Gastrodin relieves Parkinson's disease-related motor deficits by facilitating the MEK-dependent VMAT2 to maintain dopamine homeostasis.

BACKGROUND: Dysfunction of dopamine homeostasis (DAH), which is regulated by vesicular monoamine transporter 2 (VMAT2), is a vital cause of dopamine (DA) neurotoxicity and motor deficits in Parkinson's disease (PD). Gastrodin (4-hydroxybenzyl alcohol 4-O-ß-D-glucoside; GTD), a natural active compound derived from Gastrodia elata Blume, can be used to treat multiple neurological disorders, including PD. However, whether GTD regulates VMAT2-mediated DAH dysfunction in PD models remains unclear. PURPOSE: To explore whether GTD confers dopaminergic neuroprotection by facilitating DA vesicle storage and maintaining DAH in PD models. METHODS: Mice were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and PC12 cells with 1-methyl-4-phenyl-pyridinium (MPP+) to induce PD characteristics. Multiple behavioural tests were performed to evaluate the motor functions of the mice. HPLC was used to measure DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. Transmission electron microscopy was used to observe synaptic vesicles. Molecular docking and molecular dynamics were used to determine the binding affinity of GTD to the target protein. Reserpine (Res, a VMAT2 inhibitor) and PD0325901 (901, a MEK inhibitor) were employed to investigate the mechanism of GTD. Western blotting and immunohistochemistry were used to assess the expression of the target proteins. RESULTS: GTD attenuated motor deficits and dopaminergic neuronal injury, reversed the imbalance of DAH, and increased VMAT2 levels and vesicle volume in MPTP-induced mice. GTD ameliorated cell damage, ROS release, and dysfunction of DAH in MPP+-induced PC12 cells. Moreover, the neuroprotective effects of GTD were reversed by Res in vitro and in vivo. Furthermore, GTD can activate the MEK/ERK/CREB pathway to upregulate VMAT2 in vitro and in vivo. Interestingly, 901 reversed the effects of GTD on VMAT2 and dopaminergic neuronal impairment. CONCLUSION: GTD relieved PD-related motor deficits and dopaminergic neuronal impairment by facilitating MEK-depended VMAT2 to regulate DAH, which offers new insights into its therapeutic potential.

Management of intervenable factors to reduce vascular complications in patients with internal carotid artery occlusion treated by non-emergency endovascular treatment.

Objective: This study aims to identify risk factors for vascular complications during non-emergency endovascular treatment in patients with internal carotid artery occlusion (ICAO) and to propose potential interventions. Method: A retrospective analysis of 92 patients with ICAO who received non-emergency endovascular treatment in our center from 1 January 2018 to 31 June 2023, was conducted. The correlation between intraoperative vascular complications and potential risk factors was studied, and interaction analysis was performed. Results: Our findings revealed that the use of non-neurology guide wires to open vessels (adjusted OR: 4.1, 95%CI: 1.3-12.8; p = 0.014) and glycosylated hemoglobin (HbA1c) ≥ 6.5 mmol/L (adjusted OR: 3.2, 95%CI: 1.2-8.9; p = 0.023) was significantly associated with vascular complications in non-emergency endovascular treatment of ICAO patients. The restricted cubic spline (RCS) showed that the higher the HbA1c level, the higher the risk of vascular complications. Conclusion: The use of non-neurology guide wires for vessel opening during non-emergency endovascular treatment in patients with ICAO increases the risk of vascular complications. Preoperative assessment and management of HbA1c levels can reduce the incidence of intraoperative vascular complications.

A Critical Review of Conventional and Modern Approaches to Develop Herbicide-Resistance in Rice.

Together with rice, weeds strive for nutrients and space in farmland, resulting in reduced rice yield and quality. Planting herbicide-resistant rice varieties is one of the effective ways to control weeds. In recent years, a series of breakthroughs have been made to generate herbicide-resistant germplasm, especially the emergence of biotechnological tools such as gene editing, which provides an inherent advantage for the knock-out or knock-in of the desired genes. In order to develop herbicide-resistant rice germplasm resources, gene manipulation has been conducted to enhance the herbicide tolerance of rice varieties through the utilization of techniques such as physical and chemical mutagenesis, as well as genome editing. Based on the current research and persisting problems in rice paddy fields, research on the generation of herbicide-resistant rice still needs to explore genetic mechanisms, stacking multiple resistant genes in a single genotype, and transgene-free genome editing using the CRISPR system. Current rapidly developing gene editing technologies can be used to mutate herbicide target genes, enabling targeted genes to maintain their biological functions, and reducing the binding ability of target gene encoded proteins to corresponding herbicides, ultimately resulting in herbicide-resistant crops. In this review article, we have summarized the utilization of conventional and modern approaches to develop herbicide-resistant cultivars in rice as an effective strategy for weed control in paddy fields, and discussed the technology and research directions for creating herbicide-resistant rice in the future.

Facial Expression Recognition Methods in the Wild Based on Fusion Feature of Attention Mechanism and LBP.

Facial expression methods play a vital role in human-computer interaction and other fields, but there are factors such as occlusion, illumination, and pose changes in wild facial recognition, as well as category imbalances between different datasets, that result in large variations in recognition rates and low accuracy rates for different categories of facial expression datasets. This study introduces RCL-Net, a method of recognizing wild facial expressions that is based on an attention mechanism and LBP feature fusion. The structure consists of two main branches, namely the ResNet-CBAM residual attention branch and the local binary feature (LBP) extraction branch (RCL-Net). First, by merging the residual network and hybrid attention mechanism, the residual attention network is presented to emphasize the local detail feature information of facial expressions; the significant characteristics of facial expressions are retrieved from both channel and spatial dimensions to build the residual attention classification model. Second, we present a locally improved residual network attention model. LBP features are introduced into the facial expression feature extraction stage in order to extract texture information on expression photographs in order to emphasize facial feature information and enhance the recognition accuracy of the model. Lastly, experimental validation is performed using the FER2013, FERPLUS, CK+, and RAF-DB datasets, and the experimental results demonstrate that the proposed method has superior generalization capability and robustness in the laboratory-controlled environment and field environment compared to the most recent experimental methods.

IL-17 crosses the blood-brain barrier to trigger neuroinflammation: a novel mechanism in nitroglycerin-induced chronic migraine.

BACKGROUND: Chronic migraine places a disabling burden on patients, which is extensively modeled by the nitroglycerin (NTG)-treated animal model. Although the NF-κB pathway is involved in an increase in CGRP levels and activation of the trigeminal system in the NTG model, the relationship between NTG and neuroinflammation remains unclear. This study aimed to optimize a chronic NTG rat model with hyperalgesia and the ethological capacity for estimating migraine therapies and to further explore the underlying mechanism of NTG-induced migraine. METHODS: Rats were administered different doses of NTG s.c. daily or every 2 d; 30 min and 2 h later, the mechanical threshold was tested. After 9 d, the rats were injected with EB or Cy5.5 for the permeability assay. The other animals were sacrificed, and then, brainstem and caudal trigeminal ganglion were removed to test CGRP, c-Fos and NOS activity; Cytokines levels in the tissue and serum were measured by ELISA; and NF-κB pathway and blood-brain barrier (BBB)-related indicators were analyzed using western blotting. Immunohistochemistry was performed to observe microglial polarization and IL-17A+ T cell migration in the medulla oblongata. RESULTS: NTG (10 mg/kg, s.c., every 2 d for a total of 5 injections) was the optimal condition, resulting in progressive hyperalgesia and migraine behavior. TNC neuroinflammation with increases in cytokines, CGRP and c-Fos and activation of the NF-κB pathway was observed, and these changes were alleviated by ibuprofen. Furthermore, NTG administration increased BBB permeability by altering the levels functional proteins (RAGE, LRP1, AQP4 and MFSD2A) and structural proteins (ZO-1, Occludin and VE-cadherin-2) to increase peripheral IL-17A permeation into the medulla oblongata, activating microglia and neuroinflammation, and eventually causing hyperalgesia and migraine attack. CONCLUSIONS: This study confirmed that NTG (10 mg/kg, s.c., every 2 d for a total of 5 injections) was the optimal condition to provoke migraine, resulting in mechanical hyperalgesia and observable migraine-like behavior. Furthermore, IL-17A crossed the blood-brain barrier into the medulla oblongata, triggering TNC activation through microglia-mediated neuroinflammation. This process was a novel mechanism in NTG-induced chronic migraine, suggesting that IL-17A might be a novel target in the treatment of migraine.

Correction: Inhibition of NLRP3 inflammasome activation and pyroptosis with the ethyl acetate fraction of Bungeanum ameliorated cognitive dysfunction in aged mice.

Correction for 'Inhibition of NLRP3 inflammasome activation and pyroptosis with the ethyl acetate fraction of Bungeanum ameliorated cognitive dysfunction in aged mice' by Meihuan Zhao et al., Food Funct., 2021, DOI: 10.1039/D1FO00876E.

Inhibition of NLRP3 inflammasome activation and pyroptosis with the ethyl acetate fraction of Bungeanum ameliorated cognitive dysfunction in aged mice.

Zanthoxylum bungeanum Maxim (Rutaceae), a medicinal herb and foodstuff, has previously been demonstrated as useful for the potential prevention of age-related cognitive dysfunction. However, the mechanisms and material basis remain elusively understood. The prevention of cognitive impairment by four fractions of Z. bungeanum was evaluated in D-galactose-induced aging mice, including petroleum ether (PE), methylene chloride (DCM), ethyl acetate (EA), and n-butanol (N-BAI). The results showed that mice treated with EA and N-BAI had significantly alleviated D-galactose-induced memory deficit. In addition, EA could clearly protect neurons from cell death, alleviate oxidative damage and inhibit the activation of microglia in aging mice. Our data also showed that the activation of the NLRP3 inflammasome, the expression of pyroptosis-related proteins, and the release of IL-1ß and IL-18 could be remarkably inhibited by the EA fraction in aging mice and LPS/ATP-induced BV-2 microglial cells. Besides, the chemical composition of an active EA fraction was qualitatively analyzed by using HPLC-MS/MS. Thirty-four compounds were tentatively identified based on their retention times, accurate mass, and MS/MS spectra. Moreover, eighteen reference compounds were analyzed by HPLC-MS/MS and their contents of EA were determined. The work demonstrated that the ethyl acetate fraction of Bungeanum ameliorated cognitive deficits, and its effects may be related to ameliorating oxidative stress and suppressing the NLRP3 inflammasome pathway and GSDMD-mediated pyroptosis in aging mice.

Imperatorin alleviated endometriosis by inhibiting the activation of PI3K/Akt/NF-κB pathway in rats.

AIMS: Most therapeutic drugs of endometriosis have been contraceptives but symptoms recur in up to 75% of cases, which makes it a presses need to try to find novel and safer therapeutic drugs. Imperatorin is a furanocoumarin existing in many plants, possessing multiple activities, including anti-inflammatory. The purpose of this study was to assess the effects and mechanisms of imperatorin in endometriosis. MAIN METHODS: Ectopic endometrial volume and hematoxylin-eosin staining were used to estimate the effects of imperatorin in experimental endometriosis model rats. Potential mechanisms of imperatorin in endometriosis were systematically analyzed by network pharmacology and molecular docking. Western blotting and enzyme-linked immunosorbent assay were employed to evaluate proteins expression and cytokines levels in PI3K/Akt/NF-κB pathway. KEY FINDINGS: Imperatorin could significantly inhibit the growth and ameliorate the histopathological features of ectopic endometrium in experimental endometriosis rats. Network pharmacology approaches showed that imperatorin might regulate inflammatory response and cellular function via primarily affecting PI3K-Akt pathway, Endocrine resistance, Th17 cell differentiation in endometriosis. Moreover, 7 core targets (PIK3CA, AKT1, SRC, MAPK8, MAPK14, ERBB2 and CCND1) resulted from the intersection of KEGG and PPI network topological analysis were used to dock with imperatorin, which indicated that imperatorin could preferably fit in the binding pocket of the above target proteins, except for CCND1. Lastly, imperatorin markedly inhibited the activation of PI3K/Akt/NF-κB pathway via suppressing the phosphorylation levels of PI3K, Akt and p65 in the ectopic endometrium tissue. SIGNIFICANCE: Our findings revealed that imperatorin is a significant multi-target natural active ingredient for treatment endometriosis.

Meningeal immunity: Structure, function and a potential therapeutic target of neurodegenerative diseases.

Meningeal immunity refers to immune surveillance and immune defense in the meningeal immune compartment, which depends on the unique position, structural composition of the meninges and functional characteristics of the meningeal immune cells. Recent research advances in meningeal immunity have demonstrated many new ways in which a sophisticated immune landscape affects central nervous system (CNS) function under physiological or pathological conditions. The proper function of the meningeal compartment might protect the CNS from pathogens or contribute to neurological disorders. Since the concept of meningeal immunity, especially the meningeal lymphatic system and the glymphatic system, is relatively new, we will provide a general review of the meninges' basic structural elements, organization, regulation, and functions with regards to meningeal immunity. At the same time, we will emphasize recent evidence for the role of meningeal immunity in neurodegenerative diseases. More importantly, we will speculate about the feasibility of the meningeal immune region as a drug target to provide some insights for future research of meningeal immunity.

A Structure-Guided Delineation of FOXP3 Regulation Mechanism in IPEX.

The FOXP3 transcription factor acts as a master regulator in the development and function of regulatory T cells (Tregs). Insufficient expression or mutation of FOXP3 gene impairs Treg abundancy and function and causes fatal autoimmune lymphoproliferative diseases in mice and humans. The available crystal structures of FOXP3 protein fragments provide insights into understanding details of the FOXP3 work mechanism in Tregs. This chapter consists of four sections. First, we introduce some features of Treg cells indispensable for the establishment of immune tolerance; second, we describe the critical roles of FOXP3 in Treg development and function; third, we summarize the current available crystal structures of FOXP3 functional domains and related pathogenic mutations in autoimmune diseases; finally, we discuss the potential functional and pathological relevance of FOXP3 protein structure modulation, partner interaction, and posttranslation modification based on the clinical significance in IPEX disease. The information presented in this chapter will help to consider therapeutic strategies to enhance FOXP3 activity and Treg function in the settings of autoimmune disease. Targeting Treg suppression based on FOXP3 structure and interactions hold great promises for the therapy of autoimmune diseases.

Ligustilide alleviates neurotoxicity in SH-SY5Y cells induced by Aß25-35 via regulating endoplasmic reticulum stress and autophagy.

Ligustilide is a phenolic compound isolated from Asian plants of Umbelliferae family. This study was aimed at exploring the neuroprotective effects of Ligustilide from the perspective of endoplasmic reticulum stress (ERS) and autophagy. The Alzheimer's disease (AD) cell models were constructed by SH-SY5Y cell line, which was exposed to 20 µM Aß25-35 . CCK-8 was used to evaluate the cell viability of Ligustilide on AD cell model. Hoechst staining and LysoTracker Red were used to test the cell apoptosis and Lysosome function, respectively. ERS in living cells were detected by Thioflavin T. The expression of autophagy-related proteins (LC3B-II/I, P62/SQSTM1, Beclin1, and Atg5), ERS marker proteins (PERK, GRP78, and CHOH), and apoptosis proteins (Bax, Bcl-2, and Caspase-12) were analyzed by Western blot analyses. Aß25-35 could induce ERS and autophagy in a time-dependent manner in SH-SY5Y cells. We demonstrated that Ligustilide significantly decreased the rate of apoptosis, and improved the viability of cells. Simultaneously, Ligustilide effectively modulated ERS via inhibiting the over-activation of GRP78/PERK/CHOP signaling pathway. In addition, Ligustilide alleviated the accumulation of autophagy vacuoles, reduced the ratio of LC3B-II/I and the level of P62/SQSTM1. Ligustilide significantly up-regulated lysosomal acidity and the expression of Cathepsin D (CTSD). Ligustilide could rescue lysosomal function to promote autophagy flux and inhibit the over-activation of ERS. This finding may contribute to the development of new therapeutic strategies for AD.

Endovascular recanalization for symptomatic subacute and chronically occluded internal carotid artery: feasibility, safety, a modified radiographic classification system, and clinical outcomes.

PURPOSE: To evaluate the feasibility and safety of endovascular recanalization for symptomatic subacute and chronic internal carotid artery occlusion (ICAO); to propose a newly modified radiographic classification of ICAO that can rigorously identify suitable candidates for endovascular ICAO treatment. METHODS: We included 42 consecutive patients who had ICAO with ischaemic symptoms refractory to medical therapy. We examined the symptomatology, complications, follow-up results and radiographic images of ICAO receiving attempted endovascular treatment. We attempted to stratify all radiographic images into categories based on morphological occlusion patterns, occlusion segments and distal ICA reconstitution on digital subtraction angiography (DSA). RESULTS: Four types (A-D) of radiographic ICAO were identified. We redefined type B as having a tapered stump but no distal lumen. The rate of successful recanalization was 83.33% (35/42 ICAOs; type A, 18/20; type B, 7/10; type C, 10/11; type D, 0/1). The perioperative complication rate was 11.90% (5/42), including 3 asymptomatic distal embolisms, 1 symptomatic cerebral infarction and 1 asymptomatic carotid artery dissection. None of these technique-related complications led to severe neurological damage or death. Modified Rankin Scale (mRS) scores after 1-20 months of follow-up were significantly decreased in successfully revascularized patients (P < 0.001). There was no significant change in mRS scores in the 7 patients in whom recanalization failed (P > 0.05). CONCLUSIONS: Endovascular recanalization seems to achieve technical success and clinical improvement for symptomatic subacute and chronic ICAO. Additionally, our newly modified radiographic classification of ICAO may be valuable in assessing the technical feasibility and safety of procedures in symptomatic ICAO patients.

Chlorogenic Acid Alleviates Aß25-35-Induced Autophagy and Cognitive Impairment via the mTOR/TFEB Signaling Pathway.

PURPOSE: Chlorogenic acid (CGA), a phenolic acid isolated from fruits and vegetables, has been established to have neuroprotective properties in relation to Alzheimer's disease (AD). However, the precise mechanism by which CGA prevents cognitive deficits in AD has not been well studied. This study aimed to explore the potential molecular mechanism of CGA action using an Aß25-35-induced SH-SY5Y neuron injury and cogxnitive deficits model in APP/PS1 mice. METHODS: Three-month-old male APP/PS1 double transgenic mice and a human neuroblastoma cell line (SH-SY5Y) were used to assess the effects of CGA on AD in vivo and in vitro, respectively. Cognitive function in mice was measured using a Morris water maze (MWM) test. Hematoxylin and eosin, monodansylcadaverine fluorescence, LysoTracker Red (LTR), and immunofluorescence staining were used to evaluate the morphological changes in vivo and in vitro. The protein expressions of autophagy markers (LC3B-II/LC3B-I, p62/SQSTM, beclin1 and Atg5) and lysosomal-function-related markers (cathepsin D, mTOR, p-mTOR P70S6K, p-p70s6k and TFEB) were analyzed with Western blot analyses. RESULTS: CGA treatment significantly improved spatial memory, relieved neuron damage, and inhibited autophagy in APP/PS1 mice (P<0.05). Moreover, CGA notably suppressed autophagosome production and enhanced autophagy flux in SH-SY5Y cells induced by Aß25-35 (P<0.05). Further analysis showed that CGA markedly promoted lysosomal activity, and this was accompanied by upregulated cathepsin D protein expression, which was induced by the mTOR/TFEB signaling pathway in APP/PS1 mice and Aß25-35-exposed SH-SY5Y cells (P<0.05). CONCLUSION: CGA treatment restored autophagic flux in the brain and alleviated cognitive impairments in APP/PS1 mice via enhanced activation of the mTOR/TFEB signaling pathway.

[Correlation of collateral circulation and prognosis in patients with acute cerebral infarction].

OBJECTIVE: To evaluate the correlation of collateral circulation with prognosis in patients with acute cerebral infarction. METHODS: A total of 260 patients with acute ischemic stroke within 1 week of symptom onset underwent digital subtraction angiogram (DSA). The National Institutes of Health Stroke Scale (NIHSS) scores were obtained at admission. And the Modified Rankin scores (mRS) were assessed at a 3-month follow-up. The follow-up data were acquired through clinic visits or telephone interviews. RESULTS: Among them, 86 were found to have intra- or extra-cranial culprit artery severe stenosis or occlusion. And 36 (75.00%) in 48 patients had collateral arterial circulation while 11 (28.64%) in 38 patients posterior circulation. There were statistical differences in the NIHSS scores at admission and favorite clinical outcome (mRS ≤ 2) at 3-month follow-up for patients with and without collateral circulation. CONCLUSION: DSA is the golden standard for the assessment of collateral circulation in patients with severe cerebral artery stenosis or occlusion. The prognosis is better in stroke patients with collateral circulation.

Clinical study of PTAS therapy for patients with ischemia cerebrovascular disease caused by artery stenosis.

The curative efficacy of percutaneous transluminal angioplasty and stenting (PTAS) in the treatment of patients with ischemia cerebrovascular disease caused by artery stenosis was explored. The clinical data of 111 patients with ischemia cerebrovascular disease receiving PTAS in Guangdong Province General Hospital from Aug. 2007 to Nov. 2009 were retrospectively analyzed. In total 132 stents were implanted in the 111 patients. The mortality and rate of neural and non-neural complications were assessed perioperatively. Outcomes [including the frequency of transient ischemic attack (TIA), stroke, or death from vascular diseases) were assessed after operation. NIHSS rating was performed in all cases before and at first week, 6th month and 12th month after the operation. The PTAS success rate was 100%. The degree of stenosis was reduced after PTAS. The total complication rate during perioperative period was 15.3% (the rate of neural complications was 3.6%). Sixty-seven patients were followed up. Three patients (4.48%) developed cerebrovascular events within 1 month, containing one case of TIA, one case of ipsilateral mild stroke and one case of contralateral mild stroke. No severe stroke or death was observed. During a follow-up period of 12 months 7 patients had cerebrovascular events (10.44%), including 2 cases of ipsilateral TIA (2.99%), 2 cases of ipsilateral mild stroke and 2 cases of contralateral mild stroke (2.99%), one case of severe stroke (1.49%). In 13 patients receiving DSA re-examination one year after PTAS, 2 patients (15.38%) had in-stent restenosis. NIHSS scores were obviously decreased during a follow-up period as compared with those pre-operation (P<0.05). It was concluded that PTAS could significantly alleviate the neural function deficit of the patients with ischemia cerebrovascular disease. The success rate of PTAS was high, and the rate of complications was lower and the clinical outcomes were satisfactory. PTAS is a safe and effective therapeutic method, though the long-term outcomes need further study.

Clinical Study of PTAS Therapy for Patients with Ischemia Cerebrovascular Disease Caused by Artery Stenosis / 华中科技大学学报（医学）（英德文版）

The curative efficacy of percutaneous transluminal angioplasty and stenting (PTAS) in the treatment of patients with ischemia cerebrovascular disease caused by artery stenosis was explored.The clinical data of 111 patients with ischemia cerebrovascular disease receiving PTAS in Guangdong Province General Hospital from Aug.2007 to Nov.2009 were retrospectively analyzed.In total 132 stents were implanted in the 111 patients.The mortality and rate of neural and non-neural complications were assessed perioperatively.Outcomes [including the frequency of transient ischemic attack (TIA),stroke,or death from vascular diseases) were assessed after operation.NIHSS rating was performed in all cases before and at first week,6th month and 12th month after the operation.The PTAS success rate was 100％.The degree of stenosis was reduced after PTAS.The total complication rate during perioperative period was 15.3％ (the rate of neural complications was 3.6％).Sixty-seven patients were followed up.Three patients (4.48％) developed cerebrovascular events within 1 month,containing one case of TIA,one case of ipsilateral mild stroke and one case of contralateral mild stroke.No severe stroke or death was observed.During a follow-up period of 12 months 7 patients had cerebrovascular events (10.44％),including 2 cases of ipsilateral TIA (2.99％),2 cases of ipsilateral mild stroke and 2 cases of contralateral mild stroke (2.99％),one case of severe stroke (1.49％).In 13 patients receiving DSA re-examination one year after PTAS,2 patients (15.38％) had in-stent restenosis.NIHSS scores were obviously decreased during a follow-up period as compared with those pre-operation (P＜0.05).It was concluded that PTAS could significantly alleviate the neural function deficit of the patients with ischemia cerebrovascular disease.The success rate of PTAS was high,and the rate of complications was lower and the clinical outcomes were satisfactory.PTAS is a safe and effective therapeutic method,though the long-term outcomes need further study.