The importance of a multi-disciplinary perspective and patient activation programmes in MS management.

BACKGROUND: Multiple sclerosis (MS) is a progressive disease associated with a large variety of symptoms and changing patients' needs during the disease course. In order to provide appropriate care in every disease stage and let patients live their lives to the full, a multi-disciplinary approach and patient activation is needed. OBJECTIVE: To summarise the multi-disciplinary perspective of MS, with focus on the organisation of a multi-disciplinary care team and possibilities to support patient activation. METHODS: This review reflects the content of the presentations, audience polling results and discussions on the multi-disciplinary perspective of MS during the second Pan-European MS Multi-stakeholder Colloquium. RESULTS: In many countries, the neurologist with or without the support of an MS nurse is responsible for the long-term care of MS patients. When needed, they should refer to other (non-)medical specialists. However, the patient should be empowered as well to manage his/her disease and to implement a physically active lifestyle in order to improve treatment outcomes and quality of life. CONCLUSION: To create equal access to care for MS patients across Europe, evidence-based standards of care, symptom self-monitoring tools and educational programmes for patients and healthcare professionals including non-medical treatment strategies should be developed at the European level.

Attenuation of ERK/RSK2-driven NFκB gene expression and cancer cell proliferation by kurarinone, a lavandulyl flavanone isolated from Sophora flavescens ait. roots.

We have analyzed in molecular detail how kurarinone, a lavandulyl flavanone isolated from Sophora flavescens, suppresses nuclear factor-κB (NFκB)-driven interleukin-6 (IL6) expression and cancer cell growth. Interleukin-6 (IL6), involved in cancer-related inflammation, acts as an autocrine and paracrine growth factor, which promotes angiogenesis, metastasis, and subversion of immunity, and changes responsivity to hormones and to chemotherapeutics. Our results in estrogen-unresponsive fibroblasts, ribosomal S6 kinase 2 kinase (RSK2) knockout cells, and estrogen receptor (ER)-deficient breast tumor cells show that kurarinone can inhibit tumor cell proliferation and selectively block nuclear NFκB transactivation of specific target genes such as IL6, cyclin D1, SOD2 but not TNFAIP2. This occurs via attenuation of extracellular signal-regulated protein (ERK) and RSK2 kinase pathways and inhibition of S6 kinase ribosomal protein (S6RP) and histone H3 S10 phosphorylation. As constitutive NFκB and RSK2 activity are important hallmarks of human cancers, including hematopoietic malignancies and solid tumors, prenylated flavanones represent an attractive class of natural inhibitors of the ERK/RSK2 signaling pathway for cancer therapy.

A critical role for p53 in the control of NF-kappaB-dependent gene expression in TLR4-stimulated dendritic cells exposed to Genistein.

Considerable research has focused on the anti-inflammatory and antiproliferative activities exhibited by the soy isoflavone genistein. We previously demonstrated that genistein suppresses TNF-alpha-induced NF-kappaB-dependent IL-6 gene expression in cancer cells by interfering with the mitogen- and stress-activated protein kinase 1 activation pathway. However, effects of isoflavones on immune cells, such as dendritic cells, remain largely unknown. Here we show that genistein markedly reduces IL-6 cytokine production and transcription in LPS-stimulated human monocyte-derived dendritic cells. More particularly, we observe that genistein inhibits IL-6 gene expression by modulating the transcription factor NF-kappaB. Examination of NF-kappaB-related events downstream of TLR4 demonstrates that genistein affects NF-kappaB subcellular localization and DNA binding, although we observe only a minor inhibitory impact of genistein on the classical LPS-induced signaling steps. Interestingly, we find that genistein significantly increases p53 protein levels. We also show that overexpression of p53 in TLR4/MD2 HEK293T cells blocks LPS-induced NF-kappaB-dependent gene transcription, indicating the occurrence of functional cross-talk between p53 and NF-kappaB. Moreover, analysis of IL-6 mRNA levels in bone marrow-derived p53 null vs wild-type dendritic cells confirms a role for p53 in the reduction of NF-kappaB-dependent gene expression, mediated by genistein.

Keeping up NF-kappaB appearances: epigenetic control of immunity or inflammation-triggered epigenetics.

Controlled expression of cytokine genes is an essential component of an immune response and is crucial for homeostasis. In order to generate an appropriate response to an infectious condition, the type of cytokine, as well as the cell type, dose range and the kinetics of its expression are of critical importance. The nuclear factor-kappaB (NF-kappaB) family of transcription factors has a crucial role in rapid responses to stress and pathogens (innate immunity), as well as in development and differentiation of immune cells (acquired immunity). Although quite a number of genes contain NF-kappaB-responsive elements in their regulatory regions, their expression pattern can significantly vary from both a kinetic and quantitative point of view, reflecting the impact of environmental and differentiative cues. At the transcription level, selectivity is conferred by the expression of specific NF-kappaB subunits and their respective posttranslational modifications, and by combinatorial interactions between NF-kappaB and other transcription factors and coactivators, that form specific enhanceosome complexes in association with particular promoters. These enhanceosome complexes represent another level of signaling integration, whereby the activities of multiple upstream pathways converge to impress a distinct pattern of gene expression upon the NF-kappaB-dependent transcriptional network. Today, several pieces of evidence suggest that the chromatin structure and epigenetic settings are the ultimate integration sites of both environmental and differentiative inputs, determining proper expression of each NF-kappaB-dependent gene. We will therefore discuss in this review the multilayered interplay of NF-kappaB signaling and epigenome dynamics, in achieving appropriate gene expression responses and transcriptional activity.

Attenuation of mitogen- and stress-activated protein kinase-1-driven nuclear factor-kappaB gene expression by soy isoflavones does not require estrogenic activity.

We have analyzed in molecular detail how soy isoflavones (genistein, daidzein, and biochanin A) suppress nuclear factor-kappaB (NF-kappaB)-driven interleukin-6 (IL6) expression. In addition to its physiologic immune function as an acute stress cytokine, sustained elevated expression levels of IL6 promote chronic inflammatory disorders, aging frailty, and tumorigenesis. Our results in estrogen-unresponsive fibroblasts, mitogen- and stress-activated protein kinase (MSK) knockout cells, and estrogen receptor (ER)-deficient breast tumor cells show that phytoestrogenic isoflavones can selectively block nuclear NF-kappaB transactivation of specific target genes (in particular IL6), independently of their estrogenic activity. This occurs via attenuation of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK activity, which further down-regulates MSK-dependent NF-kappaB p65 and histone H3 phosphorylation. As constitutive NF-kappaB and MSK activity are hallmarks of aggressive metastatic ER-deficient breast cancer, the MSK signaling pathway may become an attractive target for chemotherapy.

Soy isoflavone phyto-pharmaceuticals in interleukin-6 affections. Multi-purpose nutraceuticals at the crossroad of hormone replacement, anti-cancer and anti-inflammatory therapy.

Interleukin-6 is a pleiotropic cytokine which plays a crucial role in immune physiology and is tightly controlled by hormonal feedback mechanisms. After menopause or andropause, loss of the normally inhibiting sex steroids (estrogen, testosterone) results in elevated IL6 levels that are further progressively increasing with age. Interestingly, excessive IL6 production promotes tumorigenesis (breast, prostate, lung, colon, ovarian), and accounts for several disease-associated pathologies and phenotypical changes of advanced age, such as osteoporosis, rheumatoid arthritis, multiple myeloma, neurodegenerative diseases and frailty. In this respect, pharmacological modulation of IL6 gene expression levels may have therapeutical benefit in preventing cancer progression, ageing discomforts and restoring immune homeostasis. Although "plant extracts" are used in folk medicine within living memory, it is only since the 20th century that numerous scientific investigations have been performed to discover potential health-protective food compounds or "nutraceuticals" which might prevent cancer and ageing diseases. About 2000 years ago, Hippocrates already highlighted "Let food be your medicine and medicine be your food". Various nutrients in the diet play a crucial role in maintaining an "optimal" immune response, such that deficient or excessive intakes can have negative consequences on the organism's immune status and susceptibility to a variety of pathologies. Over the last few decades, various immune-modulating nutrients have been identified, which interfere with IL6 gene expression. Currently, a broad range of phyto-pharmaceuticals with a claimed hormonal activity, called "phyto-estrogens", is recommended for prevention of various diseases related to a disturbed hormonal balance (i.e. menopausal ailments and/or prostate/breast cancer). In this respect, there is a renewed interest in soy isoflavones (genistein, daidzein, biochanin) as potential superior alternatives to the synthetic selective estrogen receptor modulators (SERMs), which are currently applied in hormone replacement therapy (HRT). As phyto-chemicals integrate hormonal ligand activities and interference with signaling cascades, therapeutic use may not be restricted to hormonal ailments only, but may have applications in cancer chemoprevention and/or NF-kappaB-related inflammatory disorders as well.