Pharmaceutical Manipulation of Mitochondrial F0F1-ATP Synthase Enables Imaging and Protection of Myocardial Ischemia/Reperfusion Injury Through Stress-induced Selective Enrichment.

To rescue ischemic myocardium from progressing to myocardial infarction, timely identification of the infarct size and reperfusion is crucial. However, fast and accurate identification, as well as the targeted protection of injured cardiomyocytes following ischemia/reperfusion (I/R) injury, remain significantly challenging. Here, a near infrared heptamethine dye IR-780 is shown that has the potential to quickly monitor the area at risk following I/R injury by selectively entering the cardiomyocytes of the at-risk heart tissues. Preconditioning with IR-780 or timely IR-780 administration before reperfusion significantly protects the heart from ischemia and oxidative stress-induced cell death, myocardial remodeling, and heart failure in both rat and pig models. Furthermore, IR-780 can directly bind to F0F1-ATP synthase of cardiomyocytes, rapidly decrease the mitochondrial membrane potential, and subsequently slow down the mitochondrial energy metabolism, which induces the mitochondria into a "quiescent state" and results in mitochondrial permeability transition pore inhibition by preventing mitochondrial calcium overload. Collectively, the findings show the feasibility of IR-780-based imaging and protection strategy for I/R injury in a preclinical context and indicate that moderate mitochondrial function depression is a mode of action that can be targeted in the development of cardioprotective reagents.

Diversity of medium and small-sized soil fauna community in different urban-rural green spaces and its influencing factors in Nanchang, China.

Urbanization is one of the important factors leading to biodiversity loss and habitat fragmentation. As an important component of urban ecosystem, soil fauna community plays a key role in improving soil structure and fertility, and promoting material circulation of urban ecosystem. To investigate the distribution characteristics of medium and small-sized soil fauna community in green space and the mechanisms underlying their responses to environmental change during urbanization, we selected 27 green space plots with a gradient of urban, suburban, and rural areas in Nanchang City as study objects, and measured plant parameters, soil physicochemical properties, and distribution characteristics of soil fauna community in these plots. The results showed that a total of 1755 soil fauna individuals were captured, belonging to 2 phyla, 11 classes, and 16 orders. The dominant groups were Collembola, Parasiformes, and Acariformes, which accounting for 81.9% of total soil fauna community. The density, Shannon diversity index, and Simpson dominance index of soil fauna community were significantly higher in suburban area than those in rural area. In the green space of the urban-rural gradient, there were large structure variations in different trophic levels of medium and small-sized soil fauna community. Herbivores and macro-predators occupied the largest proportion in rural area, and less in other areas. Results of the redundancy analysis showed the crown diameter, forest density, soil total phosphorus contents were the main environmental factors affecting soil fauna community distribution, with interpretation rate of 55.9%, 14.0% and 9.7%, respectively. Results of the non-metric multidimensional scale analysis showed that there were variations in soil fauna community characteristics in green space of the urban-rural gradient, and that the aboveground vegetation was the dominant factor for this change. This study improved our understanding of urban ecosystem biodiversity in Nanchang, and provided basis for maintaining soil biodiversity and urban green space construction.

Effects of urbanization intensity on glomalin-related soil protein in Nanchang, China: Influencing factors and implications for greenspace soil improvement.

Glomalin-related soil protein (GRSP) is a stable and persistent glycoprotein secreted by arbuscular mycorrhizal fungi that plays an important role in sequestering soil organic carbon (SOC) and improving soil quality. Rapid urbanization disturbs and degrades the soil quality in the greenspace. However, few studies have investigated the effects of urbanization on GRSP and its influencing factors. This study selected impervious surface area as a measure of urbanization intensity. A total of 184 soil samples were collected from the 0-20 cm soil layer in the greenspace of Nanchang, China (505 km2). The GRSP content, soil properties, urban forest characteristics, and land-use configuration were determined. The total GRSP (TG) and easily extractable GRSP (EEG) contents were 2.38 and 0.57 mg g-1, respectively. TG and EEG decreased by 16.22% and 19.35%, respectively, from low to heavy urbanized areas. Moreover, SOC decreased from 39.9 to 1.4 mg g-1, while EEG/SOC and TG/SOC increased by approximately 17% and 34%, respectively, indicating the significant contribution of GRSP to the SOC pool. Pearson and redundancy analysis showed that GRSP was positively correlated with SOC, phosphorus, nitrogen, vegetation richness, and tree height, but negatively correlated with pH, bulk density, and impervious area. The partial least squares path model demonstrated that urbanization affected soil properties, forest characteristics, and land use factors, resulting in GRSP changes. This study clarifies the key factors of urbanization that affect GRSP and provides insight for urban greenspace soil improvement from the new perspective of enhancing the GRSP content.

Luminescence Imaging of Acute Liver Injury by Biodegradable and Biocompatible Nanoprobes.

Liver injury can result in different hepatic diseases such as fatty liver, liver fibrosis, hepatitis, and liver failure, which are mainly responsible for global mortality and morbidity. Early diagnosis is critical for the treatment of liver diseases. Herein we report luminescence imaging of neutrophil-mediated acute liver injury, including alcoholic liver injury (ALI) and acute liver failure (ALF). To this purpose, a biodegradable luminescent material was developed by chemical functionalization of a cyclic oligosaccharide, which can be produced into nanoprobes (defined as LaCD NPs). Luminescence of LaCD NPs was dependent on the level of reactive oxygen species and myeloperoxidase (MPO). Correspondingly, activated neutrophils could be specifically imaged by LaCD NPs, and the luminescent signal was positively associated with the neutrophil count. In mouse models of ALI and ALF, LaCD NPs enabled precise quantification and tracking of neutrophils in livers. In both cases, changes in the luminescence intensity are consistent with time-dependent profiles of neutrophils, MPO, and other parameters relevant to the pathogenesis of liver injury. Moreover, the luminescence imaging capacity of LaCD NPs can be additionally improved by surface functionalization with a neutrophil-targeting peptide. In addition, preliminary in vitro and in vivo studies demonstrated good safety of LaCD NPs. Consequently, LaCD NPs can be further developed as an effective and biocompatible luminescent nanoprobe for in vivo dynamic detection of the development of neutrophil-mediated acute liver injury. It is also promising for diagnosis of other neutrophil-associated liver diseases.

Fibrogenic fibroblast-selective near-infrared phototherapy to control scarring.

Rationale: Fibroblasts, the predominant cell type responsible for tissue fibrosis, are heterogeneous, and the targeting of unique fibrogenic population of fibroblasts is highly expected. Very recently, elevated glycolysis is demonstrated to play a pivotal role in the determination of fibrogenic phenotype of fibroblasts. However, it is lack of specific strategies for targeting and elimination of such fibrogenic populations. In this study, a novel strategy to use the a near-infrared (NIR) dye IR-780 for the targeting and elimination of a fibrogenic population of glycolytic fibroblasts to control the cutaneous scarring is developed. Methods: The identification and cell properties test of fibrogenic fibroblasts with IR-780 were conducted by using fluorescence activated cell sorting, transplantation experiments, in vivo imaging, RNA sequencing in human cell experiments and mouse and rat wound models. The uptake of IR-780 in fibroblasts mediated by HIF-1α/SLCO2A1 and the metabolic properties of IR-780H fibroblasts were investigated using RNA interference or signaling inhibitors. The fibrogenic fibroblast-selective near-infrared phototherapy of IR-780 were evaluated in human cell experiments and mouse wound models. Results: IR-780 is demonstrated to recognize a unique glycolytic fibroblast lineage, which is responsible for the bulk of connective tissue deposition during cutaneous wound healing and cancer stroma formation. Further results identified that SLCO2A1 is involved in the preferential uptake of IR-780 in fibrogenic fibroblasts, which is regulated by HIF-1α. Moreover, with intrinsic dual phototherapeutic activities, IR-780 significantly diminishes cutaneous scarring through the targeted ablation of the fibrogenic population by photothermal and photodynamic effects. Conclusion: This work provides a unique strategy for the targeted control of tissue scarring by fibrogenic fibroblast-selective near-infrared phototherapy. It is proposed that IR-780 based theranostic methodology holds promise for translational medicine aimed at regulation of fibrogenic behavior.

Cyclodextrin-Derived Intrinsically Bioactive Nanoparticles for Treatment of Acute and Chronic Inflammatory Diseases.

Inflammation is a common cause of many acute and chronic inflammatory diseases. A major limitation of existing anti-inflammatory therapeutics is that they cannot simultaneously regulate pro-inflammatory cytokine production, oxidative stress, and recruitment of neutrophils and macrophages. To overcome this limitation, nanoparticles (NPs) with multiple pharmacological activities are synthesized, using a chemically modified cyclic oligosaccharide. The manufacture of this type of bioactive, saccharide material-based NPs (defined as LCD NP) is straightforward, cost-effective, and scalable. Functionally, LCD NP effectively inhibits inflammatory response, oxidative stress, and cell migration for both neutrophils and macrophages, two major players of inflammation. Therapeutically, LCD NP shows desirable efficacies for the treatment of acute and chronic inflammatory diseases in mouse models of peritonitis, acute lung injury, and atherosclerosis. Mechanistically, the therapeutic benefits of LCD NP are achieved by inhibiting neutrophil-mediated inflammatory macrophage recruitment and by preventing subsequent pro-inflammatory events. In addition, LCD NP shows good safety profile in a mouse model. Thus, LCD NP can serve as an effective anti-inflammatory nanotherapy for the treatment of inflammatory diseases mainly associated with neutrophil and macrophage infiltration.

A Multifunctional Nanotherapy for Targeted Treatment of Colon Cancer by Simultaneously Regulating Tumor Microenvironment.

Colitis-associated colon cancer (CAC) is a widely recognized cancer, while treatment with the existing chemotherapeutic drugs affords limited clinical benefits. Herein we proposed a site-specific, combination nanotherapy strategy for targeted treatment of CAC by the oral route. Methods: A reactive oxygen species (ROS)-responsive and hydrogen peroxide-eliminating material OCD was synthesized, which was further produced into a functional nanoparticle (OCD NP). The antioxidative stress and anti-inflammatory effects of OCD NP were examined by in vitro and in vivo experiments. By packaging an anticancer drug camptothecin-11 (CPT-11) into OCD NP, a ROS-responsive nanotherapy CPT-11/OCD NP was obtained, and its antitumor activity was evaluated by both in vitro and in vivo studies. Preliminary safety studies were also performed for CPT-11/OCD NP in mice. Results: OCD NP significantly attenuated oxidative stress and inhibited inflammatory response in different cells and mice with induced colitis. CPT-11/OCD NP could selectively release drug molecules under intestinal pH conditions and at high levels of ROS. In C26 murine colon carcinoma cells, this nanotherapy showed significantly higher antitumor activity compared to free CPT-11 and a non-responsive CPT-11 nanotherapy. Correspondingly, oral delivery of CPT-11/OCD NP notably inhibited tumorigenesis and tumor growth in mice with induced CAC. By combination therapy with the nanovehicle OCD NP in the inflammatory phase, more desirable therapeutic effects were achieved. Furthermore, CPT-11/OCD NP displayed excellent safety profile for oral administration at a dose that is 87.3-fold higher than that employed in therapeutic studies. Conclusions: Anticancer nanotherapies derived from intrinsic anti-inflammatory nanocarriers are promising for targeted combination treatment of inflammation-associated tumors by simultaneously shaping pro-inflammatory microenvironment toward a relatively normal niche sensitive to chemotherapy.

Cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents.

The pathological mechanisms of radiation ulcer remain unsolved and there is currently no effective medicine. Here, we demonstrate that persistent DNA damage foci and cell senescence are involved in radiation ulcer development. Further more, we identify cordycepin, a natural nucleoside analogue, as a potent drug to block radiation ulcer (skin, intestine, tongue) in rats/mice by preventing cell senescence through the increase of NRF2 nuclear expression (the assay used is mainly on skin). Finally, cordycepin is also revealed to activate AMPK by binding with the α1 and γ1 subunit near the autoinhibitory domain of AMPK, then promotes p62-dependent autophagic degradation of Keap1, to induce NRF2 dissociate from Keap1 and translocate to the nucleus. Taken together, our findings identify cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents, and activation of AMPK or NRF2 may thus represent therapeutic targets for preventing cell senescence and radiation ulcer.

Self-assembly of affinity-controlled nanoparticles via host-guest interactions for drug delivery.

There has been increasing interest in constructing affinity-based drug delivery systems via different non-covalent interactions. Herein we report a host-guest interaction-based strategy to develop effective drug delivery systems using cyclodextrin-containing copolymers. Hydrophilic copolymers with one polyethylene glycol block and another block containing either α-cyclodextrin or ß-cyclodextrin were synthesized. Using poly(ß-benzyl l-aspartate) and pyrene as model guest compounds, we demonstrated the nanoparticle formation by host-guest interaction-mediated self-assembly. When an antioxidant and anti-inflammatory drug Tempol was used, the formation of well-defined spherical nanoparticles and therapeutic loading can be simultaneously realized. The obtained nanotherapy showed affinity-controlled drug release. In vitro cell culture experiments suggested that the host-guest nanotherapy exhibited desirable antioxidant and anti-inflammatory effects in macrophages. In a mouse model of an inflammatory disease ulcerative colitis, the orally administered host-guest nanoparticle can be effectively accumulated in the inflamed colonic tissue. Oral treatment of mice bearing colitis with the nanotherapy led to significantly improved efficacy in comparison with free drugs. A good in vivo safety profile was also observed for the developed host-guest nanotherapy. Accordingly, these types of affinity nanoparticles based on CD-containing copolymers can function as effective nanoplatforms for targeted treatment of a plethora of diseases.

Environmental concern-based site screening of carbon dioxide geological storage in China.

Environmental impacts and risks related to carbon dioxide (CO2) capture and storage (CCS) projects may have direct effects on the decision-making process during CCS site selection. This paper proposes a novel method of environmental optimization for CCS site selection using China's ecological red line approach. Moreover, this paper established a GIS based spatial analysis model of environmental optimization during CCS site selection by a large database. The comprehensive data coverage of environmental elements and fine 1 km spatial resolution were used in the database. The quartile method was used for value assignment for specific indicators including the prohibited index and restricted index. The screening results show that areas classified as having high environmental suitability (classes III and IV) in China account for 620,800 km2 and 156,600 km2, respectively, and are mainly distributed in Inner Mongolia, Qinghai and Xinjiang. The environmental suitability class IV areas of Bayingol Mongolian Autonomous Prefecture, Hotan Prefecture, Aksu Prefecture, Hulunbuir, Xilingol League and other prefecture-level regions not only cover large land areas, but also form a continuous area in the three provincial-level administrative units. This study may benefit the national macro-strategic deployment and implementation of CCS spatial layout and environmental management in China.

Increase in the radioresistance of normal skin fibroblasts but not tumor cells by mechanical injury.

The timing of radiation after mechanical injury such as in the case of surgery is considered a clinical challenge because radiation is assumed to impair wound healing. However, the physiological responses and underlying mechanisms of this healing impairment are still unclear. Here, we show that mechanical injury occurring before ionizing radiation decreases radiation-induced cell damage and increases cell repair in normal fibroblasts but not tumor cells in vitro and in vivo. At the molecular level, mechanical injury interrupts focal adhesion complexes and cell-cell cadherin interactions, transducing mechanical signals into intracellular chemical signals via activation of the phosphatidylinositol 3-kinase (PI3K), Akt, and glycogen synthase kinase 3 beta (GSK-3ß) pathways. We show that subsequent nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and ß-catenin strengthen the stemness, antioxidant capabilities, and DNA double-strand break repair abilities of fibroblasts, ultimately contributing to increased radioresistance. Our findings demonstrate that mechanical injury to normal fibroblasts enhances radioresistance and may therefore question conventional wisdom surrounding the timing of radiation after surgery.

[Investigation on the fabrication and spectrum properties of Yb3+ -doped silicate laser glasses].

Two kinds of Yb3+ doped silicate laser glass with little difference were produced by high temperature of melting process. The absorption and emission spectra of the two glass samples were tested by the correlative spectrographs; the integral absorption cross section, stimulated emission cross section, fluorescence line-width, fluorescence lifetime, least particle count, saturation pump intensity and least pump intensity of the Yb3+ -doped laser glasses were calculated respectively, and by comparison it was found that the chart of the absorption cross section is similar to the stimulated emission cross section calculated by the reciprocity method, and is very different from the stimulated emission cross section calculated by the Fuchbauer-Ladenburger method. This result is precisely in line with the theoretical analysis. The line-types of the absorption spectra of the two glass samples are almost the same, and the first peak value of absorption is located at 975 nm while the second peak value is at 908 nm. As the two components of the samples are not very different, the accord of the line-types of the absorption spectra indicates that the makeup of the glass material is the primary factor influencing the line-type of the absorption spectra. The fluorescence spectra of the two glass samples are very different, and the first fluorescence peak value of sample one is located at 993 nm with the second peak value at 1029 nm, while the first fluorescence peak value of sample two is located at 1 035 nm with the second peak value at 994 nm. The cause of the major difference in the fluorescence spectra of two samples lies in the different doping density of Yb3+. By comparison we found that the laser performance of sample two is better than that of sample one. The test shows that both samples are suitable for drawing fiber.