The master cytokine TGF-β mediates tissue fibrosis associated with inflammation and tissue injury. TGF-β induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-β signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF-β-Smad2/3 signaling in fibroblast-mediated cardiac fibrosis has not been directly evaluated in vivo. Here, we examined pressure overload-induced cardiac fibrosis in fibroblast- and myofibroblast-specific inducible Cre-expressing mouse lines with selective deletion of the TGF-β receptors Tgfbr1/2, Smad2, or Smad3. Fibroblast-specific deletion of Tgfbr1/2 or Smad3, but not Smad2, markedly reduced the pressure overload-induced fibrotic response as well as fibrosis mediated by a heart-specific, latency-resistant TGF-β mutant transgene. Interestingly, cardiac fibroblast-specific deletion of Tgfbr1/2, but not Smad2/3, attenuated the cardiac hypertrophic response to pressure overload stimulation. Mechanistically, loss of Smad2/3 from tissue-resident fibroblasts attenuated injury-induced cellular expansion within the heart and the expression of fibrosis-mediating genes. Deletion of Smad2/3 or Tgfbr1/2 from cardiac fibroblasts similarly inhibited the gene program for fibrosis and extracellular matrix remodeling, although deletion of Tgfbr1/2 uniquely altered expression of an array of regulatory genes involved in cardiomyocyte homeostasis and disease compensation. These findings implicate TGF-β-Smad2/3 signaling in activated tissue-resident cardiac fibroblasts as principal mediators of the fibrotic response.

/pdf/fibroblast-specific-tgf-b-smad2-3-signaling-underlies-3qc083u0fc.pdf

Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis

Hepatitis B virus (HBV) infection substantially increases the risk of chronic liver disease and hepatocellular carcinoma in humans. RNA interference (RNAi) of virus-specific genes has emerged as a potential antiviral mechanism. Here we show that RNAi can be applied to inhibit production of HBV replicative intermediates in cell culture and in immunocompetent and immunodeficient mice transfected with an HBV plasmid. Cotransfection with plasmids expressing short hairpin RNAs (shRNAs) homologous to HBV mRNAs induced an RNAi response. Northern and Southern analyses of mouse liver RNA and DNA showed substantially reduced levels of HBV RNAs and replicated HBV genomes upon RNAi treatment. Secreted HBV surface antigen (HBsAg) was reduced by 94.2% in cell culture and 84.5% in mouse serum, whereas immunohistochemical detection of HBV core antigen (HBcAg) revealed >99% reduction in stained hepatocytes upon RNAi treatment. Thus, RNAi effectively inhibited replication initiation in cultured cells and mammalian liver, showing that such an approach could be useful in the treatment of viral diseases.

Inhibition of hepatitis B virus in mice by RNA interference

Esophageal cancer is the sixth leading cause of death from cancer and one of the least studied cancers worldwide. The global microRNA expression profile of esophageal cancer has not been reported previously. Here, for the first time, we have investigated expressed microRNAs in cryopreserved esophageal cancer tissues using advanced microRNA microarray techniques. Our microarray analyses identified seven microRNAs that could distinguish malignant esophageal cancer lesions from adjacent normal tissues. Some microRNAs could be correlated with the different clinicopathologic classifications. High expression of hsa-miR-103/107 correlated with poor survival by univariate analysis as well as by multivariate analysis. These results indicate that microRNA expression profiles are important diagnostic and prognostic markers of esophageal cancer, which might be analyzed simply using economical approaches such as reverse transcription-PCR.

https://cancerres.aacrjournals.org/content/canres/68/1/26.full.pdf

Distinctive MicroRNA Profiles Relating to Patient Survival in Esophageal Squamous Cell Carcinoma

We designed and constructed a genome-wide microarray with 22,987 70-mer oligonucleotides covering the presently known and predicted genes in the silkworm genome, and surveyed the gene expression in multiple silkworm tissues on day 3 of the fifth instar. Clusters of tissue-prevalent and tissue-specific genes and genes that are differentially expressed in different tissues were identified, and they reflect well major tissue-specific functions on the molecular level. The data presented in this study provide a new resource for annotating the silkworm genome.

/pdf/microarray-based-gene-expression-profiles-in-multiple-27n2y30y29.pdf

Microarray-based gene expression profiles in multiple tissues of the domesticated silkworm, Bombyx mori

Preeclampsia is a leading cause of maternal and fetal/neonatal mortality and morbidity worldwide. The early identification of patients with an increased risk for preeclampsia is therefore one of the most important goals in obstetrics. The availability of highly sensitive and specific physiologic and biochemical markers would allow not only the detection of patients at risk but also permit a close surveillance, an exact diagnosis, timely intervention (e.g. lung maturation), as well as simplified recruitment for future studies looking at therapeutic medications and additional prospective markers. Today, several markers may offer the potential to be used, most likely in a combinatory analysis, as predictors or diagnostic tools. We present here the current knowledge on the biology of preeclampsia and review several biochemical markers which may be used to monitor preeclampsia in a future, that, we hope, is not to distant from today.

/pdf/potential-markers-of-preeclampsia-a-review-58nbs7g2xt.pdf

Potential markers of preeclampsia – a review

Objective: Human placentae from normal and pre-eclamptic pregnancies were evaluated for possible changes in gene expression by microarray analysis to uncover new clues for the research of the etiology of pre-eclampsia. Methods: Placentae from five normal pregnancies and five pregnancies complicated by pre-eclampsia were collected. mRNA levels of five pre-eclamptic placentae were examined using genome-wide 70-mer oligonucleotide microarrays (CapitalBio, Beijing, China) in comparison with the pooled control consisting of total RNA from five normotensive placentae. Results: Ninety-six genes were found consistently down- or up-regulated in at least four pre-eclamptic samples. Most of them were related to an imbalance of reactive oxygen metabolites in placenta, abnormal trophoblast invasion, disorders of lipoprotein metabolism and signal transduction, or some that have been reported to have close correlation to the pathology of pre-eclampsia. The microarray data were also confirmed by the measurement of real-time PCR. Conclusion: DNA microarray is a high throughput and time-saving method to monitor altered gene expression. The results could provide interesting clues to the etiology of pre-eclampsia and lead to further studies in a more targeted fashion.

Genomewide oligonucleotide microarray analysis on placentae of pre-eclamptic pregnancies.

Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. However, the signaling functions of Smad2/3-Smad4 during TGF-beta-induced responses are obscure as TGF-beta also initiates a number of other signaling pathways. In this study, we systematically assessed the contribution of TGF-beta-Smad2/3-Smad4 signaling to both target gene transcription and apoptosis. Individual Smads were selectively knocked down in Hep3B cells by stable RNA interference (RNAi). We identified TGF-beta-responsive genes using genome-wide oligonucleotide microarrays and confirmed their dependency on Smad2, Smad3, or Smad4 by the combination of RNAi and microarray assay. The major finding from our microarray analysis was that of the 2,039 target genes seen to be regulated via TGF-beta induction, 190 were differentially transcriptionally controlled by Smad2-Smad4 and Smad3-Smad4 signaling and the latter control mechanism appeared to be functionally more important. We also found indirect evidence of competition between Smad2 and Smad3 for their activation when controlling the transcription of target genes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells.

Identification of the gene transcription and apoptosis mediated by TGF‐β‐Smad2/3‐Smad4 signaling

Hepatitis B virus (HBV) causes acute and chronic hepatitis and hepatocellular carcinoma. Small interfering RNA (siRNA) and lamivudine have been shown to have anti-HBV effects through different mechanisms. However, assessment of the genome-wide effects of siRNA and lamivudine on HBV-producing cell lines has not been reported, which may provide a clue to interrogate the HBV-cell interaction and to evaluate the siRNA's side effect as a potential drug. In the present study, we designed seven siRNAs based on the conserved HBV sequences and tested their effects on the expression of HBV genes following sorting of siRNA-positive cells. Among these seven siRNAs, siRNA-1 and siRNA-7 were found to effectively suppress HBV gene expression. We further addressed the global gene expression changes in stable HBV-producing cells induced by siRNA-1 and siRNA-7 by use of human genome-wide oligonucleotide microarrays. Data from the gene expression profiling indicated that siRNA-1 and siRNA-7 altered the expression of 54 and 499 genes, respectively, in HepG2.2.15 cells, which revealed that different siRNAs had various patterns of gene expression profiles and suggested a complicated influence of siRNAs on host cells. We further observed that 18 of these genes were suppressed by both siRNA-1 and siRNA-7. Interestingly, seven of these genes were originally activated by HBV, which suggested that these seven genes might be involved in the HBV-host cell interaction. Finally, we have compared the effects of siRNA and lamivudine on HBV and host cells, which revealed that siRNA is more effective at inhibiting HBV expression at the mRNA and protein level in vitro, and the gene expression profile of HepG2.2.15 cells treated by lamivudine is totally different from that seen with siRNA.

Genomic Analysis of Anti-Hepatitis B Virus (HBV) Activity by Small Interfering RNA and Lamivudine in Stable HBV-Producing Cells

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Genomewide oligonucleotide microarray analysis on placentae of pre-eclamptic pregnancies.

Identification of the gene transcription and apoptosis mediated by TGF‐β‐Smad2/3‐Smad4 signaling

Genomic Analysis of Anti-Hepatitis B Virus (HBV) Activity by Small Interfering RNA and Lamivudine in Stable HBV-Producing Cells