Ketamine is a noncompetitive antagonist of N-methyl-d-asparate (NMDA) receptor and has been long used as an anesthetic agent in humans and veterinary medicine. The present article reviews the epidemiology, pharmacology, neurochemistry, and treatment of ketamine abuse. Ketamine has a unique mood controlling property and a number of studies have demonstrated a significant and rapid antidepressant effect of ketamine. However, the therapeutic value of ketamine to treat psychiatric disorders faces a major challenge that ketamine also owns significant reinforcing and toxic effects. Its abuse has posted severe harms on individuals and society. Disrupted learning and memory processing has long been related with ketamine use. It is hypothesized that ketamine blocks NMDA receptors on gamma-aminobutyric acid (GABA) neurons inside the thalamic reticular nucleus, which leads to disinhibition of dopaminergic neurons and increased release of dopamine. Currently, there is no specific treatment for treating every ketamine patient presenting peripheral toxicity. Interestingly, ketamine psychotherapy has been suggested to be a promising approach to treat addiction of other drugs. Future research can continue to develop creative ways to investigate potential mechanism and treatments related to ketamine abuse that have posted severe individual and social harms.

It has been demonstrated that the anti-oxidative and cardioprotective effects of melatonin are, at least in part, mediated by its membrane receptors. However, the direct downstream signaling remains unknown. We previously found that melatonin ameliorated myocardial ischemia-reperfusion (MI/R) injury in diabetic animals, although the underlying mechanisms are also incompletely understood. This study was designed to determine the role of melatonin membrane receptors in melatonin's cardioprotective actions against diabetic MI/R injury with a focus on cGMP and its downstream effector PKG. Streptozotocin-induced diabetic Sprague-Dawley rats and high-glucose medium-incubated H9c2 cardiomyoblasts were utilized to determine the effects of melatonin against MI/R injury. Melatonin treatment preserved cardiac function and reduced oxidative damage and apoptosis. Additionally, melatonin increased intracellular cGMP level, PKGIα expression, p-VASP/VASP ratio and further modulated myocardial Nrf-2-HO-1 and MAPK signaling. However, these effects were blunted by KT5823 (a selective inhibitor of PKG) or PKGIα siRNA except that intracellular cGMP level did not changed significantly. Additionally, our in vitro study showed that luzindole (a nonselective melatonin membrane receptor antagonist) or 4P-PDOT (a selective MT receptor antagonist) not only blocked the cytoprotective effect of melatonin, but also attenuated the stimulatory effect of melatonin on cGMP-PKGIα signaling and its modulatory effect on Nrf-2-HO-1 and MAPK signaling. This study showed that melatonin ameliorated diabetic MI/R injury by modulating Nrf-2-HO-1 and MAPK signaling, thus reducing myocardial apoptosis and oxidative stress and preserving cardiac function. Importantly, melatonin membrane receptors (especially MT receptor)-dependent cGMP-PKGIα signaling played a critical role in this process.

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M2-tumor associated macrophages (TAMs) play an important role in tumor genesis, progression, and metastasis, and repolarizing M2-TAMs to immune-promoting M1 type is increasingly recognized as a promising strategy against the clinically intractable carcinomas. It is observed that M2 macrophages have a high tropism to the tumor hypoxic area, with their endoplasmic reticulum (ER) stress-associated IRE1-XBP1 pathway activated to inhibit cell glycolysis, promote oxidative phosphorylation (OXPHOS), and facilitate intracellular lipid accumulation, which in turn shapes the typical phenotypes of M2-TAMs, suggesting that manipulating the ER stress response of M2-TAMs might stand as a breakthrough for antitumor therapy. However, current attempts to repolarize M2 cells remain limited and are greatly challenged by the hypoxic nature of tumors. Also, the high level of reactive oxygen species (ROS) in the tumor microenvironment (TME) is favorable for the polarization of M2-TAMs. Here, we encapsulated KIRA6, an inhibitor of the IRE1-XBP1 pathway, into a reductive nanoemulsion containing α-tocopherol. Our α-T-K had dual inhibitory effects on the ER stress and oxidative stress. Both in vitro and in vivo experiments suggested that α-T-K effectively reprogrammed M2 macrophages even under hypoxia, achieved by increasing glycolysis and suppressing fatty acid oxidation (FAO). In addition, our data revealed that α-T-K not only delayed tumor growth but elevated the curative effect of PD-1 antibody. Our research demonstrated that simultaneous inhibition of ER stress and oxidative stress could effectively repolarize M2-TAMs under hypoxia, which not only filled the current gap in regulating the biological repolarization of macrophages under hypoxia but provided a meaningful reference for the clinical immunotherapy of sensitized anti-PD-1.

Danshen is commonly used in China for the treatment of atherosclerosis-related disorders such as cardiovascular and cerebrovascular diseases. Research shows that it also has immunostimulation properties. The present study evaluates the protective effect of danshensu, an active water-extractable component isolated from danshen, on an endothelial cell line (CRL-1730) treated with hydrogen peroxide (H 2 O 2 ). Danshensu significantly inhibited endothelial cell viability induced by H 2 O 2 . The treatment of endothelial cells with danshensu resulted in most cells being arrested in the S and G 2 /M phases of the cell cycle. The fraction of cells in G 0 /G 1 phase was markedly decreased by danshensu treatment compared to the control groups. The apoptosis was also markedly decreased after danshensu treatment. Additionally, danshensu restrains decreased nitric oxide level, increased the release of lactate dehydrogenase and expression of cluster of differentiation 40 (CD40) significantly. These results suggest that danshensu protects endothelial cells from the damage induced by H 2 O 2 through its CD40 anti-inflammatory approach and cell apoptosis inhibition.Danshen, a traditional Chinese herbal medicine, is the dried roots of the plant Salvia miltiorrhiza Bunge belonging to the Labiata family. It has often been used in the prevention of cardiovascular and cerebrovascular diseases such as atherosclerosis, myocardial infarction [1]. It is known that danshen contains hydrophilic phenolics (salvianolic acid B and danshensu) and lipophilic quinines (tanshinone I, tanshinone IIA) and displays various pharmacological properties [2]. The effect of danshen on cardiovascular diseases is partially attributed to the anti-atherosclerosis property of danshensu.In vitro experiments indicate that tanshinone IIA can decrease the expression of intercellular adhesion molecular-1 in human umbilical vein endothelial cells (HUVEC) induced by tumour necrosis factor-α (TNF-α ) and inhibit the oxidation of low-density lipoprotein [3,4]. Moreover, our studies show that tanchinone IIA has a protective effect against apoptosis of endothelial cells injured by H 2 O 2 via decrease of the content of malondialdehyde [5]. However, since the water decoction is the commonly used preparation/method in preparing Chinese folk medicine for human consumption, current research is focused on the water-soluble compounds. Danshensu has received much attention as it is an abundant active constituent. The cell membrane stationary phase from the transient over the expression of cluster of differentiation (CD40) in HUVEC was prepared and used to screen the effective anti-atherosclerotic components of danshen extracts. Based on the cell membrane stationary phase experiments, it has been clearly shown that tanshinone IIA and danshensu have much higher activity than other components from danshen extracts [6]. Previous studies have established that the tanshinone IIA protective effect against atherosclerosis is mediated by decreasing the expression of CD40 in v...

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