Prostaglandin E receptors as inflammatory therapeutic targets for atherosclerosis

Prostaglandin E receptors (EPs) are the G-protein-coupled receptors (GPCRs) that respond to type E(2) prostaglandin (PGE(2)). Data has shown that PGE(2) may function as an endogenous anti-inflammatory mediator by suppressing the production of cytokines. However, other studies have demonstrated that PGE(2), a pro-inflammatory mediator produced by various cell types within the wounded vascular wall, plays a crucial role in early atherosclerotic development. These contradictory results may be due to the versatility of EPs. Experimental data suggest an individual role for each PGE(2) receptor, such as EP(1), EP(2), EP(3) and EP(4), in atherosclerosis. In this review, the roles of EPs in atherosclerosis are summarized, and the value of EPs as new therapeutic targets for atherosclerosis is explored.     

Cytokines as potential therapeutic targets for inflammatory skin diseases

A network of pro-inflammatory cytokines is a central feature in the pathophysiology of cutaneous inflammatory diseases. Thus, the delineation of precise roles for particular cytokines and the development of cytokine-directed therapeutics have become areas of intense investigation. While anti-TNF therapeutics have proven to be effective for the treatment of psoriasis, clinical investigations have now begun with other cytokine-directed therapies, such as those targeting IFN-g, IL-12p40, and IL-18. In addition to therapeutics that target cytokines directly, strategies that target cytokine signaling pathways are in development too. In this short review, we summarize key findings from a recent workshop on cytokines as potential therapeutic targets for inflammatory skin diseases.     

Eph family receptors as therapeutic targets

Anti-angiogenic therapy is currently a commonly accepted and rapidly developing approach in oncology and other pathologies linked to aberrant neovascularization. Discovery and validation of additional molecular targets in angiogenesis is needed due to the limitations of the existing clinical therapeutics inhibiting activity of vascular endothelial growth factor (VEGF) and its receptors. A brief review of normal and pathological biological functions of the Eph family of receptor tyrosine kinases and their ephrin ligands is presented, and the approaches to developing therapeutics with anti- and pro-angiogenic and anti-tumor activity based on selective molecular modulation of Eph-ephrin signaling pairs are discussed. Functional roles of Eph-kinases and ephrins in such mechanisms of carcinogenesis as cell proliferation and invasion are also addressed.     

Toll-like receptors are potential therapeutic targets in rheumatoid arthritis

Toll-like receptors (TLRs) are found on the membranes of pattern recognition receptors and not only play important roles in activating immune responses but are also involved in the pathogenesis of inflammatory disease, injury and cancer. Furthermore, TLRs are also able to recognize endogenous alarmins released by damaged tissue and necrosis and/or apoptotic cells and are present in numerous autoimmune diseases. Therefore, the release of endogenous TLR ligands plays an important role in initiating and driving inflammatory diseases. Increasing data suggest a role for TLR signaling in rheumatoid arthritis, which is an autoimmune disease. Although their involvement is not comprehensively understood, the TLRs signaling transducers may provide potential therapeutic targets.     

Metabotropic G-protein-coupled glutamate receptors as therapeutic targets.

Metabotropic glutamate receptors have received considerable attention over the past decade in view of their relevance in multiple aspects of glutamatergic transmission. Recent advances in the molecular biology, pharmacology and medicinal chemistry of this family of G-protein-coupled receptors have led to therapeutic opportunities for subtype-selective modulators in brain disorders and diseases such as ischemia and schizophrenia.     

G protein-coupled receptors: potential therapeutic targets for diabetic nephropathy

Diabetic nephropathy, a lethal microvascular complication of diabetes mellitus, is characterized by progressive albuminuria, excessive deposition of extracellular matrix, thickened glomerular basement membrane, podocyte abnormalities, and podocyte loss. The G protein-coupled receptors (GPCRs) have attracted considerable attention in diabetic nephropathy, but the specific effects have not been elucidated yet. Likewise, abnormal signaling pathways are closely interrelated to the pathologic process of diabetic nephropathy, despite the fact that the mechanisms have not been explored clearly. Therefore, GPCRs and its mediated signaling pathways are essential for priority research, so that preventative strategies and potential targets might be developed for diabetic nephropathy. This article will give us comprehensive overview of predominant GPCR types, roles, and correlative signaling pathways in diabetic nephropathy.     

Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease

Vitamin A (retinoid) is required in the adult brain to enable cognition, learning, and memory. While brain levels of retinoid diminish over the course of normal ageing, retinoid deficit is greater in late onset Alzheimer disease (LOAD) brains than in normal-aged controls. This paper reviews recent evidence supporting these statements and further suggests that genes necessary for the synthesis, transport and function of retinoid to and within the ageing brain are appropriate targets for treatment of LOAD. These genes tend to be clustered with genes that have been proposed as candidates in LOAD, are found at chromosomal regions linked to LOAD, and suggest the possibility of an overall coordinated regulation. This phenomenon is termed Chromeron and is analogous to the operon mechanism observed in prokaryotes. Suggested treatment targets are the retinoic-acid inactivating enzymes (CYP26)s, the retinol binding and transport proteins, retinol-binding protein (RBP)4 and transthyretin (TTR), and the retinoid receptors. TTR as a LOAD target is the subject of active investigation. The retinoid receptors and the retinoid-inactivating enzymes have previously been proposed as targets. This is the first report to suggest that RBP4 is an amenable treatment target in LOAD. RBP4 is elevated in type-2 diabetes and obesity, conditions associated with increased risk for LOAD. Fenretinide, a novel synthetic retinoic acid (RA) analog lowers RBP4 in glucose intolerant obese mice. The feasibility of using fenretinide either as an adjunct to present LOAD therapies, or on its own as an early prevention strategy should be determined.     

Secretases as therapeutic targets for Alzheimer's disease

Accumulation of amyloid-β (Aβ) is widely accepted as the key instigator of Alzheimer’s disease (AD). The proposed mechanism is that accumulation of Aβ results in inflammatory responses, oxidative damages, neurofibrillary tangles and, subsequently, neuronal/synaptic dysfunction and neuronal loss. Given the critical role of Aβ in the disease process, the proteases that produce this peptide are obvious targets. The goal would be to develop drugs that can inhibit the activity of these targets. Protease inhibitors have proved very effective for treating other disorders such as AIDS and hypertension. Mutations in APP (amyloid-β precursor protein), which flanks the Aβ sequence, cause early-onset familial AD, and evidence has pointed to the APP-to-Aβ conversion as a possible therapeutic target. Therapies aimed at modifying Aβ-related processes aim higher up the cascade and are therefore more likely to be able to alter the progression of the disease. However, it is not yet fully known whether the increases in Aβ levels are merely a result of earlier events that were already causing the disease.     

G protein-coupled receptors as therapeutic targets for multiple sclerosis

G protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants. They are considered as the most successful therapeutic targets for a broad spectrum of diseases. Multiple sclerosis (MS) is an inflammatory disease that is characterized by immune-mediated demyelination and degeneration of the central nervous system (CNS). It is the leading cause of non-traumatic disability in young adults. Great progress has been made over the past few decades in understanding the pathogenesis of MS. Numerous data from animal and clinical studies indicate that many GPCRs are critically involved in various aspects of MS pathogenesis, including antigen presentation, cytokine production, T-cell differentiation, T-cell proliferation, T-cell invasion, etc. In this review, we summarize the recent findings regarding the expression or functional changes of GPCRs in MS patients or animal models, and the influences of GPCRs on disease severity upon genetic or pharmacological manipulations. Hopefully some of these findings will lead to the development of novel therapies for MS in the near future.     

TRPM channels as potential therapeutic targets against pro-inflammatory diseases

The immune system protects our body against foreign pathogens. However, if it overshoots or turns against itself, pro-inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, or diabetes develop. Ions, the most basic signaling molecules, shape intracellular signaling cascades resulting in immune cell activation and subsequent immune responses. Mutations in ion channels required for calcium signaling result in human immunodeficiencies and highlight those ion channels as valued targets for therapies against pro-inflammatory diseases. Signaling pathways regulated by melastatin-like transient receptor potential (TRPM) cation channels also play crucial roles in calcium signaling and leukocyte physiology, affecting phagocytosis, degranulation, chemokine and cytokine expression, chemotaxis and invasion, as well as lymphocyte development and proliferation. Therefore, this review discusses their regulation, possible interactions and whether they can be exploited as targets for therapeutic approaches to pro-inflammatory diseases.     

Leukotriene B4 receptors as therapeutic targets for ophthalmic diseases

Leukotriene B₄ (LTB₄) is an inflammatory lipid mediator produced from arachidonic acid by multiple reactions catalyzed by two enzymes 5-lipoxygenase (5-LOX) and LTA₄ hydrolase (LTA₄H). The two receptors for LTB₄ have been identified: a high-affinity receptor, BLT1, and a low-affinity receptor, BLT2. Our group identified 12(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid (12-HHT) as a high-affinity BLT2 ligand. Numerous studies have revealed critical roles for LTB₄ and its receptors in various systemic diseases. Recently, we also reported the roles of LTB₄, BLT1 and BLT2 in the murine ophthalmic disease models of mice including cornea wound, allergic conjunctivitis, and age-related macular degeneration. Moreover, other groups revealed the evidence of the ocular function of LTB₄. In the present review, we introduce the roles of LTB₄ and its receptors both in ophthalmic diseases and systemic inflammatory diseases. LTB₄ and its receptors are putative novel therapeutic targets for systemic and ophthalmic diseases.     

Mechanisms and potential therapeutic targets for folic acid in cardiovascular disease

Folic acid (FA) is a member of the B-vitamin family with cardiovascular roles in homocysteine regulation and endothelial nitric oxide synthase (eNOS) activity. Its interaction with eNOS is thought to be due to the enhancement of tetrahydrobiopterin bioavailability, helping maintain eNOS in its coupled state to favor the generation of nitric oxide rather than oxygen free radicals. FA also plays a role in the prevention of several cardiac and noncardiac malformations, has potent direct antioxidant and antithrombotic effects, and can interfere with the production of the endothelial-derived hyperpolarizing factor. These multiple mechanisms of action have led to studies regarding the therapeutic potential of FA in cardiovascular disease. To date, studies have demonstrated that FA ameliorates endothelial dysfunction and nitrate tolerance and can improve pathological features of atherosclerosis. These effects appear to be homocysteine independent but rather related to their role in eNOS function. Given the growing evidence that nitric oxide synthase uncoupling plays a major role in many cardiovascular disorders, the potential of exogenous FA as an inexpensive and safe oral therapy is intriguing and is stimulating ongoing investigations.     

Low-n oligomers as therapeutic targets of Alzheimer's disease

The pathogenesis of Alzheimer's disease involves the progressive accumulation of amyloid β-protein (Aβ). Recent studies using synthetic Aβ peptides, a cell culture model, Aβ precursor protein transgenic mice models suggest that pre-fibrillar forms of Aβ are more deleterious than extracellular fibril forms. Recent findings obtained using synthetic Aβ peptides and human samples indicated that low-n oligomers (from dimers to octamers) may be proximate toxins for neuron and synapse. Here, we review the recent studies on the soluble oligomers, especially low-n oligomers in Alzheimer's disease.     

Tau modifiers as therapeutic targets for Alzheimer's disease

Fibrillogenesis is a major feature of Alzheimer's disease (AD) and other neurodegenerative diseases. Fibers are correlated with disease severity and they have been implicated as playing a direct role in disease pathophysiology. In studies of tau, instead of finding causality with tau fibrils, we found that tau is associated with reduction of oxidative stress. Biochemical findings show that tau oxidative modifications are regulated by phosphorylation and that tau found in neurofibrillary tangles is oxidatively modified, suggesting that tau is closely linked to the biology, not toxicity, of AD.     

Ceramide synthases as potential targets for therapeutic intervention in human diseases

Ceramide is located at a key hub in the sphingolipid metabolic pathway and also acts as an important cellular signaling molecule. Ceramide contains one acyl chain which is attached to a sphingoid long chain base via an amide bond, with the acyl chain varying in length and degree of saturation. The identification of a family of six mammalian ceramide synthases (CerS) that synthesize ceramide with distinct acyl chains, has led to significant advances in our understanding of ceramide biology, including further delineation of the role of ceramide in various pathophysiologies in both mice and humans. Since ceramides, and the complex sphingolipids generated from ceramide, are implicated in disease, the CerS might potentially be novel targets for therapeutic intervention in the diseases in which the ceramide acyl chain length is altered. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.     

Caspase-mediated programmed cell death pathways as potential therapeutic targets in cancer

The caspase family is well characterized as playing a crucial role in modulation of programmed cell death (PCD), which is a genetically regulated, evolutionarily conserved process with numerous links to many human diseases, most notably cancer. In this review, we focus on summarizing the intricate relationships between some members of the caspase family and their key apoptotic mediators, involving tumour necrosis factor receptors, the Bcl-2 family, cytochrome c, Apaf-1 and IAPs in cancer initiation and progression. We elucidate new emerging types of cross-talk between several caspases and autophagy-related genes (Atgs) in cancer. Moreover, we focus on presenting several PCD-modulating agents that may target caspases-3, -8 and -9, and their substrates PARP-1 and Beclin-1, which may help us harness caspase-modulated PCD pathways for future drug discovery.     

Identification and characterization of potential new therapeutic targets in inflammatory and autoimmune diseases.

The isoxazole derivative Leflunomide (HWA 486) is a novel immunoregulatory and anti-inflammatory drug. Affinity chromatography was used to purify and identify Leflunomide binding proteins, which might play a role as potential cellular targets in the molecular mode of action. The Leflunomide derivative A 0273 was covalently coupled to a Fractogel(R) matrix. This column was used to separate a cytosolic protein extract of the macrophage cell line RAW 264.7 by several selected and specific gradient elution steps. Proteins that were specifically eluted through the active metabolite of Leflunomide, A 1726, were identified by subsequent protein sequence analysis. This allowed us to specify 10 cytosolic proteins, which bind with high affinity to this matrix. Three of them, glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase and phosphoglycerate mutase belong to the second part of the glycolytic pathway. The binding specificity of these protein/drug interactions was further evaluated using BIAcore(R) analysis. Kd values of glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase and lactic dehydrogenase were similar to the Kd value of a known Leflunomide target protein, dihydroorotate dehydrogenase. In order to elucidate the features as well as the overall relevance of these results, cytosolic fractions of three additional cell lines MOLT-4, A20.2J, HeLa were compared using the same chromatographic protocol. The elution profiles as well as subsequent Western blot analyses confirmed the data obtained previously for the macrophage cell line RAW 264.7.     

circRNA: Regulatory factors and potential therapeutic targets in inflammatory dermatoses

The skin is the largest organ of the human body and acts as the first line of defence against injury and infection. Skin diseases are among the most common health problems and are associated with a considerable burden that encompasses financial, physical and mental consequences for patients. Exploring the pathogenesis of skin diseases can provide insights into new treatment strategies. Inflammatory dermatoses account for a large proportion of dermatoses and have a great impact on the patients'' body and quality of life. Therefore, it is important to study their pathogenesis and explore effective treatment. Circular RNAs (circRNAs) are a special type of RNA molecules that play important regulatory roles in several diseases and are involved in skin pathophysiological processes. This review summarizes the biogenesis, properties and functions of circRNAs as well as their roles in the pathogenesis of inflammatory dermatoses, including psoriasis, lupus erythematosus, atopic dermatitis, lichen planus and severe acne and their potential as therapeutic targets.     

14-3-3 proteins as potential therapeutic targets

The 14-3-3 family of phosphoserine/phosphothreonine-binding proteins dynamically regulates the activity of client proteins in various signaling pathways that control diverse physiological and pathological processes. In response to environmental cues, 14-3-3 proteins orchestrate the highly regulated flow of signals through complex networks of molecular interactions to achieve well-controlled physiological outputs, such as cell proliferation or differentiation. Accumulating evidence now supports the concept that either an abnormal state of 14-3-3 protein expression, or dysregulation of 14-3-3/client protein interactions, contributes to the development of a large number of human diseases. In particular, clinical investigations in the field of oncology have demonstrated a correlation between upregulated 14-3-3 levels and poor survival of cancer patients. These studies highlight the rapid emergence of 14-3-3 proteins as a novel class of molecular target for potential therapeutic intervention. The current status of 14-3-3 modulator discovery is discussed.