Cost-Effectiveness Analysis of Adalimumab Versus Cyclosporine for Vogt-Koyanagi-Harada Disease: A Randomized Controlled Study.

PURPOSE: To compare the 26-week cost-effectiveness of adalimumab-corticosteroids (ADA-CS) and cyclosporine-corticosteroids (CSA-CS) for Vogt-Koyanagi-Harada (VKH). METHODS: A preplanned cost-effectiveness analysis based on the per-protocol population of a randomized-controlled trial. VKH subjects were randomized to receive either cyclosporine (100-200 mg daily) combined with corticosteroids or adalimumab (40 mg twice monthly) combined with corticosteroids. The primary outcome of this cost-effectiveness study was the incremental cost-effectiveness ratio (ICER). Costs and quality-adjusted life-years (QALYs) data were calculated by the medical records and health utility, respectively. Subgroup (early and late-phase VKH) analysis and sensitivity analyses were performed. RESULTS: The ICER at 26 weeks was $62,425/QALY for the total participants. Compared to the CSA-CS group, costs in the ADA-CS group were more expensive (mean difference [ΔA-C]: $2,497) with more gains in QALYs (mean difference [ΔA-C]: 0.04). The probability of ADA-CS being cost-effective was 0.17 and 0.41 at willingness to pay (WTP) thresholds of $12,000/QALY and $36,000/QALY, respectively. Subgroup analysis and sensitivity analyses showed consistent findings with the primary analysis. CONCLUSIONS: Regardless of early or late-phase VKH, the CSA-CS strategy may be recommended as the preferred initial choice for the majority of VKH.

A combined transcriptomics and proteomics approach to reveal the mechanism of AEE relieving hyperlipidemia in ApoE-/- mice.

Hyperlipidemia caused by abnormal lipid metabolism has reached epidemic proportions. This phenomenon is also common in companion animals. Previous studies showed that AEE significantly improves abnormal blood lipids in hyperlipidemia rats and mice, but its mechanism is still not clear enough. In this study, the mechanism and potential key pathways of AEE on improving hyperlipidemia in mice were investigated through the transcriptome and proteome study of ApoE-/- mice liver and the verification study on high-fat HepG2 cells. The results showed that AEE significantly decreased the serum TC and LDL-C levels of hyperlipidemia ApoE-/- mice, and significantly increased the enzyme activity of CYP7A1. After AEE intervention, the results of mice liver transcriptome and proteome showed that differential genes and proteins were enriched in lipid metabolism-related pathways. The results of RT-qPCR showed that AEE significantly regulated the expression of genes related to lipid metabolism in mice liver tissue. AEE significantly upregulated the protein expression of CYP7A1 in hyperlipidemia ApoE-/- mice liver tissue. The results in vitro showed that AEE significantly decreased the levels of TC and TG, and improved lipid deposition in high-fat HepG2 cells. AEE significantly increased the expression of CYP7A1 protein in high-fat HepG2 cells. AEE regulates the expression of genes related to lipid metabolism in high-fat HepG2 cells, mainly by FXR-SHP-CYP7A1 and FGF19-TFEB-CYP7A1 pathways. To sum up, AEE can significantly improve the hyperlipidemia status of ApoE-/- mice and the lipid deposition of high-fat HepG2 cells, and its main pathway is probably the bile acid metabolism-related pathway centered on CYP7A1.

The effect of cognition in combination with an ACBT on dyspnea-related kinesiophobia in patients with moderate to severe COPD: Quasirandomized controlled trial study.

Patients with moderate to severe COPD frequently experience dyspnea, which causes these patients to acquire a fear of dyspnea and a fear of activity. This study developed a cognitive intervention combined with active cycle of breathing technique (ACBT) intervention program based on the fear-avoidance model, with the goal of evaluating the program's effectiveness in improving dyspnea-related kinesiophobia in patients with moderate to severe COPD. This study had a total of 106 participants. For 8 weeks, the intervention group (N=53) received cognitive combined with ACBT, while the control group (N=53) received standard care. The findings of the four times the dyspnea belief questionnaire were collected indicated that the combined intervention had a better impact on reducing dyspnea-related kinesiophobia than did routine nursing (P<0.05), and the impact persisted even after the intervention. Additionally, it may enhance dyspnea and quality of life, increase exercise capacity, and lower the BODE index.

Analysis and Evaluation of Muscle Quality in Different Parts of the Bighead Carp (Aristichthys nobilis).

In this study, the bighead carp (Aristichthys nobilis) was the object of research to compare and analyze the contents of conventional nutrients, amino acids, fatty acids, inosinic acid, and earthy-smelling compounds (geosmin and 2-methylisoborneol) in muscles of its dorsal, belly, tail, opercula, eye socket, and mandible in order to evaluate their quality. The findings could inform recommendations for the consumption and processing of different muscle parts of the bighead carp. The results showed that the water content in the abdominal muscle was significantly lower than that in other parts, and the crude fat content was significantly higher than that in other parts (p < 0.05, the same below). Seventeen kinds of amino acids were detected in the muscles of the six parts of the fish, and the dorsal muscles had the highest umami amino acids, essential amino acids and total amino acids, which were 6.45 g/100 g, 6.82 g/100 g and 17.26 g/100 g, respectively. The total amount of essential amino acids in the muscle was higher than that in the FAO/WHO standard model. According to the AAS standard, the first limiting amino acid in the muscle of the six parts was valine (Val). There were 26 kinds of fatty acids in the abdomen, under the gill cover and in the eye socket muscles, and the content of polyunsaturated fatty acids in the mandibular muscles was the highest (45.41%). The content of inosine in the dorsal muscle was significantly higher than that in other parts. Geosmin was the main substance in the muscle. There was no correlation between the distribution of earthy-smelling compounds and fat content, but the content of earthy-smelling compounds in the muscle of the belly and eye socket was the highest. Therefore, the muscle quality of different parts of the bighead carp has its own characteristics, and targeted development and utilization can make more efficient use of bighead carp resources.

Development of a behavior change intervention to improve physical activity in patients with COPD using the behavior change wheel: a non-randomized trial.

The aim of this study was to evaluate whether a theory-based behavior change intervention could promote changes in physical activity (PA) and sedentary behavior (SB) among patients with chronic obstructive pulmonary disease (COPD), as well as its effects on symptoms of dyspnea, lung function, exercise capacity, self-efficacy, and health-related quality of life (HRQoL). A quasi-experimental design and convenience sampling were adopted. A total of 92 patients with stable COPD were recruited from outpatient and inpatient centers of two hospitals in Zhejiang Province, China. Both the experimental and control groups received standard medical care provided in the hospital. The experimental group performed a PA program based on the behavior change wheel theory. Outcomes were measured at baseline (T0) and after 4 weeks (T1), 8 weeks (T2), and 12 weeks of the intervention (T3). The primary outcome was PA measured by the International Physical Activity Questionnaire (IPAQ). Secondary outcomes included SB measured by the IPAQ, dyspnea measured by the modified Medical Research Council (mMRC) questionnaire, exercise capacity assessed by 6-min walk distance (6MWD), self-efficacy measured by the Exercise Self-Regulatory Efficacy Scale (EX-SRES), and HRQoL measured by the COPD Assessment Test (CAT). In addition, we measured lung function using a spirometer at baseline and 12 weeks. Of the 89 patients included in this study, 64 were male (71.91%), with a mean age of 67.03 ± 6.15 years. At 12 weeks, the improvements in PA, SB, mMRC, 6MWD, EX-SRES and CAT were all statistically significant (P < 0.05) in the experimental group compared to the control group. Repeated measures analysis of variance showed that there were group effects and time effects on total PA, SB, mMRC, 6MWD, EX-SRES, and CAT in both groups (P < 0.001). However, there was no significant difference in pulmonary function between the two groups before and after intervention (P < 0.05). The PA program based on theory significantly increased PA levels, reduced sedentary time, enhanced exercise capacity and self-efficacy as well as HRQoL in patients with stable COPD. Due to the limited intervention time in this study, the pulmonary function of COPD patients may not be reversed in a short time, and the long-term effect of this program on the pulmonary function of patients needs to be further explored.Trial registration: Clinical Trials.gov (ChiCTR2200060590). Registered 05/06/2022.

Protective Effect and Mechanism of Aspirin Eugenol Ester on Lipopolysaccharide-Induced Intestinal Barrier Injury.

Intestinal inflammation is a complex and recurrent inflammatory disease. Pharmacological and pharmacodynamic experiments showed that aspirin eugenol ester (AEE) has good anti-inflammatory, antipyretic, and analgesic effects. However, the role of AEE in regulating intestinal inflammation has not been explored. This study aimed to investigate whether AEE could have a protective effect on LPS-induced intestinal inflammation and thus help to alleviate the damage to the intestinal barrier. This was assessed with an inflammation model in Caco-2 cells and in rats induced with LPS. The expression of inflammatory mediators, intestinal epithelial barrier-related proteins, and redox-related signals was analyzed using an enzyme-linked immunosorbent assay (ELISA), Western blotting, immunofluorescence staining, and RT-qPCR. Intestinal damage was assessed by histopathological examination. Changes in rat gut microbiota and their functions were detected by the gut microbial metagenome. AEE significantly reduced LPS-induced pro-inflammatory cytokine levels (p < 0.05) and oxidative stress levels in Caco-2 cells and rats. Compared with the LPS group, AEE could increase the relative expression of Occludin, Claudin-1, and zonula occludens-1 (ZO-1) and decrease the relative expression of kappa-B (NF-κB) and matrix metalloproteinase-9. AEE could significantly improve weight loss, diarrhea, reduced intestinal muscle thickness, and intestinal villi damage in rats. Metagenome results showed that AEE could regulate the homeostasis of the gut flora and alter the relative abundance of Firmicutes and Bacteroidetes. Flora enrichment analysis indicated that the regulation of gut flora with AEE may be related to the regulation of glucose metabolism and energy metabolism. AEE could have positive effects on intestinal inflammation-related diseases.

Effectiveness and the nomogram of small incision lenticule extraction in the correction of myopic anisometropia in adults.

AIM: To evaluate the safety, effectiveness, and predictability of small incision lenticule extraction (SMILE) for the treatment of anisometropia, and to explore the personalized design scheme of SMILE in correcting adult myopia anisometropia based on the nomogram. METHODS: It's a prospective cohort study. Patients with anisometropic myopia of refractive difference ≥ 2.0 diopters (D) who underwent SMILE between September 2020 and March 2021 were enrolled. Clinical features and visual function were assessed preoperatively and at 1wk, 1, 3, and 6mo after the operation. The examination included tests for uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), refractive errors, effectiveness index (preoperative CDVA/postoperative UDVA), safety index (postoperative CDVA/preoperative CDVA), nomogram and stereoscopic function. Paired t-test, Wilcoxon signed-rank test and repeated-measures analyses of variance were used for continuous variables, and Pearson Chi-squared test was used for categorical variables. RESULTS: The study involved 45 consecutive patients (average age: 25.0±6.9y; 82 out of 90 eyes underwent SMILE, while 8 eyes were not operated). The average preoperative spherical equivalent (SE) was -4.74±0.22 D. Six months after surgery, the effectiveness index was 1.05±0.12, and the safety index was 1.09±0.11. Seventy eyes (85.4%) exhibited SE correction error within ±0.5 D. The percentage of eyes with Titmus stereoscopic function equal to or less than 200″ significantly increased from 55.6% preoperatively to 88.9% postoperatively (P<0.05). There was statistically significant difference between higher myopia eyes and contralateral eyes in average nomogram value/spherical refraction ratio. CONCLUSION: SMILE is safe, effective and predictable in correcting myopic anisometropia, and it improves stereoscopic visual function of anisometropia patients. The precise and individualized design of the nomogram is a vital element to ensure the balance of both eyes after SMILE.

Assessing the long-term impact of cascade hydropower development on the inundation patterns of floodplain wetlands.

The inundation process of floodplain wetlands plays a crucial role in maintaining the balance of river ecosystems, which are highly sensitive to hydrological alteration. Nevertheless, the specific mechanisms through which these hydrological changes affect the inundation patterns of floodplain wetlands are still unclear. This study aimed to investigate the impact mechanism of cascade hydropower development on the inundation process of floodplain wetlands. Multitemporal remote sensing datasets and long-term hydrometeorological data series were utilized in this study. By employing the water appearance frequency (WAF) index, wetland hydrological stability assessment, and wavelet analysis, the inundation changes in floodplain wetlands and the underlying hydrological driving mechanisms were examined. The results revealed significant alterations in the inundation frequency of floodplain wetlands due to the construction of upstream dams. Specifically, the construction of the Danjiangkou and Wangfuzhou dams led to an increase in the total inundated area of Part A (16.09 km2) and Part B (76.93 km2), respectively. Conversely, the moderate frequency inundation zone in Part C decreased (26.7 km2) after the construction of the Cuijiaying Dam. The typical floodplain wetland 7 shifted from high to low (8.94 km2) stability after the construction of the Cuijiaying Dam. Furthermore, the cascade hydropower dam construction resulted in increased fluctuations in downstream water discharge. This study provides an effective approach to understanding the impact of cascade hydropower dams on the inundation process of floodplain wetlands.

Multi-omics reveals aspirin eugenol ester alleviates neurological disease.

BACKGROUND: Exosomes play an essential role in maintaining normal brain function due to their ability to cross the blood-brain barrier. Aspirin eugenol ester (AEE) is a new medicinal compound synthesized by the esterification of aspirin with eugenol using the prodrug principle. Aspirin has been reported to have neuroprotective effects and may be effective against neurodegenerative diseases. PURPOSE: This study wanted to investigate how AEE affected neurological diseases in vivo and in vitro. EXPERIMENTAL APPROACH: A multi-omics approach was used to explore the effects of AEE on the nervous system. Gene and protein expression changes of BDNF and NEFM in SY5Y cells after AEE treatment were detected using RT-qPCR and Western Blot. KEY RESULTS: The multi-omics results showed that AEE could regulate neuronal synapses, neuronal axons, neuronal migration, and neuropeptide signaling by affecting transport, inflammatory response, and regulating apoptosis. Exosomes secreted by AEE-treated Caco-2 cells could promote the growth of neurofilaments in SY5Y cells and increased the expression of BDNF and NEFM proteins in SY5Y cells. miRNAs in the exosomes of AEE-treated Caco-2 cells may play an important role in the activation of SY5Y neuronal cells. CONCLUSIONS: In conclusion, AEE could play positive effects on neurological-related diseases.

A randomized non-inferiority trial of therapeutic strategy with immunosuppressants versus biologics for Vogt-Koyanagi-Harada disease.

Biologics are increasingly used to treat Vogt-Koyanagi-Harada disease, but head-to-head comparisons with conventional immunosuppressants are lacking. Here in this randomized trial (Chinese Clinical Trial Registry, ChiCTR2100043061), we assigned 110 patients (27 early-phase and 83 late-phase) to cyclosporine-based immunosuppressant strategy (N = 56) or adalimumab-based biologic strategy (N = 54), each combined with a modified corticosteroid regimen. The primary outcome is change from baseline in best-corrected visual acuity at week 26. The margin of non-inferiority for cyclosporine is -7 letters. The primary outcome is 11.2 letters (95% CI, 7.5 to 14.9) in the cyclosporine group and 6.3 letters (95% CI, 3.1 to 9.6) in the adalimumab group (difference, 4.9; 95% CI, 0.2 to 9.5; P < 0.001 for non-inferiority). The between-group difference is -0.8 letters (95% CI, -6.1 to 4.5) in early-phase disease and 5.7 letters (95% CI, 0.2 to 11.2) in late-phase. Serious adverse events are reported less frequently in the cyclosporine group than in the adalimumab group (0.70 vs. 1.21 events per patient-year). Here, we report that combined with a non-standard corticosteroid regimen, cyclosporine-based immunosuppressant strategy is non-inferior to adalimumab-based biologic strategy by 26 weeks for visual improvement in a cohort of patients with Vogt-Koyanagi-Harada disease, 75% of whom have a late-phase disease.

Effect of flowing water on the pharmacokinetic properties of norfloxacin in channel catfish (Ictalurus punctatus) after single-dose oral administration.

BACKGROUND: The recirculating aquaculture system (RAS) is a widely used, water-saving and efficient aquaculture model. However, bacterial diseases are common in farmed fish reared at high densities. Although antibiotics effectively treat these diseases, developing efficient methods to increase drug clearance in fish and decrease the concentrations of antibiotic residues in aquatic products is essential. OBJECTIVES: This study evaluates the effect of flowing water in the RAS on norfloxacin (NOR) pharmacokinetics in channel catfish (Ictalurus punctatus). METHODS: Channel catfish were randomly divided into the control group (RAS group) and the experimental group (flow-through aquaculture system group) (120 individuals/group). A NOR dose of 20 mg/kg was then orally administered to the fish. Plasma, muscle, liver and kidney samples were collected up to 168 h after treatment. NOR concentrations were measured using liquid chromatography-mass spectrometry, and pharmacokinetic parameters were calculated using a non-compartmental method. RESULTS: Flowing water had a significant effect on the plasma pharmacokinetics and tissue distribution of NOR, increasing NOR clearance in the kidney, muscle and plasma. The time to maximum concentration of NOR was shorter in the plasma and longer in the kidney and liver. Moreover, flowing water increased the maximum concentration of NOR in the kidney, muscle and plasma and decreased the area under the concentration-time curve from time 0 to the last measurable concentration in the liver and plasma. Flowing water decreased the withdrawal period in muscle from 10 to 6 days. CONCLUSIONS: These results indicate that flowing water can potentially increase NOR clearance in channel catfish.

Dispersal and transport of microplastic particles under different flow conditions in riverine ecosystem.

Microplastic (MP) pollution is a global issue owing to its potential threats to ecosystems and human health. MP pollution in river ecosystems is widely investigated, but the transport process under different hydrological conditions remain unclear. In this study, an approach of particle tracking in conjunction with hydrodynamic modeling was developed to investigate the dispersal and transport processes of microplastic particles in riverine ecosystem. The concentration and dispersal pattern of polyamide (PA), polyethylene (PE), polypropylene (PP), polystyrene (PS), and polyethylene terephthalate (PET) particles under base flow and flood events with recurrence intervals of 10-year, 20-year and 50-year were identified. Results indicated that rainfall intensity had a significant impact on the microplastic transport in rivers. Higher suspension concentration and lower sedimented concentration were observed in high flow periods, and the sedimented concentration showed a slow increasing trend in the flood recession stage. High water velocity facilitated the microplastic particles to be migrated for a longer distance, and high water flow was conducive to transport more microplastics from source points. Besides, microplastic particles with high density had worse mobility in water and more prone to deposition. PET were likely to be transported for a relatively shorter distance, while PP had higher mobility and took less time to reach the same simulation point. This study put forward an effective approach to understand the transport of MPs in the river. The results obtained are useful to identify pollution hotspots and track pollution paths.

Corneal morphological changes after small incision lenticule extraction for myopic anisometropia.

Purpose: This research aims to study the corneal morphological changes in adult patients with myopic anisometropia after small incision lenticule extraction (SMILE) and the safety, efficacy, and predictability of clinical outcomes. Methods: This was a prospective cohort study. Patients with myopic anisometropia [refractive difference >2.0 diopters (D)] were included in this study who underwent SMILE at our hospital from September 2019 to March 2021. For the two eyes of each patient, the one with higher myopia was defined as group A, and the fellow eye was group B. The follow-up time points were set as 1 week, 1 month, 3 months, and 6 months after the surgery. The data collected were uncorrected and best-corrected distance visual acuity (UDVA and CDVA), spherical equivalent (SE), efficacy and safety indexes, posterior corneal elevation (PCE), anterior and posterior corneal radius of curvature in the 3 mm area at the center of the thinnest point of the cornea (ARC and PRC), and higher-order aberrations (HOAs). Results: The study included 36 patients (72 eyes), and the mean age was 25.2 ± 6.4 years. The preoperative SEs were -6.45 ± 1.25 D in group A and -3.76 ± 1.29 D in group B. Six months after surgery, the SEs in groups A and B were -0.09 ± 0.50 D and 0.07 ± 0.47 (P = 0.059), respectively. The efficacy indexes were 1.06 ± 0.16 in group A and 1.07 ± 0.14 in group B (P = 0.750). The safety indexes were 1.08 ± 0.14 in group A and 1.12 ± 0.15 in group B (P = 0.173). The PCE was significantly reduced at 6 months after surgery in pagebreak both groups (P < 0.05). The ARC was significantly higher than before the surgery (P < 0.05) in the two groups. The two groups showed significant increases in total HOAs, coma 90°, and spherical aberrations (P < 0.05). Conclusion: SMILE is predictable, effective, and safe in correcting myopic anisometropia. The postoperative changes in HOAs are characteristic.

HJM-561, a Potent, Selective, and Orally Bioavailable EGFR PROTAC that Overcomes Osimertinib-Resistant EGFR Triple Mutations.

The EGFR C797S mutation is the most common on-target resistance mechanism to osimertinib in patients with advanced non-small cell lung cancer (NSCLC). Currently there are no effective treatment options for patients with NSCLC harboring EGFR C797S triple mutants (Del19/T790M/C797S and L858R/T790M/C797S). Herein, we report an orally bioavailable EGFR PROTAC, HJM-561, which selectively degrades the EGFR C797S-containing triple mutants. HJM-561 potently inhibits the proliferation of Del19/T790M/C797S and L858R/T790M/C797S Ba/F3 cells while sparing cells expressing wild-type EGFR. Oral administration of HJM-561 shows robust antitumor activity in EGFR Del19/T790M/C797S-driven Ba/F3 CDX and PDX models that were resistant to osimertinib treatment. Taken together, our results suggest that HJM-561 is a promising therapeutic option for overcoming EGFR triple mutation-mediated drug resistance in NSCLC.

Considering ecological flow in multi-objective operation of cascade reservoir systems under climate variability with different hydrological periods.

The trade-off between ecological and socioeconomic benefits in the reservoir operation has become a focus issue in the watershed water resource management. However, finding a suitable reservoir ecological operation scheme in the multi-objective cascade reservoir systems remains unclear. At present, most ecological operation models are designed on the basis of water quantity balance, neglecting the dynamic variability of the hydrological process. This study proposed a multi-objective ecological operation system, which coupled a two-dimensional hydrodynamic model with a rainfall-runoff model, and integrated the ecological operation scheme into the hydrodynamic simulation system considering ecological flow. Moreover, the applicability of the operation scheme under climate variability with different hydrological periods was evaluated. Results indicated that multi-reservoir joint operation had the largest effect in normal years; the variation in the monthly hydrological magnitude, extreme events and their duration, temporal change and frequency of streamflow were significantly reduced after reservoir ecological operation. The SAM0-UNICON model performed better than the two other climate models, the ecological deficit (ED) under the Representative Concentration Pathway (RCP) 8.5 climate change scenario was larger than other scenarios with different operation schemes. Future climate change will have a larger impact on discharge change in the wet season than in other hydrological periods. This study emphasises the comprehensive application of the hydrological and hydrodynamic methods, which is of considerable importance for decision-making in basin water resource management and reservoir regulation.

Untargeted lipidomics and metagenomics reveal the mechanism of aspirin eugenol ester relieving hyperlipidemia in ApoE-/- mice.

Hyperlipidemia is induced by abnormal lipid metabolism, which can cause the occurrence of cardiovascular diseases and lead to grievous injury to health. Studies showed that AEE had a significant therapeutic effect on hyperlipidemia and is likely to be associated with the up-regulation of cholesterol 7-alpha hydroxylase (CYP7A1), the key enzyme for cholesterol conversion to bile acids, but no research confirmed whether the effect of AEE on hyperlipidemia was related to the gut microbiota and liver lipids. At the same time, more and more studies have shown that gut microbiota and lipids are closely related to hyperlipidemia. Hence, in this study, we investigated the effects of AEE on liver lipids through LC-MS-based untargeted lipidomics and the effects of AEE on gut microbiota based on cecal contents metagenomics by Illumina sequencing in HFD-induced hyperlipidemia ApoE-/- mice at the overall level. The results of lipidomics showed that AEE relieved hyperlipidemia by decreasing the concentration of 10 PEs and 12 SMs in the liver and regulating the pathways of glycerophospholipid metabolic pathway, sphingolipid signaling pathway, and NF-kB signaling pathway. The results of metagenomics concluded that AEE treatment changed the composition of gut microbiota and regulated the functions of lipid transport and metabolism, as well as the metabolism of bile acids and secondary bile acids. The results of the joint analysis between lipidomics and metagenomics showed that the abundance of Verrucomicrobia, Verrucomicrobiales, Candidatus_Gastranaerophilales, and Candidatus_Melainabacteria was significantly positively correlated with the concentration of SM (d18:1/18:0) and PE (16:0/18:1) in the process of AEE alleviating hyperlipidemia in mice. In conclusion, these results suggested that the effect of AEE on hyperlipidemia was closely related to the gut microbiota by the change of bile acids and liver lipids.

[Differences in the ecological resilience of planted and natural Pinus massoniana and Cunninghamia lanceolata forests in response to drought in subtropical China]. / 亚热带人工和天然马尾松、杉木林生长对干旱的生态弹性差异.

We sampled Pinus massoniana and Cunninghamia lanceolata in both plantation and natural forests in central and western Fujian Province, China. Using tree-ring width, tree-ring width index, and basal area increment, we reconstructed the annual growth of 109 conifer individuals from four sites for the 20-year period from 1993 to 2012. We then calculated resistance, recovery, and resilience indices of those trees in response to two consecutive extreme droughts (2003-2004 and 2011) and analyzed the differences in resistance and resilience between plantations and natural fore-sts. The results showed that there were temporal differences in moisture requirements between P. massoniana and C. lanceolata, which accounted for their inconsistent responses to drought in 2003-2004. For both species, drought induced a marked growth reduction, without any clear lag effect. The growth responses during and following the 2003-2004 drought were significantly stronger than that for the 2011 drought. Those results indicated that P. massoniana was more resilient to drought stress than C. lanceolata, and the natural forests were more sensitive than plantations, but with stronger capacity to recover. C. lanceolata plantations were more susceptible to frequent extreme drought events. To mitigate the vulnerability of plantation trees to more frequent droughts in the future, we suggested select trees from genetic provenances with strong drought resistance.

Antitumor efficacy of CHMFL-KIT-110 solid dispersion in mouse xenograft models of human gastrointestinal stromal tumors.

PURPOSE: CHMFL-KIT-110, a selective c-KIT kinase inhibitor for gastrointestinal stromal tumors (GISTs), possesses a poorly water-soluble, limiting the further development of the drug. This study was to investigate the antitumor efficacy of CHMFL-KIT-110 and CHMFL-KIT-110 solid dispersion (laboratory code: HYGT-110 SD) in GIST tumor xenograft models and to explore the PK/PD relationship of HYGT-110 SD. METHODS: Plasma concentrations of HYGT-110 and HYGT-110 SD were determined by LC-MS/MS in KM mice. Antitumor activity was evaluated by measuring tumor volume and weight in c-KIT-dependent GIST xenograft models. PK/PD relationship was assessed by LC-MS/MS and Western Blot in the GIST-T1 xenografted mice. RESULTS: HYGT-110 exhibited a low oral bioavailability (10.91%) in KM mice. Compared with HYGT-110 treatment, the Cmax and AUC0-t of HYGT-110 SD in mice plasma were substantially increased by 18.81 and 6.76-fold, respectively. HYGT-110 SD (10, 30, and 100 mg/kg/day) also could dose-dependently decrease the tumor volume and weight in the GIST-882 cell-inoculated xenograft mouse models and show 86.35% tumor growth inhibition (TGI) at 28 days at a 25 mg/kg bid dosage in the GIST-T1 cell-inoculated xenograft mouse model. The free concentration of HYGT-110 in plasma was closely correlated with the inhibition of c-KIT phosphorylation levels in tumor tissues. CONCLUSIONS: In comparison with the HPMC formulation, both improved PK and PD characteristics of the solid dispersion formulation of CHMFL-KIT-110 were observed in in vivo animal experiments.

HYR-PB21-LA, a potential extended-release bupivacaine formulation, produces long-lasting local anesthesia in rats and guinea pigs.

BACKGROUND: Effective postoperative pain management plays a key role in enhancing recovery of patients after surgery. Bupivacaine hydrochloride is one of the most commonly local anesthetics used for the postoperative pain control. However, the relatively short anesthesia duration of bupivacaine preparations limited their clinical application. METHODS: Both guinea pig pin-prick study and rat tail-flick test were performed to evaluate the local anesthesia efficacy of HYR-PB21-LA, a new microparticle suspension injection of bupivacaine pamoate. RESULTS: In the pin-prick test, the complete cutaneous trunci muscle reflex inhibitions were observed at 30 min in all treatment groups containing bupivacaine. In comparison with 6.7 mg/mL HYR-PB21-LA, both 10 and 20 mg/mL HYR-PB21-LA groups had significantly higher area under effect time curve (AUEC) values (p<0.001 and p<0.0001) and slower offset time (p<0.0001). Significantly higher AUEC (p<0.0001) and slower offset time (p<0.0001) were also found in 10 mg/mL HYR-PB21-LA treatment group compared with bupivacaine liposome injectable suspension (liposomal bupivacaine). In the rat tail-flick test, significantly increased local anesthesia effect was lasted for 5 hours after 2.5 mg/mL HYR-PB21-LA administration, which was fivefold longer than bupivacaine hydrochloride. The longer lasted efficacy of significantly increased local anesthesia was also observed in 5 mg/mLHYR-PB21-LA than those in liposomal bupivacaine (8 hour vs 1 hour). CONCLUSIONS: The results demonstrated that the HYR-PB21-LA produced longer local anesthesia effect than current clinical preparations of bupivacaine in two animal models. These findings raise the potential clinical value of HYR-PB21-LA as a long-lasting local anesthesia for controlling postsurgical pain in humans.

Cellular Metabolomics Reveal the Mechanism Underlying the Anti-Atherosclerotic Effects of Aspirin Eugenol Ester on Vascular Endothelial Dysfunction.

Aspirin eugenol ester (AEE) possesses anti-thrombotic, anti-atherosclerotic and anti-oxidative effects. The study aims to clarify the mechanism underlying the anti-atherosclerotic effects of AEE on vascular endothelial dysfunction. Both the high-fat diet (HFD)-induced atherosclerotic rat model and the H2O2-induced human umbilical vein endothelial cells (HUVECs) model were used to investigate the effects of AEE on vascular endothelial dysfunction. UPLC/QTOF-MS coupled with a multivariate data analysis method were used to profile the variations in the metabolites of HUVECs in response to different treatments. Pretreatment of HUVECs with AEE significantly ameliorated H2O2-induced apoptosis, the overexpression of E-selectin and VCAM-1, and the adhesion of THP-1 cells. Putative endogenous biomarkers associated with the inhibition of endothelial dysfunction were identified in HUVECs pretreated with AEE in the absence or presence of H2O2, and these biomarkers were involved in important metabolic pathways, including amino acid metabolism, carbohydrate metabolism, and glutathione metabolism. Moreover, in vivo, AEE also significantly reduced vascular endothelial dysfunction and decreased the overexpression of VCAM-1 and E-selectin. Based on our findings, the mechanism underlying the anti-atherosclerotic effects of AEE might be related to a reduction in vascular endothelial dysfunction mediated by ameliorating alterations in metabolism, inhibiting oxidative stress, and decreasing the expression of adhesion molecules.