Philadelphia chromosome (Ph) positive (Ph⁺) B cell acute lymphoblastic leukemia (B-ALL) is the most common genetic abnormality associated with B-ALL and has been shown to confer the worst prognosis to both children and adults. Increasing evidence has revealed that high tribbles homologue 3 (TRIB3) expression contributes to multi-cancer development and progression, but the underlying role and molecular mechanisms of TRIB3 in Ph⁺ B-ALL remain unclear. Here, we report that TRIB3 expression was enhanced in Ph⁺ B-ALL patient samples and positively associated with the expression of breakpoint cluster region-Abelson tyrosine kinase (BCR-ABL). We further demonstrated that deletion of TRIB3 attenuated the progression of Ph⁺ B-ALL by reducing BCR-ABL expression. Mechanistically, TRIB3 interacted with lysosomal cysteine proteinase cathepsin Z (CTSZ) to suppress CTSZ-mediated BCR-ABL degradation, which enhanced BCR-ABL activity, causing high proliferation of Ph⁺ B-ALL cells. Thus, our study indicated that inhibiting the expression of TRIB3 to regulate BCR-ABL kinase activity may be exploited as an additional target therapy for Ph⁺ ALL. Procedures for animal study were performed with approval of the Animal Care and Use Committee of the Chinese Academy of Medical Sciences and Peking Union Medical College. The procedure of human leukemia sample was approved by the Ethics Committee of Chinese Academy of Medical Sciences and Peking Union Medical College (KT2019055-EC-1).

The aim of this study was to evaluate the effects and mechanisms of berberine (BBR) against dexamethasone (Dex)-induced metabolic disorders. 3T3-L1 cells were differentiated by Dex treatment and then treated with BBR (2.5, 5, 10 μmol·L^-1). Lipid accumulation was detected using oil-red O staining. After review and approval of the ethics committee of the Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences, C57BL/6N mice were randomly divided into three groups. In the BBR treatment group, mice were subcutaneously implanted with an osmotic pump containing Dex and gavaged with BBR (100 mg·kg^-1·day^-1) for 4 weeks. The model control group was implanted with a Dex osmotic pump with no other treatment. Mice given a saline-filled osmotic pump were used as a negative control. During the study, food intake and body weight were measured weekly. Subcutaneous fat and visceral fat was detected by MRI. At the end of the experiment the plasma levels of total cholesterol (CHO), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), glucose (Glu), and muscle mass were measured. The expression of peroxisome proliferator-activated receptor γ (PPARγ) and AMP-activated protein kinase α (AMPKα) in 3T3-L1 cells and epididymal fat of C57BL/6N mice was evaluated through RT-PCR and Western blot analysis. The results showed that BBR inhibited Dex-induced adipocyte differentiation in 3T3-L1 preadipocytes by up to 23% in a dose-dependent manner. In C57BL/6N mice, berberine alleviated hyperlipidemia and hyperglycemia and reduced visceral fat accumulation induced by Dex. The results from RT-PCR and Western blot analysis showed that BBR reduced PPARγ expression and increased the phosphorylation of AMPKα in 3T3-L1 cells as well as in adipose tissue. Berberine might alleviate Dex-induced metabolic disorder and visceral fat accumulation by modulating PPARγ and AMPK expression.

Possible mechanisms by which Polygonati rhizoma opposes atherosclerosis (AS) were identified by network pharmacology and molecular docking analyses. The Traditional Chinese Medicine Database (TCMD) and the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) were utilized to identify the likely active components of Polygonati rhizoma. The potential targets set of Polygonati rhizoma were predicted with the PharmaDB database and the Swiss TargetPrediction database. The targets set for AS was retrieved by OMIM, DisGeNET and NCBI Gene database. We used the STRING platform to construct a protein-protein interaction network of the intersectional targets and performed visual analysis in Cytoscape. The key targets of Polygonati rhizoma in AS were searched by network topology and the resulting GO and KEGG enrichment was analyzed by Clue GO. In addition, the key targets were verified by molecular docking in Discovery Studio 4.0. A total of 45 active ingredients and 51 potential targets were obtained in the treatment of AS. The results of the topology analysis included five key targets:serum albumin, mitogen-activated protein kinase 3, mitogen-activated protein kinase 1, proto-oncogene tyrosine-protein kinase Src and matrix metalloproteinase-9. The 131 GO items showed that the biological process mainly involved the steroid receptor, cell response to steroid stimulation, the phosphatidylinositol-3 kinase signal pathway, and others. The KEGG pathway analysis included 37 pathways, which were closely related to peroxisome proliferation activated receptor signaling pathway, platelet activation pathway, vascular endothelial growth factor pathway, hypoxia inducible factor pathway and adhesion connection pathway. The results of molecular docking proved that the combined activity of the components with potential key targets is excellent. This study proposes mechanisms by which Polygonati rhizoma might act to reverse or minimize AS and provides a scientific basis for clinical research on Polygonati rhizoma.

To investigate the therapeutic effect of artesunate on mouse cytomegalovirus pneumonia, the BALB/c-nu mice were infected with murine cytomegalovirus-green fluorescent protein (MCMV-GFP) by nose dropping method. The experimental protocol was approved by the Medical Laboratory Animal Ethics Committee of Guangzhou Medical University. The BALB/c-nu mice were randomly divided into five groups:control group, MCMV pneumonia group, and artesunate (60, 120, and 240 mg·kg^-1) groups. The survival rate, weights, and virus loads in lungs among the groups were observed. The degree of histopathologic changes in lungs was assessed directly by hematoxylin-eosin (HE) assay. MCMV-GFP expression was assessed by immunofluorescence. In addition, reverse transcription polymerase chain reaction (RT-PCR) analysis was performed to investigate the content of major immediate early 1 (Mie1) mRNA, and enzyme-linked immunosorbent assay (ELISA) was used to detect the changes of inflammatory factors, interleukin 10 (IL-10), IL-6, and tumor necrosis factor-α (TNF-α). Western blot analysis was used to detect the expression of the changes of nuclear factor-kappa B (NF-κB) signaling pathways in total proteins. Compared with MCMV group, artesunate (120 mg·kg^-1) significantly increased body weights of MCMV-infected nude mice over 30 days, and decreased the viral titer in lung homogenate, lung inflammation, and histological severity. Moreover, the administration of artesunate (120 mg·kg^-1) could downregulate the expression of phospho-NF-κB (p-NF-κB) p65 in the lungs of mice. The present study suggested that artesunate can protect the immunocompromised mice from MCMV-induced interstitial pneumonia via downregulating NF-κB signaling pathway, thus attenuating inflammation in the lungs.

We used network pharmacology and molecular docking to investigate the molecular mechanism of Lishi-Kuijie decoction (KJF) in the treatment of ulcerative colitis (UC). Chemical components and targets related to the 13 herbs of Chinese Materia Medical in KJF were searched through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The UC-related targets were identified through OMIM, DisGeNet and GeneCards databases. Using Cytoscape 3.7.2 software a drug-compound-disease-target network was established. The target interaction network and core target for KJF against UC was built and selected based on the String database and topological parameters. Using the R package clusterprofile in Bioconductor, the intersection genes and the disease-drug intersection targets were transformed to Entrez gene ID, followed by gene ontology biological process enrichment analysis and KEGG pathway annotation analysis. The KJF compound-UC target network contained 149 compounds, 108 corresponding targets and 12 core targets (including signal transducer and activator of transcription 3, interleukin 6, tumor necrosis factor, c-x-c motif chemokine ligand 8, interleukin 2, etc.). We identified 2 371 GO terms and 155 pathways (mainly involving IBD, PI3K-ATK, NF-kappa B, TNF, Toll-like receptor signaling pathway) as determined by enrichment analysis. Molecular docking, used with the key molecular factors and the core targets, revealed stable binding for IL2, TNF-α, MAPK1 and RELA. These results suggest the possible molecular mechanism of KJF in treatment of UC and lay the foundation for further characterization of the components and their mechanisms.

In this study, the effect of benzo[α]pyrene (BaP) on chaperone-mediated autophagy (CMA) in a simulated hypoxia environment was observed and the relationship to heat shock protein 90 (HSP90) was clarified. With HSP90 inhibitor geldanamycin (GA) and HSP90α silenced, the mRNA and protein expression of hypoxia-inducible factor-1α (HIF-1α), HSP90, heat shock cognate protein 70 (HSC70), and lysosomal associated protein 2A (LAMP-2A) of A549 cells on hypoxic environment by BaP were tested. Alkaline comet experiment, immunofluorescence γ-H2AX focus experiment, quantitative real-time PCR (qPCR), and Western blot analyses were used to clarify the relationship between the DNA damage of different concentrations of BaP in A549 cells and the mRNA and protein expression of CMA-related factors. The results show that hypoxia can promote the expression of mRNA and protein of CMA-related factors in A549 cells. This study found that BaP has an inhibitory effect on CMA under the hypoxic environment. The inhibition or silencing of HSP90 will enhance the inhibitory effect of BaP on CMA. In a normoxic environment, BaP causes DNA damage and promotes CMA.

Three butylphthalide derivatives were isolated from the Rhizome of Ligusticum chuanxiong using a series of isolation and purification approaches including macroporous resin, ODS-A column, Sephadex LH-20 and preparative HPLC. These structures were elucidated based on extensive spectroscopic data (UV, IR, HR-ESI-MS and NMR) and identified as (3Z, 3aE)-(6R, 7R, 2'S)-6-hydroxy-7-(2-carboxyl-2-hydroxyethylthio)-3-(2-hydroxybutylidene)-4, 5, 6, 7-tetrahydro-phthalide (1), (3Z, 3aZ)-3-butylidene-6, 7-dihydroxy-4, 5, 6, 7-tetrahydro-phthalide 7-O-α-D-glucopyranosyl-(1→2)-β-D-fructo-furanoside (2) and 3-(3-β-D-glucopyranosyloxy-butylidene)-7-hydroxy-phthalide (3).

Peptidyl-prolyl cis-trans isomerase Pin1 is over-expressed in prostate cancer cells and the level of expression correlates with the malignancy grade and prognosis in patients. In this work, twenty-one 2-(1H-benzimidazol-2-ylthio) acetic acid derivatives were designed and prepared with the aid of the crystal structure of Pin1 and our previous work. The chemical structures of the target compounds were confirmed by ¹H NMR, ¹³C NMR, ESI-MS and IR. The inhibitory activity of compounds 6a-6i and 13a-13i against Pin1 were determined using a protease-coupled assay. The results indicated that twenty compounds were significantly superior to the positive control drug Juglone, and 6g, 6h and 13i exhibited the most potent Pin1 inhibitory activity, with IC₅₀ values at the sub-micromolar level. The in vitro anti-proliferative activities of these analogs were evaluated by the MTT assay and several showed a moderate effect in human prostate cancer PC-3 cells. Molecular docking studies demonstrated that both the benzimidazole skeleton and the thioacetic acid fragment were indispensable for the compounds to interact with key residues in the catalytic domain of Pin1.

A UPCC-Q-TOF-MS method was established to analyze the components of polyoxyethylene 35 castor oil. The separation was performed at 50℃ on a Waters Acquity UPCC system by an Torus Diol column (3.0 mm×100 mm, 1.7 μm) with gradient elution of CO₂ and methanol-acetonitrile (50:50); the flow rate was 1.0 mL·min^-1, the back pressure was 2 000 psi, and methanol containing 2.5 mmol·L^-1 ammonium formate was used as ionization reagent, whose flow rate was 0.2 mL·min^-1. Positive ion electrospray ionization (ESI) mode and MS^E technology were used. The qualitative analyses were carried out by using precise mass information of the parent and product ions and a PCA model was established by UPCC-Q-TOF-MS. L-02 cells and RBL-2H3 cells were used to study the cytotoxicity and histamine release of CrEL samples in vitro. A total of 13 kinds of CrEL components were obtained and their structures were identified by UPCC-Q-TOF-MS, with 255 compounds in total. The percentage content of 13 types of components was calculated by the normalization method. The content of polyoxyethylene glycerol tri-ricinoleate (PGTri-ricinoleate) in all samples was 0.36%-2.80% and the main components were polyethylene glycol, polyethylene glycerol and polyoxyethylene glycerol mono-ricinoleate. All samples have different degrees of cytotoxicity and histamine release, which is negatively correlated with the content of PGTri-ricinoleate and positively correlated with the content of polyoxyethylene glycol fatty acid esters. The UPCC-Q-TOF-MS method is simple and rapid, has strong separation ability and high accuracy. It is suitable for the analysis of CrEL components. It is suggested that the fatty acid composition should be included in the monograph of CrEL for injection to increase the content of PGTri-ricinoleate and decrease the content of polyoxyethylene glycol fatty acid esters, so as to improve the product safety.

Heavy metals and other harmful elements in traditional Chinese medicines inflict serious damage on public health. Therefore, risk assessment of Chinese raw materials has gained increasing attention. To date, few reports have been published on the health risk assessment of heavy metals and harmful elements in Chinese patent medicines. To gain a comprehensive understanding of heavy metals and other harmful elements in Chinese patent medicines and to establish proper limits, residual Pb, Cd, As, Hg, Cu and Cr in 15 054 samples of 295 drugs was analyzed with regard to distribution and variation between elements and dosage forms. In addition, in accord with procedures including hazard identification, hazard characterization, exposure assessment and risk characterization, basic procedures and specific parameters for risk assessment of heavy metals and harmful elements in Chinese patent medicines were clarified based on the health risk assessment of 14 787 samples and 276 drugs. A method and equation for establishing residual limits is proposed. The results show that content and target hazard quotients (THQs) of the investigated elements in all samples showed a skewed distribution approaching 0. Content of Pb, As, Cu, Hg, Cd or Cr in the samples exceeded 100 mg·kg^-1 and the content of Pb, As, or Cu in individual samples exceeded 1 000 mg·kg^-1. THQs of 586 samples and four drugs were above 1. We believe that the health risk of Hg, Pb and As in Chinese patent medicines with dosage forms of pill, capsule, tablet and powder, especially those in raw powder preparations, warrant concern.