Cancer Cell Membrane-Biomimetic Nanoparticles Based on Gelatin and Mitoxantrone for Synergetic Chemo-Photothermal Therapy of Metastatic Breast Cancer.

The purpose of this paper is to develop a cancer cell membrane biomimetic nanodrug delivery system (NDDS) to achieve an enhanced chemo-photothermal synergistic antitumor effect. The biomimetic NDDSs are composed of mitoxantrone (MIT)-loaded gelatin nanoparticles and IR820-encapsulated 4T1 cancer cell membrane-derived vesicles. The biomimetic NDDS displayed excellent stability and photothermal conversion efficiency. Compared to naked nanoparticles, the cell membrane-coated nanoparticles improved 4T1 cell uptake through homologous targeting and effectively reduced internalization of macrophages. In vivo photothermal imaging results further showed that the NDDS could be enriched at the tumor site for 48 h and could raise the temperature of the tumor area to 60 °C within 5 min under 808 nm laser irradiation. Finally, NDDS successfully inhibited primary tumor growth (over 89% inhibition) and significantly inhibited lung metastasis. This study may provide a new strategy for personalized chemotherapy-photothermal combination therapy of metastatic breast cancer using tumor cell membranes from cancer patients as drug carriers.

Absorption, Distribution, Metabolism, and Excretion of [14C]BS1801, a Selenium-Containing Drug Candidate, in Rats.

BS1801 is a selenium-containing drug candidate with potential for treating liver and lung fibrosis. To fully elucidate the biotransformation of BS1801 in animals and provide sufficient preclinical drug metabolism data for human mass balance study, the metabolism of BS1801 in rats was investigated. We used radiolabeling techniques to investigate the mass balance, tissue distribution, and metabolite identification of BS1801 in Sprague-Dawley/Long-Evans rats after a single oral dose of 100 mg/kg (100 µCi/kg) [14C]BS1801: 1. The mean recovery of radioactive substances in urine and feces was 93.39% within 168 h postdose, and feces were the main excretion route. 2. Additionally, less than 1.00% of the dose was recovered from either urine or bile. 3. BS1801-related components were widely distributed throughout the body. 4. Fifteen metabolites were identified in rat plasma, urine, feces, and bile, and BS1801 was detected only in feces. 5. BS1801-M484, the methylation product obtained via a N-Se bond reduction in BS1801, was the most abundant drug-related component in plasma. The main metabolic pathways of BS1801 were reduction, amide hydrolysis, oxidation, and methylation. Overall, BS1801 was distributed throughout the body, and excreted mainly as an intact BS1801 form through feces. No differences were observed between male and female rats in distribution, metabolism, and excretion of BS1801.

Therapeutic Effects of an Inhibitor of Thioredoxin Reductase on Liver Fibrosis by Inhibiting the Transforming Growth Factor-ß1/Smads Pathway.

Liver fibrosis is an important stage in the progression of liver injury into cirrhosis or even liver cancer. Hepatic stellate cells (HSCs) are induced by transforming growth factor-ß1 (TGF-ß1) to produce α-smooth muscle actin (α-SMA) and collagens in liver fibrosis. Butaselen (BS), which was previously synthesized by our group, is an organic selenium compound that exerts antioxidant and tumor cell apoptosis-promoting effects by inhibiting the thioredoxin (Trx)/thioredoxin reductase (TrxR) system. The aim of this study was to investigate the potential effects of BS on liver fibrosis and explore the underlying molecular mechanisms of its action. Liver fibrosis models were established using male BALB/c mice through intraperitoneal injection of CCl4. BS was administered orally once daily at a dose of 36, 90, or 180 mg/kg. Silymarin (Si), which is a drug used for patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, was administered at a dose of 30 mg/kg per day as a control. The action mechanisms of BS against liver fibrosis progression were examined in HSCs. The study revealed that the activity and expression levels of TrxR were elevated in the mouse liver and serum after CCl4-induced liver fibrosis. Oral administration of BS relieved the pathological state of mice with liver fibrosis, showing significant therapeutic effects against liver fibrosis. Moreover, BS not only induced HSC apoptosis but also inhibited the production of α-SMA and collagens by HSCs by downregulating the TGF-ß1 expression and blocking the TGF-ß1/Smads pathway. The results of the study indicated that BS inhibited liver fibrosis by regulating the TGF-ß1/Smads pathway.

Effects of a formula with a probiotic Bifidobacterium lactis Supplement on the gut microbiota of low birth weight infants.

PURPOSE: Low birth weight (LBW) infants have a less diverse gut microbiota, enriched in potential pathogens, which places them at high risk of systemic inflammation diseases. This study aimed to identify the differences in gut bacterial community structure between LBW infants who received probiotics and LBW infants who did not receive probiotics. METHODS: Forty-one infants were allocated to the non-probiotic group (N group) and 56 infants to the probiotic group (P group), according to whether the formula they received contained a probiotic Bifidobacterium lactis. Gut bacterial composition was identified with sequencing of the 16S rRNA gene in fecal samples collected at 14 days after birth. RESULTS: There was no significant difference between the alpha diversity of the two groups, while the beta diversity was significantly different (p < 0.05). Our results showed that Bifidobacterium and Lactobacillus (both p < 0.05) were enriched in the P group, while Veillonella, Dolosigranulum and Clostridium sensu stricto 1 (all p < 0.05) were enriched in the N group. Predicted metagenome function analysis revealed enhancement of fatty acids, peroxisome, starch, alanine, tyrosine and peroxisome pathways in the P group, and enhancement of plant pathogen, Salmonella and Helicobacter pylori infection pathways in the N group. CONCLUSIONS: Probiotic supplement in formula may affect the composition, stability and function of LBW infants' gut microbiota. LBW infants who receive probiotic intervention may benefit from gut microbiota that contains more beneficial bacteria.

The effects of zinc supplementation on primary human retinal pigment epithelium.

Population-based and interventional studies have shown that elevated zinc levels can reduce the progression to advanced age-related macular degeneration. The objective of this study was to assess whether elevated extracellular zinc has a direct effect on retinal pigment epithelial cells (RPE), by examining the phenotype and molecular characteristics of increased extracellular zinc on human primary RPE cells. Monolayers of human foetal primary RPE cells were grown on culture inserts and maintained in medium supplemented with increasing total concentrations of zinc (0, 75, 100, 125 and 150 µM) for up to 4 weeks. Changes in cell viability and differentiation as well as expression and secretion of proteins were investigated. RPE cells developed a confluent monolayer with cobblestone morphology and transepithelial resistance (TER) >200 Ω*cm2 within 4 weeks. There was a zinc concentration-dependent increase in TER and pigmentation, with the largest effects being achieved by the addition of 125 µM zinc to the culture medium, corresponding to 3.4 nM available (free) zinc levels. The cells responded to addition of zinc by significantly increasing the expression of Retinoid Isomerohydrolase (RPE65) gene; cell pigmentation; Premelanosome Protein (PMEL17) immunoreactivity; and secretion of proteins including Apolipoprotein E (APOE), Complement Factor H (CFH), and High-Temperature Requirement A Serine Peptidase 1 (HTRA1) without an effect on cell viability. This study shows that elevated extracellular zinc levels have a significant and direct effect on differentiation and function of the RPE cells in culture, which may explain, at least in part, the positive effects seen in clinical settings. The results also highlight that determining and controlling of available, as opposed to total added, zinc will be essential to be able to compare results obtained in different laboratories.

[Correlation of plasma thioredoxin reductase activity to growth of H22 hepatocellular carcinoma xenografts in Kunming mice].

BACKGROUND AND OBJECTIVE: The expression and activity of thioredoxin reductase (TrxR) are significantly higher in tumor tissues than in normal tissues, but the correlation of plasma TrxR activity to tumor growth has seldom been reported. This study was to evaluate the correlation of plasma TrxR activity to the growth of hepatocellular carcinoma (HCC) H22 cell xenografts in mice. METHODS: H22 cells were injected subcutaneously into Kunming mice to establish HCC model. The mice were divided into control group, mice group, low dose (36 mg/kg), moderate dose (72 mg/kg) and high dose (216 mg/kg) ethaselen groups. The mice in control group and model group were given 0.5% sodium carboxymethyl cellulose (CMC-Na). Blood samples were drawn before tumor cell inoculation, when tumor volume reached 100 mm3, and at Days 1, 4 and 10 of treatment. TrxR activity in plasma and tumor tissues was detected by dithio-bis-nitrobenzoic acid (DTNB) method. RESULTS: The inhibition rates of tumor growth were 59.5% in low dose ethaselen group, 74.3% in moderate dose ethaselen group, and 74.9% in high dose ethaselen group. Plasma TrxR activity was stable in control mice, and was correlated positively to tumor volume in tumor-bearing mice. At the end of treatment, the inhibition rates of TrxR activity in plasma and tumor were 59.2% and 15.3% in low dose ethaselen group, 68.4% and 25.8% in moderate dose ethaselen group, 68.9% and 29.8% in high dose ethaselen group. CONCLUSIONS: Plasma TrxR activity is correlated positively to tumor growth. Ethaselen can inhibit TrxR activity corresponding to tumor growth inhibition.

[Immune regulating activity of a novel organoselenium compound ethaselen-1 in C57/BL mice].

OBJECTIVE: To detect the Immune regulating activity of ethaselen-1 (Eb1), a novel organoselenium compound, in C57/BL mice transplanted with Lewis lung cancer(LLC). METHODS: The LLC transplanted C57/BL mice models were established, and the mice was randomly divided into four groups, including high dose Eb1 group (25.0 mg/kg),low dose Eb1 group (12.5 mg/kg), positive control group (levamisole, LMS, 2.0 mg/kg) and negative control group(solvent). Intraperitoneal injections (ip.) of the four pharmaceuticals were performed once a day through the abdominal wall separately, from the second to the eighth day after cancer was transplanted. On the eleventh day, six mice of each group were killed and relative weight of spleen, transforming activity of spleen lymphocytes, NK cell activity, LAK cell activity and percentage of CD4(+)CD8(+)T lymphocyte were detect. RESULTS: Compared with the control group, high dose Eb1 could obviously increase the relative weight of spleen (150.59% and 122.55%), transforming activity of spleen lymphocytes(162.25% and 561.98%), NK cell activity(78.60% and 219.42%) and percentage of CD4(-)/CD8(+) T lymphocyte(104.72% and 105.87%) in normal mice and LLC mice. Compared with the control group, high dose Eb1 could also increase LAK cell activity of LLC mice by 195.11%. CONCLUSION: The novel organoselenium compound Eb1 has immune regulating activity in vivo.

[The antitumor activity of Shuang-Xi-Zuo-Wan-1 in C57/BL mice].

OBJECTIVE: To detect the antitumor activity of Shuang-Xi-Zuo-Wan-1(Eb), a novel organoselenium compound, in C57/BL mice transplanted with Lewis lung cancer(LLC). METHODS: The LLC transplanted C57/BL mice model was established,and the mice were randomly divided into four groups, including high dose Eb group (25.0 mg/kg), low dose Eb group (12.5 mg/kg), positive control group (DDP, 2.0 mg/kg) and negative control group (solvent). Each group had twelve mice. Intraperitoneal injections (ip.) of four pharmaceuticals were performed once a day through the abdominal wall separately, from the second to the eighth days after cancer was transplanted. On the eleventh day, six mice of each group were killed and the influences of Eb on growth speed, size, weight, invasion, inhibitory rate, proliferation index and apoptosis rate of LLC were observed and calculated. The remaining mice were fed till all of them died naturally and the average survival time of each group was calculated. RESULTS: Eb could inhibit the growth and infiltration of LLC (the cancer inhibitory rate of high does Eb was 80.31%) obviously and prolong the average survival time of these with mice cancer. After being given Eb, the nuclear of the cancer cell concentrated and the fission phase cells reduced. In addition,the number of apoptosis cancer cells increased. CONCLUSION: The novel organoselenium compound Eb has antitumor activity in vivo. It can inhibit the growth and infiltration of LLC in mice, and induce the apoptosis of cancer cells.