Developing targeted antioxidant nanomedicines for ischemic penumbra: Novel strategies in treating brain ischemia-reperfusion injury.

During cerebral ischemia-reperfusion conditions, the excessive reactive oxygen species in the ischemic penumbra region, resulting in neuronal oxidative stress, constitute the main pathological mechanism behind ischemia-reperfusion damage. Swiftly reinstating blood perfusion in the ischemic penumbra zone and suppressing neuronal oxidative injury are key to effective treatment. Presently, antioxidants in clinical use suffer from low bioavailability, a singular mechanism of action, and substantial side effects, severely restricting their therapeutic impact and widespread clinical usage. Recently, nanomedicines, owing to their controllable size and shape and surface modifiability, have demonstrated good application potential in biomedicine, potentially breaking through the bottleneck in developing neuroprotective drugs for ischemic strokes. This manuscript intends to clarify the mechanisms of cerebral ischemia-reperfusion injury and provides a comprehensive review of the design and synthesis of antioxidant nanomedicines, their action mechanisms and applications in reversing neuronal oxidative damage, thus presenting novel approaches for ischemic stroke prevention and treatment.

Therapeutics of Extracellular Vesicles in Cardiocerebrovascular and Metabolic Diseases.

Extracellular vesicles (EVs) are nanoscale membranous vesicles containing DNA, RNA, lipids, and proteins, which play versatile roles in intercellular communications. EVs are increasingly being recognized as the promising therapeutic agents for many diseases, including cardiocerebrovascular and metabolic diseases, due to their ability to deliver functional and therapeutical molecules. In this chapter, the biological characteristics and functions of EVs are briefly summarized. Importantly, the current state of applying EVs in the prevention and treatment of cardiocerebrovascular and metabolic diseases, including myocardial infarction, atrial fibrillation, myocardial hypertrophy, stroke, diabetes, Alzheimer's disease, fatty liver, obesity, thyroid diseases, and osteoporosis, is discussed. Lastly, the challenges and prospects related to the preclinical and clinical application of EVs receive a particular focus.

Does acupuncture have advantages in the rehabilitation of vascular mild cognitive impairment? A systematic review and meta-analysis.

Background: Vascular mild cognitive impairment (VMCI) is a common impairment caused by vascular factors. VMCI often occurs after stroke, and it is the main clinical manifestation of long-term disability. Many patients are treated with acupuncture in combination with other therapies. However, evidence regarding the effectiveness of this treatment regimen is lacking. Aims: This meta-analysis aimed to evaluate the efficacy of acupuncture therapy for treating VMCI. Methods: This systematic review was conducted in accordance with the preferred reporting and meta-analysis guidelines. The CNKI, Wanfang, VIP, CBM, Cochrane Library, PubMed and Embase databases were searched from inception to August 20, 2022. After two researchers independently screened the literature, they extracted the data and evaluated the risk of bias in the included studies. Revman 5.3 software was used for the meta-analysis. Summary of review: Thirty-two randomized controlled trials (RCTs) were included. The overall effective rate of acupuncture for treating VMCI was 3.06, 95% CI [2.39, 3.91], (P < 0.05). Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Barthel Index and Activities of Daily Living (ADLs) scores significantly differed between the treatment and control groups, with weighted mean differences (WMDs) [95% CI] (P value) of 1.97 [1.44, 2.49] (P < 0.05), 2.02 [1.50, 2.54] (P < 0.05), 5.54 [3.81, 7.28] (P < 0.05), and 3.43 [2.53, 4.33] (P < 0.05), respectively. The overall effective rate of electroacupuncture (EA) for treating VMCI was better than that of the control group (RR = 2.25, 95% CI, [1.13, 4.50], P < 0.05). MoCA, MMSE, Barthel index and ADL scores differed significantly between the treatment and control groups, with WMDs [95% CI] (P value) of 1.79 [1.20, 2.38] (P < 0.05), 1.45 [0.87, 2.03] (P < 0.05), 5.78 [2.38, 9.18] (P < 0.05), and 3.15 [2.15, 4.15] (P < 0.05), respectively. Acupuncture alone and combined with drug therapy were thus superior to drug therapy alone for improving cognitive function. EA also has potential advantages. Conclusions: Acupuncture combined with another therapy is better than other therapies alone, such as simple drug therapy, for treating VMCI. However, variations in study duration (4-12 weeks) limit us from drawing any definitive conclusions about long-term effects. Therefore, more RCTs with rigorous designs and reasonable treatment and follow-up durations are needed.

Active components and molecular mechanisms of Sagacious Confucius' Pillow Elixir to treat cognitive impairment based on systems pharmacology.

BACKGROUND: Sagacious Confucius' Pillow Elixir (SCPE) is a common clinical prescription to treat cognitive impairment (CI) in East Asia. OBJECTIVE: To predict the active components of SCPE, identify the associated signaling pathway, and explore the molecular mechanism using systems pharmacology and an animal study. METHODS: Systems pharmacology and Python programming language-based molecular docking were used to select and analyze the active components and targets. Senescence-accelerated prone 8 mice were used as a CI model. The molecular mechanism was evaluated using the water maze test, neuropathological observation, cerebrospinal fluid microdialysis, and Western blotting. RESULTS: Thirty active components were revealed by screening relevant databases and performing topological analysis. Additionally, 376 differentially expressed genes for CI were identified. Pathway enrichment analysis, protein-protein interaction (PPI) network analysis and molecular docking indicated that SCPE played a crucial role in modulating the PI3K/Akt/mTOR signaling pathway, and 23 SCPE components interacted with it. In the CI model, SCPE improved cognitive function, increased the levels of the neurotransmitter 5-hydroxytryptamine (5-HT) and metabolite 5-hydroxyindole acetic acid (5-HIAA), ameliorated pathological damage and regulated the PI3K/AKT/mTOR signaling pathway. SCPE increased the LC3-II/LC3-I, p-PI3K p85/PI3K p85, p-AKT/AKT, and p-mTOR/mTOR protein expression ratios and inhibited P62 expression in the hippocampal tissue of the CI model. CONCLUSION: Our study revealed that 23 active SCPE components improve CI by increasing the levels of the neurotransmitter 5-HT and metabolite 5-HIAA, suppressing pathological injury and regulating the PI3K/Akt/mTOR signaling pathway to improve cognitive function.

Towards Natural Language-Based Visualization Authoring.

A key challenge to visualization authoring is the process of getting familiar with the complex user interfaces of authoring tools. Natural Language Interface (NLI) presents promising benefits due to its learnability and usability. However, supporting NLIs for authoring tools requires expertise in natural language processing, while existing NLIs are mostly designed for visual analytic workflow. In this paper, we propose an authoring-oriented NLI pipeline by introducing a structured representation of users' visualization editing intents, called editing actions, based on a formative study and an extensive survey on visualization construction tools. The editing actions are executable, and thus decouple natural language interpretation and visualization applications as an intermediate layer. We implement a deep learning-based NL interpreter to translate NL utterances into editing actions. The interpreter is reusable and extensible across authoring tools. The authoring tools only need to map the editing actions into tool-specific operations. To illustrate the usages of the NL interpreter, we implement an Excel chart editor and a proof-of-concept authoring tool, VisTalk. We conduct a user study with VisTalk to understand the usage patterns of NL-based authoring systems. Finally, we discuss observations on how users author charts with natural language, as well as implications for future research.

RNA modifications in aging-associated cardiovascular diseases.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide that bears an enormous healthcare burden and aging is a major contributing factor to CVDs. Functional gene expression network during aging is regulated by mRNAs transcriptionally and by non-coding RNAs epi-transcriptionally. RNA modifications alter the stability and function of both mRNAs and non-coding RNAs and are involved in differentiation, development, and diseases. Here we review major chemical RNA modifications on mRNAs and non-coding RNAs, including N6-adenosine methylation, N1-adenosine methylation, 5-methylcytidine, pseudouridylation, 2' -O-ribose-methylation, and N7-methylguanosine, in the aging process with an emphasis on cardiovascular aging. We also summarize the currently available methods to detect RNA modifications and the bioinformatic tools to study RNA modifications. More importantly, we discussed the specific implication of the RNA modifications on mRNAs and non-coding RNAs in the pathogenesis of aging-associated CVDs, including atherosclerosis, hypertension, coronary heart diseases, congestive heart failure, atrial fibrillation, peripheral artery disease, venous insufficiency, and stroke.

Electroacupuncture Enhances Neuroplasticity by Regulating the Orexin A-Mediated cAMP/PKA/CREB Signaling Pathway in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice.

Learning and memory disorders and decreased neuroplasticity are the main clinical manifestations of age-induced cognitive dysfunction. Orexin A (OxA) has been reported to show abnormally elevated expression in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) and to be associated with cognitive impairment. Here, we further assessed whether the excitatory neurotransmitter OxA is involved in neuroplasticity and cognitive function in senescence-accelerated mouse prone 8 (SAMP8) mice. In this study, we investigated the mechanism of OxA by using behavioral tests, CSF microdialysis, immunofluorescence, toluidine blue staining, gene silencing, transmission electron microscopy, and Western blotting. The results showed that 10 Hz electroacupuncture (EA) effectively alleviated learning and memory impairment in 7-month-old SAMP8 mice, reduced OxA levels in the CSF, increased the level of the neurotransmitter glutamate, alleviated pathological damage to hippocampal tissue, improved the synaptic structure, enhanced synaptic transmission, and regulated the expression of cAMP/PKA/CREB signaling pathway-related proteins. These results suggest that EA enhances neuroplasticity in SAMP8 mice by regulating the OxA-mediated cAMP/PKA/CREB signaling pathway, thus improving cognitive function. These findings suggest that EA may be beneficial for the prevention and treatment of age-induced cognitive impairment.

WITHDRAWN: Football sports safety and the health risk assessment system.

Ahead of Print article withdrawn by publisher.

Antimicrobial therapy and the potential mechanisms in Alzheimer's disease.

Alzheimer's disease treatments have been a heavily investigated research area, however, new drugs have failed one after another. Some scientists have begun to reposition drugs, including antimicrobial agents. Here, the treatment effects of nine antimicrobial agents on Alzheimer's disease and their possible therapeutic mechanisms are described to clarify their efficacy. In vivo and in vitro studies are quite encouraging and tend to demonstrate that antimicrobial therapy is effective in Alzheimer's disease. Nevertheless, unsatisfactory clinical efficacy, side effects, and insufficient knowledge have yet to be overcome. Further laboratory and clinical studies are required to recommend antimicrobial treatment regimens.

Electroacupuncture Improves Cognitive Function in Senescence-Accelerated P8 (SAMP8) Mice via the NLRP3/Caspase-1 Pathway.

Background. Clinically, electroacupuncture (EA) is the most common therapy for aging-related cognitive impairment (CI). However, the underlying pathomechanism remains unidentified. The aims of this study were to observe the effect of EA on cognitive function and explore the potential mechanism by which EA acts on the NLRP3/caspase-1 signaling pathway. Main Methods. Thirty male SAMP8 mice were randomly divided into the model, the 2 Hz EA and 10 Hz EA groups. Ten male SAMR1 mice were assigned to the control group. Cognitive function was assessed through the Morris water maze test. Hippocampal morphology and cell death were observed by HE and TUNEL staining, respectively. The serum IL-1ß, IL-6, IL-18, and TNF-α levels were measured by ELISA. Hippocampal NLRP3, ASC, caspase-1, GSDM-D, IL-1ß, IL-18, Aß, and tau proteins were detected by Western blotting. Key Findings. Cognitive function, hippocampal morphology, and TUNEL-positive cell counts were improved by both EA frequencies. The serum IL-1ß, IL-6, IL-18, and TNF-α levels were decreased by EA treatment. However, 10 Hz EA reduced the number of TUNEL-positive cells in the CA1 region and serum IL-1ß and IL-6 levels more effectively than 2 Hz EA. NLRP3/caspase-1 pathway-related proteins were significantly downregulated by EA, but 2 Hz EA did not effectively reduce ASC protein expression. Interestingly, both EA frequencies failed to reduce the expression of Aß and tau proteins. Significance. The effects of 10 Hz EA at the GV20 and ST36 acupoints on the NLRP3/caspase-1 signaling pathway may be a mechanism by which this treatment relieves aging-related CI in mice.

Beneficial Effects of Sagacious Confucius' Pillow Elixir on Cognitive Function in Senescence-Accelerated P8 Mice (SAMP8) via the NLRP3/Caspase-1 Pathway.

Sagacious Confucius' Pillow Elixir (SCPE) is a traditional Chinese medicine that is mainly used for cognitive impairment in aging; however, the underlying mechanisms remain unclear. Aging is one of the most important pathogenic factors leading to inflammation and pyroptosis in the hippocampus, which may be a potential mechanism in elderly patients with cognitive impairment. Here, we examined whether SCPE could improve cognitive impairment in SAMP8 mice by reducing hippocampal inflammation and pyroptosis. Seven-month-old senescence-accelerated P8 mice (SAMP8) received SCPE (2.3 g/kg/day; 4.6 g/kg/day; 9.2 g/kg/day) for 28 days. Cognitive function and morphometric examinations were performed followed by water maze testing, hematoxylin-eosin staining, Congo red staining, toluidine blue staining, and TUNEL analysis of hippocampal CA1 and CA3 regions. Escape latency increased and times across platforms decreased in SAMP8 mice; however, both of them were normalized by SCPE after 28 days. Aging caused significant pyroptosis in hippocampal CA1 and CA3 regions, as evidenced by neuronal degeneration and necrosis, amyloid deposition, and decreased Nissl body amounts after cognitive impairment, which were greatly improved by SCPE. SCPE reduced serum IL-1ß, IL-6, IL-18, and TNF-α levels and reduced hippocampal NLRP3, ASC, caspase-1, GSDM-D, IL-1ß, IL-6, IL-18, and Aß expression. Thus, SCPE exerts an antipyroptotic effect in aging, mainly by suppressing the NLRP3/caspase-1 signaling pathway.

[Effects of Sagacious Confucius' Pillow Elixir on cognitive function in type 2 diabetic rats].

Type 2 diabetes mellitus (T2DM) is the leading threat to human health in China, and severe cognitive impairment often occurs in most T2DM patients. Although Sagacious Confucius' Pillow Elixir is a type of classical traditional Chinese medicine for cognitive impairment in clinic, the mechanism has not yet been completely defined. In this study, an experimental model of type 2 diabetes mellitus (T2DM) was established by injecting Sprague Dawley (SD) rats with streptozocin (STZ), so as to compare the learning and memory ability, hippocampal neurons pathological changes, beta amyloid protein (A beta) content, degree of Tau protein phosphorylation, blood glucose and insulin level. The results showed that the Sagacious Confucius' Pillow Elixir could improve the learning and memory ability of STZ injected rats, reduce the level of A beta content both in hippocampus and serum, effectively reduce Tau protein phosphorylation degree, and also significantly alleviate hippocampal pathological injury, blood glucose, insulin and other basic indicators. The results showed that Sagacious Confucius' Pillow Elixir can alleviate the hippocampal pathological damage caused by STZ, and is expected to provide a theoretical basis for human T2DM patients in clinical adjuvant therapy.

[Impacts of the repetitive transcranial acupuncture stimulation on the content of serum orexin A in patients with post-stroke insomnia].

OBJECTIVE: To compare the effect on post-stroke insomnia between the repetitive transcranial acupuncture stimulation (rTAS) and the conventional western medication in the patients and to explore the mechanism. METHODS: Ninety patients of post-stroke insomnia were randomized into a rTAS group, a medication group and a placebo group, 30 cases in each one. In the rTAS group, patients were intervened by rTAS. The acupoints were Baihui (GV 20), Ningshen (Extra), emotion area, Wangu (GB 12), Taiyang (EX-HN 5), Neiguan (PC 6), Shenmen (HT 7), Sanyinjiao (SP 6), Zhaohai (KI 6), Zusanli (ST 36) and Taichong (LR 3). Fast twist with small amplitude was used at Baihui (GV 20) and emotion area for 2-3 min, 200-300 r/min, once 15 min. Electroacupuncture (EA) was applied at Baihui (GV 20) and Ningshen (Extra), bilateral Wangu (GB 12), Sanyinjiao (SP 6) and Zhaohai (KI 6) on the same side, 10 Hz, 0.5-1 mA. The treatment was given for 40 min in the rTAS group, once a day. Diazepam was prescribed orally in the medication group before sleep, 2.5 mg a day. Starch capsule was used in the placebo group before sleep, once a day. All the treatment was given for continuous 1 month. The level of serum orexin A was observed before and after treatment. The effects were compared. The recurrence rate was recorded 3 months after treatment. RESULTS: The total effective rates in the rTAS group and the medication group were 86.7% (26/30) and 90.0% (27/30) repectively after treatment, which were better than 20.0% (6/30) in the placebo group (both P<0.01). After treatment, the levels of serum orexin A in the rTAS group and the medication group were lower than those before treatment (both P<0.01), which were lower than that in the placebo group after treatment (both P<0.01), without statistical significance between the rTAS group and the medication group after treatment (P>0.05). The total effective rates in the rTAS group and the medication group were 86.7% (26/30) and 86.7% (26/30) at follow-up repectively, which were better than 16.7% (5/30) in the placebo group (both P<0.01). CONCLUSION: The rTAS is safe and effective for post-stroke insomnia, which is similar to oral medication of diazepam. The decreasing serum orexin A may be one of the mechanisms.

[Effects of Electroacupuncture Intervention on Oxygen Free Radicals and Expression of Apoptosis-related Proteins in Rats with Ischemic Learning and Memory Disorder].

OBJECTIVE: To observe the effect of electroacupuncture (EA) therapy on levels of oxygen free radicals (OFR) and hippocampal apoptosis-related protein expression in ischemic learning-memory disorder rats so as to investigate its mechanisms underlying improvement of ischemic learning-memory impairment. METHODS: A total of 60 SD rats were randomly divided into sham operation (sham), model, medication, and EA groups, with 15 rats in each group. The learning-memory disorder model was made by occlusion of bilateral carotid arteries. EA (2- 3 Hz, 2 mA) was applied to "Zhi San Zhen" ["Shenting" (GV 24) and bilateral "Benshen" (GB 13)] for 30 min, once a day for 3 weeks. The rats of the medication group were treated by lavage of Aricept (0.03 mg . kg(-1) . d(-1)), once daily for 3 weeks. The rats' learning-memory ability was detected by Morris water maze tests and the state of hippocampal apoptosis cells was observed by light microscope after TUNEL staining and the expression of hippocampal Bcl-2, Bax and Caspase-3 proteins was detected by immunohistochemistry. Serum and hippocampal superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity and malondialdehyde (MDA) contents were detected by chemical colorimetric analysis. RESULTS: Compared with the sham group, the escape latencies (place-navigation) after modeling were evidently prolonged, and the times of target-platform crossing in 90 sec (spatial probe test) considerably reduced in the model group (P<0.01), suggesting an impairment of learning-memory ability. After the treatment for 21 d, the increased escape latency and the reduced target-platform crossing time in both EA and medication groups were reversed in comparison with the model group (P<0.01), suggesting an improvement of memory ability, and the effect of the EA group was significantly superior to that of the medication group (P<0.05). Compared with the sham group, the number of apoptotic cells in hippocampal CA 1- CA 3 regions, and the expression levels of hippocampal Bcl-2, Bax and Caspase-3 proteins, and serum and hippocampal MDA contents were significantly increased in the model group (P<0.01), while serum and hippocampal SOD and GSH-Px levels obviously decreased in the model group (P<0.01). After the treatment for 21 days, compared to the model group, the number of the apoptotic cells, the expression levels of hippocampal Bax and Caspase--3 proteins, and the contents of serum and hippocampal MDA were notably decreased in the EA and medication groups (P<0.01), whereas, Bcl-2 protein expression levels, and serum and hippocampal SOD and GSH-Px activity were notably up-regulated in the EA and medication groups (P<0.01). The effects of EA group were obviously superior to those of medication group in increasing hippocampal Bcl-2 immunoactivity, serum SOD and GSH-Px and hippocampal GSH-Px activity and in down-regulating serum MDA level (P<0.01, P<0.05). CONCLUSION: Electroacupuncture intervention can improve learning-memory ability in ischemic learning-memory disorder rats which may be associated with its effects in reducing blood and hippocampal OFR contents and hippocampal cellular apoptosis.