EDA ligand triggers plasma membrane trafficking of its receptor EDAR via PKA activation and SNAP23-containing complexes.

BACKGROUND: Ectodysplasin-A (EDA), a skin-specific TNF ligand, interacts with its membrane receptor EDAR to trigger EDA signaling in skin appendage formation. Gene mutations in EDA signaling cause Anhidrotic/Hypohidrotic Ectodermal Dysplasia (A/HED), which affects the formation of skin appendages including hair, teeth, and several exocrine glands. RESULTS: We report that EDA triggers the translocation of its receptor EDAR from a cytosolic compartment into the plasma membrane. We use protein affinity purification to show that upon EDA stimulation EDAR associates with SNAP23-STX6-VAMP1/2/3 vesicle trafficking complexes. We find that EDA-dependent PKA activation is critical for the association. Notably, either of two HED-linked EDAR mutations, T346M and R420W, prevents EDA-induced EDAR translocation; and both EDA-induced PKA activation and SNAP23 are required for Meibomian gland (MG) growth in a skin appendage model. CONCLUSIONS: Overall, in a novel regulatory mechanism, EDA increases plasma membrane translocation of its own receptor EDAR, augmenting EDA-EDAR signaling in skin appendage formation. Our findings also provide PKA and SNAP23 as potential targets for the intervention of HED.

Preparation of Open-Cell Long-Chain Branched Polypropylene Foams for Oil Absorption.

This study aimed to prepare open-cell foams using a blend of long-chain branched polypropylene and polyolefin elastomer (LCBPP/POE) for the production of reusable oil absorbents. The supercritical CO2 foaming process was conducted using a two-step batch rapid depressurization method. This unique two-step foaming approach significantly expanded the temperature and pressure windows, resulting in more uniform cells with smaller sizes, ultimately leading to higher expansion ratios and an increased open cell content. The foaming process was optimized by adjusting parameters, such as the LCBPP/POE ratio, foaming temperature, and foaming pressure, reaching a maximum open cell content of 97.6% and a maximum expansion ratio of 48. The influence of polypropylene (PP) crystallization was investigated with the aid of scanning electron microscopy and differential scanning calorimetry. Furthermore, the hydrophobic and lipophilic characteristics of the LCBPP/POE open-cell foam were determined via contact angle measurements and oil/water separation tests. Oil absorption tests revealed that the blended LCBPP/POE foam has a higher oil absorption capacity than that of the pure LCBPP foam. The cyclic oil absorption tests demonstrated the outstanding ductility and recoverability of the LCBPP/POE open-cell foam in comparison to those of the pure LCBPP foam. Over 10 cycles, the LCBPP/POE foam maintained a substantial adsorption capacity, retaining 99.3% of its initial oil absorption capacity. With its notable features, including a high open cell content, excellent hydrophobic and lipophilic characteristics, superior oil absorption capacity, impressive cyclic oil absorption performance, and robust reusability, LCBPP/POE open-cell foams exhibit significant promise as potential oil adsorbents for use in oil spill cleanup applications.

The effective removal of Pb2+ by activated carbon fibers modified by l-cysteine: exploration of kinetics, thermodynamics and mechanism.

Herein, we developed a low-cost fabrication route to prepare chemically grafted activated carbon fibers, which effectively removed Pb2+ from solution. Multiple characteristic results indicated that l-cyst-ACF had abundant nitrogen-containing and sulfur-containing functional groups. Based on the XPS and EDS analyses, the capture of Pb2+ was attributed to the abundant adsorption sites on the fiber surface. According to the analysis of the pseudo-second-order kinetic model and the Langmuir isotherm model, the adsorption process could be interpreted as monolayer adsorption and chemisorption, and the equilibrium adsorption capacity was determined to be 136.80 mg g-1 by fitting the pseudo-second-order kinetic model. The maximum adsorption capacity of l-cyst-ACF for Pb2+ was calculated to be 179.53 mg g-1 using the Langmuir model. In addition, the adsorption reaction was endothermic and spontaneous, as evidenced by the thermodynamic parameters. The outcomes of this study provide a low-cost and feasible strategy for the remediation of Pb2+ pollution in the environment.

Ectodysplasin A (EDA) Signaling: From Skin Appendage to Multiple Diseases.

Ectodysplasin A (EDA) signaling is initially identified as morphogenic signaling regulating the formation of skin appendages including teeth, hair follicles, exocrine glands in mammals, feathers in birds and scales in fish. Gene mutation in EDA signaling causes hypohidrotic ectodermal dysplasia (HED), a congenital hereditary disease with malformation of skin appendages. Interestingly, emerging evidence suggests that EDA and its receptors can modulate the proliferation, apoptosis, differentiation and migration of cancer cells, and thus may regulate tumorigenesis and cancer progression. More recently, as a newly discovered hepatocyte factor, EDA pathway has been demonstrated to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and type II diabetes by regulating glucose and lipid metabolism. In this review, we summarize the function of EDA signaling from skin appendage development to multiple other diseases, and discuss the clinical application of recombinant EDA protein as well as other potential targets for disease intervention.

Porous boron nitride intercalated zero-valent iron particles for highly efficient elimination of organic contaminants and Cr (VI).

Developing novel bifunctional materials to high efficiently degrade organic pollutants and eliminate hexavalent chromium (Cr (VI)) is significantly desired in the wastewater treatment field. The porous boron nitride (p-BN) was fabricated by a two-stage calcination strategy and was innovatively employed to support zero-valent iron (ZVI), achieving the bifunctional material (p-BN@ZVI) to degrade carbamazepine (CBZ) and eliminate Cr (VI). p-BN@ZVI could degrade more than 98% CBZ in 6 min with the high apparent first-order constant (kobs) of 0.536 min-1, almost 5 times higher than that of the ZVI/PMS system and outperformed most previous reported ZVI supported catalysts, which was mainly ascribed to the fact that the introduction of p-BN with high surface area (793.97 m2/g) improved the dispersion of ZVI and exposed more active sites. Quenching tests coupled with electron paramagnetic resonance (EPR) suggested that •OH was the major reactive oxygen species with a contribution of 71.6%. Notably, the p-BN@ZVI/PMS system expressed low activation energy of 8.23 kJ/mol and reached a 65.69% TOC degradation in 20 min even at 0 °C. p-BN@ZVI possessed remarkable storage stability and could still degrade 92.3% CBZ despite three-month storage. More interestingly, p-BN@ZVI was capable to eliminate 98.1% of 50 mg/L Cr (VI) within 5 min through adsorption and reduction, where nearly 80% Cr (VI) was transformed to Cr (III), and exhibited the maximum Cr (VI) elimination capacity of 349 mg/g. This study provides new insights into the efficient organic contaminants degradation and Cr (VI) elimination in the treatment of wastewater.

Construction of durable superhydrophilic activated carbon fibers based material for highly-efficient oil/water separation and aqueous contaminants degradation.

Developing filtering materials with high permeation flux and contaminant removal rate is of great importance for oily wastewater remediation. Herein, a robust three-dimensional (3D) activated carbon fibers (ACFs) based composite with uniformly grown layered double hydroxide (LDH) on the surface was successfully constructed through a feasible hydrothermal strategy. The LDH with a high surface energy and vertically aligned structure could provide superhydrophilicity to ACFs. Systematic investigation confirmed that the 3D material could overcome the size mismatch between the ACFs macropores and tiny emulsified droplets through the combination of size-sieving filtration on the surface and oil droplet coalescence in the fiber network. This process efficiently separated the intractable surfactant-stabilized oil-in-water emulsions with high permeation flux (up to 4.16 × 106 L m-2 h-1 bar-1). Notably, the LDH also had well-dispersed catalytic active sites, which could initiate advanced oxidation processes (AOPs) to efficiently eliminate various types of water-soluble organic pollutants (e.g., pharmaceuticals, phenolic compounds and organic dyes). The resulting modified ACFs exhibited exceptional removal rates for both oil and organic pollutants in the complex sewage during the continuous filtration process. These versatile abilities integrated with the facile preparation method reported herein provide outstanding prospects for the large-scale treatment of oily wastewater.

Enhanced sorption and reduction of Cr(VI) by the flowerlike nanocomposites combined with molybdenum disulphide and polypyrrole.

Developing high-performance adsorbent for hexavalent chromium (Cr(VI)) elimination presents an enticing prospect in environmental remediation. Herein, three-dimensional flowerlike nanospheres composed of molybdenum disulphide and polypyrrole (MoS2@PPy) were successfully prepared via a one-pot hydrothermal and subsequent carbothermal reduction process for the removal of Cr(VI). The effects of pH, adsorbent dosage, co-existing ions, initial Cr(VI) concentration and temperature were investigated systematically by batch experiments. Benefiting from the incorporation of MoS2, the obtained MoS2@PPy composites showed a dramatic increase of specific surface area (149.82 m2·g-1) and adsorption capacity (230.97 mg·g-1) when compared with the pure PPy nanoparticles. Based on the thermodynamics study and X-ray photoelectron spectroscopy analyses, the removal process of Cr(VI) was proved to be exothermic and spontaneous, and accessible under-coordinated Mo(IV) and pyrrolic N groups coupled with redox reactions were conducive to the efficient removal of Cr(VI). Attractively, the MoS2@PPy acted as the electron donor could also activate peroxymonosulphate for the efficient degradation of organic contaminants. These results suggested that the MoS2@PPy was promising in Cr(VI) elimination and other kinds of organic pollutants removal in wastewater.

TNF-α-dependent neuronal necroptosis regulated in Alzheimer's disease by coordination of RIPK1-p62 complex with autophagic UVRAG.

Background: Neuronal death is a major hallmark of Alzheimer's disease (AD). Necroptosis, as a programmed necrotic process, is activated in AD. However, what signals and factors initiate necroptosis in AD is largely unknown. Methods: We examined the expression levels of critical molecules in necroptotic signaling pathway by immunohistochemistry (IHC) staining and immunoblotting using brain tissues from AD patients and AD mouse models of APP/PS1 and 5×FAD. We performed brain stereotaxic injection with recombinant TNF-α, anti-TNFR1 neutralizing antibody or AAV-mediated gene expression and knockdown in APP/PS1 mice. For in vitro studies, we used TNF-α combined with zVAD-fmk and Smac mimetic to establish neuronal necroptosis models and utilized pharmacological or molecular biological approaches to study the signaling pathways. Results: We find that activated neuronal necroptosis is dependent on upstream TNF-α/TNFR1 signaling in both neuronal cell cultures and AD mouse models. Upon TNF-α stimulation, accumulated p62 recruits RIPK1 and induces its self-oligomerization, and activates downstream RIPK1/RIPK3/MLKL cascade, leading to neuronal necroptosis. Ectopic accumulation of p62 is caused by impaired autophagy flux, which is mediated by UVRAG downregulation during the TNF-α-promoted necroptosis. Notably, UVRAG overexpression inhibits neuronal necroptosis in cell and mouse models of AD. Conclusions: We identify a finely controlled regulation of neuronal necroptosis in AD by coordinated TNF-α signaling, RIPK1/3 activity and autophagy machinery. Strategies that could fine-tune necroptosis and autophagy may bring in promising therapeutics for AD.

Well-dispersed iron and nitrogen co-doped hollow carbon microsphere anchoring by g-C3N4 for efficient peroxymonosulfate activation.

Developing single-atom Fenton-like catalysts with the maximum utilization of active sites present an attractive potential in environmental remediation. Herein, the single-atom Fe and N co-doped hollow carbon microsphere loaded g-C3N4 catalyst (HFeNC-g-C3N4) was prepared by an innovative cascade anchoring strategy using polystyrene as the hard template, iron phthalocyanine, polydopamine and urea as the Fe, N and C precursor, in which the in-situ generated g-C3N4 could not only effectively anchor Fe atom to create the well-dispersed Fe-Nx active sites, but also accelerate the electron transfer in peroxymonosulfate (PMS) activation. Taking advantages of such sequential protecting strategy, the as-synthesized HFeNC-g-C3N4 catalyst with single-atom Fe-Nx active sites, verified by XRD, XPS and HAADF-STEM, could work as an efficient Fenton-like catalyst for PMS activation, which achieved almost 100% removal of 4-chlorophenol (4-CP) in 5 min with the turnover frequency calculated to be 34.6 times higher than that of the homogeneous Fe2+ catalyst. The mechanism of O2•- dominated radical combined with nonradical 1O2 pathway was confirmed by quenching experiments and ESR analysis, which might be interrelated to the improvement of pH adaptability and interference immunity of HFeNC-g-C3N4/PMS system. Overall, the present findings provided an innovation strategy for the synthesis of excellent single-atom Fe based catalyst in wastewater purification.

High-valent iron-oxo species on pyridine-containing MWCNTs generated in a solar-induced H2O2 activation system for the removal of antimicrobials.

The overuse of antimicrobials has resulted in serious damage to the ecosystem and human health. Therefore, the development of an efficient, stable, and reusable catalyst to eliminate antimicrobials under mild conditions is highly desired. Drawing inspiration from the metabolism of drugs by the enzymes in the human body, such as heme catalase, we developed a simulated enzyme catalyst, perchloride iron phthalocyanine (FePcCl16), immobilized on pyridine-modified multiwalled carbon nanotubes (FePcCl16-Py-MWCNTs). In the catalyst, FePcCl16 worked as the active site, and the axial fifth ligand, 4-aminopyridine, was introduced to cleave H2O2 heterolytically. Inspired by the reaction mechanism of heme catalase and H2O2, the catalytic system was designed based on FePcCl16-Py-MWCNTs for oxidizing 4-chloro-3,5-dimethylphenol (PCMX) by H2O2 activation. The results showed that the catalytic activity of the system was significantly increased under simulated solar light irradiation, which can promote electron transfer for heterolytic cleavage of H2O2. The enzyme-like catalyst achieved much higher catalytic activity than the Fenton reaction when the pH was close to neutral. It turned out that the main active species was high-valent iron-oxo (Fe(Ⅳ) = O) rather than hydroxyl radial (•OH) or superoxide radical (•O2-), different from most mechanisms. Ultraperformance liquid chromatography-high-definition mass spectrometry showed that the substrate was degraded to small molecule acids by Fe(Ⅳ) = O active species and further mineralization indicated by total organic carbon. The catalytic system exhibited highly efficient, stable, recyclable catalytic performance under mild conditions and did not cause secondary pollution to the environment. This study of a simulated enzyme catalytic system offers important insight into sewage treatment.

Degradation of carbamazepine by MWCNTs-promoted generation of high-valent iron-oxo species in a mild system with O-bridged iron perfluorophthalocyanine dimers.

Metal phthalocyanine has been extensively studied as a catalyst for degradation of carbamazepine (CBZ). However, metal phthalocyanine tends to undergo their own dimerization or polymerization, thereby reducing their activity points and affecting their catalytic properties. In this study, a catalytic system consisting of O-bridged iron perfluorophthalocyanine dimers (FePcF16-O-FePcF16), multi-walled carbon nanotubes (MWCNTs) and H2O2 was proposed. The results showed MWCNTs loaded with FePcF16-O-FePcF16 can achieve excellent degradation of CBZ with smaller dosages of FePcF16-O-FePcF16 and H2O2, and milder reaction temperatures. In addition, the results of experiments revealed the reaction mechanism of non-hydroxyl radicals. The highly oxidized high-valent iron-oxo (Fe(IV)=O) species was the main reactive species in the FePcF16-O-FePcF16/MWCNTs/H2O2 system. It is noteworthy that MWCNTs can improve the dispersion of FePcF16-O-FePcF16, contributing to the production of highly oxidized Fe(IV)=O. Then, the pathway of CBZ oxidative degradation was speculated, and the study results also provide new ideas for metal phthalocyanine-loaded carbon materials to degrade emerging pollutants.

Nitrogen-doped porous carbon encapsulating iron nanoparticles for enhanced sulfathiazole removal via peroxymonosulfate activation.

Developing novel catalyst with both high efficiency and stability presents an enticing prospect for peroxymonosulfate (PMS) activation. In this paper, nitrogen-doped porous carbon encapsulating iron nanoparticles (CN-Fe) was fabricated by a facile carbothermal reduction process using polyaniline (PANI) and α-Fe2O3 as the precursors. The stubborn antibiotics, sulfathiazole (STZ), was employed as a target pollutant, demonstrating that CN-Fe coupled with PMS could achieve 96% removal efficiency and even 57% mineralization rate of STZ within 40 min. More importantly, the rate constant of CN-Fe was calculated to be 0.07665 min-1, which was 6 times higher than that of the commercial α-Fe2O3 catalyst. Furthermore, CN-Fe also presented a favorable catalytic performance for removing other organic pollutants including phenolic compounds and organic dyes. Interestingly, the catalytic activity of the used CN-Fe catalyst could be regenerated after thermal treatment (600 °C) and the as-synthesized CN-Fe catalyst exhibited excellent long-term stability with almost no loss of activity after storage for three months. The catalytic mechanism in the CN-Fe/PMS system was elucidated by electron paramagnetic resonance (EPR), linear sweep voltammetry (LSV), radical and electron trapping tests, which confirmed that sulfate radicals (SO4-), hydroxyl radicals (OH), superoxide radicals (O2-) and singlet oxygen (1O2) were generated in the oxidation process with the assistance of electron transfer between PMS and catalyst. To our knowledge, this was the first attempt for the application of PANI-derived CN-Fe hybrid materials as PMS activators and the findings would provide a simple and promising strategy to fabricate highly efficient and environment-benign catalysts for wastewater remediation.

Correction to: Artemisinin derivatives inactivate cancer-associated fibroblasts through suppressing TGF-ß signaling in breast cancer.

In the original publication of this article [1], Fig. 3 is wrong, but does not affect discussions and conclusions drawn in the article.

Correction to: Wogonoside inhibits invasion and migration through suppressing TRAF2/4 expression in breast cancer.

In the original publication of this article [1], there are mistakes in Fig. 3c and Fig. 3e.

Artemisinin derivatives inactivate cancer-associated fibroblasts through suppressing TGF-ß signaling in breast cancer.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are activated fibroblasts associated with cancer. They have an important role in tumor growth and metastasis. Artemisinin (ART) is a sesquiterpene lactone extracted from Chinese herb qinghao, and artemether (ARM), artesunate (ARS) and dihydroartemisinin (DHA) were synthesized derivatives of artemisinin, which also have anti-malarial and anti-cancer effects such as artemisinin. METHODS: In this study, we investigated the in-vitro and in-vivo effects of artemisinin derivatives on inactivating cancer-associated fibroblasts and uncovered its underlying mechanism. RESULTS: We demonstrated that ARS and DHA could revert L-929-CAFs and CAFs from activated to inactivated state in vitro. Mechanically, ARS and DHA could suppress TGF-ß signaling to inhibit activation of L-929-CAFs and CAFs, and decreased interaction between tumor and tumor microenvironment. The results showed that ARS and DHA could suppress CAFs-induced breast cancer growth and metastasis in the orthotopic model. Conformably, ARS and DHA suppressed TGF-ß signaling to inactivate cancer-associated fibroblasts and inhibit cancer metastasis in vivo. CONCLUSIONS: Artemisinin derivatives are potential therapeutic agents for the treatment of breast cancer.

Anlotinib inhibits angiogenesis via suppressing the activation of VEGFR2, PDGFRß and FGFR1.

Tumor cells recruit vascular endothelial cells and circulating endothelial progenitor cells to form new vessels to support their own growth and metastasis. VEGF, PDGF-BB and FGF-2 are three major pro-angiogenic factors and applied to promote angiogenesis. In this research, we demonstrated that anlotinib, a potent multi-tyrosine kinases inhibitor (TKI), showed a significant inhibitory effect on VEGF/PDGF-BB/FGF-2-induced angiogenesis in vitro and in vivo. Wound healing assay, chamber directional migration assay and tube formation assay indicated that anlotinib inhibited VEGF/PDGF-BB/FGF-2-induced cell migration and formation of capillary-like tubes in endothelial cells. Furthermore, anlotinib suppressed blood vessels sprout and microvessel density in rat aortic ring assay and chicken chorioallantoic membrane (CAM) assay. Importantly, according to our study, the anti-angiogenic effect of anlotinib is superior to sunitinib, sorafenib and nintedanib, which are three main anti-angiogenesis drugs in clinic. Mechanistically, anlotinib inhibits the activation of VEGFR2, PDGFRß and FGFR1 as well their common downstream ERK signaling. Therefore, anlotinib is a potential agent to inhibit angiogenesis and be applied to tumor therapy.

LYG-202 inhibits activation of endothelial cells and angiogenesis through CXCL12/CXCR7 pathway in breast cancer.

Angiogenesis is critical for the growth and metastasis of triple-negative breast cancer (TNBC) and its inhibition reduces the risk of progression of metastatic TNBC. In this study, we investigated that LYG-202, a flavonoid with a piperazine substitution, inhibited angiogenesis induced by conditioned media (CM) from MDA-MB-231 cells under hypoxia and revealed its underlying mechanism. The results showed that LYG-202 decreased CXCL12 secretion and CXCR7 expression, leading to suppression of its downstream ERK/AKT/nuclear factor kappa B (NF-κB) signaling, which eventually decreased the expression of MMP-2, MMP-9, RhoA and increased VE-cadherin expression in EA.hy 926 cells treated with CM from MDA-MB-231 cells under hypoxia. The decreased migration ability, increased cell adhesion and inhibited CXCR7 pathway by LYG-202 could also be reproduced in human umbilical vein endothelial cells. More importantly, LYG-202 also inhibited tumor angiogenesis and tumor growth of human breast cancer MDA-MB-231 cells in nude mice through CXCL12/CXCR7 pathway. In summary, LYG-202 is a potential agent to prohibit tumor angiogenesis through inhibiting the activation of endothelial cells.

Wogonoside inhibits invasion and migration through suppressing TRAF2/4 expression in breast cancer.

BACKGROUND: Twist1 is involved in tumor initiation and progression, which especially contributes to tumor invasion and metastasis. Wogonoside is the main in-vivo metabolite of wogonin, and it is also a natural product with potential treatment effects against cancer. METHODS: In this study, we investigated the in-vitro anti-invasion and in-vivo anti-metastasis effects of wogonoside on breast cancer cells and uncovered its underlying mechanism. RESULTS: The results showed that wogonoside could suppress the growth and metastasis of breast tumor in the orthotopic model of MDA-MB-231 cells. We found that wogonoside could reduce the overexpression of TNF-α, TRAF2 and TRAF4 in later stage of tumor, and improved tumor microenvironment. Therefore, TNF-α was utilized to induce metastases of breast cancer cell in vitro. Wogonoside could inhibit invasion and migration in TNF-α-induced MDA-MB-231, MDA-MB-435, and BT-474 cells. Mechanically, wogonoside inactivated NF-κB signaling through decreasing the protein expression of TRAF2/4, which further inhibited Twist1 expression. Consequently, wogonoside could down-regulate MMP-9, MMP-2, vimentin and CD44v6 expression in TNF-α-induced MDA-MB-231 and MDA-MB-435 cells. Then, these findings were proved in TNF-α + TGF-ß1-induced MCF7 cells. CONCLUSIONS: Wogonoside might be a potential therapeutic agent for the treatment of tumor metastasis in breast cancer.

Gambogic acid suppresses cancer invasion and migration by inhibiting TGFß1-induced epithelial-to-mesenchymal transition.

The epithelial-to-mesenchymal transition (EMT) contributes to the disruption of cell-cell junctions and imbues cancer cells with invasive and migratory properties. In this study, we investigated the effect of gambogic acid, a xanthone extracted from the resin of Garciania hanburyi, on transforming growth factor ß1 (TGFß1)-induced EMT. Gambogic acid inhibited the invasion and migration of TGFß1-induced A549 cells in vitro. Gambogic acid also increased the mRNA and protein expression of E-cadherin, but repressed the mRNA and protein expression of N-cadherin, vimentin, and transcription factor TWIST1. Further examination of the mechanism revealed that the nuclear factor κB (NF-κB) pathway is involved in this regulation of EMT-related biomarkers. Gambogic acid inhibited NF-κB p65 nuclear translocation and the phosphorylation of the inhibitor of NF-κB (IκBα) and IκBα kinase (IKKα). Gambogic acid also suppressed the EMT induced by TGFß1 and tumor necrosis factor α by inhibiting the NF-κB pathway. Our data also indicate that gambogic acid inhibited the primary lesion and lung metastasis of orthotopic model of A549 cells in vivo. We propose that gambogic acid might be developed as a candidate drug with therapeutic potential for the treatment of cancer invasion and migration.

Activation of phospholipase C-γ1 and translocation of phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase contribute to GL-V9-induced apoptosis in human gastric cancer cells.

Gastric cancer is the most common type of tumor in developing countries and the fourth most frequently diagnosed cancer worldwide. Here, we demonstrated the apoptotic effects of GL-V9 on several human gastric cancer cells and selected MGC-803 cells to uncover the underlying mechanism. GL-V9 elevated Bax/Bcl-2 ratio, abated mitochondrial membrane potential and triggered the onset of apoptotic execution in MGC-803 cells. Our research revealed that CHOP silencing could not inhibit apoptosis, neither could it block Ca2+ release, suggesting that GL-V9-induced apoptosis was independent of CHOP. Furthermore, GL-V9 increased mitochondrial Ca2+ uptake through 1,4,5-triphosphate (IP3) receptor via the activation of phospholipase C-γ1 and the translocation of phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase from nucleus to endoplasmic reticulum. Moreover, in-vivo studies indicated that GL-V9 exhibited significant MGC-803 xenografts regression in nude mice with low systemic toxicity. In conclusion, GL-V9 could induce apoptosis in gastric cancer cells, and would be a promising therapeutical agent against gastric cancer.