Regulating the Selectivity of Nitrate Photoreduction for Purification or Ammonia Production by Cooperating Oxidative Half-Reactions.

The removal and conversion of nitrate (NO3-) from wastewater has become an important environmental and health topic. The NO3- can be reduced to nontoxic nitrogen (N2) for environmental remediation or ammonia (NH3) for recovery, in which the tailoring of the selectivity is greatly challenging. Here, by construction of the CuOx@TiO2 photocatalyst, the NO3- conversion efficiency is enhanced to ∼100%. Moreover, the precise regulation of selectivity to NH3 (∼100%) or N2 (92.67%) is accomplished by the synergy of cooperative redox reactions. It is identified that the selectivity of the NO3- photoreduction is determined by the combination of different oxidative reactions. The key roles of intermediates and reactive radicals are revealed by comprehensive in situ characterizations, providing direct evidence for the regulated selectivity of the NO3- photoreduction. Different active radicals are produced by the interaction of oxidative reactants and light-generated holes. Specifically, the introduction of CH3CHO as the oxidative reactant results in the generation of formate radicals, which drives selective NO3- reduction into N2 for its remediation. The alkyl radicals, contributed to by the (CH2OH)2 oxidation, facilitate the deep reduction of NO3- to NH3 for its upcycling. This work provides a technological basis for radical-directed NO3- reduction for its purification and resource recovery.

Deacetylase Sirtuin 1 mitigates type I IFN- and type II IFN-induced signaling and antiviral immunity.

Type I and type II IFNs are important immune modulators in both innate and adaptive immunity. They transmit signaling by activating JAK-STAT pathways. Sirtuin 1 (SIRT1), a class III NAD+-dependent deacetylase, has multiple functions in a variety of physiological processes. Here, we characterized the novel functions of SIRT1 in the regulation of type I and type II IFN-induced signaling. Overexpression of SIRT1 inhibited type I and type II IFN-induced interferon-stimulated response element activation. In contrast, knockout of SIRT1 promoted type I and type II IFN-induced expression of ISGs and inhibited viral replication. Treatment with SIRT1 inhibitor EX527 had similar positive effects. SIRT1 physically associated with STAT1 or STAT3, and this interaction was enhanced by IFN stimulation or viral infection. By deacetylating STAT1 at K673 and STAT3 at K679/K685/K707/K709, SIRT1 downregulated the phosphorylation of STAT1 (Y701) and STAT3 (Y705). Sirt1+/- primary peritoneal macrophages and Sirt1+/- mice exhibited enhanced IFN-induced signaling and antiviral activity. Thus, SIRT1 is a novel negative regulator of type I and type II IFN-induced signaling through its deacetylase activity.IMPORTANCESIRT1 has been reported in the precise regulation of antiviral (RNA and DNA) immunity. However, its functions in type I and type II IFN-induced signaling are still unclear. In this study, we deciphered the important functions of SIRT1 in both type I and type II IFN-induced JAK-STAT signaling and explored the potential acting mechanisms. It is helpful for understanding the regulatory roles of SIRT1 at different levels of IFN signaling. It also consolidates the notion that SIRT1 is an important target for intervention in viral infection, inflammatory diseases, or even interferon-related therapies.

Emerging trends and hotspots of the itch research: A bibliometric and visualized analysis.

AIMS: Itch, a common uncomfortable sensory experience, occurs frequently in inflammatory or allergic disorders. In recent years, with the discovery of itch-specific pathways in the peripheral and central nervous system, the association between immunology and neural pathways has gradually emerged as the main mechanism of itch. Although many studies have been conducted on itch, no bibliometric analysis study focusing on this topic has been conducted. This study aimed to explore the research hotspots and trends in the itch field from a bibliometric perspective. METHODS: Publications relevant to itch, published from 2003 to 2022, were retrieved from the Science Citation Index-Expanded of Web of Science Core Collection. Publications were critically reviewed and analyzed with CiteSpace software, Vosviewer, and the bibliometric online analysis platform. Visual maps were conducted in terms of annual production, collaborating countries or institutions, productive authors, core journals, co-cited references, and keyword bursts. RESULTS: 2395 articles on itch that met our criteria were identified and the quantity of publications has been increasing rapidly since 2012. The USA was the most influential country. University Hospital Münster was the institution with the most publications. Gil Yosipovitch was the most prolific author. Atopic dermatitis (AD), intradermal serotonin, chronic pruritus, mechanical itch, gastrin-releasing peptide, substance p, interleukin-31 receptor, histamine-induced itch, bile acid, scratching behavior, and h-4 receptor were the top 11 clusters in co-citation cluster analysis. Keyword burst analysis suggested that treatment, inflammation, and AD are current research hotspots. CONCLUSION: Global publications on itch research have increased steadily and rapidly over the past 20 years. Inflammation and AD are current research hotspots. The neuroimmunological and neuroinflammatory mechanisms of itch, as well as clinical assessment methods and therapeutic targets, will be novel research directions in the future. This study provides guidance for further itch research.

Nitric oxide is involved in the regulation of guard mother cell division by inhibiting the synthesis of ACC.

A stoma forms by a series of asymmetric divisions of stomatal lineage precursor cell and the terminal division of a guard mother cell (GMC). GMC division is restricted to once through genetic regulation mechanisms. Here, we show that nitric oxide (NO) is involved in the regulation of the GMC division. NO donor treatment results in the formation of single guard cells (SGCs). SGCs are also produced in plants that accumulate high NO, whereas clustered guard cells (GCs) appear in plants with low NO accumulation. NO treatment promotes the formation of SGCs in the stomatal signalling mutants sdd1, epf1 epf2, tmm1, erl1 erl2 and er erl1 erl2, reduces the cell number per stomatal cluster in the fama-1 and flp1 myb88, but has no effect on stomatal of cdkb1;1 cyca2;234. Aminocyclopropane-1-carboxylic acid (ACC), a positive regulator of GMC division, reduces the NO-induced SGC formation. Further investigation found NO inhibits ACC synthesis by repressing the expression of several ACC SYNTHASE (ACS) genes, and in turn ACC represses NO accumulation by promoting the expression of HEMOGLOBIN 1 (HB1) encoding a NO scavenger. This work shows NO plays a role in the regulation of GMC division by modulating ACC accumulation in the Arabidopsis cotyledon.

Deubiquitinase USP47 attenuates virus-induced type I interferon signaling.

The innate immune responses are tightly regulated to ensure effective clearance of invading pathogens and avoid excessive inflammation. Ubiquitination and deubiquitination are important post-translational modifications in antiviral immune responses. Here, we discovered deubiquitinase USP47 as a novel negative immune system regulator. Overexpression of USP47 repressed Sendai virus, poly(I:C) and poly(dA:dT)-induced ISRE and IFN-ß activation, along with reduced IFNB1 transcription and enhanced viral replication. Knockdown of USP47 expression had the opposite effects. Dual-luciferase and phosphorylation assays showed that USP47 targeted downstream of MAVS and upstream of TBK1. Additional co-immunoprecipitation assays suggested that USP47 interacted with TRAF3 and TRAF6. Importantly, USP47 removed K63-linked polyubiquitin chains from TRAF3 and TRAF6. Hence, we describe a novel modulator of the antiviral innate immune response, USP47, which removes K63-linked polyubiquitins from TRAF3 and TRAF6, leading to reduced type I IFN signaling.

Carbon monoxide promotes stomatal initiation by regulating the expression of two EPF genes in Arabidopsis cotyledons.

The gaseous molecule carbon monoxide (CO) can freely pass through the cell membrane and participate in signal transduction in the cell to regulate physiological activities in plants. Here, we report that CO has a positive regulatory role in stomatal development. Exogenous CO donor CORM-2 [Tricarbonyldichlororuthenium (II) dimer] treatment resulted in an increase of stomatal index (SI) on the abaxial epidermis of cotyledons in wild-type, which can be reversed by the addition of the CO biosynthesis inhibitor ZnPPIX [Protoporphyrin IX zinc (II)]. Consistent with this result, mutation of the CO biosynthesis gene HY1 resulted in a decrease of SI in hy1-100 plants, while overexpression of HY1 led to an increase of SI. Further investigation revealed that CO acts upstream of SPCH and YDA in the stomatal development pathway, since the loss of function mutants spch-1 and yda-2 were insensitive to CORM-2. The expression of EPF2 was inhibited by CORM-2 treatment in wild type and is lower in hy1 than in wild-type plants. In contrast, the expression of STOMAGEN was promoted by CORM-2 treatment and is higher in HY1-overexpression lines. Loss of function mutants of both epf2 and stomagen are insensitive to CORM-2 treatment. These results indicated that CO positively regulates stomatal initiation and distribution by modulating the expression of EPF2 and STOMAGEN.

Parental presence and intranasal dexmedetomidine for the prevention of anxiety during anesthesia induction in children undergoing tonsillectomy and/or adenoidectomy surgery: A randomized controlled trial.

Background: During the perioperative period of pediatric surgery, it is extremely stressful for children and parents to enter the operating room and receive the anesthesia induction. This study was designed to evaluate the perioperative outcomes with parental presence at induction of anesthesia (PPIA), intranasal dexmedetomidine, and combined use of PPIA and intranasal dexmedetomidine. Methods: In this prospective study, 124 children were randomly divided into four groups: control (no parental presence or intranasal dexmedetomidine), PPIA (parental presence), DEX (intranasal dexmedetomidine (1.0 µg/kg)), and PPIA + DEX (parental presence and intranasal dexmedetomidine (1.0 µg/kg)). The anxiety of children was mainly evaluated by the modified Yale Preoperative Anxiety Scale-Short Form (mYPAS-SF). Secondary evaluation methods were, for example, the Induction Compliance Checklist (ICC), the Pediatric Anesthesia Emergence Delirium Scale (PAED), the COMFORT Behavior Scale (COMFORT-B Scale), the State-Trait Anxiety Inventory (STAI), and the Visual Analog Scale (VAS). Results: Children in the PPIA + DEX group exhibited significantly lower mYPAS-SF and ICC scores compared with all three other groups (p < 0.001), and children in that group exhibited significantly lower mYPAS-SF and ICC scores compared with the PPIA and DEX groups (p < 0.05). The children's PAED scores in the PPIA, DEX, and PPIA + DEX groups were significantly lower than the control group (p < 0.001).The STAI-S scores of the PPIA, DEX, and PPIA + DEX groups were significantly lower than the score of the control group (p < 0.001). The VAS scores of the PPIA, DEX, and PPIA + DEX groups were significantly higher than that of the control group (p < 0.001), while the score of the PPIA + DEX group was significantly higher than those of the PPIA and DEX groups (p < 0.05). Conclusion: The combined use of PPIA and intranasal dexmedetomidine is more effective than PPIA or intranasal dexmedetomidine for alleviating the preoperative anxiety of children, improving children's induction compliance and parental satisfaction.

Interferon-Inducible LINC02605 Promotes Antiviral Innate Responses by Strengthening IRF3 Nuclear Translocation.

Non-coding RNAs represent a class of important regulators in immune response. Previously, LINC02605 was identified as a candidate regulator in innate immune response by lncRNA microarray assays. In this study, we systematically analyzed the functions and the acting mechanisms of LINC02605 in antiviral innate immune response. LINC02605 was up-regulated by RNA virus, DNA virus, and type I IFNs in NF-κB and Jak-stat dependent manner. Overexpression of LINC02605 promotes RNA virus-induced type I interferon production and inhibited viral replication. Consistently, knockdown of LINC02605 resulted in reduced antiviral immune response and increased viral replication. Mechanistically, LINC02605 released the inhibition of hsa-miR-107 on the expression of phosphatase and tensin homolog (PTEN). By microRNA mimics and inhibitors, hsa-miR-107 was demonstrated to not only inhibit PTEN's expression but also negatively regulate the antiviral immune response. Knockdown of LINC02605 led to the reduction of PTEN expression both in mRNA and protein levels. Overexpression of LINC02605 had an opposite impact. Moreover, LINC02605 attenuated the serine 97 phosphorylation level of interferon regulatory factor 3 (IRF3) by promoting PTEN expression. Nucleoplasmic fragmentation assay showed that knocking down LINC02605 inhibited the nuclear translocation of IRF3, rendering the host cells more susceptible to viral invasion, while overexpression showed opposite effects. Therefore, LINC02605 is an induced lncRNA by viral infection and plays a positive feedback in antiviral immune response through modulating the nuclear translocation of IRF3.

Fault-Tolerant Adaptive Learning Control for Quadrotor UAVs With the Time-Varying CoG and Full-State Constraints.

Most existing control methods for quadrotor unmanned aerial vehicles (UAVs) are based on the primary assumption that the center of gravity (CoG) is fixed and is in the same position as the centroid, which is not necessarily true with swing load as continuously making CoG vary with the swing angle and substantially complicating the dynamic model of UAV. This article presents an adaptive learning and fault-tolerant control scheme for quadrotor UAVs with varying CoG and unknown moment of inertia. First, we establish the dynamic model of quadrotor UAVs in the presence of time-varying CoG, input saturation, and actuator fault. Then, we design a fault-tolerant adaptive learning controller for the quadrotor UAVs and show that both linear and angular velocity tracking errors are ensured to converge to a residual set around zero in the presence of full-state constraints. Furthermore, all signals in the closed-loop system are uniformly ultimately bounded. Simulation studies also confirm the effectiveness of the proposed control method.

Inhibition of cancer cell growth by oleanolic acid in multidrug resistant liver carcinoma is mediated via suppression of cancer cell migration and invasion, mitochondrial apoptosis, G2/M cell cycle arrest and deactivation of JNK/p38 signalling pathway.

PURPOSE: Liver cancer accounts for considerable mortality across the globe. The sharp upsurge in the incidence of liver cancer, unavailability of standard treatments and the adverse side effects associated with the existing drugs has made it compulsory to explore novel and more effective anticancer molecules. In this study the anticancer effects of a natural compound oleanolic acid were investigated in vitro. METHODS: The human HepG2 liver cancer cells were treated with various concentrations of oleanolic acid for 24 h. The antiproliferative effects of oleanolic acid were measured by CCK8 cell viability assay. DAPI and annexin V/propidium iodide (PI) assays were employed to examine the induction of apoptosis. Transwell assay was performed to examine the cell migration and invasion. Expression analysis was performed by western blot analysis. RESULTS: The results showed that oleanolic acid decreased the viability of the liver cancer HepG2 cells and exhibited an IC50 of 30 µM. The cytotoxicity of oleanolic acid was also investigated on the normal liver cells AML12 and it was found that oleanolic acid and exerted very low toxic effects on these cells and exhibited an IC50 of 120 µM. Oleanolic acid also caused remarkable changes in the morphology of the HepG2 cells and inhibited their colony formation potential. Flow cytometry indicated oleanolic acid triggered G2/M arrest of the liver HepG2 cancer cells. PI and DAPI staining revealed that oleanolic acid prompted apoptosis of the HepG2 cells. The apoptotic cells increased from 2.2% in control to around 35% at 30 µM concentration. Oleanolic acid also suppressed the migration and invasion of the liver cancer cells via blocking of the JNK/p38 signalling pathway. CONCLUSIONS: The results of the current research revealed that oleanolic acid can be a molecule that may be utilised in the treatment of liver cancer in the future.

UBL4A Augments Innate Immunity by Promoting the K63-Linked Ubiquitination of TRAF6.

Human UBL4A/GdX, encoding an ubiquitin-like protein, was shown in this study to be upregulated by viral infection and IFN stimulation. Then the functions of UBL4A in antiviral immune response were characterized. Overexpression of UBL4A promoted RNA virus-induced ISRE or IFN-ß or NF-κB activation, leading to enhanced type I IFN transcription and reduced virus replication. Consistently, knockdown of UBL4A resulted in reduced type I IFN transcription and enhanced virus replication. Additionally, overexpression of UBL4A promoted virus-induced phosphorylation of TBK1, IRF3, and IKKα/ß. Knockdown of UBL4A inhibited virus-induced phosphorylation of TBK1, IRF3, and IKKα/ß. Coimmunoprecipitation showed that UBL4A interacted with TRAF6, and this interaction was enhanced upon viral infection. Ubiquitination assays showed that UBL4A promoted the K63-linked ubiquitination of TRAF6. Therefore, we reveal a novel positive feedback regulation of UBL4A in innate immune response combating virus invasion by enhancing the K63-linked ubiquitination of TRAF6.

Data-driven modeling based on kernel extreme learning machine for sugarcane juice clarification.

Clarification of sugarcane juice is an important operation in the production process of sugar industry. The gravity purity and the color value of juice are the two most important evaluation indexes in the cane sugar production using the sulphitation clarification method. However, in the actual operation, the measurement of these two indexes is usually obtained by offline experimental titration, which makes it impossible to timely adjust the system indicators. A data-driven modeling based on kernel extreme learning machine is proposed to predict the gravity purity of juice and the color value of clear juice. The model parameters are optimized by particle swarm optimization. Experiments are conducted to verify the effectiveness and superiority of the modeling method. Compared with BP neural network, radial basis neural network, and support vector machine, the model has a good performance, which proves the reliability of the model.

Characterization of the transcriptional regulator CsbHLH62 that negatively regulates EGCG3"Me biosynthesis in Camellia sinensis.

Epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3"Me) in tea (Camellia sinensis (L.) O. Kuntze) is a major source of O-methylated catechin and renowned for a wide range of health effects. However, the transcriptional regulation mechanisms of EGCG3"Me biosynthesis remain unclear. In the present work, the basic Helix-Loop-Helix (bHLH) transcription factor, designated as CsbHLH62, belonging to GBOF group of bHLH families, was isolated and characterized from Camellia sinensis. CsbHLH62 contains an Open Reading Frame of 1662 bp and encodes a polypeptide of 553 amino acids. Subcellular location and transcriptional activity analysis showed it as a nucleus protein and possessed transcriptional inhibition activity. Furthermore, the expression of CsbHLH62 was decreased during EGCG3"Me accumulation. More importantly, E-box motifs (5'-CANNTG-3') were found in the promoters of CCoAOMT, CsLAR, and CsDFR, and further transient expression assays showed that CsbHLH62 repressed the transcription of CCoAOMT, CsLAR, and CsDFR. Collectively, these results suggest that CsbHLH62 acts as a transcriptional repressor that might be negatively affecting the accumulation of EGCG3"Me. These findings provide novel insights into the regulatory mechanism of EGCG3"Me biosynthesis, which might help to breed high EGCG3"Me-content tea plants.

Over-expression of OsPT2 under a rice root specific promoter Os03g01700.

Identification of root-specific promoters is a good method to drive root-specific gene expression for nutrient uptake. Constitutive over-expression of OsPT2 may have negative effects on the growth of rice seedlings under high Pi condition. Thus, characterization and utilization of root-specific promoters are critical for genetic breeding. Here, a root-specific promoter (Os03g01700) with a number of specific regulatory elements has been confirmed. Interestingly, cis-regulatory element S449 is significantly enriched in the -1475∼-2013 bp and -1077∼-1475 bp regions of Os03g01700 promoter. The activities of several deletion derivatives of Os03g01700 promoter were analyzed using both transient expression and genetic transformation system. The results showed that the root-specific cis-acting elements might be present in the -2013 bp～-1475 bp and -1077 bp～-561 bp regions of Os03g01700 promoter. To determine the actual effect of root-specific expression of OsPT2, a construction consisting of Os03g01700 promoter and OsPT2 CDS was used to transform rice. Under Pi-sufficient condition, there were a series of symptoms of phosphorus toxicity in the shoots of OsPT2 over-expressing (Ov-OsPT2) seedlings. Under Pi-deficient condition, more soluble Pi was accumulated in the shoots of Ov-OsPT2 seedlings than that in the wild type. Our data provide a candidate root-specific promoter in the breeding of rice with high phosphorus uptake variety.

Molecular Characterization of WRKY Transcription Factors That Act as Negative Regulators of O-Methylated Catechin Biosynthesis in Tea Plants ( Camellia sinensis L.).

Tea O-methylated catechins, especially (-)-epigallocatechin 3- O-(3- O-methyl)gallate (EGCG3″Me), have been attracting much attention as a result of their positive health effects. The transcription regulators of O-methylated catechin biosynthesis remain elusive. In this study, the expression pattern of genes related to O-methylated catechin biosynthesis, including CsLAR, CsANS, CsDFR, CsANR, and CCoAOMT, in three tea cultivars with different contents of EGCG3″Me was investigated. Two WRKY transcription factors (TFs), designated as CsWRKY31 and CsWRKY48, belonging to groups IIb and IIc of the WRKY family, respectively, were further identified. CsWRKY31 and CsWRKY48 were nuclear-localized proteins and possessed transcriptional repression ability. Furthermore, expression of CsWRKY31 and CsWRKY48 showed negative correlation with CsLAR, CsDFR, and CCoAOMT during EGCG3″Me accumulation in tea leaves. More importantly, W-box (C/T)TGAC(T/C) elements were located in the promoter of CsLAR, CsDFR, and CCoAOMT, and further assays revealed that CsWRKY31 and CsWRKY48 were capable of repressing the transcription of CsLAR, CsDFR, and CCoAOMT via the attachment of their promoters to the W-box elements. Collectively, our findings identify two novel negative regulators of O-methylated catechin biosynthesis in tea plants, which might provide a potential strategy to breed high-quality tea cultivar.

Transcriptome analysis identifies the potential roles of long non-coding RNAs during parainfluenza virus infection.

Parainfluenza virus infection is a common respiratory illness in children. Although lncRNAs are novel regulators of virus-induced innate immunity, a systemic attempt to characterize the differential expression of lncRNAs upon parainfluenza virus infection is lacking. In this report, we identify 207 lncRNAs and 166 mRNAs differentially expressed in SeV-infected HEK293T cells by microarray. The functional annotation analysis reveals that differentially regulated transcripts are predominantly involved in the host antiviral response pathway. The lncRNAs with the potential to regulate SeV-induced antiviral response are identified by building the lncRNA-mRNA coexpression network. Furthermore, silencing lncRNA ENST00000565297 results in reduced type I IFN signaling upon SeV infection. These catalogs may facilitate future analysis of the functions of lncRNAs in innate immunity and related diseases.

Distinct Roles of Dopamine Receptors in the Lateral Thalamus in a Rat Model of Decisional Impulsivity.

The thalamus and central dopamine signaling have been shown to play important roles in high-level cognitive processes including impulsivity. However, little is known about the role of dopamine receptors in the thalamus in decisional impulsivity. In the present study, rats were tested using a delay discounting task and divided into three groups: high impulsivity (HI), medium impulsivity (MI), and low impulsivity (LI). Subsequent in vivo voxel-based magnetic resonance imaging revealed that the HI rats displayed a markedly reduced density of gray matter in the lateral thalamus compared with the LI rats. In the MI rats, the dopamine D1 receptor antagonist SCH23390 or the D2 receptor antagonist eticlopride was microinjected into the lateral thalamus. SCH23390 significantly decreased their choice of a large, delayed reward and increased their omission of lever presses. In contrast, eticlopride increased the choice of a large, delayed reward but had no effect on the omissions. Together, our results indicate that the lateral thalamus is involved in decisional impulsivity, and dopamine D1 and D2 receptors in the lateral thalamus have distinct effects on decisional impulsive behaviors in rats. These results provide a new insight into the dopamine signaling in the lateral thalamus in decisional impulsivity.

Nifedipine Increases Iron Content in WKPT-0293 Cl.2 Cells via Up-Regulating Iron Influx Proteins.

Nifedipine was reported to enhance urinary iron excretion in iron overloaded mice. However, it remains unknown how nifedipine stimulates urinary iron excretion in the kidney. We speculated that nifedipine might inhibit the TfR1/ DMT1 (transferrin receptor 1/divalent metal transporter1)-mediated iron uptake by proximal tubule cells in addition to blocking L-type Ca2+ channels, leading to an increase in iron in lumen-fluid and then urinary iron excretion. To test this hypothesis, we investigated the effects of nifedipine on iron content and expression of TfR1, DMT1 and ferroportin1 (Fpn1) in WKPT-0293 Cl.2 cells of the S1 segment of the proximal tubule in rats, using a graphite furnace atomic absorption spectrophotometer and Western blot analysis, respectively. We demonstrated for the first time that nifedipine significantly enhanced iron content as well as TfR1 and DMT1 expression and had no effect on Fpn1 levels in the cells. We also found that ferric ammonium citrate decreased TfR1 levels, increased Fpn1 expression and had no effect on DMT1 content, while co-treatment with nifedipine and FAC increase TfR1 and DMT1 expression and also had no effect on Fpn1 levels. These findings suggest that the nifedipine-induced increase in cell iron may mainly be due to the corresponding increase in TfR1 and DMT1 expression and also imply that the effects of nifedipine on iron transport in proximal tubule cells can not explain the increase in urinary iron excretion.

SCM-198 Ameliorates Cognitive Deficits, Promotes Neuronal Survival and Enhances CREB/BDNF/TrkB Signaling without Affecting Aß Burden in AßPP/PS1 Mice.

SCM-198 is an alkaloid found only in Herba leonuri and it has been reported to possess considerable neuroprotective effects in animal models of ischemic stroke, Parkinson's disease and Alzheimer's disease (AD). In this study, we demonstrated for the first time that 3-month oral SCM-198 treatment could significantly improve both recognition and spatial memory, inhibit microgliosis and promote neuronal survival in amyloid-ß protein precursor and presenilin-1(AßPP/PS1) double-transgenic mice without affecting amyloid-ß (Aß) burden. In addition, decreases in cAMP-response element-binding protein (CREB) phosphorylation, brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) phosphorylation were attenuated by SCM-198 both in vivo and in primary cortical neurons, which could be blocked by protein kinase A (PKA) inhibitors, suggesting the involvement of upstream PKA in enhancing the BDNF/TrkB/CREB signaling by SCM-198. Our results indicate that SCM-198, a drug that could promote neuronal survival and enhance BDNF/TrkB/CREB signaling, has beneficial effects on behavioral and biochemical alterations without affecting Aß burden in AßPP/PS1 mice and might become a potential drug candidate for AD treatment in the future.

Glycosylation of ent-kaurene derivatives and an evaluation of their cytotoxic activities.

AIM: To discover more active and water-soluble derivatives of tetracyclic diterpenoids containing an exo-methylene cyclopentanone or an α-methylenelactone moiety. METHODS: All of the key intermediates were synthesized from stevioside, and the target compounds were obtained through glycosylation of the 4-carboxyl group. The cytotoxicity of the target compounds against six human cancer cell lines, HepG2, Bel-7402, A549, U251, MCF-7 and MDA-MB-231, were evaluated by the MTT assay. RESULTS: Compound 1b was more effective than the positive control adriamycin against the HepG2, Bel-7402, A549, MCF-7, and MDA-MB-231 cell lines with IC50 values of 0.12, 0.91, 0.35, 0.08, and 0.07 µmol·L(-1), respectively. Moreover, compound 3c exhibited the most potent and selective cytotoxic activity against the HepG2 cell line (IC50, 0.01 µmol·L(-1)). CONCLUSION: Compounds 1b and 3c could be considered as potential anticancer candidates for further study.