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Cuscuta chinensis Lam. is a traditional medicinal herb used to treat female sterility and male reproductive system disorders. However, the anti-lung cancer properties of Cuscuta chinensis Lam. and possible molecular mechanisms have yet to be explored. Thus, the study’s main purpose was to evaluate in vitro and in vivo anti-lung cancer properties of C. chinensis water extract (CLW) in human lung adenocarcinomas and the underlying molecular mechanism involved. Our results demonstrated that CLW caused a significant inhibition of cell viability and induced G1 cycle arrest in lung cancer cells. Furthermore, RNA-seq transcriptome analysis revealed 602 common genes with a significant expression in A549 and H1650 cells under CLW treatment. Functional enrichment analysis suggested that these common genes regulated by CLW mainly involve lung cancer cell proliferation, metastases and apoptosis processes. In addition, forty-six common genes (> 2-fold change) regulated by CLW in A549 and H1650 cells were selected for further validation. In vitro quantitative real-time PCR results confirmed that twelve genes were up-regulated, and four genes were down-regulated in A549 and H1650 cells. The in vivo experiment demonstrated CLW could significantly decrease tumour volume and tumour weight of mice compared with the control group. Moreover, in vivo quantitative real-time PCR results revealed that C11orf96, FGFBP1, FOSB and NPTX1 genes were up-regulated and EGR1, GBP4 and MAP2K6 genes were down-regulated in tumour tissues compared with the control group. These data strongly suggest that CLW could be developed as an efficacious drug for lung cancer treatment.

Radiotherapy is a key strategy in gastric cancer (GC) treatment. However, radioresistance remains a serious concern. It is unclear whether the accumulation of adenosine A2a receptor (ADO-A2aR) is related to radioresistance in GC. In this study, the molecular role of ADO-A2aR in GC radioresistance was investigated.Colony formation assays were used to assess the role of ADO-A2aR on radioresistance. GC stem cell surface marker expression (including Nanog, OCT-4, SOX-2 and CD44) and PI3K/AKT/mTOR signaling pathway associated protein levels (including phosphorylated PI3K, phosphorylated AKT and phosphorylated mTOR) were determined via western blotting, flow cytometry and immunofluorescence. In addition, the role of ADO-A2aR on radioresistance was explored in vivo using murine xenograft models.ADO-A2aR regulated GC cell stemness both in vitro and in vivo. This was shown to induce radioresistance in GC. ADO-A2aR was revealed to significantly induce cell cycle arrest and promote GC cell apoptosis. These activities were closely linked to activation of the PI3K/AKT/mTOR pathway.This study identified that ADO enhances GC cell stemness via interaction with A2aR and subsequent activation of the PI3K/AKT/mTOR pathway. Ultimately, this resulted in radioresistance. A2aR is a potential target to improve GC radiosensitivity.

Colorectal cancer (CRC) is one of the most frequent gastrointestinal malignant tumors worldwide. Immune checkpoint therapies (ICTs) have been proven to be a reliable treatment for some subtypes of CRC. Gut microbiome is closely involved in intestinal carcinogenesis through the regulation of local immune and inflammation of colonic mucosa. Numerous studies have demonstrated that the immunotherapeutic efficacy of CRC and other kinds of cancer is influenced by the immunosuppressive microenvironment constituted by intestinal microbiome and their metabolites. This Review will discuss the recent advances in how gut microbiome can modify the immune microenvironment and its potential role in ICTs of CRC.

Abstract: Emodin is a natural anthraquinone extract of Chinese medicinal herbs. Several studies demonstrated the antitumor activity of this extract, particularly for lung cancer. However, the mode of action of emodin remains obscure. In this study we evaluated in vitro and in vivo anti-lung cancer properties of emodin in human lung adenocarcinomas and the underlying molecular mechanism involved. Our results demonstrated emodin caused a significant inhibition of cell viability and induced apoptosis in lung cancer cells to a level that is relative to that of normal epithelial cells. Furthermore, RNA-seq transcriptome analysis revealed 65 common genes(>2-fold change) with a significant expression in A549, and H1650 cells under emodin treatment. In vitro qRT-PCR results confirmed that 4 genes (ATP6V0D2, C11orf96, TIPARP, and CDKN1A) were up-regulated, and 9 genes (TNFSF10, IFIT1, EGLN3, RCOR2, ARRB1, FLVCR2, BAIAP2-DT, FAM111B, and TGFB2) were down-regulated in A549 and H1650 adenocarcinoma cell lines. The in vivo experiment demonstrated emodin could significantly decrease tumor volume and tumor weight of mice compared with the control group. However, emodin treatment has no obvious effect on body weight of mice. Moreover, in vivo qRT-PCR results revealed that 3 genes (ATP6V0D2, C11orf96, and TIPARP) were up-regulated, and 6 genes (TNFSF10, IFIT1, EGLN3, BAIAP2-DT, FAM111B, and TGFB2) were down-regulated in tumor tissues compared with the control group. These findings suggested that emodin could help treat lung cancer and has a potential for further investigations as an anti-lung cancer drug.

Recently, an increasing number of biological and clinical reports have demonstrated that imbalance of microbial community has the ability to play important roles among several complex diseases concerning human health. Having a good knowledge of discovering potential of microbe-disease relationships, which provides the ability to having a better understanding of some issues, including disease pathology, further boosts disease diagnostics and prognostics, has been taken into account. Nevertheless, a few computational approaches can meet the need of huge scale of microbe-disease association discovery. In this work, we proposed the EHAI model, which is Enhanced Human microbe- disease Association Identification. EHAI employed the microbe-disease associations, and then Gaussian interaction profile kernel similarity has been utilized to enhance the basic microbe-disease association. Actually, some known microbe-disease associations and a large amount of associations are still unavailable among the datasets. The ‘super-microbe’ and ‘super-disease’ were employed to enhance the model. Computational results demonstrated that such super-classes have the ability to be helpful to the performance of EHAI. Therefore, it is anticipated that EHAI can be treated as an important biological tool in this field.

Lymph node metastasis is an independent risk factor for survival of gastric cancer, but the underlying mechanism remains unclear. Adenosine (ADO) plays an immune regulation role through binding to adenosine receptors (ARs), especially A2AR. PD-L1 plays a key role in the immune escape of tumor. However, the expression of these two indicators in lymph nodes of gastric cancer has been rarely studied. Lymph node samples of 95 gastric cancer patients, including metastatic lymph nodes and matched non-metastatic lymph nodes were collected. Expression of A2AR and PD-L1 were detected with immunohistochemistry. The relationships among their expression with clinicopathological factors and prognostic parameters were analyzed as well. The expressions of A2AR and PDL-1 were both higher in metastatic lymph node than matched non-metastatic lymph node. The expression of A2AR in metastatic lymph nodes of gastric cancer was positively correlated with PD-L1. Positive expressions of A2AR and PDL-1 were associated with tumor N stage and prognostic parameters. There was no significant relationship with other clinicopathological characteristics. Our obtained data suggested that the high expressions of A2AR and PD-L1 were associated with the lymph node metastasis and a poor prognosis in gastric cancer, which may be a potential diagnostic and a therapeutic target for gastric cancer.

Objective The incidence and mortality of colorectal cancer (CRC) is increasing yearly and CRC patients are becoming younger in global. Evidences have revealed the carcinogenic effect of p53 and DNA damage-regulated gene 1 (PDRG1) in several types of tumors. However, its biological function is yet to be investigated in CRC. This study aimed to unveil the prooncogenic role of PDRG1 in CRC. Methods We detected the expression and clinical pathological features of PDRG1 in CRC tissues and paired non-tumor adjacent tissues. The biological role and molecular mechanism of PDRG1 in CRC were characterized through a range of in vitro and in vivo experiments and datasets analysis. Result We identified the significant up-regulated expression of PDRG1 both in CRC tissues and cell, and higher expression of PDRG1 was associated with worse clinicopathological stage and poorer survival outcome. Cox regression analysis revealed that PDRG1 is an independent prognostic factor for CRC patients. Silencing of PDRG1 significantly retarded CRC cell vitality, invasion and migration, induced cell apoptosis and G0/G1 phase arrest. PDRG1 knockdown also attenuated tumor growth and metastasis as evidencing in vivo experiment. The expression of p21 and apoptosis related protein was enhanced with the knockdown of PDRG1 while cell cycle protein was inhibited. Conclusion PDRG1 function as a novel oncogene and participate in malignant progression of CRC by regulating p21-mediated signal pathway, suggesting that it can serve as a valuable predictive biomarker for diagnosing of CRC patient and a promising target for therapy.

The accumulation of adenosine in the tumor microenvironment is associated with tumor progression in many cancers. However, whether adenosine is involved in gastric cancer (GC) metastasis and progression, and the underlying molecular mechanism, is largely unclear. In this study, we find that GC tissues and cell lines had higher A2aR levels than nontumor gastric tissues and cell lines. A2aR expression correlated positively with TNMstage, and associated with poor outcomes. Adenosine enhanced the expression of the stemness and epithelial–mesenchymal transition-associated genes by binding to A2aR. A2aR expression on GC cells promoted metastasis in vivo. The PI3K-AKT-mTOR signaling pathway was involved in adenosine-stimulated GC cell migration and invasion. Our results indicate that adenosine promotes GC cell invasion and metastasis by interacting with A2aR to enhance PI3K–AKT–mTOR pathway signaling.

Background. Programmed cell death ligand 1 (PD-L1) is a key inhibitor to the immune response by binding to the specific receptor PD-1. Adenosine receptor 2 (A2aR) can play an immunosuppressive role in tumor microenvironment by binding to its ligand adenosine (ADO). However, the expression of these two markers has been rarely studied in colorectal cancer simultaneously.Materials and Methods. We, respectively, collected tumor and adjacent nontumor tissue specimens of 204 patients with colorectal cancer. The expressions of PD-L1 and A2aR were detected by immunohistochemistry. The association among their expressions with clinicopathological characteristics and prognostic parameters were analyzed as well.Results. The expressions of PD-L1 and A2aR in tumor tissues were both higher than those in matched adjacent nontumor tissues. PD-L1 expression was significantly correlated with lymph node metastasis and tumor TNM stage. A2aR expression was significantly correlated with tumor size, depth of tumor invasion, and TNM stage. Univariate analysis showed that the high expressions of PD-L1 and A2aR were inversely correlated with the overall survival, respectively. Multivariate analysis further confirmed that both of them were independent prognostic markers for patients.Conclusion. The results of this study suggested that the high expressions of PD-L1 and A2aR were associated with a poor prognosis of colorectal cancer. Coinhibition of these two proteins may be a new breakthrough in the treatment of this disease.

NADPH oxidase 4 (NOX4) is one of the main sources of reactive oxygen species, and plays a crucial role in the occurrence and development of tumors. However, there is currently little evidence demonstrating that NOX4 expression is associated with gastric cancer. To establish whether NOX4 plays a role in gastric cancer progression and prognosis, we performed immunohistochemistry on gastric cancer tissues and paired adjacent normal tissues from 90 gastric cancer patients to detect and compare NOX4 expression. Next, we analyzed the association between NOX4 expression and clinicopathological characteristics. Survival analysis was performed to explore the association between NOX4 expression and the prognosis of gastric cancer patients. Furtherly, we investigated the effect of NOX4-knockdown using siRNA on gastric cancer progression in vitro and in vivo. Our results revealed that NOX4 expression in gastric cancer tissues is higher than in paired adjacent normal tissues (P = 0.0009). NOX4 expression is significantly correlated with tumor size (P = 0.0321), lymphatic metastasis (P = 0.0125) and vascular invasion (P = 0.0017) and a poor prognosis (P = 0.0000) in gastric cancer patients. NOX4 depletion could significantly inhibit the invasion, proliferation, EMT and MMP7 expression of gastric cancer cells and suppress the progression of gastric cancer in vivo. In conclusion, NOX4 is related to gastric cancer development and predicts a poor prognosis. NOX4 may play an essential role in the progression of gastric cancer, and is a promising target for the prevention and treatment of gastric cancer.

Background. Adenosine, derived from the degradation of ATP via ectonucleotidases CD39 and CD73, is a critical immunosuppressive metabolite in the hypoxic microenvironment of tumor tissue. Adenosine signaling via A2aR can inhibit the antitumor immune response of CD8+T cells. CD39 and CD73 high-expressing Tregs play a critical role in tumor immune evasion of gastric cancer (GC). The present study investigated the underlying mechanism by which Tregs suppress antitumor immune responses in GC.Materials and Methods. Fifty-two GC samples were collected, and the frequency of FoxP3+Tregs and CD8+T cells and density ratios of A2aR+/CD8+T cells, CD39+/FoxP3+Tregs, and CD73+/FoxP3+Tregs in GC were assessed with multiplex immunofluorescence. The expression of FoxP3 and A2aR in GC tissues was also detected by the immunoblotting assay. We next investigated the relationship between density of FoxP3+Tregs, ratio of A2aR+/CD8+T cells, and clinicopathological parameters. At the same time, Tregs and CD8+T cells were isolated from peripheral blood of five GC patients, and the antagonists of CD39 and CD73 were used to assess the ability of Tregs to decompose ATP into adenosine. In addition, we cocultured CD8+T cells and Tregs with antagonists of A2aR and A2bR in order to examine the alterations in immune function of CD8+T cells.Results. The density of both FoxP3+Tregs and A2aR+/CD8+T cells was higher in GC tissue compared to peritumoral normal tissue and significantly correlated with the TNM stage, lymph node metastasis, and distant metastasis of GC. The process of Treg hydrolysis of ATP into adenosine was blocked by the antagonists of CD39 and CD73. In addition, Tregs could induce apoptosis and inhibit proliferation of CD8+T cells, while this effect could be obviously reduced by applying the antagonist of A2aR or A2aR+A2bR. Moreover, IFN-γ, TNF-α, and perforin generated by CD8+T cells could also be inhibited through the adenosine A2aR pathway.Conclusions. The FoxP3+Tregs and A2aR+/CD8+T cells were excessively infiltrated in GC tissue. Tregs from GC can decompose ATP to adenosine and in turn induce apoptosis and inhibit the proliferation of CD8+T cells through the A2aR pathway, further leading to immune escape of GC.

Ethnopharmacology relevance Cuscuta chinensis Lam. (Convolvulaceae) had received growing attention as a traditional medicinal herb widely used for treating female impotence, abortion, male reproductive system disease and cardiovascular diseases, respectively. Aim of the study The present study investigated the acute and sub-acute toxicities of C. chinensis water extract (CLW) in the ICR mice model. Materials and methods Various doses of CLW (1250, 2500, and 5000 mg/kg) were administered consecutively for 14 days to evaluate the acute toxicity level with examine mortality, general behavior, body weight, food and water intake of the mice. At the end of treatmet, macroscopic observation of the skin and major internal organs in the abdominal part and organ coefficients were taken. The same doses were administered daily for 28 days to determine the sub-acute toxicity level with examine mortality, general behavior, body weight, food and water intake of the mice. At the end of treatmet, macroscopical examination of organs, tissues, cavities, organ coefficients, pathology, hematological and biochemical parameters were carried out. Results The acute toxicity test results revealed an LD 50 of over 5000 mg/kg for CLW. Similarly, no CLW-related mortality and severe toxicities were experienced in the sub-acute study. However, the treatment of CLW had a reducing effect on body weight of both male and female mice, and feed intake in female mice at the all tested doses (1250, 2500 and 5000 mg/kg). Moreover, significant effects in organ coefficients of brain, liver, lung, testis and thymus became apparent due to CLW mainly at the 2500 and 5000 mg/kg. The hematological analysis result showed a significant decrease in platelets, lymphocytes, and hematocrit. In contrast, a significant increase in the neutrophils was observed in the CLW treated groups (2500 and 5000 mg/kg). Biochemical test results showed a significant increase in aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels while decreasing albumin, total cholesterol and triglyceride levels after treatment of CLW mostly at the doses of 2500 and 5000 mg/kg. Mild liver toxicity in both sexes treated with 5000 mg/kg of CLW was recorded in the histopathological analysis. Conclusions Overall, our results suggested that CLW is safe at its dose lower than 1250 mg/kg, although liver toxicity from daily use may be a matter of concern.

Adenosine (ADO), generated by the ectonucleotidase CD39 and CD73 from ATP, interacts with its specific G protein-coupled receptors, which can impair anti-tumor immune responses inhibiting the infiltration and function of CD8+ T cell and natural killer cell. Recent studies have also identified that ADO pathway plays a critical role in tumor immune surveillance, especially for some non-solid cancers. In addition, although immune checkpoint therapy targeting ADO pathway in gastric cancer is still in an early phase, encouraging results have come out from some drugs targeting ADO pathway. Therefore, target ADO signaling may be a new promising strategy to treat gastric cancer. In this review, we summarized recent works on the role of ADO in cancer immunotherapy and also discussed relative mechanisms underlying the function of ADO signaling in cancer immune responses.

Anoikis is a type of programmed cell death induced by detachment from the extracellular matrix. In cancer cells, anoikis resistance is essential for cancer cell survival in blood circulation and distant metastasis. However, the mechanisms behind anoikis resistance of gastric cancer remain largely unknown. Herein, we demonstrate that NADPH oxidase 4 (NOX4) expression and reactive oxygen species (ROS) generation are upregulated in suspension gastric cell cultures compared with adherent cultures. Silencing of NOX4 decreases ROS generation and downregulates EGFR, sensitizing cells to anoikis. NOX4 overexpression upregulates ROS and EGFR levels and promotes anoikis resistance. NOX4 depletion inhibits gastric cancer survival in blood circulation and attenuates distant metastasis. NOX4 expression is correlated with EGFR expression in patients. In conclusion, induction of NOX4 expression by detachment promotes anoikis resistance of gastric cancer through ROS generation and downstream upregulation of EGFR, which is critical for the metastatic progression of gastric cancer.

A one-pot Smiles rearrangement has been developed as a useful protocol for the straightforward synthesis of diverse N-aryl-nicotinamides. This method also provides chemoselective access toward diarylamines based on the different substitutions of the amide group. The potential application of the transformation is exemplified by the synthesis of an on-market succinate dehydrogenase inhibitor, boscalid.

Smiles rearrangement of amides (I) provides N-aryl-nicotinamides whereas N-phenyl substituted substrates (V) directly give diarylamines.