Microbiota-derived I3A protects the intestine against radiation injury by activating AhR/IL-10/Wnt signaling and enhancing the abundance of probiotics.

The intestine is prone to radiation damage in patients undergoing radiotherapy for pelvic tumors. However, there are currently no effective drugs available for the prevention or treatment of radiation-induced enteropathy (RIE). In this study, we aimed at investigating the impact of indole-3-carboxaldehyde (I3A) derived from the intestinal microbiota on RIE. Intestinal organoids were isolated and cultivated for screening radioprotective tryptophan metabolites. A RIE model was established using 13 Gy whole-abdominal irradiation in male C57BL/6J mice. After oral administration of I3A, its radioprotective ability was assessed through the observation of survival rates, clinical scores, and pathological analysis. Intestinal stem cell survival and changes in the intestinal barrier were observed through immunofluorescence and immunohistochemistry. Subsequently, the radioprotective mechanisms of I3A was investigated through 16S rRNA and transcriptome sequencing, respectively. Finally, human colon cancer cells and organoids were cultured to assess the influence of I3A on tumor radiotherapy. I3A exhibited the most potent radioprotective effect on intestinal organoids. Oral administration of I3A treatment significantly increased the survival rate in irradiated mice, improved clinical and histological scores, mitigated mucosal damage, enhanced the proliferation and differentiation of Lgr5+ intestinal stem cells, and maintained intestinal barrier integrity. Furthermore, I3A enhanced the abundance of probiotics, and activated the AhR/IL-10/Wnt signaling pathway to promote intestinal epithelial proliferation. As a crucial tryptophan metabolite, I3A promotes intestinal epithelial cell proliferation through the AhR/IL-10/Wnt signaling pathway and upregulates the abundance of probiotics to treat RIE. Microbiota-derived I3A demonstrates potential clinical application value for the treatment of RIE.

Probiotic Consortia Protect the Intestine Against Radiation Injury by Improving Intestinal Epithelial Homeostasis.

PURPOSE: Radiation-induced intestinal injury (RIII) commonly occur during abdominal-pelvic cancer radiation therapy; however, no effective prophylactic or therapeutic agents are available to manage RIII currently. This study aimed to clarify the potential of probiotic consortium supplementation in alleviating RIII. METHODS AND MATERIALS: Male C57BL/6J mice were orally administered a probiotic mixture comprising Bifidobacterium longum BL21, Lactobacillus paracasei LC86, and Lactobacillus plantarum Lp90 for 30 days before exposure to 13 Gy of whole abdominal irradiation. The survival rates, clinical scores, and histologic changes in the intestines of mice were assessed. The impacts of probiotic consortium treatment on intestinal stem cell proliferation, differentiation, and epithelial barrier function; oxidative stress; and inflammatory cytokines were evaluated. A comprehensive examination of the gut microbiota composition was conducted through 16S rRNA sequencing, while changes in metabolites were identified using liquid chromatography-mass spectrometry. RESULTS: The probiotic consortium alleviated RIII, as reflected by increased survival rates, improved clinical scores, and mitigated mucosal injury. The probiotic consortium treatment exhibited enhanced therapeutic effects at the histologic level compared with individual probiotic strains, although there was no corresponding improvement in survival rates and colon length. Moreover, the probiotic consortium stimulated intestinal stem cell proliferation and differentiation, enhanced the integrity of the intestinal epithelial barrier, and regulated redox imbalance and inflammatory responses in irradiated mice. Notably, the treatment induced a restructuring of the gut microbiota composition, particularly enriching short-chain fatty acid-producing bacteria. Metabolomic analysis revealed distinctive metabolic changes associated with the probiotic consortium, including elevated levels of anti-inflammatory and antiradiation metabolites. CONCLUSIONS: The probiotic consortium attenuated RIII by modulating the gut microbiota and metabolites, improving inflammatory symptoms, and regulating oxidative stress. These findings provide new insights into the maintenance of intestinal health with probiotic consortium supplementation and will facilitate the development of probiotic-based therapeutic strategies for RIII in clinical practice.

Fraxin (7-hydroxy-6-methoxycoumarin 8-glucoside) confers protection against ionizing radiation-induced intestinal epithelial injury in vitro and in vivo.

The small intestine exhibits remarkable sensitivity to ionizing radiation (IR), which significantly hampers the effectiveness of radiotherapy in the treatment of abdominal and pelvic tumors. Unfortunately, no effective medications are available to treat radiation-induced intestinal damage (RIID). Fraxin (7-hydroxy-6-methoxycoumarin 8-glucoside), is a coumarin derivative extracted from the Chinese herb Cortex Fraxini. Several studies have underscored the anti-inflammatory, antibacterial, antioxidant, and immunomodulatory properties of fraxin. However, the efficacy of fraxin at preventing or mitigating RIID remains unclear. Thus, the present study aimed to investigate the protective effects of fraxin against RIID in vitro and in vivo and to elucidate the underlying mechanisms. The study findings revealed that fraxin markedly ameliorated intestinal injuries induced by 13 Gy whole abdominal irradiation (WAI), which was accompanied by a significant increase in the population of Lgr5+ intestinal stem cells (ISCs) and Ki67+ progeny. Furthermore, fraxin mitigated WAI-induced intestinal barrier damage, and reduced oxidative stress and intestinal inflammation in mice. Transcriptome sequencing of fraxin-treated mice revealed upregulation of IL-22, a pleiotropic cytokine involved in regulating the function of intestinal epithelial cells. Moreover, in both human intestinal epithelial cells and ex vivo cultured mouse intestinal organoids, fraxin effectively ameliorated IR-induced damage by promoting the expression of IL-22. The radioprotective effects of fraxin were partially negated in the presence of an IL-22-neutralizing antibody. In summary, fraxin is demonstrated to possess the ability to alleviate RIID and maintain intestinal homeostasis, suggesting that fraxin might serve as a strategy for mitigating accidental radiation exposure- or radiotherapy-induced RIID.

Chidamide and Oxaliplatin Synergistically Inhibit Colorectal Cancer Growth by Regulating the RPS27A-MDM2-P53 Axis.

Purpose: The present study explored the anti-tumor effects of chidamide plus oxaliplatin on colorectal cancer (CRC) and examined its underlying mechanism. Material and Methods: First, the Combination Index (CI) of chidamide and oxaliplatin was evaluated via CCK-8 assay. Second, the effects of chidamide and oxaliplatin monotherapy and the combined treatment on cell proliferation, invasion, migration, and apoptosis were detected. Third, whole-transcriptome RNA sequencing (RNA-seq) was performed to seek the potential targeted gene by which chidamide plus oxaliplatin exerted anti-tumor effects. Fourth, the validation of the targeted gene and the signal pathway it regulated were performed. Finally, the anti-tumor effect of chidamide plus oxaliplatin on mice xenograft was examined. Results: Chidamide and oxaliplatin acted synergistically to inhibit CRC growth in vitro and in vivo (CI<1). Besides, compared with oxaliplatin monotherapy, chidamide could significantly enhance oxaliplatin-induced inhibition in cell proliferation, invasion, and migration, and promotion in HCT-116 and RKO cell apoptosis (P<0.05). The RNA-seq displayed that, compared to oxaliplatin monotherapy, RPS27A mRNA was evidently decreased in HCT-116 cells treated with chidamide plus oxaliplatin (P<0.001). Then, we found RPS27A was highly expressed in CRC tissues and CRC cell lines (P<0.001). Silence of RPS27A attenuated proliferation and induced apoptosis in HCT-116 and RKO cells via downregulation of MDM2 expression and upregulation of P53. Next, RPS27A overexpression could partially reverse chidamide plus oxaliplatin induced growth inhibition and apoptosis in HCT-116 and RKO cells (P<0.01). RPS27A overexpression could promote the upregulation of MDM2 and downregulation of P53 after the combined treatment of chidamide with oxaliplatin. Conclusion: Chidamide and oxaliplatin acted synergistically to suppress CRC growth by the inhibition of the RPS27A-MDM2-p53 axis.

Mussel- and nacre-inspired dual-bionic alginate-based hydrogel coating with multi-matrix applicability, high separation stability and antifouling performance for oil/water separation.

Natural hydrogel-modified porous matrices with superwetting interfaces are ideal for oil/water separation. In this study, inspired by two marine organisms, a novel hydrogel coating with multi-matrix suitability, high oil/water separation capability and antifouling properties was developed. Specifically, inspired by mussel byssus, hydrogel coating was successfully deposited on porous matrix surface based on the introduction of tannic acid (TA). Moreover, inspired by the "brick and mortar" microstructure of Pinctada nacre, silica particles were in-situ synthesized in the sodium alginate (SA)/Ca2+ hydrogel to provide the filling effect and to increase strength. Furthermore, Sodium alginate-tannic acid-tetraethyl orthosilicate (SA-TA-TEOS) hydrogel coating-modified membrane exhibited super-hydrophilic and underwater super-oleophobic performance (underwater oil contact angle >150°), and achieved efficient oil/water separation for four oil/water emulsions (flux = 493-584 L·m-2·h-1 and rejection = 97.3-99.5 %). The modified membrane also demonstrated good anti-fouling performance and flux recovery. Notably, hydrogel coating-modified non-woven fabric also had high oil/water separation capacity (rejection >98 %) and cyclic stability, which proved the universal applicability of this hydrogel coating. In short, this work provides new insights into the fabrication of hydrogel coating-modified porous materials based upon a marine organism biomimetic strategy, which has potential applications in separating oil/water emulsions in industrial scenarios.

A comprehensive pan-cancer analysis of necroptosis molecules in four gynecologic cancers.

BACKGROUND: In recent years, it has been proved that necroptosis plays an important role in the occurrence, development, invasion, metastasis and drug resistance of malignant tumors. Hence, further evaluation and targeting of necroptosis may be of clinical benefit for gynecologic cancers (GCs). METHODS: To compare consistency and difference, we explored the expression pattern and prognostic value of necroptosis-related genes (NRGs) in pan-GC analysis through Linear regression and Empirical Bayesian, Univariate Cox analysis, and public databases from TCGA and Genotype-Tissue Expression (GTEx), including CESC, OV, UCEC, and UCS. We explored the copy number variation (CNV), methylation level and enrichment pathways of NRGs in the four GCs. Based on LASSO Cox regression analysis or principal component analysis, we established the prognostic NRG-signature or necroptosis-score for the four GCs. In addition, we predicted and compared functional pathways, tumor mutational burden (TMB), somatic mutation features, immunity status, immunotherapy, chemotherapeutic drug sensitivity of the NRG-signature based on NRGs. We also examined the expression level of several NRGs in OV samples that we collected using Quantitative Real-time PCR. RESULTS: We confirmed the presence of NRGs in expression, prognosis, CNV, and methylation for four GCs, thus comparing the consistency and difference among the four GCs. The prognosis and independent prognostic value of the risk signatures based on NRGs were determined. Through the results of subclass mapping, we found that GC patients with lower risk score may be more sensitive to PDL1 response and more sensitive to immune checkpoint blockade therapy. Drug susceptibility analysis showed that, 51, 45, 64, and 29 drugs with differences between risk groups were yielded in CESC, OV, UCEC, and UCS respectively. For OV, the expression differences of several NRGs in the tissues we collected were similar to that in TCGA. CONCLUSION: Our comprehensive analysis of NRGs and NRG-signature demonstrated their similarity and difference, as well as their potential roles in prognosis and could guide therapeutic strategies, thus improving the outcome of GC patients.

Bioactive glass activates VEGF paracrine signaling of cardiomyocytes to promote cardiac angiogenesis.

The heart contains a wide range of cell types, which are not isolated but interact with one another via multifarious paracrine, autocrine and endocrine factors. In terms of cardiac angiogenesis, previous studies have proved that regulating the communication between cardiomyocytes and endothelial cells is efficacious to promote capillary formation. Firstly, this study investigated the effect and underlying mechanism of bioactive glass (BG) acted on vascular endothelial growth factor (VEGF) paracrine signaling in cardiomyocytes. We found that bioactive ions released from BG significantly promoted the VEGF production and secretion of cardiomyocytes. Subsequently, we proved that cardiomyocyte-derived VEGF played an important role in mediating the behavior of endothelial cells. Further research showed that the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/hypoxia-inducible factor 1α (HIF-1α) signaling pathway was upregulated by BG, which was involved in VEGF expression of cardiomyocytes. This study revealed that by means of modulating cellular crosstalk via paracrine signaling of host cells in heart is a new direction for the application of BGs in cardiac angiogenesis.

Bioactive glass promotes the barrier functional behaviors of keratinocytes and improves the Re-epithelialization in wound healing in diabetic rats.

Upon skin injury, re-epithelialization must be triggered promptly to restore the integrity and barrier function of the epidermis. However, this process is often delayed or interrupted in chronic wounds like diabetic foot ulcers. Considering that BG particles can activate multiple genes in various cells, herein, we hypothesized that bioactive glass (BG) might be able to modulate the barrier functional behaviors of keratinocytes. By measuring the transepithelial electrical resistance (TEER) and the paracellular tracer flux, we found the 58S-BG extracts substantially enhanced the barrier function of keratinocyte monolayers. The BG extracts might exert such effects by promoting the keratinocyte differentiation and the formation of tight junctions, as evidenced by the increased expression of critical differentiation markers (K10 and involucrin) and TJ protein claudin-1, as well as the altered subcellular location of four major TJ proteins (claudin-1, occludin, JAM-A, and ZO-1). Besides, the cell scratch assay showed that BG extracts induced the collective migration of keratinocytes, though they did not accelerate the migration rate compared to the control. The in vivo study using a diabetic rat wound model demonstrated that the BG extracts accelerated the process of re-epithelialization, stimulated keratinocyte differentiation, and promoted the formation of tight junctions in the newly regenerated epidermis. Our findings revealed the crucial effects of BGs on keratinocytes and highlighted its potential application for chronic wound healing by restoring the barrier function of the wounded skin effectively.

Coaxial nanofibrous scaffolds mimicking the extracellular matrix transition in the wound healing process promoting skin regeneration through enhancing immunomodulation.

Numerous studies have shown that scaffolds incorporated with extracellular matrix (ECM) proteins could regulate cell behaviors and improve wound healing. However, most ECM-containing scaffolds fail to capture the dynamic features of the native ECM. In this regard, nanofibrous scaffolds which mimic the composition transition of the ECM during wound healing may have great potential in promoting skin regeneration through dynamically modulating the microenvironment. Herein, we report a novel skin ECM-biomimetic coaxial nanofibrous scaffold for the repair of chronic wounds. Two essential ECM proteins, fibrinogen and collagen I, were incorporated into the shell and the core of nanofibers, respectively, to mimic the sequential appearance of fibrinogen and collagen I in the wound healing process. The regulation of the biomimetic coaxial scaffolds on adipose-derived mesenchymal stromal cells (ASCs) was compared with that of the PLGA/fibrinogen, PLGA/collagen I and PLGA uniaxial scaffolds. Our results showed that the biomimetic coaxial scaffolds remarkably promoted the immunomodulatory paracrine secretion of ASCs. By incubating macrophages with ASC conditioned medium, the enhanced immunomodulation of ASCs on the biomimetic coaxial scaffolds was confirmed by the enhanced M1-to-M2 polarization of macrophages. Furthermore, the biomimetic coaxial scaffolds effectively promoted wound repair through resolving inflammation in diabetic rats. These findings helped reveal the role of the dynamic ECM change in regulating wound healing and suggest the potential utility of the biomimetic coaxial scaffolds as a promising alternative to treat chronic wounds.

Dose-dependent modulation effects of bioactive glass particles on macrophages and diabetic wound healing.

Many pathophysiologic conditions can interrupt the normal wound healing process and lead to chronic wounds due to the arrest of macrophages in their inflammatory phenotype. Thus, strategies that promote the recovery of macrophage functions are of great benefit to heal chronic wounds. Bioactive glass (BG) dissolution has been recognized for its modulatory functions in macrophage polarization. However, further efforts are greatly needed to address how BG particles affect macrophage behaviors (such as proliferation, viability, migration and polarization) and wound healing through both direct contact and released ions. Our results showed that BG particles affect the proliferation/viability and polarization of macrophages in a dose-dependent manner. At a low concentration (20 µg mL-1), BG particles stimulated macrophage proliferation and promoted the M1-to-M2 phenotype switch; meanwhile, at a high concentration (100 µg mL-1), the particles showed significant cytotoxicity and prolonged the M1 phenotype of macrophages. The BG particles also exhibited strong chemotaxis to macrophages which appeared to be independent of their concentration. Dose-dependent regulation of macrophages and wound closure by BG particles were also observed in the healing of full-thickness wounds of diabetic rats. Our study suggests that the BG particle-mediated activities of macrophages are essential to wound healing, and these activities are greatly correlated with the amount of BG particles.

Nanosized CoO Loaded on Copper Foam for High-Performance, Binder-Free Lithium-Ion Batteries.

The synthesis of nanosized CoO anodes with unique morphologies via a hydrothermal method is investigated. By adjusting the pH values of reaction solutions, nanoflakes (CoO-NFs) and nanoflowers (CoO-FLs) are successfully located on copper foam. Compared with CoO-FLs, CoO-NFs as anodes for lithium ion batteries present ameliorated lithium storage properties, such as good rate capability, excellent cycling stability, and large CoO nanoflakes; CoO nanoflowers; anodes; binder free; lithium ion batteriesreversible capacity. The initial discharge capacity is 1470 mA h g-1, while the reversible capacity is maintained at 1776 m Ah g-1 after 80 cycles at a current density of 100 mA h g-1. The excellent electrochemical performance is ascribed to enough free space and enhanced conductivity, which play crucial roles in facilitating electron transport during repetitive Li⁺ intercalation and extraction reaction as well as buffering the volume expansion.

How to accelerate the upper urinary stone discharge after extracorporeal shockwave lithotripsy (ESWL) for < 15 mm upper urinary stones: a prospective multi-center randomized controlled trial about external physical vibration lithecbole (EPVL).

OBJECTIVE: To asset the efficacy and safety of EPVL plus ESWL compared with ESWL alone for the treatment of simple upper urinary stones (< 15 mm). MATERIALS AND METHODS: All patients with upper urinary stones (< 15 mm) were prospectively randomized into two groups. In treatment group, patients were assigned to immediate EPVL after ESWL, while in control group, ESWL alone was offered. All patients were reexamined at 1, 2, and 4 weeks after ESWL. Stone size, stone location, stone-free rate (SFR), and complication rate were compared. RESULTS: 56 males and 20 females in treatment group were compared to 52 male and 25 females in control group (p = 0.404). Median ages were 42.9 ± 1.5 years in treatment group and 42.7 ± 1.3 years in control group (p = 0.943). Median stone size was 10.0 ± 0.4 mm (3-15 mm) in treatment group and 10.4 ± 0.4 mm (4-15 mm) in control group (p = 0.622). The stone clearance rate in treatment and control group at 1 week after ESWL was 51.3% (39/76) and 45.4% (35/77) (p > 0.05), at 2 weeks was 81.6% (62/76) and 64.9% (50/77) (p < 0.05), and at 4 weeks was 90.8% (69/76) and 75.3% (58/77) (p < 0.05), respectively. CONCLUSIONS: EPVL is a noninvasive, effective, and safe adjunctive treatment which increases and accelerates upper urinary stones discharge after ESWL treatment.

Preparation and characterization of N-chitosan as a wound healing accelerator.

Chitosan is insoluble in water due to its rigid crystalline structure, which has significantly restricted its application in wound healing. The objective of this study was to synthesize a water-soluble chitosan derivative, N-succinyl-chitosan (NSC), and evaluate its ability to accelerate the wound healing process. NSC was synthesized with succinic anhydride, hydrochloric acid, and alkaline chitosan under optimized conditions, and characterized using Fourier transform infrared, proton nuclear magnetic resonance, and X-ray diffraction spectroscopy; thermal gravimetric analysis; and a solubility test. The cytotoxicity of NSC was investigated in L929 cells, and its antibacterial activity was evaluated by the inhibition zone method and bacterial growth curves analysis. The results showed that the solubility of NSC was substantially improved compared to chitosan, and NSC was non-toxic with good antibacterial properties. An animal wound healing test indicated that NSC could significantly reduce the healing time compared to chitosan. Histopathological examination suggested that the underlying mechanisms of these effects were related to NSC's ability to promote the formation of granulation tissue and enhance epithelialization. Collectively, these results demonstrate the good potential for NSC to be applied as a wound dressing material.

Healing of skin wounds with a chitosan-gelatin sponge loaded with tannins and platelet-rich plasma.

A chitosan-gelatin sponge (CSGT) was prepared using a chitosan/ascorbic acid solution blend containing gelatin, followed by crosslinking with tannin acid and freeze-drying, thereby combining the chitosan sponge and gelatin sponge. The structure of the CSGT was observed by scanning electron microscopy and was shown to have uniform and abundant pores measuring about 145-240µm in size. We also characterized the sponges by infrared spectroscopy, thermogravimetric analysis, mechanical property tests, swelling behavior analysis, water retention capacity tests, antibacterial property analysis, and cytotoxicity tests. Our data showed that the CSGT had good thermostability and mechanical properties as well as efficient water absorption and retention capacities. Moreover, the CSGT could effectively inhibit the growth of Escherichia coli and Staphylococcus aureus with low toxicity. In animal experiments, macroscopic observations and histological examinations showed that the wound covered by the CSGT healed quickly. Additionally, loading of the CSGT with platelet-rich plasma resulted in further acceleration of wound healing. Therefore, the CSGT and the CSGT with platelet-rich plasma were suitable for application as a wound dressing and may have potential for use in various biomedical applications.