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Induction of Parkinsonian-Like Alterations by way of Targeted Downregulation regarding Astrocytic Glutamate Transporter GLT-1 within the Striatum.
Background Penfluridol, a commonly used antipsychotic agent in a clinical setting, exhibits potential anti-cancer properties against various human malignancies. Here, we investigated the effect of penfluridol on the biological behavior of CRC cells. Methods Cell viability and clonogenic potential were detected by the cell counting kit-8 and colony formation assay. The cell apoptosis and cell cycle distribution were quantified through flow cytometry. Caspase-3 activity, glucose consumption, lactate production, and intracellular ATP levels were evaluated using the corresponding commercial detection kits. The protein levels of related genes were detected through Western blotting. Mitochondrial membrane potential was detected using JC-1 staining. A CRC xenograft tumor model was used to validate the anti-tumor activity of penfluridol in vivo. Results Penfluridol reduced cell survival and promoted apoptotic cell death effectively through the mitochondria-mediated intrinsic pathway in a dose-dependent manner. Further, the process of glycolysis in HCT-116 and HT-29 cells were inhibited upon penfluridol treatment, as evidenced by the decrease in glucose consumption, lactate production, and intracellular ATP levels. Further mechanistic studies revealed that penfluridol influenced cell apoptosis and glycolysis in CRC cells by down-regulating hexokinase-2 (HK-2). The pro-apoptotic effect and glycolytic inhibition-induced by penfluridol were effectively reversed by HK-2 overexpression. Consistent with in vitro results, penfluridol could also suppress tumor growth and trigger apoptosis in vivo. Conclusion Penfluridol triggers mitochondrial-mediated apoptosis and induces glycolysis inhibition via modulating HK-2 in CRC and provides a theoretical basis to support penfluridol as a repurposed drug for CRC patients.I thank Lindahl and Li for their thoughtful comments on the non‐anticoagulant properties of heparin.1 Heightened awareness of hypercoagulability has made heparin part and parcel of the COVID‐19 management algorithms. In addition, reports of prophylactic anticoagulation failure have triggered several trials where escalated doses of heparin are compared with standard doses with the aim of preventing thrombotic complications. At this juncture, we do need to consider where do the non‐anticoagulant properties of heparin fit in the COVID‐19 clinical context?Background The NIH protocol for nonmyeloablative (NMA) conditioning allogeneic stem cell transplantation (alloSCT) with alemtuzumab and low-dose total body irradiation corrected the abnormal sickle cell disease (SCD) phenotype without the risk of graft-versus-host disease. AlloSCT using NMA conditioning had been rarely applied to β-thalassemia major (β-TM) patients. Methods To avoid prolonged immunosuppression, we developed a two-stage strategy. Mixed donor chimerism was initially achieved using the protocol developed by the NIH. Thereafter, we facilitated donor chimerism using the optional reinforced stem cell (SC) infusion in cases requiring protracted immuno-suppression or experiencing impeding graft failure. Results In this study, β-TM (n=9) and SCD (n=4) patients were equally effectively treated with eradicating the abnormal hemoglobin phenotype. Five patients, including four β-TM, achieved stable mixed chimerism without receiving optional reinforced SC infusion. All patients that received optional reinforced infusion recipients achieved complete (n=4) or mixed chimerism (n=1). The overall survival rate and event-free survival at 4 years of 91.7% (95% CI; 53.9-98.8) in both groups, with a thalassemia-free survival rate in β-TM patients of 87.5% (95% CI; 38.7-98.1). Conclusion This study is the first to report successful NMA conditioning alloSCT to achieve stable mixed chimerism correcting the abnormal hemoglobin phenotype in adult β-TM patients.Several papers have described hyponatraemia with tramadol. However, in most reports, several confounding factors can be found. We used the WHO pharmacovigilance database (VigiBase®) to investigate if tramadol alone could be associated with hyponatraemia. All 1992-2019 ICSRs (individual case safety reports) with the preferred term (PT) "hyponatraemia" and tramadol were included. Two disproportionality analyses were performed (1) after inclusion of all reports, and (2) after exclusion of concomitant hyponatraemic drugs. Results are expressed as reporting odds ratios (ROR; 95% CI) and information component (IC). Of 19 747 604 ICSRs, 225 575 were included. A significant association was found between tramadol use and reports of hyponatraemia (ROR = 1.49 [1.39-1.60], IC = 0.57 [IC025 = 0.47]). After exclusion of hyponatraemic drugs, the previously found association disappeared. The study failed to find any pharmacovigilance signal of hyponatraemia with tramadol alone. We suggest that reports of hyponatraemia with tramadol can be explained principally by other underlying causes of hyponatraemia, especially other concomitant hyponatraemic drugs.Kyiv is Ukraine's capital and largest city. Home to 3 million people, this area has a rich history of agriculture and industry. The Dnieper River is Ukraine's largest river and it passes through the center of Kyiv. Little information on emerging and legacy compounds or their toxicity in the Dnieper River exists. For this investigation, water was sampled for PAHs, PCBs, metals and emerging contaminants including pharmaceuticals and personal care products. The effects of surface waters in the Dnieper were evaluated using the Ames, chronic and acute daphnia, and a ciliate (Colpoda stennii) assays. Concentrations of legacy and emerging contaminants were found in seven stations near the municipal water treatment plant (MWTP) and receiving waters. The MWTP appeared to remove some of the emerging contaminants, however the legacy compounds (PCBs and PAHs) were not affected by the MWTP and appeared to be more wide-spread indicating a number of sources to the Dnieper River. Acute and chronic toxicity were associated with the influent and effluent of the MWTP, however mutagenicity was noted in surface waters throughout the Dnieper River including upstream of the MWTP. NSC 19893 This study provides the first snapshot of possible human health and ecological risks associated with surface waters of the Dnieper. More research on seasonal changes and sources of toxicity, mutagenicity and contaminants would aid in completing a more comprehensive risk assessment of surface waters of the Dnieper River.
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