Inflammasomes are multiprotein complexes that trigger the activation of caspases-1 and subsequently the maturation of proinflammatory cytokines interleukin-1β and interleukin-18. These cytokines play ...a critical role in mediating inflammation and innate immunity response. Among various inflammasome complexes, the NLRP3 inflammasome is the best characterized, which has been demonstrated as a crucial role in various diseases. Here, we review recently described mechanisms that are involved in the activation and regulation of NLRP3 inflammasome. In addition, we summarize the recent researches on the role of NLRP3 inflammasome in central nervous system (CNS) diseases, including traumatic brain injury, ischemic stroke and hemorrhagic stroke, brain tumor, neurodegenerative diseases, and other CNS diseases. In conclusion, the NLRP3 inflammasome may be a promising therapeutic target for these CNS diseases.
Neuronal apoptosis is considered to be a crucial therapeutic target against early brain injury (EBI) after subarachnoid hemorrhage (SAH). Emerging evidence indicates that Exendin-4 (Ex-4), a ...glucagon-like peptide 1 receptor (GLP-1R) agonist, plays a neuroprotective role in cerebrovascular disease. This study was conducted in order to verify the neuroprotective role of EX-4 in EBI after SAH in rats. The endovascular perforation model of SAH was performed in Sprague-Dawley rats (n = 153). Ex-4 was intraperitoneally injected 1 h after SAH induction in the rats (SAH + Ex-4). To elucidate the underlying molecular mechanism, small interfering ribonucleic acid (siRNA) for GLP-1R and a specific inhibitor of PI3K, LY294002, were injected intracerebroventricularly into SAH + Ex-4 rats before induction of SAH (n = 6 per group). SAH grading evaluation, immunohistochemistry, Western blots, neurobehavioral assessment, and Fluoro-Jade C (FJC) staining experiments were performed. Expression of GLP-1R was significantly increased and mainly expressed in neurons at 24 h after SAH induction. Administration of Ex-4 significantly improved both short- and long-term neurobehavior in SAH + Ex-4 group compared to SAH + Vehicle group after SAH. Ex-4 treatment significantly increased the expression of GLP-1R, PI3K, p-Akt, Bcl-xl, and Bcl-2, while at the same time was found to decrease expression of Bax in the brain. Effects of Ex-4 were reversed by the intervention of GLP-1R siRNA and LY294002 in SAH + Ex-4+GLP-1R siRNA and SAH + Ex-4+LY294002 groups, respectively. In conclusion, the neuroprotective effect of Ex-4 in EBI after SAH was mediated by attenuation of neuronal apoptosis via GLP-1R/PI3K/Akt signaling pathway, therefore EX-4 should be further investigated as a potential therapeutic agent in stroke patients.
•Ex-4 significantly improved neurological function after SAH.•GLP-1R mainly expressed in neurons after SAH.•Ex-4 did not increased risk of hypoglycemia after SAH in SD rats.•Ex-4 improved spatial learning capacity and reference memory after SAH.•The anti-apoptotic effect of Ex-4 was mediated via GLP-1R/PI3K/Akt pathway.
Oxidative stress and neuronal apoptosis have been demonstrated to be key features in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have indicated that Mas receptor ...activation initiates an anti-oxidative and anti-apoptotic role in the brain. However, whether Mas activation can attenuate oxidative stress and neuronal apoptosis after SAH remains unknown. To investigate the beneficial effect of Mas on oxidative stress injury and neuronal apoptosis induced by SAH, a total of 196 rats were subjected to an endovascular perforation model of SAH. AVE 0991 (AVE), a selective agonist of Mas, was administered intranasally 1 h after SAH induction. A779, a selective inhibitor of Mas, and small interfering ribonucleic acid (siRNA) for UCP-2 were administered by intracerebroventricular (i.c.v) injection at 1 h and 48 h before SAH induction respectively. Neurological tests, immunofluorescence, TUNEL, Fluoro-Jade C, DHE staining, and Western blot experiments were performed. We found that Mas activation with AVE significantly improved neurobehavioral scores and reduced oxidative stress and neuronal apoptosis in SAH+AVE group compared with SAH+vehicle group. Moreover, AVE treatment significantly promoted phosphorylation of CREB and the expression UCP-2, as well as upregulated expression of Bcl-2 and downregulation of Romo-1 and Bax. The protective effects of AVE were reversed by i.c.v injection of A779 and UCP-2 siRNA in SAH+AVE+A779 and SAH+AVE+UCP-2 siRNA groups, respectively. In conclusion, our data provides evidence that Mas activation with AVE reduces oxidative stress injury and neuronal apoptosis through Mas/PKA/p-CREB/UCP-2 pathway after SAH. Furthermore, our study indicates that Mas may be a novel therapeutic treatment target in early brain injury of SAH.
Up to 80% of the human genome produces "dark matter" RNAs, most of which are noncapped RNAs (napRNAs) that frequently act as noncoding RNAs (ncRNAs) to modulate gene expression. Here, by developing a ...method, NAP-seq, to globally profile the full-length sequences of napRNAs with various terminal modifications at single-nucleotide resolution, we reveal diverse classes of structured ncRNAs. We discover stably expressed linear intron RNAs (sliRNAs), a class of snoRNA-intron RNAs (snotrons), a class of RNAs embedded in miRNA spacers (misRNAs) and thousands of previously uncharacterized structured napRNAs in humans and mice. These napRNAs undergo dynamic changes in response to various stimuli and differentiation stages. Importantly, we show that a structured napRNA regulates myoblast differentiation and a napRNA DINAP interacts with dyskerin pseudouridine synthase 1 (DKC1) to promote cell proliferation by maintaining DKC1 protein stability. Our approach establishes a paradigm for discovering various classes of ncRNAs with regulatory functions.
In patients with primary hyperaldosteronism (PA), adrenal vein sampling (AVS) can identify patients suitable for unilateral adrenalectomy. However, in AVS with an indeterminate ...aldosterone‐to‐cortisol lateralization (ACL) ratio of 3.0–4.0, clinical guidance is unclear. The authors screened all patients undergoing AVS at the Cleveland Clinic from October 2010 to January 2021 and identified 18 patients with indeterminate ACL results. Ten underwent adrenalectomy and eight continued medical management. The surgical group was younger (58.5 vs. 68 years, p = .17), and more likely to have a unilateral imaging adrenal abnormality (90% vs. 38%, p = .043) and a lower contralateral suppression index (0.63 vs. 1.1, p = .14). Post‐treatment, the surgical group had a significant reduction in diastolic blood pressure (–5.5 mmHg, p = .043) and aldosterone (4.40 vs. 35.80 ng/mL, p = .035) and required fewer anti‐hypertensive medications (2 vs. 3, p = .015). These findings may support the benefit of adrenalectomy in a select group of patients with indeterminate ACL.
3 Additional data collected for further analysis included the patients’ general condition, comorbidities, PN characteristics, and clinical scores, such as Investigator Global Assessment (IGA), ...Peak-Numerical Rating Scale (Peak-NRS), Dermatology Life Quality Index (DLQI), and Hospital Anxiety and Depression Scale (HADS). Based on previous research, we selected 18 distinct diseases to investigate, including common systemic diseases in the Chinese community, dermatologic diseases, allergic diseases, and mental health disorders potentially associated with PN. ...adolescents demonstrated a lower risk of comorbid coronary heart disease (odds ratio OR, 0.127, 95% confidence interval CI, 0.025–0.641), and a higher risk of comorbid atopic stigmata (OR, 4.110, 95% CI, 1.271–13.290). ...a lower occurrence rate of systemic, mental, and certain allergic disorders was observed, such as hypertension in adults (3.4% in Chinese PN, 31.61% in German PN, and 25.2% in Chinese general population), which indicates a noteworthy gap in the data collection efforts.
Compelling evidence has indicated that imbalance between apoptosis and autophagy may be involved in subarachnoid hemorrhage (SAH). We aimed to investigate the effects and mechanisms of melatonin in ...the homeostasis of apoptosis and autophagy. One-hundred and forty-eight male Sprague-Dawley rats were intraperitoneally injected with melatonin or vehicle 2 h after SAH induction. Western blotting and an immunofluorescent assay were performed to detect the expression of apoptosis- and autophagy-related proteins. The neuroprotective effect of melatonin attenuating SAH-induced neurological deficit and brain edema may be associated with the suppression of SAH-induced neuronal apoptosis and autophagy. Furthermore, melatonin inhibited the cleavage of mammalian sterile 20-like kinase 1 (MST1) protein by reducing reactive oxygen species (ROS) content. These effects of melatonin on regulating the homeostasis between apoptosis and autophagy could be reversed by an MST1 agonist, chelerythrine, via enhancement of MST1 cleavage. In conclusion, exogenous melatonin alleviates SAH-induced early brain injury (EBI) by suppressing excessive neuronal apoptosis and autophagy. The underlying mechanism may, at least in part, involve the ROS-MST1 pathway.
Pseudomonas aeruginosa
(
P. aeruginosa
) is a phenazine-producing pathogen recognized for its biofilm-mediated antibiotic resistance, showing up to 1000 times higher resistance compared to planktonic ...cells. In particular, it is shown that a phenazine called pyocyanin promotes antibiotic tolerance in
P. aeruginosa
cultures by upregulating efflux pumps and inducing biofilm formation. Therefore, real-time study of phenazine production in response to antibiotics could offer new insights for early detection and management of the infection. Toward this goal, this work demonstrates real-time monitoring of
P. aeruginosa
colony biofilms challenged by antibiotics using electrochemical sensors based on direct laser functionalization of laser induced graphene (LIG) with gold (Au) nanostructures. Specifically, two routes for functionalization of the LIG electrodes with Au-containing solutions are studied: electroless deposition and direct laser functionalization (E-Au/LIG and L-Au/LIG, respectively). While both methods show comparable sensitivity (1.276 vs 1.205
μ
A
μ
M
−1
), E-Au/LIG has bactericidal effects which make it unsuitable as a sensor material. The effect of antibiotics (gentamicin as a model drug) on the production rate of phenazines before (i.e., in planktonic phase) or after biofilm formation is studied. The sensor data confirms that the
P. aeruginosa
biofilms are at least 100 times more tolerant to the antibiotic compared to planktonic cells. The biosensors are developed using a scalable and facile manufacturing approach and may pave the way toward simple-to-use antibiotic susceptibility testing devices for early infection diagnosis and real-time study of antibiotic resistance evolution.
Highlights
A low-cost electrochemical sensor for real time monitoring of the effect of antibiotics on phenazine production in
P. aeruginosa
biofilms is developed.
The gold nanocrystals improve the performance of LIG-based sensors.
Two routes for functionalization of LIG with gold are studied which show different properties.
The real time sensor data shows that pyocyanin promotes cell survival when exposed to antibiotics.
PDF
