Mitochondrial ATP synthase as a direct molecular target of chromium(III) to ameliorate hyperglycaemia stress.

Chromium(III) is extensively used as a supplement for muscle development and the treatment of diabetes mellitus. However, its mode of action, essentiality, and physiological/pharmacological effects have been a subject of scientific debate for over half a century owing to the failure in identifying the molecular targets of Cr(III). Herein, by integrating fluorescence imaging with a proteomic approach, we visualized the Cr(III) proteome being mainly localized in the mitochondria, and subsequently identified and validated eight Cr(III)-binding proteins, which are predominately associated with ATP synthesis. We show that Cr(III) binds to ATP synthase at its beta subunit via the catalytic residues of Thr213/Glu242 and the nucleotide in the active site. Such a binding suppresses ATP synthase activity, leading to the activation of AMPK, improving glucose metabolism, and rescuing mitochondria from hyperglycaemia-induced fragmentation. The mode of action of Cr(III) in cells also holds true in type II diabetic male mice. Through this study, we resolve the long-standing question of how Cr(III) ameliorates hyperglycaemia stress at the molecular level, opening a new horizon for further exploration of the pharmacological effects of Cr(III).

Sorafenib as adjuvant therapy following radiofrequency ablation for recurrent hepatocellular carcinoma within Milan criteria: a multicenter analysis.

BACKGROUND: Radiofrequency ablation (RFA) is considered as a convenient treatment with mild damage in treating recurrent hepatocellular carcinoma (RHCC). However, for patients with high risk of progression after RFA still needs new strategies to decrease the repeat recurrence. METHODS: A total of 460 patients with RHCC within Milan criteria in four institutions were enrolled. 174 pairs were enrolled after propensity score matching (PSM). Overall survival (OS) and tumor-free survival (TFS) were compared between the two groups. A quantitative score system was established to screen out the beneficial population from RFA-sorafenib treatment. RESULTS: The 1-, 3-, and 5-year OS rates were 97.7%, 83.7%, 54.7% for RFA-sorafenib group, and 93.1%, 61.3%, 30.9% for RFA group after PSM, respectively. Compared with the RFA group, the RFA-sorafenib group had significantly better OS (P < 0.001). The 1-, 3-, and 5-year TFS rates were 90.8%, 49.0%, 20.4% for RFA-sorafenib group, and 67.8%, 28.0%, 14.5% for RFA group after PSM. The difference was observed significantly between RFA-sorafenib group and RFA group (P < 0.001). A quantitative risk score system was established to precisely screen out the beneficial population from RFA-sorafenib treatment. CONCLUSIONS: Adjuvant sorafenib after RFA was superior to RFA alone in improving survival outcomes in patients with recurrent HCC within Milan criteria after initial hepatectomy. Subgroup analyses concluded that patients with high risk score had significantly longer survival from sorafenib administration.

Developmental Toxicity of Few-Layered Black Phosphorus toward Zebrafish.

Black phosphorus (BP) has extensive applications in various fields. The release of BP into aquatic ecosystems and the potential toxic effects on aquatic organisms are becoming major concerns. Here, we investigated the developmental toxicity of few-layered BP toward the zebrafish. We found that BP could adsorb on the surface of the chorion and could subsequently penetrate within the embryo. After exposure of embryos to 10 mg/L BP, developmental malformations appeared at 96 hpf, especially heart deformities such as pericardial edema and bradycardia, accompanied by severe circulatory system failure. Using transgenic zebrafish larvae, we further characterized cardiovascular defects with cardiac enlargement and impaired cardiac vessels as indicators of damage to the cardiovascular system upon BP exposure. We performed transcriptomic analysis on zebrafish embryos treated with a lower concentration of 2 mg/L. The results showed disruption in genes associated with muscle development, oxygen involved processes, focal adhesion, and VEGF and MAPK signaling pathways. These alterations also indicated that BP carries a risk of developmental perturbation at lower concentrations. This study provides new insights into the effects of BP on aquatic organisms.

Advances in Nanostructure-mediated Hyperthermia in Tumor Therapies.

BACKGROUND: Hyperthermia has been proposed as a promising treatment modality for its advantageous profiles such as mini/non-invasiveness, good tolerability and cost-effectiveness. Quick development of nanotechnology in recent years has greatly broadened the application area of hyperthermia and endowed it with attractive new functions. This review aims to present an overview of different nanostructures mediated hyperthermia in terms of external stimuli source. METHODS: We performed to review for the development and current status of nanostructure-mediated hyperthermia, by searching MEDLINE, EMBASE, and Cochrane Library database for identification of relevant articles. RESULTS: In the present study, the systemic results of hyperthermia mediated by nanostructures were researched, and five different kinds of external sources were found and listed in this review. The brief mechanism and commonly explored nanostructures were introduced and then combined therapies of nanostructure-mediated hyperthermia stimulated by different external sources were investigated. Finally, challenges with current nanostructures mediated hyperthermia were discussed in order to give advice to the future development of nanostructure-mediated hyperthermia. CONCLUSIONS: Despite all the achievements the new technology of nanostructure-mediated hyperthermia have made in pre-clinical animal experiments, there are still much to be pursued in the further development to be biocompatible, effective and precise.

Improved Biocompatibility of Black Phosphorus Nanosheets by Chemical Modification.

Black phosphorus nanosheets (BPs) show great potential for various applications including biomedicine, thus their potential side effects and corresponding improvement strategy deserve investigation. Here, in vitro and in vivo biological effects of BPs with and without titanium sulfonate ligand (TiL4 ) modification are investigated. Compared to bare BPs, BPs with TiL4 modification (TiL4 @BPs) can efficiently escape from macrophages uptake, and reduce cytotoxicity and proinflammation. The corresponding mechanisms are also discussed. These findings may not only guide the applications of BPs, but also propose an efficient strategy to further improve the biocompatibility of BPs.

Renal Clearable Ag Nanodots for in Vivo Computer Tomography Imaging and Photothermal Therapy.

Albumin-stabilized Ag nanodots (ANDs) are prepared by a one-step biomineralization method. The highly crystallized nanodots have ultrasmall sizes (approximately 5.8 nm) and robust X-ray attenuation (5.7313 HU per mM Ag). The unlabeled ANDs are directly excreted from the body via the urine after in vivo X-ray computer tomography (CT) imaging application. ANDs could be used as CT imaging agents and effective photothermal therapy agents. Tumor growth inhibition reaches 90.2% after photothermal treatment with ANDs. ANDs are promising tools for in vivo CT imaging and clearable near-infrared-triggered theranostic agents.

Vitamin E attenuates silver nanoparticle-induced effects on body weight and neurotoxicity in rats.

Silver nanoparticles (AgNPs) are one of the most commonly used nanomaterials; however, it remains unclear whether AgNPs induce neurotoxicity. Here, we investigated the potential neurological effects of AgNPs and the neuroprotective effect of vitamin E (VE). We found that intranasal instillation of AgNPs in neonatal Sprague-Dawley rats caused significant body weight loss. Moreover, histological examinations revealed activation of neuroglial cells with concomitant destruction of the granular layer of the cerebellum. Furthermore, western blot analyses showed an increase in the levels of the glial fibrillary acidic protein (GFAP), a marker of astrocyte activation. These observations suggest that AgNPs have significant neurotoxic effects on the rat cerebellum. Strikingly, oral administration of VE counterbalanced the toxic effects triggered by AgNPs. Taken together, our findings suggest that nasal administration of AgNPs may produce neurotoxicity in rats, and that VE supplementation attenuates these effects.

Elemental selenium particles at nano-size (Nano-Se) are more toxic to Medaka (Oryzias latipes) as a consequence of hyper-accumulation of selenium: a comparison with sodium selenite.

Recent studies have shown that elemental selenium particles at nano-size (Nano-Se) exhibited comparable bioavailability and less toxicity in mice and rats when compared to sodium selenite, selenomethinine and methylselenocysteine. However, little is known about the toxicity profile of Nano-Se in aquatic animals. In the present study, toxicities of Nano-Se and selenite in selenium-sufficient Medaka fish were compared. Selenium bioaccumulation and subsequent clearance in fish livers, gills, muscles and whole bodies were examined after 10 days of exposure to Nano-Se and selenite (100 microg Se/L) and again after 7 days of depuration. Both forms of selenium exposure effectively increased selenium concentrations in the investigated tissues. Surprisingly, Nano-Se was found to be more hyper-accumulated in the liver compared to selenite with differences as high as sixfold. Selenium clearance of both Nano-Se and selenite occurred at similar ratios in whole bodies and muscles but was not rapidly cleared from livers and gills. Nano-Se exhibited strong toxicity for Medaka with an approximately fivefold difference in terms of LC(50) compared to selenite. Nano-Se also caused larger effects on oxidative stress, most likely due to more hyper-accumulation of selenium in liver. The present study suggests that toxicity of nanoparticles can largely vary between different species and concludes that the evaluation of nanotoxicology should be carried out on a case-by-case basis.

Determination of alkali-labile phosphoprotein phosphorus from fish plasma using the Tb(3+)-tiron complex as a fluorescence probe.

A sensitive method based on the fluorescence quenching effect of the Tb(3+)-Tiron complex is proposed for the determination of alkali-labile phosphoprotein phosphorus (ALP) released from fish plasma. The detection limit was 5.4 ng/ml (S/N = 2), and the relative standard deviation of the quenching effect (6 replicates) was 4.6%. The results obtained by the proposed method were in good agreement with those obtained by the colorimetric assay. The advantages of the present method are its relatively simple detection procedure, the lack of toxic organic solvents, and high sensitivity.

Interaction of methylmercury and selenium on the bioaccumulation and histopathology in medaka (Oryzias latipes).

Interaction of methylmercury and selenium in medaka (Oryzias latipes) on bioaccumulation of pollutants and histopathological changes in liver and gill were studied. Juvenile medaka fish were submitted to a series of waterborne methylmercury chloride (MMC), sodium selenite (Na(2)SeO(3)) and their mixture for 210 days, respectively. The methylmercury (MeHg) and selenium contents in the whole body of medaka were determined. The dose- and time-dependent increase of MeHg and selenium contents in medaka were observed. Histopathological changes, such as edema, vacuoles, pyknotic nucleus, and telangiectasis, could clearly be observed in the slices from the exposed medaka's liver and gill. Concurrent exposure to MMC and Na(2)SeO(3) showed the increased selenium accumulation. When the exposure molar ratio of MeHg:Se was about 1, the interaction between MeHg and selenium offered a limited protection against the serious intoxication of both MMC and Na(2)SeO(3) to medaka.

Determination of volatile residual solvents in traditional Chinese medicines by headspace solid-phase microextraction and cryogenic gas chromatography with flame ionization detection.

A method based on headspace solid-phase microextraction and cryogenic gas chromatography with flame ionization detection was developed for the determination of volatile residual solvents in traditional Chinese medicines. A laboratory-made cryogenic chromatographic system was used for the separation of 15 kinds of residual solvents. During the analysis, a 65 microm PDMS/DVB fiber was used to extract the residual solvents, the extraction time was controlled at 0 degrees C for 15 min, and the NaCl content of the sample was maintained at 30%. The limits of detection ranged from 0.08 (for octane) to 5000 microg/L (for ethanol), and the relative standard deviations were < 8%. The recoveries from spiked samples ranged from 88 to 112%. Trace levels of residual solvents in several traditional Chinese medicines were effectively identified and quantified.