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The review focuses on the neuroprotective mechanisms of therapeutic hypothermia from the standpoint of metabolic depression and genomic reprogramming of neurons that develop when brain temperature decreases.The concept of hypothermic pre-conditioning based on the development of typical nonspecific reactions for the formation of the cytoprotective phenotype of neurons due to potentially dangerous stimuli, such as ischemia, reperfusion, and hypothermia, was used to explain the effects of low temperatures. The data confirming the role of therapeutic cerebral hypothermia as a technique of selective brain exposure to mild cold for the neuroprotection and correction of temperature balance disorders are shown.The approach to therapeutic hypothermia as a hypothermic pre-conditioning allows to significantly expand the scope of its use in various procedural variants.

Stiffness control is critical in human manipulation. The ability to transition between a low stiffness state, allowing for compliant interactions with the environment, through to rigid states, where it is possible to exert high forces, enables much functionality. Particle jamming provides an elegant method of modulating stiffness online. We develop an un-actuated anthropomorphic hand, with jamming particles enclosed in the joints surrounded by a moulded silicone skin. This approach to stiffness control also allows for control of posture, through 'pre-conditioning' by interacting with the environment in a soft state and then jamming the joints when in a new posture using a single vacuum source and control valve. To demonstrate the capabilities of this new design and fabrication approach, we introduce a 'pre-conditioning' algorithm for exploiting the soft/rigid state transition and environmental interactions to fix the hand in a given demand posture. This approach allows for accurate posture control, which translates to high grasping success rates. In conclusion, we demonstrate the advantages of the new design and fabrication approach, where jamming joints can be used to passively perform a variety of tasks through pre-conditioning of the hand posture. © 2021 IEEE.

This study aimed to investigate the cardioprotection of rosuvastatin pre-conditioning (R-Pre) in a rat model of myocardial ischemia / reperfusion (I/R). Male SD rats were assigned into three groups: sham group, I/R group and R-Pre group. Rats in I/R group and R-Pre group received ischemia for 30 min and reperfusion for 2 h. In R-Pre group, rats received intragastrical administration with rosuvastatin at 5 mg/kg once daily for 1 week. After 2-h reperfusion, the cardiac function was detected by ultrasonography; the blood was collected for biochemical analysis; the heart was collected for the TUNEL staining and immunohistochemistry for Bcl-2 and Bax. Our results showed rosuvastatin pre-conditioning for 1 week could significantly reduce the infarct ratio and improve the cardiac function after myocardial I/R injury, in which attenuation of oxidative stress and cell apoptosis played an important role. Our study provides evidence on the cardioprotection of rosuvastatin pre-conditioning and highlight the use of rosuvastatin before cardiopulmonary bypass.

It has recently been revealed that during the aorta-clamped period, D-Ala2, D-Leu5-Enkephalin (DADLE) infusion can protect the spinal cord against ischemia and reperfusion (I/R) injury. However, the protective effects of DADLE administration prior to ischemia or at the time of early reperfusion have not yet been investigated. Drug pre- or post-conditioning can serve as a more valuable clinical strategy. Therefore, the present study was designed to investigate the neuroprotective effect of DADLE infusion at different time intervals in order to determine the optimum time point for ischemic spinal cord protection. A total of 40 New Zealand white rabbits were randomly divided into 5 groups: Sham-operated (Sham), normal saline pre-conditioning (NS), DADLE per-conditioning (Dper), DADLE pre-conditioning (Dpre) and DADLE post-conditioning (Dpost). All animals were subjected to spinal cord ischemia for 30 min followed by 48 h reperfusion. Hind limb motor functions were assessed according to the Tarlov criterion when the animals regained consciousness, 6, 24 and 48 h after reperfusion. Histological analysis and the number of viable α-motor neurons were also used to assess the extent of spinal cord injury. Compared with the NS group, the Tarlov scores and the number of normal neurons were significantly higher in the Dper group (P

The risk for decompression sickness (DCS) after hyperbaric exposures (such as SCUBA diving) has been linked to the presence and quantity of vascular gas emboli (VGE) after surfacing from the dive. These VGE can be semi-quantified by ultrasound Doppler and quantified via precordial echocardiography. However, for an identical dive, VGE monitoring of divers shows variations related to individual susceptibility, and, for a same diver, dive-to-dive variations which may be influenced by pre-dive pre-conditioning. These variations are not explained by currently used algorithms. In this paper, we present a new hypothesis: individual metabolic processes, through the oxygen window (OW) or Inherent Unsaturation of tissues, modulate the presence and volume of static metabolic bubbles (SMB) that in turn act as precursors of circulating VGE after a dive., info:eu-repo/semantics/published

Isoflurane, a volatile and inhalational anesthetic, has been extensively used in perioperative period for several decades. A large amount of experimental studies have indicated that isoflurane exhibits neuroprotective properties when it is administrated before or after (pre-conditioning and post-conditioning) neurodegenerative diseases (e.g., hypoxic ischemia, stroke and trauma). Multiple mechanisms are involved in isoflurane induced neuroprotection, including activation of glycine and γ-aminobutyric acid receptors, antagonism of ionic channels and alteration of the function and activity of other cellular proteins. Although neuroprotection provided by isoflurane is observed in many animal studies, convincing evidence is lacking in human trials. Therefore, there is still a long way to go before translating its neuroprotective properties into clinical practice.

Background: To evaluate the effect of anaesthesia and ICU sedation with sevoflurane to protect the myocardium against ischemia-reperfusion injury associated to cardiac surgery assessed by troponin release. Methods: We performed a prospective, open-label, randomized study in cardiac surgery with cardiopulmonary bypass. Patients were randomized to an algorithm-based intervention group and a control group. The main outcome was the perioperative kinetic of cardiac troponin I (cTnI). The secondary outcomes included composite endpoint, GDF-15 (macrophage inhibitory cytokine-1) value, arterial lactate levels, and the length of stay (LOS) in the ICU. Results: Of 82 included patients, 81 were analyzed on an intention-to-treat basis (intervention group: n = 42; control group: n = 39). On inclusion, the intervention and control groups did not differ significantly in terms of demographic and surgical data. The postoperative kinetics of cTnI did not differ significantly between groups: the mean difference was 0.44 ± 1.09 μg/ml, P = .69. Incidence of composite endpoint and GDF-15 values were higher in the sevoflurane group than in propofol group. The intervention and control groups did not differ significantly in terms of ICU stay and hospital stay. Conclusion: The use of an anaesthesia and ICU sedation with sevoflurane was not associated with a lower incidence of myocardial injury assessed by cTnI. Sevoflurane administration was associated with higher prevalence of acute renal failure and higher GDF-15 values.

Objective The purpose of this study was to evaluate potential relationships between cytokine gene expression, complete blood counts (CBC) and animals that were sick or would become sick. The CBC and the transcript abundance of cytokines and their receptors expressed in leukocytes were measured from calves at two early timepoints, and again after diagnosis with bovine respiratory disease (BRD). Results Blood was collected from calves at pre-conditioning (n = 796) and weaning (n = 791) for CBC. Blood counts were also measured for the calves with BRD (n = 13), and asymptomatic calves (n = 75) after weaning. The CBC were compared for these animals at 3 time points. At diagnosis, neutrophils were higher and basophils lower in sick animals (P

In the CNS short episodes of acute hypoxia can result in a decrease in synaptic transmission which may be fully reversible upon re-oxygenation. Stabilization of hypoxia-inducible factor (HIF) by inhibition of prolyl hydroxylase domain (PHD) enzymes has been shown to regulate the cellular response to hypoxia and confer neuroprotection both in vivo and in vitro. Hypoxic preconditioning has become a novel therapeutic target to induce neuroprotection during hypoxic insults. However, there is little understanding of the effects of repeated hypoxic insults or pharmacological PHD inhibition on synaptic signalling. In this study we have assessed the effects of hypoxic exposure and PHD inhibition on synaptic transmission in the rat CA1 hippocampus. Field excitatory postsynaptic potentials (fEPSPs) were elicited by stimulation of the Schaffer collatoral pathway. 30 min hypoxia (gas mixture 95% N2/5% CO2) resulted in a significant and fully reversible decrease in fEPSP slope associated with decreases in partial pressures of tissue oxygen. 15-30 min of hypoxia was sufficient to induce stabilization of HIF in hippocampal slices. Exposure to a second hypoxic insult after 60 min resulted in a similar depression of fEPSP slope but with a significantly greater rate of recovery of the fEPSP. Prior single treatment of slices with the PHD inhibitor, dimethyloxalylglycine (DMOG) also resulted in a significantly greater rate of recovery of fEPSP post hypoxia. These results suggest that hypoxia and ‘pseudohypoxia’ preconditioning may improve the rate of recovery of hippocampal neurons to a subsequent acute hypoxia. University College Dublin Science Foundation Ireland (SFI)

Irreversible myocardial damage happens in the presence of prolonged and severe ischemia. Several phenomena protect the heart against myocardial infarction and other adverse outcomes of ischemia and reperfusion (IR), namely: hibernation related to stunned myocardium, ischemic preconditioning (IPC), ischemic post-conditioning, and their pharmacological surrogates. Ischemic preconditioning consists in the induction of a brief IR to reduce damage of the tissue caused by prolonged and severe ischemia. Nitric oxide (NO) signaling plays an essential role in IPC. Nitric oxide-sensitive guanylate cyclase/cyclic guanosine-3′,5′-monophosphate (cGMP)-dependent protein kinase type I-signaling pathway protects against the IR injury during myocardial infarction. Mitochondrial ATP-sensitive and Ca2+-activated K+ channels are involved in NO-mediated signaling in IPC. Independently of the cGMP-mediated induction of NO production, S-nitrosation represents a regulatory molecular mechanism similar to phosphorylation and is essential for IPC. Unlike conditioning phenomena, the mechanistic basis of myocardial stunning and hibernation remains poorly understood. In this review article, we hypothesize that the disruption of electrical syncytium of the myocardium may underly myocardial stunning and hibernation. Considering that the connexins are the building blocks of gap junctions which represent primary structural basis of electrical syncytium, we discuss data on the involvement of connexins into myocardial conditioning, stunning, and hibernation. We also show how NO-mediated signaling is involved in myocardial stunning and hibernation. Connexins represent an essential element of adaptation phenomena of the heart at the level of both the cardio- myocytes and the mitochondria. Nitric oxide targets mitochondrial connexins which may affect electrical syncytium continuum in the heart. Mitochondrial connexins may play an essential role in NO-dependent mechanisms of myocardial adaptation to ischemia.

Acute brain injury is a critical and emergent condition in clinical settings, which needs to be addressed urgently. Commonly acute brain injuries include traumatic brain injury, ischemic and hemorrhagic strokes. Oxidative stress is a key contributor to the subsequent injuries and impedes the reparative process after acute brain injury; therefore, facilitating an anti-oxidative approach is important in the care of those diseases. Readiness to deliver and permeability to blood brain barrier are essential for the use of this purpose. Inhaled anesthetic gases are a group of such agents. In this article, we discuss the anti-oxidative roles of anesthetic gases against acute brain injury.

The aim of the present study was to explore the roles and possible molecular mechanism of the alleviating effect of sevoflurane pre‑treatment on the extracorporeal circulation and to investigate the possible involvement of the Toll‑like receptor (TLR3) signaling pathway. A total of 64 male Sprague Dawley rats were randomly divided into three groups: The sham operation group (H group; n=8), cardiopulmonary bypass (CPB) group (C group; n=24) and sevoflurane pre‑conditioning group (S group; n=32). The C group was subjected to tracheal intubation and mechanical ventilation, vessel puncture and catheter placement in the right femoral artery and right internal jugular vein, while no CPB was performed in the H group. The S group was pre‑treated with 2.4% sevoflurane for 1 h prior to establishing the CPB model. The CPB in the C and S groups was performed for 1 h. Blood of the rats was analyzed and clinical parameters were detected prior to, during and at various time‑points after CPB. In addition, eight rats from the C and S groups each were sacrificed at these time‑points and brain tissue samples were analyzed. The levels of the brain damage‑specific protein S100‑β as well as IL‑6 and IFN‑β in the serum were detected by ELISA; furthermore, the expression levels of TLR3 and TIR‑domain‑containing adapter‑inducing interferon‑β (TRIF) in the left hippocampus were assessed by ELISA and/or western blot analysis. The right hippocampus was assessed for neuronal apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The mean arterial pressure, heart rate and hematocrit were significantly decreased following CPB (P

Unexpected cardiac adverse effects are the leading causes of discontinuation of clinical trials and withdrawal of drugs from the market. Since the original observations in the mid-90s, it has been well established that cardiovascular risk factors and comorbidities (such as ageing, hyperlipidaemia, and diabetes) and their medications (e.g. nitrate tolerance, adenosine triphosphate-dependent potassium inhibitor antidiabetic drugs, statins, etc.) may interfere with cardiac ischaemic tolerance and endogenous cardioprotective signalling pathways. Indeed drugs may exert unwanted effects on the diseased and treated heart that is hidden in the healthy myocardium. Hidden cardiotoxic effects may be due to (i) drug-induced enhancement of deleterious signalling due to ischaemia/reperfusion injury and/or the presence of risk factors and/or (ii) inhibition of cardioprotective survival signalling pathways, both of which may lead to ischaemia-related cell death and/or pro-arrhythmic effects. This led to a novel concept of ‘hidden cardiotoxicity’, defined as cardiotoxity of a drug that manifests only in the diseased heart with e.g. ischaemia/reperfusion injury and/or in the presence of its major comorbidities. Little is known on the mechanism of hidden cardiotoxocity, moreover, hidden cardiotoxicity cannot be revealed by the routinely used non-clinical cardiac safety testing methods on healthy animals or tissues. Therefore, here, we emphasize the need for development of novel cardiac safety testing platform involving combined experimental models of cardiac diseases (especially myocardial ischaemia/reperfusion and ischaemic conditioning) in the presence and absence of major cardiovascular comorbidities and/or cotreatments.

Team-sport athletes and coaches use varied strategies to enhance repeated-sprint ability (RSA). Aside from physical training, a well-conducted warm-up enhances RSA via increased oxidative metabolism. Strategies that impede blood flow could potentiate the effects of a warm-up due to their effects on the endothelial and metabolic functions. This study investigated whether performing a warm-up combined with blood-flow restriction (WFR) induces ergogenic changes in blood volume, muscle oxygenation, and RSA. In a pair-matched, single-blind, pre-post parallel group design, 15 American football players completed an RSA test (12 &times, 20 m, 20 s rest), preceded by WFR or a regular warm-up (SHAM). Pressure was applied on the athletes&rsquo, upper thighs for &asymp, 15 min using elastic bands. Both legs were wrapped at a perceived pressure of 7 and 3 out of 10 in WFR and SHAM, respectively. Changes in gastrocnemius muscle oxygen saturation (SmO2) and total hemoglobin concentration ([THb]) were monitored with near-infrared spectroscopy. Cohen&rsquo, s effect sizes (ES) were used to estimate the impact of WFR. WFR did not clearly alter best sprint time (ES &minus, 0.25), average speed (ES 0.25), total time (ES &minus, 0.12), and percent decrement score (ES 0.39). While WFR did not meaningfully alter average SmO2 and [THb], the intervention clearly increased the maximum [THb] and the minimum and maximum SmO2 during some of the 12 sprint/recovery periods (ES 0.34&ndash, 1.43). Results indicate that WFR positively alters skeletal muscle hemodynamics during an RSA test. These physiological changes did not improve short-term RSA, but could be beneficial to players during longer activities such as games.

This paper tells the story of how hormesis became recognized as a fundamental concept in biology, affecting toxicology, microbiology, medicine, public health, agriculture, and all areas related to enhancing biological performance. This paper assesses how hormesis enhances resilience to normal aging and protects against a broad spectrum of neurodegenerative, cardiovascular, and other diseases, as well as trauma and other threats to health and well-being. This paper also explains the application of hormesis to several neurodegenerative diseases such as Parkinson’s and Huntington’s disease, macrophage polarization and its systematic adaptive protections, and the role of hormesis in enhancing stem cell functioning and medical applications.

Ischaemic pre-conditioning has a powerful protective potential against ischaemia-induced cell death, and acidosis is an important featur of ischaemia and can lead to apoptosis. Here we tested whether pre-conditioning with acidosis, that is, acidic pre-conditioning (APC), may protect coronary endothelial cells (EC) against apoptosis induced by simulated ischaemia. For pre-conditioning, EC were exposed fo 40 min. to acidosis (pH 6.4) followed by a 14-hrs recovery period (pH 7.4) and finally treated for 2 hrs with simulated ischaemia (glucose-free anoxia at pH 6.4). Cells undergoing apoptosis were visualized by chromatin staining or by determination of caspase-3 activit Simulated ischaemia in untreated EC increased caspase-3 activity and the number of apoptotic cell (31.3 ± 1.3%versus 3.9 ± 0.6% in control). APC significantly reduced the rate of apoptosis (14.2 ± 1.3%) and caspase-3 activity. Western blot analysis exploring the under lying mechanism leading to this protection revealed suppression of the endoplasmic reticulum- (reduced cleavage of caspase-12) and mitochondria-mediated (reduced cytochrome C release) pathways of apoptosis. These effects were associated with an over-expression of the anti-apoptotic protein Bcl-xL 14 hrs after APC, whereas no effect on the expression of Bcl-2, Bax, Bak, procaspase-12, reticulum-localized chaperones (GRP78, calreticulin), HSP70, HSP32 and HSP27 could be detected. Knock-down of Bcl-xL by siRNA-treatment prevented the protective effect of APC. In conclusion, short acidic pre-treatment can protect EC against ischaemic apoptosis. The mechanism of this protection consists of suppression of the endoplasmic reticulum- and mitochondria-mediated pathways. Over-expression of the anti apoptotic protein Bcl-xL is responsible for the increased resistance to apoptosis during ischaemic insult.

Although, beneficial in determined contexts, eccentric exercise-induced muscle damage (EIMD) might be unwanted during training regimens, competitions and daily activities. There are a vast number of studies investigating strategies to attenuate EIMD response after damaging exercise bouts. Many of them consist of performing exercises that induce EIMD, consuming supplements or using equipment that are not accessible for most people. It appears that performing maximal isometric contractions (ISOs) 2-4 days prior to damaging bouts promotes significant attenuation of EIMD symptoms that are not related to muscle function. It has been shown that the volume of ISOs, muscle length in which they are performed, and interval between them and the damaging bout influence the magnitude of this protection. In addition, it appears that this protection is not long-lived, lasting no longer than 4 days. Although no particular mechanisms for these adaptations were identified, professionals should consider applying this non-damaging stimulus before submitting their patients to unaccustomed exercised. However, it seems not to be the best option for athletes or relatively trained individuals. Future, studies should focus on establishing if ISOs protect other populations (i.e., trained individuals) or muscle groups (i.e., knee extensors) against EIMD, as well as investigate different mechanisms for ISO-induced protection.

Acute myocardial infarction (MI) is one of the leading causes of mortality worldwide. MI is the heart muscle irreversible death secondary to prolonged ischemia. Over the last few decades, medical progress in how and when to restore blood flow to the ischemic area have markedly improved patient survival. Although early heart reperfusion is acknowledged to be the most effective way to limit infarct size, post-ischemic reperfusion is associated with detrimental effects, such as myocardial stunning, ventricular arrhythmias, microvascular dysfunction, and cell death. The molecular mechanisms of these reperfusion injuries remain to be elucidated and their management is very challenging. Among the various therapeutic molecular approaches proposed by experimental studies, nitric oxide (NO) role in protecting heart against MI and reperfusion injuries has been widely assessed and discussed (1–4). NO is a gasotransmitter that is abundantly produced in the cardiovascular system mainly by the NO synthase (NOS) enzymes system. Two isoforms, endothelial NOS (eNOS) and neuronal NOS (nNOS), are constitutively expressed in both myocardium and vessels, whereas inducible NOS (iNOS) is detected only in pathological conditions, such as inflammatory and/or oxidative stress. Both eNOS and nNOS are low-NO output Ca2+-dependent enzymes, while iNOS is a high-NO output Ca2+-independent enzyme. In physiological conditions, NOS form homodimers (“coupled” NOS) that catalyze NO production from l-arginine and O2 through electron transfer from NADPH on the reductase domain of one monomer to the oxidase domain of the second monomer. In pathological conditions, such as in the absence of the essential cofactor tetrahydrobiopterin (BH4), eNOS can be “uncoupled” to produce O2− instead of NO. In stress conditions, NO protects tissues through two distinct pathways. In the first one, NO activates the soluble guanylate cyclase (sGC) that initiates cyclic guanosine monophosphate (cGMP) production, leading to the activation of protein kinase G (PKG). As sGC is the major cell receptor for NO and the NO/sGC/cGMP/PKG pathway plays a critical role in both myocardium excitation–contraction coupling and cardiovascular function regulation (5–8), NO cardioprotective role was first attributed to PKG activation (9–11). However, a second pathway in which proteins are directly modified by NO addition to sulfhydryl residues, a process known as S-nitrosylation (SNO), has recently emerged in the scientific literature. Although PKG activation pathway has been largely involved in NO-mediated cardioprotection (11–13), SNO is now taking the front stage and is considered to be a key player in cardioprotection through (i) the transient modification of protein activity and/or (ii) their protection from irreversible oxidation (14–17). Indeed, Sun et al. (18) showed that reduced heart vulnerability to ischemia–reperfusion (IR) following acute ischemic preconditioning is mainly related to SNO signaling and not to PKG activation through the NO–SGC–cGMP pathway. Accordingly, we found that in exercise training-induced cardioprotection against IR injuries, protein SNO level, but not cGMP level, increased during early reperfusion (19). The same year, Methner et al. (20), using a Cre/loxP approach to selectively ablate type I PKG in cardiomyocytes, demonstrated that ischemic post-conditioning reduced infarct size in these mice like in wild type controls. Moreover, they showed that the cardioprotective effect against IR injury of mitochondria-targeted S-nitrosothiol (MitoSNO), which allows NO and S-nitrosothiol accumulation in mitochondria, was comparable in mice that specifically lack PKG in cardiomyocytes and in controls. This indicates that MitoSNO cardioprotective effect is independent of PKG. The current literature strongly supports NO implication in cardioprotection. However, the mechanism is still debated and whether increased NO availability during IR is cytoprotective remains to be demonstrated. Here, we discuss how NO might contribute to protect heart and particularly the importance of NO (i) localization, (ii) concentration, and (iii) time of availability during IR.

The reduction or cessation of the blood supply to an organ results in tissue ischemia. Ischemia can cause significant tissue damage, and is observed as a result of a thrombosis, as part of a disease process, and during surgery. However, the restoration of the blood supply often causes more damage to the tissue than the ischemic episode itself. Research is therefore focused on identifying the cellular pathways involved in the protection of organs from the damage incurred by this process of ischemia reperfusion (I/R). The hypoxia-inducible factors (HIFs) are a family of heterodimeric transcription factors that are stabilized during ischemia. The genes that are expressed downstream of HIF activity enhance oxygen-independent ATP generation, cell survival, and angiogenesis, amongst other phenotypes. They are, therefore, important factors in the protection of tissues from I/R injury. Interestingly, a number of the mechanisms already known to induce organ protection against I/R injury, including preconditioning, postconditioning, and activation of signaling pathways such as adenosine receptor signaling, converge on the HIF system. This review describes the evidence for HIFs playing a role in I/R protection mediated by these factors, highlights areas that require further study, and discuss whether HIFs themselves are good therapeutic targets for protecting tissues from I/R injury.

Small-conductance Ca(2+)-activated K(+) channel activation is an emerging therapeutic approach for treatment of neurological diseases, including stroke, amyotrophic lateral sclerosis and schizophrenia. Our previous studies showed that activation of SK channels exerted neuroprotective effects through inhibition of NMDAR-mediated excitotoxicity. In this study, we tested the therapeutic potential of SK channel activation of NS309 (25 μM) in cultured human postmitotic dopaminergic neurons in vitro conditionally immortalized and differentiated from human fetal mesencephalic cells. Quantitative RT-PCR and western blotting analysis showed that differentiated dopaminergic neurons expressed low levels of SK2 channels and high levels of SK1 and SK3 channels. Further, protein analysis of subcellular fractions revealed expression of SK2 channel subtype in mitochondrial-enriched fraction. Mitochondrial complex I inhibitor rotenone (0.5 μM) disrupted the dendritic network of human dopaminergic neurons and induced neuronal death. SK channel activation reduced mitochondrial membrane potential, while it preserved the dendritic network, cell viability and ATP levels after rotenone challenge. Mitochondrial dysfunction and delayed dopaminergic cell death were prevented by increasing and/or stabilizing SK channel activity. Overall, our findings show that activation of SK channels provides protective effects in human dopaminergic neurons, likely via activation of both membrane and mitochondrial SK channels. Thus, SK channels are promising therapeutic targets for neurodegenerative disorders such as Parkinson's disease, where dopaminergic cell loss is associated with progression of the disease.

Despite current treatment options, cardiac failure is associated with significant morbidity and mortality highlighting a compelling clinical need for novel therapeutic approaches. Based on promising pre-clinical data, stem cell therapy has been suggested as a possible therapeutic strategy. Of the candidate cell types evaluated, mesenchymal stromal/stem cells (MSCs) have been widely evaluated due to their ease of isolation and ex vivo expansion, potential allogeneic utility and capacity to promote neo-angiogenesis and endogenous cardiac repair. However, the clinical application of MSCs for mainstream cardiovascular use is currently hindered by several important limitations, including suboptimal retention and engraftment and restricted capacity for bona fide cardiomyocyte regeneration. Consequently, this has prompted intense efforts to advance the therapeutic properties of MSCs for cardiovascular disease. In this review, we consider the scope of benefit from traditional plastic adherence-isolated MSCs and the lessons learned from their conventional use in preclinical and clinical studies. Focus is then given to the evolving strategies aimed at optimizing MSC therapy, including discussion of cell-targeted techniques that encompass the preparation, pre-conditioning and manipulation of these cells ex vivo, methods to improve their delivery to the heart and innovative substrate-directed strategies to support their interaction with the host myocardium. Refereed/Peer-reviewed

Mesenchymal stem cells (MSCs) are an attractive candidate for autologous cell therapy, but their ability to repair damaged myocardium is severely compromised with advanced age. Development of viable autologous cell therapy for treatment of heart failure in the elderly requires the need to address MSC ageing. In this study, MSCs from young (2 months) and aged (24 months) C57BL/6 mice were characterized for gene expression of IGF-1, FGF-2, VEGF, SIRT-1, AKT, p16(INK4a) , p21 and p53 along with measurements of population doubling (PD), superoxide dismutase (SOD) activity and apoptosis. Aged MSCs displayed senescent features compared with cells isolated from young animals and therefore were pre-conditioned with glucose depletion to enhance age affected function. Pre-conditioning of aged MSCs led to an increase in expression of IGF-1, AKT and SIRT-1 concomitant with enhanced viability, proliferation and delayed senescence. To determine the myocardial repair capability of pre-conditioned aged MSCs, myocardial infarction (MI) was induced in 24 months old C57BL/6 wild type mice and GFP expressing untreated and pre-conditioned aged MSCs were transplanted. Hearts transplanted with pre-conditioned aged MSCs showed increased expression of paracrine factors, such as IGF-1, FGF-2, VEGF and SDF-1α. This was associated with significantly improved cardiac performance as measured by dp/dt(max), dp/dt(min), LVEDP and LVDP, declined left ventricle (LV) fibrosis and apoptosis as measured by Masson's Trichrome and TUNEL assays, respectively, after 30 days of transplantation. In conclusion, pre-conditioning of aged MSCs with glucose depletion can enhance proliferation, delay senescence and restore the ability of aged cells to repair senescent infarcted myocardium.

Nephrotoxicity is the main side effect of antibiotics such as gentamicin. Preconditioning has been reported to protect against injuries as ischemia/reperfusion. The objective of the present study was to determine the effect of preconditioning with gentamicin on LLC-PK1 cells. Preconditioning was induced in LLC-PK1 cells by 24-h exposure to 2.0 mM gentamicin (G/IU). After 4 or 15 days of preconditioning, cells were again exposed to gentamicin (2.0 mM) and compared to untreated control or G/IU cells. Necrosis and apoptosis were assessed by acridine orange and HOESCHT 33346. Nitric oxide (NO) and endothelin-1 were assessed by the Griess method and available kit. Heat shock proteins were analyzed by Western blotting. After 15 days of preconditioning, LLC-PK1 cells exhibited a significant decrease in necrosis (23.5 ± 4.3 to 6.5 ± 0.3%) and apoptosis (23.5 ± 4.3 to 6.5 ± 2.1%) and an increase in cell proliferation compared to G/IU. NO (0.177 ± 0.05 to 0.368 ± 0.073 µg/mg protein) and endothelin-1 (1.88 ± 0.47 to 2.75 ± 0.53 pg/mL) production significantly increased after 15 days of preconditioning compared to G/IU. No difference in inducible HSP 70, constitutive HSC 70 or HSP 90 synthesis in tubular cells was observed after preconditioning with gentamicin. The present data suggest that preconditioning with gentamicin has protective effects on proximal tubular cells, that involved NO synthesis but not reduction of endothelin-1 or production of HSP 70, HSC 70, or HSP 90. We conclude that preconditioning could be a useful tool to prevent the nephrotoxicity induced by gentamicin. Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de Medicina UNIFESP, EPM, Depto. de Medicina SciELO

In recent years, hyperbaric oxygen (HBO) has been used in the treatment of a lot of diseases such as decompression sickness, arterial gas embolism, carbon dioxide poisoning, soft tissue infection, refractory osteomyelitis, and problematic wound, but little is known about its application in liver transplantation. Although several studies have been conducted to investigate the protective effects of HBO on liver transplantation and liver preservation, there are still some controversies on this issue, especially its immunomodulatory effect. In this short review, we briefly summarize the findings supporting the application of HBO during liver transplantation (including donors and recipients).

Background Ischemia is the major cause of acute kidney injury (AKI), associated with high mortality and morbidity. Mesenchymal stem cells (MSCs) have multilineage differentiation potential and can be a potent therapeutic option for the cure of AKI. Methods MSCs were cultured in four groups SNAP (S-nitroso N-acetyl penicillamine), SNAP + Methylene Blue (MB), MB and a control for in vitro analysis. Cultured MSCs were pre-conditioned with either SNAP (100 μM) or MB (1 μM) or both for 6 hours. Renal ischemia was induced in four groups (as in in vitro study) of rats by clamping the left renal padicle for 45 minutes and then different pre-conditioned stem cells were transplanted. Results We report that pre-conditioning of MSCs with SNAP enhances their proliferation, survival and engraftment in ischemic kidney. Rat MSCs pre-conditioned with SNAP decreased cell apoptosis and increased proliferation and cytoprotective genes’ expression in vitro. Our in vivo data showed enhanced survival and engraftment, proliferation, reduction in fibrosis, significant improvement in renal function and higher expression of pro-survival and pro-angiogenic factors in ischemic renal tissue in SNAP pre-conditioned group of animals. Cytoprotective effects of SNAP pre-conditioning were abrogated by MB, an inhibitor of nitric oxide synthase (NOS) and guanylate cyclase. Conclusion The results of these studies demonstrate that SNAP pre-conditioning might be useful to enhance therapeutic potential of MSCs in attenuating renal ischemia reperfusion injury.

Visual Abstract, Highlights • Pre-conditioning has emerged as a potentially powerful means of reducing ischemia-reperfusion injury. • Several animal models have implicated adenosine in pre-conditioning pathways, but its role in human physiology is unknown. • In human volunteers, the authors demonstrate that adenosine receptor activation in “trigger” tissue is an important step in initiating a pre-conditioning signal, but adenosine receptor blockade in “target” tissue does not block the protection afforded by pre-conditioning. • The authors also demonstrate that pre-conditioning elaborates a transferrable cardioprotective factor(s) into the serum. This elaboration is prevented by adenosine receptor blockade but can be mirrored by the infusion of exogenous adenosine. • An improved understanding of the physiological effectors of pre-conditioning may allow for better targeted clinical studies of pre-conditioning and pre-conditioning mimetics in the future., Summary Remote ischemic pre-conditioning (rIPC) has emerged as a potential mechanism to reduce ischemia-reperfusion injury. Clinical data, however, have been mixed, and its physiological basis remains unclear, although it appears to involve release of circulating factor(s) and/or neural pathways. Here, the authors demonstrate that adenosine receptor activation is an important step in initiating human pre-conditioning; that pre-conditioning liberates circulating cardioprotective factor(s); and that exogenous adenosine infusion is able to recapitulate release of this factor. However, blockade of adenosine receptors in ischemic tissue does not block the protection afforded by pre-conditioning. These data have important implications for defining the physiology of human pre-conditioning and its translation to future clinical trials.

Background Major depressive disorder is a prevalent disease that is inadequately treated with currently available interventions. Stress increases susceptibility to depression in patients and rodent models. Depression is also associated with aberrant activation of inflammation, such as increases in circulating levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNFα). The two main goals of this study were (i) to identify cytokine changes measuring a broad panel of 19 cytokines, and (ii) to test if a pre-conditioning stress altered the inflammatory response to a subsequent stress. Result Stress-induced changes in mouse plasma cytokines were measured by multiplex following administration of one or two daily stresses of inescapable foot shocks using the learned helplessness paradigm for modeling depression-like behavior. Administration of inescapable foot shocks increased plasma levels of IL-1β, IL-6, TNFα, IL-3, IL-10, IL-13, IL-17A, IL-5, GM-CSF, IL-12(p70), IFN-γ, MIP-1α, MIP-1β, IL-1α, IL-2, KC, RANTES and G-CSF, with peak levels occurring in the range of 6 to 12 hr after stress. Pre-conditioning the mice 24 hr before with an equivalent inescapable foot shock stress resulted in similar magnitudes of increases in most cytokines as occurred after a single stress, but accelerated the increase, causing the levels of most cytokines to peak 1 hr after stress. These results demonstrate that a single stress induces the expression of many cytokines, and that sequential, daily stresses accelerates the rate of cytokine production. Conclusions Acute stress broadly activates inflammation in mice, and the inflammatory response is more rapid following repeated stress, actions that may contribute to deleterious effects of stress on depression and other stress-linked diseases.