Matrix mechanics regulate the polarization state of bone marrow-derived neutrophils through the JAK1/STAT3 signaling pathway.

Matrix mechanics regulate essential cell behaviors through mechanotransduction, and as one of its most important elements, substrate stiffness was reported to regulate cell functions such as viability, communication, migration, and differentiation. Neutrophils (Neus) predominate the early inflammatory response and initiate regeneration. The activation of Neus can be regulated by physical cues; however, the functional alterations of Neus by substrate stiffness remain unknown, which is critical in determining the outcomes of engineered tissue mimics. Herein, a three-dimensional (3D) culture system made of hydrogels was developed to explore the effects of varying stiffnesses (1.5, 2.6, and 5.7 kPa) on the states of Neus. Neus showed better cell integrity and viability in the 3D system. Moreover, it was shown that the stiffer matrix tended to induce Neus toward an anti-inflammatory phenotype (N2) with less adhesion molecule expression, less reactive oxygen species (ROS) production, and more anti-inflammatory cytokine secretion. Additionally, the aortic ring assay indicated that Neus cultured in a stiffer matrix significantly increased vascular sprouting. RNA sequencing showed that a stiffer matrix could significantly activate JAK1/STAT3 signaling in Neus and the inhibition of JAK1 ablated the stiffness-dependent increase in the expression of CD182 (an N2 marker). Taken together, these results demonstrate that a stiffer matrix promotes Neus to shift to the N2 phenotype, which was regulated by JAK1/STAT3 pathway. This study lays the groundwork for further research on fabricating engineered tissue mimics, which may provide more treatment options for ischemic diseases and bone defects. STATEMENT OF SIGNIFICANCE.

Combination of DNA Damage, Autophagy, and ERK Inhibition: Novel Evodiamine-Inspired Multi-Action Pt(IV) Prodrugs with High-Efficiency and Low-Toxicity Antitumor Activity.

Exploring multi-targeting chemotherapeutants with advantages over single-targeting agents and drug combinations is of great significance in drug discovery. Herein, we employed phytogenic evodiamine (EVO) and conventional Pt(II) drugs to design and synthesize multi-target EVO-Pt(IV) anticancer prodrugs (4-14). Among them, compound 10 exhibited a 118-fold enhancement in the IC50 value compared to cisplatin and low toxicity to normal cells. Further studies proved that 10 significantly enhanced intracellular Pt accumulation and DNA damage, perturbed mitochondrial membrane potential, inhibited cell migration and invasion, upregulated reactive oxygen species levels, and induced apoptosis and autophagic cell death. Molecular docking assay revealed that 10 fits perfectly into the extracellular signal-regulated protein kinase (ERK)-1 pocket, which was verified to produce profound ERK suppression. Most strikingly, compound 10 exhibited superior in vivo antitumor efficiency and effectively attenuated systemic toxicity. Our results emphasize that functionalizing platinum drugs with the multi-target EVO could generate synergistically excellent anticancer activity with low toxicity and decreased resistance, which may represent a brand-new cancer therapy modality.

Identification of potential serum exosomal microRNAs involved in acinar-ductal metaplasia that is a precursor of pancreatic cancer associated with chronic pancreatitis.

BACKGROUNDS: Due to difficulty in early diagnosis of chronic pancreatitis (CP), it is urgent to find novel biomarkers to detect CP. Exosomal microRNAs (Exo-miRNAs) located in the serum may be potential diagnostic and therapeutic targets for CP. OBJECTIVE: To identify differentially expressed Exo-miRNAs (DE-Exo-miRNAs) in the serum of CP patients, we performed a bioinformatics analysis. METHODS: The dataset GSE128508 was downloaded from the Gene Expression Omnibus (GEO) database. The analysis was carried out using BRB-ArrayTools and significance analysis of microarrays (SAM). The target genes of DE-S-Exo-miRNAs were predicted by miRWalk databases. Further gene ontology (GO) term and Kyoto Encyclopedia of Genomes (KEGG) pathway analyses were performed with plug-in ClueGO in Cytoscape software 3.7.0. Subsequently, the interaction regulatory network between encoded proteins of target genes was performed with the Search Tool for the Retrieval of Interacting Genes (STRING) database and analyzed using plug-in Molecular Complex Detection (MCODE) and cytoHubba in Cytoscape software 3.7.0. RESULTS: We identified 227 DE-Exo-miRNAs in the serum. Further analysis using the miRWalk database identified 5164 target genes of these miRNAs. The protein-protein interaction (PPI) regulatory network of 1912 potential target genes for hub 10 up-regulated miRNAs with high degrees and one down-regulated miRNAs were constructed using the STRING database and Cytoscape software. The functional analysis using Cytoscape software tool highlighted that target genes involved in pancreatic cancer. Acinar-ductal metaplasia (ADM) in the inflammatory environment of CP is a precursor of pancreatic cancer. Subsequently, we constructed a network of target genes associated with ADM and their miRNAs. CONCLUSIONS: Exo-miRNAs in the serum as well as their target genes may be promising targets for the early diagnosis and treatment of CP. In addition, we identified potential Exo-miRNAs involved in ADM that is a precursor of pancreatic cancer associated with CP.

Watching Videos of Colonoscopies and Receiving Interpretations Reduce Pain and Anxiety While Increasing the Satisfaction of Patients.

BACKGROUND: Pain associated with colonoscopies is a major barrier to patients participating in colorectal cancer screenings. While sedation and analgesia are used to reduce pain during the procedure, they are associated with increased complications and costs. Thus, it is necessary to identity novel techniques to relieve pain in a safe and cost-effective way. AIMS: To test whether watching real-time videos of colonoscopies while receiving detailed interpretations of the procedures reduces pain and anxiety and increases a patient's satisfaction. METHODS: Patients were randomized into three groups including a group who watched real-time videos of their colonoscopies (Group A), a group who watched real-time videos of their colonoscopies while receiving detailed interpretations of the procedures from the endoscopists (Group B), and a group who did not receive either method (Group C). RESULTS: Pain and anxiety scores were significantly (Group A vs. Group C, [Formula: see text]; Group B vs. Group C, [Formula: see text]) lower in Groups A and B compared to Group C. Additionally, significantly (Group A vs. Group C, [Formula: see text]; Group B vs. Group C, [Formula: see text]) increased satisfaction was observed in Groups A and B compared to Group C. There were no statistically significant differences observed in the pain and anxiety scores when comparing Groups A and B. However, the overall satisfaction score was significantly ([Formula: see text]) higher in Group B compared to Group A. CONCLUSIONS: Real-time videos of colonoscopies as well as videos along with detailed interpretations of the procedures decrease pain and anxiety while improving satisfaction in patients undergoing colonoscopies without sedation. Videos combined with interpretations lead to a greater increase in patient satisfaction.

Hemophagocytic syndrome as a complication of acute pancreatitis: A case report.

BACKGROUND: Haemophagocytic syndrome (HPS) is rarely seen in patients with acute pancreatitis (AP). HPS as a complication of AP in patients without any previous history has not been elucidated. CASE SUMMARY: A 46-year-old man was admitted for symptom of persistent abdominal pain, nausea, and vomiting for 2 d after heavy drinking. During hospital stay, he suddenly developed skin rash and a secondary fever. The laboratory findings revealed progressive pancytopenia, abnormal hepatic tests, and elevation of serum triglyceride, ferritin, and lactate dehydrogenase levels. However, apparent bacterial or viral infections were not detected. He was also possibly related to autoimmune diseases because of positive expression of various autoimmune antibodies and no remarkable past history. Finally, the bone marrow examination showed a histiocytic reactive growth and prominent hemophagocytosis, which resulted in a diagnosis of HPS. Unexpectedly, the patient responded well to the immunosuppressive therapy. CONCLUSION: HPS is a very rare extrapancreatic manifestation of AP. The diagnosis relies on bone marrow examination and immunosuppressive therapy is effective. For AP with skin changes, the possibility of HPS should be considered during clinical work.