Network pharmacology- and molecular docking-based investigation on the mechanism of action of Si-ni San in the treatment of depression combined with anxiety and experimental verification in adolescent rats.

Background: The incidence rate of adolescent depression and anxiety has been increasing since the outbreak of COVID-19, which there are no effective therapeutic drugs available. Si-ni San is commonly used in traditional Chinese medicine for the treatment of depression-like as well as anxiety-like behavior, but its mechanism for treating depression combined with anxiety during adolescence is not yet clear. Methods: Network pharmacology was used to explore potential drug molecules and related targets, molecular docking and molecular dynamics (MD) simulation were used to evaluate the interaction between the potential drug molecules and related targets, and a model of anxiety combined with depression in adolescent rats as well as the following behavioral tests and molecular biology tests were used to verify the results from network pharmacology and molecular docking. Results: As a result, 256 active ingredients of Si-ni San and 1128 potential targets were screened out. Among them, quercetin, Luteolin, kaempferol, 7-Methoxy-2-methyl isoflavone, formononetin showed to be the most potential ingredients; while STAT3, IL6, TNF, AKT1, AKT1, TP53, IL1B, MAPK3, VEGFA, CASP3, MMP9 showed to be the most potential targets. AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, HIF-1 signaling pathway, PI3K-Akt signaling pathway and TNF signaling pathway, which are involved in anti-inflammation processes, showed to be the most probable pathways regulated by Si-ni San. Molecular docking and MD simulation between the compounds to inflammation-associated targets revealed good binding abilities of quercetin, Luteolin, kaempferol, nobiletin and formononetin to PTGS2 and PPARγ. In the experiment with adolescent rats, Si-ni San markedly suppressed early maternal separation (MS) combined with adolescent chronic unpredictable mild stress (CUMS)-induced depression combined with anxiety. The qPCR results further indicated that Si-ni San regulated the oxidative stress and inflammatory response. Conclusion: This study demonstrates that adolescent anxiety- and depression-like behavior induced by MS combined CUMS can be ameliorated by Si-ni San by improved inflammation in hippocampus via targeting TNF pathway and Nrf2 pathway, helping to reveal the mechanism of Si-ni San in treating adolescent depression combined with anxiety.

Comparative Study on the Pharmacokinetics of Paeoniflorin, White Peony Root Water Extract, and Taohong Siwu Decoction After Oral Administration in Rats.

BACKGROUND AND OBJECTIVE: Taohong Siwu Decoction (TSD) is a classic traditional Chinese medicine (TCM) compound with pharmacological effects such as vasodilation and hypolipidemia. Paeoniflorin (PF) is one of the active ingredients of TSD. The aim of this study was to evaluate the pharmacokinetics of PF in herbal extracts and their purified forms in rats. METHOD: A sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) method for the determination of PF in rat plasma was developed. Rats were divided into three groups, and given PF solution, water extract of white peony root (WPR), or TSD by gavage. At different predetermined timepoints after gavage, blood was collected from the orbital vein. The pharmacokinetic parameters of PF in the plasma of rats in the three groups was determined. RESULTS: The pharmacokinetic studies showed that the time to reach maximum concentration (Tmax) of PF in the purified forms group was relatively high, while the half-lives (T½) of PF in the TSD and WPR groups were longer. Among the three groups, PF in the purified forms group had the maximum area under the concentration-time curve (AUC0-t = 732.997 µg/L·h) and the largest maximum concentration (Cmax = 313.460 µg/L), which showed a significant difference compared with the TSD group (P < 0.05). Compared with the purified group, the clearance (CLz/F = 86.004 L/h/kg) and the apparent volume of distribution (Vz/F = 254.787 L/kg) of PF in the TSD group increased significantly (P < 0.05). CONCLUSIONS: A highly specific, sensitive, and rapid HPLC-MS-MS method was developed and applied for the determination of PF in rat plasma. It was found that TSD and WPR can prolong the action time of paeoniflorin in the body.

Connecting the Dots Between Hypercholesterolemia and Alzheimer's Disease: A Potential Mechanism Based on 27-Hydroxycholesterol.

Alzheimer's disease (AD), the most common cause of dementia, is a complex and multifactorial disease involving genetic and environmental factors, with hypercholesterolemia considered as one of the risk factors. Numerous epidemiological studies have reported a positive association between AD and serum cholesterol levels, and experimental studies also provide evidence that elevated cholesterol levels accelerate AD pathology. However, the underlying mechanism of hypercholesterolemia accelerating AD pathogenesis is not clear. Here, we review the metabolism of cholesterol in the brain and focus on the role of oxysterols, aiming to reveal the link between hypercholesterolemia and AD. 27-hydroxycholesterol (27-OHC) is the major peripheral oxysterol that flows into the brain, and it affects ß-amyloid (Aß) production and elimination as well as influencing other pathogenic mechanisms of AD. Although the potential link between hypercholesterolemia and AD is well established, cholesterol-lowering drugs show mixed results in improving cognitive function. Nevertheless, drugs that target cholesterol exocytosis and conversion show benefits in improving AD pathology. Herbs and natural compounds with cholesterol-lowering properties also have a potential role in ameliorating cognition. Collectively, hypercholesterolemia is a causative risk factor for AD, and 27-OHC is likely a potential mechanism for hypercholesterolemia to promote AD pathology. Drugs that regulate cholesterol metabolism are probably beneficial for AD, but more research is needed to unravel the mechanisms involved in 27-OHC, which may lead to new therapeutic strategies for AD.

Extract of Danggui-Shaoyao-San ameliorates cognition deficits by regulating DHA metabolism in APP/PS1 mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine formula Danggui-Shaoyao-San (DSS) has been reported to show therapeutic effect on alleviating the symptoms of Alzheimer's disease (AD). AIM OF THE STUDY: The present study aims to investigate the relation between DSS treatment of AD and DHA metabolism and evaluates its neuroprotective effect on cognitive in APP/PS1 mice. MATERIAL AND METHODS: DSS (1.6, 3.2, 6.4 g/kg/day) or Aricept (3 mg/kg/day) was orally administered (i.g.) to APP/PS1 mice, and saline was orally administered to Wild-type (WT) male mice as control group. Then, the Morris water maze (MWM) test, Y-maze spontaneous alternation test, open filed test and fear conditioning test were conducted for evaluation of learning and memory abilities. The DHA content was assessed by HPLC-MS/MS. Physiological indices were determined, including triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), ROS level, activity of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), PEG2, TXB2 and LTB4. The expressions of COX-1, COX-2, cPLA2, iPLA2, 15-LOX, and were assessed by Western blot. RESULTS: APP/PS1 mice showed serious cognitive impairment in behavioral tests. However, treatment of DSS extract significantly ameliorated the cognitive deficits of APP/PS1 mice. Biochemical measurements showed the increases in TG, TC, LDL-c and the decrease in HDL-c in APP/PS1 mice compared with WT mice, and DSS extract significantly retarded these changes. Low content of DHA, low expression of iPLA2 and 15-LOX were observed both in hippocampus and cortex of APP/PS1 mice, while DSS extract significantly restored these changes. Additionally, the abnormal activity of SOD and ROS level, the decreased levels of MDA and GSH were observed in APP/PS1 mice, while DSS extract prominently lessened these changes. Moreover, DSS extract decreased the level of PEG2, TXB2 and LTB4 and also attenuated the expression of cPLA2, COX-1 and COX-2 in hippocampus as well as cortex of APP/PS1 mice. CONCLUSIONS: Based on these results, we suggest that DSS play a positive effective role in increasing DHA content by up-regulating iPLA2 and 15-LOX, resulting in ameliorating oxidative stress and inflammation and finally ameliorating cognition deficits in APP/PS1 mice.

New Insights into the Role of Weak Electron⁻Phonon Coupling in Nanostructured ZnO Thin Films.

High-quality crystalline nanostructured ZnO thin films were grown on sapphire substrates by reactive sputtering. As-grown and post-annealed films (in air) with various grain sizes (2 to 29 nm) were investigated by scanning electron microscopy, X-ray diffraction, and Raman scattering. The electron⁻phonon coupling (EPC) strength, deduced from the ratio of the second- to the first-order Raman scattering intensity, diminished by reducing the ZnO grain size, which mainly relates to the Fröhlich interactions. Our finding suggests that in the spatially quantum-confined system the low polar nature leads to weak EPC. The outcome of this study is important for the development of nanoscale high-performance optoelectronic devices.