Project description:Verteporfin (VP) inhibts colon cancer growth in vivo and in cell lines by inducing high molecular weight oligomerization of proteins. The antitumor effect of VP is independent of its YAP inhibitor activity. Tumor hypoxia contributes partly to antitumor effect of VP by impairing clearance of VP-induced high molecular weight aggregates.
Project description:The ventral pallidum (VP) is critical for motivated behaviors. While contemporary work has begun to elucidate the functional diversity of VP neurons, the molecular heterogeneity underlying this functional diversity remains incompletely understood. We used snRNA-seq and in situ hybridization to define the transcriptional taxonomy of VP cell types in mice, macaques, and baboons. We found transcriptional conservation between all three species, within the broader neurochemical cell types. Unique dopaminoceptive and cholinergic subclusters were identified and conserved across both primate species but had no homolog in mice. This harmonized consensus VP cellular atlas will pave the way for understanding the structure and function of the VP and identified key neuropeptides, neurotransmitters, and neuro receptors that could be targeted within specific VP cell types for functional investigations.
Project description:Atherosclerosis, characterized by the buildup of plaque in arteries, is a major cause of cardiovascular mortality worldwide, as there is no efficient strategy for targeted therapy. However, we have developed a new drug delivery platform called MoNP, which is loaded with VP, a potent inhibitor of YAP/TAZ signaling. To investigate the MoNP-VP treatment effect, EC were pretreated with MoNP or MoNP-VP then induced the inflammation by TNFalpha. After TNFalpha treatment, the cells were collected and extracted the RNA for RNA sequencing (RNA-Seq). The results showed that MoNP-VP significantly decreased the expression of YAP/TAZ-targeted genes and inflammatory markers while upregulating atheroprotective genes. Overall, these findings suggest that MoNP-VP has the potential to serve as an effective drug delivery platform for atherosclerosis.
Project description:Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we reveal that intestinal GUCY2C is selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons, in mice and humans. GUCY2CHigh neuropod cells associate with co-cultured dorsal root ganglia neurons and induce hyperexcitability, reducing the rheobase and increasing the resulting number of evoked action potentials. Conversely, the GUCY2C agonist linaclotide eliminated neuronal hyperexcitability produced by GUCY2C-sufficient, but not GUCY2C-deficient, neuropod cells, an effect independent of bulk epithelial cells or extracellular cGMP. Genetic elimination of intestinal GUCY2C amplified nociceptive signaling and VP that was comparable to chemically-induced VP but refractory to linaclotide. Importantly, eliminating GUCY2C selectively in neuropod cells also increased nociceptive signaling and VP that was refractory to linaclotide. In the context of loss of GUCY2C hormones in patients with VP, these observations suggest a specific role for neuropod GUCY2C signaling in the pathophysiology and treatment of these pain syndromes.
Project description:Differences in DNA-methylation between VP- and UV-MCCs mainly refer to heterogeneity in carcinogenesis rather than an origin in utterly different cell types. Indeed, a principal component derived scoring suggest an epithelial for UV-MCC as well as VP-MCC cell lines.
Project description:Global gene expression analysis of FACS-purified CD31+CD146+ vascular progenitors (VP) derived from (a) human embryonic stem cells (VP-hESC), (b) adult fibroblast derived induced pluripotent stem cells (VP-AdF-iPSC), (c) stromal primed cord blood CD34+ myeloid progenitor derived iPSC (VP-sp-CB-iPSC), (d) corresponding starting fibroblasts and myeloid progenitors, (e) human umbilical vein endothelial cells, and (f) human dermal microvascular endothelial cells. Total RNA was harvested from (a) adult fibroblasts, (b) human myeloid progenitors: Non-nucloefected CD34+ CB cells that were expanded with growth factors from Day -3 until Day 0 and harvested, (c) FACS-purified CD31+CD146+ vascular progenitors (VP) that were differentiated from human embryonic stem cells (hESC), (d) VP differentiated from low passage stromal-primed episomal iPSC derived from growth-factor activated cord blood myeloid progenitors, (e) VP differentiated from iPSC derived from adult fibroblasts, (f) human umbilical vein endothelial cells, and (g) human dermal microvascular endothelial cells.. Illumina HumanHT-12 V4.0 expression beadchips were used for all analyses in this series. Three or independent samples of each sample type were each run on individual microarrays.
