Unfolded protein response-mediated modulation of mesenchymal stem cells

The endoplasmic reticulum (ER) receives unfolded proteins predestined for the secretory pathway or to be incorporated as transmembrane proteins. The ER has to accommodate the proper folding and glycosylation of these proteins and also to properly incorporate transmembrane proteins. However, under various circumstances, the proteins shuttling through the ER can be misfolded and undergo aggregation, which causes activation of the unfolded protein response (UPR). The UPR is mediated through three primary pathways: activating transcription factor-6, inositol-requiring enzyme-1 (IRE1), and PKR-like endoplasmic reticulum kinase, which up-regulate ER folding chaperones and temporarily suppress protein translation. The UPR can be both cytoprotective and/or cytotoxic depending on the duration of UPR activation and the type of host cell. Proteostasis controls stem cell function, while stress responses affect stem cell identity and differentiation. The present review aimed to explore and discuss the effects of the UPR pathways on mesenchymal stem cells

Alkaloid production and response to natural adverse conditions in Peganum harmala : in silico transcriptome analyses

Peganum harmala is a valuable wild plant that grows and survives under adverse conditions and produces pharmaceutical alkaloid metabolites. Using different assemblers to develop a transcriptome improves the quality of assembled transcriptome. In this study, a concrete and accurate method for detecting stress-responsive transcripts by comparing stress-related gene ontology (GO) terms and public domains was designed. An integrated transcriptome for P. harmala including 42656 coding sequences was created by merging de novo assembled transcriptomes. Around 35000 transcripts were annotated with more than 90% resemblance to three closely related species of Citrus , which confirmed the robustness of the assembled transcriptome; 4853 stress-responsive transcripts were identified. CYP82 involved in alkaloid biosynthesis showed a higher number of transcripts in P. harmala than in other plants, indicating its diverse alkaloid biosynthesis attributes. Transcription factors (TFs) and regulatory elements with 3887 transcripts comprised 9% of the transcriptome. Among the TFs of the integrated transcriptome, cystein2/histidine2 (C2H2) and WD40 repeat families were the most abundant. The Kyoto Encyclopedia of Genes and Genomes (KEGG) MAPK (mitogen-activated protein kinase) signaling map and the plant hormone signal transduction map showed the highest assigned genes to these pathways, suggesting their potential stress resistance. The P. harmala whole-transcriptome survey provides important resources and paves the way for functional and comparative genomic studies on this plant to discover stress-tolerance-related markers and response mechanisms in stress physiology, phytochemistry, ecology, biodiversity, and evolution. P. harmala can be a potential model for studying adverse environmental cues and metabolite biosynthesis and a major source for the production of various alkaloids

Reactivation of Camp Pathway by Pde4D Inhibition Represents A Novel Druggable Axis for Overcoming Tamoxifen Resistance in Er-Positive Breast Cancer

Purpose: Tamoxifen remains an important hormonal therapy for ER-positive breast cancer; however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms of tamoxifen resistance and provide actionable drug targets overcoming resistance. Experimental Design: Whole-transcriptome sequencing, downstream pathway analysis, and drug repositioning approaches were used to identify novel modulators [here: phosphodiesterase 4D (PDE4D)] of tamoxifen resistance. Clinical data involving tamoxifen-treated patients with ER-positive breast cancer were used to assess the impact of PDE4D in tamoxifen resistance. Tamoxifen sensitization role of PDE4D was tested in vitro and in vivo. Cytobiology, biochemistry, and functional genomics tools were used to elucidate the mechanisms of PDE4D-mediated tamoxifen resistance. Results: PDE4D, which hydrolyzes cyclic AMP (cAMP), was significantly overexpressed in both MCF-7 and T47D tamoxifen-resistant (TamR) cells. Higher PDE4D expression predicted worse survival in tamoxifen-treated patients with breast cancer (n = 469, P = 0.0036 for DMFS; n = 561, P = 0.0229 for RFS) and remained an independent prognostic factor for RFS in multivariate analysis (n = 132, P = 0.049). Inhibition of PDE4D by either siRNAs or pharmacologic inhibitors (dipyridamole and Gebr-7b) restored tamoxifen sensitivity. Sensitization to tamoxifen is achieved via cAMP-mediated induction of unfolded protein response/ER stress pathway leading to activation of p38/JNK signaling and apoptosis. Remarkably, acetylsalicylic acid (aspirin) was predicted to be a tamoxifen sensitizer using a drug repositioning approach and was shown to reverse resistance by targeting PDE4D/cAMP/ER stress axis. Finally, combining PDE4D inhibitors and tamoxifen suppressed tumor growth better than individual groups in vivo. Conclusions: PDE4D plays a pivotal role in acquired tamoxifen resistance via blocking cAMP/ER stress/p38-JNK signaling and apoptosis. (C) 2018 AACR.WoSScopu

Alkaloid production and response to natural adverse conditions in <i>Peganum harmala</i>: <i>in silico</i> transcriptome analyses

Peganum harmala is a valuable wild plant that grows and survives under adverse conditions and produces pharmaceutical alkaloid metabolites. Using different assemblers to develop a transcriptome improves the quality of assembled transcriptome. In this study, a concrete and accurate method for detecting stress-responsive transcripts by comparing stress-related gene ontology (GO) terms and public domains was designed. An integrated transcriptome for P. harmala including 42 656 coding sequences was created by merging de novo assembled transcriptomes. Around 35 000 transcripts were annotated with more than 90% resemblance to three closely related species of Citrus, which confirmed the robustness of the assembled transcriptome; 4853 stress responsive transcripts were identified. CYP82 involved in alkaloid biosynthesis showed a higher number of transcripts in P. harmala than in other plants, indicating its diverse alkaloid biosynthesis attributes. Transcription factors (TFs) and regulatory elements with 3887 transcripts comprised 9% of the transcriptome. Among the TFs of the integrated transcriptome, cystein2/histidine2 (C2H2) and WD40 repeat families were the most abundant. The Kyoto Encyclopedia of Genes and Genomes (KEGG) MAPK (mitogen-activated protein kinase) signaling map and the plant hormone signal transduction map showed the highest assigned genes to these pathways, suggesting their potential stress resistance. The P. harmala whole-transcriptome survey provides important resources and paves the way for functional and comparative genomic studies on this plant to discover stress-tolerance-related markers and response mechanisms in stress physiology, phytochemistry, ecology, biodiversity, and evolution. P. harmala can be a potential model for studying adverse environmental cues and metabolite biosynthesis and a major source for the production of various alkaloids