Target engagement of ginsenosides in mild cognitive impairment using mass spectrometry-based drug affinity responsive target stability

Zhu, Zhu,Li, Ruimei,Qin, Wei,Zhang, Hantao,Cheng, Yao,Chen, Feiyan,Chen, Cuihua,Chen, Lin,Zhao, Yunan The Korean Society of Ginseng 2022 Journal of Ginseng Research Vol.46 No.6

Background: Mild cognitive impairment (MCI) is a transitional condition between normality and dementia. Ginseng is known to have effects on attenuating cognitive deficits in neurogenerative diseases. Ginsenosides are the main bioactive component of ginseng, and their protein targets have not been fully understood. Furthermore, no thorough analysis is reported in ginsenoside-related protein targets in MCI. Methods: The candidate protein targets of ginsenosides in brain tissues were identified by drug affinity responsive target stability (DARTS) coupled with label-free liquid chromatography-mass spectrometry (LC-MS) analysis. Network pharmacology approach was used to collect the therapeutic targets for MCI. Based on the above-mentioned overlapping targets, we built up a proteineprotein interaction (PPI) network in STRING database and conducted gene ontology (GO) enrichment analysis. Finally, we assessed the effects of ginseng total saponins (GTS) and different ginsenosides on mitochondrial function by measuring the activity of the mitochondrial respiratory chain complex and performing molecular docking. Results: We screened 2526 MCI-related protein targets by databases and 349 ginsenoside-related protein targets by DARTS. On the basis of these 81 overlapping genes, enrichment analysis showed the mitochondria played an important role in GTS-mediated MCI pharmacological process. Mitochondrial function analysis showed GTS, protopanaxatriol (PPT), and Rd increased the activities of complex I in a dose-dependent manner. Molecular docking also predicted the docking pockets between PPT or Rd and mitochondrial respiratory chain complex I. Conclusion: This study indicated that ginsenosides might alleviate MCI by targeting respiratory chain complex I and regulating mitochondrial function, supporting ginseng's therapeutic application in cognitive deficits.

Discovery and validation of PURA as a transcription target of 20(S)-protopanaxadiol: Implications for the treatment of cognitive dysfunction

Feiyan Chen,Wenjing Zhang,Shuyi Xu,Hantao Zhang,Lin Chen,Cuihua Chen,Zhu Zhu,Yunan Zhao 고려인삼학회 2023 Journal of Ginseng Research Vol.47 No.5

Background: 20(S)-protopanaxadiol (PPD), a ginsenoside metabolite, has prominent benefits for thecentral nervous system, especially in improving learning and memory. However, its transcriptionaltargets in brain tissue remain unknown. Methods: In this study, we first used mass spectrometry-based drug affinity responsive target stability(DARTS) to identify the potential proteins of ginsenosides and intersected them with the transcriptionfactor library. Second, the transcription factor PURA was confirmed as a target of PPD by biolayerinterferometry (BLI) and molecular docking. Next, the effect of PPD on the transcriptional levels of targetgenes of PURA in brain tissues was determined by qRT-PCR. Finally, bioinformatics analysis was used toanalyze the potential biological features of these target proteins. Results: The results showed three overlapping transcription factors between the proteomics of DARTSand transcription factor library. BLI analysis further showed that PPD had a higher direct interaction withPURA than parent ginsenosides. Subsequently, BLI kinetic analysis, molecular docking, and mutations inkey amino acids of PURA indicated that PPD specifically bound to PURA. The results of qRT-PCR showedthat PPD could increase the transcription levels of PURA target genes in brain. Finally, bioinformaticsanalysis showed that these target proteins were involved in learning and memory function. Conclusion: The above-mentioned findings indicate that PURA is a transcription target of PPD in brain,and PPD upregulate the transcription levels of target genes related to cognitive dysfunction by bindingPURA, which could provide a chemical and biological basis for the study of treating cognitive impairmentby targeting PURA.

Identification and confirmation of 14-3-3 ζ as a novel target of ginsenosides in brain tissues

Feiyan Chen,Lin Chen,Weifeng Liang,Zhengguang Zhang,Jiao Li,Wan Zheng,Zhu Zhu,Jiapeng Zhu,Yunan Zhao 고려인삼학회 2021 Journal of Ginseng Research Vol.45 No.4

Background: Ginseng can help regulate brain excitability, promote learning and memory, and resist cerebral ischemia in the central nervous system. Ginsenosides are the major effective compounds of Ginseng, but their protein targets in the brain have not been determined. Methods: We screened proteins that interact with the main components of ginseng (ginsenosides) by affinity chromatography and identified the 14-3-3 ζ protein as a potential target of ginsenosides in brain tissues. Results: Biolayer interferometry (BLI) analysis showed that 20(S)-protopanaxadiol (PPD), a ginseng saponin metabolite, exhibited the highest direct interaction to the 14-3-3 ζ protein. Subsequently, BLI kinetics analysis and isothermal titration calorimetry (ITC) assay showed that PPD specifically bound to the 14-3-3 ζ protein. The cocrystal structure of the 14-3-3 ζ protein-PPD complex showed that the main interactions occurred between the residues R56, R127, and Y128 of the 14-3-3 ζ protein and a portion of PPD. Moreover, mutating any of the above residues resulted in a significant decrease of affinity between PPD and the 14-3-3 ζ protein. Conclusion: Our results indicate the 14-3-3 ζ protein is the target of PPD, a ginsenoside metabolite. Crystallographic and mutagenesis studies suggest a direct interaction between PPD and the 14-3-3 ζ protein. This finding can help in the development of small-molecular compounds that bind to the 14-3-3 ζ protein on the basis of the structure of dammarane-type triterpenoid.

PERCEIVED RESIDENTIAL ENVIRONMENT QUALITY, PLACE ATTACHMENT, AND ENVIRONMENTAL SATISFACTION: THE COMPETING MODELS IN RURAL AND URBAN AREAS OF CHINA

Kangkang Yu,Ning (Chris) Chen,Xinkai Zhu,Jian Gao 글로벌지식마케팅경영학회 2016 Global Marketing Conference Vol.2016 No.7

Level of urbanization in China has reached 53.73% in 2013, indicating a tremendous progress on the urbanization of China. On the other hand, the number of villages in China reduces by around one million from 3.6 million in 2000 to 2.7 million in 2010 (Zhang, 2014). Issues in both urban and rural areas of China appear, including the imbalance between increased population and limited resources in urban region, and more significantly, the increasing disparity between rural and urban areas. Chinese researchers interpret and analyse these matters from different perspectives. For instance, Zheng (2006) and Ma (2006) suggest the importance of the infrastructure construction and public service. Wu (2006) advises that the government should pay attention to the development of the secondary and tertiary industry. Wen (2005) proposes that the improvement of social institution and the recovery of social cultural environment are required to achieve sustainability in the urbanization process in China. Previous studies in environmental psychology put quality of life, attachment to place, and residence satisfaction at the center to understand the relationship between inhabitants and their neighborhood of residence. However, there are gaps in this research realm in both practice and theories. Firstly, very limited research studies this environmental psychology issue in China (e.g. Mao, Fornara, Manca, Bonnes, & Bonaiuto, 2015). Secondly, there are different opinions on the causal order between quality, attachment, and satisfaction. Research on the relationship between perceived residential environment quality (PREQ), place attachment, and environmental satisfaction has not reached a consensus. The debate on the direction of the causal relationship between perceived quality and satisfaction has been summarized by Bradya and Robertson (2001). They conclude that the quality to satisfaction causal order holds up well across diverse cultures. However, relevant debate is still ongoing. A number of research articles place satisfaction as an antecedent to attachment, e.g. Chen, Dwyer, and Firth (2014); Lee, Kyle, and Scott (2012); Ramkissoon and Mavondo (2015); etc. Some argue that place attachment is an indicator of satisfaction. Kyle et al. (2004) investigate the effect of place attachment on the perceived values of tourists and find that place attachment is an important factor explaining the variance of perceived values. This is supported by research e.g. Hwang, Lee, and Chen (2005); Prayag and Ryan (2012); Yuksel, Yuksel, Biljm (2010); etc. As to the relationship between perceived quality and attachment, the debate has not stopped. Through comparisons, Mesch and Manor (1996) conclude that the residents who give a higher evaluation of the social and natural environment may have greater place attachment. Brown, Perkins, and Brown (2003) also suggest that the residents who agree that the street environment is better would attach to this place. Sam, Bayram, and Bilgel (2012) have certified the relationship between residential environment quality and place attachment. Furthermore, Borrie and Roggenbuck (2001) and Walker and Ryan (2008) find that the connection between human beings and the nature environment would affect their affection toward the environment. It means that the closer the relationship with the nature environment is, the stronger the attachment would be, which in turn, enhances the intentions to protect the environment. This quality to satisfaction relationship is supported by other research such as Bonaiuto, Aiello, Perugini, Bonnes, and Ercolani (1999); Grisaffe and Nguyen (2011); Yu, Chen, and Chen (2015); etc. Nevertheless, a different opinion arguing that attachment to a place may affect one’s perception on the quality related to a place is emerging in tourism research (e.g. Neuvonen, Pouta, & Siev?nen, 2010). This paper takes the credit of quality → attachment → satisfaction causal order as the initial model and proposes three hypotheses as follows. H1a: One’s PREQ has a positive impact on his/her attachment to this place; H2a: One’s attachment to a place has a positive impact on his/her satisfaction to the environmental settings in this place; H3a: Place attachment in addition performs as a mediating role between PREQ and environment satisfaction.To be noted, the initial model has its theoretical basis as discussed above but is not necessarily the absolute optimal model. Relatively, this model provides more theoretical interpretation and practical implications in the specific research context: residential psychology in urban and rural areas of China. On this basis, this article further examines a competing model illustrating an alternative theoretical framework on the relationships between these three constructs (satisfaction → attachment → quality). Relatively, another group of hypotheses in this competing model is listed as follows. H1b: One’s attachment to a place has a positive impact on his/her PREQ; H2b: One’s satisfaction to the environmental settings in this place has a positive impact on his/her attachment to this place; H3b: Place attachment in addition performs as a mediating role between environment satisfaction and PREQ. A survey approach is employed and data are collected from several backgrounds. Dataset A (rural) is collected from three villages from Heilongjiang Province and two villages from Shandong Province in China from July to August 2014. The choices of the provinces, rural areas, and the sampling process are random. 490 valid questionnaires are included in the data analysis. Dataset B (urban) is collected via an online survey portal, which allows a nationwide sampling reach. In total 1368 online survey entries are recorded and 420 valid questionnaires are included, resulting in a valid rate of 30.7%. The measures for each construct are based on an extensive literature review. The measurement of perceived residential environment quality is from Sam, Bayram, & Bilgel’s (2012) development on the perception of residential environment. The measurement of place attachment in this study is adopted from Kyle, Graefe, and Manning’s (2005) and Chen, Dwyer, and Firth’s (2014) evaluation based place attachment dimensionality and scales. As for the scale of environmental satisfaction, Pelletier, Legault, and Tuson’s (1996) measure was applied. All the entire variables adopted multiple-item, 5-point Likert scales were adopted, where “1” indicated “strongly disagree” and “5” indicated “strongly agree”. After pre-testing the preliminary version of the survey instrument, a revised version was developed. This study adopts structural equation modeling (SEM) based on partial least squares (PLS) modeling given the small sample size and the explorative purpose of this study (Dijkstra & Henseler, 2015a). The software used was Smart PLS 3.0. The reliability and validity of the constructs were assessed. Cronbach’s alpha and the value of CR of each construct were found to exceed the cut-off value of 0.70 (Fornell & Larcker, 1981), except for adequacy of education which is close to 0.70 (only for Cronbach’s alpha but not for CR). Furthermore, the AVE of each construct exceeded the variance attributable to its measurement error cut-off value of 0.50 (Chin, 1998; Fornell & Larcker, 1981). In addition, heterotrait-monotrait ratio (HTMT) is recommended as a better method to test discriminant validity (Henseler, Dijkstra, Sarstedt, Ringle, Diamantopoulos, Straub, Ketchen, Hair, Hult, & Calantone, 2014). The result shows that there is neither value of the HTMT higher than the threshold of 0.85 nor confidence interval containing the value one, indicating that all the constructs exhibit satisfactory discriminant validity. The hypothesized effects in the theoretical model were tested by structural equation modeling (SEM). The first group of models tested the effect of perceived environmental quality on environmental satisfaction through place attachment i.e. initial model (Model A, Model B, Model C), while the second group of models tested the reverse effect of environmental satisfaction on perceived environmental quality through place attachment (Model D, Model E, Model F). Both the full model and the multi-group model were tested. The value of SRMR of the full model that tests either the effect of perceived environmental quality on environmental satisfaction (SRMR = 0.104, t = 41.826, p < 0.001) or the reversed effect (SRMR = 0.106, t = 37.736, p < 0.001) shows that the models fit the data quite well (Dijkstra & Henseler, 2015b). However, the former is little bit more significant. In this study, PREQI is found different impacts on place attachment and environmental satisfaction. This provides evidence to support a similar mechanism of studying residents’ psychology with SERVEQUAL model. However, the model testing is found significantly different between rural and urban samples, indicating a systematic difference in the psychology of rural and urban populations. Quality ? attachment ? satisfaction causal order is found significant and supported by both samples in this study. However, a reversed causal order model (satisfaction ? attachment ? quality) is also supported by the samples. Although the results may not be able to end the debate on alternative models between PREQ, place attachment, and environmental satisfaction, this paper provides empirical evidence from a specific context (urban and rural China) for further research. Specifically, PREQ has a significant impact on place attachment in both urban and rural areas in China. As for the impact of place attachment on environmental satisfaction as well as the indirect impact of PREQ on environmental satisfaction, the influence is more significant in cities of China compared to rural areas. This suggests in the urban areas in China, affective and emotional responses to their lives play an important role to residents. Local government in cities should balance between improving and maintaining quality of the environment and strengthening local residents’ psychological attachment to the place. Governments in rural areas, on the other hand, should lay great focus on the physical aspects of the environment including nature, health, education, commerce, and venture of the rural areas, to enhance residents’ living experience and satisfaction. Further, there are some limitations. Although this study attempts to clarify the framework of “perception-affection-attitude” in the field of environment management, considering the practical implications, the future study could bring the individuals’ behaviors or intentions into this model such as willingness-to-pay for environment-friendly products. It will also benefit from reviewing more literature on community-based social marketing.

CircFam190a: a critical positive regulator of osteoclast differentiation via enhancement of the AKT1/HSP90β complex

Chen Kun,Chen Xi,Lang Chuandong,Yuan Xingshi,Huang Junming,Li Zhi,Xu Mingyou,Wu Kerong,Zhou Chenhe,Li Qidong,Zhu Chen,Liu Lianxin,Shang Xifu 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-

The identification of key regulatory factors that control osteoclastogenesis is important. Accumulating evidence indicates that circular RNAs (circRNAs) are discrete functional entities. However, the complexities of circRNA expression as well as the extent of their regulatory functions during osteoclastogenesis have yet to be revealed. Here, based on circular RNA sequencing data, we identified a circular RNA, circFam190a, as a critical regulator of osteoclast differentiation and function. During osteoclastogenesis, circFam190a is significantly upregulated. In vitro, circFam190a enhanced osteoclast formation and function. In vivo, overexpression of circFam190a induced significant bone loss, while knockdown of circFam190a prevented pathological bone loss in an ovariectomized (OVX) mouse osteoporosis model. Mechanistically, our data suggest that circFam90a enhances the binding of AKT1 and HSP90β, promoting AKT1 stability. Altogether, our findings highlight the critical role of circFam190a as a positive regulator of osteoclastogenesis, and targeting circFam190a might be a promising therapeutic strategy for treating pathological bone loss.

A possible mechanism to the antidepressant-like effects of 20 (S)-protopanaxadiol based on its target protein 14-3-3 ζ

Chen, Lin,Li, Ruimei,Chen, Feiyan,Zhang, Hantao,Zhu, Zhu,Xu, Shuyi,Cheng, Yao,Zhao, Yunan The Korean Society of Ginseng 2022 Journal of Ginseng Research Vol.46 No.5

Background: Ginsenosides and their metabolites have antidepressant-like effects, but the underlying mechanisms remain unclear. We previously identified 14-3-3 ζ as one of the target proteins of 20 (S)-protopanaxadiol (PPD), a fully deglycosylated ginsenoside metabolite. Methods: Corticosterone (CORT) was administered repeatedly to induce the depression model, and PPD was given concurrently. The tail suspension test (TST) and the forced swimming test (FST) were used for behavioral evaluation. All mice were sacrificed. Golgi-cox staining, GSK 3β activity assay, and Western blot analysis were performed. In vitro, the kinetic binding analysis with the Biolayer Interferometry (BLI) was used to determine the molecular interactions. Results: TST and FST both revealed that PPD reversed CORT-induced behavioral deficits. PPD also ameliorated the CORT-induced expression alterations of hippocampal Ser9 phosphorylated glycogen synthase kinase 3β (p-Ser9 GSK 3β), Ser133 phosphorylated cAMP response element-binding protein (p-Ser133 CREB), and brain-derived neurotrophic factor (BDNF). Moreover, PPD attenuated the CORT-induced increase in GSK 3β activity and decrease in dendritic spine density in the hippocampus. In vitro, 14-3-3 ζ protein specifically bound to p-Ser9 GSK 3β polypeptide. PPD promoted the binding and subsequently decreased GSK 3β activity. Conclusion: These findings demonstrated the antidepressant-like effects of PPD on the CORT-induced mouse depression model and indicated a possible target-based mechanism. The combination of PPD with the 14-3-3 ζ protein may promote the binding of 14-3-3 ζ to p-GSK 3β (Ser9) and enhance the inhibition of Ser9 phosphorylation on GSK 3β kinase activity, thereby activating the plasticity-related CREBeBDNF signaling pathway.

Constructing all-in-one graphene-based supercapacitors for electrochemical energy storage via interface integration strategy

Zhu Yucan,Peng Long,Chen Song,Feng Yuchao,Xia Jianxing,Wang Wei,Chen Liang,Yin Hong,Zhou Minjie,Hou Zhaohui 한국탄소학회 2023 Carbon Letters Vol.33 No.3

With the rapid development of flexible wearable electronic products, flexible all graphene-based supercapacitors (FGSCs) with reduced graphene oxide rGO//graphene oxide (GO)//rGO structure have attracted substantial attention due to their unique structures and energy storage mechanism. However, restricted by design idea and preparation technology, improvement of capacitance performance for the FGSCs is not obvious recently. Herein, we demonstrate that an interface integration strategy of constructing the high-performance FGSCs with compact structure. Hydroquinone (HQ)-modified rGO (HQ-rGO) films (electrode materials) and sulfuric acid-intercalated GO films (electrolyte/separator) are assembled into the FGSCs utilizing hydrogen bonding and capillary contractility. The HQ further improves the electrochemical capacitance of electrode materials. The synergistic effect of the hydrogen bonding and capillary contractility guarantees compact and stable structure of the device. The resulting FGSCs exhibit an excellent areal capacitance of 804.6 mF cm−2 (@2 mA cm−2) and 441 mF cm−2 (@30 mA cm−2), and their highest energy and power densities can achieve 109.5 μWh cm−2 and 21,060 μW cm−2, respectively. These performances are superior to other all-in-one graphene-based SCs reported. Therefore, the construction technology of the FGSCs is a promising for developing all graphene-based SCs with high-performance.

Comprehensive analysis of miRNAs, lncRNAs and mRNAs profiles in backfat tissue between Daweizi and Yorkshire pigs

Chen Chen,Yitong Chang,Yuan Deng,Qingming Cui,Yingying Liu,Huali Li,Huibo Ren,Ji Zhu,Qi Liu,Yinglin Peng Asian Australasian Association of Animal Productio 2023 Animal Bioscience Vol.36 No.3

Objective: Daweizi (DWZ) is a famous indigenous pig breed in China and characterized by tender meat and high fat percentage. However, the expression profiles and functions of transcripts in DWZ pigs is still in infancy. The object of this study was to depict the transcript profiles in DWZ pigs and screen the potential pathway influence adipogenesis and fat deposition, Methods: Histological analysis of backfat tissue was firstly performed between DWZ and lean-type Yorkshire pigs, and then RNA sequencing technology was utilized to explore miRNAs, lncRNAs and mRNAs profiles in backfat tissue. 18 differentially expressed (DE) transcripts were randomly selected for quantitative real-time polymerase chain reaction (QPCR) to validate the reliability of the sequencing results. Finally, gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis were conducted to investigate the potential pathways influence adipocyte differentiation, adipogenesis and lipid metabolism, and a schematic model was further proposed. Results: A total of 1,625 differentially expressed transcripts were identified in DWZ pigs, including 27 upregulated and 45 downregulated miRNAs, 64 upregulated and 119 down-regulated lncRNA, 814 upregulated and 556 downregulated mRNAs. QPCR analysis exhibited strong consistency with the sequencing data. GO and KEGG analysis elucidated that the differentially expressed transcripts were mainly associated with cell growth and death, signal transduction, peroxisome proliferator-activated receptors (PPAR), AMP-activated protein kinase (AMPK), PI3K-Akt, adipocytokine and foxo signaling pathways, all of which are strongly involved in cell development, lipid metabolism and adipogenesis. Further analysis indicated that the BGIR9823_87926/miR-194a-5p/AQP7 network may be effective in the process of adipocyte differentiation or adipogenesis. Conclusion: Our study provides comprehensive insights into the regulatory network of backfat deposition and lipid metabolism in pigs from the point of view of miRNAs, lncRNAs and mRNAs.

Dose-Dependent Associations between Wine Drinking and Breast Cancer Risk - Meta-Analysis Findings

Chen, Jia-Yan,Zhu, Hong-Cheng,Guo, Qing,Shu, Zheng,Bao, Xu-Hui,Sun, Feng,Qin, Qin,Yang, Xi,Zhang, Chi,Cheng, Hong-Yan,Sun, Xin-Chen Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.3

Purpose: To investigate any potential association between wine and breast cancer risk. Materials and Methods: We quantitatively assessed associations by conducting a meta-analysis based on evidence from observational studies. In May 2014, we performed electronic searches in PubMed, EmBase and the Cochrane Library to identify studies examining the effect of wine drinking on breast cancer incidence. The relative risk (RR) or odds ratio (OR) were used to measure any such association. Results: The analysis was further stratified by confounding factors that could influence the results. A total of twenty-six studies (eight case-control and eighteen cohort studies) involving 21,149 cases were included in our meta-analysis. Our study demonstrated that wine drinking was associated with breast cancer risk. A 36% increase in breast cancer risk was observed across overall studies based on the highest versus lowest model, with a combined RR of 1.0059 (95%CI 0.97-1.05) in dose-response analysis. However, 5 g/d ethanol from wine seemed to have protective value from our non-linear model. Conclusions: Our findings indicate that wine drinking is associated with breast cancer risk in a dose-dependent manner. High consumption of wine contributes to breast cancer risk with protection exerted by low doses. Further investigations are needed for clarification.

IPOS three-state boost converter and its volt-second balance method based output voltage sharing control strategy for bipolar DC bus applications

Chen, Zhangyong,Feng, Chenchen,Chen, Gen,Chen, Yong,Zhu, Xintong The Korean Institute of Power Electronics 2022 JOURNAL OF POWER ELECTRONICS Vol.22 No.9

The bipolar DC bus configuration has been widely used in DC nano-grids due to its flexibility and stability. Input-parallel-output-series (IPOS) converters are utilized in bipolar DC bus and RES applications due to their simple structure. However, there is a big challenge with this structure. To ensure system safety and stability, the two output voltages of an IPOS converter need to be balanced. On this basis, an IPOS three-state boost converter with a balanced output voltage is proposed in this paper. At the same time, output voltage balance can be obtained by adjusting the duration of the three-state converter based on the volt-second balance method. In the proposed strategy, a switch series diode is added to the IPOS Boost converter topology, and the voltage across the main inductor can be changed through one degree of freedom, where the corresponding output voltage is regulated due to a change in inductor voltage. In addition, under different dead time conditions, adjusting the gate drive of the switch can be used to achieve voltage balance. Moreover, a comprehensive analysis and relative calculations are provided. Finally, a 20-200 V prototype is built to verify the analysis.