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The surface activity and compound synergy of Panax notoginseng root extract were studied. The results show that the cmc of Panax notoginseng root extract at 25 °C is 0.1 g/L and γcmc is 43.67 mN/m. In the salinity mass fraction range of 0%-1%, the surface activity increases with the increasing saltness. In the pH between 4.0-8.0, the surface tension of Panax notoginseng root extract decreases with the decreasing pH. According to Rosen's theory, the optimal compound mass ratio between Panax notoginseng root extract and Tween 20 is 4:1, and it is found that the ability of the mixed system to form micelles increases by 41.18% compared with the theoretical results. The emulsifying ability results show that the emulsifying ability and emulsifying stability of the mixed system are close to Tween 20 alone, indicating that the combination of Panax notoginseng root extract and Tween 20 has a good synergistic effect, but not on Tween 60. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Cancer Biotherapy is the property of Editorial Office of Chinese Journal of Cancer Biotherapy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Chinese Journal of Cancer Biotherapy is the property of Editorial Office of Chinese Journal of Cancer Biotherapy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective To investigate the synergistic bacteriostatic effect of terpinen-4-ol (T4O) and α-bisabolol (Bis) on Staphylococcus aureus (S.aureus) and Cutibacterium acnes (C.acnes). Methods The microdilution checkerboard technique was used to determine the minimum inhibitory concentration (MIC) of T4O combined with Bis on the two etu perimental bacteria, and fractional inhibitory concentration index (FICI) was calculated. An MIC group (T4O and Bis at a concentration of MIC), a 2×MIC group (T4O and Bis at a concentration of 2×MIC), and a negative control group (no T4O or Bis added) were set up for each experimental bacterium; the time-bactericidal curve was plotted for each experimental bacterium after the addition of both T4O and Bis; each group of the two experimental bacteria was measured in terms of Zeta potential (ZP) on the surface of the strain, leakage of intracellular nucleic acid and protein, damage of bacterial biofilm, and respiratory chain dehydrogenase activity in S.aureus after the addition of both T4O and Bis; a transmission electron microscope was used to observe the influence of T4O combined with Bis on the morphology of the two experimental bacteria. Results The combination of T4O and Bis for S.aureus and C.acnes had an FICI of

Copyright of Practical Oncology Journal is the property of Journal of Practical Oncology Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Drug combination therapy has important application value in the cancer treatment. Predicting drug synergistic combinations through computational methods can provide targeted guidance for biological research, thereby improving research efficiency and reducing experimental costs. This paper proposed a multi-view graph neural network for drug synergy prediction to solve the problem of existing algorithms lack effective drug interaction modeling methods and could not consider the relationship between cell lines. Firstly, the algorithm used variational graph auto-encoder to learn the drug embedding of a specific cell line . Then, the algorithm integrated the drug information of other cell lines in the same tissue through a multi-view framework to improve the reliability of the drug embedding. Finally, the algorithm used the known drug combination scores as a supervisory signal to supervised training of the model to achieve reliable prediction of drug synergy effects. The experimental results on the DrugComb dataset demonstrate the effectiveness of the method. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether sodium butyrate (NaB) and sorafenib synergistically induces ferroptosis to suppress proliferation of hepatocellular carcinoma cells and the possible underlying mechanisms., Methods: CCK8 assay and colony formation assay were used to assess the effects of NaB and sorafenib, alone or in combination, on proliferation of HepG2 cells, and ferroptosis of the treated cells was detected with GSH assay and C11-BODIPY 581/591 fluorescent probe. TCGA database was used to analyze differential YAP gene expression between liver cancer and normal tissues. The effects of NaB and sorafenib on YAP and p-YAP expressions in HepG2 cells were invesitigated using Western blotting., Results: NaB (2 mmol/L) significantly reduced the IC 50 of sorafenib in HepG2 cells, and combination index analysis confirmed the synergy between sorafenib and NaB. The ferroptosis inhibitor Fer-1 and the YAP activator (XMU) obviously reversed the growthinhibitory effects of the combined treatment with NaB and sorafenib in HepG2 cells. The combined treatment with NaB and sorafenib, as compared with the two agents used alone, significantly inhibited colony formation of HepG2 cells, further enhanced cellular shrinkage and dispersion, and decreased intracellular GSH and lipid ROS levels, and these effects were reversed by Fer-1 and XMU. TCGA analysis revealed a higher YAP mRNA expression in liver cancer tissues than in normal liver tissues. NaB combined with sorafenib produced significantly stronger effects than the individual agents for downregulating YAP protein expression and upregulating YAP phosphorylation level in HepG2 cells., Conclusion: NaB combined with sorafenib synergistically inhibit hepatocellular carcinoma cell proliferation possibly by inducing ferroptosis via inhibiting YAP expression.

The synergistic effect and compatibility structure of active anti-inflammatory ingredients(iridoid glycosides: shanzhiside methylester and 8-O-acetylshanzhiside methyl ester, flavonoid glycoside: luteoloside, and phenylethanoid glycoside: forsythoside B) from Lamiophlomis rotata were explored based on network pharmacology and component structure theory. In network pharmacology, CTD, SwisseTargetPrediction, and PharmMapper databases were used to collect and screen the targets of all active ingredients. The inflammation-related targets were obtained from CTD and GeneCards databases. The core targets were obtained by Venny 2.1.0, STRING, and Cytoscape 3.9.1. Core targets were annotated by the GO function and enriched by the KEGG pathway based on the DAVID database. In terms of component structure, based on a uniform design method and xylene-induced ear swelling model in mice, tumor necrosis factor-α and interleukin-6 were taken as the dependent variables, and the compatibility relationship among anti-inflammatory ingredients from L. rotata was explored through the quadratic polynomial stepwise regression. In addition, in vivo pharmacological experiments were conducted to verify the results. A network pharmacology study showed that compared with a single ingredient, the combined action of the three ingredients can synergistically exert anti-inflammatory effects through more biological processes, pathways, and targets. Component structure study showed that the optimal structural ratio of shanzhiside methylester and 8-O-acetylshanzhiside methyl ester in the iridoid glycoside ingredient was 1.21∶1. The optimal structural ratio among the three types of ingredients(iridoid glycosides∶phenylethanol glycoside∶flavonoid glycoside) was 4.8∶1.6∶1. In conclusion, each anti-inflammatory ingredient from L. rotata can work synergistically, and there is an optimal compatibility ratio relationship among these ingredients. This work provides a new experimental basis for the intrinsic quality control of L. rotata.

Copyright of Chinese Journal of Cancer Biotherapy is the property of Editorial Office of Chinese Journal of Cancer Biotherapy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Treatments for advanced non-small cell lung cancer (NSCLC) include chemotherapy, targeted therapy, and immunotherapy represented by immune checkpoint inhibitors. However, the efficacy of monotherapy is still limited. Nowdays, combination strategy has drawn great attention. Anti-angiogenic agents are widely used in treating advanced NSCLC, which can not only suppress the growth and metastasis of tumor by suppressing tumor vessels, and also have synergic effect with other anti-tumor agents because they can normalize vessels and regulate immune micro-environment. This article summarizes the underlying mechanism of combining anti-angiogenic agents and other anti-tumor agents, reviews the clinical trials on the combination strategy including monoclonal antibodies and tyrosine kinase inhibitor, so as to provide a potential strategy for treating advanced NSCLC. [ABSTRACT FROM AUTHOR]

Lung cancer has the highest incidence rate and mortality in China, even in the world, and non-small cell lung cancer (NSCLC) accounts for about 85%. The growth and metastasis of tumor depend on the generation of blood vessels, and anti-angiogenic therapy is playing an increasingly important role, however, no significant improvement was observed in the underwent anti-angiogenic agents used for patients alone. In recent years, the application of immune checkpoint inhibitor (ICI) has significantly improved the prognosis of some lung cancer patients, however, the objective response rate of patients receiving ICI alone is low. While anti-angiogenic agents and ICI both regulate the tumor immune microenvironment and have a potential synergistic mechanism, showing a bright prospect in the combined application of anti-tumor therapy. In this review, we focused on the research and application of anti-angiogenic agents in combination with ICI in advanced non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

This study explore the molecular mechanism of the synergistic effect of Chinese Yam polysaccharides and nucleoside analogues(NAs) on hepatitis B virus(HBV) resistance. Different concentrations of Chinese Yam polysaccharide and entecavir were ad-ded to HepG2.2.15 cells. After the cytotoxicity was detected by cell counting kit-8(CCK-8), the optimal concentration and time of the two drugs to inhibit HepG2.2.15 cells were screened out. They were divided into control group, Chinese Yam polysaccharide group, entecavir group and combination drug group(Chinese Yam polysaccharide + entecavir). The drugs were added to HepG2.2.15 cells, ELISA was used to detect the effects of each group of drugs on the secretion of hepatitis B virus surface antigen(HBsAg) and hepatitis B virus e antigen(HBeAg) in cell supernatant, probe quantitative real-time PCR(probe qRT-PCR) was used to detect the effects of drugs on HBV-DNA in HepG2.2.15 cells, and Western blot was used to detect the effects of each group of drugs on the expression of p38 MAPK, p-p38 MAPK, NTCP proteins in HepG2.2.15 cells. The qRT-PCR was used to detect the effect of drugs on the expression of p38 MAPK and NTCP mRNA in HepG2.2.15 cells. The results showed that compared with control group, the concentrations of HBeAg and HBsAg in Chinese Yam polysaccharide group, entecavir group and combination group decreased(P<0.01 or P<0.001), and both of them inhibited HBV-DNA in HepG2.2.15 cells(P<0.01), and the HBV-DNA inhibition of HepG2.2.15 cells in the combination group was more obvious(P<0.001), and the protein expression levels of p-p38 MAPK and NTCP were significantly decreased(P<0.05 or P<0.01), the mRNA expression level of p38 MAPK increased, and the mRNA expression level of NTCP decreased(P<0.05 or P<0.01). To sum up, Chinese Yam polysaccharide can reduce the expression of NTCP protein and mRNA through p38 MAPK signaling pathway and cooperate with entecavir in anti-HBV.

Copyright of Shipin Kexue/ Food Science is the property of Food Science Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Agro-Environment Science is the property of Journal of Agro-Environment Science Editorial Board and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective To investigate the inhibitory effect of intervention of glypican-3 (GPC3) gene transcription combined with antitumor drugs on hepatoma cell proliferation. Methods Four types of GPC3-shRNA plasmids were established and transfected into HepG2 hepatoma cells. Quantitative real-time PCR and Western blot were used to measure the mRNA and protein expression of GPC3 to analyze its association with hepatoma cell proliferation and apoptosis. The independent samples t-test was used for comparison of continuous data between any two groups, and a one-way analysis of variance was used for comparison between multiple groups. Results Among these four plasmids, shRNA1 had a transfection efficiency of ＞85% in the transfection of HepG2 cells and a silence efficiency of 89.3% at the mRNA level, and the protein expression of GPC3 was significantly inhibited(P＜001）. At 72 hours, the GPC3-shRNA1 co-intervention group had an HepG2 cell inhibition rate of 71.1%, significantly different from that in the negative group (t=18.092, P＜0.001), an inhibition rate of migration of 89.1%, significantly lower than that in the negative group (t=8.326, P＜0.001), and inhibition rates of HepG2 cell movement and invasion of 53.6% and 60.1%, which were significantly different from those in the negative group (t=52.400 and 48.245, both P＜0001). The GPC3-shRNA1 co-intervention group had a β-catenin mRNA inhibition rate of 46.9% and a Gli1 mRNA upregulation rate of 7.4%, significantly different from those in the negative group (t=30.108 and -3.551, P＜0.001 and P=0.009). At 24 hours, 10 μmol/L sorafenib combined with shRNA1 had an inhibition rate of tumor cells of 52.6% and 100 μmol/L sorafenib combined with shRNA1 had an inhibition rate of tumor cells of 79.5%, which were significantly different from that in the control group (t=23.314 and 50.352, both P＜0001). The half-maximal inhibitory concentrations of sorafenib, rapamycin, and erlotinib for HepG2 were 4.67±1.20 μmol/L, 7.85±2.00 nmol/L, and 18.36±0.56 μmol/L, respectively, and their combination with shRNA1 had an HepG2 cell inhibition rate of 95.11%. ConclusionIntervention of GPC3 gene transcription with specific shRNA can inhibit hepatoma cell proliferation, migration and movement, and invasion ability, induce hepatoma cell apoptosis, and inhibit hepatoma cell proliferation when combined with antitumor drugs in a synergistic manner. This suggests that GPC3 may be an effective therapeutic target for liver cancer and that combined targeted therapy can provide better strategies for the treatment of liver cancer. [ABSTRACT FROM AUTHOR]

Obj'ective To investigate the potential effects and molecular mechanisms of heme oxygenase - 1 ( HO - 1 ) - mediated modula-tion of nuclear factor - kappa B ( NF - kB ), and its downstream activation of intercellular adhesion molecule 1 ( ICAM - 1 ) and platelet de-rived growth factor ( PDGF ), in fibrosis progression of non - alcoholic steatohepatitis ( NASH ) using the methionine and choline deficient ( MCD) mouse model of NASH. Methods Forty C57BL6J male mice (18 -20 g) were randomly divided into four groups ( n = 10 each) : NASH model group, administered the MCD diet; HO - 1 agonist group, administered the MCD diet with intraperitoneal (ip) injec-tions of hemin (30 imolkg every other day) ; HO - 1 inhibitor group, administered the MCD diet with ip injections of zinc protoporphyrin ( ZnPP - IX ; 20 iimolkg every other day ) ; and control group, administered a methionine and choline sufficient ( MCS ) diet, without ago-nist nor inhibitor injections. After eight weeks, the mice were sacrificed and resected liver tissues used to assess successful model establish-ment by histological analysis (hematoxylin - eosin and Masson staining) and the differential mRNA expression of HO - 1, NF - kB, ICAM - 1, and PDGF by real - time quantitative PCR ( GAPDH normalized ) and protein expression of HO - 1 and PDGF by western blotting ( ß -actin normalized). Significance of an intergroup diference was assessed by single - factor analysis of variance test, and the Student -Newman - Keuls test was used for pairwise comparisons. Results The NASH model group showed the appropriate histologic features of he-patic steatosis, necroinflammation and fibrogenesis, while the control group showed normal lobular architecture. In addition, the NASH mod-el group showed significantly higher expression of HO - 1, NF - kB, ICAM - 1 and PDGF mRNA ( all P <0. 05 ), and concomitant increa-ses in HO - 1 and PDGF protein. The group treated with HO - 1 agonist showed significant down - regulation of the NASH - induced NF -kB, ICAM - 1 and PDGF expressions, while the opposite effect (accompanied by severe liver injury) was observed in the group treated with HO - 1 inhibitor. Conclusion Inhibiting HO - 1 activation in NASH could attenuate NF - kB signaling and expression of its downstream effectors ICAM - 1 and PDGF to protect against fibrosis - and inflammation - related liver injury. [ABSTRACT FROM AUTHOR]

Objective: To explore the significance of the resistance to polymyxin resistance of the extensively drug resistant Acinetobacter baumannii (XDRAB) lipopolysaccharide (LPS) lpx A , lpx C , lpx D and to screen appropriate combination therapy., Methods: In the past two years, 72 XDRAB in the secretions of our patients were selected as the research object. According to the minimum inhibitory concentration (MIC) of the XDRAB strain on polymyxin, they were included in the drug resistance group and the sensitive group. The gene sequences of strains lpx A , lpx C , lpx D were compared with the standard strains to analyze gene mutations and compared the mutation rates in the drug resistant group and the sensitive group. The efficacy of the combination drugs was evaluated by microcheckerboard dilution method, including polymyxin+imipenem group, polymyxin+meropenem group, polymyxin+cefoperazone/sulbactam group, polymyxin+levofloxacin group, and polymyxin+fosfomycin group. Calculated the fractional inhibitory concentration (FIC) index of the combined medication regimen and compared the percentage of strains that exhibited synergistic, additive, irrelevant, and antagonistic effects., Results: Tentyone were in the drug resistant group, accounting for 21 (29.17%,) and 51 were in the sensitive group, accounting for 70.83%. Some strains had mutations in lpx A , lpx C , lpx D genes. The mutation rate in the drug resistant group was 90.48%, which was significantly higher than 11.76% in the sensitive group, the difference was statistically significant ( P <0.05). The combined drug sensitivity test showed, compared with the polymyxin+fosfomycin group, the mycotin+fosfomycin group had a higher percentage of strains with synergistic FIC index in the polymyxin+imipenem group, the difference was statistically significant ( P <0.01)., Conclusion: XDRAB is resistant to polymyxin, which is related to mutations in LPS lipid A biosynthesis genes lpx A , lpx C , lpx D . Clinical treatment should adopt a combination of polymyxin+imipenem/meropenem and other drug combination to reduce the secondary infection of drug resistant bacteria., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

In this study, we explored the antibacterial effect and mechanism of dihydroartemisinin(DHA) combined with cefuroxime(CFX) or ampicillin against Escherichia coli. The minimum inhibitory concentration(MIC) of DHA, cefuroxime, and ampicillin against E. coli was 300,25,25 μmol·L~(-1), respectively, determined by broth microdilution method and 2,3,5-triphenyltetrazolium chloride(TTC) method. The minimum bactericidal concentration(MBC) was 25 μmol·L~(-1) for cefuroxime, above 600 μmol·L~(-1) for DHA. The fractional inhibitory concentration index(FICI) of DHA combined with cefuroxime or ampicillin was 0.375 and 0.75, respectively, determined by checkerboard microdilution assay, suggesting the synergistic effect or additive effect of the drug combination. Moreover, the time-effect curve showed that the antibacterial activity of DHA and CFX combination was much stronger than that of either of the drugs, suggesting that combination with DHA can decrease the CFX dosage. Then we studied the synergistic mechanism of DHA combined with cefuroxime and found that the combination of the two drugs had a significant inhibitory effect on the total protein bands, as shown by the results of polypropylene gel electrophoresis. The results of conductivity method and alkaline phosphatase test respectively showed that its conductivity value and alkaline phosphatase(AKP) leak were significantly higher than either of the drugs, suggesting that the integrity of bacteria may be damaged. The scanning electron microscope(SEM) results showed that the morphology of E. coli was destroyed most in the combination group. The quantitative fluorescence PCR technology showed that the combination of two drugs can inhibit the expression of superoxide stress gene soxS. In summary, the combination of dihydroartemisinin and cefuroxime has a synergistic antibacterial effect on E. coli.

Objective: To investigate the effect of 2-deoxy-d-glucose (2-DG) combined with hydroxycamptothecin (HCPT) on anti-tumor activity of breast cancer cells and its mechanism., Methods: MDA-MB-231 and MCF-7 breast cancer cells were incubated with varying concentrations of 2-DG (0, 1.25, 2.5, 5, 10, 20 mmol/L), HCPT(0, 5, 10, 20, 40 μmol/L) and 2-DG (5 mmol/L) combined with HCPT. Cell viability was measured using the MTT assay; Propidium iodide (PI) detected the apoptosis of MDA-MB-231 cells by 5 mmol/L 2-DG, 10 μmol/L HCPT alone or in combination; MDA-MB-231 cells were treated with 2-DG (0, 2.5, 5, 10, 20 mmol/L) and the level of ATP was detected by ATP kit; the expression of Akt, p-Akt, Bcl-2/Bax, PARP, Caspase-8 and Caspase-3 proteins in MDA-MB-231 cells were measured by Western blot assay., Results: The combination of 2-DG (5 mmol/L) and HCPT had a synergistic effect. The 48 h combination index (CI < 1) was higher than that of the single-use group ( P < 0.05). At the same time, the combination of the two drugs inhibits the phosphorylation of Akt protein and increases the activation of Caspase-3 protein, thereby increasing the cleavage of PARP proteins., Conclusion: The combination of 2-DG and HCPT can synergistically induce the apoptosis of breast cancer cells, which may be caused by inhibiting the energy generation of tumor cells, inhibiting the phosphorylation of Akt protein and enhancing the activity of caspase-3 protein., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).)

Background: Lung cancer is one of the common malignant tumors that impair human health. With the development of epigenetics, the researchers found that enhancer of Zeste homolog 2 (EZH2) is highly expressed in lung cancer tissue and its expression is closely related to the prognosis. EZH2 inhibitor can also enhance the sensitivity of tumor cells to a variety of anti-tumor drugs. The purpose of this study is to investigate the effect of combination of EZH2 inhibitor and gefitinib on the proliferation, apoptosis and migration of Gefitinib-resistant lung cancer cells., Methods: PC9 and PC9/AB2 cells were used for this study. CCK-8 and EdU experiment were used to detect combined treatment on cell viability and proliferation activity; Wound healing assay and Transwell chamber experiment were used to determine the effects of combination therapy on cell migration ability; Flow cytometry was used to detect the effect of combination therapy on EZH2 and apoptosis; Western blot was used to observe the effect of combination therapy on epidermal growth factor receptor (EGFR) signaling pathway-related proteins expression., Results: In gefitinib-resistant cell line PC9/AB2, gefitinib combined with EZH2 inhibitor GSK343 can significantly inhibit cell viability, reduce cell migration and increase cell apoptosis. At the same time, combination therapy can significantly inhibit the expression of EZH2 and phosphorylation EGFR proteins., Conclusions: The combination of EZH2 inhibitor GSK343 and gefitinib sensitize PC9/AB2 cell to gefitinib response. This study also suggests that synergistic therapy plays a role in the reversal of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) resistance in lung cancer.

Objective: To explore whether bortezomib and a Bcl-2 inhibitor exhibit synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells., Methods: MTT assay was used to determine the cytotoxicity of bortezomib in the absence or presence of Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) in Jurkat cells. The effects of drug treatment on the expression of Bcl-2 family proteins, LC3B, p62, ubiquitin, BiP/Grp78, p-JNK, p-p38 and CHOP proteins were examined by Western blotting. Flow cytometry was used to determine the effects of bortezomib and Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) on cell apoptosis. Quantitative real-time PCR was used to measure the mRNA expression levels of the key regulatory factors of unfolded protein reaction (UPR). A zebrafish xenograft model was used to study the anti-tumor effect of bortezomib, obatoclax and their combination in vivo., Results: Bortezomib or Bcl-2 inhibitors alone inhibited the cell viability of Jurkat cells, but only obatoclax and bortezomib showed synergistic cytotoxicity and pro-apoptotic effect. Obatoclax, rather than AT-101 and ABT- 199, blocked autophagic flux in the cells evidenced by concomitant accumulation of LC3B-Ⅱ and p62. Both bortezomib and obatoclax alone caused accumulation of polyubiquinated proteins, and their combination showed a synergistic effect, which was consistent with their synergistic cytotoxicity. The dual blockade of proteasome and autophagy by the combination of bortezomib and obatoclax triggered unfolded protein response followed by cell apoptosis. Preventing UPS dysfunction by tauroursodeoxycholic acid (TUDCA) significantly attenuated the cytotoxicity and pro-apoptotic effect of bortezomib in combination with obatoclax. In zebrafish xenograft models, bortezomib combined with obatoclax significantly decreased tumor foci formation., Conclusions: Bortezomib and obatoclax for dual blockade of protein degradation pathways show synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells.

Synergistic effect is main pharmacological mechanism of traditional Chinese medicine(TCM). The research method based on the key targets combination is an important method to explore the synergistic effect of TCM. Peptide transporter 1 (PepT1) is an essential target for drug uptake into the bloodstream, accounting for about 50% of the total transporter protein content from the small intestine. Peroxisome proliferator-activated receptor α(PPARα) is the lipid-lowering target of fibrates, which have a good hypolipidemic effect by activating PPARα. It has been reported that PPARα could activate the gene expression of PepT1s, and PPARα agonists can promote the uptake of PepT1 substrates, indicating their synergistic effect. In this paper, PepT1 substrates and PPARα agonists from TCM were discovered, and their synergistic mechanism was also been discussed based on the target combination of PepT1 and PPARα. The support vector machine(SVM) model of PepT1 substrates was first constructed and utilized to predict potential TCM components. Meanwhile, merged pharmacophore and docking model of PPARα agonists was used to screen the potential active ingredients from TCM. According to the analysis results of two groups, the TCM combination of Panax notoginseng and Ganoderma lucidum, as well as TCM combination of P. notoginseng and Salvia miltiorrhiza were identified to have the synergistic mechanism based on target combination of PepT1 and PPARα. In this study, synergistic mechanism of TCM was analyzed for absorption and hypolipidemic effect based on target combination, which provides a new way to explore the synergetic mechanism of TCM related to pharmacokinetics., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Herb pairs are usual clinical compatibility forms and one of compound prescription sources in Chinese medicine. Pharmacokinetic research in vivo is one of the important items in elucidating the mechanism for synergistic and attenuated mechanisms of herb pairs. The paper comprehensively summarized and systemized the pharmacokinetic researches of marker-ingredients about Danshen-Honghua and Danshen-Bingpian in order to elucidate the rationality and scientificity of herb pairs and provide some feasible suggestions on the pharmacokinetics of drugs in the future. In view of complicated system of Traditional Chinese medicines and a chemical system that is not separated from its natural state, comparative pharmacokinetic researches on marker-ingredients from the herb pairs are reasonable to elucidate the synergistic and attenuated mechanisms of monarch-subjects compatible herbs and monarch-guide compatible herbs. Such pharmacokinetic research can better explain the mechanism of drug compatibility, while the pharmacokinetic researches based on the monomer chemical compositions and marker-ingredients that have been separated from complex chemical environment of traditional Chinese Medicine are still unreasonable and should be discussed deeply., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Objective: To investigate the combination effect of anti-tumor agent rapamycin and anti-autophagy agent chloroquine on osteosarcoma. Methods: The inhibition effect of rapamycin or chloroquine and combination of both on human osteosarcoma cell line 143B measured with CCK-8 box.The combination index at different concentration was calculated, and the synergism effect range was analysed.The effect of combined therapy on cell cycle and apoptosis via flow cytometric was analyzted.Setting up murine subcutaneous xenograft model, the combination effect of antitumor in vivo observed. Results: Either of them, rapamycin or chloroquine had an antitumor effect in vitro (RAPA: IC50=1.5 nmol/L; CQ: IC50=400 μmol/L). When the inhibition rate 40%

To analyze the drug combination characteristics of Qingkailing injection for treating abnormal inflammatory factors such as elevated white blood cells and C reactive protein in real world. The patients with Qingkailing injection for abnormal C reactive proteins and abnormal white blood cells were extracted from hospital information system (HIS) of 16 Class 3A hospitals. Then the basic information, traditional Chinese medicine and Western medicine diagnostic information, doctor's advice information, and laboratory information were analyzed; Apriori algorithm was used to construct the models, and Clementine 12.0 was used for correlation analysis to analyze the clinical medication rules and drug combination characteristics in the patients with Qingkailing injection for treatment of elevated C reactive protein and white blood cells in the real world. The results of the study showed that when Qingkailing injection was combined with one kind of western medicine and traditional Chinese medicine in treatment of patients with abnormal C reactive protein, vitamin C (159 cases, 74.30%) and Tanreqing injection (71 cases, 33.18%) were most frequently used; when it was combined with 2 kinds of traditional Chinese medicines, Xueshuantong injection plus Tanreqing injection (support degree 10.75%) were most frequently used. When Qingkailing injection was combined with one kind of western medicine and traditional Chinese medicine in treatment of patients with abnormal white blood cells, vitamin C (596 cases, 56.02%) and Ganmao Qingre granules (247 cases, 23.21%) were most frequently used; when it was combined with 2 kinds of traditional Chinese medicines, Shuanghuanglian+Ganmao Qingre granules (support degree 5.26%) were most frequently used. In the patients with abnormal C-reactive protein and white blood cells, its combinations with antibiotics and nutritional support agents were most common from the pharmacological perspective, indicating that in the treatment of abnormal C-reactive protein, white blood cells and other increased inflammatory indicators, Qingkailing injection was most frequently combined with antibiotic drugs to achieve synergistic effect., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Objective: To investigate the synergistic lethal effect and mechanism of arsenic trioxide (ATO) and aclacinomycin (ACM) on human acute myeloid leukemia cell line KG-1a. Methods: Colony-forming assay was used to detect the proliferation of KG-1a cells treated with different concentration of ATO and ACM. Compusyn software was used to analyze the synergistic effect of ATO and ACM. Flow cytometry and Wright's staining were used to analyze the apoptotic rate of KG-1a cells induced by combined treatment of ATO and ACM. Western blot was used to determine the expression of proteins associated with apoptosis. Results: The cytotoxicity of arsenic trioxide or aclacinomycin alone was in a dose-dependent manner. Flow cytometry analysis showed that the apoptotic rate of KG-1a cells treated with both 0.4 μmol/L ATO and 10 nmol/L ACM was (34.5±3.1)%, significantly higher than (7.6±1.1)% of 0.4 μmol/L ATO treatment or (18.7±2.3) % of 10 nmol/L ACM treatment alone ( P <0.05). The apoptotic rate of KG-1a cells treated with both 1.5 μmol/L ATO and 37.5 nmol/L ACM was (52.5±4.7)%, significantly higher than (19.1±3.2)% of 1.5 μmol/L ATO treatment or (27.7±2.2)% of 37.5 nmol/L ACM treatment alone ( P <0.05). The apoptotic rate of KG-1a cells treated with both 3.0 μmol/L ATO and 75 nmol/L ACM was (61.3±4.5)%, significantly higher than (29.5±2.5)% of 3.0 μmol/L ATO treatment or (28.6±3.4) % of 75 nmol/L ACM treatment alone ( P <0.05). In addition, the result of Wright's staining showed that combined treatment of ATO and ACM induced a more apparent phenotype of apoptosis when compared with single agent treatment. Compusyn software analysis showed that the combination index (CI) value of combined treatment group was less than 1, which indicated the synergistic effect of these two agents. Conclusions: Combined treatment of ATO and ACM shows a synergistic lethal effect on human acute myeloid leukemia cell line KG-1a via activating the apoptotic pathway, which inhibits cell growth and induces apoptosis.

Among the literatures of the prevention and treatment of community-acquired pneumonia (CAP) published in recent years, there were 16 kinds of classic prescription, including 52 RCTs about Maxingshigan Decoction, 21Chinese patent medicines. There are eight kinds of indications for the drug specification, among which the literatures of Tan Reqing injection accounted for the most about 136 RCTs; There were literatures about non-drug treatment, including： acupuncture, Chinese medicine paste, enema, Chinese medicine ionization, Chinese medicine fumigation, bamboo cans and so on. In this study, author has analysed the classic prescription, Chinese patent medicine and non-drug therapy referring to advantages and disadvantages of CAP, which could be used to treat virus infection instead of antibiotic therapy. Based on antibiotic therapy, Chinese medicine treatment could increase synergistic interaction while decrease the antibiotic side-effects. In addition, Chinese medicine could perform synergistic interaction in CAP every period, which resulted from classified analysis of basic studies about Chinese medicine treatment in CPA. This study is aimed to provides an important basis for clarifying the direction of scientific research., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

To explore the effect of Shuxuetong injection on the pharmacodynamics and pharmacokinetics of warfarin in rats, and to provide reference for rational drug use. In studies on the single dose of warfarin, Wistar rats were randomly divided into four groups： blank control group(group A), Shuxuetong injection group(group B), warfarin control group(group C), and warfarin+Shuxuetong injection group(group D). In studies on the steady state of warfarin, Wistar rats were randomly divided into warfarin control group(group E) and warfarin+Shuxuetong injection group(group F). To investigate the pharmacodynamic effect of Shuxuetong injection on warfarin, prothrombin time(PT) and activated partial thromboplastin time(APTT) were measured by coagulation analyzer, and international normalized ratio(INR) was calculated. To investigate the pharmacokinetic effect of Shuxuetong injection on warfarin, the blood concentrations of S-warfarin and R-warfarin were determined by UPLC-MS/MS combined with technology of chiral chromatographic column, and the related pharmacokinetic parameters were calculated accordingly. The results on the single dose of warfarin showed that Shuxuetong injection markedly increased PT, INR(P<0.01), and APTT(P<0.05). Meanwhile, when Shuxuetong injection was co-administrated with warfarin, it significantly increased PT, INR(P<0.01), and APTT(P<0.05) as compared with warfarin control group. In addition, increased pharmacokinetic parameters including Cmax, AUC0-t and AUC0-∞, prolonged t1/2, and decreased CL/F were observed for S-warfarin and R-warfarin. The results of the steady state of warfarin suggested that Shuxuetong injection significantly increased PT and INR of warfarin(P<0.01), and elevated the plasma concentrations of S-warfarin and R-warfarin when co-administrated with warfarin. These findings indicated that Shuxuetong injection had anticoagulant effect, and would produce pharmacodynamics synergistic action when it was co-administrated with warfarin. Shuxuetong injection also decelerated the metabolism of warfarin, and resulted in pharmacokinetics interaction. Therefore, Shuxuetong injection could significantly increase anticoagulant effect of warfarin, indicating that the combination use of these two drugs should be refrained in order to avoid the risk of bleeding in clinical application. If they need to be used in combination, special attention should be paid to ensure the safety of patients., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Background: T peptide is extensively used in anti-tumor treatment. The aims of this study were to investigate whether T peptide enhances cisplatinum efficiency while reducing its side effects and to identify its effective mechanisms., Methods: (1) Human macrophage U937 cells were treated with T peptide and/or cisplatinum. The levels of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) of each group were detected by enzyme-linked immunosorbent assay (ELISA); (2) Xenograft mouse models of human lung cancer were treated with T peptide and/or cisplatinum once every five days for three times. Tumor volumes were measured during treatment; (3) The percentages of macrophages in the peripheral blood of the xenograft mouse models were measured by FACS., Results: (1) Compared with other groups, the level of TNF-α was significantly higher in the human macrophage U937 cells that were treated with T peptide combined with cisplatinum. The levels of IFN-γ were significantly higher in human macrophage U937 cells that were treated with T peptide alone or T peptide combined with cisplatinum; (2) In the xenograft mouse models, T peptide combined with cisplatinum treatment significantly inhibited tumor growth without weight loss compared with the other groups; (3) The percentages of macrophages in the peripheral blood were significantly higher in the xenograft mouse models that were treated with T peptide combined with cisplatinum compared with in the other groups., Conclusions: T peptide promotes macrophage proliferation and increases tumor cell killing factors (TNF-α, IFN-γ) in vitro. Moreover, T peptide enhances the efficacy of cisplatin and reduces its toxicity in vivo.
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Background: Tumor necrosis factor-related apoptosis-inducting ligand (TRAIL) can induce apoptosis of tumor cells, however, various of tumor cells may survive because of resistance to TRAIL-mediated apoptosis. This study is to observe the proliferation inhibition effect of TRAIL sensitized by thioridazine on PC9 cells through endoplasmic reticulum (ER) stress mediated up-regulation of death receptor 5 (DR5) and investigate its mechanism., Methods: PC9 cells were treated with different concentrations of thioridazine and TRAIL alone or in combination. Cell proliferation was measured by MTT assay, and cell apoptosis and cell-surface DR5 were detected by flow cytometry. Western blotting was utilized to measure the expressions of ER stress-related proteins glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), p-PKR-like ER kinase (PERK), p-eukaryotic initiation factor-2α (eIF2α), activating transcription factor 4 (ATF4) and apoptosis-related proteins caspase-3, caspase-9, caspase-8, PARP, DR5., Results: Thioridazine inhibited the proliferation of PC9 cells in a dose-dependent manner (P<0.05). Thioridazine increased the inhibition and apoptosis of PC9 cells and up-regulated the expression of cell-surface DR5 induced by TRAIL. Flow cytometry showed that compared with TRAIL group, combination group of TRAIL and thioridazine increased cell apoptotic rates significantly (P<0.05). Western blotting indicated that compared with TRAIL group, expressions of Cleaved-caspase-8, Cleaved-PARP and DR5 increased significantly in combination group of TRAIL and thioridazine. The induction of DR5 and pro-apoptotic effect were mediated through activation of ER stress accompanying by increased synthesis of GRP78 and CHOP, which can be blocked by adding of ER stress inhibitor 4-PBA., Conclusions: Thioridazine enhanced proliferation inhibition effect of TRAIL in PC9 cells may be facilitated through ER stress mediated upregulation of DR5.
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Objective: To investigate the regulation of JAK2 tyrosine kinase inhibitor ruxolitinib on extracellular matrix metalloproteinase (MMP in JAK2V617F positive myeloproliferative neoplasms (MPN) cells. Methods: ①Forty cases of newly diagnosed JAK2V617F positive MPN patients and 15 healthy volunteers as control in Baoding No.1 Hospital between January 2012 and December 2015 were enrolled in this study. JAK2V617F/JAK2 ratio was detected by real-time-PCR; the expression levels of phosphorylation protein tyrosine kinase 2 (p-JAK2) , MMP-2 and MMP-9 in pathological tissues of bone marrow were detected by immunohistochemistry. The bone marrow cells of JAK2V617F positive MPN patients were treated with ruxolitinib, then the migration ability and MMP-2, MMP-9 gene and protein expression levels were detected. ②The human erythroleukemia cell line HEL cells were treated with different concentrations of ruxolitinib (0, 50, 100, 250, 500, 1 000 nmol/L) . The cell viability was detected by CCK-8 test; cell migration ability was tested by transwell chambers. The mRNA expression levels of JAK2, MMP-2 and MMP-9 were detected by real-time-PCR. The protein expression levels of p-JAK2, MMP-2 and MMP-9 were detected by Western blot. Results: ①The expression levels of p-JAK2, MMP-2 and MMP-9 in the newly diagnosed group were significantly higher than control group respectively [ (78.56±24.55) % vs (41.59±17.29) %, P <0.05; (48.25±18.74) % vs (22.79±13.89) %, P <0.05; (53.29±19.28) % vs (15.56±14.96) %, P <0.05]. Spearman correlation analysis showed the positive correlation of MMP-2 and MMP-9 protein expression levels with JAK2V617F mutation ( r =0.526, P =0.001; r =0.543, P =0.001) . ② The proliferation of HEL cells was inhibited by different concentrations of ruxolitinib in time and dose dependent manner. ③Cell migration test showed the number of cells leaked to the low chamber in MPN patients bone marrow cells and HEL cells treated with 5 nmol/L of ruxolitinib group were significantly lower than that without ruxolitinib treatment after 24 h [ (154.7±27.5) vs (320.3±67.3) , t =13.47, P <0.05; (70.7±10.5) vs (135.3±16.7) , t =13.89, P <0.05]. The mRNA and protein expression levels of JAK2, MMP-2 and MMP-9 decreased with the increased concentration of ruxolitinib. Conclusion: Ruxolitinib inhibits MPN cell migration and expression of MMP-2 and MMP-9 via JAK2 signal pathway.

Background: Amorphigenin, a rotenoid compouns, from seeds of Amorpha fruticosa, has been shown to possess anti-proliferation activities in several cancer cells. To explore the antitumor effects of amorphigenin on cisplatin-resistant human lung adenocarcinoma A549/DDP cells and explore the underlying mechanisms., Methods: CCK-8 assay was used to measure the proliferation of A549/DDP cells; Colony formation assay was used to measure the colony formation of A549/DDP cells; Flow cytometry assay was used to detect the apoptosis rates; Western blot analysis was used to explore the expression of apoptosis-related proteins (caspase-3 protein, PARP protein) and lung resistance protein (LRP)., Results: Our results demonstrated that amorphigenin could inhibit the proliferation of A549/DDP cells with a inhibition concentration of 50% cell growth (IC50) at 48 h of (2.19±0.92) μmol/L. Amorphigenin could inhibit the colony formation ability and induce apoptosis of A549/DDP cells; Furthermore, amorphigenin combined with cisplatin showed synergistic proliferation-inhibitory effect and apoptosis-promoting effect in A549/DDP cells; reduced the expression of LRP of A549/DDP cells., Conclusions: Amorphigenin remarkably inhibits the proliferation and induces apoptosis in A549/DDP cells. Combination of amorphigenin with cisplatin had the synergistic inhibitory effect on A549/DDP cells by downregulating the expression of LRP.
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Objective: To investigate the synergistic analgesic effect of choline and parecoxib sodium and study its mechanism., Methods: In male Kunming mice with acetic acid-induced writhing, the ED 50 of choline and parecoxib sodium (administered via the tail vein at 2 h and 30 min before modeling, respectively) and their combined use were determined. In saline (control) group, ED 50 choline (C) group, ED 50 parecoxib sodium (P) group, and 1/2ED 50 choline and parecoxib sodium (1/2[C+P]) group, blood samples were collected from the eyeball 10 min after intraperitoneal administration of acetic acid to detect the levels of IL-1, TNF-α, PGE2, NF-κB, and I-κB levels using ELISA kits., Results: In the acetic acid-induced writhing model, the ED 50 of choline and parecoxib sodium was 8.64 and 6.33 mg/kg, and when combined, their ED50 was 2.13 and 1.56 mg/kg, respectively. The isobolograms of parecoxib sodium and choline showed that the measured ED 50 of the two drugs combined was below the theoretical ED 50 value (P<0.05) with a combination index (CI) of <0.9. Compared with the control group, C group, P group, and 1/2 (C+P) group all showed significantly lowered IL-1 and TNF-α levels (P<0.05), especially in 1/2 (C+P) group (P<0.05). PGE2 level was significantly lower in P group and 1/2 (C+P) group compared with the control group (P<0.05). NF-κB and I-κB levels were significantly lowered in C, P, and 1/2 (C+P) groups (P<0.05), and the reduction was the most obvious in 1/2 (C+P) group (P<0.05)., Conclusion: Choline and parecoxib sodium has a synergistic analgesic effect, and their interactions may involve the in vivo expression of NF-κB.

Xin-Sheng-Hua granule (XSHG) is a popular remedy commonly used in clinic for the treatment of lochiostasis after delivery. To comparatively investigate the roles of herb pairs containing Angelicae Sinensis Radix (Danggui) upon the formula by evaluating the blood coagulation and hemorheology function in acute blood stasis rats, acute blood stasis rat model was established by ice water bath and subcutaneous injection of adrenaline. And the blood stasis mice were administrated intragastrically with different samples of the formula minus herb pairs containing Danggui and the whole formula (XSHG, SHD, DY, DC, DT, DH, DJ and DZ). The whole blood viscosity (WBV), plasma viscosity (PV), erythrocyte sedimentation rate (ESR) and haematocrit (HCT) were applied to evaluate the effects of the formula minus herb pairs containing Danggui on hemorheology of blood stasis rats. The thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT), and plasma fibrinogen (FIB) were used to observe the effects of the formula minus herb pairs containing Danggui on blood coagulation function of blood stasis rats. Additionally, the maximum aggregation induced by adenosine diphosphate (ADP) was tested to observe the effect of different samples on platelet aggregation index of blood stasis rats.Afterwards, multi-attribute comprehensive index methods and principal component analysis were both applied to comprehensively assess the total effects of the formula minus herb pairs containing Danggui on promoting blood circulation and dissipating blood stasis. Compared with normal group, the hemorheological parameters and coagulation indexes of model group had statistical differences (P<0.01). Compared with model group, different samples (XSHG, SHD, DY, DC, DT, DH, DJ and DZ) could improve the blood hemorheology indexes, coagulation parameters and platelet aggregation in acute blood stasis rats. According to multi-attribute comprehensive index methods and the principal component analysis, the effects of promoting blood circulation by removing blood stasis became poor when excluding herb pairs containing Danggui from the formula, the sample DY and DC had the weakest effect of activating blood circulation and dissipating blood stasis, and the effect of sample DY was slightly poorer than DC. The orders of contribution of herb pairs containing Danggui on the formula were Danggui-Yimucao>Danggui-Chuanxiong>Danggui-Honghua>Danggui-Zhigancao>Danggui-Taoren>Danggui-Jiangtan. In conclusion, various herb pairs containing Danggui played different roles on the effects of improving the abnormality of hemorheology and coagulation function. And the herb pairs Danggui-Yimucao were particularly important for the formula, which was consistent with the characteristics of XSHG and the traditional effect of Yimucao. Moreover, it could lay foundation to further reveal the compatibility mechanism of XSHG., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Objective: To explore the feasibility of using enhancin as synergist to Bacillus thuringiensis (Bt), the truncated fragments of enhancin gene from Pseudaletia unipuncta granulovirus (PuGV-Ps) were optimized and the enhancing effects were studied., Methods: Based on bioinformational analysis of the function domain of PuGV-Ps enhancin, the prokaryotic expression vectors were constructed, and the protein expression levels as well as their enhancing effects on the degradation of peritrophic membrane (PM) proteins were analyzed, and the function domains of PuGV-Ps enhancin were confirmed., Results: Three domains were found in the enhancin of PuGV-Ps, including M60-like domain, Zincins catalytic domain and putative mucin or carbohydrate-binding domain. Thirteen predicted N-glycosylation sites were also identified. Based on the sequences of truncated M60-like domain (P69) and carbohydrate-binding domain (P77), two expression vectors, pET15b-P69 and pET15b-P77, were constructed. The expressed P69 and P77 abundance were higher than that of full length enhancing (P104). The degradation activity of purified P69 on the PM proteins of Spodoptera litura was higher than that of purified P77, but both showed lower degradation activities than P104. Both P69 and P77 improved the toxicity of Bt against larvae of Plutella xylostella. However, their synergistic effects were significantly lower than that of P104., Conclusion: The results revealed that the M60-like domain in N-terminus and carbohydrate-binding domain in C-terminus of PuGV-Ps enhancin all contributed to the enhancing effects of enhancin as well as the maintenance of its native conformation. The truncated P69 fragment may function in keeping the activity of enhacin and improving prokaryotic expression levels. These results provide some useful guidance for the industrialized production of enhancin.

To study the synergistic anti-tumor effects of doxorubicin and axitinib in combination, and investigate the underlying mechanism, we performed the MTT cytotoxic assay and tumor spheroids inhibition to investigate in vitro using A549 cells. The cell internalization, cell cycle distribution and DNA ladder experiments were performed to study the synergistic mechanisms. A549 xenograft was established in nude mice and adopted to study the in vivo anti-tumor effect of doxorubicin and axitinib. Results showed that combination of doxorubicin and axitinib exerted significantly higher cytotoxicity than each single drug, and induced a synergistic effect on tumor spheroids growth inhibition. The combination achieved the highest tumor growth suppression in vivo in the A549 xenograft. The combination of axitinib and doxorubicin exhibited the best anti-tumor effects both in vitro and in vivo than each single drug.

Objective To investigate the effect of interferon-β (IFN-β) combined with all-trans retinoic acid (ATRA) on the proliferation and apoptosis of HepG2 human hepatocarcinoma cells and the role of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signal pathway in the process. Methods HepG2 cells were randomly divided intro three groups and treated with 1000 U/mL IFN-β, 10 μmol/L ATRA and 1000 U/mL IFN-β combined with 10 μmol/L ATRA, respectively for 24 hours. Cell viability was measured by MTT assay and apoptosis rate was detected by flow cytometry. Western blotting was applied to detect the protein levels of p-JAK2, p-STAT3, gene associated with retinoid-interferon-induced mortality-19 (GRIM-19), Bcl-2, Bcl-xl and Bax. Results IFN-β or ATRA inhibited the proliferation and induced the apoptosis of HepG2 cells. The effect was enhanced when IFN-β was combined with ATRA. The expressions of p-JAK2 and p-STAT3 were down-regulated while the expressions of GRIM-19 and Bax were up-regulated after treated with IFN-β or ATRA on HepG2 cells, especially the combination of IFN-β and ATRA. Conclusion Combination of IFN-β and ATRA could suppress the proliferation and induced the apoptosis of HepG2 hepatocarcinoma cells by inhibiting JAK2/STAT3 signal pathway.

Column chromatography was used for enrichment and separation of flavonoids, alkaloids and polysaccharides from the extracts of Morus alba leaves; glucose oxidase method was used with sucrose as the substrate to evaluate the multi-components of M. alba leaves in α-glucosidase inhibitory models; isobole method, Chou-Talalay combination index analysis and isobolographic analysis were used to evaluate the interaction effects and dose-effect characteristics of two components, providing scientific basis for revealing the hpyerglycemic mechanism of M. alba leaves. The components analysis showed that flavonoid content was 5.3%; organic phenolic acids content was 10.8%; DNJ content was 39.4%; and polysaccharide content was 18.9%. Activity evaluation results demonstrated that flavonoids, alkaloids and polysaccharides of M. alba leaves had significant inhibitory effects on α-glucosidase, and the inhibitory rate was increased with the increasing concentration. Alkaloids showed most significant inhibitory effects among these three components. Both compatibility of alkaloids and flavonoids, and the compatibility of alkaloids and polysaccharides demonstrated synergistic effects, but the compatibility of flavonoids and polysaccharides showed no obvious synergistic effects. The results have confirmed the interaction of multi-components from M. alba leaves to regulate blood sugar, and provided scientific basis for revealing hpyerglycemic effectiveness and mechanism of the multi-components from M. alba leaves., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Objective: In order to detect the in vitro synergistic effect of 4 drugs-pasiniazid (PA), moxifloxacin, rifabutin and rifapentini on multidrug-resistant mycobacterium tuberculosis (MDR-MTB) and extensively drug-resistant mycobacterium tuberculosis(XDR-MTB), which were core drugs of"The program of retreatment research of tuberculosis"., Method: The checkerboard method was used to detect the minimum inhibitory concentration (MIC) of antituberculosis drug combination schemes (moxifloxacin-PA, moxifloxacin-PA-rifabutin and moxifloxacin-PA-rifapentini) to 40 strains of clinical drug resistant MTB(20 strains of MDR-MTB and 20 XDR-MTB) and the standard strain H37Rv, by calculating the fractional inhibitory concentration index of joint action in vitro to judge the combined effect, with fractional inhibitory concentration index(FICI)≤0.5 and FICI≤0.75 as the basis of 2 drugs and 3 drugs showing synergy., Results: The FICI of moxifloxacin-PA scheme for DR-MTB was 0.125 to 1.000, only 5 strains with a FICI ≤0.5, showing synergistic effect. The FICI of moxifloxacin-Pa-rifabutin scheme with 20 strains of MDR-MTB ranged from 0.310 to 1.260, 10 strains with a FICI≤0.75, showing synergistic effect. The FICI of moxifloxacin-PA-rifabutin scheme with 20 strains of XDR-MTB ranged from 0.215 to 1.250, 11 strains with a FICI≤0.75, showing synergistic effect. The FICI of moxifloxacin-PA-rifapentini scheme with 20 strains of MDR-MTB ranged from 0.150 to 0.780, 19 strains with a FICI≤0.75, showing synergistic effect. The FICI of moxifloxacin-PA-rifapentini scheme with 20 strains of XDR-MTB ranged from 0.200 to 1.280, 16 strains with a FICI≤0.75, showing synergistic effect., Conclusions: The synergistic effect of moxifloxacin-PA scheme was poor, but showing better synergy when further combined with rifabutin or rifapentini. Rifabutin showed better effect than rifapentini, but the synergistic effect of moxifloxacin-PA-rifabutin combination scheme was poor than that of moxifloxacin-PA-rifapentini combination scheme.

Poly (ADP-ribose) polymerase 1/2 (PARP1/2) can catalyze the poly (ADP ribose) (PAR) substrate protein modification and play an important role in the regulation of DNA damage repair, cell death and transcriptional activity. The PARP inhibitor olaparib (AZD2281) can be used as a sensitizer of radiotherapy and chemotherapy in the cancer treatment. Through establishment of biological fluorescent labeled 4T1 ectopic breast tumor model, we found that olaparib exhibited a poor effect on 4T1 breast cancer alone. However, in the combination with Taxol, olaparib significantly increased the anti-tumor effect of Taxol, and reduced the PAR levels of the tumor tissues. Importantly, olaparib did not amplify the toxicity of chemotherapy drugs. This study suggests that olaparib is a representative of the PARP inhibitor that can enhance Taxol’s antitumor effect in the 4T1 ectopic breast tumor model, which sets the foundation for future study of the mechanism of olaparib action.

Objective: To explore the inhibition and molecular mechanism of icaritin (ICT) combined doxorubicin (DOX) on human osteosarcoma MG-63 cells in vitro., Methods: The control group, ICT groups (10, 20, 40, 80, and 160 µmol/L), DOX groups (1, 2, 4, 8, and 16 µg/mL), and combination groups (20 µmol/ L ICT +1 µg/mL DOX, 20 µmol/L ICT +2 µg/mL DOX, 20 µmol/L ICT +4 µg/mL DOX, 40 µmol/L ICT +1 µg/mL DOX, 40 µmol/L ICT +2 µg/mL DOX, 40 µmol/L ICT +4 µg/mL DOX, 80 µmol/L ICT +1 µg/mL DOX, 80 µmol/L ICT +2 µg/mL DOX, 80 µmol/L ICT +4 µg/mL DOX) were set up. Human osteosarcoma MG-63 cells were respectively cultured and their effects on morphological changes were observed using inverted phase contrast microscope after 24-and 48-h intervention. The cell proliferation inhibition rate of each group was de- termined using CCK-8, and IC50 calculated. The MG-63 apoptosis rate was detected using Annexin V-FITC/ PI double dye flow cytometry. Expression levels of bcl-2, caspase-3, and p21 were detected using RT-PCR., Results: ICT and DOX could obviously inhibit the proliferation of MG-63 cell. Along with ICT concentration increasing from 10 µmol/L to 160 µmol/L, the cell proliferation inhibition rate also increased gradually from 9.67% ± 3.62% to 89.18% ± 9.66%. The IC50 was 46.93 µmol/L and 3.87 µg/mL respectively. ICT and DOX could cause either early or late stage apoptosis, down-regulate Bcl-2 gene expression, and up-regulate gene expressions of Caspase-3 and p21 respectively (P < 0.05). Aforesaid changes were more obviously seen in combination groups than in lCT groups and DOX groups (P < 0.05)., Conclusion: CT combined DOX had additive or synergistic inhibition effect for the proliferation of osteosarcoma MG-63 cells, which might be related with regulating gene expressions of bcl-2, caspase-3, and p21.

Objective: To investigate the effect of RAD18-siRNA on cell proliferation and chemotherapy sensitivity of esophageal squamous cell carcinoma (ESCC) ECA-109 cells. Methods: RAD18-siRNA was transfected into human ECA-109 cells by Lipofectamine 3000. Quantitative PCR and Western blot were performed to detect RAD18 and CyclinD1 expression; CCK-8 assay was used to determine cell proliferation and chemotherapy drug sensitivity; flow cytometry was used to determine cell cycle. Correlation between RAD18 and CyclinD1 mRNA expression was analyzed by Pearson's correlation. Results: Compared with non-transfected cells, the expression of RAD18 in RAD18-siRNA group was significantly decreased ( P <0.05). The cell proliferation was inhibited ( P <0.05) and the cell number of G1 phase was increased, G2/M phase cells decreased ( P <0.05) in RAD18-siRNA group. After treatment with different concentrations of cisplatin or 5-FU, the survival rate of the two cell groups was reduced (all P <0.05), and the IC50 of RAD18-siRNA group was significantly lower than that of non-transfected group ( P <0.05). The mRNA expression of RAD18 was positively correlated with CyclinD1 expression in ESCC tissues( r =0.478, P <0.01). Conclusion: Down-regulated expression of RAD18 can decrease the cell proliferation and increase chemo-sensitivity of ESCC cells, and CyclinD1 may participate in the process.

Objective: To investigate the molecular mechanism underlying that dasatinib enhances the killing effect of gefitinib on HCC827 lung cancer cells., Methods: HCC827 cells and gefitinib-resistant HCC827GR cells were treated with 0, 100, 500, 1000 nmol/L gefitinib alone or in combination with 1000 nmol/L dasatinib. The proliferation of HCC827 cells and HCC827GR cells was detected by MTT assay, the activity of caspase 3 was tested by spectrophotometry, and the protein phosphorylation levels of Src and epidermal growth factor receptor (EGFR) were examined by Western blotting., Results: Src phosphorylation level was obviously enhanced in HCC827GR cells. Dasatinib significantly inhibited Src phosphorylation, promoted the cell proliferation and the expression of caspase 3. The combination of gefitinib and dasatinib had the stronger killing effect than gefitinib alone did., Conclusion: The combination of dasatinib and gefitinib can enhance the inhibition on the expression of Src protein and the killing effect of gefitinib on HCC827 lung cancer cells.

To prepare ginsenoside-Rh₂ lipid nanoparticles, and investigate the synergistic effect with borneol in resisting tumor activity in vitro. Ginsenoside-Rh₂ lipid nanoparticles were prepared by ultrasonic-assisted solvent evaporation method, and orthogonal design was adopted to optimize formulation process. Its encapsulation efficiency, drug loading ratio, particle size distribution, Zeta potential, morphology and in vitro drug release behavior were characterized, and synergistic effect with borneol in resisting tumor activity were preliminarily studied by MTT. These nanoemulsion particles prepared by the optimized process method were rounding and even in a good shape. Encapsulation efficiency and drug loading ratio of three batches of nanoemulsion particles were (77.3±2.5)% and (7.2±0.2)%, respectively. Nanoemulsion particles showed an obvious sustained release characteristics, with 52.42% cumulative release within 96 h. The killing effect of nanoemulsion particles on glioma cells was dose-dependent, with IC₅₀ of 22.33 μmol•L⁻¹ and 11.46 μmol•L⁻¹ after 24 h and 48 h, respectively. After the combination with borneol, the killing effect of nanoemulsion particles on glioma cells was dose-dependent, with IC₅₀ of 16.36 μmol•L⁻¹ and 8.04 μmol•L⁻¹ after 24 h and 48 h, respectively., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Dioscoreae Bulibferae Rhizoma (RDB) is commonly used in clinical Chinese medicine. It has been used in many kinds of traditional Chinese medicine (TCM), but the toxicity of RDB, easily leads to hepatotoxicity. The objective of the present study is to investigate the synergistic protective effect of Scutellariae Radix (SR) with Phellodendri Chinensis Cortex (PCC) on RDB caused liver toxicity in rats. SD female rats were adopted to establish the hepatotoxicity models by RDB (9 g•kg⁻¹, ig) once daily for 28 consecutive days. After 28 days, liver histological changes were observed, and the activity of transaminase and antioxidant enzymes was evaluated. Morphological and biochemical indicators evaluation showed that, Dioscoreae Bulibferae Rhizoma-induced hepatotoxicity models were successful, and the liver cells were dissolved and swelling with fatty degeneration； inflammatory cells were present in gaps; local punctiformed or lamellar hydropic degeneration was found in liver tissues, with partial necrosis. Indexes of liver function (ALT, AST and ALP) were significantly increased (P<0.05 or P<0.01). The combination of SR and PCC has protective effect on RDB-induced hepatotoxicity in rats. SR+PCC exerted the strongest protective effects against RDB-induced hepatotoxicity. SR, PCC, and SB+CP were observed to exhibit hepatoprotective effect as demonstrated by significant decrease in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) (P<0.05 or P<0.01), and MAD level in liver tissue (P<0.001), significant increase in GSH content in liver tissue (P<0.001), and significant improvement in his to pathologic changes of liver tissues in rats. SR, PCC and their combinations could achieve liver protection effect by reducing ALT, ALP and AST level in serum, increasing GSH level and anti-oxidantability of liver tissues, and reducing hepatic tissue cells injury., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Objective: To explore whether quninalizarin, an specific inhibitor of protein kinase CK2, could sensitize icotinib in EGFR-TKIs (epithelial growth factor receptor-tyrosine kinase inhibitor)-resistant cell lines and uncover the underlying mechanisms., Methods: MTT assay was performed to evaluate the inhibitory effect of quninalizarin, icotinib or the combination of both on cell proliferation in several lung adenocarcinoma cell lines. Western blot assay was used to assess if combined inhibition of EGFR and protein kinase CK2 by icotinib and quninalizarin, exerts effect on the expression and phosphorylation of major proteins of EGFR signaling pathways., Results: The IC50 of HCC827, H1650, H1975 and A549 cells for icotinib were (8.07±2.00)μmol/L, (66.01±6.64)μmol/L, (265.60±9.47)μmol/L and (87.88±6.8)μmol/L, respectively, indicating that HCC827 cells are sensitive to icotinib, and the H1650, H1975 and A549 cells are relatively resistant to icotinib. When treated with both quninalizarin and icotinib in the concentration of 50 μmol/L, the viability of H1650, H1975 and A549 cells was (40.64±3.73)%, (65.74±3.27)% and (44.96±0.48)%, respectively, significantly lower than that of H1650, H1975 and A549 cells treated with 50 μmol/L icotinib alone (55.05±1.22)%, (71.98±1.60)% and (61.74±6.18)%, respectively (P<0.01 for all). When treated with both 100 μmol/L quninalizarin and 100 μmol/L icotinib, the viability of H1650, H1975 and A549 ells were (23.35±0.81)%, (55.70±1.03)%, (33.42±1.33)%, respectively, significantly lower than the viability of H1650, H1975 and A549 cells treated with 100 μmol/L icotinib alone (40.57±2.65)%, (62.40±2.05)% and (44.97±8.20)%, respectively, (P<0.01 for all). The two-way ANOVA analysis showed that compared with the viability of EGFR-TKIs-resistant cells (H1650, H1975, A549) treated with 50 μmol/L and 100 μmol/L icotinib alone, the viability of cells treated with icotinib and quinalizarin were significantly suppressed, and the differences were statistically significant (P<0.01). In addition, the phosphorylation form of Akt and ERK (namely p-Akt and p-ERK) were significantly down-regulated by treating with quninalizarin and icotinib together in the H1650 cells while the expression of Akt and ERK changed little., Conclusions: Quinalizarin, as a specific CK2 inhibitor, may overcome icotinib resistance by inhibiting proliferation mediated by Akt and ERK in human lung adenocarcinoma cell lines, and enhances the suppressive effect of icotinib on the proliferation of EGFR-TKIs-resistant human lung adenocarcinoma cells.

Honokiol(HNK), one of major biological active constituents of Mangnolia officinalis, exerts a wide range of biological functions, such as moderate anticancer effects. It inhibits the growth of lung cancer, gastrointestinal cancer, head and neck squamous cell carcinoma, breast cancer, prostate cancer, ovarian cancer, in vitro and in vivo through multiple potential molecular targets. It modulates apoptosis-associated signaling pathway, inhibits growth factor receptor-mediated signal transduction pathway, blocks nuclear factor-κB signaling pathway, decreases the expression level of androgen receptors, subsides m TOR and STAT3 signaling pathway, and so on. HNK enhances the inhibitory effects of traditional anticancer drugs or targeted antitumor drugs in vitro and in vivo. It reverses multidrug resistances of cancer cells to cisplatin, doxorubicin and paclitaxol. Therefore, HNK plays a role in the augmentation of antitumor effects of cancer drugs and the reversal of multidrug resistance of tumor cells. HNK is a promising biochemical modulator of anti-cancer medicines in the cancer therapy.

Objective: To explore the synergistically effects and mechanisms of resveratrol (RES) enhanced the oxidative stress and apoptotic cell death induced by As2O3 (arsenic trioxide)., Methods: According to the result of MTT assay, human lung adenocarcinoma A549 cells were divided into four treatment groups as follow: control group, single RES or As2O3 treated group and the group treated with RES and As2O3. Then the differences of cell viability, colony formation, level of ROS, GSH content, mitochondrial membrane potential and apoptosis rate were compared with single or combined treatment. In addition, pre-treatment with L-buthionine sulfoximine (L-BSO), the inhibitory of GSH synthesis, was used to identify the role of GSH in synergistically apoptosis induced by RES and As2O3., Results: The detected results demonstrated that RES could effectively inhibited the growth of A549 cells when its concentration above 20 μmol/L, and inhibition effects was concentration dependent manner. The rate of colony formation, GSH content, mitochondrial membrane potential and apoptosis rate in combination group were significantly lower than that of single RES or As2O3 treatment group (P < 0.05), whereas, RES markedly increased the level of ROS, the expression of cytochrome c and caspase 3 induced by As2O3. When pre-treatment with BSO before RES and As2O3 combination incubation, beside the apoptosis rate was increased from 30.0% to 77.7%, the GSH content was sharply depleted while ROS massively accumulated in intracellular., Conclusion: RES could significantly intensified the effects of As2O3 in inhibiting the proliferation, depleting GSH content, ROS accumulation, mitochondrial membrane potential decline and cytochrome c releasing, thus leading to cells apoptosis via Cas-3 activation in a mitochondria-dependent pathway.

Objective: To investigate the molluscicidal mechanism of combining use of the extract of Glycyrrhiza uralensis (GE) and niclosamide (Nic)., Methods: The Oncomelania hupensis snails were immersed in Nic, GE and GE+Nic solutions for 24 h and 48 h respectively, and then were put into fresh water to confirm their survival condition. The alive ones were dissected to obtain their livers. The effects of the drugs on the protein and glycogen of the liver of O. hupensis were observed, and the effects on contractile activity of vola pedis of the snails were studied by the experimental method of isolated smooth muscles of 0. hupensis., Results: GE had no obvious effects on the protein and glycogen in the liver of O. hupensis (all P > 0.05), but it could inhibit the contractions and decrease the contractile frequency of smooth muscles of vola pedis of O. hupensis (all P < 0.05). Nic could significantly decrease the levels of protein and glycogen in the liver of O. hupensis (all P < 0.05) , as well as enhance the contractions and contractile frequencies of smooth muscles of vola pedis of O. hupensis (P < 0.05). GE combined with Nic could further decrease the levels of protein and glycogen in the liver of O. hupensis (all P < 0.05), meanwhile, it could inhibit the contractions and decrease the contractile frequency of smooth muscles of vola pedis of O. hupensis (all P < 0.05)., Conclusions: The combining use of GE and Nic can accelerate the liver damage of O. hupensis, and also can inhibit the contractions of smooth muscles of vola pedis of O. hupensis which increases the contacting time of the drug, thus leads to the synergism of molluscicidal effect.