Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses

Abstract Wild-type and mutant transthyretin (TTR) can misfold and deposit in the heart, peripheral nerves, and other sites causing amyloid disease. Pharmacological chaperones, Tafamidis® and diflunisal, inhibit TTR misfolding by stabilizing native tetrameric TTR; however, their minimal effective concentration is in the micromolar range. By immune-targeting sparsely populated TTR misfolding intermediates (i.e. monomers), we achieved fibril inhibition at substoichiometric concentrations. We developed an antibody (misTTR) that targets TTR residues 89–97, an epitope buried in the tetramer but exposed in the monomer. Nanomolar misTTR inhibits fibrillogenesis of misfolded TTR under micromolar concentrations. Pan-specific TTR antibodies do not possess such fibril inhibiting properties. We show that selective targeting of misfolding intermediates is an alternative to native state stabilization and requires substoichiometric concentrations. MisTTR or its derivative may have both diagnostic and therapeutic potential.

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Abstract P283: Parkin Mediates Mitophagy in Cardioprotection

Circulation Research ◽

10.1161/res.109.suppl_1.ap283 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

Allen M Andres ◽

Chengqun Huang ◽

Eric P Ratliff ◽

Genaro Hernandez ◽

Pamela Lee ◽

...

Keyword(s):

Ex Vivo ◽

Wild Type ◽

Simulated Ischemia ◽

Selective Targeting ◽

Cardioprotective Effects ◽

Mitochondrial Turnover ◽

First Time

Autophagy-dependent mitochondrial turnover in response to cellular stress is necessary for maintaining cellular homeostasis. However, the mechanisms that govern the selective targeting of damaged mitochondria are poorly understood. Parkin, an E3 ubiquitin ligase, has been shown to be essential for the selective clearance of damaged mitochondria. Parkin is expressed in the heart, yet its function has not been investigated in the context of cardioprotection. We previously reported that autophagy is required for cardioprotection by ischemic preconditioning (IPC). In the present study, we used simulated ischemia in vitro and IPC in hearts (in vivo and ex vivo) to investigate the role of Parkin in mediating cardioprotection. In HL-1 cells, simulated ischemia induced Parkin translocation to mitochondria and mitochondrial elimination. Mitochondrial loss was blunted in Atg5-deficient cells, revealing the requirement for autophagy in mitochondrial elimination. Consistent with previous reports implicating p62/SQSTM1 in mitophagy, we found that downregulation of p62 attenuated mitophagy and exacerbated cell death in HL-1 cardiomyocytes subjected to simulated ischemia. While wild type mice showed p62 translocation to mitochondria after IPC, Parkin knockout mice exhibited attenuated translocation of p62 to mitochondria. Importantly, ablation of Parkin in mice abolished the cardioprotective effects of IPC. These results reveal for the first time the crucial role of Parkin and mitophagy in cardioprotection.

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Stimulus Processing during Apparent Unconsciousness in Anesthetized Volunteers

Perceptual and Motor Skills ◽

10.2466/pms.1986.62.2.587 ◽

1986 ◽

Vol 62 (2) ◽

pp. 587-591 ◽

Cited By ~ 1

Author(s):

Benno Bonke ◽

Jože Rupreht ◽

John H. M. Van Eijndhoven

Keyword(s):

Nitrous Oxide ◽

General Anesthesia ◽

Motor Response ◽

Effective Concentration ◽

Healthy Male ◽

Unconscious Perception ◽

Stimulus Processing ◽

Motor Responses ◽

Minimal Effective Concentration ◽

Period Return

Return of motor-responses upon request as an indicator of stimulus processing during apparent unconsciousness in general anesthesia was studied in 8 healthy, male volunteers during prolonged inhalation of nitrous oxide. First the minimal effective concentration of nitrous oxide was established for each volunteer, based upon continued absence of motor-responses to repeated verbal commands. One week later this concentration of nitrous oxide was administered for a 3-hr. period; return of motor-responses after at least 30 min. of absence was considered a sign of so-called unconscious perception. Four volunteers showed return of motor-response within the 3 hr. of exposure, but two of these had been rather restless throughout the session. Results indicate that unexpected processing of information by patients may occur during presumed unconsciousness after a prolonged inhalation of nitrous oxide in general anesthesia.

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Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-018-0820-5 ◽

2018 ◽

Vol 37 (1) ◽

Cited By ~ 13

Author(s):

Anais Del Curatolo ◽

Fabiana Conciatori ◽

Ursula Cesta Incani ◽

Chiara Bazzichetto ◽

Italia Falcone ◽

...

Keyword(s):

Therapeutic Potential ◽

Wild Type ◽

Tumor Models

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Minimal effective concentration and efficacy of epoetins

Journal of Bioequivalence & Bioavailability ◽

10.4172/0975-0851.1000070 ◽

2010 ◽

Vol 01 (01) ◽

Author(s):

Wojciech Krzyzanski

Keyword(s):

Effective Concentration ◽

Minimal Effective Concentration

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Advances in bioelectronic medicine: noninvasive electrical, ultrasound and magnetic nerve stimulation

Bioelectronics in Medicine ◽

10.2217/bem-2020-0001 ◽

2019 ◽

Vol 2 (4) ◽

pp. 143-150

Author(s):

Jason R Fritz ◽

Jared M Huston

Keyword(s):

Nervous System ◽

Nerve Stimulation ◽

Peripheral Nerves ◽

Therapeutic Potential ◽

Acute Onset ◽

Neural Pathways ◽

Pulse Generators ◽

Bioelectronic Medicine ◽

Potential Impact ◽

Electrical Signaling

The mammalian nervous system has evolved over millions of years to protect the host. Harnessing neural pathways for therapeutic purposes is postulated to enhance treatment specificity and minimize adverse reactions. Bioelectronic medicine aims to diagnose and treat diseases through devices that regulate electrical signaling within the nervous system. Traditionally, this was accomplished via surgical implantation of electrical pulse generators directly onto peripheral nerves. While efficacious, this approach has significant limitations, including complications and associated costs of surgical procedures, and practical issues with treating acute onset and/or short-lived diseases with invasive approaches. Novel stimulation paradigms are currently under development to overcome these clinical challenges and ultimately expand the therapeutic potential of bioelectronic medicine. Here we review noninvasive electrical, ultrasound and magnetic nerve stimulation strategies in the context of more invasive electrical therapies, and discuss their potential impact on the field of bioelectronic medicine.

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Microglial autophagy–associated phagocytosis is essential for recovery from neuroinflammation

Science Immunology ◽

10.1126/sciimmunol.abb5077 ◽

2020 ◽

Vol 5 (52) ◽

pp. eabb5077

Author(s):

Rasmus Berglund ◽

Andre Ortlieb Guerreiro-Cacais ◽

Milena Z. Adzemovic ◽

Manuel Zeitelhofer ◽

Harald Lund ◽

...

Keyword(s):

Therapeutic Potential ◽

Wild Type ◽

Cns Inflammation ◽

Age Related ◽

Microglial Phenotype ◽

The Central Nervous System ◽

Underlying Mechanisms ◽

Myelin Degradation ◽

Specific Deletion ◽

Noncanonical Form

Multiple sclerosis (MS) is a leading cause of incurable progressive disability in young adults caused by inflammation and neurodegeneration in the central nervous system (CNS). The capacity of microglia to clear tissue debris is essential for maintaining and restoring CNS homeostasis. This capacity diminishes with age, and age strongly associates with MS disease progression, although the underlying mechanisms are still largely elusive. Here, we demonstrate that the recovery from CNS inflammation in a murine model of MS is dependent on the ability of microglia to clear tissue debris. Microglia-specific deletion of the autophagy regulator Atg7, but not the canonical macroautophagy protein Ulk1, led to increased intracellular accumulation of phagocytosed myelin and progressive MS-like disease. This impairment correlated with a microglial phenotype previously associated with neurodegenerative pathologies. Moreover, Atg7-deficient microglia showed notable transcriptional and functional similarities to microglia from aged wild-type mice that were also unable to clear myelin and recover from disease. In contrast, induction of autophagy in aged mice using the disaccharide trehalose found in plants and fungi led to functional myelin clearance and disease remission. Our results demonstrate that a noncanonical form of autophagy in microglia is responsible for myelin degradation and clearance leading to recovery from MS-like disease and that boosting this process has a therapeutic potential for age-related neuroinflammatory conditions.

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The Mitochondria-Targeted Methylglyoxal Sequestering Compound, MitoGamide, Is Cardioprotective in the Diabetic Heart

Cardiovascular Drugs and Therapy ◽

10.1007/s10557-019-06914-9 ◽

2019 ◽

Vol 33 (6) ◽

pp. 669-674 ◽

Cited By ~ 5

Author(s):

Mitchel Tate ◽

Gavin C. Higgins ◽

Miles J. De Blasio ◽

Runa Lindblom ◽

Darnel Prakoso ◽

...

Keyword(s):

Experimental Diabetes ◽

Therapeutic Potential ◽

Glycated Haemoglobin ◽

Wild Type ◽

Oral Gavage ◽

Glycation End Products ◽

Diabetic Myocardium ◽

Patients With Diabetes ◽

Akita Mice ◽

Targeted Approach

Abstract Purpose Methylglyoxal, a by-product of glycolysis and a precursor in the formation of advanced glycation end-products, is significantly elevated in the diabetic myocardium. Therefore, we sought to investigate the mitochondria-targeted methylglyoxal scavenger, MitoGamide, in an experimental model of spontaneous diabetic cardiomyopathy. Methods Male 6-week-old Akita or wild type mice received daily oral gavage of MitoGamide or vehicle for 10 weeks. Several morphological and systemic parameters were assessed, as well as cardiac function by echocardiography. Results Akita mice were smaller in size than wild type counterparts in terms of body weight and tibial length. Akita mice exhibited elevated blood glucose and glycated haemoglobin. Total heart and individual ventricles were all smaller in Akita mice. None of the aforementioned parameters was impacted by MitoGamide treatment. Echocardiographic analysis confirmed that cardiac dimensions were smaller in Akita hearts. Diastolic dysfunction was evident in Akita mice, and notably, MitoGamide treatment preferentially improved several of these markers, including e′/a′ ratio and E/e′ ratio. Conclusions Our findings suggest that MitoGamide, a novel mitochondria-targeted approach, offers cardioprotection in experimental diabetes and therefore may offer therapeutic potential for the treatment of cardiomyopathy in patients with diabetes.

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