Targeted suppression of heme oxygenase-1 by small interference RNAs inhibits the production of bilirubin in neonatal rat with hyperbilirubinemia

<p>Abstract</p> <p>Background</p> <p>Excessive accumulation of bilirubin contributes to neonatal hyperbilirubinemia in rats. Heme oxygenase (HO) is one of the rate-limiting enzymes in catabolizing heme to bilirubin. In the present study, we investigated whether suppression of rat HO-1 (rHO-1) expression by small interference RNAs (siRNAs) reduces bilirubin levels in hyperbilirubinemic rats.</p> <p>Results</p> <p>Four pairs of siRNA targeting rHO-1 mRNA were introduced into BRL cells and compared for their inhibitory effect on the expression of <it>rHO-1 </it>gene and production of rHO-1 protein. The siRNA exhibiting the most potent effect on HO-1 expression and activity was then administered intraperitoneally to 7 to 9-day-old rats with hyperbilirubinemia. The siRNA distributed mostly in the liver and spleen of neonatal rat. Serum bilirubin levels and hepatic HO-1 expression were further evaluated. Systemic treatment of siRNA targeting rHO-1 reduced hepatic HO-1 expression and decreased the serum bilirubin levels in a time- and dose-dependent manner, and siRNA decreased the indirect bilirubin levels more effectively than Sn-protoporphyrin (SnPP), an HO-1 inhibitor.</p> <p>Conclusion</p> <p>siRNA targeting rHO-l attenuates hepatic HO-1 expression and serum bilirubin levels. Thus this study provides a novel therapeutic rationale for the prevention and treatment of neonatal hyperbilirubinemia.</p

Inhibition of endogenous reverse transcription of human and nonhuman primate lentiviruses: Potential for development of lentivirucides

AbstractIn the current study, we extended our previous works on natural endogenous reverse transcription (NERT) and further examined its potential as a virucide molecular target in sexual transmission of primate lentiviruses. HIV-1 and SIV virions were pretreated with select nucleoside (NRTIs) and nonnucleoside RT inhibitors (NNRTIs), either alone or in combination with NERT-stimulating substances. The effects of these antiretrovirals on virion inactivation were analyzed in human T cell lines and primary cell cultures. Pretreatment of HIV-1 virions with physiologic NERT-stimulants and 3′-azido-3′-deoxythymidine 5′-triphosphate (AZT-TP) or nevirapine potently inactivated cell-free HIV-1 virions and resulted in strong inhibition of the viral infectivity. Pretreatment of chimeric SHIV-RT virions with NERT-stimulating cocktail and select antiretrovirals also resulted in virion inactivation and inhibition of viral infectivity in T cell lines. Our findings demonstrate the potential clinical utility of approaches based on inhibiting NERT in sexual transmission of HIV-1, through the development of effective anti-HIV-1 microbicides, such as NRTIs and NNRTIs

Up-regulation of interferon-a/APOBEC3G signal pathway potently inactivates HIV-1 infectivity in resting CD4-T cells

Poster Presentation

Combination of Immunotherapy With Targeted Therapy: Theory and Practice in Metastatic Melanoma

Metastatic melanoma is the most aggressive and obstinate skin cancer with poor prognosis. Variant novel applicable regimens have emerged during the past decades intensively, while the most profound approaches are oncogene-targeted therapy and T-lymphocyte mediated immunotherapy. Although targeted therapies generated remarkable and rapid clinical responses in the majority of patients, acquired resistance was developed promptly within months leading to tumor relapse. By contrast, immunotherapies elicited long-term tumor regression. However, the overall response rate was limited. In view of the above, either targeted therapy or immunotherapy cannot elicit durable clinical responses in large range of patients. Interestingly, the advantages and limitations of these regimens happened to be complementary. An increasing number of preclinical studies and clinical trials proved a synergistic antitumor effect with the combination of targeted therapy and immunotherapy, implying a promising prospect for the treatment of metastatic melanoma. In order to achieve a better therapeutic effectiveness and reduce toxicity in patients, great efforts need to be made to illuminate multifaceted interplay between targeted therapy and immunotherapy

Microarray and bioinformatic analysis reveal the parental genes of m6A modified circRNAs as novel prognostic signatures in colorectal cancer

BackgroundAccumulating evidences have revealed that the abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer. It is noteworthy that m6A modification is widely existed in circRNAs and found its key biological functions in regulating circRNAs metabolism. However, the role of m6A modified circRNAs in colorectal cancer (CRC) remains unknown. To better understand the role of circRNAs in the pathogenesis of CRC, we focus on the relationship between m6A-modified circRNAs and their parental genes.MethodsArraystar m6A-circRNA epitranscriptomic microarray was used to identify differentially m6A modified circRNAs between CRC and the control group. In addition, TCGA-COAD and GSE106582 cohort were used to identify differentially expressed mRNAs. In this study, we screened the parental genes for which both circRNAs and mRNAs were down-regulated further to analyze, including gene expression, survival prognosis, enrichment analysis. Additionally, Western Blotting was used to further validate the role of the parental gene in CRC.ResultsWe found that 1405 significantly downregulated circRNAs in CRC by our microarray data. Moreover, we obtained 113 parental genes for which both circRNAs and mRNAs were down-regulated to analyze the relationship with the prognosis of CRC based on TCGA-COAD cohort. And we identified nine potential prognostic genes, including ABCD3, ABHD6, GAB1, MIER1, MYOCD, PDE8A, RPS6KA5, TPM1 and WDR78. And low expression of these genes was associated with poor survival prognosis of the patients with CRC. In addition, we found that TPM1 is downregulated in CRC by western blotting experiment. And the calcium-signaling pathway may involve the process of the CRC progression.ConclusionsWe identified nine potential prognostic genes, after analyzed the relationship between the parental genes of m6A modified circRNAs and the progression of CRC. Above all, our study further validated TPM1 can serve as a potentail signature for CRC patients

Determining total N deposition in a winter wheat and maize cropping system

Atmospheric N deposition is a serious problem in the North China Plain (NCP) because it imposes a considerable nutrient burden on the surrounding environment. A manual integrated total N input (ITNI) method was developed using 15N-labelled monitor plants grown in pots to obtain accurate measures of total N deposition to the agroecosystems in the NCP and improve N-fertilizer recommendations. Total airborne N input into the maize-wheat rotation system is 80-90 kg N ha-1 yr-1 in the NCP, and the plant available N from deposition for maize and wheat plants is c. 50 kg N ha-1 yr-1. While total airborne N input is measured at almost 100 kg N ha-1 yr-1 when ryegrass is used as the monitoring plant, and the plant available N from deposition for ryegrass is c. 76 kg N ha-1 yr-1, accounting for 77% of the total N deposition. Dry deposition is likely to be the major contributor to the total N deposition during wheat growing season in the dry and dusty NCP

Determining total N deposition in a winter wheat and maize cropping system

Atmospheric N deposition is a serious problem in the North China Plain (NCP) because it imposes a considerable nutrient burden on the surrounding environment. A manual integrated total N input (ITNI) method was developed using 15N-labelled monitor plants grown in pots to obtain accurate measures of total N deposition to the agroecosystems in the NCP and improve N-fertilizer recommendations. Total airborne N input into the maize-wheat rotation system is 80-90 kg N ha-1 yr-1 in the NCP, and the plant available N from deposition for maize and wheat plants is c. 50 kg N ha-1 yr-1. While total airborne N input is measured at almost 100 kg N ha-1 yr-1 when ryegrass is used as the monitoring plant, and the plant available N from deposition for ryegrass is c. 76 kg N ha-1 yr-1, accounting for 77% of the total N deposition. Dry deposition is likely to be the major contributor to the total N deposition during wheat growing season in the dry and dusty NCP