Fasudil is an inhibitor of Rhoa/ROCK signaling, which is involved in anti-inflammatory and anti-injury effects. The purpose of this study was to explore the effects of Fasudil on acetaminophen (APAP)-induced liver injury and reveal its potential molecular mechanism. In this study, C57BL/6 J mice were divided into different groups and treated with APAP and specified dose of Fasudil. HE staining was used to detect the changes of liver pathological tissues induced by APAP. ELISA assay was performed to detected the level of related factors. Western blot was used to detect the expressions of Rhoa, ROCK1, ROCK2. CD86 and CD6 were determined by RT-PCR and immunohistochemical staining detected the difference in CD86 expression. Rhoa/ROCK expression was increased in APAP-induced liver injury, and Fasudil targeted the expression of Rhoa/ROCK. Fasudil inhibits APAP-induced hepatic pathological changes and liver function injury. Fasudil inhibits the release of APAP-induced systemic inflammatory factors in liver tissue. Fasudil inhibits the activity of antioxidant enzymes, lipid peroxidation and macrophage infiltration induced by APAP in liver tissues. Fasudil alleviates APAP-induced liver injury via targeting Rhoa/ROCK signal pathway, indicating the possibility for clinical use of Fasudil in APAP-induced liver injury.

Myocardial ischemia/reperfusion (I/R) injury could lead to severe cardiovascular ischemic disease, including myocardial infarction and contractile dysfunction. Remifentanil demonstrated protective effect on myocardial I/R injury. The underlying pathophysiological mechanism was then investigated in this study. In the current study, primary cardiomyocytes were isolated from rats, and then preconditioned with remifentanil. Rats, tail vein injected with miR-205 antagomir, were subjected to infusion of remifentanil, and then subjected to regional ischemia followed by reperfusion. The results demonstrated that cell viability of hypoxia/reoxygenation-induced cardiomyocytes was increased post remifentanil, while the apoptosis was decreased accompanied with reduced cleaved caspase-3 expression. Hypoxia/reoxygenation treatment increased miR-205 and decreased PINK1 (PTEN induced putative kinase 1) expression. However, preconditioning with remifentanil reduced miR-205 and enhanced PINK1. Moreover, over-expression of miR-205 decreased PINK1 expression and counteracted the effects of remifentanil-induced increase of cell viability and decrease of cell apoptosis in hypoxia/reoxygenation-induced cardiomyocytes. Injection with miR-205 antagomir improved remifentanil-induced decrease of infarct size and LDH (lactic acid dehydrogenase) activity in rat model with I/R injury. In conclusion, miR-205 might participate in the protective effect of remifentanil in rat myocardial I/R injury via regulation of PINK1, providing a potential target for amelioration of cardiovascular ischemic disease.

Quantum dots (QDs) are new types of fluorescent nanomaterials which can be utilized as ideal agents for intracellular tracking, drug delivery, biomedical imaging and diagnosis. It is urgent to understand their potential toxicity and the interactions with the toxin-susceptible vascular system, especially vascular endothelial cells. In this study, we intended to explore whether the cytotoxicity of CdTe (cadmium telluride) QDs was partly induced by nitrosative stress in vascular endothelial cells. Our results showed that the intracellular amount of CdTe QDs was gradually increased in a dose- and time-dependent manner, and a concentration-dependent decrease in viability were observed when incubated with CdTe QDs of 20-80 nM. The peroxynitrite level was significantly up-regulated by QDs treatment, which indicated the nitrosative stress was activated. Furthermore, nitrotyrosine level was increased after 24 hr CdTe QDs exposure in a dose-dependent manner, which suggested that CdTe QDs-induced nitrosative stress was associated with tyrosine nitration in EA.hy926. In addition, CdTe QDs induced EA.hy926 apoptosis, and the percentage of cells with low Δψm was increased after CdTe QDs treatment, indicating the mitochondrion depolarization was induced. The increased ROS fluorescence was observed in a QDs dose-dependent manner, which suggested that the oxidative stress was also involved in the CdTe QDs-induced endothelial cytotoxicity. Our work provided experimental evidence into QDs toxicity and potential vascular risks induced by nitrosative stress for the future applications of QDs.

Abasic sites are formed in cells by various factors including environmental mutagens and considered to be involved in cancer initiation, promotion, and progression. A chemically stable abasic site analog (tetrahydrofuran-type analog, THF) induces untargeted base substitutions as well as targeted substitution and large deletion mutations in human cells. The untargeted substitutions may be initiated by the cleavage of the DNA strand bearing THF by the human apurinic/apyrimidinic endonuclease 1 (APE1) protein, the major repair enzyme for THF and abasic sites. To examine the effects of lower APE1 levels, the protein was knocked down by siRNA in human U2OS cells. A plasmid containing a single THF modification outside the supF gene was introduced into the knockdown cells, and the untargeted substitution mutations in the reporter gene were analyzed. Unexpectedly, the knockdown had no evident impact on their frequency and spectrum. The G bases of 5′-GpA-3′ dinucleotides on the modified strand were quite frequently substituted, with and without the APE1 knockdown. These results suggested that the DNA strand cleavage by APE1 is not essential for the THF-induced untargeted base substitutions.

Background: Harmine is a β-carboline alkaloid that displays antidepressant, antitumor and other pharmacological effects. However, the strong toxic effects limit its clinical application, and should be first considered. Purpose: To evaluate the in vivo toxicity of harmine and explore intervention strategies against its toxicity. Methods: The in vivo toxicity of harmine was assessed from the symptoms, biochemical indices, and cardiovascular effects in mice. The intervention experiments were performed by using anesthetics, central drugs, and peripheral anticholinergics. Results: The acute toxicity of harmine is significantly dose-dependent and the median lethal dose is 26.9 mg/kg in vivo. The typical symptoms include convulsion, tremor, jumping, restlessness, ataxia, opisthotonos, and death; it also changes cardiovascular function. The anesthetics improved the survival rate and abolished the symptoms after harmine poisoning. Two central inhibitors, benzhexol and phenytoin sodium, uniformly improved the survival rates of mice poisoned with harmine. The peripheral anticholinergics didn’t show any effects. Conclusion: Harmine exposure leads to central neurological symptoms, cardiovascular effects and even death through direct inhibition of the central AChE activity, where the death primarily comes from central neurological symptoms and is cooperated by the secondary cardiovascular collapse. Central inhibition prevents the acute toxicity of harmine, and especially rapid gaseous anesthetics such as isoflurane, might have potential application in the treatment of harmine poisoning.

Methylmercury (MeHg), the causal substrate in Minamata disease, can lead to severe and chronic neurological disorders. The main symptom of Minamata disease is sensory impairment in the four extremities; however, the sensitivity of individual sensory modalities to MeHg has not been investigated extensively. In the present study, we performed stimulus-response behavioral experiments in MeHg-exposed rats to compare the sensitivities to pain, heat, cold, and mechanical sensations. MeHg (6.7 mg/kg/day) was orally administered to 9-week-old Wistar rats for 5 days and discontinued for 2 days, then administered daily for another 5 days. The four behavioral experiments were performed daily on each rat from the beginning of MeHg treatment for 68 days. The pain sensation decreased significantly from day 11 onwards, but recovered to control levels on day 48. Other sensory modalities were not affected by MeHg exposure. These findings suggest that the pain sensation is the sensory modality most susceptive to MeHg toxicity and that this sensitivity is reversible following discontinuation of the exposure.