Background Nuciferine (NF), extracted from the leaves of N. nucifera Gaertn , has been shown to exhibit anti-tumor and anti-viral pharmacological properties. It can also penetrate the blood brain barrier (BBB). However, the mechanism by which NF inhibits glioblastoma (GBM) progression is not well understood. We aimed to determine the anti-tumor effect of NF on GBM cell lines and clarify the potential molecular mechanism involved. Methods U87MG and U251 cell lines were used in vitro to assess the anti-tumor efficacy of NF. Cytotoxicity, viability, and proliferation were evaluated by MTT and colony formation assay. After Annexin V-FITC and PI staining, flow cytometry was performed to evaluate apoptosis and cell cycle changes in NF-treated GBM cells. Wound healing and Transwell assays were used to assess migration and invasion of GBM cells. Western blot analysis, immunofluorescence staining, immunohistochemistry, and bioinformatics were used to gain insights into the molecular mechanisms. Preclinical therapeutic efficacy was mainly estimated by ultrasound and MRI in xenograft nude mouse models. Results NF inhibited the proliferation, mobility, stemness, angiogenesis, and epithelial-to-mesenchymal transition (EMT) of GBM cells. Additionally, NF induced apoptosis and G2 cell cycle arrest. Slug expression was also decreased by NF via the AKT and STAT3 signaling pathways. Interestingly, we discovered that NF affected GBM cells partly by targeting SOX2, which may be upstream of the AKT and STAT3 pathways. Finally, NF led to significant tumor control in GBM xenograft models. Conclusions NF inhibited the progression of GBM via the SOX2-AKT/STAT3-Slug signaling pathway. SOX2-targeting with NF may offer a novel therapeutic approach for GBM treatment. Electronic supplementary material The online version of this article (10.1186/s13046-019-1134-y) contains supplementary material, which is available to authorized users.

Glioblastoma multiforme (GBM) has been considered the most aggressive glioma type. Temozolomide (TMZ) is the main first-line chemotherapeutic agent for GBM. Decreased mutS homolog 6 (MSH6) expression is clinically recognized as one of the principal reasons for GBM resistance to TMZ. However, the specific functions of MSH6 in GBM, in addition to its role in mismatch repair, remain unknown. Methods: Bioinformatics were employed to analyze MSH6 mRNA and protein levels in GBM clinical samples and to predict the potential cancer-promoting functions and mechanisms of MSH6. MSH6 levels were silenced or overexpressed in GBM cells to assess its functional effects in vitro and in vivo . Western blot, qRT-PCR, and immunofluorescence assays were used to explore the relevant molecular mechanisms. Cu 2 (OH)PO 4 @PAA nanoparticles were fabricated through a hydrothermal method. Their MRI and photothermal effects as well as their effect on restraining the MSH6-CXCR4-TGFB1 feedback loop were investigated in vitro and in vivo . Results: We demonstrated that MSH6 is an overexpressed oncogene in human GBM tissues. MSH6, CXCR4 and TGFB1 formed a triangular MSH6-CXCR4-TGFB1 feedback loop that accelerated gliomagenesis, proliferation (G1 phase), migration and invasion (epithelial-to-mesenchymal transition; EMT), stemness, angiogenesis and antiapoptotic effects by regulating the p-STAT3/Slug and p-Smad2/3/ZEB2 signaling pathways in GBM. In addition, the MSH6-CXCR4-TGFB1 feedback loop was a vital marker of GBM, making it a promising therapeutic target. Notably, photothermal therapy (PTT) mediated by Cu 2 (OH)PO 4 @PAA + near infrared (NIR) irradiation showed outstanding therapeutic effects, which might be associated with a repressed MSH6-CXCR4-TGFB1 feedback loop and its downstream factors in GBM. Simultaneously, the prominent MR imaging (T1WI) ability of Cu 2 (OH)PO 4 @PAA could provide visual guidance for PTT. Conclusions: Our findings indicate that the oncogenic MSH6-CXCR4-TGFB1 feedback loop is a novel therapeutic target for GBM and that PTT is associated with the inhibition of the MSH6-CXCR4-TGFB1 loop.

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Green synthesized 3D CuS hollow nanoflowers are for the first time proved to be a T1 positive MRI contrast agent for imaging-guided thermochemotherapy.

Background: Continuous damage from oxidative stress and apoptosis are the important mechanisms that facilitate chronic heart failure (CHF). Molecular hydrogen (H2) has potentiality in the aspects of anti-oxidation. The objectives of this study were to investigate the possible mechanism of H2 inhalation in delaying the progress of CHF.Methods and Results: A total of 60 Sprague-Dawley (SD) rats were randomly divided into four groups: Sham, Sham treated with H2, CHF and CHF treated with H2. Rats from CHF and CHF treated with H2 groups were injected isoprenaline subcutaneously to establish the rat CHF model. One month later, the rat with CHF was identified by the echocardiography. After inhalation of H2, cardiac function was improved vs. CHF (p < 0.05), whereas oxidative stress damage and apoptosis were significantly attenuated (p < 0.05). In this study, the mild oxidative stress was induced in primary cardiomyocytes of rats, and H2 treatments significantly reduced oxidative stress damage and apoptosis in cardiomyocytes (p < 0.05 or p < 0.01). Finally, as a pivotal transcription factor in reactive oxygen species (ROS)-apoptosis signaling pathway, the expression and phosphorylation of p53 were significantly reduced by H2 treatment in this rat model and H9c2 cells (p < 0.05 or p < 0.01).Conclusion: As a safe antioxidant, molecular hydrogen mitigates the progression of CHF via inhibiting apoptosis modulated by p53. Therefore, from the translational point of view and speculation, H2 is equipped with potential therapeutic application as a novel antioxidant in protecting CHF in the future.

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Psoriasis is an auto-inflammatory skin disease characterized by abnormal activation of epidermal keratinocytes, aberrant neovascularization, and dysregulation of immune cells. MicroRNAs are small non-coding RNAs that mainly function in the post-transcriptional regulation of gene expression. Recently, accumulating evidence has demonstrated that expression of microRNAs is dysregulated in psoriasis patients and microRNAs play key roles in psoriasis pathogenesis. Downregulation of miR-193b-3p has been identified to be associated with psoriasis development. However, the precise functions and action mechanisms of miR-193b-3p in psoriasis pathogenesis remain unclear. In this study, we confirmed the downregulation of miR-193b-3p in psoriasis patients, psoriasis-like inflammatory cellular models, and an imiquimod (IMQ) -induced mouse model. A negative correlation was found between miR-193b-3p level and patient Psoriasis Area and Severity Index (PASI) score. Furthermore, miR-193b-3p suppressed proliferation, inflammatory-factor secretion, and the STAT3 and NF-κB signaling pathways in keratinocytes. Importantly, intradermal injection of agomiR-193b-3p blocked, whereas antagomiR-193b-3p augmented, the psoriasis-like inflammation in the IMQ-induced mouse model. Bioinformatics analysis and the dual-luciferase reporter assay showed that miR-193b-3p targets ERBB4 3ʹ untranslated region (UTR). In addition, ERBB4 induced proliferation, inflammatory-factor production, and the STAT3 and NF-κB pathways in keratinocytes. Most importantly, forced expression of ERBB4 could attenuate the effects of miR-193b-3p in keratinocytes, indicating that miR-193b-3p inhibits keratinocyte activation by directly targeting ERBB4. In conclusion, our findings demonstrated that the miR-193b-3p–ERBB4 axis underlies the hyperproliferation and aberrant inflammatory-factor secretion of psoriatic keratinocytes, providing a novel, microRNA-related causal mechanism and a potential therapeutic target in psoriasis.