New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis

Redox Biology, Journal Year: 2018, Volume and Issue: 20, P. 247 - 260

Published: Oct. 20, 2018

Oxidative stress and inflammation interact in the development of diabetic atherosclerosis. Intracellular hyperglycemia promotes production mitochondrial reactive oxygen species (ROS), increased formation intracellular advanced glycation end-products, activation protein kinase C, polyol pathway flux. ROS directly increase expression inflammatory adhesion factors, oxidized-low density lipoprotein, insulin resistance. They activate ubiquitin pathway, inhibit AMP-protein adiponectin, decrease endothelial nitric oxide synthase activity, all which accelerate Changes composition gut microbiota changes microRNA that influence regulation target genes occur diabetes with to promote This review highlights consequences sustained acceleration atherosclerosis by diabetes. The potential contributions are discussed.

Language: Английский

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The role of ubiquitination in tumorigenesis and targeted drug discovery

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: Feb. 29, 2020

Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" "quality" various proteins, serving to ensure cell homeostasis guarantee life activities. The regulation ubiquitination is multifaceted works not only at transcriptional levels (phosphorylation, acetylation, methylation, etc.) but also level (activators or repressors). When regulatory mechanisms are aberrant, altered biological processes may induce serious human diseases, especially types cancer. In tumorigenesis, involve tumor metabolism, immunological microenvironment (TME), cancer stem (CSC) stemness so on. With regard some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc P53 significantly regulates activity mTORC1, AMPK PTEN-AKT signaling pathways. addition, TLR, RLR STING-dependent pathways modulates TME. Moreover, core regulator triplets (Nanog, Oct4 Sox2) members Wnt Hippo-YAP participates maintenance CSC stemness. Based on components, including proteasome, E3 ligases, E1, E2 deubiquitinases (DUBs), many molecular targeted drugs have been developed combat Among them, small molecule inhibitors targeting bortezomib, carfilzomib, oprozomib ixazomib, achieved tangible success. MLN7243 MLN4924 (targeting E1 enzyme), Leucettamol A CC0651 nutlin MI-219 compounds G5 F6 DUB activity) shown potential preclinical treatment. this review, we summarize latest progress understanding substrates for their special functions metabolism regulation, TME modulation maintenance. therapeutic targets reviewed, effects drugs.

Language: Английский

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PROTACs: great opportunities for academia and industry

Signal Transduction and Targeted Therapy, Journal Year: 2019, Volume and Issue: 4(1)

Published: Dec. 24, 2019

Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic limited number drug targets, which presently only 20-25% all protein targets that currently being studied. Moreover, focus current explorations their enzymatic functions, ignores functions from scaffold moiety. As promising appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both academia industry for finding available approaches to solve above problems. PROTACs regulate function by degrading target proteins instead inhibiting them, providing more sensitivity drug-resistant greater chance affect nonenzymatic functions. been proven show better selectivity compared classic inhibitors. can be described as chemical knockdown approach with rapidity reversibility, presents new different biology other gene editing tools avoiding misinterpretations arise potential genetic compensation and/or spontaneous mutations. PRTOACs widely explored throughout world outperformed not cancer diseases, but also immune disorders, viral infections neurodegenerative diseases. present very powerful crossing hurdles discovery tool development biology, efforts needed gain get deeper insight into efficacy safety clinic. More binders E3 ligases applicable developing waiting exploration.

Language: Английский

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The role of ubiquitination and deubiquitination in cancer metabolism

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: Oct. 1, 2020

Abstract Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance redox homeostasis, is considered a hallmark cancer, sustaining cancer cell growth. Multiple signaling pathways, transcription factors metabolic enzymes participate in the modulation metabolism thus, reprogramming highly complex process. Recent studies have observed that ubiquitination deubiquitination are involved regulation cells. As one most important type post-translational modifications, multistep enzymatic process, diverse cellular biological activities. Dysregulation contributes to various disease, cancer. Here, we discuss role which aimed at highlighting importance this modification supporting development new therapeutic approaches for treatment.

Language: Английский

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The PROTAC technology in drug development

Cell Biochemistry and Function, Journal Year: 2019, Volume and Issue: 37(1), P. 21 - 30

Published: Jan. 1, 2019

Currently, a new technology termed PROTAC, proteolysis targeting chimera, has been developed for inducing the protein degradation by molecule. This takes advantage of moiety targeted and recognizing E3 ubiquitin ligase produces hybrid molecule to specifically knock down protein. During first decade, three pedigreed groups worked on development this technology. To date, extended different groups, aiming develop drugs against diseases including cancers. review summarizes contributions PROTAC. Significance study summarized PROTAC readers also presented author's opinions application in tumor therapy.

Language: Английский

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BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance

Journal of Cancer, Journal Year: 2019, Volume and Issue: 10(9), P. 2109 - 2127

Published: Jan. 1, 2019

Carcinogenesis is a multistep process, and tumors frequently harbor multiple mutations regulating genome integrity, cell division death.The integrity of cellular closely controlled by the mechanisms DNA damage signaling repair.The association breast cancer susceptibility genes BRCA1 BRCA2 with ovarian development was first demonstrated over 20 years ago.Since then germline within these were linked to genomic instability increased risk many other types.Genomic an engine oncogenic transformation non-tumorigenic cells into tumor-initiating further tumor evolution.In this review we discuss biological functions role BRCA in initiation, regulation stemness, therapy resistance progression.

Language: Английский

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Proteolysis‐targeting chimeras in drug development: A safety perspective

British Journal of Pharmacology, Journal Year: 2020, Volume and Issue: 177(8), P. 1709 - 1718

Published: Feb. 5, 2020

Proteolysis‐targeting chimeras are a new drug modality that exploits the endogenous ubiquitin proteasome system to degrade protein of interest for therapeutic benefit. As first‐generation proteolysis‐targeting have now entered clinical trials oncology indications, it is timely consider theoretical safety risks inherent with this which include off‐target degradation, intracellular accumulation natural substrates E3 ligases used in system, saturation by ubiquitinated proteins, and liabilities associated “hook effect” This review describes vitro non‐clinical vivo data provide mechanistic insight these approaches being mitigate next generation chimera molecules extend applications beyond life‐threatening diseases.

Language: Английский

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Structural Diversity of Ubiquitin E3 Ligase

Molecules, Journal Year: 2021, Volume and Issue: 26(21), P. 6682 - 6682

Published: Nov. 4, 2021

The post-translational modification of proteins regulates many biological processes. Their dysfunction relates to diseases. Ubiquitination is one the modifications that target lysine residue and regulate cellular Three enzymes are required for achieving ubiquitination reaction: ubiquitin-activating enzyme (E1), ubiquitin-conjugating (E2), ubiquitin ligase (E3). E3s play a pivotal role in selecting substrates. Many structural studies have been conducted reveal molecular mechanism reaction. Recently, structure PCAF_N, newly categorized E3 ligase, was reported. We present review recent progress toward understanding ligases.

Language: Английский

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Regulation of liquid–liquid phase separation with focus on post-translational modifications

Chemical Communications, Journal Year: 2021, Volume and Issue: 57(98), P. 13275 - 13287

Published: Jan. 1, 2021

This feature article introduces some regulators of biomolecular condensates formed through liquid–liquid phase separation (LLPS), especially post-translational modifications (PTMs).

Language: Английский

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Targeting the ubiquitination/deubiquitination process to regulate immune checkpoint pathways

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Jan. 22, 2021

The immune system initiates robust responses to defend against invading pathogens or tumor cells and protect the body from damage, thus acting as a fortress of body. However, excessive cause detrimental effects, such inflammation autoimmune diseases. To balance maintain homeostasis, there are checkpoints terminate overwhelmed responses. Pathogens can also exploit checkpoint pathways suppress responses, escaping surveillance. As consequence, therapeutic antibodies that target have made great breakthroughs, in particular for cancer treatment. While overall efficacy blockade (ICB) is unsatisfactory since only small group patients benefited ICB Hence, strong need search other targets improve ICB. Ubiquitination highly conserved process which participates numerous biological activities, including innate adaptive immunity. A growing evidence emphasizes importance ubiquitination its reverse process, deubiquitination, on regulation providing rational simultaneous targeting ubiquitination/deubiquitination enhance efficacy. Our review will summarize latest findings anti-tumor immunity, discuss significance future immunotherapy.

Language: Английский

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