A critical role for persistent inflammation in the pathogenesis of multiple diseases with diverse clinical manifestations such as the immune mediated rheumatoid arthritis (RA)/multiple sclerosis (MS) or the neurodegenerative Alzheimer’s disease (AD)/Parkinson’s disease (PD) is currently well recognized 1-5 . Sustained or unregulated activation of the transcription factor, nuclear factor kappa B (NF-) is integral to the persistence of inflammation 6, 7. The term NF-B includes five structurally related and evolutionarily conserved rel proteins: RelA (p65), RelB, c-Rel (REL), NF-B1 (p50 and its precursor p105), and NF-B2 (p52 and its precursor p100) 2. In resting cells, NF- exists in the cytoplasm in several dimeric forms bound to I inhibitory proteins8. NF-B signaling can be activated via the canonical or alternative pathways. Activation of NF-B via the canonical pathway mediated by microbial products or cytokines such as tumor necrosis factor-alpha (TNF- induces proteolytic degradation of the IB inhibitory proteins releasing the p50:p65subunits. p65 is the functionally dominant subunit which upon release from the inhibitory complex translocates to the nucleus, where it binds cognate NF-B binding sites in the DNA and modulates expression of several genes involved in apoptosis, immune and inflammatory responses. The NF-B signaling by alternative pathway is primarily stimulated by ligation of TNF family of receptors, involves RelB activation and modulation of genes related to cell division, differentiation and survival2, 7.
Mechanistically many drugs used in the treatment of chronic inflammatory pathologies act at least in part by inhibiting NF-B transactivation. For example, the effects of many of the non-steroidal anti-inflammatory drugs (NSAID) are mediated by suppression of NF-B activation by inhibiting IKK complex or by activation of peroxisome proliferation-activated receptor PPAR-γ, a negative regulator of NF-B transcription2, 9. The profound anti-inflammatory potential of the widely used glucocorticoids is largely attributed to the inhibition of p65 induced transactivation of inflammatory genes10. Furthermore, targeting NF-B activation is one of the mechanisms of action of many currently approved biologics. The efficacies of anti-TNF-treatment11 or of abatacept, a T cell costimulatory antagonist in RA12 or that of glatiramer acetate in MS13 are associated with indirect inhibition of NF-B signaling. However non-specific responses, serious adverse effects and/or high cost are some of the factors that compromise the long-term use of these therapeutic agents. Hence development of potent and selective inhibitors of the NF-B canonical signaling pathway for inflammation associated chronic pathologies constitute an important goal of many researchers and pharmaceutical companies involved in drug discovery.
Ding T, Ledingham J, Luqmani R, Westlake S, Hyrich K, Lunt M, Kiely P, Bukhari M, Abernethy R, Bosworth A, Others. BSR and BHPR rheumatoid arthritis guidelines on safety of anti-TNF therapies.Rheumatology. 2010; 49 (11): 2217--2219.
Neurofibromatosis is caused by the loss of function mutation in the Nf1 gene. Nf1 encodes neurofibromin, a protein with a Ras GTPase activating domain. Neurofibromin is critical for the regulation of proliferation and differentiation of progenitor cells. It has bee...
This is due to the fact that the binding of a ligand to this receptor triggers processes which change the synthesis of proteins, such as enzymes, through gene transcription in order to bring about a response at a cellular level [5]. An example of a drug that acts on this receptor is Pazopanib, which Stenberg [6] states acts on vascular endothelial growth factor and platelet derived growth factor receptors as well as c-Kit to block tumour growth and inhibit
We are amazing human beings. Our bodies have been carefully constructed to protect ourselves from injury and harm. The protection of our body begins with the brilliant intervention of one small cell. According to Huether and McCance (2012), adaptive immunity is considered the third line of defense within our bodies. Adaptive immunity is summoned after the frontline or “external barriers” are compromised (Huether & McCance, 2012, p. 142). The process of inflammation arrives at the scene of invasion; next adaptive immunity is organized. Adaptive responses help our bodies fight disease at the scene. Additionally, adaptive responses maintain a unique memory to protect the body from future invasions. This paper will explore examples of the specific pathophysiology and associated alterations caused by adaptive responses.
COX-1 and COX-2 are isomeric enzymes that contain peroxidase and cyclooxygenase activity which can produce prostaglandins through the activity of prostaglandin G/H synthases [10]. COX-1 produces prostanoids which serve cell “housekeeping” functions. COX-2 can be activated by inflammatory stimuli and produces prostanoids in inflammatory or proliferative diseases such as cancer. Nonsteroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of COX. Thus the binding of NSAIDs can supress prostanoid formation [11].
Reinarman, Craig and Peter D. A. Cohen and Hendrien L. Kaal. “The Limited Relevance of Drug
Some severe asthmatics who require high doses of ICS and prednisone appear to be susceptible to recurrent infections. Bacterial infections can lead to chronic lower airway inflammation and worsening of asthma. This is widely believed to be a result of steroid usage which suppresses the inflammatory response. However, a recent study by Zuccaro et al., has reported a relationship between HDAC activity and the expression of scavenger receptors on macrophages, which may suggest an underlying predisposition to infection. Specifically, HDAC inhibition resulting from increased PI3K levels in severe asthmatics has been associated with a reduction in innate immune genes in macrophages including the scavenger receptor (MARCO) (Figure 2).7 MARCO has shown to play a role in anti-bacterial host defenses as it can bind gram-positive bacteria such as staphylococcus aureus and gram-negative bacteria.8 Decreased MARCO expression was seen in asthmatics that had recurrent infective neutrophilic bronchitis compared to asthmatics who did not have a history of recurrent infective bronchitis. These patients also had a significant reduction in HDAC.7 HDAC
Moreover, despite its teratogenic effects, there was a renewed interest in its potential to treat many diseases due to its anti-inflammatory and immunomodulating properties [16]. A historically important example is a report of its remarkable effects in the treatment of lesions associated with erythema nodosum leprosum (ENL) [5,6]. Erythema nodosum leprosum is an immune mediated reactional state that complicates lepromatous leprosy. It is characterized by the presence of cutaneous nodules but peripheral organs may also be affected [7]. The treatment of ENL is difficult because of prolonged requirement of high doses of steroids, which do not always control the inflammation associated with the disease. In addition, the immunosuppressive effects of corticosteroids may, per se, pose life-threatening risks for the patients [8]. Treatment with thalidomide provides an effective alternative to steroid therapy, as it shows better long-term control and avoids adverse effects of prolonged steroid therapy, primarily due to its action on TNF-α; thalidomide inhibits TNF-α synthesis by inducing TNF-α mRNA degradation [9, 24]. Most patients feel the benefit within 24-48 h starting at a dose of 25-200mg/d. [4]. As a consequence, in 1998, the Food and Drug Administration (FDA) of the United States approved thalidomide for use in
Sadly, this world is majorly affected by disease. It tears families apart, ruins lives, and brings pain to the affected. This long list of life-destroying diseases includes systemic lupus erythematosus, or SLE. “[SLE] is a multisystemic, autoimmune disease of unknown etiology, which affects multiple organ systems, including the central nervous system, or CNS” (Milovancevic et al.). This disease will literally turn a person’s body against itself. It leads to a lot of pain in the victim. The optimistic side of this coin, however, tells us that many pharmacologists, over time, have created medications that can also nullify the effects of the symptoms. This includes a list of medications, such as antimalarial drugs, non-steroidal anti-inflammatory
Nickel and Dimed: On (Not) Getting By in America, published in 2001 by Barbara Ehrenreich, is a book about an author who goes undercover and examines lives of the working lower class by living and working in similar conditions. Ehrenreich sets out to learn how people survive off of minimum wage. For her experiment, she applies rules including that she cannot use skills acquired from her education or work during her job search. She also must take the highest-paying job offered to her and try her best to keep it. For her search of a home, she has to take the cheapest she can find. For the experiment, Ehrenreich took on low-wage jobs in three cities: in Florida, Maine, and Minnesota.
Multiple Sclerosis (MS) is a chronic autoimmune neurological disease that debilitates an estimated 2.3 million people worldwide (“What is MS,” n.d.). With no identifiable cause and a cure yet to be discovered, emphasis must be placed on advancing treatments and therapies. Although its pathogenesis is not completely understood, researchers are well aware that the immune response during MS revolves around inflammatory mediators called cytokines. Over the last few decades, substantial progress has been achieved in MS research and knowledge of cytokines in MS has considerably increased, allowing for the development of numerous drugs, including the successful Glatiramer
A disproportion of pro-inflammatory and anti-inflammatory cytokines is known to be a contributory cause of pain and pain behavior. Embedded into psychoneuroendocrine and immunological feedback control systems, cytokines are able to perpetuate a vicious connection between local inflammation and systemic pain behavior (pain/sickness behavior), contributing towards chronification of nonspecific musculoskeletal pain. TNF-α (through NF-κB in astrocytes) causes release of CCL-2, which interacts positively with both NMDA and AMPA receptors in neurons. This adversely affects central descending pain modulation leading to failure of resolution state. Moreover; Co-localization of IL-1β and NMDA receptors on neuron, and, phosphorylation of NMDA on being stimulated by IL-1 explains direct role of immune system in establishing nociceptive neuronal circuit.
People incorporate inflammation whenever there is a presence of pain, swelling, or redness to a person’s body part. Inflammation gives a sign that there is an infection or tissue damage. Inflammations is part of human’s defensive response whenever their body is injured or invaded by small organism like germs and viruses. This response was then distinguished as a branch of immune system. Scientists discovered that the inflammatory response is due to the molecular structure known as the inflammasomes. Inflammasomes are molecular structure that have white blood cells, which contains macrophages; macrophages spits out protein that immobilize and weaken the microbes (Mehal 2015). Based on the study, inflammasomes can be found in every part of our body. The most common inflammasome that can be found in our body is NLRP3. For each inflammasome to be active, it has to be triggered by invaders. The concern about inflammasome is it contributes a wide range of diseases.
The dysfunction can be either inappropriately low production of glucocorticoids or an impaired response to cortisol in the systemic circulation. Molecular interactions, classified as either genomic or nongenomic pathways, may contribute to impaired cortisol response. The genomic pathways can affect the clinical interaction of cortisol with the glucocorticoid receptor (GR) via either transactivation or transrepression (4, 8). The GR plays an integral role in facilitating the activity of glucocorticoids, and GR-binding affinity has been demonstrated to be altered in severe sepsis and septic shock (4,8). The nongenomic effects include the interaction of glucocorticoids with vascular membranes, cellular junctions, and the various signaling pathways between cellular mediators
Pre-discovery process is the first stage of drug discovery. During Pre-discovery stage chemists and pharmacologists endeavor to understand and identify the factors which can play a significant role in the particular disease. After revealing the cause of disease or understanding it a target molecule against which drug will act is being chosen. In order to understand the structure the target molecule is eliminated, isolated and its various interactions are inquired. Understanding interactions of the molecule can be helpful in finding treatment of a specific disease. Next stage includes the demonstration that the chosen molecule is relevant to the disease and proof that the drug target is associated with a desired change in the behavior of diseased cells (PPD, 2011).