HE3286, an orally bioavailable synthetic analogue of an active DHEA metabolite suppresses spontaneous autoimmune diabetes in the non-obese diabetic (NOD) mouse

Kosiewicz, Michele M; Auci, Dominick L.; Fagone, Paolo; Mangano, Katia; Caponnetto, S; Tucker, Colleen; Azeem, Nabeel; White, Steven K; Frincke, James M.; Reading, Christopher L.; Nicoletti, Ferdinando

doi:10.1016/j.ejphar.2011.02.016

Cited by 9 publications

(9 citation statements)

References 45 publications

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“…HE3286 has produced therapeutic benefits in various models of inflammatory disease, in a model of Parkinson's and in clinical trials for diabetic complications (Auci et al, 2007 , 2010 ; Ahlem et al, 2009 ; Offner et al, 2009 ; Conrad et al, 2010 ; Lu et al, 2010 ; Kosiewicz et al, 2011 ; Nicoletti et al, 2012 ; Reading et al, 2013a , b ; Khan et al, 2014 ). HE3286 has been well tolerated and has presented no adverse effects in human trials (Reading et al, 2013a , b ).…”

Section: Discussionmentioning

confidence: 99%

“…HE3286 shows better oral bioavailability in humans, has low potential for toxicity, does not bind to glucocorticoid receptor or any known nuclear hormone receptor, and is not immunosuppressive (Wang et al, 2010 ; Ahlem et al, 2011 ). Treatment with HE3286 improves outcome measures in models of autoimmune disease, lung inflammation, experimental optic neuritis and Parkinson's disease, and is currently being tested in clinical trials (Auci et al, 2007 , 2010 ; Ahlem et al, 2009 ; Offner et al, 2009 ; Conrad et al, 2010 ; Lu et al, 2010 ; Kosiewicz et al, 2011 ; Nicoletti et al, 2012 ; Reading et al, 2013a , b ; Khan et al, 2014 ). It is believed HE3286 may act via binding, regulation and/or activation of MAPK or ERK, or through modulation of NFκB (Lu et al, 2010 ; Ahlem et al, 2011 ; Nicoletti et al, 2012 ; Reading et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

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Oral Delivery of a Synthetic Sterol Reduces Axonopathy and Inflammation in a Rodent Model of Glaucoma

et al. 2017

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Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). The disease is the leading cause of irreversible blindness worldwide. Early progression in glaucoma involves dysfunction of retinal ganglion cell (RGC) axons, which comprise the optic nerve. Deficits in anterograde transport along RGC axons to central visual structures precede outright degeneration, and preventing these deficits is efficacious at abating subsequent progression. HE3286 is a synthetic sterol derivative that has shown therapeutic promise in models of inflammatory disease and neurodegenerative disease. We examined the efficacy of HE3286 oral delivery in preventing loss of anterograde transport in an inducible model of glaucoma (microbead occlusion). Adult rats received HE3286 (20 or 100 mg/kg) or vehicle daily via oral gavage for 4 weeks. Microbead occlusion elevated IOP ~30% in all treatment groups, and elevation was not affected by HE3286 treatment. In the vehicle group, elevated IOP reduced anterograde axonal transport to the superior colliculus, the most distal site in the optic projection, by 43% (p = 0.003); HE3286 (100 mg/kg) prevented this reduction (p = 0.025). HE3286 increased brain-derived neurotrophic factor (BDNF) in the optic nerve head and retina, while decreasing inflammatory and pathogenic proteins associated with elevated IOP compared to vehicle treatment. Treatment with HE3286 also increased nuclear localization of the transcription factor NFκB in collicular and retinal neurons, but decreased NFκB in glial nuclei in the optic nerve head. Thus, HE3286 may have a neuroprotective influence in glaucoma, as well as other chronic neurodegenerations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oral Delivery of a Synthetic Sterol Reduces Axonopathy and Inflammation in a Rodent Model of Glaucoma

et al. 2017

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“…A possible pathway includes ligand inactivation, modulation of ion channels, interaction with atypical receptors, and modulation of steroidogenic enzymes [57,60,61]. Previous studies associated the activity of HE3286 with increased regulatory T cells, maintaining immune homeostasis and preventing autoimmune disease [57,62,63]. Moreover HE3286 plays a role in the reduction of pro-inflammatory cytokines such as IL-17 and IL-6, involved in the biology of regulatory T cells [12,57,64] and in the transition from acute to chronic inflammation [57,61,65].…”

Section: Discussionmentioning

confidence: 99%

Effects of Synthetic Anti-Inflammatory Sterol in CB3V-Induced Myocarditis: A Morphological Study on Heart Muscle Tissue

Castrogiovanni

Trovato

Szychlinska

et al. 2016

JFMK

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Cell-mediated immune events play a role in the pathogenesis of myocarditis provoked by Group B coxsackievirus (CVB). Studies indicated the synthetic derivative of androstene-3β,7β,17βtriol, HE3286 (17α-ethynyl-5-androstene-3β,7β,17β-triol), may ameliorate the course of immunoinflammatory and autoimmune diseases in rodents. The aim of this study was to evaluate effects of HE3286 on histological signs of CVB-induced myocarditis. BALB/c mice were infected with coxsackie B3 virus (CB3V) and treated by intraperitoneal administration of dexamethasone (Dex) or by oral gavage with HE3286 or with its vehicle, HERF405, for 18 days. Mice were sacrificed and hearts were explanted for histological and immunohistochemical analysis (TNF-α, IL-6, MMP9, ADAM10 and HSP-70). Heart tissues of Dex-treated mice showed a better histological structure compared with mice treated with HERF405. An almost complete resolution of myocarditis was observed in HE3286-treated mice as evidenced by lack of inflammatory infiltration. Immunohistochemical findings confirmed HE3286 had a more pronounced effect than Dex in reducing inflammatory response associated with in situ modulation of cytokine expression and tissue remodeling. Our data demonstrate HE3286 has better results in inhibiting establishment and progression of murine CVB-induced myocarditis than Dex, suggesting this drug may also have a therapeutic role in treatment of CVB-induced myocarditis.

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“…HE3286 is pharmacologically unrelated to androgens, estrogens, corticosteroids, or peroxisome proliferators, and it did not alter the concentrations of dehydroepiandrosterone (DHEA), testosterone, estradiol, progesterone, androstenedione, lutenizing hormone, follicle stimulating hormone, or adrenocorticotrophic hormone and did not affect 24‐h urinary free cortisol in nonclinical safety studies or clinical trials. HE3286 has shown broad anti‐inflammatory activity in animal models of rheumatoid arthritis , ulcerative colitis, multiple sclerosis , lung inflammation , and autoimmune type 1 diabetes . In these models, nuclear factor kappa B (NFκB) activation and proinflammatory cytokine production were consistently suppressed .…”

Section: Introductionmentioning

confidence: 99%

A synthetic anti‐inflammatory sterol improves insulin sensitivity in insulin‐resistant obese impaired glucose tolerance subjects

Reading¹,

Stickney²,

Flores-Riveros³

et al. 2013

Obesity

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Objective: To study the activity of 7b,, an antiinflammatory sterol that is active in models of obesity-induced inflammation and insulin resistance in high body mass index (BMI) subjects with impaired glucose tolerance (IGT). Design and Methods: HE3286 was explored in high BMI IGT subjects using hyperinsulinemic, euglycemic clamp studies. Results: In insulin-resistant subjects, HE3286 significantly increased day 29 insulin-stimulated glucose disposal and HDL cholesterol, and decreased C-reactive protein (CRP) compared to placebo. For HE3286, change in M value showed a significant negative correlation with baseline M value. Subjects with baseline M value below the median (4.2 mg/kg/min) had significantly lower adiponectin and higher lipopolysaccharide-stimulated peripheral blood mononuclear cell cytokine secretion. After 28 days of HE3286 treatment, adiponectin levels were significantly increased in insulin-resistant (baseline M < 4.2), but not insulin-sensitive (baseline M > 4.2) subjects, compared to placebo. Conclusions: HE3286 significantly increased the frequency of subjects with increased insulin-stimulated glucose disposal and HDL, and decreased CRP compared to placebo, in insulin-resistant, but not insulin-sensitive subjects. Thus, HE3286 may preferentially benefit insulin-resistant, inflamed, high BMI IGT subjects.

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HE3286, an orally bioavailable synthetic analogue of an active DHEA metabolite suppresses spontaneous autoimmune diabetes in the non-obese diabetic (NOD) mouse

Cited by 9 publications

References 45 publications

Oral Delivery of a Synthetic Sterol Reduces Axonopathy and Inflammation in a Rodent Model of Glaucoma

Oral Delivery of a Synthetic Sterol Reduces Axonopathy and Inflammation in a Rodent Model of Glaucoma

Effects of Synthetic Anti-Inflammatory Sterol in CB3V-Induced Myocarditis: A Morphological Study on Heart Muscle Tissue

A synthetic anti‐inflammatory sterol improves insulin sensitivity in insulin‐resistant obese impaired glucose tolerance subjects

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