PYR-41, an inhibitor of ubiquitin-activating enzyme E1, attenuates 2,4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions in mice.

PYR-41 is an irreversible and cell permeable inhibitor of ubiquitin-activating enzyme E1, and has been reported to inhibit the degradation of IκB protein. Previous studies have shown that PYR-41 has effects on anti-inflammatory, but whether it has therapeutic effects on allergic dermatitis is unclear. The aim of this research was to explore the therapeutic effects of PYR-41 on atopic dermatitis. The effects of PYR-41 on the activation of NF-κB signaling pathway and the expression of inflammatory genes in HaCat cells were tested by western blot and qPCR. A mouse model was built, and the AD-like skin lesions were induced by 2,4-dinitrochlorobenzene (DNCB). Then, the treatment effects of PYR-41 were examined by skin severity score, ear swelling, ELISA, and qPCR. The results showed that PYR-41 can significantly reduce the K63-linked ubiquitination level of nuclear factor-κB essential modulator (NEMO) and tumor necrosis factor receptor associated factor 6 (TRAF6), inhibit the proteasomal degradation of IκBα, thereby activate TNF-α-induced NF-κB signaling pathway in HaCat cells. In addition, DNCB-treated mice have significant reduction in symptoms after treated by PYR-41, including reduced ear thickening and reduced skin damage. Serum tests showed that PYR-41 significantly reduced the expression of IgE, IFN-γ, and TNF-α. In conclusion, the current results suggest that PYR-41 has potential to reduce the symptoms of atopic dermatitis.

Development of Sequence-Controlled, Degradable, and Cytocompatible Oligomers with Explicit Fragmentation Pathways.

Sequence-defined and degradable polymers can mimic biopolymers, such as peptides and DNA, to undertake life-supporting functions in a chemical way. The design and development of well-structured oligomers/polymers is the most concern for the public, even to further uncover their degradation process illustrating the degraded products and their properties. However, seldom investigation has been reported on the aforementioned aspects. In this work, the alternating photo-reversible addition-fragmentation chain-transfer (photo-RAFT) single unit monomer insertion (SUMI) of different N-substituted maleimides and thermal radical ring-opening SUMI of a cyclic ketene acetal monomer (i.e., 5,6-benzo-2-methylene-1,3-dioxepane (BMDO)) is adopted, to produce two degradable pentamers owing to the conversion of the exo-methylene group of BMDO into ester bonds along the main chains of the prepared products. Moreover, the possible degraded approach of pentamers is studied by combining high-resolution mass spectrometry (HRMS) and liquid chromatography-mass spectrometry (LC-MS) for the first time. This work also sheds light on the precise structures and cytotoxicity of SUMI products and their degraded compounds, proposing a detailed and credible outlook for biomedical applications.

Genetic compensation response could exist in colorectal cancer: UPF3A upregulates the oncogenic homologue gene SRSF3 expression corresponding to SRSF6 to promote colorectal cancer metastasis.

BACKGROUND: Genetic compensation response (GCR) is a mechanism that maintains the robustness of functional genes, which has been recently identified. Whether GCR exists in tumors and its effects on tumor progression remains unknown. METHODS: Whole exome sequencing was performed to identify premature termination codon (PTC) gene mutations in colorectal cancer (CRC) tissues. RNA sequencing, Cancer Cell Line Encyclopedia database analysis, and high-throughput output of homologous genes using the Ensemble genome database were performed to further identify homologous genes of target PTC gene mutations. RESULTS: Serine and arginine-rich splicing factor 3 (SRSF3) increased the invasion ability in CRC cells and could be the target gene of up-frameshift 3A (UPF3A). The deletion of the 660th base A in the coding sequence region of SRSF6 caused a frameshift mutation of serine at position 220 (s220fs), which contributed to a PTC UAA termination of translation in HCT116 cells. We further found that SRSF3 was the only homologue of SRSF6 with a frameshift mutation. The transfection of s220fs of SRSF6 into HCT116 cells led to upregulation of its corresponding oncogenic homologue gene SRSF3 expression to promote CRC metastasis. SRSF3 was highly expressed in CRC liver metastases and was positively correlated with UPF3A expression and contributed to poor prognosis. CONCLUSION: GCR may exist in CRC and exert effects on the progression of CRC. Targeted inhibition of UPF3A could reduce the GCR effects and suppress the expression of oncogenic homologue genes corresponding to PTC mutations, indicating a novel therapeutic strategy for treatment of CRC metastasis.

Hydrothermal treatment enhances energy recovery from pig manure digestate and improves the properties of residues.

Energy recovery from biowaste is of high significance for a sustainable society. Herein, hydrothermal treatment (HT) was applied to valorize pig manure digestate. The effects of hydrothermal operational parameters, including temperature (130-250 °C), residence time (15-90 min), and total solid (TS) concentration (10%-20%), on reducing sugar yield were investigated in this study. Among them, hydrothermal temperature was identified as the most important factor influencing reducing sugar yield, followed by the TS concentration and time. The optimal hydrothermal conditions for the pig manure digestate were 175.6 °C, 35.4 min and a TS concentration of 10% with a reduced sugar yield of 9.81 mg gTS-1. The addition of hydrolysate could enhance methane production by 21.6-50.4% from the anaerobic digestion of pig manure than that without the hydrolysate addition. After HT, the hygienic quality, including fecal coliform number and ascaris egg mortality, was improved in the residual digestate. Antibiotics such as sulfamonomethoxine, oxytetracycline, doxycycline and sulfaclodazine in the pig manure digestate were decomposed during HT and decreased environmental risk. These findings indicated that the hydrothermal process might be an effective technique to recover energy from the digestate of livestock and poultry manure and to improve the residual digestate for subsequent utilization.

Mechanisms of malignancy in glioblastoma cells are linked to mitochondrial Ca2+ uniporter upregulation and higher intracellular Ca2+ levels.

Glioblastoma (GBM) is one of the most malignant brain tumours and, despite advances in treatment modalities, it remains largely incurable. Ca2+ regulation and dynamics play crucial roles in different aspects of cancer, but they have never been investigated in detail in GBM. Here, we report that spontaneous Ca2+ waves in GBM cells cause unusual intracellular Ca2+ ([Ca2+]i) elevations (>1 µM), often propagating through tumour microtubes (TMs) connecting adjacent cells. This unusual [Ca2+]i elevation is not associated with the induction of cell death and is concomitant with overexpression of mitochondrial Ca2+ uniporter (MCU). We show that MCU silencing decreases proliferation and alters [Ca2+]i dynamics in U87 GBM cells, while MCU overexpression increases [Ca2+]i elevation in human astrocytes (HAs). These results suggest that changes in the expression level of MCU, a protein involved in intracellular Ca2+ regulation, influences GBM cell proliferation, contributing to GBM malignancy.This article has an associated First Person interview with the first author of the paper.

Qing-Fei-Pai-Du decoction and wogonoside exert anti-inflammatory action through down-regulating USP14 to promote the degradation of activating transcription factor 2.

COVID-19 is often characterized by dysregulated inflammatory and immune responses. It has been shown that the Traditional Chinese Medicine formulation Qing-Fei-Pai-Du decoction (QFPDD) is effective in the treatment of the disease, especially for patients in the early stage. Our network pharmacology analyses indicated that many inflammation and immune-related molecules were the targets of the active components of QFPDD, which propelled us to examine the effects of the decoction on inflammation. We found in the present study that QFPDD effectively alleviated dextran sulfate sodium-induced intestinal inflammation in mice. It inhibited the production of pro-inflammatory cytokines IL-6 and TNFα, and promoted the expression of anti-inflammatory cytokine IL-10 by macrophagic cells. Further investigations found that QFPDD and one of its active components wogonoside markedly reduced LPS-stimulated phosphorylation of transcription factor ATF2, an important regulator of multiple cytokines expression. Our data revealed that both QFPDD and wogonoside decreased the half-life of ATF2 and promoted its proteasomal degradation. Of note, QFPDD and wogonoside down-regulated deubiquitinating enzyme USP14 along with inducing ATF2 degradation. Inhibition of USP14 with the small molecular inhibitor IU1 also led to the decrease of ATF2 in the cells, indicating that QFPDD and wogonoside may act through regulating USP14 to promote ATF2 degradation. To further assess the importance of ubiquitination in regulating ATF2, we generated mice that were intestinal-specific KLHL5 deficiency, a CUL3-interacting protein participating in substrate recognition of E3s. In these mice, QFPDD mitigated inflammatory reaction in the spleen, but not intestinal inflammation, suggesting CUL3-KLHL5 may function as an E3 for ATF2 degradation.

Research progress of anti-environmental factor stress mechanism and anti-stress tolerance way of Saccharomyces cerevisiae during the brewing process.

Saccharomyces cerevisiae plays a decisive role in the brewing of alcohol products, and the ideal growth and fermentation characteristics can give the pure flavor of alcohol products. However, S. cerevisiae can be affected profoundly by environmental factors during the brewing process, which have negative effects on the growth and fermentation characteristics of S. cerevisiae, and seriously hindered the development of brewing industry. Therefore, we summarized the environmental stress factors (ethanol, organic acids, temperature and osmotic pressure) that affect S. cerevisiae during the brewing process. Their impact mechanisms and the metabolic adaption of S. cerevisiae in response to these stress factors. Of note, S. cerevisiae can increase the ability to resist stress factors by changing the cell membrane components, expressing transcriptional regulatory factors, activating the anti-stress metabolic pathway and enhancing ROS scavenging ability. Meantime, the strategies and methods to improve the stress- tolerant ability of S. cerevisiae during the brewing process were also introduced. Compared with the addition of exogenous anti-stress substances, mutation breeding and protoplast fusion, it appears that adaptive evolution and genetic engineering are able to generate ideal environmental stress tolerance strains of S. cerevisiae and are more in line with the needs of the current brewing industry.

Recent advances in alleviating food allergenicity through fermentation.

The increasing prevalence of food allergies is a significant challenge to global food health and safety. Various strategies have been deployed to decrease the allergenicity of food for preventing and reducing related disorders. Compared to other methods, fermentation has unique advantages in reducing the allergenicity of food and may represent a new trend in preventing food-induced allergies. This review introduces the characteristics of allergens in various foods, including shellfish, soy, peanut, milk, tree nut, egg, wheat, and fish. The mechanism and pathological symptoms of allergic reactions are then summarized. Furthermore, the advantages of fermentation for reducing the allergenicity of these foods and preventing allergies are evaluated. Fermentation is an efficient approach for reducing or eliminating food allergenicity. Simultaneously, it improved the nutritional value and physicochemical properties of food materials. It is conceivable that a combination of mixed strain fermentation with additional processing, such as heat treatment, pulsed light, and ultrasonication, will efficiently reduce the allergenicity of various foods and preserve their unique taste and nutritional components, providing significance for patients with allergies.

Food irradiation: a promising technology to produce hypoallergenic food with high quality.

The increasing incidence of food allergy cases is a public health problem of global concern. Producing hypoallergenic foods with high quality, low cost, and eco-friendly is a new trend for the food industry in the coming decades. Food irradiation, a non-thermal food processing technology, is a powerful tool to reduce the allergenicity with the above advantages. This review presents a summary of recent studies about food irradiation to reduce the allergenicity of food, including shellfish, soy, peanut, milk, tree nut, egg, wheat and fish. Principles of food irradiation, including mechanisms of allergenicity-reduction, irradiation types and characteristics, are discussed. Specific effects of food irradiation are also evaluated, involving microbial decontamination, improvement or preservation of nutritional value, harmful substances reduction of food products. Furthermore, the advantages, disadvantages and limitations of food irradiation are analyzed. It is concluded that food irradiation is a safety tool to reduce the allergenicity of food effectively, with high nutritional value and long shelf-life, making it a competitive alternative technology to traditional techniques such as heating treatments. Of note, a combination of irradiation with additional processing may be a trend for food irradiation.

Sesame allergy: mechanisms, prevalence, allergens, residue detection, effects of processing and cross-reactivity.

Sesame allergy is a serious public health problem and is mainly induced by IgE-mediated reactions, whose prevalence is distributed all over the world. Sesame has been included on the priority allergic food list in many countries. This review summarizes the mechanism and prevalence of sesame allergy. The characteristics, structures and epitopes of sesame allergens (Ses i 1 to Ses i 7) are included. Moreover, the detection methods for sesame allergens are evaluated, including nucleic-acid, immunoassays, mass spectrometry, and biosensors. Various processing techniques for reducing sesame allergenicity are discussed. Additionally, the potential cross-reactivity of sesame with other plant foods is assessed. It is found that the allergenicity of sesame is related to the structures and epitopes of sesame allergens. Immunoassays and mass spectrometry are the major analytical tools for detecting and quantifying sesame allergens in food. Limited technologies have been successfully used to reduce the antigenicity of sesame, involving microwave heating, high hydrostatic pressure, salt and pH treatment. More technologies for reducing the allergenicity of sesame should be widely investigated in future studies. The reduction of allergenicity in processed sesames should be ultimately confirmed by clinical studies. What's more, sesame may exhibit cross-reactivity with peanut and tree nuts.

Sesquiterpene lactone Bigelovin induces apoptosis of colon cancer cells through inducing IKK-ß degradation and suppressing nuclear factor kappa B activation.

Bigelovin, a sesquiterpene lactone extracted from plant Inula helianthus aquatica, exhibited multiple interesting biological activities, including anti-inflammation, antiangiogenesis and cytotoxic action against cancer cells. In the present study, we found that Bigelovin reduced the viability of human colon cancer cells and induced their apoptosis in a time- and dose-dependent manner, with an IC50-5 µM. RNAseq and luciferase reporter analyses revealed that the nuclear factor kappa B (NF-κB) signaling was one of the most significantly inhibited pathways after Bigelovin treatment. Further systemic examination showed that exposure to Bigelovin resulted in ubiquitination and degradation of inhibitor of kappa-B kinase-beta (IKK-ß) and decrease of IκB-α and p65 phosphorylation, which led to the downregulation of NF-κB-regulated genes expression. Moreover, enforced expression of exogenous IKK-ß attenuated Bigelovin-induced NF-κB suppression and cell viability reduction. These results indicated that Bigelovin exerts a cytotoxic action against colon cancer cells through the induction of IKK-ß degradation and consequently the inhibition of NF-κB signaling. Given the abnormal activation of NF-κB signaling in colorectal cancer (CRC) cells and the critical role of chronic inflammation in CRC development, it is conceivable that at least some colorectal cancer cells are addictive to NF-κB activation and targeting the pathway is an effective anti-CRC strategy.

Dynamic Expression of Platelet-Derived Growth Factor-D and Phosphorylated Platelet-Derived Growth Factor Receptor-Β after Traumatic Brain Injury in Rats.

BACKGROUND: We explored the dynamic expression of platelet-derived growth factor-D (PDGF-D) and phosphorylated platelet-derived growth factor receptor-ß (p-PDGFR-ß) after traumatic brain injury in rats to provide theoretical basis for selecting therapeutic target and intervention time after traumatic brain injury. METHODS: This study prepared the weight drop/impact acceleration-induced traumatic brain injury (TBI) model in rats, including sham group and TBI groups at different observation time points (6 hours, 12 hours, 24 hours, 3 days, and 7 days after TBI). The dynamic expression of PDGF-D and p-PDGFR-ß after TBI were detected by western blot and immunofluorescence staining. RESULTS: The expression level of PDGF-D and p-PDGFR-ß after TBI was detected by western blot. The PDGF-D level was increased (p < 0.05) 6 hours after TBI and remained at the high level until 3 days after TBI (p < 0.05). The p-PDGFR-ß level was increased (p < 0.05) 12 hours after TBI and remained at the high level until 3 days after TBI (p < 0.05). PDGF-D and p-PDGFR-ß in brain tissues were found by immunofluorescence in the perihematoma area 24 hours after TBI. CONCLUSIONS: This study revealed the expression phenomenon of PDGF-D and p-PDGFR-ß after TBI in rats, suggesting that PDGF-D participates in the process of secondary brain injury after TBI through specific binding with PDGFR-ß, which provides a theoretical basis for further research on selecting therapeutic targets and intervention times after TBI.

Fenozyme Protects the Integrity of the Blood-Brain Barrier against Experimental Cerebral Malaria.

Cerebral malaria is a lethal complication of malaria infection characterized by central nervous system dysfunction and is often not effectively treated by antimalarial combination therapies. It has been shown that the sequestration of the parasite-infected red blood cells that interact with cerebral vessel endothelial cells and the damage of the blood-brain barrier (BBB) play critical roles in the pathogenesis. In this study, we developed a ferritin nanozyme (Fenozyme) composed of recombinant human ferritin (HFn) protein shells that specifically target BBB endothelial cells (BBB ECs) and the inner Fe3O4 nanozyme core that exhibits reactive oxygen species-scavenging catalase-like activity. In the experimental cerebral malaria (ECM) mouse model, administration of the Fenozyme, but not HFn, markedly ameliorated the damage of BBB induced by the parasite and improved the survival rate of infected mice significantly. Further investigations found that Fenozyme, as well as HFn, was able to polarize the macrophages in the liver to the M1 phenotype and promote the elimination of malaria in the blood. Thus, the catalase-like activity of the Fenozyme is required for its therapeutic effect in the mouse model. Moreover, the Fenozyme significantly alleviated the brain inflammation and memory impairment in ECM mice that had been treated with artemether, indicating that combining Fenozyme with an antimalarial drug is a novel strategy for the treatment of cerebral malaria.

Increased IGF2BP3 expression promotes the aggressive phenotypes of colorectal cancer cells in vitro and vivo.

Previous literatures reported insulin-like growth factor-2 messenger RNA-binding protein 3 (IGF2BP3) is a poor prognostic marker for colorectal cancer (CRC) patients. However, basic research on the effect and biological role of IGF2BP3 in CRC was still scare. Real-time quantitative polymerase chain reaction and western blot analysis were used to examine IGF2BP3 expression level in tumors and paired normal tissues from CRC patients. Tissue microarrays with 192 CRC patients were subjected to immunohistochemical staining to analyze the prognostic value of IGF2BP3. Proliferation assays, migration assays, and xenograft tumor formation in nude mice were performed to assess the biological role of IGF2BP3 in CRC cells. IGF2BP3 expression was significantly upregulated in tumor tissues compared with the matched normal tissues both in messenger RNA and protein level and was associated with worse prognosis. IGF2BP3 knockdown made cell cycle arrest to impair the proliferation ability of CRC cells and further inhibited the xenograft tumor growth in nude mice, also inhibited the migration ability of CRC cells via inducing epithelial-mesenchymal transition. Therefore, the research demonstrated that increased IGF2BP3 expression promoted the aggressive phenotypes of CRC cells. Targeted IGF2BP3 could be a novel and effective gene therapy for CRC patients to make a better prognosis.

Nitidine chloride exerts anti-inflammatory action by targeting Topoisomerase I and enhancing IL-10 production.

In the effort to identify natural products that regulate immunity and inflammation, we found that nitidine chloride (NC), an alkaloid from herb Zanthoxylum nitidum, enhanced IL-10 production in lipopolysaccharide (LPS)-stimulated myeloid cells. While NC was shown to be capable of inhibiting topoisomerase I (TOP1), NC analogs that could not inhibit TOP1 failed to increase IL-10 production. Moreover, medicinal TOP1 inhibitors TPT and SN-38 also augmented IL-10 production significantly, whereas knockdown of TOP1 prevented NC, TPT, and SN-38 from enhancing IL-10 expression. Thus, NC promoted IL-10 production by inhibiting TOP1. In LPS-induced endotoxemic mice, NC and TOP1 inhibitors increased IL-10 production, suppressed inflammatory responses, and reduced mortality remarkably. The anti-inflammatory activities of TOP1 inhibition were markedly reduced by IL-10-neutralizing antibody and largely absent in IL-10-deficient mice. In LPS-stimulated RAW264.7 cells and in peritoneal macrophages from endotoxemic mice, NC and TOP1 inhibitors significantly enhanced the activation of Akt, a critical signal transducer for IL-10 production, and inhibition of Akt prevented these compounds from enhancing IL-10 production and ameliorating endotoxemia. These data indicated that NC and TOP1 inhibitors are able to exert anti-inflammatory action through enhancing Akt-mediated IL-10 production and may assist with the treatment of inflammatory diseases.

A nanohybrid composed of MoS2 quantum dots and MnO2 nanosheets with dual-emission and peroxidase mimicking properties for use in ratiometric fluorometric detection and cellular imaging of glutathione.

A nanohybrid probe was fabricated from manganese dioxide nanosheets (MnO2 NSs), molybdenum disulfide quantum dots (MoS2 QDs) and o-phenylenediamine (OPD) for ratiometric detection of glutathione (GSH) in aqueous solutions and living cells. The MoS2 QDs act as the fluorescent "turn off-on" units. The MnO2 NSs have 3 functions, viz. (a) as fluorescence quencher, (b) as fluorescence initiator for oxidized OPD (ox OPD) and (c) as selective recognizer of GSH. The quenched blue fluorescence of the MoS2 QDs can be restored by introducing GSH that reduces the MnO2 NSs. However, the green fluorescence of ox OPD is decreased through the loss of peroxidase activity of MnO2 NSs in the presence of GSH. Therefore, the ratio of the fluorescence intensities at 560 and 400 nm (from ox OPD and MoS2 QDs, respectively) linearly decreases with increasing concentrations of GSH. Under the optimal conditions, the detection limit for GSH is as low as 90 nM. The method was successfully applied to the determination of GSH in human serum samples. This nanohybrid also is shown to be membrane-permeable and to have low cytotoxicity. This paved the way to intracellular sensing of GSH in living normal HFF and cancerous HeLa cells. Additionally, by combining with logic gate, this assay was successfully applied to visually discriminate changes in the intracellular GSH. The combination of ratiometric fluorometry and peroxidase mimicking can provide a wide range of application in bioanalysis and intracellular imaging. Graphical abstract Schematic representation of the ratiometric fluorometric detection and cellular imaging of glutathione using a nanohybrid composed of MoS2 quantum dots and MnO2 nanosheets with dual (blue and green emission and peroxidase mimicking properties.

Synthesis, Spectroscopic Study and Radical Scavenging Activity of Kaempferol Derivatives: Enhanced Water Solubility and Antioxidant Activity.

Kaempferol (Kae) is a natural flavonoid with potent antioxidant activity, but its therapeutic use is limited by its low aqueous solubility. Here, a series of Kae derivatives were synthesized to improve Kae dissolution property in water and antioxidant activity. These compounds included sulfonated Kae (Kae-SO3), gallium (Ga) complexes with Kae (Kae-Ga) and Kae-SO3 (Kae-SO3-Ga). The compound structures were characterized by high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR) spectroscopy, ultraviolet-visible (UV-Vis) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy and thermal methods (TG/DSC). The results showed that a sulfonic group (-SO3) was successfully tethered on the C3' of Kae to form Kae-SO3. And in the metal complexation, 4-CO and 3-OH of the ligand participated in the coordination with Ga(III). The metal-to-ligand ratio 1:2 was suggested for both complexes. Interestingly, Kae-SO3-Ga was obviously superior to other compounds in terms of overcoming the poor water-solubility of free Kae, and the solubility of Kae-SO3-Ga was about 300-fold higher than that of Kae-Ga. Furthermore, the evaluation of antioxidant activities in vitro was carried out for Kae derivatives by using α,α-diphenyl-ß-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) diammonium salt (ABTS) free radical scavenging. The results showed that Kae-SO3-Ga was also optimal for scavenging free radicals in a dose-dependent manner. These data demonstrate that sulfonate kaempferol-gallium complex has a promising future as a potential antioxidant and as a potential therapeutic agent for further biomedical studies.

Antimalarial drug mefloquine inhibits nuclear factor kappa B signaling and induces apoptosis in colorectal cancer cells.

Nuclear factor kappa B (NF-κB) signaling pathway is activated in many colorectal cancer (CRC) cells and in the tumor microenvironment, which plays a critical role in cancer initiation, development, and response to therapies. In the present study, we found that the widely used antimalarial drug mefloquine was a NF-κB inhibitor that blocked the activation of IκBα kinase, leading to reduction of IκBα degradation, decrease of p65 phosphorylation, and suppressed expression of NF-κB target genes in CRC cells. We also found that mefloquine induced growth arrest and apoptosis of CRC cells harboring phosphorylated p65 in culture and in mice. Furthermore, expression of constitutive active IKKß kinase significantly attenuated the cytotoxic effect of the compound. These results showed that mefloquine could exert antitumor action through inhibiting the NF-κB signaling pathway, and indicated that the antimalarial drug might be repurposed for anti-CRC therapy in the clinic as a single agent or in combination with other anticancer drugs.

Downregulation of bone morphogenetic protein receptor 2 promotes the development of neuroblastoma.

Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. In this study, we examined the expression of bone morphogenetic protein receptor 2 (BMPR2) in primary NB and adjacent non-tumor samples (adrenal gland). BMPR2 expression was significantly downregulated in NB tissues, particularly in high-grade NB, and was inversely related to the expression of the NB differentiation markers ferritin and enolase. The significance of the downregulation was further explored in cultured NB cells. While enforced expression of BMPR2 decreased cell proliferation and colony-forming activity, shRNA-mediated knockdown of BMPR2 led to increased cell growth and clonogenicity. In mice, NB cells harboring BMPR2 shRNA showed significantly increased tumorigenicity compared with control cells. We also performed a retrospective analysis of NB patients and identified a significant positive correlation between tumor BMPR2 expression and overall survival. These findings suggest that BMPR2 may play an important role in the development of NB.

The development of Wilms tumor: from WT1 and microRNA to animal models.

Wilms tumor recapitulates the development of the kidney and represents a unique opportunity to understand the relationship between normal and tumor development. This has been illustrated by the findings that mutations of Wnt/ß-catenin pathway-related WT1, ß-catenin, and WTX together account for about one-third of Wilms tumor cases. While intense efforts are being made to explore the genetic basis of the other two-thirds of tumor cases, it is worth noting that, epigenetic changes, particularly the loss of imprinting of the DNA region encoding the major fetal growth factor IGF2, which results in its biallelic over-expression, are closely associated with the development of many Wilms tumors. Recent investigations also revealed that mutations of Drosha and Dicer, the RNases required for miRNA generation, and Dis3L2, the 3'-5' exonuclease that normally degrades miRNAs and mRNAs, could cause predisposition to Wilms tumors, demonstrating that miRNA can play a pivotal role in Wilms tumor development. Interestingly, Lin28, a direct target of miRNA let-7 and potent regulator of stem cell self-renewal and differentiation, is significantly elevated in some Wilms tumors, and enforced expression of Lin28 during kidney development could induce Wilms tumor. With the success in establishing mice nephroblastoma models through over-expressing IGF2 and deleting WT1, and advances in understanding the ENU-induced rat model, we are now able to explore the molecular and cellular mechanisms induced by these genetic, epigenetic, and miRNA alterations in animal models to understand the development of Wilms tumor. These animal models may also serve as valuable systems to assess new treatment targets and strategies for Wilms tumor.