Poly(ADP-ribose) polymerases (PARPs) are enzymes that catalyze the transfer of ADP-ribose units from β-nicotinamide adenine dinucleotide (NAD
+
) to acceptor proteins. PARP-1 is responsible for more ...than 90 % of protein poly-ADP-ribosylation in the brain and may play a role as a molecular switch for cell survival and death. The functional roles of PARP-1 are largely mediated by its activation after binding to damaged DNA. Upon binding, PARP-1 activity increases rapidly and cleaves NAD
+
into ADP-ribose and nicotinamide. Increased activity of PARP-1 can promote DNA repair and its interaction with several transcription factors, whereas hyperactivation of PARP-1 can result in poly(ADP-ribose) accumulation and depletion of NAD
+
and ATP which may lead to caspase independent apoptotic or necrotic cell death, respectively. Excessive PARP-1 activity has been implicated in the pathogenesis of numerous clinical conditions such as stroke, myocardial infarction, inflammation, diabetes, and neurodegenerative disorders. Therefore, it is not surprising that the search for PARP-1 inhibitors with specific therapeutic uses (e.g., brain ischemia, cancer) has been an active area of research. Beyond medicinal uses, naturally occurring PARP-1 inhibitors may also offer a unique preventative means at attenuating chronic inflammatory diseases through dietary supplementation. This possibility has prompted research for specific, naturally occurring inhibitors of PARP-1. Though fewer investigations focus on identifying endogenous inhibitors/modulators of PARP-1 activity in vivo, these activities are very important for better understanding the complex regulation of this enzyme and the potential long-term benefits of supplementation with PARP-1 inhibitors. With this in mind, the focus of this article will be on providing a state-of-the-science review on endogenous and naturally occurring compounds that inhibit PARP-1.
Neuronal cells injured by ischemia and reperfusion to a certain extent are committed to death in necrotic or apoptotic form. Necrosis is induced by gross ATP depletion or ‘energy crisis’ of the cell, ...whereas apoptosis is induced by a mechanism still to be defined in detail. Here, we investigated this mechanism by focusing on a DNA damage‐sensor, poly(ADP‐ribose) polymerase‐1 (PARP‐1). A 2‐h oxygen and glucose deprivation (OGD) followed by reoxygenation (Reox) induced apoptosis, rather than necrosis, in rat cortical neurons. During the Reox, PARP‐1 was much activated and autopoly(ADP‐ribosyl)ated, consuming the substrate, NAD+. Induction of apoptosis by OGD/Reox was suppressed by overexpression of Bcl‐2, indicating mitochondrial impairment in this induction process. Mitochondrial permeability transition (MPT), or membrane depolarization, and a release of proapoptotic proteins, i.e. cytochrome c, apoptosis‐inducing factor and endonuclease G, from mitochondria were observed during the Reox. These apoptotic changes of mitochondria and the nucleus were attenuated by PARP‐1 inhibitors, 1,5‐dihydroxyisoquinoline and benzamide, and also by small interfering RNA specific for PARP‐1. These results indicated that PARP‐1 plays a principal role in inducing mitochondrial impairment that ultimately leads to apoptosis of neurons after cerebral ischemia.
We evaluated the available pharmacokinetic data and human and animal toxicity data for 2,2′,3,3′,4,4′,5,5′,6,6′-decabromodiphenyl ether (BDE-209) (CASRN 1163-19-5) with the objective of deriving a ...reference dose (RfD) based on the best available science. The available studies for deriving an RfD were first screened using the Klimisch criteria and further evaluated using the United States Environmental Protection Agency's general assessment factors for data quality and relevance (i.e., soundness, applicability and utility, clarity and completeness, uncertainty and variability, and evaluation and review). The chronic 2-year dietary feeding study conducted by the United States National Toxicology Program (NTP, 1986, Technical Report Series No. 309) was selected for RfD derivation. Hepatocellular degeneration in male rats was chosen as the critical endpoint in the development of an RfD. For dose-response characterization, we applied benchmark-dose modeling to animal data and determined a point of departure (the 95% lower confidence limit for a 10% increase in hepatocellular degeneration) of 419 mg/kg-day for oral exposures. Based on the similar pharmacokinetic characteristics of BDE-209 across species, this value was converted to a human equivalence dose of 113 mg/kg-day by applying a dosimetric adjustment factor based on body weight scaling to the ¾ power. An oral RfD of 4 mg/kg-day was calculated by using a composite uncertainty factor of 30, which consisted of 10 for intraspecies uncertainty, 3 for interspecies uncertainty (i.e., 3 for toxicodynamics × 1 for toxicokinetics), and 1 for deficiencies with the database. We consider the RfD to be adequately protective of sensitive subpopulations, including women, their fetuses, children, and people with hepatocellular diseases.
Principles, advantages and range of applications of the laser welding method with the use of filler metal in the form of wire are presented. Various types of lasers and technological heads applied in ...this method and different variants of construction of welding and braze welding stations are discussed.
The paper presents the design and advantages of welding disc lasers. It shows the range of applications of these lasers for cutting and welding using various techniques: welding with deep fusion, ...hybrid welding methods, welding with beam focused at two points and scanner welding. The modernized robotic welding station of the Welding Institute equipped with the latest generation disc laser with a power of 12 kW is also described.
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