bluuebunny/crossref_metadata_2025_split huggingface dataset:
Granzyme K: An Important Mediator of Cutaneous Inflammation and Re‐epithelialization
Authors: Richardson Katlyn , Turner Chris , Zeglinski Matthew , Zhao Hongyan , Shen Yue , Granville David 
Published: June 2021

BackgroundGranzyme K (GzmK) is a serine protease traditionally thought as having a role in immune cell‐mediated killing. However, recent evidence has challenged this paradigm. We now believe GzmK is a mediator of inflammation. GzmK is elevated in plasma from patients with a variety of pro‐inflammatory disorders, including allergic asthma, endotoxemia, and sepsis. In addition, culture of endothelial cell, lung fibroblasts and activated macrophages with purified GzmK induces the secretion of pro‐inflammatory cytokines. In the present study we hypothesized that GzmK is elevated in cutaneous inflammation and contributes to impaired reepithelialization of cutaneous wounds.MethodsGzmK expression was evaluated histologically in tissue from patients with a variety of inflammatory skin diseases and compared to healthy skin controls. Using a murine model of skin injury and repair, the role of GzmK was investigated. Wound severity was assessed macroscopically, comparing onset, severity and wound resolution between GzmK−/− and wildtype mice. Wound tissue was isolated and examined histologically, including wound morphometry (wound area, re‐epithelialization, epidermal thickness), GzmK expression, collagen organization (Masson's Trichrome, picosirius red, Collage I/III), inflammation (markers of T‐cells, macrophages, NK cells), angiogenesis (CD31) and fibrosis (α‐SMA). To further verify the role of GzmK in cutaneous inflammation, cultured keratinocytes and skin fibroblasts were exposed to GzmK and cytokine expression, cellular proliferation and viability were assessed.ResultsGzmK was markedly increased in biopsies from patients with skin wounds compared to normal skin, with negligible levels observed. Macrophages, namely classically activated M1, were identified as the predominant cell type responsible for GzmK expression and secretion. GzmK−/− mice exhibited expedited wound closure and wound maturation compared to equivalent wounds in wild‐type mice. Re‐epithelialization had the greatest disparity between GzmK−/− and wild‐type mice; vastly accelerated epithelialization observed in GzmK−/− mice suggests that keratinocytes may be particularly sensitive to GzmK insult. Additionally, in vitro cultured keratinocytes exhibited impaired wound healing, including decreased cell migration and viability, and an increase in pro‐inflammatory cytokines when exposed to GzmK.ConclusionGzmK is an important mediator of cutaneous inflammation and epithelialization; functioning to enhance the pro‐inflammatory phase of wound repair whilst simultaneously hindering re‐epithelialization.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Role of Mitochondrial Peroxide Release in the Mechanisms Underlying Age‐Related Sarcopenia
Authors: Van Remmen Holly , Pharaoh Gavin , Ahn Bumsoo 
Published: June 2021

Age related loss of muscle mass and function (sarcopenia) is a major contributor to reduced quality of life in the elderly. Previous studies from our laboratory have shown that denervation induced alterations in muscle mitochondrial reactive oxygen species (ROS) generation is an integral player in this process. To specifically determine the role of mitochondrial function, generation of ROS and lipid peroxides in denervation atrophy, we utilized two transgenic mouse models with increased expression of the hydrogen peroxide scavengers catalase or peroxiredoxin 3, specifically in skeletal muscle. First, we asked whether these mitochondrial antioxidants can reduce denervation induced changes in muscle mitochondrial ROS production and reduce muscle atrophy in a surgical denervation model. Gastrocnemius mass is significantly reduced (~20%) at 7 days post‐sciatic nerve transection in wildtype, skmPrdx3 and skmMCAT mice, i.e., there was no protective effect of hydrogen peroxide scavengers on denervation atrophy. ROS production measured using the fluorescent probe Amplex Red was elevated in permeabilized muscle fibers and isolated mitochondria from denervated hindlimb 7 days post transection and neither Prdx3 or MCAT expression inhibits the signal. This data supports that the Amplex Red signal does not represent hydrogen peroxide alone, but includes the response from other lipid peroxide species and suggests that hydrogen peroxide scavenging is not sufficient to reduce denervation induced atrophy. Next, we asked whether Prdx3 muscle specific expression can modulate the sarcopenia phenotype in an established mouse model of accelerated sarcopenia, mice lacking CuZnSOD (Sod1KO/skmPrdx3Tg mice). ROS generation is significantly elevated in isolated muscle mitochondria from Sod1KO mice, and normalized by Prdx3 overexpression in the Sod1KO/skmPrdx3Tg mice. The oxygen consumption rate is reduced in skeletal muscle mitochondria isolated from Sod1KO muscle and restored by Prdx3 overexpression. We also found that in vitro contractile force generation was decreased by ~20% in Sod1KO mice, and the force reduction wwas rescued in Sod1KO/skmPrdx3Tg mice. Importantly, the muscle atrophy that occurs in the Sod1KO mice is fully restored by Prdx3 overexpression. This finding demonstrates a direct role of skeletal muscle‐specific mitochondrial H2O2 in promoting contractile abnormalities and muscle atrophy. Together these results implicate mitochondrial H2O2 generation as a novel therapeutic target to ameliorate skeletal muscle pathologies and support further studies to elucidate the role of lipid peroxide mediators released by mitochondria in denervation induced atrophy.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Transcriptional Activation of Lipogenic Genes by Insulin/Feeding
Authors: Sul Hei Sook 
Published: June 2021

Insulin treatment or feeding a high carbohydrate diet causes a marked increase in fatty acid and fat synthesis and enzymes involved in lipogenesis are coordinately induced. We are studying transcriptional activation of lipogenic genes, employing fatty acid synthase (FAS) as a model system. We defined insulin response element at ‐65 E‐box and USF binding at this site for transcriptional activation by insulin. USF and SREBP‐1c, by binding at adjacent sites, directly interact and function together. We identified various other components of the USF complex and their posttranslational modifications by feeding/insulin treatment. USF‐1 recruits and is phosphorylated by DNA‐PK allowing recruitment and acetylation by P/CAF, resulting in the FAS promoter activation, whereas, in fasting, USF‐1 is deacetylated by HDAC9. USF also recruits Brg1/Brm‐associated factor (BAF) 60c that functions as a specific chromatin‐remodeling component for lipogenic gene transcription. In response to insulin, BAF60c is phosphorylated at S247 by atypical PKCζ/λ, which causes translocation of BAF60c to the nucleus, allowing a direct interaction with USF‐1. Thus, BAF60c is recruited to form the lipoBAF complex to remodel chromatin structure. Recently, we also found that by direct interaction USF‐1 recruits specific histone demethylase for histone modification and transcriptional activation of various lipogenic genes.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hepatic Oleate Deficiency Represses De Novo Lipogenesis and Enhances Systemic Glucose Utilization Through FGF21 During High Carbohydrate Feeding
Authors: Ntambi James Mukasa , Aljohani Ahmed , Bonneville Abram , Bond Laura 
Published: June 2021

Increased carbohydrate consumption and subsequently increased hepatic de novo lipogenesis have been linked to the development of chronic metabolic diseases including hepatic steatosis and insulin resistance. Stearoyl CoA desaturase 1 (SCD1) is a critical lipogenic enzyme that catalyzes the synthesis of monounsaturated fatty acids, oleate and palmitoleate, from saturated fatty acids, stearate and palmitate, respectively. SCD1 deficient mouse models exhibit protection against diet induced adiposity, hepatic steatosis, and hyperglycemia. However, the mechanism of this protection in response to SCD1 deficiency is not fully understood. Using a liver specific SCD1 knockout (LKO) mouse model fed a high carbohydrate low fat diet, we show that hepatic SCD1 deficiency decreases de novo lipogenesis and glycogen accumulation but instead increases tissue glucose uptake and utilization. Reduced hepatic oleate levels led to increased expression of GLUT4 and adiponectin expression in WAT and BAT. High molecular weight plasma adiponectin species were also increased. Glut‐1 expression was increased in the liver, small intestine, spleen and brain. The induction of glucose utilization in LKO mice correlated with higher hepatic expression and plasma levels of fibroblast growth factor 21 (FGF21), a hepatokine known to increase systemic insulin sensitivity and regulate whole body glucose and lipid metabolism. Feeding LKO mice with a diet rich in oleate, but not stearate reduced hepatic FGF21 expression and plasma levels. Consistently, inhibition of SCD1 activity in primary hepatocytes induced FGF21 expression which was repressed by treatment with oleate but not palmitoleate. These data suggest that hepatic oleate regulates systemic glucose metabolism either directly or through modulating plasma FGF21 and adiponectin.Support or Funding InformationNIH, ADAThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Emodin, a natural anthraquinone, may help protect gastrointestinal health during chemotherapy treatment by decreasing inflammation of the gastric mucosa and preserving gut morphology
Authors: Sougiannis Alexander T. , Kelley Brittany , Velazquez Kandy E. , Enos Reilly T. , Bader Jackie E. , Chatzistamou Ioulia , Pena Marjorette M. , Nagarkatti Mitzi , Carson sJames A. , Fan Daping , Murphy E. Angela 
Published: June 2021

The clinical utility of 5‐fluorouracil (5FU) chemotherapy remains hampered by hematopoietic and gastrointestinal toxicities. Emodin, a natural anthraquinone, has been shown to have anti‐inflammatory potential and may be effective as a complementary therapeutic used during chemotherapy treatments. The purpose of this study was to evaluate the efficacy of emodin on reducing the non‐specific toxicities associated with 5FU treatment. 50 C57BL/6 were randomized into four groups; Control + Vehicle (n=5), Control + Emodin (n=5), 5FU + Vehicle (n=20), 5FU + Emodin (n=20). 5FU was administered via I.P. over 3 cycles of the following regime: 5 consecutive days of 5FU at 35mg/kg followed by 9 days of recovery. Emodin was administered via oral gavage 3x/week at 40mg/kg through the entire 3 cycles of 5FU treatment. 5FU + Emodin treated mice showed improved muscular strength (p<0.05), fun‐to‐fatigue time (P<0.05), and peripheral nociception (p<0.05) compared to 5FU + Vehicle treated mice. 5FU + Emodin treated mice did not show recovery of decreased circulating immune cells and red blood cells that is common with 5FU treatment. 5FU + Vehicle treated mice did show slightly increased splenic CD11b+ F4/80+ macrophages (6.8%) vs. control mice (4.3%), a phenotype that was not decreased in 5FU + Emodin treated mice (6.5%). 5FU treatment shows classic inflammatory damage to the gastric mucosa. 5FU + Vehicle treated mice show decreased villus length (p<0.05) compared to control mice. 5FU + Emodin treated mice showed increased villus length (p<0.05) compared to 5FU + Vehicle treated mice but remained shorter (p<0.05) than control mice. Further, small intestine tissue shows increased TNFα expression in 5FU + Vehicle treated mice which was decreased (p<0.05) in 5FU + Emodin treated mice. Similar increases in inflammatory gene expression are seen in the colon tissue of 5FU + Vehicle treated mice. 5FU + Emodin treated mice show decreased colonic TNFα expression (p<0.05) and trending decrease in MCP‐1 (p=0.052) and NOS2 (p=0.065) expression compared to 5FU + Vehicle treated mice. Taken together, Emodin treatment may contribute to improved GI health by reducing damaging inflammation which may contribute to improved overall quality of life. Future analysis will expand on the inflammatory signaling pathways involved in emodin signaling and will investigate the potential role of the gut microbiome in reducing GI inflammation in this model of 5FU treatment.Support or Funding Information1F31AT009820 to ATS.1RO1CA218578 to EAM. 1R41AT009964 to EAM. 5R21CA191966 to EAM.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
GUT BACTERIA MODULATE T CELL RESPONSES AND ADVERSE CARDIAC REMODELING IN PRESSURE OVERLOAD INDUCED HEART FAILURE
Authors: Carrillo‐Salinas Francisco J , Ngwenyama Njabulo , Anastasiou Marina , Kaur Kuljeet , Aronovitz Mark , Alcaide Pilar 
Published: June 2021

Changes in the bacterial composition of the gut, defined as gut dysbiosis, are recently becoming associated with the pathogenesis of heart failure (HF), a leading cause of mortality worldwide. Certain bacteria promote T cell activation, and T cell activation contributes to adverse cardiac remodeling and cardiac dysfunction in HF. We tested the hypothesis that gut dysbiosis modulates cardiac remodeling and function in a T cell‐dependent manner. C57/BL6 mice were orally treated with a wide spectrum antibiotic cocktail (ABX) and subjected to transverse aortic constriction (TAC), a stablished model of HF. ABX was present during the 4 week duration of TAC, thus sterilizing the gut completely, or during 3 weeks before TAC followed by removal during the 4 weeks of TAC duration to allow spontaneous reconstitution of the gut microbiota. We report that gut microbiota depletion results in reduced T cell activation in the mediastinal lymph nodes, heart T cell infiltration, and prevents cardiac fibrosis and cardiac hypertrophy in response to TAC. However, gut dysbiosis induced by bacterial reconstitution after ABX removal, only partially recovered this phenotype. We used 16S RNA sequencing to characterize the bacterial populations in Sham, TAC, and in ABX treated TAC mice after ABX removal and spontaneous bacterial colonization in the gut (TAC‐REC). TAC induced changes in the gut microbiota compared to Sham surgery, which at the genus level resulted in a higher relative abundance of Bacteroides (p=0.048) and lower relative abundance of Coprococcus (p=0.024), Lactobacillus (p=0.021) and Bifidobacterium (p=0.042), these last two normally associated to an anti‐inflammatory response. Bacterial reconstitution in TAC‐REC mice started after 2 weeks of ABX removal, but was incomplete even by 4 weeks post ABX removal, as reflected by the different relative bacterial abundance between TAC and TAC‐REC 4 weeks post TAC. Several genera were identified as colonizing the gut in TAC‐REC mice that could potentially be associated with cardiac dysfunction. Ongoing studies are focused on the characterization of bacterial populations responsible for this effect and on determining the type of T cell response involved.Support or Funding InformationThis work was supported by the NIH‐R01‐HL123658.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
β1‐Blockers Provide Cardioprotection, Attenuation of Intramyocardial Inflammation and Leukocyte Endothelial Transmigration in Septic Mice
Authors: Mansart Arnaud , Efthimiadi Laurie , Vinit Stéphane , Fayssoil Abdallah , Annane Djillali 
Published: June 2021

Septic cardiac dysfunction is a key feature of severe sepsis and septic shock, contributing to multiorgan dysfunction syndrome and death. Persistent β adrenergic stimulation is detrimental in sepsis, and specific β1 blockade mitigates excessive systemic inflammation and seems to improve myocardial function. The aim of this study was to investigate the effects of the specific β1 blocker atenolol on the septic mouse myocardium. We also evaluated the survival of septic mice and systemic inflammation in response to atenolol treatment.Mice were rendered septic using intraperitoneal injection of lipopolysaccharide (LPS). The effects of atenolol on the myocardium were assessed by a microarray technique and were confirmed by subsequent western blot, elisa protein assays and confocal microscopy. Infusion of atenolol significantly reduced the intramyocardial production of the proinflammatory cytokines tumor necrosis factor α (TNF‐α), interleukin 1β (IL‐1β) and interleukin‐6 (IL‐6) in the septic model. Cell adhesion molecules and local myocardial chemotaxis were down‐regulated, with a significant reduction in the myocardial levels of angiopoietin 2 (Ang‐2), monocyte chemoattractant protein 1 (MCP‐1), macrophage inflammatory protein 1α (MIP‐1α), MIP‐2, E‐selectin, P‐selectin, intracellular adhesion molecule 1 (ICAM‐1) and vascular cell adhesion molecule 1 (VCAM‐1). Furthermore, atenolol significantly improved left ventricular ejection fraction, arterial pressure and aortic blood flow in septic mice. The median survival time was increased by atenolol in septic model, and the plasma levels of lactate, TNF‐α, IL‐1β, IL‐6, MCP‐1 and MIP‐1α were significantly reduced in response to atenolol treatment.In mice with experimentally induced septic shock, the β1 adrenergic blocker atenolol exerts cardioprotective effects through the tempering of both systemic and local inflammation and by reducing intramyocardial chemotaxis and the synthesis of endothelial transmigration proteins.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cutaneous and Gastrointestinal Dysbiosis in Immunodeficient Mice
Authors: Fowlkes Natalie Wall , Swain Jody , Gagea Mike , Lockworth Cynthia , Tinkey Peggy , Jensen Vanessa , Whitley Elizabeth 
Published: June 2021

The health of immunodeficient rodent strains used for tumor modeling is often challenged by increased susceptibility to overgrowth of organisms which are not normally pathogenic in immunocompetent mice. Herein, we describe spontaneously occurring skin and gastrointestinal lesions in a cohort of immunodeficient mice. In the current case series, NOD‐SCID‐gamma and athymic nude mice presented clinically moribund with thickened, scaly, erythematous cutaneous lesions covering the head, neck, and trunk. Examination of hematoxylin and eosin (H&E) stained sections revealed marked acanthosis and orthokeratotic hyperkeratosis with large numbers of coccobacilli in the lamellar layers of keratin of epidermis in affected animals. Variable mild dermal inflammation was present. Gram‐positive pleomorphic rods were cultured from skin and identified as Corynebacterium bovis via qPCR. Staphylococcus xylosus was also cultured in a case that had abundant Gram‐positive cocci bacteria in the skin. C. bovis and S. xylosus have been associated with a “scaly skin” syndrome in immunodeficient mice. Acanthosis and hyperkeratosis with coccobacilli were also present in the keratinized portion of the stomach. Additionally, affected mice frequently had massive proliferation of segmented filamentous bacteria (SFB) in the small intestine. Impaired immune responses in immunodeficient strains may lead to a constellation of clinical signs and pathology which represent a form of dysbiosis. Investigation of dysbiosis in immunodeficient mice used in cancer research is important for maintaining the health of the colony and for accurate interpretation of research outcomes.Support or Funding InformationSupported by the NIH/NCI under award number P30CA016672 and the Research Animal Support Facility‐Houston.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effect of Different Auditory Stimuli on Laparoscopic Skill Acquisition
Authors: Grant Sara , Singh Aman , Roach Victoria 
Published: June 2021

INTRODUCTIONLiterature suggests that listening to music decreases the time required for a surgeon to perform surgical skills, and improves their overall performance. However, little is known about how the surgeon's preference or response to that particular music affects the rate at which they learn a novel skill. The primary goal of this study is to explore how different auditory conditions impact the rate of acquisition of an introductory surgical skill, the intracorporeal knot.METHODSParticipants will be naïve to surgical skills (medical students), and prescreened for demographics, history of musical experiences, and their use of music as a study aid. A cognitive pre‐test will be employed to assess baseline participant performance with, and without the presence of music. This will serve to stratify individuals into two groups: those whose performance thrives, or declines, in the presence of music. An equal proportion of individuals from each group will be randomly assigned to one of four auditory training conditions: participant‐preferred music, randomized music, ambient noise, and silence. Participants will watch an instructional video on the technique of the intracorporeal knot and will have 80 minutes to practice the task to proficiency. Proficiency is defined in the literature by the Fundamentals of Laparoscopic Surgery as a maximum of 112 seconds with no knots occurring outside of 1mm. Learning curves will be analyzed to determine the rate of acquisition for each group.ANTICIPATED RESULTSWe anticipate that participants will master the intracorporeal knot tying task fastest under the preferred music condition, and slowest in the randomized music condition.CONCLUSIONWhen the music is reflective of the surgeon's personal taste, it could be beneficial for the acquisition of new surgical skills. However, non‐preferred music could negatively impact skill acquisition and would suggest that minimizing of the use of music in operating rooms when residents are present would generate a more efficient learning environment.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.