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A novel norditerpenoid, sinusiaetone A (1), featuring an uncommon bicyclo[11.3.0]hexadecane carbon skeleton, and four polyoxygenated cembranoids (2-5) were isolated from the Hainan soft coral Sinularia siaesensis. Their structures were established by spectroscopic analysis, X-ray diffraction, quantum chemical computational approaches, and/or a modified Mosher's method. A plausible biosynthetic pathway of 1 and its biogenetic relationship with 2-5 were proposed. New compounds 1-3 displayed an interesting inhibitory activity against lipopolysaccharide-induced inflammation in BV-2 microglial cells.

Three new sesquiterpene polyol ester compounds angulatins S-U, together with three known compounds were isolated from Celastrus angulatus Maxim. According to mainly 1D NMR and 2D NMR analysis, the structures of the new compounds were completely determined as angulatin S (1β-furoyloxy-2β,8α-diisobutanoyloxy-9β-benzoyloxy-15-acetoxy-4α,6α-dihydroxy-β-dihydroagarofuran), angulatin T (1β,2β,6α-triacetoxy-8β,15-diisobutanoyloxy-9α-benzoyloxy-β-dihydroagrofuran), and angulatin U (1β,6α,15-triacetoxy-8β-isobutanoyloxy-9α-benzoyloxy-β-dihydroagarofuran).

Two eudesmane-guaiane/lindenane heterocoupled sesquiterpenoid dimers, horienoids A (1) and B (2) with new carbon skeletons, from Hedyosmum orientale were characterized by a combined method. Compound 1 featured a unique 2,10-dioxabicyclo[6.2.1]undecane core moiety with an anti-Bredt bridgehead double bond. Their biogenetic pathways were proposed to involve Diels-Alder and cascade rearrangement reactions as the key steps. Compound 2 exhibited a potent anti-inflammatory effect on LPS-induced BV-2 microglial cells.

Three new β-dihydroagarofuran sesquiterpene polyesters, angulatin O (1β,2β-difuroyloxy-8α-isobutanoyloxy-9β-benzoyloxy-15-acetoxy-4α,6α-dihydroxy-β-dihydroagarofuran), angulatin Q (1β,6α,15-triacetoxy-2β,9α-difuroyloxy-4α-hydroxy-8β-isobutanoyloxy-β-dihydro-agarofuran), and angulatin R (1β,2β,6α,15-tetracetoxy-8β-isobutanoyloxy-9α-benzoyloxy-β-dihydroagarofuran), as well as six related and known compounds, β-dihydroagarofuran sesquiterpene polyesters, were isolated from the root bark of Celastrus angulatus. Extensive spectroscopic studies were conducted to elucidate the structures of the new compounds. The IR, HRESI-MS, 1D, and 2D NMR techniques were used to characterise the compounds.

The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.

The chemical investigation of the South China Sea soft coral Sinularia humilis has resulted in the isolation of a library of diverse diterpenoids, including four new cembranoids, namely, humilisins A-D (1-4), two new uncommon diterpenoids possessing a tetradecahydrocyclopenta[3',4']cyclobuta[1',2':4,5]cyclonona[1,2-b]oxirene ring system, namely, humilisins E and F (5 and 6), and eight known related compounds (7-14). Humilisin A (1) is the first cembranoid with an ether linkage between C-3 and C-7. The structures and absolute configurations of 1-8 were determined by extensive spectroscopic data analyses, chemical reactions, and a series of quantum chemical calculations including quantum mechanical-nuclear magnetic resonance (QM-NMR), time-dependent density functional theory-electronic circular dichroism (TDDFT-ECD), and optical rotatory dispersion (ORD) methods. In bioassay, compound 6 displayed anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells.

Ischemic stroke is a severe disorder resulting from acute cerebral thrombosis. Here we demonstrated that post-ischemic treatment with ciclopirox olamine (CPX), a potent antifungal clinical drug, alleviated brain infarction, neurological deficits and brain edema in a classic rat model of ischemic stroke. Single dose post-ischemic administration of CPX provided a long-lasting neuroprotective effect, which can be further enhanced by multiple doses administration of CPX. CPX also effectively reversed ischemia-induced neuronal loss, glial activation as well as blood–brain barrier (BBB) damage. Employing quantitative phosphoproteomic analysis, 130 phosphosites in 122 proteins were identified to be significantly regulated by CPX treatment in oxygen glucose deprivation (OGD)-exposed SH-SY5Y cells, which revealed that phosphokinases and cell cycle-related phosphoproteins were largely influenced. Subsequently, we demonstrated that CPX markedly enhanced the AKT (protein kinase B, PKB/AKT) and GSK3β (glycogen synthase kinase 3β) phosphorylation in OGD-exposed SH-SY5Y cells, and regulated the cell cycle progression and nitric oxide (NO) release in lipopolysaccharide (LPS)-induced BV-2 cells, which may contribute to its ameliorative effects against ischemia-associated neuronal death and microglial inflammation. Our study suggests that CPX could be a promising compound to reduce multiple ischemic injuries; however, further studies will be needed to clarify the molecular mechanisms involved., Graphical abstract Ciclopirox olamine (CPX), a clinical antifungal drug, blocks ischemic damages induced by middle cerebral artery occlusion or oxygen glucose deprivation/lipopolysaccharide. Effects of CPX on AKT/GSK3β phosphorylation and cell cycle might contribute to ischemic neuronal damage and glial inflammation.Image 1

Traditional fermented soybean contains a variety of microflora. To obtain a comprehensive and accurate understanding of the microbial community structure and metabolic potential of fermented soybean, comparative metagenomics and metatranscriptomics were performed on a sample of fermented soybean in Yunnan Province. Metagenomic DNA and metatranscriptomic RNA were sequenced using Illumina HiseqTM2500, which yielded a total of 92,192,276 reads, with an average read length of 150 bp and 38,798,262 paired-end sequences, with an average length of 151 bp. The results show that Providencia stuartii was the most abundant species and the genes of carbohydrates (2296, 13.30%), protein metabolism (1530, 8.86%), and amino acids and amino acid derivatives (1423, 8.24%) were dominant. The expression levels of the genes belonging to amino acid transport and metabolism processes were the highest according to the reads per length of transcript in kilo-bases per million mapped reads (RPKM) values, followed by energy production and conversion and carbohydrate transport and metabolism. The metabolic pathways were primarily associated with carbohydrates, proteins and amino acids, which might be in accordance with the high levels of proteins and other nutrients in soybeans. Overall, these findings provide insights into the community structure and metabolic potential of the fermented soybean microbiome.

Our previous study had identified ciclopirox (CPX) as a promising lead compound for treatment of ischemic stroke. To find better neuroprotective agents, a series of N-hydroxypyridone derivatives based on CPX were designed, synthesized, and evaluated in this study. Among these derivatives, compound 11 exhibits significant neuroprotection against oxygen glucose deprivation and oxidative stress-induced injuries in neuronal cells. Moreover, compound 11 possesses good blood-brain barrier permeability and superior antioxidant capability. In addition, a complex of compound 11 with olamine-11·Ola possesses good water solubility, negligible hERG inhibition, and superior metabolic stability. The in vivo experiment demonstrates that 11·Ola significantly reduces brain infarction and alleviates neurological deficits in middle cerebral artery occlusion rats. Hence, compound 11·Ola is identified in our research as a prospective prototype in the innovation of stroke treatment.

The discovery of new therapeutic agents for ischemic stroke remains an urgent need. Here, we identified a novel phenyl carboxylic acid derivative, n-pentyl 4-(3,4-dihydroxyphenyl)-4-oxobutanoate (PDPOB), with anti-ischemic activities. The in vitro anti-ischemic neuroprotective and anti-inflammatory capacities of PDPOB were investigated using neuronal cells suffering from oxygen-glucose deprivation/reperfusion (OGD/R) and microglial cells stimulated by lipopolysaccharide (LPS). PDPOB attenuated the OGD/R-evoked cellular damage of SH-SY5Y cells and primary cortical neurons in a concentration-dependent manner. Likewise, PDPOB displayed protective roles against OGD/R-evoked multiaspect neuronal deterioration in SH-SY5Y cells, as evidenced by alleviated mitochondrial dysfunction, oxidative stress, and apoptosis. A further study unveiled the accelerated phosphorylation of protein kinase B (AKT) by PDPOB treatment, while blockade of phosphoinositide 3-kinase (PI3K)/AKT signaling substantially diminished the neuroprotective capacities of PDPOB. Additionally, the PDPOB pretreatment dampened the LPS-evoked neuroinflammation in BV2 cells, characterized by the suppressed secretion of nitric oxide (NO) and proinflammatory cytokines, as well as normalized expression of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Western blotting further revealed that PDPOB abated the overabundant phosphorylation of the extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK), and p38 in LPS-exposed BV2 cells. The intravenous application of PDPOB (30 mg/kg, single dose) attenuated ipsilateral cerebral infarction in middle cerebral artery occlusion (MCAO) rats, accompanied by recovered neurological behaviors. Collectively, the above observations provided substantial evidence for the favorable properties and mechanistic explanations of PDPOB in the regulation of ischemia-associated neuronal injury and microglial inflammation, which may furnish ideas for the discovery of new therapeutic strategies against cerebral ischemia.

A novel diterpenoid, sinunanolobatone A (1), featuring an unprecedented bicyclo[13.1.0]pentadecane carbon framework, along with two new casbane diterpenoids (2 and 3), and five known related ones (4-8) were isolated from the Sanya soft coral Sinularia nanolobata. The structures of the new compounds were established by detailed spectroscopic analysis, X-ray diffraction analysis, chemical reactions, or a quantum chemical computation method. A plausible biosynthetic pathway of 1 was proposed. In bioassay, the novel compound 1 showed significant inhibitory activity against lipopolysaccharide (LPS) induced inflammation in BV-2 microglial cells.

Twenty-one dihydro-β-agarofuran derivatives were purified from the seeds of Euonymus maackii, and eight compounds (1-8) were identified as new natural products. Their structures were deduced by extensive spectroscopic analysis, X-ray diffraction studies, and comparison of observed and reported NMR data. Compounds 10, 12, 17, and 18 significantly increased the cell viability of Aβ25-35-treated SH-SY5Y cells with effects similar to that of epigallocatechin gallate (EGCG). In addition, the abundant compound 9 reduced the seizure-like locomotor activity of zebrafish at 10 μM compared with a pentylenetetrazol-treated group.

Abnormal protein aggregation has been linked to many neurodegenerative diseases, including Parkinson’s disease (PD). The main pathological hallmark of PD is the formation of Lewy bodies (LBs) and Lewy neurites, both of which contain the presynaptic protein alpha-synuclein (α-syn). Under normal conditions, native α-syn exists in a soluble unfolded state but undergoes misfolding and aggregation into toxic aggregates under pathological conditions. Toxic α-syn species, especially oligomers, can cause oxidative stress, membrane penetration, synaptic and mitochondrial dysfunction, as well as other damage, leading to neuronal death and eventually neurodegeneration. Early diagnosis and treatments targeting PD pathogenesis are urgently needed. Given its critical role in PD, α-syn is an attractive target for the development of both diagnostic tools and effective therapeutics. This review summarizes the progress toward discovering imaging probes and aggregation inhibitors for α-syn. Relevant strategies and techniques in the discovery of α-syn-targeted drugs are also discussed.

A new polyoxometalate-based coordination polymer, Ag2(L)2(VW12O40)][Ag2(L)2]·4H2O (1) {L = 3,5-di(1H-1,2,4-triazol-1-yl)benzoic acid}, has been isolated under hydrothermal conditions and characterized by routine methods. Compound 1 exhibits an interesting 1D + 1D polypseudo-rotaxane architecture, as shown by X-ray diffraction analysis. The new compound represents a scarce example of 1D + 1D polypseudo-rotaxane architecture, namely, ladder motifs are threaded by zigzag chains rather than a straight one. The coordination stability around loop and thread motifs was investigated to expatiate on the zigzag chained polypseudo-rotaxane. In addition, crystal 1 can be used as a packing material to selectively adsorb cationic dyes such as crystal violet (CV) and methylene blue (MB) concomitant with methyl orange anionic dyes with high uptakes and rapid adsorption rate.

Catalytic diastereo- and enantioselective hydroalkenylation of 3,3-disubstituted cyclopropenes with readily accessible alkenylboronic acids, promoted by a chiral phosphine/Co complex, is presented. Such a process constitutes the unprecedented and direct introduction of a wide range of alkenyl groups onto the cyclopropane motif to afford multisubstituted cyclopropanes in up to 95 % yield with greater than 95:5 d.r. and 99:1 e.r. Functionalization of the products delivered enantioenriched cyclopropanes that are otherwise difficult to access.

Two new sesquiterpene pyridine alkaloids, Chinese bittersweet alkaloid A (1) and Chinese bittersweet alkaloid B (2), together with five known compounds 3β- hydroxyolean-9(11),12-diene, β-si...

Based on SPME‐GC‐MS analysis, it could be found that the production of acetic acid, phenethyl acetate, and isoamyl acetate gradually increased in the apple vinegar fermentation broth with the fermentation time. Consequently, in order to systematically explore the dynamic changes of microbial diversity and metabolites in the process of apple vinegar fermentation, 16S rDNA were sequenced and analyzed in this work. The present results showed that bacterial diversity was rich and exhibited a certain variation during the dynamic fermentation process of apple vinegar. Furthermore, Lactococcus and Oenococcus were the predominant bacteria in the pre‐fermentation (alcoholic fermentation) of apple vinegar, while the dominant bacteria in the middle and late fermentation stages (acetic acid fermentation) were Lactococcus and Acetobacter. In addition, during the whole fermentation process of apple vinegar, Lactococcus was the most dominant bacteria, Oenococcus was the unique species in the stage of alcohol fermentation, and Acetobacter increased rapidly in the stage of acetic acid fermentation. In conclusion, our finding provided a theoretical basis for the processing technology of apple vinegar fermentation, and a theory evidence for the safety and health assessment of apple vinegar.

Primary dysmenorrhea is a common disease among females in their reproductive age and adolescents. The main complaint is lower abdominal pain during menstruation. Females, who suffer from dysmenorrhea, widely use nonsteroidal anti-inflammatory drugs that reduce muscle spasm by inhibiting prostaglandin synthesis and vasopressin secretion. However, there are side effects when patients take them for a long time. It is therefore against this backdrop that herbal medicines are suggested as an alternative source of treatment for primary dysmenorrhea. In this paper, a review of studies demonstrating the relieving of uterine contraction and reduction in prostaglandin synthesis by alternative sources such as traditional Chinese medicines (TCM) is spelt out. TCM conceptualizes that, menstrual pain resulting from qi is due to stagnated and retained blood. Blood deficiency and coldness in the whole human body are two additional causes of dysmenorrhea. Therefore, based on these, the main focus of treatment is directed at relieving the above symptoms. Chinese herbal prescriptions exert their effects through these mechanisms: prostaglandin reduction, inhibition of cyclooxygenase, intracellular Ca2+, and nitric oxide, declining malondialdehyde, and reverse increasing superoxide dismutase. Hence, Chinese herbal prescriptions, present perhaps a more beneficial efficacious alternative in the treatment of primary dysmenorrhea, more especially in the confines of complementary and alternative medicine.

Based on a multitarget strategy, a series of novel tacrine-pyrimidone hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation results demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and glycogen synthase kinase 3 (GSK-3). The optimal compound 27g possessed excellent dual AChE/GSK-3 inhibition both in terms of potency and equilibrium (AChE: IC50 = 51.1 nM; GSK-3β: IC50 = 89.3 nM) and displayed significant amelioration on cognitive deficits in scopolamine-induced amnesia mice and efficient reduction against phosphorylation of tau protein on Ser-199 and Ser-396 sites in glyceraldehyde (GA)-stimulated differentiated SH-SY5Y cells. Furthermore, compound 27g exhibited eligible pharmacokinetic properties, good kinase selectivity, and moderate neuroprotection against GA-induced reduction in cell viability and neurite damage in SH-SY5Y-derived neurons. The multifunctional profiles of compound 27g suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.

Due to the redox properties closely related to numerous physiological and pathological processes, biothiols, including cysteine (Cys), homocysteine (Hcy) and glutathione (GSH), have received considerable attention in biological science. On account of the important physiological roles of these biothiols, it is of profound significance to develop sensitive and selective detection of biothiols to understand their biological profiles. In this work, we reported an efficient fluorescent probe, PHPQ-SH, for detecting biothiols in vitro and vivo, based on the phenothiazine-HPQ skeleton, with DNBS (2,4-dinitrobenzenesulfonate) as the response unit. Probe PHPQ-SH exhibited brilliant sensing performances toward thiols, including a large Stokes shift (138 nm), excellent sensitivity (for GSH, LOD = 18.3 nM), remarkable fluorescence enhancement (163-fold), low cytotoxicity, rapid response (8 min), and extraordinary selectivity. Finally, the probe PHPQ-SH illustrated herein was capable of responding and visualizing biothiols in MCF-7 cells and zebrafish.

28-O-caffeoyl betulin (B-CA) has been demonstrated to reduce the cerebral infarct volume caused by transient middle cerebral artery occlusion (MCAO) injury. B-CA is a novel derivative of naturally occurring caffeoyl triterpene with little information associated with its pharmacological target(s). To date no data is available regarding the effect of B-CA on brain metabolism. In the present study, a 1H-NMR-based metabolomics approach was applied to investigate the therapeutic effects of B-CA on brain metabolism following MCAO in rats. Global metabolic profiles of the cortex in acute period (9 h after focal ischemia onset) after MCAO were compared between the groups (sham; MCAO + vehicle; MCAO + B-CA). MCAO induced several changes in the ipsilateral cortex of ischemic rats, which consequently led to the neuronal damage featured with the downregulation of NAA, including energy metabolism dysfunctions, oxidative stress, and neurotransmitter metabolism. Treatment with B-CA showed statistically significant rescue effects on the ischemic cortex of MCAO rats. Specifically, treatment with B-CA ameliorated the energy metabolism dysfunctions (back-regulating the levels of succinate, lactate, BCAAs, and carnitine), oxidative stress (upregulating the level of glutathione), and neurotransmitter metabolism disturbances (back-regulating the levels of γ-aminobutyric acid and acetylcholine) associated with the progression of ischemic stroke. With the administration of B-CA, the levels of three phospholipid related metabolites (O-phosphocholine, O-phosphoethanolamine, sn-glycero-3-phosphocholine) and NAA improved significantly. Overall, our findings suggest that treatment with B-CA may provide neuroprotection by augmenting the metabolic changes observed in the cortex following MCAO in rats.

Domino cyclization reactions of N-aryl-1,4- and 1,5-benzoxazepine derivatives involving [1,5]-hydride shift or C(sp2)-H functionalization were investigated. Neuroprotective and acetylcholinesterase activities of the products were studied. Domino Knoevenagel-[1,5]-hydride shift-cyclization reaction of N-aryl-1,4-benzoxazepine derivatives with 1,3-dicarbonyl reagents having active methylene group afforded the 1,2,8,9-tetrahydro-7bH-quinolino [1,2-d][1,4]benzoxazepine scaffold with different substitution pattern. The C(sp3)-H activation step of the tertiary amine moiety occurred with complete regioselectivity and the 6-endo cyclization took place in a complete diastereoselective manner. In two cases, the enantiomers of the chiral condensed new 1,4-benzoxazepine systems were separated by chiral HPLC, HPLC-ECD spectra were recorded, and absolute configurations were determined by time-dependent density functional theory- electronic circular dichroism (TDDFT-ECD) calculations. In contrast, the analogue reaction of the regioisomeric N-aryl-1,5-benzoxazepine derivative did not follow the above mechanism but instead the Knoevenagel intermediate reacted in an SEAr reaction [C(sp2)-H functionalization] resulting in a condensed acridane derivative. The AChE inhibitory assays of the new derivatives revealed that the acridane derivative had a 6.98 &mu, M IC50 value.

Fluorescent imaging of β-amyloid (Aβ) is one of the most promising methods for Alzheimer's disease diagnosis. Several fluorescent probes have been reported to detect Aβ both in vitro and in vivo. However, highly sensitive and highly selective probes with low background signals are still greatly needed. Herein, we rationally designed and synthesized a PIET quenched near-infrared probe QAD-1 to detect Aβ. This probe contains BODIPY as fluorophore and tetrahydroquinoxaline as the quenching group. QAD-1 exhibited significant fluorescent switch-on after binding to soluble and insoluble Aβ species, and the probe had the benefit of low background signal to stain Aβ plaques without the need of wash-out procedures in vitro, which was specially found by the fluorescence off-on probe. QAD-1 could identify the overproduced Aβ in transgenic (APPSWE/PSEN 1dE9) AD mice as early as 6 months old in vivo, which indicated that QAD-1 may be a potential probe for monitoring Aβ species at an early stage of AD.

Seven new acetophenone derivatives, three couples of enantiomers (±)-cynwilforones D − F (1 − 3) together with cynwilforone G (4), were isolated form the root bark of Cynanchum wilfordii (Maxim.) Hemsl. Their structures were deduced based on spectroscopic analysis and X-ray crystallography. Each racemate was separated into individual enantiomers, and electronic circular dichroism (ECD) calculations were used to assign their absolute configurations. All compounds exhibited inhibitory effect of Aβ oligomerization in different degrees. Among them, (+)-3 and (−)-3 showed neuroprotective effects on Aβ oligomers-treated SH-SY5Y cells.

A series of novel propargylamine-modified pyrimidinylthiourea derivatives ( 1–3 ) were designed and synthesized as multifunctional agents for Alzheimer's disease (AD) therapy, and their potential was evaluated through various biological experiments. Among these derivatives, compound 1b displayed good selective inhibitory activity against AChE ( vs BuChE, IC 50 = 0.324 μM, SI > 123) and MAO-B ( vs MAO-A, IC 50 = 1.427 μM, SI > 35). Molecular docking study showed that the pyrimidinylthiourea moiety of 1b could bind to the catalytic active site (CAS) of AChE, and the propargylamine moiety interacted directly with the flavin adenine dinucleotide (FAD) of MAO-B. Moreover, 1b demonstrated mild antioxidant ability, good copper chelating property, effective inhibitory activity against Cu 2+ -induced A β 1−42 aggregation, moderate neuroprotection, low cytotoxicity, and appropriate blood−brain barrier (BBB) permeability in vitro and was capable of ameliorating scopolamine-induced cognitive impairment in mice. These results indicated that 1b has the potential to be a multifunctional candidate for the treatment of Alzheimer's disease.

In the original version of this article, unfortunately the Fig. 3C and 3F were published with incorrect version. The correct version of the Fig. 3C and 3F are given below. This has been corrected by publishing this correction article. The original article has been corrected.

Hypochlorite (ClO−), as a typical weak acidic ROS, is mainly endogenously produced by myeloperoxidase (MPO) catalyzing hydrogen peroxide (H2O2) and chloride ion (Cl−) in leukocytes. Imbalance of hypochlorite concentration will not only cause biomolecular oxidation in organism, but also are correlated with a variety of physiological diseases. In this study, a novel ratiometric fluorescence probe PHPQ for detecting ClO- by incorporating the phenothiazine moiety into the HPQ fluorophore was designed and synthesized. The probe PHPQ was shown to be capable of selectively and sensitively monitoring ClO- in a fine ratiometric manner. It also displayed the merits of large blue-shift (98 nm), rapid response (30 s), excellent sensitivity (15 nM) and significant fluorescence ratiometric variations (253-fold). Moreover, PHPQ was successfully utilized for bioimaging exogenous/endogenous ClO- in living cells (MGC-803 and RAW264.7) and in zebrafish.

A series of new benzothiazol-based 1,3,4-oxadiazole derivatives were synthesized and evaluated for their neuroprotective effects against Aβ25–35-induced toxicity in SH-SY5Y cells. The bioassay results indicated that most of the tested compounds exhibited promising neuroprotective activity. In particular, compound 2-[[[5-[(4-bromophenylmethyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole showed the most potent activity (95.7% of cell viability at 10 μM), better than the positive control EGCG (90.7% of cell viability at 10 μM). Furthermore, compounds 2-[[[5-[(2-bromophenylmethyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole, 2-[[[5-[(4-bromo-2-fluorophenylmethylyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole, and 2-[[[5-[(4-methoxyphenylmethyl)thio]-1,3,4-oxadiazol-2-yl]methyl]thio]benzothiazole displayed neuroprotective activity similar to EGCG (87.7, 89.1, and 87.7% of cell viability, respectively, at 10 μM). The preliminary SARs analysis indicated that benzene ring is the key factor for the neuroprotective activity and the bromo atom substituted at 4-position of the benzene ring favors the neuroprotective activity. In addition, the fluoro group in the benzene ring appears not beneficial for the neuroprotective activity.

This paper presents an experimental study on the chemical erosion resistance of geopolymer mortar (GM) to sulphuric acid and sodium chloride attacks. The variations of mechanical properties and mass of geopolymer mortar after soaked in water, sodium chloride and sulphuric acid solutions for different durations (30, 60, 90, 180, 270 and 360 days) were investigated. The test results showed that geopolymer mortar had good resistance to sodium chloride and sulfuric acid erosion solutions. The maximum degradation in flexural, compressive and tensile strength of geopolymer mortar soaked in sodium chloride and sulphuric acid solutions, during the whole soaking duration (360 days) was 6%, 11% and 15% respectively, compared to that in tap water. The strength fluctuation of geopolymer mortar in sulphuric acid solutions was higher than that in sodium chloride solutions. At the first 60 days of immersion, the compressive and tensile strength of geopolymer mortar in tap water, sodium chloride solutions and sulphuric acid solutions decreased, but its strength restored again after 60 days.

The effective imaging of amyloid β (Aβ) in vivo is important for the diagnosis of Aβ-related diseases such as the Alzheimer's disease (AD). Here we report a donor-acceptor-donor (D-A-D) type fluorogenic probe for the rapid imaging of amyloid β (Aβ) senile plaques in a transgenic mouse brain. The probe that features a dicyanomethylene-4H-pyran (DCM) core shows a concentration-dependent fluorescence enhancement with Aβ42 and Aβ40, which are the main components of Aβ fibrils formed in the brain of AD patients. The D-A-D probe can also be used to rapidly sense Aβ peptide monomer, oligomer and fibril in an aqueous solution and image the morphologically diverse Aβ species by confocal microscopy. In particular, we demonstrate that the probe can be used to rapidly stain Aβ senile plaques in the brain of transgenic mice by intravenous injection.

Five previously undescribed lycodine-type alkaloids, named huperzine Y (1), 8,15-epoxy-N-demethylhuperzinine (2), 7-hydroxyl-huperzinine (3), huperzine Z (4), and huperzine D N-oxide (5), were isolated from the aerial parts and roots of Lycopodiastrum casuarinoides (Lycopodiaceae), along with ten known analogues. The structures of the new compounds were elucidated by means of spectroscopic technique (IR, UV, MS and NMR). The absolute configurations of the new compounds were established on the basis of comparison of their experimental and TD-DFT (time-dependent density functional theory) calculated ECD spectra. Moreover, all the isolates were evaluated for acetylcholinesterase (AChE) inhibitory activity. Only huperzine C showed moderate activity, with an IC50 value of 0.525 ± 0.140 μM, which was comparable with the positive control, huperzine A (IC50 = 0.143 ± 0.029 μM).

High-fidelity mapping of amyloid-β (Aβ) plaques is critical for the early detection of Alzheimer’s disease. However, in vivo probing of Aβ plaques by commercially available thioflavin derivatives (ThT or ThS) has proven to be extremely limited, as evident by the restriction of enrichment quenching effect, low signal-to-noise (S/N) ratio, and poor blood–brain barrier (BBB) penetrability. Herein, we demonstrate a rational design strategy of near-infrared (NIR) aggregation-induced emission (AIE)-active probes for Aβ plaques, through introducing a lipophilic π-conjugated thiophene-bridge for extension to NIR wavelength range with enhancement of BBB penetrability, and tuning the substituted position of the sulfonate group for guaranteeing specific hydrophilicity to maintain the fluorescence-off state before binding to Aβ deposition. Probe QM-FN-SO3 has settled well the AIE dilemma between the lipophilic requirement for longer emission and aggregation behavior from water to protein fibrillogenesis, thus making ...

A new coordination polymeric chains modified polyoxometalate, H3K2[Ag5(DTB)5][SiW12O40]2·Cl2·8H2O (1) {DTB ​= ​1,4-di(1H-1,2,4-triazol-1-yl)benzene}, has been successfully synthesized under hydrothermal conditions. Single crystal X-ray diffraction analyses reveal that the Keggin POM cluster is modified by {Ag(DTB)}n chains in an unusually [2 ​+ ​4] asymmetrical mode resulting in a 2D double layer structure. By connection of K cations and π···π interactions between adjacent {Ag(DTB)}n coordination polymeric chains, the 2D structure extends to a 3D structure. In addition, crystal 1 can be used as a packing material for the highly selective adsorption and separation cationic dyes such as methylene blue (MB) and crystal violet (CV) against with methyl orange (MO) anionic dyes. The adsorption of a series of cationic organic dyes experiment demonstrated that this process is highly related to the sizes of organic dyes.

Four new lathyrane-type diterpenoids (1-4) and a novel macrocyclic diterpenoid (5) featuring a 5/7/7/4-fused ring system, together with seventeen known ones (6-22), were isolated from the seeds of Euphorbia lathyris. Their structures were elucidated by extensive spectroscopic analyses and single crystal X-ray crystallography. These isolates were evaluated for their inhibition against nitric oxide (NO) production induced by lipopolysaccharide (LPS) in BV-2 microglial cells. As a result, the inhibitory rates of compounds 1, 3, 4, 6, 7, 9-11, 13-15, 20, and 21 on NO production were more than 40% with the cell viability more than 80% at their effective concentrations. In addition, compounds 6 and 11 markedly reduced the mRNA levels of pro-inflammatory cytokines IL-6 and IL-1β in LPS-stimulated BV-2 cells.

The use of traditional two-part geopolymers is limited to small scale engineering applications, due to difficulties with the transportation, storage and prefabrication of alkaline activator solutions. In this study, “just adding water” or one-part geopolymers were developed using solid activators. Flow tests, flexural and compressive strength tests were carried out on a number of one-part and two-part geopolymer mortar specimens to evaluate the effect of concentration, modulus and type of activators on the workability and mechanical properties of geopolymer mortar. The reaction heat during the first 7 curing days and the degree of reaction of one-part and its two-part geopolymer counterparts were measured to compare their reaction mechanism. The test results showed that the flexural and compressive strengths of one-part geopolymer mortar specimens were 88%-94% and 65%-95% respectively, of the corresponding strengths of the two-part counterparts. The results also revealed that anhydrous sodium silicate (Na2SiO3) is a more effective solid activator than the combination of hydrous Na2SiO3 and sodium hydroxide (NaOH) for metakaolin and fly ash blending precursor. Due to a higher degree of geopolymerization reaction, the highest compressive strength of one-part geopolymer mortar using anhydrous Na2SiO3 with modulus of 1.4, reached 49.2 MPa after 7-day ambient temperature curing. When using a combination of solid hydrous Na2SiO3 and NaOH as an activator, the strength difference between one-part and its corresponding two-part geopolymer mortar specimens decreased with an increase in the modulus of the activator.

Four fawcettimine-type (palhicerines A-D, resp.) and two lycopodine-type (palhicerines E and F) Lycopodium alkaloids together with twenty known ones were isolated from the whole plant of Palhinhaea cernua. The structures and absolute configurations of the palhicerines A-F were determined by extensive spectroscopic methods, single-crystal X-ray diffraction analyses, chemical transformation, and electronic circular dichroism (ECD) calculations or induced electronic circular dichroism (IECD) spectra. Among the isolates, the new C/D-ring of the palhicerines A-C (trans-fused fawcettimine-type alkaloids) are rare, and each possesses a β-oriented C-16 methyl group and a distinctive tertiary methoxy group at C-13. Chemotaxonomy for differentiating species in the genus Palhinhaea is briefly discussed.

Starting from a screening-hit compound, via structure modifications and optimizations, a series of nonfused and nonassembly pyrimidinylthiourea derivatives (2-5) was designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease. Biological activity results demonstrated that compounds 5r and 5t exhibited potent inhibition and excellent selectivity toward acetylcholinesterase (AChE, 5r, IC50 = 0.204 μM, SI196; 5t, IC50 = 0.067 μM, SI597), specific metal-chelating ability, significant antioxidant effects, modulation of metal-induced Aβ aggregation, inhibition of ROS production by copper redox cycle, low cytotoxicity, and moderate neuroprotection to human neuroblastoma SH-SY5Y cells. Moreover, compound 5r displayed appropriate blood-brain barrier (BBB) permeability both in vitro and in vivo and could improve memory and cognitive function of scopolamine-induced amnesia mice. The multifunctional profiles of 5r and its effectivity in AD mice highlight these structurally distinct pyrimidinylthiourea derivatives as prospective prototypes in the research of innovative multifunctional drugs for Alzheimer's disease.

Three novel 7,8-seco-lycopodane-derived 8,5-lactones (annotinolides A-C, 1-3) were isolated from Lycopodium annotinum. Their structures were elucidated by spectroscopic methods and single-crystal X-ray diffraction. Compound 1 possesses an unusual cyclopropane ring constructed through a hitherto unknown C-6/C-12 bond. Compound 2 represents the first 7,8-seco-lycopodane-derived alkaloid with a rare cyclobutane ring formed by a new C-12/C-15 linkage, while the C-8/C-15 bond remains. Compound 3 contains an unprecedented 12-spiro-9,12-γ-lactone moiety. Their plausible biosynthetic pathways and antiaggregation effects on amyloid-β1-42 are also presented.

Iron dyshomeostasis is one of the primary causes of neuronal death in Alzheimer's disease (AD). Huperzine A (HupA), a natural inhibitor of acetylcholinesterase (AChE), is a licensed anti-AD drug in China and a nutraceutical in the United Sates. Here, we investigated the protective effects of HupA against iron overload-induced injury in neurons. Rat cortical neurons were treated with ferric ammonium citrate (FAC), and cell viability was assessed with MTT assays. Reactive oxygen species (ROS) assays and adenosine triphosphate (ATP) assays were performed to assess mitochondrial function. The labile iron pool (LIP) level, cytosolic-aconitase (c-aconitase) activity and iron uptake protein expression were measured to determine iron metabolism changes. The modified Ellman's method was used to evaluate AChE activity. HupA significantly attenuated the iron overload-induced decrease in neuronal cell viability. This neuroprotective effect of HupA occurred concurrently with a decrease in ROS and an increase in ATP. Moreover, HupA treatment significantly blocked the upregulation of the LIP level and other aberrant iron metabolism changes induced by iron overload. Additionally, another specific AChE inhibitor, donepezil (Don), at a concentration that caused AChE inhibition equivalent to that of HupA negatively, influenced the aberrant changes in ROS, ATP or LIP that were induced by excessive iron. We provide the first demonstration of the protective effects of HupA against iron overload-induced neuronal damage. This beneficial role of HupA may be attributed to its attenuation of oxidative stress and mitochondrial dysfunction and elevation of LIP, and these effects are not associated with its AChE-inhibiting effect.

Nineteen compounds mainly including pyrrole-containing alkaloids and phytosterols were isolated from the EtOH extract of the fermented mycelia of Xylaria nigripes, a precious medicinal fungus known as Wuling Shen in Chinese. On the basis of spectroscopic methods, the structures of the new naturally occurring compounds were determined to be (4S)-3,4-dihydro-4-(4-hydroxybenzyl)-3-oxo-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbaldehyde (1), methyl (2S)-2-[2-formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl]-3-(4-hydroxyphenyl)propanoate (2), and 3-{4-[(2R)-(2,3-dihydroxy-3-methylbutoxy]phenyl}-7-hydroxy-4H-chromen-4-one (3), respectively. The absolute configurations of 1 and 2 were deduced by the observed Cotton effects in their circular dichroism (CD) spectra, whereas that of the 1,2-diol moiety in 3 was determined using the Snatzke's method. Their biological activities such as neuroprotective, anti-neuroinflammatory, and cytotoxic properties were also reported.

Ethnopharmacological relevance Many bioactive constituents of Chinese herbal medicines have poor oral bioavailability. Besides oral administration, herbal medicines in China are also prepared for parenteral administration. Unlike for intravenous route, little is known about the intramuscular pharmacokinetics of herbal compounds. To facilitate rational use of herbal medicine, it is important to better understand such intramuscular pharmacokinetics. Aim of the study Bioactive constituents of XueShuanTong (a lyophilized extract of Panax notoginseng roots, extensively used in treatment of ischemic heart and cerebrovascular diseases) predominantly comprise ginsenosides Rb1 and Rd of 20(S)-protopanaxadiol-type and ginsenosides Rg1, and Re, and notoginsenoside R1 of 20(S)-protopanaxatriol-type; these saponins are poorly absorbed from the gastrointestinal tract. This study aimed to compare intramuscular and intravenous pharmacokinetics of these ginsenosides after dosing XueShuanTong. Methods Pharmacokinetics of ginsenosides was assessed in human volunteers receiving an intramuscular injection or 1.5-h intravenous infusion of XueShuanTong, both at 150 mg/person, and the plasma and urine samples were analyzed by liquid chromatography/mass spectrometry. Results Like after intravenous administration, the unchanged saponins were the major circulating forms after intramuscular administration, while their metabolites were poorly detected. These ginsenosides exhibited intramuscular bioavailability of 100%–112%, relative to the respective intravenous data. Similar to that after intravenous infusion, the 20(S)-protopanaxadiol-type ginsenosides after the intramuscular injection exhibited notably longer terminal half-lives (46–106 h) than the 20(S)-protopanaxatriol-type ginsenosides (1.1–1.4 h). Conclusions Intramuscular route might be an effective alternative to intravenous route for XueShuanTong, from the pharmacokinetic perspective.

Antarctic Krill, rich in many nutrients, is supposed to be one of the strategic food sources. However, it is not acceptable for direct consumption as traditional food, as its high content of fluoride is harmful to adults and children. Therefore, the safety of fluoride residue in Antarctic krill for food production should be investigated. In this research, the fluoride toxicity in Antarctic Krill was evaluated through mice feeding experiment. Their body weight was found not to be influenced by fluoride. However, dental fluorosis was observed in the krill group and the NaF group. Fluoride content in liver, kidney, urine, and bones are significantly different (P

Alzheimer's disease (AD) is well-known as a severe neurodegeneration disease involving complicated etiologies, and cholinesterase inhibition remain the prevailing mode of clinical intervention in AD management. Although most clinically applied cholinesterase inhibitors (ChEIs) achieve limited clinical outcomes, research on the central cholinergic system is still thriving. Recently, an impressive amount of knowledge regarding novel acetylcholinesterase functions, as well as the close association between the central cholinergic system and other key elements for AD pathogenesis, has accumulated, highlighting that this field still has great potential for future drug development. In contrast to the overwhelmingly disappointing clinical therapeutic effects of various disease-modifying drug candidates, interesting evidence has continued to emerge over the past 20 years from the wealth of preclinical and clinical data on the usage of ChEIs, indicating underestimated clinical benefits due to physician ambivalence, a lack of persistent treatment, and inappropriate medication times or doses. Here we pinpoint several topics fit for future attention, focusing on the updated cholinergic hypothesis, especially the pleiotropic relationships with key pathogenetic signaling pathways and functions in AD, as well as possible novel therapeutic strategies, including novel ChEIs and cholinesterase inhibition-based innovative multifunctional therapeutic candidates. We intend to strengthen the future value of the precise application of cholinergic drugs, especially novel ChEIs, as a cornerstone pharmacological approach to AD treatment, either alone or in combination with other targets, to relieve symptoms and to modify disease progression.

The sensitive imaging of amyloid-β (Aβ) peptides is important for the timely detection of neurodegenerative diseases, such as Alzheimer's disease (AD). Although clinically the diagnosis of AD relies on the use of radiolabeled imaging reagents, herein we report the simple construction of a "flat ensemble" formed between a quinoline-malononitrile AIEgen (EDS) and thin-layer molybdenum disulfide (2D MoS2 ) for the sensitive detection of Aβ by means of fluorescence-based techniques. Self-assembly between EDS and 2D MoS2 in aqueous buffer solution produces the flat ensemble, and the subsequent interaction of the material ensemble with oligomeric and aggregated Aβ peptides leads to up to 19-fold enhanced fluorescence of EDS. The ensemble is also applicable for staining Aβ aggregates in vivo.

Multifunctional agents aiming at cholinesterases (ChEs) and monoamine oxidases (MAOs) are promising therapy for Alzheimer’s disease (AD). Herein, a series of novel propargylamine-modified pyrimidinylthiourea derivatives (1–4) were designed and synthesized as dual inhibitors of ChEs and MAOs with other functions against AD. Most of these derivatives inhibited ChEs and MAOs with IC50 values in the micro- or nanomolar ranges. Compound 1c displayed the dual functional profile of targeting the AChE (IC50 = 0.032 ± 0.007 μM) and MAO-B (IC50 = 2.117 ± 0.061 μM), along with the improved blood-brain barrier (BBB) permeability, antioxidant ability, and good copper chelating property in vitro. Animal studies showed that compound 1c·HCl could inhibit the cerebral AChE/MAO-B activities and alleviate scopolamine-induced cognitive impairment in mice. Combined with good oral bioavailability (F = 45.55%), these findings demonstrated that compound 1c may be a potent brain permeable multifunctional candidate for the treatme...

Iron dyshomeostasis and mitochondrial impairments are both vitally important for the progression of many neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Nevertheless, how these two pathological phenomena are linked with one another remains unclear, especially in neurons. To address the question, a model of iron overload was established with exposure of rat primary cortical neurons to excessive iron. We first verified that iron overload resulted in a decrease in adenosine triphosphate (ATP) production in neurons. Meanwhile, the release of mitochondrial cytochrome c was significantly increased after iron overload and consequently triggered an apoptosis signal, as revealed by Caspase 3 cleavage. To explore the potential underlying molecular mechanisms, an unlabeled quantitative proteomics approach was applied to primary neurons. Gene Ontology enrichment analysis revealed that 58 mitochondria-associated proteins were significantly altered, including three subunits of mitochondrial complex I and optic atrophy 1(OPA1). Increased NADH-ubiquinone oxidoreductase 75 kDa subunit and decreased NADH-ubiquinone oxidoreductase subunit A10 levels were further validated by a western blot, and more importantly, complex I activity markedly declined. Iron-induced down-regulation on the OPA1 level was also validated by a western blot, which was not reversed by the anti-oxidant but was reversed by the iron chelator. Moreover, an OPA1-associated key downstream effect, mitochondrial fragmentation, was found to be aggravated in neurons exposed to excessive iron, which is consistent with the down-regulation of OPA1. Furthermore, the protein level of PTEN-induced putative kinase 1, an important protein closely related to complex I activity and mitochondrial fragmentation, also significantly declined in neurons by iron overload. Thus, our findings may shed new light on the linkage between iron toxicity and mitochondrial impairments, such as energy supply deficiency and mitochondrial fragmentation, and further expand the toxic repertoire of iron in the central nerve system. Cover Image for this issue: doi: 10.1111/jnc.14205.

Depression, a severe mental disease, is greatly difficult to treat and easy to induce other neuropsychiatric symptoms, the most frequent one is cognitive impairment. In this study, a series of novel vilazodone-tacrine hybrids were designed, synthesized and evaluated as multitarget agents against depression with cognitive impairment. Most compounds exhibited good multitarget activities and appropriate blood-brain barrier permeability. Specifically, compounds 1d and 2a exhibited excellent 5-HT1A agonist activities (1d, EC50 = 0.36 ± 0.08 nM; 2a, EC50 = 0.58 ± 0.14 nM) and 5-HT reuptake inhibitory activities (1d, IC50 = 20.42 ± 6.60 nM; 2a, IC50 = 22.10 ± 5.80 nM). In addition, they showed moderate ChE inhibitory activities (1d, AChE IC50 = 1.72 ± 0.217 μM, BuChE IC50 = 0.34 ± 0.03 μM; 2a, AChE IC50 = 2.36 ± 0.34 μM, BuChE IC50 = 0.10 ± 0.01 μM). Good multitarget activities with goodt blood-brain barrier permeability of 1d and 2a make them good lead compounds for the further study of depression with cognitive impairment.

The main purpose of the present study is to investigate the influence of donepezil, a well-known acetylcholinesterase (AChE) inhibitor, on amyloid-β (Aβ)-associated mitochondrial dysfunction, in order to gain a better understanding of the neuroprotective effects of this clinically used anti-Alzheimer's disease (AD) drug. First, our study verifies the ameliorative effects of donepezil on behavioral deficits in both working memory and anxiety in APP/PS1 double transgenic mice, at a time point that AChE is not inhibited. Meanwhile, we demonstrate that donepezil enhances the resistance of brain mitochondria of APP/PS1 mice to the induction of mitochondrial permeability transition (MPT) by calcium ions. Moreover, the level of mitochondrial Aβ in the brain of donepezil-treated APP/PS1 transgenic mice is significantly lower than that of vehicle-treated APP/PS1 mice. Our in vitro study using isolated mitochondria from rat brains, which is expected as an AChE-free subcellular system, further confirms the ameliorative effects of donepezil on oligomeric Aβ1-42 induced mitochondrial swelling and ATP reduction. In addition, donepezil treatment also significantly blocks the Aβ accumulation in the isolated mitochondria. Our study reported for the first time that the protective effects of donepezil against Aβ-associated mitochondrial dysfunction are closely associated with the reduction of Aβ accumulation in the mitochondria. Above observation led us to assume that, besides potent AChE inhibitory effect, other non-cholinergic mechanisms may be involved in the neuroprotective profiles of donepezil.

There are limitations to the use of single biomarker levels, for example phosphate and tensin homology (PTEN) or vascular endothelial growth factor (VEGF), in the diagnosis of esophageal squamous cell carcinoma (ESCC). The present study therefore aimed to evaluate the clinical implications of combined detection of multiple biomarkers. The associations between PTEN and VEGF expression status, microvessel density (MVD), and the pathological characteristics of 50 patients with ESCC were determined using χ2, analysis of variance, and t-tests. The results indicated that the PTEN-positive rate was negatively correlated with ESCC histological grade (P

Two new cucurbitacins I (1 and 2), together with eight known compounds (3-10), were isolated from the ethyl acetate extract of the fruit of Citrullus colocynthis. Compounds 3, 5-9 were isolated from C. colocynthis for the first time. The structures of new compounds were determined primarily from IR, HR-MS, 1D-, and 2D-NMR analysis.