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Adam L Haber, Moshe Biton, Noga Rogel, Rebecca H Herbst, Karthik Shekhar, Christopher Smillie, Grace Burgin, Toni M Delorey, Michael R Howitt, Yarden Katz, Itay Tirosh, Semir Beyaz, Danielle Dionne, Mei Zhang, Raktima Raychowdhury, Wendy S Garrett, Orit Rozenblatt-Rosen, Hai Ning Shi, Omer Yilmaz, Ramnik J Xavier, Aviv Regev
Intestinal epithelial cells absorb nutrients, respond to microbes, function as a barrier and help to coordinate immune responses. Here we report profiling of 53,193 individual epithelial cells from the small intestine and organoids of mice, which enabled the identification and characterization of previously unknown subtypes of intestinal epithelial cell and their gene signatures. We found unexpected diversity in hormone-secreting enteroendocrine cells and constructed the taxonomy of newly identified subtypes, and distinguished between two subtypes of tuft cell, one of which expresses the epithelial cytokine Tslp and the pan-immune marker CD45, which was not previously associated with non-haematopoietic cells...
November 16, 2017: Nature
M Pucci Molineris, V Gonzalez Polo, Federico Perez, D Ramisch, M Rumbo, G E Gondolesi, D Meier
Graft survival after small bowel transplantation remains impaired due to acute cellular rejection (ACR), the leading cause of graft loss. Although it was shown that the number of enteroendocrine progenitor cells in intestinal crypts was reduced during mild ACR, no results of Paneth and intestinal stem cells localized at the crypt bottom have been shown so far. Therefore, we wanted to elucidate integrity and functionality of the Paneth and stem cells during different degrees of ACR, and to assess whether these cells are the primary targets of the rejection process...
November 15, 2017: American Journal of Transplantation
H B Jijon, L Suarez-Lopez, O E Diaz, S Das, J De Calisto, M B Yaffe, M J Pittet, J R Mora, Y Belkaid, R J Xavier, E J Villablanca
Retinoic acid (RA), a dietary vitamin A metabolite, is crucial in maintaining intestinal homeostasis. RA acts on intestinal leukocytes to modulate their lineage commitment and function. Although the role of RA has been characterized in immune cells, whether intestinal epithelial cells (IECs) rely on RA signaling to exert their immune-regulatory function has not been examined. Here we demonstrate that lack of RA receptor α (RARα) signaling in IECs results in deregulated epithelial lineage specification, leading to increased numbers of goblet cells and Paneth cells...
November 15, 2017: Mucosal Immunology
Marion Darnaud, Alexandre Dos Santos, Patrick Gonzalez, Sandrine Augui, Claire Lacoste, Christophe Desterke, Gert De Hertogh, Emma Valentino, Emilie Braun, Jinzi Zheng, Raphael Boisgard, Christel Neut, Laurent Dubuquoy, Franck Chiappini, Didier Samuel, Patricia Lepage, Francesca Guerrieri, Joel Doré, Christian Bréchot, Nicolas Moniaux, Jamila Faivre
BACKGROUND & AIMS: Paneth cell dysfunction causes deficiencies in intestinal C-type lectins and antimicrobial peptides, which leads to dysbiosis of the intestinal microbiota, alters the mucosal barrier, and promotes development of inflammatory bowel diseases. We investigated whether transgenic expression of the human regenerating family member 3 alpha gene (REG3A) alters the fecal microbiota and affects development of colitis in mice. METHODS: We performed studies with C57BL/6 mice that express human regenerating family member 3 alpha (hREG3A) in hepatocytes, via the albumin gene promoter...
November 10, 2017: Gastroenterology
Xiaoshi Ma, Zhaolai Dai, Kaiji Sun, Yunchang Zhang, Jingqing Chen, Ying Yang, Patrick Tso, Guoyao Wu, Zhenlong Wu
The intestinal epithelial cells serve essential roles in maintaining intestinal homeostasis, which relies on appropriate endoplasmic reticulum (ER) function for proper protein folding, modification, and secretion. Exogenous or endogenous risk factors with an ability to disturb the ER function can impair the intestinal barrier function and activate inflammatory responses in the host. The last decade has witnessed considerable progress in the understanding of the functional role of ER stress and unfolded protein response (UPR) in the gut homeostasis and its significant contribution to the pathogenesis of inflammatory bowel disease (IBD)...
2017: Frontiers in Immunology
Agnieszka Krzemińska, Tomasz Frączek, P Paneth
Binding isotope effects (BIEs) associated with binding of four triazole-based ligands to HIV-1 reverse transcriptase have been calculated at the QM/MM MD level of theory. Two main binding sites: allosteric cavity and RNase H active site, as well as three other sites reported in the literature (the Knuckles, the NNRTI Adjacent, and Incoming Nucleotide Binding) have been considered. The interactions between inhibitors and these protein sites have been quantified by binding free energies obtained from free energy perturbation (FEP) calculations, supported by interaction energy analysis...
October 27, 2017: Archives of Biochemistry and Biophysics
June-Chul Lee, Hae-Youn Lee, Tae Kang Kim, Min-Soo Kim, Young Mi Park, Jinyoung Kim, Kihyoun Park, Mi-Na Kweon, Seok-Hyung Kim, Jin-Woo Bae, Kyu Yeon Hur, Myung-Shik Lee
Consumption of a typical Western diet is a risk factor for several disorders. Metabolic syndrome is the most common disease associated with intake of excess fat. However, the incidence of inflammatory bowel disease is also greater in subjects consuming a Western diet, although the mechanism of this phenomenon is not clearly understood. We examined the morphological and functional changes of the intestine, the first site contacting dietary fat, in mice fed a high-fat diet (HFD) inducing obesity. Paneth cell area and production of antimicrobial peptides by Paneth cells were decreased in HFD-fed mice...
2017: PloS One
Bernard Dan, Nigel Paneth
No abstract text is available yet for this article.
October 25, 2017: Lancet Global Health
Nazar Trotsko, Agata Przekora, Justyna Zalewska, Grażyna Ginalska, Agata Paneth, Monika Wujec
In our present research, we synthesised new thiazolidine-2,4-diones (12-28). All the newly synthesised compounds were evaluated for antiproliferative and antibacterial activity. Antiproliferative evaluation was carried out using normal human skin fibroblasts and tumour cell lines: A549, HepG2, and MCF-7. The IC50 values were determined for tested compounds revealing antiproliferative activity. Moreover, safety index (SI) was calculated. Among all tested derivatives, the compound 18 revealed the highest antiproliferative activity against human lung, breast, and liver cancer cells...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Tomasz Frączek, Rafał Kamiński, Agnieszka Krakowiak, Evelien Naessens, Bruno Verhasselt, Piotr Paneth
In search of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) with improved solubility, two series of novel diaryl ethers with phenacyl moiety were designed and evaluated for their HIV-1 reverse transcriptase inhibition potentials. All compounds exhibited good to excellent results with IC50 at low micromolar to submicromolar concentrations. Two most active compounds (7e and 7 g) exhibit inhibitory potency comparable or even better than that of nevirapine and rilpivirine. Furthermore, SupT1 and CD4(+) cell infectivity assays for the most promising (7e) have confirmed its strong antiviral potential while docking studies indicate a novel binding interactions responsible for high activity...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Lulu Huang, Qihang Hou, Lulu Ye, Qian Yang, Qinghua Yu
The spread of Avian influenza virus via animal feces makes the virus difficult to prevent, which causes great threat to human health. Therefore, it is imperative to understand the survival and invasion mechanism of H9N2 virus in the intestinal mucosa. In this study, we used mouse threedimensional intestinal organoids that contained intestinal crypts and villi differentiated from intestinal stem cells to explore interactions between H9N2 avian influenza virus and the intestinal mucosa. The HA, NA, NP and PB1 genes of H9N2 viruses could be detected in intestinal organoids at 1 h, and reached peak levels at 48 h post-infection...
November 2, 2017: Veterinary Research
Yu Matsuzawa-Ishimoto, Yusuke Shono, Luis E Gomez, Vanessa M Hubbard-Lucey, Michael Cammer, Jessica Neil, M Zahidunnabi Dewan, Sophia R Lieberman, Amina Lazrak, Jill M Marinis, Allison Beal, Philip A Harris, John Bertin, Chen Liu, Yi Ding, Marcel R M van den Brink, Ken Cadwell
A variant of the autophagy gene ATG16L1 is associated with Crohn's disease, an inflammatory bowel disease (IBD), and poor survival in allogeneic hematopoietic stem cell transplant recipients. We demonstrate that ATG16L1 in the intestinal epithelium is essential for preventing loss of Paneth cells and exaggerated cell death in animal models of virally triggered IBD and allogeneic hematopoietic stem cell transplantation. Intestinal organoids lacking ATG16L1 reproduced this loss in Paneth cells and displayed TNFα-mediated necroptosis, a form of programmed necrosis...
October 31, 2017: Journal of Experimental Medicine
Suellen Laís Vicentino-Vieira, Marcelo Biondaro Góis, Aline Rosa Trevizan, Lainy Leiny de Lima, Elen Paula Leatte, Gessilda de Alcântara Nogueira de Melo, João Luiz Garcia, Eduardo José de Almeida Araújo, Débora de Mello Gonçales Sant'Ana
AIM: To evaluate the mucosal tunic and submucosal plexus of the jejunum of rats infected with different inoculum doses of Toxoplasma gondii. MAIN METHODS: Rats were infected with different inoculum doses (50, 500, 1000 and 5000 oocysts) of the T. gondii for 30days, while a control group (CG) received saline solution. Blood and feces were collected before euthanasia for analysis of blood and fecal leukocytes (LEs). Histological analysis of the mucosa, submucosa, villi, crypts and enterocytes were performed...
October 25, 2017: Life Sciences
Anna Drzazga, Agata Sowińska, Agnieszka Krzemińska, Andrzej Okruszek, Piotr Paneth, Maria Koziołkiewicz, Edyta Gendaszewska-Darmach
GPR119 receptor has been proposed as a metabolic regulator playing a pivotal role in the modulation of glucose homeostasis in type 2 diabetes. GPR119 was identified on pancreatic β cells and its ligands have the ability to enhance glucose-stimulated insulin secretion (GSIS). Lysophosphatidylcholine (LPC) was shown to potentiate GSIS and our present studies indicate that 2-methoxy-lysophosphatidylcholine (2-OMe-LPC) analogues, unable to undergo 1→2 acyl migration, stimulate GSIS from murine βTC-3 pancreatic cells even more efficiently...
October 24, 2017: Biochimica et Biophysica Acta
Katarzyna M Romek, Agnieszka Krzemińska, Gérald S Remaud, Maxime Julien, Piotr Paneth, Richard J Robins
Many O-methyl and N-methyl groups in natural products are depleted in (13)C relative to the rest of the molecule. These methyl groups are derived from the C-1 tetrahydrofolate pool via l-methionine, the principle donor of methyl units. Depletion could occur at a number of steps in the pathway. We have tested the hypothesis that methionine biosynthesis is implicated in this depletion by using a combined experimental and theoretical approach. By using isotope ratio monitoring (13)C NMR spectrometry to measure the position-specific distribution of (13)C within l-methionine of natural origin, it is shown that the S-methyl group is depleted in (13)C by ∼20‰ relative to the other positions in the molecule...
October 23, 2017: Archives of Biochemistry and Biophysics
Agata Paneth, Tomasz Frączek, Agnieszka Grzegorczyk, Dominika Janowska, Anna Malm, Piotr Paneth
Using molecular modeling approach, potential antibacterial agents with triazole core were proposed. A moderate to weak level of antibacterial activity in most of the compounds have been observed, with best minimal inhibitory concentration (MIC) value of 0.003 mg/mL, as shown by the 15 against S. epidermidis. Studied compounds were also submitted to the antifungal assay. The best antifungal activity was detected for 16 with MIC at 0.125 and 0.25 mg/mL against C. albicans and C. parapsilosis, respectively.
October 25, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Tatsuro Murano, Mehran Najibi, Geraldine L C Paulus, Fatemeh Adiliaghdam, Aida Valencia-Guerrero, Martin Selig, Xiaofei Wang, Kate Jeffrey, Ramnik J Xavier, Kara G Lassen, Javier E Irazoqui
Understanding the transcription factors that modulate epithelial resistance to injury is necessary for understanding intestinal homeostasis and injury repair processes. Recently, transcription factor EB (TFEB) was implicated in expression of autophagy and host defense genes in nematodes and mammalian cells. However, the in vivo roles of TFEB in the mammalian intestinal epithelium were not known. Here, we used mice with a conditional deletion of Tfeb in the intestinal epithelium (Tfeb (ΔIEC)) to examine its importance in defense against injury...
October 24, 2017: Scientific Reports
Eiko Hayase, Daigo Hashimoto, Kiminori Nakamura, Clara Noizat, Reiki Ogasawara, Shuichiro Takahashi, Hiroyuki Ohigashi, Yuki Yokoi, Rina Sugimoto, Satomi Matsuoka, Takahide Ara, Emi Yokoyama, Tomohiro Yamakawa, Ko Ebata, Takeshi Kondo, Rina Hiramine, Tomoyasu Aizawa, Yoshitoshi Ogura, Tetsuya Hayashi, Hiroshi Mori, Ken Kurokawa, Kazuma Tomizuka, Tokiyoshi Ayabe, Takanori Teshima
The intestinal microbial ecosystem is actively regulated by Paneth cell-derived antimicrobial peptides such as α-defensins. Various disorders, including graft-versus-host disease (GVHD), disrupt Paneth cell functions, resulting in unfavorably altered intestinal microbiota (dysbiosis), which further accelerates the underlying diseases. Current strategies to restore the gut ecosystem are bacteriotherapy such as fecal microbiota transplantation and probiotics, and no physiological approach has been developed so far...
October 24, 2017: Journal of Experimental Medicine
Barbara Kapron, Robert Czarnomysy, Agata Paneth, Monika Wujec, Krzysztof Bielawski, Anna Bielawska, Lukasz Swiatek, Barbara Rajtar, Malgorzata Polz-Dacewicz, Tomasz Plech
A group of 4-benzoyl-1-dichlorobenzoylthiosemicarbazides endowed with antibacterial activity were evaluated towards their cytotoxic properties against breast cancer cells (MCF-7, MDA-MB-231) and head and neck squamous cell carcinomas (FaDu, SCC-25). Cytotoxicity of the investigated compounds was measured using MTT and [3H]-thymidine incorporation bioassays. 1-(2,3-Dichlorobenzoyl)-4-(2-methylbenzoyl)thiosemicarbazide (TA-4), 1-(2,4-dichlorobenzoyl)-4-(2-methylbenzoyl)thiosemicarbazide (TA-18), and 1-(2,4-dichlorobenzoyl)-4-(4-nitrolbenzoyl)thiosemicarbazide (TA-20) were found to possess anticancer activity equipotent or even stronger than that of reference drug - etoposide...
October 23, 2017: Anti-cancer Agents in Medicinal Chemistry
Agata Paneth, Wojciech Płonka, Piotr Paneth
Despite vigorous studies, effective nonnucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) are still in demand, not only due to toxicity and detrimental side effects of currently used drugs but also because of the emergence of multidrug-resistant viral strains. In this contribution, we present results of docking of 47 inhibitors to 107 allosteric centers of HIV-1 reverse transcriptase. Based on the average binding scores, we have constructed QSAR equations to elucidate directions of further developments in the inhibitor design that come from this structural data...
October 19, 2017: Journal of Molecular Modeling
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