The Challenges and Prospects of p53-Based Therapies in Ovarian Cancer

Biomolecules, Год журнала: 2023, Номер 13(1), С. 159 - 159

Опубликована: Янв. 12, 2023

It has been well established that mutations in the tumor suppressor gene, p53, occur readily a vast majority of cancer tumors, including ovarian cancer. Typically diagnosed stages three or four, is fifth leading cause death women, despite accounting for only 2.5% all female malignancies. The overall 5-year survival rate around 47%; however, this drops to an abysmal 29% most common type cancer, high-grade serous carcinoma (HGSOC). HGSOC upwards 96% cases expressing p53. Therefore, wild-type (WT) p53 and p53-based therapies have explored as treatment options via plethora drug delivery vehicles nanoparticles, viruses, polymers, liposomes. However, previous therapeutics faced many challenges, which resulted their limited translational success date. This review highlights selection these historical p53-targeted why they failed, what future could hold new generation class therapies.

Язык: Английский

---

Minerals and the Menstrual Cycle: Impacts on Ovulation and Endometrial Health

Nutrients, Год журнала: 2024, Номер 16(7), С. 1008 - 1008

Опубликована: Март 29, 2024

The role of minerals in female fertility, particularly relation to the menstrual cycle, presents a complex area study that underscores interplay between nutrition and reproductive health. This narrative review aims elucidate impacts on key aspects system: hormonal regulation, ovarian function ovulation, endometrial health, oxidative stress. Despite attention given specific micronutrients disorders, there is noticeable absence comprehensive focusing impact throughout cycle fertility. address this gap by examining influence Each mineral’s contribution explored detail provide clearer picture its importance supporting analysis not only enhances our knowledge health but also offers clinicians valuable insights into potential therapeutic strategies recommended intake promote well-being, considering cycle. stands as first offer such detailed examination context aiming elevate understanding their critical fertility

Язык: Английский

---

Current insights into the regulation of programmed cell death by TP53 mutation in cancer

Frontiers in Oncology, Год журнала: 2022, Номер 12

Опубликована: Окт. 13, 2022

Gene mutation is a complicated process that influences the onset and progression of cancer, most prevalent involves TP53 gene. One ways in which body maintains homeostasis programmed cell death, includes apoptosis, autophagic pyroptosis, ferroptosis, NETosis, more recently identified cuprotosis. Evasion these deaths hallmark cancer cells, our elucidation way cells die helps us better understands mechanisms by arises provides with to treat it.Studies have shown death requires wild-type p53 protein mutations can affect modes death. For example, mutant promotes iron-dependent ferroptosis inhibits apoptotic It clear act on than one pathway pathways do not operate isolation. They interact each other together determine This review focuses via affects Clinical investigations potential for targeted pharmacological agents be used are discussed.

Язык: Английский

---

Structural basis of p53 inactivation by cavity-creating cancer mutations and its implications for the development of mutant p53 reactivators

Cell Death and Disease, Год журнала: 2024, Номер 15(6)

Опубликована: Июнь 11, 2024

The cavity-creating p53 cancer mutation Y220C is an ideal paradigm for developing small-molecule drugs based on protein stabilization. Here, we have systematically analyzed the structural and stability effects of all oncogenic Tyr-to-Cys mutations (Y126C, Y163C, Y205C, Y220C, Y234C, Y236C) in DNA-binding domain (DBD). They were highly destabilizing, drastically lowering melting temperature by 8-17 °C. In contrast, two non-cancerous mutations, Y103C Y107C, had only a moderate effect stability. Differential stabilization mutants upon treatment with anticancer agent arsenic trioxide stibogluconate revealed interesting proximity effect. Crystallographic studies complemented MD simulations showed that Y234C Y236C, create internal cavities different size shape, whereas others induce unique surface lesions. mutation-induced pockets Y126C Y205C mutant were, however, relatively small compared already druggable mutant. Intriguingly, our suggest pronounced plasticity pocket frequently occurring Y163C mutant, which may be exploited development stabilizers. We point out general principles reactivating thermolabile highlight special cases where mutant-specific are needed pharmacological rescue function tumors.

Язык: Английский

---

Antioxidant-related enzymes and peptides as biomarkers of metallic nanoparticles (eco)toxicity in the aquatic environment

Chemosphere, Год журнала: 2024, Номер 364, С. 142988 - 142988

Опубликована: Авг. 3, 2024

Increased awareness of the impact human activities on environment has emerged in recent decades. One significant global environmental and health issue is development materials that could potentially have negative effects. These can accumulate environment, infiltrate organisms, move up food chain, causing toxic effects at various levels. Therefore, it crucial to assess comprising nano-scale particles due rapid expansion nanotechnology. The aquatic particularly vulnerable waste pollution, demands attention. This review provides an overview behavior fate metallic nanoparticles (NPs) environment. It focuses studies investigating toxicity different NPs with a specific emphasis thiol-biomarkers oxidative stress such as glutathione, thiol- related-enzymes, metallothionein. Additionally, selection suitable measurement methods for monitoring NPs' ecotoxicity assessments discussed. also describes analytical techniques employed determining levels biomarkers.

Язык: Английский

---

Zinc in Prostate Health and Disease: A Mini Review

Biomedicines, Год журнала: 2022, Номер 10(12), С. 3206 - 3206

Опубликована: Дек. 10, 2022

Introduction-With the high global prevalence of prostate cancer and associated mortalities, it is important to enhance current clinical practices for better outcomes. The review towards understanding value Zn this mission. Method-General information on in biology multiple aspects involvement health disease were referred PubMed. Results-The most influential feature its ability retain sufficient citrate levels a healthy prostate. deficiencies recorded serum, hair, tissue men with compared non-cancer controls. gut absorption, albumin binding, storage compete various factors. There are associations cellular influx efflux transporters, finger proteins, matrix metalloproteinases, signaling Such marker variations from biological matrices may improve algorithms screening, prognosis, management when coupled standard practices. Discussion-The influence prostatic multidimensional, therefore more personalized requirements be beneficial. Several opportunities exist utilize disease.

Язык: Английский

---

Coordination chemistry suggests that independently observed benefits of metformin and Zn2+ against COVID-19 are not independent

BioMetals, Год журнала: 2024, Номер 37(4), С. 983 - 1022

Опубликована: Апрель 5, 2024

Abstract Independent trials indicate that either oral Zn 2+ or metformin can separately improve COVID-19 outcomes by approximately 40%. Coordination chemistry predicts a mechanistic relationship and therapeutic synergy. deficit is known risk factor for both non-infectious inflammation. Most dietary not absorbed. Metformin naked ligand presumably increases intestinal bioavailability active absorption cation transporters to transport metformin. Intracellular provides natural buffer of many protease reactions; the variable “set point” determined regulation availability. A -interactive network suggested here. The two viral cysteine proteases are targets against COVID-19. Viral host submaximally inhibited exchangeable cell . Inhibition reportedly enhances moderating effect on bioassayed proteome degradation. Firstly, dissociable metformin–Zn complex could be actively transported transporters; thereby creating artificial pathways increased body content. Secondly, coordination create non-natural inhibitor independent Moderation peptidolytic reactions mechanisms slow (a) multiplication (b) invasion (c) pathogenic inflammatory response. These combined actions allow development acquired immunity clear infection before life-threatening Nirmatrelvir (Paxlovid®) opposes selective inhibition main -independent mechanism. Pending safety evaluation, predictable synergistic benefits , perhaps metformin/Zn /Paxlovid® co-administration should investigated.

Язык: Английский

---

Therapeutic effect of trace elements on multiple myeloma and mechanisms of cancer process

Food and Chemical Toxicology, Год журнала: 2023, Номер 179, С. 113983 - 113983

Опубликована: Авг. 9, 2023

Язык: Английский

---

Biological Effects of HDAC Inhibitors Vary with Zinc Binding Group: Differential Effects on Zinc Bioavailability, ROS Production, and R175H p53 Mutant Protein Reactivation

Biomolecules, Год журнала: 2023, Номер 13(11), С. 1588 - 1588

Опубликована: Окт. 28, 2023

The coordination of zinc by histone deacetylase inhibitors (HDACi), altering the bioavailability to deacetylases (HDACs), is key HDAC enzyme inhibition. However, ability binding groups (ZBGs) alter intracellular free Zn+2 levels, which may have far-reaching effects, has not been explored. Using two HDACis with different ZBGs, we documented shifts in concentrations that correlate subsequent ROS production. Next, assayed refolding and reactivation R175H mutant p53 protein vitro provide greater biological context as activity this depends on cellular concentration. data presented demonstrates differential HDACi promoting response element (RE) binding. After cells are treated HDACi, there differences reactivation, be related treatments. Collectively, show distinct ZBGs differentially impact concentration, R175H; therefore, significant independent their acetylation levels. Our results suggest a framework for reevaluating role variable or off-target effects suggesting bioavailable without toxicity associated metallochaperones such ZMC1.

Язык: Английский

---

Understanding the prion-like behavior of mutant p53 proteins in triple-negative breast cancer pathogenesis: The current therapeutic strategies and future directions

Heliyon, Год журнала: 2024, Номер 10(4), С. e26260 - e26260

Опубликована: Фев. 1, 2024

Breast cancer (BC) is viewed as a significant public health issue and the primary cause of cancer-related deaths among women worldwide. Triple-negative breast (TNBC) particularly aggressive subtype that predominantly affects young premenopausal women. The tumor suppressor p53 playsa vital role in cellular response to DNA damage, its loss or mutations are commonly present many cancers, including BC. Recent evidence suggests mutant proteins can aggregate form prion-like structures, which may contribute pathogenesis different types malignancies, such This review provides an overview BC molecular subtypes, epidemiology TNBC, development. We also discuss potential implications aggregation highlight future research directions. Moreover, comprehensive analysis current therapeutic approaches targeting aggregates treatment presented. Strategies small molecules, chaperone inhibitors, immunotherapy, CRISPR-Cas9, siRNA discussed, along with their benefits drawbacks. use these inhibit degradation represents promising target for therapy. Future investigations into efficacy against various binding non-p53 should be conducted develop more effective personalized therapies treatment.

Язык: Английский

---