Cell polarization in ischemic stroke: molecular mechanisms and advances

Ischemic stroke is a cerebrovascular disease associated with high mortality and disability rates. Since the inflammation and immune response play a central role in driving ischemic damage, it becomes essential to modulate excessive inflammatory reactions to promote cell survival and facilitate tissue repair around the injury site. Various cell types are involved in the inflammatory response, including microglia, astrocytes, and neutrophils, each exhibiting distinct phenotypic profiles upon stimulation. They display either proinflammatory or anti-inflammatory states, a phenomenon known as ‘cell polarization.’ There are two cell polarization therapy strategies. The first involves inducing cells into a neuroprotective phenotype in vitro, then reintroducing them autologously. The second approach utilizes small molecular substances to directly affect cells in vivo. In this review, we elucidate the polarization dynamics of the three reactive cell populations(microglia, astrocytes, and neutrophils) in the context of ischemic stroke, and provide a comprehensive summary of the molecular mechanisms involved in their phenotypic switching. By unraveling the complexity of cell polarization, we hope to offer insights for future research on neuroinflammation and novel therapeutic strategies for ischemic stroke.

Quercetin induced HepG2 cells apoptosis through ATM/JNK/STAT3 signaling pathways

Liver cancer is the seventh most common malignant tumor in the world and is the second highest cause of death due to cancer.Quercetin,a flavonoid with low toxicity,widely exists in various fruits and vegetables.It has the potential to be a therapeutic agent against various cancers.This study aimed to demonstrate the anti-tumor effect of quercetin on HepG2 cells.Quercetin suppressed the HepG2 cell proliferation in a dose-dependent manner in cell viability assay.Induction of cell apoptosis was confirmed by apoptotic cells population(sub-G1 peak)detected by flow cytometer.A decrease in mitochondrial membrane potential and caspase-3 activation were also demonstrated in this study.Furthermore,quercetin induced HepG2 cell apoptosis through ROS-mediated phosphorylated ataxia-telangiectasia mutated,c-Jun Nterminal kinases,signal transducer,and activator of transcription 3(STAT-3),and Bax signaling pathways.These results suggest that quercetin has the potential to become an effective drug against the tumor.

Inhibition of H_(2)O_(2)-induced apoptosis of GC2-spg cells by functionalized selenium nanoparticles with lentinan through ROSmediated ERK/p53 signaling pathways

AH_(2)O_(2)-induced oxidative stress injury cell model was established to investigate the antioxidant effect of nanoselenium on mouse spermatocyte lines and the regulation mechanism of the expression level and activity of seleniumcontaining antioxidant enzymes induced by oxidative stress.A safe and effective nano-drug system of functionalized selenium-containing nanoparticles(SeNPs)was developed with lentinan(LNT)(SeNPs@LNT).Mice spermatocyte line GC2-spg cells were treated with SeNPs@LNT(1,2,4,8,16,32μM)for 24-72 h to evaluate the cytotoxicity of selenium.GC2-spg cells were randomly divided into the following groups:control,hydrogen peroxide(H_(2)O_(2)),SeNPs@LNT,and H_(2)O_(2)+SeNPs@LNT groups.H_(2)O_(2)+SeNPs@LNT group was pretreated with SeNPs@LNT 4μM for 12 h,followed by H_(2)O_(2)600μM for 8 h.The cell viability decreased in the H_(2)O_(2) group and increased significantly in the SeNPs@LNT group.Compared with the H_(2)O_(2) group,the SeNPs@LNT+H_(2)O_(2) group exhibited obvious red fluorescence,indicating a higher level of mitochondrial membrane potential.The content of intracellular reactive oxygen species(ROS)in the SeNPs@LNT group reduced significantly,and the intensity of green fluorescence in the SeNPs@LNT+H_(2)O_(2) group decreased significantly compared with the H_(2)O_(2) group,indicating the inhibitory effect of SeNPs@LNT on the generation of ROS-induced oxidative stress.The activity of GPx and SOD increased significantly in the SeNPs@LNT group.The expression of p53 decreased significantly under the intervention of nano-selenium,and GPx1 expression increased.In the oxidative stress group,the expressions of DNA damage-related proteins and apoptosis-related proteins were higher than those in other groups.Thus,SeNPs@LNT can promote GC2-spg cell proliferation,improve GPx and SOD activities,remove intracellular ROS,and reduce mitochondrial damage and functional abnormalities caused by oxidative stress by regulating the ERK and p53 protein levels.SeNPs@LNT has good biological activity and antioxidant effect,which can be used to protect the male reproductive system from oxidative stress.

干扰FOXC1逆转非小细胞肺癌吉非替尼耐药的作用

背景与目的肺癌是我国发病率和死亡率最高的恶性肿瘤,其中非小细胞肺癌(non-small cell lung cancer,NSCLC)约占肺癌的80%。表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI)靶向治疗已成为NSCLC临床治疗的主要手段,然而不可避免的耐药性出现极大限制了EGFR-TKI的治疗效果。叉头框蛋白C1(forkhead box protein C1,FOXC1)是叉头框蛋白家族重要成员,在NSCLC异常表达并参与调控NSCLC进展。本研究旨在探讨干扰FOXC1对NSCLC吉非替尼耐药的影响及可能机制。方法应用Western blot、免疫组化方法检测FOXC1在NSCLC吉非替尼耐药细胞和组织中的表达情况;应用FOXC1 shRNA转染HCC827/GR细胞,筛选稳定干扰FOXC1的HCC827/GR细胞,采用新型四氮唑盐比色法(Methyl-thiazolyldiphenyl-sulfophenyl-tetrazolium bromide assay,MTS)法、流式细胞术及微球体形成实验检测细胞增殖、细胞凋亡及细胞自我更新能力;采用实时荧光定量PCR(quantitative real-time PCR,qRT-PCR)、Western blot检测干性标志物SOX2、Nanog、OCT4和CD133的表达水平;运用流式细胞术检测CD133的表达情况;免疫组化检测耐药组织中SOX2和CD133的表达情况;基于癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库的肺腺癌数据集,分析FOXC1、SOX2和CD133表达的相关性。结果FOXC1在NSCLC吉非替尼耐药细胞HCC827/GR的表达水平显著高于HCC827敏感细胞(P<0.05),免疫组化结果显示FOXC1在NSCLC吉非替尼耐药组织中高表达。与对照组相比,稳定干扰FOXC1的HCC827/GR细胞对吉非替尼的半数抑制浓度(50%inhibitory concentration,IC50)值显著降低(P<0.01),细胞增殖能力降低、凋亡率升高(P<0.05)。干扰FOXC1能够抑制SOX2、CD133的表达,并减弱HCC827/GR耐药细胞的微球体形成能力。免疫组化结果显示,吉非替尼耐药组织中SOX2和CD133表达显著高于敏感组织(P<0.01)。相关性分析结果显示,FOXC1、SOX2和CD133表达两两呈正相关(P<0.05)。结论FOXC1参与NSCLC吉非替尼耐药,其机制可能与FOXC1调控肿瘤干细胞(cancer stem cells,CSCs)特性有关。

The tomato HIGH PIGMENT1/DAMAGED DNA BINDING PROTEIN 1 gene contributes to regulation of fruit ripening

Fleshy fruit ripening is governed by multiple external and internal cues and accompanied by changes in color,texture,volatiles,and nutritional quality traits.While extended shelf-life and increased phytonutrients are desired,delaying ripening via genetic or postharvest means can be accompanied by reduced nutritional value.Here we report that the high pigment 1(hp1)mutation at the UV-DAMAGED DNA BINDING PROTEIN 1(DDB1)locus,previously shown to influence carotenoid and additional phytonutrient accumulation via altered light signal transduction,also results in delayed ripening and firmer texture,resulting at least in part from decreased ethylene evolution.Transcriptome analysis revealed multiple ethylene biosynthesis and signaling-associated genes downregulated in hp1.Furthermore,the hp1 mutation impedes softening of the pericarp,placenta,columella as well as the whole fruit,in addition to reduced expression of the FRUITFUL2(FUL2)MADS-box transcription factor and xyloglucan endotransglucosylase/hydrolase 5(XTH5).These results indicate that DDB1 influences a broader range of fruit development and ripening processes than previously thought and present an additional genetic target for increasing fruit quality and shelf-life.

Separate Least Mean Square Based Equalizer with Joint Optimization for Multi-CAP Visible Light Communication

Visible light communication(VLC) is expected to be a potential candidate of the key technologies in the sixth generation(6G) wireless communication system to support Internet of Things(IoT) applications. In this work, a separate least mean square(S-LMS) equalizer is proposed to compensate lowpass frequency response in VLC system. Joint optimization is employed to realize the proposed S-LMS equalizer with pre-part and post-part by introducing Lagrangian. For verification, the performance of VLC system based on multi-band carrier-less amplitude and phase(m-CAP) modulation with S-LMS equalizer is investigated and compared with that without equalizer,with LMS equalizer and with recursive least squares(RLS)-Volterra equalizer. Results indicate the proposed equalizer shows significant improved bit error ratio(BER) performance under the same conditions. Compared to the RLS-Volterra equalizer, SLMS equalizer achieves better performance under low data rate or high signal noise ratio(SNR) conditions with obviously lower computational complexity.

Inhibitory of EV-A71 virus-induced apoptosis by ZVAD through ROS mediated signaling pathways

Emerging evidence that Enterovirus A 71(EV-A71)infection closely related to apoptosis.The ZVAD is a caspase inhibitor that can prevent apoptosis.The aims of this project were to evaluate the mechanism of the ZVAD inhibited EV-A71 virus and to provide experiment basis for finding new antiviral drugs.In this study,after treated with ZVAD in EV-A71 infected Vero cells,the viral replication was reduced,and the cell viability was higher than EV-A71 group.Additionally,ZVAD decreased the cell apoptosis and the level of inflammatory cytokines induced by EV-A71 in the infected Vero cells.ZVAD inhibited cell apoptosis by regulating ROS mediated signaling pathway and inflammation cytokines to achieve antiviral.

OsMAPK6 Affects Male Fertility by Reducing Microspore Number and Delaying Tapetum Degradation in Oryza sativa L.

The mitogen-activated protein kinase(MAPK)cascade is important in stress signal transduction and plant development.In the present study,we identified a rice(Oryza sativa L.)mutant with reduced fertility,Oryza sativa mitogen-activated protein kinase 6(osmapk6),which harbored a mutated MAPK gene.Scanning and transmission electron microscopy,quantitative RT-PCR analysis,TUNEL assays,RNA in situ hybridization,longitudinal and transverse histological sectioning,and map-based cloning were performed to characterize the osmapk6 mutant.The gene OsMAPK6 was expressed throughout the plant but predominantly in the microspore mother cells,tapetal cells,and microspores in the anther sac.Compared with the wild type,the total number of microspores was reduced in the osmapk6 mutant.The formation of microspore mother cells was reduced in the osmapk6 anther sac at an early stage of anther development,which was the primary reason for the decrease in the total number of microspores.Programmed cell death of some tapetal cells was delayed in osmapk6 anthers and affected exine formation in neighboring microspores.These results suggest that OsMAPK6 plays pivotal roles in microspore mother cell formation and tapetal cell degradation.

L-Selenocystine induce HepG2 cells apoptosis through ROS-mediated signaling pathways

At present,Hepatocarcinoma is one of the main causes of tumor related death all over the world.However,there are still many clinical restrictions on the treatment of liver cancer.Recently,L-Selenocystine has been shown to be a novel treatment for tumors,especially human glioma cells.But,the mechanism of L-Selenocystine against hepatocellular carcinoma remains unclear.Therefore,the main objective of this study was to investigate the effects of L-Selenocystine on HepG2 cell proliferation and activation of reactive oxygen species(ROS)mediated signaling pathway.L-Selenocystine can significantly inhibit HepG2 cell proliferation by activating caspase-3 and cleaving PARP to induce apoptosis.Moreover,the excessive production of ROS and the influence of Bax signaling pathway which can promote cell apoptosis are key factors for L-Selenocystine to induce HepG2 cell apoptosis.Therefore,the date of this study suggest that ROS mediated signal transduction mechanism may provide certain reference significance for L-Selenocystine induced HepG2 cell apoptosis.

Light-triggered nitric oxide release and structure transformation of peptide for enhanced intratumoral retention and sensitized photodynamic therapy

Tumor-targeted delivery of nanomedicine is of great importance to improve therapeutic efficacy of cancer and minimize systemic side effects.Unfortunately,nowadays the targeting efficiency of nanomedicine toward tumor is still quite limited and far from clinical requirements.In this work,we develop an innovative peptide-based nanoparticle to realize light-triggered nitric oxide(NO)release and structural transformation for enhanced intratumoral retention and simultaneously sensitizing photodynamic therapy(PDT).The designed nanoparticle is self-assembled from a chimeric peptide monomer,TPP-RRRKLVFFK-Ce6,which contains a photosensitive moiety(chlorin e6,Ce6),aβ-sheet-forming peptide domain(Lys-Leu-Val-Phe-Phe,KLVFF),an oligoarginine domain(RRR)as NO donor and a triphenylphosphonium(TPP)moiety for targeting mitochondria.When irradiated by light,the constructed nanoparticles undergo rapid structural transformation from nanosphere to nanorod,enabling to achieve a significantly higher intratumoral accumulation by 3.26 times compared to that without light irradiation.More importantly,the conversion of generated NO and reactive oxygen species(ROS)in a light-responsive way to peroxynitrite anions(ONOO)with higher cytotoxicity enables NO to sensitize PDT in cancer treatment.Both in vitro and in vivo studies demonstrate that NO sensitized PDT based on the well-designed transformable nanoparticles enables to eradicate tumors efficiently.The light-triggered transformable nanoplatform developed in this work provides a new strategy for enhanced intratumoral retention and improved therapeutic outcome.

Novel photo-theranostic GdB_(6) nanoparticles for fluorescence imaging and NIR-photothermal therapy

The development of multifunctional theranostic nano-agents is an important resolution for personalized treatment of cancer.In this work,we synthesized a new kind of gadolinium boride nanoparticles(GBN)by a microwave-assisted chemical etching method,and discovered their optical characteristics including fluorescence imaging and near-infrared(NIR)photothermal conversion capability.Bright greenishyellow fluorescence enabled for intracellular localization,while effective NIR-photothermal conversion supported photothermal therapy(PTT).In vitro and in vivo results indicated that GBN exhibited a superior antitumor performance and high biocompatibility.This study demonstrated a promising multifunctional theranostic nanoplatform for cancer treatment.

A nanoconcrete welding strategy for constructing high-performance wound dressing

Engineering biomaterials to meet specific biomedical applications raises high requirements of mechanical performances,and simultaneous strengthening and toughening of polymer are frequently necessary but very challenging in many cases.In this work,we propose a new concept of nanoconcrete welding polymer chains,where mesoporous CaCO3(mCaCO_(3))nanoconcretes which are composed of amorphous and nanocrystalline phases are developed to powerfully weld polymer chains through siphoning-induced occlusion,hydration-driven crystallization and dehydration-driven compression of nanoconcretes.The mCaCO_(3) nanoconcrete welding technology is verified to be able to remarkably augment strength,toughness and anti-fatigue performances of a model polymer poly(3-hydroxybutyrate-co-3-hydroxyvalerate)-based porous membrane.Mechanistically,we have revealed polymer-occluded nanocrystal structure and welding-derived microstress which is much stronger than interfacial Van der Waals force,thus efficiently preventing the generation of microcracks and repairing initial microcracks by microcracks-induced hydration,crystallization and polymer welding of mCaCO_(3) nanoconcretes.Constructed porous membrane is used as wound dressing,exhibiting a special nanoplates-constructed surface topography as well as a porous structure with plentiful oriented,aligned and opened pore channels,improved hydrophilicity,water vapor permeability,anti-bacterial and cell adherence,in support of wound healing and skin structural/functional repairing.The proposed nanoconcrete-welding-polymer strategy breaks a new pathway for improving the mechanical performances of polymers.