Subjects: Medicine, Pharmacy >> Pharmacology submitted time 2024-05-14
Ce Wang
Donghui Pan
Siyi Tan
Lizhen Wang
Xinyu Wang
Junjie Yan
Chongyang Chen
Yuping Xu
Lianghua Zou
Abstract： Abstract Background Accumulation of α-synuclein is a major hallmark of Parkinson’s disease. The development of PET tracers to visualize aggregated α-synuclein is useful for early diagnosis and treatment of Parkinson’s disease. Purpose A small molecule compound based on benzothiazole scaffolds, 2-((3-fluorobenzyl)thio)-6-(3- fluorine-18 propoxy)benzo d thiazole ,denoted as 18F-YM,were prepared and labeled using Cu(II) mediated radiofluorination methods respectively. The imaging properties of the tracer were primarily evaluated through PET imaging at A53T mice and normal mice. Also, the imaging properties of the probe was also investigated through biodistribution experiments as well as ex vivo autoradiography and pathological analysis.
Methods Through chemical synthesis, compounds Sn-YM and 19F-YM were obtained. Compound Sn-YM was labeled with 18F using organic tin fluoride method, and the resulting product 18F-YM was verified by high performance liquid chromatography. The in vitro stability and octanol–water partition coefficient of 18F-YM were determined. Finally, small animal Micro PET imaging was used to assess the affinity of 18F-YM for α-synuclein, and autoradiography, pathological analysis, and biodistribution were used to validate the results of small animal Micro PET imaging.
Results 18F labeled small molecule compound was prepared in nearly 1 hour and obtained with an undecayed yield greater than 10% and the radiochemical purity was greater than 95%. In vivo PET imaging revealed that more radioactivity was significantly detected in the brain of A53T mice than those of normal mice after administration of 18F-YM. Quantitative analysis showed that the uptake values in the brain of A53T mice and normal mice were 2.35±0.06 %ID/g and 1.38±0.15 %ID/g.Furthermore, ex vivo autoradiography and histological examination confirmed the possibility of detection of aggregated α-synuclein in thalamus, substantia nigra and striatum using 18F-YM. A biodistribution study in normal mice found that 18F- YM was quickly cleaned from the brain of normal mice. It indicates that the non-specific binding of 18F- YM in the brain is low, which allowed for obtaining good contrast images.
Conclusion The preclinical study demonstrated that the benzothiazole analog，18F- YM，owned preferable imaging prosperities. It may be a new candidate for α-synuclein PET imaging.
Peer Review Status:
Awaiting Review
Subjects: Pharmaceutical Science >> Other Disciplines Subjects: Medicine, Pharmacy >> Pharmacology submitted time 2024-05-10
Yingquan WEN
Ziyuan ZOU
Guanguan ZHAO
Mengjiao ZHANG
Yongxin ZHANG
Gaihong WANG
Jingjing SHI
Yuanyang WANG
Yeyu SONG
Huixia WANG
Ruyue CHEN
Dongxuan ZHENG
Xiaoqun DUAN
Yameng LIU
Frank J GONZALEZ
Jian-Gao FAN
Cen XIE
Abstract： The progression of simple steatosis to non-alcoholic steatohepatitis (NASH) has emerged as a significant health concern. The activation of FXR shows promise in countering this transition and its detrimental consequences. However, the specific alterations within the NASH-related transcriptional network remain elusive, hindering the development of more precise and effective therapeutic strategies. Through a comprehensive analysis of liver RNA-seq data from human and mouse NASH samples, we identified central perturbations within the NASH-associated transcriptional network, including disrupted cellular metabolism and mitochondrial function, decreased tissue repair capability, and increased inflammation and fibrosis, thus shedding light on the complex molecular mechanisms underlying NASH progression. By employing integrated transcriptome profiling of diverse FXR agonists-treated mice, FXR liver-specific knockout mice, and publicly available human datasets, we determined that hepatic FXR activation effectively ameliorated NASH by reversing the dysregulated metabolic and inflammatory networks implicated in NASH pathogenesis. This mitigation encompassed resolving fibrosis, reducing immune infiltration, and creating an immune microenvironment that mirrors the positive trends observed in clinical disease progression. By understanding the core regulatory network of FXR, which is directly correlated with disease severity and treatment response, we identified approximately one-third of the patients who could potentially benefit from FXR agonist therapy. A similar analysis involving intestinal RNA-seq data from FXR agonists-treated mice and FXR intestine-specific knockout mice revealed that intestinal FXR activation attenuates intestinal inflammation, and has promise in attenuating hepatic inflammation and fibrosis. Collectively, our study uncovers the intricate pathophysiological features of NASH at a transcriptional level and highlights the complex interplay between FXR activation and both NASH progression and regression. These findings contribute to precise drug development, utilization, and efficacy evaluation, ultimately aiming to improve patient outcomes.
Subjects: Medicine, Pharmacy >> Pharmacology submitted time 2023-11-12
Abstract： Objective: To explore the clinical effect of tumescent technique in early operation of massively burned patients. Methods: A retrospective cohort study was conducted on 27 patients with large area burns accorded with the inclusive criteria and admitted from June 2019 to November 2022. Among them, 14 patients admitted from June 2021 to November 2022 were treated with intraoperative injection of tumescent fluid for hemostasis and were rolled in tumescent group, or observation group; 13 patients admitted from January 2019 to November 2021 were treated with tourniquet for hemostasis were rolled in tourniquet group, or control group. The operation time, blood loss, blood preparation, blood transfusion, preoperative and postoperative hemoglobin, intraoperative and postoperative blood pressure, heart rate, postoperative skin graft survival rate and other related indicators were compared between the two groups, and the clinical effects were observed. Results: There was no statistical difference in preoperative blood volume between the two groups (p > 0.05). The actual amount of blood transfusion in the observation group was less than that in the control group, and the difference was statistically significant (p < 0.05). The intraoperative blood loss and operation time in the observation group were significantly less than those in the control group, and the difference was statistically significant (P < 0.05). There was no statistical difference in preoperative and postoperative hemoglobin between the two groups (p > 0.05). The survival rate of skin grafting in the observation group were slightly higher than those in the control group, and the difference was statistically significant (P < 0.05). The vital signs of patients in the observation group were more stable than those in the control group, and the difference was statistically significant (P < 0.05). Conclusion: Tumescent technique can reduce the amount of intraoperative blood loss, shorten the operation time, improve the survival rate of postoperative skin grafting, and ensure the stability of intraoperative hemodynamics in early operation of massively burned patients.
Peer Review Status:Awaiting Review
Subjects: Medicine, Pharmacy >> Pharmacology submitted time 2022-12-26
Chen-yu Wang
Di-hong Yang
Xiao-min Niu
Lu Han
Wen Wang
Roman Filimonov
Sajid Ali Shah
Xin-yang Weng
Zheng Jiao
Abstract：
Introduction: Combining immune checkpoint inhibitor and chemotherapies provides more benefits than traditional treatment options in patients with NSCLC. However, some patients still have no clinical benefits. Clinical accessible biomarkers are necessary to predict clinical outcomes and optimize dose strategies. The study aimed to investigate accessible biomarkers that can predict clinical outcomes and optimize dosing strategies of atezolizumab and nab-paclitaxel combination therapy in patients with NSCLC by quantitative systems pharmacology (QSP).
Methods: The model was developed based on a published QSP model of triple-negative breast cancer using the SimBiology toolbox in MATLAB. The model included four compartments. With the model, we generated a virtual patient cohort to conduct in silico virtual clinical trials and used available data from real clinical trials (IMpower131) for model calibration and validation.
Results: The final QSP model predictions are consistent with clinically reported efficacy endpoints. CD8+ and CD4+ T cell densities in tumor are significantly affected by the response status. Roc analysis further implicating their potential to be predictive biomarkers for this double combination regimen. Virtual clinical trial simulation shows reduced nab-paclitaxel doses from 100 mg/m2 to 75 mg/m2 would leads to lower ORR but was higher than atezolizumab monotherapy. Three atezolizumab dosing strategies combined with nab-paclitaxel showed comparable efficacy. ?to compare different schedules of the two drugs for simulated therapeutic optimization.
Conclusion: This study provides a QSP model, which can be used to generate virtual patient cohorts and conduct virtual clinical trials. Our findings demonstrate its potential for making efficacy predictions for immunotherapies and chemotherapies, identifying predictive biomarkers, and guiding future clinical trial designs.
Peer Review Status:Awaiting Review
Subjects: Biology >> Biochemistry Subjects: Medicine, Pharmacy >> Pharmacology submitted time 2022-03-09
Abstract：
[Objective] The drug consistency evaluation of atorvastatin by urine proteomic analysis.
[Methods] Intragastric administration rat models were established by atorvastatin from two companies. Urine samples were collected from rats before and after intragastric administration. Urine proteins were profiled using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), and the biological pathway of the differential proteins was analyzed by DAVID database.
[Results] The differential proteins were selected by comparing the after intragastric administration to before intragastric administration. A total of 116 differential proteins were identified in group A and 66 differential proteins in group B, and 24 proteins were identified in common between two groups. These differential proteins tend to be involved in biological pathways such as cell adhesion, negative regulation of endopeptidase activity and proteolysis.
[Conclusions] For two kind of atorvastatin, we can detect small differences in urinary protein between them, which confirms the sensitivity of urinary protein and suggests that urine proteomics has great potential for the Drug consistency evaluation.
Peer Review Status:Awaiting Review
Subjects: Medicine, Pharmacy >> Pharmacology submitted time 2021-07-12
Abstract： Tumor angiogenesis is a hallmark of cancer. Therapeutic drug inhibitors targeting angiogenesis are clinically effective. We have previously identified GT198 (gene symbol PSMC3IP, also known as Hop2) as an oncoprotein that induces tumor angiogenesis in human cancers, including oral cancer. In this study, we show that GT198 protein is a direct drug target of more than a dozen oncology drugs and several clinically successful anticancer herbs. GT198 is a DNA repair protein that binds to DNA. Using an in vitro DNA-binding assay, we tested the approved oncology drugs set VII from NCI containing 129 oncology drugs. Identified GT198 inhibitors include but are not limited to mitoxantrone, doxorubicin, paclitaxel, etoposide, dactinomycin, and imatinib. Paclitaxel and etoposide have higher binding affinities, whereas doxorubicin has higher binding efficacy due to competitive inhibition. GT198 shares protein sequence homology with DNA topoisomerases, which are known drug targets, so that GT198 is likely a new drug target previously unrecognized. To seek more powerful GT198 inhibitors, we further tested several anticancer herbal extracts. The positive anticancer herbs with high affinity and high efficacy are all clinical successful ones, including allspice from Jamaica, Gleditsia sinensis or honey locust from China, and BIRM from Ecuador. Partial purification of allspice using organic chemical approach demonstrated great feasibility of natural product purification, when the activity is monitored by the in vitro DNA-binding assay using GT198 as target. Together, our study reveals GT198 as a new targeting mechanism for existing oncology drugs. The study also delivers an excellent drug target suitable for compound identification and natural product purification. In particular, this study opens an opportunity to rapidly identify drugs with high efficacy and low toxicity from nature.
Peer Review Status:Awaiting Review
Subjects: Medicine, Pharmacy >> Pharmacology submitted time 2020-11-24
Abstract： "
Peer Review Status:Awaiting Review
Subjects: Medicine, Pharmacy >> Pharmacology Subjects: Medicine, Pharmacy >> Preventive Medicine and Hygienics submitted time 2020-02-27
Abstract： 2019 novel coronavirus (2019-nCoV) caused severe, large-scale acute respiratory disease outbreak in Wuhan, China. The 2019-nCoV has spread to other regions and countries around the world, which is seriously threatening human health. There is an urgent need to develop drugs for the prevention and treatment of 2019-nCoV. 2019-nCoV nonstructural protein 14 (NSP14) carrying RNA cap guanine N7-methyltransferase and 3'-5' exoribonuclease activities could be a potential drug target for intervention. NSP14 of 2019-nCoV shared 98.7% similarity with the one (PDB ID: 5nfy) of acute respiratory syndrome (SARS) Coronavirus. Then, the 2019-nCoV NSP14 structures were modelled by using SARS NSP14 (PDB ID: 5nfy) as template for virtual screening. Based on the docking score, 18 small molecule drugs were selected for further evaluation. The compounds, including Saquinavir, Hypericin, Baicalein and Bromocriptine, could bind the N-terminus and C-terminus of the homology model of the 2019-nCoV Nsp14, thus providing as a candidate drug against 2019-nCoV for further study. " " "
Peer Review Status:Awaiting Review
Subjects: Medicine, Pharmacy >> Pharmacology submitted time 2020-02-23
Hua Li
Canrong Wu
Yueying Yang
Yang Liu
Peng Zhang
Yali Wang
Qiqi Wang
Yang Xu
Mingxue Li
Mengzhu Zheng
Lixia Chen
Abstract： A novel coronavirus (SARS-CoV-2) infectious disease has broken out in Wuhan, Hubei Province since December 2019, and spread rapidly from Wuhan to other areas, which has been listed as an international concerning public health emergency. We compared the Spike proteins from four sources, SARS-CoV-2, SARS-CoV, MERS-CoV and Bat-CoVRaTG13, and found that the SARS-CoV-2 virus sequence had redundant PRRA sequences. Through a series of analyses, we propose the reason why SARS-CoV-2is more infectious than other coronaviruses. And through structure based virtual ligand screening, we foundpotentialfurin inhibitors, which might be used in the treatment of new coronary pneumonia. " "
Peer Review Status:Awaiting Review
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