A Strain-Promoted Divergent Chemical Steroidation Unveils Potent Anti-Inflammatory Pseudo-Steroidal Glycosides.

The development of novel agents with immunoregulatory effects is a keen way to combat the growing threat of inflammatory storms to global health. To synthesize pseudo-steroidal glycosides tethered by ether bonds with promising immunomodulatory potential, we develop herein a highly effective deoxygenative functionalization of a novel steroidal donor (steroidation) facilitated by strain-release, leveraging cost-effective and readily available Sc(OTf)3 catalysis. This transformation produces a transient steroid-3-yl carbocation which readily reacts with O-, C-, N-, S-, and P-nucleophiles to generate structurally diverse steroid derivatives. DFT calculations were performed to shed light on the mechanistic details of the regioselectivity, underlying an acceptor-dependent steroidation mode. This approach can be readily extended to the etherification of sugar alcohols to enable the achievement of a diversity-oriented, pipeline-like synthesis of pseudo-steroidal glycosides in good to excellent yields with complete stereo- and regiospecific control for anti-inflammatory agent discovery. Immunological studies have demonstrated that a meticulously designed cholesteryl disaccharide can significantly suppress interleukin-6 secretion in macrophages, exhibiting up to 99% inhibition rates compared to the negative control. These findings affirm the potential of pseudo-steroidal glycosides as a prospective category of lead agents for the development of novel anti-inflammatory drugs.

ZnI2-Mediated ß-Galactosylation of C2-Ether-Type Donor.

Conventional glycosylation with galactosyl donors having C-2 benzyl (Bn) ether-type functionality often leads to anomeric mixtures, due to the anomeric and steric effects that stabilize the 1,2-cis-α- and 1,2-trans-ß-glycosides, respectively. Herein we report a versatile ZnI2-directed ß-galactosylation approach employing a 4,6-O-tethered and 2-O-Bn galactosyl donor for the stereoselective and efficient synthesis of ß-O-galactosides. With a broad substrate scope, the reaction tolerates a wide range of functional groups and complex molecular architectures, providing stereocontrolled ß-galactosides in moderate to excellent yields. The practicality of this transformation is demonstrated through the synthesis of a tetrasaccharide arabinogalactan fragment with high stereoselectivity.

[Research status on efficacy enhancement and toxicity reduction of Chinese medicine in treatment of malignant tumors: a review of projects supported by National Natural Science Foundation of China].

Through a retrospective analysis of the projects supported by the National Natural Science Foundation of China in the past ten years in the field of Chinese medicine for the treatment of malignant tumors, this article systematically summarized the main research contents and hotspots of Chinese medicine in efficacy enhancement and toxicity reduction. The efficacy enhancement of Chinese medicine mainly included the mitigation of molecule-targeted drug resistance, multidrug resistance, and chemotherapy resistance, synergistic efficacy enhancement, and radiotherapy sensitization. The toxicity reduction is mainly reflected in the alleviation of the side effects of radiotherapy and chemotherapy. In addition, Chinese medicine has advantages in reducing serious adverse reactions of malignant tumors, providing more options for the adjuvant treatment of tumors.

PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function.

The orphan nuclear receptor Nurr1 is critical for the development, maintenance and protection of midbrain dopaminergic (mDA) neurons. Here we show that prostaglandin E1 (PGE1) and its dehydrated metabolite, PGA1, directly interact with the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional function. We also report the crystallographic structure of Nurr1-LBD bound to PGA1 at 2.05 Å resolution. PGA1 couples covalently to Nurr1-LBD by forming a Michael adduct with Cys566, and induces notable conformational changes, including a 21° shift of the activation function-2 helix (H12) away from the protein core. Furthermore, PGE1/PGA1 exhibit neuroprotective effects in a Nurr1-dependent manner, prominently enhance expression of Nurr1 target genes in mDA neurons and improve motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse models of Parkinson's disease. Based on these results, we propose that PGE1/PGA1 represent native ligands of Nurr1 and can exert neuroprotective effects on mDA neurons, via activation of Nurr1's transcriptional function.

Novel cucurbitane-type triterpene saponins from Hemsleya amabilis.

The rhizomes of the medicinal plant Hemsleya amabilis (Cucurbitaceae) yielded three new cucurbitane-type triterpene saponins xuedanosides K-M (1-3) by silica gel column, ODS column, and pre-HPLC techniques. The structure was determined by spectroscopic analysis and examined alongside existing data from prior studies. Compounds 1-3 were evaluated for cytotoxic activity against HeLa and HCT-8 human cancer cell lines and showed significant cytotoxicity with IC50 values of 2.01-14.56 and 8.94-27.48 µM, respectively.

A similar effect of P16 hydroxymethylation and true-methylation on the prediction of malignant transformation of oral epithelial dysplasia: observation from a prospective study.

BACKGROUND: Total P16 methylation (P16M), including P16 hydroxymethylation (P16H) and true-P16M, correlates with malignant transformation of oral epithelial dysplasia (OED). Both true-P16M and P16H are early events in carcinogenesis. The aim of this study is to prospectively determine if discrimination of true-P16M from P16H is necessary for prediction of cancer development from OEDs. METHODS: Patients (n = 265) with mild or moderate OED were recruited into the double blind two-center cohort. Total-P16M and P16H were analyzed using the 115-bp MethyLight, TET-assisted bisulfite (TAB) methylation-specific PCR (MSP), and TAB-sequencing. Total-P16M-positive and P16H-negative samples were defined as true-P16M-positive. Progression of OEDs was monitored for a minimum 24 months follow-up period. RESULTS: P16H was detected in 23 of 73 (31.5%) total-P16M-positive OEDs. Follow-up information was obtained from 247 patients with an ultimate compliance rate of 93.2%. OED-derived squamous cell carcinomas were observed in 13.0% (32/247) patients during follow-up (median, 41.0 months). The cancer progression rate for total-P16M-positive patients was significantly increased when compared to total-P16M-negative patients [23.3% vs 8.6%; adjusted odds ratio = 2.67 (95% CI: 1.19-5.99)]. However, the cancer progression rates were similar between P16H- and true-P16M-positive OEDs [26.1% (6/23) vs 22.0% (11/50); odds ratio = 0.80 (95% CI: 0.22-2.92)]. The cancer-free survival was also similar for these patients. CONCLUSION: P16H and true-P16M are similar biomarkers for determining malignant potential of OEDs. Discrimination of P16H from true-P16M, at least in OED, may be not necessary in clinical applications. TRIAL REGISTRATION: This study is registered prospectively in the U.S. National Institutes of Health Clinical Trials Protocol Registration System (trial number NCT02967120, available at https://ClinicalTrials.gov/ct2/show/NCT02967120 ).

A new animal model for menopausal transition: combination of ovariectomy and empty bottle stimulation.

Previous small animal models for menopausal transition are mainly performed to mimic the biochemical changes of patients with menopausal transition. The psychological symptoms in animal models are often overlooked. To mimic clinical situation, we developed a new mouse model of menopausal transition: the combination of bilateral ovariectomy (OVX) and empty bottle stimulation (EBS). After OVX and 21 days of EBS, behavioral test and pentobarbital-induced sleep test were carried out. Then all the animals were euthanized for further investigations. Compared with the control group, the combination of OVX and EBS group (OVX + EBS) showed higher bodyweight, lower organ index of uteri, and lower concentrations of serum estradiol. In addition, behavioral manifestations, sleep quality, and morphologic features in OVX + EBS group showed significant differences compared with the control group. OVX alone or EBS alone failed to include all the changes of OVX + EBS group. These findings indicate ovariectomy or EBS alone could not well mimic the symptoms of menopausal transition. The combination of bilateral ovariectomy and EBS offers an easy and repeatable method for building comprehensive menopausal transition model in mice.

Nanoparticles of Short Cationic Peptidopolysaccharide Self-Assembled by Hydrogen Bonding with Antibacterial Effect against Multidrug-Resistant Bacteria.

Cationic antimicrobial peptides (AMPs) and polymers are active against many multidrug-resistant (MDR) bacteria, but only a limited number of these compounds are in clinical use due to their unselective toxicity. The typical strategy for achieving selective antibacterial efficacy with low mammalian cell toxicity is through balancing the ratio of cationicity to hydrophobicity. Herein, we report a cationic nanoparticle self-assembled from chitosan-graft-oligolysine (CSM5-K5) chains with ultralow molecular weight (1450 Da) that selectively kills bacteria. Further, hydrogen bonding rather than the typical hydrophobic interaction causes the polymer chains to be aggregated together in water into small nanoparticles (with about 37 nm hydrodynamic radius) to concentrate the cationic charge of the lysine. When complexed with bacterial membrane, these cationic nanoparticles synergistically cluster anionic membrane lipids and produce a greater membrane perturbation and antibacterial effect than would be achievable by the same quantity of charge if dispersed in individual copolymer molecules in solution. The small zeta potential (+15 mV) and lack of hydrophobicity of the nanoparticles impedes the insertion of the copolymer into the cell bilayer to improve biocompatibility. In vivo study (using a murine excisional wound model) shows that CSM5-K5 suppresses the growth of methicillin-resistant Staphylococcus aureus (MRSA) bacteria by 4.0 orders of magnitude, an efficacy comparable to that of the last resort MRSA antibiotic vancomycin; it is also noninflammatory with little/no activation of neutrophils (CD11b and Ly6G immune cells). This study demonstrates a promising new class of cationic polymers-short cationic peptidopolysaccharides-that effectively attack MDR bacteria due to the synergistic clustering of, rather than insertion into, bacterial anionic lipids by the concentrated polymers in the resulting hydrogen-bonding-stabilized cationic nanoparticles.

Stimuli-responsive multifunctional glyconanoparticle platforms for targeted drug delivery and cancer cell imaging.

Targeted bioimaging or chemotherapeutic drug delivery to achieve the desired therapeutic effects while minimizing side effects has attracted considerable research attention and remains a clinical challenge. Presented herein is a multi-component delivery system based on carbohydrate-functionalized gold nanoparticles conjugated with a fluorophore or prodrug. The system leverages active targeting based on carbohydrate-lectin interactions and release of the payload by biological thiols. Cell-type specific delivery of the activatable fluorophore was examined by confocal imaging on HepG2 cells, and displays distinct selectivity towards HepG2 cells over HeLa and NIH3T3 cells. The system was further developed into a drug delivery vehicle with camptothecin (CPT) as a model drug. It was demonstrated that the complex exhibits similar cytotoxicity to that of free CPT towards HepG2 cells, and is significantly less cytotoxic to normal HDF and NIH3T3 cells, indicating excellent specificity. The delivery vehicle itself exhibits excellent biocompatibility and offers an attractive strategy for cell-type specific delivery depending on the carbohydrates conjugated in the system.

P16 Methylation as an Early Predictor for Cancer Development From Oral Epithelial Dysplasia: A Double-blind Multicentre Prospective Study.

BACKGROUND: Silencing of P16 through methylation and locus deletion is the most frequent early events in carcinogenesis. The aim of this study is to prospectively determine if early P16 methylation is a predictor for oral cancer development. METHODS: Patients (n = 181) with mild or moderate oral epithelial dysplasia (OED) were recruited into the double blind multicentre cohort. P16 methylation was analyzed using the MethyLight assay. Progression of OEDs was monitored for a minimum 3 year follow-up period. FINDINGS: P16 methylation-informative cases (n = 152) were enrolled in the prospective multicenter cohorts with an ultimate compliance of 96.7%. OED-derived squamous cell carcinomas were observed in 21 patients (14.3%) during the follow-up (median, 41.0 months). The cancer progression rate from the P16 methylation-positive patients was significantly increased when compared to P16 methylation-negative patients [27.1% vs 8.1%; adjusted odds ratio = 4.6; P = 0.006]. When the P16 methylation-positive criteria were used as a biomarker for early prediction of cancer development from OEDs, sensitivity and specificity of 62% and 76% were obtained, respectively. INTERPRETATION: P16 methylation is unequivocally a marker for determining the malignant potential of OED and there is no need for further research regarding this aspect. FUNDING: National Basic Research Programs of China (2011CB504201 and 2015CB553902), Beijing Science and Technology Commission (Z090507017709016), and Beijing Municipal Administration of Hospital (XM201303) to Dajun Deng. The funding agencies have no role in the actual experimental design, patient recruitment, data collection, analysis, interpretation, or writing of this manuscript.

Meta-Analysis of Randomized Controlled Trials Comparing Risk of Major Adverse Cardiac Events and Bleeding in Patients With Prasugrel Versus Clopidogrel.

The use of prasugrel in patients with coronary artery disease (CAD) has been associated with decreased major adverse cardiac events (MACEs) compared with clopidogrel but with an increased risk of bleeding. However, it remains unclear if the risks of bleeding outweigh those of MACEs in patients on prasugrel treatment. We systematically reviewed randomized controlled trials comparing prasugrel with clopidogrel in patients with CAD. We performed a literature search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trial databases from inception to November 25, 2014, and reviewed the reference lists of retrieved articles. A comparative estimate was made for the combined rates of MACEs and bleeding from the same trials in the framework of this meta-analysis and expressed as odds ratios (ORs) and 95% confidence intervals (CIs) in both random- and fixed-effects models. Nine studies involving 25,214 patients were included in our meta-analysis. In both the random- and fixed-effects models, the risks of MACEs outweighed those of major bleeding (OR 7.48, 95% CI 3.75 to 14.94, p <0.0001, random effects) and of minor bleeding (OR 3.77, 95% CI 1.73 to 8.22, p = 0.009, random effects). Results were corroborated in a standard-dose clopidogrel subgroup analysis (OR 7.46, 95% CI 3.54 to 15.68, p <0.0001, and OR 6.44, 95% CI 2.80 to 14.80, p <0.0001, random effects, respectively). In conclusion, despite the increased risk of bleeding associated with prasugrel treatment compared with clopidogrel, the risk of MACEs far outweighed the risk of bleeding.

Detection of K-ras Mutations in Predicting Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase (EGFR-TK) Inhibitor in Patients with Metastatic Colorectal Cancer.

Epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors are useful in treating different advanced human cancers; however, their clinical efficacy varies. This study detected K-ras mutations to predict the efficacy of EGFR-TK inhibitor cetuximab treatment on Chinese patients with metastatic colorectal cancer (mCRC). A total of 87 patients with metastatic colorectal cancer were treated with cetuximab for 2-16 months, in combination with chemotherapy between August 2008 and July 2012, and tissue samples were used to detect K-ras mutations. The data showed that K-ras mutation occurred in 27/87 (31%). The objective response rates and disease control rate in K-ras wild type and mutant patients were 42% (25/60) versus 11% (3/27) (p<0.05) and 60% (36/60) versus 26% (7/27) (p<0.05), respectively. Patients with the wild-type K-ras had significantly higher median survival times and progression-free survival, than patients with mutated K-ras (21 months versus 17 months, p=0.017; 10 months versus 6 months, p=0.6). These findings suggest that a high frequency of K-ras mutations occurs in Chinese mCRC patients and that K-ras mutation is required to select patients for eligibility for cetuximab therapy. Further prospective studies using a large sample size are needed to confirm these preliminary findings.

The intriguing dual-directing effect of 2-cyanobenzyl ether for a highly stereospecific glycosylation reaction.

The diverse presence as well as their very specific bio-responses of glycoconjugates found in all living species requires scientists to synthesize the precise structure of these complex oligosaccharides for various studies on glycoscience. Very few approaches were able to offer the sole α- or ß-glycosylated products, even at the cost of complicating the preparative route or usage of exotic chiral auxiliaries to drive the stereoselectivity. In this report, the unification of solvent assistance and neighbouring group participation concepts have led us to the use of 2-cyanobenzyl ether as the dual-directing auxiliary for stereospecific construction of α- and ß-glycosidic bonds from a single starting material, and both isomers can be obtained in exclusive stereoselectivity. This work demonstrates the difference in reactivities of glycosyl acceptors can be employed to completely drive the stereoselectivity, drawing the parallel comparison with the arming/disarming concept, which has been exclusively confined to glycosyl donors.

Collective synthesis of 4-hydroxy-2-pyridone alkaloids and their antiproliferation activities.

A collective synthesis of 4-hydroxy-2-pyridone alkaloids--specifically, pretenellin B, prebassianin B, farinosone A, militarione D, pyridovericin, and torrubiellone C--has been achieved. Key steps include using a strategic convergent method to synthesize the densely substituted pyridone key intermediate by Suzuki-Miyaura cross-coupling reaction, a divergent synthesis approach of target molecules by aldol condensation of pyridone intermediate with homologous aldehydes, and an iterative synthesis of homologous aldehydes with all-trans-polyene backbones. Interestingly, among the six tumor cell lines investigated, torrubiellone C was found to induce potent and apoptotic inhibitory activities on Jurkat T cells with IC50 values of 7.05 µM. Hence, this approach could potentially contribute to the synthesis of bioactive small-molecule libraries as well as drug discovery.

Benzofuran-based estrogen receptor α modulators as anti-cancer therapeutics: in silico and experimental studies.

In the search for new estrogen receptor alpha (ERα) modulators, a trial molecular screening was conducted and 5,6-dihydroxybenzofuran was identified as a possible drug target for ERα. The target molecular modelling molecule 1 and a series of 5,6-dihydroxybenzofurans have been synthesized and evaluated for their anti-proliferation activities against MCF-7 and MDA-MB-231 cells. From the SAR studies, potential functional groups have been identified, the two hydroxyl groups at C-5 and C-6 and the phenyl ring at C-2, which showed considerable cytotoxicity in MCF-7 breast cancer cells. In addition, the apoptotic abilities of the compounds have been measured in both MCF-7 ER(+) and MDA-MB-231 ER(-) breast cancer cells. The results demonstrated that our compounds inhibit MCF-7 breast cancer cells via ER(+). These preliminary results provide valuable information towards the identification of important functional groups present on 5,6-dihydroxybenzofuran, which could be a promising scaffold for designing novel ER ligands.

Copper(II)/iron(III) co-catalyzed intermolecular diamination of alkynes: facile synthesis of imidazopyridines.

A facile synthesis of imidazo[1,2-α]pyridines has been achieved by copper(II) and iron(III) co-catalyzed C-N bond formation. This reaction involves an intermolecular oxidative diamination of alkynes with high chemoselectivity and regioselectivity.

The molecular basis of distinct aggregation pathways of islet amyloid polypeptide.

Abnormal aggregation of islet amyloid polypeptide (IAPP) into amyloid fibrils is a hallmark of type 2 diabetes. In this study, we investigated the initial oligomerization and subsequent addition of monomers to growing aggregates of human IAPP at the residue-specific level using NMR, atomic force microscopy, mass spectroscopy, and computational simulations. We found that in solution IAPPs rapidly associate into transient low-order oligomers such as dimers and trimers via interactions between histidine 18 and tyrosine 37. This initial event is proceeded by slow aggregation into higher-order spherical oligomers and elongated fibrils. In these two morphologically distinct types of aggregates IAPPs adopt structures with markedly different residual flexibility. Here we show that the anti-amyloidogenic compound resveratrol inhibits oligomerization and amyloid formation via binding to histidine 18, supporting the finding that this residue is crucial for on-pathway oligomer formation.

'Nanoreactors' for photocatalytic H2 evolution in oil-water biphase systems.

Optimization of reaction systems plays a key role in preventing the backward reaction of water splitting. 'Nanoreactors' are formed with nanoporous photocatalyst in a facile H(2) production system, hexane-water biphase system. The rate of H(2) evolution could reach 63.37 mmol h(-1) g(-1) in the biphase system (40% higher than that in the single phase system).

Sugar-based synthesis of Tamiflu and its inhibitory effects on cell secretion.

Tamiflu is currently the most effective drug for the treatment of influenza, but the insufficient supply and side-effects of this drug demand urgent solutions. We present a practical synthesis of Tamiflu by using novel synthetic routes, cheap reagents, and the abundantly available starting material D-glucal. The strategy features a Claisen rearrangement of hexose to obtain the cyclohexene backbone and introduction of diamino groups through tandem intramolecular aziridination and ring opening. In addition, this synthetic protocol allows late-stage functionalization for the flexible synthesis of Tamiflu analogues. By using the synthesized Tamiflu and its active metabolite (oseltamivir carboxylate), we investigated their influences on neuroendocrine PC12 cells in various aspects. It was discovered that oseltamivir carboxylate significantly inhibits the vesicular exocytosis (regulated secretion) of PC12 cells, and suggests a mechanism underlying the Tamiflu side-effects, in particular its possible adverse influences on neurotransmitter release in the central nervous system.

Interfacing glycosylated carbon-nanotube-network devices with living cells to detect dynamic secretion of biomolecules.

A sense of cell-being: Single-walled carbon nanotubes (SWNTs) are functionalized with bioactive monosaccharides to enable their use as biosensors. The glycosylated nanotube network is biocompatible and can interface with living cells (see scheme) to electronically detect biomolecular release with high temporal resolution and high sensitivity.