SALL4 correlates with proliferation, metastasis, and poor prognosis in prostate cancer by affecting MAPK pathway.

BACKGROUND: The mechanism involved in prostate cancer (PCa) metastasis is still poorly understood, and several oncogenes are known to regulate this process. However, the role of spalt-like transcription factor 4 (SALL4) in PCa metastasis remains unclear. METHODS: We performed RNA-sequencing to compare the mRNA expression profiles of seven localized PCa tissues and six metastatic PCa tissues. SALL4 was then identified and compared in the localized PCa and metastatic PCa. Immunohistochemical studies, qRT-PCR, and Western blot were performed to analyze the expression of SALL4 in PCa patients and cell lines. SALL4 expression and its relevance to clinical traits and prognosis were further explored in the TCGA database and in our 68 clinical samples. Subsequently, we knocked down SALL4 in DU145 and PC3 cells and performed a series of functional assays to explore the effect of SALL4 on PCa progression. Finally, protein levels of SALL4 and core components of the MAPK pathway were measured by Western blot, and cells were treated with PD0325901 to observe proliferation and metastasis. RESULTS: Significantly higher expression of SALL4 was found in metastatic PCa than in localized PCa. In addition, high SALL4 expression was significantly associated with high pathological T stage, N stage, Gleason score, and poor disease-free survival in TCGA database and in our clinical samples. Functional studies indicated that knockdown of SALL4 in DU145 and PC3 inhibited proliferation, migration, and angiogenesis. Furthermore, the ERK and P38 protein phosphorylation significantly reduced after knockdown of SALL4 in DU145 and PC3, indicating the inactivation of the MAPK signaling pathway. Finally, the proliferation and migration ability of DU145 and PC3 cells were significantly decreased after PD0325901 treatment. CONCLUSIONS: SALL4 predicts unfavorable outcome and is closely associated with PCa progression, suggesting that SALL4 may be a promising prognostic marker and potential therapeutic target for PCa.

Atomic vibration as an indicator of the propensity for configurational rearrangements in metallic glasses.

In a metallic glass (MG), the propensity for atomic rearrangements varies spatially from location to location in the amorphous solid, making the prediction of their likelihood a major challenge. One can attack this problem from the "structure controls properties" standpoint. But all the current structure-centric parameters are mostly based on local atomic packing information limited to short-range order, hence falling short in reliably forecasting how the local region would respond to external stimuli (e.g., temperature and/or stress). Alternatively, one can use indicators informed by physical properties to bridge the static structure on the one hand, and the response of the local configuration on the other. A sub-group of such physics-informed quantities consists of atomic vibration parameters, which will be singled out as the focus of this article. Here we use the Cu64Zr36 alloy to systematically demonstrate the following two points, all using a single model MG. First, we show in a comprehensive manner the interrelation among common vibrational parameters characterizing the atomic vibrational amplitude and frequency, including the atomic mean square displacement, flexibility volume, participation fraction in the low-frequency vibrational modes and boson peak intensity. Second, we demonstrate that these vibrational parameters fare much better than purely static structural parameters based on local geometrical packing in providing correlation with the propensity for local configurational transitions. These vibrational parameters also share a correlation length similar to that in structural rearrangements induced by external stimuli. This success, however, also poses a challenge, as it remains to be elucidated as to why short-time dynamical (vibrational) behavior at the bottom of the energy basin can be exploited to project the height of the energy barrier for cross-basin activities and in turn the propensity for locally collective atomic rearrangements.

Substantially enhanced plasticity of bulk metallic glasses by densifying local atomic packing.

Introducing regions of looser atomic packing in bulk metallic glasses (BMGs) was reported to facilitate plastic deformation, rendering BMGs more ductile at room temperature. Here, we present a different alloy design approach, namely, doping the nonmetallic elements to form densely packed motifs. The enhanced structural fluctuations in Ti-, Zr- and Cu-based BMG systems leads to improved strength and renders these solutes' atomic neighborhoods more prone to plastic deformation at an increased critical stress. As a result, we simultaneously increased the compressive plasticity (from ∼8% to unfractured), strength (from ∼1725 to 1925 MPa) and toughness (from 87 ± 10 to 165 ± 15 MPa√m), as exemplarily demonstrated for the Zr20Cu20Hf20Ti20Ni20 BMG. Our study advances the understanding of the atomic-scale origin of structure-property relationships in amorphous solids and provides a new strategy for ductilizing BMG without sacrificing strength.

GADD45B Is a Potential Diagnostic and Therapeutic Target Gene in Chemotherapy-Resistant Prostate Cancer.

BACKGROUND: Chemoresistance is the major cause of death in advanced prostate cancer (PCa), especially in metastatic PCa (mPCa). However, the molecular mechanisms underlying the chemoresistance of PCa remain unclear. Understanding the reason behind the drug resistance would be helpful in developing new treatment approaches. METHODS: The Cancer Genome Atlas, Gene Expression Omnibus datasets, and clinical samples were used to examine the correlation between growth arrest and DNA damage-inducible 45 beta (GADD45B) with clinical characteristics and prognosis. Lentiviral transfection was used to construct GADD45B overexpression cell lines. Hypoxic incubator, low serum medium, or docetaxel was used to build environmental stress model or chemotherapy cell model. The MTS assay and colony formation assay were used to test cell viability. Apoptosis and cell cycle were detected by flow cytometry. The RNA and protein levels of related biomarkers were tested by Western blotting and quantitative polymerase chain reaction. Bioinformatics analysis after RNA sequencing was performed to identify the possible mechanism of how GADD45B regulates chemotherapy resistance. RESULTS: GADD45B was related to distant metastasis but not to Gleason score, prostate-specific antigen level, T stage, or lymph node metastasis and indicated a good prognosis. The level of GADD45B increased significantly in PCa cells that faced environmental stress. It was found that a high level of GADD45B significantly enhanced the chemosensitivity. Furthermore, high GADD45B promoted cell apoptosis via mitogen-activated protein kinase (MAPK) pathway. CONCLUSION: GADD45B promoted chemosensitivity of prostate cancer through MAPK pathway. GADD45B could serve as a diagnostic biomarker and therapeutic target for mPCa or chemotherapy-resistant patients.

Oxidative stress response mechanism of Scenedesmus obliquus to ionic liquids with different number of methyl-substituents.

Ionic liquids (ILs) have become persistent contaminants in water because of their good solubility and low biodegradability. The oxidative stress responses of Scenedesmus obliquus to three imidazole ILs with different number of methyl-substituents, i.e., 1-decyl-imidazolium chloride ([C10IM]Cl), 1-decyl-3-methylimidazolium chloride ([C10MIM]Cl), and 1-decyl-2,3-dimethylimidazolium chloride ([C10DMIM]Cl), were studied. There was a positive correlation between ROS level and IL concentration. The activities of antioxidant enzymes, i.e., superoxide dismutase, catalase, peroxidase, ascorbate peroxidase, and glutathione peroxidase, and the content of antioxidants, i.e., ascorbic acid and glutathione, changed in IL treatment with a concentration-dependent effect. Proline accumulation increased with increasing IL concentration. Integrated biomarker response (IBR) index analysis, based on the eight oxidative stress response indicators, revealed that the toxicity order was: [C10IM]Cl < [C10DMIM]Cl < [C10MIM]Cl. Proteomic analysis showed that IL affect the type and distribution of proteins in S. obliquus. Chloroplast and photosystem II were affected as cellular component, and the proteins related to oxidative stress are annotated in GO categories. IBR index and proteomic analysis indicate that oxidative stress response is one of the main biomarkers of IL stress.

Effect of differently methyl-substituted ionic liquids on Scenedesmus obliquus growth, photosynthesis, respiration, and ultrastructure.

Concerns have been raised regarding the ecotoxicity of ionic liquids (ILs) owing to their wide usage in numerous fields. Three imidazolium chloride ILs with different numbers of methyl substituents, 1-decyl-imidazolium chloride ([C10IM]Cl), 1-decyl-3-methylimidazolium chloride ([C10MIM]Cl), and 1-decyl-2,3-dimethylimidazolium chloride ([C10DMIM]Cl), were examined to assess their effects on growth, photosynthesis pigments content, chlorophyll fluorescence, photosynthetic and respiration rate, and cellular ultrastructure of Scenedesmus obliquus. The results showed that algal growth was significantly inhibited by ILs treatments. The observed IC50,48h doses were 0.10 mg/L [C10IM]Cl, 0.01 mg/L [C10MIM]Cl, and 0.02 mg/L [C10DMIM]Cl. The chlorophyll a, chlorophyll b, and total chlorophyll content declined, and the chlorophyll fluorescence parameters, minimal fluorescence yield (F0), maximal fluorescence yield (Fm), maximum quantum yield of PSII photochemistry (Fv/Fm), effective quantum yield of PSII [Y(II)], non-photochemical quenching (NPQ) and non-photosynthetic losses yield [Y(NO)] were notably affected by ILs in a dose-dependent manner. ILs affected the primary photosynthetic reaction, impaired heat dissipation capability, and diminished photosynthetic efficiency, indicating negative effects on photosystem II. The photosynthetic and respiration rates of algal cells were also reduced due to the ILs treatments. The adverse effects of ILs on plasmolysis and chloroplast deformation were examined using ultrastructural analyses; chloroplast swelling and lamellar structure almost disappeared after the [C10MIM]Cl treatment, and an increased number of starch grains and vacuoles was observed after all ILs treatments. The results indicated that one-methyl-substituted ILs were more toxic than non-methyl-substituted ILs, which were also more toxic than di-methyl-substituted ILs. The toxicity of the examined ILs showed the following order: [C10IM]Cl < [C10DMIM]Cl ≤ [C10MIM]Cl.

Growth inhibition and oxidative stress caused by four ionic liquids in Scenedesmus obliquus: Role of cations and anions.

Ionic liquids (ILs) are widely used in various industrial applications. However, they are considered potential toxins in aquatic environments because of their physical stability and solubility. The growth inhibition and oxidative stress induced by four ionic liquids with different cations and anions on the green algae Scenedesmus obliquus was investigated in this study. The order of growth inhibition was 1­hexyl­3­methylimidazolium nitrate ([HMIM]NO3) > 1­hexyl­3­methylimidazolium chloride ([HMIM]Cl) > N­hexyl­3­metylpyridinium bromide ([HMPy]Br) > N­hexyl­3­metylpyridinium chloride ([HMPy]Cl). Imidazolium IL had a higher growth inhibition effect than pyridinium IL, nitrate IL and bromide IL had a higher effect than chloride IL. Reactive oxygen species (ROS) level in S. obliquus increased with increasing IL concentrations. Green fluorescence in [HMIM]Cl treated algae showed increased brightness compared to the [HMPy]Cl treatment, and [HMIM]NO3 treatment produced increased brightness compared to the [HMPy]Br treatment, suggesting that higher ROS levels were induced by [HMIM]Cl and [HMIM]NO3. Soluble protein, catalase (CAT), and superoxide dismutase (SOD) activities were stimulated at lower concentrations but were inhibited at higher concentrations. Regression analysis suggested that ROS level is the main index responsible for oxidative stress induced by the four ILs. The ILs induced oxidative damage on S. obliquus, and ROS in high concentration treatments could not be effectively removed by the antioxidant system, leading to oxidative damage and ultimately resulting in growth inhibition and cell death.

Effect of imidazolium-based ionic liquids with varying carbon chain lengths on Arabidopsis thaliana: Response of growth and photosynthetic fluorescence parameters.

As green and novel solvents, ionic liquids (ILs) are popular in many industries, which may threaten ecosystems. The effects of three imidazolium-based ILs with different alkyl chain lengths, including 1-octyl-3-methylimidazolium chloride ([C8mim]Cl), 1-decyl-3-methylimidazolium chloride ([C10mim]Cl), and 1-dodecyl-3-methylimidazolium chloride ([C12mim]Cl) on growth and photosystem of Arabidopsis thaliana were investigated. Root length, fresh weight, cell membrane permeability, and chlorophyll content of whole plant were significantly affected by ILs. Vein clearing, leaf chlorosis, and browning on the A. thaliana leaf abaxial surface occurred, with a dose-response relationship. The effect of ILs on whole plant increased with alkyl chain lengths. Chlorophyll fluorescence parameters of photosynthetic system II (PSII) were all affected in [C8mim]Cl and [C10mim]Cl treatments, electron-transfer was blocked, and photochemical energy conversion was damaged. There were no significant changes in chlorophyll fluorescence of newly-growing leaves in [C12mim]Cl treatment, but has severe effect on aged leaves. The number and size of starch granules and osmiophilic globules increased, plasmolysis and the chloroplast swelling occurred in [C8mim]Cl, [C10mim]Cl treatments and on aged leaves in [C12mim]Cl treatment, but no significant damages occurred on newly-growing leaves of [C12mim]Cl treatment, perhaps due to plant self-protection of plant. The results indicating the appropriate use of ILs is needed.