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Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and insulin resistance and there are currently no approved drugs for its treatment. Hyperactivation of mTOR complex 1 (mTORC1) and subsequent impairment of the transcription factor EB (TFEB)-mediated autophagy-lysosomal pathway (ALP) are implicated in the development of NAFLD. Accordingly, agents that augment hepatic TFEB transcriptional activity may have therapeutic potential against NAFLD. The objective of this study was to investigate the effects of nuciferine, a major active component from lotus leaf, on NAFLD and its underlying mechanism of action. Here we show that nuciferine activated ALP and alleviated steatosis, insulin resistance in the livers of NAFLD mice and palmitic acid-challenged hepatocytes in a TFEB-dependent manner. Mechanistic investigation revealed that nuciferine interacts with the Ragulator subunit hepatitis B X-interacting protein and impairs the interaction of the Ragulator complex with Rag GTPases, thereby suppressing lysosomal localization and activity of mTORC1, which activates TFEB-mediated ALP and further ameliorates hepatic steatosis and insulin resistance. Our present results indicate that nuciferine may be a potential agent for treating NAFLD and that regulation of the mTORC1-TFEB-ALP axis could represent a novel pharmacological strategy to combat NAFLD.
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Objective The correlation and agreement of mycophenolic acid (MPA) plasma concentrations that detected by enzyme extended immunoassay (EMIT) and high performance liquid chromatography (HPLC) were studied using Pearson's correlation and Bland-Altman plots.METHODS 435 plasma samples were collected from 95 renal transplant patients who were treated with MPA from October 2014 to December 2015.The MPA plasma concentrations were simultaneously measured by EMIT and HPLC respectively,and the results were divided into two levels.Paired t test and Pearson's correlation were performed using SPSS13.0 to evaluate the relationships between the results in each level.The Bland-Altman plot was used to assess the agreement of the results of two methods.Results Higher concentrations were obtained with EMIT,there was a significant positive bias of EMIT for MPA(20.94％ ±14.42 ％,P＜0.001).Pearson's correlation analysis and Bland-Altman analysis showed that the results from different methods presented good correlation (r＞0.98) and agreement.Conclusion The results of EMIT were higher than that of HPLC.There were good correlation and agreement between the two methods.The differences between EMIT and HPLC suggest that different therapeutic window should be set up when the two methods are used for MPA therapeutic drug monitoring.
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OBJECTIVE:To explore the effects of Xinnaoxin pills on CAT score,cardiopulmonary function and hemorheology of patients with pulmonary heart disease complicating with coronary heart disease. METHODS:In retrospective study,80 cases of pulmonary heart disease complicating with coronary heart disease were randomly divided into control group and observation group with 40 cases in each group. Control group was given routine treatment as relieving asthma,eliminating phlegm and oxygen inhala-tion,anti-infective treatment,correcting acid-base balance,cardiotonic and diuretic treatment. Observation group was additionally given Xinnaoxin pills 1.0 g/time,bid after meal,on the basis of control group. CAT score,cardiopulmonary function and hemorhe-ology index were compared between 2 groups before and after treatment as well as ischemic ECG improvement effect and the occur-rence of ADR after treatment. RESULTS:After treatment,hematocrit hematocrit had changed slightly among hemorheology index-es,and CAT score,other hemorheology indexes and cardiopulmonary function indexes were improved significantly;the improve-ment of observation group was better than that of control group,with statistical significance(P0.05). There was no statistical significance in the incidence of ADR between 2 groups (P>0.05). CONCLUSIONS:Xinnaoxin pills can effectively improve CAT score and cardiopulmonary function of patients with pulmonary heart disease complicating with coronary heart dis-ease. It also can improve hemorheology and shows good clinical efficacy,but great importance should be attached to the safety of drug use in the clinic.
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Objective To investigate the efficacy of precise hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) in the treatment of advanced pancreatic cancer.Methods Thirty-six patients with advanced pancreatic cancer were analyzed retrospectively.Eighteen patients who received HIPEC combined with radiotherapy and chemotherapy were assigned as the treatment group and the other 18 patients who received chemotherapy and radiotherapy were assigned as the control group.Recent curative efficacy,Karnofsky Performance Status (KPS) score,postoperative complications and survivals between the two groups were analyzed,respectively.Results Significant differences were found between two groups in total short-term effective rate (P ＜ 0.05).The total short-term effective rate of treatment group and control group were 66.67％ (12/18) and 27.78％ (5/18),respectively.The increment of KPS score of treatment group was significantly higher than that of control group (P ＜ 0.05).There was no significant difference between two groups in postoperative complications (P ＞ 0.05).The median overall survival time (OS) of treatment group was 11 months (7 ～ 31 months),and the median OS of control group was 7 months (4 ～ 18 months).The survival of the treatment group was longer than the control group (P ＜ 0.05).Conclusions HIPEC treatment improved significantly the survival and life quality of advanced pancreatic cancer patients.With acceptable morbidity and mortality rates,HIPEC regime was an effective treatment modality for patients with advanced pancreatic cancer.
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Objective To investigate the effects of preconditioning with different concentrations of sevoflurane on the expression of Toll-like receptor 4 (TLR4) in rats with acute lung injury (ALI) induced by lipopolysaccharide (LPS).Methods Thirty adult male Sprague-Dawlcy rats,wcighing 200-250 g,were randomly divided into 5 groups (n =6 each):normal saline group (group NS),group ALI,and preconditioning with different concentrations of sevoflurane groups (groups S1-3).ALI was induced by intratracheal instillation of LPS 5 mg/kg.Groups S1-3 inhaled 1.2％,2.4 ％ and 4.8 ％ sevoflurane for 30 min respectively,and ALI was induced 30 min later.The rats were sacrificed at 12 h after administration of LPS or normal saline and lungs were removed for microscopic examination and for determination of TLR4 mRNA and protein expression in lung tissues and concentrations of TNF-α and IL-1β in broncho-alveolar lavage fluid (BALF).W/D lung weight ratio was calculated.Results Compared with group NS,W/D lung weight ratio and concentrations of TNF-a and IL-1β in BALF were significantly increased and the expression of TLR4 mRNA and protein was up-regulated in groups ALI and S1-3 (P ＜ 0.01).Compared with group ALI,the parameters mentioned above were significantly decreased in groups S2 and S3,and the concentrations of TNF-α and IL-1 β in BALF were significantly decreased and the expression of TLR4 mRNA was down-regulated in group S1 (P ＜ 0.05 or 0.01).The parameters mentioned above were significantly lower in groups S2 and S3 than in group S1 (P ＜ 0.05).The pathologic changes were significantly attenuated in groups S1-3 compared with group ALI.Conclusion Preconditioning with sevoflurane can concentration-dependently reduce LPS-induced ALI in rats through inhibiting the up-regulation of TLR4 expression in lung tissues and reducing the inflammatory response.
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Objective To investigate the pharmacodynamics of remifentanil required to prevent laryngeal mask airway (LMA) insertion response in patients anesthetized with propofol by TCI. Methods Thirty-six ASA Ⅰor Ⅱ patients aged 18-59 yr with body mass index ＜ 30 kg/m2 undergoing elective breast operation were enrolled in the study. Propofol was administered by TCI at an effect-site concentration of 4.0 μg/ml. When the patients lost conciousness, TCI of remifentanil was started. The initial target plasma concentration of remifentanil was set at 2.9 ng/ml, and the ratio of two consecutive effect-site concentrations was 1.2. LMA was inserted at 3 min after the target effect-site concentration and the plasma concentration achieved the balance. Criteria of successful insertion were defined as Muzi score≤2 and the increase in MAP and HR≤ 15% of the baseline values within 3 min after insertion. EC50 was determined by modified Dixon's up-and-down sequential trial and the 95 % confidence interval was calculated. Results The EC50 of remifentanil was 2.75 ng/ml. The 95% confidence interval was 2.51-3.01 ng/ml. Conclusion The EC50 of remifentanil for suppression of cardiovascular response to LMA insertion is 2.75 ng/ml in patients anesthetized with propofol by TCI.