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Many circular RNAs (circRNAs) are reported to be abnormally expressed during the progression of various tumors, and these circRNAs can be used as anti-tumor targets. Therefore, it is important to identify circRNAs that can be used effectively for the clinical diagnosis and treatment of colorectal cancer (CRC). Here, we report that hsa_Circ_0000826 (Circ_0000826), a significantly underexpressed circRNA in CRC tissues, is associated with a poor prognosis in patients. The silencing of Circ_0000826 promoted the proliferation of CRC cells. Conversely, the overexpression of Circ_0000826 restricted cell proliferation both in vitro and in vivo. Furthermore, Circ_0000826 could target AU-rich element RNA-binding protein 1 (AUF1). AUF1, known as heterogeneous nuclear ribonucleoprotein D (hnRNP D), could bind to the c-Myc 3'-UTR and promote c-Myc expression. When Circ_0000826 binds to AUF1, Circ_0000826 competitively inhibits the binding of AUF1 to the c-Myc 3'-UTR, which inhibits the c-Myc expression and cell proliferation. These results provide novel insights into the functional mechanism of action of Circ_0000826 in CRC progression and indicate its potential use as a therapeutic target in CRC.

Stimulator of interferon genes (STING) is a pivotal innate immune adaptor, and its functions during DNA virus infections have been extensively documented. However, its homeostatic regulation is not well understood. Our study demonstrates that Unc-93 homolog B1 (UNC93B1) is a crucial checker for STING to prevent hyperactivation. Ectopic expression of UNC93B1 attenuates IFN-β promoter activity and the transcriptions of IFN-β, ISG54, and ISG56 genes. Moreover, UNC93B1 also blocks the IRF3 nuclear translocation induced by ectopic expression of both cyclic GMP-AMP synthase (cGAS) and STING and reduces the stability of STING by facilitating its autophagy-lysosome degradation, which can be reversed by lysosome inhibitors. Mechanistically, UNC93B1 interacts with STING and suppresses STING-activated downstream signaling by delivering STING to the lysosomes for degradation, depending on its trafficking capability. UNC93B1 knockout in human embryonic kidney 293T cells facilitates IFN-β promoter activity, IFN-β, ISG54, and ISG56 transcriptions, and IRF3 nuclear translocation induced by ectopic expression of cGAS and STING. Infected with herpes simplex virus-1 (HSV-1), UNC93B1 knockdown BJ cells or primary peritoneal macrophages from Unc93b1-deficient (Unc93b1

Objective: This meta-analysis was designed to assess if pre-operative low skeletal muscle mass impacts mortality rates of patients undergoing abdominal aortic aneurysm (AAA) repair. Methods: Datasets of PubMed, CENTRAL, ScienceDirect, Embase, and Google Scholar were searched from 1st January 1980 to 15th December 2021 for studies assessing the role of low skeletal muscle mass on mortality rates of AAA repair. Studies measuring skeletal muscle mass on computed tomography scans and reporting long-term mortality (>1 year) were included. Multivariable adjusted ratios were combined in a random-effects model. Results: Fifteen studies with 3776 patients were included. Meta-analysis showed a statistically significant increased risk of all-cause mortality in patients with low skeletal muscle mass (HR: 2.07 95% CI: 1.56, 2.74 I2=65% p

Human γδ T cells hold a pivotal role in tumor immunosurveillance through their prompt activation and cytokine secretion and have received much attention in adoptive immunotherapy of clear cell renal cell carcinoma (ccRCC). However, the therapeutic effects are limited in ccRCC. Therefore, it is now critical to improve therapeutic strategies based on γδ T cells, especially identification of functional γδ T cell subsets. In this study, we aimed to identify γδ T cells that might have enhanced responses against ccRCC. Bioinformatic analysis showed that ccRCC patients with high T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression had higher levels of effector molecules. Then, we examined the changes in the TIGIT+ γδ T cell percentages of 6 ccRCC patients and 14 healthy subjects through zoledronate (ZOL) stimulation. Results indicated that percentages of TIGIT+ γδ T cells were positively correlated with activated γδ T cells in early activation stage. Further study demonstrated that TIGIT+ γδ T cells exhibited enhanced activation, contained more terminally differentiated effector γδ T cells and produced higher cytokine compared with TIGIT- γδ T cells. Finally, we investigated the functions and found that TIGIT+ γδ T cells exhibited stronger tumor reactivities and higher cytotoxicity when challenged by tumor cells. Above results imply that TIGIT+ γδ T cells are the main effectors in ZOL recognition and tumor cells challenging. The results of the present study serve as basis for future functional studies on TIGIT+ γδ T cells and provide a promising approach of immunotherapy in ccRCC.

Proteins and translationally modified proteins like phosphoproteins have essential regulatory roles in tumorigenesis. This study attempts to elucidate the dysregulated proteins driving colorectal cancer (CRC). To explore the differential proteins, we performed iTRAQ labeling proteomics and TMT labeling phosphoproteomics analysis of CRC tissues and adjacent non-cancerous tissues. The functions of quantified proteins were analyzed using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and Subcellular localization analysis. Depending on the results, we identified 330 differential proteins and 82 phosphoproteins in CRC. GO and KEGG analyses demonstrated that protein changes were primarily associated with regulating biological and metabolic processes through binding to other molecules. Co-expression relationships between proteomic and phosphoproteomic analysis revealed that TMC5, SMC4, SLBP, VSIG2, and NDRG2 were significantly dysregulated differential proteins. Additionally, based on the predicted co-expression proteins, we identified that the stem-loop binding protein (SLBP) was up-regulated in CRC cells and promoted the proliferation and migration of CRC. This study reports an integrated proteomic and phosphoproteomic analysis of CRC to discern the functional impact of protein alterations and provides a candidate diagnostic biomarker or therapeutic target for CRC. SIGNIFICANCE: Combining one or more high-throughput omics technologies with bioinformatics to analyze biological samples and explore the links between biomolecules and their functions can provide more comprehensive and multi-level insights for disease mechanism research. Proteomics, phosphoproteomics, metabolomics and their combined analysis play an important role in the auxiliary diagnosis, the discovery of biomarkers and novel therapeutic targets for colorectal cancer. In this integrated proteomic and phosphoproteomic analysis, we identified proteins and phosphoproteins in colorectal cancer tissue and analyzed potential mechanisms contributing to progression in colorectal cancer. The results of this study provide a foundation to focus future experiments on the contribution of altered protein and phosphorylation patterns to prevention and treatment of colorectal cancer.

The poly(ADP-ribose) polymerases (PARPs) family contains 17 members in humans, sharing a PARP domain to transfer ADP-ribose groups to target proteins to trigger ADP-ribosylation. The roles of PARPs have evolved from DNA damage repair to diverse biological processes, such as gene transcription, cellular stress response, etc. Recently, seminal studies have demonstrated the critical roles of PAPRs in antiviral innate immunity. PARPs catalyze ADP-ribosylation, a fundamental post-translational modification, using NAD+ as a substrate. ADP-ribosylation can occur either as mono- or poly-(ADP-ribosyl)ation, which is initially linked to DNA damage repair, as exemplified by PARP1. Recent advances in host antiviral immunity demonstrated that several PARPs, such as PARP9, 11, 12, 13, 14, etc., have broad-spectrum antiviral activities that are independent of their ADP-ribosylation.

Background Ovarian cancer is one of the common malignant tumors in female reproductive organs. Kallikrein-related peptidase (KLK) 7 is a secreted serine peptidase that is related to different cancer. To investigate the expression and significance of KLK7 in ovarian cancer. Materials and methods The expression of KLK7 in human ovarian cancer was evaluated by Oncomine and Cancer Cell Line Encyclopedia database. Then the co-expression genes relevant to the KLK7 gene were analyzed by the Pearson correlation test. Finally, the impact of KLK7 on clinical prognosis was investigated in distinct subtypes of ovarian cancer patients by UALCAN database and Kaplan–Meier plotter database. Results It was found that the expression of KLK7 was higher in ovarian cancer compared with other types of cancer, such as gastric cancer and pancreatic cancer. The expression of KLK7 was found to be increased in four various ovarian cancer data sets compared with the healthy tissues. In addition, upregulation of KLK7 expression was associated with age and cancer stage. Moreover, survival analysis revealed that higher KLK7 expression was negatively associated with progression-free survival. Conclusion Knowledge of the expression of KLK7 may be useful for better understanding the outcome in ovarian cancer patients.

Background PLEKHA5 has previously been identified as a novel molecule implicated in melanoma brain metastasis, a disease that continues to portend a poor prognosis. The aim of this study was to further investigate the functional role of PLEKHA5 in disseminated melanoma. Methods The impact of PLEKHA5 on proliferation and tumor growth was examined in vitro and in melanoma xenograft models, including brain-tropic melanomas (melanomas tending to disseminate to the brain). In vitro loss- and gain-of-function studies were used to explore the underlying mechanisms of PLEKHA5-mediated tumor growth and the crosstalk between PLEKHA5 and PI3K/AKT/mTOR or MAPK/ERK signaling. The clinical relevance of PLEKHA5 dysregulation was further investigated in a cohort of matched cranial and extracranial melanoma metastases. Results PLEKHA5 stable knockdown negatively regulated cell proliferation by inhibiting the G1 -to-S cell cycle transition, which coincided with upregulation of the cell cycle regulator PDCD4. Conversely, ectopic PLEKHA5 expression exhibited the inverse effect. PLEKHA5 knockdown significantly inhibited tumor growth, whereas its overexpression upregulated the growth of tumors, which was induced by cranial and subcutaneous inoculation of cells in nude mice. PLEKHA5 modulation affected PDCD4 protein stability and was coupled with changes in PI3K/AKT/mTOR pathway signaling. High PDCD4 expression in cerebral specimens was associated with better overall survival. Conclusions This study further supports the role of PLEKHA5 as a regulator of melanoma growth at distant sites, including the brain. Furthermore, the results highlight the significance of PDCD4 dysregulation in disseminated melanoma and implicate PDCD4 as a possible causal link between PLEKHA5 and cell proliferation and growth.

To systematically evaluate the effect of hydrocortisone combined with vitamin C and vitamin B1 on the efficacy of patients with sepsis or septic shock.Databases including CNKI, Sino Med, VIP, Wanfang, PubMed, the Cochrane Library, and Embase were searched from inception to January 2021 for the randomized controlled trial (RCT) about hydrocortisone combined with vitamin C and vitamin B1 to treat sepsis or septic shock. The experimental group was given intravenous injection of hydrocortisone, vitamin B1 and vitamin C based on conventional treatment; the control group was given conventional treatment or placebo/hydrocortisone/hydrocortisone+vitamin B1 based on conventional treatment. Outcome indicators included sequential organ failure assessment (SOFA), mortality, the duration of vasoactive drugs, new acute kidney injury (AKI) patients, length of stay in intensive care unit (ICU) and in hospital. Two researchers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. RevMan 5.3 software was then used to perform Meta-analysis. Funnel plot was used to test publication bias.A total of 6 articles involving 816 patients were included, with 411 patients in the experimental group and 405 patients in the control group. The Meta-analysis results showed that the duration of vasoactive drugs in the experimental group was significantly shorter than that in the control group [mean difference (MD) = -24.02, 95% confidence interval (95%CI) was -32.36 to -15.68, P0.000 01]. However, there were no significant differences in SOFA, mortality, new AKI patients, the length of ICU stay and hospital stay between the two groups [SOFA: MD = -0.14, 95%CI was -1.15 to 0.87, P = 0.79; mortality: relative risk (RR) = 0.99, 95%CI was 0.81 to 1.21, P = 0.92; new AKI patients: RR = 1.10, 95%CI was 0.42 to 2.87, P = 0.84; length of ICU stay: MD = 1.33, 95%CI was -2.22 to 4.89, P = 0.46; length of hospital stay: MD = 1.02, 95%CI was -0.66 to 2.69, P = 0.23]. The funnel plot showed that most of the points were symmetrical and showed an inverted funnel shape, suggesting that the publication bias among the studies was small. There was no significant publication bias on this Meta-analysis.Hydrocortisone combined with vitamin C and vitamin B1 can shorten the duration of vasoactive drugs in patients with sepsis or septic shock, but it cannot effectively reduce the SOFA score, mortality, new AKI patients, length of stay in ICU and in hospital. Limited by the number and quality of the included studies, further large-scale, multi-center, blinded, RCT are still needed for verification.

Diabetes mellitus, as a metabolic system disorder disease, aggravates the disease burden of patients and affects the quality of human life. Diabetes-associated bone complications lead to decreased bone mechanical strength and osteoporosis. Evidences show that chronic hyperglycemia and metabolic intermediates, such as inflammatory factor, reactive oxygen species (ROS) and advanced glycation end products (AGEs), are regarded as dominant hazardous factors of primary cilia/Gli2 signal disorders. Case studies have demonstrated abnormal bone metabolism in diabetics, however, how diabetes damages primary cilia/Gli2 signal is largely unknown. Therefore, we studied the effects of diabetes on femoral primary cilia by establishing a Streptozocin (STZ)-induced diabetic (Sprague Dawley) SD rat model and diabetic bone loss cell model in vitro. Our results confirmed that diabetes impaired femur primary cilia, osteoblast differentiation and mineralization by inhibiting primary cilia/Gli2 signaling pathway, additionally, Icariin(ICA) treatment could rescue the impairment of osteoblast differentiation caused by high glucose medium in vitro. ICA activated primary cilia/Gli2/osteocalcin signaling pathway of osteoblasts by protecting primary cilia from glucotoxicity imposed by diabetes, intact primary cilia could be as anchoring sites, in which Gli2 was processed and modified, and matured Gli2 entered the nucleus to initiate downstream osteocalcin gene transcription. Additionally, ICA inhibited ROS production of mitochondria, thus balanced mitochondrial energy metabolism and oxidative phosphorylation. All results suggest that ICA can protect the primary cilia and mitochondria of osteoblast by reducing intracellular ROS, thereby recover primary cilia/Gli2 signaling pathway to facilitate osteoblast differentiation and mineralization, suggesting that ICA has potential as a novel type of drug treating bone loss induced by diabetes.

Upregulation of transmembrane protein 97 (TMEM97) has been associated with progression and poor outcome in multiple human cancers, including breast cancer. Recent studies suggest that TMEM97 may be involved in the activation of the Wnt/β-catenin pathway. However, the molecular mechanism of TMEM97 action on Wnt/β-catenin signaling is completely unclear. In the current study, TMEM97 was identified as an LRP6-interacting protein. TMEM97 could interact with LRP6 intracellular domain and enhance LRP6-mediated Wnt signaling in a CK1δ/ε-dependent manner. The binding of TMEM97 to LRP6 facilitated the recruitment of CK1δ/ε to LRP6 complex, resulting in LRP6 phosphorylation at Ser 1490 and the stabilization of β-catenin. In breast cancer cells, knockout of TMEM97 attenuated the Wnt/β-catenin signaling cascade via regulating LRP6 phosphorylation, leading to a decrease in the expression of Wnt target genes AXIN2, LEF1, and survivin. TMEM97 deficiency also suppressed cell viability, proliferation, colony formation, migration, invasion, and stemness properties in breast cancer cells. Importantly, TMEM97 knockout suppressed tumor growth through downregulating the Wnt/β-catenin signaling pathway in a breast cancer xenograft model. Taken together, our results revealed that TMEM97 is a positive modulator of canonical Wnt signaling. TMEM97-mediated Wnt signaling is implicated in the tumorigenesis of breast cancer, and its targeted inhibition may be a promising therapeutic strategy for breast cancer.

This study aims to assess whether the cleft nucleus lymphocytosis could be an early promising clue for the diagnosis of pertussis in young infants. Pertussis (whooping cough) is a severe respiratory disease mainly caused by Bordetella pertussis infection and is characterized by a significant rise in the number of leukocyte and lymphocyte in infants and young children. In this study, the Bordetella pertussis DNA was detected from samples of pharyngeal swab by PCR assay. Levels of serum specific IgM against other respiratory pathogens were detected by Enzyme-linked immunosorbent assay (ELISA) assay. The routine blood test including numbers of leukocytes, lymphocytes, and platelets etc. were tested by automatic hemocyte analyzer (Sysemx XN1000). Besides, the morphology of leucocytes was observed in peripheral blood smear with microscope by Wright-Giemsa stain. Three cases of pertussis with cleft nucleus lymphocytes in young infants were discussed in in the neonatal/pediatric intensive care unit in our hospital. Leukocytosis characterized by lymphocytes, as well as thrombocytosis were observed in all patients. Our results demonstrated that cleft nucleus lymphocytosis accompanied with leukocytosis and lymphocytes would be potent assistant indicators for the early diagnosis of pertussis in young children.

Crystallinity and morphology of perovskite films can greatly influence the performance of perovskite solar cells (Pero-SCs) in terms of charge carrier generation and transportation. Incorporation of Cl (from either PbCl2 or CH3NH3Cl) in crystal growth of CH3NH3PbI3 is known as an effective method to acquire larger crystal grains and longer carrier diffusion length. It has been reported that an intermediate phase of CH3NH3PbCl3 was usually observed during crystallization, which should be critical to the quality of the resulting perovskite, however, how the intermediate phase influence the crystal growth was lack of comprehensive understanding. In this study, through varying the mixing ratio of the precursors PbI2:2CH3NH3I and PbCl2:3CH3NH3I, we were able to systematically tune the content and the converting time of CH3NH3PbCl3. We found that suppressing the formation of CH3NH3PbCl3 within the as-cast films can effectively improve the quality (crystallinity and morphology) of the resulting perovskite films. The improvement led to significant enhancement of the performance of the corresponding p-i-n planar Pero-SCs. Under optimized conditions, the best PCE was increased from 12.8% to 16.2%, which should be attributed to the alleviated charge recombination due to the improved quality of perovskite films by suppressing the formation of CH3NH3PbCl3.

Organic redox flow batteries receive increasing interest for large-scale electrical energy storage owing to the structural diversity and elemental abundance of organic compounds. However, their implementation is challenged by the cyclability, which is an order of magnitude lower than traditional redox flow batteries using inorganic redox couples. The unsatisfactory cyclability mainly arises from electrolyte contamination and irreversible losses of active material in the electrolyte. To address such issues, a highly water-soluble artificial bipolar molecule containing cathode-active ferrocene moiety and anode-active bipyridinium moiety is realized and used as the sole active material in a symmetric organic redox flow cell. Owing to the good reversibility, minimum electrolyte contamination, and stability of the synthesized molecule, the demonstrated cell boosts the cyclability to 4000 cycles with capacity retention of ca. 75% at 100% depth of discharge, which fills in the gap of cyclability between organic redox flow batteries and conventional redox flow batteries.

Morphological engineering plays a very important role to the performance of perovskite solar cells. In this study, 3,4-dihydroxybenzhydrazide employes as an additive in the perovskite precursor to control the crystallization kinetics. It is found that the doping of 3,4-dihydroxybenzhydrazide led to increase of grain size and decrease of grain boundaries, both of which facilitate charge transportation and suppress charge recombination within the photoactive layers. Consequently, the power conversion efficiencies of the corresponding perovskite solar cells are significantly enhanced, and a champion power conversion efficiencies of 17.58% with open circuit voltage of 1.06 V, short circuit current density of 21.40 mA cm−2 and fill factor of 79.1% is achieved, which is 21.5% higher than that without 3,4-dihydroxybenzhydrazide (14.47%). Moreover, upon doping the stability of the perovskite solar cells is also improved. We believe that the idea demonstrated in this research can also be applied to other lead-based perovskite systems.

Cancer stem cells (CSCs) have been implicated in metastasis, relapse, and therapeutic resistance of cancer, so successful cancer therapy may therefore require the development of drugs against CSCs or combining anti-CSCs drugs with conventional therapies. The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently activated signaling pathways in human cancer, playing a central role in tumorigenesis as well as the maintenance of CSCs. Here, we designed and identified B591, a dihydrobenzofuran-imidazolium salt, as a novel specific pan-PI3K inhibitor with potent inhibitory activity against class I PI3K isoforms, which showed effective inhibition of cellular PI3K/mTOR signaling pathway and robust antitumor activity in a set of cancer cell lines. Notably, compared with bulk tumor cell populations, B591 exhibited more potency in suppressing CSCs survival and inducing CSCs apoptosis, and presence of B591 effectively eliminated paclitaxel-enriched CSCs. B591 diminished self-renewal capacity and decreased the expression of epithelial-mesenchymal transition (EMT) markers of CSCs. In vivo, B591 preferentially decreased CSCs levels in mouse xenograft model of human breast cancer as evidenced especially by remarkable reduction of tumor-initiating ability. Consistent with the preferential targeting of CSCs, B591 effectively inhibited breast tumor metastasis and delayed tumor regrowth following paclitaxel treatment. Taken together, our findings establish B591, a novel PI3K inhibitor, as a strong candidate for clinical evaluation as a CSCs targeting agent.

To observe the effects of the Yiqi Qingdu prescription () on intermediate-stage and advanced non-small-cell lung cancer (NSCLC).In total, 300 patients with intermediate-stage or advanced NSCLC were randomly and equally divided into three groups using computer-generated random numbers as follows: Western medicine (WM), Chinese medicine (CM), and integrated Traditional Chinese and Western Medicine (IM). After 3 months of treatment, the overall response rate (ORR); disease control rate (DCR); symptom score (SS); Karnofsky performance status (KPS); adverse event score; counts of CD3 + , CD4 + , and CD8 + cells; CD4 + /CD8 + ratio; and carcinoembryonic antigen (CEA) level were compared among the groups.The ORRs were 30.36% , 20.24% , and 7.87% in the IM, CM, and WM groups, respectively, whereas the DCRs were 85%, 75%, and 73%, respectively. Compared to the CM group, the ORR was significantly higher in the WM and IM groups, whereas the DCR was significantly higher in the IM group (all P0.05). SS was obviously higher in the WM group than in the other two groups (both P0.01). KPS was significantly lower in the WM group after treatment (P = 0.005). The mean number of adverse events was significantly lower in the CM (2.2 ± 1.3) and IM (2.4 ± 1.3) groups than in the WM group (4.6 ± 1.7, both P0.05). CD3 + cell counts were significantly decreased in the WM group (P = 0.031). In the IM group, CD8+ cell counts were increased after treatment, whereas the CD4 + /CD8 + ratio was decreased (both P0.01). Compared with the WM group, CD3 + (P = 0.01), CD4 + (P = 0.044), and CD8 + (P = 0.009) cell counts were significantly higher in the IM group, whereas the CD4+ /CD8+ ratio was significantly lower (P = 0.011). Relative to the CM group, CD8 + cell counts were significantly higher (P = 0.001) and the CD4+ /CD8+ ratio was significantly lower in the IM group (P = 0.001). CEA levels were significantly increased in the CM group (P = 0.023).The Yiqi Qingdu prescription can improve the outcomes of WM in patients with NSCLC.

Herpes simplex virus 1 (HSV-1) is very successful in establishing acute and latent infections in humans by counteracting host antiviral innate immune responses. HSV-1 has evolved various strategies to evade host antiviral innate immunity and some cellular survival-associated pathways. Since there is still no vaccine available for HSV-1, a continuous update of information regarding the interaction between HSV-1 infection and the host antiviral innate immunity will provide novel insights to develop new therapeutic strategies for HSV-1 infection and its associated diseases. Here, we update recent studies about how HSV-1 evades the host antiviral innate immunity, specifically how HSV-1 proteins directly or indirectly target the adaptors in the antiviral innate immunity signaling pathways to downregulate the signal transduction. Additionally, some classical intracellular stress responses, which also play important roles in defense of viral invasion, will be discussed here. With a comprehensive review of evasion mechanisms of antiviral innate immunity by HSV-1, we will be able to develop potential new targets for therapies and a possible vaccine against HSV-1 infections.

Cancer-associated bone disease is a frequent occurrence in cancer patients and is associated with pain, bone fragility, loss, and fractures. However, whether primary or non-bone metastatic gastric cancer induces bone loss remains unclear. Here, we collected clinical evidence of bone loss by analyzing serum and X-rays of 25 non-bone metastatic gastric cancer patients. In addition, C57BL mice were injected with the human gastric cancer cell line HGC27 and its effect on bone mass was analyzed by Micro-CT, immunoblotting, and immunohistochemistry. Furthermore, the degree of the proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs) co-cultured with HGC-27 or SGC-7901 cells was analyzed by colony-formation assay, alizarin red staining, immunofluorescence, qPCR, immunoblotting, and alkaline phosphatase activity assay. These indicated that gastric cancer could damage bone tissue before the occurrence of bone metastases. We also found that cilia formation of MSCs was increased in the presence of HGC27 cells, which was associated with abnormal activation of the Wnt/β-catenin pathway. Expression of DKK1 inhibited the Wnt/β-catenin signaling pathway and partially rescued osteogenic differentiation of MSCs. In summary, our results suggest that gastric cancer cells might cause bone damage prior to the occurrence of bone metastasis via cilia-dependent activation of the Wnt/β-catenin signaling pathway.

Background: Long non-coding RNAs (lncRNAs) have been reported to play an important role in tumorigenesis and metastasis of human colorectal cancer (CRC). However, the specific role of LincHOXA10 in CRC remains unknown.Methods: The expression of LincHOXA10 and HOXA10 in CRC cells and tissue samples was measured by quantitative reverse transcription PCR (qRT-PCR). The protein expression of HOXA10, E-cadherin, N-cadherin, Vinmentin, p-smad2 and p-smad3 was assessed by Western blotting or immunofluorescence staining. Cell proliferation, migration, and invasion were assessed by the MTT and transwell assays. Tumor growth in vivo was carried out by subcutaneous tumor formation in nude mice.Results: In the present study, we found that LincHOXA10 expression was significantly higher in human CRC tissues than the paired normal tissues. In fact, LincHOXA10 level correlated with the CRC tumor sizes and lymphatic metastasis. In cultured CRC cells, knockdown of LincHOXA10 inhibited cell proliferation, migration and invasion. LincHOXA10 deficiency also attenuated CRC tumor growth in vivo. Mechanistically, LincHOXA10 interacted with HOXA10 and regulated its expression. HOXA10 levels were interrelated to the LincHOXA10 level in CRC cells. Functionally, HOXA10 was essential for TGF-β1/SMADs-induced epithelial -mesenchymal transition of CRC cells, and HOXA10 played a critical role in mediating the function of LincHOXA10. Importantly, HOXA10 expression was significantly up-regulated in human CRC tissues.Conclusions: LincHOXA10 facilitates CRC development and metastasis via regulating HOXA10-mediated epithelial-mesenchymal transition of CRC cells.

Interferon-γ (IFN-γ) is a critical cytokine in the defense against viral and bacterial infection. It is mainly produced by natural killer cells and activated T cells. Given its regulatory role in coordinating cellular and humoral immune responses, IFN-γ is considered to be an effective therapeutic agent in the treatment of viral infection. Here we established a fluorescence-based high-content screening model to find small molecules that can stimulate the production of IFN-γ in human Jurkat cells. After a primary screening of 267 natural products, two hits, Astragalus polyphenols and 6-shogaol, were identified to promote the activity of the IFN-γ promoter and subsequently validated by the flow cytometry assay. Obviously, both Astragalus polyphenols and 6-shogaol exhibited potential to induce the transcription and expression of IFN-γ in a dose-dependent manner. These results indicated that our high-content screening model could be a credible and useful platform to contribute to the discovery of novel molecules to promote the expression of IFN-γ and provide leading compounds for the treatment of viral infectious diseases.

The natural killer group 2D (NKG2D) receptor on natural killer (NK) cells play an important role in immunosurveillance to cancer cells, which could mediate the eradication of tumor cells through specific interactions with NKG2D ligands on tumor cells. Here we report one natural compound aurovertin B from basidiomycete Albatrellus confluens significantly stimulates the expression of NKG2D ligands on tumor cells, which greatly sensitizes its recognition and lysis by NK cell. It is completely a novel role for aurovertin B to target tumor cells to death mediated by NK cells and our findings indicate aurovertin B may deserve further development as sensitizing agent in NK cell mediated cancer immunotherapy.

The performance of non-viral gene delivery vehicles, especially cationic polymers, is often challenged by the multiple cellular barriers that pose inconsistent requirements for material properties. A most pronounced inconsistency is exemplified by the molecular weight (MW)-related transfection efficiency and cytotoxicity. In this study, we report the development of photo-degradable, branched poly(β-amino ester)s (BPAE-NB) to realize efficient and photo-controlled DNA and siRNA delivery. BPAE-NB possessing built-in light-responsive 2-nitrobenzene moieties in the polymer backbone was synthesized via the A2 (amine) + B3 (triacrylate) + C2 (diacrylate) polycondensation reaction from 4-amino-1-butanol (A2), trimethylolpropane triacrylate (B3), and (2-nitro-1,3-phenylene)bis(methylene) diacrylate (NPBMDA, C2). The highly branched BPAE-NB with the multivalent arrangement of cationic groups provides stronger nucleic acid binding capacity than its linear analogue LPAE-NB, and thus features stronger trans-membrane gene delivery capabilities and higher transfection efficiencies. Upon UV light irradiation, the backbone of BPAE-NB can quickly degrade into low-MW fragments as a consequence of the cleavage of the light-responsive 2-nitrobenzene, thus promoting intracellular gene release and diminishing the toxicity of materials at the post-transfection state. As such, in multiple mammalian cells, BPAE-NB exhibited remarkably higher DNA/siRNA transfection efficiency yet lower cytotoxicity than its non-responsive analogue BPAE-CC upon light irradiation, notably outperforming commercial reagents PEI 25k and Lipofectamine 2000. This study therefore provides an effective topology- and photo-controlled approach to precisely manipulate the transfection efficiency and toxicity of polycationic gene vectors, and may also provide promising additions to the existing non-viral gene delivery vectors.

Objective The natural killer (NK) group 2D (NKG2D) receptor plays a crucial role in NK cell-mediated anti-tumor immunity. NKG2D anti-proliferative effect is mediated by direct interactions of the receptor with its ligands that may be considered as a potential target for NK-based immunotherapeutic strategy in cancer cells. Methods Here we report that a natural product adenanthin significantly promotes NKG2D ligands expression in hepatoma cells. The effect was determined using flow cytometry analysis. The activity of NK cell was evaluated by measuring its degranulation activity and cytotoxicity. Results Our data indicates that the induction of NKG2D ligand binding to liver cancer cell surface receptors greatly improves the killing activity of NK cells against the cancer cells. Conclusions This is the first report of a new mechanism anti-cancer effects of adenanthin mediated by an indirect activation of NK cells. Our data suggests that adenanthin may be used to sensitize NK cells in tumor immunotherapy.

Aberrant activation of Wnt/β-catenin signaling is closely associated with the development of various human cancers, especially colorectal cancers (CRC). The ubiquitin proteasome system (UPS) is essential in the regulation of Wnt signaling and inhibitors targeting the UPS could have great potential in CRC therapy. Ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, plays a significant role in neoplastic diseases due to its well-known function of regulating the MDM2-p53 complex. Inspired by our recent study identifying the positive role of USP7 in the Wnt signaling, we report here that USP7 is overexpressed in colorectal carcinoma cell lines and tissues, which is closely related with the poor prognosis. USP7 knockdown inhibits the proliferation of CRC cells with different p53 status, and USP7 inhibition by its inhibitor P5091 attenuates the activity of Wnt signaling via enhanced ubiquitination and the subsequent degradation of β-catenin. In vitro, P5091 inhibited the proliferation and induced apoptosis of CRC cells. P5091 also suppressed in vivo tumor growth in the HCT116 xenograft mouse model, which is consistently associated with reduced expression of β-catenin and Wnt target genes. In conclusion, our preclinical study indicated that USP7 could be a potential drug target and its inhibitor P5091 deserves further development as anticancer agent for Wnt hyper-activated CRC therapy.

Redox imbalance is resulted from the destruction of balance between oxidants and antioxidants. The dominant oxidants are reactive oxygen species (ROS), which are involved in multiple cellular processes by physiologically transporting signal as a second messenger or pathologically oxidizing DNA, lipids, and proteins. Generally speaking, low concentration of ROS is indispensable for cell survival and proliferation. However, high concentration of ROS is cytotoxic. Additionally, ROS are now known to induce the oxidative modification of macromolecules especially proteins. The redox modification of proteins is involved in numerous biological processes related to diseases including CRC. Herein, we attempt to afford an overview that highlights the crosstalk between redox imbalance and CRC.

The biological function of microRNA-4513 (miR-4513) in human cancers is emerging. However, it remains unknown whether miR-4513 has a role in breast cancer (BC). In this study, we analyzed the expression of miR-4513 and tripartite motif containing 3 (TRIM3) in BC cell lines. The biological roles of miR-4513 and TRIM3 in BC were analyzed by cell counting kit-8 assay, colony formation assay, wound healing assay, and transwell invasion assay. The effects of miR-4513 or TRIM3 expression on the overall survival of BC patients were analyzed at Kaplan-Meier plotter website. We found miR-4513 expression was upregulated, whereas TRIM3 expression was downregulated in BC cell lines. Importantly, high miR-4513 or low TRIM3 expression was revealed as predictors for poorer overall survival of BC patients. Luciferase activity assay and western blot assay revealed TRIM3 was a direct target of miR-4513. Moreover, we showed miR-4513 was able to regulate BC cell proliferation, colony formation, cell migration, and cell invasion through regulating TRIM3. Taken together, our results suggested miR-4513 functions as an oncogene in the progression of BC and, therefore, miR-4513 may be validated as a potential therapeutic target in the future.

Near-infrared (NIR) organic fluorescent probes have attracted great deal of attention for application in cell imaging, where the probes demand good water solubility, strong emission and good cytocompatibility. In this study, a conjugate of anthraquinone and tetraphenylethylene is introduced into an amphiphile (denoted by BTPEAQ-10) with four pyridinium terminated aliphatic chains. The assemblies of BTPEAQ-10 show an NIR emission peaked at 670 nm. Ionic co-assembly with sodium dodecyl benzene sulfonate leads to drastic enhancement of the fluorescent emission to 30-fold. Controlling experiments on different surfactants and anionic groups show that both the hydrophilic group and the alkyl chain play critical role to the emission enhancement. Both the assemblies and co-assemblies have good water solubility and cytocompatibility, and were applied in cell imaging. The co-assemblies showed much better contrast of cell imaging due to the higher emission property.

In this study, we synthesized an amphiphilic α-cyanostilbene derivative (E-form)-1-(12-(2-(2-(benzo[d]thiazol-2-yl)-2-cyanovinyl)-5-(diethylamino)phenoxy)dodecyl)pyridin-1-ium bromide (denoted by BCPB). As being dissolved in aqueous solution, BCPB shows strong emission of excimers at around 660 nm due to the formation of aggregates. Addition of different amount of CB[7] into the solution leads to the emission shift from 660 nm, firstly to 540 nm and then to 588 nm. The emission shift is attributed to the two-step assembly driven by the concentration of CB[7], and the molar ratios of CB[7]/BCPB (denoted by Rm) play a critical role for the shift. As Rm ≤ 4, CB[7] mainly interacts with the cationic pyridinium group of BCPB to form BCPB@CB[7] complex. As Rm > 4, another CB[7] binds to the diethylamino group at one end of α-cyanostilbene to form BCPB@CB[7]2 complex. The two-step assembly well explains the emission shift of BCPB.

Aberrant activation of Wnt signaling plays a critical role in the initiation and progression of colorectal cancer (CRC). Chlorquinaldol (CQD) is a topical antimicrobial agent used to treat skin infections. Little is known about the anticancer activity of CQD and its underlying mechanisms. In this study, CQD was demonstrated to inhibit Wnt/β-catenin signaling through targeting the downstream part of this pathway. The results showed that CQD could inhibit the acetylation of β-catenin and disrupt the interaction of β-catenin with T-cell factor 4 (TCF4), leading to reduced binding of β-catenin to the promoters of Wnt target genes and downregulation of the expression of these target genes. Moreover, treatment with CQD suppressed the proliferation, migration, invasion and stemness of CRC cells. In APCmin/+ mice and CRC cell xenografts, administration of CQD suppressed tumor growth and the expression of Wnt target genes c-Myc and Leucine-rich G protein-coupled receptor-5 (LGR5). These results strongly suggest that CQD may be a promising therapeutic agent in the treatment of CRC.

Understanding the mechanisms behind melanoma brain metastasis, a disease that continues to portend a poor prognosis, will lead to the identification and development of novel drug targets. We previously identified PLEKHA5, a gene involved in brain development, as a novel molecule implicated in melanoma brain metastasis. Our aim was to further characterize the function of this protein in brain-tropic melanoma. We established stable loss- and gain-of-function cell lines to explore the underlying mechanisms of PLEKHA5-mediated tumor growth. The effect of PLEKHA5 expression silencing on proliferation and tumor growth was assessed using both in vitro systems and xenograft models of brain-tropic melanomas, respectively. The clinical relevance of PLEKHA5 dysregulation in brain metastasis was also investigated in two unique cohorts of melanoma patients with cerebrotropic disease and included analysis of matched cranial and extra-cranial specimens. Knock-down of PLEKHA5 in brain-tropic melanoma cells negatively regulated cell proliferation by inhibiting G1 to S cell cycle transition. This coincided with up-regulation of PDCD4, p21, and p27, as well as the downregulation of pRb protein, involved in the regulation of cell cycle. Conversely, the ectopic re-expression of PLEKHA5 had an inverse effect. Subcutaneous and direct cranial injections of PLEKHA5 knock-down cells in nude mice significantly inhibited tumor growth, while its overexpression upregulated the growth of tumors. This reduction in tumor growth in vivo might be attributed to decreased phosphorylation of Akt (S473) and mTOR (S2448), key mediators for tumor growth and survival. Our results demonstrate the role of PLEKHA5 as a mediator of melanoma brain metastasis. Our findings highlight the significance of PLEKHA5 as a possible regulator of cell cycle transition via crosstalk with the ubiquitin-proteasome and PI3K/AKT/mTOR signaling pathways, driving the proliferation and growth of brain-tropic melanomas. Our studies suggest that PLEKHA5 targeting should be further investigated for melanoma brain metastasis patient population.

Polypyrrole nanowires/graphene (PPyNG) nanocomposites as anticorrosive fillers were prepared by in situ polymerization in order to improve the anticorrosion performance of waterborne epoxy coatings. Field emission scanning electron microscope (FESEM) and Fourier transform infrared spectroscopy (FTIR) characterized the morphologies and structures of the synthesized PPyNG. The polypyrrole nanowires with about 50 nm in diameter were obtained. Conjugation length of PPy was increased with the addition of graphene. Open circuit potential (OCP) measurements, Tafel polarization curves, and electrochemical impedance spectroscopy (EIS) using an electrochemical workstation evaluated the anticorrosion properties of the waterborne epoxy/PPyNG coatings (EPPyNG). The studied nanocomposite coating possessed superior corrosion protection performance when the graphene content of the filler was 2 wt %. Its corrosion rate was about 100 times lower than that of neat epoxy coating. The higher barrier properties of nanocomposite coating and passivation effect of polypyrrole nanowires were beneficial in corrosion protection.