3,6-dichlorobenzo[b]thiophene-2-carboxylic acid alleviates ulcerative colitis by suppressing mammalian target of rapamycin complex 1 activation and regulating intestinal microbiota.

BACKGROUND: 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid (BT2) is a benzothiophene carboxylate derivative that can suppress the catabolism of branched-chain amino acid (BCAA)-associated mammalian target of rapamycin complex 1 (mTORC1) activation. Previous studies have demonstrated the therapeutic effects of BT2 on arthritis, liver cancer, and kidney injury. However, the effects of BT2 on ulcerative colitis (UC) are unknown. AIM: To investigate the anti-UC effects of BT2 and the underlying mechanism. METHODS: Mouse UC models were created through the administration of 3.5% dextran sodium sulfate (DSS) for 7 d. The mice in the treated groups were administered salazosulfapyridine (300 mg/kg) or BT2 (20 mg/kg) orally from day 1 to day 7. At the end of the study, all of the mice were sacrificed, and colon tissues were removed for hematoxylin and eosin staining, immunoblot analyses, and immunohistochemical assays. Cytokine levels were measured by flow cytometry. The contents of BCAAs including valine, leucine, and isoleucine, in mouse serum were detected by liquid chromatography-tandem mass spectrometry, and the abundance of intestinal flora was analyzed by 16S ribosomal DNA sequencing. RESULTS: Our results revealed that BT2 significantly ameliorated the inflammatory symptoms and pathological damage induced by DSS in mice. BT2 also reduced the production of the proinflammatory cytokines interleukin 6 (IL-6), IL-9, and IL-2 and increased the anti-inflammatory cytokine IL-10 level. In addition, BT2 notably improved BCAA catabolism and suppressed mTORC1 activation and cyclooxygenase-2 expression in the colon tissues of UC mice. Furthermore, high-throughput sequencing revealed that BT2 restored the gut microbial abundance and diversity in mice with colitis. Compared with the DSS group, BT2 treatment increased the ratio of Firmicutes to Bacteroidetes and decreased the abundance of Enterobacteriaceae and Escherichia-Shigella. CONCLUSION: Our results indicated that BT2 significantly ameliorated DSS-induced UC and that the latent mechanism involved the suppression of BCAA-associated mTORC1 activation and modulation of the intestinal flora.

Effect of midazolam on delirium in critically ill patients: a propensity score analysis.

OBJECTIVE: To observe the association between exposure to midazolam within 24 hours prior to delirium assessment and the risk of delirium. METHODS: We performed a systematic cohort study with two sets of cohorts to estimate the relative risks of outcomes among patients administered midazolam within 24 hours prior to delirium assessment. Propensity score matching was performed to generate a balanced 1:1 matched cohort and identify potential prognostic factors. The outcomes included the odds of delirium, mortality, length of intensive care unit stay, length of hospitalization, and odds of being discharged home. RESULTS: A total of 78,364 patients were included in this study, of whom 22,159 (28.28%) had positive records. Propensity matching successfully balanced covariates for 9348 patients (4674 per group). Compared with no administration of midazolam, midazolam administration was associated with a significantly higher risk of delirium, higher mortality, and a longer intensive care unit stay. Patients treated with midazolam were relatively less likely to be discharged home. There was no significant difference in hospitalization duration. CONCLUSIONS: Midazolam may be an independent risk factor for delirium in critically ill patients.

Lipoxin A4 Ameliorates Lipopolysaccharide-Induced A549 Cell Injury through Upregulation of N-myc Downstream-Regulated Gene-1.

BACKGROUND: Lipoxin A4 (LXA4) can alleviate lipopolysaccharide (LPS)-induced acute lung injury (ALI) and acute respiratory distress syndrome through promoting epithelial sodium channel (ENaC) expression in lung epithelial cells. However, how LXA4 promote ENaC expression is still largely elusive. The present study aimed to explore genes and signaling pathway involved in regulating ENaC expression induced by LXA4. METHODS: A549 cells were incubated with LPS and LXA4, or in combination, and analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) of ENaC-α/γ. Candidate genes affected by LXA4 were explored by transcriptome sequencing of A549 cells. The critical candidate gene was validated by qRT-PCR and Western blot analysis of A549 cells treated with LPS and LXA4 at different concentrations and time intervals. LXA4 receptor (ALX) inhibitor BOC-2 was used to test induction of candidate gene by LXA4. Candidate gene siRNA was adopted to analyze its influence on A549 viability and ENaC-α expression. Phosphoinositide 3-kinase (PI3K) inhibitor LY294002 was utilized to probe whether the PI3K signaling pathway was involved in LXA4 induction of candidate gene expression. RESULTS: The A549 cell models of ALI were constructed and subjected to transcriptome sequencing. Among candidate genes, N-myc downstream-regulated gene-1 (NDRG1) was validated by real-time-PCR and Western blot. NDRG1 mRNA was elevated in a dose-dependent manner of LXA4, whereas BOC-2 antagonized NDRG1 expression induced by LXA4. NDRG1 siRNA suppressed viability of LPS-treated A549 cells (treatment vs. control, 0.605 ± 0.063 vs. 0.878 ± 0.083, P = 0.040) and ENaC-α expression (treatment vs. control, 0.458 ± 0.038 vs. 0.711 ± 0.035, P = 0.008). LY294002 inhibited NDRG1 (treatment vs. control, 0.459 ± 0.023 vs. 0.726 ± 0.020, P = 0.001) and ENaC-α (treatment vs. control, 0.236 ± 0.021 vs. 0.814 ± 0.025, P < 0.001) expressions and serum- and glucocorticoid-inducible kinase 1 phosphorylation (treatment vs. control, 0.442 ± 0.024 vs. 1.046 ± 0.082, P = 0.002), indicating the PI3K signaling pathway was involved in regulating NDRG1 expression induced by LXA4. CONCLUSION: Our research uncovered a critical role of NDRG1 in LXA4 alleviation of LPS-induced A549 cell injury through mediating PI3K signaling to restore ENaC expression.

Synthesis and characterization of arginine-NIPAAm hybrid hydrogel as wound dressing: In vitro and in vivo study.

A multi-functional hybrid hydrogel P(M-Arg/NIPAAm) with temperature response, anti-protein adsorption and antibacterial properties was prepared and applied as wound dressing. The hydrogel was carried out by free radical copolymerization of methacrylate arginine (M-Arg) and N-isopropyl acrylamide (NIPAAm) monomers using N,N'-methylene bisacrylamide as a crosslinker, and ammonium persulfate/N,N,N', N'-tetramethylethylenediamine as the redox initiator. To endow the antimicrobial property, chlorhexidine diacetate (CHX) was preloaded into the hydrogel and polyhexamethylene guanidine phosphate (PHMG) was grafted on the hydrogel surface, respectively. The antimicrobial property of two series of hydrogels was evaluated and compared. The successful synthesis of M-Arg, PHMG and hydrogels was proved by 13C NMR, 1H NMR and FTIR spectroscopy. The hydrogel morphology characterized by scanning electron microscopy confirmed that the homogeneous porous and interconnected structures of the hydrogels. The swelling, protein adsorption property, in vitro release of CHX, antimicrobial assessment, cell viability as well as in vivo wound healing in a mouse model were studied. The results showed the nontoxicity and antimicrobial P(M-Arg/NIPAAm) hydrogel accelerated the full-thickness wound healing process and had the potential application in wound dressing. STATEMENT OF SIGNIFICANCE: Despite the zwitterionic characteristic and biocompatible property of arginine based hydrogels, the brittle behavior and non-transparency still remain as a significant problem for wound dressing. Furthermore promoting the antibacterial property of the zwitterionic hydrogel is also necessary to prevent the bacterial colonization and subsequent wound infection. Therefore, we created a hybrid hydrogel combined methacrylate arginine (M-Arg) and N-isopropyl acrylamide (NIPAAm). NIPAAm improves transparency and mechanical property as well as acts as a temperature-response drug release system. Additionally, chlorhexidine (CHX) was preloaded into the hydrogels and polyhexamethylene guanidine phosphate (PHMG) was grafted on the hydrogel surface, respectively, which make the hydrogel useful as a favorable antibacterial dressing. The hybrid hydrogel has a combination effect of biocompatibility, environmentally responsive transformation behavior, biodegradability, anti-protein adsorption and antimicrobial properties. This report proposes the preparation of P(M-Arg/NIPAAm) hydrogel that has a great potential for wound healing.

[Mapping of QTLs controlling leaf chlorphyll content and chlorphyll degradation speed of detached leaves in rice].

A recombinant inbred (RI) population derived from the cross between an indica variety, IR24, and a japonica variety, Asominori, was used to map QTLs controlling leaf chlorophyll content (LCC) and chlorophyll degradation speed (CDS) of detached leaves collected at the tillering stage of rice through composite interval mapping analysis (CIM). Resultantly, four QTLs (qLCC-3, qLCC-5, qLCC-7, qLCC-12) controlling LCC and three QTLs (qCDS-1, qCDS-6, qCDS-7) associated with CDS were detected respectively. Among them, qCDS-7 with the largest effect for CDS, located on chromosome 7, coincided with the genomic region of qLCC-7 for LCC detected. Those results from this study basically can explicate the genetic basis associated with leaf chlorophyll content and chlorophyll degradation speed of detached leaves in rice, which might be available for a rapid determination of leaf senescence at early growth-stages and breeding of high-photosynthetic efficiency in rice.

[Study on the combination of preozonation and post-ozonation-BAC process for drinking water treatment].

This study was conducted to illustrate the effectiveness of preozonation or O3-BAC or combination of these two process in controlling DBPs for treating a dam source water in South China through SBR and continuous flow (200 L/h) experiments and the variables in the treatment train included the point of preozonation with respect to coagulation; the point of ozonation with respect to BAC, the ozone dosage required for preozonation and the Br- content of raw water. Results indicated the reduction in DBP formation potential closely paralleled the reduction in UV absorbance, and trihalomethane and haloacetic acid formation potential can be removed under a dose of preozone at 0.5 - 1.0 mg/L, at the same time, ozone by-products (bromate and formaldehyde) can be controlled in low level. The continuous flow experiment results show that combination of preozonation and O3-BAC process has obviously positive effects on the removals of particles with a size above 2 microm, COD(Mn), and TOC. However, DBPs formation can be controlled by the removal of organic matters.