H2AX: A key player in DNA damage response and a promising target for cancer therapy

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 175, С. 116663 - 116663

Опубликована: Апрель 30, 2024

Cancer is caused by a complex interaction of factors that interrupt the normal growth and division cells. At center this process intricate relationship between DNA damage cellular mechanisms responsible for maintaining genomic stability. When not repaired, it can cause genetic mutations contribute to initiation progression cancer. On other hand, response system, which involves phosphorylation histone variant H2AX (γH2AX), crucial in preserving integrity signaling facilitating repair double-strand breaks. This review provides an explanation molecular dynamics context response. It emphasizes role recruiting localizing machinery at sites chromatin damage. The explains how phosphorylation, facilitated master kinases ATM ATR, acts as signal damage, triggering downstream pathways govern cell cycle checkpoints, apoptosis, fate decision death. critical regulatory point, ensuring survival promoting or steering cells towards apoptosis cases catastrophic Moreover, we explore therapeutic potential targeting cancer treatment, leveraging its dual function biomarker target. By delineating lead roles control, highlight significance both prognostic tool focal point intervention, offering insights into utility enhancing efficacy treatments.

Язык: Английский

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Bee Pollen Phytochemicals and Nutrients as Unequaled Pool of Epigenetic Regulators: Implications for Age-Related Diseases

Foods, Год журнала: 2025, Номер 14(3), С. 347 - 347

Опубликована: Янв. 21, 2025

Bee pollen is characterized by an exceptional diversity and abundance of micronutrients bioactive phytochemicals. This richness remains very sparsely investigated, but accumulating evidence strongly supports a promising future for bee in human nutrition medicine. Epigenetic regulation among the most compelling biomedical topics that remain completely untapped derivative research. In our current research, we identified numerous ubiquitous compounds are consistently present this matrix, regardless its botanical geographical origins, have been well studied documented as epigenetic regulators recent years. Given relative newness both research studies within nutritional, pharmaceutical, medical sciences, review aims to bridge these valuable fields advance related experimental investigations. To best knowledge, first work has aimed comprehensively investigate modulatory potential compounds. Our findings also unveiled several intriguing phenomena, such dual effect same compound depending on cellular context or some cross-generational heritability traits. Although whole extract still lacking, study clearly indicates avenue worth further We hope constitutes foundational cornerstone investigations

Язык: Английский

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Chemical Insights into Oxidative and Nitrative Modifications of DNA

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(20), С. 15240 - 15240

Опубликована: Окт. 16, 2023

This review focuses on DNA damage caused by a variety of oxidizing, alkylating, and nitrating species, it may play an important role in the pathophysiology inflammation, cancer, degenerative diseases. Infection chronic inflammation have been recognized as factors carcinogenesis. Under inflammatory conditions, reactive oxygen species (ROS) nitrogen (RNS) are generated from epithelial cells, result formation oxidative nitrative lesions, such 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) 8-nitroguanine. Cellular is continuously exposed to very high level genotoxic stress physical, chemical, biological agents, with estimated 10,000 modifications occurring every hour genetic material each our cells. highlights recent developments chemical biology toxicology 2'-deoxyribose oxidation products DNA.

Язык: Английский

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Understanding Cancer’s Defense against Topoisomerase-Active Drugs: A Comprehensive Review

Cancers, Год журнала: 2024, Номер 16(4), С. 680 - 680

Опубликована: Фев. 6, 2024

In recent years, the emergence of cancer drug resistance has been one crucial tumor hallmarks that are supported by level genetic heterogeneity and complexities at cellular levels. Oxidative stress, immune evasion, metabolic reprogramming, overexpression ABC transporters, stemness among several key contributing molecular response mechanisms. Topo-active drugs, e.g., doxorubicin topotecan, clinically active utilized extensively against a wide variety human tumors often result in development failure to therapy. Thus, there is an urgent need for incremental comprehensive understanding mechanisms specifically context topo-active drugs. This review delves into intricate mechanistic aspects these intracellular extracellular explores use potential combinatorial approaches utilizing various drugs inhibitors pathways involved resistance. We believe this will help guide basic scientists, pre-clinicians, clinicians, policymakers toward holistic interdisciplinary strategies transcend resistance, renewing optimism ongoing battle cancer.

Язык: Английский

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Poly(ADP-Ribose) Polymerase (PARP) Inhibitors for Cancer Therapy: Advances, Challenges, and Future Directions

Biomolecules, Год журнала: 2024, Номер 14(10), С. 1269 - 1269

Опубликована: Окт. 9, 2024

Poly(ADP-ribose) polymerases (PARPs) are crucial nuclear proteins that play important roles in various cellular processes, including DNA repair, gene transcription, and cell death. Among the 17 identified PARP family members, PARP1 is most abundant enzyme, with approximately 1-2 million molecules per cell, acting primarily as a damage sensor. It has become promising biological target for anticancer drug studies. Enhanced expression present several types of tumors, such melanomas, lung cancers, breast correlating low survival outcomes resistance to treatment. inhibitors, especially newly developed third-generation inhibitors currently undergoing Phase II clinical trials, have shown efficacy agents both single drugs sensitizers chemo- radiotherapy. This review explores properties, characteristics, challenges discussing their development from first-generation compounds, more sustainable synthesis methods discovery new anti-cancer agents, mechanisms therapeutic action, potential targeting additional targets beyond catalytic active site proteins. Perspectives on green chemistry also discussed.

Язык: Английский

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KLF5 promotes esophageal squamous cell carcinoma radioresistance by targeting the Keap1-Nrf2 pathway

Discover Oncology, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 7, 2025

Esophageal squamous cell carcinoma (ESCC) has high morbidity and mortality in developing countries. The purpose of this article is to study the mechanism KLF5's effect on ESCC radiosensitivity. WGCNA gene expression profiling identified core genes associated with KLF5 was detected by RT-qPCR. effects overexpression or downregulation anti-irradiated cells' proliferation, migration, invasion, apoptotic activity were studied through colony formation assay, Transwell flow cytometry. Western blot can detect Nrf2 signaling pathway cells tissues. enrichment at Keap1 promoter analyzed ChIP-base, binding ChIP dual-luciferase. They then injected into mice used radiation monitor tumor progression. a significantly upregulated drug-resistant cells. Overexpression increased viability attenuated cellular responses radiation. knockdown reduces radioresistance. After overexpression, up-regulated, after down-regulated. inhibits transcriptional Keap1. Upregulation radioresistance KLF5/Keap1 regulates vivo radiotherapy. promotes inhibiting transcription activating pathway.

Язык: Английский

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Molecular mechanisms of m6A modifications regulating tumor radioresistance

Molecular Medicine, Год журнала: 2025, Номер 31(1)

Опубликована: Фев. 19, 2025

Abstract Radiotherapy is one of the most effective treatments for malignant tumors. Radioresistance a major factor that contributes to radiotherapy failure and poor prognosis. Recent studies have elucidated pivotal role aberrant N6-methyladenosine (m6A) modification, predominant internal mRNA modification in eukaryotic cells, influences cancer progression by disrupting gene expression other critical cellular processes. Furthermore, m6A methylation provides substrate tumor therapy; however, whether it regulates radioresistance remains unclear. Methylated transferase (writer), demethylated (eraser), methylated recognition protein (reader) are three essential proteins regulate via different mechanisms This review summarizes latest research advances aims provide novel perspectives on advancement regimens overcome invasion.

Язык: Английский

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Pharmacological impact of microRNAs in head and neck squamous cell carcinoma: Prevailing insights on molecular pathways, diagnosis, and nanomedicine treatment

Frontiers in Pharmacology, Год журнала: 2023, Номер 14

Опубликована: Май 3, 2023

Head and neck squamous cell carcinoma is a disease that most commonly produce tumours from the lining of epithelial cells lips, larynx, nasopharynx, mouth, or oro-pharynx. It one deadly forms cancer. About to two percent all neo-plasm-related deaths are attributed head carcinoma, which responsible for about six cancers. MicroRNAs play critical role in proliferation, differentiation, tumorigenesis, stress response, triggering apoptosis, other physiological process. regulate gene expression provide new diagnostic, prognostic, therapeutic options carcinoma. In this work, molecular signaling pathways related emphasized. We also an overview MicroRNA downregulation overexpression its as diagnostic prognostic marker recent years, nano-based therapies have been explored. addition, nanotechnology-based alternatives discussed promising strategy exploring paradigms aimed at improving efficacy conventional cytotoxic chemotherapeutic agents against attenuating their cytotoxicity. This article provides information on ongoing recently completed clinical trials based nanotechnology.

Язык: Английский

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Innovative Strategies to Combat 5-Fluorouracil Resistance in Colorectal Cancer: The Role of Phytochemicals and Extracellular Vesicles

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(13), С. 7470 - 7470

Опубликована: Июль 8, 2024

Colorectal cancer (CRC) is a significant public health challenge, with 5-fluorouracil (5-FU) resistance being major obstacle to effective treatment. Despite advancements, 5-FU remains formidable due complex mechanisms such as alterations in drug transport, evasion of apoptosis, dysregulation cell cycle dynamics, tumor microenvironment (TME) interactions, and extracellular vesicle (EV)-mediated pathways. Traditional chemotherapy often results high toxicity, highlighting the need for alternative approaches better efficacy safety. Phytochemicals (PCs) EVs offer promising CRC therapeutic strategies. PCs, derived from natural sources, exhibit lower toxicity can target multiple pathways involved progression resistance. facilitate targeted delivery, modulate immune response, interact TME sensitize cells However, potential PCs engineered overcoming reshaping immunosuppressive underexplored. Addressing this gap crucial identifying innovative therapies enhanced reduced toxicities. This review explores multifaceted evaluates synergistic effects combining improve treatment while minimizing adverse effects. Additionally, it investigates by serving delivery vehicles modulating TME. By synthesizing current knowledge addressing research gaps, enhances academic understanding CRC, interdisciplinary involving revolutionizing therapy. Further clinical validation are essential translating these findings into improved patient outcomes.

Язык: Английский

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Depleted-MLH1 Expression Predicts Prognosis and Immunotherapeutic Efficacy in Uterine Corpus Endometrial Cancer: An In Silico Approach

BioMedInformatics, Год журнала: 2024, Номер 4(1), С. 326 - 346

Опубликована: Фев. 1, 2024

Uterine corpus endometrial carcinoma (UCEC) poses significant clinical challenges due to its high incidence and poor prognosis, exacerbated by the lack of effective screening methods. The standard treatment for UCEC typically involves surgical intervention, with radiation chemotherapy as potential adjuvant therapies. In recent years, immunotherapy has emerged a promising avenue advanced UCEC. This study employs multi-omics approach, analyzing RNA-sequencing data information from Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA), GeneMANIA databases investigate prognostic value MutL Homolog 1 (MLH1) gene expression in dysregulation MLH1 is linked adverse outcomes suppressed immune cell infiltration. Set Enrichment (GSEA) reveal MLH1’s involvement immune-related processes, while correlates tumor mutational burden (TMB) microsatellite instability (MSI). Lower associated poorer reduced responsiveness Programmed death protein (PD-1)/Programmed death-ligand (PD-L1) inhibitors, heightened sensitivity anti-cancer agents. comprehensive analysis establishes biomarker predicting response, drug UCEC, offering crucial insights management patients.

Язык: Английский

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