Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The purpose of this study was to determine the effects of daucosterol on HCC by investigating Wnt/β-catenin signaling. In this study, HepG2 and SMMC-7721 cells were treated with varying concentrations of daucosterol, and the corresponding inhibitory effects on HCC cells were examined via CCK-8 assays. Cell migration and invasion abilities were detected via transwell assays. β-Catenin and phospho (p)-β-catenin levels were analyzed via western blotting. Our results showed that daucosterol reduced the proliferation, migration, and invasion capacities of HCC cells in a concentration-dependent manner. In addition, daucosterol reduced the levels of β-catenin and p-β-catenin in HepG2 and SMMC-7721 cells. Furthermore, the Wnt signaling pathway inhibitor SB-216763 was used to treat HepG2 and SMMC-7721 cells with daucosterol. Our results showed that co-treatment with daucosterol and SB-216763 abolished the effects of daucosterol on cell inhibition ratios, cell migration, and cell invasion. These findings indicated that daucosterol inhibited cell migration and invasion in HCC cells via the Wnt/β-catenin signaling pathway. Therefore, our study highlights the use of daucosterol as a promising therapeutic strategy for HCC treatment.

Background: Tumor necrosis factor (TNF)-α can upregulate the expression of plasminogen activator inhibitor (PAI)-1, an inhibitor of fibrinolysis. Adiponectin (Adp) antagonizes TNF-α by negatively regulating its expression in various tissues. In the present study, the ability of Adp to suppress TNF-α-induced PAI-1 upregulation and the underlying mechanisms were evaluated. Methods: Human umbilical vein endothelial cells (HUVECs) were treated with TNF-α in the presence or absence of Adp, and PAI-1 mRNA and antigen expression, activated signaling pathways, and molecular mechanisms were analyzed by qRT-PCR and ELISA. Results: Adp decreased the TNF-α-induced upregulation of PAI-1 mRNA and protein expression and suppressed TNF-α-induced cAMP-PKA-AMPK inactivation. Adp also suppressed the TNF-α-induced NF-kB binding capability on the PAI-1 promoter. Moreover, these Adp-induced effects were further enhanced or prevented by treatment with the cAMP inhibitor Rp-cAMPs or activator forskolin, respectively. Conclusions: Our data suggest that Adp abrogates TNF-α-activated PAI-1 expression by activating cAMP-PKA-AMPK signaling to suppress NF-kB binding to the PAI-1 promoter in HUVECs. Given the antifibrotic effect of PAI-1 abrogation, Adp may be utilized as a novel agent in the treatment of fibrotic diseases.

Trazodone has been widely prescribed for off-label use as a sleep aid. Identifying how trazodone impacts the performance of polysomnographic sleep architecture in insomnia disorder will provide additional data that can be used to guide clinical application. To assess the efficacy of trazodone in altering the polysomnographic sleep architecture in insomnia disorder so that sleep can be facilitated. PubMed, EMBASE, Web of Science, PsycINFO, Cochrane Library, Chinese Biomedical Literature Database (SinoMed), China National Knowledge Infrastructure, Wanfang Database, and the China Science and Technology Journal Database were searched for articles published between inception and June 2022. RCTs in patients with insomnia disorder applying trazodone in one arm of interventions at least 1 week, and reporting PSG parameters in the outcomes were eligible. RoB 2 was used to evaluate the risk of bias. The results of quality of evidence assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. When I2 < 50%, the fixed effects model was used. When I2 ≥ 50%, the random effects model was used. The mean differences (MD) or standardized mean differences (SMD) and odds ratios (OR) with 95% confidence intervals (CIs) were estimated. Eleven randomized controlled trials were selected and participants were 466. Risk of bias was low in 5 trials (45.5%), and was moderate in 6 (54.5%). Compared with the control group, trazodone significantly increased total sleep time (TST, min) (MD = 39.88, 95% CI 14.44–65.32, P = 0.002) and non-rapid eye movement stage 3 (N3, mixed min and %) (SMD = 1.61, 95% CI 0.69–2.53, P = 0.0006); trazodone significantly decreased latency to onset of persistent sleep (LPS, min) (MD = − 19.30, 95% CI − 37.28 to − 1.32, P = 0.04), non-rapid eye movement stage 1 (N1, mixed min and %) (SMD = − 0.62, 95% CI − 1.13 to − 0.12, P = 0.02), the number of awakenings (NAs, including both arousal times and arousal index) (SMD = − 0.67, 95% CI − 0.91 to − 0.42, P < 0.00001), and waking time after persistent sleep onset (WASO, mixed min and %) (SMD = − 0.42, 95% CI − 0.81, − 0.03, P = 0.04), with no obvious effect on non-rapid eye movement stage 2 (N2, mixed min and %) (SMD = − 0.15, 95% CI − 0.41 to 0.11, P = 0.25), rapid eye movement (REM, mixed min and %) (SMD = 0.22, 95% CI − 0.26 to 0.70, P = 0.37), rapid eye movement latency (REML, min) (MD = 2.33, 95% CI − 27.56 to 32.22, P = 0.88), or apnea–hypopnea index (AHI) (MD = − 4.21, 95% CI − 14.02 to 5.59, P = 0.40). Daytime drowsiness (OR = 2.53, 95% CI 1.14–5.64, P = 0.02) and decreased appetite (OR = 2.81, 95% CI 1.14–6.92, P = 0.02) occurred with greater frequency in the trazodone group as compared to the control group, and the differences were significant. The results of quality of evidence were very low in TST, N3 and AHI, were low in LPS, WASO and REM, and were moderate in N1 and NAs. The sources of heterogeneity in TST and N3 were not found out from sensitive and subgroup analysis and there was no high quality of evidence in outcomes by GRADE Assessment. Trials with combination of other therapy could be a problem in this meta-analysis as the possibility of interactions were found from sungroup analysis. Trazodone could improve sleep by changing the sleep architecture in insomnia disorder, but it should be used with caution due to the adverse events that may occur.PROSPERO registration register name: The effect of trazodone on polysomnography sleep architecture in patients with insomnia: a systematic review and meta-analysis protocol; Registration Number CRD42020215332.

We performed this meta-analysis to compare the efficacy and safety of reduced-dose non-vitamin K antagonist oral anticoagulants (NOACs) versus warfarin in patients with atrial fibrillation (AF). The PubMed and Embase databases were systematically searched until July 2019 for eligible studies that comparing the effect between any reduced-dose NOAC and warfarin in patients with AF. Risk ratios (RRs) and 95% confidence intervals (CIs) were pooled by using a random-effects model. A total of 14 observational cohorts were included. Compared with warfarin use, the use of reduced-dose NOACs was associated with decreased risks of stroke or systemic embolism (RR, 0.83; 95% CI 0.74-0.93), ischemic stroke (RR, 0.87; 95% CI 0.77-0.98), major bleeding (RR, 0.71; 95% CI 0.60-0.84), intracranial hemorrhage (RR, 0.51; 95% CI 0.44-0.60), and gastrointestinal bleeding (RR, 0.72; 95% CI 0.54-0.94), but not all cause death (RR, 0.84; 95% CI 0.67-1.06). In the subgroup analyses, all NOAC users had lower or similar rates of thromboembolic and bleeding events; and the reductions in stroke or systemic embolism, all-cause death, major bleeding, and gastrointestinal bleeding were more prominent in Asians than non-Asians. In conclusion, current published data suggest that the use of reduced-dose NOACs is non-inferior to warfarin in patients with AF (in particular Asians).

BackgroundGallbladder cancer (GBC) is a malignant cancer with poor prognosis. Evidences have shown that miRNAs are closely related to the occurrence of GBC; thus, we aimed to explore miRNAs, which plays an important role in the occurrence and development of GBC.MethodsMicroarray analysis was performed to investigate the differentially expressed miRNAs between five non-neoplastic gallbladder tissues (normal tissues) and five gallbladder tumor tissues (tumor tissues). RT-qPCR was performed to detect the level of miR-181b-5p in cells, and CCK-8 was performed to detect cell viability. Then, glucose assay kit or lactic acid assay kit was performed to detect the level of glucose consumption or lactate production. Next, transwell and wound healing assays were used to assess cell migration. In addition, dual-luciferase reporter assay was used to verify the relationship between miR-181b-5p and PDHX. At last, Western blotting was performed to determine the protein level of PDHX.ResultsMicroarray analysis suggested miR-181b-5p was significantly upregulated in GBC tumor tissue. KEGG analysis for the protein targets of miR-181b-5p indicates a close relationship existed between miR-181b-5p and glycolysis. In addition, the level of miR-181b-5p was notably increased in GBC-SD or G415 cells, compared with HIBEpiC cells. GBC cell viability was significantly decreased under hypoxia, and these decreases were exacerbated by miR-181b-5p antagomir. Moreover, glucose consumption or lactate production of GBC cells was significantly upregulated under hypoxia, whereas these increases were completely revered by miR-181b-5p antagomir. Further investigation revealed that PDHX was a direct target of miR-181b-5p.ConclusionIn this study, downregulation of miR-181b-5p inhibits the viability, migration, and glycolysis of GBC by upregulating PDHX under hypoxia. This finding suggested that miR-181b-5p might be considered as a novel therapeutic target for the treatment of GBC.