Exploring the effect and mechanism of cucurbitacin B on cholestatic liver injury based on network pharmacology and experimental verification.

ETHNOPHARMACOLOGICAL RELEVANCE: Cholestatic liver injury (CLI) is a pathologic process with the impairment of liver and bile secretion and excretion, resulting in an excessive accumulation of bile acids within the liver, which leads to damage to both bile ducts and hepatocytes. This process is often accompanied by inflammation. Cucumis melo L is a folk traditional herb for the treatment of cholestasis. Cucurbitacin B (CuB), an important active ingredient in Cucumis melo L, has significant anti-inflamamatory effects and plays an important role in diseases such as neuroinflammation, skin inflammation, and chronic hepatitis. Though numerous studies have confirmed the significant therapeutic effect of CuB on liver diseases, the impact of CuB on CLI remains uncertain. Consequently, the objective of this investigation is to elucidate the therapeutic properties and potential molecular mechanisms underlying the effects of CuB on CLI. AIM OF THE STUDY: The aim of this paper was to investigate the potential protective mechanism of CuB against CLI. METHODS: First, the corresponding targets of CuB were obtained through the SwissTargetPrediction and SuperPre online platforms. Second, the DisGeNET database, GeneCards database, and OMIM database were utilized to screen therapeutic targets for CLI. Then, protein-protein interaction (PPI) was determined using the STRING 11.5 data platform. Next, the OmicShare platform was employed for the purpose of visualizing the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The molecular docking technique was then utilized to evaluate the binding affinity existing between potential targets and CuB. Subsequently, the impacts of CuB on the LO2 cell injury model induced by Lithocholic acid (LCA) and the CLI model induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) were determined by evaluating inflammation in both in vivo and in vitro settings. The potential molecular mechanism was explored by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot (WB) techniques. RESULTS: A total of 122 CuB targets were collected and high affinity targets were identified through the PPI network, namely TLR4, STAT3, HIF1A, and NFKB1. GO and KEGG analyses indicated that the treatment of CLI with CuB chiefly involved the inflammatory pathway. In vitro study results showed that CuB alleviated LCA-induced LO2 cell damage. Meanwhile, CuB reduced elevated AST and ALT levels and the release of inflammatory factors in LO2 cells induced by LCA. In vivo study results showed that CuB could alleviate DDC-induced pathological changes in mouse liver, inhibit the activity of serum transaminase, and suppress the liver and systemic inflammatory reaction of mice. Mechanically, CuB downregulated the IL-6, STAT3, and HIF-1α expression and inhibited STAT3 phosphorylation. CONCLUSION: By combining network pharmacology with in vivo and in vitro experiments, the results of this study suggested that CuB prevented the inflammatory response by inhibiting the IL-6/STAT3/HIF-1α signaling pathway, thereby demonstrating potential protective and therapeutic effects on CLI. These results establish a scientific foundation for the exploration and utilization of natural medicines for CLI.

Interactive Effects and Mediating Roles of Multiple Factors That Influence Learning Adaptative Growth of International Students: Evidence from China.

The learning adaptability of international students is pivotal to the success of sustainable international higher education development. The purpose of this study was to explore what factors affect the learning adaptability of international students in China through structural equation modelling and mediation analysis. The data collected through a questionnaire from the overseas students were analysed, and the reliability and validity were also tested. The findings show that the influencing factors that affect learning adaptability of international students in China comprise seven variables: learning attitude, motivation to study abroad, learning ability, language proficiency, learning environment, teaching management and social relations. In addition, when language proficiency is used as the mediating variable, the motivation to study abroad has a significant positive impact on learning attitudes, with an influence coefficient of 0.185 and an effect proportion of 35%, which is a partial mediator. When social relationships are used as the mediating variable, study abroad motivation has a significant positive impact on learning attitude, with an influence coefficient of 0.058, which is completely mediating.

Mesenchymal Stem Cell-Derived Extracellular Vesicles: Pleiotropic Impacts on Breast Cancer Occurrence, Development, and Therapy.

Breast cancer (BC) is one of the most devastating cancers, with high morbidity and mortality, among the female population worldwide. In BC, mesenchymal stem cells (MSCs), as pluripotent stromal stem cells, play a significant role in TME formation and tumor progression. Recently, an increasing number of studies have demonstrated that extracellular vesicles (EVs) are essential for the crosstalk between MSCs and BC cells. MSC-derived EVs (MSC-EVs) can deliver a diversity of molecules, including lipids, proteins, and nucleic acids, etc., to target cells, and produce corresponding effects. Studies have demonstrated that MSC-EVs exert both inhibitory and promotive effects in different situations and different stages of BC. Meanwhile, MSC-EVs provide novel therapeutic options for BC, such as EVs as carriers for drug delivery. Therefore, in this review, we summarize the role of MSC-EVs in BC progression and application in clinical treatment, in the hope of providing a basis for further research.

Caveolin1: its roles in normal and cancer stem cells.

PURPOSE: Stem cells are characterized by the capability of self-renewal and multi-differentiation. Normal stem cells, which are important for tissue repair and tissue regeneration, can be divided into embryonic stem cells (ESCs) and somatic stem cells (SSCs) depending on their origin. As a subpopulation of cells within cancer, cancer stem cells (CSCs) are at the root of therapeutic resistance. Tumor-initiating cells (TICs) are necessary for tumor initiation. Caveolin1 (Cav1), a membrane protein located at the caveolae, participates in cell lipid transport, cell migration, cell proliferation, and cell signal transduction. The purpose of this review was to explore the relationship between Cav1 and stem cells. RESULTS: In ESCs, Cav1 is beneficial for self-renewal, proliferation, and migration. In SSCs, Cav1 exhibits positive or/and negative effects on stem cell self-renewal, differentiation, proliferation, migration, and angiogenic capacity. Cav1 deficiency impairs normal stem cell-based tissue repair. In CSCs, Cav1 inhibits or/and promotes CSC self-renewal, differentiation, invasion, migration, tumorigenicity ability, and CSC formation. And suppressing Cav1 promotes chemo-sensitivity in CSCs and TICs. CONCLUSION: Cav1 shows dual roles in stem cell biology. Targeting the Cav1-stem cell axis would be a new way for tissue repair and cancer drug resistance.

Preventive effect on endothelial surface layer damage of Fusu agent in LPS-induced acute lung injury in rats.

Acute lung injury (ALI) is one of major causes of morbidity and mortality in intensive care. In pathophysiological events of ALI, endothelial surface layer (ESL) injury can result in capillary leakage as the initial event. The "Fusu agent", a traditional Chinese medicine, can inhibit inflammatory factors, attenuate lung capillary leak as seen in our previous study. This study was aimed to explore the molecular mechanism of Fusu agent treatment with ALI. Consistent with previous studies, we found that Fusu agent has the protective effect on LPS-induced ALI model rats. Further investigation demonstrated that heparanase activation is necessary for the LPS-induced ALI model to aggravate ESL loss. Fusu agent can inhibit heparanase activation and heparan sulfate proteoglycans' (HSPGs) degradation to mitigate the ESL injury. Furthermore, TNF-α and intercellular adhesion molecule-1 (ICAM-1) were significantly reduced upon Fusu agent pre-treatment to inhibit inflammatory cell influx and neutrophil adhesion in ALI. These findings shed light on the pharmacologic basis for the clinical application of traditional Chinese medicine in treating ALI.

Effects of recombinant human thyroid stimulating hormone on 131I therapy for the treatment of differentiated thyroid cancer.

The aim of the present study was to compare the advantages and disadvantages of the combined application of recombinant human thyroid stimulating hormone (rhTSH) with thyroid hormone withdrawal (THW) and THW alone prior to 131I therapy for the treatment of differentiated thyroid cancer. Four indicators were compared between the experimental group, who received a combined therapeutic method of rhTSH with THW, and the control group, who received THW therapy alone. With the exception of the elimination half-time of 131I in the blood in the experimental group, which was significantly shorter compared with that in the control group, the other three indicators, including the urinary iodine concentration, the relative 131I uptake ratio of the neck lesions and the one-time cure rate, were not significantly different between the two groups. In addition, the treatment efficacy of 131I therapy exhibited no statistically significant difference between the experimental and control groups. However, in the experimental group, the residence time of 131I in the blood was significantly shorter compared with that in the control group, indicating that the irradiation damage of radioactive iodine exposure to the non-target tissues was lower in the experimental group when compared with the control group. In addition, no evident hypothyroidism was observed in the patients. Thus, the combined application of rhTSH with THW prior to 131I therapy was demonstrated to be superior to the THW therapy alone.

Effect of viscosity on the mixing efficiency in a self-agitation anaerobic baffled reactor.

One special self-agitation reactor, which does not require a mechanical mixer or other equipment for mixing, has been introduced. Self-agitation is affected by variation in viscosity property. To obtain and research the effect of viscosity on mixing behavior in the self-agitation reactor, Fluent® was used to create numerical simulations and to visualize the fluid flow status. The results show that when the viscosity of the liquid is 1 mPa s, the entire self-agitation results in an almost completely mixed reactor. The substrate becomes difficult to agitate, and the diffusion of the substrate and the tracer become quite after every self-agitation, as the viscosity increases. Once the viscosity is higher than 25 mPa s, the substrate and tracer could not be mixed in the entire reactor, and the reactor is recognized as the combination of several completely mixed reactors between which little exchange of liquid occurs.

Radiotoxicity on bone marrow after 89Sr therapy radiosensitized by nicotinamide and carbogen in mice.

OBJECTIVE: To investigate the radiotoxicity to bone marrow after 89Sr therapy radiosensitized by nicotinamide and carbogen. METHODS: Chinese Kunming, NIH, BALB/c and F1 mice were divided into five groups: negative control (saline), positive control (89Sr), 89Sr+nicotinamide, 89Sr+carbogen and 89Sr+nicotinamide+carbogen. 89SrCl containing activities of 7400 kBq (200 microCi) in 200 microl of saline was administrated by injection into the tail vein. An equal volume of saline only was given to the negative control group. Chinese Kunming and NIH mice were killed on days 1, 2, 3, 4, 6, 8, 15, 20, 30, 60 and 90 after injection. BALB/c and F1 mice were killed on days 60 and 90. Femoral marrow reticulocytes were separated for assay of micronuclei. RESULTS: The average frequency of the reticulocytes is shown in a dual-peak curve after injection. The first maximum frequency occurred between the second and the fourth days, and the second between the tenth and the 14th days. A significant statistical difference in frequency was found between the negative and the positive control groups (P<0.001, F=15.517), while no difference was found among the 89Sr+nicotinamide+carbogen, 89Sr, 89Sr+nicotinamide and 89Sr+carbogen groups (P>0.05, F=0.717) and among the NIH groups, 89Sr, 89Sr+nicotinamide, 89Sr+carbogen and 89Sr+nicotinamide+carbogen (P>0.05, F=1.734). There is also no significant difference in the frequency of reticulocytes between Chinese Kunming, NIH, BALB/c and F1 mice (P>0.05). Although the intervention of the radiosensitizer accelerated the occurrence of micronuclei in reticulocytes, there was no significant statistical difference between the group with radiosensitizer and the groups without it. CONCLUSIONS: The administration of radiosensitizer did not aggravate the toxicity on bone marrow.