Since cell dying in heart failure (HF) may vary based on the aetiology, we examined the main forms of regulated necrosis, such as necroptosis and pyroptosis, in the hearts damaged due to myocardial infarction (MI) or pressure overload. We also investigated the effects of a drug inhibiting RIP3, a proposed convergent point for both these necrosis-like cell death modes. In rat hearts, left ventricular function, remodelling, pro-cell death, and pro-inflammatory events were investigated, and the pharmacodynamic action of RIP3 inhibitor (GSK'872) was assessed. Regardless of the HF aetiology, the heart cells were dying due to necroptosis, albeit the upstream signals may be different. Pyroptosis was observed only in post-MI HF. The dysregulated miRNAs in post-MI hearts were accompanied by higher levels of a predicted target, HMGB1, its receptors (TLRs), as well as the exacerbation of inflammation likely originating from macrophages. The RIP3 inhibitor suppressed necroptosis, unlike pyroptosis, normalised the dysregulated miRNAs and tended to decrease collagen content and affect macrophage infiltration without affecting cardiac function or structure. The drug also mitigated the local heart inflammation and normalised the higher circulating HMGB1 in rats with post-MI HF. Elevated serum levels of HMGB1 were also detected in HF patients and positively correlated with C-reactive protein, highlighting pro-inflammatory axis. In conclusion, in MI-, but not pressure overload-induced HF, both necroptosis and pyroptosis operate and might underlie HF pathogenesis. The RIP3-targeting pharmacological intervention might protect the heart by preventing pro-death and pro-inflammatory mechanisms, however, additional strategies targeting multiple pro-death pathways may exhibit greater cardioprotection.
- Klíčová slova
- Heart failure, High mobility group box 1, Inflammation, Necroptosis, Pyroptosis, Receptor-interacting protein kinase 3,
- MeSH
- funkce levé komory srdeční účinky léků MeSH
- inhibitory proteinkinas * farmakologie MeSH
- kardiomyocyty * účinky léků patologie enzymologie MeSH
- krysa rodu Rattus MeSH
- mikro RNA metabolismus genetika MeSH
- modely nemocí na zvířatech MeSH
- nekroptóza * účinky léků MeSH
- nekróza MeSH
- potkani Sprague-Dawley MeSH
- pyroptóza * účinky léků MeSH
- remodelace komor účinky léků MeSH
- serin-threoninkinasy interagující s receptory * antagonisté a inhibitory metabolismus MeSH
- srdeční selhání * patologie enzymologie patofyziologie farmakoterapie etiologie genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- inhibitory proteinkinas * MeSH
- mikro RNA MeSH
- Ripk3 protein, rat MeSH Prohlížeč
- serin-threoninkinasy interagující s receptory * MeSH
Aging, characterized by accumulation of senescent cells, is a driving factor of various age-related diseases. These conditions pose significant health risks globally due to their increasing prevalence and serious complications. Reduction of senescent cells therefore represents a promising strategy promoting healthy aging. Here we demonstrate that targeting tamoxifen to mitochondria via triphenyl and tricyclohexyl phosphine selectively eliminates senescent cells. Our findings show a complex effect of mitochondrially targeted tamoxifen on mitochondrial function and integrity of senescent cells, including inhibition of oxidative phosphorylation and activity of respiratory complex IV. These changes result in activation of ferroptosis as the major mode of cell death, which results in rejuvenation of tissues. Targeting mitochondria of senescent cells represents a general senolytic strategy and may extend the healthspan and improve the quality of life in aging populations.
- Publikační typ
- časopisecké články MeSH
Myokines represent important regulators of muscle metabolism. Our study aimed to explore the effects of a cyclical ketogenic reduction diet (CKD) vs. a nutritionally balanced reduction diet (RD) combined with regular resistance/aerobic training in healthy young males on serum concentrations of myokines and their potential role in changes in physical fitness. Twenty-five subjects undergoing regular resistance/aerobic training were randomized to the CKD (n = 13) or RD (n = 12) groups. Anthropometric and spiroergometric parameters, muscle strength, biochemical parameters, and serum concentrations of myokines and cytokines were assessed at baseline and after 8 weeks of intervention. Both diets reduced body weight, body fat, and BMI. Muscle strength and endurance performance were improved only by RD. Increased musclin (32.9 pg/mL vs. 74.5 pg/mL, p = 0.028) and decreased osteonectin levels (562 pg/mL vs. 511 pg/mL, p = 0.023) were observed in RD but not in the CKD group. In contrast, decreased levels of FGF21 (181 pg/mL vs. 86.4 pg/mL, p = 0.003) were found in the CKD group only. Other tested myokines and cytokines were not significantly affected by the intervention. Our data suggest that changes in systemic osteonectin and musclin levels could contribute to improved muscle strength and endurance performance and partially explain the differential effects of CKD and RD on physical fitness.
- Klíčová slova
- adipokines, body composition, cytokines, endurance, ketogenic diet, myokines, strength parameters, training,
- MeSH
- chronická renální insuficience * MeSH
- cytokiny MeSH
- ketogenní dieta * MeSH
- lidé MeSH
- odporový trénink * MeSH
- osteonektin MeSH
- redukční dieta MeSH
- složení těla fyziologie MeSH
- svalová síla fyziologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- cytokiny MeSH
- osteonektin MeSH
BACKGROUND: Mitochondria present an emerging target for cancer treatment. We have investigated the effect of mitochondrially targeted tamoxifen (MitoTam), a first-in-class anti-cancer agent, in patients with solid metastatic tumours. METHODS: MitoTam was tested in an open-label, single-centre (Department of Oncology, General Faculty Hospital, Charles University, Czech Republic), phase I/Ib trial in metastatic patients with various malignancies and terminated oncological therapies. In total, 75 patients were enrolled between May 23, 2018 and July 22, 2020. Phase I evaluated escalating doses of MitoTam in two therapeutic regimens using the 3 + 3 design to establish drug safety and maximum tolerated dose (MTD). In phase Ib, three dosing regimens were applied over 8 and 6 weeks to evaluate long-term toxicity of MitoTam as the primary objective and its anti-cancer effect as a secondary objective. This trial was registered with the European Medicines Agency under EudraCT 2017-004441-25. FINDINGS: In total, 37 patients were enrolled into phase I and 38 into phase Ib. In phase I, the initial application of MitoTam via peripheral vein indicated high risk of thrombophlebitis, which was avoided by central vein administration. The highest dose with acceptable side effects was 5.0 mg/kg. The prevailing adverse effects (AEs) in phase I were neutropenia (30%), anaemia (30%) and fever/hyperthermia (30%), and in phase Ib fever/hyperthermia (58%) together with anaemia (26%) and neutropenia (16%). Serious AEs were mostly related to thromboembolic (TE) complications that affected 5% and 13% of patients in phase I and Ib, respectively. The only statistically significant AE related to MitoTam treatment was anaemia in phase Ib (p = 0.004). Of the tested regimens weekly dosing with 3.0 mg/kg for 6 weeks afforded the best safety profile with almost all being grade 1 (G1) AEs. Altogether, five fatalities occurred during the study, two of them meeting criteria for Suspected Unexpected Serious Adverse Events Reporting (SUSAR) (G4 thrombocytopenia and G5 stroke). MitoTam showed benefit evaluated as clinical benefit rate (CBR) in 37% patients with the largest effect in renal cell carcinoma (RCC) where four out of six patients reached disease stabilisation (SD), one reached partial response (PR) so that in total, five out of six (83%) patients showed CBR. INTERPRETATION: In this study, the MTD was established as 5.0 mg/kg and the recommended dose of MitoTam as 3.0 mg/kg given once per week via central vein with recommended preventive anti-coagulation therapy. The prevailing toxicity included haematological AEs, hyperthermia/fever and TE complications. One fatal stroke and non-fatal G4 thrombocytopenia were recorded. MitoTam showed high efficacy against RCC. FUNDING: Smart Brain Ltd. TRANSLATION: For the Czech translation of the abstract see Supplementary Materials section.
- Klíčová slova
- Cancer, Mitochondrially targeted tamoxifen, Phase I/Ib clinical trial, Renal cell carcinoma,
- Publikační typ
- časopisecké články MeSH
Repetitive sequences are among the most unstable regions in the eukaryotic genome and defects in their maintenance correlate with premature aging and cancer development. Promyelocytic leukemia protein (PML) induces accumulation of proteins at distinct nuclear sites, thereby affecting a plethora of processes including DNA repair or maintenance of telomeres. Doxorubicin, the broadly used chemotherapeutic compound, induces formation of PML-nucleolar associations (PNAs). Nevertheless, molecular factors affecting formation of PNAs are still largely unknown. Here we show that PNAs can accumulate ribosomal DNA (rDNA) and, after restoration of RNA polymerase I activity, these structures transfer a fraction of rDNA outside the nucleolus. Mutagenesis of PML isoforms revealed that this process depends on the SUMO-interacting motif and adjacent serine-rich region, and is enhanced by exon8b present exclusively in PML IV isoform. Moreover, we demonstrate that PNAs formation is also regulated by p14ARF/p53 tumor suppressors and casein kinase 2. Our data elucidate how PML nucleolar compartment is assembled, bring the first evidence of PML interacting with rDNA, and show the PML-dependent translocation of rDNA away from the nucleolus.
- Klíčová slova
- Nucleolus, P14(ARF), PML, Phospho-SIM, rDNA,
- MeSH
- doxorubicin farmakologie MeSH
- jaderné proteiny * metabolismus MeSH
- nádorové supresorové proteiny genetika metabolismus MeSH
- peptidové nukleové kyseliny * MeSH
- protein - isoformy metabolismus MeSH
- ribozomální DNA genetika MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- doxorubicin MeSH
- jaderné proteiny * MeSH
- nádorové supresorové proteiny MeSH
- peptidové nukleové kyseliny * MeSH
- protein - isoformy MeSH
- ribozomální DNA MeSH
Type 2 diabetes mellitus represents a major health problem with increasing prevalence worldwide. Limited efficacy of current therapies has prompted a search for novel therapeutic options. Here we show that treatment of pre-diabetic mice with mitochondrially targeted tamoxifen, a potential anti-cancer agent with senolytic activity, improves glucose tolerance and reduces body weight with most pronounced reduction of visceral adipose tissue due to reduced food intake, suppressed adipogenesis and elimination of senescent cells. Glucose-lowering effect of mitochondrially targeted tamoxifen is linked to improvement of type 2 diabetes mellitus-related hormones profile and is accompanied by reduced lipid accumulation in liver. Lower senescent cell burden in various tissues, as well as its inhibitory effect on pre-adipocyte differentiation, results in lower level of circulating inflammatory mediators that typically enhance metabolic dysfunction. Targeting senescence with mitochodrially targeted tamoxifen thus represents an approach to the treatment of type 2 diabetes mellitus and its related comorbidities, promising a complex impact on senescence-related pathologies in aging population of patients with type 2 diabetes mellitus with potential translation into the clinic.
- MeSH
- diabetes mellitus 2. typu * komplikace farmakoterapie MeSH
- experimentální diabetes mellitus * komplikace farmakoterapie MeSH
- glukosa metabolismus MeSH
- lidé MeSH
- myši MeSH
- obezita komplikace farmakoterapie metabolismus MeSH
- senioři MeSH
- tamoxifen farmakologie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- senioři MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- glukosa MeSH
- tamoxifen MeSH
