Dictamnine inhibits pancreatic cancer cell growth and epithelial-mesenchymal transition by blocking the PI3K/AKT signaling pathway.

Many different treatments are available for pancreatic cancer (PC), including surgical resection, chemotherapy, radiotherapy, and immunotherapy, but these treatments are often ineffective at curing PC. Hence, identifying new and effective agents or strategies to improve therapeutic effects is critical. This study focused on the efficacy of dictamnine (DTM), a furan quinoline alkaloid extracted from Dictamnus dasycarpus Turcz., in treating PC. Our in vitro results showed that DTM can mitigate cell proliferation and induce cell cycle arrest and apoptosis in two different human PC cell lines. Moreover, epithelial-mesenchymal transition (EMT) was prevented during DTM treatment, reflected by reduced cell migration and invasion abilities. In vivo studies demonstrated that DTM treatment led to a remarkable inhibition of tumor growth in a xenograft nude mouse model. Mechanistic investigation showed that DTM might act by restraining constitutive and induced PI3K/AKT activity. In summary, our results demonstrated that DTM slows PC progression by inhibiting the activity of the PI3K/AKT signaling pathway and its downstream effectors and that DTM is effective as a pathway-specific cancer therapy. These findings could provide a greater understanding of the function of anticancer drugs and new options for PC treatment.

Intestinal flora imbalance affects bile acid metabolism and is associated with gallstone formation.

BACKGROUND: The gut microbiota participates in the metabolism of substances and energy, promotes the development and maturation of the immune system, forms the mucosal barrier, and protects the host from pathogen attacks. Although the pathogenesis of cholesterol gallstones is still not clear, studies have suggested that gut microbiota dysbiosis plays an important role in their formation. METHODS: Microbial DNA from faeces of normal control patients and those of patients with calculi was subjected to 16S rRNA gene sequencing to detect gene expression changes in intestinal microbes. ELISA kits were used to measure free bile acids, secondary bile acids and coprostanol according to the manufacturer's instructions. The relationship between flora and their metabolites was then analysed. RESULTS: In the gallstone group, the diversity of intestinal bacteria and the abundances of certain phylogroups were significantly decreased (p < 0.05), especially Firmicutes (p < 0.05), the largest phylum represented by the gut microbiota. This study found an increase in free bile acids (p < 0.001) and secondary bile acids (p < 0.01) in the enterohepatic circulation. Bile salt hydrolase activity was not related to the abundances of BSH-active bacteria. 7a-dehydroxylating gut bacteria were significantly increased (p < 0.01), whereas cholesterol-lowering bacteria were significantly reduced (p < 0.05). The Ruminococcus gnavus group could be used as a biomarker to distinguish the gallstone group from the control group. CONCLUSION: We conclude that intestinal flora imbalance affects bile acid and cholesterol metabolism and is associated with gallstone formation.

MiR-155 aggravates impaired autophagy of pancreatic acinar cells through targeting Rictor.

The aim of this study was to investigate the role and mechanism of miR-155 in regulating autophagy in a caerulein-induced acute pancreatitis (AP) cellular model. GFP-LC3 immunofluorescence assay was performed to detect autophagy vesicle formation in pancreatic acinar cell line AR42J. AR42J cells were transfected with miR-155 mimic, inhibitor, and corresponding controls to explore the effect of miR-155 on autophagy. The protein levels of LC3-I, LC3-II, Beclin-1, and p62 were analyzed by western blot analysis. Dual-luciferase reporter assay was performed to verify the interaction between miR-155 and Rictor (RPTOR independent companion of MTOR complex 2). The results showed that caerulein treatment induced impaired autophagy as evidenced by an increase in the accumulation of p62 together with LC3-II in AR42J cells, accompanied by miR-155 upregulation. Furthermore, miR-155 overexpression aggravated, whereas miR-155 silencing reduced the caerulein-induced impairment of autophagy. Mechanistically, Rictor was confirmed to be a direct target of miR-155, which could rescue the miR-155 overexpression-mediated aggravation of impaired autophagy. Collectively, these findings indicate that miR-155 aggravates impaired autophagy in caerulein-treated pancreatic acinar cells by targeting Rictor.

The interaction between ANXA2 and lncRNA Fendrr promotes cell apoptosis in caerulein-induced acute pancreatitis.

BACKGROUND: Annexin A2 (ANXA2) plays a crucial role in acute pancreatitis (AP). However, its potential mechanism remains unclear. METHODS: In the present study, we used caerulein-treated AR42J rat pancreatic acinar cells as cell model of AP to investigate the potential functions of ANXA2 and its predicted long noncoding RNA (lncRNA) FOXF1 adjacent noncoding developmental regulatory RNA (lncRNA Fendrr). Cell apoptosis was evaluated by flow cytometry using annexinV-fluorescein isothiocyanate/propidium iodide staining. The expressions of ANAX2 and lncRNA Fendrr were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Furthermore, Western blot analysis was performed to determine the protein levels of ANXA2, Bcl-2, and Bax. The association between lncRNA Fendrr and ANXA2 was disclosed by RNA pull-down, RNA immunoprecipitation, and electrophoretic mobility shift assays. RESULTS: ANXA2 was elevated in caerulein-induced AP model and promoted apoptosis of AR42J cells. LncRNA Fendrr was also upregulated in AP cell model and directly bound ANXA2 protein. Further studies indicated that the interaction between ANXA2 and lncRNA Fendrr contributed to the apoptosis of AR42J cells in AP cell model. CONCLUSION: Our study demonstrated that ANXA2 promoted AP progression via interacting with lncRNA Fendrr in vitro, which will provide a novel insight into the therapeutic target for AP.

STX12 lncRNA/miR-148a/SMAD5 participate in the regulation of pancreatic stellate cell activation through a mechanism involving competing endogenous RNA.

BACKGROUND: With the deepening of research, the roles of LncRNAs play in the fibrotic process have attracted great attention. At the early stage of pancreatic fibrogenesis, to effectively regulate pancreatic stellate cells (PSCs) activation is crucial for the treatment of chronic pancreatic fibrosis. METHODS: Microarray data on chronic pancreatitis were retrieved from the Gene Expression Omnibus (GEO) repository and analyzed using bioinformatic methods. A diagram of the lncRNA-miRNA-mRNA ceRNA network was constructed. In addition, activated rat PSCs were transfected with a small interfering RNA (siRNA) targeting the syntaxin-12 (STX12) lncRNA. Then, the expression of STX12, miR-148a and miR-130b were examined by RT-PCR. The expression of the interleukin 6 signal transducer (IL6ST), SMAD family member 5 (SMAD5) and alpha smooth muscle actin (α-SMA) proteins were examined by western blot. The expression of α-SMA were examined by immunofluorescence staining. RESULTS: Based on the results of bioinformatic analysis, a lncRNA-miRNA-mRNA network was established. A number of putative ceRNA pairs regulating the activation of PSCs were identified, including STX12 lncRNA/(miR-148a or miR-130b)/(SMAD5 or IL6ST). The expression of STX12 was downregulated (relative expression level: 0.23 ± 0.01, P < 0.01), while the expression of miR-148a was significantly elevated (relative expression level: 1.54 ± 0.02, p < 0.01), and the expression of miR-130b was markedly reduced (relative expression level: 0.69 ± 0.02, p < 0.01). The expression of SMAD5 was decreased (relative expression level: 0.70 ± 0.04, p < 0.05), whereas the expression of IL6ST displayed no significant change (p = 0.24). Additionally, the expression of α-SMA was dramatically reduced (relative expression level: 0.32 ± 0.04, p < 0.01), and immunofluorescence analysis confirmed that α-SMA expression was decreased in cells. CONCLUSION: During the PSCs activation in chronic pancreatitis, the existence of ceRNA interactions in pancreatic fibrosis has been demonstrated. Regulation of the STX12/miR-148a/SMAD5 axis may serve as a new gene therapy strategy for the treatment of chronic pancreatitis and reversal of pancreatic fibrosis.

Pancreatic Acinar Cells Employ miRNAs as Mediators of Intercellular Communication to Participate in the Regulation of Pancreatitis-Associated Macrophage Activation.

Macrophage activation plays an important role in the inflammatory response in acute pancreatitis. In the present study, the activation of AR42J pancreatic acinar cells was induced by taurolithocholate treatment. The results showed that the culture medium from the activated AR42J cells significantly enhanced NFκB activation in the macrophages compared to that without taurolithocholate treatment. Additionally, the precipitates obtained from ultracentrifugation of the culture media that were rich in exosomes were markedly more potent in activating macrophages compared with the supernatant fraction lacking exosomes. The results indicated that the mediators carried by the exosomes played important roles in macrophage activation. Exosomal miRNAs were extracted and examined using microarrays. A total of 115 differentially expressed miRNAs were identified, and 30 showed upregulated expression, while 85 displayed downregulated expression. Target genes of the differentially expressed miRNAs were predicted using TargetScan, MiRanda, and PicTar software programs. The putative target genes were subjected to KEGG functional analysis. The functions of the target genes were primarily enriched in MAPK pathways. Specifically, the target genes regulated macrophage activation through the TRAF6-TAB2-TAK1-NIK/IKK-NFκB pathway. As the mediators of signal transduction, miRNAs and their predicted target mRNAs regulate every step in the MAPK pathway.

Role of vitamin D receptor gene polymorphisms in pancreatic cancer: a case-control study in China.

The study was conducted to investigate the relationship between vitamin D receptor (VDR) gene rs2228570 and rs1544410 polymorphisms and pancreatic cancer (PC). Two hundred fifty-eight PC patients and 385 healthy controls were enrolled in this study. The genotypes of rs2228570 and rs1544410 were assayed using the polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) method. Univariate and multivariate logistic regression analyses were applied to determine the association between PC-onset risk and VDR gene polymorphisms. Contingency table analysis was performed to evaluate the relationship between the gene polymorphisms and clinicopathological tumor features such as location, pathological differentiation, and the TNM classification of PC. In rs2228570, the T loci and genotypes with T allele could increase the risk of PC; in rs1544410, the G loci and genotypes AG + GG could decrease the onset risk of PC significantly. The contingency table analysis indicated that the rs2228570 polymorphisms were correlated with the pathological differentiation of PC significantly, and the rs1544410 polymorphisms were correlated with the TNM classification of PC significantly. In conclusion, the VDR gene polymorphisms were correlated with incidence, pathological differentiation, and the TNM classification of PC significantly in our study population. So, the VDR polymorphisms have important implications in the incident rate and survival rate of PC.

Is preoperative MRCP necessary for patients with gallstones? An analysis of the factors related to missed diagnosis of choledocholithiasis by preoperative ultrasound.

BACKGROUND: The diagnosis of associated choledocholithiasis prior to cholecystectomy for patients with gallstones is important for the surgical decision and treatment efficacy. However, whether ultrasound is sufficient for preoperative diagnosis of choledocholithiasis remains controversial, with different opinions on whether routine magnetic resonance cholangiopancreatography (MRCP) is needed to detect the possible presence of common bile duct (CBD) stones. METHODS: In this study, a total of 413 patients with gallstones who were admitted to the Department of General Surgery of the First Affiliated Hospital of Harbin Medical University in China for a period of 3 years and underwent both ultrasound and MRCP examinations were retrospectively analysed. After reviewing and screening these cases according to the literature, 11 indicators including gender, age, alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, indirect bilirubin, alkaline phosphatase, γ-aminotransferase, CBD diameter, and concurrent acute cholecystitis were selected and comparatively analysed. RESULTS: Among the 413 patients, a total of 109 cases showed concurrent gallstones and choledocholithiasis, accounting for 26.39 % of all cases. Among them, 60 cases of choledocholithiasis were revealed by ultrasound examination, accounting for 55.05 %, while 49 cases of choledocholithiasis were not detected by ultrasound examination but were confirmed by MRCP instead (the missed diagnosis rate of ultrasound was 44.95 %). The results of statistical analysis suggested that alanine aminotransferase, acute cholecystitis, and CBD diameter were the three most relevant factors for missed diagnosis by ultrasound. CONCLUSION: The accuracy of preoperative ultrasonography for the diagnosis of associated CBD stones for patients with gallstones is not high. However, elevated alanine aminotransferase, concurrent acute cholecystitis, and CBD diameter were identified as key factors that may affect the accuracy of the diagnosis. Thus, routine preoperative MRCP examination is suggested for patients with gallstones to rule out possible concomitant CBD stones.

Database screening of herbal monomers regulating autophagy by constructing a "disease-gene-drug" network.

BACKGROUND: Studies suggest an important role of autophagy as a target for cancer therapy. We constructed a "disease-gene-drug" network using the modular approach of bioinformatics and screened herbal monomers demonstrating functions related to autophagy regulation. METHODS: Based on the microarray results of the gene expression omnibus (GEO) database (GSE2435 and GSE31040, starvation-induced autophagy model), we used the human protein reference database (HPRD) to obtain the protein-protein interaction (PPI) network. In addition, we used the CFinder software to identify several functional modules, performed gene ontology-biological process (GO-BP) functional enrichment analysis using the DAVID software, constructed a herbal monomer-module gene regulatory network using literature search and the Cytoscape software, and then analyzed the relationships between autophagy, genes, and herbal monomers. RESULTS: We screened 544 differentially expressed genes related to autophagy, 375 pairs of differentially expressed genes, and 7 gene modules, wherein the functions of module 3 (composed of 7 genes) were enriched in "cell death". Using the constructed herbal monomer-module gene regulatory network, we found that 30 herbal monomers can simultaneously regulate these 7 genes, indicating a potential regulatory role in autophagy. CONCLUSIONS: Database screening using the disease-gene-drug network can provide new strategies and ideas for the application of herbal medicines in cancer therapy.

Proteomic analysis of apoptotic and oncotic pancreatic acinar AR42J cells treated with caerulein.

This study aims to determine the differentially expressed proteins in the pancreatic acinar cells undergoing apoptosis and oncosis stimulated with caerulein to explore different cell death process of the acinar cell. AR42J cells were treated with caerulein to induce cell model of acute pancreatitis. Cells that were undergoing apoptosis and oncosis were separated by flow cytometry. Then differentially expressed proteins in the two groups of separated cells were detected by shotgun liquid chromatography-tandem mass spectrometry. The results showed that 11 proteins were detected in both apoptosis group and oncosis group, 17 proteins were detected only in apoptosis group and 29 proteins were detected only in oncosis group. KEGG analysis showed that proteins detected only in apoptosis group were significantly enriched in 10 pathways, including ECM-receptor interaction, cell adhesion molecules, and proteins detected only in oncosis group were significantly enriched in three pathways, including endocytosis, base excision repair, and RNA degradation. These proteins we detected are helpful for us to understand the process of cell death in acute pancreatitis and may be useful for changing the death mode of pancreatic acinar cells, thus attenuating the severity of pancreatitis.

Early proteome analysis of rat pancreatic acinar AR42J cells treated with taurolithocholic acid 3-sulfate.

BACKGROUND: Bile acids are the initiating factors of biliary acute pancreatitis. Bile acids can induce the activation of intracellular zymogen, thus leading injury in pancreatic acinar cells. Pathological zymogen activation in pancreatic acinar cells is a common feature of all types of acute pancreatitis. The proteins expressed in pancreatic acinar cells during the activation of zymogen may determine the severity of acute pancreatitis. The present study aims to determine the differentially expressed proteins in taurolithocholic acid 3-sulfate-stimulated pancreatic acinar cells as an in vitro model for acute pancreatitis. METHODS: Rat pancreatic acinar AR42J cells were treated with taurolithocholic acid 3-sulfate for 20 min. Laser confocal scanning microscopy and flow cytometry were used to detect activated trypsinogen in pancreatic acinar AR42J cells. After the determination of trypsinogen activation, proteome analysis was performed to identify the proteins differentially expressed in taurolithocholic acid 3-sulfate-treated cells and non-treated cells. RESULTS: After treatment with taurolithocholic acid 3-sulfate for 20 min, the activation of trypsinogen in AR42J cells was concurrent with changes in the protein expression profile. Thirty-nine differentially expressed proteins were detected; among these, 23 proteins were up-regulated and 16 proteins were down-regulated. KEGG analysis indicated that these proteins are involved in cellular metabolic pathways, cellular defensive mechanisms, intracellular calcium regulation and cytoskeletal changes. CONCLUSION: The expression of proteins in the pancreatic acinar cell changes at the early stage of biliary acute pancreatitis. These differentially expressed proteins will provide valuable information to understand the pathophysiologic mechanism biliary acute pancreatitis and may be useful for prognostic indices of acute pancreatitis.

Metabolomic study of serum from rabbits with acute acalculous cholecystitis.

OBJECTIVES: (1)H-NMR is a powerful approach of metabolomics. This study aimed to apply it to detect the serum metabolites in rabbits with acute acalculous cholecystitis (AAC), and to analyze their potential roles in AAC. METHODS: Fourteen rabbits were randomly divided into two groups, the AAC group and the CON group. In the AAC rabbit model, Escherichia coli solution was injected into the gallbladder, while same volume of saline, instead of E. coli solution, was injected into the gallbladder of the CON rabbit. General morphological, light microscopic and transmission electron microscopic observations were used to evaluate the model. Metabolic profiles of serum from rabbits with AAC were investigated through (1)H-NMR spectroscopy coupled with multivariate statistical analysis, such as principal components analysis and orthogonal partial least-squares discriminant analysis. RESULTS: The pathohistology of gallbladders showed a significant difference between the two groups, proving the successful induction of inflammation in the gallbladders of the AAC group. The serum concentration of lipids (LDL and VLDL) increased during AAC, while the concentrations of phospholipids, lactic acid, 3-hydroxybutyric acid, lysine, citric acid, asparagine, histidine, glucose and some other small molecular metabolites decreased. CONCLUSION: The profiling of serum metabolites in rabbits with acute acalculous cholecystitis changed significantly. These changes referred to the metabolic disturbance of carbohydrate, amino acids and lipids, inhibition of immunological functions and inflammation reaction.

CD8+ T cell-associated genes MS4A1 and TNFRSF17 are prognostic markers and inhibit the progression of colon cancer.

Background: Colon cancer (CC) is among the top three diseases with the highest morbidity and mortality rates worldwide. Its increasing incidence imposes a major global health burden. Immune checkpoint inhibitors, such as anti-PD-1 and anti-PD-L1, can be used for the treatment of CC; however, most patients with CC are resistant to immunotherapy. Therefore, identification of biomarkers that can predict immunotherapy sensitivity is necessary for selecting patients with CC who are eligible for immunotherapy. Methods: Differentially expressed genes associated with the high infiltration of CD8+ T cells were identified in CC and para-cancerous samples via bioinformatic analysis. Kaplan-Meier survival analysis revealed that MS4A1 and TNFRSF17 were associated with the overall survival of patients with CC. Cellular experiments were performed for verification, and the protein expression of target genes was determined via immunohistochemical staining of CC and the adjacent healthy tissues. The proliferation, migration and invasion abilities of CC cells with high expression of target genes were determined via in vitro experiments. Results: Differential gene expression, weighted gene co-expression and survival analyses revealed that patients with CC with high expression of MS4A1 and TNFRSF17 had longer overall survival. The expression of these two genes was lower in CC tissues than in healthy colon tissues and was remarkably associated with the infiltration of various immune cells, including CD8+ T cells, in the tumour microenvironment (TME) of CC. Patients with CC with high expression of MS4A1 and TNFRSF17 were more sensitive to immunotherapy. Quantitative reverse transcription-polymerase chain reaction, western blotting and immunohistochemical staining validated the differential expression of MS4A1 and TNFRSF17. In addition, Cell Counting Kit-8, wound healing and transwell assays revealed that the proliferation, migration and invasion abilities of CC cells were weakened after overexpression of MS4A1 and TNFRSF17. Conclusions: The core genes MS4A1 and TNFRSF17 can be used as markers to predict the sensitivity of patients with CC to immunotherapy and have potential applications in gene therapy to inhibit CC progression.

Diabetes, disability, and dementia risk: Results from the Hispanic Established Populations for the Epidemiologic Studies of the Elderly (H-EPESE).

BACKGROUND: Emerging research has elucidated pathophysiological relationships among diabetes, disability, cognitive impairment, and incident dementia. However, the relationships between diabetes, disability, and dementia have been largely underexamined in Latino populations, which have a disproportionate prevalence of diabetes and its complications. AIMS: This study examines diabetes as a risk factor for subsequent disability and dementia risk in a Mexican-origin older adult sample. METHODS: The data are drawn from eight waves (1993-2013) of the Hispanic Established Populations for the Epidemiologic Study of the Elderly (HEPESE; N = 3,050, mean age at baseline = 73.6 (±6.8)). Respondents' diabetes status at baseline was ascertained by self-report. Disability was assessed using eight functional domains assessed through the Lawton Instrumental Activities of Daily Living (IADL) Scale. Dementia risk was assessed using a Mini-Mental Status Exam (MMSE) score below 18 and the need for aid with at least two IADLs. We used multivariable Cox proportional hazards models to predict the relation between diabetes and time to disability, cognitive impairment, and incident dementia, adjusting for age at migration, socioeconomic status, acculturation, and health status. RESULTS: At baseline, diabetes prevalence was 28.1%, and 37.7% had IADL disability. Diabetes was associated with a higher risk of developing dementia (Hazard Ratio (HR) = 1.22, p < .001) over the approximetely 20 year study period. In addition, immigrants who migrated at age 50 or older had a higher dementia risk (HR = 1.35, p = .01) when compared to their US-born counterpart. CONCLUSION: Our results highlight the importance of better characterizing the role of diabetes and nativity in the co-occurrence of disability and dementia risk.

microRNA expression alteration after arsenic trioxide treatment in HepG-2 cells.

BACKGROUND AND AIM: More and more microRNA (miRNA) are found to be involved in tumor genesis and progress. Arsenic trioxide has been an effective chemotherapeutic drug in cancer therapy for many years. In this study, we aimed to find the miRNA involved in the mechanisms of arsenic trioxide treatment in cancer therapy. METHODS: We detected the expression profile of miRNA by miRNA microarray and quantitative real-time polymerase chain reaction. Cell viability assay, flow cytometry analysis, prediction of miRNA targets, Western blot analysis and luciferase reporter assay were carried out to determine the role of one selected miRNA, namely mir-29a, in affecting the biological behaviors of HepG-2 cells. RESULTS: Among the 677 human miRNA in the microarray, five miRNA were upregulated and four were downregulated in HepG-2 cells treated with arsenic trioxide compared to their controls. If only changes above two folds were considered, four miRNA were identified, namely miR-24, miR-29a, miR-30a and miR-210, which were all upregulated. Among them, miR-29a showed a positive therapeutic effect in liver cancer cells by inhibiting cell growth and inducing cell apoptosis, and PPM1D was confirmed to be the target gene of miR-29a. Furthermore, a synergy effect was detected between miR-29a and arsenic trioxide. CONCLUSIONS: Arsenic trioxide altered miRNA expression profile in HepG-2 cells. Among the altered miRNA, miR-29a seemed to take a role in the mechanism of arsenic trioxide in liver cancer therapy. The synergy effect between miR-29a and arsenic trioxide may offer this drug a new chance in cancer therapy by decreasing its dose and toxic side-effects.

Maternal human capital accumulation and children's well-being.

Research examining the intergenerational transmission of human capital is subject to two limitations. First, for the parental generation, most studies focus on formal education but fail to consider vocational training experience, which has more variation than formal educational attainment over the life course. Second, most studies have found consistent conclusions using income and occupation for the children's outcomes but have generated mixed findings regarding health and cognitive ability. This study aims to answer whether mothers' additional vocational training beyond formal education is beneficial to children's health and cognitive ability. Applying fixed-effects regression to the National Longitudinal Survey of Youth 1979 and the National Longitudinal Survey of Youth Child and Young Adults datasets, this study finds that mothers' human capital accumulation is positively associated with higher cognitive scores for both boys and girls, but does not significantly predict children's illnesses or behavior problems. These findings bear implications for policy aimed at mitigating the intergenerational cycles of disadvantages.

Metabolic Risk and Depression among Elderly Mexican Americans: The Roles of Nativity Status.

Objective: To evaluate the relationship between metabolic risk (MR) and depression in a sample of older Mexican Americans and examine whether the association differs by age at migration. Methods: Longitudinal study using data from the Hispanic Established Populations for the Epidemiologic Study of the Elderly (HEPESE) (N=807, mean age = 84.3). The analytical sample was compiled from wave 6 (2007) to wave 7 (2010-2011) of HEPESE. Random-effect logistic regression examined the association between MR and depression and tested the model stratified by nativity status and age at migration. Results: MR was associated with higher odds of depression for US-born Mexican Americans after controlling for potential confounders. Similarly, among Mexican Americans who migrated before age 20, MR was associated with higher odds of depression. Conclusion: The findings highlight the importance of age at migration when evaluating the health of foreign-born Mexican Americans from a life-course perspective. Particularly among Mexican Americans who migrated before age 20, those with MR were more vulnerable to depression than their counterparts without MR.

Nativity, Family, Disability: Results from the Hispanic Established Populations for the Epidemiologic Study of the Elderly.

Objectives: ativity and family support may influence attitudes and behaviors that delay or accelerate the disability process in older adults. The objectives of this study were twofold: 1) to evaluate nativity and migration cohort differences in trajectories of disability (assessed by activities of daily living [ADL]) among older Mexican Americans; and 2) to determine the role of objectively measured family support in the association between nativity, migration cohort, and disability changes over time. Methods: This is a longitudinal study with up to 18 years follow-up (1993-2011) using data from the Hispanic Established Populations for the Epidemiologic Study of the Elderly (N=2,785, mean age =72.4 years). Disability was assessed using self-reported limitations in activities of daily living (ADL). Nativity and migration cohort were self-reported. Family support was assessed by marital status and the number of their children participants saw each month. Linear growth curve models evaluated the trajectory of ADL disability over 18 years and assessed variations by nativity status, migration cohort and family support. Results: Foreign-born respondents who migrated before age 20 had more starting ADL limitations (ß= .36, P<.001) and accumulated disability faster (ß=.04, P<.01) compared with their US-born counterparts. In contrast, foreign-born respondents who migrated at later ages showed disability trajectories similar to US-born respondents. Married respondents had a lower level of disability (ß= -.14, P<.01) and a lower rate of accumulation over time (ß= -.02, P=.001) compared with participants who were not married. Discussion: Mexican Americans who migrate at younger ages may experience greater disability over time; however, family support may help mitigate the accumulation of disability among older Mexican Americans.

Regulation of Pancreatic Fibrosis by Acinar Cell-Derived Exosomal miR-130a-3p via Targeting of Stellate Cell PPAR-γ.

INTRODUCTION: As endogenous miRNA carriers, exosomes play a role in the pathophysiological processes of various diseases. However, their functions and regulation mechanisms in pancreatic fibrosis remain unclear. METHODS: In this study, an RNA microarray was used to detect differentially expressed exosomal miR-130a-3p in AR42J cells before and after taurolithocholate (TLC) treatment. mRNA-seq was used to screen differentially expressed genes before and after pancreatic stellate cell (PSC) activation. We used the STRING database to construct a protein-protein interaction (PPI) network for differentially expressed genes, used CytoNCA to analyze the centrality of the PPI network, and identified 10 essential proteins in the biological network. Then, the TargetScan and miRanda databases were used to predict the target genes of miR-130a-3p. The intersections of the target genes and the mRNAs encoding the 10 essential proteins were identified to construct miR-130a-3p/peroxisome proliferator-activated receptor gamma (PPAR-γ) pairs. Fluorescence labeling of exosomes and dynamic tracing showed that exosomes can fuse with the cell membranes of PSCs and transport miR-130a-3p into PSCs. A luciferase reporter gene assay was used to confirm that miR-130a-3p can bind to PPAR-γ to inhibit PPAR-γ expression. In vitro and in vivo functional experiments were performed for gain-of-function studies and loss-of-function studies, respectively. RESULTS: The studies showed that acinar cell-derived exosomal miR-130a-3p promotes PSC activation and collagen formation through targeting of stellate cellular PPAR-γ. Knockdown of miR-130a-3p significantly improved pancreatic fibrosis. Notably, miR-130a-3p knockdown reduced serum levels of hyaluronic acid (HA) and ß-amylase and increased the C-peptide level to protect endocrine and exocrine pancreatic functions and the function of endothelial cells. CONCLUSION: This study revealed that the exosomal miR-130a-3p/PPAR-γ axis participates in PSC activation and the mechanism of chronic pancreatitis (CP) with fibrosis, thus providing a potential new target for the treatment of chronic pancreatic fibrosis.

The nomogram based on the 6-lncRNA model can promote the prognosis prediction of patients with breast invasive carcinoma.

Long non-coding RNA (lncRNA) is a prognostic biomarker for many types of cancer. Here, we aimed to study the prognostic value of lncRNA in Breast Invasive Carcinoma (BRCA). We downloaded expression profiles from The Cancer Genome Atlas (TCGA) datasets. Subsequently, we screened the differentially expressed genes between normal tissues and tumor tissues. Univariate Cox, LASSO regression, and multivariate Cox regression analysis were used to construct a lncRNA prognostic model. Finally, a nomogram based on the lncRNAs model was developed, and weighted gene co-expression network analysis (WGCNA) was used to predict mRNAs related to the model, and to perform function and pathway enrichment. We constructed a 6-lncRNA prognostic model. Univariate and multivariate Cox regression analysis showed that the 6-lncRNA model could be used as an independent prognostic factor for BRCA patients. We developed a nomogram based on the lncRNAs model and age, and showed good performance in predicting the survival rates of BRCA patients. Also, functional pathway enrichment analysis showed that genes related to the model were enriched in cell cycle-related pathways. Tumor immune infiltration analysis showed that the types of immune cells and their expression levels in the high-risk group were significantly different from those in the low-risk group. In general, the 6-lncRNA prognostic model and nomogram could be used as a practical and reliable prognostic tool for invasive breast cancer.