scholarly journals Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway

2020 ◽  
Vol 13 (7) ◽  
pp. 140
Author(s):  
Sarah Baudet ◽  
Johann Bécret ◽  
Xavier Nicol
Keyword(s):  
Hepatocellular Carcinoma ◽  
Small Molecules ◽  
Therapeutic Strategies ◽  
Signaling Cascade ◽  
Molecular Tools ◽  
Pathological Conditions ◽  
Wide Range ◽  
Key Players ◽  
Direct Targeting ◽  
Stem Cell Niches

Erythropoietin-producing hepatocellular carcinoma A (EphA) receptors and their ephrin-A ligands are key players of developmental events shaping the mature organism. Their expression is mostly restricted to stem cell niches in adults but is reactivated in pathological conditions including lesions in the heart, lung, or nervous system. They are also often misregulated in tumors. A wide range of molecular tools enabling the manipulation of the ephrin-A:EphA system are available, ranging from small molecules to peptides and genetically-encoded strategies. Their mechanism is either direct, targeting EphA receptors, or indirect through the modification of intracellular downstream pathways. Approaches enabling manipulation of ephrin-A:EphA forward signaling for the dissection of its signaling cascade, the investigation of its physiological roles or the development of therapeutic strategies are summarized here.

scholarly journals Integration of Different “-omics” Technologies Identifies Inhibition of the IGF1R-Akt-mTOR Signaling Cascade Involved in the Cytotoxic Effect of Shikonin against Leukemia Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Benjamin Wiench ◽  
Yet-Ran Chen ◽  
Malte Paulsen ◽  
Rebecca Hamm ◽  
Sven Schröder ◽  
...  
Keyword(s):  
Hematological Malignancies ◽  
Cellular Mechanism ◽  
Mtor Signaling ◽  
Leukemia Cells ◽  
Signaling Cascade ◽  
Chinese Medicinal Herb ◽  
Dimethyl Labeling ◽  
Wide Range ◽  
Direct Targeting ◽  
Therapy Success

Hematological malignancies frequently have a poor prognosis and often remain incurable. Drug resistance, severe side effects, and relapse are major problems of currently used drugs, and new candidate compounds are required for improvement of therapy success. The naphthoquinone shikonin derived from the Chinese medicinal herb,Lithospermum erythrorhizon, is a promising candidate for the next generation of chemotherapy. The basal cellular mechanism of shikonin is the direct targeting of mitochondria. Cytotoxicity screenings showed that the compound is particularly effective against leukemia cells suggesting an additional cellular mechanism. mRNA and miRNA microarrays were used to analyze changes in gene expression in leukemia cells after shikonin treatment and combined with stable-isotope dimethyl labeling for quantitative proteomics. The integration of bioinformatics and the three “-omics” assays showed that the PI3K-Akt-mTOR pathway was affected by shikonin. Deregulations of this pathway are frequently associated with cancerogenesis, especially in a wide range of hematological malignancies. The effect on the PI3K-Akt-mTOR axis was validated by demonstrating a decreased phosphorylation of Akt and a direct inhibition of the IGF1R kinase activity after shikonin treatment. Our results indicate that inhibiting the IGF1R-Akt-mTOR signaling cascade is a new cellular mechanism of shikonin strengthening its potential for the treatment of hematological malignancies.

scholarly journals Chronic pancreatitis in children: between gastroenterologist and surgeon

2020 ◽  
pp. 84-95
Author(s):  
B. O. Kulevich ◽  
A. Yu. Razumovsky ◽  
A. N. Smirnov ◽  
V. V. Kholostova ◽  
A. I. Khavkin
Keyword(s):  
Small Intestine ◽  
Chronic Pancreatitis ◽  
Literature Review ◽  
Therapeutic Strategies ◽  
Food Ingredients ◽  
Digestive Process ◽  
Pathological Conditions ◽  
Wide Range

The pancreas is an organ that plays a key role in the digestive process, preparing food ingredients such as proteins, fats and carbohydrates for adequate absorption in the small intestine. Today, a wide range of pathological conditions is known in which the tissue of the pancreas is affected and its functions are lost. The literature review examined various diseases that phenotypically manifest as pancreatitis, as well as various diagnostic and therapeutic strategies.

scholarly journals Therapeutic Implications of TGFβ in Cancer Treatment: A Systematic Review

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 379
Author(s):  
Verónica Gómez-Gil
Keyword(s):  
Cancer Treatment ◽  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Therapeutic Strategies ◽  
Tumor Promoter ◽  
Signaling Cascade ◽  
Therapeutic Implications ◽  
Wide Range ◽  
Signaling Receptors

Transforming growth factor β (TGFβ) is a pleiotropic cytokine that participates in a wide range of biological functions. The alterations in the expression levels of this factor, or the deregulation of its signaling cascade, can lead to different pathologies, including cancer. A great variety of therapeutic strategies targeting TGFβ, or the members included in its signaling pathway, are currently being researched in cancer treatment. However, the dual role of TGFβ, as a tumor suppressor or a tumor-promoter, together with its crosstalk with other signaling pathways, has hampered the development of safe and effective treatments aimed at halting the cancer progression. This systematic literature review aims to provide insight into the different approaches available to regulate TGFβ and/or the molecules involved in its synthesis, activation, or signaling, as a cancer treatment. The therapeutic strategies most commonly investigated include antisense oligonucleotides, which prevent TGFβ synthesis, to molecules that block the interaction between TGFβ and its signaling receptors, together with inhibitors of the TGFβ signaling cascade-effectors. The effectiveness and possible complications of the different potential therapies available are also discussed.

Understanding Conformational Entropy in Small Molecules

2020 ◽  
Author(s):  
Lucian Chan ◽  
Garrett Morris ◽  
Geoffrey Hutchison
Keyword(s):  
Small Molecules ◽  
Degrees Of Freedom ◽  
Absolute Error ◽  
Low Energy ◽  
Standard Entropy ◽  
Free Energies ◽  
Conformational Entropy ◽  
Wide Range ◽  
High Degree ◽  
Empirical Corrections

The calculation of the entropy of flexible molecules can be challenging, since the number of possible conformers grows exponentially with molecule size and many low-energy conformers may be thermally accessible. Different methods have been proposed to approximate the contribution of conformational entropy to the molecular standard entropy, including performing thermochemistry calculations with all possible stable conformations, and developing empirical corrections from experimental data. We have performed conformer sampling on over 120,000 small molecules generating some 12 million conformers, to develop models to predict conformational entropy across a wide range of molecules. Using insight into the nature of conformational disorder, our cross-validated physically-motivated statistical model can outperform common machine learning and deep learning methods, with a mean absolute error ≈4.8 J/mol•K, or under 0.4 kcal/mol at 300 K. Beyond predicting molecular entropies and free energies, the model implies a high degree of correlation between torsions in most molecules, often as- sumed to be independent. While individual dihedral rotations may have low energetic barriers, the shape and chemical functionality of most molecules necessarily correlate their torsional degrees of freedom, and hence restrict the number of low-energy conformations immensely. Our simple models capture these correlations, and advance our understanding of small molecule conformational entropy.

scholarly journals Anti-Biofilm Molecules Targeting Functional Amyloids

Antibiotics ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 795
Author(s):  
Leticia Matilla-Cuenca ◽  
Alejandro Toledo-Arana ◽  
Jaione Valle
Keyword(s):  
Biofilm Formation ◽  
Therapeutic Strategy ◽  
Research Area ◽  
Therapeutic Strategies ◽  
Structural Components ◽  
Significant Issue ◽  
Wide Range ◽  
Effective Therapeutic Strategy ◽  
Functional Amyloids ◽  
Biofilm Matrix

The choice of an effective therapeutic strategy in the treatment of biofilm-related infections is a significant issue. Amyloids, which have been historically related to human diseases, are now considered to be prevailing structural components of the biofilm matrix in a wide range of bacteria. This assumption creates the potential for an exciting research area, in which functional amyloids are considered to be attractive targets for drug development to dissemble biofilm structures. The present review describes the best-characterized bacterial functional amyloids and focuses on anti-biofilm agents that target intrinsic and facultative amyloids. This study provides a better understanding of the different modes of actions of the anti-amyloid molecules to inhibit biofilm formation. This information can be further exploited to improve the therapeutic strategies to combat biofilm-related infections.

Harnessing methylation and AdoMet-utilising enzymes for selective modification in cascade reactions

2021 ◽  
Author(s):  
Freideriki Michailidou ◽  
Andrea Rentmeister
Keyword(s):  
Natural Products ◽  
Small Molecules ◽  
Cascade Reactions ◽  
Fine Tuning ◽  
Wide Range

Enzyme-mediated methylation is a very important reaction in nature, yielding a wide range of modified natural products, diversifying small molecules and fine-tuning the activity of biomacromolecules. The field has attracted...

scholarly journals When the Balance Tips: Dysregulation of Mitochondrial Dynamics as a Culprit in Disease

2021 ◽  
Vol 22 (9) ◽  
pp. 4617
Author(s):  
Styliana Kyriakoudi ◽  
Anthi Drousiotou ◽  
Petros P. Petrou
Keyword(s):  
Insulin Resistance ◽  
Mitochondrial Function ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Disease Development ◽  
Pathological Conditions ◽  
Wide Range

Mitochondria are dynamic organelles, the morphology of which is tightly linked to their functions. The interplay between the coordinated events of fusion and fission that are collectively described as mitochondrial dynamics regulates mitochondrial morphology and adjusts mitochondrial function. Over the last few years, accruing evidence established a connection between dysregulated mitochondrial dynamics and disease development and progression. Defects in key components of the machinery mediating mitochondrial fusion and fission have been linked to a wide range of pathological conditions, such as insulin resistance and obesity, neurodegenerative diseases and cancer. Here, we provide an update on the molecular mechanisms promoting mitochondrial fusion and fission in mammals and discuss the emerging association of disturbed mitochondrial dynamics with human disease.

scholarly journals Intermedin facilitates hepatocellular carcinoma cell survival and invasion via ERK1/2-EGR1/DDIT3 signaling cascade

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fei Xiao ◽  
Hongyu Li ◽  
Zhongxue Feng ◽  
Luping Huang ◽  
Lingmiao Kong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Er Stress ◽  
Cell Survival ◽  
Vascular Remodeling ◽  
Therapeutic Potential ◽  
Blood Perfusion ◽  
Signaling Cascade ◽  
Apoptotic Pathway ◽  
High Level ◽  
Hcc Cells

AbstractAs one of the most malignant cancer types, hepatocellular carcinoma (HCC) is highly invasive and capable of metastasizing to distant organs. Intermedin (IMD), an endogenous peptide belonging to the calcitonin family, has been suggested playing important roles in cancer cell survival and invasion, including in HCC. However, how IMD affects the behavior of HCC cells and the underlying mechanisms have not been fully elucidated. Here, we show that IMD maintains an important homeostatic state by activating the ERK1/2-EGR1 (early growth response 1) signaling cascade, through which HCC cells acquire a highly invasive ability via significantly enhanced filopodia formation. The inhibition of IMD blocks the phosphorylation of ERK1/2, resulting in EGR1 downregulation and endoplasmic reticulum stress (ER) stress, which is evidenced by the upregulation of ER stress marker DDIT3 (DNA damage-inducible transcript 3). The high level of DDIT3 induces HCC cells into an ER-stress related apoptotic pathway. Along with our previous finding that IMD plays critical roles in the vascular remodeling process that improves tumor blood perfusion, IMD may facilitate the acquisition of increased invasive abilities and a survival benefit by HCC cells, and it is easier for HCC cells to obtain blood supply via the vascular remodeling activities of IMD. According to these results, blockade of IMD activity may have therapeutic potential in the treatment of HCC.

scholarly journals Mini-review: antibody therapeutics targeting G protein-coupled receptors and ion channels

2020 ◽  
Vol 3 (4) ◽  
pp. 257-264
Author(s):  
Catherine J Hutchings
Keyword(s):  
Ion Channels ◽  
Research And Development ◽  
Small Molecules ◽  
G Protein ◽  
Clinical Studies ◽  
G Protein Coupled Receptors ◽  
Protein Targets ◽  
Antibody Therapeutics ◽  
Wide Range ◽  
G Protein Coupled

Abstract Antibodies are now well established as therapeutics with many additional advantages over small molecules and peptides relative to their selectivity, bioavailability, half-life and effector function. Major classes of membrane-associated protein targets include G protein-coupled receptors (GPCRs) and ion channels that are linked to a wide range of disease indications across all therapeutic areas. This mini-review summarizes the antibody target landscape for both GPCRs and ion channels as well as current progress in the respective research and development pipelines with some example case studies highlighted from clinical studies, including those being evaluated for the treatment of symptoms in COVID-19 infection.

scholarly journals COVID-19: Unmasking Emerging SARS-CoV-2 Variants, Vaccines and Therapeutic Strategies

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 993
Author(s):  
Renuka Raman ◽  
Krishna J. Patel ◽  
Kishu Ranjan
Keyword(s):  
Immune Response ◽  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Small Molecules ◽  
Viral Vector ◽  
Therapeutic Strategies ◽  
Convincing Evidence ◽  
Plasma Therapy ◽  
Therapeutic Monoclonal Antibodies ◽  
Increased Susceptibility

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, which has been a topic of major concern for global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence of several SARS-CoV-2 variants viz. B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta), which show increased transmissibility and resistance towards vaccines and therapies. Importantly, there is convincing evidence of increased susceptibility to SARS-CoV-2 infection among individuals with dysregulated immune response and comorbidities. Herein, we provide a comprehensive perspective regarding vulnerability of SARS-CoV-2 infection in patients with underlying medical comorbidities. We discuss ongoing vaccine (mRNA, protein-based, viral vector-based, etc.) and therapeutic (monoclonal antibodies, small molecules, plasma therapy, etc.) modalities designed to curb the COVID-19 pandemic. We also discuss in detail, the challenges posed by different SARS-CoV-2 variants of concern (VOC) identified across the globe and their effects on therapeutic and prophylactic interventions.

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