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Article ; Online: Salicylate induces AMPK and inhibits c-MYC to activate a NRF2/ARE/miR-34a/b/c cascade resulting in suppression of colorectal cancer metastasis.

Liu, Chunfeng / Rokavec, Matjaz / Huang, Zekai / Hermeking, Heiko

2023 Volume 14, Issue 10, Page(s) 707

Abstract: Aspirin and its active metabolite salicylate have emerged as promising agents for the chemoprevention of colorectal cancer (CRC). Moreover, aspirin suppresses the progression of established CRCs. However, the underlying molecular mechanisms are not ... ...

Abstract	Aspirin and its active metabolite salicylate have emerged as promising agents for the chemoprevention of colorectal cancer (CRC). Moreover, aspirin suppresses the progression of established CRCs. However, the underlying molecular mechanisms are not completely understood. Here we found that salicylate induces the expression of the miR-34a and miR-34b/c genes, which encode tumor suppressive microRNAs, in a p53-independent manner. Salicylate activated AMPK, thereby activating NRF2, which directly induced miR-34a/b/c expression via ARE motifs. In addition, salicylate suppressed c-MYC, a known repressor of NRF2-mediated transactivation, via activating AMPK. The suppression of c-MYC by salicylate was necessary for NRF2-mediated activation of miR-34a/b/c. Inactivation of miR-34a/b/c largely abrogated the inhibitory effects of salicylate on migration, invasion and metastasis formation by CRC cells. In the future, aspirin and its derivates may be used therapeutically to activate miR-34a and miR-34b/c in tumors that have lost p53.
MeSH term(s)	Humans ; AMP-Activated Protein Kinases/metabolism ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Salicylates/pharmacology ; Cell Line, Tumor ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Aspirin/pharmacology ; Gene Expression Regulation, Neoplastic
Chemical Substances	AMP-Activated Protein Kinases (EC 2.7.11.31) ; NF-E2-Related Factor 2 ; Tumor Suppressor Protein p53 ; Salicylates ; MicroRNAs ; Aspirin (R16CO5Y76E)
Language	English
Publishing date	2023-10-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-023-06226-9
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Article ; Online: Curcumin activates a ROS/KEAP1/NRF2/miR-34a/b/c cascade to suppress colorectal cancer metastasis.

Liu, Chunfeng / Rokavec, Matjaz / Huang, Zekai / Hermeking, Heiko

Cell death and differentiation

2023 Volume 30, Issue 7, Page(s) 1771–1785

Abstract: Curcumin, a natural phytochemical isolated from tumeric roots, represents a candidate for prevention and therapy of colorectal cancer/CRC. However, the exact mechanism of action and the downstream mediators of curcumin's tumor suppressive effects have ... ...

Abstract	Curcumin, a natural phytochemical isolated from tumeric roots, represents a candidate for prevention and therapy of colorectal cancer/CRC. However, the exact mechanism of action and the downstream mediators of curcumin's tumor suppressive effects have remained largely unknown. Here we used a genetic approach to determine the role of the p53/miR-34 pathway as mediator of the effects of curcumin. Three isogenic CRC cell lines rendered deficient for the p53, miR-34a and/or miR-34b/c genes were exposed to curcumin and subjected to cell biological analyses. siRNA-mediated inhibition and ectopic expression of NRF2, as well as Western blot, qPCR and qChIP analyses of its target genes were performed. CRC cells were i.v. injected into NOD/SCID mice and lung-metastases formation was determined by longitudinal, non-invasive imaging. In CRC cells curcumin induced apoptosis and senescence, and suppressed migration and invasion in a p53-independent manner. Curcumin activated the KEAP1/NRF2/ARE pathway by inducing ROS. Notably, curcumin induced miR-34a and miR-34b/c expression in a ROS/NRF2-dependent and p53-independent manner. NRF2 directly induced miR-34a and miR-34b/c via occupying multiple ARE motifs in their promoter regions. Curcumin reverted repression of miR-34a and miR-34b/c induced by IL6 and hypoxia. Deletion of miR-34a and miR-34b/c significantly reduced curcumin-induced apoptosis and senescence, and prevented the inhibition of migration and invasion by curcumin or ectopic NRF2. In CRC cells curcumin induced MET and prevented the formation of lung-metastases in mice in a miR-34a-dependent manner. In addition, we found that curcumin may enhance the therapeutic effects of 5-FU on CRC cells deficient for p53 and miR-34a/b/c. Activation of the KEAP1/NRF2/miR-34a/b/c axis mediates the tumor suppressive activity of curcumin and suggests a new approach for activating miR-34 genes in tumors for therapeutic purposes.
MeSH term(s)	Animals ; Mice ; Cell Line, Tumor ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/therapy ; Curcumin/pharmacology ; Gene Expression Regulation, Neoplastic ; Kelch-Like ECH-Associated Protein 1/metabolism ; Lung Neoplasms/secondary ; Lung Neoplasms/therapy ; Mice, Inbred NOD ; Mice, SCID ; MicroRNAs ; NF-E2-Related Factor 2/metabolism ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Curcumin (IT942ZTH98) ; Kelch-Like ECH-Associated Protein 1 ; MicroRNAs ; NF-E2-Related Factor 2 ; Reactive Oxygen Species ; Tumor Suppressor Protein p53
Language	English
Publishing date	2023-05-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225672-9
ISSN	1476-5403 ; 1350-9047
ISSN (online)	1476-5403
ISSN	1350-9047
DOI	10.1038/s41418-023-01178-1
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Zs.A 4230: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: CRISPR/Cas9-mediated inactivation of miR-34a and miR-34b/c in HCT116 colorectal cancer cells: comprehensive characterization after exposure to 5-FU reveals EMT and autophagy as key processes regulated by miR-34.

Huang, Zekai / Kaller, Markus / Hermeking, Heiko

Cell death and differentiation

2023 Volume 30, Issue 8, Page(s) 2017–2034

Abstract: The miR-34a and miR-34b/c encoding genes represent direct targets of the p53 transcription factor, and presumably mediate part of the tumor suppressive effects of p53. Here, we sought to determine their functional relevance by inactivating miR-34a and/or ...

Abstract	The miR-34a and miR-34b/c encoding genes represent direct targets of the p53 transcription factor, and presumably mediate part of the tumor suppressive effects of p53. Here, we sought to determine their functional relevance by inactivating miR-34a and/or miR-34b/c using a CRISPR/Cas9 approach in the colorectal cancer (CRC) cell line HCT116. Concomitant deletion of miR-34a and miR-34b/c resulted in significantly reduced suppression of proliferation after p53 activation, enhanced migration, invasion and EMT, as well as reduced sensitivity to chemotherapeutics, increased stress-induced autophagic flux, decreased apoptosis and upregulation of autophagy-related genes after 5-FU treatment. However, inactivation of singular miR-34a or miR-34b/c had little effects on the aforementioned processes. RNA-Seq analysis revealed that concomitant deletion of miR-34a/b/c caused EMT signature enrichment, impaired gene repression by the p53-DREAM pathway and elevated autophagy after 5-FU treatment. A gene signature comprised of mRNAs significantly upregulated after combined inactivation of miR-34a and miR-34b/c showed a significant association with the invasive colon cancer subtype CMS4 and poor overall survival in two CRC patient cohorts, and with 5-FU resistance in CRC cell lines. In miR-34a/b/c-deficient cells the upregulated miR-34 target FOXM1 directly induced p62 and ATG9A, which increased autophagy and consequently attenuated apoptosis and rendered the miR-34a/b/c-KO cells more resistant to 5-FU. Inhibition of autophagy by depletion of ATG9A or chloroquine re-sensitized miR-34a/b/c-deficient HCT116 cells to 5-FU. In summary, our findings show a complementary role of miR-34a and miR-34b/c in the regulation of EMT and autophagy which may be relevant for CRC therapy in the future.
MeSH term(s)	Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; HCT116 Cells ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; CRISPR-Cas Systems/genetics ; Cell Line, Tumor ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Fluorouracil/pharmacology ; Autophagy/genetics ; Gene Expression Regulation, Neoplastic
Chemical Substances	MicroRNAs ; Tumor Suppressor Protein p53 ; Fluorouracil (U3P01618RT) ; MIRN34 microRNA, human
Language	English
Publishing date	2023-07-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225672-9
ISSN	1476-5403 ; 1350-9047
ISSN (online)	1476-5403
ISSN	1350-9047
DOI	10.1038/s41418-023-01193-2
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Zs.A 4230: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Book ; Online ; Thesis: Characterization of miR-34 effectors in colorectal cancer

Huang, Zekai [Verfasser] / Hermeking, Heiko [Akademischer Betreuer]

2024

Author's details	Zekai Huang ; Betreuer: Heiko Hermeking
Keywords	Medizin, Gesundheit ; Medicine, Health
Subject code	sg610
Language	English
Publisher	Universitätsbibliothek der Ludwig-Maximilians-Universität
Publishing place	München
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article: Meta-analysis of miR-34 target mRNAs using an integrative online application.

Rokavec, Matjaz / Huang, Zekai / Hermeking, Heiko

Computational and structural biotechnology journal

2022 Volume 21, Page(s) 267–274

Abstract: Members of the microRNA-34/miR-34 family are induced by the p53 tumor suppressor and themselves possess tumor suppressive properties, as they inhibit the translation of mRNAs that encode proteins involved in processes, such as proliferation, migration, ... ...

Abstract	Members of the microRNA-34/miR-34 family are induced by the p53 tumor suppressor and themselves possess tumor suppressive properties, as they inhibit the translation of mRNAs that encode proteins involved in processes, such as proliferation, migration, invasion, and metastasis. Here we performed a comprehensive integrative meta-analysis of multiple computational and experimental miR-34 related datasets and developed tools to identify and characterize novel miR-34 targets. A miR-34 target probability score was generated for every mRNA to estimate the likelihood of representing a miR-34 target. Experimentally validated miR-34 targets were strongly enriched among mRNAs with the highest scores providing a proof of principle for our analysis. We integrated the results from the meta-analysis in a user-friendly METAmiR34TARGET website (www.metamir34target.com/) that allows to graphically represent the meta-analysis results for every mRNA. Moreover, the website harbors a screen function, which allows to select multiple miR-34-related criteria/analyses and cut-off values to facilitate the stringent and comprehensive prediction of relevant miR-34 targets in expression data obtained from cell lines and tumors/tissues. Furthermore, information on more than 200 miR-34 target mRNAs, that have been experimentally validated so far, has been integrated in the web-tool. The website and datasets provided here should facilitate further investigation into the mechanisms of tumor suppression by the p53/miR-34 connection and identification of potential cancer drug targets.
Language	English
Publishing date	2022-12-06
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2022.12.003
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Article: Development and evaluation of a robotic system for lumbar puncture and epidural steroid injection.

Lu, Jiaxin / Huang, Zekai / Zhuang, Baiyang / Cheng, Zhuoqi / Guo, Jing / Lou, Haifang

Frontiers in neurorobotics

2023 Volume 17, Page(s) 1253761

Abstract: Introduction: Lumbar puncture is an important medical procedure for various diagnostics and therapies, but it can be hazardous due to individual variances in subcutaneous soft tissue, especially in the elderly and obese. Our research describes a novel ... ...

Abstract	Introduction: Lumbar puncture is an important medical procedure for various diagnostics and therapies, but it can be hazardous due to individual variances in subcutaneous soft tissue, especially in the elderly and obese. Our research describes a novel robot-assisted puncture system that automatically controls and maintains the probe at the target tissue layer through a process of tissue recognition. Methods: The system comprises a robotic system and a master computer. The robotic system is constructed based on a probe consisting of a pair of concentric electrodes. From the probe, impedance spectroscopy measures bio-impedance signals and transforms them into spectra that are communicated to the master computer. The master computer uses a Bayesian neural network to classify the bio-impedance spectra as corresponding to different soft tissues. By feeding the bio-impedance spectra of unknown tissues into the Bayesian neural network, we can determine their categories. Based on the recognition results, the master computer controls the motion of the robotic system. Results: The proposed system is demonstrated on a realistic phantom made of ex vivo tissues to simulate the spinal environment. The findings indicate that the technology has the potential to increase the precision and security of lumbar punctures and associated procedures. Discussion: In addition to lumbar puncture, the robotic system is suitable for related puncture operations such as discography, radiofrequency ablation, facet joint injection, and epidural steroid injection, as long as the required tissue recognition features are available. These operations can only be carried out once the puncture needle and additional instruments reach the target tissue layer, despite their ensuing processes being distinct.
Language	English
Publishing date	2023-10-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2453002-5
ISSN	1662-5218
ISSN	1662-5218
DOI	10.3389/fnbot.2023.1253761
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Article: Investigation of phytoplankton community structure and formation mechanism: a case study of Lake Longhu in Jinjiang.

Jiang, Yongcan / Wang, Yi / Huang, Zekai / Zheng, Bin / Wen, Yu / Liu, Guanglong

Frontiers in microbiology

2023 Volume 14, Page(s) 1267299

Abstract: In order to explore the species composition, spatial distribution and relationship between the phytoplankton community and environmental factors in Lake Longhu, the phytoplankton community structures and environmental factors were investigated in July ... ...

Abstract	In order to explore the species composition, spatial distribution and relationship between the phytoplankton community and environmental factors in Lake Longhu, the phytoplankton community structures and environmental factors were investigated in July 2020. Clustering analysis (CA) and analysis of similarities (ANOSIM) were used to identify differences in phytoplankton community composition. Generalized additive model (GAM) and variance partitioning analysis (VPA) were further analyzed the contribution of spatial distribution and environmental factors in phytoplankton community composition. The critical environmental factors influencing phytoplankton community were identified using redundancy analysis (RDA). The results showed that a total of 68 species of phytoplankton were found in 7 phyla in Lake Longhu. Phytoplankton density ranged from 4.43 × 10
Language	English
Publishing date	2023-10-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2023.1267299
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Article ; Online: Roles of rRNA N-methyladenosine modification in the function of ribosomes.

Yang, Jingyi / Wang, Yameng / Huang, Zekai / Jiang, Yashuang / Pan, Xiaolei / Dong, Xiaowei / Yang, Geng

Cell biochemistry and function

2023 Volume 41, Issue 8, Page(s) 1106–1114

Abstract: The N-methyladenosine (m6A) modification of ribosomal RNA (rRNA) plays critical roles in regulating the function of ribosomes, the essential molecular machines that translate genetic information from mRNA into proteins. Specifically, m6A modification ... ...

Abstract	The N-methyladenosine (m6A) modification of ribosomal RNA (rRNA) plays critical roles in regulating the function of ribosomes, the essential molecular machines that translate genetic information from mRNA into proteins. Specifically, m6A modification affects ribosome biogenesis, stability, and function by regulating the processing and maturation of rRNA, the assembly and composition of ribosomes, and the accuracy and efficiency of translation. Furthermore, m6A modification allows for dynamic regulation of translation in response to environmental and cellular signals. Therefore, a deeper understanding of the mechanisms and functions of m6A modification in rRNA will advance our knowledge of ribosome-mediated gene expression and facilitate the development of new therapeutic strategies for ribosome-related diseases.
MeSH term(s)	RNA, Ribosomal/genetics ; RNA, Ribosomal/metabolism ; Ribosomes/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Methylation
Chemical Substances	RNA, Ribosomal ; RNA, Messenger
Language	English
Publishing date	2023-12-02
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	283643-9
ISSN	1099-0844 ; 0263-6484
ISSN (online)	1099-0844
ISSN	0263-6484
DOI	10.1002/cbf.3891
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Article ; Online: IO-YOLOv5: Improved Pig Detection under Various Illuminations and Heavy Occlusion

Lai, Jiajun / Liang, Yun / Kuang, Yingjie / Xie, Zhannan / He, Hongyuan / Zhuo, Yuxin / Huang, Zekai / Zhu, Shijie / Huang, Zenghang

Agriculture. 2023 July 04, v. 13, no. 7

2023

Abstract: Accurate detection and counting of live pigs are integral to scientific breeding and production in intelligent agriculture. However, existing pig counting methods are challenged by heavy occlusion and varying illumination conditions. To overcome these ... ...

Abstract	Accurate detection and counting of live pigs are integral to scientific breeding and production in intelligent agriculture. However, existing pig counting methods are challenged by heavy occlusion and varying illumination conditions. To overcome these challenges, we proposed IO-YOLOv5 (Illumination-Occlusion YOLOv5), an improved network that expands on the YOLOv5 framework with three key contributions. Firstly, we introduced the Simple Attention Receptive Field Block (SARFB) module to expand the receptive field and give greater weight to important features at different levels. The Ghost Spatial Pyramid Pooling Fast Cross Stage Partial Connections (GSPPFC) module was also introduced to enhance model feature reuse and information flow. Secondly, we optimized the loss function by using Varifocal Loss to improve the model’s learning ability on high-quality and challenging samples. Thirdly, we proposed a public dataset consisting of 1270 images and 15,672 pig labels. Experiments demonstrated that IO-YOLOv5 achieved a mean average precision (mAP) of 90.8% and a precision of 86.4%, surpassing the baseline model by 2.2% and 3.7% respectively. By using a model ensemble and test time augmentation, we further improved the mAP to 92.6%, which is a 4% improvement over the baseline model. Extensive experiments showed that IO-YOLOv5 exhibits excellent performance in pig recognition, particularly under heavy occlusion and various illuminations. These results provide a strong foundation for pig recognition in complex breeding environments.
Keywords	agriculture ; data collection ; lighting ; models ; swine
Language	English
Dates of publication	2023-0704
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2651678-0
ISSN	2077-0472
ISSN	2077-0472
DOI	10.3390/agriculture13071349
Database	NAL-Catalogue (AGRICOLA)

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Article: Development of a Genetically Encoded Magnetic Platform in Magnetospirillum gryphiswaldense MSR-1 for Downstream Processing of Protein Expression System.

Wu, Sha / Tian, Jiesheng / Xue, Xianle / Tang, Zongwen / Huang, Zekai / Hammock, Bruce D / Morisseau, Christophe / Li, Qing X / Xu, Ting

Research square

2023

Abstract: Background: Protein downstream processing remains a challenge in protein production, especially in low yields of products, in spite of ensuring effective disruption of cell and separation of target proteins. It is complicated, expensive and time- ... ...

Abstract	Background: Protein downstream processing remains a challenge in protein production, especially in low yields of products, in spite of ensuring effective disruption of cell and separation of target proteins. It is complicated, expensive and time-consuming. Here, we report a novel nano-bio-purification system for producing recombinant proteins of interest with automatic purification from engineered bacteria. Results: This system employed a complete genetic engineering downstream processing platform for proteins at low expression levels, referred to as a genetically encoded magnetic platform (GEMP). GEMP consists of four elements as follows. (1) A truncated phage lambda lysis cassette (RRz/Rz1) is controllable for lysis of Conclusions: In this work, removal of most impurities greatly simplified the subsequent purification procedure. The system also facilitated the bioproduction of nanomaterials. The developed platform can substantially simplify industrial protein production and reduce its cost.
Language	English
Publishing date	2023-03-13
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-2630343/v1
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