The research was conducted at LSU Health Sciences Center New Orleans and the papers are entitled Neurotrophins enhance retinal pigment epithelial cell survival through neuroprotectin D1 signaling and Photoreceptor outer segment phagocytosis attenuates oxidative stress-induced apoptosis with concomitant neuroprotectin D1 synthesis. RPE cells are responsible for the renewal of the tips of photoreceptor cells (rods and cones) crucial to vision.

Neuroprotectin D1 is a messenger (mediator) discovered by Nicolas Bazan, MD, PhD, Boyd Professor, Ernest C. and Yvette C. Villere Professor of Ophthalmology, and Director of the Neuroscience Center of Excellence at LSU Health Sciences Center New Orleans, and his colleagues that represents one of the most powerful endogenous (made by the body) neuroprotective mediators known. Its precursor is DHA (docosahexaenoic acid), an essential fatty acid (must be provided by the diet) of the omega-3 fatty acid family enriched in RPE cells in the retina and brain. DHA is a target of oxidative stress in pathological conditions and Dr. Bazan's research recently showed that RPE cells create NPD1 in response to oxidative stress.

The LSUHSC scientists discovered that neurotrophins (small proteins critical in cell survival and death) trigger NPD1 synthesis. They demonstrate that the endogenous toxic component (A2E) that accumulates in the retina during aging and in retinal degenerations, including those due to gene mutations, can be counteracted by NPD1.

The LSUHSC research team conducted studies on the formation and action of NPD1 on a human transformed cell line called ARPE-19. They also used primary human RPE cells and found that they also synthesize NPD1. The researchers showed that neurotrophins regulate NPD1 by stimulating its production and also controlling its release. They found that the neurotrophin PEDF not only sparks the production of NPD1, but it acts synergistically with DHA indicating that the availability of the NPD1 initial precursor is critical for its synthesis.

To answer the question about whether or not NPD1 could prevent cell death caused by an excess of A2E known to accumulate in the RPE during aging and to be exaggerated in age-related macular degeneration, the researchers added NPD1 to an A2E-induced experimental model and found it not only stopped programmed cell death, but that the protective effects were present even six hours later. The team decided to explore whether oxidative stress triggered by another experimental condition, called serum starvation/H2O2/TNF, would be similarly inhibited. NPD1 also exerted protection in this experimental condition. Addition of NPD1 even eight hours after triggering oxidative stress resulted in protection. In a series of further experiments to delineate how NPD1 acts, the scientists found that NPD1 elicits a specific action rather than antioxidant activity to counteract A2E-induced cell death in RPE cells.

One of these papers reports also the discovery that the daily interaction of photoreceptors and RPE cells balance against damage is maintained by NPD1.

"The regulation of these proteins involved in cell survival or death shown by this research will help us define NPD1 survival bioactivity in the RPE cell," notes Dr. Bazan. "These events are clinically significant because they may allow the exploration of therapeutic interventions for retinal degenerative diseases such retinitis pigmentosa."

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The UCLA researchers divided the mice into two groups “ one set received a nimesulide-enriched diet for 10 months; the other was offered only regular mouse chow. Their analyses revealed that the nimesulide diet greatly reduced the number of late-stage PanINs in KrasG12D (10 percent of pancreatic ducts had PanIN-2 or -3 in KrasG12D mice on nimesulide diet versus 40 percent of pancreatic ducts had PanIN-2 or -3 in KrasG12D mice on normal diet).

Because the pancreases of mice were analyzed at 10 months, before the typical appearance of pancreatic tumors, additional studies will be needed for researchers to conclude whether or not nimesulide can delay the onset of or prevent pancreatic cancer.

With these results, I certainly wouldn ™t say everyone should be taking COX-2 inhibitors to protect against cancer, said Eibl. However, with additional studies, we may find COX-2 inhibitors could help prevent pancreatic cancer in high risk populations.

Pancreatic cancer is so deadly because it often goes undetected until it ™s too late, said Dr. Eibl. If a patient is at a high-risk for developing pancreatic cancer, a COX-2 inhibitor may offer some protection.

In the future, Dr. Eibl and others plan to study the long-term effects of nimesulide and additional COX-2 inhibitors on the onset and progression of pancreatic cancer.

This study was funded by the National Institutes of Health, the Jonsson Cancer Center Foundation at UCLA, and the Hirshberg Foundation for Pancreatic Cancer Research.

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