Molecular basis for the action of a dietary flavonoid revealed by the comprehensive identification of apigenin human targets
Daniel Arango, Kengo Morohashi, Alper Yilmaz, Kouji Kuramochi, Arti Parihar, Bledi Brahimaj, Erich Grotewold, and Andrea I. Doseff
The beneficial health effects of dietary phytochemicals make them promising candidates for treatment and prevention of multiple diseases. However, cellular targets for dietary components remain largely unknown. By combining phage display with high-throughput sequencing, we identified 160 human targets of apigenin, a flavonoid abundant in fruits and vegetables. The apigenin targets include hnRNPA2, a factor associated with numerous cellular malignancies and involved in mRNA metabolism/splicing. We show (pp. E2153–E2162) that, by inhibiting hnRNPA2 dimerization, apigenin affects the alternative splicing of key mRNAs. These findings provide a perspective on how dietary phytochemicals function and what distinguishes their action from pharmaceutical drugs.
Epithelial neoplasia in Drosophila entails switch to primitive cell states
Sumbul J. Khan, Anjali Bajpai, Mohammad Atif Alam, Ram P. Gupta, Sneh Harsh, Ravi K. Pandey, Surbhi Goel-Bhattacharya, Aditi Nigam, Arati Mishra, and Pradip Sinha
Not all cell types in a lineage hierarchy succumb to cancer in the face of an oncogenic lesion. What turns only select cells within an organ into “cells-of-origin” in cancer is an enduring riddle of cancer biology. Here we show (pp. E2163–E2172) that in epithelial primordia of adult wings and eyes of Drosophila, oncogenically mutated cells lose their developmental commitments and, instead, switch to a primitive or progenitor-like cell state. Switch-to-a-primitive-cell-state could thus be a prevalent mechanism of epithelial carcinogenesis and, possibly, an essential characteristic of cancer cells-of-origin.
Juvenile hormone and its receptor, methoprene-tolerant, control the dynamics of mosquito gene expression
Zhen Zou, Tusar T. Saha, Sourav Roy, Sang Woon Shin, Tyler W. H. Backman, Thomas Girke, Kevin P. White, and Alexander S. Raikhel
Mosquitoes transmit some of the most dangerous human diseases. Microarray analysis of developmental gene dynamics in the female Aedes aegypti fat body has demonstrated that 6,146 genes are differentially expressed during juvenile hormone-dependent posteclosion development. These genes show striking temporal and functional separation. A RNAi microarray screen revealed a differential action of Met in the down- and up-regulation of genes expressed during early and late PE, respectively. Thus, this study (pp. E2173–E2181) provides substantial evidence of a central role for insect-specific JH and its receptor Met in the regulation of female mosquito reproductive biology.
Sequestration of a highly reactive intermediate in an evolving pathway for degradation of pentachlorophenol
Itamar Yadid, Johannes Rudolph, Klara Hlouchova, and Shelley D. Copley
Microbes in contaminated environments often evolve new metabolic pathways for detoxification or degradation of pollutants. In some cases, intermediates in newly evolving pathways are more toxic than the initial compound. The initial step in the degradation of pentachlorophenol by Sphingobium chlorophenolicum generates a particularly toxic intermediate, tetrachlorobenzoquinone (TCBQ). This paper (pp. E2182–E2190) describes how the bacterium is protected from the toxic effects of TCBQ. In the presence of tetrachlorobenzoquinone reductase, TCBQ produced by pentachlorophenol hydroxylase is sequestered until it is reduced to the less toxic tetrachlorohydroquinone.
Nontransformed, GM-CSF–dependent macrophage lines are a unique model to study tissue macrophage functions
György Fejer, Mareike Dorothee Wegner, Ildiko Györy, Idan Cohen, Peggy Engelhard, Elena Voronov, Thomas Manke, Zsolt Ruzsics, Lars Dölken, Olivia Prazeres da Costa, Nora Branzk, Michael Huber, Antje Prasse, Robert Schneider, Ron N. Apte, Chris Galanos, and Marina A. Freudenberg
Macrophages—cells crucially involved in defense against infections—exhibit, depending on their anatomical location, distinct biological properties. Studies of the underlying mechanisms are of scientific and clinical interest, but are hampered by the difficulty of obtaining primary tissue macrophages in sufficient numbers and purity. Here (pp. E2191–E2198), we report the generation of nontransformed murine macrophages, which are similar to alveolar macrophages and can be grown continuously without change of phenotype and in unlimited amounts. Such macrophages helped us to recognize several innate immune properties of alveolar macrophages that are involved in the pathogenesis of infectious lung inflammation.
Innate pro–B-cell progenitors protect against type 1 diabetes by regulating autoimmune effector T cells
Ruddy Montandon, Sarantis Korniotis, Esther Layseca-Espinosa, Christophe Gras, Jérôme Mégret, Sophie Ezine, Michel Dy, and Flora Zavala
Immunoregulatory poperties have been principally ascribed to various mature immune cell types, including regulatory B cells. An immature B-cell progenitor population endowed with suppressive properties per se or after differentiation into more mature regulatory B cells has not been demonstrated as yet. We now describe (pp. E2199–E2208) a pro–B-cell progenitor population that emerged upon stimulation with the Toll-like receptor-9 ligand CpG and prevented disease upon adoptive transfer into autoimmune type 1 diabetes-prone mice. Effector T cells were the target of immunoregulatory pro-B cells and of their mature progeny. Such protective pro-B cells could be instrumental for cell therapy of autoimmune diseases.
Antibody to a conserved antigenic target is protective against diverse prokaryotic and eukaryotic pathogens
Colette Cywes-Bentley, David Skurnik, Tanweer Zaidi, Damien Roux, Rosane B. DeOliveira, Wendy S. Garrett, Xi Lu, Jennifer O’Malley, Kathryn Kinzel, Tauqeer Zaidi, Astrid Rey, Christophe Perrin, Raina N. Fichorova, Alexander K. K. Kayatani, Tomas Maira-Litràn, Marina L. Gening, Yury E. Tsvetkov, Nikolay E. Nifantiev, Lauren O. Bakaletz, Stephen I. Pelton, Douglas T. Golenbock, and Gerald B. Pier
Poly-N-acetylglucosamine (PNAG) has been identified as a conserved surface polysaccharide produced by major bacterial, fungal, and protozoal parasites, including malarial sporozoites and blood-stage forms, which can all be targeted for vaccination using this single antigen. Surface carbohydrates are among the most successful vaccines against human microbial pathogens but have tremendous variability that complicates vaccine development. The species of bacteria, fungi, and protozoa shown here (pp. E2209–E2218) to produce PNAG lack an identifiable genetic locus for this antigen’s biosynthetic proteins based on known loci, indicative of a possible evolutionary convergent acquisition of PNAG synthesis with potential important significance for microbial biology.
Mosaic genome structure of the barley powdery mildew pathogen and conservation of transcriptional programs in divergent hosts
Stéphane Hacquard, Barbara Kracher, Takaki Maekawa, Saskia Vernaldi, Paul Schulze-Lefert, and Emiel Ver Loren van Themaat
Powdery mildew fungi are widespread plant pathogens with an obligate biotrophic lifestyle causing devastating damage to many crops. Blumeria graminis f. sp. hordei (Bgh) infects only barley and is engaged in an evolutionary arms race with the host immune system. Genome sequencing of Bgh isolates revealed an isolate-specific mosaic of monomorphic and polymorphic DNA blocks (pp. E2219–E2228), suggesting a mechanism that provides a large standing genetic variation in virulence polymorphisms. Detailed Bgh transcriptome profiles during early pathogenesis on barley and immunocompromised Arabidopsis revealed a conserved Bgh transcriptional program despite ∼200 million years of reproductive isolation of these hosts.
Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons
Luigia Cristino, Giuseppe Busetto, Roberta Imperatore, Ida Ferrandino, Letizia Palomba, Cristoforo Silvestri, Stefania Petrosino, Pierangelo Orlando, Marina Bentivoglio, Kenneth Mackie, and Vincenzo Di Marzo
Endocannabinoids act retrogradely at presynaptic sites to activate cannabinoid receptor type 1 (CB1) receptors, thereby inhibiting neurotransmitter release and fine-tuning synaptic transmission. In murine models of obesity with leptin deficiency, we report (pp. E2229–E2238) that orexin-A neurons undergo a shift from predominant control by CB1-expressing excitatory to CB1-expressing inhibitory inputs. In addition, endocannabinoid biosynthesis is increased in these neurons. CB1 activation by endocannabinoids reduces the inhibition of orexinergic neurons in obese mice, thereby enhancing orexin-A release in target brain areas and contributing to hyperphagia and increased body weight, as well as to alterations of hormone levels typical of obesity.
Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance
Sanjeev Kumar Upadhyay, Kristin L. Eckel-Mahan, M. Reza Mirbolooki, Indra Tjong, Stephen M. Griffey, Galina Schmunk, Amanda Koehne, Briac Halbout, Shawn Iadonato, Brian Pedersen, Emiliana Borrelli, Ping H. Wang, Jogeshwar Mukherjee, Paolo Sassone-Corsi, and K. George Chandy
Obesity is a global epidemic in need of novel and safe therapeutics. We show (pp. E2239–E2248) that ShK-186, a selective blocker of the Kv1.3 potassium channel, has powerful antiobesity effects in a mouse model of diet-induced obesity. ShK-186 increases energy expenditure by activating brown adipose tissue, causes profound changes in liver metabolism and reduces obesity-induced inflammation of white adipose tissue. Our studies highlight the potential use of selective Kv1.3 blockers in the treatment of obesity and insulin resistance.
Letm1, the mitochondrial Ca2+/H+ antiporter, is essential for normal glucose metabolism and alters brain function in Wolf–Hirschhorn syndrome
Dawei Jiang, Linlin Zhao, Clary B. Clish, and David E. Clapham
Wolf–Hirschhorn syndrome (WHS), caused by deletions in 4p16.3, was the first recognized subtelomeric deletion syndrome. As with other syndromes of this class, WHS has not yet been subjected to an intensive, systematic analysis using mouse or cellular models. We recently identified leucine zipper-EF-hand containing transmembrane protein 1 (Letm1) as a mitochondrial Ca2+/H+ antiporter, located in the core WHS region. In this study (pp. E2249–E2254), Letm1 null mice were generated and characterized. Deletion of Letm1 disrupts early embryonic development, reduces glucose oxidation and thus particularly affects brain function.