Photocatalytic Aerobic Cyclization of N-Propargylamides Enabled by Selenium-π-Acid Catalysis.

A dual catalytic approach combining photocatalyst and selenium-π-acid synergy has been used to cyclized of N-propargylamides. This method offers readily access to oxazole aldehydes under chemical oxidant-free conditions with low catalyst loadings, where air acts as a terminal and gratuitous oxidant. The reaction is demonstrated with a range of substrates, including aryl and alkyl propargyl amides, and in the late-stage functionalization of several amide-containing drug molecules. Mechanistic studies suggest that the acridinium catalyst is able to oxidize diselenide and generate singlet oxygen (1 O2 ), which is responsible for this transformation.

Oxidative Three-Component Selenofunctionalization of Alkenes: Convenient Access to Vicinally Functionalized Selenides.

Three-component selenofunctionalization processes of olefins, diselenides and sulfonamides, water, alcohols, or acids utilizing 1-fluoropyridinium triflate (FP-OTf) as a reaction promoter are reported. Under the optimal conditions, a broad range of vicinally functionalized selenide derivatives was accessible with high yields and excellent functional group compatibilities. Mechanistic studies revealed that the FP-OTf played a key role in this selenofunctionalization process.

An integrated approach of high-performance liquid chromatography-mass spectrometry-based chemical profiling, network pharmacology, and molecular docking to reveal the potential mechanisms of Qishen Gubiao granules for treating coronavirus disease 2019.

Qishen Gubiao granules, a traditional Chinese medicine preparation composed of nine herbs, have been widely used to prevent and treat coronavirus disease 2019 with good clinical efficacy. In the present study, an integrated strategy based on chemical profiling followed by network pharmacology and molecular docking was employed, to explore the active components and potential molecular mechanisms of Qishen Gubiao granules in the therapy of coronavirus disease 2019. Using the ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry technique, a total of 186 ingredients corresponding to eight structure types in Qishen Gubiao preparation were identified or structurally annotated with the elucidation of the fragmentation pathways in the typical compounds. The network pharmacology analysis screened 28 key compounds including quercetin, apigenin, scutellarein, luteolin and naringenin acting on 31 key targets, which possibly modulated signal pathways associated with immune and inflammatory responses in the treatment of coronavirus disease 2019. The molecular docking results observed that the top 5 core compounds had a high affinity for angiotensin-converting enzyme 2 and 3-chymotrypsin-like protease. This study proposed a reliable and feasible approach for elucidating the multi-components, multi-targets, and multi-pathways intervention mechanism of Qishen Gubiao granules against coronavirus disease 2019, providing a scientific basis for its further quality evaluation and clinical application.

Preparation and Biomedical Applications of Cucurbit[n]uril-Based Supramolecular Hydrogels.

The cucurbit[n]uril supramolecular hydrogels are driven by weak intermolecular interactions, of which exhibit good stimuli responsiveness and excellent self-healing properties. According to the composition of the gelling factor, supramolecular hydrogels comprise Q[n]-cross-linked small molecules and Q[n]-cross-linked polymers. According to different driving forces, hydrogels are driven by the outer-surface interaction, the host-guest inclusion interaction, and the host-guest exclusion interaction. Host-guest interactions are widely used in the construction of self-healing hydrogels, which can spontaneously recover after being damaged, thereby prolonging their service life. The smart Q[n]s-based supramolecular hydrogel composed is a kind of adjustable and low-toxicity soft material. By designing the structure of the hydrogel or modifying the fluorescent properties, etc., it can be widely used in biomedicine. In this review, we mainly focus on the preparation of Q[n]-based hydrogels and their biomedical applications including cell encapsulation for biocatalysis, biosensors for high sensitivity, 3D printing for potential tissue engineering, drug release for sustained delivery, and interfacial adhesion for self-healing materials. In addition, we also presented the current challenges and prospects in this field.

N-Fluorobenzenesulfonimide-Mediated Intermolecular Carboselenenylation of Olefins with Aromatics and Diselenides.

Intermolecular carboselenenylation of easily accessible alkenes by utilizing diselenides and N-fluorobenzenesulfonimide (NFSI) under metal-free and mild conditions is reported. Preliminary mechanistic studies indicate that the oxidation of diselenide by NFSI through a single-electron-transfer process produces an active selenenyl cationic radical species that initiates the intermolecular carboselenenylation of olefins, forming key Se-C and C-C bonds. Under optimized conditions, a broad spectrum of functionally and structurally diverse selenoether derivatives with promising yields is accessed with a very high functional group tolerance.

Time-economical synthesis of selenofunctionalized heterocycles via I2O5-mediated selenylative heterocyclization.

A time-economical and robust synthesis of various selenofunctionalized heterocycles was accomplished via I2O5-mediated selenocyclizations of olefins with diselenides. Using this method, 116 selenomethyl-substituted heterocycles were synthesized with up to 97% isolated yield in minutes. Additional features of this new protocol include the use of an inorganic oxidant, mild conditions, and easy operation. Preliminary investigations suggest that the transformation operates through selenenyl iodide-induced electrophilic cyclization.

Iodine pentoxide-mediated oxidative selenation and seleno/thiocyanation of electron-rich arenes.

A simple and efficient method for the regioselective selenation of electron-rich arenes by employing non-metal inorganic iodine pentoxide (I2O5) as a reaction promoter under ambient conditions has been developed. The present protocol showed broad functional group tolerance and easy-to-operate and time-economical features. Additionally, this protocol also allows access to 3-seleno and 3-thiocyanoindoles by the use of readily available selenocyanate and thiocyanate salts. A mechanistic study indicated that the transformation operated through selenenyl iodide-induced electrophilic substitution processes.

Psychological experience and social reintegration needs of young stroke patients: a systematic review and meta-aggregation of qualitative studies.

BACKGROUND: The visible physical dysfunction and invisible psychological effects after stroke prevent young patients from returning to their pre-stroke roles and social activities. PURPOSE/AIM: To comprehensively analyze the psychological experience and social reintegration needs of young stroke patients, which may be beneficial for improving quality of life and social reintegration after stroke. METHODS: We conducted a comprehensive literature search of 10 databases. The screening and quality assessment of the included articles were performed by the Qualitative Assessment and Review Instrument (QARI). Meta-aggregation was conducted to synthesize the findings of the included studies. We summarized the certainty of confidence using the Confidence in Evidence from Reviews of Qualitative Research (CERQual) approach. RESULTS: A total of 5506 studies were screened, of which 12 were included. Data synthesis suggested two new themes: (a) the self-growth process from denial of stroke to accepting stroke (high CERQual confidence), and (b) desire to regain pre-stroke normality, but having difficulty in the social reintegration process (high CERQual confidence). CONCLUSION: Stroke, as a traumatic event, disrupts the life structure of young patients, and their needs of reintegration are not adequately considered. Interventions based on the principle of individuation should focus on this issue to restore continuity in life after stroke.

A step towards sustainable environment in China: The role of eco-innovation renewable energy and environmental taxes.

In the contemporary environment, developing countries are more focused on how economic factors can reasonably utilize technological advancement and carbon neutrality target as effective mechanisms in achieving sustainable production and consumption patterns. The effort to attain carbon neutrality target on natural environment in terms of lower carbon emission (CO2), haze pollution, and greenhouse gas (GHG) requires measures like the usage of non-renewable energy, ecological innovation, and environmental taxes. In doing so, this study considers the sustainability of China's natural environment in terms of CO2 emission, haze pollution through PM2.5, and greenhouse gas emission as well as factors like ecological innovation (ECO), environmental taxes (ERT), renewable energy, and globalization as the key determinants. The Quantile ARDL approach was used to examine both long- and short-run relationships between the explanatory and outcome variables. The results confirmed that there is a significant and negative impact of ECO, renewable energy, and ERT on CO2 emission in the region of China under different quantiles. Whereas, the globalization factor was observed as positively and significantly linked with CO2 emission but only for the higher quantiles. The long-run estimation further showed that ECO, renewable energy, and ERT can significantly help to decrease haze pollution in terms of PM2.5 in China. Furthermore, QARDL also confirms the negative and long-run estimation between the ECO, REN, and ERT, whereas globalization is causing more GHG in China, subsequently creating more environmental sustainability issues. Thus, it is concluded that effective innovation, renewable energy consumption, and environmental taxes reduce carbon emission while globalization increases the carbon emission in the country.

Salidroside protects against ventilation-induced lung injury by inhibiting the expression of matrix metalloproteinase-9.

CONTEXT: Salidroside, a compound extracted from Rhodiola rosea L. (Crassulaceae), possesses many beneficial pathological effects. OBJECTIVE: To explore the effect of salidroside on ventilator-induced lung endothelial dysfunction in vivo and in vitro. MATERIALS AND METHODS: In vivo, male ICR mice were divided into sham, ventilation, salidroside, and ventilation plus salidroside groups. The mice were ventilated for 4 h, salidroside (50 mg/kg) was administrated intraperitoneally before ventilation, dexamethasone (Dex) (5 mg/kg) was used as a positive control. In vitro, mouse lung vascular endothelial cells (MLVECs) were treated with salidroside, MMP-9 siRNA, and BAY11-7082 (10 µM), and then exposed to cyclic stretch for 4 h. Afterward, lung tissues and MLVECs were collected for further analysis. RESULTS: Salidroside pre-treatment significantly reversed the expression of vascular endothelial cadherin (VE-cadherin) and zonula occluden-1 (ZO-1) proteins in cyclic stretch-treated MLVECs (0.46 ± 0.09 vs. 0.80 ± 0.14, 0.49 ± 0.05 vs. 0.88 ± 0.08) and ventilated lung tissues (0.56 ± 0.06 vs. 0.83 ± 0.46, 0.49 ± 0.08 vs. 0.80 ± 0.12). The results further indicated that salidroside inhibited the expression of matrix metalloproteinase-9 (MMP-9), whereas knockdown of its expression restored the expression levels of VE-cadherin (0.37 ± 0.08 vs. 0.85 ± 0.74) and ZO-1 (0.48 ± 0.08 vs. 0.81 ± 0.11) in stretched MLVECs. Meanwhile, salidroside inhibited the NF-κB signalling pathway and alleviated lung injury. CONCLUSIONS: Salidroside protected against stretch-induced endothelial barrier function, improving lung injury after ventilation. Thus, salidroside may be a promising therapeutic agent for patients with MV-induced lung injury.

Host-guest interaction and properties of cucurbit[8]uril with chloramphenicol.

The interaction between cucurbit[8]uril (Q[8]) and chloramphenicol (CPE) was investigated using single-crystal X-ray diffraction spectroscopy, isothermal titration calorimetry (ITC) and UV-vis, NMR and IR spectroscopy. The effects of Q[8] on the stability, in vitro release performance and antibacterial activity of CPE were also studied. The results showed that CPE and Q[8] formed a 1:1 inclusion complex (CPE@Q[8]) with an inclusion constant of 5.474 × 105 L/mol. The intervention of Q[8] did not affect the stability of CPE, but obviously reduced the release rate of CPE in artificial gastric and intestinal juice; Q[8] has a slow-release effect on CPE. The antibacterial results showed that the minimum inhibitory concentration (MIC) of CPE and CPE@Q[8] toward Escherichia coli (E. coli) was 1.5 × 10-3 and 1.0 × 10-3 mol/L, respectively, and toward Staphylococcus aureus (S. aureus), the MIC was 2.0 × 10-3 mol/L for both CPE and CPE@Q[8]. Therefore, Q[8] enhanced the inhibitory activity of CPE against E. coli.

[Association of copy number of SMN1 and SMN2 with clinical phenotypes in children with spinal muscular atrophy].

OBJECTIVE: To study the association of copy number of SMN1 and SMN2 with clinical phenotypes in children with spinal muscular atrophy (SMA). METHODS: A total of 45 children with SMA were enrolled. Multiplex ligation-dependent probe amplification was used to measure the gene copy numbers of SMN1 and SMN2. The association of copy number of SMN1 and SMN2 with clinical phenotypes was analyzed. RESULTS: Of the 45 children with SMA, 42 (93%) had a homozygous deletion of SMN1 exons 7 and 8, and 3 (7%) had a deletion of SMN1 exon 7 alone. No association was found between SMA clinical types and the deletion types of SMN1 exons 7 and 8 (P>0.05). There was a significant difference in the distribution of SMN2 gene copy numbers between the children with SMA and the healthy children (P<0.05). The children with SMA usually had two or three copies of SMN2 gene, while the healthy children usually had one or two copies of SMN2 gene. There was a significant difference in the distribution of SMN2 copy numbers among the children with different SMA clinical types (P<0.05). The children with two copies of SMN2 gene had a significantly lower age of onset than those with three or four copies. Most of the children with type I SMA had two or three copies of SMN2 gene. Most of the children with type II SMA had three copies of SMN2 gene. Most of the children with type III SMA had three or four copies of SMN2 gene. Children with a higher copy number of SMN2 gene tended to have an older age of onset and better motor function and clinical outcome, and there was a significant association between SMN2 gene copy number and clinical outcome (P<0.05). CONCLUSIONS: The SMN2 gene can reduce the severity of SMA via the dosage compensation effect. SMN2 copy number is associated with the phenotype of SMA, and therefore, it can be used to predict disease severity.

Coordination and Supramolecular Assemblies of Fully Substituted Cyclopentanocucurbit[6]uril with Lanthanide Cations in the Presence of Tetrachlorozincate Anions, and Their Potential Applications.

Coordination and supramolecular assemblies of a fully substituted cyclopentanocucurbit[6]uril (CyP6Q[6]) with a series of lanthanide cations (Ln3+) have been investigated in the presence of tetrachlorozincate anion ([ZnCl4]2-). X-ray single-crystal diffraction analysis has revealed that the interaction of CyP6Q[6] and a series of Ln3+cations unexpectedly results in the formation of at least seven different CyP6Q[6]-based coordination complex adduct and supramolecular assemblies groups, including with (1) La3+, Ce3+cations; (2) Pr3+, Nd3+cations; (3) Eu3+, Gd3+, Tb3+, Dy3+ with P1̅ or P1 space group, in which CyP6Q[6] molecules coordinate alternatively with Ln3+cations and form linear coordination polymers; (4) CyP6Q[6] molecules interact alternatively with [Ho(H2O)8]3+ aqueous complexes and form linear supramolecular chains; CyP6Q[6] molecules can assemble two different Ln3+ free porous supramolecular assemblies from CyP6Q[6]-Ln(NO3)3-ZnCl2-HCl systems, Ln = Tm, Yb, and Lu; however, no solid crystals were obtained from system containing Er3+cation. Thus, these differences could lead CyP6Q[6] to be useful in not only the isolation of lighter lanthanides from their heavier lanthanides but also special selectivity for different volatile organic compounds.

A New Member of the Inverted Cucurbit[n]uril Family.

A new inverted cucurbituril, namely inverted hexamethylcucurbit[3,3]uril (iMe6 Q[3,3]), has been isolated and characterized. It incorporates a single inverted un-substituted glycoluril unit oriented towards the interior of the cavity, shows good solubility in water and organic solvents (DMSO), and exhibits different selectivity for guests to those of iQ[6] and other known Q[6]s.

Protective Effects of Hydrogen-Rich Saline Against Lipopolysaccharide-Induced Alveolar Epithelial-to-Mesenchymal Transition and Pulmonary Fibrosis.

BACKGROUND Fibrotic change is one of the important reasons for the poor prognosis of patients with acute respiratory distress syndrome (ARDS). The present study investigated the effects of hydrogen-rich saline, a selective hydroxyl radical scavenger, on lipopolysaccharide (LPS)-induced pulmonary fibrosis. MATERIAL AND METHODS Male ICR mice were divided randomly into 5 groups: Control, LPS-treated plus vehicle treatment, and LPS-treated plus hydrogen-rich saline (2.5, 5, or 10 ml/kg) treatment. Twenty-eight days later, fibrosis was assessed by determination of collagen deposition, hydroxyproline, and type I collagen levels. Development of epithelial-to-mesenchymal transition (EMT) was identified by examining protein expressions of E-cadherin and α-smooth muscle actin (α-SMA). Transforming growth factor (TGF)-ß1 content, total antioxidant capacity (T-AOC), malondialdehyde (MDA) content, catalase (CAT), and superoxide dismutase (SOD) activity were determined. RESULTS Mice exhibited increases in collagen deposition, hydroxyproline, type I collagen contents, and TGF-ß1 production in lung tissues after LPS treatment. LPS-induced lung fibrosis was associated with increased expression of α-SMA, as well as decreased expression of E-cadherin. In addition, LPS treatment increased MDA levels but decreased T-AOC, CAT, and SOD activities in lung tissues, indicating that LPS induced pulmonary oxidative stress. Hydrogen-rich saline treatment at doses of 2.5, 5, or 10 ml/kg significantly attenuated LPS-induced pulmonary fibrosis. LPS-induced loss of E-cadherin in lung tissues was largely reversed, whereas the acquisition of α-SMA was dramatically decreased by hydrogen-rich saline treatment. In addition, hydrogen-rich saline treatment significantly attenuated LPS-induced oxidative stress. CONCLUSIONS Hydrogen-rich saline may protect against LPS-induced EMT and pulmonary fibrosis through suppressing oxidative stress.

miR-27a is up regulated and promotes inflammatory response in sepsis.

MicroRNAs (miRNAs) are short, non-coding RNAs that regulate the expression of multiple target genes. Dysregulation of miRNAs is common in sepsis. Through microRNA microarray and qRT-PCR we found that the levels of miR-27a, miR-153 and miR-143 are up regulated, while let-7a, miR-218 and miR-129-5p are down regulated in lungs of septic mice. Knocking down of miR-27a down regulates expression levels of TNF-α and IL-6 significantly via reducing the phosphorylation level of NF-κB p65 and inhibiting its DNA binding activity. Furthermore, neutralisation of miR-27a up regulates PPARγ level, down regulates TNF-α expression, relieves pulmonary inflammation and promotes survival of septic mice, which demonstrates that miR-27a plays an important role in regulating inflammatory response in sepsis and provides a potential target for clinical sepsis research and treatment.

Protective effect of resveratrol against endotoxemia-induced lung injury involves the reduction of oxidative/nitrative stress.

BACKGROUND: Resveratrol, a natural plant polyphenol, has received increasing attention because its varied bioactivities, including the inhibition of tumorigenesis, lipid modification and calorie-restriction. We aimed to investigate the effect of resveratrol on oxidative/nitrative stress in endotoxemia-associated acute lung injury. METHODS: Mice were injected with lipopolysaccharide (LPS, 5 mg/kg, ip). Resveratrol at a dose of 0.3 mg/kg was administered alone or immediately before injection of LPS. Twenty four hours later, lung tissues were collected for histopathologic examination, and determination of malondialdehyde (MDA), H2O2, reduced/oxidized glutathione (GSH/GSSG) ratio, total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, catalase (CAT) activity, inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) and peroxynitrite production. RESULTS: Resveratrol treatment improves histopathological changes in the lung during endotoxemia. Increased oxidative stress in endotoxemic lung was reversed by resveratrol treatment, as evidenced by the decreases of pro-oxidant biomarker (MDA and H2O2), and the increases of anti-oxidant biomarkers (GSH/GSSG ratio, T-AOC, CAT and SOD activity). Treatment with resveratrol inhibited endotoxemia-induced iNOS expression and NO production. Moreover, peroxynitrite formation in endotoxemic lung was significantly attenuated after resveratrol treatment. CONCLUSIONS: Resveratrol exerts protective effects against acute endotoxemia-associated lung injury. These beneficial effects may be due to both the anti-oxidant and anti-nitrative properties of resveratrol. These findings support the potential for resveratrol as a possible pharmacological agent to reduce acute lung injury resulting from oxidative/nitrative damage.

Characterization of NiCas12b for In Vivo Genome Editing.

The RNA-guided clustered regularly interspaced short palindromic repeats (CRISPR)/Cas12b system represents the third family of CRISPR-Cas systems that are harnessed for genome editing. However, only a few nucleases have demonstrated activity in human cells, and their in vivo therapeutic potential remains uncertain. In this study, a green fluorescent protein (GFP)-activation assay is conducted to screen a panel of 15 Cas12b orthologs, and four of them exhibited editing activity in mammalian cells. Particularly noteworthy is the NiCas12b derived from Nitrospira sp., which recognizes a "TTN" protospacer adjacent motif (PAM) and facilitates efficient genome editing in various cell lines. Importantly, NiCas12b also exhibits a high degree of specificity, rendering it suitable for therapeutic applications. As proof of concept, the adeno-associated virus (AAV) is employed to introduce NiCas12b to target the cholesterol regulatory gene proprotein convertase subtilisin/ kexin type 9 (Pcsk9) in the mouse liver. After 4 weeks of injections, an impressive is observed over 16.0% insertion/deletion (indel) efficiency, resulting in a significant reduction in serum cholesterol levels. NiCas12b provides a novel option for both basic research and clinical applications.

Spatial distribution, source identification, and potential risks of 14 bisphenol analogues in soil under different land uses in the megacity of Chengdu, China.

This study explored the levels, distribution, potential sources, ecological risks and estrogenic activities of 14 bisphenol analogues (BPs) in soil under eight land-use types in the megacity of Chengdu, China. Eleven BPs were detected in the soil samples and the total concentrations ranged from 32.3 to 570 ng/g d.w. Levels of bisphenol BP (BPBP) in the soil (up to 208 ng/g d.w.) only second to the most dominant compound bisphenol A (BPA) were found. Relatively higher Σ14BP accumulation in the soil was observed in the commercial and residential areas (median: 136 ng/g d.w. and 131 ng/g d.w.) compared with agricultural area (median: 67.5 ng/g d.w.). Source identification indicated the role of atmospheric particulate deposition and consecutive anthropogenic activities in BP emission. The ecotoxicity assessment implied that BPA, bisphenol S (BPS), bisphenol F (BPF) and bisphenol PH (BPPH) might pose low to medium risk to the ecosystem due to their extensive use and biological effects. The calculated 17ß-estradiol equivalents of BPs were in the range of 0.501-7.74 pg E2/g d.w, and the estrogenic activities were inferior to those contributed by natural estrogens in the soil.

Inhibition of sphingosine kinase 1 attenuates LPS-induced acute lung injury by suppressing endothelial cell pyroptosis.

Acute lung injury (ALI) is a frequent complication of sepsis, with pyroptosis playing a pivotal role. Analysis of Gene Expression Omnibus (GEO) mouse sepsis datasets revealed the upregulation of sphingosine kinase 1 (SphK1) in septic mouse lung tissues, which was validated in lipopolysaccharide (LPS)-treated mice. Therefore, this study aimed to explore the potential role and underlying mechanisms of SphK1, the primary kinase responsible for catalyzing the formation of the bioactive lipid sphingosine-1-phosphat, in sepsis development. Mice received an intraperitoneal injection of SphK1 inhibitor prior to LPS administration. Mouse lung vascular endothelial cells (MLVECs) were exposed to LPS and SphK1 inhibitor. The SphK1 inhibitor mitigated ALI, as evidenced by hematoxylin and eosin (H&E) staining and the wet-to-dry (W/D) weight ratio and reduced Evans blue dye leakage. Furthermore, the SphK1 inhibitor inhibited the activation of the NOD-like receptor protein 3 inflammasome and the subsequent induction of pyroptosis both in vivo and in vitro. Intriguingly, using co-immunoprecipitation (Co-IP) combined with mass spectrometry, our findings revealed that SphK1 associates with pyruvate kinase M2 (PKM2), facilitating PKM2 phosphorylation and its nuclear translocation. TEPP-46, which has the ability to stabilize PKM2 and inhibit the phosphorylation and nuclear translocation of PKM2, markedly reduced the expression of pyroptosis-associated markers and alleviated lung injury. Concludingly, our results suggest that targeting SphK1 is a promising therapeutic strategy for ALI.