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Open Biology Jun 2024is the predominant mould pathogen for humans. Adaption to host-imposed iron limitation has previously been demonstrated to be essential for its virulence. [2Fe-2S]...
is the predominant mould pathogen for humans. Adaption to host-imposed iron limitation has previously been demonstrated to be essential for its virulence. [2Fe-2S] clusters are crucial as cofactors of several metabolic pathways and mediate cytosolic/nuclear iron sensing in fungi including . [2Fe-2S] cluster trafficking has been shown to involve BolA family proteins in both mitochondria and the cytosol/nucleus. Interestingly, both homologues, termed Bol1 and Bol3, possess mitochondrial targeting sequences, suggesting the lack of cytosolic/nuclear versions. Here, we show by the combination of mutational, proteomic and fluorescence microscopic analyses that expression of the Bol3 encoding gene leads to dual localization of gene products to mitochondria and the cytosol/nucleus via alternative translation initiation downstream of the mitochondrial targeting sequence, which appears to be highly conserved in various species. Lack of either mitochondrial Bol1 or Bol3 was phenotypically inconspicuous while lack of cytosolic/nuclear Bol3 impaired growth during iron limitation but not iron sensing which indicates a particular importance of [2Fe-2S] cluster trafficking during iron limitation. Remarkably, cytosolic/nuclear Bol3 differs from the mitochondrial version only by N-terminal acetylation, a finding that was only possible by mutational hypothesis testing.
Topics: Aspergillus fumigatus; Fungal Proteins; Cytosol; Mitochondria; Iron; Adaptation, Physiological; Cell Nucleus; Protein Transport; Proteomics; Iron-Sulfur Proteins; Gene Expression Regulation, Fungal; Acetylation
PubMed: 38919062
DOI: 10.1098/rsob.240033 -
Scientific Reports Jun 2024Identification of an early biomarker and effective testing device to differentiate dry eye disease secondary to autoimmune disease (Sjögren's syndrome dry eye disease)...
Identification of an early biomarker and effective testing device to differentiate dry eye disease secondary to autoimmune disease (Sjögren's syndrome dry eye disease) from non-Sjögren's dry eye disease are prerequisites for appropriate treatment. We aimed to demonstrate the capacity of a new photo-detection device to evaluate tear lactoferrin levels as a tool for differentiating systemic conditions associated with dry eye disease. Patients with non-Sjögren's and Sjögren's syndrome dry eye disease (n = 54 and n = 52, respectively) and controls (n = 11) were enrolled. All participants completed the Ocular Surface Disease Index questionnaire. Tear collection was performed with Schirmer test, and tear break-up time was examined using a slit lamp. Tear lactoferrin was evaluated using our newly developed photo-detection device. The average lactoferrin concentration was significantly lower in samples from patients with non-Sjögren's dry eye disease (0.337 ± 0.227 mg/mL, n = 54) and Sjögren's syndrome dry eye disease (0.087 ± 0.010 mg/mL, n = 52) than in control samples (1.272 ± 0.54 mg/mL, n = 11) (p < 0.0001). Further, lactoferrin levels were lower in patients with Sjögren's syndrome dry eye disease than in those with non-Sjögren's dry eye disease (p < 0.001). Our cost-effective, antibody-free, highly sensitive photo-detection device for evaluating tear lactoferrin levels can assist ophthalmologists in differentiating different types of dry eye diseases.
Topics: Lactoferrin; Humans; Tears; Sjogren's Syndrome; Female; Middle Aged; Dry Eye Syndromes; Male; Adult; Biomarkers; Diagnosis, Differential; Aged; Fluorescence
PubMed: 38914667
DOI: 10.1038/s41598-024-65487-2 -
Scientific Reports Jun 2024Bivalves are an extraordinary class of animals in which species with a doubly uniparental inheritance (DUI) of mitochondrial DNA have been described. DUI is...
Bivalves are an extraordinary class of animals in which species with a doubly uniparental inheritance (DUI) of mitochondrial DNA have been described. DUI is characterized as a mitochondrial homoplasmy of females and heteroplasmy of male individuals where F-type mitogenomes are passed to the progeny with mother egg cells and divergent M-type mitogenomes are inherited with fathers sperm cells. However, in most cases only male individuals retain divergent mitogenome inherited with spermatozoa. Additionally, in many of bivalves, unique mitochondrial features, like additional genes, gene duplication, gene extensions, mitochondrial introns, and recombination, were observed. In this study, we sequenced and assembled male-type mitogenomes of three Donax species. Comparative analysis of mitochondrial sequences revealed a lack of all seven NADH dehydrogenase subunits as well as the presence of three long additional open reading frames lacking identifiable homology to any of the existing genes.
Topics: Animals; Male; Genome, Mitochondrial; Electron Transport Complex I; DNA, Mitochondrial; Female; Spermatozoa; Phylogeny; Open Reading Frames
PubMed: 38914611
DOI: 10.1038/s41598-024-63764-8 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Jun 2024Human lactoferrin (HLF), an essential nutrient found in breast milk, possesses antibacterial, anti-inflammatory, and immune-enhancing properties. In this study, the...
Human lactoferrin (HLF), an essential nutrient found in breast milk, possesses antibacterial, anti-inflammatory, and immune-enhancing properties. In this study, the effects of three constitutive promoters (P, P, and P) and three inducible promoters (P, P, and P) on the expression of HLF were compared using G601 as the host strain. The results showed that the highest expression of HLF, reaching 651.57 μg/L, was achieved when regulated by the P promoter. Furthermore, the combinational optimization of ribosome binding site (RBS) and signal peptides was investigated, and the optimal combination of RBS6 and SP resulted in increased HLF expression to 1 099.87 μg/L, with 498.68 μg/L being secreted extracellularly. To further enhance HLF secretion, the metal cations-related gene was knocked out, leading to an extracellular HLF level of 637.28 μg/L. This study successfully demonstrated the secretory expression of HLF in . through the selection and optimization of expression elements, laying the foundation for the development of efficient . cell factories for lactoprotein synthesis.
Topics: Bacillus subtilis; Lactoferrin; Humans; Promoter Regions, Genetic; Recombinant Proteins
PubMed: 38914499
DOI: 10.13345/j.cjb.230785 -
Functional & Integrative Genomics May 2024Breast cancer severely affects women health. 70% of breast cancer are estrogen receptor positive. Breast cancer stem cells are a group of tumor with plasticity, causing...
Breast cancer severely affects women health. 70% of breast cancer are estrogen receptor positive. Breast cancer stem cells are a group of tumor with plasticity, causing tumor relapse and metastasis. RUNX3 is a tumor suppressor frequently inactivated in estrogen receptor positive breast cancer. However, the mechanism of how RUNX3 is involved in the regualation of cancer stem cell traits in estrogen receptor positive breast cancer remains elusive. In this study, we utilized cut-tag assay to investigate the binding profile RUNX3 in BT474 and T47D cell, and confirmed EXOSC4 as the bona-fide target of RUNX3; RUNX3 could bind to the promoter are of EXOSC4 to suppress its expression. Furthermore, EXOSC4 could increase the colony formation, cell invasion and mammosphere formation ability of breast cancer cells and upregulate the the expression of SOX2 and ALDH1. Consistent with these findings, EXOSC4 was associated with poorer survival for Luminal B/Her2 breast cancer patiens. At last, we confirmed that EXOSC4 mediated the tumor suppressive role of RUNX3 in breast cancer cells. In conclusion, we demonstrate that RUNX3 directly binds to the promoter region of EXOSC4, leading to the suppression of EXOSC4 expression and exerting a tumor-suppressive effect in estrogen receptor postivive breast cancer cells.
Topics: Core Binding Factor Alpha 3 Subunit; Humans; Breast Neoplasms; Female; Promoter Regions, Genetic; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Aldehyde Dehydrogenase 1 Family; SOXB1 Transcription Factors; Retinal Dehydrogenase; Neoplastic Stem Cells
PubMed: 38913281
DOI: 10.1007/s10142-024-01363-6 -
Frontiers in Immunology 2024The Nipah virus (NiV), a highly deadly bat-borne paramyxovirus, poses a substantial threat due to recurrent outbreaks in specific regions, causing severe respiratory and...
The Nipah virus (NiV), a highly deadly bat-borne paramyxovirus, poses a substantial threat due to recurrent outbreaks in specific regions, causing severe respiratory and neurological diseases with high morbidity. Two distinct strains, NiV-Malaysia (NiV-M) and NiV-Bangladesh (NiV-B), contribute to outbreaks in different geographical areas. Currently, there are no commercially licensed vaccines or drugs available for prevention or treatment. In response to this urgent need for protection against NiV and related infections, we developed a novel homotypic virus-like nanoparticle (VLP) vaccine co-displaying NiV attachment glycoproteins (G) from both strains, utilizing the self-assembling properties of ferritin protein. In comparison to the NiV G subunit vaccine, our nanoparticle vaccine elicited significantly higher levels of neutralizing antibodies and provided complete protection against a lethal challenge with NiV infection in Syrian hamsters. Remarkably, the nanoparticle vaccine stimulated the production of antibodies that exhibited superior cross-reactivity to homologous or heterologous . These findings underscore the potential utility of ferritin-based nanoparticle vaccines in providing both broad-spectrum and long-term protection against NiV and emerging zoonotic challenges.
Topics: Animals; Nipah Virus; Henipavirus Infections; Ferritins; Mesocricetus; Antibodies, Viral; Antibodies, Neutralizing; Nanoparticles; Viral Vaccines; Cricetinae; Vaccines, Virus-Like Particle; Female; Humans; Nanovaccines
PubMed: 38911870
DOI: 10.3389/fimmu.2024.1387811 -
Frontiers in Endocrinology 2024Paragangliomas (PGL) are rare neuroendocrine tumors derived from the autonomic nervous system paraganglia. Urinary bladder paragangliomas (UBPGL) originate from the...
BACKGROUND
Paragangliomas (PGL) are rare neuroendocrine tumors derived from the autonomic nervous system paraganglia. Urinary bladder paragangliomas (UBPGL) originate from the sympathetic neurons of the urinary bladder wall and represent 0.7% of all paragangliomas and <0.05% of all bladder tumors. PGL and UBPGL can be associated with gene variants, with the most common germline alterations found in and .
CASE REPORT
We report a case of a 42-year-old woman who presented with menorrhagia/hematuria, uterine leiomyomas, as well as cardiac and bladder masses. The cardiac mass was favored to be a myxoma based on clinical findings, while the bladder mass was diagnosed as UBPGL. A novel mutation (c.642G>A, p Q214Q), detected in the UBPGL, was proven to be somatic. Although this variant was seemingly synonymous, it was predicted to have a loss of function due to the splice site effect, which was further supported by the immunohistochemical loss of .
CONCLUSION
This case highlights the challenges of diagnosing an extremely rare entity, bladder paraganglioma, with an emphasis on the multidisciplinary approach to navigate various clinical and imaging findings that may initially be misleading. In addition, a novel loss of function variant that could have been overlooked as a synonymous variant is herein reported, while also illustrating the importance of both germline and somatic mutation testing.
Topics: Humans; Female; Adult; Urinary Bladder Neoplasms; Paraganglioma; Succinate Dehydrogenase; Mutation
PubMed: 38911036
DOI: 10.3389/fendo.2024.1386285 -
Scientific Reports Jun 2024Breast cancer (BC) remains a significant health concern for women globally, prompting the relentless pursuit of novel therapeutic modalities. As a traditional Chinese...
Breast cancer (BC) remains a significant health concern for women globally, prompting the relentless pursuit of novel therapeutic modalities. As a traditional Chinese medicine, Boswellia carterii has been extensively used to treat various cancers, such as BC. However, the anti-BC effect and underlying mechanism of Boswellia carterii remain largely unclear. The aim of this study is to explore the therapeutic effect of Boswellia carterii n-hexane extract (BCHE) against BC as well as its underlying mechanism. The present study showed that BCHE significantly suppressed the viability of human BC cells. Moreover, BCHE exhibited potent anti-BC activity in vivo with no significant toxic effects. Additionally, BCHE induced ferroptosis via increased Transferrin expression and the intracellular accumulation of Fe, as well as decreased glutathione peroxidase 4 (GPX4) expression and the upregulation of reactive oxygen species (ROS)-induced lipid peroxidation in BC cells. In vivo experimental results also demonstrated that BCHE effectively induced ferroptosis through GPX4 downregulation and Transferrin upregulation in tumor-bearing mice. Overall, BCHE inhibited the growth of BC cells by inducing ferroptosis mediated by modulating the iron accumulation pathway and the lipid peroxidation pathway. Therefore, BCHE could serve as a potential ferroptosis-targeting drug for treating BC.
Topics: Ferroptosis; Phospholipid Hydroperoxide Glutathione Peroxidase; Humans; Breast Neoplasms; Female; Animals; Transferrin; Mice; Plant Extracts; Cell Line, Tumor; Boswellia; Reactive Oxygen Species; Xenograft Model Antitumor Assays; Cell Proliferation; Hexanes; Down-Regulation; Lipid Peroxidation; Up-Regulation; Gene Expression Regulation, Neoplastic; Mice, Nude; Mice, Inbred BALB C
PubMed: 38906931
DOI: 10.1038/s41598-024-65170-6 -
Nature Communications Jun 2024The methylerythritol phosphate (MEP) pathway is responsible for biosynthesis of the precursors of isoprenoid compounds in eubacteria and plastids. It is a metabolic... (Review)
Review
The methylerythritol phosphate (MEP) pathway is responsible for biosynthesis of the precursors of isoprenoid compounds in eubacteria and plastids. It is a metabolic alternative to the well-known mevalonate pathway for isoprenoid production found in archaea and eukaryotes. Recently, a role for the MEP pathway in oxidative stress detection, signalling, and response has been identified. This role is executed in part through the unusual cyclic intermediate, methylerythritol cyclodiphosphate (MEcDP). We postulate that this response is triggered through the oxygen sensitivity of the MEP pathway's terminal iron-sulfur (Fe-S) cluster enzymes. MEcDP is the substrate of IspG, the first Fe-S cluster enzyme in the pathway; it accumulates under oxidative stress conditions and acts as a signalling molecule. It may also act as an antioxidant. Furthermore, evidence is emerging for a broader and highly nuanced role of the MEP pathway in oxidative stress responses, implemented through a complex system of differential regulation and sensitivity at numerous nodes in the pathway. Here, we explore the evidence for such a role (including the contribution of the Fe-S cluster enzymes and different pathway metabolites, especially MEcDP), the evolutionary implications, and the many questions remaining about the behaviour of the MEP pathway in the presence of oxidative stress.
Topics: Oxidative Stress; Erythritol; Sugar Phosphates; Iron-Sulfur Proteins; Signal Transduction; Terpenes
PubMed: 38906898
DOI: 10.1038/s41467-024-49483-8 -
Molecular Biology Reports Jun 2024Protein nanocages resemble natural biomimetic carriers and can be engineered to act as targeted delivery systems, making them an attractive option for various drug...
Protein nanocages resemble natural biomimetic carriers and can be engineered to act as targeted delivery systems, making them an attractive option for various drug delivery and biomedical applications. Our research investigated the genetic link of a specific anti-HER2 peptide (LTVSPWY) to the exposed N-terminal region of the maize (Zea mays) ferritin 1 (ZmFer1) protein nanocage, employing either a 7-amino acid (for LTVS-ZmFer1) or 16-amino acid (for LTVS-L-ZmFer1) linker. We utilized a heat treatment method to load the chemotherapeutic drug doxorubicin into the protein nanocage. The construct with the longer linker (LTVS-L) produced a greater amount of soluble protein nanocage and was selected for further experiments. The average size, polydispersity index, and zeta potential of the engineered protein nanocage were 19.01 nm, 0.168, and - 2.13 mV, respectively. The LTVS-L-ZmFer1 protein nanocage exhibited excellent thermal stability, withstanding temperatures up to 100 °C with only partial denaturation. Furthermore, we observed that cellular uptake of the LTVS-L-ZmFer1 protein nanocages in HER2-positive breast cancer cells was significantly higher compared to ZmFer1 after labeling with FITC (fluorescein isothiocyanate) (P-value = 0.0001). In addition, we observed a significant decrease in the viability of SKBR3 cells when treated with DOX-loaded LTVS-L-ZmFer1 protein nanocages compared to cells treated with DOX-loaded ZmFer1 protein nanocages. Therefore, this new treatment strategy may prove to be an effective way to reduce both the side effects and toxicity associated with conventional cancer treatments in patients with HER2-positive breast cancer.
Topics: Humans; Receptor, ErbB-2; Doxorubicin; Drug Delivery Systems; Cell Line, Tumor; Breast Neoplasms; Recombinant Proteins; Ferritins; Zea mays; Protein Engineering; Female; Drug Carriers; Plant Proteins
PubMed: 38904710
DOI: 10.1007/s11033-024-09636-w