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A metal–organic framework-based nanotheranostic system was fabricated to achieve a macrophage-targeting ability and combined photodynamic and immunotherapy for Mtb.

Black carbon (BC) correlates with the occurrence and progression of atherosclerosis and other cardiovascular diseases. Increasing evidence has demonstrated that BC could impair vascular endothelial cells, but the underlying mechanisms remain obscure. It is known that IL-33 exerts a significant biological role in cardiovascular disease, but little is known about the molecular regulation of IL-33 expression at present. We first found that BC significantly increased IL-33 mRNA in EA.hy926 cells in a concentration and time-dependent manner, and we conducted this study to explore its underlying mechanism. We identified that BC induced mitochondrial damage and suppressed autophagy function in EA.hy926 cells, as evidenced by elevation of the aspartate aminotransferase (GOT2), reactive oxygen species (ROS) and p62, and the reduction of mitochondrial membrane potential (ΔΨm). However, ROS cannot induce IL-33 mRNA-production in BC-exposed EA.hy926 cells. Further, experiments revealed that BC could promote IL-33 mRNA production through the PI3K/Akt/AP-1 and p38/AP-1 signaling pathways. It is concluded that BC could induce oxidative stress and suppress autophagy function in endothelial cells. This study also provided evidence that the pro-cardiovascular-diseases properties of BC may be due to its ability to stimulate the PI3K/AKT/AP-1 and p38/AP-1 pathway, further activate IL-33 and ultimately result in a local vascular inflammation.

Programmable cancer therapies may perfectly prevent mutual drug restrictions, however, developing an efficient codelivery system with such an ability remains challenging. We herein first demonstrate the use of supramolecular-mediated dual-functional DNA nanocomposites for programmable chemodynamic therapy (CDT) and chemotherapy (CT), in which a water-soluble cyclodextrin-resveratrol (CD-Res) complex can be facilely encapsulated during the coassembly of Fe

As air pollution has been paid more attention to by public in recent years, effects and mechanism in particulate matter-triggered health problems become a focus of research. Lysosomes and mitochondria play an important role in regulation of inflammation. Interleukin-33 (IL-33) has been proved to promote inflammation in our previous studies. In this research, macrophage cell line RAW264.7 was used to explore the potential mechanism of upregulation of IL-33 induced by 1,4-naphthoquinone black carbon (1,4-NQ-BC), and to explore changes of lysosomes and mitochondria during the process.50 μg/mL 1,4-NQ-BC exposure for 24 h dramatically increased expression of IL-33 in RAW264.7 cells. Lysosomal membrane permeability was damaged by 1,4-NQ-BC treatment, and higher mitochondrial membrane potential and ROS level were induced by 1,4-NQ-BC. The results of proteomics suggested that expression of ferritin light chain was increased after cells were challenged with 1,4-NQ-BC, and it was verified by Western blot. Meanwhile, expressions of p62 and LC3B-II were increased by 50 μg/mL 1,4-NQ-BC in RAW264.7 cells. Ultimately, expression of IL-33 could return to same level as control in cells treated with 50 μg/mL 1,4-NQ-BC and 50 μM deferoxamine combined.1,4-NQ-BC induces IL-33 upregulation in RAW264.7 cells, and it is responsible for higher lysosomal membrane permeability and ROS level, lower mitochondrial membrane potential, and inhibition of autophagy. Ferritin light chain possibly plays an important role in the upregulation of IL-33 evoked by 1,4-NQ-BC.

Real-time monitoring of drug release behaviors over extended periods of time is critical in understanding the dynamics of drug progression for personalized chemotherapeutic treatment. In this work, we report a metal-organic framework (MOF)-based nanotheranostic system encapsulated with photothermal agents (CuS) and therapeutic drug (DOX) to achieve the capabilities of real-time drug release monitoring and combined chemo-photothermal therapy. Meanwhile, folic acid-conjugated polyethylene glycol (FA-PEG) antennas were connected to the MOF through coordination interactions, endowing the MOF with an enhanced active targeting effect toward cancer cells. It is anticipated that such a theranostic agent, simultaneously possessing tumor-targeting, real-time drug monitoring and effective treatment, will potentially enhance the performance in cancer therapy.

The possible role of efflux pump as a survival mechanism in Mycobacterium tuberculosis (M. tb) is gaining an increasing attention. Previously, Rv1258c (Tap) and its certain mutations confer the clinically relevant drug resistance. In this study, we found new mutations of Rv1258c in G195C, T297P and I328T. Effect of modulating T297P and I328T on the drug resistance by knockout and complement in M. tb H37Rv showed that M. tb ΔRv1258c showed a slightly lower MIC for rifampin, ethambutol, ofloxacin, amikacin, capreomycin and streptomycin than M. tb H37Rv WT and the complement. Rv1258c T297P and Rv1258c I328T showed an increased drug resistance to ethambutol and capreomycin than the complement of Rv1258c WT. Most importantly, M. tb ΔRv1258c exhibited a slow growth in the normal culture medium. TMT-based quantitative proteomics analysis of M. tb ΔRv1258c and WT showed that the knockout of Rv1258c greatly down-regulated the expression of the ribosome system and one of the special five type VII secretion systems, ESX-3, which impaired the bacterial growth. These results indicate that the newly found T297P and I328T mutations of Rv1258c contributed to an increased resistance to ethambutol and capreomycin, and Rv1258c as growth controlling factor influencing the growth of M. tb.

Precise control over signal amplification provides unparalleled opportunities for diverse applications. However, spatiotemporally controlled amplification has not been realized because of the lack of a design methodology. The aim of this study was thus to develop a conceptual approach for remote control over signal amplification at a chosen time and site in living cells. This system was constructed by re-engineering the functional units of the hybridization chain reaction (HCR) and combination with upconversion photochemistry, thus resulting in an activatable HCR with the high spatial and temporal precision of near-infrared (NIR) light. As a proof of concept, we demonstrate the spatially and temporally resolved amplified imaging of messenger RNA (mRNA) with ultrahigh sensitivity in vitro and in vivo. Furthermore, by using a system targeting subcellular sites we have developed a new technique for NIR-initiated amplified imaging of mRNA exclusively within a specific organelle.

Nanodevices have potential as intelligent sensing systems for detection of microRNAs (miRNAs) in living cells. However, the resolution offered by "always active" nanodevices is often insufficient to manipulate miRNA sensing with high spatiotemporal control. In this work, using DNA nanotechnology we constructed an activatable DNA nanodevice programmed to detect miRNAs in vitro and in vivo with the high spatial and temporal precision of NIR light. Our nanodevice is functionalized on the surface of upconversion nanoparticles (UCNPs) with a rationally designed DNA beacon that displays UV light-activatable miRNA sensing activity. The UCNPs absorb deep-tissue-penetrable NIR light and emit high-energy UV light locally, which serve as transducers to operate the nanodevice in the NIR window. The nanodevice can naturally enter cells and enable remote regulation of its fluorescent imaging activity for miRNAs in living cells by NIR light illumination in a chosen place and time. Furthermore, we demonstrate that the nanodevice can be expanded to activatable imaging of intratumoral miRNAs in living mice. This work illustrates the potential of DNA nanodevices for miRNA detection with high spatiotemporal resolution, which could expand the toolbox of technologies for precise biological and medical analysis.

Smart drug delivery nanosystems with integrated real-time monitoring capability have attracted great attention in recent years; however, they are still in a nascent stage due to a lack of proper imaging modalities. Herein, we present a novel pH-responsive drug delivery nanosystem in which a coordination complex of tannic acid and Cu2+ ions was successfully functionalized onto the surface of mesoporous silica-coated upconversion nanoparticles (UCNPs) to block premature release of the anti-cancer drug doxorubicin (DOX) from the mesopores of the particles. In addition, loading of the drug enables luminescence resonance energy transfer (LRET) from the UCNPs to DOX, which results in quenching of the emission of the UCNPs. The metal-phenolic networks are degraded in the acidic environment in living cells, leading to DOX release from the mesopores and thus to elimination of LRET. Therefore, the changes in upconversion luminescence enable monitoring of the pH-triggered drug release in real-time. This strategy will facilitate the design of smart drug delivery systems and theranostics.

DNA-based molecular circuits able to perform complex information processing in biological systems are highly desirable. However, conventional DNA circuits are constitutively always in an ON state and immediately operate when they meet the biomolecular inputs, precluding precise molecular computation at a desired time and in a desired site. In this work, we report a conceptual methodology for the construction of photonic nanocircuits that enable DNA molecular computation in vitro and in vivo with high spatial precision. Upon remote activation by spatially restricted NIR-light input, two types of cancer biomarker inputs can sequentially trigger conformational changes of the DNA circuit through a structure-switching aptamer and toehold-mediated strand exchange, leading to release of a signaling output. Of note, the NIR-light-gated nanocircuit allows for intended control over the specific timing and location of DNA computation, providing spatial and temporal capabilities for multiplexed imaging. Furthermore, an OR-AND-gated nanocircuit of higher complexity was designed to illustrate the versatility of our approach. The present work illustrates the potential of the use of upconversion nanotechnology as a regulatory tool for spatial and temporal control of DNA computation in cells and animals.

Background Air pollution increases the morbidity and mortality of cardiovascular disease (CVD). Atherosclerosis (AS) is the pathological basis of most CVD, and the progression of atherosclerosis and the increase of fragile plaque rupture are the mechanism basis of the relationship between atmospheric particulate pollution and CVD. The aim of the present study was to investigate the effects of coal-fired fine particulate matter (PM2.5) on the expression levels of atherosclerosis-related proteins (von Willebrand factor (vWF), Endothelin-1 (ET-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin, and to explore the role and mechanism of the progression of atherosclerosis induced by coal-fired PM2.5 via the mitogen-activated protein kinase (MAPK) signaling pathways. Methods Different concentrations of PM2.5 were given to apolipoprotein-E knockout (ApoE−/−) mice via intratracheal instillation for 8 weeks. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of vWF, ET-1 in serum of mice. Immunohistochemistry was used to observe the expression and distribution of ICAM-1 and E-selectin in the aorta of mice. Western blot was used to investigate the phosphoylation of proteins relevant to MAPK signaling pathways. Results Coal-fired PM2.5 exacerbated atherosclerosis induced by a high-fat diet. Fibrous cap formation, foam cells accumulation, and atherosclerotic lesions were observed in the aortas of PM2.5-treated mice. Coal-fired PM2.5 increased the protein levels of ET-1, ICAM-1, and E-selectin, but there was no significant difference in the vWF levels between the PM2.5-treatment mice and the HFD control mice. Coal-fired PM2.5 promoted the phosphorylation of p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) in aortic tissues of mice. Conclusion Coal-derived PM2.5 exacerbated the formation of atherosclerosis in mice, increased the expression levels of atherosclerosis-related proteins in mice serum, and promoted the phosphorylation of proteins relevant to MAPK signaling pathway. Thus, MAPK signaling pathway may play a role in the atherosclerosis pathogenesis induced by Coal-derived PM2.5.

Background Black carbon (BC) is a product of incomplete combustion of fossil fuels and vegetation. The compelling evidence has demonstrated that it has a close relationship with several respiratory and cardiovascular diseases. BC provides the reactive sites and surfaces to absorb various chemicals, such as polycyclic aromatic hydrocarbons (PAH). Naphthoquinone is a typical PAHs which was found in particulate matter (PM) and 1,4NQ-BC owned high oxidative potential and cytotoxicity. IL-33 is an alarmin which increases innate immunity through Th2 responses. It was reported that IL-33 was a potent inducer of pro-inflammatory cytokines, like IL-6. In our previous study, it was revealed that 1,4NQ-BC instilled intratracheally to mice could trigger zthe lung inflammation and stimulate the secretion of IL-33 in lung tissue.Results We found that IL-33 could induce inflammation in lung itself. When the macrophages were eliminated, the secretion of IL-33 was reduced and the pathological damage in the lung was relieved after exposure to 1,4NQ-BC. Both MAPK and PI3k/Akt signal pathways were involved in the process of IL-33 secretion and the lung inflammation induced by 1,4NQ-BC.Conclusions The findings herein support the notion that after exposure to 1,4NQ-BC, the increased secretion of IL-33 was mainly derived from macrophage through both MAPK and PI3k/Akt signal pathways.

Additional file 1. Highlights

Chlormequat Chloride (CCC) is a plant growth regulator that is widely applied in agriculture. Previous studies have shown that long-term exposure of CCC could decrease body weight in animals. However, the underlying mechanisms have not been studied. In this study, CCC was administered to rats daily by gavage on postnatal days 23-60 at doses of 0, 75, 150 and 300mg/kg bw/d. The results showed that body weight and the length of the right femur were significantly decreased in the 300mg/kg bw/d group. Histological analysis of proximal growth plates of the right femurs showed narrowed proliferative zones and hypertrophic zones in CCC-treated groups. The mRNA expression of growth hormone, growth hormone receptor and insulin like growth factor 1 were decreased in the CCC-treated group. The results indicated that CCC may affect the expression of growth hormone and insulin-like growth factor 1 and subsequently cause a decrease in body weight and bone length.

A novel upconversion nanoarchitecture is designed, whose 980 nm light photosensitized activity could be activated by 808 nm light., The precise control of singlet oxygen (1O2) generation is in great demand for biological studies and precision medicine. Here, a nanoarchitecture is designed and synthesized for generating 1O2 in a dual NIR light-programmable manner, while shifting to the therapeutic window. The nanoarchitecture is constructed by controlled synthesis of mesoporous silica-coated upconversion nanoparticles (UCNPs), wherein the porphyrin photosensitizers (PSs) are covalently embedded inside the silica walls while NIR (808 nm)-responsive diarylethene (DAE) photochromic switches are loaded in the nanopores. Upon irradiation with 980 nm NIR light, the UCNP core absorbs low energy photons and transfers energy to the PSs in the silica wall, leading to efficient 1O2 generation. Furthermore, this 980 nm NIR light photosensitized activity can be remotely controlled by irradiation with a distinct NIR wavelength (808 nm). The 1O2 generation is inhibited when the DAE installed in the nanopores is in the closed form, whereas irradiation of the nanoconstruct with 808 NIR light leads to the transformation of DAE to the open form, and thus enabling full recovery of the 980 nm NIR light excited 1O2 generation capability. The NIR light-mediated on-demand “activation” of the nanoarchitecture for bioimaging and controllable photodynamic therapy is further demonstrated in vitro and in vivo.

Black carbon (BC) reacts with different substances to form secondary pollutants called aged black carbon, which causes inflammation and lung damage. BC and aged BC may enhance IL-33 in vivo, which may be derived from macrophages. The pro-inflammatory effect of IL-33 makes it essential to determine the source of IL-33, so it guides us to explore how to alleviate lung injury. In this study, a human bronchial epithelial cell line of 16HBE cells was selected, and aged BC (1,4-NQ coated BC and ozone oxidized BC) was used. We found that both BC and aged BC were able to up-regulate the mRNA expression of IL-1β, IL-6, and IL-8 except IL-33. However, the Mitogen-activated protein kinases (MAPKs) and Phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (AKTs) pathways remained inactive. After pretreatment with Lipopolysaccharide (LPS), IL-33 mRNA expression was significantly increased in 16HBE cells and MAPKs and PI3K/AKT were activated. These results suggested that MAPKs and PI3K/AKT pathways were involved in the elevation of IL-33. Furthermore, epithelial cells are unlikely to be the source of lung inflammation caused by elevated IL-33 in BC and aged BC.

Black carbon (BC) is a product of incomplete combustion of fossil fuels and vegetation. The compelling evidence has demonstrated that it has a close relationship with several respiratory and cardiovascular diseases. BC provides the reactive sites and surfaces to absorb various chemicals, such as polycyclic aromatic hydrocarbons (PAH). Naphthoquinone is a typical PAHs which was found in particulate matter (PM) and 1,4NQ-BC owned high oxidative potential and cytotoxicity. IL-33 is an alarmin which increases innate immunity through Th2 responses. It was reported that IL-33 was a potent inducer of pro-inflammatory cytokines, like IL-6. In our previous study, it was revealed that 1,4NQ-BC instilled intratracheally to mice could trigger the lung inflammation and stimulate the secretion of IL-33 in lung tissue. We found that IL-33 could induce inflammation in lung itself. When the macrophages were eliminated, the secretion of IL-33 was reduced and the pathological damage in the lung was relieved after exposure to 1,4NQ-BC. Both MAPK and PI3K/AKT signal pathways were involved in the process of IL-33 secretion and the lung inflammation induced by 1,4NQ-BC. The findings herein support the notion that after exposure to 1,4NQ-BC, the increased secretion of IL-33 was mainly derived from macrophages through both MAPK and PI3K/AKT signal pathways.

As the main composition of combustion, black carbon (BC) is becoming more and more noticeable at home and abroad. Ozone-oxidized black carbon (oBC) was produced through aging of ozone, one of the near-surface pollutants, to black carbon. And oBC was found to be more oxidation and cell toxicity when compared with BC. Besides, as a key cell of immunity, whether CD4(+) T cell would involve in lung inflammation induced by particular matter is still unclear. This study aims to observe the effect of oBC on lung damage in mice and discuss how the functional MAP4K4 defect CD4(+) T cells (conditional knockout of MAP4K4) presents its role in this process. In our study, MAP4K4 deletion in CD4(+) T cells (MAP4K4 cKO) could increase cell number of macrophages, lymphocytes and neutrophils in bronchoalveolar lavage fluid (BALF) exposed to oBC. MAP4K4 deletion in CD4(+) T cell also affected CD4(+) T cell differentiation in mediastinal lymph nodes after oBC stimulation. The number of CD4(+) IL17(+) T cell increased obviously. The levels of IL-6 mRNA of lung in MAP4K4 cKO mice was higher than that in wild type mice after exposed to oBC, while the level of IL-6 in BALF had the same trend. Histological examination showed that MAP4K4 deletion in CD4(+) T cells affected lung inflammation induced by oBC. Results indicated that MAP4K4 cKO in CD4(+) T cells upgraded the level of inflammation in lung when exposed to oBC, which may be connected to the CD4(+) T cell differentiation and JNK, ERK and P38 pathways.

Black carbon and tropospheric ozone (O3 ), which are major air pollutants in China, are hazardous to humans following inhalation. Black carbon can be oxidized by O3 forming secondary particles of which the health effects are unknown. The present study utilized carbon black as a representative of black carbon to characterize the cytotoxicity induced by secondary particles in bronchial epithelial cells (16HBE) and C57BL/6J mice, and to investigate the implicated molecular pathways. Two types of carbon black including untreated carbon black (UCB) and ozonized carbon black (OCB) were presented. The effects of carbon black on cell viability, intracellular reactive oxygen species (ROS), oxidized/reduced glutathione ratio, mitochondrial membrane potential (MMP), intracellular ATP, and mitochondrial cytochrome c to cytoplasmic cytochrome c ratio were assessed in 16HBE. In addition, an alkaline comet assay and a cytokinesis-block micronucleus (CBMN) test with 16HBE cells in vitro and ELISA method for serum 8-hydroxy-2'-deoxyguanosine (8-OHdG) and a bone marrow micronucleus (BMN) test with C57BL/6J mice in vivo were performed to detect the genotoxicity. When compared with UCB exposed cells, OCB exposed cells had decreased cell viability, increased cell death rate, increased comet length and decreased MMP at 24 h exposure. UCB induced higher level of intracellular ROS than OCB from 4 to 23 h. No changes were observed for both OCB and UCB in serum 8-OHdG, intracellular ATP and mitochondrial cytochrome c to cytoplasmic cytochrome c ratio. The results of CBMN and BMN tests are negative. Intracellular ROS induced by OCB was lower than that of UCB. In summary, ozonization enhances the mitochondrial toxicity and genotoxicity of carbon black. Oxidative stress may not dominate in toxic effects of OCB. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 944-955, 2017.

Mast cells in the gut play an important role in the innate and adaptive immune responses that are relevant to human inflammatory bowel disease. However, the contribution of mast cells to the development of inflammatory bowel disease is not well understood. This study aimed to determine the role of mast cells in oxazolone-induced colitis and to explore whether the mast cell membrane stabiliser tranilast could ameliorate colonic inflammation.Wild-type rats and mast cell-deficient rats were sensitised and challenged with oxazolone, then treated with tranilast after challenge. Controls were treated with saline.Mast cell-deficient rats presented a weak response to oxazolone, while wild-type rats showed severe ulcerative colitis after stimulation with oxazolone. The mast cell-deficient rats model had a significantly lower disease activity index score than wild-type rats model (1.8±1.64 vs. 8.3±0.58 respectively; P0.01). Tranilast could reduce the secretion of cytokines, immunoglobulins and myeloperoxidase activity in tranilast treatment groups compared with the model group. The number of mast cells in the wild-type model was higher than in the other groups. There was no significant change in mast cell-deficient rats.Mast cells play an important role in oxazolone-induced colitis. The mast cell membrane stabiliser tranilast can ameliorate oxazolone-induced colitis via a mast cell-dependent pathway.

Grape-seed proanthocyanidins (GSPs) have been shown to function as an anti-oxidant and anti-inflammatory agent with little toxicity in vivo and in vitro. However, little is known about their anti-inflammatory properties and mechanisms of action. The specific focus being its effects on the MAP kinases and nuclear factor-kappaB (NF-κB) signal transduction pathways in lipopolysaccharide (LPS) -stimulated RAW264.7 cells. GSPs extract has been found to suppress the mRNA expression of pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and inflammatory molecule of cyclooxygenase-2 (COX-2) while mRNA level of IL-10 was greatly promoted. Furthermore, GSPs extract inhibited the expression of phosphorylated ERK, JNK and P38, as well as phosphorylated IKKα/β and NF-κB p65 subunit. In conclusion, our results show that GSPs extract showed its anti-inflammatory and immunomodulatory properties by suppressing the activation of MAP kinases and NF-κB signal transduction pathways.

Black carbon (BC) can combine with organic matter and form secondary pollutants known as aged BC. BC and aged BC can cause respiratory system inflammation and induce lesions at relevant sites, but the underlying mechanism has remained unknown. To gain insight into the potential mechanisms, we focused on macrophages and transforming growth factor β-activated kinase 1 (TAK1) which are a crucial factor in inflammation. Our research aims to determine the role of TAK1 in macrophages in pulmonary inflammation induced by particulate matter. In this study, BC and 1,4-naphthoquinone were mixed to model aged BC (1,4NQ-BC) in atmosphere. BC induced mice lung inflammation model, lung macrophage knock-down TAK1 animal model and primary macrophage knock-down TAK1 model were used to explore whether TAK1 in macrophage is a critical role in the process of inflammation. The results showed that the expressions of inflammatory cytokines (IL-1β, IL-6, IL-33) mRNA were significantly increased and the phosphorylation of MAPK and NF-κB signaling pathway related proteins were enhanced in RAW 264.7 cell lines. In vivo studies revealed that the indicators of pulmonary inflammation (pathology, inflammatory cell numbers) and related cytokines (IL-1β, IL-6, IL-33) mRNA expressions in CD11c-Map3k7−/− animals were significantly lower than wild-type animals after mice were instilled particles. In mice primary macrophages, the expressions of IL-6, IL-33 mRNA were inhibited after TAK1 gene was knock-down. These results unequivocally demonstrated that TAK1 plays a crucial role in BC induced lung inflammation in mice, and we can infer that BC and 1,4NQ-BC cause these inflammatory responses by stimulating pulmonary macrophages.

Black carbon (BC) is a key component of atmospheric particles which has adverse effects on human health. Oxidation could lead to chemical property and toxicity potency changes of BC. The key cytokines participating in lung damage in mice induced by BC and ozone-oxidized BC (oBC) particles have been investigated in this study. It was concluded that oBC has stronger potency of inducing lung damage in mice comparing to BC. IL-6 and IL-33 were hypothesized to play important roles in this damage. Accordingly, IL-6 and IL-33 neutralizing antibodies were used to explore which cytokine might play a key role in lung inflammation induced by BC and oBC. As a result, IL-6 neutralizing antibody did not alleviate the lung damage induced by BC and oBC. However, IL-33 neutralizing antibody prevented BC and oBC induced lung damage. Furthermore, IL-33 neutralizing antibody treatment reduced IL-6 mRNA expression. It is hypothesized that MAPK and PI3K-AKT pathways might be involved in the oBC particles caused lung damage. It was concluded that IL-33 plays a key role in BC and oBC induced lung damage in mice.

Objectives: Ambient light has a vital impact on mood and cognitive functions. Blue light has been previously reported to play a salient role in the antidepressant effect via melanopsin. Whether blue light filtered white light (BFW) affects mood and cognitive functions remains unclear. The present study aimed to investigate whether BFW led to depression-like symptoms and cognitive deficits including spatial learning and memory abilities in rats, and whether they were associated with the light-responsive function in retinal explants. Methods: Male Sprague-Dawley albino rats were randomly divided into 2 groups (n = 10) and treated with a white light-emitting diode (LED) light source and BFW light source, respectively, under a standard 12 : 12 h L/D condition over 30 days. The sucrose consumption test, forced swim test (FST) and the level of plasma corticosterone (CORT) were employed to evaluate depression-like symptoms in rats. Cognitive functions were assessed by the Morris water maze (MWM) test. A multi-electrode array (MEA) system was utilized to measure electro-retinogram (ERG) responses induced by white or BFW flashes. Results: The effect of BFW over 30 days on depression-like responses in rats was indicated by decreased sucrose consumption in the sucrose consumption test, an increased immobility time in the FST and an elevated level of plasma CORT. BFW led to temporary spatial learning deficits in rats, which was evidenced by prolonged escape latency and swimming distances in the spatial navigation test. However, no changes were observed in the short memory ability of rats treated with BFW. The micro-ERG results showed a delayed implicit time and reduced amplitudes evoked by BFW flashes compared to the white flash group. Conclusions: BFW induces depression-like symptoms and temporary spatial learning deficits in rats, which might be closely related to the impairment of light-evoked output signals in the retina.

β-Phellandrene, a plant extract, can be used as natural pesticides and synthetic materials. As a factor that human may be exposed to, the toxicity information about β-phellandrene is scared at present. This study focused on the genetic toxicity of β-phellandrene. The genetic toxicity of β-phellandrene was evaluated by micronucleus test, comet assay, Ames test, and chromosomal aberration test. In this study, 2850, 1425, 712.5mg/kg β-phellandrene were used in vivo experiments (comet assay and micronucleus test). For Ames test, pure β-phellandrene and different concentrations were used in the experiment. According to the results of cell viability assay (MTT test), the concentration of chromosomal aberration test was formulated. The result of comet assay showed that β-phellandrene can significantly induce DNA damage at the dosage of 1425 and 2850mg/kg. While the results of Micronucleus test and chromosome aberration test showed that β-phellandrene does not lead to apparently genetic toxicity on chromosome level. Ames tests suggest that β-phellandrene had the ability to increase gene mutation with or without S9 mixture. So, it could be drawn that β-phellandrene would have certain genetic toxicity, and the toxicity is reflected as DNA strand breaks and mutation. This study filled the lack of genetic toxicity study of β-phellandrene, and enriched information for risk assessment for β-phellandrene.

CD4(+) T cells are critical for adaptive immunity. MAP4K4 is a key member of germinal center kinase group. However, the physiological function of MAP4K4 in primary CD4(+) T cells is still unclear. In this study, it was demonstrated that in vitro, MAP4K4 deletion remarkably suppressed CD4(+) T cell proliferation in response to phorbol 12-myristate 13-acetate (PMA) and ionomycin, which was not due to enhancing cell apoptosis. Additionally, MAP4K4 was required for the activation of CD4(+) T cells. MAP4K4 deletion significantly down-regulated expression of interleukin 2 (IL-2) and interferon-γ (IFN-γ), while notably up-regulating the expression of regulatory T cells (Treg) transcription factor Foxp3 in peripheral CD4(+) T cells. Furthermore, western blot analysis indicated that CD4(+) T cells lacking MAP4K4 failed to phosphorylate Jnk, Erk, p38 and PKC-θ. Thus, our results provide the evidence that MAP4K4 is essential for CD4(+) T cell proliferation, activation and cytokine production.

Chlormequat Chloride (CCC), a widely used plant growth regulator, could decrease body weight in animals; however, the mechanism has not been well studied. This study was designed to evaluate the skeletal development toxicity of CCC on pubertal male Sprague-Dawley (SD) rats and to investigate whether CCC impacts the development of chondrocyte, osteoblast and osteoclast through growth hormone (GH) and insulin like growth factor 1 (IGF-I). Rats from 23 to 70 on postnatal days were exposed to CCC daily by gavage at doses of 0, 75, 150, and 300mg/kg bw/d. The results showed that the size of femurs and tibias, bone mineral density and biomechanical parameters were significantly decreased in the 300mg/kg bw/d group compared with the control group. The concentration of osteocalcin (OCN) and C-terminal telopeptide of type I collagen (CTX-I) in blood in the 150mg/kg bw/d group was also changed. The mRNA expression ratio of the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) in 150 and 300mg/kg bw/d group was increased. Histological analysis of proximal and distal epiphyseal plates of the right femurs showed that both the proliferative zone and hypertrophic zone narrowed in CCC-treated groups. The concentration of IGF-I in blood was reduced with an increase in exposure doses of CCC. The mRNA expression of growth hormone receptor (GHR) in tibia was decreased in the CCC-treated group. The results indicated that CCC might indirectly impact the formation and activation of chondrocytes, osteoblasts and osteoclasts because of the decline of GHR and IGF-I, leading to skeletal development damage.

Extracellular ATP is an emerging target for cancer treatment because it is a key messenger for shaping the tumor microenvironment (TME) and regulating tumor progression. However, it remains a great challenge to design biochemical probes for targeted imaging of extracellular ATP in the TME. A TME-driven DNA nanomachine (Apt-LIP) that permits spatially controlled imaging of ATP in the extracellular milieu of tumors with ultrahigh signal-to-background ratio is reported. It operates in response to the mild acidity in the TME with the pH (low) insertion peptide (pHLIP) module, thus allowing the specific anchoring of the structure-switching signaling aptamer unit to the membrane of tumor cells for "off-on" fluorescence imaging of the extracellular ATP. Apt-LIP allows for acidity driven visualization of different extracellular concentrations of exogenous ATP, as well as the monitoring of endogenous ATP release from cells. Furthermore, it is demonstrated that Apt-LIP represents a promising platform for the specific imaging of the extracellular ATP in both primary and metastatic tumors. Ultimately, since diverse aptamers are obtained through in vitro selection, this design strategy can be further applied for precise detection of various extracellular targets in the TME.

Fluorescent nanoprobes are indispensable tools to monitor and analyze biological species and dynamic biochemical processes in cells and living bodies. Conventional nanoprobes have limitations in obtaining imaging signals with high precision and resolution because of the interference with biological autofluorescence, off-target effects, and lack of spatiotemporal control. As a newly developed paradigm, light-activated nanoprobes, whose imaging and sensing activity can be remotely regulated with light irradiation, show good potential to overcome these limitations. Herein, recent research progress on the design and construction of light-activated nanoprobes to improve bioimaging and sensing performance in complex biological systems is introduced. First, recent innovative strategies and their underlying mechanisms for light-controlled imaging are reviewed, including photoswitchable nanoprobes and phototargeted nanosystems. Subsequently, a short highlight is provided on the development of light-activatable nanoprobes for biosensing, which offer possibilities for the remote control of biorecognition and sensing activity in a precise manner both temporally and spatially. Finally, perspectives and challenges in light-activated nanoprobes are commented.

Black carbon (BC) is a key component of atmospheric particles and has a significant effect on human health. BC can provide reactive sites and surfaces thus absorb quinones which were primarily generated from fossil fuel combustion and/or atmospheric photochemical conversions of PAHs. Oxidation could change the characteristics of BC and increase its toxicity. The comparison of lung damage in mice exposed to BC and 1,4-NQ-coated BC (1,4NQ-BC) particles is investigated in this study. Mice which were intratracheally instilled with particles have a higher expression of IL-1β, IL-6 and IL-33 in bronchoalveolar lavage fluid (BALF). Also, the IL-6, IL-33 mRNA expression in the lung tissue of mice instilled with 1,4NQ-BC were higher than that of mice instilled with BC. The pathology results showed that the lung tissue of mice instilled with 1,4NQ-BC particles have much more inflammatory cells infiltration than that of mice treated with BC. It is believed that the MAPK and PI3K-AKT pathway might be involved in the 1,4NQ-BC particles caused lung damage. Results indicated that 1,4NQ-BC particles in the atmosphere may cause more damage to health.

Black carbon (BC) is a key component of atmospheric particles and has a significant effect on human health. Oxidation could change the characteristics of BC and increase its toxicity. The comparison of lung damage in mice exposed to BC and ozone-oxidized BC (oBC) particles is investigated in this study. Mice which were intratracheally instilled with particles have a higher expression of IL-1β, IL-6 and IL-33 in bronchoalveolar lavage fluid (BALF). Also, the IL-6, IL-33 mRNA expression in the lung tissue of mice instilled with oBC was higher than that of mice instilled with BC. The expression of CD3 in the lung tissue of mice intratracheally instilled with oBC was higher than the mice distilled with BC. The pathology results showed that the lung tissue of mice instilled with oBC particles have much more inflammatory cells infiltration than that of mice treated with BC. It is believed that the PI3K-AKT pathway might be involved in the oBC particles caused lung damage. Results indicated that oBC particles in the atmosphere may cause more damage to health.