Upregulation of CoQ shifts ferroptosis dependence from GPX4 to FSP1 in acquired radioresistance.

Acquired radioresistance is the primary contributor to treatment failure of radiotherapy, with ferroptosis is identified as a significant mechanism underlying cell death during radiotherapy. Although resistance to ferroptosis has been observed in both clinical samples of radioresistant cells and cell models, its mechanism remains unidentified. Herein, our investigation revealed that radioresistant cells exhibited greater tolerance to Glutathione Peroxidase 4 (GPX4) inhibitors and, conversely, increased sensitivity to ferroptosis suppressor protein 1 (FSP1) inhibitors compared to their sensitive counterparts. This observation suggested that FSP1 might play a dominant role in the development of radioresistance. Notably, the knockout of FSP1 demonstrated considerably superior efficacy in resensitizing cells to radiotherapy compared to the knockout of GPX4. To elucidate the driving force behind this functional shift, we conducted a metabolomic assay, which revealed an upregulation of Coenzyme Q (CoQ) synthesis and a downregulation of glutathione synthesis in the acquired radioresistance cells. Mechanistically, CoQ synthesis was found to be supported by aarF domain containing kinase 3-mediated phosphorylation of CoQ synthases, while the downregulation of Solute carrier family 7 member 11 led to decreased glutathione synthesis. Remarkably, our retrospective analysis of clinical response data further validated that the additional administration of statin during radiotherapy, which could impede CoQ production, effectively resensitized radioresistant cells to radiation. In summary, our findings demonstrate a dependency shift from GPX4 to FSP1 driven by altered metabolite synthesis during the acquisition of radioresistance. Moreover, we provide a promising therapeutic strategy for reversing radioresistance by inhibiting the FSP1-CoQ pathway.

Quality markers of Polygala fallax Hemsl decoction based on qualitative and quantitative analysis combined with network pharmacology and chemometric analysis.

INTRODUCTION: Polygala fallax Hemsl (PFH) is a widely used herbal medicine in Guangxi, China. At present, research on PFH mainly focuses on extraction technology and cultivation, lacking quality control standards for systematic evaluation. OBJECTIVES: The study aimed to assess the quality of PFH from different sources and to predict markers that would help assess quality. METHODS: Fingerprinting of 15 batches of PFH samples was performed by ultra-high performance liquid chromatography (UPLC) and similarity was assessed using hierarchical cluster analysis (HCA), principal component analysis (PCA), and orthogonal partial least squares discrimination (OPLS-DA). Differential components were screened by mathematical analysis, and a "component-target-pathway" network map was constructed in combination with network pharmacology, quality markers (Q-markers) of PFH were predicted, and quantitative analysis was performed. RESULTS: Fifteen batches were fingerprinted for PFH, with 11 common peaks, and peak 5 was identified as 4-hydroxybenzoic acid, which was generally consistent with the results of HCA, PCA, and OPLS-DA. Network pharmacology screened 18 potential compounds, 45 core targets, and 20 key pathways, integrating fingerprinting, pattern recognition, and network pharmacology methods. One of the potential Q-markers that can identify the principle of testability, efficacy, and specificity is 4-hydroxybenzoic acid, whose content ranges from 0.0188 to 1.4517 mg/g. CONCLUSION: The potential Q-markers of PFH were predicted by integrating fingerprinting, pattern recognition, and network pharmacological analysis, which provided a scientific basis for the overall control and evaluation of the quality of PFH and a theoretical reference for the study of the quality standard of multi-base traditional Chinese medicine.

DSCC1 interacts with HSP90AB1 and promotes the progression of lung adenocarcinoma via regulating ER stress.

Lung cancer is a leading cause of cancer-related deaths, and the most common type is lung adenocarcinoma (LUAD). LUAD is frequently diagnosed in people who never smoked, patients are always diagnosed at advanced inoperable stages, and the prognosis is ultimately poor. Thus, there is an urgent need for the development of novel targeted therapeutics to suppress LUAD progression. In this study, we demonstrated that the expression of DNA replication and sister chromatid cohesion 1 (DSCC1) was higher in LUAD samples than normal tissues, and the overexpression of DSCC1 or its coexpressed genes were highly correlated with poor outcomes of LUAD patients, highlighting DSCC1 might be involved in LUAD progression. Furthermore, the expression of DSCC1 was positively correlated with multiple genetic mutations which drive cancer development, including TP53, TTN, CSMD, and etc. More importantly, DSCC1 could promote the cell proliferation, stemness, EMT, and metastatic potential of LUAD cells. In addition, DSCC1 interacted with HSP90AB1 and promoted the progression of LUAD via regulating ER stress. Meanwhile, DSCC1 expression negatively correlated with immune cell infiltration in lung cancer, and DSCC1 positively regulated the expression of PD-L1 in LUAD cells. Collectively, this study revealed that DSCC1 is a novel therapeutic target to treat LUAD and a biomarker for predicting the efficiency of PD-1/PD-L1 blockade treatment.

Correlation between negative life events and suicide attempts among Yi adolescents with HIV/AIDS in Liangshan Prefecture.

OBJECTIVE: To investigate the incidence of suicide attempts among adolescents with HIV/AIDS in Liangshan Prefecture, Sichuan Province, as well as the correlation between negative life events, sleep, exercise, drug therapy and suicide attempts. METHODS: A total of 180 Yi adolescents aged 11-19 years with HIV/AIDS in a county of Liangshan Prefecture, Sichuan Province, China, were investigated by census. The main outcome indicators included the incidence of suicide attempts and whether negative life events, sleep, exercise, drug therapy and other factors were related to suicide attempts. RESULTS: We found that the incidence rate of suicide attempts among Yi adolescents with HIV/AIDS in Liangshan Prefecture was 13.9%. Negative life events were a risk factor for suicide attempts (OR = 1.047, p < 0.001, 95% CI 1.027-1.067). In the factors of negative life events, adaptation was a risk factor for suicide attempts (OR = 1.203, p = 0.026, 95% CI 1.022-1.416), and academic pressure showed a tendency to be a risk factor for suicide attempts (OR = 1.149, p = 0.077, 95% CI 0.985-1.339). However, the punishment factor, interpersonal stress factor and loss factor had no significant correlation with suicide attempts. There was no significant correlation between sleep, exercise, drug therapy and suicide attempts. CONCLUSION: The proportion of suicide attempts among Yi adolescents with HIV/AIDS in Liangshan Prefecture is high and should be considered. Negative life events are independent risk factors for suicide attempts, and it is necessary to strengthen the screening and early intervention for suicide attempts in HIV/AIDS adolescents with definite negative life events.

Decreased INPP5B expression predicts poor prognosis in lung adenocarcinoma.

BACKGROUND: Inositol Polyphosphate-5-Phosphatase B (INPP5B), a inositol 5-phosphatase, plays an important role in many biological processes through phosphorylating PI(4,5)P2 and/or PI(3,4,5)P3 at the 5-position. Nevertheless, little is known about its function and cellular pathways in tumors. This study aims to investigate the potential role of INPP5B as a diagnostic and prognostic biomarker for lung adenocarcinoma (LUAD), as well as its biological functions and molecular mechanisms in LUAD. METHODS: TCGA, GEO, CTPAC, and HPA datasets were used for differential expression analysis and pathological stratification comparison. The prognostic and diagnostic role of INPP5B was determined by Kaplan-Meier curves, univariate and multivariate Cox regression analysis, and receiver operating characteristics (ROC) curve analyses. The potential mechanism of INPP5B was explored through GO, KEGG, and GSEA enrichment analysis, as well as GeneMANIA and STRING protein-protein interaction (PPI) network. PicTar, PITA, and miRmap databases were used for exploring miRNA targeting INPP5B. In molecular biology experiments, immunohistochemical analyses and Western blot analyses were used to determine protein expression. Co-immunoprecipitation assay was used to detect protein-protein interactions. CCK8 assays and colony formation assays were used for the measurement of cell proliferation. Cell cycle was assessed by PI staining with flow cytometry. Cell migration was performed by Transwell assays and wound healing assays. RESULT: INPP5B was decreased in LUAD tissues compared with normal adjacent tissues. And the low expression of INPP5B was associated with late-stage pathological features. In addition, INPP5B was found to be a significant independent prognostic and diagnostic factor for LUAD patients. Hsa-miR-582-5p was predicted as a negative regulator of INPP5B mRNA expression. INPP5B was significantly correlated with the expression of PTEN and the activity of PI3K/AKT signaling pathways, as determined by enrichment analysis and PPI network. In vitro experiments partially confirmed the aforementioned findings. INPP5B could interact directly with PTEN. INPP5B overexpression inhibited LUAD cell proliferation and migration while downregulating the AKT pathway. CONCLUSION: Our results demonstrated that INPP5B could inhibit the proliferation and metastasis of LUAD cells. It could serve as a novel diagnostic and prognostic biomarker for LUAD patients. Trial registration LUAD tissues and corresponding para-cancerous tissues were collected from 10 different LUAD patients at Hangzhou First People's Hospital. The Ethics Committee of Hangzhou First People's Hospital has approved this study. (registration number: IIT-20210907-0031-01; registration date: 2021.09.13).

DYRK1A reinforces epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma via cooperatively activating STAT3 and SMAD.

BACKGROUND: Hepatocellular carcinoma (HCC) accounts for the majority of liver cancer cases, while metastasis is considered the leading cause of HCC-related death. However, the currently available treatment strategies for efficient suppression of metastasis are limited. Therefore, novel therapeutic targets to inhibit metastasis and effectively treat HCC are urgently required. METHODS: Wound healing and Transwell assays were used to determine the migration and invasion abilities of HCC cells in vitro. Quantitative real-time PCR (qRT-PCR), protein array, immunofluorescence, and immunoprecipitation experiments were used to study the mechanism of DYRK1A-mediated metastasis. A tail vein metastasis model and H&E staining were utilized to assess metastatic potential in vivo. RESULTS: The results of the current study demonstrated that dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) was upregulated in HCC tissues compared with normal liver tissues. Additionally, the level of DYRK1A was increased in primary HCC tissues of patients with metastasis compared with those of patients without metastasis, and DYRK1A overexpression correlated with worse outcomes in liver cancer patients. Gain- and loss-of-function studies suggested that DYRK1A enhanced the invasion and migration abilities of HCC cells by promoting epithelial-mesenchymal transition (EMT). Regarding the promoting effect of DYRK1A on cell invasion, the results showed that DYRK1A was coexpressed with TGF-ß/SMAD and STAT3 signalling components in clinical tumour samples obtained from patients with HCC. DYRK1A also activated TGF-ß/SMAD signalling by interacting with tuberous sclerosis 1 (TSC1) and enhanced metastasis of HCC cells by activating STAT3. Furthermore, DYRK1A promoted EMT by cooperatively activating STAT3/SMAD signalling. CONCLUSION: Overall, the present study not only uncovered the promoting effect of DYRK1A on HCC metastasis and revealed the mechanism but also provided a new approach to predict and treat metastatic HCC.

Enhanced anticancer activity by the combination of vinpocetine and sorafenib via PI3K/AKT/GSK-3ß signaling axis in hepatocellular carcinoma cells.

Vinpocetine is widely used to treat cerebrovascular diseases. However, the effect of vinpocetine to treat hepatocellular carcinoma (HCC) has not been investigated. In this study, we revealed that vinpocetine was associated with antiproliferative activity in HCC cells, but induced cytoprotective autophagy, which restricted its antitumor activity. Autophagy inhibitors improved the antiproliferative activity of vinpocetine in HCC cells. Sorafenib is effective to treat advanced HCC, but the effect of autophagy induced by sorafenib is indistinct. We demonstrated vinpocetine plus sorafenib suppressed the cytoprotective autophagy activated by vinpocetine in HCC cells and significantly induced apoptosis and suppressed cell proliferation in HCC cells. In addition, vinpocetine plus sorafenib activates glycogen synthase kinase 3ß (GSK-3ß) and subsequently inhibits cytoprotective autophagy induced by vinpocetine in HCC cells. Meanwhile, overexpression of GSK-3ß was efficient to increase the apoptosis induced by vinpocetine plus sorafenib in HCC cells. Our study revealed that vinpocetine plus sorafenib could suppress the cytoprotective autophagy induced by vinpocetine and subsequently show synergistically anti-HCC activity via activating GSK-3ß and the combination of vinpocetine and sorafenib might reverse sorafenib resistance via the PI3K/protein kinase B/GSK-3ß signaling axis. Thus, vinpocetine may be a potential candidate for sorafenib sensitization and HCC treatment, and our results may help to elucidate more effective therapeutic options for HCC patients with sorafenib resistance.

DYRK1A inhibition suppresses STAT3/EGFR/Met signalling and sensitizes EGFR wild-type NSCLC cells to AZD9291.

DYRK1A is considered a potential cancer therapeutic target, but the role of DYRK1A in NSCLC oncogenesis and treatment requires further investigation. In our study, high DYRK1A expression was observed in tumour samples from patients with lung cancer compared with normal lung tissues, and the high levels of DYRK1A were related to a reduced survival time in patients with lung cancer. Meanwhile, the DYRK1A inhibitor harmine could suppress the proliferation of NSCLC cells compared to that of the control. As DYRK1A suppression might be effective in treating NSCLC, we next explored the possible specific molecular mechanisms that were involved. We showed that DYRK1A suppression by siRNA could suppress the levels of EGFR and Met in NSCLC cells. Furthermore, DYRK1A siRNA could inhibit the expression and nuclear translocation of STAT3. Meanwhile, harmine could also regulate the STAT3/EGFR/Met signalling pathway in human NSCLC cells. AZD9291 is effective to treat NSCLC patients with EGFR-sensitivity mutation and T790 M resistance mutation, but the clinical efficacy in patients with wild-type EGFR remains modest. We showed that DYRK1A repression could enhance the anti-cancer effect of AZD9291 by inducing apoptosis and suppressing cell proliferation in EGFR wild-type NSCLC cells. In addition, harmine could enhance the anti-NSCLC activity of AZD9291 by modulating STAT3 pathway. Finally, harmine could enhance the anti-cancer activity of AZD9291 in primary NSCLC cells. Collectively, targeting DYRK1A might be an attractive target for AZD9291 sensitization in EGFR wild-type NSCLC patients.

KLF4 functions as an oncogene in promoting cancer stem cell-like characteristics in osteosarcoma cells.

Despite more effective chemotherapy combined with limb-salvage surgery for the osteosarcoma treatment, survival rates for osteosarcoma patients have stagnated over the past three decades due to the poor prognosis. Osteosarcoma cancer stem cells (OSCs) are responsible for the growth and metastasis of osteosarcoma. The existence of OSCs offers a theoretical explanation for therapeutic failures including tumor recurrence, metastasis, and drug resistance. Understanding the pathways that regulate properties of OSCs may shed light on mechanisms that lead to osteosarcoma and suggest better modes of treatment. In this study, we showed that the expression level of Kruppel-like factor 4 (KLF4) is highly associated with human osteosarcoma cancer stemness. KLF4-overexpressed osteosarcoma cells displayed characteristics of OSCs: increased sphere-forming potential, enhanced levels of stemness-associated genes, great chemoresistance to adriamycin and CDDP, as well as more metastasis potential. Inversely, KLF4 knockdown could reduce colony formation in vitro and inhibit tumorigenesis in vivo, supporting an oncogenic role for KLF4 in osteosarcoma pathogenesis. Furthermore, KLF4 was shown to activate the p38 MAPK signaling pathway to promote cancer stemness. Altogether, our studies uncover an essential role for KLF4 in regulation of OSCs and identify KLF4-p38 MAPK axis as a potential therapeutic target for osteosarcoma treatment.

The anti-tumor effect of regorafenib in lung squamous cell carcinoma in vitro.

Lung squamous cell carcinoma (LSCC) is a common type of non-small-cell lung cancer (NSCLC) and lacks effective treatment. Regorafenib, an oral multikinase inhibitor, has demonstrated promising anti-tumor activity in various solid tumors. To study whether regorafenib inhibits LSCC cells, we investigate the compound in several LSCC cell lines and explore the possible mechanism. In this study, we confirmed that regorafenib had anti-proliferation effect on LSCC cell lines by inducing G0/G1 arrest. In addition, glycogen synthase kinase 3ß (GSK3ß) remained at the same level and Ser9 phosphorylation of GSK3ß decreased with increasing incubation time and increasing regorafenib concentration in LSCC cells. GSK3ß inhibition enhanced the anti-tumor activity of regorafenib. Thus, GSK3ß activation restricted the anti-cancer effect of regorafenib on LSCC. In conclusion, regorafenib might be a promising drug for LSCC therapy. GSK3ß might be a potential target to increase the anti-tumor effect of regorafenib in LSCC cells.

Evodiamine induces apoptosis and promotes hepatocellular carcinoma cell death induced by vorinostat via downregulating HIF-1α under hypoxia.

Hypoxia promotes HCC progression and therapy resistance, and there is no systemic treatment for HCC patients after sorafenib resistance. Thus, it is urgent to develop potential therapeutic regimens for HCC patients by targeting hypoxia signaling. In this study, we showed that evodiamine might be a potential therapeutic medicine for HCC by suppressing HIF-1α. In addition, evodiamine could sensitize the anti-HCC effect of vorinostat in HCC cells under hypoxia. Furthermore, evodiamine plus vorinostat accelerated the degradation of HIF-1α in HCC cells under hypoxia. In general, evodiamine might be a potential therapeutic candidate for HCC patients, and evodiamine combining with vorinostat might be an attractive chemotherapy strategy for HCC treatment.

Dimethyl celecoxib sensitizes gastric cancer cells to ABT-737 via AIF nuclear translocation.

Gastric cancer is the fourth most common cancer in the world. The clinical applications of both chemotherapy and targeted drugs are limited because of the complexity of gastric cancer. In this study, sulforhodamine B, colony formation assay, 4',6-diamidino-2-phenylindole (DAPI) stain, flow cytometry were used to determine the in vitro cytotoxicity, apoptosis and mitochondrial membrane potential of gastric cancer AGS and HGC-27 cells before and after treatment. Real-time PCR and Western blot were used to analyse the mRNA transcription and protein expression respectively. Confocal microscopy was used to determine the localization of target protein within the cells. Treatment with the combination of ABT-737 and 2,5-dimethyl-celecoxib (DMC) showed strong synergistic effect in both AGS and HGC-27 cells. Moreover, DMC would not influence the intracellular prostaglandin E2 (PGE2) level, thus lacking the toxicity profile of celecoxib. Interestingly, given the significant synergistic effect, combination treatment did not affect the protein expression of BH-3 proteins including Puma, Noxa and Bim. In combination treatment, cell apoptosis was found independent of caspase-3 activation. The translocation of apoptosis-inducing factor (AIF) from mitochondrion to nuclear was responsible for the induced apoptosis in the combination treatment. Taken together, this study provided a novel combination treatment regimen for gastric cancer. Furthermore, the existence of caspase-independent apoptotic pathway induced by treatment of ABT-737 was not yet seen until combined with DMC, which shed light on an alternative mechanism involved in Bcl-2 inhibitor-induced apoptosis.

Deacetylisovaltratum disrupts microtubule dynamics and causes G2/M-phase arrest in human gastric cancer cells in vitro.

AIM: Deacetylisovaltratum (DI) is isolated from the traditional Chinese herbal medicine Patrinia heterophylla Bunge, which exhibits anti-cancer activity. Here, we investigated the effects of DI on human gastric carcinoma cell lines in vitro and elucidated its anti-cancer mechanisms. METHODS: Human gastric carcinoma AGS and HGC-27 cell lines were treated with DI, and cell viability was detected with MTT assay. Cell cycle stages, apoptosis and mitochondrial membrane potential were measured using flow cytometry. Protein levels were analyzed by Western blotting. Tubulin polymerization assays and immunofluorescence were used to characterize the tubulin polymerization process. RESULTS: DI inhibited the cell viability of AGS and HGC-27 cells in a dose- and time-dependent manner with IC50 values of 12.0 and 28.8 µmol/L, respectively, at 24 h of treatment. Treatment with DI (10-100 µmol/L) dose-dependently promoted tubulin polymerization, and induced significant G2/M cell cycle arrest in AGS and HGC-27 cells. Moreover, DI treatment disrupted mitochondrial membrane potential and induced caspase-dependent apoptosis in AGS and HGC-27 cells. CONCLUSION: DI induces G2/M-phase arrest by disrupting tubulin polymerization in human gastric cancer cells, which highlights its potent anti-cancer activity and potential application in gastric cancer therapy.

Autophagy blockade sensitizes the anticancer activity of CA-4 via JNK-Bcl-2 pathway.

Combretastatin A-4 (CA-4) has already entered clinical trials of solid tumors over ten years. However, the limited anticancer activity and dose-dependent toxicity restrict its clinical application. Here, we offered convincing evidence that CA-4 induced autophagy in various cancer cells, which was demonstrated by acridine orange staining of intracellular acidic vesicles, the degradation of p62, the conversion of LC3-I to LC3-II and GFP-LC3 punctate fluorescence. Interestingly, CA-4-mediated apoptotic cell death was further potentiated by pretreatment with autophagy inhibitors (3-methyladenine and bafilomycin A1) or small interfering RNAs against the autophagic genes (Atg5 and Beclin 1). The enhanced anticancer activity of CA-4 and 3-MA was further confirmed in the SGC-7901 xenograft tumor model. These findings suggested that CA-4-elicited autophagic response played a protective role that impeded the eventual cell death while autophagy inhibition was expected to improve chemotherapeutic efficacy of CA-4. Meanwhile, CA-4 treatment led to phosphorylation/activation of JNK and JNK-dependent phosphorylation of Bcl-2. Importantly, JNK inhibitor or JNK siRNA inhibited autophagy but promoted CA-4-induced apoptosis, indicating a key requirement of JNK-Bcl-2 pathway in the activation of autophagy by CA-4. We also identified that pretreatment of Bcl-2 inhibitor (ABT-737) could significantly enhance anticancer activity of CA-4 due to inhibition of autophagy. Taken together, our data suggested that the JNK-Bcl-2 pathway was considered as the critical regulator of CA-4-induced protective autophagy and a potential drug target for chemotherapeutic combination.

SPTBN2 suppresses ferroptosis in NSCLC cells by facilitating SLC7A11 membrane trafficking and localization.

The function of SLC7A11 in the process of ferroptosis is well-established, as it regulates the synthesis of glutathione (GSH), thereby influencing tumor development along with drug resistance in non-small cell lung cancer (NSCLC). However, the determinants governing SLC7A11's membrane trafficking and localization remain unknown. Our study identified SPTBN2 as a ferroptosis suppressor, enhancing NSCLC cells resistance to ferroptosis inducers. Mechanistically, SPTBN2, through its CH domain, interacted with SLC7A11 and connected it with the motor protein Arp1, thus facilitating the membrane localization of SLC7A11 - a prerequisite for its role as System Xc-, which mediates cystine uptake and GSH synthesis. Consequently, SPTBN2 suppressed ferroptosis through preserving the functional activity of System Xc- on the membrane. Moreover, Inhibiting SPTBN2 increased the sensitivity of NSCLC cells to cisplatin through ferroptosis induction, both in vitro and in vivo. Using Abrine as a potential SPTBN2 inhibitor, its efficacy in promoting ferroptosis and sensitizing NSCLC cells to cisplatin was validated. Collectively, SPTBN2 is a potential therapeutic target for addressing ferroptosis dysfunction and cisplatin resistance in NSCLC.

POLR2J expression promotes glioblastoma malignancy by regulating oxidative stress and the STAT3 signaling pathway.

Glioblastoma is the most common cancer in the brain, resistant to conventional therapy and prone to recurrence. Therefore, it is crucial to explore novel therapeutics strategies for the treatment and prognosis of GBM. In this study, through analyzing online datasets, we elucidated the expression and prognostic value of POLR2J and its co-expressed genes in GBM patients. Functional experiments, including assays for cell apoptosis and cell migration, were used to explore the effects of POLR2J and vorinostat on the proliferation and migration of GBM cells. The highest overexpression of POLR2J, among all cancer types, was observed in GBM. Furthermore, high expression of POLR2J or its co-expressed genes predicted a poor outcome in GBM patients. DNA replication pathways were significantly enriched in the GBM clinical samples with high POLR2J expression, and POLR2J suppression inhibited proliferation and triggered cell cycle G1/S phase arrest in GBM cells. Moreover, POLR2J silencing activated the unfolded protein response (UPR) and significantly enhanced the anti-GBM activity of vorinostat by suppressing cell proliferation and inducing apoptosis. Additionally, POLR2J could interact with STAT3 to promote the metastatic potential of GBM cells. Our study identifies POLR2J as a novel oncogene in GBM progression and provides a promising strategy for the chemotherapeutic treatment of GBM.

Triacanthine enhances the sensitivity of colorectal cancer cells to 5-fluorouracil by regulating RRM2.

BACKGROUND: According to the literatures, triacanthine is isolated from the leaves of Gleditsia triacanthos L. and acts as an anti-hypertensive agent, also cardiotonic, antispasmodic and a respiratory analeptic. The 5-fluorouracil (5-FU) is widely used to treat the patients of colorectal cancer (CRC), but the resistance to 5-FU treatment restricts the therapeutic efficacy of CRC patients. PURPOSE: This study aims to explore a novel therapeutics regimen overcoming CRC resistance to 5-FU. METHODS: The cell proliferation of CRC cells was determined by SRB and colony formation assay. Transwell and wound-healing assay were applied to explore the potential metastatic abilities of CRC cells. qRT-PCR and Western blot were performed to evaluate the level of indicated mRNAs and proteins respectively. Xenograft assay was used to explore the anti-CRC effect of triacanthine. RESULTS: Triacanthine statistically restrained CRC proliferation both in vitro and in vivo. Triacanthine induced cell cycle G1/G0 phase arrest in CRC cells. Meanwhile, triacanthine also inhibited the migrative and invasive abilities of CRC cells. A Venn diagram was generated showing that O-6-Methylguanine-DNA Methyltransferase (MGMT) might be a molecular target of triacanthine in treating CRC. Furthermore, triacanthine plus 5-FU significantly suppressed the cell proliferation of CRC cells compared with single agent treatment alone, and highly synergistic anti-cancer effects were scored when 5-FU was combined with triacanthine in CRC cells. In addition, triacanthine sensitized the anti-cancer activity of 5-FU via regulating Ribonucleotide Reductase Regulatory Subunit M2 (RRM2). MGMT or RRM2 might be novel biomarkers for evaluating the therapeutical efficiency of 5-FU in CRC patients. CONCLUSION: We firstly demonstrated triacanthine suppressed cell proliferation and metastasis abilities and found the novel molecular targets of triacanthine in CRC cells. This is the first study to evaluate the anti-cancer efficiency of triacanthine plus 5-FU. Our study has revealed triacanthine as a pertinent sensitizer to 5-FU, and provided novel strategies for predicting outcomes and reversing resistance of 5-FU therapy.

Dicopper(II) metallacyclophanes with oligo(p-phenylene-ethynylene) spacers: experimental foundations and theoretical predictions on potential molecular magnetic wires.

Two novel double-stranded dicopper(II) metallacyclophanes of formula (nBu4N)4[Cu2(dpeba)2]·4MeOH·2Et2O (1) and (nBu4N)4[Cu2(tpeba)2]·12H2O (2) have been prepared by the Cu(II)-mediated self-assembly of the rigid ('rod-like') bridging ligands N,N'-4,4'-diphenylethynebis(oxamate) (dpeba) and N,N'-1,4-di(4-phenylethynyl)phenylenebis(oxamate) (tpeba), respectively. Single crystal X-ray diffraction analysis of 1 confirms the presence of a dicopper(II)tetraaza[3.3]4,4'-diphenylethynophane metallacyclic structure featuring a very long intermetallic distance between the two square planar Cu(II) ions [r = 14.95(1) Å]. The overall parallel-displaced π-stacked conformation of the two nearly planar para substituted diphenylethyne spacers [dihedral angle (ψ) of 7.8(1)°] leads to important deviations from the perpendicular orientation of the copper mean basal planes with respect to the facing benzene planes [dihedral angles (φ) of 56.4(1) and 58.4(1)°]. X-band EPR spectra together with variable-temperature magnetic susceptibility and variable-field magnetization measurements of 1 and 2, both in solution and in the solid state, show the occurrence of a non-negligible, moderate to weak intramolecular antiferromagnetic coupling [-J = 3.9-4.1 (1) and 0.5-0.9 cm(-1) (2); H = -JS1·S2 with S1 = S2 = SCu = 1/2]. Density functional calculations on the BS singlet (S = 0) and triplet (S = 1) spin states of the model complexes 1 and 2 with an ideal orthogonal molecular geometry (ψ = 0° and φ = 90°) support the occurrence of a spin polarization mechanism for the propagation of the exchange interaction between the two unpaired electrons occupying the dxy orbital of each square planar Cu(II) ion through the predominantly π-type orbital pathway of the double p-diphenylethyne (1) and di(phenylethynyl)phenylene spacers (2). Time-dependent density functional calculations reproduce the observed bathochromic shift of the main intraligand (IL) π-π* transition in the electronic absorption spectra of 1 and 2 [λ1 = 308 (1) and 316 nm (2)]. In the series of orthogonal model complexes 1-5 with linear oligo(p-phenylene-ethynylene) (OPE) spacers, -C6H4(C≡CC6H4)n- (n = 1-5), a linear increase of the IL π-π* transition energy with the reciprocal of the intermetallic distance is theoretically predicted [νmax = 1.99 × 10(4) + 2.15 × 10(5) (1/r) (S = 0) or ν = 2.01 × 10(4) + 2.18 × 10(5) (1/r) (S = 1)], which clearly indicates that the effective π-conjugation length increases with the number of phenylethyne repeating units. This is accompanied by an exponential decay of the antiferromagnetic coupling with the intermetallic distance [-J = 1.08 × 10(3) exp(-0.31r)], which supports the ability of the extended π-conjugated OPEs to mediate the exchange interaction between the unpaired electrons of the two Cu(II) centers with intermetallic distances in the range of 1.5-4.3 nm. Further developments may be then envisaged for this new family of oxamato-based dicopper(II) oligo-p-phenylethynophanes on the basis of the unique ligand capacity to act as a molecular antiferromagnetic wire.

Recent research progress of circular RNAs in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an extremely heterogeneous malignant tumor with a high morbidity and mortality. Circular RNAs (circRNAs) are noncoding RNAs with high stability, organ/tissue/cell-specific expression and are conserved across species. Accumulating evidence suggested that circRNAs play crucial roles as microRNA sponges, protein sponges, scaffolds, recruiters and could even polypeptide encoders. Many studies have since revealed that circRNAs were aberrantly expressed in HCC and acted as crucial modulators of HCC carcinogenesis and progression. Furthermore, circRNAs have also been identified as potential diagnostic and prognostic biomarkers for HCC. In this review, we thoroughly outline and evaluate the function of circRNAs in HCC development, with an emphasis on the specific molecular pathways by which they participated in the formation and progression of HCC, and we address their potential for serving as clinical biomarkers in HCC.

A facile approach to obtain super-hydrophobicity for cotton fiber fabrics.

It is a challenging task to directly apply emulsified silicone oil to the surface of cotton fabric to obtain superhydrophobic properties. In this work, a temperature-responsive microgel was first synthesized and the particle size and distribution of the microgel, thermo-responsiveness, and hydrophobicity of the microgel membrane were investigated. Then, through an emulsifying PMHS/water system with microgels as a Pickering emulsifier, a series of Pickering emulsions were obtained. The results showed that the emulsion had the best stability when the microgel content was 2.14 wt% and the mass ratio of PMHS/water was 3/7. The optical microscopy showed that the oil phase could be uniformly dispersed in aqueous solution, and the liquid phase particle size was about 10-22 µm. And stratification of the Pickering emulsion did not occur when placed at room temperature for over one month. Finally, when the addition of Pickering emulsion is 50 g L-1 and the rolling rate is 80%, through a simple two-dip-two-padding treatment, a cotton fabric can obtain the superhydrophobic effect with a static contact angle of 149.6° at 25 °C and 156.4° at 45 °C. The development of this work provides a simple method to make cotton fabric obtain superhydrophobic effects.