously once every 3 weeks. The primary endpoint was major pathological response assessed by blinded independent review committee. The secondary endpoints included pathological complete response, lymph node status after neoadjuvant therapy, margin-free resection rate, progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), and safety. Discussion The trial provides important data regarding the use of perioperative SOXAP and SOXA for patients with resectable, locally advanced gastric or GEJ adenocarcinoma. The results will contribute to optimal perioperative disease treatment. Trial registration ClinicalTrials.gov (no. NCT04208347). First posted on December 23, 2019.

Shigella flexneri is a major causative agent of bacillary dysentery in developing countries, where serotype 2a2 is the prevalent strain. To date, approximately 30 serotypes have been identified for S. flexneri, and the major contribution to the emergence of new serotypes is chemical modifications of the lipopolysaccharide (LPS) component O antigen (Oag). Glucosylation, O-acetylation, and phosphoethanolamine (PEtN) modifications increase the Oag diversity, providing benefits to S. flexneri. LPS Oag acts as a primary receptor for bacteriophage Sf6, which infects only a limited range of S. flexneri serotypes (Y and X). It uses its tailspike protein (Sf6TSP) to establish initial interaction with LPS Oags that it then hydrolyzes. Currently, there is a lack of comprehensive study on the parent and serotype variant strains from the same genetic background and an understanding of the importance of LPS Oag O-acetylations. Therefore, a set of isogenic strains (based on S. flexneri 2457T [2a2]) with deletions of different Oag modification genes (oacB, oacD, and gtrII) that resemble different naturally occurring serotype Y and 2a strains was created. The impacts of these Oag modifications on S. flexneri sensitivity to Sf6 and the pathogenesis-related properties were then compared. We found that Sf6TSP can hydrolyze serotype 2a LPS Oag, identified that 3/4-O-acetylation is essential for resistance of serotype 2a strains to Sf6, and showed that serotype 2a strains have better invasion ability. Lastly, we revealed two new serotype conversions for S. flexneri, thereby contributing to understanding the evolution of this important human pathogen. IMPORTANCE The emergence of antibiotic-resistant strains and lack of efficient vaccines have made Shigella a priority organism for the World Health Organization (1). Therefore, bacteriophage therapy has received increasing attention as an alternative therapeutic approach. LPS Oag is the most variable part of LPS due to chemical modifications and is the target of bacteriophage Sf6 (S. flexneri specific). We dissected the evolution of S. flexneri serotype Y to 2a2, which revealed a new role for a gene acquired during serotype conversion and furthermore identified new specific forms of LPS receptor for Sf6. Collectively, these results unfold the importance of the acquisition of those Oag modification genes and further our understanding of the relationship between Sf6 and S. flexneri.

Drought represents a leading constraint over crop productivity worldwide. The plant response to this stress is centered on the behavior of the cell membrane, where the transduction of abscisic acid (ABA) signaling occurs. Here, the Ras-related small GTP-binding protein RabE1c has been shown able to bind to an ABA receptor in the Arabidopsis thaliana plasma membrane, thereby positively regulating ABA signaling. RabE1c is highly induced by drought stress and expressed abundantly in guard cells. In the loss-of-function rabe1c mutant, both stomatal closure and the whole plant drought stress response showed a reduced sensitivity to ABA treatment, demonstrating that RabE1c is involved in the control over transpirative water loss through the stomata. Impairment of RabE1c's function suppressed the accumulation of the ABA receptor PYL4. The over-expression of RabE1c in A. thaliana enhanced the plants' ability to tolerate drought, and a similar phenotypic effect was achieved by constitutively expressing the gene in Chinese cabbage (Brassica rapassp. pekinensis). The leading conclusion was that RabE1c promotes the degradation of PYL4, suggesting a possible genetic strategy to engineer crop plants to better withstand drought stress.

Aim:To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET) versus ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa.Methods:This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150 mg twice daily) or placebo plus: anastrozole (1 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A.Results:In cohort A, 207 patients were randomly assigned to the abemaciclib arm and 99 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: not reached versus 14.7 months; hazard ratio 0.499; 95% confidence intervals (CI) 0.346–0.719; p = 0.0001). ORR was 65.9% in the abemaciclib arm and 36.1% in the placebo arm ( p Conclusion:The addition of abemaciclib to ET demonstrated significant and clinically meaningful improvement in PFS and ORR, without new safety signals observed in this population. Trial Registration: ClinicalTrials.gov identifier: NCT02763566.

Bromhexine is an expectorant drug repurposing as a TMPRSS2 inhibitor, which has also been proposed for potential treatment in COVID-19 infection. Multicomponent crystal strategy has been applied in bromhexine to improve its poor solubility, which limits its bioavailability and efficacy. A new bromhexine crystal and its fumarate salt crystal have been successfully obtained by slow evaporation technique. Both compounds have been characterized by X-ray single-crystal diffraction, TGA and FT-IR spectroscopy. Hirshfeld surface analysis has been carried out to further quantify the patterns of intermolecular interactions. Compared with bromhexine, the multicomponent crystal with pharmaceutically acceptable conformer of fumaric acid shows improved thermal stability and solubility in water.

Background: Gastric cancer (GC) with peritoneal metastasis has an extremely poor prognosis. Paclitaxel (PTX) intraperitoneal infusion provides an effective treatment for these patients. However, GC patients with peritoneal metastasis who receiving PTX treatments tend to occur PTX-resistance accompany with more aggressive ascites and metastasis. How does this happen is still unknown. Here, we aimed to explore the mechanisms that mediate PTX-resistance and metastasis in GC with peritoneal metastasis. Methods: Ascites samples were collected before PTX infusion and after the relapse in 3 GC patients. To determine the expression of significantly changed proteins, we performed tandem mass tag (TMT) quantitative proteomics. Immunohistochemistry (IHC) staining and western blot were performed to confirm the expression of CDH11 in the PTX-resistant tissues and MKN45P-PR cells. Invasion and migration of GC cells were examined by in vitro transwell and wound healing assays and in vivo dissemination experiments. Results: CDH11 expression was downregulated in the relapsed PTX-resistant ascites, tissues and the PTX-resistant cell line MKN45P-PR. Inhibition of CDH11 expression promoted the invasion, migration and PTX resistance of MKN45P cells, while overexpression of CDH11 repressed these biological functions. Moreover, tumors disseminated in the mice peritoneal cavity induced by MKN45P-PR cells and shCDH11 cells displayed higher metastatic ability and resistance to PTX treatment. Conclusions: Our results reveal that CDH11 is inhibited in the relapsed PTX-resistant patients and the downregulated CDH11 expression promotes GC cell invasion, migration and PTX resistance. CDH11 may have the potential to serve as a predictable marker for the occurrence of PTX resistance in GC patients with peritoneal metastasis.

Venlafaxine (VEN), a first-line antidepressant, and Zuojin Pill (ZJP), a common Chinese herbal medicine consisting of Rhizoma Coptidis and Fructus Evodiae, have high likelihood of combination usage in depression patients with gastrointestinal complications. ZJP exhibits inhibitory effects on recombinant human cytochrome P450 isoenzymes (rhCYPs), especially on CYP2D6, while VEN undergoes extensive metabolism by CYP2D6. From this prospective, we for the first time investigated the influence of ZJP on the metabolism of VEN in vitro and in rats. In this study, ZJP significantly inhibited the metabolism of VEN in both rat liver microsomes (RLM) and human liver microsomes (HLM); meanwhile, it inhibited the O-demethylation catalytic activity of RLM, HLM, rhCYP2D6*1/*1, and rhCYP2D6*10/*10, primarily through CYP2D6, with IC50 values of 129.9, 30.5, 15.4, and 2.3 μg/mL, respectively. Furthermore, the inhibitory effects of ZJP on hepatic metabolism and pharmacokinetics of VEN could also be observed in the pharmacokinetic study of rats. The AUC0-24h of VEN and its major metabolite O-desmethylvenlafaxine (ODV) increased by 39.6% and 22.8%, respectively. The hepatic exposure of ODV decreased by 57.2% 2h after administration (P = 0.014). In conclusion, ZJP displayed inhibitory effects on hepatic metabolism and pharmacokinetics of VEN in vitro and in rats mainly through inhibition of CYP2D6 activity. The human pharmacokinetic interaction between ZJP and VEN and its associated- clinical significance needed to be seriously considered.

Background: Platinum is recommended in combination with gemcitabine in the treatment of metastatic triple-negative breast cancer (mTNBC), such as carboplatin plus gemcitabine and cisplatin plus gemcitabine. However, an optimal partner with cisplatin remains to be established. Herein, Gemcitabine or Abraxane (nab-paclitaxel) combined with cisPlatin (GAP) was administered to assess the efficacy and safety of AP versus GP as first-line therapy for patients with mTNBC. Methods: In this phase 3, randomized, open-label trial, patients from nine institutions or hospitals in China with histologically confirmed mTNBC, an ECOG performance status of 0–1 and at least one measurable lesion received first-line therapy of AP (nab-paclitaxel 125 mg/m² on day 1, 8 and cisplatin 75 mg/m² on day 1) or GP (gemcitabine 1250 mg/m² on days 1, 8 and cisplatin 75 mg/m² on day 1) intravenously every 3 weeks using an interactive web response system with the stratification factors of visceral metastasis and number of metastatic sites. The primary endpoint was progression-free survival (PFS) assessed in the intention-to-treat population. The safety profile was assessed in patients who received at least one dose of the treatment. Results: Between Mar 30, 2016, and Oct 09, 2019, 254 patients were randomly assigned to treatment (127 to receive AP and 127 to receive GP). After a median follow-up of 16.3 months, the median PFS was 9.9 months (95% confidence interval [CI] 8.99-10.88) with AP as compared to 7.5 months (6.66-8.40) with GP (hazard ratio [HR], 0.6 6; 95% CI, 0.5 0- 0. 87; P=0.004). A significant higher objective response rate (ORR) (81.1% vs. 55.9%) and a trend for improved overall survival (OS) (median 26.3 vs. 22.9 months) were achieved with AP. Of the grade 3 or 4 adverse events, a significantly higher incidence of neuropathy (24 [18.9%] vs. 0 [0%]) occurred in the AP group, while thrombocytopenia was noted (5[3.9%] vs. 37 [29.4%]) in the GP group. There were no treatment-related deaths. Conclusions: AP significantly improved PFS and ORR in patients with mTNBC as first-line treatment as compared to GP; however, OS results are eagerly awaited. The current trial warrants further assessment of adding novel agents to the nab-paclitaxel/platinum backbone due to its high potency and cost-efficiency for all mTNBC patients. Trial Registration: The trial is registered with ClinicalTrials.gov, number NCT02546934. Funding: This study was funded by National Natural Science Foundation of China, grant number 81874114. Nab-paclitaxel was provided by Celgene Corporation. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All patients provided written informed consent, and the study was approved by the institutional review board at each participating center. The study was conducted in accordance with the Declaration of Helsinki.