Variation in the affinity of three representative avian adenoviruses for the cellular coxsackievirus and adenovirus receptor.

According to previous studies, three representative avian adenoviral strains utilize coxsackievirus-adenovirus receptor (CAR) as a receptor and seem to exhibit diverse binding affinities and modes. Thus, further revealing the exact molecular mechanism underlying the interaction between different FAdVs and the attachment receptor CAR is necessary. In this study, we successfully solved the crystal structure of the FAdV-4 fiber1 knob at 1.6 Šresolution. The interaction between the fibre knob and different domains of CAR was verified by confocal microscopy, coimmunoprecipitation and surface plasmon resonance (SPR) analysis. The fibre knobs of the three representative fowl adenoviruses specifically recognized CAR domain 1 (D1), but the recognition of CAR domain 2 (D2) by chicken embryo lethal orphan (CELO) strains was weak. These results provide insights into the differences in adenovirus‒host cell interactions and have important implications for the exploration of viral invasion mechanisms.

Living and Regenerative Material Encapsulating Self-Assembled Shewanella oneidensis-CdS Hybrids for Photocatalytic Biodegradation of Organic Dyes.

Reductive biodegradation by microorganisms has been widely explored for detoxifying recalcitrant contaminants; however, the biodegradation capacity of microbes is limited by the energy level of the released electrons. Here, we developed a method to self-assemble Shewanella oneidensis-CdS nanoparticle hybrids with significantly improved reductive biodegradation capacity and constructed a living material by encapsulating the hybrids in hydrogels. The material confines the nano-bacteria hybrids and protects them from environmental stress, thus improving their recyclability and long-term stability (degradation capacity unhindered after 4 weeks). The developed living materials exhibited efficient photocatalytic biodegradation of various organic dyes including azo and nitroso dyes. This study highlights the feasibility and benefits of constructing self-assembled nano-bacteria hybrids for bioremediation and sets the stage for the development of novel living materials from nano-bacteria hybrids.

Overexpressed lncRNA LINC00893 Suppresses Progression of Colon Cancer by Binding with miR-146b-3p to Upregulate PRSS8.

Background: Long noncoding RNAs (lncRNAs) play a significant role in the progression and metastasis of various cancers. LINC00893 has been reported to exert antitumor effect on various cancers such as gastric cancer and thyroid cancer. Bioinformatics analysis also predicted that LINC00893 was downregulated in colon cancer. However, the clinical significance and regulating mechanism of LINC00893 in colon cancer remain unknown. Methods: Expression of LINC00893, miR-146b-3p, and PRSS8 was detected in colon cancer tissues and adjacent nontumor tissues by RT-qPCR, and clinical significance was analyzed by receiver operating characteristic curve. The regulatory mechanism of LINC00893, miR-146b-3p, and PRSS8 was investigated by dual luciferase reporter and RNA pull-down assays. Proliferation, migration, invasion, and apoptosis were measured in HCT116 and SW620 cells by MTT, EdU staining, wound healing, Transwell, TUNEL, and flow-cytometry assays. Moreover, the effect of LINC00893 on colon cancer progression was further evaluated in tumor-bearing mice. Results: LINC00893 and PRSS8 were significantly downregulated, while miR-146b-3p was upregulated in colon cancer tissues compared to control group. LINC00893, miR-146b-3p, and PRSS8 had significant diagnostic value with area under curve of 0.9383, 0.7300, and 0.9644, respectively. Overexpressed LINC00893 or silenced miR-146b-3p suppressed the proliferation, migration, and invasion while promoting apoptosis in colon cancer cells (HCT116, SW620). Moreover, miR-146b-3p overexpression reversed the inhibitory effect of LINC00893, while PRSS8 knockdown rescued the suppressive effect of miR-146b-3p inhibitor on malignant cell behaviors in colon cancer. Furthermore, the tumor growth in mice was significantly reduced by LINC00893 overexpression. Conclusion: LINC00893 overexpression suppressed the progression of colon cancer by binding with miR-146b-3p to upregulate PRSS8. LINC00893 and its downstream molecules miR-146b-3p and PRSS8 may serve as novel biomarkers and therapeutic targets of colon cancer, providing new treatment options and research approaches towards colon cancer.

Immunity analysis against Fowl Adenovirus serotype 4 (FAdV-4) based on Fiber-2 trimer Protein with the different virulence.

Since June 2015, Fowl adenovirus outbreaks have occurred in China, causing significant economic losses to poultry industry. The FAdV-4 Fiber-2 proteins could induce effective protection, but the precise mechanism of immune protection remains unknown. Here, we have compared the biological characteristics of Fiber-2 protein of the very virulent WZ strain of FAdV-4 (vvFAdV-4) with that of non-virulent ON1 strain. The sequence analysis revealed natural deletions and sequence differences between the classical non-pathogenic strain ON1 and the vvFAdV-4 isolate. These two Fiber-2 proteins successfully expressed in E. coli resemble in structure and function to the native-like trimeric protein. The trimeric structure and bioreactivity of the recombinant Fiber-2 proteins to FAdV-4 specific antibodies were characterized. The immune protection induced by Fiber-2 proteins of FAdV-4 WZ and ON1 strains were compared in SPF chickens. All birds in the WZ-Fiber-2 immunized group generated systemic specific antibodies compared with both ON1-Fiber-2 protein and PBS immunized groups. According to the results of attack mortalities, viral shedding and tissue gross lesion, the WZ Fiber-2 protein induced complete protection at a dose of 2 µg per chicken, whereas the ON1-Fiber-2 protein induced 0 protection at 3 dpc. In view of the characteristics of Fiber-2 proteins of different strains, this study can help us to further understand the mechanism of protective immunity and provide a basis for the prevention and control of FAdV-4 in chickens.

MiR-1224 Acts as a Prognostic Biomarker and Inhibits the Progression of Gastric Cancer by Targeting SATB1.

OBJECTIVE: MiR-1224 has been reported to exhibit abnormal expression in several tumors. However, the expressing pattern and roles of miR-1224 in gastric cancer (GC) remain unclear. Our current research aimed to explore the potential involvement of miR-1224 in the GC progression. MATERIALS AND METHODS: The expression of miR-1224 was examined in tissue samples of 128 GC patients and cell lines by RT-PCR. Besides, the associations of miR-1224 expressions with clinicopathologic features and prognosis of GC patients were analyzed. Then, the possible influences of miR-1224 on cell proliferation and cell migration were determined. Afterward, the molecular target of miR-1224 was identified using bioinformatics assays and confirmed experimentally. Finally, RT-PCR and Western blot assays were performed to investigate the effect of the abnormal miR-1224 expression on the EMT and Wnt/ß-catenin pathway. RESULTS: miR-1224 was lowly expressed in the GC specimens and cell lines due to T classification and TNM stage. Survival assays demonstrated that GC patients with low expressions of miR-1224 possessed poor overall survivals. Moreover, in vitro and in vivo assays revealed that the overexpression of miR-1224 inhibited cell proliferation, migration, and invasion in GC cells. SATB homeobox 1 (SATB1) was verified as a direct target of miR-1224 in GC. Furthermore, ß-catenin and c-myc were significantly inhibited in miR-1224-overexpression cells. CONCLUSIONS: Our findings highlight the potential of miR-1224 as a therapeutic target and novel biomarker for GC patients.

LPCAT1 reprogramming cholesterol metabolism promotes the progression of esophageal squamous cell carcinoma.

Tumor cells require high levels of cholesterol for membrane biogenesis for rapid proliferation during development. Beyond the acquired cholesterol from low-density lipoprotein (LDL) taken up from circulation, tumor cells can also biosynthesize cholesterol. The molecular mechanism underlying cholesterol anabolism in esophageal squamous cell carcinoma (ESCC) and its effect on patient prognosis are unclear. Dysregulation of lipid metabolism is common in cancer. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been implicated in various cancer types; however, its role in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we identified that LPCAT1 is highly expressed in ESCC and that LPCAT1 reprograms cholesterol metabolism in ESCC. LPCAT1 expression was negatively correlated with patient prognosis. Cholesterol synthesis in ESCC cells was significantly inhibited following LPCAT1 knockdown; cell proliferation, invasion, and migration were significantly reduced, along with the growth of xenograft subcutaneous tumors. LPCAT1 could regulate the expression of the cholesterol synthesis enzyme, SQLE, by promoting the activation of PI3K, thereby regulating the entry of SP1/SREBPF2 into the nucleus. LPCAT1 also activates EGFR leading to the downregulation of INSIG-1 expression, facilitating the entry of SREBP-1 into the nucleus to promote cholesterol synthesis. Taken together, LPCAT1 reprograms tumor cell cholesterol metabolism in ESCC and can be used as a potential treatment target against ESCC.

A Biosynthesized Near-Infrared-Responsive Nanocomposite Biomaterial for Antimicrobial and Antibiofilm Treatment.

Photodynamic inactivation (PDI) has become an appealing alternative strategy to treat infections without developing resistance to microbes. In PDI treatment, near-infrared (NIR) light is preferred because it causes less damage to normal tissues and leads to better penetration in deep tissues. Here, we develop an NIR-responsive nanomedicine for efficient broad-spectrum antimicrobial photodynamic treatment. By harnessing the biosynthetic capability of a bacterial cellulose-producing microorganism, we construct a nanocomposite biomaterial to deliver and recycle the nanomedicine. Our simple one-step biosynthetic approach does not impede the antimicrobial potency of the nanomedicine under NIR activation and requires no chemical modification. The resulting nanocomposite has been tested in antimicrobial treatment of different microorganisms, exhibiting a great potential to eliminate pathogens in biofilms and to treat in vivo infections.

Enhanced Antitumor Efficacy of Macrophage-Mediated Egg Yolk Lipid-Derived Delivery System Against Breast Cancer.

BACKGROUND: Chemotherapy is the primary treatment for most cancers apart from surgery. However, the use of chemotherapeutic drugs is limited by side effects and restricted accumulation in tumors because of unique tumor microenvironments. Macrophages have excellent drug delivery potential owing to their chemotaxis and can home in on tumors. MATERIALS AND METHODS: We developed an effective drug-delivery system for doxorubicin using macrophages. Doxorubicin-loaded egg yolk lipid-derived nanovectors (EYLNs-Dox) were prepared, EYLNs-Dox-loaded macrophages (Mac/EYLNs-Dox) were developed and their tumor penetration and anti-cancer activity against 4T1 cells were analyzed. The biodistribution and anti-4T1 breast cancer activities were determined using 4T1 subcutaneous and lung metastasis models. RESULTS: EYLNs-Dox was successfully internalized into macrophages without affecting their viability and was less toxic than Dox. Mac/EYLNs-Dox penetrated the 4T1 tumor spheroids more efficiently and was more effective in inhibiting tumors in vitro. Macrophages significantly enhanced the distribution of EYLNs vectors in both inflammatory and tumor sites, playing a more effective role in the inhibition of tumors. CONCLUSION: EYLNs-Dox can be effectively delivered using macrophages and Mac/EYLNs-Dox might be a promising targeted delivery system for breast cancer.

Leukocyte-Mediated Combined Targeted Chemo and Gene Therapy for Esophageal Cancer.

Poor prognosis of esophageal cancer is associated with limited clinical treatment efficacy and lack of targeted therapies. With advances in nanomedicine, nanoparticle drug delivery systems play increasingly important roles in tumor treatment by enabling the simultaneous delivery of multiple therapeutic agents. We here propose a novel nanovector for targeted combination gene therapy and chemotherapy in esophageal cancer. A novel lipid nanovector (EYLN) was designed to carry the chemotherapy drug doxorubicin (Dox) and small interfering RNA against the lipid anabolic metabolism gene LPCAT1, which we previously showed to be significantly overexpressed in esophageal cancer tissues, and its interference inhibited the proliferation, invasion, and metastasis of esophageal cancer cells. This vector, EYLN-Dox/siLPCAT1, was further coated with leukocyte membranes to obtain mEYLNs-Dox/siLPCAT1. The particle size of the coated nanovector was approximately 136 nm, and the surface zeta potential was -21.18 mV. Compared with EYLNs-Dox/siLPCAT1, mEYLNs-Dox/siLPCAT1 were more easily internalized by esophageal cancer cells due to the LFA-1 highly expressed leukocyte membrane coating and showed significant inhibition of the proliferation, migration, and metastasis of esophageal cancer cells, along with their LPCAT1 expression, through more effective delivery of the drugs. Moreover, the nanovectors showed improved blood circulation time, tissue distribution, tumor targeting, and tumor suppression in a mouse model. Thus, combining chemo and gene therapy with this new nanodelivery system achieved greater therapeutic efficacy, providing a new strategy for the treatment of esophageal cancer.

Nanovector Assembled from Natural Egg Yolk Lipids for Tumor-Targeted Delivery of Therapeutics.

Nanomedicine uses nanotechnology-based strategies for precision tumor therapy, including passive and ligand-mediated active tumor targeting by nanocarriers. However, the possible biotoxicity of chemosynthetic nanovectors limits their clinical applications. A novel natural egg yolk lipid nanovector (EYLN) was developed for effective loading and delivery of therapeutic agents. Lipids were extracted from egg yolks and reassembled into nanosized particles. EYLNs' stability, cellular uptake, toxicity, and delivery capacity for therapeutic agents were evaluated in vitro. The systemic toxicity and biodistribution of EYLNs were analyzed in normal mice, and the therapeutic effects of doxorubicin (Dox)-loaded EYLNs were evaluated in mouse breast cancer and hepatoma models. EYLNs had a particle size of ∼40 nm and a surface ζ-potential of -45 mV and were effectively internalized by tumor cells, without showing toxicity and side effects in vitro and in vivo. Importantly, their excellent permeability and retention effect significantly enhanced the distribution of EYLNs at tumor sites, and EYLN-Dox effectively inhibited the tumor growth in both mouse models. Targeted modification with folic acid further promoted vector-mediated drug distribution in tumors. This study demonstrates that lipids with specific proportions in the egg yolk can be used to construct natural drug vectors, providing a new strategy for nano-oncology research.

Aptamer-conjugated and doxorubicin-loaded grapefruit-derived nanovectors for targeted therapy against HER2+ breast cancer.

Increased human epidermal growth factor receptor 2 (HER2) expression is a hallmark of HER2+ breast cancer. HER2 promotes the growth of cancer cells and makes them particularly aggressive. Currently, trastuzumab is the only HER2-targeted therapeutic agent approved by the FDA for HER2-overexpressing breast cancer treatment. However, clinical efficacy of trastuzumab is limited greatly by the occurrence of drug resistance. In this study, an aptamer (HA1) specific for HER2-overexpressing breast cancer cells was selected using Cell-SELEX. This allowed the development of grapefruit-derived nanovectors (GNVs) conjugated with HA1 that targeted specifically HER2+ breast cancer cells. In vitro experiments demonstrated that HA1 effectively promoted the internalisation of GNVs into cancer cells and tumour spheroids. In vivo data showed that drug delivery to tumour tissues and antitumor activities were dramatically enhanced by conjugating HA1 with drug-loaded GNVs. This study indicates that aptamers mediating targeted drug delivery by GNVs represent a promising strategy for HER2+ breast cancer therapy.

Mitotic checkpoint kinase Mps1/TTK predicts prognosis of colon cancer patients and regulates tumor proliferation and differentiation via PKCα/ERK1/2 and PI3K/Akt pathway.

Mps1/TTK plays an important role in development of many tumors. The purpose of the present study was designed to investigate the role of TTK in colon cancer. We analyzed TTK and colon cancer in the GEO database, colon cancer tissues and normal tissues were collected to verify the results by immunohistochemistry. We detected the TTK expression in the colon cancer cell lines, and overexpressed or silenced TTK expression in colon cancer cell lines. GEO database showed that the expression of TTK was higher in the colon cancer tissues than normal tissues, higher level of TTK shows unfavourable prognosis in colon patients. Furthermore, high differentiation of colon shows the lower expression of TTK. The higher expression of TTK links with the high microsatellite status. However, the expression of TTK has no significant difference among the different stages of colon cancer patients, and has no significant relationship with recurrence or relapse. Here, we also report that the differential expression of TTK in colon cancer cells alters the intrinsic negative regulation of cell proliferation and differentiation, resulting in the difference of proliferation and differentiation capacity. TTK could activate the PKCα/ERK1/2 to influence the proliferation and inactivate the PI3K/AKT pathway to inhibition the expression of MUC2 and TFF3 that related to the differentiation of colon cells. In conclusions, TTK promote the colon cancer cell proliferation via activation of PKCα/ERK1/2 and inhibit the differentiation via inactivation of PI3K/Akt pathway. TTK inhibition may be the potential therapeutic pathway for the treatment of colon cancer.

Prognostic value of the systematic immune-inflammation index among patients with operable colon cancer: A retrospective study.

The systematic immune-inflammation index (SII) has been used to predict the prognosis of patients with various cancers. This study aimed to determine whether the preoperative SII was associated with postoperative survival among patients with operable colon cancer.This retrospective study included 118 age- and sex-matched healthy subjects and 118 patients who underwent radical surgery for colon cancer between January 2011 and December 2013. The preoperative SII was calculated based on counts of neutrophils, lymphocytes, and platelets in the peripheral blood. Pearson correlation analysis was used to analyze the relationships between the SII and carcinoembryonic antigen (CEA) concentration, average length of stay (ALOS), and medical costs during hospitalization. The χ test or Fisher exact test was used to analyze the relationship between the preoperative SII and the postoperative survival rate.The median SII value was 667.75 among patients with colon cancer, which was higher than the value among healthy subjects. A high SII (>667.75) was associated with a large tumor size and advanced TNM stage, although it was not associated with age, sex, tumor location, or pathological grade. Pearson correlation analysis revealed that the SII was positively correlated with serum CEA concentration, ALOS, and medical costs. Relative to a low SII, a high SII was significantly associated with a lower overall survival rate at 3 years and 5 years after surgery.The present study's findings suggest that the preoperative SII is a useful prognostic index for patients with operative colon cancer.

Overcoming Drug Resistance in Colon Cancer by Aptamer-Mediated Targeted Co-Delivery of Drug and siRNA Using Grapefruit-Derived Nanovectors.

BACKGROUND/AIMS: Multidrug resistance (MDR) is the most common cause of chemotherapy failure. Upregulation of P-glycoprotein (P-gp) is one of the main mechanisms underlying MDR. METHODS: In this study, we developed a targeted drug and small interfering (si)RNA co-delivery system based on specific aptamer-conjugated grapefruit-derived nanovectors (GNVs) that we tested in MDR LoVo colon cancer cells. The internalization of nanovectors in cancer cells was tested by fluorescence microscopy and flow cytometry. The anti-cancer activity in vitro was determined by colony formation and cell apoptosis assays. The biodistribution of nanovectors was analyzed by live imaging and the anti-cancer activity in vivo was observed. RESULTS: GNVs loaded with aptamer increased doxorubicin (Dox) accumulation in MDR LoVo cells, an effect that was abolished by pretreatment with DNase. The LA1 aptamer effectively promoted nanovector internalization into cells at 4°C and increased the targeted delivery of Dox to tumors. Constructs harboring Dox, LA1, and P-gp siRNA more effectively inhibited proliferation and enhanced apoptosis in cultured MDR LoVo cells while exhibiting more potent anti-tumor activity in vivo than free Dox or GNVs loaded with Dox alone or in conjunction with LA1, an effect that was associated with downregulation of P-gp expression. CONCLUSION: This GNV-based system may be an effective strategy for overcoming MDR in clinical settings.