BMC Pharmacology & Toxicology最新文献

This study aimed to develop and validate a novel ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of iloperidone (ILP) and its metabolites P88, P95 in rat plasma and to investigate drug-drug interaction (DDI) between shikonin and ILP in Sprague-Dawley rats. The separation of the analytes was performed on a UPLC BEH C18 column in the mobile phase (acetonitrile and water with 0.1% formic acid) with the flow rate of 0.4 mL/min. The quantitative analysis was performed in positive ion mode. A total of 10 Sprague-Dawley rats were divided into two groups: control group (1.0 mg/kg ILP alone) and experimental group (20 mg/kg shikonin plus 1.0 mg/kg ILP) to investigate the influence of shikonin on ILP metabolism in rats. We successfully established a quick UPLC-MS/MS analytical method for simultaneously detecting ILP and its two metabolites in rat plasma. Linearity, matrix effect, recovery, accuracy, precision and stability of this quantitative method was satisfied with Food and Drug Administration (FDA) guidelines. In addition, in vitro studies demonstrated that shikonin significantly inhibited CYP3A4- and CYP2D6-mediated metabolism in both rat liver microsomes (RLM) and human liver microsomes (HLM). Furthermore, we found the main pharmacokinetic parameters of ILP, such as AUC_(0-t) and the peak plasma concentration (C_max), were obviously changed, which were about twice higher in experimental group than the values in control group. The data demonstrated that shikonin obviously changed the main pharmacokinetics of ILP and its metabolites in rats. In the future clinical use, we should pay more attention to the concomitant application of shikonin and ILP in humans.

Background: Cepharanthine (CEP), a kind of isoquinoline alkaloid extracted from stephania, is applied in the treatment of cancer. This study aimed to explore the antitumor effects and specific mechanism of CEP on oral squamous cell carcinoma (OSCC) in vitro and in vivo.

Methods: The anticancer effects of CEP were studied by evaluating cell apoptosis, viability, migration, and invasion of OSCC cells. The epithelial-mesenchymal transition (EMT) related proteins levels were detected using qRT-PCR and western blot methods. Moreover, the N6-methyladenosine (m6A) modification of high mobility histone A2 (HMGA2) was determined by methylated RNA immune-precipitation (MeRIP) assay.

Results: We found that CEP suppressed the proliferation and EMT of OSCC cells. Moreover, CEP treatment increased the expression of METTL14 and suppressed m6A modification of FOXL2. Additionally, Overexpression of METTL14 reversed the effects of CEP and induced the aggressiveness of OSCC cells.

Conclusion: CEP impeded the proliferation and EMT of OSCC cells via m6A-induced inactivation of HMGA2/FOXL2 axis, relieving the carcinogenic behaviors of OSCC.

Background: Lipopolysaccharide (LPS)-induced neuroinflammation is widely used as an animal model for studying the mechanisms of neuroinflammation. Crocin, an active component of saffron (Crocus sativus L), possesses several beneficial properties. The present study aimed to investigate the role of crocin in alleviating hippocampal toxicity induced by LPS in rats.

Method: Forty male albino rats were randomly divided into five groups. Group I served as a control. Group II intraperitoneally (i.p.) injected with LPS (1 mg/kg/day) for a week. Groups III, IV, and V were treated by oral gavage with captopril (50 mg/kg/day), crocin (50 mg/kg/day), and a combination of both captopril (50 mg/kg/day) and crocin (50 mg/kg/day), respectively for 30 consecutive days, starting on the 8th day after LPS i.p. injection. During the therapy schedule, rats were tested for memory and learning abilities. Hippocampal samples were collected for biochemical, histological, immunohistochemical, and morphometric studies. Biochemical evaluation included nuclear factor kappa B, inflammatory cytokines (tumor necrosis factor-α and interleukin-1β), amyloid beta, angiotensin-converting enzyme, markers of the cholinergic system (acetylcholinesterase and choline acetyltransferase), antioxidant enzymes (catalase and superoxide dismutase) and an oxidative stress indicator (malondialdehyde). Histological examinations, as well as immunohistochemical and histomorphometric analysis, were also performed on hippocampal tissue.

Results: The results revealed biochemical, histological, and immunohistochemical alterations in the hippocampus of the LPS group. Most of these alterations showed satisfactory improvements in hippocampal tissue when LPS-administered rats were treated with captopril and crocin, either separately or in combination.

Conclusion: The present study suggests that crocin acts as a promising therapeutic agent for alleviating memory impairments and neuroinflammation induced by LPS.

Background: Selinexor (SLX), a selective inhibitor of nuclear export (SINE), has been shown to interfere with nuclear export mechanisms and to exert antitumor effects in a variety of cancer cell types. It is known to regulate multiple fundamental cellular processes, including the DNA damage response, cell proliferation, and stress signaling pathways. Nevertheless, its potential effects on reproductive cells remain inadequately characterized. The present study was aimed to investigate the cytotoxic, apoptotic, anti-proliferative and anti-migratory effects of SLX on GC1 (spermatogonia) and GC2 (spermatid) cell lines, alongside its influence on DNA damage and oxidative stress.

Methods: Cytotoxicity was assessed using the MTT assay. Cell proliferation capacity was evaluated via colony formation assay, while cell migration was analyzed using in vitro wound healing model. Apoptosis, oxidative stress, and DNA damage were investigated using immunocytochemical analyses of Cas-3, Bax, iNOS, ATM, and BRCA1 proteins. Additionally, Annexin V-FITC/PI staining was performed to detect the apoptotic cell population by flow cytometry.

Results: SLX treatment led to concentration- and time dependent cytotoxicity and colony formation assay revealed a marked reduction in proliferative capacity, in both cell lines. Wound healing analyses demonstrated that SLX effectively suppressed cell migration. Flow cytometry analysis showed that the live cell population decreased, whereas the late apoptotic cell population increased. Additionally, it was observed that Cas-3 and Bax immunoreactivities increased in the SLX groups compared to the control groups. Moreover, a significant increase in the immunoreactivity of ATM, BRCA1 and iNOS proteins, which are key indicators of DNA damage and oxidative stress, was observed.

Conclusion: The data suggest that SLX may decrease cell viability, induce apoptosis, inhibit cell migration and increase DNA damage and cellular stress in male germ cells. Given these effects, SLX should be carefully examined for its potential reproductive toxicity. Further studies are warranted to explore its long-term impact on male fertility.