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1.
Perfusion ; : 2676591241252721, 2024 May 04.
Article in English | MEDLINE | ID: mdl-38703049

ABSTRACT

INTRODUCTION: Axillary artery cannulation (AAC) has been widely employed in total arch replacement surgeries using the frozen elephant trunk (FET) technique for acute type A aortic dissection (ATAAD), showing better clinical results than femoral artery cannulation (FAC). Nevertheless, in type II hybrid arch repair (HAR), FAC is crucial for lower body perfusion. Hence, it is unclear whether AAC remains necessary or if AAC represents a more advantageous method for initiating cardiopulmonary bypass. METHODS: We conducted a study involving patients diagnosed with ATAAD who underwent type II HAR from August 2021 to December 2022. Demographic baseline and intraoperative data were collected, and the postoperative outcomes of patients receiving FAC only were compared with those receiving AAC. RESULTS: There were no significant differences in baseline demographics between patients who underwent FAC alone (n = 46) and those who underwent AAC (n = 39). Patients who underwent AAC showed a lower incidence of transient neurological dysfunction (TND) post-surgery compared to those who underwent FAC (12.8% vs 32.6%, p = .032). There were no significant differences between the groups in terms of postoperative mortality within 30 days, permanent neurological dysfunction (PND), length of stay in the intensive care unit (ICU) and postoperative ward, duration of mechanical ventilation, and other complications. CONCLUSIONS: Axillary artery cannulation may decrease the incidence of postoperative transient neurological dysfunction (TND) in type II HAR for ATAAD. Nonetheless, studies with larger sample sizes are necessary.

2.
Bioresour Technol ; 402: 130844, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38754560

ABSTRACT

In this study, a novel magnetic Ni-Fe2O3-C catalyst combined with electromagnetic induction heating in biomass steam gasification was proposed to enhance H2 production. Better catalytic performance for H2 production was observed with the Ni-Fe2O3-C catalyst under induction heating, resulting in an increase in H2 yield from 735.1 to 2271.2 mL/g-biomass (a 209.1 % enhancement). SEM, TGA and XRD analysis demonstrated a significant decrease in coking deposition, caking, and particle agglomeration of the Ni-Fe2O3-C catalyst under induction heating, while maintaining more active sites. Importantly, the benefits of induction heating were also applicable to different magnetic catalysts like Ni-Al2O3-C, Ni-ZrO2-C, and Ni-MgO-C. Experimental results revealed a logarithmic correlation between the increase in H2 yields due to induction heating and the magnetic saturation (Ms) of the catalysts. The Ni-Fe2O3-C catalyst, with a high Ms of 50.9 emu/g, showed the highest catalytic activity for H2 production under induction heating in this study.

3.
Sci Immunol ; 9(95): eadj9730, 2024 05 10.
Article in English | MEDLINE | ID: mdl-38728414

ABSTRACT

Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti-B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8+ CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.


Subject(s)
Immunotherapy, Adoptive , Receptors, Chimeric Antigen , Single-Cell Analysis , Humans , Immunotherapy, Adoptive/methods , Receptors, Chimeric Antigen/immunology , Autoimmunity/immunology , Neuromyelitis Optica/immunology , Neuromyelitis Optica/therapy , Female , Male , Adult , Middle Aged , Central Nervous System/immunology
4.
Biosensors (Basel) ; 14(4)2024 Apr 19.
Article in English | MEDLINE | ID: mdl-38667196

ABSTRACT

Marine biotoxins (MBs), harmful metabolites of marine organisms, pose a significant threat to marine ecosystems and human health due to their diverse composition and widespread occurrence. Consequently, rapid and efficient detection technology is crucial for maintaining marine ecosystem and human health. In recent years, rapid detection technology has garnered considerable attention for its pivotal role in identifying MBs, with advancements in sensitivity, specificity, and accuracy. These technologies offer attributes such as speed, high throughput, and automation, thereby meeting detection requirements across various scenarios. This review provides an overview of the classification and risks associated with MBs. It briefly outlines the current research status of marine biotoxin biosensors and introduces the fundamental principles, advantages, and limitations of optical, electrochemical, and piezoelectric biosensors. Additionally, the review explores the current applications in the detection of MBs and presents forward-looking perspectives on their development, which aims to be a comprehensive resource for the design and implementation of tailored biosensors for effective MB detection.


Subject(s)
Aquatic Organisms , Biosensing Techniques , Marine Toxins , Humans , Aquatic Organisms/chemistry , Biosensing Techniques/methods , Marine Toxins/analysis
5.
Cell Rep ; 43(4): 114120, 2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38625796

ABSTRACT

Border-associated macrophages (BAMs) are tissue-resident macrophages that reside at the border of the central nervous system (CNS). Since BAMs originate from yolk sac progenitors that do not persist after birth, the means by which this population of cells is maintained is not well understood. Using two-photon microscopy and multiple lineage-tracing strategies, we determine that CCR2+ monocytes are significant contributors to BAM populations following disruptions of CNS homeostasis in adult mice. After BAM depletion, while the residual BAMs possess partial self-repopulation capability, the CCR2+ monocytes are a critical source of the repopulated BAMs. In addition, we demonstrate the existence of CCR2+ monocyte-derived long-lived BAMs in a brain compression model and in a sepsis model after the initial disruption of homeostasis. Our study reveals that the short-lived CCR2+ monocytes transform into long-lived BAM-like cells at the CNS border and subsequently contribute to BAM populations.


Subject(s)
Brain , Macrophages , Monocytes , Receptors, CCR2 , Animals , Receptors, CCR2/metabolism , Monocytes/metabolism , Macrophages/metabolism , Mice , Brain/pathology , Brain/metabolism , Mice, Inbred C57BL , Homeostasis
6.
Spectrochim Acta A Mol Biomol Spectrosc ; 315: 124300, 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38640626

ABSTRACT

Owing to good flexibility, prominent mechanical properties, three-dimensional (3D) nanofibrous structure and low background interference, sustainable bacterial nanocellulose (BNC) is a highly attractive matrix material for surface-enhanced Raman scattering (SERS) sensor. Herein, a highly sensitive, flexible and scalable silver nanorod-decorated BNC (AgNRs@BNC) SERS sensor is developed by a simple vacuum-assisted filtration. The AgNRs were firmly locked in the 3D nanofibrous network of cellulose nanofibers upon vacuum drying process, resulting in the formation of 3D SERS hotspots with a depth of more than 10 µm on the sensor. With 4-aminothiophenol (4-ATP) as a target molecule, a lowest distinguishable level of 10-12 M and a high enhancement factor of 1.1 × 109 were realized by the optimal AgNRs1.5@BNC SERS sensor. Moreover, the AgNRs@BNC SERS sensor exhibits high detectable level of 10-9 M for thiram molecules by integrating with a portable Raman spectrometer. Besides, toxic thiram residues on grape surface could be directly on-site identified by the combination of AgNRs@BNC SERS sensors and a portable Raman spectrometer through a feasible press-and-peel method. The flexible AgNRs@BNC SERS sensor cooperated with portable Raman system demonstrates great potential for on-site detection of pesticide residues on irregular food surfaces.


Subject(s)
Cellulose , Nanotubes , Pesticide Residues , Silver , Spectrum Analysis, Raman , Spectrum Analysis, Raman/methods , Silver/chemistry , Cellulose/chemistry , Nanotubes/chemistry , Pesticide Residues/analysis , Thiram/analysis , Aniline Compounds/chemistry , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/analysis , Bacteria , Vitis/chemistry , Limit of Detection
7.
Neuron ; 2024 Apr 10.
Article in English | MEDLINE | ID: mdl-38614103

ABSTRACT

Microglial calcium signaling is rare in a baseline state but strongly engaged during early epilepsy development. The mechanism(s) governing microglial calcium signaling are not known. By developing an in vivo uridine diphosphate (UDP) fluorescent sensor, GRABUDP1.0, we discovered that UDP release is a conserved response to seizures and excitotoxicity across brain regions. UDP can signal through the microglial-enriched P2Y6 receptor to increase calcium activity during epileptogenesis. P2Y6 calcium activity is associated with lysosome biogenesis and enhanced production of NF-κB-related cytokines. In the hippocampus, knockout of the P2Y6 receptor prevents microglia from fully engulfing neurons. Attenuating microglial calcium signaling through calcium extruder ("CalEx") expression recapitulates multiple features of P2Y6 knockout, including reduced lysosome biogenesis and phagocytic interactions. Ultimately, P2Y6 knockout mice retain more CA3 neurons and better cognitive task performance during epileptogenesis. Our results demonstrate that P2Y6 signaling impacts multiple aspects of myeloid cell immune function during epileptogenesis.

8.
J Phys Chem Lett ; 15(14): 3859-3865, 2024 Apr 11.
Article in English | MEDLINE | ID: mdl-38557200

ABSTRACT

Perovskite single crystals with excellent physical properties have broad prospects in the field of optoelectronics. However, the presence of dangling bonds, surface dislocations, and chemical impurities results in high surface defect density and sensitivity to humidity. Unfortunately, there are relatively few surface engineering strategies for single perovskite single crystals. We present a strategy utilizing atomic layer deposited SnOx to passivate surface defects in perovskite single crystals. The photodetector prepared based on the modified FAPbBr3 single crystals exhibits a low dark current of 1.89 × 10-9 A at a 5 V bias, close to 4 times lower with respect to the pristine device, a high detectivity of 2.3 × 1010 jones, and a fast response time of 27 µs. Moreover, the photodetectors feature long-term operational stability because the presence of a dense SnOx capping layer hinders the ingress of moisture and diffusion of ions. We further demonstrate the promise of our perovskite single crystal detectors for real-time subaqueous optical communication.

9.
Brain Behav Immun ; 119: 416-430, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38636563

ABSTRACT

The role of microglia in triggering the blood-brain barrier (BBB) impairment and white matter damage after chronic cerebral hypoperfusion is unclear. Here we demonstrated that the vessel-adjacent microglia were specifically activated by the leakage of plasma low-density lipoprotein (LDL), which led to BBB breakdown and ischemic demyelination. Interestingly, we found that LDL stimulation enhanced microglial phagocytosis, causing excessive engulfment of myelin debris and resulting in an overwhelming lipid burden in microglia. Surprisingly, these lipid-laden microglia exhibited a suppressed profile of inflammatory response and compromised pro-regenerative properties. Microglia-specific knockdown of LDLR or systematic medication lowering circulating LDL-C showed protective effects against ischemic demyelination. Overall, our findings demonstrated that LDL-stimulated vessel-adjacent microglia possess a disease-specific molecular signature, characterized by suppressed regenerative properties, which is associated with the propagation of demyelination during ischemic white matter damage.

10.
Sensors (Basel) ; 24(8)2024 Apr 21.
Article in English | MEDLINE | ID: mdl-38676269

ABSTRACT

The intelligent monitoring of cutting tools used in the manufacturing industry is steadily becoming more convenient. To accurately predict the state of tools and tool breakages, this study proposes a tool wear prediction technique based on multi-sensor information fusion. First, the vibrational, current, and cutting force signals transmitted during the machining process were collected, and the features were extracted. Next, the Kalman filtering algorithm was used for feature fusion, and a predictive model for tool wear was constructed by combining the ResNet and long short-term memory (LSTM) models (called ResNet-LSTM). Experimental data for thin-walled parts obtained under various machining conditions were utilized to monitor the changes in tool conditions. A comparison between the ResNet and LSTM tool wear prediction models indicated that the proposed ResNet-LSTM model significantly improved the prediction accuracy compared to the individual LSTM and ResNet models. Moreover, ResNet-LSTM exhibited adaptive noise reduction capabilities at the front end of the network for signal feature extraction, thereby enhancing the signal feature extraction capability. The ResNet-LSTM model yielded an average prediction error of 0.0085 mm and a tool wear prediction accuracy of 98.25%. These results validate the feasibility of the tool wear prediction method proposed in this study.

11.
Transplantation ; 2024 Apr 08.
Article in English | MEDLINE | ID: mdl-38587506

ABSTRACT

BACKGROUND: Despite ongoing improvements to regimens preventing allograft rejection, most cardiac and other organ grafts eventually succumb to chronic vasculopathy, interstitial fibrosis, or endothelial changes, and eventually graft failure. The events leading to chronic rejection are still poorly understood and the gut microbiota is a known driving force in immune dysfunction. We previously showed that gut microbiota dysbiosis profoundly influences the outcome of vascularized cardiac allografts and subsequently identified biomarker species associated with these differential graft outcomes. METHODS: In this study, we further detailed the multifaceted immunomodulatory properties of protolerogenic and proinflammatory bacterial species over time, using our clinically relevant model of allogenic heart transplantation. RESULTS: In addition to tracing longitudinal changes in the recipient gut microbiome over time, we observed that Bifidobacterium pseudolongum induced an early anti-inflammatory phenotype within 7 d, whereas Desulfovibrio desulfuricans resulted in a proinflammatory phenotype, defined by alterations in leukocyte distribution and lymph node (LN) structure. Indeed, in vitro results showed that B pseudolongum and D desulfuricans acted directly on primary innate immune cells. However, by 40 d after treatment, these 2 bacterial strains were associated with mixed effects in their impact on LN architecture and immune cell composition and loss of colonization within gut microbiota, despite protection of allografts from inflammation with B pseudolongum treatment. CONCLUSIONS: These dynamic effects suggest a critical role for early microbiota-triggered immunologic events such as innate immune cell engagement, T-cell differentiation, and LN architectural changes in the subsequent modulation of protolerant versus proinflammatory immune responses in organ transplant recipients.

12.
Mol Psychiatry ; 2024 Mar 18.
Article in English | MEDLINE | ID: mdl-38499656

ABSTRACT

Autism spectrum disorder (ASD) is a major neurodevelopmental disorder affecting 1 in 36 children in the United States. While neurons have been the focus of understanding ASD, an altered neuro-immune response in the brain may be closely associated with ASD, and a neuro-immune interaction could play a role in the disease progression. As the resident immune cells of the brain, microglia regulate brain development and homeostasis via core functions including phagocytosis of synapses. While ASD has been traditionally considered a polygenic disorder, recent large-scale human genetic studies have identified SCN2A deficiency as a leading monogenic cause of ASD and intellectual disability. We generated a Scn2a-deficient mouse model, which displays major behavioral and neuronal phenotypes. However, the role of microglia in this disease model is unknown. Here, we reported that Scn2a-deficient mice have impaired learning and memory, accompanied by reduced synaptic transmission and lower spine density in neurons of the hippocampus. Microglia in Scn2a-deficient mice are partially activated, exerting excessive phagocytic pruning of post-synapses related to the complement C3 cascades during selective developmental stages. The ablation of microglia using PLX3397 partially restores synaptic transmission and spine density. To extend our findings from rodents to human cells, we established a microglia-incorporated human cerebral organoid model carrying an SCN2A protein-truncating mutation identified in children with ASD. We found that human microglia display increased elimination of post-synapse in cerebral organoids carrying the SCN2A mutation. Our study establishes a key role of microglia in multi-species autism-associated models of SCN2A deficiency from mouse to human cells.

13.
J Agric Food Chem ; 72(11): 5975-5982, 2024 Mar 20.
Article in English | MEDLINE | ID: mdl-38462975

ABSTRACT

Due to the high toxicity of aflatoxin B1 and its risks to human health, we developed a click reaction-mediated automated fluorescent immunosensor (CAFI) for sensitive detection of aflatoxin B1 based on the Cu(I)-catalyzed click reaction. With its large specific surface area, a copper-based metal-organic framework (Cu-MOF) was synthesized to adsorb and enrich the copper ion (Cu(II)) and then load the complete antigen (BSA-AFB1). After the immunoreaction, Cu(II) inside the Cu-MOF-Antigen conjugate would be reduced to Cu(I) in the presence of sodium ascorbate, which triggered the click reaction between the fluorescent donor-modified DNA and the receptor-modified complementary DNA to lead to a fluorescence signal readout. The whole reaction steps were finished by the self-developed automated immunoreaction device. This CAFI method showed a limit of detection (LOD) of 0.48 pg/mL as well as a 670-fold enhancement in sensitivity compared to conventional ELISA, revealing its great potential in practical applications and automated detection.


Subject(s)
Biosensing Techniques , Metal Nanoparticles , Humans , Copper , Aflatoxin B1/analysis , Immunoassay/methods , Biosensing Techniques/methods , Coloring Agents , Limit of Detection
14.
Sci Total Environ ; 926: 172059, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38556012

ABSTRACT

Anemia in pregnancy (AIP) is associated with multiple severe maternal and perinatal adverse outcomes. However, there is a lack of evidence on the association between environmental factors and AIP. Aim to explore the association between ambient temperature and the risk of AIP, and identify susceptible exposure windows, we conducted a matched case-control study from 2013 to 2016 in Xi'an, China, which included 710 women with AIP and 1420 women without AIP. The conditional logistic regression model was used to evaluate the association between ambient temperature and AIP at different gestational weeks and gestational months. The association between extreme temperature and AIP was evaluated using the distributed lag nonlinear model (DLNM). We conducted stratified analyses of age, parity, and season of conception, and estimated the interaction between ambient temperature and air pollutants on AIP. Ambient temperature was significantly positively associated with the risk of AIP, and the susceptible exposure windows were 2-25 gestational weeks and 1-6 gestational months, respectively. The strongest effect was observed in the week 8 and month 2, for each 1 °C increase in weekly and monthly mean temperature, the odds ratio (OR) for AIP was 1.038 (95 % confidence interval (CI): 1.022, 1.055) and 1.040 (95 % CI: 1.020, 1.060), respectively. Extreme heat may increase the risk of AIP. Stratified analyses showed that there was no significant difference among different age, parity, and season of conception groups. No significant interaction effect of ambient temperature with air pollution on AIP was found. In summary, high ambient temperature may increase the risk of AIP, and the first and second trimesters may be susceptible exposure windows. Understanding the effect of temperature on pregnant women will be beneficial to reduce the occurrence of AIP.


Subject(s)
Air Pollutants , Air Pollution , Anemia , Humans , Female , Pregnancy , Case-Control Studies , Temperature , Air Pollutants/analysis , China/epidemiology , Anemia/epidemiology , Maternal Exposure , Particulate Matter/analysis
15.
J Neural Eng ; 21(2)2024 Apr 03.
Article in English | MEDLINE | ID: mdl-38484397

ABSTRACT

Objective.This study aims to characterize the time course of impedance, a crucial electrophysiological property of brain tissue, in the human thalamus (THL), amygdala-hippocampus, and posterior hippocampus over an extended period.Approach.Impedance was periodically sampled every 5-15 min over several months in five subjects with drug-resistant epilepsy using an investigational neuromodulation device. Initially, we employed descriptive piecewise and continuous mathematical models to characterize the impedance response for approximately three weeks post-electrode implantation. We then explored the temporal dynamics of impedance during periods when electrical stimulation was temporarily halted, observing a monotonic increase (rebound) in impedance before it stabilized at a higher value. Lastly, we assessed the stability of amplitude and phase over the 24 h impedance cycle throughout the multi-month recording.Main results.Immediately post-implantation, the impedance decreased, reaching a minimum value in all brain regions within approximately two days, and then increased monotonically over about 14 d to a stable value. The models accounted for the variance in short-term impedance changes. Notably, the minimum impedance of the THL in the most epileptogenic hemisphere was significantly lower than in other regions. During the gaps in electrical stimulation, the impedance rebound decreased over time and stabilized around 200 days post-implant, likely indicative of the foreign body response and fibrous tissue encapsulation around the electrodes. The amplitude and phase of the 24 h impedance oscillation remained stable throughout the multi-month recording, with circadian variation in impedance dominating the long-term measures.Significance.Our findings illustrate the complex temporal dynamics of impedance in implanted electrodes and the impact of electrical stimulation. We discuss these dynamics in the context of the known biological foreign body response of the brain to implanted electrodes. The data suggest that the temporal dynamics of impedance are dependent on the anatomical location and tissue epileptogenicity. These insights may offer additional guidance for the delivery of therapeutic stimulation at various time points post-implantation for neuromodulation therapy.


Subject(s)
Deep Brain Stimulation , Foreign Bodies , Humans , Electric Impedance , Brain/physiology , Electrodes, Implanted , Deep Brain Stimulation/methods
16.
Mikrochim Acta ; 191(4): 222, 2024 03 28.
Article in English | MEDLINE | ID: mdl-38546789

ABSTRACT

A lightweight, portable, low-cost, and accessible cotton swab was employed as surface enhanced Raman spectroscopy (SERS) matrix template. The silver nanoflowers were in situ grown on the surface of cotton swabs to form three-dimensional Ag nanoflower@cotton swabs (AgNF@CS) SERS substrate with high-density and multi-level hot spots. The SERS performance of AgNFs@CS substrates with various reaction time was systematically studied. The optimal AgNF-120@CS SERS substrate exhibits superior detection sensitivity of 10-10 M for methylene blue, good signal reproducibility, high enhancement factor of 1.4 × 107, and excellent storage stability (over 30 days). Moreover, the AgNF-120@CS SERS substrate also exhibits prominent detection sensitivity of 10-8 M for food colorant of carmine. Besides, the portable AgNF-120@CS SERS substrate is also capable of detecting food colorant residues on irregular food surfaces.


Subject(s)
Food Coloring Agents , Metal Nanoparticles , Carmine , Silver/chemistry , Reproducibility of Results , Metal Nanoparticles/chemistry
17.
BMC Geriatr ; 24(1): 222, 2024 Mar 04.
Article in English | MEDLINE | ID: mdl-38439017

ABSTRACT

BACKGROUND: This study aimed to investigate the association of high-sensitivity C-reactive protein (hs-CRP) with incident frailty as well as its effects on pre-frailty progression and regression among middle-aged and older adults. METHODS: Based on the frailty index (FI) calculated with 41 items, 6890 eligible participants without frailty at baseline from China Health and Retirement Longitudinal Study (CHARLS) were categorized into health, pre-frailty, and frailty groups. Logistic regression models were used to estimate the longitudinal association between baseline hs-CRP and incident frailty. Furthermore, a series of genetic approaches were conducted to confirm the causal relationship between CRP and frailty, including Linkage disequilibrium score regression (LDSC), pleiotropic analysis, and Mendelian randomization (MR). Finally, we evaluated the association of hs-CRP with pre-frailty progression and regression. RESULTS: The risk of developing frailty was 1.18 times (95% CI: 1.03-1.34) higher in participants with high levels of hs-CRP at baseline than low levels of hs-CRP participants during the 3-year follow-up. MR analysis suggested that genetically determined hs-CRP was potentially positively associated with the risk of frailty (OR: 1.06, 95% CI: 1.03-1.08). Among 5241 participants with pre-frailty at baseline, we found pre-frailty participants with high levels of hs-CRP exhibit increased odds of progression to frailty (OR: 1.39, 95% CI: 1.09-1.79) and decreased odds of regression to health (OR: 0.84, 95% CI: 0.72-0.98) when compared with participants with low levels of hs-CRP. CONCLUSIONS: Our results suggest that reducing systemic inflammation is significant for developing strategies for frailty prevention and pre-frailty reversion in the middle-aged and elderly population.


Subject(s)
C-Reactive Protein , Frailty , Aged , Humans , Middle Aged , Longitudinal Studies , C-Reactive Protein/genetics , Frailty/diagnosis , Frailty/epidemiology , Frailty/genetics , Cohort Studies , Inflammation
18.
J Neurochem ; 168(5): 899-909, 2024 May.
Article in English | MEDLINE | ID: mdl-38299375

ABSTRACT

Cofilactin rods (CARs), which are 1:1 aggregates of cofilin-1 and actin, lead to neurite loss in ischemic stroke and other disorders. The biochemical pathways driving CAR formation are well-established, but how these pathways are engaged under ischemic conditions is less clear. Brain ischemia produces both ATP depletion and glutamate excitotoxicity, both of which have been shown to drive CAR formation in other settings. Here, we show that CARs are formed in cultured neurons exposed to ischemia-like conditions: oxygen-glucose deprivation (OGD), glutamate, or oxidative stress. Of these conditions, only OGD produced significant ATP depletion, showing that ATP depletion is not required for CAR formation. Moreover, the OGD-induced CAR formation was blocked by the glutamate receptor antagonists MK-801 and kynurenic acid; the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors GSK2795039 and apocynin; as well as an ROS scavenger. The findings identify a biochemical pathway leading from OGD to CAR formation in which the glutamate release induced by energy failure leads to activation of neuronal glutamate receptors, which in turn activates NADPH oxidase to generate oxidative stress and CARs.


Subject(s)
Energy Metabolism , Glutamic Acid , Neurons , Animals , Cells, Cultured , Neurons/metabolism , Neurons/drug effects , Energy Metabolism/drug effects , Energy Metabolism/physiology , Glutamic Acid/metabolism , Rats , Adenosine Triphosphate/metabolism , Glucose/metabolism , Glucose/deficiency , Actins/metabolism , Oxidative Stress/drug effects , Oxidative Stress/physiology , NADPH Oxidases/metabolism , Acetophenones/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Dizocilpine Maleate/pharmacology , Kynurenic Acid/pharmacology , Kynurenic Acid/metabolism , Rats, Sprague-Dawley
19.
Pharm Dev Technol ; 29(2): 112-122, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38308442

ABSTRACT

The aim of this study was to prepare a solid self-microemulsifying drug delivery system (S-SMEDDS) of cinnamaldehyde (CA) by spray drying technique to improve the oral bioavailability of CA. The preparation of CA S-SMEDDS with maltodextrin as the solid carrier, a core-wall material mass ratio of 1:1, a solid content of 20% (w/v), an inlet air temperature of 150 °C, an injection speed of 5.2 mL/min, and an atomization pressure of 0.1 MPa was determined by using the encapsulation rate as the index of investigation. Differential scanning calorimetry (DSC) revealed the possibility of CA being encapsulated in S-SMEDDS in an amorphous form. The in-vitro release showed that the total amount of CA released by S-SMEDDS was approximately 1.3 times higher than that of the CA suspension. Pharmacokinetic results showed that the relative oral bioavailability of CA S-SMEDDS was also increased to 1.6-fold compared to CA suspension. Additionally, we explored the mechanism of CA uptake and transport of lipid-soluble drugs CA by S-SMEDDS in a Caco-2/HT29 cell co-culture system for the first time. The results showed that CA S-SMEDDS uptake on the co-culture model was mainly an energy-dependent endocytosis mechanism, including lattice protein-mediated endocytosis and vesicle-mediated endocytosis. Transport experiments showed that CA S-SMEDDS significantly increased the permeability of CA in this model. These findings suggested that CA S-SMEDDS is an effective oral solid dosage form for increasing the oral bioavailability of lipid-soluble drug CA.


Subject(s)
Acrolein/analogs & derivatives , Drug Delivery Systems , Spray Drying , Humans , Solubility , Biological Availability , Caco-2 Cells , Emulsions/chemistry , Drug Delivery Systems/methods , Lipids , Administration, Oral
20.
medRxiv ; 2024 Jan 24.
Article in English | MEDLINE | ID: mdl-38343858

ABSTRACT

Objective: This study aims to characterize the time course of impedance, a crucial electrophysiological property of brain tissue, in the human thalamus (THL), amygdala-hippocampus (AMG-HPC), and posterior hippocampus (post-HPC) over an extended period. Approach: Impedance was periodically sampled every 5-15 minutes over several months in five subjects with drug-resistant epilepsy using an experimental neuromodulation device. Initially, we employed descriptive piecewise and continuous mathematical models to characterize the impedance response for approximately three weeks post-electrode implantation. We then explored the temporal dynamics of impedance during periods when electrical stimulation was temporarily halted, observing a monotonic increase (rebound) in impedance before it stabilized at a higher value. Lastly, we assessed the stability of amplitude and phase over the 24-hour impedance cycle throughout the multi-month recording. Main results: Immediately post-implantation, the impedance decreased, reaching a minimum value in all brain regions within approximately two days, and then increased monotonically over about 14 days to a stable value. The models accounted for the variance in short-term impedance changes. Notably, the minimum impedance of the THL in the most epileptogenic hemisphere was significantly lower than in other regions. During the gaps in electrical stimulation, the impedance rebound decreased over time and stabilized around 200 days post-implant, likely indicative of the foreign body response and fibrous tissue encapsulation around the electrodes. The amplitude and phase of the 24-hour impedance oscillation remained stable throughout the multi-month recording, with circadian variation in impedance dominating the long-term measures. Significance: Our findings illustrate the complex temporal dynamics of impedance in implanted electrodes and the impact of electrical stimulation. We discuss these dynamics in the context of the known biological foreign body response of the brain to implanted electrodes. The data suggest that the temporal dynamics of impedance are dependent on the anatomical location and tissue epileptogenicity. These insights may offer additional guidance for the delivery of therapeutic stimulation at various time points post-implantation for neuromodulation therapy.

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