Harzianic acids and oxazolidinone from the endophytic fungus Ilyonectria sp. and their cytotoxicity activity.

Four undescribed compounds including three harzianic acids (1, 3 and 4) and one oxazolidinone (2), along with three known ones (5-7) were isolated from the solid fermented product of endophytic fungus Ilyonectria sp., their structures were elucidated as 1-amino-harzianic acid (1), ilyonectria-oxazolidinone (2),10'-nor- isoharzianic acid (3), isohomoharzianic acid (4), harzianic acid (5), isoharzianic acid (6), homoharzianic acid (7) by means of detailed chemical evidences and spectroscopic data analysis. All the compounds were evaluated for cytotoxicity against SMMC-7721 human cancer cell lines by MTS assay. Among the seven tested compounds, 1-amino-harzianic acid (1) demonstrated well cytotoxic activity against SMMC-7721 with IC50 value of 26.84 µM. The results of molecular docking indicated that compound exhibited moderate anti-tumor activity may through binding to apoptosis related proteins.

Molecular mechanisms of Codonopsis pilosula in inhibiting hepatocellular carcinoma growth and metastasis.

BACKGROUND: Liver cancer, one of the most common types of cancer worldwide, accounts for millions of cases annually. With its multi-target and wide-ranging therapeutic effects, traditional Chinese medicine has emerged as a potential approach for treating various tumors. Codonopsis pilosula, a traditional herb, is known for its anti-inflammatory and antioxidant properties. In this study, we investigated the potential molecular mechanisms of Codonopsis pilosula in regulating the inhibition of CDK1 and the modulation of PDK1/ß-catenin, which are involved in hepatocellular carcinoma growth and metastasis. STUDY DESIGN/METHODS: Firstly, we screened the active chemical constituents of Codonopsis pilosula and identified their respective target proteins using the Herb database. Then, we applied the GeneCards database and transcriptome sequencing analysis to screen for critical genes associated with the occurrence and development of liver cancer. The intersection of the target proteins and disease-related genes was used to determine the potential targets of Codonopsis pilosula in hepatocellular carcinoma. Protein-protein interaction analysis and GO/KEGG analysis were subsequently performed to uncover the pathways through which Codonopsis pilosula acts on liver cancer. The Huh-7 cell line, exhibiting the highest sensitivity to Codonopsis pilosula polysaccharide solution (CPP) intervention, was chosen for subsequent studies. Cell viability was evaluated using the CCK-8 assay, colony formation assay was conducted to determine cell proliferation capacity, flow cytometry was used to analyze cell cycle, TUNEL staining was performed to assess cell apoptosis, scratch assay was carried out to evaluate cell migration ability, the expression of EMT-related proteins was detected and analyzed, and cell sphere formation assay was conducted to investigate cell stemness. Finally, a liver cancer animal model was established, and different doses of CPP were administered via gavage the next day. The expression levels of CDK1, PDK1, and ß-catenin in mouse liver tissues were detected and analyzed, immunohistochemistry staining was performed to assess the expression of tumor cell proliferation-related proteins Ki67 and PCNA in mouse xenografts, and TUNEL staining was carried out to evaluate cell apoptosis in mouse liver tissues. After intervention with CDK1 expression, the expression levels of CDK1, PDK1, and ß-catenin proteins and mRNA in each group of cells were detected using Western blot and RT-qPCR. RESULTS: Through network pharmacology analysis, transcriptome sequencing, and bioinformatics analysis, 35 target genes through which Codonopsis pilosula acts on liver cancer were identified. Among them, CDK1, with the highest degree in the PPI network, was considered an essential target protein for Codonopsis pilosula in treating liver cancer. In vitro cell experiments revealed that CPP could inhibit the expression of CDK1/PDK1/ß-catenin signaling axis factors, suppress cell proliferation, decrease cell migration ability, influence the EMT process, and reduce cell stemness by inhibiting CDK1 and affecting the PDK1/ß-catenin signaling axis. Similarly, in vivo experiments demonstrated that CPP could regulate the CDK1/PDK1/ß-catenin signaling axis, inhibit tumor growth, and induce cell apoptosis. CONCLUSION: Codonopsis pilosula may inhibit hepatocellular carcinoma growth by suppressing CDK1 and affecting the PDK1/ß-catenin signaling axis, limiting cell EMT and reducing cell stemness. These findings provide insights into the potential therapeutic role of Codonopsis pilosula in liver cancer.

Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial.

Importance: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown. Objective: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone. Design, Setting, and Participants: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022. Interventions: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles. Main Outcomes and Measures: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events. Results: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups. Conclusions and Relevance: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT04158440.

Structural Analysis and Novel Mechanism of Enteromorpha prolifera Sulfated Polysaccharide in Preventing Type 2 Diabetes Mellitus.

A water-soluble polysaccharide (EP) was purified from edible algae Enteromorpha prolifera. Gel permeation chromatography (GPC), ion chromatography (IC), and fourier transform infrared (FT-IR) were performed to characterize its structure. EP was defined as a low molecular weight (6625 Da) composed of rhamnose, glucose, glucuronic acid, xylose, galactose, arabinose, and mannose. Moreover, it was a sulfated polysaccharide with a degree of substitution (DS) of 1.48. Then, the high-fat diet/streptozotocin (HFD/STZ) induced diabetic mouse model was established to support evidence for a novel hypoglycemic mechanism. Results showed that blood glucose (47.32%), liver index (7.65%), epididymal fat index (16.86%), serum total cholesterol (26.78%) and triglyceride (37.61%) in the high-dose EP (HEP) group were significantly lower than those in the HFD group. Noticeably, the content of liver glycogen in the HEP group was significantly higher (62.62%) than that in the HFD group, indicating the promotion of glycogen synthesis. These beneficial effects were attributed to significantly increased protein kinase B (AKT) phosphorylation and its downstream signaling response. Further studies showed that diabetic mice exhibited excessive O-GlcNAcylation level and high expression of O-linked ß-D-N-acetylglucosamine transferase (OGT), which were decreased by 62.21 and 30.43% in the HEP group. This result suggested that EP had a similar effect to OGT inhibitors, which restored AKT phosphorylation and prevented pathoglycemia. This work reveals a novel hypoglycemic mechanism of EP, providing a theoretical basis for further studies on its pharmacological properties in improvement of T2DM.

Isolation and identification of novel phenolic and lignan glycosides from Swertia davidii Franch.

Phytochemical analyses of Swertia davidii Franch. extracts using column chromatography and semi-preparative HPLC were performed. Two novel phenolic glycosides named swertiosides A and B (compounds 1 and 2, respectively) were isolated and characterized. Four known phenolic glycosides were also extracted (compounds 3-6). The structural characteristics of these novel compounds were analyzed using 1D, 2D NMR, and HRMS. All six compounds have never been isolated from this particular plant species before this study. Subsequent assessment of bioactive properties suggested that compounds 1 and 2 exhibited moderate levels of cytotoxicity.

Regulation of wakefulness by astrocytes in the lateral hypothalamus.

The lateral hypothalamus (LH) is an important brain region mediating sleep-wake behavior. Recent evidence has shown that astrocytes in central nervous system modulate the activity of adjacent neurons and participate in several physiological functions. However, the role of LH astrocytes in sleep-wake regulation remains unclear. Here, using synchronous recording of electroencephalogram/electromyogram in mice and calcium signals in LH astrocytes, we show that the activity of LH astrocytes is significantly increased during non-rapid eye movement (NREM) sleep-to-wake transitions and decreased during Wake-to-NREM sleep transitions. Chemogenetic activation of LH astrocytes potently promotes wakefulness and maintains long-term arousal, while chemogenetic inhibition of LH astrocytes decreases the total amount of wakefulness in mice. Moreover, by combining chemogenetics with fiber photometry, we show that activation of LH astrocytes significantly increases the calcium signals of adjacent neurons, especially among GABAergic neurons. Taken together, our results clearly illustrate that LH astrocytes are a key neural substrate regulating wakefulness and encode this behavior through surrounding GABAergic neurons. Our findings raise the possibility that overactivity of LH astrocytes may be an underlying mechanism of clinical sleep disorders.

Chlorogenic acid, a natural product as potential inhibitor of COVID-19: virtual screening experiment based on network pharmacology and molecular docking.

Chlorogenic acid (CGA) is a potential inhibitor of Coronavirus Disease 2019 (COVID-19). ACE2 and its co-expressed proteins are SARS-CoV-2 receptors, which have been linked to SARS-CoV-2 infection and considered as the key target of SARS-CoV-2 in entering target cells. Here, network pharmacology was used to investigate the mechanism by which CGA affected COVID-19. A total of 70 potential targets related to the treatment of COVID-19 were obtained, among which NFE2L2, PPARG, ESR1, ACE, IL6, and HMOX1 might be the main potential targets. Finally, CGA and potential target proteins were scored by molecular docking, and the prediction results of network pharmacology were preliminarily verified. Moreover, CGA had potential anti-SARS-CoV-2 activity via integrating three common receptors in clinical practice compared with clinical trial drugs registered for the treatment of COVID-19, as shown by molecular docking. The mechanism of CGA against COVID-19 was initially investigated using network pharmacology, followed by molecular docking.

Uncovering the molecular mechanism of Gynostemma pentaphyllum (Thunb.) Makino against breast cancer using network pharmacology and molecular docking.

Because of their strong anti-cancer efficacy with fewer side effects, traditional Chinese medicines (TCM) have attracted considerable attention for their potential application in treating breast cancer (BC). However, knowledge about the underlying systematic mechanisms is scarce. Gynostemma pentaphyllum (Thunb.) Makino (GP), a creeping herb, has been regularly used as a TCM to prevent and treat tumors including BC. Again, mechanisms underlying its anti-BC properties have remained elusive. We used network pharmacology and molecular docking to explore the mechanistic details of GP against BC. The TCM systems pharmacology database and analysis platform and PharmMapper Server database were used to retrieve the chemical constituents and potential targets in GP. In addition, targets related to BC were identified using DrugBank and Therapeutic Target Database. Protein-protein interaction network, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of crucial targets were performed using the Search Tool for the Retrieval of Interacting Genes/Proteins and database for annotation, visualization, and integrated discovery databases, whereas the network visualization analysis was performed using Cytoscape 3.8.2. In addition, the molecular docking technique was used to validate network pharmacology-based predictions. A comparison of the predicted targets of GP with those of BC-related drugs revealed 26 potential key targets related to the treatment of BC, among which ALB, EGFR, ESR1, AR, PGR, and HSP90AA1 were considered the major potential targets. Finally, network pharmacology-based prediction results were preliminarily verified by molecular docking experiments. In addition, chemical constituents and potential target proteins were scored, followed by a comparison with the ligands of the protein. We provide a network of pharmacology-based molecular mechanistic insights on the therapeutic action of GP against BC. We believe that our data will serve as a basis to conduct future studies and promote the clinical applications of GP.

The potential mechanism of Astragali Radix in the treatment of children with nephrotic syndrome.

BACKGROUND: The molecular mechanism of Astragali Radix in the treatment of children with nephrotic syndrome (NS) is unclear. This study aimed to use network pharmacology to explore this potential mechanism. METHODS: The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to identify the main active ingredients of Astragali Radix. The PharmMapper, Online Mendelian Inheritance in Man (OMIM), and GeneCards databases were then used to identify the active ingredients of Astragali Radix. The String database and Cytoscape software were used to construct the protein-protein network. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using DAVID Database. RESULTS: In the TCMSP Database, a total of 20 chemical constituents of Astragali Radix were screened. After removing the duplicates and false positive genes, 394 targets of these active ingredients were obtained from PharmMapper. By comparing the NS-related genes in the GeneCards and OMIM Databases, a total of 39 potential NS-related targets were ultimately identified. The protein-protein-interaction network included 39 nodes and 366 edges. The top 5 proteins were albumin (ALB), serine/threonine kinase (AKT1), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), and matrix metallopeptidase 9 (MMP9). The GO analysis showed that the target genes were mainly involved in biological processes (e.g., signal transduction, the positive regulation of cell proliferation, and the positive regulation of migration). The cellular components included a plasma membrane, extracellular exosome, and extracellular space. The molecular functions included protein binding, zinc-ion binding, protein tyrosine kinase activity, and enzyme binding. The KEGG analysis showed that the treatment of NS by Astragali Radix mainly involved pathways in cancer, proteoglycans in cancer, the phosphatidylinositol 3-kinase and protein kinase B (PI3K-Akt) signaling pathway, the rennin-angiotensin-system (Ras) signaling pathways, and Forkhead box protein O1 (FoxO) signaling pathways. CONCLUSIONS: In the present study, the network pharmacology method was used to explore the potential targets and pathways of Astragali Radix in the treatment of NS. We also provided future research directions for the treatment of NS with a complex pathogenesis.

Anti-Apoptotic Role of Sanhuang Xiexin Decoction and Anisodamine in Endotoxemia.

Endotoxemia is characterized by initial uncontrollable inflammation, terminal immune paralysis, significant cell apoptosis and tissue injury, which can aggravate or induce multiple diseases and become one of the complications of many diseases. Therefore, anti-inflammatory and anti-apoptotic therapy is a valuable strategy for the treatment of endotoxemia-induced tissue injury. Traditional Chinese medicine exhibits great advantages in the treatment of endotoxemia. In this review, we have analyzed and summarized the active ingredients and their metabolites of Sanhuang Xiexin Decoction, a famous formula in endotoxemia therapy. We then have summarized the mechanisms of Sanhuang Xiexin Decoction against endotoxemia and its mediated tissue injury. Furthermore, silico strategy was used to evaluate the anti-apoptotic mechanism of anisodamine, a well-known natural product that widely used to improve survival in patients with septic shock. Finally, we also have summarized other anti-apoptotic natural products as well as their therapeutic effects on endotoxemia and its mediated tissue injury.

Dahuang Zhechong Pills Suppress Silicosis Fibrosis Progression via p38 MAPK/TGF-ß1/Smad Pathway In Vitro.

BACKGROUND: Dahuang Zhechong pills (DHZCP) is a classic Chinese medicinal prescription in "Treatise on Cold Pathogenic and Miscellaneous Diseases (Shanghan Zabing Lun)," and it has the function of tonifying blood, nourishing Yin, and removing blood stasis. Previous studies have shown that DHZCP could alleviate SiO2 induced pulmonary fibrosis in mice. This study aims to further explore the preventive and therapeutic effects of DHZCP against silicosis fibrosis and the underlying mechanisms in vitro. METHODS: We used the experimental model of SiO2-induced MH-S cells to evaluate the therapeutic potential of DHZCP. MH-S cells induced by SiO2 were intervened with the drug-containing serum of DHZCP, and the effects of drug-containing serum of DHZCP on the MH-S cells were detected by CCK8, ELISA, flow cytometry, western blot, and immunofluorescence. RESULTS: DHZCP improved cell viability by reducing apoptosis. It also decreased the levels of TNF-α, IL-1ß, IL-6 in the supernatant of MH-S cells induced by SiO2, inhibited the expression of p38 MAPK, blocked the activation of NF-κB, and controlled the upstream inflammatory response by multiple targeting. Concomitantly, we observed upregulation of Smad7 and a marked decline in TGF-ß1, α-SMA, Smad2, Smad3 expression in MH-S cells treated with DHZCP. CONCLUSION: To sum up, we conclude that DHZCP protects against SiO2-induced silicosis by reducing the persistent irritation of inflammation, regulating the p38 MAPK/TGF-ß1/Smad pathway.

The Underlying Molecular Mechanisms Involved in Traditional Chinese Medicine Smilax china L. for the Treatment of Pelvic Inflammatory Disease.

Smilax china L. (SCL) is extensively used in the treatment of pelvic inflammatory disease (PID). This study aimed to clarify the potential active ingredients of SCL and mechanisms on PID. SCL was widely distributed in Japan, South Korea, and China, which was traditionally considered heat-clearing, detoxicating, and dampness-eliminating medicine. Systems pharmacology revealed that 32 compounds in SCL may interact with 19 targets for immunoenhancement, antiapoptosis, anti-inflammation, and antioxidant activity of the PID model. Molecular docking revealed that isorhamnetin, moracin M, rutin, and oxyresveratrol may have higher binding potential with prostaglandin-endoperoxide synthase 2 (PTGS2), mitogen-activated protein kinase 1 (MAPK1), siderocalin (LCN2), tumor necrosis factor (TNF), and matrix metalloprotein-9 (MMP9), respectively. Molecular dynamics simulation showed that the binding modes of moracin M-MAPK1, rutin-TNF, and oxyresveratrol-MMP9 complexes were more stable, evidenced by relatively smaller fluctuations in root mean square deviation values. Conclusively, SCL may treat PID by inhibiting inflammatory factors, antitissue fibrosis, and microbial growth.

Effects of phosphorus fertilizer on root characteristics, uptake and utilization of phosphorus and yield of dryland wheat with contrasting yearly rainfall pattern.

To understand the growth responses of dryland wheat to different application rates of phosphorus fertilizer in different rainfall years, we examined root characteristics, spike number, yield and phosphate utilization. Results would help improve phosphate fertilizer use in dryland wheat production. We carried out a field experiment at the research station of Shanxi Agricultural University from 2012 to 2016. We examined the effects of four application rates of phosphorus (0, 75, 150 and 225 kg·hm-2 on root growth, phosphate utilization and yield formation of dryland wheat in different years with contrasting rainfall pattern. Compared with the treatment without phosphorus fertilization, phosphate application increased root surface area at all growth stages and root weight density in the 0-80 cm soil layer at jointing, anthesis, and maturity stages. Phosphate application significantly increased soil water consumption from jointing to anthesis, and total soil water consumption in the growing season. Phosphate application enhanced the amount of pre-anthesis phosphate translocation and phosphate accumulation of grain. Spike number, yield and water use efficiency were increased with 75, 150 and 225 kg P·hm-2 by 9.2% to 22.5%, 11.8% to 30.0%, and 2.1% to 12.1%, respectively. In the dry years, the application rates of 150 and 225 kg P·hm-2 in comparison to 75 kg P·hm-2 significantly increased root weight density and root surface area at all stages, soil water consumption from sowing to jointing and from jointing to anthesis, and total water consumption in the growing season. In comparison to the rate of 75 kg P·hm-2, 150 and 225 kg P·hm-2 increased soil water consumption from sowing to jointing by 7.3-8.7 mm, soil water consumption from jointing to anthesis by 15.6-18.1 mm, and total water consumption by 15.6-18.1 mm. Significant increase in the pre-anthesis phosphate translocation and phosphate accumulation in grain was higher under 150 and 225 kg P·hm-2 than that under 75 kg P·hm-2 in dry years. Furthermore, the two rates (150 and 225 kg P·hm-2) in dry years increased spike number by 9.3%-10.7% and yield by 11.9%-14.6%. The application rate of 150 kg P·hm-2 significantly improved phosphorus use efficiency by 20%-82% in comparison to other rates. In normal years, the rates of 150 and 225 kg P·hm-2 increased root surface area, root weight density at both anthesis and maturity compared with 75 kg P·hm-2. Soil water consumption from anthesis to maturity and total soil water consumption in the growing season were also increased by 1.2-15.0 and 3.8-23.1 mm, respectively. In addition, phosphorus accumulation in post-anthesis and phosphate accumulation in grain were increased in both 150 and 225 kg P·hm-2, which increased spike number by 1.4%-9.6% and yield by 3.5%-10.4%. The effects of phosphate application at the rate of 150 kg P·hm-2 were significantly different from 75 and 225 kg P·hm-2. In conclusion, phosphorus fertilizer application enhanced uptake of water and phosphate in dryland wheat at early and middle growth stages in dry years and at the late growth stage in normal years. Phosphorus application increased wheat yield mainly due to the increases of spike number. The application of 150 kg P·hm-2 is the best choice for high water and phosphorus fertilizer use efficiency and high yield in both dry and normal years.

Pterocephanoside A, a new iridoid from a traditional Tibetan medicine, Pterocephalus hookeri.

This work obtained and identified pterocephanoside A (1), one new iridoid glucoside derivative with rare structure of three iridoid glycosides linked to cyclopenta[c]pyran-3(1H)-one, and 10 known iridoids (2-11) from Pterocephalus hookeri through silica gel column chromatography and semi-preparative HPLC. The structure of the new compound was confirmed by 1D and 2D NMR and HRMS data analysis. Compounds 1 and 2 were isolated from this plant for the first time. The iridoids mostly possessed seco-iridoid subtype and iridoid subtype skeletons from P. hookeri. Compounds 1, 3, 4, and 6-11 showed weak anti-inflammatory activity.

Virtual Screening Technique Used to Estimate the Mechanism of Adhatoda vasica Nees for the Treatment of Rheumatoid Arthritis Based on Network Pharmacology and Molecular Docking.

Adhatoda vasica Nees (AVN) is commonly used to treat joint diseases such as rheumatoid arthritis (RA) in ethnic minority areas of China, especially in Tibetan and Dai areas, and its molecular mechanisms on RA still remain unclear. Network pharmacology, a novel strategy, utilizes bioinformatics to predict and evaluate drug targets and interactions in disease. Here, network pharmacology was used to investigate the mechanism by which AVN acts in RA. The chemical compositions and functional targets of AVN were retrieved using the systematic pharmacological analysis platform PharmMapper. The targets of RA were queried through the DrugBank database. The protein-protein interaction network (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of key targets were constructed in the STRING database, and the network visualization analysis was performed in Cytoscape. Maestro 11.1, a type of professional software, was used for verifying prediction and analysis based on network pharmacology. By comparing the predicted target information with the targets of RA-related drugs, 25 potential targets may be related to the treatment of RA, among which MAPK1, TNF, DHODH, IL2, PTGS2, and JAK2 may be the main potential targets for the treatment of RA. Finally, the chemical components and potential target proteins were scored by molecular docking, and compared with the ligands of the protein, the prediction results of network pharmacology were preliminarily verified. The active ingredients and mechanism of AVN against RA were firstly investigated using network pharmacology. Additionally, this research provided a solid foundation for further experimental studies.

Efficacy and safety of total glucosides of paeony for rheumatoid arthritis: A protocol for systematic review and meta-analysis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by erosion of joints and surrounding tissues. RA not only causes the decline of patients' physical function and quality of life, but also brings huge economic burden to patients' families and society. Total glucosides of paeony (TGP) is commonly used in treating RA in China. At present, there are many clinical reports about this medicine, but these reports have their own flaws. Therefore, there is an urgent need for systematic review and meta-analysis of the existing clinical evidence. METHODS AND ANALYSIS: Literature search will be carried out in 6 databases, and the literatures will be screened according to the inclusion and exclusion criteria. The clinical effective rate will be taken as primary outcome. Serum rheumatoid factor, C-reactive protein, erythrocyte sedimentation rate, Western Ontario and McMaster before and after treatment and adverse effects will be secondary outcomes. The heterogeneity of the study will be examined by χ and I test. To identify the source of heterogeneity, subgroup analysis will be carried out. The sensitivity test will be conducted investigate the stability of results. Funnel plot and Egger test will be used to evaluate publication bias. Finally, the quality of evidence will be summarized. RESULTS: The results will be published in peer-reviewed journals. CONCLUSIONS: This study will systematically evaluate the efficacy of TGP in the treatment of RA. The results of this study can better guide clinical practice. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/85QVF.

Parthenolide Inhibits Angiogenesis in Esophageal Squamous Cell Carcinoma Through Suppression of VEGF.

BACKGROUND: Parthenolide (PT), the effective active ingredient of the medicinal plant, feverfew (Tanacetum parthenium), has been used as an anti-inflammatory drug due to its involvement in the inhibition of the NF-кB pathway. Moreover, recent studies have demonstrated the anti-tumor effect of PT in several cancers. However, the effect of PT on esophageal carcinoma remains unclear to date. In this study, we examined the inhibitory effects of PT and its underlying mechanism of action in human esophageal squamous cell carcinoma (ESCC) cells - Eca109 and KYSE-510. METHODS: The proliferation ability of Eca109 and KYSE-510 treated with PT was detected using the Cell Counting Kit-8 and colony forming assay. The Transwell assay and the wound healing assay were used to analyze the cell invasion and migration ability, respectively. The tube formation assay was used to investigate the effect of PT on tube formation of endothelial cells. The expression level of NF-кB, AP-1 and VEGF was analyzed by Western blot. RESULTS: We demonstrated that PT attenuates the proliferation and migration ability of ESCC cells in vitro and also inhibits tumor growth in the mouse xenograft model. In addition, PT exhibited anti-angiogenesis activity by weakening the proliferation, invasion and tube formation of endothelial cells in vitro and reduced microvessel density in the xenograft tumors. Further studies revealed that PT reduced the expression level of NF-кB, AP-1 and VEGF in ESCC cells. CONCLUSION: Collectively, the results of our study demonstrated that PT exerts anti-tumor and anti-angiogenesis effects possibly by inhibiting the NF-кB/AP-1/VEGF signaling pathway on esophageal carcinoma and might serve as a promising therapeutic agent for ESCC.

Amygdalin - A pharmacological and toxicological review.

ETHNOPHARMACOLOGICAL RELEVANCE: Amygdalin is commonly distributed in plants of the Rosaceae, such as peach, plum, loquat, apple and bayberry, but most notably in the seeds (kernels) of apricot almonds. As a naturally aromatic cyanogenic compound, it has long been used in Asia, Europe and other regions for the treatment of various diseases including cough, asthma, nausea, leprosy and leukoderma. Importantly, in recent years, an increasing attention has been paid to its antitumor effect. AIM OF THE STUDY: The paper aims to review the pharmacological activities and toxicological effects of amygdalin and provide a reference and perspective for its further investigation. METHODS: Electronic databases including the Web of Science, Cochrane Library, PubMed, EMBASE, the Chinese Biological Medicine Database, China National Knowledge Infrastructure, Wanfang database and VIP information database were searched up to November 2019 to identify eligible studies. A meticulous review was performed, an in-depth analysis on the pharmacological activity and toxicology of amygdalin was conducted, and perspectives for future research were also discussed. RESULTS: A total of 110 papers about in vitro/in vivo studies on amygdalin have been reviewed. Analysis on the data suggested that this compound presented pharmacological activities of anti-tumor, anti-fibrotic, anti-inflammatory, analgesic, immunomodulatory, anti-atherosclerosis, ameliorating digestive system and reproductive system, improving neurodegeneration and myocardial hypertrophy, as well as reducing blood glucose. In addition, studies revealed that amygdalin's toxicity was caused by its poisonous decomposite product of benzaldehyde and hydrogen cyanide after oral ingestion, toxicity of intravenous administration route was far less than the oral route, and it can be avoidable with an oral dose ranging from 0.6 to 1 g per day. CONCLUSION: This paper has systematically reviewed the pharmacology and toxicology of amygdalin and provided comprehensive information on this compound. We hope this review highlights some perspectives for the future research and development of amygdalin.

Brassica rapa Polysaccharides Ameliorate CCl4 -Induced Acute Liver Injury in Mice through Inhibiting Inflammatory Apoptotic Response and Oxidative Stress.

Brassica rapa L., also called NIUMA, is used empirically in Tibetan medicine for its antioxidant, anti-inflammatory and antiradiation activities. This study explored the hepatoprotective effects of B. rapa polysaccharides (BRPs) on acute liver injury induced by carbon tetrachloride (CCl4 ) in mice and the underlying mechanisms. Mice were treated with CCl4 after the oral administration of BRPs (55, 110 and 220 mg/kg) or bifendate (100 mg/kg) for 7 days. Blood and liver samples of mice were collected for analysis after 24 h. The ALP, ALT and AST levels and the biological activities of SOD, MDA and GSH-Px were measured. Histopathological changes in the liver were determined through hematoxylin and eosin staining. Moreover, TNF-α, IL-1ß and IL-6 expression levels were detected by commercial reagent kits. Finally, Western blot analysis was used to check the relative expression levels of caspase-3, p-JAK2 and p-STAT3. The BRP pre-treatment significantly decreased the enzymatic activities of ALT, ALP and AST in the serum, markedly increased the activities of SOD and GSH-Px in the liver and reduced the MDA concentration in the liver. BRPs alleviated hepatocyte injury and markedly inhibited the expression of TNF-α, IL-1ß and IL-6, also downregulating the CCl4 -induced hepatic tissue expression of caspase-3. Furthermore, BRPs inhibited the JAK2/STAT3 signaling pathway in a dose-dependent manner in the liver. This study demonstrated that BRPs exert hepatoprotective effect against the CCl4 -induced liver injury via modulating the apoptotic and inflammatory responses and downregulating the JAK2/STAT3 signaling pathway. Therefore, B. rapa could be considered a hepatoprotective medicine.

[Investigation on intestinal absorption ingredients and their absorption characteristics in Pterocephali Herba by everted intestinal sac method].

The intestinal absorption characteristics of ten iridoid glycosides and phenolic acids in the Pterocephali Herba were evaluated via rat intestinal valgus model. The intestinal sac fluids at different time after administration of high,medium and low concentrations of Pterocephali Herba extract were collected and ten chemical components in fluid samples were detected by UPLC-PDA. Accumulative absorbed doses( Q) and absorption rate constants( Ka) of ten chemical constituents were calculated,while proportions between Pterocephali Herba extract and intestinal absorption liquid were compared. The results showed that the intestinal absorption of 10 chemical components was linear absorption( R2>0. 9) at different concentrations,which accorded with the zero-order absorption rate. The absorption rate constant was related to the concentration of the drug and the intestinal site,which indicated that intestinal adsorption mechanism of the components were passive diffusion and active transport. Proportions of chemical constituents in intestinal sac fluid were different from those in Pterocephali Herba extract. Therefore,those ten chemical components in Pterocephali Herba extract can be absorbed in whole intestine. Everted intestinal sac model can be used to evaluate intestinal absorption characteristics of ingredients in Pterocephali Herba extract effectively.