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Objective To investigate the potential effect of Lysimachia capillipes capilliposide (LCC) on the chemo sensitivity and the stemness of human ovarian cancer cells. Methods Cell Counting Kit-8 (CCK8) was used to measure the IC50 values. The apoptosis of cells was measured through flow cytometry. Evaluation of the stemness and differentiation markers was performed by the immunoblotting and the immunostaining assays. RNA-seq was performed through the Illumina HiSeq PE150 platform and differentially expressed genes (DEGs) were screened out through the bioinformation analysis. Overexpression or knockdown of Fos gene was achieved by shRNA transfection. Results Pre-exposure of A2780T cells with 10 μg/mL LCC sensitized them to paclitaxel, of which the IC50 value reduced from 8.644 μmol/L (95%CI: 7.315–10.082 μmol/L) to 2.5 μmol/L (95%CI: 2.233–2.7882 μmol/L). Exposure with LCC enhanced the paclitaxel-induced apoptosis and inhibited the colony formation of A2780T cells. LCC exposure reduced the expression of cancer stemness markers, ALDH1, Myd88 and CD44, while promoting that of terminal differentiation markers, NFATc1, Cathepsin K and MMP9. RNA-seq analysis revealed that the expressions of FOS and JUN were upregulated in LCC-treated A2780T cells. A2780T cells overexpressing Fos gene displayed increased paclitaxel-sensitivity and reduced cell stemness, and shared common phenotypes with LCC-treated A2780T cells. Conclusion These findings suggested that LCC promoted terminal differentiations of ovarian cancer cells and sensitized them to paclitaxel through activating the Fos/Jun pathway. LCC might become a novel therapy that targets at cancer stem cells and enhances the chemotherapeutic effect of ovarian cancer treatments.

Circular RNAs (circRNAs) play vital regulatory roles in the development of ovarian cancer (OC). However, the functions of circRNA Atlastin GTPase 2 (circATL2) in paclitaxel (PTX) resistance of OC are still unclear. As a result, circATL2 was upregulated in PTX-resistant OC tissues and cells. CircATL2 knockdown reduced IC50 of PTX, inhibited colony formation ability and promoted cell cycle arrest and apoptosis in PTX-resistant OC cells. Silencing of circATL2 restrained PTX resistance in vivo. Furthermore, miR-506-3p could be targeted by circATL2 and miR-506-3p inhibition reversed the impacts of circATL2 knockdown on PTX resistance and cell progression in PTX-resistant OC cells. NFIB was identified as the target of miR-506-3p. MiR-506-3p overexpression suppressed PTX resistance and malignant behaviors of PTX-resistant OC cells, with NFIB elevation rescued the impacts. To summarize, circATL2 promoted the resistance of OC to PTX by sponging miR-506-3p to upregulate NFIB expression, providing a new sight in chemoresistance of OC.

Echinocandin B deacylase (ECBD) from Actinoplanes utahensis can be applied to produce echinocandin B nucleus (ECBN), an essential intermediate of the echinocandins antifungal drugs such as anidulafungin. To date, the expression of ECBD has been limited to Streptomyces. To achieve the active expression of ECBD in Escherichia coli (E. coli), we constructed a plasmid carrying two subunits of ECBD for T7 RNA polymerase driven transcription of dicistron messenger after codon optimization. Subsequently, the introduction of peptide tags in the recombinant ECBD was adopted to reduce the formation of inclusion bodies and enhance the ECBD solubility. The peptide tags with the opposite electrostatic charge, hexa-lysine (6K) and GEGEG (GE), exhibited the best positive effect, which was verified by activity assay and structural simulation. After that, optimization of culture conditions and characterization of ECBD were conducted, the optimal pH and temperature were 7.0 and 60 °C. It is the first report concerning the functional expression of ECBD in the host E. coli. Our results reported here can provide a reference for the high-level expression of other deacylases with respect to a possible industrial application.

Rochelle salt, as the initiator of piezoelectrics and ferroelectrics, has been a bridge between homochirality as well as piezoelectricity and ferroelectricity since the late 19th century. One can greatly increase the hit rate of constructing non-centrosymmetric or even polar materials by using enantiomeric components. It should be highlighted that the marriage of photoisomerization and piezoelectricity can endow molecular piezoelectrics with unique optical phenomena, which may realize multi-channel encryption and detection. However, it is still a great challenge to design a photoisomerized piezoelectric. Here, under the guideline of introducing homochirality, we have designed a pair of high-temperature enantiomeric azobenzene-based piezoelectrics, 4-(phenyldiazenyl)anilinium) D- and L-tartrate (D-1 and L-1), whose piezoelectric behaviors persist up to 460 K. Compared to the racemic compound 4-(phenyldiazenyl)anilinium) rac-tartrate (rac-1) which adopts the centrosymmetric space group P, the selection of homochiral anions makes the enantiomers crystallize in an enantiomeric-polar space group and thereby induce piezoelectricity and potential ferroelectricity. As piezoelectric materials, the enantiomers show relatively large piezoelectric responses of 7 pC per N, comparable to that of Rochelle salt. Besides, D-1 and L-1 possess the ability of photoisomerization; to our knowledge, this is the first azobenzene-based high-temperature enantiomeric piezoelectric which shows a photoisomerization phenomenon upon 450 nm irradiation. This combination of piezoelectricity and photoisomerization may support further exploration of optically-controlled smart devices for multi-channel information encryption and signal detection.

Stem cell transplantation is a promising therapy for wound healing, but the low retention and survival of transplanted stem cells limit their application. Injectable hydrogels exert beneficial effects in skin tissue engineering. In this study, an injectable hydrogel composed of sodium alginate (SA) and collagen type I (Col) was synthesized as a tissue scaffold to improve the efficacy of stem cells in a full-thickness excision wound model. Our results showed that SA/Col hydrogel was injectable, biodegradable, and exhibited low immunogenicity, which could promote the retention and survival of hUC-MSCs in vivo. SA/Col loaded with hUC-MSCs showed reduced wound size (p

Ferroelectric materials have a variety of technological applications, as transducers, capacitors, sensors, etc. Great interest in molecular ferroelectrics has emerged because of their structural flexibility, tunability, and homochirality. However, the discoveries of molecular ferroelectrics are not abundant. The lack of chemical design is the main challenge in realizing new molecular ferroelectrics. Consequently, chemical design approaches, including the ideas of introducing quasi-spherical theory, homochirality, and H/F substitution, have been developed recently. Through these advanced methodologies, a wide range of ferroelectrics were successfully synthesized, changing the blind search into a targeted chemical design. In this Perspective, we aim to provide insight into the fundamental chemistry and physics of molecular ferroelectrics and propose the concept of "ferroelectrochemistry", concerned with the targeted design and performance optimization of molecular ferroelectrics from the chemical point of view. We start with the basic theories used in the modification of chemical structures for new molecular ferroelectrics, such as the quasi-spherical theory. After that, we focus on the fundamentals of homochirality from the perspective of chemistry and advantages of introducing a homochiral molecule within the scope of ferroelectrics. Further, we explore another design strategy, H/F substitution, as an analogue of the H/D isotope effect. The introduction of a F atom usually does not change the polar point group but may induce a minor structural disruption that enhances physical properties such as Curie temperature and spontaneous polarization. We hope our comprehensive studies on the targeted design and performance optimization strategies for molecular ferroelectrics may build up and enrich the content of ferroelectrochemistry.

Organic-inorganic hybrid perovskites (OIHPs) hold a great potential for scientific and technological endeavors in the field of ferroelectrics, solar cells, and electroluminescent devices, because of their structural diversity, low cost of manufacture, and ease of fabrication. However, lead iodide perovskite ferroelectrics with narrow band gap have rarely been reported. Here, we present a new two-dimensional (2D) layered lead iodide perovskite ferroelectric, (4,4-DFHHA)

Molecular ferroelectrics are attracting tremendous interest because of their easy and environmental-friendly processing, low acoustic impedance, and mechanical flexibility. Their ferroelectric mechanism is mainly ascribed to the order-disorder transition of molecules such as spherical 1,4-diazabicyclo[2.2.2] octane (DABCO) and quinuclidine. Here, we present two molecular ferroelectrics, [HDABCO][TFSA] and its deuterated one [DDABCO][TFSA] (TFSA = bis(trifluoromethylsulfonyl)ammonium), whose ferroelectricity is triggered by the proton ordering. This is the first time that the protons show a thermally fluctuated bistability with a double-well potential in DABCO-based ferroelectrics. A large deuterium isotope effect (ΔT = ∼53 K) not only proves that they are hydrogen-bonded ferroelectrics but also extends the ferroelectric working temperature range to room temperature. The superfast polarization switching of 100 kHz and ultralow coercive voltage of 1 V (far less than 5 V required for commercially available ferroelectric devices), benefiting from the low energy for proton transfer, allow [DDABCO][TFSA] a great potential for memory devices with low-voltage, high-speed operation. This work should inspire further exploration of hydrogen-bonded molecular ferroelectrics for flexible and wearable devices with the low-power information storage.

Topological defects, such as vortices and skyrmions, provide a wealth of splendid possibilities for new nanoscale devices because of their marvelous electronic, magnetic, and mechanical behaviors. Recently, great advances have been made in the study of the ferroelectric vortex in conventional perovskite oxides, such as BaTiO

Despite reductions in mortality from the use of highly active antiretroviral therapy (HAART), the presence of latent or transcriptionally silent proviruses prevents HIV cure/eradication. We have previously reported that DNA-dependent protein kinase (DNA-PK) facilitates HIV transcription by interacting with the RNA polymerase II (RNAP II) complex recruited at HIV LTR. In this study, using different cell lines and peripheral blood mononuclear cells (PBMCs) of HIV-infected patients, we found that DNA-PK stimulates HIV transcription at several stages, including initiation, pause-release and elongation. We are reporting for the first time that DNA-PK increases phosphorylation of RNAP II C-terminal domain (CTD) at serine 5 (Ser5) and serine 2 (Ser2) by directly catalyzing phosphorylation and by augmenting the recruitment of the positive transcription elongation factor (P-TEFb) at HIV LTR. Our findings suggest that DNA-PK expedites the establishment of euchromatin structure at HIV LTR. DNA-PK inhibition/knockdown leads to the severe impairment of HIV replication and reactivation of latent HIV provirus. DNA-PK promotes the recruitment of Tripartite motif-containing 28 (TRIM28) at LTR and assists the release of paused RNAP II through TRIM28 phosphorylation. These results provide the mechanisms through which DNA-PK controls the HIV gene expression and, likely, can be extended to cellular gene expression, including during cell malignancy, where the role of DNA-PK has been well-established.

Due to the intriguing chemical variability and structure-property flexibility, molecular materials with striking multifunctional characteristics, including tunable physical, chemical, optical, and electronic properties, have aroused wide attention. Recently, great advances have also been made in designing molecular ferroelastics with optoelectronic properties. However, the band gaps of the most typical ferroelastics are far in excess of 2.0 eV, which severely hinder their further applications. And this corresponds to the inherent incompatibility of ferroelastics. Herein we report an organometallic compound, ferrocenium tetrachloroferrate (

Copper (Cu)-doped ZnO (CZO) films were grown by simultaneous direct current and radio frequency magnetron sputtering technique under the situation of different gas flow rates of Ar: O2 (1:1, 2:1 and 1:0). The X-ray diffraction patterns revealed the naturally polycrystalline ZnO films with the predominant reflection (002) peak, which referred to the hexagonal wurtzite structure toward c-axis. The elemental composition of thin films was analyzed by energy dispersive spectroscopy (EDS). The Cu concentrations in thin films increased with Ar ratio of up to 1:0. The EDS spectra of three kinds of elements indicate that Cu-doping has obvious and sophisticated effect on the chemical state of oxygen, but less effect on those of copper and zinc. Furthermore, the nonlinear absorption of CZO films was investigated by the way of Z-scan technique. These films demonstrated good nonlinear absorption behavior for the different gas flow rates of Ar: O2.

Our previous study indicated that streptozotocin (STZ)‐induced diabetes leads to colonic platelet‐derived growth factor receptor‐α‐positive (PDGFRα+) cell proliferation accompanied by slow colonic transit in mice; however, the mechanism of this effect is unclear. The present study used western blotting, immunohistochemistry, and quantitative PCR to investigate whether proteinase‐activated receptor 2 (PAR2) mediates PDGFRα+ cell proliferation. Our results showed that PDGFRα, PAR2, and Ki‐67 coexpression was increased in the diabetic colonic muscle layer. PDGFRα and PAR2 mRNA and protein expression levels were also markedly enhanced in the diabetic colonic muscle layer. Mice treated with 2‐furoyl‐LIGRLO‐amide (2‐F‐L‐a), a PAR2 agonist, exhibited significant colon elongation and increased smooth muscle weight. In the 2‐F‐L‐a‐treated mice, PDGFRα, PAR2, and Ki‐67 coexpression was increased and PDGFRα and PAR2 mRNA and protein expression was significantly enhanced in the colonic smooth muscle layer. 2‐F‐L‐a also increased proliferation and PDGFRα expression in NIH/3T3 cells cultured in high glucose, while LY294002, a PI3K antagonist, decreased cell proliferation and PDGFRα expression. PI3K and Akt protein and mRNA expression and p‐Akt protein expression in diabetic and 2‐F‐L‐a‐treated mice were markedly reduced in colonic smooth muscle. 2‐F‐L‐a also reduced PI3K, Akt, and p‐Akt protein expression in NIH/3T3 cells, while the PI3K antagonist LY294002 increased this expression. The results indicate that PAR2 is involved in the proliferation of PDGFRα+ cells through the PI3K/Akt signaling pathway in the colon of STZ‐induced diabetic mice, which may contribute to the slow transit and constipation that are associated with diabetes.

Small ubiquitin-like modifier (SUMO)ylation is one of the posttranslational modifications and is implicated in many tumor types. Modulation of SUMOylation can affect tumor progression, but the underlying mechanisms remain unclear. Here, we show that, for the first time, in uveal melanoma (UM), the most common intraocular malignancy in adults, global SUMOylation is upregulated and participates in tumor growth. Inhibition of SUMOylation in UM is sufficient to reduce tumor growth both in vitro and in vivo. Furthermore, we found that retinoblastoma protein (Rb) is a target protein and a critical downstream effector of the upregulated SUMOylation activity in UM. Increased SUMOylation of the Rb protein leads to its hyperphosphorylation and inactivation in UM cells, promoting UM cell proliferation. In summary, our results provide novel insight into the mechanism underlying SUMOylation-regulated tumor growth in UM.

Rutin-loaded corn protein hydrolysate-carboxymethyl chitosan (CPH-NOCC) Maillard conjugate nanoparticles (NPs) with superior stability under different NaCl concentrations (0-0.25 mol/L) and pH levels (7.0 to 3.0) were investigated. Results showed that the degree of glycosylation of 53.3%, browning index of 0.6, and SDS-PAGE lane of CPH-NOCC conjugates were obtained after dry heating for 48 hr (60 °C, 79% RH). The high encapsulation efficiency (EE, 97.8%-98.8%) and CPH-NOCC-rutin (98.8%) was significantly higher than CPH-rutin (97.8%) and CPH/NOCC-rutin (98.4%) NPs illustrated that hydrolysis was positive for zein encapsulation, and conjugation of NOCC to CPH increased the EE. Hairy carbohydrate protrusions on the surface of CPH-NOCC-rutin NPs produced a stronger steric effect and hampered the formation of salt bridges and the particle aggregation under CPH isoelectric point at pH 4.0. Therefore, the CPH-NOCC conjugate NPs may be suitable carrier for hydrophobic bioactive substances in a board range of business foodstuffs.

The prediction of grinding particle size is an effective measure to optimize the grinding process. Cassiterite polymetallic sulfide ore and lead-zinc ore, as the research object in this paper, thei...

Steep gully slopes are widespread and have been recognized as the main sediment source on the Loess Plateau. Different vegetation growth may lead to the differences in soil properties and plant roots, and thus likely affects soil resistance to flowing water erosion, reflected by rill erodibility and critical shear stress. However, few studies have been conducted to evaluate this effect on steep gully slopes on the Loess Plateau of China. This study was performed to investigate the effects of vegetation growth on soil resistance to flowing water erosion on steep gully slopes, and quantify the main potential influencing factors on the Loess Plateau. Three typical shrub communities and four typical grass communities that distributed on different gully slopes were selected. 240 undisturbed soil samples were collected from these seven gully slope lands and one slope farmland (control), and were subjected to detachment by overland flow under six different shear stresses (6.64 to 17.85 Pa). The results showed that the mean detachment capacity of slope farmland was 6.9 to 47.8 times greater than those of steep gully slopes covered with different plant communities. The rill erodibilities of steep gully slopes covered with different plant communities reduced greatly by 77.0% to 95.1% compared to the control slope. The critical shear stress of slope farmland (2.72 Pa) was only 57.2% and 39.6% of that of shrubland (4.76 Pa) and grassland (6.88 Pa). Both shrub and grass communities were effective in reducing soil detachment capacity and rill erodibility, and increasing critical shear stress on steep gully slopes. But the effects were more obvious for the grass communities. The differences in rill erodibility between slope farmland and gully slope lands were mainly explained by the changes in root mass density (82.4%). Plant roots had strong direct effects on increasing soil cohesion (0.78), organic matter content (0.56), and water stable aggregation (0.92). Rill erodibility was negatively related to root mass density as an exponential function (p

Solid-state molecular rotor-type materials such as host-guest inclusion compounds are very desirable for the construction of molecular ferroelectrics. However, they usually have a low Curie temperature (Tc) and uniaxial nature, severely hindering their practical applications. Herein, by regulating the anion to control "momentum matching" in the crystal structure, we successfully designed a high-temperature multiaxial host-guest inclusion ferroelectric [(MeO-C6H4-NH3)(18-crown-6)][TFSA] (MeO-C6H4-NH3 = 4-methoxyanilinium, TFSA = bis(trifluoromethanesulfonyl)ammonium) with the Aizu notation of mmmFm. Compared to the parent uniaxial ferroelectric [(MeO-C6H4-NH3)(18-crown-6)][BF4] with a Tc of 127 K, the introduction of larger TFSA anions brings a lower crystal symmetry at room temperature and a higher energy barrier of molecular motions in phase transition, giving [(MeO-C6H4-NH3)(18-crown-6)][TFSA] multiaxial ferroelectricity and a high Tc up to 415 K (above that of BaTiO3). To our knowledge, such a record temperature enhancement of 288 K makes its Tc the highest among the reported crown-ether-based ferroelectrics, giving a wide working temperature range for applications in data storage, temperature sensing, actuation, and so on. This work will provide guidance and inspiration for designing high-Tc host-guest inclusion ferroelectrics.

Understanding the interaction of phosphoric acid and porous electrocatalysts is of vital importance for a rational design of high performance phosphoric acid based fuel cells on a molecular level. We demonstrate for the first time that NMR spectroscopy can be used for elucidating the preferred distribution sites of phosphoric acid in various nanoporous carbons. A pore size dependent negative chemical shift of 31P is observed, serving as a distinct signature of pore occupation, and applied for analysing a commercial catalyst (Pt@Vulcan) as a practical application.

Two-dimensional (2D) hybrid organic-inorganic perovskites (HOIPs) are attracting tremendous interest for their great scientific and technological potential in photovoltaics and optoelectronics. Although the ferroelectricity in 2D HOIPs has been greatly developed, however, to date no phosphonium-based 2D HOIP ferroelectrics have yet been found. Meanwhile, electrostriction plays an important role in the electromechanical behavior of ferroelectrics, while it has never been reported for 2D HOIP ferroelectrics. Here, we present the first phosphonium-based 2D HOIP ferroelectric (EATMP)PbBr4 (EATMP = (2-aminoethyl)trimethylphosphanium) with a direct bandgap of 2.84 eV. Notably, (EATMP)PbBr4 possesses a high Curie temperature of 534 K, which is the highest among all reported 2D HOIP ferroelectrics. Moreover, it exhibits a large electrostrictive coefficient of about 3.96 m4 C-2 as well, far exceeding those of PVDF (1.3 m4 C-2) and inorganic ones (∼0.034-0.096 m4 C-2). With excellent ferroelectric and piezoelectric properties and the merit of easy fabrication, (EATMP)PbBr4 shows great potential in applications for future smart devices of actuators, transducers, and sensors.

Two-dimensional (2D) hybrid organic-inorganic perovskites (HOIPs), which possess the merits of good material stability, structural diversity, and ease of fabrication, are highly desirable for widespread applications of ferroelectrics, solar cells, and electroluminescent devices. Although some molecular design strategies toward ferroelectrics have been proposed, however, it is still a great challenge to precisely induce and optimize the ferroelectricity in 2D HOIPs. Here, for the first time through perfluorinated substitution strategy, we successfully design a high-performance 2D HOIP ferroelectric, (perfluorobenzylammonium)

Background Several evidences have proved that cancer-associated fibroblasts (CAFs) play a crucial role in tumor progression. In fact, CAFs form a major component of tumor microenvironment (TME). Therefore, the development and metastasis of tumors can be effectively inhibited by small molecular compounds that target CAFs. Methods In this study, we mainly analyzed the expression profile of colon cancer (CC). We determined the intensity of CAFs in CC tissues by using the immune cell infiltration score. Gene enrichment analysis and the screening of differentially expressed genes were performed on the basis of the intensity of CAFs in CC tissues. We screened the small molecular compounds that were converted from differentially expressed genes. The results indicated that atractyloside was a small molecular compound related to CAFs in CC tissues. We identified the relationship between atractylosides and CAFs through target protein analysis and network analysis, and verified the inhibition effect of atractylosides on CC cells (CCC) by migration assay and scratch wound-healing assays. Results We found that many target proteins of atractyloside, such as the matrix metalloproteinase family and integrin proteins, were related to the biological function of CAFs. By performing network analysis, we found that the target proteins FGF1, ITGB1, and EDNRA were closely related to tumor angiogenesis, while the target proteins MMP9 and ITGAV were correlated to an extracellular matrix (ECM) and cell motility. These findings which further confirmed the relationship between atractylosides and CAFs. In addition, transwell cell migration and scratch wound-healing assays proved that atractylosides could significantly inhibit the migration of CCCs. Conclusions The atractyloside might be a small molecular compound that potentially targets CAFs and inhibits the development as well as metastasis of CC by changing the TME.

Hybrid organic-inorganic perovskites (HOIPs) with the general formula ABX3 hold phenomenal research interest for their great scientific and technological potential in photovoltaic, piezoelectric, and electroluminescent devices. It is their considerable structural diversity that offers a good opportunity to build a variety of HOIP structures with various functionalities. However, no organometallic-based HOIP piezoelectrics have yet been found, despite the structural diversity and functional richness of organometallic compounds such as the ferrocene-based family. Here, for the first time, we report an organometallic-based HOIP piezoelectric, [(ferrocenylmethyl)trimethylammonium]PbI3. Benefitting from the stability of ferrocene-based cations, excellent piezoelectric performance, comparable to that of LiNbO3, can be obtained and optimized by tuning the anionic framework. The involvement of organometallic cations enables a narrow band gap of 2.37 eV, much lower than those of most HOIPs and some inorganic semiconductors. This work provides a new future direction for the study of perovskites and will inspire intriguing research on organometallic-based HOIP piezoelectrics.

Objective: We aimed to determine the significance of MSC-derived exosomes (MSC-Exos) in chondrocyte autophagy under normal and inflammatory conditions.Design: Human umbilical cord-derived MSCs (hMSCs) were cultured in vitro. hMSC-Exos( EX） were isolated by an ultracentrifugation method. Transmission electron microscopy and western analysis were used to identify exosomes. Human chondrocytes were extracted from five adult males with OA undergoing total knee arthroplasty. Primary cultures of chondrocytes from OA patients were stimulated with 50 ng/ml tumor necrosis factor-α (TNF-α) in the presence or absence of hMSC-Exos. Autophagy levels were determined based on expression of autophagic marker LC3, StubRFP-SensGFP-LC3 analysis, and electron microscopy. Catabolic gene and chemokine expression were evaluated using quantitative PCR. The NF-κB inhibitor NS398 was used to analyze the role of the NF-κB pathway in autophagic activation.Results: hMSC-Exos increased LC3-II levels as well as autophagosome number in chondrocytes. hMSC-Exos inhibited TNF-α–induced expression of MMP-3, -9, and -13; ADAMTS5; CCL-2 and -5; and CXCL1. NF-κB inhibition activated autophagy in TNF-α–treated chondrocytes. These results indicate that hMSC-Exos might suppress the levels of catabolic and inflammatory factors in chondrocytes by promoting autophagy via NF-κB pathway inhibition.Conclusions: Our data support the interest in hMSC-Exos to develop new therapeutic approaches for joint conditions.

The root of Lindera reflexa Hemsl. (LR) is a folk Chinses herbal medicine that has been used to treat gastritis and peptic ulcers. In this study, three new stilbenes (1–3) and two known flavonoids (4 and 5) were isolated from the antiulcer purified fractions of LR. The chemical structures of the isolated compounds were characterized comprehensively based on the basis of extensive spectroscopic data. Absolute configurations of compounds 1, 2, and 3 were determined by ECD calculations. The cytotoxic activities of compounds 1–5 were evaluated by MTT assay. Compound 4 showed the strongest inhibitory effect on the proliferation of tumor cells lines MGC803 and SMMC-7721, with IC50 values of 2.65 and 4.13 μM, respectively. The quantitative analysis of 12 compounds of the antiulcer purified fractions of LR were carried out by using the reversed-phase high-performance liquid chromatography (HPLC) method. Within the test range, all calibration curves showed good linearity (R2 > 0.9993). The LOD, LOQ, specificity, precision, and accuracy of the method were verified. Therefore, the present study may provide a valuable method for quality control the antiulcer purified fractions of LR.

Alginate oligosaccharide (AOS) was reported to possess antioxidant and free radical scavenging activities, but the specific effects and mechanisms remain unclear. We investigated the effects of AOS on H2O2-induced oxidative stress and apoptosis in human umbilical vein endothelial cells (HUVECs) and the associated mechanisms. HUVECs were treated with 100-800 µM hydrogen peroxide (H2O2) for various periods (12, 24, and 36 h) to establish an in vitro oxidative stress and apoptosis HUVEC model. AOS protects HUVEC cells against oxidative stress-induced apoptosis by decreasing the expression levels of caspase 3 and Bax, and increasing Bcl-2 expression. Microarray assay, real-time PCR and western blot results revealed that AOS was able to effectively suppress H2O2-induced apoptosis via regulated integrin-α/FAK/PI3K pathway by influencing the expression of integrin-α, FAK, PI3K, PTEN, P21, and CDK2. In conclusion, our study suggests that AOS can protect endothelial cells against oxidative stress injury caused by H2O2, providing novel alternative strategies to prevent atherosclerosis in the future.

The mitogen-activated protein kinase (MAPK) pathway plays a vital role in signal transduction networks. Severe diseases may be triggered if it is disturbed by mutated components, especially the kinase B-RafV600E . New inhibitors of the kinase are needed as cases of relapse and resistance with the known drugs have been widely reported in the clinic. In the present work, a new class of B-RafV600E inhibitors was identified by fragment linking. In vitro and in vivo assays were used to demonstrate the pharmacological properties of the compounds. 3-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}-N-[1-(4-methoxyphenyl)-1H-pyrazol-4-yl]benzamide was the most potent agent with IC50 values of 0.035±0.004 μm (B-RafV600E kinase) and 0.39±0.04 μm (A375 cells). Furthermore, no obvious toxicity was observed. Collectively, the results favored justified the design rationale and hinted that this new chemotype might be worth studying further to develop novel B-Raf inhibitor candidates.

Mixed matrix membranes (MMMs) derived from metal-organic frameworks (MOFs) nanocrystals represent a promising alternative for overcoming the trade-off between permeability and selectivity derived from the pristine polymeric membrane. The selection of MOFs fillers are mainly focused on their diffusion-selectivity property for gas-pairs. However, the improvement of both gas-permeability and selectivity through addition of sorption-selective MOFs are rarely reported. Herein, the incorporation of CO2-philic KAUST-7 (also referred to as NbOFFIVE-1-Ni) nanocrystals makes the neat 6FDA-Durene polyimide membrane more permeable and more selective, surpassing the state-of-the-art 2008 Robeson upper bound for CO2/CH4. Nano-sized (~ 80 nm) KAUST-7 crystals with sharp particle size distribution were first fabricated through a co-solvent synthesis method. The explored gas transportation mechanism indicates that the improvement of CO2/CH4 selectivity on MMMs are attributed to the significant raise of the sorption-selectivity rather than the diffusion-selectivity. The favorable interfacial interaction between the imide groups of the 6FDA and the H of the pyrazine in the KAUST-7 enhances plasticization resistance of the neat polymer membrane. The developed MMMs exhibit a promising application in CO2 capture from natural- and bio-gas.

The β amyloid (Aβ) induced neurodegeneration is believed to be one of pathological mechanisms of Alzheimer’s disease (AD). The inhibition of Aβ production or aggregation is one of the promising therapeutic strategies for anti-AD drug discovery. Here, a homogeneous neutral polysaccharide designated LBP1A1-1 with an average molecular weight of 45.0 kDa was purified from fruits of Lycium barbarum L. Its structure was characterized to possess a backbone of 1, 3-linked β-Galp, 1, 6-linked β-Galp, 1, 4-linked α-Glcp with branches substituted at C-3 position of 1, 6-linked β-Galp or C-6 position of 1, 3-linked β-Galp. The branches contained terminal (T)-linked β-Galp, T-linked α-Araf, T-linked β-Araf, 1, 5-linked α-Araf and T-linked β-Rhap. The in vitro experiments revealed that LBP1A1-1 could inhibit Aβ42 production and impede Aβ42 aggregation in a dose-dependent-manner without cytotoxicity. These results suggested that LBP1A1-1 might have the multiple potential for the treatment of AD.

The association of deregulated signal pathways with various diseases has long been a research hotspot. One of the most important signal pathways, the MAPK (mitogen-activated protein kinase) signal pathway, plays a vital role in transducing extracellular signals into vital intracellular mechanisms. While mutations on its key component Raf kinase lead to sever diseases, targeted inhibition has thereby become an attractive therapeutic strategy. Several drugs have been approved for the treatment of Raf relevant diseases, yet more candidates are ever needed as the known drugs have confronted resistance and side effects. In the present study, we primarily investigated the binding modes of type I/II and type II inhibitors with B-Raf kinase. Based on the current knowledge, these ligands were fragmented and recombined to provide new interesting insights. Afterwards, a series of derivatives has been synthesized after the validation of hit compound. In addition, in vitro assays were carried out to profile the pharmacological properties of all the entities. Of all the compounds, compound 5h showed the best profile and may be used in the future study.

Many studies suggested that polysaccharides could impact on the gut microbiota. To discover new polysaccharides which influence intestinal beneficial bacteria, a pectin polysaccharide FMP-6-S2 with an average molecular weight of 86.83 kDa was purified from Fructus Mori. The monosaccharide residue analysis indicated that FMP-6-S2 was composed of rhamnose, galacturonic acid, galactose and arabinose in a molar ratio of 30.86: 24.78: 28.70: 15.61. The backbone of FMP-6-S2 contained 1, 4-linked α-GalpA and 1, 2-linked α-Rhap with branches substituted at C-4 position of rhamnose. The branches were composed of 1, 4-linked β-Galp, terminal (T) − and 1, 3, 6-linked β-Galp, T- and 1, 5-linked α-Araf. Bioactivity test results suggested that FMP-6-S2 and its degraded product could promote growth of intestinal bacteria, B. thetaiotaomicron, which is a dominate strain in the gut of human to benefit intestinal mucosa. These results suggested that FMP-6-S2 and its degraded product might improve human wellness by modulating B. thetaiotaomicron.

The controllable synthesis of nanocrystals with a desired structure and morphology is still a great challenge in the chemistry and materials fields. In this work, we report a simple solvothermal method for the controllable synthesis of sodium and cesium doped tungsten bronze nanocrystals (NaxCsyWO3 (NaCWO)) with different morphologies and crystalline phases, through adjusting the amounts of H+ and H2O in the reactive system. Furthermore, ethocel/NaCWO films with high transparency are also fabricated via a solution mixing method. The growth mechanisms of the NaCWO nanocrystals are investigated systematically, and structure–property relationships are also explored. Results indicate that the as-prepared two kinds of crystalline phase NaCWO nanocrystals with four morphologies can be monodispersed in toluene to form transparent nanodispersions. Among these systems, the one with rod-shaped hexagonal nanocrystals exhibits the most excellent near-infrared absorption properties, with 3.5% near-infrared transmittance at 1000 nm, and it simultaneously holds high visible light transmittance of 84% at 440 nm. Owing to the good dispersion of the nanocrystals, the ethocel/NaCWO film with an NaCWO content of 10 per hundred of ethocel resin by weight maintains the same optical performance as the nanodispersion, which is significantly important for the development of NIR absorption materials applied to energy-saving glass, solar collectors, optical filters, etc.

The signal transducer and activator of transcription 3 is a constitutively activated oncogenic protein in various human tumors and represents a valid target for anticancer drug design. In this study, we have achieved a new type of STAT3 inhibitors based on structural modifications on shikonin scaffold, guided by computational modelling. By tests, PMMB-187 exhibited a more outstanding profile than shikonin on a small panel of human breast cancer cells, especially for the MDA-MB-231 cells. For the cellular mechanisms research, PMMB-187 was found to induce cell apoptosis in MDA-MB-231 cells, associated with the reduction of mitochondrial membrane potential, production of ROS and alteration of the levels of apoptosis-related proteins. Furthermore, PMMB-187 inhibited constitutive/inducible STAT3 activation, transcriptional activity, nuclear translocation and downstream target genes expression in STAT3-dependent breast cancer cells MDA-MB-231. Besides, no obvious inhibitory effect on activation of STAT1 and STAT5 was observed with PMMB-187 treatment. Most notably, the in vivo studies further revealed that PMMB-187 could dramatically suppress the MDA-MB-231 cells xenografted tumor growth. The in vitro and in vivo results collectively suggest that PMMB-187 may serve as a promising lead compound for the further development of potential therapeutic anti-neoplastic agents.

Frequent screening of at-risk individuals using paper-based point-of-care diagnostics is a promising method for attenuating the spread of chlamydia and HIV. However, such diagnostics typically suffer from limited sensitivity. The authors describe a method to improve the sensitivity of the lateral-flow immunoassay (LFA), in which the target molecules are thermodynamically concentrated using aqueous two-phase systems (ATPSs) to improve the detection limit. The novel concept of sequential ATPS component resolubilization within paper for both a PEG-potassium phosphate and a UCON-50-HB-5100-potassium phosphate system was established to provide a diagnostic tool which only requires the sample to be added without any sample preparation steps. The automated ATPS phase separation and concentration of the target into the leading phase within the paper matrix can be visually demonstrated due to the use of gold nanoparticles. The importance of resolubilization order of the dehydrated polymers and salts is discussed. The designs presented improve the detection limit of a conventional LFA setup for Chlamydia trachomatis bacteria (158 μg·mL−1) and human immunoglobulin M (IgM) antibodies (0.31 μg·mL−1) to 15.8 μg·mL−1 and 0.031 μg·mL−1, respectively. This is a 10-fold detection limit improvement and results are available in 15 min. Compared to other methods that improve LFA sensitivity, this particular method does not require additional equipment, reagents, or sample preparation steps as all necessary components are embedded into the initial setup. Therefore, this advancement enables a more sensitive LFA that can be operated by untrained or minimally trained personnel, significantly expanding its applicability as a point-of-care test.

Ferroelectric thin-films are highly desirable for their applications on energy conversion, data storage and so on. Molecular ferroelectrics had been expected to be a better candidate compared to conventional ferroelectric ceramics, due to its simple and low-cost film-processability. However, most molecular ferroelectrics are mono-polar-axial, and the polar axes of the entire thin-film must be well oriented to a specific direction to realize the macroscopic ferroelectricity. To align the polar axes, an orientation-controlled single-crystalline thin-film growth method must be employed, which is complicated, high-cost and is extremely substrate-dependent. In this work, we discover a new molecular ferroelectric of quinuclidinium periodate, which possesses six-fold rotational polar axes. The multi-axes nature allows the thin-film of quinuclidinium periodate to be simply prepared on various substrates including flexible polymer, transparent glasses and amorphous metal plates, without considering the crystallinity and crystal orientation. With those benefits and excellent ferroelectric properties, quinuclidinium periodate shows great potential in applications like wearable devices, flexible materials, bio-machines and so on., Molecular ferroelectric crystals hold promise in data storage applications, yet their preparations by maximizing molecular polarization are challenging. Here, You et al. report quinuclidinium periodate with six rotation axes and grow them in macroscopic ferroelectric thin films via a solution process.

The advancement of cancer-fighting drugs has never been a simple linear process. Those drug design professionals begin to find inspiration from the nature after failing to find the ideal products by creative drug design and high-throughput screening. To obtain new molecules for inhibiting tubulin, podophyllotoxin was adopted as the leading compound and 1,3,4-oxadiazole was brought in to the C-4 site of podophyllotoxin in this research. A series of seventeen podophyllotoxin-derived esters have been achieved and then evaluated their antitumor activities against four different cancer cell lines: A549, MCF-7, HepG2, and HeLa. Among all the compounds, compound 7c showed the best antiproliferating properties with IC50 = 2.54 ± 0.82 μm against MCF-7 cancer cell line. It was obvious that the content of ROS grew significantly in MCF-7 in a way depending on the dosage. The time- and dose-dependent cell cycle assays revealed that compound 7c could apparently block cell cycle in the phase of G2/M along with the upregulation of cyclin A2 and CDK2 protein. According to further studies, confocal microscopy experiment has certified that compound 7c could restrain cancer from growing by blocking the polymerization of microtubule. Meanwhile, compound 7c could be ideally integrated with the colchicine site of tubulin. In future, it would be feasible to selectively design tubulin inhibitors with the help of 3D-QSAR. This means that it is hopeful to develop compound 7c as a potential agent against cancer due to its biological characteristics.

The biological importance of microtubules in mitosis makes them an interesting target for the development of anticancer agents. In this study, a series of novel chalcone-containing shikonin derivatives was designed, synthesized, and evaluated for biological activities. Among them, derivative PMMB-259 [(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-2-(4-(3-oxo-3-(3-(trifluoromethoxy)phenyl)prop-1-en-1-yl)phenoxy)acetate] was identified as a potent inhibitor of tubulin polymerization. Further investigation confirmed that PMMB-259 can induce MCF-7 cell apoptosis, reduce the mitochondrial transmembrane potential, and arrest the cell cycle at the G2 /M phase. Moreover, the morphological variation of treated cells was visualized by confocal microscopy. The results, along with docking simulations, further indicated that PMMB-259 can bind well to tubulin at the colchicine site. Overall, these studies may provide a new molecular scaffold for the further development of antitumor agents that target tubulin.

Over the past few decades, the human epidermal growth factor receptor (EGFR) has been established as an attractive target for non-small cell lung cancer (NSCLC) therapy. Nevertheless, the approved EGFR inhibitors, gefitinib or erlotinib have shown minimum clinical activity to breast cancer patients, who also highly expressed EGFR. In this study, we designed and synthesized a series of novel formononetin derivatives by reference to the binding mode of lapatinib to EGFR. In vitro EGFR and cell growth inhibition assay demonstrated that compound 4v exhibited the most potent anti-EGFR (IC50 = 14.5 nM) and anti-proliferation activity (IC50 = 5.44 ± 1.28 μM) against MDA-MB-231 cell line, which was comparable to that of lapatinib (EGFR, IC50 = 5.6 nM; MDA-MB-231, IC50 = 2.48 ± 1.04 μM). Further biological experiment results demonstrated that 4v could effectively induce apoptosis, inhibit proliferation and migration in MDA-MB-231 cells through targeting EGFR and then blocking the downstream signaling pathways, EGFR/PI3K/Akt/Bad, EGFR/ERK and EGFR/PI3K/Akt/β-catenin, respectively. However, it had no significant influence on cell cycle distribution and the related proteins (Cyclin A, Cyclin D1, CDK4) expression. In vivo anti-tumor results also preliminarily confirmed the effectiveness of 4v in tumor chemotherapy in mice and indicated its potential as a new EGFR inhibitor in the treatment of MDA-MB-231 malignant tumor.

Although immunomodulatory activities of Dendrobium officinale polysaccharide has been investigated for many years, yet the potential contribution of its metabolite derived from intestinal microbes on immunoregulation effect has not been reported. In this study, polysaccharide DOW-5B with average molecular weight of 39.4 kDa was isolated from the stem of Dendrobium officinale Kimura et Migo. The carbohydrate content was 91.97% and no protein was detected. The monosaccharide analysis showed this polysaccharide was composed of glucuronic acid and glucose at a molar ratio (M/G) of 1.2:19.4. Animal test indicated DOW-5B increased the diversity of gut microbiota on mice. Beneficial microbes such as Ruminococcus, Eubacterium, Clostridium, Bifidobacterium, Parabacteroides and Akkermansiamuciniphila increased while harmful bacteria in Proteobacteria decreased. Surprisingly, DOW-5B promoted gut microbes to generate more butyrate and mainly produced by Parabacteroides_sp_HGS0025. Further, we found the health of large intestine as well as immunity response of mice was improved. In addition, Parabacteroides_sp_HGS0025 positively correlated with butyrate, IgM, IL-10, and TNF-α products in intestine and mice blood, respectively. The data suggested that Dendrobium officinale polysaccharide has function on immunity may be mediated by butyrate. It adds new evidence to support the basis of how herbal polysaccharides affect immunity.

A host-guest inclusion compound, 18-crown-6 oxonium tetrachloride-gallium(iii), was shown to undergo a 4/mmmFmm2-type ferroelectric phase transition with four crystallographically equivalent polarization directions at 337 K. To the best of our knowledge, this is the first host-guest inclusion compound shown to be a high-temperature multiaxial molecular ferroelectric.

When applying an optical current transformer (OCT) to direct current measurement, output signals exhibit a low signal-to-noise ratio and signal-to-noise band overlap. Sinusoidal wave modulation is used to solve this problem. A double correlation detection algorithm is used to extract the direct current (DC) signal, remove white noise and improve the signal-to-noise ratio. Our sensing unit uses a terbium gallium garnet crystal in order to increase the output signal-to-noise ratio and measurement sensitivity. Measurement errors of single correlation and double correlation detection algorithms are compared, and experimental results showed that this measurement method can control measurement error to about 0.3%, thus verifying its feasibility.

Dendrobium, orchid, is a traditional Chinese herb medicine applied extensively as tonic and precious food for thou-sands of years recorded in ancient Chinese medical book "Shen Nong's Materia Medica". It's well known that bioactivities are usually related to the ingredients' basis. Based on the previous research, Dendrobium species contain amino acid, sesquiterpenoids, alkaloids and polysaccharides. As the bioactive substances, carbohydrate shows extensive activities in antitumor, antiglycation, immune-enhancing, antivirus, antioxidant, antitumor and etc. Therefore, as the main biologically active substance, the exact structures and latent activities of polysaccharides from Dendrobium species are widely focused on. In this review, we focus on the advancements of extraction methods and diversity of structures and bioactivities of polysaccharides obtained from Dendrobium species.

For the purpose of synthesizing drug candidates with desirable bioactivity, a class of benzoyl amide containing nitrogen heterocyclic ring derivatives targeting VEGFR-2 was designed and screened out using Discovery Studio. Eighteen target compounds were synthesized and then selected by some biological trials sequentially including inhibition of VEGFR-2, anti-proliferation in vitro, flow cytometry. Among them, compound 8h showed the best inhibitory activity (IC50 = 0.34 ± 0.02 μM against VEGFR-2, IC50 = 1.08 ± 0.06 μM and 2.44 ± 0.15 μM against MCF-7 and HepG-2, respectively, which were at the same inhibitory level with the commercially antitumor drug: vandetanib). In addition, flow cytometry demonstrated that compound 8h induced MCF-7 cell apoptosis through a cell membrane-mediated pathway. This research highlights the therapeutic potential of novel VEGFR-2 inhibitors in treating cancers and provides a promising strategy for drug discovery.

Tumor-associated myeloid cells are one of the prominent components of solid tumors, serving as major immune regulators for the tumor microenvironment (TME) and an obstacle for immune-checkpoint blocking (ICB) therapy. However, it remains unclear how metabolic processes regulate the generation of suppressive myeloid cells in the TME. Here, we found that hematopoietic precursor cells are enriched in the tissues of several types of human cancer and can differentiate into immature myeloid cells (IMC). Tumor-infiltrating IMCs are highly immunosuppressive, glycolytic, and proliferative, as indicated by high levels of M-CSFR, Glut1, and Ki67. To elucidate the role of metabolism in regulating the generation of IMCs, we induced suppressive IMCs from hematopoietic precursor cells with GM-CSF and G-CSF in vitro. We found that the generation of suppressive IMCs was accompanied by increased glycolysis, but not affected by glucose deprivation due to alternative catabolism. Generation of IMCs relied on glutaminolysis, regardless of glucose availability. Glutamine metabolism not only supported the expansion of IMCs with glutamine-derived α-ketoglutarate but also regulated the suppressive capacity through the glutamate–NMDA receptor axis. Moreover, inhibition of glutaminase GLS1 enhanced the therapeutic efficacy of anti–PD-L1 treatment, with reduced arginase 1+ myeloid cells, increased CD8+, IFNγ+ and granzyme B+ T cells, and delayed tumor growth in an ICB-resistant mouse model. Our work identified a novel regulatory mechanism of glutamine metabolism in controlling the generation of suppressive IMCs in the TME.

A new one-dimensional organic–inorganic material, 1,5-pentanediammonium pentabromoantimonate (III) (1), exhibits a centrosymmetric-to-non-centrosymmetric symmetry breaking phase transition at 366.5 K, showing a prominent second harmonic generation (SHG) response and dielectric anomalies. The differential scanning calorimetry results indicate the phase transition is a second-order one. The variable-temperature structural analyses reveal that the space group changes from Pnma at 393 K in the high-temperature phase to P212121 at 293 K in the low-temperature phase, accompanied by the loss of a symmetry plane and inversion center. The crystal structure is composed of one-dimensional zigzag chains of corner-sharing SbBr6 octahedra and 1,5-pentanediammonium cations. The origin of the phase transition can be attributed to both the deformation of the zigzag chains and the order–disorder transition of the 1,5-pentanediammonium cations. The compound is SHG-active below the transition temperature, demonstrating its s...

In this study, we designed and synthesized eighteen podophyllotoxin-norcantharidin hybrid drugs which could exhibit more potent anti-cancer activity than the parent drugs. Through the anti-proliferation assay, the most potent anti-cancer agent was screened out, namely Q9 (IC50=0.88±0.18μM against MCF-7 cell line), and it showed lower cytotoxicity against non-cancer cells, human embryonic kidney cells (293T) (IC50=54.38±3.78μM). Additionally, based on the flow cytometry analysis result, it can cause a remarkable cell cycle arrest at G2/M phase and induce apoptosis in MCF-7 cells more significantly than podophyllotoxin or norcantharidin per se. Moreover, the expression of cell cycle relative protein CDK1 was up regulated while a protein required for mitotic initiation, Cyclin B1 was down regulated. Furthermore, according to the confocal microscopy observation results, it was shown that Q9 was a potent tubulin polymerization inhibitor and the effect is comparable to that of colchicine. For further investigation on the aforementioned mechanisms, we performed western blot experiments, thus finding the increase of the cleavage of PARP. Consistent with these new findings, molecular docking observations suggested that compound Q9 could be developed as a potential anticancer agent.

As an important enzyme in bacterial protein biosynthesis, tyrosyl-tRNA synthetase (TyrRS) has been an absorbing therapeutic target for exploring novel antibacterial agents. A series of metronidazole-based antibacterial agents has been synthesized and identified as TyrRS inhibitors with low cytotoxicity and significant antibacterial activity, especially against Gram-negative organisms. Of the compounds obtained, 4f is the most potent agent which inhibited the growth of Pseudomonas aeruginosa ATCC 13525 (MIC = 0.98 μg/mL) and exhibited TryRS inhibitory activity (IC50 = 0.92 μm). Docking simulation was performed to further understand its potency. Membrane-mediated apoptosis in P. aeruginosa was verified by flow cytometry.