Browsing by Subject "Simvastatin"

Now showing 1 - 3 of 3
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    Donor Simvastatin Treatment Is Safe and Might Improve Outcomes After Liver Transplantation: A Randomized Clinical Trial
    (Wolters Kluwer, 2022) Pagano, Duilio; Bosch, Jaime; Tuzzolino, Fabio; Oliva, Elisabetta; Ekser, Burcin; Zito, Giovanni; Cintorino, Davide; di Francesco, Fabrizio; Petri, Sergio Li; Ricotta, Calogero; Bonsignore, Pasquale; Calamia, Sergio; Magro, Bianca; Trifirò, Gianluca; Alduino, Rossella; Barbara, Marco; Conaldi, Pier Giulio; Gallo, Alessia; Venuti, Francesca; Luca, Angelo; Gruttadauria, Salvatore; Surgery, School of Medicine
    Background: The current curative approaches for ischemia/reperfusion injury on liver transplantation are still under debate for their safety and efficacy in patients with end-stage liver disease. We present the SIMVA statin donor treatment before Liver Transplants study. Methods: SIMVA statin donor treatment before Liver Transplants is a monocentric, double-blind, randomized, prospective trial aiming to compare the safety and efficacy of preoperative brain-dead donors' treatment with the intragastric administration of 80 mg of simvastatin on liver transplant recipient outcomes in a real-life setting. Primary aim was incidence of patient and graft survival at 90 and 180 d posttransplant; secondary end-points were severe complications. Results: The trial enrolled 58 adult patients (18-65 y old). The minimum follow-up was 6 mo. No patient or graft was lost at 90 or 180 d in the experimental group (n = 28), whereas patient/graft survival were 93.1% ( P = 0.016) and 89.66% ( P = 0.080) at 90 d and 86.21% ( P = 0.041) and 86.2% ( P = 0.041) at 180 d in the control group (n = 29). The percentage of patients with severe complications (Clavien-Dindo ≥IIIb) was higher in the control group, 55.2% versus 25.0% in the experimental group ( P = 0.0307). The only significant difference in liver tests was a significantly higher gamma-glutamyl transferase and alkaline phosphatase at 15 d ( P = 0.017), ( P = 0.015) in the simvastatin group. Conclusions: Donor simvastatin treatment is safe, and may significantly improve early graft and patient survival after liver transplantation, although further research is mandatory.
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    Serotonin Transporter Regulation by Cholesterol-Independent Lipid Signaling
    (Elsevier, 2021) Deveau, Carmen M.; Rodriguez, Eric; Schroering, Allen; Yamamoto, Bryan K.; Pharmacology and Toxicology, School of Medicine
    Serotonin neurotransmission is largely governed by the regulation of the serotonin transporter (SERT). SERT is modulated in part by cholesterol, but the role of cholesterol and lipid signaling intermediates in regulating SERT are unknown. Serotonergic neurons were treated with statins to decrease cholesterol and lipid signaling intermediates. Contrary to reported decreases in 5-HT uptake after cholesterol depletion, biochemical and imaging methods both showed that statins increased 5-HT uptake in a fluoxetine-dependent manner. Simvastatin lowered the Km without changing Vmax for 5-HT or SERT distribution to the plasma membrane. Cholesterol repletion did not block enhanced 5-HT uptake by simvastatin but the enhanced uptake was blocked by lipid isoprenylation intermediates farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Blockade of geranylgeranylation alone without statins also enhanced 5-HT uptake. Overall, this study revealed a specific neuronal effect of statin drugs and identified lipid signaling through geranylgeranylation within the isoprenylation pathway regulates SERT in a cholesterol-independent manner.
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    The Combined Inhibition of SREBP and mTORC1 Signaling Synergistically Inhibits B‐Cell Lymphoma
    (Wiley, 2024) Zhu, Zhenhan; Jiang, Wenxia; Zhou, Jiehao; Maldeney, Alexander Robert; Liang, Jingru; Yang, Jing; Luo, Wei; Microbiology and Immunology, School of Medicine
    Background: The sterol regulatory element-binding protein (SREBP) pathway is essential for maintaining sterol homeostasis during B cell activation and germinal center B cell proliferation. However, its potential as a therapeutic target to treat B-cell lymphoma remains unclear. Methods: We examined SREBP protein expression in human B-cell lymphoma samples using immunohistochemistry. Additionally, we conducted in vitro studies using SREBP signaling inhibitors in combination with rapamycin to assess their effects on cell proliferation and lipid metabolism in B-cell lymphoma cells. Results: Our analysis revealed high levels of SREBP2 protein expression in human B-cell lymphoma samples. Inhibiting SREBP signaling or its downstream target HMG-CoA reductase (HMGCR) with Fatostatin or Simvastatin effectively suppressed B-cell lymphoma cell proliferation. However, B-cell lymphoma cells responded to statin treatment by activating the mTORC1-pS6 pathway, suggesting a compensatory mechanism to overcome statin-induced cell cycle arrest. Combining low-dose statin treatment with the mTOR inhibitor rapamycin produced a synergistic effect, significantly inhibiting B-cell lymphoma proliferation, cell cycle progression, and lipid raft formation. Conclusions: These results highlight the potential of a combined therapeutic approach targeting both SREBP and mTORC1 as a novel strategy for treating B-cell lymphoma.