Acidic Environment-Responsive Metal Organic Framework-Mediated Dihydroartemisinin Delivery for Triggering Production of Reactive Oxygen Species in Drug-Resistant Lung Cancer.

Background: Dihydroartemisinin (DHA) has emerged as a promising candidate for anticancer therapy. However, the application of DHA in clinics has been hampered by several limitations including poor bioavailability, short circulation life, and low solubility, significantly restricting its therapeutic efficacy and leading to notable side effects during the treatment. Purpose: We present DHA-loaded zeolitic imidazolate framework-8 (D-ZIF) with controllable and targeted DHA release properties, leading to enhanced antitumor effects while reducing potential side effects. Methods: D-ZIF was prepared by one-pot synthesis method using methylimidazole (MIM), Zn(NO3)2•6H2O and DHA. We characterized the physical and chemical properties of D-ZIF by TEM, DLS, XRD, FT-IR, and TG. We measured the drug loading efficiency and the cumulative release of DHA in different pH conditions. We evaluated the cytotoxicity of D-ZIF on renal cell carcinoma (RCC786-O), glioma cells (U251), TAX-resistant human lung adenocarcinoma (A549-TAX) cells by CCK8 in vitro. We explored the possible antitumor mechanism of D-ZIF by Western blot. We evaluated the biocompatibility and hemolysis of D-ZIF and explored the in vivo antitumor efficiency in mice model by TUNEL testing and blood biomarker evaluations. Results: D-ZIF showed rhombic dodecahedral morphology with size of 129±7.2 nm and possessed a noticeable DHA encapsulation efficiency (72.9%). After 48 hours, D-ZIF released a cumulative 70.0% of the loaded DHA at pH 6.5, and only 42.1% at pH 7.4. The pH-triggered programmed release behavior of D-ZIF could enhance anticancer effect of DHA while minimizing side effects under normal physiological conditions. Compared with the free DHA group with 31.75% of A549-TAX cell apoptosis, the percentage of apoptotic cells was approximately 76.67% in the D-ZIF group. D-ZIF inhibited tumor growth by inducing tumor cell apoptosis through the mechanism of ROS production and regulation of Nrf2/HO-1 and P38 MAPK signaling pathways. D-ZIF showed potent effects in treating tumors with high safety in vivo. Conclusion: This pH-responsive release mechanism enhanced the targeting efficiency of DHA towards tumor cells, thereby increasing drug concentration in tumor sites with negligible side effects. Herein, D-ZIF holds great promise for curing cancers with minimal adverse effects.

Parthenolide alleviates microglia-mediated neuroinflammation via MAPK/TRIM31/NLRP3 signaling to ameliorate cognitive disorder.

BACKGROUND AND PURPOSE: Neuroinflammation, mainly mediated by microglia, is involved in the evolution of Alzheimer's disease (AD). Parthenolide (PTL) has diverse pharmacological effects such as anti-inflammatory and antioxidative stress. However, whether PTL can modulate microglia-mediated neuroinflammation to improve cognitive impairment in amyloid precursor protein/presenilin 1 (APP/PS1) mice is unclear. METHODS: LPS/IFN-γ-induced BV2 and HMC3 microglia were used for in vitro experiments; the roles of PTL on anti-inflammatory, anti-oxidative, phagocytic activity, and neuroprotection were assessed by inflammatory cytokines assays, dichlorodihydrofluorescein diacetate, phagocytosis, and cell counting kit-8 assays. Western blot and immunofluorescence（IF） were used to examine related molecular mechanisms. In vivo, IF and western blot were applied in LPS-treated wild-type (WT) mice and APP/PS1 mice models. The Morris water maze test was performed to evaluate the effects of PTL on cognitive disorders. RESULTS: In vitro, PTL dramatically suppressed proinflammatory cytokines IL-6, IL-1ß, and TNF-α release and increased IL-10 levels. Moreover, PTL decreased reactive oxygen species and restored microglial phagocytic activities via the AKT/MAPK/ NF-κB signaling pathway. Importantly, we discovered that PTL obviously enhanced TRIM31 expression and siTRIM31 elevated proinflammatory cytokine levels. Furthermore, we determined that the anti-inflammatory role of PTL was mostly TRIM31/NLRP3 signaling-dependent. In vivo, PTL alleviated microgliosis and astrogliosis in LPS-treated WT and APP/PS1 mice. Additionally, PTL significantly ameliorated memory and learning deficits in cognitive behaviors. CONCLUSIONS: PTL improved cognitive and behavioral dysfunction, inhibited neuroinflammation, and showed potent anti-neuroinflammatory activity and neuroprotective effects by improving the MAPK/TRIM31/NLRP3 axis. Our study emphasized the therapeutic potential of PTL for improving cognitive disorders during AD progression.

TRIM31 enhances chemoresistance in glioblastoma through activation of the PI3K/Akt signaling pathway.

Temozolomide (TMZ) resistance is a complication of treatment of glioma, and new strategies are urgently required to overcome chemoresistance in glioma cells. In the present study, it was demonstrated that tripartite motif-containing 31 (TRIM31) was abnormally upregulated in glioma tissues and cell lines compared with normal samples. Furthermore, the role of TRIM31 was assessed by overexpressing and knocking down its expression. Overexpression of TRIM31 increased cell viability, increased TMZ IC50 values and inhibited apoptosis in A172 and U251 cells; whereas overexpression of TRIM31 decreased the expression of the apoptosis-associated protein p53. Knockdown of TRIM31 increased apoptosis in cells treated with TMZ. Additionally, the mechanisms by which TRIM31 affected glioma cells treated with TMZ were determined. Overexpression of TRIM31 increased phosphorylation of AKT and inhibiting the PI3K/AKT signaling pathway abolished the increase in cell viability and decreased phospho-Akt protein expression in TRIM31 overexpressing A172 cells treated with TMZ. Together, the findings suggest that TRIM31 may be a potentially novel target for glioma chemotherapy.

[Effects of Fulvic Acid on Absorption and Form Distribution of Heavy Metals on Sediments].

Based on the extracted fulvic acid (FA) from Lake Wuliangsuhai sediments by sequential alkali extraction, this work studied the effects of FA on the adsorption and fraction distribution of heavy metals (HM) on sediments using original sediments and sediments treated with 30% H2O2 as adsorbents. The results showed both organic matter and FA had effects on the HM adsorption onto sediments; The treatments of FA-free conditions and the sediments treated by H2O2 showed relatively strong influence on Cu²âº adsorption, which decreased the Cu²âº adsorption by 17.85%. With the increasing FA addition, the adsorption percentage of HM on both types of sediments showed gradually decreasing trends, with the order of Cu²âº >> Cd²âº > Zn²âº > Pb²âº; when the FA content was more than 5% , FA became the governing factor on the decreasing adsorption percentage of HM. With increasing FA addition, forms distribution of HM showed significant changes in both types of sediments; i. e. FA additions showed significant negative and positive correlations with percentages of metals bound to carbonates and organic matter, respectively, since the FA addition increased the H⁺ concentration of the system, in which H⁺ could activate the metals bound to carbonate from the sediments. As an organophilic weak element, the fraction percentage of Cd bound to organic matter was the lowest with the minimal changes.

Environmental geochemistry of dissolved and biogenic silicon and its nutrient limitation effects in an inland lake, China.

Silicon (Si) processing and retention play a key role in nutrients biogeochemistry cycling in aquatic environment. In order to interpret the possibility of Si limitation, multivariate analysis was performed based on stoichiometric nutrients balance, distribution characteristics of dissolved silicon (DSi) and biogenic silica (BSi), adsorption behavior, and response relation of BSi with paleoenvironment in water-sediment system of Lake Daihai. The spatial distributions of DSi and BSi in the water-sediment system indicated that terrigenous inputs (such as the weathering of rock and soil in the drainage basin) was the main sources of Si. Meanwhile, grain sizes of sediments, water hydrogeochemistry, and space competition between diatoms and submergent or emerging plants also played important roles in regulating BSi spatial distributions. The sediments from the lake presented obvious releasing trend of Si at low initial concentrations (≤ 3 mg/L) in adsorption experiments, indicating that the sediments were the source of Si to the overlying water. Furthermore, the good response relation between BSi and paleoenvironment observed in the sediment profiles from Lake Daihai indicated that the main reasons for Si limitation to siliceous plankton were different during different periods. The multi-evidences of distribution characteristics, stoichiometric nutrient balance, adsorption behaviors, and response to paleoenvironment were jointly indicative of Si limitation on the primary production of siliceous plankton in Lake Daihai.

Facile preparation of hierarchically porous carbon using diatomite as both template and catalyst and methylene blue adsorption of carbon products.

Hierarchically porous carbons were prepared using a facile preparation method in which diatomite was utilized as both template and catalyst. The porous structures of the carbon products and their formation mechanisms were investigated. The macroporosity and microporosity of the diatomite-templated carbons were derived from replication of diatom shell and structure-reconfiguration of the carbon film, respectively. The macroporosity of carbons was strongly dependent on the original morphology of the diatomite template. The macroporous structure composed of carbon plates connected by the pillar- and tube-like macropores resulted from the replication of the central and edge pores of the diatom shells with disk-shaped morphology, respectively. And another macroporous carbon tubes were also replicated from canoe-shaped diatom shells. The acidity of diatomite dramatically affected the porosity of the carbons, more acid sites of diatomite template resulted in higher surface area and pore volume of the carbon products. The diatomite-templated carbons exhibited higher adsorption capacity for methylene blue than the commercial activated carbon (CAC), although the specific surface area was much smaller than that of CAC, due to the hierarchical porosity of diatomite-templated carbons. And the carbons were readily reclaimed and regenerated.

[Rapid pore cranial drilling and ventricular drainage in the treatment of ventricular hemorrhage caused by thalamic hemorrhage: an analysis of 401 cases].

OBJECTIVE: To summarize the clinical efficacies and experiences of using rapid pore cranial drilling and external ventricular drainage (EVD) in the treatment of ventricular hemorrhage caused by thalamic hemorrhage. METHODS: Retrospective analysis was conducted for 401 patients at 5 hospitals from May 1983 to December 2010. They underwent EVD with an infusion of urokinase for intraventricular hemorrhage caused by thalamic hemorrhage. There were 212 males and 189 females with an age range of 19 - 78 years. RESULTS: After a 1-month therapy, the outcomes were cure 147/401 (36.7%), improvement 192/401 (47.9%) and others (death and against-advice discharge) 62/401 (15.4%). After 1-3-month treatment, their prognoses were evaluated by activity of daily living (ADL): ADLI 147/401, ADLII 82/401, ADLIII 76/401, ADLIV 19/401, ADLV 15/401, death 43/401 and against-advice discharge 19/401. During a follow-up period of 1 - 3 years, 274 patients showed the following outcomes: ADLI 122/243, ADLII 63/243, ADLIII 58/243 while 31 patients died from pulmonary infection. CONCLUSION: The procedure of EVD (including an infusion of urokinase) with rapid pore cranial drilling is preferred treatment for ventricular hemorrhage caused by thalamic hemorrhage.

Effects of inherent/enhanced solid acidity and morphology of diatomite templates on the synthesis and porosity of hierarchically porous carbon.

The inherent or enhanced solid acidity of raw or activated diatomite is found to have significant effects on the synthesis of hierarchically porous diatomite-templated carbon with high surface area and special porous structure. The solid acidity makes raw/activated diatomite a catalyst for the generation of porous carbon, and the porous parameters of the carbon products are strongly dependent on the solid acidity of diatomite templates. The morphology of diatomite also dramatically affects the textural structure of porous carbon. Two types of macroporous structures in the carbon product, the partially solid pillars and the ordered hollow tubes, derive from the replication of the central and the edge pores of diatom shell, respectively. The hierarchically porous carbon shows good capability for the adsorption of solvent naphtha and H(2), enabling potential applications in adsorption and gas storage.

Removal of hexavalent chromium [Cr(VI)] from aqueous solutions by the diatomite-supported/unsupported magnetite nanoparticles.

Diatomite-supported/unsupported magnetite nanoparticles were prepared by co-precipitation and hydrosol methods, and characterized by X-ray diffraction, nitrogen adsorption, elemental analysis, differential scanning calorimetry, transmission electron microscopy and X-ray photoelectron spectroscopy. The average sizes of the unsupported and supported magnetite nanoparticles are around 25 and 15 nm, respectively. The supported magnetite nanoparticles exist on the surface or inside the pores of diatom shells, with better dispersing and less coaggregation than the unsupported ones. The uptake of hexavalent chromium [Cr(VI)] on the synthesized magnetite nanoparticles was mainly governed by a physico-chemical process, which included an electrostatic attraction followed by a redox process in which Cr(VI) was reduced into trivalent chromium [Cr(III)]. The adsorption of Cr(VI) was highly pH-dependent and the kinetics of the adsorption followed a pseudo-second-order model. The adsorption data of diatomite-supported/unsupported magnetite fit well with the Langmuir isotherm equation. The supported magnetite showed a better adsorption capacity per unit mass of magnetite than unsupported magnetite, and was more thermally stable than their unsupported counterparts. These results indicate that the diatomite-supported/unsupported magnetite nanoparticles are readily prepared, enabling promising applications for the removal of Cr(VI) from aqueous solution.

Montmorillonite-supported magnetite nanoparticles for the removal of hexavalent chromium [Cr(VI)] from aqueous solutions.

Montmorillonite-supported magnetite nanoparticles were prepared by co-precipitation and hydrosol method. The obtained materials were characterized by X-ray diffraction, nitrogen adsorption, elemental analysis, differential scanning calorimetry, transmission electron microscopy and X-ray photoelectron spectroscopy. The average sizes of the magnetite nanoparticles without and with montmorillonite support are around 25 and 15 nm, respectively. The montmorillonite-supported magnetite nanoparticles exist on the surface or inside the interparticle pores of clays, with better dispersing and less coaggregation than the ones without montmorillonite support. Batch tests were carried out to investigate the removal mechanism of hexavalent chromium [Cr(VI)] by these synthesized magnetite nanoparticles. The Cr(VI) uptake was mainly governed by a physico-chemical process, which included an electrostatic attraction followed by a redox process in which Cr(VI) was reduced into trivalent chromium. The adsorption of Cr(VI) was highly pH-dependent and the kinetics of the adsorption followed the Pseudo-second-order model. The adsorption data of unsupported and clay-supported magnetite nanoparticles fit well with the Langmuir and Freundlich isotherm equations. The montmorillonite-supported magnetite nanoparticles showed a much better adsorption capacity per unit mass of magnetite (15.3mg/g) than unsupported magnetite (10.6 mg/g), and were more thermally stable than their unsupported counterparts. These fundamental results demonstrate that the montmorillonite-supported magnetite nanoparticles are readily prepared, enabling promising applications for the removal of Cr(VI) from aqueous solution.

A combined study by XRD, FTIR, TG and HRTEM on the structure of delaminated Fe-intercalated/pillared clay.

Fe-PILC samples were synthesized by the reaction between Na(+)- and/or Ca(2+)-montmorillonite (Mt) and base-hydrolyzed solutions of Fe(III) nitrate. Different from the known usual microporous pillared structure, a meso-microporous delaminated structure containing intercalated or pillared fragments was found in the respective resulting Fe-intercalated or -pillared clays. XRD patterns of Na(+)-Mt-based Fe-intercalated/pillared clays show one large d-spacing above 6.4 nm corresponding to the mesoporous delaminated part, whereas another d-spacing of ca. 1.5 nm was indicative of the microporous pillared part. Fe-intercalated/pillared clays based on Ca(2+)-Mt lead to similar results, but with a d-spacing less than 6 nm and a second low intense d-spacing less than 1.5 nm. In the delaminated Fe-intercalated clays, NO(-)(3) anions were retained even after thorough washing process. They play as counterions to neutralize the positive-charged iron aggregates in the delaminated structure, and can be exchanged by heteropolyanions as [PW(12)O(40)](3-). The delaminated Fe-pillared clays show good thermal stability at 500 degrees C and exhibit at this temperature dramatically higher specific surface area and porosity than the starting montmorillonites. However, calcination at a higher temperature leads to the formation of nanocrystalline hematite. Air-drying after ethanol extraction (EAD) method has an advantage over air-drying (AD) method in preserving the delaminated structure.