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  • 1
    Online Resource
    Online Resource
    Truncated titin proteins and titin haploinsufficiency are targets for functional recovery in human cardiomyopathy due to TTN mutations
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Translational Medicine Vol. 13, No. 618 ( 2021-11-03)
    Details
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 13, No. 618 ( 2021-11-03)
    Abstract: Heterozygous truncating variants in TTN (TTNtv), the gene coding for titin, cause dilated cardiomyopathy (DCM), but the underlying pathomechanisms are unclear and disease management remains uncertain. Truncated titin proteins have not yet been considered as a contributor to disease development. Here, we studied myocardial tissues from nonfailing donor hearts and 113 patients with end-stage DCM for titin expression and identified a TTNtv in 22 patients with DCM (19.5%). We directly demonstrate titin haploinsufficiency in TTNtv-DCM hearts and the absence of compensatory changes in the alternative titin isoform Cronos. Twenty-one TTNtv-DCM hearts in our cohort showed stable expression of truncated titin proteins. Expression was variable, up to half of the total titin protein pool, and negatively correlated with patient age at heart transplantation. Truncated titin proteins were not detected in sarcomeres but were present in intracellular aggregates, with deregulated ubiquitin-dependent protein quality control. We produced human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs), comparing wild-type controls to cells with a patient-derived, prototypical A-band-TTNtv or a CRISPR-Cas9–generated M-band-TTNtv. TTNtv-hiPSC-CMs showed reduced wild-type titin expression and contained truncated titin proteins whose proportion increased upon inhibition of proteasomal activity. In engineered heart muscle generated from hiPSC-CMs, depressed contractility caused by TTNtv could be reversed by correction of the mutation using CRISPR-Cas9, eliminating truncated titin proteins and raising wild-type titin content. Functional improvement also occurred when wild-type titin protein content was increased by proteasome inhibition. Our findings reveal the major pathomechanisms of TTNtv-DCM and can be exploited for new therapies to treat TTNtv-related cardiomyopathies.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    URL: Article
    DOI: 10.1126/scitranslmed.abd3079
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
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  • 2
    Online Resource
    Online Resource
    Study of the expression of Cronos titin in TTN-truncation cardiomyopathy and heart development
    Elsevier BV ; 2022
    In:  Journal of Molecular and Cellular Cardiology Vol. 173 ( 2022-12), p. S71-
    Details
    In: Journal of Molecular and Cellular Cardiology, Elsevier BV, Vol. 173 ( 2022-12), p. S71-
    Type of Medium: Online Resource
    ISSN: 0022-2828
    URL: Article
    DOI: 10.1016/j.yjmcc.2022.08.144
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 1469767-1
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  • 3
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    Results of a Prospective Non-Interventional Post-Authorization Safety Study of Idelalisib in Germany
    Elsevier BV ; 2022
    In:  Clinical Lymphoma Myeloma and Leukemia Vol. 22, No. 8 ( 2022-08), p. e777-e787
    Details
    In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 22, No. 8 ( 2022-08), p. e777-e787
    Type of Medium: Online Resource
    ISSN: 2152-2650
    URL: Article
    DOI: 10.1016/j.clml.2022.04.007
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2540998-0
    detail.hit.zdb_id: 2193618-3
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  • 4
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    A systematic evidence map of conservation knowledge in Chilean Patagonia
    Wiley ; 2022
    In:  Conservation Science and Practice Vol. 4, No. 1 ( 2022-01)
    Details
    In: Conservation Science and Practice, Wiley, Vol. 4, No. 1 ( 2022-01)
    Abstract: Mechanisms that reliably and efficiently guide practitioners to find relevant evidence are urgent for conservation decision‐making in Chilean Patagonia. The objective of this study was to systematically collect, characterize, and synthesize the extensive evidence about conservation knowledge in Chilean Patagonia focusing on the impacts of global change drivers on ecosystems and human–nature relationships, identifying knowledge gaps, and providing policy recommendations. The quality of the evidence was assessed through a predefined level‐of‐evidence hierarchy scale, applied to a sample of the studies reviewed. We compiled ~1000 studies documenting that evidence focusing on terrestrial and marine ecosystems has grown exponentially. For terrestrial ecosystems, most studies have addressed climate change, habitat change, and invasive species; while for marine ecosystems, studies have focused on pollution, invasive species, and habitat change. We identified that an important gap is the study of the social dimensions of conservation, and future efforts should focus on incorporating traditional and local knowledge as this can help point the way to ecosystem conservation. The appraisal of the quality of the evidence showed that ~80% of the sample represented reliable evidence with underlying data and an experimental design. Enhanced efforts to deliver this evidence to decision‐makers in a user‐friendly format for evidence uptake in conservation policy are urgent. In this review, we provide a tool that can help practitioners to find evidence reliably to improve decision‐making for the conservation of ecosystems in Chilean Patagonia.
    Type of Medium: Online Resource
    ISSN: 2578-4854 , 2578-4854
    URL: Issue
    URL: Article
    DOI: 10.1111/csp2.v4.1
    DOI: 10.1111/csp2.575
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2947571-5
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  • 5
    Online Resource
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    Role of Mouse Organic Cation Transporter 2 for Nephro- and Peripheral Neurotoxicity Induced by Chemotherapeutic Treatment with Cisplatin
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 14 ( 2023-07-14), p. 11486-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 14 ( 2023-07-14), p. 11486-
    Abstract: Cisplatin (CDDP) is an efficient chemotherapeutic agent broadly used to treat solid cancers. Chemotherapy with CDDP can cause significant unwanted side effects such as renal toxicity and peripheral neurotoxicity. CDDP is a substrate of organic cation transporters (OCT), transporters that are highly expressed in renal tissue. Therefore, CDDP uptake by OCT may play a role in causing unwanted toxicities of CDDP anticancer treatment. In this study, the contribution of the mouse OCT2 (mOCT2) to CDDP nephro- and peripheral neurotoxicity was investigated by comparing the effects of cyclic treatment with low doses of CDDP on renal and neurological functions in wild-type (WT) mice and mice with genetic deletion of OCT2 (OCT2−/− mice). This CDDP treatment protocol caused significant impairment of kidneys and peripherical neurological functions in WT mice. These effects were significantly reduced in OCT2−/− mice, however, less profoundly than what was previously measured in mice with genetic deletion of both OCT1 and 2 (OCT1-2−/− mice). Comparing the apparent affinities (IC50) of mOCT1 and mOCT2 for CDDP, the mOCT1 displayed a higher affinity for CDDP than the mOCT2 (IC50: 9 and 558 µM, respectively). Also, cellular toxicity induced by incubation with 100 µM CDDP was more pronounced in cells stably expressing mOCT1 than in cells expressing mOCT2. Therefore, in mice, CDDP uptake by both OCT1 and 2 contributes to the development of CDDP undesired side effects. OCT seem to be suitable targets for establishing treatment protocols aimed at decreasing unwanted CDDP toxicity and improving anticancer treatment with CDDP.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms241411486
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Exacerbation of Cisplatin Cellular Toxicity by Regulation of the Human Organic Cation Transporter 2 through Angiotensin II
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 23, No. 24 ( 2022-12-14), p. 15866-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 24 ( 2022-12-14), p. 15866-
    Abstract: Cisplatin (CDDP) is an efficient chemotherapeutic drug, whose use is associated with the development of serious undesired toxicities, such as nephrotoxicity. The human organic cation transporter 2 (hOCT2), which is highly expressed in the basolateral membrane domain of renal proximal tubules seems to play an important role in the development of CDDP nephrotoxicity. The role of angiotensin II (AII) signaling by binding to the AII receptor type 1 (AT1R) in the development and/or progression of CDDP nephrotoxicity is debated. Therefore, in this work, the regulation of hOCT2 activity by AII and its role in the development of CDDP cellular toxicity was investigated. To do this, hOCT2 was overexpressed by viral transduction in Madin–Darby Canine Kidney (MDCK) cells which were cultivated on a filter. This approach allows the separation of an apical and a basolateral membrane domain, which are easily accessible for experimentation. In this system, hOCT2 was mainly localized on the basolateral plasma membrane domain of the cells. The transporter was functional since a specific uptake of the fluorescent organic cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP+) with an affinity (Km) of 35 µM was only detectable by the addition of ASP+ to the basolateral compartment of hOCT2 expressing MDCK (hOCT2-MDCK) cells. Similarly, CDDP toxicity was evident mainly by CDDP addition to the basolateral compartment of hOCT2-MDCK cells cultivated on a filter. The addition of 1 nM AII stimulated hOCT2 function via PKC activation and worsened CDDP cytotoxicity via binding to AT1R. Therefore, the AII signaling pathway may be implicated in the development and/or progression of CDDP nephrotoxicity. This signaling pathway may be a target for protective interventions for example by blocking AT1R in the kidneys. However, it should be further investigated whether these findings obtained in a cell culture system may have translational relevance for the clinical situation. For toxicity experiments, a 100 µM CDDP concentration was used, which is high but allows us to identify clearly toxic effects due to hOCT2. In summary, down-regulation of hOCT2 activity by the inhibition of the AII signaling pathway may protect against CDDP nephrotoxicity.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms232415866
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Rapid Regulation of Human Multidrug and Extrusion Transporters hMATE1 and hMATE2K
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 14 ( 2020-07-21), p. 5157-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 14 ( 2020-07-21), p. 5157-
    Abstract: Vectorial transport of organic cations (OCs) in renal proximal tubules is mediated by sequential action of human OC transporter 2 (hOCT2) and human multidrug and toxic extrusion protein 1 and 2K (hMATE1 and hMATE2K), expressed in the basolateral (hOCT2) and luminal (hMATE1 and hMATE2K) plasma membranes, respectively. It is well known that hOCT2 activity is subjected to rapid regulation by several signaling pathways, suggesting that renal OC secretion may be acutely adapted to physiological requirements. Therefore, in this work, the acute regulation of hMATEs stably expressed in human embryonic kidney cells was characterized using the fluorescent substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP+) as a marker. A specific regulation of ASP+ transport by hMATE1 and hMATE2K measured in uptake and efflux configurations was observed. In the example of hMATE1 efflux reduction by inhibition of casein kinase II, it was also shown that this regulation is able to modify transcellular transport of ASP+ in Madin–Darby canine kidney II cells expressing hOCT2 and hMATE1 on the basolateral and apical membrane domains, respectively. The activity of hMATEs can be rapidly regulated by some intracellular pathways, which sometimes are common to those found for hOCTs. Interference with these pathways may be important to regulate renal secretion of OCs.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21145157
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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