- Dosing depending on SIRT3 activity attenuates doxorubicin-induced cardiotoxicity via elevated tolerance against mitochondrial dysfunction and oxidative stress. [Journal Article]
- BBBiochem Biophys Res Commun 2019 Jul 12
- Doxorubicin (DOX) is a potent anti-neoplastic agent with cumulative cardiotoxicity. DOX-induced cardiotoxicity has been shown to depend on the different dosing times. However, the basis for determini…
Doxorubicin (DOX) is a potent anti-neoplastic agent with cumulative cardiotoxicity. DOX-induced cardiotoxicity has been shown to depend on the different dosing times. However, the basis for determining the dosing time to minimize DOX-induced cardiotoxicity and the underlying mechanisms remain incompletely understood. Here we first showed that SIRT3, the major mitochondrial deacetylase, is negatively correlated to DOX-induced cardiotoxicity through the regulation of ATP production, mitochondrial membrane potential (MMP) level and ROS level in human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Then, we used in vivo experiments to demonstrate that DOX significantly reduced the SIRT3 expression and the SIRT3 activity as reflected by the increased AcK68MnSOD/MnSOD ratio in rats after six weeks of treatment. Notably, the activity of SIRT3 had an obvious diurnal rhythm pattern in the myocardium of healthy rats. More importantly, an obvious lower AcK68MnSOD/MnSOD ratio was observed in rat hearts with DOX administrated at Zeitgeber time (ZT) 9 (ZT 0 was the time lights were turned on) than ZT1, which represent the peak and trough of SIRT3 activity. Moreover, DOX ZT9 reduced the body weight loss, extended the survival period, improved the heart function and alleviated the myocardial lesions compared to DOX ZT1. Mechanistic investigations demonstrated that DOX ZT1 significantly reduced ATP production, oxygen consumption rate (OCR) at various respiration states, MMP level and MnSOD activity and enhanced the H2O2 level compared with CON ZT1, whereas there was no significant effect for DOX ZT9 compared with CON ZT9. Taken together, dosing at the peak time of SIRT3 activity reduced DOX-induced cardiotoxicity, which may be related to the increased endogenous tolerance against the mitochondrial dysfunction and oxidative stress caused by DOX.
- Effects of Acclimation Temperatures on the Respiration Physiology and Thermal Coefficient of Malabar Blood Snapper. [Journal Article]
- RPRespir Physiol Neurobiol 2019 Jul 10; :103253
- This study tested the oxygen consumption rates (OCR), energy, and thermal coefficient of juvenile Lutjanus malabaricus (60 fish, size: 4.53 ± 1.14 g) at four temperatures of 22, 26, 30 and 34 °C. Dur…
This study tested the oxygen consumption rates (OCR), energy, and thermal coefficient of juvenile Lutjanus malabaricus (60 fish, size: 4.53 ± 1.14 g) at four temperatures of 22, 26, 30 and 34 °C. During 30 days of experimental period 5 fish tank-1 were reared at four temperatures with three replicates in intermittent flow respirometers in a recirculatory system under laboratory conditions. As expected, oxygen consumption rates increased significantly (P < 0.05) from 1.39 ± 0.07 to 3.11 ± 0.09 ml O2 h-1 with an increase in the exposed temperature from 22 to 34 °C. The corresponding respired energy values also increased from 27.59 ± 1.03 to 61.78 ± 0.66 Jh-1 at 22 and 34 °C respectively. The maximum and minimum temperature quotients (Q10) were observed between 22-26 °C (2.02) and 26-30 °C (1.82) respectively. Final preferred temperature (thermal coefficient) estimated between 26 and 30 °C. This bioengineering information can be used for designing and sizing a rearing facility for the intensive culture of L. malabaricus.
- Clathrin-mediated Endocytosis of Alpha-1 Antitrypsin is Essential for its Protective Function in Islet Cell Survival. [Journal Article]
- TTheranostics 2019; 9(13):3940-3951
- CONCLUSIONS: Our results suggest that AAT is internalized by β cells through clathrin-mediated endocytosis that leads to the suppression of caspase 9 activation. This process is required for the protective function of AAT in islets when challenged with proinflammatory cytokines or after islet transplantation.
- Glucose consumption assay discovers coptisine with beneficial effect on diabetic mice. [Journal Article]
- EJEur J Pharmacol 2019 Jul 04; 859:172523
- Many drugs with anti-diabetic effects regulate glucose consumption in peripheral tissues. Via cellular glucose consumption assays, we identified that coptisine, a main effective constituent from the …
Many drugs with anti-diabetic effects regulate glucose consumption in peripheral tissues. Via cellular glucose consumption assays, we identified that coptisine, a main effective constituent from the plant Coptis chinensis, enhanced hepatic and skeletal muscle glucose consumption. We further explored its effects on glucose metabolism in diabetic animals to elucidate its mechanism of action. Our results showed that coptisine did not show cytotoxicity. Intragastric administration of coptisine for ten days in normal ICR mice markedly decreased fasting blood-glucose levels without significant effects on body weight. In alloxan-induced type 1 diabetic mice, intragastric administration of coptisine for 28 days decreased fasting and non-fasting blood-glucose levels as well. In type 2 diabetic KKAy mice, intragastric administration of coptisine for nine weeks improved glucose tolerance. It decreased fasting/non-fasting blood-glucose and fructosamine levels. Coptisine decreased low-density lipoprotein and total cholesterol levels, however, had no significant effect on triglyceride levels. Coptisine increased AMPK phosphorylation while decreasing Akt phosphorylation in HepG2 hepatic cells and C2C12 myotubes. Coptisine also reduced mitochondrial respiration in isolated and cellular mitochondria, suggesting that coptisine lowered cellular energy levels. In particularly, coptisine administration (10-6 M) decreased the mitochondrial oxygen consumption rate (OCR) with a greater extracellular acidification rate (ECAR), resulting in an oxidative-to-glycolysis phosphorylation shifted for cellular energy generation. Our results demonstrate that coptisine acts as an enhancer of peripheral glucose consumption could improve glucose metabolism in diabetic animals. Coptisine may serve as a novel anti-diabetic agent and warrant further evaluation.
- "Beige" Cross Talk Between the Immune System and Metabolism. [Journal Article]
- FEFront Endocrinol (Lausanne) 2019; 10:369
- With thymic senescence the epithelial network shrinks to be replaced by adipose tissue. Transcription factor TBX-1 controls thymus organogenesis, however, the same TBX-1 has also been reported to orc…
With thymic senescence the epithelial network shrinks to be replaced by adipose tissue. Transcription factor TBX-1 controls thymus organogenesis, however, the same TBX-1 has also been reported to orchestrate beige adipose tissue development. Given these different roles of TBX-1, we have assessed if thymic TBX-1 expression persists and demonstrates this dualism during adulthood. We have also checked whether thymic adipose involution could yield beige adipose tissue. We have used adult mouse and human thymus tissue from various ages to evaluate the kinetics of TBX-1 expression, as well as mouse (TEP1) and human (1889c) thymic epithelial cells (TECs) for our studies. Electron micrographs show multi-locular lipid deposits typical of beige adipose cells. Histology staining shows the accumulation of neutral lipid deposits. qPCR measurements show persistent and/or elevating levels of beige-specific and beige-indicative markers (TBX-1, EAR-2, UCP-1, PPAR-gamma). We have performed miRNome profiling using qPCR-based QuantStudio platform and amplification-free NanoString platform. We have observed characteristic alterations, including increased miR21 level (promoting adipose tissue development) and decreased miR34a level (bias toward beige adipose tissue differentiation). Finally, using the Seahorse metabolic platform we have recorded a metabolic profile (OCR/ECAR ratio) indicative of beige adipose tissue. In summary, our results support that thymic adipose tissue emerging with senescence is bona fide beige adipose tissue. Our data show how the borders blur between a key immune tissue (the thymus) and a key metabolic tissue (beige adipose tissue) with senescence. Our work contributes to the understanding of cross talk between the immune system and metabolism.
- A new Thiocyanoacetamide protects rat sperm cells from Doxorubicin-triggered cytotoxicity whereas Selenium shows low efficacy: In vitro approach. [Journal Article]
- TVToxicol In Vitro 2019 Jul 02; 61:104587
- Doxorubicin (DOX) exhibits a wide-ranging spectrum of antitumor activities which maintain its clinical use despite its devastating impact on highly proliferating cells. The present work was designed …
Doxorubicin (DOX) exhibits a wide-ranging spectrum of antitumor activities which maintain its clinical use despite its devastating impact on highly proliferating cells. The present work was designed to develop a new approach which aims to protect male germ cells from DOX cytotoxicity. Thus, an assessment of the protective potential of a new thioamide analog (thiocyanoacetamide; TA) compared to selenium (Se) was performed in rat sperms exposed to DOX in vitro. Oxygen consumption rate (OCR) was measured after exposure to three different doses (0.5, 1, 1.5 and 2 μM) of DOX, Se or TA, and the suitable concentrations were selected for further studies afterwards. Motility, OCR in a time-dependent manner, glucose extracellular concentration and lipid peroxidation (LPO) were measured. Fatty acid (FA) content was assessed by gas chromatography (GC-FID). Cell death, superoxide anion (O2-), mitochondrial membrane potential (MMP), and DNA damage were evaluated by flow cytometry. TA association with DOX increased OCR and glucose uptake, improved cell survival and decreased DNA damage. The co-administration of DOX with Se increased OCR, significantly prevented O2- overproduction, and decreased LPO. Collected data brought new insights regarding this transformed TA, which showed better efficiency than Se in reducing DOX cytotoxic stress in sperms.
- Optimization of experimental conditions and measurement of oxygen consumption rate (OCR) in zebrafish embryos exposed to organophosphate flame retardants (OPFRs). [Journal Article]
- EEEcotoxicol Environ Saf 2019 Jun 26; 182:109377
- The measurement of oxygen consumption rate (OCR) provides a comprehensive understanding of mitochondrial metabolism. However, no study has been conducted to investigate the mitochondrial dysfunction …
The measurement of oxygen consumption rate (OCR) provides a comprehensive understanding of mitochondrial metabolism. However, no study has been conducted to investigate the mitochondrial dysfunction caused by organophosphate flame retardants (OPFRs). The objectives of this study were to optimize the experimental conditions to measure OCR in zebrafish embryos using the Seahorse XFe 24 Extracellular Flux Analyzer, and to investigate the changes of OCR in zebrafish embryos exposed to OPFRs. We first optimized the experimental conditions such as the number of embryos, concentrations of inhibitors, and time points. We determined the factors, i.e., three embryos, 12.5 μM of oligomycin, 8 μM of carbonyl cyanaide 4-(trifluoromethoxy) phenylhydrazone (FCCP), and 24 hpf (hours post-fertilization) time point, for obtaining the typical pattern of OCR in dechorinated zebrafish embryos. After confirming the determinants upon exposure of triclosan, the inhibition of OCR was measured in zebrafish embryos exposed to two major OPFRs, triphenyl phosphate (TPHP) and tris (1,3-dichloro-2-propyl) phosphate (TDCIPP). We found that significant inhibition of OCR was observed in basal respiration for TPHP, and in basal and maximal respiration for TDCIPP exposure, respectively. We suggest the optimum conditions of the Seahorse XFe 24 analyzer to better evaluate OCR in zebrafish embryos, and demonstrate the potential of TPHP and TDCIPP to cause the disruption of energy metabolism associated with mitochondrial dysfunction.
- Metabolism of Stem and Progenitor Cells: Proper Methods to Answer Specific Questions. [Review]
- FMFront Mol Neurosci 2019; 12:151
- Stem cells can stay quiescent for a long period of time or proliferate and differentiate into multiple lineages. The activity of stage-specific metabolic programs allows stem cells to best adapt thei…
Stem cells can stay quiescent for a long period of time or proliferate and differentiate into multiple lineages. The activity of stage-specific metabolic programs allows stem cells to best adapt their functions in different microenvironments. Specific cellular phenotypes can be, therefore, defined by precise metabolic signatures. Notably, not only cellular metabolism describes a defined cellular phenotype, but experimental evidence now clearly indicate that also rewiring cells towards a particular cellular metabolism can drive their cellular phenotype and function accordingly. Cellular metabolism can be studied by both targeted and untargeted approaches. Targeted analyses focus on a subset of identified metabolites and on their metabolic fluxes. In addition, the overall assessment of the oxygen consumption rate (OCR) gives a measure of the overall cellular oxidative metabolism and mitochondrial function. Untargeted approach provides a large-scale identification and quantification of the whole metabolome with the aim to describe a metabolic fingerprinting. In this review article, we overview the methodologies currently available for the study of in vitro stem cell metabolism, including metabolic fluxes, fingerprint analyses, and single-cell metabolomics. Moreover, we summarize available approaches for the study of in vivo stem cell metabolism. For all of the described methods, we highlight their specificities and limitations. In addition, we discuss practical concerns about the most threatening steps, including metabolic quenching, sample preparation and extraction. A better knowledge of the precise metabolic signature defining specific cell population is instrumental to the design of novel therapeutic strategies able to drive undifferentiated stem cells towards a selective and valuable cellular phenotype.
- Development of an "object category recognition" task for mice: Involvement of muscarinic acetylcholine receptors. [Journal Article]
- BNBehav Neurosci 2019 Jun 27
- Recent research suggests that rats are capable of object categorization-like processes. To study whether mice possess similar abilities, we developed a spontaneous one-trial object category recogniti…
Recent research suggests that rats are capable of object categorization-like processes. To study whether mice possess similar abilities, we developed a spontaneous one-trial object category recognition (OCR) task. Based on the spontaneous object recognition paradigm, mice discriminated between two otherwise equally novel objects, one from a novel category and one from a studied category. During the sample phase, mice were exposed to two different exemplars from the same category. After a retention delay, they explored a third (i.e., novel) object from that sampled category and an object from a novel category in a choice phase. Mice preferentially explored the novel category object, taken as an index of category recognition, in this OCR task when a 30-min retention delay was used. Extensive preexposure to category exemplar objects also enhanced subsequent task performance across a longer (1-h) retention delay at which mice without preexposure did not demonstrate evidence for category recognition. Prechoice administration of the acetylcholine muscarinic receptor antagonist, scopolamine, disrupted OCR performance with or without preexposure, implicating acetylcholine in category recognition. The current study presents a valuable new rodent task for the study of the mechanistic basis of categorization-like processes and its potential relevance to common cognitive disorders. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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- Host DNA integrity within blood meals of hematophagous larval gnathiid isopods (Crustacea, Isopoda, Gnathiidae). [Journal Article]
- PVParasit Vectors 2019 Jun 24; 12(1):316
- CONCLUSIONS: To our knowledge, this is the first study to examine the degradation rate of gnathiid isopod blood meals. Determining the rate at which gnathiids digest their blood meal is an important step in ensuring the successful host identification by DNA-based methods in large field studies.