Search Results (1,786)

Angiotensin II (Ang II) is an effective vasoconstriction peptide, a major effector molecule of the renin–angiotensin–aldosterone system (RAAS) and one of the important causes of endothelial dysfunction. Ferroptosis is considered to be involved in the occurrence and development of cardiovascular diseases. This study is dedicated to exploring the role and mechanism of Ang II-induced ferroptosis in HUVECs and to finding molecular targets for vascular endothelial injury and dysfunction during the progression of hypertension. In this study, we found that with the increase in exposure concentration, the intracellular ROS content and apoptosis rate increased significantly, the NO release decreased significantly in the medium- and high-concentration groups and the ET-1 content in the high-concentration group increased significantly. The expression of ZO-1 protein was significantly decreased in the high-concentration group. The expression of p-eNOS, VE-cadherin and Occludin protein showed a dose-dependent downward trend, while the ICAM-1 protein showed an upward trend. Ang II caused lipid metabolism disorders in HUVECs, and the PL–PUFAs associated with ferroptosis were significantly increased. In addition, Ang II promoted a significant increase in intracellular free Fe²⁺ content and MDA and a significant decrease in GSH content. Furthermore, the expression of GPX4, SLC7A11 and SLC3A2 was down-regulated, the expression of ACSL4, LPCAT3 and ALOX15 was up-regulated, and the ratio of p-cPLA2/cPLA2 was increased. After the intervention of ferroptosis inhibitor Fer-1, the injury and dysfunction of HUVECs induced by Ang II were significantly rescued. Immunofluorescence results showed that the expression of CD36 showed a significant increasing trend and was localized in the cytoplasm. Over-expression of CD36 promoted Ang II-induced ferroptosis and endothelial dysfunction. In conclusion, Ang II induces the injury of HUVECs, decreases vascular diastole and endothelial barrier-related molecules, and increases vascular constriction and adhesion-related molecules, which may be related to CD36 and its mediated lipid peroxidation and ferroptosis signals. Full article

Background and Objectives: Hyperornithinemia–hyperammonemia–homocitrullinuria syndrome (HHH; OMIM 238970) is one of the rare urea cycle disorders. Ornithine carrier 1 deficiency causes HHH syndrome, characterized by failure of mitochondrial ornithine uptake, hyperammonemia, and accumulation of ornithine and lysine in the cytoplasm. The initial presentation and time of diagnosis in HHH highly varies. Genetic analysis is critical for diagnosis. Materials and Methods: This study encompassed retrospective and prospective analyses of four unrelated Vietnamese children diagnosed with HHH syndrome. Results: The age of diagnosis ranged from 10 days to 46 months. All four cases demonstrated hyperornithinemia and prolonged prothrombin time. Three out of four cases presented with hyperammonemia, elevated transaminases, and uraciluria. No homocitrulline was detected in the urine. Only one case depicted oroticaciduria. Genetic analyses revealed three pathogenic variants in the SLC25A15 gene, with the c.535C>T (p.Arg179*) variant common in Vietnamese patients. The c.562_564del (p.Phe188del) and c.408del (p.Met137Cysfs*10) variants were detected in one case. The latter variant has yet to be reported in the literature on HHH patients. After intervention with a protein-restricted diet, ammonia-reducing therapy, and L-carnitine supplementation, hyperammonemia was not observed, and liver enzyme levels returned to normal. Conclusions: Our results highlighted the clinical and biochemical heterogeneity of HHH syndrome and posed that HHH syndrome should be considered when individuals have hyperammonemia, elevated transaminase, and decreased prothrombin time. Full article

Synthetic aperture radar (SAR) is often affected by other high-power electromagnetic devices during ground observation, which causes unintentional radio frequency interference (RFI) with the acquired echo, bringing adverse effects into data processing and image interpretation. When faced with the task of screening massive SAR data, there is an urgent need for the global perception and detection of interference. The existing RFI detection method usually only uses a single type of data for detection, ignoring the information association between the data at all levels of the real SAR product, resulting in some computational redundancy. Meanwhile, current deep learning-based algorithms are often unable to locate the range of RFI coverage in the azimuth direction. Therefore, a novel RFI processing framework from quick-looks to single-look complex (SLC) data and then to raw echo is proposed. We take the data of Sentinel-1 terrain observation with progressive scan (TOPS) mode as an example. By combining the statistics-assisted network with the sliding-window algorithm and the error-tolerant training strategy, it is possible to accurately detect and locate RFI in the quick looks of an SLC product. Then, through the analysis of the TOPSAR imaging principle, the position of the RFI in the SLC image is preliminarily confirmed. The possible distribution of the RFI in the corresponding raw echo is further inferred, which is one of the first attempts to use spaceborne SAR data to elucidate the RFI location mapping relationship between image data and raw echo. Compared with directly detecting all of the SLC data, the time for the proposed framework to determine the RFI distribution in the SLC data can be shortened by 53.526%. All the research in this paper is conducted on Sentinel-1 real data, which verify the feasibility and effectiveness of the proposed framework for radio frequency signals monitoring in advanced spaceborne SAR systems. Full article

(1) Background: Buffaloes are crucial livestock species for food and service in tropical and subtropical regions. Buffalo genetics, particularly in indigenous Chinese breeds such as the Xiangxi white buffalo (XWB), remains an intriguing area of study due to its unique traits and regional significance. (2) Methods: This investigation utilized the whole-genome sequences of twenty XWBs (newly sequenced), along with eighty published whole-genome sequences of other buffalo breeds (including Guizhou white buffalo, river buffalo, and Chinese buffalo in the Yangtze River). Using whole-genome sequencing analysis technology, the population structure, genomic diversity, and selection signatures of XWB were determined. (3) Results: This study revealed that the XWB, being phylogenetically positioned in the middle and lower reaches of the Yangtze River, exhibited substantial genomic diversity. Employing four selection sweep detection methods (CLR, iHS, π-ratio, and F_ST), several genes were positively identified for adaptive traits in the XWB, including coat color phenotypes (ASIP, KIT), the nervous system (GRIK2), reproduction (KCNIP4), growth and development (IFNAR1, BMP6, HDAC9, MGAT4C, and SLC30A9), the body (LINGO2, LYN, and FLI1), immunity (IRAK3 and MZB1), and lactation (TP63, LPIN1, SAE1). (4) Conclusions: In conclusion, this study enhances our understanding of the genetic distinctiveness and adaptive traits of XWB, highlighting selection signatures crucial for future breeding and conservation and ensuring sustainable use of this vital livestock resource. Full article

Abstract: The metabolism of zinc and manganese plays a pivotal role in cancer progression by mediating cancer cell growth and metastasis. The SLC30A family proteins SLC30A3 and SLC30A10 mediate the efflux of zinc, manganese, and probably other transition element ions outside the cytoplasm to the extracellular space or into intracellular membrane compartments. The SLC39A family members SLC39A8 and SLC39A14 are their functional antagonists that transfer these ions into the cytoplasm. Recently, the SLC30A10 gene was suggested as a promising methylation biomarker of colorectal cancer. Here, we investigated whether forced overexpression or inactivation of SLC30A and SLC39A family genes has an impact on the phenotype of cancer cells and their sensitivity to cancer therapeutics. In the human colon adenocarcinoma HCT-15 and duodenal adenocarcinoma HuTu80 cell lines, we generated clones with knockouts of the SLC39A8 and SLC39A14 genes and forced overexpression of the SLC30A3, SLC30A10, and SLC39A8 genes. Gene expression in the mutant and control cells was assessed by RNA sequencing. The cell growth rate, mitochondrial activity, zinc accumulation, and sensitivity to the drugs cetuximab and cisplatin were investigated in functional tests. Overexpression or depletion of SLC30A or SLC39A family genes resulted in the deep reshaping of intracellular signaling and provoked hyperactivation of mitochondrial respiration. Variation in the expression of the SLC30A/SLC39A genes did not increase the sensitivity to cetuximab but significantly altered the sensitivity to cisplatin: overexpression of SLC30A10 resulted in an ~2.7–4 times increased IC50 of cisplatin, and overexpression of SLC30A3 resulted in an ~3.3 times decreased IC50 of cisplatin. The SLC30A/SLC39A genes should be considered as potential cancer drug resistance biomarkers and putative therapeutic targets. Full article

Phosphorous is essential for many metabolic functions and the constitution of bones. Poultry have limited ability to use phosphorous from diets, which is mainly excreted and causes environmental concern. For this reason, diets are commonly supplemented with inorganic phosphorus and phytases. It has been suggested that chickens can adapt to an early nutrient restriction by increasing its efficiency of utilization, an adaptation that has been defined as nutritional conditioning. The aim of this study was to investigate a strategy of phosphorous nutritional conditioning by feeding low phosphorous diets during the first week of life as a strategy to improve the efficiency of phosphorous utilization later in life. To test this, 600 male broiler chickens were fed either a standard (control group) or a phosphorous-deficient diet (conditioned group) during the first week of life. Later in life, the effect of conditioning was tested using standard or P-deficient diets during the finishing phase (21–43 d). Conditioning did not affect overall performance, despite finding evidence for reduced relative phosphorous excretion between days 19 to 21, increased duodenal gene expression for the phosphorous transporter SLC34A2 at day 30 (−6% and +17%, respectively), and tendencies for improved phosphorous digestibility (+7%) and tibia mineralization (+6%) at the end of the trial. It is concluded that phosphorous nutritional conditioning early in life can increase subsequent dietary phosphorous utilization and bone mineralization in poultry, although it may not be able to counteract severe phosphorous deficiencies. Further research is required to assess the extent to which phosphorous supplementation in post-conditioning diets may be reduced with this strategy without compromising performance. Full article

Background: Metabolic cancers are defined by metabolic reprogramming. Although this reprograming drives rapid tumour growth and invasion, it also reveals specific metabolic vulnerabilities that can be therapeutically exploited in cancer therapy. A novel form of programmed cell death, known as disulfidptosis, was identified last year; tumour cells with high SLC7A11 expression undergo disulfidptosis when deprived of glucose. Natural products have attracted increasing attention and have shown potential to treat metabolic cancers through diverse mechanisms. Methods: We systematically searched electronic databases involving PubMed, Web of Science, Gooale Scholar. To ensue comprehensive exploration, keywords including metabolic reprogramming, metabolic cancer, disulfidptosis, natural products and some other words were employed. Results: In this review, we focus on the shared characteristics and metabolic vulnerabilities of metabolic cancers. Additionally, we discuss the molecular mechanisms underlying disulfidptosis and highlight key regulatory genes. Furthermore, we predict bioactive natural products that target disulfidptosis-related genes, offering new perspectives for anticancer strategies through the modulation of disulfidptosis. Conclusions: By summarizing current research progress, this review mainly analyzed the potential mechanisms of natural products in the treatment of metabolic cancer. Full article

Background: Multiple sclerosis is a frequent neuroinflammatory and neurodegenerative disease of the central nervous system that includes alterations in the white and gray matter of the brain. The visual system is frequently affected in multiple sclerosis. Glutamate excitotoxicity might play a role in disease pathogenesis. Methodology: In the present study, we analyzed with qualitative and quantitative immunofluorescence microscopy and Western blot analyses whether alterations in the EAAT5 (SLC1A7) glutamate transporter could be involved in the previously observed alterations in structure and function of glutamatergic photoreceptor ribbon synapses in the EAE mouse model of MS. EAAT5 is a presynaptic glutamate transporter located near the presynaptic release sites. Results: We found that EAAT5 was strongly reduced at the photoreceptor synapses of EAE retinas in comparison to the photoreceptor synapses of the respective control retinas as early as day 9 post-immunization. The Western blot analyses demonstrated a decreased EAAT5 expression in EAE retinas. Conclusions: Our data illustrate early alterations of the EAAT5 glutamate transporter in the early pre-clinical phase of EAE/MS and suggest an involvement of EAAT5 in the previously observed early synaptic changes at photoreceptor synapses. The precise mechanisms need to be elucidated by future investigations. Full article

Melanoma is an aggressive cancer characterized by rapid growth, early metastasis, and poor prognosis, with resistance to current therapies being a significant issue. BRAF mutations drive uncontrolled cell division by activating the MAPK pathway. In this study, A375 and FO-1, BRAF-mutated melanoma cell lines, were treated for 4–5 months with RAF inhibitor dabrafenib or AZ628, leading to drug resistance over time. The resistant cells showed altered molecular signatures, with differences in cell cycle regulation and the propensity of cell death. Dabrafenib-resistant cells maintained high proliferative activity, while AZ628-resistant cells, especially A375 cells, exhibited slow-cycling, and a senescent-like phenotype with high susceptibility to ferroptosis, a form of cell death driven by iron. Antiretroviral drugs doravirine and cabotegravir, known for their effects on human endogenous retroviruses, were tested for their impact on these resistant melanoma cells. Both drugs reduced cell viability and colony formation in resistant cell lines. Doravirine was particularly effective in reactivating apoptosis and reducing cell growth in highly proliferative resistant cells by increasing tumor-suppressor proteins p16^Ink4a and p27^Kip1. These findings suggest that antiretroviral drugs can influence apoptosis and cell proliferation in RAF-inhibitor-resistant melanoma cells, offering potential therapeutic strategies for overcoming drug resistance. Full article

Ferroptosis, a recently elucidated style of regulated cell death, has emerged as a significant area of investigation in cancer biology. Natural active compounds that have anti-cancer effects are promising candidates for cancer prevention. Iberverin, a natural compound derived from Brassica oleracea var. capitata, has been shown to exert anti-tumor activities in some cancers. However, its role in hepatocellular carcinoma (HCC) cells and the molecular mechanisms are still poorly understood. In this study, we proved that iberverin can induce intracellular reactive oxygen species (ROS) generation to inhibit cell proliferation and initiate ferroptotic cell death in HCC cells, which can be eradicated by the ferroptosis inhibitor ferrostatin-1 (Fer-1) or deferoxamine mesylate (DFO) and ROS scavenger (GSH or NAC). Mechanistically, iberverin treatment can simultaneously downregulate SLC7A11 mRNA level and degrade GPX4 through the ubiquitination pathway, leading to lipid peroxidation and ferroptotic cell death in HCC cells. Significantly, a low dose of iberverin can remarkably increase the sensitivity of HCC cells to ferroptosis induced by canonical ferroptosis inducers RSL3 and imidazole ketone erastin (IKE). This study uncovers a critical function of iberverin in preventing HCC through ferroptosis and provides a promising strategy for HCC treatment either via iberverin alone or in combination with canonical ferroptosis inducers in the future. Full article

Dendrolimus kikuchii Matsumura (D. kikuchii) is a serious pest of coniferous trees. Bacillus thuringiensis (Bt) has been widely studied and applied as a biological control agent for a variety of pests. Here, we found that the mortality rate of D. kikuchii larvae after being fed Bt reached 95.33% at 24 h; the midgut membrane tissue was ulcerated and liquefied, the MDA content in the midgut tissue decreased and the SOD, CAT and GPx enzyme activities increased, indicating that Bt has toxic effects on D. kikuchii larvae. In addition, transmission electron microscopy showed that Bt infection caused severe deformation of the nucleus of the midgut tissue of D. kikuchii larvae, vacuoles in the nucleolus, swelling and shedding of microvilli, severe degradation of mitochondria and endoplasmic reticulum and decreased number. Surprisingly, metabolomics and transcriptome association analysis revealed that four metabolic-related signaling pathways, Nicotinate and nicotinamide metabolism, Longevity regulating pathway—worm, Vitamin digestion and absorption and Lysine degradation, were co-annotated in larvae. More surprisingly, Niacinamide was a common differential metabolite in the first three signaling pathways, and both Niacinamide and L-2-Aminoadipic acid were reduced. The differentially expressed genes involved in the four signaling pathways, including NNT, ALDH, PNLIP, SETMAR, GST and RNASEK, were significantly down-regulated, but only SLC23A1 gene expression was up-regulated. Our results illustrate the effects of Bt on the 5th instar larvae of D. kikuchii at the tissue, cell and molecular levels, and provide theoretical support for the study of Bt as a new biological control agent for D. kikuchii. Full article

The breeding of disease-resistant pigs has consistently been a topic of significant interest and concern within the pig farming industry. The study of pig blood indicators has the potential to confer economic benefits upon the pig farming industry, whilst simultaneously providing valuable insights that can inform the study of human diseases. In this study, an F2 resource population of 489 individuals was generated through the intercrossing of Large White boars and Min pig sows. A total of 17 haematological parameters and T lymphocyte subpopulations were measured, including white blood cell count (WBC), lymphocyte count (LYM), lymphocyte count percentage (LYM%), monocyte count (MID), monocyte count percentage (MID%), neutrophilic granulocyte count (GRN), percentage of neutrophils (GRN%), mean platelet volume (MPV), platelet distribution width (PDW), platelet count (PLT), CD4+/CD8+, CD4+CD8+CD3+, CD4+CD8−CD3+, CD4−CD8+CD3+, CD4−CD8−CD3+, and CD3+. The Illumina PorcineSNP60 Genotyping BeadChip was obtained for all of the F2 animals. Subsequently, a genome-wide association study (GWAS) was conducted using the TASSEL 5.0 software to identify associated variants and candidate genes for the 17 traits. Significant association signals were identified for PCT and PLT on SSC7, with 1 and 11 significant SNP loci, respectively. A single nucleotide polymorphism (SNP) on SSC12 was identified as a significant predictor of the white blood cell (WBC) trait. Significant association signals were detected for the T lymphocyte subpopulations, namely CD4+/CD8+, CD4+CD8+CD3+, CD4+CD8−CD3+, and CD4−CD8+CD3+, with the majority of these signals observed on SSC7. The genes CLIC5, TRIM15, and SLC17A4 were identified as potential candidates for influencing CD4+/CD8+ and CD4−CD8+CD3+. A missense variant, c.2707 G>A, in the SLC17A4 gene has been demonstrated to be significantly associated with the CD4+/CD8+ and CD4-CD8+CD3+ traits. Three missense variants (c.425 A>C, c.500 C>T, and c.733 A>G) have been identified in the TRIM15 gene as being linked to the CD4+/CD8+ trait. Nevertheless, only c.425 A>C has been demonstrated to be significantly associated with CD4-CD8+CD3+. In the CLIC5 gene, one missense variant (c.957 T>C) has been identified as being associated with the CD4+/CD8+ and CD4-CD8+CD3+ traits. Additionally, significant association signals were observed for CD4+CD8+CD3+ and CD4+CD8−CD3+ on SSC2 and 5, respectively. Subsequently, a gene ontology (GO) enrichment analysis was conducted on all genes within the quantitative trait loci (QTL) intervals of platelet count, CD4+/CD8+, and CD4−CD8+CD3+. The MHC class II protein complex binding pathway was identified as the most significant pathway among the three immune traits. These results provide guidance for further research in the field of breeding disease-resistant pigs. Full article

Hypophosphatasia (HPP) is a rare inherited disorder characterized by the decreased activity of tissue-nonspecific alkaline phosphatase (TNSALP), caused by mutations in the ALPL gene. The aim of this study was to conduct differential diagnostics in HPP patients using whole-exome sequencing (WES). The medical records of HPP patients and the genetic testing of the ALPL gene were reviewed. Seven patients were recruited and underwent WES using the Illumina or MGI sequencing platforms. All of the exome samples were matched onto a GRCh38.p13 reference genome assembly by using the Genome Analysis ToolKit (GATK) and the BWA MEM read aligner. We present the clinical and molecular findings of the seven patients referred for genetic analyses due to a clinical and biochemical suspicion of HPP. In two patients out of three (with identified heterozygous variants in the ALPL gene), we also identified c.682T>A in exon 3 of the WNT10A gene and c.3470del in exon 23 of the SMC1A gene variants for the first time. In four patients, variants in the ALPL gene were not detected, but WES allowed us to identify for the first time rare variants (c.5651A>C in exon 36 of the TRIO gene, c.880T>G in exon 6 of the TRPV4 gene, c.32078-1G>T in intron 159 of the TTN gene, c.47720_47721del in exon 235 of the TTN gene, and c.1946G>A in exon 15 of the SLC5A1 gene) and to conduct differential diagnostics with HPP. Using WES, for the first time, we demonstrate the possibility of early differential diagnostics in HPP patients with other rare genetic diseases. Full article

Congenital anemias include a broad range of disorders marked by inherent abnormalities in red blood cells. These abnormalities include enzymatic, membrane, and congenital defects in erythropoiesis, as well as hemoglobinopathies such as sickle cell disease and thalassemia. These conditions range in presentation from asymptomatic cases to those requiring frequent blood transfusions, exhibiting phenotypic heterogeneity and different degrees of severity. Despite understanding their different etiologies, all of them have a common pathophysiological origin with congenital defects of erythropoiesis. We can find different types, from congenital sideroblastic anemia (CSA), which is a bone marrow failure anemia, to hemoglobinopathies as sickle cell disease and thalassemia, with a higher prevalence and clinical impact. Recent efforts have focused on understanding erythropoiesis dysfunction in these anemias but, so far, deep gene sequencing analysis comparing all of them has not been performed. Our study used Quant 3′ mRNA-Sequencing to compare transcriptomic profiles of four sickle cell disease patients, ten thalassemia patients, and one rare case of SLC25A38 CSA. Our results showed clear differentiated gene map expressions in all of them with respect to healthy controls. Our study reveals that genes related to metabolic processes, membrane genes, and erythropoiesis are upregulated with respect to healthy controls in all pathologies studied except in the SLC25A38 CSA patient, who shows a unique gene expression pattern compared to the rest of the congenital anemias studied. Our analysis is the first that compares gene expression patterns across different congenital anemias to provide a broad spectrum of genes that could have clinical relevance in these pathologies. Full article

Diabetes is a major risk factor for Alzheimer’s disease (AD). Amino acid compound 2 (AAC2) improves glycemic and cognitive functions in diabetic mouse models through mechanisms distinct from insulin. Our goal was to compare the effects of AAC2, insulin, and their nanofiber-forming combination on early asymptomatic AD pathogenesis in APP/PS1 mice. Insulin, but not AAC2 or the combination treatment (administered intraperitoneally every 48 h for 120 days), increased seizure-related mortality, altered the brain fat-to-lean mass ratio, and improved specific cognitive functions in APP/PS1 mice. NanoString and pathway analysis of cerebral gene expression revealed dysregulated synaptic mechanisms, with upregulation of Bdnf and downregulation of Slc1a6 in insulin-treated mice, correlating with insulin-induced seizures. In contrast, AAC2 promoted the expression of Syn2 and Syp synaptic genes, preserved brain composition, and improved survival. The combination of AAC2 and insulin counteracted free insulin’s effects. None of the treatments influenced canonical amyloidogenic pathways. This study highlights AAC2’s potential in regulating synaptic gene expression in AD and insulin-induced contexts related to seizure activity. Full article