Abstract:
:Calcium channel blockers (CCBs) are important in the management of hypertension and limit restenosis. Although CCB efficacy could derive from decreased blood pressure, other mechanisms independent of CCB activity also can contribute to antiproliferative action. To understand mechanisms of CCB-mediated antiproliferation, we studied two structurally dissimilar CCBs, diltiazem and verapamil, in cultured rat vascular smooth muscle cells (VSMC). To elucidate CCB-independent effects, pure stereoisomers of verapamil (R-verapamil, inactive VR; S-verapamil, active, VS) were used. The effects of CCB exposure on cell viability (MTT reduction), cell proliferation ((3)H-thymidine incorporation), VSMC morphology by light and transmission electron microscopy (TEM) and autophagy (LC3I/II, ATG5) were measured. In general, verapamil, VR or VS treatment alone (80 μM) appreciably enhanced MTT absorbance although higher concentrations (VR or VS) slightly decreased MTT absorbance. Diltiazem (140 μM) markedly decreased MTT absorbance (40%) at 120 h. VR or VS treatment inhibited (3)H-thymidine incorporation (24h) and induced cytological alterations (i.e., karyokinesis, enhanced perinuclear MTT deposition, accumulated perinuclear "vacuoles"). TEM revealed perinuclear "vacuoles" to be aggregates of highly laminated and electron-dense vesicles resembling autophagosomes and lysosomes, respectively. Increased autophagosome activity was confirmed by a concentration-dependent increase in LC3-II formation by Western blotting and by increased perinuclear LC3-GFP(+) puncta in verapamil-treated VSMC. Verapamil stereoisomers appeared to decrease perinuclear mitochondrial density. These observations indicate that antiproliferative effects of verapamil stereoisomers are produced by enhanced mitochondrial damage and upregulated autophagy in VSMC. These effects are independent of CCB activity indicating a distinct mechanism of action that could be targeted for more efficacious anti-atherosclerotic and anti-restenosis therapy.
journal_name
Toxicol Appl Pharmacoljournal_title
Toxicology and applied pharmacologyauthors
Salabei JK,Balakumaran A,Frey JC,Boor PJ,Treinen-Moslen M,Conklin DJdoi
10.1016/j.taap.2012.04.036subject
Has Abstractpub_date
2012-08-01 00:00:00pages
265-72issue
3eissn
0041-008Xissn
1096-0333pii
S0041-008X(12)00204-9journal_volume
262pub_type
杂志文章abstract::We investigated the potential effects of monosodium glutamate (MSG)-induced obesity with regards to nitric oxide and prostanoid production, as well as potassium channel function, in rat thoracic arteries. Newborn male Wistar rats were injected intraperitoneally with typically reported MSG (4.0 mg/g) once daily for 4 c...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2018.09.016
更新日期:2018-11-15 00:00:00
abstract::The relative methemoglobin (MetHgb) forming ability of two metabolites of dapsone, dapsone hydroxylamine (DDS-NOH) and monoacetyldapsone hydroxylamine (MADDS-NOH), were compared in rat and human whole blood. Concentration-response curves for the two metabolites were generated in vitro in whole blood. Data were fit to ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1994.1255
更新日期:1994-12-01 00:00:00
abstract::Cardiotoxin-III (CTX-III), a major cardiotoxin isolated from the venom of the Taiwan cobra (Naja naja atra), is a highly basic, hydrophobic, toxic protein, which can induce lysis of mononuclear cells by an unknown mechanism. This study was undertaken to investigate the effects of CTX-III on untreated and PHA-activated...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/s0041-008x(03)00327-2
更新日期:2003-11-15 00:00:00
abstract::Acrolein is a highly toxic, volatile, unsaturated aldehyde generated during incomplete combustion as in tobacco smoke and indoor fires. Because the transient receptor potential ankyrin 1 (TRPA1) channel mediates tobacco smoke-induced lung injury, we assessed its role in high-level acrolein-induced toxicity in mice. Ac...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2016.08.028
更新日期:2017-06-01 00:00:00
abstract::Cadmium chloride (CdCl2) at a dose of 1 mg/kg of body weight was injected into male Wistar rats twice a day (12-hr intervals) for 7 consecutive days. A group of treated rats was maintained without any treatment for an additional period of 10 days and killed on the following day (on Day 18). Plasma aldosterone concentr...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(84)90346-6
更新日期:1984-12-01 00:00:00
abstract::We developed an in vivo model for cadmium-induced bone loss in which mice excrete bone mineral in feces beginning 8 h after cadmium gavage. Female mice of three strains [CF1, MTN (metallothionein-wild-type), and MT1,2KO (MT1,2-deficient)] were placed on a low-calcium diet for 2 weeks. Each mouse was gavaged with 200 m...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/s0041-008x(03)00163-7
更新日期:2003-09-15 00:00:00
abstract::Staphylococcal enterotoxin C2 (SEC2), a member of bacterial superantigen, is one of the most potent known activators of T lymphocytes. With this property, SEC2 has already been used in clinic as a tumor immunotherapy agent in China. To increase the antitumor activity, a SEC2 mutant named ST-4 (GKVTG102-106WWH) with am...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2016.10.009
更新日期:2016-12-15 00:00:00
abstract::Hepa 1c1c7 (WT), TAOc1BPrc1 (CI), and BPrc1 (CII) mouse hepatoma cells were exposed to benzo[e]pyrene (B[e]P) or benzo[a]pyrene (B[a]P). B[e]P induced activity of a rat CYP1A1 reporter gene construct (-3015 to +2545 bp) by 1.8- to 2-fold and 5-fold in WT and CI cells, respectively. B[e]P caused a 2-fold induction of a...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1994.1175
更新日期:1994-09-01 00:00:00
abstract::Inflammatory responses are accompanied by increased expression of hepatocyte-derived proteins collectively known as acute phase reactants (APR). B6C3F1 female mice were exposed intraperitoneally every 24 hr to either vehicle (PBS) or DMN (5 mg/kg) for up to six exposures. Following a single treatment (acute), liver ti...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1994.1075
更新日期:1994-04-01 00:00:00
abstract::Chinese hamster cells (V79) were treated with ethylnitrosourea (ENU) and cis-diamminedichloroplatinum(II) (DDP) alone and in combination. Sister chromatid exchanges (SCEs) were quantified as measures of genotoxicity of the two agents. The combination experiment employed a factorial design in which cells were treated, ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(86)90117-1
更新日期:1986-09-15 00:00:00
abstract::Kidney is the primary target organ in chronic cadmium (Cd) toxicity, and oxidative stress plays an important role in this process. The nuclear transcription factor Nrf2 binds to antioxidant response elements (AREs) and regulates genes involved in protecting cells from oxidative damage. Whether kidney cells respond to ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2009.07.038
更新日期:2009-11-15 00:00:00
abstract::4-Hydroxy-2-trans-nonenal (4HNE), one of the major end products of lipid peroxidation (LPO), has been shown to induce apoptosis in a variety of cell lines. It appears to modulate signaling processes in more than one way because it has been suggested to have a role in signaling for differentiation and proliferation. It...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.taap.2015.10.006
更新日期:2015-12-15 00:00:00
abstract::Arsenic is a well-documented human carcinogen and is known to cause oxidative stress in cultured cells and animals. A hospital-based case-control study was conducted to evaluate the relationship among the levels of urinary 8-hydroxydeoxyguanosine (8-OHdG), the arsenic profile, and urothelial carcinoma (UC). Urinary 8-...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2007.08.021
更新日期:2008-01-01 00:00:00
abstract::Arsenic toxicity is a global health problem affecting millions of people. The objectives of this study were to determine if the toxic effects on primary cultured rat astroglia would be induced by different arsenicals. Based on alamarBlue assay and the single cell gel electrophoresis (SCGE, comet assay), the cell viabi...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2004.01.015
更新日期:2004-05-01 00:00:00
abstract::Pancreatic cancer is the fourth leading cause of cancer death in the United States with a very low survival rate of 5 years. To better design new preventive and/or therapeutic strategies for the fight against pancreatic cancer, the knowledge of the pathogenesis of pancreatic cancer at the molecular level is very impor...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.taap.2006.11.007
更新日期:2007-11-01 00:00:00
abstract::The immunosuppressive synthetic methylated polycyclic aromatic hydrocarbon (PAH), 7,12-dimethylbenz[a]anthracene (DMBA), has been shown to cause both an immediate and a sustained elevation of free intracellular calcium (Ca2+) in human T cells. In the present studies, a series of anthracene- and pyrene-based PAHs were ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1994.1161
更新日期:1994-08-01 00:00:00
abstract::Polychlorinated biphenyl (PCB)126 and perfluorooctane sulfonic acid (PFOS) are halogenated organic pollutants of high concern. Exposure to these chemicals is ubiquitous, and can lead to potential synergistic adverse effects in individuals exposed to both classes of chemicals. The present study was designed to identify...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2020.115301
更新日期:2020-12-15 00:00:00
abstract::The immunoreactivity and pharmacokinetics of a new horse F(ab')2 scorpion antivenom and its effect on Buthus occitanus mardochei venom plasma disposition in the rabbit were studied. The scorpion venom-specific F(ab')2 affinity constant determined by immunoradiometric assay was 1.6 +/- 0.6 10(8) M-1. One group received...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1996.0284
更新日期:1996-11-01 00:00:00
abstract::The effect of mucosal metallothionein (MT) preinduced by zinc (Zn) on tissue distribution of cadmium (Cd) after administration of Cd with several chelating agents was studied in rats. After Cd-cysteine (Cd-Cys) was incubated with intestinal Zn-MT in vitro, all the Cd dissociated from Cys and exchanged the Zn bound to ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(92)90129-g
更新日期:1992-04-01 00:00:00
abstract::Heavy metals in the environment originate from both human activities and natural processes. Exposure to these metals can result in important changes to immune activity. Depending on the metal and dose, these changes can result in enhanced immune function, diminished immune responses, or altered responses that produce ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.taap.2005.04.021
更新日期:2006-01-01 00:00:00
abstract::Tongue cancer is one of the most common oral malignancies. Quisinostat is a histone deacetylase inhibitor with antitumor activity. The aim of this study was to evaluate the effects of quisinostat on the viability of tongue squamous cell carcinoma (TSCC) cells (CAL-27, TCA-8113) in vitro and in vivo. Cell viability, ce...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2020.115363
更新日期:2021-01-01 00:00:00
abstract::Calcium uptake in cells occurs through specific membrane channels. Since cadmium and mercury inhibit calcium uptake, this study examined whether the calcium channels may also be involved in the uptake of these metals. Primary cultures of rat hepatocytes were incubated with 3 microM CdCl2 or HgCl2 in the absence or pre...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/s0041-008x(05)80018-3
更新日期:1991-09-01 00:00:00
abstract::Investigations have characterized addictive drug-induced developmental cardiovascular malformation in human, non-human primate and rodent. However, the underlying mechanism of malformation caused by drugs during pregnancy is still largely unknown, and preventive and therapeutic measures have been lacking. Using 1H NMR...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2012.03.003
更新日期:2012-05-01 00:00:00
abstract::The female reproductive toxicity of di-(2-ethylhexyl) phthalate and its active metabolite mono-(2-ethylhexyl) phthalate (MEHP) is attributed to suppression of ovarian granulosa cell estradiol production. In these studies, several structurally related phthalates (0-200 microM) and Wy-14,643 (0-100 microM) were compared...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.2001.9156
更新日期:2001-05-01 00:00:00
abstract::The embryotoxic and teratogenic potential of inhaled monochlorobenzene (MCB) was evaluated in rats and rabbits. Bred Fischer 344 rats and inseminated New Zealand White rabbits were exposed to 0, 75, 210, or 590 ppm of MCB via inhalation for 6 hr/day during the period of major organogenesis. Exposure to 590 ppm caused ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(84)90018-8
更新日期:1984-11-01 00:00:00
abstract::Methylmercury (MeHg) causes a multiphasic disruption of intraneuronal cation regulation. Release of Ca2+ from internal stores and entry of extracellular Ca2+ (Ca2+e) contribute to the temporally distinct early (first Ca2+ phase) and late (second Ca2+ phase) components of increased intracellular Ca2+ concentration ([Ca...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1995.1236
更新日期:1995-12-01 00:00:00
abstract::To understand the effect of thuringiensin on the lungs tissues, male Sprague-Dawley rats were administrated with thuringiensin by intratracheal instillation at doses 0.8, 1.6 and 3.2 mg/kg of body weight, respectively. The rats were sacrificed 4 h after treatment, and lungs were isolated and examined. Subsequently, an...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2006.05.013
更新日期:2006-10-15 00:00:00
abstract::Gene 33 (Mig6, ERRFI1) is an adaptor protein with multiple cellular functions. We recently reported that depletion of this protein promotes lung epithelial cell transformation induced by hexavalent chromium [Cr(VI)]. However, the early molecular events that mediate this process are not clear. In the present study, we ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2017.07.003
更新日期:2017-09-01 00:00:00
abstract::Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.taap.2015.08.022
更新日期:2015-11-15 00:00:00
abstract::Besides pathology endpoints, additional immune function endpoints have been included in the Note for Guidance on Repeated Dose Toxicity by the European Union (July 2001), which concern the analysis of antibody responses to a T-cell-dependent antigen. Guidance papers of other regulatory authorities are published as wel...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.taap.2005.02.030
更新日期:2005-09-01 00:00:00