Microglia are resident macrophage-like cells in the central nervous system (CNS). The induction of microglial activation dampens neuroinflammation-related diseases by promoting microglial ...(re)polarization to the anti-inflammatory (M2) phenotype and can serve as a potential therapeutic approach. Mitochondrial respiration and metabolic reprogramming are required for the anti-inflammatory response of M2 macrophages. However, whether these mitochondrial-dependent pathways are involved in microglial (re)polarization to the anti-inflammatory (M2) phenotype under conditions of lipopolysaccharide (LPS)-induced neuroinflammation remains unclear. Moreover, the mechanisms that coordinate mitochondrial respiration and the functional reprogramming of microglial cells have not been fully elucidated. Rosmarinic acid (RA) possesses antioxidative and anti-inflammatory activities, and we previously reported that RA markedly suppresses LPS-stimulated M1 microglial activation in mice. In this study, we found that RA suppresses M1 microglial polarization and promotes microglial polarization to the M2 phenotype under conditions of neuroinflammation. We identified an increase in mitochondrial respiration and found that metabolic reprogramming is required for the RA-mediated promotion of microglial polarization to the M2 phenotype under LPS-induced neuroinflammation conditions. Hypoxia-inducible factor (HIF) subunits are the key effector molecules responsible for the effects of RA on the restoration of mitochondrial function, metabolic reprogramming, and phenotypic polarization to M2 microglia. The phosphoinositide-dependent protein kinase 1 (PDPK1)/Akt/mTOR pathway is involved in the RA-mediated regulation of HIF expression and increase in M2 marker expression. We propose that the inhibition of PDPK1/Akt/HIFs by RA might be a potential therapeutic approach for inhibiting neuroinflammation through the regulation of microglial M1/M2 polarization.
Graphical abstract
Schematic of the mechanism through which RA suppresses LPS-induced neuroinflammation by promoting microglial polarization to the M2 phenotype
via
PDPK1/Akt/HIFs. The bold arrows indicate the direction of the effects of RA (
i.e.
, inhibitory or promoting effects on cytokines or mediators).
Abstract Background White matter injury (WMI) represents a significant etiological factor contributing to neurological impairment subsequent to Traumatic Brain Injury (TBI). CD36 receptors are ...recognized as pivotal participants in the pathogenesis of neurological disorders, including stroke and spinal cord injury. Furthermore, dynamic fluctuations in the phenotypic polarization of microglial cells have been intimately associated with the regenerative processes within the injured tissue following TBI. Nevertheless, there is a paucity of research addressing the impact of CD36 receptors on WMI and microglial polarization. This investigation aims to elucidate the functional role and mechanistic underpinnings of CD36 in modulating microglial polarization and WMI following TBI. Methods TBI models were induced in murine subjects via controlled cortical impact (CCI). The spatiotemporal patterns of CD36 expression were examined through quantitative polymerase chain reaction (qPCR), Western blot analysis, and immunofluorescence staining. The extent of white matter injury was assessed via transmission electron microscopy, Luxol Fast Blue (LFB) staining, and immunofluorescence staining. Transcriptome sequencing was employed to dissect the molecular mechanisms underlying CD36 down-regulation and its influence on white matter damage. Microglial polarization status was ascertained using qPCR, Western blot analysis, and immunofluorescence staining. In vitro, a Transwell co-culture system was employed to investigate the impact of CD36-dependent microglial polarization on oligodendrocytes subjected to oxygen-glucose deprivation (OGD). Results Western blot and qPCR analyses revealed that CD36 expression reached its zenith at 7 days post-TBI and remained sustained at this level thereafter. Immunofluorescence staining exhibited robust CD36 expression in astrocytes and microglia following TBI. Genetic deletion of CD36 ameliorated TBI-induced white matter injury, as evidenced by a reduced SMI-32/MBP ratio and G-ratio. Transcriptome sequencing unveiled differentially expressed genes enriched in processes linked to microglial activation, regulation of neuroinflammation, and the TNF signaling pathway. Additionally, bioinformatics analysis pinpointed the Traf5-p38 axis as a critical signaling pathway. In vivo and in vitro experiments indicated that inhibition of the CD36-Traf5-MAPK axis curtailed microglial polarization toward the pro-inflammatory phenotype. In a Transwell co-culture system, BV2 cells treated with LPS + IFN-γ exacerbated the damage of post-OGD oligodendrocytes, which could be rectified through CD36 knockdown in BV2 cells. Conclusions This study illuminates that the suppression of CD36 mitigates WMI by constraining microglial polarization towards the pro-inflammatory phenotype through the down-regulation of the Traf5-MAPK signaling pathway. Our findings present a potential therapeutic strategy for averting neuroinflammatory responses and ensuing WMI damage resulting from TBI. Graphical Abstract
In this article, high step-down dc-dc converters are widely employed in data center applications. Due to the higher step-down conversion ratio in the new generation 48 V voltage regulator module, a ...conventional buck converter is not suitable for such applications. To conquer this problem, a novel dc-dc converter is proposed in this article to achieve an ultrahigh step-down voltage conversion ratio for data centers. The nonisolated topology can be optimally designed to integrate both the switched-capacitor and coupled inductor techniques, which allows zero-voltage-switching (ZVS) of all active switches to be achieved and improves high efficiency. In addition, the converter presents the advantages of lower voltage stress, ultrahigh voltage gain, common ground, and simple control strategy. A comprehensive analysis of the steady-state analysis, derivation of voltage gain, voltage stress, and ZVS condition is presented in detail. Finally, a 30 W, 48-to-1 V experimental prototype is built and tested, which validates the ultrahigh step-down voltage gain and soft-switching characteristic of the proposed converter. The maximum efficiency of the prototype is 89.1% and the efficiency is 81.4% in full-load condition.
A novel transformer-less topology with high step-down voltage gain is proposed for low-voltage high-current point-of-load voltage regulator modules (VRMs). The proposed topology consists of three ...capacitors, two inductors, three active switches, and two synchronous rectifiers. It triples the effective duty-ratio and lowers the voltage stresses across active switches compared with conventional buck topologies. Converters based on the topology have a potential benefit of achieving high power density and can be capable of delivering high current to the output by two interleaving phases. Small inductance and capacitance are only needed by using interleaving technology, which results in very fast dynamic response to large load changes. A 60 W, 48-1.8 V prototype is built to verify the performance of the proposed topology.
The snubber circuit is a cost-effective solution to reduce the severe turn- off overvoltage and oscillation caused by the fast switching characteristics of SiC MOSFET. However, the turn -on switching ...losses will significantly increase as the snubber decouples the power loop parasitic inductance during the switching process. In this article, the effect of the power loop parasitic inductance on the switch performance of SiC MOSFETs and the quasi-zero voltage switching (QZVS) turn- on condition are studied. On this basis, an SiC MOSFET overvoltage and oscillation suppression circuit (OVSC) with not only the switching losses optimization feature but also the clamping energy feedback characteristic is proposed. The overvoltage and oscillation can be effectively suppressed by clamping capacitors, and those capacitors do not participate in the switching process until the overvoltage occurs, which is of benefit to the switching losses reduction compared with the other normal snubber circuits. Besides, the turn -off overvoltage and oscillation energy stored in the clamping capacitors can be feedback to dc and load side through a passive branch composed of an energy feedback inductor and a diode. The experimental studies and comprehensive comparison studies are carried out to verify the validity of the proposed OVSC. The experimental results show that OVSC has excellent overvoltage and oscillation suppression performance and can significantly reduce the switching losses.
Compared with silicon insulated-gate bipolar transistor, silicon carbide (SiC) metal-oxide-semiconductor field-effect transistor (mosfet) presents good features that it clearly shows on its switching ...and thermal performance. However, the fast switching speed of SiC mosfet makes it much more difficult for solving the dynamic voltage imbalance problem caused by the parameter fluctuations of the SiC mosfets and drive circuits when they are connected in series. This article proposes an effective gate drive circuit and its dynamic voltage balancing control method to tackle this issue. The proposed method not only balances the dynamic voltage during high-speed switching but also adapts to the variation of the dc-bus voltage by utilization of overdrive control method (ODCM). Furthermore, to widen the control range of the ODCM, a switched-capacitor compensation method by switching and combining different drive capacitors into different values is proposed. The operation principles and the parameter design method are discussed in detail. The performance of the proposed series-connected SiC mosfets gate drive circuit and its dynamic voltage balancing control method is validated by experimental results. The dynamic voltage can be well balanced within the design range.
The transmitted power and zero-voltage-switching (ZVS) are two major concerns for dual active bridge (DAB) converters. They are influenced by some nonidealities in real applications, including ...MOSFET's nonlinear output capacitance, dead time in the bridges, as well as the mismatch between the transformer turns ratio and the input-to-output voltage ratio. Despite this, little work has been undertaken to give a detailed design method considering the interaction of these nonidealities. This article aims at achieving the rated power and ZVS for the DAB converter used as a dc transformer under single-phase-shift control by inductance range calculation. The interaction of these nonidealities is considered to select the inductance range for the first time. A 3.5–7 kW experimental prototype is built to verify the effectiveness of the proposed method.
A nonisolated bidirectional dc-dc converter is proposed for energy storage systems in this article. The proposed converter is composed of three active switches, two synchronous rectifiers, two ...clamping capacitors, and two inductors. The proposed converter has advantages of being a simple structure, a fewer number of components, a common ground, lower voltage stress, and wide voltage gain range. Compared with the conventional buck converters, the novel converter triples the effective duty cycle and lowers voltage stresses across the active switches. A 300-W/500-kHz GaN-based experimental prototype is built and tested to verify the correctness and validity, demonstrating a peak efficiency of 94.54% in step-down mode and a peak efficiency of 94.88% in step-up mode.
The transmitted power and zero-voltage-switching (ZVS) are two major concerns for dual active bridge (DAB) converters. They are influenced by some non-idealities in real applications, including ...MOSFET's nonlinear output capacitance, dead time in the bridges, as well as the mismatch between the transformer turns ratio and the input-to-output voltage ratio. Despite this, little work has been undertaken to give a detailed design method considering the interaction of these non-idealities. This paper aims at achieving the rated power and ZVS for the DAB converter used as a DC transformer under single-phase-shift (SPS) control by inductance range calculation. The interaction of these non-idealities is considered to select the inductance range for the first time. A 3.5 to 7 kW experimental prototype is built to verify the effectiveness of the proposed method.
The parasitic inductor can be used as resonant component to increase the power density in resonant converters. However, the parasitic inductance value of PCB copper traces is not large enough to ...achieve zero current switching in low and medium switching frequency conditions. To tackle this problem, a novel integration method to increase parasitic inductance value is proposed in this letter. The proposed method is based on direct coupling, which utilizes lateral structure and vertical structure to increase equivalent inductance between two parasitic inductors. The proposed method not only can achieve high efficiency, high power density, and very low profile design, but also can save the cost and space of discrete inductors for the designed prototype in low and medium frequency range. The comparison and design procedure of both lateral and vertical structures of the parasitic inductor are presented in details. Two 100-W prototypes employing gallium nitride devices are built to compare the discrete inductor solution with the proposed parasitic inductor integration method. The power density of the prototype using parasitic inductor is 62.5% higher than discrete inductance and has achieved a peak efficiency of 93.4%.
