The Role of JAK/STAT Signaling Pathway and Its Downstream Influencing Factors in the Treatment of Atherosclerosis.

Atherosclerosis is now widely considered to be a chronic inflammatory disease, with increasing evidence suggesting that lipid alone is not the main factor contributing to its development. Rather, atherosclerotic plaques contain a significant amount of inflammatory cells, characterized by the accumulation of monocytes and lymphocytes on the vessel wall. This suggests that inflammation may play a crucial role in the occurrence and progression of atherosclerosis. As research deepens, other pathological factors have also been found to influence the development of the disease. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a recently discovered target of inflammation that has gained attention in recent years. Numerous studies have provided evidence for the causal role of this pathway in atherosclerosis, and its downstream signaling factors play a significant role in this process. This brief review aims to explore the crucial role of the JAK/STAT pathway and its representative downstream signaling factors in the development of atherosclerosis. It provides a new theoretical basis for clinically affecting the development of atherosclerosis by interfering with the JAK/STAT signaling pathway.

Biological Role and Related Natural Products of SIRT1 in Nonalcoholic Fatty Liver.

Non-alcoholic fatty liver disease(NAFLD) is an umbrella term for a range of diseases ranging from hepatic fat accumulation and steatosis to non-alcoholic steatohepatitis (NASH) in the absence of excessive alcohol consumption and other definite liver damage factors. The incidence of NAFLD has increased significantly in recent years and will continue to grow in the coming decades. NAFLD has become a huge health problem and economic burden. SIRT1 is a member of Sirtuins, a group of highly conserved histone deacetylases regulated by NAD+, and plays a vital role in regulating cholesterol and lipid metabolism, improving oxidative stress, inflammation, and insulin resistance through deacetylating some downstream transcription factors and thus improving NAFLD. Although there are no currently approved drugs for treating NAFLD and some unresolved limitations in developing SIRT1 activators, SIRT1 holds promise as a proper therapeutic target for NAFLD and other metabolic diseases. In recent years, natural products have played an increasingly important role in drug development due to their safety and efficacy. It has been discovered that some natural products may be able to prevent and treat NAFLD by targeting SIRT1 and its related pathways. This paper reviews the mechanism of SIRT1 in the improvement of NALFD and the natural products that regulate NAFLD through SIRT1 and its associated pathways, and discusses the potential of SIRT1 as a therapeutic target for treating NAFLD and the effectiveness of these related natural products as clinical drugs or dietary supplements. These works may provide some new ideas and directions for finding new therapeutic targets for NAFLD and the development of anti-NAFLD drugs with good pharmacodynamic properties.

Significant Enhancement of Circular Polarization in Light Emission through Controlling Helical Pitches of Semiconductor Nanohelices.

Circularly polarized light emission (CPLE) can be potentially applied to three-dimensional displays, information storage, and biometry. However, these applications are practically limited by a low purity of circular polarization, i.e., the small optical dissymmetry factor gCPLE. Herein, glancing angle deposition (GLAD) is performed to produce inorganic nanohelices (NHs) to generate CPLE with large gCPLE values. CdSe NHs emit red CPLE with gCPLE = 0.15 at a helical pitch (P) ≈ 570 nm, having a 40-fold amplification of gCPLE compared to that at P ≈ 160 nm. Ceria NHs emit ultraviolet-blue CPLE with gCPLE ≈ 0.06 at P ≈ 830 nm, with a 103-fold amplification compared to that at P ≈ 110 nm. Both the photoluminescence and scattering among the close-packed NHs complicatedly account for the large gCPLE values, as revealed by the numerical simulations. The GLAD-based NH-fabrication platform is devised to generate CPLE with engineerable color and large gCPLE = 10-2-10-1, shedding light on the commercialization of CPLE devices.

Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and has no approved treatment. The hepatic farnesoid X receptor (FXR) is one of the most promising therapeutic targets for NAFLD. Diosgenin (DG), a natural compound extracted from Chinese herbal medicine, is very effective in preventing metabolic diseases. Our research aims to determine the effects and molecular mechanisms of DG on NAFLD in vivo and in vitro. The effect of DG on hepatic steatosis was evaluated in Sprague‒Dawley (SD) rats induced by a high-fat diet (HFD) and in HepG2 cells exposed to free fatty acids (FFAs, sodium oleate:sodium palmitate = 2:1). DG treatment efficiently managed hepatic lipid deposition in vivo and in vitro. Mechanistically, DG upregulated the expression of FXR and small heterodimer partner (SHP) and downregulated the expression of genes involved in hepatic de novo lipogenesis (DNL), including sterol regulatory element-binding protein 1C (SREBP1C), acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FASN). Moreover, DG promoted the expression of peroxisome proliferator-activated receptor alpha (PPARα), which is related to fatty acid oxidation. In addition, DG inhibited the expression of the CD36 molecule (CD36) related to fatty acid uptake. However, hepatic FXR silencing weakened the regulatory effects of DG on these genes. Collectively, our data show that DG has a good effect on alleviating nonalcoholic hepatic steatosis via the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway. DG promises to be a novel candidate FXR activator that can be utilized to treat NAFLD.

Interrogation of dynamic glucose-enhanced MRI and fluorescence-based imaging reveals a perturbed glymphatic network in Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder that presents with progressive motor, mental, and cognitive impairment leading to early disability and mortality. The accumulation of mutant huntingtin protein aggregates in neurons is a pathological hallmark of HD. The glymphatic system, a brain-wide perivascular network, facilitates the exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF), supporting interstitial solute clearance including abnormal proteins from mammalian brains. In this study, we employed dynamic glucose-enhanced (DGE) MRI to measure D-glucose clearance from CSF as a tool to assess CSF clearance capacity to predict glymphatic function in a mouse model of HD. Our results demonstrate significantly diminished CSF clearance efficiency in premanifest zQ175 HD mice. The impairment of CSF clearance of D-glucose, measured by DGE MRI, worsened with disease progression. These DGE MRI findings in compromised glymphatic function in HD mice were further confirmed with fluorescence-based imaging of glymphatic CSF tracer influx, suggesting an impaired glymphatic function in premanifest stage of HD. Moreover, expression of the astroglial water channel aquaporin-4 (AQP4) in the perivascular compartment, a key mediator of glymphatic function, was significantly diminished in both HD mouse brain as well as postmortem human HD brain. Our data, acquired using a clinically translatable MRI approach, indicate a perturbed glymphatic network in the HD brain as early as in the premanifest stage. Further validation of these findings in clinical studies should provide insights into potential of glymphatic clearance as a HD biomarker and for glymphatic functioning as a disease-modifying therapeutic target for HD.

Zone of flow: A new finding on the characteristics of airflow within the zone of influence during air sparging in aquifers.

Air sparging (AS) is a popular technology for the in-situ remediation of groundwater contaminated by volatile organic compounds. The scope of the zone within which injected air exists, i.e., zone of influence (ZOI) and the airflow characteristics within ZOI are of great interest. However, few studies have shed light on the scope of the zone within which air flows, namely, the zone of flow (ZOF) and its relation with the scope of ZOI. This study focuses on the ZOF characteristics and its relation with ZOI based on quantitative observations of ZOF and ZOI using a quasi-2D transparent flow chamber. The relative transmission intensity obtained by the light transmission method presents a rapid and continuous increasing near the ZOI boundary, providing a criterion for the quantitative determination of ZOI. An integral airflow flux approach is proposed to determine the scope of ZOF based on the airflow flux distributions through aquifers. The ZOF radius decreases with the growth of particle sizes of aquifers; while it increases first and then keeps constant with the increase of sparging pressure. The ZOF radius is around 0.55- 0.82 times of the ZOI radius, which depends on air flow patterns related to particle diameters dp, that is, 0.55- 0.62 for channel flow (dp < 1- 2 mm), while 0.75- 0.82 for bubble flow (dp > 2- 3 mm). The experimental results show that the sparged air is entrapped with little flowing inside ZOI regions that are outside the ZOF, which should be considered carefully in the design of AS.

Non-contrast assessment of blood-brain barrier permeability to water in mice: An arterial spin labeling study at cerebral veins.

Blood-brain barrier (BBB) plays a critical role in protecting the brain from toxins and pathogens. However, in vivo tools to assess BBB permeability are scarce and often require the use of exogenous contrast agents. In this study, we aimed to develop a non-contrast arterial-spin-labeling (ASL) based MRI technique to estimate BBB permeability to water in mice. By determining the relative fraction of labeled water spins that were exchanged into the brain tissue as opposed to those that remained in the cerebral veins, we estimated indices of global BBB permeability to water including water extraction fraction (E) and permeability surface-area product (PS). First, using multiple post-labeling delay ASL experiments, we estimated the bolus arrival time (BAT) of the labeled spins to reach the great vein of Galen (VG) to be 691.2 ± 14.5 ms (N = 5). Next, we investigated the dependence of the VG ASL signal on labeling duration and identified an optimal imaging protocol with a labeling duration of 1200 ms and a PLD of 100 ms. Quantitative E and PS values in wild-type mice were found to be 59.9 ± 3.2% and 260.9 ± 18.9 ml/100 g/min, respectively. In contrast, mice with Huntington's disease (HD) revealed a significantly higher E (69.7 ± 2.4%, P = 0.026) and PS (318.1 ± 17.1 ml/100 g/min, P = 0.040), suggesting BBB breakdown in this mouse model. Reproducibility studies revealed a coefficient-of-variation (CoV) of 4.9 ± 1.7% and 6.1 ± 1.2% for E and PS, respectively. The proposed method may open new avenues for preclinical research on pathophysiological mechanisms of brain diseases and therapeutic trials in animal models.

An RNA-targeting CRISPR-Cas13d system alleviates disease-related phenotypes in Huntington's disease models.

Huntington's disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by CAG trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Since the reduction of pathogenic mutant HTT messenger RNA is therapeutic, we developed a mutant allele-sensitive CAGEX RNA-targeting CRISPR-Cas13d system (Cas13d-CAGEX) that eliminates toxic CAGEX RNA in fibroblasts derived from patients with HD and induced pluripotent stem cell-derived neurons. We show that intrastriatal delivery of Cas13d-CAGEX via an adeno-associated viral vector selectively reduces mutant HTT mRNA and protein levels in the striatum of heterozygous zQ175 mice, a model of HD. This also led to improved motor coordination, attenuated striatal atrophy and reduction of mutant HTT protein aggregates. These phenotypic improvements lasted for at least eight months without adverse effects and with minimal off-target transcriptomic effects. Taken together, we demonstrate proof of principle of an RNA-targeting CRISPR-Cas13d system as a therapeutic approach for HD, a strategy with implications for the treatment of other dominantly inherited disorders.

Solid-State Nanopore Array: Manufacturing and Applications.

Nanopore brings extraordinary properties for a variety of potential applications in various industrial sectors. Since manufacturing of solid-state nanopore is first reported in 2001, solid-state nanopore has become a hot topic in the recent years. An increasing number of manufacturing methods have been reported, with continuously decreased sizes from hundreds of nanometers at the beginning to ≈1 nm until recently. To enable more robust, sensitive, and reliable devices required by the industry, researchers have started to explore the possible methods to manufacture nanopore array which presents unprecedented challenges on the fabrication efficiency, accuracy and repeatability, applicable materials, and cost. As a result, the exploration of fabrication of nanopore array is still in the fledging period with various bottlenecks. In this article, a wide range of methods of manufacturing nanopores are summarized along with their achievable morphologies, sizes, inner structures for characterizing the main features, based on which the manufacturing of nanopore array is further addressed. To give a more specific idea on the potential applications of nanopore array, some representative practices are introduced such as DNA/RNA sequencing, energy conversion and storage, water desalination, nanosensors, nanoreactors, and dialysis.

Association between gastroesophageal reflux disease and stroke: a bidirectional Mendelian randomization study.

Objective: Some previous studies have suggested a potential link between stroke and gastroesophageal reflux disease (GERD). We used a two-sample bidirectional Mendelian randomization (MR) method to explore the causal relationship between stroke and GERD. Design: Summary-level data derived from the published genome-wide association studies (GWAS) were employed for analyses. Single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for stroke (n = 446,696) and its common subtypes ischemic stroke (IS) (n = 440,328), large vessel stroke (LVS) (n = 410,484), small vessel stroke (SVS) (n = 198,048), and cardioembolic stroke (CES) (n = 413,304) were obtained from the MEGASTROKE consortium. The data on intracerebral hemorrhage (ICH) (n = 721,135) come from the UK Biobank. Instrumental variables (IVs) for lacunar stroke (LS) (n = 474,348) and GERD (n = 602,604) were screened from publicly available genetic summary data. The inverse variance weighted (IVW) method was used as the main MR method. Pleiotropy was detected by the MR-Egger intercept test, MR pleiotropy residual sum and outlier, and leave-one-out analysis. Cochran Q statistics were used as supplements to detect pleiotropy. Results: We found that GERD can causally increase the risk of stroke [IVW odds ratio (OR): 1.22, 95% confidence interval (CI): 1.13-1.32, p = 1.16 × 10-6] and its common subtypes IS (OR: 1.19, 95% CI: 1.10-1.30, p = 3.22 × 10-5), LVS (OR: 1.49, 95% CI: 1.21-1.84, p = 1.47 × 10-4), and LS (OR: 1.20, 95% CI: 1.001-1.44, p = 0.048). Several important risk factors for stroke have also been implicated in the above causal relationship, including type 2 diabetes, sleep apnea syndrome, high body mass index, high waist-to-hip ratio, and elevated serum triglyceride levels. In reverse MR analysis, we found that overall stroke (OR: 1.09, 95% CI: 1.004-1.19, p = 0.039) and IS (OR: 1.10, 95% CI: 1.03-1.17, p = 0.007) have the causal potential to enhance GERD risk. Conclusion: This MR study provides evidence supporting a causal relationship between GERD and stroke and some of its common subtypes. We need to further explore the interconnected mechanisms between these two common diseases to better prevent and treat them.

Data-driven adaptive integral terminal sliding mode control for uncertain SMA actuators with input saturation and prescribed performance.

This paper focuses on the data-driven adaptive control problem of the shape memory alloy (SMA) actuators subject to uncertainties, input saturation and prescribed performance. Firstly, the uncertainties estimation method, anti-windup technology, and prescribed performance function are introduced to deal with uncertain nonlinearity, input constraint, and prespecified performance, respectively. Meanwhile, a general approach about designing asymmetrical convergence bound is presented to increase the flexibility of creating convergence area. Secondly, taking uncertainties, input saturation, and asymmetrical convergence bound into consideration, we design an integral terminal sliding mode controller to guarantee the prescribed tracking accuracy without using the knowledge of the SMA actuators model. Further, the stability of the controller and the boundedness of the convergence error are proved by rigorous theoretical analysis. Finally, the success and superiority of our controller are verified by the SMA actuator experiments.

Age-dependent cerebrospinal fluid-tissue water exchange detected by magnetization transfer indirect spin labeling MRI.

PURPOSE: A non-invasive magnetization transfer indirect spin labeling (MISL) MRI method is developed to quantify the water exchange between cerebrospinal fluid (CSF) and other tissues in the brain and to examine the age-dependence of water exchange. METHOD: In the pulsed MISL, we implemented a short selective pulse followed by a post-labeling delay before an MRI acquisition with a long echo time; in the continuous MISL, a train of saturation pulses was applied. MISL signal (∆Z) was obtained by the subtraction of the label MRI at -3.5 ppm from the control MRI at 200 ppm. CSF was extracted from the mouse ventricles for the MISL optimization and validation. Comparison between wild type (WT) and aquaporin-4 knockout (AQP4-/- ) mice was performed to examine the contributions of CSF water exchange, whereas its age-dependence was investigated by comparing the adult and young WT mice. RESULTS: The pulsed MISL method observed that the MISL signal reached the maximum at 1.5 s. The continuous MISL method showed the highest MISL signal in the fourth ventricle (∆Z = 13.5% ± 1.4%), whereas the third ventricle and the lateral ventricles had similar MISL ∆Z values (∆Z = 12.0% ± 1.8%). Additionally, significantly lower ∆Z (9.3%-18.7% reduction) was found in all ventricles for the adult mice than those of the young mice (p < 0.02). For the AQP4-/- mice, the ∆Z values were 5.9%-8.3% smaller than those of the age-matched WT mice in the lateral and fourth ventricles, but were not significant. CONCLUSION: The MISL method has a great potential to study CSF water exchange with the surrounding tissues in brain.

Huntingtin silencing delays onset and slows progression of Huntington's disease: a biomarker study.

Huntington's disease is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the huntingtin (HTT) gene, coding for pathological mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic aetiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest stage, where clinical outcomes are used to evaluate the effectiveness of therapy. However, as almost 50% of striatal volume has been lost at the time of onset of clinical manifest, it would be preferable to begin therapy in the premanifest period. An unmet challenge is how to evaluate therapeutic efficacy before the presence of clinical symptoms as outcome measures. To address this, we aim to develop non-invasive sensitive biomarkers that provide insight into therapeutic efficacy in the premanifest stage of Huntington's disease. In this study, we mapped the temporal trajectories of arteriolar cerebral blood volumes (CBVa) using inflow-based vascular-space-occupancy (iVASO) MRI in the heterozygous zQ175 mice, a full-length mHTT expressing and slowly progressing model with a premanifest period as in human Huntington's disease. Significantly elevated CBVa was evident in premanifest zQ175 mice prior to motor deficits and striatal atrophy, recapitulating altered CBVa in human premanifest Huntington's disease. CRISPR/Cas9-mediated non-allele-specific HTT silencing in striatal neurons restored altered CBVa in premanifest zQ175 mice, delayed onset of striatal atrophy, and slowed the progression of motor phenotype and brain pathology. This study-for the first time-shows that a non-invasive functional MRI measure detects therapeutic efficacy in the premanifest stage and demonstrates long-term benefits of a non-allele-selective HTT silencing treatment introduced in the premanifest Huntington's disease.

Mutant G2019S-LRRK2 Induces Abnormalities in Arteriolar Cerebral Blood Volume in Mouse Brains: An MRI Study.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease and the most common movement disorder characterized by motor impairments resulting from midbrain dopamine neuron loss. Abnormalities in small pial arteries and arterioles, which are the primary pathways of local delivery of nutrients and oxygen in brain tissue, have been reported in many neurodegenerative diseases including PD. Mutations in LRRK2 cause genetic PD and contribute to sporadic PD. The most common PD-linked mutation LRRK2 G2019S contributes 20-47% of genetic forms of PD in Caucasian populations. The human LRRK2 G2019S transgenic mouse model displays PD-like movement impairment and was used to identify novel LRRK2 inhibitors, which provides a useful model for studying microvascular abnormalities in PD. OBJECTIVES: To investigate abnormalities in arteriolar cerebral blood volume (CBVa) in various brain regions using the inflow-based vascular-space occupancy (iVASO) MRI technique in LRRK2 mouse models of PD. METHODS: Anatomical and iVASO MRI scans were performed in 5 female and 7 male nontransgenic (nTg), 3 female and 4 male wild-type (WT) LRRK2, and 5 female and 7 male G2019S-LRRK2 mice of 9 months of age. CBVa was calculated and compared in the substantia nigra (SN), olfactory cortex, and prefrontal cortex. RESULTS: Compared to nTg mice, G2019S-LRRK2 mice showed decreased CBVa in the SN, but increased CBVa in the olfactory and prefrontal cortex in both male and female groups, whereas WT-LRRK2 mice showed no change in CBVa in the SN (male and female), the olfactory (female), and prefrontal (female) cortex, but a slight increase in CBVa in the olfactory and prefrontal cortex in the male group only. CONCLUSIONS: Alterations in the blood volume of small arteries and arterioles (CBVa) were detected in the G2019S-LRRK2 mouse model of PD. The opposite changes in CBVa in the SN and the cortex indicate that PD pathology may have differential effects in different brain regions. Our results suggest the potential value of CBVa as a marker for clinical PD studies.

Abnormal Brain Development in Huntington' Disease Is Recapitulated in the zQ175 Knock-In Mouse Model.

Emerging cellular and molecular studies are providing compelling evidence that altered brain development contributes to the pathogenesis of Huntington's disease (HD). There has been lacking longitudinal system-level data obtained from in vivo HD models supporting this hypothesis. Our human MRI study in children and adolescents with HD indicates that striatal development differs between the HD and control groups, with initial hypertrophy and more rapid volume decline in HD group. In this study, we aimed to determine whether brain development recapitulates the human HD during the postnatal period. Longitudinal structural MRI scans were conducted in the heterozygous zQ175 HD mice and their littermate controls. We found that male zQ175 HD mice recapitulated the region-specific abnormal volume development in the striatum and globus pallidus, with early hypertrophy and then rapidly decline in the regional volume. In contrast, female zQ175 HD mice did not show significant difference in brain volume development with their littermate controls. This is the first longitudinal study of brain volume development at the system level in HD mice. Our results suggest that altered brain development may contribute to the HD pathogenesis. The potential effect of gene therapies targeting on neurodevelopmental event is worth to consider for HD therapeutic intervention.

Nemo-like kinase reduces mutant huntingtin levels and mitigates Huntington's disease.

Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase, is highly expressed in the brain, but its function in the adult brain remains not well understood. In this study, we identify NLK as an interactor of huntingtin protein (HTT). We report that NLK levels are significantly decreased in HD human brain and HD models. Importantly, overexpression of NLK in the striatum attenuates brain atrophy, preserves striatal DARPP32 levels and reduces mutant HTT (mHTT) aggregation in HD mice. In contrast, genetic reduction of NLK exacerbates brain atrophy and loss of DARPP32 in HD mice. Moreover, we demonstrate that NLK lowers mHTT levels in a kinase activity-dependent manner, while having no significant effect on normal HTT protein levels in mouse striatal cells, human cells and HD mouse models. The NLK-mediated lowering of mHTT is associated with enhanced phosphorylation of mHTT. Phosphorylation defective mutation of serine at amino acid 120 (S120) abolishes the mHTT-lowering effect of NLK, suggesting that S120 phosphorylation is an important step in the NLK-mediated lowering of mHTT. A further mechanistic study suggests that NLK promotes mHTT ubiquitination and degradation via the proteasome pathway. Taken together, our results indicate a protective role of NLK in HD and reveal a new molecular target to reduce mHTT levels.

Photocatalytic degradation of ethylene by Ga2O3 polymorphs.

In this work, we fabricated four different Ga2O3 polymorphs, namely, α-, ß-, γ-, δ-Ga2O3, and investigated their photocatalytic activities by the degradation of ethylene under ultraviolet (UV) light irradiation. Owing to the more positive valence band, all these Ga2O3 polymorphs are more photocatalytic reactive than P25 during the degradation of ethylene. The normalized photocatalytic ethylene degradation rate constants of the as-prepared Ga2O3 polymorphs follow the order: α-Ga2O3 > ß-Ga2O3 > γ-Ga2O3 > δ-Ga2O3, which is mainly determined by the position of VBM and the crystallinity of the samples. Among these Ga2O3 polymorphs, γ-Ga2O3, with the highest surface area, exhibits the highest activity during photocatalytic ethylene degradation, and the degradation rate constant is almost 10 times as that of P25. Furthermore, with the most positive CBM, γ-Ga2O3 produces the least CO. These attributes are beneficial for ethylene degradation during post-harvest storage of fruits and vegetables, which makes γ-Ga2O3 a potential candidate for practical photocatalytic ethylene degradations.

Isoastragaloside I inhibits NF-κB activation and inflammatory responses in BV-2 microglial cells stimulated with lipopolysaccharide.

The excessive activation of microglia in many neurodegenerative diseases is detrimental to neuronal survival. Isoastragaloside I (ISO I) is a natural saponin molecule found within the roots of Astragalus membranaceus, a famous traditional Chinese medicine. In the present study, the anti­inflammatory effects and the mechanisms of action of ISO I on activated BV-2 cells stimulated with lipopolysaccharide (LPS) were investigated. ISO I dose­dependently inhibited the excessive release of nitric oxide (NO) and tumor necrosis factor (TNF)-α in the LPS-stimulated BV-2 cells. Moreover, it decreased the production of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and mitigated the gene expression of interleukin (IL)-1ß, TNF-α and iNOS induced by LPS. Further experiments revealed that ISO I decreased the phosphorylation levels of nuclear factor-κB (NF-κB), and suppressed its nuclear translocation and transactivation activity. In addition, it inhibited the activation of signaling pathway molecules, such as PI3K, Akt and mitogen-activated protein kinases (MAPKs). Taken together, our findings suggest that ISO I prevents LPS-induced microglial activation probably by inhibiting the activation of the NF-κB via PI3K/Akt and MAPK signaling pathways, indicating its therapeutic potential for neurological diseases relevant to neuroinflammation.

Astragaloside IV inhibits microglia activation via glucocorticoid receptor mediated signaling pathway.

Inhibition of microglia activation may provide therapeutic treatment for many neurodegenerative diseases. Astragaloside IV (ASI) with anti-inflammatory properties has been tested as a therapeutic drug in clinical trials of China. However, the mechanism of ASI inhibiting neuroinflammation is unknown. In this study, we showed that ASI inhibited microglia activation both in vivo and in vitro. It could enhance glucocorticoid receptor (GR)-luciferase activity and facilitate GR nuclear translocation in microglial cells. Molecular docking and TR-FRET GR competitive binding experiments demonstrated that ASI could bind to GR in spite of relative low affinity. Meanwhile, ASI modulated GR-mediated signaling pathway, including dephosphorylation of PI3K, Akt, I κB and NF κB, therefore, decreased downstream production of proinflammatory mediators. Suppression of microglial BV-2 activation by ASI was abrogated by GR inhibitor, RU486 or GR siRNA. Similarly, RU486 counteracted the alleviative effect of ASI on microgliosis and neuronal injury in vivo. Our findings demonstrated that ASI inhibited microglia activation at least partially by activating the glucocorticoid pathway, suggesting its possible therapeutic potential for neuroinflammation in neurological diseases.

[Astragaloside IV regulates STAT1/IκB/NF-κB signaling pathway to inhibit activation of BV-2 cells].

OBJECTIVE: The study was aimed to investigate the inhibitory effect and mechanism of astragaloside IV (ASI) on the activation of microglial cells. METHOD: After pre-incubated with ASI for 2 h, microglial cells BV-2 were stimulated with interferon-γ (IFN-γ) for 1. 5 h and 24 h, respectively. Secretion of nitric oxide (NO) in the medium was measured by Griess method. Production of tumor necrosis factor alpha (TNF-α) was detected by ELISA approach. Cellular gene expressions of CD11b, TNF-α, interleukin 1ß (IL-1ß) and induced nitric oxide synthase (iNOS) were examined by quantitative-PCR analysis. Total and phosphorylation of STAT1, IκB and NF-κB was analyzed by Western blot method. RESULT: ASI could significantly inhibit the increased secretion of TNF-α and NO from BV-2 cells upon IFN-γ stimulation (P < 0.001). Further study showed that ASI significantly down-regulated gene expression of IL-1ß and TNF-α (P < 0.01, P < 0.05) and exhibited a trend to reduce that of iNOS. IFN-γ and ASI have no obvious effect on gene expression of CD11b. Moreover, ASI inhibited the phosphorylation of STAT1, IκB and NF-κB elicited by IFN-γ stimulation. CONCLUSION: ASI could restrain microglial activation through interfering STAT1/IκB/NF-κB signaling pathway, reducing gene expres- sion of IL-1ß and TNF-α, and thus inhibiting the production of proinflammatory mediators such as NO and TNF-α.