不同强度运动抑制糖尿病大鼠肾脏PI3K/AKT/mTOR信号通路改善自噬的比较

背景:2型糖尿病损害肾功能。研究表明运动干预可以保护肾脏;鸢尾素可以通过抑制磷脂酰肌醇3-激酶/蛋白激酶B/雷帕霉素靶蛋白信号通路恢复自噬,保护糖尿病肾病患者的肾功能。目的:探讨运动能否通过抑制肾脏磷脂酰肌醇3-激酶/蛋白激酶B/雷帕霉素靶蛋白信号通路过度激活来恢复自噬,改善肾损伤,以及分析不同方式运动产生影响的差异。方法:将6周龄的SD大鼠随机分为空白对照组(正常大鼠)和糖尿病组,其中糖尿病组大鼠经过高脂高糖喂养加腹腔注射低剂量1%链脲佐菌素(30 mg/kg)建立2型糖尿病模型。造模成功后再将糖尿病组大鼠随机分成糖尿病模型组、中强度持续运动组和高强度间歇运动组。两个运动组大鼠分别进行8周不同强度运动干预。取材后采用葡萄糖氧化酶法检测大鼠空腹血糖,使用试剂盒检测糖化血红蛋白水平,Elisa法检测血清胰岛素浓度,计算胰岛素抵抗指数,RT-PCR检测肾组织磷脂酰肌醇3-激酶、蛋白激酶B、雷帕霉素靶蛋白、Beclin-1、podocin、nephrin的基因表达量,Western Blot检测肾组织雷帕霉素靶蛋白及自噬标记蛋白LC3-1、LC3-2、Beclin-1的蛋白表达量。结果与结论:①2型糖尿病大鼠空腹血糖和糖化血红蛋白水平极显著性升高,胰岛素抵抗水平显著上升,胰岛素水平显著下降;两种运动均能使2型糖尿病大鼠空腹血糖和糖化血红蛋白水平极显著下降,胰岛素抵抗水平显著下降,胰岛素水平显著上升;与中强度持续运动组相比,高强度间歇运动组胰岛素水平显著上升。②2型糖尿病大鼠podocin、nephrin基因表达量显著降低;两种不同形式运动均能显著提高其表达;与高强度间歇运动组相比,中等强度持续性运动组足细胞相关蛋白基因表达有进一步上升趋势,但无显著性差异。③2型糖尿病大鼠肾组织磷脂酰肌醇3-激酶、蛋白激酶B、mTORC1的mRNA及蛋白的表达量显著增加,自噬标志蛋白Beclin-1、LC3-2表达量以及LC3-2/LC3-1显著降低;两种不同形式运动均能使肾组织磷脂酰肌醇3-激酶、蛋白激酶B、mTORC1的mRNA及雷帕霉素靶蛋白蛋白的表达量显著降低,自噬标志蛋白Beclin-1、LC3-2以及LC3-2/LC3-1显著升高;与中等强度持续性运动组相比,高强度间歇运动的磷脂酰肌醇3-激酶、蛋白激酶B、mTORC1的mRNA及雷帕霉素靶蛋白的蛋白表达量有进一步下降的趋势,Beclin-1、LC3-2以及LC3-2/LC3-1有进一步升高的趋势,但仅Beclin-1有显著性差异。④结果说明2型糖尿病肾脏足细胞损伤,自噬受到抑制,与磷脂酰肌醇3-激酶/蛋白激酶B/mTORC1信号通路被异常激活密切相关。高强度间歇运动和中等强度持续性运动可以保护糖尿病肾脏,减少足细胞损伤,促进自噬恢复,这可能与运动抑制磷脂酰肌醇3-激酶/蛋白激酶B/雷帕霉素靶蛋白信号通路过度激活有关。与中等强度持续性运动相比,高强度间歇运动恢复自噬的效果呈更优趋势,但足细胞蛋白表达稍有下降。

The Channel Branches & Network Vessels on the Tianhui Lacquered Meridian Figurine——Taking the Heart-Regulated Channel as an Example

Along with the surge of unearthed medical literature and cultural relics in recent years,a network of channels in the system of medical conduit vessels(meridians) during the early Western Han dynasty has become much clearer gradually.In it,the increasing number of channel branches,network vessels and needle insertion holes(acupoints) is an important feature of the development of channel medicine during the Western Han dynasty.This is not only a reflection of the expanding requirements of the theoretical system of the main trunk channels and other vessels,but also an inevitable result of the continuous enrichment and accumulation of clinical experience.This article integrates the information about channel branches,network vessels,inscriptions,dots and further relics on the Tianhui(天回) Lacquered Meridian Figurine to compare the unearthed literature of the channel genre with the transmitted classical literature about acupuncture.The “Heart-Regulated Channel” in Medical Manuscripts on Bamboo Slips from Tianhui(《天回医简》) serves as an example to explain the occurrence,development and changes of the channel branches and network vessels in the early system of medical channels.

Deep learning for joint channel estimation and feedback in massive MIMO systems

The great potentials of massive Multiple-Input Multiple-Output(MIMO)in Frequency Division Duplex(FDD)mode can be fully exploited when the downlink Channel State Information(CSI)is available at base stations.However,the accurate CsI is difficult to obtain due to the large amount of feedback overhead caused by massive antennas.In this paper,we propose a deep learning based joint channel estimation and feedback framework,which comprehensively realizes the estimation,compression,and reconstruction of downlink channels in FDD massive MIMO systems.Two networks are constructed to perform estimation and feedback explicitly and implicitly.The explicit network adopts a multi-Signal-to-Noise-Ratios(SNRs)technique to obtain a single trained channel estimation subnet that works well with different SNRs and employs a deep residual network to reconstruct the channels,while the implicit network directly compresses pilots and sends them back to reduce network parameters.Quantization module is also designed to generate data-bearing bitstreams.Simulation results show that the two proposed networks exhibit excellent performance of reconstruction and are robust to different environments and quantization errors.

Transient receptor potential channels as predictive marker and potential indicator of chemoresistance in colon cancer

Transient receptor potential(TRP)channels are strongly associated with colon cancer development and progression.This study leveraged a multivariate Cox regression model on publicly available datasets to construct a TRP channels-associated gene signature,with further validation of signature in real world samples from our hospital treated patient samples.Kaplan-Meier(K-M)survival analysis and receiver operating characteristic(ROC)curves were employed to evaluate this gene signature’s predictive accuracy and robustness in both training and testing cohorts,respectively.Additionally,the study utilized the CIBERSORT algorithm and single-sample gene set enrichment analysis to explore the signature’s immune infiltration landscape and underlying functional implications.The support vector machine algorithm was applied to evaluate the signature’s potential in predicting chemotherapy outcomes.The findings unveiled a novel three TRP channels-related gene signature(MCOLN1,TRPM5,and TRPV4)in colon adenocarcinoma(COAD).The ROC and K-M survival curves in the training dataset(AUC=0.761;p=1.58e-05)and testing dataset(AUC=0.699;p=0.004)showed the signature’s robust predictive capability for the overall survival of COAD patients.Analysis of the immune infiltration landscape associated with the signature revealed higher immune infiltration,especially an increased presence of M2 macrophages,in high-risk group patients compared to their low-risk counterparts.High-risk score patients also exhibited potential responsiveness to immune checkpoint inhibitor therapy,evident through increased CD86 and PD-1 expression profiles.Moreover,the TRPM5 gene within the signature was highly expressed in the chemoresistance group(p=0.00095)and associated with poor prognosis(p=0.036)in COAD patients,highlighting its role as a hub gene of chemoresistance.Ultimately,this signature emerged as an independent prognosis factor for COAD patients(p=6.48e-06)and expression of model gene are validated by public data and real-world patients.Overall,this bioinformatics study provides valuable insights into the prognostic implications and potential chemotherapy resistance mechanisms associated with TRPs-related genes in colon cancer.

A Probing Model of Secret Key Generation Based on Channel Autocorrelation Function

Secret key generation(SKG)is a promising solution to the problem of wireless communications security.As the first step of SKG,channel probing affects it significantly.Although there have been some probing schemes,there is a lack of research on the optimization of the probing process.This study investigates how to optimize correlated parameters to maximize the SKG rate(SKGR)in the time-division duplex(TDD)mode.First,we build a probing model which includes the effects of transmitting power,the probing period,and the dimension of sample vectors.Based on the model,the analytical expression of the SKGR is given.Next,we formulate an optimization problem for maximizing the SKGR and give an algorithm to solve it.We conclude the SKGR monotonically increases as the transmitting power increases.Relevant mathematical proofs are given in this study.From the simulation results,increasing appropriately the probing period and the dimension of the sample vector could increase the SKGR dramatically compared to a yardstick,which indicates the importance of optimizing the parameters related to the channel probing phase.

A Denoiser for Correlated Noise Channel Decoding: Gated-Neural Network

This letter proposes a sliced-gated-convolutional neural network with belief propagation(SGCNN-BP) architecture for decoding long codes under correlated noise. The basic idea of SGCNNBP is using Neural Networks(NN) to transform the correlated noise into white noise, setting up the optimal condition for a standard BP decoder that takes the output from the NN. A gate-controlled neuron is used to regulate information flow and an optional operation—slicing is adopted to reduce parameters and lower training complexity. Simulation results show that SGCNN-BP has much better performance(with the largest gap being 5dB improvement) than a single BP decoder and achieves a nearly 1dB improvement compared to Fully Convolutional Networks(FCN).

Dilation,discrimination and Uhlmann's theorem of link products of quantum channels

We establish the Stinespring dilation theorem of the link product of quantum channels in two different ways,discuss the discrimination of quantum channels,and show that the distinguishability can be improved by self-linking each quantum channel n times as n grows.We also find that the maximum value of Uhlmann's theorem can be achieved for diagonal channels.

RNA interference reveals chloride channel 7 gene helps short-term hypersalinity stress resistance in Hong Kong oyster Crassostrea hongkongensis

The chloride channel 7 gene(CLC 7)of the Hong Kong oyster Crassostrea hongkongensis was cloned and named ChCLC 7.The cDNA was 2572 bp in length,with a 5′non-coding region containing 25 bp,a 3′non-coding region containing 327 bp,and an open reading frame of 2298 bp.ChCLC 7 has 96.8%and 92.1%homology with CLC 7 of Crassostrea gigas and Crassostrea virginica,respectively,and it was clustered with CLC 7 of C.gigas and C.virginica.QRT-PCR showed that ChCLC 7 was expressed in all eight tissues,with the highest in adductor muscle and second in gill.The ChCLC 7 expression pattern in gill was altered significantly under high salinity stress with an overall upward and then downward trend.After RNA interference,the expression of ChCLC 7 and survival rate of oyster under high salinity stress was reduced significantly,and so did the concentration of hemolymph chloride ion in 48-96 h after RNA interference.We believed that ChCLC 7 could play an important role in osmoregulation of C.hongkongensis by regulating Cl^(-)transport.This study provided data for the analysis of molecular mechanism against oyster salinity stress.

Ultimately Bounded Output Feedback Control for Networked Nonlinear Systems With Unreliable Communication Channel: A Buffer-Aided Strategy

This paper concerns ultimately bounded output-feedback control problems for networked systems with unknown nonlinear dynamics. Sensor-to-observer signal transmission is facilitated over networks that has communication constraints.These transmissions are carried out over an unreliable communication channel. In order to enhance the utilization rate of measurement data, a buffer-aided strategy is novelly employed to store historical measurements when communication networks are inaccessible. Using the neural network technique, a novel observer-based controller is introduced to address effects of signal transmission behaviors and unknown nonlinear dynamics.Through the application of stochastic analysis and Lyapunov stability, a joint framework is constructed for analyzing resultant system performance under the introduced controller. Subsequently, existence conditions for the desired output-feedback controller are delineated. The required parameters for the observerbased controller are then determined by resolving some specific matrix inequalities. Finally, a simulation example is showcased to confirm method efficacy.

Channel assignment and power allocation for throughput improvement with PPO in B5G heterogeneous edge networks

In Beyond the Fifth Generation(B5G)heterogeneous edge networks,numerous users are multiplexed on a channel or served on the same frequency resource block,in which case the transmitter applies coding and the receiver uses interference cancellation.Unfortunately,uncoordinated radio resource allocation can reduce system throughput and lead to user inequity,for this reason,in this paper,channel allocation and power allocation problems are formulated to maximize the system sum rate and minimum user achievable rate.Since the construction model is non-convex and the response variables are high-dimensional,a distributed Deep Reinforcement Learning(DRL)framework called distributed Proximal Policy Optimization(PPO)is proposed to allocate or assign resources.Specifically,several simulated agents are trained in a heterogeneous environment to find robust behaviors that perform well in channel assignment and power allocation.Moreover,agents in the collection stage slow down,which hinders the learning of other agents.Therefore,a preemption strategy is further proposed in this paper to optimize the distributed PPO,form DP-PPO and successfully mitigate the straggler problem.The experimental results show that our mechanism named DP-PPO improves the performance over other DRL methods.

Assessment of the Recent Hydromorphological Features of Nokoue Lake and Its Channels (South-East Benin)

Based on 2022 and 2023 hydrometric data and satellite images (Sentinel 2022, SPOT 2010), this study aims to present the Nokoué Lake and its channels’ re-cent hydromorphological characteristics. Integrating flow, tributary morphology, and topography data determined specific power values along the axes studied. The values obtained range from 2.69 to 12.92 W/m2 for Ouémé River and 2.46 to 10.99 W/m2 for Sô River. The resulting water erosion on banks and bottoms is of linear, areolar, or gully and claw types. Lake bathymetry varies from -0.5 to -2.6 m (low flow period) and -1 to -4 m;in the Ouémé, Sô, and Totchè rivers, it varies from -5 m to -7 m, reaching -10 m at the Cotonou channel entrance (flood period). Bathymetric profiles reveal varied “U”, “V” and “Intermediate” bottom morphologies, influenced by erosion/sedimentation processes and human activities. The flow facies identified are lentic in the northern tributaries and lotic in the Cotonou and Totchè canals. Spatial analysis identified nine (09) thematic classes. In 2022, the surface area of the water body has increased from 274 km2 at low water to 280 km2 at high water, whereas in 2010 (a recent year of exceptional flooding), the surface area was 270 km2 at low water and 277 km2 at high water. Significant changes in land use are observed between 2010 and 2022. The floodplain area decreased slightly, from 421 km2 in 2010 (year of exceptional flooding) to 419 km2 in 2022. The evolution of land use shows a progressive expansion of the urban environment to the detriment of the natural environment. In the medium to long term, this trend could threaten the hydromorphological balance and even the existence of this important lagoon ecosystem.

Optimization of Channel Structure of Alkaline Water Electrolyzer by Using an Expanded Mesh as a Bipolar Plate

Alkaline water electrolysis(AWE)is the most mature technology for hydrogen production by water electrolysis.Alkaline water electrolyzer consists of multiple electrolysis cells,and a single cell consists of a diaphragm,electrodes,bipolar plates and end plates,etc.The existing industrial bipolar plate channel is concave-convex structure,which is manufactured by complicated and high-cost mold punching.This structure still results in uneven electrolyte flow and low current density in the electrolytic cell,further increasing in energy consumption and cost of AWE.Thereby,in this article,the electrochemical and flow model is firstly constructed,based on the existing industrial concave and convex flow channel structure of bipolar plate,to study the current density,electrolyte flow and bubble distribution in the electrolysis cell.The reliability of the model was verified by comparison with experimental data in literature.Among which,the electrochemical current density affects the bubble yield,on the other hand,the generated bubbles cover the electrode surface,affecting the active specific surface area and ohmic resistance,which in turn affects the electrochemical reaction.The result indicates that the flow velocity near the bottom of the concave ball approaches zero,while the flow velocity on the convex ball surface is significantly higher.Additionally,vortices are observed within the flow channel structure,leading to an uneven distribution of electrolyte.Next,modelling is used to optimize the bipolar plate structure of AWE by simulating the electrochemistry and fluid flow performances of four kinds of structures,namely,concave and convex,rhombus,wedge and expanded mesh,in the bipolar plate of alkaline water electrolyzer.The results show that the expanded mesh channel structure has the largest current density of 3330 A/m^(2)and electrolyte flow velocity of 0.507 m/s in the electrolytic cell.Under the same current density,the electrolytic cell with the expanded mesh runner structure has the smallest potential and energy consumption.This work provides a useful guide for the comprehensive understanding and optimization of channel structures,and a theoretical basis for the design of large-scale electrolyzer.

CNN Channel Attention Intrusion Detection SystemUsing NSL-KDD Dataset

Intrusion detection systems(IDS)are essential in the field of cybersecurity because they protect networks from a wide range of online threats.The goal of this research is to meet the urgent need for small-footprint,highly-adaptable Network Intrusion Detection Systems(NIDS)that can identify anomalies.The NSL-KDD dataset is used in the study;it is a sizable collection comprising 43 variables with the label’s“attack”and“level.”It proposes a novel approach to intrusion detection based on the combination of channel attention and convolutional neural networks(CNN).Furthermore,this dataset makes it easier to conduct a thorough assessment of the suggested intrusion detection strategy.Furthermore,maintaining operating efficiency while improving detection accuracy is the primary goal of this work.Moreover,typical NIDS examines both risky and typical behavior using a variety of techniques.On the NSL-KDD dataset,our CNN-based approach achieves an astounding 99.728%accuracy rate when paired with channel attention.Compared to previous approaches such as ensemble learning,CNN,RBM(Boltzmann machine),ANN,hybrid auto-encoders with CNN,MCNN,and ANN,and adaptive algorithms,our solution significantly improves intrusion detection performance.Moreover,the results highlight the effectiveness of our suggested method in improving intrusion detection precision,signifying a noteworthy advancement in this field.Subsequent efforts will focus on strengthening and expanding our approach in order to counteract growing cyberthreats and adjust to changing network circumstances.

Compound 3k治疗骨关节炎:调控氧化应激通路改善软骨细胞糖酵解的作用机制

背景:骨关节炎现已被认为是一种代谢性疾病,既往研究表明糖酵解在骨关节炎的发生发展中起重要作用。Compound 3k作为一种新型糖酵解小分子抑制剂,具有抗炎及抗肿瘤等功效,因此可靶向糖酵解,有望为骨关节炎治疗提供新的思路。目的:基于缺氧诱导因子1α/活性氧的氧化应激通路探究Compound 3k在糖酵解过度活跃所导致的骨关节炎中的作用机制。方法:取对数生长期的ATDC5成软骨细胞,用10 ng/mL白细胞介素1β作用24 h诱导骨关节炎体外细胞模型,以CCK-8法检测不同浓度(0.25,0.5,1,2.5,5,10,15μmol/L)Compound 3k的细胞毒性,选出合适浓度进行后续实验。将软骨细胞随机分为对照组、模型组、治疗组,模型组以10 ng/mL的白细胞介素1β诱导,治疗组以Compound 3k预刺激2 h后与白细胞介素1β共培养,用CCK-8法检测各组细胞增殖情况;用ELISA试剂盒检测各组细胞炎症水平;用试剂盒检测各组细胞活性氧、细胞外乳酸脱氢酶及葡萄糖含量;qRT-PCR及Western blot检测相关炎症因子白细胞介素6、肿瘤坏死因子α及糖酵解相关基因葡萄糖转运蛋白1、甘油醛3-磷酸脱氢酶、单羧酸转运蛋白1和缺氧诱导因子1α的表达水平。结果与结论:①与对照组相比,模型组细胞增殖活性下降、糖酵解水平活跃,表现为细胞外乳酸脱氢酶含量增加(P<0.001),葡萄糖含量减少(P<0.001),相关炎症因子白细胞介素6(P<0.0001)及肿瘤坏死因子α(P<0.001),糖酵解相关基因葡萄糖转运蛋白1(P<0.001)、甘油醛3-磷酸脱氢酶(P<0.001)、单羧酸转运蛋白1(P<0.001)及缺氧诱导因子1α(P<0.001)的表达水平均上调,并伴随氧化应激,活性氧过量产生。②与模型组相比,Compound 3k的治疗有效提高细胞增殖活性,抑制过度活跃的糖酵解水平的同时,抑制了骨关节炎软骨细胞炎症(P<0.001)及糖酵解相关基因的表达(P<0.001),且抑制氧化应激,缺氧诱导因子1α的表达水平下调(P<0.0001),活性氧水平下降。③上述结果证实,Compound 3k抑制了白细胞介素1β诱导的软骨细胞炎症,其机制可能与糖酵解及缺氧诱导因子1α/活性氧介导的氧化应激有关。

Expression levels of K_(ATP)channel subunits and morphological changes in the mouse liver after exposure to radiation

BACKGROUND ATP sensitive K+(K_(ATP))channels are ubiquitously distributed in various of cells and tissues,including the liver.They play a role in the pathogenesis of myocardial and liver ischemia.AIM To evaluate the radiation-induced changes in the expression of K_(ATP)channel subunits in the mouse liver to understand the potential role of K_(ATP)channels in radiation injury.METHODS Adult C57BL/6 mice were randomly exposed toγ-rays at 0 Gy(control,n=2),0.2 Gy(n=6),1 Gy(n=6),or 5 Gy(n=6).The livers were removed 3 and 24 h after radiation exposure.Hematoxylin and eosin staining was used for morphological observation;immunohistochemical staining was applied to determine the expression of K_(ATP)channel subunits in the liver tissue.RESULTS Compared with the control group,the livers exposed to 0.2 Gyγ-ray showed an initial increase in the expression of Kir6.1 at 3 h,followed by recovery at 24 h after exposure.Exposure to a high dose of 5.0 Gy resulted in decreased expression of Kir6.1 and increased expression of SUR2B at 24 h.However,the expression of Kir6.2,SUR1,or SUR2A had no remarkable changes at 3 and 24 h after exposure to any of these doses.CONCLUSION The expression levels of Kir6.1 and SUR2B in mouse liver changed differently in response to different radiation doses,suggesting a potential role for them in radiation-induced liver injury.

Potassium and calcium channels in different nerve cells act as therapeutic targets in neurological disorders

The central nervous system, information integration center of the body, is mainly composed of neurons and glial cells. The neuron is one of the most basic and important structural and functional units of the central nervous system, with sensory stimulation and excitation conduction functions. Astrocytes and microglia belong to the glial cell family, which is the main source of cytokines and represents the main defense system of the central nervous system. Nerve cells undergo neurotransmission or gliotransmission, which regulates neuronal activity via the ion channels, receptors, or transporters expressed on nerve cell membranes. Ion channels, composed of large transmembrane proteins, play crucial roles in maintaining nerve cell homeostasis. These channels are also important for control of the membrane potential and in the secretion of neurotransmitters. A variety of cellular functions and life activities, including functional regulation of the central nervous system, the generation and conduction of nerve excitation, the occurrence of receptor potential, heart pulsation, smooth muscle peristalsis, skeletal muscle contraction, and hormone secretion, are closely related to ion channels associated with passive transmembrane transport. Two types of ion channels in the central nervous system, potassium channels and calcium channels, are closely related to various neurological disorders, including Alzheimer's disease, Parkinson's disease, and epilepsy. Accordingly, various drugs that can affect these ion channels have been explored deeply to provide new directions for the treatment of these neurological disorders. In this review, we focus on the functions of potassium and calcium ion channels in different nerve cells and their involvement in neurological disorders such as Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism, and rare disorders. We also describe several clinical drugs that target potassium or calcium channels in nerve cells and could be used to treat these disorders. We concluded that there are few clinical drugs that can improve the pathology these diseases by acting on potassium or calcium ions. Although a few novel ion-channelspecific modulators have been discovered, meaningful therapies have largely not yet been realized. The lack of target-specific drugs, their requirement to cross the blood–brain barrier, and their exact underlying mechanisms all need further attention. This review aims to explain the urgent problems that need research progress and provide comprehensive information aiming to arouse the research community's interest in the development of ion channel-targeting drugs and the identification of new therapeutic targets for that can increase the cure rate of nervous system diseases and reduce the occurrence of adverse reactions in other systems.

Side-Channel Attacks & Data Exfiltration Using Wall Outlet USB Power Adapters

The number and creativity of side channel attacks have increased dramatically in recent years. Of particular interest are attacks leveraging power line communication to 1) gather information on power consumption from the victim and 2) exfiltrate data from compromised machines. Attack strategies of this nature on the greater power grid and building infrastructure levels have been shown to be a serious threat. This project further explores this concept of a novel attack vector by creating a new type of penetration testing tool: an USB power adapter capable of remote monitoring of device power consumption and communicating through powerline communications.

Human-induced pluripotent stem cell-derived neural stem cell exosomes improve blood-brain barrier function after intracerebral hemorrhage by activating astrocytes via PI3K/AKT/MCP-1 axis

Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.

二甲双胍抑制PI3K/AKT/mTOR信号通路保护骨关节炎模型大鼠关节软骨

背景:研究表明,二甲双胍具有抗炎、抗肿瘤、抗衰老与血管保护作用,可抑制骨关节炎的进展,但其具体的作用机制仍不明确。目的:探讨二甲双胍对骨关节炎模型大鼠软骨保护的作用机制。方法:取40只雄性SD大鼠,采用随机数字表法分4组(n=10):空白组不进行任何手术,假手术组暴露关节腔,模型组、二甲双胍组采用改良Hulth法建立骨关节炎模型;造模后1 d,二甲双胍组大鼠灌胃给予二甲双胍200 mg/(kg·d),模型组、空白组、假手术组灌胃给予生理盐水,连续给药4周。给药结束后,苏木精-伊红、甲苯胺蓝和番红O-固绿染色观察大鼠膝关节软骨病理形态,免疫组化染色与Western blotting检测大鼠软骨组织中SOX9、Ⅱ型胶原、ADAMTS5、Beclin1、P62、p-PI3K、PI3K、p-AKT、AKT、p-mTOR、mTOR的蛋白表达。结果与结论:①苏木精-伊红、甲苯胺蓝和番红O-固绿染色结果显示,空白组、假手术组大鼠膝关节软骨表面光滑,组织形态正常;模型组大鼠膝关节软骨表面不规则,软骨组织出现缺损,软骨细胞数量减少,软骨基质中蛋白多糖含量减少;相较于模型组,二甲双胍组大鼠膝关节软骨结构损伤有明显改善,软骨表面趋于平整,软骨细胞数量与软骨基质中蛋白多糖含量增加;②免疫组化染色与Western blotting检测结果显示,与空白组、假手术组比较,模型组大鼠软骨组织中SOX9、Ⅱ型胶原、Beclin1蛋白表达降低(P<0.05),ADAMTS5、P62及p-PI3K、p-AKT、p-mTOR蛋白表达升高(P<0.05);与模型组比较,二甲双胍组大鼠软骨组织中SOX9、Ⅱ型胶原、Beclin1蛋白表达升高(P<0.05),ADAMTS5、P62及p-PI3K、p-AKT、p-mTOR蛋白表达降低(P<0.05);③结果表明,二甲双胍可通过抑制PI3K/AKT/mTOR信号通路的活化提高骨关节炎模型大鼠软骨细胞自噬活性、减少软骨基质降解,进而发挥关节软骨保护作用。

The potential mechanism and clinical application value of remote ischemic conditioning in stroke

Some studies have confirmed the neuroprotective effect of remote ischemic conditioning against stroke. Although numerous animal researches have shown that the neuroprotective effect of remote ischemic conditioning may be related to neuroinflammation, cellular immunity, apoptosis, and autophagy, the exact underlying molecular mechanisms are unclear. This review summarizes the current status of different types of remote ischemic conditioning methods in animal and clinical studies and analyzes their commonalities and differences in neuroprotective mechanisms and signaling pathways. Remote ischemic conditioning has emerged as a potential therapeutic approach for improving stroke-induced brain injury owing to its simplicity, non-invasiveness, safety, and patient tolerability. Different forms of remote ischemic conditioning exhibit distinct intervention patterns, timing, and application range. Mechanistically, remote ischemic conditioning can exert neuroprotective effects by activating the Notch1/phosphatidylinositol 3-kinase/Akt signaling pathway, improving cerebral perfusion, suppressing neuroinflammation, inhibiting cell apoptosis, activating autophagy, and promoting neural regeneration. While remote ischemic conditioning has shown potential in improving stroke outcomes, its full clinical translation has not yet been achieved.