Discovery of Sesquiterpene Lactones with Cytotoxicity from the Herb of Youngia japonica.

In the process of searching for anti-breast cancer agents, five sesquiterpene lactones (1-5), including two previously undescribed ones, yjaponica B-C (1-2), were isolated from the herb of Youngia japonica. Their structures were elucidated by spectroscopic data analyses and Marfey's method. Cytotoxic activities of all compounds against A549, U87, and 4T1 cell lines were tested using the CCK8 assay. The result showed that compound 3 possessed the highest cytotoxic activity against 4T1 cells with an IC50 value of 10.60 µM. Furthermore, compound 3 distinctly induced apoptosis, inhibited immigration, and blocked the cell cycle of 4T1 cells. In addition, compound 3 induced the production of reactive oxygen species. Further anticancer mechanism studies showed that compound 3 significantly upregulated expression of the cleaved caspase 3 and PARP, whereas it downregulated the expression of Bcl-2, cyclin D1, cyclin A2, CDK4, and CDK2. Taken together, our results demonstrate that compound 3 has a high potential of being used as a leading compound for the discovery of new anti-breast cancer agent.

GADD45B in the ventral hippocampal CA1 modulates aversive memory acquisition and spatial cognition.

AIMS: This study was designed to investigate the role of growth arrest and DNA damage-inducible ß (GADD45B) in modulating fear memory acquisition and elucidate its underlying mechanisms. MAIN METHODS: Adeno-associated virus (AAV) that knockdown or overexpression GADD45B were injected into ventral hippocampal CA1 (vCA1) by stereotactic, and verified by fluorescence and Western blot. The contextual fear conditioning paradigm was employed to examine the involvement of GADD45B in modulating aversive memory acquisition. The Y-maze and novel location recognition (NLR) tests were used to examine non-aversive cognition. The synaptic plasticity and electrophysiological properties of neurons were measured by slice patch clamp. KEY FINDINGS: Knockdown of GADD45B in the vCA1 significantly enhanced fear memory acquisition, accompanied by an upregulation of long-term potentiation (LTP) expression and intrinsic excitability of vCA1 pyramidal neurons (PNs). Conversely, overexpression of GADD45B produced the opposite effects. Notably, silencing the activity of vCA1 neurons abolished the impact of GADD45B knockdown on fear memory development. Moreover, mice with vCA1 GADD45B overexpression exhibited impaired spatial cognition, whereas mice with GADD45B knockdown did not display such impairment. SIGNIFICANCE: These results provided compelling evidence for the crucial involvement of GADD45B in the formation of aversive memory and spatial cognition.

Discovery of sesquiterpene from Youngia japonica with antitumor effect.

Fourteen sesquiterpenes, including one undescribed sesquiterpene lactone, were isolated from Youngia japonica, and their structures were identified by NMR, HRESIMS, ECD and calculated ECD. Cytotoxic activities of all isolates against A549, HeLa, and 4 T1 cell lines were detected by CCK8 assay. Among them, 2 showed obvious cytotoxic activity against A549 cells. Subsequently, the production of ROS, and apoptosis of A549 cells treated with 2 were evaluated. The result showed that 2 distinctly increased the ROS level, and induced the apoptosis of A549 cells. Further anticancer mechanism studies showed that 2 increased the expression of cleaved caspase 3. Taken together, our results demonstrated that 2 might become potential leading compounds for the treatment of lung cancer.

Electroacupuncture at "Baihui, Yintang and Shuigou" Acupoints Improves Post-Stroke Cognitive Impairment in Mice.

OBJECTIVE: To study the effect and mechanism of electroacupuncture at "Baihui, Yintang and Shuigou" acupoints on learning and memory in Post-Stroke Cognitive Impairment (PSCI) mice. METHODS: 52 male C57BL/6 mice were used to establish a MACO model by using middle cerebral artery occlusion (n=38), while the Sham only ligated at the distal end of the external carotid artery (n=14). After 28 days, the MCAO was divided into three groups based on the escape latency of Morris water maze: non cognitive impairment (MNP), post-stroke cognitive impairment (MP), and electroacupuncture intervention group (MPEA). In the MPEA, electroacupuncture at "Baihui and Yintang" acupoints was performed for 20 minutes (density wave, 2/15HZ and 1mA) supplemented by acupuncture at "Shuigou" acupoints once a day with a 6-day course of treatment. The intervention last for 2 courses with a 1-day interval. Morris water maze was used to detect the cognitive function of mice in each group; Nissl staining was used to observe hippocampal neurons; Western blot was used to detect the expression of GluA1, Syp, and Syt-1 in the affected hippocampus; IHC was used to detect the expression of Syp in the CA1 region of the contralateral hippocampus. CONCLUSION: Acupuncture at points "Baihui, Yintang, and Shuigou" can improve the learning and memory abilities of PSCI mice, and its mechanism is related to synaptic plasticity of hippocampus.

Neuronal ApoE4 in Alzheimer's disease and potential therapeutic targets.

The most prevalent genetic risk factor for Alzheimer's disease (AD) is Apolipoprotein E (ApoE), a gene located on chromosome 19 that encodes three alleles (e2, e3, and e4) that give rise to the ApoE subtypes E2, E3, and E4, respectively. E2 and E4 have been linked to increased plasma triglyceride concentrations and are known to play a critical role in lipoprotein metabolism. The prominent pathological features of AD mainly include senile plaques formed by amyloid ß (Aß42) aggregation and neuronal fibrous tangles (NFTs), and the deposited plaques are mainly composed of Aß hyperphosphorylation and truncated head. In the central nervous system, the ApoE protein is primarily derived from astrocytes, but ApoE is also produced when neurons are stressed or affected by certain stress, injury, and aging conditions. ApoE4 in neurons induces Aß and tau protein pathologies, leading to neuroinflammation and neuronal damage, impairing learning and memory functions. However, how neuronal ApoE4 mediates AD pathology remains unclear. Recent studies have shown that neuronal ApoE4 may lead to greater neurotoxicity, which increases the risk of AD development. This review focuses on the pathophysiology of neuronal ApoE4 and explains how neuronal ApoE4 mediates Aß deposition, pathological mechanisms of tau protein hyperphosphorylation, and potential therapeutic targets.

Epigallocatechin-3-gallate Alleviates Cognitive Deficits in APP/PS1 Mice.

Alzheimer's disease (AD) shows cognitive impairments in clinic, which is multifactorial with different etiopathogenic mechanisms such as Aß deposition, neuroinflammation and neuronal dystrophy involved. Therefore, multi-targets drugs with neuroprotective, anti-amyloidogenic and anti-inflammatory properties will be effective in AD treatment. Epigallocatechin-3-gallate (EGCG) possesses a broad spectrum of pharmacological activities in the prevention and treatment of multiple neurodegenerative diseases. In the present study, we showed that oral administration of EGCG (50 mg/kg) for 4 months significantly attenuated the cognitive deficits in APP/PS1 transgenic mice, which served as AD model. Moreover, EGCG induced an improvement in dendritic integrity and expression levels of synaptic proteins in the brain of APP/PS1 mice. And EGCG exerted obvious anti-inflammatory effects, which was manifested by alleviating microglia activation, decreasing pro-inflammatory cytokine (IL-1ß) and increasing anti-inflammatory cytokines (IL-10, IL-13). Furthermore, ß-amyloid (Aß) plaques were markedly reduced in the hippocampus of 6-month old APP/PS1 mice after EGCG treatment. In conclusion, these findings indicate that EGCG improves AD-like cognitive impairments through neuroprotective, anti-amyloidogenic and anti-inflammatory effects, thus is a promising therapeutic candidate for AD.