Effect of exogenous γ-aminobutyric acid on physiological property, antioxidant activity, and cadmium uptake of quinoa seedlings under cadmium stress.

Increasing cadmium (Cd) pollution has negative effects on quinoa growth and production. Gamma-aminobutyric acid (GABA) confers plants with stress resistance to heavy metals; however, the mechanism remains unclear. We explored the effects of exogenous GABA on the physiological characteristics, antioxidant capacity, and Cd accumulation of quinoa seedlings under Cd stress using hydroponic experiments. Partial least-squares regression was used to identify key physical and chemical indices of seedlings affecting Cd accumulation. Compared with those of the CK group, exposure to 10 and 25 µmol·L-1 Cd significantly reduced the photosynthetic pigment contents, photosynthesis, and biomass accumulation of quinoa seedlings; resulted in shorter and thicker roots; decreased the length of the lateral roots; decreased the activities of superoxide dismutase (SOD) and peroxide (POD); and increased H2O2 and malondialdehyde (MDA) contents. Exogenous GABA reduced the Cd content in the stem/leaves and roots of quinoa seedlings under Cd stress by 13.22-21.63% and 7.92-28.32%, decreased Cd accumulation by 5.37-6.71% and 1.91-4.09%, decreased the H2O2 content by 38.21-47.46% and 45.81-55.73%, and decreased the MDA content by 37.65-48.12% and 29.87-32.51%, respectively. GABA addition increased the SOD and POD activities in the roots by 2.78-5.61% and 13.81-18.33%, respectively, under Cd stress. Thus, exogenous GABA can reduce the content and accumulation of Cd in quinoa seedlings by improving the photosynthetic characteristics and antioxidant enzyme activity and reducing the degree of lipid peroxidation in the cell membrane to alleviate the toxic effect of Cd stress on seedling growth.

Efficacy and safety of perioperative therapy for locally resectable gastric cancer: A network meta-analysis of randomized clinical trials.

BACKGROUND: Gastric cancer (GC) is the fifth most commonly diagnosed malignancy worldwide, with over 1 million new cases per year, and the third leading cause of cancer-related death. AIM: To determine the optimal perioperative treatment regimen for patients with locally resectable GC. METHODS: A comprehensive literature search was conducted, focusing on phase II/III randomized controlled trials (RCTs) assessing perioperative chemotherapy and chemoradiotherapy in treating locally resectable GC. The R0 resection rate, overall survival (OS), disease-free survival (DFS), and incidence of grade 3 or higher nonsurgical severe adverse events (SAEs) associated with various perioperative regimens were analyzed. A Bayesian network meta-analysis was performed to compare treatment regimens and rank their efficacy. RESULTS: Thirty RCTs involving 8346 patients were included in this study. Neoadjuvant XELOX plus neoadjuvant radiotherapy and neoadjuvant CF were found to significantly improve the R0 resection rate compared with surgery alone, and the former had the highest probability of being the most effective option in this context. Neoadjuvant plus adjuvant FLOT was associated with the highest probability of being the best regimen for improving OS. Owing to limited data, no definitive ranking could be determined for DFS. Considering nonsurgical SAEs, FLO has emerged as the safest treatment regimen. CONCLUSION: This study provides valuable insights for clinicians when selecting perioperative treatment regimens for patients with locally resectable GC. Further studies are required to validate these findings.

[Tetramethylpyrazine regulates angiogenesis of endothelial cells in cerebral ischemic stroke injury via SIRT1/VEGFA signaling pathway].

This study aims to investigate whether tetramethylpyrazine(TMP) can stimulate angiogenesis in cerebral microvascular endothelial cells and alleviate cerebral ischemic stroke(CIS) and to explore the underlying mechanisms. In the animal study, adult Sprague-Dawley rats(n=15) were assigned into sham surgery(sham), middle cerebral artery occlusion/reperfusion(MCAO/R), and MCAO/R+TMP(intraperitoneal injection of 20 mg·kg~(-1)) groups. The neurological function was evaluated by the Z-Longa method. The cerebral infarction volume was detected by TTC staining. Enzyme-linked immunosorbent assay(ELISA) was employed to detect the expression of vascular endothelial growth factor(VEGF), angiopoietin(Ang), and platelet-derived growth factor(PDGF). Immunofluorescence staining was employed to detect Ki67 and the expression of vascular endothelial growth factor A(VEGFA) and slient information regulator 1(SIRT1). Western blot was employed to determine the expression levels of VEGFA, SIRT1, angiopoietin-2(Ang-2), and platelet-derived growth factor B(PDGFB). In the cell study, mouse brain-derived endothelial cells(Bend.3) were cultured, and the optimal concentration of TMP was determined. Then, VEGF, Ang, and PDGF were detected by ELISA after the addition of cabozantinib. Western blot was employed to measure the expression of VEGFA, Ang-2, and PDGFB. Immunofluorescence staining was used to detect CD31, CD34, and Ki67, and the proliferation, migration, and tube formation ability of Bend.3 cells were observed in vitro. Western blot and immunofluorescence staining were performed to measure the expression of SIRT1 and VEGFA after addition of the SIRT1-specific inhibitor selisistat(EX-527). The results showed that compared with the sham group, the MCAO/R group had severe neurological function damage, increased infarction volume, up-regulated expression of VEGF, VEGFA, Ang, Ang-2, PDGF, and PDGFB, and down-regulated expression of Ki67 and SIRT1(P<0.01). Compared with the MCAO/R group, the MCAO/R+TMP group presented alleviated neurological function damage, reduced infarction volume, and activated expression of VEGF, VEGFA, Ang, Ang-2, PDGF, PDGFB, Ki67, and SIRT1(P<0.01). The cell experiments showed that compared with the normal group, Bend.3 cells were activated by oxygen glucose deprivation/reoxygenation(OGD/R) treatment(P<0.05, P<0.01). Compared with the OGD/R group, the OGD/R+TMP group upregulated the expression levels of VEGF, VEGFA, Ang, Ang-2, PDGF, PDGFB, SIRT1, Ki67, CD31, and CD34, enhanced the angiogenic ability of Bend.3 cells without being inhibited by BMS or EX-527(P<0.05, P<0.01, P<0.001). The results suggest that TMP can activate the SIRT1/VEGFA signaling pathway to stimulate angiogenesis and alleviate CIS injury.

Afatinib Decreases P-Glycoprotein Expression to Promote Adriamycin Toxicity of A549T Cells.

We investigated the reversal effect of afatinib (AFT) on activity of adriamycin (ADR) in A549T cells and clarified the related molecular mechanisms. A549T cells overexpressing P-glycoprotein (P-gp) were resistant to anticancer drug ADR. AFT significantly increased the antitumor activity of ADR in A549T cells. AFT increased the intracellular concentration of ADR by inhibiting the function and expression of P-gp at mRNA and protein levels in A549T cells. Additionally, the reversal effect of AFT on P-gp mediated multidrug resistance (MDR) might be related to the inhibition of PI3K/Akt pathway. Cotreatment with AFT and ADR could enhance ADR-induced apoptosis and autophagy in A549T cells. Meanwhile, the co-treatment significantly induced cell apoptosis and autophagy accompanied by increased expression of cleaved caspase-3, PARP, LC3B-II, and beclin 1. Apoptosis inhibitors had no significant effect on cell activity, while autophagy inhibitors decreased cell viability, suggesting that autophagy may be a self protective mechanism of cell survival in the absence of chemotherapy drugs. Interestingly, when combined with AFT and ADR, inhibition of apoptosis and/or autophagy could enhance cell viability. These results indicated that in addition to inhibit P-gp, ADR-induced apoptosis, and autophagy promoted by AFT contributed to the antiproliferation effect of combined AFT and ADR on A549T cells. These findings provide evidence that AFT combined ADR may achieve a better therapeutic effect to lung cancer in clinic. J. Cell. Biochem. 119: 414-423, 2018. © 2017 Wiley Periodicals, Inc.

The osteogenesis-promoting effects of alpha-lipoic acid against glucocorticoid-induced osteoporosis through the NOX4, NF-kappaB, JNK and PI3K/AKT pathways.

Recently, accumulating evidence has indicated that glucocorticoid-induced osteoporosis (GIOP) is closely related to oxidative stress and apoptosis. Alpha-lipoic acid (LA), a naturally endogenous anti-oxidant, possesses anti-oxidative and anti-apoptosis activities, implicating LA as a therapeutic agent for the treatment of GIOP. In this study, the osteogenesis-promoting effects of LA against GIOP were investigated and the mechanisms were further probed. Here, the results showed that LA inhibited oxidative stress, suppressed apoptosis and improved osteopenia by promoting the expression of osteogenesis markers, including ALP, COL-I, OCN, BMP-2, RUNX2 and OSX. Further study revealed that the osteogenesis-promoting effects of LA likely occur via the regulation of the NOX4, NF-kappaB, JNK and PI3K/AKT pathways. The present study indicated that LA may prevent GIOP and promote osteogenesis and might be a candidate for the treatment of GIOP.

Alisol B 23-acetate protects against non-alcoholic steatohepatitis in mice via farnesoid X receptor activation.

Alisol B 23-acetate (AB23A) is a natural triterpenoid isolated from the traditional Chinese medicine rhizoma alismatis, which exhibits a number of pharmacological activities, including anti-hepatitis virus, anti-cancer and antibacterial effects. In this study we examined whether AB23A protected against non-alcoholic steatohepatitis (NASH) in mice, and the mechanisms underlying the protective effects. NASH was induced in mice fed a methionine and choline-deficient (MCD) diet for 4 weeks. The mice were simultaneously treated with AB23A (15, 30, and 60 mg·kg-1·d-1, ig) for 4 weeks. On the last day, blood samples and livers were collected. Serum liver functional enzymes, inflammatoru markers were assessed. The livers were histologically examined using H&E, Oil Red O, Masson's trichrome and Sirius Red staining. Mouse primary hepatocytes were used for in vitro experiments. The mechanisms underlying AB23A protection were analyzed using siRNA, qRT-PCR, and Western blot assays. AB23A treatment significantly and dose-dependently decreased the elevated levels of serum ALT and AST in MCD diet-fed mice. Furthermore, AB23A treatment significantly reduced hepatic triglyceride accumulation, inflammatory cell infiltration and hepatic fibrosis in the mice. AB23A-induced decreases in serum and hepatic lipids were related to decreased hepatic lipogenesis through decreasing hepatic levels of SREBP-1c, FAS, ACC1 and SCD1 and increased lipid metabolism via inducing PPARα, CPT1α, ACADS and LPL. The reduction in inflammatory cell infiltration corresponded to deceased serum levels of mKC and MCP-1 and decreased hepatic gene expression of MCP-1 and VCAM-1. The reduction in hepatic fibrosis was correlated with decreased hepatic gene expression of fibrosis markers. The protective effects of AB23A were FXR-dependent, because treatment with the FXR agonist CDCA mimicked AB23A-induced hepato-protection in the mice, whereas co-administration of FXR antagonist guggulsterone abrogated AB23A-induced hepato-protection. In mouse primary hepatocytes, FXR gene silencing abrogated AB23A-induced changes in gene expression of Apo C-II, CPT1α, ACADS and LPL. AB23A produces protective effects against NASH in mice via FXR activation.

[Progress in regulation of drug transporters and metabolic enzymes by resveratrol].

Drug transporters and metabolic enzymes are two major factors in the regulation of disposition of drug in the body. Interestingly, resveratrol, as a new star of anticancer drug, has a close relationship with transporters and metabolic enzymes. It is known that resveratrol can activate or inhibit the function of several transporters directly. Furthermore, the expression of several transporters was changed. Meanwhile, resveratrol is able to inhibit the function of metabolic enzymes (cytochrome P450, CYP450) and regulate the expression of metabolic enzymes. For this reason, when resveratrol is administrated in combination with other drugs, drug-drug interaction (DDI) should be considered. In this review, we summarize the distribution of transporters and metabolic enzymes in the body, the effect of resveratrol on transporters and metabolic enzymes as well as the drug-resveratrol interaction mediated by transporters and metabolic enzymes.

[Research advances in organic anion transporter].

The organic anion transporter (OAT) subfamily is an important part of the SLC22 (solute carrier 22) transporter family. OATs are expressed in many tissues, including liver, kidney, brain, placenta and so on. A great deal of attention has been paid to OAT because of its role in handling of common drugs (antibiotics, antivirals, diuretics, nonsteroidal anti-inflammatory drugs), toxins and nutrients. Data from recent metabolomics, microarray and system biology studies, phenotypes of Oat1 and Oat3 knockouts, indicate a central role of this pathway in the metabolism as well as putative uremic toxins of kidney disease. The expressions of certain OATs in conjunction with phase I and phase II drug metabolizing enzymes are regulated by nuclear receptors and other transcription factors. According to the "remote sensing and signaling hypothesis", some OATs have a strong relationship with certain particular signaling molecules. OATs may play a role in remote inter-organ communication via regulating levels of signaling molecules and key metabolites in tissues and body fluids. OATs play a significant role in the transportation of internal and external material under normal and pathological conditions.

Inhibitory Effects of Highly Oxygenated Lanostane Derivatives from the Fungus Ganoderma lucidum on P-Glycoprotein and α-Glucosidase.

Twelve new highly oxygenated lanostane triterpenoids and nine known ganoderic acids were isolated from the fruiting body of Ganoderma lucidum. The new compounds were lanostane nortriterpenoids with 27 carbons (1-5 and 8), lanostane nor-triterpenoids with 25 carbons (6 and 7), and lanostane triterpenoids (9-12) based on multiple spectroscopic data analysis, including HRESIMS, 1D-NMR, 2D-NMR, and CD. Compounds 1-5 were identified as rare nor-lanostanoids that contain a 17ß-pentatomic lactone ring. Compound 13, possessing a lactone ring, had been isolated previously. The P-glycoprotein (P-gp) inhibitory effects of compounds 1-21 were evaluated at a concentration of 20 µM using an adriamycin (ADM)-resistant human breast adenocarcinoma cell line (MCF-7/ADR). Compounds 1, 5, 18, and 20 and verapamil increased the accumulation of ADM in MCF-7/ADR cells approximately 3-fold when compared with the negative control. These data support the significant P-glycoprotein inhibitory activities of compounds 1, 5, 18, and 20. In silico docking analysis suggested these compounds had similar P-gp recognition mechanisms compared with those of verapamil (a classical inhibitor). Furthermore, in an in vitro bioassay, compounds 2, 4, 5, 6, and 18 showed moderate inhibitory effects against α-glucosidase compared with those of the positive control acarbose.

Alpha-Lipoic Acid Promotes Osteoblastic Formation in H2O2 -Treated MC3T3-E1 Cells and Prevents Bone Loss in Ovariectomized Rats.

Alpha-lipoic acid (ALA), a naturally occurring compound and dietary supplement, has been established as a potent antioxidant that is a strong scavenger of free radicals. Recently, accumulating evidences has indicated the relationship between oxidative stress and osteoporosis (OP). Some studies have investigated the possible beneficial effects of ALA on OP both in vivo and in vitro; however, the precise mechanism(s) underlying the bone-protective action of ALA remains unclear. Considering this, we focused on the anti-oxidative capacity of ALA to exert bone-protective effects in vitro and in vivo. In the present study, the effects of ALA on osteoblastic formation in H(2)O(2) -treated MC3T3-E1 pre-osteoblasts and ovariectomy (OVX)-induced bone loss in rats were investigated. The results showed that ALA promoted osteoblast differentiation, mineralization and maturation and inhibited osteoblast apoptosis, thus increasing the OPG/receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) ratio and leading to enhanced bone formation in vitro and inhibited bone loss in vivo. Further study revealed that ALA exerted its bone-protective effects by inhibiting reactive oxygen species (ROS) generation by down-regulating Nox4 gene expression and protein synthesis and attenuating the transcriptional activation of NF-κB. In addition, ALA might exert its bone-protective effects by activating the Wnt/Lrp5/ß-catenin signaling pathway. Taken together, the present study indicated that ALA promoted osteoblastic formation in H(2)O(2) -treated MC3T3-E1 cells and prevented OVX-induced bone loss in rats by regulating Nox4/ROS/NF-κB and Wnt/Lrp5/ß-catenin signaling pathways, which provided possible mechanisms of bone-protective effects in regulating osteoblastic formation and preventing bone loss. Taken together, the results suggest that ALA may be a candidate for clinical OP treatment.

Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis.

Intrahepatic cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Appropriate regulation of bile acids in hepatocytes is critically important for protection against liver injury. In the present study, we characterized the protective effect of alisol B 23-acetate (AB23A), a natural triterpenoid, on alpha-naphthylisothiocyanate (ANIT)-induced liver injury and intrahepatic cholestasis in mice and further elucidated the mechanisms in vivo and in vitro. AB23A treatment dose-dependently protected against liver injury induced by ANIT through reducing hepatic uptake and increasing efflux of bile acid via down-regulation of hepatic uptake transporters (Ntcp) and up-regulation of efflux transporter (Bsep, Mrp2 and Mdr2) expression. Furthermore, AB23A reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, increased bile acid conjugation through inducing Bal, Baat and bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrate the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect of AB23A. The changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly demonstrated the effect of AB23A on FXR activation in a dose-dependent manner using luciferase reporter assay in HepG2 cells. In conclusion, AB23A produces protective effect against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes.

[Advances of the anti-tumor research of metformin].

Metformin is the most commonly prescibed drug for type 2 diabetes mellitus as it is inexpensive, safe, and efficient in ameliorating hyperglycemia and hyperinsulinemia. Numerous epidemiological studies indicate that diabetic population is not only at increased risk of cardiovascular complications, but also at substantially higher risk of many forms of malignancies. Meanwhile, epidemiological and clinical observation studies have shown that metformin use reduces risk of cancer in patients with type 2 diabetes mellitus and improves prognosis and survival rate of the cancer patients. Furthermore, metformin has been used for cancer therapy in clinical trials. Thus, metformin is emerging as a new cancer therapy or adjuvant anticancer drugs. This review summarizes recent progress in studies of metformin use and its molecular mechanism.

A novel oleanolic acid-loaded PLGA-TPGS nanoparticle for liver cancer treatment.

OBJECTIVES: Hepatocellular carcinoma is the third most common cause of cancer death. Oleanolic acid (OA) is a natural triterpenoid, has many important biological actions, including antitumor effect, but its poor solubility often leads to poor pharmacodynamics. The aim of our work is to make OA-loaded poly (lactide-co-glycolide)-d-α-tocopheryl polyethylene glycol 1000 succinate (PLGA-TPGS) nanoparticles (OPTN) to improve its efficacy to liver cancer and characterize it. METHODS: OPTN were prepared by ultrasonic emulsification-solvent evaporation technique using PLGA with or without the addition of TPGS (OPN). The coumarin-6-loaded nanoparticles were used as a fluorescence marker. The nanoparticles were characterized for surface morphology, surface charge, particle size, drug loading, encapsulation efficiency, in vitro drug-release, cellular uptake, cytotoxicity by human liver cancer cell line HepG2 cells, and therapeutic effect in vivo. KEY FINDINGS: The prepared nanoparticles were found to be spherical in shape. The in vitro drug-release profile of both nanoparticle formulations showed a biphasic release pattern. There was an increased level of uptake and cytotoxicity of OPTN in the HepG2 cells compared with that of OPN. The treatment of OPTN group was better than OPN and FS groups in vivo. CONCLUSION: The results showed advantages of OPTN in terms of sustainable release and efficacy in liver cancer chemotherapy compared with OPN. OPTN could be acted as a novel and new dosage form to be used in cancer treatment study.

Bioactive metabolites of Schisanlactone E transformed by Cunninghamella blakesleana AS 3.970.

Schisanlactone E (SE) is a major triterpene obtained from the plants of genus Kadsura. The aim of this research was to investigate the transformed metabolites of SE by fungi and evaluate the bioactivities of these products. After screening 10 strains of filamentous fungi, Cunninghamella blakesleana AS 3.970 was chosen as a potent organism to be used for the biotransformation of SE. 13 metabolites were obtained and determined to be new compounds through the use of spectroscopic data, including UV, 1D-, 2D-NMR, and HR-ESIMS. Furthermore, in an in vitro bioassay, metabolites 7 and 9 showed moderate inhibitory effects on the nitric oxide production in LPS-induced macrophages with IC50 values of 16.73, 5.91 µM, respectively; 9 could inhibit the proliferation of acetaldehyde-induced HSC-T6 cells, with the IC50 value of 21.4 µM. Preliminary findings on the structure-activity relationships for these metabolites were also discussed.

Pharmacokinetics of phosphocreatine and its active metabolite creatine in the mouse plasma and myocardium.

BACKGROUND: The pharmacokinetic (PK) studies of phosphocreatine (PCr) and its active metabolite creatine (Cr) are considerably lacking. This study is to comparatively investigate the PK profiles of PCr and Cr in mice plasma and myocardium as well as the ATP level. METHODS: After iv administration of equimolar PCr and preformed Cr to healthy and Pit-induced myocardial ischemic mice, plasma and myocardium samples were analyzed for exogenous PCr, Cr and related ATP concentrations using a specific ion-pair reversed-phase HPLC-UV assay. RESULTS: The plasma C-T data of iv PCr and Cr were well fitted to two-compartment model. Following iv PCr, Cr appeared in plasma as early as 1.0 min postdose with a longer t1/2 than PCr and had a fm of 72%. The mice dosed iv PCr preceded 5 min by ip Pit 30 U/kg showed longer t1/2ß PCr and t1/2 Cr in plasma and elevated Cmax, Cr and Cmax, ATP in myocardium compared with mice dosed iv PCr alone, and it was estimated that about 40% ATP produced by iv PCr was from Cr. CONCLUSION: The PCr in plasma is converted to Cr rapidly and mostly, and shows an elimination rate limited (ERL) metabolite disposition. Iv PCr caused a significantly elevated and long-lasing myocardial ATP and Cr levels. The Pit-induced myocardial ischemia brings slower elimination of PCr and Cr and higher peak concentrations of Cr and ATP in myocardium. The metabolite Cr at least partially mediates PCr-caused rise in myocardial ATP level and also possibly the cardio-protective effects of PCr.

[The drug-drug interaction mediated by efflux transporters and CYP450 enzymes].

Multidrug regimens and corresponding drug interactions cause many adverse reactions and treatment failures. Drug efflux transporters: P-glycoprotein (P-gp), multidrug resistance associated protein (MRP) and breast cancer resistance protein (BCRP) in conjunction with metabolizing enzymes (cytochrome P450, CYP450) are major factors in such interaction. In recent years, a large number of studies have shown that P-gp plays a role in the oxidative metabolism of its substrates that are also substrates of CYP3A4. Combined actions of P-gp and CYP3A could account in some part for the low oral bioavailability determined for many of these dual substrates. P-gp along with efflux transporters (MRP and BCRP) having overlapping substrate specificity plays critical role in drug disposition. The relationship between MRP or BCRP and CYP3A is similar to that between P-gp and CYP3A. In this paper, we summarize the classification of efflux transporters, the main metabolizing enzymes CYP3A, clinical significance interactions mediated by efflux transporters and CYP450 enzymes and in vitro studies.

Suppression of the p66shc adapter protein by protocatechuic acid prevents the development of lung injury induced by intestinal ischemia reperfusion in mice.

BACKGROUND: Intestinal ischemia/reperfusion (I/R) causes severe histological injury, reactive oxygen species activation, and cell apoptosis in the lung. In this study, we investigated, using a murine intestinal I/R model, the effect of a polyphenolic compound, protocatechuic acid (PCA), in modulation of ShcA and in protection of the lung from I/R-induced injury. METHODS: Fifty ICR mice were randomly divided into five groups, including a control group, intestinal I/R group, control + PCA group, I/R + PCA low-dose group, and I/R + PCA high-dose group. The I/R and I/R + PCA groups were subjected to mesenteric arterial ischemia for 45 minutes and reperfusion for 90 minutes. The control and control + PCA groups underwent a surgical procedure that included isolation of the superior mesenteric artery without occlusion. In all PCA-pretreated groups, the mice received intraperitoneal PCA administration for three consecutive days. Serum specimens were collected for measuring tumor necrosis factor-α and interleukin 6, while lung tissues were harvested for histopathologic assessment including glutathione (GSH) and GSH peroxidase assay. Lung expression of p66shc, phosphorylated p66shc, manganese superoxide dismutase, caspace-3, and Bcl-xL were determined by Western blotting for protein level and semiquantitative reverse transcription-polymerase chain reaction analysis for mRNA level. RESULTS: PCA pretreatment markedly reduced I/R-induced lung injury as indicated by histological alterations; the decreases in tumor necrosis factor-α, interleukin 6, and caspase-3 expression levels; and the increases in GSH, GSH peroxidase, manganese superoxide dismutase, and Bcl-xL levels in the lung. Moreover, PCA treatment down-regulated p66shc expression and phosphorylation. CONCLUSION: PCA has a significant protective effect in lung injury induced by intestinal I/R. The protective effect of PCA may be attributed to the suppression of p66shc and the modulation of downstream antioxidative/antiapoptotic factors.

Microbial transformation of deoxyandrographolide and their inhibitory activity on LPS-induced NO production in RAW 264.7 macrophages.

A series of analogues of deoxyandrographolide (1) transformed by Cunninghamella blakesleana AS 3.2004 were isolated and identified by spectral methods including 2D NMR. Among them, 3-oxo-17,19-dihydroxy-7,13-ent-labdadien-15,16-olide (9), 3-oxo-19-hydroxy-1,13-ent-labdadien-15,16-olide (16), 3-oxo-1ß-hydroxy-14-deoxy-andrographolide (17) and 3-oxo-2ß-hydroxy-14-deoxyandrographolide (18) are new compounds. And their structure-activity relationships (SAR) of inhibitory activity on LPS-induced NO production in RAW 264.7 macrophage cells were also discussed.

Ursolic acid suppresses IL-6 induced C-reactive protein expression in HepG2 and protects HUVECs from injury induced by CRP.

OBJECTIVE: To investigate the inhibitory effects of ursolic acid (UA) on the expression of C-reactive protein (CRP) induced by IL-6 in HepG2 cells and the protective effects on the CRP-induced injury to human umbilical vein endothelial cells (HUVECs). METHODS: HepG2 cells were treated with IL-6 or IL-6 and different concentrations of UA for 48 h, then the cells were collected. The total protein and RNA of the cells were extracted for western blotting and RT-PCR methods to detect CRP protein and mRNA expression. HUVECs were treated with CRP or CRP and different concentrations of UA for 24h. Cell proliferation in each group was assayed by MTT. Cells were collected for western blotting and RT-PCR methods to detect VCAM-1, LOX-1 protein or mRNA expression. RESULT: IL-6 can significantly increase CRP protein and mRNA expression in HepG2 cells, and this effect of IL-6 can be decreased by UA (6.25, 12.5, 25 µmol/L) markedly in a dose-dependent manner. UA can inhibit CRP-induced proliferation of HUVECs. CRP can obviously increase LOX-1/VCAM-1 expression in HUVECs, both on mRNA and protein levels and the effect of CRP can be inhibited by UA (5, 10, 20 µmol/L) in a dose-dependent manner. CONCLUSION: UA can reduce the over expression of CRP in HepG2 cells induced by IL-6 and inhibit the increased expression of VCAM-1 and LOX-1 in HUVECs caused by CRP. Our research suggests that UA can reduce CRP levels in plasma and prevent inflammatory cytokines from injuring endothelial cells by inhibiting the hepatic synthesis of CRP. So UA may have positive significance for prevention and treatment of atherosclerosis and other cardiovascular diseases.

Effect of injection of brucea javanica oil emulsion plus chemoradiotherapy for lung cancer: a review of clinical evidence.

OBJECTIVE: Injection of brucea javanica oil emulsion (IBJOE), one of Chinese patent drugs has been widely used for lung cancer (LC) in China, and is known to provide some favorable outcomes, in particular when it combined with conventional treatment. However, little available best evidence is known about its effect and safety. This paper aims to evaluate the effectiveness and safety of IBJOE plus chemoradiotherapy to alleviate symptoms of LC patients. METHODS: A complete literature searching was conducted in databases including Chinese Biomedical Literature Database, China Academic Journals Full-text Database, Chinese Scientific Journals Database, the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE to identify randomized controlled trials (RCTs) of IBJOE with chemoradiotherapy versus chemoradiotherapy alone for LC patients regardless of blinding, duration of treatment or duration of follow-up. All searching dates were from the beginning to December 2011. Quality of the included studies was assessed using the method by Cochrane Reviewer Handbook, and data analysis was performed using RevMan 5.10 software developed by The Cochrane Collaboration. RESULTS: The searching yielded over 1371 relevant citations, most of which did not meet the inclusion criteria. Finally, only 21 RCTs involving 1619 patients were included, and all the studies were of poor quality. Pooled analyses were performed to reveal that compared with chemoradiotherapy alone, IBJOE plus chemoradiotherapy had a better complete response rate (relative risk (RR) = 1.42; 95% CI 1.05 to 1.92; P = 0.02) and improved quality of life (RR = 1.83; 95% CI 1.63 to 2.07; P < 0.00001) measured by Karnofsky Performance Status scale. In addition, there was a significant difference on the outcome of long-term survival rate, level of immune function, and some incidences of adverse effects. CONCLUSIONS: IBJOE plus chemoradiotherapy may have positive effects on LC patients in response rate, improvement of quality of life, and reducing incidences of some adverse effects compared with chemoradiotherapy alone. However, the results need to be viewed with caution because of low quality of the included studies.