Skeletal-Muscle Metabolic Reprogramming in ALS-SOD1 G93G Mice Predates Disease Onset and is a Promising Therapeutic Target

2019 ◽  
Author(s):  
Silvia Scaricamazza ◽  
Illari Salvatori ◽  
Giacomo Giacovazzo ◽  
Jean Philippe Loeffler ◽  
Frederique Renè ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Therapeutic Target ◽  
Disease Onset ◽  
Metabolic Reprogramming ◽  
Promising Therapeutic Target

scholarly journals Skeletal-Muscle Metabolic Reprogramming in ALS-SOD1G93A Mice Predates Disease Onset and Is A Promising Therapeutic Target

iScience ◽  
2020 ◽  
Vol 23 (5) ◽  
pp. 101087 ◽  
Author(s):  
Silvia Scaricamazza ◽  
Illari Salvatori ◽  
Giacomo Giacovazzo ◽  
Jean Philippe Loeffler ◽  
Frederique Renè ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Therapeutic Target ◽  
Disease Onset ◽  
Metabolic Reprogramming ◽  
Sod1g93a Mice ◽  
Promising Therapeutic Target

scholarly journals CD38 Deregulation As Strategy to Make Multiple Myeloma Cells More Sensitive to NAD+ Depleting Agents

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5671-5671
Author(s):  
Michele Cea ◽  
Antonia Cagnetta ◽  
Debora Soncini ◽  
Paola Minetto ◽  
Micaela Bergamaschi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Therapeutic Target ◽  
Research Funding ◽  
Annexin V ◽  
Metabolic Reprogramming ◽  
Mechanistic Studies ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Myeloma Cells ◽  
Innovative Strategy ◽  
Promising Therapeutic Target

Abstract Background: The upregulated NAD+ biosynthesis, which is needed to face increased proliferation and metabolic processes, represents an important feature distinguishing cancer cells from their normal counterparts. As a result, the NAD+ biosynthetic apparatus emerges as highly promising therapeutic target for tumors, as suggested by the use of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors in a number of malignancies, including Multiple Myeloma (MM) and leukemia (Cea et al. Blood 2012; Cagnetta et al. Blood 2013; Cagnetta et al. CCR 2015). The ecto-enzyme CD38 is emerging as a novel therapeutic target for patients with hematological malignancies, including MM, with several monoclonal antibodies already tested in clinical trials with promising results. Importantly, CD38 by regulating intracellular NAD+ stores acts as member of the intricate network supporting metabolic reprogramming associated with cancer. Based on these assumptions, here we explored CD38 activity as innovative strategy to enhance the anti-tumor activity of NAMPT inhibition in Multiple Myeloma cells. Methods: A panel of different MM cell lines and primary cells, both sensitive and resistant to conventional and novel anti-MM therapies, was used in the study. The effects of Nampt inhibition was evaluated in presence of CD38-gene editing (loss/gain of approaches) by using CTG assay and Annexin-V/propidium iodide staining. Next, the anti-MM effects of chemicals affecting CD38 activity were also evaluated in combination with low doses of Nampt inhibitors. Mechanistic studies were performed with Western-blotting, lentivirus-mediated shRNAs and enzymatic assays. Results and Conclusions: By using different approaches, we found that CD38 deregulation makes MM cells more vulnerable to NAD+ depleting agents. Ongoing mechanistic studies suggest the central role played by energetic metabolism in the observed synergism. Overall our data provide the mechanistic preclinical rationale to enhance anti-MM activity of Nampt targeting agents, in order to both overcome drug resistance and improve patients outcome. Disclosures Gobbi: Mundipharma: Consultancy, Research Funding; Takeda: Consultancy; Roche: Honoraria; Celgene: Consultancy; Gilead: Honoraria; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Honoraria.

scholarly journals The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 11 (7) ◽  
pp. 671
Author(s):  
Oihane Pikatza-Menoio ◽  
Amaia Elicegui ◽  
Xabier Bengoetxea ◽  
Neia Naldaiz-Gastesi ◽  
Adolfo López de Munain ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amyotrophic Lateral Sclerosis ◽  
Muscle Tissue ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Fine Tuning ◽  
Current State ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.

Hypoxia Conditioning as a Promising Therapeutic Target in Parkinson's Disease?

2021 ◽  
Author(s):  
Johannes Burtscher ◽  
Muhammed Muazzam Kamil Syed ◽  
Hilal A. Lashuel ◽  
Grégoire P. Millet
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Therapeutic Target ◽  
Promising Therapeutic Target

scholarly journals HDAC8: A Promising Therapeutic Target for Acute Myeloid Leukemia

2020 ◽  
Vol 8 ◽  
Author(s):  
Marco Spreafico ◽  
Alicja M. Gruszka ◽  
Debora Valli ◽  
Mara Mazzola ◽  
Gianluca Deflorian ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Therapeutic Target ◽  
Myeloid Leukemia ◽  
Promising Therapeutic Target ◽  
Acute Myeloid

Annexin A4 is a promising therapeutic target for the treatment of platinum-resistant cancers

2014 ◽  
Vol 18 (4) ◽  
pp. 403-414 ◽  
Author(s):  
Shinya Matsuzaki ◽  
Satoshi Serada ◽  
Akiko Morimoto ◽  
Yutaka Ueda ◽  
Kiyoshi Yoshino ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Annexin A4 ◽  
Platinum Resistant ◽  
Promising Therapeutic Target

Design and evaluation of IKK-activated GSK3 inhibitory peptide as an inflammation-responsive anti-colitic therapeutics

2021 ◽  
Author(s):  
Sungchae Hong ◽  
Sanghyun Ju ◽  
Jin-Wook Yoo ◽  
Nam-Chul Ha ◽  
Yunjin Jung
Keyword(s):  
Therapeutic Target ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Inhibitory Peptide ◽  
Promising Therapeutic Target

Glycogen synthase kinase-3β (GSK3β), a multi-functional kinase, is a promising therapeutic target for the treatment of inflammation. Inhibitory B kinase (IKK)-activated GSK3β inhibitory peptide (IAGIP) was designed as an inflammation-responsive...

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