Publications by authors named "Chen Sun"

390 Publications

Screening ovarian cancers with Raman spectroscopy of blood plasma coupled with machine learning data processing.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Sep 4;265:120355. Epub 2021 Sep 4.

School of Physics and Astronomy, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address:

The mortality of ovarian cancer is closely related to its poor rate of early detection. In the search of an efficient diagnosis method, Raman spectroscopy of blood features as a promising technique allowing simple, rapid, minimally-invasive and cost-effective detection of cancers, in particular ovarian cancer. Although Raman spectroscopy has been demonstrated to be effective to detect ovarian cancers with respect to normal controls, a binary classification remains idealized with respect to the real clinical practice. This work considered a population of 95 woman patients initially suspected of an ovarian cancer and finally fixed with a cancer or a cyst. Additionally, 79 normal controls completed the ensemble of samples. Such sample collection proposed us a study case where a ternary classification should be realized with Raman spectroscopy of the collected blood samples coupled with suitable spectroscopic data treatment algorithms. In the medical as well as data points of view, the appearance of the cyst case considerably reduces the distances among the different populations and makes their distinction much more difficult, since the intermediate cyst case can share the specific features of the both cancer and normal cases. After a proper spectrum pretreatment, we first demonstrated the evidence of different behaviors among the Raman spectra of the 3 types of samples. Such difference was further visualized in a high dimensional space, where the data points of the cancer and the normal cases are separately clustered, whereas the data of the cyst case were scattered into the areas respectively occupied by the cancer and normal cases. We finally developed and tested an ensemble of models for a ternary classification with 2 consequent steps of binary classifications, based on machine learning algorithms, allowing identification with sensitivity and specificity of 81.0% and 97.3% for cancer samples, 63.6% and 91.5% for cyst samples, 100% and 90.6% for normal samples.
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http://dx.doi.org/10.1016/j.saa.2021.120355DOI Listing
September 2021

Association of Maternal Gestational Weight Gain With Left Ventricle Geometry and Function in Offspring at 4 Years of Age: A Prospective Birth Cohort Study.

Front Pediatr 2021 27;9:722385. Epub 2021 Aug 27.

Department of Pediatric Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Maternal gestational weight gain (GWG) may be associated with cardiovascular diseases in the offspring from childhood to adulthood. We aimed to investigate the association between maternal GWG and the left ventricle (LV) geometry and function in the offspring, and explore the influence of the intrauterine environment on early childhood cardiac change. Data of 981 mother-offspring pairs from the Shanghai Birth Cohort was used. Maternal pre-pregnancy weight and height, weight in the first trimester (≤ 12 weeks), and before delivery were measured. The echocardiography, blood pressure, and anthropometry assessment were evaluated in the offspring at 4 years of age. Interventricular septal thickness during diastole had a significantly positive correlation with total GWG [β = 0.009, (0.001, 0.017)]. In the second and third trimesters, LV mass index [β = 0.149, (0.015,0.282)], interventricular septal thickness in systole [β = 0.027, (0.011,0.043)], and in diastole [β = 0.014, (0.005,0.023)] were positively associated with GWG. The risks of eccentric [OR = 1.115, (1.232, 1.010)] and concentric hypertrophy [OR = 1.133, (1.259,1.018)] increased with the elevation of maternal GWG. This study suggested that the excessive maternal GWG was associated with the thickening of the interventricular septum in the offspring, especially during the second and third trimesters. Excessive GWG in the second and third trimesters was a risk factor for LV eccentric and concentric hypertrophy in the offspring.
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http://dx.doi.org/10.3389/fped.2021.722385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429845PMC
August 2021

Grain Boundary Design of Solid Electrolyte Actualizing Stable All-Solid-State Sodium Batteries.

Small 2021 Sep 1:e2103819. Epub 2021 Sep 1.

Department of Chemistry, Tsinghua University, Beijing, 100084, China.

Advanced inorganic solid electrolytes (SEs) are critical for all-solid-state alkaline metal batteries with high safety and high energy densities. A new interphase design to address the urgent interfacial stability issues against all-solid-state sodium metal batteries (ASSMBs) is proposed. The grain boundary phase of a Mg -doped Na Zr Si PO conductor (denoted as NZSP-xMg) is manipulated to introduce a favorable Na Mg PO -dominant interphase which facilitates its intimate contact with Na metal and works as an electron barrier to suppress Na metal dendrite penetration into the electrolyte bulk. The optimal NZSP-0.2Mg electrolyte endows a low interfacial resistance of 93 Ω cm at room temperature, over 16 times smaller than that of Na Zr Si PO . The Na plating/stripping with small polarization is retained under 0.3 mA cm for more than 290 days (7000 h), representing a record high cycling stability of SEs for ASSMBs. An all-solid-state NaCrO //Na battery is accordingly assembled manifesting a high capacity of 110 mA h g at 1 C for 1755 cycles with almost no capacity decay. Excellent rate capability at 5 C is realized with a high Coulombic efficiency of 99.8%, signifying promising application in solid-state electrochemical energy storage systems.
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http://dx.doi.org/10.1002/smll.202103819DOI Listing
September 2021

Update on Pharmacological Activities, Security, and Pharmacokinetics of Rhein.

Evid Based Complement Alternat Med 2021 17;2021:4582412. Epub 2021 Aug 17.

State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.

Rhein, belonging to anthraquinone compounds, is one of the main active components of rhubarb and . Rhein has a variety of pharmacological effects, such as cardiocerebral protective effect, hepatoprotective effect, nephroprotective effect, anti-inflammation effect, antitumor effect, antidiabetic effect, and others. The mechanism is interrelated and complex, referring to NF-B, PI3K/Akt/MAPK, p53, mitochondrial-mediated signaling pathway, oxidative stress signaling pathway, and so on. However, to some extent, its clinical application is limited by its poor water solubility and low bioavailability. Even more, rhein has potential liver and kidney toxicity. Therefore, in this paper, the pharmacological effects of rhein and its mechanism, pharmacokinetics, and safety studies were reviewed, in order to provide reference for the development and application of rhein.
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http://dx.doi.org/10.1155/2021/4582412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387172PMC
August 2021

PPARs-Orchestrated Metabolic Homeostasis in the Adipose Tissue.

Int J Mol Sci 2021 Aug 20;22(16). Epub 2021 Aug 20.

College of Pharmacy, Xinjiang Medical University, Urumqi 830054, China.

It has been more than three decades since peroxisome proliferator-activated receptors (PPARs) were first discovered. Many investigations have revealed the central regulators of PPARs in lipid and glucose homeostasis in response to different nutrient conditions. PPARs have attracted much attention due to their ability to improve metabolic syndromes, and they have also been proposed as classical drug targets for the treatment of hyperlipidemia and type 2 diabetes (T2D) mellitus. In parallel, adipose tissue is known to play a unique role in the pathogenesis of insulin resistance and metabolic syndromes due to its ability to "safely" store lipids and secrete cytokines that regulate whole-body metabolism. Adipose tissue relies on a complex and subtle network of transcription factors to maintain its normal physiological function, by coordinating various molecular events, among which PPARs play distinctive and indispensable roles in adipocyte differentiation, lipid metabolism, adipokine secretion, and insulin sensitivity. In this review, we discuss the characteristics of PPARs with special emphasis on the roles of the different isotypes in adipocyte biology.
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http://dx.doi.org/10.3390/ijms22168974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396609PMC
August 2021

Selective production of singlet oxygen from zinc-etching hierarchically porous biochar for sulfamethoxazole degradation.

Environ Pollut 2021 Aug 18;290:117991. Epub 2021 Aug 18.

State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, 310027, China.

Porous carbons are appealing low-cost and metal-free catalysts in persulfate-based advanced oxidation processes. In this study, a family of porous biochar catalysts (ZnBC) with different porous structures and surface functionalities are synthesized using a chemical activation agent (ZnCl). The functional biochars are used to activate persulfate for sulfamethoxazole (SMX) degradation. ZnBC-3 with the highest content of ketonic group (CO, 1.25 at%) exhibits the best oxidation efficiency, attaining a rate constant (k) of 0.025 min. The correlation coefficient of the density of CO to k (R = 0.992) is much higher than the linearity of the organic adsorption capacity to k (R = 0.694), implying that CO is the intrinsic active site for persulfate activation. Moreover, the volume of mesopore (R = 0.987), and Zeta potential (R = 0.976) are also positive factors in PS adsorption and catalysis. In the mechanistic study, we identified that singlet oxygen is the primary reactive oxygen species. It can attack the -NH group aligned to the benzene ring to form dimer products which could be adsorbed on the biochar surface to reach complete removal of the SMX. The optimal pH range is 4-6 which will minimize the electrostatic repulsion between ZnBCs and the reactants. The SMX degradation in ZnBC/PS system was immune to inorganic anions but would compete with organic impurities in the real wastewater. Finally, the biochar catalysts are filled in hydrogel beads and packed in a flow-through packed-bed column. The continuous system yields a high removal efficiency of over 86% for 8 h without decline, this work provided a simple biochar-based persulfate catalyst for complete antibiotics removal in salty conditions.
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http://dx.doi.org/10.1016/j.envpol.2021.117991DOI Listing
August 2021

Chemoprotective Effect of Daphnetin Against Benzene-induced Leukemia via Alteration of CYP2E1.

Appl Biochem Biotechnol 2021 Aug 24. Epub 2021 Aug 24.

Department of Hematology, Qingdao Hiser Medical Center, Shibei District, No. 4 Renmin Road, Qingdao City, 266033, Shandong Province, China.

Leukemia is the overproduction of a large number of immature blood cells entering into the peripheral blood due to the malignancy of blood-forming tissues. The modern treatment mechanisms that are associated with leukemia comprise chemotherapy, allogeneic cell transplantation, and radiation therapy that comes with adverse side effects. Thus, medicinal herbs and their bioactive compounds are gaining more attention nowadays toward the treatment of leukemia, owing to their minimal side effects. The current study was aimed to scrutinize the antileukemic effect of daphnetin against benzene-induced leukemia in rats and explore the underlying mechanism of its action. Benzene was used for the induction of leukemia in experimental rats. The rats were divided into different groups and body weight; hematological parameters, DNA fragmentation, and cell cycle regulatory parameter were also estimated. RT-PCR was used for the estimation of mRNA expression of cytochrome P450 2E1 (CYP2E1), a membrane protein widely found in liver cells. Daphnetin-treated rats showed upregulation of body weight as compared to other groups. Moreover, daphnetin reduced the blasts (67.8%) in leukemic rats. It also altered the hematological parameters such as RBC (69.8%), WBC (54.5%), lymphocytes (47.6%), neutrophils (48.9%), monocytes (44.7%), eosinophils (48.7%), and basophils (43.5%), respectively. Daphnetin-treated rats showed an increased level of proteins p21 and p53 and reduced level of cyclins D1 and E. RT-PCR showed an upregulated mRNA expression of CYP2E1 (48.4%) of the daphnetin-treated group as compared to other groups. The current study shows the antileukemic effect of daphnetin and highlights the possibility of its use in leukemia to minimize the side effect of the usual therapy.
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http://dx.doi.org/10.1007/s12010-021-03611-yDOI Listing
August 2021

Supramolecular Tropism Driven Aggregation of Nanoparticles In Situ for Tumor-Specific Bioimaging and Photothermal Therapy.

Small 2021 Aug 18:e2101332. Epub 2021 Aug 18.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, 999078, China.

Inorganic nanomedicine has attracted increasing attentions in biomedical sciences due to their excellent biocompatibility and tunable, versatile functionality. However, the relatively poor accumulation and retention of these nanomedicines in targeted tissues have often hindered their clinical translation. Herein, highly efficient, targeted delivery, and in situ aggregation of ferrocene (Fc)-capped Au nanoparticles (NPs) are reported to cucurbit[7]uril (CB[7])-capped Fe O NPs (as an artificial target) that are magnetically deposited into the tumor, driven by strong, multipoint CB[7]-Fc host-guest interactions (here defined as "supramolecular tropism" for the first time), leading to high tumor accumulation and retention of these NPs. The in vitro and in vivo studies demonstrate the precisely controlled, specific accumulation, and retention of Au NPs in the tumor cells and tissue via supramolecular tropism and in situ aggregation, which afford locally enhanced CT imaging of cancer and enable tumor-specific photothermal therapy attributed to the plasmonic coupling effects between adjacent Au NPs within the supramolecular aggregations. This work provides a novel concept of supramolecular tropism, which may drive targeted delivery and enable specific accumulation, retention, and activation of nanomedicine for improved bioimaging and therapy of cancer.
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http://dx.doi.org/10.1002/smll.202101332DOI Listing
August 2021

Precise incorporation of transition metals into organolead oxyhalide crystalline materials for photocatalysis.

Dalton Trans 2021 Sep 10;50(33):11360-11364. Epub 2021 Aug 10.

Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, 1239 Siping Rd., Shanghai 200092, P. R. China.

Organolead halide crystalline materials are an emerging class of high-performance photocatalysts. However, limited studies have been performed to tune their photoactive properties by precise introduction of transition metals. Herein, we report the successful incorporation of four different transition metal centers (Mn, Co, Ni and Zn) into a lead oxyhalide crystalline matrix via isoreticular synthesis. Importantly, the precise control of the incoming transition metal positions has been achieved by its octahedral coordination with three organic ligands. Among them, the Zn-incorporated material exhibits the highest catalytic activity and recyclable activity in benzylamine oxidation under UV light, which is probably ascribed to the long carrier lifetime and efficient carrier transfer.
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http://dx.doi.org/10.1039/d1dt01621kDOI Listing
September 2021

Large-Section Histopathology Can Better Indicate the Immune Microenvironment and Predict the Prognosis of Pancreatic Ductal Adenocarcinoma Than Small-Section Histopathology.

Front Oncol 2021 12;11:694933. Epub 2021 Jul 12.

Department of Pathology, Changhai Hospital Affiliated to Navy Medical University (Second Military Medical University), Shanghai, China.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor and is insensitive to radiotherapy and chemotherapy, as it is highly correlated with its complex tumor microenvironment (TME). A comprehensive description of PDAC's immune microenvironment at the pathological level has not been reported, thus limiting its treatment. Previous studies have shown that large-section histopathology (LSH) can reveal the complete structure and margin of the tumor on a single slice and effectively reflect intratumoral heterogeneity. LSH, as opposed to classic small-section histopathology (SSH), can also be used to explore the infiltration state of immune cells in different regions. In the current study, EnVision immunohistochemical staining was used to explore the panoramic distribution of CD4-, CD8-, CD15-, CD20-, and CD56 (surface markers of helper T cells, cytotoxic T cells, neutrophils, B cells, and NK cells, respectively)-positive cells in 102 pairs of paraffin wax-embedded PDAC samples (LSH SSH) for the first time. These indicators were then analyzed, and correlations of clinicopathological characteristics with clinical prognoses were analyzed. The findings of this study show that LSH can effectively indicate more immune cells than SSH. Upregulated CD4, CD8, CD20, and CD56 or downregulated CD15 was correlated with a good prognosis in PDAC patients. However, analysis of SSH showed that only upregulated CD4 and CD8 can be used as indicators of a good prognosis. Multivariate Cox regression analysis showed that 7 variables, namely, pTNM stage (=0.002), PDL1 expression (=0.001), CDX2 expression (=0.008), DPC4 expression (=0.004), CD4 expression in LSH (<0.001), CD8 expression in LSH (=0.010) and CD15 expression in LSH (=0.031), were significantly correlated with the prognosis of PDAC patients. The findings of this study indicate that LSH is an effective tool for a panoramic assessment of the immune microenvironment in pancreatic cancer patients.
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http://dx.doi.org/10.3389/fonc.2021.694933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340684PMC
July 2021

Genetic and functional analyses detect one pathological NFATC1 mutation in a Chinese tricuspid atresia family.

Mol Genet Genomic Med 2021 Aug 7:e1771. Epub 2021 Aug 7.

Scientific Research Center, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Background: Cardiac valvulogenesis is a highly conserved process among vertebrates and cause unidirectional flow of blood in the heart. It was precisely regulated by signal pathways such as VEGF, NOTCH, and WNT and transcriptional factors such as TWIST1, TBX20, NFATC1, and SOX9. Tricuspid atresia refers to morphological deficiency of the valve and confined right atrioventricular traffic due to tricuspid maldevelopment, and is one of the most common types of congenital valve defects.

Methods: We recruited a healthy couple with two fetuses aborted due to tricuspid atresia and identified related gene mutations using whole-exome sequencing. We then discussed the pathogenic significance of this mutation by bioinformatic and functional analyses.

Results: PROVEAN, PolyPhen, MutationTaster, and HOPE indicated the mutation could change the protein function and cause disease; Western blotting showed the expression of NFATC1 c.964G>A mutation was lower than the wild type. What's more, dual-luciferase reporter assay showed the transcriptional activity of NFATC1 was impact by mutation and the expression of downstream DEGS1 was influenced.

Conclusion: Taken together, the c.964G>A mutation might be pathological and related to the occurrence of disease. Our research tended to deepen the understanding of etiology of tricuspid atresia and gene function of NFATC1, and provide some references or suggestions for genetic diagnosis of tricuspid atresia.
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http://dx.doi.org/10.1002/mgg3.1771DOI Listing
August 2021

Investigation of iron-ammine and amido complexes within a C-symmetrical phosphinic amido tripodal ligand.

Dalton Trans 2021 Aug 2;50(32):11197-11205. Epub 2021 Aug 2.

Department of Chemistry, University of California-Irvine, 1102 Natural Sciences II, Irvine, CA 92697-2025, USA.

The primary and secondary coordination spheres can have large regulatory effects on the properties of metal complexes. To examine their influences on the properties of monomeric Fe complexes, the tripodal ligand containing phosphinic amido groups, N,N',N''-[nitrilotris(ethane-2,1-diyl)]tris(P,P-diphenylphosphinic amido) ([poat]), was used to prepare [Fepoat] complexes. The Fe complex was four-coordinate with 4 N-atom donors comprising the primary coordination sphere. The Fe complex was six-coordinate with two additional ligands coming from coordination of O-atom donors on two of the phosphinic amido groups in [poat]. In the crystalline phase, each complex was part of a cluster containing potassium ions in which KO[double bond, length as m-dash]P interactions served to connect two metal complexes. The [Fepoat] complexes bound an NH molecule to form trigonal bipyramidal structures that also formed three intramolecular hydrogen bonds between the ammine ligand and the O[double bond, length as m-dash]P units of [poat]. The relatively negative one-electron redox potential of -1.21 V vs. [FeCp] is attributed to the phosphinic amido group of the [poat] ligand. Attempts to form the Fe-amido complex via deprotonation were not conclusive but isolation of [Fepoat(NHtol)] using the p-toluidine anion was successful, allowing for the full characterization of this complex.
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http://dx.doi.org/10.1039/d1dt01032hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376781PMC
August 2021

Variants in a cis-regulatory element of TBX1 in conotruncal heart defect patients impair GATA6-mediated transactivation.

Orphanet J Rare Dis 2021 07 31;16(1):334. Epub 2021 Jul 31.

Department of Pediatric Cardiology, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.

Background: TBX1 (T-box transcription factor 1) is a major candidate gene that likely contributes to the etiology of velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS). Although the haploinsufficiency of TBX1 in both mice and humans results in congenital cardiac malformations, little has been elucidated about its upstream regulation. We aimed to explore the transcriptional regulation and dysregulation of TBX1.

Methods: Different TBX1 promoter reporters were constructed. Luciferase assays and electrophoretic mobility shift assays (EMSAs) were used to identify a cis-regulatory element within the TBX1 promoter region and its trans-acting factor. The expression of proteins was identified by immunohistochemistry and immunofluorescence. Variants in the cis-regulatory element were screened in conotruncal defect (CTD) patients. In vitro functional assays were performed to show the effects of the variants found in CTD patients on the transactivation of TBX1.

Results: We identified a cis-regulatory element within intron 1 of TBX1 that was found to be responsive to GATA6 (GATA binding protein 6), a transcription factor crucial for cardiogenesis. The expression patterns of GATA6 and TBX1 overlapped in the pharyngeal arches of human embryos. Transfection experiments and EMSA indicated that GATA6 could activate the transcription of TBX1 by directly binding with its GATA cis-regulatory element in vitro. Furthermore, sequencing analyses of 195 sporadic CTD patients without the 22q11.2 deletion or duplication identified 3 variants (NC_000022.11:g.19756832C > G, NC_000022.11:g.19756845C > T, and NC_000022.11:g. 19756902G > T) in the non-coding cis-regulatory element of TBX1. Luciferase assays showed that all 3 variants led to reduced transcription of TBX1 when incubated with GATA6.

Conclusions: Our findings showed that TBX1 might be a direct transcriptional target of GATA6, and variants in the non-coding cis-regulatory element of TBX1 disrupted GATA6-mediated transactivation.
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http://dx.doi.org/10.1186/s13023-021-01981-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325851PMC
July 2021

A quick protocol for the preparation of mouse retinal cryosections for immunohistochemistry.

Open Biol 2021 Jul 28;11(7):210076. Epub 2021 Jul 28.

The Key Laboratory for Human Disease Gene Study of Sichuan Province and Institute of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, People's Republic of China.

Immunohistochemistry (IHC) using mouse retinal cryosections is widely used to study the expression and intracellular localization of proteins in mouse retinas. Conventionally, the preparation of retinal cryosections from mice involves tissue fixation, cryoprotection, the removal of the cornea and lens, embedding and sectioning. The procedure takes 1-2 days to complete. Recently, we developed a new technique for the preparation of murine retinal cryosections by coating the sclera with a layer of Super Glue. This enables us to remove the cornea and extract the lens from the unfixed murine eye without causing the eyecup to collapse. In the present study, based on this new technique, we move a step forward to modify the conventional protocol. Unlike in the conventional protocol, in this method, we first coat the unfixed mouse eyeball on the sclera with Super Glue and then remove the cornea and lens. The eyecup is then fixed, cryoprotected and sectioned. This new protocol for the preparation of retinal cryosections reduces the time for the procedure to as little as 2 h. Importantly, the new protocol consistently improves the morphology of retinal sections as well as the image quality of IHC. Thus, this new quick protocol will be greatly beneficial to the community of visual sciences by expediting research progress and improving the results of IHC.
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http://dx.doi.org/10.1098/rsob.210076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316803PMC
July 2021

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Drug Metab Dispos 2021 Jul 26. Epub 2021 Jul 26.

Center for Developmental Pharmacol & Toxicol, Shenyang Pharmaceutical University, China

Icotinib (ICT) is an anti-tumor drug approved by China National Medical Products Administration and is found to be effective to conquer non-small cell lung cancer. The present study aimed at the interaction of ICT with CYP3A. ICT exhibited time-, concentration- and NADPH-dependent inhibitory effect on recombinant human CYP3A4/5 (rhCYP3A4/5). About 60% of CYP3A activity was suppressed by ICT at 50 μM after 30 min. The observed enzyme inhibition could not be recovered by dialysis. Nifedipine protected CYP3A from the inactivation by ICT. The inhibitory effects of ICT on CYP3A were neither influenced by GSH/NAL nor by SOD/catalase. Incubation of ICT with human hepatic microsomes produced a ketene reactive intermediate trapped by 4-bromobenzylamine. CYP3A4 dominated the metabolic activation of ICT to the ketene intermediate. Ethyl and vinyl analogs of ICT did not induce inactivation of rhCYP3A4/5, which indicates that acetylenic bioactivation of ICT contributed to the enzyme inactivation. Moreover, the metabolic activation of ICT resulted in heme destruction. In conclusion, this study demonstrated that ICT was a mechanism-based inactivator of rhCYP3A4/5, and heme destruction by the ketene metabolite may be responsible for the observed CYP3A inactivation. Cytochrome P450 enzymes play an important role in drug-drug interactions. The present study demonstrated icotinib (ICT), an inhibitor of epidermal growth factor receptor (EGFR) for the treatment of non-small cell lung cancer, is a mechanism-based inactivator of rhCYP3A4/5. The study provided solid evidence for the involvement of acetylene moiety in the metabolic activation as well as the inactivation of the enzyme. Furthermore, the resulting ketene intermediate was found to destruct heme, which is possibly responsible for the observed enzyme inactivation.
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http://dx.doi.org/10.1124/dmd.121.000369DOI Listing
July 2021

The pros and cons of motor, memory, and emotion-related behavioral tests in the mouse traumatic brain injury model.

Neurol Res 2021 Jul 26:1-25. Epub 2021 Jul 26.

Department of Human Anatomy, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.

Traumatic brain injury (TBI) is a medical emergency with high morbidity and mortality. Motor, memory, and emotion-related deficits are common symptoms following TBI, yet treatment is very limited. To develop new drugs and find new therapeutic avenues, a wide variety of TBI models have been established to mimic the heterogeneity of TBI. In this regard, along with histologic measures, behavioral functional outcomes provide valuable insight into the underlying neuropathology and guide neurorehabilitation efforts for neuropsychiatric impairment after TBI. Development, characterization, and application of behavioral tests that can assess functional neurologic deficits are essential to the development of translational therapies. This comprehensive review aims to summarize 19 common behavioral tests from three aspects (motor, memory, and emotion-related) that are associated with TBI pathology. Discussion covers the apparatus, the test steps, the evaluation indexes, data collection and analysis, animal performance and applications, advantages and disadvantages as well as precautions to eliminate bias wherever possible. We discussed recent studies on TBI-related preconditioning, biomarkers, and optimized behavioral protocols. The neuropsychologic tests employed in clinics were correlated with those used in mouse TBI models. In summary, this review provides a comprehensive, up-to-date reference for TBI researchers to choose the right neurobehavioral protocol according to the research objectives of their translational investigation.
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http://dx.doi.org/10.1080/01616412.2021.1956290DOI Listing
July 2021

Supramolecular micelles as multifunctional theranostic agents for synergistic photodynamic therapy and hypoxia-activated chemotherapy.

Acta Biomater 2021 09 13;131:483-492. Epub 2021 Jul 13.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, and MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau 999078, China. Electronic address:

Photodynamic therapy (PDT), where a photosensitizer (under light irradiation) converts molecular oxygen to singlet oxygen to elicit programmed cell death, is a promising cancer treatment modality with a high temporal and spatial resolution. However, only limited cancer treatment efficacy has been achieved in clinical PDT due to the hypoxic conditions of solid tumor microenvironment that limits the generation of singlet oxygen, and PDT process often leads to even more hypoxic microenvironment due to the consumption of oxygens during therapy. Herein, we designed novel supramolecular micelles to co-deliver photosensitizer and hypoxia-responsive prodrug to improve the overall therapeutic efficacy. The supramolecular micelles (CPC) were derived from a polyethylene glycol (PEG) system dually tagged with hydrophilic cucurbit[7]uril (CB[7]) and hydrophobic Chlorin e6 (Ce6), respectively on each end, for synergistic antitumor therapy via PDT of Ce6 and chemotherapy of a hypoxia-responsive prodrug, banoxantrone (AQ4N), loaded into the cavity of CB[7]. In addition, CPC was further modularly functionalized by folate (FA) via strong host-guest interaction between folate-amantadine (FA-ADA) and CB[7] to produce a novel nanoplatform, [email protected], for targeted delivery. [email protected] exhibited enhanced cellular uptake, negligible cytotoxicity and good biocompatibility, and improved intracellular reactive oxygen species (ROS) generation efficiency. More importantly, in vivo evaluation of [email protected] revealed a synergistic antitumor efficacy between PDT of Ce6 and hypoxia-activated chemotherapy of AQ4N (that can be converted to chemotherapeutic AQ4 for tumor chemotherapy in response to the strengthened hypoxic tumor microenvironment during PDT treatment). This study not only provides a new nanoplatform for synergistic photodynamic-chemotherapeutic treatment, but also offers important new insights to design and development of multifunctional supramolecular drug delivery system. STATEMENT OF SIGNIFICANCE: Photodynamic therapy (PDT) has exhibited a variety of advantages for cancer phototherapy as compared to traditional chemotherapy. However, the unsatisfactory therapeutic efficacy by PDT alone as a result of the enhanced tumor hypoxia during PDT has limited its clinical application. Herein, we designed multifunctional supramolecular micelles to co-deliver photosensitizer and hypoxia-responsive prodrug to improve the overall therapeutic efficacy. The supramolecular micelles are biocompatible and possess strong red absorption, controlled drug release profile, and ultimately enhanced therapeutic outcome via PDT-chemotherapy. This study not only provides a new nanoplatform for synergistic photodynamic-chemotherapeutic treatment of cancer, but also offers important new insights to design and development of multifunctional supramolecular drug delivery tool for multi-modality cancer therapy.
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http://dx.doi.org/10.1016/j.actbio.2021.07.014DOI Listing
September 2021

The development of brain rhythms at rest and its impact on vocabulary acquisition.

Dev Sci 2021 Jul 14:e13157. Epub 2021 Jul 14.

State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China.

A long-standing question in developmental science is how the neurodevelopment of the brain influences cognitive functions. Here, we examined the developmental change of resting EEG power and its links to vocabulary acquisition in school-age children. We further explored what mechanisms may mediate the relation between brain rhythm maturation and vocabulary knowledge. Eyes-opened resting-state EEG data were recorded from 53 typically-developing Chinese children every 2 years between the ages of 7 and 11. Our results showed first that delta, theta, and gamma power decreased over time, whereas alpha and beta power increased over time. Second, after controlling for general cognitive abilities, age, home literacy environment, and phonological skills, theta decreases explained 6.9% and 14.4% of unique variance in expressive vocabulary at ages 9 and 11, respectively. We also found that beta increase from age 7 to 9 significantly predicted receptive vocabulary at age 11. Finally, theta decrease predicted expressive vocabulary through the effects of phoneme deletion at age 9 and tone discrimination at age 11. These results substantiate the important role of brain oscillations at rest, especially theta rhythm, in language development. The developmental change of brain rhythms could serve as sensitive biomarkers for vocabulary development in school-age children, which would be of great value in identifying children at risk of language impairment.
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http://dx.doi.org/10.1111/desc.13157DOI Listing
July 2021

Developmental toxicity caused by sanguinarine in zebrafish embryos via regulating oxidative stress, apoptosis and wnt pathways.

Toxicol Lett 2021 Oct 9;350:71-80. Epub 2021 Jul 9.

Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Shandong Provincial Engineering Laboratory for Biological Testing Technology, 28789 Jingshidong Road, Licheng District, Jinan, 250103, Shandong Province, PR China. Electronic address:

Sanguinarine, derived from the root of Sanguinaria canadensis, have multiple biological activities, such as antimicrobial, insecticidal, antitumor, anti-inflammatory and anti-angiogenesis effect, but little is known about its toxicity on normal embryonic development. Here, we study the developmental toxicity using zebrafish model. Notably, sanguinarine caused a significant increase of the malformation rate and decrease of hatching rates and body length of zebrafish embryos. Sanguinarine also impaired the normal development of heart, liver and nerve system of zebrafish embryos. Further, the ROS level and MDA concentrations were remarkably increased, while the activity of T-SOD was decreased. In addition, obvious increase of apoptosis were observed by AO staining or TUNEL assay. Further studies showed that the oxidative stress-, apoptosis-related genes were changed, while genes of nrf2 and wnt pathways were inhibited by sangunarine. To sum up, our study will be helpful to understand the adverse effect of sanguinarine on embryonic development and the underlying molecular mechanism.
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http://dx.doi.org/10.1016/j.toxlet.2021.07.001DOI Listing
October 2021

Accurate Bulk Quantitation of Droplet Digital Polymerase Chain Reaction.

Anal Chem 2021 07 12;93(29):9974-9979. Epub 2021 Jul 12.

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California 94158, United States.

Droplet digital PCR provides superior accuracy for nucleic acid quantitation. The requirement of microfluidics to generate and analyze the emulsions, however, is a barrier to its adoption, particularly in low resource settings or clinical laboratories. Here, we report a novel method to prepare ddPCR droplets by vortexing and readout of the results by bulk analysis of recovered amplicons. We demonstrate the approach by accurately quantitating SARS-CoV-2 sequences using entirely bulk processing and no microfluidics. Our approach for quantitating reactions should extend to all digital assays that generate amplicons, including digital PCR and LAMP conducted in droplets, microchambers, or nanoliter wells. More broadly, our approach combines important attributes of ddPCR, including enhanced accuracy and robustness to inhibition, with the high-volume sample processing ability of quantitative PCR.
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http://dx.doi.org/10.1021/acs.analchem.1c00877DOI Listing
July 2021

Reply to: Extended adjuvant temozolomide in newly diagnosed glioblastoma: the more, the better?

Neuro Oncol 2021 Sep;23(9):1616-1618

Oncology Data Analytics Program (ODAP), Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain.

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http://dx.doi.org/10.1093/neuonc/noab125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408847PMC
September 2021

Tumor Purity Coexpressed Genes Related to Immune Microenvironment and Clinical Outcomes of Lung Adenocarcinoma.

J Oncol 2021 14;2021:9548648. Epub 2021 Jun 14.

Department of Radiology, Shengjing Hospital of China Medical University, Shenyang 110001, China.

Purpose: Lung cancer tissue includes tumor tissue, stromal cells, immune cells, and epithelial cells. These nontumor cells dilute the tumor purity in lung cancer tissues. Tumor purity plays an essential role in the immune response to lung cancer. At present, the biological processes related to the purity of lung cancer tumors remains unclear.

Methods: We measured tumor purity in 486 lung carcinoma tissues from TCGA-LUAD FPKM by using the "estimate" R package. Lung carcinoma tumor mutation burden was calculated by analyzing TCGA single nucleotide polymorphism data. The immune cell proportion was also evacuated via the CIBERSORT method. Lung carcinoma samples with < 0.05 were considered significant. Based on the tumor purity and lung carcinoma gene matrix, we performed weighted gene coexpression network analysis (WGCNA), and the tumor purity-related module was identified. Then, we analyzed the functions of the factors involved in the module. We screened the coexpressed factors related to clinical outcome and immunophenotype. Finally, expression levels of these factors were measured at tissue and single-cell levels.

Results: A lung cancer tumor purity correlated coexpression network was determined. Five coexpressed genes (CD4, CD53, EVI2B, PLEK, and SASH3) were identified as tumor purity coexpressed genes that negatively correlated with tumor purity. Because the factors in the coexpression network often participate in similar biological processes, we found that CD4, CD53, EVI2B, PLEK, and SASH3 were most related to positive regulation of cytokine production and interleukin-2 production through functional enrichment. In a clinical phenotype analysis, we found that these five factors can be used as independent prognostic risk factors. We found that these factors were significantly negatively correlated with tumor purity and positively correlated with the immune score in the immunophenotyping analysis. Using GSEA analysis, we found that the antigen processing and presentation pathway were related to the five tumor coexpressed genes mentioned above. SASH3 and CD53 were used to conduct a prognostic model based on the interaction analysis of the Support Vector Machine and the Least Absolute Shrinkage and Selection Operator. SASH3 was verified to be related to CD8A using a single-cell analysis.

Conclusion: Tumor purity-related coexpression factors in the tumor microenvironment have essential clinical, genomic, and biological significance in lung cancer. These coexpression factors (SASH3 and CD53) can be used to classify tumor purity phenotypes and to predict clinical outcomes.
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http://dx.doi.org/10.1155/2021/9548648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216812PMC
June 2021

Adsorption and thermal degradation of microplastics from aqueous solutions by Mg/Zn modified magnetic biochars.

J Hazard Mater 2021 Oct 25;419:126486. Epub 2021 Jun 25.

State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou 310027, China.

Microplastics (MPs) derived from plastic wastes have attracted wide attention throughout the world due to the wide distribution, easy transition, and potential threats to organisms. This study proposes efficient Mg/Zn modified magnetic biochar adsorbents for microplastic removal. For polystyrene (PS) microspheres (1 µm, 100 mg/mL) in aqueous solution, the removal efficiencies of magnetic biochar (MBC), Mg modified magnetic biochar (Mg-MBC), and Zn modified magnetic biochar (Zn-MBC) were 94.81%, 98.75%, and 99.46%, respectively. It is supposed that the adsorption process was a result of electrostatic interaction and chemical bonding interaction between microplastics and biochar. The coexisting HPO and organic matters in real water significantly affected the removal efficiency of Zn-MBC due to competitive adsorption effect. Microplastic degradation and adsorbent regeneration were accomplished by thermal treatment simultaneously. The degradation of adsorbed MPs was promoted by the catalytic active sites originated from Mg and Zn, releasing adsorption sites. Thermal regeneration maintained the adsorption capability. Even after five adsorption-pyrolysis cycles, MBC (95.02%), Mg-MBC (94.60%), and Zn-MBC (95.79%) showed high microplastic removal efficiency. Therefore, the low-cost, eco-friendly, and robust Mg/Zn-MBCs have promising potential for application in microplastic removal.
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http://dx.doi.org/10.1016/j.jhazmat.2021.126486DOI Listing
October 2021

The HSP90 inhibitor, XL888, enhanced cell apoptosis via downregulating STAT3 after insufficient radiofrequency ablation in hepatocellular carcinoma.

Life Sci 2021 Oct 26;282:119762. Epub 2021 Jun 26.

Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang 110004, China. Electronic address:

Aims: Radiofrequency ablation (RFA) is the first-line option for early-stage hepatocellular carcinoma (HCC). However, the residual tumor attributed to insufficient RFA (iRFA) led to tumor recurrence and metastasis. Novel combination strategies are urgently needed to enhance efficiency of RFA.

Main Methods: For in vitro iRFA models, HCC cells were placed in a water bath at 46 °C for 10 min and then returned to the original incubator. For in vivo models, HCC cells were implanted subcutaneously into nude mice. The nude mice were then randomly assigned into 4 groups: control group, XL888 group, iRFA group, combination of XL888 and iRFA group. CCK8 was performed to detect cell viability; Hoechst 33258 was used to explore nuclear morphology; The expression levels of proteins were demonstrated by western blotting; Co-localization of HSP90 and STAT3 was elucidated by immunofluorescence confocal microscopy; Immunohistochemistry was used to explore expression levels of proteins at tissue level.

Key Findings: XL888 promoted apoptosis of HCC cells induced by heat via inhibiting expression levels of Mcl-1 and cleaved-caspase 3 in vivo and in vitro. XL888 attenuated the complex formation of HSP90 and STAT3, leading to decreased expression levels of STAT3 and p-STAT3. In human HCC tissues, IHC scores of HSP90 were positively correlated with those of STAT3. Overexpression of STAT3 rescued cell apoptosis induced by co-treatment of XL888 and heat.

Significance: We implied that XL888 promoted apoptosis of HCC cells induced by heat via disrupting the binding of HSP90 and STAT3, providing theoretical basis for a novel combination strategy for HCC.
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http://dx.doi.org/10.1016/j.lfs.2021.119762DOI Listing
October 2021

Circular RNA circUBR4 regulates ox-LDL-induced proliferation and migration of vascular smooth muscle cells through miR-185-5p/FRS2 axis.

Mol Cell Biochem 2021 Jun 22. Epub 2021 Jun 22.

Department of Cardiovascular Medicine, Chongqing Dazu District People's Hospital, No. 1073 Erhuan South Road, Tangxiang Street, Dazu County, Chongqing, 402360, China.

Circular RNAs (circRNAs) have been reported to play vital roles in atherosclerosis. However, the precise roles of circUBR4 in atherosclerosis remain unclear. The purpose of this study is to investigate the regulatory roles of circUBR4 in atherosclerosis. The expression levels of circUBR4, miR-185-5p, and Fibroblast growth factor receptor substrate 2 (FRS2) were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR) assay. Human vascular smooth muscle cells (VSMCs) were treated with oxidized low-density lipoprotein (ox-LDL) to mimic atherosclerosis condition in vitro. Cell proliferation was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide (MTT), colony-forming, and 5-ethynyl-2'-deoxyuridine (EdU) assays. Wound healing and transwell assays were used to assess cell migration. The interaction relationship between miR-185-5p and circUBR4 or FRS2 was confirmed by dual-luciferase reporter and RNA pull-down assays. CircUBR4 was overexpressed in atherosclerosis patients and VSMCs treated with ox-LDL, and the knockdown of circUBR4 abolished ox-LDL-induced enhanced effects on the proliferation and migration of VSMCs. MiR-185-5p, interacted with FRS2, was a target of circUBR4 in VSMCs. The silencing of miR-185-5p reversed the effects caused by circUBR4 knockdown on ox-LDL-induced VSMCs. In addition, overexpression of miR-185-5p suppressed the proliferation and migration of VSMCs by targeting FRS2. CircUBR4 contributed to ox-LDL-induced VSMC proliferation and migration through up-regulating FRS2 via miR-185-5p.
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http://dx.doi.org/10.1007/s11010-021-04207-0DOI Listing
June 2021

Machine learning-based LIBS spectrum analysis of human blood plasma allows ovarian cancer diagnosis.

Biomed Opt Express 2021 May 2;12(5):2559-2574. Epub 2021 Apr 2.

School of Physics and Astronomy, Shanghai Jiao Tong University, Shanghai 200240, China.

Early-stage screening and diagnosis of ovarian cancer represent an urgent need in medicine. Usual ultrasound imaging and cancer antigen CA-125 test when prescribed to a suspicious population still require reconfirmations. Spectroscopic analyses of blood, at the molecular and atomic levels, provide useful supplementary tests when coupled with effective information extraction methods. Laser-induced breakdown spectroscopy (LIBS) was employed in this work to record the elemental fingerprint of human blood plasma. A machine learning data treatment process was developed combining feature selection and regression with a back-propagation neural network, resulting in classification models for cancer detection among 176 blood plasma samples collected from patients, including also ovarian cyst and normal cases. Cancer diagnosis sensitivity and specificity of respectively 71.4% and 86.5% were obtained for randomly selected validation samples.
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http://dx.doi.org/10.1364/BOE.421961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176811PMC
May 2021

Polyamine-Responsive Morphological Transformation of a Supramolecular Peptide for Specific Drug Accumulation and Retention in Cancer Cells.

Small 2021 Jun 10:e2101139. Epub 2021 Jun 10.

State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, 999078, China.

The precise accumulation and extended retention of nanomedicines in the tumor tissue has been highly desired for cancer therapy. Here a novel supramolecular-peptide derived nanodrug (SPN) that can be transformed to microfibers in response to intracellular polyamine in cancer cells for significantly enhanced tumor specific accumulation and retention is developed. The supramolecular-peptide is constructed via the non-covalent interactions between cucurbit[7]uril (CB[7]) and Phe on Phe-Phe-Val-Leu-Lys-camptothecin conjugates (FFVLK-CPT, PC). The resultant amphiphilic supramolecular complex subsequently self-assembles into nanoparticles with a hydrodynamic diameter of 164.2 ± 3.7 nm. Upon internalization into spermine-overexpressed cancer cells, the CB[7]-Phe host-guest pairs can be competitively dissociated by spermine and can release free PC, which immediately form β-sheet structures and subsequently reorganize into microfibers, leading to dramatically improved accumulation, retention, and sustained release of CPT in tumor cells for highly effective cancer therapy. Accordingly, this SPN exhibit rather low toxicity against non-cancerous cells due to the morphological stability and fast exocytosis of the nanodrugs in those cells without abundant spermine. This study reports the first supramolecular peptide capable of polyamine-responsive "nanoparticle-to-microfiber" transformation for specific tumor therapy with minimal side effects. This work also offers novel insights to the design and development of stimuli-responsive nanomaterials as precision medicine.
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http://dx.doi.org/10.1002/smll.202101139DOI Listing
June 2021

Metabolic activation of zolmitriptan mediated by CYP2D6.

Xenobiotica 2021 Jun 7:1-29. Epub 2021 Jun 7.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P. R. China.

Zolmitriptan (ZOL), a member of triptans, has been used for the treatment of migraine with definite therapeutic effects. However, several cases of liver injury associated with ZOL have been reported and the underlying mechanisms remain unclear.The present study aimed to investigate the metabolic activation of ZOL and . ZOL-derived glutathione (GSH) and -acetyl cysteine (NAC) conjugates were detected in rat liver microsomal incubations. In addition, the GSH and NAC conjugates were also found in bile and urine of rats given ZOL, respectively.ZOL-derived GSH conjugate M1 was also observed in ZOL-treated rat primary hepatocytes, and the formation of M1 was inhibited by pre-cultured with quinidine (a selective inhibitor of CYP2D6). Combining with recombinant P450 enzymes incubations, we found that CYP2D6 was the predominant enzyme responsible for the metabolic activation of ZOL.ZOL can be metabolized to an ,-unsaturated imine intermediate by CYP2D6. Pre-treatment of primary hepatocytes with quinidine was able to reverse ZOL-induced cytotoxicity. The finding facilitates the understanding of the mechanisms involved in ZOL-associated liver adverse reactions.
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http://dx.doi.org/10.1080/00498254.2021.1938290DOI Listing
June 2021

A hypoxia responsive nanoassembly for tumor specific oxygenation and enhanced sonodynamic therapy.

Biomaterials 2021 08 3;275:120822. Epub 2021 May 3.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Science, University of Macau, Avenida da Universidade, Taipa, Macau, China. Electronic address:

The hypoxic tumor microenvironment (TME) and non-specific distribution of sonosensitizers are two major obstacles that limit practical applications of sonodynamic therapy (SDT) in combating tumors. Here we report a hypoxia-responsive nanovesicle (hMVs) as delivery vehicles of a sonosensitizer to enhance the efficacy of SDT via specific payload release and local oxygenation in the tumor. The nanovesicles are composed of densely packed manganese ferrite nanoparticles (MFNs) embedded in hypoxia-responsive amphiphilic polymer membranes. With δ-aminolevulinic acid (ALA) loaded in the hollow cavities, the hMVs could rapidly dissociate into discrete nanoparticles in the hypoxic TME to release the payload and induce the generation of reactive oxygen species (ROS) under ultrasound (US) radiation. Meanwhile, the released MFNs could catalytically generate O to overcome the hypoxic TME and thus enhance the efficacy of SDT. After treatment, the dissociated MFNs could be readily excreted from the body via renal clearance to reduce long term toxicity. In vitro and in vivo experiments displayed effective tumor inhibition via hMVs-mediated SDT, indicating the great potential of this unique nanoplatform in effective SDT by generating sufficient ROS in deep-seated hypoxic tumors that are not readily accessible by conventional photodynamic therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120822DOI Listing
August 2021
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