Aculebiphenyl A-B, new biphenyl derivatives from Ruscus aculeatus.

The investigation of chemical constituents from the rhizomes of Ruscus aculeatus resulted in the isolation of two new biphenyl derivatives, aculebiphenyls A and B (1-2), together with two known analogs (3-4). Their chemical structures were elucidated based on extensive spectroscopic interpretation and HR-ESI-MS analysis. Compounds 3-4 were isolated from the Ruscus genus for the first time. The isolated compounds were tested for anti-inflammatory activities and antibacterial activities. Compound 1 exhibited significant inhibitory effects on LPS-induced NO production and COX-2 with IC50 values of 10.8 µM and 0.4 µM. Compound 1 also significantly down-regulated the levels of inflammatory cytokines IL-1ß, IL-6, and TNF-α. Compound 1 showed moderate antibacterial activities.

Molecular Basis for Luteolin as a Natural TatD DNase Inhibitor in Trueperella pyogenes.

TatD960 and TatD825 are DNases that contribute to biofilm formation and virulence in Trueperella pyogenes (T. pyogenes). Luteolin is a natural flavonoid commonly found in plants that exhibits antimicrobial capacity. Our study aims to investigate the effects of luteolin on TatD DNases as a natural inhibitor. In this research, the expression of tatD genes and TatD proteins in T. pyogenes treated with luteolin was detected, and then the effect of luteolin on the hydrolysis of DNA by TatD DNases was analyzed using agarose gel electrophoresis. Moreover, the interactions between luteolin and TatD DNases were tested using surface plasmon resonance (SPR) assays and molecular docking analysis. After 1/2 MIC luteolin treatment, the transcription of tatD genes and expression of TatD proteins appeared to be reduced in 80-90% of T. pyogenes (n = 20). The gel assay revealed that luteolin can inhibit the activity of TatD DNases. The SPR assay showed that the KD values of luteolin to TatD960 and TatD825 were 6.268 × 10-6 M and 5.654 × 10-6 M, respectively. We found through molecular docking that hydrogen bonding is predominant in the interaction of luteolin and TatD DNases. Our data indicate that luteolin inhibited the ability of TatD DNases by decreasing their binding to DNA. The current study provides an insight into the development of luteolin as a DNase inhibitor in preventing biofilm formation and virulence in T. pyogenes.

A coherent framework for non-ionising radiation protection.

A coherent and overarching framework for health protection from non-ionising radiation (NIR) does not currently exist. Instead, many governments maintain different compliance needs targeting only some NIR exposure situations. An international framework developed by the World Health Organization would promote a globally consistent approach for the protection of people from NIR. Designed based on decades of practical experience the framework provides guidance on establishing clear national health and safety objectives and how they should be achieved. It supports multisectoral action and engagement by providing a common language and systematic approach for managing NIR. The framework should allow governments to respond to policy challenges on how to achieve effective protection of people, especially in a world that is rapidly deploying new NIR technologies. In this paper the concepts and key features are presented that underpin the framework for NIR protection, including examples of implementation.

Synthesis and biological evaluations of oleanolic acid indole derivatives as hyaluronidase inhibitors with enhanced skin permeability.

Oleanolic acid (OA) is a natural cosmeceutical compound with various skin beneficial activities including inhibitory effect on hyaluronidase but the anti-hyaluronidase activity and mechanisms of action of its synthetic analogues remain unclear. Herein, a series of OA derivatives were synthesised and evaluated for their inhibitory effects on hyaluronidase. Compared to OA, an induction of fluorinated (6c) and chlorinated (6g) indole moieties led to enhanced anti-hyaluronidase activity (IC50 = 80.3 vs. 9.97 and 9.57 µg/mL, respectively). Furthermore, spectroscopic and computational studies revealed that 6c and 6g can bind to hyaluronidase protein and alter its secondary structure leading to reduced enzyme activity. In addition, OA indole derivatives showed feasible skin permeability in a slightly acidic environment (pH = 6.5) and 6c exerted skin protective effect by reducing cellular reactive oxygen species in human skin keratinocytes. Findings from the current study support that OA indole derivatives are potential cosmeceuticals with anti-hyaluronidase activity.

Direct interactions between cationic liposomes and bacterial cells ameliorate the systemic treatment of invasive multidrug-resistant Staphylococcus aureus infections.

Invasive infections caused by antibiotic-resistant Staphylococcus aureus have posed a great threat to human health. To tackle this problem, a cationic liposomal Curcumin (C-LS/Cur) was developed and its effect against antibiotic-resistant S. aureus was investigated in this study. As expected, C-LS/Cur exhibited greater bactericidal capacity compared with its counterparts, probably because the negatively charged S. aureus favors electrostatic interactions rather than intercalation with cationic liposomal vesicles at the beginning of endocytic process, thereby effectively delivering Cur to its targets. We confirmed this hypothesis by monitoring zeta potential variation, collecting visual evidences through CLSM, FCM and TEM, and determining binding kinetics by BLI. Moreover, an excellent therapeutic efficacy of C-LS/Cur against invasive murine infection was also observed, which was due to the enhanced accumulation and retention in the targets. Therefore, cationic liposomes have great potential for the clinical application in the treatment of invasive antibiotic-resistant S. aureus infections.

Two new prenylated coumarins from roots of Zanthoxylum nitidum.

Two new prenylated coumarins, 3'-hydroxytoddanone (1), and isotoddalolactone (2), along with four known analogues (3-6) were isolated from the roots of Zanthoxylum nitidum. Their chemical structures were elucidated based on extensive spectroscopic interpretation and HR-ESI-MS analysis. The absolute configuration of compound 2 was determined by comparing experimental ECD spectrum with that calculated by the time-dependent density functional theory (TDDFT) method. Compounds 4-6 were isolated from the Zanthoxylum genus for the first time. The two new compounds were tested for antiproliferative activities in vitro on the HL-60, K562 and THP-1 cell lines. Compounds 1 and 2 exhibited moderate cell growth inhibitory activities in vitro against human leukemic HL-60 cell lines, with IC50 values of 32.64 and 33.15 µM, respectively.

The Inter-Agency Committee on Radiation Safety-30 years of international coordination of radiation protection and safety matters.

The Inter-Agency Committee on Radiation Safety (IACRS) was constituted in 1990, as a forum for collaboration and coordination between international bodies with regards to radiation safety. It consists today of representatives of eight intergovernmental member organizations (the European Commision, Food and Agriculture Organization, International Atomic Energy Agency (IAEA), International Labour Office, Organisation for Economic Co-operation and Development/ Nuclear Energy Agency (OECD/NEA), Pan American Health Organization, United Nations Scientific Committee on the Effects of Atomic Radiation and the World Health Organization) and five observer non-governmental organizations (International Commission on Radiological Protection, International Commission on Radiation Units & Measurements, International Electrotechnical Commission, International Radiation Protection Association and International Organization for Standardization). The IACRS provides a platform for interaction between these relevant international bodies to contribute to a common understanding of the scientific basis and legal framework for the application of the system of radiation protection, towards global harmonisation of radiation safety standards. The IACRS played a key role in the development of the International Basic Safety Standards (BSS) in 1996 and in its revision in 2014. Further, an IACRS specific Task Group-chaired by the IAEA-fosters the implementation of the BSS in a consistent and coherent manner in all Member States of the United Nations. The IACRS operates via a standing secretariat jointly provided by the IAEA and OECD/NEA and is chaired by one of its member organizations on a rotating basis for periods of about 18 months. This approach has proved to be effective and was the foundation for ensuring continuity of the work of the committee and at the same time allowing a rotating leadership for all member organizations. Currently, the IACRS is chaired by the WHO. The International Radiation Safety Framework under which the IACRS works is structured around four main areas: (a) science; (b) principles; (c) standards; and (d) practice. This paper presents briefly the mandates, roles and functions of the various international bodies that are relevant to the four above mentioned areas of work, discusses how these bodies coordinate their actions and complement each other to enhance radiation protection and safety worldwide and describes their contribution to the achievement of the Sustainable Development Goals. The paper also provides an overview of the main accomplishments of the IACRS since its inception 30 years ago, and an outlook on key challenges for its future activities.

Selective Alkynylallylation of the C-C σ Bond of Cyclopropenes.

A Pd-catalyzed regio- and stereoselective alkynylallylation of a specific C-C σ bond in cyclopropenes, using allyl propiolates as both allylation and alkynylation reagents, has been achieved for the first time. By merging selective C(sp2 )-C(sp3 ) bond scission with conjunctive cross-couplings, this decarboxylative reorganization reaction features fascinating atom and step economy and provides an efficient approach to highly functionalized dienynes from readily available substrates. Without further optimization, gram-scale products can be easily obtained by such a simple, neutral, and low-cost catalytic system with high TONs. DFT calculations afford a rationale toward the formation of the products and indicate that the selective insertion of the double bond of cyclopropenes into the C-Pd bond of ambidentate Pd complex and the subsequent nonclassical ß-C elimination promoted by 1,4-palladium migration are critical for the success of the reaction.

A new xanthyletin-type coumarin from the roots of Peucedanum praeruptorum.

A new xanthyletin-type coumarin, neopeucedalactone (1), was isolated from the roots of Peucedanum praeruptorum Dunn. Its chemical structure was elucidated based on extensive spectroscopic interpretation. The absolute configurations of xanthyletin-type coumarin were determined by comparing experimental and calculated ECD spectra for the first time. Compound 1 exhibited moderate cell growth inhibitory activities in vitro against human leukemic HL-60, THP-1 cell lines, and human prostate cancer PC-3 cell lines, with IC50 values of 9.97, 27.80, and 48.68 µM, respectively. [Formula: see text].

Bioassay- and Chemistry-Guided Isolation of Scalemic Caged Prenylxanthones from the Leaves of Garcinia bracteata.

With bioassay- and chemistry-guided fractionation, seven new caged prenylxanthones including two scalemic mixtures, epiisobractatin (1), 13-hydroxyisobractatin (2), 13-hydroxyepiisobractatin (3), 8-methoxy-8,8a-dihydrobractatin (4), 8-ethoxy-8,8a-dihydrobractatin (5), garcibracteatone (6), and 8-methoxy-8,8a-dihydroneobractiatin (7), and the eight known compounds 8-15 were isolated from the leaves of Garcinia bracteata. The structures were unambiguously elucidated through analysis of spectroscopic data. The 2D structures and relative configurations of 1 and 5 were confirmed by X-ray crystallographic analysis. The separation of the enantiomers of 1-5 was accomplished by chiral-phase HPLC. The absolute configurations of the enantiomers of 1 and 5 were assigned by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. The absolute configurations of the related compounds were determined via comparisons of their ECD data with those of the enantiomers of 1 and 5, respectively. Notably, compound 7, with a neo caged skeleton, is the first representative of a novel type of caged xanthone lacking a Δ8(8a) double bond. The isolated compounds exhibited significant cell growth inhibitory activities in vitro against human leukemic HL-60 and K562 cell lines, with GI50 values ranging from 0.2 to 8.8 µM. A preliminary structure-activity relationship is discussed.

The phylogenetic group, antimicrobial susceptibility, and virulence genes of Escherichia coli from clinical bovine mastitis.

Bovine mastitis is still a central problem on dairy farms despite control programs, and Escherichia coli is a crucial pathogen during the development of bovine mastitis. The virulence genes, antimicrobial susceptibility, and mortality of mice infected with different E. coli isolates from bovine mastitis were determined in this study. According to the presence of the specific genes chuA, yjaA, and TspE4.C2, these isolates mainly belonged to 2 different groups: group A (47/79) and group B1 (22/79). The ompC gene was detected in all the isolates, followed by fimH (89.9%), ECs3703 (88.6%), and ompF (73.4%), whereas most of the virulence genes were not detected in these isolates. The results of the antimicrobial susceptibility tests indicated that the isolates were susceptible to the fluoroquinolones and aminoglycosides. An inverse relationship was shown between the expression level of ompF and antimicrobial resistance; additionally, the isolates that were nonsusceptible to at least 4 classes of antimicrobial agents showed a lower mortality to mice in comparison with the susceptible isolates. This study indicated that antibiotic resistance had emerged in E. coli from bovine mastitis in this area, and appropriate measures should be taken to avoid potential threats to humans and other animals.

Neobraclactones A-C, three unprecedented chaise longue-shaped xanthones from Garcinia bracteata.

Neobraclactones A-C (1-3), featuring an unprecedented further rearranged prenylxanthone skeleton with a unique octahydro-2H-1,3-dioxacyclopenta[c,d]inden-2-one scaffold, along with their biosynthesis-related known compound neobractatin (4), were isolated from the leaves of Garcinia bracteata. Their structures with absolute configurations were determined by extensive analyses of spectroscopic data and ECD calculations. Compounds 1 and 2 showed significant growth inhibition activities against the human leukaemia HL-60 and K562 cell lines with GI50 values from 0.40 to 0.86 µM.

Enantioselective [4 + 1] Annulation Reactions of α-Substituted Ammonium Ylides To Construct Spirocyclic Oxindoles.

Ammonium ylides have a long history in organic synthesis, but their application in asymmetric catalysis is still underdeveloped in regard to both substrate scope and reaction pathways compared with phosphorus and sulfur ylides. Here a previously unreported asymmetric [4 + 1] annulation reaction of 3-bromooxindoles and electron-deficient 1-azadienes has been developed through ammonium ylide catalysis of a newly designed 2'-methyl α-isocupreine (α-MeIC), efficiently delivering spirocyclic oxindole compounds incorporating a dihydropyrrole motif in excellent enantioselectivity (up to 99% ee). To the best of our knowledge, this work represents the first example of asymmetric catalysis of ammonium ylides bearing α-substitutions, and the catalytic [4 + 1] annulation pathway of ammonium ylides is also unprecedented. Moreover, (1)H NMR, mass spectroscopy, and computational calculation studies were conducted, and the catalytic cycle and a tentative explanation of the enantioselective mechanism have been successfully elucidated.

Investigation of the Binding Interaction of Mfsd2a with NEDD4-2 via Molecular Dynamics Simulations.

Major facilitator superfamily domain-containing 2a (Mfsd2a) is a sodium-dependent lysophosphatidylcholine cotransporter that plays an important role in maintaining the integrity of the blood-brain barrier and neurological function. Abnormal degradation of Mfsd2a often leads to dysfunction of the blood-brain barrier, while upregulation of Mfsd2a can retrieve neurological damage. It has been reported that Mfsd2a can be specifically recognized and ubiquitinated by neural precursor cell-expressed developmentally downregulated gene 4 type 2 (NEDD4-2) ubiquitin ligase and finally degraded through the proteasome pathway. However, the structural basis for the specific binding of Mfsd2a to NEDD4-2 is unclear. In this work, we combined deep learning and molecular dynamics simulations to obtain a Mfsd2a structure with high quality and a stable Mfsd2a/NEDD4-2-WW3 interaction model. Moreover, molecular mechanics generalized Born surface area (MM-GBSA) methods coupled with per-residue energy decomposition studies were carried out to analyze the key residues that dominate the binding interaction. Based on these results, we designed three peptides containing the key residues by truncating the Mfsd2a sequences. One of them was found to significantly inhibit Mfsd2a ubiquitination, which was further validated in an oxygen-glucose deprivation (OGD) model in a human microvascular endothelial cell line. This work provides some new insights into the understanding of Mfsd2a and NEDD4-2 interaction and might promote further development of drugs targeting Mfsd2a ubiquitination.

Study on fast algorithm of neutron radiation field under complex terrain scenario based on ensemble learning approach.

In this study a prediction algorithm has been proposed to rapidly figure out neutron radiation field for nuclear explosion under complex terrain scenario based on ensemble learning approach, which could be an impossibility for traditional radiation transport simulation methodology. By analyzing the influence of complex surface morphology on the radiation field, a series of characteristic parameters which could characterize the topographic features and their influence on the transport of neutrons and secondary gamma in the atmosphere have been extracted with the application of DEM, and the sample sethas been constructedwith the MC simulation results of terrain samples generated by random algorithm, to be used to train the prediction model for the neutron radiation field of nuclear explosion. In order to verify the actual prediction performance of the model, the study has implemented the prediction for the neutron flux, neutron tissue dose and secondary gamma tissue dose under the authentic urban and mountainous terrain scenarios, and analyzed and compared the results from fast prediction and MC simulation in different evaluation dimensions. The comparisons suggest that both of the results are in good agreement with each other, demonstrating that the fast prediction models preliminarily possess the engineering application value. In addition, a feasible approach to improve the generalization performance of the prediction model for various radiation scenarios has been proposed, which could be deemed as a reference for further research.

Simplified Derivatives of Tetrandrine as Potent and Specific P-gp Inhibitors to Reverse Multidrug Resistance in Cancer Chemotherapy.

Targeted inhibition of a drug efflux transporter P-glycoprotein (P-gp) is an important strategy to reverse multidrug resistance in cancer chemotherapy. In this study, a rationally structural simplification to natural tetrandrine was performed based on molecular dynamics simulation and fragment growth, leading to an easily prepared, novel, and simplified compound OY-101 with high reversal activity and low cytotoxicity. Its excellent synergistic anti-cancer effect with vincristine (VCR) against drug-resistant cells Eca109/VCR was confirmed by reversal activity assay, flow cytometry, plate clone formation assay, and drug synergism analysis (IC50 = 9.9 nM, RF = 690). Further mechanism study confirmed that the OY-101 was a specific and efficient P-gp inhibitor. Importantly, OY-101 increased VCR sensitization in vivo without obvious toxicity. Overall, our findings may provide an alternative strategy for the design of novel specific P-gp inhibitor as an anti-tumor chemotherapy sensitizer.

Apoptotic effects of phenols from the twigs and leaves of Garcinia nujiangensis.

In order to find potential agents for treating cancer disease in naturally occurring compounds, we conducted a systematic phytochemical investigation on the endemic species of Garcinia nujiangensis. Three new biphenyl derivatives (1-3) and one new polycyclic polyprenylated benzophenone (4), together with four known benzophenone analogues (5-8), have been isolated from the CH2Cl2 extract of the twigs and leaves of G. nujiangensis. Their structures were determined by detailed spectroscopic analyses and comparison with structurally related known analogues. Experimental and calculated ECD method was used to determine the absolute configuration of 1 and 4. Moreover, compounds 5-7 were isolated for the first time from this species. The cytotoxicities of the new compounds were evaluated using HL-60, HepG2, and A549 human cancer cell lines. Compound 4 showed more significant antiproliferative effects against HepG2 cells with an IC50 value of 11.38 ± 0.79 µM than that of three biphenyl derivatives. The morphological features of apoptosis were evaluated in 4-treated HepG2 cells. Compound 4 effectively prevented the cell cycle progression of HepG2 cells in G2 phase. Additionally, western blot analysis indicated that treatment of 4 on HepG2 cells led to decreased expression of anti-apoptotic Bcl-2 and pro-Caspase-3, and increased protein expression of both pro-apoptotic Bax and cleaved PARP with reference to ß-actin. Overall, our results suggested that the active polycyclic polyprenylated benzophenone derivatives in the twigs and leaves of G. nujiangensis can be used as a valuable source of bioactive compounds for the pharmaceutical industry.

Development of sertraline analogues as potential anti-ischemic stroke agents.

Ischemic stroke (IS) is harmful to human health and social development, and there is no medicine available at present. To find the hit compound for treating ischemic stroke, we screened 28 FDA approved nervous system drugs by using an in vitro OGD-induced stroke model. Notably, our in vitro and in vivo studies demonstrated that low-dose sertraline had good neuroprotective activities, while high-dose sertraline showed significant toxicity. Interestingly, the same high-dose sertraline in the control group did not exhibit any obvious toxic effect. Therefore, it is important to modify the structure of sertraline to improve the activity and reduce the toxicity. Stereoisomers of sertraline were first investigated to analyze the influence of stereochemistry on the neuroprotective activities, which showed no obvious difference. Then we evaluated the activity of our previously reported sertraline analogues and found that introducing amide or alkane groups to the amino moiety might be beneficial to enhance the activity and reduce the toxicity. Thus, 10 new analogues were designed, synthesized, and evaluated. Among them, compound OY-201 showed the best safety and neuroprotective activity in both in vitro and in vivo models. Moreover, it exhibited good blood-brain barrier (BBB) permeability, indicating its potential for the development of anti-ischemic stroke drugs.

Inhibitory Mechanism of Prenylated Flavonoids Isolated from Mulberry Leaves on α-Glucosidase by Multi-Spectroscopy and Molecular Dynamics Simulation.

Flavonoids have always been considered as the chemical basis for the hypoglycemic effect of mulberry leaves. In the course of our search for hypoglycemic effect agents from natural sources, a systematic study was launched to explore prenylated flavonoids from mulberry leaves. Herein, chemical investigation led to the isolation of 10 characteristic prenylated flavonoids, including two new compounds (1 and 3). Their structures were elucidated based on spectroscopic data. All compounds exhibited good α-glucosidase inhibitory activity in vitro, among which compound 2 had the best activity (IC50 = 2.6 µM), better than acarbose (IC50 = 19.6 µM). Additional in vivo tests have further demonstrated compound that compound 2 has a good ability to reduce postprandial blood glucose. Then, multi-spectroscopic methods and molecular simulation studies were used to study the inhibition mechanism. The results showed that compound 2 was a mixed inhibition of α-glucosidase and the binding process was spontaneous, with van der Waals forces as the main driving force, followed by hydrogen bonding and electrostatic forces. The above studies enriched the chemical basis of mulberry leaves, and the application of computational chemistry also provided a reference for future research on such structures.

Solid fuel production from co-hydrothermal carbonization of polyvinyl chloride and corncob: Higher dechlorination efficiency and process water recycling.

The hydrothermal carbonization (HTC) of polyvinyl chloride (PVC) and wet herbal agricultural wastes for solid fuel production remains bleak economics and sustainability because of high chloride residual, wastewater burden and low production capacity. In this study, the HTC dechlorination was investigated using the first-order reaction kinetic analysis. We found that the co-hydrothermal carbonization (co-HTC) of PVC and the typical biomass (corncob) achieved a staggering drop of dechlorination activation energy from 189.95 kJ/mol to 110.04 kJ/mol. The co-HTC process achieved rapid dechlorination and carbonization due to synergistic effect, to suppress the chlorine content in bituminous-coal-like hydrochar less than 0.05 %. The process wastewater (process water) from co-HTC was recycled four times to evaluate the reusability and chemical evolution. The organics in co-HTC environment enhanced the carbonization which was confirmed by the improved heating value (30.06 to 32.42 MJ·kg-1), hydrochar yield (33.33 % to 36.47 %) and energy recovery efficiency (57.73 % to 68.13 %). The Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) evidenced the process water recirculation maintained high chloride removal. Moreover, the possible formation pathways of two kinds of hydrochars were discussed through the chemical composition of the aqueous phase and the characteristic structures of hydrochar. The co-HTC and process water recycling strategies provide a more promising prospect to convert PVC and biomass wastes into solid fuels.