bluuebunny/crossref_metadata_2025_split huggingface dataset:
15d-PGJ2 ameliorates the inflammatory process on rheumatoid arthritis-induced into rats’ temporomandibular joint (CAM5P.240)
Authors: Clemente-Napimoga Juliana , Quinteiro Mariana , Macedo Cristina , Freitas Fabiana , Napimoga Marcelo 
Published: January 2023

Abstract
The aim of this study was to evaluate the peripheral effect of 15d-PGJ2 in Rheumatoid Arthritis-induced inflammation in the temporomandibular joint (TMJ) of rats. Antigen-induced arthritis (AIA) was generated in rats with methylated bovine serum albumin (mBSA) diluted in complete Freund's adjuvant. Pretreatment with an intra-articular injection of 15d-PGJ2 (100 ng/TMJ) before mBSA intra-articular injection (10 µg/TMJ) (challenge) in immunized rats significantly reduced the RA-induced hypernociception (p&lt;0.05; ANOVA, Tukey test). Corroborating these results, 15d-PGJ2 was able to inhibit plasma extravasation, leukocyte migration and the release of inflammatory cytokines TNF-α, IL-1β, IL-6, IL-12, IL-18 and the chemokine KC and CINC-1 (p&lt;0,05: ANOVA, Tukey Test). Moreover, the effect of 15d-PGJ2 to increase the decay accelerating factor (CD55) expression associated to decrease pro-inflammatory cytokines release may explain the inhibition of leukocyte infiltration, through a shift in the balance of the pro- and anti-adhesive properties. To confirm these results histopathological analysis showed that 15d-PGJ2 reduced the inflammatory parameters induced by RA. Thus, 15d-PGJ2 might be used as a potential anti-inflammatory drug to treat RA inflammation of the temporomandibular joint.
Evolutionary origins and structural analysis of phosphatidylserine binding by the TIM gene family (CAM5P.244)
Authors: Jones Jennifer , Brandmaier Andrew , Umetsu Sarah , Bu Xia , Umetsu Dale , DeKruyff Rosemarie , Freeman Gordon 
Published: January 2023

Abstract
The T cell Immunoglobulin and Mucin-like domain (TIM) proteins are a family of receptors that bind phosphatidylserine (PS) and regulate adaptive and innate immune cell functions. We find that two TIM-specific motifs: a G(W/L/I/F)(F/M)ND (GWFNDor) sequence and four conserved cysteine residues in the FG and CC’ segments of the TIM IgV domain form the distinctive PS-binding pocket identified in TIM-PS co-crystal structures. Because BALB/c and C57BL/6 mice have significant polymorphisms in TIM-3 and TIM-1, we determined the haplotypes of immunologically diverse and genetically divergent mice. Despite a high degree of variation in the IgV domain and in the mucin like stalk, the GWFNDor motif is unmodified in all known polymorphisms of TIM-1, -3, and 4. We identified two genomic alterations that cause divergent expression profiles of TIM-1 in commonly studied mouse strains. A major polymorphism in mouse TIM-1 deletes 23 amino acids of the mucin domain, and is caused by a retroviral insertion in the C57BL/6 genome that prevents expression of part of the mucin domain. Genomic and phylogenetic analyses show that a sytenic locus encoding generally 3 TIMs (1, 3, and 4) is conserved from bony fish to primates, and with emergence of the GWFND-4 motif in the most primitive TIM loci in bony fish, and the TIM family occupies a distinct PS-binding branch among the family of V-domain receptors that modulate immune activation via lipid, glycan, or protein binding.
Administration of phospholipase D1 inhibitor attenuates aminoacetophenone-induced acute liver injury (CAM5P.245)
Authors: Kwon Soonil , Lee Sung Kyun , Lee Mingyu , Lee Ha Young , Kim Sang Doo , Bae Yoe-Sik 
Published: January 2023

Abstract
A phospholipase D1 (PLD1)-selective inhibitor, N-[2-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]-1-methylethyl]-2-naphthalenecarboxamide, strongly blocked aminoacetophenone-induced acute liver injury. Administration of 500 mg/kg aminoacetophenone strongly increased alanine transaminase levels in serum, which was markedly decreased by PLD1 inhibitor administration in a dose-dependent manner, showing almost complete inhibition by 4 mg/kg of the inhibitor. During the pathological progress of acute liver injury, GSH levels are decreased, which is recovered by the administration of PLD1 inhibitor. JNK mediates aminoacetophenone-induced oxidative stress and liver injury. PLD1 inhibitor administration strongly blocked JNK phosphorylation in aminoacetophenone-induced acute liver injury model. Several inflammatory cytokines including TNF-α, IFN-γ, CCL2, and IL-1β were strongly increased from liver in aminoacetophenone-induced acute liver injury, which were also markedly decreased by PLD1 inhibitor administration. Taken together, the results indicate that the PLD1 inhibitor strongly show therapeutic effects reverse the progression of acute liver injury, and PLD1 can be regarded as an important target molecule to develop therapeutic agents against acute liver injury.
Copper nanoparticles suppresses nitric oxide production in macrophages (CAM5P.234)
Authors: Arancibia Sergio , Barrientos Andrea 
Published: January 2023

Abstract
Copper and copper oxide nanoparticles (CuNP) have been utilized as anti-microbial agent, metal catalyst, diet supplement, high thermal conductive material, lubricant additive, among others. Although the uses of CuNP are relatively new, there is an increasing interest to know their immunotoxicology. CuNP have shown to induce one of the most potent acute inflammatory reactions among several types of nanoparticles. Recently, in a pulmonary infection model, it was demonstrated that mice, which had been previously exposed to CuNP, presented an impaired bacterial clearance. These effects were due to a reduction in macrophage function; however, the precise molecular mechanism underlying these effects is still unknown. Here, we described the effects of CuNP in the response of peritoneal macrophages against microbial products. Transmission electron microscopy (TEM) data showed that CuNP were rapidly internalized by macrophages. The internalization of the particles induced a significant reduction of cell viability in comparison with other nanoparticles. The challenge with CuNP inhibited LPS-mediated nitric oxide (NO) production in a dose dependent manner. These results showed that CuNP modulate the expression of a key inflammatory mediator that is crucial to eliminate bacterial infection.
Inhibitory effect of 5-Pyridin-2-ylmethylene-6,7-dihydro-5H-benzo[b]thiophen-4-one (PT-2-318) on NF-kB and AP-1 activation in macrophages (CAM5P.235)
Authors: Baek Seung-il , Lee Eung-Seok , Han Sang-Bae , Kim Youngsoo 
Published: January 2023

Abstract
TGF-beta activated kinase1 (TAK1) has been reported to play an essential role in pro-inflammatory cellular signaling pathway. Activated TAK1 phosphorylates IkB kinase β (IKKβ), leading to NF-kB activation. Nuclear factor-kB (NF-kB) is a ubiquitous transcriptional factor that controls the expression of genes involved in immune responses. Here, treatment with 5-Pyridin-2-ylmethylene-6,7-dihydro-5H-benzo[b]thiophen-4-one (PT-2-318) inhibited not only autophosphorylation of TAK1 but also acute liver injury of E.coli LPS/D-galactosamine-challenged mice. As a mechanism, PT-2-318 directly inhibited autophosphorylation of TAK1. So, phosphorylation of both IkB and MAPKs was inhibited. Also, LPS-induced NF-kB and AP-1 promotor activity in lipololysaccharides (LPS)-stimulated macrophages RAW 264.7 was inhibited by blocked TAK1. As TAK1 was blocked, PT-2-318 attenuated LPS-induced mRNA expression of cytokines (IL-1β, TNF-α). On the other hand, PT-2-318 did not inhibit phosphorylation of IRAK4 and degradation of IRAK1. in vivo, intravenous treatment with PT-2-318 protected against LPS/GalN-induced acute liver failure in C57/BL7 mice. These results suggest that PT-2-318 might be considered as a potential agents for the treatment of inflammatory diseases.
A novel population of myeloid Gr-1+ cells expressing FasL and perforin mediate contact hypersensitivity responses in skin (CAM5P.236)
Authors: Kish Danielle , Fairchild Robert 
Published: January 2023

Abstract
Allergic contact hypersensitivity (CHS) is a CD8 T cell mediated response to hapten sensitization and challenge of the skin. Hapten-primed CD8 cell infiltration into the skin challenge site requires prior Gr-1+ cell infiltration into the site. Despite WT levels of CD8 priming, sensitized gld/perforin-/- mice have no CHS to hapten challenge. The response is restored in these mice by transfer of WT bone marrow derived Gr-1+ cells at the time of hapten challenge. The goal of this study was to further characterize these Gr-1+ cells. Gr-1+cells were purified from the bone marrow of sensitized and challenged mice by depletion of CD3+, B220+, NK1+, F4/80+, and Ly6G+ cells. qRT-PCR and Western Blot analyses confirm expression of FasL and perforin by the negatively selected cells that are 90% Gr-1+CXCR2+. Flow cytometry analyses indicate the FasL+ cells within this population express CD11c, CXCR2, CCR2, Ly6C, and CX3CR1. These Gr-1+cells, but not neutrophils, induce apoptosis of cultured endothelial cells. Transfer of these Gr-1+ myeloid cells to sensitized gld/perforin-/- mice during hapten challenge induces expression of the T cell chemoattractants CCL1, CCL2, and CCL5 in the challenged skin. These results describe a novel population of bone marrow derived Gr-1+CXCR2+ myeloid cells expressing FasL and perforin that induce expression of the chemoattractants required to direct hapten-primed T cell infiltration into the challenged skin site to mediate CHS.
Blood monocytes expressing CCR6 and monocyte-derived dendritic cells in dermis and epidermis are critical for IL-23-induced psoriasis-like inflammation in mice (CAM5P.238)
Authors: Singh Tej Pratap , Zhang Howard , Farber Joshua 
Published: January 2023

Abstract
Human studies have implicated IL-23 in psoriasis, and injecting IL-23 in mouse skin produces IL-22-dependent, psoriasis-like inflammation. IL-23 injection leads to accumulation of dendritic cells (DCs), which are also abundant in psoriatic skin, and depleting CD11c+ cells blocked IL-23-induced IL-22 and inflammation. In analyzing myeloid cells, we found monocyte-derived langerin+ cells (mLCs) appearing in the epidermis and more of other monocyte-derived cells, including mDCs, plus non-monocyte derived DCs in the dermis after IL-23 injection. Batf3-/-, diphtheria toxin-treated Bdca2-DTR, and Flt3l-/- mice, which lack CD103+ cDCs, pDCs, and all cDCs and pDCs, respectively, each showed only modest protection against IL-23-induced changes. Although depleting conventional LCs alone had no effect, inflammation was much diminished in langerin-DTR mice also depleted of mLCs. Together, these data suggested that CD11c+ mDCs and mLCs contributed significantly to pathology. We have reported that Ccr6-/- mice are resistant to IL-23-induced pathology, and the skin of Ccr6-/- mice showed no changes in DCs after IL-23 injection. Using Ccr6-EGFP mice, we identified expression of Ccr6 in blood monocytes, and found that Ccr6+/+, but not Ccr6-/- monocytes restored inflammation when injected i.v. into Ccr6-/- mice. Together, our data suggest that blood monocytes are recruited to inflamed skin using CCR6 and give rise to mDCs and mLCs, which are critical for IL-23-induced psoriasis-like pathology.
Direct binding and inhibition of interleukin-2 with a small molecule, HH-236 (CCR5P.259)
Authors: Oh Jin-Gyo , Heo Tae-Hwe 
Published: January 2023

Abstract
Interleukin-2 (IL-2) is a growth factor for regulatory, activated and memory T cells. Thus, IL-2 plays a critical role in stimulation as well as suppression of immune responses. Recently, IL-2/anti-IL-2 antibody (Ab) complexes were found to significantly enhance the activity of IL-2, leading either to expansion of regulatory T cells or that of memory CD8+ T cells and NK cells. In this study, we had tried to discover a small molecule that regulates IL-2 activities and identified HH-236 as a direct IL-2 binder and inhibitor of the biological activity of IL-2. HH-236 competes with anti-mouse IL-2 Ab (S4B6) for IL-2 binding, however, unexpectedly promotes the interaction between IL-2 and IL-2 receptor-alpha, CD25. HH-236 neutralized the proliferative activity of IL-2 on the IL-2 dependent cell line, CTLL-2. In addition, anti-tumor activity of IL-2 in B16F10 melanoma mouse model was blocked by HH-236 co-treatment. Small molecule IL-2 modulators may have a potential to be used as an oral therapeutics for IL-2-related pathological conditions.
Involvement of CGRP in peripheral nerve injury-induced behavioral hypersensitivity and chemokine production (CCR5P.260)
Authors: Malon Jennifer , Cao Ling 
Published: January 2023

Abstract
Previously, we have observed increased expression of Calcitonin Gene Related Peptide (CGRP), a pro-nociceptive neuropeptide, along with selected cytokines and chemokines, in the lumbar spinal cord following spinal nerve L5 transection (L5Tx, a murine model of neuropathic pain) in BALB/c mice. To further study the effects of CGRP in neuropathic pain, we intrathecally (i.t.) injected a CGRP antagonist (CGRP8-37) into BABL/c mice following L5Tx. Mice injected with CGRP8-37 displayed a reduced L5Tx-induced mechanical hypersensitivity, but not heat hypersensitivity. CGRP8-37 also caused significant reduction of the level of lumbar spinal cord CCL5 (RANTES) post-L5Tx when compared to vehicle injected-mice and non-injected mice. i.t. injection of a CCL5 neutralizing antibody significantly inhibited L5Tx-induced mechanical hypersensitivity. To test whether CGRP played its pro-nociceptive role through stimulating glial response, mixed glial cells were treated with various doses of CGRP. CGRP induced a slight increase of CCL5 24 hours post-treatment, which was correlated with the increased expression of MAP Kinase (MAPK) signaling pathway molecules: p38 and JNK. Thus, CGRP may promote MAPK-mediated glial activation and the subsequent production of CCL5, which potentiate behavioral hypersensitivity following L5Tx.
Meprin α mediates CCL2 activity in murine bone marrow cells using a model of breast cancer chemotherapy (CCR5P.262)
Authors: Crisman Jackie , Sena Maria , Ishmael Faoud , Gerwitz Andrew , Marshall Joseph , Ferry Michelle , Vandervoort Brittany , Salamone James 
Published: January 2023

Abstract
Meprins metalloproteases are comprised of hetero or homo-oligomers of α and β subunits. These proteases degrade extracellular matrix proteins and have been linked to cancer cell metastasis and leukocyte transmigration. Meprins are also known to cleave cytokines like interleukin-1 and cytokine receptors like the epidermal growth factor receptor, thereby modifying their activity. Thus the expression of meprins in a tissue can have a profound impact on cytokine activity in tissue microenvironments. Breast cancer metastases to bone marrow often elude the apoptotic effects of chemotherapy. One potentially important chemokine is CCL2, which supports the chemotaxis of cancer cell and monocytes that support metastatic disease. Additionally, patients with elevated levels of CCL2 in tissue microenvironments and serum have a poor prognosis. Herein, data is presented supporting the role of meprin α in the inactivation of chemokines by N-terminal truncation, including CCL2 (monocyte chemoattractant protein-1), CCL5 (RANTES), CCL3 (macrophage inflammatory proteins-1α) and CCL4 (macrophage inflammatory proteins-1β). Additionally, while the abundance of MCP-1 transcripts increased after induction of bone marrow apoptosis, the abundance of meprin α transcripts decreased below detection. These data indicate that apoptosis induced by chemotherapeutic agents can increase CCL2 activity in bone marrow due to a decline in meprin α, thus supporting cancer cell growth in bone marrow.
A novel recombinant chemokine protein TAT-SDF-1/54-KDEL for blocking CXCR4: bioinformatics analysis and prokaryotic expression (CCR5P.263)
Authors: Chen Hongyuan 
Published: January 2023

Abstract
To explore the potential application of SDF-1/54 mutant in Immunology, a prokaryotic vector pTAT-HA was exerted to express a novel recombinant protein ,TAT/SDF-1/54/KDEL, which contains three distinct functional domains: murine SDF-1/54, a 11-peptide TAT (47-57) derived from human immunodeficiency virus tat trans-activator protein and an endoplasmic reticulum retention four-peptide sequence KDEL.Bioinformatics analysis showed that the estimated half-life of the protein in mammalian reticulocytes,yeast,Escherichia coli in vitro are 2.8h, 10h and 2min. Respectively.Endoplasmic reticulum distribution and localization ratio is 13.0%. The data also shows the novel protein on the secondary structure and topology proteins , protein-binding sites, the three-dimensional map and a possible prediction catalytic pocket and the binding sites. Our expression experiment showed that the expected band of the protein appeared in the precipitate by SDS-PAGE electrophoresis. Western blot confirmed the specificity of the immune response of this protein to the rabbit anti-His-probe antibody.These suggest that the bioinformatics analysis for TAT/54R/KDEL might be an effective approach to predict its structure and functional expression. The expression of the protein in pTAT-HA prokaryotic vector is in the form of inclusion bodies. It offered a new method targeting for CXCR4 implicated immunity regulation,such as HIV, WHIM syndrome, cancer and stem cells mobilization and so on.
Leptin induction of aggrecanases-1 and -2 genes expression in human chondrocytes is mediated by p38 mitogen-activated protein kinase pathway (CCR5P.265)
Authors: Hatipoglu Omer , Yaykasli Kursat , Dogan Mustafa , Yaykasli Emine , Kaya Ertugrul , Ozsahin Mustafa , Uslu Mustafa 
Published: January 2023

Abstract
The cloning of leptin initiated to explore new functions of adipose tissue. The studies revealed that adipose tissue like endocrine organ involves in critical roles by secreting adipokines. Among them, leptin is the most studied and characterized adipokine, and involves in several pivotal processes including inflammation. The degradation of articular cartilage components by aggrecanases-1 and -2 (called also a disintegrin and metalloproteinase with thrombospondin motifs -4 and -5) is a key event for arthritic diseases. The catabolic effect of leptin on articular cartilage degradation by increasing aggrecanases was established, but the pathways involved in this upregulation have not been elucidated. It was aimed to investigate putative molecular pathways involving in the upregulation of aggrecanases by leptin. The cultured human articular chondrocytes were incubated with SB203580 (a specific inhibitor of p38) and subsequently recombinant human leptin. At the end of the 48 hours, total RNA was extracted. The mRNA was reverse-transcribed into cDNA and the expression levels of aggrecanases were analyzed using real-time polymerase chain reaction. The leptin induced aggrecanases expressions were suppressed by SB203580. The elucidation of underlying pathways for aggrecanases upregulation may promote the new approaches for the treatment of arthritic diseases. It can be concluded from our result, p38 MAPK might be one of the potential target for cartilage degradation caused by leptin.
Regulation of IL-4-induced IRS-2 activation by serine phosphorylation. (CCR5P.248)
Authors: Warren Kristi , Gowda Nagaraj , Thompson Joshua , Heller Nicola 
Published: January 2023

Abstract
Allergic asthma is characterized by acute inflammation of the airways with alternatively activated (M2) macrophages as key regulators of disease severity. Robust, yet transient tyrosine phosphorylation (pY) of IRS-2 in response to IL-4 leads to enhanced M2 gene activation. Mechanisms for downregulation of IL-4-induced IRS-2 signaling have not been determined although serine phosphorylation (pS) of the IRS proteins terminates insulin-activated IRS signaling. We hypothesize that serine phosphorylation of IRS-2 plays a role in inhibiting IL-4-induced responses. Human monocytic U937 cells were stimulated with IL-4 ± calyculin A, a Ser/Thr phosphatase inhibitor. In separate experiments, U937 cells and bone marrow derived macrophages (BMM) were stimulated with IL-4 and four kinase (JNK, GSK-3, TORC1, and TORC2) inhibitors. The amount of total IRS-2, pY-IRS-2 and pS-IRS-2 was determined. pY-IRS-2 inversely correlated with pS-IRS-2 following IL-4 stimulation. Calyculin A prevented pY-IRS-2, while increasing pS-IRS-2, thus diminishing the IL-4 signal. Rapamycin treatment prolonged pY-IRS-2 in U937 cells and BMM in a similar manner. More specifically, TORC2 inhibition did not prolong IRS-2 activation. These results suggest that inhibiting TORC1 activity prolonged pY-IRS-2 by diminishing pS-IRS-2. Understanding how IRS-2 signaling is regulated is crucial for finding novel targets to suppress the differentiation of M2 macrophages and lower severity of allergic lung inflammation.
IFN-γ controls IL-33 protein level through a STAT1- and LMP2-dependent mechanism (CCR5P.268)
Authors: Kopach Pavel , Lockatell Virginia , Todd Nevins , Luzina Irina , Atamas Sergei 
Published: January 2023

Abstract
IL-33 levels and activity are differentially associated with Th1 and Th2 phenotypes. IL-33 mRNA is rapidly regulated but the fate of synthesized IL-33 protein is unknown. To assess the interplay between IL-33, IFN-γ, and IL-4 proteins, replication-deficient adenoviruses (AdV) were constructed for dual expression of IL-33 & IFN-γ or of IL-33 & IL-4. Combined IL-33 & IFN-γ or IL-33 & IL-4 effects were compared with similar AdV expression of each of these cytokines alone. Co-delivery of IL-33 & IFN-γ led to mutual suppression, and co-delivery of IL-33 & IL-4 led to mutual elevation of these proteins in cell culture and in vivo. Purified IFN-γ also attenuated IL-33 protein but not mRNA driven by the recombinant CMV promoter in AdV-IL-33-infected cells, suggesting that IFN-γ controls IL-33 protein degradation. Pharmacological inhibition, siRNA-mediated silencing, or gene deficiency of STAT1 potently upregulated IL-33 protein expression levels and attenuated the downregulating effect of IFN-γ on IL-33. Inhibition of caspase-1, -3, or -8 had minimal effect on IFN-γ-driven IL-33 protein downregulation. siRNA-mediated silencing of LMP2 proteasome subunit, which is known to be essential for IFN-γ-regulated antigen processing, also abrogated the effect of IFN-γ on IL-33. Thus, IL-33, IFN-γ, and IL-4 are engaged in a complex interplay, part of which involves IFN-γ-activated, caspase-independent, STAT1-mediated degradation of IL-33 protein through non-canonical use of LMP2 proteasome.
C-kit/SCF autocrine loop in human NK cells (CCR5P.254)
Authors: Zakiryanova Gulnur , Karpova Oxana , Khamdiyeva Ozada , Kopytina Dilyara , Urazalieva Nataliya , Kustova Elena , Biyasheva Zarema 
Published: January 2023

Abstract
Expression of c-kit receptor on CD56bright subset of NK cells has been previously reported. Based on the fact that c-kit receptor and its ligand - stem cells factor (SCF), are co-expressed on many cell types, we have tested the hypothesis that c-kit and SCF might be co-expressed on human peripheral blood NK cells using RT-PCR, flow cytometry and DNA sequencing. NK cells were harvested using the immunomagnetic NK isolation kit and their purity was confirmed by flow cytometry. Analysis of RT-PCR data revealed the presence of two DNA fragments (about 330 bp and 420 bp) in NK cells. Identity of PCR products was directly confirmed by sequencing. To determine the specificity of SCF transcript formation only in c-kit-positive cell subset, NK cells were separated on c-kit-positive and c-kit-negative subsets using CD117 microbeads. No SCF mRNA expression was found in c-kit-negative NK cells even after increasing the quantity of total RNA to 2 μg and the number of amplification cycles to 40. Intracellular flow cytometry analysis with specific anti-SCF antibodies confirmed the expression of SCF protein in human NK cells. Thus, our results provide a definite proof of the existence of c-kit/SCF autocrine loop in c-kit-positive subset of human peripheral blood NK cells. The verification of the functional significance of this new phenomenon is in progress in our laboratory.