Discovery of novel selective phosphodiesterase­1 inhibitors for the treatment of acute myelogenous leukemia.

Acute myelogenous leukemia (AML) is the most common form of acute leukemia in adults. PDE1 (Phosphodiesterase 1) is a subfamily of the PDE super-enzyme families that can hydrolyze the second messengers cAMP and cGMP simultaneously. Previous research has shown that suppressing the gene expression of PDE1 can trigger apoptosis of human leukemia cells. However, no selective PDE1 inhibitors have been used to explore whether PDE1 is a potential target for treating AML. Based on our previously reported PDE9/PDE1 dual inhibitor 11a, a series of novel pyrazolopyrimidinone derivatives were designed in this study. The lead compound 6c showed an IC50 of 7.5 nM against PDE1, excellent selectivity over other PDEs and good metabolic stability. In AML cells, compound 6c significantly inhibited the proliferation and induced apoptosis. Further experiments indicated that the apoptosis induced by 6c was through a mitochondria-dependent pathway by decreasing the ratio of Bcl-2/Bax and increasing the cleavage of caspase-3, 7, 9, and PARP. All these results suggested that PDE1 might be a novel target for AML.

Blockchain Private File Storage-Sharing Method Based on IPFS.

Under the current national network environment, anyone can participate in publishing. As an important information resource, knowledge files reflect the workload of publishers. Moreover, high-quality knowledge files can promote the progress of society. However, pirated inferior files have the opposite effect. At present, most organizations use centralized servers to centrally manage the knowledge files released by users. In addition, it is necessary to introduce an untrusted third party to examine and encrypt the contents of files, which leads to an opaque process of file storage transactions, tampering with intellectual copyright, and the inability to have consistent systems of file management among institutions due to the lack of uniform standards for the same intellectual files. The purpose of this paper is to ensure the safe storage of knowledge files on the one hand and to realize efficient sharing of copyrighted files on the other hand. Therefore, this paper combines NDN (Named Data Network) technology with a distributed blockchain and an Interplanetary File System (IPFS) and proposes a blockchain knowledge file storage and sharing method based on an NDN. The method uses the NDN itself for the file content signature and encryption, thereby separating the file security and transmission process. At the same time, the method uses a flexible NDN reverse path forwarding and routing strategy, combining an IPFS private storage network to improve the safety of the encrypted data storage security. Finally, the method takes advantage of all participating nodes consensus and shares files in the synchronized blockchain to ensure traceability. This paper introduces the structure and principles of the method and describes the process of file upload and transfer. Finally, the performance of the method is compared and evaluated, and the advantages and disadvantages of the method and the future research direction are summarized.

Hypocholesterolaemic effect of whole-grain highland hull-less barley in rats fed a high-fat diet.

Whole-grain highland hull-less barley (WHLB) contains high amounts of bioactive compounds that potentially exhibit cholesterol-lowering effects. This study investigated the hypocholesterolaemic effect of WHLB. A total of seventy-two male Sprague-Dawley rats were divided into four groups and were fed with the normal control diet, high-fat diet (HFD) and HFD containing low or high dose (10 or 48·95 %) of WHLB. High dose of WHLB significantly decreased the organ indexes of liver and abdominal fat and lipid levels of plasma and liver in HFD rats. The lipid regulation effect of WHLB, which was reconfirmed through hepatocyte morphologic observation, was accompanied by a large excretion of bile acids in the small intestinal contents and the faeces. Real-time PCR analyses, which were further reconfirmed through Western blot analyses, revealed that a high dose of WHLB significantly enhanced the hepatic expressions of AMP-activated protein kinase α, cholesterol 7α-hydroxylase, LDL receptor, liver X receptor, and PPARα and decreased the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase. It also enhanced the ileal expression of farnesoid X receptor and resulted in the decrease of expression of apical sodium-dependent bile acid transporter. WHLB exhibited hypocholesterolaemic effects mainly by inhibiting cholesterol synthesis, cholesterol accumulation in peripheral tissue, and bile acid reabsorption and by stimulating bile acid synthesis.

Preparation of konjac glucomannan/casein blending gels optimized by response surface methodology and assessment of the effects of high-pressure processing on their gel properties and structure.

BACKGROUND: In order to improve the compatibility of polysaccharide-protein mixtures and enhance their performance, a response surface methodology was used to optimize the preparation conditions of konjac glucomannan/casein blend gel. Moreover, the effects of high-pressure processing (HPP) on the gel properties and structure were also investigated. RESULTS: The optimal preparation parameters were a temperature of 60 °C, a total concentration 40 g kg-1 , and a dietary alkali concentration 5 g kg-1 . Under these conditions, the experimental value of hardness was 38.7 g, which was close to the predicted value. HPP increased gel hardness by 161-223% and led to a more compact structure at 200-600 MPa/10 min, while a hardness increase of ∼120% and damaged structure were observed at 600 MPa/30 min. Fourier transform infrared spectroscopy showed that noncovalent interactions are likely the most important factor in the modification of gel hardness; indeed, hydrogen bonding interactions in the gels are enhanced when subjected to HPP, but are weakened at 600 MPa/30 min. COUCLUSION: Protein-polysaccharide complexes with excellent properties could be obtained through this method, with broad application prospects in the food industry. © 2018 Society of Chemical Industry.

Complete earlobe keloid resection with fistulectomy.

BACKGROUND: The earlobe is a location with a high risk of keloid scar formation. Keloid scars pose a surgical challenge from recidivation. The objective of this study was to investigate a new surgical approach for the treatment of auricular keloids. METHODS AND RESULTS: In the past 4 years, 11 earlobe keloids of 9 patients have been excised by fistulectomy (perforation operation). All of the patients were followed up for at least 12 months without recurrence. CONCLUSIONS: As a new surgical approach, a perforation operation together with fistulectomy is suitable for lobular keloids.

Purification and Structural Identification of Polysaccharides from Bamboo Shoots (Dendrocalamus latiflorus).

Three kinds of polysaccharides, namely, BSP1A, BSP2A, and BSP3B, were isolated from raw bamboo shoot (Dendrocalamus latiflorus) after purification and classification by DEAE cellulose-52 (ion-exchange chromatography) and Sephadex G-50. The molecular weights of BSP1A, BSP2A, and BSP3B were 10.2, 17.0 and 20.0 kDa, respectively, which were measured through GPC (gel performance chromatography) methods. BSP1A contained arabinose, glucose, and galactose in a molar ratio of 1.0:40.6:8.7. BSP2A and BSP3B contained arabinose, xylose, glucose, and galactose in molar ratios of 6.6:1.0:5.2:10.4 and 8.5:1.0:5.1:11.1, respectively. The existence of the O-glycopeptide bond in BSP1A, BSP2A, and BSP3B was demonstrated by ß-elimination reaction. FTIR spectra of the three polysaccharides showed that both BSP2A and BSP3B contained ß-D-pyranose sugar rings. However, BSP1A exhibited both ß-D-pyranose and α-D-pyranose sugar rings. Congo red test indicated that BSP1A and BSP2A displayed triple helix structures, but BSP3B did not. NMR spectroscopy revealed that BSP1A may exhibit a ß-1,6-Glucan pyran type as the main link, and few 1,6-glycosidic galactose pyranose and arabinose bonds were connected; BSP2A mainly demonstrated → 5)ß-Ara(1 → and → 3)ß-Gal(1 → connection. Furthermore, BSP3B mainly presented → 3)ß-Glu(1 → and → 3)ß-Gal(1 → connection and may also contain few other glycosidic bonds.

New insights into the interaction between bamboo shoot polysaccharides and lotus root starch during gelatinization, retrogradation, and digestion of starch.

In this study, the interaction between bamboo shoot polysaccharides (BSP) and lotus root starch (LS) during gelatinization, retrogradation, and digestion of starch was investigated. The addition of BSP inhibited the gelatinization of LS and decreased the peak viscosity, valley viscosity, and final viscosity. Amylose leaching initially increased and then decreased with the increase in BSP addition. The apparent viscosity and viscoelasticity of LS decreased with the increase in BSP addition. Moreover, 3 % BSP increased the hardness and cohesiveness of LS gel, whereas 6 %-15 % BSP decreased them. In addition, 3 %-6 % BSP promoted the uniform distribution of water molecules in the starch paste, whereas the addition of 12 % and 15 % BSP resulted in the inhomogeneous distribution of the water. The retrogradation degree of LS gel gradually increased with the increase in BSP addition from 3 % to 6 %, whereas 9 %-15 % BSP restricted the short-term and long-term retrogradation of LS. After 12 % BSP was added, the RDS content reduced by 11.6 %, the RS content significantly increased by 75 %, and the digestibility of starch decreased. This work revealed the interaction between BSP and LS during starch gelatinization, retrogradation, and digestion to improve the physicochemical properties and digestive characteristics of LS.

Rheological properties, multiscale structure, and in vitro digestibility of a maize starch-konjac glucomannan-bamboo leaf flavonoid complex modified by dynamic high-pressure microfluidization.

The effects of dynamic high-pressure microfluidization (DHPM) treatment on the rheological properties, multiscale structure and in vitro digestibility of complex of maize starch (MS), konjac glucomannan (KGM), and bamboo leaf flavonoids (BLFs) were investigated. Compared with MS, the MS-KGM-BLF complex exhibited reduced viscosity and crystallinity, along with increased lamellar thickness to 10.26 nm. MS-KGM-BLF complex had lower viscosity after DHPM treatment. The highest ordered structure and crystallinity were observed at 50 MPa, with the α value increasing from 3.40 to 3.59 and the d value decreasing from 10.26 to 9.81 nm. However, higher DHPM pressures resulted in a decrease in the α value and an increase in the d value. The highest gelatinization enthalpy and resistant starch content were achieved at 100 MPa DHPM, while the fractal structure shifted from surface fractal to mass fractal at 150 MPa. This study presents an innovative method for enhancing the properties of MS.

Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis.

Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-ß-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.

Sucrose ester alleviates the agglomeration behavior of bamboo shoot dietary fiber treated via high pressure homogenization: Influence on physicochemical, rheological, and structural properties.

High-pressure homogenization (HPH) is a physical modification method that can rapidly reduce the particle size of bamboo shoot dietary fiber (BSDF), but it can lead to agglomeration. Therefore, the effects of the addition of sucrose ester (SE) to alleviate the agglomeration of BSDF during HPH were investigated. Compared with BSDF without added SE, BSDF obtained the smallest particle size (276.5 nm) and highest ζ-Potential (53.6 mV) when SE was 5 g/L. Water-holding capacity, oil-holding capacity, swelling capacity, and b* increased, whereas L* and a* decreased significantly with the addition of SE. The shear stress and viscoelasticity of BSDF solution were minimized when 5 g/L SE was added. SE reduced relative crystallinity and thermal stability of BSDF. SE could effectively alleviate the aggregation of BSDF through the mechanism of electrostatic repulsion. This study highlights an innovative and promising strategy for alleviating the agglomeration behavior of BSDF during HPH treatment.

Physicochemical, structure properties and in vitro hypoglycemic activity of soluble dietary fiber from adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) bran treated by steam explosion.

To enhance the content of adlay bran soluble dietary fiber (SDF) and improve its functionality, we investigated the influences of steam explosion (SE) on the physicochemical, structural properties, and in vitro hypoglycemic activities of adlay bran SDF. The cellulose, hemicellulose, and lignin contents of adlay bran decreased significantly after SE treatment. When the SE strength was 0.8 MPa for 3 min, the SDF content was 9.37%, which was a significant increase of 27.48% compared to the control. Under these conditions, SDF showed the highest oil-holding capacity (OHC) (2.18 g/g), cholesterol adsorption capacity (CAC) (27.29 mg/g), glucose adsorption capacity (GAC) (15.54 mg/g), glucose dialysis retardation index (GDRI) (36.57%), and α-Amylase activity inhibition ratio (α-AAIR) (74.14%). Compared with SDF from untreated adlay bran, SDF from SE-treated adlay bran showed lower weight molecular. In addition, differential scanning calorimetry (DSC) measurement showed that the peak temperature of SDF from adlay bran treated by SE increased by 4.19°C compared to the untreated SDF sample. The structure of SDF from adlay bran treated by SE showed that the SDF surface was rough and poriferous and the specific surface areas increased. In conclusion, SE pretreatment increases the content of SDF in adlay bran and improves its physicochemical, structural properties, and biological activities, which will be beneficial for the further exploitation of adlay bran.

Synergistic modification of ultrasound and bamboo leaf flavonoid on the rheological properties, multi-scale structure, and in vitro digestibility of pea starch.

In this study, the effect of ultrasonic treatment (UT), bamboo leaf flavonoid (BLF), ultrasonic treatment prior to bamboo leaf flavonoid (UT-BLF), and bamboo leaf flavonoid prior to the ultrasonic treatment (BLF-UT) on the rheological properties, multi-scale structure, and digestibility of pea starch (PS) were investigated. The morphology and crystal structure of starch granules were destroyed by UT, thereby promoting starch retrogradation and digestion. The binding between BLF and starch through hydrophobic interactions and hydrogen bonds inhibited the interaction between starch molecular chains and impaired their double helix structure, thus effectively retarding starch retrogradation. The anti-digestibility of starch was enhanced after synergistic treatment. Compared with single treatment, synergistic treatment increased the ordered structure and gelatinization enthalpy of starch. In comparison with the UT-BLF group, the viscoelastic and thermal stability of BLF-UT group were improved with the increase in ordered structure. This study could provide valuable information for PS modification.

Lotus starch/bamboo shoot polysaccharide composite system treated via ultrasound: Pasting, gelling properties and multiscale structure.

This study investigated the effects of ultrasound treatment on the physicochemical properties, digestion properties, and multiscale structure of a lotus root starch (LS) and bamboo shoot polysaccharide (BSP) composite system. It also preliminarily revealed the mechanism underlying the modification effect of ultrasound treatment. After 180-360 W ultrasound treatment, the viscosity, thixotropy, and gel viscoelasticity of the LS/BSP paste increased. However, treatment with the ultrasound power of 540 and 720 W decreased viscoelasticity. After 14 days of retrogradation, the hardness and cohesiveness of the LS/BSP gel increased under 180 and 360 W ultrasound treatment but decreased under 540 and 720 W ultrasound treatment. After 540 W ultrasound treatment, RDS content decreased by 17.2 % and resistant starch content increased by 32.5 %. After 180 min of in vitro digestion, the hydrolysis rate of LS/BSP decreased from 97.82 % to 93.13 % as the ultrasound power increased to 540 W. Ultrasound promoted the uniform dispersion of BSP in the starch paste and the movement, orientation, rearrangement, and aggregation of starch and BSP molecular chains. These effects further enhanced the interaction between BSP and starch, resulting in the formation of a dense paste structure with strong resistance to digestive enzymes. This work revealed the mechanism of the effects of ultrasound treatment on LS/BSP and found that 360-540 W ultrasound treatment could improve the physicochemical properties and digestion properties of LS/BSP.

Relationship between the Dynamics of Flavor Compounds and Microbial Succession in the Natural Fermentation of Zhalajiao, a Popular Traditional Chinese Fermented Chili Paste.

Zhalajiao, a traditional Chinese fermented food, is popular due to its unique flavor. Traditional Zhalajiao fermentation is closely related to flavor compounds production. However, the mechanisms underlying the formation of these crucial flavor components in Zhalajiao remain unclear. Here, we explored the dynamic changes in physical and chemical properties, microbial diversity, and flavor components of Zhalajiao at various fermentation times. In total, 6 organic acids, 17 amino acids, and 21 key volatile compounds were determined as flavor components. In Zhalajiao, Lactobacillus and Cyanobacterium were the main bacteria that were involved in the formation of crucial flavor compounds. Candida showed a significant correlation with 14 key flavor compounds during fermentation (p < 0.05) and was the main fungal genus associated with flavor formation in Zhalajiao. This research offers a theoretical foundation for the flavor regulation and quality assurance of Zhalajiao.

Identification of Novel Quinolin-2(1H)-ones as Phosphodiesterase 1 Inhibitors for the Treatment of Inflammatory Bowel Disease.

Phosphodiesterase 1 (PDE1) is a subfamily of PDE super enzyme families that can hydrolyze cyclic adenosine monophosphate and cyclic guanosine monophosphate simultaneously. Currently, the number of PDE1 inhibitors is relatively few, significantly limiting their application. Herein, a novel series of quinolin-2(1H)-ones were designed rationally, leading to compound 10c with an IC50 of 15 nM against PDE1C, high selectivity across other PDEs, and remarkable safety properties. Furthermore, we used the lead compound 10c as a chemical tool to explore whether PDE1 could work as a novel potential target for the treatment of inflammatory bowel disease (IBD), a disease which is a chronic, relapsing disorder of the gastrointestinal tract inflammation lacking effective treatment. Our results showed that administration of 10c exerted significant anti-IBD effects in the dextran sodium sulfate-induced mice model and alleviated the inflammatory response, indicating that PDE1 could work as a potent target for IBD.

Comparison of different extraction methods on the physicochemical, structural properties, and in vitro hypoglycemic activity of bamboo shoot dietary fibers.

The effect of alkali extraction (AE), enzymatic extraction (EE), ultrasonic-assisted enzymatic extraction (UAEE), and shear homogeneous-assisted enzymatic extraction (SHAEE) on the physicochemical, structural properties, and in vitro hypoglycemic activity of bamboo shoot dietary fibers (BSDF) were investigated and compared. BSDF obtained by AE had the lowest protein content and crystallinity index. The lowest oil holding capacity (OHC) and highest protein content were observed in EE. BSDF generated highest OHC and glucose adsorption capacity by UAEE. SHAEE obtained the highest SDF content (17.89%), water-holding capacity (8.81 g/g), and α-amylase activity inhibition ratio (19.89%) and the smallest particle size (351.33 µm). BSDF extracted by SHAEE and UAEE presented a porous and loose structure. Furthermore, the in vitro hypoglycemic activity of the four BSDF samples generally followed the order of SHAEE > UAEE > EE > AE. Results show that SHAEE is an innovative and promising method to obtain BSDF with its excellent physicochemical and functional properties.

Modifying the rheological properties, in vitro digestion, and structure of rice starch by extrusion assisted addition with bamboo shoot dietary fiber.

This paper investigated the effect of extrusion treatment on the rheological properties, in vitro digestibility, and multi-structure of starch with or without bamboo shoot dietary fiber (BSDF). The viscoelasticity and thixotropy decreased after extrusion treatment, however, they increased after BSDF addition, and decreased with increasing BSDF content. The starch granules became smooth and formed big lumps after extrusion treatment. The dense lumps became loose after the addition of BSDF. Extrusion treatment changed the movement and arrangement of starch chains and thus the relative crystallinity and branching degree decreased by 92.6% and 40.9%, respectively. The disruption of starch further increased rapid digestion starch (RDS) content by 10%. The decreased disruption of starch granules and increased entanglement between BSDF and starch decreased the RDS content. The addition of BSDF is a novelty method to enhance the nutritional properties and control the physicochemical properties of extruded starchy foods.

In vitro digestion and structural properties of rice starch modified by high methoxyl pectin and dynamic high-pressure microfluidization.

The rheological, structural properties and in vitro digestibility of starch with high methoxyl pectin (HMP) and further modified by dynamic high-pressure microfluidization (DHPM) were investigated. The viscosity and elasticity increased on addition of HMP and were more pronouncedly affected by 10% HMP. However, after DHPM treatment, the viscosity and elasticity decreased with increasing DHPM pressure. After 100 MPa DHPM treatment, the ordered and crystalline structures were further increased compared with starch-HMP mixtures. A compact and dense surface of starch paste was formed under 100 MPa DHPM and 10% HMP treatment, thus significantly slowing down the digestibility. In contrast, the crystalline and semicrystalline structure of starch were disrupted by intense shear force under 200 MPa DHPM. This study provides theoretical information regarding starch-HMP interaction and improves their functional and physicochemical properties through a promising strategy for better applications in food formulation.

Effects of Salts on Structural, Physicochemical and Rheological Properties of Low-Methoxyl Pectin/Sodium Caseinate Complex.

The addition of salts is an effective way to improve the properties of polysaccharide/protein complexes for use in foods. However, there is no comparative study on the effects of different ions on the complex system of low methoxyl pectin (LMP)/ sodium caseinate (CAS) complex. The effects of different concentrations of three salt ions (Na+, K+, Ca2+) on the physicochemical and rheological properties of the LMP/CAS complex were determined in this study, and the structure of LMP/CAS complex was characterized. The results showed that the addition of these three salt ions affected zeta potential, particle size, and turbidity of the LMP/CAS complex, and lead the LMP/CAS complex to form a more regular and uniform network structure, which helped improve its stability, solubility, and rheological properties. The particle size and turbidity value of the complex achieved with Ca2+ were higher than those obtained using Na+ and K+. Moreover, the secondary structure of the proteins in the complex changed to adding high concentrations of Ca2+. Our study provides valuable information for the application of the LMP/CAS complex in the food industry.

Effect of four viscous soluble dietary fibers on the physicochemical, structural properties, and in vitro digestibility of rice starch: A comparison study.

The effect of carboxymethyl cellulose (CMC), high-methoxyl pectin (HMP), konjac glucomannan (KGM), and xanthan gum (XG) on the physicochemical, structural properties, and digestibility of rice starch were investigated and compared. The four viscous soluble dietary fibers (VSDFs) increased the viscosity, storage modulus and loss modulus while decreased the pasting temperature and gelatinization enthalpy. Moreover, XG produced the lowest peak viscosity and dynamic modulus compared with the other VSDFs. Furthermore, the degree of short-range ordered structure of starch with KGM increased from 0.8448 to 0.8716; and the relative crystallinity of starch with XG increased by 12%. An ordered and reunited network structure was observed in SEM. In addition, VSDF inhibited the digestibility of rice starch and significantly increased the resistant starch content. This study compared the effect of four VSDFs on the physicochemical, structural and digestion properties of rice starch to fully understand and develop their application to starchy foods.