Self-evolving persistent luminescence nanoprobes for autofluorescence-free ratiometric imaging and on-demand enhanced chemodynamic therapy of pulmonary metastatic tumors.

Precise imaging-guided therapy of a pulmonary metastasis tumor is of great significance for tumor management and prognosis. Persistent luminescence nanoparticles (PLNPs) are promising probes due to their in situ excitation-free and low-background imaging characteristics. However, most of the PLNP-based probes cannot intelligently distinguish between normal and tumor tissues or balance the needs of targeted accumulation and rapid metabolism, resulting in false positive signals and potential side effects. Besides, the luminescence intensity of single-emissive PLNPs is affected by external factors. Herein, we report a self-evolving double-emissive PLNP-based nanoprobe ZGMC@ZGC-TAT for pulmonary metastatic tumor imaging and therapy. Acid-degradable green-emitting PLNPs (ZGMC) with good afterglow performance and therapeutic potential are synthesized by systematic optimization of dopants. Ultra-small red-emitting PLNPs (ZGC) are then prepared as imaging and reference probes. The two PLNPs are finally covalently coupled and further modified with a cell-penetrating peptide (TAT) to obtain ZGMC@ZGC-TAT. Dual emission ensures a stable luminescence ratio (I700/I537) independent of probe concentration, test voltage and time gate. ZGMC degrades and phosphorescence disappears in a tumor microenvironment (TME), resulting in an increase in I700/I537, thus enabling tumor-specific ratiometric imaging. Cu2+ and Mn2+ released by ZGMC degradation achieve GSH depletion and enhance CDT, effectively inhibiting tumor cell proliferation. Meanwhile, the size of ZGMC@ZGC-TAT decreases sharply, and the resulting ZGC-TAT further causes nuclear pyknosis and quickly clear metabolism. The developed ZGMC@ZGC-TAT turns non-targeted lung aggregation of nanomaterials into a unique advantage, and integrates TME-triggered phosphorescence and size self-evolution, and on-demand therapeutic functions, showing outstanding prospects in precise imaging and efficient treatment of pulmonary metastatic tumors.

Comparative metabolome profiling of Paris polyphylla var. yunnanensis cultivars and Paris luquanensis and their biological activity in zebrafish model.

ETHNOPHARMACOLOGICAL RELEVANCE: Paris polyphylla var. Yunnanensis (Franch.) Hand.-Mazz., a perennial medicinal herb commonly known as "Chonglou" in Chinese, is mainly effective against innominate toxin swelling, insect sting, snake bite, traumatic injuries and various inflammatory. It is also recorded with mild toxicity. The rare species Paris luquanensis H. Li has been also used as folk medicine in Yunnan province for the same effects. Compared with P. polyphylla var. Yunnanensis (35-100 cm in height), this species has variegated leaves, and grows slower and is therefore shorter (6-23 cm in height). There are a number of different cultivars based on the shape of the petal and the height of Paris plant. However, currently, investigations into the differences of the chemical profiling of these cultivars are lacking. AIM OF THE STUDY: This study aims to: (1) examine metabolites variations in Paris polyphylla var. Yunnanensis cultivars and Paris luquanensis; (2) investigate the different metabolite accumulation patterns between rhizomes and leaves and provide more useful information for the application of P. polyphylla var. Yunnanensis leaves; (3) compare in vivo effects on the recruitment of reactive oxygen species (ROS) and Neutrophils and toxic effects in zebrafish model between leaves and rhizomes of P. polyphylla var. Yunnanensis and P. luquanensis. MATERIALS AND METHODS: The change patterns of metabolites in the leaves and rhizomes of four P. polyphylla var. Yunnanensis cultivars and one P. luquanensis cultivar were analyzed using an UPLC-ESI-MS/MS system. The total phenolic acid, total flavonoid, total saponin components and in vitro antioxidant activities were determined by spectrophotometric methods. The in vivo toxicity and their effects on the recruitment of ROS and neutrophils in zebrafish model were performed. RESULTS: The widely targeted metabolomics method detected 695 metabolites in tested samples and classified as 15 known classes according to structures of the metabolites. By overall-comparing the SDMs discerned between leaves and rhizomes of each samples, 161 metabolites were substantially altered in all the cultivars. There are 62 and 64 SDMs showing constitutive differential accumulation between leaves and rhizomes of P. polyphylla var. Yunnanensis (samples A-D) and P. luquanensis (sample E), respectively. The levels of TSC, TPC and TFC decreased significantly in leaves as compared to rhizomes for all cultivars, with the exception of TPC in cultivar A, which is almost the same in leave and rhizome. The DPPH scavenging property and FRAP values of rhizomes are higher than those of leaves for all cultivars. However, there is no distinct different between leaves and rhizomes of different sample extracts for in vivo effects on the recruitment of ROS and neutrophils in zebrafish model. BL extracts showed high toxicity to the developing embryos. CONCLUSION: As far as we are concerned, this study analyzes the P. polyphylla var. Yunnanensis and P. luquanensis variegation from the perspective of the metabolites pattern for the first time. The results give a valuable insight into the specie metabolic profiling and in vivo anti-oxidant, anti-inflammatory and toxic effects of these Paris plants.

Netrin-1 promotes the vasculogenic capacity of human adipose-derived stem cells.

Adipose derived stem cells (ADSCs) have been increasingly explored for use in cell-based therapy against ischemic diseases. However, unsatisfactory angiogenesis limits the therapeutic efficacy. Netrin-1, a known axon guidance molecule, improves neovascularization in the ischemic region. Thus, our study was performed to evaluate the potential effect of Netrin-1 on the angiogenic behaviors of human ADSCs (hADSCs). hADSCs acquired from human abdominal adipose tissue were modified by liposome transfection of Netrin-1 plasmid, and the proliferation of hADSCs was determined by Cell Counting Kit-8 (CCK-8) assay. The transcript levels of pro-invasive proteins such as matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP-9), were measured to test migratory and invasive capabilities, and the levels of vascular endothelial growth factors were assayed to monitor angiogenic activity. Our results showed that Netrin-1 overexpression enhanced the proliferation of hADSCs, and promoted the migration and invasion of hADSCs, as indicated by increased levels of MMP-2 and MMP-9. Furthermore, Netrin-1 overexpression increased the expression of vascular endothelial growth factor and placental growth factor in hADSCs. Our results highlighted the possibility that genetic modification of hADSCs by Netrin-1 overexpression might be beneficial for cell transplantation therapy against ischemic diseases.

Diagnostic value of dual-energy CT and clinicopathological and imaging feature analysis of mixed endometrial stromal and smooth muscle tumors with intracardiac extension.

Objective: To describe the clinicopathological and imaging features of mixed endometrial stromal and smooth muscle tumors with intracardiac extension and to explore the diagnostic value of dual-energy computed tomography (DECT) for this rare entity. Materials and methods: This retrospective study analyzed the clinicopathological data and images of a 41-year-old female patient with pathologically documented mixed endometrial stromal and smooth muscle tumors with intracardiac extension who had undergone DECT examination. Seven virtual monoenergetic images (VMIs) in 10-kiloelectron volt (keV) intervals (range = 40-100 keV), iodine density (ID) maps, and Z effective (Zeff) maps were reconstructed, and lesion conspicuity was assessed. Tumor homology was analyzed using quantitative DECT parameters and energy spectrum attenuation curve. Results: The patient complained of a 10-day history of bilateral lower extremity edema. Computed tomography showed a hypoattenuating filling defect located within the paracervical vein that extended into the right atrium to the ventricle through the right iliac veins and inferior vena cava (IVC). Intracardiac and intravenous lesions mainly demonstrated moderate progressive enhancement, with localized non-enhancing necrotic areas on contrast-enhanced CT. Multiple nodules showing progressive enhancement (long-T1 signal, long-T2 signal) were observed at the fundus of the uterus on dynamic contrast-enhanced magnetic resonance imaging (MRI), which were deemed the primary lesions of the tumor. Overall, the tumor was characterized by a small primary lesion with extensive vascular extension. In addition, the 40 keV VMIs reconstructions were found to provide best visualization for the early detection of tumors. Conclusion: Although a definitive diagnosis of MESSMT with intracardiac extension requires confirmation by histopathological examination, imaging examination can be used to characterize the extent of the lesion. The dual-energy dataset facilitates tumor visualization and homology evaluation.

Transcriptome analysis of developing zebrafish (Danio rerio) embryo following exposure to Gaudichaudione H reveals teratogenicity and cardiovascular defects caused by abnormal iron metabolism.

Gaudichaudione H (GH), a caged polyprenylated xanthone from Garcinia plants, showed anti-cancer and anti-inflammatory effects in vitro. However, the in vivo toxicity of this compound has never been reported. The present study was aimed to address the toxic effects of Gaudichaudione H using zebrafish embryos and larvae as an in vivo test model. The zebrafish embryos were treated with GH having different concentrations (0, 0.28, 0.38 and 0.57 µg/mL). The results revealed that GH induces significant embryonic mortality, decreased heartbeat, cardiotoxicity, cardiovascular defects, increased apoptosis and decreased hemoglobinization in zebrafish embryos and larvae. According to transcriptome analysis, 1841 genes were significantly differentially expressed (1185 down-regulated and 656 up-regulated) after GH treatment. The main functions of these genes were related to iron metabolism pathways. The toxicity of GH on zebrafish embryonic development and cardiovascular may due to large amounts of downregulated genes involved in metabolic pathways and DEGs related to 'Iron ion binding' and 'Heme binding' functions.

Circ_0000388 Exerts Oncogenic Function in Cervical Cancer Cells by Regulating miR-337-3p/TCF12 Axis.

Background: Cervical cancer (CC) is one of the most common cancers among women worldwide. Circular RNAs (circRNAs) are recently identified as important gene regulators with critical roles in cancer biology. In this study, we explored the effects of circ_0000388 on the malignant phenotypes of CC cells and its mechanism. Materials and Methods: Circ_0000388 expression and miR-337-3p expression in CC tissue samples were measured using quantitative real time polymerase chain reaction. CCK-8 was adopted to assess the effect of circ_0000388 on CC cell line proliferation. TUNEL assay was employed to probe the effect of circ_0000388 on apoptosis. Wound healing assay and transwell assay were conducted to detect the effect of circ_0000388 on migration and invasion. Further, interaction among circ_0000388, miR-337-3p, and TCF12 (transcription factor 12) was determined by bioinformatics analysis, RT-PCR, Western blot, RNA immunoprecipitation assay, and luciferase reporter assay. Results: Circ_0000388 expression in CC clinical samples was upregulated and this was correlated with unfavorable pathological indexes. Circ_0000388 remarkably enhanced the proliferation and metastasis of CC cells. Circ_0000388 overexpression dramatically impeded miR-337-3p expression and it was identified as a sponge of miR-337-3p. Furthermore, circ_00003888 also enhanced the TCF12 expression, while the effect could be reversed by co-transfection with miR-377-3p. Conclusions: Circ_0000388 was a novel oncogenic circRNA in CC, and promoted cancer progression via regulating miR-337-3p and TCF12, and could be potentially used as a diagnostic biomarker and therapy target.

Vulvar Cancer in China: Epidemiological Features and Risk Analysis.

Objective: Describe for the first time the clinical, epidemiological features of vulvar cancer in southwest China. Identify risk factors and provide reference for the prevention of vulvar cancer. Method: We retrospectively analyzed 885 patients admitted to the West China Second University Hospital for vulvar diseases between 2006 and 2016. Vulvar cancer patients with previously diagnosed vulvar nonneoplastic epithelial disorders (n=132) were analyzed and compared to those without prior history of vulvar nonneoplastic epithelial disorders (n=219). Comparisons were also made among cancer patients and non-cancer patients with vulvar nonneoplastic epithelial disorders (n=288) and vulvar squamous intraepithelial lesions (n=246). The risk factors leading to vulvar cancer for the patients with vulvar nonneoplastic epithelial disorder were analyzed by univariate analysis. Furthermore, differences of the epidemiological features of vulvar nonneoplastic epithelial disorders, vulvar squamous intraepithelial lesion and vulvar cancer were identified. Results: According to the univariate analysis, age, first coital age, educational level, smoking, history of vaginal atrophy, HPV infection, lesion sites of the upper vulva and histo-pathological changes are strongly positively correlated with vulvar cancer. By comparing the features of vulvar cancer with those of the vulvar nonneoplastic epithelial disorder and vulvar squamous intraepithelial lesion, we found that on average patients with vulvar cancer had the highest age (ranged from 50 to 59), the lowest first coital age and the highest number of pregnancies and births. The incidences of vulvar nonneoplastic epithelial disorder and vulvar cancer were 1/1000 and 2.5/100,000 respectively with an increasing trend during last 10 years. Conclusion: Age, first coital age, educational level, smoking, atrophic vagina history, HPV infection, lesion sites of the upper vulva and histo-pathological changes are the risk factors that lead to vulvar cancer. Vulvar nonneoplastic epithelial disorder, vulvar squamous intraepithelial lesion and vulvar cancer each has distinct epidemiological features. Prompt surgical intervention and subsequent treatments are the key to a better outcome of vulvar cancer.

Versicolols A and B, two new prenylated isocoumarins from endophytic fungus Aspergillus versicolor and their cytotoxic activity.

Versicolols A and B (1 and 2), two rare prenylated isocoumarin derivatives, along with five known isocoumarins (3-7) were isolated from the fermentation products of an endophytic fungus Aspergillus versicolor. Their structures were elucidated on the basis of extensive spectroscopic analysis, including 1D- and 2D-NMR techniques. Compounds 1 and 2 were evaluated for their cytotoxicity against five human tumor cell lines. The results showed that compounds 1 exhibited weak cytotoxicity against A549 and MCF7 cells with IC50 values of 9.4 and 8.8 µm, and compound 2 exhibited weak cytotoxicity against SHSY5Y and MCF7 cells with IC50 values of 8.2 and 6.8 µm, respectively.

Three new biphenyls from the twigs of Garcinia tetralata and their anti-tobacco mosaic virus activity.

Phytochemical investigations on the ethanol extract of the twigs of Garcinia tetralata resulted in the isolation of three new biphenyls, tetralatabiphenyls A-C (1-3), along with three known biphenyl derivatives (4-6). Structural elucidations of 1-3 were performed by spectroscopic methods such as 1D and 2D NMR spectra, in addition to high-resolution mass spectra. Compounds 1-6 were also evaluated for their anti-tobacco mosaic virus (anti-TMV) activity. The results showed that compound 3 showed high anti-TMV activity with inhibition rate of 31.1%. Compounds 1, 2, and 4-6 also showed modest anti-TMV activities with inhibition rates in the range of 18.9-24.5%, respectively.

[A new cytotoxic isocoumarin from endophytic fungus Aspergillus versicolor].

A new isocoumarin, along with five known ones,were isolated from the fermentation products of an endophytic fungus Aspergillus versicolorby using various chromatographic techniques.Their structures were elucidated on the basis of extensivespectroscopic analysis, including 1D-and 2D-NMR techniques. Compound 1 was evaluated for cytotoxicity against five human tumor cell lines. The results showed that 1 exhibited weak cytotoxicityagainst NB4, SHSY5Y and MCF7 cells with IC50 values of 6.8, 4.3,8.8 µmol•L⁻¹, respectively.

Flavones from Cassia siamea and their anti-tobacco mosaic virus activity.

Two new flavones, siameflavones A and B (1 and 2), together with five known flavones (3-7) were isolated from the stem of Cassia siamea. Their structures were elucidated by spectroscopic methods including extensive 1D and 2D NMR techniques. Compounds 1-5 were evaluated for their anti-tobacco mosaic virus (Anti-TMV) activity. The results showed that compounds 1-5 showed weak anti-TMV activity with inhibition rates in the range of 11.6-18.5%.

[Gynecologic cancers in a hospital: a retrospective analysis of admission data over ten years].

OBJECTIVE: To investigate admission patterns of patients with gynecologic cancers over a ten year period, which will provide a basis for further epidemiological studies. METHODS: We reviewed medical records of patients with gynecologic cancers who were admitt d to the West China Second University Hospital of Sichuan University from 2003 to 2012. Their clinicopathological data were extracted and analysed. RESULTS: The number of admitted patients increased over the years, with cervical, uterine and ovary cancers as the top three gynaecological cancers. They accounted for 92.13% of total gynaecological cancers. The peak age of gynaecological cancers was 40-49 years, which accounted for 34.02% (3132/9207) of all patients, followed by 50-59 years (26.64%, 2453/9207). Most (72.46%, 3062/4226) cervical cancer patients aged 30-49 years, compared with 40-59 years for uterine cancers (69.77%, 1768/2534) and 40-59 years for ovarian cancers (58.30%, 1004/1722). Patients in their 20th account for 4.43% (408/9 207) of total cancers, with in which cervical and ovarian cancers as the most common pathological type. Patients under 20 years of age accounted for only 0.98% (90/9207) of total cancers, with ovarian cancers as the most common pathological type. Patients over 60 years accounted for 12.90% (1188/9207) of total cancers, with uterine and ovarian cancers as the most common pathological type. Most patients were at an early stage of cancers when they were admitted to the hospital. CONCLUSION: Hospitalized patients with gynecologic cancers increase over years. Cervical, uterine and ovary cancers remain to be a focus of treatment. Peak age of those cancers varies.

Fistulains A and B, New Bischromones from the Bark of Cassia fistula, and Their Activities.

Fistulains A and B (1 and 2), two novel bischromones with unique coupling patterns, alone with their biosynthetic related compound 3, were isolated from the bark of Cassia fistula. Fistulain A represents a new type of dimeric chromone alkaloid biogenetically derived from a chromone and a tricyclic alkaloid through an unusual C-14-N linkage. Fistulain B has a new carbon skeleton with a C-14-C-5' linkage formed between two different chromone units. Fistulain A displayed anti-TMV activity, and both 1 and 2 showed weak cytotoxicities.

Antiviral butyrolactones from the endophytic fungus Aspergillus versicolor.

Versicolactones A-D (1-4), four new butyrolactones, along with four known butyrolactones (5-8) were isolated from the fermentation products of the endophytic fungus Aspergillus versicolor. The structures of compounds 1-4, including absolute configuration, were elucidated by interpretation of the NMR and CD data. Compound 2 was further confirmed by single-crystal X-ray diffraction analysis. In particular, compound 1 is the first naturally occurring butyrolactone possessing an unusual 2-oxopropyl group. More importantly, compounds 1 and 8 displayed significant antitobacco mosaic virus activities with inhibition rates of 46.4 % and 35.4 %, even more potent than the positive control ningnanmycin (30.8 %). Compound 1 also showed moderate cytotoxicity against A549 and MCF7 cells with IC50 values of 3.2 and 2.5 µM, respectively.

7,8-Secolignans from the fruits of Schisandra neglecta.

Two new 7,8-secolignans, neglectahenols E and F (1 and 2), together with four known 7,8-secolignans (3-6), were isolated from the fruits of Schisandra neglecta. The structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1-6 were tested for their anti-tobacco mosaic virus (anti-TMV) activities at the concentration of 20 µM. Compounds 1 and 6 showed high anti-TMV activities with inhibition rates of 38.2% and 32.7%, respectively. These rates are higher than that of a positive control. Compounds 2-5 also showed modest anti-TMV activities with inhibition rates in the range of 22.8-28.7%. These rates are close to that of a positive control.

Dihydroxanthenones from the fermentation product of an endophytic fungus Gliomastix murorum.

Three new dihydroxanthones, muroxanthenones A-C (1-3), together with three known dihydroxanthones (4-6) were isolated from the fermentation products of an endophytic fungus Gliomastix murorum. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compound 3 showed high cytotoxicities against NB4 and PC3 cell with IC(50) values of 2.2 and 2.8 µM. The other compounds also showed moderate cytotoxicities for some tested cell lines with IC(50) values between 4.1 and 9.5 µM.

[A new flavone from stems of Garcinia bracteata and its anti-TMV activity].

A phytochemical investigation on the stems of Garcinia bracteata collected from Xishuangbanna resulted in the isolation of a new flavone. By analysis of the HRESIMS, IR, UV, 1D and 2D NMR spectra, the structure of the new compound was determined as 7-methoxy-4',6-dihydroxy-8-isobutyryl-flavone(1). Compound 1 was also tested for its anti-tobacco mosaic virus(TMV) activity. Results suggested the 1 possessed remarkable anti-TMV activity, with an inhibition rate of 28.2%.

Aspergillines A-E, highly oxygenated hexacyclic indole-tetrahydrofuran-tetramic acid derivatives from Aspergillus versicolor.

Aspergillines A-E (1-5) are highly oxygenated cyclopiazonic acid (CPA)-derived alkaloids bearing a rigid and sterically congested hexacyclic indole-tetrahydrofuran-tetramate scaffold, isolated from the endophytic fungus Aspergillus vesicolor. Apergillines A-C represent a new subclass of CPA-derived alkaloids, and aspergillines B and E possess a butanoic acid methyl ester moiety. The structures, including absolute configuration, were elucidated by interpretation of the NMR, X-ray crystallographic, and circular dichroism data. All compounds displayed anti-TMV and cytotoxic activities.

Five new prenylated chalcones from Desmodium renifolium.

Five unusual new prenylated chalcones, renifolins D-H (1-5), were isolated from whole Desmodium renifolium plants. All of their structures were determined by spectroscopic methods including 1D and 2D NMR. All of the isolates were evaluated for cytotoxicity using five tumor cell lines. Compounds 2 and 3 exhibited cytotoxicity against A549 cells, with IC50 values of 2.8 and 2.2 µM, respectively.

Characterization of proapoptotic compounds from the bark of Garcinia oblongifolia.

Twenty compounds from Garcinia oblongifolia were screened for proapoptotic activity using FRET-based HeLa-C3 sensor cells. Among them, oblongifolins F and G (1 and 2), 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran[7,6-b]xanthone (3), nigrolineaxanthone T (4), and garcicowin B (5) showed significant proapoptotic activity at a concentration of 10 µM. Bioassessments were then performed to evaluate the potential of these compounds for therapeutic application. All five compounds showed significant cytotoxicity and caspase-3-activating ability in cervical cancer HeLa cells, with compounds 1 and 2 having the highest potencies. All five compounds specifically induced caspase-dependent apoptosis, which could be prevented by the pan-caspase inhibitor zVAD-fmk. In particular, 3 induced apoptosis through mitotic arrest. Compounds 1-5 displayed similar IC50 values (3.9-16.5 µM) against the three cancer cell lines HeLa, MDA-MB-435, and HepG2. In addition, compounds 1, 2, and 4 exhibited similar and potent IC50 values (2.4-5.1 µM) against several breast and colon cancer cell lines, including those overexpressing either HER2 or P-glycoprotein. HER2 and P-glycoprotein are known factors that confer resistance to anticancer drugs in cancer cells. This is the first study on the cytotoxicity, caspase-3-activing ability, and specificity of proapoptotic compounds isolated from G. oblongifolia in HeLa cells. The potential application of these compounds against HER2- or P-glycoprotein-overexpressing cancer cells was investigated.