ABSTRACT
Biological ion channels exhibit switchable cation transport with ultrahigh selectivity for efficient energy conversion, such as Ca2+-activated TRPM4 channels tuned by cation-π interactions, but achieving an analogous highly selective function is challenging in artificial nanochannels. Here, we design a TRPM4-inspired cation-selective nanochannel (CN) assembled by two poly(ether sulfone)s, respectively, with sulfonate acid and indole moieties, which act as cation-selective activators to manage Na+/Cl- selectivity via ionic and cation-π interactions. The cation selectivity of CNs can be activated by Na+, and thereby the Na+ transference number significantly improves from 0.720 to 0.982 (Na+/Cl- selectivity ratio from 2.6 to 54.6) under a 50-fold salinity gradient, surpassing the K+ transference number (0.886) and Li+ transference number (0.900). The TRPM4-inspired nanochannel membrane enabled a maximum output power density of 5.7 W m-2 for salinity-gradient power harvesting. Moreover, a record energy conversion efficiency of up to 46.5% is provided, superior to most nanochannel membranes (below 30%). This work proposes a novel strategy to biomimetic nanochannels for highly selective cation transport and high-efficiency salinity-gradient energy conversion.
ABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and deficits in cognitive domains. Low choline levels, oxidative stress, and neuroinflammation are the primary mechanisms implicated in AD progression. Simultaneous inhibition of acetylcholinesterase (AChE) and reactive oxygen species (ROS) production by a single molecule may provide a new breath of hope for AD treatment. Here, we describe donepezil-tacrine hybrids as inhibitors of AChE and ROS. Four series of derivatives with a ß-amino alcohol linker were designed and synthesized. In this study, the target compounds were evaluated for their ability to inhibit AChE and butyrylcholinesterase (BuChE) in vitro, using tacrine (hAChE, IC50 = 305.78 nM; hBuChE, IC50 = 56.72 nM) and donepezil (hAChE, IC50 = 89.32 nM; hBuChE, IC50 = 9137.16 nM) as positive controls. Compound B19 exhibited an excellent and balanced inhibitory potency against AChE (IC50 = 30.68 nM) and BuChE (IC50 = 124.57 nM). The cytotoxicity assays demonstrated that the PC12 cell viability rates of compound B19 (84.37 %) were close to that of tacrine (87.73 %) and donepezil (79.71 %). Potential therapeutic effects in AD were evaluated using the neuroprotective effect of compounds against H2O2-induced toxicity, and compound B19 (68.77 %) exhibited substantially neuroprotective activity at the concentration of 25 µM, compared with the model group (30.34 %). Furthermore, compound B19 protected PC12 cells from H2O2-induced apoptosis and ROS production. These properties of compound B19 suggested that it was a multi-functional agent with AChE inhibition, anti-oxidative, anti-inflammatory activities, and low toxicity and that it deserves further investigation as a promising agent for AD treatment.
Subject(s)
Alzheimer Disease , Neuroprotective Agents , Animals , Rats , Tacrine/pharmacology , Tacrine/therapeutic use , Donepezil/therapeutic use , Alzheimer Disease/drug therapy , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors , Acetylcholinesterase/metabolism , Hydrogen Peroxide , Reactive Oxygen Species , Molecular Docking Simulation , Structure-Activity RelationshipABSTRACT
The broadband constant beam pattern (CBP) spherical array synthesis theory is applied to suppress or to cancel wideband three-dimensional interfering noise sources by implanting zeros in the array's original synthesized shading function. This modified array angular shading function can be expanded by a series of spherical harmonics that will converge to the beam pattern in the far-field such that the created nulls are in the wideband interfering noise source directions per the CBP theory where the ratio of the spherical array radius to the operating frequency wavelength is large. The simulated numerical examples given for this wideband noise source suppression method demonstrate that a broadband CBP performance is maintained for the spherical array with a Legendre polynomial shading function, the classic Dolph-Chebyshev shading function, or a combination. With the CBP design, one set of the real shading functions works for all frequencies in the array's operating band to cancel or to suppress three-dimensional wideband interfering noise sources.
ABSTRACT
A cathepsin B (Cat B)-responsive optical nanoprobe is designed and prepared for report of HL60 differentiation into macrophage. A peptide sequence FRFK is linked to fluorescein (FITC) via the distant amino group of its lysine and N-terminated with acrylic acid (AA) to yield a molecular fluorescent probe AA-FRFK (FITC). The molecular probe is further embedded in poly(lactic-co-glycolic acid) (PLGA) to form a fluorescent nanoprobe AA-FRFK (FITC)@PLGA. The resultant optical nanoprobe is degradable by lysosomal Cat B, which is expressed in macrophages with a level of 5-10 times of that in HL60 cells. As a result, a significant decrease in fluorescence intensity is associated with the differentiation process of HL60 to macrophage and can be used as an indication of the differentiation process. The findings may pave a way toward the development of a universal in vitro labeling strategy of exogenous stem cells for report of in vivo cell differentiation by a dual-mode imaging modality involving optical imaging and magnetic resonance imaging.
Subject(s)
Cathepsin B , Macrophages , Cell Differentiation , Fluorescein-5-isothiocyanate/chemistry , HL-60 Cells , HumansABSTRACT
BACKGROUND: The association of transient acute kidney injury (AKI) with mortality was controversial. Our study aims to investigate the prevalence and impact of transient AKI on mortality in patients following coronary angiography (CAG). METHODS: Our study retrospectively enrolled 3970 patients with pre-operative serum creatinine (Scr) and twice measurements within 48 h after procedure. Transient AKI defined as the diagnosis of AKI (Scr > 0.3 mg/dL or > 50% from the baseline level) on day 1 when Scr failed to meet the criteria for AKI on the day 2. Maintained AKI was defined as AKI not meeting the definition for transient AKI. The primary outcome was 1-year all-cause mortality. Multivariable logistic regression was used to assess the association between transient AKI and 1-year mortality. RESULTS: Among 3,970 participants, 861 (21.7%) occurred AKI, of whom 128 (14.9%) was transient AKI and 733 (85.1%) was maintained AKI. 312 (7.9%) patients died within 1-year after admission. After multivariable analysis, transient AKI was not associated with higher 1-year mortality [adjusted odds ratio (aOR), 1.37; CI 0.68-2.51] compared without AKI. Among AKI patients, transient AKI was associated with a 52% lower 1-year mortality compared with maintained AKI. Additionally, maintained AKI was significantly associated with higher 1-year mortality (aOR, 2.67; CI 2.05-3.47). CONCLUSIONS: Our data suggested that transient AKI within 48 h was a common subtype of AKI following CAG, without increasing mortality. More attention needs to be paid to the patients suffering from maintained AKI following CAG.
Subject(s)
Acute Kidney Injury , Acute Kidney Injury/diagnosis , Cohort Studies , Coronary Angiography/adverse effects , Creatinine , Humans , Prevalence , Retrospective Studies , Risk FactorsABSTRACT
The broadband azimuthal constant beam pattern (CBP) cylindrical array synthesis theory is applied to suppress or to cancel wideband interfering directional noise sources on this plane by implanting zeros in the array's original synthesized shading function. This modified array shading function can be expanded by Fourier cosine and sine series, which are converged to the beam pattern in the far-field such that the created nulls (or reduced-response beam sidelobes) are in the wideband interfering noise source directions per the CBP theory for the large ratio of the cylindrical array radius to the operating frequency wavelength. The simulated numerical examples given for this wideband noise source suppression method for modified Legendre polynomial, classic Dolph-Chebyshev, and Taylor shading functions maintain a broadband CBP performance in the azimuthal plane for a cylindrical array. With the CBP design, one set of the real shading functions works for all frequencies in the array's operating band to cancel or to suppress wideband interfering noise sources.
ABSTRACT
A broadband constant beam pattern (CBP) array is an acoustic array whose beam patterns are independent of operating frequencies. In this article, the theoretical far-field acoustic beam pattern analytic formulations have been mathematically derived for a cylindrical array on an infinite rigid cylinder, after applying the Fourier series expansion, the Fourier sine or cosine transform, and the stationary phase method to the Helmholtz equation with boundary conditions. When the ratio of the array radius over the operating frequency wavelength was large, the horizontal (xoy) plane beam patterns demonstrated broadband CBP performances under the far-field conditions. The vertical (xoz) plane acoustic beam patterns are determined by the array vertical aperture shading's Fourier spectrum coupled with the residuals from the asymptotic approximations of the Hankel function and its derivative. The theoretical results matched with the results by Kirchhoff's integral numerical simulation with various horizontal shading examples for directional acoustic beams by the broadband CBP approach.
ABSTRACT
Stem-cell-based regenerative medicine holds great promise in clinical practices. However, the fate of stem cells after transplantation, including the distribution, viability, and the cell clearance, is not fully understood, which is critical to understand the process and the underlying mechanism of regeneration for better therapeutic effects. Herein, we develop a dual-labeling strategy to in situ visualize the fate of transplanted stem cells in vivo by combining the exogenous near-infrared fluorescence imaging in the second window (NIR-II) and endogenous red bioluminescence imaging (BLI). The NIR-II fluorescence of Ag2 S quantum dots is employed to dynamically monitor the trafficking and distribution of all transplanted stem cells in vivo due to its deep tissue penetration and high spatiotemporal resolution, while BLI of red-emitting firefly luciferase (RfLuc) identifies the living stem cells after transplantation in vivo because only the living stem cells express RfLuc. This facile strategy allows for in situ visualization of the dynamic trafficking of stem cells in vivo and the quantitative evaluation of cell translocation and viability with high temporal and spatial resolution, and thus reports the fate of transplanted stem cells and how the living stem cells help, regeneration, for an instance, of a mouse with acute liver failure.
Subject(s)
Optical Imaging/methods , Stem Cells/cytology , Animals , Humans , Liver Failure/diagnostic imaging , Liver Regeneration/physiology , Luminescent Measurements , Male , Mice , Mice, Inbred BALB C , Quantum DotsABSTRACT
Early reproductive development in cereals is crucial for final grain number per spike and hence the yield potential of the crop. To date, however, no systematic analyses of gene expression profiles during this important process have been conducted for common wheat (Triticum aestivum). Here, we studied the transcriptome profiles at four stages of early wheat reproductive development, from spikelet initiation to floral organ differentiation. K-means clustering and stage-specific transcript identification detected dynamically expressed homeologs of important transcription regulators in spikelet and floral meristems that may be involved in spikelet initiation, floret meristem specification, and floral organ patterning, as inferred from their homologs in model plants. Small RNA transcriptome sequencing discovered key microRNAs that were differentially expressed during wheat inflorescence development alongside their target genes, suggesting that miRNA-mediated regulatory mechanisms for floral development may be conserved in cereals and Arabidopsis. Our analysis was further substantiated by the functional characterization of the ARGONAUTE1d (AGO1d) gene, which was initially expressed in stamen primordia and later in the tapetum during anther maturation. In agreement with its stage-specific expression pattern, the loss of function of the predominantly expressed B homeolog of AGO1d in a tetraploid durum wheat mutant resulted in smaller anthers with more infertile pollens than the wild type and a reduced grain number per spike. Together, our work provides a first glimpse of the gene regulatory networks in wheat inflorescence development that may be pivotal for floral and grain development, highlighting potential targets for genetic manipulation to improve future wheat yields.
Subject(s)
Body Patterning/genetics , Flowers/genetics , Gene Expression Profiling , Genes, Plant , Genes, Regulator , Inflorescence/growth & development , Inflorescence/genetics , Triticum/genetics , Base Sequence , Cluster Analysis , Fertility/genetics , Gene Expression Regulation, Plant , MADS Domain Proteins/metabolism , Meristem/genetics , Meristem/growth & development , Organogenesis/genetics , Pollen/genetics , Pollen/growth & development , Sequence Analysis, RNA , TetraploidyABSTRACT
The theory and numerical simulations for the constant beam pattern (CBP) broadband transducer design are introduced. For a large spherical transducer, if the normal direction radial velocity distribution on the surface of the sphere transducer is a single Legendre polynomial, the far field angular beam pattern shows the same Legendre polynomial distribution due to a spherical Hankel function asymptotic approximation. Arbitrary radial velocity shading functions, including the equal sidelobe classic Dolph-Chebyshev shading, can be expanded by the Legendre series per Sturm-Liouville theory, such that the converging acoustic beam pattern displays the same angular shape as the original shading function itself for the broadband CBP transducer.
ABSTRACT
BACKGROUND: Despite the considerable progress made in preventative methods, medication, and interventional therapies, it remains evident that cardiovascular events (CVEs) continue to be the primary cause of both death and morbidity among individuals diagnosed with coronary artery disease (CAD). OBJECTIVE: To compare the connection between lipoprotein a (Lp[a]), fibrinogen (Fib), and both parameters combined with all-cause mortality to detect their value as prognostic biomarkers. METHODS: This is a retrospective study. Patients diagnosed with CAD between January 2007 and December 2020 at the Guangdong Provincial People's Hospital (China) were involved in the study. 43,367 patients met the eligibility criteria. The Lp(a) and Fib levels were distributed into three tertile groups (low, medium, and high). All of the patients included in the study were followed up for all-cause mortality. Kaplan-Meier and Cox regression were performed to determine the relationship between Lp(a), Fib, and all-cause mortality. A concordance statistics model was developed to detect the impact of Fib and Lp(a) in terms of anticipating poor outcomes in patients with CAD. RESULTS: Throughout a median follow-up of 67.0 months, 6,883 (15.9%) patients died. Participants with high Lp(a) (above 27.60 mg/dL) levels had a significantly higher risk for all-cause mortality than individuals with low Lp(a) levels (below 11.13 mg/dL; adjusted hazard ratio [aHR] 1.219, 95% confidence interval [CI]: 1.141-1.304, p< 0.001). Similarly, patients with high Fib levels (above 4.32 g/L) had a significantly greater risk of developing all-cause mortality compared with those with reduced Fib levels (below 3.41 g/L; aHR 1.415, 95% CI: 1.323-1.514, p< 0.001). Patients with raised Lp(a) and Fib levels had the maximum risk for all-cause mortality (aHR 1.702; 95% CI: 1.558-1.859, p< 0.001). When considered together, Lp(a) and Fib caused a significant elevation of the concordance statistic by 0.009 (p< 0.05), suggesting a higher value for predicting mortality when combining the two indicators. CONCLUSION: High Lp(a) and Fib levels could be used as predictive biomarkers for all-cause mortality in individuals with CAD. The prediction accuracy for all-cause mortality improved after combining the two parameters.
ABSTRACT
Stem cell-based cancer treatment has garnered significant attention, yet its safety and efficacy remain incompletely understood. The nuclear factor-kappa B (NF-κB) pathway, a critical signaling mechanism involved in tumor growth, angiogenesis, and invasion, serves as an essential metric for evaluating the behavior of stem cells in tumor models. Herein, we report the development of a triple-channel imaging system capable of simultaneously monitoring the tropism of stem cells towards tumors, assessing tumor proliferation, and quantifying tumor NF-κB activity. In this system, we generated a CRISPR-Cas9 gene-edited human glioblastoma cell line, GE-U87-MG, which provided a reliable readout of the proliferation and NF-κB activity of tumors by EF1α-RFLuc- and NF-κB-GLuc-based bioluminescent imaging, respectively. Additionally, near infrared-II emitting Tat-PEG-AgAuSe quantum dots were developed for tracking of stem cell tropism towards tumor. In a representative case involving human mesenchymal stem cells (hMSCs), multichannel imaging revealed no discernible effect of hMSCs on the proliferation and NF-κB activity of GE-U87-MG tumors. Moreover, hMSCs engineered to overexpress the necrosis factor-related apoptosis-inducing ligand were able to inhibit NF-κB activity and growth of GE-U87-MG in vivo. Taken together, our imaging system represents a powerful and feasible approach to evaluating the safety and therapeutic efficacy of stem cells in tumor models.
Subject(s)
Glioblastoma , NF-kappa B , Humans , NF-kappa B/metabolism , Cell Line, Tumor , Stem Cells/metabolism , Apoptosis , Glioblastoma/diagnostic imaging , Glioblastoma/therapy , Glioblastoma/metabolism , Cell Proliferation , Optical Imaging , TropismABSTRACT
Multiple lines of evidence suggest that Retinoic Acid Related Orphan Nuclear Receptor gamma t (RORγt) is a potent therapeutic target for inflammatory bowel disease (IBD). However, systemic blockade of RORγt easily leads to thymic lymphoma and aberrant liver function. Therefore, the development of gut-limited RORγt antagonists may lead to the development of innovative IBD therapeutics that improve safety and retain effectiveness. We discovered SPH7854, a potent and selective RORγt antagonist. The effect of SPH7854 on the differentiation of T helper 1 (Th1)/Th17/regulatory T (Treg) cells was evaluated in mouse and human primary cells. SPH7854 (2-(4-(ethylsulfonyl)phenyl)-N- (6-(2-methyl-2-(pyridin-2-yl) propanoyl)pyridin-3-yl)acetamide) dose-dependently inhibited interleukin-17A (IL-17A) secretion from mouse CD4 + T cells and human peripheral blood mononuclear cells (PBMC). Additionally, SPH7854 strongly suppressed Th17 cell differentiation and considerably promoted Treg cell differentiation while slightly affected Th1 cell differentiation from mouse CD4 + T cells. The pharmacokinetic (PK) studies indicated that SPH7854 was restricted to the gut: the bioavailability and maximal plasma concentration of SPH7854 after oral administration (6 mg/kg) were 1.24 ± 0.33 % and 4.92 ± 11.81 nM, respectively, in rats. Strikingly, oral administration of SPH7854 (5 mg/kg and 15 mg/kg) twice daily significantly alleviated 2, 4, 6-trinitrobenzensulfonic acid (TNBS)-induced colitis in rats. SPH7854, especially at 15 mg/kg, significantly alleviated symptoms and improved macroscopic signs and microscopic structure in rat colitis, with decreased colonic mucosal levels of IL-17A, IL-6, tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and myeloperoxidase (MPO). These evidences indicated that blockade of RORγt activity via a gut-limited antagonist may be an effective and safe therapeutic strategy for IBD treatment.
ABSTRACT
Effective drug delivery in the central nervous system (CNS) needs to have long blood-circulation half-lives, to pass through the blood-brain barrier (BBB), and subsequently to be taken up by target cells. Herein, a traceable CNS delivery nanoformulation (RVG-NV-NPs) is developed by encapsulating bexarotene (Bex) and AgAuSe quantum dots (QDs) within Lamp2b-RVG-overexpressed neural stem cell (NSC) membranes. The high-fidelity near-infrared-II imaging by AgAuSe QDs offers a possibility of in vivo monitoring the multiscale delivery process of the nanoformulation from the whole-body to the single-cell scale. It was revealed the synergy of acetylcholine receptor-targeting of RVG and the natural brain-homing and low immunogenicity of NSC membranes prolong the blood circulation, facilitate BBB crossing and nerve cell targeting of RVG-NV-NPs. Thus, in Alzheimer's disease (AD) mice, the intravenous delivery of as low as 0.5% of oral dose Bex showed highly effective up-regulation of the apolipoprotein E expression, resulting rapid alleviation of â¼40% ß-amyloid (Aß) level in the brain interstitial fluid after a single dose administration. The pathological progression of Aß in AD mice is completely suppressed during a 1 month treatment, thus effectively protecting neurons from Aß-induced apoptosis and maintaining the cognitive abilities of AD mice.
Subject(s)
Alzheimer Disease , Mice , Animals , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/drug therapy , Brain/metabolism , Blood-Brain Barrier/metabolism , Amyloid beta-Peptides/metabolism , Cell Membrane/metabolismABSTRACT
Chaigui granules (CG) are a compound composed of six herbal medicines with significant antidepressant effects. However, the antidepressant mechanism of CG remains unclear. In the present study, we attempted to elucidate the antidepressant mechanism of CG by regulating purine metabolism and purinergic signaling. First, the regulatory effect of CG on purine metabolites in the prefrontal cortex (PFC) of chronic unpredictable mild stress (CUMS) rats was analyzed by ultra high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) targeted quantitative analysis. Meanwhile, purinergic receptors (P2X7 receptor (P2X7R), A1 receptor (A1R) and A2A receptor (A2AR)) and signaling pathways (nod-like receptor protein 3 (NLRP3) inflammasome pathway and cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway) associated with purine metabolism were analyzed by western blotting and enzyme-linked immunosorbent assay (ELISA). Besides, antidepressant mechanism of CG by modulating purine metabolites to activate purinergic receptors and related signaling pathways was dissected by exogenous supplementation of purine metabolites and antagonism of purinergic receptors in vitro. An in vivo study showed that the decrease in xanthine and the increase in four purine nucleosides were closely related to the antidepressant effects of CG. Additionally, purinergic receptors (P2X7R, A1R and A2AR) and related signaling pathways (NLRP3 inflammasome pathway and cAMP-PKA pathway) were also significantly regulated by CG. The results of exogenous supplementation of purine metabolites and antagonism of purinergic receptors showed that excessive accumulation of xanthine led to activation of the P2X7R-NLRP3 inflammasome pathway, and the reduction of adenosine and inosine inhibited the A1R-cAMP-PKA pathway, which was significantly ameliorated by CG. Overall, CG could promote neuroprotection and ultimately play an antidepressant role by inhibiting the xanthine-P2X7R-NLRP3 inflammasome pathway and activating the adenosine/inosine-A1R-cAMP-PKA pathway.
ABSTRACT
Modulating the chemical composition of cereblon (CRBN) binders is a critical step in the optimization process of protein degraders that seek to hijack the function of this E3 ligase. Small structural changes can have profound impacts on the overall profile of these compounds, including depth of on-target degradation, neosubstrate degradation selectivity, as well as other drug-like properties. Herein, we report the design and synthesis of a series of novel CRBN binding moieties. These CRBN binders were evaluated for CRBN binding and degradation of common neosubstrates Aiolos and GSPT1. A selection of these binders was employed for an exploratory matrix of heterobifunctional molecules, targeting CRBN-mediated degradation of the androgen receptor.
Subject(s)
Peptide Hydrolases , Ubiquitin-Protein Ligases , Proteolysis , Peptide Hydrolases/metabolism , Ubiquitin-Protein Ligases/metabolism , UbiquitinationABSTRACT
Controllable regulation of stem cell differentiation is a critical concern in stem cell-based regenerative medicine. In particular, there are still great challenges in controlling the directional differentiation of neural stem cells (NSCs) into neurons. Herein, we developed a novel linear-branched poly(ß-amino esters) (S4-TMPTA-BDA-DT, STBD) through a two-step reaction. The synthesized linear-branched polymers possess multiple positively charged amine terminus and degradable intermolecular ester bonds, thus endowing them with excellent properties such as high gene load, efficient gene delivery, and effective gene release and transcription in cells. In the mCherry transfection test, a high transfection efficiency of approximately 70% was achieved in primary NSCs after a single transfection. Moreover, STBD also showed high biocompatibility to NSCs without disturbing their viability and neural differentiation. With the high gene delivery property, STBD is capable of delivering siRNA (shSOX9) expression plasmid into NSCs to significantly interfere with the expression of SOX9, thus enhancing the neuronal differentiation and maturation of NSCs. The STBD/DNA nano-polyplex represents a powerful non-viral approach of gene delivery for manipulating the differentiation of stem cells, showing broad application prospects in NSC-based regenerative therapy for treating neurodegenerative diseases.
Subject(s)
Esters , Neural Stem Cells , Cell Differentiation/genetics , DNA/chemistry , TransfectionABSTRACT
Chaigui granules were a traditional Chinese medicine (TCM) preparation with antidepressant effects derived from a famous antidepressant prescription. It was of great significance to clarify the antidepressant mechanism of Chaigui granules for the clinical application of this drug. In this study, a chronic unpredictable mild stress (CUMS) depression model was successfully established, and behavioral indicators were used to evaluate the antidepressant effect. Second, the CD4+, CD8+, and CD4+/CD8+ levels were detected in peripheral blood. Meanwhile, the amount of inflammatory cytokines was determined in serum. Correspondingly, LC/MS-based peripheral blood mononuclear cell (PBMC) metabolomics was used to investigate vital metabolic pathways participating in the antidepressive effects of Chaigui granules. Finally, bioinformatics technology was further employed to discover the potential antidepressant mechanism of Chaigui granules regulating the immune system. The results suggested that the administration of Chaigui granules significantly improved CUMS-induced depressive symptoms. Chaigui granules could improve immune function by regulating T lymphocyte subsets, increasing anti-inflammatory cytokine levels of IL-2 and IL-10, and reducing pro-inflammatory cytokine levels of TNF-α, IL-1ß, and IL-6. In addition, metabolomics results of PBMCs showed that Chaigui granules improved 14 of the 25 potential biomarkers induced by CUMS. Metabolic pathway analyses indicated that purine metabolism was the critical metabolic pathway regulated by Chaigui granules. Furthermore, correlation analysis indicated that 13 key biomarkers were related to immune-related indicators. The metabolite-gene network of 13 key biomarkers was investigated by using bioinformatics. The investigation showed that 10 targets (5'-nucleotidase ecto; 5'-nucleotidase, cytosolic IB; 5'-nucleotidase, cytosolic II; etc.), mainly belong to the purine metabolism, might be potential targets for Chaigui granules to exert their antidepressant effects by improving immune function impairment. Together, our results suggested that Chaigui granules might exert antidepressant effects by improving immune function and regulating the purine metabolic pathway in PBMCs. This work used PBMCs metabolomics as an entry point to study the antidepressant mechanism of Chaigui granules, which provided a new way to elucidate the mechanism of a traditional Chinese medicine prescription.
ABSTRACT
Axonal transport plays a significant role in the establishment of neuronal polarity, axon growth, and synapse formation during neuronal development. The axon of a naturally growing neuron is a highly complex and multifurcated structure with a large number of bends and branches. Nowadays, the study of dynamic axonal transport in morphologically complex neurons is greatly limited by the technological barrier. Here, a sparse gene transfection strategy was developed to locate fluorescent mCherry in the lysosome of primary neurons, thus enabling us to track the lysosome-based axonal transport with a single-particle resolution. Thereby, several axonal transport models were observed, including the forward or backward transport model, stop-and-go model, repeated back-and-forth transport model, and cross-branch transport model. Then, the accurate single-particle velocity quantification by TrackMate revealed a highly heterogeneous and discontinuous transportation process of lysosome-based axonal transport in freely orientated axons. And, multiple physical factors, such as the axonal structure and the size of particles, were disclosed to affect the velocity of particle transporting in freely orientated axons. The combined single-particle fluorescence tracking and TrackMate assay can be served as a facile tool for evaluating axonal transport in neuronal development and axonal transport-related diseases.
Subject(s)
Axonal Transport , Axons , Axonal Transport/physiology , Axons/metabolism , Fluorescence , Lysosomes , NeuronsABSTRACT
Background: Associations between high serum uric acid (SUA) and cardiovascular diseases have been reported. However, few studies have been conducted to explore the relationship between SUA and long-term all-cause mortality in coronary artery disease (CAD) patients. Our study aims to investigate the relationship between SUA and long-term all-cause mortality in patients with CAD. Methods: From January 2007 to December 2018, we divided 33,034 patients with CAD admitted in the Guangdong Provincial People's Hospital into five groups (quintile 1: SUA <5.05 mg/dl, quintile 2: 5.05 mg/dl ≤ SUA <5.59 mg/dl, quintile 3:5.59 mg/dl ≤ SUA <6.8 mg/dl, quintile 4, 6.8 mg/dl ≤ SUA <7.93 mg/dl, and quintile 5, SUA ≥7.93 mg/d;). This study used Kaplan-Meier survival analysis to evaluate patient outcomes with different ranges of SUA. Cox proportional hazards regression models and restricted cubic spline were applied to determine the association between serum uric and long-term all-cause mortality. Results: A total of 33,034 participants were recruited, including 24,780 (75.01%) men and 8,254 (24.99) women in this cohort study. Median follow-up was 4.91 years. We found that SUA is an independent risk factor of long-term all-cause mortality according to the result of Cox proportional hazards models. This study also illustrated an approximate U-shape association between SUA and all-cause mortality when compared with 5.95 mg/lL ≤ SUA <6.8 mg/dl, SUA <5.0 5mg/dl (adjusted hazard ratio (aHR) =1.13, 95% CI: 1.01-1.26, p = 0.03), and SUA ≥8 mg/dL (aHR = 1.18, 95% CI: 1.06-1.32, p = 0.003). Conclusion: Our study indicated a U-shaped relationship between SUA and long-term all-cause mortality in patients with CAD. No matter whether SUA is too high or too low, it increased the all-cause mortality in the CAD population, which deserves to be closely monitored.