Design, synthesis and biological evaluation of 2,4,6- trisubstituted triazine derivatives as new nonpeptide small-molecule SIRT5 inhibitors.

Human sirtuin 5 (SIRT5) participates in a variety of metabolic disorder-associated diseases, including cancer. Inhibition of SIRT5 has been confirmed to provide a new strategy for treatment of related diseases. Previously, we discovered a pyrimidine skeleton inhibitor XIV, which showed low micromolar inhibitory activity against SIRT5. Herein, we utilized the scaffold-hopping strategy to design and synthesize a series of 2,4,6- trisubstituted triazine derivatives. The SAR analysis led to the discovery of several new SIRT5 inhibitors with low micromolar inhibition levels. The most potent compounds 10 (IC50 = 5.38 µM), and 14 (IC50 = 4.07 µM) were further confirmed to be the substrate-competitive SIRT5 inhibitors through enzyme kinetic assays, which is consistent with the molecular docking analyses. Fluorescence-based thermal shift assays proved that these compounds may stabilize SIRT5 by binding withprotein.. In addition, compounds 10 and 14 were also revealed to have moderate selectivity to SIRT5 over SIRT1-3. This study will aid further efforts to develop highly potent and selective SIRT5 inhibitors for the treatment of cancer and other related diseases.

Structure-Activity Relationship Studies of 2,4,5-Trisubstituted Pyrimidine Derivatives Leading to the Identification of a Novel and Potent Sirtuin 5 Inhibitor against Sepsis-Associated Acute Kidney Injury.

Sepsis-associated acute kidney injury (AKI) is a serious clinical problem without effective drugs. Inhibition of sirtuin 5 (SIRT5) has been confirmed to protect against AKI, suggesting that SIRT5 inhibitors might be a promising therapeutic approach for AKI. Herein, structural optimization was performed on our previous compound 1 (IC50 = 3.0 µM), and a series of 2,4,5-trisubstituted pyrimidine derivatives have been synthesized. The structure-activity relationship (SAR) analysis led to the discovery of three nanomolar level SIRT5 inhibitors, of which the most potent compound 58 (IC50 = 310 nM) was demonstrated to be a substrate-competitive and selective inhibitor. Importantly, 58 significantly alleviated kidney dysfunction and pathological injury in both lipopolysaccharide (LPS)- and cecal ligation/perforation (CLP)-induced septic AKI mice. Further studies revealed that 58 regulated protein succinylation and the release of proinflammatory cytokines in the kidneys of septic AKI mice. Collectively, these results highlighted that targeting SIRT5 has a therapeutic potential against septic AKI.

DNA-Programmable AgAuS-Primed Conductive Nanowelding Wires-Up Wet Colloids.

Self-assembly of nanomaterials, directed by molecular or supramolecular interactions, is a powerful strategy to build nanoscale devices. Despite many advantages of such solution-based processes, a big challenge is to realize interparticle ohmic contacts toward facilitated charge transport over a long distance. We report a new concept of primed nanowelding to thread solution-borne nanoparticles in prescribed assemblies. The process starts with a gap-specific deposition of Ag2 E (E=S, Se) materials in pre-assembled gold structures, which spontaneously transform into AgAuE semiconductors via directional gold diffusion. Treatment with tributylphosphine generates alloyed Au/Ag welding spots that conductively wire-up nanoparticles into discrete "molecules" and micron-long "polymers". This method is compatible with DNA programming and delivers a possible way to solve the problem of the carrier-transport dilemma in solution-processed nanostructures for better-functioning nanodevices.

Decoupled Roles of DNA-Surfactant Interactions: Instant Charge Inversion, Enhanced Colloidal and Chemical Stabilities, and Fully Tunable DNA Conjugation of Shaped Plasmonic Nanocrystals.

Surfactant-dictated syntheses of nanomaterials with well-defined shapes offer an extra dimension of control beyond nanoparticle size and chemical composition on the properties and self-assembly behaviors of colloidal materials. However, the surfactant bilayers on nanocrystals often cause great difficulty toward DNA grafting due to their unfavorable electrostatic charges and dense surface packing. Herein a revisit to this dilemma unveils a rapid charge inversion and enhanced colloidal/chemical stabilities of cationic-bilayer-covered nanocrystals upon DNA adsorption. Decoupling this hidden scenario provides a rationale to significantly improve DNA functionalization of surfactant-capped nanocrystals. Accordingly, fully tunable DNA conjugation (via Au-S bonding) on up to seven classes of surfactant-coated metal nanounits is easily and consistently achievable. The DNA-nanocrystal complexes featuring a continuously variable DNA density function well in DNA-guided nanoassembly. Our method opens the door to a wealth of material building blocks derived by surfactant-directed nanosyntheses toward DNA-programmable, extremely diversified, and highly complicated structures and functions.

Boosting framework via clinical monitoring data to predict the depth of anesthesia.

BACKGROUND: Prediction of the depth of anesthesia is a difficult job in the biomedical field. OBJECTIVE: This study aimed to build a boosting-based prediction model to predict the depth of anesthesia based on four clinical monitoring data. METHODS: Boosting is a framework algorithm that is used to train a series of weak learners into strong learners by assigning different weights according to their classification accuracy. The input of the boosting-based prediction model included four types of clinical monitoring data: electromyography, end-tidal carbon dioxide partial pressure, remifentanil dosage, and flow rate. The output was the depth of anesthesia. RESULTS: The boosting framework model built in this study achieved higher prediction accuracy and a lower discrete degree in predicting the depth of anesthesia compared with the DT-, KNN-, and SVM-based models. CONCLUSIONS: The boosting framework was used to set up a prediction model to predict the depth of anesthesia based on four clinical monitoring data. In the experiments, the boosting framework model of this study achieved higher prediction accuracy and a lower discrete degree. This model will be useful in predicting the depth of anesthesia.

5-HTT, BMPR2, EDN1, ENG, KCNA5 gene polymorphisms and susceptibility to pulmonary arterial hypertension: A meta-analysis.

BACKGROUND: The influence of 5-HTT, BMPR2, EDN1, ENG, KCNA5 genes polymorphisms on susceptibility of pulmonary arterial hypertension remains uncertain. This meta-analysis is conducted for further study. METHODS: We conducted a literature search on PubMed and ISI web of science databases for searching relevant articles until November 2017. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. A total of 17 articles with 2631 PAH subjects and 5139 controls were included in the final meta-analysis. Statistical software Stata13.0 was used for data-analysis. RESULTS: A significant relationship was found between the 5-HTT L/S polymorphism and PAH in all the genetic models [LL vs. SS: OR = 1.60, 95% CI, 1.11-2.32; LS vs. SS: OR = 1.55, 95% CI, 1.10-2.21; (LS + LL) vs. SS: OR = 1.56, 95% CI, 1.13-2.17; L vs. S: OR = 1.32, 95% CI, 1.08-1.62]. There were also associations of the SERT L/S polymorphism with IPAH and PAH in COPD [IPAH L/S: OR = 1.26, 95% CI, 1.01-1.57; PAH in COPD L/S: OR = 1.42, 95% CI, 1.04-1.94]. In addition, the results showed a statistically significant association between EDN1 rs5370 polymorphism and the risk of PAH in all the genetic models [TT vs. GG: OR = 3.32, 95% CI, 1.30-8.51; TG vs. GG: OR = 2.68, 95% CI, 1.54-4.66; (TG + TT) vs. GG: OR = 2.82, 95% CI, 1.69-4.71; T vs. G: OR = 2.43, 95% CI, 1.60-3.68]. However, the significant association was not found between BMPR2 rs1061157, KCNA5 rs10744676, ENG rs3739817 polymorphisms and the risk of PAH (all p > 0.05). CONCLUSIONS: 5-HTT L/S polymorphism and END1 rs5370 polymorphism were correlated with significantly increased risk of PAH. Moreover, L allele in 5-HTT gene increased susceptibility to IPAH and PAH in COPD.

Identification of four novel XPC mutations in two xeroderma pigmentosum complementation group C patients and functional study of XPC Q320X mutant.

Xeroderma pigmentosum (XP) is a rare, recessive hereditary disease characterized by sunlight hypersensitivity and high incidence of skin cancer with clinical and genetic heterogeneity. We collected two unrelated Chinese patients showing typical symptoms of XPC without neurologic symptoms. Direct sequencing of XPC gene revealed that patient 1 carried IVS1+1G>A and c.958 C>T mutations, and patient 2 carried c.545_546delTA and c.2257_2258insC mutations. All these four mutations introduced premature terminal codons (PTCs) in XPC gene. The nonsense mutation c.958 C>T yielded truncated mutant Q320X, and we studied its function for global genome repair kinetics. Overexpressed Q320X mutant can localize to site of DNA damage, but it is defective in CPD and 6-4PP repair. Readthrough of PTCs is a new approach to treatment of genetic diseases. We found that aminoglycosides could significantly increase the full length protein expression of Q320X mutant, but NER defects were not rescued in vitro.

Genotype-phenotype correlation in Chinese patients with dystrophic epidermolysis bullosa pruriginosa.

Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) is a rare variant of dystrophic epidermolysis bullosa (DEB) due to dominant or recessive mutations in the COL7A1 gene. More than 40 mutations in COL7A1 have been described in DEB-Pr. The aim of this study was to understand the genotype-phenotype correlation in Chinese patients with DEB-Pr. Three Chinese families with typical clinical features of DEB-Pr were studied. The results were analysed in association with the eight Chinese DEB-Pr patients reported in the literature. In the three Chinese families with DEB-Pr, we found two dominant cases with G1773R and c.6900+1G>C mutations, and one case with heterozygous G2701W mutation of uncertain inheritance mode. In the 10 Chinese patients with dominant type of DEB-Pr, 7 glycine substitutions and three splicing site mutations of exon 87 skipping were identified. Glycine substitution mutations in the triple helix region and exon 87 skipping, leading to the in-frame deletion of 23 amino acid residues in the triple-helix, are often seen in Chinese patients with dominant DEB-Pr, although the glycine substitutions are also frequently present in dominant DEB.

[Therapeutic efficiency of amphotericin B liposome modified by RMP-7 to transport drug across blood brain barrier].

AIM: To study the therapeutic efficiency of amphotericin B liposome (AmB-L) targeting to the brain in mice with meningitis. METHODS: Amphotericin B liposome targeting to the brain were prepared by film-sonication method. Their concentration and encapsulation percentage were determined. The Candida albicans was injected into the brain of BALB/c mice and the meningitis model was set up. Then the therapeutic efficiency of amphotericin B liposome targeting to the brain was studied. RESULTS: The encapsulation percentage of amphotericin B liposome was 93.3%. The meningitis model was set up after the Candida albicans was injected into the brain of BALB/c mice for 2 h. The therapeutic efficiency was increased after conjugating RMP-7 (the commercial nama is Cereport) to the surface of amphotericin B liposome. CONCLUSION: The therapeutic efficiency of Amphotericin B liposome targeting to the brain in the mice with meningitis was better than that of the common amphotericin B liposome and the life of the mice in AmB-L-PEG-RMP-7 group was longer than that of the mice in AmB-L-PEG group and AmB-L-PEG + RMP-7 group.

Histopathologic and scanning electron microscope examination of the nail and hair in chronic mucocutaneous candidiasis.

The case of a 4-year-old boy with chronic mucocutaneous candidiasis is reported. Nail sections stained with periodic acid-Schiff and Grocott-Gomori methenamine-silver showed pseudohyphae running haphazardly within the nail. Scanning electron microscopy showed hyphae penetrating into the nail plate and the hair shaft.