Mechanism of targeting the mTOR pathway to regulate ferroptosis in NSCLC with different EGFR mutations.

Patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations can be treated with EGFR-tyrosine kinase inhibitors (TKIs). Although EGFR-TKI-targeted drugs bring survival promotion in patients with EGFR mutations, drug resistance is inevitable, so it is urgent to explore new treatments to overcome drug resistance. In addition, wild-type EGFR lacks targeted drugs, and new targeted therapies need to be explored. Ferroptosis is a key research direction for overcoming drug resistance. However, the role and mechanism of regulating ferroptosis in different EGFR-mutant NSCLC types remains unclear. In the present study, H1975 (EGFR T790M/L858R mutant), A549 (EGFR wild-type) and H3255 (EGFR L858R mutant) NSCLC cell lines were used. The expression of ferroptosis markers in these cell lines was detected using western blotting and reverse transcription-quantitative PCR. Cell viability was determined using the MTT assay and reactive oxygen species (ROS) levels were measured using flow cytometry. The results showed that, compared with EGFR wild-type/sensitive mutant cells, EGFR-resistant mutant cells were more sensitive to the ferroptosis inducer, erastin. Furthermore, the mammalian target of rapamycin (mTOR) inhibitor, everolimus (RAD001), induced cell death in all three cell lines in a dose-dependent manner. The ferroptosis inhibitor, ferrostatin-1, could reverse cell death in EGFR-resistant mutant and EGFR wild-type cells induced by RAD001, but could not reverse cell death in EGFR-sensitive mutant cells. Compared with EGFR wild-type/sensitive mutant cells, EGFR-resistant mutant cells were more sensitive to RAD001 combined with erastin. In addition, a high-dose of RAD001 reduced the expression levels of ferritin heavy-chain polypeptide 1 (FTH1), glutathione peroxidase 4 (GPX4) and ferroportin and significantly increased ROS and malondialdehyde (MDA) levels in EGFR-resistant mutant and EGFR wild-type cells. In the present study, GPX4 inhibitor only or combined with RAD001 inhibited the AKT/mTOR pathway in EGFR-resistant mutant cells. Therefore, the results of the present study suggested that inhibition of the mTOR pathway may downregulate the expression of ferroptosis-related proteins in EGFR-resistant and EGFR wild-type NSCLC cells, increase the ROS and MDA levels and ultimately induce ferroptosis.

Conductometric Gas Sensor Based on MoO3 Nanoribbon Modified with rGO Nanosheets for Ethylenediamine Detection at Room Temperature.

An ethylenediamine (EDA) gas sensor based on a composite of MoO3 nanoribbon and reduced graphene oxide (rGO) was fabricated in this work. MoO3 nanoribbon/rGO composites were synthesized using a hydrothermal process. The crystal structure, morphology, and elemental composition of MoO3/rGO were analyzed via XRD, FT-IR, Raman, TEM, SEM, XPS, and EPR characterization. The response value of MoO3/rGO to 100 ppm ethylenediamine was 843.7 at room temperature, 1.9 times higher than that of MoO3 nanoribbons. The MoO3/rGO sensor has a low detection limit (LOD) of 0.235 ppm, short response time (8 s), good selectivity, and long-term stability. The improved gas-sensitive performance of MoO3/rGO composites is mainly due to the excellent electron transport properties of graphene, the generation of heterojunctions, the higher content of oxygen vacancies, and the large specific surface area in the composites. This study presents a new approach to efficiently and selectively detect ethylenediamine vapor with low power.

Colony­stimulating factor CSF2 mediates the phenotypic plasticity of small­cell lung cancer by regulating the p­STAT3/MYC pathway.

Relapse and drug resistance are the main causes of mortality in patients with small­cell lung cancer (SCLC). Intratumoral heterogeneity (ITH) is a key biological mechanism that leads to relapse and drug resistance. Phenotypic plasticity is an important factor that leads to ITH in SCLC, although its mechanisms and key regulatory factors remain to be elucidated. In the present study, cell proliferation and cell switch assay were measured using trypan blue. Alamar Blue was used to test drug sensitivity. Differential genes were screened by RNA sequencing. Reverse transcription­quantitative PCR and western blotting were performed to assess the expressions of CSF2/p­STAT3/MYC pathway related molecules, neuroendocrine (NE)/non­neuroendocrine (non­NE), transcription factors and drug­related targets. The present study found that SCLC cell line NCI­H69 exhibited adherent (H69A) and suspensive (H69S) phenotypes, which could switch back and forth. The two phenotypic cells had significant differences in cellular NE and non­NE characteristics, drug sensitivity and expression of drug­related targets. RNA sequencing showed that granulocyte­macrophage colony­stimulating factor [i.e., colony­stimulating factor 2 (CSF2)] was the main differentially expressed gene between the two phenotypes and that H69A cells highly expressed CSF2. The inhibition of CSF2 promoted the transformation from H69A to H69S, increased drug sensitivity and NE marker expression and decreased the non­NE marker expression in H69A. The STRING, Pathway Commons and Reactome databases showed a potential regulatory relationship between CSF2 and phosphorylated signal transducer and activator of transcription 3 (p­STAT3)/MYC. p­STAT3 and MYC expression was higher in H69A cells than in H69S cells and CSF2 silencing inhibited their expression. Taken together, these results indicated that CSF2 may regulate the phenotypic plasticity of SCLC through the phosphorylated STAT3/MYC pathway, thereby limiting the transformation between cell clones with different phenotypes and changing the sensitivity of specific cell clones to targeted drugs. Targeting CSF2 may be a potential therapeutic strategy to overcome drug resistance in SCLC treatment by influencing ITH.

Relationship between Classification of Fabellae and the Severity of Knee Osteoarthritis: A Relevant Study in the Chinese Population.

OBJECTIVE: To classify the fabellae and discuss the relationship between the classification of fabellae and the severity of knee osteoarthritis (KOA) in Chinese. METHODS: From February 2019 to February 2020, 136 patients were measured and classified using three-dimensional computed tomography (CT) reconstruction. According to the CT imaging characteristics, the fabellae were divided into five types: type I, a fabella on the lateral femoral condyle; type II, a fabella on the medial femoral condyle; type III, a fabella on the lateral femoral condyle and a fabella on the medial femoral condyle; type IV, two fabellae on the medial femoral condyle; and type V, two fabellae on the lateral femoral condyle. The severity of KOA was assessed on the Recht grade by magnetic resonance imaging (MRI). The data were analyzed with SPSS 24.0. RESULTS: The classification of fabellae were correlated with KOA grades (χ2  = 35.026, P < 0.05). In terms of KOA grades, grade I and grade II were occupied most by fabellar type II (32, 72.8%); type II and other types showed significant statistical difference (P < 0.05). Grade I and grade II were also mainly fabellar type IV (four, 100%). Fabellar type V's biggest component was grade III and grade IV (six, 75%). Type IV and type V showed significant statistical difference (P < 0.05). CONCLUSION: The classification of fabellae were correlated with KOA grades. The type II may mean the lower KOA grades while type V may mean the higher KOA grades.

Generalized Synthesis of Ultrathin Cobalt-Based Nanosheets from Metallophthalocyanine-Modulated Self-Assemblies for Complementary Water Electrolysis.

The development of effective approaches for preparing large-area, self-standing, ultrathin metal-based nanosheets, which have proved to be favorable for catalytic applications such as water electrolysis, is highly desirable but remains a great challenge. Reported herein is a simple and versatile strategy to synthesize ultrathin Co3 O4 and CoP NSs consisting of close-packed nanoparticles by pyrolyzing cobalt(II) phthalocyanine/graphene oxide (CoPc/GO) assemblies in air and subsequent topotactic phosphidation while preserving the graphene-like morphology. The strong π-π stacking interactions between CoPc and GO, and the inhibiting effect of the tetrapyrrole-derived macrocycle for grain growth during the catalytic carbon gasification contribute to the NSs forming. The resulting homologous Co3 O4 and CoP NSs display outstanding catalytic activity in alkaline media toward the oxygen evolution reaction and the hydrogen evolution reaction, respectively, ascribed to the richly exposed active sites, and the expedited electrolyte/ion transmission path. The integrated asymmetrical two-electrode configuration also presents a superior cell voltage of 1.63 V at 10 mA cm-2 for overall water splitting, accompanied with the excellent durability during long-term cycling. Further evidences validate that this strategy is appropriate to fabricate graphene-like ultrathin NSs of many other metal oxides, such as Fe2 O3 , NiO, MoO3 , and mixed-metal oxides, for various applications.

Ethylenediamine-modified graphene oxide covalently functionalized with a tetracarboxylic Zn(ii) phthalocyanine hybrid for enhanced nonlinear optical properties.

Tetracarboxylic Zn(ii) phthalocyanine-amino functionalized graphene oxide (ZnPcC4-NGO) hybrid materials have been prepared by a covalent functionalization method. The characterizations indicate that the amino-functionalization of GO has an important influence on the structure and photophysical properties of the ZnPcC4-NGO hybrid. The ZnPcC4-NGO hybrid exhibits enhanced photo-induced electron transfer or energy transfer (PET/ET), compared to the ZnPcC4 covalent functionalized GO (ZnPcC4-GO), owing to the presence of the extended sp(2) carbon configurations, along with the partial reduction of the NGO nanosheets and the introduction of electron-donating ethylenediamine. The nonlinear optical (NLO) properties of the hybrids were investigated using the Z-scan technique at 532 nm with 4 ns laser pulses. The results show that the efficient covalent functionalization and partial reduction of NGO cause the ZnPcC4-NGO hybrid to possess evidently larger NLO properties than the individual NGO, ZnPcC4 and the ZnPcC4-GO hybrid. The enhanced NLO performance can be attributed to the increased excited state absorption from the extended sp(2) carbon configurations of the NGO moiety, reverse saturable absorption arising from ZnPcC4 moiety, and the contribution of the efficient PET/ET process between the ZnPcC4 and NGO moieties in the hybrid.

An electrochemical bifunctional sensor for the detection of nitrite and hydrogen peroxide based on layer-by-layer multilayer films of cationic phthalocyanine cobalt(ii) and carbon nanotubes.

As vital biological mediators, the accurate detection of nitrite (NO2 -) and hydrogen peroxide (H2O2) is desirable for clinical monitoring and diagnosis. Herein, cationic 2,9,16,23-tetra[4-(N-methyl)pyridinyloxy]phthalocyanine cobalt(ii) ([TMPyPcCo]4+) and acid-treated multiwalled carbon nanotubes (aCNTs) were alternately self-assembled on the glassy carbon electrode (GCE) by means of the electrostatic interaction, leading to a 3D loose and interconnected assembly of [TMPyPcCo/aCNTs]n multilayer films. In the [TMPyPcCo/aCNTs]n films, [TMPyPcCo]4+ is anchored onto the surface of aCNTs without any inert polymer binders, which is beneficial to expose more active sites for electrocatalysis. The effective combination of [TMPyPcCo]4+ and aCNTs brings many advantages in electrochemical detection, involving the fast oriented transmission of charges, permeable channels for ion adsorption and transport, and more sensing sites, thus the [TMPyPcCo/aCNTs]n films display excellent electrochemical sensitivity towards both NO2 - and H2O2. The responses of NO2 - and H2O2 vary linearly with respect to the concentration from 5 µM to 30 mM and 10 µM to 9 mM. Furthermore, the superior cycling stability, reproducibility, and selectivity make [TMPyPcCo/aCNTs]n films suitable for the real samples.

Enhanced NH3-Sensitivity of Reduced Graphene Oxide Modified by Tetra-α-Iso-Pentyloxymetallophthalocyanine Derivatives.

Three kinds of novel hybrid materials were prepared by noncovalent functionalized reduced graphene oxide (rGO) with tetra-α-iso-pentyloxyphthalocyanine copper (CuPc), tetra-α-iso-pentyloxyphthalocyanine nickel (NiPc) and tetra-α-iso-pentyloxyphthalocyanine lead (PbPc) and characterized by Fourier transform infrared spectroscopy (FT-IR), ultraviolet-visible spectroscopy (UV-vis), Raman spectra, X-ray photoelectron spectroscopy (XPS), transmission electron microscope (TEM), and atomic force microscope (AFM). The as-synthesized MPc/rGO hybrids show excellent NH3 gas-sensing performance with high response value and fast recovery time compared with bare rGO. The enhancement of the sensing response is mainly attributed to the synergism of gas adsorption of MPc to NH3 gas and conducting network of rGO with greater electron transfer efficiency. Strategies for combining the good properties of rGO and MPc derivatives will open new opportunities for preparing and designing highly efficient rGO chemiresistive gas-sensing hybrid materials for potential applications in gas sensor field.

The effects of central metals on the photophysical and nonlinear optical properties of reduced graphene oxide-metal(II) phthalocyanine hybrids.

Reduced graphene oxide-metal(II) phthalocyanine (RGO-MPc, M = Cu, Zn and Pb) hybrid materials have been prepared by the covalent functionalization method. The resultant RGO-MPc hybrids are characterized by scanning electron microscopy, atomic force microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared, ultraviolet-visible absorption and fluorescence spectroscopy. The RGO-MPc hybrids exhibit strong fluorescence quenching by means of the photo-induced electron transfer or the energy transfer (PET/ET) process between the RGO and MPc moieties. The PET/ET process particularly depends on the fluorescence quantum yield of MPc molecules with different central metals. The nonlinear optical (NLO) properties of the RGO-MPc hybrids are investigated by using the Z-scan technique at 532 nm with 4 ns laser pulses. The results show that the NLO properties of MPc molecules increase in the order of Zn < Pb < Cu, but the RGO-MPc hybrids exhibit NLO performance in the inverse sequence of Zn > Pb > Cu, implying that the NLO response arising from the efficient PET/ET process between RGO and MPc may play a more important role in the NLO properties of RGO-MPc hybrids than that originating from the MPc moiety.

A multiwalled carbon nanotube/tetra-ß-isoheptyloxyphthalocyanine cobalt(ii) composite with high dispersibility for electrochemical detection of ascorbic acid.

A sensitive electrochemical sensor for ascorbic acid (AA) is designed and synthesized via the following steps. The novel tetra-ß-isoheptyloxyphthalocyanine cobalt(ii) (PcCo) spontaneously adsorbs on the surface of acid-treated multi-walled carbon nanotubes (aMWCNTs). Then, the aMWCNT/PcCo composite was immobilized on the glassy carbon electrode (GCE). The results of UV-vis, FT-IR, TG, XPS, SEM and TEM revealed the successful self-assembly between PcCo and aMWCNTs via the π-π stacking interaction, and the aMWCNT/PcCo composite appears to have a uniform network-like structure on the GCE surface due to the four peripheral isoheptyl substituents of PcCo. Such a structure can effectively increase the electrode area, facilitate the mass transport of analytes and provide continuous conducting pathways for the transportation of electrons. Synchronously, benefitting from the synergistic effect between PcCo and aMWCNTs, the obtained electrochemical sensor has a high current and low potential for the oxidation of AA. The linear range for the AA detection is from 10 µM to 1.2 mM and the detection limit is as low as 4.0 µM. The developed biosensor exhibited good reproducibility and acceptable stability, providing a simple method for the analysis of AA.

Ultrafast third-order nonlinear optical properties of ZnPc(OBu)(6)(NCS)/DMSO solution.

The ultrafast third-order nonlinear optical properties of ZnPc(OBu)(6)(NCS)/dimethyl sulfoxide solution are investigated by optical Kerr effect (OKE) and pump-probe techniques with femtosecond pulses. Using CS(2) as the reference, the third-order susceptibility of the sample solution is obtained as about 1.40x10(-14) esu at a concentration of 3.00x10(-5) M. The second hyperpolarizability for the sample solution is deduced to be as large as 2.35x10(-31) esu. The dynamic characteristics of the nonlinear optical response and the origins of the OKE signal can be attributed to excited singlet state populations.

[Synthesis and spectra of novel metal complexes of multi-nitrogen heterocyclic ligand].

Novel multi-nitrogen heterocyclic metal complexes M(HMPB)2 (M = Co, Ni) using 2-(2'-hydroxy-5'-methyl phenyl) benzotriazole (HMPB) as ligand, were synthesized by the methanol aqueous solution precipitation method for the first time. The as-prepared samples were characterized by element analysis and laser-desorption ionization time-of-flight mass spectrometry (LDI-TOF-MS). The Fourier transform infrared characteristic spectra (FTIR) and ultraviolet visible electronic absorption spectrum (UV-Vis) of the new complexes were also studied especially. The results show that the HMPB ligand coordinates with the center metal ions by nitrogen and oxygen atoms in the form of bidentate ligand, and the coordination number of the center metal ions is four in the complexes; FTIR characteristic absorption band of the complexes is located in the region of 400-2 500 cm(-1). After the complexes formation, the stretching vibration of the hydroxy group of 2-(2'-hydroxy-5'-methyl phenyl) benzotriazole, the vibration peak of C = N bond and the characteristic absorption of C-O bond showed distinct changes. The IR characteristic absorption peak positions of M-N and M-O bond were also confirmed. These complexes exhibited a strong absorption in the ultraviolet region and the maximum absorption peak located in the range of 335-345 nm.

[Spectral study of monoisothiocyanato-substituted 3:1 asymmetrical phthalocyanine zinc(II)].

Electronic absorption spectra of three monoisothiocyanato-substituted asymmetrical phthalocyanine zinc(II), 2-isothiocyanato-9,10,16,17,23,24-alkyloxyphthalocyanine zinc(II) [(RO)6 (NCS)PcZn(II)] (R = n-C4H9, n-C5H11, n-C10H21), were measured in five organic solvents. The effect and order of the substitute groups and solvents were studied by electronic absorption spectra. The changes of lamda(max) data are very small between monoamino- and monoisothiocyanato-substituted asymmetrical phthalocyanines. The order of lamda(max), data is listed here, CHCl3>CH2Cl2>toluene in non-coordination solvents; DMF>THF in O-coordination solvents. The fluorescence spectra of these complexes were measured in organic solvents at the same time. The effect and order of the substitute groups, solvents and concentrations were studied on the maximum wavelength of emission and fluorescence intensity. The lamda(em,max) data of fluorescence emission are among 690-700 nm. The order of lamda(em,max) data is listed here, DMF>THF in O-coordination solvents and almost the same in non-coordination solvents. The fluorescence intensity is very strong in DMF and THF. The order of fluorescence intensity is listed here, DMF>THF in O-coordination solvents; toluene> CH2Clz > CHCl3 in non-coordination solvents. They have special fluorescent effect and should be expected to become a photosensitizer of photodynamic therapy in future.