The molecular targets and therapeutic mechanisms of Er Miao San treating atopic dermatitis based on network pharmacology / 国际中医中药杂志

Objective:To explore the molecular targets and therapeutic mechanism of Er Miao San in the treatment of atopic dermatitis (AD), analyzing its active ingredients, moleculartargets and network analysis. Methods:The active ingredients and targets of Er Miao San were obtained from Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and Drugbank databases. The differential expression genes of AD were obtained by Intergovernmental Group on Earth Observations (GEO) database. The target genes of Er Miao San in the treatment of AD were obtained by using Cytoscape plugin Bisogenet and CytoNCA. Enrichment analysis was obtained from the DAVID database. Results:In total, 12 active ingredients and 107 targets of Er Miao San were screened out by TCMSP and Drugbank databases; 274 differential expression genes (with an adjust P value < 0.005 and |log2 (fold change)|>1.5) were identified between AD patient and control groups using the intergovernmental Group on Earth Observations (GEO) database. 187 target genes of Er Miao San against AD were finally identified by using Cytoscape plugin Bisogenet and CytoNCA. The functional annotations of target genes were related to telomere organization, protein heterotetramerization, regulation of gene expression and so on. Twenty pathways including PI3K-Akt, MAPK and HIF-1 signaling pathway were significantly enriched. Several genes including MAPK1, AKT, RELA and TP53 were the key genes in the gene-pathway network of Er Miao San treating AD. Conclusion:This study suggested that quercetin, tetrahydroberberine, stigmastol and other core ingredientss in Er Miao San may treat AD by participating in PI3K-Akt, MAPK, HIF-1 and other signaling pathways, and regulating the core gene targets of MAPK1, Akt, Rela and TP53.

Calcium Dialkylamine Diazeniumdiolates: Synthesis, Stability, and Nitric Oxide Generation.

The therapeutic application of nitric oxide, an endogenous cellular signaling molecule, has been limited due to the difficulty of developing stable pro-drugs with slow kinetics of NO release. Diazeniumdiolates are valuable NO donors; however, synthetic challenges have hampered their use. O2-alkylation or arylation of diazeniumdiolates form stable pro-drugs which have found application in hypertension, cancer, and as antimicrobial agents. The synthesis of sodium diazeniumdiolates has proven to be challenging due to hazardous reaction conditions (high N2O concentrations, and flammable solvents), which can lead to detonation and suffered from limited scope. We have previously disclosed that synthesis of calcium diazeniumdiolate salts are a safer and more scalable alternative. Herein, we report the expanded scope of calcium diazeniumdiolates from benzylic amines, amides, and sterically bulky amines hitherto inaccessible and a comparison of their reactivity in comparison to sodium diazeniumdiolate.

Discovery of [11C]MK-6884: A Positron Emission Tomography (PET) Imaging Agent for the Study of M4Muscarinic Receptor Positive Allosteric Modulators (PAMs) in Neurodegenerative Diseases.

The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development of CNS directed therapeutics. We and others have investigated muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs) for the treatment of symptoms associated with neuropsychiatric disorders. In this article, we describe the synthesis, in vitro, and in vivo characterization of a series of central pyridine-related M4 PAMs that can be conveniently radiolabeled with carbon-11 as PET tracers for the in vivo imaging of an allosteric binding site of the M4 receptor. We first demonstrated its feasibility by mapping the receptor distribution in mouse brain and confirming that a lead molecule 1 binds selectively to the receptor only in the presence of the orthosteric agonist carbachol. Through a competitive binding affinity assay and a number of physiochemical properties filters, several related compounds were identified as candidates for in vivo evaluation. These candidates were then radiolabeled with 11C and studied in vivo in rhesus monkeys. This research eventually led to the discovery of the clinical radiotracer candidate [11C]MK-6884.

Video-assisted thoracic surgery for tiny pulmonary nodules with real-time image guidance in the hybrid theatre: the initial experience.

BACKGROUND: Localization of tiny lung nodules during video-assisted thoracic surgery (VATS) resection can be challenging. Real-time image-guided hookwire localization of the target lesions immediately followed by VATS lung resection in the hybrid operating theatre setting is an emerging approach. METHODS: We retrospectively reviewed our experience with this form of hybrid operating theatre image-guided VATS (iVATS) for lung nodules 1.5 cm or less, or soft in consistency. These patients were compared with matched cohort who received standard hookwire localization in the radiology department. RESULTS: From February 2014 to September 2017, lung nodules of indeterminate nature in 32 consecutive patients with mean size 9.1±4.6 mm underwent iVATS. All were accurately localized by hookwire and successfully resected. There was no postoperative mortality. There were 21 (66%) malignant lesions, all with adequate resection margins. Major outcomes were compared with a comparable cohort of 8 patients who received standard hookwire localization and VATS (sVATS) performed at separate departments operation suites. sVATS groups has significantly longer 'at-risk' period for pneumothorax progression and hookwire dislodgement (109.5±57.1 minutes for sVATS vs. 41.1±15.0 minutes for iVATS, P=0.011), and a higher risk of hookwire dislodgement (25% for sVATS vs. 0 for iVATS, P=0.036). CONCLUSIONS: Real-time image-guided hookwire localization in the hybrid theatre setting is an effective facilitator of VATS resection of tiny lung nodules in selected patients, and may have added advantages in terms of safety and localization accuracy over the conventional sVATS method.

Self-Assembled Binuclear Cu(II)-Histidine Complex for Absolute Configuration and Enantiomeric Excess Determination of Naproxen by Tandem Mass Spectrometry.

Naproxen is one of the most consumed nonsteroidal anti-inflammatory drugs and marketed as S-naproxen since R-naproxen is hepatotoxic. In this study, chiral recognition of naproxen has been investigated by tandem mass spectrometry (MS/MS). Among all diastereomeric complexes formed between naproxen and the examined chiral selectors, including cyclodextrins (α/ß/γ-CD), modified phenylalanines ( N-acetyl-phenylalanine, N-t-butoxycarbonyl-phenylalanine, N-9-fluorenylmethyloxycarbonyl-phenylalanine), amino acids (Trp, Phe, Tyr, His), glucose, tartaric acid, and vancomycin, a novel binuclear metal bound diastereomeric complexes [(M(II))2( S/ R-naproxen)(l-His)2-3H]+ (M = Cu, Ni, or Co with Cu being the best) could allow effective identification of the absolute configuration of naproxen and determination of its enantiomeric excess ( ee) through MS/MS analysis. The key candidate structure of [(Cu(II))2( S/ R-naproxen)(l-His)2-3H]+ has been revealed by means of collision-induced dissociation, ion mobility mass spectrometry and density functional theory calculations, indicating an interesting and unusual self-assembled compact geometry with the two Cu(II) ions bridged closely together (Cu-Cu distance is 3.04 Å) by the carboxylate groups of the two histidines. It was shown that the difference in dissociation efficiency between the two diastereomers was attributed to the interaction between the NH2 bond of the amino group of one histidine and the naphthyl ring of naproxen. The present report is the first to observe and characterize the complex of (Cu(II))2(His)2 with aromatic acid, which could contribute to the chiral recognition of other chiral aromatic acids, design of catalysts based on binuclear copper bound complex, as well as the better understanding of metal ion complexation by His or His-containing ligands.

Discovery and Clinical Evaluation of MK-8150, A Novel Nitric Oxide Donor With a Unique Mechanism of Nitric Oxide Release.

BACKGROUND: Nitric oxide donors are widely used to treat cardiovascular disease, but their major limitation is the development of tolerance, a multifactorial process to which the in vivo release of nitric oxide is thought to contribute. Here we describe the preclinical and clinical results of a translational drug development effort to create a next-generation nitric oxide donor with improved pharmacokinetic properties and a unique mechanism of nitric oxide release through CYP3A4 metabolism that was designed to circumvent the development of tolerance. METHODS AND RESULTS: Single- and multiple-dose studies in telemetered dogs showed that MK-8150 induced robust blood-pressure lowering that was sustained over 14 days. The molecule was safe and well tolerated in humans, and single doses reduced systolic blood pressure by 5 to 20 mm Hg in hypertensive patients. Multiple-dose studies in hypertensive patients showed that the blood-pressure-lowering effect diminished after 10 days, and 28-day studies showed that the hemodynamic effects were completely lost by day 28, even when the dose of MK-8150 was increased during the dosing period. CONCLUSIONS: The novel nitric oxide donor MK-8150 induced significant blood-pressure lowering in dogs and humans for up to 14 days. However, despite a unique mechanism of nitric oxide release mediated by CYP3A4 metabolism, tolerance developed over 28 days, suggesting that tolerance to nitric oxide donors is multifactorial and cannot be overcome solely through altered in vivo release of nitric oxide. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01590810 and NCT01656408.

Hybrid DynaCT scan-guided localization single-port lobectomy. [corrected].

Small pulmonary lesions can be difficult to locate intraoperatively. Preoperative CT scan-guided localization, for example with hookwire, is a popular method to help localize such lesions. However, the delay between CT scan localization with hookwire and surgery can lead to risks of pneumothorax and wire dislodgement. We describe a 56-year-old woman who underwent DynaCT-guided hookwire localization of a ground-glass opacity in the hybrid operating room followed immediately by single-port video-assisted thoracic surgery lobectomy. The advantages, disadvantages, and special considerations in adopting this approach are discussed.

Novel pyridyl substituted 4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines as potent and selective aldosterone synthase inhibitors with improved in vitro metabolic stability.

CYP11B2 inhibition is a promising treatment for diseases caused by excessive aldosterone. To improve the metabolic stability in human liver miscrosomes of previously reported CYP11B2 inhibitors, modifications were performed via a combination of ligand- and structure-based drug design approaches, leading to pyridyl 4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolones. Compound 26 not only exhibited a much longer half-life (t1/2 ≫ 120 min), but also sustained inhibitory potency (IC50 = 4.2 nM) and selectivity over CYP11B1 (SF = 422), CYP17, CYP19, and a panel of hepatic CYP enzymes.

Novel pyridyl- or isoquinolinyl-substituted indolines and indoles as potent and selective aldosterone synthase inhibitors.

Pathologically, high levels of aldosterone are associated with severe cardiovascular diseases such as congestive heart failure, hypertension, and myocardial fibrosis. The inhibition of aldosterone synthase (CYP11B2) to reduce aldosterone levels has been proposed as a promising treatment for diseases related to CYP11B2 because it is the crucial enzyme in the biosynthesis of aldosterone. A series of novel pyridyl- or isoquinolinyl-substituted indolines and indoles was designed via a ligand-based approach. The synthesized compounds were tested and found to be strong CYP11B2 inhibitors. The most potent ones showed IC50 values of less than 3 nM, being similarly potent as fadrozole and LCI699. Among them, compounds 14 and 23 showed good selectivity over the highly homologous CYP11B1, with selectivity factors (SF = IC50 CYP11B1/IC50 CYP11B2) around 170; thus, they are superior to fadrozole and LCI699 (SFs < 15). These potent CYP11B2 inhibitors exhibited no inhibition (IC50 > 50 µM) of a panel of hepatic CYP enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 and the crucial steroidogenic enzymes, CYP17 and CYP19. Because of these advantageous profiles, compounds 14 and 23 are considered to be candidates for further in vivo evaluation.

Two adenovirus serotype 3 outbreaks associated with febrile respiratory disease and pharyngoconjunctival fever in children under 15 years of age in Hangzhou, China, during 2011.

Adenovirus serotype 3 and 7 outbreaks have occurred periodically in northern, eastern, and southern China since 1955, but there has been no report since the adenovirus serotype 7 outbreak first occurred in Hangzhou, China, in 1991. Here we explored the epidemiology and etiology of two adenovirus serotype 3 outbreaks in Hangzhou in 2011. One acute respiratory outbreak was found in Chun'an County, where a total of 371 cases were confirmed in 5 of 23 towns from 4 to 31 May 2011. The outbreak affected 18.57% (13/70) of schools and 14.49% (90/621) of classes. The incidence was 5.18% (371/7,163). The population was distributed among individuals ages 7 to 15 years. No parents or teachers were infected. Another pharyngoconjunctival fever outbreak was discovered in the Chenjinglun Swimming Center located in the Xihu District between 1 and 15 July 2011. A total of 134 cases were confirmed in 900 amateur swimmers, with an incidence of 14.89% (134/900). The ages ranged from 4 to 9 years. The two outbreaks had no severe complications or death. The viruses in 66.67% (10/15) of throat swabs from children with acute respiratory infections and 100% (10/10) of the swabs from children with pharyngoconjunctival fever were confirmed to be adenovirus serotype 3 with 100% homology by PCR. Of these samples, 60.0% (12/20) had a classical characteristic cytopathic effect, presented as grape-like clusters at 72 h after infection in HEp-2 cells. In conclusion, the acute respiratory infection and pharyngoconjunctival fever outbreak in Hangzhou were caused by the completely homologous type 3 adenovirus in subgenus B. Moreover, these outbreaks demonstrated rapid transmission rates, possibly due to close contact and droplet transmission.

Mycobacterium tuberculosis in the adjuvant modulates the balance of Th immune response to self-antigen of the CNS without influencing a "core" repertoire of specific T cells.

In the present study, we use modified CDR3 beta-chain spectratyping (immunoscope) to dissect the effect of Mycobacterium tuberculosis (MT)-derived proteins on individual PLP139-151-specific cells in the SJL mouse strain. In this model, the immunoscope technique allows the characterization of a public TCR that involves rearrangement of Vbeta10 and Jbeta1.1 and a semi-private TCR characterized by rearrangement of Vbeta4 and Jbeta1.6. Both rearrangements are specific for PLP139-151 and sequences of the CDR3 region of the two beta-chains show a conserved motif for the public rearrangement and related but more variable sequences for the semi-private rearrangement. MT-derived proteins promote increase of IFN-gamma-secreting cells. However, we observe that the presence and amount of MT used during immunization have no effect on the frequency of usage, polarization and in vivo expansion of cells carrying the studied rearrangements. Rather, the strong Th1-promoting effect of adjuvant is possibly due to recruitment toward Th1 of a wider spectrum of TCR repertoires. Therefore, instead of having a comprehensive effect on the entire repertoire, MT modulates the immune response by affecting a subset of antigen-specific T cells whose polarization can be adapted to the environment. This step establishes the final balance between Th1 and Th2 and may be essential for the enhancement or protection of disease.