-
Cardiovascular Diabetology May 2024Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. Recently, ferroptosis has been recognised as a novel therapeutic target for...
BACKGROUND
Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. Recently, ferroptosis has been recognised as a novel therapeutic target for cardiovascular diseases. Although an association between ferroptosis and vascular calcification has been reported, the role and mechanism of iron overload in vascular calcification are still poorly understood. Specifically, further in-depth research is required on whether metalloproteins SLC39a14 and SLC39a8 are involved in ferroptosis induced by iron overload.
METHODS
R language was employed for the differential analysis of the dataset, revealing the correlation between ferroptosis and calcification. The experimental approaches encompassed both in vitro and in vivo studies, incorporating the use of iron chelators and models of iron overload. Additionally, gain- and loss-of-function experiments were conducted to investigate iron's effects on vascular calcification comprehensively. Electron microscopy, immunofluorescence, western blotting, and real-time polymerase chain reaction were used to elucidate how Slc39a14 and Slc39a8 mediate iron overload and promote calcification.
RESULTS
Ferroptosis was observed in conjunction with vascular calcification (VC); the association was consistently confirmed by in vitro and in vivo studies. Our results showed a positive correlation between iron overload in VSMCs and calcification. Iron chelators are effective in reversing VC and iron overload exacerbates this process. The expression levels of the metal transport proteins Slc39a14 and Slc39a8 were significantly upregulated during calcification; the inhibition of their expression alleviated VC. Conversely, Slc39a14 overexpression exacerbates calcification and promotes intracellular iron accumulation in VSMCs.
CONCLUSIONS
Our research demonstrates that iron overload occurs during VC, and that inhibition of Slc39a14 and Slc39a8 significantly relieves VC by intercepting iron overload-induced ferroptosis in VSMCs, providing new insights into the VC treatment.
Topics: Ferroptosis; Vascular Calcification; Animals; Cation Transport Proteins; Myocytes, Smooth Muscle; Disease Models, Animal; Muscle, Smooth, Vascular; Mice, Inbred C57BL; Iron Chelating Agents; Signal Transduction; Male; Humans; Iron; Iron Overload
PubMed: 38812011
DOI: 10.1186/s12933-024-02224-z -
BMC Cancer May 2024The aim is to establish and verify reference intervals (RIs) for serum tumor markers for an apparently healthy elderly population in Southwestern China using an indirect...
BACKGROUND
The aim is to establish and verify reference intervals (RIs) for serum tumor markers for an apparently healthy elderly population in Southwestern China using an indirect method.
METHODS
Data from 35,635 apparently healthy elderly individuals aged 60 years and above were obtained in West China Hospital from April 2020 to December 2021. We utilized the Box-Cox conversion combined with the Tukey method to normalize the data and eliminate outliers. Subgroups are divided according to gender and age to examine the division of RIs. The Z-test was used to compare differences between groups, and 95% distribution RIs were calculated using a nonparametric method.
RESULTS
In the study, we observed that the RIs for serum ferritin and Des-γ-carboxy prothrombin (DCP) were wider for men, ranging from 64.18 to 865.80 ng/ml and 14.00 to 33.00 mAU/ml, respectively, compared to women, whose ranges were 52.58 to 585.88 ng/ml and 13.00 to 29.00 mAU/ml. For other biomarkers, the overall RIs were established as follows: alpha-fetoprotein (AFP) 0-6.75 ng/ml, carcinoembryonic antigen (CEA) 0-4.85 ng/ml, carbohydrate antigen15-3 (CA15-3) for females 0-22.00 U/ml, carbohydrate antigen19-9 (CA19-9) 0-28.10 U/ml, carbohydrate antigen125 (CA125) 0-20.96 U/ml, cytokeratin 19 fragment (CYFRA21-1) 0-4.66 U/ml, neuron-specific enolase (NSE) 0-19.41 ng/ml, total and free prostate-specific antigens (tPSA and fPSA) for males 0-5.26 ng/ml and 0-1.09 ng/ml. The RIs for all these biomarkers have been validated through our rigorous processes.
CONCLUSION
This study preliminarily established 95% RIs for an apparently healthy elderly population in Southwestern China. Using real-world data and an indirect method, simple and reliable RIs for an elderly population can be both established and verified, which are suitable for application in various clinical laboratories.
Topics: Humans; Male; Female; Aged; Biomarkers, Tumor; China; Reference Values; Middle Aged; Aged, 80 and over; Prothrombin; Neoplasms; alpha-Fetoproteins; Ferritins; CA-19-9 Antigen; Carcinoembryonic Antigen; CA-125 Antigen; Phosphopyruvate Hydratase; Keratin-19; Protein Precursors; Biomarkers
PubMed: 38811867
DOI: 10.1186/s12885-024-12408-1 -
Metallomics : Integrated Biometal... Jun 2024Red blood cells (RBCs) constitute ∼50% of the bloodstream and represent an important target for environmental pollutants and bacterial/viral infections, which can...
Red blood cells (RBCs) constitute ∼50% of the bloodstream and represent an important target for environmental pollutants and bacterial/viral infections, which can result in their rupture. In addition, diseases such as sickle cell anaemia and paroxysmal nocturnal haemoglobinuria can also result in the rupture of RBCs, which can be potentially life-threatening. With regard to the release of cytosolic metalloproteins from RBCs into the blood-organ system, the biochemical fate of haemoglobin is rather well understood, while comparatively little is known about another highly abundant Zn-metalloprotein, carbonic anhydrase (CA I). To gain insight into the interaction of CA I with human blood plasma constituents, we have employed a metallomics tool comprised of size-exclusion chromatography (SEC) coupled online with an inductively coupled plasma atomic emission spectrometer (ICP-AES), which allows to simultaneously observe all Cu, Fe, and Zn-metalloproteins. After the addition of CA I to human blood plasma incubated at 37°C, the SEC-ICP-AES analysis using phosphate buffered saline (pH 7.4) after 5 min, 1 h, and 2 h revealed that CA I eluted after all endogenous Zn-metalloproteins in the 30 kDa range. Matrix-assisted laser desorption-time of flight mass spectrometry analysis of the collected Zn-peak confirmed that CA I eluted from the column intact. Our in vitro results suggest that CA I released from RBCs to plasma remains free and may be actively involved in health-relevant adverse processes that unfold at the bloodstream-endothelial interface, including atherosclerosis and vision loss.
Topics: Humans; Erythrocytes; Carbonic Anhydrase I; Zinc; Chromatography, Gel; Plasma; Spectrophotometry, Atomic
PubMed: 38811147
DOI: 10.1093/mtomcs/mfae028 -
Current Biology : CB Jun 2024The mitochondrial proteome is comprised of approximately 1,100 proteins, all but 12 of which are encoded by the nuclear genome in C. elegans. The expression of...
The mitochondrial proteome is comprised of approximately 1,100 proteins, all but 12 of which are encoded by the nuclear genome in C. elegans. The expression of nuclear-encoded mitochondrial proteins varies widely across cell lineages and metabolic states, but the factors that specify these programs are not known. Here, we identify mutations in two nuclear-localized mRNA processing proteins, CMTR1/CMTR-1 and SRRT/ARS2/SRRT-1, which we show act via the same mechanism to rescue the mitochondrial complex I mutant NDUFS2/gas-1(fc21). CMTR-1 is an FtsJ-family RNA methyltransferase that, in mammals, 2'-O-methylates the first nucleotide 3' to the mRNA CAP to promote RNA stability and translation. The mutations isolated in cmtr-1 are dominant and lie exclusively in the regulatory G-patch domain. SRRT-1 is an RNA binding partner of the nuclear cap-binding complex and determines mRNA transcript fate. We show that cmtr-1 and srrt-1 mutations activate embryonic expression of NDUFS2/nduf-2.2, a paralog of NDUFS2/gas-1 normally expressed only in dopaminergic neurons, and that nduf-2.2 is necessary for the complex I rescue by the cmtr-1 G-patch mutant. Additionally, we find that loss of the cmtr-1 G-patch domain cause ectopic localization of CMTR-1 protein to processing bodies (P bodies), phase-separated organelles involved in mRNA storage and decay. P-body localization of the G-patch mutant CMTR-1 contributes to the rescue of the hyperoxia sensitivity of the NDUFS2/gas-1 mutant. This study suggests that mRNA methylation at P bodies may control nduf-2.2 gene expression, with broader implications for how the mitochondrial proteome is translationally remodeled in the face of tissue-specific metabolic requirements and stress.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Electron Transport Complex I; Dopaminergic Neurons; Mutation; Methyltransferases; Mitochondria; Mitochondrial Proteins; NADH Dehydrogenase
PubMed: 38810637
DOI: 10.1016/j.cub.2024.04.079 -
Scientific Reports May 2024Extremophile organisms are known that can metabolize at temperatures down to - 25 °C (psychrophiles) and up to 122 °C (hyperthermophiles). Understanding...
Extremophile organisms are known that can metabolize at temperatures down to - 25 °C (psychrophiles) and up to 122 °C (hyperthermophiles). Understanding viability under extreme conditions is relevant for human health, biotechnological applications, and our search for life elsewhere in the universe. Information about the stability and dynamics of proteins under environmental extremes is an important factor in this regard. Here we compare the dynamics of small Fe-S proteins - rubredoxins - from psychrophilic and hyperthermophilic microorganisms, using three different nuclear techniques as well as molecular dynamics calculations to quantify motion at the Fe site. The theory of 'corresponding states' posits that homologous proteins from different extremophiles have comparable flexibilities at the optimum growth temperatures of their respective organisms. Although 'corresponding states' would predict greater flexibility for rubredoxins that operate at low temperatures, we find that from 4 to 300 K, the dynamics of the Fe sites in these homologous proteins are essentially equivalent.
Topics: Iron; Extremophiles; Rubredoxins; Molecular Dynamics Simulation; Temperature
PubMed: 38806591
DOI: 10.1038/s41598-024-62261-2 -
Molecular Genetics & Genomic Medicine May 2024Bone tissue homeostasis relies on the coordinated activity of the bone-forming osteoblasts and bone-resorbing osteoclasts. Osteomesopyknosis is considered a distinctive...
BACKGROUND
Bone tissue homeostasis relies on the coordinated activity of the bone-forming osteoblasts and bone-resorbing osteoclasts. Osteomesopyknosis is considered a distinctive rare sclerosing skeletal disorder of unelucidated pathophysiology and presumably autosomal dominant transmission. However, the causal genes are unknown.
METHODS
We present a case report encompassing clinical assessments, imaging studies, and whole-exome sequencing analysis, complemented by functional in vitro experiments.
RESULTS
This new case of osteomesopyknosis was associated with a missense ALOX5 variant predicted to induce protein misfolding and proteasomal degradation. Transfection experiments demonstrated that the variant was associated with reduced protein levels restored by proteasomal inhibition with bortezomib. Likewise, gene expression analysis showed that the mutated gene was associated with a decreased RANKL/OPG ratio, which is a critical driver of osteoclast precursor differentiation.
CONCLUSION
Our data indicate impaired bone resorption as the underlying mechanism of this rare osteosclerosis, implicating ALOX5 pathogenic variants as potential etiological factors.
Topics: Female; Humans; Arachidonate 5-Lipoxygenase; Mutation, Missense; Osteoclasts; Osteosclerosis; RANK Ligand; Signal Transduction; Middle Aged
PubMed: 38803233
DOI: 10.1002/mgg3.2471 -
Zhongguo Dang Dai Er Ke Za Zhi =... May 2024To study predictive indicators for coronary artery lesions (CAL) and construct a risk prediction model for CAL in Kawasaki disease (KD) children over 5 years old.
OBJECTIVES
To study predictive indicators for coronary artery lesions (CAL) and construct a risk prediction model for CAL in Kawasaki disease (KD) children over 5 years old.
METHODS
A retrospective analysis of KD children over 5 years old at Wuhan Children's Hospital of Tongji Medical College of Huazhong University of Science and Technology from January 2018 to January 2023 was conducted. Among them, 47 cases were complicated with CAL, and 178 cases were not. Multivariate logistic regression analysis was used to explore predictive indicators for CAL in KD children over 5 years old and construct a risk prediction model. The receiver operating characteristic curve was used to evaluate the effectiveness of the prediction model. Finally, the Framingham risk scoring method was used to quantify the predictive indicators, calculate the contribution of each indicator to the prediction of CAL in KD children over 5 years old, and construct a risk prediction scoring model.
RESULTS
The multivariate logistic regression analysis showed that the duration of fever before the initial intravenous immunoglobulin (IVIG) treatment (=1.374, 95%: 1.117-1.689), levels of hypersensitive C-reactive protein (hs-CRP; =1.008, 95%: 1.001-1.015), and serum ferritin levels (=1.002, 95%: 1.001-1.003) were predictive indicators for CAL in KD children over 5 years old. The optimal cutoff values for predicting CAL were: duration of fever before initial IVIG treatment of 6.5 days (AUC=0.654, 95%: 0.565-0.744), hs-CRP of 110.50 mg/L (AUC=0.686, 95%: 0.597-0.774), and ferritin of 313.62 mg/L (AUC=0.724, 95%: 0.642-0.805). According to the Framingham risk scoring method, the low, medium, and high-risk states of CAL occurrence were defined as probabilities of <10%, 10%-20%, and >20%, respectively, with corresponding scores of 0-4 points, 5-6 points, and ≥7 points.
CONCLUSIONS
In KD children over 5 years old, those with a longer duration of fever before initial IVIG treatment, higher levels of hs-CRP, or elevated serum ferritin levels are more likely to develop CAL.
Topics: Humans; Mucocutaneous Lymph Node Syndrome; Male; Child, Preschool; Female; Retrospective Studies; Coronary Artery Disease; Logistic Models; C-Reactive Protein; Child; Risk Factors; Immunoglobulins, Intravenous; Ferritins
PubMed: 38802905
DOI: 10.7499/j.issn.1008-8830.2309103 -
Journal of Translational Medicine May 2024Lung adenocarcinoma (LUAD) is a highly lethal form of lung cancer. Despite advancements in treatments, managing LUAD is still challenging due to its aggressive behavior....
BACKGROUND
Lung adenocarcinoma (LUAD) is a highly lethal form of lung cancer. Despite advancements in treatments, managing LUAD is still challenging due to its aggressive behavior. Recent studies indicate that various molecular pathways, including the dysregulation of ferredoxin 1 (FDX1), play roles in LUAD progression. FDX1, a crucial protein in cellular redox reactions and energy metabolism, has been linked to several cancers. However, its exact role in the development of LUAD is not yet fully understood.
METHODS
We investigated the role of ferredoxin 1 (FDX1) in LUAD progression through analysis of its expression in LUAD tissues and its impact on patient survival. Functional assays were performed to assess the effects of FDX1 overexpression on LUAD cell proliferation, migration, and invasion. A xenograft model was employed to evaluate the tumorigenesis potential of LUAD cells with FDX1 overexpression. Mechanistic insights into FDX1 regulation were gained through depletion experiments targeting the G protein-regulated inducer of neurite outgrowth 2 (GPRIN2)/PI3K signaling pathway.
RESULTS
FDX1 expression was down-regulated in LUAD tissues, correlating with shorter patient survival. Overexpression of FDX1 suppressed LUAD cell proliferation, migration, and invasion in vitro, and inhibited tumorigenesis in vivo. Mechanistically, the GPRIN2/PI3K signaling pathway was implicated in FDX1 regulation, as depletion of GPRIN2 reversed the effects of FDX1 overexpression on cellular functions.
CONCLUSIONS
Our findings highlight FDX1 as a potential tumor suppressor in LUAD, acting through modulation of the GPRIN2/PI3K signaling pathway. These results suggest FDX1 as a promising therapeutic target for LUAD treatment, warranting further investigation into its clinical relevance.
Topics: Animals; Female; Humans; Male; Mice; Adenocarcinoma of Lung; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Ferredoxins; Gene Expression Regulation, Neoplastic; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 38802900
DOI: 10.1186/s12967-024-05277-6 -
World Journal of Surgical Oncology May 2024In clinical practice, genetic testing has become standard for many cancerous diseases. While a diagnosis of a single hereditary syndrome is not uncommon, the coexistence...
BACKGROUND
In clinical practice, genetic testing has become standard for many cancerous diseases. While a diagnosis of a single hereditary syndrome is not uncommon, the coexistence of two genetic diseases, even with partially common symptoms, remains unusual. Therefore, targeted next-generation sequencing (NGS), along with genetic consultation and imaging studies, is essential for every patient with confirmed paraganglioma. In this report, we present two sisters diagnosed with multiple endocrine neoplasia type 2 (MEN2A) and familial paraganglioma syndrome type 1 (FPGL1).
CASE PRESENTATION
After presenting to the clinic with neck tumors persisting for several months, both patients underwent tumor removal procedures following imaging and laboratory studies. Pathological reports confirmed the diagnosis of paragangliomas. Subsequently, genetic testing, including NGS, revealed a mutation in the rearranged during transfection (RET) gene: the heterozygous change (c.2410G > A), (p.Val804Met), and a variant of the succinate dehydrogenase complex subunit D (SDHD) gene: (c.64 C > T), (p.Arg22Ter). Subsequently, thyroidectomy procedures were scheduled in both cases.
CONCLUSION
To the best of our knowledge, this is the first report presenting these two mutations in two related patients, resulting in distinctive genetic syndromes with similar manifestations. This underscores that although infrequent, multiple hereditary disorders may co-occur in the same individual.
Topics: Humans; Female; Multiple Endocrine Neoplasia Type 2a; Siblings; Succinate Dehydrogenase; Adult; Proto-Oncogene Proteins c-ret; Prognosis; Thyroidectomy; Mutation; Genetic Testing; Pedigree; Paraganglioma; High-Throughput Nucleotide Sequencing
PubMed: 38802890
DOI: 10.1186/s12957-024-03418-1 -
BMC Genomics May 2024The filamentous temperature-sensitive H protease (ftsH) gene family belongs to the ATP-dependent zinc metalloproteins, and ftsH genes play critical roles in plant...
BACKGROUND
The filamentous temperature-sensitive H protease (ftsH) gene family belongs to the ATP-dependent zinc metalloproteins, and ftsH genes play critical roles in plant chloroplast development and photosynthesis.
RESULTS
In this study, we performed genome-wide identification and a systematic analysis of soybean ftsH genes. A total of 18 GmftsH genes were identified. The subcellular localization was predicted to be mainly in cell membranes and chloroplasts, and the gene structures, conserved motifs, evolutionary relationships, and expression patterns were comprehensively analyzed. Phylogenetic analysis of the ftsH gene family from soybean and various other species revealed six distinct clades, all of which showed a close relationship to Arabidopsis thaliana. The members of the GmftsH gene family were distributed on 13 soybean chromosomes, with intron numbers ranging from 3 to 15, 13 pairs of repetitive segment. The covariance between these genes and related genes in different species of Oryza sativa, Zea mays, and Arabidopsis thaliana was further investigated. The transcript expression data revealed that the genes of this family showed different expression patterns in three parts, the root, stem, and leaf, and most of the genes were highly expressed in the leaves of the soybean plants. Fluorescence-based real-time quantitative PCR (qRT-PCR) showed that the expression level of GmftsH genes varied under different stress treatments. Specifically, the genes within this family exhibited various induction levels in response to stress conditions of 4℃, 20% PEG-6000, and 100 mmol/L NaCl. These findings suggest that the GmftsH gene family may play a crucial role in the abiotic stress response in soybeans. It was also found that the GmftsH7 gene was localized on the cell membrane, and its expression was significantly upregulated under 4 ℃ treatment. In summary, by conducting a genome-wide analysis of the GmftsH gene family, a strong theoretical basis is established for future studies on the functionality of GmftsH genes.
CONCLUSIONS
This research can potentially serve as a guide for enhancing the stress tolerance characteristics of soybean.
Topics: Glycine max; Phylogeny; Multigene Family; Gene Expression Regulation, Plant; Plant Proteins; Genome, Plant; Gene Expression Profiling; Arabidopsis; Stress, Physiological; Genome-Wide Association Study; Chromosomes, Plant
PubMed: 38802777
DOI: 10.1186/s12864-024-10389-w