EDITOR'S PICK: Separating the beneficial effects of a drug from the adverse side effects
Nicotinic acid is one of the most effective drugs for raising levels of "good" cholesterol and lowering levels of "bad" cholesterol and other lipids (fats), thereby reducing the risk of heart attack. However, patients often stop taking the drug due to one specific side effect, flushing of the skin that often includes an intense burning and itching sensation. A way to separate the beneficial effects of nicotinic acid from the flushing response has now been elucidated in mice by Robert Lefkowitz and colleagues, at Duke University Medical Center, Durham.
In the study, analysis of human cell lines determined a signaling pathway by which nicotinic acid could initiate the flushing response. This pathway involved the recruitment of beta-arrestin proteins to the GPR109A receptor to which nicotinic acid binds. Interestingly, mice lacking beta-arrestin1 showed a decreased flushing response when treated with nicotinic acid, but the drug retained its beneficial effects on the levels of lipids in the blood. The authors therefore suggest that designing a drug that binds GPR109A but does not stimulate the recruitment of beta-arrestin1 might result in a therapeutic that has beneficial effects on lipid levels without the side effect of flushing.
TITLE: Beta-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice
AUTHOR CONTACT:
Robert J. Lefkowitz
Duke University Medical Center, Durham, North Carolina, USA.
Phone: (919) 684-3755; Fax: (919) 684-8875; E-mail: lefko001@receptor-biol.duke.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36806
ONCOLOGY: Harnessing immune cells to target skin cancer
One subset of immune cells known to contribute to the immune response that targets tumors is the NK cell subset. Although this suggests that NK cell–based therapeutics have anticancer potential, more information is needed about the interactions between NK cells and human tumor cells if this promise is to be realized. A team of researchers, at The Babraham Institute, United Kingdom, and the University of Catanzaro "Magna Graecia", Italy, has now provided insight into this issue by studying both human metastatic melanomas (aggressive forms of skin cancer that have spread to other sites) and spontaneous mouse melanomas.
The team, led by Francesco Colucci and Ennio Carbone, found that human melanoma cell lines derived from lymph node metastases expressed proteins that interacted with the NK cell protein DNAM-1 and with a group of NK cell proteins known as NCRs. These cell lines were particularly susceptible to being killed by NK cells both in vitro and after being transplanted into mice. Consistent with these data from human cell lines, mouse spontaneous melanomas and melanoma cell lines both expressed proteins that bound DNAM-1 and NCRs. Further, interfering with the interaction of DNAM-1 and NCRs with proteins on melanoma cells reduced NK cell–mediated killing of human and mouse melanoma cells lines in vitro and in vivo. The authors therefore conclude that DNAM-1 and NCRs are critical for NK cell–mediated killing of melanoma cells and suggest that NK cells could be harnessed to prevent melanoma metastasis.
TITLE: NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo
AUTHOR CONTACT:
Francesco Colucci
The Babraham Institute, Cambridge, United Kingdom.
Phone: 44-1223-496612; Fax: 44-1223-496023; E-mail: francesco.colucci@bbsrc.ac.uk.
Ennio Carbone
University of Catanzaro "Magna Graecia", Catanzaro, Italy.
Phone: 39-0961-3694088; Fax: 39-0961-3694090; E-mail: ennio.carbone@ki.se.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36022
GASTROENTEROLOGY: The protein Cd1d controls intestinal colonization with bacteria
The intestines of all mammals, including humans, are home to a large number of species of bacteria. The identity of these bacteria affects both the normal functioning of the intestines and the occurrence of immune-mediated intestinal diseases, such as inflammatory bowel disease. Despite the importance of these bacteria, little is known about the host factors that control their colonization of the intestines. However, Edward Nieuwenhuis and colleagues, at Erasmus Medical Center, The Netherlands, have now identified a role for the protein Cd1d in regulating intestinal colonization by bacteria in mice.
In the study, when analyzed under specific pathogen–free or germ-free conditions and compared with Cd1d-sufficient mice, Cd1d-deficient mice exhibited increased colonization of the small intestine following administration of a number of species of bacteria (Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, or Lactobacillus gasseri) into their stomachs. By contrast, activation of immune cells that bind Cd1d prevented intestinal colonization of specific pathogen–free Cd1d-sufficient mice with P. aeruginosa and E. coli. Further analysis revealed a role for Paneth cells, which are found only in the small intestine, in the process. The authors therefore conclude that Cd1d controls colonization of the intestines with bacteria via a mechanism that involves Paneth cells and suggest that manipulating Cd1d might provide a way to modulate the identity of the bacteria in the intestines.
TITLE: Cd1d-dependent regulation of bacterial colonization in the intestine of mice
AUTHOR CONTACT:
Edward E.S. Nieuwenhuis
Erasmus Medical Center, Rotterdam, The Netherlands.
Phone: 31-10-7037093; Fax: 31-10-7036811; E-mail: e.nieuwenhuis@erasmusmc.nl.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36509
PHYSIOLOGY: A link between low oxygen levels and intestinal iron absorption
The only way for iron, which is an essential nutrient, to be taken up by the body is for it to be absorbed by the intestine. Low iron levels can lead to anemia, which is characterized by weakness and fatigue and, in severe cases, heart failure. In a new study, Carole Peyssonnaux and her colleagues at Université Paris Descartes, France, have identified a link between one of the HIF proteins that help cells adapt to low oxygen levels (hypoxia) and iron absorption in the small intestine, which they found was hypoxic. Using transgenic mice, they showed that HIF-2-alpha (but not HIF-1-alpha) helped maintain iron levels in the intestine by regulating expression of the primary iron transporter gene. Furthermore, mice lacking HIF-2-alpha displayed low levels of iron in the blood and liver. The authors therefore conclude that strategies targeting HIF-2-alpha may be useful in treating patients with iron disorders.
TITLE: HIF-2-alpha, but not HIF-1-alpha, promotes iron absorption in mice
AUTHOR CONTACT:
Carole Peyssonnaux
Université Paris Descartes, CNRS (UMR 8104), Paris, France.
Phone: 33-1-44-41-24-52; Fax: 33-1-44-41-24-21; E-mail: carole.peyssonnaux@inserm.fr.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38499
NEPHROLOGY: Fragmenting mitochondria underlie acute kidney failure
Damage to kidney cells known as renal tubular cells is a major cause of acute kidney failure, which is increasing in prevalence. In particular, damage to the energy generating compartments of the cell, which are known as mitochondria, is central to renal tubular cell death. Zheng Dong and colleagues, at the Medical College of Georgia, Augusta, have now provided new insight into the mitochondrial changes that occur in acute rodent kidney injury, information that they hope might provide new avenues of research for those developing drugs to combat this condition.
In the study, analysis of rat renal tubular cells in vitro following exposure to conditions that induce acute kidney injury in vivo, revealed that mitochondria fragmented before the cells died. Furthermore, both knocking down expression of the protein Drp1, which is known to be involved in mitochondrial fission, and blocking its function substantially reduced mitochondrial fragmentation and apoptotic cell death. Consistent with these data, mitochondrial fragmentation was observed in two mouse models of acute kidney injury and treatment with a newly identified pharmacological inhibitor of Drp1 reduced renal tubular cell apoptosis and acute kidney injury.
TITLE: Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models
AUTHOR CONTACT:
Zheng Dong
Medical College of Georgia, Augusta, Georgia, USA.
Phone: (706) 721-2825; Fax: (706) 721-6120; E-mail: zdong@mail.mcg.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37829
Journal
Journal of Clinical Investigation