Radiotherapy or accidental exposure to high-dose radiation can cause severe damage to healthy organs. The gastrointestinal (GI) tract is a radiation-sensitive organ of the body. The intestinal ...barrier is the first line of defense in the GI tract, and consists of mucus secreted by goblet cells and a monolayer of epithelium. Intestinal stem cells (ISCs) help in barrier maintenance and intestinal function after injury by regulating efficient regeneration of the epithelium. The Wnt/β-catenin pathway plays a critical role in maintaining the intestinal epithelium and regulates ISC self-renewal. Metformin is the most widely used antidiabetic drug in clinical practice, and its anti-inflammatory, antioxidative, and antiapoptotic effects have also been widely studied. In this study, we investigated whether metformin alleviated radiation-induced enteropathy by focusing on its role in protecting the epithelial barrier. We found that metformin alleviated radiation-induced enteropathy, with increased villi length and crypt numbers, and restored the intestinal barrier function in the irradiated intestine. In a radiation-induced enteropathy mouse model, metformin treatment increased tight-junction expression in the epithelium and inhibited bacterial translocation to mesenteric lymph nodes. Metformin increased the number of ISCs from radiation toxicity and enhanced epithelial repair by activating Wnt/β-catenin signaling. These data suggested that metformin may be a potential therapeutic agent for radiation-induced enteropathy.
Abstract Objective Stent graft-induced new entry (SINE) has been increasingly observed after thoracic endovascular aortic repair (TEVAR) for Stanford type B aortic dissection. SINE is often life ...threatening, and reintervention is required. This study investigated risk factors for SINE after TEVAR. Methods From July 2001 to June 2013, we retrospectively analyzed data from 79 patients who underwent TEVAR for Stanford type B aortic dissection. TEVAR was performed in 17 patients ≤2 weeks (acute) after the diagnosis of aortic dissection and in the remaining 62 patients >2 weeks (chronic) after diagnosis. Forty-two of the patients underwent TEVAR with modified stent graft with an “inwardly bent” margin, and the remaining 37 underwent TEVAR with a conventional stent graft. The maximal diameter, minimal diameter, mean diameter, circumference, and area of the true lumen were analyzed. Taper ratio and oversizing ratio were evaluated and compared between the SINE and non-SINE groups, and cutoff values of taper ratio and oversizing ratio for prediction of SINE were determined using receiver-operating characteristic curve analysis. The cumulative incidence of SINE was estimated with the Kaplan-Meier method. The multivariate Cox proportional hazards model was used to identify independent predictive variables for SINE. Results SINE occurred in 21 patients (26.5%) and occurred more frequently in patients with chronic dissection than in those with acute dissection (32.3% vs 5.9%; P = .032). The Kaplan-Meier curves were significantly different ( P = .016) between these groups. The incidence of SINE events was not significantly different between the modified stent group and nonmodified stent group (23.8% vs 36.0%; P = .284). The taper ratio and oversizing ratio by maximal diameter, mean diameter, circumference, and area were significantly higher in the SINE group than in the non-SINE group, and Kaplan-Meier curves were significantly different between groups above and below optimal cutoff value ( P < .0005 to .003). According to multivariate analysis, the hazard ratios of chronic aortic dissection were 6.30 (95% confidence interval, 0.83-47.74; P = .075) to 7.80 (95% confidence interval, 1.03-59.07; P = .047). The taper ratio and oversizing ratio calculated by maximal diameter, mean diameter, circumference, and area were independent predictors of the development of SINE. Conclusions Distal oversizing of the stent graft was an independent predictor of the development of SINE. Appropriate size selection of stent graft without distal oversizing might reduce the risk of late SINE events.
Intestinal organoids have recently emerged as an in vitro model relevant to the gut system owing to their recapitulation of the native intestinal epithelium with crypt–villus architecture. However, ...it is unclear whether intestinal organoids reflect the physiology of the in vivo stress response. Here, we systemically investigated the radiation response in organoids and animal models using mesenchymal stem cell‐conditioned medium (MSC‐CM), which contains secreted paracrine factors. Irradiated organoids exhibited sequential induction of viability loss and regrowth after irradiation (within 12 days), similar to the response of the native intestinal epithelium. Notably, treatment with MSC‐CM facilitated the reproliferation of intestinal stem cells (ISCs) and restoration of damaged crypt‐villus structures in both models. Furthermore, Wnt/Notch signaling pathways were commonly upregulated by MSC‐CM, but not radiation, and pharmacologically selective inhibition of Wnt or Notch signaling attenuated the enhanced recovery of irradiated organoids, with increases in ISCs, following MSC‐CM treatment. Interestingly, the expression of Wnt4, Wnt7a, and active β‐catenin was increased, but not notch family members, in MSC‐CM‐treated organoid after irradiation. Treatment of recombinant mouse Wnt4 and Wnt7a after irradiation improved to some extent intestinal epithelial regeneration both in vitro and in vivo. Overall, these results suggested that intestinal organoids recapitulated the physiological stress response of the intestinal epithelium in vivo. Thus, our findings provided important insights into the physiology of intestinal organoids and may contribute to the development of strategies to enhance the functional maturation of engineered organoids.
The extent to which in vitro intestinal organoids system recapitulate the physiology of in vivo stress response remains unclear. Kim and colleagues reported that intestinal organoids recapitulated the in vivo physiological response to radiation exhibiting specific responses to damage and regeneration. Moreover, the authors revealed that MSC‐CM‐activated Wnt4/7a signaling pathway partially improve the intestinal epithelial regeneration both in vitro and in vivo. These findings may contribute to the development of strategies to enhance the functional maturation of engineered organoids.
► We evaluate the effect of microwave with NaOH treatment on digestibility of sludge. ► Our findings show better performance in the anaerobic digester with pretreatment. ► The solubilization in ...pretreated sludge was 18 times higher than in raw sludge. ► The relative improvement of digester properties increased as HRT was reduced. ► Microwave/alkali pretreatment is effective in anaerobic biodegradability of sludge.
This work experimentally determined the effect of microwave irradiation with NaOH pretreatment on anaerobic digestion of thickened waste activated sludge in semi-continuous mesophilic digesters at hydraulic retention times (HRT) of 15, 10, 7, and 5days. The degree of substrate solubilization was 18 times higher in pretreated sludge (53.2%) than in raw sludge (3.0%). Removal efficiency of volatile solid in digesters fed with raw (control) and pretreated sludges (PD) decreased as HRT reduced. The highest relative improvement of properties compared with the control occurred at 5day HRT. Improvements in biogas production compared with the control increased in the PD as HRT was reduced to 5days (205% higher at 5days). However, digested sludges in the control and PD increased capillary suction time compared with raw sludge. The results show that microwave irradiation combined with alkali pretreatment is effective in increasing mesophilic anaerobic biodegradability of sewage sludge.
This study aims to investigate antioxidative and antibacterial properties of fresh garlic (non-aged, NG) and aged garlic (AG) by-products extracted with distilled water, ethanol, or chloroform. To ...determine their antioxidative and antibacterial capacities, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging assay, and H
2
O
2
radical scavenging activity, Fe
2+
chelating activity, total ferric reducing antioxidant power (FRAP), and disc diffusion tests were performed. Total phenol and flavonoid contents from distilled water extract of AG were significantly higher than those of NG. DPPH, ABTS, FRAP, and H
2
O
2
scavenging activities of distilled water extract of AG were higher than those of NG. However, Fe
2+
chelating activities of ethanol and chloroform extracts were higher than those of distilled water extracts for both NG and AG. Antibacterial effects of AG were higher than those of NG. In conclusion, aged garlic showed more potent antioxidant and antibacterial effects than fresh garlic.
Human umbilical cord blood‐derived mesenchymal stem cells (hUCB‐MSCs) exhibit potency for the regeneration of infarcted hearts. Vascular endothelial growth factor (VEGF) is capable of inducing ...angiogenesis and can boost stem cell‐based therapeutic effects. However, high levels of VEGF can cause abnormal blood vessel growth and hemangiomas. Thus, a controllable system to induce therapeutic levels of VEGF is required for cell therapy. We generated an inducible VEGF‐secreting stem cell (VEGF/hUCB‐MSC) that controls the expression of VEGF and tested the therapeutic efficacy in rat myocardial infarction (MI) model to apply functional stem cells to MI. To introduce the inducible VEGF gene cassette into a safe harbor site of the hUCB‐MSC chromosome, the transcription activator‐like effector nucleases system was used. After confirming the integration of the cassette into the locus, VEGF secretion in physiological concentration from VEGF/hUCB‐MSCs after doxycycline (Dox) induction was proved in conditioned media. VEGF secretion was detected in mice implanted with VEGF/hUCB‐MSCs grown via a cell sheet system. Vessel formation was induced in mice transplanted with Matrigel containing VEGF/hUCB‐MSCs treated with Dox. Moreover, seeding of the VEGF/hUCB‐MSCs onto the cardiac patch significantly improved the left ventricle ejection fraction and fractional shortening in a rat MI model upon VEGF induction. Induced VEGF/hUCB‐MSC patches significantly decreased the MI size and fibrosis and increased muscle thickness, suggesting improved survival of cardiomyocytes and protection from MI damage. These results suggest that our inducible VEGF‐secreting stem cell system is an effective therapeutic approach for the treatment of MI. Stem Cells Translational Medicine 2017;6:1040–1051
Background and aims
Endoscopic submucosal dissection (ESD) for undifferentiated early gastric cancer (UD EGC) has debate due to the risk of lymph node metastasis. We investigated the outcomes of ESD ...compared to those of surgery for the UD EGC within expanded indication.
Methods
We reviewed 971 UD EGC patients performed ESD across 18 hospitals in Korea and 1812 patients who underwent surgical resection in two hospitals between February 2005 and May 2015. Of these cases, we enrolled a curative resected ESD group of 328 patients and surgery group of 383 cases within an expanded indication. Overall outcomes and one-to-one propensity score-matched (218 ESD group vs 218 surgery group cases) outcomes for these two groups were analyzed.
Results
Over the 75.6 month median follow-up period for the 711 enrolled cases, recurrences occurred in 22 patients (6.7%) in the ESD group but not in the surgery group. Overall survival (OS) was higher in the surgery group (
p
= 0.0316) in all cases, but there was no significant difference after propensity score matching (
p
= 0.069). According to the histologic type in propensity score matching, the OS of signet ring cell carcinoma and poorly differentiated carcinoma patients did not differ between the ESD and surgery groups (
p
= 0.1189 and
p
= 0.3087, respectively). In the surgery group involving expanded criteria, lymph node metastasis was found in six cases (1.56%).
Conclusions
Although ESD shows comparable outcomes to surgery for the UD EGC within expanded indications, appropriate patient selection is needed for the ESD due to the possibility of lymph node metastasis.
Atopic dermatitis (AD) is a common inflammatory skin disease, and its pathogenesis is closely associated with microbial homeostasis in the gut, namely the gut-skin axis. Particularly, recent ...metagenomics studies revealed that the abundance of two major bacterial species in the gut, Faecalibacterium prausnitzii and Akkermansia muciniphila, may play a critical role in the pathogenesis of AD, but the effect of these species in AD has not yet been elucidated. To evaluate the potential beneficial effect of F. prausnitzii or A. muciniphila in AD, we conducted an animal model study where F. prausnitzii EB-FPDK11 or A. muciniphila EB-AMDK19, isolated from humans, was orally administered to 2,5-dinitrochlorobenzene (DNCB)-induced AD models using NC/Nga mice at a daily dose of 10
CFUs/mouse for six weeks. As a result, the administration of each strain of F. prausnitzii and A. muciniphila improved AD-related markers, such as dermatitis score, scratching behavior, and serum immunoglobulin E level. Also, the F. prausnitzii and A. muciniphila treatments decreased the level of thymic stromal lymphopoietin (TSLP), triggering the production of T helper (Th) 2 cytokines, and improved the imbalance between the Th1 and Th2 immune responses induced by DNCB. Meanwhile, the oral administration of the bacteria enhanced the production of filaggrin in the skin and ZO-1 in the gut barrier, leading to the recovery of functions. Taken together, our findings suggest that F. prausnitzii EB-FPDK11 and A. muciniphila EB-AMDK19 have a therapeutic potential in AD, which should be verified in humans.
Sulfur-containing amino acids such as methionine, cysteine, and taurine are present in animals and plants with biological functions. The aim of this study was to determine the antioxidant activities ...of representative sulfur-containing amino acids using various in vitro antioxidant assays including radical scavenger activities against DPPH, ABTS, and superoxide radicals, ferric reducing antioxidant power, hydrogen peroxide scavenging activity, and metal chelating activities. Of the three sulfur-containing amino acids, cysteine had the highest DPPH, ABTS, and O2− radical and H2O2 scavenging activities, FRAP, and metal chelating activities except for Fe2+ chelating. However, methionine and taurine failed to show DPPH or ABTS radical scavenging activity. Based on the results of the present study, sulfur-containing amino acids with excellent antioxidant abilities might be useful for the food processing industry as antioxidant additives to extend shelf-life of food or food products and offer beneficial pharmacological effect against cell damage caused by oxidative stress.
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