Raised pH conferred the ability to maintain a balance between production and detoxification of reactive oxygen species and methylglyoxal in aluminum-toxic Citrus sinensis leaves and roots.

Little is known about interactive effects of pH-aluminum (Al) on reactive oxygen species (ROS) and methylglyoxal (MG) metabolisms in plants. Citrus sinensis seedlings were fertilized with nutrient solution at an Al concentration of 1 or 0 mM and a pH of 4.0, 3.5, 3.0 or 2.5 for 18 weeks. Thereafter, gas exchange and chlorophylls in leaves, H2O2 generation, electrolyte leakage, total soluble proteins, MG, malondialdehyde (MDA), antioxidants, sulfur-containing compounds, enzymes [viz., antioxidant enzymes, sulfur metabolism-related enzymes, ascorbate oxidase, phosphomannose isomerase, glyoxalase I and glyoxalase II] involved in ROS and MG detoxification in leaves and roots were measured. Effects of low pH and Al-toxicity on these parameters displayed obvious synergism. Without Al-toxicity, low pH increased H2O2 production, electrolyte leakage, MDA and MG concentrations by 45.7%-90.3% (52.4%-73.6%), 24.3%-74.5% (26.7%-86.2%), 18.6%-44.8% (35.6%-53.7%) and 16.3%-47.1% (13.8%-51.7%) in leaves (roots) relative to pH 4, respectively; low pH-induced upregulation of enzymes involved in ROS and MG detoxification and sulfur-containing compounds in leaves and/or roots could not protect them against oxidative damage. At pH 2.5-3.0, Al-toxicity increased H2O2 production, electrolyte leakage, MDA and MG concentrations by 34.2%-35.5% (23.9%-72.7%), 10.2%-29.5% (23.7%-56.8%), 15.6%-35.7% (27.5%-33.9%) and 21.5%-26.8% (21.0%-49.2%) in leaves (roots), respectively, and decreased total soluble protein concentration by 46.2%-47.4% (18.8%-20.8%) in leaves (roots); at pH 3.5-4.0, Al-toxicity did not affect significantly the five parameters in leaves and roots except for Al-induced increases in root MDA concentration at pH 3.5-4.0 and root electrolyte leakage at pH 3.5, and Al-induced decrease in root total soluble protein concentration at pH 4.0. Raised pH conferred the ability to maintain a balance between production and detoxification of ROS and MG in leaves and roots, thus protecting them against oxidative damage, and hence alleviating Al-induced increase in electrolyte leakage and decrease in total soluble protein level.

PRDX1 is a Tumor Suppressor for Nasopharyngeal Carcinoma by Inhibiting PI3K/AKT/TRAF1 Signaling.

BACKGROUND: Peroxiredoxin 1 (PRDX1) has been identified as a dual regulator of tumorigenesis. However, its expression, clinical significance, and biological function in nasopharyngeal carcinoma (NPC) remain unknown. This study aimed to explore the role and underlying mechanisms of PRDX1 in NPC. MATERIALS AND METHODS: The expression of PRDX1 in NPC tissues was evaluated by immunohistochemistry, and the relationships between the expression of PRDX1 and clinical features and prognosis of NPC patients were analyzed. The effects of PRDX1 on NPC cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) were examined. A tumor-bearing model of nude mouse was established to verify the function of PRDX1 in vivo. RESULTS: PRDX1 expression level was negatively associated with recurrence and metastasis of NPC. PRDX1 knockdown promoted NPC cell proliferation, migration, invasion and EMT in vitro, and enhanced tumor growth in vivo, while PRDX1 overexpression had opposite effects. Furthermore, transcriptome analysis showed that PRDX1 inhibited the activation of PI3K/AKT/TRAF1 signaling in NPC cells. CONCLUSION: PRDX1 inhibits NPC by inhibiting the activation of PI3K/AKT/TRAF1 signaling. PRDX1 is a tumor suppressor in human NPC and may be a prognostic biomarker for NPC patients.

Transformation of Fe-B@Fe into Fe-B@Ni for efficient photocatalytic hydrogen evolution.

It is highly desirable to develop efficient and cost-effective composite catalysts to replace noble metal Pt for hydrogen evolution reaction (HER). For an excellent HER catalyst, both the adsorption and desorption of intermediate H atoms on it should be easy. However, except metal platinum, most individual species cannot satisfy this requirement. Fe-B is an active HER catalyst with strong ability to adsorb H atoms. In our previous work, we found that when Fe-B alloy was decorated with metal Fe particles (Fe-B@Fe), the resultant composite displayed a significant synergic effect for HER compared to single Fe-B and Fe. The role of the decorated Fe on Fe-B is to improve H2 desorption. Because the desorption of H2 molecule from Ni is easier than from Fe, we expect Fe-B@Ni to be a more efficient HER catalyst than Fe-B@Fe. Herein, we transform Fe-B@Fe into Fe-B@Ni by a facile displacement reaction. As a proof of concept, the as-prepared Fe-B@Ni catalyst exhibits much higher electrocatalytic and photocatalytic activity for hydrogen production than the pristine Fe-B@Fe. At the current density of -100 mA cm-2, the overpotential of Fe-B@Ni in 1.0 mol L-1 KOH is close to that of 20 wt% Pt/C. The highest apparent quantum yield (AQY) for dye-sensitized photocatalytic hydrogen evolution reaches 51% at 420 nm. The possible mechanisms have been proposed. These findings provide new insights for designing and fabricating new HER composite catalysts for electrocatalytic and photocatalytic hydrogen evolution.

Interactive effects of pH and aluminum on the secretion of organic acid anions by roots and related metabolic factors in Citrus sinensis roots and leaves.

Low pH and aluminum (Al)-toxicity often coexist in acidic soils. Citrus sinensis seedlings were treated with nutrient solution at a pH of 2.5, 3.0, 3.5 or 4.0 and an Al concentration of 0 or 1 mM for 18 weeks. Thereafter, malate, citrate, isocitrate, acid-metabolizing enzymes, and nonstructural carbohydrates in roots and leaves, and release of malate and citrate from roots were measured. Al concentration in roots and leaves increased under Al-toxicity, but it declined with elevating nutrient solution pH. Al-toxicity increased the levels of glucose, fructose, sucrose and total soluble sugars in leaves and roots at each given pH except for a similar sucrose level at pH 2.5-3.0, but it reduced or did not alter the levels of starch and total nonstructural carbohydrates (TNC) in leaves and roots with the exception that Al improved TNC level in roots at pH 4.0. Levels of nonstructural carbohydrates in roots and leaves rose with reducing pH with a few exceptions with or without Al-toxicity. A potential model for the possible role of root organic acid (OA) metabolism (anions) in C. sinensis Al-tolerance was proposed. With Al-toxicity, the elevated pH upregulated the OA metabolism, and increased the flow of carbon to OA metabolism, and the accumulation of malate and citrate in roots and subsequent release of them, thus reducing root and leaf Al and hence eliminating Al-toxicity. Without Al-toxicity, low pH stimulated the exudation of malate and citrate, an adaptive response of Citrus to low pH. The interactive effects of pH and pH on OA metabolism were different between roots and leaves.

INPP4B exerts a dual function in the stemness of colorectal cancer stem-like cells through regulating Sox2 and Nanog expression.

Inositol polyphosphate 4-phosphatase type II (INPP4B), a lipid phosphatase, was identified as a negative regulator of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in several cancers. The expression and biological function of INPP4B in human colorectal cancer (CRC) are controversial, while the role and molecular mechanism of INPP4B in colorectal cancer stem-like cells (CR-CSLCs) remains unclear. Here, we observed that INPP4B expression was markedly decreased in primary non-metastatic CR-CSLCs and increased in highly metastatic CR-CSLCs compared with corresponding control non-CSLCs. INPP4B overexpression inhibited self-renewal, and chemoresistance of primary non-metastatic CR-CSLCs, but exerted the opposite roles in highly metastatic CR-CSLCs in vitro. Similarly, INPP4B knockdown had dual functions in the self-renewal and chemoresistance of different CR-CSLCs. In addition, we demonstrated that INPP4B overexpression suppressed the tumorigenicity of primary non-metastatic CR-CSLCs while induced the tumorigenicity of highly metastatic CR-CSLCs in nude mice. Furthermore, INPP4B was found to modulate the stemness of CR-CSLCs by regulating Sox2 and Nanog expression, which was dependent on PI3K/PTEN/Akt signaling. In conclusion, our results highlight an important role of INPP4B in the stemness of CR-CSLCs for the first time and emphasize INPP4B as a dual therapeutic target for suppressing primary cancer cell proliferation and for preventing metastasis in CRC patients.

Increasing Nutrient Solution pH Alleviated Aluminum-Induced Inhibition of Growth and Impairment of Photosynthetic Electron Transport Chain in Citrus sinensis Seedlings.

Although the physiological and molecular responses of Citrus to Al-toxicity or low pH have been examined in some details, little information is available on Citrus responses to pH and aluminum (Al) interactions. Citrus sinensis seedlings were irrigated for 18 weeks with nutrient solution at a concentration of 0 or 1 mM AlCl3•6H2O and a pH of 2.5, 3.0, 3.5, or 4.0. Thereafter, biomass, root, stem, and leaf concentrations of Al and nutrients, leaf gas exchange, chlorophyll a fluorescence (OJIP) transients, and related parameters were investigated to understand the physiological mechanisms underlying the elevated pH-induced alleviation of Citrus toxicity. Increasing the nutrient solution pH from 2.5 to 4.0 alleviated the Al-toxic effects on biomass, photosynthesis, OJIP transients and related parameters, and element concentrations, uptake, and distributions. In addition, low pH effects on the above physiological parameters were intensified by Al-toxicity. Evidently, a synergism existed between low pH and Al-toxicity. Increasing pH decreased Al uptake per root dry weight and its concentration in roots, stems, and leaves and increased nitrogen, phosphorus, calcium, magnesium, sulfur, and boron uptake per plant and their concentrations in roots, stems, and leaves. This might be responsible for the elevated pH-induced alleviation of growth inhibition and the impairment of the whole photosynthetic electron transport chain, thus preventing the decrease of CO2 assimilation.

INPP4B inhibits cell proliferation, invasion and chemoresistance in human hepatocellular carcinoma.

Background: Inositol polyphosphate 4-phosphatase type II (INPP4B) has been identified as a negative regulator of phosphatidyl inositol 3-kinase (PI3K)/Akt signaling in human several cancers. However, the expression, clinical significance and biological function of INPP4B in human hepatocellular carcinoma (HCC) clinical tissues and cell lines are little known. Materials and methods: We evaluated the expression of INPP4B in 86 cases of paired human HCC samples by immunohistochemistry, and the clinical significance of INPP4B expression was analyzed. The expression of INPP4B in five HCC cell lines was detected through using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analyses. The role of INPP4B gene on HCC cell proliferation, apoptosis, migration, invasion as well as epithelial-to-mesenchymal transition (EMT) and chemoresistance was examined via INPP4B mammalian expression vector and small interfering RNA (siRNA) transfection in vitro. Western blot analysis was used to explore the downstream molecules modulated by INPP4B. Results: Immunohistochemistry analysis revealed that INPP4B was significantly downregulated in HCC tissues compared with the corresponding normal tissues. The rate of INPP4B-positive staining was markedly lower in metastatic samples than in those of non-metastatic samples. Univariate analysis showed that INPP4B expression was indicated to have a marked association with histological grades, tumor size and tumor metastasis. Moreover, INPP4B overexpression suppressed cell proliferation, migration, invasion and EMT, but induced cell apoptosis and chemosensitivity in human HCC cell lines. In contrast, INPP4B knockdown had the opposite effects on the biological behaviors of HCC cells. Furthermore, INPP4B was found to inhibit the activation of PI3K/Akt signaling in HCC cells. Conclusion: Our findings suggest that INPP4B is a tumor suppressing gene in human HCC, and might act as a novel therapeutic target for HCC patients.

Aluminum effects on photosynthesis, reactive oxygen species and methylglyoxal detoxification in two Citrus species differing in aluminum tolerance.

Citrus are mainly grown in low pH soils with high active aluminum (Al). 'Xuegan' (Citrus sinensis (L.) Osbeck) and 'Shatian pummelo' (Citrus grandis (L.) Osbeck) seedlings were fertilized for 18 weeks with nutrient solution containing either 0 mM (control) or 1 mM (Al toxicity) AlCl3·6H2O. Aluminum induced decreases of biomass, leaf photosynthesis, relative water content and total soluble protein levels, and increases of methylglyoxal levels only occurred in C. grandis roots and leaves. Besides, the Al-induced decreases of pigments and alterations of chlorophyll a fluorescence transients and fluorescence parameters were greater in C. grandis leaves than those in C. sinensis leaves. Aluminum-treated C. grandis had higher stem and leaf Al levels and similar root Al levels relative to Al-treated C. sinensis, but lower Al distribution in roots and Al uptake per plant. Aluminum toxicity decreased nitrogen, phosphorus, potassium, calcium, magnesium and sulfur uptake per plant in C. grandis and C. sinensis seedlings, with the exception of Al-treated C. sinensis seedlings exhibiting increased sulfur uptake per plant and unaltered magnesium uptake per plant. Under Al-stress, macroelement uptake per plant was higher in C. sinensis than that in C. grandis. Aluminum toxicity decreased the ratios of reduced glutathione/(reduced + oxidized glutathione) and of ascorbate/(ascorbate + dehydroascorbate) only in C. grandis roots and leaves. The activities of most antioxidant enzymes, sulfur metabolism-related enzymes and glyoxalases and the levels of S-containing compounds were higher in Al-treated C. sinensis roots and leaves than those in Al-treated C. grandis ones. Thus, C. sinensis displayed higher Al tolerance than C. grandis did. The higher Al tolerance of C. sinensis might involve: (i) more Al accumulation in roots and less transport of Al from roots to shoots; (ii) efficient maintenance of nutrient homeostasis; and (iii) efficient maintenance of redox homeostasis via detoxification systems of reactive oxygen species and methylglyoxal.

Combined application of anti-VEGF and anti-EGFR attenuates the growth and angiogenesis of colorectal cancer mainly through suppressing AKT and ERK signaling in mice model.

BACKGROUND: Angiogenesis is generally involved during the cancer development and hematogenous metastasis. Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) are considered to have an important role in tumor-associated angiogenesis. However, the effects of simultaneously targeting on VEGF and EGFR on the growth and angiogenesis of colorectal cancer (CRC), and its underlying mechanisms remain unknown. METHODS: Immunohistochemical staining was used to detect the VEGF and EGFR expression in different CRC tissue specimens, and the correlation between VEGF/EGFR expression with the clinicopathologic features was analyzed. Cell counting kit­8 (CCK-8) and transwell assays were used to assess the cellular proliferation and invasion of CRC cells after treated with anti-VEGF antibody and/or anti-EGFR antibody in vitro, respectively. Moreover, in vivo tumor formation was performed on nude mice model, and the tumor microvessel density (MVD) was determined by anti-CD34 staining in different groups. Finally, we evaluated the impact of anti-VEGF antibody and/or anti-EGFR antibody on the activation of downstream signaling effectors using western blot. RESULTS: VEGF and EGFR were upregulated in CRC tissues, and their expression levels were correlated with hepatic metastasis. Blockage on VEGF or EGFR alone could inhibit the cellular proliferation and metastasis while their combination could reach a good synergism in vitro. In addition, in vivo xenograft mice model demonstrated that the tumor formation and angiogenesis were strongly suppressed by combination treatment of anti-VEGF and anti-EGFR antibodies. Besides, the combination treatment significantly reduced the activation of AKT and ERK1/2, but barely affected the activation of c-Myc, NF-κB/p65 and IκBα in CRC cells tumors. Interestingly, anti-VEGF antibody or anti-EGFR antibody alone could attenuate the phosphorylation of STAT3 as compared with negative control group, whereas the combined application not further suppressed but at least partially restored the activation of STAT3 in vivo. CONCLUSIONS: Simultaneous targeting on VEGF and EGFR does show significant inhibition on CRC tumor growth and angiogenesis in mice model, and these effects are mainly attributed to suppression of the AKT and ERK signaling pathways.