Endoplasmic reticulum stress: molecular mechanism and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 15, 2023

Abstract The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or “proteostasis”. quality control systems involve ER-associated degradation, chaperons, and autophagy. ER stress is activated when proteostasis broken with an accumulation of misfolded unfolded proteins in the ER. activates adaptive response to restore by initiating kinase R-like kinase, activating transcription factor 6, inositol requiring enzyme 1. multifaceted, acts on aspects at epigenetic level, including processing. Accumulated data indicates its key role homeostasis other diverse involved various ocular diseases, such glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, tumors, surface myopia. This review summarizes molecular mechanisms underlying aforementioned diseases from perspective. Drugs (chemicals, neurotrophic factors, nanoparticles), gene therapy, stem cell therapy are used treat alleviating stress. We delineate advancement targeting provide new treatment strategies diseases.

Language: Английский

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Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma

Clinical Cancer Research, Journal Year: 2020, Volume and Issue: 26(22), P. 5869 - 5878

Published: Aug. 18, 2020

Tebentafusp is a first-in-class bispecific fusion protein designed to target gp100 (a melanoma-associated antigen) through high affinity T-cell receptor (TCR) binding domain and an anti-CD3 engaging domain, which redirects T cells kill gp100-expressing tumor cells. Here, we report multicenter phase I/II trial of tebentafusp in metastatic melanoma (NCT01211262) focusing on the mechanism action tebentafusp.

Language: Английский

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Human health in relation to exposure to solar ultraviolet radiation under changing stratospheric ozone and climate

Photochemical & Photobiological Sciences, Journal Year: 2019, Volume and Issue: 18(3), P. 641 - 680

Published: Feb. 27, 2019

Language: Английский

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Targeting the ERK Signaling Pathway in Melanoma

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(6), P. 1483 - 1483

Published: March 25, 2019

The discovery of the role RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era treatment this tumor. Vemurafenib was first specific kinase inhibitor approved for therapy advanced melanomas harboring BRAF-activating mutations, followed by dabrafenib encorafenib. However, despite excellent results first-generation inhibitors terms response rate, average duration short, due to onset genetic epigenetic resistance mechanisms. combination with MEK is an strategy circumvent drug resistance, additional advantage reducing side effects paradoxical reactivation MAPK pathway. recent development RAS extracellular signal-related kinases (ERK) promises add players ultimate suppression signaling control pathway-related resistance. In review, we analyze pharmacological, preclinical, clinical trial data various inhibitors, keen interest their applicability management melanoma.

Language: Английский

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MicroRNAs; their therapeutic and biomarker properties

Cellular Molecular and Biomedical Reports, Journal Year: 2023, Volume and Issue: 3(2), P. 73 - 88

Published: April 11, 2023

MicroRNAs (miRNAs) are, small (roughly 19–25 nucleotides in length), conserved, non-coding, single-stranded, and functional RNA molecules with the properties of gene expression regulation through mRNA degradation, translation repression, deadenylation as well silencing via histone methylation. They even have ability to increase levels. The biogenesis miRNAs is divided into two canonical non-canonical pathways. second pathway has a divergent mechanism for miRNAs. can be transcribed from specific genes or introns protein-coding genes. A single miRNA species control hundreds genes, also one target different These been identified eukaryotic organisms such mammals plants viruses. play an inevitable role life cycle cells. are involved any biological processes cell proliferation differentiation, apoptosis, signaling, defense responses their spatio-temporal manner. Aberrant large number disorders, which illustrates great potential applied diagnosis treatment various diseases. inhibitors (anti-miRs) artificial (miRNA mimics) general approaches balance dysregulated levels that make it possible treat disorders. In this study, general, miRNAs, origin viral detection procedures, silico analysis tools, miRNA-based therapies obstacles, non-invasive biomarkers discussed. Finally, stated importance dietary

Language: Английский

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BAP1: Not just a BRCA1-associated protein

Cancer Treatment Reviews, Journal Year: 2020, Volume and Issue: 90, P. 102091 - 102091

Published: Aug. 20, 2020

BRCA1-Associated Protein 1 (BAP1) is a ubiquitin carboxy-terminal hydrolase that has been established as tumor suppressor, utilizing its deubiquitinating activity to regulate number of processes including DNA damage repair, cell cycle control, chromatin modification, programmed death, and the immune response. Mutations in BAP1 gene commonly result aggressive cancers; predominantly uveal melanoma, malignant mesothelioma, renal carcinoma, cutaneous melanoma. Importantly, germline mutations have novel predisposition syndrome, conferring an increased risk hereditary, early-onset cancers. Current treatment options for cancers with alterations are limited standard therapies. However, several therapeutic avenues proposed specifically target cancer. Molecularly targeted approaches include histone deacetylase inhibitors EZH2 role modification transcriptional regulation, respectively. PARP platinum chemotherapy agents potential BAP1-altered tumors, due repair. Lastly, emerging reports suggest cancer confer distinct immunogenic phenotypes may be particularly susceptible immunotherapies. This review aims present concise up date report on cancer, surveying functional roles, characteristics clinical manifestations. Furthermore, we highlight BAP1-mutated

Language: Английский

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Tebentafusp: T Cell Redirection for the Treatment of Metastatic Uveal Melanoma

Cancers, Journal Year: 2019, Volume and Issue: 11(7), P. 971 - 971

Published: July 11, 2019

Metastatic disease from uveal melanoma occurs in almost 50% of patients suffering this ocular tumour, with median survival development symptoms being around 1 year. In contrast to cutaneous melanoma, kinase inhibitors and immune checkpoint are usually ineffective metastatic melanoma. Tebentafusp is a novel form immunotherapy based on the immune-mobilising monoclonal T cell receptor against cancer (ImmTAC) platform, which comprises soluble that fused an anti-CD3 single-chain variable fragment. The domain tebentafusp targets cells present human leukocyte antigen-A*02:01 complexed peptide derived melanoma-associated antigen gp100, expressed strongly by cells, weakly normal melanocytes minimally other tissues. recruits CD3+ (and, indirectly, cells), redirecting these cells. most common adverse events manageable transient. Early data promising when considered alongside historical data. Based encouraging results, randomised study comparing investigator’s choice therapy ongoing.

Language: Английский

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Current molecular and clinical insights into uveal melanoma (Review)

International Journal of Oncology, Journal Year: 2021, Volume and Issue: 58(4)

Published: Feb. 18, 2021

Uveal melanoma (UM) represents the most prominent primary eye cancer in adults. With an incidence of approximately 5 cases per million individuals annually United States, UM could be considered a relatively rare cancer. The 90‑95% arise from choroid. Diagnosis is based mainly on clinical examination and ancillary tests, with ocular ultrasonography being greatest value. Differential diagnosis can prove challenging case indeterminate choroidal lesions and, sometimes, monitoring for documented growth may proper approach. Fine needle aspiration biopsy tends to performed prognostic purpose, often combination radiotherapy. Gene expression profiling has allowed grading UMs into two classes, which feature different metastatic risks. Patients require specialized multidisciplinary management. Primary tumor treatment either enucleation or globe preserving. Usually, reserved larger tumors, while radiotherapy preferred small/medium melanomas. prognosis unfavorable due high mortality rate tendency metastasize. Following development disease, increases 80% within one year, both absence effective aggressiveness condition. Novel molecular studies have better understanding genetic epigenetic mechanisms involved biological activity, differs compared skin commonly mutated genes are GNAQ, GNA11 BAP1. Research this field help identify diagnostic biomarkers, as well novel therapeutic targets.

Language: Английский

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CircRNA Is a Rising Star in Researches of Ocular Diseases

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: Sept. 3, 2020

A newly re-discovered subclass of non-coding RNAs, circRNAs, is produced by a back-splicing mechanism with covalently closed loop structure. They not only serve as the sponge for miRNAs and proteins but also regulate gene expression epigenetic modification, translate into peptides, generate pseudogenes. Dysregulation circRNA has opened new chapter in etiology various human disorders, including cancer cardiovascular, neurodegenerative, ocular diseases. Recent studies recognized vital roles circRNAs play pathogenesis eye diseases, highlighting promising biomarkers diagnosis, assessment progression, prognosis. Interventions targeting provide insights developing novel treatments these This review summarizes our current perception properties, biogenesis, functions development research related to ophthalmologic diabetic retinopathy, age-related macular degeneration, retinopathy prematurity, glaucoma, corneal neovascularization, cataract, pterygium, proliferative vitreoretinopathy, retinoblastoma, melanoma.

Language: Английский

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The Role of Immune Checkpoint Blockade in Uveal Melanoma

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(3), P. 879 - 879

Published: Jan. 29, 2020

Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential metastatic spread, especially to liver. Despite its clinical genetic heterogeneity, largely been adopted from cutaneous (CM) with discouraging results until now. The introduction antibodies targeting CTLA-4 PD-1 immune checkpoint blockade (ICB) revolutionized field cancer achieved pioneering CM. Thus, expectations were that patients would also benefit these new options. This review provides comprehensive up-to-date overview on role ICB UM. We give summary biology, features, how it differs studies have investigating are presented. discuss possible reasons lack efficacy compared CM, highlight pitfalls this entity, explain why other immune-modulating therapies could still an option future therapies.

Language: Английский

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