Biomimetic Yolk-Shell Nanocatalysts for Activatable Dual-Modal-Image-Guided Triple-Augmented Chemodynamic Therapy of Cancer.

Fenton reaction-based chemodynamic therapy (CDT), which applies metal ions to convert less active hydrogen peroxide (H2O2) into more harmful hydroxyl peroxide (·OH) for tumor treatment, has attracted increasing interest recently. However, the CDT is substantially hindered by glutathione (GSH) scavenging effect on ·OH, low intracellular H2O2 level, and low reaction rate, resulting in unsatisfactory efficacy. Here, a cancer cell membrane (CM)-camouflaged Au nanorod core/mesoporous MnO2 shell yolk-shell nanocatalyst embedded with glucose oxidase (GOD) and Dox (denoted as AMGDC) is constructed for synergistic triple-augmented CDT and chemotherapy of tumor under MRI/PAI guidance. Benefiting from the homologous adhesion and immune escaping property of the cancer CM, the nanocatalysts can target tumor and gradually accumulate in tumor site. For triple-augmented CDT, first, the MnO2 shell reacts with intratumoral GSH to generate Mn2+ and glutathione disulfide, which achieves Fenton-like ion delivery and weakening of GSH-mediated scavenging effect, leading to GSH depletion-enhanced CDT. Second, the intratumoral glucose can be oxidized to H2O2 and gluconic acid by GOD, achieving supplementary H2O2-enhanced CDT. Next, the AuNRs absorbing in NIR-II elevate the local tumor temperature upon NIR-II laser irradiation, achieving photothermal-enhanced CDT. Dox is rapidly released for adjuvant chemotherapy due to responsive degradation of MnO2 shell. Moreover, GSH-activated PAI/MRI can be used to monitor CDT process. This study provides a great paradigm for enhancing CDT-mediated antitumor efficacy.

Toxicity and toxicokinetics of the ethanol extract of Zuojin formula.

BACKGROUND: Zuojin formula, a traditional Chinese medicine, comprises Coptis chinensis and Evodia rutaecarpa. In our previous study, the total alkaloid extract from Zuojin formula (TAZF) showed potent and improved efficacy. However, its safety and toxicokinetics remain unknown. The objective of this study was to evaluate the safety of repeated administrations of TAZF and investigate the internal exposure of the main components and its relationship with toxic symptoms. METHODS: Sprague-Dawley rats were orally administered TAZF at 0.4, 1.2 and 3.7 g/kg for 28 days, which was followed by a 14-day recovery period. The toxic effects were evaluated weekly by assessing body weight changes, food intake, blood biochemistry and haematological indices, organ weights and histological changes. A total of eight components were detected, including berberine, coptisine, epiberberine, palmatine, jatrorrhizine, columbamine, evodiamine, and rutaecarpine. The toxicokinetic profiles of the eight components were investigated after single and repeated administrations. Linear mixed effect models were applied to analyse the associations between internal exposure and toxic symptoms. Network pharmacology analysis was applied to explore the potential toxic mechanisms. RESULTS: Compared with the vehicle group, the rats in the low- and medium-dose groups did not show noticeable abnormal changes, while rats in the high-dose group exhibited inhibition of weight gain, a slight reduction in food consumption, abdominal bloating and atrophy of the splenic white pulp during drug administration. The concentration of berberine in plasma was the highest among all compounds. Epiberberine was found to be associated with the inhibition of weight gain. Network pharmacology analysis suggested that the alkaloids might cause abdominal bloating by affecting the proliferation of smooth muscle cells. The benchmark dose lower confidence limits (based on body weight inhibition) of TAZF were 1.27 g/kg (male) and 1.91 g/kg (female). CONCLUSIONS: TAZF has no notable liver or kidney toxicity but carries risks of gastrointestinal and immune toxicity at high doses. Alkaloids from Coptis chinensis are the main plasma components related to the toxic effects of TAZF.

Mechanism underlying how a chitosan-based phosphorus adsorbent alleviates cadmium-induced oxidative stress in Bidens pilosa L. and its impact on soil microbial communities: A field study.

In the present study, field experiments were conducted in Side village, Yangshuo, Guilin, Guangxi Province, China, using four C-BPA application levels (control (0 mg m-2), T1 (100 mg m-2), T2 (200 mg m-2) and T3 (400 mg m-2)) to clarify the mechanism by which a chitosan-based phosphorus adsorbent (C-BPA) applied as a passivator helps Bidens pilosa L. (B. pilosa L.) alleviate cadmium (Cd)-induced oxidative stress in Cd-contaminated soil. In the aqueous phase, C-BPA successfully adsorbed Cd2+ on the surface primarily via ion exchange, and C-BPA has potential Cd2+ adsorption capacity, enabling its use as a passivator in real Cd-contaminated environments. In Cd-contaminated soils, under C-BPA application at the T3 level, the pH value increased by 11.2%, and the acid-soluble form of Cd decreased by 26.5%. Additionally, the application of C-BPA improved the rhizosphere soil environment and impacted the soil microbial community diversity and structure. Among soil microbes, the soil fungal community was more sensitive than bacteria to C-BPA application. Dehydrogenase, acetic acid, soil pH and Eurotiomycetes or Dothideomycetes significantly impacted Cd accumulation in the leaves of B. pilosa L.; Cd accumulation in leaves was decreased by 68.1% under C-BPA application at the T3 level. Additionally, the variation of increased catalase (CAT) and peroxidase (POD) jointly promoted plant growth; the plant weight was increased by 112.7% under the C-BPA application at the T3 level. Notably, the production of CAT and POD by B. pilosa L. was more effective than the synthesis of glutathione (GSH) in helping B. pilosa L. eliminate excess reactive oxygen species (ROS). Therefore, our findings demonstrated that the application of C-BPA to Cd-contaminated soil can greatly improve the rhizosphere soil environment, help B. pilosa L. eliminate ROS and promote plant growth.

Validation and Assessment of Diffusive Gradients in Thin-Films (DGT) Technique for Measuring Nutrients in Taihu Lake Water with Algae Bloom.

DGT (diffusive gradients in thin films) technique has been developed for measuring nitrogen in freshwaters and applied to assess the bioavailability of phosphorus in soils/sediments. These two elements are the main nutrients causing algae bloom, but DGT has never been used in the field water conditions with algae bloom. In our study, a pair of DGT devices were used in comparison with grab sampling to characterize the performance of this technique to measure labile NO3-N, NH4-N, and PO4-P concentrations in algae-cultivated Taihu Lake water. The results showed that DGT measurement was highly affected by algae bloom and the environmental conditions using the current assemblies, especially for NH4-N measurement. For in situ measurement of nutrients in the real environment, an improvement to the DGT technique is required. The comprehensive assessment of the level of eutrophication needs to consider a variety of environmental factors rather than just the concentration of nutrients.

Use of the Dynamic Technique DGT to Determine the Labile Pool Size and Kinetic Resupply of Pesticides in Soils and Sediments.

The diffusive gradients in thin films (DGT) technique has been successfully and widely applied to investigate the labile fractions of inorganic contaminants in soils and sediments, but there have been almost no applications to organic contaminants. Here we developed and tested the approach for the pesticide Atrazine (ATR) in a controlled soil experiment and in situ in an intact lake sediment core. The soil study explored the relationships between soil solution, DGT measured labile ATR and solvent extractable ATR in dosed soils of different organic matter, pH status and incubation times. The results are further interpreted using the DIFS (DGT-induced fluxes in soils and sediments) model. Resupply of ATR to the soil solution was partially sustained by the solid phase in all the soils. This was due to small labile pool size and slow kinetics, with soil pH being an important controlling factor. The in situ sediment study successfully used a DGT probe to examine labile ATR distribution through the core on the subcm scale. It demonstrated-for the first time-an easy to use in situ technique to investigate the effects of redox on resupply kinetics and biogeochemical processes of trace organic contaminants in sediments.

Metal-Free Organo-Theranostic Nanosystem with High Nitroxide Stability and Loading for Image-Guided Targeted Tumor Therapy.

The desire for all-organic-composed nanoparticles (NPs) of considerable biocompatibility to simultaneously diagnose and treat cancer is undeniably interminable. Heretofore, metal-based agents dominate the landscape of available magnetic resonance imaging (MRI) contrast agents and photothermal therapeutic agents, but with associated metal-specific downsides. Here, an all-organic metal-free nanoprobe, whose appreciable biocompatibility is synergistically contributed by its tetra-organo-components, is developed as a viable alternative to metal-based probes for MRI-guided tumor-targeted photothermal therapy (PTT). This rationally entails a glycol chitosan (GC)-linked polypyrrole (PP) nanoscaffold that provides abundant primary and secondary amino groups for amidation with the carboxyl groups in a nitroxide radical (TEMPO) and folic acid (FA), to obtain GC-PP@TEMPO-FA NPs. Advantageously, the appreciably benign GC-PP@TEMPO-FA features high nitroxide loading (r1 = 1.58 mM-1 s-1) and in vivo nitroxide-reduction resistance, prolonged nitroxide-systemic circulation times, appreciable water dispersibility, potential photodynamic therapeutic and electron paramagnetic resonance imaging capabilities, considerable biocompatibility, and ultimately achieves a 17 h commensurate MRI contrast enhancement. Moreover, its GC component conveys a plethora of PP to tumor sites, where FA-mediated tumor targeting enables substantial NP accumulation with consequential near-complete tumor regression within 16 days in an MRI-guided PTT. The present work therefore promotes the engineering of organic-based metal-free biocompatible NPs in synergism, in furtherance of tumor-targeted image-guided therapy.

Selenium ameliorates aflatoxin B1-induced uterine injury in female mice and necrosis of human endometrial microvascular endothelial cells.

This study aimed to observe the effects of Selenium (Se) on aflatoxin B1 (AFB1)-induced uterine injury in female mice and necrosis of human endometrial microvascular endothelial cells (HEMECs). Fifty female mice were randomly divided into control group; AFB1 group; Se group (0.2 mg/kg each day); AFB1 + Se group; and positive control group. After continuous treatment for 30 days, uterine tissues were harvested, which were used for hematoxylin and eosin (H&E) staining. Necrosis-related proteins including RIPK1, RIPK3, and MLKL were examined in uterine tissues using western blot and immunohistochemistry. HEMECs were treated with different concentrations of AFB1 or Se, which were used for selecting the optimal concentrations. RIPK1, RIPK3 and MLKL expression was detected in HEMECs exposed to AFB1 and/or Se via western blot and immunofluorescence. H&E staining results showed that AFB1 induced uterine injury of female male, which was ameliorated by Se treatment. According to western blot and immunohistochemistry, RIPK1, RIPK3, and MLKL expression was distinctly increased in uterine tissues of AFB1-treated mice, which was decreased by Se treatment. Cell viability of HEMECs was gradually lowered as the concentrations of AFB1and Se increased. A 10-µM AFB1 exposure significantly increased RIPK1, RIPK3, and MLKL expression in HEMECs, which was improved following co-treatment with 5-µM Se. Thus, our findings revealed that Se may ameliorate AFB1-induced uterine injury in female mice and necrosis of HEMECs.

Simultaneous Qualitative and Quantitative Evaluation of the Coptidis Rhizoma and Euodiae Fructus Herbal Pair by Using UHPLC-ESI-QTOF-MS and UHPLC-DAD.

The herbal pair of Coptidis Rhizoma (CR) and Euodiae Fructus (EF) is a classical traditional Chinese medicine formula used for treating gastro-intestinal disorders. In this study, we established a systematic method for chemical profiling and quantification analysis of the major constituents in the CR-EF herbal pair. A method of ultra high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) for qualitative analysis was developed. Sixty-five compounds, including alkaloids, phenolics, and limonoids, were identified or tentatively assigned by comparison with reference standards or literature data. The UHPLC fingerprints of 19 batches of the CR-EF herbal pair samples were obtained and the reference fingerprint chromatograms were established. Furthermore, nine compounds among 24 common peaks of fingerprints were considered as marker components, which either had high contents or significant bioactivities, were applied to quality control of the CR-EF herbal pair by quantitative analysis. This UHPLC-DAD analysis method was validated by precision, linearity, repeatability, stability, recovery, and so on. The method was simple and sensitive, and thus reliable for quantitative and chemical fingerprint analysis for the quality evaluation and control of the CR-EF herbal pair and related traditional Chinese medicines.

A Hybrid Organo-Nanotheranostic Platform of Superlative Biocompatibility for Near-Infrared-Triggered Fluorescence Imaging and Synergistically Enhanced Ablation of Tumors.

The quest for an all-organic nanosystem with negligible cytotoxicity and remarkable in vivo tumor theranostic capability is inescapably unending. Hitherto, the landscape of available photothermal agents is dominated by metal-based nanoparticles (NPs) with attendant in vivo negatives. Here, an all-organic-composed theranostic nanosystem with outstanding biocompatibility for fluorescence image-guided tumor photothermal therapy, and as a potential alternative to metal-based photothermal agents is developed. This is rationally achieved by compartmentalizing indocyanine green (ICG) in glycol chitosan (GC)-polypyrrole (PP) nanocarrier to form hybrid ICG@GC-PP NPs (≈65 nm). The compartmentalization strategy, alongside the high photothermal conversion ability of PP jointly enhances the low photostability of free ICG. Advantageously, ICG@GC-PP is endowed with an impeccable in vivo performance by the well-known biocompatibility track records of its individual tri organo-components (GC, PP, and ICG). As a proof of concept, ICG@GC-PP NPs enables a sufficiently prolonged tumor diagnosis by fluorescence imaging up to 20 h post-injection. Furthermore, owing to the complementary heating performances of PP and ICG, ICG@GC-PP NPs-treated mice by one-time near-infrared irradiation exhibit total tumor regression within 14 days post-treatment. Therefore, leveraging the underlying benefits of this study will help to guide the development of new all-organic biocompatible systems in synergism, for safer tumor theranostics.

[Treatment of type 2 diabetic peripheral neuropathy patients of qi-yin deficiency complicated phlegm-dampness blocking collaterals syndrome by internal application of qigui mixture and external application of qigui huoxue lotion: a clinical study].

OBJECTIVE: To evaluate the efficacy of internal application of Qigui Mixture (QM) and external application of Qigui Huoxue Lotion (QHL) in treating type 2 diabetic peripheral neuropathy (DNP) patients of qi-yin deficiency complicated phlegm-dampness blocking collaterals syndrome (QYD-PDBCS), and to primarily discuss its mechanism. METHODS: Totally 62 DPN patients of QYD-PDBCS were randomly assigned to the treatment group (31 cases) and the control group (31 cases). All patients received routine comprehensive therapy. Patients in the control group took Mecobalamine Tablet, 500 microg each time, 3 times per day. Patients in the treatment group additionally took QM, 200 mL per day, twice daily. Besides, they had foot bath in QHL 10 - 15 min every evening for 3 months. The efficacy was assessed by Chinese medical symptom integrals and Toronto clinical scoring system (TCSS) before treatment, 2 and 3 months after treatment. The nerve conduction velocity was determined; the serum levels of total antioxidant capacity (T- AOC), malondialdehyde (MDA), and superoxide dismutase (SOD) were detected 2 and 3 months after treatment. RESULTS: The total effective rates of Chinese medical symptom integrals and TCSS score were obviously higher in the treatment group than in the control group (P < 0.05). The nerve conduction velocity was significantly improved in the treatment group, when compared with before treatment (P < 0.01). There was statistical difference in the nerve conduction velocity difference of right median nerve motor branch, bilateral tibial nerve motor branches, bilateral common peroneal nerve motor branches, bilateral ulnar nerve sensory branches, and left tibial nerve sensory branch (P < 0.05). Compared with before treatment, serum levels of T-AOC and SOD significantly increased, and the level of MDA decreased significantly in the treatment group after 2 and 3 months of treatment (P < 0.01). But only the SOD level increased significantly in the control group (P < 0.01). There was no statistical difference in increased T-AOC level between the two groups after 2 months of treatment (P > 0.05), but there was statistical difference in increased SOD level and decreased MDA level (P < 0.05). There was statistical difference in increased T-AOC and SOD levels and decreased MDA level between the two groups after 3 months of treatment (P < 0.05). No adverse reaction occurred during the therapeutic course. CONCLUSIONS: The internal application of QM and external application of QHL combined with Mecobalamine in treating DPN was safe and effective, with more significant efficacy than using Mecobalamine alone. Its mechanism might be associated with resistance to oxidative stress.