Discovery of novel dual Bruton's tyrosine kinase (BTK) and Janus kinase 3 (JAK3) inhibitors as a promising strategy for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronically systemic autoimmune disorder, which is related with various cellular signal pathways. Both BTK (Bruton's Tyrosine Kinase) and JAK3 (Janus Kinase 3) play important roles in the pathogenesis of rheumatoid arthritis. Herein, we reported the discovery of dual BTK/JAK3 inhibitors through bioisosterism and computer-aided drug design based on the structure of BTK inhibitor ibrutinib. We reported the discovery of dual BTK/JAK3 inhibitors which are based on the structure of BTK inhibitor ibrutinib via the method of bioisosterism and computer-aided drug design) Most of the target compounds exhibited moderate to strong inhibitory activities against BTK and JAK3. Among them, compound XL-12 stood out as the most promising candidate targeting BTK and JAK3 with potent inhibitory activities (IC50 = 2.0 nM and IC50 = 14.0 nM respectively). In the in vivo studies, compound XL-12 (40 mg/kg) exhibited more potent antiarthritic activity than ibrutinib (10 mg/kg) in adjuvant arthritis (AA) rat model. Furthermore, compound XL-12 (LD50 > 1600 mg/kg) exerted improved safety compared with ibrutinib (LD50 = 750 mg/kg). These results indicated that compound XL-12, the dual BTK/JAK3 inhibitor, might be a potent drug candidate for the treatment of RA.

Effects of salt and heat treatment on the physicochemical properties, microstructure, secondary structure, and simulated in vitro gastrointestinal digestion of duck egg white.

BACKGROUND: The texture and structure of the duck egg white (DEW) gel under salt and heat treatment are crucial to its digestibility. Specifically, the structural changes of food protein gels have been recognized for their potential to regulate in vitro digestion. In this study, the effects of gel characteristics and simulated in vitro gastrointestinal digestion of DEW under combined salt and heat treatment were investigated. RESULTS: With the increase in salting time and temperature, a porous opaque gel with large particles was formed, the moisture content of DEW showed a downward trend, and the same was true for hardness changes. The microstructure suggested that, with the penetration of NaCl, DEW proteins were denatured, and the protein molecules gradually unfolded and then aggregated after 7 days. The secondary structure revealed that, as the salting time and temperature increased, the proportion of intermolecular ß-sheets and α-helices decreased. In terms of in vitro digestion, the highest digestibility was obtained at 14 days of salting combined with 100 °C heat treatment, and the digestibility was the lowest when marinated for 7 days at 121 °C. Liquid chromatography and tandem mass spectrometry (LC-MS/MS) indicated that the number of different types of peptides and specific peptides was positively correlated with the salting time and temperature of the DEW at the end of gastric digestion. CONCLUSIONS: Heat treatment at 100 °C has a higher in vitro digestibility than at 121 °C. Gels with low hardness, large pores, and rough textures are easier to digest by pepsin and release more peptides. © 2021 Society of Chemical Industry.

TiO2 Nanorod Array Constructed Nanotopography for Regulation of Mesenchymal Stem Cells Fate and the Realization of Location-Committed Stem Cell Differentiation.

As a physical cue for controlling the fate of stem cells, surface nanotopography has attracted much attention to improve the integration between implants and local host tissues and cells. A biocompatible surface TiO2 nanorod array is proposed to regulate the fate of bone marrow derived mesenchymal stem cells (MSCs). TiO2 substrates with different surface nanotopographies: a TiO2 nanorod array and a polished TiO2 ceramic are built by hydrothermal and sintering processes, respectively. The assessment of morphology, viability, gene expression, and protein characterization of the MSCs cultured on the different TiO2 substrates proves that a TiO2 nanorod array promotes the osteogenic differentiation of MSCs, while a TiO2 ceramic with a smooth surface suppresses it. Periodically assembled TiO2 nanorod array stripes on the smooth TiO2 ceramic are constructed by a combination of microfabrication and a chemical synthesis process, which realizes the location-committed osteogenic differentiation of MSCs. A route to control the differentiation of MSCs by a nanostructured surface, which can also control the location and direction of MSCs on the surface of biomaterials with micro-nano scale surface engineering, is demonstrated.

Rutile Nanorod/Anatase Nanowire Junction Array as Both Sensor and Power Supplier for High-Performance, Self-Powered, Wireless UV Photodetector.

Self-powered UV photodetectors based on TiO2 nanotree arrays have captured much attention in recent years because of their many advantages. In this work, rutile/anatase TiO2 (R/A-TiO2 ) heterostructured nanotree arrays are fabricated by assembling anatase nanowires as branches on rutile nanorods. External quantum efficiencies as high as 90% are reached at 325 nm. These high quantum efficiencies are related to the higher amount of light harvesting due to the larger surface area, the better separation ability of the photogenerated carriers by the rutile/anatase heterostructure, and the faster electron transport, related to the 1D nanostructure and lattice connection at the interface of the two kinds of TiO2 . Furthermore, a self-powered wireless UV photodetector is shown with excellent wireless detection performance. Such devices will enable significant advances for next-generation photodetection and photosensing applications.

A new species of Hemiphyllodactylus Bleeker, 1860 (Squamata: Gekkonidae) from western Yunnan, China.

A new species of the genus Hemiphyllodactylus is described from mountainous area of Changning County, Yunnan Province, China. Hemiphyllodactylus changningensis sp. nov. is distinguished from all other congeners by morphology and a significant genetic divergence of greater than 17% (ND2 gene). The new species from Changning is characterized by the following features: a maximum SVL of 40.1 mm in males and 43.8 mm in females; 11-15 dorsal scale rows; 6-8 ventral scale rows; a forefoot lamellar formula of 3-3/4-3/4-3; a hindfoot lamellar formula of 3-4-4-4 or 3-3-3-3; precloacal and femoral pore series continuous; cloacal spurs present in both sexes; dark dorsal transverse blotches; dark postorbital stripe; a brown postsacral mark bearing anteriorly projecting arms; and unpigmented caecum and gonads. The new species occurs also in Longyang District of Baoshan City, Yunnan Province, China.

Discovery of Highly Potent Small-Molecule PD-1/PD-L1 Inhibitors with a Novel Scaffold for Cancer Immunotherapy.

Inhibition of the PD-1/PD-L1 interaction through small-molecule inhibitors is a promising therapeutic approach in cancer immunotherapy. Herein, we utilized BMS-202 as the lead compound to develop a series of novel PD-1/PD-L1 small-molecule inhibitors with a naphthyridin scaffold. Among these compounds, X14 displayed the most potent inhibitory activity for the PD-1/PD-L1 interaction (IC50 = 15.73 nM). Furthermore, X14 exhibited good binding affinity to both human PD-L1 (KD = 14.62 nM) and mouse PD-L1 (KD = 392 nM). In particular, X14 showed favorable pharmacokinetic properties (oral bioavailability, F = 58.0%). In the 4T1 (mouse breast cancer cells) syngeneic mouse model, intragastric administration of X14 at 10 mg/kg displayed significant antitumor efficacy (TGI = 66%). Mechanistic investigations revealed that X14 effectively enhanced T-cell infiltration within the tumor microenvironment. Our study demonstrates that compound X14 exhibits potential as a candidate compound for the development of orally effective small-molecule inhibitors targeting PD-1/PD-L1.

Correlation analysis of metabolic characteristics and the risk of metabolic-associated fatty liver disease - related hepatocellular carcinoma.

Metabolic-associated fatty liver disease (MAFLD) is currently the most common chronic liver disease worldwide and the main cause of hepatocellular carcinoma (HCC). To explore the risk factors of MAFLD-HCC, we evaluated the independent and combined effects of metabolic characteristics on the risk of MAFLD-HCC. We retrospectively analyzed 135 MAFLD-HCC patients who were treated at the Second Affiliated Hospital of Kunming Medical University from January 2015 to December 2020 and 135 MAFLD patients as the control group. Independent and joint effects of metabolic traits on the risk of HCC were evaluated. Each metabolic feature was significantly correlated with the increased risk of MAFLD-HCC (p < 0.05); obesity had the strongest correlation (adjusted odds ratio [OR] 3.63, 95% confidence interval [CI] 1.99-6.62). In patients with superimposed features, HCC risk was higher with more metabolic features (p < 0.05). The correlation between metabolic characteristics and risk of MAFLD-HCC in patients without cirrhosis or advanced fibrosis was basically consistent with the overall analysis. Metabolic characteristics increase the risk of MAFLD-HCC, and the risk is positively correlated with the number of metabolic characteristics. Obesity has the strongest correlation with HCC.

First-In-Human Study on Pharmacokinetics, Safety, and Tolerability of Single and Multiple Escalating Doses of Hepenofovir, a Novel Hepatic Targeting Prodrug of Tenofovir in Healthy Chinese Subjects.

Objective: Hepenofovir, a novel hepatic targeting prodrug of tenofovir, has been developed for the treatment of chronic hepatitis B (CHB). This is a first-in-human study to evaluate the pharmacokinetics (PK) and tolerability of single and multiple escalating doses of hepenofovir in healthy Chinese subjects. Methods: This phase Ia study included two parts: a double-blinded, randomized, placebo-controlled single-ascending-dose (SAD) (25-200 mg) study under fasted conditions comprising a food-effect investigation (200 mg) and a multiple-ascending-dose (MAD) (25 mg) study under fasted conditions. Results: Hepenofovir was well tolerated in healthy Chinese subjects. There was no significant difference in adverse reaction rates between hepenofovir and placebo groups. Hepenofovir was rapidly absorbed and metabolized into tenofovir after dosing. In healthy participants, the median Tmax of hepenofovir and tenofovir was 0.33-0.50 h and 0.62-0.75 h, respectively, and their mean half-life was 2.5-12.3 h and 49.7-53.8 h, respectively. Systemic exposure to tenofovir increased in proportion to the dose. The mean accumulation indexes of hepenofovir and tenofovir were 1.1 vs. 1.8. Moreover, food could reduce the Cmax of both hepenofovir and tenofovir, but did not affect their area under the curve (AUC). Conclusions: Hepenofovir has shown a favorable safety and PK profile, which support the further evaluation of its safety and efficacy in CHB patients. Clinical trial registration number: The trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html # CTR20191953).

Changes in physicochemical properties, gel structure and in vitro digestion of marinated egg white gel during braising.

In this paper, changes in physicochemical properties, gel structure and in vitro digestion of marinated egg with spice or tea during braising were investigated. Results indicated that the moisture content and surface hydrophobicity of marinated egg white showed an overall decreased trend. The springiness of marinated egg white showed an increased trend, and the hardness in the late stage showed an increased trend. Microstructure showed that compact gel structures formed many holes during the braising. Intermolecular forces showed that ionic bonds and disulfide bonds played a dominant role in the marinated egg white. Secondary structure showed that the ß-turn showed a decreased trend, contrary to that of random coils and α-helices. Appropriate braising increased the digestibility of marinated egg white, but excessively long-time braising could reduce it. Both spice and tea braising could improve the gel strength of protein, and the tea braising was also slightly better than spice braising.

Comparison of plasma exchange, double plasma molecular adsorption system, and their combination in treating acute-on-chronic liver failure.

OBJECTIVE: Our objective was to compare the effectiveness of nonbiological artificial liver (NBAL) support, particularly short-term (28-day) survival rates, in patients who underwent treatment using double plasma molecular adsorption system (DPMAS), plasma exchange (PE), or combined PE+DPMAS, in addition to comprehensive physical treatment for different stages of acute-on-chronic liver failure (ACLF). METHODS: We retrospectively reviewed clinical data of 135 patients with ACLF who received NBAL treatment between November 2015 and February 2019. The patients were categorized into PE, DPMAS, and PE+DPMAS groups. Short-term effectiveness of treatment was assessed and compared based on selected clinical findings, laboratory parameters, and liver function markers. RESULTS: Coagulation function improved significantly in all groups after treatment. In the PE and PE+DPMAS groups, prothrombin time decreased to different degrees, whereas plasma thromboplastin antecedent increased significantly after treatment. White blood cell counts increased and platelet counts decreased in all groups after treatment. The model for end-stage liver disease score, Child-Pugh grade, systematic inflammatory syndrome score, and sepsis-related organ failure score decreased in all three groups after treatment. CONCLUSIONS: PE, DPMAS, and PE+DPMAS improved disease indicators in all patients with ACLF. The combined treatment improved the short-term effectiveness of treatment, especially in patients with mild ACLF.