Ibogaine Has Sex-Specific Plasma Bioavailability, Histopathological and Redox/Antioxidant Effects in Rat Liver and Kidneys: A Study on Females

Ibogaine induces rapid changes in cellular energetics followed by the elevation of antioxidant activities. As shown earlier in male rats, ibogaine treatment with both 1 and 20 mg/kg b.w. per os led to significant glycogenolytic activity in the liver. In this work, female rats treated with the same doses of ibogaine per os displayed lower liver glycogenolytic activity relative to males, dilatation of the central vein and branches of the portal vein, and increased concentration of thiols 6 h after treatment. These changes were followed by increased catalase activity and lipid peroxidation, and decreased xanthine oxidase activity after 24 h. In kidneys, mild histopathological changes were found in all treated animals, accompanied by a decrease of glutathione reductase (after 6 and 24 h at both doses) and an increase of catalase (6 h) and xanthine oxidase activity (6 and 24 h). Ibogaine did not affect antioxidant enzymes activity in erythrocytes. Bioavailability of ibogaine was two to three times higher in females than males, with similar kinetic profiles. Compared to previous results in males, ibogaine showed sex specific effect at the level of antioxidant cellular system. Effects of ibogaine in rats are sex- and tissue-specific, and also dose- and time-dependent.

lncRNA MIR600HG Knockdown Alleviates Cognitive Impairment in Alzheimer’s Disease Through NEDD4L Mediated PINK1 Degradation

Background: Growing evidence has demonstrated that long non-coding RNAs (lncRNAs) play a critical role in Alzheimer’s disease (AD), which is characterized by sustained mitochondrial dysfunction, inevitable memory loss, and cognitive decline. However, the potential function of lncRNAs MIR600 Host Gene (MIR600HG) in AD remains unanswered. Objective: Our study aimed to investigate the role of MIR600HG and its related molecular mechanism in AD. Methods: The expression of MIR600HG was examined by qRT-PCR. The MIR600HG interacting proteins were identified by RNA pull-down assay and mass spectrometry and verified by RNA immunoprecipitation. Immunofluorescence staining was applied to examine the colocalization of PINK1 and NEDD4L. The PINK1 level and the activation of autophagy were detected by immunoblotting. Morris water maze test was performed to evaluate cognitive decline in AD mice model. Results: MIR600HG expression was elevated during aging in two different types of AD transgenic mouse models. Next, we found that increased MIR600HG directly interact with NEDD4L, which promoted PINK1 ubiquitination and degradation, and as well as autophagy activation. Additionally, MIR600HG promoted Aβ production and suppressed Cytochrome C Oxidase activity. Administration of AAV-shMIR600HG restored the Cytochrome C Oxidase activity and inhibited Aβ production. Furthermore, PINK1 overexpression or MIR600HG knockdown significantly ameliorated the cognitive impairment in APP/PS1 mice. PINK1 depletion recovered the spatial memory defect in the AAV-shMIR600HG injected APP/PS1 mice. Conclusion: MIR600HG was increased in AD and promoted AD pathogenesis. Targeting MIR600HG significantly improved cognitive function in AD mice, which could pave the way for exciting new avenues in AD therapeutic strategy research.

Relationship Between Plasma Cell-Free DNA Changes and Lysyl Oxidase During the Treatment and Prognosis of Canine Transmissible Venereal Tumor

BackgroundTransmissible Venereal Tumor (TVT) is a wide tumor of canine, there are no effective markers to monitor the therapeutic response in real-time. Circulating biomarkers may be valuable for the early diagnosis and prognosis of cancers, so in this study, we aimed to investigate the significance of the cell-free DNA (cfDNA) and cfDNA integrity index to monitor the response of TVT to vincristine and compare them with lysyl oxidase activity. Plasma and sera were collected before drug administration within four weeks from fifteen male dogs. The analytical method was mainly based on quantitative polymerase chain reaction for short and long cfDNA, and lysyl oxidase activity was measured in serum.ResultsThe results of cfDNA integrity index showed significant (p<0.05) difference in a baseline to 2nd and 3rd week (with cut-off value 1.118 and 93.33% specificity). We found that the cfDNA integrity index was increased during weeks due to the reduction of shorts cfDNA in the 1st week after treatment. lysyl Oxidase activity was increased during the 4th week (p<0.001) but there were no significant differences in the other weeks compared to baseline. ROC analysis of lysyl Oxidase revealed high sensitivity (100%) and specificity (93%) 2nd, 3rd weeks on comparison between Baseline. Multivariate analysis between cfDNA integrity index and lysyl Oxidase showed significant correlation (p<0.05) only baseline results. ConclusionsTaken together, we propose short cfDNA, cfDNA integrity index, and lysyl Oxidase activity as a diagnostic biomarker and a putative prognostic candidate in TVT patients. These biomarkers could be used simultaneously for quickly diagnose TVT in combination with cytology.