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The potato tuber moth, Phthorimaea operculella, is the most damaging potato pest in the world and is difficult to control as the larvae are internal feeders in the foliage and tubers. Entomopathogenic fungi that colonize plants as endophytes have lethal and sublethal pathological effects on insect pests. We show that Beauveria bassiana colonizes the aerial parts of potato plants endophytically after inoculation through soil drenching. Endophytic B. bassiana persisted in potato foliage for more than 50 days postinoculation. Bioassays indicated that foliage of B. bassiana‐inoculated potato plants were pathogenic against larvae of P. operculella. Sublethal experiments indicated that B. bassiana negatively affected the growth, development, and reproduction of P. operculella. Development experiments showed that the weight of P. operculella pupae reared on B. bassiana‐colonized potato plants (4.25 mg) was significantly less than that of those reared on uninoculated control plants (8.89 mg). Compared with newly eclosed larvae fed on control plants, those fed on B. bassiana‐inoculated plants had significantly lower survivorship, with only 17.8% developing to the adult stage. Oviposition of P. operculella females reared on B. bassiana endophytically colonized plants was significantly lower (35 eggs/female) than of those reared on uninoculated plants (115 eggs/female). This study demonstrates that endophytic B. bassiana can be a potential biological control agent for the control and management of P. operculella. Comparing pupal weights of P. operculella reared on potato plants inoculated with the B. bassiana strain GZGY‐1‐3 and on untreated control plants, pupae from the control plants were significantly heavier than those from treated plants. [ABSTRACT FROM AUTHOR]

Cancers resist targeted therapeutics by drug‐escape signaling. Multitarget drugs co‐targeting cancer and drug‐escape mediators (DEMs) are clinically advantageous. DEM coverage may be expanded by drug combinations. This work evaluated to what extent the kinase DEMs (KDEMs) can be optimally co‐targeted by drug combinations based on target promiscuities of individual drugs. We focused on 41 approved and 28 clinical trial small molecule kinase inhibitor drugs with available experimental kinome and clinical pharmacokinetic data. From the kinome inhibitory profiles of these drugs, drug combinations were assembled for optimally co‐targeting an established cancer target (EGFR, HER2, ABL1, or MEK1) and 9–16 target‐associated KDEMs at comparable potency levels as that against the cancer target. Each set of two‐, three‐, and four‐drug combinations co‐target 36–71%, 44–89%, 50–88%, and 27–55% KDEMs of EGFR, HER2, ABL1, and MEK1, respectively, compared with the 36, 33, 38, and 18% KDEMs maximally co‐targeted by an existing drug or drug combination approved or clinically tested for the respective cancer. Some co‐targeted KDEMs are not covered by any existing drug or drug combination. Our work suggested that novel drug combinations may be constructed for optimally co‐targeting cancer and drug escape by the exploitation of drug target promiscuities. [ABSTRACT FROM AUTHOR]

The clinical advantage of co‐targeting cancer drug escape has been indicated by the percentage of these co‐targeting drugs among all multi‐target drugs in clinics and clinical trials. This clinical advantage needs to be further interrogated from such perspectives as the clinical impact of multi‐target inhibition of drug‐escape mediators. This impact may be reflected by drug sales data, that is, multi‐target inhibition of higher number of drug‐escape mediators favors the expanded coverage of drug‐resistant patients leading to higher sales. We investigated whether this expectation is followed by the 25 FDA‐approved anticancer kinase inhibitors, which were divided into 11 groups of comparable therapeutic mechanisms and approval years. We found 19 (76%) drugs to follow and 3 (12%) drugs not to follow this expectation. The remaining two (8%) and one (4%) drugs cannot be assessed due to insufficient data and incomparability. Therefore, drug sales strongly indicate the clinical advantage of multi‐target inhibition of cancer drug escapes. [ABSTRACT FROM AUTHOR]

Currently, knowledge about the impact of high-grain ( HG) feeding on rumen microbiota and metabolome is limited. In this study, a combination of the 454 pyrosequencing strategy and the mass spectrometry-based metabolomics technique was applied to investigate the effects of increased dietary grain (0%, 25% and 50% maize grain) on changes in whole ruminal microbiota and their metabolites using goat as a ruminant model. We observed a significant influence of HG feeding in shaping the ruminal bacterial community structure, diversity and composition, with an overall dominance of bacteria of the phylum Firmicutes along with a low abundance of Bacteriodetes in the HG group. High-grain feeding increased the number of ciliate and methanogens, and decreased the density of anaerobic fungi and the richness of the archaeal community. The metabolomics analysis revealed that HG feeding increased the levels of several toxic, inflammatory and unnatural compounds, including endotoxin, tryptamine, tyramine, histamine and phenylacetate. Correlation analysis on the combined datasets revealed some potential relationships between ruminal metabolites and certain microbial species. Information about these relationships may prove useful in either direct (therapeutic) or indirect (dietary) interventions for ruminal disorders due to microbial compositional shifts, such as ruminal acidosis. [ABSTRACT FROM AUTHOR]

1,8‐Diazabicyclo[5.4.0]undec‐7‐ene (DBU) catalyzed Michael addition reactions between α,β‐unsaturated esters and benzophenone‐imines of glycine esters have been realized in THF at room temperature by using LiBr as an additive, effectively enabling the glutamation of phenols, thiophenols, secondary amines and imides. 3‐Substituted glutamic acid esters were obtained in excellent yields and diastereoselectivities (up to quantitative yield and >20 : 1 dr). These glutamic acid esters were readily converted into their corresponding pyroglutamic acid esters in high yields through acidic hydrolysis followed by lactamization. [ABSTRACT FROM AUTHOR]

The gastrointestinal tract is protected by a mucus barrier with both secreted and cell-surface mucins contributing to the exclusion of luminal microbes and toxins. Alterations in the structure and/or quantity of mucins alter the barrier function of mucus and could play roles in initiating and maintaining mucosal inflammation in inflammatory bowel diseases (IBD), and in driving cancer development in the intestine. The aim of this review is to focus on the roles of the mucins in IBD. The polymorphisms of mucin genes that have been associated with susceptibility to IBD, and alterations in mucin expression as well as factors that regulate production of the mucins in IBD, are summarized. Data from animal models of intestinal inflammation, which support the importance of mucins in IBD and cancer development, are also discussed. [ABSTRACT FROM AUTHOR]

Background and Aim: Recent investigations demonstrate that adult stem cells may be targets for malignant transformation and that the stem-like cells in diseased livers possess the capacity of tumorigenicity in animal models. The aim of this study is to examine expression patterns of stem-cell markers in hepatitis B virus–associated cirrhotic livers and hepatocellular carcinomas (HCC), and to investigate the stem-like cell capacity of tumorigenicity in these tissues. Methods: Twenty surgically resected HCCs and corresponding adjacent tissues as well as 10 cirrhotic liver tissues were collected and immunohistochemical staining were performed to detect the expression of CD34, Thy-1, CD133, and c-kit. Then the non-cancerous tissues were transplanted into immunodeficient mice and the characteristics of the cells from primary tissue cultures were explored in vitro. Results: Immunohistochemical analysis characterized different expression patterns of stem-cell markers among these tissues. First, CD34 and Thy-1 expression was identified in proliferating bile ductules and it represented hepatic progenitor cells; CD133 and c-kit-positive cells were observed in the parenchyma of these tissues, and some of them were characterized as intermediate hepatocytes morphologically and spatially. Second, in two groups including three mice transplanted with tissues adjacent to HCC-initiated tumors, CD133 and c-kit expression was detected. Finally, our study also indicated that stem-like cells from tissue could express hepatic-lineage markers and possessed great capacities to proliferate, self-renew, and form clones in vitro. Conclusion: Our results suggest that the stem-like cells in cirrhotic livers possess the capacity of tumorigenicity and may contain candidates for HCC cancer stem cells. [ABSTRACT FROM AUTHOR]

Protonation state of the triphosphate tail of ATP (adenosine triphosphate) in protein environment is a fundamental issue, which has significant impact on the mechanism investigation of biochemical processes with ATP involved. Proton transition from surroundings (water molecule coordinating to magnesium, HW; amino group of Lys, HL) to the ATP tail in the catalytic core of protein kinase found recently disproved the commonly accepted deprotonation state of ATP tail. In this account, Car-Parrinello ab initio molecular dynamics (CP-AIMD) method has been employed to examine whether the proton transition occurs. To provide a comparison basis for the dynamics simulations, static quantum mechanics (QM), and combined quantum mechanics and molecular mechanics (QM/MM) calculations have also been carried out. Consistent results have been obtained that complete transition of hydrogen from the surroundings to the triphosphate tail of ATP is not allowed. The most dominant conformations correspond to the ones with HW bonding to O(W) and H-bonding to O(ATP), [O(W)-HW···O(ATP)], HL bonding to N(Lys) and H-bonding to O(ATP), [N(Lys)-HL···O(ATP)]. Metastable structures with one hydrogen atom bonding with two heavy atoms (hydrogen acceptors) were also located by our dynamic simulations. This bonding mode can satisfy the hungering for hydrogen of the two heavy atoms simultaneously. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008 [ABSTRACT FROM AUTHOR]

Density functional theory together with Car-Parrinello ab initio molecular dynamics simulation has been used to investigate the free energy profiles (FEP) of monomer capture in Grubbs- and SHOP-type olefin polymerization catalysts. The FEPs along the reaction coordinates at 300 K were determined directly by a point wise thermodynamic integration technique. Comparison between potential energy profile (PEP) and the FEP has been made. The results show that, for both catalysts, the PEP for the monomer ethylene uptake by the metal center is a typical Morse curve without energy barrier. However, a small barrier (1.8 kcal/mol for Grubbs catalyst and 2.4 kcal/mol for SHOP catalyst) exists on the FEP. The π complexation energy on the FES at 300 K is higher by 10–12 kcal/mol over that on the PES. The differences between FES and PES are due to entropy contribution. Slow growth simulations on the ethylene capture process show that the ethylene attacks the metal center by an asynchronous mode. This indicates that the forming of the π-bonding between the metal and ethylene is initiated by electrophilic attack of the metal to one of the ethylene carbons. © 2006 Wiley Periodicals, Inc. J Comput Chem 28: 513–518, 2007 [ABSTRACT FROM AUTHOR]

Objectives: Tumor‐associated autoantibodies (AAbs) in individuals with cancer can precede clinical diagnosis by several months to years. The objective of this study was to determine whether the primary immune response in form of IgM and gut mucosa‐associated IgA can aid IgG AAbs in the detection of early‐stage colorectal cancer (CRC). Methods: We developed a novel protein array comprising 492 antigens seropositive in CRC. The array was used to profile IgG, IgM and IgA antibody signatures in 99 CRC patients and 99 sex‐ and age‐matched non‐cancer controls. A receiver operating curve (ROC), Kaplan–Meier survival analysis and univariate and multivariate Cox regression analyses were conducted. Results: We identified a panel of 16 multi‐isotype AAbs with a cumulative sensitivity of 91% and specificity of 74% (AUC 0.90, 95% CI: 0.850–0.940) across all CRC stages. IgM and IgG isotypes were conversely associated with disease stage with IgM contributing significantly to improved stage I and II sensitivity of 96% at 78% specificity (AUC 0.928, 95% CI: 0.884–0.973). A single identified IgA AAb reached an overall sensitivity of 5% at 99% specificity (AUC 0.520, 95% CI: 0.440–0.601) balanced across all CRC stages. Kaplan–Meier analysis revealed that se33‐1 (ZNF638) IgG AAbs were associated with reduced 5‐year overall survival (log‐rank test, P = 0.012), whereas cumulative IgM isotype signatures were associated with improved 5‐year overall survival (log‐rank test, P = 0.024). Conclusion: IgM AAbs are associated with early‐stage colorectal cancer. Combining IgG, IgM and IgA AAbs is a novel strategy to improve early diagnosis of cancers. [ABSTRACT FROM AUTHOR]

Review: [28 refs. [ABSTRACT FROM AUTHOR]

A highly efficient asymmetric Michael addition of bulky glycine imine to α,β‐unsaturated isoxazoles has been achieved by using 5 mol% of chiral cyclopropenimine as a chiral organo‐superbase catalyst under mild conditions. Michael adducts were obtained in excellent yields (up to 97%) and stereoselectivities (up to >99 : 1 dr and 98% ee). A significant solvent effect was found in these chiral organosuperbase catalyzed asymmetric Michael reactions. Gram‐scale preparation of Michael adducts and their transformations are realized to provide corresponding products without loss of stereoselectivities. The configurations of Michael adduct was determined by single‐crystal X‐ray diffraction analysis. [ABSTRACT FROM AUTHOR]

Background: Direct moxibustion (DM) is reported to be useful for cervical spondylotic radiculopathy (CSR), but the analgesic mechanism remains unknown. Autophagy plays a protective role in neuronal apoptosis, Act A/Smads signaling pathway has been confirmed to be associated with the activation of autophagy. The study aimed to explore the effect of DM on autophagy in rats with CSR and the involvement of Act A/Smads signaling pathway. Methods: Rats were randomly divided into Sham, CSR, CSR + DM, CSR + DM + 3‐MA (PI3K inhibitor), and CSR + DM + SB (Act A inhibitor) group. Three days after establishment of CSR model with a fish line inserted under the axilla of the nerve roots, DM at Dazhui (GV14) was performed six times once for seven consecutive days. Western blot and immunofluorescence staining were used to observe the expression of the neuronal autophagy molecule LC3II/I, Atg7, and Act A/Smads signaling molecule Act A, p‐Smad2, and p‐Smad3. Bcl‐2/Bax mRNA expression was measured by real time PCR. Results: DM improved the pain threshold and motor function of CSR rats and promoted the expression of Act A, p‐Smad2, p‐Smad3, LC3II/I, and Atg7 in the entrapped‐nerve root spinal dorsal horn. DM reduced the expression of Bax mRNA and decreased the number of apoptotic neurons. 3‐MA and Act A inhibitor SB suppressed the expression of above‐mentioned proteins and reduced the protective effect of DM on apoptotic neurons. Conclusion: DM exerts analgesic effects by regulating the autophagy to reduce cell apoptosis and repair nerve injury, and this feature may be related to the Act A/Smads signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Ethnic‐specific genetic risk assessment framework for Parkinson's disease (PD) is lacking for the Asian population. Objective: We investigated the association of a polygenic risk score (PRS) with PD incidence in a population‐based Asian prospective cohort. Methods: Genetic, dietary, and lifestyle information were prospectively collected from 25,646 participants within the Singapore Chinese Health Study cohort. PRS was constructed with Asian‐specific and top genome‐wide association study variants. The association between PRS and PD incidence was evaluated with multivariable Cox proportional hazard models, Kaplan–Meier survival analysis, and concordance statistics. Results: A total of 333 incident cases were identified after a follow‐up period of more than 20 years. Participants with PRS in the top tertile (hazard ratio [HR], 1.81; 95% confidence interval [CI], 1.37–2.39) and middle tertile (HR, 1.35; 95% CI, 1.00–1.83) are at higher risk of developing PD after adjusting for dietary and lifestyle risk factors, with a shorter time to PD event in a Kaplan–Meier survival analysis (P < 0.001). Conclusion: We identified a PRS that was significantly associated with PD incidence in a prospective Chinese cohort after adjusting for dietary and lifestyle factors. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Ab initio calculations were performed to investigate the charge separation and charge recombination processes in the photoinduced electron transfer reaction between tetracyanoethylene and acenaphthylene. The excited states of the charge-balanced electron donor–acceptor complex and the singlet state of ion pair complex were studied by employing configuration interaction singles method. The equilibrium geometry of electron donor–acceptor complex was obtained by the second-order Møller–Plesset method, with the interaction energy corrected by the counterpoise method. The theoretical study of ground state and excited states of electron donor–acceptor complex in this work reveals that the S1 and S2 states of the electron donor–acceptor complexes are excited charge transfer states, and charge transfer absorptions that corresponds to the S0 → S1 and S0 → S2 transitions arise from π–π* excitations. The charge recombination in the ion pair complex will produce the charge-balanced ground state or excited triplet state. According to the generalized Mulliken–Hush model, the electron coupling matrix elements of the charge separation process and the charge recombination process were obtained. Based on the continuum model, charge transfer absorption and charge transfer emission in the polar solvent of 1,2-dichloroethane were investigated. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem 94: 23–35, 2003 [ABSTRACT FROM AUTHOR]

Western flower thrip, Frankliniella occidentalis (Pergande), is among the most economically important agricultural pests globally, attacking a wide range of vegetable and horticultural crops. In addition to causing extensive crop damage, the species is notorious for vectoring destructive plant viruses, mainly belonging to the genera Orthotospovirus, Ilarvirus, Alphacarmovirus and Machlomovirus. Once infected by orthotospoviruses, thrips can remain virulent throughout their lifespan and continue transmitting viruses to host plants when and wherever they feed. These irruptive viral outbreaks in crops will permanently disrupt functional integrated pest management systems, and typically require a remedial treatment involving insecticides, contributing to further development of insecticide resistance. To mitigate against this continuing cycle, the most effective management is early and comprehensive surveillance of the pest species and recognition of plant viruses in the field. This review provides information on the pest status of F. occidentalis, discusses the current global status of the viruses vectored by this thrip species, examines the mechanisms involved in transmitting virus‐induced diseases by thrips, and reviews different management strategies, highlighting the potential management tactics developed for various cropping systems. The early surveillance and the utilization of potential methods for control of both F. occidentalis and viruses are proposed. [ABSTRACT FROM AUTHOR]

Peptidyl‐prolyl cis‐trans isomerase Pin1 plays a crucial role in the development of human cancers. Recently, we have disclosed that Pin1 regulates the biogenesis of miRNA, which is aberrantly expressed in HCC and promotes HCC progression, indicating the therapeutic role of Pin1 in HCC therapy. Here, 7‐(benzyloxy)‐3,5‐dihydroxy‐2‐(4‐methoxyphenyl)‐8‐(3‐methylbut‐2‐en‐1‐yl)‐4H‐chromen‐4‐one (AF‐39) was identified as a novel Pin1 inhibitor. Biochemical tests indicate that AF‐39 potently inhibits Pin1 activity with an IC50 values of 1.008 μm, and also displays high selectivity for Pin1 among peptidyl prolyl isomerases. Furthermore, AF‐39 significantly suppresses cell proliferation of HCC cells in a dose‐ and time‐dependent manner. Mechanistically, AF‐39 regulates the subcellular distribution of XPO5 and increases miRNAs biogenesis in HCC cells. This work provides a promising lead compound for HCC treatment, highlighting the therapeutic potential of miRNA‐based therapy against human cancer. Neat as a pin: Prenylated flavonol AF‐39 was discovered as a novel and selective Pin1 inhibitor with an IC50 value of 1.008 μm. In hepatocellular carcinoma (HCC) cells, AF‐39 significantly suppresses HCC proliferation via restoring ERK‐phosphorylated exportin‐5 (XPO5) nucleus–cytoplasm distribution and upregulating microRNA biogenesis. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase 5 (PRMT5) is an important protein arginine methyltransferase that catalyzes the symmetric dimethylation of arginine resides on histones or non-histone substrate proteins. It has been thought as a promising target for many diseases, particularly cancer. Despite the potential applications of PRMT5 inhibitors in cancer treatment, very few of PRMT5i have been publicly reported. In this investigation, virtual screening and structure-activity relationship studies were carried out to discover novel PRMT5i, which finally led to the identification of a number of new PRMT5i. The most active compound, P5i-6, exhibited a considerable inhibitory potency against PRMT5 with an IC50 value of 0.57 μ m, and a high selectivity for PRMT5 against other tested PRMTs. It displayed a very good antiviability activity against two colorectal cancer cell lines, HT-29 and DLD-1, and one hepatic cancer cell line, HepG2, in a sensitivity assay against 36 different cancer cell lines. Western blot assays indicated that P5i-6 selectively inhibited the symmetric dimethylations of H4R3 and H3R8 in DLD-1 cells. Overall, P5i-6 could be used as a chemical probe to investigate new functions of PRMT5 in biology and also served as a good lead compound for the development of new PRMT5-targeting therapeutic agents. [ABSTRACT FROM AUTHOR]

P450 119 peroxygenase and its site-directed mutants are discovered to catalyze the enantioselective epoxidation of methyl-substituted styrenes. Two new site-directed P450 119 mutants, namely T213Y and T213M, which were designed to improve the enantioselectivity and activity for the epoxidation of styrene and its methyl substituted derivatives, were studied. The T213M mutant is found to be the first engineered P450 peroxygenase that shows highly enantioselective epoxidation of cis-β-methylstyrenes, with up to 91 % ee. Molecular modeling studies provide insights into the different catalytic activity of the T213M mutant and the T213Y mutant in the epoxidation of cis-β-methylstyrene. The results of the calculations also contribute to a better understanding of the substrate specificity and configuration control for the regio- and stereoselective peroxygenation catalyzed by the T213M mutant. [ABSTRACT FROM AUTHOR]

Receptor interacting protein 1 ( RIP1) kinase plays an important role in necroptosis, and inhibitors of the RIP1 kinase are thought to have a potential therapeutic value in the treatment of diseases related to necrosis. Herein, we report the structural optimization of a RIP1 kinase inhibitor, 1-(2,4-dichlorobenzyl)-3-nitro-1 H-pyrazole ( 1a). A number of 1-benzyl-1 H-pyrazole derivatives were synthesized and structure-activity relationship ( SAR) analysis led to the discovery of a potent compound, 4b, which showed a Kd value of 0.078 μ m against the RIP1 kinase and an EC50 value of 0.160 μ m in a cell necroptosis inhibitory assay. Compound 4b also displayed considerable ability to protect the pancreas in an l-arginine-induced pancreatitis mouse model. [ABSTRACT FROM AUTHOR]

The objective of this research was to compare the composition of bacterial microbiota associated with the ruminal content ( RC), ruminal epithelium ( RE) and faeces of Holstein dairy cows. The RC, RE and faecal samples were collected from six Holstein dairy cows when the animals were slaughtered. Community compositions of bacterial 16S rRNA genes from RC, RE and faeces were determined using a MiSeq sequencing platform with bacterial-targeting universal primers 338F and 806R. UniFrac analysis revealed that the bacterial communities of RC, RE and faeces were clearly separated from each other. Statistically significant dissimilarities were observed between RC and faeces ( P = 0.002), between RC and RE ( P = 0.003), and between RE and faeces ( P = 0.001). A assignment of sequences to taxa showed that the abundance of the predominant phyla Bacteroidetes was lower in RE than in RC, while a significant higher ( P < 0.01) abundance of Proteobacteria was present in RE than in RC. When compared with the RC, the abundance of Firmicutes and Verrucomicrobia was higher in faeces, and RC contained a greater abundance of Bacteroidetes and Tenericutes. A higher proportions of Butyrivibrio and Campylobacter dominated RE as compared to RC. The faecal microbiota was less diverse than RC and dominated by genera Turicibacter and Clostridium. In general, these findings clearly demonstrated the striking compositional differences among RC, RE and faeces, indicating that bacterial communities are specific and adapted to the harbouring environment. [ABSTRACT FROM AUTHOR]

Background and Purpose: Ischaemic stroke is a serious disease with limited therapy options. Glycoprotein (GP)Ib binding to von Willebrand factor (vWF) exposed at vascular injury initiates platelet adhesion and contributes to platelet aggregation. GPIb has been suggested as an effective target for antithrombotic therapy in stroke. Anfibatide is a GPIb antagonist derived from snake venom and we investigated its protective effect on experimental brain ischaemia in mice.Experimental Approach: Focal cerebral ischaemia was induced by 90 min of transient middle cerebral artery occlusion (MCAO). These mice were then treated with anfibatide (4, 2, 1 μg·kg(-1) ), injected i.v., after 90 min of MCAO, followed by 1 h of reperfusion. Tirofiban, a GPIIb/IIIα antagonist, was used as a positive control.Key Results: Twenty-four hours after MCAO, anfibatide-treated mice showed significantly improved ischaemic lesions in a dose-dependent manner. The mice had smaller infarct volumes, less severe neurological deficits and histopathology of cerebrum tissues compared with the untreated MCAO mice. Moreover, anfibatide decreased the amount of GPIbα, vWF and accumulation of fibrin(ogen) in the vasculature of the ischaemic hemisphere. Tirofiban had similar effects on infarct size and fibrin(ogen) deposition compared with the MCAO group. Importantly, the anfibatide-treated mice showed a lower incidence of intracerebral haemorrhage and shorter tail bleeding time compared with the tirofiban-treated mice.Conclusions and Implications: Our data indicate anfibatide is a safe GPIb antagonist that exerts a protective effect on cerebral ischaemia and reperfusion injury. Anfibatide is a promising candidate that could be beneficial for the treatment of ischaemic stroke. [ABSTRACT FROM AUTHOR]

Background and Purpose Ischaemic stroke is a serious disease with limited therapy options. Glycoprotein ( GP)Ib binding to von Willebrand factor ( vWF) exposed at vascular injury initiates platelet adhesion and contributes to platelet aggregation. GPIb has been suggested as an effective target for antithrombotic therapy in stroke. Anfibatide is a GPIb antagonist derived from snake venom and we investigated its protective effect on experimental brain ischaemia in mice. Experimental Approach Focal cerebral ischaemia was induced by 90 min of transient middle cerebral artery occlusion ( MCAO). These mice were then treated with anfibatide (4, 2, 1 μg·kg−1), injected i.v., after 90 min of MCAO, followed by 1 h of reperfusion. Tirofiban, a GPIIb/ IIIα antagonist, was used as a positive control. Key Results Twenty-four hours after MCAO, anfibatide-treated mice showed significantly improved ischaemic lesions in a dose-dependent manner. The mice had smaller infarct volumes, less severe neurological deficits and histopathology of cerebrum tissues compared with the untreated MCAO mice. Moreover, anfibatide decreased the amount of GPIbα, vWF and accumulation of fibrin(ogen) in the vasculature of the ischaemic hemisphere. Tirofiban had similar effects on infarct size and fibrin(ogen) deposition compared with the MCAO group. Importantly, the anfibatide-treated mice showed a lower incidence of intracerebral haemorrhage and shorter tail bleeding time compared with the tirofiban-treated mice. Conclusions and Implications Our data indicate anfibatide is a safe GPIb antagonist that exerts a protective effect on cerebral ischaemia and reperfusion injury. Anfibatide is a promising candidate that could be beneficial for the treatment of ischaemic stroke. [ABSTRACT FROM AUTHOR]

A series of dipeptide-like organocatalysts are easily synthesized from commercially available materials in multi-gram scale and applied in asymmetric Aldol reactions. [ABSTRACT FROM AUTHOR]

Most of the scoring functions currently used in structure-based drug design belong to 'universal' scoring functions, which often give a poor correlation between the calculated scores and experimental binding affinities. In this investigation, we proposed a simple strategy to construct target-specific scoring functions based on known 'universal' scoring functions. This strategy was applied to Chemscore, a widely used empirical scoring function, which led to a new scoring function, termed TS-Chemscore. TS-Chemscore was validated on 14 protein targets, which cover a wide range of biological target categories. The results showed that TS-Chemscore significantly improved the correlation between the calculated scores and experimental binding affinities compared with the original Chemscore. TS-Chemscore was then applied in virtual screening to retrieve novel JAK3 and YopH inhibitors. Top 30 compounds for each target were selected for experimental validation. Six active compounds for JAK3 and four for YopH were obtained. These compounds were out of the lists of top 30 compounds sorted by Chemscore. Collectively, TS-Chemscore established in this study showed a better performance in virtual screening than its counterpart Chemscore. [ABSTRACT FROM AUTHOR]

In this investigation, a common feature pharmacophore model of anaplastic lymphoma kinase inhibitors was developed based on several known anaplastic lymphoma kinase inhibitors that were co-crystallized with anaplastic lymphoma kinase. The established pharmacophore model Hypo1 was carefully validated and then adopted to screen two in silico chemical databases, Specs (202 408 compounds) and Enamine (1 105 894 compounds), for retrieving novel anaplastic lymphoma kinase inhibitors. The hit compounds were further filtered using a fast bumping-check tool and molecular docking. Finally, 25 compounds were selected and purchased from market. The bioactivity of these compounds was firstly measured at the cellular level against a typical anaplastic lymphoma kinase mutant-driven cancer cell line, Karpas299. And six of them showed a good anti-viability activity. The kinase inhibitory potency against the recombinant human anaplastic lymphoma kinase kinase was tested to the most active compound at the cellular level, T0508-5181 (from Specs), which gave a half maximal inhibitory concentration (IC50) of 5.3 μ m. [ABSTRACT FROM AUTHOR]

Bruton's tyrosine kinase has emerged as a potential target for the treatment for B-cell malignancies and autoimmune diseases. Discovery of Bruton's tyrosine kinase inhibitors has thus attracted much attention recently. In this investigation, we introduced a hybrid protocol of virtual screening methods including support vector machine model-based virtual screening, pharmacophore model-based virtual screening and docking-based virtual screening for retrieving new Bruton's tyrosine kinase inhibitors from commercially available chemical databases. Performances of the hybrid virtual screening approach were evaluated against a test set, which results showed that the hybrid virtual screening approach significantly shortened the overall screening time, and considerably increased the hit rate and enrichment factor compared with the individual method (SB-VS, PB-VS and DB-VS) or their combinations by twos. This hybrid virtual screening approach was then applied to screen several chemical databases including Specs (202 408 compounds) and Enamine (980 000 compounds) databases. Thirty-nine compounds were selected from the final hits and have been shifted to experimental studies. [ABSTRACT FROM AUTHOR]

FAK (focal adhesion kinase), which plays a pivotal role in mediating cell proliferation, survival and migration, is frequently overexpressed in human malignant glioma. The expression of FAK increases with the advance of tumour grade and stage. Based on these observations, we hypothesized that attenuation of FAK expression may have inhibitory effects on the growth of malignant glioma. In the present study, human glioma cell line U251 was transfected with plasmids containing U6 promoter-driven shRNAs (small-hairpin RNAs) against human FAK using cationic liposome. The effects of FAK knockdown in U251 cells in vitro were analysed by using flow cytometry and PI (propidium iodide)-staining assays. Based on the encouraging in vitro results with FAK silencing, plasmids encoding FAK-targeted shRNA were encapsulated by DOTAP (dioleoyltrimethylammonium propane): Chol (cholesterol) cationic liposome and injected via tail vein to evaluate its therapeutic efficiency on suppressing tumour growth in a human glioma xenograft model. PCNA (proliferating-cell nuclear antigen), CD34 immunostaining and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay were used to assess the changes in tumour angiogenesis, apoptosis and proliferation respectively. The results indicated that DOTAP:Chol cationic liposome could deliver therapeutic plasmids systemically to tumour xenografts, resulting in suppression of tumour growth. Treatment with plasmid encoding FAK-targeted shRNA reduced mean tumour volume by approx. 70% compared with control groups ( P<0.05), accompanied with angiogenesis inhibition ( P<0.05), tumour cell proliferation suppression ( P<0.05) and apoptosis induction ( P<0.05). Taken together, our results demonstrated that shRNA-mediated silencing of FAK might be a potential therapeutic approach against human malignant glioma. [ABSTRACT FROM AUTHOR]

In this study, 3D-pharmacophore models of Aurora B kinase inhibitors have been developed by using HipHop and HypoGen modules in Catalyst software package. The best pharmacophore model, Hypo1, which has the highest correlation coefficient (0.9911), consists of one hydrogen-bond acceptor, one hydrogen-bond donor, one hydrophobic aliphatic moiety and one ring aromatic feature. Hypo1 was validated by test set and cross-validation methods. And the specificity of Hypo1 to Aurora B inhibitors was examined with the use of selective inhibitors against Aurora B and its paralogue Aurora A. The results clearly indicate that Hypo1 can differentiate selective inhibitors of Aurora B from those of Aurora A, and the ring aromatic feature likely plays some important roles for the specificity of Hypo1. Then Hypo1 was used as a 3D query to screen several databases including Specs, NCI, Maybridge and Chinese Nature Product Database (CNPD) for identifying new inhibitors of Aurora B. The hit compounds were subsequently subjected to filtering by Lipinski’s rule of five and docking studies to refine the retrieved hits, and some compounds selected from the top ranked hits have been suggested for further experimental assay studies. [ABSTRACT FROM AUTHOR]

Aurora-A has been identified as one of the most attractive targets for cancer therapy and a considerable number of Aurora-A inhibitors have been reported recently. In order to clarify the essential structure–activity relationship for the known Aurora-A inhibitors as well as identify new lead compounds against Aurora-A, 3D pharmacophore models were developed based on the known inhibitors. The best hypothesis, Hypo1, was used to screen molecular structural databases, including Specs and China Natural Products Database for potential lead compounds. The hit compounds were subsequently subjected to filtering by Lipinski’s rules and docking study to refine the retrieved hits and as a result to reduce the rate of false positive. Finally, 39 compounds were purchased for further in vitro assay against several human tumour cell lines including A549, MCF-7, HepG2 and PC-3, in which Aurora-A is overexpressed. Two compounds show very low micromolar inhibition potency against some of these tumour cells. And they have been selected for further investigation. [ABSTRACT FROM AUTHOR]

Six ferrocene-based chiral ligands are prepared and applied in the asymmetric transfer hydrogenation of a series of γ-aryl-α,γ-dioxo-butyric acid esters. [ABSTRACT FROM AUTHOR]