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Organic & Biomolecular Chemistry Jul 2024Phosphatidic acid and phosphatidylserine are anionic phospholipids with emerging signalling roles in cells. Determination of how phosphatidic acid and phosphatidylserine...
Phosphatidic acid and phosphatidylserine are anionic phospholipids with emerging signalling roles in cells. Determination of how phosphatidic acid and phosphatidylserine change location and quantity in cells over time requires selective fluorescent sensors that can distinguish these two anionic phospholipids. However, the design of such synthetic sensors that can selectively bind and respond to a single phospholipid within the complex membrane milieu remains challenging. In this work, we present a simple and robust strategy to control the selectivity of synthetic sensors for phosphatidic acid and phosphatidylserine. By changing the coordination metal of a dipicolylamine (DPA) ligand from Zn(II) to Ni(II) on the same synthetic sensor with a peptide backbone, we achieve a complete switch in selectivity from phosphatidic acid to phosphatidylserine in model lipid membranes. Furthermore, this strategy was largely unaffected by the choice and the position of the fluorophores. We envision that this strategy will provide a platform for the rational design of targeted synthetic phospholipid sensors to probe plasma and intracellular membranes.
PubMed: 38957899
DOI: 10.1039/d4ob00418c -
Ghana Medical Journal Sep 2023To determine if the number of vaso-occlusive events in SCD relates to plasma concentration of fucosyltransferase 7 (FUT7), which catalyses the synthesis of selectin...
OBJECTIVE
To determine if the number of vaso-occlusive events in SCD relates to plasma concentration of fucosyltransferase 7 (FUT7), which catalyses the synthesis of selectin ligands.
DESIGN
A prospective, analytical study.
SETTING
Haematology and Chemical Pathology Departments of tertiary healthcare centres.
PARTICIPANTS
Steady state HbSS individuals aged 13-45 years, 20 had 3 or more vaso-occlusive crises that required hospital admission in the previous year (with or without complications of SCD); 17 other HbSS persons had 0-1 vaso-occlusive crisis that required hospital admission in the previous year and no disease complications.
INTERVENTION
Steady-state plasma concentrations of FUT7 measured by ELISA were compared between SCD patients who had one vaso-occlusive crisis requiring hospital treatment in the previous year but no disease complications and those who had >3 crises with or without complications.
MAIN OUTCOME MEASURES
Plasma level of FUT7and the number of vaso-occlusive events in each HbSS patient.
RESULTS
Mean + standard deviation plasma concentration of FUT7 was 8.6 + 2.7 ng/ml in patients with >3 vasoocclusive crises in the previous year and 7.3 + 1.7 ng/ml in those with 0-1 crisis and no complications; independent sample t-test, p > 0.05, not significantly different.
CONCLUSION
Plasma concentration of fucosyltransferase7 is not associated with the number of vaso-occlusive events in sickle cell disease.
FUNDING
None declared.
Topics: Humans; Fucosyltransferases; Anemia, Sickle Cell; Adult; Female; Male; Prospective Studies; Adolescent; Young Adult; Middle Aged; Vascular Diseases; Enzyme-Linked Immunosorbent Assay; Biomarkers
PubMed: 38957672
DOI: 10.4314/gmj.v57i3.6 -
International Journal of Hypertension 2024Ouabain, a Na, K-ATPase inhibitor, is elevated in hypertensive patients. Evidence suggests ouabain contributes to hypertension mainly through activation of the...
BACKGROUND
Ouabain, a Na, K-ATPase inhibitor, is elevated in hypertensive patients. Evidence suggests ouabain contributes to hypertension mainly through activation of the sympathetic nervous system (SNS). Renal nerves play a vital role in the regulation of SNS activity, so we hypothesize that renal denervation may attenuate the development of ouabain-induced hypertension.
METHODS AND RESULTS
Forty Sprague-Dawley rats were divided into following groups ( = 10 each): control group (sham surgery plus intraperitoneal saline injection), RDN group (renal denervation (RDN) plus intraperitoneal saline injection), ouabain group (sham surgery plus intraperitoneal ouabain injection), and ouabain + RDN group (RDN plus intraperitoneal ouabain injection). After eight weeks, compared with the control group, rats in the ouabain group exhibited elevated blood pressure ( < 0.05), increased plasma epinephrine, norepinephrine, angiotensin II, and aldosterone levels ( < 0.05). These indexes could be significantly ameliorated by RDN. RDN also reduced the thickening of aortic tunica media and downregulated the expression of proliferating cell nuclear antigen (PCNA) in the thoracic aorta induced by ouabain. Masson staining and echocardiography showed that myocardial fibrosis and increased left ventricular mass in the ouabain group could be attenuated by RDN.
CONCLUSIONS
The present study reveals that renal nerves play an important role in the development of ouabain-induced hypertension. RDN could inhibit the pressor effect and the myocardial remodeling induced by ouabain potentially via inhibiting catecholamine release and vascular smooth muscle cell proliferation. Clinical studies are needed to explore whether RDN may exhibit better antihypertensive effects on hypertensive patients with high plasma ouabain levels as compared to those with normal plasma ouabain levels.
PubMed: 38957519
DOI: 10.1155/2024/4763189 -
Cureus Jul 2024This study describes an unusual case of multiple myeloma that progressed to anaplastic multiple myeloma in the pleural fluid. The Wright-stained cytospin of the pleural...
This study describes an unusual case of multiple myeloma that progressed to anaplastic multiple myeloma in the pleural fluid. The Wright-stained cytospin of the pleural fluid showed a predominant population of mononuclear plasma cells with pleomorphic nuclei, characterized by both small and large nuclei, which is typical of anaplastic multiple myeloma. However, there were also more binuclear plasma cells with pleomorphic nuclei. Morphometric analysis showed that the mean nuclear length was 1.9-fold and 2.3-fold higher in the large nuclei compared to the small nuclei for the mononuclear plasma cells and binuclear plasma cells, respectively (p<0.001). The patient received B cell maturation antigen chimeric antigen receptor T cell (CAR-T) therapy for relapsed disease, with a significant reduction of the serum monoclonal paraprotein level at day 51 post-therapy. Pathologists should be aware that pleomorphic binuclear plasma cells can be part of the morphologic spectrum in anaplastic multiple myeloma.
PubMed: 38957510
DOI: 10.7759/cureus.63597 -
Frontiers in Immunology 2024Chemoresistance constitutes a prevalent factor that significantly impacts thesurvival of patients undergoing treatment for smal-cell lung cancer (SCLC). Chemotherapy...
INTRODUCTION
Chemoresistance constitutes a prevalent factor that significantly impacts thesurvival of patients undergoing treatment for smal-cell lung cancer (SCLC). Chemotherapy resistance in SCLC patients is generally classified as primary or acquired resistance, each governedby distinct mechanisms that remain inadequately researched.
METHODS
In this study, we performed transcriptome screening of peripheral blood plasma obtainedfrom 17 patients before and after receiving combined etoposide and platinum treatment. We firs testimated pseudo-single-cell analysis using xCell and ESTIMATE and identified differentially expressed genes (DEGs), then performed network analysis to discover key hub genes involved in chemotherapy resistance.
RESULTS
Our analysis showed a significant increase in class-switched memory B cell scores acrossboth chemotherapy resistance patterns, indicating their potential crucial role in mediatingresistance. Moreover, network analysis identifed , , and as potential contributors to primary resistance, with , and emerging assignificant factors in acquired resistance, providing valuable insights into chemotherapy resistancein SCLC.
DISCUSSION
These findings offer valuable insights for understanding chemotherapy resistance and related gene signatures in SCLC, which could help further biological validation studies.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Drug Resistance, Neoplasm; Biomarkers, Tumor; Transcriptome; Female; Male; Gene Expression Profiling; Middle Aged; Gene Expression Regulation, Neoplastic; Aged; Antineoplastic Combined Chemotherapy Protocols; Etoposide
PubMed: 38957470
DOI: 10.3389/fimmu.2024.1338162 -
Frontiers in Immunology 2024There is a reciprocal relationship between extracellular matrix (ECM) remodelling and inflammation that could be operating in the progression of severe COVID-19. To...
There is a reciprocal relationship between extracellular matrix (ECM) remodelling and inflammation that could be operating in the progression of severe COVID-19. To explore the immune-driven ECM remodelling in COVID-19, we in this explorative study analysed these interactions in hospitalised COVID-19 patients. RNA sequencing and flow analysis were performed on peripheral blood mononuclear cells. Inflammatory mediators in plasma were measured by ELISA and MSD, and clinical information from hospitalised COVID-19 patients (N=15) at admission was included in the analysis. Further, we reanalysed two publicly available datasets: (1) lung tissue RNA-sequencing dataset (N=5) and (2) proteomics dataset from PBCM. ECM remodelling pathways were enriched in PBMC from COVID-19 patients compared to healthy controls. Patients treated at the intensive care unit (ICU) expressed distinct ECM remodelling gene profiles compared to patients in the hospital ward. Several markers were strongly correlated to immune cell subsets, and the dysregulation in the ICU patients was positively associated with plasma levels of inflammatory cytokines and negatively associated with B-cell activating factors. Finally, our analysis of publicly accessible datasets revealed (i) an augmented ECM remodelling signature in inflamed lung tissue compared to non-inflamed tissue and (ii) proteomics analysis of PBMC from severe COVID-19 patients demonstrated an up-regulation in an ECM remodelling pathway. Our results may suggest the presence of an interaction between ECM remodelling, inflammation, and immune cells, potentially initiating or perpetuating pulmonary pathology in severe COVID-19.
Topics: Humans; COVID-19; Leukocytes, Mononuclear; Extracellular Matrix; Male; Female; Middle Aged; SARS-CoV-2; Aged; Cytokines; Proteomics; Lung; Adult
PubMed: 38957465
DOI: 10.3389/fimmu.2024.1379570 -
Frontiers in Endocrinology 2024Cannabidiol (CBD), a non-psychoactive phytocannabinoid of cannabis, is therapeutically used as an analgesic, anti-convulsant, anti-inflammatory, and anti-psychotic drug....
BACKGROUND
Cannabidiol (CBD), a non-psychoactive phytocannabinoid of cannabis, is therapeutically used as an analgesic, anti-convulsant, anti-inflammatory, and anti-psychotic drug. There is a growing concern about the adverse side effects posed by CBD usage. Pregnane X receptor (PXR) is a nuclear receptor activated by a variety of dietary steroids, pharmaceutical agents, and environmental chemicals. In addition to the role in xenobiotic metabolism, the atherogenic and dyslipidemic effects of PXR have been revealed in animal models. CBD has a low affinity for cannabinoid receptors, thus it is important to elucidate the molecular mechanisms by which CBD activates cellular signaling and to assess the possible adverse impacts of CBD on pro-atherosclerotic events in cardiovascular system, such as dyslipidemia.
OBJECTIVE
Our study aims to explore the cellular and molecular mechanisms by which exposure to CBD activates human PXR and increases the risk of dyslipidemia.
METHODS
Both human hepatic and intestinal cells were used to test if CBD was a PXR agonist via cell-based transfection assay. The key residues within PXR's ligand-binding pocket that CBD interacted with were investigated using computational docking study together with site-directed mutagenesis assay. The C57BL/6 wildtype mice were orally fed CBD in the presence of PXR antagonist resveratrol (RES) to determine how CBD exposure could change the plasma lipid profiles in a PXR-dependent manner. Human intestinal cells were treated with CBD and/or RES to estimate the functions of CBD in cholesterol uptake.
RESULTS
CBD was a selective agonist of PXR with higher activities on human PXR than rodents PXRs and promoted the dissociation of human PXR from nuclear co-repressors. The key amino acid residues Met246, Ser247, Phe251, Phe288, Trp299, and Tyr306 within PXR's ligand binding pocket were identified to be necessary for the agonistic effects of CBD. Exposure to CBD increased the circulating total cholesterol levels in mice which was partially caused by the induced expression levels of the key intestinal PXR-regulated lipogenic genes. Mechanistically, CBD induced the gene expression of key intestinal cholesterol transporters, which led to the increased cholesterol uptake by intestinal cells.
CONCLUSION
CBD was identified as a selective PXR agonist. Exposure to CBD activated PXR signaling and increased the atherogenic cholesterol levels in plasma, which partially resulted from the ascended cholesterol uptake by intestinal cells. Our study provides potential evidence for the future risk assessment of CBD on cardiovascular disease, such as dyslipidemia.
Topics: Pregnane X Receptor; Animals; Humans; Mice; Cannabidiol; Mice, Inbred C57BL; Cholesterol; Male; Intestinal Mucosa; Molecular Docking Simulation
PubMed: 38957441
DOI: 10.3389/fendo.2024.1398462 -
European Journal of Haematology Jul 2024PCAB (prednisone, cyclophosphamide, doxorubicin, carmustine) is a single-day regimen previously used for induction and now in relapsed/refractory multiple myeloma...
PCAB (prednisone, cyclophosphamide, doxorubicin, carmustine) is a single-day regimen previously used for induction and now in relapsed/refractory multiple myeloma (RRMM). We retrospectively analysed the outcomes of 85 patients from five Australian centres. These included 30 patients (35.3%) who received PCAB with one additional agent (bortezomib most frequently). Median age of the patients was 65 years (37-80), with a median of four (1-8) prior lines of therapy. ORR was 37% (CR 4.9%). Median progression free survival and overall survival were 4.4 months (95% CI 3.5-6.7) and 7.4 months (95% CI 6.4-10.2), respectively. Extramedullary disease (EMD) was associated with shorter survival. Grade 3 or 4 cytopenia and febrile neutropenia occurred in 76.2% and 39.1%, respectively, with six (7.1%) treatment-related mortalities. Median inpatient stay was 3.3 days/28-day cycle (IQR 0.6-13), and for patients who died, a median of 20.2% of days alive were spent inpatient (IQR 6.4-39.1%). Three patients were successfully bridged to CAR T-cell therapy using PCAB, despite being penta-exposed and having EMD. PCAB may be considered as a useful salvage therapy amongst other polychemotherapy regimens in late relapse. Further studies is warranted to investigate and define its role as a bridging therapy to novel therapeutics.
PubMed: 38956924
DOI: 10.1111/ejh.14266 -
Trials Jul 2024Postoperative delirium (POD) is a common complication that is characterized by acute onset of impaired cognitive function and is associated with an increased mortality,...
Short-term inhalation of xenon during anesthesia for prevention of postoperative delirium in elderly patients undergoing laparoscopic radical colectomy: study protocol for a randomized controlled clinical trial.
BACKGROUND
Postoperative delirium (POD) is a common complication that is characterized by acute onset of impaired cognitive function and is associated with an increased mortality, a prolonged duration of hospital stay, and additional healthcare expenditures. The incidence of POD in elderly patients undergoing laparoscopic radical colectomy ranges from 8 to 54%. Xenon has been shown to provide neuroprotection in various neural injury models, but the clinical researches assessing the preventive effect of xenon inhalation on the occurrence of POD obtained controversial findings. This study aims to investigate the effects of a short xenon inhalation on the occurrence of POD in elderly patients undergoing laparoscopic radical colectomy.
METHODS/DESIGN
This is a prospective, randomized, controlled trial and 132 patients aged 65-80 years and scheduled for laparoscopic radical colectomy will be enrolled. The participants will be randomly assigned to either the control group or the xenon group (n = 66 in each group). The primary outcome will be the incidence of POD in the first 5 days after surgery. Secondary outcomes will include the subtype, severity, and duration of POD, postoperative pain score, Pittsburgh Sleep Quality Index (PQSI), perioperative non-delirium complications, and economic parameters. Additionally, the study will investigate the activation of microglial cells, expression of inflammatory factors in colon tissues, plasma inflammatory factors, and neurochemical markers.
DISCUSSION
Elderly patients undergoing laparoscopic radical colectomy are at a high risk of POD, with delayed postoperative recovery and increased healthcare costs. The primary objective of this study is to determine the preventive effect of a short xenon inhalation on the occurrence of POD in these patients.
TRIAL REGISTRATION
Chinese Clinical Trial Registry ChiCTR2300076666. Registered on October 16, 2023, http://www.chictr.org.cn .
Topics: Humans; Xenon; Aged; Laparoscopy; Colectomy; Prospective Studies; Aged, 80 and over; Male; Female; Randomized Controlled Trials as Topic; Anesthetics, Inhalation; Delirium; Time Factors; Treatment Outcome; Administration, Inhalation; Postoperative Complications
PubMed: 38956691
DOI: 10.1186/s13063-024-08290-8 -
Journal of Neuroinflammation Jul 2024Deposition of amyloid β, which is produced by amyloidogenic cleavage of APP by β- and γ-secretase, is one of the primary hallmarks of AD pathology. APP can also be...
BACKGROUND
Deposition of amyloid β, which is produced by amyloidogenic cleavage of APP by β- and γ-secretase, is one of the primary hallmarks of AD pathology. APP can also be processed by α- and γ-secretase sequentially, to generate sAPPα, which has been shown to be neuroprotective by promoting neurite outgrowth and neuronal survival, etc. METHODS: The global expression profiles of miRNA in blood plasma samples taken from 11 AD patients as well as from 14 age and sex matched cognitively normal volunteers were analyzed using miRNA-seq. Then, overexpressed miR-140 and miR-122 both in vivo and in vitro, and knock-down of the endogenous expression of miR-140 and miR-122 in vitro. Used a combination of techniques, including molecular biology, immunohistochemistry, to detect the impact of miRNAs on AD pathology.
RESULTS
In this study, we identified that two miRNAs, miR-140-3p and miR-122-5p, both targeting ADAM10, the main α-secretase in CNS, were upregulated in the blood plasma of AD patients. Overexpression of these two miRNAs in mouse brains induced cognitive decline in wild type C57BL/6J mice as well as exacerbated dyscognition in APP/PS1 mice. Although significant changes in APP and total Aβ were not detected, significantly downregulated ADAM10 and its non-amyloidogenic product, sAPPα, were observed in the mouse brains overexpressing miR-140/miR-122. Immunohistology analysis revealed increased neurite dystrophy that correlated with the reduced microglial chemotaxis in the hippocampi of these mice, independent of the other two ADAM10 substrates (neuronal CX3CL1 and microglial TREM2) that were involved in regulating the microglial immunoactivity. Further in vitro analysis demonstrated that both the reduced neuritic outgrowth of mouse embryonic neuronal cells overexpressing miR-140/miR-122 and the reduced Aβ phagocytosis in microglia cells co-cultured with HT22 cells overexpressing miR-140/miR-122 could be rescued by overexpressing the specific inhibitory sequence of miR-140/miR-122 TuD as well as by addition of sAPPα, rendering these miRNAs as potential therapeutic targets.
CONCLUSIONS
Our results suggested that neuroprotective sAPPα was a key player in the neuropathological progression induced by dysregulated expression of miR-140 and miR-122. Targeting these miRNAs might serve as a promising therapeutic strategy in AD treatment.
Topics: MicroRNAs; Animals; Alzheimer Disease; Mice; Humans; Microglia; Mice, Inbred C57BL; Male; Chemotaxis; Female; ADAM10 Protein; Amyloid Precursor Protein Secretases; Mice, Transgenic; Aged; Gene Expression Regulation
PubMed: 38956605
DOI: 10.1186/s12974-024-03162-z