Publications by authors named "Miaojuan Qiu"

7 Publications

  • Page 1 of 1

A calcium phosphate drug carrier loading with 5-fluorouracil achieving a synergistic effect for pancreatic cancer therapy.

J Colloid Interface Sci 2021 Jul 20;605:263-273. Epub 2021 Jul 20.

The Seventh Hospital of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China. Electronic address:

Calcium based biomaterials were widely used for drug delivery application due to their biodegradability, biocompatibility, and high drug loading capacity. Herein, amino-capped polyamidoamine (PAMAM) dendrimer was applied as a macromolecular template to form amino-modified calcium phosphate hollow sphere (CaPO-NH). After loading with 5-fluorouracil (5Fu), this system performed synergistic cancer chemotherapy. In this study, the 5Fu/CaPO-NH particles could be efficiently uptaken by cancer cells, and then decompose into Ca and release 5Fu drug in the cytoplasm; therefore calcium overload and reactive oxygen species (ROS) accumulation were found in PSN1 cells that could induce cell membrane damage and elicit cell apoptosis through a series of biochemical reactions including endoplasmic reticulum stress, lipid peroxidation and mitochondrial apoptosis. In the PSN1 pancreatic cancer xenograft model, the 5Fu/CaPO-NH system performed high tumor inhibition via chemotherapy and calcium overload induced apoptosis. Comparingly, the normal cells and organs were insensitive to this synergistic therapy, which indicated the well biocompatibility of delivery system. Thus, this study provided a promising CaPO-NH drug delivery platform for enhanced 5Fu chemotherapeutic effect.
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http://dx.doi.org/10.1016/j.jcis.2021.07.080DOI Listing
July 2021

Systematic Chromatin Accessibility Analysis Based on Different Immunological Subtypes of Clear Cell Renal Cell Carcinoma.

Front Oncol 2021 16;11:575425. Epub 2021 Apr 16.

Department of Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.

Background: Recent research of clear cell renal cell carcinoma (ccRCC) is focused on the tumor immune microenvironment (TIME). Chromatin accessibility is critical for regulation of gene expression. However, its role in different immunological subtypes of ccRCC based on immune cell infiltration has not been systematically studied.

Methods: Five hundred thirty patient data from The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) were adopted to estimate immune cell infiltration. Twenty-four types of immune cells were evaluated with single-sample Gene Set Enrichment Analysis (ssGSEA). Patients were divided into two clusters based on immune cell infiltration. Systematic chromatin accessibility analysis was conducted based on the two clusters.

Results: We compared the relative expression of the immune gene signatures among 530 patients of TCGA-KIRC using ssGSEA. Overall survival (OS) analysis revealed 10 types of immune cells were significantly associated with prognosis. Patients were divided into two clusters based on 24 types of immune cell infiltration. Immune cell signals as well as PD-1/PD-L1 signal were higher in cluster 1. Among the two clusters, 2,400 differential peaks were found in TCGA-KIRC Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) data. The distribution of differential peaks and prognosis-related immune cells in 23 chromosomes are essentially the same. There is no peak distribution downstream. The proportion of peaks upstream of the 5' transcription start site decreases, and both sides of binding regions of the TSS 0.1-1 kb becomes smaller. Enrichment analysis of GO and KEGG of these differential peaks showed that they are remarkably related to the immune regulation in tumor microenvironment. Known motifs and motifs were found by linking motif annotations to different peaks. Survival analysis of related motif transcription factors were prognostic. The GSEA enrichment analysis showed that high SP1 expression positively correlates with TGF-beta signaling and inflammatory response, while negatively correlates with TNF-alpha signaling NFKB. High KLF12 expression negatively correlates with interferon gamma response, IL2-STAT5 signaling, TNF-alpha signaling NFKB, IL6-JAK-STAT3 signaling.

Conclusion: The abnormality of chromatin accessibility may play an important regulatory role in ccRCC immunity.
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http://dx.doi.org/10.3389/fonc.2021.575425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085385PMC
April 2021

Tubular Mas receptor mediates lipid-induced kidney injury.

Cell Death Dis 2021 01 21;12(1):110. Epub 2021 Jan 21.

Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.

Obesity-related kidney diseases are becoming serious health problems worldwide, yet the mechanism by which obesity causes kidney injury is not fully understood. The purpose of current study was to investigate the role of Mas receptor in lipid-induced kidney injury. In mice fed with high-fat diet (HFD), the protein abundance of markers of autophagy, endoplasmic reticulum stress (ER stress) and apoptosis was dramatically increased in the kidney cortex, which was markedly prevented by Mas deletion (Mas) or Mas receptor antagonist A779. Palmitic acid (PA) induced persistently increased autophagy, ER stress, and apoptosis as well as mitochondrial injuries in primary cultured proximal tubular cells from wild type, but not from Mas mice. In human proximal tubular HK2 cells, PA-induced autophagy and ER stress was aggravated by Mas agonists Ang (1-7) or AVE0991, but attenuated by A779 or Mas knockdown. Stimulation of Mas resulted in elevated intracellular calcium levels [Ca] in HK2 cells treated with PA, whereas inhibition or knockdown of Mas decreased [Ca]. Mitochondrial outer membrane located voltage-dependent anion channel (VDAC1) was markedly upregulated in HK2 cells treated with PA, which was associated with impaired mitochondrial morphology and depolarization. These were enhanced by AVE0991 and suppressed by A779 or Mas knockdown. Mas knockdown in HK2 cells prevented impaired interactions among VDAC1, autophagy adaptor P62, and ubiquitin, induced by PA, leading to a potential ubiquitination of VDAC1. In conclusion, Mas receptor-mediated lipid-induced impaired autophagy and ER stress in the kidney, likely contributing to tubular injuries in obesity-related kidney diseases.
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http://dx.doi.org/10.1038/s41419-020-03375-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817966PMC
January 2021

Bile Acid G Protein-Coupled Membrane Receptor TGR5 Modulates Aquaporin 2-Mediated Water Homeostasis.

J Am Soc Nephrol 2018 11 10;29(11):2658-2670. Epub 2018 Oct 10.

Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;

Background: The bile acid-activated receptors, including the membrane G protein-coupled receptor TGR5 and nuclear farnesoid X receptor (FXR), have roles in kidney diseases. In this study, we investigated the role of TGR5 in renal water handling and the underlying molecular mechanisms.

Methods: We used tubule suspensions of inner medullary collecting duct (IMCD) cells from rat kidneys to investigate the effect of TGR5 signaling on aquaporin-2 (AQP2) expression, and examined the effects of TGR5 in mice with lithium-induced nephrogenic diabetes insipidus (NDI) and knockout ( ) mice.

Results: Activation of TGR5 by lithocholic acid (LCA), an endogenous TGR5 ligand, or INT-777, a synthetic TGR5-specific agonist, induced AQP2 expression and intracellular trafficking in rat IMCD cells a cAMP-protein kinase A signaling pathway. In mice with NDI, dietary supplementation with LCA markedly decreased urine output and increased urine osmolality, which was associated with significantly upregulated AQP2 expression in the kidney inner medulla. Supplementation with endogenous FXR agonist had no effect. In primary IMCD suspensions from lithium-treated rats, treatment with INT-767 (FXR and TGR5 dual agonist) or INT-777, but not INT-747 (FXR agonist), increased AQP2 expression. mice exhibited an attenuated ability to concentrate urine in response to dehydration, which was associated with decreased AQP2 expression in the kidney inner medulla. In lithium-treated mice, LCA treatment failed to prevent reduction of AQP2 expression.

Conclusions: TGR5 stimulation increases renal AQP2 expression and improves impaired urinary concentration in lithium-induced NDI. TGR5 is thus involved in regulating water metabolism in the kidney.
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http://dx.doi.org/10.1681/ASN.2018030271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218869PMC
November 2018

Combination of Chymostatin and Aliskiren attenuates ER stress induced by lipid overload in kidney tubular cells.

Lipids Health Dis 2018 Jul 31;17(1):183. Epub 2018 Jul 31.

Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, 74# Zhongshan 2nd Road, Guangzhou, 510080, China.

Background: Lipotoxicity plays an important role in the pathogenesis of kidney injury. Our previous study demonstrated that activation of local renin-angiotensin system (RAS) was involved in saturated free fatty acids palmitic acid (PA)-induced tubular cell injuries. The current study aims to investigate whether suppression of RAS by combination of direct renin inhibitor aliskiren and noncanonical RAS pathway chymase inhibitor chymostatin attenuates PA or cholesterol induced-endoplasmic reticulum stress (ER stress) and apopotosis in cultured human proximal tubular HK2 cells.

Methods: HK2 cells were treated with saturated fatty acid PA (0.6 mM) for 24 h or cholesterol (10 μg/ml) for 6d with or without chymostatin and/or aliskiren. Expressions of the ER stress associated proteins and apoptosis markers were detected by western blotting. The mRNA levels of RAS components were measured by real-time qPCR.

Results: Combination treatment of chymostatin and aliskiren markedly suppressed PA or cholesterol-induced ER stress, as reflected by increased BiP, IRE1α, phosphorylated-eIF2α and ATF4 as well as proapoptotic transcription factor CHOP. The ratio of Bax/Bcl-2 and cleaved caspase-3, two markers of apoptosis were upregulated by PA or cholesterol treatment. PA treatment was also associated with increased levels of angiotensinogen and angiotensin type 1 receptor (AT1R) mRNA expression. Combination treatment of chymostatin and aliskiren markedly suppressed PA or cholesterol-induced ER stress and apoptosis. The protective effect of two inhibitors was also observed in primary cultured cortical tubular cells treated with PA. In contrast, chymostatin and/or aliskiren failed to prevent ER stress induced by tunicamycin.

Conclusions: These results suggested that combination treatment of chymostatin and aliskiren attenuates lipid-induced renal tubular cell injury, likely through suppressing activation of intracellular RAS.
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http://dx.doi.org/10.1186/s12944-018-0818-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069859PMC
July 2018

Hydrogen sulfide upregulates renal AQP-2 protein expression and promotes urine concentration.

FASEB J 2019 01 23;33(1):469-483. Epub 2018 Jul 23.

Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.

Increasing evidence supports the important role of HS in renal physiology and the pathogenesis of kidney injury. Whether HS regulates water metabolism in the kidney and the potential mechanism are still unknown. The present study was conducted to determine the role of HS in urine concentration. Inhibition of both cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS), 2 major enzymes for endogenous HS production, with propargylglycine (PPG) and amino-oxyacetate (AOAA), respectively, caused increased urine output and reduced urine osmolality in mice that was associated with decreased expression of aquaporin (AQP)-2 in the renal inner medulla. Mice treated with both PPG and AOAA developed a urine concentration defect in response to dehydration that was accompanied by reduced AQP-2 protein expression. Inhibition of CSE alone was associated with a mild decrease in AQP-2 protein level in the renal medulla of heterozygous CBS mice. GYY4137, a slow HS donor, markedly improved urine concentration and prevented the down-regulation of renal AQP-2 protein expression in mice with lithium-induced nephrogenic diabetes insipidus (NDI). GYY4137 significantly increased cAMP levels in cell lysates prepared from inner medullary collecting duct (IMCD) suspensions. AQP-2 protein expression was also upregulated, but was significantly inhibited by the adenyl cyclase inhibitor MDL12330A or the PKA inhibitor H89, but not the vasopressin 2 receptor (VR) antagonist tolvaptan. Inhibition of endogenous HS production impaired urine concentration in mice, whereas an exogenous HS donor improved urine concentration in lithium-induced NDI by increasing AQP-2 expression in the collecting duct principal cells. HS upregulated AQP-2 protein expression, probably via the cAMP-PKA pathway.-Luo, R., Hu, S., Liu, Q., Han, M., Wang, F., Qiu, M., Li, S., Li, X., Yang, T., Fu, X., Wang, W., Li, C. Hydrogen sulfide upregulates renal AQP-2 protein expression and promotes urine concentration.
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http://dx.doi.org/10.1096/fj.201800436RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988842PMC
January 2019

Aliskiren increases aquaporin-2 expression and attenuates lithium-induced nephrogenic diabetes insipidus.

Am J Physiol Renal Physiol 2017 Oct 22;313(4):F914-F925. Epub 2017 Feb 22.

Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;

The direct renin inhibitor aliskiren has been shown to be retained and persist in medullary collecting ducts even after treatment is discontinued, suggesting a new mechanism of action for this drug. The purpose of the present study was to investigate whether aliskiren regulates renal aquaporin expression in the collecting ducts and improves urinary concentrating defect induced by lithium in mice. The mice were fed with either normal chow or LiCl diet (40 mmol·kg dry food·day for 4 days and 20 mmol·kg dry food·day for the last 3 days) for 7 days. Some mice were intraperitoneally injected with aliskiren (50 mg·kg body wt·day in saline). Aliskiren significantly increased protein abundance of aquaporin-2 (AQP2) in the kidney inner medulla in mice. In inner medulla collecting duct cell suspension, aliskiren markedly increased AQP2 and phosphorylated AQP2 at serine 256 (pS256-AQP2) protein abundance, which was significantly inhibited both by adenylyl cyclase inhibitor MDL-12330A and by PKA inhibitor H89, indicating an involvement of the cAMP-PKA signaling pathway in aliskiren-induced increased AQP2 expression. Aliskiren treatment improved urinary concentrating defect in lithium-treated mice and partially prevented the decrease of AQP2 and pS256-AQP2 protein abundance in the inner medulla of the kidney. In conclusion, the direct renin inhibitor aliskiren upregulates AQP2 protein expression in inner medullary collecting duct principal cells and prevents lithium-induced nephrogenic diabetes insipidus likely via cAMP-PKA pathways.
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http://dx.doi.org/10.1152/ajprenal.00553.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148297PMC
October 2017
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