TY - JOUR AB - Parkinson's disease (PD) is a still incurable neurodegenerative disorder with a highly complex etiology. While about 10% of cases are associated with single-gene mutations, the majority of PD is thought to originate from a combination of factors such as environmental impact, lifestyle and aging. Even though investigations into the genetically caused cases have uncovered major pathomechanisms of the disease there still exists a wide gap concerning the molecular impact of the other risk factors. All of them are known to have a major impact on the oxidative burden of the cell and thus strongly influence the non-enzymatic posttranslational modifications (nePTMs) of proteins. These modifications are by now known to dramatically alter the stability of proteins, their interactomes, and also their functions. However, the knowledge of nePTMs and their possible causative role in the pathoetiology of PD is just starting to emerge again guided by research on PD-associated genes. In this short review, we will thus concentrate on known nePTMs of two PD-associated genes, SCNA and DJ-1, and discuss their role in the pathoetiology of PD. In the future, it will, however, be essential to unravel the complete “environmental proteome” to understand the impact of nePTMs on PD etiology. This might open up new pathways urgently needed to develop new diagnostic and therapeutic tools for this still incurable disease. AU - Schmidt, S. AU - Vogt Weisenhorn, D.M. AU - Wurst, W. C1 - 64740 C2 - 51918 CY - Radarweg 29, 1043 Nx Amsterdam, Netherlands TI - Chapter 5 – “Parkinson's disease – A role of non-enzymatic posttranslational modifications in disease onset and progression?”. JO - Mol. Aspects Med. VL - 86 PB - Elsevier PY - 2022 SN - 0098-2997 ER - TY - JOUR AB - Thyroid hormones (TH) are known to play a critical role in regulating many biological processes including growth and development, energy homeostasis, thermogenesis, lipolysis and metabolism of cholesterol. Severe TH deficiency especially during fetal development results in cretinism, but can also lead to an imbalance in metabolism with, among others, an alteration in body weight composition. Over the past two decades, increasing evidence has shown that certain persistent organic pollutants (POP) can interfere with the endocrine system. These POP referred to as "endocrine disrupting chemicals" are widely present in the environment and populations are exposed globally. Moreover, epidemiological studies have shown that a particularly sensitive period is the pre- and postnatal time. Indeed, perinatal exposure to such chemicals could lead to the onset diseases in later life. It is known, that, maternal thyroid hormones are transported by the placenta to the fetus from 6 weeks of gestation and it seems that during the first trimester, and part of the second, the fetus is entirely dependent on maternal TH supply for its development. Interferences in the TH-network as a consequence of the exposure to such pollutants could cause variations in TH concentration. Only small changes in maternal thyroid hormone levels in early stages of pregnancy can influence fetal neurological and cardiovascular development, as well as according to recent studies, have effect on childhood body composition. With this review, we will report the most recent and important studies concerning the association between thyroid hormone concentration and POP levels measured during the perinatal period. We will mostly focus on the data recently reported on placenta and breastmilk as main sources for understanding the potential consequences of exposure. The possible link between exposure to pollutants, TH dysregulation and possible adverse outcome will also be briefly discussed. From our literature search, several studies support the hypothesis that pre- and postnatal exposure to different pollutants might play a role in causing variation in thyroid hormone concentration. However, few research papers have so far studied the relationship linking exposure to pollutants, TH concentration and possible health consequences. Therefore, this review highlights the need for further research in this direction. AU - de Angelis, M. AU - Schramm, K.-W. C1 - 62519 C2 - 50902 TI - Perinatal effects of persistent organic pollutants on thyroid hormone concentration in placenta and breastmilk. JO - Mol. Aspects Med. VL - 87 PY - 2021 SN - 0098-2997 ER - TY - JOUR AB - To explore the etiology of diseases is one of the major goals in epidemiological study. Meet-in-metabolite analysis reconstitutes biomonitoring-based adverse outcome (AO) pathways from environmental exposure to a disease, in which the chemical exposome-related metabolism responses are transmitted to incur the AO-related metabolism phenotypes. However, the ongoing data-dependent acquisition of non-targeted biomonitoring by high-resolution mass spectrometry (HRMS) is biased against the low abundance molecules, which forms the major of molecular internal exposome, i.e., the totality of trace levels of environmental pollutants and/or their metabolites in human samples. The recent development of data-independent acquisition protocols for HRMS screening has opened new opportunities to enhance unbiased measurement of the extremely low abundance molecules, which can encompass a wide range of analytes and has been applied in metabolomics, DNA, and protein adductomics. In addition, computational MS for small molecules is urgently required for the top-down exposome databases. Although a holistic analysis of the exposome and endogenous metabolites is plausible, multiple and flexible strategies, instead of "putting one thing above all" are proposed. AU - Shen, H.* AU - Zhang, Y.* AU - Schramm, K.-W. C1 - 62632 C2 - 50891 TI - Analytical aspects of meet-in-metabolite analysis for molecular pathway reconstitution from exposure to adverse outcome. JO - Mol. Aspects Med. VL - 87 PY - 2021 SN - 0098-2997 ER - TY - JOUR AB - For the past decade, brown adipose tissue (BAT) has been extensively studied as a potential therapy for obesity and metabolic diseases due to its thermogenic and glucose-consuming properties. It is now clear that the function of BAT goes beyond heat production, as it also plays an important endocrine role by secreting the so-called batokines to communicate with other metabolic tissues and regulate systemic energy homeostasis. However, despite numerous studies showing the benefits of BAT in rodents, it is still not clear whether recruitment of BAT can be utilized to treat human patients. Here, we review the advances on understanding the role of BAT in metabolism and its benefits on glucose and lipid homeostasis in both humans and rodents. Moreover, we discuss the latest methodological approaches to assess the contribution of BAT to human metabolism as well as the possibility to target BAT, pharmacologically or by lifestyle adaptations, to treat metabolic disorders. AU - Klepac, K. AU - Georgiadi, A. AU - Tschöp, M.H. AU - Herzig, S. C1 - 56544 C2 - 47096 CY - Radarweg 29, 1043 Nx Amsterdam, Netherlands SP - 90-100 TI - The role of brown and beige adipose tissue in glycaemic control. JO - Mol. Aspects Med. VL - 68 PB - Elsevier PY - 2019 SN - 0098-2997 ER - TY - JOUR AB - Mitochondria are required for cellular survival, yet can also orchestrate cell death. The peculiar biochemical properties of these organelles, which are intimately linked to their compartmentalized ultrastructure, provide an optimal microenvironment for multiple biosynthetic and bioenergetic pathways. Most intracellular ATP is generated by mitochondrial respiration, which also represents the most relevant source of intracellular reactive oxygen species. Mitochondria participate in a plethora of anabolic pathways, including cholesterol, cardiolipin, heme and nucleotide biosynthesis. Moreover, mitochondria integrate numerous pro-survival and pro-death signals, thereby exerting a decisive control over several biochemical cascades leading to cell death, in particular the intrinsic pathway of apoptosis. Therefore, it is not surprising that cancer cells often manifest the deregulation of one or several mitochondrial functions. The six classical hallmarks of cancer (i.e., limitless replication, self-provision of proliferative stimuli, insensitivity to antiproliferative signals, disabled apoptosis, sustained angiogenesis, invasiveness/metastatic potential), as well as other common features of tumors (i.e., avoidance of the immune response, enhanced anabolic metabolism, disabled autophagy) may directly or indirectly implicate deregulated mitochondria. In this review, we discuss several mechanisms by which mitochondria can contribute to malignant transformation and tumor progression. AU - Galluzzi, L.* AU - Morselli, E.* AU - Kepp, O.* AU - Vitale, I.* AU - Rigon, A.* AU - Vacchelli, E.* AU - Michaud, M.* AU - Zischka, H. AU - Castedo, M.* AU - Kroemer, G.* C1 - 1500 C2 - 26822 CY - Amsterdam SP - 1-20 TI - Mitochondrial gateways to cancer. JO - Mol. Aspects Med. VL - 31 IS - 1 PB - Elsevier PY - 2010 SN - 0098-2997 ER - TY - JOUR AB - Ifosfamide, an isomer of cyclophosphamide, has been shown to be one of the most effective antineoplastic agents for the treatment of human malignancies. There is considerable evidence that the intracellular status of glutathione (GSH) plays a major role in modifying the cytotoxicity of ifosfamide in cells and tissues. We have studied the effects of 4-hydroperoxyifosfamide (4-OOH-IF) upon the proliferation of human peripheral blood lymphocytes (PBL) and the intracellular GSH content. The major finding was that occurence of significant inhibition of [3H]-thymidine incorporation in interleukine-2 (IL-2) expanded PBL after exposure with 4-OOH-IF was accompanied by substantial depletion of intracellular GSH content in these cells. PBL seemed to be more sensitive to this drug induced effect comparing our results obtained in other cells (e.g. Ewing sarcoma, Chinese hamster ovary). In PBL 4-OOH-IF also induced rapid phosphorylation of the small heat shock protein (HSP27) signaling a similar type of stress response as reported for several other agents (e.g. arsenite, phorbol ester, tumor necrosis factor). Reconstitution of the depleted GSH content in PBL after treatment with 4-OOH-IF could be achieved by GSH-monoethylester and mesna within 24 hours of postincubation time. From these results we conclude that human lymphocytes are sensitive targets for ifosfamide induced metabolic stress during treatment. This might have further importance in regard to the immunological function of these cells. AU - Issels, R.D. AU - Meier, T.H. AU - Müller, E. AU - Multhoff, G. AU - Wilmanns, W. C1 - 40368 C2 - 40095 SP - 281-286 TI - Ifosfamide induced stress response in human lymphocytes. JO - Mol. Aspects Med. VL - 14 IS - 3 PY - 1993 SN - 0098-2997 ER -