INFLAMMATION: A POTENTIAL SCENARIO ON NOVEL TARGETS AND TARGETED DRUG THERAPY

INFLAMMATION: A POTENTIAL SCENARIO ON NOVEL TARGETS AND TARGETED DRUG THERAPY

P. A. Karale ^{* 1}, M. A. Karale ³, P. R. Chavan ² and P. Thaware ⁴

School of Pharmacy ¹, School of Life Sciences ³, Swami Ramanand Teerth Marathwada University, Nanded - 431606, Maharashtra, India.

Shivlingeshwar College of Pharmacy ², Almala, Latur - 413520, Maharashtra, India.

Dagadojirao Deshmukh D. Pharmacy College ⁴, Almala, Latur - 413520, Maharashtra, India.

ABSTRACT: Inflammation is the vascular event shown by the body against the external material by activating different cells and releasing various chemical mediators to prevent noxious effects. Many drugs like steroidal and non-steroidal drugs are available till the date to treat inflammation but have a number of side effects and centralized on to counteract the COX and LOX pathways. This perspective will use to search for new drugs that can work to target other pro-inflammatory mediators involve in inflammation and act as target for the inhibition of inflammatory processes and minimize the side effects. The therapeutic targets are any proteins, receptors, pro-inflammatory mediators or enzymes that can be involved in the inflammatory reaction. The targeted therapy acts on it and inhibits targets to combat the inflammation. The recent study assembles the data on novel targets and future anti-inflammatory drugs and the best treatment for incurable inflammatory diseases.

Inflammation, MAP kinase, PPARγ, C5a receptors, Inflammasome, Anti-inflammatory drugs

INTRODUCTION: Inflammation is the patho-physiological response of vascular tissues to any injury, infectious agents, or chemicals and involves the five characteristic signs as redness, swelling, fever, pain, and loss of function. The inflammation is the defense mechanism of the body and also involve in the healing mechanism of the body; it prevents any noxious effects due to external material ¹. However, if untreated it may produce diseases like rheumatoid arthritis, inflammatory bowel diseases, etc. The mechanism of inflammation involves number of cells of body and their secretions to produce inflammatory signs.

The most important cell involved in the inflammatory reaction is the mast cells and release histamine in response to stimuli ². The steps involved in the mechanism of inflammation as shown in Fig. 1.

FIG. 1: MECHANISM OF INFLAMMATION

The steroidal and non-steroidal anti-inflammatory drugs are helpful to minimize the symptoms of inflammation. The salicylates were the active compound in the 19^th century and discovered from the Willow species and synthesized into the aspirin ³. The inhibition of the mediator prostaglandin was the mechanisms of NSAIDs were developed in 1970. The drugs to control selectively the COX-2 and COX-1 that is central to physiological processes and whose inhibition was considered a major factor in the development of adverse reactions were discovered and developed in 1990s ⁴. The drugs from analgesics such as aspirin and other NSAIDs nowadays have been restricted due to their potential side effects. The gastrointestinal ulceration and bleeding, hypertension, hyperglycemia, renal damage is most common side effects of the non-steroidal anti-inflammatory drugs ^{5, 6}. Besides these side effects, the greatest disadvantage in presently available potent drugs lies in their toxicity and reappearance of symptoms after discontinuation.

The biochemicals play vital role in the progression of inflammation like interleukins ^{7, 8}, tumor necrotic factors ⁹, MAP kinases ^10-12, matrix metalloproteinases, etc. Pathophysiological studies indicate the presence of other chemical mediators and inhibition of such mediators can relief inflammatory diseases, thus offering new targets for anti-inflammatory drugs. Therefore, the present review gathers information on the novel targets of anti-inflammatory drugs and the future anti-inflammatory agents to treat chronic and incurable inflammatory diseases.

Novel Targets of Anti-Inflammatory Agents:

FIG. 2: NOVEL TARGETS OF ANTI-INFLAMMATORY AGENTS

C5a Receptors: C5a is a 74 amino acid protein that is superfluous during the inflammation reaction, and both C5a and C3a show their potential by binding with receptors located on the surface of cells. C5a plays a crucial role in variety of inflammatory reactions and serves up as a target to battle processes ^{13, 14}. The recruitment of neutrophils and stimulation of mast cell for degranulation to release histamine which causes vasodilation and muscle contraction due to activation of complement anaphylatoxins produces chemotactic agents [thesis Finckh 2009]. The C5a receptor antagonists attract the attention of new targets to design anti-inflammatory agents. The C5a interaction its receptor is well understood, a two-site binding model has been proposed and C-terminal region of C5a may fit into a binding pocket formed around the fifth transmembrane domain effector site ¹⁵. C5a receptor antagonists are of two types such small peptides and non-peptides. Few reports indicate that anti-C5a antibodies block C5a actions which inhibited the complement, induced inflammation in rats and primates ¹⁶ and also resulted in decreased polymorphonuclear cell activity in-vitro including chemotaxis, chemi-luminescence and lysosomal enzyme release ¹⁷.

Based on the C5a and C5a receptor interactions, designed peptide antagonists consisting of 64-75 amino acids of carboxy-terminal of C5a ¹⁸. Modification at the tail would make antagonistic property retaining other peptide portions intact. C5aRAM a monomer and C5a RAD a dimmer these new C-terminal tail truncated cysteine-containing antagonists have been reported to have antagonistic activity on neutrophils in-vivo without agonistic activity with Ki 79 ¹⁹.

A cyclic small, six amino acids peptide, AcPhe [L-ornithine-Pro-D cyclohexylalanine-Trp-Arg] and AcF-[OPdChaWR] effective against C5a and LPS-induced neutropenia. This was acetylated analog of F-[OPd-ChaWR] with better metabolic stability and intravenous administration of this compound also reduced the serum TNF-α level ²⁰.

Many non-peptide small molecules have been synthesized and screened for C5a receptor antagonistic activity. The synthesis of N-(4-dimethyl amino) phenylmethyl N-(4-isopropyl)-phenyl-7-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-carboxamide that inhibited binding of ¹²⁵I-labeled C5a to human neutrophils with Ki 2.2 nM. The C5a induced Ca⁺² mobilization, chemotaxis, and superoxide species generation in human neutrophils also inhibited ²¹. Substituted 4, 6-diamino-quinolines were stated to possess weak C5a antagonistic property targeting the site 1 binding region of the C5a receptor ²².

p38 MAP Kinases: A member of MAP kinase involved in multiple signaling processes, which is activated in inflammation by LPS, stress or cytokines ²³. The production of pro-inflammatory cytokines takes place due to the activation of p38 MAP kinase along with capsase-1 which is involved in apoptosis of cells and activation of transcription factors ^{24, 25}. p38 MAP kinases were involved in LPS-induced mesencephalic neurons death in rats ²⁶ and phosphorylation of transcription factors responsible for 5-LO synthesis ²⁷. Increase expression of COX-2 has been reported due to oxidative stress in antigen-stimulated mast cells is mediated by p38 MAP kinases resulting in increased levels of eicosanoids ²⁸. Hence, inhibition of p38 MAP kinase forms a new strategy for treatment of inflammatory disease ^{29, 30}.

Pyridinyl imidazole as aryl or hetero aryl-substituted imidazoles has been identified as potential leads for p38 MAP kinase inhibition ³¹. Isotopically labeled studies revealed that imidazole bind to p38 is molecular target, but previously triaryl imidazoles were known as cytokine production inhibitors. Generally pyridine at the Ar1 or Ar2 demonstrated better p38 MAP kinase inhibition activity which is attributed to strong hydrogen bond formation between the nitrogen of pyridyl with NH of Met109 and penetration of aryl group into hydrophobic area of the enzyme that is not accessed by ATP’s ³².

The pyridinyl imidazole competes at the ATP binding site of the enzyme were illustrated in crystallographic studies and biochemical information ^{33, 34}. Though pyridinyl imidazoles have potent p38 kinase inhibitors they are also establishing hepatotoxicity due to interference with hepatic cytochrome P450. Thus, widespread investigation has been completed to take apart the p38 inhibition and hepatotoxicity of pyridinyl imidazoles ³⁵.

The synthesis of dihydroquinazolinones have been done and tested for p38 MAP kinase inhibitory activity ^{36, 37}. The dihydroquinazolinones have similar binding interactions with the enzyme as those of pyrimidynyl or pyridinyl imidazoles. The hydrogen bond formation with the enzyme backbone by the carbonyl group at the 2^nd position showed a similar pattern to that of hydrogen bond formed by the nitrogen of pyridine or pyrimidine ring in imidazoles.

The novel p38 kinase inhibitors like urease substituted with pyrazoles ^{38, 39}, theophanies ⁴⁰, and alkyl-substituted isoxazoles ⁴¹ and purines ⁴² were discovered. The urea group acts as hydrogen bond donor and acceptor site shown by molecular modeling and crystallography information. Disubstituted urease containing t-butyl-pyrazoles binds with the allosteric domain of p38 α other than ATP binding site. BIRB 796 a pyrazole urea derivative is in the clinical phase II trials, demonstrated inhibition potency in picomolar concentration. The crystallographic examinations reveal that large conformational changes occur when the urea inhibitor binds with the kinase.

VX-745 had to be terminated after clinical trials phase II due to adverse effects on CNS revealed by the annual report of Vertex Pharmaceuticals Cambridge, USA, while few p38 inhibitors VX-702 and VX-850 have shown encouraging results in phase II clinical trials to study the safety, tolerability and clinical activity.

Matrix Metalloproteinase: MMPs are a subfamily of metzincins functionally related to zinc-dependent endopeptidases, which hydrolyze extracellular matrix in human body ⁴³. Identification of more than 24 MMPs have been reported and are divided into five subgroups based on the substrate specificity as stromelysins (MMP-3, -7, 10 and -11), collagenase, (MMP-1, -8, -13 and -18), gelatinases (MMP-2 and -9), membrane-type MMPs (MT-MMPs) (MMP-14, -15, -16, -17, -24 and -25) and nonclassified other MMPs (MMP-19, -20, -23, -26, -27 and -28) ^{44, 45}. The vital role played by activated MMPs in degradation of extracellular matrix during tissue repair and angiogenesis. The degradation of collagen types I, II and III carried out by MMP-2, -14 along with collagenases ^{46, 47}.

Several pathological conditions like metastatic tumors and several inflammatory diseases such as inflammatory bowel disease, RA and osteoarthritis in which MMPs play a critical role ^{48, 49}.

Many research strategies have been progressed to decrease the biochemical actions of MMPs like hindered one or more MMP activations. The design of synthetic molecule that inhibits MMPs aimed to mimic the natural inhibition by TIMP, but more accomplishment is associated with synthetic small molecules that bind the active site of MMPs. Zinc is the core center for MMPs activity and thus synthetic molecules have investigated that bind the zinc moiety of MMPs. Several zinc-binding groups have demonstrated wide range MMP inhibition. The zinc-binding groups are hydroxymate, carboxylate ⁵⁰, phosphoric acid, sulfonamide, sulfyhydril, and phosphonamide and among them hydroxymate have shown heartening activity.

Several nonselective MMP inhibitors experienced set back during the clinical trial studies due to the unexpected adverse effects. These adverse effects of inhibitors were established due to inhibition of other MMPs that are involved in normal physiological functions, and inhibition of these MMPs cause excessive deposition of matrix leading to fibrosis ^{51, 52}. Thus, selective MMP inhibitors have the advantage over the classical broad range of MMP inhibitors. As the protein crystal structures of several MMPs have revealed the binding interactions between the inhibitors and MMPs thus the process of new lead identification for selective MMP inhibitors have been expedited.

Several broad-spectrum and selective MMP inhibitors have been tested in animal models and human clinical trials and hydroxymate MMP inhibitors like CGS-270230, RO-323555 and BAY-129566 have been well studied. The selective collagenase inhibitory activity shown by BAY-129566 and was effective in animal, small and short level clinical trials but failed in large and long-term clinical trials ⁵³. Succinyl hydroximates are the first generation broad-spectrum MMP inhibitors. British Biotech developed Batimastat (BB-9421) and marimastat (BB-2516) are the two succinyl hydroximates ⁵⁴. The inhibitory activity of hydroxymates is due to formation of strong hydrogen bond with carbonyl group of enzyme backbone. The selective MMP-2 activity of ilomastat analogs containing an isobutylidene group illustrated to fit in S1 packet of enzyme and a 2-substituted indole analog nucleus ⁵⁵.

Some new hydroximates were synthesized and tested for MMP inhibitory activity that also contains phosphonamide zinc-binding group, compounds with an R configuration at phosphorus were found to be potent inhibitors ⁵⁶. The piperazine carboxylic acid was novel cyclic MMP inhibitors and the piperazine makes central backbone and provides conformational stability ⁵⁷. A series of α-sulfonylhydroxamic acid derivatives as potent MMP inhibitors have synthesized and explained the structure-activity relationship. A dialkyl substituted derivatives displayed potent activity against MMP-9 and MMP–13 while reduced action against MMP-1. These derivatives have also shown to have slighter activity against TACE ⁵⁸.

NF-Kb: NF-κB is a redox-sensitive transcription factor, heterodimeric protein composed of different transcription factors of the Rel family ⁵⁹. NF-κB is composed of homo and heterodimers of five members of the Rel family including NF-κB1 (p50), NF-κB2 (p52), Rel A (p65), Rel B and c-Rel (Rel) ⁶⁰. The inhibitor protein called IKappa B (IκB) forms non-covalent bond with NF-κB resides in the cytoplasm of the cell in inactive form. Seven isoforms of IκBs have been identified namely IκBα, IκBβ, I-κBγ, IκBε, BCL3, p100 and p105 containing 30-35 amino acids ⁶¹. NF-κB can be stimulated by LPS or inflammatory cytokines and free radicals which consequence in phosphorylation of IκBs by IKappa B Kinase Complex (IKK) on the conserved serine residue at N-terminal portion of IκB ^{62, 63}.

Activated NF-κB complex translocates into the nucleus and binds DNA at Kappa-B binding motifs such as 5-prime GGGRNNYYCC 3-prime or 5-prime HGGARNYYCC 3-prime and provokes gene expression and further expression of cytokines, chemokine, growth factors, cellular ligands, and adhesion molecules ^{64, 65}. NF-κB plays a role in several diseases, such as asthma ⁶⁶, neurodegeneration, ischemia or reperfusion injury, hepatitis, glomerulonephritis and inflammatory bowel disease ^67-69.

The potential role played by NF-kB in inflammation opened another feasible approach to control these inflammatory diseases. It was concluded that inflammatory cytokines, including IL-1b, IL-6, and TNF-α are induced by the activation of NF-kB in synoviocytes ⁷⁰. Many of the NSAIDs such as aspirin and sodium salicylate have demonstrated to result in NF-kB inhibitory activity followed by inhibition of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) ^{71, 72}, which are encoded by NF-kB target genes.

Several heterocyclic compounds have been identified as lead molecules to inhibit IKKb with increased selectivity. Quinazoline analogs have been extensively studied for selective IKKb inhibition, one of most potent compounds in this series SPC-839 with IC₅₀ 60 nM having more than 200 times selectivity for IKKb ⁷³. BMS-345541 an imidazoquinaxaline derivative exhibited ten folds selectivity for IKKb (IC₅₀ 0.3 mM) and reported to bind the allosteric center of the kinase instead of regular ATP binding site. Diaryl pyridines have been reported to possess more selectivity for IKKb inhibition, a most potent molecule in this series exhibited in vitro inhibition of LPS induced TNF-a formation with IC₅₀ value 0.6 mM and in-vivo inhibition with ED₅₀ 2 mg/kg body weight ^{74, 75}.

JNK Inhibitors: The c-Jun N-terminal kinases (JNK) are an evolutionarily conserved family of serine or threonine MAP kinases. JNK was acknowledged in 1990 as 54 kDa stress-activated protein kinase ⁷⁶. The pro-inflammatory cytokines such as TNF-α and IL-1β as well as environmental stress, such as anisomycin, UV irradiation, hypoxia, and osmotic shock activate JNKs ⁷⁷. A wide variety of cellular processes such as proliferation, apoptosis, migration and transcriptional regulation were governed by members of the JNK family ^78-82. NKs are activated by their serine or threonine upstream kinases, mitogen-activated protein kinase (MKK) namely MKK4 and MKK7 ⁸³.

The inhibition of JNK has been reported to be a valuable approach in the development of agents for the treatment of oncological, apoptosis-related and inflammatory diseases ⁸³. A specific JNK inhibitor, SP 600125 an anthrapyrazole derivative was identified during high throughput screening. SP 600125 is competitive inhibitor of JNK binding at the ATP binding site. It has revealed to be active against all isoforms of JNK having 300 folds selectivity over other MAP kinases ⁸⁴. AS-007149 reported as prospective JNK inhibitor by library search and the effect of structural modifications on JNK inhibition. The SAR revealed that the benzothiazol-2-yl acetonitrile pyridine core plays a role in retaining a good level of JNK inhibition ⁸⁵. The 3-(4-pyridyl)-imidazole as novel gallows for JNK inhibition identified in high throughput screening with pIC₅₀ value 5.8 ⁸⁶.

Inflammasome: Inflammasome is cytoplasmic caspase-1-activating protein complexes that promote maturation and secretion of the pro-inflammatory cytokines. The activation of inflammasome by different stimuli triggers the proteolytic cleavage of pro-caspase 1 into active caspase 1, which, in turn converts pro-interleukin 1b (pro-IL1b) into the mature IL1b. The nucleotide-binding domain leucine-rich repeat-containing families of receptors are members of the innate immune system and have a critical role in host defense ^87-89. These molecules are key to driving inflammatory responses to abnormal cellular conditions. Many NLRs provide this role on establishment by forming a multiprotein complex called an inflammasome. Nucleotide-binding domain leucine-rich repeat (LRR)-containing receptors (NLRs) are pattern recognition receptors (PRRs) that initiate inflammatory responses to a wide range of stimuli.

The NLPR3 inflammasome is the best characterized and participates in immune responses to infectious and noninfectious agents. It consists of the aforesaid NLRP3 receptor, the adaptor protein ASC and caspases. Martinon et al., described, for the first time, an inducible high-molecular-weight complex containing NLRP3, an adaptor protein, and pro-inflammatory caspases, which they called the inflammasome ⁹⁰. The activators of NLRP3 are quite varied and include environmental irritants, endogenous danger signals, pathogens, and distinct pathogen-associated molecular patterns (PAMPs) and have been associated with a wide range of diseases including infectious, auto-inflammatory, and autoimmune disorders ^{91, 92}.

Adipokines: White adipose tissue has been recognized to be a true endocrine organ, which is able to secrete a wide variety of factors termed Adipokines ^{93, 94}. In spite of their metabolic activities, adipokines represent a new family of compounds that could participate in several processes, including inflammation and immunity, and are also involved in the pathophysiology of rheumatic diseases ^95-97. Adipokines consist of a variety of pro-inflammatory factors most of them being increased in obesity and appearing to contribute to the so-called ‘low-grade inflammatory state’ in obese individuals. Obesity, the condition that stimulates the research on adipokines, has been considered a risk factor for developing osteoarthritis ^{98, 99}.

PPARγ Receptors: PPARγ considered as important target in the development of new drugs and belongs to the nuclear family consisting of a group of approximately 50 transcription factors implicated in many different biological processes ¹⁰⁰. A large number of regulatory genes in lipid metabolism and insulin sensitization, as well as in inflammation and cell proliferation were controlled by PPAR ^{101, 102}. Its activation requires heterodimerization in the nucleus of the cells with another nuclear receptor, known as the retinoid X receptor α (RXR α), leading to binding of this heterodimer to specific DNA sequence elements termed peroxisome proliferator response elements ¹⁰³.

It has been established that these two nuclear factors play a central role in the regulation of inflammatory signaling pathways by acting on kinases and transcription factors, such as nuclear factor-kB (NF kB), c-Jun, c-Fos, and nuclear factor of activated T cell ^104-106, and inhibiting mucosal production of inflammatory cytokines (interleukin (IL)-1β and tumor necrosis factor α (TNF-α)) and chemokines ¹⁰⁷, proliferation of inflammatory cells ¹⁰⁸, and expression of some adhesion molecules ¹⁰⁹.

Interestingly PPAR- γ was the first reported to undergo agonist-dependent simulation, which promotes binding to nuclear receptor co-repressor-1 protein (NCoR) and stabilizes association with promoter-bound NF-kB, thus leading to the transrepression of inflammatory genes in macrophages ^110-112.

Other beneficial and inhibitory effects of PPAR- γ agonists on inflammation were reduction in the production of pro-inflammatory molecules in T lymphocytes, promotion of the expression of anti-inflammatory mediators in the innate immune system, reduce cytokines (TNF-α, IL-1, and IL-6) productions by inhibition of genes encoding pro-inflammatory molecules, and reduction of transcriptional activities Nuclear Factor- kB (NF-kB), AP-1, and STAT ^{113, 114}. PPAR- γ also reduces vascular smooth muscle cell proliferation, increases monocyte apoptosis, and suppresses metalloproteinase-9 expression in atherotic plaques ^115-118.

Novel antagonist and partial agonists of PPAR- γ have recently been identified; tri-terpenoids 2-cyano- 3, 12- dioxoole-ana-1, 9- dien- 28- oic acid (CDDO) is a partial agonist with anti-inflammatory properties ¹¹⁹ and bisphenol diglycidyl ether (BADGE) and LG-100641 have been identified as antagonists for PPAR- γ ^{120, 121}. Even though these compounds have little clinical significance, they can be used to understand the physiology of the PPAR- γ and for the identification of new ligands. In addition to synthetic chemical methods, research in natural products has also yielded potent PPAR- γ agonists from several medicinal plants.

CONCLUSION: In treating the inflammatory diseases, NSAIDs and selective COX-2 inhibitors have been conventionally the most extensively used drugs to date. However, their long-term treatment has been demonstrated to have highly adverse side effects and it has been observed that the use of rofecoxib, selective COX-2 inhibitor might even lead to fatalities due to cardiovascular and thrombotic events. Pro-inflammatory cytokines and components of signal transduction play a central role in the pathology of inflammation, some proteinaceous cytokine inhibitors viz. infliximab was effective either as a monotherapy or in combination with other drugs effective in treating RA. Prolonged use of these cytokine inhibitors may lead to post-treatment infections, and therefore there is a quest to obtain small molecules that may inhibit these pro-inflammatory or intracellular signals.

Further, the cost-effectiveness and mode of administration of the cytokine inhibitors are not at desirable levels. Apart from these pro-inflammatory cytokines as a target for new anti-inflammatory drug discovery, the components of signal transduction like p38 kinase, JNK, and NF-kappaB can be targeted. Some of small molecules that inhibit p38 kinase are in the final stages of clinical trials. The success of these inhibitors depends on how best they pass through the clinical trials for safe use in human beings. Therefore, the present review proposes that there is a paradigm shift in the drug design and discovery attempts towards anti-inflammatory diseases.

ACKNOWLEDGEMENT: Nil

CONFLICTS OF INTEREST: Nil

REFERENCES:

1. Noah TA, Zachary MW and Randy JN: Inflammation: mechanisms, costs, and natural variation. Natural Variation of Inflammation 2012; 43: 385-06.
2. Hua X and Shao-Heng H: Roles of histamine and its receptors in allergic and inflammatory bowel diseases. World J Gastroenterol 2005; 11(19): 2851-57.
3. Ippokratis P, Theodora G, Howard B and Peter VG: Nonsteroidal anti-inflammatory drugs: prostaglandins, indications, and side effects. Int J of Interferon, Cytokine and Mediator Research 2011; 3: 19-27.
4. Carmine S, Veronica DS, Francesco P and Giovanni M: Mechanisms of action of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and mesalazine in the chemoprevention of colorectal cancer. Int J Mol Sci 2013; 14: 17972-85.
5. Hassan MM, Khan SA, Shaikat AH, Hossain ME, Hoque MA, Ullah MH and Islam S: Analgesic and anti-inflammatory effects of ethanol extracted leaves of selected medicinal plants in animal model. Vet World 2013; 6(2): 68-71.
6. Gupta V, Chauhan S, Archana P and Mathur A: Evaluation of in-vitro and in-vivo anti-inflammatory activities of Parthenium camphora. Recent Research in Science and Technology 2013; 5(1): 33-9.
7. Woolley DE and Tetlow LC: Mast cell activation and its relation to pro-inflammatory cytokine production in the rheumatoid lesion. Arthritis Res 2000; 2: 65-74.
8. Dinarello CA, Endres S, Meydani SN, Meydani M and Hellerstein MK: Interleukin-1, anorexia, and dietary fatty acids. Ann N Y Acad Sci 1990; 587: 332-8.
9. Dinarello CA: Interleukin-1 and tumor necrosis factor: effecter cytokines in autoimmune diseases. Semin Immunol 1992; 4: 133-45.
10. Herlaar E and Brown Z: p38 MAPK signalling cascades in inflammatory disease. Mol Med Today 1999; 5: 439-47.
11. Ono K and Han J: The p38 signal transduction pathway: activation and function. Cell Signal 2000, 12: 1-13.
12. Tyler Z and Han J: Activation and signaling of the p38 MAP kinase pathway. Cell Research 2005; 15: 11-18.
13. Zhang X, Schmudde I, Laumonnier Y, Pandey MK, Clark JR and Konig P: A critical role for C5L2 in the pathogenesis of experimental allergic asthma. J Immunol 2010; 185: 6741-52.
14. Lajoie S, Lewkowich IP, Suzuki Y, Clark JR, Sproles AA and Dienger K: Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol 2010; 11; 928-35.
15. Siciliano SJ, Rollins TE, DeMartino J, Konteatis Z, Malkowitz L and Van Riper G: Two-site binding of C5a by its receptor: an alternative binding paradigm for G protein-coupled receptors. Proc Natl Acad Sci USA 1994; 91: 1214-18.
16. Wu MC, Brennan FH, Lynch JP, Mantovani S, Phipps S and Wetsel RA: The receptor for complement component C3a mediates protection from intestinal ischemia-reperfusion injuries by inhibiting neutrophil mobilization. Proc Natl Acad Sci USA 2013; 110: 9439-44.
17. Jacob A, Hack B, Chen P, Quigg RJ and Alexander JJ: C5a/CD88 signaling alters blood-brain barrier integrity in lupus through nuclear factor-kappaB. J Neurochem 2011; 119: 1041-51.
18. Han G, Geng S, Li Y, Chen G, Wang R and Li X: gammadeltaT-cell function in sepsis is modulated by C5a receptor signalling. Immunology 2011; 133: 340-9.
19. Pellas TC and Wennogle LP: C5a receptor antagonists. Curr Pharm Des 1999; 5: 737-55.
20. Bosmann M, Sarma JV, Atefi G, Zetoune FS and Ward PA: Evidence for anti-inflammatory effects of C5a on the innate IL-17A/IL-23 axis. FASEB J 2012; 26: 1640-51.
21. Hiroshi S, Kei S, Noriko S, Sanae T, Seigo I, Mitsuharu N and Takao K: Identification of a Potent and Orally Active Non-peptide C5a Receptor Antagonist. J Biol Chem 2002; 51: 49403-07.
22. Lanza TJ, Durette PL, Rollins T, Siciliano S, Cianciarulo DN, Kobayashi SV, Caldwell CG, Springer MS and Hagmann WK: Substituted 4, 6- Diaminoquinolines as Inhibitors of C5a Receptor Binding. J Med Chem 1992; 35: 252-58.
23. Chunguang Y and Hongwei G: New insights for C5a and C5a receptors in sepsis. Front Immunol. 2012; 3: 368.
24. Sabio YGCA, Yokobori N and Basile JI: C5aR contributes to the weak Th1 profile induced by an outbreak strain of tuberculosis. Tuberculosis 2017; 103: 16-23.
25. Lee M, Park SC and Yang YG: Involvement of reactive oxygen species and p38 kinase in TRAIL/APO2L induced apoptosis. FEBS Lett 2002; 512: 313-18.
26. Grant SK: Therapeutic protein kinase inhibitors. Cell Mol Life Sci 2009; 66: 1163-77.
27. Ivan del BB and Angel RN: Role of p38 MAPKs in invasion and metastasis. Biochemical Society Transactions 2012; 40(1): 79-84.
28. Hundly T, Prasad A and Beaven MA: Elevated levels of COX-2 in antigen stimulated mast cells is associated with minimal activation of p38 MAP kinase. J Immunol 2001; 167: 1629-36.
29. Branger J, Van Den Blink B and Weijer S: Anti-inflammatory effects of a p38 MAP kinase inhibitor during human endotoxemia. J Immunol 2002; 168: 4070-77.
30. Newton R and Holden N: Inhibition of p38 MAP kinase: potential as anti-inflammatory agents in asthma? BioDrugs 2003; 17: 113-29.
31. Leclerc M, Naserian S, Pilon C, Thiolat A, Martin GH and Pouchy C: Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells. Blood 2016; 128(12): 1651-9.
32. Jessica G and Jan R: The Expanding Role of p38 Mitogen-Activated Protein Kinase in Programmed Host Cell Death. Microbiology Insights 2019; 12: 1-3.
33. Marengo B, Ciucis CG De, Ricciarelli R, Furfaro AL, Colla R and Canepa E: p38MAPK inhibition: a new combined approach to reduce neuroblastoma resistance under etoposide treatment. Cell Death and Disease 2013; 4: 1-14.
34. So T and Croft M: Regulation of PI-3-kinase and Akt signaling in T lymphocytes and other cells by TNFR family molecules. Front Immunol 2013; 4: 139.
35. Laufer SA, Gerd KW, Dunja AK and Albrecht W: Novel substituted pyridinyl imidazoles as potent anticytokine agets with low activity against hepatic cytochrome P450 enzymes. J Med Chem 2003; 46: 3230-44.
36. Julianne AH, Florida K, Rowena DR, Peter JS, Ida I and James VP: p38 Inhibitors: Piperidine- and 4-Amino-piperidine-Substituted Naphthyridinones, Quinolinones, & Dihydroquinazolinones. Bio Med Ch Le 2003; 13: 467-70.
37. Achim S, Richard H and Franco DP: A novel Pd-catalyzed cyclization reaction of ureas for the synthesis of dihydroquinazolinone p38 kinase inhibitors. Bioorg Med Chem Lett 2004; 14: 357-60.
38. Jacques D, Holia HM, Robert NS, Roger AS, William JS and Uday K: Synthesis and Pharmacological Characterization of a Potent, Orally Active p38 Kinase Inhibitor. Bioorg Med Chem Lett 2002: 12: 1559-62.
39. Jacques D, Holia HM, Robert S, Bernd R, William J and Mary KM: 1-Phenyl-5-pyrazolyl Ureas: Potent and Selective p38 KinaseInhibitors. Bioorg Med Chem Lett 2000; 10: 2051-54.
40. Aniko MR, Jeffrey SJ, Robert D, Steve S, Hanno W and Holgar P: p38 kinase inhibitor for the treatment of arthritis and osteoporosis: Thienyl, furyl and pyrrolyl ureas. Bioorg Med Chem Lett 2001; 11: 9-12.
41. Jacques D, Robert S, Bernd R, Mary KM, Wendy L and Timothy BL: Discovery of a New Class of p38 Kinase Inhibitors. Bioorg Med Chem Lett 2000; 10: 2047-50.
42. Zehong W, Jerey CB, Michael JB, Shouki K, John CL and Baoguang Z: N-Phenyl-N-purin-6-yl Ureas: The Design and Synthesis of P38α MAP Kinase inhibitors. Bioorg Med Chem Lett 2003; 13: 1191-94.
43. Nissinen, L and Kahari, VM: Matrix metalloproteinases in inflammation. Biochimica et Biophysica Acta (BBA)-General Subjects 2014; 1840(8): 2571-80.
44. Roderick JT, Cheryl LF, Laura MN, Jacob MT, Lana EH and Qinglang L: Matrix metalloproteinases promote inflammation and fibrosis in asbestos-induced lung injury in mice. American Journal of Respiratory Cell and Molecular Biology 2006; 35: 289-97.
45. Ravanti L and Kahari VM: Matrix metalloproteinases in wound repair (Review). Int J Mol Med 2000; 6: 391-407.
46. Manicone AM and McGuire JK: Matrix metallo-proteinases as modulators of inflammation. Semin Cell Dev Biol 2008; 19(1): 34-41.
47. Chen Q, Min J, Yang F, Zhu J, Xiao Q and Zhang L: Matrix metalloproteinases: inflammatory regulators of cell behaviors in vascular formation and remodeling. Mediators of Inflammation 2013; 1-14.
48. Cathcart J, Pulkoski-Gross A and Cao J: Targeting matrix metalloproteinases in cancer: Bringing new life to old ideas. Genes & Diseases 2015; 2: 26-34.
49. Bigg HF and Rowan AD: The inhibition of metallo-proteinases as a therapeutic target in rheumatoid arthritis and osteoarthritis. Curr Opin Pharmacol 2001; 1: 314-20.
50. Michael GN, Roger GB, Matthew JL, Staszek P, Neil GA and Biswanath D: Development of new carboxylic acid-based mmp inhibitors derived from functionalized propargylglycines. J Med Chem 2001; 44: 1060-71.
51. Bode W, Fernandez-Catalan C, Tschesche H, Grams F, Nagase H and Maskos K: Structural properties of matrix metalloproteinases. Cell Mol Life Sci 1999, 55: 639-52.
52. Shapiro SD: Mighty mice: transgenic technology ‘knocks out’ questions of metalloproteinase function. Matrix Biol 1997, 15: 527-33.
53. Leff RL: Clinical trials of a stromelysin inhibitor. Ann NY Acad Sci 1999, 878: 201-07.
54. Rasmussen HS and McCann PP: Matrix metalloproteinase inhibition as a novel anticancer strategy: a review with special focus on batimastat and marimastat. Pharmacol Therapeut 1997; 75: 69-75.
55. Valerie M, Catherine M, Martine D and William H: MMPs Inhibitors: New succinylhydroxamates with selective inhibition of MMP-2 over MMP-3. Bioorg Med Chem Lett 2003; 13: 2843-46.
56. Stanislaw P, Kelly L, McDow D, Neil GA, Biswanath D and Michael GN: Design and synthesis of phosphinamide-based hydroxamic acids as inhibitors of matrix metalloproteinases. J Med Chem 1999; 42: 87-94.
57. Menyan C, Biswanath D, Stanislaw PL, Neil GA, Michael GN and Melanie VA: Design and Synthesis of Piperazine-Based Matrix Metalloproteinase Inhibitors. J Med Chem 2000; 43: 369-80.
58. Aranapakam V, Grosu GT, Davis JM, Baihua H and Ellingboe J: Synthesis and structure-activity relationship of sulfonylhydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis. J Med Chem 2003; 46: 2361-75.
59. Barnes PJ: Nuclear factor-kappa B. Int J Biochem Cell Biol 1997; 29: 867-70.
60. Aggarwal BB, Takada Y and Shishodia S: Nuclear transcription faactor NF-κB: role in biology and medicine. Ind J Expt Biol 2004; 42: 341-53.
61. Selftleben U and Karni M: The IKK/NFκB pathway. Crit Care Med 2002; 30: s18-26.
62. Karin M and Lin M: NFκB at the crossroads of life and death. Nat Immunol 2002; 3: 221-27.
63. Kumar A and Boriek AM: Mechanical stress activates the nuclear factor kappa B pathway in skeletal muscle fibres: A possible role in duchenne muscular dystropy. FASEB J 2003; 17: 386-96.
64. Muller LU, Gay RE and Gay S: Role of nuclear factor kappaB in synovial inflammation. Curr Rheumatol Rep 2002; 4: 201-07.
65. Joel LP and David B: Two pathways to NF-KappaB. Molecular Cell 2002; 10: 693-5.
66. Yamamoto Y and Gaynor RB: Therapeutic potential of inhibition of the NFκB pathway in the treatment of inflammation and cancer. J Clin Invest 2001; 107: 135-42.
67. Valen G, Yan ZQ and Hansson GK: Nuclear factor kappa-B and the heart. J Am Coll Cardiol 2001; 38: 307-14.
68. Lentsch AB and Ward PA: The NFkappaBb/IkappaB system in acute inflammation. Arch Immunol Ther Exp (Warsz) 2000; 48: 59-63.
69. Feldmann MAE, Smith C, Bondeson J, Yoshimura S, Kiriakidis S, Monaco C, Gasparini C, Sacre S, Lundberg A, Paleolog E, Horwood NJ, Brennan FM and Foxwell BM: Is NF-kappaB a useful therapeutic target in rheumatoid arthritis? Ann Rheum Dis 2002; 61: 13-18.
70. Alexei VM, Dmitry VK, Chadwick EB, John RD, John PCl and Stephen AS: NF-kB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proc Natl Acad Sci USA 1998; 95: 13859-64.
71. Kopp E and Ghosh S: Inhibition of NF-kappaB by sodium salicylate and aspirin. Science 1994; 266: 956-59.
72. Yin MJ, Yamamoto Y and Gaynor RB: Anti-inflammatory agents aspirin and sodium salicylate inhibit the activity of IkB kinase b. Nature 1998; 396: 77-80.
73. Palanki MS, Gayo-Fung LM, Shevlin GI, Erdman P, Sato M and Goldman M: Structure-activity relationship studies of ethyl 2-[(3-methyl-2, 5-dioxo(3-pyrrolinyl))amino]-4-(trifluoromethyl)pyrimidine-5-carboxylate: an inhibitor of AP-1 and NF-κB mediatedgene expression. Bioorg Med Chem Lett 2002; 12: 2573-77.
74. Murata T, Shimada M, Sakakibara S, Yoshino T, Masuda T and Shintani T: Synthesis and structure activity relationships of novel IKK-b inhibitors. Part 3: Orally active anti-inflammatory agents. Bioorg Med Chem Lett 2004; 14: 4019-22.
75. Murata T, Shimada M, Sakakibara S, Yoshino T, Kadono H and Masuda T: Discovery of Novel and Selective IKK-Serine-Threonine Protein Kinase Inhibitors. Part 1. Bioorg Med Chem Lett 2003; 13: 913-18.
76. Kyriakis JM, Brautigan DL, Ingebritsen TS and Avruch J: p54 Microtubule- associated protein-2 kinase requires both tyrosine and threonine phosphorylation for activity. J Biol Chem 1991; 266: 10043-46.
77. Barr RK and Bogoyevitch MA: The c-Jun N-terminal protein kinase family of mitogen-activated protein kinases (JNK MAPKs). Int J Bioche Cell Biol 2001; 33: 1047-63.
78. Du L, Lyle CS, Obey TB, Gaarde WA, Muir JA and Bennett BL: Inhibition of cell proliferation and cell cycle progression by specific inhibition of basal JNK activity: evidence that mitotic bcl-2 phosphorylation is JNK independent. J Biol Chem 2004; 279: 11957-66.
79. Cheng Y, Zhizhin I, Perlman RL and Mangoura D: Prolactin-induced cell proliferation in PC12 cells depends on JNK but not ERK activation. J Biol Chem 2000; 275: 23326-32.
80. Ammendrup A, Maillard A, Nielsen K, Andersen NA, Serup P and Madsen OD: The JNK pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic beta-cells Diabetes 2000; 49: 1468-76.
81. Javelaud D, Laboureau J, Gabison E, Verrecchia F and Mauviel A: Disruption of basal JNK activity differentially affects key fibroblast functions important for wound healing. J Biol Chem 2003; 278: 24624-28.
82. Higuchi H, Grambihler A, Canbay A, Bronk SF and Gores GJ: Bile acids up- regulate death receptor 5/TRAIL-rece-ptor 2 expression via a c-Jun N-terminal kinase-dependent pathway involving Sp1. J Biol Chem 2004; 279: 51-60.
83. Fleming Y, Armstrong CG, Morrice N, Paterson A, Goedert M and Cohen P: Synergistic activation of stress-activated protein kinase 1/c-Jun terminal kinase (SAPK1/ JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7. Biochem J 2000; 352: 145-54.
84. Resnick L and Fennell M: Targeting JNK3 for the treatment of neurodegenerative disorders. Drug Discovery Today 2004; 9: 932-39.
85. Bennett BL, Sasaki DT, Murray BW, O’Leary EC, Sakata ST and Xu W: SP600125, and anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA 2001; 98: 13681-86.
86. Gaillard P, Jeanclaude-Etter I, Ardissone V, Arkinstall S, Cambet Y and Camps M: Design and synthesis of the first generation of novel potent, selective, and in-vivo active (benzothiazol-2-yl)-acetonitrile inhibitors of the c-jun n- terminal kinase. J Med Chem 2005; 48: 4596-07.
87. Menu P and Vince JE: The NLRP3 inflammasome in health and disease: The good, the bad and the ugly. Clin Exp Immunol 2011; 166: 1-15.
88. Santos GD, Kutuzov MA and Ridge KM: The inflammasome in lung diseases. Am J Physiol Lung Cell Mol Physiol 2012; 303: L627-L633.
89. Jaklien CL, Cassel SL and Sutterwala FS: Sensing damage by the NLRP3 inflammasome. Immunol Rev 2011; 243(1): 152-62.
90. Martinon F, Petrilli V, Mayor A, Tardivel A and Tschop J: Gout associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440: 237-41.
91. Ozkurede, VU and Franchi L: Immunology in clinic review series; focus on auto-inflammatory diseases: role of inflammasomes in auto-inflammatory diseases: role of inflammasomes in auto-inflammatory syndromes. Clin Exp Immunol 2012; 167(3): 382-90.
92. Wilson SP and Cassel SL: Inflammasome- mediated auto-inflammatory disorders. Postg Med 2010; 122(5): 125-33.
93. Hotamisligil GS, Shargill NS and Spiegelman BM: Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87-91.
94. Fantuzzi G: Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 2005; 115: 911-19.
95. Otero M, Lago R, Lago F, Reino JJ and Gualillo O: Signalling pathway involved in nitric oxide synthase type II activation in chondrocytes: synergistic effect of leptin with interleukin-1. Arthritis Res Ther 2005; 7: R581-91.
96. Tilg H, Moschen AR: Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 772-83.
97. Lago F, Dieguez C, Gomez-Reino J and Gualillo O: Adipokines as emerging mediators of immune response and inflammation. Nat Clin Pract Rheumatol 2007; 3: 716-24.
98. Edwards C, Rogers A, Lynch S, Pylawka T, Silvis M and Chinchilli V: The effects of bariatric surgery weight loss on knee pain in patients with osteoarthritis of the knee. Arthritis 2012; 504189.
99. Vincent HK, Heywood K, Connelly J and Hurley RW: Obesity and weight loss in the treatment and prevention of osteoarthritis. PMR 2012; 4: S59-67.
100. A unified nomenclature system for the nuclear receptor superfamily. Cell 1999; 97:161-3.
101. Debril MB, Renaud JP and Fajas L: The pleiotropic functions of peroxisome proliferator-activated receptor gamma. J Mol Med 2001; 79: 30-47.
102. Fajas L, Debril MB, Auwerx J: Peroxisome proliferator-activated receptor-gamma: from adipogenesis to carcinogenesis. J Mol Endocrinol 2001; 27: 1-9.
103. Kliewer SA, Umesono K and Noonan DJ: Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 1992; 358: 771-4.
104. Su CG, Wen X and Bailey ST: A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response. J Clin Invest 1999; 104: 383-9.
105. Desreumaux P, Dubuquoy L and Nutten S: Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies. J Exp Med 2001; 193: 827-38.
106. Yang XY, Wang LH and Chen T: Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. PPARgamma co-association with transcription factor NFAT. J Biol Chem 2000; 275: 4541-4.
107. Marx N, Mach F and Sauty A: Peroxisome proliferator-activated receptor-gamma activators inhibit IFN-gamma-induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells. J Immunol 2000; 164: 6503-8.
108. Harris SG and Phipps RP: The nuclear receptor PPAR gamma is expressed by mouse T lymphocytes and PPAR gamma agonists induce apoptosis. Eur J Immunol 2001; 31: 1098-05.
109. Jackson SM, Parhami F and Xi XP: Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction. Arterios Throm Vas Biol 1999; 19: 2094-104.
110. Welters HJ, McBain SC, Tadayyon MJ, Scarpello HB, Smith SA and Morgan NG: Expression and functional activity of PPAR gamma in pancreatic β-cells. British Journal of Pharmacology 2004; 142: 1162-70.
111. Kota BP, Huang THW and Roufogalis BD: An overview on biological mechanisms of PPARs. Pharmacological Research 2005; 51: 85-94.
112. Schmidt MV, Brune B and Knethen AV: The nuclear hormone receptor PPAR γ as a therapeutic target in major diseases. The Scientific World Journal 2010; 10: 2181-97.
113. Jiang C, Ting AT and Seed B: PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 1998; 391: 82-86.
114. Poynter ME and Daynes RA: Peroxisome proliferator-activated receptor γ activation modulates cellular redox status, represses nuclear factor-kB signaling, and reduces inflammatory cytokine production in aging. The Journal of Biological Chemistry 1998; 273: 32833-41.
115. Chinetti G, Griglio S and Antonucci M: Activation of proliferator-activated receptors α and γ induces apoptosis of human monocyte-derived macrophages. The Journal of Biological Chemistry 1998; 273: 25573-80.
116. Law RE, Meehan WP and Xi XP: Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia, The Journal of Clinical Investigation 1996; 98: 1897-05.
117. Law RE, Goetze S and Xi XP: Expression and function of PPAR γ in rat and human vascular smooth muscle cells. Circulation 2000; 101: 1311-18.
118. Marx N, Schonbeck U, Lazar MA, Libby P and Plutzky J: Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circulation Research 1998; 83: 1097-03.
119. Wang Y, Porter WW and Suh N: A synthetic triterpenoids 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor-γ. Molecular Endocrinology 2000; 14: 1550-56.
120. Wright HM, Clish CB and Mikami T: A synthetic antagonist for the peroxisome proliferator-activated receptor-γ inhibits adipocyte differentiation, The Journal of Biological Chemistry 2000; 275: 1873-77.
121. Mukherjee R, Hoener PA and Jow L: A selective peroxisome proliferator-activated receptor-γ (PPAR-γ) modulator blocks adipocyte differentiation but stimulates glucose uptake in 3T3-L1 adipocytes. Molecular Endocrinology 2000; 14: 1425-33.
     

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     Karale PA, Karale MA, Chavan PR and Thaware P: Inflammation: a potential scenario on novel targets and targeted drug therapy. Int J Pharm Sci & Res 2019; 10(12): 5284-93. doi: 10.13040/IJPSR.0975-8232.10(12).5284-93.

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