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Antioxidants (Basel, Switzerland) May 2024Statins are 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors widely used in the treatment of hyperlipidemia. The inhibition of HMG-CoA reductase in...
Statins are 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors widely used in the treatment of hyperlipidemia. The inhibition of HMG-CoA reductase in the mevalonate pathway leads to the suppression of cell proliferation and induction of apoptosis. The cyclic GMP-AMP synthase (cGAS) stimulator of the interferon genes (STING) signaling pathway has been suggested to not only facilitate inflammatory responses and the production of type I interferons (IFN), but also activate other cellular processes, such as apoptosis. It has not been studied, however, whether cGAS-STING activation is involved in the apoptosis induced by statin treatment in human colorectal cancer cells. In this study, we reported that lovastatin impaired mitochondrial function, including the depolarization of mitochondrial membrane potential, reduction of oxygen consumption, mitochondrial DNA (mtDNA) integrity, and mtDNA abundance in human colorectal cancer HCT116 cells. The mitochondrial dysfunction markedly induced ROS production in mitochondria, whereas the defect in mitochondria respiration or depletion of mitochondria eliminated reactive oxygen species (ROS) production. The ROS-induced oxidative DNA damage by lovastatin treatment was attenuated by mitochondrial-targeted antioxidant mitoquinone (mitoQ). Upon DNA damage, mtDNA was released into the cytosol and bound to DNA sensor cGAS, thus activating the cGAS-STING signaling pathway to trigger a type I interferon response. This effect was not activated by nuclear DNA (nuDNA) or mitochondrial RNA, as the depletion of mitochondria compromised this effect, but not the knockdown of retinoic acid-inducible gene-1/melanoma differentiation-associated protein 5 (RIG-I/MDA5) adaptor or mitochondrial antiviral signaling protein (MAVS). Moreover, lovastatin-induced apoptosis was partly dependent on the cGAS-STING signaling pathway in HCT116 cells as the knockdown of cGAS or STING expression rescued cell viability and mitigated apoptosis. Similarly, the knockdown of cGAS or STING also attenuated the antitumor effect of lovastatin in the HCT116 xenograft model in vivo. Our findings suggest that lovastatin-induced apoptosis is at least partly mediated through the cGAS-STING signaling pathway by triggering mtDNA accumulation in the cytosol in human colorectal cancer HCT116 cells.
PubMed: 38929118
DOI: 10.3390/antiox13060679 -
International Journal of Molecular... Jun 2024Water is a major requirement for our bodies, and alkaline water has induced an antioxidant response in a model of natural aging. A series of recent reports have shown...
Water is a major requirement for our bodies, and alkaline water has induced an antioxidant response in a model of natural aging. A series of recent reports have shown that aging is related to reduced water intake. Hydrogen-rich water has been suggested to exert a general antioxidant effect in relation to both improving lifestyle and preventing a series of diseases. Here, we wanted to investigate the effect of the daily intake of hydrogen-rich alkaline water (HAW) in counteracting the redox imbalance induced in a model of HO-treated mice. Mice were treated with HO for two weeks and either left untreated or supplied with HAW. The results show that HAW induced a reduction in the ROS plasmatic levels that was consistent with the increase in the circulating glutathione. At the same time, the reduction in plasmatic 8-hydroxy-2'-deoxyguanosine was associated with reduced DNA damage in the whole body. Further analysis of the spleen and bone marrow cells showed a reduced ROS content consistent with a significantly reduced mitochondrial membrane potential and superoxide accumulation and an increase in spontaneous proliferation. This study provides evidence for a clear preventive and curative effect of HAW in a condition of systemic toxic condition and redox imbalance.
Topics: Animals; Mice; Hydrogen Peroxide; Hydrogen; Oxidation-Reduction; Reactive Oxygen Species; Water; Oxidative Stress; Antioxidants; DNA Damage; Male; Membrane Potential, Mitochondrial; 8-Hydroxy-2'-Deoxyguanosine; Glutathione; Dietary Supplements
PubMed: 38928440
DOI: 10.3390/ijms25126736 -
International Journal of Molecular... Jun 2024Thyroid cancer diagnosis primarily relies on imaging techniques and cytological analyses. In cases where the diagnosis is uncertain, the quantification of molecular... (Review)
Review
Thyroid cancer diagnosis primarily relies on imaging techniques and cytological analyses. In cases where the diagnosis is uncertain, the quantification of molecular markers has been incorporated after cytological examination. This approach helps physicians to make surgical decisions, estimate cancer aggressiveness, and monitor the response to treatments. Despite the availability of commercial molecular tests, their widespread use has been hindered in our experience due to cost constraints and variability between them. Thus, numerous groups are currently evaluating new molecular markers that ultimately will lead to improved diagnostic certainty, as well as better classification of prognosis and recurrence. In this review, we start reviewing the current preoperative testing methodologies, followed by a comprehensive review of emerging molecular markers. We focus on micro RNAs, long non-coding RNAs, and mitochondrial (mt) signatures, including mtDNA genes and circulating cell-free mtDNA. We envision that a robust set of molecular markers will complement the national and international clinical guides for proper assessment of the disease.
Topics: Humans; Biomarkers, Tumor; Thyroid Neoplasms; DNA, Mitochondrial; Mitochondria; RNA, Untranslated; RNA, Long Noncoding; MicroRNAs; Prognosis
PubMed: 38928426
DOI: 10.3390/ijms25126719 -
International Journal of Molecular... Jun 2024Mitochondrial quality control is essential in mitochondrial function. To examine the importance of Parkin-dependent mechanisms in mitochondrial quality control, we...
Mitochondrial quality control is essential in mitochondrial function. To examine the importance of Parkin-dependent mechanisms in mitochondrial quality control, we assessed the impact of modulating Parkin on proteome flux and mitochondrial function in a context of reduced mtDNA fidelity. To accomplish this, we crossed either the Parkin knockout mouse or ParkinW402A knock-in mouse lines to the Polg mitochondrial mutator line to generate homozygous double mutants. In vivo longitudinal isotopic metabolic labeling was followed by isolation of liver mitochondria and synaptic terminals from the brain, which are rich in mitochondria. Mass spectrometry and bioenergetics analysis were assessed. We demonstrate that slower mitochondrial protein turnover is associated with loss of mtDNA fidelity in liver mitochondria but not synaptic terminals, and bioenergetic function in both tissues is impaired. Pathway analysis revealed loss of mtDNA fidelity is associated with disturbances of key metabolic pathways, consistent with its association with metabolic disorders and neurodegeneration. Furthermore, we find that loss of Parkin leads to exacerbation of Polg-driven proteomic consequences, though it may be bioenergetically protective in tissues exhibiting rapid mitochondrial turnover. Finally, we provide evidence that, surprisingly, dis-autoinhibition of Parkin (ParkinW402A) functionally resembles Parkin knockout and fails to rescue deleterious Polg-driven effects. Our study accomplishes three main outcomes: (1) it supports recent studies suggesting that Parkin dependence is low in response to an increased mtDNA mutational load, (2) it provides evidence of a potential protective role of Parkin insufficiency, and (3) it draws into question the therapeutic attractiveness of enhancing Parkin function.
Topics: Animals; DNA Polymerase gamma; Ubiquitin-Protein Ligases; Mice; DNA, Mitochondrial; Mice, Knockout; Mutation; Proteomics; Proteome; Mitochondria; Mitochondria, Liver; Mitochondrial Proteins
PubMed: 38928146
DOI: 10.3390/ijms25126441 -
Cancers Jun 2024During the cell life cycle, extracellular vesicles (EVs) transport different cargos, including organelles, proteins, RNAs, DNAs, metabolites, etc., that influence cell... (Review)
Review
During the cell life cycle, extracellular vesicles (EVs) transport different cargos, including organelles, proteins, RNAs, DNAs, metabolites, etc., that influence cell proliferation and apoptosis in recipient cells. EVs from metastatic cancer cells remodel the extracellular matrix and cells of the tumor microenvironment (TME), promoting tumor invasion and metastatic niche preparation. Although the process is not fully understood, evidence suggests that EVs facilitate genetic material transfer between cells. In the context of NSCLC, EVs can mediate intercellular mitochondrial (Mt) transfer, delivering mitochondria organelle (MtO), mitochondrial DNA (mtDNA), and/or mtRNA/proteinaceous cargo signatures (MtS) through different mechanisms. On the other hand, certain populations of cancer cells can hijack the MtO from TME cells mainly by using tunneling nanotubes (TNTs). This transfer aids in restoring mitochondrial function, benefiting benign cells with impaired metabolism and enabling restoration of their metabolic activity. However, the impact of transferring mitochondria versus transplanting intact mitochondrial organelles in cancer remains uncertain and the subject of debate. Some studies suggest that EV-mediated mitochondria delivery to cancer cells can impact how cancer responds to radiation. It might make the cancer more resistant or more sensitive to radiation. In our review, we aimed to point out the current controversy surrounding experimental data and to highlight new paradigm-shifting modalities in radiation therapy that could potentially overcome cancer resistance mechanisms in NSCLC.
PubMed: 38927940
DOI: 10.3390/cancers16122235 -
Genes Jun 2024Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG expansion on the huntingtin () gene and is characterized by progressive... (Review)
Review
Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG expansion on the huntingtin () gene and is characterized by progressive motor, cognitive, and neuropsychiatric decline. Recently, new genetic factors besides CAG repeats have been implicated in the disease pathogenesis. Most genetic modifiers are involved in DNA repair pathways and, as the cause of the loss of CAA interruption in the gene, they exert their main influence through somatic expansion. However, this mechanism might not be the only driver of HD pathogenesis, and future studies are warranted in this field. The aim of the present review is to dissect the many faces of genetics in HD pathogenesis, from cis- and trans-acting genetic modifiers to RNA toxicity, mitochondrial DNA mutations, and epigenetics factors. Exploring genetic modifiers of HD onset and progression appears crucial to elucidate not only disease pathogenesis, but also to improve disease prediction and prevention, develop biomarkers of disease progression and response to therapies, and recognize new therapeutic opportunities. Since the same genetic mechanisms are also described in other repeat expansion diseases, their implications might encompass the whole spectrum of these disorders.
Topics: Huntington Disease; Humans; Huntingtin Protein; Trinucleotide Repeat Expansion; Animals; Epigenesis, Genetic; DNA, Mitochondrial
PubMed: 38927742
DOI: 10.3390/genes15060807 -
Genes Jun 2024This study analyzed ancient DNA from the remains of horses unearthed from the Shihuyao tombs. These were found to date from the Han and Tang Dynasties in Xinjiang...
This study analyzed ancient DNA from the remains of horses unearthed from the Shihuyao tombs. These were found to date from the Han and Tang Dynasties in Xinjiang (approximately 2200 to 1100 years ago). Two high-quality mitochondrial genomes were acquired and analyzed using next-generation sequencing. The genomes were split into two maternal haplogroups, B and D, according to a study that included ancient and contemporary samples from Eurasia. A close genetic affinity was observed between the horse of the Tang Dynasty and Akhal-Teke horses according to the primitive horse haplotype G1. Historical evidence suggests that the ancient Silk Road had a vital role in their dissemination. Additionally, the matrilineal history of the Akhal-Teke horse was accessed and suggested that the early domestication of the breed was for military purposes.
Topics: Animals; Horses; Genome, Mitochondrial; China; DNA, Ancient; Haplotypes; DNA, Mitochondrial; Phylogeny; History, Ancient; High-Throughput Nucleotide Sequencing; Domestication
PubMed: 38927726
DOI: 10.3390/genes15060790 -
Genes Jun 2024Little is known about the underlying mechanisms that contribute to the persistence and degradation of DNA within soil. The goals of this study are to determine the...
Little is known about the underlying mechanisms that contribute to the persistence and degradation of DNA within soil. The goals of this study are to determine the duration of mitochondrial DNA (mtDNA) and nuclear DNA (nuDNA) persistence in soils enriched by surface-level human decomposition and to better understand the contribution of environmental factors. The surface-level decomposition of three human cadavers was documented over 11 weeks. Based on quantitative PCR results, we found nuDNA to persist in soils six weeks post-placement, while mtDNA was recoverable for the entire 11-week decomposition period. Principle components analyses and Spearman's rank correlations revealed that (1) time, (2) total body score, and (3) weekly average air temperature were significantly correlated with concentrations of nuDNA and mtDNA in soil, suggesting these factors play a role in the degradation of DNA in soils.
Topics: Humans; Soil; DNA, Mitochondrial; Real-Time Polymerase Chain Reaction; DNA; Cadaver
PubMed: 38927677
DOI: 10.3390/genes15060741 -
Genes May 2024A 23-month-old neutered male dog of unknown ancestry presented with a history of progressive neurological signs that included anxiety, cognitive impairment, tremors,...
A 23-month-old neutered male dog of unknown ancestry presented with a history of progressive neurological signs that included anxiety, cognitive impairment, tremors, seizure activity, ataxia, and pronounced visual impairment. The clinical signs were accompanied by global brain atrophy. Due to progression in the severity of disease signs, the dog was euthanized at 26 months of age. An examination of the tissues collected at necropsy revealed dramatic intracellular accumulations of autofluorescent inclusions in the brain, retina, and cardiac muscle. The inclusions were immunopositive for subunit c of mitochondrial ATP synthase, and their ultrastructural appearances were similar to those of lysosomal storage bodies that accumulate in some neuronal ceroid lipofuscinosis (NCL) diseases. The dog also exhibited widespread neuroinflammation. Based on these findings, the dog was deemed likely to have suffered from a form of NCL. A whole genome sequence analysis of the proband's DNA revealed a homozygous C to T substitution that altered the intron 3-exon 4 splice site of . Other mutations in cause NCL diseases in humans and animals, including dogs. The CLN6 protein was undetectable with immunolabeling in the tissues of the proband. Based on the clinical history, fluorescence and electron-microscopy, immunohistochemistry, and molecular genetic findings, the disorder in this dog was classified as an NCL resulting from the absence of the CLN6 protein. Screening the dog's genome for a panel of breed-specific polymorphisms indicated that its ancestry included numerous breeds, with no single breed predominating. This suggests that the disease variant is likely to be present in other mixed-breed dogs and at least some ancestral breeds, although it is likely to be rare since other cases have not been reported to date.
Topics: Neuronal Ceroid-Lipofuscinoses; Animals; Dogs; Male; Dog Diseases; RNA Splice Sites; Membrane Proteins; Mitochondrial Proton-Translocating ATPases; Brain; Mutation
PubMed: 38927597
DOI: 10.3390/genes15060661 -
Biomedicines Jun 2024The GeneCaRNA human gene database is a member of the GeneCards Suite. It presents ~280,000 human non-coding RNA genes, identified algorithmically from ~690,000...
The GeneCaRNA human gene database is a member of the GeneCards Suite. It presents ~280,000 human non-coding RNA genes, identified algorithmically from ~690,000 RNAcentral transcripts. This expands by ~tenfold the ncRNA gene count relative to other sources. GeneCaRNA thus contains ~120,000 long non-coding RNAs (LncRNAs, >200 bases long), including ~100,000 novel genes. The latter have sparse functional information, a vast terra incognita for future research. LncRNA genes are uniformly represented on all nuclear chromosomes, with 10 genes on mitochondrial DNA. Data obtained from MalaCards, another GeneCards Suite member, finds 1547 genes associated with 1 to 50 diseases. About 15% of the associations portray experimental evidence, with cancers tending to be multigenic. Preliminary text mining within GeneCaRNA discovers interactions of lncRNA transcripts with target gene products, with 25% being ncRNAs and 75% proteins. GeneCaRNA has a biological pathways section, which at present shows 131 pathways for 38 lncRNA genes, a basis for future expansion. Finally, our GeneHancer database provides regulatory elements for ~110,000 lncRNA genes, offering pointers for co-regulated genes and genetic linkages from enhancers to diseases. We anticipate that the broad vista provided by GeneCaRNA will serve as an essential guide for further lncRNA research in disease decipherment.
PubMed: 38927512
DOI: 10.3390/biomedicines12061305