Antifungal effects and biocontrol potential of lipopeptide-producing Streptomyces against banana Fusarium wilt fungus Fusarium oxysporum f. sp. cubense.

Fusarium wilt of banana (FWB), caused by Fusarium oxysporum f. sp. cubense (Foc), especially tropical race 4 (TR4), presents the foremost menace to the global banana production. Extensive efforts have been made to search for efficient biological control agents for disease management. Our previous study showed that Streptomyces sp. XY006 exhibited a strong inhibitory activity against several phytopathogenic fungi, including F. oxysporum. Here, the corresponding antifungal metabolites were purified and determined to be two cyclic lipopeptide homologs, lipopeptin A and lipopeptin B. Combined treatment with lipopeptin complex antagonized Foc TR4 by inhibiting mycelial growth and conidial sporulation, suppressing the synthesis of ergosterol and fatty acids and lowering the production of fusaric acid. Electron microscopy observation showed that lipopeptide treatment induced a severe disruption of the plasma membrane, leading to cell leakage. Lipopeptin A displayed a more pronounced antifungal activity against Foc TR4 than lipopeptin B. In pot experiments, strain XY006 successfully colonized banana plantlets and suppressed the incidence of FWB, with a biocontrol efficacy of up to 87.7%. Additionally, XY006 fermentation culture application improved plant growth parameters and induced peroxidase activity in treated plantlets, suggesting a possible role in induced resistance. Our findings highlight the potential of strain XY006 as a biological agent for FWB, and further research is needed to enhance its efficacy and mode of action in planta.

Long-term results of synovectomy in total knee arthroplasty: a prospective, randomized controlled trial.

BACKGROUND: Synovectomy has been introduced into total knee arthroplasty (TKA) with the aim of relieving pain and inflammation of the synovium. However, there are no long-term, comparative data to evaluate the effect of synovectomy in TKA. This study was aimed at assessing pain, function, and complications in patients undergoing synovectomy during TKA for osteoarthritis (OA) at long-term follow-up. METHODS: This was a prospective randomized controlled trial of 42 consecutive patients who underwent staged bilateral TKA. Patients undergoing the first-side TKA were allocated to receive TKA with or without synovectomy followed by a 3-month washout period and crossover to the other strategy for the opposite-side TKA. The overall efficacy of both strategies was evaluated by determination of blood loss, the Knee Society score (KSS), and knee inflammation conditions during a 3-month postoperative period. The postoperative pain, range of motion (ROM), and complications were sequentially evaluated to compare the two groups until 10 years after surgery. RESULTS: At the 10-year follow-up, both groups had a similarly significantly improved ROM (114.88 ±â€Š9.84° vs. 114.02 ±â€Š9.43°, t  = 0.221, P  = 0.815) and pain relief with no differences between the two groups (1.0 [1.0] vs. 1.0 [1.5], U  = 789.500, P  = 0.613). Similar changes in total blood loss, KSS, and knee inflammation were found in both groups during 3 months postoperatively ( P  > 0.05). Additionally, there was no significant difference regarding complications and satisfaction between the two groups ( P  > 0.05). CONCLUSIONS: Synovectomy in conjunction with TKA for primary OA does not seem to provide any benefit regarding postoperative pain, ROM, and satisfaction during a 10-year follow-up. In addition, it may not result in more blood loss and increased incidence of long-term complications. Based on our long-term findings, it should not be performed routinely. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-INR-16008245; https://www.chictr.org.cn/showproj.aspx?proj=13334 .

Multi-Source Data Fusion and Hydrodynamics for Urban Waterlogging Risk Identification.

The complex formation mechanism and numerous influencing factors of urban waterlogging disasters make the identification of their risk an essential matter. This paper proposes a framework for identifying urban waterlogging risk that combines multi-source data fusion with hydrodynamics (MDF-H). The framework consists of a source data layer, a model parameter layer, and a calculation layer. Using multi-source data fusion technology, we processed urban meteorological information, geographic information, and municipal engineering information in a unified computation-oriented manner to form a deep fusion of a globalized multi-data layer. In conjunction with the hydrological analysis results, the irregular sub-catchment regions are divided and utilized as calculating containers for the localized runoff yield and flow concentration. Four categories of source data, meteorological data, topographic data, urban underlying surface data, and municipal and traffic data, with a total of 12 factors, are considered the model input variables to define a real-time and comprehensive runoff coefficient. The computational layer consists of three calculating levels: total study area, sub-catchment, and grid. The surface runoff inter-regional connectivity is realized at all levels of the urban road network when combined with hydrodynamic theory. A two-level drainage capacity assessment model is proposed based on the drainage pipe volume density. The final result is the extent and depth of waterlogging in the study area, and a real-time waterlogging distribution map is formed. It demonstrates a mathematical study and an effective simulation of the horizontal transition of rainfall into the surface runoff in a large-scale urban area. The proposed method was validated by the sudden rainstorm event in Futian District, Shenzhen, on 11 April 2019. The average accuracy for identifying waterlogging depth was greater than 95%. The MDF-H framework has the advantages of precise prediction, rapid calculation speed, and wide applicability to large-scale regions.

Anticipated cancer burden of low individual fruit and vegetable consumption under climate change: A modelling study in China.

BACKGROUND: Dietary patterns with a high intake of fruits and vegetables (FV) are associated with a reduced risk of various cancers. It is not yet clear where and to what extent a decline in crop productivity caused by climate change may modify the distribution of related cancer burdens through reducing FV consumption in China. To design policies and interventions aimed at improving FV intake, regional monitoring is required on how consumption-changing factors might impact the associated cancer burdens by socio-demographic subpopulations. METHODS: A microsimulation study was conducted from a societal perspective to project the effects of cancers associated with inadequate FV intake attributable to climate change. We linked the International Model for Policy Analysis of Agricultural Commodities and Trade to a health modelling framework for obesity, gastric cancer, lung cancer, and oesophageal cancer in a close-to-reality synthetic population. RESULTS: In the presence of climate constantly change, the relative reduction in FV consumption would induce an additional 9.73 million disability-adjusted life years (DALYs) nationally over the period 2010-2050 ([CrI]: 7.83-12.13). The climate change-induced cancer burden is projected to disproportionately affect socio-demographic index regions from 0.65 to 5.06 million DALYs. CONCLUSIONS: Effects of climate change on FV consumption are anticipated to exacerbate intra-regional inequalities in the associated cancer burdens of China by 2050. By quantitatively analysing the impact of such dietary changes on regional health in light of climate change, our research can inform the design of public health interventions for heterogeneous populations, as health impact assessments based solely on the population as a whole cannot reflect significant differences across subpopulations.

Predicting the effectiveness of interventions on population-level sodium reduction: A simulation modeling study.

Background and Aims: Interventions that significantly reduce dietary sodium intake are anticipated to decrease gastric cancer (GCa) burden. However, the optimal restriction strategies remain unknown at present. This study aims to understand where and to what extent policies modifying sodium consumption change the distribution of GCa burden, and the effects of potential salt reduction strategies in China. Methods: The synthetic population in this microscopic simulation study is close to reality. We incorporated estimates of dietary patterns and GCa risk into the model of excess salt consumption. These estimates and simulated population were obtained from the China Health and Nutrition Survey, Global Burden of Disease Project, and the sixth census of China's National Bureau of Statistics, respectively. Results: In the no intervention scenario, we estimated that disease burdens due to excess sodium intake would be at 472.9 million disability-adjusted life years (DALYs) nationally between 2010 and 2030 (95% credible interval [CrI]: 371.1-567.7). The GCa burden caused by high sodium is projected to have a disproportionate impact on the central and southern provinces of China (9.2 and 4.5 million DALYs, respectively). Implementing a cooking salt substitute strategy would be expected to avoid a larger portion of GCa burden (about 67.2%, 95% CrI: 66.8%-67.6%) than the salt-restriction spoon program (about 16.7%, 95% CrI: 16.1%-17.4%). Conclusion: Dietary salt reduction policy is very powerfully effective in reducing the GCa burden overall. It is expected that proposed salt substitutes are more effective than traditional salt-restriction spoons to avoid increased inequality.

Analysis of the Interaction Mechanism of the Risk Factors of Gas Explosions in Chinese Underground Coal Mines.

Gas explosion accidents easily cause severe casualties in Chinese underground coal mines. Systematic analysis of accident causation is crucial for the prevention of gas explosions. This study identifies the representative risk factors of gas explosions and determines the interrelationship among these risk factors to highlight weak links and develop countermeasures. A total of 21 representative risk factors of gas explosions were identified through 128 case studies and front-line investigations. On this basis, a five-level hierarchical structure model of gas explosions was established to explore the complex interrelationships among the representative risk factors based on a combination of the Decision-Making Trial and Evaluation Laboratory (DEMATEL) and Interpretive Structural Modeling (ISM) methods. Moreover, the Matrix of Cross Impact Multiplications Applied to Classification (MICMAC) method was applied to achieve risk factor classification into four clusters, namely, driving factors, linkage factors, dependent factors and autonomous factors. The results indicated that the interrelationships and emergence properties among the risk factors may cause gas explosions, which should give more attention to the interrelationships among multiple factors and multiple subsystems for coal enterprises. Meanwhile, the complex geological conditions, poor safety supervision, inadequate safety education and training, incomplete execution safety regulations and poor safety technology and input are the long-term focus of risk management for coal enterprises. Finally, 10 countermeasures were proposed to control these representative risk factors and interrelationships. The results are helpful to the development of gas explosion risk management policies and to the preferential allocation of limited resources to resolve these issues.

Intra-articular Injection of Kartogenin-Enhanced Bone Marrow-Derived Mesenchymal Stem Cells in the Treatment of Knee Osteoarthritis in a Rat Model.

BACKGROUND: In this study, we investigated the in vitro and in vivo chondrogenic capacity of kartogenin (KGN)-enhanced bone marrow-derived mesenchymal stem cells (BMSCs) for cartilage regeneration. PURPOSE: To determine (1) whether functionalized nanographene oxide (NGO) can effectively deliver KGN into BMSCs and (2) whether KGN would enhance BMSCs during chondrogenesis in vitro and in vivo in an animal model. STUDY DESIGN: Controlled laboratory study. METHODS: Functionalized NGO with line chain amine-terminated polyethylene glycol (PEG) and branched polyethylenimine (BPEI) were used to synthesize biocompatible NGO-PEG-BPEI (PPG) and for loading hydrophobic KGN molecules noncovalently via π-π stacking and hydrophobic interactions (PPG-KGN). Then, PPG-KGN was used for the intracellular delivery of hydrophobic KGN by simple mixing and co-incubation with BMSCs to acquire KGN-enhanced BMSCs. The chondrogenic efficacy of KGN-enhanced BMSCs was evaluated in vitro. In vivo, osteoarthritis (OA) was induced by anterior cruciate ligament transection in rats. A total of 5 groups were established: normal (OA treated with nothing), phosphate-buffered saline (PBS; intra-articular injection of PBS), PPG-KGN (intra-articular injection of PPG-KGN), BMSCs (intra-articular injection of BMSCs), and BMSCs + PPG-KGN (intra-articular injection of PPG-KGN-preconditioned BMSCs). At 6 and 9 weeks after the surgical induction of OA, the rats received intra-articular injections of PPG-KGN, BMSCs, or KGN-enhanced BMSCs. At 14 weeks after the surgical induction of OA, radiographic and behavioral evaluations as well as histological analysis of the knee joints were performed. RESULTS: The in vitro study showed that PPG could be rapidly uptaken in the first 4 hours after incubation, reaching saturation at 12 hours and accumulating in the lysosome and cytoplasm of BMSCs. Thus, PPG-KGN could enhance the efficiency of the intracellular delivery of KGN, which showed a remarkably high chondrogenic differentiation capacity of BMSCs. When applied to an OA model of cartilage injuries in rats, PPG-KGN-preconditioned BMSCs contributed to protection from joint space narrowing, pathological mineralization, OA development, and OA-induced pain, as well as improved tissue regeneration, as evidenced by radiographic, weightbearing, and histological findings. CONCLUSION: Our results demonstrate that KGN-enhanced BMSCs showed markedly improved capacities for chondrogenesis and articular cartilage repair. We believe that this work demonstrates that a multifunctional nanoparticle-based drug delivery system could be beneficial for stem cell therapy. Our results present an opportunity to reverse the symptoms and pathophysiology of OA. CLINICAL RELEVANCE: The intracellular delivery of KGN to produce BMSCs with enhanced chondrogenic potential may offer a new approach for the treatment of OA.

Mitochondria-targeting graphene oxide nanocomposites for fluorescence imaging-guided synergistic phototherapy of drug-resistant osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor occurring in children and young adults. Drug-resistant osteosarcoma often results in chemotherapy failure. Therefore, new treatments aimed at novel therapeutic targets are urgently needed for the treatment of drug-resistant osteosarcoma. Mitochondria-targeted phototherapy, i.e., synergistic photodynamic/photothermal therapy, has emerged as a highly promising strategy for treating drug-resistant tumors. This study proposed a new nano-drug delivery system based on near-infrared imaging and multifunctional graphene, which can target mitochondria and show synergistic phototherapy, with preferential accumulation in tumors. METHODS AND RESULTS: Based on our previous study, (4-carboxybutyl) triphenyl phosphonium bromide (TPP), a mitochondria-targeting ligand, was conjugated to indocyanine green (ICG)-loaded, polyethylenimine-modified PEGylated nanographene oxide sheets (TPP-PPG@ICG) to promote mitochondrial accumulation after cellular internalization. Thereafter, exposure to a single dose of near-infrared irradiation enabled synergistic photodynamic and photothermal therapy, which simultaneously inhibited adenosine triphosphate synthesis and mitochondrial function. Induction of intrinsic apoptosis assisted in surmounting drug resistance and caused tumor cell death. After fluorescence imaging-guided synergistic phototherapy, the mitochondria-targeting, multifunctional graphene-based, drug-delivery system showed highly selective anticancer efficiency in vitro and in vivo, resulting in marked inhibition of tumor progression without noticeable toxicity in mice bearing doxorubicin-resistant MG63 tumor cells. CONCLUSION: The mitochondria-targeting TPP-PPG@ICG nanocomposite constitutes a new class of nanomedicine for fluorescence imaging-guided synergistic phototherapy and shows promise for treating drug-resistant osteosarcoma.

Impact of different control policies for COVID-19 outbreak on the air transportation industry: A comparison between China, the U.S. and Singapore.

Many countries have been implementing various control measures with different strictness levels to prevent the coronavirus disease 2019 (COVID-19) from spreading. With the great reduction in human mobility and daily activities, considerable impacts have been imposed on the global air transportation industry. This study applies a hybrid SARIMA-based intervention model to measure the differences in the impacts of different control measures implemented in China, the U.S. and Singapore on air passenger and air freight traffic. To explore the effect of time span for the measures to be in force, two scenarios are invented, namely a long-term intervention and a short-term intervention, and predictions are made till the end of 2020 for all three countries under both scenarios. As a result, predictive patterns of the selected metrics for the three countries are rather different. China is predicted to have the mildest economic impact on the air transportation industry in this year in terms of air passenger revenue and air cargo traffic, provided that the control measures were prompt and effective. The U.S. would suffer from a far-reaching impact on the industry if the same control measures are maintained. More uncertainties are found for Singapore, as it is strongly associated with international travel demands. Suggestions are made for the three countries and the rest of the world on how to seek a balance between the strictness of control measures and the potential long-term industrial losses.

Klotho deficiency aggravates diabetes-induced podocyte injury due to DNA damage caused by mitochondrial dysfunction.

Diabetic nephropathy (DN) is a progressive disease, the main pathogeny of which is podocyte injury inducing glomerular filtration barrier and proteinuria. The occurrence and development of DN could be partly attributed to the reactive oxygen species (ROS) generated by mitochondria. However, research on how mitochondrial dysfunction (MtD) ultimately causes DNA damage is poor. Here, we investigated the influence of Klotho deficiency on high glucose (HG)-induced DNA damage in vivo and in vitro. First, we found that the absence of Klotho aggravated diabetic phenotypes indicated by podocyte injury accompanied by elevated urea albumin creatinine ratio (UACR), creatinine and urea nitrogen. Then, we further confirmed that Klotho deficiency could significantly aggravate DNA damage by increasing 8-OHdG and reducing OGG1. Finally, we demonstrated Klotho deficiency may promote MtD to promote 8-OHdG-induced podocyte injury. Therefore, we came to a conclusion that Klotho deficiency may promote diabetes-induced podocytic MtD and aggravate 8-OHdG-induced DNA damage by affecting OOG1.

Transmissibility of COVID-19 in 11 major cities in China and its association with temperature and humidity in Beijing, Shanghai, Guangzhou, and Chengdu.

BACKGROUND: The new coronavirus disease COVID-19 began in December 2019 and has spread rapidly by human-to-human transmission. This study evaluated the transmissibility of the infectious disease and analyzed its association with temperature and humidity to study the propagation pattern of COVID-19. METHODS: In this study, we revised the reported data in Wuhan based on several assumptions to estimate the actual number of confirmed cases considering that perhaps not all cases could be detected and reported in the complex situation there. Then we used the equation derived from the Susceptible-Exposed-Infectious-Recovered (SEIR) model to calculate R0 from January 24, 2020 to February 13, 2020 in 11 major cities in China for comparison. With the calculation results, we conducted correlation analysis and regression analysis between R0 and temperature and humidity for four major cities in China to see the association between the transmissibility of COVID-19 and the weather variables. RESULTS: It was estimated that the cumulative number of confirmed cases had exceeded 45 000 by February 13, 2020 in Wuhan. The average R0 in Wuhan was 2.7, significantly higher than those in other cities ranging from 1.8 to 2.4. The inflection points in the cities outside Hubei Province were between January 30, 2020 and February 3, 2020, while there had not been an obvious downward trend of R0 in Wuhan. R0 negatively correlated with both temperature and humidity, which was significant at the 0.01 level. CONCLUSIONS: The transmissibility of COVID-19 was strong and importance should be attached to the intervention of its transmission especially in Wuhan. According to the correlation between R0 and weather, the spread of disease will be suppressed as the weather warms.

Design and application of terahertz metamaterial sensor based on DSRRs in clinical quantitative detection of carcinoembryonic antigen.

The terahertz (THz) metamaterial biosensor has great potential for label-free and rapid specificity testing. Here, we designed two highly sensitive structures to detect the carcinoembryonic antigen (CEA) of the cancer biomarker in early stages. There was about 29 GHz (500 ng/ml) resonance shift for CEA with an insert grate metamaterial, which was consistent with simulation results. Moreover, the concentration of CEA was gained through the relationship between the cancer marker concentration and frequency shift (Δƒ). Our design and detection methods may provide a potential route for the early warning stages of cancer.

Access to chiral α-substituted-ß-hydroxy arylphosphonates enabled by biocatalytic dynamic reductive kinetic resolution.

Ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) of α-substituted-ß-keto arylphosphonates was developed as a generic and stereoselective approach to synthesize chiral α-substituted-ß-hydroxy arylphosphonates, with moderate-to-excellent isolated yield (up to 96%), good-to-excellent diastereoselectivity (up to >99 : <1 dr), and excellent enantioselectivity (up to >99% ee) being achieved.

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.

Albumin-Mediated Biomineralization of Shape-Controllable and Biocompatible Ceria Nanomaterials.

Although ceria-based nanostructures have emerged as fascinating materials with diverse biological activities, developing a facile, rapid, and biocompatible method of their preparation remains a major challenge. Herein we describe bovine serum albumin (BSA) protein-directed synthesis of ceria-based nanostructures, including ceria nanoclusters (CNLs), nanoparticles (CNPs), and nanochains (CNHs). Their preparation is simple, one-pot, and performed in a mild reaction condition with a "green" synthetic approach. Most importantly, these three kinds of ceria-based nanostructures can be synthesized in a shape and size controllable manner by tuning the reaction time, temperature, and molar ratio. The formation mechanism shows that growth of these ceria nanostructures is mediated by Ce3+/Ce4+ switchable redox system, reducible disulfide bonds, and unique spatial structures in albumin proteins. More importantly, these albumin-based ceria nanostructures exhibit high superoxide dismutase (SOD) mimetic activity and good biocompatibility, providing a promising prospect in biomedical application.

Ghrelin accelerates wound healing in combined radiation and wound injury in mice.

Impaired wound healing caused by radiation happens frequently in clinical practice, and the exact mechanisms remain partly unclear. Various countermeasures have been taken to tackle with this issue. Ghrelin was considered as a potent endogenous growth hormone-releasing peptide, and its role in enhancing wound repair and regeneration was firstly investigated in whole-body irradiated (γ-ray) mice in this study. Collagen deposition and neovascularization were mostly discussed. The results demonstrated that ghrelin administration promoted cutaneous wound healing in irradiated mice, followed with reduced average wound closure time, increased spleen index (SI) and improved haematopoiesis. After isolation and analysis of granulation tissues in combined radiation and wound injury (CRWI) mice treated with and without ghrelin, a phenomenon of increased DNA, hexosamine, nitrate and nitrite synthesis, elevated collagen content and enhanced neovascularization was observed after ghrelin treatment. Western blotting indicated that ghrelin also increased the expression of vascular endothelial growth factor (VEGF) and transforming growth factor-ß (TGF-ß), both responsible for wound healing. However, previous administration of growth hormone secretagogue receptor 1a (GHS-R1a) blocker blunted these therapeutic effects of ghrelin on CRWI mice. Our results identify ghrelin as a novel peptide that could be used for radiation-induced impaired wound healing.

Nanoceria-Mediated Drug Delivery for Targeted Photodynamic Therapy on Drug-Resistant Breast Cancer.

Photodynamic therapy (PDT) has shown great potential for overcoming drug-resistant cancers. Here, we report a multifunctional drug delivery system based on chlorin e6 (Ce6)/folic acid (FA)-loaded branched polyethylenimine-PEGylation ceria nanoparticles (PPCNPs-Ce6/FA), which was developed for targeted PDT to overcome drug-resistant breast cancers. Nanocarrier delivery and FA targeting significantly promoted the cellular uptake of photosensitizers (PSs), followed by their accumulation in lysosomes. PPCNPs-Ce6/FA generated reactive oxygen species (ROS) after near-infrared irradiation (NIR, 660 nm), leading to reduced P-glycoprotein (P-gp) expression, lysosomal membrane permeabilization (LMP), and excellent phototoxicity toward resistant MCF-7/ADR cells, even at ultralow doses. Moreover, we identified NIR-triggered lysosomal-PDT using the higher dose of PPCNPs-Ce6/FA, which stimulated cell death by plasma membrane blebbing, cell swelling, and energy depletion, indicating an oncosis-like cell death pathway, despite the occurrence of apoptotic or autophagic mechanisms at lower drug doses. In vivo studies showed prolonged blood circulation times, low toxicity in mice, and high tumor accumulation of PPCNPs-Ce6/FA. In addition, using NIR-triggered PDT, PPCNPs-Ce6/FA displayed excellent potency for tumor regression in the MCF-7/ADR xenograft murine model. This study suggested that multifunctional PPCNPs-Ce6/FA nanocomposites are a versatile and effective drug delivery system that may potentially be exploited for phototherapy to overcome drug-resistant cancers, and the mechanisms of cell death induced by PDT should be considered in the design of clinical protocols.

Differential protein expression in metallothionein protection from depleted uranium-induced nephrotoxicity.

The purpose of this study was to investigate the underlying mechanism of metallothionein (MT) protection from depleted uranium (DU) using a proteomics approach to search for a DU toxicity-differential protein. MT-/- and MT+/+ mice were administrated with a single dose of DU (10 mg/kg, i.p.) or equal volume of saline. After 4 days, protein changes in kidney tissues were evaluated using a proteomics approach. A total of 13 differentially expressed proteins were identified using two-dimensional electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The validating results showed that the expression of aminoacylase-3 (ACY-3) and the mitochondrial ethylmalonic encephalopathy 1 (ETHE1) decreased significantly after DU exposure; in addition, the reduction in MT-/- mice was more significant than that in MT+/+ mice. The results also showed that exogenous ETHE1 or ACY-3 could increase the survival rate of human embryonic kidney 293 (HEK293) cells after DU exposure. A specific siRNA of ETHE1 significantly increased cell apoptosis rates after DU exposure, whereas exogenous ETHE1 significantly decreased cell apoptosis rates. In summary, ACY-3 and ETHE1 might involve in protection roles of MT. ETHE1 could be a new sensitive molecular target of DU-induced cell apoptosis.

Multifunctional Photosensitizer Grafted on Polyethylene Glycol and Polyethylenimine Dual-Functionalized Nanographene Oxide for Cancer-Targeted Near-Infrared Imaging and Synergistic Phototherapy.

The integration of photodynamic therapy (PDT) with photothermal therapy (PTT) offers improved efficacy in cancer phototherapy. Herein, a PDT photosensitizer (IR-808) with cancer-targeting ability and near-infrared (NIR) sensitivity was chemically conjugated to both polyethylene glycol (PEG)- and branched polyethylenimine (BPEI)-functionalized nanographene oxide (NGO). Because the optimal laser wavelength (808 nm) of NGO for PTT is consistent with that of IR-808 for PDT, the IR-808-conjugated NGO sheets (NGO-808, 20-50 nm) generated both large amounts of reactive oxygen species (ROS) and local hyperthermia as a result of 808 nm laser irradiation. With PEG- and BPEI-modified NGO as the carrier, the tumor cellular uptake of NGO-808 exhibited higher efficacy than that of strongly hydrophobic free IR-808. Through evaluation with both human and mouse cancer cells, NGO-808 was demonstrated to provide significantly enhanced PDT and PTT effects compared to individual PDT using IR-808 or PTT using NGO. Furthermore, NGO-808 preferentially accumulated in cancer cells as mediated by organic-anion transporting polypeptides (OATPs) overexpressed in many cancer cells, providing the potential for highly specific cancer phototherapy. Using the targeting ability of NGO-808, in vivo NIR fluorescence imaging enabled tumors and their margins to be clearly visualized at 48 h after intravenous injection, providing a theranostic platform for imaging-guided cancer phototherapy. Remarkably, after a single injection of NGO-808 and 808 nm laser irradiation for 5 min, the tumors in two tumor xenograft models were ablated completely, and no tumor recurrence was observed. After treatment with NGO-808, no obvious toxicity was detected in comparison to control groups. Thus, high-performance cancer phototherapy with minimal side effects was afforded from synergistic PDT/PTT treatment and cancer-targeted accumulation of NGO-808.

Ghrelin accelerates wound healing through GHS-R1a-mediated MAPK-NF-κB/GR signaling pathways in combined radiation and burn injury in rats.

The therapeutic effect of ghrelin on wound healing was assessed using a rat model of combined radiation and burn injury (CRBI). Rat ghrelin, anti-rat tumor necrosis factor (TNF) α polyclonal antibody (PcAb), or selective antagonists of p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and growth hormone secretagogue receptor (GHS-R) 1a (SB203580, SP600125, and [D-Lys3]-GHRP-6, respectively), were administered for seven consecutive days. Levels of various signaling molecules were assessed in isolated rat peritoneal macrophages. The results showed that serum ghrelin levels and levels of macrophage glucocorticoid receptor (GR) decreased, while phosphorylation of p38MAPK, JNK, and p65 nuclear factor (NF) κB increased. Ghrelin inhibited the serum induction of proinflammatory mediators, especially TNF-α, and promoted wound healing in a dose-dependent manner. Ghrelin treatment decreased phosphorylation of p38MAPK, JNK, and p65NF-κB, and increased GR levels in the presence of GHS-R1a. SB203580 or co-administration of SB203580 and SP600125 decreased TNF-α level, which may have contributed to the inactivation of p65NF-κB and increase in GR expression, as confirmed by western blotting. In conclusion, ghrelin enhances wound recovery in CRBI rats, possibly by decreasing the induction of TNF-α or other proinflammatory mediators that are involved in the regulation of GHS-R1a-mediated MAPK-NF-κB/GR signaling pathways.