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A chiral metal-organic framework L-Histidine-Zeolitic imidazolate framework-67 (L-His-ZIF-67) was synthesized by the mixture of chiral organic ligand L-histidine and non-chiral organic ligand 2-methylimidazole directly, and to the author's knowledge, the chiral L-His-ZIF-67 coated capillary column we prepared has still not been reported to date in the field of capillary electrophoresis. This chiral metal-organic frameworks material was used as the chiral stationary phase for enantioseparation of drugs by open-tubular capillary electrochromatography. The separation conditions such as pH value, buffer concentration and proportion of organic modifier were optimized. Under optimal conditions, the established enantioseparation system achieved good separation effect, and the resolution of five chiral drugs: esmolol (7.93), nefopam (3.03), salbutamol (2.42), scopolamine (1.08) and sotalol (0.81). In addition, the chiral recognition mechanism of L-His-ZIF-67 was elucidated by a series of mechanism experiments, and the specific interaction force was preliminarily speculated., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The neutrophil plays an important role during abdominal aortic aneurysm (AAA) formation by undergoing histone citrullination with peptidyl arginine deiminase 4 (encoded by Padi4) and releasing neutrophil extracellular traps (NETs). However, the specific role of NETs during AAA formation is elusive. We found the levels of NET components in serum and tissues were found to be significantly associated with the clinical outcome of AAA patients. Furthermore, we reported that NETs induced the synthetic and proinflammatory smooth muscle cells (SMCs) phenotype and promoted AAA formation in a Hippo-YAP pathway-dependent manner by in vitro and in vivo experiments. Padi4 or Yap global knockout mice, exhibited significantly less synthetic and proinflammatory phenotypes of SMCs and developed AAA with lower frequency and severity compared with those of controls. Further studies indicated that the phenotypic switch of SMCs was associated with NETs-regulated enrichment status of H3K4me3 and H3K27me3 at promoters of synthetic and proinflammatory genes in SMCs. Cumulatively, these data suggest that NETs contribute to AAA formation by promoting the synthetic and proinflammatory phenotype of SMCs via inhibiting the Hippo-YAP pathway. A better understanding of the molecular mechanisms that regulate NETs and SMC phenotype is important to provide suitable cellular targets to prevent AAA., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Diabetic foot ulcer (DFU) is among the most frequent complications of diabetes and is associated with significant morbidity and mortality. Excessive neutrophil extracellular traps (NETs) delay wound healing in diabetic patients. Therefore, interventions targeting NET release need to be developed to effectively prevent NET-based wound healing impairment. Gasdermin D (GSDMD), a pore-forming protein acts as a central executioner of inflammatory cell death and can activate inflammasomes in neutrophils to release NETs. A precise understanding of the mechanism underlying NET-mediated delay in diabetic wound healing may be valuable in identifying potential therapeutic targets to improve clinical outcomes. In this study, we reported that neutrophils were more susceptible to NETosis in diabetic wound environments of patients with DFU. By in vitro experiments and using in vivo mouse models of diabetic wound healing (wide-type, Nlrp3 -/- , Casp-1 -/- , and Gsdmd -/- mice), we demonstrated that NLRP3/caspase-1/GSDMD pathway on activation controls NET release by neutrophils in diabetic wound tissue. Furthermore, inhibition of GSDMD with disulfiram or genic deletion of Gsdmd abrogated NET formation, thereby accelerating diabetic wound healing. Disulfiram could inhibit NETs-mediated diabetic foot ulcer healing impairment by suppressing the NLRP3/Caspase-1/GSDMD pathway. In summary, our findings uncover a novel therapeutic role of disulfiram in inhibiting NET formation, which is of considerable value in accelerating wound healing in patients with DFU., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aim: Acute lung injury (ALI) is characterized by alveolar macrophage overactivation and uncontrolled pulmonary inflammation. Mitochondrial damage-associated molecular patterns (MTDs), one type of damage-associated molecular patterns (DAMPs) released from ruptured mitochondrial, can induce inflammation which participates in the pathogenesis of ALI. Despite the critical role of autophagy in inflammatory response, little is known about its function in MTDs-induced ALI. Herein we have studied how autophagy attenuates MTDs-induced ALI in vitro and in vivo., Main Methods: Exogenous MTDs were injected into mice through tail vein injection or directly treated with cultured alveolar macrophage cell lines to construct MTDs-induced ALI models. Rapamycin and 3-MA were used to regulate autophagy in vivo and in vitro. The expressions of Caspase-1, IL-1β, and their precursor were measured. Inhibition the activation of NLRP3 inflammasome to discover the candidate targets and potential molecular pathways involved in autophagy mitigating the MTDs-induced ALI., Key Findings: After treatment with MTDs the expression levels of inflammatory cytokines and NLRP3 inflammasome-associated proteins were gradually increased in vitro and in vivo. Most importantly, with autophagy enhanced by rapamycin, all the secretion of inflammation cytokine, the level of lung injury, and the expression level of NLRP3 inflammasome-associated proteins were greatly decreased in MTDs-induced mouse model. MTDs-induced inflammation and lung injury were alleviated by autophagy enhancement. Autophagy can function as an effective way to alleviate inflammation in MTDs-induced ALI by inhibiting NLRP3 inflammasome and may represent a therapeutic target in modulating MTDs-induced inflammatory response., (Copyright © 2020. Published by Elsevier Inc.)

Background and Aims: Phenotypic switch of vascular smooth muscle cells (VSMC) plays a key role in the pathogenesis of atherosclerosis and restenosis after artery intervention. Transcription repressor element 1-silencing transcription factor (REST) has been identified as key regulator of VSMC proliferation. In the present study, we sought to investigate the potential association of E3-ubiquitin ligase β-TRCP mediated REST protein degradation with Kv1.3 expression during VSMC phenotypic switch., Methods: Protein and mRNA expression was measured in ex vivo and in vitro models. Protein interaction and ubiquitination were analyzed by immunoprecipitation assays. ChIP assays were performed to assess the relationship between REST and targeted DNA binding site., Results: We found that the expression level of E3-ubiquitin ligase β-TRCP is significantly increased during VSMC phenotypic switch. REST protein ubiquitination mediated by β-TRCP is critical for VSMC proliferation and migration. We also found that the gene KCNA3 encoding potassium channel protein Kv1.3 contains a functional REST binding site and is repressed by REST. Downregulation of REST by β-TRCP and consequently upregulation of Kv1.3 are important events during VSMC phenotypic switch. Furthermore, upregulated Kv1.3 accelerates β-TRCP modulated REST degradation through Erk1/2 signaling., Conclusions: Our results reveal a fundamental role for regulatory interactions between β-TRCP modulated REST degradation and Kv1.3 in the control of the multilayered regulatory programs required for VSMC phenotype switch., (Copyright © 2020. Published by Elsevier B.V.)

Background: Little data evaluate the enteral nutrition (EN) for patients with acute mesenteric ischaemia (AMI) in the intensive care unit (ICU). This study assessed the outcomes of EN for recanalised AMI patients in the ICU., Methods: In this retrospective study, 183 AMI patients with mesenteric recanalisation admitted to two surgical ICUs were included. Patients were divided into EN (EN within first week, n = 95) and total parenteral nutrition (TPN) group (TPN in 1st week, n = 88). The etiology, outcomes and complications were compared. Nutritional, immunologic, inflammatory response and mesenteric reperfusion were evaluated. Subgroup analysis and cost-assessment were performed., Results: No significant difference of demographics and illness severity at baseline were found. The rates of TPN for ≥6 months (7.4% vs. 18.2%, P < 0.01), infectious complications (7.4% vs. 20.5%, P = 0.01) and acute respiratory distress syndrome (4.2% vs. 13.6%, P < 0.01) were lower in EN group. For patients with mesenteric infarction (n = 101), EN was associated with earlier bowel continuity restoration (P < 0.01) and lower 30-day mortality (7.3% vs. 26.1%, P = 0.01). For patients without initial bowel resection (n = 82), length of ICU and hospital stay was significantly shortened in EN group. The 1-year survival was 88.4% in EN group and 78.4% in TPN group (P = 0.031). EN was cost-effective, with improved inflammatory response and elevated peak velocity of mesenteric flow., Conclusions: For recanalised AMI patients, EN starting within the first week represents a favourable alternative to TPN. A multicentre randomised controlled trial with high level of evidence is warranted in the future., Clinical Relevancy Statement: Acute mesenteric ischaemia (AMI) is a catastrophic abdominal vascular emergency in the surgical intensive care unit (ICU), and the mortality of AMI remains unchanged despite significant progress of endovascular techniques. A multidisciplinary and multimodal management approach of AMI in the ICU has been recently proposed to improve patient's survival and prevent the intestinal failure. Post-recanalisation nutrition therapy may significantly improve the overall survival of AMI patients is quite underemphasised in the ICU. Definitive data comparing EN with TPN for this patient population are very lacking. This study provides the clinical data to suggest that early EN starting after ICU admission represents a favourable alternative to TPN for recanalised AMI patients. The nutrition therapy protocol in the ICU for this special cohort needs to be updated with more high-level evidence in the future., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objective: Pin1 is prevalently overexpressed in human cancers and implicated to regulate cell growth and apoptosis. Thus far, however, no role for Pin1 has been described in modulating vascular smooth muscle cell (VSMC) senescence., Methods: Immunohistochemistry and Western blotting were used to assess Pin1 protein level in human normal and atherosclerotic tissues. β-galactosidase staining, cumulative population doubling level, telomerase activity, and relative telomere length measurement were used to confirm VSMC senescence. The expressions of Pin1 and other genes involved in this research were analyzed by quantitative reverse-transcription polymerase chain reaction and Western blotting in VSMCs. Apolipoprotein E gene-deleted mice (ApoE -/- ) fed a high-fat diet were treated with juglone or 10% ethanol, respectively, for 3 weeks. The extent of atherosclerosis was evaluated by Oil Red O, Masson trichrome staining, and immunohistology., Results: Pin1 protein level decreased in human atherosclerotic tissues and VSMCs, synchronously with increased VSMC senescence. Adenoviral-mediated Pin1 overexpression rescued cellular senescence in atherosclerotic VSMCs, with concurrent down-regulation of P53, p21, growth arrest and DNA-damage-inducible protein 45-alpha (Gadd45a), phosphorylated retinoblastoma (p-pRb), p65 and upregulation of cyclin subfamilies (cyclin B, D, and E), and cyclin-dependent kinase subfamilies (2, 4, and 6), whereas Pin1 knockdown resulted in the converse effects, indicating that VSMC senescence mediated by Pin1 is an integrated response to diverse signals. In vivo data from ApoE -/- mice showed that treatment of juglone led to accelerated atherosclerosis development., Conclusions: Altogether this work supports a role for Pin1 as a vital modulator of VSMC senescence, thereby providing a novel target for regulation and control of atherosclerosis., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Nauclea officinalis has long been used in China for the treatment of cold, fever, swelling of throat, pink eyes, and so on; however, the in vivo integrated metabolism of its multiple bioactive components remains unknown. In this paper, an ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) method was established to identify chemical constituents in N. officinalis and metabolites in rat biological fluids after oral administration of N. officinalis. First, 40 chemical constituents in N. officinalis were detected within 19min by UPLC-QTOF/MS. Among them, 18 alkaloids and 7 phenolic acids and iridoids were identified or tentatively characterized. Secondly, 22 metabolites were identified after oral administration of N. officinalis extract, including 3, 9, 6 and 4 metabolites in the plasma, feces, urine and bile samples, respectively. Finally, the metabolic pathway was proposed, which were the hydroxylation, the hydroxylation of deglycosyation product of parent compound, the hydroxylation and dehydrogenation product of parent compound, and acetylation. Among these, hydroxylation was considered as the main metabolic processes. This work suggests that the integrative metabolism approach makes a useful template for drug metabolism research of traditional Chinese medicine (TCM)., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Danmu injection and Danmu tablet are two widely used traditional Chinese medicine made of Nauclea officinalis (commonly known as Danmu), in which the alkaloids are the major active substances. In this paper, an ultra fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) method was developed for simultaneous determination and the pharmacokinetic characteristics study of six main active alkaloids (naucleamide A-10-O-β-d-glucopyranosid, naucleamide G, pumiloside, 3-epi-pumiloside, strictosamide and vincosamide) of the two above-mentioned Danmu preparations in rat plasma. In the course of the experiment, following sample preparation by protein precipitation with methanol-ethyl acetate (2:1, v/v), the nitrogen-dried extraction was reconstituted in methanol and assayed on a C18 column using a gradient elution program with mobile phase consisting of acetonitrile and water containing 0.1% formic acid. The MS detection was performed in positive ionization mode with selected ion transitions. The established method was fully validated and proved to be sensitive and specific with lower limits of quantification (LLOQs) all less than 0.32ng/mL in rat plasma and matrix effects ranged from 88.87 to 108.27%. Good linearities of six alkaloids were obtained in respective concentration ranges (r(2)>0.995). The average extract recoveries for each compound at three quality control concentration levels were no less than 79.70%, and the precision and accuracy were within the acceptable limits. The validated method was successfully applied to the pharmacokinetic study of six alkaloid components of Danmu injection and tablet in rat plasma. The obtained results may be helpful to reveal the action mechanism and guide the clinical application of Danmu preparations., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: The objective of this study was to explore the effect of conservative surgery plus postoperative axillary radiotherapy without axillary lymph node dissection vs. modified radical mastectomy in patients with stage I breast cancer., Patients and Methods: In this study, 186 patients with stage I breast cancer were enrolled. Among them, 98 patients underwent breast-conserving surgery without axillary node dissection. From the first day after surgery, each of them received 6 cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy, and thereafter radical radiotherapy for 5 to 6 weeks. Eighty-eight patients received modified radical mastectomy with postoperative chemotherapy and radiotherapy. The clinical data of these 186 patients were analyzed., Results: There was no significant difference (P > .05) in local recurrence and survival rates between the conservative plus axillary radiotherapy group and the modified radical mastectomy group, although a significantly greater incidence of upper limb dysfunction and edema were observed in the modified mastectomy group (P < .05)., Conclusion: The efficacy of conservative surgery plus axillary radiotherapy alone is superior to that of axillary node dissection for stage I breast cancer patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Recently, chiral ionic liquids (ILs) have drawn more and more attention in chiral separation by capillary electrophoresis (CE). In this paper, two chiral ILs based on amino acid derivatives, L-alanine and L-valine tert butyl ester bis (trifluoromethane) sulfonimide, were applied for the first time in CE to evaluate their potential synergistic effects with classical chiral selectors (β-cyclodextrin derivatives) for enantiomeric separation. As observed, improved separation of tested drug enantiomers was obtained with the presence of chiral ILs compared to the conventional β-cyclodextrin derivatives separation system. Parameters such as type and proportion of organic modifier, type and concentration of chiral ILs, concentration of chiral selector, buffer pH and applied voltage were systematically investigated with Me-β-CD/chiral ILs as model system to optimize the novel synergistic system, and the best results were obtained when 15 mM chiral ILs were introduced into the 30 mM sodium citrate/citric acid (20% organic modifier included) buffer solution containing 20 mM Me-β-CD at pH 5.0 with a 20 kV applied voltage for naproxen, pranoprofen and warfarin., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Several chiral reagents including cyclodextrins (CDs) and derivatives, crown ethers, proteins, chiral surfactants and polymers have been involved in dual selector systems for enantioseparation of a series of chiral compounds by capillary electrophoresis (CE). In comparison to the chiral reagents above-mentioned, there is no report concerning the use of polysaccharides in dual chiral CE system. In this paper we first investigate the enantioselectivity of polysaccharide-based dual selector systems towards some chiral drugs. During our recent work, glycogen belonging to the class of branched polysaccharides has been used as a novel chiral selector in CE. In this study, three glycogen-based dual chiral CE systems have been established for enantiomeric separations of several racemic basic drugs consisting of duloxetine, cetirizine, citalopram, sulconazole, laudanosine, amlodipine, propranolol, atenolol and nefopam. These three dual systems combined glycogen (neutral polysaccharide) with chondroitin sulfate A (CSA, ionic polysaccharide), β-CD and HP-β-CD, respectively. It was found that the dual system of glycogen/CSA exhibited good enantioselective properties toward the tested drugs. More importantly, compared to the single selector systems, synergistic effect was observed when glycogen was used with CSA for most of the analytes. This indicated the enhancement of enantioseparation observed for these analytes in glycogen/CSA system might be due to some favorable interaction effects between glycogen and CSA. Moreover, in order to evaluate the stereoselectivity of glycogen/CSA, the influences of buffer pH and selector concentration on enantioseparation of the studied drugs were also investigated., (Copyright © 2010 Elsevier B.V. All rights reserved.)