[Core connotation of compatibility of Aconiti Lateralis Radix Praeparata-Glycyrrhizae Radix et Rhizoma herb pair under physiological/ pathological conditions based on metabolomics and network pharmacology].

This study aims to explore the core connotation of the compatibility of Aconiti Lateralis Radix Praeparata(Fuzi)-Glycyrrhizae Radix et Rhizoma(Gancao) herb pair under physiological and pathological conditions. The biochemical indicators of serum/myocardial tissue, pathological changes of the myocardial tissue, and serum metabolic profiles of normal rats and heart failure model rats treated with Fuzi Decoction and Fuzi Gancao Decoction were determined. Network pharmacology and metabolomics were employed to establish the metabolite-target-pathway network for Glycyrrhizae Radix et Rhizoma in enhancing the efficacy and reducing the toxicity of Aconiti Lateralis Radix Praeparata, Western blotting was employed to verify the representative pathways in the network. The results showed that both decoctions lowered the levels of creatine kinase and other indicators and mitigate myocardial pathological injury in model rats. However, they caused the abnormal rises in creatine kinase and other indicators and myocardial pathological injury in normal rats. The results indicated that the compatibility reduced the toxicity in normal rats and enhanced the efficacy in model rats. The results of metabolomics showed that Fuzi Gancao Decoction recovered more metabolites in model rats and had weaker effect on interfe-ring with the metabolites in normal rats than Fuzi Decoction. The association analysis showed that the network of Glycyrrhizae Radix et Rhizoma enhancing the efficacy of Aconiti Lateralis Radix Praeparata involved 112 metabolites, 89 targets, and 15 pathways, including calcium and cAMP signaling pathways. The network of Glycyrrhizae Radix et Rhizoma reducing the cardiotoxicity of Aconiti Lateralis Radix Praeparata involved 36 metabolites, 59 targets, and 11 pathways, including adrenergic signaling and tricarboxylic acid cycle in cardiomyocytes. The experimental results of protein expression verified the reliability of the association analysis. This study demonstrated that the core connotation of the herb pair of Aconiti Lateralis Radix Praeparata-Glycyrrhizae Radix et Rhizoma changed under physio-logical and pathological states, and the compatibility results of enhancing efficacy and reducing toxicity were achieved with different metabolic pathways and biological processes.

Monotropein: A comprehensive review of biosynthesis, physicochemical properties, pharmacokinetics, and pharmacology.

Monotropein, a principal natural compound in iridoid glycosides extracted from Morindae officinalis radix, has potent pharmacological activities. To understand and utilize monotropein, we systematically summarized the studies on monotropein, including its biosynthetic pathway, physicochemical properties, pharmacokinetics, and pharmacology. Interestingly, we found that the multiple bioactivities of monotropein, such as anti-osteoporosis, anti-inflammation, anti-oxidation, anti-nociception, and hepatic or renal protection, are closely associated with its capability of downregulating the nuclear factor-κB signaling pathway, inhibiting the mitogen-activated protein kinase signaling pathway, attenuating the activation of nuclear factor E2-related factor 2/heme oxygenase-1 signaling pathway, and regulating the mammalian target of rapamycin/autophagy signaling pathway. However, the clinically therapeutic effects and the potential problems need to be addressed. This review highlights the current research progress on monotropein, which provides a reference for further investigation of monotropein.

The Evaluation of Xiaozeng Qianggu Tablets for Treating Postmenopausal Osteoporosis via up-Regulated Autophagy.

Objective: Postmenopausal osteoporosis (PMOP) is a common age-associated disease in the life course. Clinically, Xiaozeng Qianggu Tablets (XQT) have a potent therapeutic effect on the PMOP. However, the bioactive components and the mechanism of XQT underlying the PMOP treatment were unclear and it should be explored to discover the scientific connotation in traditional medical practice. Methods: The components in XQT were identified by UPLC-Q-TOF/MS. The animal model of PMOP was established by surgical ovariectomy in the female Sprague-Dawley rats. After treatment of XQT, the therapeutic effect was assessed by the determination of bone metabolism biomarkers in serum and histopathological examination. The effect of XQT on the autophagy and bone micro-situation were tested using western blot, RT-qPCR, and transmission electron microscope. Results: There were 27 compounds identified in XQT, including catalpol, monotropein, verbascoside, cryptochlorogenic acid, 5,7-dihydroxychromone 7-rutinoside, biorobin, and so on. The bone metabolism markers (alkaline phosphatase, bone alkaline phosphatase, procollagen type I intact N-terminal propeptide, cross-linked carboxy-terminal telopeptide of type I collagen, and tartrate-resistant acid phosphatase) were significantly increased in the PMOP rats and reversed by XQT administration. Moreover, the width of bone trabeculae and the ratio of the area of calcium deposition to bone trabeculae were also improved after treating the middle dose of XQT. Meanwhile, the bone micro-structure was improved by XQT. The mRNA and protein expression of unc-51 like kinase 1, beclin-1, and microtubule-associated protein 1B-light chain 3 in PMOP rats were down-regulated and up-regulated by XQT administration. Conclusions: The compounds in XQT, including catalpol, monotropein, verbascoside cryptochlorogenic acid, and so on, were valuable for further pharmacy evaluation. The pathological changes and bone micro-structure were improved by XQT, and the down-regulated autophagy level was also restored, which suggested a potent effect of XQT on treating PMOP, corresponding to its clinic use.

Anti-inflammatory effect of Rhein on ulcerative colitis via inhibiting PI3K/Akt/mTOR signaling pathway and regulating gut microbiota.

This study aimed to analyze the therapeutic effect of Rhein on ulcerative colitis (UC) in mice and its possible mechanism. LPS-induced UC cell model and DSS-induced UC mouse model were used to analyze the antiinflammatory effect of Rhein on UC in vitro and in vivo, respectively. Network pharmacology analysis was conducted to identify potential signaling pathways involved in Rhein treating UC, and the results were further confirmed through western blotting assay. 16sRNA sequencing was performed to study the regulatory effect of Rhein on gut microbiota in UC mice. As indicated by the results, Rhein could significantly inhibit the production of pro-inflammatory cytokines (e.g., TNF-α, IL-6 and IL-1ß) in vivo and in vitro, and alleviate DSS-induced UC-associated symptoms in mice (e.g., colon shortening, weight loss, diarrhea and hematochezia). The PI3K/Akt/mTOR signaling pathway was predicted as the potential interacting protein of Rhein in the treatment of UC through network pharmacology analysis. It was found through western blotting assay that the Rhein treatment could significantly inhibit the PI3K/Akt/mTOR signaling pathway by decreasing the phosphorylated protein levels of PI3K, Akt, mTOR and p70S6K1. By 16sRNA gene sequencing analysis, Rhein administration could partially reverse the gut dysbacteriosis of mice induced by DSS and decrease pathogenic bacteria (e.g., Enterobacteriaceae and Turicibacter). It was positively correlated with the production of pro-inflammatory cytokines above, whereas the increase in probiotics (e.g., Unspecified-S24-7 and Rikenellaceae) was negatively correlated with the production of pro-inflammatory cytokines. In conclusion, Rhine had anti-UC efficacy, which was demonstrated by mitigating the UC symptoms and reducing intestinal inflammation by inhibiting the PI3K/Akt/mTOR signaling pathway and modulating gut microbiota.

SYT-SSX1 enhances the invasiveness and maintains stem-like cell properties in synovial sarcoma via induction of TGF-ß1/Smad signaling.

BACKGROUND: Synovial sarcoma (SS) is a type of soft tissue sarcoma (STS) of undetermined tissue origin, which is characterized by the recurrent pathognomonic chromosomal translocation t (X;18)(p11.2; q11.2). Studies have shown that SS is a malignant tumor originating from cancer stem cells or pluripotent mesenchymal stem cells and may be related to fusion genes. In addition, some studies have indicated that the induction of epithelial-mesenchymal transition (EMT) via the TGF-ß1/Smad signaling pathway leads to SS metastasis. METHODS: We analyzed the effects of SYT-SSX1 on the stemness of SS cells via TGF-ß1/Smad signaling in vitro. The SYT-SSX1 fusion gene high expression cell was constructed by lentiviral stable transfer technology. SYT-SSX1 and SW982 cells were cultured and tested for sphere-forming ability. The transwell migration assay and flow cytometry were used to assess the migration ability of the sphere cells as well as the expression of CSC-related markers. We treated SYT-SSX1 cells with rhTGF-ß1 (a recombinant agent of the TGF-ß1 signaling pathway) and SB431542 and observed morphological changes. A CCK-8 experiment and a western blot (WB) experiment were conducted to detect the expression of TGF-ß1 signaling pathway- and EMT-related proteins after treatment. The SYT-SSX1 cells were then cultured and their ability to form spheres was tested. Flow cytometry, WB, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of CSC surface markers on SYT-SSX1 sphere cells. RESULTS: It was found that SYT-SSX1 has stronger sphere-forming ability, migration ability, and higher expression of CSC-related molecules than SW982 cells. Through treating SYT-SSX1 and SW982 cells with rhTGF-ß1 and SB431542, we found that TGF-ß1 enhanced the proliferation of cells, induced EMT, and that TGF-ß1 enhanced the characteristics of tumor stem cells. CONCLUSIONS: Our results suggest that SYT-SSX1 enhances invasiveness and maintains stemness in SS cells via TGF-ß1/Smad signaling. These findings reveal an effective way to potentially improve the prognosis of patients with SS by eliminating the characteristics of cancer stem cells (CSCs) during treatment.

A systematic review on botany, processing, application, phytochemistry and pharmacological action of Radix Rehmnniae.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Rehmanniae (RR) is the tuber root of Rehmannia glutionsa Libosch, which was firstly recorded in Shennong's Classic of Materia Medica (⟪⟫). RR is a non-toxic and wide used traditional Chinese medicine. RR has the effect of clearing heat, generating essence, cooling blood, stopping bleeding, nourishing yin and blood, and filling marrow. It is used in clinic in the form of processed decoction pieces, including Dry Radix Rehmnniae (DRR) and Rehmanniae Radix Praeparata (RRP). The application of RR in traditional Chinese medicine (TCM) prescriptions can treat various diseases, such as anemia, irregular menstruation, deficiency of liver yin, renal failure and so on. AIM OF REVIEW: This paper aims to provide a comprehensive and productive review of RR, which mainly contains botanical characteristics, processing methods, traditional application, chemical composition, quality control and pharmacological action. MATERIALS AND METHODS: Literature search was conducted through the Web of Science, Baidu Scholar, ScienceDirect, PubMed, CNKI, and WanFang DATA using the keywords "Radix Rehmnniae", "Rehmanniae Radix Praeparata", "processing", "clinical application", "chemical composition", "quality control", and "pharmacological action". In addition, information was collected from relevant textbooks, reviews, and documents. RESULTS: RR is a traditional Chinese herbal medicine with clinical value and rich resources. More than 100 components have been isolated and identified from RR. It has multiple pharmacological actions, such as hemostasis, antioxidation, anti-osteoporosis, lowering blood sugar, improving renal function, anti-inflammation, protecting neuronal function, antidepression and anti-anxiety. DRR and RRP are two different processed products of RR. After processing, there are great changes in property, taste, efficacy, clinical application, chemical composition and pharmacological action. At present, identifying chemical constituents of RR and its medicinal value has been deeply studied. However, there is a lack of research on the reasons for the differences in pharmacological effects between DRR and RRP. The reasons for these differences need to be further verified. Catalpol, the active component of RR, has been studied extensively in the literature, but the pharmacological effects of catalpol cannot represent the pharmacological effects of the whole RR. In the future, effective components such as rehmannioside D, polysaccharide, total glycosides, and effective parts in RR need to be further studied and developed. The pharmacodynamic material basis and mechanism of RR need to be further discussed. The scientific connotation and processing methods of RRP need to be studied and standardized.

Targeted therapy of rheumatoid arthritis via macrophage repolarization.

The polarization of macrophages plays a critical role in the physiological and pathological progression of rheumatoid arthritis (RA). Activated M1 macrophages overexpress folate receptors in arthritic joints. Hence, we developed folic acid (FA)-modified liposomes (FA-Lips) to encapsulate triptolide (TP) (FA-Lips/TP) for the targeted therapy of RA. FA-Lips exhibited significantly higher internalization efficiency in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells than liposomes (Lips) in the absence of folate. Next, an adjuvant-induced arthritis (AIA) rat model was established to explore the biodistribution profiles of FA-Lips which showed markedly selective accumulation in inflammatory paws. Moreover, FA-Lips/TP exhibited greatly improved therapeutic efficacy and low toxicity in AIA rats by targeting M1 macrophages and repolarizing macrophages from M1 to M2 subtypes. Overall, a safe FA-modified liposomal delivery system encapsulating TP was shown to achieve inflammation-targeted therapy against RA via macrophage repolarization.

Identification of Potential Genomic Alterations and the circRNA-miRNA-mRNA Regulatory Network in Primary and Recurrent Synovial Sarcomas.

Introduction: Synovial sarcoma (SS) is one of the most invasive soft tissue sarcomas, prone to recurrence and metastasis, and the efficacy of surgical treatment and chemotherapy for SS remains poor. Therefore, the diagnosis and treatment of SS remain a significant challenge. This study aimed to analyze the mutated genes of primary SS (PSS) and recurrent SS (RSS), discover whether these sarcomas exhibit some potential mutated genes, and then predict associated microRNAs (miRNA) and circular RNAs (circRNA) by analyzing the mutated genes. We focused on the regulation mechanism of the circRNA-miRNA-mutated hub gene in PSS and RSS. Methods: We performed a comprehensive genomic analysis of four pairs of formalin-fixed paraffin-embedded samples of PSS and RSS, using Illumina human exon microarrays. The gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) function, and pathway enrichment of the mutated genes were analyzed, and the protein-protein interaction (PPI) network was forecast using String software 11.0. The hub genes were then obtained using the Molecular Complex Detection (MCODE) plug-in for Cytoscape 3.7.2 and were used to analyze overall survival (OS) using the Gene Expression Profiling Interactive Analysis (GEPIA) database. The corresponding miRNAs were obtained from the miRDB 5.0 and TargetScan 7.2 databases. The corresponding circRNAs of the hub genes were found through the miRNAs from these databases: Circbank, CircInteractome, and StarBase v2.0. Thereafter we set up a competing endogenous RNA (ceRNA) network with circRNA-miRNA and miRNA-messenger RNA (mRNA) pairs. Results: Using the chi-squared test, 391 mutated genes were screened using a significance level of p-values < 0.01 from the four pairs of PSS and RSS samples. A GO pathway analysis of 391 mutated genes demonstrated that differential expression mRNAs (DEmRNAs) might be bound up with the "positive regulation of neurogenesis," "cell growth," "axon part," "cell-substrate junction," or "protein phosphatase binding" of SS. The PPI network was constructed using 391 mutated genes, and 53 hub genes were identified (p < 0.05). Eight variant hub genes were discovered to be statistically significant using the OS analysis (p < 0.05). The circRNA-miRNA-mRNA (ceRNA) network was constructed, and it identified two circRNAs (hsa_circ_0070557 and hsa_circ_0070558), 10 miRNAs (hsa-let-7a-3p, hsa-let-7b-3p, hsa-let-7f-1-3p, hsa-let-7f-2-3p, hsa-mir-1244, hsa-mir-1197, hsa-mir-124-3p, hsa-mir-1249-5p, hsa-mir-1253, and hsa-mir-1271-5p) and five hub genes (CENPE, ENPP3, GPR18, MDC1, and PLOD2). Conclusion: This study screened novel biological markers and investigated the differentiated circRNA-miRNA-mutated hub gene axis, which may play a pivotal role in the nosogenesis of PSS and RSS. Some circRNAs may be deemed new diagnostic or therapeutic targets that could be conducive to the future clinical treatment of SS.

A Case of Phyllodes Tumor of the Breast with Mixed Liposarcoma: Case Report and Literature Review.

Phyllodes tumors (PTs) account for less than 1% of breast tumors, and malignant PTs account for even less. Here, we described an unusual case of malignant PT with mixed liposarcoma (myxoid liposarcoma [MLP] and pleomorphic liposarcoma [PLP]). A 52-year-old woman discovered a small lump in her left breast. Twenty years later, the lump suddenly grew within 1 month. Mammography showed space-occupying lesions of the left breast. Histologically, the tumor was characterized by hypercellular stroma covering the epithelium and protrusion of the myoepithelium into the cyst to form a lobulated structure; regions of loose mucus and hypercellular structures alternated. A region of peripheral benign fibroadenoma was also observed, and many stellate and spindle cells or signet ring-like cells were identified in loose areas. Some areas showed a characteristic thin branching vascular pattern. In the cell-rich area, adipocytes and odd megakaryocytes were observed. Atypical mitotic figures were observed in the cell-rich and mucus areas (16 mitoses/10 high-power fields [HPF] and 2 mitoses/10 HPF, respectively). In the immunohistochemical analysis, a small number of tumor cells were positive for AE1/3 and vimentin, whereas all cells were negative for cytokeratin 34ßE12, E-cadherin, p63, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and S-100, ruling out the possibility of metaplastic carcinoma. Interestingly, cyclin-dependent kinase 4, mouse double minute 2 (MDM2), and p16 were strongly positive in both loose mucus and cell-rich areas. However, the fluorescence in situ hybridization test results showed that MDM2 was not amplified. Combined with morphological characteristics, these findings supported that the tumor was a mixed malignant PT with MLP and PLP. Our patient did not receive radiation therapy, and after 47 months of follow-up, no recurrence or metastasis occurred. This case report serves to expand the morphologic spectrum of mixed malignant PT with liposarcoma.

Network Pharmacology-Based Analysis of the Underlying Mechanism of Huajiao for Pain Relief.

OBJECTIVE: Pain is a common symptom among patients, and pain management is an important clinical practice topic. The mechanism of Huajiao (HJ; Zanthoxylum bungeanum Maxim.) and its effective components for treating pain was explored using network pharmacology and molecular docking to verify its pain relief function in traditional medical practice. METHODS: HJ's components were collected via the Traditional Chinese Medicine Systems Pharmacology platform and published studies. HJ-associated target proteins were predicted using the drug similarity rule via Swiss Target Prediction. Online Mendelian Inheritance in Man was used to search for pain-related genes and proteins, and the Database of Interacting Proteins was used to obtain the human interactive target proteins. The compound-target-disease network of HJ for pain relief was constructed with protein-protein interaction networks. The obtained target proteins were uploaded on the Database for Annotation, Visualization, and Integrated Discovery to annotate, visualize, and integrally discover the related signaling pathway, and semiflexible molecular docking by Autodock Vina was applied to verify the potential mechanism. RESULTS: A total of 157 molecules in HJ were obtained, and the top 20 active components or active groups were mainly focused on the amide alkaloids (e.g., [6RS]-[2E,7E,9E]-6-hydroxy-N-[2-hydroxy-2-methylpropyl]-11-oxo-2,7,9-dodecatrienamide and [2E,7E,9E]-N-[2-hydroxy-2-methylpropyl]-11-ethoxy-6-hydroxy-dodeca-2,7,9-trienamide). Also, the 66 main targets were filtered from 746 predicted targets and 928 pain-related targets through module Network Analyzer in Cytoscape 3.6.0. Finally, there were 3 critical signaling pathways, including mitogen-activated protein kinase, phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin, and IκB kinase-nuclear factor κB-cyclooxygenase 2 based on integrated discovery with 54 enriched signaling pathways. CONCLUSIONS: HJ is used as a pain relief and has multicomponents, multitargets, and multiapproaches. Amide alkaloids are important substance bases, and HJ is more suitable for treating inflammatory pain.

Molecular basis of neurophysiological and antioxidant roles of Szechuan pepper.

The balance between anti- and pro-oxidant activities is of great important to maintain the biochemical and physiological homeostasis in the human body. Developing new therapeutic strategies to reduce health risks caused by free radicals has always been research focus over the past decades. Szechuan pepper, a characteristic pungent-flavored spice in Sichuanese cuisine, recently attracts the attention of researchers for its widespread therapeutic effects on acute and chronic diseases. The plant produces the innocuous 'tingling and numbing' sensations across the oral cavity by stirring specific neuron types, which are mechanically distinct from those excited by capsaicin. Furthermore, the extracts or the compounds of Szechuan pepper are biochemically proven to possess strong antioxidant activities that could scavenge free radicals and inhibit overactive peroxidase system in pathological models. Herein, the review emphasizes the molecular basis underlying the neurophysiological and antioxidant activities of the plant by a comprehensive analysis of various signaling pathways in disease models treated by Szechuan pepper. Further, we performed a broadening analysis to unearth potential signaling pathways associated with the antioxidant roles of the plant.

Inflammation-Targeted Delivery of Celastrol via Neutrophil Membrane-Coated Nanoparticles in the Management of Acute Pancreatitis.

Celastrol (CLT)-loaded PEG-PLGA nanoparticles (NPs/CLT) coated with neutrophil membranes (NNPs/CLT) were explored for the management of acute pancreatitis (AP). PEG-PLGA nanoparticles sized around 150 nm were proven to selectively accumulate in the pancreas in rats with AP. NNPs were found to overcome the blood-pancreas barrier and specifically distributed to the pancreatic tissues. Moreover, NNPs showed more selective accumulation in the pancreas than nanoparticles without any membrane coating in AP rats. Compared to CLT solution and the NPs/CLT group, NNPs/CLT significantly downregulated the levels of serum amylase and pancreatic myeloperoxidase in AP rats. Also, using NNPs as the delivery vehicle significantly reduced the systemic toxicity of CLT in AP rats. Together, these results suggest that NNPs/CLT represent a highly promising delivery vehicle for the targeted therapy of AP.

[Study on Dinggui gel paste on analgesic and anti-inflammatory effects].

OBJECTIVE: To observe effects and mechanism of Dinggui gel paste analgesic anti-inflammatory. METHODS: Eighty-four male KM mice weighted from 18 to 22 g and aged 4 to 5 weeks were randomly divided into 7 groups, named blank group, model group, matrix control group, Votalin group, high dosage of Dinggui gel paste group with group, equivalent dosage of Dinggui gel paste group, Dinggui gel paste group, 12 mice in each group. Except blank and model group, the other groups were paste ointment for 7 days, and one time a day, matrix control group were pasted isodose blank matrix gel patch. Pain threshold were tested at 30, 60, 90 and 120 min after the last ad-ministration. Hot plate test were performed by injection of 5% formalin for 20 µL on right hindfoot sole after the last administration. The cumulative time of mice licking right rear foot were observed at stage of I and II, and content of IL-1, TNF-α were tested by ELISA method. Differences of weight between right and left ears were measured by ear swelling method and anti-inflammation experiment. RESULTS: In hot plate test at 90 min, pain threshold in equivalent dosage of Dinggui gel paste group was (24.87 ± 14.67) s and (15.28 ± 8.23) s in model group; (26.33 ± 15.45) s in high dosage of Dinggui gel paste group and (15.31 ± 5.02) s in model group at 120 min in hot plate test, there were no statistical differences between two groups. Pain period at stage I, licking cumulative time in high dosage of Dinggui gel paste group was (66.70 ± 22.83) s and (101.80 ± 33.65) s in model group,and had significant differences between two groups; there were statistical differences in licking cumulative time at stage I of pain period among high dosage of Dinggui gel paste group (51.30 ± 43.60)s, equivalent dosage of Dinggui gel paste group (64.00 ± 47.27) sand model group (109.50 ± 36.78) s. Content of IL-1 in model group was (28.70 ± 8.24) ng/L and (13.33 ± 2.20) ng/L in high dosage of Dinggui gel paste group, there was obvious meaning between two groups; There were significant differences in TNF-α content among model group (93.60 ± 23.65) ng/L,high dosage of Dinggui gel paste group (63.21 ± 10.54)ng/L and equivalent dosage of Dinggui gel paste group (72.69 ± 16.26) ng/L; while there were no statistical meaning in ear swelling degree among model group (5.73 ± 0.80) mg,high dosage of Dinggui gel paste group (5.42 ± 0.68) mg and equivalent dosage of Dinggui gel paste group (4.98 ± 1.52) mg. CONCLUSION: Dinggui gel paste could increase pain threshold, reduce licking accumulative time, and decrease ear swelling degree, and relief pain by regulating level of TNF-α and IL-1.

Protein and mRNA expression of CTGF, CYR61, VEGF-C and VEGFR-2 in bone marrow of leukemia patients and its correlation with clinical features / 中国实验血液学杂志

This study was aimed to investigate the mRNA and protein expression of CTGF, CYR61, VEGF-C and VEGFR-2 in bone marrow of patients with leukemia, and to analyze the role and clinical significance of these 4 factors in genesis and development of leukemia, infiltration and metastasis of leukemic cells. A total of 100 cases of newly diagnosed leukemia, 26 cases of acute leukemia in complete remission and 30 controls were enrolled in this study. The mononuclear cells of bone marrow were collected, the mRNA and protein expression levels of CTGF, CYR61, VEGF-C, VEGFR-2 in leukemia patients and controls were detected by real time PCR and Western blot, respectively. The results showed that the mRNA and protein expression levels of above mentioned 4 factors were significantly higher than those in control (P < 0.05), only CTGF mRNA expression in AL patients after complete remission showed statistical difference as compared with control (P < 0.05), but the expression of CTGF mRNA showed statistical significance in different bone marrow hyperplasia of acute leukemia (P < 0.05). The expression level of CTGF protein showed difference in different chromosome karyotypes of leukemia (P < 0.05). The expression levels of CYR61 and VEGF-C proteins showed statistical difference in different bone marrow hyperplasia of acute leukemia (P < 0.05). The expression level of CTGF, CYR61, VEGF-C mRNA and protein in CML group were higher than that in control group. The expression levels of CTGF and CYR61 protein were higher than that in control. The mRNA and protein expression levels of above-mentioned 4 factors in sex and infiltration lf leukemic cells did not show statistical significance(P < 0.05). In correlative analysis, the mRNA expressions of above mentioned 4 factors were positively correlated with bone marrow blast count(P < 0.05), the protein expression of CTGF, CYR61 and VEGF-C were positively correlated with bone marrow blast count. It is concluded that the CTGF, CYR61, VEGF-C and VEGFR-2 mRNA and protein play a role in acute leukemia. In acute leukemia (AML/ALL), the expression of above mentioned factor was high, but except VEGFR-2. Most of them were positively correlated with bone marrow blast count. Joint block of these angiogenesis-related factors is likely to play an important role in targeting treatment of leukemia.

Expression of heparanase and its coagulation proteins on the surface of leukemic cells / 白血病·淋巴瘤

Objective To explore whether the expression level of heparanase (HPA) and its coagulation proteins on leukemic blast membrane could determine the hemostatic balance on the surface of leukemia cells.Methods Forty patients of leukemia were studied,and 20 patients with iron dificient anemia as the control group.Expression of tissue factor (TF),heparanase (HPA),tissue factor pathway inhibitor (TFPI),and urokinase plasminogen activator receptor (UPAR) on leukemic blast surfaces were analyzed by flowcytometry.Results The expression of TF,UPAR,and HPA in AML,ALL,CML,CLL and CRAL groups were significantly higher compared with the control group (t =.3.289,3.507,2.701,P ＜0.05; t =2.498,0.802,3.090,P ＜0.05; t =2.642,3.308,2.696,P ＜0.05; t =3.417,3.434,2.382,P ＜0.05; t =2.193,2.272,2.263,P ＜0.05).There were no significantly differences between the leukemic cell expression of TFPI and the control group (P ＞0.05).Expression of TF,UPAR,HPA in AML patients were significantly higher than ALL,CML and CLL groups (t =2.463,2.179,2.276,P ＜0.05; t =2.637,2.402,2.095,P ＜0.05; t =2.548,2.425,2.412,P ＜0.05).The levels of TF,UPAR and HPA in M3,M4 and M5 patients were higher than that of M1,M2 groups (P ＜0.05).There were no significantly differences among M3,M4 and M5 (P ＞0.05).Conclusions These results suggest that TF,UPAR and HPA are predominately expressed on leukemic blast surface,particularly in M3and M4,5 subtypes.The expression of coagulation proteins on blast membrane might determine the hemostatic balance on the surface of leukemia cells.

Expression of CYR61, CTGF, VEGF-C, VEGFR-2 mRNA in bone marrow of leukemia patients and its clinical significance / 中国实验血液学杂志

The study was aimed to detect the levels of CYR61, CTGF, VEGF-C, VEGFR-2 mRNA in bone marrow (BM) of leukemia patients and investigate the interaction of CYR61, CTGF, VEGF-C, VEGFR-2 proteins in occurrence, development, infiltration and metastasis of leukemia and its clinical significance, to find a new tumor marker for diagnosis and treatment of leukemia with some new directions. 74 patients with leukemia were enrolled in this study, 38 out of them were males and 36 were females, aged from 6 to 77 years old with the median age of 45 years old. In the control group, 7 males and 5 females, aged from 16 to 78 years old with the median age of 46. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to detect the levels of CYR61, CTGF, VEGF-C, VEGFR-2 mRNA. The results showed that the levels of CYR61, CTGF, VEGF-C, VEGFR-2 mRNA in BM of newly diagnosed patients with acute and chronic leukemia of each group were significantly higher as compared with the control group (p < 0.05). The levels of CYR61, CTGF mRNA in acute leukemia remission group were significantly higher than those in control group (p = 0.039, 0.025). The level of CTGF mRNA was highest in B-ALL group, and was higher than that in AML, CML, CLL, T-ALL groups (p = 0.002, 0.034, 0.002, 0.010). In AML group, mRNA expressions of CYR61 and CTGF, CYR61 and VEGF-C, CTGF and VEGFR-2 were positively correlated (r = 0.452, 0.466, 0.464; p = 0.045, 0.038, 0.039), and in CML group mRNA expression of CYR61 and VEGF-C was positively correlated (r = 0.882, p = 0.000). The expression levels of VEGF-C, VEGFR-2 mRNA in acute leukemia patients with extramedullary infiltration were higher than those in acute leukemia patients without extramedullary infiltration (p = 0.028, 0.047). VEGF-C mRNA expression and the original cell counts in AML group were positively correlated (r = 0.418, p = 0.034). It is concluded that CYR61, CTGF, VEGF-C and VEGFR-2 interact each other in the pathogenesis of leukemia, promote the development, metastasis and infiltration of leukemia; and these factors in different types of leukemia and extramedullary infiltration are different, which may become tumor markers of leukemia; and blocking VEGF-C and VEGFR-2 may block tumor growth and metastasis.

Role of Notch signaling pathway in pathogenesis of leukemia and angiogenesis / 中国实验血液学杂志

The occurrence and development of many tumors all relate with abnormal expression of the Notch receptor. The role of different Notch receptors may be different, even contrary in different tissues at different stages of tumor development, as well as in the same system tumors. Notch signaling pathway plays an important role in cell proliferation, differentiation, apoptosis and tumor angiogenesis, and is as a meeting point for many important cell signaling pathway. Angiogenesis is regulated by complex interactions of multiple activators and inhibitors. Vascular endothelial growth factor (VEGF) and Notch signaling pathway are involved in such process. Many studies have confirmed that Notch signaling pathway plays a key role in the embryonic development and tumour angiogenesis. Recent studies have also revealed that Notch signaling pathway has many potential drug targets. Based on study of Notch signaling pathway and its molecular mechanism of leukemia, to design drugs effecting these targets to block and activate Notch signaling pathway for therapy of leukemia and angiogenesis diseases has a broad application prospects. This review summarises the components of Notch signaling pathway and the role of Notch signaling pathway in occurrence of leukemia and angiogenesis.

Expression of cyclooxygenase-2 in bone marrow cells of leukemia patients and its association with angiogenesis / 中国实验血液学杂志

The objective of this study was to investigate the effect of cyclooxygenase-2 (COX-2) in the angiogenesis of bone marrow in leukemia patients. 51 patients with newly diagnosed acute leukemia were taken as study objects, 18 healthy volunteers were enrolled in the control group. Bone marrow microvessel density (MVD) in bone marrow biopsy tissue section was determined with immunohistochemistry method, the vascular endothelial growth factor level in serum was detected with ELISA method and the expression of cyclooxygenase-2 in bone marrow cells was assayed by flow cytometry. The results showed that the MVD, VEGF level, positive rate of COX-2 expression in leukemia group all obviously increased as compared with the control group (p < 0.05). The correlative coefficients of MVD, VEGF level and COX-2 expression rate were 0.614, 0.423 and 0.577 respectively (p < 0.05). In conclusion, as well as solid tumors, leukemia may be also a angiogenesis-dependent malignant tumor. Coordination of COX-2 with VEGF may promote angiogenesis in bone marrow.

Advance of research on SDF-1/CXCR4 axis and angiogenesis in leukemia--review / 中国实验血液学杂志

The study on biological effects of SDF-1/CXCR4 axis composed of stromal cell derived factor-1 (SDF-1) and its receptor CXCR4 is progressing rapidly in the recent years. The SDF-1/CXCR4 axis plays an important role in occurrence and development of tumors and closely correlate with angiogenesis of tumors. This review focuses the progress of study on SDF-1/CXCR4 axis and angiogenesis in leukemia including SDF-1/ and its receptor CXCR4, the expression of SDF-1/CXCR4 axis in leukemic cells, the mechanism of relation between SDF-1/CXCR4 axis and angiogenesis in leukemia, the application of inhibitors against SDF-1/CXCR4 in treatment of angiogenesis and so on.