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Free Radical Biology & Medicine Jun 2024To date, Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver disease associated with clinical complications. Dietary fatty acids have been...
BACKGROUND
To date, Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver disease associated with clinical complications. Dietary fatty acids have been suggested to be involved in preventing or reversing the accumulation of hepatic fat. However, contradicting roles of monounsaturated fatty acids to the liver have been implicated in various human and murine models, mainly due to the insolubility nature of fatty acids.
METHODS
High pressure homogenization methods were used to fabricate oleic acid embedded lipid nanoparticles (OALNs). The in vitro and in vivo models were used to validate the physiological effect of this OALNs via various cellular and molecular approaches including cell viability essay, fluorescent staining, electron microscope, RNAseq, qPCR, Western blots, and IHC staining.
RESULTS
We successfully fabricated OALNs with enhanced stability and solubility. More importantly, lipid accumulation was successfully induced in hepatocytes via the application of OALNs in a dose-dependent manner. Overload of OALNs resulted in ROS accumulation and apoptosis of hepatocytes dose-dependently. With the help of transcriptome sequencing and traditional experimental approaches, we demonstrated that the lipotoxic effect induced by OALNs was exerted via the DDIT3/BCL2/BAX/Caspases signaling. Moreover, we also verified that OALNs induced steatosis and subsequent apoptosis in the liver of mice via the activation of DDIT3 in vivo.
CONCLUSIONS
In all, our results established a potential pathogenic model of NAFLD for further studies and indicated the possible involvement of DDIT3 signaling in abnormal steatosis process of the liver.
PubMed: 38945456
DOI: 10.1016/j.freeradbiomed.2024.06.024 -
The Journal of Pediatrics Jun 2024To demonstrate a high-yield molecular diagnostic workflow for lateralized overgrowth (LO), a congenital condition with abnormal enlargement of body parts, and to...
OBJECTIVE
To demonstrate a high-yield molecular diagnostic workflow for lateralized overgrowth (LO), a congenital condition with abnormal enlargement of body parts, and to classify it by molecular genetics. and STUDY DESIGN: We categorized 186 retrospective cases of LO diagnosed between 2003 and 2023 into suspected Beckwith-Wiedemann spectrum (BWSp), PIK3CA-Related Overgrowth Spectrum (PROS), vascular overgrowth (VO) , or isolated (ILO), based on initial clinical assessments, to determine the appropriate first-tier molecular tests and tissue for analysis. Patients underwent testing for 11p15 epigenetic abnormalities or somatic variants in genes related to PI3K/AKT/mTOR, vascular proliferation, and RAS-MAPK cascades using blood or skin DNA. For cases with negative initial tests, a sequential cascade molecular approach was employed to improve diagnostic yield.
RESULTS
This approach led to a molecular diagnosis in 54% of cases, 89% of cases consistent with initial clinical suspicions and 11% reclassified. BWSp was the most common cause, with 43% of cases exhibiting 11p15 abnormalities. PROS had the highest confirmation rate, with 74% of clinically diagnosed patients showing a PIK3CA variant. VO demonstrated significant clinical overlap with other syndromes. Molecular diagnosis of ILO proved challenging, with only 21% of cases classifiable into a specific condition.
CONCLUSION
Despite, LO is underdiagnosed from a molecular viewpoint and to date has had no diagnostic guidelines, which would be crucial for addressing potential cancer predisposition, enabling precision medicine treatments, or guiding management. This study sheds light on the molecular etiology of LO, highlighting the importance of tailored diagnostic approach and of selecting appropriate testing to achieve the highest diagnostic yield.
PubMed: 38945442
DOI: 10.1016/j.jpeds.2024.114177 -
The Journal of Pain Jun 2024The human brain is a dynamic system that shows frequency-specific features. Neuroimaging studies have shown that both healthy individuals and those with chronic pain...
The human brain is a dynamic system that shows frequency-specific features. Neuroimaging studies have shown that both healthy individuals and those with chronic pain disorders experience pain influenced by various processes that fluctuate over time. Primary dysmenorrhea is a chronic visceral pain that disrupts the coordinated activity of brain's functional network. However, it remains unclear whether the dynamic interactions across the whole-brain network over time and their associations with neurobehavioral symptoms are dependent on the frequency bands in patients with primary dysmenorrhea during the pain-free periovulation phase. In this study, we used an energy landscape analysis to examine the interactions over time across the large-scale network in a sample of 59 patients with primary dysmenorrhea and 57 healthy controls at different frequency bands. Compared to healthy controls, patients with primary dysmenorrhea exhibit aberrant brain dynamics, with more significant differences in the slow-4 frequency band. Patients with primary dysmenorrhea show more indirect neural transition times due to an unstable intermediate state, whereas neurotypical brain activity frequently transitions between two major states. This data-driven approach further revealed that the brains of individuals with primary dysmenorrhea have more abnormal brain dynamics than healthy controls. Our results suggested that unstable brain dynamics were associated with the strength of brain functional segregation and the Pain Catastrophizing Scale (PCS) score. Our findings provide preliminary evidence that atypical dynamics in the functional network may serve as a potential key feature and biological marker of patients with PDM during the pain-free phase. PERSPECTIVE: We applied energy landscape analysis on brain-imaging data to identify relatively stable and dominant brain activity patterns for patients with primary dysmenorrhea(PDM). More atypical brain dynamics were found in the slow-4 band and were related to the strength of functional segregation, providing new insights into the dysfunction brain dynamics.
PubMed: 38945381
DOI: 10.1016/j.jpain.2024.104618 -
Translational Research : the Journal of... Jun 2024Renal aging and the subsequent rise in kidney-related diseases are attributed to senescence in renal tubular epithelial cells (RTECs). Our study revealed that the...
Renal aging and the subsequent rise in kidney-related diseases are attributed to senescence in renal tubular epithelial cells (RTECs). Our study revealed that the abnormal expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader of RNA N6-methyladenosine, is critically involved in cisplatin-induced renal tubular senescence. In cisplatin-induced senescence of RTECs, the promoter activity and transcription of IGF2BP3 is markedly suppressed. It was due to the down regulation of MYC proto-oncogene (MYC), which regulates IGF2BP3 transcription by binding to the putative site at 1852 to 1863 of the IGF2BP3 promoter. Overexpression of IGF2BP3 ameliorated cisplatin-induced renal tubular senescence in vitro. Mechanistic studies revealed that IGF2BP3 inhibits cellular senescence in RTECs by enhancing cyclin-dependent kinase 6 (CDK6) mRNA stability and increasing its expression. The inhibition effect of IGF2BP3 on tubular senescence is partially reversed by the knockdown of CDK6. Further, IGF2BP3 recruits nuclear cap binding protein subunit 1 (NCBP1) and inhibits CDK6 mRNA decay, by recognizing mA modification. Specifically, IGF2BP3 recognizes mA motif "GGACU" at nucleotides 110-114 in the 5' untranslated region (UTR) field of CDK6 mRNA. The involvement of IGF2BP3/CDK6 in alleviating tubular senescence was confirmed in a cisplatin-induced acute kidney injury (AKI)-to-chronic kidney disease (CKD) model. Clinical data also suggests an age-related decrease in IGF2BP3 and CDK6 levels in renal tissue or serum samples from patients. These findings suggest that IGF2BP3/CDK6 may be a promising target in cisplatin-induced tubular senescence and renal failure.
PubMed: 38945255
DOI: 10.1016/j.trsl.2024.06.004 -
Placenta Jun 2024This study aimed to explore the association between ferroptosis, a newly identified type of cell death, and the role of retinoic acid in developing pregnancy...
INTRODUCTION
This study aimed to explore the association between ferroptosis, a newly identified type of cell death, and the role of retinoic acid in developing pregnancy complications. Therefore, the effects of all-trans retinoic acid (ATRA) on ferroptosis susceptibility in BeWo cells were assessed to understand abnormal placental development.
METHODS
BeWo cells were used as surrogates for cytotrophoblasts. The effect of ATRA on ferroptosis sensitivity was assessed on BeWo cells pretreated with ATRA or dimethyl sulfoxide (DMSO; control), following which the LDH-releasing assay was performed. The effects of ATRA pretreatment on the antioxidant defense system (including glutathione [GSH], mitochondrial membrane potential, and heme oxygenase-1 [HMOX1]) in BeWo cells were assessed using assay kits, RT-qPCR, and HMOX1 immunostaining. To evaluate the effect of ATRA on BeWo cells, HMOX1 was silenced in BeWo cells using shRNA.
RESULTS
ATRA pretreatment increased ferroptosis resistance in BeWo cells. Although with pretreatment, qPCR indicated upregulation of HMOX1, no significant change was observed in the GSH levels or mitochondrial membrane potential. This was corroborated by intensified immunostaining for heme oxygenase-1 protein (HO-1). Notably, the protective effect of ATRA against ferroptosis was negated when HO-1 was inhibited. Although HMOX1-silenced BeWo cells exhibited heightened ferroptosis sensitivity compared with controls, ATRA pretreatment counteracted ferroptosis in these cells.
DISCUSSION
ATRA pretreatment promotes BeWo cell viability by suppressing ferroptosis and upregulating HMOX1 and this can be used as a potential therapeutic strategy for addressing placental complications associated with ferroptosis.
PubMed: 38945098
DOI: 10.1016/j.placenta.2024.06.012 -
Cytotherapy Jun 2024Natural killer (NK) cells make only a small fraction of immune cells in the human body, however, play a pivotal role in the fight against cancer by the immune system.... (Review)
Review
Natural killer (NK) cells make only a small fraction of immune cells in the human body, however, play a pivotal role in the fight against cancer by the immune system. They are capable of eliminating abnormal cells via several direct or indirect cytotoxicity pathways in a self-regulating manner, which makes them a favorable choice as a cellular therapy against cancer. Additionally, allogeneic NK cells, unlike other lymphocytes, do not or only minimally cause graft-versus-host diseases opening the door for an off-the-shelf therapy. However, to date, the production of NK cells faces several difficulties, especially because the critical process parameters (CPPs) influencing the critical quality attributes (CQAs) are difficult to identify or correlate. There are numerous different cultivation platforms available, all with own characteristics, benefits and disadvantages that add further difficulty to define CPPs and relate them to CQAs. Our goal in this contribution was to summarize the current knowledge about NK cell expansion CPPs and CQAs, therefore we analyzed the available literature of both dynamic and static culture format experiments in a systematic manner. We present a list of the identified CQAs and CPPs and discuss the role of each CPP in the regulation of the CQAs. Furthermore, we could identify potential relationships between certain CPPs and CQAs. The findings based on this systematic literature research can be the foundation for meaningful experiments leading to better process understanding and eventually control.
PubMed: 38944794
DOI: 10.1016/j.jcyt.2024.05.025 -
BMC Pulmonary Medicine Jun 2024For patients with congenital heart disease-related pulmonary arterial hypertension (CHD-PAH), cardiopulmonary exercise testing (CPET) can reflect cardiopulmonary reserve...
BACKGROUND
For patients with congenital heart disease-related pulmonary arterial hypertension (CHD-PAH), cardiopulmonary exercise testing (CPET) can reflect cardiopulmonary reserve function. However, CPET may not be readily accessible for patients with high-risk conditions or limited mobility due to disability. Echocardiography, on the other hand, serves as a widely available diagnostic tool for all CHD-PAH patients. This study was aimed to identify the parameters of echocardiography that could serve as indicators of cardiopulmonary function and exercise capacity.
METHODS
A cohort of 70 patients contributed a total of 110 paired echocardiogram and CPET results to this study, with 1 year interval for repeated examinations. Echocardiography and exercise testing were conducted following standardized procedures, and the data were collected together with clinically relevant indicators for subsequent statistical analysis. Demographic comparisons were performed using t-tests and chi-square tests. Univariate and multivariate analyses were conducted to identify potential predictors of peak oxygen uptake (peak VO) and the carbon dioxide ventilation equivalent slope (VE/VCO slope). Receiver operating characteristic (ROC) analysis was used to assess the performance of the parameters.
RESULTS
The ratio of tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) was found to be the only independent indicator significantly associated with both peak VO and VE/VCO slope (both p < 0.05). Additionally, left ventricular ejection fraction (LVEF) and right ventricular fractional area change (FAC) were independently correlated with the VE/VCO slope (both p < 0.05). TAPSE/PASP showed the highest area under the ROC curve (AUC) for predicting both a peak VO ≤ 15 mL/kg/min and a VE/VCO slope ≥ 36 (AUC = 0.91, AUC = 0.90, respectively). The sensitivity and specificity of TAPSE/PASP at the optimal threshold exceeded 0.85 for both parameters.
CONCLUSIONS
TAPSE/PASP may be a feasible echocardiographic indicator for evaluating exercise tolerance.
Topics: Humans; Female; Male; Exercise Test; Heart Defects, Congenital; Echocardiography; Adult; ROC Curve; Exercise Tolerance; Pulmonary Arterial Hypertension; Oxygen Consumption; Middle Aged; Young Adult; Hypertension, Pulmonary; Pulmonary Artery
PubMed: 38944669
DOI: 10.1186/s12890-024-03113-7 -
Photodiagnosis and Photodynamic Therapy Jun 2024Diabetes, characterized by heightened blood sugar levels, can lead to a condition called Diabetic Retinopathy (DR), which adversely impacts the eyes due to elevated...
Diabetes, characterized by heightened blood sugar levels, can lead to a condition called Diabetic Retinopathy (DR), which adversely impacts the eyes due to elevated blood sugar affecting the retinal blood vessels. The most common cause of blindness in diabetics is thought to be Diabetic Retinopathy (DR), particularly in working-age individuals living in poor nations. People with type 1 or type 2 diabetes may develop this illness, and the risk rises with the length of diabetes and inadequate blood sugar management. There are limits to traditional approaches for the early identification of diabetic retinopathy (DR). In order to diagnose diabetic retinopathy, a model based on Convolutional neural network (CNN) is used in a unique way in this research. The suggested model uses a number of deep learning (DL) models, such as VGG19, Resnet50, and InceptionV3, to extract features. After concatenation, these characteristics are sent through the CNN algorithm for classification. By combining the advantages of several models, ensemble approaches can be effective tools for detecting diabetic retinopathy and increase overall performance and resilience. Classification and image recognition are just a few of the tasks that may be accomplished with ensemble approaches like combination of VGG19,Inception V3 and Resnet 50 to achieve high accuracy. The proposed model is evaluated using a publicly accessible collection of fundus images.VGG19, ResNet50, and InceptionV3 differ in their neural network architectures, feature extraction capabilities, object detection methods, and approaches to retinal delineation. VGG19 may excel in capturing fine details, ResNet50 in recognizing complex patterns, and InceptionV3 in efficiently capturing multi-scale features. Their combined use in an ensemble approach can provide a comprehensive analysis of retinal images, aiding in the delineation of retinal regions and identification of abnormalities associated with diabetic retinopathy. For instance, micro aneurysms, the earliest signs of DR, often require precise detection of subtle vascular abnormalities. VGG19's proficiency in capturing fine details allows for the identification of these minute changes in retinal morphology. On the other hand, ResNet50's strength lies in recognizing intricate patterns, making it effective in detecting neo neo-vascularization and complex hemorrhagic lesions. Meanwhile, InceptionV3's multi-scale feature extraction enables comprehensive analysis, crucial for assessing macular edema and ischemic changes across different retinal layers.
PubMed: 38944405
DOI: 10.1016/j.pdpdt.2024.104259 -
Journal of Stroke and Cerebrovascular... Jun 2024Anomalous vascular variants pose unique challenges in clinical management, especially in the context of neuroendovascular intervention. We present a case report...
Anomalous vascular variants pose unique challenges in clinical management, especially in the context of neuroendovascular intervention. We present a case report detailing an extremely rare anatomic variant involving the left anterior choroidal artery, which arises proximal to the fetal posterior communicating artery. Our patient presented with confusion and speech abnormalities following a benzodiazepine overdose. Subsequent computed tomography of the head revealed an aneurysm originating from the left supraclinoid carotid artery. This aneurysm was located 2 mm more proximal to the origin of the left posterior communicating artery and was initially misidentified as originating from the left posterior communicating artery due to its proximity. Further diagnostic cerebral angiography revealed an extremely rare anatomical variant where the left anterior choroidal artery anomalously arose proximal to a fetal posterior communicating artery, with the aneurysm being correctly identified as arising from the left anterior choroidal artery. The patient underwent successful detoxification and has since shown remarkable improvement, with plans for elective endovascular flow diversion treatment under dual antiplatelet therapy. Considering the critical role of the anterior choroidal artery in supplying vital cerebral structures, awareness of such variants is paramount to prevent inadvertent vascular injury and optimize patient outcomes. This case highlights the necessity of meticulous pre-procedural imaging and multidisciplinary collaboration in managing neurovascular anomalies effectively.
PubMed: 38944362
DOI: 10.1016/j.jstrokecerebrovasdis.2024.107835 -
Cell Reports. Medicine Jun 2024Solid tumor pathology, characterized by abnormalities in the tumor microenvironment (TME), challenges therapeutic effectiveness. Mechanical factors, including increased... (Review)
Review
Solid tumor pathology, characterized by abnormalities in the tumor microenvironment (TME), challenges therapeutic effectiveness. Mechanical factors, including increased tumor stiffness and accumulation of intratumoral forces, can determine the success of cancer treatments, defining the tumor's "mechanopathology" profile. These abnormalities cause extensive vascular compression, leading to hypoperfusion and hypoxia. Hypoperfusion hinders drug delivery, while hypoxia creates an unfavorable TME, promoting tumor progression through immunosuppression, heightened metastatic potential, drug resistance, and chaotic angiogenesis. Strategies targeting TME mechanopathology, such as vascular and stroma normalization, hold promise in enhancing cancer therapies with some already advancing to the clinic. Normalization can be achieved using anti-angiogenic agents, mechanotherapeutics, immune checkpoint inhibitors, engineered bacterial therapeutics, metronomic nanomedicine, and ultrasound sonopermeation. Here, we review the methods developed to rectify tumor mechanopathology, which have even led to cures in preclinical models, and discuss their bench-to-bedside translation, including the derivation of biomarkers from tumor mechanopathology for personalized therapy.
PubMed: 38944037
DOI: 10.1016/j.xcrm.2024.101626