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Sphingosine kinase (SphK), sphingosine-1-phosphate (S1P) and S1P receptor (S1PR) are involved in the tumor biological processes such as tumor cell proliferation and migration, and play an important role in the development of cancer. In recent years, researchers have increasingly focused on the interaction between cancer cells and the tumor microenvironment. The tumor microenvironment is genetically stable and can be induced to an antitumor phenotype, which has significant therapeutic advantages. Studies have shown that SphK/S1P/S1PR can regulate multiple aspects of the tumor microenvironment. This review summarizes the effects of SphK and S1P/S1PR signaling on the tumor microenvironment from four perspectives: tumor immune microenvironment, cancer associated fibroblasts, tumor angiogenesis and tumor hypoxic microenvironment, and also outlines potential drug research related to these signal molecules, aiming to elucidate the role of SphK/S1P/S1PR in tumor occurrence and development and provide new ideas for the research of anti-tumor drugs.
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The secondary metabolites of plants are important sources of natural drugs. Betula plants have abundant pharmacological value, complex mechanism and wide applications, which are closely related to the triterpenoids of theirs. Triterpenoids in Betula species are mainly divided into dammarane-type, ocotillol-type, oleanane-type, lupane-type and cycloaltunane-type. The extracts of Betula species have varieties of activities such as anti-tumor, anti-inflammatory, anti-oxidant, anti-bacterial, etc. And the biosynthetic pathways of triterpenoids after 2,3-oxidosqualene are split into four branches of dammarenediol-II, lupeol, cycloartenol and amyrin according to the different oxidosqualene cyclases. This review summarizes the chemical constituents, pharmacological activities and biosynthetic pathways of triterpenoids in Betula plants. It provides a reference for the research and development of new drugs and the production of these triterpenoids in microbial cell factories by synthetic biology methods.
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Objective To summarize the integrative rehabilitation treatment of traditional Chinese medicine (TCM) and Western medicine in hypertrophic olivary degeneration (HOD) secondary to the operation of brain stem cavernous malformation. Methods The clinical data of medication, rehabilitation and follow-up of a patient with HOD secondary to operation on brain stem cavernous malformation was retrospectively analyzed. Results Three months after operation, limb static and motor tremor, dysarthria, palate spasm, eye movement disorder and walking difficulty appeared. The patient was diagnosed as HOD according to clinical features and brain magnetic resonance imaging (MRI). He was treated with pertinence rehabilitation training combined with TCM including acupuncture and herbs. After integrative rehabilitation, he could stand and walk independently, the tremor was alleviated, the balance function improved, the activities of daily living improved, and the dosage of oral western medicine also decreased. Conclusion After intracranial surgery, secondary neurodegeneration and movement disorder may appear, and it could be improved by integrative rehabilitation treatment of TCM and Western medicine
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Objective To summarize the integrative rehabilitation treatment of traditional Chinese medicine (TCM) and Western medicine in hypertrophic olivary degeneration (HOD) secondary to the operation of brain stem cavernous malformation. Methods The clinical data of medication, rehabilitation and follow-up of a patient with HOD secondary to operation on brain stem cavernous malformation was retrospectively analyzed. Results Three months after operation, limb static and motor tremor, dysarthria, palate spasm, eye movement disorder and walking difficulty appeared. The patient was diagnosed as HOD according to clinical features and brain magnetic resonance imaging (MRI). He was treated with pertinence rehabilitation training combined with TCM including acupuncture and herbs. After integrative rehabilitation, he could stand and walk independently, the tremor was alleviated, the balance function improved, the activities of daily living improved, and the dosage of oral western medicine also decreased. Conclusion After intracranial surgery, secondary neurodegeneration and movement disorder may appear, and it could be improved by integrative rehabilitation treatment of TCM and Western medicine
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10-Deacetylbaccatin III (10-DAB) C10 acetylation is an indispensable procedure for Taxol semi-synthesis, which often requires harsh conditions. 10-Deacetylbaccatin III-10-
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Objective:To analyze the general situation and traditional Chinese medicine (TCM) syndrome characteristics in patients with coronavirus disease-2019（COVID-19） in Anhui province, and to provide a basis for clinical diagnosis and treatment. Method:The 144 cases of COVID-19 patients in Anhui province were collected from designated hospitals by means of multi-center cross-sectional epidemiological survey. The TCM syndrome information collection table of patients with novel coronavirus pneumonia was created to collect the general data, etiology and pathogenesis, pulse and signs, syndrome type and frequency statistics of the patients, and then summarize and analyze the main symptoms and syndrome distribution characteristics of patients with novel coronavirus pneumonia. Result:The mean age of 144 patients with COVID-19 infection was （43.54±15.91） years old, and the number of males was larger than the number of females (9/7). The age distribution and gender difference of the patients were statistically significant (P<0.05). 36.11%（52/144） of the patients had a history of travel/residence in Wuhan/Hubei province, and 63.89% (92/144) of the patients had a history of close contact with the confirmed patients. The main clinical manifestations included fever, cough, diarrhea, fatigue and poor tolerance. Light red tongue and red tongue were dominant in tongue quality, with mainly greasy coating, slippery pulse, rapid pulse and soft pulse were the main types of pulse. The main types of syndrome differentiation were the common type (76.38%, 110/144), most of which were demonstrated as dampness obstructing the lung and spleen (56.25%, 81/144). There was no significant difference in gender composition and age distribution between two groups. Conclusion:The pathogenesis of COVID-19 patients in Anhui province is closely related to the lung and spleen, and the dampness caused by pathogen of the epidemic virus is the main pathological factor of disease, which is in line with characteristics of dampness epidemic in TCM, also can see concurrently "heat, poison, stasis" for a characteristic.
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In the 1970s, the Framingham study found that smoking increased the risk of stroke. Subsequent laboratory and clinical studies have demonstrated that a variety of harmful components in tobacco can damage the vascular endothelium and interfere with the clotting mechanism, giving rise to atherosclerosis and hypercoagulability, which eventually leads to stroke. Furthermore, the harmful ingredients in tobacco may induce hypertension, diabetes, atrial fibrillation and other diseases, which indirectly increase the risk of stroke. However, there are still a lot of questions about the relationship between smoking and stroke. This paper will analyze the correlation between them and its mechanism, and discuss the influence of smoking cessation on the prognosis of stroke, so as to provide reference for the prevention and treatment of related diseases.
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OBJECTIVE: To explore the clinical value of pathological evaluation of incision margin of breast-conserving operation specimens for early breast cancer. METHODS: The clinical data of early breast cancer patients undergone breast-conserving surgery in the Breast Disease Center of the Peking University First Hospital from January 1,2013 to December 31,2017 were analyzed retrospectively. The consistency of intraoperative frozen pathology with postoperative paraffin pathology and the relationship between pathological margin and prognosis were discussed. RESULTS: A total of474 breast-conserving cases were included in the study. The overall recurrence and metastasis rate was 3.4%; the local recurrence rate(LRR)was 1.5%; the 5-year disease-free survival rate(DFS)was 95.7%,and the 5-year overall survival rate(OS)was 96.8%. The coincidence rate of paraffin pathology and intraoperative frozen pathology in evaluating the breast-conserving margin was 100%. There was no significant difference in local recurrence rate between positive and negative first margin(χ~2=1.371,P=0.242). There was no significant difference in disease-free survival rate and overall survival rate among patients with negative margin width(χ~2=0.123,P=0.726;χ~2=0.077,P=0.781),and no significant difference in local recurrence rate(χ~2=1.808,P=0.613). CONCLUSION: Rapid frozen pathological examination is safe and reliable in evaluating the incision margin of breast-conserving surgery. On the premise of the negative incision margin,there is no significant difference in disease-free survival rate and local recurrence rate among different incision margin widths.
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Taxol is a "blockbuster" antitumor drug produced by species with extremely low amount, while its analogue 7--xylosyl-10-deacetyltaxol is generally much higher in the plants. Both the fungal enzymes LXYL-P1-1 and LXYL-P1-2 can convert 7--xylosyl-10-deacetyltaxol into 10-deacetyltaxol for Taxol semi-synthesis. Of them, LXYL-P1-2 is twice more active than LXYL-P1-1, but there are only 11 significantly different amino acids in terms of the polarity and acidic-basic properties between them. In this study, single and multiple site-directed mutations at the 11 sites from LXYL-P1-1 to LXYL-P1-2 were performed to define the amino acids with upward bias in activities and to acquire variants with improved catalytic properties. Among all the 17 mutants, E12 (A72T/V91S) was the most active and even displayed 2.8- and 3-fold higher than LXYL-P1-2 on -xylosidase and -glucosidase activities. The possible mechanism for such improvement was proposed by homology modeling and molecular docking between E12 and 7--xylosyl-10-deacetyltaxol. The recombinant yeast GS115-P1E12-7 was constructed by introducing variant , the molecular chaperone gene and the bacterial hemoglobin gene . This engineered yeast rendered 4 times higher biomass enzyme activity than GS115-3.5K-P1-2 that had been used for demo-scale fermentation. Thus, GS115-P1E12-7 becomes a promising candidate to replace GS115-3.5K-P1-2 for industrial purpose.
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Aim To investigate the therapeutic efficacy of DTP-mediated photodynamic therapy (PDT) on SGC7901/VCR human vincristine ( VCR )-resistant gastric cancer cells, and to reveal the relationship between DTP-PDT and P-gp. Methods MTT assay was employed to evaluate the cytotoxicity of DTP-PDT and combination treatment with DTP-PDT and VCR. A SGC7901/VCR-bearing nude mouse model was established, and the tumor volume was measured to draw the growth curve. Cell apoptosis was detected by flow cytometry, and the yield of intracellular singlet oxygen (O2) was determined after DTP-PDT. The expression of MDR1 mRNA and P-gp was determined by qPCR and flow cytometry, respectively. Results DTP-PDT demonstrated significant cytotoxicity on SGC7901/VCR cells and the nude mice transplanted tumor. DTP-PDT could induce the apoptosis of SGC7901/VCR cells and the generation of intracellular O2. DTP-PDT could inhibit the expression of MDR1 mRNA and P-gp, which could be reduced by a-tocopherol. Combined treatment with DTP-PDT and VCR demonstrated synergistic efficacy on resistant cells, which could be reduced by or-tocopherol. Conclusions O2 generated by DTP-me-diated PDT could inhibit the growth of SGC7901/VCR cells and induce cell apoptosis. Meanwhile, it inhibits the over-expression of P-gp on cell membranes, leading to reduced efflux of VCR and synergistic efficacy with DTP-PDT and VCR eventually.
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Nonribosomal peptide synthetases (NRPS) catalyze the synthesis of nonribosomal peptide (NRP) compounds with structural and functional diversities, including more than 20 marketed drugs. This review focuses on the recent advances in the functional domains of NRPS and their mechanisms of action, as well as the unconventional assembly patterns such as iterative NRPS, module skipping, in trans aminoacylation and tandem adenylation domains. This review provides the theoretical basis for exploring new nonribosomal peptide compounds and the development of new drugs.
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The relationship between glucocorticoids and cleft palate has been constantly highlighted in researches on oral clefts etiology.Recently, some studies have been conducted to further investigate the mechanism of cleft palate induced by excessive glucocor -ticoids.In this review, the epidemiological study on the role of glucocorticoids in cleft palate and mechanism of excessive glucocorti -coids-induced cleft palate were provided to elucidate the role of glucocorticoids in palatal development .
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AIM To establish an HPLC method for the simultaneous content determination of catalpol,acteoside,jionoside B1,martynoside,lobetyolin,methylophiopogonanone A and methylophiopogonanone B in Dangshen Guben Pills (Rehmanniae Radix,Rehmanniae Radix Preparata,Codonopsis Radix,etc.).METHODS The analysis of 50％ methanol extract of this drug was performed on a 30 ℃C thermostatic Agilent TC-C1s column (200 mm ×4.6 mm,5 μm),with the mobile phase comprising of acetonitrile-0.2％ phosphoric acid flowing at 1.0 mL/min in a gradient elution manner,and the detection wavelengths were set at 210,330,269 and 296 nm.RESULTS Seven constituents showed good linear relationships within their own ranges (r ≥0.999 2),whose average recoveries were 96.96％-99.65％ with the RSDs of 0.88％-1.74％.CONCLUSION This simple,accurate and reproducible method can be used for the quality control of Dangshen Guben Pills.
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Guizhi Decoction was one of the most commonly used traditional Chinese Medicine which possesses the effects of "jie-ji-fa-biao, regulating Ying and Wei". It was mainly used to treat mind-cold due to exogenous evils such as fever, headache, sweating, hate the wind, et al. Modern studies indicated that the chemical constituents of Guizhi decoction mainly include phenylpropanoid, monoterpenes, organic acids, flavonoids, triterpenoid saponins and so on. Pharmacological experimental studies had shown that Guizhi decoction could play a big role in dual-directional regulation on sweat gland, body temperature, immune function, gastrointestinal peristalsis, and blood pressure, and could also play the role of anti-inflammatory, antibacterial, antiviral, anti-allergic, analgesic, hypoglycemic, and cardiovascular protection. Many diseases such as internal, external, gynecological and pediatric diseases were treated in the clinical by using Guizhi decoction and its analogous formulae involving circulatory, immune, urinary, reproductive, endocrine, digestive, nervous and other systems. This article reviews the latest research progress of Guizhi decoction from three aspects: chemical constituents, pharmacological mechanism and clinical application. It will provide reference for further research and development of Guizhi decoction.
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AIM To establish an HPLC method for the simultaneous content determination of catalpol,acteoside,jionoside B1,martynoside,lobetyolin,methylophiopogonanone A and methylophiopogonanone B in Dangshen Guben Pills (Rehmanniae Radix,Rehmanniae Radix Preparata,Codonopsis Radix,etc.).METHODS The analysis of 50％ methanol extract of this drug was performed on a 30 ℃C thermostatic Agilent TC-C1s column (200 mm ×4.6 mm,5 μm),with the mobile phase comprising of acetonitrile-0.2％ phosphoric acid flowing at 1.0 mL/min in a gradient elution manner,and the detection wavelengths were set at 210,330,269 and 296 nm.RESULTS Seven constituents showed good linear relationships within their own ranges (r ≥0.999 2),whose average recoveries were 96.96％-99.65％ with the RSDs of 0.88％-1.74％.CONCLUSION This simple,accurate and reproducible method can be used for the quality control of Dangshen Guben Pills.
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Objective: To establish a quantitative analysis method for determining the contents of artemisinin, quercetin, isorhamnetin, Ginkgo esters, and lactones a, b, c in Shuxuening Injection by using multi-components with a single marker (QAMS), and set up methodological evaluation model of the above experiment. Methods: With artemisinin and Ginkgo esters as indexes, the relative correction factor (fk/s) between artemisinin and the other two total flavonoids and the fk/s between Ginkgo esters and lactones a, b, c were established. The contents of artemisinin and Ginkgo esters in Shuxuening Injection were determined by external standard method, the contents of other five components in Shuxuening Injection were calculated by the relative correction factor. The results of the content of five batches of Shuxuening Injection determined by QAMS and tested by external standard method were carried out by t test. Results: The fk/s of quercetin and isorhamnetin with reference to artemisinin were 1.873 and 0.324, the fk/s of ginkgolide A, B, C with reference to Ginkgo esters were 2.280, 1.659, and 1.429. And the repeatability was good under different experimental conditions. There were no significant differences between the calculated value and estimated value on QAMS and external standard method of five batches of Shuxuening Injection, and the results showed that fk/s was authentic. Conclusion: The established correction factor has good repeatability, and could be used for quantitative analysis and quality evaluation of multiple components in Shuxuening Injection.
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To study the expression and subcellular localization of recombinant dammarenediol-Ⅱ synthase (DS) in Saccharomyces cerevisiae, the dammarenediol-Ⅱ synthase gene ds was cloned from Panax ginseng, and the gene ds was fused with the gene of green fluorescent protein to obtain the fusion gene ds-gfp. The recombinant expression plasmids pESC-HIS-DS and pESC-HIS-DS-GFP were constructed and transformed into S. cerevisiae INVSc1 to obtain recombinant strains INVSc1-DS and INVSc1-DS-GFP. Microsomes of recombinant strains were prepared by differential centrifugation and observed by fluorescence microscope. The green fluorescence was only detected in INVSc1-DS-GFP microsomes, which indicated that DS was a membrane protein. It was also proved that dammarenediol-Ⅱ was produced from the cyclization of 2, 3-oxidosqualene catalyzed by DS through in vitro enzymatic reaction. In addition, our results revealed that the fusion expression of ds with gfp significantly improved the production of dammarenediol-Ⅱ from 7.53 mg·g-1 to 12.24 mg·g-1. This study provides a new strategy in the optimization of the pathway of ginsenosides biosynthesis in S. cerevisiae.
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Claviceps pururea Cp-1 strain established in our lab is capable of producing variety of bioactive ergot alkaloids, and is broadly used by the pharmaceutical companies. To engineer the strain genetically for the production of specific ergot alkaloid, an effective transformation system must be set up first. However, the reported transformation system is not suitable for this strain due to different genetic backgrounds and the heterogeneity of Claviceps. Thus, in this paper, the hyphae of Cp-1 strain were used to prepare protoplasts by lywallzyme. The formation of protoplasts was investigated under different concentrations and incubation time of enzyme. The strain was tested for sensitivity to several antibiotics at different concentrations. Finally, the genetic transformation system of Cp-1 strain was established. The results suggest that protoplasts were formed efficiently by using 1% lywallzyme at 25℃ for 2 h. Transformants were obtained by PEG mediated protoplast transformation of Cp-1 strain with plasmid pAN7-1, using 1.5 mg·mL-1 hygromycin B as the selective marker. The exogenous gene in the plasmid pAN7-1 was integrated into the genome of Cp-1 strain transformant as demonstrated by PCR result. This study laid an important foundation for genetic manipulation of Cp-1 strain.
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BmK AngM1 is a long-chain scorpion toxin purified from the venom of Buthus martensii Karsch. It has been reported to exhibit evident analgesic effect and low toxicity, and has the potential to be a novel analgesic drug. The BmKAngM1 gene was transformed into Pichiapastoris GS115. Mut+ and Mut(s) recombinant strains were screened by phenotype and Mut+ recombinant strains were used to detect BmK AngMl gene copy number in the real-time PCR. Expression of BmK AngM1 in the Mut+ recombinant strain was compared with that of the Mut(s) recombinant strain with the same single copy of BmK AngM1 gene under the same condition. The results indicated that the transcription level of BmK AngM1 gene in the Mut(s) recombinant strain was 2.7 fold of that in the Mut recombinant strain in the real-time PCR, and the expression of BmK AngM 1 in the Mut(s) recombinant strain was 1.5 fold of that in the Mut+ recombinant strain. Therefore, Mut(s) recombinant strain showed better ability to express BmK AngM1 than Mut+ recombinant strain.
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Animals , Arthropod Proteins , Gene Dosage , Pichia , Metabolism , Recombinant Proteins , Scorpion Venoms , ChemistryABSTRACT
<p><b>OBJECTIVE</b>To observe the peripheral neurotoxicity of 1-bromopropane (1-BP) by developing an animal model of peripheral neuropathy through oral administration of 1-BP.</p><p><b>METHODS</b>Forty male Wistar rats were randomly and equally divided into low-dose group (200 mg/kg), medium-dose group (400 mg/kg), high-dose group (800 mg/kg), and control group. The rats in the low-dose, medium-dose, and high-dose groups were orally given 1-BP (dissolved in corn oil), while the rats in the control group were orally given an equal volume of corn oil. The oral administration (0.2 ml/100 g BW) was performed once per day, 5 days per week, for 16 consecutive weeks. Neurobehavioral indices including gait score, hindlimb grip strength, and hindlimb landing foot splay were recorded periodically. Hematological and biochemical parameters were also measured during and after 1-BP exposure.</p><p><b>RESULTS</b>The gait scores were significantly higher in the high-dose group (after 8 ∼ 16 weeks of 1-BP exposure), medium-dose group (after 14 ∼ 16 weeks of 1-BP exposure), and low-dose group (after 15 ∼ 16 weeks of 1-BP exposure) than in the control group (P < 0.05, P < 0.01). Compared with the control group, the high-dose group showed significantly decreased hindlimb grip strength after 9, 12, and 14 weeks of 1-BP exposure (P < 0.05, P < 0.01), with the hindlimbs paralyzed after 16 weeks of 1-BP exposure. After 16 weeks of 1-BP exposure, the hindlimb grip strengths of rats in the medium-dose and low-dose groups were decreased to 72.6% and 91.2% of the control value (P < 0.01, P < 0.05). Compared with the control group, the high-dose group showed significantly increased hindlimb landing foot splay after 12, 14, and 16 weeks of 1-BP exposure, and the medium-dose group showed significantly increased hindlimb landing foot splay after 14 and 16 weeks of 1-BP exposure (P < 0.05, P < 0.01). The high-dose and medium-dose groups showed significantly higher serum alanine aminotransferase (ALT) activity than the control group after 8 weeks of 1-BP exposure, and so did the low-dose group after 16 weeks of 1-BP exposure (P < 0.01).</p><p><b>CONCLUSION</b>The nervous system is sensitive to the toxic effect of 1-BP, and 1-BP exposure can induce peripheral neuropathy in rats.</p>