Browsing by Subject "Tissue Distribution"
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Item CRISPR based editing of SIV proviral DNA in ART treated non-human primates(Springer Nature, 2020-11-27) Mancuso, Pietro; Chen, Chen; Kaminski, Rafal; Gordon, Jennifer; Liao, Shuren; Robinson, Jake A.; Smith, Mandy D.; Liu, Hong; Sariyer, Ilker K.; Sariyer, Rahsan; Peterson, Tiffany A.; Donadoni, Martina; Williams, Jaclyn B.; Siddiqui, Summer; Bunnell, Bruce A.; Ling, Binhua; MacLean, Andrew G.; Burdo, Tricia H.; Khalili, KamelElimination of HIV DNA from infected individuals remains a challenge in medicine. Here, we demonstrate that intravenous inoculation of SIV-infected macaques, a well-accepted non-human primate model of HIV infection, with adeno-associated virus 9 (AAV9)-CRISPR/Cas9 gene editing construct designed for eliminating proviral SIV DNA, leads to broad distribution of editing molecules and precise cleavage and removal of fragments of the integrated proviral DNA from the genome of infected blood cells and tissues known to be viral reservoirs including lymph nodes, spleen, bone marrow, and brain among others. Accordingly, AAV9-CRISPR treatment results in a reduction in the percent of proviral DNA in blood and tissues. These proof-of-concept observations offer a promising step toward the elimination of HIV reservoirs in the clinic.Item Determination of metformin bio-distribution by LC-MS/MS in mice treated with a clinically relevant paradigm(PLOS, 2020-06-11) Chaudhari, Kiran; Wang, Jianmei; Xu, Yong; Winters, Ali; Wang, Linshu; Dong, Xiaowei; Cheng, Eric Y.; Liu, Ran; Yang, ShaohuaMetformin, an anti-diabetes drug, has been recently emerging as a potential "anti-aging" intervention based on its reported beneficial actions against aging in preclinical studies. Nonetheless, very few metformin studies using mice have determined metformin concentrations and many effects of metformin have been observed in preclinical studies using doses/concentrations that were not relevant to therapeutic levels in human. We developed a liquid chromatography-tandem mass spectrometry protocol for metformin measurement in plasma, liver, brain, kidney, and muscle of mice. Young adult male and female C57BL/6 mice were voluntarily treated with metformin of 4 mg/ml in drinking water which translated to the maximum dose of 2.5 g/day in humans. A clinically relevant steady-state plasma metformin concentrations were achieved at 7 and 30 days after treatment in male and female mice. Metformin concentrations were slightly higher in muscle than in plasma, while, ~3 and 6-fold higher in the liver and kidney than in plasma, respectively. Low metformin concentration was found in the brain at ~20% of the plasma level. Furthermore, gender difference in steady-state metformin bio-distribution was observed. Our study established steady-state metformin levels in plasma, liver, muscle, kidney, and brain of normoglycemic mice treated with a clinically relevant dose, providing insight into future metformin preclinical studies for potential clinical translation.