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Abstract: The East Asian respond with a marked facial flushing and mild to moderate symptoms of intoxication after drinking the amounts of alcohol that has no detectable effect on European. The alcohol sensitivity in Orientals is due to a delayed oxidation of acetaldehyde by an atypical aldehyde dehydrogenase ALDH2⁎487Lys, which is resulted from a structural mutation in gene ALDH2. The atypical ALDH2⁎487Lys allele has been associated with various phenotypic statuses, such as protective against alcohol dependence and the risk of alcohol-related digestive tract cancers. Here, we have examined this SNP, adjacent four non-coding SNPs, and one downstream STRP on ALDH2 gene, in total of 1072 unrelated healthy individuals from 14 Chinese populations and 130 Indian individuals. Five major haplotypes based on five SNPs across the ALDH2 gene 40 kb were found in all East Asian populations. The frequencies of the ancestral haplotype GCCTG and the East Asian special haplotype GCCTA containing the atypical ALDH2⁎487Lys allele were 44.8% and 14.9%, respectively. The frequency of the atypical ALDH2⁎487Lys allele or the East Asian specific haplotype GCCTA is high in Yunnan, South coastal, east coastal of China, and decreased gradually toward inland China, West, Northwest and North China. Combined with demographic history in East Asian, our results showed that the presence of ALDH2⁎487Lys allele in peripheral regions of China might be the results of historical migration events from China to these regions. The origin of ALDH2⁎487Lys could be possibly traced back to ancient Pai-Yuei tribe in South China. [Copyright &y& Elsevier]

Abstract: The human D2 dopamine receptor gene (DRD2) plays a central role in the neuromodulation of appetitive behaviors and is implicated in having a possible role in susceptibility to alcoholism. We genotyped an SNP in DRD2 Exon 8 in 251 nonalcoholic, unrelated, healthy controls and 200 alcoholic Mexican Americans. The DRD2 haplotypes were analyzed using the Exon 8 genotype in combination with five other SNP genotypes, which were obtained from our previous study. The ancestral origins of the DRD2 polymorphisms have been determined by sequencing the homologous region in other higher primates. Twenty DRD2 haplotypes, defined as H1 to H20 based on their frequency from high to low, were obtained in this major minority population. The ancestral haplotype “I-B2-G-C-G-A1” and two one-step mutation haplotypes were absent in our study population. The haplotype H1, “I-B1-T-C-A-A1”, with the highest frequency in the population, is a three-step mutation from the ancestral form. The first five or eight major haplotypes make up 87% or 95% of the entire population, respectively. The prevalence of the haplotype H1+ (H1/H1 and H1/Hn genotypes) is significantly higher in alcoholics and alcoholic subgroups, including early onset drinkers and benders, than in their respective control groups. The Promoter −141C allele is in linkage disequilibrium (LD) with five other loci in the nonalcoholic group, but not in the alcoholic group. All of the other five loci are in LD in both the alcoholic and control groups. The DRD2 TaqI B allele is in complete LD with the allele located in intron 6. Five SNPs, Promoter −141C, TaqI B (or Intron 6), Exon 7, Exon 8, and TaqI A, are sufficient to define the DRD2 haplotypes in Mexican Americans. Our data indicate that the DRD2 haplotypes are associated with alcoholism in Mexican Americans. [Copyright &y& Elsevier]

The upstream regulatory region of the human thymidylate synthase gene (thymidylate synthase enhancer region, TSER) is length polymorphic, attributable to variable numbers of tandemly repeated copies of a 28-bp fragment. It has been found that TSER length polymorphism is correlated to malignancy risk. To further our understanding of the origin and evolution of TSER, this region was investigated among different primates, including hominoids, two subfamilies of the Old World monkeys (OWMs): colobines and cercopithecines, and two species of the New World monkeys (NWMs). In addition to humans, our results show that length polymorphism in TSER is also present in some primate populations, although it appears that this region is length monomorphic in many other primates. We identified three unique repeat motifs in TSER and defined them as R1, R2, and R3, respectively, starting from the 3′ end. The same repeat motifs from different species are more similar to each other than different repeat motifs within same species are. Such a paraphyletic pattern suggests that divergence of the three repeat motifs predated divergence of the OWMs/hominoids and the NWMs. The most recent common ancestor (MRCA) of hominoids and the OWMs probably possessed triple repeats but now double and triple repeats are two dominant types in hominoids and the OWMs. In addition, our results show that each of the three repeat motifs may be lost independently. We have also found clues that recombination was involved in formation of tandem repeat polymorphism in TSER. [Copyright &y& Elsevier]

• IPMK-1 is the major IP3K in C. elegans. • IPMK-1 kinase activity is required for defecation rhythmic behavior and development. • The mutant IPP-5 could rescue the phenotypes of IPMK-1 mutant. • IPMK-1 regulates IP3/Ca2+ homeostasis. • IPMK-1 regulates defecation rhythmic behavior and development through IP3/Ca2+ signaling. Inositol polyphosphate multikinase (IPMK) is a conserved protein that initiates the production of inositol phosphate intracellular messengers and is critical for regulating a variety of cellular processes. Here, we report that the C. elegans IPMK-1, which is homologous to the mammalian inositol polyphosphate multikinase, plays a crucial role in regulating rhythmic behavior and development. The deletion mutant ipmk-1(tm2687) displays a long defecation cycle period and retarded postembryonic growth. The expression of functional ipmk-1 ::GFP was detected in the pharyngeal muscles, amphid sheath cells, the intestine, excretory (canal) cells, proximal gonad, and spermatheca. The expression of IPMK-1 in the intestine was sufficient for the wild-type phenotype. The IP3-kinase activity of IPMK-1 is required for defecation rhythms and postembryonic development. The defective phenotypes of ipmk-1(tm2687) could be rescued by a loss-of-function mutation in type I inositol 5-phosphatase homolog (IPP-5) and improved by a supplemental Ca2+ in the medium. Our work demonstrates that IPMK-1 and the signaling molecule inositol triphosphate (IP3) pathway modulate rhythmic behaviors and development by dynamically regulating the concentration of intracellular Ca2+ in C. elegans. Advances in understanding the molecular regulation of Ca2+ homeostasis and regulation of organism development may lead to therapeutic strategies that modulate Ca2+ signaling to enhance function and counteract disease processes. Unraveling the physiological role of IPMK and the underlying functional mechanism in C. elegans would contribute to understanding the role of IPMK in other species, especially in mammals, and benefit further research on the involvement of IPMK in disease. [ABSTRACT FROM AUTHOR]

Volvalerine A ( 1 ), a novel N -containing bisesquiterpenoid derivative with a dihydroisoxazole ring, and its possible biosynthetic precursor, 1-hydroxy-1,11,11-trimethyldecahydrocyclopropane azulene-10-one ( 2 ), were isolated from the roots of Valeriana officinalis var. latifolia . Their structures and relative configurations were identified using spectroscopic data and X-ray crystallography. A plausible biosynthetic pathway for 1 is also presented. [ABSTRACT FROM AUTHOR]

Abstract: Nardokanshone A (1), a new type of sesquieterpenoid–chalcone hybird, with a 2,3-dihydrofuran ring fusing an aristolane-type sesquiterpenoid and a chalcone, along with its possible bioprecursor, kanshone C (2), together with four known flavones were isolated from Nardostachys chinensis. Their structures were elucidated by spectroscopic methods, and the absolute configuration of 1 was determined by quantum chemical DFT calculations. The possible biosynthetic pathway of 1 was also proposed. [Copyright &y& Elsevier]

Transient receptor potential canonical 6 (TRPC6) proteins form receptor-operated Ca2+-permeable channels, which have been thought to bring benefit to the treatment of diseases, including cancer. However, selective antagonists for TRPC channels are rare and none of them has been tested against gastric cancer. Compound 14a and analogs were synthesized by chemical elaboration of previously reported TRPC3/6/7 agonist 4o. 14a had very weak agonist activity at TRPC6 expressed in HEK293 cells but exhibited strong inhibition on both 4o-mediated and receptor-operated activation of TRPC6 with an IC50 of about 1 μM. When applied to the culture media, 14a suppressed proliferation of AGS and MKN45 cells with IC50 values of 17.1 ± 0.3 and 18.5 ± 1.0 μM, respectively, and inhibited tube formation and migration of cultured human endothelial cells. This anti-tumor effect on gastric cancer was further verified in xenograft models using nude mice. This study has found a new tool compound which shows excellent therapeutic potential against human gastric cancer most likely through targeting TRPC6 channels. [ABSTRACT FROM AUTHOR]

D-chiro-inositol (DCI) is an isomer of inositol, abundant in many foods, such as beans and buckwheat, with insulin-sensitizing, anti-inflammatory, and antioxidant effects. DCI has been used to relieve insulin resistance in diabetes and polycystic ovary syndrome in combination with inositol or D-pinitol. Here, we investigated the effect of DCI on aging and stress resistance in C. elegans. We found that DCI could prolong the lifespan of C. elegans by up to 29.6 %. DCI significantly delayed the onset of neurodegenerative diseases in models of C. elegans. DCI decreased the accumulation of Aβ 1 – 42 , alpha-synuclein, and poly-glutamine, the pathological causes of Alzheimer's, Parkinson's, and Huntington's diseases, respectively. DCI significantly increased the stress resistances against pathogens, oxidants and heat shock. Moreover, D-chiro-inositol reduced the content of ROS and malondialdehyde by increasing the total antioxidant capacity and the activity of superoxide dismutase and catalase. Above effects of DCI requires the transcription factors FOXO/DAF-16 and Nrf-2/SKN-1. DCI also increased the expression of downstream genes regulated by FOXO/DAF-16 and Nrf-2/SKN-1. In conclusion, DCI enhanced the antioxidant capacity and healthy lifespan of C. elegans by activating DAF-16, SKN-1, and HSF-1. Our results showed that DCI could be a promising antiaging agent that is worth further research on the mechanism and health supplemental application of DCI. • D-chiro-inositol extends the lifespan and slows the aging-related phenotypes of C. elegans. • D-chiro-inositol delays the development of neurodegenerative diseases in models of C. elegans. • D-chiro-inositol enhances the healthy lifespan of C. elegans by activating DAF-16, SKN-1/NRF-2, and HSF-1. [ABSTRACT FROM AUTHOR]

The hippocampal formation plays a critical role in episodic memory formation and spatial navigation. Within the hippocampus, the subiculum is considered to be a hub connecting the hippocampal formation to the remainder of the brain. There are functional differences between the dorsal and ventral part of subiculum, while the ventral subiculum (vSub) plays a role in anxiety, stress and emotion. In the present study, we examined the projection of the ventral subiculum to the whole brain in mice by using a modified herpes simplex virus 1 strain H129 with an inserted fluorescent protein gene. In our experiments, the modified H129 transits the primary-order, second-order, and third-order neuronal projections at 36–44, 52–60 and 68–76 h after inoculation in mice, respectively. Our data revealed that vSub directly projects to the medial entorhinal cortex, amygdalohippocampal area, anterodorsal thalamic nucleus, medial hypothalamus, supramammillary nucleus, medial septal nucleus and adjacent diagonal band, the connections between median raphe nucleus and interpeduncular nucleus in brain stem, while ventral prefrontal cortex, laterodorsal tegmental nucleus and locus coeruleus receives second-order projections from vSub. Our data would help further understanding the functional connections of vSub with other brain regions. [ABSTRACT FROM AUTHOR]

Twenty-one compounds (nine iridoids and twelve sesquiterpenoids), including ten previously unknown (five iridoids and five sesquiterpenoids) were isolated from whole dried material of Valeriana stenoptera . Structures were established on the basis of extensive spectroscopic analysis and the relative stereochemistry of 13-hydroxypatchoulol A was further confirmed by X-ray crystallographic data. All isolates were evaluated for their effects on nerve growth factor (NGF)-mediated neurite outgrowth in pheochromocytoma (PC12) cells and seven compounds showed potent promoting effects. [ABSTRACT FROM AUTHOR]

Nine new minor dehydrogenated and cleavaged dammarane-type triterpenoid saponins, namely notoginsenosides ST6-ST14 ( 1 – 9 ) were isolated from the steamed roots of Panax notoginseng , together with 14 known ones. Among them, 5–7 and 21–22 were protopanaxadiol type and the left 18 compounds, including 1–4 , 8–20 , and 23 were protopanaxatriol type saponins. Their structures were identified by extensive analysis of MS, 1D and 2D NMR spectra, and acidic hydrolysis. Resulted from the side chain cleavage, the new saponins 1 and 2 featured in a ketone group at C-25, and 3–5 had an aldehyde unit at C-23. The known saponins 12 , 16 and 18 displayed the enhancing potential of neurite outgrowth of NGF-mediated PC12 cells at a concentration of 10 μM, while 20 exhibited acetyl cholinesterase inhibitory activity, with IC 50 value of 13.97 μM. [ABSTRACT FROM AUTHOR]

Three new iridoids, jatamanvaltrates R–S ( 1 – 2 ) and jatamanin Q ( 3 ), as well as three new sesquiterpenoids, valeriananoids D–E ( 4 , 5 ) and clovane-2 β -isovaleroxy-9 α -ol ( 6 ), together with nine known compounds were isolated from the roots of Valeriana jatamansi Jones. Compound 2 was the first reported iridoid with fatty acid esters in the Valerianaceae family. The structures of new compounds were established on the basis of extensive spectroscopic analysis. Moreover, all the isolates were evaluated for inhibitory activity on acetylcholinesterase (AChE). [ABSTRACT FROM AUTHOR]

Abstract: Intramolecular hetero-DA reaction and unexpected retro-aldol like ring opening reaction were performed. As a result, six derivatives with different skeletons of vibsane-type diterpenoids were synthesized from vibsanin B within three steps. Moreover, compounds 2, 3, and 6 enhanced the neurite outgrowth of NGF-mediated PC12 cells. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Schisandra chinensis has a long history of use as a famous traditional Chinese medicine. The plants of genus Schisandra, especially Schisandra neglecta, Schisandra rubriflora, and Schisandra sphaerandra are used in the same way as Schisandra chinensis in the folk medicine to treat insomnia, fatigue, increasing intelligence, and tranquilizing. Many studies showed that lignans were the major active components of Schisandra genus, whereas the bioactivity of abundant triterpenoids in Schisandra genus, such as nigranoic acid (SBB1, 3,4-secocycloartene triterpenoid), has not been examined yet in neuropathology. Materials and methods: After treating with SBB1, intracellular Ca2+ concentration was analyzed by Ca2+ fluorescent indicator (Fluo-4 AM) in NGF-differentiated PC12 cells. Intracellular nitric oxide (NO) level was analyzed using NO fluorescent indicator (DAF-FM). The expression of extracellular signal regulated kinase 1 and 2 (ERK1/2) was analyzed by western blotting, and the temporal mRNA for BDNF and c-fos was analyzed using reverse transcription quantitative PCR. Result: We found that SBB1 induced Ca2+ influx in a time- and concentration-dependent manner, which was significantly attenuated in Ca2+ free media. SBB1 promoted the intracellular NO production which depended on increasing cytoplasmic Ca2+ level. Moreover, SBB1 stimulated activation of ERK1/2 through Ca2+-CaMKII pathway. In addition, we found that SBB1 increased the expression of BDNF and c-fos mRNA. Conclusion: These results suggest that SBB1 is able to promote NO production and stimulate phosphorylation of ERK1/2 through Ca2+ influx, further impact expression of BDNF and c-fos, which provides evidence for the effects of SBB1 that may be benefit to enhance mental and intellectual functions. [Copyright &y& Elsevier]

Abstract: Twelve new nortriterpenoids, namely wuweizidilactones J–P (1–7), schindilactones I–K (8–10), preschisanartanin N (11), and schisdilactone J (12), as well as 23 known analogues, were isolated from the leaves and stems of Schisandra chinensis. The absolute configurations of 1 and 11 were established by calculated electronic circular dichroism (ECD) spectra and that of 7 was confirmed by single-crystal X-ray diffraction. The absolute configurations of 2–6, 8, and 9 were determined by an empirical comparison of their experimental ECD spectra with that of 1. It is the first time that the ECD spectra of 18(13→14)-abeo-schiartane-, 18-norschiartane-, and schisanartane-type nortriterpenoids possessing an α,β-unsaturated-γ-lactone moiety are presented, this method providing an alternative means of obtaining absolute configurational assignments for these types of nortriterpenoids. All isolates were evaluated for their anti-acetylcholinesterase and anti-butyrylcholinesterase activities, and compounds 8, 13, 23, and 31 show anti-acetylcholinesterase activity at concentrations of 50 μM, with 12.7, 10.7, 16.6, and 32.1% inhibition, respectively. [Copyright &y& Elsevier]

Highlights: [•] Eight new lanostane triterpenoids were isolated from G. resinaceum. [•] Ganoderesin B, ganoderol B and lucidone A notably decreased ALT and AST levels. [•] Ganoderol B showed significant activation on CYP3A4. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel 2-aminobenzimidazole derivatives were synthesized under microwave irradiation. Their biological activities were evaluated on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A number of the 2-aminobenzimidazole derivatives showed good inhibitory activities to AChE and BuChE. Among them, compounds 9, 12 and 13 were found to be >25-fold more selective for BuChE than AChE. No evidence of cytotoxicity was observed by MTT assay in PC12 cells or HepG2 cells exposed to 100μM of the compounds. Molecular modeling studies indicate that the benzimidazole moiety of compounds 9, 12 and 13 forms a face-to-face π–π stacking interaction in a ‘sandwich’ form with the indole ring of Trp82 (4.09Å) in the active gorge, and compounds 12 and 13 form a hydrogen bond with His438 at the catalytic site of BuChE. In addition, compounds 12 and 13 fit well into the hydrophobic pocket formed by Ala328, Trp430 and Tyr332 of BuChE. Our data suggest the 2-aminobenzimidazole drugs as promising new selective inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases. [Copyright &y& Elsevier]

Abstract: Aspirin has been revealed to have many beneficial effects for health since it was discovered as a nonsteroidal anti-inflammatory drug (NSAID) to treat pain and inflammation. Here, we investigated the molecular mechanism of aspirin on the lifespan extension of Caenorhabditis elegans. Our results showed that aspirin could extend the lifespan of C. elegans, and increase its health span and stress resistance. The extension of lifespan by aspirin requires DAF-16/FOXO, AMPK, and LKB1, but not SIR-2.1. Aspirin could not extend the lifespan of the mutants of eat-2, clk-1, and isp-1. Aspirin could marginally extend the lifespan of long-live insulin-like receptor mutant daf-2(e1370) III. Taken together, aspirin might act through a dietary restriction-like mechanism, via increasing the AMP:ATP ratio and activating LKB1, subsequently activating AMPK, which stimulates DAF-16 to induce downstream effects through a DAF-16 translocation independent manner. [Copyright &y& Elsevier]

Abstract: Four new compounds, maninsigins A–D (1–4), including two new neolignans (1–2) and two new sesquiterpenes (3–4), as well as ten known compounds (5–14), were isolated from the leaves and stems of Manglietia insignis. Their structures were established on the basis of extensive spectroscopic analyses. In addition, some compounds were tested for their cytotoxic and neurite outgrowth-promoting activities, as well as their antagonistic activity toward FXR ligand. [Copyright &y& Elsevier]

Abstract: Bioassay-guided isolation of the stems of Gelsemium elegans has led to the isolation of two new Gelsemium alkaloids, 21-(2-oxopropyl)-koumine (1) and 11-methoxygelselegine (2), and two known alkaloids, koumine (3) and gelselegine (4). The structures of 1–2 were determined by spectroscopic (for both) and single-crystal X-ray diffraction (for 1) analysis. All compounds isolated were evaluated for their potential as immunosuppressive agents and the data suggested that Gelsemium alkaloids of different structural types possibly have potential as immunosuppressive agents. [Copyright &y& Elsevier]

Abstract: Penicilliumine (1), a new structure was isolated from the fermentation Penicillium commune 366606, a marine-derived fungus isolated from the sea water collected at Qingdao, China. HPLC chiral separation of 1 afforded two enantiomers (−)-penicilliumine and (+)-penicilliumine, respectively. The structure of 1 was established by comprehensive spectroscopic data, and single-crystal X-ray diffraction. The absolute configuration of enantiomers was determined by quantum mechanical computation of electronic circular dichroism (ECD). [Copyright &y& Elsevier]

Abstract: A phytochemical study on Lycopodium casuarinoides has led to the isolation of two new C16N2-type Lycopodium alkaloids, casuarine A (1), a cage-like structure featured with a fused 6/6/6/6/6 pentacyclic ring system, and casuarine B (2). Their structures were elucidated based on the spectroscopic data and further confirmed by X-ray analysis. In vitro acetylcholinesterase (AChE) inhibitory activity assay showed that compound 2 exhibited moderate anti-AChE activity with IC50 46.40μM. [Copyright &y& Elsevier]

Abstract: Volvalerenone A (1), a new type of mononorsesquiterpenoid with an unprecedented 5/6/6 tricyclic ring system, was isolated from the roots of Valeriana officinalis, the official species of valerian used in Europe. The structure of volvalerenone A was elucidated based on its spectroscopic and single-crystal X-ray crystallography data. The absolute configuration was assigned by the computational method. A possible biosynthetic pathway of volvalerenone A was also proposed. Preliminary biological studies showed that volvalerenone A had weak inhibitory activity on acetylcholine esterase (AChE), and no enhancing activity on nerve growth factor (NGF)-mediated neurite outgrowth in PC12 cells was observed at 50μM. [Copyright &y& Elsevier]