bluuebunny/crossref_metadata_2025_split huggingface dataset:
A new rapid titration protocol for lamotrigine with reduced risk of skin rash
Authors: Jang Yoonhyuk , Moon Jangsup , Son Hyoshin , Lee Woo-Jin , Sunwoo Jun-Sang , Lee Soon-Tae , Park Kyung-Il , Jeon Daejong , Chu Kon , Lee Sang Kun 
Published: January 2023

Abstract

Introduction
Lamotrigine is one of the most widely used antiepileptic drugs, but it has a critical issue of a skin rash if the starting dose is too high or the escalation rate is too rapid. We investigated the efficacy and safety of a novel and rapid titration protocol for lamotrigine that takes only 11 days to reach a daily dose of 200 mg.

Methods
We prospectively enrolled 33 adult patients (age 18–85) who were diagnosed with epilepsy and started lamotrigine administration for the first time at a single tertiary hospital. Our new protocol starts with a subthreshold dose of the drug and then administer a stepwise-incremental dose until reaching the full therapeutic dose within 11 days.

Results
Of 29 patients analyzed, only two (6.9%) experienced idiosyncratic skin rash before the first follow-up visit at 2 weeks (±3 days). In addition, a therapeutic concentration was reached in more than 75% of studied patients after 2 weeks of lamotrigine administration

Discussion
These findings demonstrate the value of the novel tolerance induction protocol for lamotrigine, which could widen the available application of lamotrigine in various situations.
Effects of human LDLR overexpression on apoE-related tau pathology and brain dysfunction
Authors: wang chao , Li Aimin , Spellman Rebecca , Bao Xin , Scott Nathan , Manis Melissa , Finn Mary Beth , Xiong Monica , Serrano Javier Remolina , Sullivan Patrick , Holtzman David 
Published: January 2023

Abstract
ApoE4 is the strongest genetic risk factor for late-onset Alzheimer Disease. It has been reported that apoE isoforms directly affect tauopathy and tau-mediated neurodegeneration in P301S tau transgenic mice expressing different human apoE isoforms, with apoE4 resulting in markedly increased tau-mediated neurodegeneration and the absence of apoE being marked protective against neurodegeneration. In the brain, low-density lipoprotein receptor (LDLR) is one of the main apoE receptors that regulates apoE levels, but LDLR has very few identified ligands compared to other apoE receptors. LDLR overexpression in the brain can dramatically lower apoE and Aβ levels, as well as decrease Aβ accumulation and deposition. Therefore, we propose to evaluate whether AAV-mediated overexpression of human LDLR (hLDLR) is an efficient way to reduce apoE levels, tau pathology, and neurodegeneration. To study the effect of LDLR overexpression on apoE4-related tau pathology and neurodegeneration, P301S Tau/ApoE4 (TE4) male mice received bilateral intracerebroventricular injection with AAV expressing hLDLR or GFP-control, starting before the onset of tau pathology development. Brains were isolated after 9 month, divided into hemispheres, and analyzed by histological and biochemical techniques. Widespread expression of hLDLR throughout the brain was observed and apoE levels were significantly decreased. Furthermore, mouse nest-building impairment was rescued after hLDLR overexpression. Strikingly, there is a significant decrease in brain atrophy, phosphorylated tau deposition in TE4 mice overexpressing hLDLR. In summary, these data suggest that LDLR may be a promising target to lower apoE levels and decrease neurodegeneration.
RGC-32 regulates astrocyte differentiation during experimental autoimmune encephalomyelitis
Authors: Tatomir Alexandru , Boodhoo Dallas , Nguyen Vinh , Cudrici Cornelia , Badea Tudor Constantin , Rus Violeta , Rus Horea 
Published: January 2023

Abstract
Astrocytes are increasingly recognized as critical contributors to multiple sclerosis pathogenesis. We have previously shown that lack of response gene to complement 32 (RGC-32) alters astrocyte morphology in spinal cords during experimental autoimmune encephalomyelitis (EAE), suggesting a role for RGC-32 in astrocyte differentiation. In addition, we found that RGC-32 regulates TGF-β-induced extracellular matrix production and growth factors expression. We investigated if the lack of RGC-32 alters the expression of the glial fibrillary acidic protein (GFAP) and of astrocytes progenitor markers vimentin and fatty acid binding protein 7 (FABP7) during EAE. Immunohistochemical analysis of spinal cords during the acute phase of EAE (day 14 post EAE induction) showed that the elongated, radial glial cell-like astrocytes from RGC-32 knock-out (KO) mice expressed higher levels of vimentin and FABP7 as compared to wild type (WT) mice, confirming their immature phenotype. In addition, we found that the density of white matter GFAP+ astrocytes was higher in WT as compared to KO mice (p=0.02). Using double staining immunohistochemistry for GFAP and connective tissue growth factor (CTGF), known to be involved in astrocyte differentiation, we found a lower number of CTGF+ astrocytes during EAE in spinal cords of RGC-32 KO when compared with WT mice (p=0.002). We next purified neonatal astrocytes from WT and RGC-32 KO mice, and we found significantly lower levels of GFAP and CTGF mRNA and protein and higher levels of vimentin in RGC-32 KO astrocytes when compared with WT astrocytes. The expression pattern of astrocytic progenitor markers and that of CTGF suggests that RGC-32 is an important regulator of astrocyte differentiation during EAE.
Phenotype-driven screening of 150 strains of mice for allergic lung inflammation identified strains representative of heterogeneous human asthma cohorts
Authors: Howard Emily Diane , Maazi Hadi , Hurrell Benjamin P , Galle-Treger Lauriane , Helou Doumet Georges , Jahani Pedram Shafiei , Painter Jacob , Allayee Hooman , Akbari Omid 
Published: January 2023

Abstract
Asthma is a highly prevalent and heterogeneous disease characterized by airway hyperreactivity (AHR) and an influx of immune cells including eosinophils and neutrophils in the bronchoalveolar lavage (BAL). Furthermore, there are patient subsets, such as severe asthmatics, who are unresponsive to corticosteroids or bronchodilators. Research efforts targeting these cohorts of asthma patients however are severely lacking due to an inadequacy in relevant biological mouse models. For the first time, we immunophenotyped 150+ inbred and RI mouse strains in the Hybrid Mouse Diversity Panel (HMDP) under steady state conditions and after house dust mite (HDM) challenge to assess the lung function, BAL cell composition, serum immunoglobulin levels, as well as quantification of lung and peripheral immune cells. These results revealed at least three unique groups of strains that, when exposed to the same allergen, respond with three distinct systemic and local phenotypes of lung inflammation, specifically a high Th-2 response, a low Th-2 response, and neutrophilia. These murine models of AHR mirror human cohorts of asthma previously underrepresented in ongoing research efforts. We are currently designing mechanistic studies focusing on identifying the genetic factors responsible for these distinct phenotypes. The results of these combined studies may lead to a better understanding of asthma heterogeneity and provide a foundation for further elucidation of the pathogenetic mechanisms of each phenotype of asthma utilizing relevant animal models.
Transdermal sensitization and oral elicitation of anaphylaxis to salt-soluble wheat protein in an adjuvant-free mouse model of food allergy
Authors: Gangur Venugopal , Gao Haoran , Jorgensen Rick , Othman Aqilah , Raghunath Rajsri , Wade Labrawn , Chandra Shivam , Ng Perry KW 
Published: January 2023

Abstract
Occupational exposure to wheat proteins in the baking industry is linked to a variety of allergic diseases including atopic dermatitis, allergic rhinitis, allergic conjunctivitis, and asthma. Mechanisms of occupational hypersensitivity to wheat are incompletely understood at present. For example, the role of route of exposure to wheat proteins in an occupational setting that results in sensitization and wheat allergic disease is largely unknown. Here, we tested the hypothesis that exposure to salt-soluble wheat protein (SSWP) extract via the skin, in the absence of external adjuvant, can cause sensitization for oral wheat-induced anaphylaxis in mice. Balb/c mice were produced and maintained on a wheat-free diet during this study. Groups of mice were exposed to SSWP prepared from a durum wheat, without adjuvant, using a novel transdermal exposure (TDE) method. Mice were sensitized with SSWP by nine weekly exposures. In both males and females, significant and robust wheat-specific IgE antibody responses were observed by the 6th TDE. Anaphylaxis upon oral challenge with SSWP after the 9th TDE was quantified by measuring elevation of plasma MMCP-1, which is a specific immune marker of IgE-mediated anaphylaxis in mice. Sensitized mice showed significant elevation of MMCP-1, confirming IgE-mediated anaphylaxis. These data demonstrate for the first time that skin exposure to SSWP, without an adjuvant, can clinically sensitize mice for oral SSWP-induced anaphylaxis.
Obesity alters the immune landscape of the small intestine and exacerbates food allergy
Authors: Schmiechen Zoe C , Fredrickson Gavin , Robert Sacha , Barrow Fanta , Revelo Xavier 
Published: January 2023

Abstract
In the past few decades, higher rates of obesity have coincided with a rising number of individuals affected by allergic disease. Our study objective was to determine if obesity alters the immune cell landscape of the small intestine towards an inflammatory environment that aggravates the development of food allergy. Obesity was induced by feeding male BALB/c mice a western diet for 8 weeks. To induce food allergy, mice were epicutaneously sensitized and orally-challenged with OVA. Compared with lean controls, sensitized obese mice showed a lower body temperature after challenge and increased OVA-specific IgE in serum, suggesting an exacerbated allergic response. Mass cytometry analysis of the intestinal lamina propria revealed that OVA-sensitized obese mice had decreased T regulatory cells, which are critical for the oral tolerance to food allergens. In the mesenteric lymph node, obese mice showed increased frequencies of T follicular helper cells (Tfh) compared with lean controls. Tfh cells are required for the production of allergen-specific IgE, and implicated in allergic disease pathogenesis. To further define the transcriptional mechanisms underpinning the increased inflammatory and allergic responses during obesity, we performed single-cell RNA sequencing of more than 28,000 barcoded CD45+ enriched lamina propria cells from lean and obese mice, with and without OVA sensitization. We provide a transcriptional map of inflammatory cells and define a module of gene expression that distinguishes immune cell-driven allergic responses in the obese intestine. Overall, our findings highlight obesity-induced inflammatory changes in the intestine that may mediate the increased food allergic sensitization during obesity.
MicroRNA-155 promotes cardiac inflammation, fibrosis, and impairs heart function during Pseudomonas aeruginosa infection
Authors: Rajaram Murugesan , Pestrak Matthew , Murphy Nathaniel , Wu Qian , Lubbers Ellen , Dellos-Nolan Sheri , Saljoughian Noushin , Yu Lianbo , Lafuse William P , Ganesan Latha P. , Mohler Peter , Wozniak Daniel 
Published: January 2023

Abstract
Pneumonia in ICU patients carries a bleak prognosis with high risk for cardiac dysfunction, largely due to cardiac inflammation with subsequent tissue remodeling and fibrosis. Growing evidence indicates that resident macrophages are important regulators of cardiac electrical activity and damage following myocardial infarction. After tissue injury, inflammatory monocytes are recruited to the heart and differentiate into macrophages, which contribute to cardiac dysfunction. MicroRNAs have a key role in the regulation and maintenance of macrophage function and cardiac inflammation. However, it is unclear if microRNAs regulate immune cell recruitment or the function of cardiac resident macrophages. To investigate how bacterial pneumonia promotes cardiac dysfunction, we used P. aeruginosa infection in a murine pulmonary model of infection. Our results show an aberrant cardiac electrical activity, and compromised pump function in P. aeruginosa infected animals. Notably, we found increased cardiac fibrosis mainly due to the accumulation of inflammatory macrophages in the heart. Additionally, we found that miR-155 deficiency reversed the P. aeruginosa mediated cardiac dysfunction by limiting the immune cell migration in to the heart. These findings demonstrate that P. aeruginosa infection induces miR-155 dependent immune cell recruitment to the heart, which changes the phenotype and function of resident macrophages, resulting in elevated cardiac fibrosis and heart function.
A butyrate-producing bacterium Clostridium butyricum prevents Clostridioides difficile infection independent of GPR43/109a
Authors: Hayashi Atsushi , Kamada Nobuhiko 
Published: January 2023

Abstract
Short-chain fatty acids, such as butyrate, are microbial metabolites that harbor bioactivities beneficial to the gastrointestinal health. Clostridium butyricum MIYAIRI588 (CBM) is a bacterium that produces a robust amount of butyrate and therefore used as a live biotherapeutic product in clinical settings. Clostridioides difficile (C. diff) is a bacterium that causes life-threatening diarrhea and colitis. The gut resident microbiota plays a critical role in the prevention of C. diff infection (CDI), as the disruption of the healthy microbiota by antibiotics greatly increases the risk of CDI. In this study, we examined how CBM protects the host from CDI, the mechanism which is not yet completely understood.
Mice were pre-treated with cefoperazone to disrupt the gut microbiota and then infected with the C. diff VPI10463 strain to induce CDI. CBM treatment significantly improved body weight loss and mortality caused by CDI and increased neutrophils in colonic lamina propria (cLP) in the early phase of CDI. The protective effect of CBM was canceled when neutrophils were depleted by an anti-Ly6G antibody, suggesting that neutrophils may play a key role in the process. The administration of tributyrin, which elevates the concentration of butyrate in the colon, increased neutrophils in the cLP, indicating that increased butyrate produced by CBM regulates the neutrophil pool. Since it has been reported that butyrate-GPR43 signaling is crucial for neutrophils migration, we next examined the effect of CBM on CDI in GPR43/109a double knockout mice. Unexpectedly, the protective effect of CBM was retained in these mice. These results indicated that CBM prevents CDI possibly through butyrate but independent of GPR43/109a-mediated signaling.
DDX3X Cellular Valency Allows Stressed Cells to Make a Live or Die Cell Fate Decision by Regulating Stress Granules and the NLRP3 Inflammasome
Authors: Samir Parimal , Kesavardana Sannula , Kanneganti Thirumala-Devi 
Published: January 2023

AbstractCells of the immune system have to respond to a variety of stressors to help maintain organismal homeostasis. Stress sensing can lead to the assembly of a cytoplasmic membraneless compartment called stress granules (SGs) that helps the cells survive. Cellular stress can also lead to activation of the NLRP3 inflammasome and induction of pyroptosis – a pro-inflammatory programmed cell death. Thus SGs and the NLRP3 inflammasome provide contrasting cell fate choices to a stressed cell – cell survival or pyroptosis. DDX3X is an integral component of SGs [1]. We show that DDX3X promotes the NLRP3 inflammasome activation and ASC speck assembly[2]. Our data suggests that induction of SGs inhibits the NLRP3 inflammasome activation by sequestering the DDX3X molecules. It also suggests that SGs and the NLRP3 inflammasome compete for DDX3X molecules, which makes DDX3X cellular valency critical for this decision making process[3]. Using LPS mediated peritonitis model, we further show that DDX3X promotes and SGs inhibit the NLRP3 inflammasome activation in vivo. Our data points towards a mechanistic paradigm where cells can exploit the cellular valency of biomolecules and a competition between biological processes for common essential factors to make cell fate decisions.
GITR expressed on macrophages functions as an inflammatory amplifier by promoting NLRP3 inflammasome activation
Authors: Liang Siping , Liu Yiting , Wu Yongjian , Ming Siqi , Wu Minhao 
Published: January 2023

Abstract
Glucocorticoid-induced tumor necrosis factor receptor (GITR) is an important co-stimulatory molecule on lymphocytes, however, its role on innate immunity and inflammatory response remains unclear. Our in vivo and in vitro data showed that bacterial infection up-regulated GITR expression in mouse macrophages. Treatment with agonistic anti-GITR Ab (DTA-1) enhanced, while knockout of GITR reduced the macrophage pyroptosis after bacterial infection. Furthermore, ELISA, Western blot and immune-fluorescence staining data indicated that GITR promoted NLRP3 inflammasome activation by inducing NLRP3 deubiquitination and ASC oligomerization, without affecting the priming stage. More importantly, we found that GITR expression was enhanced on peripheral monocytes/macrophages of sepsis patients vs healthy donors. Using cecal ligation and puncture (CLP) model of sepsis, we demonstrated that GITR triggered NLRP3 inflammasome activation to exacerbate disease progression, while this effect was reversed by treatment with specific inhibitor for NLRP3 or Caspase-1. Overall, our study demonstrated that GITR expressed on macrophages functions as an inflammatory amplifier by promoting NLRP3 inflammasome activation. These findings give a better understanding of GITR in innate immune response, which may also provide potential therapeutic targets of infectious and inflammatory diseases.
Cell-type specific role of non-canonical inflammasome during LPS septic shock
Authors: Kumari Puja , Russo Ashley , Rathinam Vijay 
Published: January 2023

Abstract
Cytosolic sensing of LPS through caspase-11 is the key step of non-canonical inflammasome activation and innate immune defense against Gram-negative bacterial infections. Upon LPS sensing, caspase-11 induces GSDMD-mediated pore formation in the plasma membrane, followed by maturation and secretion of caspase-1 and pro-inflammatory cytokines (IL1band IL18). Excessive pore formation on the membrane leads to pyroptotic death of cell and release of intracellular proteins; many of which exacerbate the immune responses to infection, leading to cytokine storm, tissue damage, organ failure, and death. Caspase-11 sensing of LPS occurs in various cell-types, however the contribution of these cell-types to non-canonical inflammasome mediated pyroptosis, cytokine release, and lethality during LPS septic shock is poorly understood. To understand the cell type-specific role of caspase-11 during LPS septic shock, caspase-11 was conditionally deleted in multiple cell-types including macrophages by utilizing caspase-11 floxed mice and several appropriate Cre strains. The conditional KOs of caspase-11 were subjected to LPS challenge and various responses were assessed. Our in vivostudies showed cell-type specific contribution of caspase-11 to intracellular LPS-induced responses such as gasdermin D activation and lethality. Particularly, myeloid cell-intrinsic expression of caspase-11 is required for pathological manifestations of intracellular LPS sensing. Overall, our findings provide new insights into the cell type-specific role of cytosolic LPS sensing.
Mitochondria-targeted Sulfide Delivery Molecules – New and Novel Players that can Suppress and Reverse Cigarette Smoke-induced Inflammasome Activity
Authors: Hansbro Nicole G , Pacitti Dario , Brown Alexandra , Torregrossa Roberta , Balachandran Lois , Kumar Vinod , Wood Mark , Haw Tatt-Jhong , Scotton Chris , Whiteman Matt , Hansbro Philip 
Published: January 2023

Abstract

RATIONALE
Cigarette smoke (CS) is the major risk factor in development of chronic obstructive pulmonary disease (COPD). Interventions that can prevent and/or reverse disease are urgently needed. Hydrogen sulfide (H2S) is generated in mitochondria (mt) and crucial in maintaining mt respiration, suppressing oxidative stress/inflammation. Lung H2S levels are reduced after CS exposure. Lung inflammation, mitochondrial damage and oxidative injury are exacerbated as a result of inhibition/silencing of H2S enzymes, suggesting impairment of H2S synthesis/loss of bioavailability is detrimental in COPD and negatively impacts mitochondrial health.

METHODS
We have produced novel mt-targeted H2S donors (mtH2SD) AP39 and RT01 to investigate whether these molecules could suppress and/or reverse CS-induced inflammation and lung injury. To investigate suppression, mice were exposed to CS (or air) for 8 wks (with 1.0 mg/kg). To investigate reversal, mice were exposed to CS for 8 wks followed by either 4 wks rest or continued CS exposure, each with mtH2SD (1.0 mg/kg). Airway inflammation (BALF differential cell counts, IL-1β by ELISA) and lung function were assessed.

RESULTS
Lung H2S levels were reduced and inflammasome activity increased in response to CS exposure. mtH2SD significantly suppressed CS-induced alveolar destruction, fibrosis and improved lung function. mtH2SD treatment reversed CS-induced lung neutrophil, eosinophil and macrophage infiltration, loss of lung function, and partially reversed airway resistance in both models.

CONCLUSIONS
Targeting H2S to mitochondria may be a novel therapeutic approach to prevent and/or reverse mitochondria-driven inflammation and lung injury in COPD and related diseases.
Effect of tobacco smoke on respiratory syncytial virus-induced high-mobility group box 1-mediated innate antiviral signaling
Authors: Hosakote Yashoda Madaiah , Kempaiah Kempaiah Rayavara , Kurosky Alexander 
Published: January 2023

Abstract
Exposure to tobacco smoke (TS), either direct or secondhand, is associated with an increase in the severity of lower respiratory tract infections, including bronchiolitis, mainly caused by respiratory syncytial virus (RSV). No vaccine or effective treatment is available for RSV. Although the mechanism of TS-induced RSV severity remains largely unknown, lung immune responses are key. High Mobility Group Box-1 (HMGB1) is a multifunctional nuclear protein that is released to the extracellular space during infection and regulates inflammatory responses as damage-associated molecular pattern. The goal of this study is to dissect the role of HMGB1 in the activation of antiviral signaling in RSV and TS-induced airway inflammation. Studies were conducted in airway epithelial cells, including A549 and normal small alveolar epithelial cells. We show that RSV and TS-induced oxidative stress post-translationally modifies HMGB1 including hyperacetylation, phosphorylation, and oxidation, leading to its enhanced extracellular secretion from lung epithelial cells. Secreted HMGB1 activates signaling cascades to activate p38 MAPK and NF-κB to induce proinflammatory mediator release from immune cells and induce inflammation. We also show that hmgb1 knockdown exacerbates inflammation in RSV-infected and TS-exposed cells and that treatment with recombinant HMGB1 activates immune cells to induce an inflammatory response, promotes the activation of antiviral pathways and inhibits viral replication. Our studies suggest an important role for HMGB1 in TS-induced RSV pathogenesis and guide the development of novel therapeutic strategies against respiratory infections that are caused or exacerbated by environmental toxicants such as TS.