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Fully activated innate immune cells are required for effective responses to infection, but their prompt deactivation and removal are essential for limiting tissue damage. Here, we have identified a critical role for the prolyl hydroxylase enzyme Phd2 in maintaining the balance between appropriate, predominantly neutrophil -mediated pathogen clearance and resolution of the innate immune response. We demonstrate that myeloid-specific loss of Phd2 resulted in an exaggerated inflammatory response to Streptococcus pneumonia, with increases in neutrophil motility, functional capacity, and survival. These enhanced neutrophil responses were dependent upon increases in glycolytic flux and glycogen stores. Systemic administration of a HIF-prolyl hydroxylase inhibitor replicated the Phd2-deficient phenotype of delayed inflammation resolution. Together, these data identify Phd2 as the dominant HIF-hydroxylase in neutrophils under normoxic conditions and link intrinsic regulation of glycolysis and glycogen stores to the resolution of neutrophil-mediated inflammatory responses. These results demonstrate the therapeutic potential of targeting metabolic pathways in the treatment of inflammatory disease., Introduction Inappropriate or persistent neutrophilic inflammation is implicated in a number of disease states exemplified by acute lung injury responses and chronic obstructive pulmonary disease. There are, to date, no [...]

Arachidonic acid (AA) is a precursor that is metabolized by several enzymes to many biological eicosanoids. Accumulating data indicate that the ω-hydroxylation metabolite of AA, 20-hydroxyeicosatetraenoic acid (20-HETE), is considered to be involved in the myocardial ischemia-reperfusion injury (MIRI). The inhibitors of AA ω-hydroxylase, however, are demonstrated to exhibit protective effects on MIRI. Dihydrotanshinone I (DI), a bioactive constituent of danshen, is proven to be a potent inhibitor of AA ω-hydroxylase by our preliminary study in vitro. The purpose of the present study was to investigate the cardioprotection of DI against MIRI and its effects on the concentrations of 20-HETE in vivo. Rats subjected to 30 min of ischemia followed by 24 h of reperfusion were assigned to intravenously receive vehicle (sham and ischemia-reperfusion), low (1 mg/kg), middle (2 mg/kg), or high (4 mg/kg) doses of DI before reperfusion. The results demonstrated that DI treatment could improve cardiac function, reduce infarct size, ameliorate the variations in myocardial zymogram and histopathological disorders, decrease 20-HETE generation, and regulate apoptosis-related protein in myocardial ischemia-reperfusion rats. These findings suggested DI could exert considerable cardioprotective action on MIRI by the attenuation of 20-HETE generation, subsequent myocardial injury, and apoptosis through inhibition on AA ω-hydroxylase. Key words: dihydrotanshinone I, myocardial ischemia-reperfusion injury, arachidonic acid, 20-hydroxyeicosatetraenoic acid, ω-hydroxylase, apoptosis, danshen. L'acide arachidonique (AA) est un precurseur metabolise par plusieurs enzymes en de nombreux eicosanoides biologiques. De plus en plus de donnees indiquent que le metabolite issu de la ω-hydroxylation de l'AA, l'acide 20- hydroxyeicosatetraenoique (20-HETE), est implique dans le dommage d'ischemie-reperfusion myocardique (DIRM). Les inhibiteurs de la ω- hydroxylase d'AA, cependant, ont demontre qu'ils exercaient des effets protecteurs contre le DIRM. Le dihydrotanshinone I (DI), un constituant bioactif du danshen, a montre qu'il est un inhibiteur puissant de la ω-hydroxylase d'AA selon les etudes preliminaires in vitro realisees par les auteurs. Le but de l'etude presente etait d'examiner la cardioprotection par le DI contre le DIRM et ses effets sur les concentrations de 20-HETE in vivo. Des rats soumis a une ischemie de 30 min suivie d'une reperfusion de 24 h ont recu par voie intraveineuse le vehicule (operation fictive et ischemie-reperfusion), une dose faible (1 mg/kg), moyenne (2 mg/kg) ou elevee (4 mg/kg) de DI avant la reperfusion. Les resultats ont demontre que le traitement au DI pouvait ameliorer la fonction cardiaque, reduire la taille de l'infarctus, ameliorer les variations du zymogramme myocardique et les manifestations histopathologiques, diminuer la generation de 20-HETE, et reguler les proteines reliees a l'apoptose dans le myocarde des rats soumis a l'ischemie-reperfusion. Ces donnees suggeraient que le DI pouvait exercer une action cardioprotectrice considerable contre le DIRM en attenuant la generation de 20-HETE, le dommage myocardique subsequent et l'apoptose, par l'inhibition de ω-hydroxylase d'AA. [Traduit par la Redaction] Mots-cles: dihydrotanshinone I, dommage d'ischemie-reperfusion myocardique, acide arachidonique, acide 20- hydroxyeicosatetraenoique, ω-hydroxylase, apoptose, danshen., Introduction Arachidonic acid (AA) is a polyunsaturated fatty acid present in the phospholipids of membranes of the body's cells. It can be metabolized by 3 oxygenase systems: cyclooxygenases (COXs), lipoxygenases [...]

Background Hypercalcemia is caused by many different conditions and may lead to severe complications. Loss-offunction mutations of CYP24A1, encoding vitamin D-24-hydroxylase, have recently been identified in idiopathic infantile hypercalcemia and in adult kidney stone disease. The aim of this study was to investigate the genetics and clinical features of both infantile and maternal hypercalcemia. Methods We studied members of four unrelated Israeli families with hypercalcemia, namely, one woman during pregnancy and after delivery and three infants. Clinical and biochemical data were obtained from probands' medical charts. Genomic DNA was isolated from peripheral blood and CYP24A1 was sequenced. Results Typical symptoms of hypercalcemia associated with the intake of recommended doses of vitamin D developed in the infants and pregnant woman. Four different loss-of-function CYP24A1 mutations were identified, two of which are reported here for the first time (p.Trp134Gly and p.Glu315*). The infants from families 1 and 2, respectively, were found to be compound heterozygotes, and the infant from family 3 and the pregnant woman were found to be homozygous. Conclusions This is the first report of maternal hypercalcemia caused by a CYP24A1 mutation, showing that not only infants are at risk for this complication. Our findings emphasize the importance of recognition, genetic diagnosis and proper treatment of this recently identified hypercalcemic disorder in this era of widespread vitamin D supplements. Keywords CYP24A1 * Hypercalciuria * Infantile hypercalcemia * Maternal hypercalcemia * Nephrocalcinosis * Nephrolithiasis * Vitamin D, Introduction Hypercalcemia is caused by many different conditions, including primary hyperparathyroidism, cancer, granulomatous diseases (e.g. sarcoidosis), drugs (e.g. thiazides) and a high intake of calcium and/or vitamin D. In the [...]