Hybridization and divergent climatic preferences drive divergence of two allopatric Gentiana species on the Qinghai-Tibet Plateau.

BACKGROUND AND AIMS: Exploring how species diverge is vital for understanding the drivers of speciation. Factors such as geographical separation and ecological selection, hybridization, polyploidization and shifts in mating system are all major mechanisms of plant speciation, but their contributions to divergence are rarely well understood. Here we test these mechanisms in two plant species, Gentiana lhassica and G. hoae, with the goal of understanding recent allopatric species divergence on the Qinghai-Tibet Plateau (QTP). METHODS: We performed Bayesian clustering, phylogenetic analysis and estimates of hybridization using 561 302 nuclear genomic single nucleotide polymorphisms (SNPs). We performed redundancy analysis, and identified and annotated species-specific SNPs (ssSNPs) to explore the association between climatic preference and genetic divergence. We also estimated genome sizes using flow cytometry to test for overlooked polyploidy. KEY RESULTS: Genomic evidence confirms that G. lhassica and G. hoae are closely related but distinct species, while genome size estimates show divergence occurred without polyploidy. Gentiana hoae has significantly higher average FIS values than G. lhassica. Population clustering based on genomic SNPs shows no signature of recent hybridization, but each species is characterized by a distinct history of hybridization with congeners that has shaped genome-wide variation. Gentiana lhassica has captured the chloroplast and experienced introgression with a divergent gentian species, while G. hoae has experienced recurrent hybridization with related taxa. Species distribution modelling suggested range overlap in the Last Interglacial Period, while redundancy analysis showed that precipitation and temperature are the major climatic differences explaining the separation of the species. The species differ by 2993 ssSNPs, with genome annotation showing missense variants in genes involved in stress resistance. CONCLUSIONS: This study suggests that the distinctiveness of these species on the QTP is driven by a combination of hybridization, geographical isolation, mating system differences and evolution of divergent climatic preferences.

Regulated Ion/Electron-Conducting Interphase Enables Stable Zinc-Metal Anodes for Aqueous Zinc-Ions Batteries.

Metallic Zinc (Zn) is considered as a remarkably promising anode for aqueous Zn-ion batteries due to its high volumetric capacity and low redox potential. Unfortunately, dendritic growth and severe side reactions destabilizes the electrode/electrolyte interface, and ultimately reduce the electrochemical performance. Here, an artificial protective layer (APL) with a regulated ion and electron-conducting interphase is constructed on the Zn-metal anode to provide excellent interfacial stability in high-rate cycling. The superior ionic and moderate electronic conductivity of the APL derives from the co-embedding of MXene and Zn(CF3 SO3 )2 salts into the polyvinyl alcohol hydrogel, which enables a synergistic effect of local current density reduction during plating and ion transport acceleration during stripping for Zn anode. Furthermore, the high Young's modulus of the protective layer and dendrite-free deposition morphology during cycling suppresses hydrogen evolution reactions (2.5 mmol h-1 cm-2 ) and passivation. As a result, in symmetrical cell tests, the modified battery presents a stable life of over 2000 cycles at ultra-high current density of 20 mA cm-2 . This research presents a new insight into the formation and regulation of stable electrode-electrolyte interface for the Zn-metal anode.

A metabolic intervention strategy to break evolutionary adaptability of tumor for reinforced immunotherapy.

The typical hallmark of tumor evolution is metabolic dysregulation. In addition to secreting immunoregulatory metabolites, tumor cells and various immune cells display different metabolic pathways and plasticity. Harnessing the metabolic differences to reduce the tumor and immunosuppressive cells while enhancing the activity of positive immunoregulatory cells is a promising strategy. We develop a nanoplatform (CLCeMOF) based on cerium metal-organic framework (CeMOF) by lactate oxidase (LOX) modification and glutaminase inhibitor (CB839) loading. The cascade catalytic reactions induced by CLCeMOF generate reactive oxygen species "storm" to elicit immune responses. Meanwhile, LOX-mediated metabolite lactate exhaustion relieves the immunosuppressive tumor microenvironment, preparing the ground for intracellular regulation. Most noticeably, the immunometabolic checkpoint blockade therapy, as a result of glutamine antagonism, is exploited for overall cell mobilization. It is found that CLCeMOF inhibited glutamine metabolism-dependent cells (tumor cells, immunosuppressive cells, etc.), increased infiltration of dendritic cells, and especially reprogrammed CD8+ T lymphocytes with considerable metabolic flexibility toward a highly activated, long-lived, and memory-like phenotype. Such an idea intervenes both metabolite (lactate) and cellular metabolic pathway, which essentially alters overall cell fates toward the desired situation. Collectively, the metabolic intervention strategy is bound to break the evolutionary adaptability of tumors for reinforced immunotherapy.

Establishing Thermal Infusion Method for Stable Zinc Metal Anodes in Aqueous Zinc-Ion Batteries.

Metallic zinc (Zn) having low cost, high capacity, environmentally friendly features is considered to be an attractive anode material for aqueous energy storage devices. However, dendritic growth and severe side reactions restrict the development of Zn-metal anodes. Numerous 3D hosts are extensively explored to settle these issues, whereas the accessible prestoring of Zn metal into structured electrodes is challenging. Here, a thermal infusion strategy is first reported to create a stable composite Zn-based anode. Upon this melting-wetting-cooling process, the metallic Zn is densely and firmly encapsulated in the 3D skeleton, efficiently inhibiting the dendritic growth. Meanwhile, through in/ex situ tests, the formation of ZnO layer on the metallic Zn surface inhibits the hydrogen evolution reactions (1.8 mmol h-1 cm-2 ) and passivation during cycling. Consequently, the electrode enables a long-cycling life of over 1000 cycles at 10 mA cm-2 in a symmetrical cell. The pouch cells pairing this novel anode and LiMn2 O4 cathode maintain over 94 mAh g-1 capacity retention after 300 cycles. This research presents an innovative Zn anode structure and extendable prestoring metallic Zn method for aqueous Zn-ion batteries.

Encapsulation of Metallic Zn in a Hybrid MXene/Graphene Aerogel as a Stable Zn Anode for Foldable Zn-Ion Batteries.

A 3D host can effectively mitigate the dendritic growth of a zinc (Zn)-metal anode. However, the increased electrode/electrolyte reaction area using the 3D substrate accelerates the passivation and corrosion at the anode interface, ultimately degrading the electrochemical performance. Here, an oriented freezing process is used to create a flexible MXene/graphene scaffold. Based on the abundant zincophilic traits and micropores in the structure, Zn is densely encapsulated inside the host by the electrodeposition process. During cycling, the composite anode endows an in situ solid electrolyte interface with zinc fluoride at the electrode/electrolyte interface due to inherent fluorine terminations in MXene, efficiently inhibiting the dendritic growth. Furthermore, the design wherein bulk Zn is distributed in a 3D microscale manner suppresses hydrogen evolution reactions (3.8 mmol h-1 cm-2 ) and passivation, through in/ex situ tests. As a result, in a symmetrical cell test, the electrode has a long-cycling life of over 1000 h at 10 mA cm-2 . After continuous single folding followed by double folding, a quasi-solid-state foldable cell with the composite anode and a LiMn2 O4 cathode (60% depth of discharge) maintains high-capacity retention of over 91%. This research presents a revolutionary encapsulating idea for aqueous Zn-ion batteries, as well as foldable investigation.

Ultrathin Surface Coating of Nitrogen-Doped Graphene Enables Stable Zinc Anodes for Aqueous Zinc-Ion Batteries.

Owing to the high volumetric capacity and low redox potential, zinc (Zn) metal is considered to be a remarkably prospective anode for aqueous Zn-ion batteries (AZIBs). However, dendrite growth severely destabilizes the electrode/electrolyte interface, and accelerates the generation of side reactions, which eventually degrade the electrochemical performance. Here, an artificial interface film of nitrogen (N)-doped graphene oxide (NGO) is one-step synthesized by a Langmuir-Blodgett method to achieve a parallel and ultrathin interface modification layer (≈120 nm) on Zn foil. The directional deposition of Zn crystal in the (002) planes is revealed because of the parallel graphene layer and beneficial zincophilic-traits of the N-doped groups. Meanwhile, through the in situ differential electrochemical mass spectrometry and in situ Raman tests, the directional plating morphology of metallic Zn at the interface effectively suppresses the hydrogen evolution reactions and passivation. Consequently, the pouch cells pairing this new anode with LiMn2 O4 cathode maintain exceptional energy density (164 Wh kg-1 after 178 cycles) at a reasonable depth of discharge, 36%. This work provides an accessible synthesis method and in-depth mechanistic analysis to accelerate the application of high-specific-energy AZIBs.

Cascade catalytic nanoplatform based on ions interference strategy for calcium overload therapy and ferroptosis.

Intracellular ions played prominent part in cell function and behavior. Disrupting intracellular ions homeostasis might switch ions signal from "regulating" to "destroying". Inspired by this, we introduced the ions interference strategy for tumor therapy. Herein, curcumin (CUR) and transferrin (Tf) co-loaded calcium peroxide nanoparticles (CaO2 NPs) were formulated. With tumor targeting ability, CaO2/Tf/CUR pinpointed tumor cells and then instantaneously decomposed in acidic lysosomes, concurrently accompanying with the release of Ca2+ and CUR, as well as the production of H2O2. Then H2O2 not only damaged structure of Tf to release Fe3+, but also was converted to hydroxyl radicals via ferric ions mediated Fenton reaction for ferroptosis. In addition, the released Ca2+ and CUR induced Ca2+ overload via exogenous and endogenous calcium ions accumulation, respectively, further activating mitochondria apoptosis signaling pathway for cell injury. Therefore, based on calcium and ferric ions interference strategy, the cascade catalytic CaO2/Tf/CUR offered synergistic combination of ferroptosis, Ca2+ overload therapy and chemotherapy, which held a great promise in cancer treatment.

Biomimetic Ca2+ nanogenerator based on ions interference strategy for tumour-specific therapy.

Intracellular Ca2+ ions as second messenger played key role in cell behaviour, which was often overlooked in traditional antitumor treatment. Disrupting Ca2+ ion homeostasis by Ca2+ overload might switch ions signal from 'regulating' to 'destroying'. Inspired by this, a biomimetic Ca2+ nanogenerator was constructed. Briefly, the curcumin (CUR) was loaded into mesoporous calcium carbonate nanoparticles (MCC NPs), and then coated with platelet (PLT) membrane. Upon reaching tumour cells by PLT membrane-mediated tumour targeting effect, PLT@MCC/CUR would instantaneously decompose in acidic lysosomes, concurrently accompanying with Ca2+ generation and CUR release. The CUR could further facilitate Ca2+ release from endoplasmic reticulum (ER) and inhibit Ca2+ efflux, aggravating Ca2+ overload to disrupt mitochondrial Ca2+ homeostasis for mitochondria apoptosis signalling pathway activation. Interestingly, such effect was ineffective in normal cells, realising the tumour-specific therapeutic therapy. Based on ions interference strategy, PLT@MCC/CUR herein offered synergistic combination of Ca2+ overload therapy and chemotherapy, which would pave the way towards more effective nanotherapeutics.

Bimetallic Antimony-Vanadium Oxide Nanoparticles Embedded in Graphene for Stable Lithium and Sodium Storage.

Bimetallic oxides have received considerable attention as anodes for lithium/sodium-ion batteries (LIBs/SIBs) due to their high electrochemical activity and theoretical specific capacity. However, their cycling performance is limited by large volume variation, severe aggregation, and pulverization of bimetallic oxide nanoparticles during repeated metal ion insertion/extraction processes. Herein, bimetallic antimony-vanadium oxide nanoparticles embedded in graphene (SbVO4/G) composites are prepared by a one-step hydrothermal method. Bimetallic SbVO4 with abundant redox reaction sites can provide high specific capacity by a multi-electron reaction. A robust graphene substrate can not only alleviate volume expansion but also prevent aggregation and collapse of highly active bimetallic SbVO4. Due to the excellent synergy between the two building components, SbVO4/G hybrids exhibit excellent electrochemical activity, structural stability, and electrochemical performance. When employed as anodes for LIBs and SIBs, SbVO4/G composites display excellent cycling performance (1079.5 mAh g-1 at 0.1 A g-1 after 150 cycles for LIBs and 401.6 mAh g-1 at 0.1 A g-1 after 450 cycles for SIBs) and impressive rate capability. This work demonstrates that SbVO4/G composites are promising anodes for both LIBs and SIBs.

Cascade Catalytic Nanoplatform Based on "Butterfly Effect" for Enhanced Immunotherapy.

The unique tumor microenvironment (TME) characteristics such as immunosuppression impeded traditional cancer treatments. In contrast, developing cascade catalytic nanoplatforms by fully making use of substances in TME for cancer therapy may deserve full credit. Herein, a cascade catalytic nanoplatform based on glucose oxidase (GOD) modified mesoporous iron oxide nanoparticles (IONP) loaded with Artemisinin (ART) is developed, which is designed as IONP-GOD@ART. GOD can catalyze the oxidization of glucose into gluconic acid and H2 O2 , which not only realizes tumor starvation therapy, but also provides H2 O2 for IONP mediated Fenton reaction. Simultaneously, mesoporous IONP releases Fe2+ and Fe3+ ions in acidic TME. On the one hand, iron ions undergo Fenton reaction to generate hydroxyl radicals for chemodynamic therapy. On the other hand, the endoperoxide bridge in ART is broken in presence of Fe2+ and further generates reactive oxygen species (ROS) to achieve therapeutic purpose. In this sense, IONP-GOD@ART manipulates TME characteristics and leads to "butterfly effect", which brings out a large amount of ROS for eliciting immunogenic cell death, inducing M1-TAMs polarization, and further reprogramming immunosuppressive TME for enhanced immunotherapy. By this delicate design, the cascade catalytic nanoplatform of IONP-GOD@ART realizes potent cancer immunotherapy for tumor regression and metastasis prevention.

A Biomimetic Nanogenerator of Reactive Nitrogen Species Based on Battlefield Transfer Strategy for Enhanced Immunotherapy.

Currently, cell membrane is always utilized for the construction of biomimetic nanoparticles. By contrast, mimicking the intracellular activity seems more meaningful. Inspired by the specific killing mechanism of deoxy-hemoglobin (Hb) dependent drug (RRx-001) in hypoxic red blood cells (RBC), this work aims to develop an inner and outer RBC-biomimetic antitumor nanoplatform that replicates both membrane surface properties and intracellularly certain therapeutic mechanisms of RRx-001 in hypoxic RBC. Herein, RRx-001 and Hb are introduced into RBC membrane camouflaged TiO2 nanoparticles. Upon arrival at hypoxic tumor microenvironment (TME), the biomimetic nanoplatform (R@HTR) is activated and triggers a series of reactions to generate reactive nitrogen species (RNS). More importantly, the potent antitumor immunity and immunomodulatory function of RNS in TME are demonstrated. Such an idea would transfer the battlefield of RRx-001 from hypoxic RBC to hypoxic TME, enhancing its combat capability. As a proof of concept, this biomimetic nanoreactor of RNS exhibits efficient tumor regression and metastasis prevention. The battlefield transfer strategy would not only present meaningful insights for immunotherapy, but also realize substantial breakthroughs in biomimetic nanotechnology.

PPy nanoneedle based nanoplatform capable of overcoming biological barriers for synergistic chemo-photothermal therapy.

The biological barriers in vivo have limited the site-specific bioavailability and impeded therapeutic efficacy. To tackle these issues, nonspherical particles with a shape effect have attracted wide attention to affect the in vivo translocation of a drug delivery system. Herein, we constructed a nanoplatform based on polypyrrole (PPy) nanoneedles by hyaluronic acid (HA) modification and doxorubicin (DOX) loading. The PPy-HA@DOX nanoneedles with high aspect ratios could enhance the extravasation through the fenestrated vasculature of tumors, transport across tumor cell membrane via an endocytosis mechanism or even penetrated the membrane directly, and ultimately enter the nucleus easily via the nuclear pore complex by passive diffusion. With the ability of overcoming biological barriers, the PPy nanoneedle based nanoplatform would deliver drugs into the organelles more effectively. Under near infrared (NIR) laser irradiation, PPy as the photothermal agent could lead to tumor cellular structure damage for photothermal therapy (PTT). Therefore, PPy-HA@DOX developed here would exploit the merits of synergistic combination of chemo-photothermal therapy, which would pave the way toward more effective nanotherapeutics.

Cancer Cell Membrane-Biomimetic Nanoplatform for Enhanced Sonodynamic Therapy on Breast Cancer via Autophagy Regulation Strategy.

Autophagy was considered as a double-edged sword that might cooperate, aggravate, or antagonize apoptosis. We found that the sonodynamic therapy (SDT) in low dosage induced autophagy and might function as a survival pathway for breast cancer and exhibit resistance to SDT-mediated apoptosis. In this sense, it was highly desired to enhance SDT via autophagy regulation strategy. Herein, we reported a biomimetic nanoplatform based on hollow mesoporous titanium dioxide nanoparticles (HMTNPs) by autophagy inhibitor (hydroxychloroquine sulphate, HCQ) loading and cancer cell membrane (CCM) coating. Owing to the biomimetic surface functionalization, the CCM-HMTNPs/HCQ could escape from macrophage phagocytosis, actively recognize and home in on the tumor by homologous targeting ability. Afterward, the released HCQ in response to the ultrasound stimulus was capable of blocking the autophagic flux and cutting off the nutrients supply derived from the damaged organelles, which was anticipated to abrogate the cells' resistance to SDT. Meanwhile, the vessel normalization effect of HCQ alleviated the tumor hypoxia, which was bound to enhance the oxygen-dependent HMTNPs-mediated SDT treatment. Based on the above findings, it was undoubtedly logical that CCM-HMTNPs/HCQ would sensitize breast cancer cells to SDT via autophagy regulation strategy, which held a great promise in cancer treatment.

A signal-decreased electrochemical immunosensor for the sensitive detection of LAG-3 protein based on a hollow nanobox-MOFs/AuPt alloy.

In this work, hollow nanobox metal-organic framework (HNM) nanocomposites were synthesised and utilised for the first time in a signal decreased electrochemical immunosensor for the ultrasensitive quantitative determination of lymphocyte activation gene-3 (LAG-3) protein, which is a newly discovered biomarker. With the aid of signal materials, namely, SiO2-tagged anti-LAG-3 antibody (SiO2-Ab2) and the biotin-streptavidin system, the sensor can achieve signal amplification. Encapsulation of tin dioxide-functionalised reduced graphene oxide (rGO-SnO2) and gold and platinum alloys (AuPt alloys) onto the surface of hollow nanobox metal-organic frameworks (MOFs) was performed to prepare rGO-SnO2/hollow nanobox-MOFs/AuPt alloys (rGO-SnO2/HNMs/AuPt) as the matrix. SiO2-Ab2, which is used as the signal-decreased label, can be utilised to enhance the distinction of the electrochemical signal after the specific recognition between antibodies and antigens, owing to its large steric hindrance property. In this sensor, this proposed sandwich immunosensor can achieve a high sensitivity, especially in the presence of low concentrations of the LAG-3 protein. Under optimal conditions, this sandwich-designed immunosensor exhibited a sensitive detection of the LAG-3 protein from concentrations of 0.01 ng mL-1 to 1 µg mL-1, with a lower detection limit of 1.1 pg mL-1 (based on 3σ). We proposed that this ultrasensitive biosensor can be utilised for the detection of the LAG-3 protein in early clinical tumour diagnosis.

Vaccination knowledge, attitude and practice among Chinese travelers who visit travel clinics in Preparation for international travel.

BACKGROUND: Although international travel has become increasingly more common in main land China, few data are available on vaccination knowledge, attitude and practice (KAP) among Chinese travelers. METHOD: In each of 14 International Travel Healthcare Centers (ITHCs) situated in mainland China 200 volunteers were recruited for a cross-sectional investigation by questionnaire on KAP related to travel vaccinations. For the evaluation the study subjects were grouped by demographic data, past travel experience, travel destination, duration of stay abroad, purpose of travel. RESULTS: Among the 2,800 Chinese travelers who participated in the study, 67.1% were aware of national and travel vaccination recommendations. The knowledge about vaccine preventable diseases was low. The most common sources (73.4%) of information were requirements by destination countries obtained in connection with the visa application, Chinese companies employing workers/laborers for assignments overseas, and foreign schools. The overall acceptance rate of recommended vaccines was 68.7%, but yellow fever was accepted by 99.8% of the participants when recommended. Among 81.1% respondents who recalled to have received vaccinations in the past, only 25.9% of them brought the old vaccination records with them to their ITHC consultations. CONCLUSION: The results indicate that increased awareness of the importance of pre-travel vaccination is needed among the travellers in order to improve their KAP.

Exposure to 2.45 GHz electromagnetic fields elicits an HSP-related stress response in rat hippocampus.

The issue of possible neurobiological effects of the electromagnetic field (EMF) exposure is highly controversial. To determine whether electromagnetic field exposure could act as an environmental stimulus capable of producing stress responses, we employed the hippocampus, a sensitive target of electromagnetic radiation, to assess the changes in its stress-related gene and protein expression after EMF exposure. Adult male Sprague-Dawley rats with body restrained were exposed to a 2.45 GHz EMF at a specific absorption rate (SAR) of 6 W/kg or sham conditions. cDNA microarray was performed to examine the changes of gene expression involved in the biological effects of electromagnetic radiation. Of 2048 candidate genes, 23 upregulated and 18 downregulated genes were identified. Of these differential expression genes, two heat shock proteins (HSP), HSP27 and HSP70, are notable because expression levels of both proteins are increased in the rat hippocampus. Result from immunocytochemistry revealed that EMF caused intensive staining for HSP27 and HSP70 in the hippocampus, especially in the pyramidal neurons of cornu ammonis 3 (CA3) and granular cells of dentate gyrus (DG). The gene and protein expression profiles of HSP27 and HSP70 were further confirmed by reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Our data provide direct evidence that exposure to electromagnetic fields elicits a stress response in the rat hippocampus.

[Relationship between activation of microglia and Jaks phosphorylation induced by microwave irradiation].

OBJECTIVE: To explore the relationship between microglial proinflammatory and electromagnetic radiation and unveil the role of microglia in microwave radiation induced central nervous system injury. METHODS: N9 microglia cells cultured in vitro were exposed to microwave at 90 mW/cm2. Cell flow cytometry was used to observe the expression of CD11b at different time points after exposure; ELISA was used to detect the concentration of TNF-alpha in N9 cell culture supernatant; RT-PCR analysis confirmed iNOS mRNA expression in N9 microglia cells; and Nitrate Reductase Method was used to test NO amount in culture supernatant. RESULTS: The CD11b positive microglial cells increased significantly at 3 h after microwave exposure (P < 0.05), continued to increase until 24 h and peaked at 6 h after exposure. The amount of TNF-alpha rose dramatically from 1 h to 24 h after exposure (P < 0.01) and peaked at 3 h [(762.1 +/- 61.5) pg/ml] after exposure (P < 0.01). The level of NO started to increase at 1 h [(4.48-0.59) micromol/L] and lasted for 24 h after exposure. The expression of iNOS mRNA increased significantly at 1 h (P < 0.05), and tripled the original expression at 6 h after exposure, hereafter, it decreased slightly, but all were higher than the control group within 24 h after exposure. CONCLUSION: Microwave radiation could induce the activation of microglia cells. The activated microglia cells could induce microglial proinflammatory by producing large amounts of TNF-alpha, NO, etc.

The role of the JAK2-STAT3 pathway in pro-inflammatory responses of EMF-stimulated N9 microglial cells.

BACKGROUND: In several neuropathological conditions, microglia can become overactivated and cause neurotoxicity by initiating neuronal damage in response to pro-inflammatory stimuli. Our previous studies have shown that exposure to electromagnetic fields (EMF) activates cultured microglia to produce tumor necrosis factor (TNF)-α and nitric oxide (NO) through signal transduction involving the activator of transcription STAT3. Here, we investigated the role of STAT3 signaling in EMF-induced microglial activation and pro-inflammatory responses in more detail than the previous study. METHODS: N9 microglial cells were treated with EMF exposure or a sham treatment, with or without pretreatment with an inhibitor (Pyridone 6, P6) of the Janus family of tyrosine kinases (JAK). The activation state of microglia was assessed via immunoreaction using the microglial marker CD11b. Levels of inducible nitric oxide synthase (iNOS), TNF-α and NO were measured using real-time reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA) and the nitrate reductase method. Activation of JAKs and STAT3 proteins was evaluated by western blotting for specific tyrosine phosphorylation. The ability of STAT3 to bind to DNA was detected with an electrophoresis mobility shift assay (EMSA). RESULTS: EMF was found to significantly induce phosphorylation of JAK2 and STAT3, and DNA-binding ability of STAT3 in N9 microglia. In addition, EMF dramatically increased the expression of CD11b, TNF-α and iNOS, and the production of NO. P6 strongly suppressed the phosphorylation of JAK2 and STAT3 and diminished STAT3 activity in EMF-stimulated microglia. Interestingly, expression of CD11b as well as gene expression and production of TNF-α and iNOS were suppressed by P6 at 12 h, but not at 3 h, after EMF exposure. CONCLUSIONS: EMF exposure directly triggers initial activation of microglia and produces a significant pro-inflammatory response. Our findings confirm that the JAK2-STAT3 pathway may not mediate this initial microglial activation but does promote pro-inflammatory responses in EMF-stimulated microglial cells. Thus, the JAK2-STAT3 pathway might be a therapeutic target for reducing pro-inflammatory responses in EMF-activated microglia.

STAT3 signalling pathway is involved in the activation of microglia induced by 2.45 GHz electromagnetic fields.

PURPOSE: Microglia activation plays a pivotal role in the initiation and progression of central nervous system (CNS) insult. The aim of the present work was to investigate the activation of microglia and involvement of signal transducer and activator of transcription 3 (STAT3) in microglia activation after 2.45 GHz electromagnetic fields (EMF) exposure. MATERIALS AND METHODS: In this study, murine N9 microglial cells were exposed to 2.45 GHz EMF, the protein expressions of STAT3, Janus Tyrosine kinase 1 and 2(JAK1 and JAK2), phosphor-(Try705)STAT3 and DNA binding activity of STAT3 were examined by Western blot analysis and electrophoresis mobility shift assay (EMSA). Levels of the nitric oxide (NO) derivative nitrite were determined in the culture medium by the Griess reaction. The mRNA expression of tumour necrosis factor alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) were detected by reverse transcription and polymerase chain reaction (RT-PCR). RESULTS: A significant increase of STAT3 DNA-binding ability was noted after exposure. Consistent with this, EMF rapidly induced phosphorylation of STAT3 and activated JAK1 and JAK2. In addition, EMF exposure increased transcription levels of the inflammation-associated genes, iNOS and TNF-alpha, which are reported to contain STAT-binding elements in their promoter region. P6, a JAK inhibitor, reduced induction of iNOS and TNF-alpha, nuclear factor binding activity, and activation of STAT3 in EMF-stimulated microglia. CONCLUSION: These results provide evidence that EMF exposure can initiate the activation of microglia cells and STAT3 signalling involves in EMF-induced microglial activation.

Overexpression of Tfam protects mitochondria against beta-amyloid-induced oxidative damage in SH-SY5Y cells.

There is strong evidence that beta-amyloid (Abeta) causes oxidative stress and induces mitochondrial dysfunction in the pathogenesis of Alzheimer's disease. Mitochondrial transcription factor A (Tfam) has multiple roles in the maintenance of mtDNA. To study the protective roles of Tfam against amyloid neurotoxicity, we established SH-SY5Y cell lines stably overexpressing Tfam and exposed them to 10 microm Abeta1-42 for 24 h. We found that Tfam overexpression attenuated Abeta1-42-induced cell viability damage and apoptosis. In addition, Tfam overexpression significantly suppressed the increase in excess reactive oxygen species and reversed the reduction in cytochrome c oxidase activity and ATP production induced by Abeta1-42. Furthermore, overexpression of DeltaC-Tfam, which has no functional domain for stimulating mtDNA transcription but can still maintain the mtDNA nucleoid formation and mtDNA copy number, also exhibited protective effects against Abeta1-42 cytotoxicity in SH-SY5Y cells. Together, our data suggest that Tfam overexpression protects mitochondria against Abeta-induced oxidative damage in SH-SY5Y cells. These beneficial effects may be attributable to the roles of Tfam in maintaining mtDNA nucleoid formation and mtDNA copy number.