bims-heshmo 2021-07-25 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–07–25
thirteen papers selected by
Andreia Luís, Ludwig Boltzmann Institute

"Low initial pre-hospital end-tidal carbon dioxide predicts inferior clinical outcomes in trauma patients".
The effect of prehospital intravenous access in traumatic shock: a Japanese nationwide cohort study.
Extracellular CIRP activates STING to exacerbate hemorrhagic shock.
miR‑140‑5p alleviates mouse liver ischemia/reperfusion injury by targeting CAPN1.
Hypoxia-inducible factor-1alpha protects the liver against ischemia-reperfusion injury by regulating the A2B adenosine receptor.
Morphine Prevents Ischemia/Reperfusion-Induced Myocardial Mitochondrial Damage by Activating δ-opioid Receptor/EGFR/ROS Pathway.
The effect of silymarin on liver enzymes and antioxidant status in trauma patients in the intensive care unit: a randomized double blinded placebo-controlled clinical trial.
Complement Factor C5a Inhibits Apoptosis of Neutrophils-A Mechanism in Polytrauma?
Tranexamic acid evidence and controversies: An illustrated review.
Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway.
Artificial hyperventilation normalizes haemodynamics and arterial oxygen content in hypoxic rats.
Angiotensin II and hypoxia induce autophagy in cardiomyocytes via activating specific protein kinase C subtypes.
Effect of coenzyme Q10 supplementation on oxidative stress and clinical outcomes in patients with low levels of coenzyme Q10 admitted to the intensive care unit.

Injury. 2021 Jul 09. pii: S0020-1383(21)00624-0. [Epub ahead of print]

"Low initial pre-hospital end-tidal carbon dioxide predicts inferior clinical outcomes in trauma patients".

Mary Kate Bryant, Jaclyn N Portelli Tremont, Zachary Patel, Nicole Cook, Pascal Udekwu, Trista Reid, Rebecca G Maine, Scott M Moore.

   INTRODUCTION: Current guidelines continue to lead to under- and over-triage of injured patients in the pre-hospital setting. End-tidal carbon dioxide (ETCO2) has been correlated with mortality and hemorrhagic shock in trauma patients. This study examines the correlation between ETCO2 and in-hospital outcomes among non-intubated patients in the pre-hospital setting.
METHODS: We retrospectively studied a cohort of non-intubated adult trauma patients with initial pre-hospital side-stream capnography-obtained ETCO2 presenting via ground transport from a single North Carolina EMS agency to a level one trauma center from January 2018 to December 2018. Using the Liu method, the optimal threshold for low ETCO2 was ≤ 28.5 mmHg.
RESULTS: Initial pre-hospital ETCO2 was recorded for 324 (22.0%) of 1473 patients with EMS data. Patients with low ETCO2 (N = 98, 30.3% of cohort) were older (median 58y vs 45y), but mechanisms of injury and scene vital signs were similar (p>0.05) between low and normal/high ETCO2 cohorts. Median injury severity score (ISS) did not differ significantly between the low and normal/high ETCO2 groups (5 vs 8, p=0.48). Compared to normal/high ETCO2, low ETCO2 correlated with increased unadjusted odds of mortality (OR 5.06), in-hospital complications (OR 2.06), and blood transfusion requirement (OR 3.05), p<0.05. Low ETCO2 was associated with 7.25 odds of mortality (95% CI 2.19,23.97, p=0.001) and 3.94 odds of blood transfusion (95% CI 1.32-11.78) after adjusting for age, ISS, and scene GCS. All but one of the massive transfusion patients (N = 8/9) had a low pre-hospital ETCO2.
CONCLUSIONS: Low initial pre-hospital ETCO2 associates with poor clinical outcomes despite similar ISS and mechanisms of injury. ETCO2 is a potentially useful pre-hospital point-of-care tool to aid triage of trauma patients as it may identify hemorrhaging patients and predict mortality.

Keywords:  Clinical outcomes; End-tidal carbon dioxide; Hemorrhagic shock; Trauma; Triage

DOI:  https://doi.org/10.1016/j.injury.2021.07.019
Acute Med Surg. 2021 Jan-Dec;8(1):8(1): e681

The effect of prehospital intravenous access in traumatic shock: a Japanese nationwide cohort study.

Hiroki Nagasawa, Keita Shibahashi, Kazuhiko Omori, Youichi Yanagawa.

   Aim: We aimed to evaluate effect of prehospital intravenous (IV) access on mortality in traumatic shock using a large nationwide dataset.
Methods: We used the Japan Trauma Data Bank to identify adults (≥18 years) with a systolic blood pressure <90 mm Hg at the trauma scene and were directly transported to the hospital between 2010 and 2019. We compared patients who had prehospital IV access (IV (+)) or not (IV (-)), using propensity score-matched analysis, and 1:1 nearest-neighbor matching without replacement. Standardized mean difference was used to evaluate the match balance between the two matched groups; a standardized mean difference >0.1 was considered a significant imbalance. Primary outcome was 72-h mortality.
Results: Propensity scores matching generated 479 pairs from 5,857 patients. No significant between group differences occurred in 72-h mortality (7.8 versus 8.8%; difference, -1.0%; 95% confidence interval [CI]: -2.5-4.5%), 28-day mortality (11.8 versus 11.3%; 95% CI: -4.6-3.6%), blood transfusion administration within 24 h (55.3 versus 49.1%; 95% CI: -0.1-12.6%), prehospital time (56.3 versus 53.0 min; 95% CI: -1.8-8.4 min), and cardiopulmonary arrest on hospital arrival (1.3 versus 1.3%; 95% CI: -1.4-1.4%). However, significantly higher systolic blood pressure on hospital arrival was found in the IV (+) than in the IV (-) group (104.6 versus 100.1 mm Hg; 95% CI: 0.3-8.7 mm Hg).
Conclusion: We found no significant effect of establishing IV access in the prehospital setting on survival outcomes of patients with traumatic shock.

Keywords:  Blood pressure; blood transfusion; intravenous access; prehospital care; traumatic shock

DOI:  https://doi.org/10.1002/ams2.681
JCI Insight. 2021 Jul 22. pii: 143715. [Epub ahead of print]6(14):

Extracellular CIRP activates STING to exacerbate hemorrhagic shock.

Kehong Chen, Joaquin Cagliani, Monowar Aziz, Chuyi Tan, Max Brenner, Ping Wang.

  Stimulator of IFN genes (STING) activates TANK-binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3) to produce type I IFNs. Extracellular cold-inducible RNA-binding protein (eCIRP) is released from cells during hemorrhagic shock (HS). We hypothesized that eCIRP activates STING to induce inflammation and acute lung injury (ALI) after HS. WT and STING-/- mice underwent controlled hemorrhage by bleeding, followed by fluid resuscitation. Blood and lungs were collected at 4 hours after resuscitation. Serum ALT, AST, LDH, IL-6, and IFN-β were significantly decreased in STING-/- mice compared with WT mice after HS. In STING-/- mice, the levels of pTBK1 and pIRF3, and expression of TNF-α, IL-6, and IL-1β mRNAs and proteins in the lungs, were significantly decreased compared with WT HS mice. The 10-day mortality rate in STING-/- mice was significantly reduced. I.v. injection of recombinant mouse CIRP (rmCIRP) in STING-/- mice showed a significant decrease in pTBK1 and pIRF3 and in IFN-α and IFN-β mRNAs and proteins in the lungs compared with rmCIRP-treated WT mice. Treatment of TLR4-/-, MyD88-/-, and TRIF-/- macrophages with rmCIRP significantly decreased pTBK1 and pIRF3 levels and IFN-α and IFN-β mRNAs and proteins compared with WT macrophages. HS increases eCIRP levels, which activate STING through TLR4/MyD88/TRIF pathways to exacerbate inflammation.

Keywords:  Bacterial infections; Inflammation

DOI:  https://doi.org/10.1172/jci.insight.143715
Mol Med Rep. 2021 Sep;pii: 675. [Epub ahead of print]24(3):

miR‑140‑5p alleviates mouse liver ischemia/reperfusion injury by targeting CAPN1.

Qiwen Yu, Sanyang Chen, Hongwei Tang, Han Yang, Jiakai Zhang, Xiaoyi Shi, Jie Li, Wenzhi Guo, Shuijun Zhang.

  Ischemia/reperfusion (I/R)‑induced liver injury remains a primary concern in liver transplantation and hepatectomy. Previous studies have indicated that microRNAs (miRs) are involved in multiple pathophysiological processes, including liver I/R. miR‑140‑5p reportedly inhibits inflammatory responses and apoptosis in several diseases; however, the role of miR‑140‑5p in liver I/R remains unknown. The present study aimed to investigate the potential role and mechanism of miR‑140‑5p on liver I/R injury. Mouse liver I/R and mouse AML12 cell hypoxia/reoxygenation (H/R) models were established. miR‑140‑5p mimics, inhibitor or agonists were used to overexpress or inhibit miR‑140‑5p in vitro and in vivo. Reverse transcription‑quantitative polymerase chain reaction was used to detect miR‑140‑5p expression. Liver and cell injury were evaluated using several biochemical assays. The association between miR‑140‑5p and calpain‑1 (CAPN1) was confirmed using a dual‑luciferase reporter assay. The results revealed that miR‑140‑5p expression was decreased in the mouse model of liver I/R injury and AML12 cells subjected to H/R, while overexpressed miR‑140‑5p reduced liver injury in vivo and cell injury in vitro. In addition, CAPN1 was determined to be a target of miR‑140‑5p; overexpressed CAPN1 abrogated the effect of miR‑140‑5p on H/R‑induced cell injury. The present study indicated that miR‑140‑5p protected against liver I/R by targeting CAPN1, which may provide a novel therapeutic target for liver I/R injury.

Keywords:  CAPN1; apoptosis; inflammation; liver ischemia/reperfusion injury; miR‑140‑5p

DOI:  https://doi.org/10.3892/mmr.2021.12314
Bioengineered. 2021 Dec;12(1): 3737-3752

Hypoxia-inducible factor-1alpha protects the liver against ischemia-reperfusion injury by regulating the A2B adenosine receptor.

Xingjian Zhang, Peng Du, Kaifeng Luo, Yong Li, Zhongzhong Liu, Wei Wang, Cheng Zeng, Qifa Ye, Qi Xiao.

  Hepatic ischemia-reperfusion injury (IRI) is an inevitable complication associated with liver surgical procedures, and its pathological process remains elusive. Therefore, the present study investigated the role and mechanism of hypoxia-inducible factor-1alpha (HIF-1α) in hepatic IRI. Here, we constructed rat models with hepatic IRI and BRL-3A cell models with hypoxia/reoxygenation (H/R) insult. The extent of liver injury was assayed by measuring serum ALT/AST levels and performing H&E staining; the levels of SOD, MDA, MPO, IL-6 and TNF-α were determined using commercial kits; apoptosis was detected using the TUNEL assay and flow cytometry; and the expression of HIF-1α/A2BAR signaling-related molecules and apoptosis-associated indicators was detected using Western blotting or qRT-PCR. The expression level of HIF-1α was significantly upregulated in the liver of rats subjected to IRI, as well as in BRL-3A cells treated with H/R. HIF-1α overexpression exerted a protective effect on hepatic IRI or H/R insult by reducing serum aminotransferase levels and hepatic necrosis, inhibiting inflammation and apoptosis of hepatocytes, and alleviating oxidative stress. In contrast, inhibition of HIF-1α expression exacerbated hepatic injury induced by IR or H/R. Mechanistically, the expression level of A2BAR was markedly increased during hepatic IRI or H/R insult. Moreover, A2BAR expression increased with HIF-1α upregulation and decreased with HIF-1α downregulation. Importantly, inhibition of A2BAR signaling abolished HIF-1α overexpression-mediated hepatoprotection. Taken together, HIF-1α exerts protective effects on hepatic IRI by attenuating liver necrosis, the inflammatory response, oxidative stress and apoptosis, and its mechanism may be related to the upregulation of A2BAR signaling.

Keywords:  A2B adenosine receptor; Ischemia-reperfusion injury; hypoxia inducible factor-1α; liver

DOI:  https://doi.org/10.1080/21655979.2021.1953217
Cardiovasc Drugs Ther. 2021 Jul 19.

Morphine Prevents Ischemia/Reperfusion-Induced Myocardial Mitochondrial Damage by Activating δ-opioid Receptor/EGFR/ROS Pathway.

Jingman Xu, Xiyun Bian, Huanhuan Zhao, Yujie Sun, Yanyi Tian, Xiaodong Li, Wei Tian.

   OBJECTIVE: The purpose of this study was to determine whether the epidermal growth factor receptor (EGFR), which is a classical receptor tyrosine kinase, is involved in the protective effect of morphine against ischemia/reperfusion (I/R)-induced myocardial mitochondrial damage.
METHODS: Isolated rats hearts were subjected to global ischemia followed by reperfusion. Cardiac H9c2 cells were exposed to a simulated ischemia solution followed by Tyrode's solution to induce hypoxia/reoxygenation (H/R) injury. Triphenyltetrazolium chloride (TTC) was used to measure infarct size. The mitochondrial morphological and functional changes were determined using transmission election microscopy (TEM), mitochondrial stress assay, and mitochondrial swelling, respectively. Mitochondrial fluorescence indicator JC-1, DCFH-DA, and Mitosox Red were used to determine mitochondrial membrane potential (△Ψm), intracellular reactive oxygen species (ROS) and mitochondrial superoxide. A TUNUL assay kit was used to detect the level of apoptosis. Western blotting analysis was used to measure the expression of proteins.
RESULTS: Treatment of isolated rat hearts with morphine prevented I/R-induced myocardial mitochondrial injury, which was inhibited by the selective EGFR inhibitor AG1478, suggesting that EGFR is involved in the mitochondrial protective effect of morphine under I/R conditions. In support of this hypothesis, the selective EGFR agonist epidermal growth factor (EGF) reduced mitochondrial morphological and functional damage similarly to morphine. Further study demonstrated that morphine may alleviate I/R-induced cardiac damage by inhibiting autophagy but not apoptosis. Morphine increased protein kinase B (Akt), extracellular regulated protein kinases (ERK) and signal transducer and activator of transcription-3 (STAT-3) phosphorylation, which was inhibited by AG1478, and EGF had similar effects, indicating that morphine may activate Akt, ERK, and STAT-3 via EGFR. Morphine and EGF increased intracellular reactive oxygen species (ROS) generation. This effect of morphine was inhibited by AG1478, indicating that morphine promotes intracellular ROS generation by activating EGFR. However, morphine did not increase ROS generation when cells were transfected with siRNA against EGFR. In addition, EGFR activity was markedly increased by morphine, but the effect of morphine was reversed by naltrindole. These results suggest that morphine may activate EGFR via δ-opioid receptor activation.
CONCLUSIONS: Morphine may prevent I/R-induced myocardial mitochondrial damage by activating EGFR through δ-opioid receptors, in turn increasing RISK and SAFE pathway activity via intracellular ROS. Moreover, morphine may reduce myocardial injury by regulating autophagy but not apoptosis.

Keywords:  Epidermal growth factor receptor; Morphine; Reactive oxygen species; δ-Opioid receptor

DOI:  https://doi.org/10.1007/s10557-021-07215-w
Clin Exp Hepatol. 2021 Jun;7(2): 149-155

The effect of silymarin on liver enzymes and antioxidant status in trauma patients in the intensive care unit: a randomized double blinded placebo-controlled clinical trial.

Ehsan Mirzaei, Golnar Sabetian, Mansoor Masjedi, Reza Heidari, Mahtabalsadat Mirjalili, Amirreza Dehghanian, Afsaneh Vazin.

   Aim of the study: This study was conducted to investigate the positive effect of silymarin on liver enzymes and antioxidant status in trauma patients with elevated liver enzymes due to trauma-induced liver injury, admitted to the intensive care unit.
Material and methods: This one-year, randomized, double-blinded, placebo-controlled clinical trial was conducted on 90 trauma patients. The participants were assigned to either receiving Livergol tablets containing 140 mg of silymarin or 140 mg of placebo three times daily for 14 days. Liver enzymes, including aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP), were measured at baseline and days 3, 7, 9 and 14 after intervention. Also, antioxidant markers were measured at baseline and day 14 after treatment.
Results: Receiving silymarin supplement significantly lowered the liver enzymes, compared to placebo (p < 0.05). The mean serum level of malondialdehyde (MDA) was significantly decreased and the mean serum levels of total antioxidant capacity (TAC) and thiol groups were significantly increased in the silymarin group from baseline to day 14. In the placebo group, mean serum levels of MDA and thiol groups were significantly increased, while serum level of TAC was not significantly changed at day 14, compared to baseline. Also, the mean serum level of MDA was significantly lower, while the serum levels of thiol groups and TAC were significantly higher in the silymarin group.
Conclusions: Silymarin supplementation significantly improved some antioxidant markers (TAC and thiol) and decreased liver enzymes in patients with trauma-induced liver injury.

Keywords:  antioxidant status; liver enzymes; liver injury; silymarin; trauma

DOI:  https://doi.org/10.5114/ceh.2021.107067
J Clin Med. 2021 Jul 17. pii: 3157. [Epub ahead of print]10(14):

Complement Factor C5a Inhibits Apoptosis of Neutrophils-A Mechanism in Polytrauma?

Christian Ehrnthaller, Sonja Braumüller, Stephanie Kellermann, Florian Gebhard, Mario Perl, Markus Huber-Lang.

  Life-threatening polytrauma results in early activation of the complement and apoptotic system, as well as leukocytes, ultimately leading to the clearance of damaged cells. However, little is known about interactions between the complement and apoptotic systems in PMN (polymorphonuclear neutrophils) after multiple injuries. PMN from polytrauma patients and healthy volunteers were obtained and assessed for apoptotic events along the post-traumatic time course. In vitro studies simulated complement activation by the exposure of PMN to C3a or C5a and addressed both the intrinsic and extrinsic apoptotic pathway. Specific blockade of the C5a-receptor 1 (C5aR1) on PMN was evaluated for efficacy to reverse complement-driven alterations. PMN from polytrauma patients exhibited significantly reduced apoptotic rates up to 10 days post trauma compared to healthy controls. Polytrauma-induced resistance was associated with significantly reduced Fas-ligand (FasL) and Fas-receptor (FasR) on PMN and in contrast, significantly enhanced FasL and FasR in serum. Simulation of systemic complement activation revealed for C5a, but not for C3a, a dose-dependent abrogation of PMN apoptosis in both intrinsic and extrinsic pathways. Furthermore, specific blockade of the C5aR1 reversed C5a-induced PMN resistance to apoptosis. The data suggest an important regulatory and putative mechanistic and therapeutic role of the C5a/C5aR1 interaction on PMN apoptosis after polytrauma.

Keywords:  C5a; apoptosis; neutrophils; polytrauma

DOI:  https://doi.org/10.3390/jcm10143157
Res Pract Thromb Haemost. 2021 Jul;5(5): e12546

Tranexamic acid evidence and controversies: An illustrated review.

Nicole Relke, Nicholas L J Chornenki, Michelle Sholzberg.

  Tranexamic acid (TXA) is an antifibrinolytic agent commonly used for the treatment or prevention of bleeding. Indications for TXA are diverse, including heavy menstrual bleeding, trauma, postpartum hemorrhage, traumatic brain injury, and surgical site bleeding. Despite decades of use and a robust body of evidence, hesitancy using TXA persists in many clinical settings. This illustrated review describes the history, pharmacology, and practical considerations of TXA use. We also describe the major landmark randomized controlled trials of TXA and their implications. Finally, we review the evidence around common controversies surrounding TXA such as the risk of thrombosis, prescription along with combined hormonal contraceptives, and use in patients with gross hematuria.

Keywords:  antifibrinolytic agents; blood coagulation; contraceptive agents; thrombosis; tranexamic acid

DOI:  https://doi.org/10.1002/rth2.12546
Nat Commun. 2021 07 19. 12(1): 4391

Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway.

Dali Zhang, Junlan Huang, Xianding Sun, Hangang Chen, Shuo Huang, Jing Yang, Xiaolan Du, Qiaoyan Tan, Fengtao Luo, Ruobin Zhang, Siru Zhou, Wanling Jiang, Zhenhong Ni, Zuqiang Wang, Min Jin, Meng Xu, Fangfang Li, Liang Chen, Mi Liu, Nan Su, Xiaoqing Luo, Liangjun Yin, Ying Zhu, Jerry Q Feng, Di Chen, Huabing Qi, Lin Chen, Yangli Xie.

Acquired heterotopic ossification (HO) is the extraskeletal bone formation after trauma. Various mesenchymal progenitors are reported to participate in ectopic bone formation. Here we induce acquired HO in mice by Achilles tenotomy and observe that conditional knockout (cKO) of fibroblast growth factor receptor 3 (FGFR3) in Col2+ cells promote acquired HO development. Lineage tracing studies reveal that Col2+ cells adopt fate of lymphatic endothelial cells (LECs) instead of chondrocytes or osteoblasts during HO development. FGFR3 cKO in Prox1+ LECs causes even more aggravated HO formation. We further demonstrate that FGFR3 deficiency in LECs leads to decreased local lymphatic formation in a BMPR1a-pSmad1/5-dependent manner, which exacerbates inflammatory levels in the repaired tendon. Local administration of FGF9 in Matrigel inhibits heterotopic bone formation, which is dependent on FGFR3 expression in LECs. Here we uncover Col2+ lineage cells as an origin of lymphatic endothelium, which regulates local inflammatory microenvironment after trauma and thus influences HO development via FGFR3-BMPR1a pathway. Activation of FGFR3 in LECs may be a therapeutic strategy to inhibit acquired HO formation via increasing local lymphangiogenesis.

DOI: https://doi.org/10.1038/s41467-021-24643-2
Anaesthesiol Intensive Ther. 2021 Jul 21. pii: 44218. [Epub ahead of print]

Artificial hyperventilation normalizes haemodynamics and arterial oxygen content in hypoxic rats.

Diego de Villalobos, Andres Laserna, Cosmo Fowler, John A Cuenca, Peyton Martin, Michele Guindani, Wenli Dong, Howard B Gutstein, Kristen J Price, Joseph L Nates.

   INTRODUCTION: Although humans are capable of enduring critically low levels of oxygen, many hypoxaemic patients die despite aggressive therapies. Mimicking the physiological hyperventilation necessary to survive extreme hypoxic conditions could minimize the derangements caused by acute hypoxic-hypoxia. The objective of this study was to measure the haemodynamic-biochemical response to artificially induced hyperventilation in hypoxic rats.
MATERIAL AND METHODS: Twenty-four deeply anaesthetized and mechanically ventilated rats were allocated to 3 groups: control (n = 5, FiO2 = 1); hypoxic spontaneously hyperventilating (n = 10, FiO2 = 0.08); and hypoxic artificially induced hyperventilation (n = 9, targeting PaCO2 = 10 mm Hg, FiO2 = 0.08). We compared the spontaneously and artificially hyperventilating groups. P-values < 0.01 were considered statistically significant. Mean arterial pressure (MAP) and serum chemistry were measured for 180 minutes.
RESULTS: The control group remained stable throughout the experiment. The hypoxic groups developed profound hypotension after the decrease in FiO2. However, the artificially induced hyperventilated rats recovered their MAP to levels higher than the spontaneously hyperventilating group (117.1 ± 17.2 vs. 68.1 ± 16.0, P = 0.0048). In regard to the biochemical derangements, even though the serum lactate and PaO2 were not different among the hypoxic groups, the artificially hyperventilated group achieved significantly higher SaO2 (94.3 ± 3.6 vs. 58.6 ± 9.6, P = 0.005), pH (7.87 ± 0.04 vs. 7.50 ± 0.13, P = 0.005), and CaO2 (17.7 ± 2.6 vs. 10.2 ± 1.3, P = 0.005) at 180 minutes.
CONCLUSIONS: Artificially induced hyperventilation led to the correction of arterial oxygen content, severe serum chemistry, and haemodynamic derangements. These findings may represent a novel rescue manoeuvre and serve as a bridge to a permanent form of support, but should be further studied before being translated to the clinical setting.

Keywords:   artificial respiration; critical illness; hyperventilation.; hypocapnia; hypoxia; respiratory insufficiency

DOI:  https://doi.org/10.5114/ait.2021.106562
Cardiovasc Diagn Ther. 2021 Jun;11(3): 744-759

Angiotensin II and hypoxia induce autophagy in cardiomyocytes via activating specific protein kinase C subtypes.

Rong Xiao, Hai-Chun Zhao, Tian-Tian Yan, Qiong Zhang, Yue-Sheng Huang.

   Background: The purpose of this study was to explore the role of protein kinase C (PKC) isozymes and reactive oxygen species (ROS) in hypoxia and angiotensin (Ang) II-induced autophagy.
Methods: Primary cardiomyocytes were isolated from Sprague-Dawley (SD) neonatal rats and cultured in hypoxia and/or Ang II conditions. Dihydroethidium fluorescence staining was used to detect the content of ROS. Cardiomyocyte autophagy was determined using Monodansylcadaverine fluorescence staining and Western blot. We also inhibited ROS production to explore the relationship between ROS and autophagy. ELISA was used to detect the contents of PKC δ and PKC ε. After inhibition of PKC δ activation and PKC ε expression by lentiviral siRNA, ROS content and autophagy of cultured cardiomyocytes were detected.
Results: Hypoxia and Ang II stimulation increased autophagy in cardiomyocytes, accompanied by increased intracellular ROS production. Inhibiting ROS following hypoxia or Ang II stimulation significantly suppressed autophagy in comparison with hypoxia or Ang II stimulation group. Inhibiting PKC δ significantly reduced ROS production and autophagy activity following hypoxia or accompanied with Ang II stimulation except Ang II stimulation alone. Knockdown of PKC ε notably decreased ROS production and autophagy in response to Ang II alone and in combination with hypoxia rather than hypoxia alone.
Conclusions: Both hypoxia and Ang II stimulation can induce autophagy in cardiomyocytes through increasing intracellular ROS. However, hypoxia and Ang II stimulation induced myocardial autophagy via PKC δ and PKC ε, respectively.

Keywords:  Autophagy; angiotensin II (Ang II); cardiomyocytes; hypoxia/ischemia injury; protein kinase C (PKC)

DOI:  https://doi.org/10.21037/cdt-20-883
J Nutr Sci. 2021 ;10 e48

Effect of coenzyme Q10 supplementation on oxidative stress and clinical outcomes in patients with low levels of coenzyme Q10 admitted to the intensive care unit.

Mohammad Amin Valizade Hasanloei, Aidin Zeinaly, Mehran Rahimlou, Hadi Houshyar, Solma Moonesirad, Reza Hashemi.

  Today, trauma is known to be the third leading cause of death in most countries. Studies have demonstrated below-normal plasma levels of antioxidants in trauma patients. The present study aimed to assess the efficacy of Coenzyme Q10 (CoQ10) on oxidative stress, clinical outcomes and anthropometrical parameters in traumatic mechanical ventilated patients admitted to the intensive care unit. Patients were randomised to receive sublingual CoQ10 (400 mg/d) or placebo for 7 d. Primary and secondary outcomes were measured at the baseline and end of the study. We enrolled forty patients for this trial: twenty in the CoQ10 group and twenty in the placebo group. There was not any significant difference in the baseline variables (P > 0⋅05). At the end of the study, CoQ10 administration caused a considerable reduction in the Malondialdehyde (MDA) and Interleukin 6 (IL-6) concentrations (P < 0⋅001), Glasgow Coma Score (GCS; P = 0⋅02), ICU and hospital length of stay and mechanical ventilation (MV) duration (P < 0⋅001). We found that CoQ10 administration could increase Fat-Free Mass (P < 0⋅001) (FFM; P = 0⋅04), Skeletal Muscle Mass (SMM; P = 0⋅04) and Body Cell Mass (BCM) percent (P = 0⋅03). There was not any significant difference in other factors between the two groups (P > 0⋅05). CoQ10 administration has beneficial effects on patients with traumatic injury and has no side effects. However, since the possibility of the type II error was high, the outcomes on the duration of MV, ICU stay and hospital stay, and GCS may very well be false positives.

Keywords:  Clinical trial; Coenzyme Q10; Mechanical ventilation; Trauma

DOI:  https://doi.org/10.1017/jns.2021.39