Perceptions of pelvic floor dysfunction and rehabilitation care amongst women in southeast China after radical hysterectomy: a qualitative study.

OBJECTIVE: To investigate the perceptions of pelvic floor dysfunction (PFD) and rehabilitation care amongst women after radical hysterectomy and to explore ways to improve quality of care. METHODS: Thirty-six women who underwent radical hysterectomy at a hospital in southeast China were enrolled via purposive sampling. Semi-structured in-depth interviews were conducted. The texts were analysed via qualitative content analysis. RESULTS: Four themes were obtained: serious lack of knowledge, heavy psychological burden, different coping strategies and great eagerness to receive multiparty support on PFD rehabilitation care. CONCLUSION: The society and professional staff should strengthen health education on PFD. Professionals should offer education before and after surgery and actively provide rehabilitation consultation to promote the availability of rehabilitation to support women with PFD rehabilitation care. In addition, family-centred care is an important way to support women to return to normal life, and women's need for family support should be more actively expressed. Moreover, knowledge of medical insurance should be popularised, especially in rural areas in China.

Design, synthesis, biological evaluation and molecular dynamics simulation studies of imidazolidine-2,4-dione derivatives as novel PTP1B inhibitors.

Protein tyrosine phosphatase 1B (PTP1B) is a member of the phosphotyrosine phosphatase family and plays an important role in the signal transduction of diabetes. Inhibition of PTP1B activity can increase insulin sensitivity and reduce blood sugar levels. Therefore, it is urgent to find compounds with novel structures that can inhibit PTP1B. This study designed imidazolidine-2,4-dione derivatives through the computer-aided drug design (CADD) strategy, and the Comp#10 showed outstanding inhibitory ability. (IC50 = 2.07 µM) and selectivity. The inhibitory mechanism at molecular level of Comp#10 on PTP1B was studied by molecular dynamics simulation. The results show that the catalytic region of PTP1B protein is more stable, which makes the catalytic sites unsuitable for exposure. Interestingly, the most obvious changes in the interaction between residues in the P-loop region (such as: His214, Cys215, and Ser216). In short, this study reported for the first time that imidazolidine-2,4-dione derivatives as novel PTP1B inhibitors had good inhibitory activity and selectivity, providing new ideas for the development of small molecule PTP1B inhibitors.

Inducing secondary metabolite production of Aspergillus sydowii through microbial co-culture with Bacillus subtilis.

BACKGROUND: The co-culture strategy which mimics natural ecology by constructing an artificial microbial community is a useful tool to activate the biosynthetic gene clusters to generate new metabolites. However, the conventional method to study the co-culture is to isolate and purify compounds separated by HPLC, which is inefficient and time-consuming. Furthermore, the overall changes in the metabolite profile cannot be well characterized. RESULTS: A new approach which integrates computational programs, MS-DIAL, MS-FINDER and web-based tools including GNPS and MetaboAnalyst, was developed to analyze and identify the metabolites of the co-culture of Aspergillus sydowii and Bacillus subtilis. A total of 25 newly biosynthesized metabolites were detected only in co-culture. The structures of the newly synthesized metabolites were elucidated, four of which were identified as novel compounds by the new approach. The accuracy of the new approach was confirmed by purification and NMR data analysis of 7 newly biosynthesized metabolites. The bioassay of newly synthesized metabolites showed that four of the compounds exhibited different degrees of PTP1b inhibitory activity, and compound N2 had the strongest inhibition activity with an IC50 value of 7.967 µM. CONCLUSIONS: Co-culture led to global changes of the metabolite profile and is an effective way to induce the biosynthesis of novel natural products. The new approach in this study is one of the effective and relatively accurate methods to characterize the changes of metabolite profiles and to identify novel compounds in co-culture systems.

Mycotoxins as inhibitors of protein tyrosine phosphatases from the deep-sea-derived fungus Aspergillus puniceus SCSIO z021.

Nine new xanthone-type and anthraquinone-type mycotoxins including austocystins J-N (1-5), 7-chloro versicolorin A (6), 3'-hydroxy-8-O-methyl versicolorin B (7), 8-O-methyl versiconol (8) and 2',3'-dihydroxy versiconol (9), together with 17 known analogues (10-26) were isolated from an extract of the deep-sea-derived fungus Aspergillus puniceus SCSIO z021. Their structures were elucidated by detailed analysis of spectroscopic data, and their absolute configurations were further determined by quantum chemical calculations of ECD spectra or comparison of the experimental ECD spectra. Eleven hydrogenated austocystins were synthesized from 1-2, 10-15 and 17 by catalytic hydrogenation for bioactivities evaluation. Totally, 18 of the all 37 compounds showed strong toxicity against brine shrimps or Vero cell, and the toxicity of 8-O-methyldemethylsterigmatocystin (18) (LC50 = 0.020 µM) against brine shrimps was higher than those of three positive controls. In addition, 22 of the isolated compounds also exhibited significant inhibitory activity against seven different protein tyrosine phosphatases (PTPs), among them austocystin H (15) and methyl-averantin (24) were the most potent inhibitors with IC50 values of 0.20-3.0 µM. Their structure-bioactivity relationship was also discussed.

Indole-Diterpenoids with Protein Tyrosine Phosphatase Inhibitory Activities from the Marine-Derived Fungus Penicillium sp. KFD28.

Five new indole-terpenoids named penerpenes E-I (1-5), along with seven known ones (6-12), were isolated from the marine-derived fungus Penicillium sp. KFD28 from a bivalve mollusk, Meretrix lusoria. The structures of the new compounds were elucidated from spectroscopic data and ECD spectroscopic analyses. Compound 1 was assigned as an indole-diterpenoid with a unique 6/5/5/6/6/5/5 heptacyclic ring system. Compound 2 represents an indole-diterpenoid with a new carbon skeleton derived from paxilline by the loss of three carbons (C-23/24/25). Compound 3 contains an additional oxygen atom between C-21 and C-22 compared to paxilline to form an unusual 6/5/5/6/6/7 hexacyclic ring system bearing a 1,3-dioxepane ring, which is rarely encountered in natural products. Compounds 1, 2, 4, and 6 showed inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 14, 27, 23, and 13 µM, respectively.

Wortmannilactones I-L, new NADH-fumarate reductase inhibitors, induced by adding suberoylanilide hydroxamic acid to the culture medium of Talaromyces wortmannii.

With the aim of finding more potential inhibitors against NADH-fumarate reductase (specific target for treating helminthiasis and cancer) from natural resources, Talaromyces wortmannii was treated with the epigenome regulatory agent suberoylanilide hydroxamic acid, which resulted in the isolation of four new wortmannilactones derivatives (wortmannilactones I-L, 1-4). The structures of these new compounds were elucidated based on IR, HRESIMS and NMR spectroscopic data analyses. These four new compounds showed potent inhibitory activity against NADH-fumarate reductase with the IC50 values ranging from 0.84 to 1.35µM.

A novel oxybis cresol verticilatin with highly varying degrees of biological activities from the insect pathogenic fungus Paecilomyces verticillatus.

A novel oxybis cresol compound named verticilatin (1), together with two known compounds, 5-methylresorcinol (2) and 2,4-dihydroxy-3,6-dimethylbenzaldehyde (3), was isolated from cultures of the insect pathogenic fungi Paecilomyces verticillatus. The structures of compounds were determined by extensive spectroscopic analysis of HR-ESI-MS and 1D and 2D NMR including HSQC, HMBC, COSY, and ROESY. Fortunately, compound 1 exhibited significant inhibitory activities against CDC25B, cathepsin B, MEG2, and SHP2 enzyme, with IC50 values of 11.5, 3.5, 7.8, and 15 µg/ml, respectively.

Penostatin derivatives, a novel kind of protein phosphatase 1b inhibitors isolated from solid cultures of the entomogenous fungus Isaria tenuipes.

Protein tyrosine phosphatase 1B (PTP1B) is implicated as a negative regulator of insulin receptor (IR) signaling and a potential drug target for the treatment of type II diabetes and other associated metabolic syndromes. Therefore, small molecular inhibitors of PTP1B can be considered as an attractive approach for the design of new therapeutic agents of type II diabetes diseases. In a continuing search for new protein phosphatase inhibitors from fungi, we have isolated a new compound, named penostatin J (1), together with three known ones, penostatin C (2), penostatin A (3), and penostatin B (4), from cultures of the entomogenous fungus Isaria tenuipes. The structure of penostatin J (1) was elucidated by extensive spectroscopic analysis. We also demonstrate for the first time that penostatin derivatives exhibit the best PTP1B inhibitory action. These findings suggest that penostatin derivatives are a potential novel kind of PTP1B inhibitors.

Polyketides from a marine-derived fungus Xylariaceae sp.

Eighteen polyketides (1-18) including six citrinin derivatives, two phenol derivatives, one cyclopentenone, two naphthol derivatives, and seven tetralone derivatives were isolated from the culture broth of a marine-derived fungal strain Xylariaceae sp. SCSGAF0086. Five of these compounds (1, 2, 8, 9, and 10) were new, and their structures were determined by spectroscopic methods. Compounds 4, 6, 7, and 17 showed enzyme-inhibitory activities towards several tested enzymes, and 6 and 7 showed strong antifouling activity against Bugula neritina larvae settlement. This is the first time that the antifouling and enzyme-inhibitory activities of these compounds has been reported.

[Coumarins of Anemone raddeana Regel and their biological activity].

To study the coumarins of Anemone raddeana Regel, the compounds were separated by silica gel column chromatography and HPLC. Their structures were identified by their physicochemical property and spectral analysis. Two new compounds were isolated and identified as 4, 7-dimethoxyl-5-methyl-6-hydroxy coumarin (1) and 4, 7-dimethoxyl-5-formyl-6-hydroxycoumarin (2). The bioassays indicated that compounds 1 and 2 could significantly inhibit the proliferation of cancer cell, and showed the agonist effect on the transactivity of retinoic acid receptor-alpha (RARalpha). In addition, the two compounds had inhibitory effect against human leukocyte elastase (HLE).

[Phenolic acid derivatives from Bauhinia glauca subsp. pernervosa].

To study the chemical constituents of Bauhinia glauca subsp. pernervosa, eleven phenolic acids were isolated from a 95% ethanol extract by using a combination of various chromatographic techniques including column chromatography over silica gel, ODS, MCI, Sephadex LH-20, and semi-preparative HPLC. By spectroscopic techniques including 1H NMR, 13C NMR, 2D NMR, and HR-ESI-MS, these compounds were identified as isopropyl O-beta-(6'-O-galloyl)-glucopyranoside (1), ethyl O-beta-(6'-O-galloyl)-glucopyranoside (2), 3, 4, 5-trimethoxyphenyl-(6'-O-galloyl)-O-beta-D-glucopyranoside (3), 3, 4, 5-trimethoxyphenyl-beta-D-glucopyranoside (4), gallic acid (5), methyl gallate (6), ethyl gallate (7), protocatechuic acid (8), 3, 5-dimethoxy-4-hydroxybenzoic acid (9), erigeside C (10) and glucosyringic acid (11). Among them, compound 1 is a new polyhydroxyl compound; compounds 2, 10, and 11 were isolated from the genus Bauhinia for the first time, and the other compounds were isolated from the plant for the first time. Compounds 6 and 8 showed significant protein tyrosine phosphatase1B (PTP1B) inhibitory activity in vitro with the IC50 values of 72.3 and 54.1 micromol x L(-1), respectively.

Impacts of different promoters on the mammalian one-hybrid assay for detecting nuclear receptor agonists.

Nuclear receptors are a superfamily of ligand-activated transcription factors that play key roles in many biological processes, and have become one class of the most important targets in drug discovery. Mammalian one-hybrid system has been used to develop a cell-based functional transactivation high-throughput screening (HTS) assay for detecting nuclear receptors ligands. In the present study, we proved that different promoters used in the reporter vector had significant different impacts on the performance of HTS assays. The assay using the SV40 promoter in the reporter vector showed the characteristics of much higher signal/noise ratios, acceptable Z' factors (>0.6), low coefficient variation (<12.5%) and higher hits rate, which could be more robust, reproducible, and sensitive. In contrast, utilizing a TATA box promoter in the assay resulted in higher variance and low sensitivity. In addition, it was found that the assay using SV40 had longer signal decay time and was easier to be miniaturized in 384-well format. It has been confirmed that the choice of a promoter is a critical factor in developing a reporter gene HTS assay. However, the SV40 promoter used in the present study has been shown to be more adaptable than the minimal promoter TATA box in the Mammalian one-hybrid HTS assays for detecting nuclear receptor agonists.

Penicimeroterpenoids A-C, Meroterpenoids with Rearrangement Skeletons from the Marine-Derived Fungus Penicillium sp. SCSIO 41512.

Three novel andrastin-type meroterpenoids, penicimeroterpenoids A-C (1-3), possessing two unprecedented skeletons consisting of fused 6/5/6/6/7 and 6/5/6/6/4 polycyclic systems, were obtained from the marine-derived fungus Penicillium sp. SCSIO 41512. Their structures were determined by spectroscopic methods, and the absolute configurations were further determined by single-crystal X-ray diffraction analysis for 1 and quantum chemical calculations of ECD spectra for 2 and 3, respectively. A plausible biosynthetic pathway for 1-3 was proposed.

Identification of potential leukocyte antigen-related protein (PTP-LAR) inhibitors through 3D QSAR pharmacophore-based virtual screening and molecular dynamics simulation.

Owing to its negative regulatory role in insulin signaling, protein tyrosine phosphatase of leukocyte antigen-related protein (PTP-LAR) was widely thought as a potential drug target for diabetes. Now, it was urgent to search for potential LAR inhibitors targeting diabetes. Initially, the pharmacophore models of LAR inhibitors were established with the application of the HypoGen module. The cost analysis, test set validation, as well as Fischer's test was used to verify the efficiency of pharmacophore model. Then, the best pharmacophore model (Hypo-1-LAR) was applied for the virtual screening of the ZINC database. And 30 compounds met the Lipinski's rule of five. Among them, 10 compounds with better binding affinity than the known LAR inhibitor (BDBM50296375) were discovered by docking studies. Finally, molecular dynamics simulations and post-analysis experiments (RMSD, RMSF, PCA, DCCM and RIN) were conducted to explore the effect of ligands (ZINC97018474 and Compound 1) on LAR and preliminary understand why ZINC97018474 had better inhibitory activity than Compound 1 (BDBM50296375). Communicated by Ramaswamy H. Sarma.

Identification of novel inhibitor of protein tyrosine phosphatases delta: structure-based pharmacophore modeling, virtual screening, flexible docking, molecular dynamics simulation, and post-molecular dynamics analysis.

Owing to their unique functions in regulating the synapse activity of protein tyrosine phosphatases delta (PTPδ) that has drawn special attention for developing drugs to autism spectrum disorders (ASDs). In this study, the PTPδ pharmacophore was first established by the structure-based pharmacophore method. Subsequently, 10 compounds contented Lipinski's rule of five was acquired by the virtual screening of the PTPδ pharmacophore against ZINC and PubChem databases. Then, the 10 identified molecules were discovered that had better binding affinity than a known PTPδ inhibitors compound SCHEMBL16375396. Two compounds SCHEMBL16375408 and ZINC19796658 with high binding score, low toxicity were gained. They were observed by docking analysis and molecular dynamics simulations that the novel potential inhibitors not only possessed the same function as SCHEMBL16375396 did in inhibiting PTPδ, but also had more favorable conformation to bind with the catalytic active regions. This study provides a new method for identify PTPδ inhibitor for the treatment of ASDs disease.Communicated by Ramaswamy H. Sarma.

Design, synthesis, biological evaluation and molecular dynamics studies of 4-thiazolinone derivatives as protein tyrosine phosphatase 1B (PTP1B) inhibitors.

Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling pathway, and more and more studies have shown that it is a potential target for the treatment of type 2 diabetes mellitus (T2DM). In this study, 17 new 4-thiazolinone derivatives were designed and synthesized as novel PTP1B inhibitors, and ADMET prediction confirmed that these compounds were to be drug-like. In vitro enzyme activity experiments were performed on these compounds, and it was found that a plurality of compounds had good inhibitory activity and high selectivity against PTP1B protein. Among them, compound 7p exhibited the best inhibitory activity with an IC50 of 0.92 µM. The binding mode of compound 7p and PTP1B protein was explored, revealing the reason for its high efficiency. In addition, molecular dynamics simulations for the PTP1BWT and PTP1Bcomp#7p systems revealed the effects of compound 7p on PTP1B protein at the molecular level. In summary, the study reported for the first time that 4-thiazolinone derivatives as a novel PTP1B inhibitor had good inhibitory activity and selectivity for the treatment of T2DM, providing more options for the development of PTP1B inhibitors. AbbreviationsBBBblood-brain barrierCDC25Bcell division cycle 25 homolog BCYP2D6Cytochrome P450 2D6 bindingDCCMdynamic cross-correlation mapDSDiscovery StudioH bondhydrogen bondHIAhuman intestinal absorptionLARleukocyte antigen-related phosphataseMDmolecular dynamicsMEG-2maternal-effect germ-cell defective 2MM-PBSAmolecular mechanics Poisson Boltzmann surface area)PCAprincipal component analysisPDBProtein Data BankpNPPp-nitrophenyl phosphatePPBplasma protein bindingPTP1Bprotein tyrosine phosphotase 1BRMSDroot mean square deviationRMSFroot mean square fluctuationSHP-1src homologous phosphatase-1SHP-2src homologous phosphatase-2SPCsingle-point chargeTCPTPT cell protein tyrosine phosphataseT2DMType 2 diabetes mellitusVDWvan der WaalsCommunicated by Ramaswamy H. Sarma.

Design potential selective inhibitors for human leukocyte common antigen-related (PTP-LAR) with fragment replace approach.

The overexpression of PTP-LAR could cause the insulin resistance, so PTP-LAR might be a promising target for treating diabetes. In this study, we applied the computer modeling methods with fragment replace approach to screen the fragment database by targeting PTP domain and site B with the aim to discover potent and selective PTP-LAR inhibitors. A series of novel 4-thiazolidone derivatives were gained. The results of their ADMET predictions indicated that these new compounds might become drug candidates. The series of these derivatives were synthesized. Subsequently, their PTP-LAR inhibitory activities were assayed. The compound7d showed highly selectivity for PTP-LAR (10.41 µM) over its close homolog PTP1B (IC50=44.40 µM), SHP2 (IC50>122.81 µM) and CDC25B (IC50>122.81 µM) and docking and molecular dynamics simulation were applied to propose the most likely binding mode of compound7d with PTP-LAR. Thus, our findings reported here may pave a way for discovering potential selective PTP-LAR inhibitors.AbbreviationsPTP-LARHuman leukocyte common antigen-relatedPTPProtein Tyrosine PhosphataseIRinsulin receptorPTP1BProtein tyrosine phosphatase-1BLRPLung resistance proteinADMETabsorption, distribution, metabolism, excretion, toxicityPPBplasma protein bindingBBBblood brain barrier penetrationCYP450cytochrome P450HIAhuman intestinal absorptionTLCthin-layer chromatographyUVUltra VioletNMRnuclear magnetic resonanceTMStetramethylsilaneMSmass spectrometryANManisotropic network modePDBProtein Data BankDMFN,N-DimethylformamidepNPPpara-nitrophenyl phosphateDTTdithiothreitolMDmolecular dynamicRMSDroot-mean-square deviationRMSFroot-mean-square fluctuationSPCsingle-point chargePMEParticle Mesh EwaldMM-PBSAmolecular mechanics Poisson Boltzmann surface areaH bond, hydrogen bondVDWVan der WaalsCommunicated by Ramaswamy H. Sarma.

Penerpenes A-D, Four Indole Terpenoids with Potent Protein Tyrosine Phosphatase Inhibitory Activity from the Marine-Derived Fungus Penicillium sp. KFD28.

Four unusual indole-terpenoids, penerpenes A-D (1-4), along with two known ones paxilline (5) and emindole SB (6), were isolated from the marine-derived fungus Penicillium sp. KFD28. The absolute structures of 1-4 were elucidated on the basis of spectroscopic data and ECD spectra analysis along with quantum ECD calculations. Compounds 1 and 2 showed potent inhibitory activity toward protein tyrosine phosphatases (PTP1B and TCPTP). Plausible biosynthetic pathways of compounds 1-4 are proposed.

A cell-based high-throughput screening assay for Farnesoid X receptor agonists.

OBJECTIVE: To develop a high-throughput screening assay for Farnesoid X receptor (FXR) agonists based on mammalian one-hybrid system (a chimera receptor gene system) for the purpose of identifying new lead compounds for dyslipidaemia drug from the chemical library. METHODS: cDNA encoding the human FXR ligand binding domain (LBD) was amplified by RT-PCR from a human liver total mRNA and fused to the DNA binding domain (DBD) of yeast GAL4 of pBIND to construct a GAL4-FXR (LBD) chimera expression plasmid. Five copies of the GAL4 DNA binding site were synthesized and inserted into upstream of the SV40 promoter of pGL3-promoter vector to construct a reporter plasmid pG5-SV40 Luc. The assay was developed by transient co-transfection with pG5-SV40 Luc reporter plasmid and pBIND-FXR-LBD (189-472) chimera expression plasmid. RESULTS: After optimization, CDCA, a FXR natural agonist, could induce expression of the luciferase gene in a dose-dependent manner, and had a signal/noise ratio of 10 and Z' factor value of 0.65. CONCLUSION: A stable and sensitive cell-based high-throughput screening model can be used in high-throughput screening for FXR agonists from the synthetic and natural compound library.

[Relativity between occupational stress and psychosocial factors in nurses].

OBJECTIVE: To explore the effect of coping strategies, social support and personality factors, such as locus of control and type A behavior on occupational stress in nurses. METHODS: Descriptive correlation research method was used in this investigation. One thousand nine hundred and one nurses were included by using instruments of Occupational Stress Instrument, and these nurses were divided into four groups according to the scores of occupational stress. RESULTS: There were significant differences in general health status, coping strategies, social support, type A behavior and locus of control in the 4 groups (P < 0.05). The level of individual occupational stress increased with the fall of the scores of coping strategies, social support and with the elevation of type A behavior, locus of control and general health. Occupational stress had negative relation with coping strategies, social support, and positive relation with personalities and general bad health. CONCLUSION: The level of occupational stress is affected by coping strategies, social support, type A behavior and locus of control.