Trichinella spiralis -induced immunomodulation signatures on gut microbiota and metabolic pathways in mice.

The hygiene hypothesis proposes that decreased exposure to infectious agents in developed countries may contribute to the development of allergic and autoimmune diseases. Trichinella spiralis, a parasitic roundworm, causes trichinellosis, also known as trichinosis, in humans. T. spiralis had many hosts, and almost any mammal could become infected. Adult worms lived in the small intestine, while the larvae lived in muscle cells of the same mammal. T. spiralis was a significant public health threat because it could cause severe illness and even death in humans who eat undercooked or raw meat containing the parasite. The complex interactions between gastrointestinal helminths, gut microbiota, and the host immune system present a challenge for researchers. Two groups of mice were infected with T. spiralis vs uninfected control, and the experiment was conducted over 60 days. The 16S rRNA gene sequences and untargeted LC/MS-based metabolomics of fecal and serum samples, respectively, from different stages of development of the Trichinella spiralis-mouse model, were examined in this study. Gut microbiota alterations and metabolic activity accompanied by parasite-induced immunomodulation were detected. The inflammation parameters of the duodenum (villus/crypt ratio, goblet cell number and size, and histological score) were involved in active inflammation and oxidative metabolite profiles. These profiles included increased biosynthesis of phenylalanine, tyrosine, and tryptophan while decreasing cholesterol metabolism and primary and secondary bile acid biosynthesis. These disrupted metabolisms adapted to infection stress during the enteral and parenteral phases and then return to homeostasis during the encapsulated phase. There was a shift from an abundance of Bacteroides in the parenteral phase to an abundance of probiotic Lactobacillus and Treg-associated-Clostridia in the encapsulated phase. Th2 immune response (IL-4/IL-5/IL-13), lamina propria Treg, and immune hyporesponsiveness metabolic pathways (decreased tropane, piperidine and pyridine alkaloid biosynthesis and biosynthesis of alkaloids derived from ornithine, lysine, and nicotinic acid) were all altered. These findings enhanced our understanding of gut microbiota and metabolic profiles of Trichinella -infected mice, which could be a driving force in parasite-shaping immune system maintenance.

Artificial fluorescent sensor reveals pre-synaptic NMDA receptors switch cholecystokinin release and LTP in the hippocampus.

Cholecystokinin (CCK) has been confirmed to be essential in NMDA-dependent long-term potentiation (LTP) at mouse cortical synapses. This paper has proven that CCK is necessary for LTP induced by high-frequency stimulation of mouse hippocampal synapses projected from the entorhinal cortex. We show that the subunit of the axonal NMDA receptor dominant modulates the activity-induced LTP by triggering pre-synaptic CCK release. A functional pre-synaptic NMDA receptor is required to induce LTP mediated by the axonal Ca2+ elevation and CCK exocytosis at CCK-specific neurons. Genetic depletion of the GluN1 subunit of NMDA receptors on CCK neurons, which projected from the entorhinal cortex largely abolished the axonal Ca2+ elevation and disturbed the secretion of CCK in hippocampus. These results demonstrate that activity-induced LTP at the hippocampal synapse is CCK-dependent, and CCK secretion from the axonal terminal is modulated by pre-synaptic NMDA receptors.

Collaborative model of care between orthopaedics and allied healthcare professionals (CONNACT) in knee osteoarthritis: Effectiveness-implementation hybrid randomized controlled trial of a community-based, multidisciplinary, stratified intervention.

OBJECTIVE: To compare the clinical and cost effectiveness of the Collaborative Model of Care between Orthopaedics and Allied Healthcare Professionals (CONNACT), a community-based, stratified, multidisciplinary intervention consisting of exercise, education, psychological and nutrition delivered through a chronic care model to usual hospital care in adults with knee osteoarthritis (OA). METHODS: Pragmatic, parallel-arm, single-blinded superiority RCT trial. Community-dwelling, ambulant adults with knee OA (Kellgren-Lawrence grade > 1; Knee Injury and OA Outcome Score (KOOS4) ≤75) were enrolled. Primary outcome was KOOS4 at 12-months; secondary outcomes included: quality of life, physical performance measures, symptom satisfaction, psychological outcomes, dietary habits, and global perceived effect. Intention-to-treat analysis using generalized linear model (GLM) and regression modeling were conducted. Economic evaluation through a societal approach was embedded. RESULTS: 110 participants (55 control, 55 intervention) were randomized. No between-group difference found for the primary outcome (MD [95%CI]: -1.86 [-9.11. 5.38]), although both groups demonstrated within-group improvement over 12-months. Among the secondary outcomes, the CONNACT group demonstrated superior dietary change (12 months) and physical performance measures (3 months), and global perceived effect (6 months). While there was no between-group difference in total cost, significant productivity gains (reduced indirect cost) were seen in the CONNACT group. CONCLUSION: CONNACT was not superior to usual care at 1 year. Further efforts are needed to understand the underlying contextual and implementation factors in order to further improve and refine such community-based, stratified care models moving forward. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03809975. Registered January 18, 2019. https://clinicaltrials.gov/ct2/show/NCT03809975.

Computer-directed rational design enhanced the thermostability of carbonyl reductase LsCR for the synthesis of ticagrelor precursor.

Carbonyl reductases are useful for producing optically active alcohols from their corresponding prochiral ketones. Herein, we applied a computer-assisted strategy to increase the thermostability of a previously constructed carbonyl reductase, LsCRM4 (N101D/A117G/F147L/E145A), which showed an outstanding activity in the synthesis of the ticagrelor precursor (1S)-2-chloro-1-(3,4-difluorophenyl)ethanol. The stability changes introduced by mutations at the flexible sites were predicted using the computational tools FoldX, I-Mutant 3.0, and DeepDDG, which demonstrated that 12 virtually screened mutants could be thermally stable; 11 of these mutants exhibited increased thermostability. Then a superior mutant LsCRM4-V99L/D150F was screened out from the library that was constructed by iteratively combining the beneficial sites, which showed a 78% increase in activity and a 17.4°C increase in melting temperature compared to LsCRM4. Our computer-assisted design and combinatorial strategy dramatically increased the efficiency of thermostable enzyme production.

Sleep and internalizing problems in primary school children with attention-deficit hyperactivity disorder.

BACKGROUND: Internalizing and externalizing problems have received great attention, and children with ADHD exhibit high rates of comorbid internalizing and externalizing disorders. This study aimed to explore the relationship between sleep and internalizing problems in children with attention-deficit hyperactivity disorder (ADHD) and the probable mediating role of externalizing problems. METHODS: A total of 203 primary school children diagnosed with ADHD for the first time were recruited for this study. Children with ADHD were evaluated by Children's Sleep Habits Questionnaire (CSHQ), Strengths and Difficulties Questionnaire (SDQ). Internalizing problems were represented by emotional symptoms and peer problems of SDQ, and externalizing problems were represented by conduct problems and hyperactivity-inattention problems of SDQ. Multi-step linear regression analysis was used to investigate the mediating effect of externalizing problems on the relationship between sleep and internalizing problems. RESULTS: Sleep in children with ADHD was associated with emotional problems in internalizing problems, and conduct problems in externalizing problems mediated the association between sleep and emotional problems. CONCLUSION: For children with ADHD, when it is difficult to identify internalizing problems, especially emotional problems, we can take sleep and externalizing problems as clues to improve our clinical ability to recognize and deal with emotional problems. IMPACT: 1. We first explored the possible mediating role of conduct problems between sleep and emotional problems in primary school children with ADHD. 2. When it is difficult to identify internalizing problems, especially emotional problems, we can take sleep and externalizing problems as clues to improve our clinical ability to recognize emotional problems for children with ADHD. 3. For children with ADHD with potential internalizing problems, especially emotional problems, interventions for their sleep and externalizing problems may be the possible methods to deal with.

Myeloid-derived growth factor suppresses VSMC dedifferentiation and attenuates postinjury neointimal formation in rats by activating S1PR2 and its downstream signaling.

Restenosis after angioplasty is caused usually by neointima formation characterized by aberrant vascular smooth muscle cell (VSMC) dedifferentiation. Myeloid-derived growth factor (MYDGF), secreted from bone marrow-derived monocytes and macrophages, has been found to have cardioprotective effects. In this study we investigated the effect of MYDGF to postinjury neointimal formation and the underlying mechanisms. Rat carotid arteries balloon-injured model was established. We found that plasma MYDGF content and the level of MYDGF in injured arteries were significantly decreased after balloon injury. Local application of exogenous MYDGF (50 µg/mL) around the injured vessel during balloon injury markedly ameliorated the development of neointimal formation evidenced by relieving the narrow endovascular diameter, improving hemodynamics, and reducing collagen deposition. In addition, local application of MYDGF inhibited VSMC dedifferentiation, which was proved by reversing the elevated levels of osteopontin (OPN) protein and decreased levels of α-smooth muscle actin (α-SMA) in the left carotid arteries. We showed that PDGF-BB (30 ng/mL) stimulated VSMC proliferation, migration and dedifferentiation in vitro; pretreatment with MYDGF (50-200 ng/mL) concentration-dependently eliminated PDGF-BB-induced cell proliferation, migration and dedifferentiation. Molecular docking revealed that MYDGF had the potential to bind with sphingosine-1-phosphate receptor 2 (S1PR2), which was confirmed by SPR assay and Co-IP analysis. Pretreatment with CCG-1423 (Rho signaling inhibitor), JTE-013 (S1PR2 antagonist) or Ripasudil (ROCK inhibitor) circumvented the inhibitory effects of MYDGF on VSMC phenotypic switching through inhibiting S1PR2 or its downstream RhoA-actin monomers (G-actin) /actin filaments (F-actin)-MRTF-A signaling. In summary, this study proves that MYDGF relieves neointimal formation of carotid arteries in response to balloon injury in rats, and suppresses VSMC dedifferentiation induced by PDGF-BB via S1PR2-RhoA-G/F-actin-MRTF-A signaling pathway. In addition, our results provide evidence for cross talk between bone marrow and vasculature.

Coevolving stability and activity of LsCR by a single point mutation and constructing neat substrate bioreaction system.

Carbonyl reductase (CR)-catalyzed bioreduction in the organic phase and the neat substrate reaction system is a lasting challenge, placing higher requirements on the performance of enzymes. Protein engineering is an effective method to enhance the properties of enzymes for industrial applications. In the present work, a single point mutation E145A on our previously constructed CR mutant LsCRM3 , coevolved thermostability, and activity. Compared with LsCRM3 , the catalytic efficiency kcat /KM of LsCRM3 -E145A (LsCRM4 ) was increased from 6.6 to 21.9 s-1 mM-1 . Moreover, E145A prolonged the half-life t1/2 at 40°C from 4.1 to 117 h, T m ${T}_{m}$ was increased by 5°C, T 50 30 ${T}_{50}^{30}$ was increased by 14.6°C, and Topt was increased by 15°C. Only 1 g/L of lyophilized Escherichia coli cells expressing LsCRM4 completely reduced up to 600 g/L 2-chloro-1-(3,4-difluorophenyl)ethanone (CFPO) within 13 h at 45°C, yielding the corresponding (1S)-2-chloro-1-(3,4-difluorophenyl)ethanol ((S)-CFPL) in 99.5% eeP , with a space-time yield of 1.0 kg/L d, the substrate to catalyst ratios (S/C) of 600 g/g. Compared with LsCRM3 , the substrate loading was increased by 50%, with the S/C increased by 14 times. Compared with LsCRWT , the substrate loading was increased by 6.5 times. In contrast, LsCRM4 completely converted 600 g/L CFPO within 12 h in the neat substrate bioreaction system.

Discordance Between Self-Reported and Performance-Based Physical Function in Patients Who Have Knee Osteoarthritis: Associations With Pain Intensity and Negative Affect.

BACKGROUND: Although self-reported measures of physical disability are strong indication criterion for total knee arthroplasty (TKA) in painful knee osteoarthritis (OA), some patients may report greater-than-observed disability. Contributing factors to this discordance are relatively unexplored. We aimed to examine whether pain and negative affect, including anxiety and depression, were associated with the discordance of self-reported measures with performance-based measures (PPM) of physical function. METHODS: We used cross-sectional data (n = 212) from two randomized rehabilitation trials in knee OA. All patients were assessed for knee pain intensity and symptoms of anxiety and depression. Self-reported function was assessed by the Western Ontario and McMaster Universities Arthritis Index (WOMAC) physical-function subscale. Objective performance-based measures (PPMs) of physical function were assessed by timed gait and stair tests. Continuous discordance scores were quantified by the difference in percentiles between WOMAC and PPMs (WOMAC-PPM), where a positive discordance, WOMAC-PPM >0, implied greater perceived than observed disability. RESULTS: Around 1 in 4 patients had >20 percentile units in WOMAC-PPM discordance. In Bayesian regression analyses, knee pain intensity had >99% posterior probability of positive associations with WOMAC-PPM discordance. Among patients awaiting TKA, anxiety intensity had approximately 99% probability of positive associations with discordance, and these associations had >65% probability of exceeding 10 percentile units. In contrast, depression had low (79% to 88%) probability of any association with discordance. CONCLUSION: In patients who have knee OA, a sizable proportion reported substantially greater physical disability than actually observed. Pain and anxiety intensity, but not depression, were meaningful predictors of this discordance. If validated, our findings may help in refining patient selection criteria for TKA.

Cytotoxic Cyclodepsipeptides and Cyclopentane Derivatives from a Plant-Associated Fungus Fusarium sp.

In this work, four new cyclodepsipeptides, fusarihexins C-E (1-3) and enniatin Q (4), four new cyclopentane derivatives, fusarilins A-D (5-8), together with eight known compounds (9-16), were isolated from cultures of the endophytic fungus Fusarium sp. The structures of the isolated compounds were elucidated by analysis of HRMS and NMR spectroscopic data. The absolute configurations were determined using Marfey's method, a modified Mosher's method, single-crystal X-ray diffraction analysis, and ECD analysis. The antitumor activities of the isolated compounds in vitro were evaluated. Cyclodepsipeptides displayed cytotoxicities against the Huh-7, MRMT-1, and HepG-2 cell lines. Compounds 4, 9, 10, and 12 with IC50 values of 1.0-9.1 µM exhibited the most potent cytotoxicities against the three cell lines as compared to the positive control-5-fluorouracil. Compounds 1-3 and 11 exhibited moderate cytotoxic activities (IC50 values of 10.7-20.1 µM).

Directed evolution of a carbonyl reductase LsCR for the enantioselective synthesis of (1S)-2-chloro-1-(3,4-difluorophenyl) ethanol.

Traditional screening methods of enzyme engineering often require building large mutant libraries to screen for potentially beneficial sites, which are often time-consuming and labor-intensive with low mining efficiency. In this study, a novel enzyme engineering strategy was established to modify carbonyl reductase LsCR for the synthesis of (1S)-2-chloro-1-(3,4-difluorophenyl) ethanol ((S)-CFPL), which is a key intermediate of anticoagulant drug ticagrelor. The strategy was developed by combining HotSpot, FireProt and multiple sequence alignment, resulting in the construction of a "small and smart" mutant library including 10 mutations. Among them, 5 mutations were positive, resulting in a 50% mining accuracy of beneficial sites. Finally, a highly active mutant LsCRM3 (N101D/A117G/F147L) was obtained by further screening through saturation mutation and iterative mutation. Compared with wild type (WT) LsCR, the catalytic activity of LsCRM3 was increased by 4.7 times, the catalytic efficiency kcat/KM value was increased by 2.9 times, and the half-life t1/2 at 40 °C was increased by 1.3 times. Due to the low aqueous solubility of the substrate 2-chloro-1-(3,4-difluorophenyl) ethanone (CFPO), isopropanol was used as not only the co-substrate but also co-solvent. In the presence of 40% (v/v) isopropanol, LsCRM3 completely reduced 400 g/L CFPO to enantiomerically pure CFPL (99.9%, e.e.) in 11 h with a space-time yield (STY) as high as 809 g/L∙d.

Analysis of Genetic Polymorphism and Population Genetic Structure of 57 Autosomal InDel Loci in Beichuan Qiang Population.

OBJECTIVES: To investigate the genetic information of 57 autosomal InDel loci (A-InDels) included in AGCU InDel 60 fluorescence detection kit in the Beichuan Qiang population of Sichuan Province and evaluate its application value in forensic medicine. METHODS: A total of 200 unrelated healthy individuals from Beichuan Qiang population of Sichuan Province were typing detected by AGCU InDel 60 fluorescence detection kit. Allele frequencies and population genetic parameters of the 57 A-InDels were statistically analyzed and compared with the available data of 26 populations. RESULTS: After Bonferroni correction, there was no linkage disequilibrium between the 57 A-InDels, and all loci were in Hardy-Weinberg equilibrium. Except for rs66595817 and rs72085595, the minor allele frequencies of 55 A-InDels were above 0.3. PIC ranged from 0.298 3 to 0.375 0, CDP was 1-2.974 8×10-24, CPEduo was 0.999 062 660, and CPEtrio was 0.999 999 999. The calculation of the genetic distance showed that Beichuan Qiang population had the closest genetic distances with Beijing Han and South China Han populations, but far away from African populations. CONCLUSIONS: The 57 A-InDels in AGCU InDel 60 fluorescence detection kit have a good genetic polymorphism in Beichuan Qiang population of Sichuan Province, which can be used as effective supplemental for individual identification and paternity identification in forensic medicine.

Small nucleolar RNA of silkworm can translocate from the nucleolus to the cytoplasm under abiotic stress.

Small nucleolar RNAs (snoRNAs) are thought to be exclusively nuclear and guide nucleotide modifications of ribosomal RNAs. Recently, more and more evidence has suggested that the nucleolus is a stress sensor for changes in growth status and that snoRNAs may orchestrate the response to environmental stress through molecular interactions outside of the nucleus. We previously showed that a box C/D snoRNA Bm-15 had both nuclear and cytoplasmic location in BmN4 cell line of the silkworm, Bombyx mori. To further study the functional roles of Bm-15, changes in expression level and cellular location of Bm-15 were examined in BmN4 cells subjected to serum starvation and ultraviolet (UV) ray radiation. Results indicated that total RNA level of Bm-15 was unchanged after 24 h serum starvation, but exhibited 3-fold increases in the cytoplasm, and the nuclear-to-cytosolic distribution ratio was reduced from 5:1 to 2:1. Moreover, UV radiation also causes rapid decline in nuclear Bm-15 and progressive cytoplasmic accumulation with a percentage of 22% and 57% after 6 and 24 h UV radiation. UV treatment results in a dramatic decrease in Bm-15 nuclear-to-cytosolic ratio from 7:1 to 2:1 and 2:1 to 1:20 after 6 and 24 h UV radiation, respectively. We show here for the first time that box C/D snoRNAs can translocate from the nucleus to the cytoplasm under the abiotic stress of nutritional deficiency and UV radiation. The rapid translocation of snoRNAs from nucleus to cytoplasm may slow down the maturation of rRNAs and synthesis of ribosomes to enhance the stress resistance of cells.

Construction of a ceRNA coregulatory network and screening of hub biomarkers for salt-sensitive hypertension.

Salt-sensitive hypertension (SSH) is an independent risk factor for cardiovascular disease. The regulation of long non-coding RNAs, mRNAs and competing endogenous RNAs (ceRNAs) in the pathogenesis of SSH is uncertain. An RNA microarray was performed to discover SSH-associated differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs), and 296 DElncRNAs and 44 DEmRNAs were identified, and 247 DElncRNAs and 44 DEmRNAs among these RNAs were included in the coexpression network. The coregulatory network included 23 ceRNA loops, and six hub RNAs (lnc-ILK-8:1, lnc-OTX1-7:1, lnc-RCAN1-6:1, GIMAP8, SUV420H1 and PIGV) were identified for further population validation. The ceRNA correlations among lnc-OTX1-7:1, hsa-miR-361-5p and GIMAP8 were confirmed in SSH and SRH patients. A larger-sample validation confirmed that GIMAP8, SUV420H1 and PIGV were differentially expressed between the SSH and SRH groups. In addition, SUV420H1 was included in the SSH screening model, and the area under the curve of the model was 0.720 (95% CI: 0.624-0.816). Our study explored the transcriptome profiles of SSH and constructed a ceRNA network to help elucidate the mechanism of SSH. In addition, SUV420H1 was identified as a hub element that participates in SSH transcriptional regulation and as a potential biomarker for the early diagnosis of SSH.

A Genome-Scale Metabolic Model of Soybean (Glycine max) Highlights Metabolic Fluxes in Seedlings.

Until they become photoautotrophic juvenile plants, seedlings depend upon the reserves stored in seed tissues. These reserves must be mobilized and metabolized, and their breakdown products must be distributed to the different organs of the growing seedling. Here, we investigated the mobilization of soybean (Glycine max) seed reserves during seedling growth by initially constructing a genome-scale stoichiometric model for this important crop plant and then adapting the model to reflect metabolism in the cotyledons and hypocotyl/root axis (HRA). A detailed analysis of seedling growth and alterations in biomass composition was performed over 4 d of postgerminative growth and used to constrain the stoichiometric model. Flux balance analysis revealed marked differences in metabolism between the two organs, together with shifts in primary metabolism occurring during different periods postgermination. In particular, from 48 h onward, cotyledons were characterized by the oxidation of fatty acids to supply carbon for the tricarboxylic acid cycle as well as production of sucrose and glutamate for export to the HRA, while the HRA was characterized by the use of a range of imported amino acids in protein synthesis and catabolic processes. Overall, the use of flux balance modeling provided new insight into well-characterized metabolic processes in an important crop plant due to their analysis within the context of a metabolic network and reinforces the relevance of the application of this technique to the analysis of complex plant metabolic systems.

Blastobotrys baotianmanensis sp. nov. and Blastobotrys xishuangbannaensis f.a., sp. nov., two novel yeast species associated with insects and rotting wood.

Five yeast strains were isolated from the gut of the groundbeetle Pterostichus gebleri and rotting wood, which were collected from two different localities in China. These strains were identified as representing two novel species of the genus Blastobotrys through comparison of sequences in the D1/D2 domains of the LSU rRNA gene and other taxonomic characteristics. Blastobotrys baotianmanensis sp. nov. produces two to three spherical ascospores per ascus, and is most closely related to the type strains of B. elegans, B. capitulata, B. arbuscula, and an undescribed species represented by strain BG02-7-20-006A-3-1. Blastobotrys baotianmanensis sp. nov. differed from these strains by 3.6-8.4 % divergence (21-46 substitutions and 0-4 gaps) in the D1/D2 sequences. Blastobotrys xishuangbannaensis f.a., sp. nov. is closely related to B. nivea, B. elegans and B. aristata but the formation of ascospores was not observed on various sporulation media, and it differed from its relatives by 6.2-8.5 % divergence (34-43 substitutions and 2-6 gaps) in the D1/D2 sequences. The holotype of Blastobotrys baotianmanensis sp. nov. is NYNU 1581 and the holotype of Blastobotrys xishuangbannaensis f.a., sp. nov. is NYNU 181030.

A novel series of cysteine-dependent, allosteric inverse agonists of the nuclear receptor RORγt.

Inhibition of the nuclear receptor Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) is a promising strategy for the treatment of autoimmune diseases. In this paper, we describe a series of allosteric, cysteine-dependent, inverse agonists of RORγt. Site-directed mutagenesis and molecular dynamics simulations are supportive of a mechanism of action through specific binding to Cys476 on alpha helix 11 of the ligand binding domain (LBD). Representative compounds in the series selectively inhibit RORγt, potently suppress interleukin-17A (IL-17A) production by human CD4+ T cells, and inhibit T helper 17 (Th17) differentiation from human naïve CD4+ T cells. The advanced compound 13 is orally bioavailable and active at a dose of 3 mg/kg in a murine collagen-induced model of rheumatoid arthritis. Collectively, these data are supportive of the development of compound 13 in autoimmune diseases.

Omaveloxolone and TX63682 are hepatoprotective in the STAM mouse model of nonalcoholic steatohepatitis.

Omaveloxolone is a potent activator of Nrf2, a master transcriptional regulator of a multitude of cytoprotective functions, including antioxidative, anti-inflammatory, and mitochondrial bioenergetic effects. Some of the most potent known effects of Nrf2 involve hepatoprotective functions. The purpose of this study was to evaluate the effects of omaveloxolone and TX63682, a closely related structural analog with similar oral bioavailability, in the STAM mouse model of nonalcoholic steatohepatitis (NASH). C57Bl/6 mice received a single subcutaneous injection of streptozotocin two days after birth and were fed a high-fat diet from 4 to 9 weeks of age. Omaveloxolone and TX63682 were orally administered at doses of 1, 3, and 10 mg/kg/d from 6 to 9 weeks of age. Consistent with the beneficial effects of Nrf2 on hepatoprotection and improved lipid handling, both omaveloxolone and TX63682 decreased hepatic fat deposition, hepatocellular ballooning, inflammatory cell infiltration, and collagen deposition. Omaveloxolone and TX63682 also improved blood glucose control, as evidenced by reductions in nonfasting blood glucose and glycated hemoglobin A1C concentrations. Reductions in liver and serum triglycerides with omaveloxolone and TX63682 treatment were also observed. Both omaveloxolone and TX63682 decreased leptin and increased adiponectin in serum, which is consistent with the anti-inflammatory and antifibrotic effects observed in the liver. These results were associated with significant induction of Nrf2 target gene expression in the liver, including NAD(P)H:quinone oxidoreductase 1, sulfiredoxin 1, and ferritin heavy chain 1. Overall, these data suggest that omaveloxolone and related Nrf2 activators may be useful for the treatment of NASH.

Integrated bioinformatics analyses identified SCL3-induced regulatory network in Arabidopsis thaliana roots.

OBJECTIVES: To uncover key genes and pathways regulated by SCL3, a GRAS transcription factor, in the context of gibberellin (GA) in the roots of the model plant Arabidopsis thaliana. RESULTS: Gene expression profiles of ga1-3 mutant and ga1-3 and scl3 double mutant are considerably similar to each other, revealed by Principal Component Analysis (PCA). More than 400 significantly Differentially Expressed Genes (DEGs) among the Arabidopsis thaliana roots of ga1-3 mutant, ga1-3 and scl3 double mutant and GA loss/SCL3 gain mutant were uncovered by comprehensive bioinformatics analyses. Protein synthesis pathway, including RPL proteins, RPS proteins, etc., and flavonoid biosynthesis pathway, including TT4, F3H, TT5, CHIL, etc. were significantly increased when SCL3 expression was higher than normal by means of pathway enrichment analysis and protein-protein interaction analysis, which is further supported by comparison analyses between wild type samples and SCL3 overexpressed roots. CONCLUSION: Protein synthesis and flavonoid biosynthesis were regulated by SCL3 in the context of GA in Arabidopsis thaliana root system identified by comprehensive bioinformatic analyses.

Exploring genetic dependence of lipase activity to improve the quality of whole-grain wheat.

BACKGROUND: Whole-grain wheat flour is facing the quality challenge of lipid rancidity, which decreases its nutritional, sensory, and technological properties. One of the major causes of lipid rancidity is endogenous esterases and lipases. This study evaluated 66 European wheat varieties grown at a single site over three years (2014, 2015, and 2016). RESULTS: The 66 wheat varieties showed up to threefold variance on esterase and lipase activities. Wheat varieties that are suitable for lipid-stable whole-grain products ('Julius', 'Lona', and 'Banquet') were selected according to their consistently low esterase and lipase activities. The 3-year mean-based broad-sense heritability of esterase and lipase was 0.75 and 0.44 respectively. CONCLUSIONS: The findings indicate great genetic dependence of both esterase and lipase activities in wheat. The moderate to high heritability brings a new prospect of breeding selection of low-lipase-activity wheat for stable whole-grain products. This result will improve the use of wheat as raw material, benefit cultivation selection, and provide consumers with better quality products. © 2020 Society of Chemical Industry.

[Preparation and pharmacodynamics in vivo of nano graphene oxide-based matrine in situ gel].

With matrine(MAT) as the model drug, to prepare nano graphene oxide(NGO)-based MAT in situ gel(MAT-NGO-gel), a kind of drug for tumor treatment in combination with phototheraphy, and investigate the physicochemical properties and anti-tumor effects in vivo of MAT-NGO-gel. First, HPLC method was established to measure the content of MAT in the gel. The ultrasonic method was used to load MAT onto the surface of NGO, and then poloxamer 188 and poloxamer 407 were chosen as the main materials to prepare MAT-NGO-gel. The optimum prescription was selected with the gelation temperature as the index. Finally, the drug loading rate, micromorphology, phototherrmal conversion characteristics and drug release in vitro of MAT-NGO-gel were characterized. In the optimized prescription, the concentration of poloxamer 188 and poloxamer 407 was 2% and 20% respectively, and the mass ratio of NGO and MAT was 1∶1. The gelation temperature and drug loading rate of MAT-NGO-gel prepared by the optimal prescription process was 37.5 ℃ and 16.7%. Under 808 nm laser irradiation, MAT-NGO-gel showed obvious concentration-and time-dependent photothermal conversion characteristics. In vitro release experiments showed that MAT-NGO-gel had temperature-dependent release characteristics. The pharmacodynamics of MAT solution, NGO-gel and MAT-NGO-gel were studied by using S180 tumor-bearing mice and 808 nm laser. The relative tumor volume and body weight of the tumor-bearing mice were plotted over time. After the experiment, the tumor tissues of each group were taken and the histopathological changes were observed by HE staining. The results of pharmacodynamic studies demonstrated that when compared with NS group and NGO-gel group, the body weights of mice in MAT-NGO-gel group and MAT-NGO-gel + laser group were higher, and the relative tumor volume growth was slower. The results of HE stained pathological sections showed that the tumor cells count for the mice in MAT-NGO-gel group and MAT-NGO-gel + laser group was significantly reduced, with obvious nuclear fragmentation and nucleolysis in these two groups. These results suggested that MAT-NGO-gel, especially combined with 808 nm laser, had stronger anti-tumor activity in vivo. The prescription process of MAT-NGO-gel in this experiment was stable and feasible. As compared with MAT solution, MAT-NGO-gel showed obvious sustained and temperature-dependent drug release characteristics. MAT-NGO-gel had much more obvious anti-tumor activity in vivo when combined with 808 nm laser irradiation. This study could provide certain theoretical basis for the therapy of malignant tumor with multiple mechanisms.