Neuritogenic Activity Research Articles

Advances in the Synthesis of 3‐Acyl‐2‐Pyridones: Strategies and Methods for Accessing the Versatile Scaffold

ABSTRACTThe syntheses and bioevaluation of 3‐acyl‐2‐pyridones have garnered significant interest in recent years as a novel class of compounds with diverse biological activities. The bioactivities cover a wide range of therapeutic areas including antimicrobial, antitumor, anti‐inflammatory, antifungal, antibiotic, neuritogenic, cytotoxic, and antiviral activities. Therefore, 3‐acyl‐2‐pyridone scaffold offers a versatile platform for the development of new molecules with potential applications in medicinal chemistry. The recent exploration on synthesis and bioevaluation of 3‐acyl‐2‐pyridones has yielded promising results, making them attractive targets for further optimization and development of new therapeutic agents. This review summarizes the available information on total synthesis of 3‐acyl‐2‐pyridone containing natural products, and the other synthetic strategies developed for accessing the 3‐acyl pyridones such as multicomponent synthesis, condensation reaction, microwave‐assisted synthesis, catalytic hydrogenation reactions, metalation reaction, Michael addition, and formylation reactions. The presented information may serve as a valuable resource for researchers working in the field of medicinal chemistry and drug discovery, stimulating further exploration and development of this intriguing scaffold.

Acylhydrazone Derivative A5 Promotes Neurogenesis by Up-Regulating Neurogenesis-Related Genes and Inhibiting Cell-Cycle Progression in Neural Stem/Progenitor Cells.

Adult neurogenesis involves the generation of functional neurons from neural progenitor cells, which have the potential to complement and restore damaged neurons and neural circuits. Therefore, the development of drugs that stimulate neurogenesis represents a promising strategy in stem cell therapy and neural regeneration, greatly facilitating the reconstruction of neural circuits in cases of neurodegeneration and brain injury. Our study reveals that compound A5, previously designed and synthesized by our team, exhibits remarkable neuritogenic activities, effectively inducing neurogenesis in neural stem/progenitor cells (NSPCs). Subsequently, transcriptome analysis using high-throughput Illumina RNA-seq technology was performed to further elucidate the underlying molecular mechanisms by which Compound A5 promotes neurogenesis. Notably, comparative transcriptome analysis showed that the up-regulated genes were mainly associated with neurogenesis, and the down-regulated genes were mainly concerned with cell cycle progression. Furthermore, we confirmed that Compound A5 significantly affected the expression of transcription factors related to neurogenesis and cell cycle regulatory proteins. Collectively, these findings identify a new compound with neurogenic activity and may provide insights into drug discovery for neural repair and regeneration.

The expression system affects the binding affinity between p75NTR and proNGF

ProNGF (nerve growth factor) is a precursor of NGF and a signaling peptide exerting opposite effects on neuronal cells, i.e., apoptotic or neuritogenic. The conflicting biological activity of proNGF depends on the relative levels of two membrane receptors, TrkA and p75NTR. The effect of proNGF depends on the expression levels of these receptor proteins and their affinity to proNGF. Since the affinity of proteins has been studied with various recombinant proteins, it is worth comparing the affinity of these proteins within one experiment with the same method. This study examined the affinity between a recombinant proNGF and p75NTR expressed in common systems: bacterial, insect, and mammalian cells. The extracellular domain of p75NTR expressed in the insect or mammalian systems bound to native mature NGF, with a higher affinity for the insect receptor. The uncleavable proNGF was expressed in the three systems and they showed neuritogenic activity in PC12 cells. These recombinant proteins were used to compare their binding affinity to p75NTR. The insect p75NTR showed a higher binding affinity to proNGF than the mammalian p75NTR. The insect p75NTR bound proNGF from the insect system with the highest affinity, then from the mammalian system, and the lowest from the bacterial system. Conversely, the mammalian p75NTR showed no such preference for proNGF. Because the recombinant proNGF and p75NTR from different expression systems are supposed to have the same amino acid sequences, these differences in the affinity depend likely on their post-translational modifications, most probably on their glycans. Each recombinant proNGF and p75NTR in various expression systems exhibited different mobilities on SDS-PAGE and reactivities with glycosidases and lectins.

Chemoenzymatic Synthesis of GAA-7 Glycan Analogues and Evaluation of Their Neuritogenic Activities.

Ganglioside GAA-7 exhibits higher neurite outgrowth than ganglioside GM1a and most echinodermatous gangliosides (EGs) when tested on neuron-like rat adrenal pheochromocytoma (PC12) cells in the presence of nerve growth factor (NGF). The unique structure of GAA-7 glycan, containing an uncommon sialic acid (8-O-methyl-N-glycolylneuraminic acid) and sialic acid-α-2,3-GalNAc linkage, makes it challenging to synthesize. We recently developed a streamlined method to chemoenzymatically synthesize GAA-7 glycan and employed this modular strategy to efficiently prepare a library of GAA-7 glycan analogues incorporating N-modified or 8-methoxyl sialic acids. Most of these synthetic glycans exhibited moderate efficacy in promoting neuronal differentiation of PC12 cells. Among them, the analogue containing common sialic acid shows greater potential than the GAA-7 glycan itself. This result reveals that methoxy modification is not essential for neurite outgrowth. Consequently, the readily available analogue presents a promising model for further biological investigations.

Neuroprotective, neurite enhancing, and cholinesterase inhibitory effects of Lamiaceae family essential oils in Alzheimer’s disease model

IntroductionThe present study investigates the cholinesterase inhibitory and neuritogenic activities of selected essential oils from the Lamiaceae family, as well as their neuroprotective and antioxidant potential against scopolamine-induced cytotoxicity in SH-SY5Y cells. MethodsThe anticholinesterase activity was analysed using a modified Ellman’s assay. The neuroprotective potential was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Intracellular reactive oxygen species (ROS) levels were quantified using 2',7’- dichlorofluorescin diacetate assay. A neurite outgrowth assay was employed to evaluate the neuritogenic activity. ResultsOregano leaf (terpineol-type), peppermint leaf, rosemary, and sage essential oils have antibutyrylcholinesterase activity, while oregano leaf (phenol-type) essential oil has both acetylcholinesterase and butyrylcholinesterase inhibitory activities. Pretreatment with lavender flower essential oil (30 µg/mL), linalool, and linalyl acetate for 24 hours protects against scopolamine-induced toxicity. Linalool also displayed a significant decrease in intracellular ROS. The oregano leaf (terpineol-type), peppermint, rosemary, and sage essential oils at 100 µg/mL exhibited neuritogenic activity, with the highest activity being observed with oregano leaf (terpineol-type) essential oil. Discussion/ConclusionsEssential oils from plants of Lamiaceae family displayed anticholinesterase, neuroprotective, antioxidant, and neuritogenic activities. These properties demonstrate their potential as complementary treatments to prevent and/or delay dementia-related diseases such as Alzheimer’s disease.

The effect of the sulfation patterns of dermatan and chondroitin sulfate from vertebrates and ascidians on their neuritogenic and neuroprotective properties

Neurodegeneration is caused by the progressive loss of the structure and function of neurons, leading to cell death, and it is the main cause of many neurodegenerative diseases. Many molecules, such as glycosaminoglycans (GAGs), have been studied for their potential to prevent or treat these diseases. They are widespread in nature and perform an important role in neuritogenesis and neuroprotection. Here we investigated the neuritogenic and neuroprotective role of Phallusia nigra dermatan sulfate (PnD2,6S) and compared it with two distinct structures of chondroitin sulfate (C6S) and dermatan sulfate (D4S). For this study, a neuro 2A murine neuroblastoma cell line was used, and a chemical lesion was induced by the pesticide rotenone (ROT). We observed that PnD2,6S + ROT had a better neuritogenic effect than either C6S + ROT or D4S + ROT at a lower concentration (0.05 μg/mL). When evaluating the mitochondrial membrane potential, PnD2,6S showed a neuroprotective effect at a concentration of 0.4 μg/mL. These data indicate different mechanisms underlying this neuronal potential, in which the sulfation pattern is important for neuritogenic activity, while for neuroprotection all DS/CS structures had similar effects. This finding leads to a better understanding the chemical structures of PnD2,6S, C6S, and D4S and their therapeutic potential.

Chemoenzymatic Total Synthesis of the Neuritogenic Echinoderm Ganglioside LLG‐5 and Related Analogues

AbstractLLG‐5 1 is a Neu5Gc8Me‐containing echinoderm ganglioside (EG) isolated from starfish Linckia laevigata. It showed neuritogenic activity toward the rat adrenal pheochromocytoma cell line PC‐12. The first chemoenzymatic total synthesis of the trisialoganglioside LLG‐5 1 has been accomplished by utilizing a convergent [2+3] coupling between a Neu5Gc8Meα(2→5)Neu5Gc‐linked disialoside and a C5‐amino GM3 ceramide, Neu5NH2(2→3)Galβ(1→4)Glcβ‐Cer. A photoactivatable lactosyl phytosphingosine bearing a sulphonate moiety was developed to permit aqueous buffer solubility of the hydrophobic glycolipid acceptor for enzymatic α(2,3) sialylation. In addition, the synthetic route is flexible, allowing non‐natural LLG‐5 analogues in native lengths with or without modification at C8 of the terminal Neu5Gc and/or N‐acyl component, further expanding the diversity of LLG‐5 structures that could be achieved. The developed synthetic strategy may enable access to other EGs.magnified image

Unveiling the effect of Withania somnifera on neuronal cytoarchitecture and synaptogenesis: A combined in vitro and network pharmacology approach.

Withania somnifera (WS), is known for its remarkable contribution in herbal medicine and Ayurveda, which is therapeutically applied to improve memory and anxiety in patients. However, the pharmacological details of this plant on memory boosting yet remained undefined. This study provides mechanistic insights on the effect of ethanol solution extract of the whole plant of WS (WSEE) on neuritogenesis by combining in vitro and in silico network pharmacology approaches. WSEE promoted significant neuronal growth through early differentiation, axodendritic arborization, and synaptogenesis on primary hippocampal neurons. The network pharmacological study confirmed that the neuritogenic activity is potentially mediated by modulating the neurotrophin signaling pathway, where NRTK1 (TrkA) was revealed as the primary target of WS secondary metabolites. This neurotrophic activity of WSEE was significantly stifled by the presence of TrkA inhibitor, which further confirms the TrkA-dependent activity of WSEE. In addition, a molecular docking study suggested steroidal lactones present in the WS might act as nerve growth factor (NGF)-mimetics, activating TrkA by binding to the NGF-binding domain. As a whole, the findings of the study suggest a significant role of WSEE on neuritogenesis and its potential to function as a therapeutic agent and in drug designing for the prevention and treatment of memory-related neurological disorders.

Heat Shock Cognate 70 kDa Protein Is the Target of Tetradecyl 2,3-Dihydroxybenzoate for Neuritogenic Effect in PC12 Cells.

Tetradecyl 2,3-dihydroxybenzoate (ABG-001) is a lead compound derived from gentisides with a remarkable neuritogenic activity. However, the target of ABG-001 is yet to be defined to date. In this study, the potential target of ABG-001 was investigated via an activity-based protein profiling (ABPP) analysis, which is a chemical proteomic method for target identification by using chemical probes. Results indicated that the potential target proteins of ABG-001 were heat shock cognate 70 kDa protein (Hsc70), 78 kDa glucose-regulated protein (GRP78), and 14-3-3 theta protein. Then, the potential target of ABG-001 was confirmed by using inhibitors, the cellular thermal shift assay (CETSA) and small-interfering RNA (siRNA) analysis. The inhibitor of Hsc70 and siRNA significantly decreased the neurite outgrowth induced by ABG-001. Furthermore, ABG-001 induced neurite outgrowth was reduced by siRNA against Hsc70, and the results of CETSA suggested that Hsc70 showed a significant thermal stability-shifted effect upon ABG-001 treatment. These results indicated that Hsc70 is the target protein of ABG-001 in PC12 cells.

Investigation of the neuroprotective and neuritogenic effects of halotolerant Penicillium flavigenum-derived sorbicillin-like compounds on PC-12 Adh cells.

The online version contains supplementary material available at 10.1007/s10616-021-00498-9.

Neuritogenic Activities of Various Kappaphycus alvarezii Extracts in Hippocampal Neurons

The carrageenophyte Kappaphycus alvarezii seaweed is known to have neuritogenic activities. Post-harvest treatment of seaweed affects its biological activities. Five drying treatments of K. alvarezii, including oven-drying, sun-drying, freeze-drying, shade-drying, and salting followed by shade-drying, were evaluated for their effects on neuritogenic activities. We also evaluated the neuritogenic activity of different parts of K. alvarezii thalli and its carrageenan waste. Neuron cells of the 19th day pregnant rat fetuses were collected from the hippocampus by brain dissection. Neuron cells were isolated by dissociation of the hippocampal tissue. Cells were plated onto poly-DL-lysine-coated glass coverslips in 24-well plates and treated with extracts. All tested extracts were obtained from maceration using 95% ethanol. Freeze and shade-drying extracts exhibited significantly higher neuritogenic activities (p 0.05) compared to that of the vehicle control. Carrageenan waste also significantly promoted the neuritogenic activities (p 0.05) with an optimal dose at 1 µg mL-1. Old and young thalli showed insignificant differences in neuritogenic activities. The carrageenan waste extract retained neuritogenic activities. Thus, the utilization of carrageenan waste for neuritogenic material provides added value to the waste in the carrageenan industry. Freeze and shade dried K. alvarezii can be used as a neuritogenic agent to provide optimum biological activity.

Phytochemical Profiling and in vitro Screening for Neuritogenic and Antioxidant Activities of Spirulina platensis

Abstract: Background: In neurological diseases, neuronal loss is frequently associated with overproduction of free radicals and reduced level of endogenous neurotrophic factors. The blue-green microalga, Spirulina platensis is a well-known superfood with a high content of diverse nutrients and possesses several therapeutic properties. Here, we aimed to study the neuritogenic and antioxidant activities of Spirulina platensis UMACC 159. Materials and Methods: PC-12Adh (rat pheochromocytoma) cell was used to investigate the cytotoxicity effect of S. platensis UMACC 159 extracts (water, methanol, and ethanol) via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Neuritogenic activity of the extracts towards PC-12Adh cell line was studied using neurite outgrowth assay and immunofluorescence imaging of neurofilaments. The extracts were screened for the phytochemical contents, and antioxidant activities using 2,2’-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-Diphenyl-1- pircrylhydrazyl (DPPH) and reducing power. Results: Ethanol extract was found to exhibit the highest neuritogenic effect and enhanced the cytoskeleton formation in PC-12Adh cells at 6.25 μg/mL. Ethanol extract also showed the highest total phenolic content (49.09 ± 1.35 mg GAE/g), ABTS (EC50 of 1.34 ± 0.01 mg/mL) and DPPH (EC50 of 0.45 ± 0.04 mg/mL) scavenging activities (P ≤ 0.05), suggesting that the neuritogenic effect of ethanol extract was attributed to the phenolic compound(s) via antioxidant activity. Conclusion: Ethanol extract contains bioactive compound(s) with similar neuritogenic activity as nerve growth factor for neuronal survival, growth, and axonal regeneration. S. platensis has been proposed as a promising cognitive supplement. Key words: Spirulina platensis, Antioxidants, Cytotoxicity, Neuronal outgrowth, Phytochemicals.

The Insulin Receptor: A Potential Target of Amarogentin Isolated from Gentiana rigescens Franch That Induces Neurogenesis in PC12 Cells.

Amarogentin (AMA) is a secoiridoid glycoside isolated from the traditional Chinese medicine, Gentiana rigescens Franch. AMA exhibits nerve growth factor (NGF)-mimicking and NGF-enhancing activities in PC12 cells and in primary cortical neuron cells. In this study, a possible mechanism was found showing the remarkable induction of phosphorylation of the insulin receptor (INSR) and protein kinase B (AKT). The potential target of AMA was predicted by using a small-interfering RNA (siRNA) and the cellular thermal shift assay (CETSA). The AMA-induced neurite outgrowth was reduced by the siRNA against the INSR and the results of the CETSA suggested that the INSR showed a significant thermal stability-shifted effect upon AMA treatment. Other neurotrophic signaling pathways in PC12 cells were investigated using specific inhibitors, Western blotting and PC12(rasN17) and PC12(mtGAP) mutants. The inhibitors of the glucocorticoid receptor (GR), phospholipase C (PLC) and protein kinase C (PKC), Ras, Raf and mitogen-activated protein kinase (MEK) significantly reduced the neurite outgrowth induced by AMA in PC12 cells. Furthermore, the phosphorylation reactions of GR, PLC, PKC and an extracellular signal-regulated kinase (ERK) were significantly increased after inducing AMA and markedly decreased after treatment with the corresponding inhibitors. Collectively, these results suggested that AMA-induced neuritogenic activity in PC12 cells potentially depended on targeting the INSR and activating the downstream Ras/Raf/ERK and PI3K/AKT signaling pathways. In addition, the GR/PLC/PKC signaling pathway was found to be involved in the neurogenesis effect of AMA.

Investigating the Role of Guanosine on Human Neuroblastoma Cell Differentiation and the Underlying Molecular Mechanisms

Neuroblastoma arises from neural crest cell precursors failing to complete the process of differentiation. Thus, agents helping tumor cells to differentiate into normal cells can represent a valid therapeutic strategy. Here, we evaluated whether guanosine (GUO), a natural purine nucleoside, which is able to induce differentiation of many cell types, may cause the differentiation of human neuroblastoma SH-SY5Y cells and the molecular mechanisms involved. We found that GUO, added to the cell culture medium, promoted neuron-like cell differentiation in a time- and concentration-dependent manner. This effect was mainly due to an extracellular GUO action since nucleoside transporter inhibitors reduced but not abolished it. Importantly, GUO-mediated neuron-like cell differentiation was independent of adenosine receptor activation as it was not altered by the blockade of these receptors. Noteworthy, the neuritogenic activity of GUO was not affected by blocking the phosphoinositide 3-kinase pathway, while it was reduced by inhibitors of protein kinase C or soluble guanylate cyclase. Furthermore, the inhibitor of the enzyme heme oxygenase-1 but not that of nitric oxide synthase reduced GUO-induced neurite outgrowth. Interestingly, we found that GUO was largely metabolized into guanine by the purine nucleoside phosphorylase (PNP) enzyme released from cells. Taken together, our results suggest that GUO, promoting neuroblastoma cell differentiation, may represent a potential therapeutic agent; however, due to its spontaneous extracellular metabolism, the role played by the GUO-PNP-guanine system needs to be further investigated.

Sea urchin gangliosides exhibit neuritogenic effects in neuronal PC12 cells via TrkA- and TrkB-related pathways.

Gangliosides (GLSs) are ubiquitously distributed in all tissues but highly enriched in nervous system. Currently, it is unclear how exogenous GLSs regulate neuritogenesis, although neural functions of endogenous GLSs are widely studied. Herein, we evaluated the neuritogenic activities and mechanism of sea urchin gangliosides (SU-GLSs) in vitro. These different glycosylated SU-GLSs, including GM4(1S), GD4(1S), GD4(2A), and GD4(2G), promoted differentiation of NGF-induced PC12 cells in a dose-dependent and structure-selective manner. Sulfate-type and disialo-type GLSs exhibited stronger neuritogenic effects than monosialoganglioside GM1. Furthermore, SU-GLSs might act as neurotrophic factors possessing neuritogenic effects, via targeting tyrosine-kinase receptors (TrkA and TrkB) and activating MEK1/2-ERK1/2-CREB and PI3K-Akt-CREB pathways. This activation resulted in increased expression and secretion of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). These pathways were verified by specific inhibitors. Our results confirmed the neuritogenic functions of SU-GLS in vitro and indicated their potential roles as natural nutrition for neuritogenesis.

Genotoxicity Evaluation of Termite Mushroom, Termitomyces albuminosus (Agaricomycetes), Powder.

Termitomyces albuminosus, also known as termite mushroom, is a palatable mushroom with therapeutic effects that has been used as a food and folk medicinal ingredient. Recent studies revealed that T. albuminosus contains pharmacologically active factors that exert anti-inflammatory, antihyperlipidemic, antidiabetic, hepatoprotective, and neuritogenic activities, leading to its increasing popularity as a supplement among the general public. Despite the increase in its use, however, lack of knowledge on the toxicity of T. albuminosus has raised safety concerns. In this study, we systemically evaluated the genotoxicity of T. albuminosus powder (TAP) by testing its potential in generating bacterial reverse mutation, in vitro chromosome aberration, and in vivo micronuclei. TAP did not increase revertant colonies in the bacterial reverse mutation test nor the number of cells with aberrant chromosomes at 5000 μg/plate and micronucleus-containing polychromatic erythrocytes at 2000 mg/kg body weight in mice, indicating that TAP is not mutagenic nor clastogenic. Our results, together with the previous data from the general toxicity studies, indicate that TAP is safe for human consumption.

BACE1 Inhibitor, Neuroprotective, and Neuritogenic Activities of Melatonin Derivatives

Alzheimer’s disease (AD) is a common chronic neurodegenerative disorders. Melatonin (MLT) has been reported to be neuroprotective agent, and its modified structures exhibit potent antioxidant and anti-inflammation activities. Therefore, the activity of MLT and its derivatives against AD was investigated. Herein, the targeted enzymes, such as β-secretase (BACE1) and acetylcholinesterase (AChE), as well as the neuroprotective and neuritogenic effects on P19-derived neurons were evaluated. All the derivatives (1–5), including MLT, displayed potent inhibitory activity for BACE1, with inhibition values of more than 75% at 5 µM. A molecular docking study predicted that MLT, 5-MT, and 5 bound with BACE1 at catalytic amino acids Asp32 and the flap region, whereas 1–4 interacted with allosteric residue Thr232 and the flap region. The additional π-π interactions between 2, 3, and 5 with Tyr71 promoted ligand-enzyme binding. In addition, MLT, 1, 3, and 5 significantly protected neuron cells from oxidative stress by increasing the cell viability to 97.95, 74.29, 70.80, and 69.50% at 1 nM, respectively. Moreover, these derivatives significantly induced neurite outgrowth by increasing the neurite length and number. The derivatives 1, 3, and 5 should be thoroughly studied as potential AD treatment and neuroprotective agents.

Induction of differentiation of the acute myeloid leukemia cell line (HL-60) by a securinine dimer

Differentiation therapy has been successfully applied clinically in cases of acute promyelocytic leukemia (APL), but few differentiation-induction agents other than all-trans retinoic acid (ATRA) have been discovered clinically. Based on our previously reported neuritogenic differentiation activity of synthetic dimeric derivatives of securinine, we explored the leukemia differentiation-induction activity of such as compound, SN3-L6. It was found that SN3-L6 induces transdifferentiation of both acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML) cells but unexpectedly, a new transdifferentiation pathway from APL cells to morphologically and immunologically normal megakaryocytes and platelets were discovered. SN3-L6 fails to induce transdifferentiation of ATRA–produced mature granulocytes into megakaryocytes, indicating its selectivity between mature and immature cells. SN3-L6 induces CML K562 cells to transdifferentiate into apoptotic megakaryocytes but without platelet formation, indicating a desirable selectivity between different leukemia cells. Our data illuminate a differentiation gap between AML cells and platelets, and promises applications in leukemia differentiation therapy strategy.

Hp-s1 Ganglioside Suppresses Proinflammatory Responses by Inhibiting MyD88-Dependent NF-κB and JNK/p38 MAPK Pathways in Lipopolysaccharide-Stimulated Microglial Cells.

Hp-s1 ganglioside is isolated from the sperm of sea urchin (Hemicentrotus pulcherrimus). In addition to neuritogenic activity, the biological function of Hp-s1 in neuroinflammation is unknown. In this study, we investigated the anti-neuroinflammatory effect of Hp-s1 on lipopolysaccharide (LPS)-stimulated microglial cells. MG6 microglial cells were stimulated with LPS in the presence or absence of different Hp-s1 concentrations. The anti-inflammatory effect and underlying mechanism of Hp-s1 in LPS-activated microglia cells were assessed through a Cell Counting kit-8 assay, Western blot analysis, and immunofluorescence. We found that Hp-s1 suppressed not only the expression of inducible nitric oxide synthase and cyclooxygenase-2 but also the expression of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6. Hp-s1 inhibited the LPS-induced NF-κB signaling pathway by attenuating the phosphorylation and translocation of NF-κB p65 and by disrupting the degradation and phosphorylation of inhibitor κB-α (IκBα). Moreover, Hp-s1 inhibited the LPS-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). Hp-s1 also reduced the expression of myeloid differentiation factor 88 (MyD88) and TNF receptor-associated factors 6 (TRAF6), which are prerequisites for NF-κB and MAPKs activation. These findings indicated that Hp-s1 alleviated LPS-induced proinflammatory responses in microglial cells by downregulating MyD88-mediated NF-κB and JNK/p38 MAPK signaling pathways, suggesting further evaluation as a new anti-neuroinflammatory drug.

Total Synthesis of the Echinodermatous Ganglioside LLG-3 Possessing the Biological Function of Promoting the Neurite Outgrowth.

A total synthesis of echinodermatous ganglioside LLG-3 with neuritogenic activity was accomplished by a convergent strategy. The synthesis of 2-hydroxyethyl 8-O-Me-α-sialoside 2 was started from the phenyl 7,8-di-O-Pico-thiosialoside 5, which can be chemoselectively removed the picoloyl group, and then the methyl group in 8-O-MeNeu5Ac moiety was chemoselectively prepared using TMSCHN2/FeCl3. For preparation of the terminal disialic unit, oxidative amidation was initially utilized by our group to efficiently construct the α(2,11) linkage of 8-O-Me-Neu5Acα(2,11)Neu5Gc. Herein, we also demonstrate that the synthesized ganglioside LLG-3 exhibited the neuritogenic activity toward the primary cortical neurons and that biological activity is superior to that of ganglioside DSG-A.