A natural small molecule aspidosperma-type alkaloid, hecubine, as a new TREM2 activator for alleviating lipopolysaccharide-induced neuroinflammation in vitro and in vivo.

Neuroinflammation and oxidative stress play a crucial role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease. The triggering receptor expressed on myeloid cells 2 (TREM2), highly expressed by microglia in the central nervous system (CNS), can modulate neuroinflammatory responses. Currently, there are no approved drugs specifically targeting TREM2 for CNS diseases. Aspidosperma alkaloids have shown potential as anti-inflammatory and neuroprotective agents. This study aimed to elucidate the potential therapeutic effect of Hecubine, a natural aspidosperma-type alkaloid, as a TREM2 activator in lipopolysaccharide (LPS)-stimulated neuroinflammation in in vitro and in vivo models. In this study, molecular docking and cellular thermal shift assay (CTSA) were employed to investigate the interaction between Hecubine and TREM2. Enzyme-linked immunosorbent assay (ELISA), quantitative PCR, immunofluorescence, Western blotting, and shRNA gene knockdown were used to assess the anti-neuroinflammatory and antioxidant effects of Hecubine in microglial cells and zebrafish. Our results revealed that Hecubine directly interacted with TREM2, leading to its activation. Knockdown of TREM2 mRNA expression significantly abolished the anti-inflammatory and antioxidant effects of Hecubine on LPS-stimulated proinflammatory mediators (NO, TNF-α, IL-6, and IL-1ß) and oxidative stress in microglia cells. Furthermore, Hecubine upregulated Nrf2 expression levels while downregulating TLR4 signaling expression levels both in vivo and in vitro. Silencing TREM2 upregulated TLR4 and downregulated Nrf2 signaling pathways, mimicking the effect of Hecubine, further supporting TREM2 as the drug target by which Hecubine inhibits neuroinflammation. In conclusion, this is the first study to identify a small molecule, namely Hecubine directly targeting TREM2 to mediate anti-neuroinflammation and anti-oxidative effects, which serves as a potential therapeutic agent for the treatment of neural inflammation-associated CNS diseases.

Two new aspidosperma-type monoterpenoid indole alkaloids from Ervatamia officinalis.

Two new aspidosperma-type monoterpenoid indole alkaloids, 16-O-methylvoafinine (1) and 14,15-diepi-voafinidine (2) were isolated from the aerial parts of Ervatamia officinalis. Their structures were established by comprehensive spectroscopic analysis including 1D and 2D NMR, HR-ESI-MS, and electronic circular dichroism calculation. The isolated compounds were evaluated for cytotoxic activities against HepG2, MCF-7, and A549 cell lines by CCK-8 assay.

New iboga-type alkaloids from Ervatamia officinalis and their anti-inflammatory activity.

Four new iboga-type alkaloids, ervaoffines H-K (1-4), along with five known compounds were obtained from the aerial parts of Ervatamia officinalis. The absolute configurations of 1-4 were confirmed by X-ray diffraction and electronic circular dichroism (ECD) analyses. The isolates were tested for their anti-inflammatory activity. Compounds 1, 5, 6, and 9 showed potential inhibitory effect of NO production in LPS-stimulated BV2 and RAW264.7 cells.

Neo-clerodane diterpenes and phytoecdysteroids from Ajuga decumbens Thunb. and evaluation of their effects on cytotoxic, superoxide anion generation and elastase release in vitro.

Five novel compounds, including four neoclerodane diterpenoids, named ajugacumbins KN (1-4) along with a phytoecdysterone, named ajugacetalsterone E (5), were isolated from the whole herbs of Ajuga decumbens (Labiatae). Their structures were elucidated on the basis of detailed spectroscopic analysis including IR, HRESIMS, CD, 1D and 2D NMR spectroscopic experiments. Compounds 1-5 were evaluated for their cytotoxic activities and the effects on superoxide anion generation and elastase release in FMLP/CB-induced human neutrophils.

Two new flavans from the roots of Dianella ensifolia (L.) DC.

Two new flavans, named (2S)-2',4'-dihydroxy-7-methoxy-8-methylflavan (1) and (2S)-2'-hydroxy-4',7-dimethoxy-8-methylflavan (2) were isolated from the roots of Dianella ensifolia. Their structures were elucidated by extensive spectroscopic measurements and comparison with data reported in literatures. Compounds 1 and 2 displayed cytotoxic effects against cancer cell lines MDA-MB-231, B16-F10, HCT116 and A549.

A new cycloartane-type triterpenoid from the roots of Dianella ensifolia (L.) DC.

A new cycloartane-type triterpenoid, named 22-hydroxy-cyclolaudenol (1), together with two known cycloartane-type triterpenoids were isolated from the roots of Dianella ensifolia. Their structures were determined based on spectroscopic methods, including UV, IR, HR-ESI-MS, NMR and X-ray diffraction. Compound 1 displayed cytotoxic effects against cancer cell lines B16-F10, A549 and MDA-MB-231.

Cytotoxic limonoids from the root bark of Dictamnus angustifolius.

Three novel limonoids, dictangustone G (1), dictangustone H (2), and dictangustone I (3) were isolated from the root bark of Dictamnus angustifolius. Their structures were elucidated on the basis of detailed spectroscopic analysis including UV, IR, HRESIMS, 1D and 2D NMR spectroscopic experiments. Compounds 1-3 were evaluated for their cytotoxic activities using Hela, A549, MCF7, and LN229 cell lines.

Iboga-Type Alkaloids from Ervatamia officinalis.

Seven new iboga-type alkaloids, ervaoffines A-D (1-4), (7S)-3-oxoibogaine hydroxyindolenine (5), ibogaine-5,6-dione (6), and 19-epi-5-oxovoacristine (7), and 10 known alkaloids were isolated from Ervatamia officinalis. The absolute configurations of 1-7 were determined through X-ray diffraction and electronic circular dichroism (ECD) analyses. Ervaoffines A and B represent the first iboga-type pseudoindoxyl alkaloids in which the C-2 spiro carbon configuration is opposite to that of other members of this class, such as iboluteine (8). The relationship between the absolute configuration of the spiro carbons and the Cotton effect in the ECD spectrum is established for the first time for iboga-type pseudoindoxyl and oxindole alkaloids. Additionally, a plausible biogenetic pathway for these alkaloids is proposed.