Sprayable and self-healing chitosan-based hydrogels for promoting healing of infected wound via anti-bacteria, anti-inflammation and angiogenesis.

Treatment of infected wound by simultaneously eliminating bacteria and inducing angiogenesis to promote wound tissue regeneration remains a clinical challenge. Dynamic and reversable hydrogels can adapt to irregular wound beds, which have raised great attention as wound dressings. Herein, a sprayable chitosan-based hydrogel (HPC/CCS/ODex-IGF1) was developed using hydroxypropyl chitosan (HPC), caffeic acid functionalized chitosan (CCS), oxidized dextran (ODex) to crosslink through the dynamic imine bond, which was pH-responsive to the acidic microenvironment and could controllably release insulin growth factor-1 (IGF1). The HPC/CCS/ODex-IGF1 hydrogels not only showed self-healing, self-adaptable and sprayable properties, but also exhibited excellent antibacterial ability, antioxidant property, low-cytotoxicity and angiogenetic activity. In vivo experiments demonstrated that hydrogels promoted tissue regeneration and healing of bacteria-infected wound with a rate of approximately 98.4 % on day 11 by eliminating bacteria, reducing inflammatory and facilitating angiogenesis, demonstrating its great potential for wound dressing.

Arenobufagin enhances T-cell anti-tumor immunity in colorectal cancer by modulating HSP90ß accessibility.

BACKGROUND: Colorectal cancer (CRC) is a significant public health issue, ranking as one of the predominant cancer types globally in terms of incidence. Intriguingly, Arenobufagin (Are), a compound extracted from toad venom, has demonstrated the potential to inhibit tumor growth effectively. PURPOSE: This study aimed to explore Are's molecular targets and unravel its antitumor mechanism in CRC. Specifically, we were interested in its impact on immune checkpoint modulation and correlations with HSP90ß-STAT3-PD-L1 axis activity. METHODS: We investigated the in vivo antitumor effects of Are by constructing a colorectalcancer subcutaneous xenograft mouse model. Subsequently, we employed single-cell multi-omics technology to study the potential mechanism by which Are inhibits CRC. Utilizing target-responsive accessibility profiling (TRAP) technology, we identified heatshock protein 90ß (HSP90ß) as the direct target of Are, and confirmed this through a microscale thermophoresis experiment (MST). Further downstream mechanisms were explored through techniques such as co-immunoprecipitation, Western blotting, qPCR, and immunofluorescence. Concurrently, we arrived at the same research conclusion at the organoid level by co-cultivating with immune cells. RESULTS: We observed that Are inhibits PD-Ll expression in CRC tumor xenografts at low concentrations. Moreover, TRAP revealed that HSP90ß's accessibility significantly decreased upon Are binding. We demonstrated a decrease in the activity of the HSP90ß-STAT3-PD-Ll axis following low-concentration Are treatment in vivo. The PDO analysis showed improved enrichment of lymphocytes, particularly T cells, on the PDOs following Are treatment. CONCLUSION: Contrary to previous research focusing on the direct cytotoxicity of Are towards tumor cells, our findings indicate that it can also inhibit tumor growth at lower concentrations through the modulation of immune checkpoints. This study unveils a novel anti-tumor mechanism of Are and stimulates contemplation on the dose-response relationship of natural products, which is beneficial for the clinical translational application of Are.

Facile preparation of fatigue-resistant Mxene-reinforced chitosan cryogel for accelerated hemostasis and wound healing.

The development of highly effective chitosan-based hemostatic materials that can be utilized for deep wound hemostasis remains a considerable challenge. In this study, a hemostatic antibacterial chitosan/N-hydroxyethyl acrylamide (NHEMAA)/Ti3C2Tx (CSNT) composite cryogel was facilely prepared through the physical interactions between the three components and the spontaneous condensation of NHEMAA. Because of the formation of strong crosslinked network, the CSNT cryogel showed a developed pore structure (~ 99.07 %) and superfast water/blood-triggered shape recovery, enabling it to fill the wound after contacting the blood. Its capillary effect, amino groups, negative charges, and affinity with lipid collectively induced rapid hemostasis, which was confirmed by in vitro and in vivo analysis. In addition, CSNT cryogel showed excellent photothermal antibacterial activities, high biosafety, and in vivo wound healing ability. Furthermore, the presence of chitosan effectively prevented the oxidation of MXene, thus enabling the long-term storage of the MXene-reinforced cryogel. Thus, our hemostatic cryogel demonstrates promising potential for clinical application and commercialization, as it combines high resilience, rapid hemostasis, efficient sterilization, long-term storage, and easy mass production.

Sophocarpine alleviates intestinal fibrosis via inhibition of inflammation and fibroblast into myofibroblast transition by targeting the Sirt1/p65 signaling axis.

In this study, we used alkaloids from Sophora flavescens to inhibit the SASP, leading to fibroblast-into-myofibroblast transition (FMT) to maintain intestinal mucosal homeostasis in vitro and in vivo. We used western blotting (WB) and immunofluorescence staining (IF) to assess whether five kinds of alkaloids inhibit the major inflammatory pathways and chose the most effective compound (sophocarpine; SPC) to ameliorate colorectal inflammation in a dextran sulfate sodium (DSS)-induced UC mouse model. IF, Immunohistochemistry staining (IHC), WB, disease activity index (DAI), and enzyme-linked immunosorbent assay (ELISA) were conducted to investigate the mechanism of action of this compound. Next, we detected the pharmacological activity of SPC on the senescence-associated secretory phenotypes (SASP) and FMT in interleukin 6 (IL-6)-induced senescence-like fibroblasts and discussed the mucosal protection ability of SPC on a fibroblast-epithelium/organoid coculture system and organ-on-chip system. Taken together, our results provide evidence that SPC alleviates the inflammatory response, improves intestinal fibrosis and maintains intestinal mucosal homeostasis in vivo. Meanwhile, SPC was able to prevent IL-6-induced SASP and FMT in fibroblasts, maintain the expression of TJ proteins, and inhibit inflammation and genomic stability of colonic mucosal epithelial cells by activating SIRT1 in vitro. In conclusion, SPC treatment attenuates intestinal fibrosis by regulating SIRT1/NF-κB p65 signaling, and it might be a promising therapeutic agent for inflammatory bowel disease.

MXene-NH2/chitosan hemostatic sponges for rapid wound healing.

Effective control of wound bleeding and sustained promotion of wound healing remain a major challenge for hemostatic materials. In this study, the hemostatic sponge with controllable antibacterial and adjustable continuous promotion of wound healing (CMNCu) was prepared by chitosan, aminated MXene and copper ion. Interestingly, the internal topological point-line-surface interaction endowed the CMN-Cu sponge longitudinal staggered tubular porous microstructure, combined with the lipophilic properties obtained by modified MXene, which greatly improved its flexibility, wet elasticity and blood enrichment capacity. In addition, the sponge achieved controlled release of active ingredients, which made it present highly effective antibacterial activity and long-lasting ability to promote wound healing. In vitro and in vivo experiments confirmed that CMN-Cu sponge presented high-efficient hemostatic performance. Last but not least, a series of cell experiments showed that the CMN-Cu sponge had excellent safety as a hemostatic material.

Incidence and risk factors for occult lesions in low-risk papillary thyroid microcarcinoma patients with tumor characteristics appropriate for thermal ablation: A retrospective study.

In recent years, thermal ablation has been increasingly employed for the treatment of low-risk papillary thyroid microcarcinoma (PTMC) across various institutions. Its use as a standard or initial treatment continues to be a subject of debate. Retrospective analyses of the surgical pathology in post-ablation patients have indicated that occult lesions are not uncommon. This retrospective study aimed to examine the incidence and risk factors of occult lesions via postoperative pathology in low-risk PTMC patients who fulfilled the criteria for thermal ablation therapy. We examined the medical records of patients who underwent thyroid surgery and had a Bethesda classification V or VI based on fine needle aspiration cytology between November 22, 2020, and December 31, 2022. A total of 413 patients with preoperative tumor characteristics appropriate for thermal ablation were included in this study. Occult lesions, encompassing ipsilateral or contralateral occult carcinoma or central lymph node metastases may have occurred in 34.7% of patients. Male gender (OR: 2.526, 95% CI: 1.521-4.195, P = .000), tumor location in the lower pole (OR: 1.969, 95% CI: 1.186-3.267, P = .009), multiple microcalcifications (OR: 5.620, 95% CI: 2.837-11.134, P = .000), and Hashimoto's thyroiditis (OR: 2.245, 95% CI: 1.292-3.899, P = .004) were independent risk factors for the presence of occult lesions. In low-risk PTMC patients exhibiting tumor characteristics amenable to thermal ablation, over one-third of the patients may present with occult lesions. Meticulous evaluation of the presence of additional lesions is necessary before performing thermal ablation, particularly in patients exhibiting high-risk factors for occult lesions.

Extraction and characterisation of pigment from Yanzhiguo [Prunus napaulensis (Ser.) Steud.].

Yanzhiguo [Prunus napaulensis (Ser.) Steud] belongs to Rosaceae family and is consumed as wild fruit, pulp and juice. However, its potential for extracting natural pigment has not yet been explored. Herein, the components in the fresh Yanzhiguo pulp were preliminarily analyzed by liquid chromatography coupled to mass spectrometry. And, the optimal pre-treatment conditions were established for further extraction of Yanzhiguo pigment based on the a* value. Then, by combining the data from single-factor experiments and response surface methodology, the optimal extraction process was established as: 35% EtOH, a liquid-solid ratio of 200:1 mL g-1, an extraction time of 65 min, and an extraction temperature of 100 °C. Moreover, it was found that the a* value and yield had high fitness except when extracted into ethanol (EtOH) with different concentrations. Meanwhile, our result demonstrated Yanzhiguo pigment had high stability in general environments with carmine (a synthetic pigment) as control, except for extreme environments such as direct (hot) sunlight, high temperature (75 °C) and strong alkaline (pH ≥ 11). Also, Yanzhiguo pigment exhibited good antioxidant activity. Our results contribute to more information on Yanzhiguo pigment and promote its application by providing efficient extraction technology.

Overview of research progress and application of experimental models of colorectal cancer.

Colorectal cancer (CRC) is the third most common malignancy in terms of global tumor incidence, and the rates of morbidity and mortality due to CRC are rising. Experimental models of CRC play a vital role in CRC research. Clinical studies aimed at investigating the evolution and mechanism underlying the formation of CRC are based on cellular and animal models with broad applications. The present review classifies the different experimental models used in CRC research, and describes the characteristics and limitations of these models by comparing the research models with the clinical symptoms. The review also discusses the future prospects of developing new experimental models of CRC.

CCDC85C suppresses colorectal cancer cells proliferation and metastasis through activating GSK-3ß and promoting ß-catenin degradation.

Coiled-coil domain-containing 85C (CCDC85C) is a member of the DIPA family and contains a pair of conserved coiled-coil motifs, which was found to be related to a therapeutic target for colorectal cancer, however, its biological effects require further elucidation. This study aimed to determine the effect of CCDC85C on Colorectal Cancer (CRC) progression and to explore the related mechanism. pLV-PURO plasmid was used to construct CCDC85C-overexpressing cells while CRISPR-CasRx was used to construct CCDC85C knockdown cells. Effects of CCDC85C on cell proliferation, cycle and migration were examined using cell counting kit-8 assay, flow cytometry, wound healing assay and transwell assay. Immunofluorescence staining, immunoprecipitation, Western blot, co-immunoprecipitation and qPCR were performed to explore the mechanism. The overexpression of CCDC85C inhibited the proliferation and migration of HCT-116 and RKO cells in vitro and in vivo, but its knockdown promoted the proliferation of HCT-116 and RKO cells in vitro. Moreover, co-immunoprecipitation experiment confirmed that CCDC85C binding with GSK-3ß in RKO cells. Excess CCDC85C promoted phosphorylation and ubiquitination of ß-catenin. Our results suggested that CCDC85C binds to GSK-3ß to promote its activity and facilitates ubiquitination of ß-catenin. ß-catenin degradation is responsible for the inhibitory effect of CCDC85C on CRC cell proliferation and migration.

Liquid chromatography-tandem mass spectrometry analysis of a ratio-optimized drug pair of Sophora flavescens Aiton and Coptis chinensis Franch and study on the mechanism of anti-colorectal cancer effect of two alkaloids thereof.

The drug pair consisting of Sophora flavescens Aiton (Sophorae flavescentis radix, Kushen) and Coptis chinensis Franch. (Coptidis rhizoma, Huanglian), as described in Prescriptions for Universal Relief (Pujifang), is widely used to treat laxation. Matrine and berberine are the major active components of Kushen and Huanglian, respectively. These agents have shown remarkable anti-cancer and anti-inflammatory effects. A mouse model of colorectal cancer was used to determine the most effective combination of Kushen and Huanglian against anti-colorectal cancer. The results showed that the combination of Kushen and Huanglian at a 1:1 ratio exerted the best anti-colorectal cancer effect versus other ratios. Moreover, the anti-colorectal cancer effect and potential mechanism underlying the effects of matrine and berberine were evaluated by the analysis of combination treatment or monotherapy. In addition, the chemical constituents of Kushen and Huanglian were identified and quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 67 chemical components were identified from the Kushen-Huanglian drug pair (water extraction), and the levels of matrine and berberine were 129 and 232 µg/g, respectively. Matrine and berberine reduced the growth of colorectal cancer and relieved the pathological conditions in mice. In addition, the combination of matrine and berberine displayed better anti-colorectal cancer efficacy than monotherapy. Moreover, matrine and berberine reduced the relative abundance of Bacteroidota and Campilobacterota at phylum level and that of Helicobacter, Lachnospiraceae_NK4A136_group, Candidatus_Arthromitus, norank_f_Lachnospiraceae, Rikenella, Odoribacter, Streptococcus, norank_f_Ruminococcaceae, and Anaerotruncus at the genus level. Western blotting results demonstrated that treatment with matrine and berberine decreased the protein expressions of c-MYC and RAS, whereas it increased that of sirtuin 3 (Sirt3). The findings indicated that the combination of matrine and berberine was more effective in inhibiting colorectal cancer than monotherapy. This beneficial effect might depend on the improvement of intestinal microbiota structure and regulation of the RAS/MEK/ERK-c-MYC-Sirt3 signaling axis.

Quaternized chitosan coated copper sulfide nanozyme with peroxidase-like activity for synergistic antibacteria and promoting infected wound healing.

Bacterial infection can hinder the infected wound healing process. Because of the growing drug-resistance bacteria, there is an urgent desire to develop alternative antibacterial strategies to the antibiotics. Herein, the quaternized chitosan coated CuS (CuS-QCS) nanozyme with peroxidase (POD)-like activity was developed through a facile biomineralized approach for synergistic efficient antibacterial therapy and wound healing. The CuS-QCS killed bacteria by the electrostatic bonding of positive charged QCS with bacteria and releasing Cu2+ to damage bacterial membrane. And importantly, CuS-QCS nanozyme exhibited higher intrinsic POD-like activity, which converted H2O2 with low concentration into highly toxic hydroxyl radical (OH) for the elimination of bacteria by oxidative stress. Through cooperation of POD-like activity, Cu2+ and QCS, CuS-QCS nanozyme exhibited excellent antibacterial efficacy of approximate 99.9 % against E. coli and S. aureus in vitro. In addition, the QCS-CuS was successfully used to promote the healing of S. aureus infected wound with good biocompatibility. This synergistic nanoplatform presented here shows great potential applications in the field of wound infection management.

High-Efficiency Antibacterial Hemostatic AgNP@Zeolite/Chitin/Bamboo Composite Sponge for Wound Healing without Heat Injury.

Chitin is a popular hemostatic material, but there are still many deficiencies in its ability to effectively stop bleeding, prevent infection, and fit wounds. Herein, AgNP@zeolite/chitin/bamboo (AgZ-CB) composite sponges with shape recovery are prepared to minimize blood loss, kill bacteria, and promote wound healing. Notably, the bamboo powder is used for the first time to remarkably enhance the softness of the composite sponge (volumetric expansion ratio >5). The fabricated AgZ-CB sponge exhibits an excellent killing effect (≈100% bactericidal rate) against both Escherichia coli and Staphylococcus aureus and activates internal and external coagulation pathways to accelerate hemostasis without causing thermal damage (≈5 °C temperature difference). Moreover, the AgZ-CB sponge shows less blood loss (26 mg) and a shorter time to hemostasis (42 s) than the commercial polyvinyl formal sponge (84 mg and 76 s) in the full-thickness liver injury model. The in vivo wound healing and biodegradation experiment indicate that AgZ-CB with excellent biocompatibility can close wounds efficiently. Overall, the AgZ-CB sponge has great potential in combating a series of obstacles in wound healing.

Identification of Significant Modules and Targets of Xian-Lian-Jie-Du Decoction Based on the Analysis of Transcriptomics, Proteomics and Single-Cell Transcriptomics in Colorectal Tumor.

Purpose: Colorectal cancer (CRC) remains the third most common tumor worldwide. Ulcerative colitis (UC) could cause chronic inflammation and ulcers in the colon and rectum. UC is a risk factor for a high incidence of CRC, and the incidence of UC-associated CRC (UC-CRC) is still increasing. Chinese medicine prescription, Xian-Lian-Jie-Du decoction (XLJDD), has been proven its efficacy in some UC-CRC patients. However, the mechanism of XLJDD in treating UC-CRC remains unknown. This study aimed to investigate the mechanism of XLJDD in treating UC-CRC. Methods: We constructed an AOM/DSS mouse model that could simulate the various stages of UC-CRC in humans. XLJDD and its 5 main components are used to treat the AOM/DSS model, respectively. With the power of high-throughput sequencing technology, we described the mechanism of XLJDD from transcriptomics, proteomics, and single-cell transcriptomics. Results: Our results showed that XLJDD could effectively suppress the occurrence and development of colorectal tumors. Using the weighted correlation network analysis (WGCNA), several mRNA and protein modules that respond to XLJDD have been identified. Moreover, two essential genes, Mfsd2a and Ccdc85c, were caught our attention. They were prognostic markers in CRC patients, and their expression could be significantly modulated by XLJDD, showing their potential as effective targets of XLJDD. In addition, we also discovered that XLJDD could affect the cell composition of the colorectal tumor environment, especially in the infiltration of B cells. Conclusion: We demonstrated that XLJDD could prevent the initiation and development of colorectal tumors by modulating the expression of Mfsd2a and Ccdc85c and reducing the infiltration of B cells in the tumor microenvironment of colorectal tumor.

MXene-Enhanced Chitin Composite Sponges with Antibacterial and Hemostatic Activity for Wound Healing.

This study shows the effective use of MXene-based nanomaterials to improve the performance of biocomposite sponges in wound healing. In this way, diverse chitin/MXene composite sponges are fabricated by incorporating MXene-based nanomaterials with various morphology (accordion-shaped, intercalated, single-layer, gold nanoparticles (AuNPs)-loaded single-layer) into the network of chitin sponge (CH), which can prevent massive blood losses and promote the healing process of bacterial-infected wounds. With the addition of MXene-based nanomaterials, the hemostatic efficacy of CH is enhanced due to the improved hemophilicity and accelerated blood coagulation kinetics. Furthermore, the composite sponges show a predominant antibacterial activity through the synergy between the capture and the photothermal effects. Importantly, the addition of AuNPs to composite sponges further improves hemostatic performance and promotes normal skin cell migration to heal the infected wound, achieving wound closure rates of 84% on day 9. These initial studies expand the applications of MXene-based nanomaterials in biomedical fields.

α-Hederin Inhibits the Proliferation of Hepatocellular Carcinoma Cells via Hippo-Yes-Associated Protein Signaling Pathway.

Aims: Yes-associated protein (YAP), a downstream protein in the Hippo signaling pathway, plays an important role in tumor proliferation, including in hepatocellular carcinoma (HCC). α-hederin, a monodesmosidic triterpenoid saponin isolated from Fructus akebiae, displayed anti-cancer effects on several cancer cell lines but the precise mechanism has not been ascertained. In the present study, we explored the effects of α-hederin on cell proliferation and apoptosis in human HCC cell lines and the underlying mechanisms. Main Method: Cell proliferation and apoptosis were assessed using 5-ethynyl-2'-deoxyuridine staining, colony formation, flow cytometry. The expression patterns of components of Hippo signaling pathway and apoptotic genes were further examined via RT-qPCR and immunoblotting. A xenograft tumor model in nude mice was used to evaluate the anti-HCC effects of α-hederin in vivo. Results: α-hederin promoted the apoptosis and inhibited the proliferation of SMMC-7721 and HepG2 cells in vitro, and remarkably inhibited the tumor size and weight in the xenograft mouse model. Additionally, α-hederin increased the expression of pro-apoptosis proteins and suppressed the expression of anti-apoptosis proteins. Moreover, α-hederin treatment upregulated the expression of Hippo signaling pathway-related proteins and genes, while, effectively reduced the level of nuclear YAP, which resulted in the inhibition of proliferation and the induction of apoptosis of HCC cells. Finally, the effects of α-hederin on HCC cell proliferation and apoptosis were alleviated by XMU-MP-1, a Mst1/2 inhibitor in vitro. Significance: We identified α-hederin is a novel agonist of Hippo signaling pathway and possesses an anti-HCC efficacy through inhibiting YAP activity.

HIPK3 Inhibition by Exosomal hsa-miR-101-3p Is Related to Metabolic Reprogramming in Colorectal Cancer.

BACKGROUND: Exosomes are extracellular vesicles secreted by most cells to deliver functional cargoes to recipient cells. MicroRNAs (miRNAs) constitute a significant part of exosomal contents. The ease of diffusion of exosomes renders them speedy and highly efficient vehicles to deliver functional molecules. Cancer cells secrete more exosomes than normal cells. Reports have showed that exosomal miRNAs of cancer cells facilitate cancer progression. Yet the complexity of cancer dictates that many more functional exosomal miRNAs remain to be discovered. METHODS: In this study, we analyzed miRNA expression profiles of tissue and plasma exosome samples collected from 10 colorectal cancer (CRC) patients and 10 healthy individuals. We focused on hsa-miR-101-3p (101-3p), a profoundly up-regulated miRNA enriched in plasma exosomes of patients bearing CRC. We performed target analysis of 101-3p and pursued functional studies of this microRNA in two colorectal cancer cell lines, namely HCT116 and SW480. RESULTS: Our results indicated that inhibiting 101-3p slowed cell growth and retarded cell migration in vivo in two colorectal cancer cell lines. Target analysis showed that Homeodomain-interacting protein kinase (HIPK3) is a target of miR-101-3p. HCT116 and SW480 cells stably overexpressing HIPK3 showed increased level of phosphorylated FADD, as well as retarded cell growth, migration, and increased sensitivity to 5-FU. In-depth analysis revealed increased mitochondrial membrane potential upon HIPK3 overexpression along with increased production of reactive oxygen species, number of mitochondria, and expression of respiratory complexes. Measurements of glycolytic parameters and enzymes revealed decreased level of glycolysis upon HIPK3 overexpression in these two cell lines. Xenograft model further confirmed a profoundly improved potency of the synergistic treatment combining both 5-FU and 101-3p inhibitor compared to 5-FU alone. CONCLUSION: This study unraveled an oncogenic nature of the exosomal 101-3p and suggested a relationship between the 101-3p-HIPK3 axis and metabolic homeostasis in colorectal cancer. Expression level of 101-3p is positively correlated with glycolytic capacity in CRC and therefore 101-3p itself is an oncomiR. Combining 101-3p inhibitor with chemotherapeutic agents is an effective strategy against CRC.

Design, synthesis and biological evaluation of imidazolopyridone derivatives as novel BRD4 inhibitors.

Bromodomain containing protein 4 (BRD4) has been demonstrated to play critical roles in cellular proliferation and cell cycle progression. In this study, using the BRD4 inhibitor Fragment 9 as a lead compound, a series of imidazolopyridone derivatives were designed and tested for their inhibitory activity against BRD4 protein in vitro. Among them, HB100-A7 showed excellent BRD4(1) inhibitory activities with an IC50 value of 0.035 µM in amplified luminescent proximity homogeneous assay (Alphascreen). The result of MTT assay showed that HB100-A7 could suppress the proliferation of pancreatic cancer cells. In addition, flow cytometry further illustrated that HB100-A7 treatment resulted in G0/G1 phase arrest and promoted apoptosis of BxPc3 cells. Furthermore, the in vivo study found that HB100-A7 displayed significant tumor growth inhibition in a pancreatic mouse tumor model (Panc-02). Moreover, IHC staining suggested that HB100-A7 induce cell apoptosis in pancreatic cancer tumor tissue. Together, this study revealed, for the first time, HB100-A7 is a promising lead compound for further development as a new generation of small molecule inhibitors targeting the BRD4 protein.

Development of small-molecule BRD4 degraders based on pyrrolopyridone derivative.

Bromodomain-containing protein 4 (BRD4) plays a crucial role in the epigenetic regulation of gene transcription and some BRD4 inhibitors have been advanced to clinical trials. Nevertheless, the clinical application of BRD4 inhibitors could be limited by drug resistance. As an alternative strategy, the emerging Proteolysis Targeting Chimeras (PROTACs) technology has the potential to overcome the drug resistance of traditional small-molecule drugs. Based on PROTACs approaches, several BRD4 degraders were developed and have been proved to degrade BRD4 protein and inhibit tumor growth. Herein, we present the design, synthesis, and biological evaluation of pyrrolopyridone derivative-based BRD4 degraders. Four synthesized compounds displayed comparative potence against BRD4 BD1 with IC50 at low nanomolar concentrations. Anti-proliferative activity of 32a against BxPC3 cell line (IC50 = 0.165 µM) was improved by about 7-fold as compared to the BRD4 inhibitor ABBV-075. Furthermore, degrader 32a potently induced the degradation of BRD4 and inhibited the expression of c-Myc in BxPC3 cell line in a time-dependent manner. The exploration of intracellular antitumor mechanism showed 32a induced cell cycle arrest and apoptosis effectively. All the results demonstrated that compound 32a could be considered as a potential BRD4 degrader for further investigation.

Antibacterial and Hemostatic Thiol-Modified Chitosan-Immobilized AgNPs Composite Sponges.

Wound bleeding and infection are two of the major threats to patients' lives, but developing safe materials with high hemostasis efficiency and antibacterial activity remains a major challenge. Silver nanoparticles (AgNPs) are suitable as antibacterial agents in the hemostatic process, but the application is hampered because of easy accumulation of toxicity. Herein, thiol-modified chitosan (TMC) was prepared by modifying with mercaptosuccinic acid and then was used to immobilize AgNPs to obtain composite sponges (TMC/AgNPs) for stemming the bleeding and preventing infection. TMC/AgNPs sponges had complex interlaced tubular porous structure with high porosity (99.42%), indicating high absorption. TMC had high immobilization efficiency for AgNPs-the release rate of AgNPs was 14.35% after 14 days-but the TMC/AgNPs sponge still had excellent antibacterial activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. In vitro and in vivo experiments confirm that the TMC/AgNPs sponge had fast and efficient hemostatic performance in comparison with the PVF sponge, and its possible mechanism was the synergistic effect of high blood absorption capacity and the interaction between amino, sulfydryl, and blood cells. Furthermore, the TMC/AgNPs sponge can promote wound healing by preventing wound infection, while the PVF sponge cannot. More importantly, the sponges had good safety due to the immobilization of TMC for AgNPs.

MicroRNAs that regulate PTEN as potential biomarkers in colorectal cancer: a systematic review.

PURPOSE: MicroRNAs (miRNAs) participate in a variety of biological processes, including tumorigenesis, progression, invasion, and drug resistance to multiple cancers. Phosphatase and tensin homolog (PTEN) is a cancer suppressor gene that has been certified to be regulated by miRNAs in various tumors, including colorectal cancer (CRC). In this review, we screened articles focusing on low PTEN expression in CRC, observed the expression of related miRNAs, analyzed their correlation and relationship with clinicopathological features, and discussed the possibility of these miRNAs as prognostic molecules. METHODS: We conducted a systematic search for articles published in the Web of Science, PubMed and EBSCO databases between January 1, 2002, and July 18, 2019. We identified these studies by using combinations of the following index entries and key words: 'colorectal tumor OR colorectal neoplasm OR colorectal carcinoma OR colorectal cancer OR CRC', 'protein tyrosine phosphatase OR PTEN', and 'microRNA OR MiRNA OR miRNA OR MicroRNA'. Moreover, we evaluated the underlying association between alterations in PTEN and CRC prognosis. RESULTS: PTEN expression was obviously lower in CRC tissues than in normal mucosa. However, PTEN expression did not differ significantly between adenoma and normal tissues. PTEN tends to be negatively associated with tumor size and metastasis. MiR-21, miR-200a, miR-543, miR-32, miR-92a, miR-26a, miR-106a and miR-181a were correlated with the downregulation of PTEN. MiR-26a, miR-106a and miR-181a were obviously higher in CRC tissues than in normal tissues, while PTEN was downregulated in CRC tissues. Additionally, miRNAs were mainly positively correlated with distant metastasis, followed by TNM stage. The relationship between miRNAs and tumor differentiation is controversial. However, there were no significant differences between miRNAs and either sex or age. CONCLUSIONS: The loss of PTEN may be a diagnostic factor for CRC patients. The above-mentioned miRNAs may function as oncogenes in CRC and represent potential targets for CRC therapy. However, further prospective clinical studies are necessary.