How does the biochar-supported sulfidized nanoscale zero-valent iron affect the soil environment and microorganisms while remediating cadmium contaminated paddy soil?

In previous studies, iron-based nanomaterials, especially biochar (BC)-supported sulfidized nanoscale zero-valent iron (S-nZVI/BC), have been widely used for the remediation of soil contaminants. However, its potential risks to the soil ecological environment are still unknown. This study aims to explore the effects of 3% added S-nZVI/BC on soil environment and microorganisms during the remediation of Cd contaminated yellow-brown soil of paddy field. The results showed that after 49 d of incubation, S-nZVI/BC significantly reduced physiologically based extraction test (PBET) extractable Cd concentration (P < 0.05), and increased the immobilization efficiency of Cd by 16.51% and 17.43% compared with S-nZVI and nZVI/BC alone, respectively. Meanwhile, the application of S-nZVI/BC significantly increased soil urease and sucrase activities by 0.153 and 0.446 times, respectively (P < 0.05), improving the soil environmental quality and promoting the soil nitrogen cycle and carbon cycle. The results from the analysis of the 16S rRNA genes indicated that S-nZVI/BC treatment had a minimal effect on the bacterial community and did not appreciably alter the species of the original dominant bacterial phylum. Importantly, compared to other iron-based nanomaterials, incorporating S-nZVI/BC significantly increased the soil organic carbon (OC) content and decreased the excessive release of iron (P < 0.05). This study also found a significant negative correlation between OC content and Fe(II) content (P < 0.05). It might originate from the reducing effect of Fe-reducing bacteria, which consumed OC to promote the reduction of Fe(III). Accompanying this process, the redistribution of Cd and Fe mineral phases in the soil as well as the generation of secondary Fe(II) minerals facilitated Cd immobilization. Overall, S-nZVI/BC could effectively reduce the bioavailability of Cd, increase soil nutrients and enzyme activities, with less toxic impacts on the soil microorganisms.

Targeting transforming growth factor beta signaling in metastatic osteosarcoma.

Osteosarcoma is a rare type of bone cancer, and half of the cases affect children and adolescents younger than 20 years of age. Despite intensive efforts to improve both chemotherapeutics and surgical management, the clinical outcome for metastatic osteosarcoma remains poor. Transforming growth factor ß (TGF-ß) is one of the most abundant growth factors in bones. The TGF-ß signaling pathway has complex and contradictory roles in the pathogenesis of human cancers. TGF-ß is primarily a tumor suppressor that inhibits proliferation and induces apoptosis of premalignant epithelial cells. In the later stages of cancer progression, however, TGF-ß functions as a metastasis promoter by promoting tumor growth, inducing epithelial-mesenchymal transition (EMT), blocking antitumor immune responses, increasing tumor-associated fibrosis, and enhancing angiogenesis. In contrast with the dual effects of TGF-ß on carcinoma (epithelial origin) progression, TGF-ß seems to mainly have a pro-tumoral effect on sarcomas including osteosarcoma (mesenchymal origin). Many drugs that target TGF-ß signaling have been developed: neutralizing antibodies that prevent TGF-ß binding to receptor complexes; ligand trap employing recombinant Fc-fusion proteins containing the soluble ectodomain of either type II (TßRII) or the type III receptor ((TßRIII), preventing TGF-ß from binding to its receptors; antisense nucleotides that reduce TGF-ß expression at the transcriptional/translational level; small molecule inhibitors of serine/threonine kinases of the type I receptor (TßRI) preventing downstream signaling; and vaccines that contain cell lines transfected with TßRII antisense genes, or target furin convertase, resulting in reduced TGF-ß signaling. TGF-ß antagonists have been shown to have effects on osteosarcoma in vitro and in vivo. One of the small molecule TßRI inhibitors, Vactosertib, is currently undergoing a phase 1/2 clinical trial to evaluate its effect on osteosarcoma. Several phase 1/2/3 clinical trials have shown TGF-ß antagonists are safe and well tolerated. For instance, Luspatercept, a TGF-ß ligand trap, has been approved by the FDA for the treatment of anemia associated with myeloid dysplastic syndrome (MDS) with ring sideroblasts/mutated SF3B1 with acceptable safety. Clinical trials evaluating the long-term safety of Luspatercept are in process.

Platelet rich plasma versus glucocorticoid for plantar fasciitis: A protocol for systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Plantar fasciitis (PF) is the most common cause of heel pain in adult. There are a variety of ways to treat PF, but these treatments have varied result in their effectiveness, and exist different degrees of limitations. At present, clinical studies focus on the effect of glucocorticoid (GC) and platelet rich plasma (PRP) in the treatment of PF, but there is a lack of systematic evaluation PRP and GC's clinical effect towards PF. This study aims to evaluate the long-term efficacy of GCs and PRP in the treatment of PF by means of meta-analysis. METHODS: The literature of a randomized controlled clinical trial of PRP in the treatment of plantantifasciitis was searched on the Internet. Retrieve 7 databases. EndNote X9 software was used for document management. The Jadad scale was used to score the literature. Risk assessment of the literature was conducted according to Cochrane's systematic evaluation manual 5.0. RevMan5.3 software was used for literature risk bias analysis. Stata12.0 software is used for sensitivity analysis. RESULTS: This study will provide effective evidence-based evidence for the long-term efficacy of PRP and GC in treating PF. CONCLUSION: A systematic review and meta-analysis were conducted for the comparison of the long-term effect of PRP and GC on plantar fascia in the treatment of PF.

Characterization and source identification of PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) in different seasons from Shanghai, China.

PM2.5 samples in four representative periods were collected from a highly industrialized district in Shanghai, China. The concentrations of PM2.5 and PM2.5-bound PAHs were analyzed. Positive matrix factorization (PMF) model was used to identify the potential sources. Relationship between PAHs distribution and meteorological parameters was assessed meanwhile. The incremental lifetime cancer risks (ILCRs) model was applied to quantitatively evaluate the exposure risk of PAHs. Hybrid Single Particle Lagrangian Integrated Trajectory (HYSPLT) model was used to track the potential pollution area of PM2.5 along with a Potential Source Contribution Function (PSCF) and Concentration Weighted Trajectory (CWT) methods. The results showed concentrations of PM2.5 and PAHs ranged from 14.83 to 185.58 µg/m3, 2.58 to 123.62 ng/m3, respectively. The source apportionment model indicated that traffic emissions were the most important sources in each sampling season, which accounted for 38.44%, 34.48%, 39.04% and 45.03%, respectively. Spearman correlation coefficient showed that PAHs had negative correlation with ambient temperature and relative humidity in some periods, while had no significant correlation with atmospheric pressure and visibility. The average estimated lifetime cancer risk for total PAHs reached 4.7 × 10-5, 4.5 × 10-5 and 4.1 × 10-5, 4.0 × 10-5 to exposed children and adults in winter and autumn, respectively, meaning that PM2.5-bound PAHs had high potential risk. HYSPLIT model suggested that monsoon greatly influenced the air quality in both winter and autumn.

Induction of hypoxia-inducible factor-1α by BDNF protects retinoblastoma cells against chemotherapy-induced apoptosis.

Alternations of environment signals such as neurotrophins may be the basis for malignant transformation of retinoblastoma (Rb), the most common primary intraocular malignancy in children. The aim of this study is to investigate the ability of brain-derived neurotrophic factor (BDNF) to decrease the chemosensitivity of Rb cells to the common chemotherapeutic agents and to explore the role of hypoxia-inducible factor-1α (HIF-1α) in such cellular process. The results showed that BDNF could induce higher expression of HIF-1α via activation of TrkB in human Y-79 retinoblastoma cells, which consequently contributed to its effect against chemotherapeutic agent-induced cytotoxicity and cell apoptosis. However, this protective effect could be potently reversed by knockdown of HIF-1α. Furthermore, BDNF strikingly prevented chemotherapeutic agent-induced alternations of apoptosis-related molecules, which could also be attenuated by silencing HIF-1α. Therefore, our findings demonstrated that BDNF could contribute to chemoresistance of Rb via modulation of HIF-1α expression, indicating that targeting at the BDNF-TrkB/HIF-1α signaling pathway might be a promising strategy for the treatment of retinoblastoma in the future.

Inhibition of hypoxia inducible factor 1α by siRNA-induced apoptosis in human retinoblastoma cells.

Hypoxia, which activates the hypoxia inducible factor 1α (HIF-1α), is an essential feature of retinoblastoma (RB) and contributes to poor prognosis and resistance to conventional therapy. In this study, the effect of HIF-1α knockdown by small interfering RNA (siRNA) on cell proliferation, apoptosis, and apoptotic pathways of human Y-79 RB cells was first investigated. Exposure to hypoxia induced the increased expression of HIF-1α both in mRNA and protein levels. Then, knockdown of HIF-1α by siRNAHIF-1α resulted in inhibition of cell proliferation and induced cell apoptosis in human Y-79 RB cells under both normoxic and hypoxic conditions, with hypoxic conditions being more sensitive. Furthermore, knockdown of HIF-1α could enhance hypoxia-induced slight increase of Bax/Bcl-2 ratio and activate caspase-9 and caspase-3. These results together indicated that suppression of HIF-1α expression may be a promising strategy for the treatment of human RB in the future.

Targeting the Transforming Growth Factor-beta pathway inhibits human basal-like breast cancer metastasis.

BACKGROUND: Transforming Growth Factor beta (TGF-beta) plays an important role in tumor invasion and metastasis. We set out to investigate the possible clinical utility of TGF-beta antagonists in a human metastatic basal-like breast cancer model. We examined the effects of two types of the TGF-beta pathway antagonists (1D11, a mouse monoclonal pan-TGF-beta neutralizing antibody and LY2109761, a chemical inhibitor of TGF-beta type I and II receptor kinases) on sublines of basal cell-like MDA-MB-231 human breast carcinoma cells that preferentially metastasize to lungs (4175TR, 4173) or bones (SCP2TR, SCP25TR, 2860TR, 3847TR). RESULTS: Both 1D11 and LY2109761 effectively blocked TGF-beta-induced phosphorylation of receptor-associated Smads in all MDA-MB-231 subclones in vitro. Moreover, both antagonists inhibited TGF-beta stimulated in vitro migration and invasiveness of MDA-MB-231 subclones, indicating that these processes are partly driven by TGF-beta. In addition, both antagonists significantly reduced the metastatic burden to either lungs or bones in vivo, seemingly independently of intrinsic differences between the individual tumor cell clones. Besides inhibiting metastasis in a tumor cell autonomous manner, the TGF-beta antagonists inhibited angiogenesis associated with lung metastases and osteoclast number and activity associated with lytic bone metastases. In aggregate, these studies support the notion that TGF-beta plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-beta signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-beta pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer. CONCLUSIONS: In aggregate, these studies support the notion that TGF-beta plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-beta signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-beta pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer.

Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-beta type I receptor kinase in vivo.

PURPOSE: Transforming growth factor-beta (TGF-beta) suppresses tumor development by inhibiting cellular proliferation, inducing differentiation and apoptosis, and maintaining genomic integrity. However, once tumor cells escape from the tumor-suppressive effects of TGF-beta, they often constitutively overexpress and activate TGF-beta, which may promote tumor progression by enhancing invasion, metastasis, and angiogenesis and by suppressing antitumor immunity. The purpose of this study was to test this hypothesis using TGF-beta pathway antagonists. EXPERIMENTAL DESIGN: We examined the effects of selective TGF-beta type I receptor kinase inhibitors, SD-093 and SD-208, on two murine mammary carcinoma cell lines (R3T and 4T1) in vitro and in vivo. RESULTS: Both agents blocked TGF-beta-induced phosphorylation of the receptor-associated Smads, Smad2 and Smad3, in a dose-dependent manner, with IC50 between 20 and 80 nmol/L. TGF-beta failed to inhibit growth of these cell lines but stimulated epithelial-to-mesenchymal transdifferentiation, migration, and invasiveness into Matrigel in vitro. These effects were inhibited by SD-093, indicating that these processes are partly driven by TGF-beta. Treatment of syngeneic R3T or 4T1 tumor-bearing mice with orally given SD-208 inhibited primary tumor growth as well as the number and size of metastases. In contrast, SD-208 failed to inhibit R3T tumor growth or metastasis in athymic nude mice. Moreover, in vitro anti-4T1 cell cytotoxic T-cell responses of splenocytes from drug-treated animals were enhanced compared with cells from control animals. In addition, SD-208 treatment resulted in a decrease in tumor angiogenesis. CONCLUSION: TGF-beta type I receptor kinase inhibitors hold promise as novel therapeutic agents for metastatic breast cancer.

A novel vitamin D derivative activates bone morphogenetic protein signaling in MCF10 breast epithelial cells.

We investigated the action of 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], a novel Gemini vitamin D(3) analog Ro-438-3582 [1alpha,25-dihydroxy-20S-21(3-hydroxy-3-methyl-butyl)-23-yne-26,27-hexafluorocholecalciferol (Ro3582)], and a classic vitamin D(3) analog Ro-26-2198 [1alpha,25-dihydroxy-16,23(Z)-diene-26,27-hexafluoro-19-nor-cholecalciferol (Ro2198)] in modulating the transforming growth factor-beta (TGF-beta)/bone morphogenetic protein (BMP) system in MCF10 immortalized breast epithelial cells. We found that 1alpha,25(OH)(2)D(3), Ro3582, and Ro2198 all enhanced BMP/Smad signaling by increasing the phosphorylation of receptor-regulated Smads. Ro3582 was more active than Ro2198, but both were considerably more active than 1alpha,25(OH)(2)D(3.) Ro3582 enhanced BMP/Smad signaling by 1) inducing the phosphorylation of receptor-regulated Smads (Smad1/5), 2) increasing the accumulation of phosphorylated Smad1/5 in the nucleus, and 3) activating BMP-mediated transcription in MCF10 breast epithelial cells. Furthermore, Ro3582 induced the synthesis of BMP-2 and BMP-6 mRNA and protein, and the expression of Smad6 mRNA in MCF10 breast epithelial cells was inhibited by Ro3582. The induction of phospho-Smad1/5 by Ro3582 was inhibited by treatment with the BMP antagonist Noggin, whereas neutralizing antibody to TGF-beta did not block the induction of phospho-Smad1/5 by Ro3582. Treatment with Noggin also blocked the effect of Ro3582 on nuclear accumulation of phospho-Smad1/5 and the induction of BMP-2 and BMP-6 mRNA synthesis. These results indicate that the activation of BMP/Smad signaling by the Gemini vitamin D(3) analog Ro3582 may be through the production of BMP ligands, including BMP-2 and BMP-6, and/or down-regulation of the inhibitory Smad6. This is the first report to show that 1alpha,25(OH)(2)D(3) and its derivatives activate BMP/Smad-specific signaling in human breast epithelial cells.

Selective inhibitors of type I receptor kinase block cellular transforming growth factor-beta signaling.

Transforming growth factor (TGFbeta) is a 25-kDa dimeric polypeptide that plays a key role in a variety of physiological processes and disease states. Blocking TGFbeta signaling represents a potentially powerful and conceptually novel approach to the treatment of disorders in which the signaling pathway is constitutively activated, such as cancer, chronic inflammation with fibrosis and select immune disorders. In this paper, we describe the biological properties of a novel series of quinazoline-derived inhibitors of the type I transforming growth factor receptor kinase (TbetaKIs) that bind to the ATP-binding site and keep the kinase in its inactive conformation. These compounds effectively inhibited TGFbeta-induced Smad2 phosphorylation in cultured cells in vitro with an IC(50) between 20 and 300 nM. Moreover, TbetaKIs were able to broadly block TGFbeta-induced reporter gene activation. Finally, TbetaKIs inhibited TGFbeta-mediated growth inhibition of normal murine mammary epithelial cells (NMuMG) and mink lung epithelial cells (Mv1Lu), and TGFbeta-induced epithelial-mesenchymal transdifferentiation (EMT) of NMuMG cells. Thus, these chemical TbetaKIs have the potential to be further developed as anti-cancer and -fibrosis agents. In addition, they represent valuable new tools for dissecting the biochemical mechanisms of TGFbeta signal transduction and understanding the role of TGFbeta signaling pathways in different physiological and disease processes.

Effect of peroxisome proliferators on the methylation and protein level of the c-myc protooncogene in B6C3F1 mice liver.

Peroxisome proliferators in general are nongenotoxic mouse liver carcinogens for which DNA hypomethylation and altered gene expression are proposed mechanisms. Therefore, the peroxisome proliferators 2,4-dichlorophenoxyacetic acid (2,4-D), dibutyl phthalate (DBP), gemfibrozil, and Wy-14,643 were evaluated for the ability to alter the methylation and expression of the c-myc protooncogene. Male B6C3F1 mice were administered for 6 days in their diet Wy-14,643 (5-500 ppm), 2,4-D (1,680 ppm), DBP (20,000 ppm), or gemfibrozil (8,000 ppm). All four peroxisome proliferators caused hypomethylation of the c-myc gene in the liver. Wy-14,643 appeared to be the most efficacious with a threshold between 10 and 50 ppm. The level of the c-myc protein was increased by Wy-14,643, but not the other peroxisome proliferators. When female B6C3F1 mice received a two-thirds partially hepatectomy and 16 h later were administered 50 mg/kg Wy-14,643 by gavage, hypomethylation of the gene occurred 24 h later. Hypomethylation was not found in mice that received Wy-14,643 following a sham operation. Hypomethylation of the c-myc gene within 24 h of administering Wy-14,643 after a partial hepatectomy but not after a sham operation supports the hypothesis that the peroxisome proliferators prevent methylation of hemimethylated sites formed by DNA replication.