Negotiating SHI-FEI and shifei: Pursuing a Moralist Self in China's Community-Based Addiction Treatment Programs.

Based on 16 months of fieldwork conducted at drug addiction treatment facilities in Yunnan, Southwest China, this article examines how Chinese drug users invent moralist selves during the frequent occurrences of shifei incidents. Shìfei, meaning literally right/wrong, is a crucial concept in Chinese society with two contradictory meanings: (1) moral norms/judgment that ought to be discerned and followed (SHI-FEI); (2) "troubles" or "quarrels" that are often morally undesirable (shifei). By delving into a typical incident of shifei, this article analyzes the logic, motivation, and interpretations of the drug users and addiction treatment facility staff who are involved in the local moral world. It argues that for drug users, the relationship between SHI-FEI and shifei is not oppositional, as often assumed. Instead, both are valuable moral experiences and useful cultural means in response to users' moral demands and tensions. Negotiating SHI-FEI and shifei enables an ambiguous space in which drug users seek, claim, and practice their moralist selves. This article also argues that under various sociopolitical and moral constraints, drug users' moral selves are characterized by an inward focus on claims of morality and legitimacy. This inward focus reflects a process of moral involution. This study contributes to understandings of moral self-making in stigmatized situations.

Sphingosine Kinase 1 Plays an Important Role in Atorvastatin-Mediated Anti-Inflammatory Effect against Acute Lung Injury.

Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor and inhibits cholesterol synthesis. Recently, atorvastatin also showed anti-inflammatory effect in acute lung injury, ameliorating pulmonary gas-blood exchanging function. Sphingosine kinase 1 plays a central role in endothelial (EC) cytoskeleton rearrangement and EC barrier integrity regulation. In this study, the role of sphingosine kinase 1 in atorvastatin anti-inflammatory effect against acute lung injury was investigated. Both wild-type (WT) and SphK1-/- mice were challenged with high tidal volume ventilation (40 ml/kg body weight, 65 breathing/min, 4 hours). The acute lung injury was evaluated and the mechanisms were explored. In WT mice, atorvastatin treatment significantly decreased acute lung injury responding to high tidal volume ventilation (HT), including protein, cellular infiltration, and cytokine releasing; comparing to WT mice, SphK1-/- mice showed significantly worsen pulmonary injuries on HT model. Moreover, the atorvastatin-mediated anti-inflammatory effect was diminished in SphK1-/- mice. To further confirm the role of SphK1 in VILI, we then compared the inflammatory response of endothelial cells that were isolated from WT and SphK1-/- mice to cyclic stretching. Similarly, atorvastatin significantly decreased cytokine generation from WT EC responding to cyclic stretching. Atorvastatin also significantly preserved endothelial junction integrity in WT EC against thrombin challenge. However, the inhibitory effect of atorvastatin on cytokine generation induced by cyclic stretching was abolished on SphK1-/- mice EC. The endothelial junction integrity effects of atorvastatin also diminished on SphK1-/- mouse EC. Signal analysis indicated that atorvastatin inhibited JNK activation induced by cyclic stretch. SphK1 knockout also blocked atorvastatin-mediated VE-cadherin junction enhancement. In summary, by inhibition of MAPK activity and maintenance of EC junction homeostasis, SphK1 plays a critical role in atorvastatin-mediated anti-inflammatory effects in both cellular and in vivo model. This study also offers an insight into mechanical stress-mediated acute lung injury and potential therapy in the future.

Application of the Tumor Site Recognizable and Dual-Responsive Nanoparticles for Combinational Treatment of the Drug-Resistant Colorectal Cancer.

PURPOSE: Combination of PCI and chemotherapy represents a promising strategy for combating drug resistance of cancer. However, poor solubility of photosensitizers and unselectively released drugs at unwanted sites significantly impaired the treatment efficacy. Therefore, in the present study, we aimed to develop a nano-platform which could efficiently co-entrapping photosensitizers and chemotherapeutics for active targeting therapy of drug resistant cancers. METHODS: Two pro-drugs were respectively developed by covalently linking the Ce6 with each other via the GSH-sensitive linkage and the PTX with mPEG-PLA-COOH through the ROS sensitive-linker. The dual-responsive nanoparticles (PNP-Ce6) was developed by emulsion/solvent evaporation method and further modified with tLyp-1 peptides. Physicochemical properties of nanoparticles were determined by the TEM and DLC. Cellular uptake assay was investigated with the Ce6 acting as the fluorescent probe and cell growth was studied by the MTT experiment. In vivo tumor targeting and anti-tumor assay was investigated on the colorectal cancer-bearing mice. RESULTS: The developed tPNP-Ce6 were stable enough under the normal physiological conditions. However, free Ce6 and PTX were completely released when exposed the tPNP-Ce6 to the redox environment. Excellent tumor-targeting drug delivery was achieved by the tPNP-Ce6, which in turn resulted in satisfactory anit-tumor effect. Of great importance, super inhibition effect on tumor progress was achieved by the combination therapy when compared with the group only received with chemotherapy.. CONCLUSION: The results obtained in the present study indicated that the developed tPNP-Ce6 may have great potential in enhancing the therapeutic efficacy of drug-resistant colorectal cancer. Graphical Abstract Left: Targeting delivery of drug to tumor site by the tumor recognizable and dual-responsive nanoparticles and penetrating into tumor inner via the mediation of irradiation. Right: Nanoparticle distribution within tumor tissues with green represents the blood vessels stained with CD31, blue signal represents the cell nuclei stained with DAPI and red shows fluorescence of Ce6 as the indicator of the nanoparticles.

D-4F, an apolipoprotein A-I mimetic, suppresses IL-4 induced macrophage alternative activation and pro-fibrotic TGF-ß1 expression.

Context: We reported that D-4F, an apolipoprotein A-I (Apo A-I) mimetic polypeptide with 18 d-amino acids, suppressed IL-4 induced macrophage alternative activation and TGF-ß1 expression in phorbol 12-myristate 13-acetate (PMA) treated human acute monocytic leukemia cells (THP-1). Objective: Macrophage alternative activation, TGF-ß1 and epithelial-mesenchymal transition (EMT) are intensively involved in pulmonary fibrosis. Recent studies demonstrated that Apo A-I resolved established pulmonary fibrotic nodules, and D-4F inhibited TGF-ß1 induced EMT in alveolar cells. Therefore, this study evaluated the effects of D-4F on IL-4 induced macrophage alternative activation and TGF-ß1 expression. Materials and methods: THP-1 cells were simulated with PMA (100 ng/mL) for 48 h and treated with medium control, IL-4 (20 ng/mL) alone, or IL-4 (20 ng/mL) in the presence of D-4F (1, 5, and 10 µg/mL) for 24 and 48 h. Flow cytometry, RT-PCR and ELISA evaluations were performed to investigate the subsequent effects of D-4F. Results: Compared to stimulation with IL-4 alone, 1, 5, and 10 µg/mL of D-4F reduced alternative activation by 45.38%, 59.98%, and 60.10%, increased TNF-α mRNA levels by 8%, 11%, and 16% and decreased TGF-ß1 mRNA levels by 21%, 37%, and 39%, respectively (all p ≤ 0.05). In addition, TNF-α protein levels increased from 388 pg/mL (IL-4 alone) to 429, 475, and 487 pg/mL (1, 5, and 10 µg/mL D-4F), while TGF-ß1 protein levels dropped from 27.01 pg/mL (IL-4 alone) to 19.15, 12.27, and 10.47 pg/mL (1, 5, and 10 µg/mL D-4F). Conclusion: D-4F suppressed IL-4 induced macrophage alternative activation and pro-fibrotic TGF-ß1 expression.

Gelsolin Inhibits the Inflammatory Process Induced by LPS.

BACKGROUND/AIMS: Endotoxemia is a life-threatening situation that signifies a key challenge in the field of intensive care medicine. Proinflammatory mediators produced by macrophages play a key role in endotoxemia. Gelsolin (GSN) is involved in the process of inflammation. METHODS: IL-6 and TNF-α in the supernatant were measured with an ELISA kit. NO production was assessed by measurement of nitrite concentration with the Griess assay. si-RNA directed against GSN (si-GSN) was transfected by Lipofectamine. RESULTS: LPS decreased the levels of GSN. Recombinant GSN inhibited the cytokines induced by LPS and rescued mice from LPS-induced death, and si-GSN increased death in the LPS-pretreated mice. CONCLUSION: GSN exhibited a protective role in endotoxemia.

Function of Deubiquitinating Enzyme USP14 as Oncogene in Different Types of Cancer.

BACKGROUND/AIMS: Non-small cell lung cancer (NSCLC) tissues overexpress USP14, which promotes tumor cell proliferation and is associated with shorter overall survival time. METHODS: The expression of USP14 was assayed in many types of cancers. USP14 was up-and down-regulated using appropriate plasmid or lentiviral vector constructs and its effects on proliferation, cell colony number, and apoptosis rate were measured. A human NSCLC cell line was inoculated into nude mice and the survival rates were recorded. RESULTS: We found USP14 amplification and overexpression in many different cancers. The overexpression of USP14 in USP14 low-expression cell lines promoted cell proliferation and migration, whereas USP14 downregulation suppressed tumor cell proliferation, decreased tumor cell colony number, increased apoptosis rate, and decreased cell migration and invasion. CONCLUSION: USP14 plays an oncogenic role in various types of cancer, and may thus represent a new cancer therapy target.

MiR-940 inhibited pancreatic ductal adenocarcinoma growth by targeting MyD88.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an almost universally lethal disease. Deregulation or dysfunction of miRNAs contribute to cancer development. The role of miR-940 in PDAC remains unclear. METHODS: The level of miR-940 in PDAC tissues and cell lines was measured by qRT-PCR. MiR-940 was over-expressed by miRNAs mimics transfection and reduced by miRNAs antisense oligonucleotides (ASO) transfection. Cell proliferation was analyzed by MTT assay and cell apoptosis was evaluated by FACS analysis. Targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. Myeloid differentiation primary response gene (88) (MyD88) protein level was assayed by immunohistochemistry and Western blot analysis. RESULTS: Low miR-940 level and high MyD88 protein level in PDAC tissues were both correlated with low survival rate. Up-regulation of miR-940 inhibited PDAC cell lines growth while down-regulation induced cell growth. The 3' UTR of MyD88 was targeted by miR-940. CONCLUSIONS: Low level of miR-940 and high level of MyD88 in PDAC promoted PDAC cells growth which might be related to the low survival rate of PDAC patients. MiR-940 exerted its effect by targeting MyD88.

MiR-4782-3p inhibited non-small cell lung cancer growth via USP14.

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality worldwide, with near 1.4 million deaths each year. NSCLC accounts for nearly 85% of all case of lung cancer. MiRNAs play important roles in regulation of gene expression at the post-transcriptional level. MiRNAs profiles may predict prognosis and disease recurrence in early-stage NSCLC. Our previous study proved that over-expression of ubiquitin specific peptidase 14 (USP14), a deubiquitinating enzyme, was associated with favorable prognosis in NSCLC patients and promoted tumor cells proliferation. Here, we tried to identify which miRNAs targeted USP14, and the roles of these miRNAs in NSCLC. METHODS: MiR-4782-3p and its potential targeted genes were identified by bioinformatics algorithm. Dual luciferase reporter assay system was used to analyze the interaction between miR-4782-3p and targeted genes. Cell proliferation was assayed by MTT and BdU assay. MiRNAs and mRNA expression were assayed by qRT-PCR. USP14 protein level was assayed by Western blot. The role of miR-4782-3p in patients survival was revealed by Kaplan-Meier plot of overall survival. RESULTS: Up-expression of miR-4782-3p in NSCLC cells decreased the USP14 expression. Down-expression of miR-4782-3p increased USP14 expression. In NSCLC specimen, Negative correlation between USP14 mRNA level and miR-4782-3p level was identified. Higher miR-4782-3p expression is associated with longer survival. USP14, ZEB2, XIAP overexpression reversed the inhibitory effect of miR-4782-3p. CONCLUSIONS: High expression of miR-4782-3p was associated with favorable prognosis in NSCLC patients. MiR-4782-3p inhibited cell proliferation in NSCLC by targeting USP14, ZEB2 and XIAP.

Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy.

PURPOSE: Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role anti-hypertensive medications will play in immunotherapy. METHODS: We examined the effects of six first-line anti-hypertensive medications on programmed cell death protein 1 antibody (PD1ab) in tumor treatment using a mouse model of subcutaneous fibrosarcoma. The drugs examined were verapamil, losartan, furosemide, spironolactone, captopril, and hydrochlorothiazide (HCTZ). The infiltration of CD8+ T cells was examined by immunohistochemistry. Additionally, several in vitro and in vivo assays were used to study the effects of HCTZ on human fibrosarcoma cancer cells to explore its mechanism. RESULTS: Verapamil suppressed tumor growth and showed an improved effect on the tumor inhibition of PD1ab. Captopril did not affect tumor growth but brought an unexpected benefit to PD1ab treatment. In contrast, spironolactone and furosemide showed no effect on tumor growth but had an offset effect on the PD1ab therapy. Consequently, the survival time of mice was also significantly reduced. Notably, losartan and HCTZ, especially HCTZ, promoted tumor growth and weakened the effect of PD1ab treatment. Consistent results were observed in vivo and in vitro using the human fibrosarcoma cell line HT1080. We determined that the Solute Carrier Family 12 Member 3 (SLC12A3), a known target of HCTZ, may be the principal factor underlying its effect-enhancing properties through mechanism studies employing The Cancer Genome Atlas (TCGA) data and in vivo and in vitro assays. CONCLUSION: Verapamil and captopril potentiated the anti-tumor effect of PD1ab, whereas spironolactone and furosemide weakened the effect of PD1ab on tumor inhibition. Alarmingly, losartan and HCTZ promoted tumor growth and impaired the effect of PD1ab. Furthermore, we preliminarily found that HCTZ may promote tumor progression through SLC12A3. Based on this study, futher mechanism researches and clinical trials should be conducted in the future.

GSK-3ß inhibition attenuates LPS-induced death but aggravates radiation-induced death via down-regulation of IL-6.

BACKGROUND: Exposure of high dose ionizing radiation is lethal. Signal pathways involved in radiation biology reaction still remain illdefined. Lipopolysaccharides (LPS), the ligands of Toll-like receptor 4(TLR4), could elicit strong immune responses. Glycogen synthase kinase-3ß(GSK-3ß) promotes the production of inflammatory molecules and cell migration. Inhibition of GSK-3ß provides protection against inflammation in animal models. The aim of the study was to investigate role of GSK-3ß in LPS shock and ionizing radiation. METHODS: WT or IL-6(-/-)mice or cells were pretreated with SB216763, a GSK-3ß inhibitor, and survival of the mice was determined. Cell viability was assayed by Cell Counting Kit. Apoptosis was assayed by Annexin V-PI double staining. Serum concentrations of IL-6 and TNF-α were determined by ELISA. RESULTS: SB216763 attenuated LPS induced mice or cell death but aggravated radiation induced mice or cell death. SB216763 reduced IL-6, but not TNF-α levels in vivo. IL-6(-/-) mice were more resistant to LPS-induced death but less resistant to radiation-induced death than wild type mice. CONCLUSIONS: Inhibition of GSK-3ß conferred resistance to LPS shock but fostered death induced by ionizing radiation. Inhibition of GSK-3ß was effective by reducing IL-6.

Identification of a novel Getah virus by Virus-Discovery-cDNA random amplified polymorphic DNA (RAPD).

BACKGROUND: The identification of new virus strains is important for the study of infectious disease, but current (or existing) molecular biology methods are limited since the target sequence must be known to design genome-specific PCR primers. Thus, we developed a new method for the discovery of unknown viruses based on the cDNA--random amplified polymorphic DNA (cDNA-RAPD) technique. Getah virus, belonging to the family Togaviridae in the genus Alphavirus, is a mosquito-borne enveloped RNA virus that was identified using the Virus-Discovery-cDNA RAPD (VIDISCR) method. RESULTS: A novel Getah virus was identified by VIDISCR from suckling mice exposed to mosquitoes (Aedes albopictus) collected in Yunnan Province, China. The non-structural protein gene, nsP3, the structural protein gene, the capsid protein gene, and the 3'-untranslated region (UTR) of the novel Getah virus isolate were cloned and sequenced. Nucleotide sequence identities of each gene were determined to be 97.1-99.3%, 94.9-99.4%, and 93.6-99.9%, respectively, when compared with the genomes of 10 other representative strains of Getah virus. CONCLUSIONS: The VIDISCR method was able to identify known virus isolates and a novel isolate of Getah virus from infected mice. Phylogenetic analysis indicated that the YN08 isolate was more closely related to the Hebei HB0234 strain than the YN0540 strain, and more genetically distinct from the MM2021 Malaysia primitive strain.

Building care amid navigating liability risks: The possibility of policy-driven care in China's drug-control arena.

For Chinese policymakers, shouldering responsibility is often associated with high liability risk, thus resulting in low-level care for risky and stigmatized populations such as drug users. Therefore, it is crucial to explore ways to improve care access in such an uneasy policy environment. Based on long-term ethnographic fieldwork conducted in Yunnan province in southwestern China from 2013 to 2021, this paper traces the policy-making process of the Yunnan Province Methadone Oral Solution Take-Home Treatment Work Proposal. All stakeholders involved considered this policy attempt "impossible" at first, as the highly addictive methadone becomes an illegal drug once it is taken outside a clinical setting. By analyzing how a group of local government officials, together with medical practitioners and drug users, strive to legitimize and ultimately implement the policy, I argue that people's concern over liability risks strengthens the boundary between methadone as a "drug" and methadone as a "medicine," between methadone solution drinkers as "drug users" and as "patients," and between "inside the clinic" and "outside the clinic." By utilizing a culturalist approach to explore the possibility of care in such a context, this paper reveals that a "heqing heli hefa worthy-of-being-cared-for" discourse is crucial in that it acts as symbolic capital to dissolve the above boundaries embedded in the dominant political culture. Moreover, it is the key cultural logic of the "building" of care. The findings also illustrate how local policymakers negotiate and balance responsibility and liability to create a potential policy space for enabling care practices. Additionally, this study sheds light on the inclusion of care for the most stigmatized and marginalized populations, and has broad implications for policy-making in other contexts.

Poly(I:C) induce bone marrow precursor cells into myeloid-derived suppressor cells.

Dendritic cells (DC) and myeloid-derived suppressor cells (MDSC) are important cells involved in immune response. DC can be generated from mouse bone marrow (BM) in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. Recent studies have revealed that combined treatment of bone marrow MDSC with LPS plus IFN-γ inhibited the DC development but enhanced MDSC functions, such as NO release and T cell suppression. In our study, bone marrow precursor cells cultures in GM-CSF and IL-4 were treated with poly(I:C) through the culture, Gr1(+)CD11b(+) cells with MDSC functions, such as NO release and T cell suppression were accumulated in the culture system. Then the similar phenomenon was observed in the vesicular stomatitis virus infection in vivo. In conclusion, we demonstrated that the bone marrow precursor cells in the presence of GM-CSF and IL-4 can differentiate into MDSC, which is dependent on the dynamic of interaction with poly(I:C).

Tumor-educated CD11bhighIalow regulatory dendritic cells suppress T cell response through arginase I.

Tumors can induce generation and accumulation of the immunosuppressive cells such as regulatory T cells in the tumor microenvironment, contributing to tumor escape from immunological attack. Although dendritic cell (DC)-based cancer vaccine can initiate antitumor immune response, regulatory DC subsets involved in the tolerance induction attracted much attention recently. Our previous studies demonstrate that the stromal microenvironment of the spleen, lung, and liver can program generation of CD11c(low)CD11b(high)Ia(low) DCs with regulatory function (CD11b(high)Ia(low) regulatory DCs). However, whether and how the tumor microenvironment can program generation of CD11b(high)Ia(low) regulatory DCs remain to be investigated. In this study, we used the freshly isolated tumor cells to mimic tumor microenvironment to coculture DCs and found that the freshly isolated tumor cells could drive DCs to differentiate into regulatory DCs with a CD11c(low)CD11b(high)Ia(low) phenotype and high expression of IL-10, NO, vascular endothelial growth factor, and arginase I. Tumor-educated CD11b(high)Ia(low) regulatory DCs inhibited CD4(+) T cell proliferation both in vitro and in vivo. 3LL lung cancer-derived TGF-beta and PGE(2) were responsible for the generation of regulatory DCs. PGE(2) was the main inducer of arginase I in regulatory DCs. Arginase I played a major role in the suppression of T cell response by regulatory DCs induced by 3LL lung cancer. A natural counterpart of CD11b(high)Ia(low) DCs was identified in tumor tissue, and CD11b(high)Ia(low) DCs sorted from 3LL lung cancer tissue expressed arginase I and inhibited T cell response. Therefore, tumors can educate DCs to differentiate into a regulatory DC subset, which contributes to constitution of the immunosuppressive tumor microenvironment and promotes tumor immune escape.

Isoalantolactone inhibits pancreatic cancer proliferation by regulation of PI3K and Wnt signal pathway.

BACKGROUND/AIMS: Isoalantolactone (IATL) is one of multiple isomeric sesquiterpene lactones and is isolated from inula helenium. IATL has multiple functions such as antibacterial, antihelminthic and antiproliferative activities. IATL also inhibits pancreatic cancer proliferation and induces apoptosis by increasing ROS production. However, the detailed mechanism of IATL-mediated pancreatic cancer apoptosis remains largely unknown. METHODS: In current study, pancreatic carcinoma cell lines (PANC-1, AsPC-1, BxPC-3) and a mouse xenograft model were used to determine the mechanism of IATL-mediated toxic effects. RESULTS: IATL (20µM) inhibited pancreatic adenocarcinoma cell lines proliferation in a time-dependent way; while scratch assay showed that IATL significantly inhibited PANC-1 scratch closure (P<0.05); Invasion assays indicated that IATL significantly attenuated pancreatic adenocarcinoma cell lines invasion on matrigel. Signal analysis showed that IATL inhibited pancreatic adenocarcinoma cell proliferation by blocking EGF-PI3K-Skp2-Akt signal axis. Moreover, IATL induced pancreatic adenocarcinoma cell apoptosis by increasing cytosolic Caspase3 and Box expression. This apoptosis was mediated by inhibition of canonical wnt signal pathway. Finally, xenograft studies showed that IATL also significantly inhibited pancreatic adenocarcinoma cell proliferation and induced pancreatic adenocarcinoma cell apoptosis in vivo. CONCLUSIONS: IATL inhibits pancreatic cancer proliferation and induces apoptosis on cellular and in vivo models. Signal pathway studies reveal that EGF-PI3K-Skp2-Akt signal axis and canonical wnt pathway are involved in IATL-mediated cellular proliferation inhibition and apoptosis. These studies indicate that IATL may provide a future potential therapy for pancreatic cancer.

Tumor suppressor role of miR-876-5p in gastric cancer.

Gastric cancer (GC) is the second most common cancer cause of cancer-related mortality worldwide. Recent studies have demonstrated the function of microRNAs (miRNAs) in the pathogenesis of GC. miR-876-5p demonstrated an antitumor role in hepatocellular carcinoma and lung cancer; however, the function of miR-876-5p has not yet been fully identified in GC. Thus, the present study aimed to investigate the role of miR-876-5p in GC. The results of the present study demonstrated low expression levels of miR-876-5p in GC tumor tissues. Furthermore, overexpression of miR-876-5p inhibited GC cell proliferation and promoted apoptosis, whilst miR-876-5p knockdown promoted GC cell proliferation and decreased cisplatin sensitivity of GC cells. Transforming growth factor ß-receptor 1 was demonstrated to be a potential target gene of miR-876-5p. Overall, the results of the present study suggest that miR-876-5p plays an antitumor role in GC.

Boosting hydrogen evolution activity of vanadyl pyrophosphate nanosheets for electrocatalytic overall water splitting.

Herein, (VO)2P2O7 nanosheets function as a highly-active electrocatalyst for the hydrogen evolution reaction with an ultralow overpotential of 30 mV at 10 mA cm-2 in basic media, being close to Pt/C. Furthermore, as a bifunctional electrocatalyst, (VO)2P2O7 not only exhibits high activity but also good stability for overall water splitting.

TLR4 signaling in cancer cells promotes chemoattraction of immature dendritic cells via autocrine CCL20.

Toll-like receptors (TLRs) are involved in the production of inflammatory mediators upon specific ligands stimuli. Chemokines are important inflammatory mediators capable of chemoattracting diverse immune cells. In addition to normal immune cells, the expression of TLRs and chemokines has been detected in various tumor cells. However, the roles of TLRs and chemokines expressed by tumor cells in the processes of tumor progression and immune escape have not been fully elucidated. Here we report that TLR4 ligation by lipopolysaccharide (LPS) significantly promotes CT-26 colon cancer cells to produce chemokine CCL20 via activation of TLR4 signaling pathways. We find that LPS treatment of CT-26 cells can significantly increase the chemoattraction of immature dendritic cells (DC) by the autocrine CCL20. Our studies suggest that TLR4 expressed by tumor cells may be involved in the induction of chemokines like CCL20, providing a potential linkage between chronic inflammation and tumor immune escape.

Plant-derived small molecule albaconol suppresses LPS-triggered proinflammatory cytokine production and antigen presentation of dendritic cells by impairing NF-kappaB activation.

Dendritic cells (DCs) play crucial roles in linking innate immunity and adaptive immunity, thus being regarded as one of the important targets of immunosuppressant. Natural small molecule products isolated from plants, such as fungal metabolites, have been shown to be effective in the treatment of cancer, inflammation and autoimmune diseases. Albaconol is a new kind of prenylated resorcinols isolated from the fruiting bodies of the inedible mushroom Albatrellus confluens, and has been shown to inhibit tumor cell growth. Considering that most of small molecule compounds with antitumor activity always exert immunosuppressive effect, so we wonder whether albaconol could inhibit maturation and antigen presentation of DCs, thus acting as immunosuppressant. Here we demonstrate that albaconol significantly inhibits LPS-induced production of proinflammatory cytokines TNF-alpha, IL-6, IL-1beta, and expression of MHC-II and co-stimulatory molecules by DCs. Furthermore, albaconol markedly inhibits T cell-stimulating capacity of DCs and DCs-initiated antigen-specific T cell response, indicating albaconol can inhibit phenotypic and functional maturation of DCs. Inhibition of LPS-induced NF-kappaB activation may contribute to the above immunosuppressive or anti-inflammatory activities of albaconol. Therefore, our results suggest that natural small molecule albaconol may be a potential immunosuppressive and anti-inflammatory agent through suppressing DCs function via impairment of NF-kappaB activation.

Small GTPase RBJ promotes cancer progression by mobilizing MDSCs via IL-6.

RBJ has been identified to be dysregulated in gastrointestinal cancer and promotes tumorigenesis and progression by mediating nuclear accumulation of active MEK1/2 and sustained activation of ERK1/2. Considering that nuclear accumulation and constitutive activation of MEK/ERK not only promotes tumor progression directly, but also induces chronic inflammation, we wonder whether and how RBJ impairs host immune-surveillance via chronic inflammation and consequently supports tumor progression. Here, we report that higher expression of RBJ in human breast cancer tissue has been significantly correlated with poorer prognosis in breast cancer patients. The forced expression of RBJ promotes tumor growth and metastasis both in vitro and in vivo. In addition, more accumulation of immune suppressive cells but less antitumor immune cell subpopulations were found in spleen and tumor tissue derived from RBJ force-expressed tumor-bearing mice. Furthermore, forced RBJ expression significantly promotes tumor cell production of pro-inflammatory cytokine IL-6 by constitutive activating MEK/ERK signaling pathway. Accordingly, RBJ knockdown significantly decreases tumor growth and metastasis in vitro and in vivo, with markedly reduced production of IL-6. Administration of anti-IL-6 neutralizing antibody could reduce MDSCs accumulation in tumor tissue in vivo. Therefore, our results demonstrate that RBJ-mediated nuclear constitutive activation of ERK1/2 leads to persistent production of IL-6 and increase of MDSCs recruitment, contributing to promotion of tumor growth and metastasis. These results suggest that RBJ contributes to tumor immune escape, maybe serving a potential target for design of antitumor drug.