Publications by authors named "Xicheng Liu"

49 Publications

Metastable interface biomimetic synthesis of a smart nanosystem for enhanced starvation/gas therapy.

J Colloid Interface Sci 2021 Oct 20;599:149-157. Epub 2021 Apr 20.

The Key Laboratory of Life-Organic Analysis, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, PR China. Electronic address:

Glucose oxidase (GOx)-mediated starvation therapy holds great promise in cancer treatment. However, the worse hypoxia conditions result into low therapeutic efficiency, and undegradability of carriers poses potential threats to living bodies. To address this, herein a bioinspired MnO nanosystem with controllable surface was developed for highly efficient starvation/gas synergistic enhanced therapy. Biomimetic design and further surface modification unprecedentedly endowed the nanosystem with ultrahigh loading capacity for GOx and l-Arginine (l-Arg) and special selectivity toward cancer cells. Especially, the dissipative O during starvation therapy was well replenished by a positive cycle formed by the nanosystem, which continuously reproduced O and accelerated glucose consumption. The abundant HO was further used to oxidize l-Arg into nitric oxide to realize gas therapy. In vitro and in vivo testing confirmed that this new treatment effectively blocked the nutrition and energy sources of cells to obtain excellent therapeutic effect. We reported the first experimental item of this nanosystem for inhibiting cancer cell migration. Considering the novel design concept with facile biomimetic methods, effective co-loading of endogenous substances, and good anti-tumor and anti-migration effects, this work provided new theoretical and experimental basis for starvation therapy and inspired people to design more delicate platform for cancer treatment.
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http://dx.doi.org/10.1016/j.jcis.2021.04.042DOI Listing
October 2021

Acid-sensing Ion Channel 3 Overexpression in Incisions Regulated by Nerve Growth Factor Participates in Postoperative Nociception in Rats.

Anesthesiology 2020 12;133(6):1244-1259

Background: Acid-sensing ion channel 3 (ASIC3) upregulation has been reported in dorsal root ganglion neurons after incision and contributes to postoperative nociception. This study hypothesized that upregulation of ASIC3 in incised tissues is induced by nerve growth factor through the phosphoinositide 3-kinase/protein kinase B signaling pathway.

Methods: A plantar incision model was established in adult male and female Sprague-Dawley rats. ASIC3 was inhibited by APETx2 treatment, small interfering RNA treatment, or ASIC3 knockout. Sciatic nerve ligation was performed to analyze ASIC3 transport. A nerve growth factor antibody and a phosphoinositide 3-kinase inhibitor were used to investigate the mechanism by which nerve growth factor regulates ASIC3 expression.

Results: Acid-sensing ion channel 3 inhibition decreased incisional guarding and mechanical nociception. ASIC3 protein levels were increased in skin and muscle 4 h after incision (mean ± SD: 5.4 ± 3.2-fold in skin, n = 6, P = 0.001; 4.3 ± 2.2-fold in muscle, n = 6, P = 0.001). Sciatic nerve ligation revealed bidirectional ASIC3 transport. Nerve growth factor antibody treatment inhibited the expression of ASIC3 (mean ± SD: antibody 2.3 ± 0.8-fold vs. vehicle 4.9 ± 2.4-fold, n = 6, P = 0.036) and phosphorylated protein kinase B (mean ± SD: antibody 0.8 ± 0.3-fold vs. vehicle 1.8 ± 0.8-fold, n = 6, P = 0.010) in incised tissues. Intraplantar injection of nerve growth factor increased the expression of ASIC3 and phosphorylated protein kinase B. ASIC3 expression and incisional pain-related behaviors were inhibited by pretreatment with the phosphoinositide 3-kinase inhibitor LY294002.

Conclusions: Acid-sensing ion channel 3 overexpression in incisions contributes to postoperative guarding and mechanical nociception. Bidirectional transport of ASIC3 between incised tissues and dorsal root ganglion neurons occurs through the sciatic nerve. Nerve growth factor regulates ASIC3 expression after plantar incision through the phosphoinositide 3-kinase/protein kinase B signaling pathway.

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http://dx.doi.org/10.1097/ALN.0000000000003576DOI Listing
December 2020

Preparation and Bioactivity of Iridium(III) Phenanthroline Complexes with Halide Ions and Pyridine Leaving Groups.

Chembiochem 2021 Feb 4;22(3):557-564. Epub 2020 Nov 4.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Phar maceutical Intermediates and, Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Jining Shi, Qufu, 273165, P. R. China.

A series of half-sandwich structural iridium(III) phenanthroline (Phen) complexes with halide ions (Cl , Br , I ) and pyridine leaving groups ([(η -Cp )Ir(Phen)Z](PF ) , Cp : electron-rich cyclopentadienyl group, Z: leaving group) have been prepared. Target complexes, especially the Cp (biphenyl-substituted cyclopentadienyl)-based one, showed favourable anticancer activity against human lung cancer (A549) cells; the best one (Ir8) was almost five times that of cisplatin under the same conditions. Compared with complexes involving halide ion leaving groups, the pyridine-based one did not display hydrolysis but effectively caused lysosomal damage, leading to accumulation in the cytosol, inducing an increase in the level of intracellular reactive oxygen species and apoptosis; this indicated an anticancer mechanism of oxidation. Additionally, these complexes could bind to serum albumin through a static quenching mechanism. The data highlight the potential value of half-sandwich iridium(III) phenanthroline complexes as anticancer drugs.
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http://dx.doi.org/10.1002/cbic.202000511DOI Listing
February 2021

Preparation and the anticancer mechanism of configuration-controlled Fe(II)-Ir(III) heteronuclear metal complexes.

Dalton Trans 2020 Sep;49(36):12599-12609

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China.

A series of configuration-controlled Fe(ii)-Ir(iii) heteronuclear metal complexes, including ferrocene and half-sandwich like iridium(iii) complex units, have been designed and prepared. These complexes show better anticancer activity than cisplatin under the same conditions, especially cis-configurational ones. Laser confocal microscopy analysis confirms that the complexes follow a non-energy-dependent cellular uptake mechanism, accumulate in lysosomes (pearson co-localization coefficient: ∼0.7), lead to lysosomal damage, and eventually induce apoptosis. These complexes can reduce the mitochondrial membrane potential, disturb the cell circle, catalyze the oxidation of nicotinamide-adenine dinucleotide (NADH) and increase the levels of intracellular reactive oxygen species (ROS), following an anticancer mechanism of oxidation. In addition, the complexes could bind to serum protein, and transport through it. Above all, the Fe(ii)-Ir(iii) heteronuclear metal complexes hold promise as potential anticancer agents for further study.
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http://dx.doi.org/10.1039/d0dt02408bDOI Listing
September 2020

Triphenylamine/carbazole-modified ruthenium(ii) Schiff base compounds: synthesis, biological activity and organelle targeting.

Dalton Trans 2020 Jul 18;49(25):8774-8784. Epub 2020 Jun 18.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China.

Four triphenylamine/carbazole-modified half-sandwich ruthenium(ii) compounds [(η-p-cymene)Ru(N/O^N)Cl] with Schiff base chelating ligands (N/O^N) are synthesized and characterized. The introduction of Schiff base units effectively increases the antitumor activity of these compounds (IC: 1.70 ± 0.56-17.75 ± 3.10 μM), which, meanwhile, can inhibit the metastasis of tumor cells effectively. These compounds follow an energy-dependent cellular uptake mechanism, mainly accumulate in lysosomes to destroy their integrity, and then eventually promote apoptosis. In addition, these compounds can induce an increase of intracellular reactive oxygen species (ROS) levels and provide an antitumor mechanism of oxidation, which is confirmed by the decrease of mitochondrial membrane potential (MMP) and the catalytic oxidation of the coenzyme nicotinamide-adenine dinucleotide (NADH). All these indicate that these ruthenium(ii) compounds are expected to be dual-functional antitumor agents: anti-metastasis and lysosomal damage.
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http://dx.doi.org/10.1039/d0dt01547dDOI Listing
July 2020

Fluorescent iridium(iii) coumarin-salicylaldehyde Schiff base compounds as lysosome-targeted antitumor agents.

Dalton Trans 2020 May;49(18):5988-5998

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China.

Six fluorescent half-sandwich iridium(iii) coumarin-salicylaldehyde Schiff base (O^N) compounds ([(η5-Cp*)Ir(O^N)Cl]) were prepared and characterized. The introduction of a coumarin unit increased the antitumor activity (IC50: 9.9 ± 0.1 μM-40.7 ± 12.9 μM) of these compounds, the best of which was nearly two times that of clinical cisplatin. The results of laser confocal microscopy demonstrated that these compounds possessed an energy-dependent cellular uptake mechanism, accumulated in the lysosomes (Pearson co-localization coefficient: ∼0.7), damaged the integrity of the lysosomes, and induced apoptosis. The compounds could also decrease the mitochondrial membrane potential, catalyze the oxidation of the coenzyme (nicotinamide-adenine dinucleotide) and improve the levels of the intracellular reactive oxygen species, following an antitumor mechanism of oxidation. Additionally, these compounds could block the metastasis of tumor cells. Above all, these iridium(iii) compounds show potential as antitumor agents with dual functions: lysosomal damage and anti-metastasis.
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http://dx.doi.org/10.1039/d0dt00627kDOI Listing
May 2020

Imidazole and Benzimidazole Modified Half-Sandwich Iridium -Heterocyclic Carbene Complexes: Synthesis, Anticancer Application, and Organelle Targeting.

Front Chem 2020 17;8:182. Epub 2020 Mar 17.

The Key Laboratory of Life-Organic Analysis, Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Institute of Anticancer Agents Development and Theranostic Application, Qufu Normal University, Qufu, China.

Herein, we report the synthesis, characterization and anticancer activity of a series of half-sandwich iridium imidazole and benzimidazole -heterocyclic carbene (NHC) anticancer complexes, and the general formula of which can be expressed as [(η-Cp)Ir(CN)Cl]Cl (Cp: pentamethylcyclopentadienyl (Cp) or biphenyl derivatives (Cp); CN: imidazole and benzimidazole NHC chelating ligands). Compared with -platin, these complexes showed interesting antitumor activity against A549 cells. Complexes could bind to bovine serum albumin (BSA) by means of static quenching mode, catalyze the oxidation of nicotinamide adenine dinucleotide (NADH) and increase the levels of reactive oxygen species (ROS). Meanwhile, these complexes could arrest the cell cycles of A549 cells and influence the mitochondrial membrane potential significantly. Due to the inherent luminescence property, laser confocal test show that complexes could enter cells followed an energy-dependent mechanism and effectively accumulate in lysosome (the value of Pearson's co-localization coefficient is 0.70 after 1 h), further destroy lysosome integrity and induce apoptosis.
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http://dx.doi.org/10.3389/fchem.2020.00182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090125PMC
March 2020

Lysosome-targeted chemotherapeutics: Anticancer mechanism of N-heterocyclic carbene iridium(III) complex.

J Inorg Biochem 2020 06 19;207:111063. Epub 2020 Mar 19.

Institute of Anticancer Agents Development and Theranostic Application, Department of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, Shandong, China. Electronic address:

N-heterocyclic carbenes-modified half-sandwich iridium(III) complex [(η-CMeCHCH)Ir(C^C)Cl]PF (C1) (where C^C is a N-heterocyclic carbene ligand) can effectively prevent the proliferation of human cervical cancer cells. Here, this study aims to investigate the in-deep anticancer effects of this complex on non-small cell lung cancer cells and explore the underlying molecular mechanism. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay showed that iridium(III) complex had potent cytotoxicity studies towards non-small cell lung cancer cells (A549), human lung squamous cells (L78), human cervical cancer cells (Hela) and human bronchial epithelial cells (BEAS-2B). Colocalization and cellular uptake studies were analyzed by confocal microscopy. Notably, C1 targeted lysosomes and entered the cancer cells partially through an energy-dependent pathway, inducing the release of cathepsins and other proteins. These proteins regulated lysosomal-mitochondrial dysfunction, thus leading to the release of cytochrome c (cyt c), which amplified apoptotic signals by activating many downstream pathways such as caspase pathways to promote cell apoptosis. The results showed that the inhibitory mechanism of this organometallic iridium(III) complex may involve caspase-associated apoptosis initiated by the lysosomal-mitochondrial pathway.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111063DOI Listing
June 2020

Dual functions of iridium(III) 2-phenylpyridine complexes: Metastasis inhibition and lysosomal damage.

J Inorg Biochem 2020 04 8;205:110983. Epub 2020 Jan 8.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China. Electronic address:

Six N-phenylcarbazole/triphenylamine-appended half-sandwich iridium(III) 2-phenylpyridine complexes ([(η-Cp*)Ir(C^N)Cl]) were prepared and characterized. Compared with cisplatin, these complexes exhibited potential antitumor activity against A549 and HeLa tumor cells, with IC values (half-maximum inhibitory concentration) that changed from 2.8 ± 0.8 μM to 39.5 ± 2.7 μM, and could block the migration of tumor cells. These complexes also effectively bound to protein (binding constant: ~10 M) and were transported through serum proteins, catalyzed the oxidation of coenzyme nicotinamide-adenine dinucleotide. Additionally, laser confocal microscopy and flow cytometry confirmed that these complexes possessed a non-energy-dependent cellular uptake mechanism, effectively accumulated in lysosomes (Pearson colocalization coefficient: ~0.74), damaged the integrity of acidic lysosomes, led to a change in the mitochondrial membrane potential, disrupted the cell cycle (G/G phase), and eventually induced apoptosis. Above all, these complexes are potential antitumor agents with dual functions: metastasis inhibition and lysosomal damage.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110983DOI Listing
April 2020

Fluorescent COFs with a highly conjugated structure for visual drug loading and responsive release.

Chem Commun (Camb) 2020 Jan 11;56(4):519-522. Epub 2019 Dec 11.

The Key Laboratory of Life-Organic Analysis, Department of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China. and Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810001, P. R. China.

For the first time, a facile solvothermal method to synthesize covalent organic frameworks (COFs) with a nanosized structure and bright fluorescence was reported to monitor drug loading with the naked eye and realize responsive release.
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http://dx.doi.org/10.1039/c9cc08217dDOI Listing
January 2020

Ferrocene-Appended Iridium(III) Complexes: Configuration Regulation, Anticancer Application, and Mechanism Research.

Inorg Chem 2019 Oct 27;58(20):14175-14184. Epub 2019 Sep 27.

Institute of Anticancer Agents Development and Theranostic Application, Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering , Qufu Normal University , Qufu 273165 , China.

A series of ferrocene-appended half-sandwiched iridium(III) phenylpyridine complexes have been designed and synthesized. These complexes show better anticancer activity than cisplatin widely used in clinic under the same conditions. Meanwhile, complexes could effectively inhibit cell migration and colony formation. Complexes could interact with protein and transport through serum protein, effectively catalyzing the oxidation of nicotinamide-adenine dinucleotid and inducing the accumulation of reactive oxygen species (ROS, O), which confirmed the anticancer mechanism of oxidation. Furthermore, laser scanning confocal detection indicates that these complexes can enter cells followed by a non-energy-dependent cellular uptake mechanism, effectively accumulating in the lysosome (Pearson's colocalization coefficient: ∼0.90), leading to lysosome damage, and reducing the mitochondrial membrane potential (MMP). Taken together, ferrocene-appended iridium(III) complexes possess the prospect of becoming a new multifunctional therapeutic platform, including lysosome-targeted imaging and anticancer drugs.
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http://dx.doi.org/10.1021/acs.inorgchem.9b02227DOI Listing
October 2019

Triphenylamine-appended cyclometallated iridium(III) complexes: Preparation, photophysical properties and application in biology/luminescence imaging.

J Inorg Biochem 2019 10 27;199:110757. Epub 2019 Jun 27.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China. Electronic address:

Four triphenylamine (TPA)-appended cyclometallated iridium(III) complexes were designed and synthesized. Photophysical properties of these complexes were studied, and density functional theory (DFT) was utilized to analyze the influence of the ancillary ligands (TPA-modified bipyridine) to these complexes. The introduction of TPA units could effectively adjust the lipid solubility of complexes (logP), and endowed complexes with potential bioactivity (anticancer, antibacterial and bactericidal activity), especially in the field of anticancer (the best value of IC is 4.34±0.01μM). Interestingly, complexe 4 show some selectivity for cancer cells versus normal cells. Meanwhile, complexes could effectively prevent the metastasis of cancer cells. Complexes can be transported by serum albumin and followed by the static quenching mechanism (K: 10Ms), disturb cell cycle at G/G phase, and induce apoptosis. The favorable fluorescence property confirmed these complexes followed by an energy-dependent cellular uptake mechanism, effectively accumulated in lysosomes (PCC: >0.95) and induced lysosomal damage, and eventually leaded to cell death. Our study demonstrates that these complexes are potential anticancer agents with dual functions, including metastasis inhibition and lysosomal damage.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110757DOI Listing
October 2019

New Organometallic Tetraphenylethylene⋅Iridium(III) Complexes with Antineoplastic Activity.

Chembiochem 2019 11 8;20(21):2767-2776. Epub 2019 Oct 8.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and, Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, 273165, China.

Iridium(III) complexes have attracted more and more attention in the past few years because of their potential antineoplastic activity. In this study, four Ir complexes of the types [(η -Cp )Ir(N^N)Cl]PF (complexes 1 and 2) and [Ir(Phpy) (N^N)]PF (complexes 3 and 4) have been synthesized and characterized. They exhibit potential antineoplastic activity towards A549 cells, especially in the case of complex 1 [IC =(3.56±0.5) μm], which was nearly six times as effective as cisplatin [(21.31±1.7) μm]. Additionally, these complexes show some selectivity towards cancer cells over normal cells. They could be transported by serum albumin (binding constants were changed from 0.37×10 to 81.71×10  m ). Ir complexes 1 and 2 could catalyze the transformation of nicotinamide adenine dinucleotide reduced form (NADH) into NAD (turnover numbers 43.2, 11.9] and induce the accumulation of reactive oxygen species, thus confirming their antineoplastic mechanism of oxidation, whereas the cyclometalated complexes 3 and 4 were able to target the lysosome [Pearson co-localization coefficient (PCC)=0.73], cause lysosomal damage, and induce apoptosis. Understanding the mechanism of action would help further structure-activity optimization on these Ir complexes as emerging cancer therapeutics.
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http://dx.doi.org/10.1002/cbic.201900268DOI Listing
November 2019

Serendipitous Synthesis of Five-Coordinated Half-Sandwich Aminoimine Iridium(III) and Ruthenium(II) Complexes and Their Application as Potent Anticancer Agents.

Inorg Chem 2019 May 15;58(9):5956-5965. Epub 2019 Apr 15.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering , Qufu Normal University , Qufu 273165 , China.

Stable five-coordinated (16-electron) half-sandwich iridium(III) and ruthenium(II) complexes are rarely reported, and their biological evaluations have not been considered to date. Herein, in an experiment designed to synthesize six-coordinated half-sandwich iridium(III) and ruthenium(II) complexes containing N,N-chelated α-keto-β-diimine ligands, we observed the serendipitous formation of half-sandwich aminoimine iridium(III) and ruthenium(II) complexes via solvent-involved rearrangement reaction. These unsaturated 16-electron complexes had sufficient stability in DMSO-water solution. Moreover, no reaction with two-electron donors (CO and PPh) and nucleobase (9-MeA and 9-EtG) was observed. Most of the complexes show good anticancer activities toward A549, HeLa, and HepG2 cancer cells, which are higher than the clinical drug cisplatin. The investigation of mechanism by flow cytometry showed that the complexes exert their anticancer efficacy by inducing apoptosis or necrosis, and increasing the intracellular ROS level. In addition, fluorescence property of these complexes makes it possible to investigate the microscopic mechanism by confocal microscopy. Notably, the complexes Ir3 and Ru1 enter A549 cancer cells through an energy-independent pathway, and they are mainly located in mitochondria and lysosomes.
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http://dx.doi.org/10.1021/acs.inorgchem.9b00282DOI Listing
May 2019

Effective treatment of post-intubation subglottic stenosis in children with holmium laser therapy and cryotherapy via flexible bronchoscopy.

Pediatr Investig 2019 Mar 22;3(1):9-16. Epub 2019 Mar 22.

China National Clinical Research Center for Respiratory Diseases Beijing China.

Importance: Post-intubation subglottic stenosis (SGS) in children can be life threatening. Definitive treatment varies and lacks a universally accepted approach.

Objective: We performed a prospective study to assess the safety and feasibility of holmium laser combined with cryotherapy delivered via flexible bronchoscopy for the treatment of post-intubation SGS in children.

Methods: This study involved all patients with post-intubation SGS seen at the Interventional Pulmonology Department of Beijing Children's Hospital between July 2014 and December 2016. Holmium laser treatment and cryotherapy was then performed under flexible bronchoscopy, whose parents refused to accept the alternative standard treatment of tracheotomy and balloon dilation under direct laryngoscopy.

Results: Sixteen patients with post-intubation SGS were included in this study. Ages ranged from 2 months to 12.25 years old. According to the Cotton-Myer grading system, three cases were Grade II, 12 cases were Grade III, and one case was Grade IV. According to the McCaffrey system, eight cases were Stage 1, two cases were Stage 2, and six cases were Stage 3. The average number of procedures was 4.88. Fifteen of the 16 patients achieved clinical cure. One patient achieved clinical improvement. The average treatment course duration was 55.31 days. No severe complications were seen. Post-treatment clinical symptoms, endoscopic findings and quality of life showed marked improvement.

Interpretation: Our study supports the conclusion that holmium laser treatment combined with cryotherapy via flexible bronchoscopy appears to be a safe and feasible treatment for post-intubation SGS in children.
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http://dx.doi.org/10.1002/ped4.12113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331425PMC
March 2019

Formal [4 + 2] Annulation of Oxindole-Embedded ortho-Quinone Methides with 1,3-Dicarbonyls: Synthesis of Spiro[Chromen-4,3'-Oxindole] Scaffolds.

J Org Chem 2019 04 15;84(7):3990-3999. Epub 2019 Mar 15.

College of Chemistry and Pharmaceutical Sciences , Qingdao Agricultural University , Qingdao 266109 , China.

The oxindole-embedded ortho-quinone methides were employed as reactive intermediates in formal [4 + 2] annulation with 1,3-dicarbonyls, providing an efficient access to spiro[chromen-4,3'-oxindole] scaffolds via a cascade conjugate addition/ketalization/dehydration process. This protocol featured metal-free conditions, wide substrate scope, and excellent yields.
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http://dx.doi.org/10.1021/acs.joc.8b03260DOI Listing
April 2019

Application of second-generation Shikani optical stylet in critically ill patients undergoing cerebral aneurysm embolization.

J Int Med Res 2019 Apr 6;47(4):1565-1572. Epub 2019 Feb 6.

Department of Anesthesiology, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China.

Objective: This study was performed to compare the clinical value of the second-generation Shikani optical stylet with that of the Macintosh laryngoscope for tracheal intubation of patients undergoing cerebral aneurysm embolization.

Methods: Thirty-six patients who underwent cerebral aneurysm embolization were included. The intubation time, intubation success rate, blood oxygen saturation, heart rate, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured. Adverse reactions during tracheal intubation and the local tissue injury rate were recorded. Comparisons between the groups were performed with one-way analysis of variance.

Results: The heart rate, SBP, and DBP upon tracheal intubation and at 1 and 3 minutes were significantly higher in the Macintosh laryngoscope group than in the Shikani optical stylet group. The time to completion of tracheal intubation was significantly shorter and the tissue injury rate was significantly lower in the Shikani optimal stylet group than in the Macintosh laryngoscope group.

Conclusions: The second-generation Shikani optical stylet is a simple, safe, and reliable tool for tracheal intubation in critically ill patients undergoing cerebral aneurysm embolization.
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http://dx.doi.org/10.1177/0300060518822243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460621PMC
April 2019

Ovaries absent links dLsd1 to HP1a for local H3K4 demethylation required for heterochromatic gene silencing.

Elife 2019 01 16;8. Epub 2019 Jan 16.

National Institute of Biological Sciences, Beijing, China.

Heterochromatin Protein 1 (HP1) is a conserved chromosomal protein in eukaryotic cells that has a major role in directing heterochromatin formation, a process that requires co-transcriptional gene silencing mediated by small RNAs and their associated argonaute proteins. Heterochromatin formation requires erasing the active epigenetic mark, such as H3K4me2, but the molecular link between HP1 and H3K4 demethylation remains unclear. In a fertility screen in female , we identified (), which functions in the stem cell niche, downstream of Piwi, to support germline stem cell differentiation. Moreover, acts as a suppressor of position effect variegation, and is required for silencing telomeric transposons in the germline. Biochemically, Ova acts to link the H3K4 demethylase dLsd1 to HP1a for local histone modifications. Therefore, our study provides a molecular connection between HP1a and local H3K4 demethylation during HP1a-mediated gene silencing that is required for ovary development, transposon silencing, and heterochromatin formation.

Editorial Note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
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http://dx.doi.org/10.7554/eLife.40806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335052PMC
January 2019

A comprehensive study of immunology repertoires in both preoperative stage and postoperative stage in patients with colorectal cancer.

Mol Genet Genomic Med 2019 03 9;7(3):e504. Epub 2019 Jan 9.

Department of Anesthesiology, Shenzhen People's Hospital, 2nd Clinical Medical College of Jinan University, Shenzhen, Guangdong, China.

Background: Colorectal cancer (CRC) is the 3rd most common cancer type in the world. The correlation between immune repertoire and prognosis of CRC has been well studied in the last decades. The diversity and stability of the immune cells can be measured by hypervariable complementarity-determining region 3 (CDR3) segments of the T-cell receptor (TCR).

Methods: In this study, we collected five healthy controls and 19 CRC patients' peripheral blood mononuclear cells (PBMCs) in three stages, namely 1 day preoperative, 3 days' postoperative, and 7 days' postoperative, respectively. Simultaneously, we have also done the comparative analysis of these two different anesthesia methods, namely TIVA and CEGA. Sequencing of the TCR segments has been performed by multiplex PCR and high-throughput next-generation sequencing. We also analyzed the distribution of CDR3 length, highly expansion clones (HECs), TRBV, and TRBJ gene usage.

Results: Our result showed a significant difference between TCR CDR3 length distribution and HEC distribution between CRC patients and healthy controls. We also found that TRBV11-2, TRBV12-1, TRBV16, TRBV3-2, TRBV4-2, TRBV4-3, TRBV5-4, TRBV6-8, TRBV7-8, TRBV7-9 and RBV11-2, TRBV12-1, TRBV16, TRBV3-2, TRBV4-2, TRBV4-3, TRBV5-4, TRBV6-8, TRBV7-8, and TRBV7-9 usages are different between CRC patients and healthy controls.

Conclusion: In conclusion, CRC patients were presented with different immune repertoire in comparison with healthy controls. In this study, significant difference in TRBV and TRBJ gene usage in between case and control group could provide some potential biomarker for the diagnosis and the treatment of the patients with CRC.
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http://dx.doi.org/10.1002/mgg3.504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418368PMC
March 2019

Half-sandwich iridium(III) complexes with α-picolinic acid frameworks and antitumor applications.

J Inorg Biochem 2019 03 24;192:52-61. Epub 2018 Dec 24.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis, Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China. Electronic address:

Eight half-sandwich iridium (Ir) complexes of the general formula [(η-Cp)Ir(O^N)Cl] (Cp is tetramethyl(biphenyl)cyclopentadienyl, and the O^N is α-picolinic acid chelating ligand and its derivatives) were synthesized and characterized. Compared with cis-platin widely used in clinic, target Ir complexes showed at most five times more potent antitumor activity against A549 cells by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Ir complexes could be transported by serum albumin, bind with DNA, catalyze the oxidation of nicotinamide-adenine dinucleotid (NADH) and induce the production of reactive oxygen species, which confirmed the antitumor mechanism of oxidation. Ir complexes could enter A549 cells followed by an energy-dependent cellular uptake mechanism, meanwhile, target the mitochondria and lysosomes with the Pearson's colocalization coefficient of 0.33 and 0.74, respectively, lead to the lysosomal destruction and the change of mitochondrial membrane potential (ΔΨm), and eventually induce apoptosis.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.12.012DOI Listing
March 2019

Ferrocenyl-Triphenyltin Complexes as Lysosome-Targeted Imaging and Anticancer Agents.

Inorg Chem 2019 Jan 28;58(2):1710-1718. Epub 2018 Dec 28.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering , Qufu Normal University , Qufu 273165 , China.

In this paper, two ferrocenyl-triphenyltin complexes were synthesized and characterized. Complex 2 is constructed as new multifunctional therapeutic platform for lysosome-targeted imaging and displayed much higher cytotoxicity than its analogue 1 by the introduction of a methyl group instead of a hydrogen atom in acylhydrazone. The cyclic voltammograms and reaction with GSH (glutathione) further confirmed that complex 1 has a reversible redox peak and can react with GSH, which indicate that complex 1 might lose its anticancer effect by undergoing reaction with GSH once it enters the cancer cell. Complex 2 could effectively catalyze the oxidation of NADH (the reduced form of nicotinamide adenine dinucleotide) to NAD and induce the production of reactive oxygen species (ROS), lead to caspase-dependent apoptosis through damaged mitochondria, simultaneously, accounting for the mitochondrial vacuolization and karyorrhexis. The caspase-3 activation and cytoplasmic vacuolation karyorrhexis induced by complex 2 revealed that the A549 cell lines might undergo cell death primarily mediated by apoptosis and oncosis; however, 1 cannot reproduce this effect. Taken together, these results indicated that complex 2 has more potential for evolution as a new bioimaging and anticancer agent.
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http://dx.doi.org/10.1021/acs.inorgchem.8b03305DOI Listing
January 2019

Triphenyltin(IV) acylhydrazone compounds: Synthesis, structure and bioactivity.

J Inorg Biochem 2019 02 24;191:194-202. Epub 2018 Nov 24.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China. Electronic address:

Four new triphenyltin(IV) acylhydrazone compounds of the type PhSnCHCHCONHN=R (where Ph = phenyl; R = isopropyl, isobutyl, cyclopentyl and cyclooctyl) were synthesized and characterized by elemental analysis, infrared spectrum (IR), nuclear magnetic resonance spectrum (NMR) and mass spectrum (MS). The crystal structures were determined and showed that tin atoms were four-coordinated and adopted a pseudo-tetrahedron configuration. Tin(IV) compounds show excellent bovine serum albumin (BSA) binding properties, and can oxidize nicotinamide-adenine dinucleotid (NADH) to generate reactive oxygen species (ROS), which inducing apoptosis effectively. Bioassay results indicated that tin(IV) compounds have stronger cytotoxic activity against A549 human lung cancer cells compared with cis-platin used clinically, and showing some selectivity.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.11.011DOI Listing
February 2019

Hydride transfer initiated ring expansion of pyrrolidines toward highly functionalized tetrahydro-1-benzazepines.

Chem Commun (Camb) 2018 Dec;54(98):13833-13836

Shandong Province Key Laboratory of Applied Mycology, College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, China.

A novel hydride transfer initiated ring expansion of 4-pyrrolidinyl isatins to synthesize tetrahydro-1-benzazepines has been developed. This methodology represents an atom- and step-economical protocol to assemble seven-membered polycyclic amines from pyrrolidine derivatives in one step.
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http://dx.doi.org/10.1039/c8cc08238cDOI Listing
December 2018

Correction: Tumor driven by gain-of-function HER2 H878Y mutant is highly sensitive to HER2 inhibitor.

Oncotarget 2018 10 16;9(81):35283. Epub 2018 Oct 16.

National Institute of Biological Sciences, Beijing, China.

[This corrects the article DOI: 10.18632/oncotarget.5221.].
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http://dx.doi.org/10.18632/oncotarget.26252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219658PMC
October 2018

Half-sandwich Iridium(III) Benzimidazole-Appended Imidazolium-Based N-heterocyclic Carbene Complexes and Antitumor Application.

Chem Asian J 2018 Dec 31;13(23):3697-3705. Epub 2018 Oct 31.

Institute of Antitumor Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of, Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, 273165, China.

A series of half-sandwich iridium(III) benzimidazole-appended imidazolium-based N-heterocyclic carbene (NHC) antitumor complexes [(η -Cp )Ir(C^N)Cl]Cl, where Cp is pentamethylcyclopentadienyl (Cp*) or its biphenyl derivative (Cp ) and C^N is a NHC chelating ligand, were successfully synthesized and characterized. The Ir complexes showed potential antitumor activity against A549 cells, at most three times more potent than cis-platin under the same conditions. Complexes could bind to BSA by a static quenching mode, catalyzing the change of NADH to NAD and inducing the production of reactive oxygen species (maximum turnover number, 9.8), which play an important role in regulating cell apoptosis. Confocal microscopy showed that the complexes could specifically target lysosomes in cells with a Pearson's co-localization coefficient 0.76 and 0.72 after 1 h and 6 h, respectively, followed an energy-dependent cellular uptake mechanism and damaged the integrity of lysosomes. At the same time, complexes caused a marked loss of mitochondrial membrane potential.
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http://dx.doi.org/10.1002/asia.201801323DOI Listing
December 2018

Half-sandwich IridiumN-heterocyclic carbene antitumor complexes and biological applications.

J Inorg Biochem 2018 12 20;189:163-171. Epub 2018 Sep 20.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China. Electronic address:

Series of half-sandwich IrN-heterocyclic carbene (NHC) antitumor complexes [(η-Cp*)Ir(C^C)Cl] have been synthesized and characterized (Cp* is pentamethyl cyclopentadienyl, and C^C are four NHC chelating ligands containing phenyl rings at different positions). Ir complexes showed potent antitumor activity with IC values ranged from 3.9 to 11.8 μM against A549 cells by the MTT assay. Complexes can catalyze the conversion of the coenzyme NADH to NAD and induce the production of reactive oxygen species (ROS), and bonding to BSA by static quenching mode. Complexes can arrest the cell cycle in G or S phase and reduce the mitochondrial membrane potential. Confocal microscopy test show complexes could target the lysosome and mitochondria in cells with the Pearson's colocalization coefficient of 0.82 and 0.21 after 12 h, respectively, and followed by an energy-dependent cellular uptake mechanism.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.09.009DOI Listing
December 2018

Ectopic expression of E3 ubiquitin-protein ligase 2 in glioma and enhances resistance to apoptosis through activating nuclear factor κ-light-chain-enhancer of B cells.

Oncol Lett 2018 Oct 17;16(4):4391-4399. Epub 2018 Jul 17.

Department of Anesthesia, Shenzhen People's Hospital, Shenzhen, Guangdong 5188020, P.R. China.

Nuclear factor κ-light-chain-enhancer of B cells (NF-κB) is one of the most important tumorigenic factors. Although it has been established that NF-κB is overly activated in human glioma cells, the molecular mechanisms that lead to the signal transduction to NF-κB and thereby the induction of resistance to apoptosis remain poorly understood. The present study demonstrated that mRNA and protein levels of E3 ubiquitin-protein ligase 2 (MIB2) were markedly upregulated in glioma cell lines and clinical samples. Immunohistochemical analysis also revealed high levels of MIB2 expression in glioma specimens. Ectopic overexpression of MIB2 was established in glioma cell lines to investigate its fundamental roles in the response of human glioma to apoptotic inducers. The results indicated that ultraviolet irradiation-induced cell apoptosis was inhibited with MIB2 overexpression in glioma cells. Notably, knockdown of MIB2 using RNA interference was able to increase the sensitivity of glioma cells to the pro-apoptotic agents. The present study identified that MIB2 induces NF-κB activation and facilitates the resistance of glioma cell to apoptosis. It was proposed that MIB2 may not only be an important hallmark to glioma disease progression, but that it may also offer novel clinical strategies to overcome resistance to cancer therapies.
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http://dx.doi.org/10.3892/ol.2018.9153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126155PMC
October 2018

Organocatalytic Dearomative [4 + 2] Cycloadditions of Biomass-Derived 2,5-Dimethylfuran with ortho-Quinone Methides: Access to Multisubstituted Chromanes.

Org Lett 2018 10 13;20(19):6069-6073. Epub 2018 Sep 13.

College of Chemistry and Pharmaceutical Sciences , Qingdao Agricultural University , Qingdao 266109 , China.

The organocatalytic dearomative [4 + 2] cycloadditions of biomass-derived 2,5-dimethylfuran with ortho-quinone methides were developed, affording two diffferent types of multisubstituted chromanes in high yields and excellent diastereoselectivities. The controllable synthesis of these two types of multisubstituted chromanes could be achieved by succinctly varying the reaction conditions.
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http://dx.doi.org/10.1021/acs.orglett.8b02448DOI Listing
October 2018

Imine-N-Heterocyclic Carbenes as Versatile Ligands in Ruthenium(II) p-Cymene Anticancer Complexes: A Structure-Activity Relationship Study.

Chem Asian J 2018 Oct 5;13(19):2923-2933. Epub 2018 Sep 5.

Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and, Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, 273165, China.

A family of novel imine-N-heterocyclic carbene ruthenium(II) complexes of the general formula [(η -p-cymene)Ru(C^N)Cl]PF (where C^N is an imine-N-heterocyclic carbene chelating ligand with varying substituents) have been prepared and characterized. In this imine-N-heterocyclic carbene chelating ligand framework, there are three potential sites that can be modified, which distinguishes this class of ligand and provides a body of flexibilities and opportunities to tune the cytotoxicity of these ruthenium(II) complexes. The influence of substituent effects of three tunable domains on the anticancer activity and catalytic ability in converting coenzyme NADH to NAD is investigated. This family of complexes displays an exceedingly distinct anticancer activity against A549 cancer cells, despite their close structural similarity. Complex 9 shows the highest anticancer activity in this series against A549 cancer cells (IC =14.36 μm), with an approximately 1.5-fold better activity than the clinical platinum drug cisplatin (IC =21.30 μm) in A549 cancer cells. Mechanistic studies reveal that complex 9 mediates cell death mainly through cell stress, including cell cycle arrest, inducing apoptosis, increasing intracellular reactive oxygen species (ROS) levels, and depolarization of the mitochondrial membrane potential (MMP). Furthermore, lysosomal damage is also detected by confocal microscopy.
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http://dx.doi.org/10.1002/asia.201801058DOI Listing
October 2018

Investigating the efficacy of a new intravenous (IV) nanoemulsified sevoflurane/arginine formulation for maintenance of general anesthesia for embolization of cerebral aneurysm.

J Photochem Photobiol B 2018 Oct 18;187:61-65. Epub 2018 Jul 18.

Department of Anesthesiology, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, PR China. Electronic address:

The aim of this research investigation was to profound analysis the mitigating impact of sevoflurane/arginine post-molding on cerebral ischemia-reperfusion damage in rats. The authors fabricated emulsions fusing sevoflurane, perfluorooctyl bromide as a settling specialist, and mixes of arginine polymer. Cell suitability and gene expression of tubulin and NeuN were assessed. The stability, morphology and functional group were evaluated utilizing dynamic light scattering (DLS), Transmission Electron Microscope (TEM), atomic force microscopy (AFM), and Fourier-transform infrared spectroscopy (FTIR). Cerebral aneurysms were prompted through hypertension and a solitary stereotactic infusion of elastase into the basal storage in rat. The capacity of the emulsions to decreased cerebral aneurysm was tried in vivo by regulating them IV delivery of Se/Arg samples to rats. Se/Arg pre-conditioning expanded cell feasibility in neuroblast (SK-N-DZ) cells. Se/Arg pre-conditioning diminished infarct volume and enhanced neurological result in rats subjected to cerebral hypoxia-ischemia. Se/Arg preconditioning expanded levels of tubulin and NeuN. The prepared sevoflurane/arginine material pre-conditioning-incited neuroprotective impacts in vitro as well as in vivo analyses. Sevoflurane/arginine post-molding decreased cerebral tissue misfortune detected 7 days after cerebrum hypoxia-ischemia. This impact was prompted by clinically significant focuses and canceled by Sevoflurane/arginine. These outcomes recommend that Sevoflurane/arginine post-conditioning ensures neonatal cerebrum against cerebrum hypoxia-ischemia.
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http://dx.doi.org/10.1016/j.jphotobiol.2018.07.017DOI Listing
October 2018
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