Tremella fuciformis polysaccharides induce ferroptosis in Epstein-Barr virus-associated gastric cancer by inactivating NRF2/HO-1 signaling.

Approximately 10% of gastric cancers are associated with Epstein-Barr virus (EBV). Tremella fuciformis polysaccharides (TFPs) are characterized by antioxidative and anti-inflammatory effects in different diseases. However, whether TFP improves EBV-associated gastric cancer (EBVaGC) has never been explored. The effects of TFP on EBV-infected GC cell viability were determined using a CCK-8 assay and flow cytometry. Western blotting and RT-qPCR were performed to explore the expression of ferroptosis-related proteins. The CCK-8 assay showed that TFP decreased EBV-infected GC cell viability in a dose- and time-dependent manner. Flow cytometry assays indicated that TFP significantly induced EBV-infected GC cell death. TFP also reduced the migratory capacity of EBV-infected GC cells. Furthermore, treatment with TFP significantly increased the mRNA levels of PTGS2 and Chac1 in EBV-infected GC cells. Western blot assays indicated that TFP suppressed the expression of NRF2, HO-1, GPX4 and xCT in EBV-infected GC cells. More importantly, overexpression of NRF2 could obviously rescue TFP-induced downregulation of GPX4 and xCT in EBV-infected GC cells. In summary, we showed novel data that TFP induced ferroptosis in EBV-infected GC cells by inhibiting NRF2/HO-1 signaling. The current findings may shed light on the potential clinical application of TFP in the treatment of EBVaGC.

[Retracted] Exosomal miR­130a­3p promotes the progression of differentiated thyroid cancer by targeting insulin­like growth factor 1.

[This retracts the article DOI: 10.3892/ol.2021.12544.].

Reinforcement methods of duodenal stump after laparoscopic gastrectomy for gastric cancer: A review.

Duodenal stump fistula is a rare but dangerous complication of gastric cancer surgery. Reinforcement of the duodenal stump was suggested as a useful method to prevent the occurrence of duodenal stump fistula. Although laparoscopic surgery has been established as a safe procedure for gastric cancer, it is acknowledged that the application of duodenal stump reinforcement is a demanding process in laparoscopic radical gastrectomy. This review aims to provide a concise description of the proposed reinforcement methods of duodenal stump after laparoscopic radical gastrectomy for gastric cancer by summarizing the relevant literature written in English. The thorough knowledge of these reinforcement techniques may help surgeons to find the most suitable reinforcement method of duodenal stump for patients.

Larotrectinib induces autophagic cell death through AMPK/mTOR signalling in colon cancer.

Larotrectinib (Lar) is a highly selective and potent small-molecule inhibitor used in patients with tropomyosin receptor kinase (TRK) fusion-positive cancers, including colon cancer. However, the underlying molecular mechanisms specifically in patients with colon cancer have not yet been explored. Our data showed that Lar significantly suppressed proliferation and migration of colon cancer cells. In addition, Lar suppressed the epithelial-mesenchymal transition (EMT) process, as evidenced by elevation in E-cadherin (E-cad), and downregulation of vimentin and matrix metalloproteinase (MMP) 2/9 expression. Furthermore, Lar was found to activate autophagic flux, in which Lar increased the ratio between LC3II/LC3I and decreased the expression of p62 in colon cancer cells. More importantly, Lar also increased AMPK phosphorylation and suppressed mTOR phosphorylation in colon cancer cells. However, when we silenced AMPK in colon cancer cells, Lar-induced accumulation of autolysomes as well as Lar-induced suppression of the EMT process were significantly diminished. An in vivo assay also confirmed that tumour volume and weight decreased in Lar-treated mice than in control mice. Taken together, this study suggests that Lar significantly suppresses colon cancer proliferation and migration by activating AMPK/mTOR-mediated autophagic cell death.

Comparative study of sarcomatoid carcinoma and carcinosarcoma of the pancreas: a population-based study.

Background: Sarcomatoid carcinoma (SCP) and carcinosarcoma (CSP) of the pancreas are extremely rare entities and little is known about their characteristics. Using a population-based cancer registry, we aimed at improving our understanding of these entities with a focus on the comparison between these two entities. Methods: Patients with SCP or CSP were identified through the Surveillance Epidemiology and End Results (SEER) database. Demographic and clinical characteristics were collected and compared. Survival was compared using the Kaplan-Meier method and analyzed using the log-rank test and Cox proportional hazards models. Results: A total of 85 patients with SCP and 32 patients with CSP were included in the study. There was no difference in the patient age, race distribution, year of diagnosis, primary site, tumor size, tumor stage, receipt of chemotherapy and receipt of radiotherapy between the two groups. However, more patients with CSP received surgical treatment (P<0.001) when compared to patients with SCP. Overall survival was comparable between the two groups (P=0.562) with a 1-year survival rate of 20.8% and 22.2% for SCP and CSP, respectively. Multivariate analysis showed that surgical resection was independent prognostic factor of both SCP (HR: 0.34, P=0.017) and CSP (HR: 0.17, P=0.017). Chemotherapy was a prognostic factor of CSP in univariate analysis, but not of SCP. Conclusions: SCP and CSP are rare malignant tumors of the pancreas with a dismal prognosis. Surgical resection was the common prognostic factor and was recommended when possible.

Long noncoding RNA (lncRNA) HOTAIR: Pathogenic roles and therapeutic opportunities in gastric cancer.

Gastric cancer is one of the first malignant cancers in the world and a large number of people die every year due to this disease. Many genetic and epigenetic risk factors have been identified that play a major role in gastric cancer. HOTAIR is an effective epigenetic agent known as long noncoding RNA (lncRNA). HOTAIR has been described to have biological functions in biochemical and cellular processes through interactions with many factors, leading to genomic stability, proliferation, survival, invasion, migration, metastasis, and drug resistance. In the present article, we reviewed the prognostic value of the molecular mechanisms underlying the HOTAIR regulation and its function in the development of Gastric Cancer, whereas elucidation of HOTAIR-protein and HOTAIR-DNA interactions can be helpful in the identification of cancer processes, leading to the development of potential therapeutic strategies.

Association of RASSF1A Ala133Ser polymorphism with cancer risk: a updated meta-analysis involving 7362 subjects.

It has been demonstrated in many studies that the polymorphism of Ras association domain family 1 isoform A (RASSF1A) is related to tumor risk; however, this conclusion remains a controversy. In this study, we systemically retrieved relevant studies in electronic databases such as PUBMED, and EMBASE, and calculated odds ratios (ORs) as well as relevant 95% confidence intervals (CIs). Besides, meta-package in STATA version 12.0 was used. This meta-analysis finally included altogether 12 studies with 16 case-control articles. According to our data, the polymorphism of RASSF1A Ala133Ser was associated with tumor risk (Ser vs. Ala: OR = 1.68,95% CI = 1.20-2.36; Ala/Ser vs. Ala/Ala:OR = 1.63,95% CI = 1.16-2.27; Ser/Ser vs. Ala/Ala:OR = 3.06,95% CI = 1.91-4.89; Recessive model:OR = 2.67, 95% CI = 1.66-4.32; Dominant model: OR =1.72, 95% CI =1.20-2.45). Further, subgroup analyses stratified based on race and cancer type indicated this polymorphism is related to lung cancer(LC) and hepatocellular carcinoma(HCC) susceptibility in Asians.In conclusion, we found that RASSF1A Ala133Ser polymorphism increased LC and HCC risk in Asians, which requires large-scale, delicately-designed researches for verification.

Ginsenoside Rg3 ameliorates acute pancreatitis by activating the NRF2/HO­1­mediated ferroptosis pathway.

Acute pancreatitis (AP) is an inflammatory disorder that has been associated with systemic inflammatory response syndrome. Ginsenoside Rg3 is a major active component of Panax ginseng, which has been demonstrated to exert potent protective effects on hyperglycemia and diabetes. However, it remains to be determined whether Rg3 ameliorates AP. Thus, an in vitro AP cell model was established in the present study by exposing AR42J cells to cerulein (Cn). AR42J cell viability was increased in the Rg3­treated group as compared with the Cn­exposed group. Simultaneously, the number of dead AR42J cells was decreased in the Rg3­treated group compared with the group treated with Cn only. Furthermore, following treatment with Rg3, the production of malondialdehyde (MDA) and ferrous ion (Fe2+) in the AR42J cells was reduced, accompanied by increased glutathione (GSH) levels. Western blot analysis revealed that the decrease in glutathione peroxidase 4 (GPX4) and cystine/glutamate transporter (xCT) levels induced by Cn were reversed by Rg3 treatment in the AR42J cells. Mice treated with Cn exhibited increased serum amylase levels, as well as increased levels of TNFα, IL­6, IL­1ß, pancreatic MDA, reactive oxygen species (ROS) and Fe2+ production. Following Rg3 treatment, ROS accumulation and cell death were decreased in the pancreatic tissues compared with the AP group. Furthermore, in the pancreatic tissues of the AP model, the expression of nuclear factor­erythroid factor 2­related factor 2 (NRF2)/heme oxygenase 1 (HO­1)/xCT/GPX4 was suppressed. In comparison, the NRF2/HO­1/xCT/GPX4 pathway was activated in pancreatic tissues following Rg3 administration. Taken together, the present study, to the best of our knowledge, is the first to reveal a protective role for Rg3 in mice with AP by suppressing oxidative stress­related ferroptosis and the activation of the NRF2/HO­1 pathway.

Adult versus paediatric undifferentiated embryonal sarcoma of the liver: a SEER database analysis.

BACKGROUND: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare liver tumour that occurs mainly in children. Herein, we aimed to identify any differences in clinical characteristics and survival between adult and paediatric patients with UESL. METHODS: From 1975 to 2015 in the Surveillance, Epidemiology and End Results (SEER) database, patients diagnosed with UESL were identified and divided into paediatric (<18 years) and adult (≥18 years) groups. We then compared the clinical characteristics, management, and overall survival (OS) of adults and children diagnosed with UESL. RESULTS: We analysed 113 patients with UESL (81 children and 32 adults). UESL was significantly more common in adult male than paediatric male patients (71.9% vs. 48.2%; P = 0.022). When compared to adult patients, paediatric patients were more likely to receive chemotherapy (93.8% vs. 65.6%; P < 0.001). Adults had a significantly worse OS than paediatric patients (5-year OS, 30.0% vs. 81.2%; P < 0.001). Univariate analysis found that adult age, surgical therapy and chemotherapy were associated with OS. Multivariate analysis revealed that adult age, SEER summary stage and surgical therapy were independent prognostic factors for OS. CONCLUSIONS: UESL had a male predominance among adult patients. Moreover, the prognosis of adult patients with UESL was significantly worse than that of paediatric patients. Surgery and chemotherapy should be considered in the treatment of patients with UESL.

Efficiency of complete omentectomy in patients with resectable gastric cancer: a meta­analysis and systematic review.

BACKGROUND: We performed a meta-analysis to investigate the efficacy of complete omentectomy (CO) in patients undergoing radical gastrectomy for gastric cancer. METHODS: We conducted a literature search in PubMed, Web of Science, and the Cochrane Library databases for clinical research that compared CO with non-complete omentectomy (NCO). These articles were published prior to April 2021. Overall survival (OS) rates, relapse-free survival (RFS) rates, recurrence rates, operation times, estimates of blood loss, numbers of harvested lymph nodes, complications, and lengths of hospital stays were compared using relative risks (RRs) and weighted mean differences (WMDs). RevMan 5.3 software was used for statistical analysis. RESULTS: Nine studies that included 3329 patients (1960 in the CO group) and 1369 in the NCO group comprised the analysis. The meta-analysis showed that CO was associated with a decreased 3-year OS rate (RR = 0.94, 95% CI 0.90-0.98, P = 0.005) and 5-year OS rate (RR = 0.93, 95% CI 0.88-0.98, P = 0.007). However, it was not associated with the 3-year RFS rate (RR = 0.97, 95% CI 0.90-1.04, P = 0.44), 5-year RFS (RR = 0.98, 95% CI 0.90-1.06, P = 0.60), or recurrence rate (RR = 1.17, 95% CI 0.95-1.45, P = 0.15) compared to the NCO group. For surgical-related outcomes, significant heterogeneity existed between the studies. Compared to the NCO group, CO was found to be associated with significantly more estimated blood loss (WMD = 250.90, 95% CI 105.90-396.28, P = 0.0007) and less harvested lymph nodes (WMD = - 3.59, 95% CI - 6.88, - 0.29, P = 0.03). Although, there was no significant difference in the surgical time (WMD = 15.93, 95% CI - 0.21, 32.07, P = 0.05). No statistically significant differences were observed in the rates of overall (P = 0.79) and major complications (P = 0.90), or the lengths of hospital stays (P = 0.11) between the two groups. CONCLUSIONS: Based on the available evidence, CO is not superior to NCO in terms of survival. CO is not recommended as a routine surgery for gastric cancer. Future well-designed high-quality RCTs are warranted.

Exosomal miR-130a-3p promotes the progression of differentiated thyroid cancer by targeting insulin-like growth factor 1.

The aim of the present study was to determine the expression and diagnostic value of exosomal miR-130a-3p in the serum of patients with differentiated thyroid cancer (DTC). Exosomes were isolated from the serum of patients with DTC and were identified using transmission electron microscopy. A novel exosomal miRNA, miR-130a-3p, was found to be significantly decreased in the serum of patients with DTC compared with those with benign thyroid tumors and healthy controls. Further study revealed that exosomal miR-130a-3p was correlated with the malignant characteristics of DTC, including tumor diameter, lymph node metastasis (LNM) and higher TNM stage. Receiver operating characteristic curve analysis demonstrated that the area under the curve of exosomal miR-130a-3p was better compared with that of TgAb and Tg in patients with DTC. More importantly, the combined use of exosomal miR-130a-3p, TgAb and Tg significantly enhanced the sensitivity and specificity, indicating that exosomal miR-130a-3p is a sensitive biomarker for DTC. A dual luciferase reporter assay indicated that insulin-like growth factor (IGF)-1 was a target gene of miR-130a-3p. Pearson's correlation analysis revealed a negative correlation between serum IGF-1 and serum exosomal miR-130a-3p levels. More importantly, exosomes from patients with DTC increased the expression of IGF-1 and p-PI3K/p-AKT, but these effects were abolished by siRNA targeting IGF-1 in TPC-1 cells. Taken together, the findings of the present study indicated that reduced exosomal miR-130a-3p levels were associated with the risk of DTC and may be used as a biomarker for the diagnosis of DTC.

Exosomal NNMT from peritoneum lavage fluid promotes peritoneal metastasis in gastric cancer.

Peritoneal metastasis (PM) is the major cause of recurrence in patients with gastric cancer (GC) and is associated with poor prognosis. The oncogenic role of Nicotinamide N-methyltransferase (NNMT) in GC has been reported, but the role of secreted NNMT that is transported by exosomes remains unknown. In this study, exosomes were isolated from GC patients with or without PM and from GC cell line, including GC-114, GC-026, MKN45, and SNU-16 cells. The contents of NNMT were significantly enhanced in exosomes isolated from GC patients with PM compared with those from GC patients without PM. Furthermore, the levels of NNMT were significantly enhanced in exosomes from GC cell lines relative to those from normal human gastric epithelial cell line GES-1 cells. These data indicate that NNMT may be involved in intercellular communication for peritoneal dissemination. Moreover, colocalization of GC-derived exosomal NNMT was found in human peritoneal mesothelial cell line HMrSV5 cells. Additionally, relative to GES-1 exosomes, SNU-16 exosomes significantly activated TGF-ß/smad2 signaling in HMrSV5 cells. However, when NNMT was silenced, the activation of TGF-ß/smad2 by SNU-16 exosomes was abolished in HMrSV5 cells. We propose that NNMT-containing exosomes derived from GC cells could promote peritoneal metastasis via TGF-ß/smad2 signaling.

Extracellular vesicle derived miR-544 downregulates expression of tumor suppressor promyelocytic leukemia zinc finger resulting in increased peritoneal metastasis in gastric cancer.

Peritoneal metastasis (PM) is the main cause of poor prognosis in patients with advanced gastric cancer (GC). Increasing evidence has suggested that cancer-associated EVs in body fluids may assist in the diagnosis and treatment of GC. Here, we investigated the role of GC-derived EVs in PM development. Our results demonstrate that expression of the tumor suppressor promyelocytic leukemia zinc finger (PLZF) is decreased in GC tissues and PM lesions from GC patients. PLZF suppression promoted migration and invasion of peritoneal mesothelial HMrSV5 cells, while PLZF overexpression suppressed HMrSV5 cell migration and invasion. Microarray analysis revealed significantly upregulated expression of several miRNAs in EVs isolated from GC patients with PM, including miR-544. The increased miR-544 expression was confirmed in GC tissues and PM-derived EVs. Transfection with miR-544 reduced PLZF expression in HMrSV5 cells, while miR-544 inhibition increased PLZF expression. Incubation of GC cells with peritoneal mesothelial HMrSV5 cells showed that miR-544 could be transferred from GC-derived EVs to peritoneal cells, where it suppressed the PLZF expression. These findings indicate that EV-mediated transfer of miR-544 decreases the PLZF expression in PM lesions, which suggests miR-544 could potentially serve as a diagnostic biomarker and therapeutic target for treatment of GC patients.

Circulating circRNA Has_Circ_0141633 Serves as a Potential Biomarker for Gastric Cancer.

BACKGROUND: The current study aims to investigate the expression of circRNA has_circ_0141633 in the tissues and serum of patients with gastric cancer (GC). METHODS: RT-qPCR was used to detect the expression of has_circ_0141633 in the tissues and serum of patients with GC. Pearson's correlation was used to analyze the relationship between the level of serum and tissue has_circ_0141633 in GC patients. Receiver characteristic curve (ROC) was used to evaluate the diagnostic value of the expression of serum has_circ_0141633 in GC patients. The relationship between serum has_circ_0141633 and the clinicopathological characteristic was analyzed in GC patients. Kaplan-Meier method was used to analyze the survival rate. RESULTS: The level of serum and tissue has_circ_0141633 in GC patients was significantly higher than that in controls. Pearson's correlation analysis showed a positive correlation between serum and tissue has_circ_0141633 levels (r = 0.846, p < 0.05). ROC curve analysis showed that the AUC of serum has_circ_0141633 was 0.835 (95% CI: 0.753 - 0.916), with the sensitivity and specificity of 84.5% and 93.6%. The level of serum has_circ_0141633 was significantly increased according to the malignant characteristics of tumor diameter, differentiation, lymph node metastasis, and TNM stage. The median survival time of GC patients with low expression of has_circ_0141633 was longer than that of GC patients with high expression of has_circ_0141633. CONCLUSIONS: In summary, upregulation of serum has_circ_0141633 may be expected to be a specific molecular marker for the diagnosis and evaluation of malignant GC.

Increased levels of miR-372 correlate with disease progression in patients with hyperlipidemic acute pancreatitis.

The aim of the present study was to investigate the expression of microRNA (miRNA)-372 in the serum of patients with hyperlipidemic acute pancreatitis (HTGAP), and its clinical significance. Patients with a serum lipid concentration ≥11.3 or 5.65-11.3 mmol/l with chylous serum were included in group A (n=40). The remaining patients did not have HTGAP and were included in group B (B). A further 25 patients with hyperlipidemia, but not AP (group C), and 30 healthy volunteers (group D) were recruited as controls. The level of miR-372 in the serum of group A (4.76±2.60) was significantly increased compared with groups B (0.98±0.80), C (0.85±0.62) and D (0.76±0.44); however, there was no significant difference in the expression of miR-372 between groups B, C and D. The expression level of miR-372 was significantly increased in the severe HTGAP group (6.45±2.20) compared with the mild HTGAP group (3.08±1.74). Further experiments suggested that the expression level of miR-372 was positively correlated with the level of triacylglycerol (r=0.666; P<0.001) but not with the level of amylase (r=-0.145; P>0.05). ROC analysis indicated that the combined use of miR-372 expression levels and Acute Physiology and Chronic Health Evaluation II scoring improved the diagnostic value for HTGAP. In summary, the expression of miR-372 in HTGAP was significantly upregulated and increased with the severity of the disease. The results of the present study may provide a novel strategy for the diagnosis and severity assessment of HTGAP in the clinic.

Efficacy of gastric decompression after pancreatic surgery: a systematic review and meta-analysis.

BACKGROUND: Gastric decompression after pancreatic surgery has been a routine procedure for many years. However, this procedure has often been waived in non-pancreatic abdominal surgeries. The aim of this meta-analysis was to determine the necessity of routine gastric decompression (RGD) following pancreatic surgery. METHODS: PubMed, the Cochrane Library, EMBASE, and Web of Science were systematically searched to identify relevant studies comparing outcomes of RGD and no gastric decompression (NGD) after pancreatic surgery. The overall complications, major complications, mortality, delayed gastric emptying (DGE); clinically relevant DGE (CR-DGE), postoperative pancreatic fistula (POPF), clinically relevant POPF (CR-POPF), secondary gastric decompression, and the length of hospital stay were evaluated. RESULTS: A total of six comparative studies with a total of 940 patients were included. There were no differences between RGD and NGD groups in terms of the overall complications (OR = 1.73, 95% CI: 0.60-5.00; p = 0.31), major complications (OR = 2.22, 95% CI: 1.00-4.91; p = 0.05), incidence of secondary gastric decompression (OR = 1.19, 95% CI: 0.60-2.02; p = 0.61), incidence of overall DGE (OR = 2.74; 95% CI: 0.88-8.56; p = 0.08; I2 = 88%), incidence of CR-POPF (OR = 1.28, 95% CI: 0.76-2.15; p = 0.36), and incidence of POPF (OR = 1.31, 95% CI: 0.81-2.14; p = 0.27). However, RGD was associated with a higher incidence of CR-DGE (OR = 5.45; 95% CI: 2.68-11.09; p < 0.001, I2 = 35%), a higher rate of mortality (OR = 1.53; 95% CI: 1.05-2.24; p = 0.03; I2 = 83%), and a longer length of hospital stay (WMD = 5.43, 95% CI: 0.30 to 10.56; p = 0.04; I2 = 93%). CONCLUSIONS: Routine gastric decompression in patients after pancreatic surgery was not associated with a better recovery, and may be unnecessary after pancreatic surgery.

Diagnostic Value of miR-142-5p and Tiam-1 in Colon Cancer Patients.

BACKGROUND: The current study aims to detect the expression of miR-142-5p and T-cell lymphoma invasion and metastasis 1 (Tiam1) in colon cancer tissues and adjacent normal tissues, thereby exploring their association with clinical stage and lymph node metastasis of colon cancer. METHODS: Thirty specimens of colon cancer tissues and adjacent tissues were collected. The expressions of miR-142-5p and Tiam1 were detected by RT-PCR. The correlation between them and clinical pathology was analyzed using person correlation assay. RESULTS: The expression of miR-142-5p in colon cancer tissues (0.46 ± 0.25) was lower than that in adjacent tissues (1.00 ± 0.23), and the difference was statistically significant. The expression of Tiam1 gene in colon cancer tissues (5.46 ± 2.34) was higher than that in adjacent tissues (1.00 ± 0.43). There was a significant negative correlation between miR-142-5p and Tiam1 (r = -0.873, p < 0.01). The expression level of miR-142-5p (0.22 ± 0.07) in stage III and IV colon cancer tissues was significantly lower than that in stage I and II colon cancer tissues (0.71 ± 0.21, p < 0.05), while the expression level of Tiam1 mRNA (6.37 ± 1.98) in stage III and IV colon cancer tissues was significantly higher than that in stage I and II colon cancer tissues (2.86 ± 1.32, p < 0.05). Furthermore, the expression of miR-142-5p in colon cancer with lymph node metastasis was significantly lower than that in colon cancer without lymph node metastasis, while the expression of Tiam1 was contrary to that in colon cancer without lymph node metastasis. CONCLUSIONS: In summary, miR-142-5p and Tiam-1 may be potential diagnostic markers for colon cancer.

A Rat Model of Radiation Vasculitis for the Study of Mesenchymal Stem Cell-Based Therapy.

Radiation vasculitis is one of the most common detrimental effects of radiotherapy for malignant tumors. This is developed at the vasculature of adjacent organs. Animal experiments have showed that transplantation of mesenchymal stem cells (MSCs) restores vascular function after irradiation. But the population of MSCs being engrafted into irradiated vessels is too low in the conventional models to make assessment of therapeutic effect difficult. This is presumably because circulating MSCs are dispersed in adjacent tissues being irradiated simultaneously. Based on the assumption, a rat model, namely, RT (radiation) plus TX (transplantation), was established to promote MSC homing by sequestering irradiated vessels. In this model, a 1.5 cm long segment of rat abdominal aorta was irradiated by 160kV X-ray at a single dose of 35Gy before being procured and grafted to the healthy counterpart. F344 inbred rats served as both donors and recipients to exclude the possibility of immune rejection. A lead shield was used to confine X-ray delivery to a 3 cm×3 cm square-shaped field covering central abdominal region. The abdominal viscera especially small bowel and colon were protected from irradiation by being pushed off the central abdominal cavity. Typical radiation-induced vasculopathy was present on the 90th day after irradiation. The recruitment of intravenously injected MSCs to irradiated aorta was significantly improved by using the RT-plus-TX model as compared to the model with irradiation only. Generally, the RT-plus-Tx model promotes MSC recruitment to irradiated aorta by separating irradiated vascular segment from adjacent tissue. Thus, the model is preferred in the study of MSC-based therapy for radiation vasculitis when the evaluation of MSC homing is demanding.

HMGB1-modified mesenchymal stem cells attenuate radiation-induced vascular injury possibly via their high motility and facilitation of endothelial differentiation.

BACKGROUND: Vascular injury is one of the most common detrimental effects of cancer radiotherapy on healthy tissues. Since the efficacy of current preventive and therapeutic strategies remains limited, the exploration of new approaches to treat radiation-induced vascular injury (RIV) is on high demands. The use of mesenchymal stem cells (MSCs) to treat RIV holds great promise thanks to their well-documented function of mediating tissue regeneration after injury. Recently, we genetically modified MSCs with high mobility group box 1 (HMGB1) and demonstrated the high efficacy of these cells in treating graft atherosclerosis. The current study was to investigate the protective effect of HMGB1-modified MSCs (MSC-H) on RIV by using a rat model. METHODS: Female F344 rats received an intravenous injection of male F344 MSC-H cells or vehicle control at four doses of 2 × 106 cells with a 15-day interval starting from 30 days after irradiation to the abdominal aorta. The aortas were procured for histological and biomedical analysis at 90 days after irradiation. Cell migration to irradiated aortas was traced by green fluorescent protein and sex determination region on the Y chromosome. In vitro cell migration and endothelial differentiation of MSC-H cells were analyzed by stromal-derived factor 1-induced transwell assay and RNA microarray, respectively. The contribution of extracellular HMGB1 to the bioactivity of MSC-H cells was investigated by inhibition experiments with HMGB1 antibody. RESULT: MSC-H cell infusion alleviated neointimal formation, vascular inflammation, and fibrosis in irradiated aortas, which was associated with local migration and endothelial differentiation of MSC-H cells. The MSC-H cells showed high motility and potential of endothelial differentiation in vitro. Microarray analysis suggested multiple pathways like MAPK and p53 signaling were activated during endothelial differentiation. MSC-H cells highly expressed CXC chemokine receptor 4 and migrated progressively after stromal-derived factor 1 stimulation, which was blocked by the antagonist of CXC chemokine receptor 4. Finally, the migration and endothelial differentiation of MSC-H cells were inhibited by HMGB1 antibody. CONCLUSION: MSC-H cell infusion significantly attenuated RIV, which was associated with their high motility and endothelial differentiation potential. Multiple pathways that possibly contributed to the efficacy of MSC-H cells were suggested and deserved further investigation.

Oxidation Prevents HMGB1 Inhibition on PDGF-Induced Differentiation of Multipotent Vascular Stem Cells to Smooth Muscle Cells: A Possible Mechanism Linking Oxidative Stress to Atherosclerosis.

Atherosclerosis is considered as a multifactorial disease in terms of the pathogenic mechanisms. Oxidative stress has been implicated in atherogenesis, and the putative mechanisms of its action include oxidative modification of redox-sensitive signaling factors. High mobility group box 1 (HMGB1) is a key inflammatory mediator in atherosclerosis, but if oxidized it loses its activity. Thus, whether and how it participates in oxidative stress-induced atherosclerosis are not clear. The current study found that exogenous HMGB1 dose-dependently inhibited the proliferation of multipotent vascular stem cells and their differentiation to smooth muscle cells induced by platelet-derived growth factor. But oxidative modification impaired the activity of HMGB1 to produce the effect. The stem cells were regarded as the source of smooth muscle cells in vascular remodeling and neointimal hyperplasia. Therefore, the findings suggested that HMGB1 participated in oxidative stress-induced atherosclerosis presumably by targeting multipotent vascular stem cells.