Human ESC-derived vascular cells promote vascular regeneration in a HIF-1α dependent manner.

Hypoxia-inducible factor (HIF-1α), a core transcription factor responding to changes in cellular oxygen levels, is closely associated with a wide range of physiological and pathological conditions. However, its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive. Here, we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-1α-deficient human vascular cells including vascular endothelial cells, vascular smooth muscle cells, and mesenchymal stem cells (MSCs), as a platform for discovering cell type-specific hypoxia-induced response mechanisms. Through comparative molecular profiling across cell types under normoxic and hypoxic conditions, we provide insight into the indispensable role of HIF-1α in the promotion of ischemic vascular regeneration. We found human MSCs to be the vascular cell type most susceptible to HIF-1α deficiency, and that transcriptional inactivation of ANKZF1, an effector of HIF-1α, impaired pro-angiogenic processes. Altogether, our findings deepen the understanding of HIF-1α in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.

GPRASP1 loss-of-function links to arteriovenous malformations by endothelial activating GPR4 signals.

Arteriovenous malformations (AVMs) are fast-flow vascular malformations and refer to important causes of intracerebral haemorrhage in young adults. Getting deep insight into the genetic pathogenesis of AVMs is necessary. Herein, we identified two vital missense variants of G protein-coupled receptor (GPCR) associated sorting protein 1 (GPRASP1) in AVM patients for the first time and congruously determined to be loss-of-function variants in endothelial cells. GPRASP1 loss-of-function caused endothelial dysfunction in vitro and in vivo. Endothelial Gprasp1 knockout mice suffered a high probability of cerebral haemorrhage, AVMs and exhibited vascular anomalies in multiple organs. GPR4 was identified to be an effective GPCR binding with GPRASP1 to develop endothelial disorders. GPRASP1 deletion activated GPR4/cAMP/MAPK signalling to disturb endothelial functions, thus contributing to vascular anomalies. Mechanistically, GPRASP1 promoted GPR4 degradation. GPRASP1 enabled GPR4 K63-linked ubiquitination, enhancing the binding of GPR4 and RABGEF1 to activate RAB5 for conversions from endocytic vesicles to endosomes, and subsequently increasing the interactions of GPR4 and ESCRT members to package GPR4 into multivesicular bodies or late endosomes for lysosome degradation. Notably, the GPR4 antagonist NE 52-QQ57 and JNK inhibitor SP600125 effectively rescued the vascular phenotype caused by endothelial Gprasp1 deletion. Our findings provided novel insights into the roles of GPRASP1 in AVMs and hinted at new therapeutic strategies.

SLC35D3 promotes white adipose tissue browning to ameliorate obesity by NOTCH signaling.

White adipose tissue browning can promote lipid burning to increase energy expenditure and improve adiposity. Here, we show that Slc35d3 expression is significantly lower in adipose tissues of obese mice. While adipocyte-specific Slc35d3 knockin is protected against diet-induced obesity, adipocyte-specific Slc35d3 knockout inhibits white adipose tissue browning and causes decreased energy expenditure and impaired insulin sensitivity in mice. Mechanistically, we confirm that SLC35D3 interacts with the NOTCH1 extracellular domain, which leads to the accumulation of NOTCH1 in the endoplasmic reticulum and thus inhibits the NOTCH1 signaling pathway. In addition, knockdown of Notch1 in mouse inguinal white adipose tissue mediated by orthotopic injection of AAV8-adiponectin-shNotch1 shows considerable improvement in obesity and glucolipid metabolism, which is more pronounced in adipocyte-specific Slc35d3 knockout mice than in knockin mice. Overall, in this study, we reveal that SLC35D3 is involved in obesity via NOTCH1 signaling, and low adipose SLC35D3 expression in obesity might be a therapeutic target for obesity and associated metabolic disorders.

ZFYVE28 mediates insulin resistance by promoting phosphorylated insulin receptor degradation via increasing late endosomes production.

Insulin resistance is associated with many pathological conditions, and an in-depth understanding of the mechanisms involved is necessary to improve insulin sensitivity. Here, we show that ZFYVE28 expression is decreased in insulin-sensitive obese individuals but increased in insulin-resistant individuals. Insulin signaling inhibits ZFYVE28 expression by inhibiting NOTCH1 via the RAS/ERK pathway, whereas ZFYVE28 expression is elevated due to impaired insulin signaling in insulin resistance. While Zfyve28 overexpression impairs insulin sensitivity and causes lipid accumulation, Zfyve28 knockout in mice can significantly improve insulin sensitivity and other indicators associated with insulin resistance. Mechanistically, ZFYVE28 colocalizes with early endosomes via the FYVE domain, which inhibits the generation of recycling endosomes but promotes the conversion of early to late endosomes, ultimately promoting phosphorylated insulin receptor degradation. This effect disappears with deletion of the FYVE domain. Overall, in this study, we reveal that ZFYVE28 is involved in insulin resistance by promoting phosphorylated insulin receptor degradation, and ZFYVE28 may be a potential therapeutic target to improve insulin sensitivity.

Single-cell profiling reveals a potent role of quercetin in promoting hair regeneration.

Hair loss affects millions of people at some time in their life, and safe and efficient treatments for hair loss are a significant unmet medical need. We report that topical delivery of quercetin (Que) stimulates resting hair follicles to grow with rapid follicular keratinocyte proliferation and replenishes perifollicular microvasculature in mice. We construct dynamic single-cell transcriptome landscape over the course of hair regrowth and find that Que treatment stimulates the differentiation trajectory in the hair follicles and induces an angiogenic signature in dermal endothelial cells by activating HIF-1α in endothelial cells. Skin administration of a HIF-1α agonist partially recapitulates the pro-angiogenesis and hair-growing effects of Que. Together, these findings provide a molecular understanding for the efficacy of Que in hair regrowth, which underscores the translational potential of targeting the hair follicle niche as a strategy for regenerative medicine, and suggest a route of pharmacological intervention that may promote hair regrowth.

Alteration of the gut microbiome and correlated metabolism in a rat model of long-term depression.

Objective: This study aims to investigate the composition and function of the gut microbiome in long-term depression using an 8-week chronic unpredictable mild stress (CUMS) rat model. Materials and methods: Animals were sacrificed after either 4 weeks or 8 weeks under CUMS to mimic long-term depression in humans. The gut microbiome was analyzed to identify potential depression-related gut microbes, and the fecal metabolome was analyzed to detect their functional metabolites. The correlations between altered gut microbes and metabolites in the long-term depression rats were explored. The crucial metabolic pathways related to long-term depression were uncovered through enrichment analysis based on these gut microbes and metabolites. Results: The microbial composition of long-term depression (8-week CUMS) showed decreased species richness indices and different profiles compared with the control group and the 4-week CUMS group, characterized by disturbance of Alistipes indistinctus, Bacteroides ovatus, and Alistipes senegalensis at the species level. Additionally, long-term depression was associated with disturbances in fecal metabolomics. D-pinitol was the only increased metabolite in the 8-week CUMS group among the top 10 differential metabolites, while the top 3 decreased metabolites in the long-term depression rats included indoxyl sulfate, trimethylaminen-oxide, and 3 alpha,7 alpha-dihydroxy-12-oxocholanoic acid. The disordered fecal metabolomics in the long-term depression rats mainly involved the biosynthesis of pantothenate, CoA, valine, leucine and isoleucine. Conclusion: Our findings suggest that the gut microbiome may participate in the long-term development of depression, and the mechanism may be related to the regulation of gut metabolism.

Effects and mechanisms of Al substitution on the catalytic ability of ferrihydrite for Mn(II) oxidation and the subsequent oxidation and immobilization of coexisting Cr(III).

Al(III)-substituted ferrihydrite existing in natural soils is more common than pure ferrihydrite; however, the effects of Al(III) incorporation on the interaction between ferrihydrite, Mn(II) catalytic oxidation, and coexisting transition metal (e.g., Cr(III)) oxidation remain elusive. To address this knowledge gap, Mn(II) oxidation on synthetic Al(III)-incorporated ferrihydrite and Cr(III) oxidation on the previously formed Fe-Mn binaries were investigated in this study via batch kinetic studies combined with various spectroscopic analyses. The results indicate that Al substitution in ferrihydrite barely changes its morphology, specific surface area, or the types of surface functional groups, but increases the total amount of hydroxyl on the ferrihydrite surface and enhances its adsorption capacity toward Mn(II). Conversely, Al substitution inhibits electron transfer in ferrihydrite, thereby weakening its electrochemical catalysis on Mn(II) oxidation. Thus, the contents of Mn(III/IV) oxides with higher Mn valence states decrease, whereas those of lower Mn valence states increase. Furthermore, the number of hydroxyl radicals formed during Mn(II) oxidation on ferrihydrite decreases. These inhibitions of Al substitution on Mn(II) catalytic oxidation subsequently cause decreased Cr(III) oxidation and poor Cr(VI) immobilization. Additionally, Mn(III) in Fe-Mn binaries is confirmed to play a dominant role in Cr(III) oxidation. This research facilitates sound decision-making regarding the management of Cr-contaminated soil environments enriched with Fe and Mn.

Transformation of zinc oxide nanoparticles in the presence of aluminum oxide with pre-sorbed phosphorus ligands.

Naturally occurring oxides could react with zinc oxide (ZnO) nanoparticles (NPs) and then change its transformation and toxicity to ecological receptors. The reaction may be affected by a variety of environmental factors, yet the relevant processes and mechanisms are limitedly investigated. Natural prevalent ligands, as an important factor, can sorb on natural oxide minerals and change its surface property, finally affecting ZnO NP transformation. This study investigated the interactions of ZnO NPs with phosphorus ligands (i.e., phytate and orthophosphate) pre-sorbed γ-alumina (γ-Al2O3) via batch experiments and multi-technique analyses. A limited amount of aqueous Zn2+ is observed when the concentration of ZnO NPs is relatively low (<64.8 mg L-1) in the presence of phytate pre-sorbed γ-Al2O3. Solid Zn(II) species includes binary/ternary surface Zn(II) complexes on γ-Al2O3 with minor amounts of zinc phytate precipitates. As the concentration of ZnO NPs increases, surface Zn(II) complexes gradually transform into zinc phytate and Zn-Al layered double hydroxide (Zn-Al LDH) precipitates. The quantitative analysis indicates that, as the concentration of ZnO NPs increases from 32.4 to 388.8 mg L-1, the proportion of Zn(II) species as binary/ternary surface complexes decreases from 81.9 to 30.2%; and the proportion as zinc phytate and Zn-Al LDH increases from 17.9 to 27.6% and 0 to 43.8%, respectively. The pre-sorption of orthophosphate can also inhibit ZnO NP transformation into Zn-Al LDH precipitates on γ-Al2O3. This study suggests that natural ligands pre-existed on natural oxide minerals could greatly influence the solubility, stability, transformation, and fate of easily dissoluble metal oxides (e.g., ZnO) in the environments.

Simultaneous oxidation of Mn(II) and As(III) on cupric oxide (CuO) promotes As(III) removal at circumneutral pH.

Oxidation of Mn(II) or As(III) by molecular oxygen is slow at pH < 9, while they can be catalytically oxidized in the presence of oxide minerals and then removed from contaminated water. However, the reaction mechanisms on simultaneous oxidation of Mn(II) and As(III) on oxide mineral surface and their accompanied removal efficiency remain unclear. This study compared Mn(II) oxidation on four common metal oxides (γ-Al2O3, CuO, α-Fe2O3 and ZnO) and investigated the simultaneous oxidation and removal of Mn(II) and As(III) through batch experiments and spectroscopic analyses. Among the tested oxides, CuO and α-Fe2O3 possess greater catalytic activity toward Mn(II) oxidation. Oxidation and removal kinetics of Mn(II) and As(III) on CuO indicate that O2 is the terminal electron acceptor for Mn(II) and As(III) oxidation on CuO, and Mn(II) acts as an electron shuttle to promote As(III) oxidation and removal. The main oxidized product of Mn(II) on CuO is high-valent MnOx species. This newly formed Mn(III) or Mn(IV) phases promote As(III) oxidation on CuO at circumneutral pH 8 and is reduced to Mn(II), which may be then released into solution. This study provides new insights into metal oxide-catalyzed oxidation of pollutants Mn(II) and As(III) and suggests that CuO should be considered as an efficient material to remediate Mn(II) and As(III) contamination.

A genome-wide association study identifies a novel association between SDC3 and apparent treatment-resistant hypertension.

BACKGROUND: Compared with patients who require fewer antihypertensive agents, those with apparent treatment-resistant hypertension (aTRH) are at increased risk for cardiovascular and all-cause mortality, independent of blood pressure control. However, the etiopathogenesis of aTRH is still poorly elucidated. METHODS: We performed a genome-wide association study (GWAS) in first cohort including 586 aTRHs and 871 healthy controls. Next, expression quantitative trait locus (eQTL) analysis was used to identify genes that are regulated by single nucleotide polymorphisms (SNPs) derived from the GWAS. Then, we verified the genes obtained from the eQTL analysis in the validation cohort including 65 aTRHs, 96 hypertensives, and 100 healthy controls through gene expression profiling analysis and real-time quantitative polymerase chain reaction (RT-qPCR) assay. RESULTS: The GWAS in first cohort revealed four suggestive loci (1p35, 4q13.2-21.1, 5q22-23.2, and 15q11.1-q12) represented by 23 SNPs. The 23 significant SNPs were in or near LAPTM5, SDC3, UGT2A1, FTMT, and NIPA1. eQTL analysis uncovered 14 SNPs in 1p35 locus all had same regulation directions for SDC3 and LAPTM5. The disease susceptible alleles of SNPs in 1p35 locus were associated with lower gene expression for SDC3 and higher gene expression for LAPTM5. The disease susceptible alleles of SNPs in 4q13.2-21.1 were associated with higher gene expression for UGT2B4. GTEx database did not show any statistically significant eQTLs between the SNPs in 5q22-23.2 and 15q11.1-q12 loci and their influenced genes. Then, gene expression profiling analysis in the validation cohort confirmed lower expression of SDC3 in aTRH but no significant differences on LAPTM5 and UGT2B4, when compared with controls and hypertensives, respectively. RT-qPCR assay further verified the lower expression of SDC3 in aTRH. CONCLUSIONS: Our study identified a novel association of SDC3 with aTRH, which contributes to the elucidation of its etiopathogenesis and provides a promising therapeutic target.

Channel HCN4 mutation R666Q associated with sporadic arrhythmia decreases channel electrophysiological function and increases protein degradation.

Mutations in the hyperpolarization-activated nucleotide-gated channel 4 (HCN4) are known to be associated with arrhythmias in which QT prolongation (delayed ventricular repolarization) is rare. Here, we identified a HCN4 mutation, HCN4-R666Q, in two sporadic arrhythmia patients with sinus bradycardia, QT prolongation, and short bursts of ventricular tachycardia. To determine the functional effect of the mutation, we conducted clinical, genetic, and functional analyses using whole-cell voltage-clamp, qPCR, Western blot, confocal microscopy, and co-immunoprecipitation. The mean current density of HEK293T cells transfected with HCN4-R666Q was lower in 24 to 36 h after transfection and was much lower in 36 to 48 h after transfection relative to cells transfected with wildtype HCN4. Additionally, we determined that the HCN4-R666Q mutant was more susceptible to ubiquitin-proteasome system-mediated protein degradation than wildtype HCN4. This decreased current density for HCN4-R666Q could be partly rescued by treatment with a proteasome inhibitor. Therefore, we conclude that HCN4-R666Q had an effect on HCN4 function in two aspects, including decreasing the current density of the channel as a biophysical effect and weakening its protein stability. Our findings provide new insights into the pathogenesis of the HCN4-R666Q mutation.

SPAG5 Activates PI3K/AKT Pathway and Promotes the Tumor Progression and Chemo-Resistance in Gastric Cancer.

The sperm-associated antigen 5 (SPAG5) is an important protein in mitosis and cell cycle checkpoint regulation, with more attention as a novel oncogene in various cancers. High level of SPAG5 expression has been detected in our clinical gastric cancer (GC) samples and The Cancer Genome Atlas GC data. However, the bio-function and potential mechanism of SPAG5 in GC remain unclear. In this study, we investigated the role of SPAG5 in GC development and the correlation between SPAG5 and 5-fluorouracil (5-FU) treatment. SPAG5 expression was increased in GC samples compared with that in normal tissues (80.8% vs. 22.0%), which was apparently associated with a worse outcome. Biological experiments showed that knockdown of SPAG5 induced apoptosis and suppressed proliferation in cells and animal models. Downregulation of SPAG5 enhanced the sensitivity of 5-FU in GC cells. Gene microarray chip identified 856 upregulated and 787 downregulated genes in SPAG5 silencing cells. Furthermore, 12 significant genes, including CDKN1A, CDKN1B, EIF4E, MAPK1, and HSP90B1, belonged to the PI3K/AKT signaling pathway using ingenuity pathway analysis. Meanwhile, real-time PCR and Western blotting results showed that knockdown of SPAG5 inhibited PI3K/AKT signaling pathway. Collectively, SPAG5 promotes the growth of GC cells by regulating PI3K/AKT signaling pathway, which could be the promising target gene in GC therapy.

Co-sorption of metal ions and inorganic anions/organic ligands on environmental minerals: A review.

Co-sorption of metal ions and anions/ligands at the mineral-water interface plays a critical role in regulating the mobility, transport, fate, and bioavailability of these components in natural environments. This review focuses on co-sorption of metal ions and naturally occurring anions/ligands on environmentally relevant minerals. The underlying mechanisms for their interfacial reactions are summarized and the environmental impacts are discussed. Co-sorption mechanisms of these components depend on a variety of factors, such as the identity and properties of minerals, pH, species and concentration of metal ions and anions/ligands, addition sequence of co-sorbed ions, and reaction time. The simultaneous presence of metal ions and anions/ligands alters the initial sorption behaviors with promotive or competitive effects. Promotive effects are mainly attributed to surface electrostatic interactions, ternary surface complexation, and surface precipitation, especially for the co-sorption systems of metal ions and inorganic anions on minerals. Competitive effects involve potential complexation of metal-anions/ligands in solution or their competition for surface adsorption sites. Organic ligands usually increase metal ion sorption on minerals at low pH via forming ternary surface complexes or surface precipitates, but inhibit metal ion sorption via the formation of aqueous complexes at high pH. The different mechanisms may act simultaneously during metal ion and anion/ligand co-sorption on minerals. Finally, the potential application for remediation of metal-contaminated sites is discussed based on the different co-sorption behaviors. Future challenges and topics are raised for metal-anion/ligand co-sorption research.

ANKRD36 Is Involved in Hypertension by Altering Expression of ENaC Genes.

[Figure: see text].

Podofilox suppresses gastric cancer cell proliferation by regulating cell cycle arrest and the c-Myc/ATG10 axis.

Gastric cancer (GC) is a malignancy for which effective therapeutic drugs are limited. Podofilox exhibits antitumor effects in various types of cancer; however, whether it may inhibit GC growth remains unknown. The aim of the present study was to investigate the role of podofilox in GC. Cell Counting Kit-8, colony formation and cell cycle assays were used to detect the role of podofilox on cellular proliferation and the cell cycle, respectively. A microarray was used to detect the transcriptional changes induced by podofilox in GC cells. The results of the present study demonstrated that podofilox inhibited GC cell proliferation and colony formation. The half maximal inhibitory concentration of podofilox in AGS and HGC-27 cells was 2.327 and 1.981 nM, respectively. In addition, treatment with podofilox induced G0/G1 cell cycle arrest. Molecular analysis based on microarray data demonstrated that podofilox altered the expression levels of genes involved in the cell cycle, c-Myc and p53 signaling. Autophagy-related 10 (ATG10), which was highly expressed in GC tissues, was also downregulated by podofilox, as demonstrated by the results of the microarray analysis and immunoblotting. To determine the involvement of ATG10 in GC, ATG10 was knocked down in GC cells by small interfering RNA, which suppressed the proliferation and colony formation of GC cells compared with those observed in the control-transfected cells. Taken together, the results of the present study suggested that podofilox may inhibit GC cell proliferation by preventing the cell cycle progression and regulating the c-Myc/ATG10 signaling pathway.

Low THRB (thyroid hormone receptor beta) Promoter Methylation Levels in Peripheral Blood Leukocytes Induced By Systematic Inflammation Are Involved in Low Thyroid Hormone Function in Metabolic Syndrome.

[Figure: see text].

Kinetics of Mn(II) adsorption and catalytic oxidation on the surface of ferrihydrite.

Mn(II) adsorption-oxidation on iron (Fe) oxides (e.g., ferrihydrite) occurs in various soils and sediments, significantly affecting the toxicities and bioavailabilities of Mn and other associated elements. However, the detailed processes of Mn(II) adsorption-oxidation on ferrihydrite remain elusive. In this study, the Mn(II) (2 mM) adsorption-oxidation kinetics on different masses of ferrihydrite (0.25, 0.50, 1.00, and 1.25 g) at pH 7 were determined using batch kinetic studies combined with X-ray diffraction, transmission electron microscopy, and wet chemistry analyses. The results indicated that the low-concentration Mn(II) adsorption-oxidation on ferrihydrite occurred in two steps. First, Mn(II) was adsorbed onto ferrihydrite, where it was partially oxidized by the catalytic effect of ferrihydrite, within ~0-60 min; subsequently, the remaining Mn(II) underwent autocatalytic oxidation on the previously generated Mn (oxyhydr)oxides. The initial adsorption-oxidation behaviors of Mn(II) on the ferrihydrite surface determined the kinetics of Mn(II) removal and oxidation, and therefore the amounts and types of Mn (oxyhydr)oxides formed. Furthermore, the specific characteristics of Mn(II) adsorption-oxidation on ferrihydrite showed a strong dependence on the Fe/Mn molar ratio. When this ratio was below 16.35, the initial process was dominated by Mn(II) adsorption onto ferrihydrite, with slight oxidation generating hausmannite (~0-60 min), followed by the catalytic oxidation of Mn(II) on the formed hausmannite, generating manganite or groutite. Conversely, when the Fe/Mn molar ratio was above 32.7, the reactions primarily involved Mn(II) adsorption onto ferrihydrite with minor oxidation to form Mn(III/IV) (oxyhydr)oxides (~0-60 min), followed by the autocatalytic oxidation of Mn(II) on the freshly-generated Mn(III/IV) (oxyhydr)oxides, forming Mn(III) (oxyhydr)oxides, i.e., feitknechtite. These results provide further insight into the interaction between Fe and Mn, Mn(II) removal, and Mn (oxyhydr)oxide formation in the environment.

Effects of miR­210­3p on the erythroid differentiation of K562 cells under hypoxia.

GATA binding protein 1 (GATA­1) is one of the most important hematopoietic transcription factors in the production of blood cells, such as platelets, eosinophils, mast cells and erythrocytes. GATA­1 regulates the participation of microRNA (miRNAs/miRs) in erythroid differentiation under normoxia. However, GATA­1 expression and the regulation of miR­210­3p in the context of erythroid differentiation under hypoxia remain unknown. The present study examined the expression levels of GATA­1 and miR­210­3p in the model of erythroid differentiation in K562 cells under hypoxia, and determined the effects of GATA­1, miR­210­3p and SMAD2 on erythroid differentiation through lentivirus transfection experiments. The present study detected increased GATA­1 expression under hypoxia. Moreover, miR­210­3p was identified as a positive regulator of erythroid differentiation, which was upregulated both during erythroid differentiation and in GATA­1 overexpression experiments under hypoxia. Importantly, in the K562 cell model of erythroid differentiation under hypoxia, miR­210­3p was upregulated in a GATA­1­dependent manner. Using a double luciferase reporter assay, miR­210­3p was identified as a downstream target of GATA­1­mediated regulation of erythropoiesis. Gain­ or loss­of­function analysis of miR­210­3p identified its importance in erythroid differentiation. Furthermore, it was found that SMAD2 may be a downstream target gene for miR­210­3p. Bioinformatics predictions suggested that SMAD2 mediated miR­210­3p­induced regulation of erythroid differentiation. Collectively, the present study provides novel insights into the miRNA regulation of erythroid differentiation.

Musk ketone induces apoptosis of gastric cancer cells via downregulation of sorbin and SH3 domain containing 2.

Musk ketone exerts antiproliferative effects on several types of cancer, such as lung and breast cancer. However, the effects and underlying mechanisms of action of musk ketone in gastric cancer (GC) are poorly understood. The present study aimed to investigate the effects of musk ketone in GC cells. The present study indicated that musk ketone exerted significant anticancer effects on GC cells. The IC50 values of musk ketone were 4.2 and 10.06 µM in AGS and HGC­27 cells, respectively. Low dosage of musk ketone significantly suppressed the proliferation and colony formation of AGS and HGC­27 cells. Cell cycle arrest and apoptosis were induced by musk ketone. Furthermore, microarray data indicated that musk ketone treatment led to downregulation of various genes, including sorbin and SH3 domain containing 2 (SORBS2). Reverse transcription­quantitative PCR and immunoblotting results indicated that musk ketone repressed mRNA and protein expression levels of SORBS2. It was also shown that knockdown of SORBS2 inhibited the proliferation and colony formation of HGC­27 cells. The antiproliferative effects of musk ketone were decreased in HGC­27 cells with SORBS2 silencing. In summary, the present study indicated that musk ketone suppressed the proliferation and growth of GC partly by downregulating SORBS2 expression.