Exosomal circRNAs in gastrointestinal cancer: Role in occurrence, development, diagnosis and clinical application (Review).

Gastrointestinal cancer is frequently detected at an advanced stage and has an undesirable prognosis due to the absence of efficient and precise biomarkers and therapeutic targets. Exosomes are small, living­cell­derived vesicles that serve a critical role in facilitating intercellular communication by transporting molecules from donor cells to receiver cells. circular RNAs (circRNAs) are mis­expressed in a variety of diseases, including gastrointestinal cancer, and are promising as diagnostic biomarkers and tumor therapeutic targets for gastrointestinal cancer. The main features of exosomes and circRNAs are discussed in the present review, along with research on the biological function of exosomal circRNAs in the development and progression of gastrointestinal cancer. It also assesses the advantages and disadvantages of implementing these findings in clinical applications.

Exosomal hsa_circ_000200 as a potential biomarker and metastasis enhancer of gastric cancer via miR-4659a/b-3p/HBEGF axis.

BACKGROUND: Exosome, a component of liquid biopsy, loaded protein, DNA, RNA and lipid gradually emerges as biomarker in tumors. However, exosomal circRNAs as biomarker and function mechanism in gastric cancer (GC) are not well understood. METHODS: Differentially expressed circRNAs in GC and healthy people were screened by database. The identification of hsa_circ_000200 was verified by RNase R and sequencing, and the expression of hsa_circ_000200 was evaluated using qRT-PCR. The biological function of hsa_circ_000200 in GC was verified in vitro. Western blot, RIP, RNA fluorescence in situ hybridization, and double luciferase assay were utilized to explore the potential mechanism of hsa_circ_000200. RESULTS: Hsa_circ_000200 up-regulated in GC tissue, serum and serum exosomes. Hsa_circ_000200 in serum exosomes showed better diagnostic ability than that of tissues and serum. Combined with clinicopathological parameters, its level was related to invasion depth, TNM staging, and distal metastasis. Functionally, knockdown of hsa_circ_000200 inhibited GC cells proliferation, migration and invasion in vitro, while its overexpression played the opposite role. Importantly, exosomes with up-regulated hsa_circ_000200 promoted the proliferation and migration of co-cultured GC cells. Mechanistically, hsa_circ_000200 acted as a "ceRNA" for miR-4659a/b-3p to increase HBEGF and TGF-ß/Smad expression, then promoted the development of GC. CONCLUSIONS: Our findings suggest that hsa_circ_000200 promotes the progression of GC through hsa_circ_000200/miR-4659a/b-3p/HBEGF axis and affecting the expression of TGF-ß/Smad. Serum exosomal hsa_circ_000200 may serve as a potential biomarker for GC.

On-Surface Synthesis of Pentagon-Incorporated Graphene-Like Nanoribbons with Multiple Precursors.

Graphene nanoribbons (GNRs) and their derivatives are receiving increasing attention as a result of their unique electronic and magnetic properties, and many novel derivative structures have been fabricated. The carbon pentagon plays a crucial role in determining both geometric structures and electronic properties of carbon-based materials. Here, we demonstrate that carbon-pentagon-incorporated graphene-like nanoribbons (GLNRs), which are an important class of GNR derivatives, are successfully fabricated via the Ullmann coupling and aromatic cyclodehydrogenation reaction on the surface by a suitable choice of multiple tailored molecular precursors. Our approach provides a basis for the impact of adatoms in the reaction and proves the steering function of the aryl-metal interaction in procedures of self-assembly and organometallic state. In addition, this study paves the way for on-surface synthesis of GNRs and their derivatives as well as the fine tuning of electronic properties of carbon nanoarchitectures by manipulating the edge structures and embedding carbon pentagon heterojunctions.

Cigarette Smoke-Induced Gastric Cancer Cell Exosomes Affected the Fate of Surrounding Normal Cells via the Circ0000670/Wnt/ß-Catenin Axis.

Cigarette smoke is a major risk factor for gastric cancer. Exosomes are an important part of intercellular and intra-organ communication systems and can carry circRNA and other components to play a regulatory role in the occurrence and development of gastric cancer. However, it is unclear whether cigarette smoke can affect exosomes and exosomal circRNA to promote the development of gastric cancer. Exosomes secreted by cancer cells promote cancer development by affecting surrounding normal cells. Herein, we aimed to clarify whether the exosomes secreted by cigarette smoke-induced gastric cancer cells can promote the development of gastric cancer by affecting the surrounding gastric mucosal epithelial cells (GES-1). In the present study, we treated gastric cancer cells with cigarette smoke extract for 4 days and demonstrated that cigarette smoke promotes the stemness and EMT of gastric cancer cells and cigarette smoke-induced exosomes promote stemness gene expression, EMT processes and the proliferation of GES-1 cells. We further found that circ0000670 was up-regulated in tissues of gastric cancer patients with smoking history, cigarette smoke-induced gastric cancer cells and their exosomes. Functional assays showed that circ0000670 knockdown inhibited the promoting effects of cigarette smoke-induced exosomes on the stemness and EMT characteristic of GES-1 cells, whereas its overexpression had the opposite effect. In addition, exosomal circ0000670 was found to promote the development of gastric cancer by regulating the Wnt/ß-catenin pathway. Our findings indicated that exosomal circ0000670 promotes cigarette smoke-induced gastric cancer development, which might provide a new basis for the treatment of cigarette smoke-related gastric cancer.

Chirality variation from self-assembly on Ullmann coupling for the DBCh adsorbate on Au(111) and Ag(111).

On-surface Ullmann coupling has been considered an appealing approach for the precise fabrication of carbon-based covalent nanostructures under solution-free conditions. However, chirality has seldom been discussed in Ullmann reactions. In this report, self-assembled two-dimensional chiral networks are initially constructed in a large area on Au(111) and Ag(111) after adsorption of the prochiral precursor, 6,12-dibromochrysene (DBCh). Self-assembled phases are then transformed into organometallic (OM) oligomers after debromination, preserving the chirality; in particular, the formation of scarcely reported OM species on Au(111) is discovered herein. With the aryl-aryl bonding induced after intensive annealing, covalent chains are fabricated via the cyclodehydrogenation between chrysene blocks, resulting in the formation of 8-armchair graphene nanoribbons with staggered valleys on both sides. Before chiral polymer chains are constructed by chrysene blocks, the high structural flexibility of OM intermediates on Ag(111) is also revealed during reactions, which is derived from the twofold coordination of Ag atoms and conformationally flexible metal-carbon bonding. Our report not only provides solid evidence of atomically precise fabrication of covalent nanostructures with a feasible bottom-up approach but also sheds insights into the comprehensive investigation of chirality variation from monomers to artificial architectures via surface coupling reactions.

Hesperidin inhibits tobacco smoke-induced pulmonary cell proliferation and EMT in mouse lung tissues via the p38 signaling pathway.

Tobacco smoke (TS) is the major cause of lung cancer. The abnormal proliferation and epithelial-mesenchymal transition (EMT) of lung cells promote occurrence and development of lung cancer. The p38 pathway intervenes in this cancer development. Hesperidin also serves a role in human health and disease prevention. The roles of p38 in TS-mediated abnormal cell proliferation and EMT, and the hesperidin intervention thereof are not yet understood. In the present study, it was demonstrated that TS upregulated proliferating cell nuclear antigen, vimentin and N-cadherin expression, whereas it downregulated E-cadherin expression, as assessed using western blotting and reverse transcription-quantitative PCR. Furthermore, it was observed that inhibition of the p38 pathway inhibit TS-induced proliferation and EMT. Hesperidin treatment prevented the TS-induced activation of the p38 pathway, EMT and cell proliferation in mouse lungs. The findings of the present study may provide insights into the pathogenesis of TS-related lung cancer.

Hesperidin Reversed Long-Term N-methyl-N-nitro-N-Nitroguanidine Exposure Induced EMT and Cell Proliferation by Activating Autophagy in Gastric Tissues of Rats.

Gastric cancer is a common malignant tumor worldwide. N-methyl-N-nitro-N-nitroguanidine (MNNG) is one of the most important inducing factors of gastric cancer. Autophagy can affect the occurrence and development of gastric cancer, but the mechanism is not clear. Chemoprevention has been shown to be a rational and very promising approach to the prevention of gastric cancer. Hesperidin is a citrus flavone, an abundant polyphenol in citrus fruits and traditional Chinese medicine. It has an excellent phytochemistry that plays an intervention role in gastric cancer. However, it is unclear whether long-term exposure to MNNG will affect the occurrence of gastric cancer by regulating autophagy and whether hesperidin can play an intervention role in this process. In the present study, we demonstrated that long-term MNNG exposure inhibits autophagy in stomach tissues of rats, promotes the epithelial-mesenchymal transition (EMT) process and cell proliferation and suppresses the activity of the PI3K/AKT pathway. We further found that after rapamycin-activated autophagy, long-term MNNG exposure promoted cell proliferation and EMT were inhibited. In addition, hesperidin promotes autophagy and the activity of the PI3K/AKT pathway, as well as the suppression of proliferation and EMT in the stomach tissues of rats. Our findings indicate that hesperidin reverses MNNG-induced gastric cancer by activating autophagy and the PI3K/AKT pathway, which may provide a new basis for the early prevention and treatment of MNNG-induced gastric cancer.

Manipulation of C-C coupling pathways using different annealing procedures.

From scanning tunnelling microscopy and density functional theory calculations, we demonstrate that different annealing mechanisms could modulate distinct reaction pathways, where in a stepwise annealing procedure the detached Br atoms may reduce the activation barrier of CH activation resulting in hierarchical cross dehydrogenative coupling, while in a one-step annealing procedure only Ullmann coupling products are observed.

Tuning Dehalogenative Coupling of Br2Py on Bimetallic Templates.

Considerable attention has been paid to on-surface Ullmann coupling during the past decade owing to the feasible synthesis of artificial nanostructures. While previous reports mainly concentrated on coupling reactions on single-metal-atom surfaces, herein we present the Ullmann coupling of 2,7-dibromopyrene (Br2Py) on bimetallic surfaces, Bi-Ag(111) and Bi-Au(111), respectively, with scanning tunneling microscopy (STM) and X-ray photoemission spectroscopy (XPS). On the Bi-decorated Ag(111), self-assembly of intact Br2Py is realized due to the reduced activity at the interface. Subsequent annealing promotes the dehalogenation of Br2Py on Bi-Ag(111), while Bi adatoms do not bring any visible influence on coupling reactions. Furthermore, post-deposition of Bi onto preassembled nanostructures on Ag(111) immediately initiates the Ullmann coupling by inducing more Ag adatoms available on the surface, while stepwise annealing afterward leads to complete polymerization and formation of covalent chains with lateral displacement compared to that on the bare Ag(111), probably due to the space hindrance and confinement. For Bi-Au(111) with the modified reconstruction, higher-temperature annealing is required to trigger Ullmann coupling compared to that on Au(111). The exception is that the C-C coupling reaction remains impervious to Bi adatoms, and recovery of the Bi-Au reconstruction is realized after intensive annealing. In principle, bimetallic surfaces herein present intriguing behavior toward the controllable Ullmann coupling, and this report might provide different insights into the comprehensive atomistic elucidation of reaction mechanisms as well as the design of a new platform to effectively regulate Ullmann coupling.

Feasible Structure Manipulation of Vanadium Selenide into VSe2 on Au(111).

Vanadium diselenide (VSe2), a member of the transition metal dichalcogenides (TMDs), is proposed with intriguing properties. However, a comprehensive investigation of VSe2 (especially regarding on the growth mechanism) is still lacking. Herein, with the molecular beam epitaxy (MBE) measures frequently utilized in surface science, we have successfully synthesized the single-layer VSe2 on Au(111) and revealed its structural transformation using a combination of scanning tunneling microscopy (STM) and density functional theory (DFT). Initially, formation of the honeycomb structure is observed with the moiré periodicity, which is assigned to VSe2. Followed by stepwise annealing, defective structures with streaked patterns start to emerge due to the depletion of Se, which can be reversed to the pristine VSe2 by resupplying Se. With more V than Se deposited, a new compound that has no bulk analogue is discovered on Au(111), which could be transformed back to VSe2 after providing excessive Se. As the realization of manipulating V selenide phases is subtly determined by the relative ratio of V to Se and post-annealing treatments, this report provides useful insights toward fundamental understanding of the growth mechanism of TMDs and might promote the wide application of VSe2 in related fields such as catalysis and nanoelectronics.

Autophagy Related Noncoding RNAs: Emerging Regulatory Factors of Gastric Cancer.

Gastric cancer (GC) is one of the most common malignant cancers that seriously affect human health. Autophagy is a highly conserved self-defense mechanism found to plays an important role in the occurrence, progression, drug resistance, and prognosis of GC. Noncoding RNAs (ncRNAs) play a critical role in the occurrence and development of a variety of diseases including GC. In recent years, increasing attention has been given to research on autophagy-related ncRNAs, such as miRNA, lncRNA, and circRNA in GC. Herein, we briefly summarize the roles, functions, and the research progress of autophagy and autophagy-related ncRNAs in GC with a focus on the potential application in GC tumorigenesis, development, prognosis, and drug resistance. We also discussed prospects of clinical application, future research direction, and challenges in future research of autophagy-related ncRNAs.

The construction and application of a blended teaching model under the strategic background of healthy China.

In order to cultivate the ability of independent learning and lifelong learning of medical students, improve the ability of students to analyze and solve problems, improve the competence of medical talents and cultivate high-level and innovative talents, we have constructed the blended teaching model of "Clinical Case Investigation-Online Open Course Learning-Classroom PBL Seminar-After-Class Health Education". At the same time, an ability-oriented performance evaluation system improved the teaching quality feedback system has also established. This article introduces the construction and application of the blended teaching model, as well as the problems it faces, provides a theoretical basis for the optimization and improvement of this model. It also provides a model theory and practical basis for creating a blended online and offline "golden course" for the professional courses of medical laboratory technology.

Anticancer applications of phytochemicals in gastric cancer: Effects and molecular mechanism.

Gastric cancer (GC) is the fourth most common malignant cancer and is a life-threatening disease worldwide. Phytochemicals have been shown to be a rational, safe, non-toxic, and very promising approach to the prevention and treatment of cancer. It has been found that phytochemicals have protective effects against GC through inhibiting cell proliferation, inducing apoptosis and autophagy, suppressing cell invasion and migration, anti-angiogenesis, inhibit Helicobacter pylori infection, regulating the microenvironment. In recent years, the role of phytochemicals in the occurrence, development, drug resistance and prognosis of GC has attracted more and more attention. In order to better understand the relationship between phytochemicals and gastric cancer, we briefly summarize the roles and functions of phytochemicals in GC tumorigenesis, development and prognosis. This review will probably help guide the public to prevent the occurrence and development of GC through phytochemicals, and develop functional foods or drugs for the prevention and treatment of gastric cancer.

Exosomes and Exosomal circRNAs: The Rising Stars in the Progression, Diagnosis and Prognosis of Gastric Cancer.

Gastric cancer (GC) is a common malignant tumor affecting human health, with occult onset and poor prognosis. Exosomes are extracellular vesicles secreted by almost all cells, which can reflect the state of source cells or tissues. It is reported that exosomes are involved in almost all processes of GC. Exosomes provided a window to understand changes in cell or tissue states by carrying active components such as circular RNAs (circRNAs). CircRNAs are a naturally occurring class of endogenous noncoding RNAs and abnormal expression during the occurrence and development of GC. Exosomal circRNAs are those circRNAs stably existing in exosomes and having high clinical values as novel potential diagnosis and prognosis biomarkers of GC, which have the characteristics of abnormal expression, tissue specificity and development stage specificity. Herein, we briefly summarize the functions and roles and the current research progress of exosomes and exosomal circRNAs in GC with a focus on the potential application for GC progression, diagnosis and prognosis. We also prospected the clinical application of exosomes and exosomal circRNAs in the future.

Exosomes in bladder cancer: novel biomarkers and targets.

Exosomes are nanometer-sized vesicles that contain various types of biologically active components, including proteins, nucleic acids, carbohydrates, and lipids, which vary with the type and physiological state of the cell. In recent years, several studies have showed that exosomes can provide new non-invasive diagnostic and prognostic biomarkers in patients affected by cancers, including bladder cancer (BC), and the lipid bilayer membrane structure makes exosomes as promising delivery vehicles for therapeutic applications. Exosomes have the characteristics of high abundance, high stability, tissue specificity, and wide distribution in body fluids, and are secreted as various types by cells in different states, thereby possessing great potential as biomarkers for BC. Herein, we briefly summarize the functions and roles of exosomes in the occurrence and development of BC and the current progress of research on exosomes in BC, while focusing on potential clinical applications of the diagnosis, treatment, and prognosis of BC.

Diallyl trisulfide inhibited tobacco smoke-mediated bladder EMT and cancer stem cell marker expression via the NF-κB pathway in vivo.

OBJECTIVE: This study examined the effect of the NF-κB pathway on tobacco smoke-elicited bladder epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) marker expression in vivo. The effect of diallyl trisulfide (DATS) treatment was also examined. METHODS: BALB/c mice were exposed to tobacco smoke and treated with an NF-κB inhibitor and DATS. Western blotting, quantitative real-time PCR, and immunohistochemical staining were used to detect the changes of relevant indices. RESULTS: Phosphorylated inhibitor of kappa-B kinase alpha/beta expression and p65 and p50 nuclear transcription were increased by tobacco smoke exposure, whereas inhibitor of kappa-B expression was decreased. In addition, tobacco smoke reduced the expression of epithelial markers but increased that of mesenchymal and CSC markers. Our study further demonstrated that tobacco smoke-mediated EMT and CSC marker expression were attenuated by inhibition of the NF-κB pathway. Moreover, DATS reversed tobacco smoke-induced NF-κB pathway activation, EMT, and the acquisition of CSC properties in bladder tissues. CONCLUSIONS: These data suggested that the NF-κB pathway regulated tobacco smoke-induced bladder EMT, CSC marker expression, and the protective effects of DATS.

Gastric-cancer-derived mesenchymal stem cells: a promising target for resveratrol in the suppression of gastric cancer metastasis.

The tumor microenvironment (TM) is an essential factor of tumor progression. Mesenchymal stem cells (MSCs) are important components of the TM and play critical roles in cancer metastasis. Resveratrol (RES) is a potential antitumor drug that has attracted extensive attention. However, it remains unclear whether RES can exert its antitumor activity by targeting MSCs located in the TM. In this study, we demonstrated that the conditioned medium of gastric-cancer-derived MSCs (GC-MSCs) promoted gastric cancer (GC) metastasis and facilitated the progression of epithelialmesenchymal transition (EMT) of GC cells. However, after pretreatment with RES, the prometastatic effect of GC-MSCs on GC cells was reversed. Furthermore, RES reduced GC-MSC (IL-6, IL-8, MCP-1, VEGF) gene expression and protein secretion, and counteracted the activation of the GC-MSC-induced Wnt/ß-catenin signaling of GC cells, with less ß-catenin nuclear transport and declined expression of ß-catenin, CD44, and CyclinD3 in GC cells. Re-expression of ß-catenin impaired the inhibitory effect of RES on GC cells. In conclusion, RES restricted the mobility increase of GC cells and reversed the progress of EMT induced by GC-MSCs by inactivating the Wnt/ß-catenin signaling. GC-MSCs are promising target for RES in the inhibition of GC metastasis.

CircRNAs: Emerging Bladder Cancer Biomarkers and Targets.

Circular RNAs (circRNAs) are newly discovered intriguing RNAs due to the covalently closed loop structure, high stability, tissue specificity, and functional diversity. In recent years, a large number of circRNAs have been identified through high-throughput sequencing technology and bioinformatics methods, the abnormal expression of circRNAs are closely related to many diseases including bladder cancer (BC). CircRNAs have been proven to have several functions, such as acting as a regulator of parental gene transcription, miRNA sponge and interacting with proteins to regulate its expression. In addition, some circRNAs have been identified to encode proteins. CircRNAs have the characteristics of high abundance, high stability, wide distribution in body fluids, tissue specificity, and developmental stage specificity, which determine that circRNAs has great potential to be utilized as biomarkers for BC. Herein, we briefly summarize the biogenesis, functions and roles, and the current research progress of circRNAs in BC with a focus on the potential application for BC diagnosis, treatment, and prognosis.

Revealing the Adsorption and Decomposition of EP-PTCDI on a Cerium Oxide Surface.

Cerium oxide has constantly attracted intense attention during the past decade both in research and industry as an appealing catalyst or a noninert support for catalysts, for instance, in the water-gas shift reaction and hydrogenation of the ketone group. Herein, the cerium oxide surface has been chosen to investigate the adsorption and decomposition behaviors of the N,N'-bis(1-ethylpropyl)-perylene-3,4,9,10-tetracarboxdiimide (EP-PTCDI) molecule by photoelectron spectroscopy. As expected, EP-PTCDI molecules self-assemble on the cerium oxide surface comprising both trivalent and tetravalent cerium at room temperature. Interestingly, the EP-PTCDI molecule exhibits selective adsorption on cerium oxide after the heating treatment. It was found that the ketone group of EP-PTCDI first undergoes hydrogenation after annealing to 400 °C, which is probably related to the fact that high temperature annealing provides sufficient thermal energy to trigger the reaction between the ketone group and trivalent cerium. Furthermore, EP-PTCDI molecules are discovered to start to decompose hierarchically on the ceria substrate from annealing at 400 °C due to the strong molecule-substrate interaction and the effective catalysis by the trivalent cerium, whereas the decomposition sequence of functional groups is revealed to be, first, the ethyl propyl group (-C5H9), followed by the hydrogenated ketone (alcohols) group. Finally, our study may provide a new platform for the fundamental understanding of complex organic reactions on the cerium oxide surface.

Electronic structures of ultra-thin tellurium nanoribbons.

The structural stability and electronic properties of monolayer and bilayer tellurium nanoribbons (TNRs) with different edge structures have been systematically investigated by means of first-principles calculations, revealing that the stability of both monolayer and bilayer TNRs largely rely on their width. Regardless of width, tip TNRs are metallic, while notch TNRs are p-type-like conductors. Interestingly, both mono- and bi-layer chain TNRs exhibit a semiconductor-to-metal transition as the width increases. The electronic structures of tip and notch TNRs are mainly determined by atomic reconstruction and the unsaturated electronic states on the edges. For chain TNRs, the origin of the semiconductor-to-metal transition can be attributed to the spontaneous in-plane electronic polarization across the ribbon. Our work reveals diverse electronic properties of one-dimensional elemental tellurium nanostructures, which considerably extend the potential applications of tellurene-based materials in nanodevices.