The exocyst subunit Sec15 is critical for proper synaptic development and function at the Drosophila NMJ.

The exocyst protein complex is important for targeted vesicle fusion in a variety of cell types, however, its function in neurons is still not entirely known. We found that presynaptic knockdown (KD) of the exocyst component sec15 by transgenic RNAi expression caused a number of unexpected morphological and physiological defects in the synapse. These include the development of active zones (AZ) devoid of essential presynaptic proteins, an increase in the branching of the presynaptic arbor, the appearance of satellite boutons, and a decrease in the amplitude of stimulated postsynaptic currents as well as a decrease in the frequency of spontaneous synaptic vesicle release. We also found the release of extracellular vesicles from the presynaptic neuron was greatly diminished in the Sec15 KDs. These effects were mimicked by presynaptic knockdown of Rab11, a protein known to interact with the exocyst. sec15 RNAi expression caused an increase in phosphorylated Mothers against decapentaplegic (pMad) in the presynaptic terminal, an indication of enhanced bone morphogenic protein (BMP) signaling. Some morphological phenotypes caused by Sec15 knockdown were reduced by attenuation of BMP signaling through knockdown of wishful thinking (Wit), while other phenotypes were unaffected. Individual knockdown of multiple proteins of the exocyst complex also displayed a morphological phenotype similar to Sec15 KD. We conclude that Sec15, functioning as part of the exocyst complex, is critically important for proper formation and function of neuronal synapses. We propose a model in which Sec15 is involved in the trafficking of vesicles from the recycling endosome to the cell membrane as well as possibly trafficking extracellular vesicles for presynaptic release and these processes are necessary for the correct structure and function of the synapse.

Prevalence of potential interactions of medications, including herbs and supplements, before, during, and after chemotherapy in patients with breast and prostate cancer.

BACKGROUND: The use of herbs and supplements (HS) is common among patients with cancer, yet limited information exists about potential medication interactions (PMIs) with HS use around chemotherapy. METHODS: Patients with breast or prostate cancer who had recently finished chemotherapy at 2 academic medical centers were surveyed by telephone. Interviewers inquired about all medications, including HS, before, during, and after chemotherapy. Micromedex, Lexicomp, and Natural Medicines Comprehensive Database interaction software programs were used to determine PMIs. RESULTS: A total of 67 subjects (age range, 39-77 years) were evaluated in this study. Participants were primarily White patients (73%) with breast cancer (87%). The median number of medications was 11 (range, 2-28) during the entire study and was highest during chemotherapy (7; range, 2-22). Approximately four-fifths (84%) used HS. A total of 1747 PMIs were identified, and they represented 635 unique PMIs across all 3 timeframes, with most occurring during chemotherapy. Prescription-related PMIs (70%) were the most common type, and they were followed by HS-related (56%) and anticancer treatment-related PMIs (22%). Approximately half of the PMIs (54%) were categorized as moderate interactions, and more than one-third (38%) were categorized as major interactions. Patient use of HS increased from 51% during chemotherapy to 66% after chemotherapy, and this correlated with an increased prevalence of HS PMIs (46% to 60%). HS users were more likely to be at risk for a major PMI than non-HS users (92% vs 70%; P = .038). CONCLUSIONS: The use of HS remains prevalent among patients with cancer and may place them at risk for PMIs both during chemotherapy and after the completion of treatment. LAY SUMMARY: This study evaluates the risk of potential medication interactions for patients with breast or prostate cancer undergoing chemotherapy. The results show that patients often use herbs and supplements during treatment. Prescription medications are most often associated with medication interactions, which are followed by herb and supplement-related interactions. More than one-third of potential medication interactions are considered major. Patients should be educated about the risk of herb and supplement-related medication interactions during treatment.