Three-Component Synthesis of Di-Keto Aziridines and Highly Functionalized Alkenes from Sulfoxonium Ylides, Nitrosoarenes, and Alkynes.

A catalyst-free one-pot three-component method of sulfoxonium ylides, nitrosoarenes, and alkynes for the synthesis of highly functionalized di-keto aziridines and alkenes is described. This strategy features the catalyst-free and additive-free approach, the employment of safe, more stable, and readily accessible sulfoxonium ylides, which bear a much wider substrate scope as starting materials. In terms of terminal alkynes, a cascade reaction of nitrone formation/1,3-diploar cycloaddition/Baldwin rearrangement is involved to afford a wide variety of di-keto aziridines. However, highly functionalized alkenes could be obtained instead of di-keto aziridines through the same nitrone formation/1,3-diploar cycloaddition and another different rearrangement reaction when internal alkynes are employed as starting materials.

Constructing MXene-PANI@MWCNTs heterojunction with high specific capacitance towards flexible micro-supercapacitor.

Micro-supercapacitors (MSCs) are considered as the promising energy supply of miniaturized electronic devices. The electrode material, as one integral part, play a crucial role on the energy storage performance of MSCs. In our work, we constructed a heterojunction in MXene-PANI@MWCNTs (MPM) ternary composite, benefitting for the synergistic enhancement effect among MXene, polyaniline (PANI) and multiwall carbon nanotubes, an outstanding specific capacitance of 414 F g-1(at 1 A g-1) has been achieved. MPM shows high capacitance retention at large current density (86.7%, at 10 A g-1) and long-term cycling stability of 90.4% for 10 000 cycles. Furthermore, we obtained MPM self-standing films, and constructed a flexible all-solid-state MSC based on the film electrode. A competitive charge storage capability of 30.2 mF cm-2and long-term stability of 70.2% retention for 10 000 cycles was obtained in the MSC. Meanwhile, the MSC shows excellent flexibility, maintaining most capacitance under bending conditions. Moreover, using an integrated strategy, MSCs can obtain tunable voltages and currents that meet various practical requirements. All these results indicate that the MPM is an excellent charge storage material and will become a potential candidate for flexible energy-storage devices.

Synthesis and antitumor activity of novel hybrid compounds between 1,4-benzodioxane and imidazolium salts.

A series of novel hybrid compounds between 1,4-benzodioxane and imidazolium salts was designed and prepared. The compounds were evaluated in vitro against a panel of human tumor cell lines (K562, SMMC-7721, and A-549). The structure-activity relationship results demonstrated that the 2-methyl-benzimidazole or 5,6-dimethyl-benzimidazole ring and substitution of the imidazolyl-3-position with a 4-phenylphenacyl substituent were critical for promoting cytotoxic activity. Particularly, compound 25 was found to be the most potent compound with IC50 values of 1.06-8.31 µM against the three human tumor cell lines and exhibited higher selectivity to K562 and SMMC-7721 cells with IC50 values 4.5- and 4.7-fold lower than cisplatin. Moreover, compound 25 inhibited cell proliferation by inducing the G0/G1 cell cycle arrest and apoptosis in SMMC-7721 cells.

Ti3C2Txnanohybrids: tunable local conductive network and efficient EMI shielding performance for multifunctional materials and devices.

Ti3C2Txis an important member of the MXenes family. Due to its excellent electrical conductivity, adjustable atomic layer, and modifiable active surface, Ti3C2Txhas attracted great attention in the field of electromagnetic interference (EMI) shielding. This paper introduces the important role of regulating conductive network to improve the EMI shielding performance of materials and summarizes the EMI shielding performance of Ti3C2Txnanohybrids reported in recent years. In addition, Ti3C2Txbased EMI shielding materials towards multifunctional devices are also systematically introduced. After that, the development status of Ti3C2Txnanohybrids in the field of EMI shielding is objectively described, and the main problems and challenges are evaluated. Finally, the prospect of Ti3C2Txnanohybrids for advanced and green EMI shielding materials is forecasted.

Function and inhibition of Haspin kinase: targeting multiple cancer therapies by antimitosis.

OBJECTIVES: Haploid germ cell-specific nuclear protein kinase (Haspin) is a serine/threonine kinase as an atypical kinase, which is structurally distinct from conventional protein kinases. KEY FINDINGS: Functionally, Haspin is involved in important cell cycle progression, particularly in critical mitosis regulating centromeric sister chromatid cohesion during prophase and prometaphase, and subsequently ensuring proper chromosome alignment during metaphase and the normal chromosome segregation during anaphase. However, increasing evidence has demonstrated that Haspin is significantly upregulated in a variety of cancer cells in addition to normal proliferating somatic cells. Its knockdown or small molecule inhibition could prevent cancer cell growth and induce apoptosis by disrupting the regular mitotic progression. Given the specificity of its expressed tissues or cells and the uniqueness of its current known substrate, Haspin can be a promising target against cancer. Consequently, selective synthetic and natural inhibitors of Haspin have been widely developed to determine their inhibitory power for various cancer cells in vivo and in vitro. SUMMARY: Here our perspective includes a comprehensive review of the roles and structure of Haspin, its relatively potent and selective inhibitors and Haspin's preliminary studies in a variety of cancers.

Synthesis and anticancer activity of podophyllotoxin derivatives with nitrogen-containing heterocycles.

Three series of podophyllotoxin derivatives with various nitrogen-containing heterocycles were designed and synthesized. The antitumor activity of these podophyllotoxin derivatives was evaluated in vitro against a panel of human tumor cell lines. The results showed that podophyllotoxin-imidazolium salts and podophyllotoxin-1,2,4-triazolium salts a1-a20 exhibited excellent cytotoxic activity. Among them, a6 was the most potent cytotoxic compound with IC50 values of 0.04-0.29 µM. Podophyllotoxin-1,2,3-triazole derivatives b1-b5 displayed medium cytotoxic activity, and podophyllotoxin-amine compounds c1-c3 has good cytotoxic activity with IC50 value of 0.04-0.58 µM. Furthermore, cell cycle and apoptosis experiments of compound a6 were carried out and the results exhibited that a6 could induce G2/M cell cycle arrest and apoptosis in HCT-116 cells.

A preliminary study on the neurotoxic mechanism of harmine in Caenorhabditis elegans.

Harmine is a beta-carboline and harmala alkaloid with extensive bioactivities. However, its toxicity, especially in neural system, is not systematically assessed and the toxic mechanism is not yet clear. Using Caenorhabditis elegans (C. elegans) as a model system, we found that harmine exhibited dosage dependent (0, 5, 10, 20, 40, 80, 160, and 320 µmol/L) toxic effect, such as growth inhibition, egg laying defects, shortened life span and increased mortality. Although harmine did not result in obvious structural alterations in neurite or death of neurons, it did show direct acetylcholinesterase inhibition activity. Further, we found that harmine treatment decreased worm pharyngeal pump rate and lowered the content of nitric oxide (NO) in worm body, implying foraging disorders, which is an indicator of acetylcholinergic neuron activity inhibition. Besides, network pharmacology and molecular docking reveals that acetylcholinesterase is one of the major neural toxicity targets as well. Above all, harmine can directly inhibit the activity of acetylcholinesterase, leading to excessive accumulation of acetylcholine, which may be one of the harmine neurotoxicity mechanisms.

Do combined assays of serum AFP, AFP-L3, DCP, GP73, and DKK-1 efficiently improve the clinical values of biomarkers in decision-making for hepatocellular carcinoma? A meta-analysis.

Objectives: Serum biomarkers are valuable for clinical decision-making for patients with hepatocellular carcinoma (HCC), among which the most promising are AFP, AFP-L3, DCP, DKK-1, and GP73; however, the efficacy of using combined biomarkers remains controversial. This meta-analysis provides insights regarding this topic.Methods: After systematically surveying the literature available in PubMed, Embase, and Cochrane Library, we identified 28 qualified articles published since January 2015. A random-effects model was used to assess pooled sensitivity, specificity, positive and negative likelihood ratios (PLRs and NLPs), and diagnostic odds ratio (DOR).Results: Values under the summary receiver operating characteristic (SROC) curve varied in different panels of the five biomarkers. Importantly, the sum of sensitivity and specificity of AFP+GP73 was 1.76 (P= 0.0001), which was the best among all the panels. The sum of the triple biomarker panel of AFP, AFP-L3, and DCP was larger (1.64, P= 0.0001) than those of any double biomarker panels of AFP, AFP-L3, and DCP.Conclusions: To the best of our knowledge, this is the first meta-analysis to focus solely on combination assays of multiple biomarkers in HCC. The combined assay of AFP and GP73 conferred the best outcome among all panels. The triple combined panel of AFP, AFP-L3, and DCP showed higher diagnostic potential than individual random double combinations of the three biomarkers. Multiple-biomarker combined assays will be clinically important for decision-making processes for HCC.

Transition-Metal-Free C(sp3)-H Coupling of Cycloalkanes Enabled by Single-Electron Transfer and Hydrogen Atom Transfer.

Here we report a unique transition-metal-free C(sp3)-H/C(sp3)-H coupling of cycloalkanes at room temperature. Unactivated cycloalkanes and 2-azaallyls underwent the combination process of single-electron transfer (SET) and hydrogen atom transfer (HAT) to deliver a wide variety of cycloalkane-functionalized products. This expedient approach enables C(sp3)-H/C(sp3)-H coupling of cycloalkanes under mild conditions without transition metals, initiators, and oxidants.

A simple lectin-based biochip might display the potential clinical value of glycomics in patients with spontaneous intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a cerebrovascular disease with extremely high disability and mortality rates. Glycans play critical roles in biological processes. However, whether glycans can serve as potential biomarkers for determining clinical diagnosis and prognosis in ICH remains determined. METHODS: In this study, we established a lectin-biochip to measure serum glycans levels in ICH patients (n=48) and healthy controls (n=16). An enzyme-linked immunosorbent assay (ELISA) was carried out to determine serum levels of IL-10 and TNF-α in the patients. Correlation analyses of the serum glycan and cytokine levels and the clinicopathological parameters of patients were performed. RESULTS: The biochip-based data revealed that the serum levels of α-Man/α-Glc (ConA), Galß3GalNAc (PNA), GalNAc (VVA), Fucα6GlcNAc (AAL), α-Fuc (LTL), and Galß3GalNAc-Ser/Thr (AIL) significantly increased in the super-acute phase of ICH in comparison with healthy controls. Clinicopathological analysis indicated the serum levels of ConA, VVA, and LTL had significant associations with the National Institute of Health Stroke Scale (NIHSS), and serum VVA levels had a significant association with the Mini-Mental State Examination (MMSE) at day 90 after ICH. Correlation coefficient analysis revealed significant correlations between TNF-α and ConA (P<0.001) as well as between IL-10 and ConA (P<0.001), PNA (P=0.02), VVA (P<0.001), and MAL (P=0.04), respectively. CONCLUSIONS: We established a proof-of-concept platform for detecting serum glycomics and highlighted their potential value in diagnosing and predicting ICH patients' outcomes.

Fufang Xueshuantong alleviates diabetic retinopathy by activating the PPAR signalling pathway and complement and coagulation cascades.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Xueshuantong (FXST) is a traditional Chinese patent medicine composed of Panax notoginseng (Burkill) F.H.Chen (Araliaceae), Salvia miltiorrhiza Bunge (Lamiaceae), Astragalus propinquus Schischkin (Leguminosae), and Scrophularia ningpoensis Hemsl. (Scrophulariaceae). It has been widely used for the treatment of diabetic retinopathy (DR) and exerts a positive clinical therapeutic effect. AIM OF THE STUDY: The aim of this study was to observe the effect of FXST on diabetic rat retinas and investigate its pharmacological mechanism for improving DR. METHODS: The diabetic rat model was established by intraperitoneal injection of streptozotocin. The rats were divided into a normal group, diabetic group, and FXST group. The rats in the FXST group were treated with FXST by intragastric administration for 12 weeks while other rats were given the same volume of normal saline. The haemodynamic parameters of the central retinal artery in the rats were measured by ultrasound. Haematoxylin-eosin staining was utilised to observe the pathological structural changes in the retina. The apoptosis of retinal nerve cells was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling. RNA sequencing was used to screen the differentially expressed genes (DEGs), and enrichment analyses were performed. The DEGs were validated through real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: The peak systolic velocity, end diastolic velocity, and mean velocity decreased while the resistance index and pulsatility index increased in the diabetic rat retinas. FXST also improved haemodynamics. In contrast with the diabetic group, FXST allayed the disorder and oedema of the retinal structure in addition to reversing the reductions in retinal thickness and retinal ganglion cell number. It also decreased the apoptosis index of retinal cells. A total of 1134 DEGs were identified by RNA sequencing in the FXST group compared to the diabetic group, including 814 upregulated genes and 320 downregulated genes. These genes were enriched in the complement and coagulation cascades as well as the peroxisome proliferator-activated receptor (PPAR) signalling pathway. Several DEGs, including PPAR gamma, perilipin 4, acyl-CoA dehydrogenase long chain, CD55 molecule, and plasminogen activator urokinase, were identified by qRT-PCR, and the results were consistent with the RNA sequencing data. CONCLUSIONS: FXST alleviates DR by improving the haemodynamics and morphological alterations of diabetic rat retinas, which are mediated by complement and coagulation cascades and the PPAR signalling pathway.

HuoXue JieDu formula improves diabetic retinopathy in rats by regulating microRNAs.

ETHNOPHARMACOLOGICAL RELEVANCE: HuoXue JieDu Formula (HXJDF) originates from classical formulas and was formed based on clinical experience. It is composed of Euonymus alatus (Thunb.) Siebold, Panax notoginseng (Burkill) F.H. Chen, the roots of Anguina kirilowii (Maxim.) Kuntze, and Coptis omeiensis (C. Chen) C.Y.Cheng. HXJDF prevents the deterioration of diabetic retinopathy. AIM OF THE STUDY: To evaluate the effects of HXJDF on diabetic retinopathy in rats and investigate the roles of miRNAs in the effects of HXJDF. MATERIALS AND METHODS: A single intraperitoneal injection of streptozotocin (STZ) (65 mg/kg) was used to induce diabetes in rats. Rats were divided into three groups: normal, diabetic, and diabetic + HXJDF. Rats were treated with HXJDF (15.4 g/kg) or water by oral gavage for twelve weeks. At the end of the treatment, rats were anaesthetized, and retinal haemodynamic changes were measured. Then, the retinas were removed and examined by haematoxylin and eosin (HE) staining and TUNEL assays. In addition, miRNA expression profiling was performed using miRNA microarrays and further validated by quantitative real-time PCR (qRT-PCR). RESULTS: Diabetes reduced peak systolic velocity (PSV), end-diastolic velocity (EDV), mean velocity (MV) and central retinal vein velocity (CRV) but increased the resistance index (RI) and pulsatility index (PI). In addition, in the diabetic group, retinal cell arrangement was disordered and loosely arranged, the retinal thickness and retinal ganglion cell (RGC) number decreased, and retinal cell apoptosis increased. In addition, 11 miRNAs were upregulated and 4 miRNAs were downregulated. After treatment, HXJDF improved retinal haemodynamics and morphologic changes, restored retinal thickness and RGC number and decreased retinal cell apoptosis. Furthermore, the changes in miRNA expression were significantly abolished by HXJDF. CONCLUSION: HXJDF may prevent DR by regulating the expression of miRNAs.

Linker-extended native cyanovirin-N facilitates PEGylation and potently inhibits HIV-1 by targeting the glycan ligand.

Cyanovirin-N (CVN) potently inhibits human immunodeficiency virus type 1 (HIV-1) infection, but both cytotoxicity and immunogenicity have hindered the translation of this protein into a viable therapeutic. A molecular docking analysis suggested that up to 12 residues were involved in the interaction of the reverse parallel CVN dimer with the oligosaccharide targets, among which Leu-1 was the most prominent hot spot residue. This finding provided a possible explanation for the lack of anti-HIV-1 activity observed with N-terminal PEGylated CVN. Therefore, linker-CVN (LCVN) was designed as a CVN derivative with a flexible and hydrophilic linker (Gly4Ser)3 at the N-terminus. The N-terminal α-amine of LCVN was PEGylated to create 10 K PEG-aldehyde (ALD)-LCVN. LCVN and 10 K PEG-ALD-LCVN retained the specificity and affinity of CVN for high mannose N-glycans. Moreover, LCVN exhibited significant anti-HIV-1 activity with attenuated cytotoxicity in the HaCaT keratinocyte cell line and MT-4 T lymphocyte cell lines. 10 K PEG-ALD-LCVN also efficiently inactivated HIV-1 with remarkably decreased cytotoxicity and pronounced cell-to-cell fusion inhibitory activity in vitro. The linker-extended CVN and the mono-PEGylated derivative were determined to be promising candidates for the development of an anti-HIV-1 agent. This derivatization approach provided a model for the PEGylation of biologic candidates without introducing point mutations.