Impact of Lifestyle on Urinary Incontinence Severity among Women: A Cross-Sectional Study in East China.

INTRODUCTION AND HYPOTHESIS: Identifying the factors influencing the development of female urinary incontinence (UI) may facilitate early intervention, potentially delaying its progression. This study was aimed at investigating the impact of lifestyle habits on the severity of UI among women in East China. METHODS: This study included 414 women from six communities in East China who reported symptoms of UI and was conducted between September and December 2020. Data were collected using a general information questionnaire, the Toileting Behaviours: Women's Elimination Behaviours scale, and the International Consultation on Incontinence Questionnaire Urinary Incontinence Short Form Chinese Version. Participants were categorised into two groups: those with mild UI and those with moderate-to-severe UI. Propensity-score matching was performed to balance confounding factors, and logistic regression was used to explore the relationship between lifestyle behaviours and UI severity. RESULTS: A total of 117 pairs were successfully matched. Logistic regression analysis revealed that daily perineal cleaning significantly protected against moderate-to-severe UI (p < 0.05). Conversely, living alone, poor sleep quality and hovering over the toilet while voiding were identified as independent risk factors for moderate-to-severe UI (p < 0.05). CONCLUSION: Several lifestyle habits significantly impact the severity of UI among adult women. Screening for mild urinary leakage symptoms and implementing timely interventions are crucial for preventing the aggravation of UI and improving ability to work and quality of life.

A randomized double-blind phase Ib clinical trial of SY-009 in patients with type 2 diabetes mellitus.

INTRODUCTION: SY-009 produces a hypoglycemic effect via inhibiting sodium/glucose cotransporter 1 (SGLT1) in type 2 diabetes mellitus (T2DM) patients. This randomized, double-blind, placebo-controlled, and multiple-dose escalation clinical trial aimed to evaluate the pharmacokinetic and pharmacodynamical characteristics as well as the safety and tolerability of SY-009 in T2DM patients. METHOD: Fifty T2DM patients were randomized into experimental and placebo groups, and hospitalized for 9 days managed with a unified diet and rest management. Subjects were given SY-009 or placebo from day 1 to day 7 at different frequencies and dosages. Single dose cohort was defined as the first dose on day 1 and multiple dose cohort included all the dose from day 1 to 7. Blood samples were collected for pharmacokinetic analysis. Mixed meal tolerance tests were performed. Blood samples were collected to determine glucose, C-peptide, insulin, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP). RESULTS: PK parameters were not obtained because blood SY-009 concentrations were below the limit of quantitation in all subjects. SY-009 decreased the postprandial glucose. Blood glucose was controlled within 4 hours after taking the drug. Short-term administration of SY-009 (7 days) had no significant effects on fasting glucose but reduced the secretion of C-peptide, insulin, and GIP and increased GLP-1 secretion. The most common adverse event was gastrointestinal disorder manifesting abdominal pain, diarrhea, and bloating. CONCLUSION: Plasma exposure of SY-009 and its metabolites was fairly low in T2DM patients at doses of 1.0-4.0 mg. SY-009 reduced postprandial glucose, C-peptide, and insulin levels, showing relative safety and tolerability in the dose range of 1.0-4.0 mg. TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT04345107.

Effect of sedated colonoscopy with different cost coverage on improving compliance with colorectal cancer screening in China.

Background: Colorectal cancer is the third most common cancer worldwide. Colonoscopy is the gold standard for colorectal cancer screening. However, the colonoscopy participation rate in China is much lower than that in Europe and the United States. As only non-sedated colonoscopies are offered in colorectal cancer screening programs in China, the absence of sedation may contribute to this gap. Methods: To explore the effect of free and partially participant-paid sedated colonoscopy on improving colorectal screening participation, we conducted a cross-sectional study under the framework of the Cancer Screening Program in Urban China in Xuzhou from May 2017 to December 2020. The Quanshan district was set as the control group and provided free non-sedated colonoscopy, the Yunlong district was set as a partial cost coverage group and offered partially participant-paid sedated colonoscopy, and the Gulou district was set as the full cost coverage group and offered free sedation colonoscopies. Multivariate logistic regression was used for multivariate analysis of colonoscopy participation and colorectal lesion detection rates between the groups. Results: From May 2017 to May 2020, 81,358 participants were recruited and completed questionnaire, 7,868 subjects who met high-risk conditions for CRC were invited to undergo colonoscopy. The colonoscopy participation rates in the control group, partially cost coverage, and full cost coverage groups were 17.33% (594/3,428), 25.66% (542/2,112), and 34.41% (801/2,328), respectively. Subjects in the partial and full cost coverage groups had 1.66-fold (95% CI: 1.48-1.86) and 2.49-fold (95% CI: 2.23-2.76) increased rates compared with those in the control group. The adjusted PARs for the partially and the full cost coverage group was 9.08 (95% CI: 6.88-11.28) and 18.97 (95% CI: 16.51-21.42), respectively. The detection rates of CAN in the control, partial-cost coverage, and full-cost coverage groups were 3.54% (21/594), 2.95% (16/542), and 5.12% (41/801), respectively. There were no significant differences in the detection rates between the group. However, sedated colonoscopy increases costs. Conclusion: Sedated colonoscopy increased colonoscopy participation rates in both the partial and full cost-covered groups. A partial cost coverage strategy may be a good way to increase colorectal cancer participation rates and quickly establish a colorectal cancer screening strategy in underfunded areas.

[Retracted] Inhibition of RKIP aggravates thioacetamide­induced acute liver failure in mice.

[This retracts the article DOI: 10.3892/etm.2018.6542.].

Validation of the Asia-Pacific colorectal screening score and its modified versions in predicting colorectal advanced neoplasia in Chinese population.

BACKGROUND: Colorectal cancer is one of the most common cancers in the world. Several studies suggest using the Asia-Pacific colorectal screening (APCS) score and its modified versions to select high-risk populations for early colonoscopy, but external validation remains rare, and which score should be selected for CRC screening in China is unclear. Validation of multiple scores in the same population might help to choose the best performing score. METHODS: We conducted a cross-sectional study under the framework of Cancer Screening Program in Urban China, data from asymptomatic colorectal cancer screening in Xuzhou was used to validate the APCS score, the colorectal neoplasia predict (CNP) score, the Korean colorectal screening (KCS) score, the Modified APCS score and the 8-point risk score in predicting colorectal advanced neoplasia (CAN). RESULTS: 1804 subjects were included in the analysis and 112 CAN (6.21%) was detected. In each score, the detection rate of CAN was higher in the high-risk group than in the non-high-risk group (P < 0.05), and the RR (95%C.I.) ranged 2.20 (1.50-3.22) [8-point risk] to 4.00 (2.41-6.65) [Modified APCS]. The c-statistics (95%C.I.) of the scoring systems ranged from 0.58 (0.53-0.62) [8-point risk] to 0.65 (0.61-0.69) [KCS]. The sensitivity (95%C.I.) of these systems ranged from 31.25 (22.83-40.70) [8-point risk] to 84.82 (76.81-90.90) [Modified APCS], while the specificity (95%C.I.) ranged from 43.50 (41.12-45.90) [Modified APCS] to 83.81 (81.96-85.53) [8-point risk]. Using the APCS scoring system as a comparator, the net reclassification improvement (NRI) of each modified version ranged from - 10.34% (95%C.I.: - 22.63 to 1.95%) [8-point risk] to 4.79% (95%C.I.: - 1.50% to 11.08) [KCS]. The colonoscopy resource load (95%C.I.) ranged from 9 [1-3] [8-point risk] to 11 [3-5] [APCS and Modified APCS]. CONCLUSIONS: The APCS score and its modified versions have certain ability to predict the risk of advanced neoplasia and reduce the resource load. The modified APCS score and the KCS score seemed the preferable systems to classify high risk subjects based on its high RR, sensitivity and predictive ability in the selected population. Future research could focus on adding risk factors or combining with laboratory test results to improve the predictive power of the scoring system.

Tolerability, Safety, Pharmacokinetics, and Pharmacodynamics of SY-004, a Glucokinase Activator, in Healthy Chinese Adults: A Randomized, Phase Ia, Single-Ascending Dose Study.

PURPOSE: SY-004, a dual-acting full glucokinase activator, is under development to provide a dose-dependent improvement of glucose control. This study aimed to assess the tolerability, safety, and pharmacokinetic and pharmacodynamic properties of SY-004 in healthy Chinese adults. METHODS: Two study participants were administered 2 mg of SY-004 in the 2-mg cohort, whereas 6 study participants were randomized with 4 study participants receiving SY-004 and 2 receiving placebo in the 20-mg cohort. In each of other 3 dose cohorts (40, 80, and 120 mg), 12 participants were randomized in a 10:2 ratio to receive single oral SY-004 capsules or placebos. Drug concentrations, glucose and insulin levels, and safety data were assessed and analyzed. Noncompartmental analysis was used to determine SY-004 pharmacokinetic parameters. FINDINGS: SY-004 was generally well tolerated. Nine of the 44 study participants reported 17 treatment-related adverse events, and most treatment-related adverse events were mild. SY-004 had approximately dose-proportional increases in systemic exposure. The mean t½ ranged from 37.6 to 49.9 hours, and CL/F values ranged from 67.1 to 110 L/h across all doses. The cumulative amounts of the unchanged drug excreted in urine were very low, accounting for no more than 1.53% of the given doses. No significant difference in sex was observed in pharmacokinetic parameters. The pharmacodynamic response appeared to slightly correlate with dose. IMPLICATIONS: SY-004, a new potential glucokinase activator, had favorable safety profiles and good PK characteristics. The glucose-lowering effects were slightly dose related. The SY-004 data in healthy Chinese adults supports further development. CLINICALTRIALS: gov identifier: NCT03171623.

First-in-human safety, tolerability, and pharmacokinetics of SY-007, a prolonged action neuroprotective drug for ischemic stroke, in healthy Chinese subjects.

BACKGROUND AND PURPOSE: SY-007 is an interfering peptide designed to disrupt the cell death signaling of phosphatase and tensin homolog deleted on chromosome ten (PTEN) nuclear translocation during ischemic stroke. Preclinical studies indicated that rats treated with 1.5 mg/kg SY-007 in the middle cerebral artery occlusion (MACO) model had significantly reduced stroke lesion size even when administered 6 h after the stroke onset. The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics of ascending doses of SY-007 administered intravenously in healthy Chinese subjects. METHODS: A total of 78 healthy Chinese subjects were enrolled in the single ascending dose study (1-60 mg) and received a 15-min intravenous infusion SY-007 or placebo. Plasma concentrations of SY-007 were measured by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were determined using non-compartmental and compartment analyses. A model based on target-mediated drug disposition was applied. Model evaluation was performed through visual predictive checks and bootstrap analysis. RESULTS: Across doses of 1-60 mg, SY-007 was well tolerated. All adverse events (AEs) were mild or moderate in intensity, and all resolved without intervention. After infusion, SY-007 plasma concentrations decreased quickly with the mean terminal half-life was shorter than 0.78 h. The area under the concentration-time curve increased with a greater than dose-dependent manner from 1 to 30 mg and resulted in a dose-dependent increased from 30 to 60 mg. The nonlinear phenomenon was well described by a simplified target-mediated drug disposition (TMDD) model. CONCLUSIONS: Intravenous dosing of SY-007 appears to be safe up to a dose of 60 mg. Nonlinear pharmacokinetics was observed across the evaluated doses and TMDD might be the primary reason. The effective dose of SY-007 for neuroprotective effect in patients with ischemic stroke is expected to be 10-30 mg and was recommended for the later multiple ascending dose study of SY-007. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT04111523.

Association of Sleep Patterns with Type 2 Diabetes Mellitus: A Cross-Sectional Study Based on Latent Class Analysis.

Sleep duration, sleep quality and circadian rhythm disruption indicated by sleep chronotype are associated with type 2 diabetes. Sleep involves multiple dimensions that are closely interrelated. However, the sleep patterns of the population, and whether these sleep patterns are significantly associated with type 2 diabetes, are unknown when considering more sleep dimensions. Our objective was to explore the latent classes of sleep patterns in the population and identify sleep patterns associated with type 2 diabetes. Latent class analysis was used to explore the best latent classes of sleep patterns based on eleven sleep dimensions of the study population. Logistic regression was used to identify sleep patterns associated with type 2 diabetes. A total of 1200 participants were included in the study. There were three classes of sleep patterns in the study population: "circadian disruption with daytime dysfunction" (class 1), "poor sleep status with daytime sleepiness" (class 2), and "favorable sleep status" (class 3). After controlling for all confounding factors, people in class 2 have significantly higher prevalence of type 2 diabetes than those in class 3 (OR: 2.24, 95% CI 1.26-4.00). Sleep problems have aggregated characteristics. People with sleep patterns involving more or worse sleep problems have higher significantly prevalence of T2DM.

Similar responses to EQ-5D-3L by two elicitation methods: visual analogue scale and time trade-off.

BACKGROUND: Health-related quality of life (HRQoL) is often measured using EQ-5D-3L by the elicitation methods of visual analogue scale (VAS) and time trade-off (TTO). Although many countries have constructed both national VAS and TTO value sets, the fact that VAS and TTO value sets produces different values bewilders researchers and policymakers. The aim of this study is to explore certain conditions which could yield similar value sets using VAS and TTO. METHODS: A homogeneous sample of medical school students was selected to value 18 hypothetical health states using VAS and TTO methods. The 18 hypothetical health states were produced by orthogonal design (L18, 2*3^7). The range of rescaled values was transformed into - 1 ~ 0 ~ 1. The investigations via different methods were carried out by computer-assisted personal interviewing with a wash-time interval of 72 h. Value sets for VAS and TTO were constructed using general least square regression models. Independent variables were composed of 10 dummy variables from 5 dimensions and including or omitting both constant and N3 terms. RESULTS: Three hundred thirteen medical students participated. The mean age was 21.03 ± 0.44 years and 56.2% were female. The four regression models (for each method with and without constant and N3 terms) were all statistically significant (P < 0.05) with high goodness-of-fit (Adj. R2 > 0.94 and MAE < 0.033). Differences between the coefficients of the 10 dummy variables corresponding to each model were all less than 0.059. Pearson correlation coefficients between observed means and predicted values exceeded 0.981. Fitted curves of VAS and TTO largely coincided. CONCLUSIONS: VAS and TTO can generate similar responses under certain conditions, suggesting that the two valuation methods could be equivalent intrinsically. The VAS method appears a more valid approach for valuation in the general population due to its greater simplicity and feasibility.

Toileting behaviors and factors associated with urinary incontinence in college-aged female students in China.

INTRODUCTION AND HYPOTHESIS: Urinary incontinence (UI) is prevalent among women, including young women (18-30 years old). This article aims to explore the prevalence of UI, as well as toileting behaviors and other factors that are associated with UI, in female college students in central China. METHODS: We used convenience sampling to recruit 1000 students from five institutions of higher education. We distributed pencil-and-paper questionnaires to obtain demographic, environmental, and general health information, including whether UI was present or not, and information regarding toileting behaviors used by the respondents. RESULTS: Most students, n = 929, responded to the questionnaire. Their ages ranged from 18 to 26 years old (average: 20.5 ± 1.6); 23.6% of these respondents reported UI, 52.7% often/always worried about public toilet cleanliness, and 25.3% often/always delayed emptying their bladder when they were busy. Respondents who were between 21 and 26 years old had a lower probability of UI (odds ratio [OR] = 0.867 and 95% confidence interval [CI] = 0.771-0.975) than younger respondents (18-21 years old). Respondents who reported constipation (OR = 2.395, 95% CI = 1.494-3.839), drank alcohol (OR = 1.763, 95% CI = 1.114-2.792), often/always delayed urination (OR = 1.738, 95% CI = 1.306-2.313), and/or often/always strained to urinate (OR = 1.433, 95% CI = 1.111-1.849) had greater odds of having UI than respondents who did not have constipation or engage in these behaviors. CONCLUSIONS: UI is prevalent in young Chinese women who are attending college. These women should be asked and given culturally appropriate information about UI and associated factors that include toileting behaviors.

Development of Quality of Life of College Students Questionnaire and its reliability and validity / 中国学校卫生

Objective@#To develop a brief version of Quality of Life of College Students Questionnaire(QOLCS-51) to measure the quality of college students conveniently in time.@*Methods@#Qualitative research and two investigations were applied to shorten and verify the brief questionnaire, and SPSS 22.0 and Lisrel 9.20 were used to analyze the reliability and validity of 2 questionnaires.@*Results@#Quality of Life of College Students Questionnaire-bref was developed by deleting 22 items through qualitative research and 6 items by the first investigation. 952 college students from Jiangsu, Anhui and Shanxi Province were selected to participate in the second investigation, which consisted of five domains and 23 items (QOLCS-23). All 23 items were accepted by analysis of difficulty(0.44-0.68), and all have passed the test of critical ratio(P<0.01), the general related index was 0.33-0.60(P<0.01). 78.3% items distinguished the students with/without dyssomnia. Reliability was tested by test-retest reliability coefficient(0.71-0.86), homogeneity reliability coefficient (Cronbach α=0.845) and exploratory factor analysis (6 factors, i.e. physics domain, three subdomains of psychology domain, behavior domain, social domain and environment domain). Validity was tested by correlations of five domains between QOLCS-51 and QOLCS23(greater than 0.8) and confirmatory factor analysis(χ2/df=12.17, RMSEA=0.05, SRMR=0.07, GFI=0.84, AGFI=0.83, CFI=0.92, IFI=0.92, NFI=0.85, NNFI=0.91).@*Conclusion@#QOLCS51 consists of 23 items of QOLCS23, after deleting 28 items, to assess 5 dimensions of physiology, psychology, behavior, environment and social support with good construction validity and criterion-related validity, and good homogeneity reliability and re-test reliability.

Time Trade-Off Value Set for EQ-5D-3L Based on a Nationally Representative Chinese Population Survey.

OBJECTIVES: To obtain a nationally representative Chinese three-level EuroQol five-dimensional questionnaire value set based on the time trade-off (TTO) method. METHODS: A multistage, stratified, clustered random nationally representative Chinese sample was used. The study design followed an adapted UK Measurement and Valuation of Health protocol. Each respondent valued 11 random states plus state 33333 and "unconscious" using the TTO method in face-to-face interviews. Three types of models were explored: ordinary least squares, general least squares, and weighted least squares models. RESULTS: In total, 5939 inhabitants aged 15 years and older were interviewed. Of these, 5503 satisfactorily interviewed participants were included in constructing models. An ordinary least squares model including 10 dummies without constant and N3 had a mean absolute error of 0.083 and a correlation coefficient of 0.899 between the predicted and mean values. Goodness-of-fit indices of two models based on split subsample were similar. CONCLUSIONS: TTO values were higher in our study compared with those in a study carried out in urban areas, which is mirrored by the higher values in rural areas. Several other aspects, in addition to the valuation procedure, might have influenced the results, such as factors beyond demographic factors such as view on life and death and believing in an afterlife, which need further investigation. Future studies using the three-level EuroQol five-dimensional questionnaire should consider using this value set based on a nationally representative sample of the Chinese population.

Inhibition of RKIP aggravates thioacetamide-induced acute liver failure in mice.

Accumulating evidence has indicated that Raf kinase inhibitor protein (RKIP) is involved in several intracellular signaling pathways; its abnormal expression is associated with tumor progression and metastasis in several human neoplasms. However, the role of RKIP in acute liver injury has remained elusive. In the present study, acute liver failure was induced by thioacetamide in mice, and locostatin was used to interfere with RKIP expression. It was found that RKIP expression was significantly inhibited by locostatin. Down-regulation of RKIP expression resulted in severe liver injury and extensive release of alanine aminotransferase and aspartate aminotransferase. In addition, reduced RKIP expression significantly enhanced the levels of reactive oxygen species and the content of pro-inflammatory factors such as tumor necrosis factor-α as well as interleukin-6 and -1ß, and decreased the levels of nuclear factor E2-related factor-2 and heme oxygenase-1. Furthermore, down-regulation of RKIP promoted the activation of the nuclear factor-κB and extracellular signal-regulated kinase signaling pathways. In conclusion, the present study indicates an inverse correlation between RKIP level and the degree of hepatic injury, that is, a decrease in RKIP expression may exacerbate acute liver failure.

A novel selective MAO-B inhibitor with neuroprotective and anti-Parkinsonian properties.

We previously reported that 1,3-bisbenzylimidazolium (DBZIM) bromide was neuroprotective for the dopaminergic system in Parkinson's disease (PD) models of rodent, however the underlying mechanism was unclear. We currently further confirmed that DBZIM ameliorated the Parkinsonian motor deficit and protected the nigrostriatal tract from the neurotoxicity of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH3-MPTP) in C57Bl/6 mice. The dopaminergic degeneration in the substantia nigra par compacta (SNc) and striatum was analyzed by immunohistochemistry while the monoamine oxidase B (MAO-B) inhibition effect of DBZIM was determined by enzyme kinetics. DBZIM was at least as effective as the clinically approved anti-PD drug, l-deprenyl (Selegiline), for both neuroprotection and correction of motor deficits. Mechanistically, DBZIM inhibited the specific activity of MAO-B in the striatum and C6 cells without affecting the protein expression. DBZIM directly inhibited the enzymatic activity of a purified MAO-B protein with an estimated Ki value from 780 to 940nM, in par with that of l-deprenyl (970nM). The physical interaction between DBZIM and MAO-B was proven by NMR analysis, with Kd around 21.5-46.8µM. Our binding and modelling data further illustrated that DBZIM is a mixed inhibitor with its binding to active site partially hindering the substrate binding. Therefore, inhibiting MAO-B is a major mechanism through which DBZIM confers neuroprotection for the dopaminergic neurons against 2'-CH3-MPTP toxicity. Remarkably, the post-lesion treatment with DBZIM provided greater anti-parkinsonian and neuroprotective effects than the l-deprenyl. The current study, together with our previous findings in a 6-OHDA PD model, demonstrated that DBZIM is a promising neuroprotectant for PD with anti-MAO-B property.

Neuropilin-1 is a glial cell line-derived neurotrophic factor receptor in glioblastoma.

The aim of this study was to identify the receptor for glial cell line-derived neurotrophic factor (GDNF) in glioblastoma multiforme (GBM). After GST pull-down assays, membrane proteins purified from C6 rat glioma cells were subjected to liquid chromatography-tandem mass spectrometry (LC-MS/MS). The differentially expressed proteins were annotated using Gene Ontology, and neuropilin-1 (NRP1) was identified as the putative GDNF receptor in glioma. NRP1 was more highly expressed in human GBM brains and C6 rat glioma cells than in normal human brains or primary rat astrocytes. Immunofluorescence staining showed that NRP1 was recruited to the membrane by GDNF, and NRP1 co-immunoprecipitated with GDNF. Using the NRP1 and GDNF protein structures to assess molecular docking in the ZDOCK server and visualization with the PyMOL Molecular Graphics System revealed 8 H-bonds and stable positive and negative electrostatic interactions between NRP1 and GDNF. RNAi knockdown of NRP1 reduced proliferation of C6 glioma cells when stimulated with GDNF. NRP1 was an independent risk factor for both survival and recurrence in GBM patients. High NRP1 mRNA expression correlated with shorter OS and DFS (OS: χ2=4.6720, P=0.0307; DFS: χ2=11.013, P=0.0009). NRP1 is thus a GDNF receptor in glioma cells and a potential therapeutic target.

Trolline Ameliorates Liver Fibrosis by Inhibiting the NF-κB Pathway, Promoting HSC Apoptosis and Suppressing Autophagy.

BACKGROUND/AIMS: Previous studies have shown that trolline possesses various forms of pharmacological activity, including antibacterial and antiviral potency. The present paper addressed the putative hepatoprotective effects of trolline. METHODS: Rats received 2 ml/kg CCl4 (mixed 1: 1 in peanut oil) intragastrically twice a week for 8 weeks to induce hepatic fibrosis. The animals were then treated with trolline for additional 4 weeks. Liver pathology and collagen accumulation were observed by hematoxylin-eosin and Masson's trichrome staining, respectively. Serum transaminase activity and collagen-related indicator level were determined by commercially available kits. NF-κB pathway activation was also examined. Moreover, the effects of trolline on hepatic stellate cell (HSC-T6) apoptosis, mitochondrial membrane potential (MMP), and autophagy were assessed. RESULTS: Trolline significantly alleviated CCl4-induced liver injury and notably reduced the accumulation of collagen in liver tissues. Trolline treatment also markedly decreased inflammatory cytokines levels by inhibiting the NF-κB pathway. Trolline strongly inhibited HSC-T6 activation and notably induced cell apoptosis by modulating the Bax/Bcl-2 ratio, caspase activity, and MMP. Moreover, trolline significantly inhibited HSC-T6 autophagy, as evidenced by the decrease in the formation of autophagic vacuoles and the number of autophagosomes, by regulating the expression levles of LC3, Beclin-1, P62, Atg 5 and 7. CONCLUSION: Our study demonstrates that trolline ameliorates liver fibrosis, possibly by inhibiting the NF-κB pathway, promoting HSCs apoptosis and suppressing autophagy.

Didymin ameliorates hepatic injury through inhibition of MAPK and NF-κB pathways by up-regulating RKIP expression.

A flavone was isolated from Origanum vulgare and identified as didymin (O. vulgare didymin, OVD). The protective effect and mechanism of OVD on acute liver injury was then assessed in vivo and in vitro. Our results showed that OVD significantly alleviated CCl4-induced liver injury in mice and markedly decreased serum ALT and AST activities. OVD treatment significantly reduced CYP2E1 activity, lipid peroxidation level, ROS generation, NO production and pro-inflammatory cytokines (such as TNF-α, IL-6 and IL-1ß) in liver tissues and RAW 264.7 cells, but enhanced the hepatic antioxidative enzymes activities. Further study showed that OVD significantly inhibited the NF-κB and MAPK pathways. Interestingly, OVD notably enhanced Raf kinase inhibitor protein (RKIP) expression, and the effects of OVD on histological changes, oxidative stress and inflammation was largely abolished by the RKIP specific inhibitor locostatin. Our findings indicate that OVD can ameliorate CCl4-induced liver injury, which may be ascribed to its radical scavenging action, antioxidant activity, and modulation of MAPK and NF-κB signaling pathways.

Raf Kinase Inhibitory Protein Down-Expression Exacerbates Hepatic Fibrosis In Vivo and In Vitro.

BACKGROUND/AIMS: Raf kinase inhibitory protein (RKIP) is closely associated with numerous tumors and participates in their development through regulating the growth, apoptosis, invasion and metastasis of tumor cells. However, the role of RKIP in chronic liver injury and particularly in liver fibrosis is still unclear. METHODS: In the present study, hepatic fibrosis was induced by porcine serum (PS) in rats and primary hepatic stellate cells (HSCs) were isolated from rat livers. Moreover, locostatin was used to interfere with RKIP expression. RESULTS: RKIP expression was significantly inhibited by locostatin in both liver tissues of rats and primary HSCs. Down-regulating RKIP expression resulted in serious liver injury, extensive accumulation of collagen, and significant increase in the levels of ALT, AST and TNF-α during liver fibrosis in rats. Moreover, down-regulating RKIP significantly promoted HSCs proliferation and colony formation in vitro. Reduced RKIP significantly increased the production of collagen and the level of α-SMA as well as the expression of MMP-1 and MMP-2 in both liver tissues and primary HSCs. Furthermore, down-regulating RKIP promoted the activation of the ERK and TLR4 signaling pathways. CONCLUSION: Our findings clearly indicate an inverse correlation between RKIP level and the degree of the liver injury and fibrosis. The decrease in RKIP expression may exacerbate chronic liver injury and liver fibrosis.