Suppression of Spry1 reduces HIF1α-dependent glycolysis and impairs angiogenesis in BRAF-mutant cutaneous melanoma

Journal of Experimental & Clinical Cancer Research, Год журнала: 2025, Номер 44(1)

Опубликована: Фев. 14, 2025

About 50% of cutaneous melanoma (CM) harbors the activating BRAFV600 mutation which exerts most oncogenic effects through MAPK signaling pathway. In last years, a number modulators have been identified, including Spry1. this context, we recently demonstrated that knockout Spry1 (Spry1KO) in BRAFV600-mutant CM led to cell cycle arrest and apoptosis, repressed proliferation vitro, reduced tumor growth vivo. Despite these findings, however, precise molecular mechanism linking remains be elucidated. Immunoprecipitation coupled mass spectrometry was employed gain insight into interactome. gene knocked-out using CRISPR strategy BRAF-mutant lines. Transmission electron microscopy used assess relationship between expression mitochondrial morphology. By vitro vivo models, Spry1KO were investigated RNA-sequencing, quantitative real-time PCR, Western blot, immunofluorescence analyses. The Seahorse XF24 assay allowed measurement cellular metabolism our model. Angiogenic potential assessed tube formation assays CD31 staining. mainly located mitochondria cells where it interacted with key molecules involved homeostasis. loss resulted shape alterations dysfunction, associated increased reactive oxygen species production. agreement, found nuclear hypoxia-inducible factor-1 alpha (HIF1α) protein levels clones both along its glycolysis related genes. Accordingly, Ingenuity Pathway Analysis identified "HIF1α Signaling" as significant function affected by silencing, whereas glycolytic significantly impaired depleted cells. addition, results indicated vascular endothelial factor A down-regulated following Spry1KO, possibly result dysfunction. Consistently, observed substantial impairment angiogenesis, staining Altogether, findings identify regulator homeostasis, uncover previously unrecognized role for regulating HIF1α angiogenesis CM. profoundly impacts on while concomitantly impairing HIF1α-dependent reducing cells, thus providing therapeutic target improve treatment.

Язык: Английский

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Pyruvate plus uridine augment mitochondrial respiration and prevent cardiac hypertrophy in zebrafish and H9c2 cells

Journal of Cell Science, Год журнала: 2025, Номер 138(9)

Опубликована: Апрель 24, 2025

ABSTRACT Dysfunction of mitochondrial pyruvate oxidation and aberrant respiratory chain components are common in cardiac defects. However, the precise role respiration cardiomyocyte hypertrophy is unclear. Phenylephrine (PE) treatment rat neonatal H9c2 cardiomyocytes promotes significant with decreased oxygen consumption rate (OCR), membrane potential, subunit NDUFB8, UQCRC2 ATP5A (ATP5F1A) expression, accumulation reactive species (ROS). Surprisingly, a 60% reduction cell survival was observed PE-treated cells relative to control when grown under respiratory-proficient galactose medium. To revert increase survival, we performed screening compounds that boost OCR scavenge ROS, identified plus uridine as best hit. As corroboration vitro study, supplementation significantly prevented PE-induced hypertrophy, pericardial edema bradycardia symptoms zebrafish embryos. Moreover, ventricular atrial area cardiomyocyte-specific GFP transgenic Tg (myl7:HRAS-EGFP) lines. Using vivo models, show boosting through scavenging ROS jointly ameliorate symptoms.

Язык: Английский

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Tricarboxylic Acid Cycle Intermediates and Individual Ageing

Biomolecules, Год журнала: 2024, Номер 14(3), С. 260 - 260

Опубликована: Фев. 22, 2024

Anti-ageing biology and medicine programmes are a focus of genetics, molecular biology, immunology, endocrinology, nutrition, therapy. This paper discusses metabolic therapies aimed at prolonging longevity and/or health. Individual components these effects postulated to be related the energy supply by tricarboxylic acid (TCA) cycle intermediates free radical production processes. article presents several theories ageing clinical descriptions top markers ageing, which define in different categories; additionally, their interactions with age-related changes diseases α-ketoglutarate (AKG) succinate SC formation metabolism pathological states explained. review describes convincingly differences mitochondrial characteristics animals, levels (high low) physiological reactivity functional systems state regulatory providing oxygen-dependent Much attention is given crucial role AKG cells amino synthesis, epigenetic regulation, cell stemness, differentiation, as well associated development conditions and, particular, cancer cells. Another goal was address issue terms individual reactivity. also demonstrated Krebs key component cellular closely various pathologies, such cancer, type 2 diabetes, cardiovascular or neurodegenerative where mTOR pathway plays role. provides postulates postischaemic phenomena an organism demonstrates dependence accelerated pathology on studies species (roundworm Caenorhabditis elegans, Drosophila, mice, humans used models). The findings suggest that this approach may useful show metabolites involved abnormalities thus induce reprogramming contributes senile phenotype degenerative diseases. compounds particularly important when considering mechanisms connected initial able initiate programmed depending intensity oxygen consumption, peculiarities, behavioural reactions.

Язык: Английский

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Mitochondrial dynamics dysfunction: Unraveling the hidden link to depression

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 175, С. 116656 - 116656

Опубликована: Апрель 27, 2024

Depression is a common mental disorder and its pathogenesis not fully understood. However, more evidence shows that mitochondrial dynamics dysfunction may play an important role in the occurrence development of depression. Mitochondria are centre energy production cells, also involved processes such as apoptosis oxidative stress. Studies have found there abnormalities function patients with depression, including morphological changes, disorders, DNA damage, impaired respiratory chain function. These cause excessive free radicals stress mitochondria, which further damage cells affect balance neurotransmitters, causing or aggravating depressive symptoms. shown participate depression by affecting neuroplasticity, inflammation neurotransmitters. This article reviews effects on potential molecular pathway. The restorers for treatment regulating were summarized possibility using biomarker was discussed.

Язык: Английский

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Redox Homeostasis and Molecular Biomarkers in Precision Therapy for Cardiovascular Diseases

Antioxidants, Год журнала: 2024, Номер 13(10), С. 1163 - 1163

Опубликована: Сен. 25, 2024

Precision medicine is envisioned as the future of cardiovascular healthcare, offering a more tailored and effective method for managing diseases compared to traditional one-size-fits-all approaches. The complex role oxidative stress in chronic within framework precision was carefully explored, delving into cellular redox status its critical involvement pathophysiological complexity (CVDs). review outlines mechanisms reactive oxygen species generation function antioxidants maintaining balance. It emphasizes elevated concentrations observed heart failure their detrimental impact on health. Various sources ROS system are examined, including mitochondrial dysfunction, which contributes DNA degradation. article also addresses stress's myocardial remodeling, process pivotal progression diseases. By integrating these aspects, underscores importance homeostasis identifies molecular biomarkers that can enhance therapy CVDs. insights provided aim pave way targeted therapeutic strategies mitigate stress, thereby improving patient outcomes medicine.

Язык: Английский

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Dysfunctional mitochondria elicit bioenergetic decline in the aged heart

The Journal of Cardiovascular Aging, Год журнала: 2024, Номер 4(2), С. 13 - 13

Опубликована: Янв. 1, 2024

Aging represents a complex biological progression affecting the entire body, marked by gradual decline in tissue function, rendering organs more susceptible to stress and diseases. The human heart holds significant importance this context, as its aging process poses life-threatening risks. It entails macroscopic morphological shifts biochemical changes that collectively contribute diminished cardiac function. Among numerous pivotal factors aging, mitochondria play critical role, intersecting with various molecular pathways housing several aging-related agents. In comprehensive review, we provide an updated overview of functional role aging.

Язык: Английский

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Molecular mechanisms for pathophysiology and therapy of cardiac dysfunction in heart failure

SCRIPTA MEDICA, Год журнала: 2025, Номер 56(1), С. 117 - 136

Опубликована: Янв. 1, 2025

Extensive work over the past 6 decades in field of cardiovascular medicine has revealed that haemodynamic, hormonal, metabolic, cellular and molecular mechanisms heart failure are not only complex but also dependent upon type stage disease. Although various agents such as b-adrenoreceptor blockers, angiotensin converting enzyme inhibitors, II receptor antagonists vasodilators available for treatment failure, these interventions delay progression without reducing mortality morbidity. In this article, literature on pathophysiology due to myocardial infarction haemodynamic overload identify targets future drug development is reviewed. Particularly, objective was focus involving pathways generation oxidative stress, inflammation Ca2+-handling abnormalities. It evident elevated levels plasma vasoactive hormones growth factors well increased preload afterload play critical roles stimulating signal transduction occurrence ventricular wall cardiac remodelling subsequent dysfunction. These alterations associated with inflammation, endothelial dysfunction, metabolic defects, intracellular abnormalities, apoptosis, fibrosis changes extracellular matrix. view pathogenic abnormalities failing hearts, it suggested parameters may serve excellent therapy failure. addition, there occurs activation proteases phospholipases depression gene expression induction subcellular hearts thus affecting be considered exert beneficial effects There an urgent need develop some existing newer antioxidants sodium-glucose cotransporter-2 inhibitors RNA based therapies

Язык: Английский

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In Vitro Embryo Culture Impacts Heart Mitochondria in Male Adolescent Sheep

Journal of Developmental Biology, Год журнала: 2025, Номер 13(2), С. 17 - 17

Опубликована: Май 13, 2025

Assisted reproductive technology (ART)such as in vitro embryo culture (IVC), is widely used human infertility treatments; however, its long-term effects on the cardiac health of offspring remain unclear. This study aimed to determine whether IVC metabolism and associated signaling pathways persist after birth into adolescence. Embryos were either transferred an intermediate ewe (ET) or cultured absence (IVC) presence serum (IVCHS) with methionine supplementation (IVCHS+M) for 6 days mating. Naturally mated (NM) ewes controls. Protein expression hormone concentrations left ventricle (LV) analyzed using Western blot LC-MS/MS analyses, respectively. was sex-specific alterations mitochondria, males exhibiting reduced mitochondrial abundance. Cardiac protein oxidative phosphorylation (OXPHOS) complexes 1 4 by IVC. Additionally, PDK-4 Mn-SOD IVCHS+M group, which may impact energy efficiency defense against stress. These changes predispose stress dysfunction, particularly males. provides insights sex-dependent health, emphasizing importance evaluating cardiovascular risks protocols.

Язык: Английский

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Transcriptomics Coupled with Proteomics Reveals Osimertinib-induced Myocardial Mitochondrial Dysfunction

Toxicology Letters, Год журнала: 2024, Номер 397, С. 23 - 33

Опубликована: Май 9, 2024

Язык: Английский

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Therapeutic potential of natural alkaloid emetine against emerging COVID-19 and future viral pandemics

European Journal of Medicinal Chemistry Reports, Год журнала: 2024, Номер 12, С. 100173 - 100173

Опубликована: Июнь 5, 2024

The outbreak of COVID-19 pandemic caused by the infection SARS-CoV-2, has become a global crisis, threatening public health and disrupting economy. Until now, effective therapeutics against other coronavirus diseases are in high demand. Several antiviral strategies drug discovery have identified many small molecules with potent anti-COVID-19 activity. Emetine, one main alkaloids Carapichea ipecacuanha, been found to exhibit activity human coronaviruses, multiple RNA DNA viruses at low nanomolar concentrations different cell lines. In silico analysis reveals that emetine directly disrupts activities SARS-CoV-2 S-protein host ACE2, RdRp-, 3CL-, PL-,and N- proteins. Moreover, shows anti-inflammatory anti-pulmonary arterial hypertensive properties down-regulating ERK1/2, NF-κB RhoA/Rho-kinase/CyPA/Bsg signaling pathways. At doses, is for treatment patients viral infections rodents. This review discusses current findings on efficacy emerging corona, viruses, as well its immunoregulatory pathways clinical potential development prodrugs treat future pandemics.

Язык: Английский

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