PI3K δ inhibitor PI-3065 induces apoptosis in hepatocellular carcinoma cells by targeting survivin.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and its clinical treatment remains challenging. The development of new treatment regimens is important for effective HCC treatment. Phosphoinositide 3-kinase (PI3K) is a lipid kinase that plays an important role in cell growth and metabolism and is overexpressed in nearly 50% of patients with HCC. Studies have shown that PI-3065, a small-molecule inhibitor of phosphatidylinositol 3-kinase delta, significantly inhibits solid breast cancer. However, its antitumor effects against HCC and the underlying mechanisms remain unclear. In the present study, we found that PI-3065 dose- and time-dependently reduced HCC cell viability and induced apoptosis while posing no obvious apoptotic toxicity in normal liver cells. Further mechanistic analysis showed that PI-3065 induced apoptosis mainly by inhibiting survivin protein expression, decreasing mitochondrial membrane potential, and promoting cytochrome C release. Simultaneously, PI-3065 markedly suppressed the colony formation, migration, and epithelial-mesenchymal transition abilities of HCC cells. Furthermore, transplantation of nude mice with HCC tumors showed that PI-3065 inhibits HCC tumor growth in vivo by targeting survivin. In summary, PI-3065 specifically inhibited survivin expression and exerted anti-HCC activity in vivo and in vitro, suggesting that it may serve as an effective antitumor drug for HCC treatment, which warrants further study.

Temporal characteristics of the light output from optical fibers with PRBS-modulated laser injection.

Pseudo-random binary sequence (PRBS) phase modulation is an effective method to promote the stimulated Brillouin scattering (SBS) threshold of high-power narrow linewidth fiber lasers. Most studies focus on the subjects of PRBS pattern selection, filter parameter optimization, threshold promotion, etc. In this paper, the temporal characteristics of the light output from optical fibers with PRBS modulated laser injection are investigated theoretically. We found that serious temporal fluctuations, i.e., high intensity pulses, existed in the output laser and backward Stokes light, even though the time-averaged backward Stokes power is only 1% of the input laser power. Based on the transient three wave coupling equations, through exploring the influence of clock rate and PRBS pattern, we demonstrate that this phenomenon arises from the long dwell times in PRBS patterns. Finally, modified PRBS patterns are proposed to significantly eliminate the intense pulses without decreasing the original SBS threshold.

p53 m6A modulation sensitizes hepatocellular carcinoma to apatinib through apoptosis.

Hepatocellular carcinoma (HCC) is insidious and prone to metastasis and recurrence. Currently, no effective treatment is available for HCC. Furthermore, HCC does not respond to various radio- and chemotherapies, and the molecular mechanism of treatment resistance is unclear. Here, we found that p53 n6-methyladenosine (m6A) played a decisive role in regulating HCC sensitivity to chemotherapy via the p53 activator RG7112 and the vascular endothelial growth factor receptor inhibitor apatinib. Our results reveal that p53 activation plays a crucial role in chemotherapy-induced apoptosis and reducing cell viability. Moreover, decreasing m6A methyltransferase (e.g., methyltransferase-like 3, METTL3) expression through chemotherapeutic drug combinations reduced p53 mRNA m6A modification. p53 mRNA m6A modification blockage induced by S-adenosyl homocysteine or siRNA-mediated METTL3 inhibition enhanced HCC sensitivity to chemotherapy. Importantly, we observed that downregulation of METTL3 and upregulation of p53 expression by oral administration of chemotherapy drugs triggered apoptosis and xenograft tumor growth inhibition in nude mice. Based on these findings, we hypothesize that a METTL3-m6A-p53 axis could be a potential target in HCC therapy.

Resina Draconis extract exerts anti-HCC effects through METTL3-m6A-Survivin axis.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Herbal medicines have become an important treasure reservoir for anti-HCC drugs because of their high efficiency and low toxicity. Herein, we investigated whether a 75% ethanol extract from Resina Draconis (ERD) exhibited comprehensive anti-HCC effects both in vivo and in vitro. We revealed that ERD effectively inhibited proliferation and triggered apoptosis of HCC cells in a dose- and time-dependent maner, posing no apparent apoptotic toxicity to normal liver cells. Moreover, ERD significantly inhibited the migration, invasion and metastasis of HCC cells. Importantly, ERD treatment effectively inhibited the growth of xenograft HCC in nude mice with low toxicity and low side effects. Molecular mechanism analysis showed that ERD strongly reduced the expression of anti-apoptotic protein Survivin, ultimately leading to the cleavage activation of apoptosis executive proteins such as Caspase 3 and Poly (ADP-ribose) polymerase (PARP). Survivin gene silencing apparently sensitized the apoptotic effect induced by ERD. Further experiments revealed that ERD inhibited N6-methyladenosine (m6 A) modification in Survivin mRNA by downregulating Methyltransferase-like 3 (METTL3) expression and reducing the binding rate of METTL3 and Survivin mRNA. Together, our findings suggest that ERD can be severed as a novel anti-HCC natural product by targeting METTL3-m6 A-Survivin axis.

The HSP90 inhibitor, XL888, enhanced cell apoptosis via downregulating STAT3 after insufficient radiofrequency ablation in hepatocellular carcinoma.

AIMS: Radiofrequency ablation (RFA) is the first-line option for early-stage hepatocellular carcinoma (HCC). However, the residual tumor attributed to insufficient RFA (iRFA) led to tumor recurrence and metastasis. Novel combination strategies are urgently needed to enhance efficiency of RFA. MAIN METHODS: For in vitro iRFA models, HCC cells were placed in a water bath at 46 °C for 10 min and then returned to the original incubator. For in vivo models, HCC cells were implanted subcutaneously into nude mice. The nude mice were then randomly assigned into 4 groups: control group, XL888 group, iRFA group, combination of XL888 and iRFA group. CCK8 was performed to detect cell viability; Hoechst 33258 was used to explore nuclear morphology; The expression levels of proteins were demonstrated by western blotting; Co-localization of HSP90 and STAT3 was elucidated by immunofluorescence confocal microscopy; Immunohistochemistry was used to explore expression levels of proteins at tissue level. KEY FINDINGS: XL888 promoted apoptosis of HCC cells induced by heat via inhibiting expression levels of Mcl-1 and cleaved-caspase 3 in vivo and in vitro. XL888 attenuated the complex formation of HSP90 and STAT3, leading to decreased expression levels of STAT3 and p-STAT3. In human HCC tissues, IHC scores of HSP90 were positively correlated with those of STAT3. Overexpression of STAT3 rescued cell apoptosis induced by co-treatment of XL888 and heat. SIGNIFICANCE: We implied that XL888 promoted apoptosis of HCC cells induced by heat via disrupting the binding of HSP90 and STAT3, providing theoretical basis for a novel combination strategy for HCC.

Foeniculum vulgare seed extract induces apoptosis in lung cancer cells partly through the down-regulation of Bcl-2.

The factors behind the pathogenesis of lung cancer are not clear, and treatment failure is generally caused by drug resistance, recurrence, and metastasis. Development of new therapeutic agents to overcome drug-resistance remains a challenge clinically. Various extracts of Foeniculum vulgare have shown promising anticancer activity; however, effects on lung cancer and the underlying molecular mechanisms of action are not clear. In the present study, we found that the ethanol extract of Foeniculum vulgare seeds (EEFS) significantly reduced lung cancer cell growth in vitro and in vivo. EEFS decreased the viability of and triggered apoptosis in the lung cancer cell lines NCI-H446 and NCI-H661. EEFS induced apoptosis mainly through inhibition of Bcl-2 protein expression, reduction of mitochondrial membrane potential, and release of Cytochrome C. Moreover, EEFS significantly inhibited colony formation and cell migration in lung cancer cells. EEFS also effectively inhibited the growth of xenograft tumors derived from NCI-446 cells by reducing Bcl-2 protein expression and inducing apoptosis. Taken together, these findings suggest that EEFS exerts anti-lung cancer activity by targeting the Bcl-2 protein and may have potential as a therapeutic drug for lung cancer.

Foeniculum vulgare seed extract exerts anti-cancer effects on hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. The prognosis of HCC is very poor due to the absence of symptoms and a lack of effective treatments. Studies have shown that various Foeniculum vulgare (fennel) extracts exhibit anti-cancer effects on malignant tumors such as skin cancer and prostate cancer. However, the anti-tumor activity of Foeniculum vulgare and its underlying molecular mechanisms towards HCC are unknown. Here, we provide fundamental evidence to show that the 75% ethanol extract of Foeniculum vulgare seeds (FVE) reduced cell viability, induced apoptosis, and effectively inhibited cell migration in HCC cells in vitro. HCC xenograft studies in nude mice showed that FVE significantly inhibited HCC growth in vivo. Mechanistic analyses showed that FVE reduced survivin protein levels and triggered mitochondrial toxicity, subsequently inducing caspase-3 activation and apoptosis. Survivin inhibition effectively sensitized HCC cells to FVE-induced apoptosis. Moreover, FVE did not induce a decrease in survivin or apoptotic toxicity in normal liver cells. Collectively, in vivo and in vitro results suggest that FVE exerts inhibitory effects in HCC by targeting the oncoprotein survivin, suggesting FVE may be a potential anti-cancer agent that may benefit patients with HCC.

1.5 kW polarization-maintained Yb-doped amplifier with 13 GHz linewidth by suppressing the self-pulsing and stimulated Brillouin scattering.

In this work, we study the characteristics of self-pulsing in a polarization-maintained fiber amplifier operated with different linewidths based on white noise source phase modulation. It indicates that the self-pulsing is almost simultaneous with the stimulated Brillouin scattering process, and its threshold is increasing near-linearly with the linewidth. By optimizing the laser structure, the threshold of self-pulsing increases by a factor of 1.5. We demonstrate a high-power linear polarization and all-fiberized amplifier with narrow linewidth and near-diffraction-limited beam quality. The output power scales to 1.5 kW with the pumping efficiency of 83%. The full width at half-maximum linewidth was measured to be 13 GHz. The polarization extinction ratio was larger than 13 dB. The beam quality M2 was about 1.14 at the maximum laser power.

NOB1: A Potential Biomarker or Target in Cancer.

Human NIN1/RPN12 binding protein 1 homolog (NOB1), an RNA binding protein, is expressed ubiquitously in normal tissues such as the lung, liver, and spleen. Its core physiological function is to regulate protease activities and participate in maintaining RNA metabolism and stability. NOB1 is overexpressed in a variety of cancers, including pancreatic cancer, non-small cell lung cancer, ovarian cancer, prostate carcinoma, osteosarcoma, papillary thyroid carcinoma, colorectal cancer, and glioma. Although existing data indicate that NOB1 overexpression is associated with cancer growth, invasion, and poor prognosis, the molecular mechanisms behind these effects and its exact roles remain unclear. Several studies have confirmed that NOB1 is clinically relevant in different cancers, and further research at the molecular level will help evaluate the role of NOB1 in tumors. NOB1 has become an attractive target in anticancer therapy because it is overexpressed in many cancers and mediates different stages of tumor development. Elucidating the role of NOB1 in different signaling pathways as a potential cancer treatment will provide new ideas for existing cancer treatment methods. This review summarizes the research progress made into NOB1 in cancer in the past decade; this information provides valuable clues and theoretical guidance for future anticancer therapy by targeting NOB1.

5kW GTWave fiber amplifier directly pumped by commercial 976nm laser diodes.

With home-made fiber perform and special fiber drawing & coating technique, a new-type of (3 + 1) GTWave fiber theoretically designed for bi-directional pump method, was successfully fabricated and justified of integrating multi-kW pump energy from commercial 976nm laser diodes. This (3 + 1) GTWave fiber amplifier demonstrated uniform absorption of pump light and easy thermal management characteristics along the whole fiber length. This amplifier is capable of simultaneously aggregating 5.19kW pump power at 976nm and finally generating 5.07kW laser output at 1066.5nm with an optical-to-optical efficiency of 74.5%, the first publically-reported multi-kW GTWave fiber directly pumped with commercial 976nm laser diodes to the best of our knowledge. No power roll-over was found at 5kW level and further power scaling can be expected with more pump power. The results indicate that GTWave fiber is a competitive integrated fiber device to collect enough pump energy from low-cost commercial laser diodes for multi-kW fiber laser development.

Thermal-induced two dimensional beam distortion in planar waveguide amplifiers.

Mode characteristics in the solid-state planar waveguide (PWG) laser amplifiers are investigated theoretically, in consideration of the temperature gradient generated by cooling across the thickness and by pumping inhomogeneity along the width direction. When variation of the refractive index along the width direction is dominated by the lower spatial frequencies, the vector wave equation is solved analytically by means of the perturbation method. It is similar to the zigzag slab amplifier in which the phase aberration depending on the width coordinate plays the most important role to cause degradation of the beam quality. The crossing mode distortions owing to two dimension nature of the index variations are illustrated, and that mode profile is varied by the index variation along both the thickness and the width directions. Modes in the single-mode or the few-mode PWGs are shown to suffer weaker thermal-induced distortion across the thickness than those in the multi-mode PWGs.

Thermally induced mode distortion and its limit to power scaling of fiber lasers.

A general model is proposed to describe thermal-induced mode distortion in the step-index fiber (SIF) high power lasers. Two normalized parameters in the model are able to determine the mode characteristic in the heated SIFs completely. Shrinking of the mode fields and excitation of the high-order modes by the thermal-optic effect are investigated. A simplified power amplification model is used to describe the output power redistribution under various guiding modes. The results suggest that fiber with large mode area is more sensitive on the thermally induced mode distortion and hence is disadvantaged in keeping the beam quality in high power operation. The model is further applied to improve the power scaling analysis of Yb-doped fiber lasers. Here the thermal effect is considered to couple with the optical damage and the stimulated Raman scattering dynamically, whereas direct constraint from the thermal lens is relaxed. The resulting maximal output power is from 67kW to 97kW, depending on power fraction of the fundamental mode.