M2-type tumor-associated macrophages (TAMs) infiltration contributes to cancer malignant progression. However, the mechanisms for controlling recruitment and M2 polarization of macrophages by cancer cells are largely unclear. NADPH oxidase 4 (NOX4) is abundantly expressed in non-small cell lung cancer (NSCLC) and mediates cancer progression. NOXs are in close relation with cancer-related inflammation, nevertheless, whether tumoral NOXs influence microenvironmental macrophages remains undentified. This study found that there was a close association between NOX4 expression and macrophage chemotaxis in patients with NSCLC analyzed using TCGA RNA-sequencing data. NOX4 in NSCLC cells (A549 and Calu-1 cell lines) efficiently enhanced murine peritoneal macrophage migration and induces M2 polarization. Immunohistochemical analysis of clinical specimens confirmed the positive correlation of NOX4 and CD68 or CD206. The mechanical study revealed that tumoral NOX4-induced reactive oxygen species (ROS) stimulated various cytokine production, including CCL7, IL8, CSF-1 and VEGF-C, via PI3K/Akt signaling-dependent manner. Blockade of the function of these cytokines reversed NOX4 effect on macrophages. Specifically, the results showed that tumoral NOX4-educated M2 macrophages exhibited elevated JNK activity, expressed and released HB-EGF, thus facilitating NSCLC proliferation in vitro. Pretreatment of macrophages with JNK inhibitor blocked tumoral NOX4-induced HB-EGF production in M2 macrophages. Finally, in a xenograft mouse model, overexpression of NOX4 in A549 cells enhanced the tumor growth. Elimination of ROS by NAC or inhibition of NOX4 activity by GKT137831 suppressed tumor growth accompanied by reduction in macrophage infiltration and the percentage of M2 macrophages. In conclusion, our study indicates that tumoral NOX4 recruits M2 TAMs via ROS/PI3K signaling-dependent various cytokine production, thus contributing NSCLC cell growth.

Background and Purpose: Non-small-cell lung cancer (NSCLC) accounts for up to 80-85% of all lung cancers and has a disappointing prognosis. Flavonoids exert anticancer properties, mostly involving stimulation of ROS production without significant toxicity to normal cells. This study was aimed to delineate the effect of diosmetin, a natural flavonoid, on NSCLC cells and its ability to enhance the antitumour activity of paclitaxel. Experimental Approach: NSCLC cells, normal cell lines HLF-1 and BEAS-2B, and immunodeficient mice were chosen as models to study the effects of diosmetin. Changes in cell viability, apoptosis, and ROS were analysed by MTT assay, flow cytometry assay, and fluorescent probe DCFH-DA. Expression of proteins and mRNA was determined by Western blotting and real-time RT-PCR. Growth of xenografted tumours was measured. Spleens and other vital organs were analysed with histological and immunohistochemical techniques. Key Results: Diosmetin induced selective apoptotic death in NSCLC cells but spared normal cells, via ROS accumulation. Diosmetin induced ROS production in NSCLC cells probably via reducing Nrf2 stability through disruption of the PI3K/Akt/GSK-3β pathway. The in vitro and in vivo xenograft studies showed that combined treatment of diosmetin and paclitaxel synergistically suppressed NSCLC cells. Histological analysis of vital organs showed no obvious toxicity of diosmetin, which matched our in vitro findings. Conclusions and Implications: Diosmetin selectively induced apoptosis and enhanced the efficacy of paclitaxel in NSCLC cells via ROS accumulation through disruption of the PI3K/Akt/GSK-3β/Nrf2 pathway. Therefore, diosmetin may be a promising candidate for adjuvant treatment of NSCLC.Abbreviations: DCFH-DA, 2′7′-dichlorodihydroflourescein diacetate; GSK-3β, glycogen synthase kinase-3β; HO-1, haem oxygenase; NAC, N-acetylcysteine; NQO-1, NAD(P)H dehydrogenase, quinone 1; Nrf2, nuclear factor E2-related factor 2; NSCLC, non-small-cell lung cancer; tBHQ, tert-Butylhydroquinone Xiangcui Chen, Qipeng Wu, and Yueming Chen made equal contributions to this work.

The present systematic review and meta-analysis was undertaken to evaluate the effects of acupuncture in women with breast cancer (BC), focusing on patient-reported outcomes (PROs).MethodsA comprehensive literature search was carried out for randomized controlled trials (RCTs) reporting PROs in BC patients with treatment-related symptoms after undergoing acupuncture for at least four weeks. Literature screening, data extraction, and risk bias assessment were independently carried out by two researchers.ResultsOut of the 2, 524 identified studies, 29 studies representing 33 articles were included in this meta-analysis. At the end of treatment (EOT), the acupuncture patients’ quality of life (QoL) was measured by the QLQ-C30 QoL subscale, the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES), the Functional Assessment of Cancer Therapy–General/Breast (FACT-G/B), and the Menopause-Specific Quality of Life Questionnaire (MENQOL), which depicted a significant improvement. The use of acupuncture in BC patients lead to a considerable reduction in the scores of all subscales of the Brief Pain Inventory-Short Form (BPI-SF) and Visual Analog Scale (VAS) measuring pain. Moreover, patients treated with acupuncture were more likely to experience improvements in hot flashes scores, fatigue, sleep disturbance, and anxiety compared to those in the control group, while the improvements in depression were comparable across both groups. Long-term follow-up results were similar to the EOT results.ConclusionsCurrent evidence suggests that acupuncture might improve BC treatment-related symptoms measured with PROs including QoL, pain, fatigue, hot flashes, sleep disturbance and anxiety. However, a number of included studies report limited amounts of certain subgroup settings, thus more rigorous, well-designed and larger RCTs are needed to confirm our results.

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Acetaminophen (APAP) overdose-induced acute liver damage is mostly due to overwhelmingly increased oxidative stress. Nuclear factor-erythroid 2-related factor2 (Nrf2) plays an important role in alleviating APAP hepatic toxicity. Shikonin (SHK) enhances Nrf2 in multiple lines of normal cells. Nevertheless, whether SHK protects against APAP-induced liver toxicity remains undefined. This study found SHK defended APAP-induced liver toxicity, as well as reversed the levels of serum alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO) activity, and reactive oxygen species (ROS), while it enhanced the liver glutathione (GSH) level in APAP-treated mice. SHK rescued the cell viability and GSH depletion, but neutralized oxidative stress in APAP-treated human normal liver L-02 cells. Mechanically, SHK increased Nrf2 expression in the exposure of APAP at the protein level but not at the mRNA level. Inhibition of Nrf2 blocked the SHK effect in APAP-treated hepatocytes. Furthermore, SHK improved Nrf2 stability through stimulating PI3K/Akt pathway, thus inhibiting GSK-3β. In vivo studies confirmed the close correlation of liver protection of SHK against APAP and Akt/GSK-3β/Nrf2 pathway. In conclusion, this study reveals that SHK prevents APAP hepatotoxicity by upregulation of Nrf2 via PI3K/Akt/GSK-3β pathway. Therefore, SHK may be a promising candidate against APAP-induced liver injury.

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