Salinomycin-loaded lipid-polymer nanoparticles with anti-CD20 aptamers selectively suppress human CD20+ melanoma stem cells.

Melanoma is the deadliest type of skin cancer. CD20+ melanoma stem cells (CSCs) are pivotal for metastasis and initiation of melanoma. Therefore, selective elimination of CD20+ melanoma CSCs represents an effective treatment to eradicate melanoma. Salinomycin has emerged as an effective drug toward various CSCs. Due to its poor solubility, its therapeutic efficacy against melanoma CSCs has never been evaluated. In order to target CD20+ melanoma CSCs, we designed salinomycin-loaded lipid-polymer nanoparticles with anti-CD20 aptamers (CD20-SA-NPs). Using a single-step nanoprecipitation method, salinomycin-loaded lipid-polymer nanoparticles (SA-NPs) were prepared, then CD20-SA-NPs were obtained through conjugation of thiolated anti-CD20 aptamers to SA-NPs via a maleimide-thiol reaction. CD20-SA-NPs displayed a small size of 96.3 nm, encapsulation efficiency higher than 60% and sustained drug release ability. The uptake of CD20-SA-NPs by CD20+ melanoma CSCs was significantly higher than that of SA-NPs and salinomycin, leading to greatly enhanced cytotoxic effects in vitro, thus the IC50 values of CD20-SA-NPs were reduced to 5.7 and 2.6 µg/mL in A375 CD+20 cells and WM266-4 CD+ cells, respectively. CD20-SA-NPs showed a selective cytotoxicity toward CD20+ melanoma CSCs, as evidenced by the best therapeutic efficacy in suppressing the formation of tumor spheres and the proportion of CD20+ cells in melanoma cell lines. In mice bearing melanoma xenografts, administration of CD20-SA-NPs (salinomycin 5 mg·kg-1·d-1, iv, for 60 d) showed a superior efficacy in inhibition of melanoma growth compared with SA-NPs and salinomycin. In conclusion, CD20 is a superior target for delivering drugs to melanoma CSCs. CD20-SA-NPs display effective delivery of salinomycin to CD20+ melanoma CSCs and represent a promising treatment for melanoma.

Histogenous Hypoxia and Acid Retention in Schizophrenia: Changes in Venous Blood Gas Analysis and SOD in Acute and Stable Schizophrenia Patients.

Background: Oxidative stress may play an important role in the pathogenesis of schizophrenia (SCH), and there is considerable indirect evidence that hypoxia is closely related to SCH, but direct evidence of hypoxia in SCH has never been found. Methods:In this study, superoxide dismutase (SOD), venous blood gas, and Positive and Negative Syndrome Scale (PANSS) were examined in 40 SCH patients and compared with those of 40 healthy controls. The patients were treated with combination of atypical antipsychotics and Ditan Huayu Lishen decoction (a Chinese medicine decoction) and examined in the acute and stable period, respectively. Comparisons of indicators between two groups were performed using an independent-samples t-test, comparison of indicators between the acute and stable periods in the SCH group was performed using paired-samples t-test. Pearson correlation and multiple linear regression analyses were performed to investigate the relationships between the effect indicators. Results: Higher venous pH, PvO2, and fasting blood glucose levels and lower SOD, lactic acid, and PvCO2 levels were found in SCH patients compared with the control group; SOD was negatively correlated with the general psychopathology subscale score (PANSS-G), and PvO2 levels were closely related to venous pH in SCH and related to PvCO2 in the control group. It was also found that SOD activity showed no significant difference in acute and stable period, whereas PvO2 showed a downward trend, and venous pH was decreased significantly after treatment. Both the venous pH and PvO2 were higher in patients with SCH than that in healthy controls. Conclusion: It suggests that histogenous hypoxia and acid retention exist in relation to SCH, and there is an improvement of acid retention and a downward trend in histogenous hypoxia after combination treatment. Venous pH, PvO2, and PvCO2 are trait variables, but not state variables of SCH. The theory of histogenous hypoxia and acid retention can well explain the decrease in pH value and the increase in lactic acid in brain tissue of patients with SCH. Histogenous hypoxia and acid retention closely related to glucose metabolism. So they may play an important role in pathophysiology for SCH.

Gut and Cutaneous Microbiome Featuring Abundance of Lactobacillus reuteri Protected Against Psoriasis-Like Inflammation in Mice.

BACKGROUND: Psoriasis is a chronic autoinflammatory skin disease, and its aetiology remains incompletely understood. Recently, gut microbial dysbiosis is found to be tightly associated with psoriasis. OBJECTIVE: We sought to reveal the causal role of gut microbiota dysbiosis in psoriasis pathogenesis and investigate the protective effect of healthy commensal bacteria against imiquimod -induced psoriasis-like skin response. METHODS: By using fecal microbial transplantation (FMT), 16S rRNA gene-based taxonomic profiling and Lactobacillus supplement, we have assessed the effect of FMT from healthy individuals on psoriasis-like skin inflammation and associated immune disorders in imiquimod-induced psoriasis mice. RESULTS: Here, by using psoriasis mice humanized with the stools from healthy donors and psoriasis patients, the imiquimod-induced psoriasis in mice with psoriasis patient stool was found to be significantly aggravated as compared to the mice with healthy donor stools. Further analysis showed fecal microbiota of healthy individuals protected against Treg/Th17 imbalance in psoriasis. Moreover, we found the gut and skin microbiome in mice receipted with gut microbiota of healthy individuals (HD) differed from those of mice receipted with gut microbiota of psoriasis patients (PSD). 16S rRNA sequencing revealed that Lactobacillus reuteri was greatly enriched in fecal and cutaneous microbiome of HD mice as compared to PSD mice. Intriguingly, supplement with Lactobacillus reuteri was sufficient to increase the expression of anti-inflammatory gene IL-10, reduce Th17 cells counts and confer resistance to imiquimod-induced inflammation on the mice with gut microbiota dysbiosis. CONCLUSION: Our results suggested that the gut microbiota dysbiosis is the potential causal factor for psoriasis and the gut microbiota may serve as promising therapy target for psoriasis patients.