Cu2WS4-PEG Nanozyme as Multifunctional Sensitizers for Enhancing Immuno-Radiotherapy by Inducing Ferroptosis.

Unavoidable damage to normal tissues and tumor microenvironment (TME) resistance make it challenging to eradicate breast carcinoma through radiotherapy. Therefore, it is urgent to develop radiotherapy sensitizers that can effectively reduce radiation doses and reverse the suppressive TME. Here, a novel biomimetic PEGylated Cu2WS4 nanozyme (CWP) with multiple enzymatic activities is synthesized by the sacrificing template method to have physical radiosensitization and biocatalyzer-responsive effects on the TME. Experiment results show that CWP can improve the damage efficiency of radiotherapy on breast cancer cell 4T1 through its large X-ray attenuation coefficient of tungsten and nucleus-penetrating capacity. CWP also exhibit strong Fenton-like reactions that produced abundant ROS and GSH oxidase-like activity decreasing GSH. This destruction of redox balance further promotes the effectiveness of radiotherapy. Transcriptome sequencing reveals that CWP induced ferroptosis by regulating the KEAP1/NRF2/HMOX1/GPX4 molecules. Therefore, owing to its multiple enzymatic activities, high-atomic W elements, nucleus-penetrating, and ferroptosis-inducing capacities, CWP effectively improves the efficiency of radiotherapy for breast carcinoma in vitro and in vivo. Furthermore, CWP-mediated radiosensitization can trigger immunogenic cell death (ICD) to improve the anti-PD-L1 treatments to inhibit the growth of primary and distant tumors effectively. These results indicate that CWP is a multifunctional nano-sensitizers for radiotherapy and immunotherapy.

Enteric α-Defensin Contributes to Recovery of Radiation-Induced Intestinal Injury by Modulating Gut Microbiota and Fecal Metabolites.

The effect of ionizing radiation on the gastrointestinal tract is a common complication of abdominal and pelvic radiotherapy. However, the pathological features of radiation enteropathy and its effective medical intervention regimen is still a global challenge. Here, we explored the role and mechanism of enteric alpha-defensins (EαDs) in protecting against radiation enteropathy. To address this, we utilized EαDs-deficiency mice, in which the matrix metallopeptidase 7 to activate Paneth cell α-defensins was knockout (KO) mice, and the complementary wild-type (WT) control mice for this study. Remarkably, the KO mice were more susceptible to 5.0 Gy total-body irradiation, resulting in worse clinic scores and lower survival rate, compared with the wild-type mice. Histological examination indicated that the KO mice were subjected to slow recovery of intestinal villus and mucosa function, characterized by the reduced expression of TFF3, Glut1 and Muc2. In addition, compared with the wild-type controls, the KO mice experienced serious inflammation response in intestinal tissue, indicated by the remarkably increased expression level of IL-1ß, IL-6 and IL-12. Using high-throughput sequencing analysis, we found that the intestinal bacterial community of the KO mice was more prone to dysbiosis than that of the WT mice, with significantly increased abundance of opportunistic pathogenic bacteria, such as Streptococcus sp. and Escherichia-Shigella sp., whereas remarkably decreased probiotics harboring Lactobacillus sp., Desulfovibrio sp. etc. Fecal metabolomics analysis indicated that the relative abundance of 31 metabolites arose significantly different between WT and KO mice on day 10 after radiation exposure. A subset of differential metabolites to regulate host metabolism and immunity, such as acetic acid, acetate, butanoic acid, was negatively correlated with the alteration of gut microbiota in the irradiated KO mice. This study provides new insight into EαDs contribution to the recovery of radiation-induced intestinal damage, and suggests a potential novel target to prevent the adverse effects of radiotherapy.

Depleted uranium induces thyroid damage through activation of ER stress via the thrombospondin 1-PERK pathway.

Depleted uranium (DU) can cause damage to the body, but its effects on the thyroid are unclear. The purpose of this study was to investigate the DU-induced thyroid damage and its potential mechanism in order to find new targets for detoxification after DU poisoning. A model of acute exposure to DU was constructed in rats. It was observed that DU accumulated in the thyroid, induced thyroid structure disorder and cell apoptosis, and decreased the serum T4 and FT4 levels. Gene screening showed that thrombospondin 1 (TSP-1) was a sensitive gene of DU, and the expression of TSP-1 decreased with the increase of DU exposure dose and time. TSP-1 knockout mice exposed to DU had more severe thyroid damage and lower serum FT4 and T4 levels than wild-type mice. Inhibiting the expression of TSP-1 in FRTL-5 cells aggravated DU-induced apoptosis, while exogenous TSP-1 protein alleviated the decreased viability in FRTL-5 cells caused by DU. It was suggested that DU may caused thyroid damage by down-regulating TSP-1. It was also found that DU increased the expressions of PERK, CHOP, and Caspase-3, and 4-Phenylbutyric (4-PBA) alleviated the DU-induced FRTL-5 cell viability decline and the decrease levels of rat serum FT4 and T4 caused by DU. After DU exposure, the PERK expression was further up-regulated in TSP-1 knockout mice, and the increased expression of PERK was alleviated in TSP-1 over-expressed cells, as well as the increased expression of CHOP and Caspase-3. Further verification showed that inhibition of PERK expression could reduce the DU-induced increased expression of CHOP and Caspase-3. These findings shed light on the mechanism that DU may activate ER stress via the TSP 1-PERK pathway, thereby leading to thyroid damage, and suggest that TSP-1 may be a potential therapeutic target for DU-induced thyroid damage.

Mannosylated polydopamine nanoparticles alleviate radiation- induced pulmonary fibrosis by targeting M2 macrophages and inhibiting the TGF-ß1/Smad3 signaling pathway.

Radiation-induced pulmonary fibrosis (RIPF), one type of pulmonary interstitial diseases, is frequently observed following radiation therapy for chest cancer or accidental radiation exposure. Current treatments against RIPF frequently fail to target lung effectively and the inhalation therapy is hard to penetrate airway mucus. Therefore, this study synthesized mannosylated polydopamine nanoparticles (MPDA NPs) through one-pot method to treat RIPF. Mannose was devised to target M2 macrophages in the lung through CD 206 receptor. MPDA NPs showed higher efficiency of penetrating mucus, cellular uptake and ROS-scavenging than original polydopamine nanoparticles (PDA NPs) in vitro. In RIPF mice, aerosol administration of MPDA NPs significantly alleviated the inflammatory, collagen deposition and fibrosis. The western blot analysis demonstrated that MPDA NPs inhibited TGF-ß1/Smad3 signaling pathway against pulmonary fibrosis. Taken together this study provide a novel M2 macrophages-targeting nanodrugs through aerosol delivery for the prevention and targeted treatment for RIPF.

Depleted uranium causes renal mitochondrial dysfunction through the ETHE1/Nrf2 pathway.

The kidney is the main organ affected by acute depleted uranium (DU) toxicity. The mechanism of nephrotoxicity induced by DU is complex and needs to be further explored. This study aimed to elucidate the function of mitochondrial dysfunction in nephrotoxicity generated by DU and confirm the latent mechanism. We verified that DU (2.5-10 mg/kg) caused mitochondrial dysfunction in male rat kidneys and decreased ATP content and the mitochondrial membrane potential. In addition, melatonin (20 mg/kg), as an antioxidant, alleviated DU-induced oxidative stress and mitochondrial dysfunction in male rats, further reducing kidney damage caused by DU. These results indicate that mitochondrial dysfunction plays a vital role in DU nephrotoxicity. When ethylmalonic encephalopathy 1 (ETHE1) was knocked down, DU-induced oxidative stress and mitochondrial dysfunction were increased, and renal injury was aggravated. When exogenous ETHE1 protein was applied to renal cells, the opposite changes were observed. We also found that ETHE1 knockdown increased the expression of NF-E2-related factor 2 (Nrf2), a vital oxidative stress regulator, and its downstream molecules heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase 1 (NQO1). Nrf2 knockout also aggravated DU-induced oxidative stress, mitochondrial dysfunction, and kidney damage. In conclusion, DU causes oxidative stress and antioxidant defense imbalance in renal cells through the ETHE1/Nrf2 pathway, further causing mitochondrial dysfunction and ultimately leading to nephrotoxicity.

Research Progress on Therapeutic Effect and Mechanism of Propolis on Wound Healing.

Propolis is a kind of reduct collected by bees from various plant sources. Because propolis is a mixture, it has a variety of biological activities, excellent anti-inflammatory and bactericidal effects. Especially in the treatment of infectious wounds, acute wounds, burns, and scalds and promoting wound healing, more and more scientists began to apply it to the research field of wound healing. The standard preparation of propolis combined with other compound components has a safer and less toxic effect in the treatment of trauma. In order to more effectively use propolis products in wound treatment. This paper reviews the effect and treatment mechanism of propolis on different types of wound healing, as well as the synergistic effect of propolis and other compounds, in order to provide ideas for the further exploration of the biological activity and pharmacological function of propolis in the future, as well as its in-depth development in the field of wound healing. It will also provide a theoretical reference for the further development and utilization of propolis.

Identification and characterization of murine adipose tissue-derived somatic stem cells of Shenque (CV8) acupoint.

BACKGROUND: Shenque (CV8) acupoint is located on the navel and has been therapeutically used for more than 2000 years in Traditional Chinese Medicine (TCM). However, clinical research on the underlying therapeutic molecular mechanisms of the CV8 acupoint lags far behind. This study aimed to study the mechanisms of umbilical acupoint therapy by using stem cells. METHODS: The morphological characteristics of CV8 acupoint were detected under a stereomicroscope using hematoxylin and eosin (H&E) staining. Oil Red, Masson, and immunohistochemical staining on multi-layered slices were used to identify the type of cells at the CV8 acupoint. Cell proliferation was measured by a cell counting kit-8 (CCK-8) method. Flow cytometry and immunohistochemistry were used for cell identification. Induced differentiation was used to compare the differentiation of cells derived from CV8 acupoint and non-acupoint somatic stem cells into other cell types, such as osteogenic, adipogenic, and neural stem cell-like cells. RESULTS: Morphological observations showed that adipose tissues at the linea alba of the CV8 acupoint in mice had a mass-like distribution. Immunohistochemical staining confirmed the distribution of stem cell antigen-1 (Sca-1) positive cells in the multi-layered slices of CV8 acupoint tissues. Cells isolated from adipose tissues at the CV8 acupoint exhibited high expression of Sca-1 and CD44 and low expression of CD31 and CD34, and these cells possessed osteogenic, adipogenic, and neurogenic stem cell-like cell differentiation ability. The cell proliferation (day 4: 0.5138 ±â€Š0.0111 vs. 0.4107 ±â€Š0.0180, t = 8.447, P = 0.0011; day 5: 0.6890 ±â€Š0.0070 vs. 0.5520 ±â€Š0.0118, t = 17.310, P < 0.0001; day 6: 0.7320 ±â€Š0.0090 vs. 0.6157 ±â€Š0.0123, t = 13.190, P = 0.0002; and day 7: 0.7550 ±â€Š0.0050 vs. 0.6313 ±â€Š0.0051, t = 42.560, P < 0.0001), adipogenic ([9.224 ±â€Š0.345]% vs. [3.933 ±â€Š1.800]%, t = 5.000, P = 0.0075), and neurogenic stem cell-like cell differentiation (diameter < 50 µm: 7.2000 ±â€Š1.3040 vs. 2.6000 ±â€Š0.5477, t = 7.273, P < 0.0001; diameter 50-100 µm: 2.6000 ±â€Š0.5477 vs. 1.0000 ±â€Š0.7071, t = 4.000, P = 0.0039; and diameter >100 µm: 2.6000 ±â€Š0.5477 vs. 0.8000 ±â€Š0.8367, t = 4.025, P = 0.0038) were significantly enhanced in somatic stem cells derived from the CV8 acupoint compared to somatic stem cells from the groin non-acupoint. However, cells possessed significantly weaker osteogenicity ([2.697 ±â€Š0.627]% vs. [7.254 ±â€Š0.958]%, t = 6.893, P = 0.0023) in the CV8 acupoint group. CONCLUSIONS: Our study showed that CV8 acupoint was rich with adipose tissues that contained abundant somatic stem cells. The biological examination of somatic stem cells derived from the CV8 acupoint provided novel insights for future research on the mechanisms of umbilical therapy.

Protective effect of melatonin entrapped PLGA nanoparticles on radiation-induced lung injury through the miR-21/TGF-ß1/Smad3 pathway.

Radiation-induced lung injury (RILI) is a complication commonly found in victims suffering from nuclear accidents and patients treated with chest tumor radiotherapy, and drugs are limited for effective prevention and treatment. Melatonin (MET) has an anti-radiation effect, but its metabolic period in the body is short. In order to prolong the metabolism period of MET, we prepared MET entrapped poly (lactic-co-glycolic acid) nanoparticles (MET/PLGANPS) for the treatment of RILI. As a result, the release rate of MET/PLGANPS in vitro was lower than MET, with stable physical properties, and it caused no changes in histopathology and biochemical indicators. After 2 weeks and 16 weeks of irradiation with the dose of 15 Gy, MET and MET/PLGANPS could reduce the expression of caspase-3 proteins, inflammatory factors, TGF-ß1 and Smad3 to alleviate radiation-induced lung injury. MET/PLGANPS showed better therapeutic effect on RILI than MET. In addition, we also found that high expression of miR-21 could increase the expression levels of TGF-ß1, and inhibit the protective effect of MET/PLGANPS. In conclusion, MET/PLGANPS may alleviate RILI by inhibiting the miR-21/TGF-ß1/Smad3 pathway, which would provide a new target for the treatment of radiation-induced lung injury.

Synthesis of Mitochondria-Anchored Nitroimidazoles with a Versatile NIR Fluorophore for Hypoxic Tumor-Targeting Imaging and Chemoradiotherapy.

Nitroimidazoles are one of the most common radiosensitizers investigated to combat hypoxia-induced resistance to cancer radiotherapy. However, due to poor selectivity distinguishing cancer cells from normal cells, effective doses of radiosensitization are much closer to the doses of toxicity induced by nitroimidazoles, limiting their clinical application. In this work, a tumor-targeting near-infrared (NIR) cyanine dye (IR-808) was utilized as a targeting ligand and an NIR fluorophore tracer to chemically conjugate with different structures of hypoxia-affinic nitroimidazoles. One of the NIR fluorophore-conjugated nitroimidazoles (808-NM2) was identified to preferentially accumulate in hypoxic tumor cells, sensitively outline the tumor contour, and effectively inhibit tumor growth synergistically by chemotherapy and radiotherapy. More importantly, nitroimidazoles were successfully taken into cancer cell mitochondria via 808-NM2 conjugate to exert the synergistic effect of chemoradiotherapy. Regarding the important roles of mitochondria on cancer cell survival and metastasis under hypoxia, 808-NM2 may be hopeful to fight against hypoxic tumors.

Neutrophils-derived Spink7 as one safeguard against experimental murine colitis.

The uncontrolled abnormal intestinal immune responses play important role in eliciting inflammatory bowel disease (IBD), yet the molecular events regulating intestinal inflammation during IBD remain poorly understood. Here, we describe an endogenous, homeostatic pattern that controls inflammatory responses in experimental murine colitis. We show that Spink7 (serine peptidase inhibitor, kazal type 7), the ortholog of human SPINK7, is significantly upregulated in dextran sodium sulfate (DSS)-induced murine colitis model. Spink7-deficient mice showed highly susceptible to experimental colitis characterized by enhanced weight loss, shorter colon length, higher disease activity index and increased colonic tissue destruction. Bone marrow reconstitution experiments demonstrated that expression of Spink7 in the immune compartment makes main contribution to its protective role in colitis. What's more, neutrophils are the primary sources of Spink7 in experimental murine colitis. Loss of Spink7 leads to augmented productions of multiple chemokines and cytokines in colitis. In summary, this study identifies neutrophils-derived endogenous Spink7-mediated control of chemokines/cytokines production as a molecular mechanism contributing to inflammation resolution during colitis.

Research progress on radioprotective effects of bee products.

Radiation exposure is an on going and serious threat in military and public health concern. There is an unmet need for effective preventative or mitigative treatments against radiation-induced injuries. The handful of Food and Drug Administration in the US approved radiation protection agents cannot be widely used due to their side effects. Some natural nontoxic compounds such as bee products have been reported to prevent and treat radiation-induced injuries (e.g. scavenging free radicals, inhibiting cell apoptosis and reducing DNA damage), indicating that they may be a potential option as a safe radioprotective agent. Bee products are nontoxic and have no known side effects on the human body, and are effective in the field of radiation protection. They are expected to be interesting drug candidates for preventing and treating radiation-induced injuries. This article reviews the prevention and treatment of bee products on radiation-induced injuries.

Chronic oral depleted uranium leads to reproductive damage in male rats through the ROS-hnRNP A2/B1-COX-2 signaling pathway.

Depleted uranium (DU) is widely used in civil and military activities. The testis is one of the target organs of DU chronic toxicity. In this study, male SD rats were chronically exposed to DU by 3, 30, 300 mg U/kg through oral intake. After 6 months and 12 months of exposure, it was found that DU could lead to increased oxidative stress levels, decreased glutathione S-transferases (GSTs) expression, resulting in testicular injury and decreased serum testosterone (T) level in rats. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) expression increases with the increase of DU exposure dose. After upregulation of hnRNP A2/B1 expression, the GC-1 cell injury caused by DU is aggravated, suggesting that hnRNP A2/B1 may play an important role in the reproductive toxicity of DU. At the same time, 12 months after chronic oral exposure to DU, the expression level of cyclooxygenase-2 (COX-2) and proinflammatory factor prostaglandin E2 (PGE2) in testicular tissue were increased, and the level of hnRNP A2/B1 caused by DU was decreased by reactive oxygen scavenger N-acetylcysteine (NAC). As hnRNP A2/B1 is a COX-2 regulator, DU may lead to the upregulation of hnRNP A2/B1 expression through the increase of oxidative stress level in germ cells, which in turn leads to the increase of COX-2 and PGE2 level, and ultimately result in the reproductive toxicity. In this study, the regulation mechanism of the ROS-hnRNP A2/B1-COX-2 pathway on DU-induced reproductive damage in male rats was hypothesized, providing a new target for the prevention and treatment of chronic poisoning of DU.

Ethylmalonic encephalopathy 1 initiates overactive autophagy in depleted uranium-induced cytotoxicity in the human embryonic kidney 293 cells.

The kidney is the target of the acute toxicity of depleted uranium (DU). However, the mechanism of DU-induced cytotoxicity is not clear. The study was to demonstrate the role of autophagy in DU-induced cytotoxicity and to determine the potential mechanism. We confirmed that after a 4-h exposure to DU, the autophagic vacuoles and the autophagy marker light chain 3-II in the human embryonic kidney 293 cells (HEK293) increased, and cytotoxicity decreased by abrogation of excessive autophagy using autophagy inhibitor. We also found activation of nucleus p53 and inhibiting mTOR pathways in DU-treated HEK293 cells. Meanwhile, ethylmalonic encephalopathy 1 (ETHE1) decreased as the exposure dose of DU increased, with increasing autophagy flux. We suggested that by reducing ETHE1, activation of the p53 pathway, and inhibiting mTOR pathways, DU might induce overactive autophagy, which affected the cytotoxicity. This study will provide a novel therapeutic target for the treatment of DU-induced cytotoxicity.

Methods and Influencing Factors for the Simple and Rapid Identification of Depleted Uranium Weapon Use under Battlefield Conditions.

The purpose of this paper is to explore how to rapidly and easily identify depleted uranium (DU) samples under battlefield conditions and to study the factors that influence their measurement. The air-absorbed dose rate and surface contamination levels for DU samples of 2-330 g were measured using a patrol instrument and portable energy spectrometer. The results were analyzed in accordance with IAEA standards for judging radioactive substances. The energy spectra of 5-g quantities of DU samples were analyzed using a high-purity germanium gamma spectrometer, and the uranium content of 100 mg DU samples was determined with an inductively coupled plasma mass spectrometer to clarify the type and composition of the uranium. The same batches of DU samples were identified using a portable gamma-ray spectrometer. We added 0-5 g environmental soil powders at different proportions. After sealing, the spectra were collected with a detection distance of 1-5 cm for 10 min. The activities of U and U nuclides in the samples were detected with an NaI(TI) scintillation detector. The U and U mass abundances in samples were calculated from measured specific activities. The sample was determined to contain DU if the U to U ratio was below 0.00723. It is found that for detecting DU materials with a low activity, surface contamination level measurements are more effective than calculating the air-absorbed external irradiation dose rate. Hence, for low-activity samples suspected to be radioactive, a radiometer with a high sensitivity for surface contamination is recommended, and the optimal measurement distance is 1-3 cm. Under all detection conditions, U can be identified using a portable gamma spectrometer, whereas U can only be detected under certain conditions. If these nuclides can be detected simultaneously, a U to U ratio of below 0.00723 indicates the presence of DU. The main factors affecting this identification include the sample mass, sample purity, measurement distance, and measurement time. For the rapid identification of DU with a portable gamma-ray spectrometer, the mass of uranium in the sample must be more than 1 g, the measuring distance needs to be less than 1 cm, and the measuring time must be 1-10 min. It is feasible to use a portable gamma-ray spectrometer to rapidly identify the types and composition of nuclides in DU samples. The detection of U activity is a precondition for the identification of DU.

A review of biological effects and treatments of inhaled depleted uranium aerosol.

Depleted uranium (DU) is primarily used for DU bombs and DU tanks in the military. Aerosol inhalation is considered the primary route of DU exposure. Although laboratory tests have confirmed that inhalation of DU aerosol can cause lung, kidney, and other organ damage, epidemiological studies have found no conclusive evidence that persons in areas with prolonged exposure to DU-containing bombs are affected. After the body inhaled DU aerosols, we first clear the insoluble DU through whole-lung lavage (WLL). Then we eliminate the soluble uranium by the chelating agent. Besides, reducing DU damage to tissues and cells through drugs is also an important treatment method. In future research, emphasis should be placed on the damage mechanism of DU aerosol, the laboratory and clinical research of DU chelating agents, the research on the combination of DU chelating agent and WLL, and the research and development of new drugs to prevent DU damage.

A Review of Uranium-Induced Reproductive Toxicity.

As a heavy metal nuclear fuel, uranium is used in various civil and military projects, resulting in environmental pollution. Uranium can enter the body through the mouth, nose and skin, threatening human health. The reproductive organs are sensitive to uranium. For certain exposure times, doses and modes, uranium can produce toxic effects on the reproductive organs. The reproductive toxicity of uranium can be produced through different mechanisms of action, such as changing the level of sex hormones in the body, disrupting the expression of genes or proteins related to reproduction and causing oxidative stress and inflammation. Uranium thus can cause toxic effects to the reproductive system, leading to histopathological changes and decreased conception rates, and may damage the health of the body. This paper reviews the research progress on uranium reproductive toxicity in recent years and indicates a direction for future research on uranium reproductive toxicity and its mechanisms.

dTMP-GH Fusion Protein Therapy Improves Survival after Radiation Injury Combined with Skin-Burn Trauma in Mice.

Exposure to ionizing radiation combined with traumatic tissue injury is an important life-threatening condition found in the civilian populations after nuclear and radiological events. The significance feature of radiation combined injury (RCI) is the severe combined effect, which makes the injury more complicated. At present, there are limited measures available to treat RCI. Here we show that a chimeric protein dTMP-GH, fusing human growth hormone (hGH) with a tandem dimer of thrombopoietin mimetic peptide (dTMP), could be an effective therapy agent for RCI in a mice model. In this study, using a RCI mouse model exposed to 60Co γ-ray photons (6.0 Gy, 0.3 Gy/min) followed by a 20% total-body-surface-area burns (henceforth called: RB-CI) was established. Administration of dTMP-GH (200 ug/kg) for 10 consecutive days beginning at 24 h after injury improved survival rate during a 30-day observation period compared with the control vehicle group. dTMP-GH treatment also showed enhanced bone marrow hematopoiesis recovery determined by peripheral blood analysis and bone marrow histopathology. Meanwhile, dTMP-GH treatment accelerated skin wound closure and mitigated ileum injury in the RCI model. These results suggest that dTMP-GH may prove to be an effective therapeutic drug for RCI.

Therapeutic Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells on Canine Radiation-Induced Lung Injury.

PURPOSE: To investigate the effect of human umbilical cord-derived mesenchymal stem cell (MSC) transplantation on canine radiation-induced lung injury. METHODS AND MATERIALS: Beagle dogs received localized 15-Gy x-ray radiation to the right lower lung to establish the model of radiation-induced lung injury. After 180 days, dogs were divided into 2 groups (4 per group). The MSC group received intratracheal MSC transplantation, and the saline group received the same volume of normal saline by lavage. The effect of MSC transplantation on lung injury was then evaluated 180 days after transplantation. RESULTS: At 180 days after 15-Gy radiation, canine arterial blood oxygen partial pressure was significantly decreased, and the levels of hydroxyproline and transforming growth factor (TGF)-ß in peripheral blood were significantly increased, whereas that of TGF-α was significantly decreased. Computed tomography evaluation revealed visible honeycomb shadows in the right middle and lower pulmonary pleurae. Blood oxygen partial pressure of the MSC group gradually increased over time, whereas the levels of hydroxyproline and TGF-ß in the peripheral blood showed a decreasing trend; TGF-α levels gradually increased, which differed significantly from the results observed in the saline group. In addition, computed tomography and pathologic examination showed that the degree of lung injury in the MSC group was milder. The MSC group also showed significantly increased pulmonary superoxide dismutase levels and significantly decreased tumor necrosis factor-α, Interleukein-1, and hyaluronic acid levels. Further study confirmed that MSC transplantation inhibited the activation of TGF-ß-Smad2/3 in lung tissues, and in vitro experiments showed that medium conditioned with MSCs effectively inhibited the increase in Smad2 and 3 levels induced by TGF-ß1. CONCLUSION: Canine radiation-induced lung injury could be observed at 180 days after radiation at 15 Gy. MSC transplantation can reduce oxidative stress, inflammatory reactions, and TGF-ß-Smad2/3 pathway activation, thereby reducing lung injury.

Ghrelin protects against depleted uranium-induced bone damage by increasing osteoprotegerin/RANKL ratio.

Depleted uranium (DU) is widely used in military and civil activities, and bone is the main target organ of chronic DU toxicity. The aim of this study was to evaluate the effects of ghrelin on rats implanted with DU and explore the underlying mechanisms. The results showed that ghrelin could increase the expression of ghrelin receptor in bone tissue, thus alleviate the apoptosis of bone tissue after 3 months of 0.3 g DU embedded in the tibia. Micro-computed tomography examination showed that after DU implantation, the density of cortical bone showed no significant difference, but the trabecular bone decreased in amount, density and connectivity. Ghrelin treatment can significantly reduce the changes caused by DU. Moreover, ghrelin can inhibit the increase of serum tartrate resistant acid phosphatase and the decrease of alkaline phosphatase and osteocalcin. Furthermore, ghrelin can also significantly reduce the receptor activator of nuclear factor κB ligand (RANKL) and phosphorylated p38-MAPK expression, and increase the level of osteoprotegerin (OPG) in tissues after exposure to DU. Based on cell experimental research, p38-MAPK specific agonist can reverse the function of ghrelin, significantly inhibit the level of OPG and increase the level of RANKL. On the contrary, the use of p38-MAPK specific inhibitor or p38-MAPK siRNA can enhance the function of ghrelin. These results suggest that ghrelin may inhibit p38 MAPK activation induced by DU, and increase the OPG/RANKL ratio caused by DU exposure, hence alleviating the bone damage caused by long-term DU exposure.

Effect of a novel polyethylene glycol compound on lung lavage in dogs after the inhalation of depleted uranium dust.

PURPOSE: The purpose of this study was to assess the effect of a lavage solution containing methoxypolyethylene glycol 4-(3,4-dihydroxyphenethylamino)-4-oxobutanoate (MDO) for whole lung lavage (WLL) in dogs after the inhalation of depleted uranium (DU) dust at a dose of 30 mgUkg-1. MATERIALS AND METHODS: WLL was performed using lavage solutions made of normal saline (saline group) or normal saline plus MDO (MDO group) at 2 days post-DU exposure. Meanwhile, a control group was set up without any treatment. RESULTS: At 10 days post-DU exposure, the saline and MDO groups had a lower DU content in urine and lung compared with the DU group (without lavage), while the MDO group content was significantly lower than that in the saline group. In terms of blood urea nitrogen and creatinine levels, the DU group maintained relatively high levels from day 3 to day 10; the saline group levels were reduced compared with the DU group at day 8 and day 10, while the MDO group levels remained markedly lower than both the DU and saline group levels. Pathological changes in the lungs and kidneys showed that the saline group was improved compared with the DU group, but not as significantly as the MDO group. CONCLUSIONS: In brief, WLL has a remarkable effect in promoting the decorporation of inhaled DU dust in the lungs of dogs. By comparison, a MDO-containing lavage solution has a better lavage effect than normal saline.