scholarly journals Ubiquitylation of nuclear receptors: new linkages and therapeutic implications

2015 ◽  
Vol 54 (3) ◽  
pp. R151-R167 ◽  
Author(s):  
Kyle T Helzer ◽  
Christopher Hooper ◽  
Shigeki Miyamoto ◽  
Elaine T Alarid
Keyword(s):  
Nuclear Receptors ◽  
Targeted Therapies ◽  
Drug Targets ◽  
Transcriptional Regulators ◽  
Receptor Function ◽  
Therapeutic Implications ◽  
Clinical Challenge ◽  
Entry Points ◽  
Therapeutic Development

The nuclear receptor (NR) superfamily is a group of transcriptional regulators that control multiple aspects of both physiology and pathology and are broadly recognized as viable therapeutic targets. While receptor-modulating drugs have been successful in many cases, the discovery of new drug targets is still an active area of research, because resistance to NR-targeting therapies remains a significant clinical challenge. Many successful targeted therapies have harnessed the control of receptor activity by targeting events within the NR signaling pathway. In this review, we explore the role of NR ubiquitylation and discuss how the expanding roles of ubiquitin could be leveraged to identify additional entry points to control receptor function for future therapeutic development.

scholarly journals Roles of Nuclear Receptors in Vascular Calcification

2021 ◽  
Vol 22 (12) ◽  
pp. 6491
Author(s):  
Giulia Chinetti ◽  
Jaap G. Neels
Keyword(s):  
Nuclear Receptors ◽  
Vascular Calcification ◽  
Drug Targets ◽  
Target Genes ◽  
Soft Tissues ◽  
Vascular Wall ◽  
Calcium Deposition ◽  
Wall Calcification ◽  
Clinical Consequences

Vascular calcification is defined as an inappropriate accumulation of calcium depots occurring in soft tissues, including the vascular wall. Growing evidence suggests that vascular calcification is an actively regulated process, sharing similar mechanisms with bone formation, implicating both inhibitory and inducible factors, mediated by osteoclast-like and osteoblast-like cells, respectively. This process, which occurs in nearly all the arterial beds and in both the medial and intimal layers, mainly involves vascular smooth muscle cells. In the vascular wall, calcification can have different clinical consequences, depending on the pattern, localization and nature of calcium deposition. Nuclear receptors are transcription factors widely expressed, activated by specific ligands that control the expression of target genes involved in a multitude of pathophysiological processes, including metabolism, cancer, inflammation and cell differentiation. Some of them act as drug targets. In this review we describe and discuss the role of different nuclear receptors in the control of vascular calcification.

scholarly journals Getting the message across: Pathophysiology and signaling via receptors for polypeptide hormones and proteinases

2010 ◽  
Vol 33 (2) ◽  
pp. 133 ◽  
Author(s):  
Morley D Hollenberg
Keyword(s):  
Drug Targets ◽  
Time Span ◽  
Activation Mechanism ◽  
Therapeutic Implications ◽  
Proteinase Activated Receptors ◽  
Tethered Ligand ◽  
Polypeptide Hormones ◽  
G Protein Coupled ◽  
Receptor Family

This article provides a personalized overview of the role of proteinases in generating hormone-like cell signals. Also outlined is the unexpected route of discovery that led one investigator over a four-decade time span, from early studies of the interactions of oxytocin and vasopressin with their neurophysin binding proteins to current studies of the tethered ligand activation mechanism that is unique for the G-protein-coupled family of proteinase-activated receptors (PARs). The focus is not only on the intriguing PAR receptor family, but also on alternative mechanisms whereby proteinases activate signal transduction pathways. Also summarized are the potential physiological and pathophysiological roles that PARs may play in the setting of inflammatory disorders ranging from arthritis to colitis. The therapeutic implications of considering PARs as drug targets are also discussed.

Role of melatonin in regulating neurogenesis: Implications for the neurodegenerative pathology and analogous therapeutics for Alzheimer’s disease

2020 ◽  
Vol 3 (2) ◽  
pp. 216-242 ◽  
Author(s):  
Mayuri Shukla ◽  
Areechun Sotthibundhu ◽  
Piyarat Govitrapong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adult Neurogenesis ◽  
Adult Brain ◽  
Therapeutic Approaches ◽  
Therapeutic Implications ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Progenitor Cell Proliferation

The revelation of adult brain exhibiting neurogenesis has established that the brain possesses great plasticity and that neurons could be spawned in the neurogenic zones where hippocampal adult neurogenesis attributes to learning and memory processes. With strong implications in brain functional homeostasis, aging and cognition, various aspects of adult neurogenesis reveal exuberant mechanistic associations thereby further aiding in facilitating the therapeutic approaches regarding the development of neurodegenerative processes in Alzheimer’s Disease (AD). Impaired neurogenesis has been significantly evident in AD with compromised hippocampal function and cognitive deficits. Melatonin the pineal indolamine augments neurogenesis and has been linked to AD development as its levels are compromised with disease progression. Here, in this review, we discuss and appraise the mechanisms via which melatonin regulates neurogenesis in pathophysiological conditions which would unravel the molecular basis in such conditions and its role in endogenous brain repair. Also, its components as key regulators of neural stem and progenitor cell proliferation and differentiation in the embryonic and adult brain would aid in accentuating the therapeutic implications of this indoleamine in line of prevention and treatment of AD.   

Structure, Function and Interactions of Tau: Particular Focus on Potential Drug Targets for the Treatment of Tauopathies

2018 ◽  
Vol 17 (5) ◽  
pp. 325-337 ◽  
Author(s):  
Hojjat Borna ◽  
Kasim Assadoulahei ◽  
Gholamhossein Riazi ◽  
Asghar Beigi Harchegani ◽  
Alireza Shahriary
Keyword(s):  
Tau Protein ◽  
Drug Targets ◽  
Brain Injuries ◽  
Potential Drug ◽  
Microtubule Network ◽  
Wide Range ◽  
Potential Risk Factors ◽  
Range Of Functions ◽  
Potential Drug Targets

Background & Objective: Neurodegenrative diseases are among the most widespread lifethreatening disorders around the world in elderly ages. The common feature of a group of neurodegenerative disorders, called tauopathies, is an accumulation of microtubule associated protein tau inside the neurons. The exact mechanism underlying tauopathies is not well-understood but several factors such as traumatic brain injuries and genetics are considered as potential risk factors. Although tau protein is well-known for its key role in stabilizing and organization of axonal microtubule network, it bears a broad range of functions including DNA protection and participation in signaling pathways. Moreover, the flexible unfolded structure of tau facilitates modification of tau by a wide range of intracellular enzymes which in turn broadens tau function and interaction spectrum. The distinctive properties of tau protein concomitant with the crucial role of tau interaction partners in the progression of neurodegeneration suggest tau and its binding partners as potential drug targets for the treatment of neurodegenerative diseases. Conclusion: This review aims to give a detailed description of structure, functions and interactions of tau protein in order to provide insight into potential therapeutic targets for treatment of tauopathies.

scholarly journals Overview on the Different Patterns of Tumor Vascularization

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 639
Author(s):  
Domenico Ribatti ◽  
Francesco Pezzella
Keyword(s):  
Vasculogenic Mimicry ◽  
Endothelial Cell Proliferation ◽  
Published Data ◽  
Alternative Mechanism ◽  
Tumor Vascularization ◽  
Angiogenic Therapy ◽  
Physiological Processes ◽  
Inhibition Of Angiogenesis ◽  
Therapeutic Development

Angiogenesis is a crucial event in the physiological processes of embryogenesis and wound healing. During malignant transformation, dysregulation of angiogenesis leads to the formation of a vascular network of tumor-associated capillaries promoting survival and proliferation of the tumor cells. Starting with the hypothesis formulated by Judah Folkman that tumor growth is angiogenesis-dependent, this area of research has a solid scientific foundation and inhibition of angiogenesis is a major area of therapeutic development for the treatment of cancer. Over this period numerous authors published data of vascularization of tumors, which attributed the cause of neo-vascularization to various factors including inflammation, release of angiogenic cytokines, vasodilatation, and increased tumor metabolism. More recently, it has been demonstrated that tumor vasculature is not necessarily derived by endothelial cell proliferation and sprouting of new capillaries, but alternative vascularization mechanisms have been described, namely vascular co-option and vasculogenic mimicry. In this article, we have analyzed the mechanisms involved in tumor vascularization in association with classical angiogenesis, including post-natal vasculogenesis, intussusceptive microvascular growth, vascular co-option, and vasculogenic mimicry. We have also discussed the role of these alternative mechanism in resistance to anti-angiogenic therapy and potential therapeutic approaches to overcome resistance.

scholarly journals Gastric Sensory and Motor Functions and Energy Intake in Health and Obesity—Therapeutic Implications

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1158
Author(s):  
Lizeth Cifuentes ◽  
Michael Camilleri ◽  
Andres Acosta
Keyword(s):  
Energy Consumption ◽  
Gastric Emptying ◽  
Food Intake ◽  
Gastric Volume ◽  
Obesity Management ◽  
Bariatric Endoscopy ◽  
Motor Functions ◽  
Therapeutic Implications ◽  
Intestinal Functions

Sensory and motor functions of the stomach, including gastric emptying and accommodation, have significant effects on energy consumption and appetite. Obesity is characterized by energy imbalance; altered gastric functions, such as rapid gastric emptying and large fasting gastric volume in obesity, may result in increased food intake prior to reaching usual fullness and increased appetite. Thus, many different interventions for obesity, including different diets, anti-obesity medications, bariatric endoscopy, and surgery, alter gastric functions and gastrointestinal motility. In this review, we focus on the role of the gastric and intestinal functions in food intake, pathophysiology of obesity, and obesity management.

scholarly journals The MarR-Type Regulator PA3458 Is Involved in Osmoadaptation Control in Pseudomonas aeruginosa

2021 ◽  
Vol 22 (8) ◽  
pp. 3982
Author(s):  
Karolina Kotecka ◽  
Adam Kawalek ◽  
Kamil Kobylecki ◽  
Aneta Agnieszka Bartosik
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Binding Sites ◽  
Transcriptional Profiling ◽  
Mrna Level ◽  
Transcriptional Regulators ◽  
Resistance Mechanisms ◽  
Chronic Infections ◽  
Environmental Signals ◽  
Regulatory Systems

Pseudomonas aeruginosa is a facultative human pathogen, causing acute and chronic infections that are especially dangerous for immunocompromised patients. The eradication of P. aeruginosa is difficult due to its intrinsic antibiotic resistance mechanisms, high adaptability, and genetic plasticity. The bacterium possesses multilevel regulatory systems engaging a huge repertoire of transcriptional regulators (TRs). Among these, the MarR family encompasses a number of proteins, mainly acting as repressors, which are involved in response to various environmental signals. In this work, we aimed to decipher the role of PA3458, a putative MarR-type TR from P. aeruginosa. Transcriptional profiling of P. aeruginosa PAO1161 overexpressing PA3458 showed changes in the mRNA level of 133 genes; among them, 100 were down-regulated, suggesting the repressor function of PA3458. Concomitantly, ChIP-seq analysis identified more than 300 PA3458 binding sites in P. aeruginosa. The PA3458 regulon encompasses genes involved in stress response, including the PA3459–PA3461 operon, which is divergent to PA3458. This operon encodes an asparagine synthase, a GNAT-family acetyltransferase, and a glutamyl aminopeptidase engaged in the production of N-acetylglutaminylglutamine amide (NAGGN), which is a potent bacterial osmoprotectant. We showed that PA3458-mediated control of PA3459–PA3461 expression is required for the adaptation of P. aeruginosa growth in high osmolarity. Overall, our data indicate that PA3458 plays a role in osmoadaptation control in P. aeruginosa.

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