Towards the development of novel bicomponent phytosterol-based oleogels with natural phenolics.

Structuring liquid oils into edible oleogels from natural and abundant plant ingredients has great significance in fields ranging from foods to pharmaceuticals but has proven challenging. Herein, novel bicomponent phytosterol-based oleogels were developed with natural phenolics. Investigating diverse natural phenolics, cinnamic acid (CA) and ethyl ferulate (EF) successfully formed oleogels in combination with phytosterols (PS), where a synergistic effect on the oleogelation and crystallization was observed compared to the corresponding single component formulations. FTIR and UV-vis spectra showed that the gel network was primarily driven by hydrogen bonding and π-π stacking. Furthermore, oscillatory shear demonstrated oleogels featured higher elastic and network structure deformation at molar ratio of 5:5 and 3:7. Moreover, the bicomponent phytosterol-based oleogels displayed partially reversible shear deformation and a reversible solid-liquid transition. Such information was useful for engineering the functional properties of oleogel-based lipidic materials, providing significance for the application in foods, cosmetics and pharmaceuticals industries.

Influence of the casing layer on the specific volatile compounds and microorganisms by Agaricus bisporus.

One of the major variables affecting yield of the mushroom Agaricus bisporus is the casing layer, which directly affects the productivity and mass. Here, volatile organic compounds were extracted by headspace solid-phase microextraction and high-throughput sequencing was used to analyze the microbial community diversity. The relationship between mushroom yield at different cropping stages and the contents of volatile organic compounds and microorganisms in three different casing layers: peat, peat + soil and soil were systematically evaluated. The result shows that Benzaldehyde and (E)-2-octenal which stimulate yield, obviously increased as mushrooms grew, while 3-octanone, which inhibits yield, decreased over time in all three casing layers. However, there was not a strong correlation between the concentration of volatile compounds and yield. In addition, more than 3,000 bacterial operational taxonomic units (OTUs) by performing high throughput sequencing of the microbes were obtained in the three casing layers. Interestingly, the microbial community compositions were very similar between the three casing layers at a later cropping stage, but the community richness varied significantly in different casing layers and at different cropping stages. At the phylum level, the communities had similar structures but were quantitively very different, and this was even more obvious at the genus level. Principal component analysis revealed significant alterations in microbial community structure in different casing layers. Sphingomonas, Dongia and Achromobacter were the dominant genera at cropping stage 1, and the stage 3 were abundant in Saccharibacteria_norank, Pseudomonas, Flavobacterium and Brevundimonas, which was positively correlated with yield, while the abundance of Pseudomonas at stage 1 and Lactococcus and Bacillus at stage 3 was negatively correlated with yield. These results provide a guide for the development and agricultural application of microbial agents for yield improvement in the production of A. bisporus.

Derivation of copper water quality criteria in Bohai Bay for the protection of local aquatic life and the ecological risk assessment.

Developing effective marine water quality criteria (WQC) is crucial for controlling marine contamination and protecting marine life. The WQC for copper is urgently needed due to the toxicity and widespread of copper contamination. In this work, both short-term water quality criteria (SWQC) and long-term water quality criteria (LWQC) under 10 % effect endpoints were derived by using the model averaging of species sensitivity distribution (SSD10) method for Bohai Bay. The WQC values were obtained directly from the hazardous concentration for 5 % of species (HC5) values, which removes the influence of arbitrary assessment factor (AF). Modifications to the acute-chronic ratio (ACR) strategies and the inclusion of the test toxicity data of local species also improved the accuracy and applicability of the WQC values. The derived SWQC and LWQC were 2.21 and 0.45 µg/L, respectively. Furthermore, the overall risk level of copper in Bohai Bay was evaluated by using the risk quotient (RQ) method, and the results showed it was at a moderate-low level. This study provides a new approach for the derivation of the WQC for Cu and the risk assessment of Bohai Bay, which is essential for the protection of local aquatic life and provides guidance to the establishment of the national WQC.

Scientometric analysis of kidney disease and gut microbiota from 2001 to 2020 based on Web of Science.

This study aims to demonstrate current research priorities and predict future trends in the link between kidney disease and gut microbiota by means of scientometric analysis. We collected nearly 20 years (2001-2020) of publications related to kidney disease and gut microbiota in the Web of Science database. CiteSpace was used to evaluate the knowledge mapping. There are 965 manuscripts about kidney disease and gut microbiota in total, and faster growth after 2016. The country, institution, and author who posted the most are the USA, Univ Calif Irvine, and DENISE MAFRA, respectively. The frequencies are 109, 16, and 17. The most important of them are FRANCE (0.23), Fed Univ Parana UFPR (0.13), and VAZIRI ND (1.14), owing to their highest centrality. In addition, the cited documents that have contributed the most to the co-citations are Wong J (2014); the most key cited reference is Rossi M (2016); the most commonly used keywords are chronic kidney disease, gut microbiota and indoxyl sulfate. Through scientometric analysis of the past 20 years, we obtained the knowledge map of this information, which has important guiding significance for accurately and quickly locating trends in this field.

Relationship Between Subclinical Cardiovascular Diseases and Cardiac Morpho-Functional Parameters in Preclinical Stage A/B Heart Failure Adults with Type 2 Diabetes.

Purpose: Type 2 diabetes mellitus (T2DM) is a common risk factor for cardiovascular disease which increases the risk of heart failure. This study aimed to determine whether clinical characteristics and subclinical cardiovascular disease (CVD) features are correlated with echocardiographic morpho-functional parameters of T2DM patients. Patients and Methods: Two hundred and fifty-five T2DM patients without a history of coronary heart disease were enrolled in this cross-sectional study. The demographic characteristics, glucose and lipid levels were assessed for each patient. Carotid ultrasonography and peripheral artery examination were performed to measure carotid intima-media thickness (cIMT), carotid plaque, ankle-brachial index (ABI), brachial artery pulse wave velocity (baPWV), and carotid-femoral pulse wave velocity (cfPWV). Furthermore, echocardiography was conducted to evaluate cardiac morphology and systolic and diastolic function. The relationship between clinical characteristics, subclinical cardiovascular diseases, and cardiac morpho-functional parameters was explored with the Pearson and stepwise multivariable linear regression analyses. Results: A total of 255 subjects aged 18-80 years were enrolled in the study. Multiple regression analysis revealed that left ventricular mass index (LVMI) was correlated with age (ß=0.463, p = 0.000) and systolic blood pressure (SBP) (ß=0.179, p = 0.003). Relative wall thickness (RWT) was related to cfPWV (ß=0.006, p = 0.007) and homeostasis model assessment of insulin resistance (HOMA-IR) (ß=0.000, p = 0.036). In contrast, left ventricular ejection fraction (LVEF) was inversely related to cIMT (ß=-0.925, p = 0.019). The ratio of the peak flow velocity of early diastole to atrial contraction (peak E/A) was correlated with age (ß=-0.014, p = 0.000), diastolic blood pressure (DBP) (ß=-0.006, p = 0.001) and cfPWV (ß=-0.025, p = 0.044). Conclusion: In preclinical stage A/B heart failure adults with T2DM, age, BP, HOMA-IR, cfPWV and cIMT are correlated with cardiac morpho-functional parameters.

[Effects of vitamin C on antioxidant function of testis in cadmium-loaded mice].

Objective: To investigate the effects of cadmium (Cd) on antioxidant enzymes in testis of mice and the protective effect of vitamin C (VC). Methods: A total of 72 male Kunming mice of clean grade were divided into four groups (n=18): the control group, the Cd group (CdCl2 3 mg/kg), the VC group (200 mg/kg), and the VC (200 mg/kg) +Cd group (CdCl2 3 mg/kg). Mice were poisoned once a day, exposed for 1 and 3 days and were treated with VC at the same time. Twenty-four hours after exposure on the 1st and 3rd day, half of the mice in each group were weighed, the serum and testis tissues were collected. Testicular organ coefficient, malondialdehyde (MDA) and superoxide dismutase (SOD) in serum and testis tissues, and glutathione peroxidase (GSH-Px), reduced glutathione (GSH), oxidized glutathione (GSSG) and total glutathione (T-GSH) in testis tissues were detected. Results: Compared with the control group, the body weight and testicle organ coefficient of mice in the Cd group were decreased on the 1st and 3rd day; after 3 days of exposure, the serum SOD in the Cd group was decreased significantly and MDA was increased significantly (P＜0.05); the levels of SOD, GSH-Px, T-GSH and GSH/GSSG of testis in the Cd group were increased significantly on the 1st day (P＜0.05), while all the above indexes were decreased significantly on the 3rd day (P＜0.05), and the content of MDA was increased significantly on the 1st and 3rd days in the Cd group (P＜0.05); after VC treatment, the degree of reduction was decreased. Compared with the Cd group, the serum SOD and MDA levels in the VC+ Cd group were significantly different after 3 days of exposure (P＜0.05); the changes of SOD, GSH-Px, T-GSH and GSH/GSSG levels of the testis in the VC+ Cd group were significantly different on the 1st and 3rd day of exposure (P＜0.05), and the MDA level of the testis in the VC+ Cd group was decreased significantly on the 3rd day of exposure (P＜0.05). Compared with the Cd group for 1 day, the level of serum SOD exposed for 3 days was decreased significantly (P＜0.05), and the changes of testis indexes were also significantly different (P＜0.05). Conclusion: VC treatment can improve the antioxidant function of cadmium-loaded mice to some extent, and has protective effect on oxidative damage of testis.

Amorphous poly-N-vinylcarbazole polymer as a novel matrix for the determination of low molecular weight compounds by MALDI-TOF MS.

Traditional matrices for matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS) are usually crystalline small molecules. The heterogeneous co-crystallization of the analyte and the matrix creates a sweet spot effect and reduces point-to-point reproducibility. In this study, an amorphous poly-N-vinylcarbazole polymer (PVK) was studied as a novel matrix for MALDI-TOF MS to detect various low molecular weight compounds (LMWCs) in the negative ion mode. The PVK achieved excellent matrix action and showed high sensitivity, good salt tolerance, and reproducibility. These results significantly broaden the design rules for new and efficient polymeric MALDI matrices.

Efficient Electrochemical Detection of Hydrogen Peroxide Based on Silver-Centered Preyssler-Type Polyoxometalate Hybrids.

Four polyoxometalate (POM)-based organic-inorganic hybrid compounds, namely, (H2bimb)6H8[((Mn(H2O)3(µ-bimb))0.5(Mn(H2O)4)(Mn(H2O)5)0.5(AgP5W30O110))2]·29H2O (1), [(Cu(Hbimb)(H2O)2(µ-bimb)Cu(Hbimb)(H2O))(Cu(H2O)2(µ-bimb)Cu(H2O)3)((Cu(H2O)2)0.5(µ-bimb)(Cu(H2O)3)0.5)H2(AgP5W30O110)]·12.5H2O (2), (H2bimb)2H[(Zn(Hbimb)(H2O)4(Zn(Hbimb)(H2O)2)0.5)2(AgP5W30O110)]·12H2O (3), and (H2bimb)3H2[(Ag(H2O)2)0.5(Ag(Hbimb)Ag(Hbimb)(µ-bimb)Ag)(Ag(H2O)2)0.5(AgP5W30O110)]·7H2O (4) (bimb = 1,4-bis(1H-imidazol-1-yl)benzene), were hydrothermally synthesized using a silver-centered Preyssler-type POM K14[AgP5W30O110]·18H2O (abbreviated as K-{AgP5W30}) as a precursor. In 1-4, {AgP5W30} clusters integrating the merits of Ag+ and {P5W30} units are modified by different transition metal (TM)-organic fragments to extend the structures into three-dimensional frameworks. As nonenzymatic electrochemical sensor materials, 1-4 show good electrocatalytic activity, high sensitivity, and a low detection limit for detecting hydrogen peroxide (H2O2); 4 possesses the highest sensitivity of 195.47 µA·mM-1·cm-2 for H2O2 detection. Most importantly, the average level of H2O2 detection of these {AgP5W30}-based materials outperforms that of Na-centered Preyssler-type {NaP5W30} and most Keggin-type POM-based materials. The performances of such {AgP5W30} materials mainly stem from the unique advantage of high-negatively charged {AgP5W30} clusters together with the good synergistic effect between {AgP5W30} and TMs. This work expands on the research of high-efficiency POM-based nonenzymatic electrochemical H2O2 sensors using Ag-containing POMs with high negative charges, which is also of great theoretical and practical significance to carry out health monitoring and environmental analysis.

Fabrication of Magnetic Al-Based Fe3O4@MIL-53 Metal Organic Framework for Capture of Multi-Pollutants Residue in Milk Followed by HPLC-UV.

The efficient capture of multi-pollutant residues in food is vital for food safety monitoring. In this study, in-situ-fabricated magnetic MIL-53(Al) metal organic frameworks (MOFs), with good magnetic responsiveness, were synthesized and applied for the magnetic solid-phase extraction (MSPE) of chloramphenicol, bisphenol A, estradiol, and diethylstilbestrol. Terephthalic acid (H2BDC) organic ligands were pre-coupled on the surface of amino-Fe3O4 composites (H2BDC@Fe3O4). Fe3O4@MIL-53(Al) MOF was fabricated by in-situ hydrothermal polymerization of H2BDC, Al (NO3)3, and H2BDC@Fe3O4. This approach highly increased the stability of the material. The magnetic Fe3O4@MIL-53(Al) MOF-based MSPE was combined with high-performance liquid chromatography-photo diode array detection, to establish a novel sensitive method for analyzing multi-pollutant residues in milk. This method showed good linear correlations, in the range of 0.05-5.00 µg/mL, with good reproducibility. The limit of detection was 0.004-0.108 µg/mL. The presented method was verified using a milk sample, spiked with four pollutants, which enabled high-throughput detection and the accuracies of 88.17-107.58% confirmed its applicability, in real sample analysis.

Educational Attainment Affects the Early Rehabilitation of Total Knee Arthroplasty in Southwest China.

OBJECTIVE: To assess if the educational level of patients in Southwestern China will affect the functional recovery after total knee arthroplasty (TKA). METHODS: This retrospective study included a total of 334 patients (48 males, 286 females, with an average age of 68 years, range from 51 to 84 years) who had undergone primary unilateral TKA from March 2017 to April 2018. Patients were screened for enrollment and classified into four groups (illiterate group, the primary school group, high school group, and university group) according to their educational attainment. All patients were monitored for at least 2 years after TKA. The primary outcome was determined using the Hospital for Special Surgery knee (HSS) score at the time of follow-up. The secondary outcomes were determined using the 12-Item Short Form Health Survey (SF-12) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, the satisfaction level, and complications of the surgery. RESULTS: Three hundred and thirty-four patients were divided into four groups based on their highest educational level: 83 patients in the illiteracy group, 84 in the primary school group, 91 in the high school group, and 76 in the university group. They were followed up for at least 2 years. For the primary outcome, patients with high school and university education had noteworthy better HSS scores on the surgical-side knee than those in the primary school and illiterate groups (illiteracy group 86.71 ± 5.94 vs primary school group 85.36 ± 5.88 vs high school group 89.48 ± 3.66 vs university group 88.95 ± 3.55; P < 0.05). For secondary outcomes, the mental component summary (MCS) in the university group was significantly lower than the other three groups (P < 0.05). The results of WOMAC scores were consistent with the results of the HSS score: patients in the university group and the high school group had better results when compared with the other two groups (P < 0.05). There were no statistical differences in the comparison of additional indicators and complications among the four groups, but more patients (12 peoples, 15.8%) in the university group were dissatisfied with knee function after TKA. CONCLUSION: In Southwest China, patients with high school education or above can achieve better joint function after TKA but do not get better postoperative satisfaction, which may be related to the patients' higher surgical expectations for social and mental needs.

Effects of early-life zinc deficiency on learning and memory in offspring and the changes in DNA methylation patterns.

OBJECTIVE: To investigate the effect of maternal zinc deficiency on learning and memory in offspring and the changes in DNA methylation patterns. METHODS: Pregnant rats were divided into zinc adequate (ZA), zinc deficient (ZD), and paired fed (PF) groups. Serum zinc contents and AKP activity in mother rats and offspring at P21 (end of lactation) and P60 (weaned, adult) were detected. Cognitive ability of offspring at P21 and P60 were determined by Morris water maze. The expression of proteins including DNMT3a, DNMT1, GADD45ß, MeCP2 and BDNF in the offspring hippocampus were detected by Western-blot. The methylation status of BDNF promoter region in hippocampus of offspring rats was detected by MS-qPCR. RESULTS: Compared with the ZA and PF groups, pups in the ZD group had lower zinc levels and AKP activity in the serum, spent more time finding the platform and spent less time going through the platform area. Protein expression of DNMT1 and GADD45b were downregulated in the ZD group during P0 and P21 but not P60 compared with the ZA and PF group, these results were consistent with a reduction in BDNF protein at P0 (neonate), P21. However, when pups of rats in the ZD group were supplemented with zinc ion from P21 to P60, MeCP2 and GADD45b expression were significantly downregulated compared with the ZA and PF group. CONCLUSION: Post-weaning zinc supplementation may improve cognitive impairment induced by early life zinc deficiency, whereas it may not completely reverse the abnormal expression of particular genes that are involved in DNA methylation, binding to methylated DNA and neurogenesis.

RORγt agonist synergizes with CTLA-4 antibody to inhibit tumor growth through inhibition of Treg cells via TGF-ß signaling in cancer.

To date, the overall response rate to checkpoint blockade remains unsatisfactory, partially due to the limited understanding of the tumor immune microenvironment. The retinoic acid-related orphan receptor γt (RORγt) is the key transcription factor of T helper cell 17 (Th17) cells and plays an essential role in tumor immunity. In this study, we used JG-1, a potent and selective small-molecule RORγt agonist to evaluate the therapeutic potential and mechanism of action of targeting RORγt in tumor immunity. JG-1 promotes Th17 cells differentiation and inhibition of regulatory T (Treg) cells differentiation. JG-1 demonstrates robust tumor growth inhibition in multiple syngeneic models and shows a synergic effect with the Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) antibody. In tumors, JG-1 not only promotes Th17 cells differentiation and increases C-C Motif Chemokine Receptor 6 (CCR6)- Chemokine (C-C motif) ligand 20 (CCL20) expression, but also inhibits both the expression of transforming growth factor-ß1 (TGF-ß1) and the differentiation and infiltration of Treg cells. In summary, JG-1 is a lead compound showing a potent activity in vitro and robust tumor growth inhibition in vivo with synergetic effects with anti-CTLA-4.

Genome sequencing identified novel mechanisms underlying virescent mutation in upland cotton Gossypiuma hirsutum.

BACKGROUND: Virescent mutation broadly exists in plants and is an ideal experimental material to investigate regulatory mechanisms underlying chlorophyll synthesis, photosynthesis and plant growth. Up to date, the molecular mechanisms in two virescent mutations have been clarified in cottons (Gossypiuma hirsutum). A virescent mutation has been found in the cotton strain Sumian 22, and the underlying molecular mechanisms have been studied. METHODS: The virescent mutant and wild type (WT) of Sumian 22 were cross-bred, and the F1 population were self-pollinated to calculate the segregation ratio. Green and yellow leaves from F2 populations were subjected to genome sequencing and bulked-segregant analysis was performed to screen mutations. Real-time quantitative PCR (RT-qPCR) were performed to identify genes in relations to chlorophyll synthesis. Intermediate products for chlorophyll synthesis were determined to validate the RT-qPCR results. RESULTS: The segregation ratio of green and virescent plants in F2 population complied with 3:1. Compared with WT, a 0.34 Mb highly mutated interval was identified on the chromosome D10 in mutant, which contained 31 genes. Among them, only ABCI1 displayed significantly lower levels in mutant than in WT. Meanwhile, the contents of Mg-protoporphyrin IX, protochlorophyllide, chlorophyll a and b were all significantly lower in mutant than in WT, which were consistent with the inhibited levels of ABCI1. In addition, a mutation from A to T at the -317 bp position from the start codon of ABCI1 was observed in the genome sequence of mutant. CONCLUSIONS: Inhibited transcription of ABCI1 might be the mechanism causing virescent mutation in Sumian 22 cotton, which reduced the transportation of protoporphyrin IX to plastid, and then inhibited Mg-protoporphyrin IX, Protochlorophyllide and finally chlorophyll synthesis. These results provided novel insights into the molecular mechanisms underlying virescent mutation in cotton.

Comparison of two vasopressor protocols for preventing hypotension post-spinal anesthesia during cesarean section: a randomized controlled trial.

BACKGROUND: Norepinephrine infusion decreases hypotension after spinal anesthesia during cesarean section. This study aimed to compare the efficacy of norepinephrine infusion and ephedrine bolus against post-spinal hypotension in parturients. METHODS: In this double-blinded, randomized controlled clinical trial, parturients scheduled for elective cesarean section were randomly allocated to receive norepinephrine infusion (0.05 µg·kg-1·min-1) just before spinal anesthesia continuing for 30 min or ephedrine bolus (0.15 mg/kg) just before spinal anesthesia. A rescue bolus (5 µg norepinephrine for the norepinephrine group, and 5 mg ephedrine for the ephedrine group) was administered whenever hypotension occurred. Our primary outcome was the incidence of hypotension within 30 min of spinal anesthesia administration. Secondary outcomes included maternal and neonatal outcomes 30 min after spinal block, and neonatal cerebral oxygenation 10 min after birth. RESULTS: In total, 190 patients were enrolled; of these patients, 177 were included in the final analysis. Fewer patients suffered hypotension in the norepinephrine group than in the ephedrine group (29.5% vs. 44.9%, odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.28-0.95, P = 0.034). Moreover, the tachycardia frequency was lower in the norepinephrine group than in the ephedrine group (OR: 0.22, 95% CI: 0.11-0.44, P < 0.001), and patients suffered less nausea and vomiting (OR: 0.28, 95% CI: 0.11-0.70, P = 0.004). There was no difference in Apgar scores and umbilical arterial blood gas analysis between the two groups. However, neonatal cerebral regional saturations were significantly higher after birth in the norepinephrine group than in the ephedrine group (mean difference: 2.0%, 95% CI: 0.55%-3.45%, P = 0.008). CONCLUSION: In patients undergoing elective cesarean section with spinal anesthesia, norepinephrine infusion compared to ephedrine bolus resulted in less hypotension and tachycardia, and exhibited potential neonatal benefits. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02542748; https://clinicaltrials.gov/ct2/show/record/NCT02542748.

Two-dimensional ultrathin surfactant-encapsulating polyoxometalate assemblies as carriers for monodispersing noble-metal nanoparticles with high catalytic activity and stability.

Noble metal nanoparticles (NMNPs) with excellent catalytic activity and stability play an important role in the field of environmental governance. A uniform distribution and a strong binding force with the carriers of the noble metal nanoparticles are important, but avoidance of the use of additional reducing agents is a promising direction of research. Herein, 2D ultrathin surfactant-encapsulating polyoxometalate (SEP) nanosheets constructed by the self-assembly of dodecyldimethylammonium bromide (DODA) and molybdophosphate (H3PMo12O40, PMo12) are designed to be versatile carriers for Ag nanoparticles. Under the synergistic effect of the well-arranged PMo12 units, encapsulating hydrophobic oleic acid (OA) and reductive molybdophosphate under Xe lamp irradiation, the silver oleate (AgOA)-derived Ag nanoparticles (5 ± 2 nm) are monodispersed on the DODA-PMo12 assemblies and form the Agx/DODA-PMo12 composite. The optimized Ag4.89/DODA-PMo12 composite exhibits high catalytic activity and stability in the degradation of 4-nitrophenol (4-NP), which reaches a superior rate constant of 6.49 × 10-3 s-1 and without significant deterioration after three recycles. This technique can be facilely promoted to other noble metal nanoparticles with excellent catalytic activity and stability.

Crystallography-guided discovery of carbazole-based retinoic acid-related orphan receptor gamma-t (RORγt) modulators: insights into different protein behaviors with "short" and "long" inverse agonists.

A series of 6-substituted carbazole-based retinoic acid-related orphan receptor gamma-t (RORγt) modulators were discovered through 6-position modification guided by insights from the crystallographic profiles of the "short" inverse agonist 6. With the increase in the size of the 6-position substituents, the "short" inverse agonist 6 first reversed its function to agonists and then to "long" inverse agonists. The cocrystal structures of RORγt complexed with the representative "short" inverse agonist 6 (PDB: 6LOB), the agonist 7d (PDB: 6LOA) and the "long" inverse agonist 7h (PDB: 6LO9) were revealed by X-ray analysis. However, minor differences were found in the binding modes of "short" inverse agonist 6 and "long" inverse agonist 7h. To further reveal the molecular mechanisms of different RORγt inverse agonists, we performed molecular dynamics simulations and found that "short" or "long" inverse agonists led to different behaviors of helixes H11, H11', and H12 of RORγt. The "short" inverse agonist 6 destabilizes H11' and dislocates H12, while the "long" inverse agonist 7h separates H11 and unwinds H12. The results indicate that the two types of inverse agonists may behave differently in downstream signaling, which may help identify novel inverse agonists with different regulatory mechanisms.

Anti-PD-L1 mediating tumor-targeted codelivery of liposomal irinotecan/JQ1 for chemo-immunotherapy.

Immune checkpoint blockade therapy has become a first-line treatment in various cancers. But there are only a small percent of colorectal patients responding to PD-1/PD-L1 blockage immunotherapy. How to increase their treatment efficacy is an urgent and clinically unmet need. It is acknowledged that immunogenic cell death (ICD) induced by some specific chemotherapy can enhance antitumor immunity. Chemo-based combination therapy can yield improved outcomes by activating the immune system to eliminate the tumor, compared with monotherapy. Here, we develop a PD-L1-targeting immune liposome (P-Lipo) for co-delivering irinotecan (IRI) and JQ1, and this system can successfully elicit antitumor immunity in colorectal cancer through inducing ICD by IRI and interfering in the immunosuppressive PD-1/PD-L1 pathway by JQ1. P-Lipo increases intratumoral drug accumulation and promotes DC maturation, and thereby facilitates adaptive immune responses against tumor growth. The remodeling tumor immune microenvironment was reflected by the increased amount of CD8+ T cells and the release of IFN-γ, and the reduced CD4+Foxp3+ regulatory T cells (Tregs). Collectively, the P-Lipo codelivery system provides a chemo-immunotherapy strategy that can effectively remodel the tumor immune microenvironment and activate the host immune system and arrest tumor growth.

Comparison of Two Different Natural Oil Body Emulsions: in vitro Gastrointestinal Digestion.

The surface compositions and structure of oil bodies (OBs) are dependent on the oil crop, and these factors affect in vitro gastrointestinal digestion behaviors. Herein, a comparative study was conducted to examine the in vitro gastrointestinal digestion characteristics of two natural emulsions prepared with soybean seeds and rapeseed OBs during gastrointestinal digestion process. The average particle size of soybean OBs and rapeseed OBs emulsions was 0.46 and 5.02 µm, respectively. The droplet size of soybean seed and rapeseed OBs emulsions was large with relatively low zeta-potentials at 30 min digestion time in simulated gastric fluid condition. The droplet size of two natural OBs emulsions decreased with increasing digestion time in simulated gastric fluid condition. The average droplet size of both emulsions gradually decreased with increasing digestion time in simulated intestinal fluid conditions. The zeta-potential of the two emulsions increased with increasing digestion time in simulated intestinal fluid conditions. The extent of free fatty acids of soybean OBs emulsions was significantly higher than rapeseed after 20 min digestion time in simulated intestinal fluid conditions. The obtained results suggested that plant OBs could be useful as natural emulsifiers in the development of functional food and achieve controlled release of bioactive compounds from emulsions during gastrointestinal digestion.

[Anti-tumor effect and its related mechanisms of cinobufotalin combined with cisplatin on H22 liver cancer mice].

In order to observe the anti-tumor effect of cinobufotalin on H22 liver cancer mice and to explore its regulatory mechanism, 50 Kunming mice were subcutaneously inoculated with H22 intraperitoneal passage cells under the armpit to establish H22 hepatocellular carcinoma model. They were then randomly divided into model group, cinobufotalin low dose group, cinobufotalin high dose group, cisplatin group and cisplatin+cinobufotalin group, which received 0.01% ethanol solution, 1 mg·kg~(-1) cinobufotalin, 5 mg·kg~(-1) cinobufotalin, 5 mg·kg~(-1) cisplatin, 5 mg·kg~(-1)cisplatin + 5 mg·kg~(-1) cinobufotalin respectively for 10 days. The general condition of mice during the intervention was observed, and the inhibition rate, tumor mass, thymus index, histopathological changes of the tumors, apoptotic rate of the tumors, the expressions of phosphatidylinositol 3-kinase(PI3 K), protein kinase B(Akt), apoptosis related gene(Fas), Fas ligand(FasL) mRNA and protein phosphorylated Akt(pAkt) protein in the tumors of each group were compared. The results showed that during the modeling period, the mice showed a decline in food intake, dark fur, poor mental status, and gradually worsened over time. The mental status of mice in each intervention group was improved gradually, especially in the cisplatin+cinobufotalin group. As compared with the model group, the tumor mass of each intervention group was lower(P<0.05). As compared with the cinobufotalin low dose group, the tumor mass was lower and inhibition rate was higher in the cinobufotalin high dose group, cisplatin group and cisplatin+cinobufotalin group(P<0.05). As compared with the cinobufotalin high dose group and the cisplatin group, the tumor mass was lower and the inhibition rate was higher in cisplatin+cinobufotalin group(P<0.05). As compared with the model group, the thymus index was higher in cinobufotalin high dose group and cisplatin + cinobufotalin group, while was lower in cisplatin group(P<0.05). As compared with the cinobufotalin low dose group, the thymus index was higher in the cinobufotalin high dose group and lower in the cisplatin group(P<0.05). As compared with the cinobufotalin high dose group, the thymus index was lower in cisplatin group(P<0.05). As compared with cisplatin group, the thymus index was higher in cisplatin+cinobufotalin group(P<0.05). Pathological staining showed that a large number of heterogeneous cells and mitotic phenomena were observed in the model group. Cell fragments and neutrophils were observed in the tumor tissues of the intervention groups, showing diffuse necrosis, and the diffuse necrosis was more obvious in the cisplatin+cinobufotalin group. As compared with the model group, the apoptotic rate of the tumors and the relative expressions of Fas mRNA and protein were higher in the intervention groups, while the relative expressions of PI3 K, FasL mRNA and protein and the relative expression of pAkt protein were lower in the intervention groups(P<0.05). As compared with the cinobufotalin low dose group, the apoptotic rate of the tumors and relative expression of Fas and protein were higher in the cinobufotalin high dose group, cisplatin group and cisplatin+cinobufotalin group, while the relative expressions of PI3 K, FasL mRNA and protein and pAkt protein were lower(P<0.05). As compared with the cinobufotalin high dose group and the cisplatin group, apoptotic rate of the tumors and the relative expression of Fas mRNA and protein were higher in the cisplatin+cinobufotalin group, while the relative expressions of PI3 K, FasL mRNA and protein and pAkt protein were lower in the cisplatin+cinobufotalin group(P<0.05). In summary, cinobufotalin has significant anti-tumor effect on H22 liver cancer mice, and can enhance the immune function of mice and synergistically enhance the effect of chemotherapy. Its mechanism may be associated with regulating PI3 K/Akt/Fas/FasL signaling pathway related genes and protein expression.