Tissue Distribution and Anti-Lung Cancer Effect of 10-Hydroxycamptothecin Combined with Platycodonis Radix and Glycyrrhizae Radix ET Rhizoma.

10-Hydroxycamptothecin (HCPT) is a broad-spectrum chemotherapeutic drug, although its side effects and multidrug resistance (MDR) limit its clinical application. A range of drug delivery systems have been utilized to overcome its shortcomings and maintain its therapeutic efficacy, however the use of the transport effect of traditional Chinese medicines (TCMs) to improve the distribution of chemotherapeutic drugs has not been widely reported. Platycodonis Radix (JG) and Glycyrrhizae Radix ET Rhizoma (GC) are common TCMs in clinics and are often combined as drug pairs to act as "transport agents". In the present study, the effect of JG and GC (JGGC) on the distribution of HCPT in tissues and its antitumor efficacy after being combined as a therapy were investigated, for which ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was used. Furthermore, the effect on the protein expression of multidrug resistance proteins (P-gp and LRP), and the immunomodulatory and synergistic antiapoptotic effect on Lewis lung cancer-bearing C57BL/6J mice were also evaluated. The results demonstrate that JGGC significantly increased the area under the concentration time curve (AUC) and mean residence time (MRT) and reduced the clearance rate (CL) of HCPT. In addition, the combined use of JGGC decreased the levels of LRP, P-gp and Bcl-2/Bax when treated with HCPT. JGGC also significantly elevated the levels of RBCs, PLTs, HGB, IL-2, and IFN-γ, and decreased IL-10 levels. In summary, an increased concentration of HCPT in tissues was observed when it was combined with JGGC through inhibition of efflux protein, with a synergistic enhancement of the anticancer effect observed through promotion of apoptosis and immunity due to a reversion of the Th1/Th2 shift. Our findings provide a reference for the feasibility of combining JGGC with chemotherapy drugs in clinical applications.

Isolation and Identification of the Anti-Oxidant Constituents from Loropetalum chinense (R. Brown) Oliv. Based on UHPLC⁻Q-TOF-MS/MS.

The aim of this study was to identify the chemical constituents of Loropetalum chinense (R. Brown) Oliv. (LCO) and determine which of these had antioxidant effects. The chemical composition of a 70% ethanol extract of LCO was analyzed systematically using UHPLC⁻Q-TOF-MS/MS. The chemical components of the 70% ethanol extract of LCO were then separated and purified using macroporous resin and chromatographic techniques. Antioxidant activity was evaluated using a DPPH assay. In total, 100 compounds were identified tentatively, including 42 gallic acid tannins, 49 flavones, and 9 phenolic compounds. Of these, 7 gallium gallate, 4 flavonoid and 8 quinic acid compounds were separated and purified from the 70% ethanol extract of LCO. The compounds identified for the first time in LCO and in the genus Loropetalum were 3,4,5-trimethoxyphenyl-(6'-O-galloyl)-O-ß-d-glucopyranoside, protocatechuic acid, ethyl gallate, 5-O-caffeoylquinic acid, 3-O-caffeoylquinic acid, 3,5-O-diocaffeoylquinic acid, 4,5-O-diocaffeoylquinic acid and 3,4-O-diocaffeoylquinic acid. The 50% inhibitory concentration (IC50) values of compounds 1,2,3,4,6-penta-O-galloyl-ß-d-glucose, gallic acid, protocatechuic acid, and ethyl gallate were 1.88, 1.05, 1.18, and 1.05 µg/mL, respectively. Compared with the control group (VC) (2.08 µg/mL), these compounds exhibited stronger anti-oxidation activity. This study offered considerable insight into the chemical composition of LCO, with preliminary identification of the antioxidant ingredients.

Breast cancer: early prediction of response to neoadjuvant chemotherapy using parametric response maps for MR imaging.

PURPOSE: To prospectively compare the performance of dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging using parametric response map (PRM) analysis with that using pharmacokinetic parameters (transfer constant [K(trans)], rate constant [kep ], and relative extravascular extracellular space [ve]) in the early prediction of pathologic responses to neoadjuvant chemotherapy (NAC) in breast cancer patients. MATERIALS AND METHODS: The institutional review board approved this study; informed consent was obtained. Between August 2010 and December 2012, 48 women (mean age, 46.4 years; range, 29-65 years) with breast cancer were enrolled and treated with an anthracycline-taxane regimen. DCE MR imaging was performed before and after the first cycle of chemotherapy, and the pathologic response was assessed after surgery. Tumor size and volume, PRM characteristics, and pharmacokinetic parameters (K(trans), kep, and ve) on MR images were assessed and compared according to the pathologic responses by using the Fisher exact test or the independent-sample t test. RESULTS: Six of 48 (12%) patients showed pathologic complete response (CR) (pCR) and 42 (88%) showed nonpathologic CR (npCR). Thirty-eight (79%) patients showed a good response (Miller-Payne score of 3, 4, or 5), and 10 (21%) showed a minor response (Miller-Payne score of 1 or 2). The mean proportion of voxels with increased signal intensity (PRMSI+) in the pCR or good response group was significantly lower than that in the npCR or minor response group (14.0% ± 6.5 vs 40.7% ± 27.2, P < .001; 34.3% ± 26.4 vs 52.8% ± 24.9, P = .041). Area under the receiver operating characteristic curve for PRMSI+ in the pCR group was 0.770 (95% confidence interval: 0.626, 0.879), and that for the good response group was 0.716 (95% confidence interval: 0.567, 0.837). No difference in tumor size, tumor volume, or pharmacokinetic parameters was found between groups. CONCLUSION: PRM analysis of DCE MR images may enable the early identification of the pathologic response to NAC after the first cycle of chemotherapy, whereas pharmacokinetic parameters (K(trans), kep, and ve) do not.

Col1a1 mediates the focal adhesion pathway affecting hearing in miR-29a mouse model by RNA-seq analysis.

Age-related hearing loss (ARHL) is a common neurodegenerative disease. Its molecular mechanisms have not been fully elucidated. In the present study, we obtained differential mRNA expression in the cochlea of 2-month-old miR-29a+/+ mice and miR-29a-/- mice by RNA-seq. Gene ontology (GO) analysis was used to identify molecular functions associated with hearing in miR-29a-/- mice, including being actin binding (GO: 0003779) and immune processes. We focused on the intersection of differential genes, miR-29a target genes and the sensory perception of sound (GO:0007605) genes, with six mRNA at this intersection, and we selected Col1a1 as our target gene. We validated Col1a1 as the direct target of miR-29a by molecular and cellular experiments. Total 6 pathways involved in Col1a1 were identified by through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. We selected the focal adhesion pathway as our target pathway based. Their expression levels in miR-29a-/- mice were verified by qRT-PCR and Western blot. Compared with miR-29a+/+ mice, the expression levels of Col1a1, Itga4, Itga2, Itgb3, Itgb7, Pik3r3 and Ptk2 were different in miR-29a-/- mice. Immunofluorescence was used to locate genes in the cochlea. Col1a1, Itga4 and Itgb3 were differentially expressed in the basilar membranes and stria vascularis and spiral ganglion neurons compared to miR-29a+/+ mice. Pik3r3 and Ptk2 were differentially expressed in the basilar membranes and stria vascularis, but not at the s spiral ganglion neurons compared to miR-29a+/+ mice. Our results show that when miR-29a is knocked out, the Col1a1 mediates the focal adhesion pathway may affect the hearing of miR-29a-/- mice. These findings may provide a new direction for effective treatment of age-related hearing loss.

The dynamic causality between Chinese and ASEAN stock markets.

COVID-19 has caused severe shocks to the Chinese and ASEAN stock markets. This paper investigates the relationship between the Chinese and ASEAN stock markets using the bootstrap rolling-window causality test. The results show that there is a bidirectional Granger causality relationship between the Chinese and ASEAN stock markets with time-varying characteristics. Before the COVID-19 outbreak, the interaction between the Chinese and ASEAN stock markets was mainly positive. After the COVID-19 outbreak, during the off-peak period, the interaction between the Chinese and ASEAN stock markets was positive or negative at different periods; during the peak period of the epidemic, the ASEAN stock markets had negative impacts on the Chinese stock market. In addition, the relationship between the Chinese and ASEAN stock markets was enhanced during COVID-19. According to the interaction mechanism, economic and political factors would affect the relationship between the Chinese and ASEAN stock markets, but major events such as COVID-19 have a greater impact. Therefore, macroeconomic policy should play a positive role in the stock market.

Recent advances in nanoantibiotics against multidrug-resistant bacteria.

Multidrug-resistant (MDR) bacteria-caused infections have been a major threat to human health. The abuse of conventional antibiotics accelerates the generation of MDR bacteria and makes the situation worse. The emergence of nanomaterials holds great promise for solving this tricky problem due to their multiple antibacterial mechanisms, tunable antibacterial spectra, and low probabilities of inducing drug resistance. In this review, we summarize the mechanism of the generation of drug resistance, and introduce the recently developed nanomaterials for dealing with MDR bacteria via various antibacterial mechanisms. Considering that biosafety and mass production are the major bottlenecks hurdling the commercialization of nanoantibiotics, we introduce the related development in these two aspects. We discuss urgent challenges in this field and future perspectives to promote the development and translation of nanoantibiotics as alternatives against MDR pathogens to traditional antibiotics-based approaches.

MiR-29a-deficiency causes thickening of the basilar membrane and age-related hearing loss by upregulating collagen IV and laminin.

Age-related hearing loss (ARHL) is the most common sensory degenerative disease and can significantly impact the quality of life in elderly people. A previous study using GeneChip miRNA microarray assays showed that the expression of miR-29a changes with age, however, its role in hearing loss is still unclear. In this study, we characterized the cochlear phenotype of miR-29a knockout (miR-29a-/-) mice and found that miR-29a-deficient mice had a rapid progressive elevation of the hearing threshold from 2 to 5 months of age compared with littermate controls as measured by the auditory brainstem response. Stereocilia degeneration, hair cell loss and abnormal stria vascularis (SV) were observed in miR-29a-/- mice at 4 months of age. Transcriptome sequencing results showed elevated extracellular matrix (ECM) gene expression in miR-29a-/- mice. Both Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the key differences were closely related to ECM. Further examination with a transmission electron microscope showed thickening of the basilar membrane in the cochlea of miR-29a-/- mice. Five Col4a genes (Col4a1-a5) and two laminin genes (Lamb2 and Lamc1) were validated as miR-29a direct targets by dual luciferase assays and miR-29a inhibition assays with a miR-29a inhibitor. Consistent with the target gene validation results, the expression of these genes was significantly increased in the cochlea of miR-29a-/- mice, as shown by RT-PCR and Western blot. These findings suggest that miR-29a plays an important role in maintaining cochlear structure and function by regulating the expression of collagen and laminin and that the disturbance of its expression could be a cause of progressive hearing loss.

Study on anti-hyperuricemia effects and active ingredients of traditional Tibetan medicine TongFengTangSan (TFTS) by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.

TongFengTangSan (TFTS), a traditional Tibetan medicine comprising of Tinospora sinensis (TS), Terminalia chebula Retz (TC) and Trogopterori faeces (TF), is used to treat joint diseases like gout, gout arthritis, swelling, pain etc. Despite the significant therapeutic effects of TFTS, its pharmacological components have not been analyzed so far. Therefore, the chemical composition of the effective part of TFTS was analyzed by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS). The results show that the ethanol extract (EE) of TFTS was more effective in reducing the serum uric acid (SUA) and XOD (Serum and Liver) levels in a hyperuricemic rats model compared to the TFTS raw powder (RP). UHPLC-Q-TOF-MS/MS identified a total of 106 compounds in the positive and negative ion mode, of which 87 were from TC, 13 from TS and 6 from TF. In addition, 106 compounds contained 57 tannins, 6 triterpenoids, 10 alkaloids, 7 flavonoids, 22 organic acids and 4 phenylpropanoids. The preliminary results indicate that the EE of TFTS includes the active anti hyperuricemic substances. The present study first investigated the efficacy and the active components of TFTS in hyperuricemic treatment, and further summarized the diagnostic ion and neutral loss patterns of MS/MS cracking of tannic compounds. These findings lay the foundation for the further study and clinical application of TFTS.

The Spatial Relationship of Malignant and Benign Breast Lesions with Respect to the Fat-Gland Interface on Magnetic Resonance Imaging.

The fat-gland interface in the breast is noteworthy in that major vessels and lymphatic channels supplying the breast are located there; however, the relationship between breast lesion formation and the fat-gland interface is poorly understood. Here we evaluate the location of malignant and benign breast lesions with respect to the fat-gland interface in 881 women 50 years of age and younger, utilizing MR imaging. We find that most breast lesions are located in or near the interface in qualitative (89.7%) and quantitative (90.0%, 1 cm within the interface) analyses. This propensity for the fat-gland interface is not accounted for by breast anatomy, whereby 12.3% and 55.7% of breast volume is within 2 mm and 1 cm of the interface, respectively. Malignant lesions were located in or near the interface in significantly higher proportions than benign lesions in qualitative (94.3% vs. 67.3%, P < 0.001) and quantitative (49.7% vs. 34.5%, P < 0.001, 2 mm within the interface) analyses. This phenomenon may reflect a biological importance of the fat-gland interface in breast cancer development and progression.

[Adult nasal metal foreign bodies: 2 cases report].

To analysis the data of 2 patients who had nasal metal foreign bodies after the pressure cooker explosion, the main clinical symptoms include head facial swelling after trauma, nose bleeding, or vision loss, etc. Specialized examination: facial swelling, the left eye content of one patient has been removed, the other patient's right side of the nasal dorsal skin was missing, which diameter was about 1.5 cm, and nasal cavity was interlinked. We could see that metal foreign bodies blocked the bilateral nasal cavity of the two patients. And emergency CT examination showed that most of the nasal cavity reserved for high-density foreign body. Two patients were diagnosed: (1) metal foreign bodies after nasal trauma; (2) nose bleeding.

Intratumoral heterogeneity of breast cancer xenograft models: texture analysis of diffusion-weighted MR imaging.

OBJECTIVE: To investigate whether there is a relationship between texture analysis parameters of apparent diffusion coefficient (ADC) maps and histopathologic features of MCF-7 and MDA-MB-231 xenograft models. MATERIALS AND METHODS: MCF-7 estradiol (+), MCF-7 estradiol (-), and MDA-MB-231 xenograft models were made with approval of the animal care committee. Twelve tumors of MCF-7 estradiol (+), 9 tumors of MCF-7 estradiol (-), and 6 tumors in MDA-MB-231 were included. Diffusion-weighted MR images were obtained on a 9.4-T system. An analysis of the first and second order texture analysis of ADC maps was performed. The texture analysis parameters and histopathologic features were compared among these groups by the analysis of variance test. Correlations between texture parameters and histopathologic features were analyzed. We also evaluated the intraobserver agreement in assessing the texture parameters. RESULTS: MCF-7 estradiol (+) showed a higher standard deviation, maximum, skewness, and kurtosis of ADC values than MCF-7 estradiol (-) and MDA-MB-231 (p < 0.01 for all). The contrast of the MCF-7 groups was higher than that of the MDA-MB-231 (p = 0.004). The correlation (COR) of the texture analysis of MCF-7 groups was lower than that of MDA-MB-231 (p < 0.001). The histopathologic analysis showed that Ki-67mean and Ki-67diff of MCF-7 estradiol (+) were higher than that of MCF-7 estradiol (-) or MDA-MB-231 (p < 0.05). The microvessel density (MVD)mean and MVDdiff of MDA-MB-231 were higher than those of MCF-7 groups (p < 0.001). A diffuse-multifocal necrosis was more frequently found in MDA-MB-231 (p < 0.001). The proportion of necrosis moderately correlated with the contrast (r = -0.438, p = 0.022) and strongly with COR (r = 0.540, p = 0.004). Standard deviation (r = 0.622, r = 0.437), skewness (r = 0.404, r = 0.484), and kurtosis (r = 0.408, r = 0.452) correlated with Ki-67mean and Ki-67diff (p < 0.05 for all). COR moderately correlated with Ki-67diff (r = -0.388, p = 0.045). Skewness (r = -0.643, r = -0.464), kurtosis (r = -0.581, r = -0.389), contrast (r = -0.473, r = -0.549) and COR (r = 0.588, r = 0.580) correlated with MVDmean and MVDdiff (p < 0.05 for all). CONCLUSION: The texture analysis of ADC maps may help to determine the intratumoral spatial heterogeneity of necrosis patterns, amount of cellular proliferation and the vascularity in MCF-7 and MDA-MB-231 xenograft breast cancer models.

MRI of breast tumor initiating cells using the extra domain-B of fibronectin targeting nanoparticles.

The identification of breast tumor initiating cells (BTICs) is important for the diagnosis and therapy of breast cancers. This study was undertaken to evaluate whether the extra domain-B of fibronectin (EDB-FN) could be used as a new biomarker for BTICs and whether EDB-FN targeting superparamagnetic iron oxide nanoparticles (SPIONs) could be used as a magnetic resonance imaging (MRI) contrast agent for BTIC imaging in vitro and in vivo. BTICs (NDY-1) exhibited high EDB-FN expression, whereas non-BTICs (MCF-7, BT-474, SUM-225, MDA-MB-231) did not exhibit EDB-FN expression. Furthermore, Cy3.3-labeled EDB-FN specific peptides (APTEDB) showed preferential binding to the targeted NDY-1 cells. To construct an EDB-FN targeted imaging probe, APTEDB was covalently attached to a thermally cross-linked SPION (TCL-SPION) to yield APTEDB-TCL-SPION. In the in vitro MRI of cell phantoms, selective binding of APTEDB-TCL-SPION to NDY-1 cells was evident, but little binding was observed in MCF-7 cells. After the intravenous injection of APTEDB-TCL-SPION into the NDY-1 mouse tumor xenograft model, a significant decrease in the signal within the tumor was observed in the T2*-weighted images; however, there was only a marginal change in the signal of non-targeting SPIONs such as APTscramble-TCL-SPION or TCL-SPION. Taken together, we report for the first time that EDB-FN was abundantly expressed in BTICs and may therefore be useful as a new biomarker for identifying BTICs. Our study also suggests that APTEDB-TCL-SPION could be used as an MRI contrast agent for BTIC imaging.

Effect of sulfated polysaccharides from Laminaria japonica on vascular endothelial cells in psychological stress rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Laminaria japonica is a popular seafood and medicinal plant in China. Laminaria japonica is used in traditional Chinese medicine to treat and prevent hypertension and edema. MATERIALS AND METHODS: The vascular protective activity and mechanism of sulfated polysaccharides were studied in adrenalin-induced vascular endothelial damage in rats after psychological stress (PS). Vehicle (sham and PS groups), sulfated polysaccharide from Laminaria japonica (LP; 1mg/kg and 5mg/kg) and enoxaparin sodium (1IU/kg, reference drug) were all administered for 10 days. Behavioral changes were recorded. Plasma levels of adrenalin, cortisol, monoamine oxidase (MAO), semicarbazide-sensitive amine oxidase (SSAO), formaldehyde, H2O2, nitric oxide (NO), endothelin-1 (ET-1), 6-keto-prostaglandin F1a (6-keto-PGF1a), and thromboxane B2 (TXB2) were measured. Endothelium-dependent relaxation of the thoracic aorta was measured and transmission electron microscopy of aortic vessels was performed. RESULTS: Adrenalin metabolites in plasma were significantly lower (P<0.01) in rats after LP administration compared with those in the PS groups. The normalized ratios of plasma NO/ET-1 and 6-keto-PGF1a/TXB2 were maintained and endothelium-dependent relaxation of the aorta was greatly enhanced after LP treatment (P<0.05). Morphological alterations were observed in vascular endothelial cells (VECs) in PS rats, with a higher number of lysosomes and vague mitochondrial cristae compared with those in the sham group. However, these histopathological changes were markedly alleviated after LP treatment. CONCLUSIONS: This study shows a protective effect of LP on VECs in PS rats. LP can regulate plasma levels of NO, ET-1, and 6-keto-PGF1a, enhance endothelium-dependent relaxation, and alleviate histopathological changes of lysosomes and mitochondria in VECs. The potential mechanism of LP on VECs in PS rats is related to its function of reducing metabolites of adrenalin.

Comparison of Two Ultrasmall Superparamagnetic Iron Oxides on Cytotoxicity and MR Imaging of Tumors.

PURPOSE: This study was performed to compare the cytotoxicity and magnetic resonance (MR) contrast in diverse cultured cells and xenograft tumors models of two ultra-small superparamagnetic iron oxides (USPIOs), thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPION) and monocrystalline iron oxide nanoparticles (MION-47). MATERIALS AND METHODS: Transmission electron microscopy (TEM) images and R(2) relaxivity values of the TCL-SPION and MION-47 were obtained and the cell viability and cell growth velocity of treated and untreated human fibroblasts and human umbilical vein endothelial cells (HUVEC) were evaluated. The effect of TCL-SPION and MION-47 on the secretion of interlukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), the production of nitric oxides and the mitochondrial membrane potentials in murine macrophage cells (RAW264.7) was compared. Human hepatocellular carcinoma cells (HepG2, 5x10(5)) were subcutaneously injected into nude mice (BALB/c) and in vivo MR imaging of tumors before and after injection with TCL-SPION or MION-47 (12.5 mg Fe/kg) was performed on a 1.5 Tesla MRI scanner. RESULTS: On TEM images, the average core diameter of TCL-SPION was 9 nm whereas that of MION-47 was 5 nm. TCL- SPION (345.0 ± 6.2 mM(-1)sec(-1)) had higher relaxivity (R(2)) than MION-47 (130.7 ± 1.1 mM(-1)sec(-1)). Significant changes in cell viability and growth were not found in human fibroblasts and HUVEC exposed to TCL-SPION and MION-47. However, IL-6 and TNF-α secretions increased dose-dependently and significantly in the macrophages treated with MION-47 or TCL-SPION. TCL-SPION had a lower stimulatory effect on IL-6 secretions than did MION-47 (P <0.05) and nitric oxides were produced in the macrophages by MION-47 but not TCL-SPION. A change in the mitochondrial membrane potential of the macrophages was observed 24 hours after the exposure, and MION-47 induced more collapses of the mitochondrial membrane potential than did TCL-SPION. In the in vivo MR imaging, 33.0 ± 1.3% and 7.5 ± 0.4% signal intensity decrease on T(2)*-weighted images was observed in the tumors injected with TCL-SPION and MION-47, respectively. CONCLUSION: Due to the modified surface properties and larger core size of its iron oxide nanoparticles, TCL-SPION achieves lower cytotoxicity and better tumor MR contrast than MION-47. Our study suggests that TCL-SPION may be used as a new platform for tumor imaging and therapy monitoring.

An HR-MAS MR metabolomics study on breast tissues obtained with core needle biopsy.

BACKGROUND: Much research has been devoted to the development of new breast cancer diagnostic measures, including those involving high-resolution magic angle spinning (HR-MAS) magnetic resonance (MR) spectroscopic techniques. Previous HR-MAS MR results have been obtained from post-surgery samples, which limits their direct clinical applicability. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we performed HR-MAS MR spectroscopic studies on 31 breast tissue samples (13 cancer and 18 non-cancer) obtained by percutaneous core needle biopsy. We showed that cancer and non-cancer samples can be discriminated very well with Orthogonal Projections to Latent Structure-Discriminant Analysis (OPLS-DA) multivariate model on the MR spectra. A subsequent blind test showed 69% sensitivity and 94% specificity in the prediction of the cancer status. A spectral analysis showed that in cancer cells, taurine- and choline-containing compounds are elevated. Our approach, additionally, could predict the progesterone receptor statuses of the cancer patients. CONCLUSIONS/SIGNIFICANCE: HR-MAS MR metabolomics on intact breast tissues obtained by core needle biopsy may have a potential to be used as a complement to the current diagnostic and prognostic measures for breast cancers.