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...

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 ...

Chronic ethanol exposure (CEE), which can lead to neuroinflammation, is an increasing risk factor for depression disorder, but the underlying mechanism is not clear. Recent observations have revealed the associations among psychiatric disorders, ethanol exposure and alterations of the gut microbiota. Here, we found that CEE induced depressive-like behavior, which could be alleviated by probiotics and transferred from donor to recipient mice by fecal microbiota transplantation (FMT). Neuroinflammation and the activation of the NLRP3 inflammasome were also observed in recipient mice. The downregulation of NLRP3 in the hippocampus mitigated CEE-induced depressive-like behavior and neuroinflammation but had no significant effect on FMT recipient mice. Moreover, elevated serum inflammatory factors in recipient mice showed a significant mediation effect between the gut microbiota and depressive-like behavior. Together, our study findings indicate that the gut microbiota contributes to both hippocampal NLRP3-mediated neuroinflammation and depressive-like behavior induced by CEE, which may open avenues for potential interventions against CEE-associated psychiatric disorders.

Inhaled antibiotics such as colistin and ciprofloxacin are increasingly used to treat bacterial lung infections in cystic fibrosis patients. In this study, we established and validated a new HPLC-MS/MS method that could simultaneously detect drug concentrations of ciprofloxacin, colistin and ivacaftor in rat plasma, human epithelial cell lysate, cell culture medium, and drug transport media. An aliquot of 200 μL drug-containing rat plasma or cell culture medium was treated with 600 μL of extraction solution (acetonitrile containing 0.1% formic acid and 0.2% trifluoroacetic acid (TFA)). The addition of 0.2% TFA helped to break the drug-protein bonds. Moreover, the addition of 0.1% formic acid to the transport medium and cell lysate samples could significantly improve the response and reproducibility. After vortexing and centrifuging, the sample components were analyzed by HPLC-MS/MS. The multiple reaction monitoring mode was used to detect the following transitions: 585.5–101.1 (colistin A), 578.5–101.1 (colistin B), 393.2–337.2 (ivacaftor), 332.2–314.2 (ciprofloxacin), 602.3–101.1 (polymyxin B1 as internal standard (IS)) and 595.4–101.1 (polymyxin B2 as IS). The running time of a single sample was only 6 min, making this a time-efficient method. Linear correlations were found for colistin A at 0.029–5.82 μg/mL, colistin B at 0.016–3.14 μg/mL, ivacaftor at 0.05–10.0 μg/mL, and ciprofloxacin at 0.043–8.58 μg/mL. Accuracy, precision, and stability of the method were within the acceptable range. This method would be highly useful for research on cytotoxicity, animal pharmacokinetics, and in vitro drug delivery.