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Nature Communications Jul 2024Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers...
Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with CN Diagnostics' PrecivityAD test for Aβ42 and Aβ40. Compared to white individuals, Black individuals had higher average plasma Aβ42/40 levels at baseline, consistent with a lower average level of amyloid pathology. Interestingly, this difference resulted from lower average levels of plasma Aβ40 in Black participants. Despite the differences, Black and white individuals had similar longitudinal rates of change in Aβ42/40, consistent with a similar rate of amyloid accumulation. Our results agree with multiple recent studies demonstrating a lower prevalence of amyloid pathology in Black individuals, and additionally suggest that amyloid accumulates consistently across both groups.
Topics: Humans; Amyloid beta-Peptides; White People; Male; Female; Alzheimer Disease; Longitudinal Studies; Aged; Peptide Fragments; Biomarkers; Black or African American; Middle Aged; Aged, 80 and over; Black People
PubMed: 38956096
DOI: 10.1038/s41467-024-49859-w -
Scientific Reports Jul 2024The EMMY trial was a multicentre, investigator-initiated, placebo-controlled, double-blind trial, which enrolled 476 patients immediately following AMI and the first... (Randomized Controlled Trial)
Randomized Controlled Trial
The EMMY trial was a multicentre, investigator-initiated, placebo-controlled, double-blind trial, which enrolled 476 patients immediately following AMI and the first study demonstrating a significant reduction in NT-proBNP-levels as well as significant improvements in cardiac structure and function in patients after acute myocardial infarction treated with empagliflozin vs. placebo. However, hardly any data are available investigating the prognostic role of baseline electrocardiogram metrics in SGLT2-inhibitor-treated patients. This post-hoc analysis investigated the association of baseline ECG metrics collected in one centre of the trial (181 patients) with changes in structural and functional cardiac parameters as well as cardiac biomarkers in response to Empagliflozin treatment. A total of 181 patients (146 men; mean age 58 ± 14 years) were included. Median PQ-interval was 156 (IQR 144-174) milliseconds (ms), QRS width 92 (84-98) ms, QTc interval 453 (428-478) ms, Q-wave duration 45 (40-60) ms, Q-wave amplitude 0.40 (0.30-0.70) millivolt (mV), and heart rate was 71 (64-85) bpm. For functional cardiac parameters (LVEF and E/e') of the entire cohort, a greater decrease of E/e' from baseline to week 26 was observed in shorter QRS width (P = 0.005).Structural cardiac endpoints were only found to have a significant positive correlation between LVEDD and Q wave duration (P = 0.037). Higher heart rate was significantly correlated with better response in LVEF (P = 0.001), E/e' (P = 0.021), and NT-proBNP (P = 0.005). Empagliflozin-treatment showed no interaction with the results. Baseline ECG characteristics post AMI are neither predictive for beneficial NTproBNP effects of Empagliflozin post AMI, nor for functional or structural changes within 26 weeks post AMI.
Topics: Humans; Benzhydryl Compounds; Glucosides; Male; Middle Aged; Female; Electrocardiography; Biomarkers; Myocardial Infarction; Aged; Double-Blind Method; Echocardiography; Natriuretic Peptide, Brain; Sodium-Glucose Transporter 2 Inhibitors; Peptide Fragments
PubMed: 38956086
DOI: 10.1038/s41598-024-64175-5 -
Signal Transduction and Targeted Therapy Jul 2024More than 90% of hepatocellular carcinoma (HCC) cases develop in the presence of fibrosis or cirrhosis, making the tumor microenvironment (TME) of HCC distinctive due to...
More than 90% of hepatocellular carcinoma (HCC) cases develop in the presence of fibrosis or cirrhosis, making the tumor microenvironment (TME) of HCC distinctive due to the intricate interplay between cancer-associated fibroblasts (CAFs) and cancer stem cells (CSCs), which collectively regulate HCC progression. However, the mechanisms through which CSCs orchestrate the dynamics of the tumor stroma during HCC development remain elusive. Our study unveils a significant upregulation of Sema3C in fibrotic liver, HCC tissues, peripheral blood of HCC patients, as well as sorafenib-resistant tissues and cells, with its overexpression correlating with the acquisition of stemness properties in HCC. We further identify NRP1 and ITGB1 as pivotal functional receptors of Sema3C, activating downstream AKT/Gli1/c-Myc signaling pathways to bolster HCC self-renewal and tumor initiation. Additionally, HCC cells-derived Sema3C facilitated extracellular matrix (ECM) contraction and collagen deposition in vivo, while also promoting the proliferation and activation of hepatic stellate cells (HSCs). Mechanistically, Sema3C interacted with NRP1 and ITGB1 in HSCs, activating downstream NF-kB signaling, thereby stimulating the release of IL-6 and upregulating HMGCR expression, consequently enhancing cholesterol synthesis in HSCs. Furthermore, CAF-secreted TGF-β1 activates AP1 signaling to augment Sema3C expression in HCC cells, establishing a positive feedback loop that accelerates HCC progression. Notably, blockade of Sema3C effectively inhibits tumor growth and sensitizes HCC cells to sorafenib in vivo. In sum, our findings spotlight Sema3C as a novel biomarker facilitating the crosstalk between CSCs and stroma during hepatocarcinogenesis, thereby offering a promising avenue for enhancing treatment efficacy and overcoming drug resistance in HCC.
Topics: Liver Neoplasms; Humans; Carcinoma, Hepatocellular; Tumor Microenvironment; Semaphorins; Integrin beta1; Mice; Signal Transduction; Hepatic Stellate Cells; Neuropilin-1; Cell Line, Tumor; Neoplastic Stem Cells; Animals; Gene Expression Regulation, Neoplastic; Sorafenib; Cancer-Associated Fibroblasts; Disease Progression
PubMed: 38956074
DOI: 10.1038/s41392-024-01887-0 -
Scientific Reports Jul 2024This study aimed to explore the effects of peroxisome proliferator-activated receptor α (PPAR-α), a known inhibitor of ferroptosis, in Myocardial ischemia/reperfusion...
This study aimed to explore the effects of peroxisome proliferator-activated receptor α (PPAR-α), a known inhibitor of ferroptosis, in Myocardial ischemia/reperfusion injury (MIRI) and its related mechanisms. In vivo and in vitro MIRI models were established. Our results showed that activation of PPAR-α decreased the size of the myocardial infarct, maintained cardiac function, and decreased the serum contents of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and Fe in ischemia/reperfusion (I/R)-treated mice. Additionally, the results of H&E staining, DHE staining, TUNEL staining, and transmission electron microscopy demonstrated that activation of PPAR-α inhibited MIRI-induced heart tissue and mitochondrial damage. It was also found that activation of PPAR-α attenuated MIRI-induced ferroptosis as shown by a reduction in malondialdehyde, total iron, and reactive oxygen species (ROS). In vitro experiments showed that intracellular contents of malondialdehyde, total iron, LDH, reactive oxygen species (ROS), lipid ROS, oxidized glutathione disulphide (GSSG), and Fe were reduced by the activation of PPAR-α in H9c2 cells treated with anoxia/reoxygenation (A/R), while the cell viability and GSH were increased after PPAR-α activation. Additionally, changes in protein levels of the ferroptosis marker further confirmed the beneficial effects of PPAR-α activation on MIRI-induced ferroptosis. Moreover, the results of immunofluorescence and dual-luciferase reporter assay revealed that PPAR-α achieved its activity via binding to the 14-3-3η promoter, promoting its expression level. Moreover, the cardioprotective effects of PPAR-α could be canceled by pAd/14-3-3η-shRNA or Compound C11 (14-3-3η inhibitor). In conclusion, our results indicated that ferroptosis plays a key role in aggravating MIRI, and PPAR-α/14-3-3η pathway-mediated ferroptosis and mitochondrial injury might be an effective therapeutic target against MIRI.
Topics: Ferroptosis; Animals; PPAR alpha; Myocardial Reperfusion Injury; 14-3-3 Proteins; Mice; Male; Reactive Oxygen Species; Up-Regulation; Mitochondria; Cell Line; Myocytes, Cardiac; Mice, Inbred C57BL; Rats; Disease Models, Animal
PubMed: 38956068
DOI: 10.1038/s41598-024-64638-9 -
Scientific Reports Jul 2024Ferroptosis is an iron-dependent cell death form characterized by reactive oxygen species (ROS) overgeneration and lipid peroxidation. Myricetin, a flavonoid that exists...
Ferroptosis is an iron-dependent cell death form characterized by reactive oxygen species (ROS) overgeneration and lipid peroxidation. Myricetin, a flavonoid that exists in numerous plants, exhibits potent antioxidant capacity. Given that iron accumulation and ROS-provoked dopaminergic neuron death are the two main pathological hallmarks of Parkinson's disease (PD), we aimed to investigate whether myricetin decreases neuronal death through suppressing ferroptosis. The PD models were established by intraperitoneally injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into rats and by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP), respectively. Ferroptosis was identified by assessing the levels of Fe, ROS, malondialdehyde (MDA), and glutathione (GSH). The results demonstrated that myricetin treatment effectively mitigated MPTP-triggered motor impairment, dopamine neuronal death, and α-synuclein (α-Syn) accumulation in PD models. Myricetin also alleviated MPTP-induced ferroptosis, as evidenced by decreased levels of Fe, ROS, and MDA and increased levels of GSH in the substantia nigra (SN) and serum in PD models. All these changes were reversed by erastin, a ferroptosis activator. In vitro, myricetin treatment restored SH-SY5Y cell viability and alleviated MPP-induced SH-SY5Y cell ferroptosis. Mechanistically, myricetin accelerated nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and subsequent glutathione peroxidase 4 (Gpx4) expression in MPP-treated SH-SY5Y cells, two critical inhibitors of ferroptosis. Collectively, these data demonstrate that myricetin may be a potential agent for decreasing dopaminergic neuron death by inhibiting ferroptosis in PD.
Topics: Ferroptosis; Animals; Flavonoids; Rats; Disease Models, Animal; Male; Reactive Oxygen Species; Dopaminergic Neurons; Humans; Parkinson Disease; Cell Line, Tumor; Iron; alpha-Synuclein; Rats, Sprague-Dawley; Glutathione; Lipid Peroxidation; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NF-E2-Related Factor 2
PubMed: 38956066
DOI: 10.1038/s41598-024-62910-6 -
Cell Death & Disease Jul 2024Damage to renal tubular epithelial cells (RTECs) signaled the onset and progression of sepsis-associated acute kidney injury (SA-AKI). Recent research on mitochondria...
Damage to renal tubular epithelial cells (RTECs) signaled the onset and progression of sepsis-associated acute kidney injury (SA-AKI). Recent research on mitochondria has revealed that mitophagy plays a crucial physiological role in alleviating injury to RTECs and it is suppressed progressively by the inflammation response in SA-AKI. However, the mechanism by which inflammation influences mitophagy remains poorly understood. We examined how macrophage migration inhibitory factor (MIF), a pro-inflammatory protein, influences the PINK1-Parkin pathway of mitophagy by studying protein-protein interactions when MIF was inhibited or overexpressed. Surprisingly, elevated levels of MIF were found to directly bind to PINK1, disrupting its interaction with Parkin. This interference hindered the recruitment of Parkin to mitochondria and impeded the initiation of mitophagy. Furthermore, this outcome led to significant apoptosis of RTECs, which could, however, be reversed by an MIF inhibitor ISO-1 and/or a new mitophagy activator T0467. These findings highlight the detrimental impact of MIF on renal damage through its disruption of the interaction between PINK1 and Parkin, and the therapeutic potential of ISO-1 and T0467 in mitigating SA-AKI. This study offers a fresh perspective on treating SA-AKI by targeting MIF and mitophagy.
Topics: Macrophage Migration-Inhibitory Factors; Mitophagy; Acute Kidney Injury; Ubiquitin-Protein Ligases; Protein Kinases; Sepsis; Animals; Humans; Mitochondria; Kidney Tubules; Epithelial Cells; Apoptosis; Protein Binding; Male; Intramolecular Oxidoreductases
PubMed: 38956064
DOI: 10.1038/s41419-024-06826-z -
Nature Communications Jul 2024Long-term treatment of myocardial infarction is challenging despite medical advances. Tissue engineering shows promise for MI repair, but implantation complexity and...
Long-term treatment of myocardial infarction is challenging despite medical advances. Tissue engineering shows promise for MI repair, but implantation complexity and uncertain outcomes pose obstacles. microRNAs regulate genes involved in apoptosis, angiogenesis, and myocardial contraction, making them valuable for long-term repair. In this study, we find downregulated miR-199a-5p expression in MI. Intramyocardial injection of miR-199a-5p into the infarcted region of male rats revealed its dual protective effects on the heart. Specifically, miR-199a-5p targets AGTR1, diminishing early oxidative damage post-myocardial infarction, and MARK4, which influences long-term myocardial contractility and enhances cardiac function. To deliver miR-199a-5p efficiently and specifically to ischemic myocardial tissue, we use CSTSMLKAC peptide to construct P-MSN/miR199a-5p nanoparticles. Intravenous administration of these nanoparticles reduces myocardial injury and protects cardiac function. Our findings demonstrate the effectiveness of P-MSN/miR199a-5p nanoparticles in repairing MI through enhanced contraction and anti-apoptosis. miR199a-5p holds significant therapeutic potential for long-term repair of myocardial infarction.
Topics: MicroRNAs; Animals; Myocardial Infarction; Male; Rats; Nanoparticles; Rats, Sprague-Dawley; Apoptosis; Myocardium; Disease Models, Animal; Myocardial Contraction; Administration, Intravenous; Myocardial Ischemia
PubMed: 38956062
DOI: 10.1038/s41467-024-49901-x -
Scientific Reports Jul 2024The etiology of tic disorders (TDs) is not precisely known, although several lines of evidence suggest involvement of the immune system in pathogenesis. Here, we aimed...
The etiology of tic disorders (TDs) is not precisely known, although several lines of evidence suggest involvement of the immune system in pathogenesis. Here, we aimed to determine the expression levels of pro-inflammatory and anti-inflammatory cytokines in children with TD and compare them with those of healthy controls. Furthermore, we also evaluated their association with clinical variables in the TD group. Within the study period, 88 children with tic disorders and 111 healthy control children were enrolled. Most children with tic disorders were diagnosed with Tourette's disorder (n = 47, 53.4%) or persistent motor tic disorder (n = 39, 44.3%), while the remainder (n = 2, 2.3%) were diagnosed with persistent vocal tic disorder. We found that children with tic disorders had significantly elevated levels of IL-1β, TNF-α, IL-6 and IL-4 expression, while we detected lower expression levels of IL-17 in children with tic disorders. Our findings provide a molecular landscape of cytokine expression in children with TD, which may suggest a proinflammatory state not affected by the presence of comorbidity and symptom severity. Delineating the contribution of alterations in the immune system to the pathogenesis of tic disorders may pave the way for better therapeutic interventions.
Topics: Humans; Child; Male; Female; Tic Disorders; Adolescent; Cytokines; Case-Control Studies; Child, Preschool
PubMed: 38956051
DOI: 10.1038/s41598-024-62121-z -
Scientific Reports Jul 2024Antibiotic resistance is a worldwide problem that imposes a devastating effect on developing countries and requires immediate interventions. Initially, most of the...
Antibiotic resistance is a worldwide problem that imposes a devastating effect on developing countries and requires immediate interventions. Initially, most of the antibiotic drugs were identified by culturing soil microbes. However, this method is prone to discovering the same antibiotics repeatedly. The present study employed a shotgun metagenomics approach to investigate the taxonomic diversity, functional potential, and biosynthetic capacity of microbiomes from two natural agricultural farmlands located in Bekeka and Welmera Choke Kebelle in Ethiopia for the first time. Analysis of the small subunit rRNA revealed bacterial domain accounting for 83.33% and 87.24% in the two selected natural farmlands. Additionally, the analysis showed the dominance of Proteobacteria representing 27.27% and 28.79% followed by Actinobacteria making up 12.73% and 13.64% of the phyla composition. Furthermore, the analysis revealed the presence of unassigned bacteria in the studied samples. The metagenome functional analysis showed 176,961 and 104, 636 number of protein-coding sequences (pCDS) from the two samples found a match with 172,655 and 102, 275 numbers of InterPro entries, respectively. The Genome ontology annotation suggests the presence of 5517 and 3293 pCDS assigned to the "biosynthesis process". Numerous Kyoto Encyclopedia of Genes and Genomes modules (KEGG modules) involved in the biosynthesis of terpenoids and polyketides were identified. Furthermore, both known and novel Biosynthetic gene clusters, responsible for the production of secondary metabolites, such as polyketide synthases, non-ribosomal peptide synthetase, ribosomally synthesized and post-translationally modified peptides (Ripp), and Terpene, were discovered. Generally, from the results it can be concluded that the microbiomes in the selected sampling sites have a hidden functional potential for the biosynthesis of secondary metabolites. Overall, this study can serve as a strong preliminary step in the long journey of bringing new antibiotics to the market.
Topics: Soil Microbiology; Metagenomics; Microbiota; Multigene Family; Secondary Metabolism; Metagenome; Farms; Bacteria; Ethiopia; Phylogeny
PubMed: 38956049
DOI: 10.1038/s41598-024-63254-x -
Cell Death & Disease Jul 2024Metastasis is the major culprit of treatment failure in nasopharyngeal carcinoma (NPC). Aryl hydrocarbon receptor nuclear translocator like 2 (ARNTL2), a core circadian...
Metastasis is the major culprit of treatment failure in nasopharyngeal carcinoma (NPC). Aryl hydrocarbon receptor nuclear translocator like 2 (ARNTL2), a core circadian gene, plays a crucial role in the development of various tumors. Nevertheless, the biological role and mechanism of ARNTL2 are not fully elucidated in NPC. In this study, ARNTL2 expression was significantly upregulated in NPC tissues and cells. Overexpression of ARNTL2 facilitated NPC cell migration and invasion abilities, while inhibition of ARNTL2 in similarly treated cells blunted migration and invasion abilities in vitro. Consistently, in vivo xenograft tumor models revealed that ARNTL2 silencing reduced nude mice inguinal lymph node and lung metastases, as well as tumor growth. Mechanistically, ARNTL2 negatively regulated the transcription expression of AMOTL2 by directly binding to the AMOTL2 promoter, thus reducing the recruitment and stabilization of AMOTL2 to LATS1/2 kinases, which strengthened YAP nuclear translocation by suppressing LATS-dependent YAP phosphorylation. Inhibition of AMOTL2 counteracted the effects of ARNTL2 knockdown on NPC cell migration and invasion abilities. These findings suggest that ARNTL2 may be a promising therapeutic target to combat NPC metastasis and further supports the crucial roles of circadian genes in cancer development.
Topics: Humans; Animals; Nasopharyngeal Carcinoma; Neoplasm Invasiveness; Cell Line, Tumor; Adaptor Proteins, Signal Transducing; Mice, Nude; YAP-Signaling Proteins; Angiomotins; Cell Movement; Mice; Transcription Factors; ARNTL Transcription Factors; Nasopharyngeal Neoplasms; Basic Helix-Loop-Helix Transcription Factors; Signal Transduction; Gene Expression Regulation, Neoplastic; Mice, Inbred BALB C; Protein Serine-Threonine Kinases; Male; Neoplasm Metastasis; Female; Tumor Suppressor Proteins
PubMed: 38956029
DOI: 10.1038/s41419-024-06860-x