Ischemia‐reperfusion injury. A phenomenon,that also occurs in the bone

Ischemia‐reperfusion injury of the bone occurs due to traumatic and non‐traumatic alterations affecting blood supply to the bone. It is likely to occur also upon insertion of an implant. Ischemia‐reperfusion injury of the bone has been studied by interruption of blood supply in situ, in limb replantation/transplantation models, in revascularized bone grafts and non‐vascularized bone fragments, as well as in isolated cultured cells. All cells of the bone are affected, including osteoblasts, osteocytes, osteoclasts, chondrocytes, and bone marrow cells. Critical ischemia times for induction of bone cell death, either in the ischemic period or following reperfusion, are in the range of 3 to 7 h. These critical ischemia times are significantly increased by decreasing the temperature from 37 °C to 0–4 °C. Anoxia is the most likely trigger of cell injury in the ischemic phase. In the reperfusion phase, reactive oxygen species are decisively involved in the injurious process. In general, however, the available information on the mechanism of ischemia‐reperfusion injury of the bone is relatively sparse. On the other hand, there are clear similarities to the mechanisms of ischemia‐reperfusion injury known from other organs, and there is a clear potential for protection against ischemia‐reperfusion injury of the bone.     

Ivabradine Induces Cardiac Protection against Myocardial Infarction by Preventing Cyclophilin-A Secretion in Pigs under Coronary Ischemia/Reperfusion

In response to cardiac ischemia/reperfusion, proteolysis mediated by extracellular matrix metalloproteinase inducer (EMMPRIN) and its secreted ligand cyclophilin-A (CyPA) significantly contributes to cardiac injury and necrosis. Here, we aimed to investigate if, in addition to the effect on the funny current (I(f)), Ivabradine may also play a role against cardiac necrosis by reducing EMMPRIN/CyPA-mediated cardiac inflammation. In a porcine model of cardiac ischemia/reperfusion (IR), we found that administration of 0.3 mg/kg Ivabradine significantly improved cardiac function and reduced cardiac necrosis by day 7 after IR, detecting a significant increase in cardiac CyPA in the necrotic compared to the risk areas, which was inversely correlated with the levels of circulating CyPA detected in plasma samples from the same subjects. In testing whether Ivabradine may regulate the levels of CyPA, no changes in tissue CyPA were found in healthy pigs treated with 0.3 mg/kg Ivabradine, but interestingly, when analyzing the complex EMMPRIN/CyPA, rather high glycosylated EMMPRIN, which is required for EMMPRIN-mediated matrix metalloproteinase (MMP) activation and increased CyPA bonding to low-glycosylated forms of EMMPRIN were detected by day 7 after IR in pigs treated with Ivabradine. To study the mechanism by which Ivabradine may prevent secretion of CyPA, we first found that Ivabradine was time-dependent in inhibiting co-localization of CyPA with the granule exocytosis marker vesicle-associated membrane protein 1 (VAMP1). However, Ivabradine had no effect on mRNA expression nor in the proteasome and lysosome degradation of CyPA. In conclusion, our results point toward CyPA, its ligand EMMPRIN, and the complex CyPA/EMMPRIN as important targets of Ivabradine in cardiac protection against IR.     

Change of short-term memory effect in acute ischemic ventricular myocardium: A computational study

The ionic mechanism of change in short-term memory (STM) during acute myocardial ischemia has not been well understood. In this paper, an advanced guinea pig ventricular model developed by Luo and Rudy was used to investigate STM property of ischemic ventricular myocardium. STM response was calculated by testing the time to reach steady-state action potential duration (APD) after an abrupt shortening of basic cycling length (BCL) in the pacing protocol. Electrical restitution curves (RCs), which can simultaneously visualize multiple aspects of APD restitution and STM, were obtained from dynamic and local S1S2 restitution portrait (RP), which consist of a longer interval stimulus (S1) and a shorter interval stimulus (S2). The angle between dynamic RC and local S1S2 RC reflects the amount of STM. Our results indicated that compared with control (normal) condition, time constant of STM response in the ischemic condition decreased significantly. Meanwhile the angle which reflects STM amount is less in ischemic model than that in control model. By tracking the effect of ischemia on intracellular ion concentration and membrane currents, we declared that changes in membrane currents caused by ischemia exert subtle influences on STM; it is only the decline of intracellular calcium concentration that give rise to the most decrement of STM.     

A model of cerebral cortex formation during fetal development using reaction-diffusion-convection equations with Turing space parameters

The cerebral cortex is a gray lamina formed by bodies of neurons covering the cerebral hemispheres, varying in thickness from 1.25 mm in the occipital lobe to 4 mm in the anterior lobe. The brain's surface is about 30 times greater that of the skull because of its many folds; such folds form the gyri, sulci and fissures and mark out areas having specific functions, divided into five lobes. Convolution formation may vary between individuals and is an important feature of brain formation; such patterns can be mathematically represented as Turing patterns. This article describes how a phenomenological model was developed by describing the formation pattern for the gyri occurring in the cerebral cortex by reaction diffusion equations with Turing space parameters. Numerical examples for simplified geometries of a brain were solved to study pattern formation. The finite element method was used for the numerical solution, in conjunction with the Newton–Raphson method. The numerical examples showed that the model can represent cerebral cortex fold formation and reproduce pathologies related to gyri formation, such as polymicrogyria and lissencephaly.     

Texture analysis of poly-adenylated mRNA staining following global brain ischemia and reperfusion

Texture analysis provides a means to quantify complex changes in microscope images. We previously showed that cytoplasmic poly-adenylated mRNAs form mRNA granules in post-ischemic neurons and that these granules correlated with protein synthesis inhibition and hence cell death. Here we utilized the texture analysis software MaZda to quantify mRNA granules in photomicrographs of the pyramidal cell layer of rat hippocampal region CA3 around 1 h of reperfusion after 10 min of normothermic global cerebral ischemia. At 1 h reperfusion, we observed variations in the texture of mRNA granules amongst samples that were readily quantified by texture analysis. Individual sample variation was consistent with the interpretation that animal-to-animal variations in mRNA granules reflected the time-course of mRNA granule formation. We also used texture analysis to quantify the effect of cycloheximide, given either before or after brain ischemia, on mRNA granules. If administered before ischemia, cycloheximide inhibited mRNA granule formation, but if administered after ischemia did not prevent mRNA granulation, indicating mRNA granule formation is dependent on dissociation of polysomes. We conclude that texture analysis is an effective means for quantifying the complex morphological changes induced in neurons by brain ischemia and reperfusion.     

实验大鼠脑缺血模型的制作及效果评价

缺血性脑血管病是临床上常见的一类疾病，其致残率和死亡率均较高。采用一种线栓法，制备大鼠局灶性脑缺血再灌注模型，并从动物神经病学评分、鼠脑整体观、鼠脑切面氯化三苯四氮唑染色、鼠脑组织光镜下观察等进行评价，表明该模型达到脑缺血的效果。在此基础上可进行缺血性脑血管病的多种实验性研究。     

Nicotinamide Mononucleotide Protects against Retinal Dysfunction in a Murine Model of Carotid Artery Occlusion

Cardiovascular abnormality-mediated retinal ischemia causes severe visual impairment. Retinal ischemia is involved in enormous pathological processes including oxidative stress, reactive gliosis, and retinal functional deficits. Thus, maintaining retinal function by modulating those pathological processes may prevent or protect against vision loss. Over the decades, nicotinamide mononucleotide (NMN), a crucial nicotinamide adenine dinucleotide (NAD⁺) intermediate, has been nominated as a promising therapeutic target in retinal diseases. Nonetheless, a protective effect of NMN has not been examined in cardiovascular diseases-induced retinal ischemia. In our study, we aimed to investigate its promising effect of NMN in the ischemic retina of a murine model of carotid artery occlusion. After surgical unilateral common carotid artery occlusion (UCCAO) in adult male C57BL/6 mice, NMN (500 mg/kg/day) was intraperitoneally injected to mice every day until the end of experiments. Electroretinography and biomolecular assays were utilized to measure ocular functional and further molecular alterations in the retina. We found that UCCAO-induced retinal dysfunction was suppressed, pathological gliosis was reduced, retinal NAD⁺ levels were preserved, and the expression of an antioxidant molecule (nuclear factor erythroid-2-related factor 2; Nrf2) was upregulated by consecutive administration of NMN. Our present outcomes first suggest a promising NMN therapy for the suppression of cardiovascular diseases-mediated retinal ischemic dysfunction.     

Postconditioning by Delayed Administration of Ciclosporin A: Implication for Donation after Circulatory Death (DCD)

Heart transplantation is facing a shortage of grafts. Donation after Circulatory Death (DCD) would constitute a new potential of available organs. In the present work, we aimed to evaluate whether Postconditioning (ischemic or with ciclosporin-A (CsA)) could reduce ischemia-reperfusion injury in a cardiac arrest model when applied at the start of reperfusion or after a delay. An isolated rat heart model was used as a model of DCD. Hearts were submitted to a cardiac arrest of 40 min of global warm ischemia (37 °C) followed by 3 h of 4 °C-cold preservation, then 60 min reperfusion. Hearts were randomly allocated into the following groups: control, ischemic postconditioning (POST, consisting of two episodes each of 30 s ischemia and 30 s reperfusion at the onset of reperfusion), and CsA group (CsA was perfused at 250 nM for 10 min at reperfusion). In respective subgroups, POST and CsA were applied after a delay of 3, 10, and 20 min. Necrosis was lower in CsA and POST versus controls (p < 0.01) whereas heart functions were improved (p < 0.01). However, while the POST lost its efficacy if delayed beyond 3 min of reperfusion, CsA treatment surprisingly showed a reduction of necrosis even if applied after a delay of 3 and 10 min of reperfusion (p < 0.01). This cardioprotection by delayed CsA application correlated with better functional recovery and higher mitochondrial respiratory index. Furthermore, calcium overload necessary to induce mitochondrial permeability transition pore (MPTP) opening was similar in all cardioprotection groups, suggesting a crucial role of MPTP in this delayed protection of DCD hearts.     

Hypothermia Alleviates Reductive Stress,a Root Cause of Ischemia Reperfusion Injury

Ischemia reperfusion injury is common in transplantation. Previous studies have shown that cooling can protect against hypoxic injury. To date, the protective effects of hypothermia have been largely associated with metabolic suppression. Since kidney transplantation is one of the most common organ transplant surgeries, we used human-derived renal proximal tubular cells (HKC8 cell line) as a model of normal renal cells. We performed a temperature titration curve from 37 °C to 22 °C and evaluated cellular respiration and molecular mechanisms that can counteract the build-up of reducing equivalents in hypoxic conditions. We show that the protective effects of hypothermia are likely to stem both from metabolic suppression (inhibitory component) and augmentation of stress tolerance (activating component), with the highest overlap between activating and suppressing mechanisms emerging in the window of mild hypothermia (32 °C). Hypothermia decreased hypoxia-induced rise in the extracellular lactate:pyruvate ratio, increased ATP/ADP ratio and mitochondrial content, normalized lipid content, and improved the recovery of respiration after anoxia. Importantly, it was observed that in contrast to mild hypothermia, moderate and deep hypothermia interfere with HIF1 (hypoxia inducible factor 1)-dependent HRE (hypoxia response element) induction in hypoxia. This work also demonstrates that hypothermia alleviates reductive stress, a conceptually novel and largely overlooked phenomenon at the root of ischemia reperfusion injury.