DNA damage signaling in Drosophila macrophages modulates systemic cytokine levels in response to oxidative stress.

Environmental factors, infection, or injury can cause oxidative stress in diverse tissues and loss of tissue homeostasis. Effective stress response cascades, conserved from invertebrates to mammals, ensure reestablishment of homeostasis and tissue repair. Hemocytes, the Drosophila blood-like cells, rapidly respond to oxidative stress by immune activation. However, the precise signals how they sense oxidative stress and integrate these signals to modulate and balance the response to oxidative stress in the adult fly are ill-defined. Furthermore, hemocyte diversification was not explored yet on oxidative stress. Here, we employed high-throughput single nuclei RNA-sequencing to explore hemocytes and other cell types, such as fat body, during oxidative stress in the adult fly. We identified distinct cellular responder states in plasmatocytes, the Drosophila macrophages, associated with immune response and metabolic activation upon oxidative stress. We further define oxidative stress-induced DNA damage signaling as a key sensor and a rate-limiting step in immune-activated plasmatocytes controlling JNK-mediated release of the pro-inflammatory cytokine unpaired-3. We subsequently tested the role of this specific immune activated cell stage during oxidative stress and found that inhibition of DNA damage signaling in plasmatocytes, as well as JNK or upd3 overactivation, result in a higher susceptibility to oxidative stress. Our findings uncover that a balanced composition and response of hemocyte subclusters is essential for the survival of adult Drosophila on oxidative stress by regulating systemic cytokine levels and cross-talk to other organs, such as the fat body, to control energy mobilization.

Acute Low-Dose Hyperoxia during a Single Bout of High-Intensity Interval Exercise Does Not Affect Red Blood Cell Deformability and Muscle Oxygenation in Trained Men-A Randomized Crossover Study.

Recent technological developments provide easy access to use an artificial oxygen supply (hyperoxia) during exercise training. The aim of this study was to assess the efficacy of a commercially available oxygen compressor inducing low-dose hyperoxia, on limiting factors of endurance performance. Thirteen active men (age 24 ± 3 years) performed a high-intensity interval exercise (HIIE) session (5 × 3 min at 80% of Wmax, separated by 2 min at 40% Wmax) on a cycle ergometer, both in hyperoxia (4 L∙min-1, 94% O2, HYP) or ambient conditions (21% O2, NORM) in randomized order. The primary outcome was defined as red blood cell deformability (RBC-D), while our secondary interest included changes in muscle oxygenation. RBC-D was expressed by the ratio of shear stress at half-maximal deformation (SS1/2) and maximal deformability (EImax) and muscle oxygenation of the rectus femoris muscle was assessed by near-infrared spectroscopy. No statistically significant changes occurred in SS1/2 and EImax in either condition. The ratio of SS1/2 to EImax statistically decreased in NORM (p < 0.01; Δ: -0.10; 95%CI: -0.22, 0.02) but not HYP (p > 0.05; Δ: -0.16; 95%CI: -0.23, -0.08). Muscle oxygenation remained unchanged. This study showed that low-dose hyperoxia during HIIE using a commercially available device with a flow rate of only 4 L·min-1 may not be sufficient to induce acute ergogenic effects compared to normoxic conditions.

High-intensity interval training and hyperoxia during chemotherapy: A case report about the feasibility, safety and physical functioning in a colorectal cancer patient.

INTRODUCTION: We conducted a case study to examine the feasibility and safety of high-intensity interval training (HIIT) with increased inspired oxygen content in a colon cancer patient undergoing chemotherapy. A secondary purpose was to investigate the effects of such training regimen on physical functioning. CASE PRESENTATION: A female patient (51 years; 49.1 kg; 1.65 m; tumor stage: pT3, pN2a (5/29), pM1a (HEP), L0, V0, R0) performed 8 sessions of HIIT (5 × 3 minutes at 90% of Wmax, separated by 2 minutes at 45% Wmax) with an increased inspired oxygen fraction of 30%. Patient safety, training adherence, cardiorespiratory fitness (peak oxygen uptake and maximal power output during an incremental cycle ergometer test), autonomous nervous function (i.e., heart rate variability during an orthostatic test) as well as questionnaire-assessed quality of life (EORTC QLQ-C30) were evaluated before and after the intervention.No adverse events were reported throughout the training intervention and a 3 months follow-up. While the patient attended all sessions, adherence to total training time was only 51% (102 of 200 minutes; mean training time per session 12:44 min:sec). VO2peak and Wmax increased by 13% (from 23.0 to 26.1 mL min kg) and 21% (from 83 to 100 W), respectively. Heart rate variability represented by the root mean squares of successive differences both in supine and upright positions were increased after the training by 143 and 100%, respectively. The EORTC QLQ-C30 score for physical functioning (7.5%) as well as the global health score (10.7%) improved, while social function decreased (17%). CONCLUSIONS: Our results show that a already short period of HIIT with concomitant hyperoxia was safe and feasible for a patient undergoing chemotherapy for colon cancer. Furthermore, the low overall training adherence of only 51% and an overall low training time per session (∼13 minutes) was sufficient to induce clinically meaningful improvements in physical functioning. However, this case also underlines that intensity and/or length of the HIIT-bouts might need further adjustments to increase training compliance.

Mechanism and consequences of the shift in cardiac arginine metabolism following ischaemia and reperfusion in rats.

Cardiac ischaemia and reperfusion leads to irreversible injury and subsequent tissue remodelling. Initial reperfusion seems to shift arginine metabolism from nitric oxide (NO) to polyamine formation. This may limit functional recovery at reperfusion. The hypothesis was tested whether ischaemia/reperfusion translates such a shift in arginine metabolism in a tumour necrosis factor (TNF)-α-dependent way and renin-angiotensin system (RAS)-dependent way into a sustained effect. Both, the early post-ischaemic recovery and molecular adaptation to ischaemia/reperfusion were analysed in saline perfused rat hearts undergoing global no-flow ischaemia and reperfusion. Local TNF-α activation was blocked by inhibition of TNF-α sheddase ADAM17. To interfere with RAS captopril was administered. Arginase was inhibited by administration of Nor-NOHA. Long-term effects of ischemia/reperfusion on arginine metabolism were analysed in vivo in rats receiving an established ischaemia/reperfusion protocol in the closed chest mode. mRNA expression analysis indicated a shift in the arginine metabolism from NO formation to polyamine metabolism starting within 2 hours (h) of reperfusion and translated into protein expression within 24 h. Inhibition of the TNF-α pathway and captopril attenuated these delayed effects on post-ischaemic recovery. This shift in arginine metabolism was associated with functional impairment of hearts within 24 h. Inhibition of arginase but not that of TNF-α and RAS pathways improved functional recovery immediately. However, no benefit was observed after four months. In conclusion, this study identified TNF-α and RAS to be responsible for depressed cardiac function that occurred a few hours after reperfusion.