Smart Biomimetic Nanozymes for Precise Molecular Imaging: Application and Challenges.

New nanotechnologies for imaging molecules are widely being applied to visualize the expression of specific molecules (e.g., ions, biomarkers) for disease diagnosis. Among various nanoplatforms, nanozymes, which exhibit enzyme-like catalytic activities in vivo, have gained tremendously increasing attention in molecular imaging due to their unique properties such as diverse enzyme-mimicking activities, excellent biocompatibility, ease of surface tenability, and low cost. In addition, by integrating different nanoparticles with superparamagnetic, photoacoustic, fluorescence, and photothermal properties, the nanoenzymes are able to increase the imaging sensitivity and accuracy for better understanding the complexity and the biological process of disease. Moreover, these functions encourage the utilization of nanozymes as therapeutic agents to assist in treatment. In this review, we focus on the applications of nanozymes in molecular imaging and discuss the use of peroxidase (POD), oxidase (OXD), catalase (CAT), and superoxide dismutase (SOD) with different imaging modalities. Further, the applications of nanozymes for cancer treatment, bacterial infection, and inflammation image-guided therapy are discussed. Overall, this review aims to provide a complete reference for research in the interdisciplinary fields of nanotechnology and molecular imaging to promote the advancement and clinical translation of novel biomimetic nanozymes.

Burden of typical diseases attributed to the sources of PM2.5-bound toxic metals in Beijing: An integrated approach to source apportionment and QALYs.

PM2.5-bound toxic metals (TMs) are derived from various sources, and they can cause many adverse health effects on the human body. To effectively reduce the disease burden of TMs by controlling the relative sources, an integrated approach of quality-adjusted life years (QALYs) and source-apportionment (positive matrix factorization, PMF) was proposed and applied to some typical diseases induced by TMs in 2017 in Beijing. The estimation included two parts; first, the number of potentially affected people was calculated based on the source mass contribution from PMF and the inhalation unit risk of TMs; second, the QALYs lost per affected person was calculated based on the disease duration, expected years of life lost (EYLL) and quality of life (QoL) for both affected people and the general population. The results showed that QALYs lost per person for renal cancer (17.3 QALYs), pneumonia (14.4 QALYs), lung cancer (14.2 QALYs), skin cancer (12.7 QALYs) and diabetes mellitus (12.6 QALYs) were higher than those for other diseases. Combined with PMF, the source contributions to the overall burden of typical diseases from the TMs followed the order of coal combustion (50.2%) > vehicle emissions (24.4%) > fuel oil combustion (11.4%) > Cr-related industry (10.9%) > resuspended dust (3.0%). The rank was further compared with that assessed for noncancer and cancer risks, and we verified the reasonability of the QALYs method. For seasonal contributions to coal combustion, winter and spring had the highest contributions, which coincided with the fact that coal was the main fuel for heating in Beijing. The QALYs lost attributed to TMs for coal combustion decreased by 49.1% from 2016 to 2017, which may indicate an effective policy associated with coal control. Overall, the integrated approach was successfully employed for estimating the disease burden induced by TMs from each source and was an effective solution to identify the control rank of sources for TM reduction.

Implications of seasonal control of PM2.5-bound PAHs: An integrated approach for source apportionment, source region identification and health risk assessment.

PM2.5-bound PAHs are ubiquitous in urban atmospheres and are characterized as carcinogenic, teratogenic and mutagenic upon inhalation. A total of 218 daily PM2.5 samples were collected during one year in the urban district of Beijing, China. Analysis showed that the annual mean concentration of total PAHs (TPAHs) was 66.2 ng/m3, with benzo(a)pyrene (BaP) accounting for 12.4%. High-molecular-weight (HMW, 4-6 rings) PAHs were the dominant components. Seasonal TPAH concentrations decreased in the order of heating season (156 ng/m3) > autumn (20.4 ng/m3) > spring (16.0 ng/m3) > summer (12.5 ng/m3) and were related to meteorological conditions and source emission intensity. The source-attributed mass contribution and source regions of three sources (i.e., (1) vehicle emissions; (2) coal combustion; and (3) petroleum volatilization, natural gas and biomass combustion) were identified by integrating the positive matrix factorization (PMF), potential source contribution function (PSCF) and conditional probability function (CPF). Vehicle emissions contributed the most mass (54.6%), followed by coal combustion (29.8%), on an annual basis. Combined with actual regional emissions, vehicle emissions were mainly derived from local sources, while coal combustion mainly came from regional transport from surrounding areas. Vehicle emissions and coal combustion have much higher mass contributions in the heating season. The source-attributed cancer risk was further evaluated based on source mass contribution and inhalation unit risk. Vehicle emissions contributed the largest risk (2.8 × 10-6, accounting for 71%) as a result of 30 years of exposure for local residents, exceeding the acceptable level (10-6). The heating season showed the most risk, especially in response to vehicle emissions and coal combustion. Overall, the source-attributed cancer risk was regarded as the better index for the development of a control strategy of PM2.5-bound PAHs for protecting residents. Based on this index, priority control sources in each season were identified to supply a more effective management solution.

Levels and health risks of PM2.5-bound toxic metals from firework/firecracker burning during festival periods in response to management strategies.

Daily PM2.5 was collected in the periods before, during and after the Chinese Spring Festival (CSF) in both 2016 and 2018 to clarify the annual variation in the concentrations and health risks of toxic metals under different firework/firecracker (FF) management strategies. PM2.5 and bound metals all decreased during the CSF from 2016 to 2018. According to relative abundance analysis, toxic metals, i.e., Ba, Pb, Cu and Cr, showed obvious peak concentrations and abundance levels on intensive FF burning days, i.e., New Year's Eve, Chinese New Year and the Lunar Festival. In both CSF periods, three sources of toxic metals, namely, FF burning, coal combustion, and resuspended dust and vehicle emissions, were identified by positive matrix factorization (PMF). Among them, the mass contribution of FF decreased from 0.83 µg m-3 (11%) in the 2016 CSF to 0.23 µg m-3 (9.0%) in the 2018 CSF. The FF-attributed noncancer and cancer risks due to metals for residents under long-term exposure were 0.02 (19.9%) and 1.76 × 10-7 (17.9%) in the 2016 CSF and 0.01 (20.2%) and 8.59 × 10-8 (14.7%) in the 2018 CSF. Although a policy shift from "restriction" to "prohibition" regarding FF has indeed decreased toxic metal concentrations and health risk, Cr(VI) and Ba should be examined more closely in the future because they have become dominant contributors to cancer risk and noncancer risk, respectively.

Emission control priority of PM2.5-bound heavy metals in different seasons: A comprehensive analysis from health risk perspective.

Source-specific health risks of PM2.5-bound metals were analyzed for emission control by integrating source apportionment with health risk assessments of residents affected via inhalation pathways. A total of 218 daily PM2.5 samples were collected in 2016 in the central urban district of Beijing, China. Analyses showed that the mean annual concentrations of total heavy metals (THMs) and PM2.5 were 0.39 and 104.37 µg m-3, respectively. The heating season had significantly higher concentrations of THMs and PM2.5 (0.61, 134 µg m-3) than the non-heating season (0.27, 88.1 µg m-3) (p < 0.05). Among all metals, arsenic had the largest incremental cancer risk of 7.04 × 10-6. Six sources were identified by positive matrix factorization combined with conditional probability function and potential source contribution function analyses. The order of contribution to PM2.5-bound metal concentrations was resuspended dust (61.0%), traffic emission (16.3%), Cu-related industry (14.1%), coal combustion (3.7%), Cr-related industry (3.4%), and fuel oil combustion (1.6%). During the heating season, the contribution of coal combustion decreased slightly, which may have been due to the countermeasure of substituting coal for gas or electric heat in 2016. However, in terms of cancer risk contribution, coal combustion was the top contributor in both heating (3.5 × 10-6, 51.6%) and non-heating (2.7 × 10-6, 59.6%) seasons due to high attributable contents of the toxic metals, As, Cd and Pb. The Cr-related and Cu-related industries were the next controlled sources in the heating and non-heating seasons, respectively. Thus, these sources should receive priority in the development of control measures.

Impacts of silicon addition on arsenic fractionation in soils and arsenic speciation in Panax notoginseng planted in soils contaminated with high levels of arsenic.

Arsenic (As) is a well-known carcinogenic substance whose biological toxicity in soils and plants depends on its concentration and chemical forms. Silicon (Si) generally can alleviate biotic and abiotic stresses, including As stress. However, its effects vary depending on As chemical form, plant species and other factors. A pot experiment was performed to investigate the effects of Si addition on the content and forms of As in red soil and its uptake, transport and speciation in Panax notoginseng. The results showed that additions of 25 and 75 mg kg-1 of Si both significantly decreased the concentrations of water-soluble As and exchangeable As in soil and therefore decreased the bioavailability of soil As. However, the As uptake by Panax notoginseng (PN) was increased, which resulted in increases in As concentration by 18.5% and 2.3% in roots and by 56.7% and 58.3% in shoots, respectively, when compared with the control. Arsenate (As(V)) was the dominant As species in all the treatment soils (99.8-100%), whereas arsenite (As(III)) was prevalent in plant roots (75.2-92.4%), shoots (74.1-87.9%) and leaves (73.9-84.3%). Si addition (25 and 75 mg kg-1) significantly increased As(III) concentration in roots by 167.5% and 83.3%, respectively. Monomethylarsonic acid (MMA) was the only detected methylated As but at low concentrations (0.01-0.29 mg kg-1) and only in PN leaves. Si addition (25 and 75 mg kg-1) significantly increased the copy number of the arsenite methyltransferase (arsM) gene by 31.0% and 47.2% but did not increase the methylated As species content in PN leaves. The detected copy number of the arsM gene did not represent the capacity of soil to methylate As, and the sources of MMA in leaves need to be explored in further research.

Upregulation of microRNA-3129 suppresses epithelial ovarian cancer through CD44.

The purpose of this work is to evaluate whether human microRNA-3129 (hsa-miR-3129) may functionally regulate cancer development, possibly through downstream target CD44 in human epithelial ovarian cancer (EOC). Direct targeting of hsa-miR-3129 on human CD44 transcript was evaluated using a dual-luciferase reporter assay. Gene expression of hsa-miR-3129 in immortal EOC cell lines was evaluated by qRT-PCR. Lentivirus-mediated hsa-miR-3129 upregulation or downregulation was conducted in SK-OV-3 and CAOV-3 cells, in which endogenous hsa-miR-3129 and CD44 expressions were then measured. In hsa-miR-3129 upregulated or downregulated EOC cells, functional assays were applied to evaluate EOC proliferation, bufalin chemoresistance in vitro, or xenotransplantation in vivo. Moreover, CD44 was ectopically overexposed in hsa-miR-3129 upregulated EOC cells to functionally evaluate the correlation between hsa-miR-3129 and CD44 in EOC. Dual-luciferase reporter assay confirmed hsa-miR-3129 directly binds CD44. QRT-PCR revealed that hsa-miR-3129 was substantially downregulated in EOC cell lines. In SK-OV-3 and CAOV-3 cells, lentivirus-induced hsa-miR-3129 upregulation downregulated CD44 whereas hsa-miR-3129 downregulation did not affect CD44 expression. Hsa-miR-3129 upregulation had significant anti-cancer effects by inhibiting EOC proliferation, increasing bufalin chemoresistance, and suppressing xenotransplantation. On the other hand, overexpressing CD44 reversed the anti-cancer functions by hsa-miR-3129 upregulation in EOC cells. In conclusion, Has-miR-3129 is a functional regulator, possibly through reverse targeting on CD44, in EOC.

Source apportionment and health risk assessment of heavy metals in soil for a township in Jiangsu Province, China.

Human activities contribute greatly to heavy metal pollution in soils. Concentrations of 15 metal elements were detected in 105 soil samples collected from a typical rural-industrial town in southern Jiangsu, China. Among them, 7 heavy metals-lead, copper, zinc, arsenic, chromium, cadmium, and nickel-were considered in the health risk assessment for residents via soil inhalation, dermal contact, and/or direct/indirect ingestion. Their potential sources were quantitatively apportioned by positive matrix factorization using the data set of all metal elements, in combination with geostatistical analysis, land use investigation, and industrial composition analysis. Furthermore, the health risks imposed by sources of heavy metal in soil were estimated for the first time. The results indicated that Cr, Cu, Cd, Pb, Ni, and Co accumulated in the soil, attaining a mild pollution level. The total hazard index values were 3.62 and 6.11, and the total cancer risks were 9.78 × 10-4 and 4.03 × 10-4 for adults and children, respectively. That is, both non-carcinogenic and carcinogenic risks posed by soil metals were above acceptable levels. Cr and As require special attention because the health risks of Cr and As individually exceeded the acceptable levels. The ingestion of homegrown produce was predominantly responsible for the high risks. The potential sources were apportioned as: a) waste incineration and textile/dyeing industries (28.3%), b) natural sources (45.4%), c) traffic emissions (5.3%), and d) electroplating industries and livestock/poultry breeding (21.0%). Health risks of four sources accounted for 23.5%, 32.7%, 7.4%, and 36.4% of the total risk, respectively.

MiR-548c impairs migration and invasion of endometrial and ovarian cancer cells via downregulation of Twist.

BACKGROUND: MicroRNAs (miRNAs) are a class of small non-coding RNAs, which post-transcriptionally repress the expression of genes involved in cancer initiation and progression. Although some miRNAs that target many signaling pathways (also called universe miRNAs) are supposed to play a global role in diverse human tumors, their regulatory functions in gynecological cancers remain largely unknown. We investigated the biological role and underlying mechanism of miR-548c (one universe miRNA) in endometrial and ovarian cancer. METHODS: The effects of miR-548c overexpression on cell proliferation, migration and invasion were studied in endometrial and ovarian cancer cells. TWIST1 (Twist) was identified as a direct miR-548c target by western blot analysis and luciferase activity assay. The expression of miR-548c and Twist were examined by qRT-PCR in endometrial and ovarian cancer tissues. RESULTS: Here, we report that miR-548c is down-regulated in endometrial and ovarian cancer tissues when compared to normal tissues, and our meta-analysis reveal that decreased miR-548c expression correlates with poor prognosis in endometrial cancer patients. We show that in endometrial and ovarian cancer cells, ectopic expression of miR-548c significantly inhibits whereas knockdown of miR-548c dramatically induces cancer cell proliferation, migration and invasion. By using luciferase reporter assay, we demonstrate that Twist, a known oncogene in endometrial and ovarian cancers, is a direct target of miR-548c. Furthermore, the expression of Twist partially abrogates the tumor suppressive effects of miR-548c on cell migration and invasion. CONCLUSION: These findings suggest that miR-548c directly downregulates Twist, and provide a novel mechanism for Twist upregulation in both endometrial and ovarian cancers. The use of miR-548c may hold therapeutic potential for the treatment of Twist-overexpressing tumors.

The effect of LfcinB9 on human ovarian cancer cell SK-OV-3 is mediated by inducing apoptosis.

LfcinB9 is a peptide derived from lactoferricin B. In the present study, the effect and relative mechanism of LfcinB9 on human ovarian cancer cell line (SK-OV-3) in vitro and in vivo was investigated. The data obtained indicated that LfcinB9 exhibited low hemolysis activity and significantly inhibited the proliferation of SK-OV-3 cells in vitro. In addition, the apoptosis of SK-OV-3 cells was induced through up-regulating the production of reactive oxygen species and activating caspase-3, caspase-9 on both transcription and translation level. Finally, LfcinB9 significantly prevented the tumor growth in the SK-OV-3-bearing mice model. These results indicated that LfcinB9 could be a potential agent for the treatment of ovarian cancer.

The mismatch repair gene hPMS1 (human postmeiotic segregation1) is down regulated in oral squamous cell carcinoma.

Genomic instability or microsatellite instability (MSI) was initially recognized in colonic carcinoma and subsequently in other tumors. MSI has been associated with mutations in genes that play a role in DNA replication and repair. In a previous study we detected MSI in 85% of young patients with OSCC and excluded the involvement of MMR genes hMLH1 and hMSH2. In the present study, we screened the mutation and expression status of the MMR genes hMSH3, hMSH6, hPMS1 and hPMS2 in OSCC and found expression of the hPMS1 protein to be down regulated. Genomic analysis of hPMS1 did not show any mutational changes in exonic or promoter regions. Expression of hPMS1 mRNA was not deregulated in either MSI positive or MSI negative tumor cell lines by Northern blot analysis. In contrast, analysis by Western blot showed that 100% of MSI positive tumor cell lines had decreased or no expression of hPMS1 while MSI negative cell lines had normal protein expression. Our data indicate that hPMS1 is most likely deregulated by post-transcriptional modification in OSCC while hMLH1 and hPMS2 has no detectable changes. Furthermore, our results are consistent with the hypothesis that hPMS1 is associated with MSI in OSCC.

[Expression and clinical significance of platelet-derived growth factor A in placenta of pre-eclampsia.].

OBJECTIVE: To investigate the expression and clinical significance of platelet-derived growth factor A (PDGF-A) on placenta tissue from pre-eclampsia. METHODS: The expression of PDGF-A in the placenta of 38 pre-eclampsia patients and 22 normal pregnant women at third trimester was detected by immunohistochemistry method. RESULTS: (1) PDGF-A was mainly expressed in the cytomembrane and cytoplasm of cytotrophoblasts and the endothelial cell of capillary in placenta. (2) The rates of PDGF-A expression of cytotrophoblasts were 63% (24/38) in pre-eclampsia group and 32% (7/22) in normal pregnancy group, which exhibited significant difference (P < 0.05). (3) The rates of PDGF-A expression of endothelial cell were 68% (26/38) in pre-eclampsia group and 27% (6/22) in normal pregnancy group, which also showed significant difference (P < 0.01). (4) The rates of PDGF-A expression of cytotrophoblasts were 39% (7/18) in mild pre-eclampsia patients and 85% (17/20) in severe pre-eclampsia, which reached statistical difference (P < 0.01). CONCLUSION: The increasing expression of PDGF-A in cytotrophoblast and endothelial cell in placenta might confer the occurrence and progression of pre-eclampsia.