- Glutaminase 1 Inhibition Reduces Glycolysis and Ameliorates Lupus-like Disease in MRL/lpr Mice and Experimental Autoimmune Encephalomyelitis. [Journal Article]
- ARArthritis Rheumatol 2019 Jun 24
- CONCLUSIONS: We have demonstrated that inhibition of glutaminolysis represents a potential new treatment strategy for patients with SLE and Th17-related autoimmune diseases. Mechanistically we have shown that inhibition of glutaminolysis affects the glycolysis pathway by reducing Hif1α protein in Th17 cells. This article is protected by copyright. All rights reserved.
- Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and the Emerging Osteopathic Approach: A Narrative Review. [Journal Article]
- JAJ Am Osteopath Assoc 2019 Jul 01; 119(7):446-455
- Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating syndrome of unknown origin, characterized by profound postexertional malaise and fatigue, unrefreshing sleep, cognitive i…
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating syndrome of unknown origin, characterized by profound postexertional malaise and fatigue, unrefreshing sleep, cognitive impairments, immune dysfunction, pain, autonomic dysfunction, and neuroendocrine symptoms. Although ME/CFS is well documented within the medical literature, it remains difficult to diagnosis and manage. Some of the current challenges include an absence of diagnostic markers, differing diagnostic criteria, and an overall lack of awareness within the medical community. As a result, patients are often frustrated by the difficulties in acquiring a diagnosis and from the overall lack of available treatments. In an effort to increase awareness, this review discusses disease pathophysiology, clinical presentation, and treatment options, while also highlighting the benefits of an osteopathic approach.
- Experimental autoimmune encephalomyelitis accelerates remyelination after lysophosphatidylcholine-induced demyelination in the corpus callosum. [Journal Article]
- JNJ Neuroimmunol 2019 Jun 15; 334:576995
- Experimental autoimmune encephalomyelitis (EAE) and lysophosphatidylcholine (LPC)-induced demyelination were combined to study remyelination in a pro-inflammatory context. Two groups of female C57BL/…
Experimental autoimmune encephalomyelitis (EAE) and lysophosphatidylcholine (LPC)-induced demyelination were combined to study remyelination in a pro-inflammatory context. Two groups of female C57BL/6 mice were subjected either to EAE (EAE mice) or injected with just complete Freund's adjuvant (CFA) and pertussis toxin (PTX) followed by bilateral LPC and phosphate buffered saline injections in the corpus callosum on day 7 (CFA controls). Relative to CFA controls, EAE accelerated remyelination and increased innate immune cell activation, lymphocyte infiltration and cytokine gene expression in the LPC lesions. However, compared to CFA mice, remyelination was reduced (day 14) suggesting this aggressive immune response also compromised myelin repair in EAE mice.
- The adenosine A2A receptor antagonist SCH58261 reduces macrophage/microglia activation and protects against experimental autoimmune encephalomyelitis in mice. [Journal Article]
- NINeurochem Int 2019 Jun 18; :104490
- Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) affecting more than 2.5 million individuals worldwide. In the present study, myelin oligodendr…
Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) affecting more than 2.5 million individuals worldwide. In the present study, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) mice were treated with adenosine receptor A2A antagonist SCH58261 at different periods of EAE development. The administration of SCH58261 at 11-28 days post-immunization (d.p.i.) with MOG improved the neurological deficits. This time window corresponds to the therapeutic time window for MS treatment. SCH58261 significantly reduced the CNS neuroinflammation including reduced local infiltration of inflammatory cells, demyelination, and the numbers of macrophage/microglia in the spinal cord. Importantly, SCH58261 ameliorated the EAE-induced neurobehavioral deficits. By contrast, the SCH58261 treatment was ineffective when administered at the beginning of the onset of EAE (i.e., 1-10 d.p.i). The identification of the effective therapeutic window of A2A receptor antagonist provide insight into the role of A2A receptor signaling in EAE, and support SCH58261 as a candidate for the treatment of MS in human.
- Mechanism of gut microbiota and Axl/SOCS3 in experimental autoimmune encephalomyelitis. [Journal Article]
- BRBiosci Rep 2019 Jun 20
- Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS). The present study explored the role of intestinal microbiota in the initiation and propagation of mice induc…
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS). The present study explored the role of intestinal microbiota in the initiation and propagation of mice induced by experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. 48 C57BL/6 were randomly divided into control group and EAE group. The changes of body weight and the scores of neurological function were recorded. The mRNA expression of the receptor tyrosine kinase subfamily (AXL) was detected by real-time quantitative PCR. The levels of IL-17 and IFN-γ in blood samples were examined by ELISA. The intestinal microbial composition of mice at different time points during the EAE induction was analyzed by 16S rRNA gene-based sequencing. In EAE group, the body weight began to reduce at day 3 and neurological symptoms began to appear at day 7 after EAE induction. The levels of IL-17 and IFN-γ in EAE group reached the peak at day 21 and then decreased gradually. However, the expression of Axl and SOCS3 reached the lowest level at day 21 and then increased gradually. The microbiome analyses revealed that the abundances of Alistipes , Blautia , Lachnospiraceae _NK4A136_group were significantly changed at day 14, whereas the abundances of Allobaculum , Eubacterium , Helicobacter were significantly changed at day 30 of EAE induction. The prevotellaceae_NK3B31_group may be key bacteria that contribute to the development of MS. Regulation of intestinal microbiota composition can become a new therapeutic target for the treatment of MS.
- A co-ultramicronized palmitoylethanolamide/luteolin composite mitigates clinical score and disease-relevant molecular markers in a mouse model of experimental autoimmune encephalomyelitis. [Journal Article]
- JNJ Neuroinflammation 2019 Jun 20; 16(1):126
- CONCLUSIONS: The present results demonstrate that the intraperitoneal administration of the composite PEALut significantly reduces the development of clinical signs in the MOG35-55 model of EAE. The dose-dependent improvement of clinical score induced by PEALut was associated with a reduction in transcript expression of the acute-phase protein SAA1, TNF-α, IL-1β, IFN-γ, and NLRP3 proinflammatory proteins and TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB2 receptors.
- Chlamydia pneumoniae Polioencephalomyelitis and Ganglionitis in Captive Houston Toads (Anaxyrus houstonensis). [Journal Article]
- VPVet Pathol 2019 Jun 20; :300985819844818
- Chlamydia pneumoniae is a ubiquitous pathogen causing disease in humans, mammals, birds, reptiles, and amphibians. Since 2012, C. pneumoniae infection has caused neurologic disease and mortality in a…
Chlamydia pneumoniae is a ubiquitous pathogen causing disease in humans, mammals, birds, reptiles, and amphibians. Since 2012, C. pneumoniae infection has caused neurologic disease and mortality in a breeding colony of endangered Houston toads (Anaxyrus houstonensis) at the Houston Zoo. The purpose of this report is to present the histopathologic and ultrastructural characteristics of C. pneumoniae infection in Houston toads. Fourteen cases were evaluated by histopathology and 1 case was evaluated by electron microscopy. The major histopathologic finding was necrotizing and histiocytic polioencephalomyelitis and ganglionitis. Bacteria formed intracytoplasmic inclusions within neurons but frequently extended into the surrounding tissue from necrotic cells. Ultrastructural evaluation showed the bacteria formed reticulate and elementary bodies characteristic of Chlamydia spp.
- Exogenous activation of tumor necrosis factor receptor 2 promotes recovery from sensory and motor disease in a model of multiple sclerosis. [Journal Article]
- BBBrain Behav Immun 2019 Jun 17
- Tumor necrosis factor receptor 2 (TNFR2) is a transmembrane receptor that promotes immune modulation and tissue regeneration and is recognized as a potential therapeutic target for multiple sclerosis…
Tumor necrosis factor receptor 2 (TNFR2) is a transmembrane receptor that promotes immune modulation and tissue regeneration and is recognized as a potential therapeutic target for multiple sclerosis (MS). However, TNFR2 also contributes to T effector cell function and macrophage-TNFR2 recently was shown to promote disease development in the experimental autoimmune encephalomyelitis (EAE) model of MS. We here demonstrate that systemic administration of a TNFR2 agonist alleviates peripheral and central inflammation, and reduces demyelination and neurodegeneration, indicating that protective signals induced by TNFR2 exceed potential pathogenic TNFR2-dependent responses. Our behavioral data show that systemic treatment of female EAE mice with a TNFR2 agonist is therapeutic on motor symptoms and promotes long-term recovery from neuropathic pain. Mechanistically, our data indicate that TNFR2 agonist treatment follows a dual mode of action and promotes both suppression of CNS autoimmunity and remyelination. Strategies based on the concept of exogenous activation of TNFR2 therefore hold great promise as a new therapeutic approach to treat motor and sensory disease in MS as well as other inflammatory diseases or neuropathic pain conditions.
- Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation. [Journal Article]
- JIJCI Insight 2019 Jun 20; 4(12)
- Th1 and Th17 are important in the pathogenesis of autoimmune diseases and they depend on glycolysis as a source of energy. T cell antigen receptor signaling phosphorylates a serine/threonine kinase, …
Th1 and Th17 are important in the pathogenesis of autoimmune diseases and they depend on glycolysis as a source of energy. T cell antigen receptor signaling phosphorylates a serine/threonine kinase, calcium/calmodulin-dependent protein kinase IV (CaMK4), and promotes glycolysis. Based on these findings we hypothesized that CaMK4 promotes glycolysis. Camk4-deficient CD4+ T cells and cells treated with a CaMK4 inhibitor had less glycolysis compared with their counterparts. Pull-down of CaMK4 and mass spectrometry identified pyruvate kinase muscle isozyme (PKM), the final rate-limiting enzyme in glycolysis, as a binding partner. Coimmunoprecipitation and Western blotting showed that CaMK4 interacts directly with PKM2. Camk4-deficient CD4+ T cells displayed decreased pyruvate kinase activity. Silencing or pharmacological inhibition of PKM2 reduced glycolysis and in vitro differentiation to Th1 and Th17 cells, while PKM2 overexpression restored Th17 cell differentiation. Treatment with a PKM2 inhibitor ameliorated experimental autoimmune encephalomyelitis and CD4+ T cells treated with PKM2 inhibitor or Pkm2-shRNA caused limited disease activity in an adoptive cell transfer model of experimental autoimmune encephalomyelitis. Our data demonstrate that CaMK4 binds to PKM2 and promotes its activity, which is requisite for Th1 and Th17 differentiation in vitro and in vivo. PKM2 represents a therapeutic target for T cell-dependent autoimmune diseases.
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- Therapeutic Potential of Ponesimod Alone and in Combination with Dimethyl Fumarate in Experimental Models of Multiple Sclerosis. [Journal Article]
- ICInnov Clin Neurosci 2019 Mar 01; 16(3-4):22-30
- CONCLUSIONS: The results support the potential therapeutic benefits of combining ponesimod with DMF to improve disease activity control in patients with MS. Additionally, the results suggest that combining ponesimod with other oral agents that have different mechanisms of action might also be therapeutically beneficial to patients with MS.