Facile Synthesis of a Multifunctional Porous Organic Polymer Nanosonosensitizer (mHM@HMME) for Enhanced Cancer Sonodynamic Therapy.

Sonodynamic therapy (SDT), which involves the activation of sonosensitizers to generate cytotoxic reactive oxygen species under ultrasound irradiation, is a promising noninvasive modality for cancer treatment. However, the clinical translational application of SDT is impeded by the lack of efficient sonosensitizers, the inefficient accumulation of sonosensitizers at tumor sites, and the complicated immunosuppressive tumor microenvironment. Herein, we developed a facilely synthesized multifunctional porous organic polymer nanosonosensitizer (mHM@HMME) for enhanced SDT. Specifically, mHM@HMME nanosonosensitizers were prepared by incorporating chemotherapeutic mitoxantrone into the one-step synthesis process of disulfide bond containing porous organic polymers, followed by loading with organic sonosensitizer (HMME) and camouflaging with a cancer cell membrane. Due to the cancer cell membrane camouflage, this multifunctional mHM@HMME nanosonosensitizer showed prolonged blood circulation and tumor targeting aggregation. Under ultrasound irradiation, the mHM@HMME nanosonosensitizer exhibited a satisfactory SDT performance both in vitro and in vivo. Moreover, the potent SDT combined with glutathione-responsive drug release in tumor cells induced robust immunogenic cell death to enhance the antitumor effect of SDT in turn. Overall, this facilely synthesized multifunctional mHM@HMME nanosonosensitizer shows great potential application in enhanced SDT.

Construction of BaTiO3-TiO2 hollow sphere heterojunctions for enhanced microwave dynamic therapy in cancer treatment.

Cancer is one of the primary health concerns among humans due to its high incidence rate and lack of effective treatment. Currently, medical techniques to achieve the precise elimination of local cancer lesions with negligible damage to normal tissues are still intensely desired. Herein, we synthesized BaTiO3-TiO2 hollow spheres (BTHSs) for use in microwave dynamic therapy (MWDT) for cancer. Under UV irradiation, BTHSs can mediate the production of multiple reactive oxygen species (ROS), mainly 1O2, which results in a rapid photocatalytic degradation rate (97%), 1.6-fold that of commercial P25. Importantly, the ROS production process can be triggered by microwaves to effectively execute MWDT for cancer. Under microwave irradiation, BTHSs exhibit a remarkable therapeutic effect and slight cytotoxicity. In terms of mechanism, the enhanced ROS production efficiency of BTHSs can be attributed to their unique hollow structure and the formation of a type-II heterojunction by the incorporation of BaTiO3. The hollow structure increases the availability of active sites and enhances light scattering, while the BaTiO3-TiO2 heterojunction enhances the photocatalytic activity of TiO2 through charge transfer and electron-hole separation. Overall, this study provides important insights into the design and optimization of sensitizers for MWDT applications.

A novel combined therapeutic strategy of Nano-EN-IR@Lip mediated photothermal therapy and stem cell inhibition for gastric cancer.

Recurrence and metastasis of gastric cancer is a major therapeutic challenge for treatment. The presence of cancer stem cells (CSCs) is a major obstacle to the success of current cancer therapy, often leading to treatment resistance and tumor recurrence and metastasis. Therefore, it is important to develop effective strategies to eradicate CSCs. In this study, we developed a combined therapeutic strategy of photothermal therapy (PTT) and gastric cancer stem cells (GCSCs) inhibition by successfully synthesizing nanoliposomes loaded with IR780 (photosensitizer) and EN4 (c-Myc inhibitor). The nanocomposites are biocompatible and exhibit superior photoacoustic (PA) imaging properties. Under laser irradiation, IR780-mediated PTT effectively and rapidly killed tumor cells, while EN4 synergistically inhibited the self-renewal and stemness of GCSCs by suppressing the expression and activity of the pluripotent transcription factor c-Myc, preventing the tumor progression of gastric cancer. This Nano-EN-IR@Lip is expected to be a novel clinical nanomedicine for the integration of gastric cancer diagnosis, treatment and prevention.

Assessment of human exposure to cadmium and its nephrotoxicity in the Chinese population.

BACKGROUND: Cadmium (Cd) is a toxic heavy metal that widely detected in environment and accumulated in kidney, posing a great threat to human health. However, there is a lack of systematic investigation of exposure profile and association of Cd exposure with renal function in the Chinese population. METHODS: Related articles were searched from PubMed, Web of Science, China National Knowledge Internet, and Wanfang to construct an aggregate exposure pathway (AEP) framework for Cd and to explore the correlation between Cd and renal function using random effects models. RESULTS: A total of 220 articles were included in this study, among which 215 investigated human exposure and 12 investigated the association of Cd with renal outcomes. The AEP framework showed that 96.5 % and 62.5 % of total Cd intake were attributed to dietary intake in nonsmokers and smokers, respectively. And 35.2 % originated from cigarette smoke inhalation in smokers. In human body, Cd was detected in blood, urine, placenta, etc. Although the concentrations of Cd in blood and urine from subjects living in polluted areas showed a sharp downward trend since the early 21st century, higher concentration of Cd in the environment and human body in polluted areas was found. Kidney was the target organ. The level of blood Cd was positively associated with urinary ß2-microglobulin [ß2-MG, r (95 % CI) = 0.12 (0.05, 0.19)], albumin [0.13 (0.06, 0.20)], and retinol-binding protein [RBP, 0.14 (0.03, 0.24)]. Elevated urinary Cd was correlated with increases in ß2-MG [0.22 (0.15, 0.29)], albumin [0.23 (0.16, 0.29)], N-acetyl-ß-d-glucosaminidase [NAG, 0.33 (0.22, 0.44)], and RBP [0.22 (0.14, 0.30)]. CONCLUSIONS: Foods and cigarette smoke were two major ways for Cd intake, and Cd induced renal injury in the Chinese population. This study enhanced the understanding of human exposure and nephrotoxicity of Cd, and emphasized the need for controlling Cd level in polluted areas.

Conditioned medium from human dental pulp stem cells treats spinal cord injury by inhibiting microglial pyroptosis.

Human dental pulp stem cell transplantation has been shown to be an effective therapeutic strategy for spinal cord injury. However, whether the human dental pulp stem cell secretome can contribute to functional recovery after spinal cord injury remains unclear. In the present study, we established a rat model of spinal cord injury based on impact injury from a dropped weight and then intraperitoneally injected the rats with conditioned medium from human dental pulp stem cells. We found that the conditioned medium effectively promoted the recovery of sensory and motor functions in rats with spinal cord injury, decreased expression of the microglial pyroptosis markers NLRP3, GSDMD, caspase-1, and interleukin-1ß, promoted axonal and myelin regeneration, and inhibited the formation of glial scars. In addition, in a lipopolysaccharide-induced BV2 microglia model, conditioned medium from human dental pulp stem cells protected cells from pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1ß pathway. These results indicate that conditioned medium from human dental pulp stem cells can reduce microglial pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1ß pathway, thereby promoting the recovery of neurological function after spinal cord injury. Therefore, conditioned medium from human dental pulp stem cells may become an alternative therapy for spinal cord injury.

Biomedical Application of Porphyrin-Based Amphiphiles and Their Self-Assembled Nanomaterials.

Porphyrins have been vastly explored and applied in many cutting-edge fields with plenty of encouraging achievements because of their excellent properties. As important derivatives of porphyrins, porphyrin-based amphiphiles (PBAs) not only maintain the advanced properties of porphyrins (catalysis, imaging, and energy transfer) but also possess self-assembly and encapsulation capability in aqueous solution. Accordingly, PBAs and their self-assembles have had important roles in diagnosing and treating tumors and inflammation lesions in vivo, but not limited to these. In this article, we introduce the research progress of PBAs, including their constitution, structure design strategies, and performances in tumor and inflammation lesion diagnosis and treatments. On that basis, the defects of synthesized PBAs during their application and the possible effective strategies to overcome the limitations are also proposed. Finally, perspectives on PBAs exploration are updated based on our knowledge. We hope this review will bring researchers from various domains insights about PBAs.

Engineering Diselenide-IR780 Homodimeric Nanoassemblies with Enhanced Photodynamic and Immunotherapeutic Effects for Triple-Negative Breast Cancer Treatment.

Photodynamic therapy (PDT) has emerged as an efficient approach for non-invasive cancer treatment. However, organic small-molecule photosensitizers are often associated with defects in hydrophobicity, poor photostability, and aggregation-caused quenching, which limit their application. Usually, the carrier-assisted drug delivery system is a common strategy to solve the above obstacles, but additional carrier material could increase the risk of potential biological toxicity. The carrier-free drug delivery system with easy preparation and high drug-loading capability is proposed subsequently as a potential strategy to develop the clinical use of hydrophobic drugs. Herein, we rationally designed three IR780-based carrier-free nanosystems formed by carbon/disulfide/diselenide bond conjugated IR780-based homodimers. The IR780-based homodimers could self-assemble to form nanoparticles (DC-NP, DS-NP, DSe-NP) and exhibited higher reactive oxygen species generation capability and photostability than free IR780, in which DSe-NP with 808 nm laser irradiation performed best and resulted in the strongest cytotoxicity to 4T1 cells. Meanwhile, the glutathione consumption ability of DSe-NP boosted its PDT effect and then induced excessive oxidative stress of 4T1 cells, increasing antitumor efficacy by enhancing immunogenic cell death further. In tumor-bearing mice, DSe-NP displayed obvious tumor site accumulation, which obviously inhibited tumor growth and metastasis, and enhanced the immunological effect by effectively inducing dendritic cells to mature and activating T lymphocytes and natural killer cells. In summary, our study presented an IR780-based carrier-free nanodelivery system for a combination of PDT and immunity therapy and established expanding the application of organic small-molecule photosensitizers by an approach of carrier-free drug delivery system.

Polydatin protects against calcium oxalate crystal-induced renal injury through the cytoplasmic/mitochondrial reactive oxygen species-NLRP3 inflammasome pathway.

BACKGROUND: Oxidative stress and inflammatory responses are critical factors in calcium oxalate (CaOx) crystal-induced renal injury. Reactive oxygen species (ROS) are usually produced in the cytoplasm and mitochondria and trigger the priming and activation of the NLRP3 inflammasome, thereby regulating cytokines and inflammation. Polydatin is a plant rhizome extract with anti-inflammatory, antioxidant, and antitumor effects. However, it remains not clear whether and how these pathophysiological processes exists in CaOx crystal-induced renal inflammatory injury. METHODS: Here, we measured the expression of the NLRP3 inflammasome, IL-18, IL-1ß, intracellular and mitochondrial ROS (mtROS) levels and relevant morphological changes in treated renal tubular epithelial cells (TECs) and stone-forming rats. The study further explored the action of intracellular ROS and mtROS on these inflammatory damage, and the beneficial effects and pathway of polydatin. RESULTS: We verified that CaOx crystal-induced cytoplasmic ROS and mtROS upregulation promoted the priming and activation of the NLRP3 inflammasome, thereby stimulating IL-18/1ß maturation and activation. Polydatin can relieve oxidative stress and inflammatory damage by decreasing ROS. We further demonstrated that mtROS is the main target for polydatin to exert the NLRP3 inflammasome-regulating function. The inhibition of mtROS can effectively relieve the inflammatory damage to TECs and kidney caused by CaOx crystal. CONCLUSION: These findings provide new insight into the relationship between mitochondrial damage and inflammation in nephrolithiasis and show that polydatin-mediated anti-inflammatory and antioxidative protection is a therapeutic strategy for, but not limited to, crystalline nephropathy.

Exosomal miR-105-5p derived from bladder cancer stem cells targets for GPR12 to promote the malignancy of bladder cancer.

Bladder cancer stem cells (BCSCs) are considered as the root cause of BC initiation and recurrence, and exosomes derived from BCSCs (CSCs-exo) are the vital tool for establishing a stable tumor microenvironment. miR-105-5p has been revealed to promote tumor growth in a variety of cancers, but the effects on BC are still not included.Characteristics of CSCs-exo were examined by transmission electron microscope and nanoparticle tracking analysis. PKH67 dye was used to observe the cellular uptake of exosomes. Cell viability, migration and invasion were detected by CCK-8, wound healing and transwell invasion assays, respectively. The interaction between miR-105-5p and GPR12 was verified by luciferase activity assay. Xenografts were induced in the nude mice, and H&E staining method was applied to analyze the histological changes of xenografts. CSCs-exo efficiently promoted BC cell viability, migration and invasion. miR-105-5p was highly expressed in CSCs and CSCs-exo treatment significantly upregulated the expression of miR-105-5p in BC cells.GPR12 was subsequently verified to be the target gene of miR-105-5p, and overexpression of GPR12 abrogated the effects of miR-105-5p on BC cell growth and metastasis. Reversely, the anti-tumor function of miR-105-5p antagomir was observed in the xenograft mice.CSCs aggravated the malignancy of BC partly through transmitting exosomal miR-105-5p to BC cells to inhibit the expression of GPR12, which developed a novel aspect for CSC-targeted therapies.

A high proportion of caseous necrosis, abscess, and granulation tissue formation in spinal tuberculosis.

The special blood circulation, anatomy, and tissue structure of the spine may lead to significant differences in pathological features and drug resistance between spinal tuberculosis and pulmonary tuberculosis. Here, we collected 168 spinal tuberculosis cases and 207 pulmonary tuberculosis cases, and compared their clinical and pathological features as well as drug resistance. From the anatomical location, the highest incidence was of lumbar tuberculosis, followed by thoracic tuberculosis. PET-CT scans showed increased FDG uptake in the diseased vertebrae, discernible peripheral soft tissue shadow, visible internal capsular shadow, and an abnormal increase in FDG uptake. MRI showed infectious lesions in the diseased vertebral body, formation of paravertebral and bilateral psoas muscle abscess, and edema of surrounding soft tissues. As with control tuberculosis, the typical pathological features of spinal tuberculosis were chronic granulomatous inflammation with caseous necrosis. The incidence of granulomas was not statistically different between the groups. However, the proportions of caseous necrosis, acute inflammation, abscess, exudation, and granulation tissue formation in the spinal tuberculosis group were all significantly increased relative to the control tuberculosis group. Compared to the control tuberculosis group, the incidences of resistance to rifampicin (RFP) + isoniazid (INH) + streptomycin (STR) and INH + ethambutol (EMB) were lower in the spinal tuberculosis group, while the incidences of resistance to RFP + INH + EMB and RFP + EMB were higher. Moreover, we also found some differences in drug-resistance gene mutations. In conclusion, there are noticeable differences between spinal Mycobacterium tuberculosis and pulmonary tuberculosis in pathological characteristics, drug resistance, and drug resistance gene mutations.

Multifunctional hybrid exosomes enhanced cancer chemo-immunotherapy by activating the STING pathway.

Due to the immunosuppressive tumor microenvironment (ITM) resulting from tumor-associated macrophages (TAMs) and regulatory T cells, immune checkpoint blockade and vaccine therapies often lead to an inadequate immune response. Recently, cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon gene (cGAS/STING)-mediated innate immunity has emerged as a promising cancer therapeutic, as STING pathway activation could promote dendritic cells (DCs) maturation and tumor-specific cytotoxic T lymphocyte (CTL) and natural killer (NK) cell infiltration. Herein, multifunctional hybrid exosomes for cGAS/STING activation are designed by fusing genetically engineered exosomes carrying CD47 derived from tumor cells with exosomes from M1 macrophages, which are further encapsulated with DNA-targeting agent (SN38) and STING-agonist (MnO2). The hybrid exosomes demonstrate great tumor-targeting capacity and prolong blood circulation time due to the surface decoration of CD47. At the tumor site, the hybrid exosomes induce TAMs polarization to the M1 phenotype and release SN38 to induce DNA damage and Mn2+ to stimulate cGAS/STING activation. Furthermore, the resulting multifunctional hybrid exosomes (SN/Mn@gHE) promote DCs maturation and facilitate CTL infiltration and NK cell recruitment to the tumor region, leading to significant anti-tumor and antimetastatic efficacy. Our study suggests a novel strategy to enhance cancer immunotherapy by activating the STING pathway and ameliorating ITM.

Reversible Iron Oxyfluoride (FeOF)-Graphene Composites as Sustainable Cathodes for High Energy Density Lithium Batteries.

Two large barriers are impeding the wide implementation of electric vehicles, namely driving-range and cost, primarily due to the low specific energy and high cost of mono-valence cathodes used in lithium-ion batteries. Iron is the ideal element for cathode materials considering its abundance, low cost and toxicity. However, the poor reversibility of (de)lithiation and low electronic conductivity prevent iron-based high specific energy multi-valence conversion cathodes from practical applications. In this work, a sustainable FeOF nanocomposite is developed with extraordinary performance. The specific capacity and energy reach 621 mAh g-1 and 1124 Wh kg-1 with more than 100 cycles, which triples the specific capacity, and doubles the specific energy of current mono-valence intercalation LiCoO2 . This is the result of an effective approach, combing the nanostructured FeOF with graphene, realized by making the (de)lithiation reversible by immobilizing FeOF nanoparticles and the discharge products over the graphene surface and providing the interparticle electric conduction. Importantly, it demonstrates that introducing small amount of graphene can create new materials with desired properties, opening a new avenue for altering the (de)lithiation process. Such extraordinary performance represents a significant breakthrough in developing sustainable conversion materials, eventually overcoming the driving range and cost barriers.

Polarization clustering of biological structures with Mueller matrix parameters.

Mueller matrix imaging polarimetry (MMIP) is a promising technique for the characterization of biological tissues, including the classification of microstructures in pathological diagnosis. To expand the parameter space of Mueller matrix parameters, we propose new vector parameters (VPs) according to the Mueller matrix polar decomposition method. We measure invasive bladder cancer (IBC) with extensive necrosis and high-grade ductal carcinoma in situ (DCIS) with MMIP, and the regions of cancer cells and fibrotic stroma are classified with the VPs. Then the proposed and existing VPs are mapped on the Poincaré sphere with 3D visualization, and an indicator of spatial feature is defined based on the minimum enclosing sphere to evaluate the classification capability of the VPs. For both IBC and DCIS, the results show that the proposed VPs exhibit evident contrast between the regions of cancer cells and fibrotic stroma. This study broadens the fundamental Mueller matrix parameters and helps to improve the characterization ability of the MMIP technique.

Exosomal miR-93-5p from cancer-associated fibroblasts confers malignant phenotypes on bladder cancer cells by targeting PAFAH1B1.

BACKGROUND: Dysregulation of cancer-associated fibroblasts (CAFs) still greatly challenges the treatments for bladder cancer (BC), where exosomal miRNAs derived from CAFs are one of the essential effectors for tumor progression. miR-93-5p is reported to be upregulated in BC, however, it is barely investigated in BC-derived CAFs. METHOD: The CAF markers were immunofluorescent-labeled and examined by western blotting assay in CAFs and normal fibroblasts (NFs). CAFs- and NFs-derived exosomes (CAFs-exo/NFs-exo) were authenticated by transmission electron microscope and nanoparticle tracking analysis. Cell viability was determined by cell counting kit-8 assay, and cell mobility was evaluated by wound healing and transwell assays. Real-time quantitative PCR was used to quantify the RNA expressions, and a western blotting assay was used for protein expression. Interaction between miR-93-5p and Platelet-Activating Factor Acetylhydrolase IB Subunit Beta (PAFAH1B1) was verified by luciferase reporter assay. HE staining assay was applied to assess the histological changes of xenografts. RESULTS: CAFs-exo notably enhanced cell mobility and the expression levels of miR-93-5p of BC cells compared to NFs-exo. However, inhibition of miR-93-5p in CAFs-exo exhibited attenuated pro-metastatic ability on BC cells. PAFAH1B1 was one of the predicted targets of miR-93-5p, whose mRNA level was most significantly downregulated after miR-93-5p transfection. The interaction between PAFAH1B1 and miR-93-5p was verified, and miR-93-5p negatively regulated the protein level of PAFAH1B1. Overexpression of PAFAH1B1 could efficiently reverse the effects of miR-93-5p mimic on BC cell mobility. Finally, inhibition of miR-93-5p was proved to impair the carcinogenic function of CAFs-exo in vivo . CONCLUSION: Exosomal miR-93-5p derived from CAFs confers oncogenicity on BC cells via sponging PAFAH1B1, suggesting a novel therapeutic strategy for BC.

Puerarin prevents calcium oxalate crystal-induced renal epithelial cell autophagy by activating the SIRT1-mediated signaling pathway.

Calcium oxalate (CaOx) crystals can activate autophagy, causing damage to renal tubular epithelial cells (TECs). Puerarin has been shown to have protective and therapeutic effects against a variety of diseases by inhibiting autophagy activation. However, the protective effect of puerarin against CaOx crystals and the underlying molecular mechanisms are unclear. Cell Counting Kit-8 (CCK-8) assays were used to evaluate the effects of puerarin on cell viability. Intracellular reactive oxygen species (ROS) levels were measured by the cell-permeable fluorogenic probe 2,7-dichlorofluorescein diacetate (DCFH-DA). Immunofluorescence, immunohistochemistry, and western blotting were used to examine the expression of SIRT1, Beclin1, p62, and LC3, and explore the underlying molecular mechanisms in vivo and in vitro. Puerarin treatment significantly attenuated CaOx crystal-induced autophagy of TECs and CaOx cytotoxicity to TECs by altering SIRT1 expression in vitro and in vivo, whereas the SIRT1-specific inhibitor EX527 exerted contrasting effects. In addition, we found that the protective effect of puerarin was related to the SIRT1/AKT/p38 signaling pathway. The findings suggest that puerarin regulates CaOx crystal-induced autophagy by activating the SIRT1-mediated signaling pathway, and they suggest a series of potential therapeutic targets and strategies for treating nephrolithiasis.

ROS-responsive liposomes as an inhaled drug delivery nanoplatform for idiopathic pulmonary fibrosis treatment via Nrf2 signaling.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease with pathophysiological characteristics of transforming growth factor-ß (TGF-ß), and reactive oxygen species (ROS)-induced excessive fibroblast-to-myofibroblast transition and extracellular matrix deposition. Macrophages are closely involved in the development of fibrosis. Nuclear factor erythroid 2 related factor 2 (Nrf2) is a key molecule regulating ROS and TGF-ß expression. Therefore, Nrf2 signaling modulation might be a promising therapy for fibrosis. The inhalation-based drug delivery can reduce systemic side effects and improve therapeutic effects, and is currently receiving increasing attention, but direct inhaled drugs are easily cleared and difficult to exert their efficacy. Therefore, we aimed to design a ROS-responsive liposome for the Nrf2 agonist dimethyl fumarate (DMF) delivery in the fibrotic lung. Moreover, we explored its therapeutic effect on pulmonary fibrosis and macrophage activation. RESULTS: We synthesized DMF-loaded ROS-responsive DSPE-TK-PEG@DMF liposomes (DTP@DMF NPs). DTP@DMF NPs had suitable size and negative zeta potential and excellent capability to rapidly release DMF in a high-ROS environment. We found that macrophage accumulation and polarization were closely related to fibrosis development, while DTP@DMF NPs could attenuate macrophage activity and fibrosis in mice. RAW264.7 and NIH-3T3 cells coculture revealed that DTP@DMF NPs could promote Nrf2 and downstream heme oxygenase-1 (HO-1) expression and suppress TGF-ß and ROS production in macrophages, thereby reducing fibroblast-to-myofibroblast transition and collagen production by NIH-3T3 cells. In vivo experiments confirmed the above findings. Compared with direct DMF instillation, DTP@DMF NPs treatment presented enhanced antifibrotic effect. DTP@DMF NPs also had a prolonged residence time in the lung as well as excellent biocompatibility. CONCLUSIONS: DTP@DMF NPs can reduce macrophage-mediated fibroblast-to-myofibroblast transition and extracellular matrix deposition to attenuate lung fibrosis by upregulating Nrf2 signaling. This ROS-responsive liposome is clinically promising as an ideal delivery system for inhaled drug delivery.

Genetic variants in choline metabolism pathway are associated with the risk of bladder cancer in the Chinese population.

Choline metabolism alteration is considered as a metabolic hallmark in cancer, reflecting the complex interactions between carcinogenic signaling pathways and cancer metabolism, but little is known about whether genetic variants in the metabolism pathway contribute to the susceptibility of bladder cancer. Herein, a case-control study comprising 580 patients and 1,101 controls was carried out to analyze the association of bladder cancer with genetic variants on candidate genes involved in the choline metabolism pathway using unconditional logistic regression. Gene expression data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were applied for differential gene expression analysis. Cox regression was also applied to estimate the role of candidate genes on bladder cancer prognosis. Our results demonstrated that C allele of rs6810830 in ENPP6 was a significant protective allele of bladder cancer, compared to the T allele [Odds ratio (OR) = 0.74, 95% confidence interval (CI) = 0.64-0.86, P = 7.14 × 10-5 in additive model]. Besides, we also found that the expression of ENPP6 remarkably decreased in bladder tumors compared with normal tissues. Moreover, high expression of ENPP6 was associated with worse overall survival (OS) in bladder cancer patients [hazard ratio (HR) with their 95% CI 1.39 (1.02-1.90), P = 0.039]. In conclusion, our results suggested that SNP rs6810830 (T > C) in ENPP6 might be a potential susceptibility loci for bladder cancer, and these findings provided novel insights into the underlying mechanism of choline metabolism in cancers.

Multiple stimuli-responsive nanosystem for potent, ROS-amplifying, chemo-sonodynamic antitumor therapy.

Although sonodynamic therapy (SDT) is a promising non-invasive tumor treatment strategy due to its safety, tissue penetration depth and low cost, the hypoxic tumor microenvironment limits its therapeutic effects. Herein, we have designed and developed an oxygen-independent, ROS-amplifying chemo-sonodynamic antitumor therapy based on novel pH/GSH/ROS triple-responsive PEG-PPMDT nanoparticles. The formulated artemether (ART)/Fe3O4-loaded PEG-PPMDT NPs can rapidly release drug under the synergistic effect of acidic endoplasmic pH and high intracellular GSH/ROS levels to inhibit cancer cell growth. Besides, the ROS level in the NPs-treated tumor cells is magnified by ART via interactions with both Fe2+ ions formed in situ at acidic pH and external ultrasound irradiation, which is not affected by hypoxia tumor microenvironment. Consequently, the enriched intracellular ROS level can cause direct necrosis of ROS-stressed tumor cells and further accelerate the drug release from the ROS-responsive PEG-PPMDT NPs, achieving an incredible antitumor potency. Specifically, upon the chemo-sonodynamic therapy by ART/Fe3O4-loaded PEG-PPMDT NPs, all xenotransplants of human hepatocellular carcinoma (HepG2) in nude mice shrank significantly, and 40% of the tumors were completely eliminated. Importantly, the Fe3O4 encapsulated in the NPs is an efficient MRI contrast agent and can be used to guide the therapeutic procedures. Further, biosafety analyses show that the PEG-PPMDT NPs possess minimal toxicity to main organs. Thus, our combined chemo-sonodynamic therapeutic method is promising for potent antitumor treatment by controlled release of drug and facile exogenous generation of abundant ROS at target tumor sites.

Long non-coding RNA (lncRNA) CYTOR promotes hepatocellular carcinoma proliferation by targeting the microRNA-125a-5p/LASP1 axis.

This study investigated the function of long non-coding RNA (lncRNA) cytoskeleton regulator RNA (CYTOR) in hepatocellular carcinoma (HCC). In HCC, the expression of CYTOR and microRNA (miR)-125a-5p were measured by quantitative real-time PCR (qRT-PCR). The expression of actin skeletal protein 1 (LASP1) was evaluated by Western blot analysis. Flow cytometry assays, transwell assays, colony formation assay, and cell counting kit-8 (CCK-8) assay were used to evaluate the roles of miR-125a-5p and CYTOR in HCC cells. The target genes of CYTOR and miR-125a-5p were identified by bioinformatics analysis and Luciferase assay. CYTOR was upregulated in HCC cell lines, and knockdown of CYTOR inhibited HCC cell growth. MiR-125a-5p was downregulated in HCC cells and a target of CYTOR in regulating HCC progression. Furthermore, LASP1 was a downstream target of miR-125a-5p. Finally, CYTOR was found to be involved in HCC progression in vivo. CYTOR promotes HCC development by regulating the miR-125a-5p/LASP1 axis.

Cyclovirobuxine inhibits the progression of clear cell renal cell carcinoma by suppressing the IGFBP3-AKT/STAT3/MAPK-Snail signalling pathway.

Of all pathological types of renal cell cancer (RCC), clear cell renal cell carcinoma (ccRCC) has the highest incidence. Cyclovirobuxine (CVB), a triterpenoid alkaloid isolated from Buxus microphylla, exhibits antitumour activity against gastric cancer and breast cancer; however, the mechanism by which CVB inhibits ccRCC remains unclear. The aim of our study was to explore the antitumour effects of CVB on ccRCC and to elucidate its exact mechanism. Cell viability, proliferation, cell cycle distribution, apoptosis, wound healing and invasion were evaluated. Furthermore, Western blotting, immunofluorescence staining, immunohistochemical staining, and bioinformatics analyses were utilized to comprehensively probe the molecular mechanisms. The in vivo curative effect of CVB was explored using a 786-O xenograft model established in nude mice. CVB reduced cell viability, proliferation, angiogenesis, the epithelial-mesenchymal transition (EMT), migration and invasion. In addition, CVB induced cell cycle arrest in S phase and promoted apoptosis. The expression of the EMT-related transcription factor Snail was significantly downregulated by CVB via the inhibition of the AKT, STAT3 and MAPK pathways. We revealed that insulin-like growth factor binding protein 3 (IGFBP3) was the true therapeutic target of CVB. CVB exerted anti-ccRCC effects by blocking the IGFBP3-AKT/STAT3/MAPK-Snail pathway. Targeted inhibition of IGFBP3 with CVB treatment may become a promising therapeutic regimen for ccRCC.