Lupus

While estrogen has been suggested to account for the higher survival rates in many female species due to heightened immunoreactive states, we propose that this may contribute to autoimmunity if dysregulated. Our research investigating systemic lupus erythematosus (SLE) has explored the estrogenic effects over inflammatory gene expression and has led to the discovery of several novel genes and pathways. Most notably, we identified the regulation of endosomal toll-like receptors (TLR) and characterized a novel, exosome-mediated microRNA stimulatory pathway for TLR8, which has a provisional patent approval as a therapeutic target and is being developed further currently. The immunoregulatory role of exosome- encapsulated RNA has been characterized in our work to be pro-inflammatory through TLR signaling and anti-inflammatory when secreted by mesenchymal stem cells. 


Publications

1. Young NA, Friedman AK, Kaffenberger B, Rajaram MV, Birmingham DJ, Rovin BH et al. Novel estrogen target gene ZAS3 is overexpressed in systemic lupus erythematosus. Mol Immunol, 2013; 54:23-31.  


2. Young NA, Wu L, Burd CJ, Friedman AK, Kaffenberger B, Rajaram MV et al. Estrogen modulation of endosome-associated toll-like receptor 8: an IFNα-independent mechanism of sex-bias in systemic lupus erythematosus. Clin Immunol, 2014; 151(1): p. 66-77.  


3. Young NA, Valiente GR, Hampton JM, Wu LC, Burd CJ, Willis WL…Jarjour WN. Estrogen-regulated STAT1 activation promotes TLR8 expression to facilitate signaling via microRNA-21 in systemic lupus erythematosus. Clinical immunology 2016, 176: 12-22.  


4. Young NA, Williams, M.V, Bruss M, Ariza ME, and Jarjour W. Epstein-Barr virus (EBV) encoded dUTPase exacerbates the immune pathology of lupus nephritis in vivo by up-regulation of TLR2 and IL-17. Int J Immunol Immunother 2016, 3:023.  


5. Sharma J, Hampton JM, Valiente GR, Wada T, Steigelman H …, Jarjour WN, Young NA. Therapeutic development of mesenchymal stem cells or their extracellular vesicles to inhibit autoimmune-mediated inflammatory processes in systemic lupus erythematosus. Frontiers in Immunology 2017, 8 (526).  


Selected Press Releases and News Articles

1. Newswise April 15, 2014. Immune System Genes Activated by Estrogen May Hold Clues to Lupus Origin. New study supports connection between estrogen and autoimmune disease 



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Health and Wellness Therapy to Treat Inflammatory Disease

Lupus: Chronic inflammation is the hallmark of autoimmune disease and both psychological stress and exercise have been shown to elicit immunomodulatory effects.  We demonstrated that repeated social stress induces more severe inflammatory pathology while daily moderate exercise significantly improves disease in mouse models. Therefore, these novel, comprehensive animal model data provide molecular evidence at the immunological level and suggest that both stress reduction and moderate exercise could be used as potent therapeutic modalities to control the inflammation associated with lupus. Ongoing studies in mouse models and human trials are aimed at suppressing autoimmune-mediated inflammation.


Publications

1. Aqel SI, Hampton JM, Bruss M, Jones KT, Valiente GR…,Jarjour WN, Young NA. Daily Moderate Exercise Is Beneficial and Social Stress Is Detrimental to Disease Pathology in Murine Lupus Nephritis. Frontiers in Physiology 2017, 8(236).  


Selected Press Releases and News Articles

1. U.S. News and World Report Sept 19, 2017. Exercise May Stem Kidney Damage in Lupus Patients 


2. Science Daily June 12, 2014. Regular exercise beneficial in suppressing inflammation in rheumatic disease.


3. Orthopedics this week June 18th, 2014. Regular Exercise Helps Suppress Inflammation.


4. Arthritis research UK June 16th, 2014. Exercise 'can help to prevent inflammation associated with rheumatic disease'.


5. Medical News Today (MNT) June 15, 2014. Exercise results in physiological changes that suppress inflammation in rheumatic disease.


6. Le Populaire Du Centre (article in French) Sept 20, 2017. L'activité physique serait un outil efficace dans le traitement du lupus 


7. Gaianews.it (article in Italian) June 6th, 2014. L’esercizio fisico riduce l’infiammazione nelle malattie 


8. lainformacion.com (article in Spanish) June 12th, 2014. El ejercicio regular ayuda a suprimir la inflamación en la enfermedad reumática


9. Regalos Para Mujeres Originales (article in Spanish)  July 28th, 2014. El ejercicio regular beneficiosa en la supresión de la inflamación en la enfermedad reumática 


Gout: We are investigating the effects of exercise both before and after the induction of gout to examine the influence of exercise frequency and intensity on the inflammatory response. This will allow us to identify the most optimal exercise regimen and will serve as a proof of concept by suppressing establishment of the disease. However, since patients do not walk into the clinic before they have gout, we are also examining the effects of exercise after the induction of gout to determine whether exercise can minimize the pathology associated with flares. But, there are surprisingly no animal models that examine gouty inflammation in this context. Consequently, we are designing a novel animal model where gout will be induced in several rounds with a rest/recovery period in-between. This should better represent the chronic inflammatory milieu that persists in patients with gout. Using the optimal exercise regimen we define, we will exercise during a recovery period to determine if this has an effect over a subsequent flare. We propose that exercise will help suppress the smoldering levels of inflammation that are present in this situation.


We believe that this is a very novel and effective approach to evaluating the influence of exercise in gout. Ultimately, we feel that exercise will be helpful to a patient with gout that is in a recovery period between flares to hopefully prevent or limit future ones. While rest and decreased movement will still be recommended to a patient with a flare presenting with a red, painful, and swollen foot, we envision a standardized exercise regimen being prescribed during times of clinical inactivity to help the severity and frequency of future occurrences. This research is the first step toward this reality.


Publications

1. Young NA, Jablonski K, Sharma J, Thomas E, Snoad B, Hampton J, Jarjour W, Schlesinger N. Low and Moderate Intensity Exercise Suppresses Inflammatory Responses in an Acute Mouse Model of Gout and Suggests Therapeutic Efficacy [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). 


Selected Press Releases and News Articles

1. 2017 Update: Division of Rheumatology and Immunology. Researchers from Ohio State & Rutgers Examine How Exercise  May Influence the Management of Gout(story on page 5) 


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Nutraceutical Therapy to Suppress Inflammation

To inquire about purchasing  a more recently developed formulation of the nanoemulsified curcumin (NEC) compound described below, please contact us at the The Inflammation Foundation (nicholas.young@theinflammationfoundation.org) to discuss your order. This nutraceutical compound is recommended for daily use to suppress the negative effects of unwanted inflammation in healthy individuals proactively and in those combatting inflammatory disease reactively. NEC regimens are shipped in the mail as a suspension that is taken in daily aliquots.


Curcumin is a naturally occurring compound found in the spice turmeric that has been used for centuries in Ayurvedic medicine. Anecdotal and scientific evidence suggests curcumin promotes health because it lowers inflammation, but it is not absorbed well by the body. Most curcumin in food or supplements stays in the gastrointestinal tract, and any portion that’s absorbed is metabolized quickly. We studied a novel formulation of curcumin through nanoemulsification that increased curcumin bioavailability 10.5-fold in mice. Our work characterized the pharmacodynamics of our novel, patented formulation and showed a significant suppression of inflammatory responses in an acute mouse model. This preclinical data was used to help establish a human clinical trial currently using this drug in breast cancer patients.

 

Publications

1. Young NA, Bruss MS, Gardner M, Willis WL, Xiaokui M, Valiente GR, Cao Y, Liu Z, Wu L, Jarjour WN.  Oral administration of nano-emulsion curcumin suppresses LPS-induced NFkB signaling in inflammation and inhibits macrophage migration. PloS one 2014; 9(11): e111559.  


Selected Press Releases and News Articles

1. Newsmax November 6, 2014. Curcumin Eases Inflammation, Boosts Health: Study


2. Business Standard November 14, 2014. Health benefits of curcumin just got better


3. Ohio State University Center for Clinical and Translational Science Newsroom. November 6th, 2014. New Research Adds Spice to Curcumin’s Health-Promoting Benefits.  


4. WorldNetDaily (WND). November 14th, 2014. Chuck Norris explains what's better than calcium.  


5. About Why. (article in German). Neue Forschung für mehr Geschmack auf die gesundheitlichen Vorteile von Curcumin  


6. Nguon News. (article in Vietnamese). Curcumin loai moi giup gia tang kha nang chong viem toan November 10th, 2014


7. Системная красная волчанка (article in Russian) November 10, 2014. Куркума обладает выраженным противовоспалительным действием  


8. Zdravotnické  Noviny (article in Czech) July 3rd, 2014. O čem také revmatologové diskutovali v pařížském kongresovém centru. Pravidelné cvičení prospěšné při potlačování zánětu?


9. perpustakaan.or.id (article in Indonesian) June 13th, 2014. Olahraga Teratur Bermanfaat untuk Menekan Peradangan pada Penyakit Rematik.    


The pomegranate has been used for centuries as a therapeutic agent for the treatment of inflammatory diseases and disorders of the digestive tract by the practitioners of the Ayurvedic and Unani systems of medicine. More recently, standardized extracts of pomegranate have been shown to have anti-inflammatory and cartilage sparing effects in vitro as well as cancer preventing and cardiovascular disease preventing effects in vivo. In this work, we are characterizing a novel formulation of pomegranate juice extract to determine efficacy in limiting pathological inflammation.


Publications

1. Young NA, Mobeen M, Haqqi TM, Jarjour WN. Nutraceutical Therapy with Polyphenol-Rich Pomegranate Fruit Extract Inhibits Systemic NFκB-Mediated Inflammation in a Murine Model of Endotoxemia [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). 


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Cancer Biology

Brain Cancer: We identified novel signaling pathways, established a clinical relationship of sphingosine 1-phospate (S1P) signaling to glioblastoma multiforme (GBM) brain cancer carcinogenesis, and identified novel therapeutic targets. We demonstrated that blocking these molecular targets and suppressing S1P synthesis inhibited cancer cell invasiveness in vitro. Since no animal model of this disease demonstrated surrounding tissue invasion from the tumor, we developed one using cancer stem cells derived from neurospheres cultured from primary human GBM tissue. 


Publications

1. Young N, Pearl DK, Van Brocklyn JR. Sphingosine-1-phosphate regulates glioblastoma cell invasiveness through the urokinase plasminogen activator system and CCN1/Cyr61. Mol Cancer Res, 2009; 7:23-32.  


2. Young N Regulation of Invasiveness of Glioblastoma Multiforme Cell Lines and Tumor Stem Cells by Sphingosine Kinase and Sphingosine 1-Phosphate Reveals Potential Molecular Therapeutic Targets


3. Young N and Van Brocklyn JR. Roles of sphingosine-1-phosphate (S1P) receptors in malignant behavior of glioma cells. Differential effects of S1P2 on cell migration and invasiveness. Exp Cell Res, 2007; 313(8): p. 1615-27.  


4. Young N and JR Van Brocklyn. Signal transduction of sphingosine-1-phosphate G protein-coupled receptors. ScientificWorldJournal, 2006; 6: p. 946-66. 


5. Van Brocklyn JR, Young N, and Roof R. Sphingosine-1-phosphate stimulates motility and invasiveness of human glioblastoma multiforme cells. Cancer Lett, 2003; 199(1): p. 53-60. 


Breast Cancer: Aromatase Inhibitors (AIs) block estrogen production and significantly improve overall survival rates of post-menopausal breast cancer patients by reducing tumor recurrences. However, half of patients taking these drugs develop aromatase inhibitor induced arthralgia (AIIA), which is characterized by severe pain and inflammation in various joints. Since AIIA leads to suspension of therapy in 20% of patients, reducing incidence may provide sustained AI treatment and enhanced long-term survival. Our research has established a novel animal model of this inflammatory disease and the data suggests that the pathogenesis of AI-induced inflammation is estrogen-independent. 


Publications

1. Young, N., Thomas, E., Snoad, B., Sharma, J., Mobeen, M., DeVries, A., Bratasz, A., Lustberg, M., Jarjour, W., and Reinbolt, R. (2017). Novel animal model of aromatase inhibitor-induced arthralgia suggests an estrogen-independent inflammatory mechanism. Annals of the rheumatic diseases 76, 222-222.  


Selected Press Releases and News Articles

1. 2017 Update: Division of Rheumatology and Immunology. Research Collaboration May Lead to Treatment and Possible Prevention of Aromatase Inhibitor-Induced Arthralgias (story on page 6) 


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Rheumatoid Arthritis

Through our collaboration with Navidea Biopharmaceuticals, we have generated the preclinical data necessary for a human clinical trial of their novel imaging agent Lymphoseek (Tilmanocept) in patients with rheumatoid arthritis (RA). This drug targets CD206+ macrophages and is currently administred to breast or head/neck cancer patients to identify metastatic lymph nodes and label them for resection prior to surgery. We plan to examine the efficacy of this drug in RA patients for both earlier/more sensitive diagnostic detection of inflamed joints and to monitor the response of patients to treatment. 


Publications 

1. Cope FO, Abbruzzese B, Sanders J, Metz W, Young NA, Sturms K, Ralph D,…Rosol T, Jarjour WN, Toribio R, Scheslinger L, and McGrath, M. The inextricable axis of targeted diagnostic imaging and therapy: An immunological natural history approach. Nucl Med Biol 2016; 43, 215-225  


Selected Press Releases and News Articles

1. The Wall Street Journal October 24, 2013. Navidea Biopharmaceuticals Manocept(TM) Platform Featured in Nature Outlook: Medical Imaging.  


2. Nature Outlook: Medical Imaging October 31, 2013 issue of Nature.  Innovations in receptor-targeted precision imaging at Navidea: diagnosis up close and personal.


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Sjögren’s Syndrome

The successes observed in treating animal models of a disease do not always translate into positive results with humans in the clinic. To circumvent this problem, researchers have developed humanized mice. In our research in this area, we developed a human-mouse hybrid model that can be used to study Sjögren’s syndrome (SjS). Human cells from SjS patients were transferred to mice to recapitulate immunological disease progression just as it is observed in humans. Our results showed enhanced target organ inflammation and established a novel humanized mouse model to study SjS pathology and to use in therapeutic development. 


Publications

1. Young NA, Wu L, Hampton J, Bruss MS, Kaffenberger BH, Bolon B, Jarjour WN. A chimeric human-mouse model of Sjögren's Syndrome. Clin immunol 2014; 156(1): 1-8.  


Selected Press Releases and News Articles

1. Global Medical Discovery. A chimeric human-mouse model of Sjögren’s syndrome. 04/11/2015


2. Science Daily February 10, 2015. First humanized mouse model of Sjögren’s syndrome opens door to study other autoimmune diseases


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Myositis

Myositis is an autoimmune disease that targets muscle tissue and our studies investigate the involvement of self-antigens in pathogenesis. We have shown that intra-cellular antigens can be abnormally exposed via cell damage or improper membrane resealing and contribute to inflammation targeting muscle tissue. In addition, we have demonstrated that adoptive transfer of Regulatory T-cells can suppress this response and are a plausible immunotherapy to pursue therapeutically. This novel animal model of myositis will permit the future examination of abnormal exposure of intra-cellular antigens in this disease. 


Publications

1. Young NA, Sharma R, Friedman AK, Kaffenberger BH, Bolon B, Jarjour WN. Aberrant muscle antigen exposure in mice is sufficient to cause myositis in a Treg cell-deficient milieu.  Arthritis Rheum, 2013; 65:3259-70.  


Selected Press Releases and News Articles

1. Nature Reviews Rheumatology October 1, 2013.  Inflammatory myopathies: TREG-cell deficiency and abnormal muscle antigen exposure important to the development of myositis. Ray K. Nat Rev Rheumatol;9:638.     

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