dysfunctionality
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The focus of this review is on the proteomic approaches applied to the study of the qualitative/quantitative changes in mitochondrial proteins that are related to impaired mitochondrial function and consequently different types of pathologies. Proteomic techniques developed in recent years have created a powerful tool for the characterization of both static and dynamic proteomes. They can detect protein-protein interactions and a broad repertoire of post-translation modifications that play pivotal roles in mitochondrial regulation, maintenance and proper function. Based on accumulated proteomic data, conclusions can be derived on how to proceed in disease prevention and treatment. In addition, this article will present an overview of the recently published proteomic papers that deal with the regulatory roles of post-translational modifications of mitochondrial proteins and specifically with cardiovascular diseases connected to mitochondrial dysfunction.
Cellular immunotherapy is becoming a new pillar in cancer treatment after recent striking results in different clinical trials with chimeric antigen receptor T cells. However, this innovative therapy is not exempt from challenges such as off-tumor toxicity, tumor recurrence in heterogeneous tumors, and affordability. To surpass these limitations, we exploit the unique anti-tumor characteristics of natural killer (NK) cells. In this study, we aimed to obtain a clinically relevant number of allogeneic NK cells derived from peripheral blood (median of 14,050 million cells from a single donor) to target a broad spectrum of solid and liquid tumor types. To boost their anti-tumor activity, we combined allogeneic NK cells with the approved anti-cluster of differentiation 38 (CD-38) monoclonal antibody Daratumumab to obtain a synergistic therapeutic effect against incurable multiple myeloma. The combination therapy was refined with CD16 polymorphism donor selection and uncomplicated novel in vitro pretreatment to avoid undesired fratricide, increasing the in vitro therapeutic effect against the CD-38 positive multiple myeloma cell line by more than 20%. Time-lapse imaging of mice with established human multiple myeloma xenografts revealed that combination therapy of selected and pretreated NK cells with Daratumumab presented tumor volumes 43-fold smaller than control ones. Combination therapy with an allogeneic source of fully functional NK cells could be beneficial in future clinical settings to circumvent monoclonal antibodies' low therapeutic efficiency due to NK cell dysfunctionality in MM patients.
- MeSH
- buněčná a tkáňová terapie metody MeSH
- buňky NK imunologie MeSH
- imunoterapie metody MeSH
- lidé MeSH
- mnohočetný myelom farmakoterapie MeSH
- monoklonální protilátky farmakologie MeSH
- myši SCID MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- protinádorové látky imunologicky aktivní farmakologie MeSH
- studie případů a kontrol MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In patients with testicular germ cell tumours (TGCT), sperm cryopreservation prior to anti-cancer treatment represents the main fertility preservation approach. However, it is associated with a low sperm recovery rate after thawing. Since sperm is a high-energy demanding cell, which is supplied by glycolysis and oxidative phosphorylation (OXPHOS), mitochondrial dysfunctionality can directly result in sperm anomalies. In this study, we investigated the bioenergetic pattern of cryopreserved sperm of TGCT patients in comparison with normozoospermic samples using two state-of-the-art methods: the Extracellular Flux Analyzer (XF Analyzer) and two-photon fluorescence lifetime imaging microscopy (2P-FLIM), in order to assess the contributions of OXPHOS and glycolysis to energy provision. A novel protocol for the combined measurement of OXPHOS (oxygen consumption rate: OCR) and glycolysis (extracellular acidification rate: ECAR) using the XF Analyzer was developed together with a unique customized AI-based approach for semiautomated processing of 2P-FLIM images. Our study delivers optimized low-HEPES modified human tubal fluid media (mHTF) for sperm handling during pre-analytical and analytical phases, to maintain sperm physiological parameters and optimal OCR, equivalent to OXPHOS. The negative effect of cryopreservation was signified by the deterioration of both bioenergetic pathways represented by modified OCR and ECAR curves and the derived parameters. This was true for normozoospermic as well as samples from TGCT patients, which showed even stronger damage within the respiratory chain compared to the level of glycolytic activity impairment. The impact of cryopreservation and pathology are supported by 2P-FLIM analysis, showing a significant decrease in bound NADH in contrast to unbound NAD(P)H, which reflects decreased metabolic activity in samples from TGCT patients. Our study provides novel insights into the impact of TGCT on sperm bioenergetics and delivers a verified protocol to be used for the assessment of human sperm metabolic activity, which can be a valuable tool for further research and clinical andrology.
- MeSH
- dospělí MeSH
- energetický metabolismus * MeSH
- germinální a embryonální nádory * metabolismus patologie MeSH
- glykolýza * MeSH
- kryoprezervace * metody MeSH
- lidé MeSH
- mitochondrie metabolismus MeSH
- oxidativní fosforylace * MeSH
- spermie * metabolismus MeSH
- spotřeba kyslíku fyziologie MeSH
- testikulární nádory * metabolismus patologie MeSH
- uchování spermatu metody MeSH
- zachování plodnosti metody MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
