Ibuprofen-based advanced therapeutics: breaking the inflammatory link in cancer, neurodegeneration, and diseases.
TL;DR: Ibuprofen is a classical nonsteroidal anti-inflammatory drug (NSAID) highly prescribed to reduce acute pain and inflammation under an array of conditions, including rheumatoid arthritis, osteoarthritis, dysmenorrhea, and gout.
Abstract: Ibuprofen is a classical nonsteroidal anti-inflammatory drug (NSAID) highly prescribed to reduce acute pain and inflammation under an array of conditions, including rheumatoid arthritis, osteoarthritis, dysmenorrhea, and gout. Ibuprofen acts as a potential inhibitor for cyclooxygenase enzymes (COX-1 and COX-2). In the past few decades, research on this small molecule has led to identifying other possible therapeutic benefits. Anti-tumorigenic and neuroprotective functions of Ibuprofen are majorly recognized in recent literature and need further consideration. Additionally, several other roles of this anti-inflammatory molecule have been discovered and subjected to experimental assessment in various diseases. However, the major challenge faced by Ibuprofen and other drugs of similar classes is their side effects, and tendency to cause gastrointestinal injury, generate cardiovascular risks, modulate hepatic and acute kidney diseases. Future research should also be conducted to deduce new methods and approaches of suppressing the unwanted toxic changes mediated by these drugs and develop new therapeutic avenues so that these small molecules continue to serve the purposes. This article primarily aims to develop a comprehensive and better understanding of Ibuprofen, its pharmacological features, therapeutic benefits, and possible but less understood medicinal properties apart from major challenges in its future application.KEY POINTSIbuprofen, an NSAID, is a classical anti-inflammatory therapeutic agent.Pro-apoptotic roles of NSAIDs have been explored in detail in the past, holding the key in anti-cancer therapies.Excessive and continuous use of NSAIDs may have several side effects and multiple organ damage.Hyperactivated Inflammation initiates multifold detrimental changes in multiple pathological conditions.Targeting inflammatory pathways hold the key to several therapeutic strategies against many diseases, including cancer, microbial infections, multiple sclerosis, and many other brain diseases.
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TL;DR: In this article, a review of the emerging evidence enlightening the neuroprotective outcomes of PPAR agonists in in vivo and in vitro models experiencing Parkinson's disease is presented.
Abstract: One of the utmost frequently emerging neurodegenerative diseases, Parkinson’s disease (PD) must be comprehended through the forfeit of dopamine (DA)-generating nerve cells in the substantia nigra pars compacta (SN-PC). The etiology and pathogenesis underlying the emergence of PD is still obscure. However, expanding corroboration encourages the involvement of genetic and environmental factors in the etiology of PD. The destruction of numerous cellular components, namely oxidative stress, ubiquitin-proteasome system (UPS) dysfunction, autophagy-lysosome system dysfunction, neuroinflammation and programmed cell death, and mitochondrial dysfunction partake in the pathogenesis of PD. Present-day pharmacotherapy can alleviate the manifestations, but no therapy has been demonstrated to cease disease progression. Peroxisome proliferator-activated receptors (PPARs) are ligand-directed transcription factors pertaining to the class of nuclear hormone receptors (NHR), and are implicated in the modulation of mitochondrial operation, inflammation, wound healing, redox equilibrium, and metabolism of blood sugar and lipids. Numerous PPAR agonists have been recognized to safeguard nerve cells from oxidative destruction, inflammation, and programmed cell death in PD and other neurodegenerative diseases. Additionally, various investigations suggest that regular administration of PPAR-activating non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, indomethacin), and leukotriene receptor antagonists (montelukast) were related to the de-escalated evolution of neurodegenerative diseases. The present review elucidates the emerging evidence enlightening the neuroprotective outcomes of PPAR agonists in in vivo and in vitro models experiencing PD. Existing articles up to the present were procured through PubMed, MEDLINE, etc., utilizing specific keywords spotlighted in this review. Furthermore, the authors aim to provide insight into the neuroprotective actions of PPAR agonists by outlining the pharmacological mechanism. As a conclusion, PPAR agonists exhibit neuroprotection through modulating the expression of a group of genes implicated in cellular survival pathways, and may be a propitious target in the therapy of incapacitating neurodegenerative diseases like PD.
9 citations
TL;DR: In this article , a series of novel 1-aryl-3-(4-methylsulfonylphenyl) pyrazole derivatives were synthesized, characterized by several spectroscopic techniques, and investigated as potential anti-inflammatory and anticancer agents.
2 citations
TL;DR: In this paper , the authors focused on the enzymatic esterification of glycerol and ibuprofen at high concentrations in two triphasic systems composed of toluene+ibuprofene (apolar) liquid phases, and a solid phase with the industrial immobilized lipase B from Candida antarctica named Novozym®435 (N435) acting as the biocatalyst.
Abstract: This work was focused on the enzymatic esterification of glycerol and ibuprofen at high concentrations in two triphasic systems composed of toluene+ibuprofene (apolar) and glycerol or glycerol–water (polar) liquid phases, and a solid phase with the industrial immobilized lipase B from Candida antarctica named Novozym®435 (N435) acting as the biocatalyst. Based on a preliminary study, the concentration of the enzyme was set at 30 g·L−1 and the stirring speed at 720 r.p.m to reduce external mass transfer limitations. To obtain more information on the reaction system, it was conducted at a wide range of temperatures (50 to 80 °C) and initial concentrations of ibuprofen (20–100 g·L−1, that is, 97 to 483 mM). Under these experimental conditions, the external mass transfer, according to the Mears criterion (Me = 1.47–3.33·10−4 << 0.15), was fast, presenting no limitation to the system productivity, regardless of the presence of water and from 50 to 80 °C. Considering that the enzyme is immobilized in a porous ion-exchange resin, limitations due to internal mass transfer can exist, depending on the values of the effectiveness factor (η). It varied from 0.14 to 0.23 at 50 to 80 °C and 0.32–1 mm particle diameter range in the absence of water, and in the same ranges, from 0.40 to 0.66 in the presence of 7.4% w/w water in the glycerol phase. Thus, it is evident that some limitation occurs due to mass transfer inside the pores, while the presence of water in the polar phase increases the productivity 3–4 fold. During the kinetic study, several kinetic models were proposed for both triphasic reacting systems, with and without first-order biocatalyst deactivation, and their fit to all relevant experimental data led to the observation that the best kinetic model was a reversible hyperbolic model with first-order deactivation in the anhydrous reaction system and a similar model, but without deactivation, for the system with added water at zero time. This fact is in sharp contrast to the use of N435 in a water-glycerol monophasic system, where progressive dissolution of ibuprofen in the reacting media, together with a notable enzyme deactivation, is observed.
1 citations
TL;DR: In this article , the effect of 3,6′-dimethoxychalcone on melanogenesis and lipopolysaccharides (LPS)-induced inflammation in mouse B16F10 and RAW 264.7 cells was investigated.
Abstract: In this study, we demonstrated that 2′-hydroxy-3,6′-dimethoxychalcone (3,6′-DMC) alleviated α-MSH-induced melanogenesis and lipopolysaccharides (LPS)-induced inflammation in mouse B16F10 and RAW 264.7 cells. In vitro analysis results showed that the melanin content and intracellular tyrosinase activity were significantly decreased by 3,6′-DMC, without cytotoxicity, via decreases in tyrosinase and the tyrosinase-related protein 1 (TRP-1) and TRP-2 melanogenic proteins, as well as the downregulation of microphthalmia-associated transcription factor (MITF) expression through the upregulation of the phosphorylation of extracellular-signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K)/Akt, and glycogen synthase kinase-3β (GSK-3β)/catenin, and downregulation of the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and protein kinase A (PKA). Furthermore, we investigated the effect of 3,6′-DMC on macrophage RAW264.7 cells with LPS stimulation. 3,6′-DMC significantly inhibited LPS-stimulated nitric oxide production. 3,6′-DMC also suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 on the protein level. In addition, 3,6′-DMC decreased the production of the tumor necrosis factor-α and interleukin-6. Successively, our mechanistic studies revealed that 3,6′-DMC also suppressed the LPS-induced phosphorylation of the inhibitor of IκBα, p38MAPK, ERK, and JNK. The Western blot assay results showed that 3,6′-DMC suppresses LPS-induced p65 translocation from cytosol to the nucleus. Finally, the topical applicability of 3,6′-DMC was tested through primary skin irritation, and it was found that 3,6′-DMC, at 5 and 10 μM concentrations, did not cause any adverse effects. Therefore, 3,6′-DMC may provide a potential candidate for preventing and treating melanogenic and inflammatory skin diseases.
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398 citations
TL;DR: New anti-inflammatory drugs are being discovered and developed based on their effects on signal transduction and as anti-cytokine agents and these drugs are now being heralded as the new therapies to control those diseases where cytokines and other nonprostaglandin components of chronic inflammatory and neurodegenerative diseases are manifest.
Abstract: Historically, anti-inflammatory drugs had their originsin the serendipitous discovery of certain plants and their extracts being applied for the relief of pain, fever and inflammation. When salicylates were discovered in the mid-19th century to be the active components of Willow Spp., thisenabled these compounds to be synthesized and from this,acetyl-salicylic acid or Aspirin trademark was developed.Likewise, the chemical advances of the 19th–20th centuries leadto development of the non-steroidal anti-inflammatory drugs(NSAIDs), most of which were initially organic acids, but laternon-acidic compounds were discovered. There were two periods ofNSAID drug discovery post-World War 2, the period up to the 1970’swhich was the pre-prostaglandin period and thereafter up to the latter part of the last century in which their effects on prostaglandin production formed part of the screening in thedrug-discovery process. Those drugs developed up to the 1980-late90’s were largely discovered empirically following screening for anti-inflammatory, analgesic and antipyretic activities inlaboratory animal models. Some were successfully developed thatshowed low incidence of gastro-intestinal (GI) side effects (theprincipal adverse reaction seen with NSAIDs) than seen with their predecessors (e.g. aspirin, indomethacin, phenylbutazone); the GIreactions being detected and screened out in animal assays. In the1990’s an important discovery was made from elegant molecular andcellular biological studies that there are two cyclo-oxygenase(COX) enzyme systems controlling the production of prostanoids [prostaglandins (PGs) and thromboxane (TxA2) ]; COX-1that produces PGs and TxA2 that regulategastrointestinal, renal, vascular and other physiological functions, and COX-2 that regulates production of PGs involved in inflammation, pain and fever. The stage was set in the 1990’s forthe discovery and development of drugs to selectively controlCOX-2 and spare the COX-1 that is central to physiological processes whose inhibition was considered a major factor indevelopment of adverse reactions, including those in the GI tract.At the turn of this century, there was enormous commercialdevelopment following the introduction of two new highly selectiveCOX-2 inhibitors, known as coxibs (celecoxib and rofecoxib) whichwere claimed to have low GI side effects. While found to have fulfilled these aims in part, an alarming turn of events tookplace in the late 2004 period when rofecoxib was withdrawn worldwide because of serious cardiovascular events and other coxibs were subsequently suspected to have this adverse reaction, although to a varying degree. Major efforts are currently underwayto discover why cardiovascular reactions took place with coxibs, identify safer coxibs, as well as elucidate the roles of COX-2 andCOX-1 in cardiovascular diseases and stroke in the hope that there may be some basis for developing newer agents (e.g. nitricoxide-donating NSAIDs) to control these conditions
393 citations
TL;DR: Dual 5-LOX/COX inhibitors act by blocking the formation of both prostaglandins and leucotrienes but do not affect lipoxin formation, which avoids some of the disadvantages of selective COX-2 inhibitors and spares the gatrointestinal mucosa.
Abstract: Dual 5-LOX/COX inhibitors are potential new drugs to treat inflammation. They act by blocking the formation of both prostaglandins and leucotrienes but do not affect lipoxin formation. Such combined inhibition avoids some of the disadvantages of selective COX-2 inhibitors and spares the gatrointestinal mucosa.
391 citations
TL;DR: Experiments with isolated uterus of various animals showed that prostaglandin enhanced the uterus activity; it has similar action on isolated human uterus and atropine did not abolish these biological actions.
Abstract: Experiments to determine the occurrence formation and biological properties of the pharmacodynamically active substance (prostaglandin or vesiglandin) in the prostate and seminal vesicles of male humans and in the visicular gland of sheep are reviewed. The substance which is water soluble alcohol soluble acetone soluble and under certain conditions ether and chloroform soluble is stable at pH 1-7 but is easily destroyed in normal acid and alkali and by free halogens. In cataphoresis experiments prostaglandin was found to migrate to the anode with a velocity of 5.4 times 10 cm. sq. per second per volt at pH 6.54. The prostaglandin substance dilates vessels for frog hindlimbs and lowers the blood pressure in rabbits cats and dogs. Prostaglandin has no great effect on mammalian hearts but it does cause an increased frequency and predominance of the systolic phase of frogs isolated heart. Intestinal activity of various animals is increased both in vivo and vitro by addition of prostaglandin. Experiments with isolated uterus of various animals showed that prostaglandin enhanced the uterus activity; it has similar action on isolated human uterus. Atropine did not abolish these biological actions. In horses bulls and pigs the prostaglandin could not be found in ejaculates.
390 citations
TL;DR: In a prospective study, ibuprofen and indomethacin are compared with regard to efficacy and safety for the early treatment of patent ductus arteriosus in preterm infants.
Abstract: Background Indomethacin is the conventional treatment for patent ductus arteriosus in preterm infants. However, its use is associated with various side effects. In a prospective study, we compared ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of patent ductus arteriosus in preterm infants. Methods We studied 148 infants (gestational age, 24 to 32 weeks) who had the respiratory distress syndrome and an echocardiographically confirmed patent ductus arteriosus. The infants were randomly assigned at five neonatal intensive care centers to receive three intravenous doses of either indomethacin (0.2 mg per kilogram of body weight, given at 12-hour intervals) or ibuprofen (a first dose of 10 mg per kilogram, followed at 24-hour intervals by two doses of 5 mg per kilogram each), starting on the third day of life. The rate of ductal closure, the need for additional treatment, side effects, complications, and the infants' clinical course were recorded. Results The rate of duc...
382 citations