3,128 research outputs found
Mitochondrial DNA haplogroup-dependence of drugs and xenobiotics toxicity
No full textPharmacogenomics is the study of how genes affect a individual response to drugs to develop medications tailored to a person’s genetic makeup because the efficacy/safety profile have not be the same way for everyone.
Mitochondria are characterized by a unique milieu, with an alkaline and negatively charged interior (pH value 8) due to the proton pumping associated with OXPHOS and a series of specific channels and carrier proteins. As a consequence, mitochondria can easily accumulate lipophilic compounds of cationic character and weak acids in their anionic form, particularly amphiphilic xenobiotics including ethidium bromide, 1-methyl-4 phenylpyridinium (MPP+), paraquat (1,1’-dimethyl-4,4’-bipyridinium dichloride; PQ) and others that can penetrate the inner mitochondrial membrane (IMM) freely since in their undissociated forms. Indeed, it is well understood that many drugs and chemicals can cause mitochondrial dysfunction (mitotoxicity) by interacting with mitochondrial DNA (mtDNA), protein synthesis, respiratory chain, other metabolic processes, channels and transporters Moreover, due to its peculiar uniparental maternal inheritance and high mutation rate, mtDNA presents different clusters of population-specific-polymorphism (SNPs) that characterize different maternal lineages (mitochondrial haplogroups). It has been demonstrated that many non-synonymous SNPs, cause amino acid variations in the mitochondrial-encoded proteins, potentially modifying OXPHOS activity and ROS production. Some of these haplotypes may confer vulnerability to, or protection from, various common diseases. Well-documented examples are the role of mtDNA haplotype in Parkinson’s disease (PD) and Leber’s hereditary optic neuropathy (LHON). It has been proposed that European haplogroups J and K are protective for PD. On the other hand the haplogroups J and T may influence mitochondrial dysfunction, resulting in an increased risk of PD. In addition the 11778/ND4, 14484/ND6 and 3460/ND1 LHON mutations are associated respectively with mitochondrial subhaplogroup J2b, J1c and K, as these mtDNA backgrounds may increase penetrance of LHON mutations.
Several reports suggest that environmental factors such as pesticides (e.g. rotenone), herbicides (e.g. paraquat) and MPTP or 1-methyl 4-phenyl 1,2,3,6-tetrahydro-pyridine (contaminant in the illicit synthesis of opiates) increase the risk of PD due to a reduction in ATP synthesis and increase of reactive oxygen species (ROS). Furthermore, tobacco smoking has been proposed as an environmental trigger of visual loss in LHON, due to the presence of substances, contained in the tobacco that can directly act inhibiting CI.
Researchers have also associated non synonymous variants in mtDNA with the development of side effects of drugs. Effectively the analysis of mtDNA haplogroup in patients with cancer treated with chemioterapic agent cisplatin (cisPt) revealed an increased incidence of hearing loss in haplogroup J, due to inhibition of mtDNA replication. It has also been shown that patients treated with the antibiotic Linezolid may develop LHON-like optic neuropathy, myelosuppression and lactic acidosis. This is possibly due to the inhibition of mitochondrial protein synthesis, which is modulated by the SNPs at positions 2706 and 3010, in the 16S gene of mtDNA. This sequence region is predicted to be very close to the Peptidyl Transferase Center (PTC) that is the binding site of several antibiotics.
To demonstrate that mitochondrial genetic variability may influence individual susceptibility to drugs toxicity (Linezolid and CisPt) or to toxic environmental factors (rotenone, MPP+, paraquat and cigarette smoking) we assessed in vitro cell viability, mitochondrial functions including ATP synthesis, activity of OXPHOS complexes and ROS generation, and biogenesis (mtDNA copy number) in a collection of transmitochondrial cytoplasmic hybrids (cybrids) carrying divergent human mtDNA haplogroups (N1b, H, J, T, U, and K) or LHON mutations, that have been defined by sequencing of D-loop region and then of the entire mtDNA. Cybrids were constructed from fibroblasts obtained, after informed consent, from skin biopsies of unrelated healthy subjects and LHON patients.
The results of this study demonstrated that mitochondrial genetic variability may influence individual susceptibility to drugs or environmental factors toxicity, highlighting interesting associations between specific haplogroups, mitochondrial functional alterations, and toxic agent. More in details: 1) haplogroup K1 was found to play a protective role against rotenone toxicity, whereas haplogroup J1 seem to be more susceptible to the action of both rotenone and MPP+; 2) haplogroup T seems to be more susceptible to the action of paraquat; 3) haplogroups H12 and T1 in association with the LHON mutation 3460/ND1, and haplogroups J1c and J2A all increase the susceptibility to mitochondrial damage after smoke exposure. Moreover haplogroup H1, characterized by SNPs 2706A/3010A in 16SrRNA is the most sensitive to Linezolid toxicity and haplogroup J appears to act as risk factor in CisPt toxicity.
Even though future studies will be necessary to better understand the mechanism of action of some of these molecules, studying the association between mitochondrial haplogroup and toxicity of drugs and chemicals is extremely useful to prevent toxicity in predisposed subjects. This may avoid the occurrence of adverse reactions leading to the withdrawal of drugs from the market or Black Box warnings by FDA. For these reasons, pharmaceutical companies have introduced early in the drug-development process stringent in vitro studies to evaluate mitochondrial function (respiratory chain, ROS, membrane potential and mtDNA)
Anxiolytic Therapy: A Paradigm of Successful Mitochondrial Pharmacology
No full textThe complex biochemistry and dynamic structure of mitochondria have prevented them from being prominent pharmacological targets. New mechanistic understanding of cholesterol transport and associated neurosteroidogenesis is providing evidence on therapeutic outcomes in mental disorders that is achievable via mitochondrial pharmacology. This warrants general attention on mitochondrial pharmacology to inform therapies
Pyroptosis targeting via mitochondria: An educated guess to innovate COVID‐19 therapies
No full textPyroptosis is a specialized form of inflammatory cell death which aids the defensive response against invading pathogens. Its normally tight regulation is lost during infection by the severe acute respiratory coronavirus 2 (SARS-CoV-2), and thus, uncontrolled pyroptosis disrupts the immune system and the integrity of organs defining the critical conditions in patients with high viral load. Molecular pathways engaged downstream of the formation and stabilization of the inflammasome, which are necessary to execute the process, have been uncovered and drugs are available for their regulation. However, the pharmacology of the upstream events, which are critical to sense and interpret the initial damage by the pathogen, is far from being elucidated. This limits our capacity to identify early markers and targets to ameliorate SARS-CoV-2 linked pyroptosis. Here, we focus attention on the mitochondria and pathways leading to their dysfunction, in order to elucidate the early steps of inflammasome formation and devise tools to predict and counter pathological states induced by SARS-CoV-2
Variations on the Author
No full text“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Imparare le lingue per abbracciare il mondo
No full textL’autrice che si colloca, come Daniela Zorzi, tra i fautori di una linguistica “impegnata”, propone in ricordo della studiosa amica, una riflessione sul ruolo cruciale del multilinguismo e delle lingue- culture, per il successo professionale e il benessere sociale, nella società contemporanea. Il multilinguismo appare come un’urgenza educativa che interpella studiosi e formatori a tutti i livelli al fine di promuovere nei giovani un apprendimento consapevole efficace ed autonomo.Multilingualism constitutes an urgent objective for education, which needs to involve teachers and researchers at all levels if we are to promote effective and autonomous learning in the young. Like Daniela Zorzi, the author considers herself a socially engaged linguist, and in memory of her friend’s work, offers a reflection on the key roles of languages and cultures and of multilingualism for professional success and social welfare today
Reclamações ambientais em Aveiro, Portugal: atores, preocupações, padrão territorial e resoluções
No full textThis paper presents an environmental diagnosis based on public complaints on environmental
issues submitted to the Environmental Department of the Aveiro City Council, Portugal, between
2000 and 2005. It discusses the potential influences of these in local environmental planning
and governance. The paper has been organised into five sections. The first of these introduces
the study. The second section focuses on the conceptual approaches relating to environmental
grassroots movements, the main actors involved in these movements and the role played by
local government. It also contains a brief review of the most recent urban environmental
quality challenges in the European context together with a description of the main features of
the associated political and legal framework in Portugal. The third section describes the case
study and the methodology used. The results of the empirical study are detailed in the fourth
section. The final section critically analyses these results with emphases on the temporal
evolution of the submission of complaints, the actors involved, the local environmental problems
and their associated spatial pattern as well as the responses given by the City Council. This
information may then be used to provide a useful indicator for the perception of environmental
quality as well as a credible instrument for the visualisation and evaluation of local performance
in terms of environmental planning and management.AlBan Programme - n. E05M053040B
Jak rozumieć „historyczność” biblijnego Daniela? Różne kierunki wyjaśniania orędzia Księgi Daniela
No full textThe subject of this article is the issue of the historicity of the figure of Daniel, who is the main character of the biblical book bearing his name. The question of whether Daniel is a historical or just a literary figure is important because it influences the exegesis of the text of the Book of Daniel. First, the author will indicate the reasons for questioning the historicity of Daniel, and then he will present different approaches to interpreting the content of the Book of Daniel.Przedmiotem artykułu jest kwestia historyczności postaci Daniela, który jest głównym bohaterem księgi biblijnej noszącej jego imię. Pytanie o to, czy Daniel jest postacią historyczną, czy tylko literacką, jest ważne z tego powodu, że ma wpływ na egzegezę tekstu Księgi Daniela. Najpierw autor wskaże powody, na podstawie których podważa się historyczność Daniela, a następnie przedstawi różne podejścia w interpretacji treści Księgi Daniela
Selected Works of Daniela Krolupperová in Leisure Education for Reading
No full textThis thesis is concerned with usage of selected works of contemporary Czech author Daniela Krolupperová in leisure time education to reading. The thesis is divided into two parts - theoretical and practical. In theoretical part the curriculum vitae and literary creation of the crucial author of publishing houses Albatros, Mladá fronta and Portál Daniela Kroulupperová is presented. Further, literary genre preferred by the author, target groups and selected methods of her work incl. texts used in practical parts, are described. There are also working sheets, their verification in practice and reflection in practical part
Interactions between Reflection and Praxis in the History of Economic Thought. The case of the Franciscan Cicles from XIII Century Assisi to the Present
No full textResumen: Daniela Parisi analiza el impacto de la vida de San F rancisco de Asís desde la perspectiva de la historia del pensamiento económico. Haciendo referencia particularmente a la atención otorgada en los círculos franciscanos a los signos de los tiempos, la autora traza el camino desde la vida de San Francisco, pasando por la vida de la Orden hasta el presente, y revela los orígenes del movimiento franciscano como un intento de reforma social y religiosa. En primer lugar, el artículo presenta la vida que llevó San Francisco como una “pobreza material voluntaria” en el contexto de los cambios socio-económicos que tuvieron lugar en el siglo XIII, con el advenimiento de la sociedad comercial. Luego, explica cómo la propuesta de San Francisco creció hasta convertirse en una orden religiosa. Finalmente, el artículo intenta iluminar aquellos aspectos en que la Orden Franciscana puede todavía considerarse un signo de los tiempos a través de una existencia comprometida con la pobreza, eliminando lo superfluo de nuestra vida y viviendo en consonancia con el Evangelio.Abstract: Daniela Parisi analyses the impact of the life of Saint Francis of Assisi, from the perspective of the history of economic thought. By referring in particular to the attention given in Franciscan circles to the signs of times, the author draws the path from Saint Francis’s life to the life of the Order until the present, and reveals the origins of the Franciscan movement as an attempt for social and religious reformation. First, the article presents St. Francis’s life of a “voluntary material poverty” in the context of the social and economic changes that took place in the XIII century, with the rise of the commercial society. Then, the author explains how St. Francis’ proposal grew into an Order. Finally, the article aims at illuminating the aspects in which the Franciscan Order can be still considered a sign of the times by living the commitment to poverty and minority, eliminating the superfluous from our lives and living close to the Gospel
Impact of the single nucleotide polymorphism S218G on the functionality and structure of Orai1 channels
No full textAuthor Daniela Geishüttner BScMasterarbeit Universität Linz 202
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