Publications by authors named "Chunbo Yang"

33 Publications

Optimal Dose of Pituitrin in Laparoscopic Uterine Myomectomy: A Double-Blinded, Randomized Controlled Trial.

J Minim Invasive Gynecol 2021 Jun 18. Epub 2021 Jun 18.

Departments of Anesthesia (Drs. Guo, Jiao, L. Xu, and Xinzhong). Electronic address:

Study Objective: To determine the optimal effective dose of pituitrin in laparoscopic myomectomy for uterine leiomyoma.

Design: Double-blinded, randomized controlled trial.

Setting: Tertiary women's hospital in China.

Patients: Total of 118 patients who underwent laparoscopic myomectomy.

Interventions: Patients randomly received 0, 2, 4, or 6 units of pituitrin injected into the myometrium surrounding the myoma.

Measurements And Main Results: Rate of satisfactory surgical condition, hemodynamic changes, total surgical time, and blood loss were recorded. The rates of satisfactory surgical conditions were 6.7%, 72.4%, 89.7%, and 93.3% in groups 0U, 2U, 4U, and 6U, respectively; they were higher in groups 2U, 4U, and 6U than those in group 0U, but there were no significant differences among the groups 2U, 4U, and 6U. The blood loss was higher in group 0U than that in groups 2U, 4U, and 6U (p < .01). Pituitrin was associated with a transient decrease in blood pressures and an increase in heart rate in a dose-dependent fashion, with more pronounced changes in groups 4U and 6U, and these groups also required a higher amount of vasoactive drug to correct hemodynamic changes (p < .05).

Conclusion: Two units of pituitrin could provide a satisfactory surgical field with minimal hemodynamic changes for laparoscopic uterine myomectomy.
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http://dx.doi.org/10.1016/j.jmig.2021.06.008DOI Listing
June 2021

[Effects of resveratrol-mediated inhibition of NOD-like receptor protein 3 inflammasomevia activating silent information regulator 1 on the injury of intestinal mucosal barrier function after sepsis].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2021 May;33(5):535-540

Department of Critical Care Medicine, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang Uygur Autonomous Region, China. Corresponding author: Yu Xiangyou, Email:

Objective: To explore whether resveratrol (RSV) could activate silent information regulator 1 (SIRT1) to regulate the activation of NOD-like receptor protein 3 (NLRP3) inflammasome in sepsis induced intestinal injury model, and then reduce intestinal inflammation and cell apoptosis, so as to play a protective role in intestinal barrier function.

Methods: (1) In vitro experiment: human Colorectal adenocarcinoma cells (Caco-2) were cultured, which were divided into normal group (normal culture on complete medium for 48 hours), lipopolysaccharide (LPS) group (normal culture on complete medium for 24 hours, then LPS containing 2 mg/L complete medium intervention for 6 hours), RSV low, medium and high concentration groups and SIRT1 inhibitor (EX-527) group (complete medium normal culture for 24 hours, LPS containing 2 mg/L complete medium intervention for 6 hours, followed by RSV 10, 20, 40 μmol/L or EX-527 10 μmol/L intervention for 6 hours, respectively). The levels of tumor necrosis factor-α (TNF-α) and interleukins (IL-6, IL-18, IL-1β) in the cell supernatant were determined by enzyme linked immunosorbent assay (ELISA). The apoptosis level of the cells was detected by flow cytometry. Western blotting was used to detect the protein levels of NLRP3, SIRT1, caspase-1 and apoptosis-related point-like protein (ASC). (2) In vivo experiment: according to random number table method, 24 male Wistar rats were divided into sham operation group (Sham group), cecal ligation and perforation (CLP) 6 hours group (CLP 6 h group), CLP 24 h group and RSV intervention group [RSV (20 mg/kg) was intraperitoneally injected 6 hours and 12 hours after CLP], with 6 rats in each group. The levels of NLRP3, caspase-1 and ASC in the intestine of rats were detected by immunohistochemistry.

Results: (1) Compared with the normal group, the levels of inflammatory factors in the cell supernatant of the LPS group were increased and the expression of SIRT1 protein was decreased, while the protein expressions of NLRP3, caspase-1 and ASC were increased. Compared with LPS group, different concentrations of RSV reduced the level of inflammatory factors, increased the activity of SIRT1, inhibited the expression of NLRP3 inflammasome and its downstream products caspase-1 and ASC, and the effect of high concentration of RSV (40 μmol/L) was the most significant [TNF-α (ng/L): 8.77±0.43 vs. 12.66±0.81, IL-6 (ng/L): 1.35±0.20 vs. 1.93±0.09, IL-1β (ng/L): 1.05±0.04 vs. 1.31±0.07, IL-18 (ng/L): 519.50±11.16 vs. 622.70±30.69, SIRT1/β-actin: 0.80±0.05 vs. 0.58±0.02, caspase-1/β-actin: 0.55±0.06 vs. 0.78±0.06, ASC/β-actin: 0.78±0.08 vs. 1.04±0.15, all P < 0.05], while SIRT1 inhibitor EX-527 had the opposite effects. There was no significant difference in the apoptosis rate among normal group, LPS group, and low, medium and high concentration RSV groups, as well as EX-527 group [(7.03±0.57)%, (9.67±0.55)%, (9.57±0.70)%, (9.30±2.15)%, (9.87±0.97)%, (9.07±0.93)%, F = 2.590, P = 0.082]. (2) Immunohistochemical results showed that compared with the Sham group, the expressions of NLRP3 inflammasomes and downstream products caspase-1 and ASC in the intestinal epithelial cells in CLP 6 h group, CLP 24 h group and RSV intervention group were significantly increased. The percentage of ASC-positive area in intestinal epithelium of RSV intervention group was significantly lower than that of CLP 6 h group [(15.22±2.73)% vs. (19.88±2.67)%, P < 0.05], and the expressions of NLRP3 and caspase-1 were significantly lower than those of CLP 24 h group [(9.31±1.37)% vs. (13.19±1.92)%, (19.57±3.92)% vs. (27.28±6.33)%, both P < 0.05].

Conclusions: After sepsis, high concentration of RSV could inhibit the activation of NLRP3 inflammasome by activating SIRT1, thereby reduce the expression of caspase-1 and ASC, and inhibit the secretion of inflammatory factors to reduce the inflammatory response.
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http://dx.doi.org/10.3760/cma.j.cn121430-20210218-00249DOI Listing
May 2021

A single cell atlas of human cornea that defines its development, limbal progenitor cells and their interactions with the immune cells.

Ocul Surf 2021 Apr 16. Epub 2021 Apr 16.

Biosciences Institute, Faculty of Medical Sciences, Newcastle University, UK. Electronic address:

Purpose: Single cell (sc) analyses of key embryonic, fetal and adult stages were performed to generate a comprehensive single cell atlas of all the corneal and adjacent conjunctival cell types from development to adulthood.

Methods: Four human adult and seventeen embryonic and fetal corneas from 10 to 21 post conception week (PCW) specimens were dissociated to single cells and subjected to scRNA- and/or ATAC-Seq using the 10x Genomics platform. These were embedded using Uniform Manifold Approximation and Projection (UMAP) and clustered using Seurat graph-based clustering. Cluster identification was performed based on marker gene expression, bioinformatic data mining and immunofluorescence (IF) analysis. RNA interference, IF, colony forming efficiency and clonal assays were performed on cultured limbal epithelial cells (LECs).

Results: scRNA-Seq analysis of 21,343 cells from four adult human corneas and adjacent conjunctivas revealed the presence of 21 cell clusters, representing the progenitor and differentiated cells in all layers of cornea and conjunctiva as well as immune cells, melanocytes, fibroblasts, and blood/lymphatic vessels. A small cell cluster with high expression of limbal progenitor cell (LPC) markers was identified and shown via pseudotime analysis to give rise to five other cell types representing all the subtypes of differentiated limbal and corneal epithelial cells. A novel putative LPCs surface marker, GPHA2, expressed on the surface of 0.41% ± 0.21 of the cultured LECs, was identified, based on predominant expression in the limbal crypts of adult and developing cornea and RNAi validation in cultured LECs. Combining scRNA- and ATAC-Seq analyses, we identified multiple upstream regulators for LPCs and demonstrated a close interaction between the immune cells and limbal progenitor cells. RNA-Seq analysis indicated the loss of GPHA2 expression and acquisition of proliferative limbal basal epithelial cell markers during ex vivo LEC expansion, independently of the culture method used. Extending the single cell analyses to keratoconus, we were able to reveal activation of collagenase in the corneal stroma and a reduced pool of limbal suprabasal cells as two key changes underlying the disease phenotype. Single cell RNA-Seq of 89,897 cells obtained from embryonic and fetal cornea indicated that during development, the conjunctival epithelium is the first to be specified from the ocular surface epithelium, followed by the corneal epithelium and the establishment of LPCs, which predate the formation of limbal niche by a few weeks.

Conclusions: Our scRNA-and ATAC-Seq data of developing and adult cornea in steady state and disease conditions provide a unique resource for defining genes/pathways that can lead to improvement in ex vivo LPCs expansion, stem cell differentiation methods and better understanding and treatment of ocular surface disorders.
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http://dx.doi.org/10.1016/j.jtos.2021.03.010DOI Listing
April 2021

[Ulinastatin protects intestinal mucosal barrier by inhibiting the activation of intestinal NLRP3 inflammasomes in septic rats].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2021 Feb;33(2):192-197

Critical Medicine Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang Uygur Autonomous Region, China.

Objective: To explore the damage of the intestinal mucosal barrier of septic rats by the activation of NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasomes and the role of Ulinastatin (UTI) on the expression of intestinal nuclear factor-κB (NF-κB)/NLRP3 inflammasome signaling pathway in septic rats.

Methods: According to the random number table method, 64 male Wistar rats were divided into sham operation group (Sham group), cecal ligation and puncture (CLP) group, UTI treatment group (100 kU/kg UTI was intraperitoneally injected 1, 6, 12 and 18 hours after CLP), and UTI pretreatment group (100 kU/kg UTI was given 1 hour before CLP), with 16 rats in each group. The survival of rats was observed after 24 hours, and the blood was collected from abdominal aorta at 24 hours after modeling, then rats were killed and their ileum tissues were taken. Hematoxylin-eosin (HE) staining was used to observe histopathological changes and Chiu score. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and intestinal fatty acid binding protein (I-FABP) in serum were detected by enzyme linked immunosorbent assay (ELISA). The protein expression of NF-κB p65 in intestinal tissue was detected by Western blotting. The expression of intestinal tight junction proteins Claudin-1, Occludin and the inflammasome NLRP3, apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1 were detected by immunohistochemistry.

Results: Compared with Sham group, the 24-hour survival rate of CLP group was significantly reduced. Histopathological results showed that the CLP group had severe edema of mucosa and submucosal stroma with obvious infiltration of inflammatory cells and disordered villi arrangement. Some glands were incomplete, and the villus structure was severely damaged. The Chiu score was significantly increased. The levels of TNF-α, IL-1β, I-FABP in serum and the protein expression of NF-κB p65 in intestinal tissue were significantly increased. The positive expressions of NLRP3, caspase-1 and ASC were also significantly increased. However, the positive expression of tight junction protein in small intestine tissue such as Occludin and Claudin-1 were significantly reduced. It suggested that when sepsis occurs, small intestinal mucosal barrier dysfunction happens, and mucosal permeability increases, while tight junction protein expression decreases, NLRP3 inflammasome and its upstream molecule NF-κB p65 were activated. After UTI treatment and UTI pretreatment intervention, although there was no significant difference in 24-hour survival compared with CLP group (62.5%, 68.8% vs. 43.8%, both P > 0.05), the intestinal tissue damage of septic rats was significantly improved. Specifically: Chiu score and the levels of TNF-α, IL-1β, I-FABP in serum were significantly decreased [Chiu score: 3.37±0.25, 3.23±0.16 vs. 4.08±0.13, TNF-α (ng/L): 147.62±20.74, 140.71±24.81 vs. 222.82±16.84, IL-1β (ng/L): 80.64±5.68, 78.11±4.75 vs. 133.73±3.92, I-FABP (μg/L): 38.29±3.60, 35.88±4.52 vs. 59.81±4.66, all P < 0.05]; the protein expression of NF-κB p65 was significantly decreased (NF-κB p65/β-actin: 0.65±0.10, 0.69±0.11 vs. 0.99±0.10, both P < 0.05), the positive expressions of Claudin-1 and Occludin in the small intestine tissue were increased [Claudin-1 positive expression area: (19.43±3.08)%, (23.99±6.27)% vs. (7.77±2.03)%; Occludin positive expression area: (19.58±4.75)%, (23.28±3.68)% vs. (11.69±4.30)%, all P < 0.05], while the positive expressions of NLRP3, caspase-1, ASC were decreased [NLRP3 positive expression area: (7.80±3.14)%, (6.86±2.63)% vs. (14.44±3.68)%; caspase-1 positive expression area: (10.62±3.52)%, (9.49±3.09)% vs. (26.69±8.05)%; ASC positive expression area: (9.95±2.81)%, (10.53±3.61)% vs. (24.16±5.48)%, all P < 0.05]. However, there was no significant difference in the improvement effect between UTI treatment group and UTI pretreatment group.

Conclusions: Intestinal barrier dysfunction in sepsis may be related to the activation of NLRP3 inflammasomes in the intestinal mucosa. The protective effect of UTI in the intestinal mucosa may be related to inhibiting the activation of NLRP3 inflammasomes in the intestinal mucosa, but UTI pretreatment has no obvious advantage compared with UTI treatment.
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http://dx.doi.org/10.3760/cma.j.cn121430-20201208-00747DOI Listing
February 2021

The association between serum testosterone levels and metabolic syndrome among women.

Diabetol Metab Syndr 2021 Mar 6;13(1):26. Epub 2021 Mar 6.

Department of Obstetrics and Gynecology, Women's Hospital School of Medicine Zhejiang University, No.1, Xueshi Road, Shangcheng District, Hangzhou, 310006, Zhejiang, China.

Background: This study aimed to investigate the relationship between total serum testosterone level (TT) and metabolic syndrome (MetS) among adult female population. Subgroup analysis further stratified the population by menopausal status to address the potential hormonal difference in postmenopausal women.

Methods: A total of 1966 participants from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 cycle was included for analysis in this study. MetS was defined based on the National Cholesterol Education Program Adult Treatment Panel III guidelines. Serum TT was collected during the physical examination of the NHANES program and divided into quartiles (Q) in this analysis. Menopausal status was determined based on NHANES Reproductive Health Questionnaire. Logistic regression models were applied for analysis.

Results: The odds of MetS in Q2: 12.99-19.38 ng/mL (OR = 0.641, 95%CI 0.493-0.835, P < 0.01), Q3: 19.39-28.38 ng/mL (OR = 0.476, 95%CI 0.362-0.626, P < 0.001), and Q4: ≥28.40 ng/mL (OR = 0.390, 95%CI 0.294-0.517, P < 0.001) were statistically lower compared to the reference Q1: <12.99 ng/mL. For the postmenopausal group, a significantly lower odds of MetS was observed in the Q2 (OR = 0.689, 95%CI 0.486-0.977, P < 0.05) and Q4 (OR = 0.606, 95%CI 0.399-0.922, P < 0.05), while the odds of Q3 (OR = 0.439, 95%CI 0.248-0.779, P < 0.01) and Q4 (OR = 0.464, 95%CI 0.261-0.825, P < 0.01) were significantly lower than the reference Q1 in the premenopausal group.

Conclusions: Elevated TT levels are associated with incremental reductions in the odds of metabolic syndrome among adult females. Although, serum testosterone level is associated with the occurrence of metabolic syndrome in both the postmenopausal and the premenopausal group, the patterns of the relationship are different.
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http://dx.doi.org/10.1186/s13098-021-00643-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937283PMC
March 2021

Correction to: Human embryonic stem cell-derived extracellular vesicles alleviate retinal degeneration by upregulating Oct4 to promote retinal Müller cell retrodifferentiation via HSP90.

Stem Cell Res Ther 2021 Feb 15;12(1):134. Epub 2021 Feb 15.

Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medica lUniversity Eye Hospital, No 251, Fukang Road, Nankai District, Tianjin, 300384, People's Republic of China.

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http://dx.doi.org/10.1186/s13287-021-02213-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885354PMC
February 2021

Human embryonic stem cell-derived extracellular vesicles alleviate retinal degeneration by upregulating Oct4 to promote retinal Müller cell retrodifferentiation via HSP90.

Stem Cell Res Ther 2021 01 7;12(1):21. Epub 2021 Jan 7.

Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, No 251, Fukang Road, Nankai District, Tianjin, 300384, People's Republic of China.

Objective: Retinal degenerative diseases remain the dominant causes of blindness worldwide, and cell replacement is viewed as a promising therapeutic direction. However, the resources of seed cells are hard to obtain. To further explore this therapeutic approach, human embryonic stem extracellular vesicles (hESEVs) were extracted from human embryonic stem cells (hESCs) to inspect its effect and the possible mechanism on retinal Müller cells and retinal function.

Methods: hESEVs were extracted by multi-step differential centrifugation, whose morphologies and specific biomarkers (TSG101, CD9, CD63, and CD81) were observed and measured. After hESEVs were injected into the vitreous cavity of RCS rats, the retinal tissues and retinal functions of rats were assessed. The alteration of Müller cells and retinal progenitor cells was also recorded. Microvesicles (MVs) or exosomes (EXOs) were extracted from hESCs transfected with sh-HSP90 or pcDNA3.1-HSP9, and then incubated with Müller cells to measure the uptake of EVs, MVs, or EXOs in Müller cells by immunofluorescence. The retrodifferentiation of Müller cells was determined by measuring Vimentin and CHX10. qRT-PCR and western blot were used to detect HSP90 expression in MVs and evaluate Oct4 level in Müller cells, and Co-IP to inspect the interaction of HSP90 and Oct4.

Results: RCS rats at the postnatal 30 days had increased retinal progenitor cells which were dedifferentiated from Müller cells. hESEVs were successfully extracted from hESCs, evidenced by morphology observation and positive expressions of specific biomarkers (TSG101, CD9, CD63, and CD81). hESEVs promoted Müller cells dedifferentiated and retrodifferentiated into retinal progenitor cells evidenced by the existence of a large amount of CHX10-positive cells in the retinal inner layer of RCS rats in response to hESEV injection. The promotive role of hESEVs was exerted by MVs demonstrated by elevated fluorescence intensity of CHX10 and suppressed Vimentin fluorescence intensity in MVs rather than in EXOs. HSP90 in MVs inhibited the retrodifferentiation of Müller cells and suppressed the expression level of Oct4 in Müller cells. Co-IP revealed that HSP90 can target Oct4 in Müller cells.

Conclusion: hESEVs could promote the retrodifferentiation of Müller cells into retinal progenitor cells by regulating the expression of Oct4 in Müller cells by HSP90 mediation in MVs.
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http://dx.doi.org/10.1186/s13287-020-02034-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792097PMC
January 2021

Prediction of the Factors Influencing the Shengjing Classification of Portal Vein Thrombosis after Splenectomy for Portal Hypertension in Cirrhosis: A Single-Center Retrospective Case-Control Study.

Biomed Res Int 2020 7;2020:2396710. Epub 2020 Sep 7.

Department of General Surgery, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004 Liaoning Province, China.

Objective: To compare the survival time of patients with portal vein thrombosis after splenectomy for portal hypertension in cirrhosis and explore the influencing factors of the Shengjing classification.

Methods: Clinical data of 108 patients with portal vein thrombosis after splenectomy in the department of general surgery of our hospital from November 2011 to December 2018 were selected, and a retrospective analysis was performed.

Results: Among 108 patients with postoperative PVST formation, 9 had type Ia, 32 type Ib, 39 type IIa, 20 type IIb, 5 type IIIa, 3 type IIIb, and 0 type IV. Survival analysis showed that the difference in survival time distribution among the Shengjing typing groups was statistically significant ( < 0.05). The higher the classification level, the shorter the survival time and the higher the risk of death. The results of a single-factor analysis showed that there were statistically significant differences in the PVST Shengjing typing groups between the preoperative group with or without hepatitis, preoperative d-dimer level, and postoperative day 14 fibrinogen (FIB) level ( < 0.05). Multivariate logistic regression analysis showed that the OR value of higher PVST Shengjing typing in patients with hepatitis was 4.634 times higher than that in patients without hepatitis (95% CI: 1.593-13.478, = 7.922, = 0.005 < 0.05). Preoperative d-dimer volume increased by 1 g/L; the OR value of higher grade PVST Shengjing typing was 1.001 times higher (95% CI: 1.000-1.002) than that of lower grade PVST Shengjing typing ( = 8.369, = 0.004 < 0.05).

Conclusions: The survival time of patients with portal vein system thrombosis after splenectomy was significantly different among Shengjing typing groups, and the higher the classification level, the shorter the survival time and the higher the risk of death. In patients with portal hypertension in cirrhosis and PVST formation after splenectomy, if the preoperative d-dimer level is high or accompanied by hepatitis virus, the formation of PVST will involve a wide range, the disease is more serious, and the prognosis is also poor, so corresponding preventive measures should be taken to avoid the aggravation of PVST.
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http://dx.doi.org/10.1155/2020/2396710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492894PMC
April 2021

Author Correction: Targeting QKI-7 in vivo restores endothelial cell function in diabetes.

Nat Commun 2020 09 16;11(1):4770. Epub 2020 Sep 16.

The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-18712-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495446PMC
September 2020

Targeting QKI-7 in vivo restores endothelial cell function in diabetes.

Nat Commun 2020 07 30;11(1):3812. Epub 2020 Jul 30.

The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK.

Vascular endothelial cell (EC) dysfunction plays a key role in diabetic complications. This study discovers significant upregulation of Quaking-7 (QKI-7) in iPS cell-derived ECs when exposed to hyperglycemia, and in human iPS-ECs from diabetic patients. QKI-7 is also highly expressed in human coronary arterial ECs from diabetic donors, and on blood vessels from diabetic critical limb ischemia patients undergoing a lower-limb amputation. QKI-7 expression is tightly controlled by RNA splicing factors CUG-BP and hnRNPM through direct binding. QKI-7 upregulation is correlated with disrupted cell barrier, compromised angiogenesis and enhanced monocyte adhesion. RNA immunoprecipitation (RIP) and mRNA-decay assays reveal that QKI-7 binds and promotes mRNA degradation of downstream targets CD144, Neuroligin 1 (NLGN1), and TNF-α-stimulated gene/protein 6 (TSG-6). When hindlimb ischemia is induced in diabetic mice and QKI-7 is knocked-down in vivo in ECs, reperfusion and blood flow recovery are markedly promoted. Manipulation of QKI-7 represents a promising strategy for the treatment of diabetic vascular complications.
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http://dx.doi.org/10.1038/s41467-020-17468-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393072PMC
July 2020

An Adjustable pH-Responsive Drug Delivery System Based on Self-Assembly Polypeptide-Modified Mesoporous Silica.

Macromol Biosci 2020 06 24;20(6):e2000034. Epub 2020 Apr 24.

School of Chemical Engineering, Sichuan University, Chengdu, 610065, China.

In this study, an adjustable pH-responsive drug delivery system using mesoporous silica nanoparticles (MSNs) as the host materials and the modified polypeptides as the nanovalves is reported. Since the polypeptide can self-assemble via electrostatic interaction at pH 7.4 and be disassembled by pH changes, the modified poly(l-lysine) and poly(l-glutamate) are utilized for pore blocking and opening in the study. Poly(l-lysine)-MSN (PLL-MSN) and poly(l-glutamate)-MSN (PLG-MSN) are synthesized via the ring opening polymerization of N-carboxyanhydrides onto the surface of mesoporous silica nanoparticles. The successful modification of the polypeptide on MSN is proved by Zeta potential change, X-ray photoelectron spectroscopy (XPS), solid state NMR, and MALDI-TOF MS. In vitro simulated dye release studies show that PLL-MSN and PLG-MSN can successfully load the dye molecules. The release study shows that the controlled release can be constructed at different pH by adjusting the ratio of PLL-MSN to PLG-MSN. Cellular uptake study indicates that the drug is detected in both cytoplasm and nucleus, especially in the nucleus. In vitro cytotoxicity assay indicates that DOX loaded mixture nanoparticles (ratio of PLL-MSN to PLG-MSN is 1:1) can be triggered for drug release in HeLa cells, resulting in 88% of cell killing.
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http://dx.doi.org/10.1002/mabi.202000034DOI Listing
June 2020

Effect of incubation with lipopolysaccharide and interferon-γ on reactive astrogliosis.

J Integr Neurosci 2019 Dec;18(4):415-421

Department of Intensive Care Unit, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P. R. China.

Sepsis associated encephalopathy is a common complication of sepsis, but its pathogenesis of sepsis-associated encephalopathy remains unclear. Astrocytes are the most abundant brain glial cells, and reactive astrogliosis, a pathological response to central nervous system diseases, has a clear disease and disease-stage specificity. Functional changes of astrocytes are of great significance for the detection and prognosis of sepsis-associated encephalopathy. The pathogenesis of sepsis-associated encephalopathy was explored at the cellular level by examining astrogliosis in an in vitro model of sepsis-associated encephalopathy. Astrocytes of Wistar neonatal rats were incubated with different concentrations of lipopolysaccharide combined with interferon-γ. Cell viability was assessed by levels of tumor necrosis factor-α, interleukin-6, nitric oxide, reactive oxygen species, glial fibrillary acidic protein, changes of astrocyte morphology, and prevalence of apoptosis and necrosis. Compared with the control group, the cell viability of treated groups was decreased. The levels of tumor necrosis factor-α, interleukin-6, nitric oxide, reactive oxygen species, and glial fibrillary acidic protein were increased, hypertrophy of astrocytes was observed, and apoptosis was increased. The pathogenic outcomes of astrogliosis in sepsis-associated encephalopathy is discussed and a new tool provided to explore the pathogenesis of sepsis-associated encephalopathy at the cellular level.
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http://dx.doi.org/10.31083/j.jin.2019.04.1138DOI Listing
December 2019

[Effect of vitamin C on prognosis of critically ill patients: a Meta-analysis].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2019 Aug;31(8):942-948

Department of Critical Care Medicine, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang Uygur Autonomous Region, China. Corresponding author: Yu Xiangyou, Email:

Objective: To systematically evaluate the effect of vitamin C on prognosis of critically ill patients.

Methods: Randomized controlled trials (RCT) about vitamin C treatment for critically ill patients were searched in CNKI, CBM, VIP database, Wanfang database, PubMed, Springer Link, Embase, Web of Science, and Cochrane Library from their inception to May 2019. Patients in the treatment group received ascorbic acid while patients in the control group received placebo or other treatment. Outcome measures included mortality, the length of intensive care unit (ICU) stay, the length of hospital stay, and incidence of atrial fibrillation. Two researchers were responsible for literature screening, data extraction and quality evaluation independently. Meta-analysis was performed with RevMan 5.2 software. The publication bias was analyzed by funnel plot.

Results: A total of 28 RCTs were enrolled and 4 420 patients were included (2 207 in intervention group and 2 213 in control group). Meta-analysis showed that there was no significant difference in mortality between intervention group and control group [odds ratio (OR) = 0.90, 95% confidence interval (95%CI) = 0.75 to 1.08, P = 0.27]. The length of ICU stay [mean difference (MD) = -0.23, 95%CI = -0.29 to -0.16, P < 0.000 01] and the length of hospital stay (MD = -0.96, 95%CI = -1.21 to -0.70, P < 0.000 01) in intervention group were less than those in control group. Subgroup analysis showed that mortality of patients with sepsis and septic shock in intervention group was lower than that in control group (OR = 0.65, 95%CI = 0.43 to 0.99, P = 0.04). For patients undergoing cardiac surgery, the incidence of postoperative atrial fibrillation in intervention group was lower than that in control group (OR = 0.43, 95%CI = 0.34 to 0.54, P < 0.000 01). It was shown by funnel plot that there was less publication bias among studies.

Conclusions: Vitamin C does not reduce mortality in critically ill patients, but it can reduce the length of ICU stay and hospital stay. In addition, vitamin C can reduce mortality of patients with sepsis and septic shock and reduce the incidence of atrial fibrillation post operation in patients undergoing cardiac surgery.
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http://dx.doi.org/10.3760/cma.j.issn.2095-4352.2019.08.006DOI Listing
August 2019

The RNA-binding protein QKI controls alternative splicing in vascular cells, producing an effective model for therapy.

J Cell Sci 2019 08 15;132(16). Epub 2019 Aug 15.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL

Dysfunction of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) leads to ischaemia, the central pathology of cardiovascular disease. Stem cell technology will revolutionise regenerative medicine, but a need remains to understand key mechanisms of vascular differentiation. RNA-binding proteins have emerged as novel post-transcriptional regulators of alternative splicing and we have previously shown that the RNA-binding protein Quaking (QKI) plays roles in EC differentiation. In this study, we decipher the role of the alternative splicing isoform Quaking 6 (QKI-6) to induce VSMC differentiation from induced pluripotent stem cells (iPSCs). PDGF-BB stimulation induced QKI-6, which bound to HDAC7 intron 1 via the QKI-binding motif, promoting HDAC7 splicing and iPS-VSMC differentiation. Overexpression of QKI-6 transcriptionally activated SM22 (also known as TAGLN), while QKI-6 knockdown diminished differentiation capability. VSMCs overexpressing QKI-6 demonstrated greater contractile ability, and upon combination with iPS-ECs-overexpressing the alternative splicing isoform Quaking 5 (QKI-5), exhibited higher angiogenic potential  than control cells alone. This study demonstrates that QKI-6 is critical for modulation of HDAC7 splicing, regulating phenotypically and functionally robust iPS-VSMCs. These findings also highlight that the QKI isoforms hold key roles in alternative splicing, giving rise to cells which can be used in vascular therapy or for disease modelling.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/jcs.230276DOI Listing
August 2019

Enhanced Function of Induced Pluripotent Stem Cell-Derived Endothelial Cells Through ESM1 Signaling.

Stem Cells 2019 02 17;37(2):226-239. Epub 2018 Nov 17.

Centre for Experimental Medicine, Queen's University Belfast, Belfast, Co Antrim, United Kingdom.

The mortality rate for (cardio)-vascular disease is one of the highest in the world, so a healthy functional endothelium is of outmost importance against vascular disease. In this study, human induced pluripotent stem (iPS) cells were reprogrammed from 1 ml blood of healthy donors and subsequently differentiated into endothelial cells (iPS-ECs) with typical EC characteristics. This research combined iPS cell technologies and next-generation sequencing to acquire an insight into the transcriptional regulation of iPS-ECs. We identified endothelial cell-specific molecule 1 (ESM1) as one of the highest expressed genes during EC differentiation, playing a key role in EC enrichment and function by regulating connexin 40 (CX40) and eNOS. Importantly, ESM1 enhanced the iPS-ECs potential to improve angiogenesis and neovascularisation in in vivo models of angiogenesis and hind limb ischemia. These findings demonstrated for the first time that enriched functional ECs are derived through cell reprogramming and ESM1 signaling, opening the horizon for drug screening and cell-based therapies for vascular diseases. Therefore, this study showcases a new approach for enriching and enhancing the function of induced pluripotent stem (iPS) cell-derived ECs from a very small amount of blood through ESM1 signaling, which greatly enhances their functionality and increases their therapeutic potential. Stem Cells 2019;37:226-239.
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http://dx.doi.org/10.1002/stem.2936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392130PMC
February 2019

RBPs Play Important Roles in Vascular Endothelial Dysfunction Under Diabetic Conditions.

Front Physiol 2018 20;9:1310. Epub 2018 Sep 20.

Centre for Experimental Medicine, Queens University Belfast, Belfast, United Kingdom.

Diabetes is one of the major health care problems worldwide leading to huge suffering and burden to patients and society. Diabetes is also considered as a cardiovascular disorder because of the correlation between diabetes and an increased incidence of cardiovascular disease. Vascular endothelial cell dysfunction is a major mediator of diabetic vascular complications. It has been established that diabetes contributes to significant alteration of the gene expression profile of vascular endothelial cells. Post-transcriptional regulation by RNA binding proteins (RBPs) plays an important role in the alteration of gene expression profile under diabetic conditions. The review focuses on the roles and mechanisms of critical RBPs toward diabetic vascular endothelial dysfunction. Deeper understanding of the post- transcriptional regulation by RBPs could lead to new therapeutic strategies against diabetic manifestation in the future.
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http://dx.doi.org/10.3389/fphys.2018.01310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158626PMC
September 2018

[Effect of high-flow nasal cannula oxygen therapy on improving the atelectasis in adults after cardiac surgeries: a Meta-analysis].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2018 Aug;30(8):748-753

Department of Critical Care Medicine, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang, China. Corresponding author: Yu Xiangyou, Email:

Objective: To systematically evaluate the effect of high-flow nasal cannula oxygen (HFNC) on improving the atelectasis and respiratory function in adults after cardiac surgeries.

Methods: All randomized controlled trials (RCTs) about HFNC therapy for adults after cardiac surgeries published from January 2000 to March 2018 were searched through CNKI, CBM, VIP, Wanfang, PubMed, Springer Link, Embase, Web of Science, Cochrane Library. The references from relevant articles were searched. The experimental group was treated with HFNC while the control group treated with conventional oxygen therapy (COT). The outcome measurements included radiological atelectasis score (RAS), endotracheal reintubation rate and the length of intensive care unit (ICU) stay. Two researchers were responsible for literature screening, data extraction and quality evaluation respectively. Meta-analysis was performed with RevMan 5.2 software. Funnel plot was used to analyze the publication bias.

Results: A total of 4 RCTs were enrolled and 643 patients were included (325 in experimental group and 318 in control group). Meta-analysis showed that the tracheal reintubation rate in experimental group was lower than that in control group [odds ratio (OR) = 0.26, 95% confidence interval (95%CI) = 0.09-0.74, P = 0.01], but there was no significant difference in RAS [mean difference (MD) = -0.15, 95%CI = -0.50-0.21, P = 0.41] and the length of ICU stay (MD = 0.09, 95%CI = -0.09-0.26, P = 0.33) between experimental group and control group. Sensitivity analysis was performed in two trials with low risk of bias, which demonstrated that there was no significant difference in RAS between the two groups (MD = 0.06, 95%CI = -0.26-0.37, P = 0.73). It was shown by the funnel analysis that there was bias in the study of the length of ICU stay in the literature, while the bias of RAS and tracheal reintubation rate was low.

Conclusions: Compared with COT, HFNC could reduce the rate of tracheal reintubation in adults after cardiac surgeries, but no difference was found in improving atelectasis or reducing the length of ICU stay.
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http://dx.doi.org/10.3760/cma.j.issn.2095-4352.2018.08.007DOI Listing
August 2018

Regenerating the Cardiovascular System Through Cell Reprogramming; Current Approaches and a Look Into the Future.

Front Cardiovasc Med 2018 20;5:109. Epub 2018 Aug 20.

The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom.

Cardiovascular disease (CVD), despite the advances of the medical field, remains one of the leading causes of mortality worldwide. Discovering novel treatments based on cell therapy or drugs is critical, and induced pluripotent stem cells (iPS Cells) technology has made it possible to design extensive disease-specific models. Elucidating the differentiation process challenged our previous knowledge of cell plasticity and capabilities and allows the concept of cell reprogramming technology to be established, which has inspired the creation of both and techniques. Patient-specific cell lines provide the opportunity of studying their pathophysiology , which can lead to novel drug development. At the same time, models have been designed where transdifferentiation of cell populations into cardiomyocytes or endothelial cells (ECs) give hope toward effective cell therapies. Unfortunately, the efficiency as well as the concerns about the safety of all these methods make it exceedingly difficult to pass to the clinical trial phase. It is our opinion that creating an model out of patient-specific cells will be one of the most important goals in the future to help surpass all these hindrances. Thus, in this review we aim to present the current state of research in reprogramming toward the cardiovascular system's regeneration, and showcase how the development and study of a multicellular 3D model will improve our fighting chances.
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http://dx.doi.org/10.3389/fcvm.2018.00109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109758PMC
August 2018

Follistatin-Like 3 Enhances the Function of Endothelial Cells Derived from Pluripotent Stem Cells by Facilitating β-Catenin Nuclear Translocation Through Inhibition of Glycogen Synthase Kinase-3β Activity.

Stem Cells 2018 07 10;36(7):1033-1044. Epub 2018 Apr 10.

Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom.

The fight against vascular disease requires functional endothelial cells (ECs) which could be provided by differentiation of induced Pluripotent Stem Cells (iPS Cells) in great numbers for use in the clinic. However, the great promise of the generated ECs (iPS-ECs) in therapy is often restricted due to the challenge in iPS-ECs preserving their phenotype and function. We identified that Follistatin-Like 3 (FSTL3) is highly expressed in iPS-ECs, and, as such, we sought to clarify its possible role in retaining and improving iPS-ECs function and phenotype, which are crucial in increasing the cells' potential as a therapeutic tool. We overexpressed FSTL3 in iPS-ECs and found that FSTL3 could induce and enhance endothelial features by facilitating β-catenin nuclear translocation through inhibition of glycogen synthase kinase-3β activity and induction of Endothelin-1. The angiogenic potential of FSTL3 was also confirmed both in vitro and in vivo. When iPS-ECs overexpressing FSTL3 were subcutaneously injected in in vivo angiogenic model or intramuscularly injected in a hind limb ischemia NOD.CB17-Prkdcscid/NcrCrl SCID mice model, FSTL3 significantly induced angiogenesis and blood flow recovery, respectively. This study, for the first time, demonstrates that FSTL3 can greatly enhance the function and maturity of iPS-ECs. It advances our understanding of iPS-ECs and identifies a novel pathway that can be applied in cell therapy. These findings could therefore help improve efficiency and generation of therapeutically relevant numbers of ECs for use in patient-specific cell-based therapies. In addition, it can be particularly useful toward the treatment of vascular diseases instigated by EC dysfunction. Stem Cells 2018;36:1033-1044.
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http://dx.doi.org/10.1002/stem.2820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099345PMC
July 2018

Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis.

Hum Mol Genet 2017 08;26(16):3031-3045

Institute of Genetic Medicine, Newcastle University, Newcastle, UK.

Hypoplastic left heart syndrome (HLHS) is among the most severe forms of congenital heart disease. Although the consensus view is that reduced flow through the left heart during development is a key factor in the development of the condition, the molecular mechanisms leading to hypoplasia of left heart structures are unknown. We have generated induced pluripotent stem cells (iPSC) from five HLHS patients and two unaffected controls, differentiated these to cardiomyocytes and identified reproducible in vitro cellular and functional correlates of the HLHS phenotype. Our data indicate that HLHS-iPSC have a reduced ability to give rise to mesodermal, cardiac progenitors and mature cardiomyocytes and an enhanced ability to differentiate to smooth muscle cells. HLHS-iPSC-derived cardiomyocytes are characterised by a lower beating rate, disorganised sarcomeres and sarcoplasmic reticulum and a blunted response to isoprenaline. Whole exome sequencing of HLHS fibroblasts identified deleterious variants in NOTCH receptors and other genes involved in the NOTCH signalling pathway. Our data indicate that the expression of NOTCH receptors was significantly downregulated in HLHS-iPSC-derived cardiomyocytes alongside NOTCH target genes confirming downregulation of NOTCH signalling activity. Activation of NOTCH signalling via addition of Jagged peptide ligand during the differentiation of HLHS-iPSC restored their cardiomyocyte differentiation capacity and beating rate and suppressed the smooth muscle cell formation. Together, our data provide firm evidence for involvement of NOTCH signalling in HLHS pathogenesis, reveal novel genetic insights important for HLHS pathology and shed new insights into the role of this pathway during human cardiac development.
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http://dx.doi.org/10.1093/hmg/ddx140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886295PMC
August 2017

Concise Review: Cardiac Disease Modeling Using Induced Pluripotent Stem Cells.

Stem Cells 2015 Sep 23;33(9):2643-51. Epub 2015 Jun 23.

Institute of Genetic Medicine, Newcastle University, The International Centre for Life, Central Parkway, Newcastle upon Tyne, United Kingdom.

Genetic cardiac diseases are major causes of morbidity and mortality. Although animal models have been created to provide some useful insights into the pathogenesis of genetic cardiac diseases, the significant species differences and the lack of genetic information for complex genetic diseases markedly attenuate the application values of such data. Generation of induced pluripotent stem cells (iPSCs) from patient-specific specimens and subsequent derivation of cardiomyocytes offer novel avenues to study the mechanisms underlying cardiac diseases, to identify new causative genes, and to provide insights into the disease aetiology. In recent years, the list of human iPSC-based models for genetic cardiac diseases has been expanding rapidly, although there are still remaining concerns on the level of functionality of iPSC-derived cardiomyocytes and their ability to be used for modeling complex cardiac diseases in adults. This review focuses on the development of cardiomyocyte induction from pluripotent stem cells, the recent progress in heart disease modeling using iPSC-derived cardiomyocytes, and the challenges associated with understanding complex genetic diseases. To address these issues, we examine the similarity between iPSC-derived cardiomyocytes and their ex vivo counterparts and how this relates to the method used to differentiate the pluripotent stem cells into a cardiomyocyte phenotype. We progress to examine categories of congenital cardiac abnormalities that are suitable for iPSC-based disease modeling.
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http://dx.doi.org/10.1002/stem.2070DOI Listing
September 2015

Polysaccharide hydrogel combined with mesenchymal stem cells promotes the healing of corneal alkali burn in rats.

PLoS One 2015 19;10(3):e0119725. Epub 2015 Mar 19.

TianjinMedical University Eye Hospital, The College of Optometry,Tianjin Medical University Eye Institute, Tianjin, China.

Corneal chemical burns are common ophthalmic injuries that may result in permanent visual impairment. Although significant advances have been achieved on the treatment of such cases, the structural and functional restoration of a chemical burn-injured cornea remains challenging. The applications of polysaccharide hydrogel and subconjunctival injection of mesenchymal stem cells (MSCs) have been reported to promote the healing of corneal wounds. In this study, polysaccharide was extracted from Hardy Orchid and mesenchymal stem cells (MSCs) were derived from Sprague-Dawley rats. Supplementation of the polysaccharide significantly enhanced the migration rate of primarily cultured rat corneal epithelial cells. We examined the therapeutic effects of polysaccharide in conjunction with MSCs application on the healing of corneal alkali burns in rats. Compared with either treatment alone, the combination strategy resulted in significantly better recovery of corneal epithelium and reduction in inflammation, neovascularization and opacity of healed cornea. Polysaccharide and MSCs acted additively to increase the expression of anti-inflammatory cytokine (TGF-β), antiangiogenic cytokine (TSP-1) and decrease those promoting inflammation (TNF-α), chemotaxis (MIP-1α and MCP-1) and angiogenesis (VEGF and MMP-2). This study provided evidence that Hardy Orchid derived polysaccharide and MSCs are safe and effective treatments for corneal alkali burns and that their benefits are additive when used in combination. We concluded that combination therapy with polysaccharide and MSCs is a promising clinical treatment for corneal alkali burns and may be applicable for other types of corneal disorder.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119725PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366244PMC
February 2016

Qing Hua Chang Yin inhibits the LPS-induced activation of the IL-6/STAT3 signaling pathway in human intestinal Caco-2 cells.

Int J Mol Med 2015 Apr 28;35(4):1133-7. Epub 2015 Jan 28.

Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.

Increasing evidence indicates that the pathogenesis of ulcerative colitis (UC) is highly regulated by the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway and its negative feedback regulator, suppressor of cytokine signaling 3 (SOCS3). Therefore, modulating the signaling feedback loop of IL-6/STAT3/SOCS3 may prove to be a novel therapeutic approach for the treatment of UC. Qing Hua Chang Yin (QHCY) is a traditional Chinese formulation that has long been used in clinic for the treatment of UC. We have previously reported that QHCY ameliorates acute intestinal inflammation in vivo and in vitro through the suppression of the nuclear factor-κB (NF-κB) pathway. In the present study, in order to further elucidate the mechanisms responsible for the anti-inflammatory activities of QHCY, we stimulated human intestinal Caco-2 cells with lipopolysaccharide (LPS) to create an in vitro model of an inflamed human intestinal epithelium, and evaluated the effects of QHCY on the IL-6/STAT3/SOCS3 signaling network in inflamed Caco-2 cells. The levels of IL-6 were measured by ELISA and the levels of STAT3 and SOCS3 were measured by western blot analysis. We found that QHCY significantly inhibited the LPS-induced secretion of pro-inflammatory IL-6 in the Caco-2 cells in a dose-dependent manner. Moreover, QHCY profoundly suppressed the LPS-induced phosphorylation of Janus-activated kinase 1 (JAK1), JAK2 and STAT3. Furthermore, treatment with QHCY markedly augmented the expression of SOCS3. Taken together, the findings of the present study suggest that the modulation of the IL-6/STAT3/SOCS3 signaling network may be one of the mechanisms through which QHCY exerts its anti-inflammatory effects.
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http://dx.doi.org/10.3892/ijmm.2015.2083DOI Listing
April 2015

Unilateral ovarian and fallopian tube agenesis in an infertile patient with a normal uterus.

Exp Ther Med 2014 Sep 4;8(3):831-835. Epub 2014 Jul 4.

Department of Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China.

Congenital agenesis of the unilateral adnexa is a condition that has rarely been described in the literature. The current study presents the case of a 26-year-old female who was admitted to the Department of Gynecology at the Women's Hospital of Zhejiang University (Hangzhou, Zhejiang) for primary infertility. The patient was diagnosed with unilateral ovarian and fallopian tubal agenesis, without malformations of the uterus and urinary tract, during diagnostic laparoscopy and hysteroscopy. A literature review was conducted with the aim of determining the possible causes of these anomalies. However, the etiology of the adnexal anomaly remained unclear, although torsion or congenital defects were the most likely explanation. Therefore, the observations of the present study indicate that contralateral tubal pathologies may contribute to sterility.
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http://dx.doi.org/10.3892/etm.2014.1825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113523PMC
September 2014

Maternal high-fat diet affects Msi/Notch/Hes signaling in neural stem cells of offspring mice.

J Nutr Biochem 2014 Feb 15;25(2):227-31. Epub 2013 Nov 15.

Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, P.R. China. Electronic address:

Numerous research have begun to reveal the importance of maternal nutrition in offspring brain development. Particularly, the maternal obesity or exposure to high-fat diet has been strongly suggested to exert irreversible impact on the structure and function of offspring's brain. However, it remains obscure about whether neonatal neural stem cells (NSCs) in offspring's brain are susceptible to maternal exposure to high-fat diet. Here we focused on the alternation in the Notch signaling in NSCs derived from neonatal mice, which had been given birth by female mice with a high-fat diet and found that, in fact, the high-fat diet administration imposed effects on not only maternal mice, indicated by the accumulation of viscera fat as well as the increase in body weight and serum total cholesterol, but also NSCs in the offspring's brain, where significant increase was observed in the expression of genes, either downstream of Notch signaling or regulating this pathway, which have been shown essential for the maturation of NSCs. Therefore, our data provided the first evidence for the potential effect of maternal exposure to the high-fat diet on the Notch signaling pathway in offspring's NSCs, indicating this altered signaling response might contribute to a profound change in offspring's brains as a result of maternal high-fat diet prior to and during gestation.
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http://dx.doi.org/10.1016/j.jnutbio.2013.10.011DOI Listing
February 2014

Qing Hua Chang Yin attenuates lipopolysaccharide-induced inflammatory response in human intestinal cells by inhibiting NF-κB activation.

Exp Ther Med 2013 Jul 22;6(1):189-193. Epub 2013 Apr 22.

Department of Gastroenterology, Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350003;

Ulcerative colitis (UC) is a major form of inflammatory bowel disease (IBD), which is tightly regulated by the nuclear factor κB (NF-κB) pathway. Thus, the suppression of NF-κB signaling may provide a promising strategy for the treatment of UC. Qing Hua Chang Yin (QHCY) is a traditional Chinese formulation, which has been used for a number of years to clinically treat UC. However, little is known with regard to its anti-inflammatory properties. In the present study, lipopolysaccharide (LPS)-stimulated Caco-2 cells were used as an inflammatory model of the human intestinal epithelium to evaluate the anti-inflammatory effects of QHCY and its underlying molecular mechanisms. We observed that QHCY inhibited the inflammatory response in intestinal epithelial cells as it significantly and concentration-dependently reduced the LPS-induced secretion of pro-inflammatory TNF-α and IL-8 in Caco-2 cells. Furthermore, QHCY treatment inhibited the phosphorylation of IκB and the nuclear translocation of NF-κB in Caco-2 cells in a concentration-dependent manner, indicating that QHCY suppressed the activation of the NF-κB signaling pathway. Collectively, our results suggest that the inhibition of NF-κB-mediated inflammation may constitute a potential mechanism by which QHCY treats UC.
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http://dx.doi.org/10.3892/etm.2013.1071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3735875PMC
July 2013

Reconstruction of orbital defects by implantation of antigen-free bovine cancellous bone scaffold combined with bone marrow mesenchymal stem cells in rats.

Graefes Arch Clin Exp Ophthalmol 2013 May 22;251(5):1325-33. Epub 2013 Mar 22.

Tianjin Medical University, 22 Qixiangtai Rd, Tianjin, 300070, The People's Republic of China.

Background: Tissue-engineering approach can result in significant bone regeneration. We aimed to reconstruct the segmental orbital rim defects with antigen-free bovine cancellous bone (BCB) scaffolds combined with bone marrow mesenchymal stem cells (BMSCs) in rats.

Methods: BCB was prepared by degreasing, deproteinization and partly decalcification. BMSCs isolated from green fluorescent protein (GFP) transgenic rats were osteogenically induced and seeded onto BCB scaffolds to construct induced BMSCs/BCB composites. An 8-mm full-thickness defect on the rat inferior-orbit rim was established. Induced BMSCs/BCB composites cultured for 5 days were implanted into the orbital defects as the experimental group. Noninduced BMSCs/BCB group, BCB group and exclusive group were set. General condition, spiral CT, 3D orbital reconstruction, histological and histomorphometric analysis were performed after implantation.

Results: BCB presented reticular porous structure. GFP-BMSCs adhering to BCB appeared bright green fluorescence and grew vigorously. Infection and graft dislocation were not observed. In induced BMSCs/BCB group, CT and 3D reconstruction showed perfect orbital repair situation. Histological analysis indicated BCB was mostly biodegraded; newly formed bone and complete synostosis were observed. The percentage of newly formed bone was (57.12 ± 6.28) %. In contrast, more residual BCB, less newly formed bone and nonunion were observed in the noninduced BMSCs/BCB group. Slowly absorbed BCB enwrapped by fibrous connective tissue and a small amount of new bone occurred in BCB group. Fibrous connective tissue appeared in exclusive group.

Conclusions: Antigen-free bovine cancellous bone that retains natural bone porous structure and moderate mechanical strength with elimination of antigen is the ideal carrier for mesenchymal stem cells in vitro. BCB combined with BMSCs is a promising composite for tissue engineering, and can effectively reconstruct the orbit rim defects in rats.
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http://dx.doi.org/10.1007/s00417-013-2300-0DOI Listing
May 2013

Opposing putative roles for canonical and noncanonical NFκB signaling on the survival, proliferation, and differentiation potential of human embryonic stem cells.

Stem Cells 2010 Nov;28(11):1970-80

Institute of Human Genetics, International Centre for Life, Newcastle University, Newcastle Upon Tyne, United Kingdom.

The canonical and noncanonical NFκB signaling pathways regulate a variety of cellular activities; however, their functions in human embryonic stem cells (hESCs) have not been fully investigated. Expression studies during hESC differentiation indicated a significant increase in the expression of two key components of the canonical NFκB pathway (p50 and Ser529 phosphorylated form of p65) as well as a significant reduction in expression of key components of the noncanonical NFκB pathway [v-rel reticuloendotheliosis viral oncogene homolog B (RELB), p52, NIK]. Inhibition of canonical NFκB resulted in hESC apoptosis, changes in cell cycle distribution, and reduced hESC proliferation. In addition, inhibition of canonical NFκB was associated with significant changes in NANOG and OCT4 expression, suppression of differentiation toward all primitive extraembryonic and embryonic lineages with the exception of primitive ectoderm and ectodermal lineages. Inhibition of noncanonical NFκB via small interfering RNA-mediated downregulation of RELB resulted in reduced hESC proliferation and opposite changes to expression of key differentiation lineage markers genes when compared with downregulation of canonical NF-κB. Chromatin immunoprecipitation assays indicated binding of p65 and RELB to regulatory regions of key differentiation marker genes suggesting a direct transcriptional role for both branches of this pathway in hESC. These findings coupled with opposing trends in expression of key components during hESC differentiation, suggests a fine and opposing balance between the two branches of NFκB signaling pathways and their involvement in two distinct processes: the canonical pathway regulating hESC differentiation and the noncanonical pathway maintaining hESC pluripotency.
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http://dx.doi.org/10.1002/stem.528DOI Listing
November 2010

Efficient generation of lens progenitor cells and lentoid bodies from human embryonic stem cells in chemically defined conditions.

FASEB J 2010 Sep 21;24(9):3274-83. Epub 2010 Apr 21.

Department of Ophthalmology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.

The eye lens is an encapsulated avascular organ whose function is to focus light on the retina. Lens comprises a single progenitor cell lineage in multiple states of differentiation. Disruption of lens function leading to protein aggregation and opacity results in age-onset cataract. Cataract is a complex disease involving genetic and environmental factors. Here, we report the development of a new 3-stage system that differentiates human embryonic stem cells (hESCs) into large quantities of lens progenitor-like cells and differentiated 3-dimensional lentoid bodies. Inhibition of BMP signaling by noggin triggered differentiation of hESCs toward neuroectoderm. Subsequent reactivation of BMP and activation of FGF signaling stimulated formation of lens progenitor cells marked by the expression of PAX6 and alpha-crystallins. The formation of lentoid bodies was most efficient in the presence of FGF2 and Wnt-3a, yielding approximately 1000 lentoid bodies/30-mm well. Lentoid bodies expressed and accumulated lens-specific markers including alphaA-, alphaB-, beta-, and gamma-crystallins, filensin, CP49, and MIP/aquaporin 0. Collectively, these studies identify a novel procedure to generate lens cells from hESCs that can be applied for studies of lens differentiation and cataractogenesis using induced pluripotent stem (iPS) cells derived from various cataract patients.
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http://dx.doi.org/10.1096/fj.10-157255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923359PMC
September 2010

A role for NANOG in G1 to S transition in human embryonic stem cells through direct binding of CDK6 and CDC25A.

J Cell Biol 2009 Jan;184(1):67-82

NorthEast England Stem Cell Institute, Institute of Human Genetics, Newcastle University, International Centre for Life, Newcastle upon Tyne, England, UK.

In this study, we show that NANOG, a master transcription factor, regulates S-phase entry in human embryonic stem cells (hESCs) via transcriptional regulation of cell cycle regulatory components. Chromatin immunoprecipitation combined with reporter-based transfection assays show that the C-terminal region of NANOG binds to the regulatory regions of CDK6 and CDC25A genes under normal physiological conditions. Decreased CDK6 and CDC25A expression in hESCs suggest that both CDK6 and CDC25A are involved in S-phase regulation. The effects of NANOG overexpression on S-phase regulation are mitigated by the down-regulation of CDK6 or CDC25A alone. Overexpression of CDK6 or CDC25A alone can rescue the impact of NANOG down-regulation on S-phase entry, suggesting that CDK6 and CDC25A are downstream cell cycle effectors of NANOG during the G1 to S transition.
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http://dx.doi.org/10.1083/jcb.200801009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2615089PMC
January 2009
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