Network Pharmacology-Based Identification of Key Pharmacological Mechanism of Shen-qi-di-huang Decoction Acting on Uremia.

This study employs network pharmacology to uncover the pharmacological mechanisms underlying Shen-qi-di-huang decoction's efficacy in treating uremia. We identified a total of 927 differentially expressed genes (DEGs) through differential expression analysis and the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and analysis platform, of which 607 were downregulated and 320 were upregulated. We also obtained the effective biological components and related target gene information of Chinese herbal medicines such as Renshen, Huangqi, shudihuang, Shanyao, Fuling, Mudanpi, and Shanzhuyu in Shen-qi-di-huang decoction and constructed a regulatory relationship network between molecular components and target genes in Shen-qi-di-huang decoction. We then constructed a protein-protein interaction (PPI) network of 15 targeted genes (RXRA, ND6, CYP1B1, SLPI, CDKN1A, RB1, HIF1A, MYC, HSPB1, IFNGR1, NQO1, IRF1, RASA1, PSMG1 and MAP2K4) using the STRING database and visualized the PPI network using the software Cytoscape. In addition, we revealed the key molecular functions of uremia through Gene Ontology (GO) enrichment analysis, mainly including neuron apoptotic process, cellular response to oxidative stress, regulation of neuron apoptotic process, neuron projection cytoplasm, RNA polymerase II transcription regulator complex, plasma membrane bounded cell projection cytoplasm, NADH and NADPH dehydrogenase (quinone) activity, protein kinase inhibitor and ubiquitin protein ligase binding, etc. Finally, we identified important biological pathways in uremia through Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, which mainly concentrated in Kaposi sarcoma-associated, small cell lung cancer, Gastric cancer, Hepatitis B and C, Hepatocellular carcinoma, Thyroid cancer, Bladder cancer, MAPK signaling pathway, ErbB signaling pathway, Th17 cell differentiation, HIF-1 signaling pathway, Thyroid hormone signaling pathway and Cell cycle, etc. Using integrated bioinformatical analysis, we elucidated key pharmacological mechanisms based on targeted genes, which was enable early identification of patients with uremia and would contribute to early clinical diagnosis and treatment of patients.

Exosomes derived from adipose tissue, bone marrow, and umbilical cord blood for cardioprotection after myocardial infarction.

Human mesenchymal stem cells (MSCs) have the potential for improving cardiac function following myocardial infarction (MI). This study was performed to explore the cardioprotection of bone marrow mesenchymal stem cells (BMMSCs), adipose tissue-derived mesenchymal stem cells (ADMSCs), and umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) for myocardium in rats after MI. MI models were established in rats, which were injected with PBS, BMMSCs, ADMSCs, and UCMSCs. Cardiac function was detected by ultrasonic cardiogram. TTC staining, TUNEL staining, and immunohistochemistry were adopted to determine infarction area, cardiomyocyte apoptosis, and microvascular density (MVD), respectively. Exosomes were derived from BMMSCs, ADMSCs, and UCBMSCs, and identified by morphological observation and CD63 expression detection. Neonatal rat cardiomyocytes (NRCMs) were isolated and cultured with hypoxia, subjected to PBS and exosomes derived from BMMSCs, ADMSCs, and UCMSCs. Flow cytometry and enzyme-linked immunosorbent assay were used to determine NRCM apoptosis and the levels of angiogenesis-related markers (VEGF, bFGF, and HGF). According to ultrasonic cardiogram, BMMSCs, ADMSCs, and UCMSCs facilitated the cardiac function of MI rats. Furthermore, three kinds of MSCs inhibited cardiomyocyte apoptosis, infarction area, and increased MVD. NRCMs treated with exosomes derived from BMMSCs, ADMSCs, and UCMSCs reduced the NRCM apoptosis and promoted angiogenesis by increasing levels of VEGF, bFGF, and HGF. Notably, exosomes from ADMSCs had the most significant effect. On the basis of the results obtained from this study, exosomes derived from BMMSCs, ADMSCs, and UCBMSCs inhibited the cardiomyocyte apoptosis and promoted angiogenesis, thereby improving cardiac function and protecting myocardium. Notably, exosomes from ADMSCs stimulated most of the cardioprotection factors.

[Research about formulas for activating blood and resolving stasis Xuesaitong capsule regulate CD117+ hemopoietic stem cell to produce new blood].

OBJECTIVE: To investigate the mechanism that the formulas for activating blood and resolving stasis can regulate hemopoietic stem cell to produce new blood. METHOD: Rats were established animal model of acute cerebral infarction by referencing Olivette' method. They were randomly divided into model group, the group of the high, middle, low dose of the formulas for activating blood and resolving stasis. Each group and then wasrandomly divided into subgroups by 1, 3, 7, 14, 28 d. Xuesaitong capsule was formulated into 20, 40, 60 g x L(-1) with normal saline. The rats were given gavage drugs once a day until the experient ended, and the model group was administrated by intragastrical perfusion of normal saline. ELISA was used to detect the expression of SCF in peripheral blood and bone marrow among different groups at different time points. Flow cytometry was used to observe the changes of CD117 in blood and bone marrow. RESULT: The CD117+ HSC and SCF concentration in peripheral blood and bone marrow of model group were increasing during 1-14 d,there was a peak on the 14th day, then the expression was reducing. CD117+ HSC and SCF concentration rising trend in the group of the high, middle dose of the formulas for activating blood and resolving stasis was preceded model group (P < 0.05). CONCLUSION: Activating blood and resolving stasis can regulate hemopoietic stem cell to produce new blood, and it is through the regulation of CD117+ HSC number to achieve the purpose.

Clinical efficacy of adjuvant treatments for patients with resected biliary tract cancer: a systematic review and network meta-analysis.

OBJECTIVE: This study aimed to determine the benefits of adjuvant therapy in patients with resected biliary tract cancer (BTC) and identify the optimal adjuvant treatment scheme. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Studies comparing different adjuvant therapies in patients with BTC were searched in PubMed, Embase, CINAHL, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov databases from inception to December 2021. Additionally, the references were manually searched for the related literature. MATERIALS AND METHODS: Eligible studies were identified, and data were extracted independently by two authors. A random-effects network meta-analysis was performed using R software. The pooled outcomes of overall survival (OS) and disease-free survival (DFS) were measured using the combined HRs with 95% CIs. RESULTS: Nineteen eligible studies reporting three types of adjuvant therapies were included in our network meta-analysis. Adjuvant radiotherapy (ART, HR 0.62; 95% CI 0.42 to 0.93), adjuvant chemoradiotherapy (ACRT; HR 0.71; 95% CI 0.54 to 0.83) and adjuvant chemotherapy (ACT; HR 0.84; 95% CI 0.68 to 0.98) were more effective in prolonging OS than that of observation, with no significant difference between the three adjuvant therapies. Moreover, the improvement in DFS was also found in ACRT and ACT compared with that of observation (HR 0.60; 95% CI 0.45 to 0.75; HR 0.82; 95% CI 0.68 to 0.97, respectively). Furthermore, ACRT obtained a slightly better DFS benefit compared with that of ACT (HR 0.73; 95% CI 0.53 to 0.95). CONCLUSIONS: Our primary results demonstrated that, compared with that of observation, ACRT and ACT after radical resection could provide better OS and DFS benefits in patients with BTC. However, ART only showed improvement in OS, but not in DFS. Due to the lack of head-to-head studies of ACT, ACRT and ART, the above results need to be further verified by prospective randomised controlled trials.

Effects of panax notoginseng saponins on homing of C-kit+ bone mesenchymal stem cells to the infarction heart in rats.

OBJECTIVE: To investigate the effects of panax notoginseng saponins (PNS) on homing of C-kit+ bone mesenchymal stem cells (BMSCs) to the infarction heart. METHODS: The acute myocardial infraction (AMI) model was established in 140 Wistar rats, 105 model rats survived after operation, and the model rats were randomly divided into five groups, 21 rats in each group: Western medicine group mobilized by subcutaneous injection of human granuloctye colony stimulating factor (G-CSF) 50 microg x kg(-1) x d(-1); sham operation group and a model group treated by subcutaneous injection of normal saline 50 microg x kg(-1) x d(-1); Chinese medicine group mobilized by intraperitoneal injection of Xuesaitong (see text) (ingredients of PNS) 150 mg x kg(-1) x d(-1); integrative medicine group mobilized by subcutaneous injection of G-CSF 50 microg x kg(-1) x d(-1) and intraperitoneal injection of Xuesaitong 150 mg x kg(-1) x d(-1). Except for the sham-operated group, each group was divided into three sub-groups by three time points of 1 d, 7 d and 14 d. G-CSF was injected once a day for 7 d. Xuesaitong was injected once a day until the rats were killed. The flow cytometry was used for detection of C-kit+ cells in the peripheral blood in different time points, and immunohistochemical method was used for detection of the changes of C-kit+ cell and Ki-67+ cell numbers in the marginal zone of AMI. RESULTS: Twenty-four hours after the operation, C-kit+ cells had a slight increase in the model group compared with the sham operation group (P > 0.05). The peripheral blood C-kit+ cells in the integrative group increased significantly compared with the other groups on 7 d and 14 d (all P < 0.05). Meanwhile the expression of C-kit+ cells and Ki-67+ cells in the marginal zone of AMI in the integrative group increased significantly compared with the Chinese medicine group, the western medicine group and the model group on 1 d, 7 d and 14 d (all P < 0.05), and the cells in the integrative group decreased significantly on 14 d compared with that on 7 d (P < 0.05). CONCLUSION: PNS can cooperate with G-CSF to mobilize C-kit+ BMSCs from the marrow into the peripheral blood and promote them "homing" to the infarction heart.

[The effect of combination of Brandt-Daroff training and otolith reposition instrument pair in benign paroxysmal positional vertigo].

Objective:To observe the effect of Brandt-Daroff training combined with otolith reduction instrument in the treatment of benign paroxysmal positional vertigo（BPPV）. Methods:The patients were randomly divided into control group and study group, with 54 cases and 56 cases, respectively. The patients in control group were treated with otolith reposition and health education, while those in study group were treated with aforementioned treatment plus Brandt-Daroff acclimatization training. Effectiveness, vestibular symptoms index, dizziness disability degree and the duration of residual symptoms were compared between two groups. Results:The total efficiency rate was 96.3% in the observation group and 92.5% in the control group, and the difference was not statistically significant （P>0.05） , but on the 7th and 14th days after treatment, the DHI scores of the observation group were 20.11±3.95 and 7.89±1.88; VSI scores were 4.15±1.07 and 1.52±0.634, respectively. The duration of residual symptoms was （7.41±2.04） d. In the control group, the DHI scores of the observation group were 23.81±4.34 and 11.08±2.39, respectively. VSI scores were 5.17±1.12 and 3.64±1.50; The duration of residual symptoms was （11.06 ±1.89） d. The observation group was significantly improved compared with the control group, and the differences were statistically significant（P<0.05）. Conclusion:The Brandt-Daroff training combined with otolith reduction instrument has a significant effect in the treatment of BPPV, which can effectively reduce the clinical symptoms and vertigo disability, reduce residual symptoms after reduction, and improve the quality of life of patients. Therefore, it is worthy of clinical promotion.

Chinese preparation Xuesaitong promotes the mobilization of bone marrow mesenchymal stem cells in rats with cerebral infarction.

After cerebral ischemia, bone marrow mesenchymal stem cells are mobilized and travel from the bone marrow through peripheral circulation to the focal point of ischemia to initiate tissue regeneration. However, the number of bone marrow mesenchymal stem cells mobilized into peripheral circulation is not enough to exert therapeutic effects, and the method by which blood circulation is promoted to remove blood stasis influences stem cell homing. The main ingredient of Xuesaitong capsules is Panax notoginseng saponins, and Xuesaitong is one of the main drugs used for promoting blood circulation and removing blood stasis. We established rat models of cerebral infarction by occlusion of the middle cerebral artery and then intragastrically administered Xuesaitong capsules (20, 40 and 60 mg/kg per day) for 28 successive days. Enzyme-linked immunosorbent assay showed that in rats with cerebral infarction, middle- and high-dose Xuesaitong significantly increased the level of stem cell factors and the number of CD117-positive cells in plasma and bone marrow and significantly decreased the number of CD54- and CD106-positive cells in plasma and bone marrow. The effect of low-dose Xuesaitong on these factors was not obvious. These findings demonstrate that middle- and high-dose Xuesaitong and hence Panax notoginseng saponins promote and increase the level and mobilization of bone marrow mesenchymal stem cells in peripheral blood.

A C-terminally truncated mouse Best3 splice variant targets and alters the ion balance in lysosome-endosome hybrids and the endoplasmic reticulum.

The Bestrophin family has been characterized as Cl(-) channels in mammals and Na(+) channels in bacteria, but their exact physiological roles remian unknown. In this study, a natural C-terminally truncated variant of mouse Bestrophin 3 (Best3V2) expression in myoblasts and muscles is demonstrated. Unlike full-length Best3, Best3V2 targets the two important intracellular Ca stores: the lysosome and the ER. Heterologous overexpression leads to lysosome swelling and renders it less acidic. Best3V2 overexpression also results in compromised Ca(2+) release from the ER. Knocking down endogenous Best3 expression in myoblasts makes these cells more excitable in response to Ca(2+) mobilizing reagents, such as caffeine. We propose that Best3V2 in myoblasts may work as a tuner to control Ca(2+) release from intracellular Ca(2+) stores.