SDHi fungicides: An example of mitotoxic pesticides targeting the succinate dehydrogenase complex

Environment International, Год журнала: 2023, Номер 180, С. 108219 - 108219

Опубликована: Сен. 20, 2023

Succinate dehydrogenase inhibitors (SDHi) are fungicides used to control the proliferation of pathogenic fungi in crops. Their mode action is based on blocking activity succinate (SDH), a universal enzyme expressed by all species harboring mitochondria. The SDH involved two interconnected metabolic processes for energy production: transfer electrons mitochondrial respiratory chain and oxidation fumarate Krebs cycle. In humans, inherited deficiencies may cause major pathologies including encephalopathies cancers. cellular molecular mechanisms related such genetic inactivation have been well described neuroendocrine tumors, which it induces an oxidative stress, pseudohypoxic phenotype, metabolic, epigenetic transcriptomic remodeling, alterations migration invasion capacities cancer cells, connection with accumulation succinate, oncometabolite, substrate SDH. We will discuss recent studies reporting toxic effects SDHi non-target organisms their implications risk assessment pesticides. Recent data show that structure highly conserved during evolution can inhibit mitochondria species, humans. These observations suggest not specific fungal hypothesize could other Moreover, analysis regulatory reports shows most induce tumors animals without evidence genotoxicity. Thus, these substances non-genotoxic mechanism carcinogenicity still needs be fully characterized inhibition. use pesticides targeting enzymes encoded tumor suppressor genes raises questions framework mitotoxic issue therefore textbook case highlights urgent need changes assessment.

Язык: Английский

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Significance of flavonoids targeting PI3K/Akt/HIF-1α signaling pathway in therapy-resistant cancer cells – A potential contribution to the predictive, preventive, and personalized medicine

Journal of Advanced Research, Год журнала: 2023, Номер 55, С. 103 - 118

Опубликована: Март 4, 2023

Cancer management faces multiple obstacles, including resistance to current therapeutic approaches. In the face of challenging microenvironments, cancer cells adapt metabolically maintain their supply energy and precursor molecules for biosynthesis thus sustain rapid proliferation tumor growth. Among various metabolic adaptations observed in cells, altered glucose metabolism is most widely studied. The aberrant glycolytic modification has been associated with cell division, growth, progression, drug resistance. higher rates glycolysis as a hallmark modulated by transcription factor hypoxia inducible 1 alpha (HIF-1α), downstream target PI3K/Akt signaling, deregulated pathway cancer. We provide detailed overview current, primarily experimental, evidence on potential effectiveness flavonoids combat glycolysis-induced conventional targeted therapies. manuscript focuses reducing via affecting PI3K/Akt, HIF-1α (as critical that regulated pathway), key mediators PI3K/Akt/HIF-1α signaling (glucose transporters enzymes). working hypothesis proposes – an attractive application mitigate Phytochemicals represent source promising substances applicable primary, secondary, tertiary care. However, accurate patient stratification individualized profiling crucial steps paradigm shift from reactive predictive, preventive, personalized medicine (PPPM / 3PM). article focused targeting molecular patterns natural provides evidence-based recommendations 3PM relevant implementation.

Язык: Английский

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Single-cell analysis identifies conserved features of immune dysfunction in simulated microgravity and spaceflight

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июнь 11, 2024

Abstract Microgravity is associated with immunological dysfunction, though the mechanisms are poorly understood. Here, using single-cell analysis of human peripheral blood mononuclear cells (PBMCs) exposed to short term (25 hours) simulated microgravity, we characterize altered genes and pathways at basal stimulated states a Toll-like Receptor-7/8 agonist. We validate by RNA sequencing super-resolution microscopy, against data from Inspiration-4 (I4) mission, JAXA (Cell-Free Epigenome) Twins study, spleens mice on International Space Station. Overall, microgravity alters specific for optimal immunity, including cytoskeleton, interferon signaling, pyroptosis, temperature-shock, innate inflammation (e.g., Coronavirus pathogenesis pathway IL-6 signaling), nuclear receptors, sirtuin signaling. directs monocyte inflammatory parameters, impairs T cell NK functionality. Using machine learning, identify numerous compounds linking immune transcription, demonstrate that flavonol, quercetin, can reverse most abnormal pathways. These results define alterations in provide opportunities countermeasures maintain normal immunity space.

Язык: Английский

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Gene Expression Profiling Reveals Fundamental Sex-Specific Differences in SIRT3-Mediated Redox and Metabolic Signaling in Mouse Embryonic Fibroblasts

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(7), С. 3868 - 3868

Опубликована: Март 30, 2024

Sirt-3 is an important regulator of mitochondrial function and cellular energy homeostasis, whose associated with aging various pathologies such as Alzheimer’s disease, Parkinson’s cardiovascular diseases, cancers. Many these conditions show differences in incidence, onset, progression between the sexes. In search hormone-independent, sex-specific roles Sirt-3, we performed mRNA sequencing male female WT KO mouse embryonic fibroblasts (MEFs). The aim this study was to investigate responses loss Sirt-3. By comparing MEF both sexes, global gene expression patterns well metabolic stress have been elucidated. Significant activities basal pathways were found genotypes In-depth pathway analysis revealed several phenomena. Male cells mount adaptive Hif-1a response, shifting their metabolism toward glycolysis production from fatty acids. Furthermore, MEFs leads endoplasmic reticulum stress. Since knock-out permanent, are forced a state persistent oxidative Female able at least partially compensate for by higher antioxidant enzymes. activation neither Hif-1a, nor response observed lacking These findings emphasize role which should be considered future research.

Язык: Английский

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HIF1α/ATF3 partake in PGK1 K191/K192 succinylation by modulating P4HA1/succinate signaling in glioblastoma

Neuro-Oncology, Год журнала: 2024, Номер unknown

Опубликована: Март 2, 2024

Hypoxia is a pathological hallmark in most cancers, including glioblastoma (GBM). Hypoxic signaling activation and post-translational modification (PTM) of oncogenic proteins are well-studied cancers. Accumulating studies indicate glycolytic enzyme PGK1 plays crucial role tumorigenesis, yet the underlying mechanisms remain unknown.

Язык: Английский

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