β−Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives

Pharmacological Reviews, Год журнала: 2023, Номер 75(5), С. 854 - 884

Опубликована: Апрель 7, 2023

The two beta-arrestins, beta-arrestin-1 and -2 (systematic names: arrestin-2 -3, respectively), are multifunctional intracellular proteins that regulate the activity of a very large number cellular signaling pathways physiological functions. were discovered for their ability to disrupt via G protein-coupled receptors (GPCRs) binding activated receptors. However, it is now well recognized both beta-arrestins can also act as direct modulators numerous processes either GPCR-dependent or -independent mechanisms. Recent structural, biophysical, biochemical studies have provided novel insights into how bind GPCRs downstream effector proteins. Studies with beta-arrestin mutant mice identified pathophysiological regulated by and/or -2. Following brief summary recent structural studies, this review will primarily focus on beta-arrestin-regulated functions, particular central nervous system roles in carcinogenesis key metabolic including maintenance glucose energy homeostasis. This highlight potential therapeutic implications these discuss strategies could prove useful targeting specific purposes. Significance Statement structurally closely related evolutionarily highly conserved, emerged able vast array outcome cultured cells, complemented structure function, should pave way development classes therapeutically drugs capable regulating

Язык: Английский

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Melanoma biology and treatment: a review of novel regulated cell death-based approaches

Cancer Cell International, Год журнала: 2024, Номер 24(1)

Опубликована: Фев. 9, 2024

Abstract The incidence of melanoma, the most lethal form skin cancer, has increased due to ultraviolet exposure. treatment advanced particularly metastatic cases, remains challenging with poor outcomes. Targeted therapies involving BRAF/MEK inhibitors and immunotherapy based on anti-PD1/anti-CTLA4 antibodies have achieved long-term survival rates approximately 50% for patients melanoma. However, therapy resistance inadequate response continue hinder further breakthroughs in treatments that increase rates. This review provides an introduction molecular-level pathogenesis melanoma offers overview current options their limitations. Cells can die by either accidental or regulated cell death (RCD). RCD is orderly controlled a variety macromolecules maintain stability internal environment. Since uncontrolled proliferation tumor cells requires evasion programs, inducing may be strategy. summarizes studies various types nonapoptotic RCDs, such as autophagy-dependent death, necroptosis, ferroptosis, pyroptosis, recently discovered cuproptosis, context relationships between these RCDs are examined, interplay targeted discussed. Given findings demonstrating different stimuli associated induction shows promise integral component strategies

Язык: Английский

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Autophagy as a targeted therapeutic approach for skin cancer: Evaluating natural and synthetic molecular interventions

Cancer Pathogenesis and Therapy, Год журнала: 2024, Номер 2(4), С. 231 - 245

Опубликована: Фев. 2, 2024

Skin cancer, a prevalent malignancy worldwide, poses significant health concerns owing to its increasing incidence. Autophagy, natural cellular process, is pivotal event in skin cancer and has advantageous detrimental effects. This duality prompted extensive investigations into medical interventions targeting autophagy modulation for their substantial therapeutic potential. systematic review aimed investigate the relationship between contribution mechanism of modulators cancer. We outlined effectiveness safety as promising strategy treatment comprehensive identified diverse array with potential Each these compounds demonstrates efficacy through distinct physiological mechanisms that have been elucidated detail. Interestingly, findings from literature search indicated none natural, synthetic, or semisynthetic exhibited notable adverse effects either human animal models. Consequently, this offers novel mechanistic perspectives on targeted

Язык: Английский

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A Narrative Review of Current Knowledge on Cutaneous Melanoma

Clinics and Practice, Год журнала: 2024, Номер 14(1), С. 214 - 241

Опубликована: Янв. 26, 2024

Cutaneous melanoma is a public health problem. Efforts to reduce its incidence have failed, as it continues increase. In recent years, many risk factors been identified. Numerous diagnostic systems exist that greatly assist in early clinical diagnosis. The histopathological aspect illustrates the grim nature of these cancers. Currently, pathogenic pathways and tumor microclimate are key development therapeutic methods. Revolutionary therapies like targeted therapy immune checkpoint inhibitors starting replace traditional Targeted aims at specific molecule chain block it, stopping cell growth dissemination. main function boost cellular immunity order combat cancer cells. Unfortunately, different rates effectiveness side effects, cannot be applied all patients. These shortcomings basis increased mortality rates. This study covers stages evolutionary sequence melanoma. With data front us, we see need for new research efforts directed will bring greater benefits terms patient survival prognosis, with fewer adverse effects.

Язык: Английский

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Cobalt oxide nanoparticles induce cytotoxicity and excessive ROS mediated mitochondrial dysfunction and p53-independent apoptosis in melanoma cells

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 17, 2025

Nanotherapy has emerged as a promising strategy for the targeted and efficient treatment of melanoma, most aggressive lethal form skin cancer, with minimized systemic toxicity. However, therapeutic efficacy cobalt oxide nanoparticles (Co3O4NPs) in melanoma remains unexplored. This study aimed to assess potential Co3O4NPs by evaluating their impact on cell viability, genomic DNA mitochondrial integrity, reactive oxygen species (ROS) generation apoptosis induction A-375 cells. Our findings demonstrated concentration-dependent reduction viability upon five Co3O4NP concentrations (0.2, 2, 20, 200, 2000 µg/ml), an IC50 value 303.80 µg/ml. Treatment this concentration significantly increased ROS generation, induced dramatic damage, disrupted membrane integrity. Flow cytometric analysis revealed necrosis following exposure at value. Results qRT-PCR remarkable dysregulation apoptotic genes, including significant downregulation p53 ND3 genes marked upregulation anti-apoptotic gene Bcl2. These highlight novel potent inducers death manner through excessive production, instability, dysfunction expression, ultimately promoting thus underscores nanotherapeutic candidate treatment, warranting further exploration elucidate full biological clinical applicability.

Язык: Английский

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Advances in Materials Science for Precision Melanoma Therapy: Nanotechnology-Enhanced Drug Delivery Systems

Pharmaceutics, Год журнала: 2025, Номер 17(3), С. 296 - 296

Опубликована: Фев. 24, 2025

Melanoma, a highly aggressive form of skin cancer, poses major therapeutic challenge due to its metastatic potential, resistance conventional therapies, and the complexity tumor microenvironment (TME). Materials science nanotechnology advances have led using nanocarriers such as liposomes, dendrimers, polymeric nanoparticles, metallic nanoparticles transformative solutions for precision melanoma therapy. This review summarizes findings from Web Science, PubMed, EMBASE, Scopus, Google Scholar highlights role in overcoming treatment barriers. Nanoparticles facilitate passive active targeting through mechanisms enhanced permeability retention (EPR) effect functionalization with tumor-specific ligands, thereby improving accuracy drug delivery reducing systemic toxicity. Stimuli-responsive systems multi-stage further improve overcome challenges poor penetration resistance. Emerging platforms combine diagnostic imaging delivery, paving way personalized medicine. However, there are still issues scalability, biocompatibility, regulatory compliance. comprehensive potential integrating genetics proteomics, scalable, patient-specific therapies. These interdisciplinary innovations promise redefine provide safer, more effective, accessible treatments. Continued research is essential bridge gap between evidence-based scientific clinical applications.

Язык: Английский

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BRAF V600-Mutated Metastatic Melanoma and Targeted Therapy Resistance: An Update of the Current Knowledge

Cancers, Год журнала: 2023, Номер 15(9), С. 2607 - 2607

Опубликована: Май 4, 2023

Melanoma is the most common cause of death in skin cancer due to its high metastatic potential. While targeted therapies have improved care patients with melanoma harboring BRAFV600E mutation, these treatments are associated a frequency resistance. Resistance factors related cellular adaptation as well changes tumor microenvironment. At level, resistance involves mutations, overexpression, activation, or inhibition effectors involved cell signaling pathways such MAPK, PI3K/AKT, MITF, and epigenetic (miRNAs). In addition, several components microenvironment, soluble factors, collagen, stromal cells also play crucial role this fact, extracellular matrix remodeling impacts physical chemical properties stiffness acidity, respectively The immune stroma affected, including CAF. aim manuscript review mechanisms responsible for BRAFV600E-mutated melanoma.

Язык: Английский

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Cu(II) and Zn(II) Complexes of New 8-Hydroxyquinoline Schiff Bases: Investigating Their Structure, Solution Speciation, and Anticancer Potential

Inorganic Chemistry, Год журнала: 2023, Номер 62(29), С. 11466 - 11486

Опубликована: Июль 13, 2023

We report the synthesis and characterization of three novel Schiff bases (L1-L3) derived from condensation 2-carbaldehyde-8-hydroxyquinoline with amines containing morpholine or piperidine moieties. These were reacted CuCl2 ZnCl2 yielding six new coordination compounds, general formula ML2, where M = Cu(II) Zn(II) L L1-L3, which all characterized by analytical, spectroscopic (Fourier transform infrared (FTIR), UV-visible absorption, nuclear magnetic resonance (NMR), electron paramagnetic (EPR)), mass spectrometric techniques, as well single-crystal X-ray diffraction. In solid state, two complexes, L1 L2, are obtained dinuclear relatively short Cu-Cu distances (3.146 3.171 Å for Cu2(L1)4 Cu2(L2)4, respectively). The free ligands show moderate lipophilicity, while their complexes more lipophilic. pKa values L1-L3 formation constants complex (for ML ML2) species determined spectrophotometric titrations, showing higher stability than complexes. EPR indicated presence several in solution pH varied binding modes proposed. to bovine serum albumin (BSA) was evaluated fluorescence circular dichroism (CD) spectroscopies. All bind BSA, demonstrated CD, process takes hours reach equilibrium. antiproliferative activity malignant melanoma cells (A375) noncancerous keratinocytes (HaCaT). display significant cytotoxicity (IC50 < 10 μM) but modest selectivity. ligands, being active approximately twice cytotoxic cisplatin. A Guava ViaCount assay corroborated activity.

Язык: Английский

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Cyclodextrin encapsulation enabling the anticancer repositioning of disulfiram: Preparation, analytical and in vitro biological characterization of the inclusion complexes

International Journal of Pharmaceutics, Год журнала: 2024, Номер 657, С. 124187 - 124187

Опубликована: Май 1, 2024

Drug repositioning is a high-priority and feasible strategy in the field of oncology research, where unmet medical needs are continuously unbalanced. Disulfiram potential non-chemotherapeutic, adjuvant anticancer agent. However, clinical translation limited by drug's poor bioavailability. Therefore, molecular encapsulation disulfiram with cyclodextrins evaluated to enhance solubility stability drug. The present work describes for first time complexation randomly methylated-β-cyclodextrin. A parallel analytical vitro biological comparison inclusion complexes hydroxypropyl-β-cyclodextrin, methylated-β-cyclodextrin sulfobutylether-β-cyclodextrin conducted. significant drug enhancement about 1000-folds fast dissolution 1 min demonstrated. dissolution-permeation studies proliferation assays demonstrate solubility-dependent efficacy Throughout different cancer cell lines' characteristics unspecific antitumoral activity, inhibitory cyclodextrin encapsulated on melanoma (IC50 100 nM) glioblastoma 7000 lines differ magnitude. This pre-formulation screening experiment serves as proof concept using platform tool further delivery development areas.

Язык: Английский

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Primary Cutaneous Melanoma—Management in 2024

Journal of Clinical Medicine, Год журнала: 2024, Номер 13(6), С. 1607 - 1607

Опубликована: Март 11, 2024

Background: Maximizing survival for patients with primary cutaneous melanomas (melanomas) depends on an early diagnosis and appropriate management. Several new drugs have been shown to improve in high-risk melanoma patients. Despite well-documented guidelines, many do not receive optimal management, particularly when considering patient age. Objective: provide update management from the time of decision biopsy a suspicious skin lesion. Methods: We reviewed melanoma-management research published between 2018 2023 identified where such findings impact confirmed melanomas. Pubmed, Google Scholar, Ovid Cochrane Library were used as search tools. Results: 81 publications since 2017 that changed management; 11 2018, 12 2019, 10 2020, 2021, 17 2022 18 2023. Discussion: Delayed or inaccurate is more likely occur partial shave punch obtain histopathology. Wherever feasible, local excision narrow margin should be method choice suspected melanoma. The Breslow thickness remains single most important predictor outcome, followed by age then ulceration. BAUSSS biomarker, (Breslow thickness, Age, Ulceration, Subtype, Sex Site) provides accurate determining mortality risk than older currently employed approaches, including sentinel lymph node biopsy. Patients metastatic and/or nodal disease considered adjuvant drug therapy (ADT). Further, are increasingly ADT, even without spread. Invasive less 1 mm thick usually managed radial mms normal skin. If 2 mm, select 20 mm. When over clinical undertaken. In situ 5 Mohs control surgery. Such wide excisions around given only surgery can regarded therapeutic required. who had one at increased another Ideal ongoing includes regular lifelong checks. Total body photography if has naevi, especially atypical/dysplastic naevi identified. Targeted approaches occupational lifestyle exposure ultraviolet light important. Management also needs include consideration vitamin D supplementary therapy.

Язык: Английский

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