Theoretical Study of Triphenylphosphine Oxide Derivatives for Blue Thermally Activated Delayed Fluorescence.

We designed novel thermally activated delayed fluorescence (TADF) materials by combining the electron donor 10,10-diphenyl-5,10-dihydrodibenzo[b,e][1,4]azasiline (DDA) with the electron acceptor triphenylphosphine oxide (PO) unit (mDDA-PO and o-mDDA-PO) and compared their characteristics with those of a reference material using 1,3-Bis(N-carbazolyl)benzene (mCP) as an electron donor (mCP-PO) for blue organic light-emitting diodes (OLEDs). Using density functional theory (DFT) and time-dependent DFT calculations, we obtained the electron distributions of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) as well as the energies of the lowest singlet (S1) and lowest triplet (T1) excited states. The calculated energy difference (ΔEST) between the S1 and T1 states of mDDA-PO (0.16 eV) and o-mDDA-PO (0.07 eV) were smaller than that of mCP-PO (0.48 eV). The results showed that o-mDDA-PO is a suitable blue OLED emitter because it has sufficiently small ΔEST values, which is favorable in a reverse-intersystem process crossing from the T1 state to S1 states, as well as an emission wavelength of 446.7 nm.

Theoretical Study of Phenoxaphosphine-Based Blue Organic Light-Emitting Diode Exhibiting Thermally Activated Delayed Fluorescence.

We designed novel thermally activated delayed fluorescence (TADF) materials by combining the electron donors spiro[acridine-9,9'-fluorene] (D1) and 9,9-diphenyl acridan (PAC) with the electron acceptor phenoxaphosphine (OPO) unit (2D1-OPO and 2PAC-OPO) and used those property to compare it with that of the reference material using dimethylacridan (Ac) as an electron donor (Ac-OPO) for blue organic light-emitting diodes (OLEDs). To calculate electron distribution of highest occupied molecular orbitals (HOMO), lowest occupied molecular orbital (LUMO), lowest singlet (S1) energy and lowest triplet (T1) excitation states, density functional theory (DFT) and time-dependent DFT calculation have been used. The calculated energy difference (ΔEST) between the S1 and T1 states of 2D1-OPO (0.125 eV) and 2PAC-OPO (0.153 eV) were as small as that of Ac-OPO (0.127 eV). The results showed that 2D1-OPO is a good candidate for blue OLED emitter because it has an emission wavelength of 441.0 nm as well as a sufficiently small ΔEST value and large oscillator intensity value.

Noble Dibenzothiophene-Based Bipolar Hosts for Blue Organic Light-Emitting Diodes Using Thermally Activated Delayed Fluorescence.

Novel thermally activated delayed fluorescence (TADF) host materials for blue electrophosphores-cence were designed by combining the electron acceptor dibenzothiophene (DBT) unit and the electron donor acridine derivatives into a single molecular unit by density functional theory (DFT). Depending on the optimal charge transfer, DFT and time-dependent DFT (TD-DFT) calculations for the ground state were performed to obtain the energy of the singlet (S1) and triplet (T1) excited states of the TADF material for Hartree-Fock percentage of TD-DFT. The sufficiently large separation between the HOMO and LUMO resulted in a small difference in energy (ΔEST) between the S1 and T1 states using DFT and TD-DFT calculations. The host molecules retained high triplet energy and showed great potential for use in blue organic light-emitting diodes (OLED). The results showed that these molecules are a good TADF host materials because they have a low barrier to hole and electron injection with a balanced charge transporting property for both holes and electrons, and a small ΔEST.

Designing Noble Benzimidazole-Based Bipolar Hosts for Blue Organic Light-Emitting Diodes Using Thermally Activated Delayed Fluorescence Materials.

We designed a novel thermally activated delayed fluorescence (TADF) host molecules for blue elec-trophosphorescence by combining the electron acceptor benzimidazole (BI) unit and the electron donor acridine derivatives into a single molecular unit based on density functional theory (DFT). We obtained the energies of the first singlet (S1) and the first triplet (T1) excited states of the TADF materials by performing DFT and time-dependent DFT (TD-DFT) calculations on the ground state using dependence on charge transfer amounts for the optimal Hartree-Fock percentage in the exchange-correlation of TD-DFT. The DFT and TD-DFT calculations showed that the large separation between the highest occupied molecular orbital and the lowest unoccupied molecular orbital caused a small difference in energy (ΔEST) between the S1 and T1 states. The host molecules retained a high triplet energy and demonstrated a great potential for use in blue phosphorescent organic light-emitting diodes. The results showed that these molecules are promising host materials for TADF OLEDs because they have a low barrier to hole and electron injection, a balanced charge transport for both holes and electrons, and a small ΔEST.

Highly Charge Transport Thermally Activated Delayed Fluorescence Host Materials Based on Benzimidazole-Acridine Derivatives.

We designed novel thermally activated delayed fluorescence (TADF) host molecules for blue electrophosphorescence by combining the electron acceptor benzimidazole (BI) unit and the electron donor acridine derivatives into a single molecular unit based on density functional theory (DFT). We obtained the energies of the first singlet (S1) and the first triplet (T1) excited states of the TADF materials by performing DFT and time-dependent DFT (TD-DFT) calculations to the ground state using dependence on charge transfer amounts for the optimal Hartree-Fock percentage in the exchange-correlation of TD-DFT. Using DFT and TD-DFT calculations, the large separation between the HOMO and LUMO caused a small difference in energy (ΔEST) between the S1 and T1 states. The host molecules retained high triplet energy and showed great potential for use in blue phosphorescent organic light-emitting diodes. The results showed that these molecules are promising TADF host materials because they have a low barrier to hole and electron injection, balanced charge transport for both holes and electrons, and a small ΔEST.

COMP-Angiopoietin-1 accelerates muscle regeneration through N-cadherin activation.

Angiopoietin-1 modulates vascular stability via Tie2 on endothelial cells. In our previous study, we also showed it acts as an inhibitor of cardiomyocyte death. However, it remains poorly understood how Ang1 regulates myogenesis during muscle regeneration. Here we found that COMP-Ang1 (cAng1) enhances muscle regeneration through N-cadherin activation. Muscle fiber regeneration after limb muscle damage by ischemic injury was enhanced with cAng1 treatment. Mechanistically cAng1 directly bound to N-cadherin on the myoblast surface in a Ca2+ dependent manner. The interaction enhanced N-cadherin activation via N-cadherin/p120-catenin complex formation, which in turn activated p38MAPK (but not AKT or ERK) and myogenin expression (but not myoD) as well as increasing myogenin+ cells in/ex vivo. After transplantation of GFP-expressing myoblasts (GFP-MB), we showed an increased generation of GFP+ myotubes with adenovirus cAng1 (Adv-cAng1) injection. Adv-cAng1, however, could not stimulate myotube formation in N-cadherin-depleted GFP-MB. Taken together, this study uncovers the mechanism of how cAng1 promotes myoblast differentiation and muscle regeneration through the N-cadherin/p120-catenin/p38MAPK/myogenin axis.

Histological and functional assessment of the efficacy of constraint-induced movement therapy in rats following neonatal hypoxic-ischemic brain injury.

Constraint-induced movement therapy (CIMT) is used in stroke rehabilitation to promote recovery of upper limb motor function. However, its efficacy in improving functional outcomes in children with hemiplegic cerebral palsy has not been clearly determined in clinical or experimental research. The aim of our study was to assess the efficacy of a new experimental model of CIMT, evaluated in terms of mortality, stress, motor and cognitive function in rats having undergone a neonatal hypoxic-ischemic (HI) brain injury. Neonatal HI injury was induced at post-natal day 7 through unilateral ligation of the common carotid artery followed by exposure to hypoxia for 2 h. CIMT was implemented at 3 weeks, post-HI injury, using a pouch to constrain the unimpaired forelimb and forcing use of the affected forelimb using a motorized treadmill. After HI injury, animals demonstrated motor and cognitive deficits, as well as volumetric decreases in the ipsilateral hemisphere to arterial occlusion. CIMT yielded a modest recovery of motor and cognitive function, with no effect in reducing the size of the HI lesion or post-HI volumetric decreases in brain tissue. Therefore, although animal models of stroke have identified benefits of CIMT, CIMT was not sufficient to enhance brain tissue development and functional outcomes in an animal model of hemiplegic cerebral palsy. Based on our outcomes, we suggest that CIMT can be used as an adjunct treatment to further enhance the efficacy of a program of rehabilitation in children with hemiplegic cerebral palsy.

Low-level light emitting diode therapy promotes long-term functional recovery after experimental stroke in mice.

We aimed to investigate the effects of low-level light emitting diode therapy (LED-T) on the long-term functional outcomes after cerebral ischemia, and the optimal timing of LED-T initiation for achieving suitable functional recovery. Focal cerebral ischemia was induced in mice via photothrombosis. These mice were assigned to a sham-operated (control), ischemic (vehicle), or LED-T group [initiation immediately (acute), 4 days (subacute) or 10 days (delayed) after ischemia, followed by once-daily treatment for 7 days]. Behavioral outcomes were assessed 21 and 28 days post-ischemia, and histopathological analysis was performed 28 days post-ischemia. The acute and subacute LED-T groups showed a significant improvement in motor function up to 28 days post-ischemia, although no brain atrophy recovery was noted. We observed proliferating cells (BrdU+ ) in the ischemic brain, and significant increases in BrdU+ /GFAP+ , BrdU+ /DCX+ , BrdU+ /NeuN+ , and CD31+ cells in the subacute LED-T group. However, the BrdU+ /Iba-1+ cell count was reduced in the subacute LED-T group. Furthermore, the brain-derived neurotrophic factor (BDNF) was significantly upregulated in the subacute LED-T group. We concluded that LED-T administered during the subacute stage had a positive impact on the long-term functional outcome, probably via neuron and astrocyte proliferation, blood vessel reconstruction, and increased BDNF expression. Picture: The rotarod test for motor coordination showed that acute and subacute LED-T improves long-term functional recovery after cerebral ischemia.

Modulation of neurogenesis via neurotrophic factors in acupuncture treatments for neurological diseases.

Acupuncture is one of the main healing arts in Oriental medicine. It has long been used in East Asian countries, including Korea and China, and is thought to be an effective alternative treatment for various neurological diseases. The therapeutic effects of acupuncture come from inserting a needle at specific acupoints on the body surface, with subsequent delivery of stimulation via manual rotation or electric pulses (electroacupuncture, EA). In various neurological disease models, peripheral nerve stimulation using acupuncture or EA may have protective effects on neural tissues by increasing expression of neurotrophic factors (NTFs), such as brain-derived neurotrophic factor and glial-derived neurotrophic factor, in the central nervous system, especially the brain. In addition, acupuncture may contribute to recovery from functional impairments following brain damage by encouraging neural stem cell proliferation, which is active at the initial stage of injury, and by further facilitating differentiation. Hence, acupuncture may act as a stimulator activating peripheral nerves at specific acupoints and inducing the expression of various NTFs in the brain. Subsequently, NTFs induced by this treatment trigger autocrine or paracrine signaling, which stimulates adult neurogenesis, thereby exerting therapeutic effects on functional impairments in neurological diseases. Acupuncture may offer an alternative treatment that promotes adult neurogenesis through the expression of NTFs in the brain. It may also have synergistic effects when combined with pharmacological interventions, again facilitating neurogenesis. This review examines recent studies concerning the effects of acupuncture and EA on adult neurogenesis associated with NTF expression in neurological diseases, in particular stroke, Alzheimer's disease, and Parkinson's disease.

The Short Isoform of DNAJB6 Protects against 1-Methyl-4-phenylpridinium Ion-Induced Apoptosis in LN18 Cells via Inhibiting Both ROS Formation and Mitochondrial Membrane Potential Loss.

In a previous study, we found that the short isoform of DNAJB6 (DNAJB6(S)) had been decreased in the striatum of a mouse model of Parkinson's disease (PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). DNAJB6, one of the heat shock proteins, has been implicated in the pathogenesis of PD. In this study, we explored the cytoprotective effect of DNAJB6(S) against 1-methyl-4-phenylpyridinium ion- (MPP+-) induced apoptosis and the underlying molecular mechanisms in cultured LN18 cells from astrocytic tumors. We observed that MPP+ significantly reduced the cell viability and induced apoptosis in LN18 glioblastoma cells. DNAJB6(S) protected LN18 cells against MPP+-induced apoptosis not only by suppressing Bax cleavage but also by inhibiting a series of apoptotic events including loss of mitochondrial membrane potential, increase in intracellular reactive oxygen species, and activation of caspase-9. These observations suggest that the cytoprotective effects of DNAJB6(S) may be mediated, at least in part, by the mitochondrial pathway of apoptosis.

Pretreatment with light-emitting diode therapy reduces ischemic brain injury in mice through endothelial nitric oxide synthase-dependent mechanisms.

Photostimulation with low-level light emitting diode therapy (LED-T) modulates neurological and psychological functions. The purpose of this study was to evaluate the effects of LED-T pretreatment on the mouse brain after ischemia/reperfusion and to investigate the underlying mechanisms. Ischemia/reperfusion brain injury was induced by middle cerebral artery occlusion. The mice received LED-T twice a day for 2 days prior to cerebral ischemia. After reperfusion, the LED-T group showed significantly smaller infarct and edema volumes, fewer behavioral deficits compared to injured mice that did not receive LED-T and significantly higher cerebral blood flow compared to the vehicle group. We observed lower levels of endothelial nitric oxide synthase (eNOS) phosphorylation in the injured mouse brains, but significantly higher eNOS phosphorylation in LED-T-pretreated mice. The enhanced phospho-eNOS was inhibited by LY294002, indicating that the effects of LED-T on the ischemic brain could be attributed to the upregulation of eNOS phosphorylation through the phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, no reductions in infarct or edema volume were observed in LED-T-pretreated eNOS-deficient (eNOS-/-) mice. Collectively, we found that pretreatment with LED-T reduced the amount of ischemia-induced brain damage. Importantly, we revealed that these effects were mediated by the stimulation of eNOS phosphorylation via the PI3K/Akt pathway.

Low-level light emitting diode (LED) therapy suppresses inflammasome-mediated brain damage in experimental ischemic stroke.

Use of photostimulation including low-level light emitting diode (LED) therapy has broadened greatly in recent years because it is compact, portable, and easy to use. Here, the effects of photostimulation by LED (610 nm) therapy on ischemic brain damage was investigated in mice in which treatment started after a stroke in a clinically relevant setting. The mice underwent LED therapy (20 min) twice a day for 3 days, commencing at 4 hours post-ischemia. LED therapy group generated a significantly smaller infarct size and improvements in neurological function based on neurologic test score. LED therapy profoundly reduced neuroinflammatory responses including neutrophil infiltration and microglia activation in the ischemic cortex. LED therapy also decreased cell death and attenuated the NLRP3 inflammasome, in accordance with down-regulation of pro-inflammatory cytokines IL-1ß and IL-18 in the ischemic brain. Moreover, the mice with post-ischemic LED therapy showed suppressed TLR-2 levels, MAPK signaling and NF-kB activation. These findings suggest that by suppressing the inflammasome, LED therapy can attenuate neuroinflammatory responses and tissue damage following ischemic stroke. Therapeutic interventions targeting the inflammasome via photostimulation with LED may be a novel approach to ameliorate brain injury following ischemic stroke. Effect of post-ischemic low-level light emitting diode therapy (LED-T) on infarct reduction was mediated by inflammasome suppression.

Analysis of the FGF gene family provides insights into aquatic adaptation in cetaceans.

Cetacean body structure and physiology exhibit dramatic adaptations to their aquatic environment. Fibroblast growth factors (FGFs) are a family of essential factors that regulate animal development and physiology; however, their role in cetacean evolution is not clearly understood. Here, we sequenced the fin whale genome and analysed FGFs from 8 cetaceans. FGF22, a hair follicle-enriched gene, exhibited pseudogenization, indicating that the function of this gene is no longer necessary in cetaceans that have lost most of their body hair. An evolutionary analysis revealed signatures of positive selection for FGF3 and FGF11, genes related to ear and tooth development and hypoxia, respectively. We found a D203G substitution in cetacean FGF9, which was predicted to affect FGF9 homodimerization, suggesting that this gene plays a role in the acquisition of rigid flippers for efficient manoeuvring. Cetaceans utilize low bone density as a buoyancy control mechanism, but the underlying genes are not known. We found that the expression of FGF23, a gene associated with reduced bone density, is greatly increased in the cetacean liver under hypoxic conditions, thus implicating FGF23 in low bone density in cetaceans. Altogether, our results provide novel insights into the roles of FGFs in cetacean adaptation to the aquatic environment.

Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice.

AIM: Increasing evidence suggests that probucol, a lipid-lowering agent with anti-oxidant activities, may be useful for the treatment of ischemic stroke with hyperlipidemia via reduction in cholesterol and neuroinflammation. In this study we examined whether probucol could protect against brain ischemic injury via anti-neuroinflammatory action in normal and hyperlipidemic mice. METHODS: Primary mouse microglia and murine BV2 microglia were exposed to lipopolysaccharide (LPS) for 3 h, and the release NO, PGE2, IL-1ß and IL-6, as well as the changes in NF-κB, MAPK and AP-1 signaling pathways were assessed. ApoE KO mice were fed a high-fat diet containing 0.004%, 0.02%, 0.1% (wt/wt) probucol for 10 weeks, whereas normal C57BL/6J mice received probucol (3, 10, 30 mg·kg(-1)·d(-1), po) for 4 d. Then all the mice were subjected to focal cerebral ischemia through middle cerebral artery occlusion (MCAO). The neurological deficits were scored 24 h after the surgery, and then brains were removed for measuring the cerebral infarct size and the production of pro-inflammatory mediators. RESULTS: In LPS-treated BV2 cells and primary microglial cells, pretreatment with probucol (1, 5, 10 µmol/L) dose-dependently inhibited the release of NO, PGE2, IL-1ß and IL-6, which occurred at the transcription levels. Furthermore, the inhibitory actions of probucol were associated with the downregulation of the NF-κB, MAPK and AP-1 signaling pathways. In the normal mice with MCAO, pre-administration of probucol dose-dependently decreased the infarct volume and improved neurological function. These effects were accompanied by the decreased production of pro-inflammatory mediators (iNOS, COX-2, IL-1, IL-6). In ApoE KO mice fed a high-fat diet, pre-administration of 0.1% probucol significantly reduced the infarct volume, improved the neurological deficits following MCAO, and decreased the total- and LDL-cholesterol levels. CONCLUSION: Probucol inhibits LPS-induced microglia activation and ameliorates cerebral ischemic injury in normal and hyperlipidemic mice via its anti-neuroinflammatory actions, suggesting that probucol has potential for the treatment of patients with or at risk for ischemic stroke and hyperlipidemia.

Electroacupuncture preconditioning reduces ROS generation with NOX4 down-regulation and ameliorates blood-brain barrier disruption after ischemic stroke.

BACKGROUND: Electroacupuncture (EA) is a modern application based on combination of traditional manual acupuncture and electrotherapy that is frequently recommended as an adjuvant treatment for ischemic stroke. EA preconditioning can ameliorate blood-brain barrier (BBB) dysfunction and brain edema in ischemia-reperfusion injury; however, its mechanism remains unclear. This study investigated the preventive effects of EA preconditioning, particularly on BBB injury, followed by a transient middle cerebral artery occlusion (MCAO) model in mice. RESULTS: Mice were treated with EA (20 min) at Baihui (GV20) and Dazhui (GV14) acupoints once a day for 3 days before ischemic injury. Infarct volume, neurological deficits, oxidative stress, Evans blue leakage and brain edema were evaluated at 24 h after ischemia-reperfusion injury. EA preconditioning significantly decreased infarct volume and improved neurological function even after ischemic injury. In addition, both Evans blue leakage and water content were significantly reduced in EA preconditioned mice. Whereas the expression of tight junction proteins, ZO-1 and claudin-5, were remarkably increased by EA preconditioning. Mice with EA preconditioning showed the reduction of astrocytic aquaporin 4, which is involved in BBB permeabilization. In addition, we found that EA preconditioning decreased reactive oxygen species (ROS) in brain tissues after ischemic injury. The expression of NADPH oxidase 4 (NOX4), not NOX2, was significantly suppressed in EA preconditioned mice. CONCLUSIONS: These results suggest that EA preconditioning improve neural function after ischemic injury through diminishing BBB disruption and brain edema. And, the reduction of ROS generation and NOX4 expression by EA preconditioning might be involved in BBB recovery. Therefore, EA may serve as a potential preventive strategy for patients at high risk of ischemic stroke.

AKAP6 inhibition impairs myoblast differentiation and muscle regeneration: Positive loop between AKAP6 and myogenin.

Skeletal muscle regeneration occurs continuously to repair muscle damage incurred during normal activity and in chronic disease or injury. Herein, we report that A-kinase anchoring protein 6 (AKAP6) is important for skeletal myoblast differentiation and muscle regeneration. Compared with unstimulated skeletal myoblasts that underwent proliferation, differentiated cells show significant stimulation of AKAP6 expression. AKAP6 knockdown with siRNA effectively halts the formation of myotubes and decreases the expression of the differentiation markers myogenin and myosin heavy chain. When shAKAP6-lentivirus is delivered to mice with cardiotoxin (CTX)-induced muscle injury, muscle regeneration is impaired compared with that of mice injected with control shMock-lentivirus. The motor functions of mice infected with shAKAP6-lentivirus (CTX+shAK6) are significantly worse than those of mice infected with shMock-lentivirus (CTX+shMock). Mechanistic analysis showed that AKAP6 promotes myogenin expression through myocyte enhancer factor 2A (MEF2A). Notably, myogenin increases AKAP6 expression as well. The results of chromatin immunoprecipitation and luciferase assays showed that myogenin binds to an E-box site on the AKAP6 promoter. Taken together, our findings demonstrate a novel interplay between AKAP6 and myogenin, and we suggest that AKAP6 is an important regulator of myoblast differentiation, myotube formation, and muscle regeneration.

Hypoxia-induced fibroblast growth factor 11 stimulates capillary-like endothelial tube formation.

Low oxygen or hypoxia can be observed in the central region of solid tumors. Hypoxia is a strong stimulus for new blood vessel formation or angiogenesis, which is essential for tumor growth and progression. Fibroblast growth factor 11 (FGF11) is an intracellular non-secretory FGF whose function has not yet been fully characterized. In the present study, we demonstrated that FGF11 expression is upregulated under hypoxic conditions in human umbilical vein endothelial cells (HUVECs). FGF11 overexpression stimulated capillary-like tube formation, yet did not affect cell migration. Notably, FGF11 markedly increased the levels of tight junction proteins including occludin, zonula occludens-1 (ZO-1) and claudin-5 in HUVECs. The FGF11 promoter contains hypoxia response elements (HREs), and hypoxia-inducible factor-1 (HIF-1) binds to HREs to activate hypoxia-related genes. We demonstrated that hypoxia or HIF-1 expression under normoxic conditions increased the luciferase activity driven by the FGF11 promoter. However, deletion of the HREs from the FGF11 promoter rendered reporter gene activity unresponsive to hypoxia or HIF-1. Taken together, we propose that FGF11 may be involved in the stabilization of capillary-like tube structures associated with angiogenesis and may act as a modulator of hypoxia-induced pathological processes such as tumorigenesis.

Designed angiopoietin-1 variant, COMP-angiopoietin-1, rescues erectile function through healthy cavernous angiogenesis in a hypercholesterolemic mouse.

Despite the advent of oral phosphodiesterase-5 inhibitors, curative treatment for erectile dysfunction (ED) remains unavailable. Recently, the link between ED and cardiovascular disease was unveiled and the main etiology of ED was found to be vasculogenic. Therefore, neovascularization is a promising strategy for curing ED. Angiopoietin-1 (Ang1) is an angiogenic growth factor that promotes the generation of stable and functional vasculature. Here, we demonstrate that local delivery of the soluble, stable, and potent Ang1 variant, COMP-Ang1 gene or protein, into the penises of hypercholesterolemic mice increases cavernous angiogenesis, eNOS phosphorylation, and cGMP expression, resulting in full recovery of erectile function and cavernous blood flow up to 8 weeks after treatment. COMP-Ang1-induced promotion of cavernous angiogenesis and erectile function was abolished in Nos3(-/-) mice and in the presence of the NOS inhibitor, L-NAME. COMP-Ang1 also restored the integrity of endothelial cell-cell junction by down-regulating the expression of histone deacetylase 2 in the penis of hypercholesterolemic mice and in primary cultured mouse cavernous endothelial cells. These findings constitute a new paradigm toward curative treatment of both cavernous angiopathy and ED.

MicroRNA-26a induced by hypoxia targets HDAC6 in myogenic differentiation of embryonic stem cells.

The importance of epigenetic regulation for maintenance of embryonic stem cell (ESC) pluripotency or for initiation of differentiation is widely accepted. However, the molecular mechanisms are poorly understood. We recently reported that a hypoxic microenvironment induces ESC differentiation. In the present study, we found that hypoxia-responsive histone deacetylase 6 (HDAC6) performs an essential signaling function for myogenic differentiation of ESCs. HDAC6 was downregulated in hypoxic ESCs or during differentiation. A knock-down of HDAC6 in ESCs resulted in induction of myogenic markers, including Pax7. Suppression of HDAC6 increased acetylation of core histones H3 and H4, leading to enhanced binding of RNA polymerase II to the Pax7 promoter. Transplantation of HDAC6 knock-down cells facilitated muscle regeneration in vivo. Importantly, the downregulation of HDAC6 by hypoxia was not mediated by HIF1α or HIF2α, master transcription regulators under hypoxia, but by induction of microRNA-26a that directly targeted the 3'-untranslated region (3'-UTR) of HDAC6. A point mutation of the microRNA-26a-binding sequence in the HDAC6 3'-UTR diminished the luciferase reporter activity. Taken together, these results suggest that environmental cues of differentiation modulate the epigenetic machinery and guide stem cells to commit to a specific lineage.

Prompt meningeal reconstruction mediated by oxygen-sensitive AKAP12 scaffolding protein after central nervous system injury.

The meninges forms a critical epithelial barrier, which protects the central nervous system (CNS), and therefore its prompt reconstruction after CNS injury is essential for reducing neuronal damage. Meningeal cells migrate into the lesion site after undergoing an epithelial-mesenchymal transition (EMT) and repair the impaired meninges. However, the molecular mechanisms of meningeal EMT remain largely undefined. Here we show that TGF-ß1 and retinoic acid (RA) released from the meninges, together with oxygen tension, could constitute the mechanism for rapid meningeal reconstruction. AKAP12 is an effector of this mechanism, and its expression in meningeal cells is regulated by integrated upstream signals composed of TGF-ß1, RA and oxygen tension. Functionally, AKAP12 modulates meningeal EMT by regulating the TGF-ß1-non-Smad-SNAI1 signalling pathway. Collectively, TGF-ß1, RA and oxygen tension can modulate the dynamic change in AKAP12 expression, causing prompt meningeal reconstruction after CNS injury by regulating the transition between the epithelial and mesenchymal states of meningeal cells.