pH/glutathione-responsive theranostic nanoprobes for chemoimmunotherapy and magnetic resonance imaging of ovarian cancer cells.

The integration of immunotherapy and standard chemotherapy holds great promise for enhanced anticancer effects. In this study, we prepared a pH- and glutathione (GSH)-sensitive manganese-doped mesoporous silicon (MMSNs) based drug delivery system by integrating paclitaxel (PTX) and anti-programmed cell death-ligand 1 antibody (aPD-L1), and encapsulating with polydopamine (PDA) for chemoimmunosynergic treatment of ovarian cancer cells. The nanosystem was degraded in response to the tumor weakly acidic and reductive microenvironment. The Mn2+ produced by degradation can be used as a contrast agent for magnetic resonance (MR) imaging to provide visual exposure to tumor tissue. The released PTX can not only kill tumor cells directly, but also induce immunogenic death (ICD) of tumor cells, which can play a synergistic therapeutic effect with aPD-L1. Therefore, our study is expected to provide a promising strategy for improving the efficacy of cancer immunotherapy and the detection rate of cancer.

Effect of Alkyl Chain Length on the Corrosion Inhibition Performance of Imidazolium-Based Ionic Liquids for Carbon Steel in 1 M HCl Solution: Experimental Evaluation and Theoretical Analysis.

In this study, five kinds of 1-alkyl-3-methylimidazolium bromide ([CXami]Br) ionic liquids with different alkyl chain lengths (8, 10, 12, 14, and 16) were selected as inhibitors. Then, their corrosion inhibition performances for Q235 steel in 1.0 mol L-1 HCl solution were investigated via a weight loss test, polarization curve method, and surface analysis techniques. The results show that these five imidazolium-based ionic liquids are all mixed-type inhibitors, and they can be spontaneously adsorbed onto the Q235 steel surface. The adsorption process follows the Langmuir model and involves mixed physical-chemical adsorption. Theoretical calculations confirm that the increase in alkyl chain length is conducive to the imidazolium-based ionic liquids exhibiting stronger chemical bonding abilities and forming denser adsorption films. The inhibition efficiency significantly increases below the critical micelle concentration (CMC) with an increase in alkyl chain length, and the highest inhibition efficiency is 95.17% for the [C16ami]Br inhibitor at the concentration of 0.005 mM. However, above the CMC, the inhibition efficiency is minimally affected by the alkyl chain length since all ionic liquid inhibitors have reached adsorption saturation on the steel surface.

O2-Generating Fluorescent Carbon Dot-Decorated MnO2 Nanosheets for "Off/On" MR/Fluorescence Imaging and Enhanced Photodynamic Therapy.

Imaging-guided photodynamic therapy (PDT) has emerged as a promising protocol for cancer theragnostic. However, facile preparation of such a theranostic system for simultaneously achieving tumor location, real-time monitoring, and high-performance reactive oxygen species generation is highly desirable but remains challenging. Herein, we developed a reasonable tumor-targeting strategy based on carbon dots (CDs)-decorated MnO2 nanosheets (HA-MnO2-CDs) with an active magnetic resonance (MR)/fluorescence imaging and enhanced PDT effect. Under light irradiation, the addition of HA-MnO2-CDs increased the production of 1O2 by 2.5 times compared with CDs, providing favorable conditions for the PDT treatment effect on breast cancer. Moreover, HA-MnO2-CDs exhibited excellent performance in producing O2 in the presence of endogenous H2O2, which alleviated hypoxia in tumors and improved the therapeutic effect of PDT. In the presence of glutathione (GSH), the degraded MnO2 nanosheets released CDs and Mn2+ from HA-MnO2-CDs, restoring their fluorescence imaging function and increasing T1 relaxivity (r1) by 23 times. In vivo fluorescence and MR imaging suggested the excellent tumor-targeting property of HA-MnO2-CDs. By combining the complementary properties of nanoprobes and tumor microenvironments, the in vivo PDT therapeutic effect was significantly improved under the action of HA-MnO2-CDs. Overall, our reasonably designed HA-MnO2-CDs may inspire the future development of the next generation of high-performance tumor-responsive diagnostic and therapeutic agents to further enhance the targeted therapy effect of tumors.

Mongolian medicine in treating type 2 diabetes mellitus combined with nonalcoholic fatty liver disease via FXR/LXR-mediated P2X7R/NLRP3/NF-κB pathway activation.

Type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) are the most problematic metabolic diseases in the world. NAFLD encompasses a spectrum of severity, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis, increasing the risk of cirrhosis and hepatocellular carcinoma. Importantly, NAFLD is closely linked to obesity and tightly interrelated with insulin resistance and T2DM. T2DM and NAFLD (T2DM-NAFLD) are called as the Xike Rixijing Disease and Tonglaga Indigestion Disease respectively, in Mongolian medicine. Xike Rixijing Disease maybe develop into Tonglaga Indigestion Disease. Forturnately many Mongolian medicines show efficient treatment of T2DM-NAFLD, such as Agriophyllum squarrosum, Haliyasu (dried powder of camel placenta), Digeda-4 (herbs of Lomatogonium carinthiacum, rhizomata of Coptis chinensis, ripe fruits of Gardenia jasminoides, herbs of Dianthus superbus), Guangmingyan Siwei Decoction Powder (Halite, ripe fruits of Terminalia chebula, rhizomata of Zingiber officinale, fruit clusters of Piper longum), Tonglaga-5 (ripe fruits of Punica granatum, barks of Cinnamomum cassia, ripe fruits of Amomum kravanh, fruit clusters of Piper longum, flowers of Carthamus tinctorius), Tegexidegeqi (rhizomata of Inula helenium, ripe fruits of Gardenia jasminoides, rhizomata of Platycodon grandiflorum, rhizomata of Coptis chinensis, heartwood of Caesalpinia sappan), Ligan Shiliu Bawei San (ripe fruits of Punica granatum, barks of Cinnamomum cassia, ripe fruits of Amomum kravanh, fruit clusters of Piper longum, flowers of Carthamus tinctorius, ripe fruits of Amomum tsao-ko, rhizomata of Zingiber officinale), etc. Principles of Mongolian medicine in treating diseases: by balancing "three essences or roots" and "seven elements", strengthening liver and kidney function, transporting nutrients to enhance physical strength and disease resistance, and combined with drugs for comprehensive conditioning treatment. However, their molecular mechanisms remain unclear. In this review, we prospect that Mongolian medicines might be a promising treatment for T2DM-NAFLD by activating P2X7R/NLRP3/NF-κB inflammatory pathway via lipid-sensitive nuclear receptors (i.e., FXR and LXR).

Agriophyllum oligosaccharides ameliorate hepatic injury in type 2 diabetic db/db mice targeting INS-R/IRS-2/PI3K/AKT/PPAR-γ/Glut4 signal pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Agriophyllum squarrosum (L.) Moq. is a traditional Mongol medicine generally used to treat diabetes. OBJECTIVE: To investigate the protective effects and potential mechanisms of Agriophyllum oligosaccharides (AOS) on liver injury in type 2 diabetic db/db mice. MATERIALS AND METHODS: The db/db mice were divided into the model group (Model), metformin group (MET), high-dose AOS group (HAOS), and low-dose AOS group (LAOS). Nondiabetic littermate control db/m mice were used as the normal control group (Control). Mice in AOS groups were treated with AOS (380 or 750 mg/kg) daily, for 8 weeks. At 8 weeks, blood samples were collected to detect lipid and enzyme parameters concerning hepatic function, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein (TP), albumin (ALB), globulin (GLB), triglyceride (TG), total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C). Random blood glucose (RBG) test, oral glucose tolerance test (OGTT), and oral maltose tolerance test (OMTT) were also conducted. Microscopy was used to observe morphological changes in the liver of AOS-treated groups. Real-time PCR was used to detect the mRNA expression, including insulin receptor substrate 2 (IRS-2), phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), peroxisome proliferator-activated receptor (PPAR)-γ, insulin receptor (INS-R), and Glut4. Furthermore, western blotting was performed to identify proteins, including phosphorylation of IRS-2 (p-IRS-2), PI3K, p-AKT, PPAR-γ, INS-R, and Glut4. Hepatic protein expression of p-IRS-2, PI3K, p-AKT, PPAR-γ, INS-R, and Glut4 was observed using immunohistochemical staining. RESULTS: AOS treatment significantly decreased RBG, OGTT, and OMTT in mice, as well as serum ALT and AST activities. AOS groups demonstrated significantly higher expressions of p-IRS-2, PI3K, PPAR-γ, p-AKT, INS-R, and Glut4 protein and IRS-2, PI3K, AKT, PPAR-γ, INS-R, and Glut4 mRNA in the liver tissue of db/db mice; the degeneration and necrosis of hepatocytes and formation of collagen fibres markedly reduced, improving the structural disorder in the liver. CONCLUSION: The results suggest that AOS could protect the liver in type 2 diabetes, in part by activating insulin in the INS-R/IRS2/PI3K/AKT/Glut4/PPAR-γ signal pathway, facilitating hepatocyte proliferation, and further reducing the blood glucose levels.

Assessment of radiation dose and iodine load reduction in head-neck CT angiography using two scan protocols with wide-detector.

OBJECTIVE: To compare image quality, radiation dose, and iodine intake of head-neck CT angiography (CTA) acquired by wide-detector with the gemstone spectral imaging (GSI) combination with low iodine intake or routine scan protocol. METHODS: Three hundred patients who had head-neck CTA were enrolled and divided into three groups according to their BMI values: group A (18.5 kg/m2 ≦ BMI <24.9 kg/m2), group B (24.9 kg/m2 ≦ BMI <29.9 kg/m2) and group C (29.9 kg/m2 ≦ BMI ≦ 34.9 kg/m2) with 100 patients in each group. Patients in each group were randomly divided into two subgroups (n = 50) namely, A1, A2, B1, B2, C1 and C2. The patients in subgroups A1, B1 and C1 underwent GSI with low iodine intake (270 mgI/ml, 50 ml) and combined with the ASiR-V algorithm. Other patients underwent three dimensional (3D) smart mA modulation with routine iodine intake (350 mgI/ml, 60 ml). Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of all images were calculated after angiography. Images were then subjectively assessed using a 5-point scale. CT dose index of volume and dose-length product (DLP) was converted to the effective dose (ED) and then compared. RESULTS: The mean CT values, SNR, CNR and subjective image quality in subgroups A2, B2 and C2 are significantly lower than in subgroups A1, B1, and C1 (P < 0.01), respectively. The ED values in subgroup A1, B1, and C1 are 55.18%, 61.89%, and 69.64% lower than those in A2, B2, and C2, respectively (P < 0.01). The total iodine intakes in subgroups A1, B1, and C1 are 35.72% lower than those in subgroups A2, B2, and C2. CONCLUSIONS: The gemstone spectral imaging with monochromatic images at 53-57 keV combined with ASiR-V algorithm allows significant reduction in iodine load and radiation dose in head-neck CT angiography than those yielded in routine scan protocol. It also enhances signal intensity of head-neck CTA and maintains image quality.

SUMO-Specific Protease 1 Is Critical for Myeloid-Derived Suppressor Cell Development and Function.

Myeloid-derived suppressor cells (MDSC) can suppress immunity and promote tumorigenesis, and their abundance is associated with poor prognosis. In this study, we show that SUMO1/sentrin-specific peptidase 1 (SENP1) regulates the development and function of MDSC. SENP1 deficiency in myeloid cells promoted MDSC expansion in bone marrow, spleen, and other organs. Senp1-/- MDSC showed stronger immunosuppressive activity than Senp1+/+ MDSC; we observed no defects in the differentiation of myeloid precursor cell in Senp1-/- mice. Mechanistically, SENP1-mediated regulation of MDSC was dependent on STAT3 signaling. We identified CD45 as a specific STAT3 phosphatase in MDSC. CD45 was SUMOylated in MDSC and SENP1 could deconjugate SUMOylated CD45. In Senp1-/- MDSC, CD45 was highly SUMOylated, which reduced its phosphatase activity toward STAT3, leading to STAT3-mediated MDSC development and function. These results reveal a suppressive function of SENP1 in modulating MDSC expansion and function via CD45-STAT3 signaling axis. SIGNIFICANCE: These findings show that increased SUMOylation of CD45 via loss of SENP1 suppresses CD45-mediated dephosphorylation of STAT3, which promotes MDSC development and function, leading to tumorigenesis.

Senp2 regulates adipose lipid storage by de-SUMOylation of Setdb1.

One major function of adipocytes is to store excess energy in the form of triglycerides. Insufficient adipose lipid storage is associated with many pathological conditions including hyperlipidemia, insulin resistance, and type 2 diabetes. In this study, we observed the overexpression of SUMO-specific protease 2 (Senp2) in adipose tissues during obesity. Adipocyte Senp2 deficiency resulted in less adipose lipid storage accompanied by an ectopic fat accumulation and insulin resistance under high-fat diet feeding. We further found that SET domain bifurcated 1 (Setdb1) was a SUMOylated protein and that SUMOylation promoted Setdb1 occupancy on the promoter locus of Pparg and Cebpa genes to suppress their expressions by H3K9me3. Senp2 could suppress Setdb1 function by de-SUMOylation. In adipocyte Senp2-deficiency mice, accumulation of the SUMOylated Setdb1 suppressed the expression of Pparg and Cebpa genes as well as lipid metabolism-related target genes, which would decrease the ability of lipid storage in adipocytes. These results revealed the crucial role of Senp2-Setdb1 axis in controlling adipose lipid storage.

A parenteral docetaxel-loaded lipid microsphere with decreased 7-epidocetaxel conversion in vitro and in vivo.

The purpose of the study was to develop a parenteral docetaxel lipid microsphere to inhibit its 7-epidocetaxel conversion in vitro and in vivo. 7-epidocetaxel conversion as the main indicator was investigated to optimize the formulation and process. 10% medium-chain triglyceride/long-chain triglyceride (3:1) as the oil phase, egg lecithin E80 as the emulsifier and 0.02% NaHSO3 as the acidity regulator were selected to prepare docetaxel lipid microsphere. This study found that pH and temperature were dominant factors on the epimerization of docetaxel in lipid microsphere, and that optimum conditions were a pH of 5.3 and thermal sterilization conditions of 121°Cautoclaving for 8min. According to the degradation kinetics, docetaxel lipid microsphere had a wider pH range where 7-epidocetaxel(%) stayed at low levels than Docetaxel for Injection, and might improve the docetaxel stability by loading drug in lecithin layer instead of altering the degradation mechanism. Docetaxel lipid microsphere decreased epimerization in plasma in vitro obviously. Pharmacokinetics of docetaxel and 7-epidocetaxel were investigated to quantify the 7-epidocetaxel conversion in vivo. The resulrs indicated that there was less conversion of docetaxel in lipid microspheres than in Docetaxel for Injection. The convert ratios were 0.61% and 3.04% respectively. In conclusion, lipid microsphere is a promising delivery system for intravenous administration of docetaxel with decreased 7-epidocetaxel conversion.

Design, synthesis, anti-inflammatory activity, and molecular docking studies of perimidine derivatives containing triazole.

We report here the design, synthesis, and anti-inflammatory activities of a series of perimidine derivatives containing triazole (5a-s). The chemical structures of the synthesized compounds have been assigned on the basis of IR, 1H NMR, 13C NMR, and HRMS spectral analyses. The anti-inflammatory properties of the synthesized perimidine derivatives were evaluated in a lipopolysaccharide (LPS)-stimulated inflammation model. Among the tested compounds, compound 7-(3-methylbenzyl)-7H-[1,2,4]triazolo[4,3-a]perimidine (hereafter referred to as 5h) and compound 7-(2-fluorobenzyl)-7H-[1,2,4]triazolo[4,3-a]perimidine (hereafter referred to as 5n) caused a reduction in the levels of the pro-inflammatory cytokines-tumor necrosis factor (TNF)-α and interleukin (IL)-6-in RAW264.7 cells. The anti-inflammatory potential of compounds 5h and 5n was also evaluated in vivo in a xylene-induced ear inflammation model. Compound 5n showed the most potent anti-inflammatory activity with an inhibition of 49.26% at a dose of 50mg/kg. This activity is more potent than that of the reference drug ibuprofen (28.13%), and slightly less than that of indometacin (49.36%). To further elucidate the mechanisms underlying these inhibitory effects, LPS-induced nuclear factor-κB (NF-κB) activation and mitogen-activated protein kinase (MAPK) phosphorylation were studied. The results of western blotting showed that the extract obtained from compound 5n inhibited NF-κB (p65) activation and MAPK (extracellular signal-regulated kinase (ERK) and p38) phosphorylation in a dose-dependent manner. Moreover, the results of a docking study of compound 5n into the COX-2 binding site revealed that its mechanism was possibly similar to that of naproxen, a COX-2 inhibitor. The effect of compound 5n on COX-2 antibody was showed it could significantly inhibit COX-2 activity.

Asiaticoside attenuates lipopolysaccharide-induced acute lung injury via down-regulation of NF-κB signaling pathway.

Asiaticoside (AS), a triterpene glycoside isolated from Centella asiatica, has been shown to possess potent anti-inflammatory activity. However, the detailed molecular mechanisms of AS on lipopolysaccharide (LPS)-induced acute lung injury (ALI) model in mice are scanty. The purpose of this study was to evaluate the effect of AS on LPS-induced mouse ALI via down-regulation of NF-κB signaling pathway. We investigated the efficacy of AS on cytokine levels induced by LPS in bronchoalveolar lavage fluid (BALF) and RAW 264.7 cells. The production of cytokine (TNF-α and IL-6) was measured by enzyme-linked immunosorbent assay (ELISA). The lung wet-to-dry weight ratios were measured in LPS-challenged mice, and lung histopathologic changes observed via paraffin section were assessed. To further study the mechanism of AS protective effects on ALI, the activation of NF-κB p65 subunit and the degradation of IκBα were tested by western blot assay. We found that AS treatment at 15, 30 or 45mg/kg dose-dependently attenuated LPS-induced pulmonary inflammation by reducing inflammatory infiltration, histopathological changes, descended cytokine production, and pulmonary edema initiated by LPS. Furthermore, our results suggested that AS suppressed inflammatory responses in LPS-induced ALI through inhibition of the phosphorylation of NF-κB p65 subunit and the degradation of its inhibitor IκBα, and might be a new preventive agent of ALI in the clinical setting.

Role of DNA methylation in cell cycle arrest induced by Cr (VI) in two cell lines.

Hexavalent chromium [Cr(IV)], a well-known industrial waste product and an environmental pollutant, is recognized as a human carcinogen. But its mechanisms of carcinogenicity remain unclear, and recent studies suggest that DNA methylation may play an important role in the carcinogenesis of Cr(IV). The aim of our study was to investigate the effects of Cr(IV) on cell cycle progress, global DNA methylation, and DNA methylation of p16 gene. A human B lymphoblastoid cell line and a human lung cell line A549 were exposed to 5-15 µM potassium dichromate or 1.25-5 µg/cm² lead chromate for 2-24 hours. Cell cycle was arrested at G1 phase by both compounds in 24 hours exposure group, but global hypomethylation occurred earlier than cell cycle arrest, and the hypomethylation status maintained for more than 20 hours. The mRNA expression of p16 was significantly up-regulated by Cr(IV), especially by potassium dichromate, and the mRNA expression of cyclin-dependent kinases (CDK4 and CDK6) was significantly down-regulated. But protein expression analysis showed very little change of p16 gene. Both qualitative and quantitative results showed that DNA methylation status of p16 remained unchanged. Collectively, our data suggested that global hypomethylation was possibly responsible for Cr(IV)-induced G1 phase arrest, but DNA methylation might not be related to up-regulation of p16 gene by Cr(IV).

[Effect of electroacupuncture on plasma endogenous endothelial progenitor cell counts in cerebral ischemia-reperfusion rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on peripheral blood endothelial progenitor cell (EPC) counts, vascular endothelial growth factor (VEGF) level and total nitric oxide synthase (TNOS) and inducible nitric oxide synthase (iNOS) activity in cerebral ischemia-reperfusion injury (CI/RI) rats. METHODS: A total of 72 male rats were randomly and evenly assigned to normal control, sham-operation (sham), model and EA groups which were further divided into 24 h, 48 h and 72 h subgroups, with 6 cases in each. Acute focal cerebral ischemia model was established by occlusion of the middle cerebral artery (MCAO, 120 min) and reperfusion. EA (2/15 Hz, 1 mA) was applied to "Quchi" (LI 11) and "Zusanli" (ST 36) for 30 min, once daily. Peripheral blood was collected from abdominal aorta for detecting EPC count by using flow cytometry, serum VEGF level by using enzyme-linked immunosorbent assay (ELISA), and serum TNOS and iNOS activity by spectrophotometry, respectively. RESULTS: Compared with the corresponding normal control subgroups, blood EPC counts, serum TNOS and INOS activity and serum VEGF content at 24 h, INOS activity and VEGF level at 48 h, and EPCs and INOS at 72 h in model subgroups all increased significantly (P < 0.01, P < 0.05). In comparison with the corresponding model subgroups, EPC count at 24 h and 72 h, and TNOS activity at 24 h in EA subgroups decreased considerably (P < 0.01, P < 0.05); while EPC and VEGF levels at 48 h in EA subgroup increased evidently (P < 0.05, P < 0.01). No significant differences were found among normal, sham, model and EA subgroups in serum TNOS activity at 48 h and 72 h (P > 0.05). CONCLUSION: EA of LI 11 and ST 36 can suppress CI/ RI induced increase of blood EPC count and serum TNOS activity, and upregulate serum VEGF level, which may contribute to its effect in relieving CI/RI.

[Identification and analysis of F2 stable population derived from the cross of triploid x diploid in rice].

Polyploid strain 149-B, that was generated naturally from a rice twin-seedling population SAR-2, has been determined as triploid (2n = 36). It was then used as the female parent crossing with a normal diploid variety SH R363. From its F2 generation we obtained a genetic-stable population. To prove the uniformity of such a population, SSR markers were used to survey the F2 individual plants. The results showed that F2 individuals carried only one parental molecular marker at each polymorphic locus, and their genotypes were identical with F1 progeny. Based on the above experiments, we consider that this F2 population is definitely an early-generation stable population. Meanwhile, we discussed the possible mechanism of the special phenomenon as well.