Gliadin-reactive vitamin D-sensitive proinflammatory ILCPs are enriched in celiac patients.

Celiac disease (CD) is a multisystem disease in which different organs may be affected. We investigate whether circulating innate lymphoid cells (ILCs) contribute to the CD peripheral inflammatory status. We find that the CD cytokine profile is characterized by high concentrations of IL-12p40, IL-18, and IFN-γ, paralleled by an expansion of ILC precursors (ILCPs). In the presence of the gliadin peptides p31-43 and pα-9, ILCPs from CD patients increase transglutaminase 2 (TG2) expression, produce IL-18 and IFN-γ, and stimulate CD4+ T lymphocytes. IFN-γ is also produced upon stimulation with IL-12p40 and IL-18 and is inhibited by the addition of vitamin D. Low levels of blood vitamin D correlate with high IFN-γ and ILCP presence and mark the CD population mostly affected by extraintestinal symptoms. Dietary vitamin D supplementation appears to be an interesting therapeutic approach to dampen ILCP-mediated IFN-γ production.

Comparative efficacy and safety of biologic therapies for moderate-to-severe Crohn's disease: a systematic review and network meta-analysis.

BACKGROUND: Data are needed to inform the positioning of biologic therapy in the treatment of moderate-to-severe Crohn's disease, both first line and after previous biologic exposure. We aimed to assess the comparative efficacy and safety of biologics in patients with Crohn's disease. METHODS: We did a systematic review and network meta-analysis of phase 2 and phase 3 randomised controlled trials done in adults (≥18 years) with moderate-to-severe Crohn's disease (Crohn's Disease Activity Index [CDAI] 220-450) treated with tumour necrosis factor (TNF) antagonists, anti-integrin, anti-interleukin (IL)-12 and IL-23p40, or anti-IL23p19 agents, either alone or in combination with immunosuppressants, as their first-line biologic or after previous biologic exposure, compared with placebo or an active comparator. The minimum duration of therapy was 14 days for trials reporting induction of remission in active disease and 22 weeks in trials reporting maintenance of remission. We searched Medline, EMBASE, the Cochrane CENTRAL Register of Controlled Trials, conference proceedings, trial registries, and unpublished data from inception to June 3, 2021, without any language restrictions. Summary estimates of the primary and secondary outcomes were extracted from the published reports; individual patient-level data were not sought. The primary endpoint was induction of clinical remission in patients with active disease (CDAI <150) and maintenance of remission in patients with response to induction therapy, with data extracted from published reports. A network meta-analysis with multivariate consistency model random-effects meta-regression was done, with rankings based on surface under the cumulative ranking curve (SUCRA) values. FINDINGS: The search strategy yielded 18 382 citations, of which 31 trials were eligible for inclusion. On the basis of 15 randomised controlled trials including 2931 biologic-naive patients, infliximab monotherapy (odds ratio [OR] 4·53 [95% CI 1·49-13·79]), infliximab combined with azathioprine (7·49 [2·04-27·49]), adalimumab (3·01 [1·25-7·27]), and ustekinumab (2·63 [1·10-6·28]) were associated with significantly higher odds of inducing remission compared to certolizumab pegol (all moderate confidence); infliximab and azathioprine combination therapy was also associated with significantly higher odds of inducing remission than vedolizumab (3·76 [1·01-14·03]; low confidence). On the basis of ten randomised controlled trials including 2479 patients with previous biologic exposure, adalimumab after loss of response to infliximab (OR 2·82 [95% CI 1·20-6·62]; low confidence), and risankizumab (2·10 [1·12-3·92]; moderate confidence), were associated with higher odds of inducing remission than vedolizumab. No differences between active interventions were observed in maintenance trials. Most trials were at low or uncertain risk of bias. INTERPRETATION: Although biologic treatment choices in patients with moderate-to-severe Crohn's disease must be individualised for each patient, this analysis suggests that either infliximab with azathioprine or adalimumab might be preferred as a first-line therapy, and adalimumab (after infliximab loss of response) or risankizumab might be preferred as a second-line therapy, for induction of clinical remission. FUNDING: None.

Leishmanicidal potentials of Gossypium hirsutum extract and its fractions on Leishmania major in a murine model: parasite burden, gene expression, and histopathological profile.

Introduction. Leishmaniasis is a neglected tropical and subtropical disease caused by over 20 protozoan species.Hypothesis. Treatment of this complex disease with traditional synthetic drugs is a major challenge worldwide. Natural constituents are unique candidates for future therapeutic development.Aim. This study aimed to assess the in vivo anti-leishmanial effect of the Gossypium hirsutum extract, and its fractions compared to the standard drug (Glucantime, MA) in a murine model and explore the mechanism of action.Methodology. Footpads of BALB/c mice were infected with stationary phase promastigotes and treated topically and intraperitoneally with G. hirsutum extract, its fractions, or Glucantime, 4 weeks post-infection. The extract and fractions were prepared using the Soxhlet apparatus with chloroform followed by the column procedure.Results. The crude extract significantly decreased the footpad parasite load and lesion size compared to the untreated control group (P<0.05), as revealed by dilution assay, quantitative real-time PCR, and histopathological analyses. The primary mode of action involved an immunomodulatory role towards the Th1 response in the up-regulation of IFN-γ and IL-12 and the suppression of IL-10 gene expression profiling against cutaneous leishmaniasis caused by Leishmania major.Conclusion. This finding suggests that the extract possesses multiple combinatory effects of diverse bioactive phytochemical compositions that exert its mechanisms of action through agonistic-synergistic interactions. The topical extract formulation could be a suitable and unique candidate for future investigation and pharmacological development. Further studies are crucial to evaluate the therapeutic potentials of the extract alone and in combination with conventional drugs using clinical settings.

N6-methylated adenine on the target sites of mamA from Mycobacterium bovis BCG enhances macrophage activation by CpG DNA in mice.

CpG motifs in DNA sequences are recognized by Toll-like receptor 9 and activate immune cells. Bacterial genomic DNA (gDNA) has modified cytosine bases (5-methylcytosine [5 mC]) and modified adenine bases (6-methyladenine [6 mA]). 5 mC inhibits immune activation by CpG DNA; however, it is unclear whether 6 mA inhibits immune activation by CpG DNA. Mycobacterium bovis BCG (BCG) has three adenine methyltransferases (MTases) that act on specific target sequences. In this study, we examined whether the 6 mA at the target sites of adenine MTases affected the immunostimulatory activity of CpG DNA. Our results showed that only 6 mA located at the target sequence of mamA, an adenine MTase from BCG, enhanced interleukin (IL)-12p40 production from murine bone marrow-derived macrophages (BMDMs) stimulated with CpG DNA. Enhancement of IL-12p40 production in BMDMs was also observed when BMDMs were stimulated with CpG DNA ligated to oligodeoxynucleotides (ODNs) harboring 6 mA. Accordingly, we then evaluated whether gDNA from adenine MTase-deficient BCG was less efficient with regard to stimulation of BMDMs. Indeed, gDNA from a mamA-deficient BCG had less ability to activate BMDMs than that from wild-type BCG. We concluded from these results that adenine methylation on ODNs and bacterial gDNA may enhance immune activity induced by CpG DNA.

In-depth serum proteomics reveals biomarkers of psoriasis severity and response to traditional Chinese medicine.

Serum and plasma contain abundant biological information that reflect the body's physiological and pathological conditions and are therefore a valuable sample type for disease biomarkers. However, comprehensive profiling of the serological proteome is challenging due to the wide range of protein concentrations in serum. Methods: To address this challenge, we developed a novel in-depth serum proteomics platform capable of analyzing the serum proteome across ~10 orders or magnitude by combining data obtained from Data Independent Acquisition Mass Spectrometry (DIA-MS) and customizable antibody microarrays. Results: Using psoriasis as a proof-of-concept disease model, we screened 50 serum proteomes from healthy controls and psoriasis patients before and after treatment with traditional Chinese medicine (YinXieLing) on our in-depth serum proteomics platform. We identified 106 differentially-expressed proteins in psoriasis patients involved in psoriasis-relevant biological processes, such as blood coagulation, inflammation, apoptosis and angiogenesis signaling pathways. In addition, unbiased clustering and principle component analysis revealed 58 proteins discriminating healthy volunteers from psoriasis patients and 12 proteins distinguishing responders from non-responders to YinXieLing. To further demonstrate the clinical utility of our platform, we performed correlation analyses between serum proteomes and psoriasis activity and found a positive association between the psoriasis area and severity index (PASI) score with three serum proteins (PI3, CCL22, IL-12B). Conclusion: Taken together, these results demonstrate the clinical utility of our in-depth serum proteomics platform to identify specific diagnostic and predictive biomarkers of psoriasis and other immune-mediated diseases.

Case of pityriasis rubra pilaris progressed to generalized erythroderma following blockade of interleukin-17A, but improved after blockade of interleukin-12/23 p40.

We report herein a case of a 72-year-old man with pityriasis rubra pilaris (PRP) that was refractory to conventional therapies. His skin lesions progressed to generalized erythroderma despite anti-interleukin (IL)-17A antibody therapy. Topical corticosteroids, emollients, systemic retinoid, methotrexate, cyclosporin and phototherapy yielded no therapeutic response. However, blockade of IL-12/23 p40 dramatically improved his cutaneous lesions. Complete remission was achieved 4 weeks after the first injection of ustekinumab and maintained for more than 48 weeks. Our data indicate that IL-12 was associated with the onset of PRP in this patient, rather than IL-23. IL-12 is critical for the differentiation of T-helper (Th)1 cells. Thus, the Th1 pathway may be associated with the onset of PRP.

Mechanism of Lycium barbarum polysaccharides liposomes on activating murine dendritic cells.

Dendritic cells (DCs) are professional antigen-presenting cells (APC) that play a central role in the initiation and regulation of immune responses. We have previously demonstrated that Lycium barbarum polysaccharides liposomes (LBPL) as immune adjuvant elicits strong antigen-specific Th1 immune responses. The purpose of this study was to investigate underlying mechanism of liposomes promoting effect of Lycium barbarum polysaccharides (LBP) on activating DCs. LBP were loaded with high entrapment efficiency (86%) into liposomes using reverse phase evaporation. LBPL activation of phenotypic and functional maturation of DCs was explored through mechanistic studies of the TLR4-MyD88-NF-κB signaling pathway and amount of proinflammatory cytokines released. We found that LBPL indeed activated immature DCs and induced DCs maturation characterized by up-regulation of co-stimulatory molecules (MHCII, CD80, CD86), production of cytokines (IL-12p40, TNF-α), and enhancement of antigen uptake. Additionally, we demonstrated that liposomes could promote LBP up-regulation of TLR4, MyD88, TRAF6, NF-κB gene and protein expression.

Isolation and Identification of Benzochroman and Acylglycerols from Massa Medicata Fermentata and Their Inhibitory Effects on LPS-Stimulated Cytokine Production in Bone Marrow-Derived Dendritic Cells.

Massa Medicata Fermentata (MMF), known as Shenqu, is an important traditional Chinese medicine widely used to treat indigestion, vomiting, and diarrhea. In this study, a new benzochroman, 3(S)-3,4-dihydro-5,10-di-ß-d-glucopyranoside-2,2-dimethyl-2H-naphtho(2,3-b)pyran-3-ol (1), and five known galactosyl acylglycerols (2⁻6) were isolated from a methanol extract from MMF. In addition, their chemical structures were determined by chemical and spectroscopic methods, which were compared with the previously reported data. Furthermore, the effects of isolated compounds on lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells were investigated. Compounds 1⁻3 exhibited significant inhibitory effects on the LPS-induced production of IL-6 and IL-12 p40, with IC50 values ranging from 1.6 to 10.2 µM. Compounds 2 and 3 also exhibited strong inhibitory effects on the LPS-stimulated production of TNF-α with IC50 values of 12.0 and 11.2 µM, respectively. The results might provide a scientific basis for the development of the active components in MMF, as well as for novel anti-inflammatory agents.

Capparis spinosa Fruit Ethanol Extracts Exert Different Effects on the Maturation of Dendritic Cells.

Capparis spinosa L. (C. spinosa) has been used as food and traditional medicine and shows anti-inflammatory and anti-oxidant activities. Here, we prepared the C. spinosa fruit ethanol extracts (CSEs) using different procedures and investigated the effects of CSE on the maturation of mouse bone marrow-derived dendritic cells (DCs) in the absence or presence of lipopolysaccharide (LPS). DC maturation and cytokine production were detected by flow cytometry and ELISA, respectively. We obtained three different CSEs and dissolved in water or DMSO, named CSE2W, CSEMW, CSE3W, CSE2D, CSEMD, and CSE3D, respectively. These CSEs showed different effects on DC maturation. CSEMW and CSEMD significantly increased the expressions of CD40, CD80, and CD86, in a dose-dependent manner. CSE2W and CSE2D also showed a modest effect on DC maturation, which enhanced the expression of CD40. CSE3W and CSE3D did not change DC maturation but suppressed LPS-induced DC maturation characterized by the decreased levels of CD40 and CD80. CSE3W and CSE3D also significantly inhibited the secretions of IL-12p40, IL-6, IL-1ß, and TNF-α induced by LPS. CSE3W further increased the level of IL-10 induced by LPS. Moreover, CSE3D suppressed LPS-induced DC maturation in vivo, which decreased the expressions of CD40 and CD80. These results suggested that CSE3W and CSE3D might be used to treat inflammatory diseases.

Differential expression of the inflammation marker IL12p40 in the at-risk mental state for psychosis: a predictor of transition to psychotic disorder?

BACKGROUND: The identification of biomarkers of transition from the at-risk mental state (ARMS) to psychotic disorder is important because early treatment of psychosis is associated with improved outcome. Increasing evidence points to an inflammatory contribution to psychosis. We questioned whether raised levels of plasma inflammatory markers predict transition from ARMS to psychotic disorder and whether any such predictors could be reduced by omega-3 (ω-3) polyunsaturated fatty acids (PUFAs). METHODS: We measured the levels of 40 neuroinflammation biomarkers using a commercially available immunoassay kit. Firstly, we compared inflammatory markers in subjects in the ARMS who transitioned to psychotic disorder (n = 11) compared to subjects who did not (n = 28). Then we compared inflammatory markers in all subjects before and after ω-3 PUFA treatment (n = 40). RESULTS: Our data provides preliminary evidence that elevations in the baseline plasma levels of the inflammatory marker IL12/IL23p40 are associated with transition from ARMS to psychotic disorder. IL12/IL23p40 levels did not change following 12 weeks administration of ω-3 PUFAs. These findings provide evidence that elevated plasma IL12/IL23p40 is a potential biomarker of increased risk for transition to psychotic disorder. CONCLUSION: Further studies are required to confirm and extend this finding. Our results do not provide support for the possibility that administration of ω-3 PUFAs act to reduced transition to psychotic disorder by reducing blood levels of IL12/IL23p40. TRIAL REGISTRATION: ClinicalTrials.gov, a service of the U.S. National Institutes of Health, Identifier: NCT00396643 , last updated December 20, 2007. Retrospectively registered.

Potential of specialized pro-resolving lipid mediators against rheumatic diseases.

While arachidonic acid (AA), which is classified into n-6 polyunsaturated fatty acid (PUFA), has been mainly recognized as a substrate of pro-inflammatory mediators, eicosapentaenoic acid or docosahexaenoic acid, which are classified into n-3 PUFA, is currently identified as substrates of mediators inducing resolution of inflammation, namely pro-resolving mediators (SPM). As with any other pathological conditions, it is gradually elucidated that SPMs contributes a certain effect on joint inflammation. In osteoarthritis (OA), Lipid fractions extracted from adipocytes, especially in infrapatellar fat pad rather than subcutaneous tissue induce T cell skewing for producing IFN-γ or decrease the production of IL-12p40 from macrophages. In synovial tissues form OA, there are some of known receptors for SPM. In the synovial fluid from rheumatoid arthritis (RA), it could be identified and quantified a certain kind of SPMs such as maresin 1, lipoxin A4 and resolvin D5. In murine models of arthritis, some of SPMs are found to have some functions to reduce tissue damage. Correctively, SPMs might have some potential to a novel therapeutic target for arthritis or any other rheumatic diseases.

A polysaccharide fraction from Achillea millefolium increases cytokine secretion and reduces activation of Akt, ERK and NF-κB in THP-1 monocytes.

Achillea millefolium has been used in traditional medicine for a number of ailments, including skin inflammation and wounds. A polysaccharide fraction (Am-25-d) isolated from aqueous extract from A. millefolium had an average molecular weight of 270 kDa and a monosaccharide composition of GalA, Gal, Ara, Xyl, Rha in molar ratio of 28:26:23:9:7. THP-1 cells primed with IFN-γ and stimulated with LPS in the presence of Am-25-d secreted more IL-1ß, IL-8, IL-10, IL-12p40, IL-23 and TNF-α than THP-1 cells stimulated in the absence of Am-25-d. However, when added to unstimulated cells Am-25-d did not increase secretion of the cytokines examined. Stimulating THP-1 monocytes in the presence of Am-25-d led to decreased nuclear concentrations of NF-κB and phosphorylation of ERK1/2 and Akt kinases compared with that when the cells were stimulated without Am-25-d. These findings indicate that Am-25-d isolated from A. millefolium has immunoenhancing properties that may be mediated via the Akt pathway.

Effects of Caffeine Supplementation on Plasma and Blood Mononuclear Cell Interleukin-10 Levels After Exercise.

This study compared the response of interleukin (IL)-10, and also of IL-6 and IL-12 p40, to exercise and caffeine supplementation between plasma and blood mononuclear cells (BMNCs). Participants in the study (n = 28) were randomly allocated in a double-blind fashion to either caffeine (n = 14) or placebo (n = 14) treatments. One hour before completing a 15-km run competition, athletes took 6 mg/kg body mass of caffeine or a placebo. Plasma and BMNCs were purified from blood samples taken before and after competition. Concentrations of interleukins (IL-10, IL-6, and IL-12 p40), cyclic adenosine monophosphate (cAMP), caffeine, adrenaline, and cortisol were measured in plasma. IL-10, IL-6, and IL-12 p40 and cAMP levels were also determined in BMNCs. Exercise induced significant increases in IL-6 and IL-10 plasma levels, with higher increases in the caffeine-supplemented group. After 2-hr recovery, these levels returned to almost preexercise values. However, no effect of caffeine on BMNC cytokines was observed. IL-10, IL-6, and IL-12 p40 levels in BMNCs increased mainly at 2 hr postexercise. cAMP levels increased postexercise in plasma and after recovery in BMNCs, but no effects of caffeine were observed. In conclusion, caffeine did not modify cytokine levels in BMNCs in response to exercise. However, higher increases of IL-10 were observed in plasma after exercise in the supplemented participants, which could suppose an enhancement of the anti-inflammatory properties of exercise.

IL-12p40 Homodimer Ameliorates Experimental Autoimmune Arthritis.

IL-23 is the key cytokine that induces the expansion of Th17 cells. It is composed of p19 and p40 subunits of IL-12. The p40 subunit binds competitively to the receptor of IL-23 and blocks its activity. Our aim was to assess the preventive and therapeutic effect of the IL-12p40 homodimer (p40)2 subunit in autoimmune arthritis animal models. In the current study, using IL-1R antagonist-knockout mice and a collagen-induced arthritis model, we investigated the suppressive effect of (p40)2 on inflammatory arthritis. We demonstrated that the recombinant adenovirus-expressing mouse (p40)2 model prevented the development of arthritis when given before the onset of arthritis. It also decreased the arthritis index and joint erosions in the mouse model if transferred after arthritis was established. (p40)2 inhibited the production of inflammatory cytokines and Ag-specific T cell proliferation. It also induced CD4(+)CD25(+)Foxp3 regulatory T (Treg) cells in vitro and in vivo, whereas the generation of retinoic acid receptor-related organ receptor γt and Th17 cells was suppressed. The induction of Treg cells and the suppression of Th17 cells were mediated via activated STAT5 and suppressed STAT3. Our data suggest that (p40)2 suppressed inflammatory arthritis successfully. This could be a useful therapeutic approach in autoimmune arthritis to regulate the Th17/Treg balance and IL-23 signaling.

Biological therapy induces expression changes in Notch pathway in psoriasis.

Psoriasis is a chronic inflammatory skin disease, characterized by hyperproliferation of keratinocytes and by skin infiltration of activated T cells. To date, the pathophysiology of psoriasis has not yet been fully elucidated. The Notch pathway plays a determinant role in cell fate determination, proliferation, differentiation, immune cell development and function. Many biological agents, used in the treatment of psoriasis, include TFN-α inhibitors, such as etanercept, adalimumab, and anti IL-12/IL-23 p40 antibody, such as ustekinumab. This study aimed to determine mRNA expression levels by real-time RT-PCR, and protein expression levels, analysed by Western blot and immunohistochemistry, of some components of the Notch pathway, such as NOTCH1, NOTCH2, JAGGED1, and HES1 after biological treatments in psoriatic patients. mRNA and protein levels of NOTCH1, NOTCH2, JAGGED1 and HES1 were upregulated in skin samples from untreated psoriatic patients compared with normal controls. Biological therapy showed to downregulate differently the protein expression levels of the molecules under study. Our study suggests that Notch pathway components might be a potential therapeutic target against psoriasis.

Role of IL-23 in the pathogenesis of psoriasis: a novel potential therapeutic target?

INTRODUCTION: Psoriasis is a chronic inflammatory skin disorder determined by the activation of several immune cells and resident tissue cells. Various cytokines mediate inflammatory signals, including IL-23, which is an important factor involved in the differentiation of T helper (Th17) cells. AREAS COVERED: Increasing evidence suggests that IL-23 is a central cytokine to the pathogenesis of psoriasis. An overview on both experimental and human data will be reported in order to support the hypothesis of a key pathogenic role of IL-23/Th17 axis. EXPERT OPINION: Targeting IL-23 might be a more selective, valid and effective therapeutic approach, which, potentially, may show important advantages in terms of long-term efficacy and safety in the treatment of psoriasis.

Genetic susceptibility to increased bacterial translocation influences the response to biological therapy in patients with Crohn's disease.

OBJECTIVE: The aetiology of Crohn's disease (CD) has been related to nucleotide-binding oligomerisation domain containing 2 (NOD2) and ATG16L1 gene variants. The observation of bacterial DNA translocation in patients with CD led us to hypothesise that this process may be facilitated in patients with NOD2/ATG16L1-variant genotypes, affecting the efficacy of anti-tumour necrosis factor (TNF) therapies. DESIGN: 179 patients with Crohn's disease were included. CD-related NOD2 and ATG16L1 variants were genotyped. Phagocytic and bactericidal activities were evaluated in blood neutrophils. Bacterial DNA, TNFα, IFNγ, IL-12p40, free serum infliximab/adalimumab levels and antidrug antibodies were measured. RESULTS: Bacterial DNA was found in 44% of patients with active disease versus 23% of patients with remitting disease (p=0.01). A NOD2-variant or ATG16L1-variant genotype was associated with bacterial DNA presence (OR 4.8; 95% CI 1.1 to 13.2; p=0.001; and OR 2.4; 95% CI 1.4 to 4.7; p=0.01, respectively). This OR was 12.6 (95% CI 4.2 to 37.8; p=0.001) for patients with a double-variant genotype. Bacterial DNA was associated with disease activity (OR 2.6; 95% CI 1.3 to 5.4; p=0.005). Single and double-gene variants were not associated with disease activity (p=0.19). Patients with a NOD2-variant genotype showed decreased phagocytic and bactericidal activities in blood neutrophils, increased TNFα levels in response to bacterial DNA and decreased trough levels of free anti-TNFα. The proportion of patients on an intensified biological therapy was significantly higher in the NOD2-variant groups. CONCLUSIONS: Our results characterise a subgroup of patients with CD who may require a more aggressive therapy to reduce the extent of inflammation and the risk of relapse.

Dietary cocoa ameliorates obesity-related inflammation in high fat-fed mice.

PURPOSE: To investigate the effect of cocoa powder supplementation on obesity-related inflammation in high fat (HF)-fed obese mice. METHODS: Male C57BL/6J (n = 126) were fed with either low-fat (LF, 10 % kcal from fat) or HF (60 % kcal from fat) diet for 18 weeks. After 8 weeks, mice from HF group were randomized to HF diet or HF diet supplemented with 8 % cocoa powder (HF-HFC group) for 10 weeks. Blood and tissue samples were collected for biochemical analyses. RESULTS: Cocoa powder supplementation significantly reduced the rate of body weight gain (15.8 %) and increased fecal lipid content (55.2 %) compared to HF-fed control mice. Further, cocoa supplementation attenuated insulin resistance, as indicated by improved HOMA-IR, and reduced the severity of obesity-related fatty liver disease (decreased plasma alanine aminotransferase and liver triglyceride) compared to HF group. Cocoa supplementation also significantly decreased plasma levels of the pro-inflammatory mediators interleukin-6 (IL-6, 30.4 %), monocyte chemoattractant protein-1 (MCP-1, 25.2 %), and increased adiponectin (33.7 %) compared to HF-fed mice. Expression of pro-inflammatory genes (Il6, Il12b, Nos2, and Emr1) in the stromal vascular fraction (SVF) of the epididymal white adipose tissue (WAT) was significantly reduced (37-56 %) in the cocoa-supplemented mice. CONCLUSIONS: Dietary supplementation with cocoa ameliorates obesity-related inflammation, insulin resistance, and fatty liver disease in HF-fed obese mice, principally through the down-regulation of pro-inflammatory gene expression in WAT. These effects appear to be mediated in part by a modulation of dietary fat absorption and inhibition of macrophage infiltration in WAT.

Lycium barbarum polysaccharides induce Toll-like receptor 2- and 4-mediated phenotypic and functional maturation of murine dendritic cells via activation of NF-κB.

Dendritic cells (DCs) are potent antigen­presenting cells that play pivotal roles in the initiation of primary immune responses. Lycium barbarum polysaccharides (LBPs) are known to have a variety of immunomodulatory functions. However, the cellular and molecular mechanisms underlying their therapeutic effects are poorly understood. In this study, we report that LBPs induce phenotypic and functional maturation of DCs. LBPs upregulated DC expression of I­A/I­E and CD11c, enhanced DC allostimulatory activity and induced IL­12p40 production. Furthermore, the activity of LBPs on DCs was significantly reduced by treating the cells with anti­TLR2 or anti­TLR4 antibody prior to LBPs, indicating that both are possible receptors of LBPs. Maturation of DCs by LBPs was able to directly activate the nuclear transcription factor NF­κB p65. The results revealed that LBP stimulation induces the phenotypic and functional maturation of DCs via TLR2- and/or TLR4-mediated NF­κB signaling pathways.

Antiangiogenic therapy promoted metastasis of hepatocellular carcinoma by suppressing host-derived interleukin-12b in mouse models.

Antiangiogenic therapy, specially sorafenib, has become the standard of care for patients with advanced hepatocellular carcinoma (HCC), however, the improvement in survival time is not satisfactory. Previous studies have found that, in some circumstances, antiangiogenic therapy promoted tumor metastasis and the mechanistic studies were mainly focus on cancer-cell-autonomous manners. In two experimental metastasis models with tail-vein injection with hepatoma cells and an orthotopic HCC mouse model, we found that pretreatment with two vascular endothelial growth factor receptor (VEGFR) inhibitors, sunitinib and sorafenib, facilitated tumor cell survival in blood stream and promoted lung metastasis from tumors that were subsequently incubated after drug discontinuation, indicating that host response joined into the pro-metastatic effects. An antibody microarray identified that interleukin (IL)-12b was decreased in the peripheral blood of the mice treated with the two VEGFR inhibitors. IL-12b suppression in macrophages and dendritic cells from host organs was found to play a crucial role in treatment-induced metastasis. Supplement with recombinant mouse IL-12b or restoration of IL-12b expression in the host by zoledronic acid, which was previously reported to enhance IL-12 expression in vitro and in vivo, alleviated the metastasis-promoting effects of sunitinib and sorafenib. These studies suggest that host response to VEGFR inhibitors facilitates HCC metastasis and restoration of IL-12b expression could translate into clinical benefits.