The Double-stranded RNA–dependent Protein Kinase Differentially Regulates Insulin Receptor Substrates 1 and 2 in HepG2 Cells

The RNA-dependent protein kinase (PKR), initially known as a virus infection response protein, is found to differentially regulate two major players in the insulin signaling pathway, IRS1 and IRS2. PKR up-regulates the inhibitory phosphorylation of IRS1 and the expression of IRS2 at the transcriptional level

Synergy analysis reveals association between insulin signaling and desmoplakin expression in palmitate treated HepG2 cells.

The regulation of complex cellular activities in palmitate treated HepG2 cells, and the ensuing cytotoxic phenotype, involves cooperative interactions between genes. While previous approaches have largely focused on identifying individual target genes, elucidating interacting genes has thus far remained elusive. We applied the concept of information synergy to reconstruct a "gene-cooperativity" network for palmititate-induced cytotoxicity in liver cells. Our approach integrated gene expression data with metabolic profiles to select a subset of genes for network reconstruction. Subsequent analysis of the network revealed insulin signaling as the most significantly enriched pathway, and desmoplakin (DSP) as its top neighbor. We determined that palmitate significantly reduces DSP expression, and treatment with insulin restores the lost expression of DSP. Insulin resistance is a common pathological feature of fatty liver and related ailments, whereas loss of DSP has been noted in liver carcinoma. Reduced DSP expression can lead to loss of cell-cell adhesion via desmosomes, and disrupt the keratin intermediate filament network. Our findings suggest that DSP expression may be perturbed by palmitate and, along with insulin resistance, may play a role in palmitate induced cytotoxicity, and serve as potential targets for further studies on non-alcoholic fatty liver disease (NAFLD)

Trigonotis guilielmii A. Gray

原著和名: タチカメバサウ科名: ムラサキ科 = Boraginaceae採集地: 長野県 松本市 袴越山 (信濃 松本市 袴越山)採集日: 1979/6/2採集者: 萩庭丈壽整理番号: JH001328国立科学博物館整理番号: TNS-VS-95132

Role of fibulin-5 insufficiency and prolapse progression on murine vaginal biomechanical function

AbstractThe vagina plays a critical role in supporting the pelvic organs and loss of support leads to pelvic organ prolapse. It is unknown what microstructural changes influence prolapse progression nor how decreased elastic fibers contributes to vaginal remodeling and smooth muscle contractility. The objective for this study was to evaluate the effect of fibulin-5 haploinsufficiency, and deficiency with progressive prolapse on the biaxial contractile and biomechanical function of the murine vagina. Vaginas from wildtype (n = 13), haploinsufficient (n = 13), and deficient mice with grade 1 (n = 9) and grade 2 or 3 (n = 9) prolapse were explanted for biaxial contractile and biomechanical testing. Multiaxial histology (n = 3/group) evaluated elastic and collagen fiber microstructure. Western blotting quantified protein expression (n = 6/group). A one-way ANOVA or Kruskal–Wallis test evaluated statistical significance. Pearson’s or Spearman’s test determined correlations with prolapse grade. Axial contractility decreased with fibulin-5 deficiency and POP (p &lt; 0.001), negatively correlated with prolapse grade (ρ = − 0.80; p &lt; 0.001), and positively correlated with muscularis elastin area fraction (ρ = − 0.78; p = 0.004). Circumferential (ρ = 0.71; p &lt; 0.001) and axial (ρ = 0.69; p &lt; 0.001) vaginal wall stresses positively correlated with prolapse grade. These findings demonstrated that fibulin-5 deficiency and prolapse progression decreased vaginal contractility and increased vaginal wall stress. Future work is needed to better understand the processes that contribute to prolapse progression in order to guide diagnostic, preventative, and treatment strategies.</jats:p

Discovering long noncoding RNA predictors of anticancer drug sensitivity beyond protein-coding genes

Significance Identification of genomic biomarkers that predict response to anticancer agents is the central research problem of cancer precision medicine. While the vast majority of the human genome encodes long noncoding RNAs (lncRNAs) as compared to protein-coding genes, thus far the characterization of lncRNAs as potential biomarkers has proved challenging. Here, we leverage data from large-scale cancer cell line screens to model response to hundreds of drugs as a function of lncRNA expression or somatic alteration. By carefully accounting for the confounding effects of tissue type, neighboring genes, and established biomarkers, the lncRNA models predict response to most drugs better than existing biomarkers. Thus, our framework can be applied for the discovery of lncRNAs as pharmacogenomic biomarkers in cancer research.</jats:p

Anti-Müllerian hormone treatment enhances oocyte quality, embryonic development and live birth rate

Abstract The anti-Müllerian hormone (AMH) produced by the granulosa cells of growing follicles is critical for folliculogenesis and is clinically used as a diagnostic and prognostic marker of female fertility. Previous studies report that AMH-pretreatment in mice creates a pool of quiescent follicles that are released following superovulation, resulting in an increased number of ovulated oocytes. However, the quality and developmental competency of oocytes derived from AMH-induced accumulated follicles as well as the effect of AMH treatment on live birth are not known. This study reports that AMH priming positively affects oocyte maturation and early embryonic development culminating in higher number of live births. Our results show that AMH treatment results in good-quality oocytes with greater developmental competence that enhances embryonic development resulting in blastocysts with higher gene expression. The transcriptomic analysis of oocytes from AMH-primed mice compared with those of control mice reveal that AMH upregulates a large number of genes and pathways associated with oocyte quality and embryonic development. Mitochondrial function is the most affected pathway by AMH priming, which is supported by more abundant active mitochondria, mitochondrial DNA content and adenosine triphosphate levels in oocytes and embryos isolated from AMH-primed animals compared with control animals. These studies for the first time provide an insight into the overall impact of AMH on female fertility and highlight the critical knowledge necessary to develop AMH as a therapeutic option to improve female fertility.</jats:p

Ecological interactions in breast cancer: Cell facilitation promotes growth and survival under drug pressure

AbstractThe interplay of positive and negative interactions between drug sensitive and resistant cells influences the effectiveness of treatment in heterogeneous cancer cell populations. In a study of isogenic estrogen receptor positive (ER+) breast cancer cell lineages sensitive and resistant to ribociclib-induced CDK4/6 inhibition in mono- and co-culture, we find that sensitive cells grow and compete more effectively in the absence of treatment. During treatment with ribociclib, sensitive cells survive and proliferate better when grown together with resistant cells than when grown in monoculture, termed facilitation in ecology. Both liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays and single cell RNA-sequencing (scRNAseq) indicate that resistant cell production of estradiol, a highly active estrogen metabolite, is the mechanism of facilitation. Higher estradiol production by resistant cells drives a shift in sensitive cell phenotype to a resistant cell state in coculture. Adding estradiol in monoculture provides sensitive cells with increased resistance to therapy, and cancels facilitation in coculture. Mathematical modeling quantifies the strength of competition and facilitation and predicts that blocking facilitation has the potential to control both resistant and sensitive cell populations and inhibit the emergence of a refractory population.</jats:p

Palmitate-Induced IRE1–XBP1–ZEB Signaling Represses Desmoplakin Expression and Promotes Cancer Cell Migration

Abstract Elevated uptake of saturated fatty acid palmitate is associated with metastatic progression of cancer cells; however, the precise signaling mechanism behind the phenomenon is unclear. The loss of cell adhesion proteins, such as desmoplakin (DSP), is a key driving event in the transformation of cancer cells to more aggressive phenotypes. Here, we investigated the mechanism by which palmitate induces the loss of DSP in liver and breast cancer cells. We propose that palmitate activates the IRE1–XBP1 branch of the endoplasmic reticulum (ER) stress pathway to upregulate the ZEB transcription factor, leading to transcriptional repression of DSP. Using liver and breast cancer cells treated with palmitate, we found loss of DSP leads to increased cell migration independent of E-cadherin. We report that the ZEB family of transcription factors function as direct transcriptional repressors of DSP. CRISPR-mediated knockdown of IRE1 confirmed that the transcription of ZEB, loss of DSP, and enhanced migration in the presence of palmitate is dependent on the IRE1–XBP1 pathway. In addition, by analyzing the somatic expression and copy number variation profiles of over 11,000 tumor samples, we corroborate our hypothesis and establish the clinical relevance of DSP loss via ZEB in human cancers. Implications: Provides mechanistic link on palmitate-induced activation of IRE1α to cancer cell migration. </jats:sec