Interleukin 4 inhibition as a potential therapeutic in pemphigus

Pemphigus is an autoimmune bullous skin disease that results from desmosomal protein desmoglein 3 and 1 loss in pemphigus vulgaris and foliaceus, respectively. It can be considered as a Th2-dominant disease over-expressed by Th2 cell cytokines. Interleukin (IL)-4 is a key cytokine which can exacerbate Th2 over-expression in addition to isotype switching to immunoglobin (Ig)G1 and IgG4 that are responsible for desmoglein loss. Elevation of IL-4 level has also been reported in various studies. Considering the important role of IL-4 in severe phase of pemphigus and lack of effective and safeness therapy for this potentially fatal disease, anti-IL-4 therapy was introduced as a potential curative for pemphigus disease. This study reviewed all studies about any roles of IL-4 that can directly and indirectly be played in the development of pemphigus and IL-4 inhibition with interferons and dupilumab therapy were introduced as a novel pemphigus treatment for patients who are in relapse phase of the disease. Dupilumab was also introduced as a possible treatment for patients with severe pemphigus. It can directly inhibit IL-4 by targeting IL-4 α-chain receptor. IL-4 inhibition can lead to the creation of Th1:Th2 balance by various pathways, discussed in this study.     

Modulation of cellular membrane properties as a potential therapeutic strategy to counter lipointoxication in obstructive pulmonary diseases

Maintaining the equilibrium between saturated and unsaturated fatty acids within membrane phospholipids (PLs) is crucial to sustain the optimal membrane biophysical properties, compatible with selective organelle-based processes. Lipointoxication is a pathological condition under which saturated PLs tend to accumulate within the cell at the expense of unsaturated species, with major impacts on organelle function. Here, we show that human bronchial epithelial cells extracted from lungs of patients with Obstructive Pulmonary Diseases (OPDs), i. e. Cystic Fibrosis (CF) individuals and Smokers, display a characteristic lipointoxication signature, with excessive amounts of saturated PLs. Reconstitution of this signature in cellulo and in silico revealed that such an imbalance results in altered membrane properties and in a dramatic disorganization of the intracellular network of bronchial epithelial cells, in a process which can account for several OPD traits. Such features include Endoplasmic Reticulum-stress, constitutive IL8 secretion, bronchoconstriction and, ultimately, epithelial cell death by apoptosis. We also demonstrate that a recently-identified lipid-like molecule, which has been shown to behave as a “membrane-reshaper”, counters all the lipointoxication hallmarks tested. Altogether, these insights highlight the modulation of membrane properties as a potential new strategy to heal and prevent highly detrimental symptoms associated with OPDs.     

Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection

The oxidative pathway for the metabolism of tryptophan along the kynurenine pathway generates quinolinic acid, an agonist at N-methyl-D-aspartate receptors, as well as kynurenic acid which is an antagonist at glutamate and nicotinic receptors. The pathway has become recognized as a key player in the mechanisms of neuronal damage and neurodegenerative disorders. As a result, manipulation of the pathway, so that the balance between the levels of components of the pathway can be modified, has become an attractive target for the development of pharmacological agents with the potential to treat those disorders. This review summarizes some of the relevant background information on the pathway itself before identifying some of the chemical strategies for its modification, with examples of their successful application in animal models of infection, stroke, traumatic brain damage, cerebral malaria and cerebral trypanosomiasis.     

Caspase dependent programmed cell death in developing embryos: a potential target for therapeutic intervention against pathogenic nematodes

Background

Successful embryogenesis is a critical rate limiting step for the survival and transmission of parasitic worms as well as pathology mediated by them. Hence, blockage of this important process through therapeutic induction of apoptosis in their embryonic stages offers promise for developing effective anti-parasitic measures against these extra cellular parasites. However, unlike in the case of protozoan parasites, induction of apoptosis as a therapeutic approach is yet to be explored against metazoan helminth parasites.

Methodology/Principal Findings

For the first time, here we developed and evaluated flow cytometry based assays to assess several conserved features of apoptosis in developing embryos of a pathogenic filarial nematode Setaria digitata, in-vitro as well as ex-vivo. We validated programmed cell death in developing embryos by using immuno-fluorescence microscopy and scoring expression profile of nematode specific proteins related to apoptosis [e.g. CED-3, CED-4 and CED-9]. Mechanistically, apoptotic death of embryonic stages was found to be a caspase dependent phenomenon mediated primarily through induction of intracellular ROS. The apoptogenicity of some pharmacological compounds viz. DEC, Chloroquine, Primaquine and Curcumin were also evaluated. Curcumin was found to be the most effective pharmacological agent followed by Primaquine while Chloroquine displayed minimal effect and DEC had no demonstrable effect. Further, demonstration of induction of apoptosis in embryonic stages by lipid peroxidation products [molecules commonly associated with inflammatory responses in filarial disease] and demonstration of in-situ apoptosis of developing embryos in adult parasites in a natural bovine model of filariasis have offered a framework to understand anti-fecundity host immunity operational against parasitic helminths.

Conclusions/Significance

Our observations have revealed for the first time, that induction of apoptosis in developing embryos can be a potential approach for therapeutic intervention against pathogenic nematodes and flow cytometry can be used to address different issues of biological importance during embryogenesis of parasitic worms.     

Blocking endothelial adhesion molecules: a potential therapeutic strategy to combat atherogenesis

PURPOSE OF REVIEW: This review provides a concise update of the involvement of endothelial adhesion molecules in atherogenesis, an overview of current advances in the development of adhesion molecule blocking agents, as well as an insight into the potential of these molecules in cardiovascular therapy. RECENT FINDINGS: As endothelial adhesion molecules are deemed to play an important role in the development and progression of atherosclerotic lesions, they are interesting targets for therapeutic intervention in this process. In particular, P-selectin and vascular cell adhesion molecule 1 are widely considered to hold promise in this regard. Current research efforts centre on the design of agents that directly block the interaction of the receptor with its ligand (e.g. soluble P-selectin glycoprotein ligand 1, blocking antibodies, EWVD-based peptides) or that interfere with their synthesis (e.g. antisense oligonucleotides) or their regulatory control by nuclear factor kappa B or peroxisome proliferator-activated receptor gamma. Furthermore, adhesion molecules have been exploited as a target for the specific delivery of drug carriers (e.g. biodegradable particles with entrapped dexamethasone) or therapeutic compounds (e.g. dexamethasone) to the plaque. All approaches have been shown to be effective in blocking adhesion molecule function in in-vitro studies and in-vivo models for inflammation or atherosclerosis. SUMMARY: Although the field has achieved considerable progress in recent years, leading to the development of a number of interesting leads, final proof of their efficacy in cardiovascular therapy is eagerly awaited.     

Correction of lysosomal dysfunction as a therapeutic strategy for neurodegenerative diseases

Mutations in the gene that encodes the lysosomal enzyme acid β-glucosidase lead to reduced cellular activity and accumulation of glycosphingolipid substrates, biochemical hallmarks of the lysosomal storage disorder Gaucher disease (GD). Recently such mutations have been identified as risk factors for Parkinson’s disease (PD) and related disorders. Both gain-of-function (due to toxic cellular accumulation of mutant enzyme) and loss-of-function (due to accumulation of lipid substrates) hypotheses have been put forth to address the biochemical link between GD and PD. Similarly, links between Alzheimer’s disease and other lysosomal enzyme deficiencies have begun to emerge. The use of pharmacological chaperones to restore the cellular trafficking and activity of mutant lysosomal enzymes may offer a novel approach to treat these debilitating neurodegenerative diseases.     

Caspase activation, inhibition, and reactivation: a mechanistic view

Caspases, a unique family of cysteine proteases, execute programmed cell death (apoptosis). Caspases exist as inactive zymogens in cells and undergo a cascade of catalytic activation at the onset of apoptosis. The activated caspases are subject to inhibition by the inhibitor-of-apoptosis (IAP) family of proteins. This inhibition can be effectively removed by diverse proteins that share an IAP-binding tetrapeptide motif. Recent structural and biochemical studies have revealed the underlying molecular mechanisms for these processes in mammals and in Drosophila. This paper reviews these latest advances.     

Eukaryotic ribosome quality control system: a potential therapeutic target for human diseases

Protein homeostasis is well accepted as the prerequisite for proper operation of various life activities. As the main apparatus of protein translation, ribosomes play an indispensable role in the maintenance of protein homeostasis. Nevertheless, upon stimulation of various internal and external factors, malfunction of ribosomes may be evident with the excessive production of aberrant proteins, accumulation of which can result in deleterious effects on cellular fate and even cell death. Ribosomopathies are characterized as a series of diseases caused by abnormalities of ribosomal compositions and functions. Correspondingly, cell evolves several ribosome quality control mechanisms in maintaining the quantity and quality of intracellular ribosomes, namely ribosome quality control system (RQCS). Of note, RQCS can tightly monitor the entire process from ribosome biogenesis to its degradation, with the capacity of coping with ribosomal dysfunction, including misassembled ribosomes and incorrectly synthesized ribosomal proteins. In the current literature review, we mainly introduce the RQCS and elaborate on the underlying pathogenesis of several ribosomopathies. With the in-depth understanding of ribosomal dysfunction and molecular basis of RQCS, therapeutic strategy by specifically targeting RQCS remains a promising option in treating patients with ribosomopathies and other ribosome-associated human diseases.     

Platelet-activating factor and cardiac diseases: therapeutic potential for PAF inhibitors

Platelet-activating factor (PAF) is a potent phospholipid mediator released from inflammatory cells in response to diverse immunologic and non-immunologic stimuli. Animal studies have implicated PAF as a major mediator involved in coronary artery constriction, modulation of myocardial contractility and the generation of arrhythmias which may bear on cardiac disorders such as ischemia, infarction and sudden cardiac death. PAF effects are induced by direct actions of PAF on cardiac tissue to modify chronotropic and inotropic activity, or indirectly via the release of eicosanoids such as thromboxane A₂ (TXA,), leukotrienes (LT) or cytokines (TNFx). The development of selective, high affinity PAF receptor antagonists has permitted investigations on the role of PAF in experimental animal models of cardiac injury. In vivo and in vitro studies strongly suggest that PAF receptor antagonists might convey therapeutic benefits in ischemic conditions and certain arrhythmias. In addition, PAF antagonists might have a cardiac allograft-preservation effect. Although clinical studies with PAF receptor antagonists in patients with cardiac diseases have not yet been reported, the experimental results to date suggest that PAF receptor antagonist might be useful in some specific cardiac disorders in humans.     

RAGE and soluble RAGE: potential therapeutic targets for cardiovascular diseases

Receptor for advanced glycation end-products (RAGE) is known to be involved in microvascular complications in diabetes. RAGE is also profoundly associated with macrovascular complications in diabetes through regulation of atherogenesis, angiogenic response, vascular injury, and inflammatory response. The potential significance of RAGE in the pathogenesis of cardiovascular disease appears not to be confined solely to nondiabetic rather than diabetic conditions. Numerous truncated forms of RAGE have recently been described, and the C-terminally truncated soluble form of RAGE has received much attention. Soluble RAGE consists of several forms, including endogenous secretory RAGE (esRAGE), which is a spliced variant of RAGE, and a shedded form derived from cell-surface RAGE. These heterogeneous forms of soluble RAGE, which carry all of the extracellular domains but are devoid of the transmembrane and intracytoplasmic domains, bind ligands including AGEs and can antagonize RAGE signaling in vitro and in vivo. ELISA systems have been developed to measure plasma esRAGE and total soluble RAGE, and the pathophysiological roles of soluble RAGE have begun to be unveiled clinically. In this review, we summarize recent findings regarding pathophysiological roles in cardiovascular disease of RAGE and soluble RAGE and discuss their potential usefulness as therapeutic targets and biomarkers for the disease.     

Antisense-mediated inhibition of ICAM-1 expression: a therapeutic strategy against inflammation of human periodontal tissue

Periodontal diseases, such as gingivitis and periodontitis, are caused by a mixed infection by several types of bacteria in the dental plaque, causing a chronic inflammation of the gingival mucosa. Inflammatory processes in conjunction with immune responses to bacterial attacks are generally protective. In profound periodontitis, however, hyperresponsiveness and hypersensitivity of the immune system are counterproductive because of the destruction of the affected periodontal connective tissues. The intercellular adhesion molecule type 1 (ICAM-1) plays a key role in the onset and manifestation of inflammatory responses. Thus, inhibition of ICAM-1 expression could be of therapeutic relevance for the treatment of destructive periodontitis. Here, antisense oligonucleotides (AS-ON) directed against ICAM-1 suppress protein expression and mRNA levels specifically and effectively in primary human endothelial cells of different tissue origin. Moreover, downregulation of ICAM-1 expression is also observed in AS-ON-transfected inflamed gingival mucosal tissue of patients with periodontal diseases. This work strongly suggests exploiting the local topical application of ICAM-1-directed AS-ON as a therapeutic tool against inflammatory processes of the human gingiva.     

Demethylation of E-cadherin gene in nasopharyngeal carcinoma could serve as a potential therapeutic strategy

E-cadherin has been proven to be widely down-regulated and tightly associated with tumour invasion and metastasis in multiple human cancer types. Recent research demonstrated that aberrant methylation around gene promoter region attributes to E-cadherin silencing. However, the detailed information about this epigenetic inactivation in nasopharyngeal carcinoma (NPC) is rare. The aim of this study was to probe more into the basic mechanism of E-cadherin methylation in NPC and elucidate the application of demethylating agents to restore E-cadherin expression. To address this question, we initially studied E-cadherin methylation status in NPC primary tumours and cell lines by methylation-specific PCR, and compared it with E-cadherin expression. Methylated E-cadherin was detected in 13 of 20 (65%) NPC clinical specimens and 2 of 2 (100%) NPC cell lines (HNE-1 and CNE-2), which was inversely correlated with E-cadherin expression. The detailed methylation profile at individual CpGs within CpG island of E-cadherin promoter region was confirmed by bisulphite sequencing. E-cadherin gene could be demethylated and reactivated in HNE-1 and CNE-2 cells upon treatment with 5-aza-dC, a DNA demethylating agent. Our findings indicate that frequent aberrant methylation of E-cadherin may play an important role in downregulation of E-cadherin, and demethylation therapy could serve as a promising strategy for NPC patients. Furthermore, a high frequency of E-cadherin methylation (9/20, 45%) in peripheral blood of NPC patients suggests its potential clinical application as an early diagnostic or predictive marker.     

Acid-sensing ion channels (ASICs): therapeutic targets for neurological diseases and their regulation

Extracellular acidification occurs not only in pathological conditions such as inflammation and brain ischemia, but also in normal physiological conditions such as synaptic transmission. Acid-sensing ion channels (ASICs) can detect a broad range of physiological pH changes during pathological and synaptic cellular activities. ASICs are voltage-independent, proton-gated cation channels widely expressed throughout the central and peripheral nervous system. Activation of ASICs is involved in pain perception, synaptic plasticity, learning and memory, fear, ischemic neuronal injury, seizure termination, neuronal degeneration, and mechanosensation. Therefore, ASICs emerge as potential therapeutic targets for manipulating pain and neurological diseases. The activity of these channels can be regulated by many factors such as lactate, Zn²⁺, and Phe-Met-Arg-Phe amide (FMRFamide)-like neuropeptides by interacting with the channel’s large extracellular loop. ASICs are also modulated by G protein-coupled receptors such as CB₁ cannabinoid receptors and 5-HT₂. This review focuses on the physiological roles of ASICs and the molecular mechanisms by which these channels are regulated. [BMB Reports 2013; 46(6): 295-304]     

Mesenchymal stem cell-derived extracellular vesicles as a new therapeutic strategy for ocular diseases

Mesenchymal stem cells (MSCs) have attracted considerable attention for their activity in the treatment of refractory visual disorders. Since MSCs were found to possess the beneficial effects by secreting paracrine factors rather than direct differentiation, MSC-derived extracellular vesicles (EVs) were widely studied in various disease models. MSCs generate abundant EVs, which act as important mediators by exchanging protein and genetic information between MSCs and target cells. It has been confirmed that MSC-derived EVs possess unique anti-inflammatory, anti-apoptotic, tissue repairing, neuroprotective, and immunomodulatory properties, similar to their parent cells. Upon intravitreal injection, MSC-derived EVs rapidly diffuse through the retina to alleviate retinal injury or inflammation. Due to possible risks associated with MSC transplantation, such as vitreous opacity and pathological proliferation, EVs appear to be a better choice for intravitreal injection. Small size EVs can pass through biological barriers easily and their contents can be modified genetically for optimal therapeutic effect. Hence, currently, they are also explored for the possibility of serving as drug delivery vehicles. In the current review, we describe the characteristics of MSC-derived EVs briefly, comprehensively summarize their biological functions in ocular diseases, and discuss their potential applications in clinical settings.