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Metabolites May 2024For either healthy or diseased organisms, lipids are key components for cellular membranes; they play important roles in numerous cellular processes including cell... (Review)
Review
For either healthy or diseased organisms, lipids are key components for cellular membranes; they play important roles in numerous cellular processes including cell growth, proliferation, differentiation, energy storage and signaling. Exercise and disease development are examples of cellular environment alterations which produce changes in these networks. There are indications that alterations in lipid metabolism contribute to the development and progression of a variety of cancers. Measuring such alterations and understanding the pathways involved is critical to fully understand cellular metabolism. The demands for this information have led to the emergence of lipidomics, which enables the large-scale study of lipids using mass spectrometry (MS) techniques. Mass spectrometry has been widely used in lipidomics and allows us to analyze detailed lipid profiles of cancers. In this article, we discuss emerging strategies for lipidomics by mass spectrometry; targeted, as opposed to global, lipid analysis provides an exciting new alternative method. Additionally, we provide an introduction to lipidomics, lipid categories and their major biological functions, along with lipidomics studies by mass spectrometry in cancer samples. Further, we summarize the importance of lipid metabolism in oncology and tumor microenvironment, some of the challenges for lipodomics, and the potential for targeted approaches for screening pharmaceutical candidates to improve the therapeutic efficacy of treatment in cancer patients.
PubMed: 38921447
DOI: 10.3390/metabo14060312 -
AJOG Global Reports May 2024In vitro fertilization is the most used assisted reproductive technology in the United States that is increasing in efficiency and in demand. Certain states have...
BACKGROUND
In vitro fertilization is the most used assisted reproductive technology in the United States that is increasing in efficiency and in demand. Certain states have mandated coverage that enable individuals with low income to undergo in vitro fertilization treatment.
OBJECTIVE
This study aimed to evaluate if socioeconomic status has an impact on the perinatal outcomes in in vitro fertilization pregnancies. We hypothesized that with greater coverage there may be an alleviation of the financial burden of in vitro fertilization that can facilitate the application of evidence-based practices.
STUDY DESIGN
This was a retrospective, population-based, observational study that was conducted in accordance with the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample database over the 6-year period from 2008 to 2014 during which period 10,000 in vitro fertilization deliveries were examined. Maternal outcomes of interest included preterm prelabor rupture of membranes, preterm birth (ie, before 37 weeks of gestation), placental abruption, cesarean delivery, operative vaginal delivery, spontaneous vaginal delivery, maternal infection, chorioamnionitis, hysterectomy, and postpartum hemorrhage. Neonatal outcomes included small for gestational age neonates, defined as birthweight <10th percentile, intrauterine fetal death, and congenital anomalies.
RESULTS
Our study found that the socioeconomic status did not have a statistically relevant effect on the perinatal outcomes among women who underwent in vitro fertilization to conceive after adjusting for the potential confounding effects of maternal demographic, preexisting clinical characteristics, and comorbidities.
CONCLUSION
The literature suggests that in states with mandated in vitro fertilization coverage, there are better perinatal outcomes because, in part, of the increased use of best in vitro fertilization practices, such as single-embryo transfers. Moreover, the quality of medical care in states with coverage is in the highest quartile in the country. Therefore, our findings of equivalent perinatal outcomes in in vitro fertilization care irrespective of socioeconomic status possibly suggests that a lack of access to quality medical care may be a factor in the health disparities usually seen among individuals with lower socioeconomic status.
PubMed: 38919707
DOI: 10.1016/j.xagr.2024.100329 -
Nature Communications Jun 2024Heparan sulfate (HS) is degraded in lysosome by a series of glycosidases. Before the glycosidases can act, the terminal glucosamine of HS must be acetylated by the...
Heparan sulfate (HS) is degraded in lysosome by a series of glycosidases. Before the glycosidases can act, the terminal glucosamine of HS must be acetylated by the integral lysosomal membrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT). Mutations of HGSNAT cause HS accumulation and consequently mucopolysaccharidosis IIIC, a devastating lysosomal storage disease characterized by progressive neurological deterioration and early death where no treatment is available. HGSNAT catalyzes a unique transmembrane acetylation reaction where the acetyl group of cytosolic acetyl-CoA is transported across the lysosomal membrane and attached to HS in one reaction. However, the reaction mechanism remains elusive. Here we report six cryo-EM structures of HGSNAT along the reaction pathway. These structures reveal a dimer arrangement and a unique structural fold, which enables the elucidation of the reaction mechanism. We find that a central pore within each monomer traverses the membrane and controls access of cytosolic acetyl-CoA to the active site at its luminal mouth where glucosamine binds. A histidine-aspartic acid catalytic dyad catalyzes the transfer reaction via a ternary complex mechanism. Furthermore, the structures allow the mapping of disease-causing variants and reveal their potential impact on the function, thus creating a framework to guide structure-based drug discovery efforts.
Topics: Mucopolysaccharidosis III; Humans; Lysosomes; Acetyltransferases; Cryoelectron Microscopy; Catalytic Domain; Mutation; Heparitin Sulfate; Acetyl Coenzyme A; Models, Molecular; Glucosamine; Acetylation; Intracellular Membranes
PubMed: 38918376
DOI: 10.1038/s41467-024-49614-1 -
BioRxiv : the Preprint Server For... Jun 2024Certain areas of the brain involved in episodic memory and behavior, such as the hippocampus, express high levels of insulin receptors and glucose transporter-4 (GLUT4)...
Certain areas of the brain involved in episodic memory and behavior, such as the hippocampus, express high levels of insulin receptors and glucose transporter-4 (GLUT4) and are responsive to insulin. Insulin and neuronal glucose metabolism improve cognitive functions and regulate mood in humans. Insulin-dependent GLUT4 trafficking has been extensively studied in muscle and adipose tissue, but little work has demonstrated either how it is controlled in insulin-responsive brain regions or its mechanistic connection to cognitive functions. In this study, we demonstrate that inhibition of WNK (With-No-lysine (K)) kinases improves learning and memory in mice. Neuronal inhibition of WNK enhances in vivo hippocampal glucose uptake. Inhibition of WNK enhances insulin signaling output and insulin-dependent GLUT4 trafficking to the plasma membrane in mice primary neuronal cultures and hippocampal slices. Therefore, we propose that the extent of neuronal WNK kinase activity has an important influence on learning, memory and anxiety-related behaviors, in part, by modulation of neuronal insulin signaling.
PubMed: 38915673
DOI: 10.1101/2024.06.09.598125 -
JCI Insight May 2024Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators...
Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts "immune desert phenotypes" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.
Topics: Animals; Membrane Proteins; Mice; Female; Signal Transduction; T-Lymphocytes, Cytotoxic; Triple Negative Breast Neoplasms; Indomethacin; Cell Line, Tumor; Humans; Lung Neoplasms; Cyclooxygenase Inhibitors; Nucleotidyltransferases; Interferon Type I; Cyclooxygenase 2; Lymphocytes, Tumor-Infiltrating; Mice, Inbred BALB C
PubMed: 38912586
DOI: 10.1172/jci.insight.165356 -
Industrial & Engineering Chemistry... May 2024The basic principles of a steady-state mass transfer model and the resistance-in-series film model are assessed with the aid of a series of experiments in a gas-liquid...
The basic principles of a steady-state mass transfer model and the resistance-in-series film model are assessed with the aid of a series of experiments in a gas-liquid contact membrane mini-module (3 M Liqui-Cel MM-1.7 × 5.5) using an aqueous solution of diethanolamine (DEA) of 0.25 M (mol/L) for biogas upgrading. Experimental data show that CO removal may exceed 67% and reach 100% in combination with the highest possible recovery of CH when employing biogas flow rates in the range of 2.8 × 10 - 3.6 × 10 m/s and solvent flow rates within 0.47 × 10 - 0.58 × 10 m/s. For the experimental data set, a correlation has been developed, effectively interpolating CO removal with the gas and liquid flow rates. The wetting values calculated are concentrated close to each other for the same liquid flow rate without considerably depending on the gas flow rate, especially when applying the Hikita-Yun (reaction rate-shell-side correlation) compared with the Hikita-Costello pair. Furthermore, the calculated wetting diminishes with increasing liquid flow rate, a result that is consistent with previous modeling attempts and relevant literature indications. The assumption of enhanced mass transfer in the liquid-filled part of the membrane pores due to the reaction is scrutinized, leading to objectionable computational wetting values. It is shown that for a concentration of DEA equal to 0.25 M the Hatta numbers and the enhancement factors are not equal in the whole reaction path; thus, the choice of the shell-side correlation has an appreciable impact on the overall analysis, especially for the determination of the wetting values.
PubMed: 38911336
DOI: 10.1021/acs.iecr.4c00525 -
Seminars in Nuclear Medicine Jun 2024The aim of this overview was to consolidate existing evidence syntheses and provide a comprehensive overview of the evidence for F-prostate specific membrane antigen... (Review)
Review
Diagnostic Accuracy of F-Prostate Specific Membrane Antigen (PSMA) PET/CT Radiotracers in Staging and Restaging of Patients With High-Risk Prostate Cancer or Biochemical Recurrence: An Overview of Reviews.
The aim of this overview was to consolidate existing evidence syntheses and provide a comprehensive overview of the evidence for F-prostate specific membrane antigen (PSMA) PET/CT in the staging of high-risk prostate cancer and restaging after biochemical recurrence. An overview of reviews was performed and reported in line with the preferred reporting items for overview of reviews (PRIOR) statement and synthesis without meta-analysis (SWiM) reporting guidelines. A comprehensive database and grey literature search were conducted up to July 18, 2023. Systematic reviews were assessed using the risk of bias in systematic reviews (ROBIS) tool. The certainty of the evidence was assessed using grading of recommendations, assessment, development and evaluations (GRADE). 11 systematic reviews were identified; 10 were at high or unclear risk of bias. Evidence reported on a per-patient, per-lymph node, and per-lesion basis for sensitivity, specificity and overall accuracy was identified. There was a lack of data on dose, adverse events and evidence directly comparing F-PSMA PET/CT to other imaging modalities. Evidence with moderate to very low certainty indicated high sensitivity, specificity and accuracy of F-PSMA PET/CT in patients with high-risk prostate cancer and biochemical recurrence. There was considerably lower certainty evidence and greater variability in effect estimates for outcomes for the combined intermediate/high-risk cohort. While evidence gaps remain for some outcomes, and most systematic reviews were at high or unclear risk of bias, the current evidence base is broadly supportive of F-PSMA PET/CT imaging in the staging and restaging of patients with high-risk prostate cancer and biochemical recurrence.
PubMed: 38906759
DOI: 10.1053/j.semnuclmed.2024.05.003 -
BioRxiv : the Preprint Server For... Feb 2024Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease characterized by vascular remodeling of small pulmonary arteries. Endothelial dysfunction...
Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease characterized by vascular remodeling of small pulmonary arteries. Endothelial dysfunction in advanced PAH is associated with proliferation, apoptosis resistance, and endothelial to mesenchymal transition (EndoMT) due to aberrant signaling. DLL4, a cell membrane associated NOTCH ligand, activates NOTCH1 signaling and plays a pivotal role maintaining vascular integrity. Inhibition of DLL4 has been associated with the development of pulmonary hypertension, but the mechanism is incompletely understood. Here we report that silencing in PAECs activated AKT and decreased DLL4 expression. DLL4 loss was also seen in lungs of patients with IPAH and HPAH. Over-expression of DLL4 in PAECs induced promoter activity and exogenous DLL4 increased mRNA through NOTCH1 activation. Furthermore, DLL4/NOTCH1 signaling blocked AKT activation, decreased proliferation and reversed EndoMT in - silenced PAECs and ECs from IPAH patients. PPARγ, suppressed by BMPR2 loss, was induced and activated by DLL4/NOTCH1 signaling in both -silenced and IPAH PAECs, reversing aberrant phenotypic changes, in part through AKT inhibition. Finally, leniolisib, a well-tolerated oral PI3K8/AKT inhibitor, decreased cell proliferation, induced apoptosis and reversed markers of EndoMT in -silenced PAECs. Restoring DLL4/NOTCH1/PPARγ signaling and/or suppressing AKT activation may be beneficial in preventing or reversing the pathologic vascular remodeling of PAH.
PubMed: 38903104
DOI: 10.1101/2024.01.31.578230 -
International Journal of Ophthalmology 2024To identify genetic defects in a Chinese family with congenital posterior polar cataracts and assess the pathogenicity.
AIM
To identify genetic defects in a Chinese family with congenital posterior polar cataracts and assess the pathogenicity.
METHODS
A four-generation Chinese family affected with autosomal dominant congenital cataract was recruited. Nineteen individuals took part in this study including 5 affected and 14 unaffected individuals. Sanger sequencing targeted hot-spot regions of 27 congenital cataract-causing genes for variant discovery. The pathogenicity of the variant was evaluated by the guidelines of American College of Medical Genetics and InterVar software. Confocal microscopy was applied to detect the subcellular localization of fluorescence-labeled ephrin type-A receptor 2 (EPHA2). Co-immunoprecipitation assay was implemented to estimate the interaction between EphA2 and other lens membrane proteins. The mRNA and protein expression were analyzed by reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting assay, respectively. The cell migration was analyzed by wound healing assay. Zebrafish model was generated by ectopic expression of human /p.R957P mutant to demonstrate whether the mutant could cause lens opacity .
RESULTS
A novel missense and pathogenic variant c.2870G>C was identified in the sterile alpha motif (SAM) domain of . Functional studies demonstrated the variant's impact: reduced EPHA2 protein expression, altered subcellular localization, and disrupted interactions with other lens membrane proteins. This mutant notably enhanced human lens epithelial cell migration, and induced a central cloudy region and roughness in zebrafish lenses with ectopic expression of human /p.R957P mutant under differential interference contrast (DIC) optics.
CONCLUSION
Novel pathogenic c.2870G>C variant of in a Chinese congenital cataract family contributes to disease pathogenesis.
PubMed: 38895685
DOI: 10.18240/ijo.2024.06.04 -
BioRxiv : the Preprint Server For... Jun 2024Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease (PD). Here we show that VPS13C, a bridge-like lipid...
Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease (PD). Here we show that VPS13C, a bridge-like lipid transport protein and a PD gene, is a sensor of lysosome stress/damage. Upon lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires release of a brake, most likely an intramolecular interaction within VPS13C, which hinders access of its VAB domain to lysosome-bound Rab7. While another PD protein, LRRK2, is also recruited to stressed/damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the putative role of VPS13 proteins in bulk lipid transport, these findings suggest lipid delivery to lysosomes by VPS13C is part of an early response to lysosome damage.
PubMed: 38895395
DOI: 10.1101/2024.06.08.598070