[Advances in molecular mechanisms and therapeutic strategies of white matter injury after intracerebral hemorrhage].

Intracerebral hemorrhage (ICH) is the most common subtype of stroke with high disability and high mortality rates. Due to the hypertension with arteriosclerosis, hemopathy and cerebrovascular amyloidosis, the influx of blood from ruptured vessels into the brain destroys the cerebral parenchyma and results in dysfunction of central nervous system because of hematoma compression and a series of toxic metabolites. The cerebral parenchyma consists of gray and white matter. The white matter consists of myelinated axons and oligodendrocytes, whereas the gray matter consists of neuronal cell bodies and dendrites. Currently, most of studies have explored the mechanisms of gray matter injury. But researches of white matter injury (WMI) are still in their infancy, which may be partially responsible for the failure of treatments with neuroprotectants targeting degenerating neuronal cells. In recent years, researchers have progressively identified pathophysiological mechanisms of WMI after ICH including mass effect, neuroinflammation and oxidative stress, but information on the molecular mechanisms of WMI and its effective treatment remains limited. In this paper, we will describe the structure and function of white matter, summarize pathology of WMI and focus on the research advances in the molecular mechanisms and therapeutic strategies of WMI after ICH.

Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/ß-catenin signaling.

Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their roles in skeletal diseases are largely unknown. We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast (OB) differentiation in osteosarcoma. However, how Trim21 contributes to skeletal degenerative disorders, including osteoporosis, remains unknown. First, human and mouse bone specimens were evaluated, and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients. Next, we found that global knockout of the Trim21 gene (KO, Trim21-/-) resulted in higher bone mass compared to that of the control littermates. We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and elevating the activity of OBs; moreover, Trim21 depletion suppressed osteoclast (OC) formation of RAW264.7 cells. In addition, the differentiation of OCs from bone marrow-derived macrophages (BMMs) isolated from Trim21-/- and Ctsk-cre; Trim21f/f mice was largely compromised compared to that of the littermate control mice. Mechanistically, YAP1/ß-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs. More importantly, the loss of Trim21 prevented ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling. Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption, thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.

GBP2 as a potential prognostic predictor with immune-related characteristics in glioma.

Guanylate binding protein 2 (GBP2) is a member of the guanine binding protein family, and its relationship with prognostic outcomes and tumor immune microenvironments in glioma remains elusive. We found GBP2 were increased in glioma tissues at both mRNA and protein levels. Kaplan-Meier curves revealed that high GBP2 expression was linked with worse survival of glioma patients, and multivariate Cox regression analysis indicated that high GBP2 expression was an independent prognostic factor for glioma. Combined analysis in immune database revealed that the expression of GBP2 was significantly related to the level of immune infiltration and immunomodulators. Single-cell analysis illustrated the high expression of GBP2 in malignant glioma cells showed the high antigen presentation capability, which were confirmed by real-time polymerase chain reaction (qRT-PCR) data. Additionally, the hsa-mir-26b-5p and hsa-mir-335-5p were predicted as GBP2 regulators and were validated in U87 and U251 cells. Our results first decipher immune-related characteristics and noncoding regulators of GBP2 in glioma, which may provide insights into associated immunotherapies and prognostic predictor.

FRAT1 promotes the angiogenic properties of human glioblastoma cells via VEGFA.

Glioblastoma is a common central nervous system tumor and despite considerable advancements in treatment patient prognosis remains poor. Angiogenesis is a significant prognostic factor in glioblastoma, anti­angiogenic treatments represent a promising therapeutic approach. Vascular endothelial growth factor A (VEGFA) is a predominant regulator of angiogenesis and mounting evidence suggests that the Wnt signaling pathway serves a significant role in tumor angiogenesis. As a positive regulator of the Wnt/ß­catenin signaling pathway, frequently rearranged in advanced T­cell lymphomas­1 (FRAT1) is highly expressed in human glioblastoma and is significantly associated with glioblastoma growth, invasion and migration, as well as poor patient prognosis. Bioinformatics analysis demonstrated that both VEGFA and FRAT1 were highly expressed in most tumor tissues and associated with prognosis. However, whether and how FRAT1 is involved in angiogenesis remains to be elucidated. In the present study, the relationship between FRAT1 and VEGFA in angiogenesis was investigated using the human glioblastoma U251 cell line. Small interfering RNAs (siRNAs) were used to silence FRAT1 expression in U251 cells, and the mRNA and protein expression levels of VEGFA, as well as the concentration of VEGFA in U251 cell supernatants, were determined using reverse transcription­quantitative PCR, western blotting and ELISA. A tube formation assay was conducted to assess angiogenesis. The results demonstrated that siRNA knockdown significantly decreased the protein expression levels of FRAT1 in U251 cells and markedly decreased the mRNA and protein expression levels of VEGFA. Furthermore, the concentration of VEGFA in the cell supernatant was significantly reduced and angiogenesis was suppressed. These results suggested that FRAT1 may promote VEGFA secretion and angiogenesis in human glioblastoma cells via the Wnt/ß­catenin signaling pathway, supporting the potential use of FRAT1 as a promising therapeutic target in human glioblastoma.

Construction of Flexible-on-Rigid Hybrid-Phase Metal-Organic Frameworks for Controllable Multi-Drug Delivery.

Multi-component MOFs contain multiple sets of unique and hierarchical pores, with different functions for different applications, distributed in their inter-linked domains. Herein, we report the construction of a class of precisely aligned flexible-on-rigid hybrid-phase MOFs with a unique rods-on-octahedron morphology. We demonstrated that hybrid-phase MOFs can be constructed based on two prerequisites: the partially matched topology at the interface of the two frameworks, and the structural flexibility of MOFs with acs topology, which can compensate for the differences in lattice parameters. Furthermore, we achieved domain selective loading of multiple guest molecules into the hybrid-phase MOF, as observed by scanning transmission electron microscopy-energy-dispersive X-ray spectrometry elemental mapping. Most importantly, we successfully applied the constructed hybrid-phase MOF to develop a dual-drug delivery system with controllable loading ratio and release kinetics.

Hypoxia-induced USP22-BMI1 axis promotes the stemness and malignancy of glioma stem cells via regulation of HIF-1α.

AIMS: This study intends to investigate the mechanisms of ubiqutin-specific protease 22 (USP22)/B cell-specific Moloney murine leukemia virus integration site 1 (BMI1) on the biological phenotypes of glioma stem cells (GSCs) under hypoxia. MAIN METHODS: Western blot, Cell Counting Kit-8, colony formation and flow cytometry assays were preformed to evaluate cells biological behaviors. Luciferase assay was utilized to identify the associations among USP22, HIF-1α and BMI1. KEY FINDINGS: Silencing USP22 reduced the stemness and proliferation of GSCs, and increased its apoptosis in response to hypoxia. Whilst, overexpression of BMI1 reversed these phenomena. Whilst, a significant decrease in proliferation and stemness of GSCs caused by HIF-1α exhaustion were inversed by overexpression of USP22 or BMI1. SIGNIFICANCE: Function of USP22-BMI1 on biological behaviors of GSCs was regulated by HIF-1α in response to hypoxia.

Double-Targeting Explosible Nanofirework for Tumor Ignition to Guide Tumor-Depth Photothermal Therapy.

This study reports a double-targeting "nanofirework" for tumor-ignited imaging to guide effective tumor-depth photothermal therapy (PTT). Typically, ≈30 nm upconversion nanoparticles (UCNP) are enveloped with a hybrid corona composed of ≈4 nm CuS tethered hyaluronic acid (CuS-HA). The HA corona provides active tumor-targeted functionality together with excellent stability and improved biocompatibility. The dimension of UCNP@CuS-HA is specifically set within the optimal size window for passive tumor-targeting effect, demonstrating significant contributions to both the in vivo prolonged circulation duration and the enhanced size-dependent tumor accumulation compared with ultrasmall CuS nanoparticles. The tumors featuring hyaluronidase (HAase) overexpression could induce the escape of CuS away from UCNP@CuS-HA due to HAase-catalyzed HA degradation, in turn activating the recovery of initially CuS-quenched luminescence of UCNP and also driving the tumor-depth infiltration of ultrasmall CuS for effective PTT. This in vivo transition has proven to be highly dependent on tumor occurrence like a tumor-ignited explosible firework. Together with the double-targeting functionality, the pathology-selective tumor ignition permits precise tumor detection and imaging-guided spatiotemporal control over PTT operation, leading to complete tumor ablation under near infrared (NIR) irradiation. This study offers a new paradigm of utilizing pathological characteristics to design nanotheranostics for precise detection and personalized therapy of tumors.

18F-FDG PET/CT in the Detection of Undifferentiated Carcinoma With Osteoclast-like Giant Cells of the Pancreas.

Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas (UCOGCP) is a rare nonendocrine pancreatic tumor. We present a case of a very small UCOGCP. F-FDG PET/CT revealed a solid mass measuring 1.0 × 0.8 cm on CT images with an SUVmax of 5.0 in the body of the pancreas. CT revealed a solid mass with significant enhancement. The histopathologic and immunohistochemical studies confirmed the diagnosis. Our findings indicate F-FDG PET/CT is a useful imaging modality for UCOGCP diagnosis.

A multifunctional metal-organic framework based tumor targeting drug delivery system for cancer therapy.

Drug delivery systems (DDSs) with biocompatibility and precise drug delivery are eagerly needed to overcome the paradox in chemotherapy that high drug doses are required to compensate for the poor biodistribution of drugs with frequent dose-related side effects. In this work, we reported a metal-organic framework (MOF) based tumor targeting DDS developed by a one-pot, and organic solvent-free "green" post-synthetic surface modification procedure, starting from the nanoscale MOF MIL-101. Owing to the multifunctional surface coating, premature drug release from this DDS was prevented. Due to the pH responsive benzoic imine bond and the redox responsive disulfide bond at the modified surface, this DDS exhibited tumor acid environment enhanced cellular uptake and intracellular reducing environment triggered drug release. In vitro and in vivo results showed that DOX loaded into this DDS exhibited effective cancer cell inhibition with much reduced side effects.

miR-98 suppresses melanoma metastasis through a negative feedback loop with its target gene IL-6.

Dysregulated microRNA (miRNA) expression has a critical role in tumor development and metastasis. However, the mechanism by which miRNAs control melanoma metastasis is unknown. Here, we report reduced miR-98 expression in melanoma tissues with increasing tumor stage as well as metastasis; its expression is also negatively associated with melanoma patient survival. Furthermore, we demonstrate that miR-98 inhibits melanoma cell migration in vitro as well as metastatic tumor size in vivo. We also found that IL-6 is a target gene of miR-98, and IL-6 represses miR-98 levels via the Stat3-NF-κB-lin28B pathway. In an in vivo melanoma model, we demonstrate that miR-98 reduces melanoma metastasis and increases survival in part by reducing IL-6 levels; it also decreases Stat3 and p65 phosphorylation as well as lin28B mRNA levels. These results suggest that miR-98 inhibits melanoma metastasis in part through a novel miR-98-IL-6-negative feedback loop.

Sodium tanshinone IIA sulfonate attenuates radiation-induced fibrosis damage in cardiac fibroblasts.

The main pathological change in radiation-induced heart disease is fibrosis. Emerging evidence has indicated that sodium tanshinone IIA sulfonate (STS) was used for treating fibrosis diseases. The present study was undertaken to characterize the effect of STS on radiation-induced cardiac fibrosis (RICF) on cultured cardiac fibroblasts (CFs). CFs were irradiated with 1 or 2 Gy X-rays, and the expression of TGF-ß1 and collagen I (Col-1) increased, indicating that low-dose X-rays promoted fibrosis damage effect. The fibrosis damage was accompanied by morphologic changes in the endoplasmic reticulum (ER), as well as an increase in the expression of the ER stress-related molecules, GRP78 and CHOP. Administration of STS reduced ROS production and decreased the expression of Col-1, TGF-ß1, p-Smad2/3, GRP78, and CHOP in irradiated CFs, thus weakening the radiation-induced fibrosis damage and ER stress. Radiation-induced fibrosis damage was observed on a cellular level. The involvement of ER stress in radiation-induced fibrosis damage was demonstrated for the first time. STS attenuated the fibrosis damage effect in CFs and this effect may be related to its antioxidant action, and also related to its inhibition of ER stress and TGF-ß1-Smad pathway. These results suggest that STS shows a good prospect in clinical prevention and treatment of RICF.

A rare case of pulmonary malignant granular cell tumor detected with 18F-FDG PET/CT imaging.

Malignant granular cell tumor is rarely involved in the lungs. We present a rare case with 18F-FDG PET/CT images showing a hypermetabolic lesion in the lower lobe of the left lung with posterior mediastinum invasion. Histopathologic study proved it as malignant granular cell tumor.

Two new compounds from Schisandra glaucescens.

One new lignan (7S,8R,7'R,8'R)-7-(3,4-methylenedioxyphenyl)-8,8'-dimethyl-8'-hydroxyl-7'-methoxyl-7'-(3',4'-methylenedioxyphenyl)-tetrahydrofuran (1), one new sesquiterpene 2-hydroxy-11,12-dehydrocalamenene (2), one new natural product erythro-1-(3,4-dimethoxyphenyl)-4-(3,4-methylenedioxyphenyl)-2,3-dimethyl-butane (3), and two known lignans (+)-anwulignan(erythro-1-(4-hydroxy-3-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-2,3-dimethyl-butane) (4) and ( - )-zuonin-A (5) were isolated from the stems of Schisandra glaucescens Diels. Their structures were elucidated by spectroscopic methods. The cytotoxicity of compounds 1 and 2 was assayed.

Interface self-assembly to construct vertical peptide nanorods on quartz template.

A rationally designed glycyl-glycine derivative containing a light cleaved pyrenylmethyl ester tail was covalently bound onto the surface of quartz template. The interface self-assembly of this dipeptide building block induced the formation of chemically bound vertically aligned nanorods (CBVANs) with light sensitivity on the template.

Tanshinone IIA inhibits constitutive STAT3 activation, suppresses proliferation, and induces apoptosis in rat C6 glioma cells.

Signal transducer and activator of transcription 3 (STAT3) is usually constitutively activated in a variety of malignancies. Thus, STAT3 may be a promising target for treatment of tumor cells. Recently, Tanshinone IIA (Tan IIA), a major active constituent from the root of Salvia miltiorrhiza Bunge, was reported to have apoptosis inducing effects on a large variety of cancer cells. In this study, we evaluate the anti-proliferation and apoptosis inducing effects of Tan IIA on C6 glioma cells. Cell growth and proliferation were measured by MTT assay, cell apoptosis was observed by flow cytometry and DNA-fragmentation analysis. Further more, we investigated inhibitory effects of Tan IIA on STAT3 activity and its downstream targets: Bcl-XL, cyclin D1. Alteration of STAT3 activity was examined by measuring their DNA binding activity and tyrosine phosphorylation. Changes in the expression levels of Bcl-XL and cyclin D1 were examined by Western blot analysis. We found that the cellular growth were inhibited and cell apoptosis were observed after the treatment with Tan IIA. The STAT3 activity was significantly reduced by Tan IIA parallel with a significant attenuation of expression of Bcl-XL and cyclin D1. These results suggest that Tan IIA may serve as an effective adjunctive reagent in the treatment of glioma for its targeting of constitutive STAT3 signaling.

The prevalence of Th17 cells and FOXP3 regulate T cells (Treg) in children with primary nephrotic syndrome.

The aim of this study was to investigate the prevalence of interleukin (IL)-17-producing CD4+ T cells (Th17) and regulatory T (Treg) cells in children with primary nephrotic syndrome. The study cohort consisted of 62 children who were randomly divided into control, primary nephrotic syndrome, and isolated hematuria groups. Flow cytometric analysis revealed the presence of Th17 cells in the peripheral blood mononuclear cells (PBMCs) of 35 children and Tregs in the PBMCs of all children. In addition, mRNA expression of Th17-related factors [IL-17, -23p19 and retinoid orphan nuclear receptor (RORc)] and the concentration of plasma inflammatory mediators such as IL-6 and IL-1beta were consistently detected in all children. Protein expression of IL-17 and transforming growth factor-beta1 were also detected in renal biopsy tissue and compared between different groups. Patients with PNS were found to have an increased number of Th17 cells and decreased numbers of Tregs in their PBMCs, and there was significant difference in the prevalence of Th17 and Tregs between the patients with PNS and those with isolated hematuria. Our data show that among our study cohort, there was a dynamic equilibrium between Th17 and Treg cells in children with PNS following the development of PNS with apparent renal tubular epithelial cell and interstitium lesions. The dynamic interaction between Th17 and Treg cells may be important in the development of PNS.

[Immunotherapeutic effects of beta-elemene combined with interleukin-23 gene-modified dendritic cells on murine pancreatic carcinoma].

BACKGROUND & OBJECTIVE: Dendritic cell (DC) vaccine is a kind of treatment vaccine with clinical application potency. Functional cytokines can enhance anti-tumor immune response of dendritic cells. This study was to investigate the protective effects on murine pancreatic carcinoma by beta-elemene combined with bone marrow-derived dendritic cells (BM-DCs) modified with murine interleukin (IL)-23 gene. METHODS: The murine IL-23 cDNA was sub-cloned into dual-expression vector. DCs were pulsed with tumor cell lysate after modified by IL-23 gene. Mice were injected with IL-23-transfected DC vaccine, non-transfected DC vaccine, and sodium, respectively. The immune preventative and immunotherapeutic effects of DC vaccines on mice and the cytokine release in vivo were assessed. Effects of vaccine combined with beta-elemene on tumor growth and survival period of the mice were observed. RESULTS: IL-23 protein apparently increased the antigen-presenting ability of DCs. After the vaccination of DC vaccines, IFN-gamma production in treatment group was significantly more than that of the control group (P<0.01), as well as, IL-4 production was less than that in the normal group (P<0.05). Tumor growth was obviously inhibited and the survival period of the mice was obviously prolonged in beta-elemene combined with DC vaccine group than in DC, beta-elemene, or control group (P<0.01). CONCLUSIONS: IL-23-modified DC vaccines can enhance specific Th1-type and CTL response against pancreatic carcinoma cells, induce not only preventative immunity, but also auto-immunity against pancreatic carcinoma. Moreover, beta-elemene has great collaborative anti-tumor function.