Polysaccharide hydrogel containing silver nanoparticle@catechol microspheres with photothermal, antibacterial and anti-inflammatory activities for infected-wounds repair.

Anti-infection hydrogels have recently aroused enormous attraction, particularly in the treatment of chronic wounds. Herein, silver nanoparticle@catechol formaldehyde resin microspheres (Ag@CFRs) were fabricated by one-step hydrothermal method and subsequently encapsulated in hydrogels which were developed by Schiff base reaction between aldehyde groups in oxidized hyaluronic acid and amino groups in carboxymethyl chitosan. The developed polysaccharide hydrogel exhibited microporous structure, high swelling capacity, favorable mechanical strength, enhanced tissue adhesion and photothermal activities. Additionally, the hydrogel not only ensured long-term and high-efficiency antibacterial performance (99.9 %) toward E. coli and S. aureus, but also realized superior cytocompatibility in vitro. Moreover, based on the triple antibacterial strategies endowed by chitosan, silver nanoparticles and the photothermal properties of catechol microspheres, the composite hydrogel exhibited excellent anti-infection function, significantly downregulated inflammatory factors (TNF-α and IL-1ß) and promoted in vivo infected-wound healing. These results demonstrated that the polysaccharide hydrogel containing Ag@CFRs has great potential for infected-wounds repair.

Dual-crosslinked methacrylamide chitosan/poly(ε-caprolactone) nanofibers sequential releasing of tannic acid and curcumin drugs for accelerating wound healing.

The objective of this research study is to develop novel composite nanofibers based on methacrylamide chitosan (ChMA)/poly(ε-caprolactone) (PCL) materials by the dual crosslinking and coaxial-electrospinning strategies. The prepared ChMA/PCL composite nanofibers can sequentially deliver tannic acid and curcumin drugs to synergistically inhibit bacterial reproduction and accelerate wound healing. The rapid delivery of tannic acid is expected to inhibit pathogenic microorganisms and accelerate epithelialization in the early stage, while the slow and sustained release of curcumin is with the aim of relieving chronic inflammatory response and inducing dermal tissue maturation in the late stage. Meanwhile, dual-drugs sequentially released from the membrane exhibited a DPPH free radical scavenging rate of ca. 95 % and an antibacterial rate of above 85 %. Moreover, the membrane possessed great biocompatibility in vitro and significantly inhibited the release of pro-inflammatory factors (IL-1ß and TNF-α) in vivo. Animal experiments showed that the composite membrane by means of the synergistic effect of polyphenol drugs and ChMA nanofibers, could significantly alleviate macrophage infiltration and accelerate the healing process of wounds. From the above, the as-prepared ChMA-based membrane with a stage-wise release pattern of drugs could be a promising bioengineered construct for wound healing application.

[Spatial Distribution Characteristics and Influencing Factors of Soil Organic Carbon Density in Yellow River Basin Based on MGWR Model].

As the largest terrestrial carbon pool, the spatial distribution characteristics and influencing factors of soil organic carbon have important implications for global carbon cycle processes. Soil organic carbon density (SOCD) and influencing factors were predicted in the Yellow River basin using a mixed geographically weighted regression (MGWR) model based on soil organic carbon density data and environmental factors. The results showed that:① the SOCD ranged from 0-14.82 kg·m-2 and 0-32.39 kg·m-2 for the soil depths of 0-20 cm and 0-100 cm, with mean values of 3.48 kg·m-2 and 8.07 kg·m-2 and reserves of 2.76 Pg and 6.48 Pg, respectively. The high SOCD value areas were mainly located in the southern part of the Qinghai-Tibet Plateau and Loess Plateau, and the low value areas were located in the eastern part of the upper Yellow River and the inland flow area. ②Among the ecosystem types, the SOCD of soil depth in 0-20 cm was in the descending order of:forest>water body and wetland>other>grassland>farmland>settlement>desert, with mean values of 4.52, 4.31, 3.84, 3.73, 2.89, 2.78, and 2.22 kg·m-2, respectively, and the SOCD of the 0-100 cm soil depth was in the descending order of:water bodies and wetlands>forest>other>grassland>farmland>settlement>desert, with mean values of 9.58, 9.58, 8.85, 8.66, 7.07, 6.81, and 5.29 kg·m-2, respectively. The SOCR in descending order was:grassland>farmland>forest>desert>water bodies and wetlands>settlement>others, with 1.40, 0.60, 0.47, 0.11, 0.07, 0.06, and 0.05 Pg at a soil depth of 0-20 cm and 3.31, 1.49, 0.99, 0.26, 0.17, 0.14, and 0.12 Pg at a soil depth of 0-100 cm, respectively. ③ The main factors affecting the SOCD distribution were intercept, profile curvature, NDVI, and precipitation; in addition, curvature and silt also had important effects on the deep SOCD distribution in the Yellow River basin. Among the ecosystem types, precipitation and NDVI were the main factors affecting the SOCD distribution. The intercept also had important effects on the SOCD distribution in the all ecosystems except forests, whereas curvature and silt only had important effects on deserts and other ecosystems. These results revealed the spatial distribution of SOCD, influencing factors, and SOCR in the Yellow River basin and can provide a scientific basis for carbon balance, soil quality evaluation, and ecological management restoration and consolidation in the region.

4-methylpteridinones as orally active and selective PI3K/mTOR dual inhibitors.

Pteridinones were designed based on a non-selective kinase template. Because of the uniqueness of the PI3K and mTOR binding pockets, a methyl group was introduced to C-4 position of the peteridinone core to give compounds with excellent selectivity for PI3K and mTOR. This series of compounds were further optimized to improve their potency against PI3Kα and mTOR. Finally, orally active compounds with improved solubility and robust in vivo efficacy in tumor growth inhibition were identified as well.

Azaindole N-methyl hydroxamic acids as HIV-1 integrase inhibitors-II. The impact of physicochemical properties on ADME and PK.

HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase 2 glucuronidation pathways. We were able to introduce polar groups at the ß-position of the azaindole core thereby altering physical properties by lowering calculated log D values (c Log D) which resulted in attenuated clearance rates in human hepatocytes. Pharmacokinetic data in dog for representative compounds demonstrated moderate oral bioavailability and reasonable half-lives. These ends were accomplished without a large negative impact on enzymatic and antiviral activity, thus suggesting opportunities to alter clearance parameters in future series.

Sensing behavior and logic operation of a colorimetric fluorescence sensor for Hg(2+)/Cu(2+) ions.

A BODIPY-based 1 as a colorimetric fluorescence sensor was synthesized, and its metal sensing property was investigated. 1 displayed high selectivity and sensitivity towards Hg(2+) and Cu(2+) ions among 15 different metal cations. The addition of Hg(2+) and Cu(2+) ions into 1 in CH3CN resulted in a significant bathochromic shift of the UV absorption spectra from 533nm to 560nm and 593nm, respectively, changing the corresponding colors from pink to purple and blue. When excited at 530nm, the fluorescence intensity of 1 was quenched over 75% upon addition of Hg(2+) ions, while 1 with Cu(2+) ions exhibited significant fluorescence enhancement with a 23nm red-shift. Based on these results, three logic gates (OR, IMPLICATION, and INHIBIT) were obtained by controlling the chemical inputs.

Discovery of pyrroloaminopyrazoles as novel PAK inhibitors.

The P21-activated kinases (PAK) are emerging antitumor therapeutic targets. In this paper, we describe the discovery of potent PAK inhibitors guided by structure-based drug design. In addition, the efflux of the pyrrolopyrazole series was effectively reduced by applying multiple medicinal chemistry strategies, leading to a series of PAK inhibitors that are orally active in inhibiting tumor growth in vivo.

Azaindole hydroxamic acids are potent HIV-1 integrase inhibitors.

HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication. Recently, HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Herein, we report the discovery of azaindole carboxylic acids and azaindole hydroxamic acids as potent inhibitors of the HIV-1 IN enzyme and their structure-activity relationships. Several 4-fluorobenzyl substituted azaindole hydroxamic acids showed potent antiviral activities in cell-based assays and offered a structurally simple scaffold for the development of novel HIV-1 IN inhibitors.

A molecular modeling analysis of novel non-hydroxamate inhibitors of TACE.

Recently, an X-ray co-crystal structure of our hydroxamate inhibitor IK682 and TACE [Niu, X.; Umland, S.; Ingram, R.; Beyer, B. M.; Liu, Y.-H.; Sun, J.; Lundell, D.; Orth, P. Arch. Biochem. Biophys. 2006, 451, 43-50] was published that explicitly shows the orientation of the hydroxamate and the TACE-selective 4-[(2-methyl-4-quinolinyl)methoxy]phenyl P1' group in the S1' and S3' sites. The preceding paper described a novel series of potent and TACE-selective hydantoins and we previously described pyrimidinetrione (barbiturate) inhibitors of TACE, both of which contain the same P1' group as IK682. Using this TACE-selective P1' group as an anchor, stereochemical and conformational constraints in the inhibitors, and restrictions to the active site Zn coordination geometry, we developed a highly plausible and predictive pharmacophore model that rationalizes the observed TACE activity of all three inhibitors.

Discovery of novel hydantoins as selective non-hydroxamate inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).

A series of novel hydantoins was designed and synthesized as structural alternatives to hydroxamate inhibitors of TACE. 5-Mono- and di-substituted hydantoins exhibited activity with IC50 values of 11-60 nM against porcine TACE in vitro and excellent selectivity against other MMPs.