Calycosin decreases cerebral ischemia/reperfusion injury by suppressing ACSL4-dependent ferroptosis.

Ischemic stroke is the second leading cause of death globally. Calycosin is a typical phytoestrogen that protects against cerebral ischemia/reperfusion (I/R) injury. However, the role of ferroptosis in this effect remains unknown. In the present study, we investigated the ferroptosis mechanism of calycosin against cerebral I/R injury using transient middle cerebral artery occlusion/reperfusion (tMCAO/R)-exposed rats and oxygen-glucose deprivation/reperfusion (OGD/R)-stimulated PC12 cells. We found that calycosin treatment significantly improved neurological deficits, brain edema, blood-brain barrier (BBB) breakdown, infarction volume, and neuronal injuries in rats that underwent tMCAO/R; similar to ferrostatin-1 (a ferroptosis inhibitor), calycosin prevented cell viability loss in PC12 cells exposed to OGD/R stimulation. In addition, calycosin intervention decreased ferroptosis, as assessed by iron accumulation, malondialdehyde (MDA), superoxide dismutase (SOD), ceramide, and reactive oxygen species (ROS) levels, as well as ferroptosis-related protein expression (ACSL4, TfR1, FTH1, and GPX4). Furthermore, overexpression of ACSL4 reversed calycosin-induced beneficial efficacy in OGD/R-stimulated PC12 cells. The molecular docking analysis demonstrated that calycosin binds to ACSL4 by forming stable hydrogen bonds at G465, K690, and D573. Collectively, these findings indicate that calycosin ameliorates cerebral I/R injury by depressing ACSL4-dependent ferroptosis.

Inhibition of autophagy-dependent pyroptosis attenuates cerebral ischaemia/reperfusion injury.

Autophagy is closely associated with cerebral ischaemia/reperfusion injury, but the underlying mechanisms are unknown. We investigated whether Spautin-1 ameliorates cerebral ischaemia/reperfusion injury by inhibiting autophagy and whether its derived pyroptosis is involved in this process. We explored the mechanism of Spautin-1 in cerebral ischaemia/reperfusion. To answer these questions, healthy male Sprague-Dawley rats were exposed to middle cerebral artery occlusion for 60 minutes followed by reperfusion for 24 hours. We found that cerebral ischaemia/reperfusion increased the expression levels of autophagy and pyroptosis-related proteins. Treatment with Spautin-1 reduced the infarct size and water content and restored some neurological functions. In vitro experiments were performed using oxygen-glucose deprivation/reoxygenation to model PC12 cells. The results showed that PC12 cells showed a significant decrease in cell viability and a significant increase in ROS and autophagy levels. Spautin-1 treatment reduced autophagy and ROS accumulation and attenuated NLRP3 inflammasome-dependent pyroptosis. However, these beneficial effects were greatly blocked by USP13 overexpression, which significantly counteracted the inhibition of autophagy and NLRP3 inflammasome-dependent ferroptosis by Spautin-1. Together, these results suggest that Spautin-1 may ameliorate cerebral ischaemia-reperfusion injury via the autophagy/pyroptosis pathway. Thus, inhibition of autophagy may be considered as a promising therapeutic approach for cerebral ischaemia-reperfusion injury.

Association between subjective autonomic dysfunction and fatigue in Parkinson's disease in southern Chinese.

STUDY OBJECTIVES: The aim was to investigate the association between autonomic symptoms and fatigue of Parkinson's disease (PD) in southern Chinese population. METHODS: In this study, 602 PD patients were recruited. All patients were evaluated by Scales for Outcomes in Parkinson's Disease-Autonomic questionnaire (SCOPA-AUT), Hamilton anxiety rating scale and Hamilton depression rating scale, non-motor symptoms scale (NMSS), and fatigue severity scale (FSS). RESULTS: Total score and gastrointestinal subpart, urinary subpart, and cardiovascular subpart of NMSS and SCOPA-AUT were associated with FSS scores (NMSS: total score: p < 0.001; gastrointestinal: p = 0.006; urinary: p = 0.001; cardiovascular: p < 0.001; SCOPA-AUT: total score: p < 0.001; gastrointestinal: p = 0.011; urinary: p < 0.001; cardiovascular: p = 0.003). CONCLUSIONS: Autonomic symptoms were associated with fatigue of PD.

Copper-Catalyzed Regioselective sp3 C-H Azidation of Alkyl Substituents of Indoles and Tetrahydrocarbazoles.

An efficient regioselective sp3 C-H azidation is developed using CuBr as the catalyst and Zhdankin azidoiodinane as the "N3" source. Under simple and mild reaction conditions, the azido group could be successfully incorporated into the sp3 C-H alkyl substituents of indoles and tetrahydrocarbazoles.

The Association of IL7R rs6897932 with Risk of Multiple Sclerosis in Southern Chinese.

Objective: To investigate the association between IL7R rs6897932 and multiple sclerosis (MS) in southern Chinese people. Methods: In total, 147 MS patients and 530 healthy controls were recruited according to the revised McDonald criteria. The TaqMan method was used for genotyping. Results: With genetic models, we can observe that the additive model, the dominant model, and the recessive model of IL7R rs6897932 were significantly associated with MS [additive model: p=0.032; dominant model (adjusted): p<0.001, OR=3.61 (95% CI 2.25-5.83); recessive model (adjusted): p<0.001, OR=6.80 (95% CI 3.49-13.89)]. Conclusion: Our results suggest that IL7R rs6897932 is associated with MS in a southern Chinese population. More and larger MS studies to explore the genetic risk factors of MS are warranted.

A prospective controlled study: minimally invasive stereotactic puncture therapy versus conventional craniotomy in the treatment of acute intracerebral hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke with the high mortality twofold to sixfold higher than that for ischemic stroke. But the treatment of haematomas within the basal ganglia continues to be a matter of debate among neurologists and neurosurgeons. The purpose of this study is to judge the clinical value of minimally invasive stereotactic puncture therapy (MISPT) on acute ICH. METHODS: A prospective controlled study was undertaken. The clinical trial was in compliance with the WMA Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects. According to the enrollment criterion, there were 168 acute ICH cases analyzed, of which 90 cases were performed by MISPT (MISPT group, MG) and 78 cases by Conventional craniotomy (CC group, CG), by means of compare of Glasgow Coma Scale (GCS) score, postoperative complications (PC) and rebleeding incidence (RI), moreover, long-term outcome of 1 year postoperation judged by Glasgow Outcome Scale (GOS), Barthel Index (BI), modified Rankin Scale (mRS) and case fatality(CF). RESULTS: MG patients showed obvious amelioration in GCS score compared with that of CG. The total incidence of PC in MG decreased obviously compared with that of CG. The incidences of rebleeding in MG and CG were 10.0% and 15.4% respectively. There was no obvious difference between CFs of MG and CG. For three parameters representing long-term outcome, the GOS, BI and mRS in MG were ameliorated significantly than that of CG. CONCLUSION: These data suggested that the advantage of MISPT was displayed in minute trauma and safety, and seemed to be feasible and to had a trend towards improved long-term outcome. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ANZCTR), the registration number: ACTRN12610000945022.

A Nomogram to Predict Symptomatic Intracranial Hemorrhage After Intravenous Thrombolysis in Chinese Patients.

BACKGROUND AND AIMS: A reliable predictive score system to identify the risk of symptomatic intracranial hemorrhage (sICH) after intravenous thrombolysis (IVT) in acute ischemic stroke patients is of great essence. We aimed to develop a nomogram for predicting the risk of sICH after IVT in Chinese patients. METHODS: We recruited acute ischemic stroke patients who were treated with IVT from five advanced stroke centers in China from April 2014 to November 2020. sICH was diagnosed according to the European Cooperative Acute Stroke Study II (ECASS-II) definition. Multivariable logistic regression was performed to construct the best-fit nomogram. The discrimination and calibration of the nomogram were evaluated by the area under the receiver operating characteristic curve (AUC-ROC) and calibration plot. RESULTS: A total of 1200 patients were enrolled, of whom 66 (5.5%) developed sICH. In the multivariate logistic regression model, atrial fibrillation (odds ratio [OR] 3.25; 95% confidence interval [CI], 1.89-5.60; P < 0.001), baseline glucose level (OR, 1.13; 95% CI, 1.07-1.20; P < 0.001), neutrophil to lymphocyte ratio (OR, 1.05; 95% CI, 1.01-1.09; P = 0.024) and baseline National Institute of Health Stroke Scale (NIHSS) (OR, 1.07; 95% CI, 1.04-1.10; P < 0.001) were independent predictors for sICH and were used to generate the nomogram. The nomogram demonstrated good discrimination as the AUC-ROC value was 0.788 (95% CI, 0.737-0.840). The calibration plot revealed good calibration. CONCLUSION: The nomogram consisted of atrial fibrillation, baseline glucose level, neutrophil to lymphocyte ratio, and NIHSS score may predict the risk of sICH in Chinese acute ischemic stroke patients treated with IVT.

A Score of Low-Grade Inflammation for Predicting Stroke Recurrence in Patients with Ischemic Stroke.

BACKGROUND AND PURPOSE: The impact of low-grade inflammation (LGI) on stroke recurrence has not been well studied yet. We aimed to evaluate the association between LGI and stroke recurrence in patients with ischemic stroke. METHODS: Patients with first-ever ischemic stroke diagnosed within 72 hours of symptoms onset were consecutively recruited from the Nanjing Stroke Registry Program. C-reactive protein (CRP) level, white blood cell (WBC) count, platelet (PLT) count, and neutrophil-to-lymphocyte ratio (NLR) were conceived as low-grade inflammation biomarkers and combined into a standardized LGI score. The association of LGI score with the risk of stroke recurrence was analyzed with multivariate Cox regression models. Analyses accounting for the competing risk of stroke recurrence and death were also performed. RESULTS: Of the 1214 patients studied (median age, 61 years; male, 71.6%), 177 (14.6%) patients experienced a recurrent stroke with a median follow-up of 23.0 (interquartile ranges, 14.5-34.0) months. Patients with stroke recurrence had a higher LGI score (median, 3 versus -2; P < 0.001) than those without recurrence. The univariate analysis indicated that patients with LGI scores in the fourth quartile were more likely to have a stroke recurrence (hazard ratios [HR], 4.312; 95% confidence interval [CI], 2.675-6.952; P < 0.001). After adjusting for potential confounders, the association remained significant in the multivariate Cox regression model (HR, 4.080; 95% CI, 2.420-6.879; P < 0.001). Competing risks model and sensitivity analysis further confirmed this conclusion. CONCLUSION: This study showed that an elevated LGI score was associated with a higher risk of stroke recurrence, independent of other vascular risk factors.

A novel palmitic acid hydroxy stearic acid (5-PAHSA) plays a neuroprotective role by inhibiting phosphorylation of the m-TOR-ULK1 pathway and regulating autophagy.

AIMS: Type 2 diabetes mellitus (T2DM) can lead to brain dysfunction and a series of neurological complications. Previous research demonstrated that a novel palmitic acid (5-PAHSA) exerts effect on glucose tolerance and chronic inflammation. Autophagy was important in diabetic-related neurodegeneration. The aim of the present study was to investigate whether 5-PAHSA has specific therapeutic effects on neurological dysfunction in diabetics, particularly with regard to autophagy. METHODS: 5-PAHSA was successfully synthesized according to a previously described protocol. We then carried out a series of in vitro and in vivo experiments using PC12 cells under diabetic conditions, and DB/DB mice, respectively. PC12 cells were treated with 5-PAHSA for 24 h, while mice were administered with 5-PAHSA for 30 days. At the end of each experiment, we analyzed glucolipid metabolism, autophagy, apoptosis, oxidative stress, cognition, and a range of inflammatory factors. RESULTS: Although there was no significant improvement in glucose metabolism in mice administered with 5-PAHSA, ox-LDL decreased significantly following the administration of 5-PAHSA in serum of DB/DB mice (p < 0.0001). We also found that the phosphorylation of m-TOR and ULK-1 was suppressed in both PC12 cells and DB/DB mice following the administration of 5-PAHSA (p < 0.05 and p < 0.01), although increased levels of autophagy were only observed in vitro (p < 0.05). Following the administration of 5-PAHSA, the concentration of ROS decreased in PC12 cells and the levels of CRP increased in high-dose group of 5-PAHSA (p < 0.01). There were no significant changes in terms of apoptosis, other inflammatory factors, or cognition in DB/DB mice following the administration of 5-PAHSA. CONCLUSION: We found that 5-PAHSA can enhance autophagy in PC12 cells under diabetic conditions. Our data demonstrated that 5-PAHSA inhibits phosphorylation of the m-TOR-ULK1 pathway and suppressed oxidative stress in PC12 cells, and exerted influence on lipid metabolism in DB/DB mice.

Efficient synthesis of cyclic amidine-based fluorophores via 6π-electrocyclic ring closure.

Novel 10π-electron cyclic amidines with excellent fluorescence properties were synthesized by a general and efficient 6π-electrocyclic ring closure of ketenimine and imine starting from N-sulfonyl triazoles and arylamines. The photophysical properties of cyclic amidine fluorophores have been studied in detail and have shown good properties of a large Stokes shift, pH insensitivity, low cytotoxicity and higher photostability, which have great potential for biological imaging. Furthermore, this novel fluorophore was successfully applied to the localization of the NK-1 receptor in living systems.

Difunctionalization of Alkenylpyridine N-Oxides by the Tandem Addition/Boekelheide Rearrangement.

A convenient and efficient approach for the difunctionalization of alkenylpyridine N-oxides through the tandem addition/Boekelheide rearrangement has been developed. The C-O and C-X (S, O, Cl) bonds are constructed simultaneously at the α- and ß-positions under mild reaction conditions in 100% atom economy, which complements previously reported α- or ß-functionalizations.

[Feature extraction and classification of EEG for mental tasks based on wavelet packet analysis].

This paper explores the use of wavelet packet analysis to extract features from spontaneous electroencephalogram (EEG) during three different mental tasks. Artifact-free EEG segments are transformed to multi-scale representations by dyadic wavelet packet decomposition channel by channel. Their feature vectors formed by energy values of different sub-spaces EEG components are used as inputs of a radial basis function network to test the classification accuracies of three task pairs. The results indicate that the classification accuracies of the wavelet packet analysis method are significantly better than those of autoregressive model method. Wavelet packet analysis would be a promising method to extract features from EEG signals.

Minimally invasive stereotactic puncture and thrombolysis therapy improves long-term outcome after acute intracerebral hemorrhage.

The purpose of this study was to judge the clinical value of minimally invasive stereotactic puncture and thrombolysis therapy (MISPTT) for acute intracerebral hemorrhage (ICH). A randomized control clinical trial was undertaken. According to the enrollment criteria, 122 acute ICH cases were analyzed, of which 64 cases received MISPTT (MISPTT group, MG) and 58 cases received conventional craniotomy (CC group, CG). The Glasgow coma scale (GCS) scores, postoperative complications (PC), and rebleeding incidences were compared. Moreover, 1 year postoperation, the long-term outcomes of patients with regard to hematoma volume (HV) <50 mL and HV ≥50 mL were judged, respectively, by the Glasgow outcome scale (GOS), Barthel index (BI), modified Rankin Scale (mRS), and case fatality (CF). MG patients showed obvious amelioration in GCS score compared with that of CG patients. The total incidence of PC in MG decreased compared with that of CG. The incidences of rebleeding in MG and CG were 9.4 and 17.2%, respectively (P = 0.243). There were no obvious differences between the CFs of MG and CG (17.2 and 25.9%, respectively, P = 0.199). The GOS, BI, and mRS representing long-term outcome for both HV <50 mL and HV ≥50 mL in MG were ameliorated significantly greater than that in CG patients (all P < 0.05). These data suggest that there are advantages with MISPTT not only in trauma and safety, but the MISPTT group had fewer complications and a trend toward improved short-term and long-term outcomes.