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In order to investigate the application of high temperature resistant profragrances in the aromatic modification of polyester, three POSS-based profragrances (M1, M2 and M3) were successfully synthesized by Schiff reaction using different fragrance aldehyde molecules and octa (γ-chloroaminopropyl) polyhedral oligomeric silsesquioxane (OCAP-POSS) as raw materials based on molecular hybridization method. The structure of the profragrances was characterized by nuclear magnetic resonance spectrum, infrared spectrum and ultraviolet-visible spectrum. We investigated the fragrance release kinetics characteristics of the profragrances in the environments, including simulated human acidic sweat, neutral and alkaline soap solutions. The results show that the thermal decomposition temperature of all the three profragrances exceeds 285 °C, indicating their good thermal stability. The structure of profragrances has significant effect on their release performance, with M1 reaching an equilibrium release rate of 57.86%, but M3 only 33.32%, and the sustained release time is in the order of M1(29 h)>M2 (16 h)>M3 (12 h). The profragrances are relatively stable in the soap environment, but exhibit a slow release in acidic sweat. The release behaviors follow the first-order reaction kinetics characteristics. [ABSTRACT FROM AUTHOR]

Autophagy is typically activated in cancer cells as a rescue strategy in response to cellular stress (e.g., chemotherapy). Herein, we found that Berbamine Hydrochloride (Ber) can act as an effective inhibitor of the late stage of autophagic flux, thereby potentiating the killing effect of chemotherapy agents. Lung carcinoma cells exposed to Ber exhibited increased autophagosomes, marked by LC3-II upregulation. The increased level of p62 after Ber treatment indicated that the autophagic flux was blocked at the late stage. The lysosome staining assay and cathepsin maturation detection indicated impaired lysosomal acidification. We found that Nox2 exhibited intensified co-localization with lysosomes in Ber-treated cells. Nox2 is a key enzyme for superoxide anion production capable of transferring electrons into the lysosomal lumen, thereby neutralizing the inner protons; this might explain the aberrant acidification. This hypothesis is further supported by the observed reversal of lysosomal cathepsin maturation by Nox2 inhibitors. Finally, Ber combined with cisplatin exhibited a synergistic killing effect on lung carcinoma cells. Further data suggested that lung carcinoma cells co-treated with Ber and cisplatin accumulated excessive reactive oxygen species (ROS), which typically activated MAPK-mediated mitochondria-dependent apoptosis. The enhanced anti-cancer effect of Ber combined with cisplatin was also confirmed in an in vivo xenograft mouse model. These findings indicate that Ber might be a promising adjuvant for enhancing the cancer cell killing effect of chemotherapy via the inhibition of autophagy. In this process, Nox2 might be a significant mediator of Ber-induced aberrant lysosomal acidification. [ABSTRACT FROM AUTHOR]

To improve corrosion inhibition performance of copper foil with a novel two-step electrochemical modification processes, the surface of 35 µm copper foils was coated with graphene oxide(GO) via electrochemical method at first step, then was further coated with 3-aminopropyltrimethoxysilane(APTS) at the second step. For the first step the copper foil acted as anode, and as cathode for the second one(we labeled it as E-GO). Optimum coating parameters for the preparation of E-GO coating are 5 V and 1 min with ratio of APTS/deionized water(DI) 1.5/98.5(v/v). The physicochemical properties of modified coating were studied by X-ray diffraction(XRD), scanning electron microscopy(SEM) and hydrophilicity test. Electrochemical behavior of different samples were also investigated. The experimental results indicate that anti-corrosion performance is significantly improved with two-step modified coating. And E-GO coating shows more positive corrosion potential and the highest corrosion resistance rate than others according to the Tafel curve. It is also found that surface hydrophobicity of E-GO coating is significantly improved. [ABSTRACT FROM AUTHOR]

Background: Clinically, although chemotherapy is one of the most commonly used methods of treating tumors, chemotherapeutic drugs can induce autophagic flux and increase tumor cell resistance, leading to drug tolerance. Therefore, theoretically, inhibiting autophagy may improve the efficacy of chemotherapy. The discovery of autophagy regulators and their potential application as adjuvant anti-cancer drugs is of substantial importance. In this study, we clarified that Fangjihuangqi Decoction (FJHQ, traditional Chinese medicine) is an autophagy inhibitor, which can synergistically enhance the effect of cisplatin and paclitaxel on non-small cell lung cancer (NSCLC) cells. Methods: We observed the changes of autophagy level in NSCLC cells under the effect of FJHQ, and verified the level of the autophagy marker protein and cathepsin. Apoptosis was detected after the combination of FJHQ with cisplatin or paclitaxel, and NAC (ROS scavenger) was further used to verify the activation of ROS-MAPK pathway by FJHQ. Results: We observed that FJHQ induced autophagosomes in NSCLC cells and increased the levels of P62 and LC3-II protein expression in a concentration- and time-gradient-dependent manner, indicating that autophagic flux was inhibited. Co-localization experiments further showed that while FJHQ did not inhibit autophagosome and lysosome fusion, it affected the maturation of cathepsin and thus inhibited the autophagic pathway. Finally, we found that the combination of FJHQ with cisplatin or paclitaxel increased the apoptosis rate of NSCLC cells, due to increased ROS accumulation and further activation of the ROS-MAPK pathway. This synergistic effect could be reversed by NAC. Conclusion: Collectively, these results demonstrate that FJHQ is a novel late-stage autophagy inhibitor that can amplify the anti-tumor effect of cisplatin and paclitaxel against NSCLC cells. [ABSTRACT FROM AUTHOR]

Satisfying the animals feed demand from the forage supply by grasslands remains a major challenge in the grassland–livestock ecosystem. To provide an alternative forage sources, this study conducted two feeding trials in the summer of 2015 and 2016 to compare the nutritive value, digestibility and nutrients utilization of native pasture (NH) and oat forage (OT) fed to Tibetan sheep (Ovis aries). Twelve Tibetan sheep with a mean body weight of 39.11 ± 3.66 kg in 2015 and 27.97 ± 2.69 kg in 2016 were use in this study. The experiment was 2 (year: 2015 and 2016) by 2 (forage: NH and OT) factorial. Data on proximate analysis, fiber fraction and nutrients digestibility were collected and analyzed using general linear model. However, the crude protein (CP) and water‐soluble carbohydrates contents in OT were higher (P <.001) than those in NH by 7.81–8.93% and 46.40–47.05%, respectively. In contrast, the neutral detergent fiber (NDF) and acid detergent fiber contents were higher (P <.001) in NH by 14.28–15.78% and 15.62–18.00%, respectively. The dry matter digestibility coefficient in OT (0.82 in 2015 and 0.79 in 2016) was significantly higher than that in NH (0.68 in both years). In addition, the OT diet had higher (P <.001) organic matter, NDF and CP digestibilities. Animals fed OT retained significantly more nitrogen (2.66 g/day in 2015 and 1.93 g/day in 2016) than those fed NH (0.96 g/day in 2015 and 0.42 g/day in 2016). The digestible energy and metabolizable energy were higher (P <.001) in OT than in NH. Our data indicated that Tibetan sheep urinary N excretion increased by 0.726 g with increase of 1 g in the nitrogen intake. Conclusively, the OT had higher nutritive value than NH and could therefore use to satisfy livestock demand and reduce the grazing pressure on grasslands. [ABSTRACT FROM AUTHOR]

Domestic yak (Bos grunniens) have coexisted with plateau pika (Ochotona curzoniae) for thousands of and they play irreplaceable roles in shaping the structure and function of alpine meadow ecosystem. However, the mechanisms whereby the greenhouse gas (GHG) emissions change in response to the interactive effects between yak grazing and plateau pika burrowing remain unclear. In this study, we examined the response of ecosystem GHG emissions (CO2, CH4, and N2O flux) to yak grazing and pika burrowing in alpine meadow in Zoige County, China. The GHG emissions was measured with a static opaque chamber method. Our results revealed that CO2, CH4, N2O flux and CO2‐eq were significantly influenced by yak grazing and pika burrowing independently, and in conjunction. Crucially, the relative importance of pika burrowing was higher than yak grazing on a pastoral scale. Specifically, high pika burrowing led to an increase of 440.29%, and 110.72% for CO2‐eq relative to low pika burrowing under moderate and heavy yak grazing situations, respectively. The value of CO2‐eq with low pika burrowing was negative, especially under light yak grazing conditions. Furthermore, we found that GHG emissions were sensitive to plant species richness, soil temperature, soil moisture, soil organic carbon, and soil microbial factors. Structural equation modeling indicated that pika burrowing can affect CO2‐eq though altering soil temperature and belowground biomass under heavy yak grazing conditions and changing soil moisture and soil microbe under light yak grazing. The results of this study enrich our understanding of the role of small burrowing mammals in the carbon sequestration of alpine meadow. In the context of the carbon neutrality of alpine grassland ecosystem, small mammals' activities and their interactions with domestic livestock‐induced changes in microtopography on GHG emissions should not be neglected. [ABSTRACT FROM AUTHOR]

Zero-dimensional perovskites have received extensive attention in recent years due to their unique structural properties, including large exciton binding energies, strong quantum confinement effects, and good stability. Target products were precisely constructed from existing organic–inorganic hybrid perovskite material phase-transition systems via exploiting the ideas of molecular design, modification, and assembly. Herein we report an organic–inorganic hybrid perovskite compound, [C6H18F6N3SbBr6] (1), with excellent reversible phase transition and dielectric switching properties. The symmetry of the structure was reduced upon introducing fluorine atoms to the ethylamine moiety. The results showed that compound 1 had a narrow bandgap of 2.90 eV and three distinct dielectric anomalies at ∼175.9, 205.9, and 257.5 K. UV-vis absorption spectra and density-functional theory (DFT) calculations confirmed this bandgap. It was revealed that the octahedral framework of inorganic [SbBr6]3− was the main contributor to this bandgap. This work highlights that the substitution of hydrogen atoms by halogens has important effects on the structural phase transition mechanism and physical properties of the synthesized product, therefore, it provides an effective strategy for the synthesis of novel organic–inorganic hybrid perovskite phase-transition materials. [ABSTRACT FROM AUTHOR]

Piezoelectric responsive molecular ferroelectrics have become a research hotspot due to their advantages of simple fabrication, environmental friendliness, light weight and good mechanical flexibility. Here we proposed a new kind of multipole rare earth molecular ferroelectric, ((nBu)4N)3[Ce(NO3)4(SCN)2]((CH3CH2CH2CH2)4N = tetrabutylammonium) (1). Compound 1 undergoes a high temperature ferroelectric phase transition at 408 K. It is worth noting that compound 1 has a narrow band gap of 2.61 eV, flexible switchable SHG effect, moderate spontaneous polarization Ps = 3.6 μC cm−2, and piezoelectric constant = 3 pC N−1. The results show that these findings provide ideas for exploring multifunctional rare earth molecular ferroelectrics with a piezoelectric effect. [ABSTRACT FROM AUTHOR]

Bistable switches (electrical switching between "ON" and "OFF" bistable states) have gradually developed into an ideal category of highly intelligent materials, due to their significant applications in optical technology, signal processors, data storage and other switchable media applications in the field of electrical devices. Here, we successfully designed and synthesized [(FC6H4C2H4NH3)2MCl4]n(FC6H4C2H4NH3+)=deprotonated 4‐fluoro‐ phenethylamine; M=Cd (1), Mn (2)), which realized the coupling of thermo‐dielectric switching characteristics, semi‐conductor characteristics and photo‐luminescent properties. DSC (differential scanning calorimetry) and dielectric measurements show that 1 is a sensitive dielectric bistable switch between the high dielectric (ON) and low dielectric (OFF) states. The temperature‐variable single crystal structure shows that the both 1 and 2 undergo a high‐temperature reversible phase transition around 383 K/380 K, which is caused by the order‐disordered transformation of organic cations and the slight distortion of the inorganic framework. In particular, 1 shows outstanding switchable dielectric behavior and semiconducting properties. Further, 1 and 2 emit strong green and yellow luminescence at 527 and 595 nm, respectively. [ABSTRACT FROM AUTHOR]

The tetracyanopyridine (4-cyanopyridine and 3-cyanopyridine) was reacted with rare earth nitrates (Ln = La, Gd, Er) under hydrothermal conditions by the Demko-Sharpless method, and four rare earth tetrazolium ionic compound were synthesized safely and effectively, named [Ln(H2O)8 ⋅ 3(p-TPD) ⋅ 2(p-HTPD) ⋅ 7H2O], (Ln = La( 1), Gd(2), Er (3), p-TPD = 4-tetrazolpyridine), [Ln(H2O)8 ⋅ 3(m-TPD) ⋅ 6H2O], (m-TPD = 3-tetrazolpyridine, Ln = Er(4)). These four rare earth tetrazolium ionic compounds were characterized by the single crystal X-ray diffraction, infrared spectroscopy, thermogravimetry, dielectric properties, X-ray powder diffraction. The X-ray single crystal structure analysis shows that the four rare earth tetrazolium compounds were all ionic, and the rare earth metal ions and ligands were in two different layers. The [Ln(H2O)8]3+ structure unit and p-TPD and water molecules formed a cationic layer through hydrogen bonding, while p-TPD and p-HTPD formed an anion layer through π-π stacking and hydrogen bonding. The cation layer and anion layer alternately form a regular network structure. Moreover, the dielectric properties tests indicate that the compounds 1, 2 have good dielectric properties. [ABSTRACT FROM AUTHOR]

Selenium (Se) deficiency is a widespread and seasonally chronic phenomenon observed in Tibetan sheep (Ovis aries) traditionally grazed on the Qinghai–Tibet Plateau (QTP). Effects of the dietary addition of Se-enriched yeast (SeY) on the bacterial community in sheep rumen and rumen fermentation were evaluated with the aim of gaining a better understanding of the rumen prokaryotic community. Twenty-four yearling Tibetan rams [initial average body weight (BW) of 31.0 ± 0.64 kg] were randomly divided into four treatment groups, namely, control (CK), low Se (L), medium Se (M), and high Se (H). Each group comprised six rams and was fed a basic diet of fresh forage cut from the alpine meadow, to which SeY was added at prescribed dose rates. This feed trial was conducted for over 35 days. On the final day, rumen fluid was collected using a transesophageal sampler for analyzing rumen pH, NH3-N content, volatile fatty acid (VFA) level, and the rumen microbial community. Our analyses showed that NH3-N, total VFA, and propionate concentrations in the M group were significantly higher than in the other groups (P < 0.05). Both the principal coordinates analysis (PCoA) and the analysis of similarities revealed that the bacterial population structure of rumen differed among the four groups. The predominant rumen bacterial phyla were found to be Bacteroidetes and Firmicutes, and the three dominant genera in all the samples across all treatments were Christensenellaceae R7 group, Rikenellaceae RC9 gut group, and Prevotella 1. The relative abundances of Prevotella 1, Rikenellaceae RC9 gut group, Ruminococcus 2, Lachnospiraceae XPB1014 group, Carnobacterium , and Hafnia- Obesumbacterium were found to differ significantly among the four treatment groups (P < 0.05). Moreover, Tax4fun metagenome estimation revealed that gene functions and metabolic pathways associated with carbohydrate and other amino acids were overexpressed in the rumen microbiota of SeY-supplemented sheep. To conclude, SeY significantly affects the abundance of rumen bacteria and ultimately affects the rumen microbial fermentation. [ABSTRACT FROM AUTHOR]

The high pressure and elastic properties of a hybrid ABX3-type perovskite, [C(NH2)3][Cd(HCOO)3] (CdGF), based on the A-site guest molecules are revealed via combining the high-pressure synchrotron X-ray diffraction experiments with density functional theory (DFT) calculations. The experimental results indicate that the anisotropic axial compressibilities are Ka = 2.8(4) and Kc = 20.9(10) TPa−1 within the pressure scope of 4.12 GPa, and calculations reveal the microscopic evolution of structure under pressure and demonstrate that this structural anisotropy is a consequence of the directional guest molecule and the cooperative effect of hydrogen bonding and octahedral tilting. In addition, full elastic constants of the perovskite were calculated to describe Young's moduli, shear moduli and Poisson's ratios. Notably, these discrete moduli are governed by the orientational guest molecule suggesting that the perovskite may display positive (negative) linear compression if it is flexible (rigid) along one principal axis. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the synergistic effect of resveratrol on the bystander effect of TK/GCV suicide gene system in melanoma cells. Methods: The effect of resveratrol on the growth of B16 cells and the synergistic effect of resveratrol with or without GCV were detected by MTT assay and high content screening assay. The effect of resveratrol on GJIC function was detected by flow cytometry combined with fluorescence tracer and fluorescence microscope, and the expression of gap junction protein was detected by western blotting. Synergistic killing effect of resveratrol plus TK/GCV was tested in vivo using transplanted melanoma model. Results: In vitro, resveratrol can enhanced GJ function and upregulated Cx32 and Cx43 protein expression in B16 cells. Resveratrol synergized with GCV to kill mixed B16 melanoma cells (20% TK+ cells and 80% TK− cells) and to improve apoptosis rate of TK− cells (the bystander effect of TK system), and the synergistic action was reversed by the GJ inhibitor AGA. In vivo, when B16 cells were mixed with 30% TK+ B16 cells, significantly reduced tumor weight and volume were observed after combinational treatment with resveratrol plus GCV as compared with GCV or resveratrol treatment alone. Conclusions: Resveratrol could synergistically enhance the killing effect of TK/GCV suicide gene system in melanoma B16 cells and transplanted melanoma. It might be a promising adjuvant of TK/GCV therapy. [ABSTRACT FROM AUTHOR]

Despite its low transfer efficiency, suicide gene therapy with HSV-TK is known for its bystander killing effect. The connexin-based gap junction is believed to mediate the bystander effect. Recently, we found that resveratrol, a polyphenol compound, increased the expression of Cx26 and Cx43, which are connexins and important constituents of gap junctions, in murine hepatoma cells. Hypothetically, the resveratrol-induced upregulation of gap junctions may improve the bystander effect that HSV-TK/GCV has on hepatoma cells. Our present investigation revealed that resveratrol could enhance intercellular communication at the gap junctions in CBRH7919 hepatoma cells and thereby enhance the bystander killing effect of GCV on CBRH7919TK cells. However, inhibition of gap junction using its long-term inhibitor alpha-glycyrrhetinic acid had a negative influence on the bystander effect of gene therapy with HSV-TK/GCV. In addition, combined resveratrol and GCV treatment in tumor-bearing mice with CBRH7919TK and CBRH7919WT cells at a ratio of 2:3 resulted in a significant decrease in the volume and weight of the tumor in comparison to GCV or only resveratrol. The present results demonstrate that resveratrol can enhance the bystander effect exerted by the HSV-TK/GCV system by enhancing connexin-mediated gap junctional communication. [ABSTRACT FROM AUTHOR]

Abstract: Although great progress has been made for H‐bonds type molecular ferroelectrics, the systems accompanying with chiral to chiral phase transitions are still very spare. Here we display a new hydrogen bond type molecular ferroelectric, the salt of 1‐(1‐naphthyl) ethylammonium‐nopinate, 1, which undergoes a paraelectric–ferroelectric phase transition around 202 K from one chiral point group (P212121) to another chiral point group (P21). The electric hysteresis loop under 100 K directly indicates it is a potential ferroelectric material with maximum spontaneous polarization (Ps) 2.3 uC/cm2. X‐ray single crystal diffraction analysis shows that the significant hydrogen bond change along the b‐axis direction results net dipole moment and leads to the spontaneous polarization. The exceptional dielectric response in the vicinity of 202 K exhibits remarkable dielectric anomalies along the b‐axis direction than the other two directions. The strong SHG (second harmonic generation) signal (‐1.31) without obvious changes dependence on temperature further confirm the chiral to chiral structural phase transition. [ABSTRACT FROM AUTHOR]

Two new different Cu(II) MOFs with the same 1,3,5-tris(1-imidazolyl) benzene (tib) ligand {[Cu(tib)]·(HO)·Br} ( 1) and {[Cu(tib)·Br·Cl]·2Br} ( 2) were obtained by one pot synthesized of tib with CuBr in the presences of HCl and water. X-ray single crystal diffraction analyses indicate that both complexes 1 and 2 have two dimensional frameworks containing different building blocks. Each Cu(II) atom in complex 1 is coordinated by four N atoms from different tib ligands. However, there are two different cryptographic Cu(II) atoms in complex 2, one is four coordinated by two bromine atoms and two N atoms from different tib ligands, the other is six coordinated by two chloride atoms and four N atoms from different tib ligands. The thermal gravimetric analysis of complexes 1 and 2 are depicted in the paper. [ABSTRACT FROM AUTHOR]

The bystander effect is an intriguing phenomenon by which adjacent cells become sensitized to drug treatment during gene therapy with herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV). This effect is reported to be mediated by gap junctional intercellular communication (GJIC), and therefore, we postulated that upregulation of genes that facilitate GJIC may enhance the HSV-tk/GCV bystander effect. Previous findings have shown Tanshinone IIA (Tan IIA), a chemical substance derived from a Chinese medicine herb, promotes the upregulation of the connexins Cx26 and Cx43 in B16 cells. Because gap junctions are formed by connexins, we hypothesized that Tan IIA might increase GJIC. Our results show that Tan IIA increased GJIC in B16 melanoma cells, leading to more efficient GCV-induced bystander killing in cells stably expressing HSV-tk. Additionally, in vivo experiments demonstrated that tumors in mice with 10% HSV-tk positive B16 cells and 90% wild-type B16 cells became smaller following treatment with the combination of GCV and Tan IIA as compared to GCV or Tan IIA alone. These data demonstrate that Tan IIA can augment the bystander effect of HSV-tk/GCV system through increased gap junction coupling, which adds strength to the promising strategy that develops connexins inducer to potentiate the effects of suicide gene therapy. [ABSTRACT FROM AUTHOR]

This study examined the incidence, neuropsychological characteristics and risk factors of cognitive impairment 3 months after stroke in China. Five regions that differed in geography and economy in China were selected. Patients from the hospitals located in the five regions were prescreened at admission, and the demographic data, vascular risk factors and clinical characteristics of stroke were obtained. A battery of cognitive-specific domain tests was performed in the patients who failed to pass cognitive screening 3 months post stroke. Patients were diagnosed as having post-stroke cognitive impairment (PSCI) or no cognitive impairment (NCI) based on the results of the neuropsychological tests. Univariate analysis was performed for suspect risk factors, and significant variables were entered in multivariable logistic regression analysis. Our results showed that a total of 633 patients were recruited 3 months after stroke; complete cognitive tests were performed in 577 of the stroke patients. The incidence of PSCI in these Chinese patients was 30.7%. There were 129 (22.4%) patients with visuospatial impairment, 67 (11.6%) with executive impairment, 60 (10.4%) with memory impairment and 18 (3.1%) with attention impairment. The risk factors associated with PSCI were older age (odds ratio [OR] 1.76, 95% confidence interval [CI] 1.20-2.58), low education level (OR 2.45, 95% CI 1.65-3.64), depressive symptom (OR 1.69, 95% CI 1.09-2.61), obesity (OR 2.57, 95% CI 1.41-4.71), stroke severity 3 months post stroke (OR 1.62, 95%CI 1.10-2.37) and cortex lesion (OR 1.55, 95% CI 1.04-2.31). It was concluded that PSCI occurs commonly 3 months after first-ever stroke in Chinese patients. Visuospatial ability may be the most frequently impaired cognitive domain for the patients with stroke. The critical risk factors of PSCI are older age, low education level, depressive symptom, obesity, stroke severity 3 months post stroke and cortex lesion. [ABSTRACT FROM AUTHOR]

Efficient building instance segmentation is necessary for many applications such as parallel reconstruction, management and analysis. However, most of the existing instance segmentation methods still suffer from low completeness, low correctness and low quality for building instance segmentation, which are especially obvious for complex building scenes. This paper proposes a novel unsupervised building instance segmentation (UBIS) method of airborne Light Detection and Ranging (LiDAR) point clouds for parallel reconstruction analysis, which combines a clustering algorithm and a novel model consistency evaluation method. The proposed method first divides building point clouds into building instances by the improved kd tree 2D shared nearest neighbor clustering algorithm (Ikd-2DSNN). Then, the geometric feature of the building instance is obtained using the model consistency evaluation method, which is used to determine whether the building instance is a single building instance or a multi-building instance. Finally, for multiple building instances, the improved kd tree 3D shared nearest neighbor clustering algorithm (Ikd-3DSNN) is used to divide multi-building instances again to improve the accuracy of building instance segmentation. Our experimental results demonstrate that the proposed UBIS method obtained good performances for various buildings in different scenes such as high-rise building, podium buildings and a residential area with detached houses. A comparative analysis confirms that the proposed UBIS method performed better than state-of-the-art methods. [ABSTRACT FROM AUTHOR]

The main mechanistic function of most chemotherapeutic drugs is mediated by inducing mitochondria-dependent apoptosis. Tumor cells usually respond to upregulate autophagy to eliminate impaired mitochondria for survival. Hypothetically, inhibiting autophagy might promote mitochondria-dependent apoptosis, thus enhancing the efficacy of chemotherapeutic therapies. We previously identified N-methylparoxetine (NMP) as an inducer of mitochondrial fragmentation with subsequent apoptosis in non-small cell lung cancer (NSCLC) cells. We discovered that ROS was accumulated in NMP-treated NSCLC cells, followed by c-Jun N-terminal kinase (JNK) and p38 MAP kinase (p38) activation. This was reversed by the application of a reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC), leading to a reduction in apoptosis. Our data suggested that NMP induced apoptosis in NSCLC cells by activating mitogen-activated protein kinase (MAPK) pathway. We further speculated that the remarkable increase of ROS in NMP-treated NSCLC cells might result from an inhibition of autophagy. Our current data confirmed that NMP blocked autophagy flux at late stage wherein lysosomal acidification was inhibited. Taken together, this study demonstrated that NMP could exert dual apoptotic functions—mitochondria impairment and, concomitantly, autophagy inhibition. NMP-related excessive ROS accumulation induced apoptosis by activating the MAPK pathway in NSCLC cells. [ABSTRACT FROM AUTHOR]

Chemoresistance is a major limiting factor that impairs the outcome of non-small cell lung cancer (NSCLC) chemotherapy. Paclitaxel (Tax) induces protective autophagy in NSCLC cells, leading to the development of drug resistance. We recently identified a new autophagy inhibitor (alpha-hederin) and hypothesized that it may promote the killing effect of Tax on NSCLC cells. We found that alpha-hederin (α-Hed) could block late autophagic flux in NSCLC cells by altering lysosomal pH and inhibiting lysosomal cathepsin D maturation. Combination treatment of α-Hed and Tax synergistically reduced NSCLC cell proliferation and increased NSCLC cell apoptosis compared with treatment with α-Hed or Tax alone. Furthermore, α-Hed plus Tax enhanced the accumulation of intracellular reactive oxygen species (ROS) in NSCLC cells, while the ROS inhibitor N-acetylcysteine reversed the inhibitory effect of the combination treatment. Our findings suggest that α-Hed can increase the killing effect of Tax on NSCLC cells by promoting ROS accumulation, and that combining α-Hed with classical Tax represents a novel strategy for treating NSCLC. [ABSTRACT FROM AUTHOR]