Human & Experimental Toxicology

Shalkami, Abdel-Gawad S.; El-Shoura, Ehab A. M.; Hassan, Mohammed I. A.

doi: 10.1177/09603271241269003pmid: 39080824

PurposeDrug-induced liver injury is becoming an increasingly important topic in drug research and clinical practice. Due to a lack of experimental animal models, predicting drug-induced liver injury in humans is challenging. Azathioprine (AZA) is a classical immunosuppressant with hepatotoxic adverse effects. The present study aimed to address the hepatoprotective effect of carvedilol (CAR) against AZA-induced hepatocellular injury via assessing redox-sensitive signals.MethodTo achieve this purpose, rats were allocated into four groups: control, CAR only, AZA only, and CAR plus AZA groups. The induction of hepatic injury was induced by a single intraperitoneal injection of AZA at a dose of 50 mg/kg on the 6th day of the experiment. Each experimental protocol was approved and supervised by the Ethics Committee for Animal Experiments.ResultsThe results of the present study revealed that CAR administration significantly diminished AZA-induced hepatic dysfunction, as evidenced by relief of hepatic function biomarkers and histopathological aberration induced by AZA injection. Besides, CAR restored oxidant/antioxidant balance as well as NRF2 expression. In addition, CAR suppressed inflammatory response induced by AZA challenge as evidenced by downregulation of TLR4, TNF-α, MPO, and eNOS/iNOS levels in hepatic tissue. Moreover, CAR recovered apoptotic/anti-apoptotic status by modulation of caspase-3/Bcl2 expression.ConclusionTaken together, CAR protects against AZA-induced hepatic injury via antioxidant, anti-inflammatory, and anti-apoptotic activities. These findings revealed that CAR could be a good candidate for hepatic injury protection and can be added to AZA therapeutic regimen to reduce their adverse effect.

Oldham, Michael J; Desai, Rahat Wadhwa; Randazzo, James; Walling, Brent E; Lalonde, Guy; Weil, Roxana

doi: 10.1177/09603271241269022pmid: 39101688

BackgroundOne of the challenges to using some flavor chemicals in aerosol products is the lack of route of administration specific toxicology data.MethodsFlavor chemicals (88) were divided into four different flavor mixtures based upon chemical compatibility and evaluated in 2-week dose-range-finding and subsequent 90-day nose-only rodent inhalation studies (OECD 413 and GLP compliant). Sprague-Dawley rats were exposed to vehicle control or one of three increasing concentrations of each flavor mixture.ResultsIn the dose-range-range-finding studies, exposure to flavor mixture four resulted in adverse nasal histopathology in female rats at the high dose, resulting in this flavor mixture not being evaluated in a 90-day study. In the 90-day studies daily exposures to the three flavor mixtures did not induce biologically meaningful adverse effects (food consumption, body weights, respiratory physiology, serum chemistry, hematology, coagulation, urinalysis, bronchoalveolar lavage fluid analysis and terminal organ weights). All histopathology findings were observed in both vehicle control and flavor mixture exposed animals, with similar incidences and/or severities, and therefore were not considered flavor mixture related.ConclusionBased on the absence of adverse effects, the no-observed-adverse-effect concentration for each 90-day inhalation study was the highest dose tested, 2.5 mg/L of the aerosolized high dose of the three flavor mixtures.

Jin, Yutong; Li, Zhengyang; Qi, Lin; Zhang, Lingling; Gao, Dandan; Liu, Haizhao; Cao, Qingwen; Tian, Chenchen; Xia, Qun; Wang, Yue

doi: 10.1177/09603271241269028pmid: 39197164

Background and objectiveThe objective of this study was to investigate the potential of salidroside (SAL) (a major active compound in Rhodiola rosea L.) in regulating osteoclast differentiation and function by modulating the HIF-1α pathway and its downstream target genes.MethodsThe expression of HIF-1α and its downstream target genes was examined at both mRNA and protein levels in osteoclasts treated with SAL. Immunofluorescence analysis was performed to assess the nuclear translocation and transcriptional activity of HIF-1α in response to SAL. MTT, flow cytometry, qPCR, TRAP staining and bone resorption assays were used to evaluate the potential effect of salidroside on osteoclasts.ResultsSAL enhanced the expression of HIF-1α and its downstream target genes in osteoclasts. Immunofluorescence analysis confirmed the facilitation of HIF-1α nuclear translocation and transcriptional activity by SAL. In addition, SAL enhanced osteoclast viability, differentiation and bone resorption activity in an autocrine manner through HIF-1α/VEGF, IL-6 and ANGPTL4 pathways.ConclusionSAL promotes osteoclast proliferation, differentiation and bone resorption through HIF-1α/VEGF, IL-6 and ANGPTL4 pathways.

Cheung, Kwun Lok; Lam, Rex Pui Kin; Chan, Chi Keung; Tse, Man Li; Tsui, Matthew Sik Hon; Rainer, Timothy Hudson

doi: 10.1177/09603271241269024pmid: 39075331

IntroductionCocaine is commonly consumed with ethanol, which leads to the formation of cocaethylene through transesterification. Cocaethylene is an active metabolite of cocaine with a longer duration of action. Literature on the combined toxicity of cocaine, ethanol, and cocaethylene is conflicting. We aimed to compare the acute toxicities of co-exposure to cocaine and ethanol versus cocaine alone in Hong Kong.MethodsThis was a retrospective study on acute cocaine toxicities reported to the Hong Kong Poison Control Center from 1 January 2010 to 22 January 2023. Cocaine exposure was confirmed by urine immunoassays/laboratory tests and ethanol co-ingestion was confirmed by blood ethanol concentrations. A serious outcome was defined as a National Poison Data System outcome moderate or above. Univariate analyses and multivariable logistic regression were performed to compare the associations of clinical outcomes with and without ethanol, followed by subgroup analyses of cases with complete data.ResultsWe analyzed 109 patients (median age 29 years, 71% men, 68% Chinese), of whom 20 had confirmed ethanol co-ingestion (mean blood ethanol concentration 1350 mg/L). Multivariable analysis showed that co-exposure to cocaine and ethanol was associated with a lower risk of serious outcomes (adjusted odds ratio 0.09, 95% confidence interval 0.01–0.77; p = 0.03) after adjusting for age, sex, ethnicity, route of cocaine administration, and physical health status. Subgroup analyses showed similar findings.ConclusionsIn contrast to previous studies, we did not identify a higher risk of serious outcomes after co-exposure to cocaine and ethanol compared to cocaine alone in a predominantly Chinese cohort.

Zhang, Xiaolong; Wang, Yiqiao; Xu, Feng; Zhao, Binbin; Liang, Xiangnan; Shu, Jianwei

doi: 10.1177/09603271241269021pmid: 39441175

BackgroundPropofol, a commonly utilized anesthetic, has been shown to induce neurotoxicity in developing neurons. A previous study showed that microRNA (miR)-138-5p was dysregulated in hippocampus tissue of mice administrated with propofol. The current study aimed to investigate the functions of miR-138-5p and its target gene in propofol-induced neurotoxicity.MethodsSH-SY5Y neuronal cells were treated with increasing doses of propofol for indicated time to identify the optimal concentration and treatment time. MiR-138-5p and SIRT1 expression in SH-SY5Y neuronal cells stimulated with propofol were measured by RT-qPCR. Western blotting was performed to quantify protein levels of SIRT1 and autophagy markers. After interference of miR-138-5p and/or SIRT1 expression, the toxicity of SH-SY5Y neuronal cells was evaluated by cell counting kit-8 (CCK-8) assays and flow cytometry. The formation of autophagosomes was estimated by monodansylcadaverine staining.ResultsPropofol induced neurotoxicity in a dose- or time-dependent manner. Propofol upregulated miR-138-5p while downregulating SIRT1 in SH-SY5Y neuronal cells. The propofol-stimulated neurotoxicity and autophagy was inhibited by miR-138-5p knockdown. Moreover, miR-138-5p bound to SIRT1 3′untranslated region. SIRT1 overexpression increased cell viability while inhibiting apoptosis and autophagy in the context of propofol. SIRT1 downregulation reversed the ameliorative effect of miR-138-5p inhibition on propofol-induced neurotoxicity and autophagy.ConclusionDownregulation of miR-138-5p alleviates propofol-induced neurotoxicity and autophagy via upregulation of SIRT1.

Klotz, James L; Britt, Jessica L; Greene, Maslyn A; Kent-Dennis, Coral; Duckett, Susan K

doi: 10.1177/09603271241269027pmid: 39259645

Consumption of ergot alkaloids during the second half of gestation has been shown to decrease umbilical artery vasoactivity resulting in decreased birth weights. Negative vascular effects of ergot alkaloids are mediated predominantly through serotonergic and adrenergic receptors in other tissues. Vasoactivity of serotonin (5-HT) receptors 5-HT2A and 5-HT1B/1D in umbilical artery and vein from ewes receiving endophyte-infected seed (E + 1.77 mg ergovaline/hd/d) or a control total mixed ration (CON; 0 mg ergovaline/hd/d) tall fescue seed at d-110 and d-133 of gestation was evaluated. Gravid reproduction tracts were collected from ewes. Two-mm sections of umbilical artery and vein were exposed to increasing concentrations of a 5-HT1B/1D agonist and 5-HT2A agonist. The 5-HT1B/1D agonist did not stimulate a contractile response in artery or vein or either gestation time point. 5-HT2A agonist caused large responses in artery with greatest occurring at d-110 and decreasing in magnitude as days of gestation increased (p < 0.05). On d-110 and 133 of gestation, arteries from CON ewes had greater contractile response than arteries collected from E+ ewes (p < 0.05). Veins responded to increasing concentrations of the 5-HT2A agonist. Maximal d-110 vein response was greater than d-133 when exposed to 5-HT2A agonist (p < 0.05). Unlike the artery, veins from E+ ewes had greater d-133 contractile response than CON (p < 0.05). Vascular contractions of umbilical artery and vein are induced by 5-HT2A receptor activity and not 5-HT1B/1D. Umbilical artery 5-HT2A receptor activity was more sensitive to seed treatment and could be responsible for ergot alkaloid-induced intra-uterine growth restriction.

Bahmyari, Sedigheh; Alaee, Sanaz; Khodabandeh, Zahra; Talaei-Khozani, Tahereh; Dara, Mahintaj; Mehdinejadiani, Shayesteh; Solati, Arezoo

doi: 10.1177/09603271241269019pmid: 39081119

Several studies investigated the application of Mesenchymal stem cells (MSCs) for treating spermatogenic disorders. Considering the limitation of MSC application, the present study aimed to compare Wharton’s jelly MSCs secretomes, including condition medium (CM) 10-fold concentrated (CM10), 20-fold concentrated CM (CM20), and extracellular vesicles (EVs) to restore busulfan-induced damage on male mice reproduction. So, Wharton’s jelly MSCs were cultured, CM was collected, and EVs were isolated. Seventy-two mice were randomly assigned to nine groups, including Control, Busulfan 1 month (1M), Busulfan 2 months (2M), CM10, Busulfan + CM10, CM20, Busulfan + CM20, EVs, and Busulfan + EVs groups. Sperm characteristics, DNA maturity, DNA fragmentation index (DFI), and testicular gene expression were evaluated. Data analysis revealed that CM10 significantly improved sperm plasma membrane integrity, sperm DNA maturity, and DFI in the Busulfan + CM10 group compared to the Busulfan 2M group. Although CM20 and EVs showed a non-significant improvement. Gene expression analysis showed busulfan administration significantly decreased the expression of AR, CREB1, and PLCζ genes, while CM10 significantly restored CREB1 gene expression. The present study demonstrated that CM10 is more effective than CM20 or EVs in reducing busulfan-induced reproductive toxicity.