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Exosomes released into the plasma after brief cardiac ischaemia mediate subsequent cardioprotection. Whether donor exosomes can provide cardioprotection to recipients with chronic heart failure, which confers the highest perioperative risk, is unknown. We examined whether ischaemic preconditioning (IPC)-induced plasma exosomes exerted cardioprotection after their transfer from normal donors to post-infarcted failing hearts.Plasma exosomes were obtained from adult rats after IPC or sham. An exosome inhibitor GW4869 was administrated before IPC in an in vivo model of ischaemia/reperfusion (I/R) injury in normal rats. The IPC exosomes or control exosomes from normal donor rats were perfused to the normal or post-infarcted failing rat hearts before ischaemia in Langendorff perfusion experiments. Infarct size, cardiac enzymes, cardiac function, and pro-survival kinases were quantified.The IPC stimulus increased the release of exosomes, whereas GW4869 inhibited the rise of plasma exosomes. Pre-treatment with GW4869 reversed IPC-mediated cardioprotection against in vivo I/R injury. In the Langendorff perfusion experiments, IPC exosomes from normal donor rats reduced mean infarct size from 41.05 (1.87)% to 31.43 (1.81)% and decreased lactate dehydrogenase activity in the post-infarcted failing rat hearts. IPC exosomes but not control exosomes activated pro-survival kinases in the heart tissues.Ischaemic preconditioning-induced exosomes from normal rats can restore cardioprotection in heart failure after myocardial infarction, which is associated with activation of pro-survival protein kinases. These results suggest a potential perioperative therapeutic role for ischaemic preconditioning-induced exosomes.

Composites of Titanium (IV) oxide combined with montmorillonite (MMT) with various TiO2/MMT were prepared for photocatalysis application. The prepared samples were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and diffuse reflectance UV–visible spectroscopy. The main influential factors such as the TiO2/MMT dose, calcined temperature and pH value of the solution were studied. The main intermediates of phenol degradation were determined by High Performance Liquid Chromatography (HPLC). The results showed that the average size of TiO2 nanoparticles was decreased from 22.51 nm to 10.66 nm through the immobilization on MMT. The components in the interlayer domain were replaced by titanium pillars, and the pillaring reaction proceeded in the interlayer domain, and the basic skeleton of MMT was unchanged, and also TiO2 was dispersed on the surface of the MMT. When the initial concentration of phenol is 10 mg/L, the phenol solution pH is 6 and the UV light irradiation time is 240 min, the phenol degradation rate of 30%TiO2/MMT composite is 89.8%, which is better than MMT (11.5%) and pure TiO2 (58.8%). It shows that TiO2 loaded on MMT improves its photocatalytic activity. The phenol reaction process detected by HPLC showed that it had undergone through hydroquinone and benzoquinone, and finally converted into maleic acid and carbon dioxide and small molecules. The possible photocatalysis mechanism is presented.

Pain signals are relayed to the brain via a nociceptive system, and in rare situations, this nociceptive system contains genetic variants that can limit pain response. Here we questioned whether a human transient receptor potential vanilloid 1 (TRPV1) missense variant causes a resistance to noxious stimuli and further if we can target this region by a cell-permeable peptide as a pain therapeutic. Initially using a computational approach, we identified a human K710N TRPV1 missense variant in an otherwise highly conserved region of mammalian TRPV1. After generating a TRPV1K710N knock-in mouse using CRISPR/Cas9, we discovered the K710N variant reduced capsaicin-induced calcium influx in dorsal root ganglion neurons. The TRPV1K710N rodents also had less acute behavioral response to chemical noxious stimuli and less hypersensitivity to nerve injury-induced pain, while leaving the response to noxious heat intact. Furthermore, blocking this K710 region in wild-type rodents by a cell-penetrating peptide limited acute behavioral responses to noxious stimuli and rescued pain hypersensitivity induced by nerve injury back to baseline. These findings identify K710 TRPV1 as a discrete site crucial for the control of nociception and provides new insights into how to leverage rare genetic variants in humans to uncover fresh strategies for developing pain therapeutics.

BackgroundInterleukin-6 (IL-6), a pleiotropic cytokine with both degenerative and regenerative properties, is necessary and sufficient to provoke perioperative neurocognitive disorders after aseptic trauma in mice. IL-6 initiates its actions after binding to either membrane-bound IL-6 receptor α (mIL-6Rα) through classical signalling, or soluble IL-6 receptor (IL-6R) through trans-signalling; both signalling pathways require the transducer gp130. We investigated the site and type of IL-6 signalling that pertains in a tibial fracture aseptic trauma model of perioperative neurocognitive disorder.MethodsWild-type or genetically altered adult mice that lacked molecules unique to either classical or trans-IL-6 signalling underwent tibial fracture under isoflurane anaesthesia. In separate cohorts, we assessed postoperative memory using a trace fear conditioning paradigm (72 h postoperatively), and post-receptor IL-6 signalling (24 h postoperatively) using phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) in CA1 hippocampal neurones. Fracture healing was assessed at postoperative day 15 after inhibiting either both forms of IL-6 signalling with BE0047 or only trans-signalling with sgp130Fc.ResultsThe surgical phenotype of memory decline (decrease in freezing in trace fear conditioning) and upregulated IL-6 signalling (pSTAT3) did not occur after pretreatment before surgery with either BE0047 or sgp130Fc, or after depleting gp130 from CA1 neurones. The surgical phenotype still occurred when IL-6Rα was depleted in either CA1 hippocampal neurones (freezing time, 38.9% [11.5%] vs 58.4% [12.3%]; pSTAT+ CA1 neurones, 31.7 [4.9] vs 7.0 [3.1]) or microglia (freezing time, 40.1% [13.9%] vs 65.2% [12.6%]; pSTAT+ CA1 neurones, 30.1 [5.5] vs 7.9 [3.2]). In global IL-6Rα-/- mice, hyper-IL-6, the trans-signalling agonist, produced the surgical phenotype when administered i.c.v. (freezing time, 42.4% [8.8%] vs 59.7% [10.4%]; pSTAT+ cells, 29.3 [4.3] vs 10.0 [4.4]). Bone-fracture healing (% of fracture callus comprised of new collagen) was significantly greater with sgp130Fc than with BE0047 (52.2% [8.3%] vs 39.7% [7.9%]).ConclusionsAfter orthopaedic trauma, IL-6 produces perioperative neurocognitive disorders through IL-6 trans-signalling in mouse CA1 neurones. Druggable targets of the trans-signalling pathway should be sought to reduce perioperative neurocognitive disorders while allowing the healing properties of classical IL-6 signalling.

Astrocytes play a key role in the response to injury and noxious stimuli, but its role in myocardial ischemia–reperfusion (I/R) injury remains largely unknown. Here we determined whether manipulation of spinal astrocyte activity affected myocardial I/R injury and the underlying mechanisms. By ligating the left coronary artery to establish an in vivo I/R rat model, we observed a 1.7-fold rise in glial fibrillary acidic protein (GFAP) protein level in spinal cord following myocardial I/R injury. Inhibition of spinal astrocytes by intrathecal injection of fluoro-citrate, an astrocyte inhibitor, decreased GFAP immunostaining and reduced infarct size by 29% relative to the I/R group. Using a Designer Receptor Exclusively Activated by Designer Drugs (DREADD) chemogenetic approach, we bi-directionally manipulated astrocyte activity employing GFAP promoter-driven Gq- or Gi-coupled signaling. The Gq-DREADD-mediated activation of spinal astrocytes caused transient receptor potential vanilloid 1 (TRPV1) activation and neuropeptide release leading to a 1.3-fold increase in infarct size, 1.2-fold rise in serum norepinephrine level and higher arrhythmia score relative to I/R group. In contrast, Gi-DREADD-mediated inhibition of spinal astrocytes suppressed TRPV1-mediated nociceptive signaling, resulting in 35% reduction of infarct size and 51% reduction of arrhythmia score from I/R group, as well as lowering serum norepinephrine level from 3158 ± 108 to 2047 ± 95 pg/mL. Further, intrathecal administration of TRPV1 or neuropeptide antagonists reduced infarct size and serum norepinephrine level. These findings demonstrate a functional role of spinal astrocytes in myocardial I/R injury and provide a novel potential therapeutic approach targeting spinal cord astrocytes for the prevention of cardiac injury.

MicroRNAs (miRs) can affect the progression of cervical cancer (CC). The present study investigated the function of miR‑145‑5p in CC and demonstrated its association with fascin (FSCN1). The expression levels of miR‑145‑5p in CC tissues and cell lines were analyzed using reverse transcription‑quantitative PCR, and its direct targets were explored using a luciferase reporter assay. The viability, migration and invasion of HeLa cells transfected with small interfering FSCN1 or with miR‑145‑5p mimics and inhibitors were analyzed using Cell Counting Kit‑8 and Transwell assays. The expression levels of FSCN1 mRNA and protein were investigated using reverse transcription PCR and western blotting. miR‑145‑5p was downregulated in CC tissues and cell lines. Moreover, overexpression of miR‑145‑5p inhibited the migration, invasion and viability of HeLa cells. miR‑145‑5p directly targeted FSCN1, which regulated the suppressive functions of miR‑145‑5p in CC cells. Overall, miR‑145‑5p is a tumor suppressor gene and a promising target for CC treatment.

Myocardium ischemia-reperfusion injury (IRI) is the major cause of postoperative cardiac dysfunction. While intrathecal morphine preconditioning (ITMP) can reduce IRI in animals, the molecular processes underlying IRI and ITMP remain elusive. Transient receptor potential vanilloid type 1 (TRPV1) is highly expressed in cardiac sensory neurons and has a crucial role in detecting myocardial ischemia. This study aimed to determine the role of up-regulated dorsal root ganglion (DRG)-TRPV1 in IRI and whether its inhibition contributes to ITMP-induced cardioprotection. Animal model of IRI was established by left coronary artery occlusion (30 min) and reperfusion (2 h) in rats. Intrathecal intubation was prepared for morphine preconditioning, TRPV1-shRNA or selective TRPV1 antagonist administration. After IRI, both protein and phosphorylation levels of TRPV1 were significantly increased, and the immunofluorescence intensity of TRPV1 was increased and colocalized with μ-opioid receptors in DRG. Intrathecal pre-administration of either TRPV1-shRNA or TRPV1 antagonist significantly reduced myocardial injury and the upregulation of TRPV1 in DRG induced by IRI. Simultaneously, ITMP significantly suppressed TRPV1 protein expression and phosphorylation in DRG, as well as the heart infarct size and arrhythmia score caused by IRI. The suppression of TRPV1 elevation and activation by ITMP were reversed by intrathecal injection of the selective μ receptor antagonist. Furthermore, IRI elevated DRG cAMP, while intrathecal administration of the selective cAMP-PKA inhibitor reduced myocardial injury. Finally, we showed that activation of opioid receptor by morphine inhibited PKA activator-induced TRPV1 channel activity at the cellular level. These findings suggest that the elevation and activation of TRPV1 in DRG during myocardial ischemia-reperfusion might be responsible for cardiac injury. ITMP exerts cardioprotection by inhibiting DRG-TRPV1 activity via modulation cAMP. Therefore, inhibition of TRPV1 upregulation in DRG might be used as a novel therapeutic mechanism for myocardium ischemia-reperfusion injury.

HIV subtypes convey important epidemiological information and possibly influence the rate of disease progression. In this study, HIV disease progression in patients infected with CRF01_AE, CRF07_BC, and subtype B was compared in the largest HIV molecular epidemiology study ever done in China. A national data set of HIV pol sequences was assembled by pooling sequences from public databases and the Beijing HIV laboratory network. Logistic regression was used to assess factors associated with the risk of AIDS at diagnosis ([AIDSAD], defined as a CD4 count

Nerve growth factor (NGF) has been implicated in hyperalgesia by sensitising nociceptors. A role for NGF in modulating myocardial injury through ischaemic nociceptive signalling is plausible. We examined whether inhibition of spinal NGF attenuates myocardial ischaemia-reperfusion injury and explored the underlying mechanisms.In adult rats, lentivirus-mediated short-hairpin RNA targeted at reducing NGF gene expression (NGF-shRNA) or a transient receptor potential vanilloid 1 (TRPV1) antagonist (capsazepine) was injected intrathecally before myocardial ischaemia-reperfusion. Infarct size (expressed as the ratio of area at risk) and risk of arrhythmias were quantified. Whole-cell clamp patch electrophysiology was used to record capsaicin currents in primary dorsal root ganglion neurones. The co-expression of substance P (SP) and calcitonin gene-related peptide (CGRP), plus activation of TRPV1, protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) were also quantified.NGF levels increased by 2.95 (0.34)-fold in dorsal root ganglion and 2.12 (0.27)-fold in spinal cord after myocardial ischaemia-reperfusion injury. Intrathecal injection of NGF-shRNA reduced infarct area at risk from 0.58 (0.02) to 0.37 (0.02) (P0.01) and reduced arrhythmia score from 3.67 (0.33) to 1.67 (0.33) (P0.01). Intrathecal capsazepine was similarly cardioprotective. NGF-shRNA suppressed expression of SP/CGRP and activation of Akt/ERK and TRPV1 in spinal cord. NGF increased capsaicin current amplitude from 144 (42) to 840 (132) pA (P0.05), which was blocked by the TRPV1 antagonist 5'-iodoresiniferatoxin. Exogenous NGF enhanced capsaicin-induced Akt/ERK and TRPV1 activation in PC12 neuroendocrine tumour cells in culture.Spinal NGF contributes to myocardial ischaemia-reperfusion injury by mediating nociceptive signal transmission.

Recently, liposomes have been widely used in cancer therapeutics, but their anti-tumor effects are suboptimal due to limited tumor penetration. To solve this problem, researchers have made significant efforts to optimize liposomal diameters and potentials, but little attention has been paid to liposomal membrane rigidity. Herein, we sought to demonstrate the effects of cholesterol-tuned liposomal membrane rigidity on tumor penetration and anti-tumor effects. In this study, liposomes composed of hydrogenated soybean phospholipids (HSPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000) and different concentrations of cholesterol were prepared. It was revealed that liposomal membrane rigidity decreased with the addition of cholesterol. Moderate cholesterol content conferred excellent diffusivity to liposomes in simulated diffusion medium, while excessive cholesterol limited the diffusion process. We concluded that the differences of the diffusion rates likely stemmed from the alterations in liposomal membrane rigidity, with moderate rigidity leading to improved diffusion. Next, the in vitro tumor penetration and the in vivo anti-tumor effects were analyzed. The results showed that liposomes with moderate rigidity gained excellent tumor penetration and enhanced anti-tumor effects. These findings illustrate a feasible and effective way to improve tumor penetration and therapeutic efficacy of liposomes by changing the cholesterol content, and highlight the importance of liposomal membrane rigidity., Graphical abstract Liposomes with tunable rigidity were constructed conveniently by varying the contents of cholesterol. It is revealed that liposomes with moderate rigidity gained improved tumor penetration and enhanced anti-tumor effects compared to their soft and hard counterparts.fx1

Background Myocardial ischemia and reperfusion-evoked spinal reflexes involve nociceptive signals that trigger neuronal excitation through cardiac afferents, projecting into the thoracic spinal cord. Ischemic preconditioning (IPC) involves brief episodes of sublethal ischemia and reperfusion enhances the resistance of the myocardium to subsequent ischemic insults. This study investigated the effects of IPC on ischemia-reperfusion (I/R) stimulation-induced activation in the thoracic spinal cord of rats. Methods A new remotely controlled I/R model was established. The infarct size was determined as a percentage of area at risk (IS/AAR) and arrhythmia scores were evaluated. Non-invasive in vivo fMRI was used for signal quantitative analysis of thoracic spinal spatiotemporal. The role of IPC on the excitability of substantia gelatinosa (SG) neurons was assessed by spinal patch clamp recording technique. The altered expressions of c-Fos, SP, and CGRP in T4 segment were detected by immunohistochemical staining. Results The novel I/R model was induced successfully and reliably utilized, and IPC treatment markedly reduced the myocardial infarct size. fMRI analysis revealed that IPC reduced the increased BOLD signals induced by prolonged ischemia-reperfusion. Patch clamp recording showed that IPC treatment reversed the enhanced excitability of SG neurons during I/R treatment. The results of immunofluorescent staining indicated that IPC mitigated the I/R-induced dramatic increase of c-Fos, and reduced the release of SP and CGRP in dorsal horns of spinal cord. Conclusions These results suggested that IPC suppressed neuronal activation induced by I/R stimuli in rat thoracic spinal cord using spinal cord fMRI and patch clamp recording techniques.

HIV-1 CRF01_AE and CRF07_BC have been two mainly circulating HIV-1 strains in the men who have sex with men (MSM) population in Beijing for years. These two subtypes together were accounting for 78.1% of HIV-1 positive cases newly diagnosed in Beijing, 2016. In this study, we report a novel CRF01_AE/CRF07_BC second-generation unique recombinant form (URF) (named DT1427_NFLG) of HIV-1 identified in MSM population. The near full-length genome of DT1427_NFLG is about 8.8 kb with four CRF07_BC fragments inserted into the CRF01_AE backbone. In China, several novel second-generation URFs were reported in recent years and Beijing, as the capital of China, attracting a huge number of people all over the country to work and live, is confronted with the risk of the epidemic of recombinant HIV-1 strains. Therefore, it is necessary to take measures to monitor the emergency of novel recombinant of HIV-1.

UV radiometers are used in many areas. There are many kinds of UV light sources with different peak wavelength and different wavelength range. The broadband UV radiometers are wildly used due to easy to use and low cost. However, there are some obvious disadvantages for the broadband radiometers. They cannot distinguish the spectral characteristics of UV sources. That will cause the spectral mismatch measurement error for the UV broadband radiometers calibration. Recently, the fiber spectroradiometer plays a more and more important role in this area. The fiber spectroradiometer is more portable and low cost compared to the double grating spectroradiometer. We can obtain the spectral characteristics and any UV irradiance using the fiber spectroradiometer. However, for most fiber spectroradiometers, we cannot use them to replace the UV broadband radiometers for the absolute irradiance measurement. There are four key effects for that. The first one is the stray light. Stray light effect is obvious for the fiber spectroradiometer, especially in the UV wavelength range. The second one is the temperature effect. The third one is the non-linearity effect. The fourth one is the bandwidth effect. This effect will cause the measurement error for the spectral distribution of the UV source. In this paper, we research the four factors that reduce the measurement accuracy of the fiber spectroradiometer in UV wavelength range.

This paper adopted an approximation of a melting plateau to solve the problem that temperature data cannot be monitored continuously when measuring the spectral irradiance of a large area tungsten carbide–carbon high-temperature fixed-point blackbody at each measured wavelength. Tests with fully measured curves showed that the method has a rather small deviation from the measured data of 0.017 K maximum, which corresponds to the spectral irradiance deviation of 0.005% at 500 nm. The maximum relative deviation between the Akima fitting method and the measured temperature in terms of spectral irradiance was 0.002%, which was better than − 0.067 % of a single temperature of 3020.11 K method and 0.026% of a linear interpolation method.

Myocardial infarction (MI) is a major cause of disability and mortality worldwide. A cell permeable peptide V1-Cal has shown remarkable therapeutic effects on ML However, using V1-Cal to improve long-term cardiac function after MI is presently limited by its short half-life. Herein, we co-assembled V1-Cal with a well-known hydrogelator Nap-Phe-Phe-Tyr (NapFFY) to obtain a new supramolecular hydrogel V1-Cal/NapFFY. We found that the hydrogel could significantly enhance the therapeutic effects of V1-Cal on ventricular remodeling reduction and cardiac function improvement in a myocardial infarction rat model. In vitro experiments indicated that co-assembly of V1-Cal with NapFFY significantly increased mechanic strength of the hydrogel, enabling a sustained release of V1-Cal for more than two weeks. In vivo experiments supported that sustained release of V1-Cal from V1-Cal/NapFFY hydrogel could effectively decrease the expression and activation of TRPV1, reduce apoptosis and the release of inflammatory factors in a MI rat model. In particular, V1-Cal/NapFFY hydrogel significantly decreased infarct size and fibrosis, while improved cardiac function 28 days post MI. We anticipate that V1-Cal/NapFFY hydrogel could be used clinically to treat MI in the near future.

For a nonisothermal blackbody cavity, different reference temperatures have influence on the calculation of effective emissivity. Previous studies proposed a weighted average method which can be indicated by a priori to calculate the reference temperature. However, these studies did not mention how to define the weight function but used some arbitrary temperature or the temperature of a fixed position like the central bottom of the cavity as the reference temperature. In this study, a quantitative analysis and calculation method, which is implemented in the Monte Carlo method based optical simulation software Tracepro, is proposed to define the weight coefficients and optimize the reference temperature. To do so, in the Tracepro software, a surface source is placed in front of the cavity opening and emits radiation to the blackbody cavity. The radiation from this surface source can be absorbed or reflected many times in the cavity, and finally the incident radiation distribution in the cavity can be obtained. According to the principle of light path reversibility, the normalized incident radiation can be considered as the contribution of its position to the effective emissivity. In the experiment, the actual temperatures of two different-shaped blackbody cavities are measured with the non-contact method in 873 K temperature. By dividing the inner surface of each blackbody cavity into several regions based on the positions of the actually measured temperature points, the incident radiation from the surface source to each segmented region is calculated and normalized to the total incident radiation across all regions as its weight coefficient; the reference temperature is the sum of the weighted temperature (by multiplying each weight coefficient with its measured temperature) in each region. Different from previous studies, this study optimizes the reference temperature by considering the contribution of the whole cavity to the effective emissivity, which should be more consistent with the actual situation. Moreover, the influences of different shapes of the blackbody cavities, different radiation characteristics of the inner surface materials and different viewing conditions of the effective emissivity on the reference temperature are discussed and compared. The results suggest that the optimization of reference temperature has close link with above factors and thus should be calculated individually.

The emissivity of the blackbody is a very important parameter in spectral radiance measurement systems. In the conventional method, the emissivity is calculated based on the isothermal model. However, the actual temperature distribution in the blackbody cavity is always nonisothermal; the emissivity calculated based on the isothermal model may not accurately present the radiation characteristic of the blackbody. In this study, the actual temperature distributions of two blackbodies (one has an extended cone shape, and the other a 65-mm diameter cylindrical shape) are measured, and the emissivities are calculated accordingly based on the nonisothermal model at a certain temperature (873 K). The results show there are different tendencies of temperature distributions in the two blackbodies. When compared with the isothermal model, the emissivities in the 873 K temperature and 2.0–20.0 µm wavelength condition are about 1.75% and 0.18% lower at the nonisothermal model for the extended cone shape and cylindrical blackbodies, respectively. To improve the emissivity, different types of apertures are customized for the two blackbodies. For the extended cone-shaped blackbody, the emissivity in the 873 K temperature and 2.0–20.0 µm wavelength condition increases by 1.12% when using a ring-shaped graphite aperture in the cavity, whereas for the cylindrical-shaped blackbody, the emissivity in the same condition increases by 0.09% when using a high-reflective aperture in front of the cavity opening. Different from previous studies, this study provides new insight in calculating and improving the effective emissivity of blackbodies by using the measured temperature in the cavity based on the nonisothermal model.

When viewing dichoptic stimuli in long time duration, visual percepts are always the alternation between the left and right eye inputs, while not the combination. This is known as binocular rivalry. An efficient coding theory reported that binocular visual inputs can be combined into binocular summation (S+) and difference (S−) channels in V1 brain area. In this study, we used specially designed stimuli as the previous study, in which monocular inputs caused ambiguous percepts, but S+ and S− channels had unambiguous percepts. We aim to investigate whether the visual percepts alter between S+ and S− channels in long time duration and whether vergence eye movements are involved in the process. To do so, the stimuli were presented in 300-s time duration in a trial, and a binocular eye tracker was used to record eye information. Participants’ real-time behavioral responses about the visual percepts and binocular information were recorded simultaneously. The results show there are perceptual flips between S+ and S− channels in both central and long time viewing conditions. More importantly, in central vision there are vergence eye movements before perceptual flips, suggesting the involvement of high level visual attention; the time of a perceptual flip from S+ is shorter than that of a flip from S−, which might be due to different involvements of visual attention, indicating a bias of feedback connection from higher brain areas for visual attention to S+ channel. Since S+ and S− dominated signals can be carried by different types of binocular neurons, our results provide new insights into high level visual attention and binocular neurons in V1 brain area by using specially designed dichoptic stimuli and eye vergence as measuring tools.

With the rapid growth of some novel services (e.g. video services), the demand for network bandwidth increases dramatically, which induces an intensive desire in allocating network bandwidth with high flexibility and efficiency. However, the traditional wavelength-division-multiplexing (WDM) optical networks lack mechanism to realize dynamic and efficiency resource allocation. Therefore, elastic optical networks (EONs) have been proposed to accommodate diverse services with heterogeneous network bandwidth and many techniques have been introduced into EONs. Among them, advanced reservation (AR) technique, which has obvious advantage in improving networking performance, has attracted growing interest. Thus, some algorithms employing AR technique have been proposed for EONs. In the traditional slack-based AR algorithm, the starting-time of arriving services can be postponed to release any possible conflicts between the AR services and other existing services, so as to increase the success probability of accommodating the arriving services. However, the traditional algorithm neglected spectrum fragments remained in the network. In this paper, we proposed an Invalid Spectrum Rate (ISR) based scheduling with advance reservation algorithm to optimize the starting-time of arriving services with a comprehensive consideration of both the allocated spectrum and the fragmented spectrum in monitoring the usage of the spectrum before services arrive. In addition, a network load threshold is set on the basis of ISR to trigger the postponement of an arriving request, which help reduce the service blocking probability. The performance of the ISR based scheduling algorithm with different thresholds and different delay times are evaluated by comprehensive simulations and implementations. Experimental results verify that a lower network load and service blocking probability can be achieved by the proposed algorithm compared with the traditional AR algorithm.

Spectral irradiance scale in the wavelength range from 250 nm to 2500 nm was realized at National Institute of Metrology on the basis of a large area tungsten carbide–carbon (WC–C) high temperature fixed point blackbody, which is composed of a 14 mm diameter WC–C fixed point cell and a variable temperature blackbody BB3500MP as a furnace. A series of 1000 W FEL tungsten halogen lamps were used as transfer standards. The new spectral irradiance scale was compared with the scale based on a variable-temperature blackbody BB3500M, and the divergence between these two methods varied from −0.66% to 0.79% from 280 nm to 2100 nm. The measurement uncertainty of spectral irradiance scale based on fixed-point blackbody was analyzed, and the expanded uncertainty was estimated as 3.9% at 250 nm, 1.4% at 280 nm, 0.43% at 400 nm, 0.27% at 800 nm, 0.25% at 1000 nm, 0.62% at 1500 nm, 0.76% at 2000 nm, and 2.4% at 2500 nm respectively. In the range from 300 nm to 1000 nm the fixed-point scale was improved obviously: the uncertainty decreased by more than 25% compared to the uncertainty based on the variable temperature blackbody. Below 300 nm, the uncertainty became higher because the signal to noise ratio was poor. Above 1100 nm, the contribution of temperature measurement to the uncertainty of spectral irradiance decreases, therefore the uncertainties of two methods are almost at the same level. The fixed-point blackbody was also used to realize the correlated colour temperature and distribution temperature of a tungsten filament lamp, the deviation from the variable temperature blackbody method was −0.5 K and −2.9 K, respectively.

The therapeutic effects of mitochondria-targeted antioxidants have been demonstrated in many pathological conditions, but their effect on neuropathic pain remains unclear. The objective was to study the therapeutic effects and mechanisms of mito-TEMPO (MT), as a nitroxide conjugated with a triphenylphosphonium moiety, on neuropathic pain in rats. Rats were randomly assigned to sham control (sham), chronic constrictive injury (CCI) or MT treatment groups (sham+MT and CCI+MT). All animals received CCI of the left sciatic nerve except those in the sham group. Overall, 0.7 mg/kg of MT was intraperitoneally injected once daily for 14 consecutive days starting from day 7 after surgery. Mechanical paw withdrawal threshold and thermal paw withdrawal latency were detected to assess pain behavior. Malondialdehyde and reduced glutathione content and total superoxide dismutase activity of serum and spinal cord tissues were estimated to assess oxidative stress levels. Mitochondrial morphology and dynamin-related proteins were used to evaluate mitochondrial function, such as fusion [Mitofusin (Mfn) and optic atrophy 1 gene protein (OPA1)] and fission [dynamin-related protein (DRP1) and Fis1]. Paw withdrawal threshold and thermal paw withdrawal latency were significantly increased in the CCI+MT group compared with the CCI group. The malondialdehyde content was decreased whereas glutathione content and superoxide dismutase activity were increased in the serum of CCI+MT rats. Furthermore, MT substantially attenuated the elevated number and decreased size of mitochondria induced by CCI. Finally, MT significantly increased expressions of Mfn1 and OPA1 and significantly decreased expression of DRP1 and Fis1. The mitochondria-targeted antioxidant MT relieved neuropathic pain induced by CCI by protecting mitochondria against oxidative stress injury.

Exosomes secreted from cancer cells promote tumor progression through the transfection of containing microRNA (miRNA), mRNAs and proteins. Yet, little of this knowledge has translated into the therapeutic application. Herein, we propose a tumor therapeutic strategy via decreasing exosomal miRNA secretion. The study designed small interfering RNA (siRNA) loaded nanoparticles to downregulate sphingosine kinase 2 (Sphk2) and investigate their potential in decreasing exosomal oncogenic miRNA content and inhibiting tumor growth. The synthesized lipid (2E)-4-(dioleostearin)-amino-4‑carbonyl-2-butenoic (DC) and chitosan were utilized to produce siRNA loaded nanoparticles (DC/CS-siRNA NPs), with optimal siRNA complexation and high transfection efficacy. We demonstrated that Sphk2 gene silencing induced by nanoparticles in hepatocellular carcinoma (HCC) cells could reduce miRNA-21 sorting into exosomes, contributing to the inhibition of tumor cell migration and tumorigenic function of exosomes to normal liver cells. Furthermore, in xenograft mouse model, Sphk2 siRNA loaded DC/CS NPs could significantly block tumor progression of malignancy HCC. These results suggest a new therapeutic approach for tumor treatment by ablating oncogenic miRNA in malicious exosomes.

Background The therapeutic potential of cardiac μ-opioid receptors in ischaemia-reperfusion (I/R) injury during opioid-modulating diseases, such as heart failure, is unknown. We aimed to explore the changes of cardiac μ-opioid receptor expression during heart failure, and its role in opioid-induced cardioprotection. Methods Rats received doxorubicin (DOX) or were subjected to coronary artery ligation to induce heart failure, or received normal saline (NS) as control. Hearts from NS or DOX rats were isolated and subjected to myocardial ischaemia and reperfusion in an in vitro perfusion system. The opioid [D-Ala,2 N-MePhe,4 Gly-ol]-enkephalin (DAMGO), with a high μ-opioid receptor specificity, morphine, and remifentanil were administrated before I/R with or without opioid receptor antagonists, or an extracellular signal-regulated kinase (ERK) inhibitor. Results Cardiac μ-opioid receptor mRNA concentrations were 3.2 times elevated in DOX-treated rats compared with NS rats, while cardiac μ-opioid receptor protein concentrations showed 6.1- and 3.5-fold increases in DOX-treated and post-infarcted rats, respectively. DAMGO reduced I/R-caused infarct size, expressed as the ratio of area at risk, from 0.50 (0.04) to 0.25 (0.03) in failing rat hearts, but had no effect on infarct size in control hearts. DAMGO promoted phosphorylation of ERK and glycogen synthase kinase (GSK)-3β only in failing hearts. DAMGO-mediated cardioprotection was blocked by an ERK inhibitor. The μ-opioid receptor antagonist D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) prevented morphine- and remifentanil-induced cardioprotection and phosphorylation of ERK and GSK-3β in failing hearts. In contrast, δ- and κ-opioid receptor selective antagonists were less potent than CTOP in the failing hearts. Conclusions Cardiac μ-opioid receptors were substantially up-regulated during heart failure, which increased DAMGO-induced cardioprotection against I/R injury.

Remifentanil preconditioning (RPC) exerts protection in normal hearts, but has not been investigated in heart failure. The aim of the present study was to evaluate the effect of RPC in a chronic failing rat heart model and the mechanisms involving mitogen-activated protein kinases (MAPK) and Bcl-2 protein family. The doxorubicin induced failing rat hearts were subjected to 30 min ischemia / 120 min reperfusion (IR) with or without RPC by using Langendorff apparatus. RPC was induced by three cycles of 5 min remifentanil / 5 min drug-free perfusion before IR, with three different concentrations: 25, 50 and 100 μg/l. An extracellular signal regulated kinases (ERK) inhibitor PD98059, p38MAPK inhibitor SB203580, c-Jun NH2-terminal kinases (JNK) inhibitor SP600125 were perfused at 10 min before RPC. Infarct size, cardiac function and protein kinase activity were determined. RPC significantly reduced infarct size and the rise in lactate dehydrogenase (LDH) level caused by IR injury in failing heart. The JNK inhibitor SP600125 and ERK inhibitor PD98059 abolished the RPC mediated reduction effect on the infarct size and LDH activity after reperfusion. In addition, RPC increased the phosphorylation of JNK, ERK1/2 and the downstream GSK-3β, as well as the Bcl-2/Bax ratio, while, these changes were completely reversed by SP600125 and PD98059. And of note, SB203580 had no effect. In conclusion, our results suggested that the activation of JNK and ERK pathways, by leading to inhibition of GSK-3β and regulating Bcl-2 protein family, is a major mechanism that RPC confers cardioprotection in failing rat heart.

RNA interference (RNAi) technology has shown great promise for the treatment of cancer and other genetic disorders. Despite the efforts to increase the target tissue distribution, the safe and effective delivery of siRNA to the diseased cells with sufficient cytosolic transport is another critical factor for successful RNAi clinical application. Here, the constructed lipid-based liquid crystalline nanoparticles, called nano-Transformers, can transform thestructure in the intracellular acidic environment and perform high-efficient siRNA delivery for cancer treatment. The developed nano-Transformers have satisfactory siRNA loading efficiency and low cytotoxicity. Different from the traditional cationic nanocarriers, the endosomal membrane fusion induced by the conformational transition of lipids contributes to the easy dissociation of siRNA from nanocarriers and direct release of free siRNA into cytoplasm. We show that transfection with cyclin-dependent kinase 1 (CDK1)-siRNA-loaded nano-Transformers causes up to 95% reduction of relevant mRNA in vitro and greatly inhibits the tumor growth without causing any immunogenic response in vivo. This work highlights that the lipid-based nano-Transformers may become the next generation of siRNA delivery system with higher efficacy and improved safety profiles.

There are two windows of protection for remote ischemic preconditioning (RIPC), an early (ERIPC) and a late-phase (LRIPC). While ERIPC has been well studied, works on LRIPC are relatively scarce, especially for the kidneys. We aimed to compare the effects of early-phase versus late-phase RIPC in patients with laparoscopic partial nephrectomy (LPN).A randomized controlled study SETTING: The Second Affiliated Hospital of Anhui Medical University, 1 May 2012 to 30 October 2013 PATIENTS: Sixty-five ASA 1 to 2 patients scheduled for LPN were located randomly to ERIPC group, LRIPC group and CON group (control).Three five-minute cycles of right upper limb ischaemia and reperfusion were performed after induction of anesthesia in ERIPC group. Patients in LRIPC group received similar treatment 24h before surgery, while control patients were not subjected to preconditioning.Serum neutrophil gelatinase-associated lipocalin (NGAL) and serum cystatin C (CysC) were evaluated before the induction of anesthesia (0h), 2h (2h) and 6h (6h) after surgery. Unilateral glomerular filtration rates (GFR) were assessed before and after surgery to evaluate overall renal function.Serum NGAL and CysC were significantly lower in ERIPC and LRIPC groups at 2h post-operation (P0.001), 6h post-operation (P0.001). Additionally, The GFR were significantly lower in ERIPC and LRIPC groups than in CON group at the 3rd month after surgery (P=0.019; P0.001). Moreover, compared to the ERIPC group, concentration of NGAL and CysC in LRIPC group decreased to a greater extent, while GFR and the percentage of decrement was significantly less in the LRIPC group (P=0.016; P0.001).Regardless of early-phase or late-phase intervention, limb remote ischemic preconditioning confers protection on renal ischemia-reperfusion injury in patients with laparoscopic partial nephrectomy, and the late-phase protection is more prominent.

The objective of this study was to monitor the trend of addiction drug use and its relationship with sexually transmitted infections (STIs) among female drug users (FDUs). Serial cross-sectional surveys were conducted during 2010–2014 among FDUs in Beijing to collect information on addiction drug usage, sexual behaviors, and STI prevalence. Characteristics were analyzed and compared between traditional and synthetic drug users among FDUs by logistic regression method. A total of 3859 FDUs were surveyed during 2010–2014, with the median age being 32.7 years old. The proportion of synthetic drug users among FDUs increased from 43.7% in 2010 to 70.7% in 2014. Compared with traditional drug users, synthetic drug users were younger (P

The absolute measurements of spectral radiance, irradiance and intensity in infrared wave range are very important for infrared target recognition, material emissivity measurement and so on. Recently, many researchers focus on how to accurately measure absolute infrared spectral radiation, in which one key point is how to suppress stray radiation. In this paper, an absolute infrared spectral radiance measurement system was built up. The system contained a fixed-point blackbody source, a variable temperature blackbody source, a radiant source to be measured, Fourier Transform Infrared Radiometer (FTIR), optical system, non-contact infrared thermometer and so on. Emissivities of the standard source and the radiant source to be measured are 0.999 and 0.995, respectively. According to Planck’s law, their absolute spectral radiance should be similar at the same radiation temperature. In experiment, temperatures of the standard blackbody and radiant source to be measured were set to 500°C, and the FTIR was used to measure spectral radiance. The results show spectral radiance of the standard source is 14.9% smaller than the radiant source to be measured at 10μm wavelength. A thermal infrared imager and optical simulation software were used to analyze the possible reasons. To solve the problems, a shielding plate and a field aperture was installed respectively at the entrance of the optical system and before the FTIR to suppress stray radiation. Moreover, sizes and positions of the shielding plate, optical system, and field aperture were analyzed by optical simulation software and mathematical calculation. After optimization, the experimental results show the difference of spectral distributions between the standard source and the radiant source to be measured is only 1.42% at 10 μm wavelength, suggesting stray radiation is effectively suppressed in the system.

The absolute measurement of infrared spectral radiance is very important for optical radiometry. In this paper, a system for absolute measurement of infrared spectral radiance is built up. The system consists of fixed-point blackbody sources, a variable temperature blackbody, a radiant source to be measured, Fourier Transform Infrared Radiometer (FTIR), relay optical system, non-contact infrared thermometer and so on. The emissivity of the variable temperature blackbody is 0.999; the temperature range is 50°C ~ 1050°C. The emissivity of the radiant source to be measured is larger than 0.995; the temperature range is 30°C ~ 550°C. The variable temperature blackbody source was calibrated and can be traced to the fixed-point blackbody source. In experiment, it was used as the standard radiant source. The spectral range of this system is 3 μm ~ 14 μm. A serial of experiments have been implemented to analyze the uncertainty of each component, including the repeatability, size-of-source effect, stability, uniformity and so on. To improve the system’s uncertainty, we have suppressed stray radiation and optimized optical system by installing a water-cooled aperture and a field stop at the entrance of the optical system and before the FTIR, respectively; optimizing the system based on optical simulation and replacing the reflective mirrors with one off-axis parabolic mirror. Next step, we will re-evaluate the uncertainty of the improved system.

Background and Aim: Birds, unlike mammals, are resistant to the spicy hot sensation when consuming chili peppers. The inability for birds to sense the hot sensation is accredited to genetic divergence in the transient receptor potential vanilloid 1 (TRPV1) when compared to mammals. Recently, we described how TRPV1 is important for regulating myocardial ischemia-reperfusion injury in rodents. Here, we tested our hypothesis that K710 is a crucial mediator of capsaicin-induced calcium influx in myocardial H9C2 cells. Methods and Results: Sequence alignment of the C-terminus TRP domain of TRPV1 among species was performed. Unlike mammals having K710 TRPV1, birds instead have N710 TRPV1 (Fig 1A). Site-directed mutagenesis of K710N was performed on wild type (WT) rTRPV1 with a pCMV6-entry vector. The empty vector, WT and K710N plasmids were transfected into H9C2 cells and the cellular localization of TRPV1 channel were detected by immunofluorescent staining and channel activity by capsaicin challenge with live cell calcium imaging with Fura-2AM. Interestingly, the K710N mutation caused the TRPV1 channel to be retained intracellularly and co-localized with PDI, an endoplasmic reticulum marker (Fig 1B, Bar=25μM). K701N cells treated with 1μM capsaicin showed a reduced response to capsaicin compared to wild type TRPV1 transfected cells (Fig 1C-E, 011±0.01 in WT vs . 0.03±0.01 in K710N, n=10, P Conclusions: Site-directed mutagenesis of K710N caused rTRPV1 to be insensitive to capsaicin and suggests a potential target for limiting calcium influx from myocardial ischemia-reperfusion injury which could be a novel protective strategy to prevent damage from a heart attack.

Background and Aim: Spinal astrocytes activation are implicated in nociception and pain processing after noxious stimuli, while its role in cardiac ischemic nociception is unknown. We recently reported spinal nerve growth factor (NGF)-sensitized transient receptor potential vanilloid 1 (TRPV1) nociceptive signaling following cardiac ischemia and reperfusion (I/R). This study was design to investigate whether spinal astrocytes are activated following myocardial I/R and its effects on spinal NGF-TRPV1 signaling. Methods and Results: Myocardial I/R injury was induced by 30 min occlusion of the left coronary artery followed by 120 min of reperfusion in rats. Glial fibrillary acidic protein (GFAP), an astrocyte marker, was found up-regulated in thoracic spinal cord during ischemia and reperfusion. Intrathecally pre-injection of fluorocitrate (FC), an astrocyte inhibitor, reduced infarct size (IS/AAR, area at risk), from 48.4±2.67 to 29.7±3.13 (P Conclusion: Myocardial I/R induced the activation of spinal astrocytes, inhibition of which reduces infarct size and cTnT level, as well as NGF-TRPV1 signaling, which suggests a novel therapeutic target for preventing myocardial ischemic injury.

Small unilamellar vesicles (SUVs), ubiquitous in organisms, play key and active roles in various biological processes. Although the physical properties of the constituent lipid molecules (i.e., the...

National Institute of Metrology (NIM) has set up a new large-area tungsten carbide–carbon (WC-C) high-temperature fixed-point (HTFP) blackbody system as the direct radiation source for measuring spectral irradiance. The point of inflection (POI) of the HTFP melting plateau curve was important to determine the liquidus point and applied as the reference point in temperature calibration. This paper presented a selective multiple fit method. The maximum discrepancy of different factors for the new method and traditional methods were 0.001 K and 0.633 K which led to 0.0003% and 0.20% spectral irradiance errors at 500 nm. In addition, when used to calculate POIs of WC-C and Re-C small-area HTFPs, the maximum deviation between the new method and the average value of traditional methods were −0.004 K and −0.03 K. This method was verified to be insensitive to the influencing factors and more effective for large-area HTFPs applications.

Acetylthevetin B (ATB), a cardiac glycoside from the seed of Thevetia peruviana (Pers) K Schum (yellow oleander), exhibits not only antitumor activity but also potential cardiac toxicity. In the present study, we attempted to enhance its antitumor action and decrease its adverse effects via chitosan-Pluronic P123 (CP) micelle encapsulation. Two ATB-loaded CP micelles (ATB-CP1, ATB-CP2) were prepared using an emulsion/solvent evaporation technique. They were spherical in shape with a particle size of 40–50 nm, showed a neutral zeta potential, and had acceptable encapsulation efficiency (>90%). Compared to the free ATB (IC50=2.94 μmol/L), ATB-loaded CP micelles exerted much stronger cytotoxicity against human lung cancer A549 cells with lower IC50 values (0.76 and 1.44 μmol/L for ATB-CP1 and ATB-CP2, respectively). After administration of a single dose in mice, the accumulation of ATB-loaded CP1 micelles in the tumor and lungs, respectively, was 15.31-fold and 9.49-fold as high as that of free ATB. A549 xenograft tumor mice treated with ATB-loaded CP1 micelles for 21 d showed the smallest tumor volume (one-fourth of that in the control group) and the highest inhibition rate (85.6%) among all the treatment groups. After 21-d treatment, no significant pathological changes were observed in hearts and other main tissues. In summary, ATB may serve as a promising antitumor chemotherapeutic agent for lung cancer, and its antitumor efficacy was significantly improved by CP micelles, with lower adverse effects.

Remifentanil preconditioning has been demonstrated to reduce myocardial ischemia reperfusion injury in rat hearts, while the mechanisms are not fully understood. This study investigated the protective effects of remifentanil against hypoxia-reoxygenation injury in adult rat cardiomyocytes and the mechanisms involving opioid receptors and downstream phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated kinase (ERK) signaling pathways. Adult rat cardiomyocytes were pretreated with remifentanil at different concentrations and then subjected to 90min hypoxia followed by 120min reoxygenation. The δ- (naltrindole), κ- (nor-binaltorphimine), or μ-opioid receptor antagonist (CTOP), as well as ERK inhibitor (PD98059) or PI3K inhibitor (wortmannin) was added before remifentanil preconditioning, respectively. Remifentanil showed significant protective effects against hypoxia-reoxygenation injury by increasing cell survival (Trypan blue staining) while reducing LDH activity and cell apoptosis (Hoechst staining). These effects were markedly reversed by naltrindole and were partially blocked by nor-binaltorphimine. Pretreatment of either PD98059 or wortmannin also abolished the protective effects of remifentanil. Following remifentanil preconditioning, the phosphorylation level of Akt reached peak at 10min of reoxygenation. ERK phosphorylation, however, was subsequently enhanced at 120min of reoxygenation. The phosphorylation levels of Akt and ERK were both blocked by naltrindole, but not nor-binaltorphimine or CTOP. Wortmannin inhibited the phosphorylation of both Akt and ERK, whereas PD98059 suppressed the phosphorylation of ERK only. In conclusion, our results suggested that remifentanil protected adult rat cardiomyocytes from hypoxia-reoxygenation injury and its effects appears to be dependent on the δ-opioid receptor mediated activation of PI3K/Akt and subsequent ERK signaling pathways.

Summary Background Surgical site infection (SSI) causes significant mortality and morbidity. Administration of a high inspired oxygen fraction (FiO 2 ) to patients undergoing surgery may represent a potential preventive strategy. Aim To conduct a meta-analysis of randomized controlled trials in which high FiO 2 was compared with normal FiO 2 in patients undergoing surgery to estimate the effect on the development of SSI. Methods A comprehensive search was undertaken for randomized controlled trials (until December 2015) that compared high FiO 2 with normal FiO 2 in adults undergoing surgery with general anaesthesia and reported on SSI. Findings This study included 17 randomized controlled trials with 8093 patients. Infection rates were 13.11% in the control group and 11.53% in the hyperoxic group, while the overall risk ratio was 0.893 [95% confidence interval (CI) 0.794–1.003; P = 0.057]. Subgroup analyses stratified by country, definition of SSI, and type of surgery were also performed, and showed similar results. However, high FiO 2 was found to be of significant benefit in patients undergoing colorectal surgery, with a risk ratio of 0.735 (95% CI 0.573–0.944; P =0.016). Conclusions There is moderate evidence to suggest that administration of high FiO 2 to patients undergoing surgery, especially colorectal surgery, reduces the risk of SSI. Further studies with better adherence to the intervention may affect the results of this meta-analysis.

Background MicroRNAs (miRNAs) have been implicated in ischemia-reperfusion injury and ischemic preconditioning. Opioid pre- and postconditioning have powerful protective effects on the heart, but it is still not known whether miRNAs are involved in opioid-induced cardioprotection. The present study was designed to investigate the role of miRNAs in morphine preconditioning (MPC)-induced cardioprotection. Methods MiRNA microarray analysis was performed to examine the differentially expressed miRNAs caused by MPC in adult rat cardiomyocytes. A dual-luciferase reporter assay was performed to confirm the direct regulation of miR-133b-5p on the target gene Fas . MiR-133b-5p mimic or inhibitor was separately transfected into myocardial H9c2 cells to examine the role of miR-133b-5p in morphine-induced cardioprotection. Results MPC protected adult rat cardiomyocytes against hypoxia/reoxygenation (H/R) injury by reducing cell injury and death. MiRNA microarray data showed that a total of 39 miRNAs were differentially expressed after MPC treatment. A Dual-luciferase reporter assay confirmed that miR-133b-5p directly targets the Fas gene. After H/R injury, the decrease in miR-133b-5p and a contemporaneous rise in Fas mRNA and protein levels in adult rat cardiomyocytes were prevented by MPC treatment. In H9c2 cardiomyocytes, overexpression of miR-133b-5p reduced H/R-induced cell injury and apoptosis by inhibiting Fas expression. Knockdown of miR-133b-5p blocked morphine-mediated cardioprotection by reducing miR-133b-5p levels while enhancing the expression of Fas mRNA and protein. Conclusions MPC causes a change in miRNA expression in rat cardiomyocytes. Morphine may protect cardiomyocytes against H/R injury through upregulation of miR-133b-5p by targeting Fas .

Morphine has been widely used as rescue treatment for heart attack and failure in humans for many decades. Relatively little has been known about the role of spinal opioid receptors in morphine cardioprotection. Recent studies have shown that intrathecal injection of morphine can reduce the heart injury caused by ischemia (I)/reperfusion (R) in rats. However, the molecular and cellular mechanisms underlying intrathecal morphine cardioprotection has not been determined. Here, we report that intrathecal morphine postconditioning (IMPOC) rescued mean artery pressure (MAP) and reduced myocardial injury in I/R. Pretreatment with either naloxone (NAL), a selective mu-opioid receptor antagonist, or nitric oxide synthase (NOS) inhibitors via intrathecal delivery completely abolished IMPOC cardioprotection, suggesting that the spinal mu-opioid receptor and its downstream NOS signaling pathway are involved in the mechanism of the morphine-induced effect. Consistent with this, IMPOC significantly enhanced spinal neural NOS phosphorylation, nitric oxide, and cGMP content in a similar time course. Intrathecal application of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a specific inhibitor of guanylate cyclase, completely ablated IMPOC-induced enhancement of cardioprotection and spinal cGMP content. IMPOC rescue of MAP and ischemic injury is correlated with IMPOC enhancement of NOS signaling. Collectively, these findings strengthen the concept of spinal mu-opioid receptors as a therapeutic target that mediates morphine-induced cardioprotection. We also provide evidence suggesting that the activation of spinal NOS signaling is essential for morphine cardioprotection.