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    Journal of Shanghai Jiao Tong University (Medical Science) 2023 Vol.43
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    Role of methyltransferase like 3 regulating pri-miR-21 methylation in renal fibrosis of diabetes nephropathy
    WU Jiajin, ZHONG Chen, LI Dawei, CHEN Ruoyang, QU Junwen, ZHANG Ming
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 1-7.   DOI: 10.3969/j.issn.1674-8115.2023.01.001
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    Objective ·To investigate the role of methyltransferase like 3 (METTL3) acting on N6-methyladenosine (m6A) and regulating pri-miR-21 methylation in the renal fibrosis of diabetic nephropathy (DN). Methods ·Eight-week-old male db/db mice were used as DN models, and db/m mice were used as controls. The mice were randomly divided into 4 groups according to whether they received the treatment of 3-deazaadenosine (DAA) by tail vein injection or not (5 mice/group): db/m group, db/db group, db/m+DAA group and db/db+DAA group. From the age of 8 weeks, DAA was injected once per 5 d for a total of 8 times. After the DAA intervention, the mice were kept until they were 19 weeks old. The blood, the urine and the kidney tissue samples of the mice were collected, and blood glucose (BG), serum creatinine (Scr), and urinary albumin-to-creatinine ratio (ACR) were detected. The kidneys were stained with hematoxylin-eosin (H-E), Masson and sirius red to observe the pathological changes. The methylation level of m6A in total RNAs of the kidney was detected with the kit. The expression levels of METTL3 and fibrosis-related proteins in the kidney were detected by Western blotting. The overall pri-miR-21 and the mature miR-21 were detected by real-time quantitative PCR. After enrichment of the m6A-methylated RNAs in the kidney by immunomagnetic beads, the methylated pri-miR-21 at m6A was detected by PCR. Results ·Compared with the db/m group, the levels of BG, Scr, and ACR, and METTL3, m6A methylation level, fibrosis-related proteins, overall pri-miR-21, m6A-methylated pri-miR-21 and mature miR-21 in the kidney in the db/db group significantly increased (P<0.05). Furthermore, the mesangial matrix in the kidney increased, glomerular basement membrane thickened, and the accumulation of collagen fibers increased significantly in the db/db group. Compared with the db/db group, the levels of BG, Scr, and ACR, and m6A methylation level, fibrosis-related proteins, m6A-methylated pri-miR-21 and mature miR-21 in the kidney in the db/db+DAA group decreased significantly (P<0.05) and the degree of renal injury and fibrosis was significantly reduced, but the expression level of overall pri-miR-21 significantly increased (P=0.000). The expression level of METTL3 protein did not change significantly. Conclusion ·The m6A methylation modification of pri-miR-21 promotes the maturation of miR-21, thereby promoting the occurrence and development of renal fibrosis in DN mice; inhibition of METTL3 can inhibit renal fibrosis in DN mice by regulating m6A methylation of pri-miR-21.

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    Preventive effect of icariin on transition from acute kidney injury to chronic kidney disease in mouse model
    XIE Lin, CHENG Ye, ZHENG Qimin, ZHANG Xi, FU Lili, CHEN Min, WANG Yi, MEI Changlin, XIE Jingyuan, GU Xiangchen
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 8-19.   DOI: 10.3969/j.issn.1674-8115.2023.01.002
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    Objective ·To investigate the effect of icariin on the transition from acute kidney disease (AKI) to chronic kidney disease (CKD) in mice and the possible mechanism. Methods ·C57BL/6 mice were intraperitoneally injected with aristolochic acid for 2 weeks to mimic AKI to CKD transition. Icariin was intragastrically administered for 2 or 5 weeks at the end of 2 weeks of aristolochic acid injection or 1 week before modeling. The renal function and pathological injury of the mice were monitored. The mitochondrial structure of renal tubular epithelial cells was observed by transmission electron microscopy. The indexes related to fatty acid oxidative metabolic pathway, fibrosis, and inflammation were detected by quantitative PCR (qPCR) and immunohistochemical staining. The rat renal fibroblast cell line and the rat renal tubular epithelial cell lines were co-cultured in Transwell cell chambers to simulate the interaction between the two types of cells. The renal tubular epithelial cells were pretreated with icariin for 1 h, and then treated with aristolochic acid for 24 h. After removing the two drugs, the renal tubular epithelial cells and the fibroblasts were co-cultured for 24 h. The mRNA or protein expression levels of peroxisome proliferator-activated receptor α (Ppara), pro-fibrotic factors, inflammatory factors, activated caspase-3 (cleaved caspase-3), and extracellular matrix-associated genes in renal fibroblasts were detected by qPCR or Western blotting. The renal tubular epithelial cells were transfected with Ppara-siRNA to observe the expression changes of cleaved caspase-3 and the related indicators of mitochondrial fatty acid oxidative metabolism in the downstream of PPARα after icariin intervention prior to aristolochic acid. Results ·Compared with the control group, the serum creatinine and urea nitrogen levels of the mice injected with aristolochic acid only were significantly higher, with a large number of inflammatory cells infiltrating into the kidney and serious renal tubular injury at the end of 2 weeks of aristolochic acid injection and 2 weeks after the last injection (4 weeks). The renal function was significantly improved, and the pathological damage was attenuated in the mice pretreated with icariin. After 4 weeks of modeling, the mitochondrial structure of renal tubular epithelial cells was seriously damaged in the aristolochic acid group, and the mRNA levels of fatty acid oxidative metabolic pathway-related genes were significantly downregulated, compared to the control group, accompanied by macrophage infiltration and renal fibrosis. Icariin pretreatment attenuated these damages generated by aristolochic acid. The serum creatinine and urea nitrogen levels, renal pathological injury, and fibrotic markers of the mice treated with icariin at the end of 2 weeks of aristolochic acid injection showed no difference from the aristolochic acid group. In the in vitro experiments, aristolochic acid treatment suppressed Ppara mRNA expression and elevated cleaved caspase-3, inflammatory factors, and pro-fibrotic factors in renal tubular epithelial cells. It also upregulated the expression of extracellular matrix-related genes in co-cultured renal fibroblasts. In contrast, icariin pretreatment abrogated the changes caused by aristolochic acid. The knockdown of Ppara by siRNA in renal tubular epithelial cells removed the preventive effects of icariin on aristolochic acid inhibiting fatty acid oxidative metabolism and promoting cell apoptosis. Conclusion ·Icariin prevents AKI to CKD transition induced by aristolochic acid in mice. It may play its protective role by improving the mitochondrial fatty acid oxidative metabolic pathway, especially through PPARα, in renal tubular epithelial cells.

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    MicroRNA-30b-5p inhibits autophagy in ovarian granulosa cells in polycystic ovary syndrome rats by targeting Atg5
    WANG Xuemin, WANG Yanan, NIU Aiqin, YE Ying, LI Fei
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 20-28.   DOI: 10.3969/j.issn.1674-8115.2023.01.003
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    Objective ·To explore the expression of microRNA-30b-5p (miR-30b-5p) in polycystic ovary syndrome (PCOS) rats and the effect of miR-30b-5p overexpression on ovarian granulosa cell (GC) autophagy. Methods ·Dehydroepiandrosterone (DHEA) was performed to establish a PCOS rat model, and real-time fluorescent quantitative PCR (qRT-PCR) and Western blotting were performed to measure the expression of miR-30b-5p and autophagy-associated protein 5 homologue (Atg5) in the ovarian tissues of the normal group and PCOS group. Primary PCOS rat ovarian GCs were isolated and cultured, and divided into control group, miR-NC group, miR-30b-5p overexpression group, miR-30b-5p overexpression+pcDNA3.1-NC group, and miR-30b-5p overexpression+pcDNA3.1-Atg5 group. In addition, the ovarian GC of the normal group was taken as the blank group. MiR-30b-5p mimic, pcDNA3.1-Atg5 and the corresponding negative control were transfected into the cells, and 48 h after transfection, qRT-PCR was performed to measure the expression of miR-30b-5p and Atg5 mRNA of cells in each group to verify the transfection effect. CCK-8 and flow cytometer were performed to measure cell viability and apoptosis rate, respectively; immunofluorescence staining was performed to measure the positive expression of microtubule-associated protein 1 light chain 3 (LC3) in each group. Western blotting was performed to measure the protein expression of autophagy-related proteins Atg5, p62, Beclin-1 and LC3. Results ·The expression level of miR-30b-5p in the ovarian tissue of the PCOS group was significantly lower than that of the normal group, and the levels of Atg5 mRNA and protein were significantly higher than those of the normal group (all P=0.000). After transfection, compared with the blank group, the miR-30b-5p level, apoptosis rate, and p62 protein level in the ovarian GC of the control group were significantly reduced, the Atg5 mRNA and protein levels, cell proliferation activity, LC3 positive cell percentage, Beclin-1 protein level and LC3Ⅱ/LC3Ⅰ ratio were significantly increased (all P=0.000). Compared with the control group, the miR-30b-5p level, apoptosis rate, and p62 protein level in the ovarian GC of the miR-30b-5p overexpression group were significantly increased, and the Atg5 mRNA and protein levels, cell proliferation activity, LC3 positive cell percentage, Beclin-1 protein level and LC3Ⅱ/LC3Ⅰ ratio were significantly reduced (all P=0.000). Up-regulation of Atg5 can significantly attenuate the inhibitory effect of miR-30b-5p overexpression on ovarian GC proliferation and autophagy (all P=0.000). Conclusion ·MiR-30b-5p is lowly expressed in PCOS; overexpression of miR-30b-5p can inhibit the proliferation and autophagy of ovarian GC in PCOS rats, and promote cell apoptosis, and its mechanism may be related to the inhibition of Atg5 expression.

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    Characteristics and clinical significance of serum renalase in patients with acute ischemic stroke
    JIANG Wenqun, HOU Pinpin, CHEN Yan, JIA Feng, ZHANG Xiaohua, GAO Li, HU Qin
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 29-35.   DOI: 10.3969/j.issn.1674-8115.2023.01.004
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    Objective ·To examine the level change of serum renalase in the patients with acute ischemic stroke (AIS), and analyze its role in evaluating disease. Methods ·A total of 118 AIS patients admitted to the Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine from July 2020 to November 2021 were enrolled in the case group (AIS group). The patients were assessed for neurological deficits according to the National Institutes of Health Stroke Scale (NIHSS), and were classified as mild and moderate-severe neurological deficits. Another 133 healthy people who participated in physical examination in the physical examination center of the hospital during the same period were selected as the control group. The serum renalase levels of the two groups were detected by ELISA. Spearman's rank correlation analysis was used to evaluate the correlation between the levels of serum renalase and gender, age, fasting blood glucose, blood lipids and NIHSS scores in the patient with AIS. The predictive value of renalase expression level in AIS diagnosis was analyzed by receiver operator characteristic (ROC) curve. The factors that were statistically significant in the results of the univariate Logistic regression analysis were included in the multivariate Logistic regression model. Results ·The level of serum renalase in the AIS group was 2 960.01 (1 557.99, 4 053.70) pg/mL, which was higher than 821.02 (391.29, 1 752.70) pg/mL in the control group, with a statistically significant difference (P=0.000). Spearman's rank correlation analysis showed that the levels of serum renalase in the patients with AIS were negatively correlated with the NIHSS scores (r=-0.216, P=0.019), positively correlated with the serum fasting glucose (r=0.200, P=0.030), and not significantly correlated with gender, age, low-density lipoprotein levels, total cholesterol levels, and the presence of hypertension, diabetes, or coronary heart disease. Serum renalase levels were higher in the AIS with mild neurological deficit patients than those in the moderate-severe deficit patients, and the difference was statistically significant (P=0.034). The ROC curve showed that the cut-off value of serum renalase level to diagnose AIS was 1 856.49 pg/mL, the area under the curve was 0.777±0.030 and its 95%CI was 0.718?0.836 (P=0.000). Multivariate Logistic regression analysis showed that elevated serum renalase level [>1 856.49 pg/mL, odds ratio (OR)=6.980, P=0.000], hypertension (OR=5.382, P=0.000), and diabetes (OR=2.453, P=0.040) were risk factors for AIS. Conclusion ·Serum renalase level is significantly elevated in AIS patients, and negatively correlated with NIHSS score. Serum renalase might be a potential biomarker for the auxiliary diagnosis and assessment of AIS, providing new ideas for the assessment of stroke disease progression and precise treatment.

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    Effect of short-term GnRH pulse therapy on pituitary-testicular function in adolescent male patients with congenital hypogonadotropic hypogonadism
    WANG Fei, GONG Yan, XU Liya, LIU Qingxu, LI Yan, GUO Sheng, LI Pin
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 36-43.   DOI: 10.3969/j.issn.1674-8115.2023.01.005
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    Objective ·To investigate the effect of short-term gonadotropin-releasing hormone (GnRH) pulse therapy on pituitary and testicular function in the adolescent male patients with congenital hypogonadotropic hypogonadism (CHH). Methods ·A retrospective study was conducted on 20 adolescent male patients with CHH who received GnRH pulse therapy from January 2016 to June 2021, and their clinical data were collected. They were treated with subcutaneous continuous pulsed administration of gonadorelin by the pump for 1 week (20 cases), of which 5 cases were treated for 3 months. The dose was 8?10 μg per pulse, and the pulse interval was 90 min. The levels of luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone were measured before GnRH pulse therapy at 1 week, 1 month and 3 months after treatment. After 3 months of treatment, the testicular volume was measured. All 20 patients with CHH underwent whole exome sequencing. Results ·The age of 20 CHH patients was 14.35 (14.08, 15.31) years old. The clinical manifestations were infantile testis (20/20) and micropenis (20/20), followed by obesity (12/20), dysosmia (9/20), insulin resistance (4/20), cryptorchidism (4/20), and short stature (3/20). The patients' height was 161.79 (154.90, 173.25) cm, body mass index was 23.80 (20.51, 27.46) kg/m2, and testicular volume was 0.91 (0.55, 1.25) mL. Inhibin B was 39.67 (11.29, 64.97) pg/mL; the base values of LH, FSH and testosterone before therapy were 0.20 (0.10, 0.30) IU/L, 0.87 (0.23, 0.89) IU/L, and 0.92 (0.38, 1.49) nmol/L, respectively. After 1 week of continuous GnRH pulse therapy, the base and peak values of LH and FSH and the peak value of testosterone in the 20 patients significantly increased (all P<0.05). In the 5 patients treated for 3 months, the base values and peak values of LH and FSH gradually increased with the prolongation of treatment time. After 3 months of treatment, the base values and peak values of LH and FSH, and the peak value of testosterone were significantly higher than those before treatment (all P<0.05), and the testicular volume was also significantly increased (P=0.004). Gene mutations were detected in only 14 of 20 patients, including fibroblast growth factor receptor 1 (FGFR1) mutations in 7 cases, anosmin 1 (ANOS1) mutations in 4 cases, prokineticin receptor 2 (PROKR2) mutations in 2 cases, and a prokineticin 2 (PROK2) mutation in 1 case. There was no significant difference of the effect of GnRH pulse therapy for 1 week on pituitary-testicular function between the patients with FGFR1 mutations and ANOS1 mutations. Conclusion ·The continuous GnRH pulse therapy for 1 week can make pituitary-testicular function respond in adolescent male CHH patients; the treatment for 3 months helps to induce the secondary sexual characteristics of puberty.

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    A case-control study of the relationship between early-life environmental exposure and childhood asthma
    DENG Yuntian, XIONG Wenkui, ZHU Rui, LIU Enmei, LI Xuemei, ZHONG Zhaohui
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 44-51.   DOI: 10.3969/j.issn.1674-8115.2023.01.006
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    Objective ·To explore the potential impact of early-life environmental exposure on childhood asthma in Chongqing, China. Methods ·A case-control study was designed. The cases with asthma diagnosis were enrolled from outpatients of the respiratory medicine departments and the healthy children without history of asthma were enrolled from health check-up clinics of the child health care departments in two tertiary children's hospitals in Chongqing from September 2020 to January 2022. The children in the two groups had all lived in Chongqing since birth and their home addresses had not changed before they were 3 years old. A self-developed “Children's Early-Life Environment Survey” was used to collect general personal data, family information, child health status, birth history, and indoor environment from birth to 3 years old (second-hand smoke, dampness and mold points in bedroom, seen cockroaches in bedroom, bedroom cleaning frequency, air conditioning and air purifier use, and decoration). Based on the home address information before 3 years old, annual particular matter 2.5 (PM2.5) exposure levels were estimated by using a high spatiotemporal resolution model. Univariate and multivariate Logistic regression models were used to analyze the early-life environmental factors affecting the development of childhood asthma. The risk factors which were statistically significant in univariate Logistic regression or had clinical significance were included in the multivariate model. Results ·A total of 220 asthma cases and 636 healthy control children were enrolled. The mean age of the asthma cases and the controls were (7.4±2.1) and (7.6±2.1) years old, respectively. There were no statistically significant differences in age, gender, gestational age, birth weight, mode of delivery, family size, annual family income, maternal education level and living space per person. Multivariate Logistic regression analysis showed that early-life bedroom dampness and mold exposure [odds ratio (OR)=2.155, 95% confidence interval (CI) 1.304?3.559, P=0.003], bedroom cockroach exposure (OR=1.830, 95%CI 1.287?2.601, P=0.001), bedroom air conditioner use (OR=2.328, 95%CI 1.098?4.937, P=0.028), second-hand smoke exposure (OR=1.762, 95%CI 1.272?2.440, P=0.001), and long term exposure to PM2.5 at one year old (OR=1.063, 95%CI 1.034?1.093, P=0.000) increased the risk of childhood asthma. Daily use of air purifier (OR=0.416, 95%CI 0.213?0.812, P=0.010) could reduce the risk of childhood asthma. Conclusion ·Early-life environmental exposure is of great significance for the development of childhood asthma. Early-life bedroom dampness and mold exposure, cockroach exposure, second-hand smoke, incorrect use of air conditioner, and long-term exposure of children to PM2.5 in the first year after birth are independent risk factors for the development of childhood asthma.

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    Construction and evaluation of a nomogram prediction model for bacterial infection in patients with decompensated hepatitis C cirrhosis
    XUE Linlin, LI Binghan, CHANG Lixian, LI Weikun, LIU Chunyun, LIU Li
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 52-60.   DOI: 10.3969/j.issn.1674-8115.2023.01.007
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    Objective ·To explore the influencing factors of bacterial infection in decompensated stage of hepatitis C cirrhosis, and establish a risk prediction model of nomogram. Methods ·A total of 574 patients with decompensated hepatitis C cirrhosis were retrospectively collected from The Third People′s Hospital of Kunming between January 2020 and December 2021, and divided into non-infected and infected groups according to whether bacterial infection occurred. The general information, complications, and laboratory indicators were collected. The variables were screened by univariate analysis, and least absolute shrinkage and selection operator (LASSO) regression, and the nomogram model were constructed and verified by multivariate Logistic regression analysis of influencing factors. The decision curve and clinical impact curve (CIC) were used to evaluate the clinical application value of the model. Results ·Bacterial infections occurred in 28.4% (163/574) of the patients, with a total of 191 sites, mainly including spontaneous bacterial peritonitis (86/191) and pulmonary bacterial infections (79/191). Totally 78 strains of pathogens were isolated and cultured, mainly including Klebsiella pneumoniae (15/78) and Escherichia coli (15/78). Multivariate Logistic regression analysis showed that age ≥60 years [odds ratio (OR)=2.054, 95% confidence interval (CI) 1.104?3.822, P=0.023], female (OR=1.701, 95%CI 1.112?2.602, P=0.014), ascites (OR=2.386, 95%CI 1.601?3.557, P=0.000), history of invasive procedures in the last two weeks (OR=2.605, 95%CI 1.368?4.960, P=0.004), and hospitalization time≥2 weeks (OR=1.629, 95%CI 1.098?2.416, P=0.015) were independent risk factors for bacterial infection in decompensated hepatitis C cirrhosis patients, while infusing human serum albumin (OR=0.324, 95%CI 0.194?0.542, P=0.000) and high level of total cholesterol (OR=0.675, 95%CI 0.549?0.830, P=0.000) were protective factors. The nomogram model was constructed with the above seven influencing factors. Receiver operator characteristic (ROC) curve analysis showed that the area under the curve (AUC) was 0.736 and the sensitivity was 80.4%; and the specificity was 65.1%. Hosmer-lemeshow test showed that the model had a good degree of fit (χ2=9.030, P=0.340). The bootstrap method was used for internal repeated sampling for 1 000 times, the average absolute error was 0.010, the calibration curve and the ideal curve were basically fitted, and the predicted values were in good agreement with the actual values. The decision curve showed that the nomogram model had certain clinical practicability in the high risk threshold range (0.040?0.715). CIC showed that the nomogram model can be used to forecast the high-risk population in different levels. Conclusion ·The nomogram risk prediction model constructed in this study has good predictability, consistency and clinical practicability, and can provide evidence for clinicians to preliminary judge the risk of bacterial infection in patients with decompensated hepatitis C cirrhosis.

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    A meta-analysis of prevalence of mouth opening restriction in patients with oral cancer
    YANG Ling, HOU Lili, ZHAO Yan, CHEN Weihong, ZHANG Jinfeng, MAO Yan
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 61-69.   DOI: 10.3969/j.issn.1674-8115.2023.01.008
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    Objective ·To study the prevalence of mouth opening restriction in oral cancer patients by meta-analysis. Methods ·China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journal Database (VIP), Wanfang Data (Wanfang), Chinese BioMedical Literature Database (CBM), PubMed, Ovid, EMbase, Cochrane Library, Web of Science/SciSearch, and ClinicalTrials.gov were searched for observational studies about the prevalence rate of restricted mouth opening in oral cancer patients (including prospective, retrospective, and cross-sectional studies). The time limit for retrieval was from the database establishment to April 30th, 2022. The obtained documents were independently screened and extracted according to the inclusion and exclusion criteria, and the literature quality evaluation was performed by using methodological index for non-randomized studies (MINORS). The data were combined with the mouth-opening-restricted prevalence rate as the outcome indicator, the meta-analysis was performed by using Stata 15.0 software, and the subgroup analysis was performed based on the detection time, tumor site, and tumor stage. The evidence quality of outcome indicators was evaluated by using GRADE profiler 3.6 software according to GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system. Results ·A total of 3 719 documents were obtained during the initial examination, and 18 documents were finally included, including 2 701 objects. The meta-analysis results showed that the total prevalence rate of mouth opening restriction in oral cancer patients was 42.7% (95%CI 27.0%?59.1%). The results of subgroup analysis showed that the prevalence rates of mouth opening restriction in patients with oral cancer before surgery, and 3 months, 6 months and 1 year or more after surgery were 29.6% (95%CI 9.0%?55.8%), 75.2% (95%CI 68.3%?81.5%), 59.1% (95%CI 38.8%?77.9%) and 22.3% (95%CI 2.0%?54.3%), respectively. The prevalence rates of mouth opening restriction in patients with oral cancer at T1?T2 stage and T3?T4 stage were 38.6% (95%CI 26.0%?52.0%) and 99.6% (95%CI 93.9%?100.0%) respectively. The prevalence rates of mouth opening restriction in patients with oral cancer in the retromolar triangle, the gingiva, the tongue, the salivary gland, the floor of mouth and the lip were 93.1% (95%CI 68.5%?100.0%), 68.1% (95%CI 52.9%?81.7%), 46.1% (95%CI 11.6%?82.7%), 26.1% (95%CI 15.9%?37.5%), 21.9% (95%CI 0.7%?54.0%), and 3.1% (95%CI 0?9.3%), respectively. The GRADE system for evidence quality grading indicated that the quality of evidence for outcome indicator was extremely low. Conclusion ·The total prevalence rate of mouth opening restriction in patients with oral cancer is high, nearly 50%; the patients at 3 months after surgery, at 6 months after surgery, at T3?T4 stage or whose tumor located in the retromolar triangle have higher prevalence rates.

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    Effect of prehabilitation on outcomes in patients undergoing elective gastrointestinal surgery: a systematic review
    FANG Fang, TAI Rui, YU Qian, ZHANG Yaqing
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 70-78.   DOI: 10.3969/j.issn.1674-8115.2023.01.009
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    Objective ·To systematically evaluate the effect of prehabilitation on outcomes in patients undergoing elective gastrointestinal surgery. Methods ·PubMed, EMbase, Cochrane Library, Web of Science, CINAHL, Chinese BioMedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Wanfang and VIP Database were searched systematically from the establishment of each database to January 31, 2022. The literatures were screened, and evaluated according to the preset inclusion and exclusion criteria. The literature quality was evaluated and the data were extracted. Meta-analysis was performed on randomized controlled trials by using RevMan 5.4. The main observation indexes were the postoperative complication rate and the incidence of surgical site infection. The secondary indexes were hospitalization days, 6-minute walk test (6MWT), Hospital Anxiety and Depression Scale (HADS) score, mortality and compliance of prerehabilitation execution. Results ·Sixteen articles were included, including 15 articles in English and 1 article in Chinese, with a total of 1 616 patients. The overall quality of the included researches was good. The meta-analysis results showed that compared with the control group, the incidences of postoperative complications and surgical site infection were reduced [(odds ratio, OR)=0.57, 95% (confidence interval, CI) 0.35?0.94, P=0.030; OR=0.64, 95%CI 0.46?0.90, P=0.009]; the length of hospital stay was shortened [mean difference (MD)=-2.45, 95%CI -3.17 ? -1.73, P=0.000] in the experimental group after the implementation of prehabilitation. There was no significant difference in preoperative 6MWT level between the two groups. Compared with the baseline, the change of 6MWT level before operation of the experimental group was bigger than that of the control group (MD=24.19, 95%CI 3.77?44.60, P=0.020). There were no significant differences in the preoperative HADS score and the postoperative mortality between the two groups. Conclusion ·Prehabilitation can reduce the incidence of postoperative complications, especially surgical site infection, in patients undergoing elective gastrointestinal surgery, thus shortening the length of hospital stay and promoting the recovery of patients.

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    Establishment of a 3D culture model in vitro of pancreatic cancer primary cells using hydrogel microspheres
    MA Fangfang, QIN Jiejie, REN Lingjie, TANG Xiaomei, LIU Jia, SHI Minmin, JIANG Lingxi
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 79-87.   DOI: 10.3969/j.issn.1674-8115.2023.01.010
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    Objective ·To establish an in vitro culture model mimicking tumor microenvironment using hydrogel microspheres and fresh primary pancreatic cancer cells. Methods ·The morphological distribution of the hydrogel microspheres was recorded, observed and photographed under an inverted fluorescence microscope. The diameter of the microspheres was calculated by Image J, and the particle size distribution map was obtained by statistics. Renal epithelial cells (293T), pancreatic cancer cells (8988), and normal pancreatic epithelial cells (HPNE) were grown in DMEM complete medium, and passaged when the cells were 80%?90% confluent. 293T cells were cultured in DMEM medium and microsphere extract, and the proliferation curve of 293T cells cultured in the two mediums was detected by CCK-8 method to explore the biocompatibility of hydrogel microspheres. Fresh pancreatic tumor tissue was cut in the ultra-clean workbench, and pancreatic cancer tumor tissue was lysed by hyaluronidase and collagenase Ⅰ, and digested into single cell with interval shaking in a 37 ℃ water bath. The hydrogel microspheres and pancreatic cells were co-cultured in DMEM complete medium for 3 d, 1/2 of the cells were fixed with 4% paraformaldehyde, and stained with phalloidin and DAPI, and the morphology and cell distribution of the microspheres were observed under a common fluorescence microscope. The remaining 1/2 cells were used for suspension and adherent cell counting. The hydrogel microspheres and primary cells were co-cultured in the medium for 7 d, and the cell composition in the established culture model of in vitro pancreatic cancer primary cells based on the hydrogel microspheres was observed by immunofluorescence method. The pancreatic cancer tissue was embedded in paraffin, followed by paraffin tissue sectioning, hematoxylin and eosin staining of the tissue section, and observation of the pancreatic cancer tissue structure with a microscope. Results ·The size of the hydrogel microspheres was uniform, and the diameter of the microspheres was about 200 μm. The proliferation curve of 293T cells showed that the hydrogel microspheres had good biocompatibility. The co-culture experiments of hydrogel microspheres and pancreatic cell lines showed that the surface of hydrogel microspheres had strong cell affinity, which could provide support points for pancreatic cells to adhere to the surface of the microspheres and to grow normally. Through co-culture of hydrogel microspheres with fresh pancreatic cancer cells, a 3D culture model of pancreatic cancer cells in vitro was successfully established. Composition of cell types in this model was similar to that in the corresponding primary tumor tissue, which included pancreatic ductal epithelial cells, tumor stem cells, endothelial cells, fibroblasts and other cells. Conclusion ·The in vitro 3D culture model of primary pancreatic cancer cells based on hydrogel microspheres has important characteristics of pancreatic cancer tumor microenvironment.

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    A prevalence study on knowledge, attitude, belief and practice of safe medication and analysis of related factors in dialysis patients
    WEI Shan, JI Ouyang, CHEN Zhihao, HUANG Zehui, LI Pu, FANG Junyan, LIU Yingli
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 88-94.   DOI: 10.3969/j.issn.1674-8115.2023.01.011
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    Objective ·To survey the status quo of knowledge, attitude, belief and practice (KAP) of safe medication in the process of medication therapy management in dialysis patients, and analyze the related factors. Methods ·This study was a cross-sectional study with the maintenance dialysis patients selected from the Department of Nephrology, Shanghai Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine from March 2019 to March 2021. The KAP scale for safe medication in patients with chronic kidney disease verified by reliability and validity tests was used to evaluate the status quo of safe medication, and their medication list and clinical characteristics were also investigated. The occurrence of medication-related problems (MRPs) was evaluated according to the Strand classification system. The related factors of KAP level of safe medication in the dialysis patients were analyzed by univariate analysis and multiple linear regression analysis. Results ·A total of 187 maintenance dialysis patients were included, including 103 patients with maintenance hemodialysis (MHD) and 84 patients with continuous ambulatory peritoneal dialysis (CAPD). The mean age of them was (60.19±12.80) years, the mean dialysis duration was (44.31±36.90) months, and the mean numbers of comorbidities and medications were 6.37±2.17 and 7.48±2.66, respectively. In the dialysis patients, the mean score of KAP scale was (77.68±18.53) points. The mean scores of knowledge, attitude, and practice of safe medication were (24.96±8.92), (17.19±3.18), and (35.40±8.18) points, respectively. The univariate analysis results showed that there were significant differences of KAP scores for safe medication in the dialysis pattern, the educational level, the economic level and the occurrence of renal anemia in the maintenance dialysis patients (all P<0.05). In addition, the more comorbidities or medications for regulating calcium and phosphorus metabolism the patients had, or the more MRPs occurred, the lower KAP scores for safe medication the patients got (all P<0.05). Multiple linear regression results showed that the dialysis patients with CAPD (β=8.391, 95%CI 3.436?13.347, P=0.001), with higher education (β=9.159, 95%CI 0.978?17.339, P=0.028), with per capita monthly household income of over 6 000 yuan (β=8.309, 95%CI 1.891?14.727, P=0.011), with less comorbidities (β=-1.582, 95%CI -2.783?-0.382, P=0.010), and with less MRPs (β=-2.284, 95%CI -3.987?-0.581, P=0.009) had higher KAP scores. Conclusion ·The KAP level of safe medication in the patients with maintenance dialysis is low. The hemodialysis, low educational level, low economic level, high number of comorbidities, and high number of MRPs are risk factors for low level of KAP of safe medication in dialysis patients.

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    Advances in decompensated cirrhosis treatment by human serum albumin
    ZHANG Chenxi, CAO Zhujun, XIANG Xiaogang, XIE Qing, GENG Jiawei
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 95-100.   DOI: 10.3969/j.issn.1674-8115.2023.01.012
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    Human serum albumin (HSA) is one of the most abundant proteins in the plasma which participate in plenty of physiological functions. This article reviews recent advances in HSA-related researches with respect to its synthesis, metabolism, structure, function, and clinical application in decompensated cirrhosis and its adverse events. As a multidomain polyfunctional molecule, HSA has not only shown its effect on colloid osmotic pressure elevation, but also its non-colloid functions including ligand binding capacity, antioxidant ability, immunoregulatory effect, and maintaining the stability of endothelium and permeability of capillary. However, the structure of HSA is easily affected by pathology surroundings including various posttranslational modifications of HSA, such as truncated N-terminal or C-terminal, glycosylation, and oxidation of Cys-34. Among these, the oxidation modification of Cys-34 in HSA is closely related to cirrhosis progression and has a strong prognostic ability of clinical outcomes. Besides prevention of post paracentesis circulatory dysfunction, HSA administration also shows excellent treatment potentials in the cirrhotic complications, including hepatorenal syndrome (HRS) and spontaneous peritonitis (SBP). Furthermore, more clinical trials are needed to discuss the potential benefits of HSA in non-SBP infection, long-term administration of ascites, hepatic encephalopathy, acute-on-chronic liver failure (ACLF) and other cirrhotic complications.

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    Research progress in the role and mechanism of acyloxyacyl hydrolase in diseases
    WU Zhenkai, DENG Bo, PAN Yu, DING Feng
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 101-107.   DOI: 10.3969/j.issn.1674-8115.2023.01.013
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    Lipopolysaccharide (LPS) is an essential component of the outer wall of gram-negative bacteria and can induce a strong inflammatory response in the body. Acyloxyacyl hydrolase (AOAH) is a highly conserved host lipase expressed in a variety of cells, including neutrophils, macrophages and proximal tubular epithelial cells. AOAH can inactivate LPS by selectively removing the secondary acyl chains from the lipid A moiety of gram-negative bacterial LPS, which alleviates inflammation and tissue damage, promotes the recovery from the immune tolerance and regains normal responsiveness. It plays an essential role in host defenses against infection. Moreover, AOAH has been shown invivo and invitro for a variety of enzymatic activities including phospholipase, lysophospholipase and diacylglycerol lipase. Researches increasingly show that AOAH plays a critical role in various noninfectious diseases such as allergic asthma, psoriasis, chronic pelvic pain and other autoimmune diseases and chronic inflammatory diseases in addition to infections. Besides, DING Feng Research Group, Department of Nephrology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine found that AOAH was capable of attenuating renal fibrosis via proximal renal tubular epithelial cells CD74 signaling pathway. Given the increasingly diverse role of AOAH in diseases, this article reviews its sources, structure, effects and possible mechanisms in diseases in order to provide reference for future research on its roles in diseases and new lines of investigation into disease pathogenesis and novel therapeutic targets.

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    Progress of residual neuromuscular blockade after general anesthesia in elderly patients
    LIU Qiuli, JIANG Lai, WENG Xiaojian
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 108-113.   DOI: 10.3969/j.issn.1674-8115.2023.01.014
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    Muscle relaxation induced by muscle relaxants is one of the important conditions for endotracheal intubation and fixation, but sometimes muscle functions recover incompletely after operations, which is called postoperative residual neuromuscular block (PRNB). It can cause a series of serious postoperative complications and even death. Hence, it is essential to prevent and treat PRNB in the early stage during anesthesia implementation. With the rapid development of surgical technology and the gradual extension of the life span of the population, the number of operations for elderly patients is gradually increasing. Meanwhile, due to the physiological and pathological changes of the elderly and the combined underlying diseases, the elderly are more likely to suffer from PRNB in different degrees after surgery, which seriously damages the prognosis of elderly patients and increases the loss of medical resources. In these years, the successful application of short-acting muscle relaxants, new antagonists (such as sugammadex), and multi-mode neuromuscular monitoring devices in clinical practice have greatly reduced the incidence of PRNB in elderly patients. Furthermore, the basic researches which mainly based on the neuromuscular junction structure and the pharmacokinetic and pharmacodynamic studies of the elderly provide a new theoretical basis for reducing the harm of PRNB to elderly patients. This paper reviews the research progress of the mechanism, adverse events and clinical interventions of PRNB in elderly patients after general anesthesia surgeries to provide reference for muscle relaxation management and postoperative antagonism in these people.

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    A review of RIZ1 regulation of the signal pathways in obesity and tumors
    XIE Xiaolei, JIANG Peixin, ZHANG Jinghong, MO Junjian, WU Kefan, ZENG Kangyi
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 114-119.   DOI: 10.3969/j.issn.1674-8115.2023.01.015
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    Retinoblastoma-interacting zinc finger protein 1 (RIZ1) gene, also known as positive regulatory domain 2 (PRDM2), is a member of the PRDM gene family whose protein sequence consists of a PR domain, a nuclear hormone receptor binding motif, eight zinc finger domains, and an Rb (retinoblastoma protein) interacting motif. RIZ1 is mainly localized in the nucleus, where it plays a role in transcriptional repressor, gene regulation, protein-protein interactions, and other functions. RIZ1 is an important participant in the metabolic pathway, which affects basal metabolism and inhibits the development of obesity by regulating metabolism-related genes; functional mutations or insufficient content of RIZ1 are associated with the development of a variety of tumors, which participate in tumor processes by activating downstream oncogenes or regulating metabolism. RIZ1 regulates three molecular signal pathways, AKT (v-akt murine thymoma viral oncogene homolog)/mTOR (mechanistic target of rapamycin kinase), IGF-1 (insulin-like growth factor 1), and estrogen, in tumors and obesity through AKT3 and IGF-1, respectively, or acting as a co-activator. The functional differences of the three molecular pathways and the crossover of their downstream molecules suggest that RIZ1 may function differently in different ages, genders, and organs. The study of the regulatory role of RIZ1 and RIZ2 in metabolic processes can help to fully understand the mechanism of RIZ1 involvement in obesity and tumor formation. In the future, diagnostic research or functional recovery based on RIZ1 targets may be of great significance for the diagnosis and treatment of metabolic diseases and tumor.

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    Research progress in clinical characteristics, diagnosis and prognosis of TdT-negative lymphoblastic lymphoma/acute lymphoblastic leukemia
    HOU Shumin, SHAO Jingbo
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 120-124.   DOI: 10.3969/j.issn.1674-8115.2023.01.016
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    Terminal deoxynucleotide transferase (TdT) is a special deoxyribonucleic acid (DNA) polymerase. It can bind a single deoxynucleotide to the 3′-OH end of a DNA molecule in the absence of a template. TdT is a specific intracellular marker of immature lymphocytes in the hematopoietic system, which is of great significance in the diagnosis of lymphoid tumors. The diagnosis of lymphoblastic lymphoma/acute lymphoblastic leukemia (LBL/ALL) depends on immunotyping. TdT is usually positive in LBL/ALL, which is an important basis for clinical diagnosis of LBL/ALL. TdT-negative LBL/ALL is rare in clinical practice. Because of its strong specificity in diagnosis, negative TdT will bring certain difficulties to the diagnosis. There are many reasons for negative TdT. The expression of TdT is different in different differentiation stages of lymphocytes, and the sensitivity of different detection methods and the false negative of TdT can be seen occasionally. In addition, it has been reported that the clinical characteristics and prognosis of TdT-negative- and TdT-positive-LBL/ALL are different. Understanding the significance of TdT expression, the causes of negative TdT, and the different characteristics of TdT-negative- and TdT-positive-LBL/ALL are helpful for clinical diagnosis, treatment selection and prognosis judgment. In this paper, relevant literature at home and abroad is reviewed, and the causes of negative TdT, the clinical characteristics, diagnosis and prognosis of TdT-negative-LBL/ALL were reviewed.

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    Research progress in the correlation and treatment of menopause and non-alcoholic fatty liver disease in women
    LIU Weiwei, WANG Long
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 125-131.   DOI: 10.3969/j.issn.1674-8115.2023.01.017
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    Non-alcoholic fatty liver disease (NAFLD) is a chronic non-communicable disease. It is a metabolic syndrome (MS) in the liver. Menopause is a physiological phenomenon of women due to the decline of ovarian function, which is characterized by the deterioration of hypothalamic-pituitary function. Clinical and epidemiological studies have shown that the incidence trend of NAFLD has gender differences and is related to metabolic parameters such as glucose, lipids, and blood uric acid. The incidence of NAFLD in premenopausal women is lower than that in males, while the incidence of NAFLD in postmenopausal women gradually increases to the same as that in males. The mechanism may be mainly related to the changes of sex hormones in postmenopausal women (mainly the decrease of estrogen). The changes of sex hormones such as the decreased levels of estrogen and sex hormone binding globulin (SHBG) and the relatively increased level of androgen can increase the incidence of MS components such as abdominal obesity, abnormal blood lipid metabolism and insulin resistance (IR), making menopause an important independent risk factor for NAFLD in women. Estrogen, androgen receptor antagonists and phytoestrogens can improve hepatic steatosis and IR through many ways, reduce the severity of NAFLD and delay its progression to liver fibrosis, which have certain therapeutic significance for postmenopausal women with NAFLD, but also have some limitations. This paper reviews the research progress in the relationship between menopause and NAFLD in recent years, so as to provide ideas and reference for the prevention and treatment of NAFLD in postmenopausal women.

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    Monomorphic epitheliotropic intestinal T-cell lymphoma: a case with recurrent gastrointestinal hemorrhage
    HU Zeyu, ZHOU Cheng, YANG Lin, MA Xiaoyan, XIAO Haijuan, SI Hailong
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (1): 132-136.   DOI: 10.3969/j.issn.1674-8115.2023.01.018
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    A male patient, 63-year-old, went to Xianyang Central Hospital in Shaanxi Province on September 4, 2019, for "intermittent black stool for more than 1 month with aggravation for 7 h", and was admitted as "gastrointestinal bleeding". On admission, there was fresh blood stool with a large amount, accompanied by abdominal pain, abdominal distension, dizziness, fatigue, and anorexia, without other obvious special discomfort. The electrogastroscopy indicated chronic non-atrophic gastritis with erosion; the electron colonoscopy indicated ileocecal valve inflammation; the capsule endoscopy indicated ulcer and tumor possibility. The patient was finally diagnosed as having monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) after single balloon small bowel microscopy and pathological biopsy. On November 8, 2019, the patient was transferred to the Department of Oncology, Affiliated Hospital of Shaanxi University of Chinese Medicine. After 2 cycles of chemotherapy with R-CHOP regimen (rituximab combined with cyclophosphamide, adriamycin, vincristine and prednisone), the disease progressed and then the therapy was replaced with DA-EPOCH regimen (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin). After 4 months of standardized treatment, the patient′s condition worsened again; he left hospital after giving up treatment, and died on March 20, 2020. MEITL has the characteristics of strong invasiveness, high degree of deterioration, heavy tumor load, difficult diagnosis and easy misdiagnosis, so the patients often have poor prognosis and high mortality. This article reports the clinical data of this patient with MEITL, aiming to provide reference for the diagnosis and treatment of patients with similar symptoms.

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    Effect of potential pathogenic gene PDX1 variants of total anomalous pulmonary venous connection on its gene function
    FENG Weiqi, ZHANG Qi, WU Yizhuo, LU Yanan, YU Yu
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1219-1226.   DOI: 10.3969/j.issn.1674-8115.2023.10.001
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    Objective ·To explore the possible pathogenic gene of total anomalous pulmonary venous connection (TAPVC) by whole exon sequencing and verify its function. Methods ·One hundred TAPVC children (case group) and one hundred and twenty healthy children (control group) in Xinhua Hospital and Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine from 2014 to 2019 were included. The blood samples from the two groups of children were collected, and whole blood genomic DNA was extracted for exon sequencing to screen out the potential pathogenic genes of TAPVC. Harmful mutation sites of pathogenic genes were screened through Mutation Taster, SIFT and PolyPhen-2 websites, and then conducted by Sanger sequencing. The wild-type (wild-type group) and mutant (mutant group) plasmids of PDX1 were transfected into HUVEC cells. Quantitative real-time PCR (qPCR) and Western blotting were used to detect the effects of mutations on mRNA and protein levels of PDX1, respectively. The STRING database was used to analyze the interaction between proteins, and qPCR was used to determine the expressions of downstream genes regulated by PDX1. Results ·Pathogenic PDX1 was found in TAPVC children, and Sanger sequencing revealed two novel variants in the gene: c.C237A (P33T) and c. C237G (P33A). Compared with the wild-type group, there was no significant difference in PDX1 mRNA levels in the two mutant groups, but there was a significant increase in relative protein expression of the CA group and CG group, which was 2.9 and 3.4 times higher than the wild-type group, respectively (P=0.000, P=0.001). Protein interaction analysis demonstrated that PDX1 was associated with SOX17. qPCR results showed that overexpression of PDX1 could downregulate the expression of SOX17 in HUVEC. Conclusion ·The two novel PDX1 missense mutations can affect the process of PDX1 post-transcriptional translation, indicating that PDX1 may participate in the occurrence and development of TAPVC by regulating SOX17.

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    Analysis of m 6A methylation expression profiles in liver tissue of high -fat diet -induced mouse models of NAFLD
    LIU Junjun, LU Sumei, ZHANG Bingyang, LI Yongqing, MA Wanshan
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1227-1235.   DOI: 10.3969/j.issn.1674-8115.2023.10.002
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    Objective ·To detect the differences in m6A methylation modification and gene expression of liver tissue mRNA in high-fat diet-induced mouse models of non-alcoholic fatty liver disease (NAFLD) using microarray technology. Methods ·The NAFLD models were established in 6-8 weeks old male C57BL/6J mice fed with high-fat chow for 16 weeks (high-fat group, n=10). The basal group (n=10) was given 10% fat diet. Hematoxylin-eosin (H-E) staining was used to assess the histopathological changes in liver tissue and to determine the success of the NAFLD models. The changes of mRNA m6A methylation and expression levels in the liver tissues of the two groups were detected by using methylated RNA immunoprecipitation (MeRIP) and microarray expression profiling. Results ·The livers of the mice in the basal group were bright red with few fat deposits, while the livers of the mice in the high-fat group were yellowish with diffuse infiltration and fusion of lipid droplets in the hepatocytes by H-E staining, suggesting that the high-fat diet-induced NAFLD models were successfully constructed. The results of the MeRIP-microarray showed that the m6A methylation levels of 320 genes in the livers of mice in the high-fat group were significantly altered compared with those in the basal group (P<0.05 and fold change>1.5), of which 108 genes were up-regulated and 212 genes were down-regulated. Genes with significant differences in m6A methylation levels between the two groups were intersected with those with differentially expressed mRNAs, and 163 genes were found to have significant differences in both m6A methylation level and mRNA expression level. Conclusion ·The change in m6A modification of liver tissue mRNA in the high-fat diet-induced mouse models of NAFLD is significant and the change is associated with the gene expression of mRNA.

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    Research on the role of SOX9 in regulating metabolic reprogramming in diffuse large B cell lymphoma
    ZHANG Yirong, WEI Weiqing, MA Jiao, ZHANG Xue
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1236-1244.   DOI: 10.3969/j.issn.1674-8115.2023.10.003
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    Objective ·To explore the role played by the differentially expressed SRY-box transcription factor 9 (SOX9) gene in diffuse large B cell lymphoma (DLBCL), particularly in the regulation of metabolic reprogramming in the germinal center B-cell (GCB) like subtype. Methods ·The clinical information and gene expression profile data of 481 DLBCL patients retrieved from the NCICCR-DLBCL database were included. Data analysis and visualisation were performed by using R language version 4.1.3. The classification was performed by using a cell of origin subtype (COO) classification algorithm based on RNA-seq sequencing of expression. ABC/GCB features were used to annotate gene sets, and the classification was verified by gene set enrichment analysis. The ABC and GCB subgroup was dichotomised based on the mean expression of SOX9. Differential analysis was performed by using the DEseq2 package. The relationship between SOX9 and ABC-DLBCL metabolism was analysed by using KEGG (Kyoto Encyclopedia of Genes and Genomes) with the Hallmark annotation set. The survival curves were plotted by using the Kaplan-Meier method. The pan-cancer analysis was performed by using GEPIA2. The microenvironmental scoring analysis was performed by the ESTIMATE package. Results ·Of the 481 DLBCL patient samples, all the patients had RNA-seq expression data, 421 had clinical staging, 335 had international prognostic index (IPI) scores and 234 had survival data. The classification yielded 232 (48.2%) ABC subtypes, 173 (36.0%) GCB subtypes and 76 (15.8%) unclassified, consistent with the proportions declared in the database, and the enrichment analysis was verified to be consistent with the ABC/GCB expression profile. Compared to the high SOX9 expression group, the overall survival was shorter in the low SOX9 expression group and the prognostic score was worse. The pan-cancer analysis showed that this phenomenon was also seen in other tumor types. The differential analysis showed that there were 156 upregulated genes and 1 826 downregulated genes in the GCB subtype in the low SOX9 expression group, compared to the high SOX9 expression group. For metabolic processes, down-regulated genes were enriched in glycolysis. Conclusion ·In the ABC subtype of DLBCL, the SOX9 gene affects the biological features of ABC-DLBCL by regulating metabolic reprogramming, and low expression of SOX9 in DLBCL, possibly caused by high methylation, predicts decreased glycolysis in tumors. The proportion of tumor stromal cells decreases, showing a worse prognosis.

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    Effects of Escherichia coli outer membrane vesicles on proliferation of breast cancer cells and tumor growth of tumor-bearing mice
    WANG Lanxi, MA Guanrong, JIANG Yongzhu, CHANG Xiulin, FANG Liaoqiong, BAI Jin
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1245-1254.   DOI: 10.3969/j.issn.1674-8115.2023.10.004
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    Objective ·To analyze the effect of Escherichia coli outer membrane vesicle (E.coli-OMV) on the proliferation of 4T1 breast cancer cells in vitro and the inhibition of tumor growth in BALB/c-4T1 tumor-bearing mice in vivo. Methods ·OMVs were collected from the culture supernatant of E.coli and characterized. The uptake of E.coli-OMV by 4T1 cells was detected by fluorescent label tracking method. The effect of E.coli-OMV on 4T1 cell proliferation was detected by CCK-8 method. The effect of E.coli-OMV on 4T1 cell cycle was detected by flow cytometry. The BALB/c-4T1 tumor-bearing mouse models were established by subcutaneous inoculation, and the mice were divided into E.coli-OMV group and Control group, with 10 mice in each group. The mice in the E.coli-OMV group were injected with 0.25 mg/kg E.coli-OMV every 2 d, while the mice in the Control group were injected with equal doses of PBS. The changes in body weight, 40 d survival rate, tumor volume and tumor weight of the two groups of tumor-bearing mice were observed. The pathological morphology of the tumor tissues was evaluated by hematoxylin-eosin staining (H-E staining). The expression of proliferating cell nuclear antigen (PCNA) and CyclinD1 in tumor tissues was observed by immunohistochemical staining. Results ·E.coli-OMV was spherical membrane vesicle structure with a particle size of (216.00±18.30) nm, which expressed E.coli outer membrane protein A (OmpA) and OmpC. Fluorescence microscopy results showed that 4T1 cells could intake E.coli-OMV. CCK-8 results showed that the inhibitory effect of E.coli-OMV on 4T1 cells was positively correlated with time-dose. Flow cytometry results showed that E.coli-OMV arrested the growth cycle of 4T1 cells in G0/G1 phase. In vivo experiments showed that compared with the Control group, body weight of mice in the E.coli-OMV group decreased slightly after the initial injection (P=0.031), and then recovered, while 40 d survival rate increased (P=0.037). The growth of tumor volume and weight of mice in E.coli-OMV group were lower than those in the Control group (P=0.041, P=0.004). Its tumor volume inhibition rate reached 29.69%, and tumor weight inhibition rate reached 49.81%. The results of H-E staining showed that nuclear splitting images of tumor tissues of mice in the E.coli-OMV group decreased compared to the Control group (P=0.038). The results of immunohistochemical staining showed that the positive expression of PCNA and CyclinD1 in the tumor tissues of mice in the E.coli-OMV group decreased compared to the Control group (P=0.031, P=0.002). Conclusion ·Both in vitro and in vivo studies show that E.coli-OMV can significantly inhibit the proliferation of 4T1 cells.

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    Screening and functional analysis of mutations in NEUROD1 gene in pedigrees of maturity-onset diabetes of the young
    ZHANG Juan, GE Xiaoxu, ZHANG Rong, JIANG Fusong, JIANG Yanyan, LI Ming, LI Tiantian, LIU Chanwei, CHEN Yating, LIU Limei
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1255-1261.   DOI: 10.3969/j.issn.1674-8115.2023.10.005
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    Objective ·To screen the mutations of NEUROD1 gene in families of maturity-onset diabetes of the young (MODY), and investigate the correlation between the mutation and MODY6 and its potential pathogenesis in Chinese. Methods ·PCR-direct sequencing was used for screening NEUROD1 mutations from 96 MODY probands who were negative for mutations in the GCK/MODY2, HNF1A/MODY3 and HNF1B/MODY5 genes, and the genotypic frequency of NEUROD1 variations were compared between the 96 MODY probands and 100 non-diabetic control subjects. A de novo modeling method was used to predict the three-dimensional (3D) structures of wild type (WT) and mutated NEUROD1 proteins. Transcriptional activities of both WT and mutant of NEUROD1 on insulin gene were detected by using dual luciferase reporter gene system. Results ·Glu59Gln (NM_002500.5, c.175G>C), a heterozygous missense mutation in the NEUROD1 gene, was identified in a MODY pedigree. 3D structural analysis showed that the mutation transformed the negatively charged Glu59 of WT into uncharged mutation Gln59, leading to the loss of Glu59-Arg54 and Glu59-Lys88, two salt bridge bonds, and the formation of Gln59-Arg54, one new hydrogen bond. Transcriptional activity of Glu59Gln mutant for insulin gene was reduced by 36.3% when compared with that of WT (P<0.05). A common variation Ala45Thr (G-A) was identified, and AA+GA genotypic frequency of the variation was significantly elevated in the 96 MODY probands in comparison to non-diabetic control subjects (P=0.002). Conclusion ·Glu59Gln mutation alters the N-terminal molecular conformation of NEUROD1 protein, resulting in decreased transcriptional activity of insulin gene, which is the cause of the defective insulin secretion in mutation carriers of the MODY6 pedigree. The Ala45Thr variation is associated with earlier age of onset of diabetes in MODY6 probands.

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    Clinical significance of FEV 0.5 and FEV 0.75 in the determination of pulmonary function in children with bronchial asthma
    ZHENG Guimei, TANG Lanfang
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1262-1267.   DOI: 10.3969/j.issn.1674-8115.2023.10.006
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    Objective ·To evaluate the abnormal rates of measured/predicted values of forced expiratory volume in 0.5 second (FEV0.5) and FEV0.75 in lung ventilation function testing, as well as the clinical significance of different cut-off points for improvement rates before and after bronchodilation testing in the diagnosis of children with bronchial asthma (asthma). Methods ·From January 2020 to February 2021, school-age children diagnosed with asthma during their hospitalization at the Children's Hospital, Zhejiang University School of Medicine were selected. The data on lung ventilation function testing and bronchodilator testing were collected. The difference in abnormal rates of measured/predicted values of FEVt in children in lung ventilation function testing was compared. Diagnostic test four grid table was used to analyze the sensitivity and specificity of different cut-off points for the improvement rates of FEV0.5 and FEV0.75 in the diagnosis of asthma before and after bronchodilation testing. Results ·A total of 148 children were included. All enrolled cases completed lung ventilation function testing, with 51 cases completing bronchodilation testing simultaneously. The results of lung ventilation function testing showed that 21 patients had obstructive ventilation dysfunction, 30 patients had small airway dysfunction, and the remaining patients had normal, restrictive or mixed ventilation dysfunction. The results of bronchodilation testing showed that in the 51 asthmatic children with obstructive ventilation dysfunction and small airway dysfunction, 22 of them were positive for bronchodilation testing. The comparison of the abnormal rates of FEVt measured/predicted values showed that the abnormal rates of FEV0.75 measured/predicted values were higher than those of FEV1 and FEV0.5 (χ2=10.18, P=0.000; χ2=10.95, P=0.000). The sensitivity and specificity analysis results of different cut-off points for the improvement rates of EFV0.75 and FEV0.5 showed that the cut-off point for FEV0.5 improvement rate at 16% had very high sensitivity and specificity, with the highest Jordan index; the cut-off points for FEV0.75 improvement rate were 12% and 14%, respectively, with sensitivity and specificity reaching 100%. Conclusion ·The measured/predicted value of FEV0.75 in lung ventilation function testing can be considered as an alternative indicator for the measured/predicted value of FEV1 to further evaluate the presence of obstructive ventilation dysfunction. On the basis of the results of bronchodilation testing, it can be considered to analyze the airway reversibility by combining the best cut-off points of FEV0.75 and FEV0.5 improvement rates, in order to enhance the clinical value of bronchodilation testing in the diagnosis of asthma.

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    Analysis of early efficacy and safety of endovascular therapy for acute mild ischemic stroke with large vessel occlusion
    NI Ruilong, ZHAO Fei, CAO Li, DENG Jiangshan
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1268-1273.   DOI: 10.3969/j.issn.1674-8115.2023.10.007
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    Objective ·To investigate the early efficiency and safety of endovascular therapy (EVT) for patients with acute mild ischemic stroke with large vessel occlusion (LVO-MIS). Methods ·A total of 31 patients with LVO-MIS who received emergency EVT-assisted standard medical treatment at the Green Channel of Stroke in Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine from June 2016 to October 2022 were retrospectively included as endovascular therapy group (EVT group), and 32 LVO-MIS patients who only received standard medical treatment in the same period were selected as the control group. General clinical data and parameters related to EVT of the two groups were collected. The primary outcome was early efficacy, that is, the NIHSS at seventh day after treatment (d7NIHSS) score decreased by ≥3 points or directly to 0 points from baseline NIHSS score. Secondary outcomes included successful revascularization of blood vessels and early neurological deterioration (END), and safety outcomes included symptomatic intracranial hemorrhage (sICH) and mortality. The primary and secondary outcomes of the two groups of patients were analyzed to evaluate the early efficiency of EVT, and the safety evaluation indicators of the two groups of patients were analyzed to evaluate the safety of EVT. Kruskal-Wallis H test was used to analyze the NIHSS scores of 24 patients in the EVT group who underwent EVT before and after treatment. Results ·There was no statistically significant difference in the general clinical data between the two groups, as well as parameters related to EVT such as occlusion site, and onset-to-admission time. The baseline NIHSS score of the EVT group [5.0 (3.0, 5.0) points] was higher than that of the control group [3.5 (2.0, 5.0) points] (P=0.001), and their d7NIHSS score [1.0 (0, 3.0) points] was lower than that of the control group [2.0 (1.0, 5.8) points] (P=0.040). A total of 24 patients (38.1%) in the two groups achieved early efficacy, including 16 cases in the EVT group and 8 cases in the control group; and the early efficacy rate of the EVT group was higher than that of the control group (χ2=4.729, P=0.030). The END rate in the EVT group was lower than that in the control group (χ2 =6.097, P=0.014), and there were 29 cases (93.5%) in the EVT group of patients whose blood vessels were successfully reopened. There was no statistically significant difference in sICH rate and mortality rate between the two groups. In the EVT group, there was a statistically significant difference (H=16.997, P=0.000) among the baseline NIHSS scores [5.0 (3.0, 5.0) points] of 24 patients, postoperative 24hNIHSS score [2.0 (0.3, 3.8) points] and d7NIHSS scores [1.0 (0, 2.8) points]. Conclusion ·EVT is safe and effective in treating LVO-MIS, and the early efficacy rate of EVT is superior to standard medicine treatment, with a lower rate of END and no increased risk of sICH.

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    Efficacy of sternal cortical thickness ratio in adult chest CT in the diagnosis of osteopenia and osteoporosis
    YU Xi, SUN Junnan, ZHANG Jiaojiao, GAO Yue, WANG Hu, YU Yang, WANG Hairong, HONG Wen
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1274-1281.   DOI: 10.3969/j.issn.1674-8115.2023.10.008
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    Objective ·To compare the relationship between sternal cortical thickness ratio and bone mineral density in adult emergency inpatients with chest CT plain scan, and evaluate the diagnostic ability of sternal cortical thickness ratio for osteopenia and osteoporosis. Methods ·The bone density was measured by dual energy X-ray absorptiometry (DXA) in hospitalized patients collected in the adult emergency ward of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine from November 2020 to October 2022, and the patients were diagnosed as normal bone mass, osteopenia, or osteoporosis according to the bone density. The patients were grouped based on age (>65 years old, ≤65 years old) and osteoporosis status. The sternal cortical thickness ratio measured at the level of tracheal bifurcation in the chest CT scan image of each group was analyzed. Spearman correlation was used to analyze the correlation between the sternal cortical thickness ratio and bone mineral density. The sternal cortical thickness ratio was used to diagnose the osteopenia and the osteoporosis, and the receiver operator characteristic curve (ROC curve) was drawn to obtain the best cut-off value. The diagnostic efficacy of the sternal cortical thickness ratio in the diagnosis of osteopenia and osteoporosis was analyzed. Results ·A total of 198 patients were included in the study, including 78 patients with normal bone mass, 66 patients with osteopenia, and 54 patients with osteoporosis. Among patients aged >65 years old (n=115), the proportion of female patients and the age of patients in the osteoporosis group were significantly higher than those in the normal bone mass group (all P<0.05). However, in patients ≤65 years old (n=83), the difference was not statistically significant (P>0.05). Whether in patients >65 years old or ≤65 years old, the sternal cortical thickness ratio in the normal bone mass group was higher than that in the osteopenia group and the osteoporosis group, and the sternal cortical thickness ratio in the osteopenia group was higher than that in the osteoporosis group (all P<0.05); The sternal cortical thickness ratio in female patients in the normal bone mass group, osteopenia group and osteoporosis group was lower than that in male patients (all P<0.05). The sternal cortical thickness ratio in both male and female patients was positively correlated with bone mineral density (r=0.704, P=0.000; r=0.785, P=0.000; r=0.735, P=0.000; r=0.479, P=0.000). In terms of diagnostic performance, in patients >65 years old, the diagnostic accuracy rate of male patients in the normal bone mass group was higher than that in the osteopenia group and the osteoporosis group, and the diagnosis misdiagnosis rate in the osteoporosis group was lower than that in the normal bone mass group and the osteopenia group; In patients ≤65 years old, the diagnostic accuracy rate of male patients in the osteoporosis group was higher than that in the normal bone mass group and the osteopenia group, and the diagnosis misdiagnosis rate in the normal bone mass group was lower than that in the osteopenia group and the osteoporosis group. Conclusion ·The sternal cortical thickness ratio in both male and female patients is positively correlated with bone mineral density, and the sternal cortical thickness ratio has good diagnostic efficacy for osteopenia and osteoporosis.

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    Clinical characteristics and prognosis of patients with diffuse large B-cell lymphoma
    ZHAO Jie, JIANG Yan, HAO Siguo
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1282-1288.   DOI: 10.3969/j.issn.1674-8115.2023.10.009
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    Objective ·To analyze the clinical characteristics and prognostic risk factors of patients with diffuse large B-cell lymphoma (DLBCL), and evaluate the prognostic effects of autologous stem cell transplantation (ASCT) and rituximab maintenance therapy on DLBCL patients. Methods ·The clinical data of 160 patients with DLBCL who were first diagnosed by pathology and immunotyping were collected from the Department of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine from January 2015 to January 2020, and the risk factors affecting the efficacy and prognosis of patients were analyzed. Moreover, the clinical characteristics of patients with relapsed/refractory DLBCL and the effect of salvage ASCT on overall survival (OS) were assessed. For those high-risk patients who achieved complete remission (CR) in the interim assessment, the impact of ASCT and rituximab maintenance therapy on survival outcomes was further assessed. Results ·Patients with initial age of treatment >60 years (P=0.005), International Prognostic Index (IPI) 3?5 scores (P=0.032), low albumin level (P=0.001) and anemia (P=0.007) had poor efficacy. Multivariate analysis showed that the initial age of treatment >60 years (HR=2.788, 95%CI 1.575?4.936, P=0.000), non-GCB subtype (HR=2.230, 95%CI 1.150?4.324, P=0.018), elevated lactate dehydrogenase level (HR=2.064, 95%CI 1.006?4.234, P=0.048) and low albumin level (HR=2.052, 95% CI 1.169?3.602, P=0.012) were the independent risk factors for progression-free survival (PFS). The initial age of treatment >60 years (HR=2.269, 95% CI 1.060?4.860, P=0.035) and IPI scores of 3 to 5 (HR=2.557, 95%CI 1.132?5.778, P=0.024) were independent factors affecting OS. For patients with relapsed/refractory DLBCL, salvage ASCT was found to significantly improve the prognosis of these patients and was a protective factor for the death event of patients (P=0.030). For patients in the high-risk group who achieved CR in the interim evaluation after chemotherapy, there were no deaths in patients on maintenance therapy with consolidation ASCT and rituximab to the end point of follow-up; however, it did not prolong the OS of the patients (P>0.05). Conclusion ·In patients with relapsed/refractory DLBCL, salvage ASCT can significantly prolong the OS, whereas in the high-risk patients of DLBCL, consolidation ASCT and rituximab maintenance therapy can't prolong the OS.

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    Expert consensus on postoperative rehabilitation nursing of patients with head and neck cancer
    GU Fen, WANG Yueping, YANG Wenyu, ZHAO Xiaomei, TANG Yan, SHEN Shukun, MAO Yan, ZHANG Jinfeng, WU Yifan, ZHANG Yuanyuan, YANG Yue, ZHANG Jianchun, YU Hong, WANG Lan, HAO Guihua, HOU Lili
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1289-1296.   DOI: 10.3969/j.issn.1674-8115.2023.10.010
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    The location and size of tumors, treatment methods and prognosis of patients with head and neck cancer can seriously affect their oral function and neck activity, thereby affecting daily activities such as eating, speech and upper limb movement. Early rehabilitation after head and neck cancer surgery can accelerate functional recovery, alleviate discomfort symptoms, improve quality of life, and reduce unnecessary rehabilitation or treatment measures. Developing a clinical rehabilitation nursing pathway for head and neck cancer, forming personalized rehabilitation plans, and conducting early and effective nursing interventions are currently one of the key points of clinical work for patients with head and neck cancer. At present, domestic and foreign guidelines or consensus pays less attention to the impairments of speech function, chewing and swallowing function, neck and shoulder function etc., and lacks a systematic and comprehensive rehabilitation nursing guide or consensus to provide practical guidance for the care of patients with head and neck cancer. Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine organized relevant experts from Beijing, Shanghai, Sichuan, Shaanxi, Zhejiang and Anhui to draft Expert consensus on postoperative rehabilitation nursing of patients with head and neck cancer basing on previous literature and clinical nursing skills and experiences, of which the aim is to provide guidance for those patients in the aspects of oral care, nutritional support, flap donor area care, care after tracheotomy, chewing and swallowing rehabilitation, speech function rehabilitation, neck and shoulder function rehabilitation, restricted mouth opening rehabilitation, risk identification and prevention and follow-up.

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    Research progress on the association between melatonin and hypertensive disorder complicating pregnancy
    LU Ruoyu, KANG Wenhui, ZHAO Anda, LU Zhaohui, LI Shenghui
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1297-1303.   DOI: 10.3969/j.issn.1674-8115.2023.10.011
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    Melatonin (N-acetyl-5-methoxytryptamine) is a polypotent neuroendocrine lipid-soluble small molecule secreted mainly by the pineal gland. During gestation, melatonin levels in the mother at night rise as the pregnancy progresses and return to normal after delivery. The etiology of hypertensive disorder complicating pregnancy (HDCP) is multifaceted. An increasing number of evidence suggests the involvement of melatonin in the pathogenic process, and the regulation is related to its expression level, secretion rhythm and receptor level. Abnormal placental blood circulation, ischemia and hypoxia and systemic vascular endothelium dysfunction are the main pathological processes of HDCP. Through direct antioxidant effect, melatonin improves mitochondrial dysfunction and protects trophoblast cells from oxidative damage, thus participating in the regulation of placental oxidative stress level, and plays a protective role in preventing oxidative damage caused by hypoxic ischemia reperfusion of placenta, thus maintaining placental functional homeostasis. In addition, there is also evidence that melatonin can protect maternal vascular endothelium from oxidative stress by reducing the production and secretion of pro-inflammatory cytokines and vasoactive compounds, and participating in the regulation of systemic blood pressure in pregnant women. These confidences suggest that melatonin can be involved in the maintenance of placental and systemic vascular functional homeostasis during pregnancy through the regulation of oxidative stress. In this article, the effects of melatonin on HDCP and the related mechanisms are reviewed, and the positive role of melatonin in the pathogenesis of HDCP is summarized.

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    Research progress on the neural circuit of pain emotion mediated by amygdala
    MA CUI, YE Yujuan, YAN Xingke
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1304-1310.   DOI: 10.3969/j.issn.1674-8115.2023.10.012
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    The occurrence of pain emotion is closely related to the functional and structural changes of specific central nervous circuit. When pain is accompanied by depression, anxiety, pain aversion memory and other emotional states, it activates or inhibits different neural circuits. The amygdala (AMY) of the limbic system participates in the regulation of pain, anxiety, depression, aversive memory and other emotions, and has extensive connections with brain nuclei related to pain and emotion, jointly regulating pain, anxiety, depression, aversive memory and other responses. This article summarizes the main circuits related to pain emotions mediated by AMY. It is concluded that the neural circuits related to depression include central amygdala → parafascicular nucleus of thalamus (CeA GABA → PF Glu), dorsal raphe nucleus → central amygdala (DRN 5-HT → CeA SOM), central amygdala → ventrolateral periaqueductal gray (CeA GABA → vlPAG GABA). Nerve circuits related to anxiety include ventral tegmental area → central amygdala (VTA→CeADA), locus coeruleus → basolateral amygdala (LCNE→BLA). The neural circuit related to pain aversion memory is lateral parabrachial nucleus → central amygdala (lPBN CGRP→CeA CGRP). Among them, activating the CeA GABA→PF Glu circuit can lead to depression accompanied by pain, activating the CeA GABA→vlPAG GABA circuit can alleviate pain sensitivity caused by depression, and activating the DRN 5-HT→CeA SOM circuit can alleviate pain perception and depressive emotions; activating the VTA→CeA DA loop can alleviate pain sensitivity and anxiety like behavior, inhibiting LC NE→BLA loop can alleviate anxiety caused by pain; activating the lPBN CGRP→CeA CGRP loop can generate pain aversion memory.

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    Review of role of fatty acid binding protein -4 in obesity -associated tumors
    WU Ruifang, FENG Ming, MENG Jian
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1311-1316.   DOI: 10.3969/j.issn.1674-8115.2023.10.013
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    Obesity is one of the major factors threatening human health. Excessive fat accumulation not only has detrimental effects on human metabolism and cardiovascular system, but also is highly correlated to the incidence and mortality of various tumors. Fatty acid binding protein-4 (FABP4) is a small molecule protein mainly expressed in adipocytes and macrophages, and is responsible for participating in fatty acid transport and lipid response. It has been found that FABP4 levels are not only associated with body fat content, but also aberrantly expressed in various obesity-associated tumor cells and tumor microenvironment, which is closely related to obesity-associated carcinogenesis, metastasis, recurrence and patient prognosis. Since FABP4 expression varies in different types of obesity-associated tumors, suggesting a complex role of FABP4 in tumorigenesis. Based on this, this article reviews different roles of FABP4 in multiple obesity-associated tumors.

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    Research progress of MDSCs-targeted immunotherapy for pancreatic cancer
    QIN Yahan, ZHANG Ke, ZHANG Mengyu, SHEN Jie, PENG Meiyu
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1317-1323.   DOI: 10.3969/j.issn.1674-8115.2023.10.014
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    Pancreatic cancer (PC) is a highly malignant digestive system tumor with a poor survival rate and prognosis. Most patients with pancreatic cancer have no obvious clinical manifestations in the early stage of the disease, and are found to be in the middle and late stage of the disease when they seek treatment.A unique and complex tumor microenvironment (TME) is formed during its development and evolution. Due to the occult nature of pancreatic cancer, for patients with advanced pancreatic cancer, some traditional treatment methods such as surgical resection and chemotherapy are very limited, and there is a lack of effective treatment programs. Of course, this is also related to the immunosuppression of the TME of pancreatic cancer. Some immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), play an important immunosuppressive role in helping tumor immune escape. Therefore, it is considered to be a major difficulty in the treatment of pancreatic cancer. In recent years, with the in-depth study of TME, immunotherapy has gradually become a new therapeutic strategy, and has made great progress in the treatment of various malignant tumors. The study found that targeted MDSCs therapy is a new and effective treatment for pancreatic cancer.In this paper, we introduce the role of MDSCs in TME and their progress as potential targets for immunotherapy of pancreatic cancer, hoping to provide new directions for the treatment of pancreatic cancer and other tumors.

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    Recent advance in autophagy-related pathways and key biomarkers in major depressive disorder
    LI Siyuan, HE Shen, LI Huafang
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1324-1331.   DOI: 10.3969/j.issn.1674-8115.2023.10.015
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    Major depressive disorder (MDD) is a very common and severe mental disorder. Persistent emotional distress is one of its main clinical symptoms. The etiology of MDD is complex and highly heterogeneous, and has not yet been clarified. Antidepressant is a kind of important method for the treatment of MDD. However, there are still some problems such as slow onset of effect, low cure rate, safety to be further improved, and low compliance, which also reflect people's lack of understanding of the pathogenesis of MDD. Autophagy is a mechanism of cell degradation, which plays an important role in maintaining the stabilization of homeostasis. Mammalian target of rapamycin (mTOR) is an important regulator of autophagy, and adverse conditions can activate autophagy through mTOR-dependent or mTOR-independent autophagy pathways. Microtubule-associated protein light chain 3-Ⅱ (LC3-Ⅱ), Bcl-2 interacting coiled-coil protein 1 (Beclin-1) and p62 are common to be used in the measurement of autophagy flux. In recent years, more and more studies have shown that impaired autophagy may be involved in the development of MDD and antidepressant treatment may affect autophagy. Therefore, regulating impaired autophagy pathways may be a promising target of antidepressant treatment. In the future, more attention should be paid to the study of autophagy signaling pathway in the central nervous system to provide more reliable evidence for the mechanism of MDD and antidepressant treatment. This article introduces the roles of common mTOR-dependent autophagy pathways, mTOR-independent autophagy pathways and autophagic markers in the progression and treatment of MDD.

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    Advances in preoperative medical management of metabolic surgery
    SHAN Yingyi, YU Haoyong
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (10): 1332-1338.   DOI: 10.3969/j.issn.1674-8115.2023.10.016
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    Obesity is a chronic metabolic disease that is increasing in prevalence and has become a major public health problem and epidemic in many countries, including China. Obesity and its associated complications, such as type 2 diabetes (T2DM), non-alcoholic fatty liver disease, hypertension, and cardiovascular disease, seriously damage health. With the continuous development of metabolic surgery, it has become a widely used, safe and effective method for treating obesity and its associated complications. Metabolic surgery can significantly lose weight, improve metabolic indicators, reduce the risk of chronic diseases such as diabetes and hypertension, improve the quality of life of patients, and bring comprehensive health benefits to patients. However, there is currently a lack of standardized preoperative medical management for metabolic surgery, which may lead to metabolic disorders, nutrient deficiencies, and other complications, increasing the risk of surgery and postoperative complications, and affecting the efficacy of weight loss and the prognosis of patients. Through the systematic review of literature related to preoperative weight loss, glycemic control, blood pressure and lipid control, micronutrient supplementation, and psychological and behavioral modifications, this paper reviews preoperative medical management of metabolic surgery with the aim of providing reference for effectively improving the safety and efficacy of metabolic surgery and improving the prognosis of patients.

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    PTEN-regulated alternative splicing of FoxM1 affects tumor cell migration
    WANG Xiaoling, GE Mengkai, SHEN Shaoming
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (11): 1339-1347.   DOI: 10.3969/j.issn.1674-8115.2023.11.001
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    Objective ·To study the effect of phosphatase and tensin homolog on chromosome 10 (PTEN) on alternative splicing of forkhead box M1 (FoxM1), and its impact on tumor cell migration. Methods ·PTEN was knocked down by short hairpin RNA (shRNA) in human embryonic kidney 293T cells, human prostate cancer DU145 cells, human colorectal adenocarcinoma RKO cells, and human colon cancer SW480 and SW620 cells. Specific primers were designed for FoxM1 and its subtypes FoxM1B and FoxM1C, and the mRNA expression levels of FoxM1B and FoxM1C were detected by quantitative real-time PCR (qRT-PCR). FoxM1B and FoxM1C were overexpressed in DU145 cells, and their effects on tumor cell migration were tested by Transwell assay and wound healing assay. Immunofluorescence and dual luciferase reporter gene assay were used to explore the potential mechanism of differential regulation of tumor cell migration by FoxM1B and FoxM1C. Results ·① PTEN was knocked down in 293T, DU145, RKO, SW480, and SW620 cell lines. qRT-PCR results showed that compared with the control cells, the mRNA expression level of FoxM1B significantly increased in PTEN knockdown cells, while the mRNA expression level of FoxM1C decreased or remained unchanged. Knockdown of PTEN did not affect the transcription level of FoxM1, but caused the variable splicing of FoxM1 and promoted the generation of FoxM1B. ② Compared with the control cells, the number of DU145 cells migrating to the below chamber increased in the FoxM1B overexpression group (P=0.024), while the number of migrating DU145 cells in the FoxM1C overexpression group was lower (P=0.000). The healing ability of DU145 cells was significantly enhanced in the FoxM1B overexpression group (P=0.001), while the healing ability of DU145 cells was weakened in the FoxM1C overexpression group (P=0.021). Overall, FoxM1B and FoxM1C had opposite effects on tumor cell migration. FoxM1B promoted tumor cell migration, while FoxM1C inhibited tumor cell migration. ③ Neither FoxM1B nor FoxM1C overexpression could induce β-catenin to enter the nucleus. Dual luciferase reporter gene assay showed no difference in the transcriptional activity of FoxM1B and FoxM1C. The difference between FoxM1B and FoxM1C in the regulation of tumor metastasis was also not mediated by β-catenin translocation. Conclusion ·Knockdown of PTEN regulates the alternative splicing of FoxM1, leading to increasing expression of transcript FoxM1B, which plays a positive role in tumor cell migration.

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    Association between stroke and physical activities in Shanghai Community Elderly Cohort
    WANG Yayu, JIANG Huiru, YE Mengyue, LI Ping, YUAN Ancai, ZHANG Wei, PU Jun
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (11): 1348-1358.   DOI: 10.3969/j.issn.1674-8115.2023.11.002
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    Objective ·To compare the physical activities of stroke population and non-stroke population based on the baseline survey of the elderly population cohort in Shanghai communities, and explore the participation in different types of physical activities of stroke population. Methods ·The subjects were screened from Shanghai Community Elderly Cohort constructed from February to August, 2019 according to the admission criteria. The subjects were divided into non-stroke group and stroke group according to whether they had reported a history of stroke by themselves, and the two groups were matched 2 to 1 by controlling age and sex with propensity score matching. The baseline characteristics of the two groups were collected, and the physical activities related to sports, transportation and housework in the last week were investigated with the International Physical Activity Questionnaire (IPAQ). Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the sleep quality of the subjects. Generalized Anxiety Disorder (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) were used to evaluate anxiety and depression of the subjects, respectively. The above characteristics were compared between the stroke group and non-stroke group, and the participation of different types of physical activities were compared between the two groups by multivariate Logistic regression model. Results ·Among the 17 948 people included, there were 993 (5.5%) in the stroke group and 16 955 (94.5%) in the non-stroke group. After propensity score matching, there were 1 984 people (66.7%) in the non-stroke group and 992 people (33.3%) in the stroke group. There were significant differences in education level, pre-retirement occupation, waist circumference, body mass index, sleep status, anxiety symptoms, depression symptoms and disease history between the two groups (all P<0.05). In terms of physical activities, the female stroke group had shorter daily moderate exercises time, fewer riding and walking days in one week, and shorter daily riding time, compared with the non-stroke people, with statistical significance (all P<0.05). Compared with the non-stroke people, the weekly housework days and daily housework time in the male and female stroke groups were lower than those in the non-stroke group, while the daily sedentary time was longer, with statistical significance (all P=0.000). In terms of physical activity level, the proportions of men and women in the stroke group who reached medium or high level were lower than those in the non-stroke group, and the differences were statistically significant (all P=0.000). After adjusting for gender, age, occupation, anxiety symptoms, history of hyperlipidemia, history of atrial fibrillation, history of chronic gastritis and history of hip fracture by multivariate Logistic regression model, the level of vigorous exercise participation in the stroke group was lower, the proportions of no housework in the last week and sedentary time greater than 180 min per day were higher, and the proportion at medium and high activity levels was lower (all P<0.05). Conclusion ·The frequency and duration of housework participation and the physical activity level of elderly people with a history of stroke in Shanghai communities are at a lower level than those without stroke, and they also have a longer sedentary time.

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    Causal relationship between atrial fibrillation and cognitive impairment: a Mendelian randomization study
    GAO Xiong, ZHANG Qiuxia, YANG Miaomiao, LUO Wei, WANG Yuegang, XIU Jiancheng
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (11): 1359-1365.   DOI: 10.3969/j.issn.1674-8115.2023.11.003
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    Objective ·To investigate the causal relationship between atrial fibrillation (AF) and cognitive impairment. Methods ·A two-sample Mendelian randomization (TSMR) analysis was used to assess the potential causality of AF on cognitive dysfunction. Single nucleotide polymorphisms (SNPs) strongly associated with AF were extracted as instrumental variables by using a dataset of a large-scale genome-wide association study (GWAS) on AF. The associations of SNPs with Alzheimer′s disease dementia, Parkinson′s disease dementia, vascular dementia, Lewy body dementia, frontotemporal dementia, undefined dementia, and overall cognitive function assessment were extracted separately from publicly available GWAS data on cognitive dysfunction. The inverse variance-weighted (IVW) method was used for the main analysis, and sensitivity analyses were conducted by using Cochran′s Q test, MR-Egger regression, and leave-one-out method. To verify the robustness of the results, replicate analyses and meta-analyses were performed by using different GWAS data. Results ·In the initial analysis, 101 SNPs were extracted as instrumental variables from a meta-analysis of a genome-wide association study involving up to 1 030 836 individuals. The IVW analysis showed no evidence for causal associations between AF and dementia [dementia (OR=1.032; 95%CI 0.973?1.094; P=0.290), Parkinson′s disease dementia (OR=1.004; 95%CI 0.780?1.291; P=0.977), vascular dementia (OR=1.123; 95%CI 0.969?1.301; P=0.125), or unspecified dementia (OR=1.013; 95%CI 0.910?1.129; P=0.807)]. In the replication analysis, 27 SNPs were extracted as instrumental variables from the FinnGen AF GWAS data, and the IVW analysis were consistent with the initial analysis [cognitive function (OR=0.999; 95%CI 0.982?1.016; P=0.874), Alzheimer′s disease dementia (OR=0.977; 95%CI 0.943?1.012; P=0.193), Lewy body dementia (OR=1.014; 95%CI 0.898?1.145; P=0.826), or frontotemporal dementia (OR=0.996; 95%CI 0.745?1.333; P=0.980)]. Both Mendelian randomization analyses and meta-analyses showed no evidence of an association between genetically predicted AF and different types of dementia or overall cognitive function assessment. MR-Egger regression suggested no horizontal pleiotropy and leave-one-out analysis showed stable results after individually removing each SNP. Conclusion ·No evidence of a causal relationship between AF and cognitive impairment was found. The associations observed in observational studies can be partially attributed to confounding factors such as shared biology or co-morbidities.

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    Correlation analysis between sleep quality and carotid atherosclerosis in low and moderate risk individuals for cardiovascular and cerebrovascular diseases
    ZHAO Qian, WANG Ying, HAMULATI Xieyire, TUERXUN Gulijiehere, LI Xiaomei, YANG Yining
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (11): 1366-1373.   DOI: 10.3969/j.issn.1674-8115.2023.11.004
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    Objective ·To explore the relationship between sleep quality and carotid atherosclerosis in the population with low or moderate risk of cardiovascular and cerebrovascular diseases. Methods ·Based on the population-based cohort study of chronic diseases in Xinjiang, the researchers selected residents aged 35-75 from two fixed communities in Urumqi and Korla, in Northern and Southern Xinjiang, respectively, using a two-stage random cluster sampling method from July 2019 to September 2021. In the population without a history of coronary heart disease and cerebrovascular events, the prediction model for atherosclerotic cardiovascular disease (ASCVD) risk in China (China-PAR) was used to evaluate the risk of cardiovascular and cerebrovascular diseases. Low and moderate risk population of cardiovascular and cerebrovascular diseases were included. Participants completed physical examinations, questionnaires [including the Risk Factors Assessment Scale of Cardiovascular and Cerebrovascular Diseases in Xinjiang, Pittsburgh Sleep Quality Index (PSQI), International Physical Activity Questionnaire (IPAQ), and Food Frequency Questionnaire], cardiovascular and metabolic biochemical examinations, and carotid color doppler. Carotid intima-media thickness (CIMT) and plaque formation were used to determine the carotid atherosclerosis of the study subjects. Multivariate Logistic regression model and restricted cubic spline (RCS) were used to analyze the relationship between sleep quality and carotid intima-media thickening/plaque formation in the population with low and moderate risk of cardiovascular and cerebrovascular diseases. Results ·A total of 1 528 subjects were included in the study, the mean age was (49.4±8.2) years, and 685 (44.8%) were male. In the included population, there were 581 (38.0%) subjects with carotid intima-media thickening and 305 (20.0%) subjects with carotid plaque formation. Among them, intima-media thickening and plaque formation both occurred in 154 (10.1%) people. Therefore, the prevalence of carotid atherosclerosis was 47.9% (732 subjects). Compared with the group without carotid artery thickening, the group with carotid intima-media thickening/plaque formation had higher levels of general cardiovascular and cerebrovascular risk factors, including age, male ratio, blood lipid levels and obesity, and higher PSQI sleep score [(7.06±2.13) vs (7.43±2.51), P=0.001]. The proportion of patients with poor sleep quality was higher (6.5% vs 12.1%, P=0.001). Multivariate Logistic regression analysis showed that poor sleep quality was an independent risk factor for carotid atherosclerosis [adjusted OR (aOR)=1.22, 95%CI 1.004-1.492, P=0.040]. RCS analysis suggested that PSQI and the risk of carotid atherosclerosis showed a positive linear correlation, that is, the worse quality of sleep, the higher risk of carotid atherosclerosis. Conclusion ·Although the traditional metabolic risk factors are at a low risk level, the prevalence of carotid atherosclerosis is high and poor sleep quality is an independent risk factor for carotid atherosclerosis in the low and moderate risk population of cardiovascular and cerebrovascular diseases.

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    Construction of an mRNA vaccine encoding hemagglutinin of influenza A H1N1 virus and investigation on booster immunization strategy
    SHEN Haiqian, YU Kangying, CHEN Yingying, JI Ping, WANG Ying
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (11): 1374-1383.   DOI: 10.3969/j.issn.1674-8115.2023.11.005
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    Objective ·To construct an mRNA vaccine encoding hemagglutinin (HA) of influenza A H1N1 virus, and explore the protective effects of different booster vaccination strategies. Methods ·Firefly luciferase (Fluc) was used as the reporter gene to construct Fluc mRNA vaccine enveloped in lipid nanoparticles (LNP). The in vivo expression of Fluc mRNA-LNP after intramuscular injection was determined by live imaging assay in mice. Furthermore, M15-HA mRNA-LNP derived from H1N1 subtype (A/Michigan/45/2015) was constructed. Mice were immunized with 20, 10, 5, or 1 μg doses of M15-HA mRNA-LNP twice (with an interval of 3 weeks) through intramuscular injection. Serum antibody titers were measured by enzyme-linked immunosorbent assay (ELISA) at 2 weeks and 4 weeks after the second immunization, and functional antibody levels were detected by hemagglutination inhibition test. The third booster vaccination was performed 40 d after the second immunization in 1 μg dose group with 1 μg M15-HA mRNA-LNP or 10 μg HA subunit vaccine. The levels of specific antibody and functional antibody were detected by ELISA and hemagglutination inhibition test, respectively 2 weeks and 4 weeks later. Results ·Live imaging assay showed that luciferase activity could be detected in mice 1 d after injection of Fluc mRNA-LNP. At 2 weeks and 4 weeks after the second immunization of M15-HA mRNA-LNP, HA-specific antibodies were significantly higher than those before the immunization in all vaccination groups at different doses (P=0.000). The hemagglutination inhibition test showed that the levels of functional antibodies in the 20 μg dose and 10 μg dose groups were significantly higher than those in the PBS control group (P<0.05). After 1 μg dose group mice were immunized with HA protein or M15-HA mRNA-LNP, higher levels of HA-specific antibody and functional antibody were induced and maintained for a long time. There was no significant difference between the two different booster immunization strategies. Conclusion ·M15-HA mRNA-LNP vaccine is constructed with immunogenicity and antibody neutralization activity. Low-dose mRNA priming vaccination followed by both homologous mRNA vaccine and heterologous protein subunit vaccine booster vaccination can induce stronger immune recall responses.

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    Quantitative analysis of the developmental potential of cells and tissues based on evolutionary conservation of genes and regulatory regions
    WANG Zhiming, TONG Ran, YANG Chen, JIAO Huiyuan, WANG Yihao, LI Linying, WANG Yexin, ZHANG Feng, LI Lingjie
    Journal of Shanghai Jiao Tong University (Medical Science)    2023, 43 (11): 1384-1395.   DOI: 10.3969/j.issn.1674-8115.2023.11.006
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    Objective ·To study the relationship between evolution and the developmental process from the perspective of DNA sequence conservation, and explore their inherent principles. Methods ·First, conservation rate (CR) was established by analyzing the conservation of amino acid sequences of coding genes in 100 species to quantify the evolutionary conservation of genes. The relationship between CR and developmental potential was verified by using the feature genes involved in embryonic stem cells pathways. Secondly, cell type-specific genes and their characteristics in conservation were studied by analyzing the RNA sequencing (RNA-seq) data of the three early germ layers (ectoderm, mesoderm and endoderm) and their corresponding mature organs (brain, heart, liver, etc). Then, chromatin immunoprecipitation sequencing (ChIP-seq) data of enhancer histone H3 acetylated at lysine 27 (H3K27ac) from early germ layers and mature organs were collected to search for enhancer sites and identify super enhancers in various cells and tissues by using the ROSE procedure. Functional enrichment and signaling pathway analysis of genes was used to examine the identity correlation between SEs-regulated genes and the corresponding cell characteristics, to clarify whether the SEs identified in this study were consistent with the characteristics reported in previous studies. Finally, PhastCons program was used to calculate the DNA conservation score (CS) of non-coding regulatory regions to study their relationship with developmental potential. Results ·In the coding region of DNA, CR was successfully established to quantify the conservation of genes. The gene expression data of early germ layers and mature organs showed that the genes with higher conservation rate were more relevant to the stemness and early developmental process, and the differences between the tissues from early and late development could be distinguished by using CR. In the non-coding regions of DNA, it was found that the conservation of regulatory regions was also correlated with development. The CS of the SE sequences in the early developmental germ layers was significantly higher than that of the SE sequences in the corresponding mature organs. However, cell-specific typical enhancers (TEs) did not show such a trend. Conclusion ·During the developmental process, CR of genes expressed in the coding region decreases, and CS of super-enhancer DNA in the non-coding region decreases.

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