Publications by authors named "Siqi Ren"

11 Publications

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Saikosaponins and the deglycosylated metabolites exert liver meridian guiding effect through PXR/CYP3A4 inhibition.

J Ethnopharmacol 2021 Jun 18;279:114344. Epub 2021 Jun 18.

Key Laboratory of Drug Quality Control & Pharmacovigilance (China Pharmaceutical University), Ministry of Educational, Nanjing, 210009, China; State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing, 210009, China. Electronic address:

Ethnopharmacological Relevance: Radix Bupleuri (RB), traditionally used to treat inflammatory disorders and infectious diseases, represents one of the most successful and widely used herbal drugs in Asia over the past 2000 years. Being realized the role in regulating metabolism and controlling Yin/Yang, RB is not only chosen specifically for treating liver meridian and the corresponding organs, but also believed to have liver meridian guiding property and help potentiate the therapeutic effects of liver. However, the ingredients in RB with liver meridian guiding property and the underly mechanism have not been comprehensively investigated.

Aim Of Study: Considering the important role of CYP3A4 in first-pass metabolism and the liver exposure of drugs, the present study aimed to determine whether saikosaponins (SSs) and the corresponding saikogenins (SGs) have a role in inhibiting the catalytic activity of CYP3A4 in human liver microsomes and HepG2 hepatoma cells and whether they could suppress CYP3A4 expression by PXR-mediated pathways in HepG2 hepatoma cells.

Materials And Methods: The effect of SSs and SGs on CYP3A4-mediated midazolam1'-hydroxylation activities in pooled human liver microsomes (HLMs) was first studied. Dose-dependent experiments were performed to obtain the half inhibit concentration (IC) values. HepG2 cells were used to assay catalytic activity of CYP3A4, reporter function, mRNA levels, and protein expression. The inhibitory effects of SSa and SSd on CYP3A4 activity are negligible, while the corresponding SGs (SGF and SGG) have obvious inhibitory effects on CYP3A4 activity, with IC values of 0.45 and 1.30 μM. The similar results were obtained from testing CYP3A4 catalytic activity in HepG2 cells, which correlated well with the suppression of the mRNA and protein levels of CYP3A4. Time-dependent testing of CYP3A4 mRNA and protein levels, as well as co-transfection experiments using the CYP3A4 promoter luciferase plasmid, further confirmed that SSs and SGs could inhibit the expression of CYP3A4 at the transcription level. Furthermore, PXR protein expression decreased in a concentration- and time-dependent manner after cells were exposed to SSs and SGs. PXR overexpression and RNA interference experiments further showed that SSs and SGs down-regulate the catalytic activity and expression of CYP3A4 in HepG2 may be mainly through PXR-dependent manner.

Conclusion: SSs and SGs inhibit the catalytic activity and expression of CYP3A4 in a PXR-dependent manner, which may be highly related to the liver meridian guiding property of RB.
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http://dx.doi.org/10.1016/j.jep.2021.114344DOI Listing
June 2021

LA14 Alleviates Liver Injury.

mSystems 2021 Jun 15;6(3):e0038421. Epub 2021 Jun 15.

Key Laboratory of Nutrition of Zhejiang Province, Institute of Health Food, Hangzhou Medical College, Hangzhou, China.

Although the probiotic Lactobacillus acidophilus LA14 is used worldwide, its effect on liver diseases remains unelucidated. Here, 32 rats were divided into four groups, gavaged with L. acidophilus LA14 (3 × 10 CFU) or phosphate-buffered saline for 7 days, and then intraperitoneally injected with d-galactosamine or saline. After 24 h, blood, liver, ileum, and feces samples were collected for liver injury, inflammation, intestinal barrier, gut microbiota, metabolome, and transcriptome analyses. Pretreatment with L. acidophilus LA14 alleviated the d-galactosamine-induced elevation of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and bile acids; mitigated the histological injury to the liver and gut; and suppressed the inflammatory cytokines macrophage inflammatory protein 1α (MIP-1α), MIP-3α, and MCP-1. L. acidophilus LA14 also ameliorated the d-galactosamine-induced dysbiosis of the gut microbiota and metabolism, such as the enrichment of sp. strain dnLKV3 and the depletion of Streptococcus, butanoic acid, and acetyl-d-glucosamine. The underlying mechanism of L. acidophilus LA14 included prevention of not only the d-galactosamine-induced upregulation of infection- and tumor-related pathways but also the d-galactosamine-induced downregulation of antioxidation-related pathways during this process, as reflected by the liver transcriptome and proteome analyses. Furthermore, the administration of L. acidophilus LA14 to healthy rats did not alter the tested liver indicators but significantly enriched the beneficial and species, promoted metabolism and regulated pathways to improve immunity. The ability of L. acidophilus LA14 to alleviate liver injury was further confirmed with an acetaminophen-induced mouse model. These results might provide a reference for future studies on the application of L. acidophilus LA14 for the prevention of liver injury. The probiotic Lactobacillus acidophilus LA14 is widely used, but its effect on liver diseases has not been elucidated. We explored the protective effect of L. acidophilus LA14 on the liver using rats with d-galactosamine-induced liver injury. Pretreatment with L. acidophilus LA14 alleviated the d-galactosamine-induced elevation of serum ALT, AST, ALP, and bile acids, mitigated the histological injury to the liver and gut, and suppressed the inflammatory cytokines MIP-1α, MIP-3α, and MCP-1. These effects were correlated with the modulations of the gut microbiome, metabolome, and hepatic gene expression induced by L. acidophilus LA14. Moreover, the ability of L. acidophilus LA14 to alleviate liver injury was further confirmed with an acetaminophen-induced mouse model. These results might provide a reference for future studies on the application of L. acidophilus LA14 for the prevention of liver injury.
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http://dx.doi.org/10.1128/mSystems.00384-21DOI Listing
June 2021

Single-cell profiling of tumor-infiltrating TCF1/TCF7 T cells reveals a T lymphocyte subset associated with tertiary lymphoid structures/organs and a superior prognosis in oral cancer.

Oral Oncol 2021 Aug 25;119:105348. Epub 2021 May 25.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation of Sun Yat-sen Memorial Hospital, Guangzhou 510120, China; Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China. Electronic address:

Objectives: Despite substantial advances in treatment, clinical outcomes for oral squamous cell carcinoma (OSCC) remain unsatisfactory. Tumor-infiltrating lymphocytes (TILs) are an important prognostic factor for patients and are heterogeneous. Some studies have suggested that TCF1/TCF7 T cells and tertiary lymphatic structure/organ (TLS) play an important role in tumor immunity. However, how they affect tumor immunity and whether they are related to prognosis in OSCC have not been reported in detail.

Materials And Methods: We isolated OSCC cells and performed single-cell RNA sequencing (scRNA-seq). We used immunohistochemistry (IHC) to analyze the relationship between TLSs and prognosis. Multiplex immunohistochemistry (MIHC), flow cytometry (FCM) and spatial analysis were performed to verify the characteristics of TCF1/TCF7 T cells. The prognostic significance and upstream regulatory network of the TCF1/TCF7 T cell subpopulation were determined by multivariate analysis and Scenic software.

Results: We found a strong association between TCF1/TCF7 T cell subsets, TLSs and prognosis. The results suggested that TCF1/TCF7 T cells express high levels of TLS-related genes and low levels of immune checkpoint molecules. Finally, we found that TCF1/TCF7 T cells were significantly associated with favorable outcomes. We also describe the upstream drivers that these cells rely on.

Conclusions: TCF1/TCF7 T cells could be used as a new therapeutic target to regulate the immune response of OSCC and are expected to be a new prognostic marker.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105348DOI Listing
August 2021

Exploring genetic alterations in circulating tumor DNA from cerebrospinal fluid of pediatric medulloblastoma.

Sci Rep 2021 Mar 11;11(1):5638. Epub 2021 Mar 11.

Department of Pediatric Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 119E. South Fourth Ring West Road, Fengtai District, Beijing, China.

Medulloblastoma (MB) is the most common type of brain malignancy in children. Molecular profiling has become an important component to select patients for therapeutic approaches, allowing for personalized therapy. In this study, we successfully identified detectable levels of tumor-derived cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) samples of patients with MB. Furthermore, cfDNA from CSF can interrogate for tumor-associated molecular clues. MB-associated alterations from CSF, tumor, and post-chemotherapy plasma were compared by deep sequencing on next-generation sequencing platform. Shared alterations exist between CSF and matched tumor tissues. More alternations were detected in circulating tumor DNA from CSF than those in genomic DNA from primary tumor. It was feasible to detect MB-associated mutations in plasma of patients treated with chemotherapy. Collectively, CSF supernatant can be used to monitor genomic alterations, as a superior technique as long as tumor-derived cfDNA can be isolated from CSF successfully.
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http://dx.doi.org/10.1038/s41598-021-85178-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952732PMC
March 2021

Left Atrial Strain as Evaluated by Two-Dimensional Speckle Tracking Predicts Left Atrial Appendage Dysfunction in Chinese Patients with Atrial Fibrillation.

Cardiol Res Pract 2020 21;2020:5867617. Epub 2020 Mar 21.

Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510100, China.

Left atrial appendage (LAA) dysfunction identified by transesophageal echocardiography (TEE) is a powerful predictor of stroke in patients with atrial fibrillation (AF). The aim of our study is to assess if there is a correlation between the left atrial (LA) functional parameter and LAA dysfunction in the AF patients. This cross-sectional study included a total of 249 Chinese AF patients who did not have cardiac valvular diseases and were undergoing cardiac ablation. TEE was performed in all the patients who were categorized into two groups according to their left atrial appendage (LAA) function. A total of 120 of the 249 AF patients had LAA dysfunction. Univariate and multivariate logistic regression was conducted to assess the independent factors that correlated with the LAA dysfunction. Different predictive models for the LAA dysfunction were compared with the receiver operating characteristic (ROC) curve. The final ROC curve on the development and validation datasets was drawn based on the calculation of each area under the curves (AUC). Univariate and multivariate analysis showed that the peak left atrial strain (PLAS) was the most significant factor that correlated with the LAA dysfunction. PLAS did not show inferiority amongst all the models and revealed strong discrimination ability on both the development and validation datasets with AUC 0.818 and 0.817. Our study showed that a decrease in PLAS is independently associated with LAA dysfunction in the AF patients.
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http://dx.doi.org/10.1155/2020/5867617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115138PMC
March 2020

Corrigendum to "Pharmacokinetics and oral bioavailability studies of three saikogenins in rats using a validated UFLC-MS/MS method" [J. Chromatogr. B 1124 (2019) 265-272].

J Chromatogr B Analyt Technol Biomed Life Sci 2020 03 12;1141:121997. Epub 2020 Feb 12.

Key Laboratory of Drug Quality Control & Pharmacovigilance (China Pharmaceutical University), Ministry of Educational, Nanjing 210009, China; State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

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http://dx.doi.org/10.1016/j.jchromb.2020.121997DOI Listing
March 2020

Pharmacokinetics and oral bioavailability studies of three saikogenins in rats using a validated UFLC-MS/MS method.

J Chromatogr B Analyt Technol Biomed Life Sci 2019 Aug 17;1124:265-272. Epub 2019 Jun 17.

Key Laboratory of Drug Quality Control & Pharmacovigilance (China Pharmaceutical University), Ministry of Educational, Nanjing 210009, China; State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Radix Bupleuri (RB) has been widely used in Traditional Chinese Medicine with a long history. Saikosaponins (SSs), the major constituents of RB, are assumed to be transformed into saikogenins (SGs) by human intestinal microflora prior to absorption and then exert pharmacological effects. There have been detailed reports on the deglycosylation of SSs in the gastrointestinal tract. But to date, there is very limited research addressing the further absorption, distribution, metabolism, and excretion of these deglycosylated derivatives in vivo. In this study, a rapid UFLC-MS/MS method was established and fully validated for simultaneously determining four SGs (SGF, SGA, SGD, and SGG) in rat plasma. The developed method was successfully applied to the pharmacokinetics of three SGs (SGF, SGD, and SGG) in rats after oral and intravenous administrations. Finally, the absolute bioavailabilities were calculated at 0.71% for SGF and 0.66% for SGD. However, the oral bioavailability of SGG was not obtained due to the extremely poor absorption in rats.
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http://dx.doi.org/10.1016/j.jchromb.2019.06.020DOI Listing
August 2019

Left atrial strain reproducibility using vendor-dependent and vendor-independent software.

Cardiovasc Ultrasound 2019 May 15;17(1). Epub 2019 May 15.

Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Academy of Medicine Sciences, Guangdong Provincial People's Hospital, 106 Zhongshan Er Road, Guangzhou, 510100, China.

Background: Two-dimensional speckle-tracking echocardiography (2D-STE) enables objective assessment of left atrial (LA) deformation through the analysis of myocardial strain, which can be measured by different speckle-tracking software. The aim of this study was to compare the consistency of 3 different commercially available software, which include vendor-specific software for measuring left ventricle (VSS), vendor-independent software packages for measuring LV strain (VIS) and vendor-independent software packages for measuring LA strain (VIS).

Methods: Sixty-four subjects (mean age: 44 ± 16 years, 50% males) underwent conventional echocardiograms using a GE Vivid 9 (GE Ultrasound, Horten, Norway) cardiac ultrasound system. Standard apical 4 and 2 chamber views of the left atrium were obtained in each subject with a frame-rate range of 40-71 frames/s. LA strain during the contraction phase (Sct), conduit phase (Scd), reservoir phase (Sr = Sct + Scd) were analyzed by 2 independent observers and 3 different software.

Results: Sct, Scd, Sr were, respectively, - 11.26 ± 2.45%, - 16.77 ± 7.06%, and 28.03 ± 7.58% with VSS, - 14.77 ± 3.59%, - 23.17 ± 10.33%, and 38.23 ± 10.99% with VIS, and - 14.80 ± 3.88%, - 23.94 ± 10.48%, and 38.73 ± 11.56% when VIS was used. A comparison of strain measurements between VSS and VIS (VIS and VIS) showed VIS had significantly smaller mean differences and narrower limits of agreement. Similar results were observed in the coefficient of variation (CV) for measurements between VSS and VIS (VIS and VIS). Comparison of the intra-class correlation coefficients (ICCs) indicated that measurement reliability was weaker with VSS (ICC < 0.6) than with VIS (VIS and VIS) (ICC > 0.9). For intra-observer ICCs, VIS > VSS = VIS. For inter-observer ICCs, VSS > VIS > VIS.

Conclusions: Software measurement results of LA strain vary considerably. We recommended not measuring LA strain across vendor platforms.
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http://dx.doi.org/10.1186/s12947-019-0158-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521472PMC
May 2019

A Bubble-Free Microfluidic Device for Easy-to-Operate Immobilization, Culturing and Monitoring of Zebrafish Embryos.

Micromachines (Basel) 2019 Feb 28;10(3). Epub 2019 Feb 28.

Cambridge-Suda Genomic Resource Center and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou 215213, China.

The development of miniaturized devices for studying zebrafish embryos has been limited due to complicated fabrication and operation processes. Here, we reported on a microfluidic device that enabled the capture and culture of zebrafish embryos and real-time monitoring of dynamic embryonic development. The device was simply fabricated by bonding two layers of polydimethylsiloxane (PDMS) structures replicated from three-dimensional (3D) printed reusable molds onto a flat glass substrate. Embryos were easily loaded into the device with a pipette, docked in traps by gravity, and then retained in traps with hydrodynamic forces for long-term culturing. A degassing chamber bonded on top was used to remove air bubbles from the embryo-culturing channel and traps so that any embryo movement caused by air bubbles was eliminated during live imaging. Computational fluid dynamics simulations suggested this embryo-trapping and -retention regime to exert low shear stress on the immobilized embryos. Monitoring of the zebrafish embryogenesis over 20 h during the early stages successfully verified the performance of the microfluidic device for culturing the immobilized zebrafish embryos. Therefore, this rapid-prototyping, low-cost and easy-to-operate microfluidic device offers a promising platform for the long-term culturing of immobilized zebrafish embryos under continuous medium perfusion and the high-quality screening of the developmental dynamics.
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http://dx.doi.org/10.3390/mi10030168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470713PMC
February 2019

Clinical Characteristics and Outcome of Children With Relapsed Medulloblastoma: A Retrospective Study at a Single Center in China.

J Pediatr Hematol Oncol 2018 11;40(8):598-604

Department of Pediatrics, Beijing Shijitan Hospital.

Relapsed medulloblastoma (MB) has a dire prognosis, and chemotherapy remains the main therapeutic option. We retrospectively analyzed the clinical characteristics and survival rates of 60 Chinese children with relapsed MB. The patients received 11 cycles of chemotherapy in sequence, followed by 12 cycles of oral temozolomide and etoposide. Thirty patients were simultaneously administered intrathecal methotrexate (IT-MTX). The Kaplan-Meier method was used to determine survival rates; the patients' median survival time after relapse was 2.8 years, 5-year progression-free survival (PFS) and overall survival (OS) rates were 26.7%±5.7% and 31.6%±6.9%, respectively. There was no significant difference between these rates according to histology or molecular subgroup. Tumor cells were detected in the cerebrospinal fluid of over 40% of patients; such patients had significantly shorter OS and PFS rates. Patients who received IT-MTX showed significantly longer survival than those who did not (3.73 vs. 2.06 y, respectively, P=0.000); the corresponding 5-year PFS and OS rates were 43.3%±9.0% versus 10.0%±5.5% and 49.5%±11.1% versus 14.6%±6.9%, respectively (P=0.000). In addition, tumor cell-positive cerebrospinal fluid and IT-MTX use significantly influenced PFS and OS in relapsed patients. Taken together, our data show that IT-MTX improves the survival of patients with relapsed MB.
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http://dx.doi.org/10.1097/MPH.0000000000001241DOI Listing
November 2018

Optimization of a Precolumn OPA Derivatization HPLC Assay for Monitoring of l-Asparagine Depletion in Serum during l-Asparaginase Therapy.

J Chromatogr Sci 2018 Oct;56(9):794-801

Key Laboratory of Drug Quality Control and Pharmacovigilance Ministry of Education, China Pharmaceutical University, Nanjing, China.

A method for monitoring l-asparagine (ASN) depletion in patients' serum using reversed-phase high-performance liquid chromatography with precolumn o-phthalaldehyde and ethanethiol (ET) derivatization is described. In order to improve the signal and stability of analytes, several important factors including precipitant reagent, derivatization conditions and detection wavelengths were optimized. The recovery of the analytes in biological matrix was the highest when 4% sulfosalicylic acid (1:1, v/v) was used as a precipitant reagent. Optimal fluorescence detection parameters were determined as λex = 340 nm and λem = 444 nm for maximal signal. The signal of analytes was the highest when the reagent ET and borate buffer of pH 9.9 were used in the derivatization solution. And the corresponding derivative products were stable up to 19 h. The validated method had been successfully applied to monitor ASN depletion and l-aspartic acid, l-glutamine, l-glutamic acid levels in pediatric patients during l-asparaginase therapy.
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http://dx.doi.org/10.1093/chromsci/bmy053DOI Listing
October 2018