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Nutrients May 2024As women age, oocytes are susceptible to a myriad of dysfunctions, including mitochondrial dysfunction, impaired DNA repair mechanisms, epigenetic alterations, and...
As women age, oocytes are susceptible to a myriad of dysfunctions, including mitochondrial dysfunction, impaired DNA repair mechanisms, epigenetic alterations, and metabolic disturbances, culminating in reduced fertility rates among older individuals. Ferredoxin (FDX) represents a highly conserved iron-sulfur (Fe-S) protein essential for electron transport across multiple metabolic pathways. Mammalian mitochondria house two distinct ferredoxins, FDX1 and FDX2, which share structural similarities and yet perform unique functions. In our investigation into the regulatory mechanisms governing ovarian aging, we employed a comprehensive multi-omics analysis approach, integrating spatial transcriptomics, single-cell RNA sequencing, human ovarian pathology, and clinical biopsy data. Previous studies have highlighted intricate interactions involving excessive lipid peroxide accumulation, redox-induced metal ion buildup, and alterations in cellular energy metabolism observed in aging cells. Through a multi-omics analysis, we observed a notable decline in the expression of the critical gene FDX1 as ovarian age progressed. This observation prompted speculation regarding FDX1's potential as a promising biomarker for ovarian aging. Following this, we initiated a clinical trial involving 70 patients with aging ovaries. These patients were administered oral nutritional supplements consisting of DHEA, ubiquinol CoQ10, and Cleo-20 T3 for a period of two months to evaluate alterations in energy metabolism regulated by FDX1. Our results demonstrated a significant elevation in FDX1 levels among participants receiving nutritional supplementation. We hypothesize that these nutrients potentiate mitochondrial tricarboxylic acid cycle (TCA) activity or electron transport chain (ETC) efficiency, thereby augmenting FDX1 expression, an essential electron carrier in metabolic pathways, while concurrently mitigating lipid peroxide accumulation and cellular apoptosis. In summary, our findings underscore the potential of nutritional intervention to enhance in vitro fertilization outcomes in senescent cells by bolstering electron transport proteins, thus optimizing energy metabolism and improving oocyte quality in aging women.
Topics: Female; Humans; Ovary; Aging; Ferredoxins; Mitochondria; Adult; Ubiquinone; Dietary Supplements; Metabolic Networks and Pathways; Energy Metabolism; Middle Aged
PubMed: 38794708
DOI: 10.3390/nu16101470 -
Nutrients May 2024Cadmium (Cd) is recognized as being linked to several liver diseases. Currently, due to the limited spectrum of drugs available for the treatment of Cd intoxication,...
Cadmium (Cd) is recognized as being linked to several liver diseases. Currently, due to the limited spectrum of drugs available for the treatment of Cd intoxication, developing and designing antidotes with superior detoxification capacity and revealing their underlying mechanisms remains a major challenge. Therefore, we developed the first next-generation probiotic -pSK18a-MT that delivers metallothionein (MT) to overcome Cd-induced liver injury in C57BL/6 mice by utilizing bacterial surface display technology. The results demonstrate that -pSK18a-MT could efficiently express MT without altering the growth and probiotic properties of the strain. Moreover, we found that -pSK18a-MT ameliorated Cd contamination-induced hepatic steatosis, inflammatory cell infiltration, and liver fibrosis by decreasing the expression of aminotransferases along with inflammatory factors. Activation of the Nrf2-Keap1 signaling pathway also further illustrated the hepatoprotective effects of the engineered bacteria. Finally, we showed that -pSK18a-MT improved the colonic barrier function impaired by Cd induction and ameliorated intestinal flora dysbiosis in Cd-poisoned mice by increasing the relative abundance of the Verrucomicrobiota. These data revealed that the combination of and MT both alleviated Cd-induced liver injury to a greater extent and restored the integrity of colonic epithelial tissues and bacterial dysbiosis.
Topics: Animals; Probiotics; Gastrointestinal Microbiome; Escherichia coli; Metallothionein; Mice, Inbred C57BL; Cadmium; Mice; Chemical and Drug Induced Liver Injury; Dysbiosis; Male; Liver; Signal Transduction
PubMed: 38794706
DOI: 10.3390/nu16101468 -
Nutrients May 2024Human milk (HM) contains the essential macronutrients and bioactive compounds necessary for the normal growth and development of newborns. The milk collected by human...
Human milk (HM) contains the essential macronutrients and bioactive compounds necessary for the normal growth and development of newborns. The milk collected by human milk banks is stored frozen and pasteurized, reducing its nutritional and biological value. The purpose of this study was to determine the effect of hyperbaric storage at subzero temperatures (HS-ST) on the macronutrients and bioactive proteins in HM. As control samples, HM was stored at the same temperatures under 0.1 MPa. A Miris HM analyzer was used to determine the macronutrients and the energy value. The lactoferrin (LF), lysozyme (LYZ) and lactalbumin (LAC) content was checked using high-performance liquid chromatography, and an ELISA test was used to quantify secretory immunoglobulin A (sIgA). The results showed that the macronutrient content did not change significantly after 90 days of storage at 60 MPa/-5 °C, 78 MPa/-7 °C, 111 MPa/-10 °C or 130 MPa/-12 °C. Retention higher than 90% of LYZ, LAC, LF and sIgA was observed in the HM stored at conditions of up to 111 MPa/-10 °C. However, at 130 MPa/-12 °C, there was a reduction in LYZ and LF, by 39 and 89%, respectively. The storage of HM at subzero temperatures at 0.1 MPa did not affect the content of carbohydrates or crude and true protein. For fat and the energy value, significant decreases were observed at -5 °C after 90 days of storage.
Topics: Humans; Milk, Human; Nutritive Value; Lactoferrin; Food Storage; Muramidase; Lactalbumin; Immunoglobulin A, Secretory; Nutrients; Milk Proteins; Female
PubMed: 38794693
DOI: 10.3390/nu16101455 -
Medicina (Kaunas, Lithuania) May 2024: Mutations in succinate dehydrogenase (SDH) and fumarate hydratase (FH) give rise to various familial cancer syndromes, with these alterations being characteristic of...
: Mutations in succinate dehydrogenase (SDH) and fumarate hydratase (FH) give rise to various familial cancer syndromes, with these alterations being characteristic of certain types of histomorphologically specific leiomyomas that hold significant predictive value. : This study presents two cases of uterine leiomyomas exhibiting rare histomorphological and genetic characteristics, which are crucial for prognosis and further treatment. : Distinct histopathological features such as marked nuclear atypia, intracellular eosinophilic globules, and abnormal intratumoral vessels raise suspicion for specific leiomyoma subtypes, which carry predictive significance for additional hereditary cancer syndromes. Immunohistochemical analysis confirmed FH/SDH deficiency in both patients, who underwent careful follow-up. : This study describes two cases involving unusual leiomyomas, the histopathological characteristics of which may easily go unrecognized. These features hold predictive significance because their specific mutations point to additional hereditary cancer syndromes, highlighting the need for further examinations.
Topics: Humans; Female; Fumarate Hydratase; Uterine Neoplasms; Succinate Dehydrogenase; Adult; Leiomyoma; Middle Aged
PubMed: 38793008
DOI: 10.3390/medicina60050825 -
Medicina (Kaunas, Lithuania) Apr 2024: The administration of iron to premature newborns is a common intervention aimed at preventing iron deficiency (ID). However, there is no consensus on the optimal...
: The administration of iron to premature newborns is a common intervention aimed at preventing iron deficiency (ID). However, there is no consensus on the optimal timing and dosage for iron supplementation in this population. This study evaluates the effects and potential adverse outcomes of administering iron on the 7th and 21st days of life in premature infants. : This research was conducted on 108 premature neonates at the "Louis Turcanu" Children's Emergency Clinical Hospital in Timisoara, Romania. The study population was divided into a control group of 48 newborns who did not receive iron supplementation and an intervention group of 60 newborns who did. The analysis utilized univariate and multivariate regression to examine binary outcomes. : The findings indicate that iron supplementation significantly increased the risk of anemia during the premature period at 21 days of life, as demonstrated by both univariate and multivariate regression analyses, with an odds ratio (OR) of 2.40 (95% CI, 1.01-5.68) and an adjusted odds ratio (AOR) of 2.75 (95% CI, 1.06-7.11), respectively. Contrary to expectations, iron supplementation did not significantly alter the risk of abnormal serum ferritin or iron levels at 21 days of life, according to the univariate analysis ( = 0.380 and = 0.526, respectively). : The observed increase in the risk of anemia without a corresponding improvement in the serum ferritin or iron levels suggests the need for further investigation into alternative strategies for iron supplementation in premature newborns.
Topics: Humans; Infant, Newborn; Prospective Studies; Male; Infant, Premature; Female; Iron; Romania; Anemia, Iron-Deficiency; Cohort Studies; Dietary Supplements; Ferritins
PubMed: 38792868
DOI: 10.3390/medicina60050684 -
Molecules (Basel, Switzerland) May 2024is a common pathogenic microorganism in humans and animals. Type II NADH oxidoreductase (NDH-2) is the only NADH:quinone oxidoreductase present in this organism and...
BACKGROUND
is a common pathogenic microorganism in humans and animals. Type II NADH oxidoreductase (NDH-2) is the only NADH:quinone oxidoreductase present in this organism and represents a promising target for the development of anti-staphylococcal drugs. Recently, myricetin, a natural flavonoid from vegetables and fruits, was found to be a potential inhibitor of NDH-2 of . The objective of this study was to evaluate the inhibitory properties of myricetin against NDH-2 and its impact on the growth and expression of virulence factors in .
RESULTS
A screening method was established to identify effective inhibitors of NDH-2, based on heterologously expressed NDH-2. Myricetin was found to be an effective inhibitor of NDH-2 with a half maximal inhibitory concentration (IC) of 2 μM. In silico predictions and enzyme inhibition kinetics further characterized myricetin as a competitive inhibitor of NDH-2 with respect to the substrate menadione (MK). The minimum inhibitory concentrations (MICs) of myricetin against strains ranged from 64 to 128 μg/mL. Time-kill assays showed that myricetin was a bactericidal agent against . In line with being a competitive inhibitor of the NDH-2 substrate MK, the anti-staphylococcal activity of myricetin was antagonized by MK-4. In addition, myricetin was found to inhibit the gene expression of enterotoxin SeA and reduce the hemolytic activity induced by culture on rabbit erythrocytes in a dose-dependent manner.
CONCLUSIONS
Myricetin was newly discovered to be a competitive inhibitor of NDH-2 in relation to the substrate MK. This discovery offers a fresh perspective on the anti-staphylococcal activity of myricetin.
Topics: Flavonoids; Staphylococcus aureus; Microbial Sensitivity Tests; Anti-Bacterial Agents; NADH Dehydrogenase; Enzyme Inhibitors; Animals; Bacterial Proteins; Humans; Virulence Factors
PubMed: 38792214
DOI: 10.3390/molecules29102354 -
Molecules (Basel, Switzerland) May 2024The electron-electron, or zero-field interaction (ZFI) in the electron paramagnetic resonance (EPR) of high-spin transition ions in metalloproteins and coordination...
The electron-electron, or zero-field interaction (ZFI) in the electron paramagnetic resonance (EPR) of high-spin transition ions in metalloproteins and coordination complexes, is commonly described by a simple spin Hamiltonian that is second-order in the spin : H=D[Sz2-SS+1/3+E(Sx2-Sy2). Symmetry considerations, however, allow for fourth-order terms when ≥ 2. In metalloprotein EPR studies, these terms have rarely been explored. Metal ions can cluster via non-metal bridges, as, for example, in iron-sulfur clusters, in which exchange interaction can result in higher system spin, and this would allow for sixth- and higher-order ZFI terms. For metalloproteins, these have thus far been completely ignored. Single-molecule magnets (SMMs) are multi-metal ion high spin complexes, in which the ZFI usually has a negative sign, thus affording a ground state level pair with maximal spin quantum number = ±, giving rise to unusual magnetic properties at low temperatures. The description of EPR from SMMs is commonly cast in terms of the 'giant-spin model', which assumes a magnetically isolated system spin, and in which fourth-order, and recently, even sixth-order ZFI terms have been found to be required. A special version of the giant-spin model, adopted for scaling-up to system spins of order ≈ 10-10, has been applied to the ubiquitous iron-storage protein ferritin, which has an internal core containing Fe ions whose individual high spins couple in a way to create a superparamagnet at ambient temperature with very high system spin reminiscent to that of ferromagnetic nanoparticles. This scaled giant-spin model is critically evaluated; limitations and future possibilities are explicitly formulated.
PubMed: 38792115
DOI: 10.3390/molecules29102254 -
International Journal of Molecular... May 2024Chronic environmental exposure to toxic heavy metals, which often occurs as a mixture through occupational and industrial sources, has been implicated in various...
Chronic environmental exposure to toxic heavy metals, which often occurs as a mixture through occupational and industrial sources, has been implicated in various neurological disorders, including Parkinsonism. Vanadium pentoxide (VO) typically presents along with manganese (Mn), especially in welding rods and high-capacity batteries, including electric vehicle batteries; however, the neurotoxic effects of vanadium (V) and Mn co-exposure are largely unknown. In this study, we investigated the neurotoxic impact of MnCl, VO and MnCl-VO co-exposure in an animal model. C57BL/6 mice were intranasally administered either de-ionized water (vehicle), MnCl (252 µg) alone, VO (182 µg) alone, or a mixture of MnCl (252 µg) and VO (182 µg) three times a week for up to one month. Following exposure, we performed behavioral, neurochemical, and histological studies. Our results revealed dramatic decreases in olfactory bulb (OB) weight and levels of tyrosine hydroxylase, dopamine, and 3,4-dihydroxyphenylacetic acid in the treatment groups compared to the control group, with the Mn/V co-treatment group producing the most significant changes. Interestingly, increased levels of α-synuclein expression were observed in the substantia nigra (SN) of treated animals. Additionally, treatment groups exhibited locomotor deficits and olfactory dysfunction, with the co-treatment group producing the most severe deficits. The treatment groups exhibited increased levels of the oxidative stress marker 4-hydroxynonenal in the striatum and SN, as well as the upregulation of the pro-apoptotic protein PKCδ and accumulation of glomerular astroglia in the OB. The co-exposure of animals to Mn/V resulted in higher levels of these metals compared to other treatment groups. Taken together, our results suggest that co-exposure to Mn/V can adversely affect the olfactory and nigral systems. These results highlight the possible role of environmental metal mixtures in the etiology of Parkinsonism.
Topics: Animals; Mice; Manganese; Mice, Inbred C57BL; Vanadium; Manganese Compounds; Male; Olfactory Bulb; Dopamine; Vanadium Compounds; Oxidative Stress; Parkinsonian Disorders; alpha-Synuclein; Chlorides; Tyrosine 3-Monooxygenase; Aldehydes; Substantia Nigra; Disease Models, Animal; 3,4-Dihydroxyphenylacetic Acid
PubMed: 38791326
DOI: 10.3390/ijms25105285 -
International Journal of Molecular... May 2024Heme biosynthesis is a highly conserved pathway from bacteria to higher animals. Heme, which serves as a prosthetic group for various enzymes involved in multiple...
Heme biosynthesis is a highly conserved pathway from bacteria to higher animals. Heme, which serves as a prosthetic group for various enzymes involved in multiple biochemical processes, is essential in almost all species, making heme homeostasis vital for life. However, studies on the biological functions of heme in filamentous fungi are scarce. In this study, we investigated the role of heme in . A mutant lacking the rate-limiting enzymes in heme synthesis, coproporphyrinogen III oxidase (Cpo) or ferrochelatase (Fc), was constructed using a homologous recombination strategy. The results showed that the absence of these enzymes was lethal to , but the growth defect could be rescued by the addition of hemin, so we carried out further studies with the help of hemin. The results demonstrated that heme was required for the activity of FgCyp51, and its absence increased the sensitivity to tebuconazole and led to the upregulation of in . Additionally, heme plays an indispensable role in the life cycle of , which is essential for vegetative growth, conidiation, external stress response (especially oxidative stress), lipid accumulation, fatty acid β-oxidation, autophagy, and virulence.
Topics: Fusarium; Heme; Fungal Proteins; Stress, Physiological; Oxidative Stress; Triazoles; Gene Expression Regulation, Fungal; Fungicides, Industrial; Ferrochelatase
PubMed: 38791308
DOI: 10.3390/ijms25105268 -
Genes May 2024Pa0665 in shares homologous sequences with that of the essential A-type iron-sulfur (Fe-S) cluster insertion protein ErpA in . However, its essentiality in and its...
Pa0665 in shares homologous sequences with that of the essential A-type iron-sulfur (Fe-S) cluster insertion protein ErpA in . However, its essentiality in and its complementation with has not been experimentally examined. To fulfill this task, we constructed plasmid-based -mutant / using a three-step protocol. The mutant displayed growth defects at 42 °C, which were complemented by expressing . Microscopic observations indicated a petite cell phenotype for / at 42 °C, correlated with the downregulation of the gene. RNA sequencing revealed significant transcriptional changes in genes associated with the oxidative phosphorylation (OXPHOS) system, aligning with reduced ATP levels in / under 42 °C. Additionally, the -mutant showed heightened sensitivity to HO at 42 °C. Overall, our study demonstrates the essential role of for OXPHOS function and is complemented by . We propose that the plasmid-based -allele is useful for genetic analysis of essential genes of interest in .
Topics: Pseudomonas aeruginosa; Oxidative Phosphorylation; Bacterial Proteins; Mutation; Escherichia coli; Iron-Sulfur Proteins; Gene Expression Regulation, Bacterial
PubMed: 38790219
DOI: 10.3390/genes15050590