Ursodeoxycholic acid loaded dual-modified graphene oxide nanocomposite alleviates cholestatic liver injury through inhibiting hepatocyte apoptosis.

Ursodeoxycholic acid (UDCA) is the preferred treatment for various types of cholestasis, however, its effectiveness is limited because of its insolubility in water. We used polyethylene glycol (PEG) and cationic polymer polyethylenimine (PEI) to double-modify graphite oxide (PPG) as a drug delivery system. UDCA was successfully loaded onto PPG through intermolecular interactions to form UDCA-PPG nanoparticles. UDCA-PPG nanoparticles not only improve the solubility and dispersibility of UDCA, but also have good biocompatibility and stability, which significantly improve the delivery rate of UDCA. The results indicated that UDCA-PPG significantly reduced ROS levels, promoted cell proliferation, protected mitochondrial membrane potential, reduced DNA damage and reduced apoptosis in the DCA-induced cell model. In a mouse cholestasis model established by bile duct ligation (BDL), UDCA-PPG improved liver necrosis, fibrosis, and mitochondrial damage and reduced serum ALT and AST levels, which were superior to those in the UDCA-treated group. UDCA-PPG reduced the expression of the apoptosis-related proteins, Caspase-3 and Bax, increased the expression of Bcl-2, and reduced the expression of the oxidative stress-related proteins, NQO and HO-1, as well as the autophagy-related proteins LC3, p62 and p-p62. Therefore, UDCA-PPG can enhance the therapeutic effect of UDCA in cholestasis, by significantly improving drug dispersibility and stability, extending circulation time in vivo, promoting absorption, decreasing ROS levels, enhancing autophagy flow and inhibiting apoptosis via the Bcl-2/Bax signaling pathway.

Difunctionalization of 1,3-Butadiene via Sequential Radical Thiol-ene Reaction and Allylation by Dual Photoredox and Titanium Catalysis.

Recently, radical difunctionalization of the feedstock 1,3-butadiene has become an attractive strategy for increasing molecular complexity. Herein, we present a novel approach that effectively combines radical thiol-ene chemistry with TiIII catalysis to enable a three-component aldehyde allylation using 1,3-butadiene as an allyl group source under visible light conditions. This sustainable and straightforward method has facilitated the rapid production of diverse allylic 1,3-thioalcohols with exceptional regio- and diastereoselectivity.

Photocatalytic Metal Hydride Hydrogen Atom Transfer Mediated Allene Functionalization by Cobalt and Titanium Dual Catalysis.

Catalytic metal hydride hydrogen atom transfer (MHAT) reactions have proven to be a powerful method for alkene functionalization. This work reports the discovery of Co-porphines as highly efficient MHAT catalysts with a loading of only 0.01 mol % for unprecedented chemoselective allene functionalization under photoirradiation. Moreover, the newly developed bimetallic strategy by the combination of photo Co-MHAT and Ti catalysis enabled the successful carbonyl allylation with a wide range of amino, oxy, thio, aryl, and alkyl-allenes providing expedient access to valuable ß-functionalized homoallylic alcohols in over 100 examples with exceptional regio- and diastereoselectivity. Mechanism studies and DFT calculations supported that selectively transferring hydrogen atoms from cobalt hydride to allenes and generating allyl radicals is the key step in the catalytic cycle.

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.

High-Accuracy Relative Pose Measurement of Noncooperative Objects Based on Double-Constrained Intersurface Mutual Projections.

Relative pose measurement for noncooperative objects is an important part of 3D shape recognition and motion tracking. The methods based on scanning point clouds have better environmental adaptability and stability than image-based methods. However, the discrete points obtained from a continuous surface are sparse, which leads to point-to-point dislocations in the overlapping area and seriously reduces the accuracy. Therefore, this paper proposed a relative-pose-measurement algorithm based on double-constrained intersurface mutual projections. First, the initial corresponding set was constructed using mutual projections between the areas with similar feature descriptors, and then the final corresponding set was determined through the rigid-transformation-consistency constraint to improve the accuracy of the matchings and achieve a high-accuracy relative pose measurement. In the Stanford dataset, the rotation error and translation error were reduced by 19.3% and 13.4%, respectively. Furthermore, based on the proposed evaluation method, which separated the error of the pose-measurement algorithm from that of the instrument, the experiments were carried out with a self-made swept-frequency interferometer. The rotation error was reduced by 39.8%, and the surface deviation was reduced by 4.9%, which further proved the advancement of the method.

Deep Learning-Based Remaining Useful Life Estimation of Bearings with Time-Frequency Information.

In modern industrial production, the prediction ability of remaining useful life of bearings directly affects the safety and stability of the system. Traditional methods require rigorous physical modeling and perform poorly for complex systems. In this paper, an end-to-end remaining useful life prediction method is proposed, which uses short-time Fourier transform (STFT) as preprocessing. Considering the time correlation of signal sequences, a long and short-term memory network is designed in CNN, incorporating the convolutional block attention module, and understanding the decision-making process of the network from the interpretability level. Experiments were carried out on the 2012PHM dataset and compared with other methods, and the results proved the effectiveness of the method.

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.

Nucleus-Targeted Photosensitizer Nanoparticles for Photothermal and Photodynamic Therapy of Breast Carcinoma.

PURPOSE: The near-infrared fluorescent dye indocyanine green (ICG) has shown great potential in the photodynamic therapy (PDT) and photothermal therapy (PTT) of cancer. However, its disadvantages of instability in aqueous solution, short half-life, and non-targeting accumulation limit the effectiveness of ICG PDT/PTT. To overcome the disadvantages of ICG in tumor treatment, we designed PEGylated-human serum albumin (PHSA)-ICG-TAT. In this nanoparticle, PEG4000, the HSA package, and nuclear targeting peptide TAT (human immunodeficiency virus 1 [HIV-1]-transactivator protein) were used to improve the water solubility of ICG, prolong the life span of ICG in vivo, and target the nuclei of tumor cells, respectively. METHODS: The PHSA-ICG-TAT was characterized in terms of morphology and size, ultraviolet spectrum, dispersion stability, singlet oxygen and cellular uptake, and colocalization using transmission electron microscopy and dynamic light scattering, and fluorescence assay, respectively. Subsequently, the anti-tumor effect of PHSA-ICG-TAT was investigated via in vitro and in vivo experiments, including cell viability, apoptosis, comet assays, histopathology, and inhibition curves. RESULTS: The designed ICG-loaded nanoparticle had a higher cell uptake rate and stronger PDT/PTT effect than free ICG. The metabolism of PHSA-ICG-TAT in normal mice revealed that there was no perceptible toxicity. In vivo imaging of mice showed that PHSA-ICG-TAT had a good targeting effect on tumors. PHSA-ICG-TAT was used for the phototherapy of tumors, and significantly suppressed the tumor growth. The tumor tissue sections showed that the cell gap and morphology of the tumor tissue had been obviously altered after treatment with PHSA-ICG-TAT. CONCLUSION: These results indicate that the PHSA-ICG-TAT had a significant therapeutic effect against tumors.

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.

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.

Hydrogen-rich water attenuates the radiotoxicity induced by tritium exposure in vitro and in vivo.

Radionuclide tritium is widely used in the nuclear energy production industry and creates a threat to human health through radiation exposure. Herein, the radioactive elimination and radioprotective effect of hydrogen-rich water (HRW), a potential antioxidant with various medical applications, on tritiated water (HTO) exposure, was studied in vitro and in vivo. Results showed that intragastric administration of HRW effectively promoted the elimination of urinary tritium, decreased the level of serum tritium and tissue-bound tritium (OBT), and attenuated the genetic damage of blood cells in mice exposed to HTO (18.5 MBq/kg). Pretreatment with HRW effectively reduces tritium accumulation in HTO-treated human blood B lymphocyte AHH-1 cells. In addition, the anti-oxidative properties of HRW could attenuate the increased intracellular ROS (such as O2•-, •OH and ONOO-), resulting in reversing the exhaustion of cellular endogenous antioxidants (reduced GSH and SOD), decreasing lipid peroxidation (MDA), relieving DNA oxidative damage, and depressing cell apoptosis and cytotoxicity induced by HTO exposure. In conclusion, HRW is expected to be an effective radioactive elimination agent through the competition effect of isotope exchange or a radioprotective agent by scavenging free radicals induced by HTO exposure.

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.

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.

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.

Multifunctional Nanographene Oxide for Targeted Gene-Mediated Thermochemotherapy of Drug-resistant Tumour.

Drug resistance remains a major challenge for anticancer treatment, and one of the major mechanisms of drug resistance is the overexpression of drug efflux transporters in cancer. A new approach for defeating drug resistance is the use of a co-delivery strategy that utilizes small interfering RNA (siRNA) to silence the expression of efflux transporters together with a suitable anticancer drug for drug-resistant cells. In this work, multifunctional graphene capable of integrating multiple functions in one system was employed as a novel co-delivery system for siRNA and doxorubicin (Dox), as well as for the controlled release of intracellular pH-triggered and heat-triggered Dox. Additionally, it was used as a synergistic therapy based on the photothermal effect of graphene oxide (GO) under near-infrared (NIR) irradiation and the chemotherapeutic effect of Dox. The nanocomplex exhibited high drug and siRNA loading. Furthermore, the dual delivery of siRNA and Dox by folic acid (FA)-conjugated polyethylenimine-modified PEGylated nanographene (PPG-FA/siRNA/Dox) exhibited a satisfactory gene silencing effect as well as efficient intracellular delivery of Dox. Thus, Dox could access the nucleus and induce greater cytotoxicity compared with siRNA-absent delivery systems. Significantly, under irradiation, the combined treatment showed more synergistic effect for overcoming drug resistance compared with chemotherapy effect alone.