scholarly journals Lysine Acetylation, Cancer Hallmarks and Emerging Onco-Therapeutic Opportunities

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 346
Author(s):  
Meilan Hu ◽  
Fule He ◽  
Erik W. Thompson ◽  
Kostya (Ken) Ostrikov ◽  
Xiaofeng Dai
Keyword(s):  
Transcriptional Regulation ◽  
Metabolic Disorders ◽  
Cell Metabolism ◽  
Hdac Inhibitors ◽  
Therapeutic Strategies ◽  
Lysine Acetylation ◽  
Primary Cancer ◽  
Cancer Hallmarks ◽  
Structure Activity ◽  
Regulatory Systems

Acetylation, a reversible epigenetic process, is implicated in many critical cellular regulatory systems including transcriptional regulation, protein structure, activity, stability, and localization. Lysine acetylation is the most prevalent and intensively investigated among the diverse acetylation forms. Owing to the intrinsic connections of acetylation with cell metabolism, acetylation has been associated with metabolic disorders including cancers. Yet, relatively little has been reported on the features of acetylation against the cancer hallmarks, even though this knowledge may help identify appropriate therapeutic strategies or combinatorial modalities for the effective treatment and resolution of malignancies. By examining the available data related to the efficacy of lysine acetylation against tumor cells and elaborating the primary cancer hallmarks and the associated mechanisms to target the specific hallmarks, this review identifies the intrinsic connections between lysine acetylation and cancer hallmarks and proposes novel modalities that can be combined with HDAC inhibitors for cancer treatment with higher efficacy and minimum adverse effects.

Development and Validation of High-Content Analysis for Screening HDAC6-Selective Inhibitors

2021 ◽  
pp. 247255522110024
Author(s):  
Yunhong Nong ◽  
Yanyan Hou ◽  
Yuting Pu ◽  
Si Li ◽  
Yan Lan
Keyword(s):  
Content Analysis ◽  
Adverse Effects ◽  
Hdac Inhibitors ◽  
Histone H3 ◽  
Class I ◽  
Cell Seeding ◽  
Clinical Evaluations ◽  
Structure Activity ◽  
High Content Analysis ◽  
Development And Validation

Throughout recent decades, histone deacetylase (HDAC) inhibitors have shown encouraging potential in cancer treatment, and several pan-HDAC inhibitors have been approved for treating malignant cancers. Numerous adverse effects of pan-HDAC inhibitors have been reported, however, during preclinical and clinical evaluations. To avoid undesirable responses, an increasing number of investigations are focusing on the development of isotype-selective HDAC inhibitors. In this study, we present an effective and quantitative cellular assay using high-content analysis (HCA) to determine compounds’ inhibition of the activity of HDAC6 and Class I HDAC isoforms, by detecting the acetylation of their corresponding substrates (i.e., α-tubulin and histone H3). Several conditions that are critical for HCA assays, such as cell seeding number, fixation and permeabilization reagent, and antibody dilution, have been fully validated in this study. We used selective HDAC6 inhibitors and inhibitors targeting different HDAC isoforms to optimize and validate the capability of the HCA assay. The results indicated that the HCA assay is a robust assay for quantifying compounds’ selectivity of HDAC6 and Class I HDAC isoforms in cells. Moreover, we screened a panel of compounds for HDAC6 selectivity using this HCA assay, which provided valuable information for the structure–activity relationship (SAR). In summary, our results suggest that the HCA assay is a powerful tool for screening selective HDAC6 inhibitors.

scholarly journals Targeting Mitochondria as Therapeutic Strategy for Metabolic Disorders

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Daniela Sorriento ◽  
Antonietta Valeria Pascale ◽  
Rosa Finelli ◽  
Anna Lisa Carillo ◽  
Roberto Annunziata ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Mitochondrial Dysfunction ◽  
Small Molecules ◽  
Metabolic Disorders ◽  
Therapeutic Strategy ◽  
Cell Metabolism ◽  
Therapeutic Interventions ◽  
Mtdna Mutations ◽  
Pathological Conditions ◽  
Mitochondria Targeting

Mitochondria are critical regulator of cell metabolism; thus, mitochondrial dysfunction is associated with many metabolic disorders. Defects in oxidative phosphorylation, ROS production, or mtDNA mutations are the main causes of mitochondrial dysfunction in many pathological conditions such as IR/diabetes, metabolic syndrome, cardiovascular diseases, and cancer. Thus, targeting mitochondria has been proposed as therapeutic approach for these conditions, leading to the development of small molecules to be tested in the clinical scenario. Here we discuss therapeutic interventions to treat mitochondrial dysfunction associated with two major metabolic disorders, metabolic syndrome, and cancer. Finally, novel mechanisms of regulation of mitochondrial function are discussed, which open new scenarios for mitochondria targeting.

Plant-Derived Natural Compounds for the treatment of Amyotrophic Lateral Sclerosis: An Update

2021 ◽  
Vol 19 ◽  
Author(s):  
Roohi Mohi-ud-din ◽  
Reyaz Hassan Mir ◽  
Abdul Jalil Shah ◽  
Saba Sabreen ◽  
Taha Umair Wani ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Adverse Effects ◽  
Therapeutic Strategies ◽  
Structure Activity Relationships ◽  
Complex Genetics ◽  
Natural Agents ◽  
Structure Activity ◽  
Preclinical And Clinical Studies ◽  
Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease (MND) that typically causes death within 3-5 years after diagnosis. Regardless of the substantial scientific knowledge accrued from more than a century ago, truly effective therapeutic strategies remain distant. Various conventional drugs are being used but are having several adverse effects. Objective/Aim: The current study aims to thoroughly review plant-derived compounds with well-defined ALS activities and their structure-activity relationships. Moreover, the review also focuses on complex genetics, clinical trials, and the use of natural products that might decrypt the future and novel therapeutics in ALS. Methods: The collection of data for the compilation of this review work was searched in PubMed Scopus, Google Scholar, and Science Direct. Results: Results showed that phytochemicals like-Ginkgolides, Protopanaxatriol, Genistein, epigallocatechingallate, resveratrol, cassoside, and others possess Amyotrophic lateral sclerosis (ALS) activity by various mechanisms. Conclusion: These plant-derived compounds may be considered as supplements to conventional (ALS). Moreover, further preclinical and clinical studies are required to understand the structure-activity relationships, metabolism, absorption, and mechanisms of plant-derived natural agents.

scholarly journals Structure–Activity Relationships of the Tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 at the Mouse Melanocortin Receptors: Modification at the (pI)DPhe Position Leads to mMC3R Versus mMC4R Selective Ligands

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1463
Author(s):  
Katherine N. Schlasner ◽  
Mark D. Ericson ◽  
Skye R. Doering ◽  
Katie T. Freeman ◽  
Mary Weinrich ◽  
...  
Keyword(s):  
Food Intake ◽  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Biological Pathways ◽  
Melanocortin Receptors ◽  
Lead Compounds ◽  
Structure Activity ◽  
Selective Ligands ◽  
Selective Agonists

The five melanocortin receptors (MC1R–MC5R) are involved in numerous biological pathways, including steroidogenesis, pigmentation, and food intake. In particular, MC3R and MC4R knockout mice suggest that the MC3R and MC4R regulate energy homeostasis in a non-redundant manner. While MC4R-selective agonists have been utilized as appetite modulating agents, the lack of MC3R-selective agonists has impeded progress in modulating this receptor in vivo. In this study, the (pI)DPhe position of the tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 (an MC3R agonist/MC4R antagonist ligand) was investigated with a library of 12 compounds. The compounds in this library were found to have higher agonist efficacy and potency at the mouse (m) MC3R compared to the MC4R, indicating that the Arg-DPhe motif preferentially activates the mMC3R over the mMC4R. This observation may be used in the design of new MC3R-selective ligands, leading to novel probe and therapeutic lead compounds that will be useful for treating metabolic disorders.

scholarly journals Sestrins as modulators of aging processes and diseases related to age

2021 ◽  
Vol 75 ◽  
pp. 437-447
Author(s):  
Bożena Gabryel ◽  
Roksana Duszkiewicz
Keyword(s):  
Metabolic Disorders ◽  
Cell Metabolism ◽  
Genotoxic Stress ◽  
Protective Role ◽  
Mechanisms Of Action ◽  
Oxygen Species ◽  
Age Related ◽  
Regulate Cell Growth ◽  
Growth Metabolism ◽  
Amp Activated Protein Kinase

Sestrins are highly conserved proteins that regulate cell growth, metabolism, survival and proliferation under oxidative stress, genotoxic stress, hypoxia or endoplasmic reticulum stress. Sestrins affect cell signaling by inhibiting the production of reactive oxygen species, activating the AMP-activated protein kinase (AMPK), inhibiting the mTOR pathway and acting as a positive regulator of autophagy. Therefore, their protective role against cancer, metabolic disorders, cardiovascular diseases and neurodegeneration is increasingly being postulated. The article describes the mechanisms of action of sestrins and their meaning in aging and age-related diseases. The latest studies indicating their physiological significance and role in key signaling pathways controlling the cell metabolism and survival under stress conditions were also discussed.

scholarly journals Lipid Metabolism Profiles in Rheumatic Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Weilin Chen ◽  
Qi Wang ◽  
Bin Zhou ◽  
Lihua Zhang ◽  
Honglin Zhu
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Rheumatic Diseases ◽  
Fatty Acid Metabolism ◽  
High Mortality ◽  
Acid Metabolism ◽  
Cell Metabolism ◽  
Therapeutic Strategies ◽  
Clinical Applications ◽  
Multiple Organs

Rheumatic diseases are a group of chronic autoimmune disorders that involve multiple organs or systems and have high mortality. The mechanisms of these diseases are still ill-defined, and targeted therapeutic strategies are still challenging for physicians. Recent research indicates that cell metabolism plays important roles in the pathogenesis of rheumatic diseases. In this review, we mainly focus on lipid metabolism profiles (dyslipidaemia, fatty acid metabolism) and mechanisms in rheumatic diseases and discuss potential clinical applications based on lipid metabolism profiles.

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