bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-inflammatory and anti-allergic activity of Jacareubin derivatives
Authors: Castillo-Arellano Jorge Ivan , Hernandez Rosario Tavera , Camacho Antonio Nieto , Campos Omar Noel Medina , Lagunes Rodolfo Perez , Oyola Juan Francisco Leon , Chaverri José Pedraza , Gonzalez-Espinosa Claudia , Chilpa Ricardo Reyes , Estrada Manuel Jimenez 
Published: August 2023

Abstract
Xanthone Jacareubin (JAC) isolated from heartwood of Calophyllum brasiliense has shown good anti-inflammatory against spike protein of SARS-CoV2 and anti-allergic activity. Methoxylated (Met) and acetylated (Ac) derivatives of JAC and its precursor xanthone V (X-V) were analyzed in this work to identify the structural functional groups that confer their biological activity.
Met- and Ac-derivatives of JAC and X-V were synthesized and identified by 1H and 13C-NMR and MS. All compounds were evaluated for β-hexosaminidase degranulation (β-hex) of Bone Marrow Mast Cells. Both xanthones and Met-JAC derivative (3metJac) were evaluated on their inhibitory activity of xanthine oxidase (XO) and inhibition of passive cutaneous anaphylaxis (PCA). Also, both xanthones, 3metJac, and 4AcX-V were evaluated for inhibitory activity of Myeloperoxidase (MPO) and TPA-induced edema in mice.
JAC showed better inhibition of β-hex than X-V, while Met-derivatives showed greater inhibitory activity on β-hex than JAC and X-V, but Ac-derivatives showed reduced inhibitory activity. Inhibition of XO and MPO of both xanthones showed the highest activity at 1 μmol/ear compared to Met- and Ac-derivatives evaluated. Also, both xanthones showed higher anti-inflammatory activity in the TPA-induced edema compared to the Met- and Ac-derivatives. While in the PCA, JAC and 3metJac showed similar inhibition and twice the inhibition of X-V and their derivatives.
These results suggest that the fourth ring in the JAC is an important structural group for anti-allergic activity because X-V does not possess the fourth cyclized ring and has a fourth hydroxyl substituent group, showing poor inhibition of the allergic response. Supported by Conacyt Grant CF-2019-51488.
Supported by Conacyt Grant CF-2019-51488
Evaluation of salt-soluble protein extract from an ancient wheat progenitor (Aegilops tauschii) for intrinsic allergenicity in an adjuvant-free mouse model of wheat allergy
Authors: Gangur Venugopal , Gao Haoran , Jorgensen Rick Dean , Raghunath Rajsri , Chandra Shivam , Othman Aqilah , Olson Eric , Ng Perry K W 
Published: August 2023

Abstract
Wheat allergies are a growing significant health concern around the globe. The ancient diploid wheat progenitor, Aegilops tauschii (genome DD), contributed to the genetic diversity of the common soft white wheat (Triticum aestivum, genomes AABBDD). The allergenic potential of Ae. tauschii is largely unknown. Here we tested the hypothesis that the the salt-soluble protein extract (SSPE) from Ae. tauschii will be intrinsically allergenic in an adjuvant-free mouse model of wheat allergy. The ancient wheat progenitor was grown at the Michigan State University greenhouse using the seeds stored at our wheat breeding program. The SSPE was prepared, characterized for quality, and then tested in the mouse model that uses skin sensitization followed by oral allergen challenge. Balb/c mice were produced and maintained on a plant protein-free diet. Groups of adult mice (n=10/group) were repeatedly exposed to SSPE or vehicle via the skin. Allergic sensitization was assessed by specific IgE (sIgE) response. Oral anaphylaxis was quantified by hypothermic shock response (HSR). The mucosal mast cell response (MMCR) was quantified by measuring MMCP-1 in the blood. Repeated skin exposure to SSPE but not the vehicle elicited robust sIgE response. Oral SSPE challenge but not vehicle challenge elicited significant, but a modest HSR as well as MMCR. In summary, we report the characterization of intrinsic allergenicity potential of the SSPE obtained from the Ae. tauschii wheat progenitor for the first time. Funding: USDA/NIFA.
The United States Department of Agriculture (USDA)/National Institute of Food and Agriculture (NIFA); Hatch project MICL02486 (Accession Number: 1012322); Hatch project MICL01699; Agricultural and Food Research Initiative Competitive Program, grant number: 2018-67017-27876
Age and sex influence cultured rodent mast cell and basophil responses to antigen
Authors: Kulka Marianna , Wagner Ashley 
Published: August 2023

Abstract
Mast cells initiate allergic inflammatory immune responses and play a role in disease by releasing various inflammatory and immunomodulatory mediators. Several mast cell-lines and primary cultured cells have been used as mast cell models with inconsistent results among research groups. Bone marrow-derived mast cells (BMMC) cultured from mouse bone marrow progenitor cells are often used as a representative model of mucosal mast cell behaviour, however their reported phenotype is variable due to inconsistent culture protocols. RBL-2H3 is a rat basophilic histamine-releasing cell line that has some characteristics of both mast cells and basophils but is not a true representation of either cell type. The murine mast cell line MC/9 is an IL-3-dependent mucosal mast cell model but has limited mast cell characteristics. In this study, we have compared the response of BMMC (derived from C57BL/6 male or female mice), two sources of RBL-2H3 (purchased directly from ATCC and a lab curated culture), and MC/9 (ATCC) at several critical stages to some common stimuli (IgE/Ag, A23187) and analyzed mast cell morphology, expression level of common mast cell surface markers (CD117 and FcɛRI), protease expression, and function (growth kinetics, viability, ROS production, degranulation, cytokine release and FcɛRI signaling). The objective of this study was to provide insight into the effects of culture conditions, biological sex, and age of the cells on variability among reported phenotypes and, to determine optimal conditions for activation of these cells. Factors that are often overlooked such as source, age and biological sex of mast cells play an integral role in phenotypic outcomes and may account for the reported variability in their function.
National Research Council Canada
The role of Monocyte Chemoattractant Protein-Induced Protein-1 in the regulation of the immune responses to mycobacterial infection
Authors: Ramos Octavio , Wang Qinghong , Wei Jiawei , Eickhoff Christopher , Ning Huan , Hoft Daniel , Liu Jianguo 
Published: August 2023

Abstract
Mycobacterium tuberculosis (Mtb) infection is mainly controlled by protective cell-mediated immunity. TNFα and other mediators, such as nitric oxide (NO), are crucial to the macrophage’s antimicrobial activity. The RNA-binding protein MCPIP1 is a zinc-finger protein with RNase activity that targets the 3’UTR region of cytokine’s mRNA for degradation like IL-6, IL-1β, and IL-12. Here, we aim to investigate the role of MCPIP1 during infection and its contribution to Mtb’s immune evasion. Our observations show that MCPIP1 increases after Mtb infection, correlating with disease progression. Similarly, global MCPIP1 KO (MCPIP1−/−) mice showed lower lung bacterial burden than WT mice after 30 days. To address wheater the reduced number of bacteria was due to the macrophage’s absent MCPIP1 expression, we generated myeloid-specific MCPIP1 KO mice (M-MCPIP1−/−). M-MCPIP1−/−mice showed a similar reduction of bacterial growth as the MCPIP1−/−mice compared with their WT littermates. Infection of bone marrow-derived macrophages confirmed that myeloid-MCPIP1 deficient cells had improved control of bacterial growth with increased IL-1β, IL-6, IL-12, iNOS, and TNFα. To evidence the mechanism by which M-MCPIP1−/− macrophages contribute to Mtb growth control, we blocked TNFα and iNOS activity. Results showed that protection in M-MCPIP1−/− is partly due to these molecule’s high expression, as the blockade of these mediators increased the bacterial burden. Our preliminary data suggest that the induction of MCPIP1 contributes to the bacteria’s immune evasion by targeting critical anti-TB molecules. Further experiments are needed to understand the mechanisms involved and consider MCPIP1 as a target for host-directed therapy for TB.
R21AI151936 R21AI171734
Airway goblet cells resulting from conditional YAP/TAZ deletion promote distinct pulmonary inflammation
Authors: Cheng Nan , Hicks-Berthet Julia , Varelas Xaralabos 
Published: August 2023

Abstract
The aberrant presence of goblet cells, which are epithelial cells of the conducting airways that have specialized roles in secreting mucus, is frequently associated with distinct innate and adaptive immune changes that together are hallmarks of various pulmonary diseases. The transcriptional regulators YAP and TAZ, key effectors of Hippo pathway signaling, play a central role in suppressing the differentiation of airway goblet cells. Here we investigated the consequences of goblet cell production, resulting from the YAP/TAZ conditional depletion in Scgb1a1+ secretory cells, on lung immunity. We observed that loss of YAP/TAZ resulted in the production of goblet cells promoting local CD45+ immune cell expansion. To gain insight into immune changes associated with the production of YAP/TAZ-deleted goblet cells, we performed a single-cell RNA sequencing experiment on CD45+ cells isolated from control and Yap/Taz-cNull mouse lungs. Data analyses, along with follow-up validation experiments, demonstrated significant immune changes in Yap/Taz-cNull mice including an expansion of type 2 innate lymphoid cells (ILC2s), CD4+ T cells Th2 polarization, and alternative activation of alveolar macrophages, accompanied with elevated type 2 cytokine production. Gene expression analysis of YAP/TAZ-deleted airway cells revealed altered expression of notable immune-modulating factors, many of which are implicated in lung diseases. Collectively our study demonstrates that key immune-modulating signals arise from the secretory lung epithelium through reduced YAP/TAZ activity, raising interesting questions about the functions of YAP/TAZ in lung homeostasis and about the contributions of goblet cells to shaping lung immune responses.
System biology or pattern recognition of the immune response for offering immunotherapeutic cures for human diseases
Authors: Manjili Masoud H , Koelsch Nicholas 
Published: August 2023

Abstract
Our brain interprets observations by computations in the form of imaginations and creating patterns based on distinct networks of interactions. Nevertheless, collective patterns of the immune response as a system are hidden from our brain’s spontaneous computations, and should be discovered through research. Nevertheless, highly reductionist approaches hinder the discovery of immunological patterns because of getting lost in the details and seeking for a cause-effect direction. Such reductionist approaches have not been fruitful in offering a cure beyond alleviating the symptoms for immune-related diseases. Recent advances in system biology using big data, deep sequencing at single cell levels, multi-omics and artificial intelligence offer unique opportunities for pattern discovery research in immunology. Here, we provide a new interpretation for the existing data by suggesting that distinct internetwork interactions of the immune cells without any cause-effect direction create distinct immunological patterns manifesting collective functions independent from their cellular constituents. Such immunological patterns emerge from distinct proportions of the immune cell types transforming one another for producing collective functions. Based on empirical data, we propose that discovery of immunological patterns in immune-related diseases could offer better understanding of the immune response as a system as well as novel immune modulatory therapeutics for human diseases.
This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award No. W81XWH2210793. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Department of Defense.
The therapeutic role of fibronectin in the re-epithelialization response following wounding in a human skin/mouse xenografting model
Authors: Zhang Wenwu , Akhtar Nahid , Zhao Jennifer , Spandau Dan , Kaplan Mark H 
Published: August 2023

Abstract
The atopic environment diminishes wound re-epithelialization and the defect in the wound healing process is IL-4 dependent. IL-4 represses fibronectin secretion from keratinocytes and impairs the ability of keratinocytes in culture to migrate into a scratch and to close a wound in vivo. Addition of fibronectin to culture increased closure of the scratch assay in vitro and re-epithelialization of wound tissue in vivo when fibronectin was applied topically. In this study, a human skin/mouse xenografting model was used to test the ability of IL-4 to impair re-epithelialization in human skin and to test whether fibronectin can mitigate the effects of IL-4. Human skin was grafted onto immunodeficient SCID/NOD mice. Approximately 10–12 weeks post-transplantation, human skin was fully integrated onto the mouse. A shallow punch biopsy was performed on the human skin to generate a wound that did not penetrate into mouse tissue. Human IL-4 was intravenously injected twice a week before the punch and recombinant fibronectin was spread over the wound twice daily after the wounding. Anatomic wound healing was monitored, and EDC gene expression and skin histology were assessed. Our results showed that mice injected with human IL-4 had delayed wound healing, decreased human EDC gene expression and increased MMP19 and CCL26 expression in human skin tissue. Treatment of skin with fibronectin attenuated the effect of IL-4 on human gene expression and promoted wound healing and re-epithelialization. These results suggest that fibronectin has a potential therapeutic role in the treatment of atopic lesions.
Supported by grants from NIH (R01AI095282)
ADSC-derived exosomes inhibit cbl-cathepsin K-dependent osteoclast activation in inflammatory arthritis
Authors: Liao Hsiu-Jung , Shen Yi-Shan , Lu Ssu-Jung , Jiang Ni-En , Shen Chia-Ning , Chang Chih-Hung 
Published: August 2023

Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes joint inflammation and bone destruction due to increased osteoclast differentiation and activity. Adipose-derived stem cells (ADSCs) are used to treat tissue injury because they are easy to harvest and exhibit immunomodulatory and regenerative capacity. Previous studies demonstrated that ADSC-derived exosomes (ADSC-Exo) protect articular cartilage from damage and exert anti-inflammation effects. Thus, we investigated the underlying mechanisms of ADSC-Exo in regulating osteoclast activation in inflammatory arthritis. RANKL is a TNF-family cytokine that binds to the RANK required for mature osteoclasts. However, whether ADSC-Exo is functionally involved in the inhibition of osteoclast formation via regulating RANK-mediated signaling in these pathological conditions is unclear.
Our data revealed that ADSC-Exo ameliorated the RA severity and bone loss in vivo and inhibited osteoclast differentiation, RANK downstream signaling, NFATc1, cathepsin K, and cbl-b. Moreover, ADSC-Exo could significantly suppress the population of RANKL-expressing TH17 cells. In brief, ADSC-Exo protects articular cartilage and bone destruction from damage and ameliorates gait abnormality in CIA rats, which may be related to the inhibition of the RANK-signaling pathway in osteoclasts. As it is relatively feasible to obtain human adipose tissue, ADSC-Exo may be a potential therapy for RA.
This study could comprehensively understand the immunomodulatory effects of ADSC-Exo on suppressing osteoclastogenesis. This finding is critical for understanding the bone homeostasis modulated by MSC-Exo and provides biological evidence of ADSC-Exo in inflammatory arthritis.
Supported by grants from the Ministry of Science and Technology (111-2321-B-418-002, 111-2314-B-418-004), FEMH (2022-C-042 and 2022-C-123), NYCU-FEMH Cooperation grants (111DN12, 111DN22), NTUH-FEMH Cooperation (111-FTN0012).
Investigating HIV-1 TAT protein role in Atherogenesis
Authors: Kirk Cassandra Lee , Moriarty Alina , Stahr Natalie Ann , Keeter W Coles , Ma Shelby , Kim Woong-Ki , Guo Ming-Lei , Galkina Elena 
Published: August 2023

Abstract
With the recent development of antiretroviral therapy, HIV patients can live a long and normal lifespan. Recent evidence demonstrates an increased incidence of developing cardiovascular diseases (CVD) specifically atherosclerosis in aged HIV-infected patients. The adaptive and innate immune responses play a complex specific role in atherosclerotic plaque burden. However, specific mechanisms of the implication of the immune system in HIV-accelerated atherosclerosis are unclear. The protein Trans-Activator of Transcription–TAT is strongly associated with HIV infection as it enhances the efficiency of viral transcription. To understand the contributions of TAT protein in HIV-associated atherogenesis, a doxycycline-inducible astrocyte-specific HIV-1 TAT transgenic mouse was used. An injection of recombinant adeno-associated virus vector (AAV) encoding a gain-of-function mutant PCSK9 into mice and feeding with high fat with added cholesterol (DDC) and doxycycline (Dox) was used to promote atherosclerosis and TAT expression. After 16 wks of feeding, various tissues were collected and used for flow cytometry analysis (FACS) for immune profiling. Our preliminary data suggest that TAT is involved in the regulation of peripheral blood neutrophil numbers and therefore can serve as a regulator of inflammation in HIV-associated atherosclerosis. Future analysis will provide insight into potential mechanisms of HIV TAT-dependent involvement in atherosclerosis development and progression.
This work was supported by project –initiation funds from the Center for Integrative Neuroscience and Inflammatory Diseases at EVMS and NIH NHLBI R01HL142129-04S1 grant.
RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and intestinal inflammation
Authors: Singh Amir Kumar , Kumar Ritesh , Brooks John F , Conlon Kevin P , Basrur Venkatesha , Chen Zhe , Han Xialin , Hooper Lora , Burstein Ezra , K Venuprasad 
Published: August 2023

Abstract
Th17 cells that produce IL-17 are pathogenic in many human diseases, including inflammatory bowel disease (IBD), but are, paradoxically, essential for maintaining the integrity of the intestinal barrier in a non-inflammatory state. However, the intracellular mechanisms that regulate distinct transcriptional profiles and functional diversity of Th17 cells remain unclear. We have found that Raftlin1, a lipid raft protein, is specifically upregulated in and forms a complex with RORγt via its conserved LLNSL motif in pathogenic Th17 cells. Disruption of the RORγt-Raftlin1 complex in Raftlin1ΔLLNSL knock-in mice resulted in attenuated pathogenic Th17 cells elicited by Citrobacter rodentium; however, there was no effect on nonpathogenic Th17 cells induced by commensal segmented filamentous bacteria (SFB). Mechanistically, we found that Raftlin1 recruits distinct phospholipids to RORγt and promotes the pathogenicity of Th17 cells. Thus, we have identified a fundamental mechanism that drives the pathogenic function of Th17 cells, which could provide a platform for new therapeutic strategies to dampen Th17-mediated inflammatory diseases.
This work was supported by funds from the National Institutes of Health (R01-DK115668, R01-AI155786) and Cancer Prevention Research Institute of Texas (RP190527) and a stimulus grant from the Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center.
Repercussions of high extracellular K+ on T-cell antitumor responses
Authors: Wong Brandon Han Siang , Ong Seow Theng , Goay Stephanie Shee Min , Ho Ying Swan , Chen Shuwen , Bi Xuezhi , Webster Richard D , Shelat Vishalkumar G , Verma Navin Kumar 
Published: August 2023

Abstract
Tumours create an immunosuppressive microenvironment that limits the antitumor function of infiltrating T-cells. Dying/necrotic tumor cells extrude intracellular potassium (K+) into the local extracellular milieu, raising the extracellular K+ ([K+]e) by 8–15 fold, which then accumulates in tumor-infiltrating T-cells. Here, we determined the functional impact of high-[K+]e (50 mM) on human T-cells. Using molecular assays, we demonstrated that prolonged exposure to high-[K+]e reduced CD3ɛ and CD25 (intermediate activation marker) surface expression, suggesting weakened T-cell activation. High-[K+]e perturbed T-cell receptor signalling and the downstream glycolysis pathway. Using metabolomics analysis, we identified dysregulation in pathways involving fatty acid oxidation, TCA cycle and choline metabolism under high-[K+]e. Exposure to high-[K+]e impeded T-cell motility and skewed T-cell polarization towards T-helper 2 (Th2) and regulatory T-cell (Treg) subsets. A similar Th2 subset trend, although not significant, was seen towards the core of patient-derived tumor biopsies (n=7) along with the amassment of Treg cells intratumorally. Collectively, our findings substantiate the immunosuppressive effects of high-[K+]e on T-cell functions, which underlines the potential use of K+ efflux channel activators in reversing dampened T-cell antitumor responses.
Supported by Singapore Ministry of Education (MOE) under its MOE Academic Research Fund (AcRF) Tier 1 Grant (2020-T1-001-062) and Tier 2 (MOE2017-T2-2-004) grants. #LINK# #ENDLINK#
Dominant interfering CARD11 variants disrupt JNK signaling in T cells and impaired CARD11-JNK signaling increases expression of GATA3
Authors: Bauman Bradly M , Frank Andrew , Sukumar Gauthaman , Saucier Nermina , Dalgard Clifton L , Chan Alice Y , Cooper Megan A , Snow Andrew L 
Published: August 2023

Abstract
Although prior research implicated c-Jun N-terminal kinase (JNK) in helper CD4+ T cell differentiation, mechanisms governing JNK signaling and function in human lymphocytes remain nebulous. CARD11 is a lymphocyte-specific scaffold protein connecting antigen receptor (AgR) engagement to transcriptional programs necessary for effector cell survival, proliferation, and differentiation. In addition to NF-κB, CARD11 is also required for AgR-induced mTORC1 and JNK2 signaling. We sought to define the impact of dominant interfering (DI) CARD11 variants on JNK signaling and elucidate transcriptomic changes governed by CARD11-dependent JNK activation in T cells. We transfected WT and CARD11 knockout (KO) Jurkat T cells with plasmids expressing WT or DI CARD11 variants to assess effects on CARD11-dependent JNK signaling and performed RNA sequencing on mitogen-activated WT and CARD11 KO Jurkat T cells ± JNK inhibition. Our results revealed that AgR-dependent JNK1 and JNK2 activation are CARD11-dependent. Additionally, heterozygous DI CARD11 mutations derived from patients with CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease disrupted AgR-dependent JNK1/2 phosphorylation, c-Jun accumulation, and AP-1 transcriptional activity with variable potency, mirroring the extent of impaired NF-κB activation. Intriguingly, JNK inhibition in Jurkat and primary CD4+ T cells enhanced AgR-induced expression of GATA3, the master transcriptional regulator of Th2 cell differentiation. Our novel findings suggest that defects in CARD11-dependent JNK signaling in CD4+ T cells may contribute to severe allergic disease noted in CADINS patients, unveiling a new potential therapeutic target.
Supported by funding from the Jeffrey Modell Specific Defect Research Program (ALS) and the Henry M. Jackson Foundation for the Advancement of Military Medicine (BMB).