Single cell transcriptomics in endocrine system physiology: example from the pancreas

The Network of Angiotensin Receptors in Breast Cancer

Cells ◽

10.3390/cells9061336 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1336

Author(s):

Filippo Acconcia

Keyword(s):

Breast Cancer ◽

Angiotensin Ii ◽

Current Knowledge ◽

Molecular System ◽

Endocrine System ◽

Renin Angiotensin System ◽

Angiotensin Receptors ◽

Transmembrane Receptors ◽

System Physiology ◽

Breast Breast Cancer

The renin-angiotensin system (RAS) is a network of proteins regulating many aspects of human physiology, including cardiovascular, pulmonary, and immune system physiology. The RAS is a complicated network of G-protein coupled receptors (GPCRs) (i.e., AT1R, AT2R, MASR, and MRGD) orchestrating the effects of several hormones (i.e., angiotensin II, angiotensin (1–7), and alamandine) produced by protease-based transmembrane receptors (ACE1 and ACE2). Two signaling axes have been identified in the RAS endocrine system that mediate the proliferative actions of angiotensin II (i.e., the AT1R-based pathway) or the anti-proliferative effects of RAS hormones (i.e., the AT2R-, MAS-, and MRGD-based pathways). Disruption of the balance between these two axes can cause different diseases (e.g., cardiovascular pathologies and the severe acute respiratory syndrome coronavirus 2- (SARS-CoV-2)-based COVID-19 disease). It is now accepted that all the components of the RAS endocrine system are expressed in cancer, including cancer of the breast. Breast cancer (BC) is a multifactorial pathology for which there is a continuous need to identify novel drugs. Here, I reviewed the possible roles of both axes of the RAS endocrine network as potential druggable pathways in BC. Remarkably, the analysis of the current knowledge of the different GPCRs of the RAS molecular system not only confirms that AT1R could be considered a drug target and that its inhibition by losartan and candesartan could be useful in the treatment of BC, but also identifies Mas-related GPCR member D (MRGD) as a druggable protein. Overall, the RAS of GPCRs offers multifaceted opportunities for the development of additional compounds for the treatment of BC.

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New Evidence on the Role of D-Aspartate Metabolism in Regulating Brain and Endocrine System Physiology: From Preclinical Observations to Clinical Applications

International Journal of Molecular Sciences ◽

10.3390/ijms21228718 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8718

Author(s):

Alessandro Usiello ◽

Maria Maddalena Di Fiore ◽

Arianna De Rosa ◽

Sara Falvo ◽

Francesco Errico ◽

...

Keyword(s):

Animal Studies ◽

Endocrine System ◽

Postnatal Life ◽

Functional Development ◽

The Central Nervous System ◽

High Concentrations ◽

System Physiology ◽

Metabolizing Enzyme

The endogenous amino acids serine and aspartate occur at high concentrations in free D-form in mammalian organs, including the central nervous system and endocrine glands. D-serine (D-Ser) is largely localized in the forebrain structures throughout pre and postnatal life. Pharmacologically, D-Ser plays a functional role by acting as an endogenous coagonist at N-methyl-D-aspartate receptors (NMDARs). Less is known about the role of free D-aspartate (D-Asp) in mammals. Notably, D-Asp has a specific temporal pattern of occurrence. In fact, free D-Asp is abundant during prenatal life and decreases greatly after birth in concomitance with the postnatal onset of D-Asp oxidase expression, which is the only enzyme known to control endogenous levels of this molecule. Conversely, in the endocrine system, D-Asp concentrations enhance after birth during its functional development, thereby suggesting an involvement of the amino acid in the regulation of hormone biosynthesis. The substantial binding affinity for the NMDAR glutamate site has led us to investigate the in vivo implications of D-Asp on NMDAR-mediated responses. Herein we review the physiological function of free D-Asp and of its metabolizing enzyme in regulating the functions of the brain and of the neuroendocrine system based on recent genetic and pharmacological human and animal studies.

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NR0B2 regulation during Primary Sclerosing Cholangitis defines a metabolic and pre-malignant reprogramming of Cholangiocyte

10.1101/2021.09.06.459063 ◽

2021 ◽

Author(s):

Christophe Desterke ◽

Cyrille Feray

Keyword(s):

Text Mining ◽

Single Cell ◽

Primary Sclerosing Cholangitis ◽

Sclerosing Cholangitis ◽

Farnesoid X Receptor ◽

Cholestatic Liver Disease ◽

System Physiology ◽

Cell Transcriptome ◽

Cell Trajectory ◽

Mining Work

SUMMARYPrimary Sclerosing Cholangitis (PSC) is an idiopathic, cholestatic liver disease that is characterized by persistent, progressive, biliary inflammation leading to cirrhosis. These patients present higher risk for developing bile duct cancers.Biomedical text-mining related to PSC symptoms like: biliary inflammation, biliary fibrosis, biliary cholestasis was initiated to collect gene associations with this pathophysiology. The text mining work was integrated in distinct omics data such as human transcriptome of PSC liver, Farnesoid X receptor (FXR) functional liver transcriptome and liver single cell transcriptome of the Abcb4-/- model of PSC. A molecular network implicated in abnormal hepatobiliary system physiology was built and confirming a major implication of Nr0b2 and its associated nuclear receptors like FXR in a metabolic cascade that could influence immune response. TNFRSF12A/TWEAK receptor, was found up regulated in PSC liver independently of FXR regulation and TWEAK signaling is known for its implication in pre-conditioning niche of cholangiocarcinoma. NR0B2 deregulation in PSC liver was found independent of gender, age and body mass index surrogates. At single cell level, Nr0b2 up regulation was found in cholangiocytes but not in hepatocytes. In affected cholangiocytes, the cell trajectory built on Nr0b2 expression, revealed implication of several metabolic pathways for detoxification like sulfur, glutathione derivative and monocarboxylic acid metabolisms. On this cell trajectory it was discovered some molecules potentially implicated in carcinogenesis like: GSTA3, ID2 and mainly TMEM45A a transmembrane molecule from golgi apparatus considered as oncogene in several cancers. All together, these observations found in humanPSC liver and in its murine models allowed to highlight an independent deregulation of NR0B2 with a metabolic and premalignant reprogramming of cholangiocytes.

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Electron microscopy of keratinocytes cultured on a collagen substrate used as an allograft for the treatment of chronic wounds

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100130158 ◽

1992 ◽

Vol 50 (2) ◽

pp. 1104-1105

Author(s):

Debby A. Jennings ◽

Michael J. Morykwas ◽

Louis C. Argenta

Keyword(s):

Electron Microscopy ◽

Cell Suspension ◽

Single Cell ◽

Chronic Wounds ◽

Mechanical Stability ◽

Uv Light ◽

Type I ◽

Single Cell Suspension ◽

Collagen Substrate ◽

Dermal Collagen

Grafts of cultured allogenic or autogenic keratlnocytes have proven to be an effective treatment of chronic wounds and burns. This study utilized a collagen substrate for keratinocyte and fibroblast attachment. The substrate provided mechanical stability and augmented graft manipulation onto the wound bed. Graft integrity was confirmed by light and transmission electron microscopy.Bovine Type I dermal collagen sheets (100 μm thick) were crosslinked with 254 nm UV light (13.5 Joules/cm2) to improve mechanical properties and reduce degradation. A single cell suspension of third passage neonatal foreskin fibroblasts were plated onto the collagen. Five days later, a single cell suspension of first passage neonatal foreskin keratinocytes were plated on the opposite side of the collagen. The grafts were cultured for one month.The grafts were fixed in phosphate buffered 4% formaldehyde/1% glutaraldehyde for 24 hours. Graft pieces were then washed in 0.13 M phosphate buffer, post-fixed in 1% osmium tetroxide, dehydrated, and embedded in Polybed 812.

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