Staprexanthones, Xanthone-Type Stimulators of Pancreatic ß-Cell Proliferation from a Mangrove Endophytic Fungus.

This project was focused on the discovery of novel compounds that promote endogenous ß-cell regeneration. Screening of extracts identified the fungus Stachybotrys chartarum as a promising candidate. After fermentation and extraction of S. chartarum, we isolated five new prenylated xanthones, namely, staprexanthones A-E (1-5), with staprexanthone A (1) being the first natural xanthone bearing a rare 4,5-dimethyl-1,3-dioxolane moiety. Compounds 1, 2, and 5 significantly increased ß-cell numbers in vivo in a zebrafish model. Further analysis revealed that 2 and 5 promoted ß-cell mass expansion by increasing proliferation of existing ß-cells though promotion of cell-cycle progression at the G1/S transition. These findings indicate that prenylated xanthones are potential new drug leads for antidiabetes therapy by stimulating ß-cell regeneration.

Silencing of PTGS2 exerts promoting effects on angiogenesis endothelial progenitor cells in mice with ischemic stroke via repression of the NF-κB signaling pathway.

The objective of the current study is to investigate the effect of PTGS2 on proliferation, migration, angiogenesis and apoptosis of endothelial progenitor cells (EPCs) in mice with ischemic stroke through the NF-κB signaling pathway. Middle cerebral artery occlusion (MCAO) model was established in mice. EPCs were identified, in which ectopic expression and depletion experiments were conducted. The mRNA and protein expression of related factors in tissues and cells were measured. Besides, proliferation, migration, angiogenesis, and apoptosis, as well as cell cycle distribution, of cells were determined. MCAO mice showed overexpression of interleukin-6 (IL-6), IL-17, and IL-23, and increased positive protein expression of PTGS2, as well as expression of PTGS2, nuclear factor-κB (NF-κB), tumor suppressor region 1 (TSP-1) and Bcl-2-associated X protein (Bax), but underexpression of vascular endothelial growth factor (VEGF), S-phase kinase associated protein 2 (Skp2), and B-cell lymphoma 2 (Bcl-2). Moreover, ectopic expression of tumor necrosis factor-α significantly elevated the expression of PTGS2, NF-κB, TSP-1, and Bax, as well as cell apoptosis and cell cycle arrest, but decreased the expression of VEGF, Skp2, and Bcl-2, as well as proliferation, migration and angiogenesis of EPCs, and the PTGS2-siRNA group showed an opposite trend. Taken together, we conclude that the specific knockdown of PTGS2 expression could repress the NF-κB signaling pathway, thereby inhibits apoptosis and promotes proliferation, migration and angiogenesis of EPCs, providing protective effect on mice with ischemic stroke.

Aniline-Tetramic Acids from the Deep-Sea-Derived Fungus Cladosporium sphaerospermum L3P3 Cultured with the HDAC Inhibitor SAHA.

Four new tetramic acids, cladosins H-K (1-4), and a related known compound, cladodionen (5), were isolated from the culture of the Mariana Trench (depth 6562 m) sediment-derived fungus Cladosporium sphaerospermum L3P3 treated with the histone deacetylase inhibitor SAHA (suberanilohydroxamic acid). Interestingly, compounds 1-5 existed as equilibrium E/ Z mixtures and 1-4 were the first cases of tetramic acids containing aniline moieties. Their structures including absolute configurations were elucidated through a combination of NMR, MS, and Mosher's method, together with the consideration of biogenetic origins. Incubation experiments of exogenous aniline and N-phenyloctanamide revealed that the aniline moiety in cladosins H-K (1-4) is probably derived from the degradation of SAHA, indicating that the well-known histone deacetylase inhibitor SAHA could be metabolized by L3P3 and provide aniline as a precursor for biotransformation of chemically reactive polyketides. The cytotoxicity of 1-5 was evaluated against the PC-3, MGC-803, SH-SY5Y, HCT-116, K562, and HL-60 cell lines, and compound 2 showed promising cytotoxicity against the HL-60 cell line with an IC50 value of 2.8 µM.

Microvascular damage is involved in the pathogenesis of heroin induced spongiform leukoencephalopathy.

OBJECTIVE: To investigate whether microvascular damage is involved in the pathogenesis of heroin induced spongiform leukoencephalopathy (HSLE). METHODS: The brain tissues were collected from 4 HSLE patients and 5 controls and then fixed in 4% paraformaldehyde. The frontal lobe, corpus callosum and cerebellum were separated. The expressions of myelin base protein (MBP) and CD34 were detected by immunohistochemistry. TUNEL staining was applied to detect cell apoptosis. The correlation between microvascular changes and pathological vacuoles was evaluated. RESULTS: No obvious abnormalities were found in the brain of controls. Immunohistochemistry for MBP showed the collapse and fracture of myelin sheath and vacuole formation in the subcortical white matter, corpus callosum, and cerebellar white matter of HSLE patients. TUNEL staining showed the number of apoptotic cells in the cerebellar white matter and corpus callosum of HSLE patients was significantly higher than that in controls (F = 389.451, P < 0.001). Masson's trichrome staining revealed vacuolar degeneration in the cerebral white matter of HSLE patients, and the vacuoles were distributed around the microvessels. Immunohistochemistry revealed CD34 positive cells were seldom found besides the vessels in the cerebellar white matter and corpus callosum of HSLE patients, but a variety of CD34 positive cells was found in the vascular wall of controls (F = 838.500, P < 0.001). CONCLUSION: Apoptosis of oligodendrocytes may be related to the HSLE. Cerebral vascular injury and microcirculation dysfunction are involved in the pathogenesis of HSLE. The interrelation between apoptosis of oligodendrocytes and the microvascular damage are required to be studied in future investigations.

Focus on perovskite emitters in blue light-emitting diodes.

Blue perovskite light-emitting diodes (PeLEDs) are essential in pixels of perovskite displays, while their progress lags far behind their red and green counterparts. Here, we focus on recent advances of blue PeLEDs and systematically review the noteworthy strategies, which are categorized into compositional engineering, dimensional control, and size confinement, on optimizing microstructures, energy landscapes, and charge behaviors of wide-bandgap perovskite emitters (bandgap >2.5 eV). Moreover, the stability of perovskite blue emitters and related devices is discussed. In the end, we propose a technical roadmap for the fabrication of state-of-the-art blue PeLEDs to chase and achieve comparable performance with the other two primary-color devices.

[A non-invasive equation in diagnosis of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia].

OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP) are the two largest subsets of idiopathic interstitial pneumonia (IIP). They have a sharply differences in therapy and survival, however, the identification of them is difficult. In general, NSIP has a much better responsiveness to therapy and good survival. On the other hand, in IPF, was demonstrated to be associated with poorer survival and responsiveness to therapy. To diagnosis of IPF and NSIP need histopathologic classification which however, requires surgical lung biopsy. Therefore, we try to set up an equation using those data from non-invasive methods to identify IPF and NSIP. METHODS: A retrospective review of 32 patients with IPF (n = 14) and NSIP (n = 18) was carried out. General clinical data, pulmonary function, chest radiographic, and bronchoalveolar lavage fluid were recorded. The statistical methods of logistic regression and multiple linear regression are used to establish the equation. The method of curve fitting is used to find the critical value of the equation to the differential diagnosis between the IPF and NSIP. RESULTS: (1) Compare to NSIP, patients of IPF are older, more males than females, having a bigger proportion of smokers. (2) Compared with NSIP patients, IPF patients have higher CT score of "grid shadow", "cellular shadow" and lower CT score of "ground-glass shadow". (3) Bronchoalveolar lavage (BAL) lymphocytosis was more frequently observed in NSIP than IPF. (4) We get an equation: y = 0.9 + 0.123 x 1 - 0.045 x 2 + 0.009 x 3 + 0.033 x 4 and it can improve the differential diagnosis between the IPF and NSIP in this group of patients. CONCLUSION: Clinical, high resolution computerized tomography and BAL are useful non-invasive tools in diagnosis IPF and NSIP. The equation:y = 0.9 + 0.123 x 1 - 0.045 x 2 + 0.009 x 3 + 0.033 x 4 can help us to distinguish the IPF and NSIP.

[Intervention effect of dimercaptopropansulfonate sodium on central toxic induced by bromoxynil in vivo].

OBJECTIVE: to investigate the changes of γ-aminobutyric acid (GABA) and glutamate (Glu) in the cerebral cortex following acute bromoxynil intoxication in mice and the protective effect of sodium dimercaptopropane sulfonate (Na-DMPS). METHODS: 30 ICR mice were randomly divided into blank control group (10), exposure group (10) and Na-DMPS protection group (10). The levels of GABA and Glu in the cerebral cortex were measured by RP-HPLC. The glutamine (Gln) level and the glutamine synthetase (GS), glutamate decarboxylation enzyme (GAD), γ-aminobutyric acid transaminase (GABA-T) activity in the cerebral cortex were determined by UV colorimetric. RESULTS: compared with the control group [GABA: (3.41 ± 0.12) micromol/g, Glu (14.00 ± 0.16) micromol/g, Gln (1.25 ± 0.19) micromol/g, GAD (13.50 ± 0.25) micromol × g(-1) × h(-1), GABA-T (25.51 ± 0.21) micromol × g(-1) × h(-1), GS(142.19 ± 1.31) U/mg pro], the level of GABA [(3.14 ± 0.14) micromol/g] was decreased (P < 0.05), whereas the level of Glu [(17.54 ± 0.40) micromol/g] and Gln [(3.35 ± 0.27) micromol/g] were increased (P < 0.05), the activity of GAD [(11.93 ± 0.15 micromol × g(-1) × h(-1)], GABA-T [(24.15 ± 0.22) micromol × g(-1) × h(-1)], GS [(140.75 ± 1.01) U/mg pro] was decreased (P < 0.05) in acute intoxication group; Compared with the acute intoxication group, the level of GABA [(3.52 ± 0.30) micromol/g] was increased (P < 0.05), whereas the level of Glu [(14.20 ± 0.32) micromol/g] and Gln [(1.32 ± 0.17) micromol/g] were decreased (P < 0.05), the activity of GAD [(13.01 ± 0.45 micromol × g(-1) × h(-1)], GABA-T [(25.19 ± 0.26) micromol × g(-1) × h(-1), GS [(142.35 ± 1.20) U/mg pro] was increased (P < 0.05); In contrast, the levels of GABA, Glu, Gln and the activity of GAD, GABA-T, and GS in Na-DMPS protection group were not significantly different in comparison with control group (P > 0.05). CONCLUSION: the central toxic effects of mice with acute bromoxynil intoxication may be related to the changes of GABA and Glu content in the cerebral cortex;Na-DMPS can protect mice from bromoxynil-induced central toxic effects and GABA and Glu abnormal change in the cerebral cortex.

Musk Ketone Induces Neural Stem Cell Proliferation and Differentiation in Cerebral Ischemia via Activation of the PI3K/Akt Signaling Pathway.

Traditional Chinese medicine has been reported to influence the proliferation and differentiation of neural stem cells (NSCs) that may be protective against nervous system diseases. Recent evidence indicates the importance of musk ketone in nerve recovery and preventing secondary damage after cerebral ischemic injury. A middle cerebral artery occlusion (MCAO) rat model was established by a transient filament model, and rats were treated with musk ketone (0.9 or 1.8 µM). Next, an in vitro oxygen-glucose deprivation (OGD) cell model was established to study the effect of musk ketone on the proliferation and differentiation of NSCs. To determine the potential mechanisms of musk ketone involved in activities of NSCs, the effect of musk ketone on the PI3K/Akt signaling pathway activation was assessed. Furthermore, NSCs were treated with musk ketone in the presence of PI3K/Akt inhibitor Akti-1/2 to examine their roles on NSC proliferation and differentiation. Musk ketone reduced cerebral ischemic injury in a dose-dependent manner in rats. In addition, NSCs treated with musk ketone showed enhanced proliferation and differentiation along with increased PI3K/Akt signaling pathway activation. The effects of muck ketone were reversed by Akti-1/2. Altogether, musk ketone promoted NSC proliferation and differentiation and protected against cerebral ischemia by activating the PI3K/Akt signaling pathway, highlighting the potential of musk ketone as a physiologically validated approach for the treatment of cerebral ischemia.

Suppression of lncRNA RMRP ameliorates oxygen-glucose deprivation/re-oxygenation-induced neural cells injury by inhibiting autophagy and PI3K/Akt/mTOR-mediated apoptosis.

The aberrant expression of lncRNAs has been inferred to be closely related with the progression of neural ischemia/reperfusion (I/R) injury. RMRP is an lncRNA associated with I/R injury. In order to determine the role of RMRP in I/R injury, the effects of RMRP knockdown on oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced injury in SH-SY5Y cells were evaluated. The effect of OGD/R administration on the expression of RMRP and apoptosis in SH-SY5Y cells, and the effect of RMRP suppression by siRNA on the impairments of cells proliferation and mobility potential due to OGD/R administration were assessed in the current study. At the molecular level, the current study detected the expressions of indicators involved in autophagy and PI3K/Akt/mTOR-mediated apoptosis pathways. The OGD/R administration induced the expression of RMRP and apoptosis in SH-SY5Y cells. After RMRP knockdown, the proliferation potential of SH-SY5Y cells was restored, and apoptosis and cell cycle arrest were inhibited. Moreover, RMRP inhibition also increased the invasion and migration of SH-SY5Y cells which were treated with OGD/R. The effects of RMRP suppression on the phenotypes of SH-SY5Y were associated with the inhibition of LC3II, p-PI3K, p-Akt, and p-mTOR as well as the induction of P62 and Bcl-2. Inhibition of RMRP contributed to the improvement of OGD/R-induced neuronal injury, which might be mediated through the inhibition of autophagy and apoptosis pathways.

[Comparison of the effects of BiPAP ventilation combined with lung recruitment maneuvers and low tidal volume A/C ventilation in patients with acute respiratory distress syndrome].

OBJECTIVE: To compare the effects of BiPAP ventilation combined with lung recruitment maneuvers (LRM) with low tidal volume A/C ventilation in patients with acute respiratory distress syndrome (ARDS). METHODS: A prospective, randomized comparison of BiPAP mechanical ventilation combined with lung recruitment maneuvers (test group) with low tidal volume A/C ventilation (control group) was conducted in 28 patients with ARDS. FiO2/PaO2 ratio, respiratory system compliance (Cs), central venous pressure (CVP), duration of ventilation support were recorded at 0 h, 48 h and 72 h separately. The ventilation associated lung injury and mortality at 28 d were also recorded. RESULTS: The FiO2/PaO2 ratio were (298+/-16) and (309+/-16) cm H2O, Cs were (38.4+/-2.2) and (42.0+/-1.3) ml/cm H2O, CVP were (13.8+/-0.8) and (11.6+/-0.7) cm H2O in the test group at 48 h and 72 h separately. In the control group, FiO2/PaO2 ratio were (212+/-12) and (246+/-17) cm H2O, Cs were (29.5+/-1.3) and (29.0+/-1.0) ml/cm H2O, CVP were 18.6+/-1.1 and (16.8+/-1.0) cm H2O. The results were better in the test group as compared with the control group (t=10.03-29.68, all P<0.01). The duration of ventilation support in the test group was shorter than the control group [(14+/-3) d vs (19+/-3) d, t=4.80, P<0.01]. The mortality in 28 d and ventilation associated lung injury were similar in the two groups. CONCLUSION: The results show that combination of LRM with BiPAP mode ventilation, as compared with the control group, contributes to improved FiO2/PaO2 ratio, pulmonary compliance, stable hemodynamic and shorter duration of ventilation support in patients with ARDS.

[Efficacy of goal-directed therapy in the treatment of septic shock].

OBJECTIVE: To investigate the efficacy and effect on outcome of goal-directed therapy in patients with septic shock compared with conventional therapy. METHODS: Sixteen patients with septic shock were randomly assigned to receive goal-directed therapy, with central venous pressure (CVP) 8-12 mm Hg (1 mm Hg=0.133 kPa), mean arterial pressure (MAP) >or=65 mm Hg, venous oxygen saturation (SvO(2))>0.70 (superior vena cava saturation), and urine output >or=0.5 ml/min as therapeutic goals. Another 17 patients received conventional therapy as controls. The arterial oxygen saturation (SaO(2)), SvO(2), MAP, CVP, heart stroke volume cardiac index (CI), serum lactate, volume of fluid, amount of vasopressors, the numbers of organ injured and patients who needed continuity blood purification (CBP) and/or ventilation were recorded serially for 6-48 hours, and they were compared between the two groups. The mortality of the patients in two groups on 7 days and 14 days were also recorded. RESULTS: There were no significant differences between the groups with respect to base-line characteristics. During the interval from 24 to 48 hours, the patients assigned to goal-directed therapy had a significantly higher in SaO(2), SvO(2), MAP, CVP, CI (P<0.05 or P<0.01), a lower lactate concentration (P<0.01), significantly more fluid during 6-24 hours and less vasopressors (both P<0.01). Seven and 14 days in-hospital mortality were lower in goal-directed therapy group as compared with the control group(P<0.05). CONCLUSION: The efficacy of goal-directed therapy in patients with septic shock is significantly better than conventional therapy in ameliorating outcome of shock and can be easily used in intensive care unit (ICU).

Ush1c gene expression levels in the ear and eye suggest different roles for Ush1c in neurosensory organs in a new Ush1c knockout mouse.

Usher syndrome (USH) is the most common form of deaf-blindness in humans. Molecular characterization revealed that the USH gene products form a macromolecular protein network in hair cells of the inner ear and in photoreceptor cells of the retina via binding to PDZ domains in the scaffold protein harmonin encoded by the Ush1c gene in mice and humans. Although several mouse mutants for the Ush1c gene have been described, we generated a targeted null mutation Ush1c mouse model in which the first four exons of the Ush1c gene were replaced with a reporter gene. Here, we assessed the expression pattern of the reporter gene under control of Ush1c regulatory elements and characterized the phenotype of mice defective for Ush1c. These Ush1 knockout mice are deaf but do not recapitulate vision defects before 10 months of age. Our data show LacZ expression in multiple layers of the retina but in neither outer nor inner segments of the photoreceptor layers in mice bearing the knockout construct at 1-5 months of age. The fact that Ush1c expression is much higher in the ear than in the eye suggests a different role for Ush1c in ear function than in the eye and may explain why Ush1c mutant mice do not recapitulate vision defects.

[Nestin activation after rat cerebral ischemia-reperfusion injury and its changes in response to Tongxinluo treatment].

OBJECTIVE: To investigate nestin activation in rat brain subjected to ischemia-reperfusion injury and its changes in response to Tongxinluo treatment. METHODS: Cerebral ischemia was induced by temporary middle cerebral artery occlusion (MCAO) in rats. At 3, 7, 14 and 21 days after MCAO, nestin expression in the ependyma, subventricular zone (SVZ), hippocampal subdentate gyrus zone (HDG) of the rats treated with Tongxinluo were guantified by immunohistochemistry. RESULTS: Compared with the sham operation group, nestin was significantly increased 7, 14 and 21 days after MCAO (P<0.05), and immunofluorescence of BrdU+nestin-positive neurons significantly increased in the SVZ. After treatment with Tongxinluo, the number of BrdU-positive neurons and BrdU+nestin-positive neurons significantly increased as compared with MCAO group (P<0.05). CONCLUSION: Focal cerebral ischemia in the rat results in rapid response and proliferation of neural stem cells in the SVZ and HDG in the ischemic hemisphere, and Tongxinluo may enhance the differentiation and proliferation capacity of the neural stem cells after MCAO.