Pan-cancer analyses of immunogenic cell death-derived gene signatures: Potential biomarkers for prognosis and immunotherapy.

BACKGROUND: Immunogenic cell death (ICD) is a type of regulated cell death that is capable of initiating an adaptive immune response. Induction of ICD may be a potential treatment strategy, as it has been demonstrated to activate the tumor-specific immune response. AIMS: The biomarkers of ICD and their relationships with the tumor microenvironment, clinical features, and immunotherapy response are not fully understood in a clinical context. Therefore, we conducted pan-cancer analyses of ICD gene signatures across 33 cancer types from The Cancer Genome Atlas database. METHODS AND RESULTS: We identified key genes that had strong relationships with survival and the tumor microenvironment, contributing to a better understanding of the role of ICD genes in cancer therapy. In addition, we predicted therapeutic agents that target ICD genes and explored the potential mechanisms by which gemcitabine induce ICD. Moreover, we developed an ICD score based on the ICD genes and found it to be associated with patient prognosis, clinical features, tumor microenvironment, radiotherapy access, and immunotherapy response. A high ICD score was linked to the immune-hot phenotype, while a low ICD score was linked to the immune-cold phenotype. CONCLUSION: We uncovered the potential of ICD gene signatures as comprehensive biomarkers for ICD in pan-cancer. Our research provides novel insights into immuno-phenotypic assessment and cancer therapeutic strategies, which could help to broaden the application of immunotherapy to benefit more patients.

Opioid-free anesthesia reduces the severity of acute postoperative motion-induced pain and patient-controlled epidural analgesia-related adverse events in lung surgery: randomized clinical trial.

Background: Opioids have been used as pain relievers for thousands of years. However, they may also cause undesirable side effects. We therefore performed this study to compare the effect of opioid-free anesthesia (OFA) versus opioid-sparing anesthesia (OSA) on postoperative pain and patient-controlled epidural analgesia (PCEA)-related events. Methods: This is a single center randomized clinical trial that was recruited patients aged from 18 to 70 years who received video-assisted lung surgery between October 2021 and February 2022. Participants were 1:1 randomly assigned to OFA or OSA. Patients in the OFA group received propofol, rocuronium, esmolol, lidocaine, and magnesium sulfate intravenously with epidural ropivacaine. Patients in the OSA group received propofol, rocuronium, remifentanil, and sufentanil intravenously with epidural hydromorphone and ropivacaine. Results: A total number of 124 patients were randomly allocated to the OFA or OSA group. In the OFA group, the severity of pain during coughs on the first postoperative days (PODs; VAS score 1.88 ± 0.88 vs. 2.16 ± 1.1, p = 0.044) was significantly lower than that in the OSA group. The total ratio of PCEA-related adverse events in the OFA group [11 (19.6%) vs. 26 (47.3%), p = 0.003] was significantly lower than in the OSA group. Conclusion: OFA in patients who received video-assisted lung surgery led to lower severity of acute postoperative motion-induced pain and fewer PCEA-related adverse events on the first POD than in the patients in the OSA group. Clinical trial registration: clinicaltrials.gov, identifier (NCT05063396).

Artifact Detection and Restoration in Histology Images With Stain-Style and Structural Preservation.

The artifacts in histology images may encumber the accurate interpretation of medical information and cause misdiagnosis. Accordingly, prepending manual quality control of artifacts considerably decreases the degree of automation. To close this gap, we propose a methodical pre-processing framework to detect and restore artifacts, which minimizes their impact on downstream AI diagnostic tasks. First, the artifact recognition network AR-Classifier first differentiates common artifacts from normal tissues, e.g., tissue folds, marking dye, tattoo pigment, spot, and out-of-focus, and also catalogs artifact patches by their restorability. Then, the succeeding artifact restoration network AR-CycleGAN performs de-artifact processing where stain styles and tissue structures can be maximally retained. We construct a benchmark for performance evaluation, curated from both clinically collected WSIs and public datasets of colorectal and breast cancer. The functional structures are compared with state-of-the-art methods, and also comprehensively evaluated by multiple metrics across multiple tasks, including artifact classification, artifact restoration, downstream diagnostic tasks of tumor classification and nuclei segmentation. The proposed system allows full automation of deep learning based histology image analysis without human intervention. Moreover, the structure-independent characteristic enables its processing with various artifact subtypes. The source code and data in this research are available at https://github.com/yunboer/AR-classifier-and-AR-CycleGAN.

The effects of erector spinae plane block on perioperative opioid consumption and rehabilitation in video assisted thoracic surgery.

BACKGROUND: This study aimed to determine whether ultrasound-guided continuous erector spinae plane block (ESPB) had an effect on opioid consumption and postoperative rehabilitation in patients undergoing video-assisted thoracic surgery (VATS). METHODS: In this prospective study, 120 patients aged 20-70 years who underwent elective VATS were randomly allocated to one of three groups: group C (general anesthesia with patient-controlled intravenous analgesia [PCIA]), group T (general anesthesia with patient-controlled epidural analgesia [PCEA]), or group E (general anesthesia with continuous ESPB and PCIA). Perioperative opioid consumption, visual analog scale (VAS) scores, preoperative and postoperative Quality of Recovery-15 scores, and postoperative opioid-related adverse events were all assessed. RESULTS: Intraoperative sufentanil consumption in groups T and E was significantly lower than that in group C (both P < 0.001), and the postoperative sufentanil consumption in group E was also significantly lower than that in group C (P = 0.001). Compared with group C, the VAS scores at rest or during coughing immediately out of the post-anesthesia care unit at 6 h, 12 h, and 24 h postoperatively were significantly lower in group T (P < 0.05). However, the VAS scores at rest at 6 h and 12 h postoperatively in group E were lower than those of group C (P < 0.05), but were significantly higher than those of group T at all study times (P < 0.05). CONCLUSION: Ultrasound-guided continuous ESPB significantly reduced perioperative opioid consumption during VATS and improved postoperative rehabilitation. However, these effects were inferior to those of thoracic epidural anesthesia. TRIAL REGISTRATION: The present study was prospectively registered at http://www.chictr.org/cn /(registration number: ChiCTR1900023050 ); registration date: May 82,019.

Mouse parabiosis model promotes recovery of lymphocytes in irradiated mice.

PURPOSE: Total body irradiation (TBI) -induced hematopoietic system injury is mainly due to the failure of self-renewal and to the differentiation ability of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) after radiation exposure. The mouse parabiosis model is mainly used in the field of aging research to explore whether circulating factors in peripheral blood can improve the functions of aged tissues and organs. In this study, we generated a mouse model to verify whether non-irradiated peripheral circulation can improve the circulatory environment in irradiated mice and ameliorate TBI-induced hematopoietic system injury. MATERIALS AND METHODS: Six- to eight-week-old male C57BL/6 mice were adjoined by a surgical operation. Four weeks later, one mouse in the pair was exposed to 8 Gy or 6 Gy X-ray, and B and T cells in the peripheral blood, bone marrow, spleen, mesenteric lymph nodes and thymus were then detected by flow cytometry. Hematopoietic stem/progenitor cells in bone marrow cells and their levels of ROS and apoptosis were also detected in this study. RESULTS: The results showed decreased percentages of B and T lymphocytes in the peripheral blood, bone marrow (BM), spleen and mesenteric lymph nodes (MLNs) in the isotype irradiated mice. The proportions of CD4-positive, CD8-positive, and CD4 and CD8 double-negative cells were also increased, while the proportion of CD4 and CD8 double-positive cells in the irradiated thymus was decreased. Thus, all of the above lymphocyte injuries in the parabiosis model were improved to nearly the levels of the control. We further detected radiation-induced HSC and HPC injury; however, the reduced HSC and HPC numbers, ROS levels and apoptosis percentages were not ameliorated in the parabiotic irradiated mice. CONCLUSIONS: Above all, our results showed that non-irradiated peripheral circulation can promote the recovery of TBI-induced lymphocyte injury, further indicating that the recovery of immune cells may play a very important role in the repair of TBI-induced damage.

Positive Impact of Intraoperative Epidural Ropivacaine Infusion on Oncologic Outcomes in Pancreatic Cancer Patients Undergoing Pancreatectomy: A Retrospective Cohort Study.

Background: Previous literatures have demonstrated that regional anesthesia such as epidural anesthesia may affect long-term survival of cancer patients. In the present study, we conducted a retrospective cohort study to investigate the survival impact of intraoperatively epidural ropivacaine infusion on pancreatic ductal adenocarcinoma (PDAC) patients. Methods: PDAC patients who underwent pancreatic surgery in Zhongshan Hospital Fudan University from January, 2015 to June, 2018 were included. The surgical procedure was performed under combined endotracheal general anesthesia and thoracic epidural anesthesia, and patient-controlled epidural analgesia (PCEA) with 0.12% ropivacaine was given after surgery for further pain control. Patients were divided into two groups according to their intraoperative epidural ropivacaine concentration: high (0.375%-0.5%) and low (0.15%-0.25%). Survival outcome was compared between groups. Results: A total of 215 patients were enrolled and their baseline characteristics were balanced between groups, except that patients with high concentration ropivacaine received higher total dose opioid and had longer operative time. Resected PDAC patients who were administrated with high concentration ropivacaine through epidural catheter intraoperatively had improved overall survival (median overall survival, mOS, high VS low, 37.6 VS 23.7 months, p=0.04). High epidural ropivacaine concentration was an independent prognostic factor (hazard ratio [HR]=0.65, 95% confidence interval [CI], 0.44-0.94; p=0.03). Subgroups analyses shown that T3M0 PDAC patients with preoperative CA 19-9 higher than 200 U/ml, negative resection margin, and those without tumor deposit and adjuvant radiotherapy could benefit from high concentration of ropivacaine. Conclusion: Intraoperatively epidural infusion with high concentration of ropivacaine was associated with improved OS in PDAC patients undergoing pancreatectomy.

BIG1 mediates sepsis-induced lung injury by modulating lipid raft-dependent macrophage inflammatory responses.

Sepsis is a systemic inflammatory response syndrome with high mortality. It has been reported that brefeldin A-inhibited guanine nucleotide-exchange factor 1 (BIG1) is involved in the pathogenesis of sepsis. However, the mechanism is not fully elucidated. In the present study, we explored the role of BIG1 in mediating lipid raft-dependent macrophage inflammatory response and its impact on lung injury in murine sepsis. In vitro studies revealed that BIG1 deficiency reduces the upregulation and secretion of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-1ß and inhibits the activation of the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88-dependent nuclear factor kappa-B signaling pathway induced by the lipopolysaccharide (LPS) treatment. Further experiments revealed that the inhibitory effects of BIG1 deficiency on LPS-induced inflammation are due to the upregulation of adenosine triphosphate-binding cassette transporter A1. This promotes the free-cholesterol efflux from lipid rafts and results in the reduction of lipid raft TLR4 content. The decrease in TLR4 content in lipid raft thereby inhibits the LPS-induced inflammatory response. Furthermore, using the cecal ligation and puncture-induced polymicrobial sepsis mouse model, we found that conditional knockout (cKO) of the myeloid cell BIG1 significantly reduced the serum concentrations of TNF-α, IL-6, and IL-1ß, and downregulated their mRNA expressions in the lungs. Pathological analysis confirmed that the BIG1 cKO alleviated the sepsis-induced lung injury. These results revealed the crucial new role of BIG1 in mediating lipid raft-dependent macrophage inflammatory response. Hence, BIG1 may be a potential promising therapeutic target for the treatment of septic lung injury.

NICE-3-knockdown induces cell cycle arrest and autophagy in lung adenocarcinoma cells via the AKT/mTORC1 signaling pathway.

The NICE-3 protein serves an oncogenic role in hepatocellular carcinoma, but its role in lung adenocarcinoma (LUAD) remains unknown. The aim of the present study was to investigate the potential role and underlying mechanisms of NICE-3 in LUAD. In the present study, NICE-3 expression in LUAD tissues and its association with patient prognosis were analyzed using datasets from The Cancer Genome Atlas and Gene Express Omnibus. After NICE-3-knockdown with small interfering RNA in LUAD cells, cell proliferation was measured by cell counting, cell cycle was examined by flow cytometry, cell invasion and migration were detected by Transwell assays and autophagic markers LC3 and p62, as well as phosphorylation of S6K and AKT, were determined by western blotting. The results of public database analysis demonstrated that compared with normal lung tissues, NICE-3 expression was increased in LUAD tissues, where high expression levels were associated with a poor prognosis. The results of in vitro experimentation in LUAD cells indicated that NICE-3-knockdown inhibited proliferation, cell cycle, migration and invasion, but enhanced autophagy. Notably, NICE-3-knockdown inhibited AKT/mTORC1 signaling. The present results suggested that NICE-3 may serve an oncogenic role in LUAD via the AKT/mTORC1 signaling pathway and may therefore be a potential therapeutic target for LUAD.

Methyltransferase-like 1 regulates lung adenocarcinoma A549 cell proliferation and autophagy via the AKT/mTORC1 signaling pathway.

Methyltransferase-like 1 (METTL1) is a transfer RNA and microRNA modifying enzyme. However, its role in lung adenocarcinoma (LUAD) remains unknown. The present study aimed to investigate the effect of METTL1 in LUAD and determine the association between METTL1 expression and prognosis of patients with LUAD. The expression profile of METTL1 in LUAD tissues was downloaded from public cancer databases and analyzed using the Gene Expression Profiling Interactive Analysis database and UALCAN online software. In addition, the association between METTL1 expression and prognosis of patients with LUAD was assessed using the Kaplan-Meier Plotter software. The effect of METTL1 in the A549 cell line was determined in vitro via overexpression and knockdown experiments. The results demonstrated that METTL1 was upregulated in LUAD tissues, and its increased expression was associated with unfavorable prognosis. Furthermore, METTL1 promoted proliferation and colony formation of A549 cells, and inhibited autophagy via the AKT/mechanistic target of rapamycin complex 1 signaling pathway. Taken together, the results of the present study suggest that METTL1 acts as an oncogene in LUAD, thus may be a potential prognostic predictor and therapeutic target for LUAD.

MYG1 promotes proliferation and inhibits autophagy in lung adenocarcinoma cells via the AMPK/mTOR complex 1 signaling pathway.

Melanocyte proliferating gene 1 (MYG1) is an exonuclease that participates in RNA processing and is required for normal mitochondrial function. However, its role in tumorigenesis remains unknown. The present study aimed to investigate the role of MYG1 and its underlying mechanisms in human lung adenocarcinoma (LUAD). The expression levels of MYG1 in tumor tissues of patients with LUAD were obtained from public cancer databases and analyzed using the UALCAN online software. The association between MYG1 expression levels and the prognosis of patients with LUAD was analyzed using the Kaplan-Meier plotter. In addition, the role of MYG1 in the LUAD A549 and H1993 cell lines was determined by knocking down MYG1 expression with a specific small interfering RNA or by overexpressing it with a MYG1-containing plasmid. The results demonstrated that MYG1 expression levels were upregulated in LUAD tissues compared with those in normal lung tissues from healthy subjects, and high MYG1 expression levels were associated with an unfavorable prognosis. MYG1 promoted the proliferation, migration and invasion of A549 and H1993 cells. In addition, MYG1 inhibited autophagy via the AMP-activated protein kinase/mTOR complex 1 signaling pathway. Collectively, the present results suggested that MYG1 may serve an oncogenic role in LUAD and may be a potential therapeutic target for LUAD.

Intraoperative thermal insulation in off-pump coronary artery bypass grafting surgery: a prospective, double blind, randomized controlled, single-center study.

BACKGROUND: About 50% patients who underwent off-pump coronary artery bypass grafting (OPCAB) experienced perioperative hypothermia. Pre-warming and intraoperative infusion of amino acid injection are the most popular perioperative insulation measures in recent years, but neither of them can completely prevent intraoperative hypothermia. The objective is to investigate the effect of preoperative warming and/or intraoperative infusion of amino acid injection on body temperature in patients undergoing OPCAB. METHODS: A prospective, double blind, randomized controlled, single-center study. Seventy-two patients were randomly divided into 4 groups: control group, pre-warming group, amino-acid group and multi-mode group. Pre-warming and multi-mode group were pre-heated with warming blankets and forced-air warming system before induction. After that, amino-acid and multi-mode group were infused with 18-amino acid solution. The perioperative temperature and complications were monitored. RESULTS: The temperature of control and amino-acid group decreased significantly, but amino-acid group recovered to preoperative level faster. The temperature of pre-warming group was stable, and that in multi-mode group increased at 60 min after the start of surgery. There was a significant difference in temperature at each time, and no difference in the incidence of complications between the groups. CONCLUSIONS: Preoperative warming and/or intraoperative infusion of amino acid injection can effectively reduce hypothermia in OPCAB surgery. Pre-warming before anesthesia is more effective, and the combination of the two methods has the best effect.

DEPDC1 up-regulates RAS expression to inhibit autophagy in lung adenocarcinoma cells.

DEP domain containing 1(DEPDC1) is involved in the tumorigenesis of a variety of cancers. But its role in tumorigenesis of lung adenocarcinoma (LUAD) is not fully understood. Here, we investigated the role and the underlying mechanisms of DEPDC1 in the development of LUAD. The expression and prognostic values of DEPDC1 in LUAD were analysed by using the data from public databases. Gene enrichment in TCGA LUAD was analysed using GSEA software with the pre-defined gene sets. Cell proliferation, migration and invasion of A549 cells were examined with colony formation, Transwell and wound healing assays. The function of DEPDC1 in autophagy and RAS-ERK1/2 signalling was determined with Western blot assay upon DEPDC1 knockdown and/or overexpression in A549, HCC827 and H1993 cells. The results demonstrated that DEPDC1 expression was up-regulated in LUAD tissues, and its high expression was correlated with unfavourable prognosis. The data also showed that DEPDC1 knockdown impaired proliferation, migration and invasion of A549 cells. Most notably, the results showed that DEPDC1 up-regulated RAS expression and thus enhanced ERK1/2 activity, through which DEPDC1 could inhibit autophagy. In conclusion, our study revealed that DEPDC1 is up-regulated in LUAD tissues and plays an oncogenic role in LUAD, and that DEPDC1 inhibits autophagy through the RAS-ERK1/2 signalling in A549, HCC827 and H1993 cells.

Total body irradiation induced mouse small intestine senescence as a late effect.

Radiation can induce senescence in many organs and tissues; however, it is still unclear how radiation stimulates senescence in mouse small intestine. In this study, we use the bone marrow transplantation mouse model to explore the late effects of total body irradiation on small intestine. Our results showed that almost all of the body hairs of the irradiated mice were white (which is an indication of aging) 10 months after the exposure to radiation. Furthermore, compared with the age-matched control mice, there were more SA-ß-galactosidase (SA-ß-gal)-positive cells and an upregulation of p16 and p21 in 8 Gy-irradiated mice intestinal crypts, indicating that radiation induced senescence in the small intestine. Intestinal bacterial flora profile analysis showed that the diversity of the intestinal bacterial flora decreased in irradiated mice; in addition it showed that the principal components of the irradiated and control mice differed: there was increased abundance of Bacteroidia and a decreased abundance of Clostridia in irradiated mice. To explore the underlying mechanism, an RNA-sequence was executed; the results suggested that pancreatic secretion, and the digestion and absorption of proteins, carbohydrates, fats and vitamins were damaged in irradiated mice, which may be responsible for the body weight loss observed in irradiated mice. In summary, our study suggested that total body irradiation may induce senescence in the small intestine and damage the health status of the irradiated mice.

Mouse serum protects against total body irradiation-induced hematopoietic system injury by improving the systemic environment after radiation.

Reactive oxygen species (ROS) play a critical role in total body irradiation (TBI)-induced hematopoietic system injury. However, the mechanisms involved in ROS production in hematopoietic stem cells (HSCs) post TBI need to be further explored. In this study, we demonstrated that hematopoietic system injury in mice radiated with TBI was effectively alleviated when the blood circulation environment was changed via the injection of serum from non-radiated mice. Serum injection increased the survival of radiated mice and ameliorated TBI-induced hematopoietic system injury through attenuating myeloid skew, increasing HSC frequency, and promoting the reconstitution of radiated HSCs. Serum injection also decreased ROS levels in HSCs and regulated oxidative stress-related proteins. A serum proteome sequence array showed that proteins related to tissue injury and oxidative stress were regulated, and a serum-derived exosome microRNA sequence assay showed that the PI3K-Akt and Hippo signaling pathways were affected in radiated mice injected with serum from non-radiated mice. Furthermore, a significant increase in cell viability and a decrease in ROS were observed in radiated lineage-c-kit+ cells treated with serum-derived exosomes. Similarly, an improvement in the impaired differentiation of HSCs was observed in radiated mice injected with serum-derived exosomes. Taken together, our observations suggest that serum from non-radiated mice alleviates HSC injury in radiated mice by improving the systemic environment after radiation, and exosomes contribute to this radioprotective effect as important serum active component.

Theaflavin ameliorates ionizing radiation-induced hematopoietic injury via the NRF2 pathway.

It has been well established that reactive oxygen species (ROS) play a critical role in ionizing radiation (IR)-induced hematopoietic injury. Theaflavin (TF), a polyphenolic compound from black tea, has been implicated in the regulation of endogenous cellular antioxidant systems. However, it remains unclear whether TF could ameliorate IR-induced hematopoietic injury, particularly the hematopoietic stem cell (HSC) injury. In this study, we explored the potential role of TF in IR-induced HSC injury and the underlying mechanism in a total body irradiation (TBI) mouse model. Our results showed that TF improved survival of irradiated wild-type mice and ameliorated TBI-induced hematopoietic injury by attenuating myelosuppression and myeloid skewing, increasing HSC frequency, and promoting reconstitution of irradiated HSCs. Furthermore, TF inhibited TBI-induced HSC senescence. These effects of TF were associated with a decline in ROS levels and DNA damage in irradiated HSCs. TF reduced oxidative stress mainly by up-regulating nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream targets in irradiated Lineage-c-kit+ positive cells. However, TF failed to improve the survival, to increase HSC frequency and to reduce ROS levels of HSCs in irradiated Nrf2-/- mice. These findings suggest that TF ameliorates IR-induced HSC injury via the NRF2 pathway. Therefore, TF has the potential to be used as a radioprotective agent to ameliorate IR-induced hematopoietic injury.

Rutin-Enriched Extract from Coriandrum sativum L. Ameliorates Ionizing Radiation-Induced Hematopoietic Injury.

Hematopoietic injury is a major cause of mortality in radiation accidents and a primary side effect in patients undergoing radiotherapy. Ionizing radiation (IR)-induced myelosuppression is largely attributed to the injury of hematopoietic stem and progenitor cells (HSPCs). Coriander is a culinary herb with multiple pharmacological effects and has been widely used in traditional medicine. In this study, flavonoids were identified as the main component of coriander extract with rutin being the leading compound (rutin-enriched coriander extract; RE-CE). We evaluated the radioprotective effect of RE-CE against IR-induced HSPCs injury. Results showed that RE-CE treatment markedly improved survival, ameliorated organ injuries and myelosuppression, elevated HSPCs frequency, and promoted differentiation and proliferation of HSPCs in irradiated mice. The protective role of RE-CE in hematopoietic injury is probably attributed to its anti-apoptotic and anti-DNA damage effect in irradiated HSPCs. Moreover, these changes were associated with reduced reactive oxygen species (ROS) and enhanced antioxidant enzymatic activities in irradiated HSPCs. Collectively, these findings demonstrate that RE-CE is able to ameliorate IR-induced hematopoietic injury partly by reducing IR-induced oxidative stress.

Hydrogen-Rich Water Ameliorates Total Body Irradiation-Induced Hematopoietic Stem Cell Injury by Reducing Hydroxyl Radical.

We examined whether consumption of hydrogen-rich water (HW) could ameliorate hematopoietic stem cell (HSC) injury in mice with total body irradiation (TBI). The results indicated that HW alleviated TBI-induced HSC injury with respect to cell number alteration and to the self-renewal and differentiation of HSCs. HW specifically decreased hydroxyl radical (∙OH) levels in the c-kit+ cells of 4 Gy irradiated mice. Proliferative bone marrow cells (BMCs) increased and apoptotic c-kit+ cells decreased in irradiated mice uptaken with HW. In addition, the mean fluorescence intensity (MFI) of γ-H2AX and percentage of 8-oxoguanine positive cells significantly decreased in HW-treated c-kit+ cells, indicating that HW can alleviate TBI-induced DNA damage and oxidative DNA damage in c-kit+ cells. Finally, the cell cycle (P21), cell apoptosis (BCL-XL and BAK), and oxidative stress (NRF2, HO-1, NQO1, SOD, and GPX1) proteins were significantly altered by HW in irradiated mouse c-kit+ cells. Collectively, the present results suggest that HW protects against TBI-induced HSC injury.

Astaxanthin attenuates total body irradiation-induced hematopoietic system injury in mice via inhibition of oxidative stress and apoptosis.

BACKGROUND: The hematopoietic system is especially sensitive to total body irradiation (TBI), and myelosuppression is one of the major effects of TBI. Astaxanthin (ATX) is a powerful natural anti-oxidant with low toxicity. In this study, the effect of ATX on hematopoietic system injury after TBI was investigated. METHODS: Flow cytometry was used to detect the proportion of hematopoietic progenitor cells (HPCs) and hematopoietic stem cells (HSCs), the level of intracellular reactive oxygen species (ROS), expression of cytochrome C, cell apoptosis, and NRF2-related proteins. Immunofluorescence staining was used to detect Nrf2 translocation. Western blot analysis was used to evaluate the expression of apoptotic-related proteins. Enzymatic activities assay kits were used to analyze SOD2, CAT, and GPX1 activities. RESULTS: Compared with the TBI group, ATX can improve radiation-induced skewed differentiation of peripheral blood cells and accelerate hematopoietic self-renewal and regeneration. The radio-protective effect of ATX is probably attributable to the scavenging of ROS and the reduction of cell apoptosis. These changes were associated with increased activation of Nrf2 and downstream anti-oxidative proteins, and regulation of apoptotic-related proteins. CONCLUSIONS: This study suggests that ATX could be used as a potent therapeutic agent to protect the hematopoietic system against TBI-induced bone marrow suppression.

The combined effect of resveratrol and diphenyleneiodonium on irradiation-induced injury to the hematopoietic system.

Both resveratrol(Res) and diphenyleneiodonium(DPI) have been shown to have radioprotective effects on hematopoietic system injury. However, the cooperative effect of Res and DPI are unknown. In this study, we explored the radioprotective effect of the combination of Res and DPI both in vitro and in vivo. Our results showed that the combined treatment of Res and DPI was more effective in protecting irradiated BMMNCs in terms of cell viability, colony-forming ability, and reconstitution ability in vitro compared with Res or DPI treatment alone. However, in mice, the combination of Res and DPI had no enhanced protection on 4Gy total body irradiation (TBI)-induced hematopoietic system injury, including TBI-induced myelosuppression, induction of the splenic index, and increases in HSC/HPC numbers and the colony-forming ability of BMCs,compared to Res or DPI alone. An exception was the number of BMCs. These studies illustrated the inconsistency between experiments carried out in vitro and in vivo and suggest an interaction between Res or DPI in vivo.

Vam3 ameliorates total body irradiation-induced hematopoietic system injury partly by regulating the expression of Nrf2-targeted genes.

Vam3, a resveratrol dimer, has been implicated in the regulation of chronic obstructive pulmonary disease. However, the effect of Vam3 on total body irradiation (TBI)-induced hematopoietic progenitor cells (HPCs), and hematopoietic stem cells (HSCs) injury is unknown. In this study, we examined whether Vam3could ameliorate hematopoietic system injury induced by TBI. Our results indicated that Vam3 alleviated TBI-induced injury by improving the self-renewal and differentiation of HPCs, and HSCs. Vam3 decreased the intracellular ROS levels in irradiated mice HPCs/HSCs or c-kit positive cells and inhibited apoptosis and DNA damage in LSKs and HPCs after TBI. Vam3 up-regulated the expression of Nrf2 and related genes and proteins in irradiated c-kit positive cells in vitro. However, Vam3 did not increase the cell viability or the number of CFU-GM c-kit positive cells in irradiated Nrf2-/- mice but decreased the cellular ROS level. The above data showed that Vam3 ameliorates total body irradiation-induced hematopoietic system injury and that Nrf2 is essential in mediating Vam3's protective effect on the proliferation of c-kit positive cells after irradiation but not its ability to scavenge for free radicals.