Paraquat (PQ) is a non-selective herbicide and is exceedingly toxic to humans. The mechanism of PQ toxicity is very complex and has not been clearly defined. There is no specific antidote for PQ poisoning. 5-hydroxy-1-methylhydantoin (HMH) is an intrinsic antioxidant and can protect against renal damage caused by PQ. The mechanism of PQ toxicology and the possible effects of HMH on PQ-induced lung injury were determined in this study. It was found that PQ decreased superoxide dismutase (SOD) activity and elevated the level of malondialdehyde (MDA), while HMH elevated SOD activity and decreased the level of MDA. Based on metabolomics, the citrate cycle, glutathione metabolism, taurine and hypotaurine metabolism, regulation of lipolysis in adipocytes, inflammatory mediator regulation of tRp channels, purine and pyrimidine metabolism, aldosterone synthesis and secretion, and phenylalanine metabolism were changed in the PQ group. Compared with the PQ group, the levels of N-acetyl-l-aspartic acid, L-glutamic acid, L-aspartic acid, mesaconic acid, adenosine 5′ monophosphate, methylmalonic acid, cytidine, phosphonoacetic acid, hypotaurine, glutathione (reduced) and cysteinylglycine increased, while the levels of corticosterone, xanthine, citric acid, prostaglandin G2, 4-pyridoxic acid and succinyl proline decreased in the HMH group. These metabolites revealed that HMH can alleviate inflammation caused by PQ and elevate the activity of intrinsic antioxidants. In conclusion, our results revealed PQ toxicology and the pharmacology underlying the protective effect of HMH on lung injury due to PQ. Toxicity caused by PQ results in lipid peroxidation and an increase in reactive oxygen species (RoS), nitric oxide (no), damage to the biliary system, gastrointestinal system and nervous system, in addition to lungs, kidneys, and the liver. HMH is a good antioxidant and protects against lung injury caused by PQ. In summary, HMH efficiently reduced PQ-induced lung injury in mice. Paraquat (PQ, 1,1′-dimethyl-4-4′-bipyridinium dichloride) is a highly toxic quaternary ammonium herbicide widely used in agriculture. The mortality rate of PQ poisoning is as high as 60-80%, mainly due to acute lung injury and progressive pulmonary fibrosis 1-3. Moreover, there is no specific antidote for PQ poisoning. Following PQ poisoning, the lungs are the main target organs, and the redox reaction occurs after the uptake of PQ in the lungs, which interferes with mitochondrial electron transfer, generates a large number of oxygen free radicals, and induces lipid peroxidation injury 2. PQ enters the body and is excreted in the form of a prototype in the kidney, where the concentration is highest, resulting in impaired renal function. PQ cannot be excreted normally and further accumulates in the body; thus, involving other organs such as the liver, heart and lung, resulting in multiple organ failure 2. Creatinine is a degradation product of creatine, which is degraded at a constant rate. When renal function is impaired, large amounts of creatinine are acc...

Tau protein is known to play an important role in maintaining microtubule assembly and stabilization, and maintaining the normal morphology of neurons, but several studies have found that chronic stress leads to Tau hyperphosphorylation. A large number of clinical trials have found that ketamine, which is an N-methyl-D-aspartate receptor antagonist, produces a rapid, long-lasting, and potent antidepressant effect in patients suffering from major depression. This rapid antidepressant effect of ketamine, which involves many mechanisms, has attracted wide attention. However, the relationship between ketamine’s antidepressant effects and Tau protein has rarely been examined. We used C57BL/6 and Tau KO mice exposed to 42 days of chronic unpredictable mild stress (the CUMS model) to investigate the effect of ketamine on behavioral changes and synaptic functioning of the hippocampus. The results showed that a single treatment of ketamine rapidly relieved the CUMS-induced anhedonia, depression-like, and anxious behaviors of the C57BL/6 mice. The abnormal behaviors were accompanied by increased levels of specific alterations of hyperphosphorylated Tau protein in cytoplasm and synapse in the hippocampus of the C57BL/6 mice, but ketamine reduced the aggregation of hyperphosphorylated Tau protein only in the synapse. We also found that CUMS exposure reduced the levels of GluA1 and PSD95 in the hippocampus of the C57BL/6 mice and that these deficits were reversed by ketamine. However, the Tau KO mice did not develop any stress-induced depressive behaviors or deficits of hippocampal function. The antidepressant effect of ketamine may decrease the levels of hyperphosphorylated Tau protein in synapse of C57BL/6 mice.

tramadol is an opioid used as an analgesic for treating moderate or severe pain. the long-term use of tramadol can induce several adverse effects. The toxicological mechanism of tramadol abuse is unclear. Metabolomics is a very useful method for investigating the toxicology of drug abuse. We investigated the impact of chronic tramadol administration on the cerebrum of mice, focusing on the metabolites after tramadol administration. The mice received 20 or 50 mg/kg body weight tramadol dissolved in physiological saline daily for 5 weeks via oral gavage. Compared with the control group, the low dose tramadol group showed seven potential biomarkers, including gamma-hydroxybutyric acid, succinate semialdehyde, and methylmalonic acid, which were either up-or down-regulated. Compared with the control group, the high dose tramadol group showed ten potential biomarkers, including gamma-hydroxybutyric acid, glutamine, and O-phosphorylethanolamine, which were either up-or down-regulated. the up-regulated gamma-hydroxybutyric acid and the downregulated succinate semialdehyde revealed that the neurotransmitter system was disrupted after tramadol abuse. Compared with the low dose tramadol group, there were twenty-nine potential biomarkers in the high dose tramadol group, mainly related to the pentose phosphate pathway and glycerophospholipid metabolism. In conclusion, metabolomics in the tramadol abuse group demonstrated that long-term tramadol abuse can result in oxidative damage, inflammation, and disruption of the GABA neurotransmitter system, which will help to elucidate the toxicology of tramadol abuse. Tramadol is an effective analgesic agent for the treatment of moderately severe pain 1. Tramadol is considered to exert analgesic effects by binding the μ-opioid receptors and modulating the noradrenergic, GABAergic and serotonergic systems 2, 3 , or by acting as a serotonin-norepinephrine (NE) reuptake inhibitor 4. Tramadol in clinical not only can be used in general surgery, obstetrics, pediatrics and the treatment of oral surgery, as well as a variety of acute postoperative pain, is also used to relieve chronic pain, such as cancer 5. Because its analgesic action time is longer;its analgesia intensity decreased slowly, it is a relatively ideal drug for chronic pain medication.Most common side effects of tramadol include nausea, vomiting, sweating, fatigue, sedation 6, 7 , and dry mouth 8. More severe side effects include angioedema, increased effect of anticoagulants, hypoglycemia 7, 9 and serotonin toxicity 8 .Tramadol was identified as a controlled substance in the USA and UK (schedule IV drug) in 2014 10, 11 , and is also a controlled psychotropic substance in China, as more young people are abusing it to obtain psychological satisfaction. Having a lower affinity for the μ-opioid receptor, Tramadol has shown to have a lower risk for addiction with chronic use when compared with other opiates e.g. morphine and oxycodone 9, 12. Thus, many studies on the risks of opioid abuse have excluded tramadol 12-14. Mohamed HM 4 ...

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Stroke causes degeneration and death of neurones leading to the loss of motor function and frequent occurrence of cognitive impairment and depression. Lithium (Li+), the archetypal mood stabiliser, is neuroprotective in animal models of stroke, albeit underlying mechanisms remain unknown. We discover that Li+ inhibits activation of nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in the middle cerebral artery occlusion (MCAO) stroke model in mice. This action of Li+ is mediated by two signalling pathways of AKT/GSK3β/β-catenin and AKT/FoxO3a/β-catenin which converge in suppressing the production of reactive oxygen species (ROS). Using immunocytochemstry, MRI imaging, and cell sorting with subsequent mRNA and protein quantification, we demonstrate that Li+ decreases the infarct volume, improves motor function, and alleviates associated cognitive and depressive impairments. In conclusion, this study reveals molecular mechanisms of Li+ neuroprotection during brain ischaemia, thus providing the theoretical background to extend clinical applications of Li+ for treatment of ischemic stroke.