Current Drug Discovery Technologies, 2012, 9, 000-000

Insight into the Biomarkers as the Novel Anti-Psoriatic Drug Discovery Tool: A Contemporary Viewpoint
Mahfoozur Rahman1,*, Mohammad Zaki Ahmed1, Imran Kazmi2, Sohail Akhter3, Sarwar Beg3, Gaurav Gupta2, Muhammad Afzal2, Shakir Saleem3, Iqbal Ahmad3, Md.Adil Shaharyar3, Farhan Jalees Ahmed3 and Firoz Anwar2
1

Dreamz College of Pharmacy, Himachal Pradesh, India, 2Siddhartha Institute of Pharmacy, Dehradun, Uttarakhand, India. 3Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi, India 110 062
Abstract: Psoriasis is a common chronic autoimmune skin disorder with T-cell mediated multifunctional complex pathogenesis along with genetic predisposition. Conventionally, many therapies are available for the management of psoriasis, but they have limited efficacy due to higher side effects. Over the last decade, one of the major efforts in psoriasis research has been made for the development of drug molecules by understanding the potential biomolecules/biomarkers associated with psoriasis. This approach aims to provide selective immunologically directed intervention with fewer side effects than conventional therapies. The present review aims to give an exhaustive account on various biomarkers including oxidative stress, peptide, biochemical and gene markers responsible for keratocyte hyper proliferation, inflammatory responses and abnormal differentiation in psoriasis. Effective targeting of these over expressed biomarkers can serve as the novel tool for anti-psoriatic drug development. In addition, this review also gives insights into several novel biomarkers targeted drugs under pre-clinical and clinical investigation or have been registered by FDA for psoriasis management.

Keywords: Psoriasis, Biomarkers, Drug targeting, Biological agents, Gene marker. 1. INTRODUCTION Psoriasis is the most common chronic skin T-cell mediated multifactorial autoimmune disorder of skin marked by inflammation, redness and itching. Generally it is found in teens upto to 20 years of age [1-3]. At the world level approximately 0.3 to 5% population is affected by this disorder [4]. In Europe it is estimated that 2-3% of the total population has psoriasis. In Asia and Africa nearly about 1% of the population is affected with psoriasis [5]. The keratinocyte hyper proliferation in psoriasis may be due to the activation of T-cells, which produce various inflammatory mediators like cytokines and adhesion molecules etc. These mediators are produced via various pathways i.e., MAPK/AP-1, JAKSTAT and protein kinase-C (PKCs) pathways. After T-cell activation, all these mediators induce a cascade of inflammation, which results in psoriasis. These entire pathways are unique to psoriasis [6-9]. Psoriatic skin is rich in inflammatory cells, CD4+, CD8+ T-cell and infiltrating T-cells express markers such as IL-2 receptors, resulting in epidermal proliferation and endothelial cell activation [10, 11]. The exact origin of psoriasis was not well defined and documented years ago, but now it is very well defined as several reports show predominance of cytotoxic CD8+ T cells in psoriatic lesion epidermis, whereas CD4+ cells are the predominant type in lesional dermis. As per psoriasis pathology these cells express CD45RO on the surface, indicating their effectors/memory status [12-14]. Environmental stress and antigens, cause stimulation of T-cell receptor by the major histocompatibility complex (MHC I or II) on the antigen presenting cell (APC). As a result adhesion of T-cell with the APC, mediated by interaction of surface molecules such as CD2 on the T-cell with leukocyte function associated antigen (LFA)-1 on the APC [15] is a another process of pathogenesis in psoriasis. Signal 1 for psoriasis is ultimately generated due to over all formation of antigen MHC complexes with the surface of APCs to interact with T-cell receptors and CD4/CD8 co-receptors on the surface of T-cells [12]. Signal 2, is initiated by interactions between CD28 and CD80, CD40 and CD40L, CD28 and CD86, and LFA3 and CD2 respectively. Presence of signal 1 and 2 is essential for T-cell activation [16, 17]. T-cell activation further breaks down into three steps 1) activation of T-cell; 2) the migration of T-cell into the lesion skin; 3) release of cytokines by activated T-cell in the skin. If anyone of these signal is inhibited, than T-cell activation ceases. A number of new biological agents have been developed for psoriasis which inhibit T-cell activation, for example efalizumab, a humanized anti-CD11a monoclonal antibody, and alefacept, an LFA-3/IgG1 fusion protein. Activation of CD4+ and CD8+ T-cell, produces various inflammatory cytokines such as IL-5, IL-4, and IL 2012 Bentham Science Publishers

*Address correspondence to this author at the Mahfoozur Rahman, Assistant Professor, Dreamz College of Pharmacy, H.P. India 175036; Tel: +919625218477; Fax: ??????????????; E-mail: mahfoozkaifi@gmail.com 1570-1638/12 $58.00+.00

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10, IL-2, IFN- and TNF- , which stimulates keratinocytes, and dendritic cells [18, 19]. The cytokines and chemokines released in psoriasis lesional skin lead to the typical epidermal hyperplasia and keratinocyte inflammation. It is clear from above stated mechanism that psoriasis is T-cell mediated disease and the activation generates various cytokines, adhesion molecules and chemokines which as a result initiates the keratinocyte hyperproliferation and inflammation in psoriasis. As compared to normal skin, proliferative epidermal cell is higher by 26.6% of DNA synthesis in psoriasis. The relative growth increases from 60 to100% and size of proliferative cell is doubled. The cell cycle is shortened from 311hr to 36 hrs, which results in decrease in basal cells of stratum corneum from 27 to 4 days [20, 21]. Conventional treatment for psoriasis includes topical corticosteroids, tars, anthralin, vit D analogs, tazarotene and salicylic acids. All of these have severe side effects like hepatotoxicity. Nephrotoxicity is associated with methotrexate, cyclosporine etc, teratogenicity with oral retinoids and skin cancers with photo/chemotherapy [22, 23]. Modern approach with specific target action, from biological agents, has fewer side effects than conventional therapy. Long term use of these agents has few side effects [24, 25]. According to national psoriasis foundation survey only 26% of patients were satisfied with conventional treatment. Recently, a UK survey has been found that only 44% of patient prefers systemic conventional treatment than topical treatment [26]. According to a survey by European federations of psoriasis association, on 17,990 patients only 27% of patients were satisfaction with conventional treatment. The cause of dissatisfaction among the masses was due to severe side effect, time consuming, ineffective therapy which affected their quality of life [2628]. Therefore etiology and pathogenesis is very important for understanding psoriasis. Its mechanism deciphered, the biomarkers at the cellular and molecular level involved in mediating inflammatory response and other related responses during development of psoriasis. According to the National Institute of Health (NIH), Biomarkers are indicators of pathogenic process in this disease. Psoriasis is caused by multi factorial (toxin, stress, microorganism, etc) or polygenic character, therefore it is essential to identify the nature of biomarker for effective treatment of psoriasis [29-33]. NIH classified it into three types, first type is zero markers that is related to history of disease, second is, type 1 marker which is related to action of drug, and the last is type II marker which is associated with end point i.e. clinical output [32]. From various research studies it has been found that many markers may act as diagnostic tool for psoriasis such as oxidative stress, biochemical factor or enzyme, peptides and gene. 2. OXIDATIVE STRESS MARKER IN PSORIASIS Oxidative stress is prominently due to the reactive oxygen species (ROS), its major targeting site is skin. ROS is generated from endogenous and exogenous source. Endogenously ROS is formed by multiple sources such as electron transport chain (ETC) in mitochondria, radiations [34, 35], enzyme phagocytic and non phagocytic NADPH oxidase

[36, 37], lipoxygenase [38] and cycloxygenase [39] are to name a few. Exogenous sources for ROS are environmental toxins [40], exposure to heavy metal [41], ionizing radiation [42], UV irradiation [43] and antibiotics like adiramycin [44, 45]. ROS include molecular oxygen, hypochlorous acid, peroxynitrile, hydroxyl radical and superoxide anion, all these are competent enough to produce an oxygen unpaired electron, which is known as reactive oxygen species (ROS) [46, 47]. Overproduction or inadequate removal of ROS from the body results in development of oxidative stress, ultimately it leads to various abnormal functions like lipid per oxidation, damage of DNA, protein and production of various inflammatory cytokines [48]. ROS is one of the factors involved in the pathogenesis of psoriasis and also for other inflammatory diseases. ROS modulates the formation of various pro inflammatory cytokines mediators and triggers the mitogenactivated protein kinase/activator protein 1 (MAPK/AP), Janus kinasesignal transducers, activators of transcription (JAK-STAT) pathway and also modulate other protein kinase pathways like tyrosine kinase, lipid per oxidation, causing keratinocyte hyper proliferation and inflammation of psoriatic skin [49]. Pro- inflammatory cytokines in psoriasis like lymphokines, monokines, interleukins, interferons and growth factor, which are chemically glycoproteins, binds to specific cell receptors at picomolar concentration, to produce inflammation and hyper proliferation in psoriasis [50]. Development of psoriatic lesion involves epidermal keratinocyte and leukocyte cells [7]. Keratinocyte is the key centre for recruitment and activation of leukocyte in psoriatic lesion. They also play a role in the formation of various chemokines and growth regulated oncogene product. Further, these agent produces chemotactic agent, which attract the neutrophil cells to the cluster differentiation (CD11) and dendritic cell (DC) of skin. DC cell in psoriatic lesion produces the different interleukin IL-23, IL-20, IL-15, interferon-alpha (IFN), tumor necrosis factor (TNF) and inducible nitric oxide syntheses (iNOS) [51-53]. IL-23, IL-20 and IL-2 along with other many antigens further activate the T-cell and keratinocyte [54, 55]. Among different interleukins, IL-2 is the strong growth factor for T-cell activation. IL-2 also produce TNF, IL-6, IL-2R, IL-15 and IL-2 itself [56]. IL-15 induce the expression of TNF, lymphotoxin and IL-17. IL-17 is also produced by CD4+ T helper cell [57-59], moreover IL-17 also produce the IL-6, IL-8 and chemo tactic agent linked with IFN gamma, IL-4 and TNF [60-62]. IL-8 increased 50 times in psoriatic scales as compared to a normal cell. IFNinduces a variety of cytokines- IL-1, IL-16, IL-8, IL-15 and interferon inducible protein-10 [63]. Cytokine mediator are released primarily from keratinocyte and T-cell of skin under the oxidative stress condition. All these mediators are involved in over expression of keratinocyte proliferation, differentiation, hyperplasia and inflammation of psoriatic skin [64, 65]. 2.1. Induction of Mitogen Activated Protein Kinase/Activator Protein -1 (MAPK/ AP-1) Pathway by ROS It is a signaling cascade, involving extracellular-regulated kinase (ERK1/2, ERK3/4), Jun- N- terminal kinase (JNK)

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Fig (1). ROS-mediated activation of the MAPK/AP-1 signaling pathway. The major components of the MAPK/AP-1 cascade pathway are shown along with the transcription factors. ROS,Ca2+ ion, nitrite ion, protein kinase, activate receptors, Ras, MEKK1, and ASK1, which subsequently causes activation of gene expression , C-jun , B- jun ,CREB, operate in a cascade fashion and lead to many inflammatory mediators (as for PPAR ,) related gene expression.

[66-68], P38 kinase and big mitogen activated protein kinase (BMK1) pathways. All these are activated, when the ROS activates the MAPK/AP-1 [69-71]. As shown in Fig. (1). 2.1.1. Activation of Extracellular-Regulated Kinase (ERK) Pathway ROS activates the multiple factor such as, multiple receptor tyrosine kinase, G-protein coupled receptor an epidermal growth factor receptor [72-76], these all further activates the RAS/RAF/MEK signals of ERK pathways [77, 78]. Nitric oxide [79] and calcium ion [80-83] are also involved in the activation of ERK pathway via nitrosylation of cysteine residue at RAS and calcium- clamodulin protein kinase mechanism [84-87]. According to various researches, it has been found that RAS/RAF/MEK/ERK1/2 expression is increased in psoriatic skin than non psoriatic skin (Fig. 1). Therefore, it might be a potential target for treatment of psoriasis [88, 89]. 2.1.2. Activation of Jun N-Terminal kinase (JNK Pathway) It is activated by many physical and chemical agents, like UV radiation, osmotic pressure alteration [90], irradiation, heavy metals [19], chemotherapeutic agent and reactive oxygen species [44, 45, 91, 92]. ROS activate the JNK-pathway via activation of apoptosis signal-regulating kinase-1 (ASK1), TNF receptor and JNK-MEKK1. Further, its activation causes C-Jun activation, which induces the keratinocyte hyper proliferation (Fig. 1). Many reports are available which proves that over expression of TNF, C-Jun, JNK, ASK1in psoriatic skin than non psoriatic skin [93-95].

2.1.3. Activation of P38 or CDC42 (Types of Protein) Pathway Alike EPK and JNK pathway ,it is activated by ROS, reactive nitrogen species (RNS) and various growth factor receptor [96], these are responsible for activation of TNF family of receptor, and apoptosis signal regulating kinase1(ASK1) [97], which results into activation of P38 pathway via cell division cycle 42 (CDC42) [98, 99]. Furthermore, it phosphorylates many transcription factor, including activating transcription factor-1(ATF-1) [100], and cAMP-response element binding protein (CREB) [101], expresses the keratinocyte hyper proliferation in psoriasis [102] (Fig. 1). 2.2. Janus kinaseSignal Transducers and Activators of Transcription (JAK- STAT) Pathway It is activated by IFN- and IL [103]. Recent studies have shown and demonstrated that, ROS is also involved in the activation of JAK-STAT pathway. This pathway plays an important role in immune-inflammatory disorder [104]. JAK composed of JAKI, JAK2, JAK3 and tyrosine kinase -2. Various research revealed that JAK1 is associated with IFN, IL-2, IL-6 receptors, where as JAK-2 is associated with IL-3 and IFN- receptors [105-107]. STAT family comprises of seven members 1, 2, 3, 4, 5a, 5b, and 6, these members consist of 750-900 amino acid with SH2 domain. Major portion of STAT chains present in cytoplasm is in inactive form. Receptor associated JAK are activated by legand attachment which activates the SH2 domain of STAT via phosphoryla-

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Fig. (2). ROS-mediated activation of the JAKSTAT signaling pathway. ROS, protein kinases, IFN- and IL are major trigger for stimulation. These all may activate Jak2, Tyk2, and the MAPK pathway, which resultes in activation of monomerized JAK-STAT. Activated STAT dimerize and translocate into nucleus, which leads to gene expression and induce formation of interleukin particularly (IL-6, IL-10) type.

Fig. (3). Cell types and responses mediated by exemplary kinases that may contribute to pathogenesis of psoriasis. Various markers involved in psoriasis are vascular endothelial cell growth factor receptor (VEGFR) or epidermal growth factor receptor (EGFR) - induces proliferation, migration of cytokines, chemo tactic agent, survival, and adhesion of keratinocytes and endothelial cells. Janus kinase (JAK) -3 induces T-cell to promoting its proliferation, activation, and development. A tyrosine kinase 2 (Tyk2) and (IFN) induces DC and T-helper cells activation, which produce abnormal keratinocyte proliferation, differentiation, gene expression and various other activities.

tion of tyrosine receptor residue. Further STAT dimerize and translocate to the nucleus, leading to gene expression, this activation give a signal for entire interleukin (IL-6 (IL-6, IL11, IL-31) and IL-10 (IL-10, IL-19, IL-20 IL-22, IL-24) formation (Fig. 2). These all are mediator of inflammatory response in psoriasis [108, 109]. 2.3. Activation of Protein Kinase-C (PKCs) Pathways Protein kinase is a serine threonine kinase [110], it is divided into three groups, first is conventional protein kinase, which includes ( , II and form), second is novel protein kinase, including ( , , , and form) and the third is

atypical form which have mainly form [111, 112] PKCs is very sensitive to extracellular and intracellular ROS. Its activation result in transduction of TNF, CDId, human leukocyte antigen-1(HLA-class-I) molecule, when combined with keratinocyte natural- killer T-cell that mediate the cytokine production. Phosphorylation at threonine centre of PKCs finally translocate to nuclear membrane and form nuclear factor b (NF-K ) by phosphorylation of RelA P65 protein. NF-K is a key molecule for DNA binding. Its binding causes activation of other proinflammatory cytokines, chemokines and different adhesion molecule in psoriasis [112-114].

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Fig. (4). Receptor tyrosine kinase (TK) activation. A. In absence of legend attachment receptor TKs exist in monomerized inactive form. B. Legand binding to extracellular domain causes activation of receptor TKs, which leads to dimerization and autophosphorylation in cytoplasmic domain of TKs. As a result signal transduction is induced through mitogen-activated protein kinases (MAPKs), Akt, and STATs to producethe effect. C. In presence of TK inhibitor (TKI), monomerized form of TKs receptor fails to change into dimerized effective form, as a result cascade of reaction is inhibited.

Fig. (5). The origin of said mediators is from the tissues, blood vessels, and neurons under the influence of oxidative stress condition. This excervate keratinocyte hyper proliferation and differentiation of psoriatic skin.

2.4. Lipid Per Oxidation NADPH-dependent oxidase/myleoperoxidase, and various proteolytic enzymes plays a key role in production of intracellular ROS, causing lipid per oxidation and oxidative damage of cell membrane and proteins [115, 116]. When

sensitive, psoriatic skin is oxidized to low density lipoproteins (OX-LDL), malondialdehyde, and high amount of thio compound, their accumulation in psoriatic skin leads to many immune inflammatory events [117, 118]. Decrease amount of many antioxidant such as alpha- tocopherol and glutathione (Vit-E, GSH, etc) in the plasma, increases the

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Table 1. Different Gene Involved in Psoriasis

Locus name PSORS1 PSORS2 Location 6p21,6q,8q24,10q22-q23,14q31-q32 17q24-q25,19p13,20p Locus Marker HLAC,D8S284 D17S785,D19S916,D19S865 Ref [179-182] [179] [180] [183, 184] [175] [178] [179] [175]

PSORS3 PSORS4

4q34 1q21,2p

D4S2982 D1S305,D1S1664

PSORS5

3q21,4q13,4q21

D3S1768,D3S2409

Table 2. Origin/Source of Different Biomarkers

Markers Thiobarbituric acid (TBA) Superoxide dismutase C-reactive protein, neutrophil function Fibrinogen TNF-alpha,IFN-y,IL-2,6,8,12,18 Malondialdehyde Oxidized LDL Cytokeratins Heat shock protein Connexins (26,30) Bcl-x,Bax,p53,epideremal growth factor TGF-alpha, involucrin MRP-8 SP,VIP,NGF,PACAP-38 Keratin 6,16,MAPK Origin Blood Blood Blood Blood Blood Tissue Tissue Tissue Tissue Tissue Tissue Tissue Tissue Tissue Tissue

TNF, tumor necrosis factor IFN, interferon; IL, interleukin;LDL, low-density lipoprotein; TGF, transforming growth factor MRP, migration inhibitory factor-related protein SP, substance p; VIP, vasoactive intestinal peptide. MAPK, mitogen-activated protein kinase;; NGF, nerve growth factor; PACAP,pituitary adenylate cyclase activating polypeptide; MAPK, mitogen-activated protein kinase

level of malondialdehyde (MDA), which results in lipid peroxidation and keratinocyte hyperproliferation of skin [119, 120]. A very recent study has found that under oxidative stress condition, psoriatic skin shows over expressed peroxisome proliferator-activated receptors (PpAR ), a member of nuclear steroid hormone receptor, it causes abnormal lipid protein metabolism and epidermal proliferation of skin. It is mostly activated by transcription factor AP-1, Jun-B and heparin binding EGF [121]. 3. BIOCHEMICAL MARKER IN PSORIASIS Enzyme keratinocyte transglutaminase type I, increases the keratinocyte proliferation in the skin. This result in rise

of involucrin, antileucoproteinase [122] and keratin protein such as k6 and k16 in tissues, which leads to skin hyperproliferatation in psoriasis [123]. Decreasing amount of k1and k10 causes terminal differentiation of keratinocyte. Many different biomarkers such as HSP60, HSP27 (heat shock protein), IL12, toll like receptor-4 (TLR4) [124, 125], connexins (Cx) [126, 127], epidermal growth factor(EGF) [128], transforming growth factor-alpha (TGF- ,) [129] and bone morphogenetic protein-6 (BMP-6) are found mostly in plaque psoriasis, guttae psoriasis and in other type of psoriasis [130], plaque psoriasis is most common type of psoriasis. All these markers originates (Fig. 5) from tissue or blood [131]. As a biomarker, many natural death proteins such as Bcl-x and Bak are associated with psoriatic skin. Bax are

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also found along with induction of p53and ki67 positive cell, all of these mediate cell proliferation [132-136]. Rocha periera- et al. [137] has found many marker, C-reactive protein (CRP), fibrinogen, C3, C4 and also deciphered the association of CD4+ T cell, DCS and CD8+T-cell, that induces the formation of pro inflammatory cytokines such as IL-23, IL-15, IL-17, TNF alpha, IFN-alpha etc. Cumulative effect of these causes stimulation of T- cell and hyper proliferation in the skin [7, 138, 139]. Recently it has been demonstrated that, caspase is found in hyper proliferative keratinocyte cell of skin, which is a cysteine proteinases enzyme, consisting of Caspase 3, 6, 7, and 14. In the presence of external stimuli caspas-14 is cleaved and enters into keratinocyte cell nuclei to induce the keratinocyte hyper proliferation and differentiation [140-144]. Various research studies has demonstrated that tyrosine kinase is over expressed in many inflammatory disorders such as psoriasis, arthritis and and crohn disease [145-147]. Tyrosine kinases catalyzes the cellular event by reversible phosphorylation (phosphate group come from ATP or GTP) at the tyrosine residue on the protein substrate. TKs is divided into two parts first is receptor type and second is non receptor type [148]. Receptor type TKs is characteristically transmembrane protein, and it has two domains extracellular and intracellular. Extracellular domain have legand binding site, and intracellular consist of catalytic domain. Receptor type TKs is divided into twenty families, including vascular endothelial growth factor (VEGF) receptor (VEGFR), epidermal growth factor (EGF) receptor (EGFR) (Fig. 3), and platelet-derived growth factor (PDGF) receptor (PDGFR), fibroblast growth factor receptor. They are rearranged during transfection (RET) kinase [149]. EGFR is classified into 4 groups, which are known as erythroblastic leukemia oncogene homolog [ErbB1], ErbB2, ErbB3, and ErbB4. ErbB2and ErbB3 causes mainly psoriatic cell proliferation [150]. All receptor type TKs (except insulin type TKs) are present in monomeric nonphosphorylated form. Keratinocyte cell produce many different type of ligand as EGF legends TGFa, and epiregulin [151]. This legend binds to extracellular domain of TKs, which results dimereization of receptor, leading to activation of intrinsic catalytic domain, present in cytoplasm and in nucleus. This induces various transduction signals to produce inflammatory mediator that is involved in pathogenesis of psoriasis (Fig. 4). Nonreceptor TKs composed of 10 families, like sarcoma (src), Janus kinase (JAK) and Abelson (Ab1) etc [149]. Under normal condition non receptor tyrosine kinase present in inactive form as like receptor TKs1 [151]. Non receptor TKs activation, activates the other family member of TKs like TK-JAK-3 [149], resulting in development of Tcell and various signals to the other cytokine mediator, which mediates keratinocyte hyper proliferation and differentiation in psoriasis (Fig. 3) [149-154]. Presently, many tyrosine kinase inhibitor as a drug has been approved and many are under clinical stage (Table 5). Recently polymorph nuclear leukocytes (PML) identified by histological examination of psoriatic skin. PML activation lead to generation of potent chemo attractants, which are detected in the stratum corneum by immuneflourscence techniques, such as TNF and GM-CSF (Granulocyte-macrophages colony stimulating factors). PML inactivation prevents the activation or accumulation of PML in the skin and further inhibits the forma-

tion of chemo attractants and pro inflammatory mediators. All these biochemical markers might be targeted for effective treatment of psoriasis [155, 156]. 3.1. Arachidonic Acid Metabolite Biomarker Every human cell membrane consist of phospholipids, made of archidonic acid (3, 5, 8, 11 tetraecisonapentanoic acid). Action of plasma membrane bound phospholipase A2 (PLA2) and lipoxygenase enzyme cleaves it into prostaglandins (PGI2, PGE1, PGE2 etc) and leukotriens (LTB4, LTC4 etc). These are involved in the pathogenesis of psoriasis [157, 158]. Many cycloxygenase and lipoxygenase inhibitors like NSAIDS, Benoxaprofen and lonapalene etc has been used in psoriasis. Recently, it has been proved that intravenous infusion of omega-3 fatty acid based lipid emulsion containing EPA and DHA (like fish oil, linseed oil, and evening primrose oil), compete with archidonic acid as a substrate which leads to the formation of less psoriagenetic metabolites [158], and overall improvement in the severity of psoriasis. 3.2. Neuropeptides Biomarker in Psoriasis They are released from cutaneous nerve fibres. Biochemical and histochemical examinations have revealed vasoactive intestinal peptide (VIP) and substance-P in deeper dermis around eccrine gland and also found in dermal papillae of psoriatic skin. Naukrinen et al has found that mast cell and mast cell nerve fiber are more frequently present in dermis of psoriatic skin. Various stimuli stimulate these nerve fibers to release substance P and VIP. This causes formation of various pro inflammatory cytokines and degranulates the mast cell leading to releases of proinflammatory substances [159, 160]. Moreover, many neuropeptides like pituitary adenylate cyclase activating polypeptide (PACAP)-38 [161], nerve growth factor (NGF), and calcitonin gene related peptide also has been found in psoriatic plaque skin as a inflammatory agent by histochemical studies [162, 163]. 3.3. Gene Marker Involved in Psoriasis Various research studies have revealed that multiple genes are involved in the pathogenesis of psoriasis. Genome wide linkage scans is a technique used to identify a number of genetic loci such as PSORS1 in the major histocompatibilty complex (MHC) on the arm of chromosome 6 [164, 165] and chromosome 17. Another technique to prove of genetic involvement is demographic, epidemiologic, serologic, family history and twin studies [166-168]. On the basis of demography psoriasis mostly found in the age group of 20-30 (Type-1) years and found in 50-60 year (Type II). Type II is not very common in various ethnic groups. Type-1 is found in human leukocyte antigen (HLA) and is associated with family history. Type II is not associated with HLA and family history [168, 169]. HLA can be positive or negative. HLA +ve type is associated with low age patients and whereas HLA ve is associated with high age group [170172]. Recent study on 29 guttae psoriasis patients in UK confirmed that HLA-CW0602 alleles was responsible in guttae psoriasis and similar results were observed in chronic plaque psoriasis [173], chromosome 17q25 for PSORS2 and chromosome 4q for PSORS3 [174-176]. It has been found that many other linkages such as PSORS5 on 3q21 [177]

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Table 3. List of Major Targeting Drugs

Biological Actions Denilukin diftitox Brand name: ontak Mechanism Involved Act on IL-2, Receptor decreases the number of Pathogenic Tcell. FDA Approval approved Efficacy Study on 24 patients with plaque type psoriasis, administered dose of 2, 4, 6 and 9 mg/kg of Denilukin diftitox by i.v route for continuous five days of 4 week up to 6 month. In the end Psoriasis Area and Severity Index (PASI) decrease 68% with respect to baseline at higher dose > 50% reduction in PASI baseline in half of all patient. In case of plaque psoriasis a trial on 19patients at a dose of 2mg/kg followed by 1mg/kg for 8 week. 30% patients showed reduction in PASI. In the case of plaque type psoriasis two cases has been effectively treated. Adverse Effect Fever, chill, vomiting Ref [193]

Daclizumab Brand name: Zenapax

Act on IL-2, Receptor decreases the number of Pathogenic Tcell. Act on IL-2, Receptor decreases the number of pathogenic Tcell. Act on CD11a,causes T-cell Inhibition

under clinical stage

No adverse effects

[194]

Basilximab Brand name: Simulect Efalizumab Brand name: Raptiva

under clinical stage

No adverse effects

[195] [196]

approved

Study on 556 patients, at a dose of 1mg/kg for 12 week more than 75% reduction in base line, PASI score will be increased with increased in duration of therapy. A case study on 553 patients of plaque type psoriasis at a dose of 7.5mg of I.V bolus injection for a period of 12 weeks, causes 75% reduction in base line in 28% of patient after one course of treatment and 40% of patient after second course of treatment A case study on 26 patients of psoriasis at a dose of 0.4-40% mg/kg for 8 weeks. 75% reduction from mean base line PASI in 50% of the patient A case study on 28 patients of psoriasis at a dose of 20 mg/kg s.c three times a day for 12 week causes 35% reduction from baseline PASI. A case study on 148 patients of psoriasis at a dose of 40 mg every week for 12 weeks as a consequence , 75% reduction from base line PASI in 80% of the patient A case study on 12 patients of psoriasis with a dose of 2.5 or 5.0 mg /kg for 8 weeks causes 30-80% decrease from base line PASI in 91% patients. A case study on 249- patients with a dose of 3 and 5 mg/kg for 6 weeks. 75% reduction from base line PASI in 72% of the patients at 3 mg/kg, and 88% of the patients at the 5mg/kg.

may produce Thrombocytopenia (Under investigation)

[197]

Alefacept Brand name : Amevive.

Act on CD2 unit of Tcells. Block its hypersensitiveness

approved

dizziness, nausea, chills, and cough

[198] [199]

Siplizumab; Brand name: Medimmune

Act on CD2 unit of Tcells. Block its hypersensitiveness

under clinical stage

chills, and headache

[200]

rhIL-10 Brand name: Tenovil

Act on cytokines such as IL-4 IL-10 and IL-11antagonist action on cytokines

under clinical stage

headache, gastric pain

[201]

Adalimumab (Humira)

It act against TNF-a

approved

Headache, nausea, elevated triglycerides, cough, site pain.

[202]

Oprelvekin Brand name: Neumega

Antagonist action on cytokines

Under clinical stage

no adverse effect

[203]

Infliximab Brand name: Remicade

Acts against TNF-a and other cytokines

under clinical stage

only Headache

[204]

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Table 3. cont Etenercept Brand name: embrel Act against TNF- alpha approved A case study on 672 patients of psoriasis with a dose of 25 mg/kg for every week. 25 mg/kg for twice a week or 50 mg/kg twice a week. It was observed that 75% reduction from base line PASI in 44% of the patients at a 25mg/kg of every week, 59% of the patient at a dose of 50 mg/kg twice a week. Not reported. A study on 903 patients divided into three groups first 45 mg dose of ustekinumab for 0 and 4 weeks, 90 mg ustekinumab for 0 and 4 weeks and 50 mg etanercept for 0 and 4 weeks. The maximum PASI reduction was observed in 75% of patients with 90 mg of dose of ustekinumab with respect to etanercept. ----------------no adverse effect after long term it enhance diabetes, multiple sclerosis, and infection [205]

ABX-IL8 Ustekinuma (CNTO-1275)

It selectively act against IL-8. It is a novel human immunoglobulin IgG, binds with p40 subunit of both IL-12 and IL-23.

clinical stage FDA approved

still not reported upper respiratory infection, nasopharyngitis, arthralgia, headache, cough, and injection Site reaction.

[206] [207]

Briakinuma (ABT-874):

Is a recombinant fully human IgG1 monoclonal antibody that binds with high affinity to the p40 subunit of both IL12 and IL-23 cytokines

clinical stage III

Nasopharyngitis and upper respiratory tract infections

[208]

Certolizumab

It is a inhibitor of TNF.

clinical stage III

A study on moderate to severe chronic plaque type psoriasis patient swere receive 200 or 400 mg of certolizumab, every 2 week for 12 week ,in the last of 12th week PASI 75% decrease from base line.

headache, nasopharyngitis, pruritus

[209]

Table 4. Drug Targeting on STAT Pathway

Therapeutic Agent Ethyl pyruvate N-acetyl-L-cysteine Dimethyl fumarate (DMF) Ascorbic acid (Vit-C) Uric acid Vit.E ( -tocopherol) Mechanism of Action inhibits STAT signal pathway inhibits STAT signal pathway increased glutathione level in tissues and causes inhibition of ROS. inhibits STAT signal pathway Protects against oxidative damage by scavenging oxygen radicals, OH, and other cellular oxidants. it prevents lipid peroxidation and quenches free radicals [211] [212] [213] [212] Ref [210]

PSORS4 on 1q21, PSORS8 on 16q12-q13, and PSORS7 on 1q35-p34 etc are limited to psoriasis [178]. Different loci of gene marker have been shown in Table 1. Genetic approach can decipher a novel biological pathway for the effective treatment of psoriasis. This may be very effective approach among than other targeting approaches. Advancement in genetic research results in discovery of novel targeted antiproliferative agents. However identification of different loci of gene is in its juvenile stage. 4. DRUG TARGETING ON BIOMARKER Healthy skin maintains many enzyme and cellular redox system in the body, which play a vital role in prohibition of inflammatory disease. Imbalance in these systems may results in formation of various oxidative marker, biochemical marker and peptide marker, which in turn leads to psoriasis

[185]. So for its treatment or prevention it is necessary to target various signaling molecules. Many monoclonal antibodies [186] (Table 3), group of high molecular- weight antioxidant enzymes (HMWA), proteins and a group of non enzymatic low-molecular-weight antioxidants (LMWA) can be effective tools for its prevention and treatment. HMWA including superoxide dismutases (SODs) [187, 188], glutathione peroxidases (GPx), thioredoxin/thioredoxin reductase (TR), glutathione reductase (GR), catalase, metallothioneins, and ferritin system, whereas the LMWA include -tocopherol (vitamin E), reduced glutathione (GSH), ascorbic acid (vitamin C), and uric acid [189-192] are to name a few for treatment of psoriasis. These drugs have been listed in Table 3-5. Most of the biological agents, which are presently used in the treatment of cancer, have been shown very effective against psoriasis, through different markers. Many

10 Current Drug Discovery Technologies, 2012, Vol. 9, No. 2

Rahman et al.

Table 5. Drug Targeting on Different Tyrosine Kinase

Tyrosine kinase VEGFR1,VEGFR2VEGFR3,PDGFRb RET. JAK1, JAK3. EGFR, ErbB2. VEGFR1,VEGFR2,VEGFR3, PDGFRa PDGFRb, c-Fms, c-Kit, FLT3, RET. PDGFRa,PDGFRb c-Fms,c-Abl, Lck. EGFR, ErbB2. Targeting on Tyrosine kinase (Generic Name) NVP-BAW2881 (Novartis, Cambridge, MA). R333, (Rigel Pharmaceuticals Inc, San Francisco, CA). PD169540 (Pfizer Inc, New York, NY). Sunitinib, (Pfizer Inc, New York, NY). Status Preclinical stage Preclinical Stage Preclinical Stage Approved Ref 214] 215] 215] [216]

Imatinib, (Novartis, Cambridge, MA) lapatinib, (GlaxoSmithKline, London), England)

Approved Approved

[217] [218] [219]

of these have been approved and many are under clinical trial at various stages as discussed in (Table 3, 5). The results of clinical trial show that these are good therapeutic targets, specific and selective in action, with fewer side effects. Some biological agents like, Daclizuumab, Etanercept, Infliximab and Ustekinumab etc have found as immunosuppressive agents; these are listed only in Table 3. Major existing limitation with biological agents is cost and they are administered in injection form [24]. The cost can managed, if the dosage forms of these drugs are altered, formulating it into a gel, resulting in direct penetratation, thus reducing systemic availability of the drug, directly reducing the side effects. Moreover, optimum dosing regimens and administration methods for many of these biologics must be established. Presently research is under process to search a phytoconstituents, which may show targeted action against these different markers responsible for psoriasis. 5. CONCLUSION This review has provided expression of various molecules or marker that monitor the initiation and progress of psoriasis. Over or under expression of markers, like ROS, biochemical and peptides markers exerts their action in normal and abnormal condition. In normal condition they perform normal cell function and immune function. Due to various stimuli, the level of markers may increase and causes induction of several cellular signal transduction pathways such as MAPK/AP-1, NF-k , JAK-STAT, lipid per oxidation and genes activation, which are involved in pathogenesis of psoriasis. This may pave the way to discover a novel targeting drug molecules for psoriasis like monoclonal antibodies, tyrosine kinase inhibitors, JAK-STAT pathway targeting drugs and may exert their action as an antiproliferative and antioxidative effect. These all can help in better understanding and can open new avenues for effective treatment of psoriasis, its identification to eliminate conventional way of treatment and its serious adverse effects. The discussed markers may be involved in other inflammatory disorders like arthritis/rheumatism. In the current scientific development research work is in progress to establish the correlation between tissue/serum marker and clinical examination to increase the linking between biomarkers and psoriasis.

ABBREVIATIONS AP-1 ASK1 ATF CD DC DMF ERK GSH IFNiNOS IL IKK JAKSTAT JNK MAPK MAPKK or MKK MAPKKK MEK MEKK MSK1/2 NADPH NF- B PKC ROS SOD TNF = = = = = = = = = = = = = = = = = = = = = = = = = = Activator protein 1 Apoptosis signal-regulating kinase1 Activating transcription factor Cluster of differentiation Dendritic cell Dimethyl fumarate Extracellular-regulated kinase Glutathione InterferonInducible nitric oxide synthase Interleukin I B kinase Janus kinasesignal transducers and activators of transcription Jun N-terminal kinase Mitogen-activated protein kinase MAP kinase kinase MAP kinase kinase kinase MAPERK kinase MAPERK kinase kinase Mitogen- and stress-activated protein kinase 1/2 Reduced nicotinamide adeninedinucleotide phosphate Nuclear factor B Protein kinase C Reactive oxygen species Superoxide dismutase Tumor necrosis factor

Insight into the Biomarkers as the Novel Anti-Psoriatic Drug Discovery Tool

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Received: August 25, 2011

Revised: September 05, 2011

Accepted: September 28, 2011