Thiol-Disulfide Exchange Coordinates the Release of Nitric Oxide and Dexamethasone for Synergistic Regulation of Intestinal Microenvironment in Colitis.

The cell-specific functions of nitric oxide (NO) in the intestinal microenvironment orchestrate its therapeutic effects in ulcerative colitis. While most biomaterials show promise by eliciting the characteristics of NO, the insufficient storage, burst release, and pro-inflammatory side effects of NO remain as challenges. Herein, we report the development of thiol-disulfide hybrid mesoporous organosilica nanoparticles (MONs) that improve the storage and sustained release of NO, broadening the therapeutic window of NO-based therapy against colitis. The tailored NO-storing nanomaterials coordinated the release of NO and the immunoregulator dexamethasone (Dex) in the intestinal microenvironment, specifically integrating the alleviation of oxidative stress in enterocytes and the reversal of NO-exacerbated macrophage activation. Mechanistically, such a synchronous operation was achieved by a self-motivated process wherein the thiyl radicals produced by NO release cleaved the disulfide bonds to degrade the matrix and release Dex via thiol-disulfide exchange. Specifically, the MON-mediated combination of NO and Dex greatly ameliorated intractable colitis compared with 5-aminosalicylic acid, even after delayed treatment. Together, our results reveal a key contribution of synergistic modulation of the intestinal microenvironment in NO-based colitis therapy and introduce thiol-disulfide hybrid nanotherapeutics for the management of inflammatory diseases and cancer.

A Design of Quad-Element Dual-Band MIMO Antenna for 5G Application.

A dual-band four-element MIMO antenna was designed and fabricated with enhanced isolation. The introduced antenna was fed by a coplanar waveguide (CPW) and consisted of four identical monopole antenna elements placed perpendicular to each other. A cross-shaped stub and orthogonal placement of four elements were introduced for high isolation. Modified ground structure was used for extending bandwidths. The measured results demonstrate that the introduced antenna has double bands (S11 < -10 dB) covering 3.28-4.15 GHz and 4.69-6.01 GHz, with fractional bandwidths of 23.4% and 24.7% and a high isolation S21, S31 better than 19 dB. The curves of the envelope correlation coefficient (ECC) and diversity gain (DG) were less than 0.0025 and higher than 9.999, respectively, indicating a low correlation between antenna elements. Furthermore, gain, efficiency, channel capacity loss (CCL), total active reflection coefficient (TARC) and mean effective gain (MEG) have all been investigated over the operating band to determine the antenna's diversity performance. In accordance with the simulated and measured results, it confirms that the proposed antenna is appropriate for 5G applications.

Altered gut microbiome composition by appendectomy contributes to colorectal cancer.

Appendectomy impacts the homeostasis of gut microbiome in patients. We aimed to study the role of appendectomy in colorectal cancer (CRC) risk through causing gut microbial dysbiosis. Population-based longitudinal study (cohort 1, n = 129,155) showed a 73.0% increase in CRC risk among appendectomy cases throughout 20 years follow-up (Adjusted sub-distribution hazard ratio (SHR) 1.73, 95% CI 1.49-2.01, P < 0.001). Shotgun metagenomic sequencing was performed on fecal samples from cohort 2 (n = 314). Gut microbial dysbiosis in appendectomy subjects was observed with significant enrichment of 7 CRC-promoting bacteria (Bacteroides vulgatus, Bacteroides fragilis, Veillonella dispar, Prevotella ruminicola, Prevotella fucsa, Prevotella dentalis, Prevotella denticola) and depletion of 5 beneficial commensals (Blautia sp YL58, Enterococcus hirae, Lachnospiraceae bacterium Choco86, Collinsella aerofaciens, Blautia sp SC05B48). Microbial network analysis showed increased correlation strengths among enriched bacteria and their enriched oncogenic pathways in appendectomy subjects compared to controls. Of which, B. fragilis was the centrality in the network of the enriched bacteria. We further confirmed that appendectomy promoted colorectal tumorigenesis in mice by causing gut microbial dysbiosis and impaired intestinal barrier function. Collectively, this study revealed appendectomy-induced microbial dysbiosis characterized by enriched CRC-promoting bacteria and depleted beneficial commensals, signifying that the gut microbiome may play a crucial role in CRC development induced by appendectomy.

Bioactive Injectable Hydrogel Dressings for Bacteria-Infected Diabetic Wound Healing: A "Pull-Push" Approach.

Chronic diabetic wound healing remains a challenge due to the existence of excessive danger molecules and bacteria in the inflammatory microenvironment. There is an urgent need for advanced wound dressings that target both inflammation and infection. Here, a bioactive hydrogel without loading any anti-inflammatory ingredients is rationally designed to achieve a "Pull-Push" approach for efficient and safe bacteria-infected diabetic wound healing by integrating danger molecule scavenging (Pull) with antibiotic delivery (Push) in the inflammatory microenvironment. The cationic hydrogel, termed the OCMC-Tob/PEI hydrogel, is fabricated by the conjugation of polyethylenimine (PEI) and tobramycin (Tob) on an oxidized carboxymethyl cellulose (OCMC) backbone via the Schiff base reaction with injectable, self-healing, and biocompatible properties. The OCMC-Tob/PEI hydrogel not only displays the remarkable capability of capturing multiple negatively charged danger molecules (e.g., cell-free DNA, lipopolysaccharides, and tumor necrosis factor-α) to ameliorate anti-inflammation effects but also achieves controllable long-term antibacterial activity by the pH-sensitive release of Tob. Consequently, this multifunctional hydrogel greatly expedites the wound closure rate with combined anti-inflammation and anti-infection effects on Pseudomonas aeruginosa-infected diabetic wounds. Our work provides a highly versatile treatment approach for chronic diabetic wounds and a promising dressing for regenerative medicine.

The Role of TMIGD1 as a Tumor Suppressor in Colorectal Cancer.

Background: Colorectal cancer (CRC) is one of the leading causes of cancer-related death, and up to 50% of individuals will suffer relapse. Although transmembrane and immunoglobulin domain-containing protein 1 (TMIGD1) was found to be a protective factor in several renal and intestinal diseases, the specific role of TMIGD1 in CRC remains unclear. Objective: To determine the tumor suppressor TMIGD1 expression and its function in inhibiting CRC. Methods: We analyzed three Gene Expression Omnibus (GEO) datasets through the GEO2R online tool to obtain the set of differentially expressed genes (DEGs) between CRC and normal tissues, and further analyzed the TMIGD1 gene's expression in databases. Real-time quantitative polymerase chain reaction and western blot assays were used to investigate expression of TMIGD1. Transwell and wound healing assays were performed to detect the migration and invasion ability. Cell Counting Kit-8 (CCK-8) and colony formation assays were used to evaluate cell proliferation. In vivo studies were conducted to illustrate the tumorigenicity. Results: We found that the TMIGD1 gene is one of the highly downregulated genes in CRC through bioinformatic analysis. We also showed that downregulation of TMIGD1 is associated with poor overall survival rate of CRC based on The Cancer Genome Atlas (TCGA) databases. In addition, we showed that overexpression of TMIGD1 protein significantly impaired the metastasis and proliferation ability of the CRC cells. Finally, TMIGD1 also repressed subcutaneous tumorigenesis of CRC cells in vivo. Conclusion: Our findings indicate that downregulation of TMIGD1 may promote CRC progression and invasion. Therefore, TMIGD1 may serve as a biomarker for CRC prognoses.

A nanoparticulate dual scavenger for targeted therapy of inflammatory bowel disease.

A therapeutic strategy that targets multiple proinflammatory factors in inflammatory bowel disease (IBD) with minimal systemic side effects would be attractive. Here, we develop a drug-free, biodegradable nanomedicine that acts against IBD by scavenging proinflammatory cell-free DNA (cfDNA) and reactive oxygen species (ROS). Polyethylenimine (PEI) was conjugated to antioxidative diselenide-bridged mesoporous organosilica nanoparticles (MONs) to formulate nanoparticles (MON-PEI) that exhibited high cfDNA binding affinity and ROS-responsive degradation. In ulcerative colitis and Crohn's disease mouse colitis models, orally administered MON-PEI accumulated preferentially in the inflamed colon and attenuated colonic and peritoneal inflammation by alleviating cfDNA- and ROS-mediated inflammatory responses, allowing a reduced dose frequency and ameliorating colitis even after delayed treatment. This work suggests a new nanomedicine strategy for IBD treatment.

Selenium-Containing Amino Acids Protect Dextran Sulfate Sodium-Induced Colitis via Ameliorating Oxidative Stress and Intestinal Inflammation.

BACKGROUND: Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation of the gastrointestinal tract. Oxidative stress plays a pivotal role in the pathogenesis of IBD. Selenium-containing amino acids reportedly have anti-oxidative and anti-inflammatory properties, but it remains unknown if selenium-containing amino acids can be used to treat IBD. This study aimed to investigate the effects of two selenium-containing amino acids - selenocysteine and selenocystine - on oxidative stress and chronic inflammation in a mouse model of dextran sulfate sodium (DSS)-induced IBD. METHODOLOGY: C57BL/6 mice were randomly assigned to the following six groups: control, DSS, DSS+selenocysteine, DSS+selenocystine, DSS+sodium selenite, and DSS+N-acetylcysteine (NAC). IBD was induced by 3% DSS. Pro-inflammatory cytokines [interleukin-1ß (IL-1ß), monocyte chemotactic protein 1 (MCP-1), IL-6, and tumor necrosis factor-α (TNF-α)] and markers for oxidative and anti-oxidative stress [malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione peroxidase (GPx)] were measured using immunohistochemical analysis. RESULTS: Selenocysteine and selenocystine significantly attenuated IBD-related symptoms, including preventing weight loss, decreasing disease activity index (DAI) scores, and increasing colon length. Selenocysteine and selenocystine significantly ameliorated the DSS-induced oxidative stress, as demonstrated by a reduction in ROS and MDA activity and an increase in SOD and GPx activity. IL-1, MCP-1, IL-6, and TNF-α levels were significantly increased in the IBD mice, while treatment with the selenium-containing amino acids significantly reduced the levels of these pro-inflammatory cytokines. In vivo safety analysis showed minimal side effects of the selenium-containing amino acids. CONCLUSION: We found that selenocysteine and selenocystine ameliorated DSS-induced IBD via reducing oxidative stress and intestinal inflammation, indicating that selenium-containing amino acids could be a novel therapeutic option for patients with IBD.

One-pot synthesis of chlorhexidine-templated biodegradable mesoporous organosilica nanoantiseptics.

Chlorhexidine (CHX) is a widely used antiseptic in various infection control practices. In this work, we have developed biodegradable mesoporous organosilica nanoparticles (MONs) through a one-pot synthesis by employing CHX as a bifunctional agent that not any acts as a cationic template to form the structure of mesopores but also serves as a broad-spectrum antiseptic. The resulting CHX@MONs exhibit a relatively high CHX content and glutathione (GSH)-responsive release of CHX via a matrix-degradation-controlled mechanism, leading to comparable antibacterial effects with CHX on both Escherichia coli and Staphylococcus aureus. Furthermore, the effective antibacterial concentration of CHX@MONs shows less cytotoxicity toward normal cells. Our findings will help increase the use of CHX as an antiseptic agent, especially for responsive drug release upon bacterial infection.

MicroRNA-1269 promotes cell proliferation via the AKT signaling pathway by targeting RASSF9 in human gastric cancer.

BACKGROUND: MicroRNAs (miRNAs) play key roles in tumorigenesis and progression of gastric cancer (GC). miR-1269 has been reported to be upregulated in several cancers and plays a crucial role in carcinogenesis and cancer progression. However, the biological function of miR-1269 in human GC and its mechanism remain unclear and need to be further elucidated. METHODS: The expression of miR-1269 in GC tissues and cell lines was detected by quantitative real-time PCR (qRT-PCR). Target prediction programs (TargetScanHuman 7.2 and miRBase) and a dual-luciferase reporter assay were used to confirm that Ras-association domain family 9 (RASSF9) is a target gene of miR-1269. The expression of RASSF9 was measured by qRT-PCR and Western blotting in GC tissues. MTT and cell counting assays were used to explore the effect of miR-1269 on GC cell proliferation. The cell cycle and apoptosis were measured by flow cytometry. RASSF9 knockdown and overexpression were used to further verify the function of the target gene. RESULTS: We found that miR-1269 expression was upregulated in human GC tissues and cell lines. The overexpression of miR-1269 promoted GC cell proliferation and cell cycle G1-S transition and suppressed apoptosis. The inhibition of miR-1269 inhibited cell growth and G1-S transition and induced apoptosis. miR-1269 expression was inversely correlated with RASSF9 expression in GC tissues. RASSF9 was verified to be a direct target of miR-1269 by using a luciferase reporter assay. The overexpression of miR-1269 decreased RASSF9 expression at both the mRNA and protein levels, and the inhibition of miR-1269 increased RASSF9 expression. Importantly, silencing RASSF9 resulted in the same biological effects in GC cells as those induced by overexpression of miR-1269. Overexpression of RASSF9 reversed the effects of miR-1269 overexpression on GC cells. Both miR-1269 overexpression and RASSF9 silencing activated the AKT signaling pathway, which modulated cell cycle regulators (Cyclin D1 and CDK2). In contrast, inhibition of miR-1269 and RASSF9 overexpression inhibited the AKT signaling pathway. Moreover, miR-1269 and RASSF9 also regulated the Bax/Bcl-2 signaling pathway. CONCLUSIONS: Our results demonstrate that miR-1269 promotes GC cell proliferation and cell cycle G1-S transition by activating the AKT signaling pathway and inhibiting cell apoptosis via regulation of the Bax/Bcl-2 signaling pathway by targeting RASSF9. Our findings indicate an oncogenic role of miR-1269 in GC pathogenesis and the potential use of miR-1269 in GC therapy.

Clinical feasibility and safety of third space robotic and endoscopic cooperative surgery for gastric gastrointestinal stromal tumors dissection : A new surgical technique for treating gastric GISTs.

BACKGROUND: Surgical management of gastric gastrointestinal stromal tumors (GISTs) has evolved towards minimal invasiveness. Laparoscopic wedge resection and laparoscopic and endoscopic cooperative surgery had been considered as standard surgical treatments for gastric GISTs > 2 cm. However, stomach deformation and the full-thickness gastric defect caused by these procedures may increase the risk of morbidity. To address these problems, we developed a novel technique, third space robotic and endoscopic cooperative surgery (TS-RECS), which could dissect the tumor entirely while preserving the intact mucosal layer. Here we performed a prospective evaluation of the feasibility and safety of TS-RECS. METHODS: Patients with gastric GISTs were recruited between April 2018 and April 2019. During the operation, the gastric GIST was located by endoscopic view firstly and the submucosal injection was performed. The tumor was then dissected through robotic surgery. Clinicopathological characteristics, operative data, adverse events, and follow-ups were prospectively collected and analyzed. RESULTS: A total of 20 patients with gastric GISTs received TS-RECS. The mean tumor size was 33.0 ± 7.3 mm. R0 resection was achieved in all patients with a median operation time of 115 min and a median blood loss of 20 ml. The integrity of mucosal layer was maintained in 95% (19/20) of the patients. All patients started oral diet on postoperative day 1 or 2, staying in the hospital for a median of 6 days after surgery. There were no major adverse events. Local or distant recurrences were not observed during a median follow-up period of 10 months. CONCLUSIONS: Our study suggests that TS-RECS appears to be a feasible and safe technique which could be an alternative method for resecting gastric GISTs > 2 cm. CLINICAL TRIALS: ClinicalTrials.gov NCT03804762.

Identification of serum proteins AHSG, FGA and APOA-I as diagnostic biomarkers for gastric cancer.

BACKGROUND: The development of clinically accessible biomarkers is critical for the early diagnosis of gastric cancer (GC) in patients. High-throughput proteomics techniques could not only effectively generate a serum peptide profile but also provide a new approach to identify potentially diagnostic and prognostic biomarkers for cancer patients. METHODS: In this study, we aim to identify potentially discriminating serum biomarkers for GC. In the discovery cohort, we screened potential biomarkers using magnetic-bead-based purification and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in 64 samples from 32 GC patients that were taken both pre- and post-operatively and 30 healthy volunteers that served as controls. In the validation cohort, the expression patterns and diagnostic values of serum FGA, AHSG and APOA-I were further confirmed by ELISA in 42 paired GC patients (pre- and post-operative samples from 16 patients with pathologic stage I/II and 26 with stage III/IV), 30 colorectal cancer patients, 30 hepatocellular carcinoma patients, and 28 healthy volunteers. RESULTS: ClinProTools software was used and annotated 107 peptides, 12 of which were differentially expressed among three groups (P < 0.0001, fold > 1.5). These 12 peptide peaks were further identified as FGA, AHSG, APOA-I, HBB, TXNRD1, GSPT2 and CAKP5. ELISA data suggested that the serum levels of FGA, AHSG and APOA-I in GC patients were significantly different compared with healthy controls and had favorable diagnostic values for GC patients. Moreover, we found that the serum levels of these three proteins were associated with TNM stages and could reflect tumor burden. CONCLUSION: Our findings suggested that FGA, AHSG and APOA-I might be potential serum biomarkers for GC diagnosis.

FOXO1: Another avenue for treating digestive malignancy?

Digestive malignancies are the leading cause of mortality among all neoplasms, contributing to estimated 3 million deaths in 2012 worldwide. The mortality rate hassurpassed lung cancer and prostate cancer in recent years. The transcription factor Forkhead Box O1 (FOXO1) is a key member of Forkhead Box family, regulating diverse cellular functions during tumor initiation, progression and metastasis. In this review, we focus on recent studies investigating the antineoplastic role of FOXO1 in digestive malignancy. This review aims to serve as a guide for further research and implicate FOXO1 as a potent therapeutic target in digestive malignancy.