Correction: 6-Gingerol as an arginase inhibitor prevents urethane-induced lung carcinogenesis by reprogramming tumor supporting M2 macrophages to M1 phenotype.

Correction for '6-Gingerol as an arginase inhibitor prevents urethane-induced lung carcinogenesis by reprogramming tumor supporting M2 macrophages to M1 phenotype' by Jingjing Yao et al., Food Funct., 2018, 9, 4611-4620, https://doi.org/10.1039/C8FO01147H.

Glaucocalyxin B protects against oxygen-glucose-deprivation/reperfusion-induced neuronal injury in PC-12 cells.

Oxidative stress has been implicated in the development of cerebral ischemia/reperfusion (I/R) injury. Glaucocalyxin B (GLB), one of five ent-kauranoid diterpenoids, was reported to possess neuroprotective activity. However, the effect of GLB on oxygen-glucose-deprivation/reperfusion (OGD/R)-induced cell injury in PC-12 cells has not been explored. PC-12 cells was treated with various concentrations of GLB (0, 2.5, 5 and 10 µM), and cell viability was detected using the MTT assay. PC-12 cells were pretreated with the indicated concentration of GLB (2.5-10 µM, 2 hours pretreatment), and were maintained under OGD for 3 hours, followed by 24 hours of reoxygenation. Cell viability was assessed using the MTT assay. The levels of superoxide dismutase, malondialdehyde, and glutathione peroxidase were detected using commercially available ELISA Kits. Intracellular reactive oxygen species level was measured using the fluorescent probe 2',7'-dichlorofluorescein diacetate. The levels of Bcl-2, Bax, p-Akt, Akt, p-mTOR, mTOR were detected using Western blot. Our results revealed that GLB significantly protected PC12 cells against OGD/R-induced cell injury. In addition, GLB efficiently inhibited oxidative stress and cell apoptosis in OGD/R-stimulated PC-12 cells. Mechanistic studies revealed that pretreatment with GLB could induce the activation of Akt/mTOR signaling pathway resulting in protection of OGD-treated PC12 cells. In conclusion, our data indicate for the first time that GLB protects against OGD/R-induced neuronal injury in PC-12 cells. The mechanism of the protective effect of GLB is partially associated with activation of the Akt/mTOR signaling pathway. Thus, GLB may be a potential agent for protection against cerebral I/R injury.

6-Gingerol as an arginase inhibitor prevents urethane-induced lung carcinogenesis by reprogramming tumor supporting M2 macrophages to M1 phenotype.

6-Gingerol (6-G) is the main bioactive component in Ginger (Zingiber officinale Roscoe). The aim of this study was to explore the contribution of macrophage polarization in 6-G-associated anti-cancer effects. In a urethane-induced lung carcinogenic model, lung carcinogenesis was positively correlated with macrophage (F4/80+) infiltration in lung interstitial in the control group. Furthermore, higher numbers of arginase+/F4/80+ M2 cells than iNOS+/F4/80+ M1 cells were observed in interstitial macrophages. Moreover, macrophage depletion by liposome-encapsulated clodronate (LEC) could significantly prevent lung carcinogenesis, whereas pexidartinib promoted lung carcinogenesis. After 6-G treatment, lung carcinogenesis was ameliorated with increased M1 macrophages and decreased M2 macrophages in the lung interstitial. ELISA showed that the levels of IFN-γ and IL-12 increased and the levels of IL-10 and TGF-ß1 decreased in the alveolar cavity compared to those in the control group. Unexpectedly, the carcinogenesis-preventing efficacy of 6-G was promoted in LEC-treated mice, but completely aborted in pexidartinib-treated mice. In the in vitro experiment, 6-G reset the IL-4-induced arginase+ M2 cells toward iNOS+ M1 cells and exhibited reduced levels of arginase 1 and ROS and elevated levels of L-arginine and NO. LEC and nor-NOHA selectively suppressed M2 macrophages but had a negligible effect on M1 macrophages, whereas pexidartinib decreased both M2 and M1 macrophages. The iNOS+ macrophage-promoting efficacy of 6-G was increased by LEC, but was completely eliminated by pretreatment with pexidartinib or nor-NOHA. M2 macrophage-resetting efficacy of 6-G was confirmed in a Lewis lung cancer allograft model. This study indicated a reprogramming effect of 6-G as an arginase inhibitor on tumor supporting macrophages.

Piperlongumine inhibits angiotensin II-induced extracellular matrix expression in cardiac fibroblasts.

Piperlongumine (PL), a single component isolated from Piper longum, has been reported to possess anti-inflammatory, antibacterial, antiangiogenic, antioxidant, antitumor, and antidiabetic activities. However, its role in cardiac fibrosis remains to be clarified. Therefore, we determined the effects of PL on cardiac fibroblasts (CFs) proliferation, and extracellular matrix (ECM) production under angiotensin II (Ang II) conditions, and further investigated the underlying molecular mechanism. Our data revealed that PL inhibited the proliferation and migration of CFs induced by Ang II. In addition, PL blocked the transformation of CFs to myofibroblasts induced by Ang II, as well as decreased cellular reactive oxygen species (ROS) production and malondialdehyde level in Ang II-stimulated CFs. Furthermore, PL significantly suppressed the Ang II-increased phosphorylation of extracellular regulated protein kinase 1/2 (ERK1/2) in CFs. Taken together, the results of the current study demonstrated that PL inhibits Ang II-induced cell proliferation, migration, and ECM expression in CFs through the inactivation of the ERR1/2 signaling pathway. These data strongly suggest that PL may be a promising therapeutic candidate for the treatment of cardiac fibrosis.

XRCC2-Deficient Cells are Highly Sensitive to 5-Fluorouracil in Colorectal Cancer.

BACKGROUND/AIMS: Inhibition of the repair of 5-fluorouracil (5-FU)-induced DNA lesions may improve the responses of tumors to anticancer agents. XRCC2 is a key factor in DNA repair. However, the role of XRCC2 in the chemoresistance of colorectal cancer (CRC) treated with 5-FU remains unclear. The aim of this study is to investigate whether XRCC2 expression affects the chemosensitivity of colorectal cancer. METHODS: XRCC2 expression in CRC tissues was assessed, and the outcomes were analyzed to determine the clinical importance of XRCC2 expression. Following treatment with 5-FU, the effect of XRCC2 on proliferation was evaluated via a CCK-8 assay, the effects on cell cycle distribution and apoptosis were analyzed using flow cytometry, and γH2AX foci formation assays were performed to examine the influence of 5-FU on DNA Double-strand breaks(DSBs) repair in CRC cells. RESULTS: XRCC2 expression in CRC tissues was significantly higher than that in normal tissues, and this increased XRCC2 expression was associated with advanced T staging, M staging, TNM staging, Duke's staging, and greater liver and lymph node metastases. XRCC2 expression might be an independent prognostic indicator for CRC patients. Patients with negative XRCC2 expression exhibit greater sensitivity to treatment with 5-FU-based chemotherapy than those with positive XRCC2 expression. Moreover, our observations revealed that the knockdown of XRCC2 in CRC cells increased the sensitivities to 5-FU in terms of cell proliferation, apoptosis and cell cycle arrest. DNA DSBs repair was slower in the XRCC2-deficient cells than in the XRCC2-wild type cells. CONCLUSION: Our study demonstrated that XRCC2 might play an important role in CRC and function as a novel prognostic indicator and that the down-regulation of XRCC2 may be useful for sensitizing CRC cells during 5-FU chemotherapy.

[Preparation and Synchronized Release Behavior on Porosity Osmotic Pump Tablets of Total Glucosides of Paeony].

Objective: To prepare porosity osmotic pump tablets of total glucosides of paeony( TGP),and to study the behavior on synchronous release of its main components. Methods: Taking the accumulative release of TGP as indexes, through single-factor test and orthogonal design to investigate the optimal formulation porosity osmotic pump tablets of TGP. The main components, paeoniflorin, albiflorin and benzoylpaeoniflorin were employed to study synchronous release of the optimal formulation. Results: The membrane weight, and the content of PEG 400,and diethyl phthalate( DEP) were the main factors influencing the behavior of TGP release. The accumulated release of the prepared osmotic pump release tablets achieved about 90%. Three main components achieved the desired zero-order release profile and had a synchronized release behavior. Conclusion: The prepared porosity osmotic pump tablets of TGP can achieve the behavior of synchronized release of multi-components with good reproducibility.

[Comparison of bioavailability of two kinds of solid dispersion from 10-hydroxycamptothecin in SD rats in vivo].

To improve the bioavailability of 10-hydroxycamptothecin, 10-hydroxycamptothecin solid dispersion(HCPT-SD) and 10-hydroxycamptothecin-phospholipid complex-solid dispersion(HCPT-PC-SD) were prepared, and their solubility and dissolution rate were evaluated in this study. SD rates were administered intragastrically with HCPT-SD or HCPT-PC-SD respectively, then their blood samples were collected at different time intervals. The concentration of HCPT in blood was detected by HPLC method with camptothecin as internal standard, and then its pharmacokinetic parameters were calculated and obtained. The results showed that the Cmax, AUC0-t and AUC0-∞ of both kinds of solid dispersion of HCPT were significantly increased than those of crude drug. The AUC0-t of HCPT-SD was increased by 176.87%, and AUC0-t of HCPT-PC-SD was increased by 254.31% as compared with crude drug. Therefore, the two kinds of solid dispersion of HCPT could significantly enhance the bioavailability of HCPT in SD rates, and the effect of HCPT-PC-SD was more obvious.

[Study and Evaluation on Preparation of Monolithic Osmotic Pump Tablet of Resveratrol].

OBJECTIVE: To prepare monolithic osmotic pump tablet of resveratrol. METHODS: Inclusion technology was adopted to enhance its solubility. The optimal formulation of resveratrol inclusion complex osmotic pump tablets was selected by the single-factor method and orthogonal design. The release in vitro of the optimized formulation was also fitted to different models. RESULTS: The tablets with optimized formulation achieved the desired zero-order release profile in 12 h (r = 0.9963) with the cumulative release over 90%. CONCLUSION: Resveratrol can be prepared into monolithic osmotic pump tablets based on the intermediate of inclusion technology, which have obvious characteristic of zero release.

[Protective effect of polysaccharides extracts from corn silk against cyclophosphamide induced host damages in mice bearing H22 tumors].

OBJECTIVE: To study the protective effect of polysaccharides from corn silk (PCS) against cyclophosphamide (CTX) induced host damages in mice bearing H22 tumors. METHODS: The ascitic and solid tumor bearing mice model were established to investigate the anti-tumor effects of different dose of PCS (100, 200 and 300 mg/kg). The effects of PCS alone and with combination of CTX on tumor weight, survival time, thymus and spleen index, white blood cell, nucleated cell of marrow, serum ALT and AST level were tested. RESULTS: The high-dose PCS (300 mg/kg) had significant inhibitory effects on tumor. After combination with CTX, the tumor inhibitory ratio was enhanced to 68.71%, the survival time of tumor-burdened ascites tumor mice was significantly prolonged to 72.07% compared with CTX group. The Q value of combination group was 0.997. Thymus and spleen index, white blood cell, nucleated cell of marrow decreased by CTX were ameliorated significantly. The level of ALT and AST increased by CTX were reduced by combination with PCS. CONCLUSION: PCS has a potent inhibitory effect on the growth of implanted H22 tumors in mice and has a synergetic effect and an attenuated toxic effect in combination with CTX.

Dietary quercetin combining intratumoral doxorubicin injection synergistically induces rejection of established breast cancer in mice.

Dietary ingredients can decrease the risk of a variety of human cancers. Quercetin (3,3',4',5,7-pentahydroxyflavone) has a long history of consumption as part of the normal human diet and is able to induce growth inhibition in multiple cancer cells. In an attempt to generate more potent therapeutic effect for breast cancer, we have designed a combinative regimen of dietary quercetin with intratumoral doxorubicin injection and evaluated their anti-tumor activity in established breast cancer mouse model. Interestingly, dietary quercetin combining intratumoral doxorubicin injection synergistically induced potent rejection of 4T1 breast cancer and led to long-term, tumor-free survival in mice bearing established breast tumor, whereas quercetin or doxorubicin alone failed to cure tumor-bearing mice. Treatment with quercetin promoted lymphocyte proliferation and regulated Th1/Th2 cytokine imbalance. Combination of quercetin and intratumoral doxorubicin injection further induced a persistent T-cell tumor-specific responses. Based on these results, the combination of quercetin as a food supplement adjunctive with intratumoral doxorubicin chemotherapy may represent a novel and highly effective strategy for inducing immune responses against tumors.

Quercetin greatly improved therapeutic index of doxorubicin against 4T1 breast cancer by its opposing effects on HIF-1α in tumor and normal cells.

PURPOSE: The anthracycline antibiotic doxorubicin (DOX) has been used successfully for treating various types of cancers. However, the therapeutic efficacy of DOX was greatly restricted by its cumulative dose-related cardiotoxicity and common side effects such as bone marrow and immune suppression. Quercetin had better cardioprotective and hepatoprotective activities. The present study was to observe whether quercetin could improve therapeutic index of DOX and explore its mechanisms. METHODS: Effects of quercetin on doxorubicin (DOX)-induced cytotoxicity were investigated in 4T1 cells and murine spleen cells by methylthiazoletetrazolium assay, flow cytometry and single cell gel electrophoresis. Influences of quercetin on therapeutic efficacy and systemic toxicity of DOX were evaluated in BALB/c mice with 4T1 breast cancer. Hypoxia-inducible factor-1 alpha (HIF-1α) in tumor and normal cells was examined to explore mechanisms of quercetin by Western blot and enzyme-linked immunosorbent assay. RESULTS: In vitro, quercetin at dose less than 100 µM had only slight effects on cell viability and DOX-induced cytotoxicity in 4T1 cells under normoxia, but it could reverse 4T1 cell resistance to DOX under hypoxia and protect spleen cells against DOX-induced cytotoxicity. In vivo, quercetin suppressed tumor growth and prolonged survival in BALB/c mice bearing 4T1 breast cancer. Importantly, quercetin enhanced therapeutic efficacy of DOX and simultaneously reduced DOX-induced toxic side effects. Further study showed that quercetin suppressed intratumoral HIF-1α in a hypoxia-dependent way but increased its accumulation in normal cells. HIF-1α siRNA abolished effects of quercetin on both tumor and normal cells. CONCLUSIONS: These results suggested that quercetin could improve therapeutic index of DOX by its opposing effects on HIF-1α in tumor and normal cells, and was a promising candidate as anticancer agents.

Baicalin suppresses lung carcinoma and lung metastasis by SOD mimic and HIF-1alpha inhibition.

The dose-related toxicity of anticancer drugs in chemotherapy of clinical carcinoma is the major obstacle to prolonged survival, we want to investigate selective therapeutic efficacy of baicalin on lung carcinoma and explain the basis underlying this phenomenon. In vitro, baicalin inhibited cell proliferation of human lung carcinoma A549 and mouse lewis lung cancer (LLC) in a dose- and time-dependent manner. The inhibitory activity of baicalin against cancer cells was promoted by superoxide dismutase (SOD) addition or hypoxia-inducible factor-1alpha (HIF-1alpha) knockdown and was reduced by SOD knockdown but not hypoxia. In vivo, baicalin suppressed tumor growth and prolonged survival in C57BL/6 mice bearing LLC tumor and nude mice bearing A549 carcinoma without systemic toxicity. Further studies showed that baicalin inhibited HIF-1alpha and enhanced SOD activity without affecting catalase and glutathione-S-transferase (GST) in cancer cells. In addition, baicalin also exhibited a superoxide anion scavenging activity. In conclusion, baicalin could selectively suppress lung carcinoma and lung metastasis by SOD mimic and HIF-1alpha inhibition.