Nitrosamine exposure exacerbates high fat diet-mediated type 2 diabetes mellitus, non-alcoholic steatohepatitis, and neurodegeneration with cognitive impairment

BACKGROUND: The current epidemics of type 2 diabetes mellitus (T2DM), non-alcoholic steatohepatitis (NASH), and Alzheimer's disease (AD) all represent insulin-resistance diseases. Previous studies linked insulin resistance diseases to high fat diets or exposure to streptozotocin, a nitrosamine-related compound that causes T2DM, NASH, and AD-type neurodegeneration. We hypothesize that low-level exposure to nitrosamines that are widely present in processed foods, amplifies the deleterious effects of high fat intake in promoting T2DM, NASH, and neurodegeneration. METHODS: Long Evans rat pups were treated with N-nitrosodiethylamine (NDEA) by i.p. Injection, and upon weaning, they were fed with high fat (60%; HFD) or low fat (5%; LFD) chow for 6 weeks. Rats were evaluated for cognitive impairment, insulin resistance, and neurodegeneration using behavioral, biochemical, molecular, and histological methods. RESULTS: NDEA and HFD +/- NDEA caused T2DM, NASH, deficits in spatial learning, and neurodegeneration with hepatic and brain insulin and/or IGF resistance, and reductions in tau and choline acetyltransferase levels in the temporal lobe. In addition, pro-ceramide genes, which promote insulin resistance, were increased in livers and brains of rats exposed to NDEA, HFD, or both. In nearly all assays, the adverse effects of HFD+NDEA were worse than either treatment alone. CONCLUSIONS: Environmental and food contaminant exposures to low, sub-mutagenic levels of nitrosamines, together with chronic HFD feeding, function synergistically to promote major insulin resistance diseases including T2DM, NASH, and AD-type neurodegeneration. Steps to minimize human exposure to nitrosamines and consumption of high-fat content foods are needed to quell these costly and devastating epidemics

Aspartyl-(asparaginyl) β-Hydroxylase, Hypoxia-Inducible Factor-1α and Notch Cross-Talk in Regulating Neuronal Motility

Aspartyl-(Asparaginyl)-β-Hydroxylase (AAH ) promotes cell motility by hydroxylating Notch. Insulin and insulin-like growth factor, type 1 (IGF-I) stimulate AAH through Erk MAP K and phosphoinositol-3-kinase-Akt (PI3K-Akt). However, hypoxia/oxidative stress may also regulate AAH . Hypoxia-inducible factor-1alpha (HIF-1α) regulates cell migration, signals through Notch, and is regulated by hypoxia/oxidative stress, insulin/IGF signaling and factor inhibiting HIF-1α (FIH) hydroxylation. To examine cross-talk between HIF-1α and AAH , we measured AAH , Notch-1, Jagged-1, FIH, HIF-1α, HIF-1β and the hairy and enhancer of split 1 (HE S-1) transcription factor expression and directional motility in primitive neuroectodermal tumor 2 (PNET2) human neuronal cells that were exposed to H2O2 or transfected with short interfering RNA duplexes (siRNA) targeting AAH , Notch-1 or HIF-1α. We found that: (1) AAH , HIF-1α and neuronal migration were stimulated by H2O2; (2) si-HIF-1α reduced AAH expression and cell motility; (3) si-AAH inhibited Notch and cell migration, but not HIF-1α and (4) si-Notch-1 increased FIH and inhibited HIF-1α. These findings suggest that AAH and HIF-1α crosstalk within a hydroxylation-regulated signaling pathway that may be transiently driven by oxidative stress and chronically regulated by insulin/IGF signaling

Rat Strain Differences in Susceptibility to Alcohol-Induced Chronic Liver Injury and Hepatic Insulin Resistance

The finding of more severe steatohepatitis in alcohol fed Long Evans (LE) compared with Sprague Dawley (SD) and Fisher 344 (FS) rats prompted us to determine whether host factors related to alcohol metabolism, inflammation, and insulin/IGF signaling predict proneness to alcohol-mediated liver injury. Adult FS, SD, and LE rats were fed liquid diets containing 0% or 37% (calories) ethanol for 8 weeks. Among controls, LE rats had significantly higher ALT and reduced GAPDH relative to SD and FS rats. Among ethanol-fed rats, despite similar blood alcohol levels, LE rats had more pronounced steatohepatitis and fibrosis, higher levels of ALT, DNA damage, pro-inflammatory cytokines, ADH, ALDH, catalase, GFAP, desmin, and collagen expression, and reduced insulin receptor binding relative to FS rats. Ethanol-exposed SD rats had intermediate degrees of steatohepatitis, increased ALT, ADH and profibrogenesis gene expression, and suppressed insulin receptor binding and GAPDH expression, while pro-inflammatory cytokines were similarly increased as in LE rats. Ethanol feeding in FS rats only reduced IL-6, ALDH1–3, CYP2E1, and GAPDH expression in liver. In conclusion, susceptibility to chronic steatohepatitis may be driven by factors related to efficiency of ethanol metabolism and degree to which ethanol exposure causes hepatic insulin resistance and cytokine activation

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon¹⁻³. With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses⁴⁻⁹. As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world’s major tropical regions. Our analysis reveals great variation in reserve ‘health’: about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.Keywords: Ecology, Environmental scienc

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon. With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses. As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world’s major tropical regions. Our analysis reveals great variation in reserve ‘health’: about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.William F. Laurance, D. Carolina Useche, Julio Rendeiro, Margareta Kalka, Corey J. A. Bradshaw, Sean P. Sloan, Susan G. Laurance, Mason Campbell, Kate Abernethy, Patricia Alvarez, Victor Arroyo-Rodriguez, Peter Ashton, Julieta Benítez-Malvido, Allard Blom, Kadiri S. Bobo, Charles H. Cannon, Min Cao, Richard Carroll, Colin Chapman, Rosamond Coates, Marina Cords, Finn Danielsen, Bart De Dijn, Eric Dinerstein, Maureen A. Donnelly, David Edwards, Felicity Edwards, Nina Farwig, Peter Fashing, Pierre-Michel Forget, Mercedes Foster, George Gale, David Harris, Rhett Harrison, John Hart, Sarah Karpanty, W. John Kress, Jagdish Krishnaswamy, Willis Logsdon, Jon Lovett, William Magnusson, Fiona Maisels, Andrew R. Marshall, Deedra McClearn, Divya Mudappa, Martin R. Nielsen, Richard Pearson, Nigel Pitman, Jan van der Ploeg, Andrew Plumptre, John Poulsen, Mauricio Quesada, Hugo Rainey, Douglas Robinson, Christiane Roetgers, Francesco Rovero, Frederick Scatena, Christian Schulze, Douglas Sheil, Thomas Struhsaker, John Terborgh, Duncan Thomas, Robert Timm, J. Nicolas Urbina-Cardona, Karthikeyan Vasudevan, S. Joseph Wright, Juan Carlos Arias-G., Luzmila Arroyo, Mark Ashton, Philippe Auzel, Dennis Babaasa, Fred Babweteera, Patrick Baker, Olaf Banki, Margot Bass, Inogwabini Bila-Isia, Stephen Blake, Warren Brockelman, Nicholas Brokaw, Carsten A. Brühl, Sarayudh Bunyavejchewin, Jung-Tai Chao, Jerome Chave, Ravi Chellam, Connie J. Clark, José Clavijo, Robert Congdon, Richard Corlett, H. S. Dattaraja, Chittaranjan Dave, Glyn Davies, Beatriz de Mello Beisiegel, Rosa de Nazaré Paes da Silva, Anthony Di Fiore, Arvin Diesmos, Rodolfo Dirzo, Diane Doran-Sheehy, Mitchell Eaton, Louise Emmons, Alejandro Estrada, Corneille Ewango, Linda Fedigan, François Feer, Barbara Fruth, Jacalyn Giacalone Willis, Uromi Goodale, Steven Goodman, Juan C. Guix, Paul Guthiga, William Haber, Keith Hamer, Ilka Herbinger, Jane Hill, Zhongliang Huang, I Fang Sun, Kalan Ickes, Akira Itoh, Natália Ivanauskas, Betsy Jackes, John Janovec, Daniel Janzen, Mo Jiangming, Chen Jin, Trevor Jones, Hermes Justiniano, Elisabeth Kalko, Aventino Kasangaki, Timothy Killeen, Hen-biau King, Erik Klop, Cheryl Knott, Inza Koné, Enoka Kudavidanage, José Lahoz da Silva Ribeiro, John Lattke, Richard Laval, Robert Lawton, Miguel Leal, Mark Leighton, Miguel Lentino, Cristiane Leonel, Jeremy Lindsell, Lee Ling-Ling, K. Eduard Linsenmair, Elizabeth Losos, Ariel Lugo, Jeremiah Lwanga, Andrew L. Mack, Marlucia Martins, W. Scott McGraw, Roan McNab, Luciano Montag, Jo Myers Thompson, Jacob Nabe-Nielsen, Michiko Nakagawa, Sanjay Nepal, Marilyn Norconk, Vojtech Novotny, Sean O'Donnell, Muse Opiang, Paul Ouboter, Kenneth Parker, N. Parthasarathy, Kátia Pisciotta, Dewi Prawiradilaga, Catherine Pringle, Subaraj Rajathurai, Ulrich Reichard, Gay Reinartz, Katherine Renton, Glen Reynolds, Vernon Reynolds, Erin Riley, Mark-Oliver Rödel, Jessica Rothman, Philip Round, Shoko Sakai, Tania Sanaiotti, Tommaso Savini, Gertrud Schaab, John Seidensticker, Alhaji Siaka, Miles R. Silman, Thomas B. Smith, Samuel Soares de Almeida, Navjot Sodhi, Craig Stanford, Kristine Stewart, Emma Stokes, Kathryn E. Stoner, Raman Sukumar, Martin Surbeck, Mathias Tobler, Teja Tscharntke, Andrea Turkalo, Govindaswamy Umapathy, Merlijn van Weerd, Jorge Vega Rivera, Meena Venkataraman, Linda Venn, Carlos Verea, Carolina Volkmer de Castilho, Matthias Waltert, Benjamin Wang, David Watts, William Weber, Paige West, David Whitacre, Ken Whitney, David Wilkie, Stephen Williams, Debra D. Wright, Patricia Wright, Lu Xiankai, Pralad Yonzon & Franky Zamzan

Postoperative continuous positive airway pressure to prevent pneumonia, re-intubation, and death after major abdominal surgery (PRISM): a multicentre, open-label, randomised, phase 3 trial

Background: Respiratory complications are an important cause of postoperative morbidity. We aimed to investigate whether continuous positive airway pressure (CPAP) administered immediately after major abdominal surgery could prevent postoperative morbidity. Methods: PRISM was an open-label, randomised, phase 3 trial done at 70 hospitals across six countries. Patients aged 50 years or older who were undergoing elective major open abdominal surgery were randomly assigned (1:1) to receive CPAP within 4 h of the end of surgery or usual postoperative care. Patients were randomly assigned using a computer-generated minimisation algorithm with inbuilt concealment. The primary outcome was a composite of pneumonia, endotracheal re-intubation, or death within 30 days after randomisation, assessed in the intention-to-treat population. Safety was assessed in all patients who received CPAP. The trial is registered with the ISRCTN registry, ISRCTN56012545. Findings: Between Feb 8, 2016, and Nov 11, 2019, 4806 patients were randomly assigned (2405 to the CPAP group and 2401 to the usual care group), of whom 4793 were included in the primary analysis (2396 in the CPAP group and 2397 in the usual care group). 195 (8\ub71%) of 2396 patients in the CPAP group and 197 (8\ub72%) of 2397 patients in the usual care group met the composite primary outcome (adjusted odds ratio 1\ub701 [95% CI 0\ub781-1\ub724]; p=0\ub795). 200 (8\ub79%) of 2241 patients in the CPAP group had adverse events. The most common adverse events were claustrophobia (78 [3\ub75%] of 2241 patients), oronasal dryness (43 [1\ub79%]), excessive air leak (36 [1\ub76%]), vomiting (26 [1\ub72%]), and pain (24 [1\ub71%]). There were two serious adverse events: one patient had significant hearing loss and one patient had obstruction of their venous catheter caused by a CPAP hood, which resulted in transient haemodynamic instability. Interpretation: In this large clinical effectiveness trial, CPAP did not reduce the incidence of pneumonia, endotracheal re-intubation, or death after major abdominal surgery. Although CPAP has an important role in the treatment of respiratory failure after surgery, routine use of prophylactic post-operative CPAP is not recommended