SOCS signaling in autoimmune diseases: Molecular mechanisms and therapeutic implications

Suppressor of cytokine signaling (SOCS) proteins are mainly induced by various cytokines and have been described as classical inhibitors of cytokine signaling. SOCS signaling is involved in the regulation of immune cells, and recent findings suggest that SOCS proteins, especially SOCS1 and SOCS3, are often dysregulated in a wide variety of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, psoriasis, and multiple sclerosis. Recent studies suggest that SOCS signaling could be therapeutically targeted in various autoimmune diseases. In this review, we discuss recent studies on the role of SOCS proteins in the development and pathogenesis of autoimmune diseases, as well as their clinical implications.     

NF-kappaB signaling pathway and its therapeutic implications in human diseases

The nuclear factor-kappaB (NF-kappaB) pathway is one of the most important cellular signal transduction pathways involved in both physiologic processes and disease conditions. It plays important roles in the control of immune function, inflammation, stress response, differentiation, apoptosis, and cell survival. Moreover, NF-kappaB is critically involved in the processes of development and progression of cancers. More importantly, recent studies have shown that NF-kappaB signaling also plays critical roles in the epithelial-mesenchymal transition (EMT) and cancer stem cells. Therefore, targeting of NF-kappaB signaling pathway could be a potent strategy for the prevention and/or treatment of human cancers and inflammatory diseases.     

Airway hyperresponsiveness: therapeutic implications

In summary, this article has reviewed the importance of airway inflammation in the pathogenesis of asthma. Inflammatory triggering factors (allergen, low molecular weight sensitizing chemicals, viral URTI) are more important in the pathogenesis of asthma than the bronchospastic triggering factors. Likewise, anti-inflammatory treatment strategies (environmental control, sodium cromoglycate, steroids) are more important in the long-term control of asthma than are the purely bronchodilator strategies.     

Neurotrophic factors in peripheral neuropathies: therapeutic implications

Neurotrophic factors are proteins which promote the survival of specific neuronal populations. Many have other physiological effects on neurons such as inducing morphological differentiation, enhancing nerve regeneration, stimulating neurotransmitter expression, and otherwise altering the physiological characteristics of neurons. These properties suggest that neurotrophic factors are highly promising as potential therapeutic agents for neurological disease. Neurotrophic factors will most likely be applied to the peripheral nervous system initially, since there are fewer problems for large proteins to gain access to peripheral neurons. Many of the most intensively studied factors are active in the peripheral nervous system. These include the neurotrophins (nerve growth factor, brain derived neurotrophic factor, neurotrophin-3, neurotrophin-4/5), the insulin like growth factors, ciliary neurotrophic factor, and glial cell derived neurotrophic factor and its related proteins. The biology of these factors and their receptors in the peripheral nervous system is reviewed here. We also review data suggesting that abnormal availability of some factors may contribute towards the pathogenesis of certain types of peripheral neuropathy. Finally, the pre-clinical data suggesting that individual factors might be effective in treating neuropathy is reviewed, along with data relating to possible side effects of neurotrophic factor therapy. Several factors have already entered clinical trials with variable success. The data from these trials is reviewed as well.     

Silk polymer-based adenosine release: therapeutic potential for epilepsy

Adenosine augmentation therapies (AAT) make rational use of the brain's own adenosine-based seizure control system and hold promise for the therapy of refractory epilepsy. In an effort to develop an AAT compatible with future clinical application, we developed a novel silk protein-based release system for adenosine. Adenosine releasing brain implants with target release doses of 0, 40, 200, and 1000ng adenosine per day were prepared by embedding adenosine containing microspheres into nanofilm-coated silk fibroin scaffolds. In vitro, the respective polymers released 0, 33.4, 170.5, and 819.0ng adenosine per day over 14 days. The therapeutic potential of the implants was validated in a dose-response study in the rat model of kindling epileptogenesis. Four days prior to the onset of kindling, adenosine releasing polymers were implanted into the infrahippocampal cleft and progressive acquisition of kindled seizures was monitored over a total of 48 stimulations. We document a dose-dependent retardation of seizure acquisition. In recipients of polymers releasing 819ng adenosine per day, kindling epileptogenesis was delayed by one week corresponding to 18 kindling stimulations. Histological analysis of brain samples confirmed the correct location of implants and electrodes. We conclude that silk-based delivery of around 1000ng adenosine per day is a safe and efficient strategy to suppress seizures.     

Bone metastasis: pathogenesis and therapeutic implications

Advanced cancers are prone to metastasize. Visceral metastases are more likely to be fatal, while patients with only metastases to bone can survive up to 10 years or more. However, effective treatments for bone metastases are not yet available and bisphosphonates improve the quality of life with no life-prolonging benefits. Bone metastases are classified as osteolytic, osteosclerotic or mixed lesions according to the bone cell types more prominently involved. Either conditions induce high morbidity and dramatically increase the risk of pathological fractures. Several molecular mechanisms bring about cancer cells to metastasize to bone, and osteotropic cancer cells are believed to acquire bone cell-like properties which improve homing, adhesion, proliferation and survival in the bone microenvironment. The acquisition of a bone cell pseudo-phenotype, denominated osteomimicry, is likely to rely on expression of osteoblastic and osteoclastic genes, thus requiring a multigenic programme. Several microenvironmental factors improve the ability of cancer cells to develop at skeletal sites, and a reciprocal deleterious stimulation generates a vicious cycle between the tumour cells and the cells residing in the bone environment. The impact of the stem cell niche in the development of bone metastases and in the phenomenon of tumour dormancy, that allows tumour cells to remain quiescent for decades before establishing overt lesions, is at present only speculative. However, the osteoblast niche, known to maintain the haematopoietic stem cell population in a quiescent status, is likely to be involved in the development of bone metastases and this promising research field is rapidly expanding.     

Androgen insufficiency in women: diagnostic and therapeutic implications

The proposed key symptoms of the female androgen insufficiency syndrome (FAIS) include reduced libido, diminished well being and lowered mood. The diagnosis of FAIS is made on the basis of these symptoms in the setting of a low serum free testosterone level. However, there is currently no readily available inexpensive assay which reliably measures free testosterone levels in the female range. The diagnosis of FAIS is further complicated by the lack of data demonstrating a minimum serum free testosterone level which, if below this, correlates with the symptoms of FAIS. Despite the complexities involved with defining FAIS, the symptoms have been reported to respond well to testosterone replacement. There is a need for formulations of testosterone therapy specifically designed for use in women, along with clear guidelines regarding optimal therapeutic doses and long-term safety data.     

Oxidative stress in schizophrenia: pathogenetic and therapeutic implications

Over a century, a wide-ranging variety of pathophysiological models and causal hypotheses have been conceptualized for schizophrenia. One among these is the role for free radical-mediated pathology in schizophrenia, indicating impaired antioxidant defense system (AODS) and presence of oxidative stress in patients with schizophrenia. For the past two decades, the whole investigative domain of AODS and oxidative stress has broadened to include the wider AODS components, direct central nervous system assays of AODS, chemical imaging studies, proteomics, genetics of AODS, and, of importance to sufferers of schizophrenia, antioxidant therapeutics. These are some of the perspectives that are reviewed by several articles in this Forum. Overall, there has been growing recognition of the importance of oxidative stress in the pathophysiology of schizophrenia and in treatment-related side effects. The totality of the evidence from biochemistry, metabolomics, proteomics, genetics, and in vivo brain imaging points to the presence of multifarious abnormalities in the AODS and redox signaling in schizophrenia.     

The VISA/GISA problem: therapeutic implications

The emergence of vancomycin intermediate resistant Staphylococcus aureus (VISA) isolates in Japan, USA, France, Hong Kong and Korea among methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates, is of great concern. Vancomycin has been the drug of choice for the treatment of multiresistant MRSA infections in the last three decades, but the management of invasive MRSA infections will become a serious problem if VISA strains become widespread. VISA isolates reported to date have a vancomycin MIC of 8 mg/L, and were isolated from patients with underlying diseases whose long-term vancomycin treatment apparently failed. Since many VISA isolates also have been resistant to teicoplanin, the term glycopeptide-intermediate S. aureus (GISA) is more appropriate. The frequency of GISA isolates appears to be extremely low; to date, only 10 GISA infections have been reported worldwide. However, heterogeneous resistance to glycopeptides (h-GISA) have been reported in Japan, Europe and Thailand. These h-GISA strains showed vancomycin MICs ranging from 1 to 4 mg/L, but had subpopulations that could grow on agar plates containing 4–8 mg/L, which may represent the first step in the development of GISA strains. Although GISA isolates have shown resistance to many antimicrobials, all GISA isolates remain susceptible to co-trimoxazole and some of them to other common antimicrobials. Currently, there are no recommended therapy guidelines for GISA infections, although in recent studies, several new drugs have shown promising activity against GISA strains. In addition, synergy between glycopeptides and β-lactams against GISA strains was observed in some in vivo and in vitro studies. Specific MRSA/GISA control programs, rational antibiotic policies, including the reduction of glycopeptide use, and rapid laboratory detection of GISA and h-GISA strains are the key measures in preventing the spread of these strains.     

Oral tolerance: therapeutic implications for autoimmune diseases

Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-beta) regulatory T cells (Tregs) plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy.     

Lysophospholipid receptors: implications for neural signaling.

Lysophospholipids (LPs) such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) represent quantitatively minor phospholipid species that nonetheless are capable of acting as extracellular signals. As an organ system dominated by lipids, the nervous system would seem a likely benefactor of this form of intercellular signaling. A major difficulty in determining the neurobiological importance of these lipids, however, has been a lack of cloned receptors. The unavailability, indeed, uncertain existence, of these receptors has been particularly problematic because of the absence of specific, competitive antagonists to block function. Further, these lipids have detergent-like chemical structures, raising the explanation that any observed effects of exogenously applied lysophospholipids could be due to nonspecific membrane perturbations. During studies of G-protein coupled receptor (GPCR) genes involved with cerebral cortical neurogenesis, the first lysophospholipid receptor gene (lpA1/vzg-1) was isolated (Hecht et al., J. Cell Biol., 135, 1071, 1996), implicating receptor-mediated lysophospholipid signaling as potentially important components of nervous system development and function. Expression studies indicated roles in neurogenesis, cortical development, and effects on glia, particularly oligodendrocyte and Schwann cell development. Reviewed here are the molecular biology of LP receptors, relevant aspects of intracellular signaling, and their possible roles in the nervous system.     

Subclinical symptoms in mood disorders: pathophysiological and therapeutic implications

BACKGROUND: The aim of this review was to survey the available literature on prodromal and residual symptoms of unipolar major depression and bipolar disorder. METHODS: Both a computerized (Medline) and a manual search of the literature were performed. RESULTS: In a substantial proportion of patients with affective disorders a prodromal phase can be identified. Most patients report residual symptoms despite successful treatment. Residual symptoms upon remission have a strong prognostic value. There appears to be a relationship between residual and prodromal symptomatology (the rollback phenomenon). CONCLUSIONS: Appraisal of subclinical symptomatology in mood disorders has important implications for pathophysiological models of disease and relapse prevention. In depression, specific treatment of residual symptoms may improve long-term outcome, by acting on those residual symptoms that progress to become prodromes of relapse. In bipolar disorder, decrease of subclinical fluctuations and improvement of level of functioning by specific therapeutic strategies may add to the benefits provided by lithium prophylaxis.