Background::Non-alcoholic fatty liver disease (NAFLD) and inflammatory bowel disease (IBD) have shown similar worsening epidemic patterns globally and shared various overlapping pathophysiological mechanisms. However, evidence on the relationship between NAFLD and IBD risk is lacking. We aimed to investigate the associations between long-term risk of incident IBD and NAFLD in a large prospective cohort.Methods::Participants from the United Kingdom Biobank cohort (https://biobank.ndph.ox.ac.uk/) who were free of IBD and alcoholic liver disease at baseline were enrolled. Baseline non-alcoholic fatty liver degree was measured by the well-established fatty liver index (FLI). The outcomes of interest included incident IBD, ulcerative colitis (UC), and Crohn’s disease (CD). Multivariable Cox proportional hazard regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).Results::Among 418,721 participants (mean FLI: 48.11 ± 30.11), 160,807 (38.40%) participants were diagnosed as NAFLD at baseline. During a median of 12.4 years’ follow-up, 2346 incident IBD cases (1545 UC, 653 CD, and 148 IBD-unclassified) were identified. Due to limited events, those IBD-unclassified were combined in UC or CD when examining the associated risk of UC or CD, separately. Compared with the lowest quartile of FLI, the highest quartile showed a separately 36.00%, 25.00%, and 58.00% higher risk of incident IBD (HR Q4 vs. Q1 =1.36, 95% CI: 1.19-1.55, Ptrend <0.001), UC (HR Q4 vs. Q1 =1.25, 95% CI: 1.07-1.46, Ptrend=0.047), and CD (HR Q4 vs. Q1 =1.58, 95% CI: 1.26-1.97, Ptrend <0.001) after multivariable adjustment. Compared with non-NAFLD, NAFLD participants had a significantly higher risk of incident IBD (HR=1.13, 95% CI: 1.04-1.24) and CD (HR =1.36, 95% CI: 1.17-1.58). Conclusions::Higher degree of non-alcoholic fatty liver is associated with increased risk of incident IBD. Interventions aimed at improving NAFLD may be a potential targeted strategy for the detection and treatment of IBD.

Objective To establish a human α-synuclein nuclear localization signal transgenic mouse model and investigate the effects of α-synuclein nuclear localization on the behavior of mice.Methods Human α-synuclein nuclear localization signal and EGFP lentiviral vectors were constructed.Transgenic mice were created with the microinjection method.Using PCR and Western Blot method to identify the genotypes and protein expression of the transgenic founder mice and their offsprings.The immunofluorescence was used to examine the localization of human α-synuclein in the mouse brain tissue.The behavioral changes of the transgenic mice were evaluated by the open field test,rotarod test,and O maze test.Results The h SNCA-NLS gene was successfully inserted into the mouse genome,the human α-syn was successfully expressed,and the human α-syn has localized with the nuclear.Further studies found that human α-synuclein nuclear localization signal transgenic mice had significant motor dysfunction,astrocyte proliferation and inflammatory response at 2 months of age and exhibited significant anxiety-like symptoms and reduced expression of the γ-aminobutyric acid(GABA)gene at 9 months of age,which persisted until 12 months of age.Conclusions A human α-synuclein nuclear localization signal transgenic mouse model has been successfully established.The mice exhibit significant motor dysfunction and anxiety-like symptoms.The successful establishment of this model provides a foundation for studying the role of α-syn nuclear localization in Parkinson's disease.

Objective To screen potential metabolites and significantly altered metabolic pathways of liver lesions by central carbon pathway metabolites. Methods 32 healthy volunteers (HC), 23 patients with biliary cysts (CYST), 19 patients with biliary stones (Stone), 45 patients with hepatocellular carcinoma (HCC), and 50 patients with hilarcholangiocarcinoma (HCCA) were recruited. Their serum samples were collected for UPLC-QQQ-MS analysis and further MPP statistical analysis. Pattern recognition was further used to discovery the differences in metabolome between groups, and to explore the significantly altered metabolic pathway and possible pathogenic mechanism of liver diseases. Results A total of 15, 7, 7, and 3 metabolites and a total of 8, 4, 4, and 1 metabolic pathway that were significantly different in serum between CYST, Stone, HCC, HCCA and healthy controls were identified and enriched through serum metabolomics analysis, respectively. Conclusion According to the above identified differential metabolites and enriched metabolic pathway results, it is shown that liver lesions mainly involved in the energy metabolism and amino acid metabolism & transport, in addition, inositol phosphate metabolism were significantly changed both in CYST, Stone, HCC and HCCA.

Molecular glues can specifically induce aggregation between two or more proteins to modulate biological functions. In recent years, molecular glues have been widely used as protein degraders. In addition, however, molecular glues play a variety of vital roles, such as complex stabilization, interactome modulation and transporter inhibition, enabling challenging therapeutic targets to be druggable and offering an exciting novel approach for drug discovery. Since most molecular glues are identified serendipitously, exploration of their systematic discovery and rational design are important. In this review, representative examples of molecular glues with various physiological functions are divided into those mediating homo-dimerization, homo-polymerization and hetero-dimerization according to their aggregation modes, and we attempt to elucidate their mechanisms of action. In particular, we aim to highlight some biochemical techniques typically exploited within these representative studies and classify them in terms of three stages of molecular glue development: starting point, optimization and identification.

Objective:To understand and determine the biological properties of Chlamydia pneumonia (Cpn) hypothetical protein Cpn0423 and the mechanisms of which involved in Cpn0423-induced inflammatory response. Methods:The biological properties of Cpn0423 gene were analyzed using bioinformatic software. The subcellular localization of nucleotide-binding oligomerization domain-like receptor 2 (NOD2) in bone marrow-derived macrophages (BMDMs) was detected by confocal microscope. NOD2-siRNA was used to inhibit the expression of NOD2 at mRNA level. Cpn0423-induced macrophage inflammatory protein 2 (MIP-2) and IL-6 production in BMDMs were detected by ELISA. PCR was performed to detect Cpn0423 DNA in bronchoalveolar lavage fluid (BALF) of Cpn-positive patients.Results:The homology between Cpn0423 and other type Ⅲ secretion system effector proteins of Chlamydia ranged from 85% to 93%. NOD2-siRNA could effectively inhibit the expression of NOD2 at mRNA level in BMDMs ( P<0.001). Moreover, Cpn0423-induced production of MIP-2 [(920.5±99.1) pg/ml vs (130.1±11.5) pg/ml, P<0.001] and IL-6 [(266.2±58.4) pg/ml vs (165.7±21.5) pg/ml, P<0.001] in BMDMs were decreased following NOD2-siRNA pre-treatment. Cpn0423 DNA was detected in the BAlF of 83.3% (10/12) of Cpn-positive cases, but not in Cpn-negative cases. Conclusions:Cpn0423 induced inflammatory response in host cells through NOD2 pathway, which was closely related to the chronic inflammatory injury caused by Cpn.

OBJECTIVE:To investigate therapeutic efficacy and safety of Naoxintong capsules combined with edaravone in the treatment of acute cerebral infarction. METHODS:80 patients with acute cerebral infarction were analyzed retrospectively and divid-ed into observation group (40 cases) and control group (40 cases) according to drug use. Both groups was given Aspirin enter-ic-coated tablets 10 mg orally,once a day,to control platelet aggregation,20% Mannitol injection 250 mL intravenously,every 12 hours,to control brain edema,Potassium chloride sustained-release tablets 0.5 g orally,3 times a day,to maintain water and elec-trolyte balance and other conventional treatment. Control group was additionally given Edaravone injection 30 mg added into 0.9%Sodium chloride injection 100 mL intravenously within 30 min,once a day;observation group was additionally given Naoxintong capsules 1.6 g,3 times a day on the basis of control group. Treatment course of both groups lasted for 10 d. Clinical efficacies of 2 groups were observed as well as the ET-1 and NO content,IL-8,hs-CRP,FT3,FT4 and TSH level,NIHSS and ADL score,the occurrence of ADR before and after treatment. RESULTS:Total response rate of observation group was significantly higher than that of control group,with statistical significance(P<0.05). Before treatment,there was no statistical significance in the ET-1 and NO content,IL-8,hs-CRP,FT3,FT4 and TSH level,NIHSS and ADL score between 2 groups(P>0.05). After treatment,the ET-1 content,IL-8 and hs-CRP level,NIHSS score in 2 groups were significantly lower than before,and the observation group was lower than the control group;the NO content,TSH,ADL score in 2 groups were significantly higher than before,and the ob-servation groups was higher than the control group,with statistical significance(P<0.05). There was no statistical significance in the levels of FT3 and FT4 between 2 groups before and after treatment(P>0.05). No severe ADR was found in 2 groups. CON-CLUSIONS:Based on routine treatment,Naoxintong capsules combined with edaravone in the treatment of acute cerebral infarc-tion can improve therapeutic efficacy and vascular endothelial function,relieve inflammatory reaction and recue TSH levels,more-over,don't increase the occurrence of ADR.

Objective: To analyze the clinicopathological features and prognosis of patients with small hepatocellular carcinoma. Methods: The clinicopathological and follow-up data of 98 patients with small hepatocellular carcinoma who underwent R0 resection from January 2009 to December 2013 were analyzed retrospectively. Results: All of the patients were followed up. Their postoperative 1-year, 3-year and 5-year overall survival rates were 99.0%, 91.7%, and 76.3%, respectively. Their postoperative median overall survival (OS) period was 52 months. The postoperative progression-free survival rates were 86.7%, 66.2% and 55.0%, respectively, and the median progression-free survival (PFS) period was 43.5 months. The univariate analysis showed that satellite nodules, liver capsule invasion and postoperative recurrence time were associated with OS (P<0.05), and long-term heavy drinking, satellite nodules and liver capsule invasion with PFS (P<0.05). The multivariate analysis indicated that long-term heavy drinking was an independent factor influencing the progression-free survival period of patients with small hepatocellular carcinoma (P=0.003) and postoperative recurrence time and liver capsule invasion were independent factors affecting their overall survival period (P<0.05). Conclusions The treatment of small hepatocellular carcinoma still concentrates on the active treatment of surgery. It is beneficial to patients to minimize the resection scope of normal liver under the premise of R0 removal of tumor. Postoperative recurrence time of ≤2 years suggests poor prognosis of small hepatocellular carcinoma. Long-term heavy drinking can accelerate the recurrence of small hepatocellular carcinoma.

Objective: To carry out a prospective cohort study of combined intra-operative radiotherapy for centrally located hepatocellular carcinomas (HCC) and to observe the safety and postoperative complications. Methods: A total of 79 patients with centrally located HCC who underwent hepatectomy were divided into two groups: experimental group (combined with targeted intra-operative radiotherapy, 32 cases) and control group (single surgical operation, 47 cases). Patients in the experimental group received intra-operative electron radiotherapy after tumor resection, while patients in the control group received to intra-operative electron radiotherapy.The haemorrhagia amount and operation time during the operation, intra-operative liver function and the recovery of liver and gastrointestinal tract of patients in these two groups were compared. Results: No postoperative 30-day mortality was observed in all of the patients. The average total operation time of patients in the experimental group was (319±76) min, significantly longer than (233±76) min of the control group (P<0.001). The average aspartate transaminase (AST) level of patients in the experimental group at postoperative day 1 was 562.5 U/L, significantly higher than 347.0 U/L of control group (P=0.031). However, the average prothrombin activity levels of patients in the experimental group at postoperative day 3 and day 7 were (68.3±17.9)% and (73.4±10.2)%, respectively, significantly lower than (78.9±15.9)% and (80.0±10.6)% of control group (both P<0.05). There were no significant differences of tumor volume, differentiation degree, satellite lesion, dorsal membrane invasion, microvascular invasion between these two groups (all P>0.05). There were no significant differences of hospital stay, ventilation time, the incidence of hepatic insufficiency, ascites, pleural effusion, infection, biliary fistula between these two groups (all P>0.05). There were no significant differences of alanine aminotransferase (ALT), albumin, total bilirubin between these two groups at postoperative day 1, 3, 5 and 7 (all of P>0.05). Conclusion: The resection of centrally located HCC combined with intra-operative radiotherapy may increase the total operation time, delay the early postoperative recovery of liver function, but it is still safe and feasible. Trial registration National Cancer Centre /Cancer Hospital, Chinese Academy of Medical Sciences, ChiCTR-TRC-12002802.

OBJECTIVE:To investigate the clinical efficacy and safety of Memantine hydrochloride tablets combined with Tianzhi granules in the treatment of vascular dementia. METHODS:A total of 94 patients with vascular dementia selected from our hospital during Jun. 2014-Jun. 2016 were divided into observation group and control group according to random number table,with 47 cases each. Besides basic therapy,control group was given Tianzhi granules 5 g,po,tid. Observation group was additionally given Memantine hydrochloride tablets with initial dose of 5 mg,increasing by 5 mg every week,maintaining dose of 20 mg/d at 4th week,po,qd,on the basis of control group. Both groups received treatment for consecutive 4 weeks. Clinical efficacies as well as MMSE,MoCA,ADL scores,the levels of brain-derived neurotrophic factor(BDNF),malondialdehyde(MDA)and super-oxide dismutase(SOD)before and after treatment were observed in 2 groups.The occurrence of ADR was recorded.RESULTS:To-tal response rate of observation group(80.85%)was significantly higher than control group(61.70%),with statistical significance (P<0.05). Before treatment,there was no statistical significance in MMSE,MoCA,ADL scores,the levels of BDNF,MDA or SOD between 2 groups(P>0.05).After treatment,MMSE,MoCA,ADL scores,the levels of BDNF and SOD in 2 groups were increased significantly,while MDA level was decreased significantly;observation group was significantly better than control group,with statistical significance(P<0.05). No obvious ADR was found in 2 groups. CONCLUSIONS:Memantine hydrochlo-ride tablets combined with Tianzhi granules in the treatment of vascular dementia show significant therapeutic efficacy,and can im-prove cognitive function,daily living activity and BDNF,MDA and SOD levels of patients with good safety.

ObjectiveTo explore the effects of enteral nutrition (EN) on intestinal permeability in patients with active ulcerative colitis (AUC). MethodsTwenty-four A UC patients were randomly divided into two groups:routine treatment group (n =11 ) and routine treatment plus EN group (n =13). Patients in routine treatment group were treated with mesalazine as well as low-residue diet, while patients in routine treatment plus EN group received mesalazine and short peptide EN for 14 days. The ratio of lactulose to mannitol in urine (L/M) before and after treatment was detected by high-performance liquid chromatography. ResultsThe L/M ratio was 0. 039 ± 0. 025 in routine treatment group and 0.072 ± 0.019 in routine treatment plus EN group (P =0.069). After 2 weeks of treatment, the L/M ratio of routine treatment plus EN group (0.038 ± 0.012 ) was significantly lower than the pretreatment level (P =0.043 ), while the L/M ratio of routine treatment group between before and after treatment had no significant difference (0.039 ± 0.025 vs. 0.032 ± 0.022, P =0.730). ConclusionEN can effectively improve the intestinal permeability in AUC patients.