Stanniocalcin-1 Reduced Intraocular Pressure in Two Models of Ocular Hypertension.

Purpose/Aim: Glaucomatous optic neuropathy (GON) remains the world's leading cause of irreversible blindness. Treatments including topical medications are directed at reducing intraocular pressure (IOP), the most significant risk factor for GON. Current medications, while generally effective, are limited by insufficient response and side-effects in some patients. In search of a more targeted therapy that acts downstream of existing medications that has a potential for a lower side effect profile, our laboratory has identified Stanniocalcin-1 (STC-1), a multifunctional hormone, as an effector molecule in latanoprost-mediated IOP reduction with similar IOP-lowering efficacy as latanoprost in normotensive mice.Materials and methods: To investigate whether STC-1 can also reduce IOP in ocular hypertensive mice, we used a steroid-induced ocular hypertensive mouse model characterized by trabecular meshwork dysfunction as well as the DBA/2J mouse as an inherited model of pigment dispersion and secondary angle closure. Steroid-induced ocular hypertension was induced by weekly injections of dexamethasone into the conjunctival fornix of wild-type C57BL/6J mice (6-8 months old). After confirmation of the steroid response, mice were administered STC-1 or phosphate buffered saline (PBS) topically once daily for six weeks. For DBA/2J mice (14 months old), after baseline IOP measurements, mice were treated topically once daily with STC-1 or PBS for 5 days and IOP was assessed twice daily.Results: In steroid-induced ocular hypertensive mice, STC-1 lowered IOP by 26% (P < .001, week three) and maintained this level of IOP reduction throughout the remainder of the treatment period (P < .001, week six). In DBA/2J mice, STC-1 lowered IOP by 37% (P < .001).Conclusions: Together, these data show that STC-1 reduced IOP in two models of ocular hypertension with different mechanisms of outflow obstruction.

Stanniocalcin-1 (STC-1), a downstream effector molecule in latanoprost signaling, acts independent of the FP receptor for intraocular pressure reduction.

Prostaglandin F2 alpha (PGF2α) analogues such as latanoprost are common first-line intraocular pressure (IOP) lowering medications. However, their clinical use is limited in some patient populations due to minimal or no IOP lowering response or side effects. In searching for a more targeted approach for IOP reduction, our lab recently identified Stanniocalcin-1 (STC-1) as a molecule that was required for latanoprost-mediated IOP reduction and also acted as a stand-alone IOP lowering agent. In order to determine whether latanoprost and STC-1 were equivalent and/or additive for IOP reduction, we treated C57BL/6J mice with one or a combination of these agents and measured IOP. Importance of the FP receptor for latanoprost- and STC-1-mediated IOP reduction was examined in C57BL/6J mice utilizing the pharmacologic FP receptor inhibitor AL-8810 as well as FP receptor knockout mice generated in our laboratory. Latanoprost-free acid (LFA) and STC-1 reduced IOP to a similar degree and were non-additive in C57BL/6J mice. As expected, the IOP lowering effects of LFA were abrogated by pharmacologic inhibition of the FP receptor with AL-8810 and in FP receptor knockout mice. In contrast, STC-1 maintained IOP-lowering effects in the presence of AL-8810 and also in FP receptor knockout mice. These results suggest that LFA and STC-1 show equivalent and non-additive IOP reduction in C57BL/6J mice and that unlike LFA, STC-1-mediated IOP reduction occurs independent of the FP receptor.

Induction and Prevention of Gastric Cancer with Combined Helicobacter Pylori and Capsaicin Administration and DFMO Treatment, Respectively.

Gastric cancer risk evolves over time due to environmental, dietary, and lifestyle changes, including Helicobacter pylori (H. pylori) infection and consumption of hot peppers (i.e., capsaicin). H. pylori infection promotes gastric mucosal injury in the early phase of capsaicin exposure. This relationship suggests a need to investigate the mechanism of how both H. pylori infection and capsaicin contribute to gastric inflammation and lead to gastric cancer. C57-Balb/c mice were infected with the H. pylori (SS1) strain and then fed capsaicin (0.05% or 0.2 g/kg/day) or not. Consequently, tumor size and phenotype were analyzed to determine the molecular mechanism driving the shift from gastritis to stomach cancer. Moreover, we used 2-difluoromethylornithine (DFMO) in mice to prevent gastric tumorigenesis by reducing inflammation and promoting recovery of disease-free stasis. This study provides evidence showing that a combination of H. pylori infection and capsaicin consumption leads to gastric carcinogenesis mediated through interleukin-6 (IL-6) stimulation with an incidence rate of 50%. The anti-inflammatory role of DFMO highlights the injurious effect of inflammation in gastric cancer development and the need to reduce gastric inflammation for cancer prevention by inhibiting IL-6. Accordingly, preventive measures such as reduced capsaicin consumption, H. pylori clearance, and DFMO treatment may lessen gastric cancer incidence.