Protective effect of a novel clinical-grade small molecule necrosis inhibitor against oxidative stress and inflammation during islet transplantation.

Inhibition of mitochondrial reactive oxygen species (ROS) and subsequent damage-associated molecular patterns (DAMPs)-induced inflammatory responses could be a novel target in clinical islet transplantation. We investigated the protective effects of NecroX-7, a novel clinical-grade necrosis inhibitor that specifically targets mitochondrial ROS, against primary islet graft failure. Islets from heterozygote human islet amyloid polypeptide transgenic (hIAPP+/- ) mice and nonhuman primates (NHPs) were isolated or cultured with or without NecroX-7 in serum-deprived medium. Supplementation with NecroX-7 during hIAPP+/- mouse islet isolation markedly increased islet viability and adenosine triphosphate content, and attenuated ROS, transcription of c-Jun N-terminal kinases, high mobility group box 1, interleukin-1beta (IL-1 ß ), IL-6, and tumor necrosis factor-alpha. Supplementation of NecroX-7 during serum-deprived culture also protected hIAPP+/- mouse and NHP islets against impaired viability, serum deprivation-induced ROS, proinflammatory response, and accumulation of toxic IAPP oligomer. Supplementation with NecroX-7 during isolation or serum-deprived culture of hIAPP+/- mouse and NHP islets also improved posttransplant glycemia in the recipient streptozotocin-induced diabetic hIAPP-/- mice and BALB/c-nu/nu mice, respectively. In conclusion, pretransplant administration of NecroX-7 during islet isolation and serum-deprived culture suppressed mitochondrial ROS injury, generation of DAMPs-induced proinflammatory responses, and accumulation of toxic IAPP oligomers ex vivo, and improved posttransplant glycemia in vivo.

Geo-clustered chronic affinity: pathways from socio-economic disadvantages to health disparities.

OBJECTIVE: Our objective was to develop and test a new concept (affinity) analogous to multimorbidity of chronic conditions for individuals at census tract level in Memphis, TN. The use of affinity will improve the surveillance of multiple chronic conditions and facilitate the design of effective interventions. METHODS: We used publicly available chronic condition data (Center for Disease Control and Prevention 500 Cities project), socio-demographic data (US Census Bureau), and demographics data (Environmental Systems Research Institute). We examined the geographic pattern of the affinity of chronic conditions using global Moran's I and Getis-Ord Gi* statistics and its association with socio-economic disadvantage (poverty, unemployment, and crime) using robust regression models. We also used the most common behavioral factor, smoking, and other demographic factors (percent of the male population, percent of the population 67 years, and over and total population size) as control variables in the model. RESULTS: A geo-distinctive pattern of clustered chronic affinity associated with socio-economic deprivation was observed. Statistical results confirmed that neighborhoods with higher rates of crime, poverty, and unemployment were associated with an increased likelihood of having a higher affinity among major chronic conditions. With the inclusion of smoking in the model, however, only the crime prevalence was statistically significantly associated with the chronic affinity. CONCLUSION: Chronic affinity disadvantages were disproportionately accumulated in socially disadvantaged areas. We showed links between commonly co-observed chronic diseases at the population level and systematically explored the complexity of affinity and socio-economic disparities. Our affinity score, based on publicly available datasets, served as a surrogate for multimorbidity at the population level, which may assist policymakers and public health planners to identify urgent hot spots for chronic disease and allocate clinical, medical and healthcare resources efficiently.