Evaluating the Usability of mHealth Apps: An Evaluation Model Based on Task Analysis Methods and Eye Movement Data.

Advancements in information technology have facilitated the emergence of mHealth apps as crucial tools for health management and chronic disease prevention. This research work focuses on mHealth apps for the management of diabetes by patients on their own. Given that China has the highest number of diabetes patients in the world, with 141 million people and a prevalence rate of 12.8% (mentioned in the Global Overview of Diabetes), the development of a usability research methodology to assess and validate the user-friendliness of apps is necessary. This study describes a usability evaluation model that combines task analysis methods and eye movement data. A blood glucose recording application was designed to be evaluated. The evaluation was designed based on the model, and the feasibility of the model was demonstrated by comparing the usability of the blood glucose logging application before and after a prototype modification based on the improvement suggestions derived from the evaluation. Tests showed that an improvement plan based on error logs and post-task questionnaires for task analysis improves interaction usability by about 24%, in addition to an improvement plan based on eye movement data analysis for hotspot movement acceleration that improves information access usability by about 15%. The results demonstrate that this study presents a usability evaluation model for mHealth apps that enables the effective evaluation of the usability of mHealth apps.

3D-Printed Ultracompact Multicore Fiber-Tip Probes for Simultaneous Measurement of Nanoforce and Temperature.

Optical fiber force sensing has attracted considerable interest in biological, materials science, micromanipulation, and medical applications owing to its compact and cost-efficient configuration. However, the glass fiber has an intrinsic high Young's modulus, resulting in force sensors being generally less sensitive. While hyperelastic polymer materials can be utilized to enhance the force sensitivity, the thermodynamic properties of the polymer may weaken the sensing accuracy and reliability. Herein, we demonstrate ultracompact three-dimensional (3D)-printed multicore fiber (MCF) tip probes for simultaneous measurement of nanoforce and temperature with high sensitivity. The sensor is highly sensitive to force-induced deformation due to the special geometric features of the polymer microcantilever, and the high-temperature sensitivity can be implemented through the poly(dimethylsiloxane) (PDMS) microcavity on the same fiber facet. Moreover, the sensitivities of the fiber interferometers are remarkably enhanced by introducing the optical analogue of the Vernier effect. Such a device exhibits a force sensitivity of 56.35 nm/µN, which is more than 103 times that of all-silica fiber force sensors. The PDMS microcavity provides a temperature sensitivity of 1.447 nm/°C, measuring the local temperature of the probe and compensating for temperature crosstalk of the force detection. The proposed compact MCF-tip sensor can simultaneously measure nanoforce and temperature with high sensitivity, facilitating multiparameter sensing in a restricted space environment and showing the potential in miniaturized all-fiber multiparameter sensors.

Ultra-Bend-Resistant 4-Core Simplex Cable Used for Short-Reach Dense Spatial Division Multiplexing Optical Transmission.

We optimized and fabricated an ultra-bend-resistant 4-core simplex cable (SXC) employing 4-core multicore fiber (MCF) suitable for short-reach dense spatial division multiplexing (DSDM) optical transmission in the O-band. The characteristics of transmission loss, macro-bending and cross-talk (XT) between adjacent cores after cabling were firstly clarified. By introducing the trapezoid index and optimizing the cabling process, the maximum values of added XT of 1.17 dB/km due to 10 loops with a bending radius of 6 mm imposed over the 4-core SXC and a macro-bending loss of 0.37 dB/10 turns were, respectively, achieved.P Then, the optical transmission with low bit error rate (BER) was presented using a 100GBASE-LR4 transceiver over the 1.2 km long 4-core SXC. The excellent bending resistance of the 4-core SXC may pave the way for a reduction in space pressure and increase in access density on short-reach optical interconnect (OI) based on DSDM.

Elucidating the hydrotropism behaviour of aqueous caffeine and sodium benzoate solution through NMR and neutron total scattering analysis.

Hydrotropism is a convenient way to increase the solubility of drugs by up to several orders of magnitude, and even though it has been researched for decades with both experimental and simulation methods, its mechanism is still unknown. Here, we use caffeine/sodium benzoate (CAF-SB) as model system to explore the behaviour of caffeine solubility enhancement in water through NMR spectroscopy and neutron total scattering. 1H NMR shows strong interaction between caffeine and sodium benzoate in water. Neutron total scattering combined with empirical potential structure refinement, a systematic method to study the solution structure, reveals π-stacking between caffeine and the benzoate anion as well as Coulombic interactions with the sodium cation. The strongest hydrogen bond interaction in the system is between benzoate and water, which help dissolve CAF-SB complex and increase the solubility of CAF in water. Besides, the stronger interaction between CAF and water and the distortion of water structure are further mechanisms of the CAF solubility enhancement. It is likely that the variety of mechanisms for hydrotropism shown in this system can be found for other hydrotropes, and NMR spectroscopy and neutron total scattering can be used as complementary techniques to generate a holistic picture of hydrotropic solutions.

Two fiber-bundle-type FI/FO devices of low insertion loss and cross talk applied for connecting 13-core 5-mode fiber.

Two fiber-bundle-typed fan-in/fan-out (FI/FO) devices, "wavy hexagon-shaped silhouette" type (W-FI/FO) and "tortoise-shaped silhouette" type (T-FI/FO), have been proposed and manufactured based on tapering glass tubes for docking with a self-made 13-core 5-mode fiber. The W-FI/FO device consists of 19 5-mode fibers and has an extended layout based on the 13-core 5-mode fiber structure. It could dock multiple fibers with 19 or 13 cores of the same size standards. When connecting it with 13-core 5-mode, the average losses (ILs) of its five modes are 1.07 dB, 2.95 dB, 3.42 dB, 3.65 dB, and 4.38 dB. The cross talks of the five linearly polarized (LP) modes are -69.1 dB, -64.7 dB, -44.2 dB, -43.9 dB, and -39.1 dB. The T-FI/FO device has a similar core arrangement to the 13-core 5-mode fiber and its average ILs of the five LP modes are 0.23 dB, 1.31 dB, 2.09 dB, 2.66 dB, and 3.03 dB. The cross talks of its five LP modes between adjacent cores are -72.8 dB, -67.8 dB, -43.6 dB, -40.0 dB, and -35.3 dB. The IL and cross talk of the LP01 mode are of satisfactory values, which are 0.23 dB and -72.8 dB, respectively. These two proposed FI/FO devices are expected to be used for high-speed optical interconnection and fiber communication.

Transmissive fluorescent temperature sensor based on Er3+/Yb3+/Mo6+ tri-doped tellurite fiber for real-time thermal monitoring of motors using the FIR technique.

In this paper, we fabricate a transmissive fluorescent temperature sensor (TFTS) that based on Er3+/Yb3+/Mo6+ tri-doped tellurite fiber, which has the advantages of compactness and simplicity, corrosion resistance, high stability and anti-electromagnetic interference. The doping of Mo6+ ions will enhance the up-conversion (UC) fluorescence emission efficiency of Er3+ ions, thus improving the signal-to-noise ratio of TFTS. Using the fluorescence intensity ratio (FIR) technique, the real-time thermal monitoring performance of TFTS is evaluated experimentally. Apart from good stability, its maximum relative sensitivity is 0.01068 K-1 at 274 K in the measured temperature range. In addition, it is successfully used to monitor the temperature variation of the stator core and stator winding of the motor in actual operation. The results show that the maximum error between the FIR-demodulated temperature and the reference temperature is less than 1.2 K, which fully confirms the effectiveness of the TFTS for temperature monitoring. Finally, the FIR-based TFTS in this work is expected to provide a new solution for accurate and real-time thermal monitoring of motors and the like.

Low crosstalk trapezoid-index thirteen-core single-mode fiber for multi-channel and high-density applications.

Multi-core fiber based on space division multiplexing technology provides a practical solution to achieve multi-channel and high-capacity signal transmission. However, long-distance and error-free transmission remains challenging due to the presence of inter-core crosstalk within the multi-core fiber. Here, we propose and prepare a novel trapezoid-index thirteen-core single-mode fiber to solve the problems that MCF has large inter-core crosstalk and the transmission capacity of single-mode fiber approaches the upper limit. The optical properties of thirteen-core single-mode fiber are measured and characterized by experimental setups. The inter-core crosstalk of the thirteen-core single-mode fiber is less than -62.50 dB/km at 1550 nm. At the same time, each core can transmit signals at a data rate of 10 Gb/s and achieve error-free signal transmission. The prepared optical fiber with a trapezoid-index core provides a new and feasible solution for reducing inter-core crosstalk, which can be loaded into current communication systems and applied in large data centers.

Using Prenucleation Aggregation of Caffeine-Benzoic Acid as a Rapid Indication of Co-crystallization from Solutions.

Co-crystal design is a convenient way to remedy the poor biopharmaceutical properties of drugs. Most studies focus on experimental co-crystal screening or computational prediction, but hardly any work has been done toward fast, efficient, and reliable prediction of solution crystallization for co-crystal formation. Here, we study the caffeine-benzoic acid co-crystal system, due to its reported difficulty to crystallize from the solution phase. With this work, we investigate whether there is a link between prenucleation aggregation in solution and co-crystal formation and how to harness this for crystallization prediction. 1H and 13C NMR spectroscopy is used to study the prenucleation interaction between caffeine and benzoic acid in methanol, acetone, and acetonitrile as examples of common solvents. In this system, crystallization from methanol leads to no co-crystallization, from acetone to concomitant crystallization of co-crystal and caffeine, and from acetonitrile to pure co-crystal formation from solution. Strong heteromeric dimers were found to exist in all three solvents. Ternary phase diagrams were defined and a solution-accessible co-crystal region was found for all solvents. For this system, the prenucleation clusters found in solution could be linked to the crystallization of the co-crystal. Crystallization from DMSO did not yield the co-crystal and there were no detectable prenucleation aggregates. NMR spectroscopy to probe dimers in solution can thus be used as a fast, reliable, and promising tool to predict co-crystallization from specific solvents and to screen for suitable solvents for manufacturing and scale-up.

Fabrication and Characterization of an Optimized Low-Loss Two-Mode Fiber for Optoacoustic Sensing.

An optimized multi-step index (MSI) 2-LP-mode fiber is proposed and fabricated with low propagation loss of 0.179 dB/km, low intermodal crosstalk and excellent bend resistance. We experimentally clarified the characteristics of backward Brillouin scattering (BBS) and forward Brillouin scattering (FBS) induced by radial acoustic modes (R0,m) in the fabricated MSI 2-LP-mode fiber, respectively. Via the use of this two-mode fiber, we demonstrated a novel discriminative measurement method of temperature and acoustic impedance based on BBS and FBS, achieving improved experimental measurement uncertainties of 0.2 °C and 0.019 kg/(s·mm2) for optoacoustic chemical sensing. The low propagation loss of the sensing fiber and the new measurement method based on both BBS and FBS may pave the way for long-distance and high spatial resolution distributed fiber sensors.

Patient-derived tumor organoids as a platform of precision treatment for malignant brain tumors.

Malignant brain tumors consist of malignancies originated primarily within the brain and the metastatic lesions disseminated from other organs. In spite of intensive studies, malignant brain tumors remain to be a medical challenge. Patient-derived organoid (PDO) can recapitulate the biological features of the primary tumor it was derived from and has emerged as a promising drug-screening model for precision therapy. Here we show a proof-of-concept based on early clinical study entailing the organoids derived from the surgically resected tumors of 26 patients with advanced malignant brain tumors enrolled during December 2020 to October 2021. The tumors included nine glioma patients, one malignant meningioma, one primary lymphoma patient, and 15 brain metastases. The primary tumor sites of the metastases included five from the lungs, three from the breasts, two from the ovaries, two from the colon, one from the testis, one of melanoma origin, and one of chondrosarcoma. Out of the 26 tissues, 13 (50%) organoids were successfully generated with a culture time of about 2 weeks. Among these patients, three were further pursued to have the organoids derived from their tumor tissues tested for the sensitivity to different therapeutic drugs in parallel to their clinical care. Our results showed that the therapeutic effects observed by the organoid models were consistent to the responses of these patients to their treatments. Our study suggests that PDO can recapitulate patient responses in the clinic with high potential of implementation in personalized medicine of malignant brain tumors.

Growth-promoting function of the cGAS-STING pathway in triple-negative breast cancer cells.

The cGAS-STING axis is one of the key mechanisms guarding cells from pathogen invasion in the cytoplasmic compartment. Sensing of foreign DNA in the cytosol by the cGAS-STING axis triggers a stress cascade, culminating at stimulation of the protein kinase TBK1 and subsequently activation of inflammatory response. In cancer cells, aberrant metabolism of the genomic DNA induced by the hostile milieu of tumor microenvironment or stresses brought about by cancer therapeutics are the major causes of the presence of nuclear DNA in the cytosol, which subsequently triggers a stress response. However, how the advanced tumors perceive and tolerate the potentially detrimental effects of cytosolic DNA remains unclear. Here we show that growth limitation by serum starvation activated the cGAS-STING pathway in breast cancer cells, and inhibition of cGAS-STING resulted in cell death through an autophagy-dependent mechanism. These results suggest that, instead of being subject to growth inhibition, tumors exploit the cGAS-STING axis and turn it to a survival advantage in the stressful microenvironment, providing a new therapeutic opportunity against advanced cancer. Concomitant inhibition of the cGAS-STING axis and growth factor signaling mediated by the epidermal growth factor receptor (EGFR) synergistically suppressed the development of tumor organoids derived from primary tumor tissues of triple-negative breast cancer (TNBC). The current study unveils an unexpected function of the cGAS-STING axis in promoting cancer cell survival and the potential of developing the stress-responding pathway as a therapeutic target, meanwhile highlights the substantial concerns of enhancing the pathway's activity as a means of anti-cancer treatment.

The Functions of PCNA in Tumor Stemness and Invasion.

Invasion is the most prominent lethal feature of malignant cancer. However, how cell proliferation, another important feature of tumor development, is integrated with tumor invasion and the subsequent cell dissemination from primary tumors is not well understood. Proliferating cell nuclear antigen (PCNA) is essential for DNA replication in cancer cells. Loss of phosphorylation at tyrosine 211 (Y211) in PCNA (pY211-PCNA) mitigates PCNA function in proliferation, triggers replication fork arrest/collapse, which in turn sets off an anti-tumor inflammatory response, and suppresses distant metastasis. Here, we show that pY211-PCNA is important in stromal activation in tumor tissues. Loss of the phosphorylation resulted in reduced expression of mesenchymal proteins as well as tumor progenitor markers, and of the ability of invasion. Spontaneous mammary tumors that developed in mice lacking Y211 phosphorylation contained fewer tumor-initiating cells compared to tumors in wild-type mice. Our study demonstrates a novel function of PCNA as an essential factor for maintaining cancer stemness through Y211 phosphorylation.

De-glycosylated membrane PD-L1 in tumor tissues as a biomarker for responsiveness to atezolizumab (Tecentriq) in advanced breast cancer patients.

The atezolizumab (Tecentriq), a humanized antibody against human programmed death ligand 1 (PD-L1), combined with nab-paclitaxel was granted with accelerated approval to treat unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) due to the encouraging positive results of the phase 3 IMpassion130 trial using PD-L1 biomarker from immune cells to stratify patients. However, the post-market study IMpassion131 did not support the original observation, resulting in the voluntary withdrawal of atezolizumab from the indication in breast cancer by Genentech in 2021. Emerging evidence has revealed a high frequency of false negative result using the standard immunohistochemical (IHC) staining due to heavy glycosylation of PD-L1. The removal of glycosylation prevents from the false negative staining, enabling more accurate assessment of PD-L1 levels and improving prediction for response to immune checkpoint therapy. In the present study, the natural and de-glycosylated PD-L1 expression in tumor and immune cells from nine TNBC patients were analyzed by using clone 28-8 monoclonal antibody to correlate with treatment outcome. Our results demonstrate that: (1) Removal of the glycosylation indeed enhances the detection of PD-L1 by IHC staining, (2) The PD-L1 levels on tumor cell surface after removal of the glycosylation correlates well with clinical responses for atezolizumab treatment; (3) The criteria used in the IMpassion130 and IMpassion131 trials which scored the natural PD-L1 in the immune cells failed to correlate with the clinical response. Taken together, tumor cell surface staining of PD-L1 with de-glycosylation has a significant correlation with the clinical response for atezolizumab treatment, suggesting that treatment of atezolizumab may be worthy of further consideration with de-glycosylation procedure as a patient stratification strategy. A larger cohort to validate this important issue is warranted to ensure right patient population who could benefit from the existing FDA-approved drugs.

miR-4759 suppresses breast cancer through immune checkpoint blockade.

Programmed cell death protein 1 (PD-1)/ programmed cell death protein ligand 1 (PD-L1) is the key immune checkpoint governing evasion of advanced cancer from immune surveillance. Immuno-oncology (IO) therapy targeting PD-1/PD-L1 with traditional antibodies is a promising approach to multiple cancer types but to which the response rate remains moderate in breast cancer, calling for the need of exploring alternative IO targeting approaches. A miRNA-gene network was integrated by a bioinformatics approach and corroborated with The Cancer Genome Atlas (TCGA) to screen miRNAs regulating immune checkpoint genes and associated with patient survival. Here we show the identification of a novel microRNA miR-4759 which repressed RNA expression of the PD-L1 gene. miR-4759 targeted the PD-L1 gene through two binding motifs in the 3' untranslated region (3'-UTR) of PD-L1. Reconstitution of miR-4759 inhibited PD-L1 expression and sensitized breast cancer cells to killing by immune cells. Treatment with miR-4759 suppressed tumor growth of orthotopic xenografts and promoted tumor infiltration of CD8+ T lymphocytes in immunocompetent mice. In contrast, miR-4759 had no effect to tumor growth in immunodeficient mice. In patients with breast cancer, expression of miR-4759 was preferentially downregulated in tumors compared to normal tissues and was associated with poor overall survival. Together, our results demonstrated miR-4759 as a novel non-coding RNA which promotes anti-tumor immunity of breast cancer.

Evading immune surveillance via tyrosine phosphorylation of nuclear PCNA.

Increased DNA replication and metastasis are hallmarks of cancer progression, while deregulated proliferation often triggers sustained replication stresses in cancer cells. How cancer cells overcome the growth stress and proceed to metastasis remains largely elusive. Proliferating cell nuclear antigen (PCNA) is an indispensable component of the DNA replication machinery. Here, we show that phosphorylation of PCNA on tyrosine 211 (pY211-PCNA) regulates DNA metabolism and tumor microenvironment. Abrogation of pY211-PCNA blocks fork processivity, resulting in biogenesis of single-stranded DNA (ssDNA) through a MRE11-dependent mechanism. The cytosolic ssDNA subsequently induces inflammatory cytokines through a cyclic GMP-AMP synthetase (cGAS)-dependent cascade, triggering an anti-tumor immunity by natural killer (NK) cells to suppress distant metastasis. Expression of pY211-PCNA is inversely correlated with cytosolic ssDNA and associated with poor survival in patients with cancer. Our results pave the way to biomarkers and therapies exploiting immune responsiveness to target metastatic cancer.

Imatinib (STI571) Inhibits the Expression of Angiotensin-Converting Enzyme 2 and Cell Entry of the SARS-CoV-2-Derived Pseudotyped Viral Particles.

A group of clinically approved cancer therapeutic tyrosine kinase inhibitors was screened to test their effects on the expression of angiotensin-converting enzyme 2 (ACE2), the cell surface receptor for SARS-CoV-2. Here, we show that the receptor tyrosine kinase inhibitor imatinib (also known as STI571, Gleevec) can inhibit the expression of the endogenous ACE2 gene at both the transcript and protein levels. Treatment with imatinib resulted in inhibition of cell entry of the viral pseudoparticles (Vpps) in cell culture. In FVB mice orally fed imatinib, tissue expression of ACE2 was reduced, specifically in the lungs and renal tubules, but not in the parenchyma of other organs such as the heart and intestine. Our finding suggests that receptor tyrosine kinases play a role in COVID-19 infection and can be therapeutic targets with combined treatments of the best conventional care of COVID-19.

Flavokawain B and Doxorubicin Work Synergistically to Impede the Propagation of Gastric Cancer Cells via ROS-Mediated Apoptosis and Autophagy Pathways.

Chalcone flavokawain B (FKB) possesses a chemopreventive and anti-cancer activity. Doxorubicin is a chemotherapeutic DNA intercalating agent widely used in malignancy treatment. The present study investigated whether synergistic effects exist between the combination of FKB (1.25-5 µg/mL) and doxorubicin (0.5 µg/mL) on the apoptosis and autophagy in human gastric cancer (AGS) cells, and the possible in vitro and in vivo mechanisms. The MTT assay measured cell viability. Various apoptotic-, autophagy-associated protein expression was determined by the Western blot technique. FKB+doxorubicin synergy was estimated by the Chou-Talalay combination index (CI) method. In vivo studies were performed on BALB/c mice. Results showed that compared to FKB/doxorubicin treatments, low doses of FKB+doxorubicin suppressed AGS cell growth. FKB potentiated doxorubicin-induced DNA fragmentation, apoptotic cell death, and enhanced doxorubicin-mediated mitochondrial, death receptor pathways. FKB+doxorubicin activated increased LC3-II accumulation, p62/SQSTM1 expression, and AVO formation as compared to the FKB/doxorubicin alone treatments indicating autophagy in these cells. The death mechanism in FKB+doxorubicin-treated AGS cells is due to the activation of autophagy. FKB+doxorubicin-mediated dysregulated Bax/Bcl-2, Beclin-1/Bcl-2 ratios suggested apoptosis, autophagy induction in AGS cells. FKB+doxorubicin-induced LC3-II/AVOs downregulation was suppressed due to an apoptotic inhibitor Z-VAD-FMK. Whereas, 3-methyladenine/chloroquine weakened FKB+doxorubicin-induced apoptosis (decreased DNA fragmentation/caspase-3). Activation of ERK/JNK may be involved in FKB+doxorubicin-induced apoptosis and autophagy. FKB+doxorubicin-triggered ROS generation, but NAC attenuated FKB+doxorubicin-induced autophagic (LC3 accumulation) and apoptotic (caspase-3 activation and PARP cleavage) cell death. FKB+doxorubicin blocked gastric cancer cell xenografts in nude mice in vivo as compared to FKB/doxorubicin alone treatments. FKB and doxorubicin wielded synergistic anti-tumor effects in gastric cancer cells and is a promising therapeutic approach.

Tannic acid suppresses SARS-CoV-2 as a dual inhibitor of the viral main protease and the cellular TMPRSS2 protease.

The cell surface protein TMPRSS2 (transmembrane protease serine 2) is an androgen-responsive serine protease important for prostate cancer progression and therefore an attractive therapeutic target. Besides its role in tumor biology, TMPRSS2 is also a key player in cellular entry by the SARS-CoV viruses. The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has resulted in huge losses in socio-economy, culture, and human lives for which safe and effective cures are highly demanded. The main protease (Mpro/3CLpro) of SARS-CoV-2 is a critical enzyme for viral propagation in host cells and, like TMPRSS2, has been exploited for treatment of the infectious disease. Numerous natural compounds abundant in common fruits have been suggested with anti-coronavirus infection in the previous outbreaks of SARS-CoV. Here we show that screening of these compounds identified tannic acid a potent inhibitor of both SARS-CoV-2 Mpro and TMPRSS2. Molecular analysis demonstrated that tannic acid formed a thermodynamically stable complex with the two proteins at a KD of 1.1 mM for Mpro and 1.77 mM for TMPRSS2. Tannic acid inhibited the activities of the two proteases with an IC50 of 13.4 mM for Mpro and 2.31 mM for TMPRSS2. Mpro protein. Consistently, functional assays using the virus particles pseudotyped (Vpp) of SARS-CoV2-S demonstrated that tannic acid suppressed viral entry into cells. Thus, our results demonstrate that tannic acid has high potential of developing anti-COVID-19 therapeutics as a potent dual inhibitor of two independent enzymes essential for SARS-CoV-2 infection.

Ganoderma tsugae induced ROS-independent apoptosis and cytoprotective autophagy in human chronic myeloid leukemia cells.

The medicinal fungus Ganoderma, known in Chinese as Lingzhi or Reishi, traditionally has various medicinal uses and has been employed in cancer treatment in Asia for centuries. This study used ethanol-extracted Ganoderma tsugae (GT) and examined its antitumor activities on human chronic myeloid leukemia cells as well as its molecular mechanism of action. Treatment with GT (200-400 µg/mL) significantly reduced cell viability and caused G2/M arrest in K562 cells. In addition, GT induced mitochondrial and death receptor mediated apoptosis, correlated with DNA fragmentation, followed by cytochrome c release, caspase-3/8/9 activation, PARP cleavage, Fas activation, Bid cleavage, and Bax/Bcl-2 dysregulation. Cytoprotective autophagy was found to be induced by GT, as was revealed by increased LC3-II accumulation, Beclin-1/Bcl-2 dysregulation, acidic vesicular organelle formation, and p62/SQSTM1 activation. Notably, pretreatment of cells with the autophagy inhibitors 3-MA and CQ enhanced GT-induced apoptosis. Interestingly, reactive oxygen species production in cells was not triggered by GT administration; equally, the antioxidant N-acetylcysteine was found to be incapable of preventing apoptosis and autophagy induced by GT treatment. Finally, this study discovered that cytoprotective autophagy induced by GT was associated with EGFR and PI3K/AKT/mTOR signaling cascade suppression. In summary, GT demonstrated antitumor activity against human chronic myeloid leukemia.

Antitumor properties of Coenzyme Q0 against human ovarian carcinoma cells via induction of ROS-mediated apoptosis and cytoprotective autophagy.

Coenzyme Q0 (CoQ0, 2,3-dimethoxy-5-methyl-1,4-benzoquinone) has been reported to exert anticancer properties against human breast/lung cancer cells. This study investigated the in vitro and in vivo anticancer properties of CoQ0 on human ovarian carcinoma (SKOV-3) cells and xenografted nude mice, and revealed the underlying molecular mechanism. CoQ0 induced G2/M arrest through downregulation of cyclin B1/A and CDK1/K2 expressions. CoQ0-induced autophagy as a survival mechanism was evidenced by increased accumulation of LC3-II, GFP-LC3 puncta, AVOs formation and Beclin-1/Bcl-2 dysregulation. Increased TUNEL-positive cells and Annexin-V/PI stained cells indicated CoQ0-induced late apoptosis. Both mitochondrial (caspase-3, PARP and Bax/Bcl-2 dysregulation) and ER stress (caspase-12 and Hsp70) signals are involved in execution of apoptosis. Interestingly, CoQ0-induced apoptosis/autophagy is associated with suppression of HER-2/neu and PI3K/AKT signalling cascades. CoQ0 triggered intracellular ROS production, whereas antioxidant N-acetylcysteine prevented CoQ0-induced apoptosis, but not autophagy. Inhibition of apoptosis by Z-VAD-FMK suppressed CoQ0-induced autophagy (diminished LC3-II/AVOs), indicates CoQ0-induced apoptosis led to evoke autophagy. Contrary, inhibition of autophagy by 3-MA/CQ potentiated CoQ0-induced apoptosis (increased DNA fragmentation/PARP cleavage). Furthermore, CoQ0 treatment to SKOV-3 xenografted nude mice reduced tumor incidence and burden. Histopathological analyses confirmed that CoQ0 modulated xenografted tumor progression by apoptosis induction. Our findings emphasize that CoQ0 triggered ROS-mediated apoptosis and cytoprotective autophagy.