Chevalones H-M: Six New α-Pyrone Meroterpenoids from the Gorgonian Coral-Derived Fungus Aspergillus hiratsukae SCSIO 7S2001.

Six new α-pyrone meroterpenoid chevalones H-M (1-6), together with six known compounds (7-12), were isolated from the gorgonian coral-derived fungus Aspergillus hiratsukae SCSIO 7S2001 collected from Mischief Reef in the South China Sea. Their structures, including absolute configurations, were elucidated on the basis of spectroscopic analysis and X-ray diffraction data. Compounds 1-5 and 7 showed different degrees of antibacterial activity with MIC values of 6.25-100 µg/mL. Compound 8 exhibited potent cytotoxicity against SF-268, MCF-7, and A549 cell lines with IC50 values of 12.75, 9.29, and 20.11 µM, respectively.

Structurally Diverse Polycyclic Salicylaldehyde Derivative Enantiomers from a Marine-Derived Fungus Eurotium sp. SCSIO F452.

To enlarge the chemical diversity of Eurotium sp. SCSIO F452, a talented marine-derived fungus, we further investigated its chemical constituents from a large-scale fermentation with modified culture. Four pairs of new salicylaldehyde derivative enantiomers, euroticins F-I (1-4), as well as a known one eurotirumin (5) were isolated and characterized. Compound 1 features an unprecedented constructed 6/6/6/5 tetracyclic structures, while 2 and 3 represent two new types of 6/6/5 scaffolds. Their structures were established by comprehensive spectroscopic analyses, X-ray diffraction, 13C NMR, and electronic circular dichroism calculations. Selected compounds showed significant inhibitory activity against α-glucosidase and moderate cytotoxic activities against SF-268, MCF-7, HepG2, and A549 cell lines.

Hypoxia-inducible factor-1 mediates pancreatic ß-cell dysfunction by intermittent hypoxia.

The role of hypoxia-inducible factor (HIF)-1 in pancreatic ß-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1α heterozygous (HET), ß-cell-specific HIF-1-/- mice and mouse insulinoma (MIN6) cells exposed to IH patterned after blood O2 profiles during obstructive sleep apnea. WT mice treated with IH showed insulin resistance, and pancreatic ß-cell dysfunction manifested as augmented basal insulin secretion, and impaired glucose-stimulated insulin secretion and these effects were absent in HIF-1α HET mice. IH increased HIF-1α expression and elevated reactive oxygen species (ROS) levels in ß-cells of WT mice. The elevated ROS levels were due to transcriptional upregulation of NADPH oxidase (NOX)-4 mRNA, protein and enzymatic activity, and these responses were absent in HIF-1α HET mice as well as in ß-HIF-1-/- mice. IH-evoked ß-cell responses were absent in adult WT mice treated with digoxin, an inhibitor of HIF-1α. MIN6 cells treated with in vitro IH showed enhanced basal insulin release and elevated HIF-1α protein expression, and these effects were abolished with genetic silencing of HIF-1α. IH increased NOX4 mRNA, protein, and enzyme activity in MIN6 cells and disruption of NOX4 function by siRNA or scavenging H2O2 with polyethylene glycol catalase blocked IH-evoked enhanced basal insulin secretion. These results demonstrate that HIF-1-mediated transcriptional activation of NOX4 and the ensuing increase in H2O2 contribute to IH-induced pancreatic ß-cell dysfunction.

Exosomal miR-486 regulates hypoxia-induced erythroid differentiation of erythroleukemia cells through targeting Sirt1.

MicroRNAs (miRNAs) regulate the hypoxia-induced erythroid differentiation of hematopoietic cells. In this study, we identified that miR-486 was a rapid response miRNA to hypoxia in erythroleukemia TF-1 cells. Hypoxia exposure increased both intracellular and miR-486 levels of TF-1 cells. Ectopic miR-486 expression enhanced the growth and erythroid differentiation of TF-1 cells, whereas miR-486 inhibition suppressed their growth and erythroid differentiation. Treatment of TF-1 and cord blood CD34+ cells with exogenous containing miR-486 resulted in an increase of intracellular miR-486 level and enhanced erythroid differentiation. Furthermore, we identified that Sirt1 is a miR-486 target gene which modulates hypoxia-induced erythroid differentiation of TF-1 cells. Thus we identified a novel miRNA regulatory network that contributes to hypoxia-induced erythroid differentiation of hematopoietic cells.

Eurotiumins A⁻E, Five New Alkaloids from the Marine-Derived Fungus Eurotium sp. SCSIO F452.

Three new prenylated indole 2,5-diketopiperazine alkaloids (1⁻3) with nine known ones (5⁻13), one new indole alkaloid (4), and one new bis-benzyl pyrimidine derivative (14) were isolated and characterized from the marine-derived fungus Eurotium sp. SCSIO F452. 1 and 2, occurring as a pair of diastereomers, both presented a hexahydropyrrolo[2,3-b]indole skeleton. Their chemical structures, including absolute configurations, were elucidated by 1D and 2D NMR, HRESIMS, quantum chemical calculations of electronic circular dichroism, and single crystal X-ray diffraction experiments. Most isolated compounds were screened for antioxidative potency. Compounds 3, 5, 6, 7, 9, 10, and 12 showed significant radical scavenging activities against DPPH with IC50 values of 13, 19, 4, 3, 24, 13, and 18 µM, respectively. Five new compounds were evaluated for cytotoxic activities.

MiRNA-486 regulates angiogenic activity and survival of mesenchymal stem cells under hypoxia through modulating Akt signal.

MicroRNA-486 (miR-486) was first identified from human fetal liver cDNA library and validated as a regulator of hematopoiesis. Its roles in regulating the biological function of bone marrow-derived mesnechymal stem cells (BM-MSCs) under hypoxia have not been explored yet. In this study, we demonstrated that exposure to hypoxia upregulates miR-486 expression in BM-MSCs. Lentivirus-mediated overexpression of miR-486 resulted in increase of hepatocyte growth factor (HGF) and vascular endothelial growth factor(VEGF) in both mRNA and protein levels. MiR-486 expression also promotes proliferation and reduces apoptosis of BM-MSCs. Whereas MiR-486 knockdown downregulated the secretion of HGF and VEGF and induced apoptosis of BM-MSCs. Furthermore, PTEN-PI3K/AKT signaling was validated to be involved in changes of BM-MSC biological functions regulated by miR-486. These results suggested that MiR-486 mediated the hypoxia-induced angiogenic activity and promoted the proliferation and survival of BM-MSCs through regulating PTEN-PI3K/AKT signaling. These findings might provide a novel understanding of effective therapeutic strategy for hypoxic-ischemic diseases.

Ptpmt1 induced by HIF-2α regulates the proliferation and glucose metabolism in erythroleukemia cells.

Hypoxia provokes metabolism misbalance, mitochondrial dysfunction and oxidative stress in both human and animal cells. However, the mechanisms which hypoxia causes mitochondrial dysfunction and energy metabolism misbalance still remain unclear. In this study, we presented evidence that mitochondrial phosphatase Ptpmt1 is a hypoxia response molecule that regulates cell proliferation, survival and glucose metabolism in human erythroleukemia TF-1 cells. Exposure to hypoxia or DFO treatment results in upregulation of HIF1-α, HIF-2α and Ptpmt1. Only inhibition of HIF-2α by shRNA transduction reduces Ptpmt1 expression in TF-1 cells under hypoxia. Ptpmt1 inhibitor suppresses the growth and induces apoptosis of TF-1 cells. Furthermore, we demonstrated that Ptpmt1 inhibition reduces the Glut1 and Glut3 expression and decreases the glucose consumption in TF-1 cells. In additional, Ptpmt1 knockdown also results in the mitochondrial dysfunction determined by JC1 staining. These results delineate a key role for HIF-2α-induced Ptpmt1 upregulation in proliferation, survival and glucose metabolism of erythroleukemia cells. It is indicated that Ptpmt1 plays important roles in hypoxia-induced cell metabolism and mitochondrial dysfunction.

[Sesquiterpenoids from gorgonian Muriceides collaris].

Seven guaiane-type sesquiterpenoids, a new compound 6-formyl-5-isopropyl-3-hydroxymethyl-7-methyl-1H-indene (1), a new natural product 5-isopropyl-3, 7-dimethyl-1H-indene-1-one (2), along with five known compounds: guaiazulene (3), 4-formyl-7-isopropyl-10-methylazulene (4), sesquiterpene ketolactone (5), alismoxide (6) and guaia-1 (5), 6-diene (7), were isolated from gorgonian Muriceides collaris collected in South China Sea. Their structures were elucidated on the basis of extensive spectroscopic analysis [MS, IR, 1H NMR, 13C NMR (DEPT), HMQC, HMBC, NOESY] and by comparison of the spectral data with those of the literatures.

[Pay attention to abnormal vision screening for infants and young children].

World Heath Organization (WHO) put forward a global initiative to eliminate avoidable blindness by 2020. The avoidable blindness includes blindness in children such as amblyopia. The critical period of human visual development is from 0 to 3 years old when is just in the period of infancy and young childhood, therefore vision screening for infants and young children should be attached importance, which is critical significant to the children blindness prevention. Due to many aspects of causes, the vision and related risk factor screening for the infants and young children in China is still faced with many challenges. The article strengthened the aspects of the importance of vision screening for infants and young children and put forward some strategies and suggestions.

Active ingredients Isorhamnetin of Croci Srigma inhibit stomach adenocarcinomas progression by MAPK/mTOR signaling pathway.

Gastric cancer (GC) remains the third leading cause of cancer-related mortality in the world, and ninety-five percent of GC are stomach adenocarcinomas (STAD). The active ingredients of Croci Stigma, such as Isorhamnetin, Crocin, Crocetin and Kaempferol, all have antitumor activity. However, their chemical and pharmacological profiles remain to be elusive. In this study, network pharmacology was used to characterize the action mechanism of Croci Stigma. All compounds were obtained from the traditional Chinese medicine systems pharmacology (TCMSP) database, and active ingredients were selected by their oral bioavailability and drug-likeness index. The targets of Croci Stigma active ingredients were obtained from the traditional Chinese medicine integrated database (TCMID), whereas the related genes of STAD were obtained from DisGeNET platform. Cytoscape was used to undertake visual analyses of the Drug Ingredients-Gene Symbols-Disease (I-G-D) network, and 2 core genes including MAPK14, ERBB3 were obtained, which are the predicted targets of isorhamnetin (IH) and quercetin, respectively. Data analysis from TCGA platform showed that MAPK14 and ERBB3 all upregulated in STAD patients, but only the effect of MAPK14 expression on STAD patients' survival was significant. Molecular docking showed that IH might affect the function of MAPK14 protein, and then the underlying action mechanisms of IH on STAD were experimentally validated using human gastric cancer cell line, HGC-27 cells. The results showed that IH can inhibit cell proliferation, migration, clonal formation, and arrest cell cycle, but promote the apoptosis of HGC-27 cells. qRT-PCR data demonstrated that IH downregulated the MAPK14 mRNA expression and EMT related genes. WB results showed that IH regulates MAPK/mTOR signaling pathway. These findings suggest that IH has the therapeutic potential for the treatment of STAD.

8R-methoxy-9R-hydroxyl-fumitremorgin C, a new diketopiperazine alkaloid from Haima cold seep-derived fungus Aspergillus fumigatus CYH-5.

One novel diketopiperazine derivative 8R-methoxy-9R-hydroxyl-fumitremorgin C (1), together with twelve known compounds, was separated from the fungus Aspergillus fumigatus CYH-5 collected from Haima cold seep. The structures of the compounds were identified by NMR, MS, optical rotation, hydrolysis reaction and comparing with literatures. Among them, compounds 10 and 11 exhibited inhibitory effect against bacteria. Compound 11 showed inhibitory activity on α-glucosidase and compound 8 displayed acetylcholinesterase (AchE) inhibitory activity.

Cytotoxic indole diketopiperazines from the deep sea-derived fungus Acrostalagmus luteoalbus SCSIO F457.

Two new indole diketopiperazines, namely luteoalbusins A-B (1-2), along with eight known ones (3-10), were isolated from the fungus Acrostalagmus luteoalbus SCSIO F457 originated from deep-sea sediment. Their structures were determined by 1D/2D NMR, MS, and CD data analyses. Each of these compounds was evaluated for their cytotoxic activities against SF-268, MCF-7, NCI-H460, and HepG-2 cell lines, and compounds 1-5 showed significant cytotoxicties against all four cancer cell lines. Moreover, new compounds 1 and 2 had more potent cytotoxicity than the other ones and cisplatin.

[The variation characters of EPSC-IPSC in rat visual cortex II/III pyramidal neurons during critical period of visual development].

OBJECTIVE: To observe the characters of EPSC-IPSC induced by paired-pulse stimulation of rat visual cortex layer II/III pyramidal neurons during critical period of visual development, and discuss their relationships, to discuss the role of short-term synaptic plasticity in the critical period of visual development of rats. METHODS: Thirty Wistar rats were used, they were divided into P10-P12, P14-P16, P21-P23, P28-P30, P35-P37 five groups, n = 6. Whole-cell voltage clamp recording was performed, the membrane potential was clamped on -50 mV, 0 mV respectively to separate EPSC and IPSC. We set the PPR as the observation indicator, analyzed the developmental features of EPSC and IPSC induced by paired-pulse stimulation of different groups. RESULTS: The PPR of layer II/III pyramidal neurons in group P10-P12, P14-P16, P21-P23, P28-P30, P35-P37 was 0.43 ± 0.08, 0.07 ± 0.08, 0.10 ± 0.10, 0.20 ± 0.07, 0.22 ± 0.12 respectively. The PPR of group P14-P16 decreased, the difference was statistically significant compared with the group before eyes open (t = -3.13, P = 0.04). The PPR of corresponding groups was 0.6036 ± 0.3021, 0.2830 ± 0.0504, 0.0287 ± 0.0907, -0.0449 ± 0.1443, -0.3089 ± 0.05553 respectively (F = 5.0799, P = 0.0037), the PPR of IPSC gradually reduced with age, and turned negative from the P28-P30 group, changed from PPF to PPD. CONCLUSIONS: The PPR of EPSC response to visual stimuli rapidly, but did not change significantly in the critical period of visual development (P19-P32). The short-term depression of IPSC increased gradually from the eyes open to the end of the critical period of visual development, which may play a more important role in the process of layer II/III pyramidal neurons maturation and the critical period of visual development ending.

The binocular intraocular lens power difference in eyes with different axial lengths.

AIM: To investigate the binocular intraocular lens (IOL) power difference in eyes with short, normal, and long axial lengths (AL) using Lenstar LS 900 optical biometry. METHODS: A total of 716 (1432 eyes) participants were included. The groups were categorized into short (group A: AL<22 mm), normal (group B: 22 mm≤AL≤25 mm), and long AL groups (group C: AL>25 mm). The central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), AL, anterior corneal keratometry, white-to-white (WTW), pupil diameter (PD), as well as IOL power calculated using embedded Barrett formula were assessed. Bland-Altman plots were used to test the agreement of the binocular parameters. RESULTS: In group A, the CCT of the right eye was significantly thinner than that of the left eye (P=0.044) with a difference of -2±8 µm [95% limits of agreement (LoA), -17.8 to 13.2 µm]. For group B, the PD and IOL power in the right eye were significantly lower than those of the left eye (P=0.001, <0.001) with a difference of -0.05±0.32 mm (95%LoA, -0.68 to 0.58 mm) and -0.18±1.01 D (95%LoA, -2.2 to 1.8 D). The AL of right eye was longer than that of the left eye (P=0.002) with a difference of 0.04±0.25 mm (95%LoA, -0.45 to 0.52 mm). No significant difference was observed for all the binocular parameters in group C. The percentage of participants with binocular IOL power difference within ±0.5 D were 62% (31/50), 68.3% (339/496), and 38.8% (66/170) in groups A, B, and C, respectively. CONCLUSION: The binocular parameters related to IOL power are in good agreement, but the binocular IOL power difference of more than half of participants with long AL is more than 0.50 D.

Different expression of circulating microRNA profile and plasma SP-D in Tibetan COPD patients.

COPD is the fourth leading cause of mortality, and is predicted to be the third leading cause of death worldwide by 2020. But few studies on Tibetan COPD of China. This study identifies distinctive miRNA signatures in Tibetan COPD patients from Tibetan healthy subjects that could serve as diagnostic biomarkers or describe differential molecular mechanisms with potential therapeutic implications. In this study, a total of 210 differentially expressed miRNAs were screened. Analysis of the functions of target genes of differentially expressed miRNAs via GO enrichment analysis revealed that they mainly influenced guanyl-nucleotide exchange factor activity, cell morphogenesis and the positive regulation of GTPase activity. KEGG pathway enrichment analysis showed that these target genes were mainly enriched in signaling by NGF, Axon guidance, developmental biology, ubiquitin mediated proteolysis, and PDGF signaling pathways. MiR-106-5p and miR-486-5p expression was validated in the complete cohort. Age, plasma miR-106-5p, miR-486-5p, SP-D protein levels, and SP-D mRNA level were also determined to be correlated with FEV1%Pred, and may as the risk factors of Tibetan COPD. The combination of plasma miR-106-5p, miR-486-5p and SP-D mRNA expression may be the best model to assist the diagnosis of Tibetan COPD.

[A pilot study on characteristics of microsaccadic eye-movements in anisometropic amblyopia].

OBJECTIVE: To quantitatively investigate the characteristics of the microsaccadic eye-movements in anisometropic amblyopia and to evaluate the using value of high-speed eye-movement recording in objective and quantitative evaluation and diagnosis of amblyopia. METHODS: From September in 2010 to March in 2011, 19 cases of anisometropic amblyopic patients (19 amblyopic eyes as group AM and 19 their sound eyes as group AS) and 19 cases of subjects with normal corrected visual acuities (19 dominant eyes as group ND and 19 non-dominant eyes as group NN) were recruited from the outpatient clinic at Tianjin Eye Hospital. A high-speed eye-movement recording system was used to monocularly record the fixational eye-movements of subjects' both eyes. A Matlab routine was used to detect and analyze the microsaccadic components of eye-movement waveforms. The microsaccadic amplitudes, peak velocities, occurrence rates, inter-microsaccadic intervals, cumulative probabilities of all groups were analyzed and compared using Origin8.0 and Matlab2008 statistics toolbox. RESULTS: The mean microsaccadic amplitude of group AM (0.76 ± 0.07)° was larger than groups AS, ND and NN (F = 49.95, P = 0.000). The mean peak velocity of group AM (79.72 ± 5.64)°/s was faster than groups AS, ND and NN (F = 4.93, P = 0.004). The mean occurrence rate of group AM (1.52 ± 0.08) Hz was less than groups AS, ND and NN (F = 120.39, P = 0.000). The mean inter-microsaccadic interval of group AM (537.40 ± 65.47) ms was longer than groups AS, ND and NN (F = 4.41, P = 0.007). The amplitude dependent cumulative probability curve of group AM shifted to right compared with other groups and its amplitude 0.67° ± 0.06° at half cumulative probability was obviously increased compared with other groups (F = 203.05, P = 0.000). CONCLUSION: Microsaccadic amplitude, peak velocity, occurrence rate, inter-microsaccadic interval and cumulative probability could be used as the parameters for objective and quantitative evaluation of eye-movement function in amblyopia. High-speed eye-movement recording could provide useful assistance in evaluation of eye-movements in amblyopic patients.

Multimodal Contrast Agents for Optoacoustic Brain Imaging in Small Animals.

Optoacoustic (photoacoustic) imaging has demonstrated versatile applications in biomedical research, visualizing the disease pathophysiology and monitoring the treatment effect in an animal model, as well as toward applications in the clinical setting. Given the complex disease mechanism, multimodal imaging provides important etiological insights with different molecular, structural, and functional readouts in vivo. Various multimodal optoacoustic molecular imaging approaches have been applied in preclinical brain imaging studies, including optoacoustic/fluorescence imaging, optoacoustic imaging/magnetic resonance imaging (MRI), optoacoustic imaging/MRI/Raman, optoacoustic imaging/positron emission tomography, and optoacoustic/computed tomography. There is a rapid development in molecular imaging contrast agents employing a multimodal imaging strategy for pathological targets involved in brain diseases. Many chemical dyes for optoacoustic imaging have fluorescence properties and have been applied in hybrid optoacoustic/fluorescence imaging. Nanoparticles are widely used as hybrid contrast agents for their capability to incorporate different imaging components, tunable spectrum, and photostability. In this review, we summarize contrast agents including chemical dyes and nanoparticles applied in multimodal optoacoustic brain imaging integrated with other modalities in small animals, and provide outlook for further research.

Asperorydines N-P, three new cyclopiazonic acid alkaloids from the marine-derived fungus Aspergillus flavus SCSIO F025.

Three new tricyclic cyclopiazonic acid (CPA) related alkaloids asperorydines N-P (1-3), together with six known compounds (4-9) were isolated and characterized from the fungus Aspergillus flavus SCSIO F025 derived from the deep-sea sediments of South China Sea. The structures including absolute configurations of 1-3 were deduced from spectroscopic data, X-ray diffraction analysis, and electronic circular dichroism (ECD). All compounds were evaluated for the antioxidative activities against DPPH, cytotoxic activities against four tumor cell lines (SF-268, HepG-2, MCF-7, and A549), and antimicrobial activities. Compound 9 showed significant radical scavenging activities against DPPH with an IC50 value of 62.23 µM and broad-spectrum cytotoxicities against four tumor cell lines with IC50 values ranging from 24.38 to 48.28 µM. Furthermore, compounds 4-9 exhibited weak antimicrobial activities against E scherichia coli, and compound 9 also showed antibacterial activity against Bacillus thuringiensis, Micrococcus lutea, Staphylococcus aureus, Bacillus subtilis, Methicillin resistant Staphylococcus aureus.

[Progress in research of pediatric ophthalmology and strabismus in China in past 5 years].

In the past 5 years of the new century, with the development of national power and the accompanied increase of international academic communication, the researchers and clinical scientists of pediatric ophthalmology and strabismus in China actively participated in the international academic communication and competition and made great achievements. Many excellent works of clinical studies or basic researches in this field were recognized by the academic community of the world. Young ophthalmologists in pediatric ophthalmology and strabismus have been trained and well developed. The position of Chinese pediatric ophthalmology and strabismus in the global academic community has been moved up gradually.

[µ-4-Benzoyl-1-(1-oxido-2-naphthyl-carbon-yl)thio-semicarbazidato(4-)]bis-[pyridine-copper(II)].

In the title dinuclear complex, [Cu(2)(C(19)H(11)N(3)O(3)S)(C(5)H(5)N)(2)], the two Cu(II) centers have different coordination environments, viz. N(2)OS and N(2)O(2), each exhibiting a distorted square-planar geometry. π-π inter-actions between the aromatic rings of neighbouring complexes [centroid-centroid distance = 3.856 (5) Å] link pairs of mol-ecules into centrosymmetric dimers, which are further packed into stacks along the b axis with relatively short Cu⋯Cu separations of 3.482 (1) Å. Weak inter-molecular C-H⋯N hydrogen bonds help to consolidate the crystal packing.