scholarly journals Marine Ligands of the Pregnane X Receptor (PXR): An Overview

Marine Drugs ◽  
2019 ◽  
Vol 17 (10) ◽  
pp. 554 ◽  
Author(s):  
Alejandro Carazo ◽  
Přemysl Mladěnka ◽  
Petr Pávek
Keyword(s):  
Transcription Factor ◽  
Therapeutic Potential ◽  
Pregnane X Receptor ◽  
Natural Compounds ◽  
Marine Organisms ◽  
Antineoplastic Drug ◽  
Physiological Processes ◽  
Novel Drugs ◽  
Endogenous Compounds ◽  
Sea Squirts

Pregnane X Receptor (PXR) is a ligand-activated transcription factor which binds many structurally different molecules. The receptor is able to regulate the expression of a wide array of genes and is involved in cancer and different key physiological processes such as the metabolism of drugs/xenobiotics and endogenous compounds including lipids and carbohydrates, and inflammation. Algae, sponges, sea squirts, and other marine organisms are some of the species from which structurally new molecules have been isolated that have been subsequently identified in recent decades as ligands for PXR. The therapeutic potential of these natural compounds is promising in different areas and has recently resulted in the registration of trabectedin by the FDA as a novel antineoplastic drug. Apart from being potentially novel drugs, these compounds can also serve as models for the development of new molecules with improved activity. The aim of this review is to succinctly summarize the currently known natural molecules isolated from marine organisms with a proven ability to interact with PXR.

Therapeutic Potential of Agonists and Antagonists of A1, A2a, A2b and A3 Adenosine Receptors

2019 ◽  
Vol 25 (26) ◽  
pp. 2892-2905 ◽  
Author(s):  
Sumit Jamwal ◽  
Ashish Mittal ◽  
Puneet Kumar ◽  
Dana M. Alhayani ◽  
Amal Al-Aboudi
Keyword(s):  
Nervous System ◽  
Therapeutic Potential ◽  
The Body ◽  
Membrane Receptors ◽  
Physiological Importance ◽  
Physiological Processes ◽  
Central Nervous Systems ◽  
Energy Consuming ◽  
Metabolic Dysfunctions ◽  
G Protein Coupled

Adenosine is a naturally occurring nucleoside and an essential component of the energy production and utilization systems of the body. Adenosine is formed by the degradation of adenosine-triphosphate (ATP) during energy-consuming processes. Adenosine regulates numerous physiological processes through activation of four subtypes of G-protein coupled membrane receptors viz. A1, A2A, A2B and A3. Its physiological importance depends on the affinity of these receptors and the extracellular concentrations reached. ATP acts as a neurotransmitter in both peripheral and central nervous systems. In the peripheral nervous system, ATP is involved in chemical transmission in sensory and autonomic ganglia, whereas in central nervous system, ATP, released from synaptic terminals, induces fast excitatory postsynaptic currents. ATP provides the energetics for all muscle movements, heart beats, nerve signals and chemical reactions inside the body. Adenosine has been traditionally considered an inhibitor of neuronal activity and a regulator of cerebral blood flow. Since adenosine is neuroprotective against excitotoxic and metabolic dysfunctions observed in neurological and ocular diseases, the search for adenosinerelated drugs regulating adenosine transporters and receptors can be important for advancement of therapeutic strategies against these diseases. This review will summarize the therapeutic potential and recent SAR and pharmacology of adenosine and its receptor agonists and antagonists.

GDNF Therapy: Can We Make It Work?

2021 ◽  
pp. 1-4
Author(s):  
Anders Björklund
Keyword(s):  
Gene Therapy ◽  
Transcription Factor ◽  
Signaling Pathway ◽  
Therapeutic Potential ◽  
Threshold Level ◽  
New Findings ◽  
The Status ◽  
Interesting Discussion ◽  
Postmortem Studies ◽  
Made In

In two recent postmortem studies, Jeffrey Kordower and colleagues report new findings that open up for an interesting discussion on the status of GDNF/NRTN signaling in patients with Parkinson’s disease (PD), adding an interesting perspective on the, admittedly very limited, signs of restorative effects previously seen in GDNF/NRTN-treated patients. Their new findings show that the level of the GDNF signaling receptor Ret is overall reduced by about 65% relative to non-PD controls, and most severely, up to 80%, in nigral neurons containing α-synuclein inclusions, accompanied by impaired signaling downstream of the Ret receptor. Notably, however, the vast majority of the remaining nigral neurons retained a low level of Ret expression, and hence a threshold level of signaling. Further observations made in two patients who had received AAV-NRTN gene therapy 8–10 years earlier suggest the intriguing possibility that NRTN is able to restore Ret expression and upregulate its own signaling pathway. This “wind-up” mechanism, which is likely to depend on an interaction with dopaminergic transcription factor Nurr1, has therapeutic potential and should encourage renewed efforts to turn GDNF/NRTN therapy into success, once the recurring problem of under-dosing is resolved.

Establishment of human OCT4 as a putative HSP90 client protein : a case for HSP90 chaperoning pluripotency

2015 ◽  
Author(s):  
◽  
Jason Neville Sterrenberg
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Stem Cell ◽  
Cell Biology ◽  
Therapeutic Potential ◽  
Stem Cell Biology ◽  
Client Protein ◽  
Hsp90 Inhibition ◽  
Regulated Gene Expression ◽  
Hsp90 Client Protein

The therapeutic potential of stem cells is already being harnessed in clinical trails. Of even greater therapeutic potential has been the discovery of mechanisms to reprogram differentiated cells into a pluripotent stem cell-like state known as induced pluripotent stem cells (iPSCs). Stem cell nature is governed and maintained by a hierarchy of transcription factors, the apex of which is OCT4. Although much research has elucidated the transcriptional regulation of OCT4, OCT4 regulated gene expression profiles and OCT4 transcriptional activation mechanisms in both stem cell biology and cellular reprogramming to iPSCs, the fundamental biochemistry surrounding the OCT4 transcription factor remains largely unknown. In order to analyze the biochemical relationship between HSP90 and human OCT4 we developed an exogenous active human OCT4 expression model with human OCT4 under transcriptional control of a constitutive promoter. We identified the direct interaction between HSP90 and human OCT4 despite the fact that the proteins predominantly display differential subcellular localizations. We show that HSP90 inhibition resulted in degradation of human OCT4 via the ubiquitin proteasome degradation pathway. As human OCT4 and HSP90 did not interact in the nucleus, we suggest that HSP90 functions in the cytoplasmic stabilization of human OCT4. Our analysis suggests HSP90 inhibition inhibits the transcriptional activity of human OCT4 dimers without affecting monomeric OCT4 activity. Additionally our data suggests that the HSP90 and human OCT4 complex is modulated by phosphorylation events either promoting or abrogating the interaction between HSP90 and human OCT4. Our data suggest that human OCT4 displays the characteristics describing HSP90 client proteins, therefore we identify human OCT4 as a putative HSP90 client protein. The regulation of the transcription factor OCT4 by HSP90 provides fundamental insights into the complex biochemistry of stem cell biology. This may also be suggestive that HSP90 not only regulates stem cell biology by maintaining routine cellular homeostasis but additionally through the direct regulation of pluripotency factors.

Moving Past Quinone-Methides: Recent Advances toward Minimizing Electrophilic Byproducts from COS/H2S Donors

2021 ◽  
Vol 21 ◽  
Author(s):  
Michael Pluth
Keyword(s):  
Hydrogen Sulfide ◽  
Carbonic Anhydrase ◽  
Therapeutic Potential ◽  
Carbonyl Sulfide ◽  
Quinone Methide ◽  
Quinone Methides ◽  
On Demand ◽  
Physiological Processes ◽  
Recent Approach ◽  
Alternative Approaches

: Hydrogen sulfide (H2S) is an important biomolecule that plays key signaling and protective roles in different physiological processes. With the goals of advancing both the available research tools and the associated therapeutic potential of H2S, researchers have developed different methods to deliver H2S on-demand in different biological contexts. A recent approach to develop such donors has been to design compounds that release carbonyl sulfide (COS), which is quickly converted to H2S in biological systems by the ubiquitous enzyme carbonic anhydrase (CA). Although highly diversifiable, many approaches using this general platform release quinone methides or related electrophiles after donor activation. Many such electrophiles are likely scavenged by water, but recent efforts have also expanded alternative approaches that minimize the formation of electrophilic byproducts generated after COS release. This mini-review focuses specifically on recent examples of COS-based H2S donors that do not generate quinone methide byproducts after donor activation.

Immunomodulatory and Therapeutic Potential of Zootoxins (Venom and Toxins) on the Way Towards Designing and Developing Novel Drugs/Medicines: An Overview

2016 ◽  
Vol 12 (2) ◽  
pp. 126-135 ◽  
Author(s):  
I. Mohanty ◽  
K. Arunvikram ◽  
D. Behera ◽  
A. Arun Prince Milton ◽  
G. Elaiyaraja ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Novel Drugs ◽  
The Way

scholarly journals The Stimulatory Effect of Purine-Type Cytokinins on Proliferation and Polyphenolic Compound Accumulation in Shoot Culture of Salvia viridis

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 178 ◽  
Author(s):  
Izabela Grzegorczyk-Karolak ◽  
Katarzyna Hnatuszko-Konka ◽  
Mariola Zarzycka ◽  
Łukasz Kuźma
Keyword(s):  
Therapeutic Potential ◽  
Shoot Culture ◽  
Total Content ◽  
Biomass Accumulation ◽  
Hormonal Control ◽  
Polyphenolic Compound ◽  
Physiological Processes ◽  
Best Response ◽  
Alternative Sources ◽  
Metabolite Content

The present study demonstrates hormonal control of Salvia viridis growth and development using four different purine-type cytokinins at different concentrations. The addition of cytokinins significantly increased biomass of cultures, proliferation rate, and, interestingly, secondary metabolite production. The best response in terms of multiplication ratio was recorded on Murashige and Skoog medium supplemented with 0.5 mg/L BPA (N-benzylotetrahydropyranyl adenine), while the greatest biomass accumulation was achieved when supplemented with 1 mg/L m-T (meta-topoline). Quantitative UPLC-DAD analysis of the hydromethanolic extract from S. viridis culture revealed the presence of 12 polyphenols: seven phenolic acids and five phenylethanoids. The highest total content of polyphenolic compounds was found in shoots cultivated on medium with 2 mg/L BPA (18.66 mg/g DW): almost twice that of control shoots. The medium was also the most optimal for the biosynthesis of rosmarinic acid, the predominant phenolic acid. However, the greater phenylethanoid accumulation was stimulated by 1 mg/L m-T: the metabolite content was above three times higher than that found in shoots grown on the control medium (8.03 mg/g DW vs. 2.37 mg/g DW). Hence, it was demonstrated that phytohormones are capable of influencing not only vital physiological processes, but therapeutic potential of plants as well. Therefore, the cytokinin-based sage cultures may be also considered as the alternative sources of bioactive compounds.

scholarly journals Natural compounds attenuate heavy metal-induced PC12 cell damage

2020 ◽  
Vol 48 (6) ◽  
pp. 030006052093084
Author(s):  
Lina Yang ◽  
Keshu Shen ◽  
Dongping Ji
Keyword(s):  
Heavy Metal ◽  
Pc12 Cells ◽  
Pc12 Cell ◽  
Therapeutic Potential ◽  
Cell Damage ◽  
Mitochondrial Protein ◽  
Natural Compounds ◽  
Alpha Tocopherol ◽  
Neuroprotective Effects

Objectives To investigate the neuroprotective effects of six natural compounds (caffeine, gallic acid, resveratrol, epigallocatechin gallate [EGCG], L-ascorbic acid and alpha tocopherol [Vitamin E] on heavy metal-induced cell damage in rat PC12 cells. Methods In this in vitro experiment, rat PC12 cells were exposed to four heavy metals (CdCl2, HgCl2, CoCl2 and PbCl2) at different concentrations and cell apoptosis, necrosis and oxidative stress were assessed with and without the addition of the six natural compounds. Results The metals decreased cell viability but the natural compounds attenuated their effects on apoptosis, necrosis and reactive oxygen species (ROS) levels. Mitochondrial protein changes were involved in the regulation. Conclusion Overall, the natural compounds did provide protection against the metal-induced PC12 cell damage. These data suggest that natural compounds may have therapeutic potential against metal-induced neurodegenerative disease.

scholarly journals Therapeutic Potential of Kappa Opioid Agonists

2019 ◽  
Vol 12 (2) ◽  
pp. 95 ◽  
Author(s):  
Tyler C. Beck ◽  
Matthew A. Hapstack ◽  
Kyle R. Beck ◽  
Thomas A. Dix
Keyword(s):  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Cartilage Degeneration ◽  
Review Article ◽  
Research Articles ◽  
Original Research ◽  
Kappa Opioid ◽  
Opioid Agonists ◽  
Novel Drugs ◽  
Post Traumatic

Many original research articles have been published that describe findings and outline areas for the development of kappa-opioid agonists (KOAs) as novel drugs; however, a single review article that summarizes the broad potential for KOAs in drug development does not exist. It is well-established that KOAs demonstrate efficacy in pain attenuation; however, KOAs also have proven to be beneficial in treating a variety of novel but often overlapping conditions including cardiovascular disease, pruritus, nausea, inflammatory diseases, spinal anesthesia, stroke, hypoxic pulmonary hypertension, multiple sclerosis, addiction, and post-traumatic cartilage degeneration. This article summarizes key findings of KOAs and discusses the untapped therapeutic potential of KOAs in the treatment of many human diseases.

Nanophytomedicine Based Novel Therapeutic Strategies in Liver Cancer

2020 ◽  
Vol 20 (22) ◽  
pp. 1999-2024
Author(s):  
Sachin Kumar ◽  
Faizana Fayaz ◽  
Faheem Hyder Pottoo ◽  
Sakshi Bajaj ◽  
Satish Manchanda ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Therapeutic Response ◽  
Water Solubility ◽  
Therapeutic Potential ◽  
Therapeutic Strategies ◽  
Resistance Development ◽  
Local Ablation ◽  
Novel Drugs ◽  
Targeted Agent ◽  
Novel Therapeutic Strategies

Liver cancer is the fifth (6.3% of all cancers i.e., 548,000 cases/year) and ninth (2.8% of all cancers i.e., 244,000 cases/year) most prevalent cancer worldwide in men and women, respectively. Although multiple choices of therapies are offered for Hepatocellular Carcinoma (HCC) like liver resection or transplant, radiofrequency ablation, transarterial chemoembolization, radioembolization, and systemic targeted agent, by the time of diagnosis, most of the cases of HCC are in an advanced stage, which renders therapies like liver transplant or resection and local ablation impractical; and targeted therapy has its shortcomings like general toxicity, imprecise selectivity, several adversative reactions, and resistance development. Therefore, novel drugs with specificity and selectivity are needed to provide the potential therapeutic response. Various researches have shown the potential of phytomedicines in liver cancer by modulating cell growth, invasion, metastasis, and apoptosis. However, their therapeutic potential is held up by their unfavorable properties like stability, poor water solubility, low absorption, and quick metabolism. Nonetheless, the advancement of nanotechnology-based innovative nanocarrier formulations has improved the phytomedicines’ profile to be used in the treatment of liver cancer. Nanocarriers not only improve the solubility and stability of phytomedicines but also extend their residence in plasma and accomplish specificity. In this review, we summarize the advancements introduced by nanotechnology in the treatment of liver cancer. In particular, we discuss quite a few applications of nanophytomedicines like curcumin, quercetin, epigallocatechin-3-gallate, berberine, apigenin, triptolide, and resveratrol in liver cancer treatment.

scholarly journals Natural Compounds as Regulators of the Cancer Cell Metabolism

2013 ◽  
Vol 2013 ◽  
pp. 1-16 ◽  
Author(s):  
Claudia Cerella ◽  
Flavia Radogna ◽  
Mario Dicato ◽  
Marc Diederich
Keyword(s):  
Cancer Cell ◽  
Therapeutic Potential ◽  
Cell Metabolism ◽  
Physiological Mechanism ◽  
Natural Compounds ◽  
Bioactive Molecules ◽  
Anticancer Activities ◽  
Cancer Cell Metabolism ◽  
Altered Metabolism ◽  
And Migration

Even though altered metabolism is an “old” physiological mechanism, only recently its targeting became a therapeutically interesting strategy and by now it is considered an emerging hallmark of cancer. Nevertheless, a very poor number of compounds are under investigation as potential modulators of cell metabolism. Candidate agents should display selectivity of action towards cancer cells without side effects. This ideal favorable profile would perfectly overlap the requisites of new anticancer therapies and chemopreventive strategies as well. Nature represents a still largely unexplored source of bioactive molecules with a therapeutic potential. Many of these compounds have already been characterized for their multiple anticancer activities. Many of them are absorbed with the diet and therefore possess a known profile in terms of tolerability and bioavailability compared to newly synthetized chemical compounds. The discovery of important cross-talks between mediators of the most therapeutically targeted aberrancies in cancer (i.e., cell proliferation, survival, and migration) and the metabolic machinery allows to predict the possibility that many anticancer activities ascribed to a number of natural compounds may be due, in part, to their ability of modulating metabolic pathways. In this review, we attempt an overview of what is currently known about the potential of natural compounds as modulators of cancer cell metabolism.

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