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Krauß D, Moreno-Viedma V, Adachi-Fernandez E, de Sá Fernandes C, Genger JW, Fari O, Blauensteiner B, Kirchhofer D, Bradaric N, Gushchina V, Fotakis G, Mohr T, Abramovich I, Mor I, Holcmann M, Bergthaler A, Haschemi A, Trajanoski Z, Winkler J, Gottlieb E, Sibilia M. EGFR controls transcriptional and metabolic rewiring in KRAS G12D colorectal cancer. EMBO Mol Med 2025:10.1038/s44321-025-00240-4. [PMID: 40329096 DOI: 10.1038/s44321-025-00240-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 03/26/2025] [Accepted: 04/02/2025] [Indexed: 05/08/2025] Open
Abstract
Inhibition of the epidermal growth factor receptor (EGFR) shows clinical benefit in metastatic colorectal cancer (CRC) patients, but KRAS-mutations are known to confer resistance. However, recent reports highlight EGFR as a crucial target to be co-inhibited with RAS inhibitors for effective treatment of KRAS mutant CRC. Here, we investigated the tumor cell-intrinsic contribution of EGFR in KRASG12D tumors by establishing murine CRC organoids with key CRC mutations (KRAS, APC, TP53) and inducible EGFR deletion. Metabolomic, transcriptomic, and scRNA-analyses revealed that EGFR deletion in KRAS-mutant organoids reduced their phenotypic heterogeneity and activated a distinct cancer-stem-cell/WNT signature associated with reduced cell size and downregulation of major signaling cascades like MAPK, PI3K, and ErbB. This was accompanied by metabolic rewiring with a decrease in glycolytic routing and increased anaplerotic glutaminolysis. Mechanistically, following EGFR loss, Smoc2 was identified as a key upregulated target mediating these phenotypes that could be rescued upon additional Smoc2 deletion. Validation in patient-datasets revealed that the identified signature is associated with better overall survival of RAS mutant CRC patients possibly allowing to predict therapy responses in patients.
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Affiliation(s)
- Dana Krauß
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Veronica Moreno-Viedma
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Emi Adachi-Fernandez
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Cristiano de Sá Fernandes
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, 1090, Austria
| | - Jakob-Wendelin Genger
- Institute of Hygiene and Applied Immunology, Department of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, 1090, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, 1090, Austria
| | - Ourania Fari
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Bernadette Blauensteiner
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Dominik Kirchhofer
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Nikolina Bradaric
- Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria
| | - Valeriya Gushchina
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Georgios Fotakis
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Thomas Mohr
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Ifat Abramovich
- Department of Cell Biology and Cancer Science, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Inbal Mor
- Department of Cell Biology and Cancer Science, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Department of Molecular Biology, Ariel University, Ariel, 4070000, Israel
| | - Martin Holcmann
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Andreas Bergthaler
- Institute of Hygiene and Applied Immunology, Department of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, 1090, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, 1090, Austria
| | - Arvand Haschemi
- Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria
| | - Zlatko Trajanoski
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Juliane Winkler
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Eyal Gottlieb
- Department of Cell Biology and Cancer Science, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Maria Sibilia
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria.
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Coxon J, Linder E, Sweet C, Magness S, Green L. Replicating Host-Microbiome Interactions: Harnessing Organ-on-a-Chip and Organoid Technologies to Model Vaginal and Lung Physiology. Annu Rev Biomed Eng 2025; 27:403-423. [PMID: 39971348 DOI: 10.1146/annurev-bioeng-110122-122343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Organ-on-a-chip (OOC) and organoid technologies are at the forefront of developing sophisticated in vitro systems that replicate complex host-microbiome interactions, including those associated with vaginal health and lung infection. We explore how these technologies provide insights into host-microbiome and host-pathogen interactions and the associated immune responses. Integrating omics data and high-resolution imaging in analyzing these models enhances our understanding of host-microbiome interactions' temporal and spatial aspects, paving the way for new diagnostic and treatment strategies. This review underscores the potential of OOC and organoid technologies in elucidating the complexities of vaginal health and lung disease, which have received less attention than other organ systems in recent organoid and OCC studies. Yet, each system presents notable characteristics, rendering them ideal candidates for these designs. Additionally, this review describes the key factors associated with each organ system and how to choose the technology setup to replicate human physiology.
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Affiliation(s)
- Jade Coxon
- Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, Indiana, USA;
| | - Emily Linder
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
| | - Caden Sweet
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Scott Magness
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, USA
- Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina, Chapel Hill, North Carolina, USA
| | - Leopold Green
- Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, Indiana, USA;
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
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Higuchi Y, Teo JL, Yi D, Kahn M. Safely Targeting Cancer, the Wound That Never Heals, Utilizing CBP/Beta-Catenin Antagonists. Cancers (Basel) 2025; 17:1503. [PMID: 40361430 DOI: 10.3390/cancers17091503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2025] [Revised: 04/25/2025] [Accepted: 04/25/2025] [Indexed: 05/15/2025] Open
Abstract
Stem cells, both normal somatic (SSC) and cancer stem cells (CSC) exist in minimally two states, i.e., quiescent and activated. Regulation of these two states, including their reliance on different metabolic processes, i.e., FAO and glycolysis in quiescent versus activated stem cells respectively, involves the analysis of a complex array of factors (nutrient and oxygen levels, adhesion molecules, cytokines, etc.) to initiate the epigenetic changes to either depart or enter quiescence. Quiescence is a critical feature of SSC that is required to maintain the genomic integrity of the stem cell pool, particularly in long lived complex organisms. Quiescence in CSC, whether they are derived from mutations arising in SSC, aberrant microenvironmental regulation, or via dedifferentiation of more committed progenitors, is a critical component of therapy resistance and disease latency and relapse. At the beginning of vertebrate evolution, approximately 450 million years ago, a gene duplication generated the two members of the Kat3 family, CREBBP (CBP) and EP300 (p300). Despite their very high degree of homology, these two Kat3 coactivators play critical and non-redundant roles at enhancers and super-enhancers via acetylation of H3K27, thereby controlling stem cell quiescence versus activation and the cells metabolic requirements. In this review/perspective, we discuss the unique regulatory roles of CBP and p300 and how specifically targeting the CBP/β-catenin interaction utilizing small molecule antagonists, can correct lineage infidelity and safely eliminate quiescent CSC.
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Affiliation(s)
- Yusuke Higuchi
- Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Jia-Ling Teo
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Daniel Yi
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Michael Kahn
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
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Nangia-Makker P, Ahrens M, Purandare N, Aras S, Li J, Gurdziel K, Jang H, Kim S, Shekhar MP. Relationship between melanoma vemurafenib tolerance thresholds and metabolic pathway choice and Wnt signaling involvement. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.06.641924. [PMID: 40093038 PMCID: PMC11908245 DOI: 10.1101/2025.03.06.641924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Vemurafenib constitutes an important therapeutic for BRAFV600 mutant melanomas, but despite high initial response rates, resistance to BRAF and MEK inhibitors quickly develops. Here, we performed an integrative analysis of metabolomic consequences and transcriptome alterations to uncover mechanisms involved in adaptive vemurafenib resistance (VemR) development and their relationship with vemurafenib tolerance thresholds. We developed BRAFV600E isogenic models of VemR utilizing M14 and A2058 lines, and patient-derived melanomas with V600E or normal BRAF to verify vemurafenib selectivity. MEK or PI3K inhibitors only partially inhibited VemR cell proliferation, indicating cross-resistance to these inhibitors. MITF and β-catenin levels were induced and treatment with Wnt/β-catenin inhibitor ICG-001 restored vemurafenib sensitivity with concomitant reductions in β-catenin-regulated gene expressions, phospho-ERK1/2, and VemR-induced mitochondrial mass and respiration. Targeted metabolite, MitoPlate-S1, Mito-stress and transcriptome/metabolomic analysis showed that melanoma cells with elevated vemurafenib tolerance thresholds such as A2058 VemR cells utilize Wnt/β-catenin signaling for mitochondrial metabolism while VemR cells with low tolerance such as M14 VemR cells rely on Wnt/β-catenin signaling for pentose phosphate pathway. Pathways associated with cytokine-cytokine receptor, ECM receptor, and neuroactive ligand receptor interactions were similarly enriched in BRAFV600E patient-derived melanoma as M14 and A2058 cells whereas distinct pathways involving cell cycle, DNA replication, Fanconi anemia and DNA repair pathways are upregulated in wild type BRAF expressing patient derived melanoma. These data show for the first time that the metabolic pathway choices made by VemR BRAF mutant melanomas are controlled by vemurafenib tolerance and endurance thresholds and Wnt/β-catenin signaling plays a central role in coordinating expression of genes controlling VemR and metabolic pathway shifts.
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Rob M, Yousef M, Lakshmanan AP, Mahboob A, Terranegra A, Chaari A. Microbial signatures and therapeutic strategies in neurodegenerative diseases. Biomed Pharmacother 2025; 184:117905. [PMID: 39933444 DOI: 10.1016/j.biopha.2025.117905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/17/2025] [Accepted: 02/05/2025] [Indexed: 02/13/2025] Open
Abstract
Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), arise from complex interactions between genetic factors, environmental exposures, and aging. Additionally, gut dysbiosis has been linked to systemic inflammation and neurodegeneration. Advances in microbiome and metabolome profiling techniques have provided deeper insights into how alterations in gut microbiota and dietary patterns affect metabolic pathways and contribute to the progression of NDs. This review explores the profiles of gut microbiome and metabolome derived biomarkers and their roles in NDs. Across phyla, families, and genera, we identified 55 microbial alterations in PD, 24 in AD, 4 in ALS, and 17 in MS. Some notable results include an increase in Akkermansia in PD, AD, and MS and a decrease in short-chain fatty acids (SCFAs) in PD and AD. We examined the effects of probiotics, prebiotics, fecal microbiota transplants (FMT), sleep, exercise, and diet on the microbiota, all of which contributed to delayed onset and alleviation of symptoms. Further, artificial intelligence (AI) and machine learning (ML) algorithms applied to omics data have been crucial in identifying novel therapeutic targets, diagnosing and predicting prognosis, and enabling personalized medicine using microbiota-modulating therapies in NDs patients.
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Affiliation(s)
- Mlaak Rob
- Weill Cornell Medical College Qatar, Education city, P.O.Box 24144, Doha, Qatar
| | - Mahmoud Yousef
- Weill Cornell Medical College Qatar, Education city, P.O.Box 24144, Doha, Qatar
| | | | - Anns Mahboob
- Weill Cornell Medical College Qatar, Education city, P.O.Box 24144, Doha, Qatar
| | - Annalisa Terranegra
- Research Department, Sidra Medicine, Education city, P.O.Box 26999, Doha, Qatar
| | - Ali Chaari
- Weill Cornell Medical College Qatar, Education city, P.O.Box 24144, Doha, Qatar.
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Michel MFV, Phillips BT. SYS-1/beta-catenin inheritance and regulation by Wnt signaling during asymmetric cell division. Mol Biol Cell 2025; 36:ar25. [PMID: 39813084 PMCID: PMC11974967 DOI: 10.1091/mbc.e24-10-0441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 12/19/2024] [Accepted: 01/08/2025] [Indexed: 01/16/2025] Open
Abstract
Asymmetric cell division (ACD) allows daughter cells of a polarized mother to acquire different developmental fates. In Caenorhabditis elegans, the Wnt/β-catenin Asymmetry (WβA) pathway regulates many embryonic and larval ACDs; here, a Wnt gradient induces an asymmetric distribution of Wnt signaling components within the dividing mother cell. One terminal nuclear effector of the WβA pathway is the transcriptional activator SYS-1/β-catenin. SYS-1 is sequentially negatively regulated during ACD; first by centrosomal regulation and subsequent proteasomal degradation and second by asymmetric activity of the β-catenin "destruction complex" in one of the two daughter cells, which decreases SYS-1 levels in the absence of WβA signaling. However, the extent to which mother cell SYS-1 influences cell fate decisions of the daughters is unknown. Here, we quantify inherited SYS-1 in the differentiating daughter cells and the role of SYS-1 inheritance in Wnt-directed ACD. Photobleaching experiments demonstrate the GFP::SYS-1 present in daughter cell nuclei is comprised of inherited and de novo translated SYS-1 pools. We used a photoconvertible DENDRA2::SYS-1, to directly observe the dynamics of inherited SYS-1. Photoconversion during mitosis reveals that SYS-1 clearance at the centrosome preferentially degrades older SYS-1 and that newly localized centrosomal SYS-1 depends on dynein trafficking. Photoconversion of DENDRA2::SYS-1 in the EMS cell during Wnt-driven ACD shows daughter cell inheritance of mother cell SYS-1. Additionally, disrupting centrosomal SYS-1 localization in mother cells increased inherited SYS-1 and, surprisingly, loss of centrosomal SYS-1 also resulted in increased levels of de novo SYS-1 in both EMS daughter cells. Last, we show that negative regulation of SYS-1 in daughter cells via the destruction complex member APR-1/APC is key to limit both the de novo and the inherited SYS-1 pools in both the E and the MS cells. We conclude that regulation of both inherited and newly translated SYS-1 via centrosomal processing in the mother cell and daughter cell regulation via Wnt signaling are critical to maintain sister SYS-1 asymmetry during ACD.
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Affiliation(s)
| | - Bryan T. Phillips
- Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242
- Department of Biology, University of Iowa, Iowa City, IA 52242
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Ma X, Li M, Zhang Y, Xu T, Zhou X, Qian M, Yang Z, Han X. Akkermansia muciniphila identified as key strain to alleviate gut barrier injury through Wnt signaling pathway. eLife 2025; 12:RP92906. [PMID: 39912727 PMCID: PMC11801796 DOI: 10.7554/elife.92906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2025] Open
Abstract
As the largest mucosal surface, the gut has built a physical, chemical, microbial, and immune barrier to protect the body against pathogen invasion. The disturbance of gut microbiota aggravates pathogenic bacteria invasion and gut barrier injury. Fecal microbiota transplantation (FMT) is a promising treatment for microbiome-related disorders, where beneficial strain engraftment is a significant factor influencing FMT outcomes. The aim of this research was to explore the effect of FMT on antibiotic-induced microbiome-disordered (AIMD) models infected with enterotoxigenic Escherichia coli (ETEC). We used piglet, mouse, and intestinal organoid models to explore the protective effects and mechanisms of FMT on ETEC infection. The results showed that FMT regulated gut microbiota and enhanced the protection of AIMD piglets against ETEC K88 challenge, as demonstrated by reduced intestinal pathogen colonization and alleviated gut barrier injury. Akkermansia muciniphila (A. muciniphila) and Bacteroides fragilis (B. fragilis) were identified as two strains that may play key roles in FMT. We further investigated the alleviatory effects of these two strains on ETEC infection in the AIMD mice model, which revealed that A. muciniphila and B. fragilis relieved ETEC-induced intestinal inflammation by maintaining the proportion of Treg/Th17 cells and epithelial damage by moderately activating the Wnt/β-catenin signaling pathway, while the effect of A. muciniphila was better than B. fragilis. We, therefore, identified whether A. muciniphila protected against ETEC infection using basal-out and apical-out intestinal organoid models. A. muciniphila did protect the intestinal stem cells and stimulate the proliferation and differentiation of intestinal epithelium, and the protective effects of A. muciniphila were reversed by Wnt inhibitor. FMT alleviated ETEC-induced gut barrier injury and intestinal inflammation in the AIMD model. A. muciniphila was identified as a key strain in FMT to promote the proliferation and differentiation of intestinal stem cells by mediating the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Xin Ma
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
- Hainan Institute of Zhejiang University, Yongyou Industry Park, Yazhou Bay Sci-Tech CitySanyaChina
| | - Meng Li
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
- Hainan Institute of Zhejiang University, Yongyou Industry Park, Yazhou Bay Sci-Tech CitySanyaChina
| | - Yuanyuan Zhang
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
| | - Tingting Xu
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
| | - Xinchen Zhou
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
- Hainan Institute of Zhejiang University, Yongyou Industry Park, Yazhou Bay Sci-Tech CitySanyaChina
| | - Mengqi Qian
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
| | - Zhiren Yang
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
- Hainan Institute of Zhejiang University, Yongyou Industry Park, Yazhou Bay Sci-Tech CitySanyaChina
| | - Xinyan Han
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
- Hainan Institute of Zhejiang University, Yongyou Industry Park, Yazhou Bay Sci-Tech CitySanyaChina
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Feng Y, Zeng N, Bordbar F, Lu Z, Gao C. Dietary fermented mixed ingredient product enhances growth performance and intestinal stem cell-mediated epithelial regeneration through Wnt/β-catenin pathway in layer chicks. Poult Sci 2025; 104:104821. [PMID: 39854967 PMCID: PMC11803830 DOI: 10.1016/j.psj.2025.104821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/12/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
This study aimed to investigate the effects of dietary supplements of fermented mixed ingredient product (FMIP) on the growth performance, intestinal health, and immune performance of layer hens during the brooding period. Four hundred eighty healthy one-day-old layer chicks were randomly divided into four groups (six replicates/group, twenty hens/replicate) and were fed with different experimental diets for eight weeks (from day 1 to day 56): (1) Corn-soybean-base diet (CON); (2) Chlortetracycline group (CTC; CON diet supplemented with 0.5g/kg chlortetracycline); (3) 4 % fermented mixed ingredient product (4 % FMIP); (4) 8 % fermented mixed ingredient product (8 % FMIP). The results showed that, compared with the CON group, feeding with CTC, 4 % or 8 % FMIP increased the average daily feed intake (ADFI), average daily gain (ADG), immune organs index, serum IgA, IgM, and IgG levels, as well as the apparent metabolic rates of dry matter, crude protein, crude fiber, and crude ash (P < 0.05). Meanwhile, FMIP supplementation improved jejunal morphology and barrier function, as reflected by increased villus height and transepithelial electrical resistance, decreased DAO activity in serum, and up-regulated Occludin protein expression (P < 0.05). Additionally, FMIP supplementation significantly increased protein expression of the stem cell markers (SOX9 and Lgr5), proliferative cell marker (PCNA), and differentiated absorptive cell marker (Villin) (P < 0.05). The immunofluorescence results were consistent with the above results, and FMIP groups have the same effects as the CTC group. Furthermore, the CTC or 4 % FMIP treatment group resulted in a remarkable increase in Wnt/β-catenin signaling proteins (including β-catenin, TCF4, c-Myc, and Cyclin-D1) compared with the CON group (P < 0.05). In conclusion, dietary supplementation of 4 % FMIP improves growth and immune performance, and promotes the intestinal stem cell expansion of layer chicks through Wnt/β-catenin pathway activation.
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Affiliation(s)
- Yuqing Feng
- College of Animal Science, Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory of Swine and Poultry Breeding Industry, South China Agricultural University, Guangzhou 510642, China
| | - Nan Zeng
- College of Animal Science, Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory of Swine and Poultry Breeding Industry, South China Agricultural University, Guangzhou 510642, China
| | - Farhad Bordbar
- College of Animal Science, Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory of Swine and Poultry Breeding Industry, South China Agricultural University, Guangzhou 510642, China
| | - Zhujin Lu
- College of Animal Science, Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory of Swine and Poultry Breeding Industry, South China Agricultural University, Guangzhou 510642, China
| | - Chunqi Gao
- College of Animal Science, Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangdong Laboratory for Lingnan Modern Agriculture, State Key Laboratory of Swine and Poultry Breeding Industry, South China Agricultural University, Guangzhou 510642, China.
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Hong W, Wang X, Huang X, Chen P, Liu Y, Zheng Z, You X, Chen Y, Xie Z, Zhan G, Huang H. CSNK1E is involved in TGF-β1 induced epithelial mesenchymal transformationas and related to melanoma immune heterogeneity. Front Pharmacol 2025; 15:1501849. [PMID: 39872053 PMCID: PMC11771321 DOI: 10.3389/fphar.2024.1501849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 11/28/2024] [Indexed: 01/29/2025] Open
Abstract
Introduction Melanoma (MM), the deadliest form of skin cancer, originates from melanocytes. Despite advances in immunotherapy that have somewhat improved the prognosis for MM patients, high levels of resistance to treatment continue to result in poor clinical outcomes. Identifying novel biomarkers and therapeutic targets is critical for improving the prognosis and treatment of MM. Methods In this study, we analyzed the expression patterns of WNT signaling pathway genes in MM and explored their potential mechanisms. Using Cox regression analysis, we identified 19 prognostic-related genes. Consistency clustering was performed to evaluate the potential of these genes as classifiers for prognosis. The Least Absolute Shrinkage and Selection Operator (LASSO) algorithm was then applied to refine the gene set and construct a 13-gene prognostic model. We validated the model at multiple time points to assess its predictive performance. Additionally, correlation analyses were performed to investigate the relationships between key genes and processes, including epithelial-to-mesenchymal transition (EMT) and immune responses. Results We identified that CSNK1E and RAC3 were significantly positively correlated with the EMT process, with CSNK1E showing a similar expression trend to EMT-related genes. Both genes were also negatively correlated with multiple immune cell types and immune checkpoint genes. The 13-gene prognostic model demonstrated excellent predictive performance in MM prognosis. Pan-cancer analysis further revealed heterogeneous expression patterns and prognostic potential of CSNK1E across various cancers. Wet experiments confirmed that CSNK1E promotes MM cell proliferation, invasion, and migration, and enhances malignant progression through the TGF-β signaling pathway. Discussion Our findings suggest that CSNK1E plays a crucial role in MM progression and could serve as a potential therapeutic target. The WNT and TGF-β pathways may work synergistically in regulating the EMT process in MM, highlighting their potential as novel therapeutic targets. These insights may contribute to the development of more effective treatments for MM, particularly for overcoming resistance to current therapies.
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Affiliation(s)
- Wangbing Hong
- Department of Plastic and Cosmetic Surgery, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China
| | - Xin Wang
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xinyu Huang
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Pengfei Chen
- Department of Plastic and Cosmetic Surgery, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China
| | - Yifan Liu
- Department of Plastic and Cosmetic Surgery, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China
| | - Ziying Zheng
- Department of Plastic and Cosmetic Surgery, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China
| | - Xin You
- Department of Plastic and Cosmetic Surgery, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China
| | - Yinghua Chen
- Department of Plastic and Cosmetic Surgery, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China
| | - Zengxin Xie
- Department of Plastic and Cosmetic Surgery, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China
| | - Gongnan Zhan
- Department of Plastic and Cosmetic Surgery, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China
| | - Heping Huang
- Department of Plastic and Cosmetic Surgery, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China
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Logsdon DM, Ming H, Ezashi T, West RC, Schoolcraft WB, Roberts RM, Jiang Z, Yuan Y. Transcriptome comparisons of trophoblasts from regenerative cell models with peri-implantation human embryos†. Biol Reprod 2024; 111:1000-1016. [PMID: 39109839 DOI: 10.1093/biolre/ioae120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 06/21/2024] [Accepted: 08/06/2024] [Indexed: 11/16/2024] Open
Abstract
Mechanisms controlling trophoblast (TB) proliferation and differentiation during embryo implantation are poorly understood. Human trophoblast stem cells (TSC) and BMP4/A83-01/PD173074-treated pluripotent stem cell-derived trophoblast cells (BAP) are two widely employed, contemporary models to study TB development and function, but how faithfully they mimic early TB cells has not been fully examined. We evaluated the transcriptomes of TB cells from BAP and TSC and directly compared them with those from peri-implantation human embryos during extended embryo culture (EEC) between embryonic days 8 to 12. The BAP and TSC grouped closely with TB cells from EEC within each TB sublineage following dimensional analysis and unsupervised hierarchical clustering. However, subtle differences in transcriptional programs existed within each TB sublineage. We also validated the presence of six genes in peri-implantation human embryos by immunolocalization. Our analysis reveals that both BAP and TSC models have features of peri-implantation TB s, while maintaining minor transcriptomic differences, and thus serve as valuable tools for studying implantation in lieu of human embryos.
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Affiliation(s)
- Deirdre M Logsdon
- Colorado Center for Reproductive Medicine, 10290 RidgeGate Circle, Lone Tree, CO 80124, USA
| | - Hao Ming
- Department of Animal Sciences, Genetics Institute, University of Florida, Gainesville, FL 32610, USA
| | - Toshihiko Ezashi
- Colorado Center for Reproductive Medicine, 10290 RidgeGate Circle, Lone Tree, CO 80124, USA
| | - Rachel C West
- Department of Anatomy, Physiology, and Pharmacology, Auburn University, Auburn, AL 36849, USA
| | - William B Schoolcraft
- Colorado Center for Reproductive Medicine, 10290 RidgeGate Circle, Lone Tree, CO 80124, USA
| | - R Michael Roberts
- Division of Animal Sciences, University of Missouri-Columbia, MO 65211, USA
| | - Zongliang Jiang
- Department of Animal Sciences, Genetics Institute, University of Florida, Gainesville, FL 32610, USA
| | - Ye Yuan
- Colorado Center for Reproductive Medicine, 10290 RidgeGate Circle, Lone Tree, CO 80124, USA
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11
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Wei B, Ren P, Qin W, Wang D, Wang Y, Chang Y, Wang Y, Xue C, Tang Q. Sulfated fucans from algae Saccharina japonica promotes intestinal stem cell-mediated intestinal development in juvenile mouse by modulating the gut microbiota. Int J Biol Macromol 2024; 281:136207. [PMID: 39362431 DOI: 10.1016/j.ijbiomac.2024.136207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/12/2024] [Accepted: 09/30/2024] [Indexed: 10/05/2024]
Abstract
Intestinal development has a crucial role in the absorption of nutrients and the ability to resist infections in the early stages of life. This study utilized a 3-week-old C57BL/6 mice model to evaluate the beneficial impacts of sulfated fucans from Saccharina japonica (SJ-FUC) on the growth and development of the intestines. SJ-FUC enhanced the dimensions of the intestine, specifically the length, height of villi, and depth of the crypts. Additionally, it raised the mRNA expression of ZO-1 and Occludin, hence enhancing the structural integrity of the intestinal epithelium. SJ-FUC significantly increased mRNA expression of Lyz1, Muc2, and Math1, which resulted in the promotion of intestinal epithelial development. Furthermore, SJ-FUC augmented the mRNA levels of the ISC markers (Lgr5, Olfm4, and Ascl2). Our further research uncovered that SJ-FUC has a positive impact on the growth of beneficial bacteria, such as Akkermansia, Dubosiella, and Lactobacillus, which in turn promotes epithelial development of the intestine. In summary, our research indicates that SJ-FUC has a beneficial impact on the growth of the intestines in young mice. This is achieved by enhancing the stemness of intestinal stem cells (ISCs) and promoting the formation of the intestinal epithelium through the regulation of gut bacteria.
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Affiliation(s)
- Biqian Wei
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Pengfei Ren
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Wanting Qin
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Dehua Wang
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Yinfeng Wang
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Yaoguang Chang
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Yuming Wang
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Changhu Xue
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Qingjuan Tang
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China.
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12
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Wang X, Zou K, Xiong Y, Zheng Y, Zheng J, Liu Y, Zhong T, Zhao X. Dietary titanium dioxide nanoparticles impair intestinal epithelial regeneration by perturbating the function of intestinal stem cells. Food Chem Toxicol 2024; 193:115057. [PMID: 39406333 DOI: 10.1016/j.fct.2024.115057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 07/01/2024] [Accepted: 10/12/2024] [Indexed: 10/19/2024]
Abstract
Intestinal health is closely linked to intestinal stem cells (ISCs), which are highly sensitive to the harmful substances in the lumen. However, there is limited knowledge regarding the effects of food additives on ISCs. This study aims to investigate the impact of dietary titanium dioxide nanoparticles (TiO2 NPs) compared with titanium dioxide microparticles (TiO2 MPs) on intestinal health associated with ISCs in response to dextran sodium sulfate (DSS)-induced enteritis in mice, as well as the related mechanism. We found that exposure to 1% (w/w) TiO2 NPs aggravated DSS-induced enteritis in mice, while this effect could not be observed under exposure to TiO2 MPs. Additionally, 1% (w/w) TiO2 NPs exposure under DSS-induced enteritis worsened the ISC-mediated regeneration of intestinal epithelium by decreasing the epithelial cell proliferation and epithelial turnover rate while increasing epithelial cell death. Meanwhile, using a 3D intestinal organoid model, we discovered that 20 μg/mL TiO2 NPs impaired ISC function and disrupted ISC fate specification both ex vivo and in vitro. Furthermore, TiO2 NPs hindered the nuclear translocation of β-catenin, reducing the overall output of Wnt signaling. Together, TiO2 NPs deteriorated the intestinal epithelial regeneration of mice with DSS-induced enteritis by perturbating ISC function and fate specification through a mechanism involving Wnt signaling. These findings highlight the adverse effect of dietary TiO2 NPs on ISCs and shed light on the particle size optimization of TiO2 food additive.
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Affiliation(s)
- Xiu Wang
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China; Jiaxing Key Laboratory for Research and Application of Green and Low-carbon Advanced Materials, Jiaxing, 314000, China.
| | - Kai Zou
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China; Jiaxing Key Laboratory for Research and Application of Green and Low-carbon Advanced Materials, Jiaxing, 314000, China
| | - Yu Xiong
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China
| | - Yongwang Zheng
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China
| | - Jiale Zheng
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China
| | - Yong Liu
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China
| | - Ting Zhong
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China
| | - Xincheng Zhao
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China
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13
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Li F, Li Z, Wei C, Xu L, Liang Y, Yan J, Li Y, He B, Sun C. Application of hydrogels for targeting cancer stem cells in cancer treatment. Biomed Pharmacother 2024; 180:117486. [PMID: 39321506 DOI: 10.1016/j.biopha.2024.117486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 08/28/2024] [Accepted: 09/20/2024] [Indexed: 09/27/2024] Open
Abstract
Cancer stem cells (CSCs) are a major hindrance to clinical cancer treatment. Owing to their high tumorigenic and metastatic potential, CSCs are vital in malignant tumor initiation, growth, metastasis, and therapeutic resistance, leading to tumorigenesis and recurrence. Compared with normal tumor cells, CSCs express high levels of surface markers (CD44, CD90, CD133, etc.) and activate specific signaling pathways (Wnt/β-catenin, Notch, and Hedgehog). Although Current drug delivery systems (DDS) precisely target CSCs, the heterogeneity and multidrug resistance of CSCs impede CSC isolation and screening. Conversely, hydrogel DDSs exhibit good biocompatibility and high drug delivery efficiency. Hydrogels are three-dimensional (3D) spatial structures for drug encapsulation that facilitate the controlled release of bioactive molecules. Hence, hydrogels can be loaded with drugs to precisely target CSCs. Their 3D structure can also culture non-CSCs and facilitate their transformation into CSCs. for identification and isolation. Given that their elastic modulus and stiffness characteristics reflect those of the cellular microenvironment, hydrogels can simulate extracellular matrix pathways and markers to regulate CSCs, disrupting the equilibrium between CSC and non-CSC transformation. This article reviews the CSC microenvironment, metabolism, signaling pathway, and surface markers. Additionally, we summarize the existing CSC targeting strategies and explore the application of hydrogels for CSC screening and treatment. Finally, we discuss potential advances in CSC research that may lead to curative measures for tumors through targeted and precise attacks on CSCs.
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Affiliation(s)
- Fashun Li
- Department of Spinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, China; Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266073, China
| | - Zhipeng Li
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266073, China
| | - Chen Wei
- Department of Pharmacy, Qingdao Women and Children's Hospital, Qingdao 266034, China
| | - Long Xu
- School of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China.
| | - Yan Liang
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266073, China.
| | - Jianqin Yan
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266073, China
| | - Yifei Li
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266073, China
| | - Bin He
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China
| | - Chong Sun
- Department of Spinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, China.
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14
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Jemal M, Getinet M, Amare GA, Tegegne BA, Baylie T, Mengistu EF, Osman EE, Chura Waritu N, Adugna A. Non-metabolic enzyme function of pyruvate kinase M2 in breast cancer. Front Oncol 2024; 14:1450325. [PMID: 39411137 PMCID: PMC11473492 DOI: 10.3389/fonc.2024.1450325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/12/2024] [Indexed: 10/19/2024] Open
Abstract
Breast cancer (BC) is a prevalent malignant tumor in women, and its incidence has been steadily increasing in recent years. Compared with other types of cancer, it has the highest mortality and morbidity rates in women. So, it is crucial to investigate the underlying mechanisms of BC development and identify specific therapeutic targets. Pyruvate kinase M2 (PKM2), an important metabolic enzyme in glycolysis, has been found to be highly expressed in BC. It can also move to the nucleus and interact with various transcription factors and proteins, including hypoxia-inducible factor-1α (HIF-1α), signal transducer and activator of transcription 3 (STAT3), β-catenin, cellular-myelocytomatosis oncogene (c-Myc), nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), and mammalian sterile 20-like kinase 1 (MST1). This interaction leads to non-metabolic functions that control the cell cycle, proliferation, apoptosis, migration, invasion, angiogenesis, and tumor microenvironment in BC. This review provides an overview of the latest advancements in understanding the interactions between PKM2 and different transcription factors and proteins that influence the initiation and progression of BC. It also examined how natural drugs and noncoding RNAs affect various biological processes in BC cells through the regulation of the non-metabolic enzyme functions of PKM2. The findings provide valuable insights for improving the prognosis and developing targeted therapies for BC in the coming years.
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Affiliation(s)
- Mohammed Jemal
- Department of Biomedical Science, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Mamaru Getinet
- Department of Biomedical Science, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Gashaw Azanaw Amare
- Department of Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Bantayehu Addis Tegegne
- Department of Pharmacy, College of Medicine and Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Temesgen Baylie
- Department of Biomedical Science, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Enyew Fenta Mengistu
- Department of Biomedical Science, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Enatnesh Essa Osman
- Department of Biomedical Science, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Nuredin Chura Waritu
- Department of Biomedical Sciences, School of Medicine, Wolaita Sodo University, Wolaita Sodo, Ethiopia
| | - Adane Adugna
- Department of Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
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15
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Masci D, Puxeddu M, Silvestri R, La Regina G. Targeting CBP and p300: Emerging Anticancer Agents. Molecules 2024; 29:4524. [PMID: 39407454 PMCID: PMC11482477 DOI: 10.3390/molecules29194524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/22/2024] [Accepted: 09/23/2024] [Indexed: 10/19/2024] Open
Abstract
CBP and p300 are versatile transcriptional co-activators that play essential roles in regulating a wide range of signaling pathways, including Wnt/β-catenin, p53, and HIF-1α. These co-activators influence various cellular processes such as proliferation, differentiation, apoptosis, and response to hypoxia, making them pivotal in normal physiology and disease progression. The Wnt/β-catenin signaling pathway, in particular, is crucial for cellular proliferation, differentiation, tissue homeostasis, and embryogenesis. Aberrant activation of this pathway is often associated with several types of cancer, such as colorectal tumor, prostate cancer, pancreatic and hepatocellular carcinomas. In recent years, significant efforts have been directed toward identifying and developing small molecules as novel anticancer agents capable of specifically inhibiting the interaction between β-catenin and the transcriptional co-activators CBP and p300, which are required for Wnt target gene expression and are consequently involved in the regulation of tumor cell proliferation, migration, and invasion. This review summarizes the most significant and original research articles published from 2010 to date, found by means of a PubMed search, highlighting recent advancements in developing both specific and non-specific inhibitors of CBP/β-catenin and p300/β-catenin interactions. For a more comprehensive view, we have also explored the therapeutic potential of CBP/p300 bromodomain and histone acetyltransferase inhibitors in disrupting the transcriptional activation of genes involved in various signaling pathways related to cancer progression. By focusing on these therapeutic strategies, this review aims to offer a detailed overview of recent approaches in cancer treatment that selectively target CBP and p300, with particular emphasis on their roles in Wnt/β-catenin-driven oncogenesis.
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Affiliation(s)
- Domiziana Masci
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy;
| | - Michela Puxeddu
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (R.S.)
| | - Romano Silvestri
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (R.S.)
| | - Giuseppe La Regina
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (R.S.)
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16
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Yang C, Li J, Luo M, Zhou W, Xing J, Yang Y, Wang L, Rao W, Tao W. Unveiling the molecular mechanisms of Dendrobium officinale polysaccharides on intestinal immunity: An integrated study of network pharmacology, molecular dynamics and in vivo experiments. Int J Biol Macromol 2024; 276:133859. [PMID: 39009260 DOI: 10.1016/j.ijbiomac.2024.133859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 06/13/2024] [Accepted: 07/11/2024] [Indexed: 07/17/2024]
Abstract
Intestinal immunity plays a pivotal role in overall immunological defenses, constructing mechanisms against pathogens while maintaining balance with commensal microbial communities. Existing therapeutic interventions may lead to drug resistance and potential toxicity when immune capacity is compromised. Dendrobium officinale, a traditional Chinese medicine, contains components identified to bolster immunity. Employing network pharmacology strategies, this study identified constituents of Dendrobium officinale and their action targets in the TCMSP and Swiss Target Prediction databases, and compared them with intestinal immunity-related targets. Protein-protein interaction networks revealed the core targets of Dendrobium officinale polysaccharides, encompassing key pathways such as cell proliferation, inflammatory response, and immune reactions, particularly in association with the Toll-like receptor 4. Molecular docking and molecular dynamics simulation further confirmed the high affinity and stability between Dendrobium officinale polysaccharides and Toll-like receptor 4. In vivo experiments demonstrated that Dendrobium officinale polysaccharides modulates the expression of Toll-like receptor 4 and its downstream key proteins in the colonic mucosa of mice. Consequently, these findings suggest that Dendrobium officinale polysaccharides may serve as a potential modulator for intestinal immune functions, with its mechanism potentially related to the Toll-like receptor 4.
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Affiliation(s)
- Chenchen Yang
- Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China
| | - Jingrui Li
- Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China
| | - Mengfan Luo
- Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China
| | - Wanyi Zhou
- Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China
| | - Jianrong Xing
- Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China
| | - Ying Yang
- Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China
| | - Lu Wang
- School of Life Sciences, Westlake University, Hangzhou 310024, China
| | - Wenjia Rao
- School of Sciences, Hangzhou Dianzi University, Hangzhou 310018, China
| | - Wenyang Tao
- Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China.
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17
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Valdes Michel MF, Phillips BT. SYS-1/beta-catenin inheritance and regulation by Wnt-signaling during asymmetric cell division. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.07.21.550069. [PMID: 37503055 PMCID: PMC10370182 DOI: 10.1101/2023.07.21.550069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Asymmetric cell division (ACD) allows daughter cells of a polarized mother to acquire different developmental fates. In C. elegans , the Wnt/β-catenin Asymmetry (WβA) pathway oversees many embryonic and larval ACDs; here, a Wnt gradient induces an asymmetric distribution of Wnt signaling components within the dividing mother cell. One terminal nuclear effector of the WβA pathway is the transcriptional activator SYS-1/β-catenin. SYS-1 is sequentially negatively regulated during ACD; first by centrosomal regulation and subsequent proteasomal degradation and second by asymmetric activity of the β-catenin "destruction complex" in one of the two daughter cells, which decreases SYS-1 levels in the absence of WβA signaling. However, the extent to which mother cell SYS-1 influences cell fate decisions of the daughters is unknown. Here, we quantify inherited SYS-1 in the differentiating daughter cells and the role of SYS-1 inheritance in Wnt-directed ACD. Photobleaching experiments demonstrate the GFP::SYS-1 present in daughter cell nuclei is comprised of inherited and de novo translated SYS-1 pools. We used a photoconvertible DENDRA2::SYS-1, to directly observe the dynamics of inherited SYS-1. Photoconversion during mitosis reveals that SYS-1 clearance at the centrosome preferentially degrades older SYS-1, and this accumulation is regulated via dynein trafficking. Photoconversion of the EMS cell during Wnt-driven ACD shows daughter cell inheritance of mother cell SYS-1. Additionally, loss of centrosomal SYS-1 increased inherited SYS-1 and, surprisingly, loss of centrosomal SYS-1 also resulted in increased levels of de novo SYS-1 in both EMS daughter cells. Lastly, we show that daughter cell negative regulation of SYS-1 via the destruction complex member APR-1/APC is key to limit both the de novo and the inherited SYS-1 pools in both the E and the MS cells. We conclude that regulation of both inherited and newly translated SYS-1 via centrosomal processing in the mother cell and daughter cell regulation via Wnt signaling are critical to maintain sister SYS-1 asymmetry during ACD.
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18
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Lee DJ, Kim P, Kim HY, Park J, Lee SJ, An H, Heo JS, Lee MJ, Ohshima H, Mizuno S, Takahashi S, Jung HS, Kim SJ. MAST4 regulates stem cell maintenance with DLX3 for epithelial development and amelogenesis. Exp Mol Med 2024; 56:1606-1619. [PMID: 38945953 PMCID: PMC11297042 DOI: 10.1038/s12276-024-01264-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 01/29/2024] [Accepted: 03/19/2024] [Indexed: 07/02/2024] Open
Abstract
The asymmetric division of stem cells permits the maintenance of the cell population and differentiation for harmonious progress. Developing mouse incisors allows inspection of the role of the stem cell niche to provide specific insights into essential developmental phases. Microtubule-associated serine/threonine kinase family member 4 (Mast4) knockout (KO) mice showed abnormal incisor development with low hardness, as the size of the apical bud was decreased and preameloblasts were shifted to the apical side, resulting in amelogenesis imperfecta. In addition, Mast4 KO incisors showed abnormal enamel maturation, and stem cell maintenance was inhibited as amelogenesis was accelerated with Wnt signal downregulation. Distal-Less Homeobox 3 (DLX3), a critical factor in tooth amelogenesis, is considered to be responsible for the development of amelogenesis imperfecta in humans. MAST4 directly binds to DLX3 and induces phosphorylation at three residues within the nuclear localization site (NLS) that promotes the nuclear translocation of DLX3. MAST4-mediated phosphorylation of DLX3 ultimately controls the transcription of DLX3 target genes, which are carbonic anhydrase and ion transporter genes involved in the pH regulation process during ameloblast maturation. Taken together, our data reveal a novel role for MAST4 as a critical regulator of the entire amelogenesis process through its control of Wnt signaling and DLX3 transcriptional activity.
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Affiliation(s)
- Dong-Joon Lee
- Division in Anatomy and Developmental Biology, Department of Oral Biology, Taste Research Center, Oral Science Research Center, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, 03722, Korea
- Department of Oral Histology, Dankook University College of Dentistry, Cheonan, 31116, Korea
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Korea
| | - Pyunggang Kim
- GILO Institute, GILO Foundation, Seoul, 06668, Korea
| | - Hyun-Yi Kim
- Division in Anatomy and Developmental Biology, Department of Oral Biology, Taste Research Center, Oral Science Research Center, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, 03722, Korea
- NGeneS Inc., Ansan-si, Gyeonggi-do, 15495, Korea
| | - Jinah Park
- GILO Institute, GILO Foundation, Seoul, 06668, Korea
| | - Seung-Jun Lee
- Division in Anatomy and Developmental Biology, Department of Oral Biology, Taste Research Center, Oral Science Research Center, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, 03722, Korea
| | - Haein An
- GILO Institute, GILO Foundation, Seoul, 06668, Korea
| | - Jin Sun Heo
- GILO Institute, GILO Foundation, Seoul, 06668, Korea
| | - Min-Jung Lee
- Division in Anatomy and Developmental Biology, Department of Oral Biology, Taste Research Center, Oral Science Research Center, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, 03722, Korea
| | - Hayato Ohshima
- Division of Anatomy and Cell Biology of the Hard Tissue, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8514, Japan
| | - Seiya Mizuno
- Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan
| | - Satoru Takahashi
- Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan
| | - Han-Sung Jung
- Division in Anatomy and Developmental Biology, Department of Oral Biology, Taste Research Center, Oral Science Research Center, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, 03722, Korea.
| | - Seong-Jin Kim
- GILO Institute, GILO Foundation, Seoul, 06668, Korea.
- Medpacto Inc., Seoul, 06668, Korea.
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19
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Abdel-Tawab MS, Fouad H, Sedeak AY, Doudar NA, Rateb EE, Faruk E, Reyad HR. Effects of mesenchymal stem cells versus curcumin on sonic hedgehog signaling in experimental model of Hepatocellular Carcinoma. Mol Biol Rep 2024; 51:740. [PMID: 38874802 DOI: 10.1007/s11033-024-09613-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 05/03/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND Sonic Hedgehog (SHH) is a fundamental signaling pathway that controls tissue reconstruction, stem cell biology, and differentiation and has a role in gut tissue homeostasis and development. Dysregulation of SHH leads to the development of HCC. METHODS, AND RESULTS The present study was conducted to compare the effects of mesenchymal stem cells (MSCs) and curcumin on SHH molecular targets in an experimental model of HCC in rats. One hundred rats were divided equally into the following groups: control group, HCC group, HCC group received MSCs, HCC group received curcumin, and HCC group received MSCs and curcumin. Histopathological examinations were performed, and gene expression of SHH signaling target genes (SHH, PTCH1, SMOH, and GLI1) was assessed by real-time PCR in rat liver tissue. Results showed that SHH target genes were significantly upregulated in HCC-untreated rat groups and in MSC-treated groups, with no significant difference between them. Administration of curcumin with or without combined administration of MSCs led to a significant down-regulation of SHH target genes, with no significant differences between both groups. As regards the histopathological examination of liver tissues, both curcumin and MSCs, either through separate use or their combined use, led to a significant restoration of normal liver pathology. CONCLUSIONS In conclusion, SHH signaling is upregulated in the HCC experimental model. MSCs do not inhibit the upregulated SHH target genes in HCC. Curcumin use with or without MSCs administration led to a significant down-regulation of SHH signaling in HCC and a significant restoration of normal liver pathology.
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Affiliation(s)
- Marwa Sayed Abdel-Tawab
- Medical Biochemistry Department, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt.
| | - Hanan Fouad
- Medical Biochemistry Department, Faculty of Medicine, Cairo University, POB 12613, Cairo, Egypt
- Faculty of Medicine, Galala University, POB 43711, Attaka, Suez Governorate, Egypt
| | - Ahmed Yahia Sedeak
- Anatomy and Embryology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Noha A Doudar
- Clinical and Chemical Pathology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Enas Ezzat Rateb
- Physiology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Eman Faruk
- Department of Anatomy, Faculty of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia
- Department of Histology and Cytology, Faculty of Medicine, Benha University, Benha, Egypt
| | - Hoda Ramadan Reyad
- Medical Biochemistry Department, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
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20
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da Silva AM, Yevdokimova V, Benoit YD. Sam68 is a druggable vulnerability point in cancer stem cells. Cancer Metastasis Rev 2024; 43:441-456. [PMID: 37792222 PMCID: PMC11016129 DOI: 10.1007/s10555-023-10145-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 09/27/2023] [Indexed: 10/05/2023]
Abstract
Sam68 (Src associated in mitosis of 68 kDa) is an RNA-binding and multifunctional protein extensively characterized in numerous cellular functions, such as RNA processing, cell cycle regulation, kinase- and growth factor signaling. Recent investigations highlighted Sam68 as a primary target of a class of reverse-turn peptidomimetic drugs, initially developed as inhibitors of Wnt/β-catenin mediated transcription. Further investigations on such compounds revealed their capacity to selectively eliminate cancer stem cell (CSC) activity upon engaging Sam68. This work highlighted previously unappreciated roles for Sam68 in the maintenance of neoplastic self-renewal and tumor-initiating functions. Here, we discuss the implication of Sam68 in tumorigenesis, where central findings support its contribution to chromatin regulation processes essential to CSCs. We also review advances in CSC-targeting drug discovery aiming to modulate Sam68 cellular distribution and protein-protein interactions. Ultimately, Sam68 constitutes a vulnerability point of CSCs and an attractive therapeutic target to impede neoplastic stemness in human tumors.
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Affiliation(s)
- Amanda Mendes da Silva
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada
| | - Veronika Yevdokimova
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada
| | - Yannick D Benoit
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
- School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
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21
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Gajos-Michniewicz A, Czyz M. WNT/β-catenin signaling in hepatocellular carcinoma: The aberrant activation, pathogenic roles, and therapeutic opportunities. Genes Dis 2024; 11:727-746. [PMID: 37692481 PMCID: PMC10491942 DOI: 10.1016/j.gendis.2023.02.050] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 12/28/2022] [Accepted: 02/14/2023] [Indexed: 09/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a liver cancer, highly heterogeneous both at the histopathological and molecular levels. It arises from hepatocytes as the result of the accumulation of numerous genomic alterations in various signaling pathways, including canonical WNT/β-catenin, AKT/mTOR, MAPK pathways as well as signaling associated with telomere maintenance, p53/cell cycle regulation, epigenetic modifiers, and oxidative stress. The role of WNT/β-catenin signaling in liver homeostasis and regeneration is well established, whereas in development and progression of HCC is extensively studied. Herein, we review recent advances in our understanding of how WNT/β-catenin signaling facilitates the HCC development, acquisition of stemness features, metastasis, and resistance to treatment. We outline genetic and epigenetic alterations that lead to activated WNT/β-catenin signaling in HCC. We discuss the pivotal roles of CTNNB1 mutations, aberrantly expressed non-coding RNAs and complexity of crosstalk between WNT/β-catenin signaling and other signaling pathways as challenging or advantageous aspects of therapy development and molecular stratification of HCC patients for treatment.
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Affiliation(s)
- Anna Gajos-Michniewicz
- Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz 92-215, Poland
| | - Malgorzata Czyz
- Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz 92-215, Poland
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22
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Amjad E, Asnaashari S, Jahanban-Esfahlan A, Sokouti B. The role of MAPK, notch and Wnt signaling pathways in papillary thyroid cancer: Evidence from a systematic review and meta-analyzing microarray datasets employing bioinformatics knowledge and literature. Biochem Biophys Rep 2024; 37:101606. [PMID: 38371530 PMCID: PMC10873880 DOI: 10.1016/j.bbrep.2023.101606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/19/2023] [Accepted: 12/07/2023] [Indexed: 02/20/2024] Open
Abstract
Papillary thyroid cancer (PTC) is a prevalent kind of thyroid cancer (TC), with the risk of metastasis increasing faster than any other malignancy. So, understanding the role of PTC in pathogenesis requires studying the various gene expressions to find out which particular molecular biomarkers will be helpful. The authors conducted a comprehensive search on the PubMed microarray database and a meta-analysis approach on the remaining ones to determine the differentially expressed genes between PTC and normal tissues, along with the analyses of overall survival (OS) and recurrence-free survival (RFS) rates in patients with PTC. We considered the associated genes with MAPK, Wnt, and Notch signaling pathways. Two GEO datasets have been included in this research, considering inclusion and exclusion criteria. Nineteen genes were found to have higher differences through the meta-analysis procedure. Among them, ten genes were upregulated, and nine genes were downregulated. The expression of 19 genes was examined using the GEPIA2 database, and the Kaplan-Meier plot statistics were used to analyze RFS and the OS rates. We discovered seven significant genes with the validation: PRICKLE1, KIT, RPS6KA5, GADD45B, FGFR2, FGF7, and DTX4. To further explain these findings, it was discovered that the mRNA expression levels of these seven genes and the remaining 12 genes were shown to be substantially linked with the results of the experimental literature investigations on the PTC. Our research found nineteen panels of genes that could be involved in the PTC progression and metastasis and the immune system infiltration of these cancers.
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23
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Bird RP. Vitamin D and cancer. ADVANCES IN FOOD AND NUTRITION RESEARCH 2024; 109:92-159. [PMID: 38777419 DOI: 10.1016/bs.afnr.2023.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
The role of vitamin D in the prevention of chronic diseases including cancer, has received a great deal of attention during the past few decades. The term "Cancer" represents multiple disease states with varying biological complexities. The strongest link between vitamin D and cancer is provided by ecological and studies like observational, in preclinical models. It is apparent that vitamin D exerts diverse biological responses in a tissue specific manner. Moreover, several human factors could affect bioactivity of vitamin D. The mechanism(s) underlying vitamin D initiated anti-carcinogenic effects are diverse and includes changes at the muti-system levels. The oncogenic environment could easily corrupt the traditional role of vitamin D or could ensure resistance to vitamin D mediated responses. Several researchers have identified gaps in our knowledge pertaining to the role of vitamin D in cancer. Further areas are identified to solidify the role of vitamin D in cancer control strategies.
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Affiliation(s)
- Ranjana P Bird
- School of Health Sciences, University of Northern British Columbia, Prince George, BC, Canada.
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24
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Sun Q, Liu B, Lan Q, Su Z, Fu Q, Wang L, Deng Y, Li C, Xue VW, Liu S, Chen X, Yang G, Lu D. Antimicrobial agent chloroxylenol targets β‑catenin‑mediated Wnt signaling and exerts anticancer activity in colorectal cancer. Int J Oncol 2023; 63:121. [PMID: 37681484 PMCID: PMC10546378 DOI: 10.3892/ijo.2023.5569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 07/18/2023] [Indexed: 09/09/2023] Open
Abstract
Chloroxylenol is the active ingredient of the antibacterial agent Dettol. The anticancer effect and underlying mechanisms of this compound and other common antimicrobial agents have not been clearly elucidated. In the present study, the effects of chloroxylenol, benzalkonium chloride, benzethonium chloride, triclosan and triclocarban on β‑catenin‑mediated Wnt signaling in colorectal cancer were evaluated using the SuperTOPFlash reporter assay. It was demonstrated that chloroxylenol, but not the other antimicrobial agents tested, inhibited the Wnt/β‑catenin signaling pathway by decreasing the nuclear translocation of β‑catenin and disrupting β‑catenin/T‑cell factor 4 complex, which resulted in the downregulation of the Wnt target genes Axin2, Survivin and Leucine‑rich G protein‑coupled receptor‑5. Chloroxylenol effectively inhibited the viability, proliferation, migration and invasion, and sphere formation, and induced apoptosis in HCT116 and SW480 cells. Notably, chloroxylenol attenuated the growth of colorectal cancer in the MC38 cell xenograft model and inhibited organoid formation by the patient‑derived cells. Chloroxylenol also demonstrated inhibitory effects on the stemness of colorectal cancer cells. The results of the present study demonstrated that chloroxylenol could exert anti‑tumor activities in colorectal cancer by targeting the Wnt/β‑catenin signaling pathway, which provided an insight into its therapeutic potential as an anticancer agent.
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Affiliation(s)
- Qi Sun
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, Guangdong 518060, P.R. China
| | - Boxin Liu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, Guangdong 518060, P.R. China
| | - Quanxue Lan
- Shenzhen Longgang District Center for Disease Control and Prevention, Shenzhen, Guangdong 518100, P.R. China
| | - Zijie Su
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, Guangdong 518060, P.R. China
- Department of Research, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Qiuxia Fu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, Guangdong 518060, P.R. China
| | - Lian Wang
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, Guangdong 518060, P.R. China
| | - Yingying Deng
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, Guangdong 518060, P.R. China
| | - Chuanli Li
- Shenzhen Academy of Metrology and Quality Inspection, National Nutrition Food Testing Center, Shenzhen, Guangdong 518102, P.R. China
| | - Vivian Weiwen Xue
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, Guangdong 518060, P.R. China
| | - Shanshan Liu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, Guangdong 518060, P.R. China
| | - Xianxiong Chen
- Department of Physiology, Shenzhen University Medical School, Shenzhen, Guangdong 518060, P.R. China
| | - Guowu Yang
- Shenzhen Academy of Metrology and Quality Inspection, National Nutrition Food Testing Center, Shenzhen, Guangdong 518102, P.R. China
| | - Desheng Lu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, Guangdong 518060, P.R. China
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25
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Fan S, Jiang Z, Zhang Z, Xing J, Wang D, Tang D. Akkermansia muciniphila: a potential booster to improve the effectiveness of cancer immunotherapy. J Cancer Res Clin Oncol 2023; 149:13477-13494. [PMID: 37491636 DOI: 10.1007/s00432-023-05199-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 07/27/2023]
Abstract
Cancer immunotherapy has emerged as a groundbreaking method of treating malignancies. However, cancer immunotherapy can only benefit a small percentage of patients, and the numerous side effects that might develop during treatment reduce its effectiveness or even put patients' lives in jeopardy. Surprisingly, the gut microbiome Akkermansia muciniphila (A. muciniphila) can significantly inhibit carcinogenesis and improve anti-tumor effects, thus increasing the effectiveness of cancer immunotherapy and decreasing the likelihood of side effects. In this review, we focus on the effects of A. muciniphila on the human immune system and the positive impacts of A. muciniphila on cancer immunotherapy, which can build on strengths and improve weaknesses of cancer immunotherapy. The potential clinical applications of A. muciniphila on cancer immunotherapy are also proposed, which have great prospects for anti-tumor therapy.
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Affiliation(s)
- Shiying Fan
- Clinical Medical College, Yangzhou University, Yangzhou, People's Republic of China
| | - Zhengting Jiang
- Clinical Medical College, Yangzhou University, Yangzhou, People's Republic of China
| | - Zhilin Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, People's Republic of China
| | - Juan Xing
- Clinical Medical College, Yangzhou University, Yangzhou, People's Republic of China
| | - Daorong Wang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Northern Jiangsu People's Hospital, Yangzhou University, Yangzhou, 225001, People's Republic of China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Northern Jiangsu People's Hospital, Yangzhou University, Yangzhou, 225001, People's Republic of China.
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26
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Mazzella M, Walker K, Cormier C, Kapanowski M, Ishmakej A, Saifee A, Govind Y, Chaudhry GR. Regulation of self-renewal and senescence in primitive mesenchymal stem cells by Wnt and TGFβ signaling. Stem Cell Res Ther 2023; 14:305. [PMID: 37880755 PMCID: PMC10601332 DOI: 10.1186/s13287-023-03533-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 10/11/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND The therapeutic application of multipotent mesenchymal stem cells (MSCs) encounters significant challenges, primarily stemming from their inadequate growth and limited self-renewal capabilities. Additionally, as MSCs are propagated, their ability to self-renew declines, and the exact cellular and molecular changes responsible for this are poorly understood. This study aims to uncover the complex molecular mechanisms that govern the self-renewal of primitive (p) MSCs. METHODS We grew pMSCs using two types of medium, fetal bovine serum (FM) and xeno-free (XM), at both low passage (LP, P3) and high passage (HP, P20). To evaluate LP and HP pMSCs, we examined their physical characteristics, cell surface markers, growth rate, colony-forming ability, BrdU assays for proliferation, telomerase activity, and potential to differentiate into three lineages. Moreover, we conducted RNA-seq to analyze their transcriptome and MNase-seq analysis to investigate nucleosome occupancies. RESULTS When grown in FM, pMSCs underwent changes in their cellular morphology, becoming larger and elongated. This was accompanied by a decrease in the expression of CD90 and CD49f, as well as a reduction in CFE, proliferation rate, and telomerase activity. In addition, these cells showed an increased tendency to differentiate into the adipogenic lineage. However, when grown in XM, pMSCs maintained their self-renewal capacity and ability to differentiate into multiple lineages while preserving their fibroblastoid morphology. Transcriptomic analysis showed an upregulation of genes associated with self-renewal, cell cycle regulation, and DNA replication in XM-cultured pMSCs, while senescence-related genes were upregulated in FM-cultured cells. Further analysis demonstrated differential nucleosomal occupancies in self-renewal and senescence-related genes for pMSCs grown in XM and FM, respectively. These findings were confirmed by qRT-PCR analysis, which revealed alterations in the expression of genes related to self-renewal, cell cycle regulation, DNA replication, differentiation, and senescence. To understand the underlying mechanisms, we investigated the involvement of Wnt and TGFβ signaling pathways by modulating them with agonists and antagonists. This experimental manipulation led to the upregulation and downregulation of self-renewal genes in pMSCs, providing further insights into the signaling pathways governing the self-renewal and senescence of pMSCs. CONCLUSION Our study shows that the self-renewal potential of pMSCs is associated with the Wnt pathway, while senescence is linked to TGFβ.
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Affiliation(s)
- Matteo Mazzella
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Keegan Walker
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Christina Cormier
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Michael Kapanowski
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Albi Ishmakej
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Azeem Saifee
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Yashvardhan Govind
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - G Rasul Chaudhry
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA.
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA.
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27
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Akhlaghipour I, Fanoodi A, Zangouei AS, Taghehchian N, Khalili-Tanha G, Moghbeli M. MicroRNAs as the Critical Regulators of Forkhead Box Protein Family in Pancreatic, Thyroid, and Liver Cancers. Biochem Genet 2023; 61:1645-1674. [PMID: 36781813 DOI: 10.1007/s10528-023-10346-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 02/02/2023] [Indexed: 02/15/2023]
Abstract
The metabolism of human body is mainly regulated by the pancreas, liver, and thyroid using the hormones or exocrine secretions that affect the metabolic processes from food digestion to intracellular metabolism. Therefore, metabolic organ disorders have wide clinical symptoms that severely affect the quality of patient's life. The pancreatic, liver, and thyroid cancers as the main malignancies of the metabolic system have always been considered as one of the serious health challenges worldwide. Despite the novel therapeutic modalities, there are still significant high mortality and recurrence rates, especially in liver and pancreatic cancer patients which are mainly related to the late diagnosis. Therefore, it is required to assess the molecular bases of tumor progressions to introduce novel early detection and therapeutic markers in these malignancies. Forkhead box (FOX) protein family is a group of transcription factors that have pivotal roles in regulation of cell proliferation, migration, and apoptosis. They function as oncogene or tumor suppressor during tumor progression. MicroRNAs (miRNAs) are also involved in regulation of cellular processes. Therefore, in the present review, we discussed the role of miRNAs during pancreatic, thyroid, and liver tumor progressions through FOX regulation. It has been shown that miRNAs were mainly involved in tumor progression via FOXM and FOXO targeting. This review paves the way for the introduction of miR/FOX axis as an efficient early detection marker and therapeutic target in pancreatic, thyroid, and liver tumors.
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Affiliation(s)
- Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Fanoodi
- Student Research Committee, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negin Taghehchian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ghazaleh Khalili-Tanha
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Houser JS, Patel M, Wright K, Onopiuk M, Tsiokas L, Humphrey MB. The inhibitor of MyoD Family A (I-MFA) regulates megakaryocyte lineage commitment and terminal differentiation. Blood Cells Mol Dis 2023; 102:102760. [PMID: 37267696 DOI: 10.1016/j.bcmd.2023.102760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/22/2023] [Accepted: 05/23/2023] [Indexed: 06/04/2023]
Abstract
Hematopoiesis and lineage commitment are regulated by several conserved cell-intrinsic signaling pathways, including MAPKs and β-catenin/TCF/LEF. The Inhibitor of MyoD Family A (I-MFA), a transcriptional repressor and tumor suppressor gene, interacts with these pathways and is dysregulated in chronic and acute myeloid leukemias, suggesting it may play a role in development and differentiation during hematopoiesis. To study this, immune cell populations in the bone marrow (BM) and periphery were analyzed in mice lacking Mdfi, encoding I-MFA (I-MFA-/-), and wild type (WT) controls. I-MFA-/- mice had reduced spleen and BM cellularity, with significant hyposplenism, compared to WT mice. In blood, total red blood cells and platelet counts were significantly reduced in I-MFA-/- mice, accompanied by a reduction in megakaryocyte (MK)/erythrocyte progenitor cells and an increase in myeloid progenitors in BM compared to WT mice. The K562 cell line exhibits PMA-induced MK differentiation, and shRNA knockdown of I-MFA resulted in reduced differentiation compared to control, with an increase and prolongation in phospho-JNK and phospho-ERK signaling. Overexpression of I-MFA promoted MK differentiation. These results suggest I-MFA plays a cell-intrinsic role in the response to differentiation signals, an effect that can be explored in the context of hematological cancers or other blood proliferative disorders.
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Affiliation(s)
- Jeremy S Houser
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America
| | - Maulin Patel
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America
| | - Kyle Wright
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America
| | - Marta Onopiuk
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America
| | - Leonidas Tsiokas
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America
| | - Mary Beth Humphrey
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America; Oklahoma City Veteran's Affairs Medical Center, Oklahoma City, OK, United States of America.
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29
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Romanová M, Židlík V, Javůrková V, Kondé A, Šimetka O, Klát J. L1CAM Is Not a Predictive Factor in Early-stage Squamous-cell Cervical Cancer. In Vivo 2023; 37:2334-2339. [PMID: 37652517 PMCID: PMC10500533 DOI: 10.21873/invivo.13337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/02/2023] [Accepted: 07/17/2023] [Indexed: 09/02/2023]
Abstract
AIM Our study aimed to assess expression of L1 cell adhesion molecule (L1CAM) in early-stage cervical squamous-cell cancer as a prognostic factor. PATIENTS AND METHODS This retrospective, single-institution study included 154 patients who underwent radical hysterectomy for early-stage squamous cell cervical cancer between 2007 and 2017. Tumor samples from 154 patients were available for L1CAM analysis by immunohistochemistry. Among all patients, radical abdominal hysterectomy was performed in 144 cases. RESULTS L1CAM expression was positive in 24 tumors (15.6%) of the whole group. In relation to the grade of differentiation and the presence of lymphovascular invasion, L1CAM expression did not show an association (p=0.154 and p=0.306, respectively). The disease-free interval and overall survival also did not significantly differ between L1CAM-positive and L1CAM-negative cases (p=0.427 and p=0.240, respectively). For histopathological characteristics, L1CAM-positive cases had a significantly higher median tumor size (p=0.015). Even in the selected group of 115 cases without nodal infiltration, L1CAM status had no effect on the relapse rate during follow-up. CONCLUSION Our study did not confirm the results of previous studies showing L1CAM expression to be a negative prognostic factor in cervical cancer. In our study, increased L1CAM expression in early-stage squamous-cell cervical cancer was not associated with adverse prognosis regarding disease recurrence, disease-free survival, nor overall survival. L1CAM expression was correlated only with the size of the tumor.
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Affiliation(s)
- Martina Romanová
- Department of Obstetrics and Gynecology, Gynecological Oncology Centre, University Hospital Ostrava, Ostrava Poruba, Czech Republic
| | - Vladimír Židlík
- Department of Clinical and Molecular Pathology and Medical Genetics, University Hospital Ostrava, Ostrava Poruba, Czech Republic
| | - Veronika Javůrková
- Department of Obstetrics and Gynecology, Gynecological Oncology Centre, University Hospital Ostrava, Ostrava Poruba, Czech Republic
| | - Adela Kondé
- Department of Applied Mathematics, Faculty of Electrical Engineering and Computer Science, VSB - Technical University of Ostrava, Ostrava Poruba, Czech Republic
- Department of Deputy Director for Science, Research and Education, University Hospital Ostrava, Ostrava Poruba, Czech Republic
| | - Ondřej Šimetka
- Department of Obstetrics and Gynecology, Gynecological Oncology Centre, University Hospital Ostrava, Ostrava Poruba, Czech Republic
| | - Jaroslav Klát
- Department of Obstetrics and Gynecology, Gynecological Oncology Centre, University Hospital Ostrava, Ostrava Poruba, Czech Republic;
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Sachdeva M, Taneja S, Sachdeva N. Stem cell-like memory T cells: Role in viral infections and autoimmunity. World J Immunol 2023; 13:11-22. [DOI: 10.5411/wji.v13.i2.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 07/06/2023] [Accepted: 07/27/2023] [Indexed: 08/14/2023] Open
Abstract
Stem cell-like memory T (TSCM) cells possess stem cell properties including multipotency and self-renewal and are being recognized as emerging players in various human diseases. Advanced technologies such as multiparametric flowcytometry and single cell sequencing have enabled their identification and molecular characterization. In case of chronic viral diseases such as human immunodeficiency virus-1, CD4+ TSCM cells, serve as major reservoirs of the latent virus. However, during immune activation and functional exhaustion of effector T cells, these cells also possess the potential to replenish the pool of functional effector cells to curtail the infection. More recently, these cells are speculated to play important role in protective immunity following acute viral infections such as coronavirus disease 2019 and might be amenable for therapeutics by ex vivo expansion. Similarly, studies are also investigating their pathological role in driving autoimmune responses. However, there are several gaps in the understanding of the role of TSCM cells in viral and autoimmune diseases to make them potential therapeutic targets. In this minireview, we have attempted an updated compilation of the dyadic role of these complex TSCM cells during such human diseases along with their biology and transcriptional programs.
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Affiliation(s)
- Meenakshi Sachdeva
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India
| | - Shivangi Taneja
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India
| | - Naresh Sachdeva
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India
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Lei W, Cheng Y, Gao J, Liu X, Shao L, Kong Q, Zheng N, Ling Z, Hu W. Akkermansia muciniphila in neuropsychiatric disorders: friend or foe? Front Cell Infect Microbiol 2023; 13:1224155. [PMID: 37492530 PMCID: PMC10363720 DOI: 10.3389/fcimb.2023.1224155] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 06/26/2023] [Indexed: 07/27/2023] Open
Abstract
An accumulating body of evidence suggests that the bacterium Akkermansia muciniphila exhibits positive systemic effects on host health, mainly by improving immunological and metabolic functions, and it is therefore regarded as a promising potential probiotic. Recent clinical and preclinical studies have shown that A. muciniphila plays a vital role in a variety of neuropsychiatric disorders by influencing the host brain through the microbiota-gut-brain axis (MGBA). Numerous studies observed that A. muciniphila and its metabolic substances can effectively improve the symptoms of neuropsychiatric disorders by restoring the gut microbiota, reestablishing the integrity of the gut mucosal barrier, regulating host immunity, and modulating gut and neuroinflammation. However, A. muciniphila was also reported to participate in the development of neuropsychiatric disorders by aggravating inflammation and influencing mucus production. Therefore, the exact mechanism of action of A. muciniphila remains much controversial. This review summarizes the proposed roles and mechanisms of A. muciniphila in various neurological and psychiatric disorders such as depression, anxiety, Parkinson's disease, Alzheimer's disease, multiple sclerosis, strokes, and autism spectrum disorders, and provides insights into the potential therapeutic application of A. muciniphila for the treatment of these conditions.
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Affiliation(s)
- Wenhui Lei
- Jinan Microecological Biomedicine Shandong Laboratory, Shandong First Medical University, Jinan, Shandong, China
| | - Yiwen Cheng
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jie Gao
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, China
| | - Xia Liu
- Department of Intensive Care Unit, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Li Shao
- School of Clinical Medicine, Institute of Hepatology and Metabolic Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Qingming Kong
- School of Biological Engineering, Hangzhou Medical College, Institute of Parasitic Diseases, Hangzhou, Zhejiang, China
| | - Nengneng Zheng
- Department of Obstetrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zongxin Ling
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Weiming Hu
- Department of Psychiatry, Quzhou Third Hospital, Quzhou, Zhejiang, China
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Giri J, Modi D. Endometrial and placental stem cells in successful and pathological pregnancies. J Assist Reprod Genet 2023; 40:1509-1522. [PMID: 37338750 PMCID: PMC10352206 DOI: 10.1007/s10815-023-02856-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 06/03/2023] [Indexed: 06/21/2023] Open
Abstract
The endometrium is a dynamic tissue that undergoes extensive remodeling during the menstrual cycle and further gets modified during pregnancy. Different kinds of stem cells are reported in the endometrium. These include epithelial stem cells, endometrial mesenchymal stem cells, side population stem cells, and very small embryonic-like stem cells. Stem cells are also reported in the placenta which includes trophoblast stem cells, side population trophoblast stem cells, and placental mesenchymal stem cells. The endometrial and placental stem cells play a pivotal role in endometrial remodeling and placental vasculogenesis during pregnancy. The dysregulation of stem cell function is reported in various pregnancy complications like preeclampsia, fetal growth restriction, and preterm birth. However, the mechanisms by which it does so are yet elusive. Herein, we review the current knowledge of the different type of stem cells involved in pregnancy initiation and also highlight how their improper functionality leads to pathological pregnancy.
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Affiliation(s)
- Jayeeta Giri
- Molecular and Cellular Biology Laboratory, ICMR-National Institute for Research in Reproductive and child Health, Indian Council of Medical Research (ICMR), JM Street, Parel, Mumbai, 400012, India.
| | - Deepak Modi
- Molecular and Cellular Biology Laboratory, ICMR-National Institute for Research in Reproductive and child Health, Indian Council of Medical Research (ICMR), JM Street, Parel, Mumbai, 400012, India.
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Guan Z, Liang Y, Zhu Z, Yang A, Li S, Guo J, Wang F, Yang H, Zhang N, Wang X, Wang J. Cytosine arabinoside exposure induced cytotoxic effects and neural tube defects in mice and embryo stem cells. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 262:115141. [PMID: 37320917 DOI: 10.1016/j.ecoenv.2023.115141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 03/16/2023] [Accepted: 06/12/2023] [Indexed: 06/17/2023]
Abstract
Cytosine arabinoside (Ara-C) is one of the most widely used chemotherapeutic agents for hematological malignancies. The residues of Ara-C have been detected in wastewater and river water with increased usage and discharge. As the ability to cross the placenta and the teratogenicity at low ng/L levels, the toxic effects on pregnant women and infants have been concerned. The toxicity of Ara-C exposure on early embryonic neurodevelopment has not been fully elucidated. In this study, pregnant C57BL/6 mice were injected with different doses of Ara-C on Gestation day (GD) 7.5 and assessed on GD11.5 and GD13.5 to explore the neural developmental effects of Ara-C. HE staining, immunofluorescence, western blot, EdU assay, and flow cytometry were utilized to determine the toxic effects of Ara-C in vivo and in vitro. Our results showed that Ara-C (15-22.5 mg/kg body weight) induced the occurrence of neural tube defects (NTDs). The expression of PH3 was markedly reduced in embryos with Ara-C-induced NTDs, compared to the control group (P < 0.05). In contrast, cell apoptosis was markedly increased. Increased expression levels of GFAP and decreased Nestin were observed in the embryonic brain tissues in Ara-C induced NTDs. The level of β-catenin was also decreased on both GD11.5 and GD13.5. These results were confirmed in vitro using mouse Sv129 embryonic stem cells (mESC). Ara-C at a dose comparable to the environment level (0.05 nM) had cytotoxicity. Impaired Wnt/β-catenin signaling pathway is involved in Ara-C exposure induced imbalance between cell proliferation, apoptosis, and differentiation, which might contribute to Ara-C-induced occurrence of NTDs. Our data indicated the environmental concentration of Ara-C had cytotoxicity and that maternal exposure to Ara-C induced NTDs. These results might provide more information to understand the environmental toxic impact of Ara-C on neurodevelopment.
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Affiliation(s)
- Zhen Guan
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing 100020, China
| | - Yingchao Liang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing 100020, China
| | - Zhiqiang Zhu
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing 100020, China
| | - Aiyun Yang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing 100020, China
| | - Shen Li
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing 100020, China
| | - Jin Guo
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China
| | - Fang Wang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China
| | - Huimin Yang
- Growth and Development Department, Capital Institute of Pediatrics, Beijing 100020, China
| | - Na Zhang
- Key Laboratory of Environmental and Viral Oncology, College of Life Science and Chemistry, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China.
| | - Xiuwei Wang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing 100020, China.
| | - Jianhua Wang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing 100020, China.
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Hou XN, Tang C. The pros and cons of ubiquitination on the formation of protein condensates. Acta Biochim Biophys Sin (Shanghai) 2023; 55:1084-1098. [PMID: 37294105 PMCID: PMC10423694 DOI: 10.3724/abbs.2023096] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 03/19/2023] [Indexed: 06/10/2023] Open
Abstract
Ubiquitination, a post-translational modification that attaches one or more ubiquitin (Ub) molecules to another protein, plays a crucial role in the phase-separation processes. Ubiquitination can modulate the formation of membrane-less organelles in two ways. First, a scaffold protein drives phase separation, and Ub is recruited to the condensates. Second, Ub actively phase-separates through the interactions with other proteins. Thus, the role of ubiquitination and the resulting polyUb chains ranges from bystanders to active participants in phase separation. Moreover, long polyUb chains may be the primary driving force for phase separation. We further discuss that the different roles can be determined by the lengths and linkages of polyUb chains which provide preorganized and multivalent binding platforms for other client proteins. Together, ubiquitination adds a new layer of regulation for the flow of material and information upon cellular compartmentalization of proteins.
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Affiliation(s)
- Xue-Ni Hou
- Beijing National Laboratory for Molecular SciencesCollege of Chemistry and Molecular EngineeringPeking UniversityBeijing100871China
| | - Chun Tang
- Beijing National Laboratory for Molecular SciencesCollege of Chemistry and Molecular EngineeringPeking UniversityBeijing100871China
- Center for Quantitate BiologyPKU-Tsinghua Center for Life ScienceAcademy for Advanced Interdisciplinary StudiesPeking UniversityBeijing100871China
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Canonical Wnt Pathway Is Involved in Chemoresistance and Cell Cycle Arrest Induction in Colon Cancer Cell Line Spheroids. Int J Mol Sci 2023; 24:ijms24065252. [PMID: 36982333 PMCID: PMC10049556 DOI: 10.3390/ijms24065252] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/14/2023] [Accepted: 02/15/2023] [Indexed: 03/12/2023] Open
Abstract
The presence of cancer stem cells (CSCs) has been associated with the induction of drug resistance and disease recurrence after therapy. 5-Fluorouracil (5FU) is widely used as the first-line treatment of colorectal cancer (CRC). However, its effectiveness may be limited by the induction of drug resistance in tumor cells. The Wnt pathway plays a key role in the development and CRC progression, but it is not clearly established how it is involved in CSCs resistance to treatment. This work aimed to investigate the role played by the canonical Wnt/β-catenin pathway in CSCs resistance to 5FU treatment. Using tumor spheroids as a model of CSCs enrichment of CRC cell lines with different Wnt/β-catenin contexts, we found that 5FU induces in all CRC spheroids tested cell death, DNA damage, and quiescence, but in different proportions for each one: RKO spheroids were very sensitive to 5FU, while SW480 were less susceptible, and the SW620 spheroids, the metastatic derivative of SW480 cells, displayed the highest resistance to death, high clonogenic capacity, and the highest ability for regrowth after 5FU treatment. Activating the canonical Wnt pathway with Wnt3a in RKO spheroids decreased the 5FU-induced cell death. But the Wnt/β-catenin pathway inhibition with Adavivint alone or in combination with 5FU in spheroids with aberrant activation of this pathway produced a severe cytostatic effect compromising their clonogenic capacity and diminishing the stem cell markers expression. Remarkably, this combined treatment also induced the survival of a small cell subpopulation that could exit the arrest, recover SOX2 levels, and re-grow after treatment.
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Li M, Li T, Yin J, Xie C, Zhu J. Evaluation of toxicological effects of bisphenol S with an in vitro human bone marrow mesenchymal stem cell: Implications for bone health. Toxicology 2023; 484:153408. [PMID: 36565802 DOI: 10.1016/j.tox.2022.153408] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 12/15/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022]
Abstract
As the use of bisphenol A (BPA) has been restricted in consumer products, bisphenol S (BPS) is one major alternative to BPA for various materials, leading to growing concerns about its health risks in human beings. However, little is known about the toxic effects of BPS on bone health. We employed human bone marrow mesenchymal stem cells (hBMSCs) for the in vitro assessment of BPS on cell proliferation, differentiation, and self-renewal. Our study revealed that BPS at concentrations of 10-10-10-7 M increased cell viability but induced the morphological changes of hBMSCs. Moreover, BPS decreased ROS generation and increased Nrf2 expression. Furthermore, BPS not only activated ERα/β expression but also increased β-catenin expression and induced the replicative senescence of hBMSCs. Furthermore, we found that the upregulation of β-catenin induced by BPS was mediated, in part, by ER signaling. Overall, our results suggested BPS exposure caused the homeostatic imbalance of hBMSCs.
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Affiliation(s)
- Mei Li
- The Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China; School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China
| | - Tenglong Li
- The Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China
| | - Juan Yin
- Department of Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215008, China
| | - Chunfeng Xie
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
| | - Jianyun Zhu
- Department of Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215008, China.
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Li JH, Trivedi V, Diz-Muñoz A. Understanding the interplay of membrane trafficking, cell surface mechanics, and stem cell differentiation. Semin Cell Dev Biol 2023; 133:123-134. [PMID: 35641408 PMCID: PMC9703995 DOI: 10.1016/j.semcdb.2022.05.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 04/08/2022] [Accepted: 05/14/2022] [Indexed: 01/17/2023]
Abstract
Stem cells can generate a diversity of cell types during development, regeneration and adult tissue homeostasis. Differentiation changes not only the cell fate in terms of gene expression but also the physical properties and functions of cells, e.g. the secretory activity, cell shape, or mechanics. Conversely, these activities and properties can also regulate differentiation itself. Membrane trafficking is known to modulate signal transduction and thus has the potential to control stem cell differentiation. On the other hand, membrane trafficking, particularly from and to the plasma membrane, depends on the mechanical properties of the cell surface such as tension within the plasma membrane or the cortex. Indeed, recent findings demonstrate that cell surface mechanics can also control cell fate. Here, we review the bidirectional relationships between these three fundamental cellular functions, i.e. membrane trafficking, cell surface mechanics, and stem cell differentiation. Furthermore, we discuss commonly used methods in each field and how combining them with new tools will enhance our understanding of their interplay. Understanding how membrane trafficking and cell surface mechanics can guide stem cell fate holds great potential as these concepts could be exploited for directed differentiation of stem cells for the fields of tissue engineering and regenerative medicine.
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Affiliation(s)
- Jia Hui Li
- Cell Biology and Biophysics Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, Heidelberg 69117, Germany
| | - Vikas Trivedi
- EMBL, PRBB, Dr. Aiguader, 88, Barcelona 08003, Spain,Developmental Biology Unit, EMBL, Meyerhofstraße 1, Heidelberg 69117, Germany
| | - Alba Diz-Muñoz
- Cell Biology and Biophysics Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, Heidelberg 69117, Germany.
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Ghotaslou R, Nabizadeh E, Memar MY, Law WMH, Ozma MA, Abdi M, Yekani M, Kadkhoda H, hosseinpour R, Bafadam S, Ghotaslou A, Leylabadlo HE, Nezhadi J. The metabolic, protective, and immune functions of Akkermansia muciniphila. Microbiol Res 2023; 266:127245. [DOI: 10.1016/j.micres.2022.127245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 10/25/2022] [Accepted: 10/25/2022] [Indexed: 11/07/2022]
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Hurvitz N, Elkhateeb N, Sigawi T, Rinsky-Halivni L, Ilan Y. Improving the effectiveness of anti-aging modalities by using the constrained disorder principle-based management algorithms. FRONTIERS IN AGING 2022; 3:1044038. [PMID: 36589143 PMCID: PMC9795077 DOI: 10.3389/fragi.2022.1044038] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 11/22/2022] [Indexed: 12/15/2022]
Abstract
Aging is a complex biological process with multifactorial nature underlined by genetic, environmental, and social factors. In the present paper, we review several mechanisms of aging and the pre-clinically and clinically studied anti-aging therapies. Variability characterizes biological processes from the genome to cellular organelles, biochemical processes, and whole organs' function. Aging is associated with alterations in the degrees of variability and complexity of systems. The constrained disorder principle defines living organisms based on their inherent disorder within arbitrary boundaries and defines aging as having a lower variability or moving outside the boundaries of variability. We focus on associations between variability and hallmarks of aging and discuss the roles of disorder and variability of systems in the pathogenesis of aging. The paper presents the concept of implementing the constrained disease principle-based second-generation artificial intelligence systems for improving anti-aging modalities. The platform uses constrained noise to enhance systems' efficiency and slow the aging process. Described is the potential use of second-generation artificial intelligence systems in patients with chronic disease and its implications for the aged population.
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Affiliation(s)
- Noa Hurvitz
- Faculty of Medicine, Hebrew University and Department of Medicine, Hadassah Medical Center, Jerusalem, Israel
| | - Narmine Elkhateeb
- Faculty of Medicine, Hebrew University and Department of Medicine, Hadassah Medical Center, Jerusalem, Israel
| | - Tal Sigawi
- Faculty of Medicine, Hebrew University and Department of Medicine, Hadassah Medical Center, Jerusalem, Israel
| | - Lilah Rinsky-Halivni
- Braun School of Public Health, Hebrew University of Jerusalem, Jerusalem, Israel,Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Yaron Ilan
- Faculty of Medicine, Hebrew University and Department of Medicine, Hadassah Medical Center, Jerusalem, Israel,*Correspondence: Yaron Ilan,
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The multifaceted role of GCM1 during trophoblast differentiation in the human placenta. Proc Natl Acad Sci U S A 2022; 119:e2203071119. [PMID: 36442132 PMCID: PMC9894182 DOI: 10.1073/pnas.2203071119] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Remodeling of the uterine vasculature by invasive extravillous trophoblasts (EVTs) is a critical aspect of human placentation. Insufficient EVT invasion can lead to severe obstetrical complications like preeclampsia, intrauterine growth restriction, and preterm birth. Glial cells missing-1 (GCM1) is a transcription factor that is crucial for proper placentation in mice, and is highly expressed in human syncytiotrophoblast (ST) and EVTs. GCM1 is classically considered a master regulator of ST formation, but little is known about its contribution to the development and function of EVTs. Therefore, in this study we test the hypothesis that GCM1 is a critical regulator of both EVT and ST development and function. We show that GCM1 is highly expressed in human trophoblast stem (TS) cells differentiated into either ST or EVTs. Knockdown of GCM1 in TS cells hindered differentiation into both ST and EVT pathways. When placed in ST media, GCM1-knockdown cells formed small, unstable clusters; when placed in EVT media, cells had altered morphology and transcript profiles resembling cells trapped in an intermediate state between CT and EVT, and invasive capacity through matrix was reduced. RNA sequencing analysis of GCM1-deficient TS cells revealed downregulation of EVT-associated genes and enrichment in transcripts related to WNT signaling, which was linked to decreased expression of the EVT master regulator ASCL2 and the WNT antagonist NOTUM. Our findings reveal an essential role of GCM1 during ST and EVT development, and suggest that GCM1 regulates differentiation of human TS cells into EVTs by inducing expression of ASCL2 and NOTUM.
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Dihydromyricetin Inhibited Migration and Invasion by Reducing S100A4 Expression through ERK1/2/β-Catenin Pathway in Human Cervical Cancer Cell Lines. Int J Mol Sci 2022; 23:ijms232315106. [PMID: 36499426 PMCID: PMC9735508 DOI: 10.3390/ijms232315106] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/25/2022] [Accepted: 11/27/2022] [Indexed: 12/03/2022] Open
Abstract
Cervical cancer has a poor prognosis and is the fourth most common cancer among women. Dihydromyricetin (DHM), a flavonoid compound, exhibits several pharmacological activities, including anticancer effects; however, the effects of DHM on cervical cancer have received insufficient research attention. This study examined the antitumor activity and underlying mechanisms of DHM on human cervical cancer. Our results indicated that DHM inhibits migration and invasion in HeLa and SiHa cell lines. Mechanistically, RNA sequencing analysis revealed that DHM suppressed S100A4 mRNA expression in HeLa cells. Moreover, DHM inhibited the protein expressions of β-catenin and GSK3β through the regulated extracellular-signal-regulated kinase (ERK)1/2 signaling pathway. By using the ERK1/2 activator, T-BHQ, reverted β-catenin and S100A4 protein expression and cell migration, which were reduced in response to DHM. In conclusion, our study indicated that DHM inhibited cell migration by reducing the S100A4 expression through the ERK1/2/β-catenin pathway in human cervical cancer cell lines.
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Chang CK, Chu SC, Huang JY, Chen PN, Hsieh YS. Terminalia catappa leaf extracts inhibited metastasis of A2058 and A375 melanoma cells via downregulating p-Src and β-catenin pathway in vitro. Front Pharmacol 2022; 13:963589. [PMID: 36238547 PMCID: PMC9551286 DOI: 10.3389/fphar.2022.963589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 09/02/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Melanoma is a highly aggressive, lethal, and malignant cancer. Once diagnosed early, it can be easily removed and cured with satisfaction. Although many methods such as surgery, chemotherapy, radiotherapy, and immunotherapy have been used to treat this disease at an advanced stage, the outcomes are poor. Terminalia catappa leaves have been shown to have various biological benefits, including antitumor activity. The specific effects and molecular mechanisms of Terminalia catappa leaf in treating A2058 and A375 melanoma cells in vitro need to be clarified.Methods: The A2058 and A375 melanoma cancer cells were treated with Terminalia catappa leaf extracts, and then the effect of Terminalia catappa leaf extracts on migration and invasion was examined. The cell migration/invasion capacities of A2058 and A375 cells were investigated by a modified Boyden chamber assay. Zymography was used to clarify the activities of matrix metalloproteinases-2 and urinary type plasminogen activator. We performed a Western blot to verify the related expression of phospho-Src (Tyr416), phospho-Focal adhesion kinase (Tyr397), Vimentin, and β-catenin.Results: Modified Boyden chamber assays demonstrated that treatment of Terminalia catappa leaf extracts significantly inhibited A2058 and A375 cell migration/invasion capacities. In the zymography results, we showed that Terminalia catappa leaf extracts negatively modulated the activities of matrix metalloproteinases-2 and urinary type plasminogen activator. Western blot indicated that Terminalia catappa leaf extracts reduced the expression of phospho-Src (Tyr416), phospho-Focal adhesion kinase (Tyr397), Vimentin, and β-catenin.Conclusion:Terminalia catappa leaf extracts affected the antimetastasis of the A2058 and A375 melanoma cell lines by inhibiting the Focal adhesion kinase/Src interaction and Wingless-int1/β-catenin pathways in vitro. Terminalia catappa leaf extracts may serve as an effective chemopreventive agent against metastasis of melanoma cancer.
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Affiliation(s)
- Chin-Kuo Chang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Shu-Chen Chu
- Institute and Department of Food Science, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Jing-Yang Huang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Pei-Ni Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
- *Correspondence: Pei-Ni Chen, ; Yih-Shou Hsieh,
| | - Yih-Shou Hsieh
- Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
- *Correspondence: Pei-Ni Chen, ; Yih-Shou Hsieh,
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Ontogeny of cellular organization and LGR5 expression in porcine cochlea revealed using tissue clearing and 3D imaging. iScience 2022; 25:104695. [PMID: 35865132 PMCID: PMC9294204 DOI: 10.1016/j.isci.2022.104695] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 04/20/2022] [Accepted: 06/27/2022] [Indexed: 11/23/2022] Open
Abstract
Over 11% of the world's population experience hearing loss. Although there are promising studies to restore hearing in rodent models, the size, ontogeny, genetics, and frequency range of hearing of most rodents' cochlea do not match that of humans. The porcine cochlea can bridge this gap as it shares many anatomical, physiological, and genetic similarities with its human counterpart. Here, we provide a detailed methodology to process and image the porcine cochlea in 3D using tissue clearing and light-sheet microscopy. The resulting 3D images can be employed to compare cochleae across different ages and conditions, investigate the ontogeny of cochlear cytoarchitecture, and produce quantitative expression maps of LGR5, a marker of cochlear progenitors in mice. These data reveal that hair cell organization, inner ear morphology, cellular cartography in the organ of Corti, and spatiotemporal expression of LGR5 are dynamic over developmental stages in a pattern not previously documented.
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44
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Prostate Cancer Secretome and Membrane Proteome from Pten Conditional Knockout Mice Identify Potential Biomarkers for Disease Progression. Int J Mol Sci 2022; 23:ijms23169224. [PMID: 36012492 PMCID: PMC9409251 DOI: 10.3390/ijms23169224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/10/2022] [Accepted: 08/12/2022] [Indexed: 12/24/2022] Open
Abstract
Prostate cancer (PCa) is the second most common cause of mortality among men. Tumor secretome is a promising strategy for understanding the biology of tumor cells and providing markers for disease progression and patient outcomes. Here, transcriptomic-based secretome analysis was performed on the PCa tumor transcriptome of Genetically Engineered Mouse Model (GEMM) Pb-Cre4/Ptenf/f mice to identify potentially secreted and membrane proteins—PSPs and PMPs. We combined a selection of transcripts from the GSE 94574 dataset and a list of protein-coding genes of the secretome and membrane proteome datasets using the Human Protein Atlas Secretome. Notably, nine deregulated PMPs and PSPs were identified in PCa (DMPK, PLN, KCNQ5, KCNQ4, MYOC, WIF1, BMP7, F3, and MUC1). We verified the gene expression patterns of Differentially Expressed Genes (DEGs) in normal and tumoral human samples using the GEPIA tool. DMPK, KCNQ4, and WIF1 targets were downregulated in PCa samples and in the GSE dataset. A significant association between shorter survival and KCNQ4, PLN, WIF1, and F3 expression was detected in the MSKCC dataset. We further identified six validated miRNAs (mmu-miR-6962-3p, mmu-miR- 6989-3p, mmu-miR-6998-3p, mmu-miR-5627-5p, mmu-miR-15a-3p, and mmu-miR-6922-3p) interactions that target MYOC, KCNQ5, MUC1, and F3. We have characterized the PCa secretome and membrane proteome and have spotted new dysregulated target candidates in PCa.
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Zheng X, Wang S, Xiao L, Han P, Xie K, Ivanovski S, Xiao Y, Zhou Y. LiCl-induced immunomodulatory periodontal regeneration via the activation of the Wnt/β-catenin signaling pathway. J Periodontal Res 2022; 57:835-848. [PMID: 35675063 PMCID: PMC9541255 DOI: 10.1111/jre.13022] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 03/23/2022] [Accepted: 05/22/2022] [Indexed: 11/28/2022]
Abstract
Background Growing evidence suggests that excessive inflammation hampers the regenerative capacity of periodontal ligament cells (PDLCs) and that activation of the Wnt/β‐catenin pathway is crucial in suppressing immune dysregulation. Objective This study aimed to establish the role of the Wnt/β‐catenin in regulating the immune microenvironment and its subsequent impact on periodontal regeneration. Methods Lithium chloride (LiCl, Wnt activator) was administered daily into the standard periodontal defects created in 12‐week‐old Lewis rats. Harvested at 1‐week and 2‐week post‐surgery, samples were then subjected to histological and immunohistochemical evaluation of macrophage distribution and phenotype (pro‐inflammatory M1 and anti‐inflammatory M2). A murine macrophage cell line, RAW 264.7, was stimulated with LiCl to activate Wnt/β‐catenin. Following treatment with the conditioned medium derived from the LiCl‐activated macrophages, the expression of bone‐ and cementum‐related markers of the PDLCs was determined. The involvement of Wnt/β‐catenin in the immunoregulation and autophagic activity was further investigated with the addition of cardamonin, a commercially available Wnt inhibitor. Results A significantly increased number of macrophages were detected around the defects during early healing upon receiving the Wnt/β‐catenin signaling cue. The defect sites in week 2 exhibited fewer M1 and more M2 macrophages along with an enhanced regeneration of alveolar bone and cementum in the Wnt/β‐catenin activation group. LiCl‐induced immunomodulatory effect was accompanied with the activation Wnt/β‐catenin signaling, which was suppressed in the presence of Wnt inhibitor. Exposure to LiCl could induce autophagy in a dose‐dependent manner, thus maintaining macrophages in a regulatory state. The expression level of bone‐ and cementum‐related markers was significantly elevated in PDLCs stimulated with LiCl‐activated macrophages. Conclusion The application of Wnt activator LiCl facilitates the recruitment of macrophages to defect sites and regulates their phenotypic switching in favor of periodontal regeneration. Suppression of Wnt/β‐catenin pathway could attenuate the LiCl‐induced immunomodulatory effect. Taken together, the Wnt/β‐catenin pathway may be targeted for therapeutic interventions in periodontal diseases.
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Affiliation(s)
- Xiumei Zheng
- Xiamen Key Laboratory of Stomatological Disease Diagnosis and Treatment, Stomatological Hospital of Xiamen Medical College, Xiamen, China.,The Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM), Queensland University of Technology, Brisbane, Queensland, Australia
| | - Shengfang Wang
- School of Mechanical, Medical and Process Engineering, Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Lan Xiao
- The Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM), Queensland University of Technology, Brisbane, Queensland, Australia.,School of Mechanical, Medical and Process Engineering, Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Pingping Han
- The Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM), Queensland University of Technology, Brisbane, Queensland, Australia.,School of Dentistry, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Kunke Xie
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Saso Ivanovski
- The Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM), Queensland University of Technology, Brisbane, Queensland, Australia.,School of Dentistry, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Yin Xiao
- The Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM), Queensland University of Technology, Brisbane, Queensland, Australia.,School of Mechanical, Medical and Process Engineering, Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, Queensland, Australia.,Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yinghong Zhou
- The Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM), Queensland University of Technology, Brisbane, Queensland, Australia.,School of Dentistry, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, Queensland, Australia.,Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
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46
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Shen D, Peng H, Xia C, Deng Z, Tong X, Wang G, Qian K. The Role of Long Non-Coding RNAs in Epithelial-Mesenchymal Transition-Related Signaling Pathways in Prostate Cancer. Front Mol Biosci 2022; 9:939070. [PMID: 35923466 PMCID: PMC9339612 DOI: 10.3389/fmolb.2022.939070] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 06/10/2022] [Indexed: 11/17/2022] Open
Abstract
Prostate cancer (PCa) is one of the most common male malignancies with frequent remote invasion and metastasis, leading to high mortality. Epithelial-mesenchymal transition (EMT) is a fundamental process in embryonic development and plays a key role in tumor proliferation, invasion and metastasis. Numerous long non-coding RNAs (lncRNAs) could regulate the occurrence and development of EMT through various complex molecular mechanisms involving multiple signaling pathways in PCa. Given the importance of EMT and lncRNAs in the progression of tumor metastasis, we recapitulate the research progress of EMT-related signaling pathways regulated by lncRNAs in PCa, including AR signaling, STAT3 signaling, Wnt/β-catenin signaling, PTEN/PI3K/AKT signaling, TGF-β/Smad and NF-κB signaling pathways. Furthermore, we summarize four modes of how lncRNAs participate in the EMT process of PCa via regulating relevant signaling pathways.
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Affiliation(s)
- Dexin Shen
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China
| | - Hongwei Peng
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Caixia Xia
- President’s Office, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhao Deng
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xi Tong
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Gang Wang
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China
- Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China
- *Correspondence: Gang Wang, ; Kaiyu Qian,
| | - Kaiyu Qian
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China
- Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China
- *Correspondence: Gang Wang, ; Kaiyu Qian,
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Ning J, Sun Q, Su Z, Tan L, Tang Y, Sayed S, Li H, Xue VW, Liu S, Chen X, Lu D. The CK1δ/ϵ-Tip60 Axis Enhances Wnt/β-Catenin Signaling via Regulating β-Catenin Acetylation in Colon Cancer. Front Oncol 2022; 12:844477. [PMID: 35494070 PMCID: PMC9039669 DOI: 10.3389/fonc.2022.844477] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 03/22/2022] [Indexed: 11/16/2022] Open
Abstract
Casein kinase 1δ/ϵ (CK1δ/ϵ) are well-established positive modulators of the Wnt/β-catenin signaling pathway. However, the molecular mechanisms involved in the regulation of β-catenin transcriptional activity by CK1δ/ϵ remain unclear. In this study, we found that CK1δ/ϵ could enhance β-catenin-mediated transcription through regulating β-catenin acetylation. CK1δ/ϵ interacted with Tip60 and facilitated the recruitment of Tip60 to β-catenin complex, resulting in increasing β-catenin acetylation at K49. Importantly, Tip60 significantly enhanced the SuperTopFlash reporter activity induced by CK1δ/ϵ or/and β-catenin. Furthermore, a CK1δ/CK1ϵ/β-catenin/Tip60 complex was detected in colon cancer cells. Simultaneous knockdown of CK1δ and CK1ϵ significantly attenuated the interaction between β-catenin and Tip60. Notably, inhibition of CK1δ/ϵ or Tip60, with shRNA or small molecular inhibitors downregulated the level of β-catenin acetylation at K49 in colon cancer cells. Finally, combined treatment with CK1 inhibitor SR3029 and Tip60 inhibitor MG149 had more potent inhibitory effect on β-catenin acetylation, the transcription of Wnt target genes and the viability and proliferation in colon cancer cells. Taken together, our results revealed that the transcriptional activity of β-catenin could be modulated by the CK1δ/ϵ-β-catenin-Tip60 axis, which may be a potential therapeutic target for colon cancer.
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Affiliation(s)
- Jiong Ning
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, China.,Shenzhen University-Friedrich Schiller Universität Jena Joint PhD Program in Biomedical Sciences, Shenzhen University School of Medicine, Shenzhen, China
| | - Qi Sun
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, China
| | - Zijie Su
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, China.,Department of Research, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Lifeng Tan
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, China
| | - Yun Tang
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, China
| | - Sapna Sayed
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, China
| | - Huan Li
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, China
| | - Vivian Weiwen Xue
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, China
| | - Shanshan Liu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, China
| | - Xianxiong Chen
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, China
| | - Desheng Lu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, China.,Shenzhen University-Friedrich Schiller Universität Jena Joint PhD Program in Biomedical Sciences, Shenzhen University School of Medicine, Shenzhen, China
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Zannoni GF, Bragantini E, Castiglione F, Fassan M, Troncone G, Inzani F, Pesci A, Santoro A, Fraggetta F. Current Prognostic and Predictive Biomarkers for Endometrial Cancer in Clinical Practice: Recommendations/Proposal from the Italian Study Group. Front Oncol 2022; 12:805613. [PMID: 35463299 PMCID: PMC9024340 DOI: 10.3389/fonc.2022.805613] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 03/11/2022] [Indexed: 12/12/2022] Open
Abstract
Endometrial carcinoma (EC) is the most common gynecological malignant disease in high-income countries, such as European countries and the USA. The 2020 edition of the World Health Organization (WHO) Classification of Tumors of the Female Genital Tract underlines the important clinical implications of the proposed new histomolecular classification system for ECs. In view of the substantial genetic and morphological heterogeneity in ECs, both classical pthological parameters and molecular classifiers have to be integrated in the pathology report. This review will focus on the most commonly adopted immunohistochemical and molecular biomarkers in daily clinical characterization of EC, referring to the most recent published recommendations, guidelines, and expert opinions.
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Affiliation(s)
- Gian Franco Zannoni
- Unità di Ginecopatologia e Patologia Mammaria, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy
- Istituto di Anatomia Patologica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Emma Bragantini
- Department of Surgical Pathology, Ospedale S. Chiara, Trento, Italy
| | - Francesca Castiglione
- Histopathology and Molecular Diagnostics, Careggi University Hospital, Florence, Italy
| | - Matteo Fassan
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Giancarlo Troncone
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Frediano Inzani
- Unità di Ginecopatologia e Patologia Mammaria, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Anna Pesci
- Department of Pathology, Sacred Heart Hospital Don Calabria Negrar, Verona, Italy
| | - Angela Santoro
- Unità di Ginecopatologia e Patologia Mammaria, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Filippo Fraggetta
- Pathology Unit, “Cannizzaro” Hospital, Catania, Italy
- Pathology Unit, “Gravina” Hospital, Caltagirone, Italy
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49
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Liang W, Huang L, Ma X, Dong L, Cheng R, Dehdarani M, Karamichos D, Ma JX. Pathogenic Role of Diabetes-Induced Overexpression of Kallistatin in Corneal Wound Healing Deficiency Through Inhibition of Canonical Wnt Signaling. Diabetes 2022; 71:747-761. [PMID: 35044447 PMCID: PMC8965664 DOI: 10.2337/db21-0740] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 12/27/2021] [Indexed: 01/21/2023]
Abstract
It was reported previously that circulation levels of kallistatin, an endogenous Wnt signaling inhibitor, are increased in patients with diabetes. The current study was conducted to determine the role of kallistatin in delayed wound healing in diabetic corneas. Immunostaining and Western blot analysis showed kallistatin levels were upregulated in corneas from humans and rodents with diabetes. In murine corneal wound healing models, the canonical Wnt signaling was activated in nondiabetic corneas and suppressed in diabetic corneas, correlating with delayed wound healing. Transgenic expression of kallistatin suppressed the activation of Wnt signaling in the cornea and delayed wound healing. Local inhibition of Wnt signaling in the cornea by kallistatin, an LRP6-blocking antibody, or the soluble VLDL receptor ectodomain (an endogenous Wnt signaling inhibitor) delayed wound healing. In contrast, ablation of the VLDL receptor resulted in overactivation of Wnt/β-catenin signaling and accelerated corneal wound healing. Activation of Wnt signaling in the cornea accelerated wound healing. Activation of Wnt signaling promoted human corneal epithelial cell migration and proliferation, which was attenuated by kallistatin. Our findings suggested that diabetes-induced overexpression of kallistatin contributes to delayed corneal wound healing by inhibiting the canonical Wnt signaling. Thus, kallistatin and Wnt/β-catenin signaling in the cornea could be potential therapeutic targets for diabetic corneal complications.
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Affiliation(s)
- Wentao Liang
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Li Huang
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Department of Ophthalmology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Xiang Ma
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Lijie Dong
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Rui Cheng
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Marcus Dehdarani
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Dimitrios Karamichos
- North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX
- Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX
| | - Jian-xing Ma
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
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50
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Abstract
The Wnt pathway is central to a host of developmental and disease-related processes. The remarkable conservation of this intercellular signaling cascade throughout metazoan lineages indicates that it coevolved with multicellularity to regulate the generation and spatial arrangement of distinct cell types. By regulating cell fate specification, mitotic activity, and cell polarity, Wnt signaling orchestrates development and tissue homeostasis, and its dysregulation is implicated in developmental defects, cancer, and degenerative disorders. We review advances in our understanding of this key pathway, from Wnt protein production and secretion to relay of the signal in the cytoplasm of the receiving cell. We discuss the evolutionary history of this pathway as well as endogenous and synthetic modulators of its activity. Finally, we highlight remaining gaps in our knowledge of Wnt signal transduction and avenues for future research. Expected final online publication date for the Annual Review of Biochemistry, Volume 91 is June 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Ellen Youngsoo Rim
- Howard Hughes Medical Institute, Department of Developmental Biology, and Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, California, USA;
| | - Hans Clevers
- Hubrecht Institute and Oncode Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, The Netherlands
| | - Roel Nusse
- Howard Hughes Medical Institute, Department of Developmental Biology, and Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, California, USA;
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