Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension.

Autophagy is required in diverse paradigms of lifespan extension, leading to the prevailing notion that autophagy is beneficial for longevity. However, why autophagy is harmful in certain contexts remains unexplained. Here, we show that mitochondrial permeability defines the impact of autophagy on aging. Elevated autophagy unexpectedly shortens lifespan in C. elegans lacking serum/glucocorticoid regulated kinase-1 (sgk-1) because of increased mitochondrial permeability. In sgk-1 mutants, reducing levels of autophagy or mitochondrial permeability transition pore (mPTP) opening restores normal lifespan. Remarkably, low mitochondrial permeability is required across all paradigms examined of autophagy-dependent lifespan extension. Genetically induced mPTP opening blocks autophagy-dependent lifespan extension resulting from caloric restriction or loss of germline stem cells. Mitochondrial permeability similarly transforms autophagy into a destructive force in mammals, as liver-specific Sgk knockout mice demonstrate marked enhancement of hepatocyte autophagy, mPTP opening, and death with ischemia/reperfusion injury. Targeting mitochondrial permeability may maximize benefits of autophagy in aging.

Lactic acid promotes nucleus pulposus cell senescence and corresponding intervertebral disc degeneration via interacting with Akt.

The accumulation of metabolites in the intervertebral disc is considered an important cause of intervertebral disc degeneration (IVDD). Lactic acid, which is a metabolite that is produced by cellular anaerobic glycolysis, has been proven to be closely associated with IVDD. However, little is known about the role of lactic acid in nucleus pulposus cells (NPCs) senescence and oxidative stress. The aim of this study was to investigate the effect of lactic acid on NPCs senescence and oxidative stress as well as the underlying mechanism. A puncture-induced disc degeneration (PIDD) model was established in rats. Metabolomics analysis revealed that lactic acid levels were significantly increased in degenerated intervertebral discs. Elimination of excessive lactic acid using a lactate oxidase (LOx)-overexpressing lentivirus alleviated the progression of IVDD. In vitro experiments showed that high concentrations of lactic acid could induce senescence and oxidative stress in NPCs. High-throughput RNA sequencing results and bioinformatic analysis demonstrated that the induction of NPCs senescence and oxidative stress by lactic acid may be related to the PI3K/Akt signaling pathway. Further study verified that high concentrations of lactic acid could induce NPCs senescence and oxidative stress by interacting with Akt and regulating its downstream Akt/p21/p27/cyclin D1 and Akt/Nrf2/HO-1 pathways. Utilizing molecular docking, site-directed mutation and microscale thermophoresis assays, we found that lactic acid could regulate Akt kinase activity by binding to the Lys39 and Leu52 residues in the PH domain of Akt. These results highlight the involvement of lactic acid in NPCs senescence and oxidative stress, and lactic acid may become a novel potential therapeutic target for the treatment of IVDD.

PHLDA2 overexpression facilitates senescence and apoptosis via the mitochondrial route in human nucleus pulposus cells by regulating Wnt/ß-catenin signalling pathway.

Low back pain is a common clinical symptom of intervertebral disc degeneration (IVDD), which seriously affects the quality of life of the patients. The abnormal apoptosis and senescence of nucleus pulposus cells (NPCs) play important roles in the pathogenesis of IVDD. PHLDA2 is an imprinted gene related to cell apoptosis and tumour progression. However, its role in NPC degeneration is not yet clear. Therefore, this study was set to explore the effects of PHLDA2 on NPC senescence and apoptosis and the underlying mechanisms. The expression of PHLDA2 was examined in human nucleus pulposus (NP) tissues and NPCs. Immunohistochemical staining, magnetic resonance imaging imaging and western blot were performed to evaluate the phenotypes of intervertebral discs. Senescence and apoptosis of NPCs were assessed by SA-ß-galactosidase, flow cytometry and western blot. Mitochondrial function was investigated by JC-1 staining and transmission electron microscopy. It was found that the expression level of PHLDA2 was abnormally elevated in degenerated human NP tissues and NPCs. Furthermore, knockdown of PHLDA2 can significantly inhibit senescence and apoptosis of NPCs, whereas overexpression of PHLDA2 can reverse senescence and apoptosis of NPCs in vitro. In vivo experiment further confirmed that PHLDA2 knockdown could alleviate IVDD in rats. Knockdown of PHLDA2 could also reverse senescence and apoptosis in IL-1ß-treated NPCs. JC-1 staining indicated PHLDA2's knockdown impaired disruption of the mitochondrial membrane potential and also ameliorated superstructural destruction of NPCs as showed by transmission electron microscopy. Finally, we found the PHLDA2 knockdown promoted Collagen-II expression and suppressed MMP3 expression in NPCs by repressing wnt/ß-catenin pathway. In conclusion, the results of the present study showed that PHLDA2 promotes IL-1ß-induced apoptosis and senescence of NP cells via mitochondrial route by activating the Wnt/ß-catenin pathway, and suggested that therapy targeting PHLDA2 may provide valuable insights into possible IVDD therapies.

Pharmacokinetic/Pharmacodynamic Assessment of the Structural Refinement of Clopidogrel Focusing on the Balance between Bioactivation and Deactivation.

The delicate balance between ischemic and bleeding risks is a critical factor in antiplatelet therapy administration. Clopidogrel and prasugrel, belonging to the thienopyridine class of antiplatelet drugs, are known for their variability in individual responsiveness and high incidence of bleeding events, respectively. The present study is centered on the development and assessment of a range of deuterated thienopyridine derivatives, leveraging insights from structure-pharmacokinetic relationships of clopidogrel and prasugrel. Our approaches were grounded in the molecular framework of clopidogrel and incorporated the C2-pharmacophore design from prasugrel. The selection of ester or carbamate substituents at the C2-position facilitated the generation of the 2-oxointermediate through hydrolysis, akin to prasugrel, thereby bypassing the issue of CYP2C19 dependency. The bulky C2-pharmacophore in our approach distinguishes itself from prasugrel's acetyloxy substituent by exhibiting a moderated hydrolysis rate, resulting in a more gradual formation of the active metabolite. Excessive and rapid release of the active metabolite, believed to be linked with an elevated risk of bleeding, is thus mitigated. Our proposed structural modification retains the hydrolysis-sensitive methyl ester of clopidogrel but substitutes it with a deuterated methyl group, shown to effectively reduce metabolic deactivation. Three promising compounds demonstrated a pharmacokinetic profile similar to that of clopidogrel at four times the dose, while also augmenting its antiplatelet activity. SIGNIFICANCE STATEMENT: Inspired by the structure-pharmacokinetic relationship of clopidogrel and prasugrel, a range of clopidogrel derivatives were designed, synthesized, and assessed. Among them, three promising compounds have been identified, striking a delicate balance between efficacy and safety for antiplatelet therapy. Additionally, the ozagrel prodrug conjugate was discovered to exert a synergistic therapeutic effect alongside clopidogrel.

Observation of anodic electrochemiluminescence from silicon quantum dots for the detection of hydrogen peroxide.

Silicon quantum dots (QDs) with stable positively charged intermediates are prepared using chemical etching to generate strong anodic electrochemiluminescence (ECL) under a positive potential. Their surfaces could be passivated in the presence of strong oxidants, leading to enhanced ECL and offering the ability to carry out analysis for hydrogen peroxide.

Sluggish and Ion-Resilient Behavior of Interfacial Aqueous Layer on Single-Layer Graphene Oxide: Insights from In Situ Atomic Force Microscopy.

Understanding interfacial interactions of graphene oxide (GO) is important to evaluate its colloidal behavior and environmental fate. Single-layer GO is the fundamental unit of GO colloids, and its interfacial aqueous layers critically dictate these interfacial interactions. However, conventional techniques like X-ray diffraction are limited to multilayer systems and are inapplicable to single-layer GO. Therefore, our study employed atomic force microscopy to precisely observe the in situ dynamic behaviors of interfacial aqueous layers on single-layer GO. The interfacial aqueous layer height was detected at the subnanometer level. In real-time monitoring, the single-layer height increased from 1.17 to 1.70 nm within 3 h immersion. This sluggish process is different from the rapid equilibration of multilayer GO in previous studies, underscoring a gradual transition in hydration kinetics. Ion strength exhibited negligible influence on the single-layer height, suggesting a resilient response of the interfacial aqueous layer to ion-related perturbations due to intricate ion interactions and electrical double-layer compression. Humic acid led to a substantial increase in the interfacial aqueous layers, improving the colloidal stability of GO and augmenting its potential for migration. These findings hold considerable significance regarding the environmental behaviors of the GO interfacial aqueous layer in ion- and organic-rich water and soil.

Molecular phylogenetics of the Umbelopsis genus-identification of new species and evaluation of their oil application value.

AIMS: The aim of this study was to reconstruct the evolutionary framework of the genus Umbelopsis by using modern taxonomic strategies and evaluating the quality of oil and prospective uses of three distinct species. METHODS AND RESULTS: Three species of Umbelopsis were identified based on morphological characteristics and phylogenetic evidence obtained from three genes (ITS, LSU, and ACT). A new species of Umbelopsis was described and illustrated, and subsequently named U. ophiocordycipiticola. The characteristics of U. ophiocordycipiticola exhibited sporangia with a diameter ranging from 8 to 17 µm. and sporangiospores that were oval to ellipsoidal in shape, irregularly angular, with dimensions of ∼1.9-2.9 × 1.7-3.0 µm. Gas chromatography and mass spectrometry (GC-MS) were used to examine the composition of fatty acids. Notably, U. ophiocordycipiticola showed a significantly higher oil content of 50.89% in dry cell weight (DCW) compared to U. vinacea and U. ramanniana. The mean proportion of polyunsaturated fatty acids (PUFAs) in U. ophiocordycipiticola was 32.38%, and the maximum levels of γ-linolenic acid (GLA), arachidonic acid (ARA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) in U. ophiocordycipiticola were found to be 14.51, 0.24, 0.54, and 0.53%, respectively. The biodiesel quality from all three species complied with applicable standards set by the American Association for Testing and Materials (ASTM 6751) and the Brazilian National Petroleum Agency (ANP 255). CONCLUSIONS: The establishment of a novel species, U. ophiocordycipiticola, was strongly supported by morphological and molecular evidence. Umbelopsis ophiocordycipiticola exhibited a high-value PUFA content. Additionally, three Umbelopsis species demonstrated good quality for biodiesel production.

The Roles of Circular RNAs in Ischemic Stroke through Modulating Neuroinflammation.

Ischemic stroke (IS) remains a serious threat to human health. Neuroinflammatory response is an important pathophysiological process after IS. Circular RNAs (circRNAs), a member of the non-coding RNA family, are highly expressed in the central nervous system and widely involved in regulating physiological and pathophysiological processes. This study reviews the current evidence on neuroinflammatory responses, the role of circRNAs in IS and their potential mechanisms in regulating inflammatory cells, and inflammatory factors affecting IS damage. This review lays a foundation for future clinical application of circRNAs as novel biomarkers and therapeutic targets.

APART-QSM: An improved sub-voxel quantitative susceptibility mapping for susceptibility source separation using an iterative data fitting method.

The brain tissue phase contrast in MRI sequences reflects the spatial distributions of multiple substances, such as iron, myelin, calcium, and proteins. These substances with paramagnetic and diamagnetic susceptibilities often colocalize in one voxel in brain regions. Both opposing susceptibilities play vital roles in brain development and neurodegenerative diseases. Conventional QSM methods only provide voxel-averaged susceptibility value and cannot disentangle intravoxel susceptibilities with opposite signs. Advanced susceptibility imaging methods have been recently developed to distinguish the contributions of opposing susceptibility sources for QSM. The basic concept of separating paramagnetic and diamagnetic susceptibility proportions is to include the relaxation rate R2* with R2' in QSM. The magnitude decay kernel, describing the proportionality coefficient between R2' and susceptibility, is an essential reconstruction coefficient for QSM separation methods. In this study, we proposed a more comprehensive complex signal model that describes the relationship between 3D GRE signal and the contributions of paramagnetic and diamagnetic susceptibility to the frequency shift and R2* relaxation. The algorithm is implemented as a constrained minimization problem in which the voxel-wise magnitude decay kernel and sub-voxel susceptibilities are determined alternately in each iteration until convergence. The calculated voxel-wise magnitude decay kernel could realistically model the relationship between the R2' relaxation and the volume susceptibility. Thus, the proposed method effectively prevents the errors of the magnitude decay kernel from propagating to the final susceptibility separation reconstruction. Phantom studies, ex vivo macaque brain experiments, and in vivo human brain imaging studies were conducted to evaluate the ability of the proposed method to distinguish paramagnetic and diamagnetic susceptibility sources. The results demonstrate that the proposed method provides state-of-the-art performances for quantifying brain iron and myelin compared to previous QSM separation methods. Our results show that the proposed method has the potential to simultaneously quantify whole brain iron and myelin during brain development and aging. The proposed model was also deployed with multiple-orientation complex GRE data input measurements, resulting in high-quality QSM separation maps with more faithful tissue delineation between brain structures compared to those reconstructed by single-orientation QSM separation methods.

Sub-voxel quantitative susceptibility mapping for assessing whole-brain magnetic susceptibility from ages 4 to 80.

The evolution of magnetic susceptibility of the brain is mainly determined by myelin in white matter (WM) and iron deposition in deep gray matter (DGM). However, existing imaging techniques have limited abilities to simultaneously quantify the myelination and iron deposition within a voxel throughout brain development and aging. For instance, the temporal trajectories of iron in the brain WM and myelination in DGM have not been investigated during the aging process. This study aimed to map the age-related iron and myelin changes in the whole brain, encompassing myelin in DGM and iron deposition in WM, using a novel sub-voxel quantitative susceptibility mapping (QSM) method. To achieve this, a cohort of 494 healthy adults (18-80 years old) was studied. The sub-voxel QSM method was employed to obtain the paramagnetic and diamagnetic susceptibility based on the approximated R 2 ' map from acquired R 2 * map. The linear relationship between R 2 * and R 2 ' maps was established from the regression coefficients on a small cohort data acquired with both 3D gradient recalled echo data and R 2 mapping. Large cohort sub-voxel susceptibility maps were used to create longitudinal and age-specific atlases via group-wise registration. To explore the differential developmental trajectories in the DGM and WM, we employed nonlinear models including exponential and Poisson functions, along with generalized additive models. The constructed atlases reveal the iron accumulation in the posterior part of the putamen and the gradual myelination process in the globus pallidus with aging. Interestingly, the developmental trajectories show that the rate of myelination differs among various DGM regions. Furthermore, the process of myelin synthesis is paralleled by an associated pattern of iron accumulation in the primary WM fiber bundles. In summary, our study offers significant insights into the distinctive developmental trajectories of iron in the brain's WM and myelination/demyelination in the DGM in vivo. These findings highlight the potential of using sub-voxel QSM to uncover new perspectives in neuroscience and improve our understanding of whole-brain myelination and iron deposit processes across the lifespan.

Direct localization and delineation of human pedunculopontine nucleus based on a self-supervised magnetic resonance image super-resolution method.

The pedunculopontine nucleus (PPN) is a small brainstem structure and has attracted attention as a potentially effective deep brain stimulation (DBS) target for the treatment of Parkinson's disease (PD). However, the in vivo location of PPN remains poorly described and barely visible on conventional structural magnetic resonance (MR) images due to a lack of high spatial resolution and tissue contrast. This study aims to delineate the PPN on a high-resolution (HR) atlas and investigate the visibility of the PPN in individual quantitative susceptibility mapping (QSM) images. We combine a recently constructed Montreal Neurological Institute (MNI) space unbiased QSM atlas (MuSus-100), with an implicit representation-based self-supervised image super-resolution (SR) technique to achieve an atlas with improved spatial resolution. Then guided by a myelin staining histology human brain atlas, we localize and delineate PPN on the atlas with improved resolution. Furthermore, we examine the feasibility of directly identifying the approximate PPN location on the 3.0-T individual QSM MR images. The proposed SR network produces atlas images with four times the higher spatial resolution (from 1 to 0.25 mm isotropic) without a training dataset. The SR process also reduces artifacts and keeps superb image contrast for further delineating small deep brain nuclei, such as PPN. Using the myelin staining histological atlas as guidance, we first identify and annotate the location of PPN on the T1-weighted (T1w)-QSM hybrid MR atlas with improved resolution in the MNI space. Then, we relocate and validate that the optimal targeting site for PPN-DBS is at the middle-to-caudal part of PPN on our atlas. Furthermore, we confirm that the PPN region can be identified in a set of individual QSM images of 10 patients with PD and 10 healthy young adults. The contrast ratios of the PPN to its adjacent structure, namely the medial lemniscus, on images of different modalities indicate that QSM substantially improves the visibility of the PPN both in the atlas and individual images. Our findings indicate that the proposed SR network is an efficient tool for small-size brain nucleus identification. HR QSM is promising for improving the visibility of the PPN. The PPN can be directly identified on the individual QSM images acquired at the 3.0-T MR scanners, facilitating a direct targeting of PPN for DBS surgery.

An improved asymmetric susceptibility tensor imaging model with frequency offset correction.

PURPOSE: To improve susceptibility tensor imaging (STI) reconstruction using the asymmetric STI model with the correction of non-bulk-magnetic-susceptibility (NBMS) effects. METHOD: A frequency offset term was introduced into the asymmetric STI model to account for the bias between measured MRI frequency signals and conventional susceptibility tensor models because of NBMS contributions. Experiments were conducted to compare the proposed model with conventional STI, conventional STI with the proposed frequency offset correction, and asymmetric STI on simulation, ex vivo mouse brain, and in vivo human brain data. RESULTS: In the simulation where NBMS contributions are head rotation-invariant, the proposed method achieves the lowest errors in mean magnetic susceptibility (MMS) and magnetic susceptibility anisotropy (MSA) and is more robust to noise in the estimation of principal eigenvector (PEV). When considering the head orientation dependency of NBMS contributions, the proposed method shows advantages in estimating MSA and PEV. On the mouse and human brain data, the proposed method produces more reliable MSA maps and more consistent white matter fiber directions when referring to those from DTI than the compared STI methods. CONCLUSION: The proposed method can reduce the effects of NBMS-related frequency shifts on the susceptibility tensors in the brain white matter. This study inspires STI reconstruction from the perspective of better modeling the sources of frequency shifts.

Resolution adjustable Lissajous scanning with piezoelectric MEMS mirrors.

We previously designed a dual-axis piezoelectric MEMS mirror with a low crosstalk gimbal structure, which is utilized as the key device for further research for laser beam scanning. This paper mainly focuses on studying the Lissajous scanning resolution of this MEMS mirror with frequency ratio and phase modulation. For accurately evaluating the scanning resolution, the center angular resolution of Lissajous scanning is redefined by theoretical calculation and verified with experimental measurement. Meanwhile, the scanning nonlinearity of MEMS mirror is studied carefully. Finally, the MEMS mirror works at the state of pseudo-resonance, and the center angular resolution better than 0.16° (H) × 0.03° (V) is achieved at a scanning Field of view (FoV) of 35.0° (H) × 16.5° (V). Moreover, a feasible route of resolution adjustable Lissajous scanning is provided by optimization of frequency ratio and phase modulation, which is helpful for high definition and high frame rate (HDHF) laser scanning imaging with the dual-axis mirror.

Age-Related Changes in the Spatial Variation of Magnetic Susceptibility of Human Articular Cartilage.

BACKGROUND: Quantitative susceptibility mapping (QSM) has shown great potential for revealing the layer structure of articular cartilage based on the laminar susceptibility difference at different depths. However, more information is needed on the effects of age on the spatial distribution of magnetic susceptibility in human cartilage. PURPOSE: To assess the ability of QSM to quantify the age-related differences in depth-wise cartilage susceptibility values in healthy populations. STUDY TYPE: Prospective. POPULATION: A total of 94 healthy asymptomatic subjects in three age cohorts: 19-30 (n = 36, 20 males), 31-50 (n = 45, 27 males), and 51-66 years (n = 13, 7 males). FIELD STRENGTH/SEQUENCE: 3D gradient echo sequences at 3.0 T. ASSESSMENT: Four cartilage compartments were analyzed, including the central lateral/medial femur (cLF/cMF) and the lateral/medial tibia (LT/MT). The spatial susceptibility profile and the corresponding 95% confidence interval (CI) of each age cohort were obtained as functions of the normalized distance from the bone-cartilage interface to the cartilage surface (cartilage depth from 0.0 to 1.0). STATISTICAL TESTS: The relationship between age and cartilage thickness of each cartilage subregion was tested by Pearson correlation with P < 0.05 considered significant. Cartilage depths with separations of 95% CIs were considered to have significant susceptibility differences between two age cohorts with a Bonferroni-corrected P < 0.05. RESULTS: The cartilage thickness did not change significantly with age (P value range: 0.06-0.85). Susceptibilities were significantly higher in the 51-66-year-olds compared with the 31-50-year-olds in the deep layer of cMF (cartilage depth: 0.0-0.22) and LT (0.05-0.28). Susceptibilities were significantly higher in the 51-66-year-olds compared with the 19-30-year-olds near the cartilage-bone interface of cMF (0.0-0.34), cLF (0.0-0.28), and LT (0.0-0.58). There were also significantly higher susceptibilities in the 31-50-year-olds compared with the 19-30-year-olds in the deeper regions of cMF (0.26-0.57), cLF (0.0-0.40), and LT (0.07-0.80). DATA CONCLUSION: Age-related susceptibility changes in the deeper regions of knee cartilage were observed using QSM. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Long-Term Exposure of Graphene Oxide Suspension to Air Leading to Spontaneous Radical-Driven Degradation.

Understanding the environmental transformation and fate of graphene oxide (GO) is critical to estimate its engineering applications and ecological risks. While there have been numerous investigations on the physicochemical stability of GO in prolonged air-exposed solution, the potential generation of reactive radicals and their impact on the structure of GO remain unexplored. In this study, using liquid-PeakForce-mode atomic force microscopy and quadrupole time-of-flight mass spectroscopy, we report that prolonged exposure of GO to the solution leads to the generation of nanopores in the 2D network and may even cause the disintegration of its bulk structure into fragment molecules. These fragments can assemble themselves into films with the same height as the GO at the interface. Further mediated electrochemical analysis supports that the electron-donating active components of GO facilitate the conversion of O2 to •O2- radicals on the GO surface, which are subsequently converted to H2O2, ultimately leading to the formation of •OH. We experimentally confirmed that attacks from •OH radicals can break down the C-C bond network of GO, resulting in the degradation of GO into small fragment molecules. Our findings suggest that GO can exhibit chemical instability when released into aqueous solutions for prolonged periods of time, undergoing transformation into fragment molecules through self-generated •OH radicals. This finding not only sheds light on the distinctive fate of GO-based nanomaterials but also offers a guideline for their engineering applications as advanced materials.

SHED-derived exosomes attenuate trigeminal neuralgia after CCI of the infraorbital nerve in mice via the miR-24-3p/IL-1R1/p-p38 MAPK pathway.

BACKGROUND: Microglial activation in the spinal trigeminal nucleus (STN) plays a crucial role in the development of trigeminal neuralgia (TN). The involvement of adenosine monophosphate-activated protein kinase (AMPK) and N-methyl-D-aspartate receptor 1 (NMDAR1, NR1) in TN has been established. Initial evidence suggests that stem cells from human exfoliated deciduous teeth (SHED) have a potential therapeutic effect in attenuating TN. In this study, we propose that SHED-derived exosomes (SHED-Exos) may alleviate TN by inhibiting microglial activation. This study sought to assess the curative effect of SHED-Exos administrated through the tail vein on a unilateral infraorbital nerve chronic constriction injury (CCI-ION) model in mice to reveal the role of SHED-Exos in TN and further clarify the potential mechanism. RESULTS: Animals subjected to CCI-ION were administered SHED-Exos extracted by differential ultracentrifugation. SHED-Exos significantly alleviated TN in CCI mice (increasing the mechanical threshold and reducing p-NR1) and suppressed microglial activation (indicated by the levels of TNF-α, IL-1ß and IBA-1, as well as p-AMPK) in vivo and in vitro. Notably, SHED-Exos worked in a concentration dependent manner. Mechanistically, miR-24-3p-upregulated SHED-Exos exerted a more significant effect, while miR-24-3p-inhibited SHED-Exos had a weakened effect. Bioinformatics analysis and luciferase reporter assays were utilized for target gene prediction and verification between miR-24-3p and IL1R1. Moreover, miR-24-3p targeted the IL1R1/p-p38 MAPK pathway in microglia was increased in CCI mice, and participated in microglial activation in the STN. CONCLUSIONS: miR-24-3p-encapsulated SHED-Exos attenuated TN by suppressing microglial activation in the STN of CCI mice. Mechanistically, miR-24-3p blocked p-p38 MAPK signaling by targeting IL1R1. Theoretically, targeted delivery of miR-24-3p may offer a potential strategy for TN.

Prevention effect of total ginsenosides and ginseng extract from Panax ginseng on cyclophosphamide-induced immunosuppression in mice.

Oral decoction is widely applied in traditional Chinese medicines. The polysaccharides of decoction promote the exposure of small molecules and increase their bioavailability. This study mainly compared the component and activities of total ginsenosides (TGS) and ginseng extract (GE) on immunosuppressed mice induced by cyclophosphamide. Thirty-two mice were randomly divided into control, model, TGS, and GE groups. The mice were orally administered for 28 days and then injected with cyclophosphamide on the last four days. The results of component analysis showed the total content of 12 ginsenosides in TGS (67.21%) was higher than GE (2.04%); the total content of 17 amino acids in TGS (1.41%) was lower than GE (5.36%); the total content of 10 monosaccharides was similar in TGS (74.12%) and GE (76.36%). The animal results showed that both TGS and GE protected the hematopoietic function of bone marrow by inhibiting cell apoptosis, and recovering the normal cell cycle of BM; maintained the dynamic balance between the Th1 and Th2 cells; also protected the spleen, thymus, and liver. Meanwhile, TGS and GE protected the intestinal bacteria of immunosuppressed mice by increasing the abundance of lactobacillus and decreasing the abundance of the odoribacter and clostridia_UCG-014. The prevention effect of GE was superior to TGS in some parameters. In conclusion, TGS and GE protected the immune function of immunosuppressed mice induced by cyclophosphamide. Meanwhile, GE showed higher bioavailability and bioactivity compared with TGS, because the synergistic effect of polysaccharides and ginsenosides plays an important role in protecting the immune function.

An outcomes-based module education via flipped classroom enhances undergraduate oral histopathology learning.

INTRODUCTION: Oral histopathology is a bridge course connecting oral basic medicine and clinical dentistry. However, the application of outcomes-based education via flipped classroom (FC) in oral histopathology has not been well explored. This study has assessed the efficacy of outcomes-based education via FC in undergraduate oral histopathology module learning in Nanjing Medical University of China. MATERIALS AND METHODS: A total of 214 third-year students were enrolled and assigned to the FC group of the batch 2022-23 (n = 110) and the traditional classroom (TC) group of the batch 2021-22 (n = 104) to participate the oral histopathology sessions respectively in the study. The FC group were required to preview the online course materials pre-class, followed by in-class quizz, in-class interactive group discussion, and slides microscopic observation. The outcomes-based formative and summative assessments for FC were designed. The TC group attended traditional laboratory class for the same glass slides microscopic observation. In addition, a questionnaire was performed to investigate the satisfaction of learning. Along with this, the performances of FC group in written theory tests and oral histopathology slide tests were compared with TC group. RESULTS: Students in the FC group gained significantly final higher scores of the course than those in the TC group (score: 83.79 ± 11 vs. 76.73 ± 10.93, P<0.0001). Data from the student questionnaires indicated a preference for outcomes-based module education via FC. In the questionnaires, most students considered outcomes-based module education via FC to be beneficial to learning motivation, knowledge comprehension, critical thinking and teamwork. FC group had a higher level of satisfaction with oral histopathology teaching than TC group (satisfaction score: 4.599 ± 0.1027 vs. 4.423 ± 0.01366, P<0.01). CONCLUSION: An outcomes-based module education via FC has a promising effect on undergraduate oral histopathology education.

Differential Mobility Spectrometry-Tandem Mass Spectrometry with Multiple Ion Monitoring Coupled with in Source-Collision Induced Dissociation: A New Strategy for the Quantitative Analysis of Pharmaceutical Polymer Excipients in Rat Plasma.

Polylactic acids (PLAs) are synthetic polymers composed of repeating lactic acid subunits. For their good biocompatibility, PLAs have been approved and widely applied as pharmaceutical excipients and scaffold materials. Liquid chromatography-tandem mass spectrometry is a powerful analytical tool not only for pharmaceutical ingredients but also for pharmaceutical excipients. However, the characterization of PLAs presents particular problems for mass spectrometry techniques. In addition to their high molecular weights and wide polydispersity, multiple charging and various adductions are intrinsic features of electrospray ionization. In the present study, a strategy combining of differential mobility spectrometry (DMS), multiple ion monitoring (MIM) and in-source collision-induced dissociation (in source-CID) has been developed and applied to the characterization and quantitation of PLAs in rat plasma. First, PLAs will be fragmented into characteristic fragment ions under high declustering potential in the ionization source. The specific fragment ions are then screened twice by quadrupoles to ensure a high signal intensity and low interference for mass spectrometry detection. Subsequently, DMS technique has been applied to further reduce the background noise. The appropriately chosen surrogate specific precursor ions could be utilized for the qualitative and quantitative analysis of PLAs, which provided results with the advantages of low endogenous interference, sufficient sensitivity and selectivity for bioassay. The linearity of the method was evaluated over the concentration range 3-100 µg/mL (r2 = 0.996) for PLA 20,000. The LC-DMS-MIM coupled with in source-CID strategy may contribute to the pharmaceutical studies of PLAs and the possible prospects of other pharmaceutical excipients.

Role of Circular RNAs in Atherosclerosis through Regulation of Inflammation, Cell Proliferation, Migration, and Apoptosis: Focus on Atherosclerotic Cerebrovascular Disease.

Atherosclerosis (AS) is a disease dangerous to human health and the main pathological cause of ischemic cardiovascular diseases. Although its pathogenesis is not fully understood, numerous basic and clinical studies have shown that AS is a chronic inflammatory disease existing in all stages of atherogenesis. It may be a common link or pathway in the pathogenesis of multiple atherogenic factors. Inflammation is associated with AS complications, such as plaque rupture and ischemic cerebral infarction. In addition to inflammation, apoptosis plays an important role in AS. Apoptosis is a type of programmed cell death, and different apoptotic cells have different or even opposite roles in the process of AS. Unlike linear RNA, circular RNA (circRNA) a covalently closed circular non-coding RNA, is stable and can sponge miRNA, which can affect the stages of AS by regulating downstream pathways. Ultimately, circRNAs play very important roles in AS by regulating inflammation, apoptosis, and some other mechanisms. The study of circular RNAs can provide new ideas for the prediction, prevention, and treatment of AS.