Publications by authors named "Xiaolu Wei"

20 Publications

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Huanglian Jiedu decoction remodels the periphery microenvironment to inhibit Alzheimer's disease progression based on the "brain-gut" axis through multiple integrated omics.

Alzheimers Res Ther 2021 02 12;13(1):44. Epub 2021 Feb 12.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.

Background: In recent years, excellent results have suggested an association between the "brain-gut" axis and Alzheimer's disease (AD) progression, yet the role of the "brain-gut" axis in AD pathogenesis still remains obscure. Herein, we provided a potential link between the central and peripheral neuroinflammatory disorders in AD progression.

Methods: The Morris water maze (MWM) test, immunohistochemistry, ELISA, ProcartaPlex Multiplex immunoassay, multiple LC-MS/MS methods, and the V3-V4 regions of 16S rRNA genes were applied to explore potential biomarkers.

Results: In Tg-APP/PS1 mice, gut dysbiosis and lipid metabolism were highly associated with AD-like neuroinflammation. The combination of inflammatory factors (IL-6 and INF-γ), phosphatidylcholines (PCs) and SCFA-producing bacteria were expected to be early diagnostic biomarkers for AD. Huanglian Jiedu decoction (HLJDD) suppressed gut dysbiosis and the associated Aβ accumulation, harnessed neuroinflammation and reversed cognitive impairment.

Conclusion: Together, our findings highlighted the roles of neuroinflammation induced by gut dysbiosis and lipid metabolism disorder in AD progression. This integrated metabolomics approach showed its potential to understand the complex mechanisms of HLJDD in the treatment of AD.
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http://dx.doi.org/10.1186/s13195-021-00779-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881564PMC
February 2021

Cost of Diabetic Foot Ulcer Management in China: A 7-Year Single-Center Retrospective Review.

Diabetes Metab Syndr Obes 2020 10;13:4249-4260. Epub 2020 Nov 10.

Department of Ulcers and Peripheral Vascular Surgery, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, People's Republic of China.

Background: The cost of care for diabetic foot ulcers has became a global economic burden. The study aimed to analyze diabetic foot ulcer cost changes over time and to identify factors associated with these variables, so as to strengthen and improve the management of diabetic foot ulcers.

Methods: We retrospectively analyzed the data in the electronic medical record system of our wound treatment center. The homepage of the system was queried using the national clinical version 2.0 disease diagnosis code (ICD-10), the data of patient's basic information were exported. Through the statistics and analysis of these data, the socioeconomic changes and possible risk factors of diabetic foot ulcers management in recent years were obtained.

Results: There were 3654 patients included in the study, an average of 522 per year. The total cost per patient increased from ¥15,535.58 in 2014 to ¥42,040.60 in 2020, with an average of ¥21,826.91. The average length of stay between 14.29 days and 31.4 days from 2014 to 2020, with an average of 18.10 days. Besides, the average incidence of peripheral arterial disease in diabetic foot ulcers patients admitted was as high as 81.9%, and the average amputation rate was 9.9%. The study reflected the total cost and length of stay of diabetic foot patients increased significantly from 2014 to 2020, which were related to age (>85 years), gender (male), peripheral arterial disease, amputation (P < 0.05).

Conclusion: A heavy cost from diabetic foot ulcers and its complications was significantly increased yearly, which was related to older age, co-morbidity, amputation and duration of hospitalization. The prevention and treatment of diabetic foot ulcers have a long way to go, early comprehensive prevention and multi-disciplinary cooperation may still be an effective way.
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http://dx.doi.org/10.2147/DMSO.S275814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667006PMC
November 2020

Hellebrigenin anti-pancreatic cancer effects based on apoptosis and autophage.

PeerJ 2020 8;8:e9011. Epub 2020 May 8.

Institute of Chinese Materia Medica, China Academy of Chinese Medicine Sciences, Beijing, China.

Hellebrigenin is a natural product found in the toad skin secretions and plants of Urginea, including Hellebores and Kalanchoe genera. It has been shown to be active against Leishmania chagasi promastigotes and Trypanosoma cruzi trypomastigotes and also reported to play an anti-tumor effect on several cancer cell lines in vitro, including pancreatic cancer. This study is aimed to investigate the effects of Hellebrigenin on pancreatic carcinoma cells, SW1990 and BxPC-3 in vitro and its molecular mechanism involved in antitumor activities. Our results showed that Hellebrigenin effectively inhibited the proliferation of SW1990 and BxPC-3 cells in dose- and time-dependent manner. Flow cytometry results showed that Hellebrigenin induced the G0/G1 arrest in both of SW1990 and BxPC-3 cells and promoted cell early apoptosis and autophagy according to morphological observation. Immunofluorescence staining results further confirmed that cell apoptosis and autophagy also increased upon the Hellebrigenin treatment. Moreover, higher dose of Hellebrigenin further increased the cell apoptosis rate while decrease the mitochondrial membrane potential 24 h after treatment. The autophagy rate increased 48 h after treatment with significant difference ( < 0.05). Western blot analysis showed that the expression of caspase 3, 7, cleaved caspase 7, Atg 12, LC3 proteins were increased in SW1990 cell after treatment with Hellebrigenin. In addition, increasing expression of caspase 3, 7, 9, PARP, cleaved caspase 3, 7, 9, PARP, the sub basic protein of the PI3K family, Beclin-1, LC 3, Atg 3, 5, 12, 16 L were also observed after BxPC-3 cells treated with Hellebrigenin. In summary, this study reported for the first time that Hellebrigenin effectively induced autophagy and apoptosis especially the early apoptosis in SW1990 and BxPC-3 cells.
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http://dx.doi.org/10.7717/peerj.9011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213012PMC
May 2020

Dynamic Evolution of Euchromatic Satellites on the X Chromosome in Drosophila melanogaster and the simulans Clade.

Mol Biol Evol 2020 08;37(8):2241-2256

Department of Biology, University of Rochester, Rochester, NY.

Satellite DNAs (satDNAs) are among the most dynamically evolving components of eukaryotic genomes and play important roles in genome regulation, genome evolution, and speciation. Despite their abundance and functional impact, we know little about the evolutionary dynamics and molecular mechanisms that shape satDNA distributions in genomes. Here, we use high-quality genome assemblies to study the evolutionary dynamics of two complex satDNAs, Rsp-like and 1.688 g/cm3, in Drosophila melanogaster and its three nearest relatives in the simulans clade. We show that large blocks of these repeats are highly dynamic in the heterochromatin, where their genomic location varies across species. We discovered that small blocks of satDNA that are abundant in X chromosome euchromatin are similarly dynamic, with repeats changing in abundance, location, and composition among species. We detail the proliferation of a rare satellite (Rsp-like) across the X chromosome in D. simulans and D. mauritiana. Rsp-like spread by inserting into existing clusters of the older, more abundant 1.688 satellite, in events likely facilitated by microhomology-mediated repair pathways. We show that Rsp-like is abundant on extrachromosomal circular DNA in D. simulans, which may have contributed to its dynamic evolution. Intralocus satDNA expansions via unequal exchange and the movement of higher order repeats also contribute to the fluidity of the repeat landscape. We find evidence that euchromatic satDNA repeats experience cycles of proliferation and diversification somewhat analogous to bursts of transposable element proliferation. Our study lays a foundation for mechanistic studies of satDNA proliferation and the functional and evolutionary consequences of satDNA movement.
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http://dx.doi.org/10.1093/molbev/msaa078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403614PMC
August 2020

Arenobufagin Inhibits the Phosphatidylinositol 3-kinase/Protein Kinase B/Mammalian Target of Rapamycin Pathway and Induces Apoptosis and Autophagy in Pancreatic Cancer Cells.

Pancreas 2020 02;49(2):261-272

From the Quality Standards, Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences.

Objective: The aim of the study was to investigate the effects of arenobufagin on pancreatic carcinoma in vitro and in vivo and its molecular mechanism.

Methods: The proliferation of pancreatic cancer cells was detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Transmission electron microscopy was used to observe the formation of autophagic vacuoles after arenobufagin treatment. Hoechst 33258 and monodansylcadaverine fluorescence staining were performed to evaluate cell apoptosis and autophagy. Annexin V-fluorescein isothiocyanate/propidium iodide double-staining and JC-1 staining assays were used to evaluate apoptosis-related changes. Reverse-transcription polymerase chain reaction and western blotting were carried out to examine the expression of apoptosis- and autophagy-related markers after arenobufagin treatment. A tumor xenograft nude mouse model was established to evaluate arenobufagin efficacy in vivo.

Results: Arenobufagin effectively inhibited the proliferation of SW1990 and BxPC3 cells and induced cell arrest, apoptosis, and autophagy. Arenobufagin upregulated the expression of apoptotic- and autophagy-related proteins while downregulated the expression of phosphatidylinositol 3-kinase family proteins. Furthermore, arenobufagin also exerted inhibitory effects on tumor growth in xenograft nude mice.

Conclusions: Arenobufagin inhibits tumor growth in vivo and in vitro. The mechanism underlying arenobufagin action may involve induction of autophagy and apoptosis through the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway.
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http://dx.doi.org/10.1097/MPA.0000000000001471DOI Listing
February 2020

Effects of Huang-Lian-Jie-Du Decoction on Oxidative Stress and AMPK-SIRT1 Pathway in Alzheimer's Disease Rat.

Evid Based Complement Alternat Med 2020 2;2020:6212907. Epub 2020 Jan 2.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.

Huang-Lian-Jie-Du Decoction (HLJDD), traditional Chinese medicine (TCM), is proven to have ameliorative effects on learning and memory deficits of Alzheimer's disease (AD). The current study aims to reveal the underlying mechanism of HLJDD in the treatment of AD by simultaneous determination on the regulation of HLJDD on oxidative stress, neurotransmitters, and AMPK-SIRT1 pathway in AD. AD model rat was successfully established by injection of D-galactose and A-ibotenic acid. Morris Water Maze (MWM) test was used to evaluate the success of AD modelling. On this basis, an advanced technique with UPLC-QqQ MS/MS was built up and applied to determine the levels of 8 neurotransmitters in rat plasma. Significant alternation in methionine, glutamine, and tryptophan was observed in AD rats' plasma after the administration of HLJDD, relative to the model group. Meanwhile, HLJDD could upregulate the levels of SOD, GSH-Px, AMPK, and SIRT1 and downregulate the content of MDA in the peripheral system of the AD rats. The underlying therapeutic mechanism of HLJDD for the treatment of AD was associated with alleviating oxidation stress, inflammation, neurotransmitters, and energy metabolism. These data provide solid foundation for the potential use of HLJDD to treat AD.
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http://dx.doi.org/10.1155/2020/6212907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959142PMC
January 2020

The Disturbance of Hepatic and Serous Lipids in Aristolochic Acid Ι Induced Rats for Hepatotoxicity Using Lipidomics Approach.

Molecules 2019 Oct 17;24(20). Epub 2019 Oct 17.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.

Aristolochic acid I (AAI) was regarded as the major toxic component of aristolochic acid (AA). In addition to aristolochic acid nephropathy (AAN), liver cancers induced by AAI has aroused increasing attention recently. In this paper, the discovery of diagnostic biomarkers for AAI-induced liver injury has been studied, especially for the lipid markers. From the histopathological characteristics, the injury was observed clearly in the liver apart from the kidney after 30 mg/kg of AAΙ treatment for one week, while the lesion alleviated after AAΙ discontinuance. The serum biochemical indexes were manifested to the normal tendency after AAΙ discontinuance for two weeks. According to the evaluation of pathology slices and serum biochemical indexes, they indicated that the hepatotoxicity induced by AAΙ was reversible to some extent. A total of 44 lipid markers were identified in the liver, as well as 59 in the serum. Twenty-six common lipid markers were observed in both serum and liver. Furthermore, nine out of 26 lipids exhibited the excellent diagnostic ability to differentiate the control group from the AAΙ group and AAΙ discontinuance group with high sensitivity and specificity. The changed lipid markers might serve as characteristics to explain the mechanisms of pathogenesis and progression in hepatotoxicity induced by AAΙ.
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http://dx.doi.org/10.3390/molecules24203745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832582PMC
October 2019

The protection of indolealkylamines from LPS-induced inflammation in zebrafish.

J Ethnopharmacol 2019 Oct 26;243:112122. Epub 2019 Jul 26.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China. Electronic address:

Ethnopharmacological Relevance: Toad skin came from Bufo bufo gargarizans Cantor and Bufo melanostictus Schneider. As the traditional Chinese medicine, it had the effect of clearing away heat and detoxification. In traditional applications, toad skin was often used for the treatment of cancer and inflammation. Total indolealkylamines (IAAs) from this medicine were proved the main compounds exert anti-inflammatory activity in our previous research.

Aim Of The Study: In the present study, we aimed to investigate the potential mechanism of anti-inflammatory activity of IAAs on LPS induced zebrafish.

Materials And Methods: LPS induced zebrafish was applicated as an in vivo inflammation model to clarify the structure-activity relationship of 4 major IAAs (N-methyl serotonin, bufotenine, dehydrobufotenine and bufothionine) from toad skin. Quantitative RT-PCR was applied to detect key cytokines and members of the MyD88-dependent signaling pathway. In addition, the targeted lipidomics was conducted to find out the potential biomarkers in the inflammatory zebrafish. Network pharmacology was used to unveil the main enzymes closely related to the target lipids.

Results: Our results showed that the anti-inflammatory activity of free IAAs (N-methyl serotonin, bufotenine and dehydrobufotenine) was more potent than that of combined IAAs (bufothionine). RT-PCR demonstrated that 4 IAAs exerted antiendotoxin inflammatory effect via suppressing the TLR4/MyD88/NF-κB and TLR4/MyD88/MAPKs signaling pathway. A total of 33 possible inflammatory biomarkers, including 14 SM, 6 Cer, 11 PC and 2 GlcCer, triggered by LPS were screened out. The levels of most of candidates could be regulated toward a normal level by IAAs, especially in N-methyl serotonin and dehydrobufotenine groups. Enzymes especially LBP, PLA, CERK, SMPD and SGMS were found closely associated with the regulation of most lipid markers.

Conclusions: Overall, the mechanism underlying the anti-inflammatory activity of IAAs probably attributed to their capability to suppress NF-κB and MAPKs inflammatory pathway. Meanwhile, IAAs could also interfere the metabolism of SM, Cer and PC probably by regulating LBP, PLA, CERK, SMPD and SGMS.
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http://dx.doi.org/10.1016/j.jep.2019.112122DOI Listing
October 2019

Scutellarin inhibits the invasive potential of malignant melanoma cells through the suppression epithelial-mesenchymal transition and angiogenesis via the PI3K/Akt/mTOR signaling pathway.

Eur J Pharmacol 2019 Sep 15;858:172463. Epub 2019 Jun 15.

Department of Integrated Chinese Traditional and Western Medicine, International Medical School, Tianjin Medical University, No. 22 Qixiangtai, Heping District, Tianjin, 300070, China.

Malignant melanoma is the leading cause of death from skin disease, due in large part to its propensity to metastasize. Scutellarin is an active flavone extracted from traditional Chinese herb Erigeron breviscapus (Vant.) Hand. Mazz. Recent studies have reported that scutellarin can be utilized to treat various types of tumors. In this study, we investigated the effects of scutellarin on melanoma cancer cell invasive potential and the molecular mechanisms underlying these effects using A375 melanoma cells lines. The in-vitro antitumor activity of scutellarin was evaluated by CCK-8 assay, wound-healing assay, transwell assays, adhesion assays, and tube formation assays to assess the cell viability, migration, invasion, adhesion, and angiogenesis, respectively. Also, western blotting assay was used to assess the level of PI3K/Akt/mTOR signaling pathway proteins in A375 cells. We found that scutellarin significantly inhibited melanoma cell lines and HUVECs viability in a time- and concentration-dependent manners. Additionally, scutellarin effectively suppressed tumor cell migration, invasion, adhesion through the suppression of EMT and angiogenesis by inhibiting the PI3K/Akt/mTOR signaling pathway. These results indicated that scutellarin could markedly inhibit the invasive potential of melanoma cell lines by suppressing the EMT and angiogenesis through the PI3K/Akt/mTOR signaling pathway. It suggests that scutellarin might be a potential compound in malignant melanoma treatment.
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http://dx.doi.org/10.1016/j.ejphar.2019.172463DOI Listing
September 2019

Islands of retroelements are major components of Drosophila centromeres.

PLoS Biol 2019 05 14;17(5):e3000241. Epub 2019 May 14.

Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut, United States of America.

Centromeres are essential chromosomal regions that mediate kinetochore assembly and spindle attachments during cell division. Despite their functional conservation, centromeres are among the most rapidly evolving genomic regions and can shape karyotype evolution and speciation across taxa. Although significant progress has been made in identifying centromere-associated proteins, the highly repetitive centromeres of metazoans have been refractory to DNA sequencing and assembly, leaving large gaps in our understanding of their functional organization and evolution. Here, we identify the sequence composition and organization of the centromeres of Drosophila melanogaster by combining long-read sequencing, chromatin immunoprecipitation for the centromeric histone CENP-A, and high-resolution chromatin fiber imaging. Contrary to previous models that heralded satellite repeats as the major functional components, we demonstrate that functional centromeres form on islands of complex DNA sequences enriched in retroelements that are flanked by large arrays of satellite repeats. Each centromere displays distinct size and arrangement of its DNA elements but is similar in composition overall. We discover that a specific retroelement, G2/Jockey-3, is the most highly enriched sequence in CENP-A chromatin and is the only element shared among all centromeres. G2/Jockey-3 is also associated with CENP-A in the sister species D. simulans, revealing an unexpected conservation despite the reported turnover of centromeric satellite DNA. Our work reveals the DNA sequence identity of the active centromeres of a premier model organism and implicates retroelements as conserved features of centromeric DNA.
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http://dx.doi.org/10.1371/journal.pbio.3000241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516634PMC
May 2019

HIF-1α/VEGF signaling-mediated epithelial-mesenchymal transition and angiogenesis is critically involved in anti-metastasis effect of luteolin in melanoma cells.

Phytother Res 2019 Mar 17;33(3):798-807. Epub 2019 Jan 17.

Department of Integrated Chinese Traditional and Western Medicine, International Medical School, Tianjin Medical University, Tianjin, China.

Tumor metastasis is still the leading cause of melanoma mortality. Luteolin, a natural flavonoid, is found in fruits, vegetables, and medicinal herbs. The pharmacological action and mechanism of luteolin on the metastasis of melanoma remain elusive. In this study, we investigated the effect of luteolin on A375 and B16-F10 cell viability, migration, invasion, adhesion, and tube formation of human umbilical vein endothelial cells. Epithelial-mesenchymal transition (EMT) markers and pivotal molecules in HIF-1α/VEGF signaling expression were analysed using western blot assays or quantitative real-time polymerase chain reaction. Results showed that luteolin inhibits cellular proliferation in A375 and B16-F10 melanoma cells in a time-dependent and concentration-dependent manner. Luteolin significantly inhibited the migratory, invasive, adhesive, and tube-forming potential of highly metastatic A375 and B16-F10 melanoma cells or human umbilical vein endothelial cells at sub-IC concentrations, where no significant cytotoxicity was observed. Luteolin effectively suppressed EMT by increased E-cadherin and decreased N-cadherin and vimentin expression both in mRNA and protein levels. Further, luteolin exerted its anti-metastasis activity through decreasing the p-Akt, HIF-1α, VEGF-A, p-VEGFR-2, MMP-2, and MMP-9 proteins expression. Overall, our findings first time suggests that HIF-1α/VEGF signaling-mediated EMT and angiogenesis is critically involved in anti-metastasis effect of luteolin as a potential therapeutic candidate for melanoma.
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http://dx.doi.org/10.1002/ptr.6273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590488PMC
March 2019

Comparative Analysis of Hydrophilic Ingredients in Toad Skin and Toad Venom Using the UHPLC-HR-MS/MS and UPLC-QqQ-MS/MS Methods Together with the Anti-Inflammatory Evaluation of Indolealkylamines.

Molecules 2018 Dec 27;24(1). Epub 2018 Dec 27.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.

Toad skin and toad venom, as two kinds of Chinese medicine, are prepared from Cantor and Schneider. However, they display distinct properties in traditional application, and the hydrophilic ingredients are the possible distinguishing chemicals between them. In this work, 36 and 22 hydrophilic components were characterized from toad skin and venom, respectively, by UHPLC-HR-MS/MS, including amino acids, nucleosides, polypeptides, and indolealkylamines (IAAs). Among them, 15 compounds were unambiguously confirmed by comparison with standards. The CID-MS/MS fragmentation behaviors of seven indolealkylamine references were investigated to ascertain three types of structures. Subsequently, 11 high abundance contents of hydrophilic ingredients were determined from 11 batches of toad skin and 4 batches of toad venom by UPLC-QqQ-MS/MS. The quantitative results showed that the content of main IAAs in toad venom was much higher than in skin. In addition, the -methyl serotonin (free IAA), bufothionine (combined IAA), and total IAAs sample were selected for anti-inflammatory evaluation in lipopolysaccharide (LPS) stimulated zebrafish embryo models. The obvious anti-inflammatory activities of IAAs were observed, especially for the free IAAs. This study illustrated IAAs were the main distinct hydrophilic components that probably lead to the difference between toad skin and toad venom in traditional applications.
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http://dx.doi.org/10.3390/molecules24010086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337282PMC
December 2018

Integrated Proteomics and Lipidomics Investigation of the Mechanism Underlying the Neuroprotective Effect of -benzylhexadecanamide.

Molecules 2018 Nov 9;23(11). Epub 2018 Nov 9.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.

Macamides are very important secondary metabolites produced by Walp, which possess multiple bioactivities, especially in the neuronal system. In a previous study, we observed that macamides exhibited excellent effects in the recovery of injured nerves after 1-methyl-4-phenylpyridinium (MPP⁺)-induced dopaminergic neuronal damage in zebrafish. However, the mechanism underlying this effect remains unclear. In the present study, we observed that -benzylhexadecanamide (XA), which is a typical constituent of macamides, improved the survival rate of neurons in vitro. We determined the concentration of neurotransmitters in MN9D cells and used it in conjunction with an integrated proteomics and lipidomics approach to investigate the mechanism underlying the neuroprotective effects of XA in an MPP⁺-induced neurodegeneration cell model using QqQ MS, Q-TOF MS, and Orbitrap MS. The statistical analysis of the results led to the identification of differentially-expressed biomarkers, including 11 proteins and 22 lipids, which may be responsible for the neuron-related activities of XA. All these potential biomarkers were closely related to the pathogenesis of neurodegenerative diseases, and their levels approached those in the normal group after treatment with XA. Furthermore, seven lipids, including five phosphatidylcholines, one lysophosphatidylcholine, and one phosphatidylethanolamine, were verified by a relative quantitative approach. Moreover, four proteins (Scarb2, Csnk2a2, Vti1b, and Bnip2) were validated by ELISA. The neurotransmitters taurine and norepinephrine, and the cholinergic constituents, correlated closely with the neuroprotective effects of XA. Finally, the protein⁻lipid interaction network was analyzed. Based on our results, the regulation of sphingolipid metabolism and mitochondrial function were determined to be the main mechanisms underlying the neuroprotective effect of XA. The present study should help us to better understand the multiple effects of macamides and their use in neurodegenerative diseases.
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http://dx.doi.org/10.3390/molecules23112929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278518PMC
November 2018

Oridonin inhibits VEGF-A-associated angiogenesis and epithelial-mesenchymal transition of breast cancer and .

Oncol Lett 2018 Aug 11;16(2):2289-2298. Epub 2018 Jun 11.

Department of Integrated Chinese Traditional and Western Medicine, International Medical School, Tianjin Medical University, Tianjin 300070, P.R. China.

Metastasis is the primary cause of mortality in patients with breast cancer and lacks effective therapeutic agents. Oridonin, an active diterpenoid compound isolated from , was identified to be the most potent anti-tumor ingredient. However, the molecular mechanisms responsible for its anti-metastatic effects remain unclear. In the present study, oridonin significantly suppressed the migration, invasion and adhesion of MDA-MB-231 and 4T1 breast cancer cells, and inhibited tube formation of human umbilical vein endothelial cells in a dose-dependent manner. The expression levels of epithelial-mesenchymal transition (EMT)-associated marker and the hypoxia inducible factor 1α (HIF-1α)/vascular endothelium growth factor (VEGF) signaling pathway mRNA and proteins were determined by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively . The results demonstrated that oridonin effectively inhibited EMT as demonstrated by the significant increases in the expression levels of E-cadherin, and decreased expression of N-cadherin, Vimentin and Snail. In addition, oridonin exerted its anti-angiogenesis activity through significantly decreasing HIF-1α, VEGF-A and VEGF receptor-2 protein expression. Furthermore, oridonin was demonstrated to decrease the micro-vessel density as evidenced by the decreased expression of cluster of differentiation 31, a marker for neovasculature. In brief, oridonin inhibits tumor cell migration, invasion and adhesion, as well as tumor angiogenesis, which are mediated by suppressing EMT and the HIF-1α/VEGF signaling pathway. The results of the present study suggest that oridonin may be a promising anti-metastatic agent in breast cancer treatment.
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http://dx.doi.org/10.3892/ol.2018.8943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036431PMC
August 2018

A New Strategy to Stabilize Capacity and Insight into the Interface Behavior in Electrochemical Reaction of LiNiMnO/Graphite System for High-Voltage Lithium-Ion Batteries.

ACS Appl Mater Interfaces 2017 Sep 18;9(38):33274-33287. Epub 2017 Sep 18.

School of Chemical and Pharmaceutical Science, Guangxi Normal University , Guilin 541004, China.

The performance of CEI and SEI configuration and formation mechanism on the cathode and anode side for LiNiMnO/natural graphite (LNMO/NG) batteries is investigated, where series permutations of the NG electrodes modified with TEOS species as the anode for the LNMO full cells. It is believed that the excellent long-term cycling performance of LNMO/NG full cells at the high voltage is a result of alleviating the devastated reaction to form the CEI and SEI on the both electrodes with electrolyte, respectively. At a voltage range from 3.4 to 4.8 V for the LNMO full cells, 95.0% capacity retention after 100 cycles is achieved when cycled with TEOS-modifying NG anode. This mechanism may be explained that eliminating the HF and absorbing water impurities in the electrolyte by introducing the TEOS group, which can transform the SiO species that react with the acid of HF at the organic solvent environment instead of destroying/forming the anode SEI and attacking the LNMO spinel structure to form the dense and high resistance CEI, meanwhile the SiO species will absorb the water molecule and precipitate into the anode surface further stabilizing the SEI configuration during the cycling.
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http://dx.doi.org/10.1021/acsami.7b08828DOI Listing
September 2017

Comparative Metabolism Study of Five Protoberberine Alkaloids in Liver Microsomes from Rat, Rhesus Monkey, and Human.

Planta Med 2017 Nov 11;83(16):1281-1288. Epub 2017 Apr 11.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.

Protoberberine alkaloids including berberine, palmatine, jatrorrhizine, coptisine, and epiberberine are major components in many medicinal plants. They have been widely used for the treatment of cancer, inflammation, diabetes, depression, hypertension, and various infectious areas. However, the metabolism of five protoberberine alkaloids among different species has not been clarified previously. In order to elaborate on the metabolism of them, a comparative analysis of their metabolic profile in rat, rhesus monkey, and human liver microsomes was carried out using ultrahigh-performance liquid chromatography coupled with a high-resolution linear trap quadrupole-Orbitrap mass spectrometer (UHPLC-electrospray ionization-Orbitrap MS) for the first time. Each metabolite was identified and semiquantified by its accurate mass data and peak area. Fifteen metabolites were characterized based on accurate MS/MS spectra and the proposed MS/MS fragmentation pathways including demethylation, hydroxylation, and methyl reduction. Among them, the content of berberine metabolites in human liver microsomes was similar with those in rhesus monkey liver microsomes, whereas berberine in rat liver microsomes showed no demethylation metabolites and the content of metabolites showed significant differences with that in human liver microsomes. On the contrary, the metabolism of palmatine in rat liver microsomes resembled that in human liver microsomes. The content of jatrorrhizine metabolites presented obvious differences in all species. The HR-ESI-MS/MS fragmentation behavior of protoberberine alkaloids and their metabolic profile in rat, rhesus monkey, and human liver microsomes were investigated for the first time. The results demonstrated that the biotransformation characteristics of protoberberine alkaloids among different species had similarities as well differences that would be beneficial for us to better understand the pharmacological activities of protoberberine alkaloids.
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http://dx.doi.org/10.1055/s-0043-108249DOI Listing
November 2017

Evaluation of Bufadienolides as the Main Antitumor Components in Cinobufacin Injection for Liver and Gastric Cancer Therapy.

PLoS One 2017 12;12(1):e0169141. Epub 2017 Jan 12.

Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences, Beijing, China.

Background: Cinobufacin injection, also known as huachansu, is a preparation form of Cinobufacini made from Cinobufacin extract liquid. Despite that Cinobufacin injection is shown to shrink liver and gastric tumors, improving patient survival and life quality, the effective components in Cinobufacin remain elusive. In this study, we aim to screen antitumor components from Cinobufacin injection to elucidate the most effective antitumor components for treatment of liver and gastric cancers.

Materials And Methods: High performance liquid chromatography (HPLC) and LC-MS/MS analysis were used to separate and determine the components in Cinobufacin injection. Inhibition rates of various components in Cinobufacin injection on liver and gastric cancer cells were determined with MTT assay; Hepatocellular carcinoma and gastric cancer models were used to assess the antitumor effect of the compounds in vivo.

Results: The major constituents in Cinobufacin injection include peptides, nucleic acids, tryptamines and bufotalins. MTT assay revealed that bufadienolides had the best antitumor activity, with peptides being the second most effective components. Bufadienolides showed significant inhibition rates on gastric and hepatocellular tumour growth in vivo.

Conclusion: Bufadienolides are the most effective components in Cinobufacini injection for the treatment of liver and gastric cancers. This discovery can greatly facilitate further research in improving the therapeutic effects of Cinobufacin injection, meanwhile reducing its adverse reaction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169141PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5231367PMC
August 2017

Omeprazole Alleviates Aristolochia manshuriensis Kom-Induced Acute Nephrotoxicity.

PLoS One 2016 7;11(10):e0164215. Epub 2016 Oct 7.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.

Aristolochia manshuriensis Kom (AMK) is a member of the Aristolochiaceae family and is a well-known cause of aristolochic acid (AA) nephropathy. In this study, we investigated the potential of omeprazole (OM) to alleviate AMK-induced nephrotoxicity. We found that OM reduced mouse mortality caused by AMK and attenuated AMK-induced acute nephrotoxicity in rats. OM enhanced hepatic Cyp 1a1/2 and renal Cyp 1a1 expression in rats, as well as CYP 1A1 expression in human renal tubular epithelial cells (HKCs). HKCs with ectopic CYP 1A1 expression were more tolerant to AA than the control cells. Therefore, OM may alleviate AMK-mediated acute nephrotoxicity through induction of CYP 1A1. We suggest that the coadministration of OM might be beneficial for reducing of AA-induced nephrotoxicity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164215PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055352PMC
June 2017

Metabolic profiling analysis of berberine, palmatine, jatrorrhizine, coptisine and epiberberine in zebrafish by ultra-high performance liquid chromatography coupled with LTQ Orbitrap mass spectrometer.

Xenobiotica 2015 Apr 5;45(4):302-11. Epub 2014 Nov 5.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences , Beijing , China and.

1. Zebrafish has been used in metabolic study of drugs as a powerful tool in recent years. In this study, we make a feasible metabolism investigation of five protoberberine alkaloids (PBAs) applied in zebrafish model for the first time, including berberine (BBR), palmatine (PAL), jatrorrhizine (JAT), coptisine (COP) and epiberberine (EBBR). 2. After exposure for 24 hours, 19 metabolites were identified by LTQ Orbitrap mass spectrometer, including 9 phase I metabolites and 10 phase II metabolites. Demethylation, hydroxylation, sulfation and glucuronidation were the major metabolic transformation of PBAs in zebrafish, which were similar to mammals. Compared with reported literatures, BBR and JAT showed high consistency between human and zebrafish in metabolic pathways. 3. To our knowledge, this is the first time to study in vivo metabolism of COP, which provides useful information to other researchers. 4. This study indicated that zebrafish model is feasible and reasonable to predict the metabolism of PBAs. It showed great potential for developing a novel and rapid method for predicting the metabolism of trace compounds of botanical drugs, with the advantages of lower cost, higher performance and easier set up.
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http://dx.doi.org/10.3109/00498254.2014.979270DOI Listing
April 2015

Mutational analysis of dimeric linkers in peri- and cytoplasmic domains of histidine kinase DctB reveals their functional roles in signal transduction.

Open Biol 2014 Jun;4(6):140023

State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, People's Republic of China

Membrane-associated histidine kinases (HKs) in two-component systems respond to environmental stimuli by autophosphorylation and phospho-transfer. HK typically contains a periplasmic sensor domain that regulates the cytoplasmic kinase domain through a conserved cytoplasmic linker. How signal is transduced from the ligand-binding site across the membrane barrier remains unclear. Here, we analyse two linker regions of a typical HK, DctB. One region connects the first transmembrane helix with the periplasmic Per-ARNT-Sim domains, while the other one connects the second transmembrane helix with the cytoplasmic kinase domains. We identify a leucine residue in the first linker region to be essential for the signal transduction and for maintaining the delicate balance of the dimeric interface, which is key to its activities. We also show that the other linker, belonging to the S-helix coiled-coil family, plays essential roles in signal transduction inside the cell. Furthermore, by combining mutations with opposing activities in the two regions, we show that these two signalling transduction elements are integrated to produce a combined effect on the final activity of DctB.
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http://dx.doi.org/10.1098/rsob.140023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077058PMC
June 2014