Vol 2-5 Commentary

Commentary: SU9516 increases α7β1 Integrin and Ameliorates Disease Progression in the mdx Mouse Model of Duchenne Muscular Dystrophy.

Apurva Sarathy1, Andreia M. Nunes1,2, Tatiana M. Fontelonga1, Tracy Y. Ogata1 and Dean J. Burkin1.

1Department of Pharmacology, University of Nevada, Reno School of Medicine, NV 89557, USA
2Departamento de Biologia Animal, Centro de Ecologia, Evolução e Alterações Ambientais, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisbon, Portugal.

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Vol 2-5 Review

A Closer Look at the Preclinical Experience of RP5063 in Pulmonary Arterial Hypertension

Laxminarayan Bhat1* and Dany Salvail2

1Reviva Pharmaceuticals, Inc., Santa Clara, CA, USA
2IPS Therapeutique Inc., Sherbrooke, Quebec, Canada

Pulmonary arterial hypertension (PAH) is a chronic, debilitating condition with a 5- to 7-year survival rate of approximately 50% following diagnosis. It is defined by pulmonary vasculature constriction and remodeling, and its pathobiology involves dysfunctional signaling of the serotonin (5-HT) receptors, 5-HT2A/2B/7 in the pulmonary arteries. RP5063 is a novel, multimodal dopamine (D)–serotonin (5-HT) stabilizer with partial agonist activity for D2/3/4 and 5-HT1A/2A antagonist activity for 5-HT2B/2C/6/7, and moderate affinity for the serotonin transporter (SERT). It received orphan status by the US Food and Drug Administration in 2016 to treat PAH. Two recent preclinical studies evaluated the effectiveness of RP5063 in PAH-induced rat models. The monocrotaline (MCT)-induced PAH model involved treatment with RP5063 (1, 3, and 10 mg/kg twice daily [BID]) over 28 days. The Sugen-hypoxia (SuHx)-induced PAH model involved treatment with RP5063 (10 and 20 mg/kg BID) over 21 days starting at Day 14 following induction. Both models demonstrated that RP5063 promoted significant functional improvements and structural changes in the pulmonary vasculature. RP5063 limited induced increases of proinflammatory cytokines in the MCT model, and limited leukotriene B4 levels, arterial obliteration, and prevented plexiform lesion formation in the SuHx model. A follow on MCT study examining the effectiveness of RP5063 alone and in combination with standard treatments corroborated these single-agent data and helped to define the framework for the clinical development of this compound. This review explores these studies, their underlying nuances, and the underlying pharmacologic rationale for the effects produced by RP5063.

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Vol 2-5 Mini Review

Diagnostic tests for caprine arthritis-encephalitis virus (CAEV) infection

Po-An Tu1, 2, Jen-Wen Shiau1, Fang-Yu Lai2, Shen-Shyuan Yang3, and Pei-Hwa Wang2*

1Hsinchu Branch, Livestock Research Institute, Council of Agriculture, Executive Yuan, No. 207-5, Bi-tou-mian, Wu-hoo village, Si-hoo Township, Miao-li County 36848, Taiwan.
2Department of Animal Science and Technology, National Taiwan University, No. 50, Ln. 155, Sec. 3, Keelung Rd., Taipei City 10617, Taiwan.
3Hualein Animal Propagation Station, Livestock Research Institute, Council of Agriculture, No. 38, Chiang Road, Sec. 6, Chiang, Hualien 97362, Taiwan.

Caprine arthritis and encephalitis (CAE) is an economically important viral disease that causes chronic inflammatory disease in goats. At present, the diagnosis of caprine arthritis-encephalitis virus (CAEV) infection is usually obtained through serological testing or molecular techniques, while the serological agar gel immunodiffusion test (AGID) and enzyme-linked immunosorbent assay (ELISA) testing focus on the detection of CAEV antibodies, the PCR and isothermal amplification methods directly detect the proviral sequence of CAEV. The use of Western blot is still considered a “gold standard” in CAEV serology. The delayed seroconversion or intermittent antibodies and the genetic heterogeneity of regional virus strains affect the effectiveness of diagnosis by the serological and molecular methods, respectively. Here, we review some of the most recent developments in diagnostic methods and their use in both laboratory and field diagnosis.

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Vol 2-5 Commentary

Commentary: "Alpha-enolase (ENO1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis"

Moitza Principe1,2, Simone Borgoni1,2, Francesco Novelli1-3

1Department of Molecular Biotechnology and Health Sciences, University of Turin, Italy
2Center for Experimental Research and Medical Studies (CeRMS), Azienda Universitaria Ospedaliera Città della Salute e della Scienza di Torino, Italy
3Molecular Biotechnology Center, University of Turin, Turin, Italy

 We have previously shown that in pancreatic ductal adenocarcinoma (PDA) cells, the glycolytic enzyme alpha-enolase (ENO1) also acts as a plasminogen receptor and promotes invasion and metastasis formation. Silencing of ENO1 in PDA cells induces oxidative stress, senescence and profoundly modifies PDA cell metabolism. Although anti-ENO1 antibodies inhibit PDA cell migration and invasion, little is known about the role of ENO1 in regulating cell-cell and cell-matrix contacts. We recently investigated the effect of ENO1 silencing on the proteome of PDA cells, and there was a significant downregulation of proteins involved in cell-cell and cell-matrix adhesion, including alphaV/beta3 integrin in ENO1-silenced PDA cells. These changes impaired the ability of ENO1-silenced cells to adhere to collagen I and IV and fibronectin, and caused an increase in RGD (tripeptide Arg-Gly-Asp)-independent adhesion to vitronectin (VN) via urokinase plasminogen activator receptor (uPAR). Binding of uPAR to VN triggers integrin-mediated signals, which results in ERK1/2 and Rac activation, accumulation of ROS (Reactive Oxygen Species) and senescence. In ENO1-silenced cancer cells, the use of an anti-uPAR antibody led to reduced ROS production and senescence, and an increase in cell apoptosis. Overall, a decrease of in vitro and in vivo cell migration and invasion of ENO1-silenced PDA cells was observed. This commentary summarizes new data demonstrating that ENO1 promotes PDA survival, migration and metastasis by cooperating with integrins and uPAR. These data represent a springboard for a novel therapeutic strategy to counteract PDA progression based on combined targeting of integrins, uPAR and ENO1.

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Vol 2-5 Mini Review

Inherited LRP2 dysfunction in human disease and animal models

Renata Kozyraki1 and Olivier Cases1

1INSERM UMRS_1138, Centre de Recherche des Cordeliers, Paris-Diderot University, France

Gp330/Megalin/Low-Density Lipoprotein Receptor-Related Protein 2 (LRP2) is an endocytic receptor that plays multiple roles in embryonic and adult tissues. It allows the cellular uptake of various bioactive molecules, morphogens, vitamins and hormones. Lack or dysfunction of the receptor affects renal protein reabsorption, lung function, brain and eye development in both man and experimental models. Mutations in LRP2 cause the polymalformative Donnai-Barrow syndrome, a rare autosomal recessive condition, combining developmental delay, facial dysmorphology, hearing defects, high myopia and low-molecular weight proteinuria.

We here summarize current knowledge on the receptor action. We particularly focus on the LRP2-associated face and eye anomalies and discuss how the receptor and its interacting proteins, including the multiligand receptor Cubilin (CUBN) may promote health or cause disease.

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