1. Lead and cadmium exposures from canned and non-canned beverages in Nigeria: a public health concern
J-M U Maduabuchi, E Obi, O E Orisakwe, C E Okocha, C N Nzegwu, R U Aloke, C N Ezomike, E O Adigba Sci Total Environ . 2006 Aug 1;366(2-3):621-6. doi: 10.1016/j.scitotenv.2005.12.015.
The lead and cadmium levels of canned and non-canned foods purchased in Nigeria were studied. Fifty samples of these beverages were digested in nitric acid and were analyzed using the Atomic Absorption Spectrophotometer (AAS). The cadmium levels ranged from 0.003-0.081 mg/L for the canned and 0.006-0.071 mg/L for non-canned beverages. About 85.71% of the canned beverages had cadmium levels that exceeded the maximum contaminant level (MCL) of 0.005 mg/L set by US EPA while 82.7% non-canned beverages had cadmium levels exceeding the MCL. The mean and median levels of cadmium exceeded the MCL in both the canned and non-canned beverages. Whereas only 79.3% of the non-canned beverages showed lead levels that exceeded the US EPA's MCL of 0.015 mg/L, 100% of the canned beverages had lead levels that were greater than the MCL. The range of the lead in the canned beverages was 0.002-0.0073 and 0.001-0.092 mg/L for the non-canned beverages. The mean and median values of lead exceeded the MCL in both the canned and non-canned beverages. The calculated amount of lead and cadmium in three beverages were 0.204 mg (204 microg) and 0.177 mg (177 microg), respectively. These represent the estimated intake of a consumer who takes three of the products selected randomly in a week; assuming an average volume of one liter (1 L) for each product. Taken together 86% and 84% of the 50 beverages (canned and non-canned) studied in March, 2005 in Nigeria failed to meet the US EPA criteria for acceptable lead and cadmium levels in consumer products.
2. PARP and CDK4/6 Inhibitor Combination Therapy Induces Apoptosis and Suppresses Neuroendocrine Differentiation in Prostate Cancer
Chuandong Geng, Shakuntala Kondraganti, Timothy C Thompson, Daoqi Wang, Jonathan L Curry, Shan Peng, Courtney W Hudgens, Paul G Corn, Debora A Ledesma, Zhe Tang, Ganiraju C Manyam, Carlos A Torres-Cabala, Yungang Lu, Sanghee Park, Bradley M Broom, Patrick G Pilié, Mario L Marques-Piubelli, Guang Yang, Patricia Troncoso, Cheng Wu Mol Cancer Ther . 2021 Sep;20(9):1680-1691. doi: 10.1158/1535-7163.MCT-20-0848.
We analyzed the efficacy and mechanistic interactions of PARP inhibition (PARPi; olaparib) and CDK4/6 inhibition (CDK4/6i; palbociclib or abemaciclib) combination therapy in castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) models. We demonstrated that combined olaparib and palbociblib or abemaciclib treatment resulted in synergistic suppression of the p-Rb1-E2F1 signaling axis at the transcriptional and posttranslational levels, leading to disruption of cell-cycle progression and inhibition of E2F1 gene targets, including genes involved in DDR signaling/damage repair, antiapoptoticBCL-2family members (BCL-2andMCL-1),CDK1, and neuroendocrine differentiation (NED) markersin vitroandin vivoIn addition, olaparib + palbociclib or olaparib + abemaciclib combination treatment resulted in significantly greater growth inhibition and apoptosis than either single agent alone. We further showed that PARPi and CDK4/6i combination treatment-induced CDK1 inhibition suppressed p-S70-BCL-2 and increased caspase cleavage, while CDK1 overexpression effectively prevented the downregulation of p-S70-BCL-2 and largely rescued the combination treatment-induced cytotoxicity. Our study defines a novel combination treatment strategy for CRPC and NEPC and demonstrates that combination PARPi and CDK4/6i synergistically promotes suppression of the p-Rb1-E2F1 axis and E2F1 target genes, includingCDK1and NED proteins, leading to growth inhibition and increased apoptosisin vitroandin vivoTaken together, our results provide a molecular rationale for PARPi and CDK4/6i combination therapy and reveal mechanism-based clinical trial opportunities for men with NEPC.
3. Intranasal Carnosine Mitigates α-Synuclein Pathology and Motor Dysfunction in the Thy1-aSyn Mouse Model of Parkinson's Disease
Lauren S Baker, Josephine M Brown, Mary Beth Genter, Kim B Seroogy ACS Chem Neurosci . 2021 Jul 7;12(13):2347-2359. doi: 10.1021/acschemneuro.1c00096.
Parkinson's disease (PD) is a debilitating neurodegenerative disorder. Early symptoms include motor dysfunction and impaired olfaction. Toxic aggregation of α-synuclein (aSyn) in the olfactory bulb (OB) and substantia nigra pars compacta (SNpc) is a hallmark of PD neuropathology. Intranasal (IN) carnosine (2 mg/d for 8 weeks) was previously demonstrated to improve motor behavior and mitochondrial function in Thy1-aSyn mice, a model of PD. The present studies evaluated the efficacy of IN carnosine at a higher dose in slowing progression of motor deficits and aSyn accumulation in Thy1-aSyn mice. After baseline neurobehavioral assessments, IN carnosine was administered (0.0, 2.0, or 4.0 mg/day) to wild-type and Thy1-aSyn mice for 8 weeks. Olfactory and motor behavioral measurements were repeated prior to end point tissue collection. Brain sections were immunostained for aSyn and tyrosine hydroxylase (TH). Immunopositive cells were counted using design-based stereology in the SNpc and OB mitral cell layer (MCL). Behavioral assessments revealed a dose-dependent improvement in motor function with increasing carnosine dose. Thy1-aSyn mice treated with 2.0 or 4.0 mg/d IN carnosine exhibited fewer aSyn-positive (aSyn(+)) cell bodies in the SNpc compared to vehicle-treated mice. Moreover, the number of aSyn(+) cell bodies in carnosine-treated Thy1-aSyn mice was reduced to vehicle-treated wild-type levels in the SNpc. Carnosine treatment did not affect the number of aSyn(+) cell bodies in the OB-MCL or the number of TH(+) cells in the SNpc. In summary, intranasal carnosine treatment decreased aSyn accumulation in the SNpc, which may underlie its mitigation of motor deficits in the Thy1-aSyn mice.
