Brønsted Acid-Catalyzed Intramolecular Tandem Double Cyclization of γ-Hydroxy Acetylenic Ketones with Alkynes into Naphtho[1,2-b]furan-3-ones.

A metal-free and atom-economic route for the synthesis of naphtho[1,2-b]furan-3-ones has been realized via p-TsOH·H2O-catalyzed intramolecular tandem double cyclization of γ-hydroxy acetylenic ketones with alkynes in formic acid. The benzene-linked furanonyl-ynes are the key intermediates obtained by the scission/recombination of C-O double bonds. Further, the structural modifications of the representative product were implemented by reduction, demethylation, substitution, and [5 + 2]-cycloaddition.

Structure-Based Discovery of the SARS-CoV-2 Main Protease Noncovalent Inhibitors from Traditional Chinese Medicine.

Traditional Chinese medicine (TCM) has been extensively employed for the treatment of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is demand for discovering more SARS-CoV-2 Mpro inhibitors with diverse scaffolds to optimize anti-SARS-CoV-2 lead compounds. In this study, comprehensive in silico and in vitro assays were utilized to determine the potential inhibitors from TCM compounds against SARS-CoV-2 Mpro, which is an important therapeutic target for SARS-CoV-2. The ensemble docking analysis of 18263 TCM compounds against 15 SARS-CoV-2 Mpro conformations identified 19 TCM compounds as promising candidates. Further in vitro testing validated three compounds as inhibitors of SARS-CoV-2 Mpro and showed IC50 values of 4.64 ± 0.11, 7.56 ± 0.78, and 11.16 ± 0.26 µM, with EC50 values of 12.25 ± 1.68, 15.58 ± 0.77, and 29.32 ± 1.25 µM, respectively. Molecular dynamics (MD) simulations indicated that the three complexes remained stable over the last 100 ns of production run. An analysis of the binding mode revealed that the active compounds occupy different subsites (S1, S2, S3, and S4) of the active site of SARS-CoV-2 Mpro via specific poses through noncovalent interactions with key amino acids (e.g., HIS 41, ASN 142, GLY 143, MET 165, GLU 166, or GLN 189). Overall, this study provides evidence indicating that the three natural products obtained from TCM could be further used for anti-COVID-19 research, justifying the investigation of Chinese herbal medicinal ingredients as bioactive constituents for therapeutic targets.

Retracted: Resveratrol Suppresses Human Nasopharyngeal Carcinoma Cell Growth Via Inhibiting Differentiation Antagonizing Non-Protein Coding RNA (DANCR) Expression.

The authors have requested retraction due to the identification of errors in the data. Reference: Jiafeng Zhang, Xiaojie Jin, Chuan Zhou, Hui Zhao, Ping He, Yalin Hao, Qiongna Dong. Resveratrol Suppresses Human Nasopharyngeal Carcinoma Cell Growth Via Inhibiting Differentiation Antagonizing Non-Protein Coding RNA (DANCR) Expression. Med Sci Monit, 2020; 26: e923622. DOI: 10.12659/MSM.923622.

Dual Proton/Silver-Catalyzed Serial (5 + 2)-Cycloaddition and Nazarov Cyclization of (E)-2-Arylidene-3-hydroxyindanones with Conjugated Eneynes: Synthesis of Indanone-Fused Benzo[cd]azulenes.

A one-pot step-economic tandem process involving (5 + 2)-cycloaddition and Nazarov cyclization reactions has been reported for the facile synthesis of indanone-fused benzo[cd]azulenes from (E)-2-arylidene-3-hydroxyindanones and conjugated eneynes. This highly regio- and stereoselective bisannulation reaction is enabled by dual silver and Brønsted acid catalysis and opens up a new avenue for the construction of important bicyclo[5.3.0]decane skeletons.

Rheumatoid arthritis drug sinomenine induces apoptosis of cervical tumor cells by targeting thioredoxin reductase in vitro and in vivo.

Overexpression of thioredoxin reductase (TrxR) has been linked to tumorigenesis and phenotypic maintenance of malignant tumors. Thus, targeting TrxR with natural molecules is a promising strategy for developing anticancer drugs. Sinomenine is a naturally occurring alkaloid isolated from Sinomenium acutum. The drug, Zhengqing Fengtongning made from sinomenine, has been universally applied in rheumatoid arthritis treatment in China as well as other Asian countries for decades. Recently, increasing evidence indicates that sinomenine appears to be a promising therapeutic agent against various cancer cells. However, the exact mechanism underlying the anticancer activity of sinomenine remains unclear. In this study, we identified sinomenine as a kind of new inhibitor for TrxR. Pharmacological inhibition of TrxR by sinomenine results in the decrease of thiols content, increases the levels of reactive oxygen species, and finally facilitates oxidative stress-mediated cancer cell apoptosis. It is vital that knockdown in TrxR1 by shRNA can increase cell sensitivity to sinomenine. Treatment with sinomenine in vivo leads to a decrease in TrxR activity and tumor growth, and an increase in apoptosis. Our findings provide a novel action mechanism related to sinomenine and presents an insight on how to develop sinomenine as a chemotherapeutic agent for cancer therapy.

Efficacy and safety of targeted drugs in advanced or metastatic gastric and gastroesophageal junction cancer: A network meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: An increasing number of targeted drugs have been used to treat advanced or metastatic gastric cancer (GC) and gastroesophageal junction cancer (GEJC). However, the optimal treatment efficacy of these drugs is still controversial. The aims of this study are to systematically summarize the efficacy and safety of current targeted drugs for advanced or metastatic GC and GEJC. METHODS: PubMed, EmBase, Cochrane Library, Web of Science and ClinicalTrials were searched for double-blind randomized controlled trials (RCTs) on GC and GEJC up to December 2019. Additionally, we updated the literature search from Jan, 1, 2020 to September 30, 2021. Narrative and quantitative analysis were performed to analyse the efficacy and safety. STATA 15.1 was used to identify publication bias, and the SUCRA (surface under the cumulative ranking) curve was conducted to rank the treatments for each outcome. RESULTS: A total of 27 RCTs with 9295 GC and GEJC patients treated by 19 drugs were included. SUCRA showed that regorafenib was the most likely to improve patients' progression-free survival (96.4%), followed by apatinib (90.7%), nivolumab (82.4%), everolimus (76.5%) and pertuzumab (68.5%). Meanwhile, apatinib (92.4%) was most likely to improve overall survival, followed by nivolumab (87.9%), regorafenib (72.5%), olaparib (67.7%) and lapatinib (63.2%). Additionally, neutropenia, diarrhoea and fatigue were the most common adverse events caused by these drugs, followed by pain, nausea, decreased appetite, anaemia and vomiting. WHAT IS NEW AND CONCLUSION: Regorafenib and nivolumab have higher efficacy and tolerability and are the most advantageous for advanced GC and GEJC. Moreover, apatinib has higher efficacy but lower tolerability. Everolimus and pertuzumab combined with chemotherapy have best secondary higher efficacy for progression-free survival and good tolerability. Lapatinib and olaparib combined with chemotherapy have moderate efficacy for overall survival and good tolerability.

[Material basis and molecular mechanism of Angelicae Sinensis Radix in activating blood:based on computer-aided drug design].

Angelicae Sinensis Radix excels in activating blood, but the scientific mechanism has not been systematically analyzed, thus limiting the development of the medicinal. This study employed the computer-aided drug design methods, such as structural similarity-based target reverse prediction, complex network analysis, molecular docking, binding free energy calculation, cluster analysis, and ADMET(absorption, distribution, metabolism, excretion, toxicity) calculation, and enzyme activity assay in vitro, to explore the components and mechanism of Angelicae Sinensis Radix in activating blood. Target reverse prediction and complex network analysis yielded 40 potential anticoagulant targets of the medicinal. Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis indicated that the targets mainly acted on the complement and coagulation cascade signaling pathway to exert the anticoagulant function. Among them, the key enzymes thrombin(THR) and coagulation factor Xa(FXa) in coagulation cascade and thrombosis were the drug targets for thromboembolic diseases. At the same time, molecular docking and cluster analysis showed that the medicinal had high selectivity for FXa. According to binding free energy score, 8 potential active components were selected for enzyme activity assay in vitro. The results demonstrated that 8 components inhibited THR and FXa, and the inhibition was stronger on FXa than on THR. The pharmacophore model of 8 active compounds was constructed, which suggested that the components had the common pharmacophore AAHH. The ADMET calculation result indicated that they had good pharmacokinetic properties and were safe. Based on target reverse prediction, complex network analysis, molecular docking and binding free energy calculation, anticoagulant activity in vitro, spatial binding conformation of molecules and targets, pharmacophore model construction, and ADMET calculation, this study preliminarily clarified the material basis and molecular mechanism of Angelicae Sinensis Radix in activating blood from the perspective of big data, and calculated the pharmacology and toxicology parameters of the active components. Our study, for the first time, revealed that the medicinal had obvious selectivity and pertinence for different coagulation proteins, reflecting the unique effect of different Chinese medicinals and the biological basis. Therefore, this study can provide clues for precision application of Angelicae Sinensis Radix and the development of the blood-activating components with modern technology.

Systematic insight into the active constituents and mechanism of Guiqi Baizhu for the treatment of gastric cancer.

Traditional Chinese medicine treatment of diseases has been recognized, but the material basis and mechanisms are not clear. In this study, target prediction of the antigastric cancer (GC) effect of Guiqi Baizhu (GQBZP) and the analysis of potential key compounds, key targets, and key pathways for the therapeutic effects against GC were carried out based on the method of network analysis and Kyoto Encyclopedia of Genes and Genomes enrichment. There were 33 proteins shared between GQBZP and GC, and 131 compounds of GQBZP had a high correlation with these proteins, indicating that the PI3K-AKT signaling pathway might play a key role in GC. From these studies, we selected human epidermal growth factor receptor 2 (HER2) and programmed cell death 1-ligand 1 (PD-L1) for docking; the results showed that 385 and 189 compounds had high docking scores with HER2 and PD-L1, respectively. Six compounds were selected for microscale thermophoresis (MST). Daidzein/quercetin and isorhamnetin/formononetin had the highest binding affinity for HER2 and PD-L1, with Kd values of 3.7 µmol/L and 490, 667, and 355 nmol/L, respectively. Molecular dynamics simulation studies based on the docking complex structures as the initial conformation yielded the binding free energy between daidzein/quercetin with HER2 and isorhamnetin/formononetin with PD-L1, calculated by molecular mechanics Poisson-Boltzmann surface area, of -26.55, -14.18, -19.41, and -11.86 kcal/mol, respectively, and were consistent with the MST results. In vitro experiments showed that quercetin, daidzein, and isorhamnetin had potential antiproliferative effects in MKN-45 cells. Enzyme activity assays showed that quercetin could inhibit the activity of HER2 with an IC50 of 570.07 nmol/L. Our study provides a systematic investigation to explain the material basis and molecular mechanism of traditional Chinese medicine in treating diseases.

Targeting thioredoxin reductase by deoxyelephantopin from Elephantopus scaber triggers cancer cell apoptosis.

Elevated expression of thioredoxin reductase (TrxR) is associated with the tumorigenesis and resistance to cancer chemoradiotherapy, highlighting the potential of TrxR inhibitors as anticancer drugs. Deoxyelephantopin (DET) is the major active ingredient of Elephantopus scaber and reveals potent anticancer activity. However, the potential mechanism of action and the cellular target of DET are still unknown. Here, we found that DET primarily targets the Sec residue of TrxR and irreversibly prohibits enzyme activity. Suppression of TrxR by DET leads to accumulation of reactive oxygen species and dysregulation in intracellular redox balance, eventually inducing cancer cell apoptosis mediated by oxidative stress. Noticeably, down-regulation of TrxR1 by shRNA increases cell sensitivity to DET. Collectively, targeting of TrxR1 by DET uncovers a novel mechanism of action in DET and deepens the understanding of developing DET as a potential chemotherapeutic agent for treating cancers.

Metal-Free Intramolecular [3+2] Cycloaddition of γ-Hydroxy Acetylenic Ketones with Alkynes for the Synthesis of Naphtho[1,2-c]furan-5-ones and Its Derivatization via a Selective C(sp2)-H Deuteration Reaction.

A metal-free intramolecular [3+2] cycloaddtion has been achieved by treating benzene-linked propynol-ynes with AcOH/H2O in a one-pot manner. The reaction provides greener, 100% atom-economic, highly regioselective, and more practical access to functionalized naphtho[1,2-c]furan-5-ones with valuable and versatile applications. The regioselective α-deuteration of naphtho[1,2-c]furan-5-ones has been also presented with excellent deuterium incorporation and chemical yields. Moreover, the fluorescent properties of naphtho[1,2-c]furan-5-one products have been investigated in solution.

The correlation of blood pressure variability and cognitive function in hypertension patients: A meta-analysis.

BACKGROUND: Cognitive impairment (CI) is very common in patients with hypertension. It is necessary to conduct a meta-analysis to evaluate the association between cognitive function and blood pressure variability in patients with hypertension, to provide insights into the clinical management of hypertension and cognitive impairment. METHODS: We searched PubMed and other databases for case-control studies on the association between blood pressure variability and cognitive function up to 15 July 2021. Two researchers independently screened the literature and retrieved the data. RevMan 5.3 was used for meta-analysis. RESULTS: A total of 13 studies involving 2754 patients were included. Meta-analysis indicated that 24-hours systolic (MD = 3.54, 95% CI [2.48, 4.60]) and diastolic (MD = 2.43, 95% CI [1.55, 3.31]) blood pressure variation coefficients in the CI group were significantly higher than that of non-CI group (all P < .05). Standard deviations of systolic (MD = 2.20, 95% CI [0.27, 4.13]) and diastolic (MD = 1.79, 95% CI [0.80, 2.79]) blood pressure variation in the CI group were significantly higher than that of the non-CI group (all P < .05). Mean systolic (MD = 3.73, 95% CI [0.92, 6.53]) and diastolic (MD = 5.41, 95% CI [0.42, 10.40]) blood pressure variation in the CI group were significantly higher than that of non-CI group (all P < .05). There were no statistically significant differences in the morning peak systolic (MD = 7.85, 95% CI [-1.30, 17.01]) and diastolic (MD = 4.44, 95% CI [-6.00, 14.89]) blood pressure drop between the CI group and non-CI group (all P > .05). CONCLUSION: CI in hypertensive patients is closely associated with increased blood pressure variability. Clinical healthcare providers should pay attention to the management of blood pressure variability in hypertensive patients to reduce the occurrence of CI.

Serum lipids and the pathogenesis of Parkinson's disease: A systematic review and meta-analysis.

BACKGROUND: The role of serum lipids in the pathogenesis of Parkinson's disease (PD) remains unclear, and the results of previous reports remain conflicting. We aimed to conduct this systematic review and meta-analysis to identify the potential relationships of blood lipids and the pathogenesis of PD. METHODS: PubMed, Medline, Web of Science, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases were searched from inception to March 31, 2020, to identify potential studies with case-control or cohort study design on the relationship of serum lipids and PD. Stata 15.1 software was used for data syntheses after extraction of relevant data. RESULTS: A total of 12 studies with 1506 PD patients and 7330 healthy controls were included. There were no significant differences in the TC (SMD = -0.08, 95% CI [-0.45, 0.33]), LDL-C (SMD = -0.12, 95% CI [-0.46, 0.18]), and TG (SMD = -0.05, 95% CI [-0.18, 0.06]) among PD patients and healthy controls. There was significant difference (SMD = -0.32, 95% CI [-0.42, -0.25]) in the TG level among PD patients and healthy controls. Subgroup analysis by Asian and non-Asian countries indicated that geographical location was not the source of heterogeneity. And no significant publication bias was found (all P > .05). CONCLUSIONS: TG serum levels are significantly lower in PD patients, more studies are needed to further elucidate role of lipid in the PD development.

LncRNA MALAT1 targeting miR-124-3p regulates DAPK1 expression contributes to cell apoptosis in Parkinson's Disease.

Death associated protein kinase 1 (DAPK1) was initially discovered in the progress of gamma-interferon induced programmed cell death, it is a key factor in the central nervous system, including Parkinson's disease (PD). However, the underlying mechanisms of DAPK1 in PD remain unclear and this research work aims to explore the potential mechanisms of DAPK1 in PD. In the study, we exposed SH-SY5Y cells to MPP+ and treated mice with MPTP to investigate the roles of DAPK1 in PD and the underlying mechanisms. The results indicated that the expression of DAPK1 is significantly upregulated and negatively correlated with miR-124-3p levels in SH-SY5Y cells treated by MPP+ , and miR-124-3p mimics could effectively inhibit DAPK1 expressions and alleviate MPP+ -induced cell apoptosis. In addition, knockdown MALAT1 reduces the levels of DAPK1 and the ratio of SH-SY5Y cell apoptosis, which is reversed via miR-124-3p inhibitor in vitro. Similarly, knockdown MALAT1 could improve behavioral changes and reduce apoptosis by miR-124-3p upregulation and DAPK1 downregulation in MPTP induced PD mice. Taken together, our data showed that lncRNA MALAT1 positively regulates DAPK1 expression by targeting miR-124-3p, and mediates cell apoptosis and motor disorders in PD. In summary, these results suggest that MALAT1/miR-124-3p /DAPK1 signaling cascade mediates cell apoptosis in vitro and in vivo, which may provide experimental evidence of developing potential therapeutic strategies for PD.

Identification of Fusarium graminearum-responsive miRNAs and their targets in wheat by sRNA sequencing and degradome analysis.

Fusarium head blight (FHB), a prevalent disease of bread wheat (Triticum aestivum L.) caused by Fusarium graminearum, leads to considerable losses of yield and quality in wheat production. MicroRNAs (miRNAs) are important regulators of plant defense responses. Here, to better understand the F. graminearum-responsive miRNAs, we constructed sRNA libraries for wheat cultivar Sumai 3 challenged with F. graminearum and sterile water, respectively. As a result, a total of 203 known miRNAs from 46 families and 68 novel miRNAs were identified. Among them, 18 known and six novel miRNAs were found to be differentially expressed between the F. graminearum-infected samples and the controls and thus were considered to be responsive to F. graminearum. The expression patterns of eight miRNAs were further validated by stem-loop qRT-PCR. Meanwhile, target genes were validated by degradome sequencing. Integrative analysis of the differentially expressed miRNAs and their targets revealed complex miRNA-mediated regulatory networks involved in the response of wheat to F. graminearum infection. Our findings are expected to facilitate a better understanding of the miRNA regulation in wheat-F. graminearum interaction.

PEGylated NALC-functionalized gold nanoparticles for colorimetric discrimination of chiral tyrosine.

In this work, acid and matrix-tolerant multifunctionalized gold nanoparticles (AuNPs) with an integrated chiral selector towards tyrosine (Tyr) and polyethylenglycol (PEG) chains were developed for visual chiral discrimination of Tyr in biological samples under acid conditions. In brief, AuNPs multifunctionalized with N-acetyl-l-cysteine (NALC) and PEG (PEG/NALC-AuNPs) were prepared via a simple strategy. In the presence of l-Tyr, the color of PEG/NALC-AuNP solution changed from red to gray, while no obvious color change was observed with the introduction of d-Tyr, which indicated that the introduction of PEG onto the surface of AuNPs has no effect on the chiral recognition between l-Tyr and NALC. A computer-aided molecular model was used to clarify the chiral recognition mechanism between NALC and Tyr enantiomers and to further guide the optimization of sensitivity. The resultant PEG/NALC-AuNP sensor presented a significantly improved stability under acid and alkali conditions compared with conventional NALC-AuNPs, resulting in a wider dynamic range (500 nM-100 µM) and a 50 times reduced detection limit by simply adjusting the pH of the sensor system under acid conditions (pH 2-2.5). More importantly, the PEG/NALC-AuNPs can realize the visual chiral discrimination of Tyr enantiomers in biological samples due to their significantly improved long-term stability and reduced interaction towards non-target species.

Resveratrol Suppresses Human Nasopharyngeal Carcinoma Cell Growth Via Inhibiting Differentiation Antagonizing Non-Protein Coding RNA (DANCR) Expression.

BACKGROUND Although resveratrol has been found to show anti-cancer effects and potential chemotherapeutic activities in several cancers, the role and molecular mechanisms of resveratrol in nasopharyngeal carcinoma (NPC) remains poorly understood. This study aimed to investigate the effect of resveratrol in NPC progression and its molecular mechanism. MATERIAL AND METHODS Quantitative real-time polymerase chain reaction and western blotting were used to detect the expression of DANCR and PTEN. MTT assay and EdU assay were performed to detect the cell proliferation in NPC cells with different treatment. The effect of resveratrol on cell migration was explored by Transwell migration assay. RNA immunoprecipitation assay and chromatin immunoprecipitation assay were performed to test the interaction between DANCR, EZH2, and PTEN. A mouse xenograft model of NPC cell was established, and immunohistochemistry assay was performed to detect the PTEN expression. RESULTS Resveratrol treatment inhibited NPC cell growth and migration in a dose-dependent manner. Additionally, resveratrol downregulated the expression of DANCR and DANCR overexpressing abrogated the inhibition effect of resveratrol on NPC cell migration. Mechanistically, DANCR could bind to EZH2 and downregulated PTEN expression through mediating the binding of EZH2 on PTEN promoter. Furthermore, rescue experiments suggested resveratrol inhibited NPC cell growth and migration by the DANCR/PTEN pathway. Resveratrol significantly decreased the tumor volume and tumor weight and increased the expression of PTEN. CONCLUSIONS Resveratrol increased PTEN expression and suppressed NPC cell growth and migration through downregulation of DANCR.

Labdane-Type Diterpenoids from Leonurus japonicus and Their Plant-Growth Regulatory Activity.

Thirteen new labdane-type diterpenoids 1-6, 9-11, 13, 14, 18, and 19 and seven known ones were isolated from the aerial parts of Leonurus japonicus. Compounds 1-5 represent rare examples of labdane-type diterpenoids, of which compounds 1-4 carry an N-chain linked at C-7 in their B-ring and compound 5 featured an α,ß-unsaturated-γ-lactam moiety. The structures and absolute configurations of these new diterpenoids were characterized by a combination of spectroscopic techniques, X-ray crystallography, electronic circular dichroism, and calculated specific rotations. The plant-growth regulatory activity of these compounds on the growth of the roots and shoots of Lactuca sativa and Lolium perenne seedlings were evaluated. Compound 3 showed a broad-spectrum inhibitory activity with the inhibition rates ranging from 60 to 83.5% at a concentration of 200 µg/mL, which were as active as those of glyphosate. Compound 8 had a selective inhibitory activity against the growth of the roots of L. perenne seedlings with an inhibition rate of 81.7%. However, compounds 11 and 16 exhibited significant stimulation effects on the roots of L. sativa with stimulation rates of 59.8 and 65.3%, respectively. In addition, compounds 3 and 8 exhibited inhibitory effects on the germination of L. perenne seeds.

SOX10 induces epithelial-mesenchymal transition and contributes to nasopharyngeal carcinoma progression.

OBJECTIVE: The aim of this study was to investigate the role of SOX10 in nasopharyngeal carcinoma (NPC) and the underlying molecular mechanisms. METHODS: The expression of SOX10 was initially assessed in human NPC tissues and a series of NPC cell lines through quantitative real-time PCR (qRT-PCR) and Western blot. Then, cell proliferation, cycle, migration, and the invasiveness of NPC cells with knockdown of SOX10 were examined by MTT, flow cytometry, and Transwell migration and invasion assays, respectively. Finally, nude mice tumorigenicity experiments were performed to evaluate the effects of SOX10 on NPC growth and metastasis in vivo. RESULTS: SOX10 was significantly increased in NPC tissues and cell lines. In-vitro experiments revealed that loss of SOX10 obviously inhibited cell proliferation, migration, and invasiveness, as well as the epithelial-mesenchymal transition (EMT) process in NPC cells. In-vivo experiments further demonstrated that disrupted SOX10 expression restrained NPC growth and metastasis, especially in lung and liver. CONCLUSION: Taken together, our data confirmed the role of SOX10 as an oncogene in NPC progression, and revealed that SOX10 may serve as a novel biomarker for diagnosis of NPC, as well as a potential therapeutic target against this disease.

Insights into conformational regulation of PfMATE transporter from Pyrococcus furiosus induced by alternating protonation state of Asp41 residue: A molecular dynamics simulation study.

BACKGROUND: Multidrug and toxic compound extrusion (MATE) family transporters induce multiple-drug resistance (MDR) of bacterial pathogens and cancer cells, thus causing critical reductions in the therapeutic efficacies of antibiotics and anti-cancer drugs. Unfortunately, to date, the details and intrinsic reason about conformational regulation mechanism of MATE transporters remain elusive. METHOD: In this work, molecular dynamics (MD) simulations were conducted to explore the conformational regulation mechanism of PfMATE transporter from Pyrococcus furiosus based on different protonation state of Asp41. Two (MD) simulation systems were investigated: a system with protonation of Asp41 and a system without protonation of Asp41, which were named by D184(H)D41(H) system and D184(H) system, respectively. RESULTS AND CONCLUSIONS: Firstly, MD simulation results indicate that conformational changes mainly happen in extracellular regions of PfMATE protein. Further analysis reveals that PfMATE protein experiences different motion mode and forms different conformation based on different protonation state of Asp41. In the D184(H)D41(H) system, PfMATE experiences an opening motion and forms a more outward-open conformation. As for the D184(H) system, the protein has an anticlockwise rotational motion with the channel axis of protein and the more outward-open conformation does not appear. It can be inferred that protonation of Asp41 is essential for conformational regulation of PfMATE during transporting substrates. GENERAL SIGNIFICANCE: These findings provide intrinsic information for understanding the conformational regulation mechanism of PfMATE and will be very meaningful to explore the MDR mechanism of PfMATE further.

Indolo-quinoline boron difluoride dyes: synthesis and spectroscopic properties.

Novel indolo-quinoline compounds were efficiently prepared via a Povarov-type reaction, and the structures were further modified by a Suzuki coupling reaction. The corresponding BF2-rigidified complexes were prepared and their spectroscopic properties were characterized with large Stokes shifts (up to 211 nm) and up to near-infrared (NIR) wavelength (667 nm). The synthetic complexes could be used as new fluorescent dyes.