Collectively, these findings indicate that EPO can ameliorate the myocardial inflammatory response in both in vitro and in vivo models of I/R. This beneficial effect of EPO is mediated by eNOS-derived NO via a PI3-kinase-dependent activation of AP-1.

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High mobility group box 1 (HMGB1) is an alarmin actively secreted by immune cells and passively released by necrotic nonimmune cells. HMGB1 has been implicated in both cardiac contractile dysfunction and the lethality associated with sepsis/endotoxemia. The aim of the current study was to assess whether viable cardiomyocytes could produce HMGB1 and whether HMGB1 can affect myocardial contractility. LPS was used as a model of sepsis/endotoxemia in mice and isolated cardiac myocytes. LPS increased myocardial expression of HMGB1 in vivo (immunohistochemistry) and production and secretion of HMGB1 by viable cardiac myocytes in vitro (Western). LPS increased the phosphorylation status of PI3Kgamma in cardiac myocytes, an effect not observed in TLR4(-/-) myocytes. Genetic (PI3Kgamma(-/-)) or pharmacologic (AS605240) blockade of PI3Kgamma ameliorated the LPS-induced 1) cardiomyocyte production and secretion of HMGB1 in vitro and 2) HMGB1 expression in the myocardium in vivo. The LPS-induced depression of myocardial contractility was prevented by the HMGB1 antagonist, A-box. Genetic (PI3Kgamma(-/-)) or pharmacologic (AS605240) blockade of PI3Kgamma ameliorated the LPS-induced decrease in myocardial contractility. No evidence of inflammatory infiltrate was noted in any of the in vivo studies. The findings of the current study indicate that 1) LPS can induce HMGB1 secretion by viable cardiac myocytes through a TLR4/PI3Kgamma signaling pathway, and 2) HMGB1 plays a role in the LPS-induced myocardial contractile dysfunction. The results of the current study also have broader implications (i.e., that viable parenchymal cells, such as cardiac myocytes, participate in the alarmin response).

1 Extracellular 5-hydroxytryptamine (5-HT) was determined in dorsal raphe nucleus (DRN), median raphe nucleus (MRN) and nucleus accumbens by use of microdialysis in unanaesthetized rats. 2 Infusion of the y-aminobutyric acid (GABA)A receptor agonist muscimol into DRN and MRN resulted in decreased 5-HT in DRN and MRN, respectively. Muscimol infusion into nucleus accumbens had no effect on 5-HT. 3 Infusion of the GABAA receptor antgonist bicuculline into DRN resulted in increased DRN and nucleus accumbens 5-HT. Bicuculline infusion into MRN had no effect on 5-HT. This suggests that endogenous GABA had a tonic, GABAA receptor-mediated inhibitory effect on 5-HT in DRN, but not in MRN. 4 Infusion of the GABAB receptor agonist baclofen into DRN produced a decrease in DRN 5-HT. Baclofen infusion into nucleus accumbens resulted in decreased nucleus accumbens 5-HT. This suggests that GABAB receptors are present in the area of cell bodies and terminals of 5-hydroxytryptaminergic neurones.5 Infusion of the GABAB receptor antagonists phaclofen and 2-hydroxysaclofen had no effect on midbrain raphe and forebrain 5-HT. This suggests that GABAB receptors did not contribute to tonic inhibition of 5-HT release. 6 In conclusion, 5-HT release is physiologically regulated by distinct subtypes of GABA receptors in presynaptic and postsynaptic sites.

Artificial optoelectronic synapses with both electrical and light‐induced synaptic behaviors have recently been studied for applications in neuromorphic computing and artificial vision systems. However, the combination of visual perception and high‐performance information processing capabilities still faces challenges. In this work, the authors demonstrate a memristor based on 2D bismuth oxyiodide (BiOI) nanosheets that can exhibit bipolar resistive switching (RS) performance as well as electrical and light‐induced synaptic plasticity eminently suitable for low‐power optoelectronic synapses. The fabricated memristor exhibits high‐performance RS behaviors with a high ON/OFF ratio up to 105, an ultralow SET voltage of ≈0.05 V which is one order of magnitude lower than that of most reported memristors based on 2D materials, and low power consumption. Furthermore, the memristor demonstrates not only electrical voltage‐driven long‐term potentiation, depression plasticity, and paired‐pulse facilitation, but also light‐induced short‐ and long‐term plasticity. Moreover, the photonic synapse can be used to simulate the “learning experience” behaviors of human brain. Consequently, not only the memristor based on BiOI nanosheets shows ultra‐low SET voltage and low‐power consumption, but also the optoelectronic synapse provides new material and strategy to construct low‐power retina‐like vision sensors with functions of perceiving and processing information.

High-mobility group box 1 (HMGB1) is a nuclear protein that has been implicated in the myocardial inflammation and injury induced by ischemia-reperfusion (I/R). The purpose of the present study was to assess the role of HMGB1 in myocardial apoptosis induced by I/R. In vivo, myocardial I/R induced an increase in myocardial HMGB1 expression and apoptosis. Inhibition of HMGB1 (A-box) ameliorated the I/R-induced myocardial apoptosis. In vitro, isolated cardiac myocytes were challenged with anoxia-reoxygenation (A/R; in vitro correlate to I/R). A/R-challenged myocytes also generated HMGB1 and underwent apoptosis. Inhibition of HMGB1 attenuated the A/R-induced myocyte apoptosis. Exogenous HMGB1 had no effect on myocyte apoptosis. However, inhibition of HMGB1 attenuated myocyte TNF-α production after the A/R was challenged; surprisingly, HMGB1 itself did not induce myocyte TNF-α production. Exogenous TNF-α induced a moderate proapoptotic effect on the myocytes, an effect substantially potentiated by coadministration of HMGB1. It is generally accepted that apoptosis induced by TNF-α is regulated by the balance of activation of c-Jun NH(2)-terminal kinase (JNK) and NF-κB. Indeed, in the present study, TNF-α increased the phosphorylation status of JNK and p65, a subunit of NF-κB; HMGB1 greatly potentiated TNF-α-induced JNK phosphorylation. Furthermore, inhibition of JNK (SP-600125) prevented the myocyte apoptosis induced by a TNF-α/HMGB1 cocktail. Finally, A/R increased HMGB1 production in both wild-type and toll-like receptor 4-deficient myocytes; however, deficiency in toll-like receptor 4 diminished A/R-induced myocyte apoptosis, TNF-α, and JNK activation. Our results indicate that myocyte-derived HMGB1 and TNF-α work in concert to promote I/R-induced myocardial apoptosis through JNK activation.

Opioid receptor subtypes may have site-specific effects and play different roles in modulating serotonergic neurotransmission in the mammalian central nervous system. To test this hypothesis, we used in vivo microdialysis to measure changes in extracellular serotonin (5-hydroxytryptamine; 5-HT) in response to local infusion of -, ␦-, and -opioid receptor ligands into the dorsal raphe nucleus (DRN), median raphe nucleus (MRN), and nucleus accumbens (NAcc) of freely behaving rats ]enkephalin (DPDPE), and deltophin-II into the DRN also increased extracellular 5-HT, an effect that was blocked by selective ␦-receptor antagonists. In contrast to the DRN, local infusion of -and ␦-opioids had no effect on 5-HT in the MRN or NAcc. These data indicate that -and ␦-opioid ligands have a selective influence on serotonergic neurons in the DRN. Finally, the -receptorbenzeneacetamide] produced similar decreases in 5-HT during local infusion into the DRN, MRN, and NAcc. These results provide evidence of differential regulation of 5-HT release by opioid receptor subtypes in the midbrain raphe and forebrain.The largest population of serotonergic cell bodies is located in the dorsal raphe nucleus (DRN) within the ventral portion of periaqueductal gray (PAG), an area richly endowed with opioids and involved in integrating responses to stress (Basbaum and Fields, 1984). Pain and stressful stimuli activate opioidergic neurons in the PAG, which in turn may modulate the activity of serotonergic neurons with projections to sites involved in arousal and emotional state (Ma and Han, 1992;Grahn et al., 1999). Immunocytochemical (Kalyuzhny et al., 1996) and neurochemical (Tao and Auerbach, 1995) studies provide further evidence that opioids modulate serotonergic neuronal activity. However, single unit recording data suggest that the opioid receptor agonist morphine does not directly stimulate serotonergic neurons (Haigler, 1978). Instead, opioids may inhibit both inhibitory and excitatory afferents to the DRN (Jolas and Aghajanian, 1997) and thus could indirectly affect the pattern of serotonergic neuronal discharge.Four types of opioid receptors, , ␦, , and ORL-1, have been identified on the basis of pharmacological and molecular criteria (Knapp et al., 1995;Neal et al., 1999). Endogenous ligands for opioid receptors have been determined, and these have distinct, albeit overlapping, patterns of distribution in the CNS (Mansour et al., 1995;Martin-Schild et al., 1999;Neal et al., 1999). In particular, the ventral PAG, which encompasses the DRN, has moderate to high densities of each of the endogenous opioids and corresponding opioid receptor types (Mansour et al., 1995;Neal et al., 1999). Moreover, there are distinctive and in some instances opposing physiological effects of selective agonists of the four opioid receptor types. For example, selective -opioid receptor agonists are strong analgesics but produce greater physical dependence relative to selective ␦-opioid receptor agonists (Maldonado et al., 1990). In contrast, -and ORL-1...

Patients are at high risk of developing serotonin-toxicity syndrome (toxidrome) when they take multiple serotonergic drugs, particularly co-administered with monoamine oxidase inhibitors or 5-hydroxytryptamine (5-HT) reuptake blockers. The toxidrome can vary from mild to severe. The primary goal of the present study was to understand the relationship between behavioral signs and degrees of toxidrome induced by 5-hydroxy-L-tryptophan (5-HTP) in clorgylinized rats. The severity was obtained by scoring behavioral signs including head shakes, penile erection, forepaw treading, hind limb abduction, Straub tail and tremor. It was found that 5-HTP produced a dosedependent increase in degrees of the toxidrome. Furthermore, correlation between the toxidrome and changes in body-core temperature (claudqcT cor ) was determined. There was hypothermia in the mild toxidrome (claudqcT cor < −1 °C), high hyperthermia in the severe toxidrome (claudqcT cor > +2 °C) and a small change in T cor in the moderate toxidrome (−1 °C < claudqcT cor < +2 °C). Thus, claudqcT cor in response to drugs can be used to estimate the severity of the toxidrome. The second attempt was to identify the receptors mediating those changes. 5-HT 1A receptors were involved in the hypothermic response while 5-HT 2A and NMDA receptors mediated head shakes, hyperthermia, forepaw treading and Straub tail. Lastly, antidotal effect of cyproheptadine and (+)-MK-801 was examined. Both drugs blocked hyperthermia and death. However, the effects on mortality became poor when the antidotes were injected 60 min after high hyperthermia had been induced. These findings demonstrate the importance of the time frame using antidotes in the treatment of the 5-HT toxidrome.