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Integrated proteomic profiling identifies amino acids selectively cytotoxic to pancreatic cancer cells

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The Innovation 2024年第3期5卷 138-145页

作者： Alfred Akinlalu Zachariah Flaten Komila Rasuleva Md Saimon Mia Aaron Bauer Santhalingam Elamurugan Nega Ejjigu Sudipa Maity Amara Arshad Min Wu Wenjie Xia Jia Fan Ang Guo Sijo Mathew Dali Sun Department of Electrical and Computer Engineering University of Denver2155 E Wesley AvenueDenverCO 80210USA Biomedical Engineering Program North Dakota State University1401 Centennial BoulevardEngineering AdministrationRoom 203FargoND 58102USA Department of Pharmaceutical Sciences School of PharmacyNorth Dakota State University1001 S.1401 Albrecht Boulevard Sudro HallFargoND 58102USA Materials and Nanotechnology Program North Dakota State University1410 North 14th AvenueCIE 201FargoND 58102USA wenzhou Institute University of Chinese Academy of SciencesWenzhouZhejiang 325000China Department of Aerospace Engineering Iowa State UniversityAmesIA 50011USA Center for Cellular and Molecular Diagnostics Tulane University School of Medicine1430 Tulane AvenueNew OrleansLA 70112USA Department of Biochemistry and Molecular Biology Tulane University School of Medicine1430 Tulane AvenueNew OrleansLA 70112USA Knoebel Institute for Healthy Aging University of Denver2155 E Wesley AvenueDenverCO 80210USA

Pancreatic adenocarcinoma(PDAC)is one of the most deadly cancers,characterized by extremely limited therapeutic options and a poor prognosis,as it is often diagnosed during late disease *** and selective treatments are urgently needed,since current therapies have limited efficacy and significant side *** proteomics analysis of extracellular vesicles,we discovered an imbalanced distribution of amino acids secreted by PDAC tumor *** findings revealed that PDAC cells preferentially excrete proteins with certain preferential amino acids,including isoleucine and histidine,via extracellular *** amino acids are associated with disease progression and can be targeted to elicit selective toxicity to PDAC tumor *** in vitro and in vivo experiments demonstrated that supplementation with these specific amino acids effectively eradicated PDAC ***,we also identified XRN1 as a potential target for these amino *** high selectivity of this treatment method allows for specific targeting of tumor metabolism with very low toxicity to normal ***,we found this treatment approach is easy-to-administer and with sustained tumor-killing ***,our findings reveal that exocytosed amino acids may serve as therapeutic targets for designing treatments of intractable PDAC and potentially offer alternative treatments for other types of cancers.

关键词： finding identif selectivity

11β-hydroxysteroid dehydrogenase types 1 and 2. in postnatal development of rat testis： gene express,on, localization and regulation by luteinizing hormone and androgens

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Asian Journal of Andrology 2014年第6期16卷 811-816页

作者： Hong-Yu Zhou Xin-Xin Chen Han Lin Ai-Li Fei Ren-Shan Ge Pharmacology Department School of Pharmacy Wenzhou Medical University Wenzhou China Institute of Molecular Toxicology and Pharmacology Wenzhou Medical University Wenzhou China The 2nd Affiliated Hospital Wenzhou Medical University Wenzhou China Population Council Rockefeller University New York USA.

11β-hydroxysteroid dehydrogenase type 1 （11β-HSD1） and type 2 （11β-HSD2） are expressed in rat testis, where they regulate the local concentrations of glucocorticoids. Here, we investigated the expression and localization of 11β-HSD in rat testis during postnatal development, and the regulation of these genes by luteinizing hormone （LH） and androgens, mRNA and protein levels were analyzed by quantitative real-time-polymerase chain reaction and western blotting, respectively, in testes collected from rats at postnatal day （PND） 7, 14, 21, 35, and 90, and from rats treated with LH, 7α.methyl-19-nortestosterone （MENT） and testosterone at PND 21 and PND 90. Immunohistochemical staining was used to identify the localization of the 11β-HSD in rat testis at PND 7, 14, and 90. We found that 11β-HSD1 expression was restricted to the interstitial areas, and that its levels increased during rat testis development. In contrast, whereas 11β-HSD2 was expressed in both the interstitial areas and seminiferous tubules at PND 7, it was present only in the interstitial areas at PND 90, and its levels declined during testicular development. Moreover, 11β-HSD1 mRNA was induced by LH in both the PND 21 and 90 testes and by MENT at PND 21, whereas 11β-HSD2 mRNA was induced by testosterone and MENT in the PND 21 testis and by LH in the PND 90 testis. In conclusion, our study indicates that the 11β-HSD1 and 11β-HSD2 genes have distinct patterns of spatiotemporal expression and hormonal regulation during postnatal development of the rat testis.

关键词： 11β-hydroxysteroid dehydrogenase type 1 11β-hydroxysteroid dehydrogenase type 2 development Leydig cell testis

Synthesis and Crystal Structure of Monocarbonyl Analogs of Curcumin

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Chinese Journal of Structural Chemistry 2012年第4期31卷 491-498页

作者：赵承光陈小燕胡杰张丽赵云洁杨树林梁广 School of pharmacy Wenzhou Medical College Institute of Biotechnology Nanjing University of Science and Technology The First Affiliated Hospital Wenzhou Medical College

Two monocarbonyl analogs of curcumin containing bis（2,6-difluorobenzyl） were synthesized,and their molecular structures were characterized by 1H NMR,ESI-MS,and X-ray *** this paper,the crystal structures of these two analogs（A75 and C75） are described and compared with their bis（2-fluorobenzyl） analogues as well as with the available data of *** cyclopentane rings in A75 have an envelope conformation,while the cyclohexane ring in C75 has a chair *** compounds are symmetrical and the central structure of A75 and C75 connects with two benzylidene rings through E,E-oriented double bonding.

关键词： bis(2 6-difluorobenzyl) X-ray crystallography mono-carbonyl analogues of curcumincurcumin

Theoretical Study on the Structures,Spectral Properties,and Drugability of Xenicane-type Diterpenoids from Dictyota dichotoma

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Chemical Research in Chinese Universities 2022年第2期38卷 622-631页

作者： HUANG Luoyi SUN Xiang CHEN Mengyi YAN Pengcheng WANG Chaojie School of Pharmaceutical Sciences Wenzhou Medical UniversityWenzhou 325035P.R.China Department of pharmacy The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000P.R.China

There are few reports on the relationship between the biological activity and structure of secondary metabolites from Dictyota dichotoma. In this work, the geometric and electronic structures, infrared spectra, ultraviolet spectra, 13C and 1H NMR spectra of 16 xenicane-type diterpenoids extracted from Dictyota dichotoma were studied by the density functional theory ωB97XD/6-311+G(2d,p) method. The analysis of the reactivity indices was carried out via the conceptual density functional theory. Furthermore, a pharmacodynamic evaluation was performed using ADME/Tox. The geometric structure analysis found that all 16 diterpenoids had the same unsaturated, branched chains and could be divided into two categories according to the ring size, including nine-membered and eight-membered rings. A hydroxyl group on the lactone ring reduced the stability of the compound. In contrast, a hydroxyl group on the parent ring had little effect on the compound's stability. The electrostatic potential results preliminarily predicted active sites for nucleophilic/electrophilic reactions. The fitting results of infrared and nuclear magnetic resonance(NMR) data showed that the theoretical values obtained by this method were consistent with the experimental values. The UV-visible absorption spectra showed that the solvent effects caused different redshifts of the absorption peaks. The absorption strength was enhanced. The sixteen diterpenoids displayed a strong absorption peak in the range of 180―200 nm, but the compound containing a carbonyl group presents a weaker absorption peak in the field of 200―240 nm. Compounds 9―11, 14, and 15 have better stability and reactivity with lower chemical potentials and higher electronegativity, electrophilic index, and hardness values. The local reactivity descriptors further identified nucleophilic/electrophilic reaction sites for the sixteen compounds. Finally, the pharmacodynamic evaluation results predicted that compounds 2, 4, 8, 11, and 14―16 have

关键词： Dictyota dichotoma Diterpenoid Conceptual density functional theory

Metabolite changes in the ipsilateral and contralateral cerebral hemispheres in rats with middle cerebral artery occlusion

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Neural Regeneration Research 2017年第6期12卷 931-937页

作者： Lei Ruan Yan Wang Shu-chao Chen Tian Zhao Qun Huang Zi-long Hu Neng-zhi Xia Jin-jin Liu Wei-jian Chen Yong Zhang Jing-liang Cheng Hong-chang Gao Yun-jun Yang Hou-zhang Sun Department of Radiology First Affiliated Hospital of Wenzhou Medical University Department of Radiology First Affiliated Hospital of Zhengzhou University School of pharmacy Wenzhou Medical University

Cerebral ischemia not only causes pathological changes in the ischemic areas but also induces a series of secondary changes in more distal brain regions（such as the contralateral cerebral hemisphere）. The impact of supratentorial lesions, which are the most common type of lesion, on the contralateral cerebellum has been studied in patients by positron emission tomography, single photon emission computed tomography, magnetic resonance imaging and diffusion tensor imaging. In the present study, we investigated metabolite changes in the contralateral cerebral hemisphere after supratentorial unilateral ischemia using nuclear magnetic resonance spectroscopy-based metabonomics. The permanent middle cerebral artery occlusion model of ischemic stroke was established in rats. Rats were randomly divided into the middle cerebral artery occlusion 1-, 3-, 9-and 24-hour groups and the sham group. ~1H nuclear magnetic resonance spectroscopy was used to detect metabolites in the left and right cerebral hemispheres. Compared with the sham group, the concentrations of lactate, alanine, γ-aminobutyric acid, choline and glycine in the ischemic cerebral hemisphere were increased in the acute stage, while the concentrations of N-acetyl aspartate, creatinine, glutamate and aspartate were decreased. This demonstrates that there is an upregulation of anaerobic glycolysis（shown by the increase in lactate）, a perturbation of choline metabolism（suggested by the increase in choline）, neuronal cell damage（shown by the decrease in N-acetyl aspartate） and neurotransmitter imbalance（evidenced by the increase in γ-aminobutyric acid and glycine and by the decrease in glutamate and aspartate） in the acute stage of cerebral ischemia. In the contralateral hemisphere, the concentrations of lactate, alanine, glycine, choline and aspartate were increased, while the concentrations of γ-aminobutyric acid, glutamate and creatinine were decreased. This suggests that there is a difference in the metabolite chan

关键词： occlusion hemisphere glutamate aspartate metabolite creatinine lactate neuronal glycine carotid

Alantolactone-loaded chitosan/hyaluronic acid nanoparticles suppress psoriasis by deactivating STAT3 pathway and restricting immune cell recruitment

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Asian Journal of Pharmaceutical Sciences 2022年第2期17卷 268-283页

作者： Ruijie Chen Yuan-Yuan Zhai Lining Sun Zeqing Wang Xing Xia Qing Yao Longfa Kou Department of pharmacy the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityWenzhou 325027China School of Pharmaceutical Sciences Wenzhou Medical UniversityWenzhou 325035China

Psoriasis is a common chronic immune-mediated skin disease characterized by hyperproliferation and aberrant differentiation of keratinocytes and massive infiltration of inflammatory immune *** studies showed that Signal Transducer and Activator of Transcription 3(STAT3),which plays an important role in cell survival,proliferation,differentiation,angiogenesis,and immune responses,is constitutively activated in epidermal keratinocytes of human psoriatic skin *** addition,STAT3 promotes the differentiation and expansion of T cells and facilitates cytokine production,thereby exacerbating the condition of ***(ALT)is a sesquiterpene lactone compound that could selectively suppress STAT3 activation,but its effectiveness and application in psoriasis treatment have not been *** this study,we developed ALT loaded chitosan/hyaluronic acid nanoparticles(CHALT),and investigated its therapeutic potential for psoriasis *** effectively abrogated the hyperproliferation by inducing ROS-mediated apoptosis with loss of mitochondrialmembrane potential,and also inhibited IL-6-induced STAT3 signaling activation and inflammatory reaction in HaCaT cell *** an Imiquimod(IMQ)-induced psoriasis model,the topical treatment of psoriasis lesions with CHALT effectively attenuated the STAT3 hyperactivation within keratinocytes and ameliorated the symptoms of *** addition,it was found that CHALT restricted the recruitment of immune *** results indicated that ALT-based nanoformulation CHALT holds great potential for psoriasis therapy.

关键词： Psoriasis Alantolactone STAT3 Chitosan Nanoparticle

The role of transporters in cancer redox homeostasis and cross-talk with nanomedicines

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Asian Journal of Pharmaceutical Sciences 2020年第2期15卷 145-157页

作者： Longfa Kou Xinyu Jiang Huirong Huang Xinlu Lin Youting Zhang Qing Yao Ruijie Chen Department of pharmacy The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityWenzhou 325027China School of Pharmaceutical Sciences Wenzhou Medical UniversityChashanWenzhou 325035China

Tumor cell usually exhibits high levels of reactive oxygen species and adaptive antioxidant system due to the metabolic,genetic,and microenvironment-associated *** altered redox homeostasis can promote tumor progression,development,and treatment *** membrane transporters are involved in the resetting redox homeostasis and play important roles in tumor ***,targeting the involved transporters to disrupt the altered redox balance emerges as a viable strategy for cancer *** addition,nanomedicines have drawn much attention in the past *** nanomedicines to target or reset the redox homeostasis alone or combined with other therapies has brought convincing data in cancer *** this review,we will introduce the altered redox balance in cancer metabolism and involved transporters,and highlight the recent advancements of redox-modulating nanomedicines for cancer treatment.

关键词： Cancer metabolism ROS,Redox homeostasis Membrane transporter xCT/SLC7A11 Nanomedicine

Novel hybrids from N-hydroxyarylamide and indole ring through click chemistry as histone deacetylase inhibitors with potent antitumor activities

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Chinese Chemical Letters 2015年第6期26卷 675-680页

作者： Mao Cai Jie Hu Ji-Lai Tian Huang Yan Chen-Guo Zheng Wan-Le Hu Department of Coloproctology The Second Affiliated Hospital of Wenzhou Medical University Department of pharmacy Wenzhou Medical University Jiangsu Key Laboratory for Biomaterials and Devices School of Biological Science and Medical EngineeringSoutheast University

Novel hybrid molecules 8a-8o were designed and synthesized by connecting indole ring with N- hydroxyarylamide through alkyl substituted triazole, and their in vitro biological activities were evaluated. It was discovered that most of target compounds showed promising anticancer activities, particularly for 8n, which had a significant HDACs inhibitory and antiproliferative activities comparable to or slightly stronger than SAHA against human carcinoma cells. Furthermore, compound 8n exhibited much better selectivity for HDAC1 over HDAC6 and HDAC8 than SAHA. In addition, compound 8n also could dose-dependently induce cancer cell cycling arrest at G0/G1 phase and promote the expression of the acetylation for histone H3 and tubulin in vitro. Therefore, our novel findings may provide a new framework for the design of new selective HDAC inhibitor for the treatment of cancer.

关键词： Synthesis Anti-tumor agents Histone deacetylase inhibitors N-Hydroxyarylamides Click chemistry

GW842166X Alleviates Osteoarthritis by Repressing LPS-mediated Chondrocyte Catabolism in Mice

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Current medical Science 2022年第5期42卷 1046-1054页

作者： Wan-ran HUANG Jun-xue TU Ai-qing QIAO Li-jia CHEN Department of pharmacy The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityWenzhou325000China

Objective To explore the role and underlying mechanism of GW842166X on osteoarthritis and osteoarthritis-associated abnormal *** The extracted mouse chondrocytes were treated with GW842166X followed by lipopolysaccharide(LPS).The chondrocytes were divided into the control group,LPS group,LPS+50 nmol/L GW842166X group,and LPS+100 nmol/L GW842166X *** cytotoxicity of GW842166X was tested using the CCK-8 *** blot,RT-qPCR,and ELISA were applied to evaluate the expression of the inflammatory biomarkers in mouse *** expression of extracellular matrix molecules was detected by the Western blot,RT-qPCR,and ***,the activity of NF-κB was checked by the Western blot and *** mouse Hulth models were generated to examine the in vivo effects of GW842166X on *** and eosin staining,safranin O/fast green staining,and immunohistochemistry were applied to detect the histological *** GW842166X below 200µmol/L had no cytotoxicity on the mouse ***-induced high expression of TGF-β1,IL-10,TNF-α,and IL-6 was significantly reduced by *** addition,GW842166X upregulated the expression of aggrecan and collagen type III,which was downregulated after the LPS *** upregulated expression of ADAMTS-5 and MMP-13 by LPS stimulation was dropped in response to the GW842166X ***,LPS decreased the IκBαexpression in the cytoplasm and increased the nuclear p65 ***,these changes were reversed by the GW842166X ***,the damages in the knees caused by the Hulth surgery in mice were restored by *** GW842166X impeded the LPS-mediated catabolism in mouse chondrocytes,thereby inhibiting the progression of osteoarthritis.

关键词： GW842166X lipopolysaccharide osteoarthritis chondrocyte catabolism cartilage extracellular matrix