Publications by authors named "Guowei Wang"

102 Publications

Machine Learning Prediction Models for Mechanically Ventilated Patients: Analyses of the MIMIC-III Database.

Front Med (Lausanne) 2021 1;8:662340. Epub 2021 Jul 1.

Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.

Mechanically ventilated patients in the intensive care unit (ICU) have high mortality rates. There are multiple prediction scores, such as the Simplified Acute Physiology Score II (SAPS II), Oxford Acute Severity of Illness Score (OASIS), and Sequential Organ Failure Assessment (SOFA), widely used in the general ICU population. We aimed to establish prediction scores on mechanically ventilated patients with the combination of these disease severity scores and other features available on the first day of admission. A retrospective administrative database study from the Medical Information Mart for Intensive Care (MIMIC-III) database was conducted. The exposures of interest consisted of the demographics, pre-ICU comorbidity, ICU diagnosis, disease severity scores, vital signs, and laboratory test results on the first day of ICU admission. Hospital mortality was used as the outcome. We used the machine learning methods of -nearest neighbors (KNN), logistic regression, bagging, decision tree, random forest, Extreme Gradient Boosting (XGBoost), and neural network for model establishment. A sample of 70% of the cohort was used for the training set; the remaining 30% was applied for testing. Areas under the receiver operating characteristic curves (AUCs) and calibration plots would be constructed for the evaluation and comparison of the models' performance. The significance of the risk factors was identified through models and the top factors were reported. A total of 28,530 subjects were enrolled through the screening of the MIMIC-III database. After data preprocessing, 25,659 adult patients with 66 predictors were included in the model analyses. With the training set, the models of KNN, logistic regression, decision tree, random forest, neural network, bagging, and XGBoost were established and the testing set obtained AUCs of 0.806, 0.818, 0.743, 0.819, 0.780, 0.803, and 0.821, respectively. The calibration curves of all the models, except for the neural network, performed well. The XGBoost model performed best among the seven models. The top five predictors were age, respiratory dysfunction, SAPS II score, maximum hemoglobin, and minimum lactate. The current study indicates that models with the risk of factors on the first day could be successfully established for predicting mortality in ventilated patients. The XGBoost model performs best among the seven machine learning models.
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http://dx.doi.org/10.3389/fmed.2021.662340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280779PMC
July 2021

Hypoxia-alleviated nanoplatform to enhance chemosensitivity and sonodynamic effect in pancreatic cancer.

Cancer Lett 2021 Jul 8;520:100-108. Epub 2021 Jul 8.

Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, China; Research Center of Ultrasound in Medicine and Biomedical Engineering, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, China. Electronic address:

Pancreatic cancer is a severe disease that threatens human health. The hypoxic tumor microenvironment in pancreatic cancer leads to resistance to conventional therapies and helps to maintain tumor malignancy. First-line drugs present the disadvantage of systemic side effects, and a synergistic method with sonodynamic therapy (SDT) has been established as an emerging approach. In this study, we produced hypoxia-alleviating nanoplatforms (denoted as PZGI NPs) with zeolitic imidazolate frameworks-90 (ZIF-90) nanoparticles nucleating on platinum (Pt) nanoparticles and co-loaded with gemcitabine and IR780. This platform can catalyze peroxide to oxygen with loaded Pt nanoparticles to alleviate tumor hypoxia. Moreover, the loaded drugs could be quickly released in the lysosome microenvironment, which has a low pH value and high ATP level microenvironment in the mitochondria. This strategy could enhance the sensitivity of cancer cells to chemotherapy. Further, under ultrasound exposure, it could transfer the produced oxygen into a highly cytotoxic singlet oxygen for the augmented sonodynamic effect. Therefore, this multifunctional hypoxia-alleviating nanoplatform offers a promising strategy for chemo-sonodynamic therapy against pancreatic cancer.
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http://dx.doi.org/10.1016/j.canlet.2021.07.008DOI Listing
July 2021

Dolomiaea souliei ethyl acetate extract protected against α-naphthylisothiocyanate-induced acute intrahepatic cholestasis through regulation of farnesoid x receptor-mediated bile acid metabolism.

Phytomedicine 2021 Jul 3;87:153588. Epub 2021 Jun 3.

College of Pharmaceutical Sciences, Key Laboratory of Luminescence Analysis and Molecular Sensing (Ministry of Education), Southwest University, No. 2 Tiansheng Road, Chongqing 400715, P.R. China. Electronic address:

Background: Cholestasis is characterized by accumulation of bile components in liver and systemic circulation. Restoration of bile acid homeostasis via activating farnesoid x receptor (FXR) is a promising strategy for the treatment of cholestasis. FXR-SHP (small heterodimer partner) axis plays an important role in maintaining bile acid homeostasis.

Purpose: To investigate the anti-cholestasis effect of Dolomiaea souliei (Franch.) C.Shih (D. souliei) and clarify its underlying mechanism against α-naphthylisothiocyanate (ANIT) induced acute intrahepatic cholestasis.

Methods: ANIT-induced Sprague-Dawley rats were employed to investigate the anti-cholestasis effect of D. souliei ethyl acetate extract (DSE). Ursodeoxycholic acid (UDCA) was used as positive control. Bile flow and blood biochemical parameters were measured. Liver histopathological examination was conducted via hematoxylin-eosin staining. Western blot analysis was carried out to evaluate the protein levels related to bile acids metabolism and inflammation. The interactions between FXR and costunolide or dehydrocostus lactone, were conducted by molecular docking experiments. The effect of costunolide and dehydrocostus lactone on aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels and FXR expression were also evaluated using guggulsterone-induced L02 cells.

Results: DSE could promote bile excretions and protect against ANIT-induced liver damage in cholestasis rats. Protein levels of FXR, SHP, Na/taurocholate cotransporter (NTCP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2) were increased and the expressions of cholesterol 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1) were decreased by DSE. Meanwhile, the anti-inflammatory factors, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) were also significantly increased, and the pro-inflammatory factor, interleukin-10 (IL-10), was significantly decreased in rats of DSE groups. Molecular docking revealed that costunolide and dehydrocostus lactone could be well docked into the FXR protein molecule, and hydrophobic interactions played the main function. Costunolide could reverse the increased AST and ALT levels and increase the FXR expression in guggulsterone-induced L02 cells.

Conclusion: DSE had an anti-cholestasis effect by activating FXR-SHP axis, inhibiting synthesis of bile acid, and increasing bile secretion, together with inflammatory response and improving liver injury. Costunolide may be the main active component. This study provided a potential therapeutic mechanism for D. souliei as an anti-cholestasis medicine in the treatment of cholestasis liver diseases.
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http://dx.doi.org/10.1016/j.phymed.2021.153588DOI Listing
July 2021

Tissue-specific transcriptome analyses reveal candidate genes for stilbene, flavonoid and anthraquinone biosynthesis in the medicinal plant Polygonum cuspidatum.

BMC Genomics 2021 May 17;22(1):353. Epub 2021 May 17.

College of Life Sciences, University of Chinese Academy of Sciences, No.19(A) Yuquan Road, Shijingshan District, Beijing, 100049, People's Republic of China.

Background: Polygonum cuspidatum Sieb. et Zucc. is a well-known medicinal plant whose pharmacological effects derive mainly from its stilbenes, anthraquinones, and flavonoids. These compounds accumulate differentially in the root, stem, and leaf; however, the molecular basis of such tissue-specific accumulation remains poorly understood. Because tissue-specific accumulation of compounds is usually associated with tissue-specific expression of the related biosynthetic enzyme genes and regulators, we aimed to clarify and compare the transcripts expressed in different tissues of P. cuspidatum in this study.

Results: High-throughput RNA sequencing was performed using three different tissues (the leaf, stem, and root) of P. cuspidatum. In total, 80,981 unigenes were obtained, of which 40,729 were annotated, and 21,235 differentially expressed genes were identified. Fifty-four candidate synthetase genes and 12 transcription factors associated with stilbene, flavonoid, and anthraquinone biosynthetic pathways were identified, and their expression levels in the three different tissues were analyzed. Phylogenetic analysis of polyketide synthase gene families revealed two novel CHS genes in P. cuspidatum. Most phenylpropanoid pathway genes were predominantly expressed in the root and stem, while methylerythritol 4-phosphate and isochorismate pathways for anthraquinone biosynthesis were dominant in the leaf. The expression patterns of synthase genes were almost in accordance with metabolite profiling in different tissues of P. cuspidatum as measured by high-performance liquid chromatography or ultraviolet spectrophotometry. All predicted transcription factors associated with regulation of the phenylpropanoid pathway were expressed at lower levels in the stem than in the leaf and root, but no consistent trend in their expression was observed between the leaf and the root.

Conclusions: The molecular knowledge of key genes involved in the biosynthesis of P. cuspidatum stilbenes, flavonoids, and anthraquinones is poor. This study offers some novel insights into the biosynthetic regulation of bioactive compounds in different P. cuspidatum tissues and provides valuable resources for the potential metabolic engineering of this important medicinal plant.
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http://dx.doi.org/10.1186/s12864-021-07658-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127498PMC
May 2021

A high-efficiency mediator-free Z-scheme BiMoO/AgI heterojunction with enhanced photocatalytic performance.

Sci Total Environ 2021 Aug 19;784:147227. Epub 2021 Apr 19.

MOE Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China. Electronic address:

A high-efficiency Z-scheme BiMoO/AgI heterojunction was designed and fabricated via in situ growth of AgI on BiMoO. Its photocatalytic activity was investigated with the degradation of malachite green (MG). After 40 min of visible light irradiation, near complete degradation of MG (20 mg/L) occurred when BA11 (BiMoO:AgI = 1:1, 2.0 g/L) was present, while only 29.0% and 49.7% of the MG could be degraded in the presence of BiMoO and AgI, respectively. The excellent photocatalytic activity of BA11 results from strong visible light absorption and the low recombination efficiency of photogenerated electron-hole pairs induced by the formation of heterojunction. Density function theory (DFT) calculations revealed that the formation of built-in electric field at the interface between BiMoO and AgI facilitates the effective separation and transfer of photogenerated charge carriers. Results of reuse experiments indicated that the heterostructured photocatalyst has excellent stability. Radical scavenging experiments and electron spin resonance spectra showed that superoxide radicals (O) and hydroxyl radicals (OH) were the major reactive oxygen species in the photocatalytic system. The photocatalytic degradation pathway of MG was proposed based on the organic degradation intermediates detected. These findings demonstrate that the mediator-free Z-scheme BiMoO/AgI heterojunction could serve as a promising photocatalyst in photocatalytic treatment of organic pollutants.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147227DOI Listing
August 2021

Co-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy.

Nat Commun 2021 04 23;12(1):2425. Epub 2021 Apr 23.

Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.

Anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibodies are currently used in the clinic to interupt the PD-1/PD-L1 immune checkpoint, which reverses T cell dysfunction/exhaustion and shows success in treating cancer. Here, we report a histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1), which inhibits tumour histone demethylase Jumonji domain-containing 1A (JMJD1A) and thus downregulates its downstream β-catenin and subsequent PD-L1, providing an antibody-independent paradigm interrupting the PD-1/PD-L1 checkpoint. Synergistically, IOX1 inhibits cancer cells' P-glycoproteins (P-gp) through the JMJD1A/β-catenin/P-gp pathway and greatly enhances doxorubicin (DOX)-induced immune-stimulatory immunogenic cell death. As a result, the IOX1 and DOX combination greatly promotes T cell infiltration and activity and significantly reduces tumour immunosuppressive factors. Their liposomal combination reduces the growth of various murine tumours, including subcutaneous, orthotopic, and lung metastasis tumours, and offers a long-term immunological memory function against tumour rechallenging. This work provides a small molecule-based potent cancer chemo-immunotherapy.
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http://dx.doi.org/10.1038/s41467-021-22407-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065121PMC
April 2021

Enhanced tumour penetration and prolonged circulation in blood of polyzwitterion-drug conjugates with cell-membrane affinity.

Nat Biomed Eng 2021 Apr 15. Epub 2021 Apr 15.

Zhejiang Key Laboratory of Smart BioMaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.

Effective anticancer nanomedicines need to exhibit prolonged circulation in blood, to extravasate and accumulate in tumours, and to be taken up by tumour cells. These contrasting criteria for persistent circulation and cell-membrane affinity have often led to complex nanoparticle designs with hampered clinical translatability. Here, we show that conjugates of small-molecule anticancer drugs with the polyzwitterion poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate) have long blood-circulation half-lives and bind reversibly to cell membranes, owing to the negligible interaction of the polyzwitterion with proteins and its weak interaction with phospholipids. Adsorption of the polyzwitterion-drug conjugates to tumour endothelial cells and then to cancer cells favoured their transcytosis-mediated extravasation into tumour interstitium and infiltration into tumours, and led to the eradication of large tumours and patient-derived tumour xenografts in mice. The simplicity and potency of the polyzwitterion-drug conjugates should facilitate the design of translational anticancer nanomedicines.
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http://dx.doi.org/10.1038/s41551-021-00701-4DOI Listing
April 2021

Pterocephin A, a novel Triterpenoid Saponin from Pterocephalus hookeri induced liver injury by activation of necroptosis.

Phytomedicine 2021 May 19;85:153548. Epub 2021 Mar 19.

College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, PR China. Electronic address:

Background: Pterocephalus hookeri (C. B. Clarke) Höeck, a Tibetan medicine widely used for treatment of rheumatoid arthritis, was recorded in Chinese Pharmacopoeia (2020 version) with slight toxicity. The liver injury was observed in mice with administration of n-butanol extract (BUE) in our previously study. However, the toxic components and the mechanism were still unrevealed.

Purpose: The present study was aimed to isolate and structural elucidate of the toxic compound pterocephin A (PA), as well as evaluate its liver toxicity and investigate its mechanism.

Methods: PA was isolated from the BUE of P. hookeri. Its structure was determined by analysis of HRMS, NMR and ECD data. L-02 cellular viability, LDH, ALT, AST, ROS, intracellular Ca and the fluidity of cell membrane were assessed by multifunctional microplate reader. The PI staining, cell membrane permeability assessment, and mitochondrial fluorescence staining analysis were determined through the fluorescence microscope. Liver samples for mice were assessed by pathological and immunohistochemistry analysis. Expression levels of indicated proteins were measured by western blotting assays.

Results: PA was determined as a previously undescribed oleanolane-type triterpenoid saponin. In vitro study revealed PA significantly induced hepatotoxicity by inhibition of L-02 cell growth, abnormally elevation of ALT and AST. Mechanically, PA induced the damage of cell membrane, fragmentation of mitochondria, and subsequently increase of intracellular Ca and ROS levels, which trigged by necroptosis with the activation of RIP1 and NF-κB signaling pathways. In vivo study confirmed PA could induce liver injury in mice with observation of the body weight loss, increasing of serum ALT and AST, and the histopathological changes in liver tissues.

Conclusion: Our present study indicated that PA was an undescribed toxic constituent in P. hookeri to induce liver injury in mice by activation of necroptosis and inflammation. And the findings are of great significance for the clinical use safely of this herb.
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http://dx.doi.org/10.1016/j.phymed.2021.153548DOI Listing
May 2021

Dolominol a and B, two new neolignans from (Franch.) C.Shih.

Nat Prod Res 2021 Mar 15:1-8. Epub 2021 Mar 15.

College of Pharmaceutical Sciences, Southwest University, Chongqing, P.R. China.

Two new neolignans, dolominol A (1) and dolominol B (2), together with 12 known lignans, -(7,8)-guaiacyl-glycerol--O-4'-dihydroconiferyl ether (3), -(7,​8)-1-​(4-​hydroxy-​3-​methoxyphenyl)​-​2-{4-[()-​3-​hydroxy-​1-​propen​yl)​]-​2-​methoxyphenoxy}-1,​3-​propanediol (4), (-)-dihydrodehydrodiconiferyl alcohol (5), (-)-massoniresinol (6), vladinol D (7), syringaresinol (8), prinsepiol (9), medioresinol (10), (+)-pinoresinol (11), 2-guaicyl-4-oxo-6-catechyl-3,7-dioxabicyclo [3.3.0]octane (12), cycloolivil (13), isolariciresinol (14) were isolated from (Franch.) C.Shih. Their structures were determined by UV, CD, HR-ESI-TOFMS, 1 D and 2 D NMR experiments. Their hepatoprotective effect against LPS-induced L-02 cells injury was also studied. Result revealed that compound showed best protective effect on LPS-induced L-02 cells.
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http://dx.doi.org/10.1080/14786419.2021.1897125DOI Listing
March 2021

Dehydrogenation of light alkanes to mono-olefins.

Chem Soc Rev 2021 Apr 18;50(7):4359-4381. Epub 2021 Feb 18.

State Key Laboratory of Heavy Oil Processing, China University of Petroleum, Qingdao, 266580, P. R. China.

In the past several decades, light alkane dehydrogenation to mono-olefins, especially propane dehydrogenation to propylene has gained widespread attention and much development in the field of research and commercial application. Under suitable conditions, the supported Pt-Sn and CrO catalysts widely used in industry exhibit satisfactory dehydrogenation activity and selectivity. However, the high cost of Pt and the potential environmental problems of CrO have driven researchers to improve the coking and sintering resistance of Pt catalysts, and to find new non-noble metal and environment-friendly catalysts. As for the development of the reactor, it should be noted that low operation pressure is beneficial for improving the single-pass conversion, decreasing the amount of unconverted alkane recycled back to the reactor, and reducing the energy consumption of the whole process. Therefore, the research direction of reactor improvement is towards reducing the pressure drop. This review is aimed at introducing the characteristics of the dehydrogenation reaction, the progress made in the development of catalysts and reactors, and a new understanding of reaction mechanism as well as its guiding role in the development of catalyst and reactor.
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http://dx.doi.org/10.1039/d0cs00983kDOI Listing
April 2021

[Determination of Immunoglobulin Content in Humoral Immunity Evaluation of Biomedical Material Products by Cytometric Beads Array].

Zhongguo Yi Liao Qi Xie Za Zhi 2021 Feb;45(1):96-99

Shandong Province Inspection Center for Medical Devices;NMPA Key Laboratory for Safety Evaluation of Biomaterials and Medical Devices;NMPA Key Laboratory for Quality Control of Pharmaceutical Packaging;Shandong Key Laboratory of Biological Evaluation for Medical Devices, Jinan, 250101.

In this study, cytometric beads array(CBA) was used to determine the immunoglobulin content in humoral immunity evaluation of biomedical materials. The bovine-derived acellular dermal matrix was selected as a test sample and implanted into Balb/C mice subcutaneously to 4 weeks according to the high, medium and low dose groups. Four weeks later, IgG1, IgG2a, IgG2b, IgG3, IgA, and IgM were measured by CBA. The data of the test group and the control group were analyzed statistically. The results showed that compared with the negative control group, there was no significant difference in the IgG3, IgA content in the positive control group, while the IgG1, IgG2a, IgG2b, and IgM contents were significantly higher than the negative control group; no significant differences were seen in the sample groups. The results show that the method is suitable for analysis of immunoglobulin content in humoral immunity evaluation of biomedical materials.
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http://dx.doi.org/10.3969/j.issn.1671-7104.2021.01.020DOI Listing
February 2021

Drinking tea before menopause is associated with higher bone mineral density in postmenopausal women.

Eur J Clin Nutr 2021 Jan 29. Epub 2021 Jan 29.

Chronic Disease Research Institute, The Children's Hospital, and National Clinical Research Center for Child Health, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

Background: Though tea drinking years and menopause stages have been indicated to be related with bone mineral density (BMD), most human studies have not considered the impact of tea drinking beginning time. Whether drinking tea before or after menopause plays a role in BMD is still unclear. This study aims to analyze whether drinking tea before or after menopause influences BMD in Chinese postmenopausal women.

Methods: A total of 1377 postmenopausal women under 80 years were enrolled from the baseline survey of the Lanxi Cohort Study. Participants were initially categorized into non-tea drinking, tea drinking beginning after menopause and tea drinking beginning before menopause groups. Tea drinking groups were subdivided according to tea drinking frequency, concentration and type. Multiple linear regression models were applied to evaluate associations between tea drinking before or after menopause and BMD and the impacts of tea drinking frequency, concentration and type on their associations in analyses including all participants. Interactions of tea drinking frequency, concentration and type with drinking tea before or after menopause were further analyzed.

Results: After adjusting for confounding factors, women who began drinking tea before menopause had significantly higher total and regional BMD than non-tea drinking participants and participants who began drinking tea after menopause. Differences in spine BMD were more significant among those who drank tea ≥four times per week. In addition, significant associations between tea drinking and BMD were found among participants who began drinking tea before menopause in both models, irrespective of the concentration and type of tea. No significant associations were found in subgroups of participants who began drinking tea after menopause in either model.

Conclusions: The results indicate that drinking tea before menopause is related to higher BMD in Chinese postmenopausal women. The relationship is independent of tea drinking concentration and type.
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http://dx.doi.org/10.1038/s41430-021-00856-yDOI Listing
January 2021

[Rapamycin alleviates the symptoms of experimental autoimmune myasthenia gravis rats by down-regulating Th17 cell/regulatory T cell ratio].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2021 Jan;37(1):24-30

Department of Neurology, General Hospital of Ningxia Medical University, Yinchuan 750004, China. *Corresponding author, E-mail:

Objective To study the therapeutic effect of rapamycin (RAPA) on experimental autoimmune myasthenia gravis (EAMG) rats and to explore the related immune mechanisms. Methods The mouse-derived acetylcholine receptor alpha subunit 97-116 peptide (R97-116) was used to immunize Lewis rats to establish an EAMG rat model. The rats were randomly divided into three groups: complete Freund's adjuvant control group (CFA group), EAMG model control group, and RAPA treatment group [1 mg/(kg.d)]. The Lennon muscle strength scoring scale was used to evaluate rats' clinical symptoms in each group once every two days, and their body mass was recorded. ELISA was performed to detect the level of anti-R97-116 antibodies in the peripheral blood of rats. Flow cytometry was used to detect the numbers of Th17 cells and regulatory T cells (Tregs) in rat splenocytes. Splenocytes were stimulated with 5 μg/mL concanavalin A (ConA), 10 μg/mL R97-116 and RPMI1640 medium, and the proliferation activity of rat splenocytes was tested by CCK-8 assay. Results RAPA treatment significantly improved the body mass and clinical scores in EAMG rats. Compared with the CFA group, the number of Th17 cells in the spleen of the EAMG group increased, and the number of Tregs decreased. Compared with the EAMG group, the number of Th17 cells in the spleen of RAPA-treated rats significantly dropped, the number of Tregs went up, and the level of anti-R97-116 antibodies in the serum went down. RAPA treatment inhibited the proliferation of lymphocytes induced by RPMI1640 medium, R97-116, and ConA stimulation. Conclusion RAPA may alleviate the clinical symptoms of EAMG rats by down-regulating the ratio of Th17 cells/Tregs.
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January 2021

Isovitexin modulates autophagy in Alzheimer's disease via miR-107 signalling.

Transl Neurosci 2020 20;11(1):391-401. Epub 2020 Oct 20.

Department of Neurology, General Hospital of Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Incubation Base of National Key Laboratory, Yinchuan, 750004, China.

Background: Alzheimer's disease (AD) is an ultimately fatal, degenerative brain disease in the elderly people. In the current work, we assessed the defensive capability of isovitexin (IVX) through an intracerebroventricular injection of streptozotocin (STZ)-induced AD mouse model.

Methods: Mice were separated into four cohorts: sham-operated control mice; STZ-intoxicated Alzheimer's mice; IVX cohort, IVX + STZ; and Ant-107 cohort, antagomiR-107 + IVX/STZ as in the IVX cohort.

Results: The outcomes indicated that IVX administration ameliorated spatial memory loss and blunted a cascade of neuro-noxious episodes - including increased amyloid-beta (Aβ) and degraded myelin basic protein burden, neuroinflammation (represented by elevated caspase-1, TNF-α and IL-6 levels) and autophagic dysfunction (represented by altered LC3-II, Atg7 and beclin-1 expressions) - via the inhibition of PI3K/Akt/mTOR signalling axis. We considered the question of whether the epigenetic role of microRNA-107 (miR-107) has any impact on these events, by using antagomiR-107.

Conclusion: This probing underscored that miR-107 could be a pivotal regulatory button in the activation of molecular signals linked with the beneficial autophagic process and anti-inflammatory activities in relation to IVX treatment. Hence, this report exemplifies that IVX could guard against Aβ toxicity and serve as an effectual treatment for patients afflicted with AD.
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http://dx.doi.org/10.1515/tnsci-2020-0109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718616PMC
October 2020

Tumor-Associated Macrophage and Tumor-Cell Dually Transfecting Polyplexes for Efficient Interleukin-12 Cancer Gene Therapy.

Adv Mater 2021 Jan 3;33(2):e2006189. Epub 2020 Dec 3.

Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, P. R. China.

Interleukin 12 (IL12) is a potent pro-inflammatory chemokine with multifunction, including promoting cytotoxic T-cell-mediated killing of cancer cells. IL12-based cancer gene therapy can overcome IL12's life-threatening adverse effects, but its clinical translation has been limited by the lack of systemic gene-delivery vectors capable of efficiently transfecting tumors to produce sufficient local IL12. Macrophages inherently excrete IL12, and tumor-associated macrophages (TAMs) are the major tumor component taking up a large fraction of the vectors arriving in the tumor. It is thus hypothesized that a gene vector efficiently transfecting both cancer cells and TAMs would make the tumor to produce sufficient IL12; however, gene transfection of TAMs is challenging due to their inherent strong degradation ability. Herein, an IL12 gene-delivery vector is designed that efficiently transfects both cancer cells and TAMs to make them as a factory for IL12 production, which efficiently activates anticancer immune responses and remodels the tumor microenvironment, for instance, increasing the M1/M2 ratio by more than fourfold. Therefore, the intravenously administered vector retards tumor growth and doubles survival in three animal models' with negligible systemic toxicities. This work reports the first nonviral IL12 gene delivery system that effectively makes use of both macrophages and tumor cells.
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http://dx.doi.org/10.1002/adma.202006189DOI Listing
January 2021

Polyphenol-cisplatin complexation forming core-shell nanoparticles with improved tumor accumulation and dual-responsive drug release for enhanced cancer chemotherapy.

J Control Release 2021 02 7;330:992-1003. Epub 2020 Nov 7.

Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, People's Republic of China; Hangzhou Global Scientific and Technological Innovation Center, Hangzhou 311215, People's Republic of China. Electronic address:

Cisplatin (CDDP) is a potent first-line antitumor drug but suffers severe side effects and poor pharmacokinetics. Its complexation with polycarboxylic acids, such as polyglutamic acids, is generally used to fabricate nanoformulations for CDDP delivery; however, the multiple strong complexations makes intracellular drug release slow. Herein, we report a novel polyphenol-metal coordination method to fabricate CDDP-incorporated core-shell nanoparticles, which are stable in blood circulation but dissociate in the tumor. Methoxyl-PEG terminated with one or two gallic acids (PEG-GA or PEG-GA2) complexed CDDP and produced well-defined nanoparticles (PEG-GAx/Pt) with CDDP loading contents as high as 17.7% to 29.8%. The PEG-GAx/Pt nanoparticles were very stable in the physiological conditions and had slow blood clearance and efficient tumor accumulation, but dissociated quickly and released CDDP in response to the tumor acidity or elevated levels of reactive oxygen species (ROS). PEG-GAx/Pt nanoparticles exhibited improved antitumor efficiency against 4 T1 breast cancer and A549 lung carcinoma with much-reduced toxicity compared to free CDDP. The work demonstrates a new strategy of cisplatin-polyphenol coordination for developing platinum drugs' nanomedicines.
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http://dx.doi.org/10.1016/j.jconrel.2020.11.006DOI Listing
February 2021

Regeneration behavior of chitosan from ionic liquid using water and alcohols as anti-solvents.

Int J Biol Macromol 2021 Jan 2;166:940-947. Epub 2020 Nov 2.

College of Food Science and Light Industry, Nanjing Tech University, Nanjing, Jiangsu 211816, China. Electronic address:

While ionic liquids (ILs) have been considered as effective and "green" solvents for biopolymer processing, regeneration of IL-dissolved biopolymers could largely impact biopolymer structure and properties. This study indicates that the reconstitution of chitosan structure during regeneration from 1-ethyl-3-methylimidazolium acetate ([Emim][OAc]) depends on anti-solvent (water, methanol or ethanol) largely. Irrespective of anti-solvent, the chitosan chemical structure was not varied by dissolution or regeneration. With water, the regenerated chitosan had the highest crystallinity index of 54.18%, followed by those with methanol (35.07%) and ethanol (25.65%). Water as an anti-solvent could promote chitosan chain rearrangement, leading to the formation of an ordered aggregated structure and crystallites. Density functional theory (DFT) simulation indicates that the number of hydrogen bonds formed between anti-solvents and [Emim][OAc] was in the order of water > methanol > ethanol. With water used for regeneration, the aggregation and rearrangement of chitosan chains occurred more easily.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.10.251DOI Listing
January 2021

Dehydrodiconiferyl alcohol, a lignan from Herpetospermum pedunculosum, alleviates cholestasis by activating pathways associated with the farnesoid X receptor.

Phytomedicine 2021 Jan 12;80:153378. Epub 2020 Oct 12.

College of Pharmaceutical Sciences, Southwest University, No.2 Tiansheng Road, Chongqing 400715, PR China. Electronic address:

Background: In our previous study, we demonstrated the hepatoprotective effect of Herpetospermum pedunculosum in cholestatic rats. A bioassay-guided study also led to the identification and isolation of a lignan, dihydrodiconiferyl alcohol (DA) from the seeds of H. pedunculosum.

Purpose: To investigate whether DA could alleviate cholestasis and determine the mechanisms underlying such action.

Methods: Male Sprague-Dawley (SD) rats were administered with DA (10, 20 or 40 mg/kg) intragastrically once daily for 7 days prior to treatment with α-naphthylisothiocyanate (ANIT) (60 mg/kg). We then evaluated the levels of a range of serum indicators, determined bile flow, and carried out histopathological analyses. Western blotting was then used to investigate the levels of inflammatory mediators and the Farnesoid X Receptor (FXR), proteins involved in the downstream biosynthesis of bile acids, and a range of transport proteins. Molecular docking was used to simulate the interaction between DA and FXR. Cell viability of human hepatocytes (L-02) cells was determined by MTT. Then, we treated guggulsterone-inhibited L-02 cells, Si-FXR L-02 cells, and FXR-overexpression cells with the FXR agonist GW4064 (6 μM) or DA (25, 50 and 100 μM) for 24 h before detecting gene and protein expression by RT-PCR and western blotting, respectively.

Results: DA significantly attenuated ANIT-induced cholestasis in SD rats by reducing liver function indicators in the serum, increasing bile flow, improving the recovery of histopathological injuries in the liver, and by alleviating pro-inflammatory cytokines in the liver. DA also increased the expression levels of FXR and altered the levels of downstream proteins in the liver tissues, thus indicating that DA might alleviate cholestasis by regulating the FXR. Molecular docking simulations predicted that DA was as an agonist of FXR. In vitro mechanical studies further showed that DA increased the mRNA and protein expression levels of FXR, Small Heterodimer Partner 1/2, Bile Salt Export Pump, Multidrug Resistance-associated Protein 2, and Na+/taurocholate Co-transporting Polypeptide, in both guggulsterone-inhibited and Si-FXR L-02 cells. Moreover, DA enhanced the mRNA and protein expression of FXR, and its downstream genes and proteins, in L-02 cells containing an FXR-overexpression plasmid.

Conclusion: DA may represent an effective agonist for FXR has significant therapeutic potential for the treatment of cholestatic liver injury.
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http://dx.doi.org/10.1016/j.phymed.2020.153378DOI Listing
January 2021

Cytotoxic triterpenoid saponins from .

Nat Prod Res 2020 Oct 15:1-8. Epub 2020 Oct 15.

College of Pharmaceutical Sciences, Southwest University, Chongqing, P.R. China.

Two new cycloartane glycosides, cycloatriosides A and B (), and a new oleanolic acid glycoside, thaliatrioside A (), along with known triterpenoids () were isolated from . The structures of the new compounds were established as 3---D-galactopyranosyl (20, 24 )-3,16,25,29-tetrahydroxy-20,24-epoxycycloartane-29-O--D-glucopyranoside (), 3---D-glucopyranosyl-(1→2)--arabinopyranosyl-3,22,30-trihydroxycycloart-24-en-21-oic acid -L-arabinopyranosyl-(1→6)--D-glucopyranoside () and 3--[-L-rhamnopyranosyl-(1→3)--D-xylopyranosyl-(1→3)--L-rhamnopyranosyl-(1→2)--L-arabinopyranosyl]-oleanolic acid 28---D-glucopyranosyl ester () on the basis of extensive NMR and HR-ESI-MS analyses, along with acid hydrolysis. Their cytotoxic activities against human lung cancer cells A549 and human breast cancer cells MDA-MB-231 were evaluated using MTT method. Compound showed cytotoxicity against MDA-MB-231 cell line with the IC value of 72.53 ± 1.08 μM.
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http://dx.doi.org/10.1080/14786419.2020.1834550DOI Listing
October 2020

Active Transportation of Liposome Enhances Tumor Accumulation, Penetration, and Therapeutic Efficacy.

Small 2020 11 8;16(44):e2004172. Epub 2020 Oct 8.

Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, China.

Liposomes are the first and mostly explored nanocarriers for cancer drug delivery, which have shown great promise in clinical applications, but their limited accumulation and penetration into the tumor interstitial space, significantly reduce the therapeutic efficacy. Here, a γ-glutamyltranspeptidase (GGT)-triggered charge-switchable approach is reported that can trigger the fast endocytosis and transcytosis of the liposome in tumor microenvironments to overcome the harsh biological barriers in tumor tissues. The active transporting liposomal nanocarrier (GCSDL) is prepared by surface modification with a glutathione (GSH) moiety and encapsulated with doxorubicin (DOX). When the GCSDL contacts with tumor vascular endothelial cells, the overexpressed GGT enzyme on cytomembrane catalyzes the hydrolysis of GSH to generate cationic primary amines. The cationic GCSDL triggers fast caveolae-mediated endocytosis and vesicle-mediated transcytosis, resulting in sequential transcytosis to augment its tumor accumulation and penetration. Along with continual intercellular transportation, GCSDL can release DOX throughout the tumor to induce cancer cell apoptosis, resulting in complete eradication of hepatocellular carcinoma and cessation of pancreatic ductal adenocarcinoma's progression. This study develops an efficient strategy to realize high tumor accumulation and deep penetration for the liposomal drug delivery system via active transcytosis.
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http://dx.doi.org/10.1002/smll.202004172DOI Listing
November 2020

The crosstalk between platelets and body fat: A reverse translational study.

Clin Nutr 2021 Apr 19;40(4):2025-2034. Epub 2020 Sep 19.

Chronic Disease Research Institute, The Children's Hospital, National Clinical Research Center for Child Health, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Department of Nutrition and Food Hygiene, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address:

Background & Aims: Our previous study found that platelet counts were positively associated with body fat percentage in human. In the present study, we conducted a reverse translational study to explore the role of platelets in modulating pre-adipocyte proliferation in mice.

Methods: Mouse pre-adipocyte cell line (3T3-L1) and human pre-adipocytes harvested from female subcutaneous fat were used. Pre-adipocytes were co-cultured with platelets or platelet releasate, which were isolated from mice or humans. The cell viability and proliferative ability of the pre-adipocytes were examined by MTT and flow cytometry assays. Western blotting analysis was used to determine the phosphorylation levels of proteins in the mTOR pathway.

Results: The number of platelets in the adipose tissues from obese mice was significantly higher than that from lean mice. Platelets and collagen-activated platelet releasate stimulated the proliferation of human pre-adipocytes and 3T3-L1 cells in vitro. Besides, platelets from obese mice were more potent in stimulating pre-adipocyte proliferation than those from lean control mice. Mechanistically, platelets enhanced pre-adipocyte proliferation through the acceleration of cell cycle progression from G0/G1 to S phase cell cycle progression. At the molecular level, platelets promoted pre-adipocyte proliferation through mTOR pathway-mediated upregulation of cyclin D1 expression.

Conclusion: In conclusion, platelets and platelet releasate play an important role in the proliferation of pre-adipocytes. Our study may provide new clues and the molecular mechanism of the causal pathways between platelets and body fat to explain the finding we observed in population study.
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http://dx.doi.org/10.1016/j.clnu.2020.09.023DOI Listing
April 2021

Occurrence and exposure risk evaluation of polyhalogenated carbazoles (PHCZs) in drinking water.

Sci Total Environ 2021 Jan 13;750:141615. Epub 2020 Aug 13.

School of Environmental Science and Engineering, Huazhong University of Science and Technology (HUST), Wuhan 430074, PR China; Hubei Provincial Engineering Laboratory of Solid Waste Treatment, Disposal and Recycling, Wuhan 430074, PR China; State Key Laboratory of Coal Combustion, Huazhong University of Science and Technology (HUST), Wuhan 430074, PR China. Electronic address:

Although polyhalogenated carbazoles (PHCZs) can be generated and detected in drinking water, their occurrence and potential health risks to humans via drinking water ingestion are not well known. In this study, 11 PHCZs were screened in drinking water samples from Wuhan, the most populous city in central China. The total concentration of PHCZs could be up to 53.48 ng/L with a median level of 8.19 ng/L, which was comparable to polychlorinated biphenyls and poly- and perfluoroalkyl substances reported in the literatures for drinking water. Composition profiles revealed that 3,6-dichlorocarbazole, 3-chlorocarbazole, 3-bromocarbazole and 3,6-dibromocarbazole were the predominant PHCZ congeners in the tested samples. Regional differences in the levels and patterns of PHCZs suggested that anthropogenic releases should be the dominant source compared to natural generation. Boiling of the water samples caused no significant change in PHCZs concentrations after correcting the volume change due to evaporation. Potential health risks associated to the levels of PHCZs in drinking water were assessed using the toxic equivalent (TEQs) method. The estimated daily intake of PHCZs via drinking water ingestion is up to 0.38 pg-TEQ/kg body weight/day for infants, nearly 4.5 times higher than that for adults, and appears to reach the maximum permissible concentration set by certain authority agencies. Overall, drinking water ingestion represents an important exposure pathway for PHCZs. This is the first comprehensive study on the abundance and health risks of PHCZs in drinking water.
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http://dx.doi.org/10.1016/j.scitotenv.2020.141615DOI Listing
January 2021

Migration inhibitory factor in spinal tuberculosis: -173G/C polymorphisms, and transcript and protein levels in a northern province of China.

Medicine (Baltimore) 2020 Jul;99(30):e21331

Weifang People's Hospital, Weifang.

The aim of this study was to elucidate the possible association between migration inhibitory factor (MIF)-173G/C gene polymorphisms and transcript and plasma levels of MIF in spinal tuberculosis (TB) patients. Clinical data were collected from 254 spinal TB patients and 262 healthy controls participating in the study. The genotype of the MIF-173G/C gene was amplified by polymerase chain reaction and genotyped by DNA sequencing technology. The level of mRNA expression was determined by real-time polymerase chain reaction and MIF plasma levels were measured by a solid-phase enzyme-linked immunosorbent assay. The frequency of the C allele and GC+CC genotype in MIF-173G/C was over-represented in spinal TB patients. The mean MIF mRNA level in spinal TB patients and patients with the GG and GC+CC genotype were significantly lower than controls; however, our study also indicated that the MIF concentration in spinal TB patients and patients with the GG and GC+CC genotypes were significantly higher than controls. Spinal TB patients with the GG genotype had higher MIF plasma levels than patients with the GC+CC genotype. The C-reactive protein level and erythrocyte sedimentation rate was correlated with the MIF plasma level. In summary, the association between the MIF-173G/C genetic polymorphism, reduced transcript and increased plasma levels of MIF in spinal TB patients, and MIF may play an important role in the occurrence, development, and damage of spinal TB in the northern Province population of China.
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http://dx.doi.org/10.1097/MD.0000000000021331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386958PMC
July 2020

Knockdown of MgMn dependent protein phosphatase 1A promotes apoptosis in BV2 cells infected with strain 2 vaccine.

Exp Ther Med 2020 Aug 13;20(2):926-932. Epub 2020 May 13.

Department of Neurology, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China.

The ability to inhibit host macrophage apoptosis is one of the survival strategies of intracellular bacteria, including . In the present study the role of MgMn dependent protein phosphatase 1A (PPM1A) in the apoptosis of () strain 2 vaccine-infected BV2 cells was investigated. Compared with control cells, the protein expression levels of cleaved caspase-3 were markedly increased in PPM1A short hairpin (sh)RNA-transfected BV2 cells. Flow cytometry analysis showed that treatment with JNK activator anisomycin significantly increased the rate of apoptosis in BV2 cells in comparison with the control cells. Furthermore, PPM1A shRNA significantly increased the levels of JNK phosphorylation and the levels of cleaved caspase-3 in BV2 cells infected with strain 2 in comparison with the control cells. DAPI staining showed nuclear condensation in infected BV2 cells transfected with PPM1A shRNA in comparison with the control shRNA cells. Flow cytometry analysis showed that PPM1A shRNA significantly increased the percentage of apoptotic BV2 cells infected with strain 2 compared with those transfected with control shRNA. Taken together, these data suggested that knockdown of PPM1A promotes apoptosis in strain 2-infected BV2 cells and that PPM1A may be a potential target in the development of treatments to inhibit intracellular growth of
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http://dx.doi.org/10.3892/etm.2020.8745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388305PMC
August 2020

Ionic channel blockage in stochastic Hodgkin-Huxley neuronal model driven by multiple oscillatory signals.

Cogn Neurodyn 2020 Aug 4;14(4):569-578. Epub 2020 May 4.

Department of Physics, Central China Normal University, Wuhan, 430079 China.

Ionic channel blockage and multiple oscillatory signals play an important role in the dynamical response of pulse sequences. The effects of ionic channel blockage and ionic channel noise on the discharge behaviors are studied in Hodgkin-Huxley neuronal model with multiple oscillatory signals. It is found that bifurcation points of spontaneous discharge are altered through tuning the amplitude of multiple oscillatory signals, and the discharge cycle is changed by increasing the frequency of multiple oscillatory signals. The effects of ionic channel blockage on neural discharge behaviors indicate that the neural excitability can be suppressed by the sodium channel blockage, however, the neural excitability can be reversed by the potassium channel blockage. There is an optimal blockage ratio of potassium channel at which the electrical activity is the most regular, while the order of neural spike is disrupted by the sodium channel blockage. In addition, the frequency of spike discharge is accelerated by increasing the ionic channel noise, the firing of neuron becomes more stable if the ionic channel noise is appropriately reduced. Our results might provide new insights into the effects of ionic channel blockages, multiple oscillatory signals, and ionic channel noises on neural discharge behaviors.
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http://dx.doi.org/10.1007/s11571-020-09593-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334323PMC
August 2020

Peripheral Blood Leukocytes and Platelets Serve as Prognostic Factors in Breast Cancer.

Cancer Biother Radiopharm 2021 Mar 29;36(2):167-173. Epub 2020 Jun 29.

Department of Thyroid and Breast Surgery, The First People's Hospital of Yunnan Province (the Affiliated Kunhua Hospital of Kunming University of Science and Technology), Kunming, China.

Tumor-infiltrating lymphocytes have been reported to be associated with response to neoadjuvant chemotherapy and survival in breast cancer (BC) patients. However, little is known about the value of peripheral blood parameter in predicting the prognosis in BC. In this study, parameters of complete blood count from 417 BC patients with a median 7.6-year follow-up after surgery were collected and correlated with patient survival. It was found that leukocyte counts were positively correlated with disease-free survival (DFS,  = 0.016) and overall survival (OS,  = 0.014), whereas platelet counts were negatively correlated with DFS ( = 0.003) and OS ( = 0.082) in BC. Leukocyte and platelet counts were independent prognostic factors for the BC patient survival. Besides, the prognostic value of leukocyte and platelet counts was further evaluated in the BC patients with different molecular subtypes. Together, BC patients with high leukocyte counts and low platelet counts had better DFS ( = 0.001) and OS ( = 0.017) than the other patients. Parameters of complete blood count could be acquired easily and serve as cost-effective prognostic biomarkers in BC.
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http://dx.doi.org/10.1089/cbr.2019.3032DOI Listing
March 2021

Design and performance of a novel direct Z-scheme NiGaO/CeO nanocomposite with enhanced sonocatalytic activity.

Sci Total Environ 2020 Nov 16;741:140192. Epub 2020 Jun 16.

MOE Key Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing 100871, PR China. Electronic address:

A novel direct Z-scheme NiGaO/CeO nanocomposite was designed and prepared via simple sol-hydrothermal and calcination methods, and its sonocatalytic activity was tested by studying the degradation of a model antimicrobial agent, malachite green (MG), under ultrasonic irradiation. Near complete (96.2%) degradation of MG (at 10 mg/L) could be achieved by the NiGaO/CeO nanocomposite (at 1.0 g/L) after ultrasonic irradiation (40 kHz, 300 W) for 60 min at 25 °C. Under the same conditions, only 51.2 and 72.0% of the MG degraded in the presence of NiGaO and CeO (at 1.0 g/L), respectively. These results demonstrate that the direct Z-scheme NiGaO/CeO nanocomposite has excellent sonocatalytic activity, which is attributed to the matching band-gaps between NiGaO and CeO. The sonocatalytic activity of NiGaO/CeO nanocomposite decreased by 17% after four cycles of reuse, which is indicative of relatively good reusability. Scavenging experiments revealed that sonocatalytic degradation of MG results from the combined action of hydroxyl radicals (OH) and holes (h), with the latter having a greater contribution. The pathways and mechanism of MG degradation were proposed based on the degradation intermediates detected. The results demonstrate that the prepared direct Z-scheme NiGaO/CeO nanocomposite worked as designed and exhibited high and stable sonocatalytic activity during MG degradation, and could thus serve as a promising candidate in sonocatalytic treatment of other organic pollutants in wastewaters. The findings also provide new insights on the mechanism of sonocatalytic degradation and the design of efficient Z-scheme sonocatalysts.
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http://dx.doi.org/10.1016/j.scitotenv.2020.140192DOI Listing
November 2020

Network pharmacology-based therapeutic mechanism of Kuanxiong aerosol for angina pectoris.

J Ethnopharmacol 2020 Oct 9;261:113079. Epub 2020 Jun 9.

Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China. Electronic address:

Ethnopharmacological Relevance: Kuanxiong aerosol has been reported to be an effective and safe clinical treatment for angina pectoris (AP).

Aim Of The Study: To explore the potential pharmacological mechanism of Kuanxiong aerosol by combined methods of network pharmacology prediction and experimental verification.

Materials And Methods: Networks of Kuanxiong aerosol-associated targets and AP-related genes were constructed through STRING database. Potential targets and pathway enrichment analysis related to the therapeutic efficacy of Kuanxiong aerosol were identified using Cytoscape and Database for Annotation, Visualization and Integrated Discovery (DAVID). To explore the mechanism of action of Kuanxiong aerosol, its in vitro effects on myocardial hypoxia, inflammatory cytokines, and oxidative injury, and its in vivo pharmacological effects on myocardial ischemia and cardiac fibrosis were studied in rat models.

Results: Network pharmacology analysis revealed that the potential targets mainly include the Fas ligand (FASLG), interleukin 4 (IL4), and catalase (CAT), which mediated the processes of apoptosis, and cellular responses to hypoxia, lipopolysaccharide (LPS), reactive oxygen species (ROS), and mechanical stimulus. Multiple pathways, such as the hypoxia-inducible factor 1 (HIF1) and tumor necrosis factor (TNF) pathways were found to be closely related to the pharmacological protective mechanism of Kuanxiong aerosol against AP. In addition, Kuanxiong aerosol suppressed the hypoxia, LPS, and hydrogen peroxide (HO)-induced injuries of H9c2 cardiomyocytes through the regulation of HIF1A, suppressed expression of IL6 and TNF, and antioxidant property. In the rat model of myocardial ischemia, Kuanxiong aerosol was found to lower the creatine kinase (CK), creatine kinase-myocardial band (CK-MB), and lactate dehydrogenase (LDH) levels, without altering the hemodynamic function. Kuanxiong aerosol was capable of attenuating cardiac fibrosis and improving cardiac function in a cardiac fibrosis rat model.

Conclusions: This study revealed that the pharmacological mechanisms of Kuanxiong aerosol for AP therapy were related to anti-myocardial ischemia, anti-inflammation, and anti-oxidation via a non-hemodynamic manner, indicating that Kuanxiong aerosol is a preferable drug clinically for AP treatment due to its both preventive and protective effects.
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http://dx.doi.org/10.1016/j.jep.2020.113079DOI Listing
October 2020
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