Ischemic stroke contributes to the majority of brain injuries and remains to be a leading cause of death and long-term disability. Despite the devastating pathology and high incidence of disease, there remain only few treatment options (tPA and endovascular procedures), which may be hampered by time dependent administration among a variety of other factors. Promising research of glutamate receptor antagonists has been unsuccessful in clinical trial. But, the mechanism by which glutamate receptors initiate injury by excessive calcium overload has spurred investigation of new and potentially successful candidates for stroke therapy. Acid sensing ion channels (ASICs) may contribute to poor stroke prognosis due to localized drop in brain pH, resulting in excessive calcium overload, independent of glutamate activation. Accumulating studies targeting ASICs have underscored the importance of understanding inhibition, regulation, desensitization and trafficking of this channel and its role in disease. This review will discuss potential directions in translational ASIC research for future stroke therapies.

Objective The expression of NILCO molecules (Notch, IL-1, and leptin crosstalk outcome) and the association with obesity were investigated in types I and II endometrial cancer (EmCa). Additionally, the involvement of NILCO in leptin-induced invasiveness of EmCa cells was investigated. Methods The expression of NILCO mRNAs and proteins were analyzed in EmCa from African-American (n = 29) and Chinese patients (tissue array, n = 120 cases). The role of NILCO in leptin-induced invasion of Ishikawa and An3ca EmCa cells was investigated using Notch, IL-1, and leptin signaling inhibitors. Results NILCO molecules were expressed higher in type II EmCa, regardless of ethnic background or obesity status of patients. NILCO proteins were mainly localized in the cellular membrane and cytoplasm of type II EmCa. Additionally, EmCa from obese African-American patients showed higher levels of NILCO molecules than EmCa from lean patients. Notably, leptin-induced EmCa cell invasion was abrogated by NILCO inhibitors. Conclusion Type II EmCa expressed higher NILCO molecules, which may suggest it is involved in the progression of the more aggressive EmCa phenotype. Obesity was associated with higher expression of NILCO molecules in EmCa. Leptin-induced cell invasion was dependent on NILCO. Hence, NILCO might be involved in tumor progression and could represent a new target/biomarker for type II EmCa.

Cultured neuronal cell lines can express properties of mature neurons if properly differentiated. Although the precise mechanisms underlying neuronal differentiation are not fully understood, the expression and activation of ion channels, particularly those of Ca2+-permeable channels, have been suggested to play a role. In this study, we explored the presence and characterized the properties of acid-sensing ion channels (ASICs) in NS20Y cells, a neuronal cell line previously used for the study of neuronal differentiation. In addition, the potential role of ASICs in cell differentiation was explored. Reverse Transcription Polymerase Chain Reaction and Western blot revealed the presence of ASIC1 subunits in these cells. Fast drops of extracellular pH activated transient inward currents which were blocked, in a dose dependent manner, by amiloride, a non-selective ASIC blocker, and by Psalmotoxin-1 (PcTX1), a specific inhibitor for homomeric ASIC1a and heteromeric ASIC1a/2b channels. Incubation of cells with PcTX1 significantly reduced the differentiation of NS20Y cells induced by cpt-cAMP, as evidenced by decreased neurite length, dendritic complexity, decreased expression of functional voltage gated Na+ channels. Consistent with ASIC1a inhibition, ASIC1a knockdown with small interference RNA significantly attenuates cpt-cAMP-induced increase of neurite outgrowth. In summary, we described the presence of functional ASICs in NS20Y cells and demonstrate that ASIC1a plays a role in the differentiation of these cells.

Acid-sensing ion channels (ASICs) are cation channels activated by protons. ASIC1a, a primary ASIC subunit in the brain, was recently characterized in the olfactory bulb. The present study tested the hypothesis that ASIC1a is essential for normal olfactory function. Olfactory behavior of wild-type (WT) and ASIC1-/- mice was evaluated by using three standard olfactory tests: (1) the buried food test, (2) the olfactory habituation test, and (3) the olfactory preference test. In buried food test, ASIC1-/- mice had significantly longer latency to uncover buried food than WT mice. In olfactory habituation test, ASIC1-/- mice had increased sniffing time with acidic odorants. In olfactory preference test, ASIC1-/- mice did not exhibit normal avoidance behavior for 2, 5- dihydro-2, 4, 5-trimethylthiazoline (TMT). Consistent with ASIC1 knockout, ASIC1 inhibition by nasal administration of PcTX1 increased the latency for WT mice to uncover the buried food. Together, these findings suggest a key role for ASIC1a in normal olfactory function.

Obesity is a pandemic in Western countries and has a significant impact on endometrial cancer (EmCa) incidence and prognosis. Although EmCa is more common in Caucasian women, higher mortality is found in African Americans who also show higher incidence of obesity. The reasons for this cancer health disparity are not completely understood. Obesity is characterized by high levels of leptin. Leptin signaling may play a key role in the progression of the more aggressive form of EmCa, Type II, which is independent from hormonal cues. We have shown that leptin induces a signaling crosstalk in breast cancer with oncogenic and angiogenic factors (NILCO: Notch, IL-1 and Leptin Crosstalk Outcome). Hence, we hypothesize that NILCO could play an important role in Type II Emca developed by obese African American women. However, no data on NILCO signaling in EmCa is currently available. Real-Time PCR, Immunohistochemistry and Western Blot analyses were used to determine whether NILCO components are differentially expressed in EmCa biopsies (Type I vs Type II EnCa) obtained from obese African American women. All tissue samples had a paired control sample from adjacent non-tumor endometrial tissue determined by pathologists. The tissue samples (n=29) were obtained from Grady Memorial Hospital, Atlanta, GA. Patient's written informed consent was obtained for all samples collected as well as IRB approval from Morehouse School of Medicine, Atlanta, GA. In addition, commercially available EmCa tissue arrays from Chinese patients were co-examined for the expression of NILCO. Biopsy features included age, grading, and TNM staging. However, no body weight or body mass index information was available. Each array contained 150 cores, including 75 cases in duplicate. Overall, NILCO molecules were expressed higher in Type II EmCa regardless of obesity status. Notably, Type II EmCa from obese African American women showed the highest expression of NILCO. Present data suggest for the first time that NILCO could be instrumental for the development of EmCa; more specifically for obesity-related Type II EmCa, and may play a role as potential biomarkers for the disease. Citation Format: Danielle Daley-Brown, Gabriela Oprea-Ilies, Regina Lee, Kiara T. Vann, Viola Lanier, Alexander Quarshie, James Lillard, Roland Pattillo, Ruben Rene Gonzalez-Perez. NILCO: A marker for obesity-related endometrial cancer in African American women. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C78.