Breakthrough Science: Hypoxia-Inducible Factors, Oxygen Sensing, and Disorders of Hematopoiesis

Blood ◽  
2021 ◽  
Author(s):  
Gregg L. Semenza
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Gene Transcription ◽  
Small Molecule ◽  
Oxygen Sensing ◽  
Hypoxia Inducible Factors ◽  
Prolyl Hydroxylases ◽  
Improve Outcome ◽  
Transcription Activity ◽  
Genes Encoding

Hypoxia-inducible factors (HIF) were discovered as activators of erythropoietin gene transcription in response to reduced O2 availability. O2-dependent hydroxylation of HIFs on proline and asparagine residues regulates protein stability and transcription activity, respectively. Mutations in genes encoding components of the oxygen sensing pathway cause familial erythrocytosis. Several small molecule inhibitors of HIF prolyl hydroxylases are currently in clinical trials as erythropoiesis stimulating agents. HIFs are overexpressed in bone marrow neoplasms, and the development of HIF inhibitors may improve outcome in these disorders.

Pharmacologic Targeting of Hypoxia-Inducible Factors

2019 ◽  
Vol 59 (1) ◽  
pp. 379-403 ◽  
Author(s):  
Gregg L. Semenza
Keyword(s):  
Renal Cell Carcinoma ◽  
Clinical Trials ◽  
Cell Carcinoma ◽  
Small Molecule ◽  
Renal Cell ◽  
Phase Iii ◽  
Hypoxia Inducible Factors ◽  
Transcriptional Responses ◽  
Α Subunit ◽  
Α Subunits

Hypoxia-inducible factors (HIFs) control transcriptional responses to reduced O2availability. HIFs are heterodimeric proteins composed of an O2-regulated HIF-α subunit and a constitutively expressed HIF-1β subunit. HIF-α subunits are subject to prolyl hydroxylation, which targets the proteins for degradation under normoxic conditions. Small molecule prolyl hydroxylase inhibitors, which stabilize the HIF-α subunits and increase HIF-dependent expression of erythropoietin, are in phase III clinical trials for the treatment of anemia in patients with chronic kidney disease. HIFs contribute to the pathogenesis of many cancers, particularly the clear cell type of renal cell carcinoma in which loss of function of the von Hippel-Lindau tumor suppressor blocks HIF-2α degradation. A small molecule inhibitor that binds to HIF-2α and blocks dimerization with HIF-1β is in clinical trials for the treatment of renal cell carcinoma. Targeting HIFs for stabilization or inhibition may improve outcomes in diseases that are common causes of mortality in the US population.

Transcriptional Activity of TP53 and MDM2 in Chronically Exposed People at Later Time Points

2018 ◽  
pp. 33-39
Author(s):  
В. Никифоров ◽  
V. Nikiforov ◽  
А. Аклеев ◽  
A. Akleev
Keyword(s):  
Bone Marrow ◽  
Gene Transcription ◽  
Transcriptional Activity ◽  
Dose Range ◽  
Study Groups ◽  
Control Group ◽  
Mdm2 Gene ◽  
Red Bone Marrow ◽  
Transcription Activity ◽  
Accumulated Dose

Purpose: To study the levels of transcriptional activity of TP53 and MDM2 genes in the residents of the Techa riverside villages chronically exposed at a wide dose range. Material and methods: transcriptional activity of TP53 and MDM2 genes was assessed in 95 persons. The main study group included 80 people exposed to combined external and internal radiation (peripheral blood samples were taken 60–70 years after the beginning of chronic radiation exposure), mean accumulated dose to red bone marrow was 0.86 ± 0.08 Gy (doses varied in the range 0.1–3.65 Gy). The control group consisted of 15 people living in similar socio-economic conditions in the Southern Urals; the accumulated doses to red bone marrow did not exceed 0.07 Gy. Gene transcription activity profile was studied with real-time PCR assay. The data were analyzed using a comparative CT method with normalization to the “housekeeping” gene transcription in each sample. Statistical analysis was performed using the software PAST. Results and conclusion: In the course of the analysis we did not receive statistically significant differences between the study groups, but there was a tendency to a decrease in gene transcription in the group of exposed persons. The correlation analysis showed a weak negative dependence for TP53 and MDM2 genes, and this dependence was characterized not only by the accumulated dose value but was also associated with the age of the individuals under study. A tendency to a decrease in the transcription activity of the genes under study was noted when studying the effect of the dose. Statistically significant differences were shown for MDM2 gene in the group of individuals whose accumulated doses exceeded 2 Gy (p = 0.044). The analysis of age-peculiarities on gene transcription revealed a statistically significant decrease in TP53 gene transcription with increasing age of patients (p = 0.02). Non-radiation factors including smoking were also studied. The levels of gene transcription were compared between men and women of 2 main ethnicities (Bashkirs/Tartars and Slavs). Results of the study showed that neither sex nor ethnicity had any effect on the levels of TP53 and MDM2 gene transcription in the study groups. The effect of smoking on the activity of the genes under study was negligible.

Targeting p53-MDM2 Interaction Using Small Molecule Inhibitors and the Challenges Needed to be Addressed

2019 ◽  
Vol 20 (11) ◽  
pp. 1091-1111 ◽  
Author(s):  
Maryam Zanjirband ◽  
Soheila Rahgozar
Keyword(s):  
Clinical Trials ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Tp53 Gene ◽  
Therapeutic Agents ◽  
Negative Regulator ◽  
Mdm2 Protein ◽  
Independent Effects ◽  
Small Hydrophobic ◽  
Targeted Therapeutic

MDM2 protein is the core negative regulator of p53 that maintains the cellular levels of p53 at a low level in normal cells. Mutation of the TP53 gene accounts for 50% of all human cancers. In the remaining malignancies with wild-type TP53, p53 function is inhibited through other mechanisms. Recently, synthetic small molecule inhibitors have been developed which target a small hydrophobic pocket on MDM2 to which p53 normally binds. Given that MDM2-p53 antagonists have been undergoing clinical trials for different types of cancer, this review illustrates different aspects of these new cancer targeted therapeutic agents with the focus on the major advances in the field. It emphasizes on the p53 function, regulation of p53, targeting of the p53-MDM2 interaction for cancer therapy, and p53-dependent and -independent effects of inhibition of p53-MDM2 interaction. Then, representatives of small molecule MDM2-p53 binding antagonists are introduced with a focus on those entered into clinical trials. Furthermore, the review discusses the gene signatures in order to predict sensitivity to MDM2 antagonists, potential side effects and the reasons for the observed hematotoxicity, mechanisms of resistance to these drugs, their evaluation as monotherapy or in combination with conventional chemotherapy or with other targeted therapeutic agents. Finally, it highlights the certainly intriguing questions and challenges which would be addressed in future studies.

Repurposed Antiviral Drugs for the Treatment of COVID-19: Syntheses, Mechanism of Infection and Clinical Trials

2020 ◽  
Vol 21 ◽  
Author(s):  
Subha Sankar Paul ◽  
Goutam Biswas
Keyword(s):  
Public Health ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Small Molecule ◽  
Mode Of Action ◽  
Antiviral Drugs ◽  
Public Health Emergency ◽  
Advanced Stage ◽  
Clinical Trial Results

: COVID-19 is a public health emergency of international concern. Although, considerable knowledge has been acquired with time about the viral mechanism of infection and mode of replication, yet no specific drugs or vaccines have been discovered against SARS-CoV-2, till date. There are few small molecule antiviral drugs like Remdesivir and Favipiravir which have shown promising results in different advanced stage of clinical trials. Chloroquinine, Hydroxychloroquine, and Lopinavir-Ritonavir combination, although initially was hypothesized to be effective against SARS-CoV-2, are now discontinued from the solidarity clinical trials. This review provides a brief description of their chemical syntheses along with their mode of action and clinical trial results available in Google and different peer reviewed journals till 24th October 2020.

scholarly journals Toxicity of Combinations of Kinase Pathway Inhibitors to Normal Human Cells in a Three-Dimensional Culture

2021 ◽  
pp. 247263032110088
Author(s):  
Pouria Rafsanjani Nejad ◽  
Pradip Shahi Thakuri ◽  
Sunil Singh ◽  
Astha Lamichhane ◽  
Jacob Heiss ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Protein Kinase ◽  
Single Agent ◽  
Three Dimensional ◽  
Drug Combinations ◽  
Toxic Effects ◽  
Combination Drug ◽  
Normal Cells ◽  
Colon Cells

Resistance to single-agent chemotherapy and molecularly targeted drugs prevents sustained efficacy of treatments. To address this challenge, combination drug treatments have been used to improve outcomes for patients. Potential toxicity of combination treatments is a major concern, however, and has led to the failure of several clinical trials in different cancers. The use of cell-based models of normal tissues in preclinical studies enables testing and identifying toxic effects of drug combinations and facilitates an informed decision-making process for advancing the treatments to animal models and clinical trials. Recently, we established that combinations of molecular inhibitors of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase–protein kinase B (PI3K/Akt) pathways effectively and synergistically inhibit growth of BRAFmut and KRASmut colorectal tumor spheroids by blocking feedback signaling of downstream kinase pathways. These pathways are important for cell proliferation, however, and their simultaneous inhibition may cause toxicity to normal cells. We used a cellular spheroid model to study toxicities of drug combinations to human bone marrow and colon. Our results indicated that MAPK and PI3K/Akt inhibitors used simultaneously were only moderately toxic to bone marrow cells but significantly more toxic to colon cells. Our molecular analysis of proliferative cell activities and housekeeping proteins further corroborated these results. Overall, our approach to identify toxic effects of combinations of cancer drugs to normal cells in three-dimensional cultures will facilitate more informed treatment selections for subsequent animal studies.

scholarly journals Increasing the Power of Polyphenols through Nanoencapsulation for Adjuvant Therapy against Cardiovascular Diseases

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4621
Author(s):  
Lucileno Rodrigues Trindade ◽  
Davi Vieira Teixeira da da Silva ◽  
Diego dos Santos Baião ◽  
Vania Margaret Flosi Paschoalin
Keyword(s):  
Clinical Trials ◽  
Cardiovascular Diseases ◽  
Adjuvant Therapy ◽  
Vascular Diseases ◽  
Ppar Γ ◽  
Epidemiological Surveys ◽  
Genes Encoding ◽  
And Oxidative Stress ◽  
Gradual Release ◽  
Inflammatory Action

Polyphenols play a therapeutic role in vascular diseases, acting in inherent illness-associate conditions such as inflammation, diabetes, dyslipidemia, hypertension, and oxidative stress, as demonstrated by clinical trials and epidemiological surveys. The main polyphenol cardioprotective mechanisms rely on increased nitric oxide, decreased asymmetric dimethylarginine levels, upregulation of genes encoding antioxidant enzymes via the Nrf2-ARE pathway and anti-inflammatory action through the redox-sensitive transcription factor NF-κB and PPAR-γ receptor. However, poor polyphenol bioavailability and extensive metabolization restrict their applicability. Polyphenols carried by nanoparticles circumvent these limitations providing controlled release and better solubility, chemical protection, and target achievement. Nano-encapsulate polyphenols loaded in food grade polymers and lipids appear to be safe, gaining resistance in the enteric route for intestinal absorption, in which the mucoadhesiveness ensures their increased uptake, achieving high systemic levels in non-metabolized forms. Nano-capsules confer a gradual release to these compounds, as well as longer half-lives and cell and whole organism permanence, reinforcing their effectiveness, as demonstrated in pre-clinical trials, enabling their application as an adjuvant therapy against cardiovascular diseases. Polyphenol entrapment in nanoparticles should be encouraged in nutraceutical manufacturing for the fortification of foods and beverages. This study discusses pre-clinical trials evaluating how nano-encapsulate polyphenols following oral administration can aid in cardiovascular performance.

P2-310: Exebryl-1: A novel small-molecule drug that markedly reduces amyloid plaque load and improves memory, enters human clinical trials

2008 ◽  
Vol 4 ◽  
pp. T463-T463 ◽  
Author(s):  
Alan D. Snow ◽  
Joel A. Cummings ◽  
Thomas P. Lake ◽  
Luke A. Esposito ◽  
F. Michael Hudson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Small Molecule ◽  
Amyloid Plaque ◽  
Small Molecule Drug ◽  
Plaque Load

scholarly journals Targeted Tumor Therapy Remixed—An Update on the Use of Small-Molecule Drugs in Combination Therapies

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 155 ◽  
Author(s):  
Martina Gatzka
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Small Molecule ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Therapy ◽  
Metabolic Reprogramming ◽  
Comprehensive Overview ◽  
Small Molecule Drugs ◽  
Mutational Status

Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies. Depending on the mutational status, BRAF and MEK inhibitor combinations or immune checkpoint inhibitors are current first-line treatments for metastatic melanoma. However, despite great improvements of survival rates limitations due to tumor heterogeneity, primary and acquired therapy resistance, immune evasion, and economical considerations will need to be overcome. Accordingly, ongoing clinical trials explore the individualized use of small-molecule drugs in new targeted therapy combinations based on patient parameters and tumor biopsies. With focus on melanoma therapy this review aims at providing a comprehensive overview of such novel alternative and combinational therapy strategies currently emerging from basic research. The molecular principles and drug classes that may hold promise for improved tumor therapy combination regimens including kinase inhibition, induction of apoptosis, DNA-damage response inhibition, epigenetic reprogramming, telomerase inhibition, redox modulation, metabolic reprogramming, proteasome inhibition, cancer stem cell transdifferentiation, immune cell signaling modulation, and others, are explained in brief. In addition, relevant targeted therapy combinations in current clinical trials and individualized treatment strategies are highlighted.

scholarly journals The Use of Endothelial Progenitor Cells for the Regeneration of Musculoskeletal and Neural Tissues

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Naosuke Kamei ◽  
Kivanc Atesok ◽  
Mitsuo Ochi
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Endothelial Cells ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Tissue Repair ◽  
Cell Populations ◽  
Neural Tissues ◽  
Cell Source ◽  
Stem Cell Populations

Endothelial progenitor cells (EPCs) derived from bone marrow and blood can differentiate into endothelial cells and promote neovascularization. In addition, EPCs are a promising cell source for the repair of various types of vascularized tissues and have been used in animal experiments and clinical trials for tissue repair. In this review, we focused on the kinetics of endogenous EPCs during tissue repair and the application of EPCs or stem cell populations containing EPCs for tissue regeneration in musculoskeletal and neural tissues including the bone, skeletal muscle, ligaments, spinal cord, and peripheral nerves. EPCs can be mobilized from bone marrow and recruited to injured tissue to contribute to neovascularization and tissue repair. In addition, EPCs or stem cell populations containing EPCs promote neovascularization and tissue repair through their differentiation to endothelial cells or tissue-specific cells, the upregulation of growth factors, and the induction and activation of endogenous stem cells. Human peripheral blood CD34(+) cells containing EPCs have been used in clinical trials of bone repair. Thus, EPCs are a promising cell source for the treatment of musculoskeletal and neural tissue injury.

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