Jun and JunB members of the AP-1 complex are potential therapeutic targets for silicosis.

Silicosis is a systemic disease with predominantly diffuse fibrosis of the lungs due to prolonged inhalation of free SiO2 dust during the manufacturing process, for which there is no effective treatment. In this study, we used a combined epigenetic and transcriptomic approach to reveal the chromatin-opening features of silicosis and identify the key transcription factor activator protein 1 (AP-1) that responds to silicosis fibrosis. Therapeutic administration of an AP-1 inhibitor inhibits the PI3K/AKT signaling pathway, reduces fibrosis marker proteins, and significantly ameliorates lung fibrosis in a mouse model of silicosis. In addition, it was observed that the expression of Jun and JunB was significantly up-regulated in a TGF-ß1-induced in vitro transdifferentiation model of NIH/3T3 cells, and Co-IP confirmed that a protein complex could be formed between Jun and JunB. Mechanistically, silencing of Jun and JunB expression reversed the activation of the PI3K/AKT signaling pathway and the upregulation of fibrosis marker proteins in NIH/3 T3 cells after TGF-ß1 stimulation. Taken together, Jun/JunB is expected to be a potential therapeutic target for silicosis fibrosis.

Exposure to micron-grade silica particles triggers pulmonary fibrosis through cell-to-cell delivery of exosomal miR-107.

Long-term exposure to inhalable silica particles may lead to severe systemic pulmonary disease, such as silicosis. Exosomes have been demonstrated to dominate the pathogenesis of silicosis, but the underlying mechanisms remain unclear. Therefore, this study aimed to explore the roles of exosomes by transmitting miR-107, which has been linked to the toxic pulmonary effects of silica particles. We found that miR-107, miR-122-5p, miR-125a-5p, miR-126-5p, and miR-335-5p were elevated in exosomes extracted from the serum of patients with silicosis. Notably, an increase in miR-107 in serum exosomes and lung tissue was observed in the experimental silicosis mouse model, while the inhibition of miR-107 reduced pulmonary fibrosis. Moreover, exosomes helped the migration of miR-107 from macrophages to lung fibroblasts, triggering the transdifferentiation of cell phenotypes. Further experiments demonstrated that miR-107 targets CDK6 and suppresses the expression of retinoblastoma protein phosphorylation and E2F1, resulting in cell-cycle arrest. Overall, micron-grade silica particles induced lung fibrosis through exosomal miR-107 negatively regulating the cell cycle signaling pathway. These findings may open a new avenue for understanding how silicosis is regulated by exosome-mediated cell-to-cell communication and suggest the prospect of exosomes as therapeutic targets.

PD-1/PD-L1 axis in organ fibrosis.

Fibrosis is a pathological tissue repair activity in which many myofibroblasts are activated and extracellular matrix are excessively accumulated, leading to the formation of permanent scars and finally organ failure. A variety of organs, including the lung, liver, kidney, heart, and skin, can undergo fibrosis under the stimulation of various exogenous or endogenous pathogenic factors. At present, the pathogenesis of fibrosis is still not fully elucidated, but it is known that the immune system plays a key role in the initiation and progression of fibrosis. Immune checkpoint molecules are key regulators to maintain immune tolerance and homeostasis, among which the programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) axis has attracted much attention. The exciting achievements of tumor immunotherapy targeting PD-1/PD-L1 provide new insights into its use as a therapeutic target for other diseases. In recent years, the role of PD-1/PD-L1 axis in fibrosis has been preliminarily explored, further confirming the close relationship among PD-1/PD-L1 signaling, immune regulation, and fibrosis. This review discusses the structure, expression, function, and regulatory mechanism of PD-1 and PD-L1, and summarizes the research progress of PD-1/PD-L1 signaling in fibrotic diseases.

Dynamics of the inhibitory immune checkpoint TIM-3 in mouse pulmonary phagocytes after silica exposure.

Long-term inhalation of silica particles in the workplace causes silicosis, which is incurable and seriously endangers the health of workers. It is believed that silicosis is caused by an imbalance of the pulmonary immune microenvironment, in which pulmonary phagocytes play a crucial role. As an emerging immunomodulatory factor, it is unclear whether T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) participate in silicosis by modulating pulmonary phagocytes function. The purpose of this study was to investigate the dynamic changes of the TIM-3 in pulmonary macrophages, dendritic cells (DCs), and monocytes during the development of silicosis in mice. The plasma levels of soluble TIM-3 in silicosis patients were also examined. Flow cytometry was used to identify alveolar macrophages (AMs), interstitial macrophages (IMs), CD11b+ DC, CD103+ DC, Ly6C+, and Ly6C- monocytes in mouse lung tissues, and further analyses were conducted on the expression of TIM-3. Results showed that soluble TIM-3 was significantly elevated in plasma of silicosis patients, and the level of which was higher in stage II and III patients than that in stage I. In silicosis mice, the protein and mRNA levels of TIM-3 and Galectin9 were significantly upregulated in lung tissues. Specific to pulmonary phagocytes, silica exposure affected TIM-3 expression in a cell-specific and dynamic manner. In macrophages, TIM-3 expression upregulated in AM after 28 days and 56 days of silica instillation, while the expression of TIM-3 in IM decreased at all observation time points. In DCs, silica exposure only caused a decrease of TIM-3 expression in CD11b+ DCs. In monocytes, TIM-3 dynamics in Ly6C+ and Ly6C- monocytes were generally consistent during silicosis development, which significant decrease after 7 and 28 days of silica exposure. In conclusion, TIM-3 may mediate the development of silicosis by regulating pulmonary phagocytes.

Self-healing pectin/cellulose hydrogel loaded with limonin as TMEM16A inhibitor for lung adenocarcinoma treatment.

Lung cancer as one of the highest incident malignant tumors did not receive satisfactory chemotherapy due to lack of specific drug targets and targeted drugs. This study screened a new effective lung tumor inhibitor limonin from herbal medicine, which inhibited proliferation and promoted apoptosis of lung adenocarcinoma cells by targeting specific high expressed TMEM16A ion channel. Moreover, a novel biodegradable self-healing hydrogel was prepared from acylhydrazide functionalized carboxymethyl cellulose (CMC-AH) and oxidized pectin (pec-CHO) to reduce the side effects of the limonin to the body. The hydrogels showed fast gelation, good biocompatibility and sustained limonin release property. The limonin-loaded hydrogel significantly inhibited the growth of lung adenocarcinoma in xenografts mice because the limonin inhibited the proliferation, migration and promoted apoptosis of LA795 cells, and eliminated the acute toxicity through sustained release from the hydrogel. Combined the antitumor performance of the limonin and sustained release of pec-CHO/CMC-AH hydrogel, this limonin/hydrogel system achieved satisfactory antitumor effect and eliminated side effects in vivo. Therefore, this system has great potential application for enhanced lung adenocarcinoma therapy.

Cellulose-based thermo-responsive hydrogel with NIR photothermal enhanced DOX released property for anti-tumor chemotherapy.

Thermo-sensitive hydrogels change their properties through phase transition, which could be used to regulate various behaviors by changing the temperature. In this study, degradable hydrogels with thermo-response were designed by reaction of oxidized carboxymethyl cellulose (CMC-CHO) with functional P(NIPAM-co-AH). The hydrogels showed biocompatibility and thermo-response with lower critical solution temperature (LCST) regulated by weight ratio of P(NIPAM-co-AH)/CMC-CHO. The photo-thermal property of gold nanorod was triggered by the near-infrared (NIR) to enhance the DOX release for in vivo anti-tumor therapy of model mice. The results showed good biocompatibility and biodegradability of the hydrogel both in vitro and in vivo, and the DOX with hydrogel loading reduced the toxicity through sustained release behavior. The anti-tumor performance further enhanced with NIR triggered drug release regulated by photo-thermal property. In conclusion, the injectable P(NIPAM-co-AH)/CMC-CHO based self-healing hydrogels could act as promising drug delivery vehicle for potential localized anti-tumor therapy.

Dendritic cells activated by cimetidine induce Th1/Th17 polarization in vitro and in vivo.

Dendritic cells (DCs) are powerful antigen presentation cells and the initiator of adaptive immune response. Cimetidine, a widely used drug for gastric ulcers treatment, has significant immunomodulatory ability. However, the effects of cimetidine on DC-mediated T cell activation need to be further explored. In this study, we constructed the in vitro and in vivo model of cimetidine exposure, and our data showed that cimetidine stimulated the maturity of immature DCs, and further enhanced its T cell priming capacity. In vivo, the number of rat splenic CD103+ DC were not altered after cimetidine exposure, but the expression of surface markers CD54, CD11c, and MHC-II of which were up-regulated. Importantly, cimetidine interfered with DC-mediated T cell polarization, which was reflected in the up-regulation of Th1 and Th17 cells and the down-regulation of Th2 and Treg cells in vitro and in vivo. These results indicate that cimetidine can induce DC activation and promote DC mediated pro-inflammatory T cell response while weaken immunosuppressive T cell response.

PD-1/PD-L1 inhibitor ameliorates silica-induced pulmonary fibrosis by maintaining systemic immune homeostasis.

Pulmonary fibrosis induced by silica particles is defined as silicosis, which is an incurable disease. The pathogenesis of silicosis is not completely clear, but it's certain that immune system dysfunction is closely related to it. Immune checkpoint inhibitors (ICIs) are emerging immunotherapeutic agents that mainly target adaptive immune cells, and there is abundant evidence that ICIs are of great value in cancer treatment. However, whether these attractive agents can be implemented in silicosis treatment is unclear. In this study, we explored the efficacy of small molecule inhibitors targeted PD-1/PD-L1 and CTLA-4 on silica-induced pulmonary fibrosis in mice. ICIs were injected intraperitoneally into mice that received silica instillation twice a week. The mice were sacrificed 7 and 28 days after the injection. The lungs, spleen, hilar lymph nodes, thymus, and peripheral blood of mice were collected and subjected to histological examination, flow cytometry analysis, and mRNA and protein quantification. Our results demonstrated that silica exposure caused damage to multiple immune organs in mice, leading to an imbalance in systemic immune homeostasis. Specifically, proportions and subtypes of T and B cells were significantly altered, and the expressions of PD-1, PD-L1 and CTLA-4 were abnormal on these cells. Both PD-1/PD-L1 and CTLA-4 inhibitor administration modulated silica-induced immune system disruption, however, only PD-1/PD-L1 signaling inhibition showed significant amelioration of silicosis. Our findings confirmed for the first time the potential value of ICIs for the treatment of silica-induced pulmonary fibrosis, and this may provide new ideas for the treatment of other fibrosis-related diseases.

Poly(aspartic acid) based self-healing hydrogel with blood coagulation characteristic for rapid hemostasis and wound healing applications.

External hemorrhage, caused by insufficient hemostasis or surgical failure, could leads to shock or even tissue necrosis as the results of excessive blood loss. Furthermore, delayed coagulation, chronic inflammation, bacterial infection and slow cell proliferation are also major challenges to effective wound repairing. In this study, a novel hemostatic hydrogel was prepared by cross-linking inorganic polyphosphate (PolyP) conjugated poly(aspartic acid) hydrazide (PAHP) and PEO90 dialdehyde (PEO90 DA). Based on the dynamic characteristics of the acylhydrazone bond, the hydrogel could repair its cracks when broken under external forces. At the same time, the hydrogel showed outstanding biocompatibility and tissue adhesion with remarkable hemostatic performance. The New Zealand rabbit ear artery used as a in vivo hemostasis model and the results showed the PAHP hydrogel could stop bleeding of traumatic wound and reduce blood loss significantly. Meanwhile, the PAHP hydrogel presented intrinsic antibacterial activity, thus could inhibit the bacterial infection. In addition, the hydrogel loaded with mouse epidermal growth factor (mEGF) accelerated the wound repair rate and promoted the regeneration of fresh tissue in the mouse full thickness skin defect model. Altogether, the PAHP hydrogels exhibits great potential in the biomedical application, especially in wound dressing materials and tissue repairing.

In vitro co-culture model of human monocyte-derived dendritic cells and T cells to evaluate the sensitization of dinitrochlorobenzene.

Exposure to sensitizer has been suggested to be hazardous to human health, evaluation the sensitization of sensitizer is particularly important and urgently needed. Dendritic cells (DCs) exert an irreplaceable function in immunity, and the T cell receptor (TCR) repertoire is key to ensuring immune response to foreign antigens. We hypothesized that a co-culture model of human monocyte-derived dendritic cells (Mo-DCs) and T cells could be employed to evaluate the sensitization of DNCB. An experimental model of DNCB-induced sensitization in rat was employed to examine alterations of cluster of differentiation CD103+ DCs and T cells. A co-cultured model of Mo-DCs and T cells was developed in vitro to assess the sensitization of DNCB through the phenotypic and functional alterations of Mo-DCs, as well as the TCR repertoire. We found that the CD103+ DCs phenotype and T-helper (Th) cells polarization altered in sensitization rats. In vitro, phenotypic alteration of Mo-DCs caused by DNCB were consistent with in vivo results, antigen uptake capacity of Mo-DCs diminished and capacity of Mo-DCs to prime T cell increased. Clones of the TCR repertoire and the diversity of TCR repertoire were enhanced, changes were noted in the usage of variable, joining, and variable-joining gene combinations. DNCB exposure potentiated alterations and characteristics of Mo-DCs and the TCR repertoire in a co-culture model. Such changes provided innovative ideas for evaluating sensitization of DNCB.

Effect of RGD content in poly(ethylene glycol)-crosslinked poly(methyl vinyl ether-alt-maleic acid) hydrogels on the expansion of ovarian cancer stem-like cells.

The extracellular matrix (ECM) affects cell behaviors, such as survival, proliferation, motility, invasion, and differentiation. The arginine-glycine-aspartic acid (RGD) sequence is present in several ECM proteins, such as fibronectin, collagen type I, fibrinogen, laminin, vitronectin, and osteopontin. It is very critical to develop ECM-like substrates with well-controlled features for the investigation of influence of RGD on the behavior of tumor cells. In this study, poly(ethylene glycol) (PEG)-crosslinked poly(methyl vinyl ether-alt-maleic acid) (P(MVE-alt-MA)) hydrogels (PEMM) with different RGD contents were synthesized, fully characterized, and established as in vitro culture platforms to investigate the effects of RGD content on cancer stem cell (CSC) enrichment. The morphology, proliferation, and viability of SK-OV-3 ovarian cancer cells cultured on hydrogels with different RGD contents, the expression of CSC markers and malignant signaling pathway-related genes, and drug resistance were systematically evaluated. The cell aggregates formed on the hydrogel surface with a lower RGD content acquired certain CSC-like properties, thus drug resistance was enhanced. In contrast, the drug sensitivity of cells on the higher RGD content surface increased because of less CSC-like properties. However, the presence of RGD in the stiff hydrogels (PEMM2) had less effect on the stemness expression than did its presence in the soft hydrogels (PEMM1). The results suggest that RGD content and matrix stiffness can lead to synergetic effects on the expression of cancer cell stemness and the epithelial-mesenchymal transition (EMT), interleukin-6 (IL-6), and Wnt pathways.

High-Dose Cyclophosphamide Administration Orchestrates Phenotypic and Functional Alterations of Immature Dendritic Cells and Regulates Th Cell Polarization.

High-dose cyclophosphamide (CTX) inhibits the immune response. Dendritic cells (DCs) are professional antigen presenting cells (APCs) with a crucial role in initiating immune responses and sustaining immune tolerance. The relative contribution of DCs to immunosuppression induced by high-dose CTX is not well-documented. In this study, we employed the CTX-induced immunosuppressive rat model to examine alterations in DCs. We generated and cultured monocyte-derived immature DCs (imDCs) in vitro and explored their capacity of antigen uptake, T cell priming, cytokine production, and surface marker expression following high-dose CTX. Subsequently, we co-cultured CTX-treated imDCs with Th cells to determine Th cell polarization, and further explored the Toll-like receptor/Myeloid differentiation primary response 88/Mitogen-activated protein kinase (TLR/MyD88/MAPK) pathway. Our results show reduced cell number and surface maker alterations in splenic CD103+ DCs of CTX-treated immunosuppressed rats. In vitro, high-dose CTX weakened the antigen uptake capacity and enhanced the T cell priming capacity of imDCs, in addition to triggering imDC surface marker alterations. TLR, MyD88, and MAPK expression levels, involved in mediating Th cell polarization, were also significantly elevated. Our collective findings indicate that high-dose CTX administration potentiates phenotypic and functional alterations of imDC. Such changes may contribute to the regulation of Th polarization.

Human monocyte-derived dendritic cells as an in vitro alternative model cell to evaluate the immunotoxicity of 2, 4-Dinitrochlorobenzene.

Improvements in science and technology have led to the increasing threats of new chemicals to the public health. It is crucial to evaluate the toxicity, especially immunotoxicology. Dendritic cells (DCs) are believed to be more favorable choices in immunotoxicity evaluations. To obtain and evaluate the value of human monocyte-derived immature DCs (imDCs) in vitro applications in immunotoxicology, compared the results in vitro. DCs were obtained from enriched leukocytes of peripheral blood by using magnetic cell sorting and cytokine (rhGM-CSF + rhIL-4) co-induction. imDCs function in vitro and the surface antigens changes both in imDCs and THP-1 after 24 h of 2,4-dinitrochlorobenzene (DNCB) exposure were determined. The results were compared with those of DNCB-induced rats. The feasibility of imDCs applications in immunotoxicology was evaluated. In vivo, the splenic nodules, lymphocytes, and CD103+DC surface antigen expression were altered in the spleen of DNCB-induced rats. Moreover, DNCB exposure increased CD8+ T cell numbers both in peripheral blood and in the spleen of DNCB-induced rats. In vitro, DNCB exposure reduced the antigen uptake capacity and enhanced the T cell proliferative capacity of imDCs. The results are consistent with in vivo, but superior to that of the THP-1. Our results suggest that human monocyte-derived DCs may have potential applications as an attractive in vitro alternative cell model to evaluate the sensitization of DNCB.

The effects of intro-oral parathyroid hormone on the healing of tooth extraction socket: an experimental study on hyperglycemic rats.

Objective To investigate the effects of intro-oral injection of parathyroid hormone (PTH) on tooth extraction wound healing in hyperglycemic rats. Methodology 60 male Sprague-Dawley rats were randomly divided into the normal group (n=30) and DM group (n=30). Type 1 diabetes mellitus (DM) was induced by streptozotocin. After extracting the left first molar of all rats, each group was further divided into 3 subgroups (n=10 per subgroup), receiving the administration of intermittent PTH, continuous PTH and saline (control), respectively. The intermittent-PTH group received intra-oral injection of PTH three times per week for two weeks. A thermosensitive controlled-release hydrogel was synthesized for continuous-PTH administration. The serum chemistry was determined to evaluate the systemic condition. All animals were sacrificed after 14 days. Micro-computed tomography (Micro-CT) and histological analyses were used to evaluate the healing of extraction sockets. Results The level of serum glucose in the DM groups was significantly higher than that in the non-DM groups (p<0.05); the level of serum calcium was similar in all groups (p>0.05). Micro-CT analysis showed that the DM group had a significantly lower alveolar bone trabecular number (Tb.N) and higher trabecular separation (Tb.Sp) than the normal group (p<0.05). The histological analyses showed that no significant difference in the amount of new bone (hard tissue) formation was found between the PTH and non-PTH groups (p>0.05). Conclusions Bone formation in the extraction socket of the type 1 diabetic rats was reduced. PTH did not improve the healing of hard and soft tissues. The different PTH administration regimes (continuous vs. intermittent) had similar effect on tissue healing. These results demonstrated that the metabolic characteristics of the hyperglycemic rats produced a condition that was unable to respond to PTH treatment.

Silica particles disorganize the polarization of pulmonary macrophages in mice.

Silicosis is a fatal fibrotic lung disease caused by long-term silica particle exposure, in which pulmonary macrophages play an important role. However, the relationship between macrophage polarization and silicosis remains unclear. We established an experimental silicosis mouse model to investigate macrophage polarization during silicosis development. C57BL/c mice were exposed to silica by intra-tracheal instillation and sacrificed at different time points. Lung tissues and bronchoalveolar lavage fluid were collected for flow cytometry, quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assays, western blotting, and histology examinations. The polarization of pulmonary macrophages was dysregulated during silicosis development. In the early stage of silicosis, M1 macrophages were induced and played a leading role in eliciting inflammatory; in the late stage, M2 macrophages were induced to promote tissue repair. Levels of several cytokines in lung tissue microenvironment changed with macrophage polarization. Inflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-1ß and IL-6 were upregulated in the inflammation stage, while the anti-inflammatory cytokine IL-10 was upregulated in the fibrosis stage. Furthermore, we found that STAT (signal transducer and activator of transcription) and IRF (interferon regulatory factor) signaling pathway were involved in the regulation of macrophage polarization in silicosis. In summary, macrophage polarization is closely related to the occurrence and development of silicosis and may be a key point for further elucidating silicosis pathogenesis.

Exosomal miR-125a-5p derived from silica-exposed macrophages induces fibroblast transdifferentiation.

Silica particles can cause a systemic disease in workers termed lung silicosis, characterized by diffuse fibrosis. The development of lung silicosis involves various signaling pathway networks comprising numerous cell types and cytokines. As an important medium for communication between cells, exosomes have emerged as a hot research topic; however, the role of exosomal microRNAs (miRNAs) in silicosis remains unclear. In this study, we conducted high-throughput sequencing to generate exosomal miRNAs profiles from macrophages that were either exposed to silica or not. A total of 298 miRNAs were differentially expressed, with 155 up-regulated and 143 down-regulated. Highly conserved differentially expressed miRNAs were functionally annotated and analyzed to predict target genes. Among target interactions associated with the TGF-ß signaling pathway, miR-125a-5p and its putative target gene, Smurf1, were subjected to further research. As expected, levels of miR-125a-5p were upregulated in human serous exosomes and vitro, and inhibit the exosomal miR-125a-5p suppressed the expression of the fibrosis hallmarks. Besides, high levels of the miRNA led to upregulation of smooth muscle actin alpha and repression of Smurf1 in NIH-3T3 and MRC-5 cells. ID1 and SMAD1, downstream of TGF-ß signaling, were upregulated, indicating potential activation of this signaling pathway. These results contribute to understanding of the intercellular communication mediated by exosomal miRNAs and its critical role in fibroblast to myofibroblast transition and silicosis.

The effects of intro-oral parathyroid hormone on the healing of tooth extraction socket: an experimental study on hyperglycemic rats

Abstract Objective To investigate the effects of intro-oral injection of parathyroid hormone (PTH) on tooth extraction wound healing in hyperglycemic rats. Methodology 60 male Sprague-Dawley rats were randomly divided into the normal group (n=30) and DM group (n=30). Type 1 diabetes mellitus (DM) was induced by streptozotocin. After extracting the left first molar of all rats, each group was further divided into 3 subgroups (n=10 per subgroup), receiving the administration of intermittent PTH, continuous PTH and saline (control), respectively. The intermittent-PTH group received intra-oral injection of PTH three times per week for two weeks. A thermosensitive controlled-release hydrogel was synthesized for continuous-PTH administration. The serum chemistry was determined to evaluate the systemic condition. All animals were sacrificed after 14 days. Micro-computed tomography (Micro-CT) and histological analyses were used to evaluate the healing of extraction sockets. Results The level of serum glucose in the DM groups was significantly higher than that in the non-DM groups (p<0.05); the level of serum calcium was similar in all groups (p>0.05). Micro-CT analysis showed that the DM group had a significantly lower alveolar bone trabecular number (Tb.N) and higher trabecular separation (Tb.Sp) than the normal group (p<0.05). The histological analyses showed that no significant difference in the amount of new bone (hard tissue) formation was found between the PTH and non-PTH groups (p>0.05). Conclusions Bone formation in the extraction socket of the type 1 diabetic rats was reduced. PTH did not improve the healing of hard and soft tissues. The different PTH administration regimes (continuous vs. intermittent) had similar effect on tissue healing. These results demonstrated that the metabolic characteristics of the hyperglycemic rats produced a condition that was unable to respond to PTH treatment.

Effects of cyclophosphamide on the phenotypes and functions of THP-1 cells.

Early and accurate evaluation of immunotoxicity is crucial. However, there are few in vitro models for immunosuppressive evaluation. THP-1 cells has long been used for in vitro sensitivity evaluation. Whether it can be used for immunosuppressive evaluation remains unclear. In this study, effects of immunosuppressant cyclophosphamide (CY) on THP-1 cells were observed while 2, 4-Dinitrochlorobenzene (DNCB) was used as a control. The phenotypes of THP-1 cells, the ability to activate naïve T cells, intracellular reactive oxygen species (ROS) level, gene markers, phagocytic ability and cell apoptosis were detected after THP-1 cells being exposed to different concentrations of CY and DNCB. Both CY and DNCB were able to activate THP-1 cells, but there were a lot of differences in their effects on THP-1 cells, such as the changes in phenotypes, in the ability to activate naïve T cells, in ROS production and in marker gene expression. Firstly, CY down-regulated the expression of CD86 on THP-1 cells while DNCB up-regulated its expression. Secondly, the ability of THP-1 cells to activate naïve T cells was enhanced by CY and suppressed by DNCB. Thirdly, CY raised rapid and transient elevation of ROS level in THP-1 cells, while the effects of DNCB were slower and longer-lasting. Finally, only CY could lead to an increase in heme oxygenase 1 (HMOX1) expression. Taken all these results into account, we suggested that THP-1 cell line possesses the potency to be an in vitro model of immunosuppressive evaluation. And the surface molecule CD86, the ability to activate naïve T cells, the ROS production and the gene marker HMOX1 of THP-1 cells are promising markers.

Temperature and solvent isotope dependent hierarchical self-assembly of a heterografted block copolymer.

A heterografted block copolymer with doubly thermoresponsive grafts is designed to address the challenge in hierarchical self-assembly. Upon heating, solvent isotope dependent morphology transitions from spheres to nanobowls, vesicles, disks, nanosheets, nanoribbons and hyperbranched micelles can be achieved. The strategy provides a general platform to prepare diverse thermoreversible nano-objects.

Facile Synthesis and Topological Transformation of Multicomponent Miktoarm Star Copolymers.

Multicomponent miktoarm stars (MMSs) comprising at least three kinds of chemically different arm segments are extremely important due to their great potential as multiphase materials to elucidate composition/topology-dependent properties and applications. At present, a "core first" route gives ABC stars, "coupling onto" and combinatorial methods afford ABC and ABCD stars, and modular and iterative approaches enable facile synthesis of MMSs with five or more components. Meanwhile, the introduction of stimuli-labile linkages and couplable groups into star polymers further enriches the family of smart materials. Upon external stimuli, linking reaction, or postpolymerization modification, miktoarm stars are potentially converted into other architectural polymers such as linear, tadpole-like, graft, and dendrimer-like polymers via cleavage and rearrangement in the chain structure. This feature article aims to systematically summarize the synthetic methods and versatile topological transitions of ABC, ABCD, and ABCDE stars. The advantages and limitations of each approach are highlighted, and the future considerations on developments and challenges are discussed.