Exploring TβRI inhibitors from Arenaria kansuensis based on 3D-QSAR, molecular docking and molecular dynamics simulation methods and its anti-pulmonary fibrosis molecular mechanism validation

Article

Author: Cui, Yulei ; Xin, Huawei ; Che, Fengyuan ; Shao, Ziyao ; Shen, Na

ETHNOPHARMACOLOGICAL RELEVANCEPulmonary fibrosis (PF) is a kind of interstitial lung disease that seriously threatens human life and health. Up to now, there is no specifically therapeutic drug. Arenaria kansuensis, a typical Tibetan medicine, has been previously proved to have anti-PF pharmacological activity by our group. However, the specific target and molecular mechanism of pharmacological active ingredients from it are still unknown.AIM OF THE STUDYThis study aimed to explore the molecular mechanism and specific target of pharmacological active ingredients from A. kansuensis for treating PF.MATERIALS AND METHODSVirtual screening including 3D-QSAR, molecular docking and molecular dynamics simulation were used to screen TβRI inhibitor. CETSA experiment was used to verify the interaction between GAK (a β-carboline alkaloid isolated from A. kansuensis) and TβRI. Cell and molecular experiments including observation of cell morphology and Western blot were applied to investigate the molecular mechanism of action of GAK for treating PF. Animal experiments including physiological index, immunohistochemistry and ELISA were used to comprehensively evaluate the anti-PF effect of GAK and explore the corresponding mechanism of action.RESULTSResults of 3D-QSAR experiment indicated that GAK is a much stronger potential TβRI inhibitor, molecular mechanism study showed that 30 μM GAK could significantly keep TβRI more stable which indicated that the direct binding interaction between GAK and TβRI, it targetedly inhibited TβRI through forming hydrogen bonds with LYS232, SER280 and ASP351 and the binding energies is -56.05 kcal/mol. In vitro experiment showed GAK could suppress downstream signal pathways of TβRI including MAPK, PI3K/AKT and NF-κB pathways during EMT process. In vivo experiment showed that GAK could improve the survival rate and body weight of PF mice, alleviate the symptoms of histopathological severity, inflammatory cell infiltration and collagen deposition in lung tissue of PF mice through inhibiting EMT process of PF.CONCLUSIONSThis work not only provided evidence to support GAK as a novel TβRI inhibitor for treating PF through multiple pathways, but also reveal the specific target and molecular mechanism of β-carboline alkaloids from A. kansuensis for treating PF.

01 Jan 2025·Journal of Ethnopharmacology

Effects and mechanisms of harmine on ameliorating ethanol-induced memory impairment

Article

Author: Xiang, Zedong ; Hu, Xianrun ; Zhao, Xiang ; Cai, Fujie ; Liu, Wenkang ; Wang, Changhong ; Xie, Zhejun ; Cheng, Xuemei ; Dang, Rui

ETHNOPHARMACOLOGICAL RELEVANCEPeganum harmala L., a traditional Uyghur ethnic medicine widely used in China, is commonly used in the treatment of conditions such as hemiplegia, forgetfulness, cough, and asthma. Harmine and other β-carboline alkaloids, one of the main active ingredients in P. harmala, have exhibited various pharmacological activities, including anti-Alzheimer's, antidepressant, anti-inflammatory, and antioxidant effects. However, the effects and underlying mechanisms of harmine on improving ethanol-induced memory impairment remain unclear.AIM OF THE STUDYThis study aimed to investigate the effects of harmine on ameliorating ethanol-induced memory impairment, and to explore potential mechanisms.MATERIALS AND METHODSEthanol (30%, i. g.) was used to induce memory impairment model. The effect of harmine on memory impairment was evaluated by Morris water maze (MWM). The histopathological analysis, immunofluorescence staining, RT-qPCR and UHPLC-MS/MS methods were performed to further investigate the underlying mechanisms.RESULTSMWM experiments showed that harmine significantly improved ethanol-induced spatial learning memory deficit. Harmine exhibited anti-inflammatory effect by downregulating inflammatory factors such as IL-6, IL-1β and tumor necrosis factor-α (TNF-α) induced by ethanol. Harmine also upregulated brain-derived neurotrophic factor (BDNF) levels to exert neuroprotective effect. Moreover, harmine protected neuronal cells and increased the protein expression of myelin basic protein (MBP). The cellular results indicated that harmine protected SH-SY5Y cells from ethanol-induced cytotoxicity and upregulated the relative mRNA expression of synaptosome associated protein 25 (SNAP25), syntaxin 1 A (STX1A), vesicle associated membrane protein 2 (VAMP2), synaptotagmin 1 (SYT1) and synaptophysin (SYP).CONCLUSIONSHarmine improved ethanol-induced memory impairment by ameliorating inflammation, increasing BDNF levels, promoting synaptic vesicle fusion, protecting myelin sheath, and modulating neurotransmitter levels. These findings provided a scientific basis for development of therapeutic drugs for alcohol-induced memory impairments and other related disorders.

01 Dec 2024·Food Chemistry

Development of a simultaneous analytical method for the dietary exposure determination of β-Carboline alkaloids in foods

Article

Author: Lim, Kyung-Jik ; Son, Junghyun ; Jeong, Woo Yeon ; Hwang, Sungmin ; Park, Hana ; Heo, Soohyun ; Shin, Han-Seung ; Na, Sunhwan ; Cho, Yoeseph ; Park, Saeyeon

As β-carboline (βC) alkaloids, posing potential health risks, are present in a wide variety of foods, determining the exposure degrees of food to these alkaloids from dietary activity is key to ensuring food safety. Here, we developed a rapid and sensitive simultaneous analytical method for six βC alkaloids in food. We optimized the buffered QuEChERS method, which includes a clean-up process through dispersive solid phase extraction, to extract the target compounds from food matrices; then, these compounds were detected via liquid chromatography-tandem mass spectrometry. We established calibration ranges for each target compound and matrix within the range of 0.05-250 μg/kg, and verified linearity (R² ≥ 0.99) and limit of quantitation (≤1.63 μg/kg). Furthermore, we validated trueness (85.8%-118.8%) and precision (≤18.7%) at three levels within the calibration range, including the lowest and highest concentrations. Finally, we employed the developed method to determine the βC alkaloid contents in 304 samples of 41 food items and dietary exposure of six βC alkaloids resulting from daily intake. Although βC alkaloids were detected in 86.2% of the samples, exposure level to the 41 food items was insufficient to cause toxicity.

100 Deals associated with CDR-007

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	MY	Universiti Sains Malaysia	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

CDR-007

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation