Synthesis and Anti-gastric Cancer Activity by Targeting FGFR1 Pathway of Novel Asymmetric Bis-chalcone Compounds.

BACKGROUP: Bis-chalcone compounds with symmetrical structures, either isolated from natural products or chemically synthesized, have multiple pharmacological activities. Asymmetric Bis-chalcone compounds have not been reported before, which might be attributed to the synthetic challenges involved, and it remains unknown whether these compounds possess any potential pharmacological activities. AIMS: The aim of this study is to investigate the synthesis route of asymmetric bis-chalcone compounds and identify potential candidates with efficient anti-tumor activity. METHOD: The two-step structural optimization of the bis-chalcone compounds was carried out sequentially, guided by the screening of the compounds for their growth inhibitory activity against gastric cancer cells by MTT assay. The QSAR model of compounds was established through random forest (RF) algorithm. The activities of the optimal compound J3 on growth inhibition, apoptosis, and apoptosis-inducing protein expression in gastric cancer cells were investigated sequentially by colony formation assay, flow cytometry, and western blotting. Further, the inhibitory effects of J3 on the FGFR1 signaling pathway were explored by Wester Blotting, siRNA, and MTT assays. Finally, the in vivo anti-tumor activity and mechanism of J3 were studied through nude mouse xenograft assay, western blotting. RESULT: 27 asymmetric bis-chalcone compounds, including two types (N and J) were sequentially designed and synthesized. Some N-class compounds have good inhibitory activity on the growth of gastric cancer cells. The vast majority of J-class compounds optimized on the basis of N3 exhibit excellent inhibitory activity on gastric cancer cell growth. We established a QSAR model (R2 = 0.851627) by applying random forest algorithms. The optimal compound J3, which has better activity, concentration-dependently inhibited the formation of gastric cancer cell colonies and led to cell apoptosis by inducing the expression of the pro-apoptotic protein cleaved PARP. J3 may exert anti-gastric cancer effects by inhibiting the activation of FGFR1/ERK pathway. Moreover, at a dose of 10 mg/kg/day, J3 inhibited tumor growth in nude mice by nearly 70% in vivo with no significant toxic effect on body weight and organs. CONCLUSION: In summary, this study outlines a viable method for the synthesis of novel asymmetric bischalcone compounds. Furthermore, the compound J3 demonstrates substantial promise as a potential candidate for an anti-tumor drug.

Discovery of Pyroptosis-inducing Drugs and Antineoplastic Activity Based on the ROS/ER Stress/Pyroptosis Axis.

BACKGROUND: Pyroptosis, a cell death process triggered by chemotherapy drugs, has emerged as a highly promising mechanism for combating tumors in recent years. As the lead of new drugs, natural products play an important role in the discovery of anticancer drugs. Compared to other natural products, the medicine food homologous natural products (MFHNP) exhibit a superior safety profile. Among a series of MFHNP molecular skeletons, this study found that only benzylideneacetophenone (1) could induce cancer cell pyroptosis. However, the anti-cancer activity of 1 remains to be improved. AIMS: This study aimed to find a pyroptosis inducer with highly effective antitumor activity by modifying the chalcone structure. METHODS: To examine the effect of the Michael receptor in compound 1 on the induction of pyroptosis, several analogs were synthesized by modifying the Michael acceptor. Subsequently, the anticancer activity was tested by MTT assay, and morphological indications of pyroptosis were observed in human lung carcinoma NCI-H460 and human ovarian cancer CP-70 cell lines. Furthermore, to improve the activity of the chalcone skeleton, the anticancer group 3,4,5- trimethoxyphenyl was incorporated into the phenyl ring. Subsequently, compounds 2-22 were designed, synthesized, and screened in human lung cancer cells (NCI-H460, H1975, and A549). Additionally, a quantitative structure-activity relationship (QSAR) model was established using the eXtreme Gradient Boosting (XGBoost) machine learning library to identify the pharmacophore. Furthermore, both in vitro and in vivo experiments were conducted to investigate the molecular mechanisms of pyroptosis induced by the active compound. RESULTS: α, ß-unsaturated ketone was the functional group of the chalcone skeleton and played a pivotal role in inducing cancer cell pyroptosis. QSAR models showed that the regression coefficients (R2) were 0.992 (A549 cells), 0.990 (NCI-H460 cells), and 0.998 (H1975 cells). Among these compounds, compound 7 was selected to be the active compound. Moreover, compound 7 was found to induce pyroptosis in lung cancer cells by upregulating the expression of CHOP by increasing the ROS level. Furthermore, it effectively suppressed the growth of lung cancer xenograft tumors. CONCLUSION: Compound 7 exhibits antineoplastic activity by regulating the ROS/ER stress/pyroptosis axis and is a kind of promising pyroptosis inducer.

GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21.

As a major neuron type in the brain, the excitatory neuron (EN) regulates the lifespan in C. elegans. How the EN acquires senescence, however, is unknown. Here, we show that growth differentiation factor 11 (GDF11) is predominantly expressed in the EN in the adult mouse, marmoset and human brain. In mice, selective knock-out of GDF11 in the post-mitotic EN shapes the brain ageing-related transcriptional profile, induces EN senescence and hyperexcitability, prunes their dendrites, impedes their synaptic input, impairs object recognition memory and shortens the lifespan, establishing a functional link between GDF11, brain ageing and cognition. In vitro GDF11 deletion causes cellular senescence in Neuro-2a cells. Mechanistically, GDF11 deletion induces neuronal senescence via Smad2-induced transcription of the pro-senescence factor p21. This work indicates that endogenous GDF11 acts as a brake on EN senescence and brain ageing.

Quantitatively regulating the ketone structure of triazine-based covalent organic frameworks for efficient visible-light photocatalytic degradation of organic pollutants: Tunable performance and mechanisms.

As promising visible-light-responsive photocatalysts, triazine-based covalent organic frameworks (CTFs) still suffer from broad bandgap and high electron-hole recombination. As such, different contents of electron-rich ketone group were introduced to CTFs (X % keto-CTF), aiming to clarify the mechanism of quantitatively regulating ketone for enhanced visible-light photocatalytic performance of CTFs. As ketone content increased, the bandgap narrowed, electron-hole recombination decreased, charge transfer and quantum yield increased. As a result, keto-CTF outperformed other keto-CTFs in visible-light photocatalytic degradation of tetracycline, and apparent rate constant of TC (kobs) was 3.69 times higher than that of CTF. Importantly, ketone tuning induced varied types and concentrations of reactive species. Integrated with quantitative structure-activity relationships (QSARs) analysis and density functional theory (DFT) calculations, this study unravels how ketone content regulates bandgap structure of CTF, affects the contribution of varied reactive species, and quantitatively enhances the photocatalytic performance of CTFs. It also provides novel insights into the precise design and synthesis of CTFs-based catalyst structures for high-efficient visible-light photocatalytic degradation of organic pollutants.

Rational design, synthesis, and pharmacological characterisation of dicarbonyl curcuminoid analogues with improved stability against lung cancer via ROS and ER stress mediated cell apoptosis and pyroptosis.

Curcumin is a natural medicine with a wide range of anti-tumour activities. However, due to ß-diketone moiety, curcumin exhibits poor stability and pharmacokinetics which significantly limits its clinical applications. In this article, two types of dicarbonyl curcumin analogues with improved stability were designed through the calculation of molecular stability by density functional theory. Twenty compounds were synthesised, and their anti-tumour activity was screened. A plurality of analogues had significantly stronger activity than curcumin. In particular, compound B2 ((2E,2'E)-3,3'-(1,4-phenylene)bis(1-(2-chlorophenyl)prop-2-en-1-one)) exhibited excellent anti-lung cancer activity in vivo and in vitro. In addition, B2 could upregulate the level of reactive oxygen species in lung cancer cells, which in turn activated the endoplasmic reticulum stress and led to cell apoptosis and pyroptosis. Taken together, curcumin analogue B2 is expected to be a novel candidate for lung cancer treatment with improved chemical and biological characteristics.

Autochthonous sources and drought conditions drive anomalous oxygen-consuming pollution increase in a sluice-controlled reservoir in eastern China.

Freshwater reservoirs are an important type of inland waterbody. However, they can suffer from oxygen-consuming pollution, which can seriously threaten drinking water safety and negatively impact the health of aquatic ecosystems. Oxygen-consuming pollutants originate from both allochthonous and autochthonous sources, and have temporally and spatially heterogeneous drivers. Datanggang Reservoir, China, is located in a small agricultural watershed; it is controlled by multiple sluice gates. Anomalously high oxygen consumption indicators were observed in this reservoir in March 2021. Here, it was hypothesized that autochthonous sources were the primary drivers of oxygen-consuming pollution in the reservoir under drought conditions. Datasets of water quality, precipitation, primary productivity, and sediment were used to analyze water quality trends in the reservoir and inflow rivers, demonstrating the effects of allochthonous inputs and autochthonous pollution. No correlation was found between reservoir oxygen consumption indicators and allochthonous inputs; reservoir oxygen consumption indicators and chlorophyll-a concentration were significantly positively correlated (p < 0.05). Substantially lower precipitation and higher water temperature and pH (compared to historical levels) were also observed before the pollution event. Therefore, during this period the hydrological conditions, water temperature, pH, and other variables caused by short-term drought conditions may have facilitated phytoplankton growth in the reservoir. This contributed to a large increase in autochthonous oxygen-consuming pollutants, as reflected by the abnormally high indicators. Sediments contaminated with organic matter may also have been an important contributor. As the effects of environmental management and pollution control continue to emerge, exogenous pollutants imported from the land to reservoirs are currently effectively controlled. However, endogenous pollutants driven by a variety of factors, such as meteorology and hydrology, will likely become the main drivers of short-term changes in oxygen-consuming pollution in freshwater reservoirs in the foreseeable future.

Inhibition of RIPK1 by ZJU-37 promotes oligodendrocyte progenitor proliferation and remyelination via NF-κB pathway.

Receptor interacting serine/threonine protein kinase 1 (RIPK1) activation and necroptosis have been genetically and mechanistically linked with human multiple sclerosis and neurodegenerative diseases for which demyelination is a common key pathology. Demyelination can be healed through remyelination which is mediated by new oligodendrocytes derived from the adult oligodendrocyte progenitor cells (OPCs). Unfortunately, the efficiency of remyelination declines with progressive aging partially due to the depletion of OPCs following chronic or repeated demyelination. However, to our knowledge, so far there is no drug which enhances proliferation of OPCs, and it is unknown whether inhibiting RIPK1 activity directly affect OPCs, the central player of remyelination. Using TNFα induced RIPK1-dependent necroptosis in Jurkat FADD-/- cells as a cell death assay, we screened from 2112 FDA-approved drugs and the drug candidates of new RIPK1 inhibitors selected by ourselves, and identified ZJU-37, a small molecule modified by introducing an amide bond to Nec-1s, is a new RIPK1 kinase inhibitor with higher potency than Nec-1s which has the best reported potency. We unveil in addition to protecting myelin from demyelination and axons from degeneration, ZJU-37 exhibits a new role on promoting proliferation of OPCs and enhancing remyelination by inhibiting RIPK1 kinase activity with higher potency than Nec-1s. Mechanistically, ZJU-37 promotes proliferation of OPCs by enhancing the transcription of platelet derived growth factor receptor alpha via NF-κB pathway. This work identifies ZJU-37 as a new drug candidate which enhances remyelination by promoting proliferation of OPCs, paving the way for a potential drug to enhance myelin repair.

Impaired metabolism of oligodendrocyte progenitor cells and axons in demyelinated lesion and in the aged CNS.

The key pathology of multiple sclerosis (MS) comprises demyelination, axonal damage, and neuronal loss, and when MS develops into the progressive phase it is essentially untreatable. Identifying new targets in both axons and oligodendrocyte progenitor cells (OPCs) and rejuvenating the aged OPCs holds promise for this unmet medical need. We summarize here the recent evidence showing that mitochondria in both axons and OPCs are impaired, and lipid metabolism of OPCs within demyelinated lesion and in the aged CNS is disturbed. Given that emerging evidence shows that rewiring cellular metabolism regulates stem cell aging, to protect axons from degeneration and promote differentiation of OPCs, we propose that restoring the impaired metabolism of both OPCs and axons in the aged CNS in a synergistic way could be a promising strategy to enhance remyelination in the aged CNS, leading to novel drug-based approaches to treat the progressive phase of MS.

Restoring nuclear entry of Sirtuin 2 in oligodendrocyte progenitor cells promotes remyelination during ageing.

The age-dependent decline in remyelination potential of the central nervous system during ageing is associated with a declined differentiation capacity of oligodendrocyte progenitor cells (OPCs). The molecular players that can enhance OPC differentiation or rejuvenate OPCs are unclear. Here we show that, in mouse OPCs, nuclear entry of SIRT2 is impaired and NAD+ levels are reduced during ageing. When we supplement ß-nicotinamide mononucleotide (ß-NMN), an NAD+ precursor, nuclear entry of SIRT2 in OPCs, OPC differentiation, and remyelination were rescued in aged animals. We show that the effects on myelination are mediated via the NAD+-SIRT2-H3K18Ac-ID4 axis, and SIRT2 is required for rejuvenating OPCs. Our results show that SIRT2 and NAD+ levels rescue the aged OPC differentiation potential to levels comparable to young age, providing potential targets to enhance remyelination during ageing.

Neutralization of Hv1/HVCN1 With Antibody Enhances Microglia/Macrophages Myelin Clearance by Promoting Their Migration in the Brain.

Microglia dynamically monitor the microenvironment of the central nervous system (CNS) by constantly extending and retracting their processes in physiological conditions, and microglia/macrophages rapidly migrate into lesion sites in response to injuries or diseases in the CNS. Consequently, their migration ability is fundamentally important for their proper functioning. However, the mechanisms underlying their migration have not been fully understood. We wonder whether the voltage-gated proton channel HVCN1 in microglia/macrophages in the brain plays a role in their migration. We show in this study that in physiological conditions, microglia and bone marrow derived macrophage (BMDM) express HVCN1 with the highest level among glial cells, and upregulation of HVCN1 in microglia/macrophages is presented in multiple injuries and diseases of the CNS, reflecting the overactivation of HVCN1. In parallel, myelin debris accumulation occurs in both the focal lesion and the site where neurodegeneration takes place. Importantly, both genetic deletion of the HVCN1 gene in cells in vitro and neutralization of HVCN1 with antibody in the brain in vivo promotes migration of microglia/macrophages. Furthermore, neutralization of HVCN1 with antibody in the brain in vivo promotes myelin debris clearance by microglia/macrophages. This study uncovers a new role of HVCN1 in microglia/macrophages, coupling the proton channel HVCN1 to the migration of microglia/macrophages for the first time.

Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity.

Maintenance of telomere length is essential to delay replicative cellular senescence. It is controversial on whether growth differentiation factor 11 (GDF11) can reverse cellular senescence, and this work aims to establish the causality between GDF11 and the telomere maintenance unequivocally. Using CRISPR/Cas9 technique and a long-term in vitro culture model of cellular senescence, we show here that in vitro genetic deletion of GDF11 causes shortening of telomere length, downregulation of telomeric reverse transcriptase (TERT) and telomeric RNA component (TERC), the key enzyme and the RNA component for extension of the telomere, and reduction of telomerase activity. In contrast, both recombinant and overexpressed GDF11 restore the transcription of TERT in GDF11KO cells to the wild-type level. Furthermore, loss of GDF11-induced telomere shortening is likely caused by enhancing the nuclear entry of SMAD2 which inhibits the transcription of TERT and TERC. Our results provide the first proof-of-cause-and-effect evidence that endogenous GDF11 plays a causal role for proliferative cells to maintain telomere length, paving the way for potential rejuvenation of the proliferative cells, tissues, and organs.

Design, synthesis, and biological evaluation of indazole derivatives as selective and potent FGFR4 inhibitors for the treatment of FGF19-driven hepatocellular cancer.

Fibroblast growth factor receptor 4 (FGFR4) is a member of the fibroblast growth factor receptor family, which is closely related to the occurrence and development of hepatocellular carcinoma (HCC). In this article, a series of indazole derivatives were designed and synthesized by using computer-aided drug design (CADD) and structure-based design strategies, and then they were evaluated for their inhibition of FGFR4 kinase and antitumor activity. F-30 was subtly selective for FGFR4 compared to FGFR1; it affected cell growth and migration by inhibiting FGFR4 pathways in HCC cell lines in a dose-dependent manner.

Design and Synthesis of Novel Nordihydroguaiaretic Acid (NDGA) Analogues as Potential FGFR1 Kinase Inhibitors With Anti-Gastric Activity and Chemosensitizing Effect.

Aberrant fibroblast growth factor receptor-1 (FGFR1), a key driver promoting gastric cancer (GC) progression and chemo-resistance, has been increasingly recognized as a potential therapeutic target in GC. Hereon, we designed and synthesized a series of asymmetric analogues using Af23 and NDGA as lead compounds by retaining the basic structural framework (bisaryl-1,4-dien-3-one) and the unilateral active functional groups (3,4-dihydroxyl). Thereinto, Y14 showed considerable inhibitory activity against FGFR1. Next, pharmacological experiments showed that Y14 could significantly inhibit the phosphorylation of FGFR1 and its downstream kinase AKT and ERK, thus inhibiting the growth, survival, and migration of gastric cancer cells. Furthermore, compared with 5-FU treatment alone, the combination of Y14 and 5-FU significantly reduced the phosphorylation level of FGFR1, and enhanced the anti-cancer effect by inhibiting the viability and colony formation in two gastric cancer cell lines. These results confirmed that Y14 exerted anti-gastric activity and chemosensitizing effect by inhibiting FGFR1 phosphorylation and its downstream signaling pathway in vitro. This work also provides evidence that Y14, an effective FGFR1 inhibitor, could be used alone or in combination with chemotherapy to treat gastric cancer in the future.

Facile synthesis and synergistic mechanism of CoFe2O4@three-dimensional graphene aerogels towards peroxymonosulfate activation for highly efficient degradation of recalcitrant organic pollutants.

Magnetic CoFe2O4 is a promising heterogeneous catalyst with great separation and catalytic performance on peroxymonosulfate (PMS) activation. However, for extremely recalcitrant organic pollutants (e.g. Benzotriazole (BTA)), CoFe2O4/PMS system exhibits much low catalytic performance and high metal ion leaching. As such, CoFe2O4 supported on three-dimensional graphene aerogels (CoFe2O4@3DG) was synthesized via facile hydrothermal method. It turns out that 3DG as supporter significantly enhances specific surface area, redox activity and electron transfer of composite. The degradation rate constant in the CoFe2O4@3DG/PMS system (0.0203 min-1) is 15 times higher than that in the CoFe2O4/PMS system (0.0013 min-1). It results from synergistic activation of PMS by CoFe2O4 and 3DG to generate multiple reactive oxygen species (•OH, SO4-•, O2-• and 1O2). Particularly, high graphitization structure and low oxygen groups content of 3DG facilitate PMS adsorption on its surface and electron transfer from BTA to PMS. Ultimately, BTA is degraded into CO2, NH3 and intermediates through benzene and triazole ring-opening reactions. Moreover, CoFe2O4@3DG/PMS system displays good stability and recyclability. Therefore, this study provides a new way to improve CoFe2O4 activity for extremely recalcitrant organic pollutants degradation and new insights into synergistic activation of PMS by CoFe2O4 and 3DG, which further advances cobalt-based catalysts in heterogeneous catalysis.

Dataset for NiO/ZnO biomorphic nanocomposite using a poplar tree leaf template to generate an enhanced gas sensing platform to detect n-butanol.

The SEM image data presented in this article was collected by the Scanning electron microscopy (SEM) performed on an XL-30 ESEM FEG scanning electron microscopy. The diameter stastics data was collected and calculated by the Image-Pro Plus software system. The UV-Vis Res spectrum was collected by solid state UV diffuse reflector Shimadzu UV-4100 at wavelength 200-800 nm. The SEM image data showed more details of the poplar tree leave template(PTLT). The diameter stastics data show the diameter averagely distributed in the material. The UV-Vis Res spectrum reflected the physical property of PTLT NiO/ZnO. Interpretation of this data can be found in a research article titled "One-step facile synthesis of a NiO/ZnO biomorphic nanocomposite using a poplar tree leaf template to generate an enhanced gas sensing platform to detect n-butanol" (Qingrui Zeng et al., 2019) [1], Research Article DOI: 10.1016/j.jallcom.2019.05.018•The SEM image provide the more details about the distinction of the PTLT ZnO and conventional ZnO, further present more morphology information of the PTLT biotemplate. Exhibiting a facile and green way for synthesising ZnO and narrow down the size of ZnO crystal, present the advantage of PTLT ZnO in morphology control. Motivating gas sensor researcher to fabricate ZnO by a biotemplate method, which owned biomorphic and extraordinary gas sensing properties.•The UV-Vis Res spectrum present more detail of the energy band information of PTLT ZnO and PTLT NiO/ZnO, which is use for the gas sensing mechanism analysis. Inspiring researcher forcus on the construction on p-n heterojunction type gas sensor to enhance the gas sensing properties.•The material researchers work on the morphic investigation, gas sensor, and application of semiconductor.•These data are benefit for the application of biotemplate method for material fabrication and material application.

The Different Effects of Organic Amines on Synthetic Metal Phosphites/Phosphates.

Four metal phosphites/phosphates crystal materials C8N4H34Al2P4O18 (1), C3N2H17GaP2O8 (2), H5In2P3O10 (3), and H9In2P3O13 (4) have been solvothermally synthesized by organic amines in the presence of mixed solvents. Structural analyses indicate that compound 1 and 2 show one-dimensional (1D) chain structures; compound 3 and 4 are three-dimensional (3D) inorganic open-framework indium phosphites. Organic amines show different mechanisms in the four compounds. The 2,2'-bipyridine organic amine acts as a template source and it breaks down small molecules, which enter into the structure of compound 1. For compound 2, 1,2-propanediamine has a role as protonated template and it forms a hydrogen bond with the inorganic skeleton structure. As for compound 3 and 4 without the organic template, the benzylamine and 2,2'-bipyridine mainly serve as structure-directing agent. Especially, compound 3 has an odd seven-ring channel, and compound 4 contains 3D intersecting six-ring, eight-ring, and 10-ring channels. X-ray diffraction (XRD), scanning electron microscopy (SEM), CHN, inductive coupled plasma (ICP), Infrared (IR), and thermal gravimetric (TG) analyze the four compounds.

Enhanced Ethanol-Sensing Properties Based on Modified NiO-ZnO p-n Heterojunction Nanotubes.

NiO/ZnO gas-sensing nanotube materials were prepared by electrospinning. The structure and morphology of the samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), energydispersive X-ray detection (EDX) and Brunauer-Emmett-Teller (BET) analysis. The template, PAN (peroxyacetyl nitrate) fibers, was completely removed, as evidenced by the EDX results. The final NiO/ZnO composite materials were composed of hexagonal wurtzite ZnO and cubic NiO and exhibited hollow tubular structures. In the composites, p-n heterojunctions were formed at the interface of NiO and ZnO. The results of gas sensitivity tests showed that the incorporation of NiO considerably improved the gas sensitivity of ZnO to ethanol. When the doping ratio was 0.125 mol/mol, the composites exhibited the highest sensitivity to ethanol (100.92 at 300 °C) and showed high selectivity.

The discovery of potent and stable short peptide FGFR1 antagonist for cancer therapy.

Fibroblast growth factor receptor 1 (FGFR1) is one of the attractive pharmaceutical targets for cancer therapy. The FGFR1 targeting antagonist peptides, especially of the short peptides harbouring only coding amino acid might highlights promising aspects for their higher affinity, specificity and lower adverse reactions. However, most of peptides inhibitors remain in preclinical research, likely associating with their instability and short half-life. In this study, we found a stable short peptide inhibitor P48 and speculated that its stability might be related to its non-linear spatial structure. In addition, P48 could target the extracellular immunoglobulin domain of FGFR1, and effectively block the particular signaling pathways of FGFR1, which lead to the inhibition of cancer proliferation, invasion in vitro and restraint of tumor growth in vivo. Together, this study provided a promising FGFR1 inhibitor with the potential to be developed as an antitumor drug.

Integrated transcriptomic analysis reveals hub genes involved in diagnosis and prognosis of pancreatic cancer.

BACKGROUND: The hunt for the molecular markers with specificity and sensitivity has been a hot area for the tumor treatment. Due to the poor diagnosis and prognosis of pancreatic cancer (PC), the excision rate is often low, which makes it more urgent to find the ideal tumor markers. METHODS: Robust Rank Aggreg (RRA) methods was firstly applied to identify the differentially expressed genes (DEGs) between PC tissues and normal tissues from GSE28735, GSE15471, GSE16515, and GSE101448. Among these DEGs, the highly correlated genes were clustered using WGCNA analysis. The co-expression networks and molecular complex detection (MCODE) Cytoscape app were then performed to find the sub-clusters and confirm 35 candidate genes. For these genes, least absolute shrinkage and selection operator (lasso) regression model was applied and validated to build a diagnostic risk score model. Cox proportional hazard regression analysis was used and validated to build a prognostic model. RESULTS: Based on integrated transcriptomic analysis, we identified a 19 gene module (SYCN, PNLIPRP1, CAP2, GNMT, MAT1A, ABAT, GPT2, ADHFE1, PHGDH, PSAT1, ERP27, PDIA2, MT1H, COMP, COL5A2, FN1, COL1A2, FAP and POSTN) as a specific predictive signature for the diagnosis of PC. Based on the two consideration, accuracy and feasibility, we simplified the diagnostic risk model as a four-gene model: 0.3034*log2(MAT1A)-0.1526*log2(MT1H) + 0.4645*log2(FN1) -0.2244*log2(FAP), log2(gene count). Besides, a four-hub gene module was also identified as prognostic model = - 1.400*log2(CEL) + 1.321*log2(CPA1) + 0.454*log2(POSTN) + 1.011*log2(PM20D1), log2(gene count). CONCLUSION: Integrated transcriptomic analysis identifies two four-hub gene modules as specific predictive signatures for the diagnosis and prognosis of PC, which may bring new sight for the clinical practice of PC.

Piperlongumine analogue L50377 induces pyroptosis via ROS mediated NF-κB suppression in non-small-cell lung cancer.

Natural products with potent activity and less toxicity provide major sources for development of novel anti-cancer drugs. Herein, we evaluated the effects and the underlying mechanisms of a novel piperlongumine (PL) analogue L50377 on non-small-cell lung cancer (NSCLC) cells. The results revealed that L50377 displayed greater potentials of suppressing cell growth than PL. In addition, L50377 promoted cell apoptosis and pyroptosis via stimulating reactive oxygen species (ROS) generation in NSCLC cells. More interestingly, ROS mediated NF-κB suppression might be implicated in the mechanisms of L50377-induced pyroptosis in NSCLC cells. Taken together, our results suggested that L50377 served as a novel chemical agent might have great potentials for NSCLC treatment.