Wrinkle Structure Regulating Electromagnetic Parameters in Constructed Core-shell ZnFe2O4@PPy Microspheres as Absorption Materials.

Structure engineering of magnetic-dielectric multi-components is emerging as an effective approach for presuming high-performance electromagnetic (EM) absorption, but still faces bottlenecks due to the ambiguous regulation mechanism of surface morphology. Here, a novel wrinkled surface structure is tailored on the ZnFe2O4 microsphere via a spray-pyrolysis induced Kirkendall diffusion effect, the conductivity of the sample is affected, and a better impedance matching is adjusted by modulating the concentration of metal nitrate precursors. Driven by a vapor phase polymerization, conductive polypyrrole (PPy) shell are in situ decorated on the ZnFe2O4 microsphere surfaces, ingeniously constructing a core-shell ZnFe2O4@PPy composites. Moreover, a systematic investigation reveals that this unique wrinkled surface structure is highly dependent on the metal salt concentration. Optimized wrinkle ZnFe2O4@PPy composite exhibits a minimum reflection loss (RLmin) reached -41.0 dB and the effective absorption bandwidth (EAB) can cover as wide as 4.1 GHz. The enhanced interfacial polarization originated from high-density ZnFe2O4-PPy heterostructure, and the conduction loss of PPy contributes to the boosted dielectric loss capability. This study gives a significant guidance for preparing high-performance EM composites by tailoring the surface wrinkle structure.

PARP1 negatively regulates transcription of BLM through its interaction with HSP90AB1 in prostate cancer.

BACKGROUND: Prostate cancer (PCa) is a prevalent malignant disease affecting a significant number of males globally. Elevated expression of the Bloom's syndrome protein (BLM) helicase has emerged as a promising cancer biomarker, being associated with the onset and progression of PCa. Nevertheless, the precise molecular mechanisms governing BLM regulation in PCa remain elusive. METHODS: The expression of BLM in human specimens was analyzed using immnohistochemistry (IHC). A 5'-biotin-labeled DNA probe containing the promoter region of BLM was synthesized to pull down BLM promoter-binding proteins. Functional studies were conducted using a range of assays, including CCK-8, EdU incorporation, clone formation, wound scratch, transwell migration, alkaline comet assay, xenograft mouse model, and H&E staining. Mechanistic studies were carried out using various techniques, including streptavidin-agarose-mediated DNA pull-down, mass spectrometry (MS), immunofluorescence (IF), dual luciferase reporter assay system, RT-qPCR, ChIP-qPCR, co-immunoprecipitation (co-IP), and western blot. RESULTS: The results revealed significant upregulation of BLM in human PCa tissues, and its overexpression was associated with an unfavorable prognosis in PCa patients. Increased BLM expression showed significant correlations with advanced clinical stage (P = 0.022) and Gleason grade (P = 0.006). In vitro experiments demonstrated that BLM knockdown exerted inhibitory effects on cell proliferation, clone formation, invasion, and migration. Furthermore, PARP1 (poly (ADP-ribose) polymerase 1) was identified as a BLM promoter-binding protein. Further investigations revealed that the downregulation of PARP1 led to increased BLM promoter activity and expression, while the overexpression of PARP1 exerted opposite effects. Through mechanistic studies, we elucidated that the interaction between PARP1 and HSP90AB1 (heat shock protein alpha family class B) enhanced the transcriptional regulation of BLM by counteracting the inhibitory influence of PARP1 on BLM. Furthermore, the combination treatment of olaparib with ML216 demonstrated enhanced inhibitory effects on cell proliferation, clone formation, invasion, and migration. It also induced more severe DNA damage in vitro and exhibited superior inhibitory effects on the proliferation of PC3 xenograft tumors in vivo. CONCLUSIONS: The results of this study underscore the significance of BLM overexpression as a prognostic biomarker for PCa, while also demonstrating the negative regulatory impact of PARP1 on BLM transcription. The concurrent targeting of BLM and PARP1 emerges as a promising therapeutic approach for PCa treatment, holding potential clinical significance.

BLM promotes malignancy in PCa by inducing KRAS expression and RhoA suppression via its interaction with HDGF and activation of MAPK/ERK pathway.

Prostate cancer (PCa) has long been the leading cause of cancer-associated deaths among male worldwide. Our previous studies have shown that Bloom syndrome protein (BLM) plays a vital role in PCa proliferation, yet the underlying molecular mechanism remains largely obscure. Mechanistically, BLM directly interacted with hepatoma-derived growth factor (HDGF). Functionally, BLM and HDGF knockdown resulted in the higher impairment of PC3 proliferation, clonogenicity, migration and invasion than that their counterpart with either BLM or HDGF knockdown exclusively. Of note, HDGF overexpression expedited, whereas its knockdown suppressed, PC3 proliferation, clonogenicity, migration and invasion. Additionally, the potentiation or attenuation was partially antagonized upon BLM depletion or overexpression. In line with the vitro data, the impact of BLM and HDGF on tumor growth was investigated in mouse xenograft models. ChIP-seq, dual-luciferase reporter and western blotting assays were employed to expound the regulatory network in PC3 cells. The results unveiled that HDGF activated KRAS and suppressed RhoA transcription, and that the function of HDGF was mediated, in part, by interaction with BLM. Accordingly, the MAPK/ERK pathway was activated. Moreover, the regulation of HDGF on KRAS and RhoA had a signal crosstalk. To recapitulate, BLM and HDGF may serve as novel prognostic markers and potential therapeutic targets in PCa.

Inhibition of NOS1 promotes the interferon response of melanoma cells.

BACKGROUND: NOS1 expression predicts poor prognosis in patients with melanoma. However, the molecular function of NOS1 in the type I IFN response and immune escape of melanoma is still unknown. METHODS: The CRISPR/Cas9 system was used to generate NOS1-knockout melanoma cells and the biological characteristics of NOS1-knockout cells were evaluated by MTT assay, clonogenic assay, EdU assay, and flow cytometric assay. The effect on tumor growth was tested in BALB/c-nu and C57BL/6 mouse models. The gene expression profiles were detected with Affymetrix microarray and RNA-seq and KEGG (Kyoto Encyclopedia of Genes and Genomes) and CLUE GO analysis was done. The clinical data and transcriptional profiles of melanoma patients from the public database TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus, GSE32611) were analyzed by Qlucore Omics Explorer. RESULTS: NOS1 deletion suppressed the proliferation of melanoma A375 cells in culture, blocked cell cycling at the G0/G1 phase, and decreased the tumor growth in lung metastasis nodes in a B16 melanoma xenograft mouse model. Moreover, NOS1 knockout increased the infiltration of CD3+ immune cells in tumors. The transcriptomics analysis identified 2203 differential expression genes (DEGs) after NOS1 deletion. These DEGs indicated that NOS1 deletion downregulated mostly metabolic functions but upregulated immune response pathways. After inhibiting with NOS1 inhibitor N-PLA, melanoma cells significantly increased the response to IFN[Formula: see text] by upregulation expression of IFN[Formula: see text] simulation genes (ISGs), especially the components in innate immune signaling, JAK-STAT, and TOLL-LIKE pathway. Furthermore, these NOS1-regulating immune genes (NOS1-ISGs) worked as a signature to predict poor overall survival and lower response to chemotherapy in melanoma patients. CONCLUSION: These findings provided a transcriptional evidence of NOS1 promotion on tumor growth, which is correlated with metabolic regulation and immune escape in melanoma cells.

Selection of appropriate post-harvest processing methods based on the metabolomics analysis of Salvia miltiorrhiza Bunge.

Post-harvest processing is a leading cause of metabolic changes and quality loss in food products. An untargeted metabolomics approach based on UHPLC-QTOF-MS was conducted to explain metabolic changes during post-harvest processing of Salvia miltiorrhiza. A rapid identification method was established for comprehensive characterization of 56 phenolic acids and 45 tanshinones. Enzymatic browning was found to be the primary factor impacting the metabolic profile. A decreasing in free phenolic acids along with increasing in bound polyphenols was observed correlated with the deepening of browning degree. The various substructures of bound polyphenols were explored to interpret the composition of browning-associated products. It has also been found that the steaming process and control of the moisture content during slicing can effectively reduce the influence of enzymatic browning. This metabolomics study will contribute to select the optimal post-harvest processing methods for S. miltiorrhiza and provide information for post-harvest processing of similar products.

The role of S-nitrosylation of PFKM in regulation of glycolysis in ovarian cancer cells.

One of the malignant transformation hallmarks is metabolism reprogramming, which plays a critical role in the biosynthetic needs of unchecked proliferation, abrogating cell death programs, and immunologic escape. However, the mechanism of the metabolic switch is not fully understood. Here, we found that the S-nitrosoproteomic profile of endogenous nitrogen oxide in ovarian cancer cells targeted multiple components in metabolism processes. Phosphofructokinase (PFKM), one of the most important regulatory enzymes of glycolysis, was S-nitrosylated by nitric oxide synthase NOS1 at Cys351. S-nitrosylation at Cys351 stabilized the tetramer of PFKM, leading to resist negative feedback of downstream metabolic intermediates. The PFKM-C351S mutation decreased the proliferation rate of cultured cancer cells, and reduced tumor growth and metastasis in the mouse xenograft model. These findings indicated that S-nitrosylation at Cys351 of PFKM by NOS1 contributes to the metabolic reprogramming of ovarian cancer cells, highlighting a critical role of endogenous nitrogen oxide on metabolism regulations in tumor progression.

The heterocyclic compound Tempol inhibits the growth of cancer cells by interfering with glutamine metabolism.

Tempol (4-hydroxy-2,2,6,6-Tetramethylpiperidine-1-oxyl, TPL), a nitroxide compound, inhibits proliferation and increases the vulnerability of cancer cells to apoptosis induced by cytotoxic agents. However, the molecular mechanism of TPL inhibiting cancer cell proliferation has not been fully understood. In this study, we evaluated the metabolic effect of TPL on cancer cells and explored its cancer therapeutic potential. Extracellular flow assays showed that TPL inhibited cellular basal and maximal oxygen consumption rates of mitochondrial. 13C metabolic flux analysis showed that TPL treatment had minimal effect on glycolysis. However, we found that TPL inhibits glutamine metabolism by interfering with the oxidative tricarboxylic acid cycle (TCA) process and reductive glutamine process. We found that the inhibitory effect of TPL on metabolism occurs mainly on the step from citrate to α-ketoglutarate or vice versa. We also found that activity of isocitrate dehydrogenase IDH1 and IDH2, the key enzymes in TCA, were inhibited by TPL treatment. In xenograft mouse model, TPL treatment reduced tumor growth by inhibiting cellular proliferation of xenograft tumors. Thus, we provided a mechanism of TPL inhibiting cancer cell proliferation by interfering with glutamine utilization that is important for survival and proliferation of cancer cells. The study may help the development of a therapeutic strategy of TPL combined with other anticancer medicines.

Microcystins-LR induced apoptosis via S-nitrosylation of GAPDH in colorectal cancer cells.

Microcystins-LR (MC-LR), a cyanobacterial toxins, initiate apoptosis in normal and tumor cells. Nitric oxide produced by iNOS is necessary for MC-LR-induced apoptosis. However, the underlying mechanism of NO mediated MC-LR cytotoxicity remains unclear. Here, we performed in vitro experiments on MC-LR cytotoxicity associated with NO induced S-nitrosyation of GAPDH in human colon cancer cells SW480. MTT assay indicated that MC-LR decreased the cellular viability by high concentration (>1 µM). Flow cytometer assay revealed that apoptosis was core mode for MC-LR cytotoxicity. Griess assay showed that MC-LR exposure increased the release of NO through the function of NOS1 and NOS2 in SW480 cells. In turn, NO stress induced the S-nitrosylated modification of GAPDH leading to its nuclear translocation following Siah1 binding. CHIP assay showed that the nuclear GADPH increased P53 transcript of a panner of apoptosis related genes. Moreover, apoptosis induced by MC-LR could be reduced by GAPDH or si-Siah1 or NOSs inhibitor, L-NAME. Thus, our study verified a molecular mechanism of NO/GAPDH/Siah1 cascade in MC-LR mediated apoptosis in colorectal cancer cells, providing a further understanding the in vitro molecular mechanism of MC-LR colorectal toxicity.

NOS1 inhibits the interferon response of cancer cells by S-nitrosylation of HDAC2.

BACKGROUND: The dysfunction of type I interferon (IFN) signaling is an important mechanism of immune escape and metastasis in tumors. Increased NOS1 expression has been detected in melanoma, which correlated with dysfunctional IFN signaling and poor response to immunotherapy, but the specific mechanism has not been determined. In this study, we investigated the regulation of NOS1 on the interferon response and clarified the relevant molecular mechanisms. METHODS: After stable transfection of A375 cells with NOS1 expression plasmids, the transcription and expression of IFNα-stimulated genes (ISGs) were assessed using pISRE luciferase reporter gene analysis, RT-PCR, and western blotting, respectively. The effect of NOS1 on lung metastasis was assessed in melanoma mouse models. A biotin-switch assay was performed to detect the S-nitrosylation of HDAC2 by NOS1. ChIP-qPCR was conducted to measure the binding of HDAC2, H4K16ac, H4K5ac, H3ac, and RNA polymerase II in the promoters of ISGs after IFNα stimulation. This effect was further evaluated by altering the expression level of HDAC2 or by transfecting the HDAC2-C262A/C274A site mutant plasmids into cells. The coimmunoprecipitation assay was performed to detect the interaction of HDAC2 with STAT1 and STAT2. Loss-of-function and gain-of-function approaches were used to examine the effect of HDAC2-C262A/C274A on lung metastasis. Tumor infiltrating lymphocytes were analyzed by flow cytometry. RESULTS: HDAC2 is recruited to the promoter of ISGs and deacetylates H4K16 for the optimal expression of ISGs in response to IFNα treatment. Overexpression of NOS1 in melanoma cells decreases IFNα-responsiveness and induces the S-nitrosylation of HDAC2-C262/C274. This modification decreases the binding of HDAC2 with STAT1, thereby reducing the recruitment of HDAC2 to the ISG promoter and the deacetylation of H4K16. Moreover, expression of a mutant form of HDAC2, which cannot be nitrosylated, reverses the inhibition of ISG expression by NOS1 in vitro and decreases NOS1-induced lung metastasis and inhibition of tumor infiltrating lymphocytes in a melanoma mouse model. CONCLUSIONS: This study provides evidence that NOS1 induces dysfunctional IFN signaling to promote lung metastasis in melanoma, highlighting NOS1-induced S-nitrosylation of HDAC2 in the regulation of IFN signaling via histone modification.

Metformin attenuates hepatoma cell proliferation by decreasing glycolytic flux through the HIF-1α/PFKFB3/PFK1 pathway.

AIMS: Enhanced aerobic glycolysis is an essential hallmark of malignant cancer. Blocking the glycolytic pathway has been suggested as a therapeutic strategy to impair the proliferation of tumor cells. Metformin, a widely used anti-diabetes drug, exhibits anti-tumor properties. However, the underlying molecular mechanism of its action linking glucose metabolism with the suppression of proliferation has not been fully clarified. MAIN METHODS: Stable isotope tracing technology and gas chromatography-mass spectrometry method were utilized to analyze the effect of metformin on glycolytic flux in HCC cells. Western blot and immunohistochemistry were utilized to analyze the expression of phosphofructokinase-1 (PFK1) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in HCC cells or xenograft tumor tissues. Lactate measurement and glucose uptake assay were used to analyze the level of lactate and glucose in the presence of frucose-2,6-diphosphate (F2,6BP) in HCC cells treated with metformin. KEY FINDINGS: We found that metformin significantly impaired hepatoma cell proliferation by inhibiting the glycolytic flux via PFK1 blockade. Interestingly, activation of PFK1 by F2,6BP reverses the inhibitory effect of metformin on hepatoma cell proliferation and glycolysis. Mechanistically, PFKFB3，a potent allosteric activator of PFK1, was markedly suppressed through inhibiting hypoxia-induced factor 1 (HIF-1α) accumulation mediated by metformin. SIGNIFICANCE: Taken together these data indicate that HIF-1α/PFKFB3/PFK1 regulatory axis is a vital determinant of glucose metabolic reprogramming in hepatocellular carcinoma, which gives new insights into the action of metformin in combatting liver cancer.

[Effect of the chemoprotectant tempol on anti-tumor activity of cisplatin].

OBJECTIVE: To investigate the effect of the chemoprotectant tempol on the anti-tumor activity of cisplatin (DDP). METHODS: The cellular toxicity of tempol in human colon cancer SW480 cells and mouse colon cancer CT26 cells were evaluated using MTT and cell counting kit-8 assays. CalcuSyn software analysis was used to determine the interaction between tempol and DDP in inhibition of the cell viability. A subcutaneous homograft mouse model of colon cancer was established. The mice were randomly divided into control group, tempol group, cisplatin group and tempol + DDP treatment group with intraperitoneal injections of the indicated agents. The tumor size, body weight and lifespan of the mice were measured, and HE staining was used to analyze the cytotoxic effect of the agents on the kidney and liver. Immunohistochemistry and Western blotting were performed to detect the expression of Bax and Bcl2 in the tumor tissue, and TUNEL staining was used to analyze the tumor cell apoptosis. The level of reactive oxygen species (ROS) in the tumor tissue was determined using flow cytometry. RESULTS: Tempol showed inhibitory effects on the viability of SW480 and CT26 cells. CalcuSyn software analysis showed that tempol had a synergistic anti-tumor effect with DDP (CI < 1). In the homograft mouse model, tempol treatment alone did not produce obvious anti-tumor effect. HE staining showed that the combined use of tempol and DDP alleviated DDP-induced fibrogenesis in the kidneys, but tempol also reduced the anti-tumor activity of DDP. Compared with the mice treated with DDP alone, the mice treated with both tempol and DDP had a significantly larger tumor size (P < 0.01) and a shorter lifespan (P < 0.05). Tempol significantly reversed DDP-induced expression of Bax and Bcl2 in the tumor tissue and tumor cell apoptosis (P < 0.001), and obviously reduced the elevation of ROS level in the tumor tissue induced by DDP treatment (P < 0.05). CONCLUSIONS: Tempol can attenuate the anti-tumor effect of DDP while reducing the side effects of DDP. Caution must be taken and the risks and benefits should be carefully weighed when considering the use of tempol as an anti-oxidant to reduce the toxicities of DDP.

Mitochondrial NOS1 suppresses apoptosis in colon cancer cells through increasing SIRT3 activity.

Previous studies have suggested that nitric oxide (NO) which is synthetized by nitric oxide synthase (NOS) is closely related to the carcinogenesis and progression of colon cancer. However, the precise physiopathological role of NO on colon cancer remains unclear, and a lot of related studies focused on NOS2 and NOS3, but little on NOS1. Here, stable overexpression NOS1 of colon cancer cells were constructed to investigate whether NOS1 plays a special role in colon cancer. We observed that NOS1 protein was presented in mitochondria. Both the basal and cisplatin-induced mitochondrial superoxide were inhibited by NOS1, and the cisplatin-induced apoptosis was also inhibited by NOS1. Geldanamycin, a Hsp90 N-terminal inhibitor, was able to impede NOS1 translocation into mitochondria and reverse NOS1-induced apoptosis resistance. Importantly, SIRT3 activity was enhanced by NOS1, which contributes to the low level of mitochondrial superoxide and apoptosis resistance. Our data suggest a link between NOS1 and apoptosis resistance in colon cancer cells through mtNOS1-SIRT3-SOD2 axis. Furthermore, NOS1-induced apoptosis resistance could be reversed by inhibiting mitochondrial translocation of NOS1.

Psychosocial Predictors of Adjustment to Disability Among Patients With Breast Cancer: A Cross-Sectional Descriptive Study.

BACKGROUND: Acceptance of disability relates to the process of adaptation, which reflects how the values of a patient change over time to accept herself or himself as an intrinsically worthy person. Acceptance of disability (AOD) plays an important role in the adjustment of persons with physical disability to their environment. However, no studies on the level of AOD in patients with breast cancer are available in the literature. PURPOSE: The aim of this study was to explore the significant factors that influence disability acceptance in Chinese women with breast cancer. METHODS: A cross-sectional study was conducted on 292 patients with breast cancer between January and April 2017. Participants were assessed using the Acceptance of Disability Scale-Revised, Medical Coping Modes Questionnaire, Sense of Coherence Scale, Social Relational Quality Scale, and general information questionnaire. Multiple regression analysis was used to determine the factors associated with the level of disability acceptance. RESULTS: The mean score for AOD was 79.14 and ranged from 32 to 128. Multiple regression analysis indicated that family intimacy, friendships, confrontation, manageability, family commitment, marital status, surgery, and acceptance-resignation significantly affected disability acceptance, explaining 49.1% of the total variance in disability acceptance. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The participants had a moderate level of disability acceptance. Disability acceptance is an important factor in the psychosocial adaptation to cancer. Healthcare staff should pay special attention to low scores for this factor and explore the potential of psychological interventions to effectively reduce the posttraumatic stress response, encourage the adoption of positive coping strategies, and hasten disability acceptance and return to society.

iNOS-derived nitric oxide promotes glycolysis by inducing pyruvate kinase M2 nuclear translocation in ovarian cancer.

Aerobic glycolysis is essential for tumor growth and survival. Activation of multiple carcinogenic signals contributes to metabolism reprogramming during malignant transformation of cancer. Recently nitric oxide has been noted to promote glycolysis but the mechanism remains elusive. We report here the dual role of nitric oxide in glycolysis: low/physiological nitric oxide (≤ 100 nM) promotes glycolysis for ATP production, oxidative defense and cell proliferation of ovary cancer cells, whereas excess nitric oxide (≥ 500 nM) inhibits it. Nitric oxide has a positive effect on glycolysis by inducing PKM2 nuclear translocation in an EGFR/ERK2 signaling-dependent manner. Moreover, iNOS induced by mild inflammatory stimulation increased glycolysis and cell proliferation by producing low doses of nitric oxide, while hyper inflammation induced iNOS inhibited it by producing excess nitric oxide. Finally, iNOS expression is abnormally increased in ovarian cancer tissues and is correlated with PKM2 expression. Overexpression of iNOS is associated with aggressive phenotype and poor survival outcome in ovarian cancer patients. Our study indicated that iNOS/NO play a dual role of in tumor glycolysis and progression, and established a bridge between iNOS/NO signaling pathway and EGFR/ERK2/PKM2 signaling pathway, suggesting that interfering glycolysis by targeting the iNOS/NO/PKM2 axis may be a valuable new therapeutic approach of treating ovarian cancer.

[New processing procedure for Croton tiglium with study on comparison of Croton tiglium and processed product].

OBJECTIVE: To build a new processing procedure for Croton tiglium, providing a more simple, efficient and safe way of processing. METHODS: Used the contents of isoguanosine and toxic protein in Croton tiglium as the indexes to investigate the effect of different temperature, thickness and baked time on processing for Croton tiglium. After established all factors and levels, processed a batch of Croton tiglium under optimum processing conditions and compared it with raw Croton tiglium in the test of acute toxicity and gastrointestinal propulsive motility. RESULTS: The parameters of optimum processing were as follows:the temperature was set at 180 degrees C, the thickness of placement was 3 cm and baked time was 90 min. The LD50 value of raw Croton tiglium and the processed Croton tiglium was 888 mg/kg and 2139 mg/kg respectively. CONCLUSION: The processing procedure is simple, affordable, safe and efficient, deserved to promote for application.