Acetaminophen

With all living organisms, a process known as cell respiration is integral in order to provide the body with an essential form of energy, adenosine triphosphate (ATP). Oxygen, although an essential part of this process, can form reactants from colliding with electrons associated with carrier molecules. (pb101.rcsb.org, 2017). Hydrogen peroxide is an integral product of this reaction but is known to impose negative effects on the body if high levels are introduced. Explicitly, this reaction is caused “If oxygen runs into (one of these) carrier molecules, the electron may be accidentally transferred to it. This converts oxygen into dangerous compounds such as superoxide radicals and hydrogen peroxide, which can attack the delicate sulphur atoms and metal ions in proteins.” (pdbh101.rcb.org, 2017). Research has suggested that the hydrogen peroxide can be converted into hydroxyl radicals, known to mutate DNA, which can potentially cause bodily harm due to DNA’s role in the synthesis of proteins. These radicals can cause detrimental effects on the human body, and studies have suggested a link to ageing. Due to the harmful effects of these H2o2, it is important that the body finds a way to dispose of hydrogen peroxide before concentrations are too great.

Similarly, an increase in the levels of lipid peroxidation was observed in Aβ-induced rat hippocampal cells, confirming previous reports [17]. Enzymatic antioxidants such as SOD, catalase, and GPX act as the cellular antioxidant defense mechanism against free radicals. Since NADPH is required for the regeneration of catalase from its inactive form, catalase activity might be decreased in Aβ induced toxicity due to reduced NADPH levels. In this study, we have reported that Honokiol treatment significantly increased the enzymatic antioxidant activities in APP-CHO cells. In addition, non-enzymatic antioxidants like GSH also exhibited beneficial neuroprotective effects against oxidative stress. GSH is an endogenous nonenzymatic antioxidant that prevents damage to cellular components caused by ROS such as free radicals and peroxides. GSH is oxidized to glutathione disulfide (GSSG) by ROS, thereby causing a reduction in the level of GSH. GR reduces GSSG to GSH via NADPH, which in turn is released by glucose-6-phosphate dehydrogenase [18]. Honokiol treatment upregulated the activity of these antioxidants in APP-CHO cells. In addition to oxidative stress, a strong association between insulin resistance and the development of AD has been demonstrated. Several studies have reported that insulin resistance (IR), an underlying characteristic of type 2 diabetes, is an important risk factor for AD

For example, although the unesterified form of AA is in nM range in blood (Brash 2001), in the other tissues the unesterified AA concentration has been reported to be remarkably higher, for example ~13-44 µM in umbilical cord and intervillous space (Benassayag, Mignot et al. 1997), ~19 µg/g (approximately equivalent to 60 µM) in skin (Hammarstrom, Hamberg et al. 1975), and ~75 µg/g (approximately equivalent to 250 µM) in liver (Edpuganti and Mehvar 2013). Therefore, in several published studies investigating P450-mediated AA metabolism in vitro, 50-100 µM of AA was deemed to be mimicking the in vivo situation (Xu, Falck et al. 2004, Imaoka, Hashizume et al. 2005). Noteworthy, in response to stimuli, the release of the free AA has been reported to be remarkably increased (Buczynski, Dumlao et al. 2009). The unesterified AA is then metabolized into several biologically active metabolites, termed eicosanoids, by one of three groups of enzymes: cyclooxygenases, lipoxygenases, or microsomal P450 enzymes (Buczynski, Dumlao et al.

Although all in vitro models have limitations, our studies described in this thesis have demonstrated that these models, when used appropriately, will enable us to investigate specific research questions under different circumstances. By using different human-based in vitro models, our current findings have indicated that the high-dose APAP induces mitochondrial dysfunction, including the decrease in ATP synthesis and the increase in mitochondrial ROS formation, by disrupting the expression of key genes encoding the elements of respiratory chain complexes and mitochondrial and cellular specific antioxidants in both normal and inflamed livers (Chapter III and Chapter V). Besides, the whole-genome expression data obtained from PHH have suggested the high interindividual variation in the expression of genes participating in the Phase I/III drug metabolism/transport at baseline and the APAP-induced variation in genes involved in immune response may influence susceptibility to APAP hepatotoxicity (Chapter IV). The exposure of a 3D co-culture model to APAP with/without LPS has revealed the interaction between PHH and KCs (Chapter V). Through this novel model, we have identified that the median-dose APAP may reduce the KC phagocytic capacity by inhibiting the expression of Fcγ receptor-coding genes and prolong the clearance of pathogen and cell debris, which enhance KC mediated inflammatory response and exacerbate liver damage in

Oxidation factors such as smoking cigarettes or bacterial infection can split apart molecules held by weak bonds, resulting in an unstable molecule with unpaired electron known as free radical.35 These free radicals start attacking the healthy nearby cells and attempt to replace their missing electron. When an attacked molecule loses its electron, it becomes a free radical itself. The damaged cell can release free radicals and continue the effects of oxidative stress to surrounding cells. The resulting oxidative stress can damage the endothelial cell wall by lipid peroxidation. Reactive oxidative species attack the cell membrane composed of polyunsaturated fatty acids by initiating the self-propagating chain reaction. Destruction of the cell membrane causes the osmotic disequilibrium that imbalances the entry/exit pathway of water molecules, proteins, enzymes, and other nutrients inside the cell. This further leads to cross-linking of proteins which disrupts extracellular signaling molecules to recognize their target proteins and utilize them for fulfilling specific functions in the body. Lipid peroxidation

the defensive systems can be enzyme hunters of reactive oxygen species such as catalase enzyme etc. they can also be non-enzyme hunter molecules like certain vitamins like vitamin a c e also can consist of various antioxidants present in food chemical biological effects the oxidative stress can have two types of effects. they are:- chemical effects of oxidative stress is mainly due to increased production of reactive oxygen species reactive nitrogen species. due to this increased production of reactive species there is a decrease in the efficiency of antioxidant or detoxifying defences. the effect of oxidative stress depends upon the types of changes it brings. if changes are small cells can overcome these changes thus retains its original state. if the changes are moderate then oxidative stress can cause programmed cell death while on the other hand heavy or intense changes can cause either direct cell death or can cause any type of cell injury which ultimately causes cell death. the generation of ros is a destructive aspect of oxidative

Microarray analysis displays activated the expression of genes related in apoptosis pathways and suppressed the expression of genes involved in cell cycle and DNA replication and repair process after idiosyncratic drug exposure. Meanwhile, the specific immune reaction induced-TNF secretion disrupts the balance of the metabolism of sphingolipids and boosts the concentration of ceramides. The increase in ceramides, especially the long-chain and very long-chain ceramides, alters mitochondrial membrane permeability. Taken together, the inflammatory

There are three major classifications of drug induced liver injury that occur as a result of both intrinsic and idiosyncratic hepatotoxicity: Hepatocellular injury, cholestatic injury and mixed hepatostatic and cholestatic injury. Hepatocellular injury, as the name suggest, refers to the injury to the liver cell. Cholestatic injury refers to injury to the biliary system. Mixed hepatocellular and cholestatic injury refers to injury to both the liver cells and the biliary system. Other less common types of DILI include chronic hepatitis, chronic cholestatis, granulomatous hepatitis, fibrosis or cirrhosis, and

The major harmful effects of free radicals include oxidative stress and nitrosative death. Oxidative death is caused by ROS and nitrosative death by RNS. When the cells are unable to maintain the state of ‘Redox Homeostasis’ (keeping equilibrium between the beneficial and harmful effects of free radicals) it causes oxidative stress through the generation of ROS (12) and resultant oxidative injury. Potential biological damage happens when there is an overproduction of ROS and RNS and a down regulation of enzymatic and non-enzymatic antioxidants. Since ROS owns impact of powerful oxidizing agents, they interfere with the expression of a number of genes involved in the activation of signal transduction cascades (13, 14), apoptosis (15,16) etc.

The mechanism by which adenine induces CKD is not well elucidated. Adenine and its metabolite, DHA, have low solubility and precipitate in the renal tubules leading to their occlusion and the development of uremia [7, 14]. It has been reported that, adenine has an affinity to cause several oxidative and inflammatory reactions in renal tissues which might cause an increase in several oxidative and inflammatory markers such as catalase, GSH, SOD [12, 17, 22-24]. Adenin treatment caused oxidative stress within the cells. Which demonstrated by the increase in the oxidative derivative of deoxyguanosine, 8-OHdG, one of the major DNA oxidative products

Mechanisms of 4-HNE detoxification, clearance, and inhibition. A.) Subjection to sources of oxidative stress leads to production of ROS. These reactive species induce lipid peroxidation at cell and organelle membranes, which gives rise to a toxic byproduct: 4-HNE. This cytotoxic aldehyde is then free to form protein adducts with various targets via Michael addition, which often results in protein dysfunction and even cell death. B. & C.) Two molecules were recently identified as possible therapeutic targets for 4-HNE mediated cellular damage in hyperoxic acute lung injury. B.) Deletion of ASK1 is associated with a decrease in ROS production, which subsequently prevents formation of lipid peroxidation byproducts. C.) Knockdown of the P2X7 membrane

The importance of oxidative stress in cisplatin-induced toxicity was documented by several studies which found that the drug was able to generate reactive oxygen species (ROS), such as superoxide anion and

DJ-1 protects against mtDNA damage, mitophagy and cell death. DJ-1 is a multifunctional protein that protects cells from oxidative stress via several molecular processes including regulating gene transcription, mediating cell signal transduction pathways, stabilizing cytoprotective proteins and scavenging ROS (3). DJ-1 is expressed in human primary alveolar type II cells (preliminary data) and we have recently postulated that plays a role in the antioxidant defense system in the lung (REF). The importance of DJ-1 can be supported by several observations. First, DJ-1 mutations are pathogenic (4), second, oxidation of cysteine and methionine residues within DJ-1 was reported as a sensor of its activity (5) and third, the novel oxidized

The role of oxidative stress is the imbalance of detoxified free radicals. When the body fails to detoxify free radicals, the free radicals take an electron from another molecule. As a result, the molecule is no longer stable. An unstable molecule can lead to damage within the cell and cause the cell to function improperly. Therefore, preventing oxidative stress is very important for the cell to maintain its proper function. If the cell does not function properly, an increase in antioxidants can help to repair the cell. Antioxidants are produced by the cell but increasing antioxidants for example in ones diet can reduce the amount of free radicals in the body that cause harm and as a result lead to oxidative stress in the body.

An increase of peroxidase activity is one of the key points, which contributes to the mitochondrial synthesis of reactive oxygen species (ROS) for example CL oxidation. Since ROSs are normally regarded as harmful factors to the cell, the increase level of ROS has a significant role in inducing apoptosis. Thus, the oxidation of CL might be necessary to induce the mitochondria membrane leakage, and release of pro-apoptotic substances, such as protein tyrosine phosphatases (PTP) into the cytosol.Additionally, the released cyt c can play some other roles. It can interact with and oxidize another phospholipid phosphatidylserine (PS) with negative charges, which is another important function of cyt c in apoptosis.12 It is also able to bind to the apoptotic protease-activation factor-1 (APAF1), and stimulate its heptamerization to finally activate the caspase based apoptosis.13 Lots of detailed studies have been done on the cyt c-lipid interaction which will be discussed later in the