Pathways

Vinorelbine (also named Navelbine) is a semisynthetic vinca alkaloid. Vinorelbine are used as chemotherapy medication such as an antimitotic anticancer agent. The mechanism of vinorelbine is the inhibition of microtubule dynamics that would cause mitotic arrest and eventual cell death. As a microtubule destabilizing agent, vinorelbine stimulates mitotic spindle destruction and microtubule depolymerization at high concentrations. At lower clinically relevant concentrations, vinorelbine can block mitotic progression. Unlike the taxanes, which bind poorly to soluble tubulin, vinorelbine can bind both soluble and microtubule-associated tubulin. To be able stabilizing the kinetics of microtule, vinorelbine rapidly and reversibly bind to soluble tubulin which can increase the affinity of tublin by the induction of conformational changes of tubulin. Vinorelbine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding between vinorelbine and solubale tubulin decreases the rate of microtubule dynamics (lengthening and shortening) and increases the duration of attenuated state of microtubules. Therefore, the proper assembly of the mitotic spindle could be prevented; and the tension at the kinetochores of the chromosomes could be reduced. Subsequently, chromosomes can not progress to the spindle equator at the spindle poles. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.

Vinorelbine is a semi-synthetic third generation vinca alkaloid used in chemotherapy treatment for cervical, lung, breast, and esophageal cancers. It is differentiated from natural alkaloids by its eight-catharanine ring. Administered intravenously, vinorelbine acts on tumorous cells in the body to suppress their growth. Its main mechanism of action works by binding microtubules that are formed during the M phase of mitosis. This ceases the polymerization of microtubules, effectively pausing the cell at its G2/M phase. The disarray of microtubules induces two proteins; cellular tumor antigen p53 and cyclin-dependent kinase inhibitor p21. The latter protein works to inhibit cyclin-dependent kinases in the cell, which disrupt the phosphorylation of the apoptosis inhibitor Bcl-2. Bcl-2 suppresses apoptosis by regulating the permeability of the mitochondrial membrane but is unable to do so due to interrupted phosphorylation. The former protein, p53, acts on BAK and BAX to enact conformational changes, creating pores in the mitochondrial membrane that allow the exit of cytochrome c. Cytochrome c further activates caspases in the cell, which cleave essential cellular proteins. In this way, p53 and p21 work alongside each other to promote apoptosis and terminate unhealthy cells. Vinorelbine is especially valuable as a drug because it binds specifically to mitotic microtubules, likely decreasing its neurotoxicity.

Metabolites of Vinorelbine are predicted with biotransformer.

Viomycin is an antibiotic used to treat Mycobacterium tuberculosis and binds to the ribosome displacing structures leading to inhibition of protein synthesis. It binds to the interface between helix 44 of the small ribosomal subunit and helix 69 of the large ribosomal subunit which stops tRNA from binding to the A site and the addition of amino acids to a polypeptide chain.

Metabolites of Viomycin are predicted with biotransformer.

Viral sepsis begins when viral coat proteins activate the Toll-like receptors TLR4 and TLR2 on the membranes of macrophages, T-cells and dendritic cells. In addition to this protein activation, the viral DNA (or RNA if it is an RNA virus) is taken up by macrophage endosomes. Viral DNA fragments (such as CpG DNA) activates the endosomal TLR9, while viral double-stranded DNA fragments activates the endosomal TLR3 and viral single stranded RNA (if it is an RNA virus) activates endosomal TLR7/8 proteins. Different TRL receptors activate different processes for the innate immune response [1]. The TLR4 activates the production of interferon regulatory factor 3 (IRF3), TIR-domain-containing adapter-inducing interferon-β (TRIF), signal transducer and activator of transcription 1 (STAT1) and nuclear factor kappa B (NF-kB) in the cytoplasm, while TLR9, TRL3 and TLR7/8 activates the production of myeloid differentiation primary response 88 (MyD88), TRIF, interferon regulatory factor 7 (IRF7) and NF-kB in the cytoplasm [1]. The NF-kB protein then goes to nucleus and activates expression of nitric oxide synthase (iNOS) which generates nitric oxide (NO). It also activates aconitate decarboxylase (Irg1), tumor necrosis factor (TNF), interleukin 6 (IL-6) and interleukin 1 beta (IL-1β). These are the pro-inflammatory proteins while nitric oxide (NO) is also a pro-inflammatory molecule that can lead to the production of oxidized tyrosines (i.e., nitrotyrosine). Similarly, the newly expressed IRF3 and IRF7 proteins go to nucleus and activate the production of interferon beta (IFN- β), which is another pro-inflammatory cytokine. The other cytokines, TNF, IL-6, IL-1β and IFN-β move into the bloodstream and head to the brain and into the hypothalamus, leading to release of the hypothalamic corticotropin releasing hormone (CRH) [2]. CRH, in turn, activates the release of pituitary adrenocorticotropic hormone (ACTH), which then moves down through the blood stream towards the adrenal glands (located at the top of the kidneys) to produce cortisol and epinephrine. Cortisol and epinephrine stimulate the ”flight or fight” response, leading to the increased production of glucose from the liver (via glycogen breakdown) and the release of short-chain acylcarnitines (also from the liver) to help support beta-oxidation of fatty acids. These compounds support cell synthesis and growth of the macrophages and neutrophils used in the innate immune response. The liver also produces more IL-6, more TNF and more NO to further stimulate the innate immune response. Higher nitric oxide (NO) levels lead to blood vessel dilation and reduced blood pressure, which in its most extreme form, can be a major problem in sepsis. Higher iNOS expression in macrophages, neutrophils and dendritic cells consumes the amino acid arginine to produce more NO which disrupts the mitochondrial TCA cycle leading to the accumulation of citrate and the production of fatty acids and acylcarnitines (needed for lipid synthesis). Increased Irg1 (actonitate decarboxylase) expression leads to accumulation of succinate, which results in the succinylation of phosphofructokinase M2 (PKM2) [3]. Succinate also leads to the release of hypoxia inducible factor 1-alpha (HIF-1α) from its PHD-mediated inhibition. HIF-1α interacts with succinylated PKM2 and induces the expression of glycolytic genes such as Glut1 (the glucose transporter) and the pro-inflammatory cytokine IL-1β [3]. As a result of these metabolic changes and the deactivation of the oxidative phosphorylation pathway in their mitochondria, macrophages, neutrophils, T-cells and dendritic cells shift to aerobic glycolysis [4]. This leads to the production of more reactive oxygen species (ROS) which results in the oxidation of certain amino acids, such as methionine. This leads to the increased production of methionine sulfoxide (Met-SO). As the inflammatory response continues, more glucose and arginine in the bloodstream are consumed by dividing white blood cells to produce more lactate and more NO to further push the aerobic glycolytic pathway [4]. This aerobic glycolysis occurs primarily in white blood cells leading to active cell division and rapid white cell propagation (growing by a factor of three to four in a few hours). Hexokinase (HK) along with increased levels of lactate from aerobic glycolysis activate the inflammasome inside macrophages and dendritic cells, leading to the secretion of IL-1β. This cytokine further drives the aerobic glycolysis pathway for these white blood cells. All these signals and effects combine to lead to the rapid and sustained production of large numbers of macrophages, neutrophils, dendritic cells and T-cells to fight the viral infection. This often leads to a reduction in essential amino acids (threonine, lysine, tryptophan, leucine, isoleucine, valine, arginine) and a mild reduction in gluconeogenic acids (glycine, serine) in the bloodstram. The reduction in essential amino acids is intended to “starve” the invading viruses (and other pathogens) of the amino acids they need to reproduce [4]. Some of the reduction in amino acid levels is moderated by the proteolysis of myosin in the muscle and the proteolysis of serum albumin in the blood (the most abundant protein in the blood, which is produced by the liver). These proteins act as amino acid reservoirs to help support rapid immune cell production. The loss of serum albumin in the blood to help support amino acid synthesis elsewhere can lead to hypoalbuminemia, a common feature of infections, inflammation, late-stage cancer and sepsis. At some point during the innate immune response, the kynurenine pathway becomes dysregulated, potentially through over-stimulation by interferon gamma (IFNG). This hyperstimulation leads to large reductions in tryptophan levels as the indole dioxygenase (IDO) enzyme becomes more active. IDO activation results in the generation (from tryptophan) of large amounts of kynurenine (and its other metabolites) through a self-stimulating autocrine process. Kynurenine binds to the arylhydrocarbon receptor (AhR) found in most immune cells [5-7]. In addition to increased kynurenine production via IDO mediated synthesis, hyopalbuminemia can also lead to the release of bound kynurenine (and other immunosuppressive LysoPCs) into the bloodstream to fuel this kynurenine-mediated process. Regardless of the source of kynurenine, the kynurenine-bound AhR will migrate to the nucleus to bind to NF-kB which leads to more production of the IDO enzyme, which leads to more production of kynureneine and more loss of tryptophan. High kynurenine levels and low tryptophan levels leads to a shift in T-cell differentiation from a TH1 response (pro-inflammatory) to the production of Treg cells and an anti-inflammatory response [5-7]. High kynurenine levels also lead to the production of more IL10R (the interluekin-10 receptor) via binding of kynurenine to the arylhydrocarbon receptor (AhR). Activated AhR effectively increases the anti-inflammatory response from interleukin 10 (an anti-inflammatory cytokine). Low tryptophan levels also lead to the activation of the general control non-depressible 2 kinase (GCN2K) pathway, which inhibits the mammalian target of rapamycin (mTOR), and protein kinase C signaling. This leads to T cell autophagy and anergy. High levels of kynurenine also lead to the inhibition of T cell proliferation through induction of T cell apoptosis [5-7]. In other words, kynurenine leads to a blunted immune response as neither sufficient B-cells, macrophages nor T-cells (which are needed for B-cell production) are produced, leading to further immune suppression. This allows for uncontrolled viral propagation. As a result, the invading viruses are NOT successfully cleared. This leads to a “vicious” or futile cycle where the growing virus population pushes the body to produce more B-cells and T-cells and various organs (muscles, heart, liver) exhaust themselves to produce a more metabolites to fuel the pro-inflammatory response, while the kynurenine/tryptophan cycle keeps on killing off T-cells and blunting the immune response [5-7]. This “futile” cycle of producing ineffective B and T cells, leads to heightened lactate production resulting in lactic acidosis. Likewise, as more NO is produced, this leads to a further loss of blood pressure – both lactic acidosis and hypotension can lead to organ failure. The continuous release of proinflammatory cytokines through the failed fight to eliminate the virus can also damage the alveolar-capillary barrier in the lungs. Loss of integrity of this lung barrier leads to influx of pulmonary edema fluid and lung injury or fluid in the lungs. Excessive, long-term release of glucose, short-chain acylcarnitines and fatty acids from the liver along with higher amino acid production from the blood and liver via proteolysis of albumin (leading to more extreme hypoalbuminemia), results in reduced uremic toxin clearance and increased levels of uremic solutes in the blood. High levels of uremic toxins lead to liver, heart, brain and kidney injury [8]. Likewise excessive release of acylcarnitines from the heart and liver leads to heart and liver injury. Organ failure often develops in end-stage sepsis, leading to death.

Although abdominal obesity or visceral obesity is considered to be one of the components of metabolic syndrome and to have an important role in a cluster of cardiovascular risks, there is no consensus about the definition and diagnostic criteria for this syndrome, probably because there is considerable disagreement about the location and definition of abdominal obesity or visceral obesity. The importance of diagnosing metabolic syndrome, in which visceral fat accumulation plays an essential role in the development of multiple risk factors, should be emphasized because lifestyle modification for the reduction of visceral fat may be very effective for the reduction of risks of this type, namely metabolic syndrome in the narrow sense.