Integrated metabolomics and network pharmacology study on the mechanism of herbal pair of danggui-kushen for treating ischemia heart disease.

DangGui-KuShen (DK) is a well-known classic traditional Chinese medicine recipe that improves blood circulation, eliminates moisture, and detoxifies, and is frequently used in the treatment of cardiovascular problems. Some protective effects of DK on cardiovascular disease have previously been identified, but its precise mechanism remains unknown. The goal of this study is to combine metabolomics and network pharmacology to investigate DK's protective mechanism in Ischemic Heart Disease(IHD) rat models. A combination of metabolomics and network pharmacology based on UPLC-Q-TOF/MS technology was used in this study to verify the effect of DK on IHD through enzyme-linked immunosorbent assay, HE staining, and electrocardiogram, and it was determined that DK improves the synergistic mechanism of IHD. In total, 22 serum differential metabolites and 26 urine differential metabolites were discovered, with the majority of them involved in phenylalanine, tyrosine, and tryptophan biosynthesis, glycine, serine, and threonine metabolism, arginine and proline metabolism, aminoacyl-tRNA biosynthesis, purine metabolism, and other metabolic pathways. Furthermore, using network pharmacology, a composite target pathway network of DangGui and KuShen for treating IHD was created, which is primarily associated to the tumor necrosis factor (TNF) signaling pathway, P53 signaling, and HIF-1 signaling pathways. The combined research indicated that the NF-B signaling pathway and the HIF-1 signaling pathway are critical in DK treatment of IHD. This study clearly confirms and expands on current knowledge of the synergistic effects of DG and KS in IHD.

Therapeutic Effects of the major alkaloid constituents of Evodia rutaecarpa in Alzheimer's disease.

Since the report of Alzheimer's disease (AD) in 1907, it has garnered widespread attention due to its intricate pathogenic mechanisms, significant impact on patients' lives, and the substantial burden it places on society. Presently, effective treatments for AD remain elusive. Recent pharmacological studies on the traditional East Asian herb, Evodia rutaecarpa, have revealed that the bioactive alkaloid components within it can ameliorate AD-related cognitive impairments and neurological damage through various pathways, including anti-inflammatory, antioxidant, and anti-acetylcholinesterase activities. Consequently, this article provides an overview of the pharmacological effects and research status of the four main alkaloid components found in Evodia concerning AD. We hope this article will serve as a valuable reference for experimental and clinical research on the use of Evodia in AD prevention and treatment.

Protective effect and mechanism of different proportions of "Danggui-Kushen" herb pair on ischemic heart disease.

This study aims to investigate the protective effect and mechanism of "Danggui-Kushen" herb pair (DKHP) on ischemic heart disease (IHD). The rat model of myocardial reperfusion injury (MIRI) was established by ligation of the left anterior descending coronary artery. Rats were randomly divided into seven groups and administered orally for 7 days: control group, IHD group, DKHP1:1 group, DKHP1:2 group, DKHP2:1 group, DKHP1:3 group, DKHP3:1 group, the dosage was 2.7 g/kg. Measure electrocardiogram (ECG), myocardial infarction and injury assessment, Hematoxylin and eosin (HE) staining to evaluate myocardial injury and the protective effect of DKHP. Lactate dehydrogenase (LDH), Reactive oxygen species (ROS), IL-1ß and IL-6 kit detection, immunohistochemical analysis, establishment of H9c2 cardiomyocyte hypoxia (Hypoxia) model, DKHP pretreatment for 3 h, MTT method to detect cell survival rate, cell immunofluorescence to observe NF- The expression of TLR-4, NF-κB, p-NF-κB, IKßα, p-IKßα, HIF-1α, VEGF and other genes and proteins were detected by κB nuclear translocation, mitochondrial membrane potential measurement, Western blot and Polymerase Chain Reaction (PCR). Compared with the model group, DKHP can reduce the size of myocardial infarction, reduce the levels of factors such as LDH, ROS, IL-1ß and IL-6, and improve the cell survival rate; Compared with the model group, DKHP can inhibit the nuclear transfer of NF-κB and reduce mitochondrial damage; the results of immunohistochemical analysis, PCR and Western blot showed that compared with the model group, DKHP can reduce TLR-4, p-NF-κB, Expression levels of p-IKßα, HIF-1α, VEGF and other proteins. Reveal that DKHP may play a protective role in ischemic heart disease by reducing inflammation and oxidative stress damage. DKHP may have protective effect on ischemic heart disease, and its mechanism may be through reducing inflammatory response and oxidative stress damage to achieve this protective effect.

The study of therapeutic efficacy and mechanisms of Schisandra chinensis and Evodia rutaecarpa combined treatment in a rat model of Alzheimer's disease.

Schisandra chinensis and Evodia rutaecarpa are traditional Chinese herbs used to treat neurodegenerative diseases. This study investigates the combined effects of SC and ER on learning and memory in an Alzheimer's disease rat model and their underlying mechanisms. Methods: High-performance liquid chromatography was employed to analyze the primary active constituents of Schisandra and Evodia. The effects of the combined treatment of Schisandra and Evodia on learning and memory in an Alzheimer's disease rat model were evaluated through Morris water maze and Hematoxylin-Eosin staining experiments. Immunohistochemical analysis was conducted to investigate the impact of S-E on Aß1-42 and P-tau proteins. Western blotting and real-time quantitative polymerase chain reaction were utilized to quantify the expression of pivotal proteins and genes within the BDNF/TRKB/CREB and GSK-3ß/Tau pathways. Results: The treatment group exhibited significant neuroprotective effects, ameliorating learning and memory impairments in the Alzheimer's disease rat model. The treatment regimen modulated the activity of the BDNF/TRKB/CREB and GSK-3ß/Tau pathways by influencing the expression of relevant genes, thereby reducing the generation of Aß1-42 and P-Tau proteins and inhibiting the deposition of senile plaques. Furthermore, among the three treatment groups, the combined treatment demonstrated notably superior therapeutic effects on Alzheimer's disease compared to the single-drug treatment groups.

Different ratios of Schisandra chinensis and Evodia rutaecarpa combination for treating Alzheimer's disease.

Schisandra chinensis and Evodia rutaecarpa are traditional Chinese herbs that have been used for many years to treat neurodegenerative diseases. In Chinese medicine, multiple herbs are often used in combination to enhance their efficacy, and different combination ratios can produce different therapeutic effects, thus flexibly responding to the needs of various patients. This study aimed to investigate the effects of different ratios of Schisandra and Evodia herbs on learning and memory impairment in rats with Alzheimer's disease (AD) and their specific mechanisms of action. Morris water maze and hematoxylin and eosin (HE) staining experiments were performed to evaluate the effects of different ratios of Schisandra-Evodia on learning memory in AD model rats. Immunohistochemical experiments were performed to investigate the effects of Schisandra-Evodia on the Aß1-42 and P-Tau proteins, and protein immunoblotting (WB) was performed to determine the expression of key proteins in two pathways, BDNF/TrkB/CREB and GSK-3ß/Tau. Our experimental results show that all Schisandra-Evodia groups showed significant neuroprotective effects, improved learning memory impairment, and reduced levels of Aß1-42 and P-Tau proteins in AD model rats. Schisandra-Evodia upregulated BDNF, P-TrkB/TrkB, and P-CREB/CREB protein expression and downregulated GSK-3ß and P-Tau/Tau protein expression. Among the different Schisandra-Evodia ratio groups, the 2:1 group showed the strongest therapeutic effect on AD. Our research results indicate that Schisandra-Evodia can reduce Aß1-42 and P-Tau protein content by modulating the activity of two pathways, BDNF/TrkB/CREB and GSK-3ß/Tau, thus improving neuronal cell damage and cognitive deficits caused by AD. In addition, we found that a Schisandra-Evodia ratio of 2:1 had the most profound therapeutic effect on AD.

Characterization of chemical constituents and metabolites in vivo and in vitro after oral administration of Wuteng tablets in rats by UHPLC-Q/TOF-MS.

Waste medicinal plants are widely used in drug production. With the increasing demand for botanical drugs, there is an urgent need to identify new and effective drugs and improve the utilization of medicinal plant resources. Wuteng tablets (WTP) are extracted from the stem of Schisandra chinensis and have a good therapeutic effect on Alzheimer's disease. In this study, a holistic identification strategy based on UHPLC-Q/TOF-MS was developed for the first time to investigate the metabolites and metabolic pathways involved in the in vitro metabolism and liver microsomal incubation and in the in vivo metabolic system of rats after WTP administration. After the oral administration of WTP, 21 metabolites were identified in the serum and 25 metabolites were identified in the urine, of which six were new metabolites; 33 metabolites were inferred from the microsomal metabolites in vitro. The metabolic pathways related to WTP mainly involve demethylation, hydroxylation, dehydroxylation and dehydrogenation. In this study, the metabolites and metabolic pathways of WTP were elucidated via UHPLC-Q/TOF-MS, which provided a basis for an in-depth study of the pharmacodynamic and pharmacotoxicological effects of WTP.

The Role of NF-κB in Myocardial Ischemia/Reperfusion Injury.

Acute myocardial infarction (AMI) is a threat to human life and physical health worldwide. Timely reperfusion is very important to limit infarct size and protect ischemic myocardium. Unfortunately, it has also caused severer myocardial damage, which is called "myocardial ischemia/ reperfusion injury (MIRI)". There is no effective clinical treatment for it. Over the past two decades, biological studies of NF-κB have improved the understanding of MIRI. Nuclear Factor-κB (NF-κB) is a major transcription factor associated with cardiovascular health and disease. It is involved in the release of pro-inflammatory factors and apoptosis of cardiomyocytes. Recent studies have shown that inhibition of NF-κB plays a protective role in acute hypoxia and reperfusion injury. Here we review the molecular regulation of NF-κB in MIRI, better understanding of NF-κB signaling mechanisms related to inflammation and crosstalk with endogenous small molecules. We hope this review will aid in improving therapeutic approaches to clinical diagnosing. This review provides evidence for the role of NF-κB in MIRI and supports its use as a therapeutic target.

HIF­1α in cerebral ischemia (Review).

Cerebral ischemic injury may lead to a series of serious brain diseases, death or different degrees of disability. Hypoxia­inducible factor­1α (HIF­1α) is an oxygen­sensitive transcription factor, which mediates the adaptive metabolic response to hypoxia and serves a key role in cerebral ischemia. HIF­1α is the main molecule that responds to hypoxia. HIF­1α serves an important role in the development of cerebral ischemia by participating in numerous processes, including metabolism, proliferation and angiogenesis. The present review focuses on the endogenous protective mechanism of cerebral ischemia and elaborates on the role of HIF­1α in cerebral ischemia. In addition, it focuses on cerebral ischemia interventions that act on the HIF­1α target, including biological factors, non­coding RNA, hypoxic­ischemic preconditioning and drugs, and expands upon the measures to strengthen the endogenous compensatory response to support HIF­1α as a therapeutic target, thus providing novel suggestions for the treatment of cerebral ischemia.

Synthesis and evolution of neuroprotective effects of oxymatrine derivatives as anti-Alzheimer's disease agents.

While screening for natural product scaffolds as potential anti-Alzheimer's disease (AD), oxymatrine (OMT) was found to relieve symptoms of AD through diminishing death of neuronal cells caused by microglia-induced inflammation. In this study, 13 derivatives of OMT were synthesized and their neuroprotective effects were evaluated on Aß1-42 -induced PC12 cells using MTT method. In addition, the best neuroprotective potencies were obtained with compounds 4, 6e, and 6f, which were selected for evaluation of decrease in IL-1ß and TNF-α in Aß1-42 -treated PC12 cells. Collectively, these data reveal that derivatives 6e and 6f possess the best ability of diminish IL-1ß production and reverse cell damage in all compounds, which are possible to develop as therapeutic agents for AD.

Hepatoprotective activity assessment of amino acids derivatives of picroside I and II.

Picrorhiza kurroa has a long medicinal history as a traditional medicinal plant in China and India that is widely used in clinical treatments. It is a common treatment for liver diseases, fever, diarrhoea, indigestion, and some other diseases. Modern pharmacological studies proved that P. kurroa rhizomes have high levels of picroside I and II, which were identified as main constituents with anti-inflammatory and hepatoprotective activities. In our study, we used picroside I and II as the lead compounds to generate derivatives by reactions with Boc-valine or Boc-proline, which underwent dehydration and condensation with the hydroxyl groups in the lead compounds in the presence of coupling reagent N,N'-dicyclohexylcarbodiimide. We synthesized 11 derivatives and examined their hepatoprotective effects in vitro by assessing the proliferation rates of H2 O2 -exposed HepG2 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. We found that some derivatives promoted higher proliferation rates in HepG2 cells than the natural compounds before derivatization, suggesting that those derivatives possessed an improved hepatoprotective capacity. The novel derivatization strategy for picrosides had the additional benefit that the esterification of their hydroxyl groups created derivatives not only with increased stability but also with improved pharmacokinetic properties and potentially prolonged half-life.

Oxymatrine exhibits anti-neuroinflammatory effects on Aß1-42-induced primary microglia cells by inhibiting NF-κB and MAPK signaling pathways.

Oxymatrine (OMT), isolated from Sophora flavescens or Sophora alopecuroides, possesses various pharmacological and biological activities, including anti-inflammatory, anti-oxidant, and anti-diabetic properties. Microglia cells, the resident immune cells in the central nervous system (CNS), play a key role in neurodegenerative diseases. In this study, the neuroinflammatory effects of OMT and its mechanisms were investigated by Aß1-42-induced rat brain tissue model and primary microglia cells model. The hematoxylin-eosin (HE) staining and immunohistochemistry results showed that OMT could reduce neuronal damage and inhibit microglia activation in the model tissue. The in vitro experiments revealed that OMT could decrease the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and nitric oxide (NO), and down-regulate the expression of iNOS and COX-2 in a dose-dependent manner. Furthermore, OMT inhibited phosphorylation of JNK, ERK 1/2, P-p38 and NF-κB in Aß1-42-induced microglia cells. In summary, OMT exhibits anti-neuroinflammatory effects and the anti-inflammatory activity of OMT is related to the regulation of MAPK and NF-κB signaling pathways.

Oxymatrine attenuates amyloid beta 42 (Aß1-42)-induced neurotoxicity in primary neuronal cells and memory impairment in rats.

Amyloid beta 42 (Aß1-42)-induced oxidative stress causes the death of neuronal cells and is involved in the development of Alzheimer's disease. Oxymatrine (OMT) inhibits oxidative stress. In this study, we investigated the effect of OMT on Aß1-42-induced neurotoxicity in vivo and in vitro. In the Morris water maze test, OMT significantly decreased escape latency and increased the number of platform crossings. In vitro, OMT markedly increased cell viability and superoxide dismutase activity. Moreover, OMT decreased lactate dehydrogenase leakage, malondialdehyde content, and reactive oxygen species in a dose-dependent manner. OMT upregulated the ratio of Bcl-2/Bax and downregulated the level of caspase-3. Furthermore, OMT inhibited the activation of MAP kinase (ERK 1/2, JNK) and nuclear factor κB. In summary, OMT may potentially be used in the treatment of Alzheimer's disease.

Synthesis and biological evaluation of picroside derivatives as hepatoprotective agents.

Picrorhizae Rhizoma as a hepatoprotective herb, has been applied for thousands of years, and picroside was proved to be its active constituent. In this study, twelve derivatives of picroside were synthesized and the hepatoprotective activity of the derivatives was evaluated on SMMC-7721 cells. Six out of the derivatives had shown a better protective effect on H2O2-induced SMMC-7221 cells than picroside, and the activity of two derivatives (2 and 4) was stronger than that of the reference compound, silybin. Compound 2 shown the strongest protective effect (EC50 = 6.064 ± 1.295 µM).

Synthesis and Promotion of the Osteoblast Proliferation Effect of Morroniside Derivatives.

Sambucus williamsii Hance has been used in fractures for thousands of years, but research on its active components, such as morroniside, until now had not been carried out. In this study, morroniside was taken as the leading compound, and fourteen derivatives were synthesized. The promotion of osteoblast proliferation effect of the derivatives was evaluated on MC3T3-E1 cells. Five derivatives (2, 3, 4, 5, and 14) showed a good proliferation effect on MC3T3-E1 cells, and their promoted expression effects on OC (Osteocalcin) and ALP (Alkaline phosphatase) in MC3T3-E1 cells were measured. Compound 3 was shown to have the strongest proliferation effect (EC50 = 14.78 ± 1.17 µg/mL) and to significantly promote the expression of OC and ALP.

P­glycoprotein inhibition increases the transport of dauricine across the blood­brain barrier.

Dauricine is the major bioactive component isolated from the roots of Menispermum dauricum D.C. The aim of the present study was to investigate the role of P­glycoprotein in the transport of dauricine across the blood­brain barrier by pre­treatment with the P­glycoprotein inhibitor verapamil. Sprague Dawley rats were divided into a verapamil group (pretreated with verapamil at a dose of 20 mg/kg) and a control group (pretreated with the same volume of normal saline). After 90 min, the animals were injected intravenously with dauricine (10 mg/kg). At 15, 30 and 60 min after dauricine administration, the levels of dauricine in the blood and brain were detected by high­performance liquid chromatography. Compared with the control group, the dauricine concentration in the brains of the rats in the verapamil group was significantly increased. Furthermore, the brain­plasma ratio of dauricine in the rats pretreated with verapamil was significantly higher than that of the animals in the control group. However, there was no difference identified between dauricine levels in the plasma of the verapamil and the control groups. The results indicated that dauricine is able to pass the blood­brain barrier, and that P­glycoprotein has an important role in the transportation of dauricine across the blood­brain barrier.