pH responsive and zwitterionic micelle for enhanced cellular uptake and antitumor performance.

The side effects of small molecule chemotherapeutic drugs (SMCD) have brought great pain to the cancer patients. Many nanodrug carriers can relieve the shortcomings of SMCD, but they have complex synthesis processes and lack biodegradability. To overcome both problems, we synthesized a pH responsive biodegradable zwitterionic molecules (EK-D) by linking zwitterionic polypeptide (EK7) and dodecyl acrylate through a simple click reaction. Subsequently, doxorubicin (DOX) was physically encapsulated within the EK-D micelles to produce EK-D-DOX micelles, and polyethylene glycol monooleate (POO) employed as a comparative group for the preparation of POO-DOX micelles. The results show that EK-D-DOX micelles have good aqueous stability and anti-protein non-specific adsorption performance at pH 7.4, but EK-D-DOX micelles aggregate under the condition of pH = 5.5 due to the biodegradability of EK-D. The tumor cell uptake rate of EK-D-DOX micelles is higher than that of POO-DOX micelles and free DOX, which makes EK-D-DOX micelles the highest cytotoxic. Additionally, EK-D-DOX micelles release more DOX in a slightly acidic environment than at pH 7.4, and the release of DOX reaches a significant cumulative value of 75.20 % under pH conditions of 5.5. More importantly, EK-D-DOX micelles exhibit superior in vivo tumor inhibitory efficacy compared to free DOX, resulting in a remarkable tumor inhibition rate of 95.7 %. EK-D-DOX micelles not only have lower biological toxicity to normal tissues than free DOX, but also have a longer blood circulation time in mice. The method of EK-D-DOX micelles preparation represents a new method to prepare biodegradable zwitterionic nanodrug.

Achieving deep intratumoral penetration and multimodal combined therapy for tumor through algal photosynthesis.

BACKGROUND: Elevated interstitial fluid pressure within tumors, resulting from impaired lymphatic drainage, constitutes a critical barrier to effective drug penetration and therapeutic outcomes. RESULTS: In this study, based on the photosynthetic characteristics of algae, an active drug carrier (CP@ICG) derived from Chlorella pyrenoidosa (CP) was designed and constructed. Leveraging the hypoxia tropism and phototropism exhibited by CP, we achieved targeted transport of the carrier to tumor sites. Additionally, dual near-infrared (NIR) irradiation at the tumor site facilitated photosynthesis in CP, enabling the breakdown of excessive intratumoral interstitial fluid by generating oxygen from water decomposition. This process effectively reduced the interstitial pressure, thereby promoting enhanced perfusion of blood into the tumor, significantly improving deep-seated penetration of chemotherapeutic agents, and alleviating tumor hypoxia. CONCLUSIONS: CP@ICG demonstrated a combined effect of photothermal/photodynamic/starvation therapy, exhibiting excellent in vitro/in vivo anti-tumor efficacy and favorable biocompatibility. This work provides a scientific foundation for the application of microbial-enhanced intratumoral drug delivery and tumor therapy.

Zwitterionic dendrimer self-assembled nanodrugs with high drug loading for enhanced anti-tumor ability.

Zwitterionic dendrimers have been used to construct many nanomedicines due to their ability to achieve controlled drug release, but their low drug loading content limits their application in nanodrug delivery. To solve this problem, the surface of second generation polypropylimine (G2 PPI) was modified with mercapturized paclitaxel (PTX-SH) and zwitterionic groups to prepare zwitterionic prodrug molecule (PPIMPC), and then zwitterionic dendrimer self-assembled nanodrugs (PPIMPC-DOX micelles) were prepared by incorporating doxorubicin (DOX) into the micelles. The DOX loading and paclitaxel (PTX) loading in PPIMPC-DOX micelles was 6.7% and 26.2%, respectively, and the total drug loading of PPIMPC-DOX was high to 32.9%. In addition, PPIMPC-DOX micelles showed enhanced cytotoxicity due to improved cell uptake of DOX. More importantly, the inhibition rate of tumor was much higher than free DOX. The zwitterionic property and high drug loading of PPIMPC-DOX micelles enhanced anti-tumor ability of chemotherapeutic drugs. The method of preparation of zwitterionic and high drug loading of nanodrugs shows good application prospects in the future.

Design and Test of Spatial Cognitive Training and Evaluation System Based on Virtual Reality Head-Mounted Display With EEG Recording.

The field of spatial cognitive training and evaluation has rapidly evolved. However, the low learning motivation and engagement of the subjects hinder the widespread use of spatial cognitive training. This study designed a home-based spatial cognitive training and evaluation system (SCTES), which aimed to train subjects on spatial cognitive tasks for 20 days, and compared the brain activities before and after the training. This study also evaluated the feasibility of using a portable all-in-one prototype for cognitive training that combined a virtual reality (VR) head-mounted display with high-quality electroencephalogram (EEG) recording. During the course of training, the length of the navigation path and the distance between the starting position and the platform position revealed significant behavioral differences. In the testing sessions, the subjects showed significant behavioral differences in the time it took to complete the test task before and after training. After only four days of training, the subjects demonstrated significant differences in the Granger causality analysis (GCA) characteristics of brain regions in the δ , θ , α1 , ß2 , and γ frequency bands of the EEG, as well as significant differences in the GCA of the EEG in the ß1 , ß2 , and γ frequency bands between the two test sessions. The proposed SCTES used a compact and all-in-one form factor to train and evaluate spatial cognition and collect EEG signals and behavioral data simultaneously. The recorded EEG data can be used to quantitatively assess the efficacy of spatial training in patients with spatial cognitive impairments.

Feature Extraction Method of EEG Signals Evaluating Spatial Cognition of Community Elderly With Permutation Conditional Mutual Information Common Space Model.

In order to improve the traditional common space pattern (CSP) algorithm pattern in EEG feature extraction, this study proposes a feature extraction method of EEG signals based on permutation conditional mutual information common space pattern (PCMICSP), which used the sum of the permutation condition mutual information matrices of each lead to replacing the mixed spatial covariance matrix in the traditional CSP algorithm, and its eigenvectors and eigenvalues are used to construct a new spatial filter. Then the spatial features in the different time domains and frequency domains are combined to construct the two-dimensional pixel map, Finally, a convolutional neural network (CNN) is used for binary classification. The EEG signals of 7 community elderly before and after spatial cognitive training in virtual reality (VR) scenes were used as the test data set. The average classification accuracy of the PCMICSP algorithm for pre-test and post-test EEG signals is 98%, which was higher than that of CSP based on CMI (conditional mutual information), CSP based on MI (mutual information), and traditional CSP in the combination of four frequency bands. Compared with the traditional CSP method, PCMICSP can be used as a more effective method to extract the spatial features of EEG signals. Therefore, this paper provides a new approach to solving the strict linear hypothesis of CSP and can be used as a valuable biomarker for the spatial cognitive evaluation of the elderly in the community.

Low-intensity pulsed ultrasound triggers a beneficial neuromodulation in dementia mice with chronic cerebral hypoperfusion via activation of hippocampal Fndc5/irisin signaling.

BACKGROUND: Exercise-related signaling Fndc5/irisin expresses in brain and acts as a crucial regulator of cognitive function, but its detailed roles in vascular dementia (VaD) are still unclear. Low intensity pulsed ultrasound (LIPUS), a novel brain stimulation approach, has been suggested as a promising treatment for dementia. Here, we investigated the activity and efficacy of Fndc5/irisin in experimental VaD, further explored whether the potential effects of LIPUS on VaD is related to Fndc5/irisin. METHODS: Mouse model of VaD was established with chronic cerebral hypoperfusion (CCH) using bilateral common carotid arteries stenosis (BCAS). Transcranial LIPUS was applied 24 h after BCAS and subsequently daily with a stimulation time of 5 min at an ultrasound pressure of 0.51 MPa for a period of 28 days. The levels of Fndc5/irisin in different brain regions, the hippocampal long-term potentiation and anti-inflammatory cytokines were investigated at day 28 after cognitive evaluation. Global Fndc5 knock-out (F5KO), forced expression or knockdown of Fndc5, and recombinant irisin application were respectively employed for mechanism exploration. The neuron dendritic spine density and astrocyte phenotype were detected in vitro. RESULTS: Fndc5/irisin was reduced in hippocampus of BCAS mice, forced expression hippocampal Fndc5 or bilateral intrahippocampal injection of recombinant irisin respectively improved hippocampal synaptic plasticity or inflammatory microenvironment, and then alleviated the cognitive impairments. LIPUS existed a positive efficacy in enhancing hippocampal Fndc5/irisin in BCAS mice, thus triggering a beneficial neuromodulation for VaD protection. Importantly, the neurorestorative effects of LIPUS on CCH-induced damages were totally reversed by knockdown the expression of hippocampal Fndc5 in WT mice, or in F5KO mice. Moreover, Fndc5 mediated the upregulated effects of LIPUS on spine density as well as irisin secretion of hippocampal neurons. The neuron-secreted irisin further drove reactive astrocytes to a neuroprotective phenotype. CONCLUSION: LIPUS induced a neurorestorative stimulation against VaD may be through upregulation of the hippocampal Fndc5/irisin levels. Hippocampal Fndc5/irisin signaling might be a promising strategic target for VaD.

Task-State EEG Signal Classification for Spatial Cognitive Evaluation Based on Multiscale High-Density Convolutional Neural Network.

In this study, a multi-scale high-density convolutional neural network (MHCNN) classification method for spatial cognitive ability assessment was proposed, aiming at achieving the binary classification of task-state EEG signals before and after spatial cognitive training. Besides, the multi-dimensional conditional mutual information method was used to extract the frequency band features of the EEG data. And the coupling features under the combination of multi-frequency bands were transformed into multi-spectral images. At the same time, the idea of Densenet was introduced to improve the multi-scale convolutional neural network. Firstly, according to the discreteness of multispectral EEG image features, two-scale convolution kernels were used to calculate and learn useful channel and frequency band feature information in multispectral image data. Secondly, to enhance feature propagation and reduce the number of parameters, the dense network was connected after the multi-scale convolutional network, and the learning rate change function of the stochastic gradient descent algorithm was optimized to objectively evaluate the training effect. The experimental results showed that compared with the classical convolution neural network (CNN) and multi-scale convolution neural network, the proposed MHCNN had better classification performance in the six frequency band combinations with the highest accuracy of 98%: Theta-Alpha2-Gamma, Alpha2-Beta2-Gamma, Beta1-Beta2-Gamma, Theta-Beta2-Gamma, Theta- Alpha1-Gamma, and Alpha1-Alpha2-Gamma. By comparing the classification results of six frequency band combinations, it was found that the combination of the Theta-Beta2-Gamma band had the best classification effect. The MHCNN classification method proposed in this research could be used as an effective biological indicator of spatial cognitive training effect and could be extended to other brain function evaluations.

Facile preparation of nanomicelles using polymyxin E for enhanced antitumor effects.

Chemotherapy is a major cancer treatment that uses antitumor drugs to kill fast-growing cancer cells. Many kinds of drug carriers have been developed to deliver and achieve controlled release of small-molecule therapeutic agents. However, many therapeutic agent carriers need complex preparation process. The natural polypeptides may serve as proper drug carriers. More specifically, polymyxin E (PE) is a kind of natural antibiotic lipopeptides. It is commonly used to treat infections caused by multidrug-resistant Gram-negative bacteria. Herein, we present a facile method to prepare DOX-loaded polymyxin E micelles (PE-DOX micelles) to enhance the therapeutic effect of anticancer drug doxorubicin (DOX). The hydrodynamic sizes and zeta potential of the prepared nanomedicine (PE-DOX micelles) were 142.0 nm and 6.47 mV, respectively. The release of DOX from PE-DOX micelles was faster at pH 5.5 than that at pH 7.4. Furthermore, PE exhibited negligible cytotoxicity to A549 cells and HeLa cells within 50 µg/mL, while PE-DOX micelles caused higher cytotoxicity than that of free DOX. Moreover, the intravenously injected PE-DOX micelles showed good biocompatibility and obvious antitumor effect after 14 days' treatment in vivo. The PE-DOX micelles have great potential to be used as anticancer agent in the future.

Green synthesis of platinum nanoclusters using lentinan for sensitively colorimetric detection of glucose.

The sensitive colorimetric detection of glucose using nanomaterials has been attracting considerable attention. To improve the detection sensitivity, highly stable lentinan stabilized platinum nanoclusters (Pt-LNT NCs) were prepared, in which lentinan was employed as a mild reductant and stabilizer. The size of platinum nanoclusters (Pt NCs) was only 1.20 ± 0.29 nm. Pt-LNT NCs catalyzed the oxidation of substrate 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of hydrogen peroxide (H2O2) to produce a blue oxidation product with absorption peak at 652 nm, indicating their peroxidase-like properties. Their enzymatic kinetics followed typical Michaelis-Menten theory. In addition, fluorescence experiments confirmed their ability to efficiently catalyze the decomposition of H2O2 to generate •OH, which resulted in the peroxidase-like mechanism of Pt-LNT NCs. Moreover, a colorimetric method for highly selective and sensitive detection of glucose was established by using Pt-LNT NCs and glucose oxidase. The linear range of glucose detection was 5-1000 µM and the detection limit was 1.79 µM. Finally, this method was further used for detection of glucose in human serum and human urine. The established colorimetric method may promote the development of biological detection and environmental chemistry in the future.

Combining brain-computer interface and virtual reality for rehabilitation in neurological diseases: A narrative review.

BACKGROUND: The traditional rehabilitation for neurological diseases lacks the active participation of patients, its process is monotonous and tedious, and the effects need to be improved. Therefore, a new type of rehabilitation technology with more active participation combining brain-computer interface (BCI) with virtual reality (VR) has developed rapidly in recent years and has been used in rehabilitation in neurological diseases. OBJECTIVES: This narrative review analyzed and characterized the development and application of the new training system (BCI-VR) in rehabilitation of neurological diseases from the perspective of the BCI paradigm, to provide a pathway for future research in this field. METHODS: The review involved a search of the Web of Science-Science Citation Index/Social Sciences Citation Index and the China National Knowledge Infrastructure databases; 39 papers were selected. Advantages and challenges of BCI-VR - based neurological rehabilitation were analyzed in detail. RESULTS: Most BCI-VR studies included could be classified by 3 major BCI paradigms: motor imagery, P300, and steady-state visual-evoked potential. Integrating VR scenes into BCI systems could effectively promote the recovery process from nervous system injuries as compared with traditional methods. CONCLUSION: As compared with rehabilitation based on traditional BCI, rehabilitation based on BCI-VR can provide better feedback information for patients and promote the recovery of brain function. By solving the challenges and continual development, the BCI-VR system can be broadly applied to the clinical treatment of various neurological diseases.

Association of Small Dense Low-Density Lipoprotein Cholesterol with Stroke Risk, Severity and Prognosis.

AIM: To investigate the association of small dense low-density lipoprotein cholesterol (sdLDL-C) and acute ischemic stroke (AIS) in terms of risk, severity, and outcomes. Prediction models were established to screen high-risk patients and predict prognosis of AIS patients. METHODS: We enrolled in this study 355 AIS patients and 171 non-AIS controls. AIS was subtyped according to TOAST criteria, and the severity and outcomes of AIS were measured. Blood glucose and lipid profiles including total cholesterol, triglyceride, and lipoproteins were measured in all patients using automatic measure. Lipoprotein subfractions were detected by the Lipoprint LDL system. RESULTS: As compared with the non-AIS control group, the AIS group had higher sdLDL-C levels. Pearson correlation analysis revealed that the sdLDL-C level and risk of AIS, especially non-cardioembolic stroke, were positively correlated. The area under the curve of sdLDL-C for AIS risk was 0.665, better than that of other lipids. Additionally, the sdLDL-C level was significantly correlated with AIS severity and bad outcomes. A logistic regression model for assessing the probability of AIS occurrence and a prognostic prediction model were established based on sdLDL-C and other variables. CONCLUSIONS: Elevated levels of sdLDL-C were associated with a higher prevalence of AIS, especially in non-cardioembolic stroke subtypes. After adjustment for other risk factors, sdLDL-C was found to be an independent risk factor for AIS. Also, sdLDL-C level was strongly associated with AIS severity and poor functional outcomes. Logistic regression models for AIS risk and prognosis prediction were established to help clinicians provide better prevention for high-risk subjects and monitor their prognosis.

Wnt canonical pathway activator TWS119 drives microglial anti-inflammatory activation and facilitates neurological recovery following experimental stroke.

BACKGROUND: Ischemic stroke is a leading cause of disability worldwide and characteristically accompanied by downregulation of the Wnt/ß-catenin signaling. Activation of Wnt/ß-catenin signaling emerges to attenuate neuroinflammation after ischemic stroke; however, its effect on modulating microglial polarization is largely unknown. Here, we explored whether Wnt/ß-catenin pathway activator TWS119 facilitated long-term neurological recovery via modulating microglia polarization after experimental stroke. METHODS: Ischemic stroke mice model was induced by permanent distal middle cerebral artery occlusion plus 1 h hypoxia. TWS119 was administrated from day 1 to 14 after stroke. Neurological deficits were monitored up to 21 days after stroke. Angiogenesis, neural plasticity, microglial polarization, and microglia-associated inflammatory cytokines were detected in the peri-infarct cortex at days 14 and 21 after stroke. Primary microglia and mouse brain microvascular endothelial cell lines were employed to explore the underlying mechanism in vitro. RESULTS: TWS119 mitigated neurological deficits at days 14 and 21 after experimental stroke, paralleled by acceleration on angiogenesis and neural plasticity in the peri-infarct cortex. Mechanistically, cerebral ischemia induced production of microglia-associated proinflammatory cytokines and priming of activated microglia toward pro-inflammatory polarization, whereas TWS119 ameliorated microglia-mediated neuroinflammatory status following ischemic stroke and promoted angiogenesis by modulating microglia to anti-inflammatory phenotype. The beneficial efficacy of TWS119 in microglial polarization was largely reversed by selective Wnt/ß-catenin pathway blockade in vitro, suggesting that TWS119-enabled pro-inflammatory to anti-inflammatory phenotype switch of microglia was possibly mediated by Wnt/ß-catenin signaling. CONCLUSIONS: Wnt/ß-catenin pathway activator TWS119 ameliorated neuroinflammatory microenvironment following chronic cerebral ischemia via modulating microglia towards anti-inflammatory phenotype, and facilitates neurological recovery in an anti-inflammatory phenotype polarization-dependent manner. Activation of Wnt/ß-catenin pathway following ischemic stroke might be a potential restorative strategy targeting microglia-mediated neuroinflammation.

Estimating coupling strength between multivariate neural series with multivariate permutation conditional mutual information.

Recently, coupling between groups of neurons or different brain regions has been widely studied to provide insights into underlying mechanisms of brain functions. To comprehensively understand the effect of such coupling, it is necessary to accurately extract the coupling strength information among multivariate neural signals from the whole brain. This study proposed a new method named multivariate permutation conditional mutual information (MPCMI) to quantitatively estimate the coupling strength of multivariate neural signals (MNS). The performance of the MPCMI method was validated on the simulated MNS generated by multi-channel neural mass model (MNMM). The coupling strength feature of simulated MNS extracted by MPCMI showed better performance compared with standard methods, such as permutation conditional mutual information (PCMI), multivariate Granger causality (MVGC), and Granger causality analysis (GCA). Furthermore, the MPCMI was applied to estimate the coupling strengths of two-channel resting-state electroencephalographic (rsEEG) signals from different brain regions of 19 patients with amnestic mild cognitive impairment (aMCI) with type 2 diabetes mellitus (T2DM) and 20 normal control (NC) with T2DM in Alpha1 and Alpha2 frequency bands. Empirical results showed that the MPCMI could effectively extract the coupling strength features that were significantly different between the aMCI and the NC. Hence, the proposed MPCMI method could be an effective estimate of coupling strengths of MNS, and might be a viable biomarker for clinical applications.

Enhanced glucose detection using dendrimer encapsulated gold nanoparticles benefiting from their zwitterionic surface.

The application of ultrasmall gold nanoparticles as enzyme mimics has been drawing great attention. Herein, we developed zwitterionic dendrimer encapsulated gold nanoparticles (Au-G5MC NPs) for highly sensitive and simple colorimetric detection of glucose. Au-G5MC NPs showed peroxidase-like property, which could efficiently catalyze oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of H2O2, producing a blue color product (oxTMB). This peroxidase-like reaction follows a typical Michaelis-Menten kinetics. The Km towards TMB exhibited a lower value (0.194 mM) than that of horseradish peroxidase (HRP, 0.434 mM). Furthermore, the peroxidase-like properties of Au-G5MC NPs enable colorimetric detection of the concentration of glucose with high selectivity. The linear concentration range of this method was from 14 µM to 166 µM with the detection limit down to 3.8 µM. More importantly, the detection was not interfered by proteins due to the single zwitterionic layer on the Au-G5MC NPs surface. These excellent properties are attributed to the ultrasmall size of gold nanoparticles and high stability of Au-G5MC NPs in complex medium. This catalytic system might have great potential applications for glucose detection in medical diagnostics and biochemistry in the future.

Granulocyte-colony stimulating factor inhibits neuronal apoptosis in a rat model of diabetic cerebral ischemia.

Incidence of cerebral vascular disease (CVD) is higher in patients with diabetes mellitus (DM) than that in individuals without DM, and neuronal apoptosis determines the severity of cerebral infarction. However, there is no effective therapy for CVD. Granulocyte-colony stimulating factor (G-CSF), a potent hematopoietic factor, could inhibit apoptosis of hematopoietic progenitor cells. However, its effect on neuronal cells is still unclear. In this study, we investigated the anti-apoptosis properties of G-CSF in neurons following focal cerebral ischemia in diabetic rats. The diabetic condition was generated in rats by intravenous injection of streptozotocin. After 6 weeks, diabetic rats underwent middle cerebral artery occlusion (MCAO) and received subcutaneous administration of G-CSF (50 microg/kg) daily for 7, 14 or 21 days. We analyzed the changes in neurological severity scores, infarct volume, number of apoptotic neurons, and the expression of G-CSF receptor, phosphorylated signal transducer and activator of transcription 3 (pSTAT3), cellular inhibitor of apoptosis protein 2 (cIAP2), Bcl-2, and Bax in the brain tissue. Bax is a pro-apoptotic member of the Bcl-2 protein family. The DM rats treated with G-CSF not only showed the reduced infarct volume and decreased apoptosis cell number, but also presented improved neurological scores. The G-CSF also increased the expression of pSTAT3, Bcl-2, and cIAP2 proteins as well as Bcl-2 mRNA, but inhibited Bax protein expression in the brain. These results indicate that G-CSF partially increases neuronal survival by affecting apoptosis pathways. G-CSF provides a potential treatment for stroke and other neurological dysfunction accompanied by neuronal apoptosis.