Abstract:
:Novel therapeutics to overcome the toxic effects of organophosphorus (OP) chemical agents are needed due to the documented use of OPs in warfare (e.g. 1980-1988 Iran/Iraq war) and terrorism (e.g. 1995 Tokyo subway attacks). Standard OP exposure therapy in the United States consists of atropine sulfate (to block muscarinic receptors), the acetylcholinesterase (AChE) reactivator (oxime) pralidoxime chloride (2-PAM), and a benzodiazepine anticonvulsant to ameliorate seizures. A major disadvantage is that quaternary nitrogen charged oximes, including 2-PAM, do not cross the blood brain barrier (BBB) to treat brain AChE. Therefore, we have synthesized and evaluated pro-2-PAM (a lipid permeable 2-PAM derivative) that can enter the brain and reactivate CNS AChE, preventing seizures in guinea pigs after exposure to OPs. The protective effects of the pro-2-PAM after OP exposure were shown using (a) surgically implanted radiotelemetry probes for electroencephalogram (EEG), (b) neurohistopathology of brain, (c) cholinesterase activities in the PNS and CNS, and (d) survivability. The PNS oxime 2-PAM was ineffective at reducing seizures/status epilepticus (SE) in diisopropylfluorophosphate (DFP)-exposed animals. In contrast, pro-2-PAM significantly suppressed and then eliminated seizure activity. In OP-exposed guinea pigs, there was a significant reduction in neurological damage with pro-2-PAM but not 2-PAM. Distinct regional areas of the brains showed significantly higher AChE activity 1.5h after OP exposure in pro-2-PAM treated animals compared to the 2-PAM treated ones. However, blood and diaphragm showed similar AChE activities in animals treated with either oxime, as both 2-PAM and pro-2-PAM are PNS active oximes. In conclusion, pro-2-PAM can cross the BBB, is rapidly metabolized inside the brain to 2-PAM, and protects against OP-induced SE through restoration of brain AChE activity. Pro-2-PAM represents the first non-invasive means of administering a CNS therapeutic for the deleterious effects of OP poisoning by reactivating CNS AChE.
journal_name
Chem Biol Interactjournal_title
Chemico-biological interactionsauthors
Demar JC,Clarkson ED,Ratcliffe RH,Campbell AJ,Thangavelu SG,Herdman CA,Leader H,Schulz SM,Marek E,Medynets MA,Ku TC,Evans SA,Khan FA,Owens RR,Nambiar MP,Gordon RKdoi
10.1016/j.cbi.2010.02.015subject
Has Abstractpub_date
2010-09-06 00:00:00pages
191-8issue
1-3eissn
0009-2797issn
1872-7786pii
S0009-2797(10)00083-9journal_volume
187pub_type
杂志文章abstract::A series of prenylated xanthones are variously potent inhibitors of the catalytic subunit (cAK) of rat liver cyclic AMP-dependent protein kinase (PKA), rat brain Ca2+ and phospholipid-dependent protein kinase C (PKC), chicken gizzard myosin light chain kinase (MLCK), wheat embryo Ca2+-dependent protein kinase (CDPK) a...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/s0009-2797(98)00049-0
更新日期:1998-07-03 00:00:00
abstract::2-azetidinones and 2H-azirines show antibacterial and cytotoxic activities, however the biological properties of molecules containing both 2H-azirine and 2-azetidinone functions in the same structure had never been evaluated before. In the present study, two 2H-azirine-2-azetidinones (1 and 2) and three 2H-azirines (3...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2009.02.015
更新日期:2009-07-15 00:00:00
abstract::Balbisia peduncularis, also known as "Amancay", is a plant of the Ledocarpaceae family that can be found in the Atacama Desert in northern Chile. Infusions of the plant have long being used in traditional herbal medicine. Its chemical composition indicates the presence of flavonoids, which have antioxidant properties....
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2008.12.011
更新日期:2009-05-15 00:00:00
abstract::Cucurbitacin E (CuE) is a triterpenoid with potent anticancer activities while the underlying mechanisms remain elusive. In the present study, the anticancer effects of CuE on 95D lung cancer cells were investigated. CuE decreased cell viability, inhibited colony formation, and increased reactive oxygen species (ROS) ...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2016.04.028
更新日期:2016-06-25 00:00:00
abstract::Tumor cells are able to survive and proliferate in spite of their increased oxidative stress. This was taken as a hint for the implication of oxidants/antioxidants in the proliferation of glial-tumor cells. In the present study, an anti-proliferative effect of Naringenin, an antioxidant against cerebrally implanted C6...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2010.09.028
更新日期:2011-01-15 00:00:00
abstract::The present study was undertaken to assess the effect of imatinib mesylate; a tyrosine kinase inhibitor and a well-known anticancer with numerous medical benefits on blood sugar levels, insulin, and glucagon secretion in an experimental model of STZ-induced diabetes mellitus. Type 1 diabetes mellitus (T1DM) was induce...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2020.109197
更新日期:2020-09-01 00:00:00
abstract::Treatment of isolated mitochondria from rat hepatoma tumor cells (AS-30D) with the oxidant, t-butyl hydroperoxide (tBuOOH, 1 or 5 mumol/ml) resulted in the oxidation of glutathione (GSH to GSSG) and the formation of protein-glutathione mixed disulfides (ProSSG). The GSSG was retained inside of the hepatoma mitochondri...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(92)90073-t
更新日期:1992-09-28 00:00:00
abstract::In the present study, a flavonoid was isolated from Origanum vulgare and identified as didymin. The effect and mechanism of O. vulgare didymin (OVD) on human HepG2 liver carcinoma cell was then assessed. Our results showed that OVD strongly inhibited the viability, clonogenicity and migration of HepG2 cells. OVD signi...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2016.11.026
更新日期:2017-01-05 00:00:00
abstract::UDP-glucuronosyltransferases (UGTs) are a family of phase II drug metabolizing enzymes that catalyze glucuronidation of numerous endogenous and exogenous substrates. Carbon tetrachloride (CCl4) is widely used to develop liver injuries mimicking human liver diseases. However, effects of CCl4 on the expression and activ...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2020.109115
更新日期:2020-07-01 00:00:00
abstract::In the series of tetraalkylammonium ions from tetramethylammonium to tetra-n-heptylammonium, tetra-n-pentylammonium ion was a potent protector of both murine L1210 leukemia and bone marrow progenitor cells against mechlorethamine cytotoxicity. It was also a non-competitive inhibitor of choline uptake. Phosphonium anal...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(82)90095-3
更新日期:1982-06-01 00:00:00
abstract::Evidence for the reversible binding of paraquat to calf thymus DNA has been obtained using equilibrium dialysis and thermal melting point determinations. The data indicated the presence of at least two populations of binding site with affinity constants of 6.2 X 10(4) and 7.1 X 10(3) M-1, respectively. The binding cap...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(87)90035-4
更新日期:1987-02-01 00:00:00
abstract::A natural ursolic compound, 2β, 3β, 23-trihydroxy-urs-12-ene-28-olic acid (TUA) was isolated from the root of Actinidia chinensis Planch (A. chinensis Radix). Since a large number of triterpenoid compound has marked anticancer effects toward various types of cancer cell lines in vitro, this study was carried out to in...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2015.06.038
更新日期:2015-10-05 00:00:00
abstract::Cholinesterases (ChEs) are classified as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) according to their substrate specificity and sensitivity to selected inhibitors. The activities of AChE in red blood cells (RBC-AChE) and BChE in serum can be used as potential biomarkers of suppressed and/or heighten...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2005.10.031
更新日期:2005-12-15 00:00:00
abstract::Lon protease, an ATP dependent mitochondrial protease, is important in mitochondrial protein maintenance. Disruption of protein homeostasis and mitochondrial dysfunction is associated with lipodystrophy, metabolic syndrome and accelerated aging, and are commonly observed in patients on long term antiretroviral therapy...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2016.03.021
更新日期:2016-05-25 00:00:00
abstract:BACKGROUND:The human body is a home to thousands of microbiotas. It is defined as a community of symbiotic, commensal and pathogenic microorganisms that have existed in all exposed sites of the body, which have co-evolved with diet, lifestyle, genetic factors and immune factors. Human microbiotas have been studied for ...
journal_title:Chemico-biological interactions
pub_type: 杂志文章,评审
doi:10.1016/j.cbi.2019.108732
更新日期:2019-09-01 00:00:00
abstract::Exposure to lead (Pb) poses a threat to human bone health, including changes in bone mineral composition and the inhibition of skeletal growth and bone maturation. However, little is known about how Pb directly affects osteoblasts. In this work, we found that sub-toxic Pb concentrations suppressed bone nodule formatio...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2019.01.039
更新日期:2019-04-25 00:00:00
abstract::The organ specificity of tris(2,3-dibromopropyl)phosphate(Tris-BP)-induced DNA damage was investigated in the rat 2 h after a single i.p. injection of 350 mumol/kg. Extensive DNA damage, measured with the alkaline elution method, was found in the kidney, liver and small intestine. Less, but significant DNA damage was ...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(92)90110-7
更新日期:1992-04-15 00:00:00
abstract::Pogostemonis Herba is an important Chinese medicine widely used in the treatment of gastrointestinal dysfunction. Patchouli alcohol (PA), a tricyclic sesquiterpene, is the major active constituent of Pogostemonis Herba. This study aimed to investigate the possible anti-ulcerogenic potential of PA and the underlying me...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2014.08.008
更新日期:2014-10-05 00:00:00
abstract::Incubation of Ca2(+)-loaded rat liver mitochondria with N-acetyl-p-benzoquinone imine (NAPQI) or its two dimethylated analogues resulted in a concentration dependent Ca2+ release, with the following order of potency: 2,6-(Me)2-NAPQI greater than NAPQI greater than 3,5-(Me)2-NAPQI. The quinone imine-induced Ca2+ releas...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(90)90090-a
更新日期:1990-01-01 00:00:00
abstract::The biological and physicochemical effects of reacting bacteriophages R17 and T7 with acetoxy-dimethylnitrosamine (ADMN) have been studied. The rate-determining step in the reactions appeared to be the loss of the acetoxy group by hydrolysis, the hydroxymethyl-methylnitrosamine generated decomposing rapidly to give a ...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(76)90019-3
更新日期:1976-07-01 00:00:00
abstract::The degradation in alkali of normal DNA and DNA alkylated with dimethyl sulphate (DMS), N-methyl-N-nitrosourea (MNUA) and N-ethyl-N-nitrosourea (ENUA) has been investigated using analytical ultracentrifugation techniques. For control T7-DNA (w.st. denatured form 12.5 - 10(6) daltons) the rate of degradation at 37 degr...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(76)90004-1
更新日期:1976-05-01 00:00:00
abstract::The goal of this research was to test the hypothesis that bioactivation reactions could be exploited to deliver and activate mitochondria-targeted antioxidant prodrugs. The concept that bioactivation reactions could be used for prodrug delivery and activation has received little attention. Most bioactivation reactions...
journal_title:Chemico-biological interactions
pub_type: 杂志文章,评审
doi:10.1016/j.cbi.2010.10.004
更新日期:2011-06-30 00:00:00
abstract::Since endogenous glutathione (GSH), the main non-protein intracellular thiol compound, is known to provide protection against reactive radical species, its depletion by diethylmaleate (DEM) was used to assess the role of free radical formation mediated by doxorubicin in DNA damage, cytotoxicity and mutagenicity of the...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(86)90037-2
更新日期:1986-02-01 00:00:00
abstract::The microsomal metabolism of pentachlorophenol (PCP) was investigated, with special attention to the conversion dependent covalent binding to protein and DNA. The two metabolites detected were tetrachloro-1,2- and tetrachloro-1,4-hydroquinone. Microsomes from isosafrole (ISF)-induced rats were by far the most effectiv...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(86)90013-x
更新日期:1986-10-15 00:00:00
abstract::Hepatocyte growth factor (HGF), also known as scatter factor (SF), and its receptor, the c-Met tyrosine kinase, play roles in cancer invasion and metastasis in a wide variety of tumor cells. Clinical observations suggest that HGF can promote metastasis of hepatoma cells while stimulating tumor invasiveness. We use HGF...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2006.01.002
更新日期:2006-03-25 00:00:00
abstract::Pyrazolone based metal complexes have strong bio-activity but the anti-cancer mechanism of these derivatives is not fully understood. In recent years, Cu(II) complexes have attracted the interest of researchers increasingly because of their high antitumor activities that are usually related to DNA binding. The reactio...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2015.08.022
更新日期:2015-10-05 00:00:00
abstract::Stearoyl-CoA desaturase (SCD) generates monounsaturated fatty acids (MUFAs) which contribute to cell growth, survival, differentiation, metabolic regulation and signal transduction. Overexpression of SCD is evident and implicated in metabolic diseases such as diabetes and non-alcoholic fatty liver disease. SCD also st...
journal_title:Chemico-biological interactions
pub_type: 杂志文章,评审
doi:10.1016/j.cbi.2019.108917
更新日期:2020-01-25 00:00:00
abstract::10-(2-pyrazolyl-ethoxy)-(20S)-camptothecin (CPT13) is a novel semi-synthetic analogue of camptothecin, our previous report had shown that it possessed higher in vitro cytoxicity activity towards human colon cancer HCT8 cell line than topotecan. In this study, the anti-proliferative effect of CPT13 on HCT8 cell line in...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2008.07.005
更新日期:2008-11-25 00:00:00
abstract::We investigated the chemopreventive effect of p-methoxycinnamic acid (p-MCA), an active phenolic acid of rice bran, turmeric, and Kaemperfia galanga against 1,2-dimethylhydrazine-induced rat colon carcinogenesis. Male albino Wistar rats were randomly divided into six groups. Group 1 consisted of control rats that rece...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2012.01.008
更新日期:2012-03-05 00:00:00
abstract::The carcinogenic compound 2,4,6-trichlorophenol (2,4,6-TCP) was incubated with rat liver S-9 fraction. Three metabolites were identified: 2,6-dichloro-1,4-hydroquinone (DHQ), and two isomers of hydroxypentachlorodiphenyl ether (OH-Cl5-DPE). The latter are probably products of microsomal .OH radical attack on the trich...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(89)90119-1
更新日期:1989-01-01 00:00:00