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JCI Insight Jun 2024The diffuse axonal damage in white matter and neuronal loss, along with excessive neuroinflammation, hinder long-term functional recovery after traumatic brain injury...
The diffuse axonal damage in white matter and neuronal loss, along with excessive neuroinflammation, hinder long-term functional recovery after traumatic brain injury (TBI). MicroRNAs (miRs) are small noncoding RNAs that negatively regulate protein-coding target genes in a posttranscriptional manner. Recent studies have shown that loss of function of the miR-15a/16-1 cluster reduced neurovascular damage and improved functional recovery in ischemic stroke and vascular dementia. However, the role of the miR-15a/16-1 cluster in neurotrauma is poorly explored. Here, we report that genetic deletion of the miR-15a/16-1 cluster facilitated the recovery of sensorimotor and cognitive functions, alleviated white matter/gray matter lesions, reduced cerebral glial cell activation, and inhibited infiltration of peripheral blood immune cells to brain parenchyma in a murine model of TBI when compared with WT controls. Moreover, intranasal delivery of the miR-15a/16-1 antagomir provided similar brain-protective effects conferred by genetic deletion of the miR-15a/16-1 cluster after experimental TBI, as evidenced by showing improved sensorimotor and cognitive outcomes, better white/gray matter integrity, and less inflammatory responses than the control antagomir-treated mice after brain trauma. miR-15a/16-1 genetic deficiency and miR-15a/16-1 antagomir also significantly suppressed inflammatory mediators in posttrauma brains. These results suggest miR-15a/16-1 as a potential therapeutic target for TBI.
Topics: Animals; MicroRNAs; Brain Injuries, Traumatic; Mice; Recovery of Function; Disease Models, Animal; Male; Mice, Knockout; Mice, Inbred C57BL; Brain
PubMed: 38912585
DOI: 10.1172/jci.insight.178650 -
Iranian Journal of Public Health May 2024Thalassemia is an inherited blood disorder with a defect in the sufficient production of a protein called hemoglobin. We aimed to investigate the simple blood indices of...
BACKGROUND
Thalassemia is an inherited blood disorder with a defect in the sufficient production of a protein called hemoglobin. We aimed to investigate the simple blood indices of patients with Beta Thalassemia Trait (BTT) and Iron Deficiency Anemia (IDA) to propose a new formula using logistic regression for differentiate two characteristics from each other.
METHODS
Among the 702 records of the BTT Counseling Center (Khoy, Iran-2022), 292 cases (219 iron deficiency anemia (IDA) and 73 BTT) were eligible for the study. Blood indices such as RBC, HGB, HbA2 described and used to diagnose two types of participants. Blood indices had high multicollinearity that was modified. Logistic regression for blood indices fitted and goodness of fit indices with Area Under ROC curve (AUC) estimated.
RESULTS
The average age of the participants was 24.56 yr. The status of Multicollinearity between independent variables was modified. The HGB, MCV, HbA2, and HbA variables were used in the model and only HbA2 status was significant (<0.001). According to the output of the model, for each unit increase in HbA2, the chance of having BTT was about 8.5 times higher than IDA. The sensitivity, specificity, AUC curve, and accuracy of the final model were estimated to be 97, 72, 84, and 93%, respectively. A regression formula to differentiate BTT from IDA proposed.
CONCLUSION
In studies related to the differentiation of the BTT from IDA, the presence of the HbA2 index in the model and prediction is very necessary.
PubMed: 38912153
DOI: 10.18502/ijph.v53i5.15601 -
ACS Omega Jun 2024Millets are currently employed in a variety of ways, including direct consumption and usage in the manufacture of certain cuisines or snacks. The present investigation...
Millets are currently employed in a variety of ways, including direct consumption and usage in the manufacture of certain cuisines or snacks. The present investigation was aimed at optimizing functionally enriched millet-based nutri-cereal mix comprising chicken and vegetable for a nutrition-deficient population. A total of 16 experiments were carried out by using optimal (custom) design model of mixture design with 60% major ingredients, including malted sorghum flour (20-30%), malted green gram flour (15-25%), and boiled chicken powder (5-15%). To make 100% of the total nutri-cereal mixture, other ingredients such as malted pearl millet (10%), finger millet flour (10%), beetroot powder (2.5%), pumpkin powder (7.5%), skimmed milk powder (9.5%), and stevia powder (0.5%) were added. Numerical optimization was done using Design Expert software, version 13. The optimized ratio was 30% malted sorghum flour, 15% malted green gram flour, and 15% chicken powder. The predicted values of responses 5.101%, 3.616%, 1.963%, 11.165%, 28.005%, 50.149%, 330.282 kcal, and 0.373 were in accordance with experimental values 6.426%, 3.455%, 1.714%, 11.432%, 29.12%, 47.853%, 323.318 kcal, and 0.385 for moisture, ash, fat, fiber, protein, carbohydrates, energy, and water activity, respectively, with a small error percentage. The results of mineral content, phenolic content, and amino acid profiling revealed that the optimized Nutri-cereal mix have higher amounts of these components. The results also suggested that the optimized Nutri-cereal mix of these malted millet flours can potentially enhance the nutritional deficiency as well as improve food and nutritional security.
PubMed: 38911719
DOI: 10.1021/acsomega.4c02126 -
International Journal of Nanomedicine 2024Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects social interaction and communication and can cause stereotypic behavior. Fullerenols, a...
BACKGROUND
Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects social interaction and communication and can cause stereotypic behavior. Fullerenols, a type of carbon nanomaterial known for its neuroprotective properties, have not yet been studied for their potential in treating ASD. We aimed to investigate its role in improving autistic behaviors in BTBR TItpr3/J (BTBR) mice and its underlying mechanism, which could provide reliable clues for future ASD treatments.
METHODS
Our research involved treating C57BL/6J (C57) and BTBR mice with either 0.9% NaCl or fullerenols (10 mg/kg) daily for one week at seven weeks of age. We then conducted ASD-related behavioral tests in the eighth week and used RNA-seq to screen for vital pathways in the mouse hippocampus. Additionally, we used real-time quantitative PCR (RT-qPCR) to verify related pathway genes and evaluated the number of stem cells in the hippocampal dentate gyrus (DG) by Immunofluorescence staining.
RESULTS
Our findings revealed that fullerenols treatment significantly improved the related ASD-like behaviors of BTBR mice, manifested by enhanced social ability and improved cognitive deficits. Immunofluorescence results showed that fullerenols treatment increased the number of DCX and SOX2/GFAP cells in the DG region of BTBR mice, indicating an expanded neural progenitor cell (NPC) pool of BTBR mice. RNA-seq analysis of the mouse hippocampus showed that VEGFA was involved in the rescued hippocampal neurogenesis by fullerenols treatment.
CONCLUSION
In conclusion, our findings suggest that fullerenols treatment improves ASD-like behavior in BTBR mice by upregulating VEGFA, making nanoparticle- fullerenols a promising drug for ASD treatment.
Topics: Animals; Mice, Inbred C57BL; Mice; Fullerenes; Autism Spectrum Disorder; Cognitive Dysfunction; Disease Models, Animal; Male; Doublecortin Protein; Social Behavior; Behavior, Animal; Hippocampus; Vascular Endothelial Growth Factor A; Neuroprotective Agents; Neurogenesis; Autistic Disorder
PubMed: 38911505
DOI: 10.2147/IJN.S459511 -
Scientific Reports Jun 2024Idiopathic pulmonary fibrosis (IPF) is believed to be associated with a notable disruption of cellular energy metabolism. By detecting the changes of energy metabolites...
Idiopathic pulmonary fibrosis (IPF) is believed to be associated with a notable disruption of cellular energy metabolism. By detecting the changes of energy metabolites in the serum of patients with pulmonary fibrosis, we aimed to investigate the diagnostic and prognostic value of energy metabolites in IPF, and further elucidated the mechanism of their involvement in pulmonary fibrosis. Through metabolomics research, it was discovered that the TCA cycle intermediates changed dramatically in IPF patients. In another validation cohort of 55 patients with IPF compared to 19 healthy controls, it was found that succinate, an intermediate product of TCA cycle, has diagnostic and prognostic value in IPF. The cut-off levels of serum succinate were 98.36 μM for distinguishing IPF from healthy controls (sensitivity, 83.64%; specificity, 63.16%; likelihood ratio, 2.27, respectively). Moreover, a high serum succinate level was independently associated with higher rates of disease progression (OR 13.087, 95%CI (2.819-60.761)) and mortality (HR 3.418, 95% CI (1.308-8.927)). In addition, accumulation of succinate and increased expression of the succinate receptor GPR91 were found in both IPF patients and BLM mouse models of pulmonary fibrosis. Reducing succinate accumulation in BLM mice alleviated pulmonary fibrosis and 21d mortality, while exogenous administration of succinate can aggravate pulmonary fibrosis in BLM mice. Furthermore, GPR91 deficiency protected against lung fibrosis caused by BLM. In vitro, succinate promoted the activation of lung fibroblasts by activating ERK pathway through GPR91. In summary, succinate is a promising biomarker for diagnosis and prognosis of IPF. The accumulation of succinate may promote fibroblast activation through GPR91 and pulmonary fibrosis.
Topics: Succinic Acid; Receptors, G-Protein-Coupled; Humans; Idiopathic Pulmonary Fibrosis; Animals; Male; Mice; Female; Middle Aged; Prognosis; Aged; Disease Models, Animal; Biomarkers; Fibroblasts; Citric Acid Cycle
PubMed: 38909094
DOI: 10.1038/s41598-024-64844-5 -
Cell Death Discovery Jun 2024Ubiquitin-proteasome system (UPS) is involved in vascular smooth muscle cell (VSMC) proliferation. Deubiquitinating enzymes (DUBs) have an essential role in the...
Ubiquitin-proteasome system (UPS) is involved in vascular smooth muscle cell (VSMC) proliferation. Deubiquitinating enzymes (DUBs) have an essential role in the UPS-regulated stability of the substrate; however, the function of DUBs in intimal hyperplasia remains unclear. We screened DUBs to identify a protein responsible for regulating VSMC proliferation and identified USP14 protein that mediates cancer development, inflammation, and foam cell formation. USP14 promotes human aortic smooth muscle cell and A7r5 cell growth in vitro, and its inhibition or deficiency decreases the intimal area in the mice carotid artery ligation model. In addition, USP14 stabilizes Skp2 expression by decreasing its degradation, while Skp2 overexpression rescues USP14 loss-induced issues. The current findings suggested an essential role of USP14 in the pathology of vascular remodeling, deeming it a promising target for arterial restenosis therapy.
PubMed: 38909015
DOI: 10.1038/s41420-024-02069-1 -
BMC Ophthalmology Jun 2024Sleep deprivation (SD) is a common public health problem that contributes to various physiological disorders and increases the risk of ocular diseases. However, whether...
BACKGROUND
Sleep deprivation (SD) is a common public health problem that contributes to various physiological disorders and increases the risk of ocular diseases. However, whether sleep loss can damage corneal endothelial function remains unclear. This study aimed to determine the effect and possible mechanism of SD on the corneal endothelium.
METHODS
Male C57BL/6J mice were subjected to establish SD models. After 10 days, quantitative RT-PCR (qRT-PCR) and western blot or immunostaining for the expression levels of zonula occludens-1 (ZO-1), ATPase Na+/K + transporting subunit alpha 1 (Atp1a1), and core clock genes in the corneal endothelium were evaluated. Reactive oxygen species staining and mitochondrial abundance characterized the mitochondrial function. The regulatory role of Bmal1 was confirmed by specifically knocking down or overexpressing basic helix-loop-helix ARNT like 1 protein (Bmal1) in vivo. In vitro, a mitochondrial stress test was conducted on cultured human corneal endothelial cells upon Bmal1 knockdown.
RESULTS
SD damaged the barrier and pump functions of mouse corneal endothelium, accompanied by mitochondrial dysfunction. Interestingly, SD dramatically downregulated the core clock gene Bmal1 expression level. Bmal1 knockdown disrupted corneal endothelial function, while overexpression of Bmal1 ameliorated the dysfunction induced by SD. Mitochondrial bioenergetic deficiency mediated by Bmal1 was an underlying mechanism for SD induced corneal endothelial dysfunction.
CONCLUSION
The downregulation of Bmal1 expression caused by SD led to corneal endothelial dysfunction via impairing mitochondrial bioenergetics. Our findings offered insight into how SD impairs the physiological function of the corneal endothelium and expanded the understanding of sleep loss leading to ocular diseases.
Topics: Sleep Deprivation; Animals; Mice, Inbred C57BL; Male; Mice; ARNTL Transcription Factors; Down-Regulation; Endothelium, Corneal; Disease Models, Animal; Cells, Cultured; Mitochondria; Blotting, Western; Gene Expression Regulation
PubMed: 38907352
DOI: 10.1186/s12886-024-03524-4 -
Scientific Reports Jun 2024Humoral primary immunodeficiencies are the most prevalent form of primary immunodeficiency (PID). Currently, there is no convenient method to quantify newly formed B...
Humoral primary immunodeficiencies are the most prevalent form of primary immunodeficiency (PID). Currently, there is no convenient method to quantify newly formed B cells. The aim of this proof-of-concept study was to quantitate the ratio of coding joints (CJs) to Kappa-deleting recombination excision circles (KRECs) and serum B cell activating factor (BAFF) in patients with humoral primary immunodeficiency and assess if they correlate with disease severity. This IRB-approved study was conducted at one academic children's hospital. Patients with humoral PIDs and healthy controls were included. CJ and KREC levels were measured via qPCR. Serum BAFF levels were measured using Mesoscale. 16 patients with humoral PID and 5 healthy controls were included. The mean CJ:KREC ratio in the CVID, antibody deficiency syndromes, and controls groups, respectively were 13.04 ± 9.5, 5.25 ± 4.1, and 4.38 ± 2.5 (p = 0.059). The mean serum BAFF levels in CVID, antibody deficiency syndromes and controls were 216.3 ± 290 pg/mL, 107.9 ± 94 pg/mL and 50.9 ± 12 pg/mL, respectively (p = 0.271). When the CVID patients were subdivided into CVID with or without lymphoproliferative features, the BAFF level was substantially higher in the CVID with lymphoproliferation cohort (mean 372.4 ± 361 pg/mL, p = 0.031). Elevated CJ:KREC ratio was observed in CVID, although statistical significance was not achieved, likely due to the small sample size. Serum BAFF levels were significantly higher in CVID patients with lymphoproliferative features. We speculate that the CJ:KREC ratio and serum BAFF levels can be utilized in patients with humoral PID, once more extensive studies confirm this exploratory investigation.
Topics: Humans; B-Cell Activating Factor; Female; Male; Child; Child, Preschool; Adolescent; Proof of Concept Study; B-Lymphocytes; Infant; Primary Immunodeficiency Diseases; Immunity, Humoral; Case-Control Studies; Immunologic Deficiency Syndromes
PubMed: 38906917
DOI: 10.1038/s41598-024-64942-4 -
Nature Communications Jun 2024Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for...
Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). Using this method, we show that patient-derived glioblastoma (GBM) samples with acquired temozolomide (TMZ) resistance display elevated HR and MMEJ activity, suggesting that these pathways contribute to treatment resistance. We screen clinically relevant small molecules for DSBR inhibition with the aim of identifying improved GBM combination therapy regimens. We identify the ATM kinase inhibitor, AZD1390, as a potent dual HR/MMEJ inhibitor that suppresses radiation-induced phosphorylation of DSBR proteins, blocks DSB end resection, and enhances the cytotoxic effects of TMZ in treatment-naïve and treatment-resistant GBMs with TP53 mutation. We further show that a combination of G2/M checkpoint deficiency and reliance upon ATM-dependent DSBR renders TP53 mutant GBMs hypersensitive to TMZ/AZD1390 and radiation/AZD1390 combinations. This report identifies ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes an approach for simultaneously measuring multiple DSBR pathways in treatment selection and oncology research.
Topics: Humans; Ataxia Telangiectasia Mutated Proteins; Glioblastoma; Tumor Suppressor Protein p53; DNA Breaks, Double-Stranded; Temozolomide; Cell Line, Tumor; Mutation; Drug Resistance, Neoplasm; DNA Repair; Brain Neoplasms; Animals; DNA End-Joining Repair; Mice; Phosphorylation
PubMed: 38906885
DOI: 10.1038/s41467-024-49316-8 -
Biochimica Et Biophysica Acta.... Jun 2024Ubiquinone (UQ) is an essential player in the respiratory electron transfer system. In Saccharomyces cerevisiae strains lacking the ability to synthesize UQ, exogenously...
Ubiquinone (UQ) is an essential player in the respiratory electron transfer system. In Saccharomyces cerevisiae strains lacking the ability to synthesize UQ, exogenously supplied UQs can be taken up and delivered to mitochondria through an unknown mechanism, restoring the growth of UQ-deficient yeast in non-fermentable medium. Since elucidating the mechanism responsible may markedly contribute to therapeutic strategies for patients with UQ deficiency, many attempts have been made to identify the machinery involved in UQ trafficking in the yeast model. However, definite experimental evidence of the direct interaction of UQ with a specific protein(s) has not yet been demonstrated. To gain insight into intracellular UQ trafficking via a chemistry-based strategy, we synthesized a hydrophobic UQ probe (pUQ5), which has a photoreactive diazirine group attached to a five-unit isoprenyl chain and a terminal alkyne to visualize and/or capture the labeled proteins via click chemistry. pUQ5 successfully restored the growth of UQ-deficient S. cerevisiae (Δcoq2) on a non-fermentable carbon source, indicating that this UQ was taken up and delivered to mitochondria, and served as a UQ substrate of respiratory enzymes. Through photoaffinity labeling of the mitochondria isolated from Δcoq2 yeast cells cultured in the presence of pUQ5, we identified many labeled proteins, including voltage-dependent anion channel 1 (VDAC1) and cytochrome c oxidase subunit 3 (Cox3). The physiological relevance of UQ binding to these proteins is discussed.
PubMed: 38906315
DOI: 10.1016/j.bbabio.2024.149147