Search bioRxivSearch

bioRxiv · 10.1101/2020.06.27.175026

Intense expression of Neurokinin-1 Receptor is associated with Urothelial carcinoma

Abstract

I+ntroductionSubstance P (SP)/ Neurokinin-1 Receptor (NK-1R), induces inflammatory reactions in peripheral tissues but its regulatory effects in target tissues are dependent on receptor signaling. SP has a high affinity for the NK-1 receptor, to which it binds preferentially. SP/NK-1R complex plays a key role in the interaction in the onset of pain and inflammation. ObjectiveThe aim of this study was to investigate the expression of NK-1R in Urotheilial carcinoma and its association with cancer progression. MethodThe study included ten biopsy samples of Urinary bladder, obtained retrospectively from a tertiary care hospital of Lahore. An Immunohistochemical study was performed using monoclonal antibodies against NK-1R. The presence or absence of staining and the intensity of the immunoreactivity were noted, as well as the number and type of cells. Evaluation of the Immunohistochemical expression was determined by the semi-quantitative method and scored. ResultNK-1 receptor was intensely expressed in patients with higher grade Urotheilial carcinoma. The cases clinically diagnosed as High Grade Urotheilial Carcinoma showed intense expression of NK-1R. However, the cases clinically diagnosed as low grade Urotheilial carcinoma showed very weak staining with NK-1R. However, the normal margins of the same tissue showed negative expression. ConclusionsElevated expression of NK-1R was associated with advanced stage of urothelial carcinoma. It is the first study to our knowledge to report this association. It may serve as a good diagnostic as well as prognostic marker and therapeutic strategy.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

mehboob, r., Hassan, a., Perveen, S., Gilani, S. A., Waseem, H., Ahmad, f. J., Akram, J.. 2020-06-28. Intense expression of Neurokinin-1 Receptor is associated with Urothelial carcinoma. https://doi.org/10.1101/2020.06.27.175026

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

NAE1-Dependent Protein Neddylation Preserves Endothelial Identity and Vascular Integrity

Background: Endothelial dysfunction is a central driver of cardiovascular and inflammatory diseases, yet the post-translational mechanisms that preserve endothelial homeostasis remain incompletely understood. Protein neddylation, the covalent conjugation of a ubiquitin-like modifier, regulates diverse cellular processes, yet its physiological role in the vascular endothelium remains unknown. This study investigated whether protein neddylation is required to preserve endothelial identity and vascular homeostasis. Methods: We generated tamoxifen-inducible endothelial-specific Nae1 knockout mice to inhibit neddylation and combined bulk RNA sequencing, single-cell and single-nucleus transcriptomics, quantitative proteomics, biochemical analyses, and gain- and loss-of-function approaches to define the role of endothelial neddylation in vascular homeostasis and inflammatory injury. Results: Endothelial-specific Nae1 deletion caused rapid mortality associated with vascular leakage, platelet accumulation, inflammation, and multi-organ injury. Multi-omics analyses demonstrated profound loss of endothelial identity, characterized by suppression of core endothelial programs and activation of inflammatory, procoagulant, and pyroptotic pathways. Single-cell analyses revealed progressive endothelial dysfunction culminating in depletion of the endothelial population and remodeling of the vascular niche. Mechanistically, endothelial neddylation deficiency activated gasdermin D (GSDMD)- and gasdermin E (GSDME)-dependent pyroptosis, whereas dual inhibition of GSDMD and GSDME markedly attenuated inflammatory transcriptomic remodeling, vascular injury, hepatocyte death, immune cell infiltration, and platelet accumulation. Translational analyses demonstrated reduced endothelial neddylation in experimental endotoxemia and decreased expression of neddylation pathway components in human atherosclerosis and COVID-19 datasets. Conversely, restoration of endothelial neddylation partially reversed inflammatory endothelial transcriptomic reprogramming in vivo. Conclusions: NAE1-dependent protein neddylation is an essential regulator of endothelial identity and vascular integrity. Loss of endothelial neddylation promotes gasdermin-dependent pyroptosis and thrombo-inflammatory vascular injury, whereas restoration of the neddylation pathway mitigates inflammatory endothelial dysfunction. These findings identify endothelial neddylation as a fundamental mechanism maintaining vascular homeostasis and a potential therapeutic target for cardiovascular and inflammatory diseases.

pathology

Fragile X Premutation rCGG Repeats Impairs Synaptic Growth and Synaptic Transmission at Drosophila larval Neuromuscular Junction

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disease manifesting in the premutation (PM) carriers of the FMR1 gene with alleles bearing 55-200 CGG repeats. The discovery of a broad spectrum of clinical and cell developmental abnormalities among PM carriers with or without FXTAS, and in model systems suggests that neurodegeneration seen in FXTAS could be the inevitable end-result of pathophysiological processes set during early development. Hence, it is imperative to trace early pathological abnormalities. Our previous studies have shown that transgenic Drosophila carrying human-derived fragile X premutation-length CGG repeats are sufficient to cause neurodegeneration. Here, we used the same transgenic Drosophila model to understand the effects of fragile X premutation-length CGG repeats on the structure and function of the developing nervous system. We show that presynaptic expression of the premutation length CGG repeats restricts synaptic growth, reduces the number of synaptic boutons, leads to aberrant presynaptic varicosities, and impairs synaptic transmission at the larval neuromuscular junctions (NMJs). The postsynaptic analysis shows both glutamate receptor and subsynaptic reticulum proteins are normal. However, a high percentage of boutons show the reduced density of Bruchpilot protein, a key component of presynaptic active zones required for vesicle release. The electrophysiological analysis shows a significant reduction in the quantal content, a measure of total synaptic vesicles released per excitation potential. Together these findings endorse that synapse perturbation caused by rCGG repeats mediate presynaptically during larval NMJ development.

pathology

Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors

YAP1 regulates cell plasticity during liver injury, regeneration and cancer, but its role in liver development is unknown. YAP1 activity was detected in biliary cells and in cells at the hepato-biliary bifurcation in single-cell RNA-sequencing analysis of developing livers. Hepatoblast deletion of Yap1 led to no impairment in Notch-driven SOX9+ ductal plate formation, but prevented the formation of the abutting second layer of SOX9+ ductal cells, blocking the formation of a patent intrahepatic biliary tree. Intriguingly, the mice survived for 8 months with severe cholestatic injury and without any hepatocyte-to-biliary transdifferentiation. Ductular reaction in the perihilar region suggested extrahepatic biliary proliferation likely seeking the missing intrahepatic biliary network. Long-term survival of these mice occurred through hepatocyte adaptation via reduced metabolic and synthetic function including altered bile acid metabolism and transport. Overall, we show YAP1 as a key regulator of bile duct development while highlighting a profound adaptive capability of hepatocytes.

pathology