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Title:
Dietary carbohydrate restriction improves metabolic syndrome independent of weight loss
Authors:
Hyde, Parker N; Sapper, Teryn N; Crabtree, Christopher D; LaFountain, Richard A; Bowling, Madison L; Buga, Alex; Fell, Brandon; McSwiney, Fionn T; Dickerson, Ryan M; Miller, Vincent J; Scandling, Debbie; Simonetti, Orlando P; Phinney, Stephen D; Kraemer, William J; King, Sarah A; Krauss, Ronald M; Volek, Jeff S
Abstract:
BACKGROUNDMetabolic syndrome (MetS) is highly correlated with obesity and cardiovascular risk, but the importance of dietary carbohydrate independent of weight loss in MetS treatment remains controversial. Here, we test the theory that dietary carbohydrate intolerance (i.e., the inability to process carbohydrate in a healthy manner) rather than obesity per se is a fundamental feature of MetS.METHODSIndividuals who were obese with a diagnosis of MetS were fed three 4-week weight-maintenance diets that were low, moderate, and high in carbohydrate. Protein was constant and fat was exchanged isocalorically for carbohydrate across all diets.RESULTSDespite maintaining body mass, low-carbohydrate (LC) intake enhanced fat oxidation and was more effective in reversing MetS, especially high triglycerides, low HDL-C, and the small LDL subclass phenotype. Carbohydrate restriction also improved abnormal fatty acid composition, an emerging MetS feature. Despite containing 2.5 times more saturated fat than the high-carbohydrate diet, an LC diet decreased plasma total saturated fat and palmitoleate and increased arachidonate.CONCLUSIONConsistent with the perspective that MetS is a pathologic state that manifests as dietary carbohydrate intolerance, these results show that compared with eucaloric high-carbohydrate intake, LC/high-fat diets benefit MetS independent of whole-body or fat mass.TRIAL REGISTRATIONClinicalTrials.gov Identifier: NCT02918422.FUNDINGDairy Management Inc. and the Dutch Dairy Association.
Published:
June 20, 2019
Title:
An Atlas of Human Glycosylation Pathways Enables Display of the Human Glycome by Gene Engineered Cells
Authors:
Narimatsu, Yoshiki; Joshi, Hiren J.; Nason, Rebecca; Coillie, Julie Van; Karlsson, Richard; Sun, Lingbo; Ye, Zilu; Chen, Yen-Hsi; Schjoldager, Katrine T.; Steentoft, Catharina; Furukawa, Sanae; Bensing, Barbara A.; Sullam, Paul M.; Thompson, Andrew J.; Paulson, James C.; Büll, Christian; Adema, Gosse J.; Mandel, Ulla; Hansen, Lars; Bennett, Eric Paul; Varki, Ajit; Vakhrushev, Sergey Y.; Yang, Zhang; Clausen, Henrik
Abstract:
Summary
The structural diversity of glycans on cells—the glycome—is vast and complex to decipher. Glycan arrays display oligosaccharides and are used to report glycan hapten binding epitopes. Glycan arrays are limited resources and present saccharides without the context of other glycans and glycoconjugates. We used maps of glycosylation pathways to generate a library of isogenic HEK293 cells with combinatorially engineered glycosylation capacities designed to display and dissect the genetic, biosynthetic, and structural basis for glycan binding in a natural context. The cell-based glycan array is self-renewable and reports glycosyltransferase genes required (or blocking) for interactions through logical sequential biosynthetic steps, which is predictive of structural glycan features involved and provides instructions for synthesis, recombinant production, and genetic dissection strategies. Broad utility of the cell-based glycan array is demonstrated, and we uncover higher order binding of microbial adhesins to clustered patches of O-glycans organized by their presentation on proteins.
Published:
June 18, 2019
Title:
Doxorubicin-Induced p53 Interferes with Mitophagy in Cardiac Fibroblasts
Authors:
Mancilla, T. R.; Aune, G. J.
Abstract:
Doxorubicin is a mainstay in pediatric chemotherapy treatment because of its efficacy treating leukemia and lymphoma. Unfortunately, every childhood cancer survivor will develop a chronic health problem, one of the most serious being cardiac disease. How doxorubicin damages the heart in such a way that disease progression occurs over multiple decades is still not understood. The dose of doxorubicin selected does not cause apoptosis but does arrest cell cycle. It also decreases the cells ability to migrate. Gene profiling indicated a cardiac remodeling and inflammatory profile. Mitochondria increased ROS production and underwent membrane depolarization. Secondly, the Parkin:p53 interaction mechanism was investigated. Doxorubicin was found to increase p53 expression and it was shown to sequester Parkin. As a result, mitophagy in doxorubicin-treated cells was decreased. Lastly, cardiac fibroblasts were isolated from p53 null mice and treated with doxorubicin. The gene expression phenotype in these cells was attenuated and migration was restored. Proliferation was still decreased. Mitochondrial dysfunction was also partially attenuated. Without p53, Parkin could now localize to the mitochondria and mitophagy was restored. Doxorubicin induces a deleterious phenotype in cardiac fibroblasts that may be due to the interaction between two stress responses caused by doxorubicin-induced DNA and mitochondrial damage. Cardiac fibroblasts are a viable target and further research needs to be done to elucidate other harmful mechanisms at play in the fibroblast. Knowledge about the importance of cardiac fibroblasts in the development of doxorubicin-induced cardiotoxicity and a pathological mechanism broadens our understanding and ability to develop protective therapies to improve the quality of life of cancer survivors.
Published:
June 17, 2019
Title:
Evolution of facial muscle anatomy in dogs
Authors:
Kaminski, Juliane; Waller, Bridget; Diogo, Rui; Hartstone-Rose, Adam; Burrows, Anne
Abstract:
Domestication shaped wolves into dogs and transformed both their behavior and their anatomy. Here we show that, in only 33,000 y, domestication transformed the facial muscle anatomy of dogs specifically for facial communication with humans. Based on dissections of dog and wolf heads, we show that the levator anguli oculi medialis, a muscle responsible for raising the inner eyebrow intensely, is uniformly present in dogs but not in wolves. Behavioral data, collected from dogs and wolves, show that dogs produce the eyebrow movement significantly more often and with higher intensity than wolves do, with highest-intensity movements produced exclusively by dogs. Interestingly, this movement increases paedomorphism and resembles an expression that humans produce when sad, so its production in dogs may trigger a nurturing response in humans. We hypothesize that dogs with expressive eyebrows had a selection advantage and that “puppy dog eyes” are the result of selection based on humans’ preferences.
Published:
June 17, 2019
Title:
SIRT3 Regulates Macrophage-Mediated Inflammation in Diabetic Wound Repair
Authors:
Boniakowski, Anna M.; denDekker, Aaron D.; Davis, Frank M.; Joshi, Amrita; Kimball, Andrew S.; Schaller, Matthew; Allen, Ron; Bermick, Jennifer; Nycz, Dylan; Skinner, Mary E.; Robinson, Scott; Obi, Andrea T.; Moore, Bethany B.; Gudjonsson, Johann E.; Lombard, David; Kunkel, Steve L.; Gallagher, Katherine A.
Abstract:
Control of inflammation is critical for the treatment of nonhealing wounds, but a delicate balance exists between early inflammation that is essential for normal tissue repair and the pathologic inflammation that can occur later in the repair process. This necessitates the development of novel therapies that can target inflammation at the appropriate time during repair. Here, we found that SIRT3 is essential for normal healing and regulates inflammation in wound macrophages after injury. Under prediabetic conditions, SIRT3 was decreased in wound macrophages and resulted in dysregulated inflammation. In addition, we found that FABP4 regulates SIRT3 in human blood monocytes, and inhibition of FABP4 in wound macrophages decreases inflammatory cytokine expression, making FABP4 a viable target for the regulation of excess inflammation and wound repair in diabetes. Using a series of ex vivo and in vivo studies with genetically engineered mouse models and diabetic human monocytes, we showed that FABP4 expression is epigenetically upregulated in diabetic wound macrophages and, in turn, diminishes SIRT3 expression, thereby promoting inflammation. These findings have significant implications for controlling inflammation and promoting tissue repair in diabetic wounds.
Published:
June 15, 2019
Title:
IL-23–producing IL-10Rα–deficient gut macrophages elicit an IL-22–driven proinflammatory epithelial cell response
Authors:
Bernshtein, Biana; Curato, Caterina; Ioannou, Marianna; Thaiss, Christoph A.; Gross-Vered, Mor; Kolesnikov, Masha; Wang, Qian; David, Eyal; Chappell-Maor, Louise; Harmelin, Alon; Elinav, Eran; Thakker, Paresh; Papayannopoulos, Venizelos; Jung, Steffen
Abstract:
A Colitis Circuit Cytokines are known to play a critical role in maintaining gut homeostasis, but their specific cellular sources are less well understood. Here, Bernshtein et al. used a murine model of inflammatory bowel disease (IBD) in which macrophages specifically lack expression of interleukin-10 receptor (IL-10R), and mice developed symptoms of spontaneous colitis similar to that observed in children with IL-10R mutations. They identified macrophage-derived IL-23 as the cytokine critical to induce the pathology. IL-23 triggered accumulation and IL-22 production by TH17 cells that, in turn, promoted production of chemokines by colonic epithelial cells and destructive neutrophil recruitment. Together, these results reveal the mechanism by which intestinal IL-10R–deficient macrophages drive IBD pathogenesis. Cytokines maintain intestinal health, but precise intercellular communication networks remain poorly understood. Macrophages are immune sentinels of the intestinal tissue and are critical for gut homeostasis. Here, we show that in a murine inflammatory bowel disease (IBD) model based on macrophage-restricted interleukin-10 (IL-10) receptor deficiency (Cx3cr1Cre:Il10rafl/fl mice), proinflammatory mutant gut macrophages cause severe spontaneous colitis resembling the condition observed in children carrying IL-10R mutations. We establish macrophage-derived IL-23 as the driving factor of this pathology. Specifically, we report that Cx3cr1Cre:Il10rafl/fl:Il23afl/fl mice harboring macrophages deficient for both IL-10R and IL-23 are protected from colitis. By analyzing the epithelial response to proinflammatory macrophages, we provide evidence that T cells of colitic animals produce IL-22, which induces epithelial chemokine expression and detrimental neutrophil recruitment. Collectively, we define macrophage-specific contributions to the induction and pathogenesis of colitis, as manifested in mice harboring IL-10R deficiencies and human IBDs. Proinflammatory IL-10R–deficient colonic macrophages trigger defined T cell and epithelial responses causing colitis. Proinflammatory IL-10R–deficient colonic macrophages trigger defined T cell and epithelial responses causing colitis.
Published:
June 14, 2019
Title:
The Association Between Lower Levels of Low-Density Lipoprotein Cholesterol and Cancer Predates the Diagnosis of Cancer by 18 Years
Authors:
Lavigne, Paul Michael; Jafri, Haseeb; Karas, Richard
Abstract:
We recently reported, in a meta-analysis of statin trials, a strong association between low concentrations of low-density lipoprotein cholesterol (LDL-C) and incident cancer risk. Interpretation of these data has been a point of significant debate. At issue is whether low LDL-C concentration
Published:
June 11, 2019
Title:
Single-photon emission computed tomography/computed tomography imaging of RAGE in smoking-induced lung injury
Authors:
Goldklang, Monica P.; Tekabe, Yared; Zelonina, Tina; Trischler, Jordis; Xiao, Rui; Stearns, Kyle; Rodriguez, Krissy; Shields, Alexander; Romanov, Alexander; D’Armiento, Jeanine M.; Johnson, Lynne L.
Abstract:
Expression of the Receptor for Advanced Glycation Endproducts (RAGE) initiates pro-inflammatory pathways resulting in lung destruction. We hypothesized that RAGE directed imaging demonstrates increased lung uptake in smoke-exposure.
Published:
June 10, 2019
Title:
The subunit assembly state of the Mediator complex is nutrient-regulated and is dysregulated in a genetic model of insulin resistance and obesity
Authors:
Youn, Dou Yeon; Xiaoli, Alus M.; Kwon, Hyokjoon; Yang, Fajun; Pessin, Jeffrey E.
Abstract:
The Mediator complex plays a critical role in the regulation of transcription by linking transcription factors to RNA polymerase II. By examining mouse livers, we have found that in the fasted state, the Mediator complex exists primarily as an approximately 1.2-MDa complex, consistent with the size of the large Mediator complex, whereas following feeding, it converts to an approximately 600-kDa complex, consistent with the size of the core Mediator complex. This dynamic change is due to the dissociation and degradation of the kinase module that includes the MED13, MED12, cyclin-dependent kinase 8 (CDK8), and cyclin C (CCNC) subunits. The dissociation and degradation of the kinase module are dependent upon nutrient activation of mTORC1 that is necessary for the induction of lipogenic gene expression because pharmacological or genetic inhibition of mTORC1 in the fed state restores the kinase module. The degradation but not dissociation of the kinase module depends upon the E3 ligase, SCFFBW7. In addition, genetically insulin-resistant and obese db/db mice in the fasted state displayed elevated lipogenic gene expression and loss of the kinase module that was reversed following mTORC1 inhibition. These data demonstrate that the assembly state of the Mediator complex undergoes physiologic regulation during normal cycles of fasting and feeding in the mouse liver. Furthermore, the assembly state of the Mediator complex is dysregulated in states of obesity and insulin resistance.
Published:
June 7, 2019
Title:
The Spatiotemporal Pattern and Intensity of p53 Activation Dictates Phenotypic Diversity in p53-Driven Developmental Syndromes
Authors:
Bowen, Margot E.; McClendon, Jacob; Long, Hannah K.; Sorayya, Aryo; Nostrand, Jeanine L. Van; Wysocka, Joanna; Attardi, Laura D.
Abstract:
Summary
Inappropriate activation of the p53 transcription factor contributes to numerous developmental syndromes characterized by distinct constellations of phenotypes. How p53 drives exquisitely specific sets of symptoms in diverse syndromes, however, remains enigmatic. Here, we deconvolute the basis of p53-driven developmental syndromes by leveraging an array of mouse strains to modulate the spatial expression pattern, temporal profile, and magnitude of p53 activation during embryogenesis. We demonstrate that inappropriate p53 activation in the neural crest, facial ectoderm, anterior heart field, and endothelium induces distinct spectra of phenotypes. Moreover, altering the timing and degree of p53 hyperactivation substantially affects the phenotypic outcomes. Phenotypes are associated with p53-driven cell-cycle arrest or apoptosis, depending on the cell type, with gene expression programs, rather than extent of mitochondrial priming, largely governing the specific response. Together, our findings provide a critical framework for decoding the role of p53 as a mediator of diverse developmental syndromes.
Published:
June 6, 2019
Title:
Tumor cell-intrinsic EPHA2 suppresses anti-tumor immunity by regulating PTGS2 (COX-2)
Authors:
Markosyan, Nune; Li, Jinyang; Sun, Yu H.; Richman, Lee P.; Lin, Jeffrey H.; Yan, Fangxue; Quinones, Liz; Sela, Yogev; Yamazoe, Taiji; Gordon, Naomi; Tobias, John W.; Byrne, Katelyn T.; Rech, Andrew J.; FitzGerald, Garret A.; Stanger, Ben Z.; Vonderheide, Robert H.
Abstract:
Published:
June 4, 2019
Title:
Breast milk alkylglycerols sustain beige adipocytes through adipose tissue macrophages
Authors:
Yu, Haidong; Dilbaz, Sedat; Coßmann, Jonas; Hoang, Anh Cuong; Diedrich, Victoria; Herwig, Annika; Harauma, Akiko; Hoshi, Yukino; Moriguchi, Toru; Landgraf, Kathrin; Körner, Antje; Lucas, Christina; Brodesser, Susanne; Balogh, Lajos; Thuróczy, Julianna; Karemore, Gopal; Kuefner, Michael Scott; Park, Edwards A.; Rapp, Christine; Travers, Jeffrey Bryant; Röszer, Tamás
Abstract:
Published:
June 3, 2019
Title:
The Anthropogenic Use of Firewood During the European Middle Pleistocene: Charcoal Evidence from Levels XIII and XI of Bolomor Cave, Eastern Iberia (230–160 ka)
Authors:
Vidal Matutano, Paloma; Blasco, Ruth; Die, Pablo; Peris, Josep
Abstract:
Human control of fire is a widely debated issue in the field of Palaeolithic archaeology, since it involved significant technological innovations for human subsistence. Although fire evidence has been the subject of intense debate regarding its natural or anthropogenic nature, most authors agree that combustion structures represent the most direct evidence of human control of fire. Wood charcoal fragments from these contexts represent the fuel remains that result from humans’ collection of firewood, which means they can reveal significant behavioural and palaeoenvironmental information relevant to our understanding of Middle Palaeolithic societies. In this work, we present anthracological data derived from combustion structure 2 (level XIII, ca. 230 ka, MIS 7) and combustion structure 4 (level XI, ca. 160 ka, MIS 6) from Bolomor Cave, which are chronologically among the earliest combustion structures found in Europe. The present work discusses how the presence of black pine and / or scots pine in both levels sheds light on the characterisation of the local landscape. Additional analyses focussing on the pre- and post-depositional processes affecting charcoal preservation point to biodegradation patterns. The aim of this work is to provide the first discussion concerning the anthracological data derived from Bolomor Cave in order to contribute to the general debate regarding the use of fire during the European Middle Pleistocene.
Published:
June 3, 2019
Title:
A Review of the Science of Colorful, Plant-Based Food and Practical Strategies for “Eating the Rainbow”
Authors:
Minich, Deanna M.
Abstract:
Over the past decades, thousands of published studies have amassed supporting recommendations to consume fruits and vegetables for physiological and psychological health. Newer research has emerged to suggest that these plant-based foods contain a plethora of not only vitamins and minerals, but perhaps, most importantly, phytonutrients. These phytonutrients have known pleiotropic effects on cellular structure and function, ultimately resulting in the modulation of protein kinases and subsequent epigenetic modification in a manner that leads to improved outcomes. Even though eating fruits and vegetables is a well-known feature of a healthy dietary pattern, population intakes continue to be below federal recommendations. To encourage consumers to include fruits and vegetables into their diet, an “eat by color” approach is proposed in this review. Although each individual food may have numerous effects based on its constituents, the goal of this simplified approach was to identify general patterns of benefits based on the preponderance of scientific data and known mechanisms of food-based constituents. It is suggested that such a consumer-oriented categorization of these plant-based foods may lead to greater recognition of their importance in the daily diet throughout the lifespan. Other adjunctive strategies to heighten awareness of fruits and vegetables are discussed.
Published:
June 2, 2019
Title:
1906-P: Effects of a Carbohydrate-Restricted Diet on Hepatic Lipid Content in Adolescents with Nonalcoholic Fatty Liver Disease
Authors:
GOSS, AMY M.; DOWLA, SHIMA; ASHRAF, AMBIKA P.; BOLDING, MARK; MORRISON, SHANNON A.; GOWER, BARBARA
Abstract:
Background: NAFLD has emerged as the most common liver disease among adolescents in industrialized countries. Results from trials in adults with NAFLD suggest that reducing CHO intake may deplete liver fat to a greater extent than other dietary approaches, even when there was no difference in weight loss between diet groups. The objective of this study was to determine the effects of a CHO-restricted vs. fat-restricted diet in adolescents with NAFLD on reduction in hepatic lipid and insulin resistance.Methods: Twenty-three adolescents (age 9-17) with obesity (BMI ≥85th percentile) and confirmed NAFLD were randomized to a CHO-restricted (<10:25:>65% energy from CHO:protein:fat) or fat-restricted diet (55:25:20) for 8 weeks. Caloric intakes were calculated to be weight maintaining. Participants and one parent attended bi-weekly counselling with a registered dietitian. To encourage compliance, groceries were delivered to participants’ families during the first 2 weeks of the study. Both diets included minimally processed foods with limited added sugar. Change in hepatic lipid content was measured via MRI, body composition via DXA, and insulin resistance via a fasting blood sample.Results: After 8 weeks, the CHO-restricted diet group experienced a significant decrease in hepatic lipid content (-6.0±4.7%, p<0.001), whereas the fat-restricted diet group showed no change. We found significantly greater decreases in insulin resistance (HOMA-IR, -1.2±5.1, <0.05), abdominal fat mass (-1.7 ±1.1 kg, p<0.01), and body fat mass (-3.1±4.0 kg, p<0.01) in response to the CHO-restricted vs. fat-restricted diet.Conclusion: The CHO-restricted diet approach may be markedly beneficial in improving fatty liver, body composition, and insulin resistance in adolescents with NAFLD even in the absence of intentional caloric restriction. Practitioners should consider recommending this diet approach to effectively improve disease course in this patient population.Disclosure A.M. Goss: None. S. Dowla: None. A.P. Ashraf: Research Support; Self; Opko. Speaker's Bureau; Spouse/Partner; Bristol-Myers Squibb Company, Celgene Corporation, Insys, Pfizer Inc. M. Bolding: None. S.A. Morrison: None. B. Gower: None.Funding National Institute of Diabetes and Digestive and Kidney Diseases; Thrasher Research Fund
Published:
June 1, 2019
Title:
An experimental investigation of changing cut mark cross-sectional size during butchery: Implications for interpreting tool-assisted carcass processing from cut mark samples
Authors:
Merritt, Stephen R.
Abstract:
Butchery occurs at the intersection between technology, carcass processing behavior, and animal anatomy, and records traces on fragmentary specimens including cut marks. The causal factors and contexts that generate bone surface modifications have been well-studied in experimental archaeology but the ways in which cut mark size or morphology change with time during butchery in response to tool edge dulling or carcass desiccation is currently unknown. This study examines cut mark cross-sectional width and depth change during a sequence of experimental butchery trials that control for the effects of animal size, bone portion density, tool weight, and flake versus core tool type. Mark size is measured from vinyl molds under low-power magnification (40×) and compared to more precise 3d measurement techniques. Tool type and the order of carcass segment defleshing was systematically varied across the experiment, and a linear mixed effect regression model was used to explore the impact of these fixed factors and consider random variability introduced by potential differences in the four cows butchered by eight tools. Mark width and depth samples were negatively related to the density of the portion where marks occur, tool weight had a weak, but significant influence on mark size, and marks incised at different stages in the sequence of defleshing events were similar in width and depth. With current measurement techniques and the large variability in mark size produced during butchery, it is not impossible to infer the timing of mark creation during a tool's use life or its place in a sequence of butchery events, but methodological advancement may overturn this pessimistic conclusion.
Published:
June 1, 2019
Title:
Cooking in Pestenacker - Evidence from Organic Residues in Vessels from one Household in a Late Neolithic Wetland Settlement in Bavaria (3496-3410 BC)
Authors:
Oudemans, Tania; Kubiak-Martens, Lucy; Limmer, Barbara; Kooistra, Laura
Abstract:
The Late Neolithic wetland settlement of Pestenacker (Lkr. Landsberg am Lech/D) in southern Bavaria is well known for its extraordinary preservation of wooden house structures and thick cultural layers (Schönfeld 2009). The enclosed settlement was used only for a short period between 3496 and 3410 BC (Bauer 2009, 179-181). The ceramic assemblage excavated at Pestenacker was thoroughly studied for typo-chronological characteristics and for indications of trade and exchange. It shows a form spectrum comparable to the "Altheimer Group". Although possible functions were proposed fro various pottypes from Pestenacker, no study was ever undertaken to specifically address the actual Neolithic use of vessels from the Altheimer form groups. The ceramic assemblage of Pestenacker offers an optimal opportunity for such a study because many individual vessels could be restored, their dating is - dues are preserved. lithic use of vessels from the Altheimer form groups. The ceramic assemblage of Pestenacker offers an optimal opportunity for such a study because many individual vessels could be restored, their dating is extremely precise, their find location within house structures is known, and many organic surface residues are preserved. In this paper, organic residue analysis was applied in order to identify the way a group of large vessels (»funnel pots« and »lug vessels«) from a single household was used. This study combines microbotanical analysis of plant remains using scanning electron microscopy (SEM) with chemical analysis using Fourier-transform infrared spectroscopy (FTIR) and direct temperature-resolved mass spectrometry (DTMS). This combined approach has been proven effective in determining the original foods and non-foods prepared in Neolithic vessels from the Netherlands. This study aims to identify the original vessel contents of the large pots from Pestenacker and give a detailed insight in the nature of food and non-food preparation, the use of the larger pot types as well as identify activity areas within the house- hold. This way the theories of the original excavators can be checked using independent evidence.
Published:
June 1, 2019
Title:
Immunotherapeutic Blockade of Macrophage Clever-1 Reactivates the CD8+ T-cell Response against Immunosuppressive Tumors
Authors:
Viitala, Miro; Virtakoivu, Reetta; Tadayon, Sina; Rannikko, Jenna; Jalkanen, Sirpa; Hollmén, Maija
Abstract:
PURPOSE: As foremost regulators of cancer-related inflammation and immunotherapeutic resistance, tumor-associated macrophages have garnered major interest as immunotherapeutic drug targets. However, depletory strategies have yielded little benefit in clinical studies to date. An alternative approach is to exploit macrophage plasticity and "reeducate" tumorigenic macrophages toward an immunostimulatory phenotype to activate the host's antitumor immunity.Experimental Design: We investigated the role of the macrophage scavenger receptor common lymphatic endothelial and vascular endothelial receptor-1 (Clever-1) on tumor growth in multiple mouse cancer models with inflammatory and noninflammatory characteristics by using conditional knockouts, bone marrow chimeras, and cell depletion experiments. In addition, the efficacy of immunotherapeutic Clever-1 blockade as monotherapy or in combination with anti-PD-1 was tested. RESULTS: Genetic deficiency of macrophage Clever-1 markedly impaired solid tumor growth. This effect was mediated by macrophages that became immunostimulatory in the absence of Clever-1, skewing the suppressive tumor microenvironment toward inflammation and activating endogenous antitumor CD8+ T cells. Comparable effects were achieved with immunotherapeutic blockade of Clever-1. Notably, these effects were similar to those achieved by PD-1 checkpoint inhibition. Moreover, combining anti-Clever-1 with anti-PD-1 provided synergistic benefit in aggressive, nonresponsive tumors. CONCLUSIONS: These findings demonstrate the importance of macrophages in mediating antitumor immune responses and support the clinical evaluation of immunotherapeutic Clever-1 blockade as a novel cancer treatment strategy.See related commentary by Mantovani and Bonecchi, p. 3202.
Published:
June 1, 2019
Title:
Quality of Diabetes Care Among Recent Immigrants to the USA
Authors:
Srivastava, Romik; Bishu, Kinfe G.; Walker, Rebekah J.; Williams, Joni Strom; Egede, Leonard E.
Abstract:
This study investigated the relationship between immigration status and quality of care for patients with diabetes.
Published:
June 1, 2019
Title:
Soluble receptor for advanced glycation end-products enhanced the production of IFN-γ through the NF-κB pathway in macrophages recruited by ischemia/reperfusion
Authors:
Zhang, Xiuling; Zhang, Xiuling; Cao, Xianxian; Cao, Xianxian; Dang, Mengqiu; Dang, Mengqiu; Wang, Hongxia; Wang, Hongxia; Chen, Buxing; Chen, Buxing; Du, Fenghe; Du, Fenghe; Li, Huihua; Li, Huihua; Zeng, Xiangjun; Zeng, Xiangjun; Guo, Caixia; Guo, Caixia
Abstract:
Published:
June 1, 2019
Title:
Wild chimpanzees deprived a leopard of its kill: Implications for the origin of hominin confrontational scavenging
Authors:
Nakamura, Michio; Hosaka, Kazuhiko; Itoh, Noriko; Matsumoto, Takuya; Matsusaka, Takahisa; Nakazawa, Nobuko; Nishie, Hitonaru; Sakamaki, Tetsuya; Shimada, Masaki; Takahata, Yukio; Yamagami, Masahiro; Zamma, Koichiro
Abstract:
This study reports the first observed case of wild chimpanzees (Pan troglodytes) obtaining animal prey freshly killed by a sympatric leopard (Panthera pardus) and scavenging it with the leopard still nearby. This observation has important implications for the emergence of confrontational scavenging, which may have played a significant role in human evolution. Many scholars agree that eating meat became important during human evolution, and hominins first obtained meat by scavenging. However, it is debatable whether scavenging behavior was “passive” or “confrontational (power).” The latter is more dangerous, as it requires facing the original predator, and it is thus considered to have been important for the evolution of several human traits, including cooperation and language. Chimpanzees do scavenge meat, although rarely, but no previous evidence of confrontational scavenging has hitherto emerged. Thus, it was assumed that they are averse to confrontation with even leopard-sized predators. However, in the observed case the chimpanzees frequently emitted waa barks, which indicated that they were aware of the leopard's presence but they nevertheless continued to eat the scavenged meat. In addition, we compiled and reviewed 49 cases of chimpanzee encounters with animal carcasses in the Mahale Mountains of Tanzania in 1980–2017. Chimpanzees scavenged meat in 36.7% of these cases, and tended to eat the meat when it was fresh or if the animal species was usually hunted by chimpanzees. However, no evidence indicated that carcasses were avoided when leopard involvement was likely. These results suggest that chimpanzee-sized hominins could potentially confront and deprive leopard-size carnivores of meat.
Published:
June 1, 2019
Title:
Amino Acids Influencing Intestinal Development and Health of the Piglets
Authors:
Mou, Qi; Yang, Huan-Sheng; Yin, Yu-Long; Huang, Peng-Fei
Abstract:
The amino acids and other components of diet provide nourishment for piglet intestinal development and maturation. However, early-weaned piglets struggle with tremendous stress, impairing normal intestinal health and leading to intestinal dysfunction and even death. The high prevalence worldwide of post-weaning diarrhoea syndrome (PWDS) in piglets has led to much interest in understanding the important role of nutrients in the establishment and maintenance of a functional intestinal tract. In particular, the impacts of amino acids on these functions must be considered. Amino acid levels greatly influence intestinal development in weaning piglets. The lack of amino acids can cause marked structural and functional changes in the intestine. Therefore, a comprehensive understanding of the functions of amino acids is necessary to optimize amino acid requirements of the developing intestinal tract to maximize piglet health and growth performance. This review summarizes the role of specific amino acids (arginine, glutamate, threonine, sulphur-containing amino acids (SCAAs), and branched-chain amino acids (BCAAs)) that have been proven to be beneficial for the intestinal health of weaned piglets.
Published:
May 31, 2019
Title:
Australians are falling short on vital gut health
Authors:
Kellogg's
Abstract:
Two-thirds of Australians aren’t meeting their daily recommended intake of fibre despite a growing awareness of gut health. Two-thirds of Australians aren’t meeting their daily recommended intake of fibre despite a growing awareness of gut health. Today is World Digestive Health Day, aiming to raise awareness of the importance of having a healthy gut, which can contribute to a range of improved outcomes. According to the CSIRO, a growing body of research has linked gut health to conditions like cancer, auto-immune disease and obesity. A new study commissioned by cereal maker Kellogg’s, released today, found four-in-five Aussies know a high-fibre diet can improve gut health, but two-in-three don’t eat enough each day. When probed about their low intake, 45 per cent of respondents said they couldn’t resist takeaway, chips and lollies, while 31 per cent blamed the high cost of products marketed as high in fibre. Large amounts of saturated fats can promote bad bacteria and cause gut stress. Nutritionist Jacqueline Alwill said the gut health trend had exploded in popularity, with a boom in the sale of probiotics, kombucha and fermented foods. “Although we aren’t able to see inside our bodies, the science tells us that we can help our gut by eating fibre-rich foods daily,” Ms Alwill said. “This can be from whole grains such as cereal, vegetables, fruits, nuts, seeds and legumes — essentially, fibre is found in plant-based foods.” The gastrointestinal tract is home to trillions of microorganisms and up to 1000 different bacterial species. Collectively known as the “microbiota”, they are vital to the proper function of the body.
Published:
May 28, 2019
Title:
SOCE, mitochondria, and inflammation
Authors:
Foley, John F.
Abstract:
Store-operated calcium entry regulates mitochondrial function to support pathogenic TH17 cells and promote inflammation. Store-operated calcium entry regulates mitochondrial function to support pathogenic TH17 cells and promote inflammation. Store-operated calcium entry regulates mitochondrial function to support pathogenic TH17 cells and promote inflammation.
Published:
May 28, 2019
Title:
The association of dietary animal and plant protein with putative risk markers of colorectal cancer in overweight pre-diabetic individuals during a weight-reducing programme: a PREVIEW sub-study
Authors:
Møller, Grith; Andersen, Jens; Jalo, Elli; Ritz, C.; Brand-Miller, Jennie; Larsen, T.; Silvestre, Marta; Fogelholm, M.; Poppitt, S.; Raben, A.; Dragsted, L.
Abstract:
Purpose Diets with increased protein content are popular strategies for body weight regulation, but the effect of such diets for the colonic luminal environment is unclear. We aimed to investigate the associations between putative colorectal cancer-related markers and total protein intake, plant and animal proteins, and protein from red and processed meat in pre-diabetic adults (> 25 years). Methods Analyses were based on clinical and dietary assessments at baseline and after 1 year of intervention. Protein intake was assessed from 4-day dietary records. Putative colorectal cancer-related markers identified from 24-h faecal samples collected over three consecutive days were: concentration of short-chain fatty acids, phenols, ammonia, and pH. Results In total, 79 participants were included in the analyses. We found a positive association between change in total protein intake (slope: 74.72 ± 28.84 µmol per g faeces/E%, p = 0.01), including animal protein intake (slope: 87.63 ± 32.04 µmol per g faeces/E%, p = 0.009), and change in faecal ammonia concentration. For change in ammonia, there was a dose–response trend from the most negative (lowest tertile) to the most positive (highest tertile) association (p = 0.01): in the high tertile, a change in intake of red meat was positively associated with an increase in ammonia excretion (slope: 2.0 ± 0.5 µmol per g faeces/g/day, p
Published:
May 28, 2019
Title:
RELMα-expressing macrophages protect against fatal lung damage and reduce parasite burden during helminth infection
Authors:
Krljanac, Branislav; Schubart, Christoph; Naumann, Ronald; Wirtz, Stefan; Culemann, Stephan; Krönke, Gerhard; Voehringer, David
Abstract:
In the RELMα realm Alternatively activated macrophages (AAMs) are critical to many different immune responses. Krljanac et al. developed a tool to track and characterize AAMs based on expression of the immunomodulatory protein resistin-like molecule (RELM) α. They generated RELMα reporter/deleter mice and observed that RELMα+ macrophages are enriched in white adipose tissue, gut, and peritoneum at steady state. Primary infection with the helminth Nippostrongylus brasiliensis induces expansion of RELMα+ lung interstitial macrophages but not alveolar macrophages in a STAT6-dependent manner. The presence of RELMα+ macrophages was required for protection from fatal primary infection and resistance against secondary infection. Together, these data define RELMα as a marker of AAMs and reveal its role in defense against helminth infection in the lung. Alternatively activated macrophages (AAMs) can contribute to wound healing, regulation of glucose and fat metabolism, resolution of inflammation, and protective immunity against helminths. Their differentiation, tissue distribution, and effector functions are incompletely understood. Murine AAMs express high levels of resistin-like molecule (RELM) α, an effector protein with potent immunomodulatory functions. To visualize RELMα+ macrophages (MΦs) in vivo and evaluate their role in defense against helminths, we generated RELMα reporter/deleter mice. Infection with the helminth Nippostrongylus brasiliensis induced expansion of RELMα+ lung interstitial but not alveolar MΦs in a STAT6-dependent manner. RELMα+ MΦs were required for prevention of fatal lung damage during primary infection. Furthermore, protective immunity was lost upon specific deletion of RELMα+ MΦs during secondary infection. Thus, RELMα reporter/deleter mice reveal compartmentalization of AAMs in different tissues and demonstrate their critical role in resolution of severe lung inflammation and protection against migrating helminths. RetnlaCre fate mapping mice reveal differentiation, tissue localization, and in vivo functions of RELMα+ macrophages. RetnlaCre fate mapping mice reveal differentiation, tissue localization, and in vivo functions of RELMα+ macrophages.
Published:
May 24, 2019
Title:
Cytosolic translational responses differ under conditions of severe short-term and long-term mitochondrial stress
Authors:
Samluk, Lukasz; Urbanska, Malgorzata; Kisielewska, Katarzyna; Mohanraj, Karthik; Kim, Min-Ji; Machnicka, Katarzyna; Liszewska, Ewa; Jaworski, Jacek; Chacinska, Agnieszka
Abstract:
Previous studies demonstrated that cells inhibit protein synthesis as a compensatory mechanism for mitochondrial dysfunction. Protein synthesis can be attenuated by 1) the inhibition of mTOR kinase, which results in a decrease in the phosphorylation of S6K1 and 4E-BP1 proteins, and 2) an increase in the phosphorylation of eIF2α protein. The present study investigated both of these pathways under conditions of short-term acute and long-term mitochondrial stress. Short-term responses were triggered in mammalian cells by treatment with menadione, antimycin A, or CCCP. Long-term mitochondrial stress was induced by prolonged treatment with menadione or rotenone and expression of genetic alterations, such as knocking down the MIA40 oxidoreductase or knocking out NDUFA11 protein. Short-term menadione, antimycin A, or CCCP cell treatment led to the inhibition of protein synthesis, accompanied by a decrease in mTOR kinase activity, an increase in the phosphorylation of eIF2α (Ser51), and an increase in the level of ATF4 transcription factor. Conversely, long-term stress led to a decrease in eIF2α (Ser51) phosphorylation and ATF4 expression and to an increase in S6K1 (Thr389) phosphorylation. Thus, under long-term mitochondrial stress, cells trigger long-lasting adaptive responses for protection against excessive inhibition of protein synthesis.
Published:
May 22, 2019
Title:
Dietary xylo-oligosaccharide improves intestinal functions in weaned piglets
Authors:
Yin, Jie; Li, Fengna; Kong, Xiangfeng; Wen, Chaoyue; Guo, Qiuping; Zhang, Lingyu; Wang, Wenlong; Duan, Yehui; Li, Tiejun; Tan, Zhiliang; Yin, Yulong
Abstract:
This study aimed at investigating the effects of dietary xylo-oligosaccharide (XOS) on intestinal functions (i.e., intestinal morphology, tight junctions, gut microbiota and metabolism) and growth performance in weaned piglets. 19 weaned piglets were randomly divided into two groups (n = 9/10): a control group (basic diet) and a XOS treated group in which piglets were fed 0.01% XOS for 28 days. Growth performance, blood cells and biochemical parameters, serum cytokines, intestinal morphology, tight junctions, gut microbiota, and the metabolic profiles of the gut digesta were analyzed. The results showed that dietary supplementation with XOS had little effects on growth performance, blood cells and biochemical parameters, and intestinal morphology. However, the inflammatory status and intestinal barrier were improved in XOS-fed piglets evidenced by the reduction of IFN-γ and upregulation of ZO-1. Microbiota analysis showed that XOS enhanced α-diversity and affected the relative abundances of Lactobacillus, Streptococcus, and Turicibacter at the genus level. The alterations in the microbiota might be further involved in carbohydrate metabolism, cell motility, cellular processes and signaling, lipid metabolism, and metabolism of other amino acids by functional prediction. A metabolomics study identified three differentiated metabolites, including coenzyme Q6, zizyphine A, and pentadecanal, which might be produced by the microbiota and further affect host metabolism. In conclusion, dietary XOS improved the inflammatory status, gut barrier, and microbiota communities, which might be used as a potential feed additive to prevent gut dysfunction caused by weaning in the pig industry.
Published:
May 22, 2019
Title:
Effects of dietary supplementation with yeast glycoprotein on growth performance, intestinal mucosal morphology, immune response and colonic microbiota in weaned piglets
Authors:
Qin, Longshan; Ji, Wei; Wang, Jianlin; Li, Biao; Hu, Junpeng; Wu, Xin
Abstract:
Antibiotics are commonly provided to weaned piglets; however, this practice has become controversial due to the increased occurrences of microbial resistance, and alternatives are needed. This study aimed to investigate the effects of dietary supplementation with yeast glycoprotein (YG) on growth performance, intestinal mucosal morphology, immune response and colonic microbiota in weaned piglets. A total of 240 weaned piglets (d 23 ± 2) from 16 pens (15 piglets per pen) were randomly allocated to an antibiotics group (25% quinocetone 200 mg kg-1 and 4% enduracidin 800 mg kg-1 of the basal diet) or a YG group (800 mg kg-1 YG of the basal diet), respectively. The trial lasted 14 days, and at the end of the trial, one piglet per pen was chosen to collect plasma, intestinal tissue and colonic digesta samples. The results indicate that piglets fed diets containing YG tended to show increased final body weight (0.05 < P < 0.1), increased average daily gain (P < 0.05) and decreased F/G (P < 0.05) when compared with the antibiotics group. Moreover, intestinal permeability showed that YG led to an improvement in the intestinal development via decreasing serum content of DAO (P < 0.01). Histological evaluations showed that YG contributed to the improvement of the intestinal development via increasing villous height (P < 0.05) and the villous height to crypt depth ratio (P < 0.01), and decreasing crypt depth (P < 0.01) and villous width (P < 0.05) in the ileum. Intestinal integrity also showed that YG was conducive to improvement of the intestinal development via upregulating the m-RNA expression of occludin (P < 0.05) in the duodenal and jejunal mucosa. Interestingly, YG supplementation downregulated the m-RNA expression of IL-12 (P < 0.05), upregulated the m-RNA expression of Hsp-70 (P < 0.05) in the duodenal mucosa, downregulated the m-RNA expression of Hsp-70 (P < 0.05) and IFN-γ (P < 0.05), upregulated the m-RNA expression of Hsp-90 (P < 0.05) in the jejunal mucosa, and upregulated the m-RNA expression of Hsp-70 (P < 0.05) in the ileal mucosa. On the other hand, colonic microbiota results showed that YG supplementation increased the relative abundance of Lactobacillus (P < 0.05) in the genus level. Colonic metabolite results showed that YG supplementation decreased the content of acetate (P
Published:
May 22, 2019
Title:
The impacts of natural polysaccharides on intestinal microbiota and immune responses - a review
Authors:
Tang, Chao; Ding, Ruoxi; Sun, Jian; Liu, Jun; Kan, Juan; Jin, Changhai
Abstract:
In recent years, natural polysaccharides have received increasing attention and become one type of popular dietary nutrient because of their various biological functions. In this paper, the sources, extraction, purification and structural characterization methods of natural polysaccharides are introduced. Natural polysaccharides are favorable for the proliferation of short chain fatty acid (SCFA)-producing bacteria, the presence of which can improve the intestinal microenvironment. Natural polysaccharides can not only enhance immunity, but also suppress excessive immune responses caused by various stimuli. In particular, natural polysaccharides can regulate immunity by acting directly on the immune cells and targeting the gut microbiota. Natural polysaccharides can enhance immunity by promoting beneficial microorganisms and strengthening the function of immune cells. However, natural polysaccharides can also suppress excessive inflammatory responses by improving the intestinal microbiota composition, strengthening intestinal barrier function, enhancing antioxidant activities, promoting SCFA production and reducing pro-inflammatory mediators. Therefore, a comprehensive review is presented on the impacts of natural polysaccharides on the gut microbiota and immune responses, as well as their interactions.
Published:
May 22, 2019
Title:
New connections: Decoding macrophages in disease
Authors:
Ferrarelli, Leslie K.
Abstract:
Deciphering how macrophages are reprogrammed in disease may lead to better patient therapies. Deciphering how macrophages are reprogrammed in disease may lead to better patient therapies. Deciphering how macrophages are reprogrammed in disease may lead to better patient therapies.
Published:
May 21, 2019
Title:
mTORC1 amplifies the ATF4-dependent de novo serine-glycine pathway to supply glycine during TGF-β1–induced collagen biosynthesis
Authors:
Selvarajah, Brintha; Azuelos, Ilan; Platé, Manuela; Guillotin, Delphine; Forty, Ellen J.; Contento, Greg; Woodcock, Hannah V.; Redding, Matthew; Taylor, Adam; Brunori, Gino; Durrenberger, Pascal F.; Ronzoni, Riccardo; Blanchard, Andy D.; Mercer, Paul F.; Anastasiou, Dimitrios; Chambers, Rachel C.
Abstract:
Glucose supports fibrosis Transforming growth factor–β (TGF-β) stimulates fibrosis by promoting the differentiation of fibroblasts into collagen-secreting myofibroblasts, a process associated with alterations in cellular metabolism. Selvarajah et al. found that TGF-β1 promoted the expression of glycine biosynthesis genes in primary human lung fibroblasts, which depended on Smad3 signaling and mTORC1-dependent generation of the transcription factor ATF4. ATF4 stimulated the expression of genes encoding the glucose transporter GLUT1 and enzymes for the biosynthesis of glycine from glucose. Interfering with the mTOR-ATF4 axis reduced the incorporation of glucose-derived glycine into collagen in TGF-β1 stimulated fibroblasts. The mTORC1-ATF4 axis therefore enhances the de novo glycine pathway to meet the biosynthetic requirements associated with TGF-β1–induced collagen production and could potentially be therapeutically targeted as an anti-fibrotic strategy. The differentiation of fibroblasts into a transient population of highly activated, extracellular matrix (ECM)–producing myofibroblasts at sites of tissue injury is critical for normal tissue repair. Excessive myofibroblast accumulation and persistence, often as a result of a failure to undergo apoptosis when tissue repair is complete, lead to pathological fibrosis and are also features of the stromal response in cancer. Myofibroblast differentiation is accompanied by changes in cellular metabolism, including increased glycolysis, to meet the biosynthetic demands of enhanced ECM production. Here, we showed that transforming growth factor–β1 (TGF-β1), the key pro-fibrotic cytokine implicated in multiple fibrotic conditions, increased the production of activating transcription factor 4 (ATF4), the transcriptional master regulator of amino acid metabolism, to supply glucose-derived glycine to meet the amino acid requirements associated with enhanced collagen production in response to myofibroblast differentiation. We further delineated the signaling pathways involved and showed that TGF-β1–induced ATF4 production depended on cooperation between canonical TGF-β1 signaling through Smad3 and activation of mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). ATF4, in turn, promoted the transcription of genes encoding enzymes of the de novo serine-glycine biosynthetic pathway and glucose transporter 1 (GLUT1). Our findings suggest that targeting the TGF-β1–mTORC1–ATF4 axis may represent a novel therapeutic strategy for interfering with myofibroblast function in fibrosis and potentially in other conditions, including cancer. Through mTORC1 signaling, TGF-β1 stimulates glycine synthesis from glucose to support collagen production in lung fibroblasts. Through mTORC1 signaling, TGF-β1 stimulates glycine synthesis from glucose to support collagen production in lung fibroblasts.
Published:
May 21, 2019
Title:
P2Y2R activation by ATP induces oxLDL-mediated inflammasome activation through modulation of mitochondrial damage in human endothelial cells
Authors:
Jin, Hana; Ko, Young Shin; Park, Sang Won; Kim, Hye Jung
Abstract:
Oxidative stress and the related inflammatory responses are closely associated with many diseases including cardiovascular diseases such as atherosclerosis. Especially, mitochondrial damage and inflammasome activation have been reported to be directly involved in atherogenesis. In addition, we previously reported that endothelial cells (ECs) exposed to oxidized LDL (oxLDL) release ATP, which activates P2Y2R, resulting in the expression of receptors for advanced glycation end products and adhesion molecules that are involved in the pathogenesis of atherosclerosis. Therefore, it is expected that P2Y2R activation by ATP released under inflammatory conditions may be linked to the inflammasome-mediated pathogenesis of cardiovascular diseases such as atherosclerosis. However, the exact association remains unclear. Thus, in this study, we investigated the role of P2Y2R in oxLDL-mediated inflammasome activation and the related atherosclerotic pathogenesis in ECs. ECs stimulated with oxLDL demonstrated increased intracellular production and extracellular secretion of ATP. In addition, mitochondrial reactive oxygen species (mtROS) production and mitochondrial DNA (mtDNA) expression and cytosolic release were increased in ECs stimulated with oxLDL or the P2Y2R agonists ATP and UTP. Moreover, caspase-1 activity and IL-1β production were increased in ECs stimulated with oxLDL, ATP or UTP through the modulation of mtROS production and mtDNA expression, in a P2Y2R-dependent manner. Furthermore, TLR-9 and NF-κB activation was increased in ECs in response to oxLDL, ATP or UTP, in a mtDNA-dependent manner. Taken together, our findings suggest that P2Y2R activation by ATP is involved in oxLDL-mediated inflammasome activation and subsequent IL-1β production through the modulation of mtROS-mtDNA induction and the TLR9-NF-κB signaling pathway.
Published:
May 20, 2019
Title:
Challenges in IBD Research: Precision Medicine
Authors:
Denson, Lee A.; Curran, Mark; McGovern, Dermot P. B.; Koltun, Walter A.; Duerr, Richard H.; Kim, Sandra C.; Sartor, R. Balfour; Sylvester, Francisco A.; Abraham, Clara; de Zoeten, Edwin F.; Siegel, Corey A.; Burns, Richéal M.; Dobes, Angela M.; Shtraizent, Nataly; Honig, Gerard; Heller, Caren A.; Hurtado-Lorenzo, Andrés; Cho, Judy H.
Abstract:
This section is focused on the gaps that must be addressed to get closer to treatments tailored to the biological and clinical characteristics of each patient,
Published:
May 16, 2019
Title:
Ultra-Processed Diets Cause Excess Calorie Intake and Weight Gain: An Inpatient Randomized Controlled Trial of Ad Libitum Food Intake
Authors:
Hall, Kevin D.; Ayuketah, Alexis; Brychta, Robert; Cai, Hongyi; Cassimatis, Thomas; Chen, Kong Y.; Chung, Stephanie T.; Costa, Elise; Courville, Amber; Darcey, Valerie; Fletcher, Laura A.; Forde, Ciaran G.; Gharib, Ahmed M.; Guo, Juen; Howard, Rebecca; Joseph, Paule V.; McGehee, Suzanne; Ouwerkerk, Ronald; Raisinger, Klaudia; Rozga, Irene; Stagliano, Michael; Walter, Mary; Walter, Peter J.; Yang, Shanna; Zhou, Megan
Abstract:
We investigated whether ultra-processed foods affect energy intake in 20 weight-stable adults, aged (mean ± SE) 31.2 ± 1.6 years and BMI = 27 ± 1.5 kg/m2. Subjects were admitted to the NIH Clinical Center and randomized to receive either ultra-processed or unprocessed diets for 2 weeks immediately followed by the alternate diet for 2 weeks. Meals were designed to be matched for presented calories, energy density, macronutrients, sugar, sodium, and fiber. Subjects were instructed to consume as much or as little as desired. Energy intake was greater during the ultra-processed diet (508 ± 106 kcal/day; p = 0.0001), with increased consumption of carbohydrate (280 ± 54 kcal/day; p < 0.0001) and fat (230 ± 53 kcal/day; p = 0.0004), but not protein (-2 ± 12 kcal/day; p = 0.85). Weight changes were highly correlated with energy intake (r = 0.8, p
Published:
May 16, 2019
Title:
Correction to: Heads, Jaws, and Muscles
Authors:
Ziermann, Janine; Diaz, Raul; Diogo, Rui
Abstract:
Published:
May 15, 2019
Title:
Oxidized LDL, homocysteine, homocysteine thiolactone and advanced glycation end products act as pro-oxidant metabolites inducing cytokine release, macrophage infiltration and pro-angiogenic effect in ARPE-19 cells
Authors:
AnandBabu, Kannadasan; Sen, Parveen; Angayarkanni, Narayanasamy
Abstract:
Age-related Macular Degeneration (AMD) is one of the major vision-threatening diseases of the eye. Oxidative stress is one of the key factors in the onset and progression of AMD. In this study, metabolites associated with AMD pathology more so at the systemic level namely, oxidized LDL (oxLDL), homocysteine (Hcy), homocysteine thiolactone (HCTL), advanced glycation end product (AGE) were evaluated for their pro-oxidant nature in a localized ocular environment based on in vitro studies in human retinal pigment epithelial cells (ARPE-19 cells). Human ARPE-19 cells were treated with pro-oxidants 50 μg/mL oxLDL, 500 μM Hcy, 500 nM HCTL, 100 μg/mL AGE, 200 μM H2O2 and 200 μM H2O2 with and without pre-treatment of 5 mM N-acetyl cysteine (NAC). The cytokines IL-6, IL-8 and vascular endothelial growth factor (VEGF) secreted from ARPE-19 cells exposed to pro-oxidants were estimated by ELISA. In vitro angiogenesis assay was performed with conditioned media of the pro-oxidant treated ARPE-19 cells in Geltrex-Matrigel coated 96-well plate. The human acute monocytic leukemia cell line (THP-1) was differentiated into macrophages and its migration in response to conditioned media of ARPE-19 cells insulted with the pro-oxidants was studied by transwell migration assay. Western blot was performed to detect the protein expression of Bax, Bcl-2 and NF-κB to assess apoptotic changes. The compounds involved in the study showed a significant increase in reactive oxygen species (ROS) generation in ARPE-19 cells (oxLDL; Hcy; AGE: p < 0.001 and HCTL: p < 0.05). NAC pre-treatment significantly lowered the oxidative stress brought about by pro-oxidants as seen by lowered ROS and MDA levels in the cells. Treatment with pro-oxidants significantly increased the secretion of IL-6 (oxLDL: p < 0.05; Hcy, HCTL and AGE: p < 0.01) and IL-8 cytokines (oxLDL: p < 0.05; HCTL: p <. 001 and AGE: p < 0.01) in ARPE-19 cells. Serum samples of AMD patients (n = 23) revealed significantly higher IL-6 and IL-8 levels compared to control subjects (n = 23) (IL6: p < 0.01 and IL8: p < 0.05). The pro-oxidants also promoted VEGF secretion by ARPE-19 cells compared to untreated control (oxLDL: p < 0.001; Hcy: p < 0.01; HCTL and AGE: p
Published:
May 14, 2019
Title:
Protein restriction and succedent realimentation affecting ileal morphology, ileal microbial composition and metabolites in weaned piglets
Authors:
Shi, Q.; Zhu, Y.; Wang, J.; Yang, H.; Zhu, W.
Abstract:
Dietary protein restriction is one of the effective ways to reduce post-weaning diarrhoea and intestinal fermentation in piglets, but it may also reduce growth performance. The compensatory growth induced by subsequent protein realimentation may solve the issue. However, little research has been done on the impact of protein realimentation on the gut. In this study, the effects of protein restriction and realimentation on ileal morphology, ileal microbial composition and metabolites in weaned piglets were investigated. Thirty-six 28-day-old weaned piglets with an average body weight of 6.47 ± 0.04 kg were randomly divided into a control group and a treatment group. The CP level in the diet of the control group was 18.83% for the entire experimental period. The piglets in the treatment group were fed 13.05% CP between days 0 and 14 and restored to a diet of 18.83% CP for days 14 to 28. On day 14 and 28, six pigs from each group were sacrificed and sampled. It was found that the abundance of Lactobacillus and Salmonella in the ileal digesta was significantly lower in the treatment group than the control group on day 14, whereas the abundance of Clostridium sensu stricto 1, Streptococcus, Halomonas and Pseudomonas significantly increased in the ileal digesta of the treatment group on day 14 compared with the control group. In addition, reduced concentrations of lactic acid, total short-chain fatty acids (total SCFAs), total branched chain fatty acids, ammonia and impaired ileal morphology and mucosal barrier were observed in the treatment group on day 14. However, diarrhoea levels decreased in the treatment group throughout the experiment. During the succedent protein realimentation stage, the treatment group demonstrated compensatory growth. Compared with the control group, the treatment group showed increased abundance of Lactobacillus and reduced abundance of Salmonella, Halomonas and Pseudomonas in the ileum on day 28. The concentrations of lactic acid and total SCFAs increased significantly, whereas the concentration of ammonia remained at a lower level in the treatment group on day 28 compared with the control group. Overall, protein realimentation could improve ileal morphology and barrier functions and promote ileal digestive and absorptive functions. In conclusion, ileal microbial composition and metabolites could change according to dietary protein restriction and realimentation and eventually influence ileal morphology and barrier functions.
Published:
May 14, 2019
Title:
Signals trigger state-specific transcriptional programs to support diversity and homeostasis in immune cells
Authors:
Fischer, Cornelius; Metsger, Maria; Bauch, Sophia; Vidal, Ramon; Böttcher, Michael; Grote, Phillip; Kliem, Magdalena; Sauer, Sascha
Abstract:
Defining macrophage states Macrophages are immune cells that play a major role in maintaining tissue homeostasis. Because of their high plasticity, macrophages can rapidly respond to various external and internal cues, such as exposure to infectious agents or metabolic stress. Through single-cell analyses of mRNA and proteins in macrophage populations and computational analysis, Fischer et al. characterized the differential transcriptional programs driven by the microbial product LPS and the free fatty acid palmitate, both of which engage the same cell surface receptor, TLR4. These data helped to characterize the pro- and anti-inflammatory macrophage states induced by both stimuli, determine how antagonistic genes interacted with each other, and measure transcriptional signaling efficiency in these cells. Macrophages play key roles in the immune systems of humans and other mammals. Here, we performed single-cell analyses of the mRNAs and proteins of human macrophages to compare their responses to the signaling molecules lipopolysaccharide (LPS), a component of Gram-negative bacteria, and palmitate (PAL), a free fatty acid. We found that, although both molecules signal through the cell surface protein Toll-like receptor 4 (TLR4), they stimulated the expression of different genes, resulting in specific pro- and anti-inflammatory cellular states for each signal. The effects of the glucocorticoid receptor, which antagonizes LPS signaling, and cyclic AMP–dependent transcription factor 3, which inhibits PAL-induced inflammation, on inflammatory response seemed largely determined by digital on-off events. Furthermore, the quantification of transcriptional variance and signaling entropy enabled the identification of cell state–specific deregulated molecular pathways. These data suggest that the preservation of signaling in distinct cells might confer diversity on macrophage populations essential to maintaining major cellular functions. Single-cell data reveal the major transcriptional regulators for distinct macrophage states. Single-cell data reveal the major transcriptional regulators for distinct macrophage states.
Published:
May 14, 2019
Title:
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Authors:
Esteve-Altava, Borja; Pierce, Stephanie; Molnar, Julia; Johnston, Peter; Diogo, Rui; Hutchinson, John
Abstract:
Published:
May 8, 2019
Title:
Evolutionary parallelisms of pectoral and pelvic network-anatomy from fins to limbs
Authors:
Esteve-Altava, Borja; Pierce, Stephanie; Molnar, Julia; Johnston, Peter; Diogo, Rui; Hutchinson, John
Abstract:
Lobe-fins transformed into limbs during the Devonian period, facilitating the water-to-land transition in tetra-pods. We traced the evolution of well-articulated skeletons across the fins-to-limbs transition, using a network-based approach to quantify and compare topological features of fins and limbs. We show that the topological arrangement of bones in pectoral and pelvic appendages evolved in parallel during the fins-to-limbs transition, occupying overlapping regions of the morphospace, following a directional trend, and decreasing their disparity over time. We identify the presence of digits as the morphological novelty triggering topological changes that discriminated limbs from fins. The origin of digits caused an evolutionary shift toward appendages that were less densely and heterogeneously connected, but more assortative and modular. Disparity likewise decreased for both appendages, more markedly until a time concomitant with the earliest-known tetrapod tracks. Last, we rejected the presence of a pectoral-pelvic similarity bottleneck at the origin of tetrapods.
Published:
May 8, 2019
Title:
HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness
Authors:
Kuo, David; Ding, Jennifer; Cohn, Ian S.; Zhang, Fan; Wei, Kevin; Rao, Deepak A.; Rozo, Cristina; Sokhi, Upneet K.; Shanaj, Sara; Oliver, David J.; Echeverria, Adriana P.; DiCarlo, Edward F.; Brenner, Michael B.; Bykerk, Vivian P.; Goodman, Susan M.; Raychaudhuri, Soumya; Rätsch, Gunnar; Ivashkiv, Lionel B.; Donlin, Laura T.
Abstract:
Malleable and manipulative macrophages Macrophages play a critical role in rheumatoid arthritis (RA), an autoimmune disease characterized by chronic joint inflammation. Kuo et al. used single-cell RNA sequencing to identify a subset of inflammatory macrophages within human RA joints that promoted synovial fibroblast invasiveness. Testing several approved treatments for RA in ex vivo explants revealed that most drugs target inflammatory macrophages but may not resolve pathologic response. An epidermal growth factor receptor inhibitor used to treat cancer could block macrophage-fibroblast cross-talk in RA samples. This study helps elucidate macrophage phenotypes and macrophage-fibroblast cross-talk in RA, with implications for therapeutic targeting. Macrophages tailor their function according to the signals found in tissue microenvironments, assuming a wide spectrum of phenotypes. A detailed understanding of macrophage phenotypes in human tissues is limited. Using single-cell RNA sequencing, we defined distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects ~1% of the population. The subset we refer to as HBEGF+ inflammatory macrophages is enriched in RA tissues and is shaped by resident fibroblasts and the cytokine tumor necrosis factor (TNF). These macrophages promoted fibroblast invasiveness in an epidermal growth factor receptor–dependent manner, indicating that intercellular cross-talk in this inflamed setting reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo synovial tissue assay, most medications used to treat RA patients targeted HBEGF+ inflammatory macrophages; however, in some cases, medication redirected them into a state that is not expected to resolve inflammation. These data highlight how advances in our understanding of chronically inflamed human tissues and the effects of medications therein can be achieved by studies on local macrophage phenotypes and intercellular interactions. Macrophages promote fibroblast invasiveness and demonstrate variable response to anti-inflammatory medications in patients with rheumatoid arthritis. Macrophages promote fibroblast invasiveness and demonstrate variable response to anti-inflammatory medications in patients with rheumatoid arthritis.
Published:
May 8, 2019
Title:
Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma
Authors:
Zhang, Liang; Yao, Yixin; Zhang, Shaojun; Liu, Yang; Guo, Hui; Ahmed, Makhdum; Bell, Taylor; Zhang, Hui; Han, Guangchun; Lorence, Elizabeth; Badillo, Maria; Zhou, Shouhao; Sun, Yuting; Francesco, M. Emilia Di; Feng, Ningping; Haun, Randy; Lan, Renny; Mackintosh, Samuel G.; Mao, Xizeng; Song, Xingzhi; Zhang, Jianhua; Pham, Lan V.; Lorenzi, Philip L.; Marszalek, Joseph; Heffernan, Tim; Draetta, Giulio; Jones, Philip; Futreal, Andrew; Nomie, Krystle; Wang, Linghua; Wang, Michael
Abstract:
Dismantling lymphoma metabolism Mantle cell lymphoma is a B cell malignancy that often responds to initial treatment with ibrutinib, an inhibitor of Bruton’s tyrosine kinase. Unfortunately, the therapeutic response is typically short lived for reasons that are not yet fully understood. Zhang et al. found that resistance to ibrutinib in mantle cell lymphoma can be associated with metabolic reprogramming and a shift toward reliance on glutaminolysis and oxidative phosphorylation by the cancer cells. The authors demonstrated that these drug-resistant cells can be effectively targeted with a small-molecule inhibitor of oxidative phosphorylation, showing promising therapeutic results in patient-derived mouse models. Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, and therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways to overcome resistance, an urgent clinical need in all relapsed/refractory cancers, remains difficult. Through genomic analyses of clinical specimens, we show that metabolic reprogramming toward oxidative phosphorylation (OXPHOS) and glutaminolysis is associated with therapeutic resistance to the Bruton’s tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma (MCL), a B cell lymphoma subtype with poor clinical outcomes. Inhibition of OXPHOS with a clinically applicable small molecule, IACS-010759, which targets complex I of the mitochondrial electron transport chain, results in marked growth inhibition in vitro and in vivo in ibrutinib-resistant patient-derived cancer models. This work suggests that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies. Targeting oxidative phosphorylation overcomes ibrutinib resistance in mantle cell lymphoma. Targeting oxidative phosphorylation overcomes ibrutinib resistance in mantle cell lymphoma.
Published:
May 8, 2019
Title:
Metabolomic approach in milk from calorie-restricted rats during lactation: a potential link to the programming of a healthy phenotype in offspring
Authors:
Palou, Mariona; Torrens, Juana María; Castillo, Pedro; Sánchez, Juana; Palou, Andreu; Picó, Catalina
Abstract:
PURPOSE: Mild/moderate maternal calorie restriction during lactation in rats has been associated with a lower predisposition to obesity and a healthier metabolic profile in adult offspring. Here, we aimed to assess the impact of maternal calorie restriction during lactation on milk composition to identify potential candidate components that could be involved in the programming effects in offspring. METHODS: An untargeted metabolomic approach in milk samples from 20%-calorie-restricted lactating (CRL) dams and their controls was performed. Levels of leptin, adiponectin, and irisin hormones in milk were also determined at lactating days 5, 10, and 15. RESULTS: Metabolomic analyses revealed a different metabolite pattern in milk between controls and CRL dams. 29 differential metabolites were tentatively identified (p 1.5). Among them, myo-inositol, which showed greater levels in milk from CRL rats than controls, may be highlighted as one of the biologically plausible candidates that could be related to the beneficial effects of CRL in offspring. Results regarding myo-inositol were validated spectrophotometrically at days 10 and 15 of lactation, and levels in milk were correlated with maternal plasma levels. In addition, milk from CRL dams presented increased levels of adiponectin, decreased levels of irisin, and no changes in leptin levels vs controls throughout lactation. CONCLUSION: These data reveal important changes in milk composition due to calorie restriction during lactation that may be involved in the metabolic programming of the healthier phenotype of adult offspring. However, the possible contribution of the specific components is yet to be determined.
Published:
May 8, 2019
Title:
Calcium Signaling Controls Pathogenic Th17 Cell-Mediated Inflammation by Regulating Mitochondrial Function
Authors:
Kaufmann, Ulrike; Kahlfuss, Sascha; Yang, Jun; Ivanova, Elitza; Koralov, Sergei B.; Feske, Stefan
Abstract:
Summary Pathogenic Th17 cells play important roles in many autoimmune and inflammatory diseases. Their function depends on T cell receptor (TCR) signaling and cytokines that activate signal transducer and activator of transcription 3 (STAT3). TCR engagement activates stromal interaction molecule 1 (STIM1) and calcium (Ca2+) influx through Ca2+-release-activated Ca2+ (CRAC) channels. Here, we show that abolishing STIM1 and Ca2+ influx in T cells expressing a hyperactive form of STAT3 (STAT3C) attenuates pathogenic Th17 cell function and inflammation associated with STAT3C expression. Deletion of STIM1 in pathogenic Th17 cells reduces the expression of genes required for mitochondrial function and oxidative phosphorylation (OXPHOS) but enhances reactive oxygen species (ROS) production. STIM1 deletion or inhibition of OXPHOS is associated with a non-pathogenic Th17 gene expression signature and impaired pathogenic Th17 cell function. Our findings establish Ca2+ influx as a critical regulator of mitochondrial function and oxidative stress in pathogenic Th17 cell-mediated multiorgan inflammation.
Published:
May 7, 2019
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