Identification of the Synthetic Cannabinoid R()WIN55,212-2 as a Novel Regulator of IFN Regulatory Factor 3 Activation and IFN- Expression

Beta Interferons (IFN-βs) represent one of the first line treatments for relapsing remitting multiple sclerosis (RRMS), slowing disease progression whilst reducing the frequency of relapses. Despite this, more effective, well tolerated therapeutic strategies are needed. Cannabinoids palliate experimental autoimmune encephalomyelitis (EAE) symptoms and have therapeutic potential in MS patients although the precise molecular mechanism for these effects is not understood. Toll-like receptor (TLR) signaling controls innate immune responses and TLRs are implicated in MS. Here we demonstrate that the synthetic cannabinoid R(+)WIN55,212-2 is a novel regulator of TLR3 and TLR4 signaling by inhibiting the pro-inflammatory signaling axis triggered by TLR3 and TLR4 whilst selectively augmenting TLR3-induced activation of IFN regulatory factor 3 (IRF3) and expression of IFN-β. We present evidence that R(+)WIN55,212-2 strongly promotes the nuclear localization of IRF3. The potentiation of IFN-β expression by R(+)WIN55,212-2 is critical for manifesting its protective effects in the murine MS model EAE as evidenced by its reduced therapeutic efficacy in the presence of an anti-IFN-β antibody. R(+)WIN55,212-2 also induces IFN-β expression in MS patient peripheral blood mononuclear cells (PBMCs), whilst downregulating inflammatory signaling in these cells. These findings identify R(+)WIN55,212-2 as a novel regulator of TLR3 signaling to IRF3 activation and IFN-β expression and highlights a new mechanism that may be open to exploitation in the development of new therapeutics for the treatment of MS

Identification of the Synthetic Cannabinoid R()WIN55,212-2 as a Novel Regulator of IFN Regulatory Factor 3 Activation and IFN- Expression

Beta Interferons (IFN-βs) represent one of the first line treatments for relapsing remitting multiple sclerosis (RRMS), slowing disease progression whilst reducing the frequency of relapses. Despite this, more effective, well tolerated therapeutic strategies are needed. Cannabinoids palliate experimental autoimmune encephalomyelitis (EAE) symptoms and have therapeutic potential in MS patients although the precise molecular mechanism for these effects is not understood. Toll-like receptor (TLR) signaling controls innate immune responses and TLRs are implicated in MS. Here we demonstrate that the synthetic cannabinoid R(+)WIN55,212-2 is a novel regulator of TLR3 and TLR4 signaling by inhibiting the pro-inflammatory signaling axis triggered by TLR3 and TLR4 whilst selectively augmenting TLR3-induced activation of IFN regulatory factor 3 (IRF3) and expression of IFN-β. We present evidence that R(+)WIN55,212-2 strongly promotes the nuclear localization of IRF3. The potentiation of IFN-β expression by R(+)WIN55,212-2 is critical for manifesting its protective effects in the murine MS model EAE as evidenced by its reduced therapeutic efficacy in the presence of an anti-IFN-β antibody. R(+)WIN55,212-2 also induces IFN-β expression in MS patient peripheral blood mononuclear cells (PBMCs), whilst downregulating inflammatory signaling in these cells. These findings identify R(+)WIN55,212-2 as a novel regulator of TLR3 signaling to IRF3 activation and IFN-β expression and highlights a new mechanism that may be open to exploitation in the development of new therapeutics for the treatment of MS

Analysis of the Impact of CD200 on Neurodegenerative Diseases

Neuroinflammation, accompanied by neuronal loss and dysfunction, is a characteristic of neurodegenerative disorders like Alzheimer’s disease (AD) and Parkinson’s disease (PD). It is well documented that inappropriate activation of glia is the primary cause of neuroinflammation (Masocha, 2009), but their role in the pathogenesis of neurodegenerative diseases is not known. However it is certainly the case that dying neurons act to stimulate glia since they release alarmins which activate pathogen recognition receptors (PRR) and therefore the possibility exists that activation of glia especially microglia, may be a consequence, rather than a cause, of neurodegenerative processes which characterize diseases like AD and PD. Understanding microglial function remains a major goal since it is widely believed that modulating glial function will provide a possible strategy for limiting the progression of neurodegenerative diseases. Consequently it is imperative to increase our understanding of the factors which control microglial function and the mechanisms by which expression of these factors are controlled

The Synthetic Cannabinoid R(+)WIN55,212-2 Augments Interferon-β Expression via Peroxisome Proliferator-activated Receptor-α

We have demonstrated that R()WIN55,212-2, a synthetic cannabinoid that possesses cannabimimetic properties, acts as a novel regulator of Toll-like receptor 3 (TLR3) signaling to interferon (IFN) regulatory factor 3 (IRF3) activation and IFN- expression, and this is critical for manifesting its protective effects in a murine multiple sclerosis model. Here we investigated the role of peroxisome proliferator-activated receptor- (PPAR) in mediating the effects of R()WIN55,212-2 on this pathway. Data herein demonstrate that the TLR3 agonist poly(I:C) promotes IFN- expression and R()WIN55,212-2 enhances TLR3-induced IFN- expression in a stereoselective manner via PPAR. R()WIN55,212-2 promotes increased transactivation and expression of PPAR. Using the PPAR antagonist GW6471, we demonstrate that R()WIN55,212-2 acts via PPAR to activate JNK, activator protein-1, and positive regulatory domain IV to transcriptionally regulate the IFN- promoter. Furthermore, GW6471 ameliorated the protective effects of R()WIN55,212-2 during the initial phase of experimental autoimmune encephalomyelitis. Overall, these findings define PPAR as an important mediator in manifesting the effects of R()WIN55,212-2 on the signaling cascade regulating IFN- expression. The study adds to our molecular appreciation of potential therapeutic effects of R()WIN55,212-2 in multiple sclerosis

Impact of exercise on innate immunity in multiple sclerosis progression and symptomatology

Multiple Sclerosis (MS), an idiopathic progressive immune-mediated neurological disorder of the central nervous system (CNS), is characterized by recurrent episodes of inflammatory demyelination and consequent axonal deterioration. It accounts for functional deterioration and lasting disability among young adults. A body of literature demonstrates that physical activity counteracts fatigue and depression and may improve overall quality of life in MS patients. Furthermore, much data indicates that exercise ameliorates chronic neuroinflammation and its related pathologies by tipping cytokine profiles toward an anti-inflammatory signature. Recent data has focused on the direct impact of exercise training on the innate immune system by targeting toll-like receptors (TLRs), signaling pattern recognition receptors that govern the innate immune response, shedding light on the physiological role of TLRs in health and disease. Indeed, TLRs continue to emerge as players in the neuroinflammatory processes underpinning MS. This review will highlight evidence that physical activity and exercise are potential immunomodulatory therapies, targeting innate signaling mechanism(s) to modulate MS symptom development and progression

Change in alcohol intake in relation to weight change in a cohort of United States men with 24 years of follow-up

Objective: We sought to prospectively investigate potential effects of alcohol by subtype on reported long-term weight change. Methods: We examined change in alcohol intake (total, wine, light beer, regular beer, liquor) and simultaneous change in reported body weight within four-year periods from 1986 to 2010 from U.S. men in the Health Professionals Follow-Up Study. We adjusted for age, change in lifestyle and dietary covariates and cardiovascular risk factors. Results: We observed 44,603 four-year periods from 14,971 men. Total alcohol, total beer, regular beer, and liquor, modeled as the increase in weight per increase in drink/day, were each directly associated with moderate weight gain over four-year periods, in pounds: total alcohol: 0.23 (0.10–0.35); total beer: 0.29 (0.08–0.51); regular beer: 0.61 (0.22–1.00); liquor: 0.28 (0.09–0.48). Results for wine and light beer were wine: 0.16 (−0.04–0.36); light beer: −0.38 (−1.07–0.08). Results were strongest for men <55 years old. Conclusions: Increased alcohol consumption was associated with minor reported weight gain at levels unlikely to be clinically meaningful. Beverage specific differences are not substantial enough to make dietary recommendations for weight loss or maintenance by beverage type. The greatest risk of weight gain was among men that increased consumption to levels well above moderation

Cycle ergometer training enhances plasma interleukin-10 in multiple sclerosis

The objective was to determine plasma levels of pro- (IL-12p70/IL-6) and anti-inflammatory (IL-10) cytokines before and after cycle ergometer training in healthy control (HC) and people with multiple sclerosis (pwMS), and to correlate plasma cytokines with physical/mental health. Study participants cycled for 30 min at 65–75% age-predicted maximal heart rate, twice a week for 8 weeks during supervised sessions. We determined that plasma IL-10 expression was lower in pwMS, compared to HCs, and that exercise augmented IL-10 in pwMS to baseline levels in HCs. Furthermore, plasma isolated from pwMS displayed enhanced expression of the pro-inflammatory cytokines IL-12p70/IL-6. Plasma cytokine signatures correlated with physical/mental health. Overall, this study highlights the potential of a short-term exercise programme to regulate circulating cytokine profiles with relevance to pwMS

Development and assessment of a 3D tooth morphology quiz for dental students

Tooth morphology has a pivotal role in the dental curriculum and provides one of the important foundations of clinical practice. To supplement tooth morphology teaching a three‐dimensional (3D) quiz application (app) was developed. The 3D resource enables students to study tooth morphology actively by selecting teeth from an interactive quiz, modify their viewpoint and level of zoom. Additionally, students are able to rotate the tooth to obtain a 3D spatial understanding of the different surfaces of the tooth. A cross‐over study was designed to allow comparison of students’ results after studying with the new application or traditionally with extracted/model teeth. Data show that the app provides an efficient learning tool and that students’ scores improve with usage (18% increase over three weeks, P < 0.001). Data also show that student assessment scores were correlated with scores obtained while using the app but were not influenced by the teaching modality initially accessed (r2 = 0.175, P < 0.01). Comparison of the 2016 and 2017 class performance shows that the class that had access to the app performed significantly better on their final tooth morphology assessment (68.0% ±15.0 vs. 75.3% ±13.4, P < 0.01). Furthermore, students reported that the 3D application was intuitive, provided useful feedback, presented the key features of the teeth, and assisted in learning tooth morphology. The 3D tooth morphology app thus provides students with a useful adjunct teaching tool for learning dental anatomy