Influenza vaccination is associated with a reduced risk of invasive aspergillosis in high-risk individuals in Taiwan: a population-based cohort study.

Invasive aspergillosis (IA) has become the emerging life-threatening disease in recent years. Influenza has been identified as an independent risk factor for IA. Vaccination is the most effective way to prevent influenza, while whether it can reduce IA in high-risk population still uncertain. We aimed to investigate the association between influenza vaccination and the risk of IA in high-risk population. We performed a population-based cohort study of people who qualified for government-funded influenza vaccination and were at high risk for IA at the start of the influenza season each year between 2016 and 2019. We utilized Taiwan's National Health Insurance Research Database to identify the influenza vaccination status and IA diagnosis during the follow-up period. We compared the risk of IA between people with and without vaccination using multivariable logistic regression analysis. Out of total 8,544,451 people who were eligible during the 3 influenza seasons, 3,136,477 (36.7%) were vaccinated. A total of 1179 IA cases with the incidence of 13.8 cases per 100,000 high-risk individuals were identified during the follow-up. Compared to non-vaccinated group, vaccinated individuals had a 21% risk reduction of IA (adjusted odds ratio 0.79, 95% confidence interval 0.70-0.90). Influenza vaccination was associated with a lower risk of IA among males, immunosuppressive conditions, malignancy, diabetes, and those having host factors according to the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Influenza vaccination is recommended for high-risk population to reduce the risk of IA.

Microneedle patches integrated with lateral flow cassettes for blood-free chronic kidney disease point-of-care testing during a pandemic.

Chronic kidney disease (CKD) is the most neglected chronic disease affecting over 750 million persons in the world. Currently, many patients with cancers or other chronic diseases (i.e., CKD) struggle to receive clinical treatment or examination due to hospitals cancelling or delaying in the COVID-19 pandemic, which may increase the risk of death. Cystatin C (Cys C) has been proposed as a potential glomerular filtration rate (GFR) marker for the early detection of acute kidney injury and CKD. However, most traditional methods for Cys C detection are immunoassays using serum as a sample and are tedious to perform and economically burdensome. To diagnose the disease in the early stage and carry out daily management during the current pandemic, we developed an integration of hydrogel microneedle patch (HMNP) and lateral flow cassette (LFC) to rapidly detect Cys C in skin interstitial fluid (ISF) in 25 min for blood-free CKD management anytime and anywhere by the naked eye that can reduce the impact of an individual's quality of life and life expectancy. Conceivably, this strategy presents a wide scope in the application of numerous other diseases if corresponding analytes are available in skin ISF.

Diversity and Function of Appressoria.

Endophytic, saprobic, and pathogenic fungi have evolved elaborate strategies to obtain nutrients from plants. Among the diverse plant-fungi interactions, the most crucial event is the attachment and penetration of the plant surface. Appressoria, specialized infection structures, have been evolved to facilitate this purpose. In this review, we describe the diversity of these appressoria and classify them into two main groups: single-celled appressoria (proto-appressoria, hyaline appressoria, melanized (dark) appressoria) and compound appressoria. The ultrastructure of appressoria, their initiation, their formation, and their function in fungi are discussed. We reviewed the molecular mechanisms regulating the formation and function of appressoria, their strategies to evade host defenses, and the related genomics and transcriptomics. The current review provides a foundation for comprehensive studies regarding their evolution and diversity in different fungal groups.

Static Magnetic Field Induced Neural Stem/Progenitor Cell Early Differentiation and Promotes Maturation.

The potential impacts of magnetic field exposures on brain development have raised public concern. In the present study, we aimed to investigate the biophysical effects of moderate-intensity (0.5 T, Tesla) static magnetic field (SMF) on mice neural progenitor cells (mNPCs). Our results showed that the SMF exposure increased the number of neurosphere formation and enhanced proliferative activity in mNPCs. In addition, our flow cytometry data demonstrated that the proportions of S phase and G2/M phase mNPCs were remarkably increased following 5 days of SMF exposure. Moreover, the level of a mitotic regulatory protein, cyclin B, was upregulated after SMF exposure. Furthermore, the mNPCs exposed to SMF exhibited a significant increase in Sox2 expression. When mNPCs were induced to differentiation, our immunofluorescence assay revealed that the percentage of neurons (Tuj-1-positive cells) but not astrocyte (s100ß-positive cells) was significantly higher and displayed morphological complexity in the SMF group. Finally, our electrophysiological results demonstrated the mNPC-derived neurons from the SMF group showing a significantly increased in input resistance, which indicated more functional maturation. Based on these findings, it appears reasonable to suggest that SMF exposure could affect normal neurogenesis and promote neural lineage differentiation as well as neuronal maturation.

Delivery of Antigen to CD8+ Dendritic Cells by Fusing Antigen With Formyl Peptide Receptor-Like 1 Inhibitor Protein Induces Antitumor Immunity.

A major challenge for vaccine development is targeting antigens to dendritic cells (DCs) in vivo, enabling cross-presentation, and inducing the memory responses. Fcγ receptors (FcγRs) are expressed on many cell types including DCs. Therefore, targeting of antigen to DCs via FcγRs is an attractive strategy for vaccine development. This study employ formyl peptide receptor-like 1 inhibitory protein (FLIPr), an FcγR binding protein secreted by Staphylococcus aureus, to deliver antigen to DCs. Our results show that FLIPr is a competent vehicle in delivering antigen to CD8+ DCs for induction of potent immunities without extra adjuvant formulation. Fusion antigen with FLIPr enables effective antigen presentation on both MHC class II and class I to induce memory T cell responses. Altogether, using FLIPr as an antigen delivery vector has great potential to apply antigens for cancer immunotherapy as well as other infectious disease vaccines.

Efficient Uptake of Recombinant Lipidated Survivin by Antigen-Presenting Cells Initiates Antigen Cross-Presentation and Antitumor Immunity.

Survivin is overexpressed in various types of human cancer, but rarely expressed in terminally differentiated adult tissues. Thus, survivin is a potential target antigen for a cancer vaccine. However, self-tumor-associated antigens are not highly immunogenic. Bacteria-derived lipoproteins can activate antigen-presenting cells through their toll-like receptors to enhance immune responses. In this context, lipidated survivin is an attractive candidate for cancer immunotherapy. In the present study, recombinant lipidated human survivin (LSur) was prepared from an Escherichia coli-based system. We investigated whether LSur is efficiently captured by antigen-presenting cells then facilitating effective induction of survivin cross-presentation and generation of immunity against cancer cells. Our results demonstrate that LSur, but not its non-lipidated counterpart, can activate mouse bone-marrow-derived-dendritic cells (BMDCs) to enhance cytokine (IL-6, TNF-α, and IL-12) secretion and costimulatory molecules (CD40, CD80, CD86, and MHC II) expression. However, the pathways involved in the capture of the recombinant lipidated antigen by antigen-presenting cells have not yet been elucidated. To this end, we employ various endocytosis inhibitors to study the effect on LSur internalization. We show that the internalization of LSur is suppressed by the inhibition of various routes of endocytosis. These results suggest that endocytosis of LSur by BMDCs can be mediated by multiple mechanisms. Furthermore, LSur is trafficked to the early endosome after internalization by BMDCs. These features of LSur are advantageous for cross-presentation and the induction of antitumor immunity. We demonstrate that immunization of C57BL/6 mice with LSur under treatment with exogenous adjuvant-free formulation induce survivin-specific CD8+ T-cell responses and suppress tumor growth. The antitumor responses are mediated by CD8+ cells. Our findings indicate that LSur is a potential candidate for stimulating protective antitumor immunity. This study suggests that lipidated tumor antigens may be a promising approach for raising a robust antitumor response in cancer immunotherapy.

The proteomic response of the reef coral Pocillopora acuta to experimentally elevated temperatures.

Although most reef-building corals live near the upper threshold of their thermotolerance, some scleractinians are resilient to temperature increases. For instance, Pocillopora acuta specimens from an upwelling habitat in Southern Taiwan survived a nine-month experimental exposure to 30°C, a temperature hypothesized to induce stress. To gain a greater understanding of the molecular pathways underlying such high-temperature acclimation, the protein profiles of experimental controls incubated at 27°C were compared to those of conspecific P. acuta specimens exposed to 30°C for two, four, or eight weeks, and differentially concentrated proteins (DCPs) were removed from the gels and sequenced with mass spectrometry. Sixty unique DCPs were uncovered across both eukaryotic compartments of the P. acuta-dinoflagellate (genus Symbiodinium) mutualism, and Symbiodinium were more responsive to high temperature at the protein-level than the coral hosts in which they resided at the two-week sampling time. Furthermore, proteins involved in the stress response were more likely to be documented at different cellular concentrations across temperature treatments in Symbiodinium, whereas the temperature-sensitive host coral proteome featured numerous proteins involved in cytoskeletal structure, immunity, and metabolism. These proteome-scale data suggest that the coral host and its intracellular dinoflagellates have differing strategies for acclimating to elevated temperatures.

dBRWD3 Regulates Tissue Overgrowth and Ectopic Gene Expression Caused by Polycomb Group Mutations.

To maintain a particular cell fate, a unique set of genes should be expressed while another set is repressed. One way to repress gene expression is through Polycomb group (PcG) proteins that compact chromatin into a silent configuration. In addition to cell fate maintenance, PcG proteins also maintain normal cell physiology, for example cell cycle. In the absence of PcG, ectopic activation of the PcG-repressed genes leads to developmental defects and malignant tumors. Little is known about the molecular nature of ectopic gene expression; especially what differentiates expression of a given gene in the orthotopic tissue (orthotopic expression) and the ectopic expression of the same gene due to PcG mutations. Here we present that ectopic gene expression in PcG mutant cells specifically requires dBRWD3, a negative regulator of HIRA/Yemanuclein (YEM)-mediated histone variant H3.3 deposition. dBRWD3 mutations suppress both the ectopic gene expression and aberrant tissue overgrowth in PcG mutants through a YEM-dependent mechanism. Our findings identified dBRWD3 as a critical regulator that is uniquely required for ectopic gene expression and aberrant tissue overgrowth caused by PcG mutations.

Integrating RNA-seq and ChIP-seq data to characterize long non-coding RNAs in Drosophila melanogaster.

BACKGROUND: Recent advances in sequencing technology have opened a new era in RNA studies. Novel types of RNAs such as long non-coding RNAs (lncRNAs) have been discovered by transcriptomic sequencing and some lncRNAs have been found to play essential roles in biological processes. However, only limited information is available for lncRNAs in Drosophila melanogaster, an important model organism. Therefore, the characterization of lncRNAs and identification of new lncRNAs in D. melanogaster is an important area of research. Moreover, there is an increasing interest in the use of ChIP-seq data (H3K4me3, H3K36me3 and Pol II) to detect signatures of active transcription for reported lncRNAs. RESULTS: We have developed a computational approach to identify new lncRNAs from two tissue-specific RNA-seq datasets using the poly(A)-enriched and the ribo-zero method, respectively. In our results, we identified 462 novel lncRNA transcripts, which we combined with 4137 previously published lncRNA transcripts into a curated dataset. We then utilized 61 RNA-seq and 32 ChIP-seq datasets to improve the annotation of the curated lncRNAs with regards to transcriptional direction, exon regions, classification, expression in the brain, possession of a poly(A) tail, and presence of conventional chromatin signatures. Furthermore, we used 30 time-course RNA-seq datasets and 32 ChIP-seq datasets to investigate whether the lncRNAs reported by RNA-seq have active transcription signatures. The results showed that more than half of the reported lncRNAs did not have chromatin signatures related to active transcription. To clarify this issue, we conducted RT-qPCR experiments and found that ~95.24% of the selected lncRNAs were truly transcribed, regardless of whether they were associated with active chromatin signatures or not. CONCLUSIONS: In this study, we discovered a large number of novel lncRNAs, which suggests that many remain to be identified in D. melanogaster. For the lncRNAs that are known, we improved their characterization by integrating a large number of sequencing datasets (93 sets in total) from multiple sources (lncRNAs, RNA-seq and ChIP-seq). The RT-qPCR experiments demonstrated that RNA-seq is a reliable platform to discover lncRNAs. This set of curated lncRNAs with improved annotations can serve as an important resource for investigating the function of lncRNAs in D. melanogaster.

A Compartmental Comparison of Major Lipid Species in a Coral-Symbiodinium Endosymbiosis: Evidence that the Coral Host Regulates Lipogenesis of Its Cytosolic Lipid Bodies.

The lipid body (LB) formation in the host coral gastrodermal cell cytoplasm is a hallmark of the coral-Symbiodinium endosymbiosis, and such lipid-based entities are not found in endosymbiont-free cnidarian cells. Therefore, the elucidation of lipogenesis regulation in LBs and how it is related to the lipid metabolism of the host and endosymbiont could provide direct insight to understand the symbiosis mechanism. Herein, the lipid composition of host cells of the stony coral Euphyllia glabrescens, as well as that of their cytoplasmic LBs and in hospite Symbiodinium populations, was examined by high performance liquid chromatography (HPLC) and gas chromatography/mass spectrometry (GC/MS), and six major lipid species were identified: wax esters, sterol esters, triacylglycerols, cholesterols, free fatty acids, and phospholipids. Their concentrations differed significantly between host coral cells, LBs, and Symbiodinium, suggesting compartmental regulation. WE were only present in the host coral and were particularly highly concentrated in LBs. Amongst the four species of WE, the monoene R = C18:1/R = C16 was found to be LB-specific and was not present in the host gastrodermal cell cytoplasm. Furthermore, the acyl pool profiles of the individual LB lipid species were more similar, but not equal to, those of the host gastrodermal cells in which they were located, indicating partially autonomous lipid metabolism in these LBs. Nevertheless, given the overall similarity in the host gastrodermal cell and LB lipid profiles, these data suggest that a significant portion of the LB lipids may be of host coral origin. Finally, lipid profiles of the in hospite Symbiodinium populations were significantly distinct from those of the cultured Symbiodinium, potentially suggesting a host regulation effect that may be fundamental to lipid metabolism in endosymbiotic associations involving clade C Symbiodinium.

Using calcium silicate to regulate the physicochemical and biological properties when using ß-tricalcium phosphate as bone cement.

ß-Tricalcium phosphate (ß-TCP) is an osteoconductive material. For this research we have combined it with a low degradation calcium silicate (CS) to enhance its bioactive and osteostimulative properties. To check its effectiveness, a series of ß-TCP/CS composites with different ratios were prepared to make new bioactive and biodegradable biocomposites for bone repair. Regarding the formation of bone-like apatite, the diametral tensile strength as well as the ion release and weight loss of composites were compared both before and after immersions in simulated body fluid (SBF). In addition, we also examined the behavior of human dental pulp cells (hDPCs) cultured on ß-TCP/CS composites. The results show that the apatite deposition ability of the ß-TCP/CS composites improves as the CS content is increased. For composites with more than a 60% CS content, the samples become completely covered by a dense bone-like apatite layer. At the end of the immersion period, weight losses of 24%, 32%, 34%, 38%, 41%, and 45% were observed for the composites containing 0%, 20%, 40%, 80%, 80% and 100% ß-TCP cements, respectively. In addition, the antibacterial activity of CS/ß-TCP composite improves as the CS-content is increased. In vitro cell experiments show that the CS-rich composites promote human dental pulp cell (hDPC) proliferation and differentiation. However, when the CS quantity in the composite is less than 60%, the quantity of cells and osteogenesis protein of hDPCs is stimulated by Si released from the ß-TCP/CS composites. The degradation of ß-TCP and the osteogenesis of CS give strong reason to believe that these calcium-based composite cements will prove to be effective bone repair materials.

Development of lycopene micelle and lycopene chylomicron and a comparison of bioavailability.

The objectives of this study were to develop lycopene micelles and lycopene chylomicrons from tomato extracts for the enhancement and comparison of bioavailability. Lycopene micelles and chylomicrons were prepared by a microemulsion technique involving tomato extract, soybean oil, water, vitamin E and surfactant Tween 80 or lecithin in different proportions. The encapsulation efficiency of lycopene was 78% in micelles and 80% in chylomicrons, with shape being roughly spherical and mean particle size being 7.5 and 131.5 nm. A bioavailability study was conducted in rats by both gavage and i.v. administration, with oral bioavailability of lycopene, phytoene and phytofluene being 6.8, 4.3 and 3.1% in micelles and 9.5, 9.4 and 7.1% in chylomicrons, respectively. This outcome reveals higher lycopene bioavailability through incorporation into micelle or chylomicron systems. Both size and shape should be considered for oral bioavailability determination. For i.v. injection, lycopene micelles should be more important than lycopene chylomicrons for future clinical applications.

Regulation of physicochemical properties, osteogenesis activity, and fibroblast growth factor-2 release ability of ß-tricalcium phosphate for bone cement by calcium silicate.

ß-Tricalcium phosphate (ß-TCP) is an osteoconductive material. For this research we have combined it with a low degradation calcium silicate (CS) to enhance its bioactive and osteostimulative properties. To check its effectiveness, a series of ß-TCP/CS composites with different ratios were prepared to make new bioactive and biodegradable biocomposites for bone repair. Formation of bone-like apatite, the diametral tensile strength, and weight loss of composites were considered before and after immersion in simulated body fluid (SBF). In addition, we also examined the effects of fibroblast growth factor-2 (FGF-2) released from ß-TCP/CS composites and in vitro human dental pulp cell (hDPC) and studied its behavior. The results showed that the apatite deposition ability of the ß-TCP/CS composites was enhanced as the CS content was increased. For composites with more than 50% CS contents, the samples were completely covered by a dense bone-like apatite layer. At the end of the immersion point, weight losses of 19%, 24%, 33%, 42%, and 51% were observed for the composites containing 0%, 30%, 50%, 70% and 100% ß-TCP cements, respectively. In vitro cell experiments show that the CS-rich composites promote human dental pulp cell (hDPC) proliferation and differentiation. However, when the CS quantity in the composite is less than 70%, the amount of cells and osteogenesis protein of hDPCs was stimulated by FGF-2 released from ß-TCP/CS composites. The combination of FGF-2 in degradation of ß-TCP and osteogenesis of CS gives a strong reason to believe that these calcium-based composite cements may prove to be promising bone repair materials.

Activation of focal adhesion kinase induces extracellular signal-regulated kinase-mediated osteogenesis in tensile force-subjected periodontal ligament fibroblasts but not in osteoblasts.

The exact mechanism by which focal adhesion kinase (FAK) translates mechanical signals into osteogenesis differentiation in force-subjected cells has not been elucidated. The responses to different forces differ according to the origin of cells and the type of stress applied. Therefore, the recruitment of osteoclast and osteoblast progenitor cells, and the balanced activation of these cells around and within the periodontal ligament (PDL) are essential for alveolar bone remodeling. Cells within the PDL and MG63 cells were subjected to tensile forces of -100 kPa for different periods of time. At various times during the tensile force application, they were processed for the purpose of analyzing cell viability, cell cycle, and osteogenic protein. The effect of small interfering RNA transfection targeting FAK was also evaluated. Tensile force enhanced a rapid increase in the phosphorylation of FAK and up-regulated osteogenic protein expression in PDL cells, but not in MG63 cells. Transfecting PDL cells with FAK antisense oligonucleotide diminished alkaline phosphatase and osteocalcin secretion. These findings suggest that tensile force activates FAK pathways in PDL cells, which down-regulate immune cytokine and up-regulate osteogenic protein.

Antiosteoclastogenic activity of silicate-based materials antagonizing receptor activator for nuclear factor kappaB ligand-induced osteoclast differentiation of murine marcophages.

INTRODUCTION: This study investigated whether calcium silicate cement extract exerted antiosteoclastogenic actions in murine RAW 264.7 macrophages cultured with receptor activator for nuclear factor kappaB (RANKL). METHODS: The RAW 264.7 macrophage cell was treated with RANKL to osteoclastogenesis. Then, cell viability, cell death, and cathepsin K expression were examined. RESULTS: The silicon (Si)-inhibited RANKL-induced formation of osteoclasts during the osteoclast differentiation process. It was also found that ≥4 mmol/L Si reduced RANKL-enhanced tartrate-resistant acid phosphatase (TRAP) activity in a dose-dependent manner. Furthermore, Si diminished the expression and secretion of cathepsin K elevated by RANKL and was concurrent with the inhibition of TRAF6 induction and nuclear factor kappaB activation. CONCLUSIONS: The current report shows that silicate abrogated RANKL-induced osteoclastogenesis by retarding osteoclast differentiation. The Si can modulate every cell through dose-dependent in vitro RANKL-mediated osteoclastogenesis, such as the proliferation and fusion of preosteoclasts, and the function of osteoclasts. Therefore, silicate-based materials may be a potential therapeutic agent targeting osteoclast differentiation in bone defects.

KHC-4 anti-cancer effects on human PC3 prostate cancer cell line.

A bicyclic chemical structure, such as that found in flavonoids, was discovered to have anti-cancer activity. Further synthetic structural modification created a series of 2-phenyl-4-quinolone analogs, especially KHC-4, with the same bicyclic chemical structure. This new structure was reported to have stronger anti-cancer activity. In KHC-4 treatments for 72 h on human prostate cancer PC3 cells, cytotoxic effects (IC(50) =0.1 µM) increased dose dependently, causing Cdk1/cyclin B1 complex activity mannered cell cycle and proliferation. KHC-4 treatments suppressed Bcl-2 and Bcl-xL protein levels and upregulated Bax. At the same concentration, pro-caspase 9 protein was cleaved to an activated form, leading to cell apoptosis. Furthermore, the MMP-2 protein levels also decreased through KHC-4 treatment in PC3. In conclusion, KHC-4 presents great prostate cancer therapeutic effects for cell proliferation inhibition, induction of apoptosis and protection against tumor migration.

p38α MAPK mediates 17ß-estradiol inhibition of MMP-2 and -9 expression and cell migration in human lovo colon cancer cells.

Epidemiological studies demonstrate that the incidence and mortality rates of colorectal cancer in women are lower than in men. However, it is unknown if 17ß-estradiol (E(2)) treatment is sufficient to inhibit cell proliferation and cell migration in human colon cancer cells. Up-regulation of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and matrix metallopeptidases (MMPs) is reported to associate with the development of cancer cell mobility, metastasis, and subsequent malignant tumor. In the present study, we treated human LoVo colon cancer cells with E(2) to explore whether E(2) down-regulates cell proliferation and migration, and to identify the precise molecular and cellular mechanisms behind the down-regulatory responses. Here, we found that E(2) treatment decreased cell proliferation and cell cycle-regulating factors such as cyclin A, cyclin D1 and cyclin E. At the same time, E(2) significantly inhibited cell migration and migration-related factors such as uPA, tPA, MMP-2, and MMP-9. However, E(2) treatment showed no effects on upregulating expression of plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinase-1, -2, -3, and -4 (TIMP-1, -2, -3, and -4). After administration of inhibitors including QNZ (NFκB inhibitor), LY294002 (Akt activation inhibitor), U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor) or SP600125 (JNK1/2 inhibitor), E(2) -downregulated cell migration and expression of MMP-2 and MMP-9 in LoVo cells is markedly inhibited only by p38 MAPK inhibitors, SB203580. Application of specific target gene siRNA (ERα, ERß, p38α, and p38ß) to LoVo cells further confirmed that p38 MAPK mediates E(2) /ERs inhibition of MMP-2 and -9 expression and cell motility in LoVo cells. Collectively, these results suggest that E(2) treatment down-regulates cell proliferation by modulating the expression of cyclin A, cyclin D1 and cyclin E. E(2) treatment simultaneously impaired cell migration by inhibiting the expression of uPA, tPA, MMP-2, and MMP-9 through E(2) /ERs - p38α MAPK signaling pathway in human LoVo colon cancer cells.

Topical application of marine briarane-type diterpenes effectively inhibits 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and dermatitis in murine skin.

BACKGROUND: Skin is the largest organ in the body, and is directly exposed to extrinsic assaults. As such, the skin plays a central role in host defense and the cutaneous immune system is able to elicit specific local inflammatory and systemic immune responses against harmful stimuli. 12-O-tetradecanoylphorbol-13-acetate (TPA) can stimulate acute and chronic inflammation and tumor promotion in skin. TPA-induced dermatitis is thus a useful in vivo pharmacological platform for drug discovery. In this study, the inhibitory effect of briarane-type diterpenes (BrDs) from marine coral Briareum excavatum on TPA-induced dermatitis and dendritic cell (DC) function was explored. METHODS: Evans blue dye exudation was used to determine vascular permeability. H&E-stained skin section was used to determine the formation of edema in mouse abdominal skin. We also used immunohistochemistry staining and western blot assays to evaluate the activation of specific inflammation makers and key mediators of signaling pathway in the mouse skin. Furthermore, mouse bone marrow DCs were used to determine the relationship between the chemical structure of BrDs and their regulation of DC function. RESULTS: BrD1 remarkably suppressed TPA-induced vascular permeability and edema in skin. At the biochemical level, BrD1 inhibited TPA-induced expression of cyclooxygenase-2, inducible nitric oxide synthase and matrix metalloproteinase-9, the key indicators of cutaneous inflammation. This inhibition was apparently mediated by interference with the Akt/NF-κB-mediated signaling network. BrD1 also inhibited TNF-α and IL-6 expression in LPS-stimulated BMDCs. The 8, 17-epoxide of BrDs played a crucial role in the inhibition of IL-6 expression, and replacement of the C-12 hydroxyl group with longer esters in BrDs gradually decreased this inhibitory activity. CONCLUSIONS: Our results suggest that BrDs warrant further investigation as natural immunomodulatory agents for control of inflammatory skin diseases.