A systematic review of possible serious adverse health effects of nicotine replacement therapy.

We conducted a systematic literature review to identify and critically evaluate studies of serious adverse health effects (SAHEs) in humans using nicotine replacement therapy (NRT) products. Serious adverse health effects refer to adverse events, leading to substantial disruption of the ability to conduct normal life functions. Strength of evidence evaluations and conclusions were also determined for the identified SAHEs.

Comprehensive review of epidemiological and animal studies on the potential carcinogenic effects of nicotine per se.

The effects of long-term use of nicotine per se on cancer risk, in the absence of tobacco extract or smoke, are not clearly understood. This review evaluates the strength of published scientific evidence, in both epidemiological and animal studies, for the potential carcinogenic effects of nicotine per se; that is to act as a complete carcinogen or as a modulator of carcinogenesis. For human studies, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a carcinogenic effect due to the limited information available.

Chemical, physical, and in vitro characterization of research cigarettes containing denicotinized tobacco.

The use of very low nicotine tobacco cigarettes is currently being investigated as a possible harm reduction strategy. Here, we report the smoke chemistry, toxicity, and physical characteristics of very low nicotine cigarettes that were made using blended tobacco processed through a supercritical CO2 fluid extraction, which resulted in elimination of 96% of nicotine content (denicotinized (denic) tobacco). Three types of test cigarettes (TCs) were manufactured with tobacco filler containing 100% denic tobacco (TC100), 50% denic tobacco and 50% unextracted tobacco (TC50/50), and 100% unextracted tobacco (TC0).

Emerging mechanistic targets in lung injury induced by combustion-generated particles.

The mechanism for biological effect following exposure to combustion-generated particles is incompletely defined. The identification of pathways regulating the acute toxicological effects of these particles provides specific targets for therapeutic manipulation in an attempt to impact disease following exposures. Transient receptor potential (TRP) cation channels were identified as "particle sensors" in that their activation was coupled with the initiation of protective responses limiting airway deposition and inflammatory responses, which promote degradation and clearance of the particles.

Reference moist smokeless tobacco-induced apoptosis in human monocytes/macrophages cell line MM6.

Moist smokeless tobacco use is associated with various types of oral injury, including leukoplakia and dipper's pouch, although the mechanism by which the injury is caused still remains unclear. One possible mechanism is that moist smokeless tobacco affects the inflammatory response. For example, a study by Johnson et al.

Role of plasma membrane disruption in reference moist smokeless tobacco-induced cell death.

An oral injury is thought to presage the development of mucosal lesions that are common in moist smokeless tobacco (MST) users. The abrasion or mechanical stress caused by direct contact of MST with the oral mucosa may contribute to this injury by causing transient disruptions in the cell membrane. In order to test this hypothesis, we developed an in vitro exposure system that directly exposes cells to reference MST on a rocking platform to simulate the abrasion that might be experienced in the oral cavity when using MST.

Role of oxidative stress and MAPK signaling in reference moist smokeless tobacco-induced HOK-16B cell death.

The use of smokeless tobacco products is often associated with an oral injury at the site of repeated use. To further our understanding of this injury process, the effect of reference moist smokeless tobacco extract (STE) on cell death, oxidative stress, and MAPK signaling in a human oral keratinocyte cell line, HOK-16B, was investigated. STE caused dose-dependent cell death and reactive oxygen species (ROS) production within 30 min to 3h of exposure.

Direct high-performance liquid chromatographic analysis of D-tocopheryl acid succinate and derivatives.

A method of analysis of a Vitamin E derivative D-tocopheryl acid succinate (TS) in biological fluids and commercially available products is necessary to study the kinetics of in vitro and in vivo metabolism, tissue distribution, and content uniformity. A simple and inexpensive high-performance liquid chromatographic method was developed for the direct determination of D-tocopheryl acid succinate in commercially available products, rat serum, and rat tissues. This method can also be applied to the determination of 15 Vitamin E derivatives.

Angiotensin II protects cultured midbrain dopaminergic neurons against rotenone-induced cell death.

In this study, we demonstrate that angiotensin II (Ang II) protects dopamine (DA) neurons from rotenone toxicity in vitro. Primary ventral mesencephalic (VM) cultures from E15 rats were grown for 5 days and then cultured in the presence of the mitochondrial complex I inhibitor, rotenone. Acute exposure (20 h) to 20 nM rotenone reduced the number of tyrosine hydroxylase-positive (TH+) neurons by 50 +/- 6% when compared to untreated cultures.

Pharmacokinetics and tissue distribution of d-alpha-tocopheryl succinate formulations following intravenous administration in the rat.

Unlike d-alpha tocopherol (T), d-alpha tocopheryl succinate (TS) has the unique ability to selectively kill tumor cells while protecting normal tissue from toxic oxidative stress. The pharmacokinetics of TS and the serum and tissue disposition of TS were studied in male Sprague-Dawley rats to delineate formulation dependent disposition between TS administered as the Tris salt (TS-T) (a liposomal formulation) or as the free acid (TS-FA) dissolved in polyethylene glycol (PEG) 400. The pharmacokinetics of TS was studied after single intravenous (i.

Role of mitochondria in toxic oxidative stress.

Oxidative stress and mitochondrial oxidative damage have been implicated in the etiology of numerous common diseases. The critical mitochondrial events responsible for oxidative stress-mediated cell death (toxic oxidative stress), however, have yet to be defined. Several oxidative events implicated in toxic oxidative stress include alterations in mitochondrial lipids (e.

Chemopreventive effect of dietary d-alpha-tocopheryl succinate supplementation on precancer colon aberrant crypt formation and vitamin E analogue levels in young and old rats.

This study examined the effects of dietary d-alpha-tocopheryl succinate (TS) in female rats, 20 mo (OLD) or 2 mo (YNG) of age, on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) and tissue distribution of d-alpha-tocopherol (alphaT), d-gamma-tocopherol (gammaT), and alphaTS. Rats were fed a commercial rodent chow supplemented with or without 1 (YNG) or 2 (OLD) g alphaTS/kg diet for 1 week prior to ip administration of AOM to induce colon ACF. The animals were sacrificed after 49 days of exposure.

Vitamin E analogues: a new class of inducers of apoptosis with selective anti-cancer effects.

In spite of unrelenting effort, the net incidence of neoplastic diseases appears not to have been curbed. While some types of cancer have been suppressed significantly, others are either stagnating or on the increase. Therefore, the need for a cure is imperative, in particularly a drug or combination of drugs that would be selective for malignant cells, i.

Fluorescence microplate reader measurement of tissue susceptibility to lipid peroxidation.

This unit describes a method for the measurement of cellular membrane antioxidant capacity or susceptibility of tissue samples to lipid peroxidation using a fluorescence microplate reader. The assay is simple and has the advantage of monitoring susceptibility to lipid peroxidation in a large number of samples in real time.

Chemotherapy induced gastrointestinal toxicity in rats: involvement of mitochondrial DNA, gastrointestinal permeability and cyclooxygenase -2.

Purpose: The gastrointestinal damage induced by xenobiotics is occurring more frequently and with greater toxicological significance than previously thought. Although there are some preliminary clinical studies and reports, there does not appear to be an extensive examination of gastrointestinal toxicity of various chemotherapeutic agents in the rat. This study was undertaken to examine the suitability of a rat model to detect the gastrointestinal damage after administration of various anti-neoplastic agents including etoposide, teniposide, melphalan, 5-fluorouracil, methotrexate and cisplatin.

Role of lipid peroxidation as a mechanism of liver injury after acetaminophen overdose in mice.

Mitochondrial oxidant stress and peroxynitrite formation have been implicated in the pathophysiology of acetaminophen-induced (AAP-induced) liver injury. Therefore, we tested the hypothesis that lipid peroxidation (LPO) might be involved in the injury mechanism. Male C3Heb/FeJ mice fed a diet high in vitamin E (1 g d-alpha-tocopheryl acetate/kg diet) for 1 week had 6.

Vitamin E therapy in Parkinson's disease.

Though the etiology is not well understood, late-onset Parkinson's disease (PD) appears to result from several key factors including exposure to unknown environmental toxicants, toxic endogenous compounds and genetic alterations. A plethora of scientific evidence suggest that these environmental and endogenous factors cause PD by producing mitochondrial (mito) oxidative stress and damage in the substantia nigra, leading to cell death. Thus assuming a critical role for mito oxidative stress in PD, therapies to treat or prevent PD must target these mito and protect them against oxidative damage.

Thenoyltrifluoroacetone, a potent inhibitor of carboxylesterase activity.

Thenoyltrifluoroacetone (TTFA), a conventional mitochondrial complex II inhibitor, was found to inhibit purified porcine liver carboxylesterase non-competitively with a K(i) of 0.61x10(-6)M and an IC(50) of 0.54x10(-6)M.

Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) in vivo.

Alpha-tocopheryl succinate (alpha-TOS), a redox-inactive analogue of vitamin E, is a strong inducer of apoptosis, whereas alpha-tocopherol (alpha-TOH) lacks apoptogenic activity (J. Neuzil et al., FASEB J.