Nanomedicine Remodels Tumor Microenvironment for Solid Tumor Immunotherapy.

Although immunotherapy is relatively effective in treating hematological malignancies, their efficacy against solid tumors is still suboptimal or even noneffective presently. Compared to hematological cancers, solid tumors exhibit strikingly different immunosuppressive microenvironment, severely deteriorating the efficacy of immunotherapy: (1) chemical features such as hypoxia and mild acidity suppress the activity of immune cells, (2) the pro-tumorigenic domestication of immune cells in the microenvironment within the solid tumors further undermines the effectiveness of immunotherapy, and (3) the dense physical barrier of solid tumor tissues prevents the effective intratumoral infiltration and contact killing of active immune cells. Therefore, we believe that reversing the immunosuppressive microenvironment are of critical priority for the immunotherapy against solid tumors. Due to their unique morphologies, structures, and compositions, nanomedicines have become powerful tools for achieving this goal. In this Perspective, we will first briefly introduce the immunosuppressive microenvironment of solid tumors and then summarize the most recent progresses in nanomedicine-based immunotherapy for solid tumors by remodeling tumor immune-microenvironment in a comprehensive manner. It is highly expected that this Perspective will aid in advancing immunotherapy against solid tumors, and we are highly optimistic on the future development in this burgeoning field.

Mild magnetic hyperthermia-activated immuno-responses for primary bladder cancer therapy.

Surgical intervention followed by chemotherapy is the principal treatment strategy for bladder cancer, which is hindered by significant surgical risks, toxicity from chemotherapy, and high rates of recurrence after surgery. In this context, a novel approach using mild magnetic hyperthermia therapy (MHT) for bladder cancer treatment through the intra-bladder delivery of magnetic nanoparticles is presented for the first time. This method overcomes the limitations of low magnetic thermal efficiency, inadequate tumor targeting, and reduced therapeutic effectiveness associated with the traditional intravenous administration of magnetic nanoparticles. Core-shell Zn-CoFe2O4@Zn-MnFe2O4 (MNP) nanoparticles were developed and further modified with hyaluronic acid (HA) to enhance their targeting ability toward tumor cells. The application of controlled mild MHT using MNP-HA at temperatures of 43-44 °C successfully suppressed the proliferation of bladder tumor cells and tumor growth, while also decreasing the expression levels of heat shock protein 70 (HSP70). Crucially, this therapeutic approach also activated the body's innate immune response involving macrophages, as well as the adaptive immune responses of dendritic cells (DCs) and T cells, thereby reversing the immunosuppressive environment of the bladder tumor and effectively reducing tumor recurrence. This study uncovers the potential immune-activating mechanism of mild MHT in the treatment of bladder cancer and confirms the effectiveness and safety of this strategy, indicating its promising potential for the clinical management of bladder cancer with a high tendency for relapse.

Catechol-Isolated Atomically Dispersed Nanocatalysts for Self-Motivated Cocatalytic Tumor Therapy.

Nanocatalytic tumor therapy based on Fenton nanocatalysts has attracted considerable attention because of its therapeutic specificity, enhanced outcomes, and high biocompatibility. Nevertheless, the rate-determining step in Fenton chemistry, which involves the transition of a high-valence metallic center (FeIII ) to a Fenton-active low-valence metallic center (FeII ), has hindered advances in nanocatalyst-based therapeutics. In this study, we constructed mesoporous single iron atomic nanocatalysts (mSAFe NCs) by employing catechols from dopamine to coordinate and isolate single iron atoms. The catechols also serve as reductive ligands, generating a field-effect-based cocatalytic system that instantly reduces FeIII species to FeII species within the mSAFe NCs. This self-motivated cocatalytic strategy enabled by mSAFe NCs accelerates the kinetics of the Fenton catalytic reaction, resulting in remarkable performance for nanocatalytic tumor therapy both in vitro and in vivo.

Anti-Acidification and Immune Regulation by Nano-Ceria-Loaded Mg-Al Layered Double Hydroxide for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease featuring an abnormal immune microenvironment and resultant accumulation of hydrogen ions (H+ ) produced by activated osteoclasts (OCs). Currently, clinic RA therapy can hardly achieve sustained or efficient therapeutic outcomes due to the failures in generating sufficient immune modulation and manipulating the accumulation of H+ that deteriorates bone damage. Herein, a highly effective immune modulatory nanocatalytic platform, nanoceria-loaded magnesium aluminum layered double hydroxide (LDH-CeO2 ), is proposed for enhanced immune modulation based on acid neutralization and metal ion inherent bioactivity. Specifically, the mild alkaline LDH initiates significant M2 repolarization of macrophages triggered by the elevated antioxidation effect of CeO2 via neutralizing excessive H+ in RA microenvironment, thus resulting in the efficient recruitment of regulatory T cell (Treg) and suppressions on T helper 17 cell (Th 17) and plasma cells. Moreover, the osteogenic activity is stimulated by the Mg ion released from LDH, thereby promoting the damaged bone healing. The encouraging therapeutic outcomes in adjuvant-induced RA model mice demonstrate the high feasibility of such a therapeutic concept, which provides a novel and efficient RA therapeutic modality by the immune modulatory and bone-repairing effects of inorganic nanocatalytic material.

Nanomedicine-based co-delivery of a calcium channel inhibitor and a small molecule targeting CD47 for lung cancer immunotherapy.

Pro-tumoral macrophages in lung tumors present a significant challenge in immunotherapy. Here, we introduce a pH-responsive nanomedicine approach for activating anti-tumoral macrophages and dendritic cells. Using a layered double hydroxide nanosheet carrier, we co-deliver a T-type calcium channel inhibitor (TTA-Q6) and a CD47 inhibitor (RRX-001) into lung tumors. In the tumor acidic environment, TTA-Q6 is released, disrupting cancer cell calcium uptake, causing endoplasmic reticulum stress and inducing calreticulin transfer to the cell surface. Surface calreticulin activates macrophages and triggers dendritic cell maturation, promoting effective antigen presentation and therefore activating antitumor T cells. Simultaneously, RRX-001 reduces CD47 protein levels, aiding in preventing immune escape by calreticulin-rich cancer cells. In lung tumor models in male mice, this combined approach shows anti-tumor effects and immunity against tumor re-exposure, highlighting its potential for lung cancer immunotherapy.

Warming-induced vapor pressure deficit suppression of vegetation growth diminished in northern peatlands.

Recent studies have reported worldwide vegetation suppression in response to increasing atmospheric vapor pressure deficit (VPD). Here, we integrate multisource datasets to show that increasing VPD caused by warming alone does not suppress vegetation growth in northern peatlands. A site-level manipulation experiment and a multiple-site synthesis find a neutral impact of rising VPD on vegetation growth; regional analysis manifests a strong declining gradient of VPD suppression impacts from sparsely distributed peatland to densely distributed peatland. The major mechanism adopted by plants in response to rising VPD is the "open" water-use strategy, where stomatal regulation is relaxed to maximize carbon uptake. These unique surface characteristics evolve in the wet soil‒air environment in the northern peatlands. The neutral VPD impacts observed in northern peatlands contrast with the vegetation suppression reported in global nonpeatland areas under rising VPD caused by concurrent warming and decreasing relative humidity, suggesting model improvement for representing VPD impacts in northern peatlands remains necessary.

Nebulized Therapy of Early Orthotopic Lung Cancer by Iron-Based Nanoparticles: Macrophage-Regulated Ferroptosis of Cancer Stem Cells.

Cancer stem cells (CSCs) within protumorigenic microlesions are a critical driver in the initiation and progression of early stage lung cancer, where immune cells provide an immunosuppressive niche to strengthen the CSC stemness. As the mutual interactions between CSCs and immune cells are increasingly recognized, regulating the immune cells to identify and effectively eliminate CSCs has recently become one of the most attractive therapeutic options, especially for abundant tumor-associated macrophages (TAMs). Herein, we developed a nebulized nanocatalytic medicine strategy in which iron-based nanoparticle-regulated TAMs effectively target CSC niches and trigger CSC ferroptosis in the early stage of lung cancer. Briefly, the iron-based nanoparticles can effectively accumulate in lung cancer microlesions (minimum 122 µm in diameter) through dextran-mediated TAM targeting by nebulization administration, and as a result, nanoparticle-internalized TAMs can play a predominant role of the iron factory in elevating the iron level surrounding CSC niches and destroying redox equilibrium through downregulating glucose-6-phosphate metabolite following their lysosomal degradation and iron metabolism. The altered microenvironment results in the enhanced sensitivity of CSCs to ferroptosis due to their high expression of the CD44 receptor mediating iron endocytosis. In an orthotopic mouse model of lung cancer, the initiation and progression of early lung cancer are significantly suppressed through ferroptosis-induced stemness reduction of CSCs by nebulization administration. This work presents a nebulized therapeutic strategy for early lung cancer through modulation of communications between TAMs and CSCs, which is expected to be a general approach for regulating primary microlesions and micrometastatic niches of lung cancer.

Mineral protection controls soil organic carbon stability in permafrost wetlands.

Mineral protection can slow the effect of warming on the mineralization of organic carbon (OC) in permafrost wetlands, which has an important impact on the dynamics of soil OC. However, the response mechanisms of wetland mineral soil to warming in permafrost areas are unclear. In this study, the soil of the southern edge of the Eurasian permafrost area was selected, and bulk and heavy fraction (HF) soil was subjected to indoor warming incubation experiments using physical fractionation. The results showed that the HF accounted for 51.25 % of the total OC mineralization in the bulk soil, and the δ13C value of the CO2 that was emitted in the HF soil was higher than that of the bulk soil. This indicates the potential availability of mineral soil and that the mineralized OC in the HF was the more stable component. Additionally, the mineralization of the mineral subsoil after warming by 10 °C was only about half of the increase in the organic topsoil, and the temperature sensitivity was significantly negatively correlated with the Fe/Al oxides to OC ratio. The results indicate that under conditions of permafrost degradation, the physical protection of mineral soil at high latitudes is essential for the stability of OC, which may slow the trend of permafrost wetlands becoming carbon sources.

Nanocatalytic bacteria disintegration reverses immunosuppression of colorectal cancer.

Tumor-associated bacteria (TAB) play a critically important role in regulating the microenvironment of a tumor, which consequently greatly deteriorates the therapeutic effects by chemo- and radiotherapy deactivation and, more considerably, leads to substantial immunosuppression. On the contrary, herein we propose a nanocatalytic tumor-immunotherapeutic modality based on the bacteria disintegration by bacteria-specific oxidative damage under magnetic hyperthermia for highly effective immune response activation-promoted tumor regression. A monodispersed and superparamagnetic nanocatalytic medicine modified by arginyl-glycyl-aspartic acid (RGD) and (3-carboxypropyl)triphenylphosphonium bromide (TPP), named as MNP-RGD-TPP herein, has been synthesized, which features selective accumulation at the TAB by the electrostatic affinity, enabling effective TAB disintegration by the nanocatalytic Fenton reaction producing abundant cytotoxic hydroxyl radicals in situ under alternating magnetic field-induced hyperthermia. More importantly, the lipopolysaccharide has been metabolically secreted from the destructed TAB as pathogen-associated molecular patterns (PAMPs) to M1-polarize tumor-associated macrophages (TAMs) and promote the maturation of dendritic cells (DCs) for innate immuno-response activation of TAMs, followed by cytotoxic T lymphocytes awakening under the PAMPs presentation by the mature DCs against tumor cells. The integrated innate and adaptive immunity activations based on this TAB-promoted nanocatalytic immunomedicine, instead of magnetic heating-induced hyperthermia or the released Fe2+/Fe3+ Fenton agent, has been found to achieve excellent therapeutic efficacy in an orthotopic colorectal cancer model, demonstrating the great potential of such an integrated immunity strategy in clinical tumor immunotherapy.

Evoking tumor associated macrophages by mitochondria-targeted magnetothermal immunogenic cell death for cancer immunotherapy.

Immunogenic cell death (ICD) based on endoplasmic reticulum (ER) stress has been widely studied as the fundamentals of cancer immunotherapy. However, the currently available ICD inducers are still very rare and mostly highly toxic chemotherapeutic drugs. Herein, a novel ICD modality based on mitochondrial heat stress by magnetic hyperthermia treatment (MHT), is proposed for effectively evoking tumor-associated macrophages (TAMs) against cancer cells. A monodisperse and biocompatible nanomedicine by grafting arginyl-glycyl-aspartic acid (RGD) and (3-carboxypropyl)triphenylphosphonium bromide (TPP) onto the surface of superparamagnetic ZnCoFe2O4@ZnMnFe2O4 nanoparticles (MNPs), named as MNPs-RGD-TPP (MRT), was synthesized for mitochondrial heat stress-induced oxidative damage of tumor cells under the magnetothermal manipulation. Such heat stress-damaged mitochondria can cause the immunogenic death of tumor cells to release damage-associated molecular patterns (DAMPs), including ATP and HSP 70, to M1-polarize TAMs, resulting in the reactivated immunoresponse of macrophages against cancer cells. The effectiveness and robustness of MRT nanomedicine in evoking TAMs-mediated extracellular killing or phagocytosis are verified both in vitro and in vivo. Such a therapeutic approach based on mitochondria-targeted magnetothermal ICD for activating TAMs may be instructive to future anticancer immunotherapy.

Dual Inhibitions on Glucose/Glutamine Metabolisms for Nontoxic Pancreatic Cancer Therapy.

Glucose and glutamine are two principal nutrients in mammalian cells that provide energy and biomass for cell growth and proliferation. Especially in cancer cells, glutamine could be a main alternative for energy and biomass supply once glucose metabolism is suppressed. Therefore, single inhibition of enzymes in either glucose metabolism or glutaminolysis, though maybe efficient in vitro, is far from being satisfactory for efficient in vivo cancer therapy. Here, we proposed a new strategy for dual inhibitions on both glucose and glutamine metabolisms concurrently by silencing mutated gene Kras and glutaminase 1 (GLS1) via nanomaterial-based siKras and siGLS1 delivery, rather than conventional highly toxic chemodrugs. Such a combination therapy could overcome the challenge that glucose and glutamine are alternatives to each other in the biosynthesis and energy production for cancer cells, resulting in much elevated treatment efficacy. In addition, layered double hydroxide (LDH), the siRNA carrier, enables an enhanced gene delivery efficiency compared to the commercial transfection agent Lipofectamine 2000. Briefly, Mg-Al LDH nanosheets, loaded with siKras and siGLS1 onto their surfaces by electrostatic adsorption, could release siRNA from lysosomes into the cytoplasm via the proton sponge effect of LDH, favoring the siRNA stability and gene silencing efficiency enhancements. The thus released siRNA could downregulate the expressions of Kras, GLS1, and other enzymes involved in glucose metabolism, resulting in the downregulations of ATP and other metabolites. Such a biosafe LDH/siRNA nanomedicine is able to efficiently suppress the growth of xenografts through cancer cell proliferation suppression, displaying its great potential as a simultaneous glucose/glutamine metabolism coinhibitor for treating pancreatic cancer.

Enhancing Tumor Catalytic Therapy by Co-Catalysis.

Fenton reactions have been recently applied in tumor catalytic therapy, whose efficacy suffers from the unsatisfactory reaction kinetics of Fe3+ to Fe2+ conversion. Here we introduce a co-catalytic concept in tumor catalytic therapy by using a two-dimensional molybdenum disulfide (MoS2 ) nanosheet atomically dispersed with Fe species. The single-atom Fe species act as active sites for triggering Fenton reactions, while the abundant sulfur vacancies generated on the nanosheet favor electron capture by hydrogen peroxide for promoting hydroxyl radical production. Moreover, the 2D MoS2 support also acts as a co-catalyst to accelerate the conversion of Fe3+ to Fe2+ by the oxidation of active Mo4+ sites to Mo6+ , thereby promoting the whole catalytic process. The 2D nanocatalyst exhibits a desirable catalytic performance, as well as a significantly enhanced anticancer efficacy both in vitro and in vivo, which indicates the feasibility for applying such a co-catalytic concept in tumor therapy.

In Situ Synthesis of Natural Antioxidase Mimics for Catalytic Anti-Inflammatory Treatments: Rheumatoid Arthritis as an Example.

Mimicking the coordination geometry of the active metal sites of natural enzymes is an efficient strategy in designing therapeutic chemicals with enzymelike in vivo reaction thermodynamics and kinetics. In this study, this chemical concept has been applied for the in situ synthesis of natural antioxidase mimics for catalytic anti-inflammatory treatment by using rheumatoid arthritis, a common and hardly curable immune-mediated diseases, as an example. Briefly, a composite nanomedicine has been first constructed by loading cationic porphyrin ligands into a manganese-engineered mesoporous silica nanocarrier, which can respond to a mildly acidic environment to concurrently release manganous ions and porphyrin ligands, enabling their subsequent coordination and synthesis of manganese porphyrin with a coordination environment of an active Mn site similar to those of the metal sites in natural superoxide dismutase (SOD) and catalase. Due to the strong metal-ligand exchange coupling enabled by the N-ethylpyridinium-2-yl groups tetrasubstituted in the meso positions of N4-macroheterocycles, such a manganese porphyrin presents the SOD-like activity of disproportionating superoxide anions via outer-sphere proton-coupled one-electron transfer (diaquamanganese(III)/monoaquamanganese(II) cycling), as well as the catalase-like activity of disproportionating hydrogen peroxide via inner-sphere proton-coupled two-electron transfer (diaquamanganese(III)/dioxomanganese(V) cycling). Cellular experiments demonstrated the high antioxidative efficacy of the composite nanomedicine in M1 macrophages by promoting their polarization shift to the anti-inflammatory M2 phenotype. Equally importantly, the silicon-containing oligomers released from the manganese silicate nanocarrier can act as heterogeneous nucleation centers of hydroxyapatite for facilitating biomineralization by bone mesenchymal stem cells. Finally, an in vivo adjuvant-induced arthritis animal model further reveals the high efficacy of the nanomedicine in treating rheumatoid arthritis.

Shift in competitive ability mediated by soil biota in an invasive plant.

Understanding the shifts in competitive ability and its driving forces is key to predict the future of plant invasion. Changes in the competition environment and soil biota are two selective forces that impose remarkable influences on competitive ability. By far, evidence of the interactive effects of competition environment and soil biota on competitive ability of invasive species is rare. Here, we investigated their interactive effects using an invasive perennial vine, Mikania micrantha. The competitive performance of seven M. micrantha populations varying in their conspecific and heterospecific abundance were monitored in a greenhouse experiment, by manipulating soil biota (live and sterilized) and competition conditions (competition-free, intraspecific, and interspecific competition). Our results showed that with increasing conspecific abundance and decreasing heterospecific abundance, (1) M. micrantha increased intraspecific competition tolerance and intra- vs. interspecific competitive ability but decreased interspecific competition tolerance; (2) M. micrantha increased tolerance of the negative soil biota effect; and (3) interspecific competition tolerance of M. micrantha was increasingly suppressed by the presence of soil biota, but intraspecific competition tolerance was less affected. These results highlight the importance of the soil biota effect on the evolution of competitive ability during the invasion process. To better control M. micrantha invasion, our results imply that introduction of competition-tolerant native plants that align with conservation priorities may be effective where M. micrantha populations are long-established and inferior in inter- vs. intraspecific competitive ability, whereas eradication may be effective where populations are newly invaded and fast-growing.

Endogenous Copper for Nanocatalytic Oxidative Damage and Self-Protection Pathway Breakage of Cancer.

Nanocatalytic medicine is one of the most recent advances in the development of nanomedicine, which catalyzes intratumoral chemical reactions to produce toxins such as reactive oxygen species in situ for cancer specific treatment by using exogenous-delivered catalysts such as Fenton agents. However, the overexpression of reductive glutathione and Cu-Zn superoxide dismutase in cancer cells will significantly counteract the therapeutic efficacy by reactive oxygen species-mediated oxidative damages. Additionally, the direct delivery of iron-based Fenton agents may arouse undesired detrimental effects such as anaphylactic reactions. In this study, instead of exogenously delivering Fenton agents, the endogenous copper ions from intracellular Cu-Zn superoxide dismutase have been employed as the source of Fenton-like agents by chelating the Cu ions from the superoxide dismutase using a common metal ion chelator, N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN), followed by the TPEN-Cu(II) chelate reduction to TPEN-Cu(I) by reductive glutathione. Briefly, TPEN was loaded in a disulfide bond-containing link poly(acrylic acid) shell-coated hybrid mesoporous silica/organosilicate (MSN@MON) nanocomposite as a reductive glutathione-responsive nanoplatform, which features inter-related triple functions: intratumoral reductive glutathione-responsive link poly(acrylic acid) disruption and TPEN release; the accompanying reductive glutathione consumption and Cu-Zn superoxide dismutase deactivation by TPEN chelating Cu ions from this superoxide dismutase; and the Fenton reaction catalyzed by TPEN-Cu(I) chelate as a Fenton-like agent generated from TPEN-Cu(II) reduction by the remaining reductive glutathione in cancer cells, thereby cutting off the self-protection pathway of cancer cells under severe oxidation stress and ensuring cancer cell apoptosis by reactive oxygen species produced by the catalytic Fenton-like reactions. Such a nanocatalyst demonstrates excellent biosafety and augmented therapeutic efficacy by simultaneous nanocatalytic oxidative damage and intrinsic protection pathway breakage of cancer cells.

Tumor chemical suffocation therapy by dual respiratory inhibitions.

The extraordinarily rapid growth of malignant tumors depends heavily on the glucose metabolism by the pathways of glycolysis and mitochondrial oxidative phosphorylation to generate adenosine 5'-triphosphate (ATP) for maintaining cell proliferation and tumor growth. This study reports a tumor chemical suffocation therapeutic strategy by concurrently suppressing both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) via the co-deliveries of EDTA and rotenone into a glutathione (GSH)-overexpressed tumor microenvironment. EDTA is to block the glycolytic pathway through inhibiting the activity of glycolytic enzymes via the chelation of magnesium ion, a co-worker of glycolytic enzymes, despite the presence of Ca2+. Meanwhile rotenone is to inhibit the mitochondrial OXPHOS. This work provides a novel tumor suffocation strategy by the co-deliveries of glucose metabolism inhibitors, especially by de-functioning glycolytic enzymes via eliminating their co-worker magnesium.

Intratumoral synthesis of nano-metalchelate for tumor catalytic therapy by ligand field-enhanced coordination.

The iron gall ink-triggered chemical corrosion of hand-written documents is a big threat to Western cultural heritages, which was demonstrated to result from the iron gall (GA-Fe) chelate-promoted reactive oxygen species generation. Such a phenomenon has inspired us to apply the pro-oxidative mechanism of GA-Fe to anticancer therapy. In this work, we construct a composite cancer nanomedicine by loading gallate into a Fe-engineered mesoporous silica nanocarrier, which can degrade in acidic tumor to release the doped Fe3+ and the loaded gallate, forming GA-Fe nanocomplex in situ. The nanocomplex with a highly reductive ligand field can promote oxygen reduction reactions generating hydrogen peroxide. Moreover, the resultant two-electron oxidation form of GA-Fe is an excellent Fenton-like agent that can catalyze hydrogen peroxide decomposition into hydroxyl radical, finally triggering severe oxidative damage to tumors. Such a therapeutic approach by intratumoral synthesis of GA-Fe nano-metalchelate may be instructive to future anticancer researches.

Investigation into effects of warmer conditions on seasonal runoff and dissolved carbon fluxes in permafrost catchments in northeast China.

Eurasian permafrost serves as an important carbon pool and water resource for linked aquatic ecosystems. To investigate the effects of expected warmer climate under climate change, and also to fill the data gaps in the south margin of the Eurasian permafrost, the seasonal runoff and the associated dissolved carbon fluxes in a pair of catchments in the Great Khingan Mountains of northeast China were investigated in 2018-2019. Two similar small catchments, a south-facing (SF) and a north-facing (NF), were used to check the effects of warmer climate on the dynamics of runoff and dissolved carbon yields. The SF catchment, with a warmer condition compared to the NF catchment, presented much larger snowmelt runoff during spring and more gentle rainfall flood peaks in the summer-autumn period, but similar concentrations of dissolved carbons during both the periods. As a result, the dissolved carbon fluxes were greatly elevated during the snowmelt period. However, the runoff and carbon yield in the two catchments showed no significant difference during the summer rainfall periods, in spite of a much deeper active layer of permafrost in the SF. As indicated by two fluorescence indices, the humification (HIX) and biological index (BIX), the chemical characteristics of dissolved carbon were similar in both the snowmelt and rainfall runoff periods in the two catchments. These results emphasize that warmer climate would largely alter the seasonal runoff patterns and promote dissolved carbon export in the snowmelt period, which would lead to more unexpected ecological impacts on the aquatic systems in the south Eurasian permafrost.

Nanocatalytic Innate Immunity Activation by Mitochondrial DNA Oxidative Damage for Tumor-Specific Therapy.

The innate immune system plays a key role in protecting the human body from tumors, which, unfortunately, is largely counteracted by their immune-suppression function. Such an immune suppression has been reported to be induced by the immunosuppressive microenvironment, including the exhausted cytotoxic T lymphocytes (CTLs) and tumor-promoting M2-polarized macrophages. Here, a novel tumor-immunotherapeutic modality based on the nanocatalytic innate immunity activation by tumor-specific mitochondrial DNA (mtDNA) oxidative damage is proposed. In detail, a nanocatalytic medicine, Fe2+ -Ru2+ -loaded mesoporous silica nanoparticle named as MSN-Ru2+ /Fe2+ (MRF), is constructed to induce oxidative damage in the mtDNA of tumor cells. Such an oxidative mtDNA is able to escape from the tumor cells and acts as an immunogenic damage-associated molecular pattern to M1-polarize tumor-associated macrophages (TAMs), resulting in the reactivated immunoresponse of macrophages against cancer cells, and the subsequent inflammatory response of innate immunity. Most importantly, the treatment strategy based on regulating the innate immune response of TAMs not only stops the primary tumor progression, but also almost completely inhibits the growth of distant tumors in the periods of treatments.

Nos2 deficiency enhances carbon tetrachloride-induced liver injury in aged mice.

OBJECTIVES: As a multifunctional molecule, NO has different effects on liver injury. The present work aimed to investigate the effects of Nos2 knockout (KO) on acute liver injury in aged mice treated with carbon tetrachloride (CCl4). MATERIALS AND METHODS: The acute liver injury model was produced by CCl4 at 10 ml/kg body weight in 24-month-old Nos2 KO mice and wild type (WT) mice groups. The histological changes, transaminase and glutathione (GSH) contents, and the expressions of liver function genes superoxide dismutase (SOD2) and butyrylcholinesterase (BCHE), as well as apoptosis- and inflammation-associated genes were detected at 0, 6, 16, 20, 28, and 48 hr, respectively. RESULTS: Compared with WT aged mice, there are more fat droplets in liver tissues of Nos2 KO aged mice, and the serum levels of ALT and AST were elevated in the KO group; in addition, there was a decrease in the expression of SOD2 and BCHE and GSH content at multiple time-points. Furthermore, the expression of apoptosis protein CASPASE-3 was elevated from 20 to 48 hr, the same as CASPASE-9 at 28 and 48 hr and pro-apoptotic protein BAX at 6 and 28 hr, while the expression of apoptosis inhibitory protein BCL2 declined at 6 and 28 hr; at the same time the mRNA expressions of genes related to inflammation were increased at different extents in liver extracts of Nos2 KO aged mice. CONCLUSION: Nos2 KO exacerbated liver injury probably by elevated oxidative stress, apoptosis and inflammation response in CCl4-induced aged mice liver intoxication model.