bluuebunny/crossref_metadata_2025_split huggingface dataset:
FcγR cross-linking mediates NF-κB activation, reduced antigen presentation capacity, and decreased IL-12 production in monocytes without modulation of myeloid dendritic cell development
Authors: Drechsler Yvonne , Chavan Sangeeta , Catalano Donna , Mandrekar Pranoti , Szabo Gyongyi 
Published: September 2022

AbstractStimulation of monocytes (MO) through receptors for the Fc region of immunoglobulin G (FcγR) activates a variety of responses, including phagocytosis, antibody (Ab)-dependent cellular cytotoxicity, and production of cytokines. We previously reported that the MO subpopulation that expresses FcγR in high density produces high levels of tumor necrosis factor α (TNF-α) compared with FcγR-negative MO. Here, we show that cross-linking MO via FcγRI or FcγRII but not via FcγRIII activates nuclear regulatory factor-κB (NF-κB), a transcription factor involved in regulation of TNF-α. NF-κB activation peaked at 2.75 h after FcγRI cross-linking, involved p65 and p50 (heterodimer) and not c-rel-containing NF-κB complexes, and was mediated via IκB degradation. Cross-linking FcγRI, -II, as well as -III inhibited interleukin (IL)-12 (p70) production in MO, whether stimulated with Staphylococcal enterotoxin B (P&lt;0.02) or lipopolysaccharide (P&lt;0.02). Inhibition of IL-12 by FcγR cross-linking was not mediated by TNF-α, as the presence of an anti-TNF-α Ab could not restore the reduced IL-12 production. Decreased IL-12 production correlated with reduced antigen presentation capacity (P&lt;0.01) in the FcγR-cross-linked MO. Blood MO can give rise to myeloid dendritic cells (DC). FcγR cross-linking did not modulate in vitro maturation of MO to fully functional myeloid DC. Allostimulatory capacity in mixed leukocyte reaction and DC marker expression (CDla, CD80, CD86) was not different between control and FcγRI cross-linked DC. These results suggest that signals mediated via FcγRI, -II, and -III have overlapping yet distinct effects on MO, which are likely to be involved in the fine-tuning of the immune responses to various stimuli.
Alternative activation and increase ofTrypanosoma cruzisurvival in murine macrophages stimulated by cruzipain, a parasite antigen
Authors: Stempin Cinthia , Giordanengo Laura , Gea Susana , Cerbán Fabio 
Published: September 2022

AbstractWe studied the macrophage (Mo) activation pathways through Mo interaction with immunogenic Trypanosoma cruzi antigens as cruzipain (Cz) and R13. J774 cells, peritoneal and spleen Mo from normal mice, were used. Although Mo classic activation was observed in the presence of lipopolysaccharide, evaluated through nitric oxide (NO) and interleukin (IL)-12 production, Cz and R13 did not activate Mo in this way. To study the alternative pathway, we examined the arginase activity in Mo cultured with Cz. An increase of arginase activity was detected in all Mo sources assayed. An increase of IL-10 and transforming growth factor-β in culture supernatants from Mo stimulated with Cz was observed. The study of expression of B7.1 and B7.2 in spleen Mo revealed that Cz induces preferential expression of B7.2. In vitro studies revealed that Cz stimulated J774 cells and then, infected with trypomastigotes of T. cruzi, developed a higher number of intracellular parasites than unstimulated infected Mo. Thus, Cz favors the perpetuation of T. cruzi infection. In addition, a down-regulation of inducible NO synthase was observed in J774 cells stimulated with Cz. These results suggest that Cz interaction with Mo could modulate the immune response generated against T. cruzi through the induction of a preferential metabolic pathway in Mo.
Salmonellavirulence factor SipB induces activation and release of IL-18 in human dendritic cells
Authors: Dreher Donatus , Kok Menno , Obregon Carolina , Kiama Stephen G , Gehr Peter , Nicod Laurent P 
Published: September 2022

AbstractInterleukin-18 (IL-18) plays an important role in innate and acquired immunity, in particular against intracellular pathogens. However, little is known about the microbial factors that trigger IL-18 secretion by dendritic cells (DCs). To determine the influence of bacterial virulence factors on the activation and release of IL-18, we infected human monocyte-derived DCs with virulence mutants of the facultative intracellular pathogen Salmonella typhimurium. Our results show that infection by S. typhimurium causes caspase-1-dependent activation of IL-18 and triggers the release of IL-18 in human DCs. The secretion of IL-18 by the DCs was closely correlated with the ability of the S. typhimurium strains to induce apoptosis. We demonstrate that activation and release of IL-18 are blocked by mutations in the Salmonella sipB gene, which encodes a virulence factor that activates caspase-1 to induce apoptosis. These findings indicate that the activation and release of IL-18 induced by bacterial virulence factors may represent one component of innate immunity against the intracellular bacteria.
Nitric oxide participates in the intestinal pathology associated with murine syngeneic graft-versus-host disease
Authors: Flanagan D M , Jennings C D , Goes S W , Caywood B E , Gross R , Kaplan A M , Bryson J S 
Published: September 2022

AbstractSyngeneic graft-versus-host disease (SGVHD) develops following lethal irradiation, reconstitution with syngeneic bone marrow, and treatment with a short course of cyclosporin A (CsA) therapy. The disease is characterized by the development of a T helper cell type 1-like cytokine response [interleukin (IL)-12, interferon-γ (IFN-γ), and tumor necrosis factor α], and macrophage activation is central to development of the syndrome. It has been shown that nitric oxide (NO) participates significantly in the development of allogeneic GVHD. Studies were initiated to determine if NO participates in the pathology associated with SGVHD. Significant increases in inducible NO synthase (iNOS) mRNA and circulating NO were found in the tissues of SGVHD versus control animals. Treatment of SGVHD animals with the iNOS inhibitor aminoguanidine (AG) reversed the pathology associated with this disease. Furthermore, AG treatment reduced the production of IL-12 and IFN-γ mRNA in the colons of CsA-treated mice. These studies demonstrate that NO participates in the pathological processes that are associated with the development of murine SGVHD.
CpG-DNA-induced IFN-α production involves p38 MAPK-dependent STAT1 phosphorylation in human plasmacytoid dendritic cell precursors
Authors: Takauji Rumiko , Iho Sumiko , Takatsuka Hisakazu , Yamamoto Saburo , Takahashi Takayuki , Kitagawa Harukazu , Iwasaki Hiromichi , Iida Reiko , Yokochi Takashi , Matsuki Takasumi 
Published: September 2022

AbstractHuman plasmacytoid or CD4+CD11c− type 2 dendritic cell precursors (PDC) were identified as natural type I interferon (IFN)-producing cells in response to viral and bacterial infection. They represent effector cells of innate immunity and link it to the distinct adaptive immunity by differentiating into mature DC. It has been reported that oligodeoxyribonucleotides containing unmethylated CpG motifs (CpG DNA) stimulate PDC to produce IFN-α, but the molecular mechanisms involved remain unknown. We found that CpG-DNA-induced IFN-α production in PDC was completely impaired by the inhibitor of the p38 mitogen-activated protein kinase (MAPK) pathway. Expression of IFN regulatory factor (IRF)-7 was enhanced by CpG-DNA treatment, which was preceded by the phosphorylation of signal transducer and activator of transcription (STAT)1 on Tyr-701, as well as its enhanced phosphorylation on Ser-727. All of these events were also suppressed by the p38 MAPK inhibitor. STAT1, STAT2, and IRF-9, components of IFN-stimulated gene factor 3 (ISGF3), were recognized in the nuclear fraction of CpG-DNA-treated cells. Neither anti-IFN-α/β antibodies (Ab) nor anti-IFNAR Ab suppressed STAT1 phosphorylation, enhancement of IRF-7 expression, or IFN-α production in the early phase of the culture. These results suggest that CpG DNA induces p38 MAPK-dependent phosphorylation of STAT1 in a manner independent of IFN-α/β, which may cause ISGF3 formation to increase the transcription of the IRF-7 gene, thereby leading to IFN-α production in human PDC.
The A2A receptor mediates an endogenous regulatory pathway of cytokine expression in THP-1 cells
Authors: Bshesh Khaled , Zhao Bin , Spight Donn , Biaggioni Italo , Feokistov Igor , Denenberg Alvin , Wong Hector R , Shanley Thomas P 
Published: September 2022

AbstractAdenosine is an endogenous nucleoside that regulates numerous cellular functions including inflammation. Adenosine acts via cell-surface receptors subtyped as A1, A2A, A2B, and A3. The A2A receptor (A2AR) has been linked to anti-inflammatory effects of adenosine. Furthermore, microarray analysis revealed increased A2AR mRNA in lipopolysaccharide (LPS)-stimulated monocytes. We hypothesized that endogenous adenosine inhibited LPS-mediated tumor necrosis factor (TNF) production via A2AR stimulation. Using THP-1 cells, our results demonstrated that LPS increased expression of cellular A2AR and adenosine. A2AR agonism with 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamido adenosine (CGS 21680) after LPS decreased TNF production in a dose- and time-dependent manner, whereas A2AR antagonism significantly increased TNF and blocked the inhibitory effect of CGS 21680. This inhibitory pathway involved A2AR stimulation of cyclic adenosine monophosphate (cAMP) to activate protein kinase A, resulting in phosphorylation of cAMP response element-binding protein (CREB). Phospho-CREB had been shown to inhibit nuclear factor-κB transcriptional activity, as was observed with CGS 21680 treatment. Thus, following immune activation with LPS, endogenous adenosine mediates a negative feedback pathway to modulate cytokine expression in THP-1 cells.
IL-5-induced integrin adhesion of human eosinophils caused by ERK1/2-mediated activation of cPLA2
Authors: Zhu Xiangdong , Jacobs Benjamin , Boetticher Evan , Myou Shigeharu , Meliton Angelo , Sano Hiroyuki , Lambertino Anissa T , Muñoz Nilda M , Leff Alan R 
Published: September 2022

AbstractWe examined the mechanism by which interleukin (IL)-5 causes β2-integrin adhesion of human eosinophils. IL-5 caused time-dependent activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38α in eosinophils as detected by their phosphorylation. Preincubation of eosinophils with U0126, a mitogen-activated protein kinase/ERK kinase inhibitor, suppressed IL-5-induced activation of cytosolic phospholipase A2 (cPLA2) and eosinophil adhesion, and p38 inhibition by SB203580 had neither effect. ERK1/2 phosphorylation and eosinophil adhesion were blocked by inhibition of the src-family tyrosine kinase, Janus tyrosine kinase (JAK)2, or phosphoinositide-3 kinase (PI3K). Coimmunoprecipitation assay demonstrated that Lyn, a src-family tyrosine kinase, was constitutively associated with PI3K. Inhibition of src-tyrosine kinase but not JAK2 suppressed PI3K activation. Our data suggest that IL-5 induces β2-integrin adhesion of human eosinophils by regulation of cPLA2 activation caused by ERK1/2 phosphorylation. This phosphorylation results from activation of PI3K and protein tyrosine kinases. We also find that src-family tyrosine kinase, possibly Lyn, is the upstream kinase causing PI3K activation.
Monocytes are progressively activated in the circulation of pregnant women
Authors: Luppi Patrizia , Haluszczak Catherine , Betters Dawn , Richard Craig A H , Trucco Massimo , DeLoia Julie A 
Published: September 2022

AbstractPregnancy is characterized by the presence of generalized leukocyte activation. We used flow cytometry to investigate changes in phenotype and intracellular cytokines of circulating granulocytes, monocytes, and T lymphocytes of pregnant women during gestation. We report that peripheral circulation of pregnancy is characterized by an increased percentage of granulocytes and a decrease in lymphocytes. The proportion of monocytes remains stable throughout gestation; however, a progressive up-regulation of surface markers CD11a, CD54, and CD64 was detected. Monocytes also showed higher production of interleukin (IL)-12 and IL-1β compared with the nonpregnant state, and granulocytes had greater potential to synthesize IL-8. All these changes were particularly marked in late gestation. T lymphocytes did not have any characteristics of the activated state and showed a decreased IL-6 production. These findings demonstrate that activation of maternal monocytes and granulocytes increases during pregnancy and support the idea that pregnancy results in an elevation of the innate immune system and suppression of the adaptive immune system.
Differential regulation of dendritic cell function by the immunomodulatory drug thalidomide
Authors: Mohty Mohamad , Stoppa Anne-Marie , Blaise Didier , Isnardon Daniel , Gastaut Jean-Albert , Olive Daniel , Gaugler Béatrice 
Published: September 2022

AbstractThalidomide (Thal) was shown to be a potent immunomodulating agent. Because of their central role in controlling immunity, we investigated the effects of Thal on monocyte-derived dendritic cells (Mo-DC). The addition of 10 μg/ml or 20 μg/ml Thal from the beginning of monocyte culture with granulocyte macrophage-colony stimulating factor and interleukin (IL)-4 did not block Mo-DC differentiation. Moreover, Thal alone could not induce Mo-DC maturation. However, Thal exerted a modulation of Mo-DC functional properties. At 10 μg/ml, Thal modified the allostimulatory capacity of DC little, whereas a dose of 20 μg/ml up-regulated this capacity (P=.05) and increased IL-12p70 production in a dose-dependent manner between 10 and 20 μg/ml (P=.001). Mo-DC generated with 10 μg/ml Thal were poor stimulators of T helper cell type 1 (Th1) responses (P=.01), but 20 μg/ml was able to strengthen Th1 responses (P=.03). Also, Thal induced a significant reduction of IL-10 production in response to the maturation-inducing stimulus CD40L. Similarly, tumor necrosis factor α production was significantly decreased when Mo-DC were exposed to 10 μg/ml Thal, and a dose of 20 μg/ml did not induce any significant changes. The effects of Thal in vitro on the secretion of IL-12p70 and strengthening of Th1 responses might contribute to the antitumor effects of Thal. Thus, DC appear to be potential targets for the immunomodulatory capacity of Thal, defining a new mechanism of action of this drug.
TNF-related apoptosis-inducing ligand (TRAIL) up-regulates cyclooxygenase (COX)-1 activity and PGE2 production in cells of the myeloid lineage
Authors: Secchiero Paola , Gonelli Arianna , Ciabattoni Giovanni , Melloni Elisabetta , Grill Vittorio , Rocca Bianca , Delbello Giorgio , Zauli Giorgio 
Published: September 2022

AbstractTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) up-regulated the expression of constitutive cyclooxygenase (COX)-1 protein in HL-60 cells without affecting COX-2. The TRAIL-mediated COX-1 up-regulation was accompanied by a significant increase of the PGE2 synthesis and release, which was suppressed by the COX-1 inhibitor valeryl salicylate but not by the COX-2 inhibitor NS-398. Experiments carried out by adding exogenous PGE2 to HL-60 cells indicated that PGE2 was not involved in TRAIL cytotoxicity and rather showed a dose-dependent protection against TRAIL-induced apoptosis. Importantly, the ability of TRAIL to increase PGE2 production was also observed in normal, human CD34-derived myeloid cells and in freshly isolated peripheral blood CD14+ monocytes. Moreover, in contrast to HL-60 cells, primary, normal cells were not susceptible to TRAIL cytotoxicity. These data indicate that the ability of TRAIL to up-regulate eicosanoid production and release is not confined to malignant leukemic cells, but it may also play a role in normal hematopoiesis.
The immune system and prion diseases: a relationship of complicity and blindness
Authors: Aucouturier Pierre , Carnaud Claude 
Published: September 2022

AbstractIn most documented infectious forms of transmissible spongiform encephalopathies, prions must transit through the lymphoreticular compartment before invading the central nervous system. A major goal has been to identify the cell susbsets that support replication and propagation of prions from sites of penetration to sites of neuroinvasion. The conclusions, still fragmentary and confusing, point at a few candidates: follicular dendritic cells (FDCs) and more recently, dendritic cells (DCs). It is clear, however, that lymphoinvasion does not depend on a single-cell type but needs a coordinated network of cells. Discrepancies between models suggest that the actors may vary according to prion strains. A second center of interest has emerged following reports that anti-prion protein (PrP) antibodies blocked in vitro cell conversion of normal PrP into pathological PrP and cured infected cell lines. As isoform conversion is a critical event in prion propagation and formation of lesions, the identification of immune agents capable of inhibiting the reaction is of major importance. In vivo experiments suggest that antibodies produced in transgenic mice or an ongoing immune reaction induced by peptides can prevent PrP conversion and retard disease progression. These results do not say whether clinical disease can be durably delayed and if immunological tolerance to PrP can be easily broken in infected individuals. Altogether, these results suggest that the unconventional relationship between prions and the immune system is on the eve of new and fascinating developments. Whether they will provide innovative strategies for early diagnosis and preventive treatments is still an open question.
Identification and characterization of a novel mouse gene encoding a Ras-associated guanine nucleotide exchange factor: expression in macrophages and myocarditis elicited byTrypanosoma cruziparasites
Authors: Ferreira Ludmila R P , Abrantes Eduardo F , Rodrigues Cibele V , Caetano Braulia , Cerqueira Gustavo C , Salim Anna Christina , Reis Luiz F L , Gazzinelli Ricardo T 
Published: September 2022

AbstractThe ability of Trypanosoma cruzi to activate macrophages is, at least in part, attributed to the glycosylphosphatidylinositol-anchored mucin-like glycoproteins (GPI-mucins) expressed in the surface of the trypomastigote stage of the parasite. The differential display reverse transcriptase-polymerase chain reaction and the reverse Northern blot were used to study modulation of gene expression in murine macrophages exposed to GPI-mucins and in cardiac tissues from mice infected with T. cruzi. Among several cDNAs that were more abundant in lanes corresponding to macrophages stimulated with GPI-mucins as compared with resting cells, we confirmed the differential expression of A1, interleukin-18, and GPIγ4. Some of these genes were also shown to have enhanced expression in the cardiac tissue (DAP-12, A1, and GPIγ4) from infected animals. The expression of GPIγ4 was also enhanced in human monocytes stimulated with GPI-mucins or bacterial lipopolysaccharides. The complete sequence of the GPIγ4 transcript and its gene including the 5′ upstream region was defined. GPIγ4 was encoded by a novel, single copy gene present in mouse as well as human genomes and showed conserved homology to different members of the guanine nucleotide exchange factor family.
Circulating Tumor DNA After Neoadjuvant Chemotherapy in Breast Cancer Is Associated With Disease Relapse
Authors: Cailleux Frédéric , Agostinetto Elisa , Lambertini Matteo , Rothé Françoise , Wu Hsin-Ta , Balcioglu Mustafa , Kalashnikova Ekaterina , Vincent Delphine , Viglietti Giulia , Gombos Andrea , Papagiannis Andreas , Veys Isabelle , Awada Ahmad , Sethi Himanshu , Aleshin Alexey , Larsimont Denis , Sotiriou Christos , Venet David , Ignatiadis Michail 
Published: September 2022

PURPOSE Detection of circulating tumor DNA (ctDNA) after neoadjuvant chemotherapy in patients with early-stage breast cancer may allow for early detection of relapse. In this study, we analyzed ctDNA using a personalized, tumor-informed multiplex polymerase chain reaction–based next-generation sequencing assay. METHODS Plasma samples (n = 157) from 44 patients were collected before neoadjuvant therapy (baseline), after neoadjuvant therapy and before surgery (presurgery), and serially postsurgery including a last follow-up sample. The primary end point was event-free survival (EFS) analyzed using Cox regression models. RESULTS Thirty-eight (86%), 41 (93%), and 38 (86%) patients had baseline, presurgical, and last follow-up samples, respectively. Twenty patients had hormone receptor–positive/human epidermal growth factor receptor 2–negative, 13 had triple-negative breast cancer, and 11 had human epidermal growth factor receptor 2–positive disease. Baseline ctDNA detection was observed in 22/38 (58%) patients and was significantly associated with Ki67 > 20% ( P = .036) and MYC copy-number gain ( P = .0025, false discovery rate = 0.036). ctDNA detection at presurgery and at last follow-up was observed in 2/41 (5%) and 2/38 (5%) patients, respectively. Eight relapses (seven distant and one local) were noted (median follow-up 3.03 years [range, 0.39-5.85 years]). After adjusting for pathologic complete response (pCR), ctDNA detection at presurgery and at last follow-up was associated with shorter EFS (hazard ratio [HR], 53; 95% CI, 4.5 to 624; P < .01, and HR, 31; 95% CI, 2.7 to 352; P < .01, respectively). Association between baseline detection and EFS was not observed (HR, 1.4; 95% CI, 0.3 to 5.9; P = .67). CONCLUSION The presence of ctDNA after neoadjuvant chemotherapy is associated with relapse in early-stage breast cancer, supporting interventional trials for testing the clinical utility of ctDNA monitoring in this setting.
Antidiabetogenic action of Morus rubra L. leaf extract in streptozotocin-induced diabetic rats
Authors: Sharma Suman Bala , Gupta Shipra , Ac Rini , Singh Usha Rani , Rajpoot Reenu , Shukla Santosh Kumar 
Published: September 2022

Abstract

Objectives
Researchers all over the world are exploring herbal supplements to control diabetes and its complications. This study evaluated the antidiabetic action of Morus rubra L. aqueous leaf extract through its effect on hyperglycaemia, dyslipidaemia and oxidative stress in streptozotocin-induced diabetic rats.

Methods
The extract was orally administered to diabetic rats (100, 200 and 400 mg/kg body weight) daily for 21 days. Fasting blood glucose was measured on days 0, 7, 14 and 21. At the end of the experiment, blood samples were drawn to measure glucose tolerance, glycosylated haemoglobin, insulin, C-peptide and lipid parameters. Antioxidant enzymes (superoxide dismutase and catalase), reduced glutathione and lipid peroxides were determined in blood and liver tissue. Histopathological examination of pancreatic tissue was also performed.

Key findings
The extract showed a dose-dependent fall in fasting blood glucose. Treatment with 400 mg/kg extract produced a significant reduction in glycosylated haemoglobin with a concomitant elevation in plasma insulin and C-peptide levels. The altered serum lipids in diabetic rats were significantly restored following treatment with the extract. In erythrocytes, as well as liver, the activity of antioxidant enzymes and content of reduced glutathione were found to be significantly enhanced, while levels of serum and hepatic lipid peroxides were suppressed in extract-fed diabetic rats. Histopathological examination of pancreatic tissue revealed an increased number of islets and β-cells in extract-treated diabetic rats.

Conclusions
M. rubra aqueous leaf extract leads to control over hyperglycaemia and dyslipidaemia. The study also demonstrates its antioxidant nature, and hence it may be protective against diabetic complications.