Targeted deletion of PAC1 receptors in retinal neurons enhances neuron loss and axonopathy in a model of multiple sclerosis and optic neuritis

Van, Christina; Condro, Michael C.; Ko, Henly H.; Hoang, Anh Q; Zhu, Ruoyan; Lov, Kenny; Ricaflanca, Patrick T; Diep, Anna; Nguyen, Nhat N.M.; Lipshutz, Gerald S.; MacKenzie-Graham, Allan; Waschek, James A.

doi:10.1016/j.nbd.2021.105524

Cited by 16 publications

(10 citation statements)

References 63 publications

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“…This has been demonstrated in numerous in vitro and in vivo studies (Reglodi et al 2011 , 2017 ). Recently, it has been shown that in addition to the long-known protective effects in models of stroke and Parkinson’s disease (Ohtaki et al 2008 ; Zheng et al 2021 ), PACAP is protective in models of spinal and bulbar muscular atrophy (Martinez-Rojas et al 2021 ), fetal alcohol syndrome (Shili et al 2021 ), diabetic neuropathy (Kiss et al 2021 ), optic neuritis in multiple sclerosis (Van et al 2021 ), and noise-induced hearing loss (Ruel et al 2021 ). The large body of evidence, showing that PACAP is protective in animal models of several diseases, places PACAP on the list of emerging protective therapeutic agents in neurodegenerative disorders (Cheng et al 2020 ; Soles-Tarres et al 2020 ) and stroke (Cherait et al 2021 ; Fang et al 2020 ; Sadanandan et al 2021 ; Zheng et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Distribution of PACAP and PAC1 Receptor in the Human Eye

et al. 2022

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Pituitary adenylate cyclase–activating polypeptide (PACAP) is a neuropeptide with widespread distribution and diverse biological functions. Several studies show that PACAP has strong cytoprotective effects mediated mostly through its specific PAC1 receptor (PAC1-R) and it plays important roles in several pathological conditions. Its distribution and altered expression are known in various human tissues, but there is no descriptive data about PACAP and its receptors in the human eyebulb. Since PACAP38 is the dominant form of the naturally occurring PACAP, our aim was to investigate the distribution of PACAP38-like immunoreactivity in the human eye and to describe the presence of PAC1-R. Semiquantitative evaluation was performed after routine histology and immunohistochemical labeling on human eye sections. Our results showed high level of immunopositivity in the corneal epithelium and endothelium. Within the vascular layer, the iris and the ciliary body had strong immunopositivity for both PACAP and PAC1-R. Several layers of the retina showed immunoreactivity for PACAP and PAC1-R, but the ganglion cell layer had a special pattern in the immunolabeling. Labeling was observed in the neuropil within the optic nerve in both cases and glial cells displayed immunoreactivity for PAC1-R. In summary, our study indicates the widespread occurrence of PACAP and its specific receptor in the human eye, implying that the results from in vitro and animal studies have translational value and most probably are also present in the human eye.

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Section: Introductionmentioning

confidence: 99%

Distribution of PACAP and PAC1 Receptor in the Human Eye

et al. 2022

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“…In fact, microglia are in constant communication with astrocytes to regulate the immune responses within the CNS (Morales et al 2021), and both PACAP and VIP play an important role in mediating the activity of astrocytes (Masmoudi-Kouki et al 2007). This is further validated in a recent study that demonstrated increased axonal pathology and expression of microglia activation markers following the conditional deletion of the PAC1 receptor in retinal neurons (Van et al 2021).…”

Section: Discussionmentioning

confidence: 77%

PACAP and VIP Mitigate Rotenone-Induced Inflammation in BV-2 Microglial Cells

2022

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Rotenone is a commercial pesticide commonly used to model Parkinson’s disease (PD) due to its ability to induce dopaminergic degeneration. Studies have confirmed that rotenone causes microglial activation, which seems to contribute to the toxic effects seen in rodent models. Pituitary adenylate cyclase–activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two structurally related neuropeptides that have robust neuroprotective and anti-inflammatory properties. However, their ability to regulate microglial activity in response to rotenone is not fully understood. Using rotenone as an inflammatory stimulus, we tested whether PACAP or VIP could mitigate microglial activation in BV2 microglial cells. Rotenone dose-dependently reduced cell viability and the percentage of apoptotic cells. It also increased the release of nitric oxide (NO) in culture media and the expression of microglial activation markers and pro-inflammatory markers, including CD11b, MMP-9 and IL-6, and heightened the endogenous levels of PACAP and its preferring receptor PAC1. Co-treatment with PACAP or VIP prevented rotenone-induced increase of NO, CD11b, MMP-9 and IL-6. These results indicate that both PACAP and VIP are able to prevent the pro-inflammatory effects of rotenone in BV2 cells, supporting the idea that these molecules can have therapeutic value in slowing down PD progression. Graphical Abstract

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“…ADCYAP1R1 has anti-inflammatory, neuroprotective and regenerative properties, and its expression may also be influenced by immune/inflammatory stimuli ( 18 ). It has been shown that deletion of ADCYAP1R1 in naïve mice results in the absence of retinal ganglion neurons and their dendrites, while increased axonal pathology and secondary increases in microglia/macrophages are also evident in the optic nerve ( 19 ). CDH19 is thought to be a member of calmodulin and establishes and maintains intercellular junctions ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

Identification by Bioinformatics Analysis of Potential Key Genes Related to the Progression and Prognosis of Gastric Cancer

Gao

Yang

2022

Front. Oncol.

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ObjectiveDespite increasingly sophisticated medical technology, the prognosis of patients with advanced gastric cancer is still not objectively certain. Therefore, it is urgent to identify new diagnostic and prognostic biomarkers. To identify potential critical genes related to gastric cancer’s staging mechanism and to the prognosis of gastric cancer.MethodsDynamic trend analysis was conducted to find genes with similar trends in gastric cancer staging in order to explore the differentially expressed genes in gastric cancer and identify the intersection of the results of the dynamic trend analysis. Functional predictive analysis were performed on the obtained genes to observe the expression of prognostic genes in gastric cancer and in gastric cancer stages as well as the correlation with tumor immune cell infiltration. Gastric cancer samples were collected and sequenced for follow-up analysis based on the results of the Cancer Genome Atlas (TCGA) database analysis.ResultsThe expression of genes enriched in module 0 had a similar trend in gastric cancer staging. 3213 differential genes were screened. A total of 50 intersection genes were obtained among genes with similar trends, of which only 10 genes have prognostic significance in gastric cancer. These 10 genes were correlated with macrophage infiltration in varying degrees. In addition, we found that AGT was significantly abnormally expressed in the results of sample sequencing. AGT was related to the occurrence of gastric cancer and interacted with brd9, golph3, nom1, klhl25, and psmd11.ConclusionAGT has prominent abnormal expression in gastric cancer and may promote gastric cancer progression. This study provides a new direction for further exploring potential biomarkers and molecular targeted gastric cancer therapy.

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Targeted deletion of PAC1 receptors in retinal neurons enhances neuron loss and axonopathy in a model of multiple sclerosis and optic neuritis

Cited by 16 publications

References 63 publications

Distribution of PACAP and PAC1 Receptor in the Human Eye

Distribution of PACAP and PAC1 Receptor in the Human Eye

PACAP and VIP Mitigate Rotenone-Induced Inflammation in BV-2 Microglial Cells

Identification by Bioinformatics Analysis of Potential Key Genes Related to the Progression and Prognosis of Gastric Cancer

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