ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation.

Exploring the potential lead compounds for Alzheimer's disease (AD) remains one of the challenging tasks. Here, we report that the plant extract conophylline (CNP) impeded amyloidogenesis by preferentially inhibiting BACE1 translation via the 5' untranslated region (5'UTR) and rescued cognitive decline in an animal model of APP/PS1 mice. ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1) was then found to mediate the effect of CNP on BACE1 translation, amyloidogenesis, glial activation, and cognitive function. Through analysis of the 5'UTR-targetd RNA-binding proteins by RNA pulldown combined with LC-MS/MS, we found that FMR1 autosomal homolog 1 (FXR1) interacted with ARL6IP1 and mediated CNP-induced reduction of BACE1 by regulating the 5'UTR activity. Without altering the protein levels of ARL6IP1 and FXR1, CNP treatment promoted ARL6IP1 interaction with FXR1 and inhibited FXR1 binding to the 5'UTR both in vitro and in vivo. Collectively, CNP exhibited a therapeutic potential for AD via ARL6IP1. Through pharmacological manipulation, we uncovered a dynamic interaction between FXR1 and the 5'UTR in translational control of BACE1, adding to the understanding of the pathophysiology of AD.

Sesquiterpenoids from cigar tobacco leaves.

Phytochemical investigation on cigar tobacco leaves led to four unknown sesquiterpenoids as well as nine reported ones. Among of them, 3-acetoxy-ß-damascone was first found in tobacco leaves. All the structures were elucidated by intensive spectroscopic analyses and X-ray diffraction. The relationship between the newly isolates and known ones was tried to describe.

Ionones from cigar tobacco leaves.

Phytochemical studies on cigar tobacco leaves led to the isolation of 18 ionone-type compounds, including previously undescribed cigatobanes E (1) and F (2). Additionally, compounds vomifoliol acetate (3), dehydrovomifoliol (4), 8,9-dihydromegastigmane-4,6-diene-3-one (5), 7α,8α-epoxyblumenol B (6), 3-oxoactinidol (12), and loliolide acetate (15), 4ß-hydroxy-dihydroactinidiolide (17), were found in tobacco leaves for the first time. The structural elucidation of all compounds was accomplished through rigorous spectral analysis.

Nematocidal alkaloids from the roots of Stemona mairei (H.Lév.)K.Krause and identification of their pharmacophoric moiety.

Fifteen undescribed Stemona alkaloids, named as stemarines A-O (1-15), along with 25 known alkaloids (16-40), were isolated and identified from the roots of Stemona mairei (H.Lév.)K.Krause (Stemonaceae). Their structures were elucidated through the analysis of the NMR spectra, mass data, and computational chemistry. All the hitherto undescribed compounds possess a pyrrolo[1,2-α]azepine core structure but differ in important structural features, which reflects their nematocidal activities. Alkaloids 3-6 featured a carboxylic side chain and exhibited significant nematocidal activity against the nematode Caenorhabditis elegans. Transections of fresh roots combined with application of the Dragendorff' reagent on the tissue indicated accumulation of alkaloids mainly in the epidermis and the pith. These results suggest the key pharmacophore of these alkaloids lies in the aliphatic side chain of these compounds and its spatial distribution in the roots indicate protective effects against underground herbivores.

Two Novel Iboga-Type and an Oxindole Glucuronide Alkaloid from Tabernaemontana peduncularis Disclose Related Biosynthetic Pathways to Tabernaemontana divaricata.

Phytochemical investigation of the two Tabernaemontana species (Apocynaceae) T. peduncularis Wall. and T. divaricata (L.) R.Br. ex Roem. & Schult. indicated closely related biosynthetic pathways leading to lipophilic and hydrophilic alkaloids. In total, 18 specialized metabolites comprising indole-derived alkaloid aglycones, three oxindole-derived alkaloid glycosides, and two iridoid glucosides could be identified in the studied species. Among the alkaloids, the two Iboga-type alkaloids 3,7-coronaridine isoindolenine, coronaridine 3,4-iminium and a javaniside derivative bearing a glucuronic acid, named javanuronic acid, could be described by spectroscopic and spectrometric methods for the first time. A docking experiment using alpha-fold was performed to generate a protein model of the enzyme 7-deoxyloganetic acid glucosyl transferase. Performed bioassays exhibited a growth reduction of neonate Spodoptera littoralis larvae and reduced cell viability of HepG2 cells of the extracts containing Iboga alkaloids, whilst the javaniside derivatives containing hydrophilic fraction did not show any effects. These findings indicate a high flexibility in the formation of bioactive indole alkaloid aglycones by Tabernaemontana species and also evidence similar accumulation trends in both species as well as indicate that biosynthetic routes leading to oxindole alkaloids like javanisides are more widespread than reported. Furthermore, the incorporation of the three novel compounds into potential biosynthetic pathways is discussed.

Colored Dimeric Alkaloids from the Barks of Erythrina variegata and Their Neuroprotective Effects.

Five dimeric Erythrina alkaloids, named erythrivarines J-N, were isolated from the barks of Erythrina variegata L. (Fabaceae). The erythrivarines J-L featured a 6/6/5/6/6/5/6/6/6 ring system and super conjugated double bond systems, causing intense color from blue to wine red, while erythrivarines M-N looked orange. The structures of the isolated compounds were elucidated by 1D and 2D NMR experiments combined with MS and confirmed by the X-ray crystal diffraction technique. The performed bioassay using HEI-OC-1 cells revealed neuroprotective properties of erythrivarine N against the hearing loss causing antibiotics, neomycin.

3-Hydroxy-4-methyldecanoic Acid-Containing Cyclotetradepsipeptides from an Endolichenic Beauveria sp.

An investigation of an endolichenic Beauveria sp. led to the discovery of seven new cyclotetradepsipeptides, beauveamides A-G (2-8), along with the known beauverolide Ka (1). All incorporate a 3-hydroxy-4-methyldecanoic acid (HMDA) moiety in their structures. Their configuration was determined through Marfey's, J-based configuration analysis, and NMR computational methods, representing the first time that the stereostructures of HMDA-moiety-containing cyclotetradepsipeptides have been established. Compounds 1 and 2 exhibited protecting effects on HEI-OC1 cells at 10 µM, while 1, 4, and 5 could stimulate glucose uptake in cultured rat L6 myoblasts at 50 µM. Compound 1 showed dose-dependent activity in both L6 myoblasts and myotubes.

Trimeric and dimeric Aspidosperma-type alkaloids from leaves of Tabernaemontana divaricata 'Dwaft'.

Continued interest in bioactive monoterpenoid indole alkaloids and the purpose to explore the artificial cultivation influence on the chemical composition in the same plant species, 8 undescribed Aspidosperma-type alkaloids including two unprecedented trimers, taberdivarines A-B (1-2), and six new dimers, taberdivarines CH (3-8), together with 9 known bisindoles were isolated from the leaves of Tabernaemontana divaricata 'Dwaft'. Notably, taberdivarines A and B were the first cases of Aspidosperma-Aspidosperma-Aspidosperma-type alkaloids with furan ring linkage patterns of the natural products. Their structures were elucidated by comprehensive spectroscopic analyse. Compounds 1-8 were screened for the cytotoxicity against three human cancer cell lines, SMMC-7721, HT-29 and A549. Among them, Compound 6 exhibited significant activity against three cell lines with IC50 values of 0.30, 0.75 and 3.41 µM, respectively (IC50 = 3.02, 0.14 and 2.23 µM for the positive control, vinorelbine). Compound 1, 3, 4, 6, 7 and 8 also expressed varying degrees of activity. The structure-activity relationships (SARs) of these alkaloids were discussed.

Indole Alkaloids from Hunteria zeylanica.

Six new bisindole alkaloids, hunterizeylines A-F (1-6), three new monomers, hunterizeylines G-I (7-9), and 13 known alkaloids were isolated from an aqueous MeOH extract of the twigs and leaves of Hunteria zeylanica. Hunterizeyline H, geissoschizol, and dihydrocorynantheol displayed weak insecticidal activity against the aphid Rhodobium porosum, with IC50 values of 168.2, 360.5, and 290.6 µM, respectively.

Two new lignans from twigs of Aglaia odorata.

HPLC-guided separation of twigs of Aglaia odorata led to the isolation of eight lignans, including two new ones, 3'-methoxy-N-demethylrocaglamide (1) and 4'-O-demethyl-deacetylaglaxiflorin A (2). Compound 1 showed excellent cytotoxicity against three human cancer cell lines, HeLa, SGC-7901 gastric cancer, and A-549 lung cancer with the values of 0.32, 0.12, and 0.25 µM, respectively.