scholarly journals Biological effects and osteoarthritic disease-modifying activity of small molecule CM-01

2017 ◽  
Author(s):  
Yubo Sun ◽  
Andrea Roberts ◽  
David R. Mauerhan ◽  
Edward N. Hanley
Keyword(s):  
Small Molecule ◽  
Biological Effects ◽  
Disease Modifying

scholarly journals Disease-Modifying Adjunctive Therapy (DMAT) in Osteoarthritis—The Biological Effects of a Multi-Mineral Complex, LithoLexal® Joint—A Review

2021 ◽  
Vol 11 (4) ◽  
pp. 901-913
Author(s):  
Erik Fink Eriksen ◽  
Osvandre Lech ◽  
Gilberto Yoshinobu Nakama ◽  
Denise M. O’Gorman
Keyword(s):  
Adjunctive Therapy ◽  
Chondroitin Sulphate ◽  
Biological Effects ◽  
Joint Destruction ◽  
Molecular Medicine ◽  
Inflammatory Disorder ◽  
Walking Ability ◽  
Contributing Factors ◽  
Mineral Complex ◽  
Disease Modifying

Modern advances in molecular medicine have led to the reframing of osteoarthritis as a metabolically active, inflammatory disorder with local and systemic contributing factors. According to the ‘inflammatory theory’ of osteoarthritis, immune response to an initial damage is the key trigger that leads to progressive joint destruction. Several intertwined pathways are known to induce and govern articular inflammation, cartilage matrix degradation, and subchondral bone changes. Effective treatments capable of halting or delaying the progression of osteoarthritis remain elusive. As a result, supplements such as glucosamine and chondroitin sulphate are commonly used despite the lack of scientific consensus. A novel option for adjunctive therapy of osteoarthritis is LithoLexal® Joint, a marine-derived, mineral-rich extract, that exhibited significant efficacy in clinical trials. LithoLexal® has a lattice microstructure containing a combination of bioactive rare minerals. Mechanistic research suggests that this novel treatment possesses various potential disease-modifying properties, such as suppression of nuclear factor kappa-B, interleukin 1β, tumor necrosis factor α, and cyclooxygenase-2. Accordingly, LithoLexal® Joint can be considered a disease-modifying adjunctive therapy (DMAT). LithoLexal® Joint monotherapy in patients with knee osteoarthritis has significantly improved symptoms and walking ability with higher efficacy than glucosamine. Preliminary evidence also suggests that LithoLexal® Joint may allow clinicians to reduce the dose of nonsteroidal anti-inflammatory drugs in osteoarthritic patients by up to 50%. In conclusion, the multi-mineral complex, LithoLexal® Joint, appears to be a promising candidate for DMAT of osteoarthritis, which may narrow the existing gap in clinical practice.

scholarly journals Targeted enhancement of the therapeutic window of L19-TNF by transient and selective inhibition of RIPK1-signaling cascade

2019 ◽  
Author(s):  
Sheila Dakhel ◽  
Tiziano Ongaro ◽  
Baptiste Gouyou ◽  
Mattia Matasci ◽  
Alessandra Villa ◽  
...  
Keyword(s):  
Small Molecule ◽  
Biological Effects ◽  
Clinical Stage ◽  
Selective Inhibition ◽  
Therapeutic Window ◽  
Tumor Bearing ◽  
Hemorrhagic Necrosis ◽  
Molecule Inhibitor ◽  
Selective Localization ◽  
Pro Inflammatory Cytokines

AbstractIntroductionCytokine-based products are gaining importance for cancer immunotherapy. L19-TNF is a clinical-stage antibody-cytokine fusion protein that selectively accumulates to tumors and displays potent anticancer activity in preclinical models. Here, we describe an innovative approach to transiently inhibit off-target toxicity of L19-TNF, while maintaining antitumor activity.MethodsGSK’963, a potent small molecule inhibitor of RIPK1, was tested in tumor-bearing mice for its ability to reduce acute toxicity associated with TNF signaling. The biological effects of L19-TNF on tumor cells, lymphocytes and tumor vessels were investigated with the aim to enable the administration of TNF doses, which would otherwise be lethal.ResultsTransient inhibition of RIPK1 allowed to increase the maximal tolerated dose of L19-TNF. The protective effect of GSK’963 did not affect the selective localization of the immunocytokine to tumors as evidenced by quantitative biodistribution analysis and allowed to reach high local TNF concentrations around tumor blood vessels, causing diffused vascular shutdown and hemorrhagic necrosis within the neoplastic mass.ConclusionsThe selective inhibition of RIPK1 with small molecule inhibitors can be used as a pharmaceutical tool to transiently mask TNF activity and improve the therapeutic window of TNF-based biopharmaceuticals. Similar approaches may be applicable to other pro-inflammatory cytokines.

scholarly journals P3-254: Exebryl-1: A novel small molecule currently in human clinical trials as a disease-modifying drug for the treatment of Alzheimer's disease

2009 ◽  
Vol 5 (4S_Part_14) ◽  
pp. P418-P418 ◽  
Author(s):  
Alan D. Snow ◽  
Joel Cummings ◽  
Thomas Lake ◽  
Qubai Hu ◽  
Luke Esposito ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Small Molecule ◽  
Disease Modifying

scholarly journals Targeting Lipocalin-2 in Inflammatory Breast Cancer Cells with Small Interference RNA and Small Molecule Inhibitors

2021 ◽  
Vol 22 (16) ◽  
pp. 8581
Author(s):  
Ginette S. Santiago-Sánchez ◽  
Ricardo Noriega-Rivera ◽  
Eliud Hernández-O’Farrill ◽  
Fatma Valiyeva ◽  
Blanca Quiñones-Diaz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Small Molecule ◽  
Inflammatory Breast Cancer ◽  
Small Molecule Inhibitors ◽  
Biological Effects ◽  
The United States ◽  
Migration And Invasion ◽  
Lipocalin 2 ◽  
Small Interference Rna

Inflammatory Breast Cancer (IBC) is an aggressive form of invasive breast cancer, highly metastatic, representing 2–4% of all breast cancer cases in the United States. Despite its rare nature, IBC is responsible for 7–10% of all breast cancer deaths, with a 5-year survival rate of 40%. Thus, targeted and effective therapies against IBC are needed. Here, we proposed Lipocalin-2 (LCN2)—a secreted glycoprotein aberrantly abundant in different cancers—as a plausible target for IBC. In immunoblotting, we observed higher LCN2 protein levels in IBC cells than non-IBC cells, where the LCN2 levels were almost undetectable. We assessed the biological effects of targeting LCN2 in IBC cells with small interference RNAs (siRNAs) and small molecule inhibitors. siRNA-mediated LCN2 silencing in IBC cells significantly reduced cell proliferation, viability, migration, and invasion. Furthermore, LCN2 silencing promoted apoptosis and arrested the cell cycle progression in the G0/G1 to S phase transition. We used in silico analysis with a library of 25,000 compounds to identify potential LCN2 inhibitors, and four out of sixteen selected compounds significantly decreased cell proliferation, cell viability, and the AKT phosphorylation levels in SUM149 cells. Moreover, ectopically expressing LCN2 MCF7 cells, treated with two potential LCN2 inhibitors (ZINC00784494 and ZINC00640089) showed a significant decrease in cell proliferation. Our findings suggest LCN2 as a promising target for IBC treatment using siRNA and small molecule inhibitors.

scholarly journals Small Molecule Drugs for Treatment of Alzheimer’s Diseases Developed on the Basis of Mechanistic Understanding of the Serotonin Receptors 4 and 6

2021 ◽  
Author(s):  
Charlotte Uldahl Jansen ◽  
Katrine M. Qvortrup
Keyword(s):  
Small Molecule ◽  
Serotonin Receptors ◽  
Medicinal Chemistry ◽  
Neurotransmitter System ◽  
Biological Targets ◽  
System A ◽  
Small Molecule Drugs ◽  
Promising Target ◽  
Disease Modifying ◽  
Number Of Publications

Alzheimer’s disease (AD) is the most common form of dementia affecting millions of people worldwide and currently, the only possible treatment is the use of symptomatic drugs. Therefore, there is a need for new and disease-modifying approaches. Among the numbers of biological targets which are today explored in order to prevent or limit the progression of AD, the modulation of serotonin receptors the subtype 4 and 6 receptors (5-HT4R and 5-HT6R) has received increasing attention and has become a promising target for improving cognition and limit the amyloid pathology through modulation of the neurotransmitter system. A large number of publications describing the development of ligands for these serotonin receptors have emerged, and their pharmaceutical potential is now quite evident. However, 5-HT4R and 5-HT6R functionality is much more complex than initially defined. This chapter describes recent advances in the understanding of this modulation as well as the medicinal chemistry efforts towards development of selective 5-HT4R or 5-HT6R ligands.

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