Promotion of perineural invasion of cholangiocarcinoma by Schwann cells via nerve growth factor.

Background: Cholangiocarcinoma (CCA), a highly lethal tumor of the hepatobiliary system originating from bile duct epithelium, can be divided into the intrahepatic, hilar, and extrahepatic types. Due to its insidious onset and atypical early clinical symptoms, the overall prognosis is poor. One of the important factors contributing to the poor prognosis of CCA is the occurrence of perineural invasion (PNI), but the specific mechanisms regarding how it contributes to the occurrence of PNI are still unclear. The main purpose of this study is to explore the molecular mechanism leading to the occurrence of PNI and provide new ideas for clinical treatment. Methods: CCA cell lines and Schwann cells (SCs) were stimulated to observe the changes in cell behavior. SCs cocultured with tumor supernatant and SCs cultured in normal medium were subjected to transcriptome sequencing to screen the significantly upregulated genes. Following this, the two types of tumor cells were cultured with SC supernatant, and the changes in behavior of the tumor cells were observed. Nonobese diabetic-severe combined immunodeficiency disease (NOD-SCID) mice were injected with cell suspension supplemented with nerve growth factor (NGF) via the sciatic nerve. Four weeks later, the mice were euthanized and the tumor sections were removed and stained. Results: Nerve invasion by tumor cells was common in CCA tissues. SCs were observed in tumor tissues, and the number of SCs in tumor tissues and the degree of PNI were much higher than were those in normal tissues or tissues without PNI. The overall survival time was shorter in patients with CCA with PNI than in patients without PNI. SCs were enriched in CCA tissues, indicating the presence of PNI and associated with poor prognosis in CCA patients. CCA was found to promote NGF secretion from SCs in vitro. After the addition of exogenous NGF in CCA cell culture medium, the proliferation activity and migration ability of CCA cells were significantly increased, suggesting that SCs can promote the proliferation and migration of CCA through the secretion of NGF. NGF, in turn, was observed to promote epithelial-mesenchymal transition in CCA through tropomyosin receptor kinase A (TrkA), thus promoting its progression. Tumor growth in mice shows that NGF can promote PNI in CCA. Conclusions: In CCA, tumor cells can promote the secretion of NGF by SCs, which promotes the progression of CCA and PNI by binding to its high-affinity receptor TrkA, leading to poor prognosis.

A systems approach to multilingual language attitudes: A case study of Montréal, Québec, Canada.

Purpose: People are shaped holistically by dynamic and interrelated individual and social-ecological systems. This perspective has been discussed in the context of varied aspects of bilingual experiences, namely language acquisition and development. Here, we applied a Systems Framework of Bilingualism to language attitudes, which may be especially responsive to social-ecological influences. Methodology: One hundred twenty-three French-English bilingual adults (M age = 21.20, SD = 3.21) completed self-report questionnaires on demographic information and their attitudes toward languages. A subset of these bilinguals (n = 73) completed a social network survey. Data and analysis: We used language-tagged social network analysis and geospatial demographic analysis to examine the role of individual characteristics (i.e., first language), interpersonal language dynamics (i.e., person-to-person interactions), and ecological language dynamics (i.e., neighborhood language exposure). Findings and Conclusions: At an individual level, we found that bilinguals' language background (i.e., first language) predicted attitudes of solidarity toward a language (i.e., whether a language is associated with personal identity and belongingness). When considering sociolinguistic layers of influence, we found that bilinguals' social network and neighborhood-level language exposure jointly predicted their attitudes of solidarity toward a language, as well as their attitudes toward the protection of minority languages. Originality: While most studies have examined language experience in a unidimensional nature, the present study investigated multilingual language attitudes by considering multiple systems within a social-ecological framework. Implications: Taken together, the results suggest that several interrelated interpersonal and ecological systems are associated with language attitudes, which could have important implications for planning future language policies in multilingual societies such as Montréal.

Serum Isthmin-1 is negatively correlated with HDL-C in type 2 diabetes mellitus.

BACKGROUND: Isthmin-1 (Ism-1) is a newly identified insulin-like adipokine that increases glucose uptake by adipocytes and inhibits hepatic lipid synthesis. Recent studies have shown that Ism-1 can improve the metabolic disorders associated with type 2 diabetes mellitus (T2DM) and improve lipid metabolism. The classic function of high-density lipoprotein cholesterol (HDL-C) is to transport cholesterol from extra-hepatic tissues to the liver for metabolism. In contrast, disorders of lipid metabolism and inflammation are the leading causes of atherosclerosis (As). Atherosclerosis often manifests as loss of elasticity, lipid accumulation, fibrous tissue proliferation and calcium deposits in the affected arteries, eventually forming plaques. AIM: To illustrate the correlation between HDL-C and Ism-1 in T2DM, and the relationship between lipoprotein cholesterol and carotid plaque. METHODS: A total of 128 patients with T2DM were enrolled in the study and basic information was collected. HDL-C levels were measured chemically. Serum Ism-1 levels were measured using an enzyme-linked immunosorbent assay (ELISA). Linear regression analysis was used to assess the correlation between serum Ism-1 levels and HDL-C in patients with T2DM. Basic information was again collected from 226 patients with T2DM. Independent sample t-tests were performed to explore the relationship between carotid plaque formation and lipids. RESULTS: HDL-C was divided into four groups according to quartiles and there was a between-group difference in Ism-1 (p = 0.040). Multivariable linear regression showed a negative association between Ism-1 and HDL-C in T2DM (ß = -0.235, p < 0.001), even after adjusting for related factors (ß = -0.165, p = 0.009). Low-density lipoprotein cholesterol (LDL-C) and HDL-C showed significant differences between the carotid plaque group and the non-carotid plaque group (pLDL-C = 0.007, pHDL-C = 0.003). CONCLUSION: Serum Ism-1 and HDL-C are negatively correlated in T2DM. LDL-C is significantly higher in carotid plaque group than non-carotid plaque group, while HDL-C is significantly lower than in the non-carotid plaque group.

Experiences of racial microaggression among immigrant and Canadian-born young adults: Effects of double stigma on mental health and service use.

BACKGROUND: Significant disparities in utilization of mental health services exist among immigrant and Canadian-born populations. These gaps may be associated with a 'double stigma' - stigma related to being from a racialized background exacerbated by mental health stigma. Immigrant young adults may be particularly susceptible to this phenomenon, given developmental and social transitions from adolescence to adulthood. AIMS: To investigate the joint effects of racial microaggression and mental health stigma on mental health and service use among first-generation immigrant and Canadian-born university students. METHOD: We conducted an online cross-sectional study among first-generation immigrant and Canadian-born university students (N = 1,280, Mage = 19.10, SD = 1.50). RESULTS: Despite no differences in anxiety or depression symptoms, first-generation (foreign-born) immigrants were less likely to have received therapy and to have taken medication for mental health issues compared to Canadian-born participants. First-generation immigrants also reported experiencing higher levels of racial microaggression and stigma toward service use. Results suggest the presence of a double stigma, mental health stigma and racial microaggression, each explained significant additional variance in symptoms of anxiety and depression and medication use. No effects of double stigma for therapy use were found - while higher mental health stigma predicted lower use of therapy, racial microaggression did not predict unique variance in therapy use. CONCLUSIONS: Our findings highlight the joint effects of racial microaggression and stigma toward mental health and service as barriers to help-seeking among immigrant young adults. Mental health intervention and outreach programmes should target overt and covert forms of racial discrimination while incorporating culturally sensitive anti-stigma approaches to help reduce disparities in mental health service use among immigrants in Canada.

A Comparative Investigation of the Predictive Validity of Four Indirect Measures of Bias and Prejudice.

Although measures of implicit associations are influential in the prejudice literature, comparative tests of the predictive power of these measures are lacking. A large-scale (N > 100,000) analysis of four commonly used measures-the Implicit Association Test (IAT), Single-Category IAT (SC-IAT), evaluative priming task (EPT), and sorting paired features task (SPF)-across 10 intergroup domains and 250 outcomes found clear evidence for the superiority of the SC-IAT in predictive and incremental predictive validity. Follow-up analyses suggested that the SC-IAT benefited from an exclusive focus on associations toward stigmatized group members, as associations toward non-stigmatized group members diluted the predictive strength of relative measures like the IAT, SPF, and EPT. These results highlight how conclusions about predictive validity can vary drastically depending on the measure selected and reveal novel insights about the value of different measures when focusing on predictive than convergent validity.

Effects of anthocyanin-rich supplementation on cognition of the cognitively healthy middle-aged and older adults: a systematic review and meta-analysis of randomized controlled trials.

CONTEXT: The prevalence of age-related cognitive decline has been on the rise as the global population age, putting the independence and quality of life of elderly at risk. Anthocyanin, as a subclass of dietary flavonoids, may have a beneficial impact on cognitive outcomes. OBJECTIVES: To examine the effects of dietary anthocyanin supplementation on cognition of the cognitively healthy middle-aged and older adults. DATA SOURCES: PubMed, ScienceDirect, CINAHL, EMBASE, ProQuest and Cochrane databases were searched. DATA EXTRACTION AND ANALYSIS: Thirteen studies were included in this meta-analysis. Anthocyanin-rich supplementation was found to significantly improve the processing speed of the older adults (95%CI 0.08, 0.44; P = 0.004). No significant differences were observed between intervention and control groups on memory, attention, executive function and psychomotor performance. Current neuroimaging studies have found promising effects of anthocyanin supplementation on brain activation and cerebral perfusion. CONCLUSION: Anthocyanin-rich supplementation may preserve cognitive processing speed and neuro-activities in older adults, which improves their daily functioning and quality of life. This review provides useful insights to guide direction and methodological designs for future studies to explore the underlying mechanisms of anthocyanins. SYSTEMATIC REVIEW AND META-ANALYSIS REGISTRATION: PROSPERO registration No. CRD42021228007.

Quantitative analysis for detection and grading of hepatocellular carcinoma: Comparison of diffusion kurtosis imaging, intravoxel incoherent motion and conventional diffusion-weighted imaging.

The aim of the present study was to compare the diagnostic performance of the main parameters derived from diffusion kurtosis imaging (DKI), intravoxel incoherent motion (IVIM) and diffusion-weighted imaging (DWI) regarding the detection and grading of hepatocellular carcinoma (HCC). A total of 78 patients diagnosed with HCC by biopsy were prospectively enrolled in the present study, and underwent routine magnetic resonance imaging (MRI), DWI, IVIM, DKI and contrast-enhanced MRI prior to surgery. Measurements, including mean diffusivity (MD), mean diffusional kurtosis (MK), true diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f) and apparent diffusion coefficient (ADC), were compared with grading HCC using one-way ANOVA followed by the Student-Neuman-Keuls-q post-hoc test. Spearman's correlation coefficient was used to analyze the correlation between each parameter and pathological grade, while the diagnostic efficiency was evaluated using a receiver operating characteristic (ROC) curve. The 78 patients enrolled in the present study were grouped into highly (n=22), moderately (n=41) or poorly (n=15) differentiated HCC groups according to the criteria of Pathology and Genetics Tumors of the Digestive System. MK values differed significantly between different grades and decreased gradually with the degree of tumor differentiation. The MD, D and ADC values in the highly differentiated HCC group were significantly higher than those in the moderately or poorly differentiated HCC groups (all P<0.001), whereas no significant differences were observed in D* or f (P=0.502 and P=0.853, respectively). A significant correlation was observed between MK, MD, D and ADC, and HCC grades (r=0.705, r=0.570, r=0.423 and r=0.687, respectively). The comparison of the ROC curves of MK, MD, D, ADC, D* and f values for predicting highly differentiated HCC suggested that MK and D were the best indicators for predicting highly differentiated HCC, as the area under the ROC curve (AUC) of MK and D was significantly higher than that of ADC (Z=2.247 and 2.428, P=0.025 and 0.016, respectively), whereas non-statistically significant differences were observed in the AUC values between MK and D (Z=0.072; P=0.942). The DKI-derived MK and IVIM-derived D values had a similar diagnostic performance and were superior to ADC in discriminating the histological grade of HCC. In addition, the combination of MK and D values exhibited an improved diagnostic performance.

Bridging interpersonal and ecological dynamics of cognition through a systems framework of bilingualism.

Human cognition occurs within social contexts, and nowhere is this more evident than language behavior. Regularly using multiple languages is a globally ubiquitous individual experience that is shaped by social environmental forces, ranging from interpersonal interactions to ambient language exposure. Here, we develop a Systems Framework of Bilingualism, where embedded layers of individual, interpersonal, and ecological sociolinguistic factors jointly predict people's language behavior. Of note, we quantify interpersonal and ecological language dynamics through the novel applications of language-tagged social network analysis and geospatial demographic analysis among 106 English-French bilingual adults in Montréal, Canada. Consistent with a Systems view, we found that people's individual language behavior, on a global level (i.e., overall language use), was jointly predicted by the language characteristics of their interpersonal social networks and the ambient linguistic patterns of their residential neighborhood environments, whereas more granular aspects of language behavior (i.e., word-level proficiency) was mainly driven by local, interpersonal social networks. Together, this work offers a novel theoretical framework, bolstered by innovative analytic techniques to quantify complex social information and empower more holistic assessments of multifaceted human behaviors and cognition, like language. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Methicillin-resistant Staphylococcus aureus of the clonal lineage ST5-SCCmecII-t2460 was associated with high mortality in a Wuhan hospital.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important human pathogen that can cause serious infectious diseases. An emerging MRSA strain, ST5-SCCmecII spa-type-t2460 (SMRSA), has spread rapidly since its recent emergence in China, but little information is available about this lineage. In this study, 91 MRSA isolates were collected from patients treated in the Zhongnan Hospital, Wuhan University, from 2018 to 2019, and investigated for their molecular characteristics, antibiotic resistance profiles, and clinical characteristics. The predominant lineage, SMRSA, accounted for 37.4% (34/91) of the isolates, followed by ST239-SCCmecIII-t030 (19.8%, 18/91) and ST59-SCCmecIV-t437 (8.8%, 8/91). In contrast to the latter two non-SMRSA (nSMRSA) lineages, which are among the main MRSA found in Chinese settings, SMRSA exhibited small colony variant (SCV) phenotype and had extremely high resistance rates to erythromycin (100.0%), clindamycin (100.0%), levofloxacin (100.0%), tetracycline (97.1%), moxifloxacin (97.1%), and ciprofloxacin (100%), but was more susceptible to rifampicin (resistance rate 3%). The levels of white blood cells (WBC) and procalcitonin (PCT) and the 30-day mortality in patients infected with SMRSA were (12.54 ± 6.61) × 109/L, 0.66 ng/mL, and 52.9%, respectively, which were much higher than those in patients infected with nSMRSA. In addition, patients infected with SMRSA were more frequently admitted to the intensive care unit (ICU) and submitted to invasive procedures than those infected with nSMRSA. In conclusion, SMRSA showed SCV phenotype and exhibited multiple antibiotic-resistance profiles. In this study, SMRSA was associated with serious infections and poor prognosis. Compared with ST239, ST59, or other nSMRSA strains, patients infected with SMRSA strains have higher 30-day mortality, increased levels of inflammatory biomarkers, and more frequent ICU hospitalization and invasive procedures.

Lenvatinib induces anticancer activity in gallbladder cancer by targeting AKT.

Gallbladder cancer (GBC) is characterized by poor prognosis, early metastasis, and high recurrence rates, which seriously threaten human health. The effect of lenvatinib, a widely used drug in anti-hepatocellular carcinoma in China, on GBC progress, as well as its underlying molecular mechanism, remains unclear. Therefore, the present study investigated the effect of lenvatinib on human GBC GBC-SD and NOZ cells and its underlying mechanisms. A series of experiments, including cell proliferation, clone formation, wound healing, and cell migration and invasion assays, as well as flow cytometry, were performed to investigate the anticancer effect of lenvatinib on GBC. Western blotting was used to detect alterations in protein expression of CKD2, CKD4, cyclin D1, caspase-9, matrix metalloproteinase (MMP)-2, cell migration-inducing protein (CEMIP) and phospho-AKT (p-AKT). In addition, the chemosensitivity of lenvatinib-treated GBC cells to gemcitabine (GEM) and whether the activation of phosphoinositide 3 kinase (PI3K)/AKT contributed to the chemoresistance were determined. Finally, the anticancer effect of lenvatinib in vivo was detected using a xenograft mouse model. These data showed that treatment with lenvatinib inhibited cell proliferation, colony formation ability, migration, induced apoptosis, regulated cell cycle and resulted in decreased resistance to GEM. Treatment with lenvatinib decreased the expression of MMP-2, CEMIP, CDK2, CDK4 and cyclin D1, and increased the expression of cleaved caspase-9, which was mediated by the inactivation of the PI3K/AKT pathway in vitro. In addition, lenvatinib inhibited autophagy in GBC-SD and NOZ cells. Besides, Lenvatinib suppressed GBC cell growth in vivo by targeting p-AKT. In combination, the present data indicated that lenvatinib plays a potential anticancer role in GBC by downregulating the expression of p-AKT.

An Apoptotic Gene Signature for the Prognosis of Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a major public health burden worldwide owing to high incidence and poor prognosis. Although numerous apoptotic genes were disclosed in HCC, the prognostic value and clinical utility of the genes remained unclear. METHODS: The differentially expressed genes (DEGs) were identified in the microarray and RNA sequencing data from public databases. The apoptosis-related differentially expressed genes (AR-DEGs) were selected to construct a Lasso-penalized Cox regression model. The signature including five apoptotic genes was used to calculate risk score. Then, the receiver operating characteristic (ROC) and survival analysis were conducted based on the signature. A nomogram containing the signature and clinical characteristics was plotted to visualized the prognosis prediction. Finally, the enrichment analysis was performed in the Gene Ontology (GO) to investigate the potential mechanism. RESULTS: Patients with high risk scores were related to worse overall survival than those with low risk. The 3-year and 5-year area under curve (AUC) values of the signature were above 0.7 in databases. And the nomogram presented reliable net benefits for the survival prediction. The nomogram was also tested by probability calibration curves and Decision Curve Analysis (DCA). Furthermore, the five differentially expressed genes were verified again in the HCC clinical specimens with real-time PCR and Western Blot. CONCLUSION: Collectively, the present study formed a novel signature based on five apoptotic genes, and this possibly predicted prognosis and strengthened the communication with HCC patients about the likely treatment.

Calreticulin: a potential diagnostic and therapeutic biomarker in gallbladder cancer.

Recent studies suggested that calreticulin (CRT) has an important role in the progression of various types of cancer. Our previous study suggested that CRT was upregulated and acted as an oncogene in hepatocellular carcinoma. However, the role of CRT in gallbladder cancer (GBC) remains unclear. The expression level of CRT was upregulated in GBC tissues in comparison with adjacent non-tumor tissues and chronic cholecystitis tissues. Moreover, CRT expression was found to be correlated with the tumor size. Knockdown of CRT inhibited cell proliferation, induced apoptosis, arrested cell cycle and resulted in decreased resistance to gemcitabine, which was mediated by the inactivation of the PI3K/Akt pathway. Collectively, the present results suggested a potential role of CRT in GBC progression and provided novel insights into the mechanism underlying the CRT-mediated chemosensitivity in GBC cells.

Diagnostic and prognostic values of AKR1C3 and AKR1D1 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common histological type of primary liver cancer and the majority of patients are diagnosed at an advanced stage and have a poor prognosis. AKR1C3 (Aldo-keto reductase family 1 member C3) and AKR1D1 (Aldo-keto reductase family 1 member D1) catalyze the conversion of aldehydes and ketones to alcohols and play crucial roles in multiple cancers. However, the functions of AKR1C3 and AKR1D1 in HCC remain unclear. In our study, data from the public databases were selected as training and validation sets, then 76 HCC patients in our center were chosen as a test set. Bioinformatics methods suggested AKR1C3 was overexpressed in HCC and AKR1D1 was down-regulated. The receiver operating characteristic curve (ROC) analysis was performed and the area under curve (AUC) values of AKR1C3 and AKR1D1 were above 0.7 (0.948, 0.836, respectively). Also, the high expression of AKR1C3 and low expression of AKR1D1 predicted poor prognosis and short median survival time. Then, the knockdown of AKR1C3 and overexpression of AKR1D1 in HCC cells were achieved with lentivirus. And both decreased cell proliferation, restrained cell viability, and inhibited tumorigenesis. Moreover, the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted and the results showed that AKR1C3 and AKR1D1 might participate in the MAPK/ERK and androgen receptor (AR) signaling pathway. Furthermore, the AR and phosphorylated ERK1/2 were significantly reduced after the suppression of AKR1C3 or overexpression of AKR1D1. Collectively, AKR1C3 and AKR1D1 might serve as candidate diagnostic and prognostic biomarkers for HCC and provide potential targets for HCC treatment.

Diagnostic Model of Superficial Lymph Nodes Based on Clinical History and Ultrasound Findings: A Prospective Cohort Study.

OBJECTIVES: Differentiation of benign and malignant changes in lymph nodes is extremely important. We aimed to identify the ultrasound and clinical diagnostic criteria permitting this differentiation. METHODS: Clinical and ultrasound data were collected at Beijing Friendship Hospital from May 2019 to November 2020. Univariate and multivariate analysis were performed using statistical methods, and a mathematical model was established to evaluate benign and malignant lymph nodes. RESULTS: A total of 1343 LNs (person) with US-guided core needle or fine needle biopsy (CNB or FNB) were evaluated in the analysis. Variables with a high predictive power were sex (odds ratio, OR: 3.360, p<0.001), short diameter (OR: 4.660, p<0.001), short/long diameter (S/L) ratio (OR: 1.515, P=0.007), border (OR: 1.626, p=0.002), cortex echogenicity (OR: 2.089, P<0.001), fusion (OR: 2.313, p=0.002), vascularity (peripheral vascularity, OR: 3.424, p<0.001; mixed vascularity, OR: 4.127, p<0.001), and medical history (fever/local pain, OR: 0.316, p<0.001; tumor history in the drainage area, OR: 4.595, p<0.001; both, OR: 5.554, p<0.001). The cut-off score on receiver operating characteristic (ROC) curve analysis using these eight variables was 2.5. The largest area under the ROC curve (Az) value was 82.3% (95% confidence interval (CI), 0.805-0.851), and the sensitivity (79.4%), specificity (72.3%), and accuracy (74.8%) were higher than those for nearly all the single indices. CONCLUSION: The model of combination of ultrasound and clinical symptoms can preliminarily evaluate the benign and malignant of lymph nodes.

Using Network Science to Map What Montréal Bilinguals Talk about Across Languages and Communicative Contexts.

Recent work within the language sciences, particularly bilingualism, has sought new methods to evaluate and characterize how people differentially use language across different communicative contexts. These differences have thus far been linked to changes in cognitive control strategy, reading behavior, and brain organization. Here, we approach this issue using a novel application of Network Science to map the conversational topics that Montréal bilinguals discuss across communicative contexts (e.g., work, home, family, school, social), in their dominant vs. non-dominant language. Our results demonstrate that all communicative contexts display a unique pattern in which conversational topics are discussed, but only a few communicative contexts (work and social) display a unique pattern of how many languages are used to discuss particular topics. We also demonstrate that the dominant language has greater network size, strength, and density than the non-dominant language, suggesting that more topics are used in a wider variety of contexts in this language. Lastly, using community detection to thematically group the topics in each language, we find evidence of greater specificity in the non-dominant language than the dominant language. We contend that Network Science is a valuable tool for representing complex information, such as individual differences in bilingual language use, in a rich and granular manner, that may be used to better understand brain and behavior.

TGF-ß- and lipopolysaccharide-induced upregulation of circular RNA PWWP2A promotes hepatic fibrosis via sponging miR-203 and miR-223.

Both transforming growth factor-beta (TGF-ß) and lipopolysaccharide (LPS) can activate hepatic stellate cells (HSCs), thus increasing expressions of alpha smooth muscle actin (α-SMA) and type I collagen alpha 1 (Col1α1) and promoting liver fibrosis. However, whether TGF-ß and LPS have a common downstream reactor remains unclear. Recently, a strong relationship of circular RNAs (circRNAs) and fibrogenesis has been elucidated. In this study, we compared the expressions of several circRNAs in TGF-ß- and LPS-activated HSCs, and found that circ-PWWP2A was upregulated in both TGF-ß- and LPS-activated HSCs and in mouse fibrotic liver tissues. Meanwhile, circ-PWWP2A was positively correlated with HSC activation and proliferation. Two microRNAs, miR-203 and miR-223, were identified to be the downstream targets of circ-PWWP2A using luciferase reporter assay and pull-down interaction assay. Circ-PWWP2A was suggested to promote HSC activation and proliferation via sponging miR-203 and miR-223, and subsequently increasing Fstl1 and TLR4, respectively. Furthermore, downregulating circ-PWWP2A was indicated to alleviate hepatic fibrosis in vivo. In conclusion, our findings indicated that circ-PWWP2A is the common downstream reactor of TGF-ß and LPS in HSC activation, and that circ-PWWP2A plays a critical role in hepatic fibrogenesis via sponging miR-203 and miR-223.

Oridonin inhibits hypoxia-induced epithelial-mesenchymal transition and cell migration by the hypoxia-inducible factor-1α/matrix metallopeptidase-9 signal pathway in gallbladder cancer.

Hypoxia has crucial roles in cancer development and progression. Our previous study indicated that cell migration was increased in a hypoxic microenvironment in GBC-SD gallbladder cancer (GBC) cells. Oridonin, a bioactive diterpenoid compound that is isolated from the plant Rabdosia rubescens, has been identified as an anticancer agent in various types of cancer. However, its roles in cell proliferation, apoptosis, and migration in a hypoxic microenvironment and the associated regulatory mechanisms have not yet to be fully elucidated in GBC. The present study investigated the effect of oridonin on cell proliferation, apoptosis, the cell cycle and cell migration in GBC in vitro and in vivo. Furthermore, the role of oridonin in hypoxia-induced cell migration and its underlying mechanisms were explored in GBC. The results indicated that treatment with oridonin significantly suppressed cell proliferation and the metastatic ability of GBC-SD cells in a dose-dependent manner, increased the level of cell apoptosis and induced cell cycle arrest at the G0/G1 phase. Further experiments demonstrated that oridonin could inhibit hypoxia-induced epithelial-mesenchymal transition and cell migration by downregulating the expression levels of hypoxia-inducible factor (HIF)-1α/matrix metallopeptidase (MMP)-9. In addition, oridonin suppressed GBC cell growth and downregulated the expression levels of HIF-1α and MMP-9 in a GBC-SD cell xenograft model. Taken together, these results suggest that oridonin possesses anticancer properties in GBC. Notably, oridonin can suppress tumor epithelial-mesenchymal transition and cell migration by targeting the HIF-1α/MMP-9 signaling pathway.

Effects of a Lactulose-Rich Diet on Fecal Microbiome and Metabolome in Pregnant Mice.

Lactulose, a safe and beneficial molecule, can be used in food as a prebiotic and as an osmotic laxative during pregnancy. This work evaluated the effects of dietary lactulose on the gut microenvironment of pregnant mice using the fecal microbiota and metabolomic profiling. After 2 weeks of feeding, the Bifidobacterium and Bacteroides abundances in the mouse feces were significantly increased in the LAC-high (the diet supplemented with 15% lactulose) group. A total of 15 metabolites, including 1-monoolein, glucose-6-phosphate, and short-chain fatty acids, were increased significantly in the LAC-high group. The serum glucose and total cholesterol concentrations were significantly decreased, while the progesterone level was significantly increased in the lactulose-fed mice. In the LAC-high group, the colonic pH and intestinal permeability were decreased, while the immunoglobulins in the colonic epithelial cells and the small intestinal absorption capacity were significantly increased. These findings indicated that lactulose supplementation benefitted pregnancy performance in mice.