BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses.

Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases.

Celastrol induces lipophagy via the LXRα/ABCA1 pathway in clear cell renal cell carcinoma.

Celastrol is a triterpene derived from the traditional Chinese medicine Tripterygium wilfordii Hook f, which displays potential anticancer activity. In the present study, we investigated the anticancer effects of celastrol against clear cell renal cell carcinoma (ccRCC) and the underlying mechanisms. Using Cancer Genome Atlas (TCGA) database and genotype-tissue expression (GTEx) database we conducted a bioinformatics analysis, which showed that the mRNA levels of liver-X receptors α (LXRα) and ATP-binding cassette transporter A1 (ABCA1) in ccRCC tissues were significantly lower than those in adjacent normal tissues. This result was confirmed by immunoblotting analysis of 4 ccRCC clinical specimens, which showed that the protein expression of LXRα and ABCA1 was downregulated. Similar results were obtained in a panel of ccRCC cell lines (786-O, A498, SN12C, and OS-RC-2). In 786-O and SN12C cells, treatment with celastrol (0.25-2.0 µM) concentration-dependently inhibited the cell proliferation, migration, and invasion as well as the epithelial-mesenchymal transition (EMT) process. Furthermore, we demonstrated that celastrol inhibited the invasion of 786-O cells through reducing lipid accumulation; celastrol concentration-dependently promoted autophagy to reduce lipid storage. Moreover, we revealed that celastrol dramatically activated LXRα signaling, and degraded lipid droplets by inducing lipophagy in 786-O cells. Finally, celastrol promoted cholesterol efflux from 786-O cells via ABCA1. In high-fat diet-promoted ccRCC cell line 786-O xenograft model, administration of celastrol (0.25, 0.5, 1.0 mg·kg-1·d-1, for 4 weeks, i.p.) dose-dependently inhibited the tumor growth with upregulated LXRα and ABCA1 protein in tumor tissue. In conclusion, this study reveals that celastrol triggers lipophagy in ccRCC by activating LXRα, promotes ABCA1-mediated cholesterol efflux, suppresses EMT progress, and ultimately inhibits cell proliferation, migration, and invasion as well as tumor growth. Thus, our study provides evidence that celastrol can be used as a lipid metabolism-based anticancer therapeutic approach.

Friend or foe: Multiple roles of adipose tissue in cancer formation and progression.

Obesity is well-known as the second factor for tumorigenesis after smoking and is bound up with the malignant progression of several kinds of cancers, including esophageal cancer, liver cancer, colorectal cancer, kidney cancer, and ovarian cancer. The increased morbidity and mortality of obesity-related cancer are mostly attributed to dysfunctional adipose tissue. The possible mechanisms connecting dysfunctional adipose tissue to high cancer risk mainly focus on chronic inflammation, obesity-related microenvironment, adipokine secretion disorder, and browning of adipose tissue, and so forth. The stromal vascular cells in adipose tissue trigger chronic inflammation through secreting inflammatory factors and promote cancer cell proliferation. Hypertrophic adipose tissues lead to metabolic disorders of adipocytes, such as abnormal levels of adipokines that mediate cancer progression and metastasis. Cancer patients often show adipose tissue browning and cancerous cachexia in an advanced stage, which lead to unsatisfied chemotherapy effect and poor prognosis. However, increasing evidence has shown that adipose tissue may display quite opposite effects in cancer development. Therefore, the interaction between cancers and adipose tissue exert a vital role in mediates adipose tissue dysfunction and further leads to cancer progression. In conclusion, targeting the dysfunction of adipose tissue provides a promising strategy for cancer prevention and therapy.

Effect of cisplatin-based neoadjuvant chemotherapy on survival in patients with bladder cancer: a meta-analysis.

PURPOSE: Cisplatin-based neoadjuvant chemotherapy (NAC) has been shown to improve survival in patients with muscle-invasive bladder cancer (MIBC) who underwent radical cystectomy as compared with patients who underwent surgery alone. It has also been suggested as current standard of care in surgically-fit patients with MIBC. This meta-analysis assessed the effect of cisplatin-based NAC on survival in patients with bladder cancer. SOURCE: PubMed, CENTRAL, and Embase were searched until November 22, 2016. Two-arm randomized controlled trials that compared cisplatin-based neoadjuvant chemotherapy plus local treatment versus the same local treatment without neoadjuvant chemotherapy were selected. Patients with histologically-confirmed bladder cancer (adenocarcinoma, transitional, or squamous-cell carcinoma) were included. The primary outcome was overall survival (OS). PRINCIPAL FINDINGS: Of the 292 articles initially identified, 14 were included in the final analysis. Patients in the NAC group had similar OS as the local treatment (i.e., radiation therapy or cystectomy) group (pooled hazard ratio [HR] = 0.92, 95% confidence interval [CI]: 0.84 to 1.00, P=0.056). No difference in progress-free survival between two groups was observed (P=0.725). Subgroup analysis showed that OS was similar in patients treated with NAC plus radiotherapy or cystectomy compared with patients who received local treatment alone. CONCLUSIONS: Platinum-based NAC was associated with similar survival benefit as patients undergoing cystectomy and/or radiotherapy. No conclusion can be drawn about the optimal platinum-based combination to be used in the neoadjuvant setting.

[Crosstalk between Wnt5a and inflammatory signaling in inflammation].

Wnt5a belongs to the large WNT family of cysteine-rich secreted glycoproteins, which is involved in multiple signaling pathways that regulate a variety of cellular processes, including cell motility, proliferation differentiation and so on during development. The regulation and signaling transduction of Wnt5a have been reported to closely relate to inflammatory response, which indicates that Wnt5a plays a critical role in the occurrence and development of inflammatory diseases. In this review, we summarized data on Wnt5a and its signaling pathway, as well as their involvement in inflammatory response. Further comprehensive understanding of the function and relationship between Wnt5a and inflammatory response would help us to develop novel diagnostic and therapeutic strategies for prevention and treatment of inflammatory diseases.

Celastrol Attenuates Lipid Accumulation and Stemness of Clear Cell Renal Cell Carcinoma via CAV-1/LOX-1 Pathway.

Clear cell renal cell carcinoma (ccRCC) is characterized by abnormal lipid accumulation. Celastrol is a pentacyclic triterpene extracted from Tripterygium wilfordii Hook F with anti-cancer activity. In the present study, the anticancer effects of celastrol on ccRCC and the underlying mechanisms were studied. Patients with reduced high density lipoprotein (HDL) and elevated levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL) was found to have higher risk of ccRCC. In ccRCC clinical samples and cell lines, caveolin-1 (CAV-1) was highly expressed. CAV-1 was identified as a potential prognostic biomarker for ccRCC. Celastrol inhibited tumor growth and decreased lipid deposition promoted by high-fat diet in vivo. Celastrol reduced lipid accumulation and caveolae abundance, inhibited the binding of CAV-1 and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in ccRCC cells. Furthermore, celastrol attenuated stemness through blocking Wnt/ß-catenin pathway after knockdown of CAV-1 and LOX-1. Therefore, the findings suggest that celastrol may be a promising active ingredient from traditional Chinese medicine for anti-cancer therapy.

[Effect of Phosphorus Addition on N2O Emissions from Rice-Rapeseed Rotation Soils].

The red soils in southern China are generally classified as phosphorus-deficient, and therefore planting crops in these regions usually requires high applications of phosphate fertilizer. However, the effect of phosphorus addition on N2O emissions in rice-rapeseed rotation soils is not clear. We carried out an incubation experiment with the rice-rapeseed rotation soil from Qianjiang and Xianning to explore the effect of different concentrations of phosphorus (0, 15, and 30 mg·kg-1) and different concentrations of nitrogen (0 and 100 mg·kg-1) on N2O emission. Studies have shown that the addition of phosphorus has a significant effect on soil N2O emissions, but the pathways of impact are varied:in the case of low nitrogen soil, the addition of phosphorus promotes the fixation of nitrogen in the soil by microorganisms and thus reduces N2O emissions; in case of sufficient nitrogen content in soil, adding less phosphorus promotes the activity of nitrifies and thereby promotes the emission of N2O, while adding more phosphorus also promotes fixation by microorganisms in the soil; when there is a high content of available phosphorus in the soil, whether the nitrogen is sufficient or not, the addition of phosphorus will inhibit the emission of N2O.

[Monitoring of graft flow with color Doppler in simultaneous pancreas-kidney transplant recipients].

OBJECTIVE: To evaluate the clinical value of color Doppler in monitoring graft flow in patients who underwent simultaneous pancreas-kidney (SPK) transplantation. METHODS: Totally 18 patients received color Doppler ultrasonography on day 1, 3, and 7 after SPK. Volumes and arteriovenous velocities of the kidney and pancreas grafts were recorded, and resistance index (RI) was calculated. RESULTS: Color Doppler ultrasound clearly displayed the modality, size, and flow of the kidney and pancreas grafts. Compared with the single kidney grafts, the modality, volume, and arteriovenous velocity of kidney grafts in SPK was not significantly different. Although the volume of pancreas graft was remarkably larger than the normal control pancreas early after transplantation, no difference in artery velocity was found between pancreas graft and normal pancreas. The spectrum of the portal vein in pancreas grafts showed the typical spectrum of iliac veins. CONCLUSION: Color Doppler ultrasound is sensitive in monitoring the graft flow of SPK recipients and can be used to identify postoperative vascular complications and evaluate tissue perfusion.

Serum miR-130b level, an ideal marker for monitoring the recurrence and prognosis of primary hepatocellular carcinoma after radiofrequency ablation treatment.

OBJECTIVE: This study was aimed to explore the potential roles of miR-130b for the efficacy of radiofrequency ablation (RFA) in patients with primary hepatocellular carcinoma (PHC). METHODS: The serum sample of 110 PHC patients, which underwent RFA treatment, was collected on 1d pre-operation (Pre 1), 7d (POD 7) and 14d post-operation (POD 14). qRT-PCR was used to detect miR-130b expression. The relationship between miR-130b expression and clinicopathological features, postoperative recurrence and survival rate were analyzed. RESULTS: The liver function of PHC patients was improved after RFA treatment. The level of alpha fetoprotein (AFP) was gradually reduced on POD 7 and POD 14 (all P < 0.05). Before RFA, the expression of miR-130b in PHC patients was upregulated, while the expression of miR-130b decreased significantly with time after RFA treatment. And high expression of miR-130b was closely related to cirrhosis (P = 0.027) and tumor differentiation degree (P < 0.01). Serum miR-130b levels were significantly higher in patients with recurrence than in patients without recurrence (P < 0.05). Patients were divided into two groups according to miR-130b expression level (median ΔCt), compared with low ΔCt group, the incidence of recurrence in high ΔCt group was significantly higher after RFA (P = 0.020). Kaplan-Meier survival analysis showed that the survival rate of high ΔCt group was significantly shorter than that of low ΔCt group (P < 0.001). CONCLUSION: Our study provided evidence that serum miR-130b level may be used as an ideal marker for monitoring the recurrence and prognosis of PHC after RFA treatment.

Myostatin knockout induces apoptosis in human cervical cancer cells via elevated reactive oxygen species generation.

Myostatin (Mstn) is postulated to be a key determinant of muscle loss and cachexia in cancer. However, no experimental evidence supports a role for Mstn in cancer, particularly in regulating the survival and growth of cancer cells. In this study, we showed that the expression of Mstn was significantly increased in different tumor tissues and human cancer cells. Mstn knockdown inhibited the proliferation of cancer cells. A knockout (KO) of Mstn created by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) 9 (CRISPR/Cas9) induced mitochondria-dependent apoptosis in HeLa cells. Furthermore, KO of Mstn reduced the lipid content. Molecular analyses demonstrated that the expression levels of fatty acid oxidation-related genes were upregulated and then increased rate of fatty acid oxidation. Mstn deficiency-induced apoptosis took place along with generation of reactive oxygen species (ROS) and elevated fatty acid oxidation, which may play a role in triggering mitochondrial membrane depolarization, the release of cytochrome c (Cyt-c), and caspase activation. Importantly, apoptosis induced by Mstn KO was partially rescued by antioxidants and etomoxir, thereby suggesting that the increased level of ROS was functionally involved in mediating apoptosis. Overall, our findings demonstrate a novel function of Mstn in regulating mitochondrial metabolism and apoptosis within cancer cells. Hence, inhibiting the production and function of Mstn may be an effective therapeutic intervention during cancer progression and muscle loss in cachexia.

Wnt5a and its signaling pathway in angiogenesis.

Wnt5a, a secreted glycoprotein, belongs to the noncanonical Wnt family involved in a wide range of organism development and tissue homeostasis. Wnt5a and its signaling pathway can regulate fundamental cellular processes, including specification of cell fate, proliferation, and survival. Accumulating evidence indicates that Wnt5a exhibits dual effects on angiogenesis. The formation of new blood vessels derives from pre-existing vessels via canonical and non-canonical Wnt pathways, depending on cell types, receptors, downstream effectors, and microenvironment. Given that the regulation of angiogenesis has been implicated in many diseases, such as cancer, neovascular eye diseases, and cardiovascular diseases, these findings suggest that Wnt5a may be a potential target for the treatment of angiogenesis-related diseases.

Relationships between humic substance-bound mercury contents and soil properties in subtropical zone.

The bioavailability of humic substance-bound mercury (HS-Hg) has been established, while the distribution of HS-Hg in soils in relation to soil properties remains obscure. Path analysis and principal component analysis were employed in present study to investigate how soil factors influence the contents of HS-Hg in soils. Results showed that HS-Hg ranged from 0.0192 to 0.2051 mg/kg in soils. The two fractions existed in soils as humic acid-bound mercury (HA-Hg) > fulvic acid-bound mercury (FA-Hg) and the ratio of HA-Hg/FA-Hg was 1.61 on the average. Soil organic carbon (OC) and HS favorably determined soil HS-Hg and the two fractions. The mercury source forming HS-Hg derived from soil total mercury and HS-Hg. FA-Hg and HA-Hg served as mercury source for each other. In acidic soils, FA-Hg and HA-Hg consistently rose with the increase of OC, and generally HA-Hg increased more dramatically. Soils with lower pH and lighter texture contained more HS-Hg, particularly fraction of FA-Hg. Among all influencing factors, organic material source showed the strongest effect, followed by other soil properties and soil mercury source.

Steroid receptor RNA activator: Biologic function and role in disease.

Steroid receptor RNA activator (SRA) is a type of long noncoding RNA (lncRNA) which coordinates the functions of various transcription factors, enhances steroid receptor-dependent gene expression, and also serves as a distinct scaffold. The novel, profound and expanded roles of SRA are emerging in critical aspects of coactivation of nuclear receptors (NRs). As a nuclear receptor coactivator, SRA can coactivate androgen receptor (AR), estrogen receptor α (ERα), ERß, progesterone receptor (PR), glucocorticoid receptor (GR), thyroid hormone receptor and retinoic acid receptor (RAR). Although SRA is one of the least well-understood molecules, increasing studies have revealed that SRA plays a key role in both biological processes, such as myogenesis and steroidogenesis, and pathological changes, including obesity, cardiomyopathy, and tumorigenesis. Furthermore, the SRA-related signaling pathways, such as the mitogen-activated protein kinase (p38 MAPK), Notch and tumor necrosis factor α (TNFα) pathways, play critical roles in the pathogenesis of estrogen-dependent breast cancers. In addition, the most recent data demonstrates that SRA expression may serve as a new prognostic marker in patients with ER-positive breast cancer. Thus, elucidating the molecular mechanisms underlying SRA-mediated functions is important to develop proper novel strategies to target SRA in the diagnosis and treatment of human diseases.

Assessment of heavy metal pollution in surface soils of urban parks in Beijing, China.

Assessing the concentration of potentially harmful heavy metals in the soil of urban parks is imperative in order to evaluate the potential risks to residents and tourists. To date, little research on soil pollution in China's urban parks has been conducted. To identify the concentrations and sources of heavy metals, and to assess the soil environmental quality, samples were collected from 30 urban parks located in the city of Beijing. Subsequently, the concentrations of Cu, Ni, Pb and Zn in the samples were analyzed. The investigation revealed that the accumulations of Cu and Pb were readily apparent in the soils. The integrated pollution index (IPI) of these four metals ranged from 0.97 to 9.21, with the highest IPI in the densely populated historic center district (HCD). Using multivariate statistic approaches (principal components analysis and hierarchical cluster analysis), two factors controlling the heavy metal variability were obtained, which accounted for nearly 80% of the total variance. Nickel and Zn levels were controlled by parent material in the soils, whereas Cu, Pb and, in part, Zn were accounted for mainly by anthropogenic activities. The findings presented here indicate that the location and the age of the park are important factors in determining the extent of heavy metal, particularly Cu and Pb, pollution. In addition, the accumulation of Zn did not appear to reach pollution levels, and no obvious pollution by Ni was observed in the soils of the parks in Beijing.

Rare incidence of primary adrenocortical carcinosarcoma: A case report and literature review.

Adrenocortical carcinoma (ACC) is a rare, but highly aggressive type of tumor with an incidence of one to two per million annually. Adrenocortical carcinosarcoma is an exceptional variant of ACC, which is characterized by the presence of histological regions of carcinoma and sarcoma. To date, to the best of our knowledge, there have only been 12 reported cases of adrenocortical carcinosarcoma. In the present study, a case of primary, non-functional adrenocortical carcinosarcoma is described, as well as a review of the literature to raise awareness of this particularly rare type of malignant neoplasm that is associated with a worse diagnosis and prognosis than adrenocortical carcinoma. In the present study, the patient underwent a laparoscopic left adrenalectomy and the tumor was dissected without complication from the left kidney. Microscopic observations showed the tumor comprised of epithelial and spindle cell components. The patient did not exhibit signs of tumor recurrence at the one-month follow-up. The potential diagnosis of adrenocortical carcinosarcoma must be considered when diagnosing adrenal malignancies in adults. In addition, comphrensive imunohistochemical staining may be required to identify possible sarcomatous patterns. To the best of our knowledge, the present case is the first to report an incidence of adrenocortical carcinosarcoma in China. Details of the patient are presented and the pathology of adrenocortical carcinosarcoma is discussed.

[Intra-arterial thrombolysis for the treatment of restricted cochlear microcirculation disorder in guinea pigs].

OBJECTIVE: To ascertain a new treatment method for restricted cochlear microcirculation disorder. METHODS: Photochemical reaction was utilized to induce localized microcirculation damage to the second cochlear turn of every guinea pig. The animals were divided into 5 groups. Group 1 was blank control. Group 2 and Group 3 were injected urokinase (UK) through left subclavian artery or left external jugular vein 30 minutes after photochemical reaction. Group 4 and Group 5 were two control groups. Instead of urokinase, saline injection was applied accordingly. RESULTS: Both intra-arterial thrombolysis and intravenous thrombolysis were effective to improve the hearing levels and the blood supply to the inner ear. 50 minutes after urokinase injection, animals with intra-arterial thrombolysis showed a lower action potential threshold than that with intravenous thrombolysis (P = 0.025). And this phenomenon lasted 30 minutes. Cochlear blood flow of the animals with intra-arterial thrombolysis began to decrease and action potential began to increase 80-90 minutes after UK injection. CONCLUSION: Both intra-arterial thrombolysis and intravenous thrombolysis were effective to the restricted thrombosis in the stria vascularis, and intra-arterial thrombolysis showed a better improvement in the early stage of thrombolysis.