1.Development and validation of a novel criterion of histologic healing in ulcerative colitis defined by inflammatory cell enumeration in lamina propria mucosa: A multicenter retrospective cohort in China
Han GAO ; Kangsheng PENG ; Yadi SHI ; Shenshen ZHU ; Ruicong SUN ; Chunjin XU ; Ping LIU ; Zhi PANG ; Lanxiang ZHU ; Weichang CHEN ; Baisui FENG ; Huili WU ; Guangxi ZHOU ; Mingsong LI ; Junxiang LI ; Baijing DING ; Zhanju LIU
Chinese Medical Journal 2024;137(11):1316-1323
Background::Histological healing is closely associated with improved long-term clinical outcomes and lowered relapses in patients with ulcerative colitis (UC). Here, we developed a novel diagnostic criterion for assessing histological healing in UC patients.Methods::We conducted a retrospective cohort study in UC patients, whose treatment was iteratively optimized to achieve mucosal healing at Shanghai Tenth People’s Hospital of Tongji University from January 2017 to May 2022. We identified an inflammatory cell enumeration index (ICEI) for assessing histological healing based on the proportions of eosinophils, CD177 + neutrophils, and CD40L + T cells in the colonic lamina propria under high power field (HPF), and the outcomes (risks of symptomatic relapses) of achieving histological remission vs. persistent histological inflammation using Kaplan-Meier curves. Intrareader reliability and inter-reader reliability were evaluated by each reader. The relationships to the changes in the Nancy index and the Geboes score were also assessed for responsiveness. The ICEI was further validated in a new cohort of UC patients from other nine university hospitals. Results::We developed an ICEI for clinical diagnosis of histological healing, i.e., Y = 1.701X 1 + 0.758X 2 + 1.347X 3 - 7.745 (X 1, X 2, and X 3 represent the proportions of CD177 + neutrophils, eosinophils, and CD40L + T cells, respectively, in the colonic lamina propria under HPF). The receiver operating characteristics curve (ROC) analysis revealed that Y <-0.391 was the cutoff value for the diagnosis of histological healing and that an area under the curve (AUC) was 0.942 (95% confidence interval [CI]: 0.905-0.979) with a sensitivity of 92.5% and a specificity of 83.6% ( P <0.001). The intraclass correlation coefficient (ICC) for the intrareader reliability was 0.855 (95% CI: 0.781-0.909), and ICEI had good inter-reader reliability of 0.832 (95% CI: 0.748-0.894). During an 18-month follow-up, patients with histological healing had a substantially better outcome compared with those with unachieved histological healing ( P <0.001) using ICEI. During a 12-month follow-up from other nine hospitals, patients with histological healing also had a lower risk of relapse than patients with unachieved histological healing. Conclusions::ICEI can be used to predict histological healing and identify patients with a risk of relapse 12 months and 18 months after clinical therapy. Therefore, ICEI provides a promising, simplified approach to monitor histological healing and to predict the prognosis of UC.Registration::Chinese Clinical Trial Registry, No. ChiCTR2300077792.
2.Bladder microenvironment actuated proteomotors with ammonia amplification for enhanced cancer treatment.
Hao TIAN ; Juanfeng OU ; Yong WANG ; Jia SUN ; Junbin GAO ; Yicheng YE ; Ruotian ZHANG ; Bin CHEN ; Fei WANG ; Weichang HUANG ; Huaan LI ; Lu LIU ; Chuxiao SHAO ; Zhili XU ; Fei PENG ; Yingfeng TU
Acta Pharmaceutica Sinica B 2023;13(9):3862-3875
Enzyme-driven micro/nanomotors consuming in situ chemical fuels have attracted lots of attention for biomedical applications. However, motor systems composed by organism-derived organics that maximize the therapeutic efficacy of enzymatic products remain challenging. Herein, swimming proteomotors based on biocompatible urease and human serum albumin are constructed for enhanced antitumor therapy via active motion and ammonia amplification. By decomposing urea into carbon dioxide and ammonia, the designed proteomotors are endowed with self-propulsive capability, which leads to improved internalization and enhanced penetration in vitro. As a glutamine synthetase inhibitor, the loaded l-methionine sulfoximine further prevents the conversion of toxic ammonia into non-toxic glutamine in both tumor and stromal cells, resulting in local ammonia amplification. After intravesical instillation, the proteomotors achieve longer bladder retention and thus significantly inhibit the growth of orthotopic bladder tumor in vivo without adverse effects. We envision that the as-developed swimming proteomotors with amplification of the product toxicity may be a potential platform for active cancer treatment.
3.Effects of early supplement of exogenous L-carnitine on renal function in severely scalded rats
Xixi TIAN ; Weichang KONG ; Pengtao LI ; Zhengguo XIA ; Jiegou XU ; Qinglian XU
Chinese Journal of Burns 2020;36(7):553-559
Objective:To explore the effects of early exogenous L-carnitine supplementation on renal function in severely scalded rats.Methods:According to the random number table, sixty-six adult female Sprague-Dawly rats were divided into healthy control group ( n=6), scald alone group ( n=30), and scald+ carnitine group ( n=30). In the latter two groups, the rats were inflicted with full-thickness scald of 30% total body surface area on the back, and the lactated Ringer′s solution was injected through the tail vein for resuscitation immediately after scald. At post injury hour (PIH) 1, rats in scald+ carnitine group were intraperitoneally injected with 100 mg/mL L-carnitine solution 400 mg/kg, while rats in scald alone group were intraperitoneally injected with the same volume of normal saline. Rats in these two groups were injected once every 24 hours thereafter. Six rats were taken from each of scald alone group and scald+ carnitine group to collect the renal tissue and abdominal aorta blood at PIH 6, 12, 24, 48, and 72, respectively. The serum content of total protein, albumin, urea nitrogen, creatinine, and cystatin C were determined by the automatic biochemical analyzer. Renal tissue was stained with hematoxylin-eosin to observe histopathological changes. Rats in healthy control group did not undergo any treatment, and their renal tissue and blood sample were extracted and analyzed in the same way as those of severely scalded rats. Data were statistically analyzed with one-way analysis of variance and Bonferroni method. Results:(1) The serum content of total protein and albumin of rats in scald alone group at each time point after injury was significantly lower than that in healthy control group ( P<0.05). The serum content of total protein of rats in scald+ carnitine group was significantly higher than that in scald alone group at PIH 12 and 24 ( P<0.05), and the serum content of albumin of rats in scald+ carnitine group was significantly higher than that in scald alone group at PIH 12 ( P<0.05). The serum content of total protein and albumin of rats in scald alone group and scald+ carnitine group showed a trend of decrease followed by an increase, with the lowest value at PIH 24. (2) The serum content of urea nitrogen and creatinine of rats in scald alone group at each time point after injury was significantly higher than that of healthy control group ( P<0.05). The serum content of urea nitrogen of rats in scald+ carnitine group was significantly lower than that in scald alone group at PIH 6, 48, and 72 ( P<0.05). The serum content of creatinine of rats in scald+ carnitine group was significantly lower than that in scald alone group at PIH 12, 24, 48, and 72 ( P<0.05). The serum content of urea nitrogen and creatinine of rats in scald alone group and scald+ carnitine group showed a trend of increase followed by a decrease, with the peak value at PIH 12. (3) The serum content of cystatin C of rats in scald alone group at PIH 6, 12, 24, 48, and 72 was (0.250±0.030), (0.330±0.070), (0.300±0.060), (0.240±0.060), and (0.190±0.030) mg/L, and the content at the first 4 time points were significantly higher than (0.170±0.020) mg/L of healthy control group ( P<0.05). At PIH 24, the serum content of cystatin C of rats in scald+ carnitine group was (0.210±0.040) mg/L, which was significantly lower than that of scald alone group ( P<0.05). The serum content of cystatin C of rats in scald alone group and scald+ carnitine group showed a trend of increase followed by a decrease, with the peak value at PIH 12. (4) The renal tissue of rats in healthy control group was almost normal, and the degree of renal tissue injury of rats in scald+ carnitine group was lighter than that in scald alone group at each time point after injury. At PIH 24, the renal tissue of rats in scald alone group showed extensive swelling of the renal tubular epithelial cells, vacuolar degeneration and necrosis, loss of brush borders, and nuclear shrinkage; more than 2/3 of the renal tubular cell nuclei disappeared, the tubular lumen was narrowed, necrotic exfoliated cells could be seen in the lumen, and edema and inflammatory cell infiltration could be seen in the renal interstitial. Compared with those of scald alone group, significantly reduced severity of edema and necrosis of renal tubular epithelial cells, as well as less inflammatory cell infiltration were observed in the renal tissue of rats in scald+ carnitine group. Conclusions:Early supplement of L-carnitine in severely scalded rats can reduce the damage of renal cells, accelerate the restoration of the content of total protein, albumin, urea nitrogen, creatinine, and cystatin C, thereby maintaining the stability of renal function metabolism level.
4. Meta-analysis of the effects of anterograde and retrograde cerebral perfusion in aortic arch surgery
Zulei ZHANG ; Wei YANG ; Yi GONG ; Miaomiao YOU ; Weichang XU ; Chao LU ; Xiao DONG
Chinese Journal of Thoracic and Cardiovascular Surgery 2019;35(9):546-550
Objective:
To explore the differences in brain protection between anterograde cerebral perfusion(ACP) and retrograde cerebral perfusion(RCP) in aortic arch surgery.
Methods:
Aortic arch circulatory surgery, ACP and RCP techniques were searched at the Cochrane Library, PubMed, EMBASE, Wanfang Database and the Chinese Biomedical Database from January 2013 to December 2018. Cohort studies were then performed with early postoperative death, transient neurological dysfunction(TND), stroke, and transient ischemic attack(TIA). For each study, data on endpoints in the ACP and RCP groups were used to generate risk ratios(
5. Influence of three-level collaboration network of pediatric burns treatment in Anhui province on treatment effects of burn children
Zhengguo XIA ; Xianliang ZHOU ; Weichang KONG ; Xingzhao LI ; Junhui SONG ; Linsen FANG ; Delin HU ; Chen CAI ; Yizhong TANG ; Youxin YU ; Chunhua WANG ; Qinglian XU
Chinese Journal of Burns 2018;34(3):143-148
Objective:
To explore the influence of three-level collaboration network of pediatric burns in Anhui province on treatment effects of burn children.
Methods:
The data of medical records of pediatric burn children transferred from Lu′an People′s Hospital and Fuyang People′s Hospital to the First Affiliated Hospital of Anhui Medical University from January 2014 to December 2015 and January 2016 to September 2017 (before and after establishing three-level collaboration network of pediatric burns treatment) were analyzed: percentage of transferred burn children to hospitalized burn children in corresponding period, gender, age, burn degree, treatment method, treatment result, occurrence and treatment result of shock, and operative and non-operative treatment time and cost. Rehabilitation result of burn children transferred back to local hospitals in 2016 and 2017. Data were processed with
6. Effect of early supplementation of exogenous carnitine on liver mitochondrial damage in severely scalded rats and its pathological mechanism
Weichang KONG ; Zhengguo XIA ; Xixi TIAN ; Jiegou XU ; Qinglian XU
Chinese Journal of Burns 2018;34(6):374-379
Objective:
To observe the effect of early supplementation of exogenous carnitine on liver mitochondrial damage in severely scalded rats and to explore its pathological mechanism.
Methods:
Seventy-two adult female Sprague-Dawley rats were divided into sham injury group, scald injury group, and scald injury+ carnitine group according to the random number table, with 24 rats in each group. Rats in sham injury group was sham injured on the back by immersing in 37 ℃ water bath for 12 s without fluid replacement. While rats in scald injury and scald injury+ carnitine groups were inflicted with 30% total body surface area (TBSA) full-thickness scald on the back by immersing in 98 ℃water bath for 12 s. Immediately after injury, rats in scald injury group and scald injury+ carnitine group were injected with Ringer′s lactate solution with the dosage of 4 mL·kg-1·%TBSA-1 via tail vein according to the Parkland formula, meanwhile rats in scald injury+ carnitine group were injected with L-carnitine solution with dosage of 300 mg·kg-1·d-1 via tail vein from post injury hour (PIH) 1. At PIH 12, 24, 48 and 72, abdominal aorta blood and liver tissue were collected from 6 rats in each group. The serum levels of carnitine, β-hydroxybutyric acid, and ornithine carbamoyltransferase (OCT) were determined with enzyme-linked immuno sorbent assay, and the serum levels of lactate dehydrogenase (LDH), alanine aminotransferase(ALT), and aspartate transaminase (AST) was determined by automatic biochemical analyzer, Pathological changes of rats liver tissue were detected with HE staining. Data were processed with analysis of variance of factorial design and Student-Newman-Keulstest or Tamhane test, Bonferroni correction.
Results:
(1) Compared with sham injury group, the serum level of carnitine of rats in scald injury group was significantly lower at each time point (
7.Urine metabolomics analysis of patients with acute pancreatitis
Shenglan LIU ; Qiang GUO ; Xinjing YANG ; Xue SUN ; Daguo ZHAO ; Jun XU ; Weichang CHEN
Chinese Journal of Pancreatology 2017;17(6):380-385
Objective To detect the small molecular metabolite profiles of urine from patients with acute pancreatitis (AP) in different severity,and screen the differential metabolites that have potential diagnostic value for AP and its severity.Methods Urine samples were collected from 65 AP patients (MSAP and SAP 29,MAP 36) in the First Affiliated Hospital of Soochow University,and 25 healthy volunteers served as controls.The liquid chromatograph mass spectrometer (LC-MS) combined method was used to detect urine small molecule metabolites of AP patients and healthy controls.Multivariate statistical analysis was used to establish and validate the principal component analysis (PCA) model and partial least squares discriminate analysis (PLS-DA) model to select the differential metabolites.Results PCA model had a good degree of interpretation (R2X >0.5),and each group of urine samples showed a good distinction between clustering trends,and good classification models were obtained.In the PLS-DA model,the differences among groups were further highlighted,and samples of each group showed distinct differentiation between clusters,with high predictability (Q2 > 0.7).The model was reliable and effective indicated by the PLS-DA permutation test.17 differential metabolites were screened out by comparing AP with control.A diagnostic model constructed with 7 differential metabolites including nonanedioic acid,succinic acid semialdehyde,D-beta-hydroxy butyric acid,acetylcarnitine,angelic acid,sebacic acid and hippuric acid had a high diagnostic value for AP,with the sensitivity of 100% and the specificity of 94%.Then control,MAP and MSAP + SAP group were compared with each other,and it was found that the model integrating urine succinic acid semialdehyde,angelic acid,D (-)-beta-hydroxy butyric acid,malic acid and acetylcarnitine had a good diagnostic value for SAP,with the sensitivity and specificity of both 90%.Conclusions LC-MS metabolomics can effectively identify the changes of urine metabolism in patients with different severity of AP.The screened differential metabolites have the potential clinical value in the diagnosis and classification of AP.
8.Effect and mechanism of exogenous carbon monoxide against excessive neutrophil infiltration in liver and lung tissues during sepsis
Xu WANG ; Mingming SONG ; Weichang SHEN ; Weiting QIN ; Wanghui LYU ; Bingwei SUN
Chinese Journal of Trauma 2015;31(3):201-206
Objective To determine the inhibitory effect and mechanism of exogenous carbon monoxide against excessive neutrophil infiltration in liver and lung tissues during sepsis.Methods Thirty-two mice were subjected to sham operation (sham group),cecal ligation and perforation (CLP) group,CLP with 8 mg/kg of exogenous carbon monoxide releasing molecule Ⅱ (CORM-2) (CORM-2 group),and CLP with 8 mg/kg of inactive variants of CORM-2 (iCORM-2) (iCORM-2 group) according to the random number table,with 8 mice per group.Liver and lung tissues were collected at 24 hours after surgery to examine the pathologic changes,myeloperoxidase (MPO) activity and malonaldehyde (MDA) content.Another 60 mice were enrolled into the same 4 groups with 15 mice per group and were tested for 72-hour survival rate.Bone marrow neutrophils were isolated and divided into normal control group,1 μg/ml lipopolysaccharide (LPS) group,1 μg/ml LPS plus 10 μmol/L CORM-2 group (low dose group),1 μg/ml LPS plus 50 μmol/L CORM-2 group (high dose group),1 μg/ml LPS plus 50 μmol/L iCORM-2 group (iCORM-2 group).Under the agarose chemotaxis,qPCR and immunofluorescence detection of formyl peptide receptor 1 (FPR1) were performed.Results CLP group presented enhanced activity of MPO [liver:(9.1 ± 1.1) U/g,lung:(16.3 ± 2.8) U/g],increased MDA content [liver:(76.5 ±11.3) nmol/mg,lung:(32.4 ± 10.3) nmol/mg] and 72-hour survival rate of 20% as compared with the sham group (all P < 0.05).CORM-2 group showed inhibited activity of MPO [liver:(5.2 ± 0.8) U/g,lung:(7.5 ± 2.4) U/g],increased MDA content [liver:(46.7 ± 6.1) nmol/mg,lung:(23.8 ±7.3) nmol/mg] and 72-hour survival rate of 67% as compared with the sham group (all P < 0.05).LPS enhanced neutrophil migration (61.3 ± 7.1) (P < 0.05) and expression of FPR1 which was enriched in the membrane.Meanwhile,neutrophil migration was significantly inhibited in a dose-dependent of CORM-2 (low dose group:43.3 ±6.1,high-dose group:23.3 ±5.9) (P<0.05).Conclusions Exogenous carbon monoxide is effective to inhibit the excessive neutrophil infiltration,attenuate oxidative stress or pathological injury,and improve the survival from sepsis.The mechanism is associated with the down-regulation of FPR1,inhibition of FPR1 enrichment in the membrane,and decreased neutrophil migration.
9.Inhibitory effects of Kukoamine B on the inflammatory response of small intestine in lipopolysaccharide- induced septic mice and its potential mechanisms
Wanghui LYU ; Weiting QIN ; Jinli ZHANG ; Weichang SHEN ; Xu WANG ; Bingwei SUN
Chinese Critical Care Medicine 2015;(2):121-126
ObjectiveTo study the role of Kukoamine B (KB) in inhibiting the inflammatory response of small intestine in septic mice and its molecular mechanisms.Methods Twenty-four male ICR mice were randomly divided into control group, model group, and KB intervention group (each,n= 8). Sepsis model was reproduced by intra-peritoneal injection of 20 mg/kg lipopolysaccharide (LPS), while equivalent normal saline was given in control group, and 20μg/kg KB was injected through caudal vein 4 hours after LPS challenge in KB intervention group. The blood/tissue samples (jejunum and ileum) were harvested 8 hours after LPS injection. The levels of plasma LPS, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured. The pathological changes in small intestine tissues were observed under light microscope, while the levels of inflammatory cytokines TNF-α and IL-1β in the tissue homogenates (jejunum and ileum) were assessed by enzyme linked immunosorbent assay (ELISA). The activity of myeloperoxidase (MPO) was measured by colorimetry. The expression of intercellular adhesion molecule-1 (ICAM-1) was determined by immunohistochemistry. The expressions of inducible nitric oxide synthase (iNOS) mRNA was assayed by reverse transcription-polymerase chain reaction (RT-PCR). The activation of nuclear factor-κΒ (NF-κΒ) was determined by Western Blot.Results The mice in model group were found to have an increase in microvascular permeability, interstitial edema, and infiltration of white blood cells, and the levels of LPS, TNF-α and IL-1β in their plasma, with an increase in concentrations of TNF-α and IL-1β, activity of MPO, positive expression of ICAM-1, expression of iNOS mRNA and NF-κB protein in small intestine (jejunum and ileum). Compared with model group, in mice with KB intervention, microvascular permeability, interstitial edema, and infiltration of white blood cells were reduced significantly, while the levels of LPS, TNF-α and IL-1β in plasma, the concentration of TNF-α and IL-1β, the activity of MPO, the positive expression of ICAM-1, the expression of iNOS mRNA and NF-κB protein in small intestine (jejunum and ileum) were significantly decreased [plasma LPS (kEU/L): 654.09±28.13 vs. 1 155.65±47.15, TNF-α (ng/L): 12.75±0.47 vs. 30.61±0.71, IL-1β (ng/L): 53.06±5.32 vs. 64.47±2.61; jejunum TNF-α(ng/L): 43.27±1.20 vs. 64.82±2.09, IL-1β (ng/L): 326.38±14.47 vs. 535.22±13.48, MPO (U/g): 0.14±0.01 vs. 0.32±0.02, iNOS mRNA (2-ΔΔCt): 2.39±0.13 vs. 10.80±0.22, NF-κB protein (gray value): 0.687±0.062 vs. 1.404±0.046; ileum TNF-α (ng/L): 62.75±3.92 vs. 104.24±2.82, IL-1β(ng/L): 408.06±1.70 vs. 521.97±1.16, MPO (U/g): 0.36±0.08 vs. 0.66±0.05, iNOS mRNA (2-ΔΔCt): 1.65±0.11 vs. 3.59±0.29, NF-κB protein (gray value):0.830±0.114 vs. 1.609±0.051, allP< 0.05].Conclusion KB can combine with LPS and inhibit LPS/Toll-like receptor 4 (TLR4) signaling pathway, thereby significantly inhibit the inflammatory response and protect the function of the small intestine in LPS-induced septic mice.
10.Effects of Compound Angelica Injection on Rats with Cerebral Ischemia Injury
Yibo TANG ; Chunyan ZHU ; Weichang YUAN ; Sai ZHANG ; Linpeng ZHANG ; Wei ZHANG ; Tianlong MU ; Xu WANG ; Xiaomin YANG ; Xuefei HE ; Yanshu PAN
Chinese Journal of Information on Traditional Chinese Medicine 2015;(2):68-70
Objective To investigate neurological function, volume of cerebral infarction, changes of lipid peroxidation, and the intervention effect of compound angelica injection (CAI) on rats with focal cerebral ischemia injury. Methods Models of rat with cerebral ischemia were reproduced by middle cerebral artery occlusion (MCAO). All animals were randomly divided into sham-operation group, model group, CAI group, and edaravone group. 1 hour after the models were established, rats in the sham-operation group and model group received intraperitoneal injection with normal saline, while rats in CAI group and edaravone group received intraperitoneal injection with relevant medicine for continuing 7 days. Volume of cerebral infarction was detected by Tetrazole staining method, neurologic function were detected by neuroethology, and concentration of MDA in brain tissue was also detected. Results After 7-day cerebral ischemia, compared with the model group, volume of cerebral infarction in CAI group was significantly reduced (P<0.05), and the concentration of MDA was a little lower. Conclusion CAI has significant protective effects which can significantly improve neurological function, reduce volume of cerebral infarction, and alleviate the effects of lipid peroxidation of rats with focal cerebral ischemia injury.

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