High Maternal Serum Estradiol in First Trimester of Multiple Pregnancy Contributes to Small for Gestational Age via DNMT1-Mediated CDKN1C Upregulation.

High maternal serum estradiol (E2) levels in the first trimester of pregnancy are associated with a high incidence of low birth weight (LBW) and small for gestational age (SGA). This study aimed to investigate the effect of first-trimester high maternal serum E2 levels on fetal growth and the underlying mechanisms in multiple pregnancies. Maternal serum E2 levels of women at 8 weeks of gestation were measured. The expression levels of imprinted genes and DNMT1 were determined by RT-qPCR, and KvDMR1 methylation in embryo tissue, placenta, and newborn cord blood samples was examined by bisulfite sequencing PCR. The effect of E2 on CDKN1C expression was investigated in HTR8 cells. The incidence of SGA was significantly higher in multiple pregnancies reduced to singleton than that in primary singleton pregnancies (11.4% vs. 2.9%) (P < 0.01) and multiple pregnancies reduced to twins than primary twins (38.5% vs. 27.3%) (P < 0.01). The maternal serum E2 level at 8 weeks of gestation increased with the number of fetuses and was negatively correlated with offspring birth weight. CDKN1C and DNMT1 expression was significantly upregulated in embryo tissue, placenta, and cord blood from multiple pregnancies. Furthermore, there was a positive correlation between CDKN1C mRNA expression and KvDMR1 methylation levels. In HTR8 cells, DNMT1 mediated the estrogen-induced upregulation of CDKN1C, which might contribute to SGA. To minimize the risks of LBW and SGA, our findings suggest that abnormally high maternal serum E2 levels should be avoided during the first trimester of multiple pregnancies from assisted reproductive technology (ART).

Discovery of a novel inhibitor of nitric oxide production with potential therapeutic effect on acute inflammation.

Inflammation as a host's excessive immune response to stimulation, is involved in the development of numerous diseases. To discover novel anti-inflammatory agents and based on our previous synthetic work on marine natural product Chrysamide B, it and a series of derivatives were synthesized and evaluated for their anti-inflammatory activity on inhibition of LPS-induced NO production. Then the preliminary structure-activity relationships were conducted. Among them, Chrysamide B is the most potent anti-inflammatory agent with low cytotoxicity and strong inhibition on the production of NO (IC50 = 0.010 µM) and the activity of iNOS (IC50 = 0.082 µM) in LPS-stimulated RAW 264.7 cells. Primary studies suggested that the mechanism of action may be that it interfered the formation of active dimeric iNOS but not affected transcription and translation. Furthermore, its good performance of anti-inflammatory effect on LPS-induced multiple inflammatory cytokines production, carrageenan-induced paw edema, and endotoxin-induced septic mice, was observed. We believe that these findings would provide an idea for the further modification and research of these analogs in the future.

Epithelial cell adhesion molecule promotes breast cancer resistance protein-mediated multidrug resistance in breast cancer by inducing partial epithelial-mesenchymal transition.

Overexpression of breast cancer resistance protein (BCRP) plays a crucial role in the acquired multidrug resistance (MDR) in breast cancer. The elucidation of molecular events that confer BCRP-mediated MDR is of major therapeutic importance in breast cancer. Epithelial cell adhesion molecule (EpCAM) has been implicated in tumor progression and drug resistance in various types of cancers, including breast cancer. However, the role of EpCAM in BCRP-mediated MDR in breast cancer remains unknown. In the present study, we revealed that EpCAM expression was upregulated in BCRP-overexpressing breast cancer MCF-7/MX cells, and EpCAM knockdown using siRNA reduced BCRP expression and increased the sensitivity of MCF-7/MX cells to mitoxantrone (MX). The epithelial-mesenchymal transition (EMT) promoted BCRP-mediated MDR in breast cancer cells, and EpCAM knockdown partially suppressed EMT progression in MCF-7/MX cells. In addition, Wnt/ß-catenin signaling was activated in MCF-7/MX cells, and the inhibition of this signaling attenuated EpCAM and BCRP expression and partially reversed EMT. Together, this study illustrates that EpCAM upregulation by Wnt/ß-catenin signaling induces partial EMT to promote BCRP-mediated MDR resistance in breast cancer cells. EpCAM may be a potential therapeutic target for overcoming BCRP-mediated resistance in human breast cancer.

BNC1 Promotes Spermatogenesis by Regulating Transcription of Ybx2 and Papolb via Direct Binding to Their Promotor Elements.

BNC1 is a transcription factor that is crucial for spermatogenesis and male fertility, although the underlying mechanism remains unclear. To study BNC1's specific role in spermatogenesis, we characterized a previously developed mouse model carrying a truncating mutation in Bnc1 (termed Bnc1+/tr for heterozygotes and Bnc1tr/tr for homozygotes) and found that the mutation decreased BNC1 protein levels and resulted in germ cell loss by apoptosis. Given that loss of functional Bnc1 is known to result in decreased expression of the spermatogenesis genes Ybx2 and Papolb, we aimed to explore whether and how BNC1 promotes transcription of Ybx2 and Papolb to mediate its role in spermatogenesis. We confirmed significant reduction in YBX2 and PAPOLB protein levels in testis tissue from Bnc1+/tr and Bnc1tr/tr males compared with wild-type mice (Bnc1+/+). Consistently, knockdown of Bnc1 led to downregulation of Ybx2 and Papolb in CRL-2196 cells in vitro. To investigate if BNC1 directly induces Ybx2 and Papolb gene expression, chromatin immunoprecipitation using mouse testicular tissue and luciferase reporter assays in HEK293 cells were used to identify functional binding of BNC1 to the Ybx2 and Papolb promoters at defined BNC1 binding sites. Taken together, this study reveals a mechanism for BNC1's role in spermatogenesis by directly binding to BNC1 binding elements in the promoter regions of both Ybx2 and Papolb and inducing transcription of these important spermatogenesis genes.

VCAM1 Labels a Subpopulation of Neural Stem Cells in the Adult Hippocampus and Contributes to Spatial Memory.

Active neural stem cells (aNSCs) and quiescent neural stem cells (qNSCs) are two distinct subpopulations found in the adult hippocampal dentate gyrus (DG). However, to date, no cell surface marker has been established to identify and profile qNSCs in the adult hippocampus. Here, we identified expression of vascular cell adhesion molecule 1 (VCAM1) on the cell surface of NSCs, through which we identified a previously unrecognized subpopulation of NSCs in the adult mouse DG. Interestingly, most VCAM1-expressing NSCs were largely quiescent. By injecting virus into Ai14 reporter mice to conduct lineage tracing in the adult DG, we confirmed that VCAM1-expressing cells were multipotent and capable of generating neurons and astrocytes. Furthermore, depletion of Vcam1 during the embryonic or adult stage impaired spatial learning and memory in mice, accompanied by a reduced number of radial glial-like cells and proliferating NSCs in the subgranular zone of Vcam1 knockout mice.

Gliomas Interact with Non-glioma Brain Cells via Extracellular Vesicles.

Emerging evidence suggests that crosstalk between glioma cells and the brain microenvironment may influence brain tumor growth. To date, known reciprocal interactions among these cells have been limited to the release of paracrine factors. Combining a genetic strategy with longitudinal live imaging, we find that individual gliomas communicate with distinct sets of non-glioma cells, including glial cells, neurons, and vascular cells. Transfer of genetic material is achieved mainly through extracellular vesicles (EVs), although cell fusion also plays a minor role. We further demonstrate that EV-mediated communication leads to the increase of synaptic activity in neurons. Blocking EV release causes a reduction of glioma growth in vivo. Our findings indicate that EV-mediated interaction between glioma cells and non-glioma brain cells alters the tumor microenvironment and contributes to glioma development.

Radial Glial Cell-Derived VCAM1 Regulates Cortical Angiogenesis Through Distinct Enrichments in the Proximal and Distal Radial Processes.

Angiogenesis in the developing cerebral cortex accompanies cortical neurogenesis. However, the precise mechanisms underlying cortical angiogenesis at the embryonic stage remain largely unknown. Here, we show that radial glia-derived vascular cell adhesion molecule 1 (VCAM1) coordinates cortical vascularization through different enrichments in the proximal and distal radial glial processes. We found that VCAM1 was highly enriched around the blood vessels in the inner ventricular zone (VZ), preventing the ingrowth of blood vessels into the mitotic cell layer along the ventricular surface. Disrupting the enrichment of VCAM1 surrounding the blood vessels by a tetraspanin-blocking peptide or conditional deletion of Vcam1 gene in neural progenitor cells increased angiogenesis in the inner VZ. Conversely, VCAM1 expressed in the basal endfeet of radial glial processes promoted angiogenic sprouting from the perineural vascular plexus (PNVP). In utero, overexpression of VCAM1 increased the vessel density in the cortical plate, while knockdown of Vcam1 accomplished the opposite. In vitro, we observed that VCAM1 bidirectionally affected endothelial cell proliferation in a concentration-dependent manner. Taken together, our findings identify that distinct concentrations of VCAM1 around VZ blood vessels and the PNVP differently organize cortical angiogenesis during late embryogenesis.

Brønsted Base-Switched Selective Mono- and Dithiolation of Benzamides via Copper Catalysis.

A versatile protocol for the direct thiolation of an inert sp2 C-H bond is presented via a catalytic amount of copper catalysis, by switching related Brønsted bases and regulating the reaction time, and the corresponding mono- and dithiolation products can be obtained selectively in moderate to good yields. The reaction exhibits a relatively broad substrate scope and a good functional group tolerance, even with different heterocyclic amides and alkyl thiols.

Estradiol promotes trophoblast viability and invasion by activating SGK1.

BACKGROUND: 17ß-Estradiol (E2) is a critical regulator of trophoblast function during pregnancy. Serum- and glucocorticoid-inducible kinase (SGK1) has been shown to regulate specific cellular targets downstream of E2. However, whether and how SGK1 directly mediates the regulatory effects of E2 on trophoblasts functions remain unknown. METHODS: SGK1 expression in human villous samples and serum E2 levels were measured in women with early pregnancy loss (EPL) and healthy pregnant women. The effect of E2 on SGK1 regulation was assessed using luciferase reporter gene assay and Chromatin Immunoprecipitation assay. The mediation of regulatory effects of E2 by SGK1 on trophoblast functions including cell viability, invasion and related signaling molecules such as B cell leukemia/lymphoma 6, E-cadherin, matrix metalloproteinase 2, α-ENaC, vascular endothelial growth factor, and the phosphorylation status of FOXO1 and AKT were evaluated in HTR8/SVneo cells transfected with SGK1 knockdown plasmid with/without E2 treatment. RESULTS: SGK1 protein levels in human villous samples and serum E2 levels were decreased in patients with EPL compared to controls. E2 (10 nM) increased SGK1 promoter activity directly through estrogen receptor. E2-activated SGK1 enhanced cell viability, invasion and downstream targets in trophoblast cells. SGK1 knockdown abrogated the above responses to E2 treatment. CONCLUSIONS: SGK1 mediates the effects of E2 on trophoblast viability and invasion, suggesting that SGK1 acts as a key node in regulating the cross-talk at the feto-maternal interface during the development of placenta and might be a potential therapeutic target for EPL.

ZEB1 Represses Neural Differentiation and Cooperates with CTBP2 to Dynamically Regulate Cell Migration during Neocortex Development.

Zinc-finger E-box binding homeobox 1 (Zeb1) is a key regulator of epithelial-mesenchymal transition and cancer metastasis. Mutation of ZEB1 is associated with human diseases and defective brain development. Here we show that downregulation of Zeb1 expression in embryonic cortical neural progenitor cells (NPCs) is necessary for proper neuronal differentiation and migration. Overexpression of Zeb1 during neuronal differentiation, when its expression normally declines, blocks NPC lineage progression and disrupts multipolar-to-bipolar transition of differentiating neurons, leading to severe migration defects and subcortical heterotopia bands at postnatal stages. ZEB1 regulates a cohort of genes involved in cell differentiation and migration, including Neurod1 and Pard6b. The interaction between ZEB1 and CTBP2 in the embryonic cerebral cortex is required for ZEB1 to elicit its effect on the multipolar-to-bipolar transition, but not its suppression of Neurod1. These findings provide insights into understanding the complexity of transcriptional regulation during neuronal differentiation.

MicroRNA-7a ameliorates neuropathic pain in a rat model of spinal nerve ligation via the neurofilament light polypeptide-dependent signal transducer and activator of transcription signaling pathway.

Neuropathic pain is a type of chronic pain induced by either central or peripheral nerve injury. MicroRNAs have been recently linked to many diseases, including neuropathic pain. However, the role of miR-7a in neuropathic pain still remains elusive. Thus, we aim to investigate the effects of miR-7a on neuropathic pain based on the spinal nerve ligation rat model. After establishment of spinal nerve ligation rat models, rats were infected with adeno-associated virus-neurofilament light polypeptide, adeno-associated virus-miR-7a or treated with metformin. The paw withdrawal threshold and paw withdrawal latency were assessed afterward, and the expression of miR-7a and neurofilament light polypeptide as well as their interaction was determined. Subsequently, miR-7a was overexpressed or silenced in dorsal root ganglion cells to investigate the role of miR-7a in neuropathic pain. Furthermore, the regulatory effect of neurofilament light polypeptide on neuropathic pain was detected using plasmid overexpressing neurofilament light polypeptide. Spinal nerve ligation rat model exhibited upregulation of neurofilament light polypeptide but downregulation of miR-7a. In addition, neurofilament light polypeptide accumulation or miR-7a inhibition decreased paw withdrawal threshold and paw withdrawal latency. Then, neurofilament light polypeptide accumulation or miR-7a inhibition was observed to increase the phosphorylation level of signal transducer and activator of transcription. miR-7a was found to directly target neurofilament light polypeptide and downregulate neurofilament light polypeptide. In addition, inhibiting the signal transducer and activator of transcription signaling pathway was also revealed to increase paw withdrawal threshold and paw withdrawal latency. Collectively, our study demonstrated that miR-7a ameliorated neuropathic pain via blocking the signal transducer and activator of transcription signaling pathway by repressing neurofilament light polypeptide. These findings, if taken further, can be of important clinical significance in treating patients with neuropathic pain.

Synthesis of α-arylthioacetones using TEMPO as the C3 synthon via a reaction cascade of sequential oxidation, skeletal rearrangement and C-S bond formation.

Here, we present an unprecedented pathway to α-sulfenylated carbonyl compounds from commercially available thiols and universally employed TEMPO and its analogues, which act as C3 synthons through skeletal rearrangement under simple and metal-free conditions. Mechanism studies suggest that this reaction involves a consecutive radical oxidation and cation coupling process. TEMPO analogues and thiols serve as oxidants and reductive reagents, respectively, along the radical process, while in the coupling process, the former ones afford C3 synthons to couple with related sulfur sources.

A concise synthesis and biological study of evodiamine and its analogues.

Efficient access to evodiamine and its analogues is presented via Lewis acid catalysis. In this reaction, three chemical bonds and two heterocyclic-fused rings are constructed in one step. The reaction shows good functional group tolerance and atom economy, and various heteroatom-containing evodiamine analogues are obtained in moderate to excellent yields even on a gram scale. An anti-tumor study in vitro demonstrates compound 2b possesses potent efficacy against hepatoma cell line (IC50 = 5.7 µM).

Follicular localization of growth differentiation factor 8 and its receptors in normal and polycystic ovary syndrome ovaries.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and its etiology has not been characterized. Growth differentiation factor 8 (GDF8) is a member of the transforming growth factor-ß superfamily that plays a critical role in the regulation of ovarian functions. However, the expression pattern of GDF8 in the human ovary is not yet clear. This study examined the cellular distribution of GDF8 and its putative cellular receptors (ACVR2A, ACVR2B, and ALK5) in a series of normal (n = 34) and PCOS ovaries (n = 14). The immunostaining of GDF8, ACVR2A, ACVR2B, and ALK5 was detected in the oocytes regardless of the developmental stage. All these proteins were localized in antral follicles in normal and PCOS ovaries, and the expression of these proteins increased with increasing follicle diameter. A significantly higher expression of GDF8 was detected in the granulosa cells than in the matched theca cells (TCs). These proteins were also localized in the luteal cells of the corpus luteum. Granulosa cells and TCs of large antral follicles in PCOS ovaries display a higher expression of these proteins. The higher expression levels of GDF8 and its functional receptors (ACVR2A, ACVR2B, and ALK5) in antral follicles of PCOS ovaries than those in normal ovaries suggest the possible involvement of dysregulated GDF8 in the pathogenesis of PCOS.

Maternal high estradiol exposure alters CDKN1C and IGF2 expression in human placenta.

INTRODUCTION: The increased maternal estradiol (E2) concentrations induced by assisted reproductive technology (ART) result in lower birth weight of offspring, which is associated with increased risk of adult diseases. However, the exact mechanism remains unknown. The present study investigated the effect of high E2 exposure on the expression of imprinted genes CDKN1C and IGF2 in human placentas and the DNA methylation status of their differential methylation regions (DMRs). METHODS: The mRNA expression of CDKN1C and IGF2 in human placentas and the human trophoblast cells (HTR8) treated with E2 were investigated by reverse transcription-real time polymerase chain reaction (PCR). The DNA methylation of their DMRs were investigated by sodium bisulfite sequencing. RESULTS: CDKN1C and IGF2 were significantly up-regulated in ART conceived placentas. The mean birth weight of ART singletons was significantly lower than that of naturally conceived (NC) ones, with the increased percentage of small-for-gestational-age (SGA) birth. The DNA methylation was significantly down-regulated in the DMR of CDKN1C (KvDMR1) and up-regulated in the DMR of IGF2 (H19 DMR) in ART placentas. The treatment of E2 altered the expression of the two genes and the DNA methylation of their DMRs in HTR8 to a similar tendency as in vivo. DISCUSSION: The maternal high E2 levels after ART up-regulate the expression of imprinted genes in human placentas through epigenetic modifications, which influences the growth potential of the offspring. Further studies are needed to follow up the growth and development of the ART offspring.

Persistent Expression of VCAM1 in Radial Glial Cells Is Required for the Embryonic Origin of Postnatal Neural Stem Cells.

During development, neural stem cells (NSCs) undergo transitions from neuroepithelial cells to radial glial cells (RGCs), and later, a subpopulation of slowly dividing RGCs gives rise to the quiescent adult NSCs that populate the ventricular-subventricular zone (V-SVZ). Here we show that VCAM1, a transmembrane protein previously found in quiescent adult NSCs, is expressed by a subpopulation of embryonic RGCs, in a temporal and region-specific manner. Loss of VCAM1 reduced the number of active embryonic RGCs by stimulating their premature neuronal differentiation while preventing quiescence in the slowly dividing RGCs. This in turn diminished the embryonic origin of postnatal NSCs, resulting in loss of adult NSCs and defective V-SVZ regeneration. VCAM1 affects the NSC fate by signaling through its intracellular domain to regulate ß-catenin signaling in a context-dependent manner. Our findings provide new insight on how stem cells in the embryo are preserved to meet the need for growth and regeneration.

A Novel LC-MS-MS Method With an Effective Antioxidant for the Determination of Edaravone, a Free-Radical Scavenger in Dog Plasma and its Application to a Pharmacokinetic Study.

The objective of this study was to investigate the stability of edaravone in dog plasma by using an added antioxidant stabilizer, with an ultimate goal of developing and validating a sensitive, reliable and robust LC-MS-MS method for determination of edaravone in plasma samples. Edaravone was unstable in plasma, but it presented a good stability performance in the plasma with sodium metabisulfite (SMB), an effective antioxidant. The blood sample was collected in the heparinized eppendorf tube containing SMB and plasma sample was deproteinized using acetonitrile containing 20 ng/mL of phenacetin (Internal standard). The chromatographic separation was performed on a Zorbax Extend-C18 analytical column (2.1 mm × 150 mm I.D., particle size 3.5 µm, Agilent Technologies, USA). The mobile phase consisted of 0.1% formic acid in water (v/v) and methanol, and gradient elution was used. The analyte detection was performed on a triple quadrupole tandem mass spectrometer equipped with positive-ion electrospray ionization by multiple reaction ion monitoring mode of the transitions at m/z [M + H]+ 175.1 → 77.1 for edaravone, and m/z [M + H]+ 180.2 → 110.0 for phenacetin. The linearity of this method was within the concentration range of 10-1000 ng/mL for edaravone in dog plasma. The lower limit of quantification was 10 ng/mL. The relative standard deviations of intra- and inter-precision were <10%. This method was successfully employed in the pharmacokinetics evaluation of edaravone in beagle dogs after intravenous administration.

Peripheral Tc17 and Tc17/Interferon-γ Cells are Increased and Associated with Lung Function in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by progressive loss of lung function and local and systemic inflammation, in which CD8+ T-cells are believed to play a key role. Activated CD8+ T-cells differentiate into distinct subpopulations, including interferon-γ (IFN-γ)-producing Tc1 and interleukin (IL)-17-producing Tc17 cells. Recent evidence indicates that Tc17 cells exhibit considerable plasticity and may convert into IL-17/IFN-γ-double producing (Tc17/IFN-γ) cells when driven by inflammatory conditions. The aim of this study was to investigate the Tc17/IFN-γ subpopulation in peripheral blood of patients with COPD and to evaluate their potential roles in this disease. METHODS: Peripheral blood samples were collected from 15 never-smokers, 23 smokers with normal lung function, and 25 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease 2-4). Proportions of the IL-17/IFN-γ-double expressing subpopulation were assessed using flow cytometry. Plasma concentrations of cytokines favoring Tc17/IFN-γ differentiation were measured by enzyme-linked immunosorbent assay. RESULTS: Patients with COPD had higher proportions of Tc17 cells and Tc17/IFN-γ cells in the peripheral blood than smokers and never-smokers. The plasticity of Tc17 cells was higher than that of Th17 cells. The percentages of Tc17 cells and Tc17/IFN-γ cells showed negative correlations with forced expiratory volume in 1 s % predicted value (r = -0.418, P = 0.03; r = -0.596, P = 0.002, respectively). The plasma concentrations of IL-6, transforming growth factor-ß1, and IL-12 were significantly higher in patients with COPD compared with smokers and never-smokers. CONCLUSIONS: Peripheral Tc17 cells are increased and more likely to convert to Tc17/IFN-γ cells in COPD, suggesting that Tc17 cell plasticity may be involved in persistent inflammation of the disease.

Binding of FGF2 to FGFR2 in an autocrine mode in trophectoderm cells is indispensable for mouse blastocyst formation through PKC-p38 pathway.

Fibroblast growth factors (FGF1, FGF2 and FGF4) and fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3 and FGFR4) have been reported to be expressed in preimplantation embryos and be required for their development. However, the functions of these molecules in trophectoderm cells (TEs) that lead to the formation of the blastocyst as well as the underlying mechanism have not been elucidated. The present study has demonstrated for the first time that endogenous FGF2 secreted by TEs can regulate protein expression and distribution in TEs via the FGFR2-mediated activation of PKC and p38, which are important for the development of expanded blastocysts. This finding provides the first explanation for the long-observed phenomenon that only high concentrations of exogenous FGFs have effects on embryonic development, but in vivo the amount of endogenous FGFs are trace. Besides, the present results suggest that FGF2/FGFR2 may act in an autocrine fashion and activate the downstream PKC/p38 pathway in TEs during expanded blastocyst formation.

Interaction Between Gastric Carcinoma Cells and Neural Cells Promotes Perineural Invasion by a Pathway Involving VCAM1.

BACKGROUND: Perineural invasion (PNI) is one of the important routes for local spread of gastric carcinoma associated with poor prognosis. However, the exact cellular characteristics and molecular mechanisms of PNI are still unclear. AIM: To identify the interaction between gastric carcinoma cells and neural cells, and whether vascular cell adhesion molecule-1 (VCAM1) is involved in this process. METHODS: We adopted in vitro cell coculture assays to investigate the cellular and molecular interaction between gastric cancer cells and neural cells. RESULTS: We find upregulation of VCAM1 in clinical gastric cancer tissue samples. In in vitro tumor-neural cell coculture system, gastric cancer cells with high level of VCAM1 promote proliferation of neural progenitor cells and induce the process outgrowth and branching of neural cells. Reciprocally, neural cells enhance neurotropic migration and mobility of tumor cells. Repressing VCAM1 function through VCAM1 blocking antibody can attenuate these effects. CONCLUSIONS: Our study indicates that VCAM1 is significantly involved in tumor invasion via mediating nerve-tumor interaction, which is a mutually beneficial process. It is possible that interaction between neural cells and tumor cells might contribute to PNI of gastric carcinoma. Inhibiting the activity of VCAM1 could be a potential strategy targeting PNI in gastric carcinoma therapy.