bluuebunny/crossref_metadata_2025_split huggingface dataset:
α‐Tocopherol–a systematic review of intake and status globally
Authors: Eggersdorfer Manfred 
Published: November 2023

ObjectiveReview the published literature reporting vitamin E intake levels and serum concentration in order to obtain a global overview of vitamin E status. Vitamin E is essential for human health and achieving an optimal status is associated with beneficial health outcomes. Dietary recommendations are established in many countries around the world and refer to the important role of vitamin E in preserving the integrity of the cell membrane. The outcome and comparison of intake versus actual status should provide new insights for recommendations.MethodA search in the Pubmed/Medline database focused on population based studies published between January 1st 2000 and July 30th 2012 and resulted in 176 articles referring to 132 single studies with reported intake and/or serum concentration.ResultsApplying a Recommended Daily Allowance (RDA) of 15 mg/d to all populations with a minimum age of 14 years, 82% and 61% of mean and median data points were below the RDA and EAR, respectively. Regarding serum concentrations, globally 13% of the included data points were below the functional deficiency threshold concentration of 12 μmol/L (F.a.N. Board 2000), mostly newborns and children. Several prospective observational studies suggest that a serum α‐tocopherol concentration of 30 μmol/L and above to have beneficial effects on human health. Of the reported study populations and subpopulations, only 21% reached this threshold globally.ConclusionsThe systematic review suggests that the vitamin E status is inadequate in a substantial part of the studies populations. This review could be a useful stepping‐stone for researchers to combine existing data, fill in data gaps and to understand more about the complex field of vitamin E and its impact on human health.
Neutrophil microparticles deliver active myeloperoxidase to injured mucosa to inhibit epithelial wound healing
Authors: Sumagin Ronen , Finkielsztein Ariel , Slater Thomas , Mascarenhas Lorraine Lorraine , Mehl Lindsey , Butin‐Israeli Veronika 
Published: November 2023

Neutrophil (PMN) infiltration of the intestinal mucosa often leads to severe epithelial injury, however how this process occurs is unclear. The current work describes a novel mechanism, whereby membrane derived microparticles released by tissue infiltrating PMNs (PMN‐MPs) serve as shuttles to protect and deliver active mediators to locally modulate cellular function during inflammation. Specifically, myeloperoxidase (MPO), which is abundantly expressed in PMN azurophilic granules and is used for microbial killing, was found to be mobilized to the PMN surface and subsequently released in association with PMN‐MPs upon PMN activation and binding to intestinal epithelial cells (IECs). The enzymatic activity of PMN‐MP‐associated MPO was enhanced compared to soluble protein, leading to potent inhibition of wound closure following PMN‐MP binding to IECs. Importantly, localized microinjection of PMN‐MPs into wounded colonic mucosa was sufficient to impair epithelial wound healing in vivo. PMN‐MPs/MPO‐dependent inhibition of IEC wound healing was due to impaired IEC migration and proliferation, resulting from impeded actin dynamics, cell spreading, and cell cycle arrest. Thus, our findings provide new insight into mechanisms governing PMN‐induced tissue injury, and implicate PMN‐MPs and MPO as important regulators of cellular function.Support or Funding InformationThis work was supported by grants from the National Institutes of Health (NIH) DK101675 as well as American Cancer Society IRG‐9303718.
Desmoglein‐2 Intracellular Cleavage and Intestinal Epithelial Barrier Compromise
Authors: Yulis Mark , Quiros Miguel , Hilgarth Roland , Nusrat Asma 
Published: November 2023

The intestinal epithelial barrier is comprised of a monolayer of simple columnar intestinal epithelial cells (IECs) that serve to protect underlying tissues from antigens and pathogens. Under conditions of intestinal inflammation this barrier breaks down, allowing these antigens and pathogens to gain access to the underlying mucosa. The aim this project is to further our understanding of the mechanisms responsible for barrier breakdown during intestinal inflammation. Epithelial barrier properties are achieved by a series of intercellular junctions that include an Apical Junctional Complex and desmosomes. The intercellular contacts of desmosomes are established by transmembrane cadherin proteins, the desmogleins and desmocollins. Pro‐inflammatory cytokines (e.g. interferon gamma (IFN‐γ) and tumor necrosis factor alpha (TNF‐α)) induce cadherin cleavage and the resulting cadherin protein fragments influence epithelial homeostasis. Using model IECs plated on transwell permeable supports, we have observed that IFN‐γ and TNF‐α or TNF‐α related apoptosis inducing ligand (TRAIL) induce desmoglein‐2 (Dsg2) intracellular cleavage resulting in generation of an intracellular fragment (ICF). This Dsg2 intracellular cleavage is, in part, mediated by caspase activation and occurs prior to Dsg2 extracellular cleavage. Previously published data suggests that Dsg2 ICF generation is associated with redistribution of another desmosomal protein, plakoglobin (Pg). We show here that exogenous expression of Myc‐tagged Dsg2 ICF using adenoviral expression constructs results in downregulation of key Pg signaling targets (c‐Myc and Bcl‐XL), increases apoptosis, and decreassd cell proliferation. Taken together, our findings suggest that IFN‐γ and TNF‐α induced Dsg2 ICF generation activates Pg signaling thereby promoting increased epithelial apoptosis and reduced proliferation.Support or Funding InformationIntestinal Epithelial Tight Junction Structure‐Function: R01 DK059888‐15
Intestinal P‐glycoprotein exports endogenous cannabinoids at the epithelial surface to prevent inflammation and maintain homeostasis
Authors: Szabady Rose L , Mrsny Randall J , McCormick Beth A 
Published: November 2023

Neutrophil influx into the intestine plays a critical protective role during infection with pathogens, but is also associated with the severe intestinal damage seen in idiopathic inflammatory bowel disease (IBD). Transmigration of neutrophils across the epithelium and into the lumen is particularly associated with tissue destruction, increased barrier permeability, and inflammatory pathology. This transepithelial migration is driven by the chemoattractant activity of hepoxilin A3 (HXA3), an eicosanoid secreted from the epithelial surface by the MRP2 efflux pump. MRP2 is upregulated in response to inflammatory stimuli including bacterial infection or epithelial damage, and we have confirmed that MRP2 secretion of HXA3 drives neutrophil transmigration in a variety of inflammatory models. Concurrent with MRP2 upregulation, a second ABC transporter, P‐glycoprotein (P‐gp), is down‐regulated at the epithelial surface during inflammation. We therefore investigated whether P‐gp was responsible for transporting immunomodulatory lipids that act to counterbalance the MRP2/HXA3 pro‐inflammatory axis.Mass spectrometry analysis of epithelial supernatants revealed that endocannabinoids were specifically secreted into the supernatant only in the presence of P‐gp. Further analysis revealed that specific P‐gp secreted endocannabinoids of the N‐acyl ethanolamine class were capable of suppressing neutrophil migration in vitro, and that this suppression was functional in vivo. Having established that under homeostatic conditions, P‐gp constitutively secretes anti‐inflammatory endocannabinoids, we investigated how perturbation of this system affects the development of intestinal inflammation.P‐gp deficient mice are known to develop spontaneous inflammation, consistent with our finding that P‐gp secretes anti‐inflammatory endocannabinoids. CB2 is the peripheral cannabinoid receptor found on immune cells, and we predicted that the neutrophils of CB2‐deficient mice would be unable to respond to P‐gp secreted endocannabinoids and would thus be primed for inflammation. Induction of colitis in CB2‐deficient mice resulted in increased pathology and neutrophil influx into the intestinal lumen. Bone marrow chimera experiments confirmed that these effects resulted from a lack of CB2 in the hematopoietic compartment. These results define a key role for epithelial cells in balancing secretion of anti‐inflammatory and pro‐inflammatory lipids via surface efflux pumps in order to maintain homeostasis in the healthy intestine, yet remain poised to drive neutrophil transmigration in response to pathogens.Support or Funding InformationThese studies were supported by NIH R01 DK056754 to B.A. McCormick and R.J. Mrsny and NIH F32 DK098973 to R.L. Szabady.
Increased Intestinal Permeability Secondary To Junctional Adhesion Molecule‐A Deficiency Results In Impaired Macrophage‐Dependent Neutrophil Recruitment In A Zymosan Peritonitis Model
Authors: Luissint Anny Claude , Williams Holly C , Kim Wooki , Hilgarth Roland S , O'Leary Monique , Flemming Sven , Reed Michelle , Denning Timothy L , Nusrat Asma , Parkos Charles A 
Published: November 2023

JAM‐A is a transmembrane protein expressed on endothelial and epithelial cells as well as on the surface of leukocytes. Studies with JAM‐A knockout mice (JAM‐A−/−), have provided evidence that JAM‐A may facilitate tissue recruitment of neutrophils (PMN); however mechanisms regulating JAM‐A‐dependent migration of PMN in‐vivo is not well understood. Here, we used a zymosan‐induced peritonitis model to study the recruitment of PMN in total knockout mice (JAM‐A −/−) and compared results to those obtained in mice with tissue selective deletion of JAM‐A in myelomonocytic cells (LysMcre; JAM‐Afl/fl) and the intestinal epithelium (Villin‐Cre; JAM‐Afl/fl). Consistent with a previous report, infiltration of PMN in the peritoneum in response to zymosan was decreased in JAM‐A−/− versus JAM+/+ mice. Surprisingly, in LysMcre; JAM‐A fl/fl mice, the number of PMN recruited into the peritoneum was not significantly affected by the specific loss of JAM‐A in myeloid cells compared to control littermates. Given that zymosan is a potent stimulus for peritoneal macrophages, we investigated the effect of the loss of JAM‐A on macrophage immune responses. While peritoneal macrophages from JAM‐A+/+ and JAM‐A−/− mice were similarly capable of phagocytizing zymosan, JAM‐A −/− macrophages showed significantly decreased production of the PMN chemokine CXCL1/KC that was dependent on the transcription factor NFkB. Interestingly, zymosan‐stimulated production of immune mediators from macrophages was not significantly affected by the specific loss of JAM‐A in myelomonocytic cells. These findings suggested that extrinsic factors contribute to the defective PMN migration observed in zymosan exposed JAM‐A−/− mice. We thus hypothesized that blunted peritoneal macrophage responses in JAM‐A−/− mice may be secondary to the known increase in intestinal permeability and bacterial translocation in these mice. Comparison of peritoneal macrophage subsets in total knockout and tissue selective JAM‐A deficient mice (Villin‐Cre; JAM‐Afl/fl) revealed increased numbers of poor CXCL1 producing macrophages (F4/80low) compared to high producers (F4/80high). Our results suggest that a leaky intestinal barrier and enhanced microbial translocation as observed in JAM‐A deficiency indirectly blunts neutrophil recruitment through effects on macrophage release of inflammatory mediators. Such observations highlight an important functional link between the intestinal barrier and regulation of innate immune responses.Support or Funding InformationRO1 DK072564‐21
Initial Autophagic Protection Switches to Disruption of Autophagic Flux by Lysosomal Instability during Cadmium Stress Accrual in Renal NRK‐52E Cells
Authors: Thevenod Frank , Lee Wing‐Kee , Santoyo‐Sánchez Mitzi P. , Probst Stephanie , Kerek Evan , Prenner Elmar J 
Published: November 2023

The renal proximal tubule (PT) is the major target of cadmium (Cd2+) toxicity where Cd2+ causes stress and apoptosis. Autophagy is induced by cell stress, e.g. endoplasmic reticulum (ER) stress, and may contribute to cell survival or death. The role of autophagy in Cd2+‐induced nephrotoxicity remains unsettled due to contradictory results and lack of evidence for autophagic machinery damage by Cd2+.Cd2+‐induced autophagy in the rat kidney PT cell line NRK‐52E and its role in cell death was investigated. Autophagy markers LC3‐II and p62 indicate rapid induction of autophagic flux by Cd2+ (5–10μM) after 1h, accompanied by ER stress (increased p‐PERK, p‐eIF2α, CHOP). Cd2+ exposure exceeding 3h results in p62/LC3‐II accumulation, but diminished effect of lysosomal inhibitors (bafilomycin A1, pepstatin A+E64d) on p62/LC3‐II levels, indicating decreased autophagic flux and cargo degradation. At 24h exposure, Cd2+ (5–25μM) activates intrinsic apoptotic pathways (Bax/Bcl‐2, PARP1), which are not evident earlier (≤ 6h) despite decreased cell viability by MTT assay. Autophagy inducer rapamycin (100nM) does not overcome autophagy inhibition or Cd2+‐induced cell viability loss. The autophagosome‐lysosome fusion inhibitor liensinine (5μM) increases CHOP and Bax/Bcl‐2 dependent apoptosis by low Cd2+ stress, but not by high Cd2+. Lysosomal instability by Cd2+ (5μM; 6h) is indicated by increased cellular sphingomyelin and membrane fluidity and decreased cathepsins and LAMP1.The data suggest dual and temporal impact of Cd2+ on autophagy: Low Cd2+ stress rapidly activates autophagy counteracting damage but Cd2+ stress accrual disrupts autophagic flux and lysosomal stability, possibly resulting in lysosomal cell death.Support or Funding InformationCenter for Biomedical Training and Research (ZBAF) of the University of Witten/Herdecke (F.T.), Deutsche Forschungsgemeinschaft (TH345/11‐1 to F.T.), Max Kade Foundation (W.‐K.L.), CONACYT (Consejo Nacional de Ciencia y Tecnología, Mexico) (235537 to M.P.S.‐S.), and NSERC Discovery grant (E.J.P.)
RNA decay and quality control by the eukaryotic RNA exosome
Authors: Lima Christopher D. 
Published: November 2023

RNA processing or decay by the multi‐subunit eukaryotic RNA exosome is catalyzed by two associated ribonucleases, Rrp44 (aka Dis3) and Rrp6. The activities of these enzymes are modulated and coordinated by a non‐catalytic nine‐subunit core in addition to other co‐factors that link the RNA exosome to processing complexes that deliver and prepare RNA substrates for processing and/or degradation. Results will be presented from ongoing biochemical and structural studies that are aimed at understanding how RNA exosome co‐factors coordinate the activities of the RNA exosome.Support or Funding InformationSupported in part by a grant from the National Institutes of Health (GM118080)
Redox control of the metabolome and the aging process
Authors: Gladyshev Vadim 
Published: November 2023

Biological diversity among mammals is remarkable and is reflected in their transcriptomes and metabolomes. By profiling metabolites in brain, heart, kidney, and liver tissues across mammalian species, we uncovered metabolite patterns characteristic of organs, lineages, and species longevity. Our data suggest different rates of metabolite divergence across organs and reveal patterns representing organ‐specific functions and lineage‐specific physiologies. We identified metabolites that correlated with species lifespan, some of which were previously implicated in longevity control. We similarly examined metabolite changes in several long‐lived mouse models. One process relevant to lifespan control is the methionine pathway. Reduced levels of this amino acid can extend lifespan in rodents, but whether this regimen represents a general strategy for regulating aging has been controversial. We found that methionine restriction can extend lifespan in several model organisms, and that this effect is dependent on the status of other amino acids. Methionine can also be easily oxidized, requiring a designated repair process. Overall, this study describes adjustments of the mammalian metabolome according to lifespan, phylogeny, and organ and lineage specialization, and highlights the role of redox regulation.Support or Funding InformationNational Institutes of Health
Role of hepatocyte nuclear factor 4 alpha (HNF4α) in hepatocyte regeneration
Authors: Huck Ian , Apte Udayan 
Published: November 2023

Liver has remarkable capacity to regenerate upon surgical resection or chemical injury, which is critical for liver homeostasis. Recent studies have shown that HNF4α, the master regulator of hepatic differentiation, inhibits hepatocyte proliferation. However, the role of HNF4α in liver regeneration is not known. We hypothesized that hepatocytes modulate HNF4α expression and function to navigate between differentiated and proliferative states during liver regeneration. First we examined HNF4α expression and activity in liver regeneration after partial hepatectomy (PH) using three‐month‐old male C57BL/6 mice over a two‐week time course. While HNF4α mRNA expression did not change, western blot analysis showed a rapid decline in nuclear HNF4α protein levels within 1 hour post‐PH, which continued until 6 hours. Nuclear HNF4α protein levels began increasing 12 hours post‐PH but remained significantly lower than normal till 3 days post‐PH and recovered to pre‐PH levels at 5 days post‐PH. Cytoplasmic levels mimicked that nuclear expression pattern. Expression of several positive target genes of HNF4α involved in hepatocyte differentiation declined and expression of negative target genes of HNF4α involved in cell proliferation increased consistent with HNF4α protein changes. Next, we studied the role of HNF4α in liver regeneration after PH using conditional hepatocyte‐specific HNF4α knockout mice (HNF4α‐KO). Despite increased proliferative marker expression in HNF4α‐KO livers at all time points following PH, we observed 100% mortality by day 11 in the HNF4α‐KO group. qPCR analysis of HNF4α target genes 7 days post‐PH showed sustained loss of HNF4α transcriptional activity lasting until the termination phase of regeneration, indicating that hepatocytes were unable to compensate for the loss of HNF4α. This correlated with decreased hepatocyte function in HNF4α‐KO livers post‐PH as measured by serum bilirubin levels. Finally, AAV8‐mediated reexpression of HNF4α into HNF4α‐KO livers post‐PH restored HNF4α protein levels and target gene expression. HNF4α re‐expression extended survival of HNF4α‐KO mice. These data indicate that decrease in HNF4α expression and activity is required for initiation of cell cycle after PH. Furthermore, resumption of HNF4α activity is necessary for the redifferentiation of hepatocytes during termination phase of regeneration. These studies, for the first time, demonstrate that HNF4α reprogramming is a critical step in liver regeneration and could have potential therapeutic benefits.Support or Funding InformationR01DK98414
Beta‐catenin dependent Wnt signaling promotes hepatocyte‐to‐cholangiocyte transdifferentiation
Authors: Kosar Karis , Nejak‐Bowen Kari 
Published: November 2023

The Wnt/β‐catenin pathway has been identified as a critical regulator of liver development and physiology, and is involved in wide variety of liver pathologies, including atypical ductular proliferation during hepatobiliary injury. Previously, we published mice expressing a mutated non‐degradable form of β‐catenin (S45D) in liver have a significant number of hepatocytes expressing cholangiocyte markers after long‐term exposure to 0.1% 3,5‐ diethoxycarbonyl‐1,4‐dihydro‐collidine (DDC) compared to wild‐type (WT) littermates. There was also marked improvement in intrahepatic cholestasis and an upregulation of Wnt7A, ‐7B, and ‐10A in the portal triad of DDC‐fed mice. Due to these findings we hypothesize that β‐catenin dependent signaling induced hepatocyte‐to‐cholangiocyte transdifferentiation, which may alleviate some of the complications caused by cholangiopathies. To study this we exposed Mdr2 knockout (KO) mice, a murine model for chronic periductular inflammation and cholestatic liver disease, to GC‐1 diet, an analog of the T3 thyroid hormone that activates β‐catenin. We determined Mdr2 KO mice on GC‐1 diet had decreased bilirubin, liver to body weight ratios, fibrosis, and total β‐catenin compared to Mdr2 KO mice on normal diet. The ratio of non‐phosphorylated, active β‐catenin to total β‐catenin was significantly increased in Mdr2 KO mice on GC‐1 diet compared to both the Mdr2 KO and WT mice on normal diet. Surprisingly, however, there was no increase in either ductular proliferation or Sox‐9 expressing transdifferentiating hepatocytes in Mdr2 KO on GC‐1 diet, indicating the activation of an alternative pathway downstream of β‐catenin that we did not initially anticipate. Thus, we demonstrate that the protective effect of b‐catenin activation in a mouse model of cholestasis, albeit through an as‐yet unknown mechanism that will be elucidated in future studies.Support or Funding InformationNational Institute of Biomedical Imaging and Bioengineering of the National Institute of Health under Award Number T32EB0010216UPP Academic Foundation Award 1R01DK103775
Differential Activation of Itch vs Pain C‐fibers by Mast Cell Stimulation in Mouse Skin
Authors: Jurcakova Danica , Ru Fei , Dong Xinzhong , Undem Bradley 
Published: November 2023

Allergic skin reactions are often itchy, but seldom painful. We addressed the hypothesis that mast cell activation preferentially stimulates itch nerves in the mouse skin. Nerves that evoke itch in mouse skin can be identified by their expression of MrgprA3 and selective activation by chloroquine (CQ) (Cell. 2009,139:1353–65). We have developed a unique innervated isolated dorsal skin preparation in which action potential discharge in single afferent nerves terminating in the skin can be evaluated with an extracellular electrode positioned in the dorsal root ganglia. The dissected section skin includes the main arterial supply through which chemical stimuli are delivered directly to the receptive field. CQ strongly stimulated (12 ± 1Hz) only C‐fibers (0.8 ± 0.01 m/s). Among 228 C‐fibers from 138 mice, 26% were CQ and histamine sensitive; so‐called “itch C‐fibers”. Capsaicin stimulated 73% of the CQ sensitive C‐fibers. The response to CQ, but not histamine was absent in Mrgpr cluster knock out animals. The majority of capsaicin‐sensitive C‐fibers are not stimulated by CQ, but are activated by ATP or 5‐HT; a population likely comprising “pain C‐fibers”. Mice were actively sensitized to ovalbumin (OVA). OVA added to the sensitized skin activates mast cells leading to mast cell mediator release strong activation of 12 of 12 CQ‐sensitive C‐fibers (6 ± 2 Hz). Conversely OVA‐activation of mast cells did not or only very modestly activated the non‐itch, pain population of C‐fibers (1.6 ± 2 Hz, n=30). The itch fibers do not respond to 5‐HT (0 of 24 responded), so it is unlikely that 5‐HT contributes to the activation of itch nerves. CQ‐sensitive C‐fibers respond to histamine 100 μM with only 4 ± 1 Hz discharge, so it is likely that mediators in addition to histamine are involved. We have previously noted that mast cells can release MrgprC11 agonists (J Immunol. 2008, 180:2251–5). BAM8‐22, a MrgprC11 agonist, stimulated 13 of 13 CQ‐sensitive C‐fibers (12 ± 2 Hz), but not CQ‐insensitive fibers (only 3 of 29 stimulated) thereby mimicking the effect of mast cells activation. We hypothesize that mast cell mediators that stimulate Mrgpr C11 may contribute to the response.Support or Funding InformationSupprted by NIH