Ginsenoside Rb1 alleviates colitis in mice via activation of endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 signaling pathway.

Endoplasmic reticulum (ER) homeostasis is regulated by ER-resident E3 ubiquitin ligase Hrd1, which has been implicated in inflammatory bowel disease (IBD). Ginsenoside Rb1 (GRb1) is the major ginsenoside in ginseng with multiple pharmacological activities. In this study we investigated the role of Hrd1 in IBD and its regulation by GRb1. Two mouse colitis models were established to mimic human IBD: drinking water containing dextran sodium sulfate (DSS) as well as intra-colonic infusion of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). Colitis mice were treated with GRb1 (20, 40 mg·kg-1·d-1, ig) or a positive control drug sulfasalazine (500 mg·kg-1·d-1, ig) for 7 days. The model mice showed typical colitis symptoms and pathological changes in colon tissue. In addition to significant inflammatory responses and cell apoptosis in colon tissue, colon epithelial expression of Hrd1 was significantly decreased, the expression of ER stress markers GRP78, PERK, CHOP, and caspase 12 was increased, and the expression of Fas was increased (Fas was removed by Hrd1-induced ubiquitination). These changes were partially, or completely, reversed by GRb1 administration, whereas injection of Hrd1 inhibitor LS102 (50 mg·kg-1· d-1, ip, for 6 days) exacerbated colitis symptoms in colitis mice. GRb1 administration not only normalized Hrd1 expression at both the mRNA and protein levels, but also alleviated the ER stress response, Fas-related apoptosis, and other colitis symptoms. In intestinal cell line IEC-6, the expression of Hrd1 was significantly decreased by LPS treatment, but was normalized by GRb1 (200 µM). GRb1 alleviated LPS-induced ER stress and cell apoptosis in IEC-6 cells, and GRb1 action was inhibited by knockdown of Hrd1 using small interfering RNA. In summary, these results reveal a pathological role of Hrd1 in colitis, and provide a novel insight into alternative treatment of colitis using GRb1 activating Hrd1 signaling pathway.

[Differences of Energy Spectrum CT Findings between Small Cell Lung Cancer with Mediastinal Lymph Node Metastasis and Mediastinal Sarcoidosis].

Objective To compare the differences of energy spectrum CT between small cell lung cancer(SCLC)with mediastinal lymph node metastasis and mediastinal sarcoidosis.Methods Twenty-five SCLC patients with mediastinal lymph node metastasis(SCLC group)and 26 patients with mediastinal sarcoidosis(sarcoidosis group)confirmed by bronchoscopy and biopsy in Tangshan People's Hospital from January 2018 to June 2019 were selected as the research objects.The CT value,iodine concentration,water concentration and energy spectrum curve slope under different single energy levels were compared between SCLC group and sarcoidosis group.Results The single-energy CT values of 40-80 keV segments in the arterial phase of the SCLC group were significantly higher than those in the sarcoidosis group(all P <0.05).The single-energy CT values of 90-140 keV segments were not significantly different from those in the sarcoidosis group(all P >0.05).The single-energy CT values of 40-90 keV segments in venous phase of the SCLC group were significantly higher than those of the sarcoidosis group(all P <0.05),and the single-energy CT values of 100-140 keV segments were not significantly different from those of the sarcoidosis group(all P >0.05).The concentrations of iodine in the arterial phase and venous phase of the SCLC group were(11.56±4.06)µg/cm 3 and(13.39±0.87)µg/cm 3,respectively,which were significantly higher than those [(4.43±3.85)µg/cm 3,t=11.564,P=0.026;(7.23±2.71)µg/cm 3,t=13.653,P=0.021] in the sarcoidosis group.The concentrations of water in the arterial and venous phases of the SCLC group were(1040.67±5.62)mg/cm 3 and(1035.23±8.57)mg/cm 3,respectively,which showed no statistically significant difference compared with those [(1028.87±6.94)mg/cm 3,t=3.155,P=1.861;(1021.53±4.68)mg/cm 3,t=3.265,P=1.687] in the sarcoidosis group.The slopes of energy spectrum curve at 40-70 keV,70-100 keV and 100-140 keV in venous phase of the SCLC group were significantly higher than those of the sarcoidosis group(all P <0.05),whereas they showed no significant difference between the two groups in arterial phase(all P >0.05).Conclusion The differences between SCLC with mediastinal lymph node metastasis and mediastinal sarcoidosis can be shown on the single-energy CT values of 40-80 keV in arterial phase and 40-90 keV in venous phase,iodine concentrations in arterial phase and venous phase,and the slope of energy spectrum curve in venous phase.

A Functional Variant in Ubiquitin Conjugating Enzyme E2 L3 Contributes to Hepatitis B Virus Infection and Maintains Covalently Closed Circular DNA Stability by Inducing Degradation of Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit 3A.

Hepatitis B virus (HBV) infection is a common infectious disease, in which nuclear covalently closed circular DNA (cccDNA) plays a key role in viral persistence, viral reactivation after treatment withdrawal, and drug resistance. A recent genome-wide association study has identified that the ubiquitin conjugating enzyme E2 L3 (UBE2L3) gene is associated with increased susceptibility to chronic HBV (CHB) infection in adults. However, the association between UBE2L3 and children with CHB and the underlying mechanism remain unclear. In this study, we performed two-stage case-control studies including adults and independent children in the Chinese Han population. The rs59391722 allele in the promoter of the UBE2L3 gene was significantly associated with HBV infection in both adults and children, and it increased the promoter activity of UBE2L3. Serum UBE2L3 protein levels were positively correlated with HBV viral load and hepatitis B e antigen (HBeAg) levels in children with CHB. In an HBV infection cell model, UBE2L3 knockdown significantly reduced total HBV RNAs, 3.5-kb RNA, as well as cccDNA in HBV-infected HepG2-Na+ /taurocholate cotransporting polypeptide cells and human primary hepatocytes. A mechanistic study found that UBE2L3 maintained cccDNA stability by inducing proteasome-dependent degradation of apolipoprotein B mRNA editing enzyme catalytic subunit 3A, which is responsible for the degradation of HBV cccDNA. Moreover, interferon-α (IFN-α) treatment markedly decreased UBE2L3 expression, while UBE2L3 silencing reinforced the antiviral activity of IFN-α on HBV RNAs, cccDNA, and DNA. rs59391722 in UBE2L3 was correlated with HBV DNA suppression and HBeAg loss in response to IFN-α treatment of children with CHB. Conclusion: These findings highlight a host gene, UBE2L3, contributing to the susceptibility to persistent HBV infection; UBE2L3 may be involved in IFN-mediated viral suppression and serve as a potential target in the prevention and treatment of HBV infection.

Cinnamaldehyde protects against rat intestinal ischemia/reperfusion injuries by synergistic inhibition of NF-κB and p53.

Our preliminary study shows that cinnamaldehyde (CA) could protect against intestinal ischemia/reperfusion (I/R) injuries, in which p53 and NF-κB p65 play a synergistic role. In this study, we conducted in vivo and in vitro experiments to verify this proposal. SD rats were pretreated with CA (10 or 40 mg · kg-1 · d-1, ig) for 3 days, then subjected to 1 h mesenteric ischemia followed by 2 h reperfusion. CA pretreatment dose-dependently ameliorated morphological damage and reduced inflammation evidenced by decreased TNF-α, IL-1ß, and IL-6 levels and MPO activity in I/R-treated intestinal tissues. CA pretreatment also attenuated oxidative stress through restoring SOD, GSH, LDH, and MDA levels in I/R-treated intestinal tissues. Furthermore, CA pretreatment significantly reduced the expression of inflammation/apoptosis-related NF-κB p65, IKKß, IK-α, and NF-κB p50, and downregulated apoptotic protein expression including p53, Bax, caspase-9 and caspase-3, and restoring Bcl-2, in I/R-treated intestinal tissues. We pretreated IEC-6 cells in vitro with CA for 24 h, followed by 4 h hypoxia and 3 h reoxygenation (H/R) incubation. Pretreatment with CA (3.125, 6.25, and 12.5 µmol · L-1) significantly reversed H/R-induced reduction of IEC-6 cell viability. CA pretreatment significantly suppressed oxidative stress, NF-κB activation and apoptosis in H/R-treated IEC-6 cells. Moreover, CA pretreatment significantly reversed mitochondrial dysfunction in H/R-treated IEC-6 cells. CA pretreatment inhibited the nuclear translocation of p53 and NF-κB p65 in H/R-treated IEC-6 cells. Double knockdown or overexpression of p53 and NF-κB p65 caused a synergistic reduction or elevation of p53 compared with knockdown or overexpression of p53 or NF-κB p65 alone. In H/R-treated IEC-6 cells with double knockdown or overexpression of NF-κB p65 and p53, CA pretreatment caused neither further decrease nor increase of NF-κB p65 or p53 expression, suggesting that CA-induced synergistic inhibition on both NF-κB and p53 played a key role in ameliorating intestinal I/R injuries. Finally, we used immunoprecipitation assay to demonstrate an interaction between p53 and NF-κB p65, showing the basis for CA-induced synergistic inhibition. Our results provide valuable information for further studies.

[Different Energy Spectrum CT Findings between Anterior Mediastinal Lymphoma and Thymic Carcinoma].

Objective To investigate the differences in energy spectrum CT findings between anterior mediastinal lymphoma and thymic carcinoma. Methods Twenty-two cases of anterior mediastinal lymphoma and 28 cases of thymic carcinoma confirmed by biopsy in Tangshan People's Hospital were selected.The CT values and changes of iodine content and water content in lesion sites were measured by energy spectrum analysis software.The differences between anterior mediastinal lymphoma and thymic carcinoma were compared. Results The single-energy CT value of 40-80 keV in thymus carcinoma was higher than that in anterior mediastinal lymphoma(P=0.001,P=0.037,P=0.042,P=0.034,P=0.002;P=0.016,P=0.013,P=0.018,P=0.024,P=0.012).The difference in the single-energy CT value of 90-110 keV between anterior mediastinal lymphoma and thymic carcinoma showed no statistical significance(all P>0.05).The concentrations of water in the arterial and venous stages of thymic carcinoma were significantly lower than those in the anterior mediastinal lymphoma(P=0.030,P=0.037),whereas the iodine concentrations were significantly higher(P=0.026,P=0.000). Conclusion Anterior mediastinal lymphoma and thymic carcinoma have remarkably different 40-80 keV single energy CT value and iodine concentration in arterial and venous phases,which may be helpful for the differential diagnosis of these two malignancies.

Enhancement of epithelial cell autophagy induced by sinensetin alleviates epithelial barrier dysfunction in colitis.

Intestinal epithelial barrier dysfunction is a key pathology of colitis. Autophagy of epithelial cells maintains homeostasis of the intestinal barrier by inhibiting apoptosis and stimulating degradation of the tight junction protein claudin-2. This study investigated the effects and mechanism of activity of sinensetin, a polymethylated flavonoid isolated from tangerine peel and citrus, on intestinal barrier dysfunction in colitis. Animal model of colitis were established by intracolonic administration of 2, 4, 6-trinitrobenzene sulfonic acid and oral treatment with dextran sulfate sodium. Epithelial barrier function was evaluated by measuring the serum recovery of fluorescein isothiocyanate-4 kD dextran in vivo and transepithelial electrical resistance in Caco-2 cells, respectively. Epithelial cell autophagy assayed by autophagosome formation and expression of autophagy-related protein. Sinensetin reversed colitis-associated increase in intestinal permeability, significantly promoted epithelial cell autophagy, and further decreased epithelial cell apoptosis, and reduced mucosal claudin-2. Sinenstetin alleviated colitis symptoms rats and mice with colitis. Knockdown of 5' adenosine monophosphate-activated protein kinase (AMPK) reversed the promotion of epithelial autophagy by sinensetin. In conclusion, sinensetin significantly alleviated intestinal barrier dysfunction in colitis by promoting epithelial cell autophagy, and further inhibiting apoptosis and promoting claudin-2 degradation. The results highlighted novel potential benefits of sinensetin in colitis.

Microwave ablation of hyperplastic parathyroid glands is a treatment option for end-stage renal disease patients ineligible for surgical resection.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a frequently encountered problem in patients with end-stage renal disease (ESRD). Some patients with severe SHPT could not be managed by medical treatment and are ineligible for surgical resection. PURPOSE: Our objective was to evaluate the efficacy, safety of microwave ablation (MWA) on these patients. MATERIALS AND METHODS: Between 1 April 2015 and 28 February 2017, 35 patients (M/F 19/16, age 49.8 ± 12.9 years) were enrolled. All patients were treated with MWA. Levels of intact parathyroid hormone (iPTH) and of serum calcium and phosphorus were compared pre- and post-ablation. Repeated-measures ANOVA was used to compare treatment outcomes pre- and post-ablation. RESULTS: Complete ablation was achieved in all 63 glands in the 35 patients with SHPT. The mean follow-up time was 15.9 ± 2.2 months. The maximum gland diameter was 6-31 mm (mean, 14.9 ± 5.5 mm). The trends of the changes in iPTH and calcium levels showed a curve: the level of iPTH and calcium at 6 months post-ablation were lower than those pre-ablation (both p < .0001); after then iPTH remained relatively stable and the end of follow up, with no rebound (p < .0001), while instead of calcium at the end of follow up was not significantly lower than pre-ablation (p = .462). The trend in the change in phosphate levels showed a straight line; the level of phosphate at 6 months post-ablation and at the end of follow up both were significantly lower than pre-MWA (p < .001). There was no major complication. CONCLUSIONS: In this series, MWA was used successfully to treat SHPT patients who are ineligible for surgical resection.

[Current status of antibiotic therapy for Staphylococcus aureus sepsis in children].

OBJECTIVE: To investigate the current status of empirical antibiotic therapy for children with Staphylococcus aureus sepsis and the effect of therapeutic paradigm on prognosis based on a retrospective analysis. METHODS: A total of 78 children with Staphylococcus aureus sepsis who were admitted from January 2014 to August 2017 were enrolled. According to the preferred empirical antibiotics before the detection of Staphylococcus aureus by blood culture, these children were divided into a carbapenem group with 16 children, a ß-lactam group with 37 children, a vancomycin group with 15 children and a vancomycin+ß-lactam group with 10 children. A retrospective analysis was performed for related clinical data including general status, underlying diseases, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, history of use of immunosuppressant, drug resistance to methicillin and prognosis. A logistic regression analysis was used to investigate the effect of empirical antibiotic therapy on the clinical outcome and prognosis of children with Staphylococcus aureus sepsis. RESULTS: There were no significant differences among these groups in general status, underlying diseases, history of use of immunosuppressant, APACHE II score, nosocomial infection and detection rate of methicillin-resistant Staphylococcus aureus (P>0.05). There were significant differences in the incidence rate of septic shock and in-hospital mortality among these four groups (P<0.05). The carbapenem group had the highest incidence rate of septic shock and in-hospital mortality (69% and 50% respectively). The multivariate logistic regression analysis showed that empirical antibiotic therapy with different antibiotics had different risks for septic shock and in-hospital death in children with Staphylococcus aureus sepsis (P<0.05), and that an APACHE II score of ≥15 was an independent risk factor for septic shock in these children (P<0.05). The carbapenem group had significantly higher risks of septic shock and in-hospital death than the vancomycin group (P<0.05). CONCLUSIONS: Inappropriate empirical use of antibiotics may lead to a poor prognosis in children with Staphylococcus aureus sepsis. Empirical use of carbapenems is not recommended for children suspected of Staphylococcus aureus sepsis.

Hesperidin alleviates rat postoperative ileus through anti-inflammation and stimulation of Ca(2+)-dependent myosin phosphorylation.

AIM: Postoperative ileus (POI) is a postoperative dysmotility disorder of gastrointestinal tract, which remains one of the most perplexing problems in medicine. In the present study we investigated the effects of hesperidin, a major flavonoid in sweet oranges and lemons, on POI in rats. METHODS: SD rats were administered hesperidin (5, 20, and 80 mg·kg(-1)·d(-1), ig) for 3 consecutive days. POI operation (gently manipulating the cecum for 1 min) was performed on d 2. The gastrointestinal motility and isolated intestinal contraction were examined 1 d after the operation. Then the myosin phosphorylation and inflammatory responses in cecum tissue were assessed. Smooth muscle cells were isolated from rat small intestine for in vitro experiments. RESULTS: The gastric emptying and intestinal transit were significantly decreased in POI rats, which were reversed by administration of hesperidin. In ileum and cecum preparations of POI rats in vitro, hesperidin (2.5-160 µmol/L) dose-dependently increased the spontaneous contraction amplitudes without affecting the contractile frequency, which was blocked by the myosin light chain kinase (MLCK) inhibitor ML-7 or verapamil, but not by TTX. Furthermore, administration of hesperidin increased the phosphorylation of MLC20 in the cecum tissue of POI rats. Moreover, administration of hesperidin reversed the increased levels of inflammatory cytokines, iNOS and COX-2 in cecum tissue of POI rats. In freshly isolated intestinal smooth muscle cells, hesperidin (5-80 µmol/L) dose-dependently increased the intracellular Ca(2+) concentration as well as the phosphorylation of MLC20, which was abrogated by ML-7 or siRNA that knocked down MLCK. CONCLUSION: Oral administration of hesperidin effectively alleviates rat POI through inhibition of inflammatory responses and stimulation of Ca(2+)-dependent MLC phosphorylation.

[Investigation of pharmacokinetics and pharmacodynamics of different doses of aminophylline in very low birth weight infants].

OBJECTIVE: To study the pharmacokinetic and pharmacodynamic features of different doses of aminophylline in very low birth weight (VLBW) infants with different postmenstrual ages, weights, and ages (in days). METHODS: A total of 40 VLBW infants with apnea were enrolled. After an intravenous loading dose of 5 mg/kg aminophylline, they were randomized into two groups with different maintenance doses of aminophylline (1 mg/kg and 2 mg/kg, once every 8 hours). Blood concentrations of aminophylline and liver and renal functions were monitored at 8 hours, 3 days, and 7 days after the loading dose. Attacks of apnea were documented. Pharmacokinetic data of aminophylline were compared between the two groups. RESULTS: The steady-state plasma concentration of aminophylline and plasma clearance in the 2 mg/kg group were significantly higher than those in the 1 mg/kg group (P<0.05). However, the elimination half life was shorter in the 2 mg/kg group (P<0.05). Days of apnea attacks within 7 days after birth in the 2 mg/kg group were significantly fewer than in the 1 mg/kg group (P<0.05). Aminophylline plasma clearance was positively correlated with age (in days) after birth and postmenstrual age in both groups. CONCLUSIONS: In VLBW infants, pharmacokinetics and pharmacodynamics are different when different maintenance doses of aminophylline are given. The maintenance dose of 2 mg/kg is associated with a better effect in the treatment of apnea. Postmenstrual age and age (in days) should be considered during the adjustment of dose, and routine blood concentration monitoring should be performed.

[Preliminary study of contrast-enhanced ultrasonography in the evaluation of angiogenesis in ovarian tumors].

OBJECTIVE: To investigate the role of contrast-enhanced ultrasonography (CEUS) with pulsed inversion harmonic imaging in the evaluation of angiogenesis in ovarian tumors. METHODS: Forty-two patients of ovarian tumor received CEUS examination, in which the rise time (RT), peak intensity (PI), area under the curve (AUC), time from peak to one half (TTH) and time to peak (TTP) of ovarian tumors were measured. The post- surgical specimens of ovarian tumors were analysed by the stain with polyclonal antibodies against vascular endothelial growth factor (VEGF) and CD34. Correlations between the index of VEGF, microvessel density (MVD) and ultrasonic perfusion parameters were studied. RESULTS: MVD and VEGF index of ovarian tumors were significantly correlated with CEUS perfusion parameters including PI, AUC and TTH. The correlation coefficients of MVD with PI, AUC and TTH were 0. 569, 0. 623 and 0. 585 respectively; and the correlation coefficients of VEGF with PI, AUG and TTH were 0. 516,0. 640 and 0. 591 respectively. There were significant differences of the perfusion parameters between high and low MVD group. CONCLUSION: The perfusion parameters PI, AUC and TTH in CEUS were correlated with MVD and VEGF in ovarian tumors, which may be useful in the evaluation of tumors angiogenesis.

Characteristics of diprophylline-induced bidirectional modulation on rat jejunal contractility.

In this study, we propose that diprophylline exerts bidirectional modulation (BM) on the isolated rat jejunal segment depending on its contractile state. The results supported the hypothesis. Diprophylline (20 µM) exerted stimulatory effects on the contractility of jejunal segment in six low contractile states while inhibitory effects in six high contractile states, showing the characteristics of BM. Diprophylline-induced stimulatory effect was significantly blocked by atropine, indicating the correlation with cholinergic activation. Diprophylline-induced inhibitory effect was partially blocked by phentolamine, propranolol, and L-N-Nitro-Arginine respectively, indicating their correlation with sympathetic activation and nitric oxide-mediated relaxing mechanisms. Diprophylline-induced BM was abolished by tetrodotoxin or in a Ca(2+) free condition or pretreated with tyrosine kinase inhibitor imatinib, suggesting that diprophylline-induced BM is Ca(2+) dependent, and that it requires the presence of enteric nervous system as well as pacemaker activity of interstitial cells of Cajal. Diprophylline significantly increased the reduced MLCK expression and myosin extent in constipation-prominent rats and significantly decreased the increased MLCK expression and myosin extent in diarrhea-prominent rats, suggesting that the change of MLCK expression may also be involved in diprophylline-induced BM on rat jejunal contractility. In summary, diprophylline-exerted BM depends on the contractile states of the jejunal segments, requires the presence of Ca(2+), enteric nervous system, pacemaker activity of interstitial cells of Cajal, and MLCK-correlated myosin phosphorylation. The results suggest the potential implication of diprophylline in relieving alternative hypo/hyper intestinal motility.

[Intracerebral transplantation of human umbilical cord-derived mesenchymal stem cells in neonatal rat model of hypoxic-ischemic brain damage: protective effect to injured brain].

OBJECTIVE: To study the brain protection and the possible mechanism of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in neonatal rat model of hypoxic-ischemic brain damage (HIBD). METHODS: Successfully establishing a neonatal rat model of HIBD, hUC-MSCs labeled with BrdU were transplanted into the lateral ventricle 24 hours after HIBD. The number of apoptotic cells and the expression of Caspase-3 were detected by TUNEL and Western blot respectively at 24 and 48 hours after transplantation. The neurological functions of HIBD rats were evaluated by Longa score, and the survival, differentiation and pro-differentiation effects of hUC-MSCs were identified by immunofluorescence at 1 to 3 weeks after transplantation. RESULTS: At 24 and 48 hours after transplantation, apoptotic cells and Caspase-3 expression in the MSCs group were less than in the HIBD group (P<0.05). At 2 and 3 weeks after transplantation, the Longa score in the MSCs group was lower than in the HIBD group (P<0.05). After transplantation, positive cells labeled with BrdU were seen in the brain tissue. The expression levels of glial fibrillary acidic protein (GFAP) and neuron specific esterase (NSE) in the MSCs group were higher than in the HIBD and sham-operated control groups (P<0.05), and increased gradually with the transplantation time (P<0.05). CONCLUSIONS: hUC-MSCs transplantation in HIBD rats can inhibit Caspase-3 expression and reduce apoptotic cells in the early stage, and in the later period, the survival hUC-MSCs can differentiate into neural-like cells and promote the differentiation of endogenous neural-like cells, providing protective effects to brain.

[Effect of integrin ß8 on TGF-ß1 activation in astrocytes with oxygen glucose deprivation].

OBJECTIVE: To study the effect of ß8 expression on transforming growth factor ß1(TGF-ß1) activation in astrocytes with oxygen glucose deprivation (OGD). METHODS: Astrocytes were cultured and then subjected to OGD to generate hypoxia-ischemia (HI) model in vitro. Immunocytochemistry was used to detect the expression and distribution of ß8 in nomoxia cultured cells. ß8 protein expression was quantified by Western blot at 12 hours, 1 day and 2 days after OGD. Astrocytes and luciferase reporter cells (TMLC) were co-cultured. ß8 RNA interference system was established to specifically inhibit ß8 expression in cultured astrocytes. TGF-ß1 activation was then detected in the co-culture system. RESULTS: ß8 was mainly located in the cytoplasm and neurites of astrocytes. OGD resulted in increase of ß8 protein expression at 12 hours after reoxygenation in astrocytes, which was peaked at 1 day after reoxygenation. TGF-ß1 activation was in accordance with ß8 expression in astrocyte-TMLC co-culture system after reoxygenation. After the inhibition of ß8, TGF-ß1 activation was significantly reduced in all time points. CONCLUSIONS: The highly expressed ß8 plays important roles in the regulation of TGF-ß1 activation in neonatal rats with hypoxic-ischemic brain damage.

Risk of cardiovascular death in patients with hepatocellular carcinoma based on the Fine-Gray model.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of cancers worldwide, ranking fifth among men and seventh among women, resulting in more than 7 million deaths annually. With the development of medical technology, the 5-year survival rate of HCC patients can be increased to 70%. However, HCC patients are often at increased risk of cardiovascular disease (CVD) death due to exposure to potentially cardiotoxic treatments compared with non-HCC patients. Moreover, CVD and cancer have become major disease burdens worldwide. Thus, further research is needed to lessen the risk of CVD death in HCC patient survivors. AIM: To determine the independent risk factors for CVD death in HCC patients and predict cardiovascular mortality (CVM) in HCC patients. METHODS: This study was conducted on the basis of the Surveillance, Epidemiology, and End Results database and included HCC patients with a diagnosis period from 2010 to 2015. The independent risk factors were identified using the Fine-Gray model. A nomograph was constructed to predict the CVM in HCC patients. The nomograph performance was measured using Harrell's concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and area under the ROC curve (AUC) value. Moreover, the net benefit was estimated via decision curve analysis (DCA). RESULTS: The study included 21545 HCC patients, of whom 619 died of CVD. Age (< 60) [1.981 (1.573-2.496), P < 0.001], marital status (married) [unmarried: 1.370 (1.076-1.745), P = 0.011], alpha fetoprotein (normal) [0.778 (0.640-0.946), P = 0.012], tumor size (≤ 2 cm) [(2, 5] cm: 1.420 (1.060-1.903), P = 0.019; > 5 cm: 2.090 (1.543-2.830), P < 0.001], surgery (no) [0.376 (0.297-0.476), P < 0.001], and chemotherapy(none/unknown) [0.578 (0.472-0.709), P < 0.001] were independent risk factors for CVD death in HCC patients. The discrimination and calibration of the nomograph were better. The C-index values for the training and validation sets were 0.736 and 0.665, respectively. The AUC values of the ROC curves at 2, 4, and 6 years were 0.702, 0.725, 0.740 in the training set and 0.697, 0.710, 0.744 in the validation set, respectively. The calibration curves showed that the predicted probabilities of the CVM prediction model in the training set vs the validation set were largely consistent with the actual probabilities. DCA demonstrated that the prediction model has a high net benefit. CONCLUSION: Risk factors for CVD death in HCC patients were investigated for the first time. The nomograph served as an important reference tool for relevant clinical management decisions.

Intratumoural microorganism can affect the progression of hepatocellular carcinoma.

BACKGROUND: Several recent studies have confirmed that intratumoural microorganisms can affect the occurrence and development of hepatocellular carcinoma (HCC); however, their role in tumor progression remains unclear. Hence, there is a need for further research on the role of intratumoural microorganisms in HCC. AIM: To investigate the changes in intratumoural microorganisms in HCC and the effect of Propionibacterium on HCC progression. METHODS: HCC and normal liver tissue specimens were subjected to fluorescence in situ hybridization (FISH). After performing 16S rRNA sequencing on HCC and peritumoral tissues to analyze the differences between the two groups. Propionibacterium was cocultured with HCC cells in vitro. Changes in cell proliferation and migration capacity were evaluated. The expression of NF-κB pathway related proteins in tumor cells was compared. The orthotopic liver implantation model and the subcutaneous xenograft model were constructed. liver tissues and subcutaneous tumors were collected 2 weeks later. RESULTS: FISH demonstrated the presence of microorganisms in HCC and normal liver tissues. 16S rRNA sequencing revealed an abundance of Lysobacter, Lachnospiraceae, Pseudomonas, and Lactobacillus in HCC tissues. The distribution and abundance of Propionibacterium showed differences between HCC and peritumoral tissues (P < 0.05). In vitro studies demonstrated that Propionibacterium and its metabolite propionic acid (PA) inhibited the proliferation and migration of HCC cells (P < 0.05). The expression of the proteins in NF-κB signaling pathway also decreased in HCC cells (P < 0.05). CONCLUSION: Microorganisms in HCC and normal liver tissues displayed significant disparities. The PA-producing bacterium Propionibacterium in HCC exerts an effect on the NF-κB pathway, thereby affecting the biological behavior of HCC.

Sulforaphane decreases oxidative stress and inhibits NLRP3 inflammasome activation in a mouse model of ulcerative colitis.

Excessive oxidative stress and NLRP3 inflammasome activation are considered the main drivers of inflammatory bowel disease (IBD), and inhibition of inflammasomes ameliorates clinical symptoms and morphological manifestations of IBD. Herein, we examined the roles of NLRP3 activation in IBD and modulation of NLRP3 by sulforaphane (SFN), a compound with multiple pharmacological activities that is extracted from cruciferous plants. To simulate human IBD, we established a mouse colitis model by administering dextran sodium sulfate in the drinking water. SFN (25, 50 mg·kg-1·d-1, ig) or the positive control sulfasalazine (500 mg/kg, ig) was administered to colitis-affected mice for 7 days. Model mice displayed pathological alterations in colon tissue as well as classic symptoms of colitis beyond substantial tissue inflammation. Expression of NLRP3, ASC, and caspase-1 was significantly elevated in the colonic epithelium. The expression of NLRP3 inflammasomes led to activation of downstream proteins and increases in the cytokines IL-18 and IL-1ß. SFN administration either fully or partially reversed these changes, thus restoring IL-18 and IL-1ß, substantially inhibiting NLRP3 activation, and decreasing inflammation. SFN alleviated the inflammation induced by LPS and NLRP3 agonists in RAW264.7 cells by decreasing the levels of reactive oxygen species. In summary, our results revealed the pathological roles of oxidative stress and NLRP3 in colitis, and indicated that SFN might serve as a natural NLRP3 inhibitor, thereby providing a new strategy for alternative colitis treatment.

[Investigation on pharmacokinetics of aminophylline in very low birth weight infants].

OBJECTIVE: To investigate the pharmacokinetics of aminophylline in very low birth weight infant. METHODS: This study investigated 104 very low birth weight infants using aminophylline 5 mg/kg treating apnea who were hospitalized in our department during 2011-2012. The blood concentration of aminophylline was measured in 30 min before, 8 h and 5 d after first time loading dose, and was counterchecked every week before aminophylline withdrawal. The pharmacokinetic parameters of aminophylline were calculated and population pharmacokinetic model was established by MW/Pharm3.6 statistical analysis. RESULTS: The average birth weight of these 104 very low birth weight infants was (1.15 +/- 0.23) kg, average gestational age was (31.19 +/- 2.50) weeks. The results of aminophylline pharmacokinetics showed: the plasma clearance was (17.88 +/- 5.61) mL/(kg x h), the apparent volume of distribution was (0.93 +/- 0.18) L/kg, the half life time was (28.6 +/- 7.59) h. The aminophylline plasma clearance was related to creatinine clearance, gestational age and days of age after birth (related coefficient was 0.68, 0.62, 0.56 respectively, P < 0.05),the apparent volume of distribution was related to birth weight (related coefficient was 0.82, P < 0.05). The population pharmacokinetics model established can predict the concentration-time curve of the patients. CONCLUSION: The pharmacokinetics of aminophylline in very low birth weight infant was quite different from adult, which suggest blood concentration monitoring and dose adjustment for the clinical use of aminophylline in low birth weight infants.

[Visualization study of current research on nutrition of premature infants in China].

OBJECTIVE: Inadequate postnatal nutritional support is an important factor contributing to growth failure, which leads to poor neurological outcome. In this study, co-word analysis was used to investigate the research on nutrition of premature infants over the last six years in China, describe the research trend in this field in China, and provide possible directions for future research. METHODS: A literature search was performed in January 2013 using the CNKI database and the key words "preterm infant" and "nutrition". A total of 772 articles were retrieved. Then high-frequency key words were extracted using Excel 2010 to create a co-occurrence matrix. Finally, a visualized network was built using Ucinet 6.0. RESULTS: The knowledge domain map of research on nutritional support for premature infants in China showed that the major topic of relevant research is still the combination of parenteral nutrition and enteral nutrition, with the goal of maintaining appropriate growth rates in premature infants. Researchers have paid much attention to the adverse effects of parenteral nutrition. Feeding intolerance is still the main problem in nutritional support, especially enteral nutrition, for premature infants. CONCLUSIONS: A visualized network of current research on nutrition of premature infants in China has been created, and a knowledge domain map has been drawn to reflect the hot topics in this field of study over the last six years.

Clinical features of Chinese children with COVID-19 and other viral respiratory infections.

OBJECTIVE: Few studies have explored the clinical features in children infected with SARS-CoV-2 and other common respiratory viruses, including respiratory syncytial virus (RSV), Influenza virus (IV), and adenovirus (ADV). Herein, we reported the clinical characteristics and cytokine profiling in children with COVID-19 or other acute respiratory tract infections (ARTI). METHODS: We enrolled 20 hospitalized children confirmed as COVID-19 positive, 58 patients with ARTI, and 20 age and sex-matched healthy children. The clinical information and blood test results were collected. A total of 27 cytokines and chemokines were measured and analyzed. RESULTS: The median age in the COVID-19 positive group was 14.5 years, which was higher than that of the ARTI groups. Around one-third of patients in the COVID-19 group experienced moderate fever, with a peak temperature of 38.27°C. None of the patients displayed wheezing or dyspnea. In addition, patients in the COVID-19 group had lower white blood cells, platelet counts as well as a neutrophil-lymphocyte ratio. Lower serum concentrations of 14 out of 27 cytokines were observed in the COVID-19 group than in healthy individuals. Seven cytokines (IL-1Ra, IL-1ß, IL-9, IL-10, TNF-α, MIP-1α, and VEGF) changed serum concentration in COVID-19 compared with other ARTI groups. CONCLUSION: Patients with COVID-19 were older and showed milder symptoms and a favorable prognosis than ARTI caused by RSV, IV, and ADV. There was a low grade or constrained innate immune reaction in children with mild COVID-19.