Iron-catalyzed fluoroalkylative alkylsulfonylation of alkenes via radical-anion relay.

Transition metal-catalyzed reductive difunctionalization of alkenes with alkyl halides is a powerful method for upgrading commodity chemicals into densely functionalized molecules. However, super stoichiometric amounts of metal reductant and the requirement of installing a directing group into alkenes to suppress the inherent ß-H elimination bring great limitations to this type of reaction. We demonstrate herein that the difunctionalization of alkenes with two different alkyl halides is accessible via a radical-anion relay with Na2S2O4 as both reductant and sulfone-source. The Na2S2O4 together with the electron-shuttle catalyst is crucial to divert the mechanistic pathway toward the formation of alkyl sulfone anion instead of the previously reported alkylmetal intermediates. Mechanistic studies allow the identification of carbon-centered alkyl radical and sulfur-centered alkyl sulfone radical, which are in equilibrium via capture or extrusion of SO2 and could be converted to alkyl sulfone anion accelerated by iron electron-shuttle catalysis, leading to the observed high chemoselectivity.

Development and validation of medical adhesive-related skin injury risk assessment scale at peripherally inserted central catheter insertion site in oncology patients.

AIMS AND OBJECTIVES: To construct a risk assessment scale for medical adhesive-related skin injuries (MARSI) at the peripherally inserted central catheter (PICC) insertion site in oncology patients and test its reliability and validity. DESIGN: The STARD 2015 statement guided this study. METHODS: Literature research and a modified Delphi method were adopted in this study. A total of 31 experts participated in two rounds of consultation to build the assessment scale. A convenient sampling method was used to select 195 oncology patients at the PICC clinic from January to June 2022. Inter-rater reliability was used to test the reliability of the scale. Validity was evaluated using the content validity index (CVI) and predictive validity. RESULTS: After the two rounds of consultation, the assessment scale with five dimensions and 13 primary entries and 36 secondary entries was developed, and the expert authority coefficients for both were 0.90. The inter-rater reliability was 0.968. The CVIs of the items ranged from 0.83 to 1.00. The area under the subject's work characteristic curve was 0.757, and the sensitivity and specificity of the scale were 80.0% and 65.6%, respectively, at a cutoff score of 15.5.

Novel dual CAFs and tumour cell targeting pH and ROS dual sensitive micelles for targeting delivery of paclitaxel to liver cancer.

Tumour development is not only an independent event of genetic mutation and overgrowth of tumour cells but is the result of a synergistic interaction between a malignant tumour and its surrounding tumour stromal microenvironment. In this paper, we address the shortcomings of current tumour therapy by focussing on the tumour itself and the surrounding microenvironment to achieve a two-pronged targeting model. In this paper, a dual-targeting, pH/reactive oxygen species (ROS) sensitive nano-drug delivery system for tumour cells and CAFs was designed. A hyaluronic acid (HA) with CD44 receptor targeting on the surface of tumour cells was selected as the main carrier material, and a dipeptide Z-glycine-proline (ZGP) with specific targeting of fibroblast activating protein (FAP) on the surface of CAFs was modified on HA to achieve precise targeting of CAFs, open the physical barrier of tumour cells and improve the deep penetration effect of the tumour, while introducing thioketone bond and ketone condensation bond to take advantage of the highly reactive ROS and low pH microenvironment at the tumour site to achieve chemical bond breaking of nano micelles encapsulating paclitaxel (PTX), drug release, and thus drug aggregation at the tumour site and improved bioavailability of the drug.

Metabolome combined with transcriptome profiling reveals the dynamic changes in flavonoids in red and green leaves of Populus × euramericana 'Zhonghuahongye'.

Flavonoids are secondary metabolites that have economic value and are essential for health. Poplar is a model perennial woody tree that is often used to study the regulatory mechanisms of flavonoid synthesis. We used a poplar bud mutant, the red leaf poplar variety 2025 (Populus × euramericana 'Zhonghuahongye'), and green leaves as study materials and selected three stages of leaf color changes for evaluation. Phenotypic and biochemical analyses showed that the total flavonoid, polyphenol, and anthocyanin contents of red leaves were higher than those of green leaves in the first stage, and the young and tender leaves of the red leaf variety had higher antioxidant activity. The analyses of widely targeted metabolites identified a total of 273 flavonoid metabolites (114 flavones, 41 flavonols, 34 flavonoids, 25 flavanones, 21 anthocyanins, 18 polyphenols, 15 isoflavones, and 5 proanthocyanidins). The greatest difference among the metabolites was found in the first stage. Most flavonoids accumulated in red leaves, and eight anthocyanin compounds contributed to red leaf coloration. A comprehensive metabolomic analysis based on RNA-seq showed that most genes in the flavonoid and anthocyanin biosynthetic pathways were differentially expressed in the two types of leaves. The flavonoid synthesis genes CHS (chalcone synthase gene), FLS (flavonol synthase gene), ANS (anthocyanidin synthase gene), and proanthocyanidin synthesis gene LAR (leucoanthocyanidin reductase gene) might play key roles in the differences in flavonoid metabolism. A correlation analysis of core metabolites and genes revealed several candidate regulators of flavonoid and anthocyanin biosynthesis, including five MYB (MYB domain), three bHLH (basic helix-loop-helix), and HY5 (elongated hypocotyl 5) transcription factors. This study provides a reference for the identification and utilization of flavonoid bioactive components in red-leaf poplar and improves the understanding of the differences in metabolism and gene expression between red and green leaves at different developmental stages.

Dextran sulfate-based MMP-2 enzyme-sensitive SR-A receptor targeting nanomicelles for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is an ordinarily occurring autoimmune disease with systemic inflammatory. Targeted drug delivery systems have many successful applications in the treatment of rheumatoid arthritis. In order to develop nanoparticles for targeted delivery of Celastrol (Cel) to rheumatoid arthritis and specific drug release, the dextran sulfate (DS) was modified as the targeting molecular by binding to the scavenger receptor of macrophage. The dextran-sulfate-PVGLIG-celastrol (DS-PVGLIG-Cel), named DPC, amphiphilic polymeric prodrug was synthesized and characterized. The resulting DPC@Cel micelles had the average size of 189.9 nm. Moreover, the micelles had ultrahigh entrapment efficiency (about 44.04%) and zeta potential of -11.91 mV. In the in vitro release study, due to the excessive production of matrix metalloproteinase-2 (MMP-2) at the inflammatory joint, the MMP-2 reactive peptide was used to crack in the inflammatory microenvironment to accelerate the release of Cel. The results have shown that the nanoparticles can effectively deliver Cel to activated macrophages and significantly improve the bioavailability. In vivo experiments showed that DPC@Cel have better anti-rheumatoid arthritis effects and lower systemic toxicity than free Cel. This study provided a new therapeutic strategy for the treatment of RA.

Direct Synthesis of N-Difluoromethyl-2-pyridones from Pyridines.

A novel method for the synthesis of N-difluoromethyl-2-pyridones was described. This protocol enables the synthesis of N-difluoromethyl-2-pyridones from readily available pyridines using mild reaction conditions that are compatible with a wide range of functional groups. The preliminary mechanistic study revealed that N-difluoromethylpyridinium salts were the key intermediates to complete this conversion.

Novel Chinese Angelica Polysaccharide Biomimetic Nanomedicine to Curcumin Delivery for Hepatocellular Carcinoma Treatment and Immunomodulatory Effect.

BACKGROUND: Using natural polysaccharides from Traditional Chinese Medicine as nanodrug delivery systems have considerable potential for tumor diagnostics and therapeutics. PURPOSE: On the basis of targeted therapy and combining the advantages of natural polysaccharides (angelica polysaccharide, APS) and natural Chinese medicine (curcumin, Cur) to design functionalized nanoparticles to improve the therapeutic through cell membrane encapsulation and immunotherapy. STUDY DESIGN AND METHODS: Cur-loaded, glycyrrhetic acid (GA)-APS-disulfide bond (DTA)-Cur nanomicelle (GACS-Cur), which were prepared by the dialysis method. GACS-Cur was encapsulated with the membranes from red blood cells (RBCm) termed GACS-Cur@RBCm, which were prepared by the principle of extrusion using a miniature extruder. The developed formulations were subjected to various in vitro and in vivo evaluation tests. RESULTS: The resulting APS nanocarriers supported a favorable drug-loading capacity, biocompatibility, and enhanced synergistic anti-hepatoma effects both in vitro and in vivo. After administration in mice, in vivo imaging results showed that the GACS-Cur and RBCm-coated groups had an obvious stronger tumor tissue targeting ability than the control treatment groups. Additionally, the immunomodulatory effect increased IL-12, TNF-α and IFN-γ expression and CD8+ T cell infiltration (1.9-fold) than that of the saline group. Notably, in comparison with hyaluronic acid (HA) nanocarriers, APS nanocarriers possess higher anti-hepatoma efficiency and targeting capabilities and, thus, should be further studied for a wide range of anti-cancer applications. CONCLUSION: Our data demonstrated that APS nanocarriers encapsulated with erythrocyte membrane mighty be a promising clinical method in the development of efficacy, safety and targeting of liver cancer therapy.

Synthesis of Indolizines from Pyridinium Salts and Ethyl Bromodifluoroacetate.

Here we present a novel annulation of pyridinium salts with BrCF2CO2Et to access the indolizine derivatives with high efficiency. The α substitution of pyridine plays a key role in determining the reaction pathways. Various types of indolizines can be conveniently accessed from easily available pyridinium salts under mild and simple reaction conditions.

In vitro/vivo evaluation of novel mitochondrial targeting charge-reversal polysaccharide-based antitumor nanoparticle.

Mitochondrial targeting drug delivery systems have made unprecedented progress in tumor treatment. Nevertheless, the stability of systemic circulation and the effectiveness of tumor accumulation are the basis for achieving tumor subcellular targeting. This study aims to overcome the biological barrier while improving the mitochondria-targeted effect of nanoparticles based on natural polysaccharides. Novel polysaccharide-based nanoparticles, with tumor microenvironment-responsive charge-reversal and mitochondrial targeting abilities, were prepared in our study. Curcumin (Cur) was loaded into the core of a positively charged chitosan oligosaccharide (COS) derivative with mitochondrial targeting ability, and a negatively charged shell based on angelica sinensis polysaccharide (AS) derivative was wrapped in the surface of the core. At the same time, the pH-sensitive borate ester bond was formed between the shell and the core. In vitro experiments showed that mitochondrial-targeted core-shell nanoparticles achieved charge-reversal and release more Cur in the acidic tumor microenvironment. After entering into the tumor cells, the lysosomes escape was effectively realized, and more Cur was transmitted to the mitochondria. This process led to the enhancement of the cytotoxicity, the reduction of the mitochondrial membrane potential and the activation of the apoptotic pathway. The results of in vivo experiments showed that the core-shell nanoparticles efficiently delivered the drug to the tumor site and significantly prolonged the retention time of the drug in the tumor tissue. At the same time, it had excellent antitumor activity and in vivo safety for tumor-bearing nude mice.

Novel dual ROS-sensitive and CD44 receptor targeting nanomicelles based on oligomeric hyaluronic acid for the efficient therapy of atherosclerosis.

Although the clinical usage of drugs administration was raising, the application of nanoparticles encapsulating the hydrophobic drugs with plummy efficiency was very scarce for atherosclerosis (AS) treatment. In this work, a novel dual ROS-sensitive and CD44 receptors targeting amphiphilic carrier material, oligomeric hyaluronic acid-2'-[propane-2,2-diyllbls (thio)] diacetic acl-hydroxymethylferrocene (oHA-TKL-Fc), named HASF, was synthesized and characterized by 1H-NMR spectra. Then, we combined curcumin (Cur) with HASF into nano-micelles (HASF@Cur micelles) by self-assembling method. The resulting HASF@Cur micelles had the average size of 150.8 nm and zeta potential of -35.04 mV to maintain the will-defined spheroidal structure and stability. Importantly, the HASF@Cur micelles had ultrahigh entrapment efficiency (about 51.41 %). Moreover, in vitro release study, Cur release from HASF@Cur micelles was effective in the reactive oxygen species (ROS) condition, and the release rate was interrelated with the concentration of hydrogen peroxide (H2O2). Further, fluorescence imaging showed that the HASF@Cur micelles could more selective access to Raw 264.7 cells than free Cur via oHA-receptor mediated endocytosis. The MTT assay attested the safety of amphiphilic carrier material HASF. Additionally, the results of in vivo Oil red O lipid staining studies showed that the lesion area of the aorta was reduced to 47.3±3.4 % with HASF@Cur micelles, compared with the lesion area of Cur group (63.2±2.7 %), HASF@Cur micelles had the more remarkable effect in reducing lesion area (*P < 0.05). Consequently, the novel dual ROS-sensitive and CD44 receptors targeting drug delivery system would become a promising strategy for atherosclerosis.

Synthesis, Characterization, and Evaluation of Redox-Sensitive Chitosan Oligosaccharide Nanoparticles Coated with Phycocyanin for Drug Delivery.

In this paper, a type of phycocyanin (PC)-functionalized and curcumin (CUR)-loaded biotin-chitosan oligosaccharide-dithiodipropionic acid-curcumin (BCSC) nanoparticles, called CUR-BCSC@PCs, were designed to enhance the biocompatibility of CUR. The structure of BCSC was confirmed using 1H-NMR. In CUR-BCSC@PCs with an average hydrodynamic diameter of 160.3 ± 9.0 nm, the biomimetic protein corona gave the nanoparticles excellent stability and the potential to avoid protein adsorption in blood circulation. The in vitro release experiment verified that CUR-BCSC@PCs with redox responsive shells were sensitive to high concentrations of glutathione. In addition, CUR-BCSC@PCs were effective at increasing the inhibitory activity on the proliferation of A549 cells by enhancing the intracellular uptake of CUR. These results indicated that CUR-BCSC@PCs have great application prospects in cancer therapy as effective drug delivery carriers.

Novel mitochondrial targeting charge-reversal polysaccharide hybrid shell/core nanoparticles for prolonged systemic circulation and antitumor drug delivery.

Stability in systemic circulation, effective tumor accumulation, and the subsequent crucial subcellular targeting are significant elements that maximize the therapeutic efficacy of a drug. Accordingly, novel nanoparticles based on polysaccharides that simultaneously presented prolonged systemic circulation and mitochondrial-targeted drug release were synthesized. First, the mitochondrial-targeted polymer, 3,4-dihydroxyphenyl propionic acid-chitosan oligosaccharide-dithiodipropionic acid-berberine (DHPA-CDB), was synthesized, which was used to form self-assembled curcumin (Cur)-encapsulated cationic micelles (DHPA-CDB/Cur). Negatively charged oligomeric hyaluronic acid-3-carboxyphenylboronic acid (oHA-PBA), a ligand to sialic acid and CD44, was further added to the surface of the preformed DHPA-CDB/Cur core to shield the positive charges and to prolong blood persistence. oHA-PBA@DHPA-CDB/Cur formed a covalent polyplex of oHA-PBA and DHPA-CDB/Cur via the pH-responsive borate ester bond between PBA and DHPA. The mildly acidic tumor environment led to the degradation of borate ester bonds, thereby realizing the exposure of the cationic micelles and causing a charge reversal from -19.47 to +12.01 mV, to promote cell internalization and mitochondrial localization. Compared with micelles without the oHA-PBA modification, the prepared oHA-PBA@DHPA-CDB/Cur showed enhanced cytotoxicity to PANC-1 cells and greater cellular uptake via receptor-mediated endocytosis. oHA-PBA@DHPA-CDB/Cur was effectively targeted to the mitochondria, which triggered mitochondrial membrane depolarization. In mice xenografted with PANC-1 cells, compared with control mice, oHA-PBA@DHPA-CDB/Cur resulted in more effective tumor suppression and greater biosafety with preferential accumulation in the tumor tissue. Thus, the long-circulating oHA-PBA@DHPA-CDB/Cur, with mitochondrial targeting and tumor environment charge-reversal capabilities, was shown to be an excellent candidate for subcellular-specific drug delivery.

Development of dual-targeted nano-dandelion based on an oligomeric hyaluronic acid polymer targeting tumor-associated macrophages for combination therapy of non-small cell lung cancer.

In this study, the novel carrier materials were screened to structure targeting nano-micelles (named 'nano-dandelion') for synchronous delivery of curcumin (Cur) and baicalin (Bai), which could effectively overcome the tumor resistance. Mannose (Man) was found to bind better to CD206 receptors on the surface of tumor-associated macrophages (TAMs), thereby increasing the number of nano-dandelion engulfed by TAMs. Furthermore, oligomeric hyaluronic acid (oHA) was able to target CD44 receptors, resulting in recruitment of a higher number of nano-dandelion to locate and engulf tumor cells. The disulfide bond (S-S) in 3,3'-dithiodipropionic acid (DA) could be broken by the high concentration of glutathione (GSH) in the tumor microenvironment (TME). Based on this, we selected DA to connect hydrophobic fragments (quercetin, Que) and oHA. A reduction-sensitive amphiphilic carrier material, quercetin-dithiodipropionic acid-oligomeric hyaluronic acid-mannose-ferulic acid (Que-S-S-oHA-Man-FA; QHMF) was fabricated and synthesized by 1H NMR. Next, QHMF self-assembled into nano-dandelion, i.e. encapsulated Cur and Bai in water. Critical experimental conditions in the preparation process of nano-dandelion that could affect its final properties were explored. Nano-dandelion with a small particle size (121.0 ± 15 nm) and good normal distribution (PI = 0.129) could easily enter tumor tissue through vascular barrier. In addition, nano-dandelion with a suitable surface potential (-20.33 ± 4.02 mV) could remain stable for a long duration. Furthermore, good cellular penetration and tumor cytotoxicity of nano-dandelion were demonstrated through in vitro cellular studies. Finally, effective antitumor activity and reduced side effects were confirmed through in vivo antitumor experiments in A549 tumor-bearing nude mice.

Novel multifunctional triple folic acid, biotin and CD44 targeting pH-sensitive nano-actiniaes for breast cancer combinational therapy.

In this study, novel multifunctional folic acid, biotin, and CD44 receptors targeted and pH-sensitive "nano-actiniaes" were fabricated with icariin (ICA) and curcumin (Cur) as loaded model drugs for breast cancer therapy. The newly synthesized polymer oligomeric hyaluronic acid-hydrazone bond-folic acid-biotin (Bio-oHA-Hyd-FA) was characterized by 1H NMR spectrogram (proton nuclear magnetic resonance). The obtained drug carrier Bio-oHA-Hyd-FA self-assembled into nanomicelles, named as "nano-actiniaes", in aqueous media with hydrodynamic diameter of 162.7 ± 5 nm. The size, surface zeta potential, and morphology of the "nano-actiniaes" were observed via TEM. The in vitro release experiment indicated that much more encapsulated icariin (ICA) and curcumin (Cur) were released from the Bio-oHA-Hyd-FA micelles (nano-actiniaes) in the acidic environment. Additionally, the cytotoxicity research demonstrated that the Bio-oHA-Hyd-FA carrier material was completely nontoxic, and the ICA&Cur "nano-actiniaes" had greater cytotoxicity compared with other control groups. In addition, the "nano-actiniaes" were found to significantly inhibit cancer cell invasion by Transwell assay. Moreover, in vivo evaluation of anti-tumor effect illustrated that the ICA and Cur "nano-actiniaes" possessed inhibitory effect on tumors. Consequently, the multi-targeted pH-sensitive "nano-actiniaes" can realize significant tumor targeting and effectively inhibit tumor growth.

Tunability in the Optical and Electronic Properties of ZnSe Microspheres via Ag and Mn Doping.

ZnSe microspheres with various Ag and Mn doping levels were prepared by the hydrothermal method using Zn(NO3)2·6H2O and Na2SeO3 as precursors and N2H4·H2O as the reducing agent. The effects of Ag and Mn doping on the phase composition, morphology, and optical and electrical properties of the final products were systematically investigated. A remarkable change in morphology from microspheres with a cubic sphalerite structure to rodlike structure was observed by Ag doping, while the pristine structure was nearly unchanged via Mn doping. Moreover, the band gap of ZnSe microspheres could be tunable in a broad range via controlling the Ag and Mn doping concentration, and ZnSe with high electrical properties could be obtained by doping with an appropriate concentration. The first-principle plane-wave method was carried out to explain the above mentioned experimental results.

An effective strategy to tune supramolecular interaction via a spiro-bridged spacer in oligothiophene-S,S-dioxides and their anomalous photoluminescent behavior.

[structure: see text] We demonstrate that incorporating nonplanar spiro-bridged structures is an effective strategy for tuning supramolecular interactions of optoelectronic functional moieties. In the model compounds spiro-bridged oligothiophene-S,S-dioxides (BSiSDTFO), unusual dimers constructed by spiro-bridged spacers do not form excimers, which is confirmed by crystallographic data and fluorescent emission spectra.

Facile synthesis of complicated 9,9-diarylfluorenes based on BF3.Et2O-mediated Friedel-Crafts reaction.

[reaction: see text] BF3.OEt2-mediated Friedel-Crafts reaction of 9-phenyl-fluoren-9-ol with electron-rich aromatic substrates to prepare a new family of complicated 9,9-diarylfluorenes is described. The 9,9-diarylfluorenes tethered with various functional substituents, e.g., bulky spiro units, hole-transporting moieties, and fluorescent dyes, will be promising building blocks for the construction of optoelectronic materials.

Unexpected one-pot method to synthesize spiro[fluorene-9,9'-xanthene] building blocks for blue-light-emitting materials.

[reaction: see text] An unexpected one-pot synthetic approach toward spiro[fluorene-9,9'-xanthene] (SFX) under excessive MeSO(3)H conditions has been developed. The key step involves a thermodynamically controlled cyclization reaction. Blue-light-emitting materials based on SFX building blocks that exhibit high thermal stability have also been synthesized.

Novel h-shaped persistent architecture based on a dispiro building block system.

[structure: see text] A novel dispiro building block, dispiro[fluorene-9,5'(7'H)-diindeno[2,1-b:1',2'-d]thiophene-7',9' '-fluorene], and its two derivatives, TBP-DSFDITF and TDOF-DSFDITF, were designed and synthesized. Because of the rigidity and orthogonality of the spiro structure, TBP-DSFDITF exhibits a well-defined H-shaped architecture, which consists of two ter(biphenyls) as the arms of the H-shape and 3,4-diphenylthiophene as the rung, connecting via completely rigid dispiro linkages with two sp(3) carbon atoms.