scholarly journals Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1313 ◽  
Author(s):  
Maryam Raeeszadeh-Sarmazdeh ◽  
Linh Do ◽  
Brianne Hritz
Keyword(s):  
Neurological Disorders ◽  
High Selectivity ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Cellular Functions ◽  
Proteolytic Activation ◽  
Ecm Remodeling ◽  
Wide Range ◽  
A Disintegrin And Metalloproteinase ◽  
Natural Inhibitors

The metalloproteinase (MP) family of zinc-dependent proteases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) plays a crucial role in the extracellular matrix (ECM) remodeling and degradation activities. A wide range of substrates of the MP family includes ECM components, chemokines, cell receptors, and growth factors. Metalloproteinases activities are tightly regulated by proteolytic activation and inhibition via their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), and the imbalance of the activation and inhibition is responsible in progression or inhibition of several diseases, e.g., cancer, neurological disorders, and cardiovascular diseases. We provide an overview of the structure, function, and the multifaceted role of MMPs, ADAMs, and TIMPs in several diseases via their cellular functions such as proteolysis of other cell signaling factors, degradation and remodeling of the ECM, and other essential protease-independent interactions in the ECM. The significance of MP inhibitors targeting specific MMP or ADAMs with high selectivity is also discussed. Recent advances and techniques used in developing novel MP inhibitors and MP responsive drug delivery tools are also reviewed.

The GCN5: its biological functions and therapeutic potentials

2021 ◽  
Vol 135 (1) ◽  
pp. 231-257
Author(s):  
Md. Ezazul Haque ◽  
Md. Jakaria ◽  
Mahbuba Akther ◽  
Duk-Yeon Cho ◽  
In-Su Kim ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Cellular Proliferation ◽  
Chromatin Modification ◽  
Structural Features ◽  
Histone Acetyltransferases ◽  
Epigenetic Landscape ◽  
General Control ◽  
Wide Range ◽  
Lysine Acetyltransferase

Abstract General control non-depressible 5 (GCN5) or lysine acetyltransferase 2A (KAT2A) is one of the most highly studied histone acetyltransferases. It acts as both histone acetyltransferase (HAT) and lysine acetyltransferase (KAT). As an HAT it plays a pivotal role in the epigenetic landscape and chromatin modification. Besides, GCN5 regulates a wide range of biological events such as gene regulation, cellular proliferation, metabolism and inflammation. Imbalance in the GCN5 activity has been reported in many disorders such as cancer, metabolic disorders, autoimmune disorders and neurological disorders. Therefore, unravelling the role of GCN5 in different diseases progression is a prerequisite for both understanding and developing novel therapeutic agents of these diseases. In this review, we have discussed the structural features, the biological function of GCN5 and the mechanical link with the diseases associated with its imbalance. Moreover, the present GCN5 modulators and their limitations will be presented in a medicinal chemistry perspective.

scholarly journals Ubiquilin Networking in Cancers

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1586
Author(s):  
Salinee Jantrapirom ◽  
Luca Lo Piccolo ◽  
Dumnoensun Pruksakorn ◽  
Saranyapin Potikanond ◽  
Wutigri Nimlamool
Keyword(s):  
Cell Cycle ◽  
Genetic Variants ◽  
Epithelial Mesenchymal Transition ◽  
Excision Repair ◽  
Cancer Therapies ◽  
Cellular Functions ◽  
Mesenchymal Transition ◽  
Wide Range ◽  
Nucleotide Excision

Ubiquilins or UBQLNs, members of the ubiquitin-like and ubiquitin-associated domain (UBL-UBA) protein family, serve as adaptors to coordinate the degradation of specific substrates via both proteasome and autophagy pathways. The UBQLN substrates reveal great diversity and impact a wide range of cellular functions. For decades, researchers have been attempting to uncover a puzzle and understand the role of UBQLNs in human cancers, particularly in the modulation of oncogene’s stability and nucleotide excision repair. In this review, we summarize the UBQLNs’ genetic variants that are associated with the most common cancers and also discuss their reliability as a prognostic marker. Moreover, we provide an overview of the UBQLNs networks that are relevant to cancers in different ways, including cell cycle, apoptosis, epithelial-mesenchymal transition, DNA repairs and miRNAs. Finally, we include a future prospective on novel ubiquilin-based cancer therapies.

scholarly journals The Role of Sirtuins in Kidney Diseases

2020 ◽  
Vol 21 (18) ◽  
pp. 6686
Author(s):  
Yu Ah Hong ◽  
Ji Eun Kim ◽  
Minjee Jo ◽  
Gang-Jee Ko
Keyword(s):  
Histone Deacetylases ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Expression Profiles ◽  
Kidney Injury ◽  
Class Iii ◽  
Cellular Functions ◽  
Wide Range

Sirtuins (SIRTs) are class III histone deacetylases (HDACs) that play important roles in aging and a wide range of cellular functions. Sirtuins are crucial to numerous biological processes, including proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammals have seven different sirtuins, SIRT1–7, and the diverse biological functions of each sirtuin are due to differences in subcellular localization, expression profiles, and cellular substrates. In this review, we summarize research advances into the role of sirtuins in the pathogenesis of various kidney diseases including acute kidney injury, diabetic kidney disease, renal fibrosis, and kidney aging along with the possible underlying molecular mechanisms. The available evidence indicates that sirtuins have great potential as novel therapeutic targets for the prevention and treatment of kidney diseases.

Role of O-Linked N-acetylglucosamine (O-GlcNAc) Protein Modification in Cellular (Patho)Physiology

2020 ◽  
Author(s):  
John C. Chatham ◽  
Jianhua Zhang ◽  
Adam Raymond Wende
Keyword(s):  
Chromatin Remodeling ◽  
Protein Modification ◽  
Protein Localization ◽  
Cellular Functions ◽  
Secretory Pathways ◽  
Cellular Physiology ◽  
Cytoplasmic Proteins ◽  
Wide Range ◽  
Glcnac Transferase

In the mid 1980s, the identification of serine and threonine residues on nuclear and cytoplasmic proteins modified by an O-linkage by a N-acetylglucosamine moiety (O-GlcNAc) overturned the widely held assumption that glycosylation only occurred in the endoplasmic reticulum, Golgi apparatus, and secretory pathways. In contrast to traditional glycosylation, the O-GlcNAc modification does not lead to complex branched glycan structures and is rapidly cycled on and off proteins by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. Since its discovery O-GlcNAcylation has been shown to contribute to numerous cellular functions including signaling, protein localization and stability, transcription, chromatin remodeling, mitochondrial function, and cell survival. Dysregulation in O-GlcNAc cycling has been implicated in the progression of a wide range of diseases such as diabetes, diabetic complications, cancer, cardiovascular, and neurodegenerative diseases. This review will outline our current understanding of the processes involved in regulating O-GlcNAc turnover, the role of O-GlcNAcylation in regulating cellular physiology, and how dysregulation in O-GlcNAc cycling contributes to pathophysiological processes.

The Jumonji family: past, present and future of histone demethylases in cancer

2014 ◽  
Vol 5 (3) ◽  
pp. 209-224 ◽  
Author(s):  
Gianluigi Franci ◽  
Alfonso Ciotta ◽  
Lucia Altucci
Keyword(s):  
Cardiac Disease ◽  
Neurological Disorders ◽  
Recent Literature ◽  
Tube Formation ◽  
Histone Demethylases ◽  
Post Translational Modifications ◽  
Biological Features ◽  
Wide Range ◽  
Expression Modulation

AbstractThe first Jumonji gene was cloned in 1995 by Takeuchi et al. [Takeuchi T, Yamazaki Y, Katoh-Fukui Y, Tsuchiya R, Kondo S, Motoyama J, Higashinakagawa T. Gene trap capture of a novel mouse gene, jumonji, required for neural tube formation. Genes Dev 1995; 9: 1211–22.]. Several genes sharing similar biological features have since been discovered, and are currently grouped into the JMJ family. Interestingly, their deregulation has been associated with cardiac disease, obesity, neurological disorders and cancer. One of the mechanisms underlying their function is gene expression modulation via histone post-translational modifications (PTMs). Increasing evidence of Jumonji deregulation in tumours such as colon, prostate, haematological and breast cancer is continually emerging, hence the need to acquire a better understanding. The Genesapiens.org database of patient arrays allows target expression levels to be investigated in a wide range of cancers, corroborating and extending the role of the JMJ family. Here, we provide an overview of the expression profile and regulation of JMJ family members in cancer, examining the most recent literature in the light of analyses drawn from this database.

scholarly journals Human Parvoviruses May Affect the Development and Clinical Course of Meningitis and Meningoencephalitis

2020 ◽  
Vol 10 (6) ◽  
pp. 339
Author(s):  
Anda Vilmane ◽  
Anna Terentjeva ◽  
Paulius L. Tamosiunas ◽  
Normunds Suna ◽  
Inga Suna ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Clinical Course ◽  
Inflammatory Diseases ◽  
Parvovirus B19 ◽  
Clinical Manifestations ◽  
Human Parvovirus B19 ◽  
Routine Diagnostics ◽  
Wide Range ◽  
Infection Markers

Meningitis and meningoencephalitis are neurological inflammatory diseases, and although routine diagnostics include testing of a wide range of pathogens, still in many cases, no causative agent is detected. Human parvovirus B19 (B19V), human bocaviruses 1–4 (HBoV1–4), and human parvovirus 4 (hPARV4) are members of the Parvoviridae family and are associated with a wide range of clinical manifestations including neurological disorders. The main aim of this study was to determine whether human parvoviruses infection markers are present among patients with meningitis/meningoencephalitis in Latvia as well as to clarify the role of these viruses on the clinical course of the mentioned diseases. Our study revealed HBoV1–4 and B19V genomic sequences in 52.38% and 16.67% of patients, respectively. Furthermore, symptoms such as the presence of a headache and its severity, fatigue, disorientation, and difficulties to concentrate were significantly frequently present in patients with active parvovirus infection in comparison with parvoviruses negative patients, therefore we suggest that HBoV1–4 and B19V infection should be included in the diagnostics to reduce the number of meningitis/meningoencephalitis with unknown/unexplained etiology.

scholarly journals R-Ras Regulates Exocytosis by Rgl2/Rlf-mediated Activation of RalA on Endosomes

2007 ◽  
Vol 18 (5) ◽  
pp. 1850-1860 ◽  
Author(s):  
Akiyuki Takaya ◽  
Takahiro Kamio ◽  
Michitaka Masuda ◽  
Naoki Mochizuki ◽  
Hirofumi Sawa ◽  
...  
Keyword(s):  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Small Gtpase ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Recycling Endosomes ◽  
Nucleotide Exchange Factor ◽  
Wide Range ◽  
Ras Family

R-Ras is a Ras-family small GTPase that regulates various cellular functions such as apoptosis and cell adhesion. Here, we demonstrate a role of R-Ras in exocytosis. By the use of specific anti-R-Ras antibody, we found that R-Ras was enriched on both early and recycling endosomes in a wide range of cell lines. Using a fluorescence resonance energy transfer-based probe for R-Ras activity, R-Ras activity was found to be higher on endosomes than on the plasma membrane. This high R-Ras activity on the endosomes correlated with the accumulation of an R-Ras effector, the Rgl2/Rlf guanine nucleotide exchange factor for RalA, and also with high RalA activity. The essential role played by R-Ras in inducing high levels of RalA activity on the endosomes was evidenced by the short hairpin RNA (shRNA)-mediated suppression of R-Ras and by the expression of R-Ras GAP. In agreement with the reported role of RalA in exocytosis, the shRNA of either R-Ras or RalA was found to suppress calcium-triggered exocytosis in PC12 pheochromocytoma cells. These data revealed that R-Ras activates RalA on endosomes and that it thereby positively regulates exocytosis.

scholarly journals METALLOTHIONEINS AS SENSORS AND CONTROLS EXCHANGE OF METALS IN THE CELLS

2014 ◽  
Vol 13 (3) ◽  
pp. 91-99 ◽  
Author(s):  
V. A. Kutyakov ◽  
A. V. Salmina
Keyword(s):  
Stress Factors ◽  
Special Role ◽  
Cellular Functions ◽  
Regulation Of Expression ◽  
Wide Range ◽  
Health And Disease ◽  
Pharmacology And Toxicology ◽  
Regulatory Functions ◽  
The Impact

The basic information on the classification, structure, induction and degradation, functions of the protein family – metallothionein (MT), including CNS in health and disease are presented in this review. It was found that four major isoforms of metallothionein perform different biological roles, are localized in dif- ferent tissues. Induction of MT is a universal reaction to the impact of a variety of stress factors. In recent years, understanding of the role of metallothioneins in metal homeostasis in the tissues in normal and pathological conditions have changed significantly. Notes polyfunctionality metallothioneins (transport of metal ions, maintaining redox reactions, tread, signal, modulated and regulatory functions) and their im- pact on basic cellular functions such as proliferation, differentiation, programmed cell death. Further- more, a special role is shown MT in the pathogenesis of cardiovascular, neurodegenerative and neoplastic disorders.Currently, these molecules are increasingly considered as potential targets for therapy of a wide range of diseases and the development of targeted approaches to the regulation of expression of MT – one of the promising areas of pharmacology and toxicology. Stressed the safety of metallothioneins as therapeutic agents.

scholarly journals CDK9: A Comprehensive Review of Its Biology, and Its Role as a Potential Target for Anti-Cancer Agents

2021 ◽  
Vol 11 ◽  
Author(s):  
Abel Tesfaye Anshabo ◽  
Robert Milne ◽  
Shudong Wang ◽  
Hugo Albrecht
Keyword(s):  
Therapeutic Potential ◽  
Continuous Production ◽  
Clinical Settings ◽  
Cellular Functions ◽  
Cyclin Dependent Kinases ◽  
Solid Malignancies ◽  
Wide Range ◽  
Hematological Cancers ◽  
Anti Cancer

Cyclin-dependent kinases (CDKs) are proteins pivotal to a wide range of cellular functions, most importantly cell division and transcription, and their dysregulations have been implicated as prominent drivers of tumorigenesis. Besides the well-established role of cell cycle CDKs in cancer, the involvement of transcriptional CDKs has been confirmed more recently. Most cancers overtly employ CDKs that serve as key regulators of transcription (e.g., CDK9) for a continuous production of short-lived gene products that maintain their survival. As such, dysregulation of the CDK9 pathway has been observed in various hematological and solid malignancies, making it a valuable anticancer target. This therapeutic potential has been utilized for the discovery of CDK9 inhibitors, some of which have entered human clinical trials. This review provides a comprehensive discussion on the structure and biology of CDK9, its role in solid and hematological cancers, and an updated review of the available inhibitors currently being investigated in preclinical and clinical settings.

scholarly journals The Role of LncRNAs in Translation

2021 ◽  
Vol 7 (1) ◽  
pp. 16
Author(s):  
Didem Karakas ◽  
Bulent Ozpolat
Keyword(s):  
Transcriptional Activation ◽  
Chromatin Modification ◽  
Protein Translation ◽  
Cellular Functions ◽  
Protein Coding ◽  
Regulate Gene Expression ◽  
Translational Machinery ◽  
Wide Range ◽  
Non Coding Rnas

Long non-coding RNAs (lncRNAs), a group of non-protein coding RNAs with lengths of more than 200 nucleotides, exert their effects by binding to DNA, mRNA, microRNA, and proteins and regulate gene expression at the transcriptional, post-transcriptional, translational, and post-translational levels. Depending on cellular location, lncRNAs are involved in a wide range of cellular functions, including chromatin modification, transcriptional activation, transcriptional interference, scaffolding and regulation of translational machinery. This review highlights recent studies on lncRNAs in the regulation of protein translation by modulating the translational factors (i.e, eIF4E, eIF4G, eIF4A, 4E-BP1, eEF5A) and signaling pathways involved in this process as wells as their potential roles as tumor suppressors or tumor promoters.

Sign in / Sign up

Export Citation Format

Share Document