Jiawei Xionggui Decoction promotes meningeal lymphatic vessels clearance of ß-amyloid by inhibiting arachidonic acid pathway.

BACKGROUND: Alzheimer's disease (AD) is an aging-associated form of dementia characterized by the pathological deposition of toxic misfolded proteins in the central nervous system (CNS), which is closely related to the clearance impairment of meningeal lymphatic vessels (mLVs). Thus, enhancement dural meningeal lymphatic drainage to remove amyloid-ß (Aß) is usually considered as a potential therapeutic target for AD. PURPOSE: This study aimed to investigate the mechanisms of Jiawei Xionggui Decoction (JWXG) to attenuate cognitive dificits in APP/PS1 mice with impaired meningeal lymphatic drainage. METHODS: Ligation of deep cervical lymph nodes (dcLNs) was performed to establish the mice model of the impaired meningeal lymphatic drainage in APP/PS1 mice. Cognitve behaviors and pathological morphology of mice were assessed. Cerebral blood flow (CBF) of mice was determined using Laser speckle contrast imaging analysis. Serum non-targeted metabolomics analysis was applied to decipher the mechanisms of JWXG in rescuing the impairment of mLVs, and C8-D1A cells were employed to validate in vitro. RESULTS: Disruption of mLVs in APP/PS1 mice deteriorated cognitive dysfunction, accelerated Aß burden and glia activation, accompanied by more severe neuropathological damage, CBF reduction and neuroinflammation exacerbation. Serum non-targeted metabolomics analysis indicates the increase of arachidonic acid (AA) metabolic pathway was the key contributor to the neuropathological exacerbation of dcLNs ligation APP/PS1 mice. Interestingly, clinically equivalent dose of JWXG was sufficient to restore mLVs drainage and rescue cognitive performance by inhibiting neuroinflammation depended by AA metabolic pathway in dcLNs ligation APP/PS1 mice. CONCLUSION: Our findings establish a novel mechanism that rescue mLVs by inhibiting AA metabolic pathway to clear brain Aß, and support JWXG as a feasible treatment strategy for AD by suppressing AA metabolic pathway to improve mLVs drainage efficiency.

Gastrodin relieves Parkinson's disease-related motor deficits by facilitating the MEK-dependent VMAT2 to maintain dopamine homeostasis.

BACKGROUND: Dysfunction of dopamine homeostasis (DAH), which is regulated by vesicular monoamine transporter 2 (VMAT2), is a vital cause of dopamine (DA) neurotoxicity and motor deficits in Parkinson's disease (PD). Gastrodin (4-hydroxybenzyl alcohol 4-O-ß-D-glucoside; GTD), a natural active compound derived from Gastrodia elata Blume, can be used to treat multiple neurological disorders, including PD. However, whether GTD regulates VMAT2-mediated DAH dysfunction in PD models remains unclear. PURPOSE: To explore whether GTD confers dopaminergic neuroprotection by facilitating DA vesicle storage and maintaining DAH in PD models. METHODS: Mice were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and PC12 cells with 1-methyl-4-phenyl-pyridinium (MPP+) to induce PD characteristics. Multiple behavioural tests were performed to evaluate the motor functions of the mice. HPLC was used to measure DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. Transmission electron microscopy was used to observe synaptic vesicles. Molecular docking and molecular dynamics were used to determine the binding affinity of GTD to the target protein. Reserpine (Res, a VMAT2 inhibitor) and PD0325901 (901, a MEK inhibitor) were employed to investigate the mechanism of GTD. Western blotting and immunohistochemistry were used to assess the expression of the target proteins. RESULTS: GTD attenuated motor deficits and dopaminergic neuronal injury, reversed the imbalance of DAH, and increased VMAT2 levels and vesicle volume in MPTP-induced mice. GTD ameliorated cell damage, ROS release, and dysfunction of DAH in MPP+-induced PC12 cells. Moreover, the neuroprotective effects of GTD were reversed by Res in vitro and in vivo. Furthermore, GTD can activate the MEK/ERK/CREB pathway to upregulate VMAT2 in vitro and in vivo. Interestingly, 901 reversed the effects of GTD on VMAT2 and dopaminergic neuronal impairment. CONCLUSION: GTD relieved PD-related motor deficits and dopaminergic neuronal impairment by facilitating MEK-depended VMAT2 to regulate DAH, which offers new insights into its therapeutic potential.

Baicalin and the liver-gut system: Pharmacological bases explaining its therapeutic effects.

With the development of high-throughput screening and bioinformatics technology, natural products with a range of pharmacological targets in multiple diseases have become important sources of new drug discovery. These compounds are derived from various plants, including the dried root of Scutellaria baicalensis Georgi, which is often used as a traditional Chinese herb named Huangqin, a popular medication used for thousands of years in China. Many studies have shown that baicalin, an extract from Scutellaria baicalensis Georgi, exerts various protective effects on liver and gut diseases. Baicalin plays a therapeutic role mainly by mediating downstream apoptosis and immune response pathways induced by upstream oxidative stress and inflammation. During oxidative stress regulation, PI3K/Akt/NRF2, Keap-1, NF-κB and HO-1 are key factors associated with the healing effects of baicalin on NAFLD/NASH, ulcerative colitis and cholestasis. In the inflammatory response, IL-6, IL-1ß, TNF-α, MIP-2 and MIP-1α are involved in the alleviation of NAFLD/NASH, cholestasis and liver fibrosis by baicalin, as are TGF-ß1/Smads, STAT3 and NF-κB. Regarding the apoptosis pathway, Bax, Bcl-2, Caspase-3 and Caspase-9 are key factors related to the suppression of hepatocellular carcinoma and attenuation of liver injury and colorectal cancer. In addition to immune regulation, PD-1/PDL-1 and TLR4-NF-κB are correlated with the alleviation of hepatocellular carcinoma, ulcerative colitis and colorectal cancer by baicalin. Moreover, baicalin regulates intestinal flora by promoting the production of SCFAs. Furthermore, BA is involved in the interactions of the liver-gut axis by regulating TGR5, FXR, bile acids and the microbiota. In general, a comprehensive analysis of this natural compound was conducted to determine the mechanism by which it regulates bile acid metabolism, the intestinal flora and related signaling pathways, providing new insights into the pharmacological effects of baicalin. The mechanism linking the liver and gut systems needs to be elucidated to draw attention to its great clinical importance.

Network pharmacology reveals the multiple mechanisms of Xiaochaihu decoction in the treatment of non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver (NAFLD) is a chronic disease worldwide, which poses a huge threat to human health. Xiaochaihu decoction is a well-known traditional Chinese medicine prescription. It has been proven effective in treating NAFLD but its mechanism is still unclear. OBJECTIVE: Multiple mechanisms of Xiaochaihu decoction are explored by identifying and connecting potential targets and active ingredients in the treatment of NAFLD. METHODS: Active ingredients and related targets of seven herbs were collected from TCMSP database. The related targets of NAFLD were obtained from Genes cards database, TDD and OMIM database. The intersected targets of disease targets and drug targets were input into STRING database to construct protein-protein interaction network. DAVID database was used for GO enrichment analysis and KEGG enrichment analysis. RESULTS: After screening and removal of duplicates, a total of 145 active ingredients and 105 potential targets were obtained. PPI network manifested that AKT1, IL6, JUN MAPK8 and STAT3 were the key target proteins. The results of GO enrichment analysis mainly involved cytokine receptor binding, cytokine activity, and heme binding. The results of KEGG analysis suggested that the mechanism mainly involved in AGE-RAGE signaling pathway in diabetic complications, Hepatitis C, fluid shear stress and atherosclerosis. The signaling pathways were further integrated as network manner, including AGE-RAGE signaling pathway in diabetic complications, Fluid shear stress and atherosclerosis, Insulin resistance, HIF-1 signaling pathway, Th17 cell differentiation and IL-17 signaling pathway. The network contained immunity regulation, metabolism regulation and oxidative stress regulation. CONCLUSION: Xiaochaihu decoction plays a key role in the treatment of NAFLD with multiple targets and pathways. Immunity regulation, metabolism regulation and oxidative stress regulation consist of the crucial regulation cores in mechanism. GRAPHICAL ABSTRACT: Design and workflow of this study.