Microglial STING activation alleviates nerve injury-induced neuropathic pain in male but not female mice.

Microglia, resident immune cells in the central nervous system, play a role in neuroinflammation and the development of neuropathic pain. We found that the stimulator of interferon genes (STING) is predominantly expressed in spinal microglia and upregulated after peripheral nerve injury. However, mechanical allodynia, as a marker of neuropathic pain following peripheral nerve injury, did not require microglial STING expression. In contrast, STING activation by specific agonists (ADU-S100, 35 nmol) significantly alleviated neuropathic pain in male mice, but not female mice. STING activation in female mice leads to increase in proinflammatory cytokines that may counteract the analgesic effect of ADU-S100. Microglial STING expression and type I interferon-ß (IFN-ß) signaling were required for the analgesic effects of STING agonists in male mice. Mechanistically, downstream activation of TANK-binding kinase 1 (TBK1) and the production of IFN-ß, may partly account for the analgesic effect observed. These findings suggest that STING activation in spinal microglia could be a potential therapeutic intervention for neuropathic pain, particularly in males.

Single-cell analysis of dorsal root ganglia reveals metalloproteinase signaling in satellite glial cells and pain.

Satellite glial cells (SGCs) are among the most abundant non-neuronal cells in dorsal root ganglia (DRGs) and closely envelop sensory neurons that detect painful stimuli. However, little is still known about their homeostatic activities and their contribution to pain. Using single-cell RNA sequencing (scRNA-seq), we were able to obtain a unique transcriptional profile for SGCs. We found enriched expression of the tissue inhibitor metalloproteinase 3 (TIMP3) and other metalloproteinases in SGCs. Small interfering RNA and neutralizing antibody experiments revealed that TIMP3 modulates somatosensory stimuli. TIMP3 expression decreased after paclitaxel treatment, and its rescue by delivery of a recombinant TIMP3 protein reversed and prevented paclitaxel-induced pain. We also established that paclitaxel directly impacts metalloproteinase signaling in cultured SGCs, which may be used to identify potential new treatments for pain. Therefore, our results reveal a metalloproteinase signaling pathway in SGCs for proper processing of somatosensory stimuli and potential discovery of novel pain treatments.

The relationship between sleep quality, daytime sleepiness, and rapid eye movement obstructive sleep apnea (REM-OSA).

PURPOSE: The prevalence of rapid eye movement obstructive sleep apnea (REM-OSA) varies among reports. It remains unclear whether or not patients with REM-OSA experience more severe daytime sleepiness and poorer sleep quality than those with sleep-stage-independent obstructive sleep apnea (IND-OSA). We investigated the prevalence of REM-OSA in a Korean population sample and determined whether or not REM-OSA was associated with poor sleep quality and daytime sleepiness. METHOD: In this retrospective study. we defined "REM-OSA 1" as an apnea-hypopnea index (AHI) ≥ 5 and AHIREM/AHINREM ratio ≥ 2. Patients who also had an AHINREM < 15 were classified as "REM-OSA 2" and those with an AHINREM < 8 and REM sleep duration ≥ 10.5 min were classified as "REM-OSA 3." Patient characteristics, Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and polysomnography variables were compared between the REM-OSA and IND-OSA groups. RESULTS: Among 483 patients, the prevalence rates of REM-OSA 1-3 were 10.3%, 5.5%, and 2.2% respectively. OSA severity was significantly lower in REM-OSA 1-3 than in IND-OSA. The proportion of women was significantly higher in REM-OSA 1-3 than IND-OSA groups. Patients with REM-OSA 2 and 3 had a significantly lower body mass index than those with IND-OSA. Patients with moderate-to-severe REM-OSA had significantly higher PSQI scores than those with IND-OSA. The AHIREM was significantly correlated with the ESS and PSQI scores. CONCLUSIONS: Despite the relatively low prevalence and severity of REM-OSA, it may reduce sleep quality and increase daytime sleepiness in some patients.

Prediction of CML contents in the Maillard reaction products for casein-monosaccharides model.

Response surface methodology (RSM) was applied to predict the processing parameters of the casein-glucose/galactose Maillard reaction (MR) for determining the level of Nε-(1-carboxymethyl)-l-lysine (CML), one of the typically harmful dietary advanced glycation end products (AGEs). The effect of industrial heating time and temperature of the MR on casein-glucose reactant (CGR) and casein-galactose reactant (CGaR) was evaluated. An increase in temperature and time was associated with an increased level of CML. A heating time of 114.8/117.9min and a temperature of 145.1/148.8°C maximised the formation of CML on CGR/CGaR and resulted in a CML production of 12.0/14.0µg/mL. Evaluation of foam stability, SDS-PAGE, and energy filtering-TEM indicated that the CGR and CGaR had different characteristics. Moreover, level of intracellular reactive oxygen species was accumulated with increasing CML contents. In summary, RSM provided a basis for understanding CGR/CGaR-reactivity and for predicting the formation of CML in heat-treated milk products.