TY - JOUR AB - One in 12 people worldwide suffers from diabetes and more than 90% of affected adult individuals are diagnosed with type 2 diabetes mellitus (T2DM). Obesity adds to the personal risk to develop T2DM, and both metabolic diseases are rampantly increasing worldwide. Over recent years, primary cilia have moved into the focus of basic and clinical research, after several human diseases have been identified as ciliopathies (i.e., they are linked to ciliary dysfunction). A subset of ciliopathies presents with obesity and diabetes, either as core symptoms or major complications. Several studies have shown a role for ciliary signaling in the satiety signaling centers of the hypothalamus and in other metabolically active tissues, such as pancreatic islets. Here, we discuss recent advances and perspectives in ciliary metabolic research. AU - Volta, F. AU - Gerdes, J.M. C1 - 49676 C2 - 40775 CY - Hoboken SP - 71-84 TI - The role of primary cilia in obesity and diabetes. JO - Ann. NY Acad. Sci. VL - 1391 IS - 1 PB - Wiley PY - 2017 SN - 0077-8923 ER - TY - JOUR AB - In Wilson's disease (WD) and related animal models, liver mitochondria are confronted with an increasing copper burden. Physiologically, the mitochondrial matrix may act as a dynamic copper buffer that efficiently distributes the metal to its copper-dependent enzymes. Mitochondria are the first responders in the event of an imbalanced copper homeostasis, as typical changes of their structure are among the earliest observable pathological features in WD. These changes are due to accumulating copper in the mitochondrial membranes and can be reversed by copper-chelating therapies. At the early stage, copper-dependent oxidative stress does not seem to occur. On the contrary, however, when copper is massively deposited in mitochondria, severe structural and respiratory impairments are observed upon disease progression. This provokes reactive oxygen species and consequently causes the mitochondrial membranes to disintegrate, which triggers hepatocyte death. Thus, in WD mitochondria are prime targets for copper, and the excessive copper burden causes their destruction, subsequently provoking tissue failure and death. AU - Zischka, H. AU - Lichtmannegger, J. C1 - 30559 C2 - 33708 CY - Oxford SP - 6-15 TI - Pathological mitochondrial copper overload in livers of Wilson's disease patients and related animal models. JO - Ann. NY Acad. Sci. VL - 1315 IS - 1 PB - Blackwell Science Publ PY - 2014 SN - 0077-8923 ER - TY - JOUR AB - Functional heterogeneity within stem and progenitor cells has been shown to influence cell fate decisions. Similarly, intracellular signaling activated by external stimuli is highly heterogeneous and its spatiotemporal activity is linked to future cell behavior. To quantify these heterogeneous states and link them to future cell fates, it is important to observe cell populations continuously with single cell resolution. Live cell imaging in combination with fluorescent biosensors for signaling activity serves as a powerful tool to study cellular and molecular heterogeneity and the long-term biological effects of signaling. Here, we describe these methodologies, their advantages over classical approaches, and we illustrate how they could be applied to improve our understanding of the importance of heterogeneous cellular and molecular responses to external signaling cues. AU - Endele, M. AU - Schroeder, T. C1 - 10833 C2 - 30428 SP - 18-27 TI - Molecular live cell bioimaging in stem cell research. JO - Ann. NY Acad. Sci. VL - 1266 IS - 1 PB - Wiley-Blackwell PY - 2012 SN - 0077-8923 ER - TY - JOUR AB - Steroid signaling involves specific receptors that mediate genomic effects and many further proteins responsible for fast nongenomic activities. Metabolism at the position 17 of the steroid scaffold plays a pivotal role in the final regulation of the biological potency of steroid hormones. Enzymes responsible for that, the 17beta-hydroxysteroid dehydrogenases (17beta-HSD), act as carbonyl reductases and require cofactors for their catalytic activity. There is a substantial amount of evidence that human 17beta-HSDs are as well involved in the metabolic pathways of retinoids and fatty acid beyond that which has so far been anticipated. At present fourteen 17beta-HSDs have been annotated and characterized, and more might follow. Many of 17beta-HSDs have been shown to be involved in the pathogenesis of human disorders and are targets for therapeutic intervention. Strategies on deciphering the physiological role of the 17beta-HSD and the genetic predisposition for associated diseases will be presented involving analyses of animal models. AU - Meier, M. AU - Möller, G. AU - Adamski, J. C1 - 1643 C2 - 26086 SP - 15-24 TI - Perspectives in understanding the role of human 17β-hydroxysteroid dehydrogenases in health and disease. JO - Ann. NY Acad. Sci. VL - 1155 IS - 2 PB - New York Academy of Sciences PY - 2009 SN - 0077-8923 ER - TY - JOUR AB - A classical view of the neuroendocrine-immune network assumes bidirectional interactions where pro-inflammatory cytokines influence hypothalamic-pituitary-adrenal (HPA) axis-derived hormones that subsequently affect cytokines in a permanently servo-controlled circle. Nevertheless, this picture has been continuously evolving over the last years as a result of the discovery of redundant expression and extended functions of many of the molecules implicated. Thus, cytokines are not only expressed in cells of the immune system but also in the central nervous system, and many hormones present at hypothalamic-pituitary level are also functionally expressed in the brain as well as in other peripheral organs, including immune cells. Because of this intermingled network of molecules redundantly expressed, the elucidation of the unique roles of HPA axis-related molecules at every level of complexity is one of the major challenges in the field. Genetic engineering in the mouse offers the most convincing method for dissecting in vivo the specific roles of distinct molecules acting in complex networks. Thus, various immunological, behavioral, and signal transduction studies performed with different HPA axis-related mutant mouse lines to delineate the roles of beta-endorphin, the type 1 receptor of corticotropin-releasing hormone (CRHR1), and its ligand CRH will be discussed here. AU - Silberstein, S.* AU - Vogl, A.M.* AU - Bonfiglio, J.J.* AU - Wurst, W. AU - Holsboer, F.* AU - Arzt, E.* AU - Deussing, J.M.* AU - Refojo, D.* A2 - Savino, W.* C1 - 1952 C2 - 26321 CY - Boston, Mass. SP - 120-130 TI - Immunology, signal transduction, and behavior in hypothalamic-pituitary-adrenal axis-related genetic mouse models. JO - Ann. NY Acad. Sci. VL - 1153 PB - Wiley-Blackwell PY - 2009 SN - 0077-8923 ER - TY - JOUR AB - Heat shock proteins (Hsps) are highly conserved and inhabit nearly all subcellular locations where they perform a variety of chaperoning functions including folding and unfolding of nascent polypeptides, proteins, transport of proteins, and support of antigen presentation processes. Apart from their intracellular location Hsps with a molecular weight of 70 kDa (Hsp70) also have been found on the plasma membrane of malignantly transformed cells, on virally/bacterial infected cells and in the extracellular space. Depending on their intra- and extracellular location Hsps exert either protection against environmental stress or act as potent stimulators of the immune response. In this review we address the dual function of intracellular and extracellular located small Hsps and members of the Hsp70 family and its immunological consequences for cancer immunity. AU - Sherman, M.* AU - Multhoff, G. C1 - 5834 C2 - 24694 SP - 192-201 TI - Heat shock proteins in cancer. JO - Ann. NY Acad. Sci. VL - 1113 PB - Blackwell PY - 2007 SN - 0077-8923 ER - TY - JOUR AB - Despite intensive research, many longstanding questions of experimental hematology remain unsolved. One major reason is the fact that hematopoiesis is usually followed by analyzing populations of cells rather than individual cells, at few points in time during an experiment and without knowing (or quickly loosing) the cells' individual identities. The static picture yielded by this approach makes it impossible to appreciate the dynamic developmental processes leading to the generation of the full hematopoietic system from individual hematopoietic stem cells (HSCs). Real-time tracking of individual cells in culture, tissues, or whole organisms would be an extremely powerful approach to fully understand the developmental complexity of hematopoiesis. To this end, a computer-aided culture and bioimaging system is being developed to follow the fate of individual cells over long periods of time. This system is used to follow the development of multilineage cobblestone colonies from adult HSCs in stroma cocultures at the single cell level over many generations. To facilitate noninvasive detection of lineage commitment in these cultures, new subcellular forms of optimized fluorescent proteins have been developed to allow simultaneous marking of multiple hematopoietic lineages within the same animal. AU - Schroeder, T. C1 - 4603 C2 - 22833 SP - 201-209 TI - Tracking hematopoiesis at the single cell level. JO - Ann. NY Acad. Sci. VL - 1044 PY - 2005 SN - 0077-8923 ER - TY - JOUR AB - Allergen-induced secretion of Th2-type cytokines and IgE production have recently been reported to be increased in mice treated with 1,25(OH)2D, the active form of vitamin D. Our objective was to investigate whether vitamin D supplementation in infancy is associated with the risk of atopy, allergic rhinitis, and asthma. The Northern Finland Birth Cohort consists of all individuals in the two most northern provinces of Finland who were due to be born in 1966. Data on vitamin D supplementation during the first year of life was obtained in 1967. Current asthma and allergic rhinitis were reported at age 31 years (n= 7,648), and atopy determined by skin-prick test in a sub-sample still living in northern Finland or the Helsinki area (n= 5,007). The prevalence of atopy and allergic rhinitis at age 31 years was higher in participants who had received vitamin D supplementation regularly during the first year compared to others (OR 1.46, 95%CI 1.4-2.0, and OR 1.66, 95%CI 1.1-1.6, respectively). A similar association was observed for asthma (OR 1.35, 95%CI 0.99-1.8). These associations persisted after adjustment for a wide range of behavioral and social factors (adjusted: OR 1.33 for all, P= 0.01 for atopy, P= 0.001 for allergic rhinitis, and P= 0.08 for asthma). We observed an association between vitamin D supplementation in infancy and an increased risk of atopy and allergic rhinitis later in life. Further study is required to determine whether these observations reflect long-term effects on immune regulation or differences in unmeasured determinants of vitamin D supplementation. AU - Hyppönen, E.* AU - Sovio, U.* AU - Wjst, M. AU - Patel, S.* AU - Pekkanen, J.* AU - Hartikainen, A.-K.* AU - Järvelin, M.-R.* C1 - 5338 C2 - 22685 SP - 84-95 TI - Infant vitamin D supplementation and allergic conditions in adulthood: Northern Finland birth cohort 1966. JO - Ann. NY Acad. Sci. VL - 1037 PY - 2004 SN - 0077-8923 ER - TY - JOUR AB - Isothiocyanates exert chemopreventive effects against chemically induced tumors in animals, modulating enzymes required for carcinogens' activation/detoxification and/or the induction of cell-cycle arrest and apoptosis in tumor cell lines. To investigate the chemopreventive potential of isothiocyanates, we studied proliferation, apoptosis induction and p53, bcl-2 and bax protein expression in Jurkat T-leukemia cells by the isothiocyanate sulforaphane. Sulforaphane caused G2/M-phase delay and increase of apoptotic cell fraction in a time- and dose-dependent manner. Necrosis was observed after prolonged exposure to elevated sulforaphane doses. Moreover, it markedly increased p53 and bax protein expression, and slightly affected bcl-2 expression. Since selective targeting and low toxicity for normal host tissues are fundamental requisites for proposed chemopreventive agents such as sulforaphane, we tested sulforaphane on non-transformed phytohemagglutinin-stimulated human T-lymphocytes. We demonstrated that sulforaphane arrested cell-cycle progression in G1 phase by a significant down-modulation of cyclin D3. Moreover, sulforaphane induced apoptosis (and also necrosis), mediated by an increase in the expression of p53, whereas it exerted little effect on bcl-2 and bax levels. These findings indicate that sulforaphane can exert protective effects inhibiting leukemic cell growth. Moreover, sulforaphane is active not only in transformed lymphocytes but also in their normal counterpart. Although in vitro studies do not necessarily predict in vivo outcomes, our findings raise important questions regarding the suitability of sulforaphane for cancer chemoprevention. AU - Fimognari, C.* AU - Nüsse, M. AU - Berti, F.* AU - Iori, R.* AU - Cantelli-Forti, G.* AU - Hrelia, P.* C1 - 10363 C2 - 22696 SP - 393-398 TI - Sulforaphane modulates cell cycle and apoptosis in transformed and non-transformed human T lymphocytes. JO - Ann. NY Acad. Sci. VL - 2010 PY - 2003 SN - 0077-8923 ER - TY - JOUR AB - Most plant-derived polyphenols exhibit strong antioxidant potentials, established by various assay procedures. With pulse radiolysis experiments, absolute scavenging rate constants can be obtained with a variety of oxidizing radicals which allow further structure-activity correlations and, combined with EPR spectroscopy, detailed insight into the mechanisms governing these antioxidant reactions. The most striking difference occurs between regular flavonoids and both condensed and hydrolyzable tannins. The tannins are considered superior antioxidants as their eventual oxidation may lead to oligomerization via phenolic coupling and enlargement of the number of reactive sites, a reaction which has never been observed with the flavonoids themselves. AU - Bors, W. AU - Michel, C. C1 - 10364 C2 - 20254 SP - 57-69 TI - Chemistry of the Antioxidant Effect of Polyphenols. JO - Ann. NY Acad. Sci. VL - 957 PB - New York Academy of Sciences PY - 2002 SN - 0077-8923 ER - TY - JOUR AB - Progress derived from the human genome project will have tremendous impact on toxicology. Questions concerning genetic susceptibility or resistance to toxic compound exposure and the dissection of the molecular mechanisms involved will be at the forefront of future toxicological research. In recent years, it was recognized that many of the molecular control mechanisms of embryogenesis have been conserved during evolution. The relevance of these observations for toxicology and the application of genetic approaches using mouse mutants as a tool for functional genome analysis are discussed. AU - Balling, R. AU - Hrabě de Angelis, M. C1 - 22319 C2 - 21140 SP - 239-245 TI - From developmental biology to developmental toxicology. JO - Ann. NY Acad. Sci. VL - 919 PY - 2000 SN - 0077-8923 ER - TY - JOUR AU - Mergenthaler, H.-G. AU - Dörmer, P. C1 - 19036 C2 - 12078 SP - 172-174 TI - Hemopoiesis Studied by Limiting Dilution of either Hemopoietic Stem of Stromal Cells in Two- Step Human Micro Lung-Term Bone Marrow Cultures. JO - Ann. NY Acad. Sci. VL - 628 PY - 1991 SN - 0077-8923 ER - TY - JOUR AU - Wiebel, F.J. AU - Wolff, T. AU - Lambiotte, M. C1 - 40919 C2 - 38857 SP - 399-400 TI - Presence and inducibility of different monooxygenase forms in various hepatoma cell lines. JO - Ann. NY Acad. Sci. VL - Vol.349 PY - 1980 SN - 0077-8923 ER -