scholarly journals “Reading” a new chapter in protozoan parasite transcriptional regulation

2021 ◽  
Vol 17 (12) ◽  
pp. e1010056
Author(s):  
Krista Fleck ◽  
Malorie Nitz ◽  
Victoria Jeffers
Keyword(s):  
Gene Regulation ◽  
Posttranslational Modifications ◽  
Drug Targets ◽  
Current Knowledge ◽  
Critical Role ◽  
Protozoan Parasite ◽  
Cellular Pathways ◽  
Transcription Complexes ◽  
Reading Domains ◽  
Significant Health

Protozoan parasites continue to cause a significant health and economic burden worldwide. As infectious organisms, they pose unique and difficult challenges due to a level of conservation of critical eukaryotic cellular pathways with their hosts. Gene regulation has been pinpointed as an essential pathway with enough divergence to warrant investigation into therapeutically targeting. Examination of human parasites such as Plasmodium falciparum, Toxoplasma gondii, and kinetoplastids have revealed that epigenetic mechanisms play a key role in their gene regulation. The enzymes involved in adding and removing epigenetic posttranslational modifications (PTMs) have historically been the focus of study. However, the reader proteins that recognize and bind PTMs, initiating recruitment of chromatin-modifying and transcription complexes, are now being realized for their critical role in regulation and their potential as drug targets. In this review, we highlight the current knowledge on epigenetic reader proteins in model parasitic protozoa, focusing on the histone acyl- and methyl-reading domains. With this knowledge base, we compare differences between medically relevant parasites, discuss conceivable functions of these understudied proteins, indicate gaps in knowledge, and provide current progress in drug development.

scholarly journals Regulation of G Protein-Coupled Receptors by Ubiquitination

2017 ◽  
Author(s):  
Kamila Skieterska ◽  
Pieter Rondou ◽  
Kathleen Van Craenenbroeck
Keyword(s):  
G Protein ◽  
Posttranslational Modifications ◽  
Drug Targets ◽  
Current Knowledge ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Deubiquitinating Enzymes ◽  
Range Of Functions ◽  
Beta Arrestins ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) comprise the largest family of membrane receptors that control many cellular processes and consequently often serve as drug targets. These receptors undergo a strict regulation by mechanisms such as internalization and desensitization, which are strongly influenced by posttranslational modifications. Ubiquitination is a posttranslational modification with a broad range of functions that is currently gaining increased appreciation as a regulator of GPCR activity. The role of ubiquitination in directing GPCRs for lysosomal degradation has already been well-established. Furthermore, this modification can also play a role in targeting membrane and endoplasmic reticulum-associated receptors to the proteasome. Most recently, ubiquitination was also shown to be involved in GPCR signaling. In this review, we present current knowledge on the molecular basis of GPCR regulation by ubiquitination, and highlight the importance of E3 ubiquitin ligases, deubiquitinating enzymes and β-arrestins. Finally, we discuss classical and newly-discovered functions of ubiquitination in controlling GPCR activity.

scholarly journals Derailed Estrogen Signaling and Breast Cancer: An Authentic Couple

2012 ◽  
Vol 34 (1) ◽  
pp. 1-32 ◽  
Author(s):  
Bramanandam Manavathi ◽  
Oindrilla Dey ◽  
Vijay Narsihma Reddy Gajulapalli ◽  
Raghavendra Singh Bhatia ◽  
Suresh Bugide ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Cancer Progression ◽  
Posttranslational Modifications ◽  
Drug Targets ◽  
Critical Role ◽  
Mammary Epithelium ◽  
Estrogen Receptor Α ◽  
Estrogen Signaling ◽  
Alternative Drug

Abstract Estrogen or 17β-estradiol, a steroid hormone, plays a critical role in the development of mammary gland via acting through specific receptors. In particular, estrogen receptor-α (ERα) acts as a transcription factor and/or a signal transducer while participating in the development of mammary gland and breast cancer. Accumulating evidence suggests that the transcriptional activity of ERα is altered by the action of nuclear receptor coregulators and might be responsible, at least in part, for the development of breast cancer. In addition, this process is driven by various posttranslational modifications of ERα, implicating active participation of the upstream receptor modifying enzymes in breast cancer progression. Emerging studies suggest that the biological outcome of breast cancer cells is also influenced by the cross talk between microRNA and ERα signaling, as well as by breast cancer stem cells. Thus, multiple regulatory controls of ERα render mammary epithelium at risk for transformation upon deregulation of normal homeostasis. Given the importance that ERα signaling has in breast cancer development, here we will highlight how the activity of ERα is controlled by various regulators in a spatial and temporal manner, impacting the progression of the disease. We will also discuss the possible therapeutic value of ERα modulators as alternative drug targets to retard the progression of breast cancer.

scholarly journals The relevance of adhesion G protein-coupled receptors in metabolic functions

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Isabell Kaczmarek ◽  
Tomáš Suchý ◽  
Simone Prömel ◽  
Torsten Schöneberg ◽  
Ines Liebscher ◽  
...  
Keyword(s):  
G Protein ◽  
Drug Targets ◽  
Metabolic Diseases ◽  
Current Knowledge ◽  
G Protein Coupled Receptors ◽  
Specific Expression ◽  
Physiological Functions ◽  
Metabolic Functions ◽  
Central Nervous Systems ◽  
G Protein Coupled

Abstract G protein-coupled receptors (GPCRs) modulate a variety of physiological functions and have been proven to be outstanding drug targets. However, approximately one-third of all non-olfactory GPCRs are still orphans in respect to their signal transduction and physiological functions. Receptors of the class of Adhesion GPCRs (aGPCRs) are among these orphan receptors. They are characterized by unique features in their structure and tissue-specific expression, which yields them interesting candidates for deorphanization and testing as potential therapeutic targets. Capable of G-protein coupling and non-G protein-mediated function, aGPCRs may extend our repertoire of influencing physiological function. Besides their described significance in the immune and central nervous systems, growing evidence indicates a high importance of these receptors in metabolic tissue. RNAseq analyses revealed high expression of several aGPCRs in pancreatic islets, adipose tissue, liver, and intestine but also in neurons governing food intake. In this review, we focus on aGPCRs and their function in regulating metabolic pathways. Based on current knowledge, this receptor class represents high potential for future pharmacological approaches addressing obesity and other metabolic diseases.

scholarly journals MicroRNAs and Oxidative Stress: An Intriguing Crosstalk to Be Exploited in the Management of Type 2 Diabetes

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 802
Author(s):  
Teresa Vezza ◽  
Aranzazu M. de Marañón ◽  
Francisco Canet ◽  
Pedro Díaz-Pozo ◽  
Miguel Marti ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Signaling Pathways ◽  
Current Knowledge ◽  
Critical Role ◽  
Cell Dysfunction ◽  
Non Coding Rnas ◽  
And Oxidative Stress ◽  
Molecular Crosstalk

Type 2 diabetes is a chronic disease widespread throughout the world, with significant human, social, and economic costs. Its multifactorial etiology leads to persistent hyperglycemia, impaired carbohydrate and fat metabolism, chronic inflammation, and defects in insulin secretion or insulin action, or both. Emerging evidence reveals that oxidative stress has a critical role in the development of type 2 diabetes. Overproduction of reactive oxygen species can promote an imbalance between the production and neutralization of antioxidant defence systems, thus favoring lipid accumulation, cellular stress, and the activation of cytosolic signaling pathways, and inducing β-cell dysfunction, insulin resistance, and tissue inflammation. Over the last few years, microRNAs (miRNAs) have attracted growing attention as important mediators of diverse aspects of oxidative stress. These small endogenous non-coding RNAs of 19–24 nucleotides act as negative regulators of gene expression, including the modulation of redox signaling pathways. The present review aims to provide an overview of the current knowledge concerning the molecular crosstalk that takes place between oxidative stress and microRNAs in the physiopathology of type 2 diabetes, with a special emphasis on its potential as a therapeutic target.

scholarly journals Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3

2021 ◽  
Vol 22 (15) ◽  
pp. 8117
Author(s):  
Nunzia D’Onofrio ◽  
Elisa Martino ◽  
Luigi Mele ◽  
Antonino Colloca ◽  
Martina Maione ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Protein Levels

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.

scholarly journals Hydrogen production from water electrolysis: role of catalysts

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Shan Wang ◽  
Aolin Lu ◽  
Chuan-Jian Zhong
Keyword(s):  
Hydrogen Production ◽  
Water Splitting ◽  
Noble Metal ◽  
Active Sites ◽  
Current Knowledge ◽  
Low Cost ◽  
Critical Role ◽  
Water Electrolysis ◽  
Efficient Production ◽  
Production Of Hydrogen

AbstractAs a promising substitute for fossil fuels, hydrogen has emerged as a clean and renewable energy. A key challenge is the efficient production of hydrogen to meet the commercial-scale demand of hydrogen. Water splitting electrolysis is a promising pathway to achieve the efficient hydrogen production in terms of energy conversion and storage in which catalysis or electrocatalysis plays a critical role. The development of active, stable, and low-cost catalysts or electrocatalysts is an essential prerequisite for achieving the desired electrocatalytic hydrogen production from water splitting for practical use, which constitutes the central focus of this review. It will start with an introduction of the water splitting performance evaluation of various electrocatalysts in terms of activity, stability, and efficiency. This will be followed by outlining current knowledge on the two half-cell reactions, hydrogen evolution reaction (HER) and oxygen evolution reaction (OER), in terms of reaction mechanisms in alkaline and acidic media. Recent advances in the design and preparation of nanostructured noble-metal and non-noble metal-based electrocatalysts will be discussed. New strategies and insights in exploring the synergistic structure, morphology, composition, and active sites of the nanostructured electrocatalysts for increasing the electrocatalytic activity and stability in HER and OER will be highlighted. Finally, future challenges and perspectives in the design of active and robust electrocatalysts for HER and OER towards efficient production of hydrogen from water splitting electrolysis will also be outlined.

The DEAH helicase DHX36 and its role in G-quadruplex-dependent processes

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Philipp Schult ◽  
Katrin Paeschke
Keyword(s):  
Current Knowledge ◽  
Future Research ◽  
Transcriptional Level ◽  
Cellular Functions ◽  
Multiple Functions ◽  
Open Questions ◽  
G Quadruplex ◽  
Cellular Pathways ◽  
Nucleic Acid Structures ◽  
Dependent Processes

AbstractDHX36 is a member of the DExD/H box helicase family, which comprises a large number of proteins involved in various cellular functions. Recently, the function of DHX36 in the regulation of G-quadruplexes (G4s) was demonstrated. G4s are alternative nucleic acid structures, which influence many cellular pathways on a transcriptional and post-transcriptional level. In this review we provide an overview of the current knowledge about DHX36 structure, substrate specificity, and mechanism of action based on the available models and crystal structures. Moreover, we outline its multiple functions in cellular homeostasis, immunity, and disease. Finally, we discuss the open questions and provide potential directions for future research.

scholarly journals Dysregulation of lipid metabolism and pathological inflammation in patients with COVID-19

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marianna Caterino ◽  
Monica Gelzo ◽  
Stefano Sol ◽  
Roberta Fedele ◽  
Anna Annunziata ◽  
...  
Keyword(s):  
Virus Entry ◽  
Critical Role ◽  
Membrane Vesicles ◽  
Virus Propagation ◽  
Lipidomic Analysis ◽  
Key Factor ◽  
Patient Profiles ◽  
Cellular Pathways ◽  
Severity Degree

AbstractIn recent months, Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread throughout the world. COVID-19 patients show mild, moderate or severe symptoms with the latter ones requiring access to specialized intensive care. SARS-CoV-2 infections, pathogenesis and progression have not been clearly elucidated yet, thus forcing the development of many complementary approaches to identify candidate cellular pathways involved in disease progression. Host lipids play a critical role in the virus life, being the double-membrane vesicles a key factor in coronavirus replication. Moreover, lipid biogenesis pathways affect receptor-mediated virus entry at the endosomal cell surface and modulate virus propagation. In this study, targeted lipidomic analysis coupled with proinflammatory cytokines and alarmins measurement were carried out in serum of COVID-19 patients characterized by different severity degree. Serum IL-26, a cytokine involved in IL-17 pathway, TSLP and adiponectin were measured and correlated to lipid COVID-19 patient profiles. These results could be important for the classification of the COVID-19 disease and the identification of therapeutic targets.

scholarly journals Re-Discovery of Giardiavirus: Genomic and Functional Analysis of Viruses from Giardia duodenalis Isolates

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 654
Author(s):  
Gianluca Marucci ◽  
Ilaria Zullino ◽  
Lucia Bertuccini ◽  
Serena Camerini ◽  
Serena Cecchetti ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
Diarrheal Disease ◽  
Current Knowledge ◽  
Biological Significance ◽  
Giardia Duodenalis ◽  
Protozoan Parasite ◽  
Protein Translation ◽  
Mass Spectrometry Analysis ◽  
Animal Origin ◽  
Spectrometry Analysis

Giardiasis, caused by the protozoan parasite Giardia duodenalis, is an intestinal diarrheal disease affecting almost one billion people worldwide. A small endosymbiotic dsRNA viruses, G. lamblia virus (GLV), genus Giardiavirus, family Totiviridae, might inhabit human and animal isolates of G. duodenalis. Three GLV genomes have been sequenced so far, and only one was intensively studied; moreover, a positive correlation between GLV and parasite virulence is yet to be proved. To understand the biological significance of GLV infection in Giardia, the characterization of several GLV strains from naturally infected G. duodenalis isolates is necessary. Here we report high-throughput sequencing of four GLVs strains, from Giardia isolates of human and animal origin. We also report on a new, unclassified viral sequence (designed GdRV-2), unrelated to Giardiavirus, encoding and expressing for a single large protein with an RdRp domain homologous to Totiviridae and Botybirnaviridae. The result of our sequencing and proteomic analyses challenge the current knowledge on GLV and strongly suggest that viral capsid protein translation unusually starts with a proline and that translation of the RNA-dependent RNA polymerase (RdRp) occurs via a +1/−2 ribosomal frameshift mechanism. Nucleotide polymorphism, confirmed by mass-spectrometry analysis, was also observed among and between GLV strains. Phylogenetic analysis indicated the occurrence of at least two GLV subtypes which display different phenotypes and transmissibility in experimental infections of a GLV naïve Giardia isolate.

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