Thioridazine (THD) is a common phenothiazine antipsychotic drug reported to suppress growth in several types of cancer cells. We previously showed that THD acts as an antiglioblastoma and anticancer ...stem-like cell agent. However, the signaling pathway underlying autophagy and apoptosis induction remains unclear. THD treatment significantly induced autophagy with upregulated AMPK activity and engendered cell death with increased sub-G1 in glioblastoma multiform (GBM) cell lines. Notably, through whole gene expression screening with THD treatment, frizzled (Fzd) proteins, a family of G-protein-coupled receptors, were found, suggesting the participation of Wnt/β-catenin signaling. After THD treatment, Fzd-1 and GSK3β-S9 phosphorylation (inactivated form) was reduced to promote β-catenin degradation, which attenuated P62 inhibition. The autophagy marker LC3-II markedly increased when P62 was released from β-catenin inhibition. Additionally, the P62-dependent caspase-8 activation that induced P53-independent apoptosis was confirmed by inhibiting T-cell factor/β-catenin and autophagy flux. Moreover, treatment with THD combined with temozolomide (TMZ) engendered increased LC3-II expression and caspase-3 activity, indicating promising drug synergism. In conclusion, THD induces autophagy in GBM cells by not only upregulating AMPK activity, but also enhancing P62-mediated autophagy and apoptosis through Wnt/β-catenin signaling. Therefore, THD is a potential alternative therapeutic agent for drug repositioning in GBM.
We aimed to determine whether cardiovascular (CV) risk in patients with prostate cancer (PCa) differs between those who receive gonadotropin-releasing hormone (GnRH) agonist (GnRHa) therapy and those ...who receive GnRH antagonist therapy.
Using the Taiwan National Health Insurance Research Database, we analyzed data by comparing 666 participants receiving GnRH antagonists and 1332 propensity score-matched participants treated with GnRHa in a 1:2 fashion during the period from May 1, 2015, to September 30, 2018. Cox proportional-hazards models were used to estimate the treatment effect on CV outcomes. Furthermore, we conducted an in vitro study to investigate the effect of a GnRHa (leuprolide) or a GnRH antagonist (degarelix) on matrix metalloproteinase-9 (MMP-9) expression and invasion ability in THP-1 differentiated macrophages.
GnRH antagonist therapy was associated with a lower risk of composite CV events of myocardial infarction, ischemic stroke, or CV death (hazard ratio HR, 0.48; 95% confidence interval CI, 0.25-0.90) than GnRHa therapy, with a mean follow-up period of 1.21 years. Significantly lower risks of CV death (HR, 0.21; 95% CI, 0.06-0.70) and all-cause mortality (HR, 0.77; 95% CI, 0.61-0.97) were observed in the GnRH antagonist group. In the in vitro study, leuprolide, but not degarelix, significantly increased the expression of MMP-9 activity and the invasive ability of THP-1 differentiated macrophages through gelatin zymography and the matrix invasion assay, respectively.
GnRH antagonists were associated with reduced risk CV events compared with the GnRHa among patients with PCa, which may be through effects on macrophages.
Few-layer black phosphorus (BP), as the most alluring graphene analogue owing to its similar structure as graphene and thickness dependent direct band-gap, has now triggered a new wave of research on ...two-dimensional (2D) materials based photonics and optoelectronics. However, a major obstacle of practical applications for few-layer BPs comes from their instabilities of laser-induced optical damage. Herein, we demonstrate that, few-layer BPs, which was fabricated through the liquid exfoliation approach, can be developed as a new and practical saturable absorber (SA) by depositing few-layer BPs with microfiber. The saturable absorption property of few-layer BPs had been verified through an open-aperture z-scan measurement at the telecommunication band. The microfiber-based BP device had been found to show a saturable average power of ~4.5 mW and a modulation depth of 10.9%, which is further confirmed through a balanced twin detection measurement. By integrating this optical SA device into an erbium-doped fiber laser, it was found that it can deliver the mode-locked pulse with duration down to 940 fs with central wavelength tunable from 1532 nm to 1570 nm. The prevention of BP from oxidation through the "lateral interaction scheme" owing to this microfiber-based few-layer BP SA device might partially mitigate the optical damage problem of BP. Our results not only demonstrate that black phosphorus might be another promising SA material for ultrafast photonics, but also provide a practical solution to solve the optical damage problem of black phosphorus by assembling with waveguide structures such as microfiber.
Liver cancers, such as hepatocellular carcinoma (HCC), are a highly prevalent cause of cancer-related deaths. Current treatments to combat liver cancer are limited. (-)-Agelasidine A, a compound ...isolated from the methanol extract of
, a sesquiterpene guanidine derived from sea sponge, has antibacterial activity. We demonstrated its anticancer capabilities by researching the associated mechanism of (-)-agelasidine A in human liver cancer cells. We found that (-)-agelasidine A significantly reduced viability in Hep3B and HepG2 cells, and we determined that apoptosis was involved in the (-)-agelasidine A-induced Hep3B cell deaths. (-)-Agelasidine A activated caspases 9, 8, and 3, as well as PARP. This effect was reversed by caspase inhibitors, suggesting caspase-mediated apoptosis in the (-)-agelasidine A-treated Hep3B cells. Moreover, the reduced mitochondrial membrane potential (MMP) and the release of cytochrome c indicated that the (-)-agelasidine A-mediated mitochondrial apoptosis was mechanistic. (-)-Agelasidine A also increased apoptosis-associated proteins (DR4, DR5, FAS), which are related to extrinsic pathways. These events were accompanied by an increase in Bim and Bax, proteins that promote apoptosis, and a decrease in the antiapoptotic protein, Bcl-2. Furthermore, our results presented that (-)-agelasidine A treatment bridged the intrinsic and extrinsic apoptotic pathways. Western blot analysis of Hep3B cells treated with (-)-agelasidine A showed that endoplasmic reticulum (ER) stress-related proteins (GRP78, phosphorylated PERK, phosphorylated eIF2α, ATF4, truncated ATF6, and CHOP) were upregulated. Moreover, 4-PBA, an ER stress inhibitor, could also abrogate (-)-agelasidine A-induced cell viability reduction, annexin V+ apoptosis, death receptor (DR4, DR5, FAS) expression, mitochondrial dysfunction, and cytochrome c release. In conclusion, by activating ER stress, (-)-agelasidine A induced the extrinsic and intrinsic apoptotic pathways of human HCC.
Epidemiological evidence for the association between postdiagnostic metformin use and survival in patients with colorectal cancer (CRC) remains limited. Using the Taiwan Cancer Registry database, a ...cohort of 16,676 diabetic patients newly diagnosed with CRC from January 1, 2004 through December 31, 2014, followed until December 31, 2016, was identified. Postdiagnostic use of metformin (two or more prescriptions after CRC diagnosis) was defined as a time‐dependent covariate with 6‐month lag. Multivariate Cox regression model and stabilized inverse probability of treatment weighting (IPTW) were used to estimate adjusted effects of metformin on all‐cause mortality and CRC‐specific mortality during follow‐up. A number of 11,438 (69%) received metformin after CRC diagnosis. Overall, 7,393 deaths, including 4,845 CRC‐specific deaths, were observed during 64,322 person‐years of follow‐up. After adjustment for demographic and clinical covariates, metformin users had lower all‐cause mortality than did nonusers (hazard ratio HR, 0.42; 95% confidence interval CI, 0.40–0.44) and lower CRC‐specific mortality (HR, 0.41; 95% CI, 0.39–0.44). Similar but somewhat attenuated effects were observed after stabilized IPTW (HR for all‐cause mortality, 0.56; 95% CI, 0.53–0.59; HR for CRC‐specific mortality, 0.58; 95% CI, 0.55–0.61). Similar results were observed in stratified analyses of 2,112 patients with no prediagnostic metformin use and 14,564 patients with prediagnostic metformin use. Findings for both outcomes were consistent in multiple sensitivity analyses. Use of postdiagnostic metformin was associated with significantly lower all‐cause mortality and CRC‐specific mortality, regardless of prior metformin use. These findings support the use of metformin as an adjunct to standard care of diabetic patients with CRC.
What's new?
While diabetic cancer patients treated with the antidiabetic drug metformin potentially experience survival benefits, multiple studies have found conflicting results regarding the effects of metformin on patient outcome. Here, investigation of associations between metformin and outcome in colorectal cancer (CRC) patients shows that metformin use post‐cancer diagnosis significantly lowers all‐cause mortality and CRC‐specific mortality in diabetic CRC patients. The beneficial effects of postdiagnostic metformin on survival were similar across diabetic patient subgroups stratified by age, CRC stage, and metformin use prior to cancer diagnosis. The findings warrant further investigation of metformin as an adjunct therapy in diabetic patients with CRC.
Dual-wavelength passively harmonic mode locking (HML) operation is demonstrated in an erbium-doped fiber laser with a microfiber-based topological insulator (TI) saturable absorber. It was found that ...the dual-wavelength pulse-trains possess different HML orders due to the different cavity nonlinear effects experienced by the two wavelengths. By properly adjusting the cavity parameters, dual-wavelength HML pulses with repetition rates of 388 and 239 MHz were achieved. Moreover, wavelength switchable operation of dual-wavelength HML pulses was also obtained. The experimental results reveal that the microfiber-based TI could indeed be employed as a high-performance dual-function photonic device with the saturable absorption and high nonlinear effects for the applications in fields of ultrafast and nonlinear photonics.
Natural astaxanthin mainly derives from a microalgae producer,
. The induction of nitrogen starvation and high light intensity is particularly significant for boosting astaxanthin production. ...However, the different responses to light intensity and nitrogen starvation needed to be analyzed for biomass growth and astaxanthin accumulation. The results showed that the highest level of astaxanthin production was achieved in nitrogen starvation, and was 1.64 times higher than the control group at 11 days. With regard to the optimization of light intensity utilization, it was at 200 μmo/m²/s under nitrogen starvation that the highest astaxanthin productivity per light intensity was achieved. In addition, both high light intensity and a nitrogen source had significant effects on multiple indicators. For example, high light intensity had a greater significant effect than a nitrogen source on biomass dry weight, astaxanthin yield and astaxanthin productivity; in contrast, nitrogen starvation was more beneficial for enhancing astaxanthin content per dry weight biomass. The data indicate that high light intensity synergizes with nitrogen starvation to stimulate the biosynthesis of astaxanthin.
We reported on the generation of femtosecond pulse in a fiber ring laser by using a polyvinyl alcohol (PVA)-based topological insulator (TI), Bi2Se3 saturable absorber (SA). The PVA-TI composite has ...a low saturable optical intensity of 12 MW/cm2 and a modulation depth of ~3.9%. By incorporating the fabricated PVA-TISA into a fiber laser, mode-locking operation could be achieved at a low pump threshold of 25 mW. After an optimization of the cavity parameters, optical pulse with ~660 fs centered at 1557.5 nm wavelength had been generated. The experimental results demonstrate that the PVA could be an excellent host material for fabricating high-performance TISA, and also indicate that the filmy PVA-TISA is indeed a good candidate for ultrafast saturable absorption device.
Abstract
Context
The association between circulating triglyceride (TG) and glycated hemoglobin A1c (HbA1c), a biomarker for type 2 diabetes, has been widely addressed, but the causal direction of the ...relationship is still ambiguous.
Objective
To confirm the causal relationship between TG and HbA1c by using bidirectional and 2-step Mendelian randomization (MR) approaches.
Methods
We carried out a bidirectional MR approach using the summarized results from the public database to examine any potential causal effects between serum TG and HbA1c in 16 000 individuals of the Taiwan Biobank cohort. We used the MR estimate and the MR inverse variance–weighted method to reveal that relationship between TG and HbA1c. To further determine whether the DNA methylation at specific sequences mediate the causal pathway between TG and HbA1c, using the 2-step MR approach.
Results
We identified that a single-unit increase in TG measured via log transformation of mg/dL data was associated with a significant increase of 10 units of HbA1c (95% CI = 1.05−18.95, P = 0.029). In contrast, the genetic determinants of HbA1c do not contribute to the amount of circulating TG (beta = 1.75, 95% CI = –11.50 to 14.90). Sensitivity analyses, included the weighted-median approach and MR-Egger regression, were performed to confirm no pleiotropic effect among these instrumental variables. Furthermore, we identified the genetic variant, rs1823200, is associated with both methylation of the CpG site adjacent to CADPS gene and HbA1c level.
Conclusion
Our study suggests that higher circulating TG can have an affect on genomic methylation status, ultimately causing elevated level of circulating HbA1c.
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