Effect of CKIP-1 on hepatocyte apoptosis in nonalcoholic fatty liver disease / 中华内科杂志

Objective:To explore the effect and underlying mechanism of casein kinase 2 interacting protein-1 (CKIP-1) on hepatocyte apoptosis in nonalcoholic fatty liver disease (NAFLD).Methods:Experimental study. An NAFLD cell model was established by inducing human hepatoma cell line, HepG 2 cells, with oleic acid (OA). Flag-CKIP-1 expression vector and shRNA-CKIP-1 were transfected into HepG 2 cells. Flow cytometry was used to detect the effect of CKIP-1 on the activity and apoptosis of NAFLD hepatocytes. The levels of apoptosis-related proteins were detected by Western blot. CKIP-1 knockout mice in C57BL/6 back-ground were fed with either standard or high-fat diet for 8 weeks. Apoptosis-related signal proteins in NAFLD hepatocytes were detected by immunohistochemistry. Results:After CKIP-1 was transfected into HepG 2 cells, the degree of OA induced cell liposis was significantly reduced ( P<0.05). Annexin V-FITC/PI flow cytometry showed that CKIP-1 reduced the apoptosis of steatotic hepatocytes. Overexpression of CKIP-1 could significantly inhibit the expression of caspase-3 and caspase-9 and increase the expression of Bcl-2/Bax ( P<0.05). Knockdown of CKIP-1 could increase the expression of caspase-3 and caspase-9 ( P<0.05). CKIP-1 knockout could further increase the expression of caspase-3 and caspase-9 in NAFLD mice ( P<0.01, P<0.05), and further decrease the expression of Bcl-2/Bax ( P<0.05). Conclusion:CKIP-1 inhibited the apoptosis of steatotic hepatocytes by up-regulating the expression of apoptosis inhibitor gene, Bcl-2/Bax, and affecting the proteases, caspase-3 and caspase-9.

Role of the Mean Nocturnal Baseline Impedance in Identifying Evidence Against Pathologic Reflux in Patients With Refractory Gastroesophageal Reflux Disease Symptoms as Classified by the Lyon Consensus

Background/Aims@#Mean nocturnal baseline impedance (MNBI) is a new reflux metric for mucosal integrity. It remains unclear whether MNBI can help identify evidence against pathological reflux by the Lyon Consensus in patients with refractory gastroesophageal reflux disease (GERD) symptoms. @*Methods@#Three hundred and forty-nine patients with refractory GERD symptoms enrolled in this study were subjected to high-resolution manometry, 24-hour multichannel intraluminal impedance-pH (MII-pH) monitoring, and endoscopy. Conventional indexes (ie, reflux events and acid exposure time) and the novel index (MNBI) of MII-pH monitoring were extracted and analyzed. The value of MNBI in diagnosing patients with evidence against pathologic reflux was evaluated by receiver-operating-characteristic analysis. @*Results@#There were 102 (29.2%) patients with evidence against pathologic reflux, 149 (42.7%) with inconclusive or borderline evidence and 98 (28.1%) with conclusive evidence for pathologic reflux. The MNBI was significantly higher while the proportion of pathological MNBI was significantly lower in subjects with evidence against pathologic reflux than in patients with inconclusive or borderline evidence and in patients with conclusive evidence for pathologic reflux (2444.3 [1977.9-2997.4] vs 1992.8 [1615.5-2253.6] and vs 1772.3 [758.6-2161.3], both P < 0.001; 42.2% vs 79.7% and vs 80.0%, both P < 0.05). When identifying evidence against pathologic reflux in patients with refractory GERD symptoms, the MNBI yielded an area under the curve of 0.749 (P < 0.001) at a cutoff value of 1941.8 Ω. @*Conclusions@#The MNBI has a good diagnostic value for evidence against pathological reflux in patients with refractory GERD symptoms. For its simplicity and reproducibility, we believe that MNBI should be referred to in reports of impedance-pH tracings by physicians.

Clinical features of patients with different types of acute drug-induced liver injury: A comparative analysis / 临床肝胆病杂志

ObjectiveTo investigate the clinical features of patients with different types of acute drug-induced liver injury (DILI) through a retrospective analysis. MethodsClinical data were collected from 790 patients who were diagnosed with acute DILI in Beijing YouAn Hospital and Beijing Tongren Hospital affiliated to Capital Medical University from December 2010 to March 2019, and according to the type of damaged target cell, the patients were divided into hepatocellular injury type group with 554 patients, cholestasis type group with 99 patients, and mixed type group with 137 patients. The patients were evaluated based on severity grade and score, clinical outcome, and Hy′s rule. An analysis of variance was used for comparison of normally distributed continuous data between three groups, and the least significant difference t-test was used for further comparison between two groups; the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between groups. The chi-square test was used for comparison of categorical data between three groups. The Kruskal-Wallis H test was used for comparison of ranked data between three groups, and the Mann-Whitney U test was used for comparison between two groups. ResultsMost of the patients were female in all three groups, and the hepatocellular injury type group had a significantly higher proportion of female patients than the cholestasis type group (70.8% vs 54.5%, P＜0.05), and the Cholestasis type group had a significantly lower proportion of female patients than the mixed type group(54.5% vs 54.7%, P＜0.05). There were 244 patients with grade 3 hepatocellular injury type DILI (244/554, 44.4%), 56 patients with grade 3 cholestasis type DILI (56/99, 56.6%), and 46 patients with grade 3 mixed type DILI (46/137, 33.6%), and there was a significant difference between the three groups (χ2=36.589, P＜0.05). Drugs inducing liver injury included traditional Chinese medicine, Western medicine, combination of traditional Chinese medicine and Western medicine, and other drugs, among which traditional Chinese medicine was the most common cause of liver injury. There was a significant difference in the outcome at discharge between the patients with different types (H=14.390, P=0.001). Compared with the cholestasis type group, the hepatocellular injury type group had a significantly higher cure rate and significantly lower uncured rate and mortality rate (all P＜0.05). Among the 554 patients with hepatocellular injury type DILI, 388 (70.0%) met Hy′s rule and 166 (300%) did not meet Hy′s rule, and there was a significant difference in clinical outcome between these two groups (U=38 372.0, P=0.033). ConclusionDILI is more common in women, and most patients have hepatocellular injury type DILI. Traditional Chinese medicine is the main cause of liver injury. There is a high proportion of patients with severe DILI among the patients with hepatocellular injury type or cholestasis type. DILI often has good prognosis with a relatively low mortality rate. Hy′s rule cannot predict the death of patients with acute DILI.

Study on the quality of life and psychological factors of 159 patients with different subtypes of refractory gastroesophageal reflux disease / 中华消化杂志

Objective:To explore the quality of life and psychological factors of patients with refractory gastroesophageal reflux disease (rGERD).Methods:From September 2016 to March 2019, 159 rGERD patients visiting the Department of Gastroenterology, Beijing Tongren Hospital Affiliated to Capital Medical University were retrospectively selected. According to the presence or absence of distal esophageal mucosal injury under gastroscopy, the patients were divided into refractory reflux esophagitis (RE) group (58 cases) and refractory non-erosive reflux disease (NERD) group (101 cases). The general data, the results of 24 h esophageal impedance pH, esophageal high-resolution manometry (HRM) and the scores of gatroesophageal reflux disease-questionnaire (GerdQ), 36-item short-form health survey (SF-36), self-rating anxiety scale(SAS) and self-rating depression scale (SDS) were recorded and compared between the two groups. Independent sample t test, rank sum test, chi-square test and multiple linear regression analysis were used for statistical analysis. Results:There were no significant differences in gender, age, abdominal circumference or body mass index between the two groups (all P>0.05). The incidence of extraesophageal symptoms of refractory NERD group was higher than that of refractory RE group (45.5%, 46/101 vs. 24.1%, 14/58), and the difference was statistically significant ( χ2=7.185, P=0.010). The episodes of gas reflux, weak-acid reflux and non-acid reflux were all more than those of refractory RE group (66.20 times, 45.20 times to 111.60 times vs. 38.40 times, 23.50 times to 59.63 times; 34.70 times, 9.05 times to 52.75 times vs. 6.35 times, 3.10 times to 24.00 times; 12.60 times, 2.15 times to 24.20 times vs. 2.15 times, 0 times to 10.30 times), GerdQ score of refractory NERD group was higher than that of refractory RE group (8.9±2.5 vs. 7.8±2.3), and DeMeester score, the symptom index and symptom association probability of refractory NERD group were all lower than those of refractory RE group (5.16, 1.75 to 14.48 vs. 15.19, 2.78 to 45.96; 33.3%, 0 to 60.0% vs. 57.5%, 40.5% to 78.0%; 87.8%, 0 to 97.8% vs. 94.0%, 82.7% to 98.2%); and the differences were statistically significant ( Z=-5.548, -5.384 and -4.338, t=3.306, Z=-2.607, -4.313 and -2.468; all P<0.05). The esophageal distal contractile integral of refractory NERD group was lower than that of refractory RE group (334.0 mmHg·s·cm, 182.5 mmHg·s·cm to 492.0 mmHg·s·cm vs. 399.0 mmHg·s·cm, 216.5 mmHg·s·cm to 756.3 mmHg·s·cm, 1 mmHg=0.133 kPa), and the difference was statistically significant ( Z=-2.204, P=0.030). There were no significant differences in lower escophageal sphincter or the length of peristaltic interruption between the two groups (both P>0.05). There were no significant differences in physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, mental health or reported health transition of SF-36 score between refractory NERD group and refractory RE group (all P>0.05). Among 159 patients with rGERD, 98 patients (61.6%) had anxiety and 55 patients (34.6%) had depression. The SAS score of refractory NERD group was higher than that of refractory RE Group (52.6±5.8 vs. 47.0±8.8), and the difference was statistically significant ( t=4.794, P<0.05), however there was no significant difference in SDS score between the two groups ( P>0.05). The results of multiple linear regression analysis showed that GerdQ score in rGERD patients was positively correlated with DeMeester score, gas reflux, weak acid reflux, SAS score and SDS score ( r=0.201, 0.228, 0.171, 0.229 and 0.276; all P<0.05). Conclusions:Among the patients with rGERD, the reflux symptoms are more severe in refractory NERD patients, which may be related to non-acid reflux, gas reflux, esophageal motor disorders, and psychological abnormalities, especially anxiety.

Correlation between esophageal motility abnormalities and characteristics of esophageal reflux in patients with different subtypes of refractory gastroesophageal reflux disease / 中华消化杂志

Objective To investigate the correlation between esophageal motility abnormalities and the characteristics of gastroesophageal reflux in patients with different subtypes of refractory gastroesophageal reflux disease (rGERD).Methods From September 2015 to May 2016,a total of 100 rGERD patients were collected,all of whom received gastroendoscopy examination,high resolution manometry (HRM) and 24 h impedance-pH monitoring.According to the results of gastroendoscopy examination,the patients were divided into refractory non-erosive reflux disease (NERD) group and refractory reflux esophagitis (RE) group.Abnormal esophageal motility and pathological gastroesophageal reflux of each group were analyzed.Chi-square test,t test and sum-rank test were performed for comparison,the correlation factors were analyzed by multivariate unconditional Logistic regression.Results Among the 100 patients with rGERD,there were 83 cases in refractory NERD group and 17 in refractory RE group.The episodes of weak acid and gas-liquid mixed reflux of refractory NERD group were both significantly higher than those of refractory RE group (80.2±56.9 vs 44.8± 13.7,56.0± 25.6 vs 25.2±16.1);and the differences were statistically significant (t=3.202 and 2.229,both P＜ 0.05).The DeMeester score,acid reflux episodes and the percentage of reflux time of refractory NERD group were all significantly lower than those of refractory RE group (24.2±8.5 vs 56.8±3.0,21.4± 11.8 vs 35.9 ± 32.6,(7.1 ± 1.6) ％ vs (16.2 ± 8.8) ％),and the differences were statistically significant (t=-2.820,-2.230 and-2.604;all P＜0.05).However,the average resting pressure of lower esophageal sphincter was higher than that of refractory RE group ((7.9±5.6) mmHg (1 mmHg=0.133 kPa) vs (4.5±2.2) mmHg),and the difference was statistically significant (t=2.443,P＜0.05).Patients with esophageal motility disorders of refractory NERD group and refractory RE group were 58 cases (69.9 ％) and 12 cases (12/17),respectively,and the difference was not significant (P＞0.05).Compared with refractory RE group,the ratio of intermittent contraction was higher (1/17 vs 26.5％,22/83) and the peristaltic contraction disorder was lower in refractory NERD group (11/17 vs 43.4％,36/83);and the differences were statistically significant (x2 =3.389 and 2.587,both P ＜ 0.05).The results of multivariate non-conditional Logistic regression analysis showed that intermittent contraction and gas reflux were risk factors of the incidence of pathological weak acid reflux (odd ratio (OR) =3.139 and 1.254,both P＜0.05),while body mass index and gas-liquid mixed reflux were the risk factors of the occurrence of pathological acid reflux (OR =1.302 and 1.026,both P＜ 0.05),whereas the distal contractile integral was a protective factor (OR=0.998,P＜0.05).Conclusion Esophageal dysmotility is common in patients with rGERD,and the dysmotility disorders are different in patients with different subtypes,which may be related to the different reflux characteristics.

Expression of inducible nitric oxide synthase in gastric mucosa in the development of portal hypertensive gastropathy in rats and the interventional effect of aminoguanidine / 中华临床营养杂志

@#arkably increases with the development of cirrhosis,which may play an important role in the development of PHG.AG may remarkably ameliorate the degree of PHG，mainly by inhibiting the expression of iNOS in gastric musosa.

Effects of vitamin E on the proliferation and collagen synthesis of rat hepatic stellate cells treated with IL-2 or TNF-alpha / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>To study the effects of vitamin E on the proliferation and collagen synthesis of rat hepatic stellate cells treated with interleukin-2 (IL-2) or tumor necrosis factor-alpha (TNF-alpha).</p><p><b>METHODS</b>Hepatic stellate cells were isolated from male Sprague-Dawley rats by using modified Friedman's method. Using the isolated cells cultured and treated with IL-2 or TNF-alpha, we studied the effects of vitamin E on their proliferation and collagen synthesis through an (3)H-thymidine and (3)H-proline incorporation assay, as well as through observation of these cells under a contrary phase microscope.</p><p><b>RESULTS</b>Adding IL-2 increased the both proliferation and collagen synthesis of hepatic stellate cells. Their proliferation was also increased by the addition of TNF-alpha, although it decreased collagen synthesis. Vitamin E had marked inhibitory effects on the ability of cells treated with IL-2 or TNF-alpha to reproduce or synthesize collagen.</p><p><b>CONCLUSION</b>Vitamin E can inhibit the proliferation and collagen synthesis of hepatic stellate cells. It is possible that vitamin E affects liver fibrosis through these activities.</p>

A comparative study on the anti-hepatofibrosis mechanism of rhubarb and tetrandrine / 中华消化杂志

Objective To study the anti-hepatofibrotic effects of rhubarb and tetrandrine in experimental rat model, and to explore its possible mechanism. Methods The experimental hepatic fibrosis was induced by subcutaneous injection of CCl 4. The rhubarb and tetrandrine were administered through gastric tube respectively. The liver function test was performed by enzyme kinetics and the extracellular matrix (ECM) contents were determined by radioimmunoassay. The pathological changes of liver tissues were detected by HE and VG staining; meanwhile, ultra microstructural changes were observed by electron microscope in randomly selected samples. Results Both rhubarb and tetrandrine could improve the liver function in liver fibrosis, decrease the contents of ECM and reduce the degree of liver fibrosis, with the best results in rats receiving high dosage of rhubarb and low dosage of tetrandrine. Conclusions Rhubarb and tetrandrine could protect hepatocytes, inhibit the ECM synthesis, and thereby could prevent the development of liver fibrosis and cirrhosis in the experimental animal models.

Octreotide inhibits proliferation and extracellular matrix synthesis in hepatic stellate cells / 中国病理生理杂志

AIM: To investigate the effects of octreotide (Oct) on the proliferation and extracellular matrix (ECM) synthesis in hepatic stellate cells (HSCs). METHODS: HSCs were isolated from normal male Sprague-Dawley rat liver by a combination of pronase-collagenase perfusion and density gradient centrifugation. The concentration of 2.5 ?g/L transforming growth factor ?1 (TGF?1) was used in all the experiment settings. Oct at concentrations of 0.01 mg/L ,0.1 mg/L,1 mg/L and 10 mg/L,respectively,or 0.01 mg/L Oct + TGF?1,0.1 mg/L Oct+TGF?1,1 mg/L Oct+TGF?1,10 mg/L Oct+TGF?1 were respectively added to the cultured HSCs. Effects of Oct on HSC proliferation and ECM synthesis were respectively determined by MTT method,-TdR and -proline incorporation,or radioimmunoassay. RESULTS: Oct inhibited MTT intake by cultured hepatic stellate cells and down-regulated -TdR incorporation,compared with control group. The concentrations of hyaluronic acid,laminin,collagen type IV in the culture supernatant and -proline incorporation in HSCs were decreased by Oct. TGF?1 obviously up-regulated proliferation and ECM synthesis in cultured HSCs,and Oct significantly blocked these actions. CONCLUSION: Oct inhibited proliferation and ECM synthesis in cultured HSCs,and elicited the effects of anti-hepatofibrogenesis.