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Selenoprotein K (SELENOK) is one of the endoplasmic reticulum (ER) proteins that mainly functions in the regulation of ER stress, calcium flux, and antioxidant defense. Reactive oxygen species (ROS) is one of the key indicators of ferroptosis, and SELENOK inhibition could disrupt ROS balance, and consequently might cause ferroptosis. However, there are no previous studies about the mechanism of SELENOK in ferroptosis by regulating ROS. In this study, we report the effect of SELENOK inhibition on cell proliferation, viability, iron recycling-associated proteins, ROS, antioxidant enzymes, and lipid peroxidation of cervical cancer cells (HeLa cells). The results showed that ROS levels and iron-dependent lipid peroxidation were significantly enhanced, whereas cell viability and proliferation were significantly downregulated, and resulted in marked reductions in tumor size after SELENOK knockdown. SELENOK knockdown also caused steep decreases in glutathione peroxidase 4/glutathione levels and deterioration in ROS scavenging ability, and exacerbated ferroptosis in HeLa cells. Our findings elucidated that SELENOK knockdown could shrink tumor size by regulating ferroptosis, which might provide a theoretical basis for treating cervical cancer.

Automated and specific picking of selenium-containing molecular entities has not been an obvious option for software tools associated with electrospray high-resolution mass spectrometry (MS). In our study, a comprehensive pattern matching approach based on intra-isotopologue distance and isotopologue ratio data was critically evaluated in terms of reproducibility and selenium isotope selection on three samples, including selenized Torula yeast and the selenium hyperaccumulator plant Cardamine violifolia. Hydrophilic interaction liquid chromatography was applied to provide a one-step separation for water soluble metabolites to put an end to the need for either orthogonal setups or poor retention on reversed phase chromatography. Assistance from inductively coupled plasma-MS was taken only for chromatographic verification purposes, and the involvement of absolute mass defect (MD) data in selenometabolite-specific screening was assessed by multivariate statistical tools. High focus was placed on screening efficiency and on the validation of discovered selenized molecules to avoid reporting of artefacts. From the >1000 molecular entries detected, selenium-containing molecules were picked up with a recovery rate of >88% and a false positive rate of <10%. Isotop(ologu)e pairs of 78Se-80Se and 80Se-82Se proved to be the most performant in the detection. On the basis of accurate mass information and hypothetical deamination processes, elemental composition could be proposed for 72 species out of the 75 selenium species encountered without taking into account selenocompound databases. Absolute MD data were used to significantly differentiate a potentially sample-specific subgroup of false positive molecular entities from non-selenized and selenized entities.

The diffuse and renewed use of silver as antimicrobial agent has caused the development of resistance to silver ions in some bacterial strains, posing a serious threat for health systems. In order to cast light on the mechanistic features of resistance, here, we aimed to understand how silver interacts with the periplasmic metal-binding protein SilE which is engaged in bacterial silver detoxification. This aim was addressed by studying two peptide portions of SilE sequence (SP2 and SP3) that contain the putative motifs involved in Ag+ binding. We demonstrate that SP2 model peptide is involved in silver binding through its histidine and methionine residues in the two HXXM binding sites. In particular, the first binding site is supposed to bind the Ag+ ion in a linear fashion, while the second binding site complexes the silver ion in a distorted trigonal planar fashion. We propose a model where the SP2 peptide binds two silver ions when the concentration ratio Ag+/SP2 is ≥10.0. We also suggest that the two binding sites of SP2 have different affinity for silver. This evidence comes from the change in the path direction of the Nuclear Magnetic Resonance (NMR) cross-peaks upon the addition of Ag+. Here, we report the conformational changes of SilE model peptides occurring upon silver binding, monitored at a deep level of molecular details. This was addressed by a multifaceted approach, combining NMR, circular dichroism, and mass spectrometry experiments.

The misfolding and aggregation of amyloid-β (Aβ) peptides are histopathological features found in the brains of Alzheimer's disease (AD). To discover effective therapeutics for AD, numerous efforts have been made to control the aggregation of Aβ species and their interactions with other pathological factors, including metal ions. Metal ions, such as Cu(II) and Zn(II), can bind to Aβ peptides forming metal-bound Aβ (metal-Aβ) complexes and, subsequently, alter their aggregation pathways. In particular, redox-active metal ions bound to Aβ species can produce reactive oxygen species leading to oxidative stress. In this review, we briefly illustrate some experimental approaches for characterizing the coordination and aggregation properties of metal-Aβ complexes.

The function of Corynebacterium glutamicum open reading frame (ORF) NCgl2684 (named nceA in this study), which was annotated to encode a metalloregulator, was assessed using physiological, genetic, and biochemical approaches. Cells with deleted-nceA (ΔnceA) showed a resistant phenotype to NiSO4 and CoSO4 and showed faster growth in minimal medium containing 20 μM NiSO4 or 10 μM CoSO4 than both the wild-type and nceA-overexpressing (P180-nceA) cells. In the ΔnceA strain, the transcription of the downstream-located ORF NCgl2685 (nceB), annotated to encode efflux protein, was increased approximately 4-fold, whereas gene transcription decreased down to 30% level in the P180-nceA strain. The transcriptions of the nceA and nceB genes were stimulated, even when as little as 5 nM NiSO4 was added to the growth medium. Protein NceA was able to bind DNA comprising the promoter region (from -14 to + 18) of the nceA--nceB operon. The protein-DNA interaction was abolished in the presence of 20 μM NiSO4, 50 μM CoSO4, or 50 μM CdSO4. Although manganese induced the transcription of the nceA and nceB genes, it failed to interrupt protein-DNA interaction. Simultaneously, the P180-nceA cells showed increased sensitivity to oxidants such as menadione, hydrogen peroxide, and cumene hydroperoxide, but not diamide. Collectively, our data show that NceA is a nickel- and cobalt-sensing transcriptional regulator that controls the transcription of the probable efflux protein-encoding nceB. The genes are able to suppress intracellular levels of nickel to prevent reactions, which can cause oxidative damage to cellular components.

Loss-of-function mutations in SLC30A10 induce hereditary manganese (Mn)-induced neuromotor disease in humans. We previously identified SLC30A10 to be a critical Mn efflux transporter that controls physiological brain Mn levels by mediating hepatic and intestinal Mn excretion in adolescence/adulthood. Our studies also revealed that in adulthood, SLC30A10 in the brain regulates brain Mn levels when Mn excretion capacity is overwhelmed (e.g. after Mn exposure). But, the functional role of brain SLC30A10 under physiological conditions is unknown. We hypothesized that, under physiological conditions, brain SLC30A10 may modulate brain Mn levels and Mn neurotoxicity in early postnatal life because body Mn excretion capacity is reduced in this developmental stage. We discovered that Mn levels of pan-neuronal/glial Slc30a10 knockout mice were elevated in specific brain regions (thalamus) during specific stages of early postnatal development (postnatal day 21), but not in adulthood. Furthermore, adolescent or adult pan-neuronal/glial Slc30a10 knockouts exhibited neuromotor deficits. The neuromotor dysfunction of adult pan-neuronal/glial Slc30a10 knockouts was associated with a profound reduction in evoked striatal dopamine release without dopaminergic neurodegeneration or changes in striatal tissue dopamine levels. Put together, our results identify a critical physiological function of brain SLC30A10-SLC30A10 in the brain regulates Mn levels in specific brain regions and periods of early postnatal life, which protects against lasting deficits in neuromotor function and dopaminergic neurotransmission. These findings further suggest that a deficit in dopamine release may be a likely cause of early-life Mn-induced motor disease.

The development of metal complexes of Schiff base has attracted much attention due to their DNA binding properties and extensive biological activities. We reported here five copper(II) complexes [Cu(L1)] (1), [Cu(L2)] (2), [Cu(L3)] (3), [Cu2(L4)(OAc)] (4), and [Cu2(L5)(HCOO)] (5) bearing the bis-Schiff base ligands of bis(5-chlorosalicylidene)-1,3-propanediamine (H2L1), bis(5-chlorosalicylidene)-2-methyl-1,3-propanediamine (H2L2), bis(5-bromosalicylidene)-2-methyl-1,3-propanediamine (H2L3), bis(5-chlorosalicylidene)-2-hydroxyl-1,3-propanediamine (H3L4), and bis(5-bromosalicylidene)-2-hydroxyl-1,3-propanediamine (H3L5), respectively. The single crystal X-ray diffraction analysis results revealed that complexes 1-3 present mononuclear structures and complexes 4 and 5 show dinuclear structures. It was also shown that all of these complexes are stable under physiological conditions. The in vitro antitumor activities of the five complexes were evaluated. Anticancer selectivity was also found for complex 2 on different cell lines with the lowest IC50 value on Hela cells. Further mechanistic studies showed that the three mononuclear Cu(II) complexes can induce apoptosis through the mitochondrial pathway by decreasing mitochondrial membrane potential and increasing the reactive oxygen species (ROS) and Ca2+ levels. They can activate caspase-3 and caspase-9, and can also regulate the expression of pro-apoptotic protein and anti-apoptotic protein in cells. All of these results showed that complex 2 is a potential anticancer drug.

Selenium performs a variety of biological functions in organisms, including antioxidant and anti-inflammatory effects. This study investigated how selenium deficiency affects weaned calves' intestines. According to Inductively coupled plasma mass spectrometry (ICP-MS) analysis of intestinal selenium concentrations in calves, the Se-D group had a significantly lower concentration of selenium. Hematoxylin-eosin staining showed that the intestinal epithelial cells were detached, the goblet cells were lost, and the intestinal villi were fragmented and loosely arranged in the Se-D group, along with hyperemia and inflammatory infiltration. Of the 22 selenoprotein genes, 9 were downregulated in response to selenium deficiency in Reverse transcription-PCR (RT-PCR), whereas 6 genes were upregulated. In the Se-D group, oxidative stress was detected by measuring redox levels in the intestines. Furthermore, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, RT-PCR, and Western blotting (WB) results indicated that both intrinsic and extrinsic apoptosis pathways are activated in the intestine during selenium deficiency. Selenium deficiency also induced necroptosis in the intestine through upregulation of MLKL, RIPK1, and RIPK3 mRNA levels. In addition, according to hematoxylin-eosin staining and ELISA, selenium-deficient calves had severe inflammation in their intestines. As a result of RT-PCR and WB analyses, we found that selenium deficiency was associated with nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Our study suggested that weaned calves' intestines are affected by selenium deficiency, which causes oxidative stress, inflammation, apoptosis, and necroptosis.

Potassium (K) is an essential electrolyte for cellular functions in living organisms, and disturbances in K+ homeostasis could lead to various chronic diseases (e.g. hypertension, cardiac disease, diabetes, and bone health). However, little is known about the natural distribution of stable K isotopes in mammals and their application to investigate bodily homeostasis and/or as biomarkers for diseases. Here, we measured K isotopic compositions (δ41K, per mil deviation of 41K/39K from the NIST SRM 3141a standard) of brain, liver, kidney, and red blood cells (RBCs) from 10 mice (five females and five males) with three different genetic backgrounds. Our results reveal that different organs and RBCs have distinct K isotopic signatures. Specifically, the RBCs have heavy K isotopes enrichment with δ41K ranging from 0.67 to 0.08‰, while the brains show lighter K isotopic compositions with δ41K ranging from -1.13 to -0.09‰ compared to the livers (δ41K = -0.12 ± 0.58‰) and kidneys (δ41K = -0.24 ± 0.57‰). We found that the K isotopic and concentration variability is mostly controlled by the organs, with a minor effect of the genetic background and sex. Our study suggests that the K isotopic composition could be used as a biomarker for changes in K+ homeostasis and related diseases such as hypertension, cardiovascular, and neurodegenerative diseases.

Understanding of how mercury species cause cellular impairments at the molecular level is critical for explaining the detrimental effects of mercury exposure on the human body. Previous studies have reported that inorganic and organic mercury compounds can induce apoptosis and necrosis in a variety of cell types, but more recent advances reveal that mercuric mercury (Hg2+) and methylmercury (CH3Hg+) may result in ferroptosis, a distinct form of programmed cell death. However, it is still unclear which protein targets are responsible for ferroptosis induced by Hg2+ and CH3Hg+. In this study, human embryonic kidney 293T cells were used to investigate how Hg2+ and CH3Hg+ trigger ferroptosis, given their nephrotoxicity. Our results demonstrate that glutathione peroxidase 4 (GPx4) plays a key role in lipid peroxidation and ferroptosis in renal cells induced by Hg2+ and CH3Hg+. The expression of GPx4, the only lipid repair enzyme in mammal cells, was downregulated in response to Hg2+ and CH3Hg+ stress. More importantly, the activity of GPx4 could be markedly inhibited by CH3Hg+, owing to the direct binding of the selenol group (-SeH) in GPx4 to CH3Hg+. Selenite supplementation was demonstrated to enhance the expression and activity of GPx4 in renal cells, and consequently relieve the cytotoxicity of CH3Hg+, suggesting that GPx4 is a crucial modulator implicated in the Hg-Se antagonism. These findings highlight the importance of GPx4 in mercury-induced ferroptosis, and provide an alternative explanation for how Hg2+ and CH3Hg+ induce cell death.