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1.
Heliyon ; 10(7): e28972, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38601519

ABSTRACT

Energy cane (Saccharum spp.) bagasse, a type of biomass waste, is often underutilized, burned, or left to dispose of itself. This research aimed to evaluate the potential of converting this bagasse into high-value cellulosic microfiber hydrogels (CMH) for water conservation and potted chili (Capsicum annuum) plant growth. CMH offers a biodegradable alternative to synthetic polyacrylamide (PA) hydrogels and provides the dual benefit of improved water use efficiency and reduced environmental impact due to their ability to naturally break down in the soil. In this study, CMH and PA hydrogels were compared for water retention value (WRV), and reswelling kinetics (RK), as well as their effects on plant height, leaf count, root-to-shoot ratios (R:S ratio), and soil moisture retention. Two versions of CMH, CMH65 and CMH60, were prepared with varying cellulose-chitosan ratios: 65:35 and 60:40, respectively. The hydrogels were tested at four concentrations (0, 0.5, 1.0, and 2.0% w/w) by being mixed in Promix® soil. Observations were recorded over a 16-day period without additional water. Also, the WRV of hydrogels at 240 min and RK (10-180 min) were compared over three swelling-deswelling cycles. The PA hydrogel exhibited higher WRV (exceeding 450%) compared to CMH (45%). However, PA led to reduced plant height, leaf count, and R:S ratio when compared to higher concentrations of CMH65 and CMH60. In general, CMH60 (0.5% and 2%) exhibited superior plant growth. All hydrogels exhibited a significant decrease (p < 0.05) in WRV across successive cycles. Notably, during cycle 2, both CMH65 and CMH60 peaked in WRV at 10 and 20 min, respectively, compared to cycle 1. This study demonstrates the potential of bagasse-derived hydrogels as a value-added product for water conservation and crop growth.

2.
J Bronchology Interv Pulmonol ; 31(1): 2-12, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-36877194

ABSTRACT

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is considered the investigation of choice for sampling mediastinal nodes. A major drawback of EBUS-TBNA is its lower diagnostic yield for lymphoma and benign diseases. EBUS-guided mediastinal cryobiopsy (EBUS-MCB) is a novel technique that provides larger nodal biopsy samples, with an acceptable safety profile. In this study, we aimed to evaluate the diagnostic yield of EBUS-MCB in patients with an inconclusive rapid on-site evaluation (ROSE). METHODS: This is a prospective study of patients who underwent EBUS-TBNA for undiagnosed mediastinal lymphadenopathy. Patients in whom ROSE did not yield a diagnosis (nondiagnostic ROSE) or ROSE revealed scanty atypical cells (inadequate ROSE) were subjected to EBUS-MCB. The diagnostic yield, adequacy, and complications of EBUS-MCB were analyzed. RESULTS: Of the 196 patients undergoing EBUS-TBNA, 46 patients underwent EBUS-MCB. Thirty-two cases underwent EBUS-MCB for a nondiagnostic ROSE. EBUS-MCB confirmed the diagnosis in 19/32 (59.3%) cases. The additive diagnostic yield of EBUS-MCB over EBUS-TBNA was 43.7% (14/32 cases). In all 14 cases where EBUS-MCB was performed for an inadequate ROSE, the material obtained by EBUS-MCB was adequate for ancillary studies. The most common complication observed was a minor bleed in 13 cases. CONCLUSION: EBUS-MCB has a diagnostic yield of 59.3% when performed in cases with a nondiagnostic EBUS-ROSE. The tissue obtained by EBUS-MCB is adequate for ancillary studies. We propose EBUS-MCB as an additional diagnostic step in cases with an inconclusive ROSE while performing EBUS-TBNA. Larger studies are, however, needed before EBUS-MCB can be incorporated in the diagnostic algorithm for the evaluation of mediastinal lesions.


Subject(s)
Lung Neoplasms , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/pathology , Prospective Studies , Mediastinum/pathology , Lymph Nodes/pathology , Endoscopic Ultrasound-Guided Fine Needle Aspiration/methods , Bronchoscopy/methods , Algorithms , Retrospective Studies
3.
Br J Dermatol ; 190(2): 163-173, 2024 Jan 23.
Article in English | MEDLINE | ID: mdl-37625798

ABSTRACT

BACKGROUND: Treatment failure is considered to be an important factor in relation to the increase in scabies incidence over the last decade. However, the regional and temporal differences, in addition to the predictors of therapy failure, are unclear. OBJECTIVES: We aimed to conduct a systematic review of the prevalence of treatment failure in patients with scabies and investigation of associated factors. METHODS: We searched MEDLINE, EMBASE, CINAHL, Web of Science, Scopus, Global Health and the Cochrane Central Register of Controlled Trials from inception to August 2021 for randomized and quasi-randomized trials, in addition to observational studies that enrolled children or adults diagnosed with confirmed or clinical scabies treated with permethrin, ivermectin, crotamiton, benzyl benzoate, malathion, sulfur or lindane, and measured treatment failure or factors associated with treatment failure. We performed a random effects meta-analysis for all outcomes reported by at least two studies. RESULTS: A total of 147 studies were eligible for inclusion in the systematic review. The overall prevalence of treatment failure was 15.2% [95% confidence interval (CI) 12.9-17.6; I2 = 95.3%, moderate-certainty evidence] with regional differences between World Health Organization regions (P = 0.003) being highest in the Western Pacific region (26.9%, 95% CI 14.5-41.2). Oral ivermectin (11.8%, 95% CI 8.4-15.4), topical ivermectin (9.3%, 95% CI 5.1-14.3) and permethrin (10.8%, 95% CI 7.5-14.5) had relatively lower failure prevalence compared with the overall prevalence. Failure prevalence was lower in patients treated with two doses of oral ivermectin (7.1%, 95% CI 3.1-12.3) compared with those treated with one dose (15.2%, 95% CI 10.8-20.2; P = 0.021). Overall and permethrin treatment failure prevalence in the included studies (1983-2021) increased by 0.27% and 0.58% per year, respectively. Only three studies conducted a multivariable risk factor analysis; no studies assessed resistance. CONCLUSIONS: A second dose of ivermectin showed lower failure prevalence than single-dose ivermectin, which should be considered in all guidelines. The increase in treatment failure over time hints at decreasing mite susceptibility for several drugs, but reasons for failure are rarely assessed. Ideally, scabicide susceptibility testing should be implemented in future studies.


Subject(s)
Scabies , Adult , Child , Humans , Scabies/drug therapy , Ivermectin , Permethrin/therapeutic use , Hexachlorocyclohexane/therapeutic use , Malathion/therapeutic use , Administration, Oral
4.
J Cereb Blood Flow Metab ; 44(4): 556-572, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37944245

ABSTRACT

Hypoglycemia increases the risk related to stroke and neurodegenerative diseases, however, the underlying mechanisms are unclear. For the first time, we studied the effect of a single episode (acute) of severe (ASH) and mild (AMH) hypoglycemia on mouse brain microvascular proteome. After four-hour fasting, insulin was administered (i.p) to lower mean blood glucose in mice and induce ∼30 minutes of ASH (∼30 mg/dL) or AMH (∼75 mg/dL), whereas a similar volume of saline was given to control mice (∼130 mg/dL). Blood glucose was allowed to recover over 60 minutes either spontaneously or by 20% dextrose administration (i.p). Twenty-four hours later, the brain microvessels (BMVs) were isolated, and tandem mass tag (TMT)-based quantitative proteomics was performed using liquid chromatography-mass spectrometry (LC/MS). When compared to control, ASH significantly downregulated 13 proteins (p ≤ 0.05) whereas 23 proteins showed a strong trend toward decrease (p ≤ 0.10). When compared to AMH, ASH significantly induced the expression of 35 proteins with 13 proteins showing an increasing trend. AMH downregulated only 3 proteins. ASH-induced downregulated proteins are involved in actin cytoskeleton maintenance needed for cell shape and migration which are critical for blood-brain barrier maintenance and angiogenesis. In contrast, ASH-induced upregulated proteins are RNA-binding proteins involved in RNA splicing, transport, and stability. Thus, ASH alters BMV proteomics to impair cytoskeletal integrity and RNA processing which are critical for cerebrovascular function.


Subject(s)
Hypoglycemia , Proteome , Mice , Animals , Proteome/metabolism , Blood Glucose , Tandem Mass Spectrometry/methods , Brain/metabolism
6.
Cell Rep ; 42(5): 112529, 2023 05 30.
Article in English | MEDLINE | ID: mdl-37200193

ABSTRACT

Male mice lacking the androgen receptor (AR) in pancreatic ß cells exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR in ß cells to amplify glucagon-like peptide-1 (GLP-1) insulinotropic action. Here, we examined the architecture of AR targets that regulate GLP-1 insulinotropic action in male ß cells. Testosterone cooperates with GLP-1 to enhance cAMP production at the plasma membrane and endosomes via: (1) increased mitochondrial production of CO2, activating the HCO3--sensitive soluble adenylate cyclase; and (2) increased Gαs recruitment to GLP-1 receptor and AR complexes, activating transmembrane adenylate cyclase. Additionally, testosterone enhances GSIS in human islets via a focal adhesion kinase/SRC/phosphatidylinositol 3-kinase/mammalian target of rapamycin complex 2 actin remodeling cascade. We describe the testosterone-stimulated AR interactome, transcriptome, proteome, and metabolome that contribute to these effects. This study identifies AR genomic and non-genomic actions that enhance GLP-1-stimulated insulin exocytosis in male ß cells.


Subject(s)
Insulin-Secreting Cells , Islets of Langerhans , Male , Mice , Humans , Animals , Glucagon-Like Peptide 1/metabolism , Insulin-Secreting Cells/metabolism , Adenylyl Cyclases/metabolism , Receptors, Androgen/metabolism , Insulin/metabolism , Glucose/pharmacology , Glucose/metabolism , Testosterone , Islets of Langerhans/metabolism , Peptide Fragments/metabolism , Mammals/metabolism
7.
Am J Physiol Heart Circ Physiol ; 324(6): H762-H775, 2023 06 01.
Article in English | MEDLINE | ID: mdl-36930656

ABSTRACT

Plasma soluble prorenin receptor (sPRR) displays sexual dimorphism and is higher in women with type 2 diabetes mellitus (T2DM). However, the contribution of plasma sPRR to the development of vascular complications in T2DM remains unclear. We investigated if plasma sPRR contributes to sex differences in the activation of the systemic renin-angiotensin-aldosterone system (RAAS) and vascular damage in a model of high-fat diet (HFD)-induced T2DM. Male and female C57BL/6J mice were fed either a normal fat diet (NFD) or an HFD for 28 wk to assess changes in blood pressure, cardiometabolic phenotype, plasma prorenin/renin, sPRR, and ANG II. After completing dietary protocols, tissues were collected from males to assess vascular reactivity and aortic reactive oxygen species (ROS). A cohort of male mice was used to determine the direct contribution of increased systemic sPRR by infusion. To investigate the role of ovarian hormones, ovariectomy (OVX) was performed at 32 wk in females fed either an NFD or HFD. Significant sex differences were found after 28 wk of HFD, where only males developed T2DM and increased plasma prorenin/renin, sPRR, and ANG II. T2DM in males was accompanied by nondipping hypertension, carotid artery stiffening, and aortic ROS. sPRR infusion in males induced vascular thickening instead of material stiffening caused by HFD-induced T2DM. While intact females were less prone to T2DM, OVX increased plasma prorenin/renin, sPRR, and systolic blood pressure. These data suggest that sPRR is a novel indicator of systemic RAAS activation and reflects the onset of vascular complications during T2DM regulated by sex.NEW & NOTEWORTHY High-fat diet (HFD) for 28 wk leads to type 2 diabetes mellitus (T2DM) phenotype, concomitant with increased plasma soluble prorenin receptor (sPRR), nondipping blood pressure, and vascular stiffness in male mice. HFD-fed female mice exhibiting a preserved cardiometabolic phenotype until ovariectomy revealed increased plasma sPRR and blood pressure. Plasma sPRR may indicate the status of systemic renin-angiotensin-aldosterone system (RAAS) activation and the onset of vascular complications during T2DM in a sex-dependent manner.


Subject(s)
Diabetes Mellitus, Type 2 , Hypertension , Vacuolar Proton-Translocating ATPases , Female , Male , Mice , Animals , Renin , Prorenin Receptor , Diet, High-Fat/adverse effects , Reactive Oxygen Species , Mice, Inbred C57BL , Renin-Angiotensin System/genetics , Receptors, Cell Surface/genetics , Blood Pressure
8.
Cells ; 12(3)2023 01 17.
Article in English | MEDLINE | ID: mdl-36766690

ABSTRACT

(1) Background: Apolipoprotein E (ApoE) is a critical plasma apolipoprotein for lipid transport and nonlipid-related functions. Humans possess three isoforms of ApoE (2, 3, and 4). ApoE2, which exhibits beneficial effects on cardiac health, has not been adequately studied. (2) Methods: We investigated the cardiac phenotypes of the humanized ApoE knock-in (hApoE KI) rats and compared to wild-type (WT) and ApoE knock-out (ApoE KO) rats using echocardiography, ultrasound, blood pressure measurements, histology strategies, cell culture, Seahorse XF, cardiomyocyte contractility and intracellular Ca2+ tests, and Western blotting; (3) Results: hApoE2 rats exhibited enhanced heart contractile function without signs of detrimental remodeling. Isolated adult hApoE2 cardiomyocytes had faster and stronger sarcomere contractility because of more mitochondrial energy generation and stimulation-induced fast and elevated intracellular Ca2+ transient. The abundant energy is a result of elevated mitochondrial function via fatty acid ß-oxidation. The fast and elevated Ca2+ transient is associated with decreased sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2) and increased expression of cardiac ryanodine receptor 2 (RyR2) conducting a potent Ca2+ release from SR.; (4) Conclusions: Our studies validated the association of polymorphic ApoEs with cardiac health in the rat model, and revealed the possible mechanisms of the protective effect of ApoE2 against heart diseases.


Subject(s)
Myocytes, Cardiac , Sarcoplasmic Reticulum , Rats , Humans , Animals , Myocytes, Cardiac/metabolism , Apolipoprotein E2/metabolism , Apolipoprotein E2/pharmacology , Sarcoplasmic Reticulum/metabolism , Echocardiography
11.
Tech Coloproctol ; 27(3): 217-226, 2023 03.
Article in English | MEDLINE | ID: mdl-36064986

ABSTRACT

BACKGROUND: Postoperative ileus (POI) is a common complication following colorectal surgery and is mediated in part by the cholinergic anti-inflammatory pathway (CAIP). Neostigmine (acetylcholinesterase inhibitor), co-administered with glycopyrrolate, is frequently given for neuromuscular reversal before tracheal extubation and modulates the CAIP. An alternative reversal agent, sugammadex (selective rocuronium or vecuronium binder), acts independently from the CAIP. The aim of our study was to assess the impact of neuromuscular reversal agents used during anaesthesia on gastrointestinal recovery. METHODS: Three hundred thirty-five patients undergoing elective colorectal surgery at the Royal Adelaide Hospital between January 2019 and December 2021 were retrospectively included. The primary outcome was GI-2, a validated composite measure of time to diet tolerance and passage of stool. Demographics, 30-day complications and length of stay were collected. Univariate and multivariate analyses were performed. RESULTS: Two hundred twenty-four (66.9%) patients (129 [57.6%] males and 95 [42.4%] females, median age 64 [19-90] years) received neostigmine/glycopyrrolate and 111 (33.1%) received sugammadex (62 [55.9%] males and 49 [44.1%] females, median age 67 [18-94] years). Sugammadex patients achieved GI-2 sooner after surgery (median 3 (0-10) vs. 3 (0-12) days, p = 0.036), and reduced time to first stool (median 2 (0-10) vs. 3 (0-12) days, p = 0.035). Rates of POI, complications and length of stay were similar. On univariate analysis, POI was associated with smoking history, previous abdominal surgery, colostomy formation, increased opioid use and postoperative hypokalaemia (p < 0.05). POI was associated with increased complications, including anastomotic leak and prolonged hospital stay (p < 0.001). On multivariate analysis, neostigmine, bowel anastomoses and increased postoperative opioid use (p < 0.05) remained predictive of time to GI-2. CONCLUSIONS: Patients who received sugammadex had a reduced time to achieving first stool and GI-2. Neostigmine use, bowel anastomoses and postoperative opioid use were associated with delayed time to achieving GI-2.


Subject(s)
Glycopyrrolate , Ileus , Neostigmine , Neuromuscular Nondepolarizing Agents , Sugammadex , Aged , Female , Humans , Male , Middle Aged , Acetylcholinesterase , Analgesics, Opioid/adverse effects , Glycopyrrolate/therapeutic use , Ileus/drug therapy , Ileus/etiology , Ileus/prevention & control , Neostigmine/therapeutic use , Neuromuscular Blockade/methods , Neuromuscular Nondepolarizing Agents/therapeutic use , Postoperative Complications/drug therapy , Postoperative Complications/etiology , Postoperative Complications/prevention & control , Retrospective Studies , Sugammadex/therapeutic use , Young Adult , Adult , Aged, 80 and over
12.
J Magn Reson Imaging ; 57(6): 1815-1818, 2023 06.
Article in English | MEDLINE | ID: mdl-36315131

ABSTRACT

BACKGROUND: Ferumoxytol, an intravenous iron supplement, is commonly used to treat anemia in pregnancy. Ferumoxytol-enhanced magnetic resonance angiography (Fe-MRA) is a viable off-label alternative to gadolinium-enhanced MRA for assessment of pulmonary embolism (PE) in pregnancy. PURPOSE: To describe our clinical experience with Fe-MRA in pregnant women with suspected PE. STUDY TYPE: Retrospective, observational, cohort. POPULATION: A total of 98 Fe-MRA exams (consecutive sample) performed in 94 pregnant women. FIELD STRENGTH/SEQUENCE: A 1.5 T and 3.0 T, 3D T1-weighted MRA. ASSESSMENT: After IRB approval including a waiver of informed consent, electronic health records were reviewed retrospectively for all Fe-MRA exams performed at our institution in pregnant between January, 2017 and March, 2022. The Fe-MRA protocol included 3D-MRA for assessment of pulmonary arteries, and T1-weighted imaging for ancillary findings. Fe-MRA exam duration was measured from image time stamps. Fe-MRA exams were reviewed by three cardiovascular imagers using a 4-point Likert scale for image quality and confidence for PE diagnosis (score 4 = best, 1 = worst), and tabulation of ancillary findings. STATISTICAL TESTS: Continuous data are presented as mean ± standard deviation. The overall image quality and confidence score is given as the mean of three readers. RESULTS: The 98 Fe-MRA exams were performed in 94 pregnant women (age 30 ± 6, range 19-48 years, gestational week 23 ± 10, range 3-38 weeks), with four undergoing two Fe-MRA exams during their pregnancy. Median Fe-MRA exam durration was 8 minutes (interquantile range 6 minutes). Overall image quality score was 3.3 ± 0.9. Confidence score for diagnosing PE was 3.5 ± 0.8. One subject was positive for PE (1/94, 1%); 42 of the 94 (45%) subjects Fe-MRA had ancillary findings including hydronephrosis or pneumonia. CONCLUSION: Ferumoxytol enhanced MRA is a radiation- and gadolinium-free alternative for diagnosis of PE during pregancy. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 5.


Subject(s)
Ferrosoferric Oxide , Pulmonary Embolism , Pregnancy , Humans , Female , Infant , Magnetic Resonance Angiography/methods , Contrast Media , Retrospective Studies , Lung , Pulmonary Embolism/diagnostic imaging
14.
Front Plant Sci ; 14: 1273363, 2023.
Article in English | MEDLINE | ID: mdl-38288416

ABSTRACT

Black gram [Vigna mungo (L.) Hepper] is a highly nutritious grain legume crop, mainly grown in South and Southeast Asia, with the largest area in India, where the crop is challenged by several biotic and abiotic stresses leading to significant yield losses. Improving genetic gains to increase on-farm yields is the primary goal of black gram breeding programs. This could be achieved by developing varieties resistant to major diseases like mungbean yellow mosaic disease, urdbean leaf crinkle virus, Cercospora leaf spot, anthracnose, powdery mildew, and insect pests such as whitefly, cowpea aphids, thrips, stem flies, and bruchids. Along with increasing on-farm yields, incorporating market-preferred traits ensures the adoption of improved varieties. Black gram breeding programs rely upon a limited number of parental lines, leading to a narrow genetic base of the developed varieties. For accelerating genetic gain, there is an urgent need to include more diverse genetic material for improving traits for better adaptability and stress resistance in breeding populations. The present review summarizes the importance of black gram, the major biotic and abiotic stresses, available genetic and genomic resources, major traits for potential crop improvement, their inheritance, and the breeding approaches being used in black gram for the development of new varieties.

15.
Geroscience ; 44(6): 2721-2739, 2022 12.
Article in English | MEDLINE | ID: mdl-35978067

ABSTRACT

Diabetes increases the risk of Alzheimer's disease (AD). We investigated the impact of glucose concentrations on the ß-amyloid (Aß)-induced alteration of mitochondrial/cellular energetics in primary human brain microvascular endothelial cells (HBMECs). HBMECs were grown and passaged in media containing 15 mmol/l glucose (normal) based on which the glucose levels in the media were designated as high (25 mmol/L) or low (5 mmol/L). HBMECs were treated with Aß (1-42) (5 µmol/l) or a scrambled peptide for 24 h and mitochondrial respiratory parameters were measured using Seahorse Mito Stress Test. Aß (1-42) decreased the mitochondrial ATP production at normal glucose levels and decreased spare respiratory capacity at high glucose levels. Aß (1-42) diminished all mitochondrial respiratory parameters markedly at low glucose levels that were not completely recovered by restoring normal glucose levels in the media. The addition of mannitol (10 mmol/l) to low and normal glucose-containing media altered the Aß (1-42)-induced bioenergetic defects. Even at normal glucose levels, pre-senescent HMBECs (passage 15) displayed greater Aß (1-42)-induced mitochondrial respiratory impairments than young cells (passages 7-9). Thus, hypoglycemia, osmolarity changes, and senescence are stronger instigators of Aß (1-42)-induced mitochondrial respiration and energetics in HBMECs and contributors to diabetes-related increased AD risk than hyperglycemia.


Subject(s)
Amyloid beta-Peptides , Endothelial Cells , Humans , Amyloid beta-Peptides/metabolism , Brain/metabolism , Respiration , Glucose/pharmacology
16.
Arch Pharm (Weinheim) ; 355(8): e2200019, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35484599

ABSTRACT

Saccharin is a cyclic secondary sulfonamide, which is a selective inhibitor of the tumor-associated carbonic anhydrase (CA; EC 4.2.1.1) enzymes CA IX and CA XII compared to many primary sulfonamides. In this study, new saccharin-1,2,3-triazole and saccharin-1,2,4-oxadiazole hybrids were synthesized. All the newly synthesized molecules were screened for their CA-inhibitory activity against four important human CA (hCA) isoforms: hCA I, hCA II, hCA IX, and hCA XII. Compounds 8a and 8f emerged as potent hCA II inhibitors (Ki = 3 µM). Compounds 6d, 6e and 7a, 7b were highly selective against hCA IX (6d, 6e) and hCA II (7a, 7b), with moderate inhibitory activity. The activity of these compounds was further confirmed by performing in silico docking studies against hCA II and hCA IX.


Subject(s)
Carbonic Anhydrase Inhibitors , Carbonic Anhydrases , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/metabolism , Humans , Molecular Structure , Saccharin/pharmacology , Structure-Activity Relationship , Sulfonamides/pharmacology
17.
Geroscience ; 44(4): 1975-1994, 2022 08.
Article in English | MEDLINE | ID: mdl-35378718

ABSTRACT

Alterations of mitochondrial and glycolytic energy pathways related to aging could contribute to cerebrovascular dysfunction. We studied the impact of aging on energetics of primary human brain microvascular endothelial cells (HBMECs) by comparing the young (passages 7-9), pre-senescent (passages 13-15), and senescent (passages 20-21) cells. Pre-senescent HBMECs displayed decreased telomere length and undetectable telomerase activity although markers of senescence were unaffected. Bioenergetics in HBMECs were determined by measuring the oxygen consumption (OCR) and extracellular acidification (ECAR) rates. Cellular ATP production in young HBMECs was predominantly dependent on glycolysis with glutamine as the preferred fuel for mitochondrial oxidative phosphorylation (OXPHOS). In contrast, pre-senescent HBMECs displayed equal contribution to ATP production rate from glycolysis and OXPHOS with equal utilization of glutamine, glucose, and fatty acids as mitofuels. Compared to young, pre-senescent HBMECs showed a lower overall ATP production rate that was characterized by diminished contribution from glycolysis. Impairments of glycolysis displayed by pre-senescent cells included reduced basal glycolysis, compensatory glycolysis, and non-glycolytic acidification. Furthermore, impairments of mitochondrial respiration in pre-senescent cells involved the reduction of maximal respiration and spare respiratory capacity but intact basal and ATP production-related OCR. Proton leak and non-mitochondrial respiration, however, were unchanged in the pre-senescent HBMECs. HBMECS at passages 20-21 displayed expression of senescence markers and continued similar defects in glycolysis and worsened OXPHOS. Thus, for the first time, we characterized the bioenergetics of pre-senescent HBMECs comprehensively to identify the alterations of the energy pathways that could contribute to aging.


Subject(s)
Endothelial Cells , Oxidative Phosphorylation , Humans , Glutamine/metabolism , Glycolysis , Brain/metabolism , Adenosine Triphosphate/metabolism
18.
J Cereb Blood Flow Metab ; 42(8): 1410-1424, 2022 08.
Article in English | MEDLINE | ID: mdl-35296173

ABSTRACT

Mitochondrial and glycolytic energy pathways regulate the vascular functions. Aging impairs the cerebrovascular function and increases the risk of stroke and cognitive dysfunction. The goal of our study is to characterize the impact of aging on brain microvascular energetics. We measured the oxygen consumption and extracellular acidification rates of freshly isolated brain microvessels (BMVs) from young (2-4 months) and aged (20-22 months) C57Bl/6 male mice. Cellular ATP production in BMVs was predominantly dependent on oxidative phosphorylation (OXPHOS) with glucose as the preferred energy substrate. Aged BMVs exhibit lower ATP production rate with diminished OXPHOS and glycolytic rate accompanied by increased utilization of glutamine. Impairments of glycolysis displayed by aged BMVs included reduced compensatory glycolysis whereas impairments of mitochondrial respiration involved reduction of spare respiratory capacity and proton leak. Aged BMVs showed reduced levels of key glycolysis proteins including glucose transporter 1 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 but normal lactate dehydrogenase activity. Mitochondrial protein levels were mostly unchanged whereas citrate synthase activity was reduced, and glutamate dehydrogenase was increased in aged BMVs. Thus, for the first time, we identified the dominant role of mitochondria in bioenergetics of BMVs and the alterations of the energy pathways that make the aged BMVs vulnerable to injury.


Subject(s)
Energy Metabolism , Oxidative Phosphorylation , Adenosine Triphosphate/metabolism , Aging , Animals , Brain/metabolism , Glycolysis/physiology , Male , Mice , Oxygen Consumption
19.
J Matern Fetal Neonatal Med ; 35(19): 3646-3652, 2022 Oct.
Article in English | MEDLINE | ID: mdl-33081557

ABSTRACT

OBJECTIVE: Since the first publication of the American College of Obstetricians and Gynecologists committee opinion in 2012, and following the update in 2017, multiple institutions in the United States (US) adopted the practice of delayed cord clamping (DCC) and/or umbilical cord milking (UCM) in preterm and term infants. However, there have been variations reported in practices with regard to method of placental transfusion, timing of cord clamping and gestational age thresholds. Furthermore, the optimal cord clamping practice in situations of depressed infants needing resuscitation or in higher-risk delivery situations, such as placental abruption, intrauterine growth restriction, multiple gestation, chorioamnionitis, maternal human immunodeficiency virus syndrome/hepatitis or maternal general anesthesia is often debated. An evaluation of these variations and exploration of associated factors was needed to optimally target opportunities for improvement and streamline research activities. The objective of this survey, specifically aimed at neonatologists working in the US was to identify and describe current cord clamping practices and evaluate factors associated with variations. STUDY DESIGN: The survey was distributed electronically to the US neonatologists in August 2019 with a reminder email sent in October 2019. Clinicians were primarily identified from Perinatal Section of AAP, with reminders also sent through various organizations including California Association of Neonatologists, Pediatrix and Envision national groups. Descriptive variables of interest included years of experience practicing neonatology, affiliation with a teaching institution, level of the neonatal intensive care unit (NICU) and practicing region of the US. Questions on variations in cord management practices included information about center specific guideline/protocol, cord clamping practices, gestational age threshold of placental transfusion, performance of UCM and practice in higher-risk delivery situations. RESULTS: The response rate was 14.8%. Among 517 neonatologists whom responded, majority (85.5%) of the practices had a guideline and performed (81.7%) DCC in all gestational ages. The cord clamping practice was predominantly DCC and it was categorized as reporting clamping times <60 s in 46.6% and ≥60 s in 48.7% of responses. A significant association was detected between time of delay in cord clamping and region of practice. The Northeast region was more likely to clamp the cord in <60 s than other regions in the US. More than half of the providers responded not performing any UCM (57.3%) in their practice. Significant associations were detected between performance of UCM and all queried demographic variables independently. Clinicians with >20 years of experience were more likely from institutions performing UCM compared to the providers with fewer years of experience. However, teaching hospitals were less likely to perform UCM compared to non-teaching hospitals. Similarly, practices with level IV NICUs were less likely to perform UCM compared to practices with level III units. Hospitals in the Midwest region of US were less likely to perform UCM compared to hospitals in the Western region. Significant variations were also noticed for not providing placental transfusion in higher-risk deliveries. Demographic and professional factors were noted to be associated with these differences. CONCLUSION: Although the majority of practices have a guideline/protocol and are performing DCC in all gestational ages, there are variations noted with regard to timing, method, and performance in higher-risk deliveries. Demographic and professional factors play an important role in these variations. Future research needs to focus on the modifiable factors to optimize the procedure and impact of DCC.


Subject(s)
Neonatologists , Umbilical Cord , Constriction , Female , Humans , Infant, Newborn , Placenta , Pregnancy , Time Factors , Umbilical Cord/surgery , Umbilical Cord Clamping , United States
20.
Blood Coagul Fibrinolysis ; 32(7): 504-512, 2021 Oct 01.
Article in English | MEDLINE | ID: mdl-34650023

ABSTRACT

Mannose-binding lectin-associated serine protease-1 (MASP-1) is known to interact with complement and coagulation pathways. Recently it was reported that MASP-1 interacts with the fibrinolytic system but details remain unclear. The objective of the study is to find MASP-1 substrates that participate in the fibrinolytic system. Commercially available fibrinogen might contain some impurities. Fibrinogen was treated with MASP-1 followed by analysis on SDS-PAGE and the obtained cleaved fragments were identified by matrix-assisted laser desorption/ionization-time of flight/time of flight. Functional analysis of identified substrate was confirmed by fluorogenic and turbidimetric assay. Statistical analysis was done by using the Student t test. This study reports that plasminogen and plasma fibronectin are two hitherto unknown substrates of MASP-1. Conversion of plasminogen to plasmin like molecule by MASP-1 was confirmed by cleavage of plasmin specific substrate and digestion of fibrin clot. The role of MASP-1 in clot dissolution was confirmed by turbidity assay. Our study shows that MASP-1 selects plasminogen over fibrinogen to be a preferable substrate. MASP-1 promotes the fibrinolytic activity by the generation of plasmin like molecule from plasminogen and further destabilizes the clot by digestion of plasma fibronectin.


Subject(s)
Fibrinogen/metabolism , Fibronectins/metabolism , Mannose-Binding Protein-Associated Serine Proteases/metabolism , Plasminogen/metabolism , Fibrin/metabolism , Fibrinolysin/metabolism , Fibrinolysis , Humans , Proteolysis
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