Introduction The main objective of this study was to explore the mechanism of nicotine improving cognitive impairments in ischemic rats. Methods Twenty adult male Sprague–Dawley (SD) rats underwent ischemic model surgery by injecting endothelin-1 into the left thalamus, which were classified into four different groups with different intervention: nicotine (1.5 mg/kg/d), dihydro-β-erythroidine (DHβE; 3 mg/kg/d), nicotine (1.5 mg/kg/d) + DHβE (3 mg/kg/d), or saline, after ischemic model surgery. Another five male SD rats also underwent same surgery, while not injecting endothelin-1 but saline, as the control group. Morris water maze (MWM) test was adopted to assess the cognition. All the rats underwent the MWM test, micro positron emission tomography imaging with 2-[18F]-A-85380, and messenger RNA (mRNA) test of α 4 nicotinic acetylcholine receptor (nAChR), β 2 nAChR, tumor necrosis factor-alpha (TNF-α), IL-1β, and IL-6. Results The MWM test showed the rats given nicotine showing better memory than ischemic rats (p < .05), whereas the rats given DHβE or both nicotine and DHβE did not show any statistical difference from the ischemic rats (p > .05). Micro positron emission tomography imaging showed higher uptake of tracer in the left thalamus and whole brain in rats given nicotine than in ischemic rats, but the rats given DHβE or both nicotine and DHβE did not. By real-time PCR test, the mRNA of α 4 nAChR and β 2 nAChR in rats given nicotine increased significantly compared with ischemic rats and decreased TNF-α, IL-1β, and IL-6 mRNA (all ps < .05). Conclusions By activating α 4β 2 nAChRs, nicotine plays a role in inhibiting the inflammatory factors, which contributes to improving cognitive impairment in ischemic rats. Implications It is well acknowledged that vascular cognitive impairment (VCI) is the second most common cause of dementia after Alzheimer’s disease. Cholinergic agents have potential for the symptomatic treatment of the cognitive symptoms of dementia, but the exact mechanism still remains unclear. There are potential complex associations and interactions between VCI and inflammation. This study showed that nicotine had anti-inflammatory potency, which is most likely because of the activation of the nAChRs. By activating α4β2 nAChRs, nicotine played a role in inhibiting the inflammatory factors, which contribute to improving cognitive impairment in ischemic rats.
Nicotine plays a role in inhibiting the in ammatory factors, which contributes to improving cognitive impairment by activating α 4 β 2 nAChRs in ischemic rats, but the underling mechanism has not been fully elucidated. Janus tyrosine kinase 2-signal transducer and activator of transcription 3 (JAK2-STAT3) signaling pathway is involved in cognitive improvement, and there seems a relationship between nAChRs and JAK2-STAT3 as well. This study was designed to investigate the role of JAK2-STAT3 signaling pathway in nicotine-mediated anti-in ammation effect. Nicotine, DHβE (the most potent competitive antagonist of α 4 β 2 nAChRs) and AG490 (a speci c JAK2-STAT3 blocker) were adopted for intervention treatment in ischemic rats and HEK-293T-hα 4 β 2 cells. Morris Water Maze (MWM) test and 2-[18F]-A-85380 PET imaging were performed to detect the cognition and α 4 β 2 nAChRs in ischemic rats. The results demonstrated that nicotine intervention increased the density of α 4 β 2 nAChRs and improved cognitive impairment, but this effect would be blocked by AG490, while receptors were still upregulated.Essentially, when JAK2-STAT3 signaling pathway was blocked, nicotine could only upregulate the expression of α 4 β 2 nAChRs, but not improve the cognitive function. The results were further con rmed by PCR and Western blot analysis. The cell experiments also showed that nicotine could reduce in ammatory factors stimulated by LPS and upregulate the expression of pJAK2 and pSTAT3 in HEK-293T-hα 4 β 2 cells, while AG490 and DHβE reversed nicotine's effect. In summary, our work indicated that JAK2-STAT3 signaling pathway played an important role in nicotine-induced cognitive improvement by up-regulating α 4 β 2 nAChRs in ischemic rats.
Nicotine plays a role in inhibiting the inflammatory factors, which contributes to improving cognitive impairment by activating α4β2 nAChRs in ischemic rats, but the underling mechanism has not been fully elucidated. Janus tyrosine kinase 2-signal transducer and activator of transcription 3 (JAK2-STAT3) signaling pathway is involved in cognitive improvement, and there seems a relationship between nAChRs and JAK2-STAT3 as well. This study was designed to investigate the role of JAK2-STAT3 signaling pathway in nicotine-mediated anti-inflammation effect. Nicotine, DHβE (the most potent competitive antagonist of α4β2 nAChRs) and AG490 (a specific JAK2-STAT3 blocker) were adopted for intervention treatment in ischemic rats and HEK-293T-hα4β2 cells. Morris Water Maze (MWM) test and 2-[18F]-A-85380 PET imaging were performed to detect the cognition and α4β2 nAChRs in ischemic rats. The results demonstrated that nicotine intervention increased the density of α4β2 nAChRs and improved cognitive impairment, but this effect would be blocked by AG490, while receptors were still upregulated. Essentially, when JAK2-STAT3 signaling pathway was blocked, nicotine could only upregulate the expression of α4β2 nAChRs, but not improve the cognitive function. The results were further confirmed by PCR and Western blot analysis. The cell experiments also showed that nicotine could reduce inflammatory factors stimulated by LPS and upregulate the expression of pJAK2 and pSTAT3 in HEK-293T-hα4β2 cells, while AG490 and DHβE reversed nicotine’s effect. In summary, our work indicated that JAK2-STAT3 signaling pathway played an important role in nicotine-induced cognitive improvement by up-regulating α4β2 nAChRs in ischemic rats.
Purpose: The purpose of this study was to investigate the prognostic relevance of metabolic parameters measured using 18F-FDG PET/CT in patients with metastatic cutaneous malignant melanoma (CMM).Materials and Methods: The prognostic impact of whole-body metabolic tumor volume (wMTV), whole-body tumor lesion glycolysis (wTLG), maximum standardized uptake value (SUVmax) and mean standardized uptake value (SUVmean) was evaluated in 42 metastatic CMM patients who underwent 18F-FDG PET/CT. The metabolic parameters were dichotomized by optimal cutoff values using time-dependent receiver operating characteristic (ROC) curves. In addition, univariate and multivariate analyses of the metabolic parameters were performed using the Kaplan-Meier method and Cox proportional hazards models.Results: The optimal cutoff values for disease-free survival (DFS) were 4.63 for SUVmax, 3.31 for SUVmean, 8.22 cm3 for wMTV, and 18.22 for wTLG. The optimal cutoff values for melanoma-specific survival (MSS) were 4.77 for SUVmax, 3.31 for SUVmean, 22.32 cm3 for wMTV, and 51.37 for wTLG. Thirty-two (72%) of the 42 patients experienced recurrence during the follow-up period, and 21 patients (50%) died from the disease. In univariate analysis, SUVmax greater than 4.63 (p= 0.025) and SUVmean greater than 3.31 (p= 0.011) affected DFS, while SUVmax greater than 4.77 (p= 0.039), wMTV greater than 22.32 (p= 0.023) and wMTV greater than 51.37 (p= 0.016) affected MSS. In multivariate analysis after adjustment for the effects of clinical parameters, SUVmax was the best predictive factor for DFS (p = 0.016), and SUVmax, wMTV and wTLG were the best predictive factors for MSS (p = 0.023, p = 0.018, and p = 0.007).Conclusions: SUVmax appears to be a strong independent prognostic factor for recurrence in metastatic CMM, and SUVmax, wMTV and wTLG were found to be the best predictive markers for melanoma-specific death.
BackgroundTo explore the mechanism of nicotine mediated improvement of cognitive impairment in an established ischemic rat model. MethodsEndothelin-1 (ET-1) was injected into the left thalamic region in adult male Sprague-Dawley (SD) rats to establish ischemia model. 6 groups of rats (6 rats in each group) were then treated with nicotine, nicotine+DHβE, DHβE, AG490, nicotine +AG490 and saline respectively via intraperitoneal injection for 9 days. Another sham operation group was treated with saline as above. Morris Water Maze (MWM) test was performed for 6 consecutive days starting on the 4th day after operation to detect the cognitive function of rats in each group. 2-[18F]-A-85380 microPET imaging was performed on day 10 to evaluate the changes of α4β2 nAChRs in different brain regions of rats. Real-time PCR and Western blot were used to detect the amount of α4β2 nAChRs, JAK2, STAT3 and inflammatory factors in thalamus of rats in each group. ResultsThe results of MWM test showed the spatial learning and memory abilities of rats in the nicotine and sham operation groups were significantly better than the saline treating group in this ischemic rat model (p<0.05). There was no significant difference in other groups (p>0.05). MicroPET imaging showed more uptake of 2-[18F]-A-85380 in the nicotine, nicotine+AG490 and sham operation groups than in saline treating group, while there was no significant difference found in other groups (p>0.05). The expression of α4- and β2-nAChR in nicotine, nicotine+AG490 and sham operation groups was significantly higher than the saline treating group (p<0.05). In the nicotine group, the expression of p-JAK2 and p-STAT3 in left thalamus of rats was significantly higher than the saline treating group (p<0.05), and the expression of IL-1β and IL-6 protein was found to be lower than the saline treating group (p<0.05). While the expression of p-JAK2, p-STAT3 and inflammatory factors was not significantly different in all the other groups (p>0.05). ConclusionThe study suggests nicotine inhibits the expression of inflammatory factors by activating α4β2 nAChRs through the activation of JAK2-STAT3 signaling pathway to improve cognitive impairment in ischemic rats.
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